2004, Vol.22, Issues 4, Psoriasis

Dermatol Clin 22 (2004) xiii xiv
Preface
Psoriasis
Alan Menter, MD Jennifer Cather, MD Guest Editors
This issue of the Dermatology Clinics reviews in a comprehensive fashion the important features of psoriasis, of relevance to the practicing dermatologist. All the authors are acknowledged leaders in the field, having written extensively on various aspects of psoriasis. The initial three articles discuss the genetics of psoriasis, immunopathogenesis of psoriasis, and the rationale for the use of biologic therapy based on our current knowledge of both genetics and immunopathogenesis of this prevalent disease. In addition, the realization of the significant impact that quality of life issues play in the lives of our psoriasis patients warrants a full article. All too often we, as busy dermatologists, do a cursory clinical evaluation without discussing the day-to-day impact that this highly visible and distressful disease has on our patients. Thereafter, the full range of therapeutic modalities in psoriasis are covered in multiple articles, starting with a review of the phototherapy arsenal available to us in clinical practice, together with a comprehensive review of the major systemic tools available to the practicing dermatologist, prior to the advent of biologic therapy. Biologic therapy of psoriasis has becomeas with other immunomediated diseases such as rheumatoid arthritis and Crohns diseaseincreasingly important. Dermatology has come lately to the biologic thera-
peutic era, with hundreds of thousands of patients already being treated over the past 5 or 10 years for the two aforementioned diseases. The promise of biologics, based on our knowledge of the specific immunopathogenesis of psoriasis reviewed in this issue, has allowed biotechnology companies to more specifically target individual molecules involved in antigen presentation and T-cell interaction with the release of individual cytokines, particularly tumor necrosis factor a, thus allowing for more precise therapeutic options for the practicing dermatologist. With the first biologic drug Alefacept, having been released in January 2003, the second, Efalizumab, in November 2003, and the third, Etanercept, in May 2004, it is important for the practicing dermatologist to have a full understanding of these agents and subsequent agents likely to be approved in the months and years ahead. All these biologic agents are reviewed in individual articles, again by physicians experienced both in clinical research as well as in the subsequent therapy of these individual agents. In addition to our standard tools and the biologic agents for psoriasis, other new agents have potential for adding to our therapeutic armamentarium in the years ahead. Dermatologists are fully versed in retinoid therapy for psoriasis, acne, and other dermatoses. With the likely advent of future systemic retinoids, particularly oral Tazarotene, it is important
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that this be reviewed in full in a separate chapter. In addition, the systemic form of pimecrolimus has received a lot of attention and is likewise discussed. The next two articles review two important issues for the practicing dermatologist. First, the realization that psoriatic arthritis is far more prevalent than we had once believed. Drs. Ruderman and Mease, two rheumatologists who are fully conversant with psoriatic arthritis and its impact on the dermatologist, review psoriatic arthritis in a way that will prove of great value to the dermatologist in clinical practice. The next article reviews how we as dermatologists can integrate all these new drugs, particularly the biologic agents, into our clinical practices. Finally, Dr. Griffiths, an acknowledged leader in investigative and clinical research as well as pso-
riasis therapy, gives a fascinating insight into how psoriasis research and therapy is likely to evolve in the years ahead. We sincerely hope that this issue of the Dermatologic Clinics, which is designed to familiarize the reader with the latest updates in psoriasis, will prove both interesting and valuable as a ready reference for practitioners who have an interest in psoriasis. Alan Menter, MD Jennifer Cather, MD Baylor University Medical Center 5310 Harvest Hill Road, Suite 260 Dallas, TX 75230, USA E-mail addresses: amresearch@texasderm.com (A. Menter); jennifercather@mac.com (J. Cather)
Dermatol Clin 22 (2004) 339 347
An update on the genetics of psoriasis

Francesca Capon, PhDa,*, Richard C. Trembath, MB, BS, FRCP, FMedScia, Jonathan N. Barker, MD, FRCP, FRCPathb
a
Division of Medical Genetics, Department of Genetics and Cardiovascular Sciences, University of Leicester, Adrian Building, University Road, Leicester LE1 7RH, UK b Division of Skin Sciences, St Johns Institute of Dermatology, St Thomas Hospital, Kings College, London SE1 7EH, UK
The existence of a genetic component to psoriasis has long been recognized, with repeated observations of familial clustering [1,2] together with increased concordance rates among monozygotic twins [3]. The increase in disease risk among patient siblings ranges from 4 to 6 [4,5], a relatively low ratio, consistent with a multifactorial mode of inheritance (Fig. 1). These observations contribute to the widely held view that psoriasis is a disorder of complex etiology, requiring the interaction between environmental triggers and inherited susceptibility alleles. The dissection of such an intricate model has proved challenging, necessitating the recruitment of increasingly large patient resources and the development of specifically designed statistical tools. Despite these difficulties, the last few years have witnessed significant progress in the field, leading several research groups to close in on the major psoriasis-susceptibility genes. It seems timely to review these advances, while highlighting the controversies and difficulties still to be faced by the research community.
Chromosome 6p21 harbors the major psoriasissusceptibility locus (psoriasis-susceptibility 1) Defining the psoriasis-susceptibility 1 interval The first step in the isolation of a disease gene is the identification of the chromosomal region (locus) bearing the gene responsible for the disorder. This has
* Corresponding author. E-mail address: fc29@le.ac.uk (F. Capon).
traditionally been achieved by genotyping markers that cover the entire genome and identifying those that are co-inherited by affected sib pairs more frequently than the 50% prior expectation. Such genome-wide scans have now been performed in several extended patient cohorts and have repeatedly identified a region of chromosome 6p21 as a contributor to psoriasis susceptibility (Table 1). This degree of consistency among genome-scan results in the analyses of complex disorders is uncommon. Many studies are typically plagued by poor reproducibility, caused in part by a number of recognized confounder issues (Table 2). Hence, the repeated identification of a 6p21 susceptibility locus (psoriasis susceptibility 1 [PSORS1]) in several independent samples clearly indicates a major pathogenic role for this region. Several attempts have been made to refine the boundaries of the PSORS1 interval, to define a minimal target region to focus the search for the 6p21 susceptibility genes. These refinement studies have sought to identify haplotypes (blocks of markers grouped together on a chromosome) that are transmitted to affected patients more often than expected by chance. The rationale behind this approach is that marker alleles lying in close proximity to a mutation tend to be in linkage disequilibrium with it (ie, they are very seldom separated from it by recombination or cross-over events) (Fig. 2). As a consequence, marker alleles whose frequency is increased in patient cohorts may be used to highlight the most likely location of a susceptibility gene (see Fig. 2). Three studies reported the fine-scale mapping of the PSORS1 interval and a consensus minimal region has emerged. The PSORS1 segment is contained within a 200-kb block of DNA in the class I major
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F. Capon et al / Dermatol Clin 22 (2004) 339347 Table 2 Major factors affecting the reproducibility of complex trait genetic analysis Confounder Genetic heterogeneity Example Different genes cause the same disease, in two unrelated populations The analyzed sample is too small to detect the effect of a given locus Part of the patients are affected by a nonhereditary form of the disease Diverse inclusion criteria have been used in different studies Different statistical tools have been used in various surveys Originally published results were in fact spurious
Lack of statistical power
Occurrence of phenocopies
Diagnostic criteria
Experimental design
False-positives
In-depth treatises of these issues can be found in Refs. [73,74]. Fig. 1. A modest degree of family clustering is consistent with a polygenic mode of disease inheritance. Upper pedigree: an individual affected by a dominant monogenic disorder caused by mutated allele A transmits the disease to half (50%) of his offspring. Lower pedigree: an individual affected by a polygenic disorder requiring the presence of mutated alleles A, B, and C transmits the disease to one (12.5%) in eight of his offspring. Square, male; circle, female; filled symbol, affected; empty symbol, unaffected.
conserved block, RH2 (see Fig. 3). The definition of the minimal PSORS1 region was based on the observation of a single Cw6-negative risk haplotype bearing RH1 only (see Fig. 3). A collaborative survey of an extended patient cohort failed to validate this chromosome as conferring risk, however, pointing to a more conservative minimal region, including HLAC and RH2, together with RH1 (see Fig. 3) [11]. Psoriasis-susceptibility 1 candidate genes The consensus 200-kb PSORS1 interval contains several genes, most of which have been investigated as positional candidates for psoriasis susceptibility. HLA-C lies at the centromeric end of the interval and has long been considered a likely psoriasis-susceptibility gene [12]. The HLA-C gene encodes a MHC class I antigen participating to the process of immune system self-recognition and self-tolerance [13]. Class I molecules also stimulate the response against intracellular pathogens, by presenting nonself cytoplasm peptides to cytotoxic T cells [13]. HLA-C polymorphisms have been investigated in a wide range of populations and a highly significant association between the HLA-Cw6 allele and psoriasis has been repeatedly reported [10,12]. Association studies have also defined the HLA-Cw6 allele as a factor that predisposes to early onset disease [14,15] and to the exacerbating action of streptococcal infections [14,16]. Despite the significance and consistency of association findings, it is not known whether the
histocompatibility complex (MHC) region (Fig. 3) [6 8]. One study reported a further refinement of the critical interval, describing a 60-kb minimal susceptibility region [7] (RH1 segment in Fig. 3). This result has generated some controversy in the field, however, with a consensus view that the larger 200-kb interval may not be discounted at this time [9,10]. The RH1 segment was defined by comparing a number of risk haplotypes, most of which also contained a second
Table 1 Studies implicating the psoriasis-susceptibility 1 region in psoriasis susceptibility Authors Nair et al [65] Trembath et al [49] Capon et al [71] Samuelsson et al [72] Lee et al [63] Veal et al [66] Zhang et al [67] Zheng et al [70] Sample origin Germany, United States United Kingdom Italy Sweden Germany United Kingdom China China
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Fig. 2. Linkage disequilibrium as a tool for the fine mapping of disease loci. The analysis of six polymorphisms spanning a susceptibility interval shows that patients from unrelated families share a core two-marker haplotype (A7 A2). The preservation of this genomic segment indicates linkage disequilibrium (ie, lack of recombination because of close proximity) between the two markers and the susceptibility mutation (asterisk). The conserved haplotype (filled bar) defines the minimal region that is most likely to harbor the disease-susceptibility gene.
HLA-Cw6 antigen participates in the cellular processes that lead to the onset of psoriasis. In the absence of functional data, it remains possible that the reported association merely reflects HLA-C proximity to an as yet undisclosed susceptibility mutation. In addition to HLA-C, the consensus PSORS1 region contains seven known genes (see Fig. 3). Of these, OTF3 and STG have been considered unlikely candidates, based on the known characteristics of their protein products. OTF3 encodes a transcriptional factor playing a major role in embryonic stem cells lineage commitment [17], whereas STG codes for an extracellular protein that is only expressed in the tongue taste buds [18]. The SC1 and SPR1 genes seem not to show association with psoriasis [19,20], and SEEK1 has not yet been characterized in terms of function, expression pattern, or polymorphism content. In contrast to this group of genes, both HCR and CDSN have been extensively investigated and have been seen in independent reports to show association
with psoriasis. HCR (alpha-Helix Coiled coil Rod homologue) encodes a highly polymorphic, ubiquitously expressed protein of unknown function, which is up-regulated in psoriatic epidermis [21,22]. An association between psoriasis and two HCR variants first reported in the Finnish population [21] has been confirmed in studies of several ethnic groups [10,22]. The pathogenicity of these variants remains unclear, however, not least because haplotypes have been identified that are overtransmitted to affected patients but lack the HCR risk alleles [23,24]. A collaborative analysis of an extended patient resource has also been reported but failed to discriminate whether the association at the HCR variants was caused by their proximity to HLA-Cw6 or vice versa [10]. The CDSN gene lies at the distal end of the PSORS1 interval (see Fig. 3) and codes for corneodesmosin, a structural protein that participates in the process of keratinocyte adhesion and desquamation [25,26]. Homozygous, nonsense CDSN mutations
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Fig. 3. The PSORS1 region refinement proposed by Nair et al [7]. The upper diagram shows the 200-kb consensus minimal region together with the eight known genes contained therein. HLA-C, HCR, and CDSN are highlighted as genes that have repeatedly been associated with psoriasis. The lower diagram schematizes the PSORS1 risk haplotypes reported by Nair et al [7], with different line styles symbolizing regions of haplotype divergence. Following to the exclusion of the bottom haplotype, the minimal region shared by all risk chromosomes expands to include both HLA-C and RH2.
have been identified in patients with the rare, autosomal-recessive disorder hypotrichosis simplex of the scalp [27]. The observation of CDSN-specific expression in cornified squamous epithelia [28], together with its up-regulation and abnormal degradation in psoriatic epidermis [29 31], have generated a considerable interest in this gene. The CDSN gene is highly polymorphic, with 37 sequence variants described [32,33]. Association analyses have identified three variants defining an intragenic haplotype that confers risk to psoriasis in a wide range of populations [33 38]. The biologic relevance of these findings has been questioned, however, based on the argument already put forward against the HCR risk alleles (ie, that the observed association could be
ascribed to linkage disequilibrium with HLA-Cw6) [39,40]. How many psoriasis-susceptibility 1 genes? The controversies surrounding the analysis of candidate genes have highlighted the difficulties of carrying out association studies in a region where extensive linkage disequilibrium between marker alleles can act as a major confounder. To unravel the relationship between the HLA-C, HCR, and CDSN associations, haplotypes spanning the PSORS1 interval and encompassing these three loci have been generated (Fig. 4) [24]. To maximize the genetic resolution of the study single nucleotide polymor-
Fig. 4. Both HLA-C and CDSN risk alleles might be required to confer psoriasis susceptibility. The upper diagram shows the 200-kb consensus PSORS1 minimal region. The lower bars schematize the PSORS1 SNP haplotypes reported by Veal et al [24] and Capon et al [33]. Risk haplotypes carry both HLA-C and CDSN related risk alleles, whereas chromosomes bearing a single set of risk SNPs (HLA-C or CDSN only) are neutral.
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phism markers distributed across the interval have been identified. Single nucleotide polymorphisms occur at a higher frequency in the genome [41], allowing the construction of more dense genetic maps. In addition, single nucleotide polymorphisms exhibit a much lower mutation rate compared with microsatellite markers [41] and as such are more suited to the reconstruction of very ancient haplotypes. The single nucleotide polymorphism based dissection of the PSORS1 interval has identified a major risk haplotype bearing HLA-C, HCR, and CDSN disease-associated alleles (cluster E in Fig. 4), together with a minor risk chromosome (cluster D in Fig. 4) carrying HLA-C and CDSN risk variants only [24]. These observations have subsequently been replicated in an independent population of northern Indian descent, where two novel haplotypes (G1 and G2 in Fig. 4) were identified that carried a single set of risk alleles and did not show any association with psoriasis [33]. Taken together, these findings have prompted the intriguing hypothesis that both HLA-C and CDSN alleles may contribute to psoriasis susceptibility. The possibility that multiple genes may underlie a single susceptibility locus is not a novel concept in the genetics of common multifactorial disorders, because compound MHC risk alleles have already been observed within loci conferring susceptibility to type I diabetes [42] and multiple sclerosis [43]. It is tempting to speculate that further MHC genes, lying outside of the minimal PSORS1 interval, might also contribute to or modify an individuals genetic susceptibility. In fact, genetic associations with psoriasis have been reported for a number of genes lying proximal to HLA-C. These include the TAP genes, which encode a heterodimeric complex delivering antigenic peptides to the endoplasmic reticulum before the assembly of class I molecules [44,45], and MICA, which codes for a ligand of the natural killer cell activating receptor NKG2D [46,47]. Significant associations have also been reported for polymorphisms of the tumor necrosis factor-beta gene, which encodes the lymphotoxin alpha cytokine [45,48].
ing. PSORS1 accounts for less than 50% of familial aggregation in psoriasis [49,50], however, hence other susceptibility loci must contribute to the disorder pathogenesis. Genome-wide scans have identified a number of such non-MHC susceptibility intervals (Table 3), but the validation of these regions in independent dataset has proved a challenging task. Unlike PSORS1, most non-MHC loci have been observed only once and, with the exception of PSORS2, none of them has been replicated in more than two populations (see Table 3). The inconsistency of these findings can be accounted for by confounders that generally complicate the genetic dissection of complex traits (see Table 2). In the case of psoriasis, the repeated observation of distinct susceptibility regions (see Table 3) highlights the likely presence of genetic heterogeneity, well known to affect the reproducibility of localization studies. The small effect of non-MHC susceptibility loci is also likely to be a confounder, with undersized patient cohorts lacking the power to replicate regions of relatively modest effect. Finally, some susceptibility loci might be unique to the population where they were identified.
Table 3 Published non major histocompatibility complex susceptibility loci Chromosome (locus name) 1p (PSORS7) 1q (PSORS4)a 2pa 2q 3q (PSORS5) 4q13a 4q31 4q34a (PSORS3) 6qa 7 8qa 10qa 14qa 15 16qa 17q25a (PSORS2) 19p13 (PSORS6) 20pa Sample origin United Kingdom [66] Italy, United States [4,68] United States, United Kingdom [4,66] United Kingdom [49] Sweden [51,72] United States, Sweden [4,72] China [67] Ireland [64] United States, Germany [65] United Kingdom [49] United Kingdom [49] United States, Germany [65] United Kingdom, United States [4,66] Sweden [72] United States, Germany, Icelandb [62,65] United States, Germany, Sweden, China [51,61,65,70,72] Germany, United Kingdom [63] Germany, United Kingdom, United States [7,49,65]
Non major histocompatibility complex susceptibility loci: separating the wheat from the chaff The non major histocompatibility complex contribution to psoriasis susceptibility The evidence supporting PSORS1 as the major psoriasis susceptibility locus is by now overwhelm-
a Loci included in the International Psoriasis Genetics Study [50]. b Psoriatic arthritis cohort.
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This might be particularly true for samples originating from genetic isolates, such as the cohort from southwest Sweden in which the PSORS5 susceptibility interval has been reported [51]. Possible approaches to locus validation The positional cloning of a susceptibility gene is a labor-intensive and costly endeavor, which is unlikely to be undertaken unless the chromosomal assignment of the relevant locus is supported by robust statistical evidence. The validation of non-MHC susceptibility loci and the identification of regions warranting further investigation are essential steps in the dissection of psoriasis genetics. To achieve these objectives, an extended clinical resource was recently established by integrating the patient cohorts from three research centers [50]. This pooled sample included 942 affected sib pairs and, being the largest yet analyzed in a psoriasis genetics study, was expected to have enough statistical power to validate non-MHC loci. The patient data set was typed using 53 markers, which spanned a number of published susceptibility regions (labeled with an asterisk in Table 3) and statistically significant evidence was gathered in support of the 10q and 16q loci [50]. Although these results undoubtedly warrant a closer scrutiny of the previously mentioned regions, they cannot be interpreted as a definite exclusion of all the remaining non-MHC loci. In fact, it is entirely possible that even a dataset as large as the Consortiums may lack the power to detect a non-MHC locus in the presence of substantial genetic heterogeneity. This interpretation is consistent with independent evidence that has emerged from the analysis of a distinct inflammatory disorder (atopic eczema). Indeed, genome-wide searches for loci predisposing to childhood atopic dermatitis have identified four chromosomal regions closely overlapping with the 1q21, 3q21, 17q25, and 20p psoriasissusceptibility intervals [52,53]. Colocalization of loci predisposing to different inflammatory disorders is not unusual and it has been hypothesized that a common set of genes influencing the immune response may underlie clinically distinct complex diseases [54]. The possibility that some of the reported colocalizations might be coincidental should always be considered, however, given the broad extension of the susceptibility regions detected by genome-wide scans and the occurrence of false-positive findings in these studies. Nonetheless, the overlap between atopic dermatitis and psoriasis-susceptibility regions is thought to underlie a set of common genetic determinants, because it has been estimated that the likelihood of identifying four atopic dermatitis loci colocalizing by
chance with an equal number of psoriasis susceptibility intervals is less than 1:100,000 [52]. Another possible instance of a shared inflammatory locus is the chromosome 16q susceptibility region, which also contains the NOD2-CARD15 Crohns disease gene [55,56]. Case-control and family-based studies have failed to detect an association between the major NOD2 risk allele and psoriasis susceptibility [57 59]. Preliminary data obtained in the Newfoundland genetic isolate, however, support an association between a distinct NOD2 variant and psoriatic arthritis [60].
Summary It will soon be 10 years since Tomfohrde et al [61] identified the first psoriasis-susceptibility locus through a genome-wide scan of eight extended American pedigrees. Nine further genome-scans totaling almost 800 pedigrees have followed [49,51,62 68] and at least 500 additional families have been analyzed in follow-up studies of published loci [50,69, 70]. This major research effort has led to considerable insights as to the genetic basis of psoriasis susceptibility, notwithstanding the inevitable appearance of contradictory findings. The evidence supporting a primary role for the PSORS1 locus is now overwhelming. Remarkably, psoriasis is the only complex disorder that has been consistently associated with an HLA-C allele. This indicates that HLA-Cw6 (or the undiscovered susceptibility variant that may be in linkage disequilibrium with it) affects the disease risk by specifically predisposing to psoriasis, rather than by conferring a generic susceptibility to inflammatory disorders. Dissecting the contribution of non-MHC loci is proving a somewhat arduous task, because of their less prominent role and the likely occurrence of genetic heterogeneity. Unlike PSORS1, several nonMHC susceptibility intervals overlap with loci predisposing to other inflammatory or autoimmune diseases. The identification of the genes underlying these loci may benefit the understanding of clinically distinct conditions. The disease model emerging from 10 years of genetic analyses is, not unexpectedly, a rather elaborate one, where psoriasis-specific determinants are likely to interact with a potentially large number of inflammatory loci and environmental triggers. In this context, the availability of the human genome sequence and the establishment of collaborative patients resources are going to prove essential tools
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to disentangle the contribution of individual psoriasis-susceptibility genes.

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[31] Simon M, Tazil-Ahnini R, Cork MJ, Serre G. Abnormal proteolysis of corneodesmosin in psoriatic skin. Br J Dermatol 2002;147:1053. [32] Guerrin M, Vincent C, Simon M, et al. Identification of six novel polymorphisms in the human corneodesmosin gene. Tissue Antigens 2001;57:32 8. [33] Capon F, Toal IK, Evans JC, et al. Haplotype analysis of distantly related populations implicates corneodesmosin in psoriasis susceptibility. J Med Genet 2003;40: 447 52. [34] Allen MH, Veal C, Faassen A, et al. A non-HLA gene within the MHC in psoriasis. Lancet 1999;353: 1589 90. [35] Chang YT, Tsai SF, Lee DD, et al. A study of candidate genes for psoriasis near HLA-C in Chinese patients with psoriasis. Br J Dermatol 2003;148:418 23. [36] Orru S, Giuressi E, Casula M, et al. Psoriasis is associated with a SNP haplotype of the corneodesmosin gene (CDSN). Tissue Antigens 2002;60:292 8. [37] Hui J, Oka A, Tamiya G, et al. Corneodesmosin DNA polymorphisms in MHC haplotypes and Japanese patients with psoriasis. Tissue Antigens 2002;60: 77 83. [38] Schmitt-Egenolf M, Windemuth C, Hennies HC, et al. Comparative association analysis reveals that corneodesmosin is more closely associated with psoriasis than HLA-Cw*0602-B*5701 in German families. Tissue Antigens 2001;57:440 6. [39] Enerback C, Nilsson S, Enlund F, et al. Stronger association with HLA-Cw6 than with corneodesmosin (Sgene) polymorphisms in Swedish psoriasis patients. Arch Dermatol Res 2000;292:525 30. [40] Jenisch S, Koch S, Henseler T, et al. Corneodesmosin gene polymorphism demonstrates strong linkage disequilibrium with HLA and association with psoriasis vulgaris. Tissue Antigens 1999;54:439 49. [41] Sachidanandam R, Weissman D, Schmidt SC, et al. A map of human genome sequence variation containing 1.42 million single nucleotide polymorphisms. Nature 2001;409:928 33. [42] Lie BA, Todd JA, Pociot F, et al. The predisposition to type 1 diabetes linked to the human leukocyte antigen complex includes at least one non-class II gene. Am J Hum Genet 1999;64:793 800. [43] Marrosu MG, Murru R, Murru MR, et al. Dissection of the HLA association with multiple sclerosis in the founder isolated population of Sardinia. Hum Mol Genet 2001;10:2907 16. [44] Pyo CW, Hur SS, Kim YK, et al. Association of TAP and HLA-DM genes with psoriasis in Koreans. J Invest Dermatol 2003;120:616 22. [45] Vasku V, Vasku A, Izakovicova Holla L, et al. Polymorphisms in inflammation genes (angiotensinogen, TAP1 and TNF-beta) in psoriasis. Arch Dermatol Res 2000;292:531 4. [46] Gonzalez S, Martinez-Borra J, Torre-Alonso JC, et al. The MICA-A9 triplet repeat polymorphism in the transmembrane region confers additional susceptibility to the development of psoriatic arthritis and is indepen-
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Dermatol Clin 22 (2004) 349 369
Current concepts in the immunopathogenesis of psoriasis

Michelle A. Lowes, MD, PhDa, Wook Lew, MD, PhDb, James G. Krueger, MD, PhDa,*
b a Rockefeller University, 1230 York Avenue, Box 178, New York, NY 10021, USA Department of Dermatology and Cutaneous Biology Research Institute, Yonsei University College of Medicine, Yongdong Severance Hospital, 146-92 Dogok-Dong, Kangnam-Ku, Seoul, South Korea
Psoriasis vulgaris affects approximately 2% of the US population, and although it varies in severity, it imposes a great burden on those who have this disease. Psoriasis was initially considered to be a primary disorder of keratinocytes, with disturbed epidermal differentiation leading to keratinocyte hyperproliferation. Now there is much evidence to support the involvement of the immune system in the pathogenesis and maintenance of psoriasis, including roles for CD8+ and CD4+ lymphocytes, dendritic cells (DCs), monocytes/macrophages, and natural killer (NK) and natural killer T (NK-T) cells. Keratinocytes may still play an integral role, responding to the leukocyte infiltration and cytokine environment. Novel anti T-lymphocyte immunotherapies, and review of the mechanisms of some traditional antipsoriatic medications, have confirmed an important role of the immune system in psoriasis (reviewed in reference [1]). Therapies aimed at different immune targets have proved successful, although there is variability in clinical response between patients, reflecting the complexity of psoriasis pathogenesis and redundancy of immune pathways. The first such treatment used the immunotoxin DAB389IL-2, which is a fusion protein carrying a cellular toxin to interleukin 2R (IL-2R) expressing cells [2]. This agent blocks proliferation of activated lymphocytes, and clinical improvement was associated with reduction in intraepidermal CD3+ and CD8+ T cells, therefore supporting the role of these cells in disease pathogenesis. Another important antilymphocyte
therapy used in individuals with psoriasis is cytotoxic T-lymphocyte associated antigen 4-immunoglobulin (CTLA4-Ig) [3]. Molecules in the B7 family on the surface of antigen-presenting cells (APCs) normally engage CD28 on T cells, which delivers costimulatory signals during T-cell activation, or CTLA4, which delivers a negative signal. Blocking this interaction with CTLA4-Ig in individuals with psoriasis showed a dose-dependent clinical response associated with reduction of cell activation markers. Other examples of immunobiologic mechanisms are discussed and tabulated in reference [4], and some are also discussed in other articles in this issue. The current theories of the roles of components and the potential functions of the innate and cell-mediated immune system are discussed, focusing on current concepts of the immunopathogenesis of psoriasis. The role of xenotransplant and other mouse models, and the contribution of recent genomic studies, are also outlined in the context of further understanding psoriasis.
Psoriasis as a type 1 T-cell mediated autoimmune disease There is mounting evidence that psoriasis may be a type 1 T-cell mediated autoimmune disease, such as type 1 diabetes or multiple sclerosis. In such type 1 autoimmune diseases, there is characteristic activation and proliferation of pathogenic antigen-specific CD4+ or CD8+ T cells, and the responsible lymphocytes are activated type 1 (interferon g [IFN-g] producing) memory cells. Initially, morphologic studies showed abundant lymphocytes within lesional skin (along
* Corresponding author. E-mail address: jgk@rockefeller.edu (J.G. Krueger).
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with characteristic neutrophils), but few monoclonal antibodies were available to classify these cells further. Fig. 1 shows the relevant cell types that have been described in psoriatic tissue and important inflammatory products that are likely to play a role in disease pathogenesis. Immunohistochemical analysis of these abundant lymphocytes in lesional tissue and fluorescence-activated cell sorting (FACS) of epidermal and dermal single-cell suspensions reveal patterns consistent with immunologic memory and specialized tissue homing. There are abundant CD4+ T cells in psoriatic dermis and CD8+ T cells in the epidermis [5,6]. Lesional T cells demonstrate the surface marker cutaneous lymphocyte antigen (CLA), which allows them to bind to endothelial P- and E-selectin, facilitating transmigration across the cutaneous vasculature [7]. Epidermal CD8+ T cells are CXCR3+. CXCR3 is a chemokine receptor that allows these cells to respond to epidermal chemokine gradients from keratinocyte-
derived monokine induced by IFN-g (MIG) and IFN inducible protein 10 (IP-10), and migrate into the epidermis [8]. Many CD8+ lymphocytes bear the aEb7 (CD103/b7) integrin, which facilitiates movement into the epidermis by way of keratinocyte E-cadherin [8,9]. Thus, there is specialization in the surface phenotype of these cells to encourage their movement into psoriatic lesional tissue. Lesional epidermal lymphocytes are persistently activated, as shown by the following: up-regulation of CD69, a rapidly induced antigen; CD25, the lowaffinity receptor for IL-2 (a chain); and the major histocompatibility complex (MHC) class II molecule HLA-DR [6]. Although a universal and specific psoriatic antigen has not yet been determined, there is oligoclonal expansion of CD8+ T-cell receptor (TCR) b-chain components within psoriatic lesions, particularly of the complementary determining region 3, or CDR3. The specific TCR chain that is preferentially expressed is not the same in all patients [10 12]. Over
Fig. 1. Psoriasis as a type 1 mediated disease. CLA+ memory T lymphocytes and polymorphonuclear (PMN) leukocytes extravasate across inflamed blood vessels, responding to chemokine gradients. CD4+ Th1 cells are found predominantly in the dermis, and CD8+ Tc1 cells are found in the epidermis. Both are able to produce type 1 cytokines IL-2, IFN-g, and TNF-a, which augment the psoriatic inflammatory process. Activated DCs play a role in T-cell activation both in the draining lymph node and within the psoriatic lesion by means of type 1 cytokines IL-12 and IL-23. The phenotype of psoriasis is likely caused by the direct and downstream effects of these locally produced cytokines and chemokines.
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time, dominant TCR rearrangements persist in relapsing psoriasis [13]. This finding suggests the presence of ongoing specific antigen, or at least favorable conditions for clonal in situ T-cell proliferation. Epidermal and dermal CD8+ cytotoxic T-cell (Tc) clones also have been developed, some of which release mediators capable of causing keratinocyte proliferation [14] or producing IFN-g [15]. T-helper (Th) cell (CD4+) differentiation can be categorized into a type 1 (IFN-g and IL-2 producing) versus type 2 (IL-4 and IL-10 producing) cytokine pattern (Th1 versus Th2, respectively). Similarly, CD8+ cytotoxic T cells can be functionally differentiated into two populations, Tc1 and Tc2, which secrete these two patterns of cytokines [16]. CD4+ and CD8+ T cells from psoriatic epidermal and dermal single-cell suspensions produce a type 1 pattern of cytokines, specifically IFN-g and IL-2, and small amounts of type 2 cytokines, IL-4 and IL-10 [17]. Tumor necrosis factor a (TNF-a), a cytokine that may be produced by many cells during innate and cellmediated immune responses, is also increased from lesional lymphocytes. Essentially all type 1 (IFN-g producing) T cells cosynthesize TNF-a when activated. Elaborated cytokines are able to orchestrate further proliferation of antigen-specific T cells, and activation of effector and responding cells, such as CD8 + T cells, macrophages, and keratinocytes. Patients with psoriasis also demonstrate systemic type 1 immune deviation (Fig. 2), with two- to threefold expansion of type 1 T cells producing IFNg and IL-2 [17 19]. The specific cytokine milieu can determine the process of type 1 versus type 2 differentiation. IL-12, produced by activated DCs, stimulates the production of a type 1 cytokine pattern. IL-13 leads to the production of IL-4 and IL-10, a more immunosuppressive type 2 pattern that is also associated with antibody production. There are increased IL-12 and IL-12R found within psoriatic lesions [20,21], which may drive type 1 T-cell differentiation. One of the major stimuli for DCs to produce IL-12 is the ligation
of DC CD40 by the CD40 ligand (CD40L) on CD4+ T cells [22,23]. This sets up a scenario where activated CD4+ T cells engage DCs by means of a CD40L CD40 interaction, resulting in IL-12 production by DCs and subsequently driving the production of the classic type 1 cytokine, IFN-g. This CD40 CD40L interaction also generates the production of IL-23 [24], another important, recently discovered type 1 cytokine. IL-23 is a heterodimer composed of one of the IL-12 chains (p40) and an IL-23 specific chain (p19; reviewed in reference [25]). This cytokine shares many features with IL-12, such as signal transduction pathways, induction of IFN-g production, target cell proliferation, and upregulation of APC costimulatory function. It acts primarily on memory CD4+ T cells, however, whereas IL-12 acts on na ve CD4+ T cells. IL-23 is upregulated in psoriasis [26] and may be the key cytokine driving type 1 T-cell expansion and the production of IFN-g. The current authors believe that IFN-g is a pivotal cytokine in the development and maintenance of psoriatic lesions. Fig. 3 outlines a sequential pathway of type 1 T-cell activation, release of T-cell derived cytokines, and production of several inflammatory mediators that the authors term the type 1 pathogenic pathway. IFN-g is produced by effector memory CD8+ T cells, epidermal Tc1, CD4+ T cells, and NK and NK-T cells. Psoriatic CD8+ Tc1 cell lines and clones have been shown to produce heterogeneous levels of IFN-g [15]. There is also evidence of the effects of IFN-g at the tissue level in psoriatic lesions: keratinocytes show increased levels of HLA-DR, intercellular adhesion molecule-1 (ICAM-1) [27], and CD40 [28]; increased CXCR3 expression on lymphocytes [8]; and greater levels of keratinocytederived MIG and IP-10 [8]. Furthermore, this cytokine may also increase expression of costimulatory molecules on DCs [29]. IFN-g potently activates macrophages and may also induce TNF-a release from monocytes and macrophages, which acts synergistically with IFN-g in an inflammatory response
Fig. 2. Immune deviation in psoriasis. In homeostatic conditions, there are more type 1 (T1) cytokines (IL-2, IFN-g, and TNF-a) than type 2 (T2) cytokines (IL-4, IL-10). In diseases characterized by a type 1 immune deviation, there are more type 1 cytokines. In type 2 immune deviations, there are more type 2 cytokines than normal.
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Fig. 3. Type 1 pathogenic pathway in psoriasis. The current authors have proposed that IL-12 and IL-23, primarily DC-derived cytokines, stimulate type 1 T cells to produce type 1 cytokines. This has many effects at the gene level, and the resultant products help explain the phenotype of psoriatic lesions. For some genes there is synergy between IFN-g and TNF-a. GAS, IFN- g activation sequence; ISRE, IFN-stimulated response element.
[30]. Endothelial cells are also responsive to IFN-g, up-regulating several adhesion molecules, such as ICAM-1 and vascular cell adhesion molecule-1 (VCAM-1), which facilitates the complex process of leukocyte trafficking into tissues. The sum of cytokines and chemokines made in response to IFN-g and TNF-a (see Fig. 3) can explain many features of the pathogenic process: angiogenesis and vascular ectasia, T-cell and neutrophil emigration into lesions, and some components of the psoriatic epidermal response. There have been several additional observations regarding the relationship between IFN-g and psoriasis. IFN-g receptors in keratinocytes [31] and IFN-g protein in papillary dermal cells [32] have been shown to be up-regulated in lesional skin of patients with psoriasis. Subcutaneous administration of IFN-g for the treatment of psoriatic arthritis can lead to the occurrence of punctiform psoriatic foci at the site of injection [33]. Patients with immunoblastic lymphadenopathy-like T-cell lymphoma showed elevated serum levels of IFN-g and were reported to develop psoriasis [34]. For treatment of lepromatous leprosy, delivery of IFN-g resulted in several features present in psoriatic lesional skin [35]. As mentioned, a type 1 bias toward activated T cells is indicated by the overexpression of IFN-g in psoriasis, both lesionally and in the circulating leukocytes [17]. There are also preliminary data that blocking IFN-g in patients with psoriasis may give a beneficial clinical effect [36]. Recent gene expression studies by microchip analysis have begun to elucidate the pattern of cytokines, inflammatory mediators, and transcriptional factors within psoriatic tissue at the message level
(discussed later). Interpretation of this vast bank of data is challenging, but the information can be ordered on the basis of IFN-g responsive genes (Fig. 4). After type 2 IFN (IFN-g) is produced, it binds to the IFN-g cell surface receptor, which is phosphorylated by janus kinase (JAK) 1 and JAK2 enzymes (reviewed in references [37 39]). This process makes available a recruitment site for an important transcriptional factor, the signal transducer and activator of transcription (STAT). Dimers of STAT-1 form an IFN-g activated factor (GAF), translocate to the nucleus, and activate transcription from IFN-g target gene promoters containing IFN-g activation sequence (GAS) elements. Thus, STAT-1 production is an important early indicator of IFN-g effects. Other primary response genes include additional IFN transcription factors and MIG. Downstream effects of IFN- g include the secondary response genes, which may contribute to the development of the psoriatic phenotype, such as IL-8 and IP-10. Type 1 IFNs (IFN-a and IFN-b) are also able to induce many genes on the IFN-g pathway, particularly the secondary response genes. APCs are central to the process of antigen-specific T-cell activation (reviewed in reference [40]). The first DC described in normal epidermis, but which can also be found in the dermis, was the Langerhans cell (LC). This cell can be identified by surface antigens MHC class I and II, CD1a, langerin, lag, and Birbeck granules. LCs are extremely efficient at capturing local antigen, and after activation, they migrate to local lymph nodes by way of cutaneous lymphatics. During migration, they mature for in-
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Fig. 4. IFN receptor binding and effects. Binding of IFN-g to its receptor causes STAT-1 phosphorylation and dimerization to form the IFN-g activating factor (GAF). GAF is able to translocate to the nucleus and bind to IFN-g activation sequence (GAS) in promoters for translation of IFN primary response genes. Binding of type 1 IFNs (IFN-a or IFN-b) to the type 1 IFN receptor causes production of IFN-stimulated gene factor 3 (ISGF3), which is composed of STAT1, STAT 2, and IFN regulatory factor 9 (IRF-9, p48). ISRE is able to bind to the ISRE sequence in gene promoters leading to transcription of IFN-g secondary response genes in the IFN-g pathway. There is cross-talk between these two IFN systems: STAT1 dimers (GAF) can bind IRF-9 and also activate ISRE (reviewed in Refs. [37 39]).
creased antigen presentation to lymphocytes, by upregulating MHC class I and II, costimulatory molecules B7.1 and B7.2 (CD80 and CD86, respectively), and CD83. These mature DCs have the capacity to stimulate resting and memory T cells, unlike other nonprofessional APCs, such as monocytes or B cells, which can only activate memory T cells. Inflamed epidermis has two additional types of DCs [41]. The inflammatory dendritic epidermal cell, or IDEC, lacks Birbeck granules; is positive for CD1a, HLA-DR, CD11b, CD11c; and expresses costimulatory molecules in situ. More recently, the plasmacytoid dendritic cell (PDC or DC2) has been identified in psoriatic lesional skin. PDCs were increased in epidermal single-cell suspensions of psoriasis compared with other inflammatory dermatoses or normal skin. This cell has a characteristic plasmacytoid morphology, is CD123+ and CD11c, and makes large amounts of type 1 IFN on viral infection or stimulation with CpG motifs within microbial DNA. Mature activated plasmacytoid DCs are functionally specialized to prime a Th2 pattern of cytokine production. Currently, there exists controversy regarding the capacity for PDC to produce IL-12 and promote an IL-12 dependent Th1 response [42]. Other DCs that are located in the dermis are factor XIIIa+ and called dermal DCs (DDC). Factor XIIIa+ DCs were increased in psoriatic skin [43]. These cells also have an excellent capacity for antigen capture,
migration, and MHC-restricted presentation to lymphocytes. DDCs can be further subdivided into three subsets: CD1a CD14, CD1a+ CD14, and CD1a CD14+ [44]. DCs from psoriatic plaques are able to present to and activate T cells [44,45], concurrently producing IL-12 and potentially setting up a local type 1 immune response that is perpetuated rather than selflimited. Psoriatic-derived DDCs were able to stimulate spontaneous T-cell proliferation and increase IL-2 and IFN-g production compared with blood-derived or normal skin derived DCs. There was involvement of HLA-DR, B7, and leukocyte function-associated antigen 1 (LFA-1). There are also activated macrophages in psoriatic tissue [46], which may represent a source of blood-derived APCs. The presence of mature epidermal and dermal DCs, defined by CD83, DC-lysome associated membrane protein (DCLAMP), and CD11c positivity [3], supports the concept of the psoriatic lesion becoming more like peripheral lymphoid tissue, capable of initiation and maintenance of inflammation. This concept will be further discussed later. The study of the actions and role of DCs in disease states is complicated because there is no uniform method for generating sufficient quantities of DCs for study in vitro, and the relationship between these DCs derived from blood or bone marrow with in vivo DCs is not yet fully understood. IFN-g can act to stimulate uncommitted myeloid immature DCs to
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produce IL-12 and polarize toward Th1 responses [47]. An alternative method to study cutaneous DCs is to culture skin biopsy specimens, which yield DC crawl outs [45]. In addition, epidermal and dermal cell suspensions can give rise to DCs suitable for surface phenotype analysis or functional studies. Although clinicians still have much to learn about the roles of different DC subsets in the regulation of normal and pathogenic immune responses, the DC repertoire in psoriasis is likely to regulate T-cell activation and clonal expansion by conventional antigen-presenting mechanisms and type 1 T-cell deviation by cytokines such as IL-12 and IL-23 (see Fig. 3). In addition, DCs are likely to contribute nitric oxide (NO) to the inflammatory environment, because inducible NO synthetase (iNOS) is highly up-regulated in activated DCs, and NO even has been postulated as a psoriasis-triggering factor [48]. Hence, DCs may be as important in the maintenance of pathogenic immunity in psoriatic plaques as T cells.
Innate immunity in psoriasis Despite all the evidence reviewed previously, there are also data to suggest that the innate immune system is activated in psoriasis and may play an important contributory role. Cellular and noncellular components of primitive innate immunity give an immediate or very fast proinflammatory cutaneous response to microbial infection or nonspecific stimuli, such as trauma [49]. Leukocytes that contribute to innate immunity possess several types of pattern recognition receptors (PRRs) that are individually nonpolymorphic, as opposed to adaptive responses where these receptors are individually variable (eg, TCRs). Proinflammatory molecules and cytokines, such as IL-1 and TNF-a, may be released from keratinoyctes, macrophages, or DCs, activating endothelial cells and recruiting additional leukocytes to the site of inflammation. Pathogens are eliminated by mechanisms such as superoxide anion release, defensins, phagocytosis, and NK-cell killing. Tissue repair in the skin is associated with additional changes, such as epidermal hyperplasia and erythema, but these changes reverse as homeostasis is restored. TNF-a is an important cytokine of the innate immune system, and recent beneficial clinical trials with anti TNF-a agents [50] point to its considerable role in psoriasis. This cytokine may be produced by many cells, including activated keratinocytes, in response to nonspecific injury or stimulation. It induces complex inflammatory cascades, initially by altering endothelial cell adhesion molecules, causing neutro-
phil and NK-cell recruitment and stimulating production of other cytokines by means of the NFkB pathway [51]. There is convergence of the TNF-a and IFN-g signaling pathways mediated by a composite GAS/kB promoter element, leading to induction of regulatory components of the IFN-g pathway [30]. Introduction of NK cells to an innate cutaneous immune response provides a back-up system to the previously mentioned keratinocyte reaction. NK cells are bone marrow derived large granular lymphocytes, which make up approximately 10% of circulating peripheral blood lymphocytes, and probably initially developed as an early host response to viral infection. NK cells lack CD3 and T-cell receptor proteins but can be identified by the following surface markers (reviewed in reference [52]): CD2+, CD16+, CD56+, CD57+, CD94+, CD158a+, and CD161. Although there are diverse NK cell activation stimuli, including IFNs, cytokines such as TNF-a, IL-2, and IL-15, chemokines, and membrane-bound molecules on surrounding tissues, effector function is tightly regulated. NK cells possess low-affinity FcgRIII (CD16), which enables them to perform one of their hallmark functions, antibody-dependent cellular cytoxicity, toward cells coated with antibody fragments. They do this by the release of granzyme and perforin. NK cells also have an additional function of specific NK-cell cytotoxicity. NK cells can recognize ubiquitous surface molecules on normal cells by means of receptors known as killing activating receptors, or KARs. If the target cell possesses MHC molecule, a killing inhibitory receptor (KIR) is engaged and no attack takes place. In abnormal cells, however, such as some virally infected cells or tumor cells that lack MHC molecules, the KIRs are not activated and perforin and granzyme are released from the NK cell to effect target cell death. Another important function of NK cells is the early production of IFN-g, which may augment immune responses to deal with the inflammatory stimulus. Most studies have shown NK cells to be increased in psoriatic tissue [53,54] and decreased in the circulation [55]. An alternative mechanism to cause type 1 T-cell activation is by the addition of proinflammatory cytokines from other cells, such as DCs or keratinocytes. A recent important observation is that there is a TCR-independent process whereby IL-12 can synergize with IL-18 or IL-1b to stimulate production of IFN-g from T cells by activating transcription factor GAAD45b [56,57]. IL-18, previously known as IFNg inducing factor, can also stimulate NK-cell IFN-g production and cytotoxicity. IL-18 and IL-1b can both be produced by keratinocytes and macrophages, monocytes, DCs, and T cells [58]. This finding
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provides a mechanism to explain type 1 T-cell activation and cytokine release in the absence of TCR engagement, and NK-cell activation. A model that encompasses the presence of lymphocytes and DCs without antigen-specific TCR engagement would require the activation of DCs by means of non antigen-specific mechanisms. This would lead to release of inflammatory mediators, such as IL-12, and lymphocyte activation and proliferation. Recent genomics data suggest that DCs may produce T-cell activating IL-2 [59]. DCs do bear PRRs for microbial antigens, which can lead to lymphocyte activation. Examples of such receptors include the following: mannose receptors; CD14, which binds LPS; heat shock protein (HSP) receptors, such as CD91; and Toll-like receptors (TLRs). Engagement of such PRR causes DC activation, leading to a cytokine environment that encourages Th1 or Th2 T-cell development, depending on the nature of the stimulus. TLRs are a recently described set of innate immune receptors first discovered based on their homology with the Drosophilia melanogaster ortholog protein, Toll. There are currently 10 described TLRs, with specific ligands for each one, some having more than one ligand (reviewed in reference [60]). For example, the respective binding ligands for TLR2, TLR3, TLR4, TLR5, and TLR9 are as follows: grampositive bacterial components, double-stranded RNA, lipopolysaccharide, bacterial flagellin, and bacterial CpG DNA. TLR signaling induces APC activation and maturation, proinflammatory cytokine production, such as TNF-a and IL-6, and increased expression of costimulatory molecules. Ligation of TLR may induce a type 1 or type 2 cytokine response, depending on the stimulus. Engagement of TLRs may also lead to peptide loading of MHC class II molecules in DCs, with enhancement of CD4+ T-cell responses [61]. These TLRs are mainly expressed on professional APCs and endothelial and epithelial cells. Studies have revealed different patterns of TLR expression in normal skin. Keratinocytes constitutively express TLR1, TLR2, TLR4, and TLR5; DCs and DDCs demonstrate TLR1 and TLR 4; and DDCs also express TLR2 [62,63]. In psoriasis, there is increased basal keratinocyte expression of TLR1, TLR2 is mainly expressed by DDCs, and TLR4 is found on epidermal DCs and DDCs with mid epidermal-layer keratinocytes displaying cell surface staining [62,63]. The alteration of TLRs in psoriasis points to their possible role in activating DCs and keratinocytes, leading to T-cell activation independent of the TCR, which implies the significance of the innate immune system in the psoriatic lesion.
HSPs are another conserved innate immune mechanism which may be involved in skin inflammation (reviewed in reference [64]). HSPs are abundant, intracellular, monoallelic proteins that can bind antigenic peptides generated within cells. They then ligate a common receptor CD91 (a2-macroglobulin receptor) and other receptors found predominantly on APCs. This process initiates a cascade of innate events, the earliest of which may be NFkB activation. Ligation of HSP receptors then leads to secretion of proinflammatory cytokines (eg, TNF-a, IL-12, IL-1b, and granulocyte macrophage-colony stimulating factor), chemokine secretion, production of iNOS and NO, and DC maturation and migration to local lymph nodes. HSPs may also chaperone their bound peptides for MCH presentation and cross-presentation and the generation of CD4+ and CD8+ responses. HSPs 27, 60, and 70 have been found in psoriatic epidermis. CD91 and other HSP binding receptors are present on DDCs and fibroblasts (but not keratinocytes) in normal skin. DDCs up-regulate their CD91 expression in psoriatic lesions [63]. Nickoloff [65] has proposed an alternative theory that the primary psoriatic abnormality is in keratinocyte response to injury. Normally, nonspecific cutaneous stimuli cause keratinocytes to desquamate and release the contents of their lamellar bodies (preformed lipid and hydrolytic enzymes), IL-1a and TNF-a. Overall, there is an effort to repair the epidermal barrier and maintain cutaneous homeostasis. In genetically predisposed patients, however, a psoriatic plaque develops, which, although disfiguring, provides ongoing resistance to infection. The current authors have previously reported numerous molecular similarities between psoriatic lesional epidermis and acute healing wounds. One idea that bridges these views is that leukocyte trafficking into the epidermis induces direct injury to the basement membrane zone and desmosomes, triggering an exuberant and unnecessary wound-healing reaction [1,66,67].
Is psoriasis a disease caused by overlap of innate and acquired immunity? The suggestion that the innate immune system alone can fully explain psoriasis is probably simplistic because it does not take into account clonal population of T cells, disease transfer by bone marrow transplantation [68], resolution of psoriasis after bone marrow transplant [69], or the beneficial effects of anti T-lymphocyte therapies. Trying to separate the pathogenesis of psoriasis into the innate or acquired immune system is therefore somewhat arti-
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ficial, for there is clearly cross-talk between cells, mediators, and receptors of these two systems. TLRs and HSPs are innate system components that may facilitate type 1 cytokine production. CD91 ligation by HSP plus peptide may generate antigenspecific responses. Several cellular components may also link these two systems: the NK-T cells because they possess cell receptors classically linked to both systems (discussed further later); DCs because they may be activated in both antigen-specific and nonantigen-specific ways to bring about T-cell activation and type 1 cytokine release; and cytokines, such as IFN-g and TNF-a, which may be produced by leukocytes of both systems and may be the final common pathway for the development of psoriatic lesions. An alternative possible theory to unite these two systems is that the innate system is responsible for the initiation of psoriatic lesions, but during this process, neoautoantigens become exposed and the acquired system becomes involved to maintain a newly developed plaque. Alternatively, a bacterial antigen or superantigen could initiate the psoriatic response, which becomes self-perpetuating in the face of the psoriatic cutaneous microenvironment. NK-T cells are a recently discovered subpopulation of NK cells that may play an important role in autoimmune diseases. They are called NK-T cells because they bear NK-cell receptors, such as CD161. They and a TCR with an invariant and highly conserved a chain, Va24, and the b chain is usually Vb11 [70]. NK-T cells can be identified by the following surface markers: CD3, V a24, CD56, CD94, and CD161, and represent less than 1/1000 peripheral blood lymphocytes in healthy individuals. Gene rearrangement is not required for their differentiation or function. These cells specifically recognize CD1d+ cells presenting a glycosphingolipid antigen, a-galactosyl ceramide (a-GalCer). It is not yet determined if a-GalCer is the natural ligand for these cells, but perhaps this or a similar antigen is unveiled during cutaneous tissue damage. The nonpolymorphic MHC class I molecule CD1d is found in normal skin on upper level keratinocytes at a low level of expression [71] and also on dermal DCs [72]. NK-T cells seem to have several functions: perforin/granzyme or fas-mediated cell killing, antiviral properties, and the capability to produce large amounts of type 1 and type 2 cytokines. NK-T cells are a heterogeneous population and distinct subsets have now been identified. In activated lymphocytes of healthy adults, CD4+ NK-T cells (defined by a-GalCer loaded CD1d-tetramer+ and Va24+ cells) can produce type 1 and type 2 cytokines. However, the CD4 (CD4CD8 and CD4CD8+) NK-T cells
only demonstrate a type 1 cytokine profile (IFN-g and TNF-a) [73,74]. These two populations also demonstrate different chemokine receptors, integrins, and NK receptor expression patterns. Cell surface markers now have been identified to distinguish these two populations of NK-T cells, with IL-18R being present on type 1 cytokine-producing cells and ST2L expressed on type 2 cytokine-producing cells [75]. There have been few studies analyzing NK-T cells in psoriasis. CD161+ cells seem to be increased in lesional psoriatic tissue [54,71], but these could be NK, NK-T, or T cells. There may be a decrease [76] or increase [75] in NK-T cells in the peripheral circulation; this finding may depend on the surface markers used to classify the NK-T cells (eg, CD3+ CD56+ versus CD161+ Va24+, respectively). It is not yet possible to determine if an increase in the tissue is simply caused by a decrease in the circulation. NK-T cells did increase slightly with various successful antipsoriatic treatments, although not to control levels, and in vitro anti CD3-activated NK-T cells could not be detected [76]. These authors hypothesized that an NK-T cell deficiency is a characteristic and intrinsic abnormality in patients with psoriasis, and that this deficiency leads to an imbalance in type 1 and type 2 cytokine profiles, with the excessive activation of type 1 responses leading to autoimmunity. Similarly, a genetically predisposed excessive NK-T cell response to infection could trigger psoriasis [65]. Increased CD1d expression is also found throughout the epidermis in psoriatic tissue. In a positive feedback loop (shown in vitro), IFN-g treatment of keratinocytes could induce CD1d expression, which activates NK-T cells and increases IFN-g production [71]. A CD94/CD161+ NK-T cell line from a patient with psoriasis (established by IL-2 and superantigen stimulation) could be cocultured with CD1d+ keratinocytes and give rise to high levels of IFN-g and IL-13. This process could be inhibited by anti-CD1d monoclonal antibodies [77]. This production of both type 1 and type 2 cytokines suggests that this NK-T cell line was CD4+. It would be helpful to know the conditions that encourage development of different cytokine-producing NK-T cells. Further work is needed to determine whether NK-T cells defined by strict criteria, such as Va24+ Vb11+, are genuinely increased in psoriasis lesions.
How can the phenotype of chronic psoriasis be explained? The usual response of the skin to an antigenic stimulus is for an immature DC to acquire the antigen
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through constant sampling of the environment, migrate to the local draining lymph nodes, mature with up-regulation of costimulatory markers, and activate a na ve antigen-specific T cell. Depending on factors such as the cytokine microenvironment, Th1 or Th2 cytokine profiles are produced. Antigen-specific lymphocytes clonally expand and develop additional skin homing receptors, which allow them to bind to selectins (eg, CLA+ binds to E- and P-selectin) for initial tethering and rolling on cutaneous endothelial cells. Locally produced chemokines cause up-regulation of T-cell integrins, such as LFA-1 and very late antigen-4, or VLA-4, for fixed lymphocyte-endothelial cell adhesion, chemotaxis, and extravasation of lymphocytes into the dermis. Up-regulation of integrin aeb7 on CD8+ T cells allows them to bind to E-cadherin on keratinocytes with subsequent infiltration into epidermis. ICAM-1 is often up-regulated on activated keratinocytes, which can also interact with lymphocyte LFA-1. Antigen-specific CD4 + and CD8+ T cells are finally present in the skin, producing cytokines and inflammatory mediators, ultimately leading to antigen eradication.
In psoriasis, however, the process becomes a chronic one. Development of lesions requires initiation and maintenance steps. The classic antigendriven process just described may indeed take place, but until a specific antigen is conclusively defined, other mechanisms must be explored. And although antigen may initiate the process, physicians need to be able to explain the chronicity of psoriatic plaques. There is some evidence that the skin in psoriasis may actually behave focally like peripheral lymphoid tissue, which may be a primary or secondary event. First, psoriatic blood vessels possess the morphology and cell surface markers found on lymph node high endothelial blood vessels (HEVs), such as L-selectin, CD31, CD34, and peripheral lymph node addressin [1,78]. Second, lymphoid-organizing chemokines CCL19 and CCL21, and the Bonzo receptor ligand (CXCL16) recently have been shown to be elevated in psoriasis [26]. Such factors may help organize T-cell/DC infiltrates in secondary lymphoid tissues and produce autoimmune inflammation [79]. Third, there are abundant aggregates of T cells and mature DCs (CD83+/DC-LAMP+) within psoriatic
Fig. 5. Epidermal hyperplasia in psoriasis may result from keratinocyte injury produced by IFN-regulated leukocyte migration. The pathways diagram inductive effects of IFN-g and TNF-a on expression of adhesion molecules and chemokines in epidermal keratinocytes. MIG, IP-10, and I-TAC stimulate intraepidermal trafficking of CXCR3+ CD8+ T cells. The inward trafficking disrupts the basement membrane and traumatically severs desmosomes from adjacent connections on keratinocytes. Regenerative epidermal hyperplasia may result from physical injury to the basement membrane or keratinocyte membranes from the process of IFN-regulated inward migration of leukocytes.
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lesions that develop spatial arrangements similar to secondary lymphoid tissue [3]. Keratinocytes may also play a role in the maintenance of lesions because once there is an inflammatory cytokine milieu, keratinocytes up-regulate surface markers such as ICAM-1 and MHC class II molecules for further stimulation of memory CD8+ and CD4+ T cells. In addition, keratinocytes may produce inflammatory cytokines, such as TNF-a, that play a role in DC activation and maturation. As discussed previously, there is also persistent T-cell activation in psoriatic tissue [6], which is able to respond to local, activated APCs. How do these changes lead to the phenotype of psoriasis? The major histopathologic features that need explaining are marked T-cell infiltrate, psoriasiform hyperplasia, dilated blood vessels filling the elongated dermal papillae, increase in mature DCs, and neutrophil accumulation. An important trigger for keratinocyte hyperplasia may actually be injury caused by the passage of lymphocytes through the epidermis, severing desmosomes as they move (Fig. 5). Electron micrographs of lesional epidermis show support for this concept (Fig. 6). As the desmosomes are disrupted, a pattern of epidermal repair with keratinocyte hyperplasia may ensue. Other cytokines may be contributing, such as IL-20 release from dermal macrophages [80], or IFN-g. How does IFN-g contribute to epidermal hyperplasia? Conditioned media from CD8+ Tc clones from psoriatic skin specimens had either proliferative or antiproliferative effects on keratinocytes, and both effects were reversed by antiserum to IFN-g [14]. Previous studies, however, have shown that IFN-g has suppressive in vitro effects on keratinocytes [81]. It is likely that the array of keratinocyte-stimulating cytokines (Table 1) made in injured skin, such as transforming growth factor a (TGF-a), amphiregulin, insulin-like growth factor 1 (IGF-1), and keratinocyte growth factor (KGF), override any suppressive effects of IFN-g, resulting in epidermal hyperplasia. IFN-g may be a key inducer of the overall injury response pathway, because IFN-g induced keratinocyte production of the chemokines MIG, IP-10, and IFN-inducible T-cell a chemoattractant (I-TAC) would set up a chemotactic gradient that regulates migration of CD8+ T cells bearing CXCR3 into the epidermis. The blood vessel changes may be more easily explained by vascular endothelial cell growth factor (VEGF) and NO, which cause neovascularization and dilatation of blood vessels, respectively [82,83]. The most likely candidate for neutrophil chemotaxis is IL-8, a cytokine that is released by many cells, including psoriatic keratinoyctes, as an early proin-
Fig. 6. Epidermal mononuclear leukocyte trafficking in psoriasis. Electron micrographs of lesional psoriatic skin showing mononuclear leukocyte trafficking through the epidermis (stars), severing desmosomes on adjacent keratinocytes (arrows). This injury, in conjunction with local inflammatory cytokines, may initiate a pattern of epidermal repair and hyperplasia.
flammatory response [84]. There are other cytokines and inflammatory mediators that may contribute to the phenotype of psoriasis, which have not been discussed in this article; these are listed in Table 1.
How do murine models help physicians to understand the pathogenesis of psoriasis? There are quite a few psoriasis mouse models with knockouts or overexpression of important epidermal and immune components. One fundamental problem with these models, however, is that human epidermis is structurally different to murine, which
M.A. Lowes et al / Dermatol Clin 22 (2004) 349369 Table 1 Changes in cytokines and growth factors with their receptors in psoriatic lesions Cytokines and growth factors/receptors Inflammatory cytokines IL-1a IL-1b IL-2 IL-2Ra(CD25) IL-6 IL-7 IL-12 IL-12Rb2 IL-15 IL-17 IL-18 IL-20/IL-20R IL-23 TNF-a IFN-g/IFN-gR MIF Inhibitory cytokines IL-1RII IL-1RA IL-4 IL-5 IL-10 IL-11 IL-13/IL-13R TGF-b Hematopoietic cytokines IL-3 GM-CSF LIF OSM Chemokines IL-8/CXCR2 GROa IP-10 MIG I-TAC MIP3a/CCR6 RANTES MCP-1 TARC MDC CTACK/CCR10 MIP3b SLC SDF-1 PARC Effect +, , F +, + + + + + (p40, p70)/ F (p35) + + + + +/+ + + +/+ + Reference [101 104] [101 104] [18,19] [21] [105 108] [109] [20,110] [21] [111] [112] [58,113] [80,114] [26] [115,116] [18,19,31, 117,118] [119,120]
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Table 1 (continued ) Cytokines and growth factors/receptors Chemokines Bonzo receptor ligand ENA-78 EMAPII HCC-1 Effect + + + Reference [26] [26] [26] [26]
Keratinocytes/tissue growth factors TGF-a/amphiregulin/ +/+ EGF-R PDGF-R + IGF-1R + KGF/KGF-R +/+ NGF + bFGF + Angiogenic factors VEGF/VEGF-R Angiopoitin/tie 2 ET-1 Angiogenic inhibitors Thrombospondin
[128,144 147] [148] [149] [150] [151,152] [153]
+/+ +/+ +
[154] [155] [156]
+ +, , F +, F F, + F/+, +, , F
[121] [121 123] [18,124] [18,124] [18,110,125] [106] [126] [127 129]
[133]
+ + + +
[124] [18,130] [131] [131]
+/+ + + + + +/+ + + + + F, /+ + + + +
[26,106, 132 136] [26,135 137] [26,138] [26,139] [26] [26,140] [141] [26,142] [8] [8,26] [26,143] [26] [26] [26] [26]
Abbreviations: bFGF, basic fibroblast growth factor; CTACK, cutaneous T-cell attracting chemokine; EGF, epidermal growth factor; EMAPII, endothelial monocyte activating polypeptide II; ENA-78, epithelial cell-derived neutrophil attractant 78; ET-1, endothelin 1; GM-CSF, granulocyte machrophage-colony stimulating factor; GROa, growth-regulated oncogenea; HCC-1, hemofiltrate CC chemokine1; LIF, leukemia inhibitory factor; MCP-1; monocyte chemoattractant protein 1; MDC, macrophagederived chemokine; MIF, migration inhibition factor; MIP, macrophage inflammatory protein; NGF, nerve growth factor; OSM, oncostatin M; PARC, pulmonary- and activation-regulated chemokine; PDGF, platelet-derived growth factor; R, receptor; RA, receptor antagonist; RANTES, regulated upon activation normal T expressed and secreted; SDF-1, stromal cell-derived factor 1; SLC, secondary lymphoid tissue chemokine; TARC, thymus- and activation-regulated chemokine; +, increase; , decrease; F, no change.
makes extrapolation to human skin disease difficult. In human skin, there is a clear difference in keratinocyte differentiation of the outer root sheath of the hair follicle and the interfollicular epidermis. Perifollicular epidermis is keratin 16-positive (K16+) and connexin 26+, and in effect represents outer root sheath differentiation, whereas normal interfollicular epidemis is K16 and connexin 26. In psoriasis, interfollicular epidemis changes to become more
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perifollicular-like. But in the mouse, there is less difference between these two structural areas, and they are K16, connexin 26+. Normal murine epidermis is much thinner than normal human interfollicular epidermis, with many fewer cell layers. Clinicians therefore need to be careful describing a skin lesion in a knockout or transgenic mouse psoriasis when the murine epidermis already has some features of this condition, such as connexin 26 positivity. Another important consideration in the use of single- or even double-gene manipulations is that they do not usually reproduce the complete phenotype of psoriasis, which is a polygenic disease [85,86]. Possibly even more important, none of the transgenic models expresses the primary genes of psoriasis susceptibility loci and are all downstream of primary genetic events. Perhaps the most relevant models are those that produce regulatory alterations in immune pathways or other cell growth responses. There is an interesting murine model of psoriasis: the IFN regulatory factor 2 (IRF-2) knockout mouse [87]. IRF-2 can be induced by IFN-a/b and IFN-g [88] and has a predominantly negative regulatory effect on IFN- a/b activated IFN-stimulated gene factor 3 (ISGF3). ISGF3 is a heterotrimer consisting of STAT1, STAT2, and IFN regulatory factor 9 (IRF-9, p48). Deletion of the IRF-2 gene caused overexpression of IFN-a/b inducible genes and led to an erythematous inflammatory skin disease with some histopathologic features of psoriasis. This includes epidermal acanthosis, activation of keratinocytes (ICAM-1+), infiltration of both CD4+ and CD8+ T cells into the basal dermis, and some CD8+ T cells into the epidermis. There were additional features not suggestive of psoriasis, such as alopecia, excoriations leading to ulceration, and a disorganized muscle layer with associated fibrosis. Experimental depletion of CD8+ T cells significantly delayed the onset of skin disease, and these CD8+ T cells were hyper-responsive to antigen stimulation, as are psoriatic T cells. There was a marked polyclonal increase in the population of memory CD8+ T cells in these mice, and lymphadenopathy developed as the skin disease progressed. Furthermore, not only was there overexpression of genes usually induced by IFN-a/b by means of ISGF3 (oligoadenylate synthetase and IRF-7) but there was also increased cutaneous expression of genes known to be primarily controlled by IFN-g (MIG and IP-10). The introduction of additional mutations in IRF-9 in these IRF-2 knockout mice abrogated the skin disease, genetic overexpression, and T-cell hyper-responsiveness. Because there is overlap between the effects of type I and II IFNs,
this model supports the role of overexpression of IFNs and IFN-related genes in the development of a psoriasis-like skin disease. In comparison, a study of transgenic mice with overexpression of epidermal IFN-g resulted in keratinocyte hyperproliferation, MHC class II and ICAM-1 induction, and dermal capillary enlargement. Although there was a dermal T-cell infiltrate, however, there were no epidermal T cells [89]. Clinically, there was an ezcematous process with hair hypopigmentation and alopecia. Overexpression of epidermal VEGF (VEGF transgenic mouse under-expression of K16 promoter) [86] led to a psoriatic phenotype at 3 months with wounding (similar to the Koebner phenomenon), or spontaneously at 6 months. These mice demonstrated epidermal hyperplasia with hyperkeratosis, parakeratosis, and K6 expression. There was a leukocyte infiltrate very similar to human psoriasis with neutrophil microabscesses within and beneath the stratum corneum, dermal CD4+ T cells, epidermal CD8+ T cells, mast cells, and macrophages. There were dilated and tortuous dermal papillae blood vessels with up-regulation of adhesion molecules, such as ICAM-1, E-selectin, VCAM-1, and platelet-endothelial cell adhesion molecule 1, or PECAM-1. An antiVEGF monoclonal antibody (VEGF Trap) was effective in reversing spontaneous changes of psoriasis unless the mice developed neutralizing antibodies to this treatment. High serum levels of E-selectin, a surrogate marker of disease activity in human disease and in this K16-VEGF transgenic mouse, were also reversed by VEGF Trap. Exactly how epidermal chronic overexpression of a potent angiogenic factor leads to psoriasis is not yet understood; perhaps it diffuses to the dermis and primarily creates inflamed blood vessels, which attract inflammatory leukocytes and allow cytokine and chemokine changes that lead to secondary epidermal alterations seen clinically as psoriasis. VEGF antagonists are obviously an interesting therapeutic modality to investigate further in patients with psoriasis. Another useful model to study psoriasis used a xenotransplant concept, with human skin of varying clinical types grafted to immunodeficient mice, which fail to reject it. Initial studies used nude or athymic mice, which are deficient in T cells. In these mice, infiltrating human T cells are eliminated from the graft quite readily. Subacute combined immunodeficiency (SCID) mice fail to rearrange variable-diversity-joining (VDJ) segments of B- and T-cell receptors, so these mice lack both humoral and cellular immunity. SCID mice still make NK and NK-T cells because these cells do not require TCR gene rearrangement for their generation. Recombination activating genes
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(RAG) knockout mice lack the RAG enzyme, which is responsible for rearranging TCRs, so these mice also still have NK and NK-T cells. RAG-deficient knockout mice now have been generated in conjunction with deletions of murine type I and II IFN receptor. Human keratome skin biopsy specimens have been grafted to these immunodeficient mice from healthy volunteers, nonlesional skin of patients with psoriasis, or lesional psoriatic skin. These skin grafts are allowed to heal and then the mice are injected with activated human leukocytes to determine the role of the transplanted cells in the initiation and maintenance of the psoriatic lesion. The initial nude mice studies demonstrated that engraftment of psoriatic skin leads to regression of histologic and immunologic features of psoriasis, correlating with elimination of infiltrating human T cells within the psoriatic skin [90]. Boehncke et al [91] showed that repeated intradermal injections of staphylococcal superantigen exfoliative toxin into grafted nonlesional skin from patients with psoriasis, along with intraperitoneal administration of autologous peripheral blood mononuclear cells (PBMCs) stimulated in vitro with the respective superantigen, were capable of triggering psoriasis. Nickoloff et al [92] extended these findings and continued to develop the SCID mouse model with injection of activated immunocytes into the graft. Experiments in 1996 showed that IL-2 and staphylococcal superantigen-stimulated, autologous peripheral blood-derived immunocytes were able to induce psoriasis in nonlesional skin of patients with psoriasis [93]. They next showed that psoriasis could be induced in normal skin with similarly activated but allogeneic blood-derived psoriatic immunocytes in three of six patients [94]. Graft versus host disease would be expected in this context, but this condition only developed in one of six transplants. In two patients, the authors looked at the surface markers of the human cells in the graft and found that many possessed NK surface markers (CD94, CD158a, CD158b, NKB1, and CD161) [95]. They next further characterized the immunocytes: injection of engrafted nonlesional psoriatic skin with activated CD4+ T-cell lines could induce psoriasis in five of five cases and in none of five cases, with CD8+ T-cell lines [53]. Cells with NK markers accumulated early in the lesion. However, it is difficult to appropriately activate and differentiate epithelial homing CD8+ T cells in vitro. Finally, the authors characterized a T-cell line from a psoriatic patient that was capable of initiating psoriasis in a nonlesional psoriatic skin graft and demonstrated CD4+ NK-T cell markers (CD94+, CD161+, Va24, Vb11+) [77]. A Th1 po-
larized cytokine profile was evident in the lesion (IFN-g and IL-15). Gilhar et al [96] also performed early experiments with SCID mice, demonstrating that intradermal or intravenous injection of autologous lesional T cells (cultured for 1 month with IL-2, APCs, and keratinocytes) were able to maintain psoriatic grafts. This group wanted to explore induction of psoriasis using these IL-2 activated T cells rather than superantigenstimulated lymphocytes, and they next used beigeSCID mice, which have less NK-cell activity [97]. The authors cultured PBMCs with IL-2 for 3 weeks to generate NK and NK-T cell lines (CD56, CD94, CD158a, CD158b, CD8, CD4, CD3+ CD161+), which were IFN-g producing and cytotoxic in vitro. Injection of autologous NK/NK-T cells initiated psoriasis in nonlesional psoriatic skin. Unlike Nickoloffs group, however, they did not find that that injection of allogeneic T cells caused psoriasis in nonlesional psoriatic skin or normal grafts; rather, in these conditions, a psoriasiform dermatitis was seen. Finally, in a new model using RAG and IFN receptor deficient mice, nonlesional psoriatic skin spontaneously converted to psoriasis in 29 of 30 grafts [98]. There was an absence of circulating human or mouse lymphocytes, with up-regulation of HLA-DR and CD91. CD91 ligands were also present (HSP 27 and 70), and CD91+ cells were adjacent to CD91 ligand-positive keratinocytes. There was expression of NFkB and TNF-a production, and the effect was abrogated with anti TNF-a antibodies in eight of nine mice. Subsequent work showed blockage of this effect by CD3 antibodies [99], thus this model is also T-cell dependent. This finding does not rule out an important role for IFN-g, because human IFN-g may still be produced by the graft and react with IFN-g receptors present on engrafted human psoriatic skin. This is an important report because this is the first experiment to show that psoriasis could develop spontaneously in grafts of nonlesional psoriatic skin without injection of exogenous lymphocytes. This finding suggests that resident immunocytes are able to proliferate in situ depending on the local environment to initiate a lesion, and that once skin homing (CLA+) memory cells have developed, lymphocyte trafficking may not be required.
What do recent genomics data add? Three large-scale analyses of psoriatic disease associated genes (mRNA expression) have been published recently [26,67,100]. These analyses differ
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primarily in their use of various gene chips, with each study examining an increasingly greater number of known genes, but also in the samples tested and approach to analysis. These experiments are not simple to evaluate because they generate such large data sets and require specific analytic approaches, such as hierarchical clustering, nonhierarchical clustering (eg, self-organizing maps [SOMs]), functional clustering, and principal components analysis (reviewed in reference [59]). This line of research will yield important information and enable further understanding about the pathogenesis of skin diseases, clinical response, and drug mechanisms. The first study used arrays containing 7000 genes [67]. An unsupervised cluster analysis approach was taken, where samples were clustered based on a hierarchical correlation coefficient (ie, fold change). Gene expression frequency patterns of normal and uninvolved skin were grouped together, and they were clearly different to a separate cluster of expression patterns of lesional skin. A differential statistical approach was then taken where average frequency of gene expression values between uninvolved and lesional skin were calculated and a paired t test was performed. Transcript levels that were statistically different with a confidence level of 95% or greater were initially identified (426 genes), and this number was subsequently refined to 159 genes when only those whose transcript levels differed on average by twofold or greater were selected. Thus, a disease classification set for chronic plaque psoriasis was generated, and these genes could be categorized into diverse functional groups. These include transcriptional regulation, metabolic control, protein processing, intracellular signaling, cell cycle control, lymphocyte regulation, and extracellular matrix destruction. Genes previously known to be differentially expressed in psoriasis included transcripts such as psoriasin (S100A7), fatty acid binding protein (FABP5), elafin (SKALP, P13), retinoic acid binding protein (CRAB2), squamous cell carcinoma antigen (SCCA), b defensin-2 (DEFB2), keratin 17 (KRT17), and keratin 16 (KRT16). There were also new genes in these lists including S100A12 (calgranulin C, ENRAGE), matrix metalloproteinases (MMP-12), and heparin-binding protein 17 (HBP-17). The significance of differential expression of many of these genes will need to be determined in the future. Findings of expression differences were confirmed by performing immunohistochemical analyses for protein products and reverse transcriptase polymerase chain reaction (RT-PCR) on additional samples where possible. Oestreicher et al [67] next examined antigen nonspecific gene responses in
delayed-type hypersensitivity (representing T-cell driven responses) and in tape stripping (indicative of active epidermal regeneration) in healthy volunteers, and there was some overlap with psoriasis. The subtraction of overlapping genes from these two groups and the psoriatic gene set revealed 94 transcripts that were differentially regulated only in psoriasis, including S100A12 (calgranulin C, ENRAGE), RAGE, and GATA3. Finally, the authors performed similar analyses in samples collected before, during, and after two immunomodulatory psoriasis treatments, comparing expression levels in lesional skin of the previously identified 159 genes in responders versus nonresponders. Treatment was either with the Th2 cytokine IL-11 (which restores Th1 and Th2 imbalance partially through inhibition of NFkB nuclear translocation) or cyclosporin A (which has a T-cell inhibitory effect through blockade of calcineurin/nuclear factor of activated transmission IL [NFAT] and p38/JNK signaling pathways). SOMs were used where the level of expression of the lesional skin before therapy was normalized to a value of 1 and the change in expression of the 159 gene set over the course of treatment was calculated relative to this baseline level. Four patterns of expression could be identified in responding patients, with no such change noted for nonresponders. In responders, gene sets could be observed that changed (increased or decreased) quickly before clinical improvement and between rhIL-11 and cyclosporin A treatment. On termination of either treatment, transcripts returned to pretreatment levels. Of the 41 gene transcripts that increased quickly with treatment, 12 can be mapped to five of the six known psoriasis susceptibility loci. The second study published the same year used Affymetrix gene chips (Santa Clara, California) with 12,000 known genes and also used gene-clustering techniques [100]. These authors found a similar number of differentially expressed gene transcripts in psoriasis (177 transcripts) compared with normal skin, independent of demographics or HLA class I status. These genes were mostly up-regulated, and approximately 80% had not been described in psoriasis previously. Some of the 17 genes that showed the highest level of expression in involved psoriatic skin were the same as those previously reported and found in the previously discussed study. The transcript that showed the greatest increase was transcobalamin 1 (vitamin B12 binding protein), which is found in mature neutrophils, suggesting an important role for neutrophil granule proteins. A complete list of genes in clusters that differentiate involved skin from normal skin can be found at http://hg.wustl.edu. Several
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of these genes have been mapped to regions previously linked to psoriasis susceptibility. Using the newer Affymetrix chips containing 63,100 oligonucleotides, the third study further extended the description of psoriatic gene expression [26]. The authors used two methods of analysis to detect differentially expressed genes: first, fold change combined with t tests comparing differences in psoriasis and nonlesional and normal skin; and second, K-means clustering to examine for small fold changes. A total of 1338 genes were identified, and these also have been reported on the previously mentioned Web site. These genes were functionally categorized according to the Gene Ontology database, demonstrating disruption of immune and inflammatory responses, response to wounding, response to pests/pathogens, cell proliferation, the JAK-STAT signaling cascade, cell growth or maintenance, and several metabolic processes such as NO biosynthesis. There were 131 genes that were significantly differentially expressed ( P V 0.05; fold change, > 1.2) in at least one pairwise comparison among the three skin groups that were involved in immune signaling. These were subsequently broken down into three groups: IL-1 cluster of genes (especially IL-1R antagonists), those involved in T-cell and DC activation, and chemokines in psoriasis. Comparing genes that were elevated in involved psoriatic skin with normal skin demonstrated many genes indicative of T-cell activation, including CD47 (general lineage marker for blood-derived cells), IL-2Ra, IL-2Rb, CD71, CD69, and IL-7R. Leukocyte integrins LFA-1 (CD11a/ CD18) and Mac-1 (CD11b/CD18), and adhesion molecules E-selectin, P-selectin, and ICAM were also elevated. There was up-regulation of genes involved in APC function, such as CD163, CD32, MHC class I and II, CD83, CD53, and CD24. Comparison of uninvolved versus normal skin also revealed some interesting expression changes: uninvolved skin showed increased CD4, CD11c (highlevel expression on monocytes, macrophages, and NK cells), CD86 (costimulatory molecule), and CD103 (epithelial homing cells), suggesting a low level of immune activation. There were 19 chemokines that were elevated in this study, including lymphoid tissue chemokines CCL19 and CCL21. Eleven of these chemokines had not been previously implicated. CCR7 is the receptor for CCL19 and it was also overexpressed (by FACS analysis); its usual role is to allow na ve and central memory T-cell migration across HEVs found in lymph nodes. Along with prior reports, these findings provide evidence for the suggestion that psoriatic skin behaves as secondary lymphoid
tissue, which could sustain chronic T-cell activation within focal skin regions. Increased CCL18 may be important for recruiting na ve T cells to skin draining lymph nodes, and CXC16 (expressed on CD11c+ DCs) is important for epidermal recruitment of CD8+ T cells. Further analysis revealed the importance of the IFN-g or type 1 pathway, consistent with the current authors hypothesis that this is a key cytokine in psoriasis. There was increased expression of the IFNg transcript, along with primary IFN-g inducible genes TRIM22 and STAT-1, and the chemokines IP-10 and MIG. In fact, more than 5% of elevated genes (>60) related to IFN signaling were identified in this study. Finally, large-scale promoter analysis demonstrated 13 coexpressed gene clusters and shared transcription factor binding sites (TFBS), including the IFN-g inducible TFBS motif IRF2ISRE (IFN-stimulated response element). A recent review described 200 genes that are considered to be regulated by IFN-g in various cell types and lines [37], and in psoriasis, there are 60 IFN-g regulated genes that can be extrapolated from the literature. This overlap supports the hypothesis that IFN-g is functional and produced by activated T cells in psoriasis; however, it is curious that the overlap is not more complete. There could be several reasons for this finding: the chronic process of psoriasis may result in different gene activation than can be found in a short-term in vitro analysis; direct IFN-g effects in skin, an organ rather than cell type or line, have not been studied; and other cytokines may be inducing the JAK-STAT pathway rather than IFN-g.
Summary This article has focused on the innate and acquired immune systems, their overlap, and the role of these components in the pathogenesis of psoriasis. Recent data on mouse models have been presented, emphasizing xenotransplant models as more representative of psoriatic lesions than knockouts or transgenic mice. Finally, a summary of recent genomics data in psoriasis was discussed to introduce these important studies and the data they generate. The authors belief of the importance of IFN-g as a pivotal cytokine in the initiation or maintenance of psoriatic lesions has been supported with evidence throughout the article, while acknowledging that TNF-a plays an important and probably synergistic role. There are topics that have not been covered but some of these are done so elsewhere in this issue, such as the genetics of psoriasis. The role of specific antigens
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M.A. Lowes et al / Dermatol Clin 22 (2004) 349369 ques indicates a common antigen in psoriasis vulgaris. Eur J Immunol 1999;29:3360 8. Lin W-J, Norris DA, Achziger M, Kotzin BL, Tomkinson B. Oligoclonal expansion of intraepidermal T cells in psoriasis skin lesions. J Invest Dermatol 2001;117:1546 53. Vollmer S, Menssen A, Prinz JC. Dominant lesional T cell receptor rearrangements persist in relapsing psoriasis but are absent from nonlesional skin: evidence for a stable antigen-specific pathogenic T cell response in psoriasis vulgaris. J Invest Dermatol 2001; 117(5):1296 301. Prinz JC, Grob B, Vollmer S, Trommler P, Strobel I, Meurer M, et al. T cell clones from psoriasis skin lesions can promote keratinocyte proliferation in vitro via secreted products. Eur J Immunol 1994;24:593 8. Ovigne JM, Baker BS, Brown DW, Powles AV, Fry L. Epidermal CD8+ T cells in chronic plaque psoriasis are Tc1 cells producing heterogeneous levels of interferon-gamma. Exp Dermatol 2001; 10(3):168 74. Salgame P, Abrams JS, Clayberger C, Goldstein H, Convit J, Modlin RL, et al. Differing lymphokine profiles of functional subsets of human CD4 and CD8 T cell clones. Science 1991;254(5029): 279 82. Austin LM, Ozawa M, Kikuchi T, Walters IB, Krueger JG. The majority of epidermal T cells in psoriasis vulgaris lesions can produce type 1 cytokines, interferon-gamma, interleukin-2, and tumor necrosis factor-alpha, defining TC1 (cytotoxic T lymphocyte) and TH1 effector populations: a type 1 differentiation bias is also measured in circulating blood T cells in psoriatic patients. J Invest Dermatol 1999; 113(5):752 9. Uyemura K, Yamamura M, Fivenson DF, Modlin RL, Nickoloff BJ. The cytokine network in lesional and lesion-free psoriatic skin is characterized by a T-helper type 1 cell-mediated response. J Invest Dermatol 1993;101(5):701 5. Schlaak JF, Buslau M, Jochum W, Hermann E, Girndt M, Gallati H, et al. T cells involved in psoriasis vulgaris belong to the Th1 subset. J Invest Dermatol 1994;102(2):145 9. Yawalkar N, Karlen S, Hunger R, Brand CU, Braathen LR. Expression of interleukin-12 is increased in psoriatic skin. J Invest Dermatol 1998; 111:1053 7. Trepicchio WL, Ozawa M, Walters IB, Kikuchi T, Gilleaudeau P, Bliss JL, et al. Interleukin-11 therapy selectively downregulates type I cytokine proinflammatory pathways in psoriasis lesions. J Clin Invest 1999;104(11):1527 37. Cella M, Scheidegger D, Palmer-Lehmann K, Lane P, Lanzavecchia A, Alber G. Ligation of CD40 on dendritic cells triggers production of high levels of interleukin-12 and enhances T cell stimulatory capacity: T-T help via APC activation. J Exp Med 1996;184: 747 52.
(autoantigens, superantigens, or microbial antigens) in triggering or maintaining lesional activity is another area that has not been discussed and requires further experimentation and attention.
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Interleukin-17 and interferon-gamma synergize in the enhancement of proinflamma tory cytokine produc tion by human keratinocytes. J Invest Dermatol 1998;111(4):645 9. Ohta Y, Hamada Y, Katsuoka K. Expression of IL-18 in psoriasis. Arch Dermatol Res 2001;293(7): 334 42. Blumberg H, Conklin D, Xu WF, Grossmann A, Brender T, Carollo S, et al. Interleukin 20: discovery, receptor identification, and role in epidermal function. Cell 2001;104(1):9 19. Nickoloff BJ, Karabin GD, Barker JN, Griffiths CE, Sarma V, Mitra RS, et al. Cellular localization of interleukin-8 and its inducer, tumor necrosis factoralpha in psoriasis. Am J Pathol 1991;138(1):129 40. Ettehadi P, Greaves MW, Wallach D, Aderka D, Camp RD. Elevated tumour necrosis factor-alpha (TNF-alpha) biological activity in psoriatic skin lesions. Clin Exp Immunol 1994;96(1):146 51. Nickoloff BJ. Role of interferon-gamma in cutaneous trafficking of lymphocytes with emphasis on molecular and cellular adhesion events. Arch Dermatol 1988;124(12):1835 43. Szabo SK, Hammerberg C, Yoshida Y, Bata-Csorgo Z, Cooper KD. Identification and quantitation of interferon-gamma producing T cells in psoriatic lesions: localization to both CD4+ and CD8+ subsets. J Invest Dermatol 1998;111(6):1072 8. Gomez RS, Diepgen TL, Neumann C, Sorg C. Detection of migration inhibitory factor (MIF) by a monoclonal antibody in the microvasculature of inflamed skin. Arch Dermatol Res 1990;282(6):374 8. Steinhoff M, Meinhardt A, Steinhoff A, Gemsa D, Bucala R, Bacher M. Evidence for a role of macrophage migration inhibitory factor in psoriatic skin disease. Br J Dermatol 1999;141(6):1061 6. Debets R, Hegmans JP, Croughs P, Troost RJ, Prins JB, Benner R, et al. The IL-1 system in psoriatic skin: IL-1 antagonist sphere of influence in lesional psoriatic epidermis. J Immunol 1997;158(6):2955 63. Kristensen M, Deleuran B, Eedy DJ, Feldmann M, Breathnach SM, Brennan FM. Distribution of interleukin 1 receptor antagonist protein (IRAP), interleukin 1 receptor, and interleukin 1 alpha in normal and psoriatic skin. Decreased expression of IRAP in psoriatic lesional epidermis. Br J Dermatol 1992; 127(4):305 11. Hammerberg C, Arend WP, Fisher GJ, Chan LS, Berger AE, Haskill JS, et al. Interleukin-1 receptor antagonist in normal and psoriatic epidermis. J Clin Invest 1992;90(2):571 83. Vollmer S, Menssen A, Trommler P, Schendel D, Prinz JC. T lymphocytes derived from skin lesions of patients with psoriasis vulgaris express a novel cytokine pattern that is distinct from that of T helper type 1 and T helper type 2 cells. Eur J Immunol 1994; 24(10):2377 82. Nickoloff BJ, Fivenson DP, Kunkel SL, Strieter RM, Turka LA. Keratinocyte interleukin-10 expression is upregulated in tape-stripped skin, poison ivy dermatitis, and Sezary syndrome, but not in psoriatic plaques. Clin Immunol Immunopathol 1994;73(1):63 8. Cancino-Diaz JC, Reyes-Maldonado E, BanuelosPanuco CA, Jimenez-Zamudio L, Garcia-Latorre E, Leon-Dorantes G, et al. Interleukin-13 receptor in psoriatic keratinocytes: overexpression of the mRNA and underexpression of the protein. J Invest Dermatol 2002;119(5):1114 20. Kane CJ, Knapp AM, Mansbridge JN, Hanawalt PC. Transforming growth factor-beta 1 localization in normal and psoriatic epidermal keratinocytes in situ. J Cell Physiol 1990;144(1):144 50. Elder JT, Klein SB, Tavakkol A, Fisher GJ, Nickoloff BJ, Voorhees JJ. Growth factor and proto-oncogene expression in psoriasis. J Invest Dermatol 1990;95(5): 7S 9S. Wataya-Kaneda M, Hashimoto K, Kato M, Miyazono K, Yoshikawa K. Differential localization of TGFbeta-precursor isotypes in psoriatic human skin. J Dermatol Sci 1996;11(3):183 8. Takematsu H, Tagami H. Granulocyte-macrophage colony-stimulating factor in psoriasis. Dermatologica 1990;181(1):16 20. Bonifati C, Mussi A, DAuria L, Carducci M, Trento E, Cordiali-Fei P, et al. Spontaneous release of leukemia inhibitory factor and oncostatin-M is increased in supernatants of short-term organ cultures from lesional psoriatic skin. Arch Dermatol Res 1998; 290(1 2):9 13. Gillitzer R, Berger R, Mielke V, Muller C, Wolff K, Stingl G. Upper keratinocytes of psoriatic skin lesions express high levels of NAP-1/IL-8 mRNA in situ. J Invest Dermatol 1991;97(1):73 9. Nickoloff BJ, Mitra RS, Varani J, Dixit VM, Polverini PJ. Aberrant production of interleukin-8 and thrombospondin-1 by psoriatic keratinocytes mediates angiogenesis. Am J Pathol 1994;144(4):820 8.
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Dermatol Clin 22 (2004) 371 377
From laboratory to clinic: rationale for biologic therapy

Stephanie Mehlis, MDa, Kenneth B. Gordon, MDb,*
b a Department of Dermatology, Northwestern University Medical School, 675 N. St. Clair Street, Chicago, IL 60611, USA Division of Dermatology, Department of Medicine, Loyola University, Stritch School of Medicine, 2160 South First Avenue, Building 112, Room 342, Maywood, IL 60153, USA
Although topical therapy can be extremely effective in cases of limited psoriasis, systemic therapy is often needed for severe cases to give patients appropriate relief. Traditional systemic medications for psoriasis include systemic retinoids, methotrexate, cyclosporin, and psoralen plus UVA. All of these treatments have well-documented side effects, the frequency of which increases with increasing length of exposure [1]. Dermatologists have devised methods including intermittent and rotational strategies to avoid these side effects [2]. Because psoriasis is a chronic disease, there has been an increased demand to develop therapies that can be used for the lifetime of the patient. The development of new treatments has been facilitated by advances in immunology and an increased understanding of the basic pathophysiology of the disease. This information, and the advent of genetic engineering techniques, has led to the creation of new targeted medicines termed biologic therapies that inhibit the basic pathologic processes while remaining relatively free of interactions with other organ systems. These treatments are proteins produced by living organisms to target specific points of the inflammation cascade, including antibodies against cell surface markers, cytokines, and adhesion molecules. This article discusses the pathogenesis of psoriasis, looks at the immunologic factors that contribute to forming a psoriatic plaque, reviews how novel biologic therapies are made, and explores how biologics can target each of these specific parts of the immunologic cascade.
The pathogenesis of psoriasis The clinical and histolopathologic presentation of psoriasis is dominated by the obvious changes in the keratinocyte of the plaque when compared with uninvolved skin. The clinical scaling and induration associated with psoriasis can be seen on biopsy as parakeratosis, acanthosis, and loss of the granular layer. Keratinocytes proliferate rapidly, with an eightfold shortening of the epidermal cell cycle [3]. Additionally, these cells mature abnormally. These keratinocyte changes are accompanied by an inflammatory infiltrate composed primarily of mononuclear cells and neutrophils. The lymphocytes are primarily T cells with a predominance of CD4+ T cells in the dermis and many CD8+ T cells in the epidermis. Some of the T cells in the epidermis express natural killer cell markers and are thought to be resident to the skin. Additionally, activated Langerhans cells, macrophages, and dermal dendritic cells are present in the psoriatic plaques. Animal and human models have helped to clarify the significance of the inflammatory infiltrate in the development of psoriatic plaques. Most experiments have focused on the role of these activated T cells and the cytokines they produce as the driving force for the induction and maintenance of psoriatic plaques [4,5]. In a model first developed by Wrone-Smith and Nickoloff [6], symptomless skin (psoriatic patient/ nonindividual skin [PN]) from a psoriatic patient was transplanted onto an immunodeficient (severe combined immunodeficiency) mouse. T cells from the same patient were activated in vitro and then injected into the xenografted skin. In time, the graft became histologically identical to skin from a plaque of psoriasis, complete with keratinocyte and vascular
* Corresponding author. E-mail address: kgordon@lumc.edu (K.B. Gordon).
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changes. This change did not occur in skin from patients without psoriasis (non-psoriatic patient/noninvolved skin [NN]) or when the T cells were not activated in vitro. The introduction of activated T cells was sufficient to induce psoriasis in genetically susceptible skin [7]. One question this model does not answer is the role played by local cells in the skin including resident T cells and antigen-presenting cells (APC). Recently, a model has been identified that addresses this issue. Boyman et al [8] have identified a novel immunodeficient mouse called the AGR mouse. When susceptible skin is transferred to the mouse, it spontaneously develops into a plaque of psoriasis. This response can be blocked by the addition of medications that inactivate tumor necrosis factor-alpha (TNF-a), a cytokine central to the immune process in psoriasis. What the results of these experiments suggest is that local cells in the skin, when properly activated, may be sufficient in themselves to create a psoriatic plaque without the requirement of inflammatory cells being introduced from the circulation. Moreover, TNF-a is a major cytokine produced by APC, including dendritic cells and macrophages. The activation of these inflammatory cells may play a major role in the early development of lesions. Additional evidence for the fundamental role of the inflammatory response, particularly of T cells, comes from the efficacy of T cell specific immunomodulation in the treatment of psoriasis. Cyclosporin has immunosuppressive effects by decreasing proliferation and cytokine production of T cells. It was incidentally noted to improve psoriatic lesions in patients on cyclosporin after solid organ transplantation [9]. Further study has definitively proved that this T cell specific medication is extremely effective as a treatment for psoriasis [10]. Psoralen plus UVA and UVB have also been shown to deplete affected skin of T cells [11]. Finally, treatment with biologic agents that decrease the number of effector T cells in psoriasis (denileukin diftitox and alefacept) has demonstrated efficacy. Further evidence for the critical role the immune response plays in psoriasis is shown by a cure of psoriasis after reconstruction of a patients immune system from an allogenic bone marrow transplant, and the development of psoriasis in a patient who had a bone marrow transplant from a psoriatic donor [12,13]. All of these therapeutic results help to prove the important role the T cell plays in the pathogenesis of psoriasis. T cells can be classified into two major phenotypes characterized by the cytokines they produce. Type 1 helper T cells and cytotoxic T cells (Th1 and Tc1) secrete interleukin (IL)-2, TNF-a, interferon
(IFN)-g, and IL-18, and stimulate cell-mediated immunity and T-cell cytotoxicity. IgE-mediated allergic and mucosal responses are generated from the type 2 T cells (Th2 and Tc2) through release of IL-4, IL-5, and IL-13. Cytokines released by type 1 reactions inhibit type 2 reactions and vice versa [14]. The T cell response in psoriasis is primarily a type 1 reaction. Skin in psoriatic lesions has increased TNF-a and IFN-g compared with nonlesional skin [15] and IL-2 has been shown to flare psoriasis. Moreover, circulating T cells of patients with psoriasis have a higher ratio of IFN-g to IL-4 than normal patients [16]. These data all help to demonstrate that the T cell directed immune response in psoriasis is primarily a type 1 reaction [17].
T cells and psoriasis Many of the new biologic treatments of psoriasis have targeted blocking the inflammatory response of the T cells. To understand how these therapies work, an analysis of the steps necessary for T cells to induce a psoriatic plaque must be understood. For ease of understanding, this complicated process can be simplified into three basic steps: (1) the initial activation of T cells, (2) the migration of T cells into the skin, and (3) reactivation of the memory T cells and the magnification of the immune cascade by cytokines on various cells in the psoriatic plaque. Activation of T cells T cells must be activated by APC. In the skin, the APC are Langerhans cells that are constantly exposed to infectious and other protein antigens from the environment. When Langerhans cells are exposed to an antigen and have an appropriate signal to mature, they display the peptides from these antigens on either class I (for intracellular antigens) or class II (for extracellular antigens) major histocompatibility complex. These mature APC migrate out of the skin and into the skins lymphatic system. It is here that a mature APC binds to a na ve T cell through adhesion molecules [18]. One of the first interactions between these cells is the binding of the leukocyte functionassociated antigen 1 (LFA-1) and its two subunits (CD11a-CD18) to the intracellular adhesion molecule (ICAM or CD54) on the APC. Additionally, CD2 on the T cell binds to LFA-3 on the APC to complete the initial recognition process [19]. Once bound, there must be a process of antigenspecific recognition, referred to as signal 1. The major histocompatibility complex presents antigens
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on the surface of the APC, and T cells sample these until there is a fit between the antigen-specific T-cell receptor and the major histocompatibility complex antigen complex. The major histocompatibility complex I recognizes the CD3-CD8 T-cell receptor of cytotoxic T cells, whereas major histocompatibility complex II recognizes the CD3-CD4 Tcell receptor of helper T cells [18]. Binding still plays an important role in this step, because it keeps the cells together while the T-cell receptor is sampling the various major histocompatibility complex antigen complexes. The third and final step in T-cell activation is referred to as signal 2 or co-stimulation. This is a not an antigen-specific reaction, but it is necessary for T-cell stimulation. If antigen recognition takes place without co-stimulation, the T cell does become active. In fact, in the absence of co-stimulation the T cell is forced to die through apoptosis or be rendered unresponsive in the future (anergy). One of the most important co-stimulatory molecules is CD28 on the T cell. CD28 binds to both CD80 and CD86 on the APC (molecules that are up-regulated during maturation). The T-cell receptor and CD28 synergistically make the T cell produce cytokines that promote activation, including IFN-g, TNF-a, and IL-2 [20]. If this response takes place in the presence of IL-12, the T cell differentiates into a type 1 cell. The activated T cell also begins to express the high-affinity IL-2 receptor (IL-2R or CD25) and promotes its own activation and clonal proliferation though IL-2 [21]. Other important co-stimulatory molecules include CD2 LFA-3 and CD40L-CD40 [22 24]. Although it has traditionally been thought that this initial activation step takes place in the draining lymph nodes of the skin, the AGR mouse suggests that this could also take place with resident T cells in the skin. Migration of T cells into the skin After the initial clonal proliferation of T cells in the lymph node, most of the newly active cells undergo apoptosis. A minority, however, become memory cells that express markers like CD45RO and migrate out of the lymph node and into the circulation and tissues. For these cells to induce lesions of psoriasis, they must migrate to the skin and be reactivated locally. This trafficking back into the skin is yet another multistep process, this time between the T cell and the endothelium. Perhaps the most important of these regulators is the cutaneous lymphocyte antigen. Cutaneous lymphocyte antigen is a skinspecific adhesion molecule that binds to selectins including both E-selectin and P-selection [25,26],
molecules that are greatly up-regulated on endothelial cells during cutaneous inflammation [27]. This cellcell interaction slows the memory T cells in the bloodstream and allows these cells to undergo a second adhesion event called adherence [25,26]. Chemokines secreted in the local inflammatory reaction induce the T cell to increase expression of the integrin molecules LFA-1 and very late antigen-4. These molecules bind respectively to ICAM and vascular cell adhesion molecule-1 on the endothelium and cause the T cell literally to stick to the blood vessel wall. Finally, a flattening and migration of the T cell through the blood vessel wall occurs in a process called diapedesis. From here they follow various chemotactic molecules into the dermis [28]. There are multiple chemokines that are thought to play a role in inflammation in psoriasis. Chemokines were originally described as primary chemoattractants, but have also been found to promote a variety of other inflammatory functions. Initially, chemokines help with adhesion and the rolling of cells along the endothelium. They can also have direct effects on T-cell differentiation by altering cytokine expression and inflammatory receptors [29]. The major influence for the secretion of chemokines (by various cells including endothelial cells, keratinocytes, monocytes, and Langerhans cells) is the synergistic action of TNF-a and IFN-g from type 1 cells. Endothelial cells secrete chemokines RANTES and TARC further to attract more type 1 cells out of the vasculature [30]. The CD8+ cells need to migrate all the way up into the epidermis. This is accomplished though the interaction of the chemokines MIG and IP-10 produced by epidermal keratinocytes to the CXCR3 receptor. In fact, CXCR3 CD8 cells are 10 times more likely to be found in psoriatic plaques than in the peripheral blood of psoriatic patients [31]. Immune cascade in the skin The keratinocyte changes of psoriasis are a reaction to the immune response in the skin initiated by activated T cells but involving many different types of inflammatory cells. The T cells are believed to promote these changes by secreting a variety of cytokines. These cytokines induce the other cells found in the skin, including epidermal keratinocytes, dendritic cells, and macrophages, to produce their own cytokines. This positive feedback cycle maintains the chronic psoriatic plaque. The type 1 cytokines induce ICAM-1, CD40, and major histocompatibility complex II proteins on epidermal keratinocytes. ICAM-1 makes it possible for the T cells to migrate into the epidermis through LFA-1 ICAM-1 interaction [30].
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Table 1 Cytokines and chemokines that play a role in the immunologic cascade of psoriasis Cytokines and chemokines TNF-a [54,55] IFN-g [29,30] Produced by Type 1 T cells, macrophages, keratinocytes Type 1 T cells Effects Promotes type 1 differentiation of T cells; induces ICAM, VCAM, and E selectin Keratinocyte proliferation; increases MHC I and II expression; Ag presentation attracts macrophages and release of TNFa; induces ICAM, VCAM, and E selectin; inhibits IL-4 (and Th2 expression) Promotes CD28-CD80-CD86 interaction and clonal proliferation of Th1 cells; activates macrophages and Tc1 Growth of dendritic cells and macrophages Activates neutrophils and mononuclear cells Promotes Th1 differentiation Promotes angiogenesis Induces IL-12; attracts lymphocytes Increases leukocyte adhesion Attracts lymphocytes and neutrophils; induces vascular response
IL-2 [29] IL-3 [29] GM-CSF [29] IL-12 [29,56] VEG-F [33,52] RANTES [29,30] MIG and IP-10 [29,31] IL-8 [51,53]
Type 1 T cells T cells T cells APC Keratinocytes, T cells Keratinocytes Keratinocytes Neutrophils, keratinocytes
Abbreviations: APC, antigen-presenting cells; GM-CSF, granulocyte macrophage colony stimulating factor; ICAM, intracellular adhesion molecule; IFN, interferon; IL, interleukin; MHC, major histocompatibility complex; TNF, tumor necrosis factor; VCAM, vascular cell adhesion molecule; VEG-f, vascular endothelial growth factor.
IFN-g produced by the Tc1 cells induces keratinocyte proliferation and differentiation. The IFN-g also is a potent stimulator for macrophages to release TNF-a. Neutrophils are attracted into the dermis by the IL-8 chemokine, released by differentiated keratinocytes as a result of multiple inflammatory cytokines [32]. Vascular growth and remodeling seen in psoriasis are likely caused by the T cell release of vascular endothelial growth factor [33]. A more extensive list of cytokines and chemokines is provided in Table 1.
Creating a novel biologic therapy The simplified immunologic cascade described previously presents a basic understanding of the different molecules and signals behind the development of a psoriatic plaque. Each of these is a potential target for the new biologic therapies. The development of these novel biologics, however, poses a challenge. After an appropriate target is chosen, whether it is a cell surface receptor or an extracellular cytokine, it must interact with that target appropriately to induce the proposed response. Kohler and Milstein [34] described the first biologic therapies with monoclonal antibodies in 1975. The spleen of a mouse immunized with a specific antigen is mixed with human myeloma cells (immortal cells). To ensure that the myeloma cells do not overgrow the fused cells, only myeloma cells that are deficient in HGPRT, a crucial enzyme in the proliferation of cells, are mixed in with the mouse spleen
cells. The medium itself does not allow spleen cells to grow. Myeloma cells cannot reproduce on their own without HGPRT. Only the hybrid of the myeloma and spleen cells is able to grow in the medium. This hybridoma is then cloned, and large amounts of monoclonal antibodies are produced. The problem with the use of these monoclonal antibodies in humans, however, is the potential for patients to develop immune reactions against the mouse protein. This reaction manifests itself as human antimouse antibodies. More recently, methods have been developed to decrease or eliminate these reactions by fusing parts of human antibodies with these mouse antibodies. Chimeric antibodies (drugs ending with -ximab) take the antigen-binding portion of mouse antibody and fuse it to a constant region of human antibody. Humanized antibodies (drugs ending with -umab) use the framework of a human antibody and selectively place it in small amino acid sequences from murine antibodies into the variable region. Fusion proteins (often ending in -cept) are receptor domains or cell surface markers of human proteins that are fixed to the constant portion of an immunoglobulin [35]. For example, if a medication is needed to block TNF-a, using an antibody that is bound to the TNF-a receptor blocks the activation of that receptor. The rational for synthesizing these proteins with the constant chain of human immunoglobulin (usually IgG) is to improve the half-life of the drug. The drug lasts longer in the circulation if it appears to be a human immunoglobulin. Organs that clear proteins, like the spleen and liver, recognize it as foreign if
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most of the antibody is murine. This allows for longer periods between dosing and easier use for patients.
Strategy 2: blocking T-cell activation Strategy 2 blocks cell-cell interaction in any of the three steps outlined in T-cell activation: (1) binding, (2) antigen-specific activation, and (3) co-stimulation. It could also target the trafficking of the T cells back into the skin. Efalizumab is a humanized monoclonal antibody that binds to the CD11a portion of the LFA1 surface molecule found on T cells [44]. By blocking the interaction with ICAM, efalizumab blocks the initial binding of T cells to the APC [45], migration into the skin by ICAM on endothelial cells [46], and Tc1 adhesion to keratinocytes [45]. Strategy 3: immune deviation away from type 1 T cells There is an inverse relationship between the balance of Th1 and Th2 cells. Promoting a Th2 response by the addition of Th2 cytokines should decrease the activity of Th1 cells. Several different biologic agents work to upset the Th1 balance. IL-4 is the primary cytokine that inhibits the activity of type 1 T cells. Small studies have demonstrated some efficacy with acute treatment with recombinant IL-4. IL-10 is an important Th2 cytokine, and subcutaneous injection of recombinant IL-10 has been shown to decrease Th1 cytokines and improve psoriasis [47]. Recombinant IL-11 has similarly induced a Th2 response and improvement in psoriatic plaques [48]. Although the induction of immune deviation has traditionally been limited to treatment with type 2 cytokines to down-regulate type 1 cells, very preliminary data from another approach suggest potential effects with immune deviation. The presence of IL-12 is necessary for type 1 T-cell differentiation. Early studies suggest a monoclonal antibody directed against IL-12 could have some efficacy in psoriasis. By blocking type 1 differentiation, a novel form of immune deviation in psoriasis, it may be possible to improve disease. Strategy 4: inactivating cytokines and chemokines The final strategy uses antibodies to target inflammatory mediators that are still bound to cells or have been excreted. There are a variety of different cytokines and chemokines implicated in the pathogenesis of psoriasis, and any of the candidates in Table 1 can be a potential target. Etanercept is a dimeric fusion protein that binds to soluble TNF-a to neutralize it [49]. Infliximab also targets TNF-a. It is a chimeric antibody that targets both soluble and bound TNF, and can neutralize the effects of TNF and can also
Targets for biologic therapies The authors have developed a model, published previously [36,37], that uses the simplified vision of the immunopathogenesis of psoriasis to develop four potential areas as target strategies for biologic immunotherapy. Strategy 1 is to decrease selectively the number of pathogenic T cells. Strategy 2 inhibits T-cell activation or reactivation in the lymph nodes or skin. Strategy 3 attempts to alter the cytokine profile of the effector T cells from type 1 to type 2, a process called immune deviation. Finally, strategy 4 inactivates specific cytokines that play a major role in the immunologic cascade of psoriasis. This section briefly discusses how some of the newer biologics may fit into this framework.
Strategy 1: targeting pathogenic T cells Psoriasis is a T-cell mediated disease. Eliminating pathogenic T cells from the periphery or the skin should decrease disease activity. One of the first biologics studied for psoriasis was denileukin difitox, a fusion protein that combines an enzymatically active diphtheria toxin with the coding sequence of IL-2. This protein binds avidly to the IL-2 R and rapidly gets internalized. The active diphtheria toxin inhibits protein synthesis and ultimately results in cell death [38]. It has no effect on any other cells other than an activated T cell that expresses the high affinity IL-2 receptor [39]. In clinical trials with this drug in psoriasis, there was an improvement in psoriasis, leading researchers to focus on blocking T cells and their function for biologics [40,41]. Another method of blocking T cells is to induce apoptosis of the cell itself by surface receptors or by activating natural killer cells or macrophages to induce their death. Alefacept, a fusion protein of LFA-3 and human IgG, works in two separate ways. First, the LFA-3 portion binds to its match on the T cell, the CD-2 receptor, blocking co-stimulation. The constant portion IgG engages the FcgIII receptor on natural killer cell, however, which induces apoptosis by the perforin-granzyme system [42]. It also reduces the number of activated T cells found in the circulation, and the response to therapy correlates to this decrease in the periphery and especially the skin [42,43].
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S. Mehlis, K.B. Gordon / Dermatol Clin 22 (2004) 371377 closporine improves psoriasis in a double-blind study. JAMA 1986;256:3110 6. Krueger JG, Wolfe JT, Nabeya RT, et al. Successful ultraviolet B treatment of psoriasis is accompanied by a reversal of keratinocyte pathology and by selective depletion of intraepidermal T cells. J Exp Med 1995;182: 2057 68. Eedy DJ, Burrows D, Bridges JM, et al. Clearance of severe psoriasis after allogenic bone marrow transplantation. BMJ 1990;300:908. Gardembas-Pain M, Ifrah N, Foussard C, et al. Psoriasis after allogeneic bone marrow transplantation. Arch Dermatol 1990;126:1523. McInnes IB. Rheumatoid arthritis: from bench to bedside. Rheum Dis Clin North Am 2001;27:373 87. Baker BS, Fry L. The immunology of psoriasis. Br J Dermatol 1992;126:1 9. Austin LM, Ozawa M, Kikuchi T, et al. The majority of epidermal T cells in psoriasis vulgaris lesions can produce type 1 cytokines, interferon-gamma, interleukin-2, and tumor necrosis factor-alpha, defining TC1 (cytotoxic T lymphocyte) and TH1 effector populations: a type 1 differentiation bias is also measured in circulating blood T cells in psoriatic patients. J Invest Dermatol 1999;113:752 9. Schlaak JF, Buslau M, Jochum W, et al. T cells involved in psoriasis vulgaris belong to the Th1 subset. J Invest Dermatol 1994;102:145 9. Trowsdale J, Powis SH. The MHC: relationship between linkage and function. Curr Opin Genet Dev 1992;2:492 7. Berridge MJ. Lymphocyte activation in health and disease. Crit Rev Immunol 1997;17:155 78. Fraser JD, Newton ME, Weiss A. CD28 and T cell antigen receptor signal transduction coordinately regulate interleukin 2 gene expression in response to superantigen stimulation. J Exp Med 1992;175:1131 4. Smith KA. Interleukin-2: inception, impact, and implications. Science 1988;240:1169 76. Aringer M. T lymphocyte activation: an inside overview. Acta Med Austriaca 2002;29:7 13. Friedl P, Gunzer M. Interaction of T cells with APCs: the serial encounter model. Trends Immunol 2001;22: 187 91. Hudrisier D, Bongrand P. Intercellular transfer of antigen-presenting cell determinants onto T cells: molecular mechanisms and biological significance. FASEB J 2002;16:477 86. Fuhlbrigge RC, Kieffer JD, Armerding D, et al. Cutaneous lymphocyte antigen is a specialized form of PSGL-1 expressed on skin-homing T cells. Nature 1997;389:978 81. Picker LJ, Kishimoto TK, Smith CW, et al. ELAM-1 is an adhesion molecule for skin-homing T cells. Nature 1991;349:796 9. Groves RW, Ross E, Barker JN, et al. Effect of in vivo interleukin-1 on adhesion molecule expression in normal human skin. J Invest Dermatol 1992;98:384 7. Robert C, Kupper TS. Inflammatory skin diseases,
result in compliment-mediated fixation and antibodydependant toxicity of T cells [50]. Other cytokines that have been targeted include IL-8 [51] and IFN-g.
[11]
Summary
[12]
Traditional systemic therapy for psoriasis is limited by either lack of efficacy or the long-term side effect profile of the medications used. Newer information about the pathophysiology of the disease has led to new perspectives on developing novel techniques for attacking psoriasis. In particular, specifically targeting the areas in the immunologic cascade that may be the central drivers for the development of psoriasis could lead to better therapy. The techniques of genetic engineering and the technology to produce bioengineered molecules in large quantities have given clinicians the ability specifically to target psoriasis and other inflammatory diseases. These biologic medications truly bridge the gap between the identification of the pathophysiologic processes of psoriasis and the treatment of patients suffering from this disease.
[13]
[14] [15] [16]
[17]
[18]
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[1] Koo JY. Current consensus and update on psoriasis therapy: a perspective from the US. J Dermatol 1999; 26:723 33. [2] Weinstein GD, White GM. An approach to the treatment of moderate to severe psoriasis with rotational therapy. J Am Acad Dermatol 1993;28:454 9. [3] Soltani K, Van Scott EJ. Patterns and sequence of tissue changes in incipient and evolving lesions of psoriasis. Arch Dermatol 1972;106:484 90. [4] Nickoloff BJ. The cytokine network in psoriasis. Arch Dermatol 1991;127:871 84. [5] Nickoloff BJ. The immunologic and genetic basis of psoriasis. Arch Dermatol 1999;135:1104 10. [6] Wrone-Smith T, Nickoloff BJ. Dermal injection of immunocytes induces psoriasis. J Clin Invest 1996;98: 1878 87. [7] Nickoloff BJ, Kunkel SL, Burdick M, et al. Severe combined immunodeficiency mouse and human psoriatic skin chimeras: validation of a new animal model. Am J Pathol 1995;146:580 8. [8] Boyman O, Hefti H, Suter M, Nickoloff BJ, Nestle FO. Conversion of uninvolved to involved psoriatic skin transplanted onto AAGR mice indicates intrinsic default pathway of psoriasis disease pathogenesis. J Invest Dermatol 2002;119:302. [9] Mueller W, Herrmann B. Cyclosporin A for psoriasis. N Engl J Med 1979;301:555. [10] Ellis CN, Gorsulowsky DC, Hamilton TA, et al. Cy[19] [20]
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S. Mehlis, K.B. Gordon / Dermatol Clin 22 (2004) 371377 T cells, and immune surveillance. N Engl J Med 1999; 341:1817 28. Borish LC, Steinke JW. 2. Cytokines and chemokines. J Allergy Clin Immunol 2003;111:S460 75. Krueger JG. The immunologic basis for the treatment of psoriasis with new biologic agents. J Am Acad Dermatol 2002;46:1 23. Rottman JB, Smith TL, Ganley KG, et al. Potential role of the chemokine receptors CXCR3, CCR4, and the integrin alphaEbeta7 in the pathogenesis of psoriasis vulgaris. Lab Invest 2001;81:335 47. Gillitzer R, Ritter U, Spandau U, et al. Differential expression of GRO-alpha and IL-8 mRNA in psoriasis: a model for neutrophil migration and accumulation in vivo. J Invest Dermatol 1996;107:778 82. Detmar M, Yeo KT, Nagy JA, et al. Keratinocyte-derived vascular permeability factor (vascular endothelial growth factor) is a potent mitogen for dermal microvascular endothelial cells. J Invest Dermatol 1995;105: 44 50. Kohler G, Milstein C. Continuous cultures of fused cells secreting antibody of predefined specificity. Biotechnology 1975;24:524 6. Reichert JM. Therapeutic monoclonal antibodies: trends in development and approval in the US. Curr Opin Mol Ther 2002;4:110 8. Mehlis SL, Gordon KB. The immunology of psoriasis and biologic immunotherapy. J Am Acad Dermatol 2003;49:S44 50. Singri P, West DP, Gordon KB. Biologic therapy for psoriasis: the new therapeutic frontier. Arch Dermatol 2002;138:657 63. Williams DP, Parker K, Bacha P, et al. Diphtheria toxin receptor binding domain substitution with interleukin-2: genetic construction and properties of a diphtheria toxin-related interleukin-2 fusion protein. Protein Eng 1987;1:493 8. Waters CA, Snider CE, Itoh K, et al. DAB486IL-2 (IL-2 toxin) selectively inactivates high-affinity IL-2 receptor-bearing human peripheral blood mononuclear cells. Ann N Y Acad Sci 1991;636:403 5. Bagel J, Garland WT, Breneman D, et al. Administration of DAB389IL-2 to patients with recalcitrant psoriasis: a double-blind, phase II multicenter trial. J Am Acad Dermatol 1998;38:938 44. Gottlieb SL, Gilleaudeau P, Johnson R, et al. Response of psoriasis to a lymphocyte-selective toxin (DAB 389IL-2) suggests a primary immune, but not keratinocyte, pathogenic basis. Nat Med 1995;1:442 7.
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[42] Ellis CN, Krueger GG. Treatment of chronic plaque psoriasis by selective targeting of memory effector T lymphocytes. N Engl J Med 2001;345:248 55. [43] Krueger GG. Selective targeting of T cell subsets: focus on alefacept, a remitive therapy for psoriasis. Expert Opin Biol Ther 2002;2:431 41. [44] Leonardi CL. Efalizumab: an overview. J Am Acad Dermatol 2003;49:S98 104. [45] Werther WA, Gonzalez TN, OConnor SJ, et al. Humanization of an anti-lymphocyte function-associated antigen (LFA)-1 monoclonal antibody and reengineering of the humanized antibody for binding to rhesus LFA-1. J Immunol 1996;157:4986 95. [46] Krueger J, Gottlieb A, Miller B, et al. Anti-CD11a treatment for psoriasis concurrently increases circulating T-cells and decreases plaque T-cells, consistent with inhibition of cutaneous T-cell trafficking. J Invest Dermatol 2000;115:333. [47] Asadullah K, Docke WD, Ebeling M, et al. Interleukin 10 treatment of psoriasis: clinical results of a phase 2 trial. Arch Dermatol 1999;135:187 92. [48] Trepicchio WL, Ozawa M, Walters IB, et al. Interleukin-11 therapy selectively downregulates type I cytokine proinflammatory pathways in psoriasis lesions. J Clin Invest 1999;104:1527 37. [49] Goffe B, Cather JC. Etanercept: an overview. J Am Acad Dermatol 2003;49:S105 11. [50] Gottlieb AB. Infliximab for psoriasis. J Am Acad Dermatol 2003;49:S112 7. [51] Biasi D, Carletto A, Caramaschi P, et al. Neutrophil functions and IL-8 in psoriatic arthritis and in cutaneous psoriasis. Inflammation 1998;22:533 43. [52] Detmar M, Brown LF, Schon MP, et al. Increased microvascular density and enhanced leukocyte rolling and adhesion in the skin of VEGF transgenic mice. J Invest Dermatol 1998;111:1 6. [53] Duan H, Koga T, Kohda F, et al. Interleukin-8-positive neutrophils in psoriasis. J Dermatol Sci 2001;26: 119 24. [54] Keystone EC. Tumor necrosis factor-alpha blockade in the treatment of rheumatoid arthritis. Rheum Dis Clin North Am 2001;27:427 43. [55] Wakefield PE, James WD, Samlaska CP, et al. Tumor necrosis factor. J Am Acad Dermatol 1991;24:675 85. [56] Yu Y, Tang L, Wang J, et al. Psoriatic lesional keratinocytes promote the maturation of human monocyte-derived Langerhans cells. Dermatology 2002; 204:94 9.
Dermatol Clin 22 (2004) 379 388
Review of therapy of psoriasis: the prebiologic armamentarium

David S. Aaronson, MD, Mark Lebwohl, MD*
Mount Sinai School of Medicine, 5 East 98th Street, Box 1048, New York, NY 10029-6574, USA
To appreciate the evolving treatments for psoriasis in the current biologic era, it is important to first examine traditional therapies. This article reviews the prebiologic armamentarium and addresses the following treatments: (1) topical agents, including topical corticosteroids, tars, anthralin, vitamin D analogs, retinoids, and salicylic acid; (2) systemic agents, such as oral acitretin, methotrexate, and cyclosporine; and (3) phototherapy with ultraviolet B (UVB) light, narrowband UVB, and psoralen with ultraviolet A (PUVA) light.
Topical therapy Topical therapy is considered the first line in psoriasis treatment. The various side-effect profiles of these agents, however, often require their rotation throughout the course of the disease. The following sections describe the medicines in this category, their side effects, and the current data on their efficacy. Corticosteroids Corticosteroids persist as the mainstay for the topical treatment of psoriasis despite the existence of safer therapies with lesser side effects. Topical corticosteroids are categorized by the StoughtonCornell classification system, based on the vasoconstriction of small blood vessels in the upper dermis [1]. This system ranges from the superpotent class 1 steroids, such as clobetasol, halobetasol propionate, betamethasone dipropionate in optimized base, and
* Corresponding author. E-mail address: lebwohl@aol.com (M. Lebwohl).
diflorasone diacetate in optimized base, to the weaker class 7 steroids, such as 1% hydrocortisone. They all reduce inflammation but vary in strength, vehicle, and cost. Many forms of topical corticosteroids exist, including solutions, foams, lotions, creams, emollient creams, gels, ointments, sprays, and tape. Topical corticosteroids come with bothersome and occasionally serious side effects that limit their longterm use in the treatment of psoriasis, however. The hypothalamic pituitary adrenal axis can be suppressed by medium-potency or stronger topical corticosteroids. This potential side effect is most worrisome for children because their ratio of surface to body mass is increased. Conversely, iatrogenic Cushings syndrome is also a rare potential side effect of topical corticosteroids. More common side effects occur locally at the site of topical corticosteroid application resulting in cutaneous atrophy. This process leads to skin fragility and tearing of dermal connective tissue, which causes irreversible striae. Telangiectases also arise, which can rupture and form purpura. These findings are most often seen when high-potency corticosteroids are used on the face and intertriginous areas for prolonged periods of time. One other major complication of topical corticosteroids is tachyphylaxis. Tachyphylaxis is defined as the cessation of therapeutic response to a substance as treatments with that substance are continued. This phenomenon is seen scientifically as the reduction or loss of small vessel vasoconstriction induced by topical corticosteroids [2]. Clinically, however, it has been questioned whether tachyphylaxis exists [3]. To avoid tachyphylaxis and other side effects, Katz et al [4] demonstrated that a regimen of three applications of superpotent betamethasone dipropionate over 24 hours per week led to improvement of psoriasis for up to 6 months in 60% of patients versus 20% of
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patients in the placebo group. This method has been termed pulse therapy or weekend therapy. Other methods to limit the side effects from topical corticosteroids include the introduction of novel agents, such as fluticasone propionate, mometasone furoate, prednicarbate, and tipredane, and novel vehicles, such as betamethasone valerate in a foam and diflorasone diacetate in an optimized base in a gel. Anthralin and tars Anthralin use has declined in Europe with the introduction of topical vitamin D analogs for psoriasis. Anthralin can be moderately irritating and can stain skin, clothes, and furniture. Micanol with 1% anthralin in a new temperature-sensitive vehicle activated at skin temperature was recently released to avoid these drawbacks. It only prevents staining of clothes and furniture, however, not skin. To reduce skin irritation, short contact regimens of anthralin have been explored to minimize exposure to the staining and irritating effects. Despite these efforts, and the equal efficacy shown for 0.25% to 2% dithranol cream applied once daily for 30 minutes versus 3 mg/g of calcitriol ointment twice daily, the quality of life in the calcitriol group was perceived as much better [5]. Application of triethanolamine after removal of anthralin may prevent irritation and staining of the skin [6]. Topical vitamin D analogs The vitamin D3 analog calcipotriene was introduced in Europe in the early 1990s in a 0.005% ointment formulation. Calcipotriene binds to the vitamin D receptor found in keratinocytes, halting proliferation and causing terminal differentiation [7]. It is currently used to treat moderate to severe plaque psoriasis alone, but primarily in combination with other treatment modalities. Side effects from vitamin D analogs are minimal when compared with topical corticosteroids and anthralin. Vitamin D analogs can cause irritant contact dermatitis, however, particularly on the face and in intertriginous sites. Yet, they are highly effective in alleviating psoriasis. Studies suggest that dilution of calcipotriene with petrolatum, when used on the face or intertriginous areas, or the addition of superpotent halobetasol ointment may prevent irritant contact dermatitis [8,9]. Another side effect, hypercalcemia, is seen rarely in case reports but is invariably associated with excess use over large surface areas [10]. In general, long-term studies of calcipotriene have
shown that it is well tolerated with few adverse effects [11,12]. Calcipotriene, when compared with topical corticosteroids in clinical trials, was shown to be as effective as class 2 (fluocinonide, 0.05%) but not as effective as class 1 corticosteroids [13]. In combination, calcipotriene plus limited application of the superpotent topical corticosteroid halobetasol worked better than either one alone, with no incidence of cutaneous atrophy [14]. Furthermore, a new combination of calcipotriol and the betamethasone dipropionate ointment used once daily was shown to be more effective than either one alone in a randomized double-blind study [15]. These studies led to the examination of combination preparations containing calcipotriene. Halobetasol (0.05%) ointment or cream and 5% tar gel (Estargel) in combination with calcipotriene (0.005%) ointment remained stable for a minimum of 13 days at room temperature. One study found, however, that 6% salicylic acid or 12% ammonium lactate lotion inactivated calcipotriene completely or by more than 30%, respectively [16]. Calcipotriene also has been combined with phototherapy. The Canadian Calcipotriol and UVB Study Group has shown in a multicenter, prospective, randomized, parallel-group, vehicle-controlled, singleblind study that calcipotriol cream plus twice-weekly broadband UVB reduced the UVB exposure to achieve total psoriasis clearance [17]. Narrowband UVB plus calcipotriol, however, does not improve psoriatic response when compared with narrowband UVB alone [18]. Importantly, calcipotriene is not inactivated by UVB and may increase the minimal erythema dose [19]. PUVA in combination with calcipotriene also has been studied. One promising study by Speight and Farr [20] showed that application of twice-daily calcipotriene ointment versus placebo to symmetrically located plaques of psoriasis on the same patient decreased the UVA dose by 26.5% without affecting time to relapse. This regimen has the advantage of reducing the long-term skin aging and carcinogenic effects of UVA. Calcipotriene is inactivated by UVA and should therefore be applied only after phototherapy [21]. Retinoids Tazarotene is a specific retinoic acid receptor (RAR) ligand and has no binding activity with the retinoic X receptor. It specifically binds b and g subtypes of RAR and is believed to reduce inflammation and cause epidermal differentiation [22,23].
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Tazarotene is available in gel and cream formulation at 0.05% and 0.1% concentrations. Tazarotene was introduced because it is less irritating when compared with topical application of nonspecific retinoids and has little of their systemic effects. Still, its major side effect is cutaneous irritation, which is worse with the more effective higher concentration [24]. Like the vitamin D analogs, it does not cause the more troublesome side effects of topical corticosteroids. Efforts have been undertaken to minimize the irritating nature of retinoids and enhance their action by combining topical corticosteroids. Tazarotene used with the topical corticosteroids, 0.1% mometasone furoate cream (class 4) or 0.05% fluocinonide (class 2), improved psoriatic plaques with reduced retinoid dermatitis [25]. Furthermore, a small-scale pilot study postulated that 0.1% tazarotene can actually reduce epidermal atrophy induced by 0.05% diflorasone diacetate ointment [26]. Regimens of 0.1% tazarotene and the corticosteroids, 0.1% mometasone furoate or clobetasol ointment, also have shown increased efficacy and decreased side effects compared with either treatment alone [27,28]. Tazarotene with phototherapy also has been examined. The addition of tazarotene to UVB quickened psoriasis improvement when compared with UVB alone but caused increased sensitivity to burning [29]. There have been recommendations to reduce UV doses by one third to avoid burning with combination tazarotene [30].
Ultraviolet B Discussion of phototherapy in the more modern era must first start with broadband UVB. UVB dose is based on minimal erythema dose or Fitzpatrick skin types [34]. UVB has enhanced efficacy with a thinlayer application of clear emollients, such as petrolatum and mineral oil, because of improved optical transmission to the skin [35]. Thick application of these same emollients and other topical treatments already discussed can block UVB [36]. Attention should be paid to agents that block or enhance UVB. The side effects of UVB are skin burning and photosensitivity. Unlike UVB in sunlight, evidence suggests that broadband UVB in phototherapy does not lead to carcinogenesis [37]. The combination of UVB with other topical and systemic treatments for psoriasis has been shown to increase skin burning and photosensitivity, and with some treatments, actually reduces the time to relapse. Care must be taken when combined treatment is considered. The benefits of combination therapy with calcipotriene or tazarotene, however, are accelerated efficacy and increased skin clearing [29,38,39]. Systemic therapy with methotrexate or acitretin in combination with UVB is another effective treatment of psoriasis. The addition of a systemic agent reduces the total cumulative dose of UVB, and conversely, addition of UVB to systemic therapy reduces drug dosages [40,41]. The synergy between systemic and UVB therapy is a critical observation when the side effects of methotrexate and oral retinoids are considered. This synergy includes reduction in liver biopsies performed for methotrexate and the hair loss, cheilitis, myalgias, and pyogenic granulomas caused by oral retinoids. Psoralen plus ultraviolet A PUVA is a major treatment of widespread or resistant psoriasis. Psoralen, 8-methoxypsoralen, when targeted with UVA, causes the formation of pyrimidine dimers and reaches peak cutaneous concentrations between 1 and 4 hours. Pyrimidine dimers lead to cross-linkage of DNA strands. Cross-linkage of DNA strands leads to genomic instability and inflammatory cell death. Psoralen is typically given orally 2 hours before UVA in a crystalline form (Oxsoralen) at 0.6 mg/kg or 90 minutes before UVA in an encapsulated liquid form (Oxsoralen Ultra) at 0.4mg/kg. PUVA increases the incidence of squamous cell carcinoma (SCC) and, to a lesser extent, malignant melanoma. One study showed that patients treated with 260 individual PUVA sessions compared with
Phototherapy UV light causes DNA damage to cutaneous tissue. It also is a proven effective psoriasis treatment. William Goeckerman [31] first introduced phototherapy at the beginning of the 20th century. Goeckermans regimen consisted of a day and night crude coal tar bath followed by exposure to a hot quartz mercury vapor lamp. At that time, patients only received phototherapy in the inpatient setting. Ingram [32], who substituted anthralin for crude coal tar, made an important modification in the 1950s. Levine et al [33] made additional modifications in the 1970s when they discovered that outpatient treatment 3 times per week and a clear lubricating base instead of crude coal tar was as effective as an equal number of inpatient treatments. Over the years, additional advances in phototherapy have occurred with the use of systemic and topical medicines.
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fewer than 170 sessions had an 11-fold increase in SCC [42]. Male genitalia should be shielded during UVA exposure because of the tendency to develop carcinoma in that region [43]. One study reported that malignant melanoma increased several-fold in individuals treated with more than 250 PUVA sessions, and that study included individuals treated at the onset of PUVA therapy with higher doses [44]. Notwithstanding, it is important for all patients receiving PUVA therapy to have periodic skin examinations to monitor for new lesions. In addition to cancer, lesser side effects, such as premature cutaneous aging, nausea, headache, and burning, can be prominent. It is important to take psoralen with food to reduce the incidence of nausea, or particularly sensitive patients can bathe in psoralen [45,46]. Also, avoidance of sun exposure should be stressed. Unlike normal sunburn, PUVA-induced burns appear within 24 hours, but peak around 48 hours. For this reason, PUVA therapy should never be given 2 days consecutively. The combination of PUVA therapy plus other topical agents has been explored to reduce the cumulative dose of UVA. PUVA and corticosteroids have yielded conflicting results [47,48]. Studies of the combination of PUVA and anthralin have not been undertaken, most likely because of the potential for a UVA-photosensitizing effect. The combination of PUVA and calcipotriene has met with greater success and was discussed earlier. It causes quicker clearing with lower UVA doses than with PUVA alone. The combination of PUVA and tazarotene gel is not widely published, but tazarotene may enhance PUVA with the caveat that tazarotene gel reduces the amount of UVA necessary [30]. The combination of PUVA with oral retinoids provides not only synergy but also a reduction in one anothers side-effect profiles. This effect is partially brought about through a reduced need for UVA exposure to achieve the same clearance of psoriasis [49,50]. The addition of oral retinoids is termed PUVA-sparing therapy. There has been work showing that the addition of oral retinoids reduces the incidence of skin cancers because the development of UVA-induced skin cancers is dose-dependent [51 53]. Another systemic agent, methotrexate, also has been proven effective in combination with PUVA in the treatment of psoriasis [54]. Yet, methotrexate is a known risk factor for SCCs and requires liver function monitoring. Narrowband ultraviolet B Narrowband UVB (Tl-01) is a wavelength of approximately 311 nm that maximizes psoriasis clear-
ance compared with its erythrogenic potential. Narrowband UVB has the disadvantage of producing more severe and longer-lasting burns than broadband UVB, however, and its long-term effect on carcinogenesis remains unknown. Its overall safety is suspected to be much greater than PUVA. Narrowband UVB has been proven superior to broadband UVB [55] and is as effective as or less effective than PUVA [56,57]. The better safety profile of narrowband UVB, especially when administered at an optimized dosage, has led to its increased use over the last few years. Studies with narrowband UVB in combination with other agents are underway.
Systemic therapy Systemic therapy for psoriasis in the prebiologic era consists of Food and Drug Administration (FDA-) approved drugs, such as methotrexate, acitretin, and cyclosporine, and nonapproved drugs, such as tacrolimus, mycophenolate mofetil, hydroxyurea, 6-thioguanine, and sulfasalazine. Typically, these systemic therapies are used for severe disabling psoriasis or psoriasis refractory to topical or phototherapeutic modalities. Methotrexate Methotrexate was implemented as an effective treatment of psoriasis back in the 1970s, and at the present time, remains widely used [58]. It also has FDA-approved uses for the treatment of neoplastic and rheumatologic disease. It reversibly inhibits dihydrofolate reductase, which is an enzyme required for the reduction of folic acid to tetrahydrofolic acid. This inhibition limits the quantity of one-carbon units needed to form purines and transform deoxyuridylate into thymidylate. Through this mechanism, methotrexate prevents the synthesis of DNA and cell replication. Inflammatory cells and cells with high turnover, such as hematopoetic and gastrointestinal cells, are most affected by systemic methotrexate therapy. It is methotrexates effects on these cell types that cause most of its side effects; most recently, attention has been drawn to the immunosuppressive effects of methotrexate. Methotrexate is 50% protein bound in plasma and primarily excreted by the kidneys. In addition, it interacts with many other drugs, making it crucial to get a complete list of patient medications. Methotrexate has a multitude of side effects, ranging from benign to life threatening. The most common side effects are nausea, vomiting, anorexia,
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stomatitis, macrocytic anemia, and phototoxicity. Stomatitis and macrocytic anemia can be prevented with oral folic acid in dosages of 1 to 5 mg daily [59]. Methotrexate phototoxicity is a unique side effect and has been given the name radiation recall, which is the development of erythema at previous sights of radiation or sunburns [60]. Methotrexate can also cause fatal seizures, hepatotoxicity, renal failure, bone marrow suppression, and pulmonary fibrosis. Consequently, methotrexate is contraindicated in patients who have renal or hepatic impairment or profound bone marrow suppression. It is also necessary to stop methotrexate in the event of infection or other illness requiring an intact immune response. The pulmonary side effects can be deadly. If a patient complains of new-onset shortness of breath or cough, methotrexate should be discontinued [61]. Persistent or worsening symptoms should be evaluated with a chest radiograph. Much like other immunosuppressive drugs, methotrexate has been reported to cause lymphoproliferative disorders. These lymphoproliferative disorders have disappeared with methotrexate cessation, suggesting possible causality [62,63]. Hepatotoxicity is the most serious long-term side effect, and how best to monitor patients taking methotrexate is a topic of much debate. It is well agreed on, though, that those patients already predisposed to cirrhosis of the liver, such as alcoholic, obese, or diabetic patients, should take methotrexate with extreme caution or not at all. Roenigk et al [58] have published guidelines on monitoring patients taking methotrexate. Patients with hepatic risk factors should have a liver biopsy after 2 to 4 months of methotrexate therapy with signs of psoriatic improvement. A biopsy should be repeated after a 1- to 1.5-g cumulative dose has been reached. Patients with no hepatic risk factors should have a liver biopsy at a 1 1.5-g cumulative dose and thereafter for every 1.5 g of methotrexate. Previously, a baseline liver biopsy was indicated for every patient starting methotrexate. Rheumatologists do not recommend routine liver biopsy for patients treated with methotrexate for rheumatoid arthritis (RA), however. Patients with psoriasis, however, are more likely to have histologic progression or cirrhosis than patients with RA [64]. There are several confounding factors that may explain this difference, including use of nonsteroidal anti-inflammatory medicine and oral steroids, population bias, and dosage. One final contraindication to the administration of methotrexate is pregnancy. It is a class X drug and therefore highly teratogenic and known to cause
miscarriages [65]. Methotrexate may also temporarily affect male fertility. Therefore, methotrexate therapy should be halted several months before conception, and all patients should be advised about its deleterious effects. Despite numerous side effects and the required monitoring of toxicity, methotrexate is effective. Psoriatic arthritis may be most alleviated with methotrexate. Methotrexate is also useful for the long-term management of severe psoriasis, especially the erythrodermic and pustular variants. Newer studies in comparing the biologics are currently underway. Retinoids Retinoids can be applied topically or systemically to treat psoriasis. Topical retinoids were discussed previously. Systemic usage is indicated for the treatment of severe psoriasis, including the erythrodermic and pustular types. There are four FDA-approved retinoids available, but only three are used in the treatment of psoriasis. Isotretinoin is useful for acne and pustular psoriasis in monotherapy [66]. It can also be combined with PUVA and UVB for enhanced effects [67,68]. Etretinate and acitretin are the other two FDA-approved systemic retinoids for the treatment of psoriasis. Acitretin is the active metabolite of etretinate. Retinoids are highly teratogenic and persist in fatty tissue long after they are discontinued. Furthermore, etretinate was withdrawn from the market once the shorter-lived acitretin was introduced. All women considering this agent must be warned that retinoids should not be taken if they plan to become pregnant while they are taking this medication, or even 3 years after they discontinue the medicine. Most physicians expect patients to use some sort of birth control to prevent accidental pregnancy. Prolongation of retinoid teratogenicity may occur if acitretin is taken with alcohol because it is esterified to longer-lived etretinate [69]. Therefore, female patients of childbearing potential must also cease drinking and be watchful of over-the-counter medications and foods containing alcohol. Acitretin is usually well tolerated at low doses, but at doses of greater than 50 mg per day, mucocutaneous lesions may develop, including hair loss, dry lips, cheilitis, dry skin, and sticky skin (retinoid-type dermatitis). Elevation of serum lipids and liver function tests are common. Triglyceride elevation can be partially negated by use of gemfibrozil or atorvastatin [70]. No cases of hepatitis have been reported, but liver function should be monitored. Other concerns after long-term treatment with retinoids include the
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following: the development of pseudotumor cerebri, although this is rare and has only been associated with isotretinoin; osteoporosis [71]; and the development of ligamentous calcifications and skeletal abnormalities [72]. Despite these minor side effects, acitretin is a highly effective systemic treatment modality for severe erythrodermic or pustular psoriasis in monotherapy or in combination with other treatment modalities. Plaque and guttate psoriasis are slower to resolve with acitretin therapy alone. In combination with PUVA or UVB, however, excellent results can be achieved with lower doses of UV light [49,50,73]. One study showed that retinoids may suppress development of cutaneous malignancies associated with UVA [74]. Acitretin in combination with calcipotriol ointment has improved resolution of psoriatic plaques and reduces total cumulative dose of acitretin to reach clearance [75]. Cyclosporine Cyclosporine is an immunosuppressive agent originally created in the 1970s for the prevention of kidney transplant rejection. Its mechanism of action is not completely understood, but cyclosporine is known to cause inhibition of the antigenic response of helper T lymphocytes by reducing the production of interleukin 2 (IL-2) and interferon g (IFN-g). The oral microemulsion formulation is FDA-approved for the treatment of psoriasis in doses of up to 4 mg/kg daily. It is highly effective for all forms of psoriasis but must be administered by knowledgeable physicians [76,77]. Cyclosporine can cause nephrotoxicity, hypertension, hyperlipidemia, hypomagnesemia, hyperkalemia, increased susceptibility to infection, and malignancy. The risk of malignancy, however, probably is only increased in those patients who are undergoing long-term treatment. Skin cancer and lymphoproliferative disorders have been witnessed in transplant patients on long-term, high-dosage cyclosporine [78,79]. In patients treated with cyclosporine for RA for a mean of 1.6 years, but at an average dose of only 2.6 mg/kg daily, the incidence of malignancy was no different from that in the control group [80]. A recent report found that a patient treated for recalcitrant psoriasis with cyclosporine developed a primary, cutaneous, large T-cell lymphoma that resolved clinically and histologically with discontinuation of therapy after 2 months. The lymphoma recurred 3 years later, however [81]. The nephrotoxicity of cyclosporine is perhaps the most worrisome side effect of this powerful drug.
Histologic changes consistent with interstitial fibrosis and renal tubular atrophy have been demonstrated in individuals treated for more than 2 years [82,83]. Nephrotoxicity is best minimized by maintaining doses of less than 5mg/kg per day and monitoring serum creatinine for a change from baseline that is greater than 30%. Patients must also be monitored periodically for hypertension, although this common side effect can be alleviated by the addition of a calcium channel blocker. It has been suggested that calcium channel blockers may actually prevent cyclosporine nephrotoxicity [84]. Hyperlipidemia can be managed with a statin-type drug. Hyperkalemia can be avoided through low-potassium diets or the use of hydrochlorothiazide. Serum levels of cyclosporine are greatly affected by numerous medicines. With proper monitoring, however, cyclosporine dosage can be altered accordingly. Unlike methotrexate and acitretin, cyclosporine is not teratogenic and is not myelosuppressive [85]. Cyclosporine is a highly effective agent for the treatment of severe psoriasis. Debate concerning intermittent versus continuous treatment has resulted in numerous studies. The use of intermittent cyclosporine is recommended; although it may be less effective, the added side effects do not warrant continuous therapy [86,87]. The administration of cyclosporine should stop or be tapered once psoriatic clearance has occurred. Tacrolimus (FK506) Tacrolimus is a macrolide antibiotic used as an immunosuppressive agent for organ transplant. It is structurally distinct from cyclosporine but behaves in a similar manner by suppressing T-lymphocyte activation. When compared with cyclosporine, it is 100 times more potent in its ability to inhibit IL-2 and IFN-g secretion [88,89]. Tacrolimus is not FDA-approved for psoriasis but is indicated in the treatment of atopic dermatitis as a topical agent. Tacrolimus has a side-effect profile similar to cyclosporine. The monitoring of renal, hematopoetic, and hepatic function is necessary if a patient is put on tacrolimus. A multicenter, double-blind, placebo-controlled study involving 50 patients with severe recalcitrant plaque psoriasis demonstrated a significant improvement based on the Psoriasis Area and Severity Index [90]. The reported side effects were not severe. Greater experience needs to be gained with tacrolimus for the treatment of psoriasis. To date, no comparisons to cyclosporine have been undertaken in patients with psoriasis.
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Mycophenolate mofetil Mycophenolate mofetil is an oral immunosuppressive agent that is hepatically metabolized to its biologically active mycophenolic acid. It currently is FDA-approved for prophylaxis against rejection of organ transplants. Mycophenolate mofetil has been used to treat severe psoriasis, with long-term remission and minimal side effects [90,91]. Its mechanism of action is the noncompetitive inhibition of inosine monophosphate dehydrogenase, thereby preventing DNA synthesis and cellular proliferation. Its other non FDA-approved uses are for the treatment of bullous pemphigoid, pemphigus vulgaris, and atopic dermatitis. Like all immunosuppressive agents, its use must be monitored. Notably, nephrotoxicity is not associated with this drug. There is a risk of increased susceptibility to infection and malignancy, however [92]. Hydroxyurea Hydroxyurea is an antimetabolite that is FDAapproved for the treatment of cancer and sickle cell anemia. It inhibits ribonucleotide reductase, a crucial enzyme necessary for the conversion of DNA bases. Its use in the treatment of severe psoriasis is not FDA-approved, but it has a three-decade history as a monotherapy for psoriasis [93,94]. Doses needed to develop psoriatic improvement, however, cause nearly 50% of patients to experience bone marrow toxicity. In addition, long-term treatment has been associated with lymphoproliferative disorders [70]. Mucocutaneous lesions can also arise as a common side effect. 6-Thioguanine The agent 6-thioguanine is a purine analog that inhibits DNA and RNA synthesis by incorporating into native strands. It is an approved antineoplastic drug, with a nonapproved indication in the treatment of severe psoriasis. Its side effects primarily involve the gastrointestinal tract, but severe myelosuppression can occur. Furthermore, initial trials with 6-thioguanine were limited by bone marrow toxicity. Silvis and Levine [95] reported that weekly dosing could achieve similar clearance of psoriasis with nearly no myelosuppression. Sulfasalazine Sulfasalazine is a conjugation of 5-aminosalicylic acid and sulfapyridine. It is indicated in the use of
ulcerative colitis but also has been implemented in the treatment of psoriatic arthritis. The mechanism of action is unknown although it is believed to disrupt prostaglandin synthesis and the arachidonic acid pathway. Multiple double-blind studies have shown moderate results in the treatment of psoriatic arthritis. One study comparing cyclosporine versus sulfasalazine in 99 patients through an open, prospective, randomized, controlled format significantly demonstrated better results with cyclosporine [96].
Summary The prebiologic armamentarium discussed in this article has a significant role in certain patients for the treatment of psoriasis. With the creation of the newer biologics and their comparatively lesser toxicity, however, the treatment of psoriasis is being re-evaluated.
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[74] McKenna DB, Murphy GM. Skin cancer chemoprophylaxis in renal transplant recipients: 5 years experience using low-dose acitretin. Br J Dermatol 1999;140: 656 60. [75] van de Kerkhof PC, Cambazard F, Hutchinson PE, Haneke E, Wong E, Souteyrand P, et al. The effect of addition of calcipotriol ointment (50microg/g) to acitretin therapy in psoriasis. Br J Dermatol 1998;138: 84 9. [76] Ellis CN, Gorsulowsky DC, Hamilton TA, Billings JK, Brown MD, Headington JT, et al. Cyclosporine improves psoriasis in a double-blind study. JAMA 1986; 256:3110 6. [77] Ellis CN, Fradin MS, Messana JM, et al. N Engl J Med 1991;324:277 84. [78] Jensen P, Hansen S, Moller B, Leivestad T, Pfeffer P, Geiran O, et al. Skin cancer in kidney and heart transplant recipients and different long-term immunosuppressive therapy regimens. J Am Acad Dermatol 1999;40: 177 86. [79] Srivastava T, Zwick DL, Rothberg PG, Warady BA. Posttransplandt lymphoproliferative disorder in pediatric renal transplantation. Pediatr Nephrol 1999;13: 748 54. [80] van der Borne BE, Landewe RB, Houkes I, Schild F, van der Heyden PC, Hazes JM, et al. No increased risk of malignancies and mortality in cyclosporine Atreated patients with rheumatoid arthritis. Arthritis Rheum 1998;41:1930 7. [81] Corazza M, Zampino MR, Montanari A, Altieri E, Virgili A. Primary cutaneous CD30+ large T-cell lymphoma in a patient with psoriasis treated with cyclosporine. Dermatology 2003;206:330 3. [82] Zachariae H, Kragballe K, Hansen HE, Marcussen N, Olsen S. Renal biopsy findings in long-term cyclosporine treatment of psoriasis. Br J Dermatol 1997;136: 531 5. [83] Lowe NJ, Wieder JM, Rosenbach A, Johnson K, Kunkel R, Bainbridge C, et al. Long-term low-dose cyclosporine therapy for severe psoriasis: effects on renal function and structure. J Am Acad Dermatol 1996; 35:710 9. [84] Raman GV, Campbell SK, Farrer A, Albano JD, Cook J. Modifying effects of amlodipine on cyclosporine
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Dermatol Clin 22 (2004) 389 395
Quality-of-life issues in psoriasis

Rita Mukhtar, BA, Jane Choi, MD, John Y.M. Koo, MD*
Psoriasis and Phototherapy Treatment Center, Department of Dermatology, University of California, 515 Spruce Street, San Francisco, CA 94118, USA
Although most skin conditions are not life threatening, they can strongly affect how patients perceive and interact with their environment, giving such diseases the potential to alter every aspect of a patients life. There is a common tendency among the general public, health professionals, and policymakers, however, to view skin disease as merely a cosmetic problem. When it comes to determining morbidity, more weight is generally assigned to the physical sequelae of disease, based on the assumption that the psychosocial impact somehow deserves less attention. Increasingly, however, studies of psoriasis show that skin disease has serious consequences for those afflicted. Psoriasis, as a disease, typically affects the skin, but as an illness, it can affect a patients relationships, finances, leisure activities, and mental health. The words of one psoriasis sufferer illustrate the significance of the disease:
Skin is contact. It is my closest contact with my surroundings. Expressions of love, etc., revolve around skin. . . . it is frustrating to have a damper placed on ones contact with people. [1]
The visibility of skin gives it a prominent role in social interactions. One study examining the psychodynamic characteristics of life stressors raises this issue, suggesting that the skin lesions of psoriasis might not simply be of biologic significance but carry psychologic meaning as well [2]. Thinking about psoConflict of interest: Dr. Koo has been a clinical researcher, consultant, and speaker for Allergan, Amgen, Biogen, Bristol-Myers Squibb, Centacor, Connetics, Elan, Fujisawa, Galderma, Genentech, GlaxoSmithKlein, ICN, Novartis, and Roche. * Corresponding author. E-mail address: john.koo@ucsfmedctr.org (J.Y.M. Koo).
riasis in such terms can be helpful in formulating a concept of how a patient might experience the disease. Although clinicians who care for people with skin disorders are most likely to be cognizant of some of the difficulties their patients face, there remains a notable gap between the patients experience of disease and the dermatologists perception thereof. A comparison of physician and patient responses to surveys showed significant differences between physician and patient assessments of patient quality of life (QOL). Physicians tended to underestimate the impact of severe skin disease, and overestimate the impact of mild disease (the authors suggested that some patients might downplay morbidity as they become accustomed to having disease) [3]. Similarly, a survey of members of the National Psoriasis Foundation (NPF) revealed the prevalent view among patients that physicians fail to appreciate the full impact psoriasis has on their lives [4,5]. It is, then, the inner world of the patient with psoriasis to which clinicians need access. Understanding exactly how psoriasis affects the patient is the purpose of queries about QOL. It has been argued that QOL assessment is the most important measure of disease severity because reductions in QOL define the patients actual experience of living with the illness. The concept of quality of life attempts to account for several dimensions of well-being in an individual. The domains that are often assessed include physical, psychologic, social, and general well-being, and cognitive functioning [6]. Health-related QOL (HRQOL) is more narrowly defined and encompasses those factors specifically relating to the disease process or its treatment. In the absence of a permanent cure, as is the current case with psoriasis, the clinician strives to reduce the severity of disease with the goal of preventing reduction in QOL [7].
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Increasingly, QOL is being used as a measurement tool in the evaluation of health care outcomes [6]. Krueger et al [8] argued that although body surface area (BSA) is often used to define severity in clinical trials, such a definition fails to be sensitive to individual differences between psoriasis sufferers. Depending on which region of the body the psoriasis affects, a low BSA can correspond with very severe functional impairment, whereas a higher BSA can have very little impact on an individuals day-to-day life. For example, psoriasis affecting the dominant hand might receive a low BSA but hinder an individuals ability to perform basic tasks, whereas psoriasis affecting a larger region of the body, such as the back, might not affect functioning as much. Because it is ultimately the impact of psoriasis on activities of daily living that matters to patients, QOL becomes a critical measure of disease severity. Measuring QOL not only gives clinicians access to important information about the individual patient, it also allows for comparisons to be made between psoriasis and other chronic medical conditions. Knowing which diseases have the most impact on patient QOL helps ensure proper allocation of research and treatment resources. In addition, accurately measuring QOL allows clinicians to assess the efficacy of new therapies and provides a patient-oriented means of measuring disease status [9].
Generic measures that have been used in studies of psoriasis include the Short Form 36 Health Survey (SF-36), a commonly used survey developed as part of the Medical Outcomes Study, which consists of 36 questions that address eight domains of HRQOL [11]. These categories can be combined to create a physical component summary score and a mental component summary score, with higher scores indicating better HRQOL [12]. Like the SF-36, surveys such as the UK Sickness Impact Profile (UKSIP), the Nottingham Health Profile, and the General Health Questionnaire allow for comparisons to be made between different diseases but can often be quite long and time-consuming to complete [7]. Dermatologyspecific tools that have been developed are discussed in the following sections. Dermatology Life Quality Index Finlay and Khan [9] developed the Dermatology Life Quality Index (DLQI), a 10-item questionnaire with the aim of creating a simple, compact measure of QOL applicable to patients with any skin disease. A Spanish study using a translated version of the DLQI found it to be generally reliable, valid, and responsive to change [13]. A pediatric version of the DLQI also exists [7]. Dermatology Quality-of-Life Scales
Tools for measuring quality of life As the importance of measuring QOL has been increasingly recognized, researchers have developed several instruments to assess the impact of skin diseases, including psoriasis, on patients. These instruments can be divided into generic, specialty-specific, or disease-specific classes, such that an instrument might be applicable to patients with any systemic illness, patients with skin disorders in general, or patients with only psoriasis. In addition, questionnaires designed to measure HRQOL are categorized as either discriminative or evaluative. Discriminative instruments attempt to differentiate between individuals at one point in time, whereas evaluative instruments are useful in quantifying change in the same individuals over time [7]. To be useful, these tools must be valid, reliable, and responsive to change, meaning that they actually measure what is intended to be measured, yield consistent results on repeated use, and are able to detect clinically meaningful changes [10]. Using a general measure along with a psoriasis-specific measure has been recommended to better assess the full impact of psoriasis on HRQOL [6].
Developed from patient-generated items, the Dermatology Quality-of-Life Scales are intended to complement the DLQI with more emphasis on the psychosocial domain of QOL, with a psychosocial score composed of four subscales of embarrassment, despair, irritableness, and distress, along with additional items addressing physical activities and symptoms [14]. Next, this article discusses disease-specific assessments that focus on the effects of psoriasis on HRQOL. Psoriasis Disability Index The Psoriasis Disability Index (PDI), a 15-item questionnaire, was developed with patients who have psoriasis to assess QOL by looking at the following areas: daily activities, work or school matters, personal relationships, leisure, and treatment [15]. Patient scores on the PDI correlate with their scores on the UKSIP, a general measure of QOL, supporting the validity of the PDI in measuring QOL [16]. It has been argued, however, that use of the PDI in the United States might be limited by the disparity between the British patients with whom the test was
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developed and the typical American patient with psoriasis, as the differing structures of health care systems mean that dermatologists in the two countries have access to different populations. Although dermatologists in the United States treat many mild to moderate cases on an outpatient basis, dermatologists in the United Kingdom have more limited access to the average patient with psoriasis, instead seeing more patients on the severe end of the disease spectrum [5]. Psoriasis Quality-of-Life Questionnaire 12 The Psoriasis Quality-of-Life Questionnaire 12 (PQOL-12) is a 12-item self-administered, diseasespecific, psychometric instrument created to specifically assess those QOL issues that are most important to the largest proportion of patients with psoriasis. It was developed using both nationwide, randomized psoriasis population samples and multicentered clinical trial subjects [17,18]. The original 41-item, twofactor domain (psychosocial and physical) version was created by testing many questions in a sample of patients with psoriasis drawn from a nationwide survey [5]. Psychometric analysis showed the original PQOL-41 had satisfactory reliability, validity, and responsiveness to change [19]; however, it was too lengthy to be practically administered in a clinical setting and there was some overlap between its questions. Therefore, a three-center study to determine validity and correlation with the Psoriasis Area and Severity Index (PASI) was conducted. A total of 474 subjects participated who had disease ranging from mild to severe. As a result of this study, a shortened version of the questionnaire was developed that contained only 12 items with one factor/domain. The PQOL-12, produced by Koo et al [17,18], is a valid, reliable, and responsive subset of the original PQOL, with a Cronbachs a of 0.95 and a mean interitem correlation of 0.62. Because this instrument was purposely designed to assess issues that were scientifically proven to be of most relevance to the largest population of patients with psoriasis, it shows a predictable correlation with PASI. Simultaneous assessment of PASI and PQOL-12 demonstrated that for every 1-point increase in PASI score, the mean PQOL-12 score increased by 6 to 11 points. There was a similar correlation found with BSA measurements and simultaneously administered DLQI surveys. The PQOL-12 takes approximately 5 minutes to complete and is appropriate to use in both clinical practice and research. In addition, it can be used across the spectrum of disease severity.
Physical impact of psoriasis

You have a disgusting body covered by marks and lesions. You feel like a leper . . . I feel unclean and sticky. Touching the rash disgusts me. [1]
In Koos [5] nationwide population study, psoriasis sufferers reported that the worst and second worst things about psoriasis were (1) itching and scratching and (2) appearance. At least two other studies reported on the high prevalence of pruritus in psoriasis, with 76% of sufferers experiencing pruritus frequently or all the time in one study, and 79% reporting pruritus in another [4,20]. Itching and skin soreness have been found to have a negative impact on the mental component of the SF-36 [21]. Because of the high prevalence of pruritus and its negative impact on the QOL of psoriasis sufferers, it has been suggested that physicians pay more attention to controlling this symptom [22]. In addition, Krueger et als [4] survey of the NPF found that 94% and 71% of patients experienced scaling and skin redness, respectively, with 39% of the total group describing involvement of more than 10% of their bodies. The location of these physical signs affects how the patient feels emotionally, with more discomfort resulting from the involvement of the face, scalp, or hands [1]. Messy, sticky, and malodorous treatments can be physically unappealing for patients as well [23]. Those individuals with psoriatic arthritis face additional physical challenges. The NPFs 1998 survey reported that roughly two thirds of these patients have difficulty using their hands, standing for long periods of time, and ambulating [4].
Mental health impact of psoriasis

I often have a feeling of being inadequate. The disease brings defeat after defeat. I am ashamed of being different. [1]
Research has shown that psoriasis has deleterious effects on an individuals psychosocial functioning. In a national study in which 67% of the original 50,000 subjects returned surveys, people with psoriasis were more likely to feel self-conscious, helpless, embarrassed, angry, and frustrated than those without psoriasis. Those who considered their psoriasis to be more severe were more likely to feel uncomfortable or apprehensive about their appearance [5]. Patients with psoriasis also report significant levels of social embarrassment, life disruption, and social withdrawal [24].
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In a study of 64 patients with psoriasis, 56% reported being markedly to extremely anxious and 46% reported moderate to extreme depression during flares of the disease. During these periods of exacerbation, 33% of patients remained housebound, with 15% of patients being essentially housebound even in between flares [24]. McKenna and Stern [25] followed up with 1113 patients who had previously been enrolled in the long-term psoralen plus ultraviolet A light, or PUVA, cohort study in 1976. Of those patients, 44% felt physically unattractive, sexually undesirable, or both, whereas 29% felt shame or embarrassment because of their psoriasis. As selfreported disease severity increases, so does use of alcohol, cigarettes, tranquilizers, sleeping pills, and antidepressant drugs [26]. Of particular concern is the increased depression and suicidal ideation found in patients who have psoriasis. Psoriasis sufferers have significantly higher rates of depression and problems with body cathexis than do control subjects [27]. One small-scale study found a 37% prevalence of depression in its sample of psoriasis sufferers, and an association between active flares of skin lesions and higher stress levels, suggesting that stress might play a causal role in psoriasis activity and initiate a self-perpetuating cycle of stress, flare, and subsequently, more stress [28]. Krueger et al [4] found that in those patients aged 18 to 34 years, 54% reported feeling depressed. Another study found links between pruritus, sleep difficulties, and depression, and reported that active suicidal ideation is found in more than 5% of patients with psoriasis [29]. Similarly, Gupta and Gupta [30] found a 5.5% prevalence of acute suicidal ideation and a 9.7% prevalence of a death wish in patients with psoriasis. One gets a sense of just how life-altering psoriasis can be by how much time and money patients would be willing to invest in a cure. Forty-nine percent of patients surveyed were willing to spend 2 to 3 hours each day on treatment if it would result in normal skin for the rest of the day [31]. In another study, patients with psoriasis were willing to pay 9% to 14% of their income each month for a cure, roughly the same amount patients with asthma were willing to pay [32].
Social interactions and psoriasis

I want to do many things; I want to be a positive person and talk to other people. But the psoriasis stops me from seeking the contact I want with others. Im afraid of rejection . . . I feel sort of alone with my disease . . . I also feel like I want to hide. [1]
Many studies have shown that the shame and embarrassment patients with psoriasis feel does not evolve simply out of self-consciousness but from actual experiences of rejection from others. Krueger et al [4] found that 40% of those with severe psoriasis had experienced problems receiving equal service or treatment in places like hair salons, barbershops, public pools, and health clubs. In a study of 137 patients with moderate to severe psoriasis, Gupta et al [33] found that 26.3% of patients with psoriasis had had an episode in the previous month where people made a conscious effort not to touch them. Although these experiences can depend on the patients perception of the social interaction, Ginsburg and Link [34] reported that 19 of 100 subjects studied had experienced a total of 50 episodes of frank rejection from a gym, pool, hairdresser, or job, despite the fact that many of these patients with psoriasis avoid these places to begin with for fear of such reactions. Even in their intimate personal relations, sufferers are not spared the negative impact of their disease. Of 120 patients with psoriasis surveyed, 40.8% reported being affected sexually, with a decline in the amount of sexual activity. These patients reported more joint pains, somewhat increased severity of disease affecting the groin region, greater scaling, and greater pruritus severity than psoriasis sufferers who were not affected sexually. Sixty percent of those affected attributed the decline in their sexual activity to the appearance caused by their psoriasis [35]. Patients with psoriasis often respond to difficulties in social interactions by avoiding them altogether. They engage in anticipatory and avoidant behavior, such as not going to a swimming pool, even if they havent experienced rejection previously [29]. The stress of avoiding negative reactions from others has a huge impact on the psyche of patients with psoriasis. Furthermore, stress resulting from anticipating other peoples reactions to psoriasis has been found to have more effect on day-to-day QOL than any other factor taken into consideration, including medical and health status [36]. This finding has led Lebwohl and Tan [37] to argue that interventions that can reduce this fear of negative evaluation can improve patient QOL. Several studies have shown that younger patients with psoriasis are more acutely affected by the difficulties they face in social interactions than older patients. Patients aged 18 to 54 years report a greater impact of psoriasis on the psychosocial aspects of their lives than do respondents aged 55 years and older, describing more difficulty in sexual activities, embarrassment, feelings of being unattractive, and frustration [4,26]. Gupta and Gupta [38] reported that
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patients aged 18 to 45 years have more problems with appearance, socialization, occupation, and finances than those older than 45 years. Younger patients also have been found to be less compliant than older patients [39]. The increased QOL impact of psoriasis coupled with poor compliance warrants clinicians paying particular attention to younger patients, especially children and adolescents [40]. Seeking social support, expressing emotions, telling others that psoriasis is not contagious, and endorsing beliefs in the controllability of the disease lessen the negative impact of psoriasis on QOL [41 43]. Furthermore, the following have been found to be significantly associated with a negative impact on QOL: telling others about psoriasis without addressing its noninfectious nature, covering the lesions, and avoiding people [41].
the cost of psoriasis treatment but also spend more time caring for psoriasis. In addition, they perceive more interference with work and activities around the home [44].
How psoriasis compares with other diseases Using the SF-36 to compare QOL impact between different conditions, Rapp et al [21] found that patients with psoriasis report reductions in physical functioning and mental health comparable to that seen in patients with cancer, arthritis, hypertension, heart disease, and diabetes. Furthermore, patients with psoriasis had among the lowest SF-36 scores of all groups. Only patients with congestive heart failure scored lower on the physical component score, and only patients with depression or chronic lung disease scored lower on the mental component score [20]. The negative effects of psoriasis on the physical, psychologic, and social aspects of life can be worse than those caused by life-threatening illnesses [22]. For a sense of comparison, 46%, 42%, and 32% of severe psoriasis sufferers considered it better or the same to have diabetes, asthma, or bronchitis, respectively. Of those subjects who happened to have both psoriasis and the comparative disease, the percentages rose to 87%, 80%, and 77%, respectively [29].
Financial impact of psoriasis

The only thing you think of is scratching, bathing, and putting on ointment, then putting on more ointment, bathing, scratching, and slathering on ointment yet again. Its in your head 24 hours a day. [1]
Psoriasis presents direct costs to the patient and health care system in terms of treatment and indirect costs in terms of time lost from work and difficulties with employment in general. In 1993, the outpatient cost of psoriasis in the United States was conservatively estimated to be between 1.6 and 3.2 billion dollars annually. The mean annual direct cost for an individual patient is estimated at $800 per year [44]. In one study, of the 54% of subjects who were not working or retired, 34% attributed their employment status to their psoriasis. Of those who were working, 59.3% had lost a mean of 26 days from work during the previous year because of their disease [31]. In addition, patients with severe psoriasis rate the quality of their work life lower than do control subjects [44], and 6% report discrimination at work [4]. Men tend to have greater work-related stresses because of their psoriasis than do women, reporting more fear of losing their job and more criticism for taking time off to go to medical appointments [38]. Psoriasis can, in fact, be so severe as to make working impossible for some patients [22]. The financial effects of psoriasis overlap with other aspects of QOL as well, with one study finding that unemployed patients suffer from more desquamation than employed patients [21]. Patients with lower family incomes not only are more affected by
Summary A preponderance of evidence clearly shows that understanding the true impact of psoriasis on patients requires assessing their QOL. Better QOL tools are necessary to further reduce the gap that exists between patient experience and clinician perception of the illness. Knowing the impact of disease on QOL can help clinicians and patients when grappling with treatment options and performing risk benefit analyses. Using tools like BSA measurements only skim the surface without really getting to the core of the illness [45]. HRQOL measurements reveal that psoriasis sufferers face challenges that demand that psoriasis be viewed and aggressively treated as a serious disease. Patients with psoriasis deserve as much attention from clinicians and policymakers as patients with other systemic illnesses. It is hoped that such mindfulness will lead to better treatments and increased public awareness of this noncontagious, disabling disease. This result, in and of itself, might help ameliorate some of the negative impact of the disease.
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R. Mukhtar et al / Dermatol Clin 22 (2004) 389395 [15] Finlay AY, Kelly SE. Psoriasis an index of disability. Clin Exp Dermatol 1987;12:8 11. [16] Kent G, Al-Abadie M. The Psoriasis Disability Index further analyses. Clin Exp Dermatol 1993;18:414 6. [17] Koo J, Menter A, Lebwohl M, et al. The relationship between quality of life and disease severity: results from a large cohort of mild, moderate, and severe psoriasis patients [abstract]. Br J Dermatol 2002;147:1078. [18] Koo J, Kozma CM, Menter A, Lebwohl M. Development of a disease specific quality of life questionnaire: the 12-item Psoriasis Quality of Life Questionnaire (PQOL-12). Presented at the 61st Annual Meeting of the American Academy of Dermatology. San Francisco, March 21 26, 2003. [19] Koo J, Kosma CM, Reinke K. The development of a disease-specific questionnaire to assess quality of life for psoriasis patients: an analysis of the reliability, validity, and responsiveness of the psoriasis quality of life questionnaire. Dermatol Psychosom 2002;3:171 9. [20] Fortune DG, Richards HL, Main CJ, Griffiths CE. What patients with psoriasis believe about their condition. J Am Acad Dermatol 1998;39:196 201. [21] Rapp SR, Feldman SR, Exum ML, Fleischer Jr AB, Reboussin DM. Psoriasis causes as much disability as other major medical illnesses. J Am Acad Dermatol 1999;41(3 pt 1):401 7. [22] de Arruda LHF, de Moraes APF. The impact of psoriasis on quality of life. Br J Dermatol 2001; 144(Suppl 58): 33 6. [23] Leary MR, Rapp SR, Herbst KC, Exum ML, Feldman SR. Interpersonal concerns and psychological difficulties of psoriasis patients: effects of disease severity and negative evaluation. Health Psychol 1998; 17(6):530 53. [24] Fried RG, Friedman S, Paradis C, et al. Trivial or terrible? The psychosocial impact of psoriasis. Int J Dermatol 1995;34(2):101 5. [25] McKenna KE, Stern RS. The impact of psoriasis on the quality of life of patients from the 16-center PUVA follow-up cohort. J Am Acad Dermatol 1997;36(3 pt 1): 388 94. [26] Zachariae R, Zachariae H, Blomqvist K, Davidsson S, Molin L, Mork C, et al. Quality of life in 6497 Nordic patients with psoriasis. Br J Dermatol 2002; 146:1006 16. [27] Devrimci-Ozguven H, Kundakci N, Kumbasar H, Boyvat A. The depression, anxiety, life satisfaction and affective expression levels in psoriasis patients. J Eur Acad Dermatol Venereol 2000;14:267 71. [28] Harvima RJ, Viinmaki H, Harvima IT, Naukkarinen A, Savolainen L, Aalto M, et al. Association of psychic stress with clinical severity and symptoms of psoriatic patients. Acta Derm Venereol [Stockh] 1996;76:467 71. [29] Griffiths CE, Richards HL. Psychological influences in psoriasis. Clin Exp Dermatol 2001;26(4):338 42. [30] Gupta MA, Gupta AK. Depression and suicidal ideation in dermatology patients with acne, alopecia, atopic dermatitis and psoriasis. Br J Dermatol 1998;139: 846 50.
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[39] Richards HL, Fortune DG, OSullivan TM, Main CJ, Griffiths CEM. Patients with psoriasis and their compliance with medication. J Am Acad Dermatol 1999; 41(4):581 3. [40] Perrott SB, Murray AH, Lowe J, Mathieson CM. The psychosocial impact of psoriasis: physical severity, quality of life, and stigmatization. Physiol Behav 2000;70:567 71. [41] Rapp SR, Cottrell CA, Leary MR. Social coping strategies associated with quality of life decrements among psoriasis patients. Br J Dermatol 2001;145:610 6. [42] Wahl A, Hanestad BR, Wiklund I, Moum T. Coping and quality of life in patients with psoriasis. Qual Life Res 1999;8:427 33. [43] Scharloo M, Kaptein AA, Weinman J, Bergman W, Vermeer BJ, Rooijmans HGM. Patients illness perceptions and coping as predictors of functional status in psoriasis: a one-year follow up. Br J Dermatol 2000; 142:899 907. [44] Feldman SR, Fleischer AB, Reboussin DM, Rapp SR, Bradham DD, Exum ML, et al. The economic impact of psoriasis increases with psoriasis severity. J Am Acad Dermatol 1997;37:564 9. [45] Kirby B, Richards HL, Woo P, Hindle E, Main CJ, Griffiths CEM. Physical and psychologic measures are necessary to assess overall psoriasis severity. J Am Acad Dermatol 2001;45:72 6.
Dermatol Clin 22 (2004) 397 406
Phototherapy arsenal in the treatment of psoriasis

Michael Zanolli, MDa,b,*
b a Dermatology Consultants, PC, 4230 Harding Road, Suite 609 East, Nashville, TN 37205, USA Division of Dermatology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
An essential method of treatment for psoriasis vulgaris in the twenty-first century will remain the option for UVB light therapy and photochemotherapy. During the last half of the twentieth century, the use of UVB therapy was one of the mainstays of treatment for psoriasis. During the last quarter century, photochemotherapy in the form of psoralen plus UVA (PUVA) emerged as one of the most effective modalities of treatment for psoriasis. Accompanying the advent of the most recent era of psoriasis with targeted biologic therapies has been a decline in the frequency of phototherapy. This does not diminish its known clinical effects and, because of a better understanding of photobiology, the therapeutic approach to treatment of psoriasis with UV light has a common basis for treatment of psoriasis along with and in combination with new biologic agents [1]. Individuals affected with psoriasis vulgaris know the natural effect of sunlight can improve psoriasis in most cases. This use of limited amounts of natural sunlight will continue as a practical approach to treatment of psoriasis for patients. Refinement of the delivery and methods for the most effective wavelengths of UV light in treating psoriasis will continue into the twenty-first century. This is evidenced by the continued prevalence of the availability of narrowband UVB, which has been recognized as more effective than broadband UVB, in addition to the devices that deliver the most effective range of UV light to the skin in a localized manner. The efficacy of PUVA for the treatment of psoriasis has not been surpassed by any other form of phototherapy. It still plays a significant role, especially in extensive resis-
tant psoriasis, and can be used with precautions and limitation of total dose with excellent response. The long-term experience with the use of photochemotherapy has been important in helping to understand potential risks and side effects for that modality. It is similar to other psoriasis treatments in that caution must be used when PUVA and other forms of photochemotherapy are used.
Natural phototherapy Natural sunlight for treatment of psoriasis has been used throughout the ages, even before the advent of Westernized medicine. It is common knowledge, evidenced by experience and observation, that a vacation to more southern latitudes or to areas of recreation, such as beaches, tends to help patients with psoriasis and in many cases contributes part of an annual practice to help clear up limited thin plaque-type psoriasis. The closer one is to the equator and the lower the latitude, there is more energy in the terrestrial light in UVB range. This is caused by the angle of incidence of the sun to the earths surface. As such, there are special geographic locations in the world today that further enhance the effects of UV light and are frequently used as a therapeutic approach to treatment. Specifically, the UV light that reaches the earths surface at the Dead Sea, which is below sea level, is unique in its spectrum [2]. Because the Dead Sea is below sea level, the terrestrial light at this location has less of the 290 to 300 nm wavelengths of light. This slight shift in the spectrum more toward the mid range of UVB enhances the ability for a person to incur less sunburning and obtain more therapeutic UVB as it relates to treatment of psoriasis. This is very beneficial because of the known enhanced effects of wavelengths closer to
* Dermatology Consultants, PC, 4230 Harding Road, Suite 609 East, Nashville, TN 37205. E-mail address: mzanolli@stthomas.org
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M. Zanolli / Dermatol Clin 22 (2004) 397406
310 to 315 nm. One can consider the Dead Sea to be more of a natural location for therapeutic UVB unique in the world. Use of this therapeutic spa and scientific investigations that have been ongoing for decades at the Dead Sea attest to this being a very special place to receive UV light in combination with the specialized salts found in the Dead Sea. The remissions obtained and the clearing percentage for persons attending the spa for 2 to 4 weeks has not been achieved at any other natural therapeutic resort for treatment of psoriasis.
Artificial UVB A mainstay of therapy for psoriasis during the midportion of the twentieth century was the use of UVB produced by an artificial light source, either alone or in combination with other agents. The refinement of this modality of therapy using either a discontinuous spectrum from hot quartz lamps or the use of fluorescent tubes has gradually evolved and facilitated ease of use in an office-based setting. The current mainstay of therapy for office-based UV light is the fluorescent tube. The fluorescent tube has the benefit of ease of mass production and depending on the phosphor used to line the inner surface of the fluorescent tube, can also have more specific emissions spectrum. The broad-spectrum fluorescent tubes remain important and contain a relatively wide range of UV light. They contain higher-energy, lower-frequency UV light, and carry a greater potential for a sunburning-type reaction and erythemogenic response. The availability of narrowband UVB on a commercial scale was made possible because of the specialized lamps produced by Phillips having the narrow spectrum between 300 and 313 nm. Because of their specialized use, however, the production of these lamps has not been a major emphasis by this company. The lamps have a relatively shorter working life of 500 to 1000 hours of operation as compared with the more durable broader-spectrum UVB lamps that can maintain fairly consistent output with thousands of hours. This fact requires that the narrowband UVB lamps be replaced more often because their fluence diminishes with less use as compared with broad-spectrum UVB lamps. Traditional broadband UVB therapy The use of conventional broadband UV light therapy is dependent on an induction phase during the initial response with thinning of the psoriatic plaques and then a variable duration of approximately
15 to 25 treatments before full therapeutic efficacy. The most efficient approach to treatment with any UVB protocol for the practitioner is first to determine the minimal erythema dose (MED), which is dependent on the response a person experiences to that particular light unit. The determination of the MED shows a dose response and allows for more precise and more aggressive therapy with UVB, which facilitates more rapid clearing and better final results. Investigation comparing erythemogenic and suberythemogenic UVB delivery demonstrates that the more aggressive monotherapy with broadband UVB produces a quicker response rate and a better overall response. With that type of approach, however, patients may experience mild discomfort because of the pink erythema that is consistently produced by the advancement of therapy on a daily basis. Patients can improve while undergoing broadband UVB light therapy without having to incur the maximal MED on each visit [3]. It is customary to obtain a MED and proceed by starting at 70% to 75% MED and increasing by up to 50% of the MED each visit. Aggressive treatment with UVB therapy is possible because the maximal erythema reaction of the effects of UVB on the skin is seen between 12 and 18 hours. Patients demonstrate the reaction on their return even if treatments are given on consecutive days. Such an aggressive treatment protocol customarily uses an average of 15 to 25 treatments during the course of therapy to achieve maximal benefit. Protocols and approaches to treatment may vary from region to region and a more simplified and slightly less aggressive approach to treatment for broadband UVB is set forth in Box 1. Narrowband UVB Narrowband UVB has finally achieved general recognition in North America as advancement in the further refinement of UV therapy for treatment of
Box 1. Broad band UVB protocol by Minimal Erythma Dose (MED) 1) Obtain MED using the following doses (mj/cm2): 20, 40, 60, 80, 100, 120 2) Start at 70% of MED 3) Increase by 20% of MED each treatment 4) Treatment frequency of 3 5X/week
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psoriasis. Before the availability of narrowband UVB in North America in 1998, Europeans had been using narrowband UVB with regularity and good success. The original reports reflecting the efficacy and preference of narrowband UVB emerged in the mid1990s. Comparison trials with right- and left-sided controls on the same individual demonstrated that narrowband UVB is more effective than broadband UVB and eliminated the need to produce erythema at each visit [4 6]. Delivery of broadband UVB is best initiated with determination of the MED, as with any UVB treatment. This is especially important because the dosimetry between the broadband and narrowband is different and to be able to have a dosage measured in millijoule per square centimeter, one needs to have the proper photometers or accurate readings of the irradiance from the lamps themselves provided by the manufacturer. This information enables one to deliver incremental doses just below the range known to cause erythema for the Fitzpatricks skin type determination of patients being treated. This is important because the more limited wavelengths of the narrowband spectrum emitted by these specialized fluorescent tubes require a much higher energy because of the absence of the more erythemogenic shorter wavelengths from 310 nm and below. The dosage range for the determination of MED by skin type is included in Box 2. There can certainly be production of erythema using narrowband UVB, and this is also on a reproducible dose response curve in an individual. As with any erythema dose response within the UV range, the higher the skin type, the higher the average mean of the millijoule per square centimeter is needed to produce erythema. Each skin type has a broader range for MED with narrowband UVB than with broadband UVB, which further illustrates the importance of determining MED before initiation of a treatment protocol. A series of experiments done in the 1990s to maximize therapeutic benefits of narrowband UVB shows therapy done three times weekly is essentially as effective as broadband UVB done five times per
Box 3. Narrow band UVB protocol by Minimal Erythma Dose (MED) 1) Obtain MED 2) Start at 50% of MED 3) Increase by 10% of MED each treatment 4) Treatment frequency of 3 4X/week week and is certainly more convenient for the patient [7]. A more aggressive approach that maximizes the erythemogenic potential of narrowband UVB does not offer substantial benefit over trying to maximize the amount of erythema produced at each visit. The less aggressive approach is certainly preferred by the patients receiving treatment. The use of lubricants that help transmit UV light on top of the skins surface and decreases reflectance from the psoriatic scale is also considered standard therapy. The protocol for the use of narrowband UVB in an office-based setting is outlined in Box 3. There is some variability of the starting dose of narrowband UVB, either at a more conservative 50% or slightly more aggressive 70% of the MED. The onset of erythema following narrowband UVB occurs within 8 to 24 hours. One of the practical advantages of using limited narrowband UVB wavelengths delivered to the skin surface is that phototoxic or photoallergic drug reactions do not occur as frequently as with the broaderspectrum broadband UV, and with UVA light used with photochemotherapy. There have been reports of photoallergic reactions in patients who are receiving narrowband UVB, but the occurrence of drug reactions while receiving narrowband UVB is uncommon. Localized UVB The traditional use of localized delivery of UV light for treatment of hands and feet has been facilitated by the availability of 2- to 3-ft fluorescent tubes with broadband wavelength. Similar systems are used for localized bath PUVA therapy with irradiation or systemic PUVA with irradiation of just the hands and feet. The use of UVB for hyperkeratotic thick plaques on the distal extremities has limited response, and combination therapy with a systemic retinoid is frequently used to enhance the efficacy of the treatments. There is more success with the use of systemic administration of psoralen with localized delivery of UVA to the hand and feet but this approach also is enhanced with addition of systemic retinoids to
Box 2. Dose range for MED testing for narrow band UVB
Six test sites of 1.5 cm2 each For skin types I III (mj/cm2): 400,
600, 800, 1000, 1200, 1400

For skin types IV VI (mj/cm2): 600,
800, 1000, 1200, 1400, 1600
400
decrease the thickness of the plaques before and during phototherapy. The application of localized delivery of laser light near the optimal wavelength for maximal efficiency in the treatment of psoriasis led to clinical investigations regarding the excimer laser for treatment of psoriasis [8]. Because noninvolved skin is left unirradiated, this offers the opportunity to test for the optimal method of delivery and dose for treatment of psoriasis without involving the surrounding skin. Using multiples of the MED when treating psoriasis has been found to enhance the benefits and therapeutic response to laser light. The durability of the clearing was also correlated with the more aggressive treatment using 4x, 6x, and 8x multiples of the MED. As expected, using multiples of the MED produced very pronounced effects of marked erythema and blistering at the sites of delivery, although scarring at the sites was not observed. Another aspect of this approach to treatment is the reduction in the number of treatments needed to achieve the response [9]. Generally 8 to 10 treatments can attain clearing of plaques. Continued experience with this method of treatment using multiples of the MED with localized treatment makes it obvious that certain locations tolerate a higher dose of UV light, such as the knees and elbows. In those locations multiples of 6 to 8x MED should be used as compared with 4 to 6x MED on more sensitive non-UV hardened skin, such as the intertriginous skin or buttocks. The same principles used with the laser-generated coherent light at 308 nm have been applied to the localized delivery of broader band UVB generated by a filamentous light source delivered through optics to a small spot target area. Less complicated technology using a high-intensity lamp as the light source has been developed and brought to the market for treatment of psoriasis and other photoresponsive dermatoses. The two main devices are being marketed through Lumenis and Theralight corporations. There are differences between the coherent light at 308 nm from the excimer laser and the range of the UVB delivered by the other localized delivery systems for UVB. Both light units have the same filamentous light source, but the Lumenis system, B Clear, transmits the light through a fiberoptic cable to a very functional handheld delivery, whereas the Theralight unit uses a liquid medium in a flexible cable to a cylindrical pencil-grip type handpiece. The Theralight system has the ability also to switch to a low-fluence UVA if localized PUVA is a consideration for therapy. Basic principles of localized delivery of UVB are the same as with the excimer laser. First, an MED needs to be obtained; then, choices for the multiple of
the MED to be used for the site to be treated are selected by the clinician. The actual setting on the device is very easy to determine on the Lumenis system, which gives a numerical reading of the actual dose to be delivered. The Theralight system requires reference to a chart to set the machine, but follows the same principles of the multiples of the MED. Once a phototherapist becomes accustomed to the use of any of the devices the actual operation becomes routine.
Photochemotherapy The development of photochemotherapy for treatment of psoriasis comprises a major advance in therapy and efficacy of treatments for psoriasis worldwide. For centuries it was known that agents with photosensitizing compounds in the class of psoralen drugs could be used for treating vitiligo and other skin disorders. The discovery, however, that the ingestion of certain psoralen molecules when combined with UV light has dramatic effects on psoriasis improved the effective available treatments further. These advances were championed primarily in the United States by Fitzpatrick and Parrish but also were recognized by European colleagues who developed the use and protocols for delivery of PUVA [10]. This therapy generated intense clinical research during the late 1960s and early 1970s. One reason that photochemotherapy is so important is that the duration of remission following clearing with PUVA is more durable than with UVB light. Refinements of photochemotherapy and improvements in the bioavailability of the chemical after ingestion help make this therapy one of the standard treatment options in the arsenal for treatment of psoriasis. Specifically in North America, 8-methoxypsoralen has been the psoralen used for PUVA therapy. In Europe this has also been a mainstay but there has been more use in the recent decade of 5-methoxypsoralen, which has therapeutic efficacy and fewer gastrointestinal side effects [11]. As with the acceptance of UVB therapy for treatment of psoriasis, the adoption and development of photochemotherapy occurred because of the observed beneficial therapeutic effect on people with psoriasis. The exact mechanisms of the psoralen molecule as it relates to treatment of psoriasis have not been entirely clear. In fact, further insights are gained into the mechanism of action for both UV light and photochemotherapy because of a better understanding of the pathogenesis of psoriasis. The known effects of photochemotherapy are dependent on both the availability of the psoralen molecule at the site of action
401
and stimulation by wavelengths of UV light within its absorption peaks. It is known that the psoralen molecule intercalates between DNA base pairs through a concentration gradient. There is no biochemical interaction between the psoralen molecule and DNA itself without activation or absorption of photons of UV light. If there is absorption of photons of UV light there is a photochemical reaction with the psoralen molecule and a pyrimidine base and DNA cross-links can occur. For a true cyclobutane ring to form another photochemical reaction must occur. If a cross-link does form, this is one of the theoretical reasons for increased development of squamous cell carcinomas with repetitive therapy over years. A second mechanism of action of PUVA therapy on inflammatory skin disorders is oxygen-dependent photochemical reactions (ie, reactive oxygen species are formed when the psoralen molecule absorbs photons in the presence of oxygen). This type of oxygen-dependent reaction causes membrane and cell damage and may be central to the observable effects of UV light on the skin. It seems that antigenpresenting cells and T lymphocytes are more susceptible to these oxygen-dependent reactions than keratinocytes, and the underlying mechanism of action of psoriasis photochemotherapy may be inhibition of immune activation and immune recruitment of additional T cells into the skin [12]. Taking this one step further one could speculate that long-term remissions induced by PUVA may be caused by depopulating the epidermis of antigenpresenting cells, natural killer T cells, and cutaneous lymphocyte antigen (CLA)-positive lymphocytes. These effects decrease the recruitment of additional cells and reduce the stimulus for the ongoing psoriasis reaction instead of just interfering with the activation of lymphocytes or cytokine messaging. A short-term remission is expected if message interference occurred. A long-term remission is expected if the cells stimulating the reaction of T lymphocytes and immune competent cells in the epidermis and dermis are reduced in number or eliminated. The use of PUVA gained more widespread availability throughout the last quarter of the twentieth century in North America. It is still a vital tool in therapy, but the availability of PUVA has declined over the past decade for two main reasons. First, other therapies have become available that are potent and modify the immune system. Examples are the known effect of the cyclosporine class of drugs and more recently the biologic protein medications that show efficacy without the need for specialized equipment and specialized personnel. The second reason is the 30 years of experience with PUVA and the known
increased risk of squamous cell carcinoma that occurs especially in fair-skinned individuals with greater than 250 treatments over time [13]. There have been reports also of increased risk of melanoma in this special population by following over three decades a cohort of patients registered in North America [14]. This group of patients has confounding factors, such as other treatments for psoriasis including systemic immunosuppressive therapy and the fact that the early protocols for PUVA used high-dose PUVA, which is not done to such a degree today. Nonetheless, now that these important observations and statistical analysis of a specialized group of patients have been done, clinicians are better able to use this tool in a way that is safer and with parameters that help ensure the overall well-being of patients. Precautions and limitations of the use of PUVA over time are listed in Box 4. The delivery of PUVA is more complicated than UVB therapy even though both must have ocular protection to prevent corneal burns in the case of UVB and lens and retinal changes more specifically with the use of PUVA. PUVA requires additional protection from any other sources of UVA light for 18 to 24 hours following treatment. In my opinion, PUVA has been a great success story in preventive medicine over time because of the awareness of the potential for ocular side effects and the institution of standardized protocols and mechanisms for proper eye protection following a treatment. A manageable but frequent side effect of psoralen is caused by the nausea that the psoralen compound commonly produces especially with the use of 8-methoxypsoralen. There is a dose-response relationship with the degree of nausea that occurs and peak blood levels of the psoralen compound that occasionally is so pronounced that patients withdraw from therapy. Management of the nausea is to take the psoralen exactly the same way at the same time of day, preferably in the afternoon, and to have a small bit of food with the psoralen dose [15]. A slight reduction in the dose can also be attempted; however,
Box 4. Precautions in selection of PUVA patients

Skin types I and II Previous history of skin cancer Previous or current immunosuppres-
sive therapy
Cumulative number of previous
PUVA treatment >200
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Box 5. PUVA protocol by skin type 1) Dose of 8-MOP = 0.5 mg/kg 2) Ingest psoralen 1.5 hours prior to treatment 3) Take psoralen at same time of day with liquid 4) If nausea take psoralen with some food 5) Dose of UVA Skin type I III Initial = 2 J/cm2 Skin type IV VI Initial = 4 J/cm2 Increase by 1 J/cm2 each treatment 6) Frequency of treatments 3X/week
therapeutic effect while reducing the dose and total number of treatments required for response. This section highlights the best and most common combination therapies to use with phototherapy and specifies important nuances in understanding the maximum benefit and the most efficient delivery of the combinations. Topical agents plus phototherapy Patients must understand that certain topical agents used with phototherapy may either inhibit the effects of the UV light by blocking UV light at the surface of the skin and not allowing it to penetrate to the proper site of action or inactivate the drug through absorption of UV light. Topical steroids are still the most common treatment for mild plaque-type psoriasis and can be used safely in combination with phototherapy. Although there might be some initial reduction in the thickness and a more rapid initial response for plaque-type psoriasis, continued use of the topical steroids throughout the course of a full therapeutic regimen with UVB does not necessarily add much long-term benefit. When superpotent topical corticosteroids are used, a regimen of using the initial treatment for induction followed by tapering and discontinuation of topical steroids should be used. This is the most effective approach to combination treatment and seems to have the best initial benefit. Calcipotriene with both UVB and PUVA therapy has also been used. Calcipotriene can enhance phototherapy; however, certain precautions must be taken to ensure that their combined use does not inhibit or alter the calcipotriene molecule. Specifically, if calcipotriene is applied immediately before UV light therapy, inactivation of the molecule may result. To realize the enhanced effect of this topical combination with phototherapy, one should deliver the UV light treatment first and then use the topical agent later that day or at least 2 hours before treatment [17]. This helps ensure the modest benefit that might be obtained with this combination therapy. Topical formulations of retinoids have also been used to help enhance the effects of UV therapy [18]. As with the vitamin D derivatives, application should not immediately precede the delivery of the UV light. Caution should be used when advancing the dose of UVB or PUVA in this circumstance because of the retinoid effect on the plaques of psoriasis. Systemic retinoids plus UV therapy The best combination therapy with UV light, whether UVB or PUVA, is with systemic retinoids
care must be taken not to reduce the dose below the therapeutic range. There is variability from person to person in the gastrointestinal absorption of the psoralen molecule. The range for dosing and the timing of dosing should remain constant for each individual throughout their particular course of therapy. Although protocols vary between regions of the country and between continents, one of the standard protocols is included in Box 5. Different psoralen molecules have been used in Europe primarily to reduce the gastrointestinal side effects while maintaining efficacy. The most widely used psoralen molecule besides 8-methoxypsoralen is 5-methoxypsoralen. It still has potential to form cyclobutane rings and with excessive long-term use is also expected to increase the risk of squamous cell carcinoma. The efficacy of 5-methoxypsoralen is approximately that of 8-methoxypsoralen, however, with much fewer complaints of gastrointestinal side effects [16]. The 5-methoxypsoralen is not available in the United States as a commercial product, however, and requires clinical trials to demonstrate its efficacy before approval by the Food and Drug Administration.
Combination therapy Phototherapy historically has been used, especially in this modern era, in combination with both topical and systemic agents. In fact, it is unusual not to have some sort of combination therapy in the form of concomitant topical agents while the patient is undergoing induction and treatment with either UVB modalities or PUVA. There are myriad combinations that have been used, with some known to enhance the
403
[19]. Various systemic retinoids are used in combination with UV light therapy, and numerous studies have demonstrated their positive effects. The treatment rationale for combining retinoids with UV light is to enable reduction of the total energy delivered to the skin and enhance the therapeutic regimen by decreasing the total number of treatments needed. The approach to such treatment is to initiate therapy with the retinoid for at least 7 to 14 days to establish the retinoid effect on the skin and its modification of psoriatic plaques. The observed effect of retinoids on plaque-type psoriasis is to reduce the thickness of the plaque and help reduce scaling through their inherent mechanisms of helping to normalize differentiation of the keratinocytes. The exact effect of retinoids relates to cellular differentiation through impact on retinoid receptors, both local and circulating. Retinoids probably also have an effect on the immune mechanisms involved with psoriasis. This cumulative effect of the retinoids helps to decrease the thickness of the plaques and the scaling, allowing the UV therapy to be more effective and encounter less blocking and scattering of light at the skin surface. The retinoid effect increases susceptibility to erythema from UVB and makes one more prone to phototoxic effects from PUVA. It is not a direct effect from UV light on the retinoid molecule itself that produces the increased susceptibility to UV treatment. It is the effect on the skin, primarily the epidermis, which enhances the UV light combination. When using a systemic retinoid 2 weeks before initiation of UV therapy, caution must be used during the initiation and induction period of phototherapy. This is another incidence in which determining the MED before UVB therapy, whether broadband UVB or narrowband UVB, is very helpful because using only skin type to determine the dose is not as accurate, and a starting point has to be estimated without any objective measurement. The dose of the retinoid can be reduced when combined with phototherapy as compared with the dose of retinoid if used only as a monotherapy. A simplified modification of the dosage of retinoid when used in combination with UVB or PUVA is contained in Box 6. Caution must be applied when considering adding a retinoid to a UV treatment program if a patient has already received multiple doses of UV light. The tolerance to UV, whether UVB or PUVA, is decreased within 1 week of introduction of the retinoid and unexpected phototoxic reactions may occur even without increase in the dose of UV light. If a retinoid is to be introduced to an ongoing protocol for phototherapy it is recommended the dose of the UV light be reduced by 50% at the start of retinoid therapy and
Box 6. Retinoids and UV therapy

Dose of Acitretin and UVB or PUVA
10 or 25 mg/day
Use the retinoid two weeks prior to
initiation of UV therapy
Obtain MED with UVB treatments Select a lower skin type determina-
tion when using PUVA

Adding acitretin to an ongoing photo-
therapy treatment Reduce the dose of UV light therapy by 50% Keep the dose of the UV the same for six treatments
kept at that level for 2 weeks before increasing the dose of UV light. Various individual retinoid molecules have been used in combination with phototherapy. Currently, the most used retinoid is acitretin [20 22]. The basic principles for the use of retinoids in conjunction with phototherapy have been applied to the combination of acitretin plus narrowband UVB, although there are no studies that have actually been performed in a prospective manner. Thirteen-cis-retinoic acid (Accutane) can also be used in combination with phototherapy, but requires adhering to the general precautions needed for all the retinoids and their use. This is especially true with regard to informed consent and the special precautions necessary for avoidance of pregnancy. There may be times when 13-cis-retinoic acid is preferred over acitretin because of the problems with long-term bioavailability of acitretin metabolites when combined with alcohol. With even minimal ethanol consumption a potential for long-term fat storage of the teratogenic metabolite occurs, which requires prolonged years of strict adherence to contraception. Other systemic agents and UV therapy There are other systemic agents that have been tried and used with phototherapy. Particular features of some of the more common systemic agents deserve mention when used in combination. Methotrexate has frequently been used in combination treatment for psoriasis [23,24]. Short-term UV light therapy may be particularly helpful in aborting psoriasis flares, which can then be brought under control with longterm use of methotrexate with appropriate monitoring. Methotrexate by itself does not inhibit the
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efficacy of UV treatments. In fact, if methotrexate is used before UV light, some of the same plaquethinning benefits realized by retinoids can occur, helping with the induction of UV light response. It is more common, however, to have UV light used as an adjunct to long-term methotrexate treatments. Early studies show that the combination can be very helpful with application of routine broadband UVB. One must prevent a generalized phototoxic reaction with excessive UV light therapy during the course of treatment. This is true whether a therapeutic use of UV light is used or a patient sustains a sunburn reaction from natural sunlight. This situation can provoke what is known as a recall reaction with methotrexate and normal doses of light subsequent to the burn. Although it is an infrequent and unexpected side effect, if the recall reaction occurs, it may be as a result of normal doses of therapeutic UV light. The combination of methotrexate and PUVA has also been used. This alternative is not considered a very common treatment choice because of the increased incidence of squamous cell carcinoma known to occur with long-term PUVA therapy with the additional relative immunosuppression of methotrexate. Short-term it can be used with caution for very resistant cases having significant plaque-type psoriasis. This is another instance in which methotrexate can be used during the pretreatment phase and then tapered before induction with PUVA. The appropriate procedure is to limit methotrexate use to the 1 or 2 months before induction and maintenance with PUVA. Another conventional therapy used for resistant plaque-type psoriasis is cyclosporine. Combination therapies with cyclosporine should be used very cautiously because the particular combination of cyclosporine and PUVA therapy, if used long-term, leads to increased risk of squamous cell carcinoma over and above the risk inherent in PUVA itself [25]. Whether broadband or narrowband, UVB combination therapy with cyclosporine generally should not be used in the long-term. If there are resistant plaques, possibly just a short-term course of UV light therapy should be considered. Of particular concern here is historical use of PUVA, especially in patients who had long-term maintenance with PUVA therapy before the advent of the use of cyclosporine. In this instance, even use of cyclosporine post-PUVA carries increased risk of developing or facilitating squamous cell carcinomas years posttherapy as demonstrated by the results of long-term follow-up of the PUVA cohort. Patients having a history of years of PUVA treatment should be considered to have a relative contraindication for any follow-up with cyclosporine.
Biologics in combination with UV light Over the next 2 to 5 years more information about use of biologic agents with UV light therapy, particularly narrowband UVB, will be available. The regulations regarding phase 2 and phase 3 clinical trials require that phototherapy be excluded as concomitant therapy during the clinical trials determining the dosage, frequency, efficacy, and safety of the biologic agents that have become part of treatment for psoriasis over the last 2 years. Small pilot studies are now starting to appear concerning UV combination treatments with alefacept and etanercept. These initial reports are few and do not define the nuances of phototherapy, which may be important for the most effective and efficient delivery of UVB therapy. The important factors are whether or not there is change in the MED with concomitant use of the biologic treatment and if there is any actual significant enhancement of effect in conjunction with UVB therapy. The general principles underlying combination therapy with UV therapy are to decrease the total dose of millijoule per square centimeter for an individual and to decrease the total number of treatments needed to obtain the desired effect. Subsequent trials will provide further insights concerning these issues. Theoretically, there could be great advantage to the combination therapy with biologics and UV light. The biologics may have actions that vary from inhibiting circulating T cells from entering the dermis, such as with efalizumab, or decreasing circulating CD4 lymphocytes, as with alefacept. The use of narrowband UVB could compliment these effects through known mechanisms of decreasing CD3 lymphocytes in the epidermis [26], thereby having potential for attacking the cutaneous immune system from the surface of the skin while the biologic agents act on cells in the circulating CLA, CD45RO+ lymphocyte pool. Although the frequency of officebased UV light treatment has diminished over the past 5 years in North America there is great potential for short-term intermittent combination therapy for patients who may be on long-term therapy with one of the new biologic agents.
Summary Ultraviolet light has been the most used and effective treatment of psoriasis over the centuries. The beneficial effects of natural sunlight for clearing of psoriasis on the exposed skin do not depend on technology or insight into the known pathogenesis of the disease. In fact, an understanding of the patho-
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genesis was not necessary to recommend one of the traditionally effective treatments of psoriasis with long-term remissions, as was done with the Goeckerman therapy for psoriasis in the mid portion of the twentieth century. Even the current advancements in therapeutics enjoyed today with the advent of the biologics and other immunomodulating systemic agents do not surpass the overall response rate and duration of remission of the previous standard of therapy that was had in the 1950s. Refinements in the delivery of UVB light, the development of photochemotherapy with PUVA, and the more recent focusing of the spectrum of UVB to the most effective region between 310 and 313 nm for narrowband UVB have given clinicians additional options in the arsenal of therapeutics to attack psoriasis. Further refinements of the delivery systems for UVB in the form of lasers and localized delivery through fiberoptics are beneficial in helping to reduce the overall exposure of noninvolved skin and permitting more aggressive doses of UV to the sites of disease while sparing noninvolved skin. Enhancement of the different modalities of UVB and PUVA has been demonstrated with systemic agents, such as retinoids, but also in combination with immunosuppressive agents for short-term treatment to hasten the initial response to treatment. The advent of the biologic agents in treating psoriasis also introduced the opportunity for combination therapy and the theoretical advantage of managing T cells and antigen-presenting cells in the epidermis with UV light, and activated T cells in the circulation.
References
[1] Duthie MS, Kimber I, Norval M. The effects of ultraviolet radiation on the human immune system. Br J Dermatol 1999;140:995 1009. [2] Kudish AI, Abels D, Harari M. Ultraviolet radiation properties as applied to photoclimatherapy at the Dead Sea. Int J Dermatol 2003;42:359 65. [3] Menkes A, Stern RS, Arndt KA. Psoriasis treatment with suberythemogenic ultraviolet B radiation and a coal tar extract. J Am Acad Dermatol 1985;12:21 5. [4] Green C, Ferguson J, Lakshmipathi T, Johnson BE. 311 nm UVB phototherapy-an effective treatment for psoriasis. Br J Dermatol 1988;119:691 6. [5] Larko O. Treatment of psoriasis with a new UVB lamp. Acta Derm Venereol 1989;69:357 9. [6] Walters IB, Burack LH, Coven TR, Gilleaudeau P, Krueger JG. Suberythemogenic narrowband UVB is markedly more effective than conventional UVB in treatment of psoriasis vulgaris. J Am Acad Dermatol 1999;40:893 900.
[7] Dawes RS, Wainwright NJ, Cameron H, Ferguson J. Narrowband ultraviolet B phototherapy for chronic plaque psoriasis: three times or five times weekly treatment? Br J Dermatol 1998;138:833 9. [8] Asawanonda P, Anderson RR, Chang Y, Taylor CR. 308 nm excimer laser for the treatment of psoriasis: a dose-response study. Arch Dermatol 2000;136: 619 24. [9] Feldman SR, Mellen BG, Housman TS, Fitzpatrick RE, Geronemus RG, et al. Efficacy of the 308 nm excimer laser for treatment of psoriasis: results of a multicenter study. J Am Acad Dermatol 2002;46: 900 6. [10] Parrish JA, Fitzpatrick TB, Tanenbaum L, Pathak MA. Photochemotherapy of psoriasis with oral methoxy psoralen and long wave ultraviolet light. N Engl J Med 1974;291:1207 11. [11] Tanew A, Ortel B, Rappersberger K, Honigsmann H. 5-methoxypsoralen for photochemotherapy. J Am Acad Dermatol 1988;18:333 8. [12] Coven TR, Walters IB, Cardinael I, Krueger JG. PUVA-induced lymphocyte apoptosis: mechanism of action in psoriasis. Photodermatol Photoimmunol Photomed 1999;15:22 7. [13] Stern RS, Laird N, Melski J, Parrish JA, Fitzpatrick TB, Bleich HL. Cutaneous squamous cell carcinoma in patients treated with PUVA. N Engl J Med 1982;310: 1156 61. [14] Stern RS. PUVA follow up group: the risk of melanoma in association with long-term exposure to PUVA. J Am Acad Dermatol 2001;44:755 61. [15] Bech-Thomson N, Angelo HR, Knudsen EA. The influence of food on 8-methoxypsoralen serum concentration and minimal phototoxic dose. Br J Dermatol 1992;127:620 4. [16] Tanew A, Ortel B, Rappersberger K, Honigsmann H. 5-methoxypsoralen for photochemotherapy. J Am Acad Dermatol 1988;18:333 8. [17] Kragballe K. Vitamin D and UVB radiation therapy. Cutis 2002;70:9S 12S. [18] Guenther LC. Optimizing treatment with topical tazarotene. Am J Clin Dermatol 2003;4:197 202. [19] Lebwohl M, Drake L, Menter A, Koo J, Gottlieb AB, Zanolli M, et al. Consensus conference: acitretin in combination with UVB or PUVA in the treatment of psoriasis. J Am Acad Dermatol 2001;45:544 53. [20] Iest J, Boer J. Combined treatment of psoriasis with acitretin and UVB phototherapy compared with acitretin alone and UVB alone. Br J Dermatol 1989;120: 665 70. [21] Tanew A, Guggenbichler A, Honigsmann H, Geiger JM, Fritsch P. Photochemotherapy for severe psoriasis without or in combination with acitretin: a randomized, double-blind comparison study. J Am Acad Dermatol 1991;25:682 4. [22] Lebwohl M. Acitretin in combination with UVB or PUVA. J Am Acad Dermatol 1999;41:S25 8. [23] Morison WL, Momtax K, Parrish JA, Fitzpatrick TB. Combined methotrexate-PUVA therapy in the treat-
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M. Zanolli / Dermatol Clin 22 (2004) 397406 [25] Marcil I, Stern RS. Squamous-cell cancer of the skin in patients given PUVA and ciclosporin: nested cohort crossover study. Lancet 2001;358:1042 5. [26] Ozawa M, Ferenczi K, Kikuchi T, et al. 312 nm UV induces apoptosis of T cells. J Exp Med 1999;189: 711 8.
ment of psoriasis. J Am Acad Dermatol 1982;6: 46 51. [24] Paul BS, Momtax K, Stern RS, Arndt KA, Parrish JA. Combined methotrexate-ultraviolet B therapy in the treatment of psoriasis. J Am Acad Dermatol 1982;7: 758 62.
Dermatol Clin 22 (2004) 407 426
Current concepts and review of alefacept in the treatment of psoriasis

Gerald G. Krueger, MD
Department of Dermatology, 4B454 School Medicine, University of Utah Health Sciences Center, 30 N 1900 E, Salt Lake City, UT 84132-2409, USA
Alefacept is the first and only biologic agent approved by the US Food and Drug Administration for the treatment of adult patients with moderate to severe chronic plaque psoriasis who are candidates for systemic therapy or phototherapy. Several reviews have been published on alefacept and new treatment options for psoriasis [1 4]. This article provides updated information on alefacept with regard to the following:
Mechanism of action New data analyses from the psoriasis clinical
program
Rationale and design of two recently completed
pilot studies, one evaluating alefacept/ultraviolet B (UVB) light combination therapy for psoriasis and the other investigating the effects of adding alefacept to methotrexate in patients with active rheumatoid arthritis (RA) Description of an ongoing psoriasis study in which alefacept is used concurrently with other systemic therapies and phototherapy Initial findings in patients with psoriatic arthritis
Mechanism of action Psoriasis is an immune-mediated disease, with memory T cells playing a key role in disease pathogenesis [3,5]. The costimulatory molecule CD2 is highly expressed on activated memory T cells [6 8]. This increased expression of CD2 provides a specific
Conflict of interest: the author has been a long-term consultant for Biogen and a lead investigator or an investigator in some of the clinical trials. E-mail address: gerald.krueger@derm.med.utah.edu
marker that can be targeted by therapeutic agents. Alefacept is a bivalent recombinant fusion protein composed of the first extracellular domain of lymphocyte function-associated antigen 3 (LFA-3) fused to the hinge, CH2 domain, and CH3 domain of human IgG1. The results of experiments in vitro and in rodents have shown that alefacept has a dual mechanism of action. The LFA-3 portion of alefacept binds to CD2 receptors on T cells, thereby blocking their natural interaction with LFA-3 on antigen-presenting cells. The IgG1 portion of alefacept binds to the FcgR receptor on accessory cells (eg, natural killer [NK] cells) to cause T-cell apoptosis [9,10]. Cytotoxic assays have shown the apoptotic effects of alefacept to be selective for the activated memory T-cell population [6], presumably because of the CD2 upregulation associated with this cell type. Recent experimentation using mutant LFA-3/IgG1 isoforms and cell depletion or antibody blockade strategies indicates that alefacept immunomodulation reflects its ability to mediate cognate interactions between cells expressing human CD2 and human CD16 (FcgRIII) [11]. To address the molecular and structural basis for the mechanisms of action of alefacept, its signal-inducing properties were investigated in transfected Jurkat cells and in interleukin 2 expanded NK cells, which express both CD2 and CD16. Alefacept induced the activation of intracellular signaling pathways (eg, phosphorylation of extracellular signal-regulated kinase, up-regulated expression of the cell surface activation marker CD25, and release of granzyme B). The binding of alefacept to both CD2 and CD16 was required for pharmacologic activity, although most of the signaling was mediated through CD16. Thus, alefacept acts as an effector molecule, mediating cognate interactions of
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Apoptosis Activation
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TNF-R
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Fig. 1. Model for the activation of apoptosis of sensitive CD2+ cells by alefacept. The LFA-3 portion of alefacept binds CD2 (eg, T cells), and the IgG1 portion binds CD16 on accessory cells (eg, NK cells). Binding of alefacept to both CD2 and CD16 is necessary for pharmacologic activity. NK cells then secrete granzyme/perforin to induce activated CD2+ target cells to undergo apoptosis. The apoptotic effects of alefacept are selective for the activated memory T-cell population because of its high level of CD2 expression. Na ve T-cell, NK-cell, and B-cell counts are not significantly affected by alefacept therapy.
cells expressing CD2 and FcgR to activate FcgR+ cells (eg, CD16+ NK cells). These cells secrete granzyme/perforin to induce activated CD2+ target cells (eg, T cells) to undergo apoptosis as measured by annexin V staining (Fig. 1). The prolonged remissions observed in patients with psoriasis who respond to alefacept (see Duration of response section) are likely the result of this targeted apoptosis.
Alefacept in chronic plaque psoriasis The clinical profile of alefacept for the treatment of psoriasis has been extensively studied. Three studies provide the primary clinical data: one phase 2 study [12] and two phase 3 studies [13,14]. These studies consistently showed improvements in psoriasis that were superior to placebo, durable (even following treatment cessation), and associated with improvements in patients quality of life (QOL). Importantly, the effect of alefacept continued well into the postdosing period, which provided confirmation of the remittive action of the drug and the importance of evaluating its effect over time. The efficacy and pharmacodynamic and QOL effects of alefacept that are presented in the following sections are primarily based on the results of the two multicenter, double-blind, placebo-controlled, paral-
lel-group, phase 3 studies involving 1060 patients with chronic plaque psoriasis. In the intramuscular (IM) study, patients were randomized to placebo (n = 168), alefacept (10 mg; n = 173), or alefacept (15 mg; n = 166) for a single course [14]. In the intravenous bolus (IV) study, patients were randomized to one of three cohorts: alefacept (7.5 mg) in courses 1 and 2 (cohort 1, n = 183), alefacept (7.5 mg) in course 1 and placebo in course 2 (cohort 2, n = 184), or placebo in course 1 and alefacept (7.5 mg) in course 2 (cohort 3, n = 186) [13]. In both studies, each course consisted of 12 once-weekly injections of the study drug followed by 12 weeks of observation. Recent analyses of safety data from the phase 3 studies are also presented. In addition, the tolerability of alefacept over up to six treatment courses is reported based on a pooled analysis of all studies in the alefacept clinical program. The latter sections describe the rationale and design of a study evaluating combination treatment with alefacept and UVB, and the design of an ongoing trial that allows alefacept to be administered concomitantly with other psoriasis systemic and phototherapies. Efficacy The benefits of targeted therapy with alefacept are evident in the overall response rates for reductions in
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80 71 70 % PASI Reduction 60 50 40 30 20 10 0 50% PASI Reduction 56
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40 28
75% PASI Reduction
Fig. 2. Overall response rates for a !50% reduction in PASI and a !75% reduction in PASI with one and two courses of IV alefacept. (Data from Krueger GG, Papp KA, Stough DB, Loven KH, Gulliver WP, Ellis CN, for the Alefacept Clinical Study Group. A randomized, double-blind, placebo-controlled phase III study evaluating efficacy and tolerability of 2 courses of alefacept in patients with chronic plaque psoriasis. J Am Acad Dermatol 2002;47(6):821 33.)
the baseline Psoriasis Area and Severity Index (PASI) from the two phase 3 studies (Figs. 2 and 3). With either IM or IV administration, most patients treated with a single course of alefacept achieved at least a 50% reduction in PASI (PASI-50), and a second course of therapy provided further benefit by increasing response rates and prolonging the duration of offtreatment response [13 15]. The following sections summarize new analyses regarding the efficacy of alefacept among important subpopulations of patients who participated in these
pivotal trials. The results demonstrate that alefacept is efficacious in a broad spectrum of patients with psoriasis and that it provides long-lasting off-treatment responses, regardless of the route of administration. Patients with severe disease At baseline, the severity of psoriasis was defined in both phase 3 studies according to PASI, body surface area (BSA) involvement, and Physician Global Assessment (PGA). The PASI is based on a formula encompassing disease severity and extent of lesions,
80 70 % PASI Reduction 60 50 40 30 20 10 0 50% PASI Reduction 75% PASI Reduction 33 57 43 69

1 Course of IM Alefacept 2 Courses of IM Alefacept
Fig. 3. Overall response rates for a !50% reduction in PASI and a !75% reduction in PASI with one and two courses of IM alefacept. (Data from Lebwohl M, Christophers E, Langley R, Ortonne J-P, Roberts J, Griffiths CEM, for the Alefacept Clinical Study Group. An international, randomized, double-blind, placebo-controlled phase 3 trial of intramuscular alefacept in patients with chronic plaque psoriasis. Arch Dermatol 2003;139:719 27.)
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100 80 66 Patients (%) 60 40 20 0 Alefacept Placebo IM (n=43) 15 mg IM (n=44) Alefacept Placebo IV 7.5 mg IV (n=56) (n=111) 41 33 29
Fig. 4. Percentage of patients who achieved a !50% reduction in PASI at any time during treatment or the follow-up period (overall response rates) for patients with severe disease at screening (PASI, > 20). Results shown are from the two phase 3 studies of alefacept (course 1 data are presented). (Data from Vaishnaw AK, Ticho B. Alefacept is efficacious in a broad spectrum of patients with psoriasis, including those with severe disease. Presented at the 61st Annual Meeting of the American Academy of Dermatology. San Francisco, March 21 26, 2003.)
weighted by the proportion of BSA involved [16]. Scores range from 0 to 72, with the highest score reflecting complete erythroderma. A PASI greater than 20 generally has been used to define severe disease. Patients who participated in the phase 3 studies had a median baseline PASI ranging from 13.2 to 15.2, and a median baseline BSA involvement of 22% to 24% [17]1. Based on physician assessment, which is likely to account for multiple factors (eg, severity, disability, and psychosocial impact), more than 80% of patients were considered to have moderate, moderate to severe, or severe disease. Among those with a screening PASI of greater than 20, more patients treated with alefacept (15 mg given IM or 7.5 mg given IV) achieved a 50% or greater reduction in PASI (PASI-50) during treatment or during the follow-up period (overall response rate) than those who received placebo (Fig. 4). Results were similar when psoriasis severity was defined by a BSA of greater than 30% or a PGA of moderate or worse. Prior treatment history and response In the two phase 3 studies, patients were queried about their prior therapies for psoriasis and then, during randomization, stratified according to their histories of prior systemic or phototherapy [18]. Patients were also asked to classify their responses to each prior systemic or phototherapy as follows: no
Data on file, Biogen, Inc.
change, worsening of disease, or improved. The treatment groups were well balanced with respect to prior treatment history; 77% and 78% of patients, respectively, in the IM and IV studies had received prior systemic or phototherapy. Substantial percentages of patients reported either no change or worsening of their psoriasis after treatment with prior therapy. Prior therapies consisted of the following: cyclosporine (21% and 28% of IM and IV patients, respectively), psoralen plus ultraviolet A light (PUVA; 26% and 36%), methotrexate (32% and 35%), UVB (35% and 45%), and retinoids (44% and 50% of IM and IV). Regardless of prior treatment history, the percentages of patients who achieved a PASI-50 at any time during treatment or during the follow-up period were higher in the alefacept group (15 mg IM or 7.5 mg IV) than in the placebo group (Fig. 5) [18]. Similar proportions of treatment-na ve and previously treated patients had a clinically meaningful response to IM or IV alefacept. As expected, treatment-na ve patients had slightly better response rates than patients who had tried other therapies before enrolling in these studies. In the alefacept 15-mg IM group, 39% of patients who reported no change or worsening of disease during prior systemic or phototherapy achieved a 75% or greater reduction in PASI (PASI-75) compared with 28% of patients who improved on prior therapy. The corresponding results in the alefacept 7.5-mg IV group were 36% and 23%, respectively. Importantly, a substantial number of patients who had not responded to
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100 80 Patients (%) 60 40 20 0

Alefacept Placebo 15 mg IM IM (n=47) (n=46) Alefacept Placebo 15 mg IM IM (n=119) (n=122) Alefacept Placebo 7.5 mg IV IV (n=92) (n=46) Alefacept Placebo 7.5 mg IV IV (n=275) (n=140)
60
55 37
61 54 34 24 24
TreatmentNave
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TreatmentNave
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Fig. 5. Percentage of patients who achieved a !50% reduction in PASI at any time during treatment or the follow-up period (overall response rates) in treatment-na ve patients and those who received prior systemic psoriasis therapies or phototherapy. Results shown are from the two phase 3 studies of alefacept (course 1 data are presented). (Data from van de Kerkhof P, Vaishnaw AK, Kragballe K, Ortonne J-P. Alefacept is efficacious in a broad spectrum of patients with psoriasis. J Eur Acad Dermatol Venereol 2003;17(Suppl):55.)
prior therapies responded to alefacept. Furthermore, patients who reported responding to prior therapies had a lesser overall response to alefacept. This finding is not understood and requires future study. Patients who were refractory to or who had contraindications to conventional systemic psoriasis therapies or phototherapy Data from both phase 3 studies were pooled to determine whether a single course of alefacept was effective in the subset of patients who were refractory to or had contraindications to other systemic psoriasis therapies or phototherapy [19]. Patients who reported no change or worsening of disease while on such treatment were considered to be refractory. The most common contraindication was a history of hypertension (21%). Among patients who were refractory to or had contraindications to one or more systemic psoriasis therapies or phototherapy, 53% of alefacept-treated patients and 26% of placebo-treated patients achieved a PASI-50 during treatment or the follow-up period. The corresponding results were 52% versus 25% among patients who were refractory to or had contraindications to two or more systemic psoriasis therapies or phototherapy, and 50% versus 21% among patients who were refractory to or had contraindications to three or more systemic therapies or phototherapy. The efficacy results were comparable to those observed among patients who were not refractory and
who had no contraindications to other systemic psoriasis therapies or phototherapy. Duration of response The remittive effect of alefacept has been demonstrated following IV administration [13]. Recently, data from the phase 3 IM study have been analyzed and confirmed this effect [20]. In the phase 3 IV study, patients who received alefacept in course 1 and placebo in course 2 (cohort 2) were observed to determine the duration of their off-treatment response. Per the prespecified analysis, patients in this cohort who achieved a PASI-75 after the first dose maintained a PASI-50 for a median of more than 7 months (216 days). In addition to improving PASI response rates, two courses of alefacept (cohort 1) provided a longer duration of response compared with a single course. The median duration of response could not be determined because more than 50% of the patients who received two courses of alefacept had maintained their PASI-50 at the final study endpoint, nearly 1 year after the first dose. Patients who completed the phase 3 IM study were eligible to enroll in a separate double-blind extension study. Patients treated with 15 mg of alefacept in the phase 3 study received another course of alefacept at the same dosage. In this treatment group, those who achieved a PASI-75 after the first dose in the phase 3 study maintained a PASI-50 for a
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100 0 12 24
100 0 12 24 Study Week Alefacept 15 mg (n=166) Placebo (n=167)
Fig. 6. Effects of IM (A) and IV (B) alefacept on circulating CD4+ memory and na ve T cells. Similar results were seen for circulating CD8+ memory and na ve T cells (data not shown). Results shown are from the two phase 3 studies of alefacept. (Reprinted from Gordon KB, Vaishnaw A, OGorman J, Haney J, Menter A. Treatment of psoriasis with alefacept. Correlation of clinical improvement with reductions of memory T-cell counts. Arch Dermatol 2003;139:1563 70; with permission; and Ortonne J-P, Lebwohl M, Griffiths CEM. Alefacept-induced decreases in circulating blood lymphocyte counts correlate with clinical response in patients with chronic plaque psoriasis. Eur J Dermatol 2003;13(2):117 23; with permission.)
median of approximately 7 months (209 days) [20]. These observations confirm and extend the data that show the duration of response to alefacept is prolonged and provides patients with an extended treatment-free period. Pharmacodynamics As expected from its mechanism of action, alefacept reduces total lymphocyte and CD4+ and CD8+ Tcell counts [21,22]. Reductions are selective for memory T cells, with relative sparing of na ve T cells (Fig. 6) and no notable effects on CD19+ B cells or CD16+/CD56+ NK cells [21,22]. Importantly, there has been no evidence of a cumulative effect of alefacept on total lymphocyte count or lymphocyte subset counts over two courses in the phase 3 IV study (Fig. 6B) [21]. Fig. 7 shows the effect of five courses of 7.5 mg of IV alefacept on CD4+ T cells based on the results of an ongoing retreatment study2. Mean reductions reached a plateau during course 3, and reductions for courses 3 through 5 appeared superimposable. At no time did mean CD4+ T-cell counts drop below the lower limit of normal (LLN; 400 cells/mL). Because of the drugs effects on T cells, the product labeling recommends that CD4+ T-cell counts
be monitored weekly during alefacept therapy. Importantly, as a part of the clinical studies, safety and tolerability assessments focused on the effect of alefacept on immune responses, including infection rates, malignancies, and the development of antibodies. Alefacept has not been associated with adverse events indicative of generalized immunosuppression, and no opportunistic infections or increased frequency of malignancies have been reported (see Safety and tolerability section). The selectivity of alefacept for memory T cells is likely responsible for the lack of effect on immune responses. Relationship between memory T-cell reductions and efficacy The relationship between the selective targeting of memory T cells by alefacept and its antipsoriatic effect was proposed in the phase 2 study and validated in the phase 3 studies [12,21,22]. In these studies, the area under the percentage change from the baseline curve for blood lymphocyte counts over the dosing interval (EAUC) was calculated for each patient to relate the cumulative effect of alefacept on memory T cells with antipsoriatic efficacy [21,22]. Patients were then divided into quartiles (Q) based on EAUC (Q1 = lowest, Q4 = highest), and the percentages of patients achieving a PASI-50, PASI-75, or PGA of clear or almost clear at any time during the treatment and follow-up periods, without the use
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Fig. 6 (continued ).
of other psoriasis systemic or phototherapies, were expressed graphically. There was a consistent relationship between the magnitude of change in memory T-cell counts and probability of response (Fig. 8) [21,22]. Regardless of the definition of response (PASI-50, PASI-75, or PGA of clear or almost clear), a greater degree
of reduction in memory T-cell counts was generally associated with a more favorable clinical outcome [21,22]. The duration of response to alefacept also was longer in patients who had more pronounced reductions in memory T cells [21]. Time-course analysis revealed that the peak effect of alefacept on memory T cells occurred during treatment, where-
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Fig. 7. Effects of repeat courses of 7.5-mg IV alefacept on circulating CD4+ T cells. Results shown are from an ongoing, retreatment study. The number of patients at each time point in courses 1 to 4 ranges from 61 to 66. The number of patients at each time point in course 5 ranges from 19 to 33. (Data on file, Biogen, Inc.)
100 80 Patients (%) 66 60 40 20 0

n=84 n=85 n=85 n=85
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Fig. 8. Percentage of patients who achieved a !50% reduction in PASI at any time during treatment or the follow-up period (overall response rates) by EAUC of CD4+ memory T cells. Similar results were seen for CD8+ memory T cells (data not shown). Results shown are from the two phase 3 studies of alefacept (course 1 data are presented). (From Gordon KB, Vaishnaw A, OGorman J, Haney J, Menter A. Treatment of psoriasis with alefacept. Correlation of clinical improvement with reductions of memory T-cell counts. Arch Dermatol 2003;139:1563 70; with permission; and Ortonne J-P, Lebwohl M, Griffiths CEM. Alefacept-induced decreases in circulating blood lymphocyte counts correlate with clinical response in patients with chronic plaque psoriasis. Eur J Dermatol 2003;13(2):117 23; with permission.)
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as the peak effect on PASI generally occurred well after treatment cessation [21,22]. This finding further suggests that reductions in memory T cells drive the therapeutic response to alefacept. The relationship between alefacept-induced T-cell changes in psoriatic skin and clinical response was also investigated. Chamian et al [23] reported data that showed a significant correlation between reductions in lesional T cells and clinical improvement with alefacept therapy. The selective targeting of memory T cells by alefacept was 11 times greater in skin lesions than in the peripheral circulation. Although the reduction in T-cell counts in circulation and skin clearly correlate with level and duration of response, it is common to find patients who seem to respond without much change in the number of memory T cells in the circulation. The same is true for those who do not respond. Clearly, if a patient experiences significant improvement, there is a decrease in T cells in skin. It would be beneficial to know the reason for this discordance, because it would allow the clinician to more accurately predict response without performing a skin biopsy.
Pharmacodynamics in subpopulations In both phase 3 studies of alefacept, analysis of circulating total lymphocyte and CD4+ and CD8+ T-cell counts in those patients who received alefacept plus concomitant immunosuppressants (methotrexate, cyclosporine, prednisone, etanercept, leflunomide, infliximab, or mycophenolate mofetil) did not reveal any patterns that suggested an increased risk for greater reductions in lymphocyte or lymphocyte subset counts [24]. In the alefacept 15-mg IM group, changes in circulating CD4+ and CD8+ T cells were determined in patients who were refractory to or had contraindications to one or more other systemic psoriasis therapies or phototherapy [19]. As mentioned previously, patients who reported no change or worsening of disease while on such treatment were considered to be refractory, and the most common contraindication was a history of hypertension (21%). Analysis showed that reductions in T cells were consistent regardless of whether patients were refractory to or had contraindications to one or more systemic therapies or phototherapymean reductions at the time of maximal effect ranged from 39% to 43% for CD4+ T cells and from 47% to 53% for CD8+ T cells. These results were comparable to those observed among patients who were not refractory to and had no contraindications to other systemic psoriasis therapies or phototherapy.
Variability in circulating T cells In the two phase 3 studies, there was a surprisingly high degree of variability in circulating levels of baseline T-cell counts [25]. For example, among placebo-treated patients across both studies, baseline CD4+ T-cell counts ranged from 325 to 2573 cells/mL (normal range, 404 1612 cells/mL) and baseline CD8+ T-cell counts ranged from 110 to 1625 cells/ mL (normal range, 220 1129 cells/mL). In the alefacept 10-mg IM study, the percentages of placebotreated patients who had at least one CD4+ T-cell count below 400, 300, 200, and 100 cells/mL at any time after the first dose were 8%, 2%, 0%, and 0%, respectively. The corresponding percentages in the alefacept 15-mg IM group were 28%, 9%, 2%, and 0%. For CD8+ T cells, 16%, 6%, less than 1%, and 0% of patients in the placebo IM group and 39%, 23%, 7%, and 2% of patients in the alefacept 15-mg IM group had counts below 200, 150, 100, and 50 cells/ mL, respectively. Most patients experienced a recovery in T-cell counts during the treatment-free follow-up period. At 12 weeks after the last IM dose, in the 10-mg group two (1%) placebo-treated patients had CD4+ T-cell counts below the LLN, and 14 (9%) had CD8+ T-cell counts below the LLN. At the same time point, 11 (7%) patients treated with 15 mg of IM alefacept had CD4+ T-cell counts below the LLN, and 32 (22%) had CD8+ T-cell counts below the LLN. Results of the IV study were similar to those of the IM study. Although these values were below the LLN, they were not associated with adverse events and, as noted previously, did not continue to decline with further administration. These findings suggest that variability in T-cell counts occurs in patients with psoriasis regardless of therapy and that T-cell counts generally recover to normal ranges following alefacept therapy. Quality of life In addition to the obvious physical characteristics of psoriasis, the disease causes significant impairment in patients QOL. A large survey (>17,000 respondents) conducted by the National Psoriasis Foundation (NPF) found that patients often report difficulty performing routine activities (eg, sleeping and exercising), interacting with peers and family, making or keeping friends, and getting a job [26]. Suicide is frequently contemplated. Approximately 50% of patients with severe psoriasis are not satisfied or only somewhat satisfied with their current treatment. More than 75% of patients with severe psoriasis are frustrated with the lack of efficacy of their current treatment, and 87% report receiving treatment with topical agents, which can be time-consuming to administer [26]. A
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survey of similar size was recently conducted in Europe by the European Federation of Psoriasis Patients Organizations (EUROPSO) [27,28]. The findings of EUROPSO paralleled those of the NPF. Further complicating the management of psoriasis is the lack of correlation between the patients perception of their disease intensity and objective measures of disease severity (eg, BSA, PASI, and PGA), which do not take into account the effect of psoriasis on the patients QOL [29]. A recent pooled analysis of baseline data from both phase 3 studies in the alefacept clinical program yielded interesting results. The primary QOL instrument used in these trials was the Dermatology Life Quality Index (DLQI) [30]. At baseline, the distribution of DLQI varied widely for any given measure of BSA. That is, patients with extensive BSA at baseline may have had high or low DLQI. This was also true for patients with low BSA at baseline who may have had high or low DLQI. In addition, there was no correlation between baseline PASI or PGA and baseline DLQI [29]. These data underscore the need to address both the physical and psychologic aspects of psoriasis. QOL assessments have been included in the phase 2 and 3 studies of alefacept and the data have been
published [31 33]. In the phase 3 studies, alefacept significantly improved overall DLQI scores at 2 weeks after treatment cessation compared with placebo, a benefit that was largely preserved at 12 weeks after the last dose [32,33]. Significant improvements over placebo were also observed for the Dermatology Quality of Life Scales and the Short Form 36 Health Survey, a general health survey. The DLQI significantly improved in patients who achieved a reduction in PASI of 50% to less than 75% (Fig. 9); these patients also experienced visible clinical improvement. It was not necessary for PASI to be reduced by 75% or more or for the PGA to be clear or almost clear for these benefits to be realized. Taken together, the results of these three studies strongly suggest that PASI-50 is clinically meaningful for both patients and physicians. Other observations lend further support to this conclusion [34]. First, the relationship between PASI and severity of psoriasis is not linear. There is a tendency for PASI to underestimate the actual improvement in psoriasis because of how the score is calculated. Second, methotrexate, widely viewed as an effective therapy for psoriasis, when given in an aggressive dosing fashion in a small-scale 25-patient trial, resulted in a PASI-75 in about one fourth of
Responder Nonresponder 50% to <75% PASI 1 0 -1 Mean Change in DLQI -2 -3 -4 -5 -6 -7 -8 -7.2 * -5.1 * -6.6 * -6.6 * -4.4 -2.2 -2.1 -2.9 -2.6 -3.1 -2.8
2 Weeks After Last Dose 12 Weeks After Last Dose
75% PASI
2 Weeks After Last Dose
PGA "Clear"/"Almost Clear"

2 Weeks 12 Weeks After Last Dose After Last Dose
12 Weeks After Last Dose
-7.1 *
Fig. 9. Mean change from baseline in DLQI by responder status at 2 weeks after the last dose. A negative change indicates improvement in QOL. Results shown are from the phase 3 intramuscular study of alefacept (all treatment groups were combined for this analysis). *P < 0.001 versus nonresponders. (Reprinted from Finlay AY, Salek MS, Haney J, for the Alefacept Clinical Study Group. Intramuscular alefacept improves health-related quality of life in patients with chronic plaque psoriasis. Dermatology 2003;206(4):307 15; with permission.)
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patients and a PASI-50 in about two thirds of patients after 6 months of treatment [35]. Third, clinical studies have shown that effective therapies for psoriasis can be consistently differentiated from placebo at PASI-50. Fourth, patients who achieve PASI-75 often choose to defer treatment until their PASI is below 50. For these and other reasons, it seems that PASI-50 would serve as an effective endpoint when defining a clinically meaningful response [34].
Safety and tolerability The data presented in the following sections demonstrate that alefacept is safe and well tolerated in a broad spectrum of patients, including those on concomitant immunosuppressant agents and those who are refractory to or have contraindications to other systemic psoriasis therapies or phototherapy. The incidence of serious adverse events, discontinuations, infections, malignancies, and antialefacept antibodies remain low over up to six alefacept courses. In addition, critical functions of the immune system are maintained during alefacept therapy.
Concomitant use of alefacept and immunosuppressants As new, targeted immunotherapies are being developed and studied in patients with psoriasis, the concomitant, sequential, or rotational use of these agents with older, nonspecific immunosuppressants is of interest. In the two phase 3 studies of alefacept, the incidence of adverse events, serious adverse events, and serious infections during the first course of 7.5-mg alefacept in the IV study (cohorts 1 and 2 pooled) and 15-mg alefacept in the IM study were analyzed according to concomitant use and prior use (within 60 d before the first alefacept dose) of the following immunosuppressants: methotrexate, cyclosporine, prednisone, etanercept, leflunomide, infliximab, and mycophenolate mofetil [24]. One or more immunosuppressant agents were used concomitantly by 21 patients (6%) in the 7.5-mg alefacept IV group and by 4 patients (2%) in the 15-mg alefacept IM group compared with 22 patients (6%) in the placebo group (IM study and cohort 3 of IV study pooled) [24]. There were no unusual patterns of adverse events in the IV study (Table 1) or IM
Table 1 Incidence of adverse events in the first course of the intravenous study among alefacept-treated patients who had and had not received concomitant immunosuppressants Alefacept Adverse event Accidental injury Pruritus Allergic reaction Anxiety Arthritis Contact dermatitis Dizziness Ear disorder Gout Headache Hyperglycemia Hypertension Infectiona Insomnia Kidney calculus Paresthesia Pharyngitis Rash Respiratory disorder Received (N = 21) n (%) 3 2 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 (14) (10) (5) (5) (5) (5) (5) (5) (5) (5) (5) (5) (5) (5) (5) (5) (5) (5) (5) Did not receive (N = 346) n (%) 70 37 1 8 15 2 16 2 0 58 0 10 33 2 2 5 51 3 0 (20) (11) (< 1) (2) (4) (< 1) (5) (< 1) (17) (3) (10) (< 1) (< 1) (1) (15) (< 1) Placebo (N = 186) n (%) 30 16 1 4 5 3 6 1 1 38 1 6 20 7 2 0 23 3 0 (16) (9) (< 1) (2) (3) (2) (3) (< 1) (< 1) (20) (< 1) (3) (11) (4) (1) (12) (2)
This table lists all adverse events that were reported among alefacept-treated patients who had received concomitant immunosuppressants. Patients may have experienced more than one adverse event. a Most episodes were common colds. Data from Vaishnaw AK, Lee S. Concomitant use of alefacept and immunosuppressants in patients with psoriasis. Presented at the 61st Annual Meeting of the American Academy of Dermatology. San Francisco, March 21 26, 2003.
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study. The nature of the adverse events was consistent between those patients who had and those who had not received concomitant immunosuppressants. Among the four patients in the 15-mg alefacept IM group who had received concomitant immunosuppressants, one patient each reported arthritis, conjunctivitis, diarrhea, eczema, edema, hypercholesteremia, and insomnia. Similar results were obtained when adverse events were analyzed according to use of one or more immunosuppressants within 60 days before the first dose of alefacept [24]. A review of the safety data collected during phase 3 studies of alefacept (administered by IM and IV injection) suggests that the frequency and spectrum of adverse events or serious infections is not altered by concomitant use or prior use of immunosuppressants. An ongoing study using combination therapy will address this question more directly (see Ongoing study of alefacept in clinical practice section for details).
Patients who were refractory to or who had contraindications to other systemic therapies or phototherapy Data from both phase 3 studies of alefacept were pooled to determined the adverse event profile in the subset of patients who were considered refractory to or who had contraindications, as defined previously, to other systemic psoriasis therapies (cyclosporine, methotrexate, and retinoids) or phototherapy (PUVA
or UVB) [36]. Among the 714 patients who were refractory to or had contraindications to one or more systemic therapies or phototherapy, the only adverse event to occur at an incidence of 5% or greater incidence in the alefacept group compared with the placebo group was pruritus (15% versus 10%). Among the 431 patients who were refractory to or had contraindications to two or more systemic therapies or phototherapy, the following adverse events were reported at an incidence of 5% or greater in the alefacept group compared with the placebo group: pruritus (15% alefacept versus 8% placebo), flu syndrome (13% versus 8%), rhinitis (12% versus 6%), myalgia (6% versus 1%), and injection site pain (5% versus 0%). Among the 206 patients who were refractory or had contraindications to three or more systemic therapies or phototherapy, the following adverse events occurred at an incidence of 5% or greater in the alefacept group versus the placebo group: pruritus (18% versus 11%), accidental injury (17% versus 8%), and injection site pain (6% versus 0%). The safety profile of alefacept in patients who were considered refractory or had contraindications to one or more other systemic psoriasis therapies or phototherapy was similar to the safety profile observed in the overall alefacept-treated patient population. Multiple courses Safety and tolerability data were obtained from all studies evaluating alefacept as a treatment for psoriasis. These data were pooled, and the integrated results
10
Serious adverse events Discontinuations for adverse events
8 Patients (%)
6
4.9 4.1
4
3.1 1.8 0.8 0.5 0.8 0.8 0 0 0
1.5
0 n=1359 1 n=826 2 n=415 3 n=133 4
n=65 5
n=36 6
Alefacept Course
Fig. 10. Incidence of serious adverse events and discontinuations because of adverse events over multiple courses of alefacept therapy. Results shown are from all studies in the alefacept clinical program. (Data on file, Biogen, Inc.)
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A.
100
CD4+ count <250 cells/L CD4+ count 250 cells/L
80 Patients (%) 63 60 47 40 26 20 0
n=121 n=1238 n=85 n=741 n=28 n=387 n=8 n=125 n=6 n=59 n=1 n=35
44 38
39 29 31 33
44
43
0 1 2 3 4 5
Alefacept Course
B.
100
CD8+ count <100 cells/L CD8+ count 100 cells/L
80 Patients (%)
60 47 40 33 31 46 36 27 40 30 35 44 30 42
20
0
n=178 n=1181 n=155 n=671 n=78 n=337 n=35 n=98 n=20 n=45 n=10 n=26
3 4 Alefacept Course
Fig. 11. Incidence of infections by circulating CD4+ (A) and CD8+ (B) T-cell counts over multiple courses of alefacept therapy. Results shown are from all studies in the alefacept clinical program. (Data on file, Biogen, Inc.)
are presented here3. A total of 1359 patients received at least a single course of alefacept, 826 received at least two courses, 415 received at least three courses, 133 received at least four courses, 65 received at least five courses, and 36 received at least six courses. Adverse events Alefacept was well tolerated over multiple courses. Across all alefacept studies, there was no
increase in the incidence of serious adverse events or discontinuations because of adverse events with repeated administration of up to six treatment courses (Fig. 10). There was a tendency for rates of serious adverse events and discontinuations to decrease with continued courses of therapy. The percentage of patients who experienced at least one serious adverse event ranged from a high of 4.9% in course 1 to a low of 0% in course 6. The most common serious adverse events were accidental injury (0.4%, 0.6%, 0.2%, 0%, 0%, and 0% of patients in courses 1 through 6, respectively) and cholelithiasis (0.2%, 0.5%, 0.2%,
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Table 2 Incidence of serious infections by course of alefacept Alefacept course Infection Cellulitis Pneumonia Bacterial infection Gastroenteritis Abscess Appendicitis Asthma Bronchitis Burn infection Herpes simplex Postprocedural site wound infection Wound infection Total 1 (N = 1359) n (%) 3 0 2 2 1 0 1 0 1 0 0 0 10 (0.7) (0.2) (0.1) (0.1) (< 0.1) (< 0.1) (< 0.1) 2 (N = 826) n (%) 0 2 (0.2) 0 0 0 0 0 0 0 1 (0.1) 1 (0.1) 1 (0.1) 5 (0.6) 3 (N = 415) n (%) 0 1 (0.2) 0 0 0 1 (0.2) 0 1 (0.2) 0 0 0 0 3 (0.7) 4 (N = 133) n (%) 0 0 0 0 0 0 0 0 0 0 0 0 0 5 (N = 65) n (%) 0 0 0 0 0 0 0 0 0 0 0 0 0 6 (N = 36) n (%) 0 0 0 0 0 0 0 0 0 0 0 0 0
0%, 0%, and 0% of patients in courses 1 through 6, respectively). Discontinuation rates because of adverse events ranged from 1.8% in course 1 to 0% in courses 5 and 6. Headache (0.2% in course 1, 0% in other courses), nausea (0.2% in course 1, 0% in other courses), and herpes zoster (0.07%, 0%, 0.2%, 0.8%, 0%, and 0% in courses 1 through 6, respectively) were the most frequent adverse events that resulted in withdrawal.
Infections Infections were analyzed by course and circulating CD4+ (<250 cells/mL and !250 cells/mL) and CD8+ (<100 cells/mL and !100 cells/mL) T-cell counts (Fig. 11). There was no evidence of an increased risk of infection over multiple courses of alefacept, nor was there an association between infections and CD4+ and CD8+ T-cell counts. Infections were generally
Table 3 Incidence of malignancies by course of alefacept Alefacept course Malignancy Skin carcinoma Skin melanoma Lung carcinoma Prostatic carcinoma Adenocarcinoma of colon Colonic polyps Esophageal carcinoma Lymphomac Renal cell carcinoma Secondary neoplasm of brain Testicular cancer Total 1 (N = 1359) n (%) 11 2 0 1 0 0 0 0 1 0 1 (0.8) (0.1) (< 0.1) 2 (N = 826) n (%) 4 1 1 1 0 0 1 1 0 1 0 (0.5) (0.1) (0.1)a (0.1) 3 (N = 415) n (%) 3 0 1 0 1 1 0 0 0 0 0 (0.7) (0.2) (0.2)b (0.2)b 4 (N = 133) n (%) 1 (0.8) 0 0 0 0 0 0 0 0 0 0 1 (0.8) 5 (N = 65) n (%) 1 (1.5) 0 0 0 0 0 0 0 0 0 0 1 (1.5) 6 (N = 36) n (%) 0 0 0 0 0 0 0 0 0 0 0 0
(0.1) (0.1) (0.1)a
(< 0.1) (< 0.1)
16 (0.7)
9 (1.1)
5 (1.2)
Data on file, Biogen, Inc. a Same patient was diagnosed with both events. b Same patient was diagnosed with both events. c Two additional cases of lymphoma were diagnosed 5 and 6 months after alefacept therapy (see text for details).
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Baseline Postbaseline
10
Patients (%)
4
2.4
2
0.8 0.3
1.5 0.7
1.3 0 0 0 0 0 0
0
n=1291 n=1268 n=826 n=606 n=415 n=157
n=133 n=77
n=65 n=40
n=36 n=14
Alefacept Course
Fig. 12. Incidence of antibodies to alefacept over multiple courses of therapy. All patients with available data were included in the analysis. Results shown are from all studies in the alefacept clinical program. (Data on file, Biogen, Inc.)
mild and responsive to conventional therapy. The vast majority of episodes were common colds. Serious infections were experienced by 0.7%, 0.6%, 0.7%, 0%, 0%, and 0% of patients in courses 1 through 6, respectively. These events are summarized in Table 2. No cases of opportunistic or unusual infections, tuberculosis, or deaths related to infections were observed in patients receiving alefacept. Malignancies The percentages of patients (n = 1359) who developed malignancies were low and did not increase over multiple courses of alefacept: these percentages were 1.2%, 1.1%, 1.2%, 0.8%, 1.5%, and 0% in courses 1 through 6, respectively. No relationship between malignancies and circulating CD4 + or CD8 + T-cell counts was observed. The specific malignancies that were diagnosed are presented in Table 3, the most common of which was skin carcinoma (basal and squamous cell carcinomas). The overall malignancy rate among alefacept-treated patients was 25.6 per 1000 person-years of exposure4, which is somewhat less than the corresponding rate in the general psoriasis population (29.0 per 1000 person-years) [37]. There were three cases of lymphoma among alefacept-treated patients. A 68-year-old woman with longstanding psoriasis and previous exposure to methotrexate and PUVA developed features consistent with sporadic B-cell non-Hodgkins lymphoma, without an immunotherapy-related lesion.
4
She had received a total of 20 alefacept injections. A 53-year-old man was diagnosed with Hodgkins disease 6 months after his last dose of alefacept (34 total doses). Before receiving alefacept, the patient had been treated with methotrexate for 15 years. The other case was a 62-year-old man who was diagnosed with Hodgkins disease (stage IV) 5 months after his last dose of alefacept (24 total doses). The patient had previously received PUVA and UVB. Two of the three patients had received significant prior immunotherapy, which is known to be associated with an increased risk of lymphoma [37,38]. Overall, total lymphoma (Hodgkins and non-Hodgkins) occurred at a rate of 0.53 per 1000 person-years of alefacept exposure versus 1.6 per 1000 person-years in the general psoriasis population [37]5. Immunogenicity Consistent with its composition as a fully human fusion protein, the immunogenicity of alefacept was low in all courses (Fig. 12). The percentage of patients who tested positive for antialefacept antibodies post baseline was highest during course 1 (2.4%) and lowest during courses 4 through 6 (0%). In the few patients who developed antialefacept antibodies after treatment initiation, antibody titers were generally low (<1:40) and transient in most patients and did not increase with sequential sampling and treatment. Antibody titers were not associated with immune hypersensitivity reactions.
5
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Primary and secondary immune responses A multicenter, randomized, open-label, parallelgroup study evaluated the effects of alefacept on primary and secondary immune responses in patients with chronic plaque psoriasis [39]. Patients were randomized into two groups: alefacept (n = 23) and control (n = 23). Antibody responses to the neoantigen bacteriophage fX174 and to the recall antigen tetanus toxoid and diphtheria were evaluated. There were no statistically significant differences between the alefacept and control groups in antibody responses to either antigen. Mean anti-fX174 titers were comparable in the two groups at all time points after the first and second immunizations [39]. The observed titers were comparable with those seen in healthy volunteers after fX174 administration [40 44]. The IgG fraction of total anti-fX174 response at 2 weeks after the second immunization was 54% in the alefacept group and 48% in the control group, indicating that alefacept does not alter immunologic memory [39]. No evaluable patient failed to show an IgG anti-fX174 antibody response. Consistent with an acquired immune response, antibody titers rose rapidly after immunization with the recall antigen, tetanus toxoid. The percentage of patients with a twofold or greater increase in antitetanus titer at 3 weeks after immunization was similar in the alefacept (89%) and control (91%) groups. Thus, a single course of alefacept does not impair primary or secondary antibody responses to a neoantigen or memory responses to a recall antigen. Concomitant alefacept and ultraviolet B The combination of alefacept and UVB has the potential to provide synergistic efficacy with each agent targeting T cells in a different way, one from within and one from the surface. It has been hypothesized that this combination might provide a faster onset of action and longer duration of response than observed with either agent alone. The combination of alefacept and either narrowband (NB) or broadband (BB) UVB was evaluated in an open-label study of patients with chronic plaque psoriasis. Patients (N = f60) were enrolled at two sites: one in France (NB UVB) [45] and one in the United States (BB UVB) [46]. All patients received 15 mg of IM alefacept once weekly for 12 weeks. Patients were randomized (1:1:1) to receive either no UVB, UVB 3 times per week until clear or for up to 6 weeks, or UVB 3 times per week until clear or for up to 12 weeks. An observation period of 12 weeks followed the treatment period. The primary objective was to determine the safety and tolerability of combination therapy.
Results from both sites have been presented [45,46]. Alefacept in combination with UVB was well tolerated; adverse events were similar among patients who received alefacept monotherapy and patients who received combination therapy. No opportunistic infections were reported. Combination therapy seemed to provide a more rapid onset of effect compared with alefacept monotherapy. Complete results will be published separately. Ongoing study of alefacept in clinical practice To understand the best way to manage existing therapies during a course of alefacept, an international study is being conducted to reflect what is projected to be an approach that will be common to the usual clinical setting [47]. Approximately 400 patients with chronic plaque psoriasis will be enrolled in this openlabel study in which topical treatments, NB or BB UVB (2 3 treatments/wk), systemic retinoids, and prednisone will be permitted as concomitant therapies. Methotrexate and cyclosporine will be tapered over the first 4 and 12 weeks of alefacept therapy, respectively. Patients must need systemic therapy, have normal circulating CD4+ T-cell counts (!300 cells/ mm3 if on a stable dose of prednisone), and be na ve to alefacept treatment. In each course, 15 mg of IM alefacept will be administered once weekly for 12 weeks followed by 12 weeks of observation. Patients may receive up to three treatment courses. The primary objective of this study is to evaluate the safety of repeat courses of alefacept [47]. Other prespecified objectives are to determine the efficacy of initial and repeat courses of alefacept and the time to retreatment with alefacept after the first two courses. The results will provide valuable insight into the management of other psoriasis therapies when used concurrently with alefacept.
Alefacept in psoriatic arthritis Although data are limited, some evidence suggests that T cells may play a role in the pathogenesis of psoriatic arthritis (PsA) [48 50]. Therefore, a prospective, single-center, open-label pilot study was conducted to determine the clinical effect and changes in the synovium of patients with active PsA treated with alefacept [51]. Patients (N = 11) had had chronic plaque psoriasis for 1 year or more and active PsA, defined as two or more swollen joints and two or more tender joints. After a 28-day washout phase in which current treatments were withdrawn, 7.5 mg of IV alefacept was administered weekly for 12 weeks with 12 weeks of treatment-free observation. No concom-
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itant treatment for PsA was allowed, with the exception of nonsteroidal anti-inflammatory drugs (NSAIDs). Clinical assessments, which were performed at baseline, after 4 and 12 weeks of treatment, and at 16 weeks (ie, 4 wk after the last dose), included a 30-joint count (28-joint count and both ankles) for joint swelling and tenderness, physician and patient assessment of disease activity, morning stiffness, pain as assessed by a visual analog scale (VAS), serum concentrations of C-reactive protein (CRP), and PASI. Serial arthroscopic synovial biopsies of the same index joint were performed under local anesthesia at baseline and after 4 and 12 weeks of treatment (knee joint, n = 7; wrist joint, n = 2; metacarpophalangeal joint, n = 1; and ankle joint, n = 1). Alefacept significantly improved the mean swollen and tender joint counts, disease activity score (DAS), VAS, and CRP concentrations from baseline. The mean PASI was lowered by 13% at 4 weeks, 23% at 12 weeks, and 28% at 16 weeks. Immunohistochemical analysis revealed significant decreases from baseline in the mean number of macrophages in the synovial sublining at 12 weeks (43% reduction), CD4+ T cells at 4 and 12 weeks (42% and 59% reductions, respectively), and CD8+ T cells at 4 and 12 weeks (13% and 60% reductions, respectively). Patients who fulfilled the DAS response criteria at 12 weeks (n = 6) achieved a greater reduction in the memory subset of T cells in both synovial tissue and peripheral blood compared with nonresponders (n = 5). The improvement in clinical joint score and skin psoriasis and changes in synovial tissue after treatment with alefacept support the hypothesis that T-cell activation plays an important role in PsA.
ate throughout the study. Additional disease-modifying antirheumatic drugs were not allowed, but stable doses of NSAIDs and corticosteroids (prednisone, V10 mg/d) were permitted. Efficacy assessments included swollen and tender joint counts and the percentages of patients achieving American College of Rheumatology (ACR) response scores of 20, 50, and 70. A total of 36 subjects with severe disease were randomized into the three treatment arms [53]. Alefacept responses were superior to placebo with 58% and 25% of subjects achieving ACR 20 at 6 months in the 7.5-mg and 3.75-mg alefacept groups, respectively, as compared with 17% in the placebo group. ACR 50 and ACR 70 responses were 17% and 8%, respectively, for each of the alefacept arms at 6 months. Without any further intervention, all subjects in the 3.75-mg alefacept group who had achieved an ACR 20 response at 14 weeks maintained this benefit during the 12-week follow-up period. Alefacept selectively reduced circulating CD4+ and CD8+ T cells, with a return toward baseline levels during the follow-up period. The author predicts that because alefacept and methotrexate were well tolerated and without identifiable safety concerns in this small cohort of patients with RA, the combination will have a similar profile in patients with psoriasis.
Summary Alefacept is the first biologic agent to be approved for the treatment of chronic plaque psoriasis. By selectively targeting the memory T-cell population involved in the pathogenesis of psoriasis, alefacept provides durable clinical improvement without generalized immunosuppression. Moreover, alefacept is a safe and effective treatment for psoriasis, regardless of disease severity, prior treatment history, response to prior therapy, or the presence of contraindications to other systemic psoriasis therapies or phototherapy. Patients who respond to alefacept benefit from extended periods free of disease and its treatments. As experience with alefacept has grown, the favorable safety and tolerability profile has been confirmed in patients who have received up to six courses of therapy. There has been no evidence of an increased risk for infection or malignancy; no correlation between rates of infection, malignancy, and circulating CD4+/ CD8+ T-cell counts; and low immunogenicity. Research is ongoing to examine the use of alefacept in PsA and RA and its use in combination with other systemic psoriasis therapies and phototherapy.
Alefacept in rheumatoid arthritis T cells are believed to mediate the painful and disabling inflammation of synovial tissues observed in patients with RA [52]. Alefacept may prove to be a valuable treatment option in RA because studies have shown that it is the CD4+ memory subset of T cells that predominate in synovium [52]. A 6-month, randomized, double-blind, placebo-controlled, pilot study was conducted to assess the safety, tolerability, and efficacy trends of alefacept in patients with active RA despite treatment with methotrexate [53]. IV alefacept (3.75 mg or 7.5 mg) or placebo (n = 12/ group) was administered weekly for 12 weeks followed by 12 weeks of observation. All patients continued treatment with a stable dose of methotrex-
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G.G. Krueger / Dermatol Clin 22 (2004) 407426 liver WP, Ellis CN, for the Alefacept Clinical Study Group. A randomized, double-blind, placebo-controlled phase III study evaluating efficacy and tolerability of 2 courses of alefacept in patients with chronic plaque psoriasis. J Am Acad Dermatol 2002;47(6): 821 33. Lebwohl M, Christophers E, Langley R, Ortonne J-P, Roberts J, Griffiths CEM, for the Alefacept Clinical Study Group. An international, randomized, doubleblind, placebo-controlled phase 3 trial of intramuscular alefacept in patients with chronic plaque psoriasis. Arch Dermatol 2003;139:719 27. Langley R, Christophers E, Lebwohl M. Efficacy and safety of multiple courses of intramuscular alefacept in patients with chronic plaque psoriasis [abstract]. J Invest Dermatol 2002;119:344. Fredriksson T, Pettersson U. Severe psoriasisoral therapy with a new retinoid. Dermatologica 1978; 157(4):238 44. Vaishnaw AK, Ticho B. Alefacept is efficacious in a broad spectrum of patients with psoriasis, including those with severe disease. Presented at the 61st Annual Meeting of the American Academy of Dermatology. San Francisco, March 21 26, 2003. van de Kerkhof P, Vaishnaw AK, Kragballe K, Ortonne J-P. Alefacept is efficacious in a broad spectrum of patients with psoriasis. J Eur Acad Dermatol Venereol 2003;17(Suppl 1):55. Christophers E, OGorman J, Vaishnaw AK. Pooled efficacy of alefacept in psoriasis patients who are refractory or have contraindications to other psoriasis systemic treatments or phototherapies. Presented at the Ninth International Psoriasis Symposium. New York, June 18 22, 2003. Gordon KB, Langley RG. Remittive effects of intramuscular alefacept in psoriasis. J Drugs Dermatol 2003; 2:624 8. Gordon KB, Vaishnaw A, OGorman J, Haney J, Menter A. Treatment of psoriasis with alefacept. Correlation of clinical improvement with reductions of memory T-cell counts. Arch Dermatol 2003;139:1563 70. Ortonne J-P, Lebwohl M, Griffiths CEM. Alefaceptinduced decreases in circulating blood lymphocyte counts correlate with clinical response in patients with chronic plaque psoriasis. Eur J Dermatol 2003;13(2): 117 23. Chamian F, Novitskaya I, Khatcherian I, Gilleaudeau P, Sullivan-Whalen M, Lee E, et al. Therapeutic improvement induced by alefacept is linked to selective elimination of CD3+, CD8+ and CD103+ T cells from skin lesions of psoriasis vulgaris [abstract 88]. Br J Dermatol 2002;147:1077 8. Vaishnaw AK, Lee S. Concomitant use of alefacept and immunosuppressants in patients with psoriasis. Presented at the 61st Annual Meeting of the American Academy of Dermatology. San Francisco, March 21 26, 2003. Lebwohl M, Vaishnaw AK. Variability in circulating T-cell subsets among alefacept-treated and placebo-
Acknowledgments The author expresses appreciation to colleagues at Biogen for their willingness to provide key data and interpretation and to Mike McNamara of Scientific Connections for editorial support.
[14]
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[1] Frampton J, Wagstaff A. Alefacept. Am J Clin Dermatol 2003;4(4):277 86. [2] Gordon KB, McCormick TS. Evolution of biologic therapies for the treatment of psoriasis. SKINmed: Dermatol Clinician 2003;2:286 94. [3] Gottlieb AB, Bos JD. Recombinantly engineered human proteins: transforming the treatment of psoriasis. Clin Immunol 2002;105(2):105 16. [4] Krueger GG. Selective targeting of T cell subsets: focus on alefacepta remittive therapy for psoriasis. Expert Opin Biol Ther 2002;2(4):431 41. [5] Prinz JC. The role of T cells in psoriasis. J Eur Acad Dermatol Venereol 2003;17(3):257 70. [6] Cooper JC, Morgan G, Harding S, Subramanyam M, Majeau GR, Moulder K, et al. Alefacept selectively promotes NK cell-mediated deletion of CD45RO+ human T cells. Eur J Immunol 2003;33(3):666 75. [7] Majeau GR, Whitty A, Yim K, Meier W, Hochman PS. Low affinity binding of an LFA-3/IgG1 fusion protein to CD2+ T cells is independent of cell activation. Cell Adhes Commun 1999;7(3):267 79. [8] Sanders ME, Makgoba MW, Sharrow SO, Stephany D, Springer TA, Young HA, et al. Human memory T lymphocytes express increased levels of three cell adhesion molecules (LFA-3, CD2, and LFA-1) and three other molecules (UCHL1, CDw29, and Pgp-1) and have enhanced IFN-g production. J Immunol 1988;140(5): 1401 7. [9] Majeau GR, Meier W, Jimmo B, Kioussis D, Hochman PS. Mechanism of lymphocyte function-associated molecule 3-Ig fusion proteins inhibition of T cell responses. Structure/function analysis in vitro and in human CD2 transgenic mice. J Immunol 1994;152(6): 2753 67. [10] Miller GT, Hochman PS, Meier W, Tizard R, Bixler SA, Rosa MD, et al. Specific interaction of lymphocyte function-associated antigen 3 with CD2 can inhibit T cell responses. J Exp Med 1993;178(1):211 22. [11] da Silva AJ, Brickelmaier M, Majeau GR, Li Z, Su L, Hsu Y-M, et al. Alefacept, an immunomodulatory recombinant LFA-3/IgG1 fusion protein, induces CD16 signaling and CD2/CD16-dependent apoptosis of CD2+ cells. J Immunol 2002;168(9):4462 71. [12] Ellis CN, Krueger GG, for the Alefacept Clinical Study Group. Treatment of chronic plaque psoriasis by selective targeting of memory effector T lymphocytes. N Engl J Med 2001;345:248 55. [13] Krueger GG, Papp KA, Stough DB, Loven KH, Gul-
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Dermatol Clin 22 (2004) 427 435
Current concepts and review of efalizumab in the treatment of psoriasis

Craig L. Leonardi, MDa,b,*
a
Department of Dermatology, St. Louis University School of Medicine, 1755 S Grand, St. Louis, MO 63104, USA b Central Dermatology, 1034 South Brentwood Boulevard, Suite 600, St. Louis, MO 63117, USA
Psoriasis is commonly a disease of young adults with an average age of onset of 28 years. Those individuals with the more severe forms of the disease are thus faced with the requirement of decades of therapy using the traditional systemic approaches. The cumulative toxicities of these therapies, however, preclude their use in a chronic setting. To reduce these treatment-related side effects, dermatologists use various creative strategies in an attempt to control psoriasis. For example, rotational treatment paradigms are sometimes used, with the patient moving from a highly effective to a less effective therapy possessing a different side-effect profile. Alternatively, combination therapy is sometimes used with multiple agents at lower doses to reduce the risk of toxicity. Last, intermittent treatments are also used, with discontinuation of treatment and subsequent recurrence of the disease [1]. Many of these patients therefore have difficulty maintaining uninterrupted control of their symptoms and thus experience a significant impact of psoriasis on their lives. Furthermore, widespread dissatisfaction exists with the treatments and with those who prescribe them. There is a substantial unmet need for effective therapies that can be safely administered on a long-term basis. The pathophysiology of psoriasis has been dramatically reshaped by recent advances in cellular and molecular immunology. Physicians now understand the key role of T cells and their cytokine products in the pathogenesis of this chronic, inflammatory disease. This new knowledge, coupled with technologi-
cal advances in large-scale protein synthesis, has resulted in the ongoing development of more than two dozen biologic therapies that target the key steps in the inflammatory cascade. Efalizumab (Raptiva) is one of the promising new targeted immunomodulators designed to reduce inflammation in the body. It is currently the only biologic agent approved by the US Food and Drug Administration for continuous administration to adult patients with moderate to severe chronic plaque psoriasis.
Mechanism of efalizumab action and evidence of immunobiologic activity Efalizumab is a recombinant, humanized, monoclonal IgG1 antibody designed to down-regulate inflammatory processes in the body (Fig. 1). Administered once weekly by subcutaneous injection, efalizumab binds to CD11a, the a subunit of leukocyte function-associated antigen 1 (LFA-1). There, it disrupts the interaction between LFA-1 and one of its ligands, intercellular adhesion molecule 1 (ICAM-1). ICAM-1 is a cell surface molecule that is expressed by antigen-presenting cells (APCs) and is up-regulated on both endothelial cells and keratinocytes within psoriatic plaques [2]. Thus, efalizumab disrupts several of the key T-cell mediated steps involved in the pathogenesis of psoriasis: it destabilizes the binding of APCs and T cells, reducing the efficiency of initial T-cell activation in lymph nodes; it decreases the trafficking of T cells from the circulation into dermal and epidermal tissues; and it interferes with the secondary activation of memory-effector T cells in the target tissues (Fig. 2). Finally, because CD11a
* Central Dermatology, 1034 South Brentwood Boulevard, Suite 600, St. Louis, MO 63117. E-mail address: leonardi@centralderm.com
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C.L. Leonardi / Dermatol Clin 22 (2004) 427435
Phase 3 clinical experience with efalizumab Efalizumab therapy has been studied in more than 2700 patients. The results from a various large-scale placebo-controlled and open-label phase 3 trials demonstrate the rapid change and sustained efficacy seen in patients with psoriasis. In blinded trials, the primary endpoint was the percentage of patients achieving a 75% reduction in their Psoriasis Area and Severity Index (PASI-75) at 12 weeks as compared with a placebo group. In addition, several secondary endpoints were also assessed, including PASI-50 response, Overall Lesion Severity (OLS), Physicians Static Global Assessment, Dermatology Life Quality Index (DLQI), an Itching scale, and the Psoriasis Symptom Assessment (PSA) frequency and severity subscales.
Fig. 1. Space-filling model of efalizumab. This full-length IgG1 was originally developed in a murine system. Human DNA sequences have replaced all but 3% of the original murine sequences to reduce antigenicity.
Short-term results Efalizumab-treated patients experienced quick onset of action. Following initiation of therapy at 1 mg/kg/week, a statistically significant reduction in PASI was noted as early as 2 to 4 weeks [8 10]. These changes were most pronounced in the erythema, induration, and scale components of the PASI. In one trial, 22% of treated patients achieved PASI-75 after 12 weeks of treatment as compared with 5% of those who received placebo (P < 0.001) [8]. At the same time point, 52% of treated patients achieved a PASI-50 response. Overall, the mean improvement in PASI was 51% versus 17% (P < 0.001) [8]. In a second trial, 27% of efalizumab-treated patients achieved PASI-75 at 12 weeks as compared with 4% receiving placebo (P < 0.001). As expected, significant PASI-50 responses were also noted, with 59% versus 14% (P < 0.001) for the efalizumab and placebo arms, respectively [10]. In a third blinded, placebo-controlled trial, 39% versus 2.4% (P < 0.001) of patients achieved PASI-75 at 12 weeks for treated versus placebo groups, respectively. The PASI-50 responses seen in this trial were 61% versus 15% of treated and placebo groups, respectively [11]. These results are summarized in Fig. 4. In addition to PASI, all other physician-assessed measures of disease severity achieved statistical significance by week 12. This efficacy noted by the investigators was also paralleled by improvements in patient-reported outcome measures. Patients periodically evaluated the extent of their symptoms using an Itching scale and the bipartite PSA scale, which incorporated symptom frequency and severity subscales. At week 12,
expression is unique to LFA-1, the effects of efalizumab are believed to be confined only to those cells expressing LFA-1. Phase 1 and 2 trials have characterized the pharmacodynamic profile of efalizumab and demonstrated its clinical activity at the molecular level in patients with psoriasis. Upon administration by either intravenous or subcutaneous routes, efalizumab rapidly saturates cell surface CD11a on T cells and downregulates CD11a expression [3 7]. The effect is quickly reversed, however, with CD11a levels returning to normal 7 to 10 days following clearance of efalizumab from the circulation (Fig. 3) [7]. Histologic changes also accompany CD11a saturation and down-modulation. Reduced keratin 16 and ICAM-1 expression suggest diminished keratinocyte hyperproliferation and reduced cytokine-mediated inflammation, respectively. Other findings include thinning of the psoriatic epidermis, with a restoration of normal phenotype, and a marked reduction in the number of dermal and epidermal CD3+ T cells in lesional skin. A concomitant increase in the number of circulating CD3+ lymphocytes suggests that efalizumab prevents T-cell trafficking from the circulation into dermal and epidermal tissues. Clinically, a marked reduction of erythema, induration, and scaling is noted early in treatment followed by reduction in the involved body surface area [5,7].
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A
Activated APC Memory T Cell
Immunologic Synapse
ICAM-1 CD11a MHC TCR Antigen-Peptide CD4/CD8 LFA-3 CD2 CD40 CD40L B7 CD28 Costimulatory Molecules ICAM-1 CD3 LFA-1
Cytokine production T-Cell Activation Signals Keratinocyte hyperproliferation Inflammatory response Costimulatory Signals Effector-mediated killing response
LFA-1
T-Cell Reactivation, Proliferation, and Cytokine Production
Fig. 2. Mechanism of action. (A) In binding to CD11a, efalizumab disrupts the interaction of LFA-1 and ICAM-1, interfering with the activation of T cells as a primary or secondary event. (B) ICAM is expressed by endothelial cells in sites of inflammation. By disrupting the binding of LFA-1 to ICAM-1, efalizumab interferes with T-cell trafficking from the circulation into the dermis and epidermis. As a consequence, blood lymphocyte counts are increased (but still normal) in efalizumabtreated patients.
430
150
Percentage of Pretreatment Levels
100
Available CD11a binding sites during and after 8 weeks of treatment with efalizumab
50
0 0 2 4 6 8 10 12 14
Week Treatment No Treatment
Fig. 3. Efalizumab rapidly saturates CD11a binding sites on lymphocytes when administered intravenously or by subcutaneous routes. On discontinuation of therapy, the number of binding sites quickly returns to pretreatment levels.
improvements were found in the Itching scale (38% versus 0.2% for placebo, P < 0.001) andin the frequency (48% versus 18% for placebo, P < 0.001) and severity (47% versus 17% for placebo, P < 0.001) of symptoms as assessed by the PSA subscales. The functional and psychosocial impact of psoriatic symptoms on patients lives was captured using the DLQI [14]. Overall DLQI scores at week 12 were significantly improved as compared with placebo (47% versus 14%, P < 0.001) [10]. These data demonstrate
that efalizumab improved patient functionality, patient well-being, and the symptoms most important to patients with psoriasis, resulting in improved healthrelated quality of life.
Intermediate-term results One of the phase 3 trials showed that prolonging efalizumab therapy from 12 to 24 weeks improved
70 60
Percent of Patients
Efalizumab
50 40 30 20 10 0 Study 1 (n = 354) Study 2 (n = 556) Study 3 (n = 332)
PASI-50 PASI-75
Placebo
PASI-50 PASI-75
Fig. 4. Percentage of patients achieving PASI-75 or PASI-50 in efalizumab-treated (1 mg/kg/wk) and placebo groups. The results from three placebo-controlled trials are shown. Statistical significance was achieved in all three trials at both PASI-75 and PASI50 levels as compared with placebo.
431
12 Weeks
24 Weeks 66.6% PASI 75 PASI 50 43.8%
Percentage of Patients (%)
70 60 50 40 30 20 10 0 Placebo (n=187) Efalizumab 1.0 mg/kg/wk (n=369) 4.3% 13.9% 26.6%* *P < 0.001 vs placebo 58.5%*
Efalizumab 1.0 mg/kg/wk (n=368)
Fig. 5. Percentage of patients achieving PASI-75 at the primary endpoint (week 12) of a blinded, placebo-controlled trial and also in an open-label treatment extension to 24 weeks. Significant numbers of patients improved in the 12- to 24-week time period.
response rates and maintained clinical responses. Significant additional improvement was noted, with 44% and 67% of patients achieving PASI-75 and PASI-50, respectively. These results are shown in Fig. 5 [10]. As might be expected, the patientreported outcome measures were also maintained or improved throughout this extended dosing period [15 18].
Long-term results An ongoing open-label phase 3 trial is examining the efficacy and safety of patients treated with up to 3 years of continuous efalizumab therapy. To date, this
First 12 Weeks (n = 339)
56.6% 51.7%
is the longest ongoing trial evaluating the use of a biologic therapy in patients with psoriasis. Three hundred and thirty-nine patients entered the trial and received efalizumab for 3 months. At the end of this initial dosing period, 290 patients (82%) achieved either a PASI-50 response or an OLS of mild or clear and were allowed to continue in the maintenance phase of the trial for up to 3 years. A preliminary analysis of this ongoing trial shows excellent results: at 21 months, 55.9% of patients in the maintenance period achieved PASI-75. Furthermore, 30% (more than half) of these patients are PASI-90 responders (Fig. 6) [13]. The clinical response of a long-term treatment patient and the kinetics of his response are shown in Fig. 7. CollectMaintenance Period (ITT* n = 290)
57.2% 58.3% 56.2%
70
PASI 75 PASI 90
55.9%
Percentage of Patients
60 50
41.3%
40
29.0%
33.4% 30.0% 22.4% 13.0% 24.5% 25.9%
30 20 10 0 Month 3
Month 6
Month 9
Month 12
Month 15
Month 18
Month 21
Fig. 6. Percent of patients achieving PASI-75 and PASI-90 during 21 months of continuous therapy. This study is ongoing and will last 36 months. The analysis is intent-to-treat with respect to entry into the maintenance period and the last observation was carried.
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A Before Treatment Day 84
PASI = 15 BSA = 18% B

16 14
PASI = 0 BSA = 0%
PASI Score
12 10 8 6 4 2 0 0 1 2 3 4 5 6 7 8
PASI Score BSA %
20 18 16 14 12 10 8 6 4 2 0
9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
Month
Fig. 7. (A) Patient response to efalizumab therapy. *Tattoo has been covered to protect patients privacy. (B) Reduction in PASI and body surface area (BSA) in response to continuous efalizumab therapy. By 24 months, the patient maintained complete control of his psoriasis by weekly subcutaneous injections.
ively, these results demonstrate that efalizumab rapidly controls psoriasis symptoms and also seems to be an effective long-term maintenance treatment.
Safety With 2762 patients with psoriasis treated in 13 clinical trials, efalizumab represents the largest evi-
dence base in the psoriasis population for a biologic therapy. To date, more than 2400 patients have received efalizumab for at least 3 months, 904 for up to 6 months, and more than 225 for up to 1 year. In general, efalizumab has been well tolerated. Some patients experience acute flulike symptoms when efalizumab therapy is initiated, however, including headache, chills, fever, nausea, and myalgia. During phase 3 trials, these events most commonly
BSA %
433
occurred within 48 hours after administration of the first two doses and were primarily mild to moderate in severity and well tolerated when a conditioning dose (0.7 mg/kg) was administered the first time. By the third and all subsequent doses, the incidence of these acute adverse events was similar to placebo [8]. In the trials, fewer than 1% of patients withdrew from efalizumab treatment because of adverse events. The adverse events that occurred at least 2% more frequently in efalizumab versus placebo groups during the first 12 weeks of treatment in randomized, placebocontrolled, double-blind phase 3 trials are summarized in Table 1. Patients receiving long-term efalizumab therapy did not exhibit any increased incidence of adverse events over time nor did the safety profile change over time [12,13,19]. To date, there has been no evidence for cumulative toxicity or end-organ damage, or increased risk of infection or malignancy with prolonged dosing [13]. Serious adverse reactions occurred infrequently and included serious infections requiring hospitalization (0.3% of efalizumab patients versus 0.1% of placebo patients), thrombocytopenia with platelet counts lower then 52,000 (0.3% of patients), and worsening of psoriasis requiring hospitalization (0.7% of patients). As part of the trial design, some patients abruptly stopped therapy after 12 weeks of treatment. Although most had a gradual recurrence of their disease, 13.8% experienced significant worsening of their psoriasis and achieved the National Psoriasis Foundation definition of rebound (PASI-125 as compared with baseline or emergence of a new psoriasis morphology within 12 wk on discontinuation of treatment). An analysis of patients who experienced
rebound showed that it was most likely to occur in those who failed to achieve PASI-50 (ie, nonresponders). In addition, some patients randomized to receive placebo also had worsening of their psoriasis and achieved PASI-125. Antibodies to efalizumab were predominantly low-titer, detected in 6.3% (67 of 1063) patients and clinically irrelevant [20]. To date, the presence of anti-efalizumab antibodies has not been associated with changes in efficacy, safety or efalizumab pharmacodynamics [8]. The combined safety and efficacy profiles suggest that efalizumab is appropriate for continuous treatment and represents a significant advance not only for patients with psoriasis but also for the dermatologists attempting to treat them.
Practical concerns Given as a once-weekly subcutaneous injection, patients can self-administer efalizumab at home once they are trained and have demonstrated competency in reconstituting the drug, in loading the syringe, and in administering the injection. Patients receive the following: a 4-week supply containing four singleuse vials, each containing 125 mg of efalizumab as a sterile lyophilized powder; preloaded single-use syringes containing 1.3 mL of sterile water; alcohol swabs; instructions; and telephone support numbers, if necessary. The experience from one trial showed that patients rapidly learned this process and most found self-administration easy or very easy [21]. When efalizumab therapy is initiated, a single 0.7-mg/kg subcutaneous conditioning dose is recommended to diminish the incidence and severity of
Table 1 Adverse events in placebo-controlled study periods reported at a 2% or higher rate in efalizumab than placebo groups Adverse event Headache Infectiona Chills Nausea Generalized pain Myalgia Flu syndrome Fever Back pain Acne Placebo (N = 715) 159 188 32 51 38 35 29 24 14 4 (22%) (26%) (4%) (7%) (5%) (5%) (4%) (3%) (2%) (1%) Efalizumab (1 mg/kg/wk) (N = 1213) 391 350 154 128 122 102 83 80 50 45 (32%) (29%) (13%) (11%) (10%) (8%) (7%) (7%) (4%) (4%)
The most common adverse reactions associated with efalizumab were a first-dose reaction complex that included headache, chills, fever, nausea, and myalgia within 2 days following the first two doses. a Includes diagnosed infections and other nonspecific infections (most commonly upper respiratory tract infection). Data from Raptiva (efalizumab) [package insert]. South San Francisco, CA: Genentech, Inc.; 2003.
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acute adverse events. This dose is followed 1 week later by subcutaneous efalizumab (1 mg/kg/wk), with no single dose to exceed 200 mg. Patients should be instructed to rotate the injection sites between the thigh, abdomen, buttocks, and upper arm with each dose. Several studies have shown that efalizumab at 1 mg/kg/week is the optimal dose and that increasing to 2 mg/kg/week or even 4 mg/kg/week is unlikely to provide additional benefit. Efalizumab is best used as a continuous therapy for psoriasis. Because the effects of efalizumab on T cells are reversible, recurrence of disease is expected on discontinuation. The rebound phenomenon is easily avoided by transition to alternative treatments in patients who must permanently stop therapy or in those who fail to respond. During therapy, patients should be monitored for signs and symptoms of thrombocytopenia, and assessment of platelet counts is recommended on initiating therapy and periodically while receiving treatment. Efalizumab should be discontinued if thrombocytopenia occurs. Because efalizumab is a T-cell modulator, caution should be exercised in patients with a history of recurrent or chronic infection, and treatment should be temporarily stopped in patients with clinically significant infections. Efalizumab should not be routinely combined with other immunosuppressive therapies without close supervision. The most relevant circumstance for dermatologists will involve transition on or off therapy. Additional studies are underway to evaluate various entry or exit strategies. Because the role of efalizumab in the development of malignancies is not clear, caution should be exercised in high-risk patients, and treatment should be discontinued in the event of malignancy. Exceptions to this situation might include development of basal cell carcinoma or cutaneous squamous cell carcinoma. Until more data have accrued, a conservative approach is recommended. The safety and efficacy of vaccines administered to patients receiving efalizumab have not been fully characterized. An early study assessing the development of humoral immunity in response to inoculation with a neoantigen suggested that efalizumab might decrease immune responses on rechallenge. Until more data exist, live or live-attenuated vaccines should be avoided.
is approved as a single, once-weekly, subcutaneous injection for continuous administration in adults with moderate to severe chronic plaque psoriasis. Continuous therapeutic use, without the need for rotation to a new therapy or intermittent treatment discontinuation, represents an advance in psoriasis management. The results of multiple randomized, placebo-controlled, double-blind phase 3 trials have demonstrated consistent efficacy, and the safety database is the largest to date of a biologic therapy approved for psoriasis. In each trial, all efficacy endpoints reached statistical significance relative to placebo. Efalizumab is associated with a rapid onset of action, with improvement relative to placebo observed as early as 2 to 4 weeks after start of therapy. Patients achieve significant clinical benefit, as measured both by physicianand patient-assessed outcomes, and this benefit is maintained over the course of prolonged treatment periods. Efalizumab seems to provide rapid, sustainable symptom control, which allows patients to return to their normal activities of daily living. Biologic therapies, such as efalizumab, are changing the treatment landscape by offering hope for improved patient safety and uninterrupted control of psoriasis. Efalizumab seems to be appropriate for a wide range of patients, with convenient and welltolerated dosing schedules. The efficacy, safety, and tolerability of prolonged efalizumab therapy demonstrate the therapeutic value of this new agent in the management of patients with moderate to severe chronic plaque psoriasis.
References
[1] Weinstein GD, White GM. An approach to the treatment of moderate to severe psoriasis with rotational therapy. J Am Acad Dermatol 1993;28(3):454 9. [2] Das PK, de Boer OJ, Visser A, Verhagen CE, Bos JD, Pals ST. Differential expression of ICAM-1, E-selectin and VCAM-1 by endothelial cells in psoriasis and contact dermatitis. Acta Derm Venereol Suppl [Stockh] 1994;186:21 2. [3] Bauer RJ, Dedrick RL, White ML, Murray MJ, Garovoy MR. Population pharmacokinetics and pharmacodynamics of the anti-CD11a antibody hu1124 in human subjects with psoriasis. J Pharmacokinet Biopharm 1999;27(4):397 420. [4] Gottlieb A, Krueger JG, Bright R, Ling M, Lebwohl M, Kang S, et al. Effects of administration of a single dose of a humanized monoclonal antibody to CD11a on the immunobiology and clinical activity of psoriasis. J Am Acad Dermatol 2000;42(3):428 35. [5] Gottlieb AB, Krueger JG, Wittkowski K, Dedrick R, Walicke PA, Garovoy M. Psoriasis as a model for T-cell-mediated disease: immunobiologic and clinical
Summary Efalizumab is a new therapeutic option that may simplify psoriasis management for some patients. It
C.L. Leonardi / Dermatol Clin 22 (2004) 427435 effects of treatment with multiple doses of efalizumab, an anti-CD11a antibody. Arch Dermatol 2002;138(5): 591 600. Gottlieb AB, Miller B, Lowe N, Shapiro W, Hudson C, Bright R, et al. Subcutaneously administered efalizumab (anti-CD11a) improves signs and symptoms of moderate to severe plaque psoriasis. J Cutan Med Surg 2003; 7:198 207. Papp K, Bissonnette R, Krueger JG, Carey W, Gratton D, Gulliver WP, et al. The treatment of moderate to severe psoriasis with a new anti-CD11a monoclonal antibody. J Am Acad Dermatol 2001;45(5):665 74. Lebwohl M, Tyring SK, Hamilton TK, Toth D, Glazer S, Tawfik NH, et al. A novel targeted T-cell modulator, efalizumab, for plaque psoriasis. N Engl J Med 2003; 349:2004 13. Gordon KB, Toth D, Papp KA, Hamilton TK, Walicke P, Li N, et al. Efalizumab provides rapid clinical benefit for patients with moderate to severe plaque psoriasis. Presented at the Ninth International Psoriasis Symposium. New York, June 17 22, 2003. Gordon KB, Papp KA, Hamilton TK, Walicke PA, Dummer W, Li N, et al. Efalizumab for patients with moderate to severe plaque psoriasis: a randomized controlled trial. JAMA 2003;290:3073 80. Leonardi C, Camisa C, Swinehart JM, Gratton D, Tschen E, Caro I, et al. Subcutaneous efalizumab (anti-CD11a): promising results when used for the treatment of moderate to severe plaque psoriasis. Presented at the Meeting of the American Academy of Dermatology. New Orleans, February 22 27, 2002. Menter A, Toth D, Glazer S, Walicke P, Li N, Garovoy M, et al. Efficacy and safety of 24-week continuous efalizumab therapy in patients with moderate to severe plaque psoriasis. Presented at the Meeting of the American Association of Dermatology Academy. Chicago, July 25 29, 2003. Gottlieb AB, Gordon KB, Koo J, Lebwohl M, Walicke P, Li N, et al. Long-term efalizumab treatment maintains clinical benefit in patients with moderate to severe plaque psoriasis: updated findings from an open-label trial. Presented at the Meeting of the American Association of Dermatology Academy. Chicago, July 25 29, 2003.
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[6]
[7]
[8]
[9]
[10]
[11]
[12]
[13]
[14] Finlay AY, Khan GK. Dermatology Life Quality Index (DLQI)a simple practical measure for routine clinical use. Clin Exp Dermatol 1994;19(3):210 6. [15] Feldman SR, Carey W, Goldman M, Walicke P, Watrous M, Kaplowitz S, et al. Subcutaneous (SC) efalizumab (anti-CD11) significantly improves patient reported symptoms in patients with moderate to severe plaque psoriasis. Presented at the Summer Meeting of the American Academy of Dermatology. New York, July 31 August 4, 2002. [16] Koo JY, Tyring S, Smith S, Gordon KB, Nelson C, Glazer S, et al. Dermatology Life Quality Index (DLQI): improvements during subcutaneous (SC) efalizumab (anti-CD11a) treatment in patients with moderate to severe plaque psoriasis. Presented at the Summer Meeting of the American Academy of Dermatology. New York, July 31 August 4, 2002. [17] Gordon KB, Siegfried E, Carey W, Walicke P, Li N, Garovoy M, et al. Impact of 24 weeks of continuous efalizumab therapy on patient-reported outcomes in patients with moderate to severe plaque psoriasis. Presented at the Meeting of the American Association of Dermatology Academy. Chicago, July 25 29, 2003. [18] Menter A, Stone SP, Swinehart JM, Scannon M, Dummer W, Tschen E, et al. Subcutaneous efalizumab (antiCD11a) provides early symptomatic relief and continuous control of moderate to severe plaque psoriasis: focus on pruritus. Presented at the Summer Meeting of the American Academy of Dermatology. New York, July 31 August 4, 2002. [19] Lebwohl M, Papp KA, Tyring S, Miller JL, Bissonnette R, Walicke P, et al. Continued treatment with subcutaneous efalizumab is safe: pooled results from two phase III trials. Presented at the Annual Meeting of the American Academy of Dermatology. New York, July 31 August 4, 2002. [20] Raptiva (efalizumab) [package insert]. South San Francisco (CA): Genentech, Inc.; 2003. [21] Papp KA, Miller B, Lynde C, Caro I, Lowe N, Dummer W, et al. Efalizumab (anti-CD11a) retreatment: final results from an open-label study. Presented at the Meeting of the American Academy of Dermatology. San Francisco, March 21 26, 2003.
Dermatol Clin 22 (2004) 437 447
Psoriasis and its treatment with infliximab-mediated tumor necrosis factor a blockade
Laura Winterfield, MDa, Alan Menter, MDa,b,c,*
a
Department of Dermatology, University of Texas Southwestern Medical School, Dallas, TX, USA b Baylor University Medical Center, 5310 Harvest Hill Road, Suite 260, Dallas, TX 75230, USA c Texas Dermatology Associates, Dallas, TX, USA
Psoriasis is a chronic inflammatory skin condition, affecting approximately 2% of the US population [1 3]. It is seen predominantly in whites ( > 80% of cases) and occurs equally in men and women, with a typical onset between the age of 20 and 30 years [2]. Marked familial aggregation (30%) and a high concordance rate in monozygotic twins (65% 72%) indicate the role of a multifactorial genetic predisposition in the emergence of psoriasis [4]. Psoriasis can be triggered in predisposed persons by several factors, including bacterial infections, inflammatory insults, local trauma, psychologic stress, drugs (eg, lithium, b-blockers, and antimalarial agents), alcohol, and overexposure to the sun [5 8]. Skin involvement may range from minimal, with small focal lesions on the elbows, knees, or scalp, to extensive, with areas on the torso and extremities and, in rarer instances, whole body involvement. The most common plaque-type psoriatic lesions are usually easily recognized by the presence of three cardinal signs: acanthosis, erythema, and white or silvery scales. Pruritus and nail dystrophy are frequently associated. A subset of patients with psoriasis (up to 35%) develop or exhibit a progressive, inflammatory arthritis (psoriatic arthritis [PsA]), marked by joint swelling and pain; in most patients (!75%), psoriatic skin lesions precede such arthritis, whereas in approxi-
mately 15% of patients, joint pain presents before obvious skin lesions [9]. Treatment options for psoriasis vary widely with respect to mechanism of action, route of administration, efficacy, and adverse event risk. Minor skin involvement usually responds well to topical therapy (eg, corticosteroid-, vitamin D3-, or retinoid-containing products), and these formulations are associated with a low risk of troublesome side effects. Such treatments target local epidermal inflammation and acanthosis caused by keratinocyte hyperproliferation. In those patients with a larger area of involved skin or more severe symptoms, traditional phototherapy, ultraviolet B, and combined psoralen/long-wave ultraviolet radiation (PUVA), or systemic therapy, including oral retinoids, methotrexate, and cyclosporine, is required. These approaches have been shown to be highly effective in clearing psoriatic lesions [10,11] but may be associated with side effects, such as hepatotoxicity (methotrexate) and nephrotoxicity (cyclosporine) [11,12], teratogenicity and skeletal hyperostosis (oral retinoids) [13], and cancer (PUVA, cyclosporine) [14,15], which limit their long-term use. The safety limitations of conventional systemic treatments, however, and a growing understanding of the pathogenesis of psoriasis have stimulated intense interest in inhibiting the immunologic processes that contribute to the causes of psoriasis.
Support for this article was provided by an unrestricted grant from Centocor, Malvern, Pennsylvania. * Corresponding author. Baylor University Medical Center, 5310 Harvest Hill Road, Suite 260, Dallas, TX 75230. E-mail address: amresearch@texasderm.com (A. Menter).
Tumor necrosis factor in the pathogenesis of psoriasis Psoriasis is an immune disease of activated T cells and an exaggerated inflammatory response in the skin
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[16]. After passage through the skins endothelial cells, activated T cells secrete type 1 (Th1) cytokines: interferon l, interleukin 2 (IL-2), IL-6, IL-8, IL-12, and tumor necrosis factor a (TNF-a) [17]. These proinflammatory cytokines mediate several biologic actions, which perpetuate and amplify the inflammatory response, including induction of keratinocyte proliferation and dermal vascular changes. Because these cytokines drive skin inflammatory reactions and other immune responses, an emerging therapeutic strategy is selective deactivation of specific cytokines. As a key contributor to the clinical features of psoriasis, TNF-a is now considered an important therapeutic target in drug development. TNF-a exists as both transmembrane and soluble proteins. The membrane-bound form of TNF-a is cleaved by an enzyme to release a soluble circulating form. Both forms of TNF-a are believed to be biologically active. The soluble form may be more potent, however [18]. TNF-a can be produced by multiple cells of the body, including cells present in the dermis and epidermis of patients with psoriasis, such as activated T cells, keratinocytes, and Langerhans cells [19]. The concentrations of TNF-a and other inflammatory mediators in lesional skin from patients with
psoriasis are up-regulated [17,20]. Immunolabeling of TNF-a and its receptors is increased when compared with uninvolved skin. Furthermore, increases in TNF-a production by monocytes in the blood of patients with both active and inactive psoriasis correlate with the clinical severity of the psoriasis [21]. Also, the distribution of TNF-a differs between psoriatic and normal skin. In normal skin, TNF-a is found mainly in the epidermal basal cell layers and around eccrine ducts and sebaceous glands. In psoriatic skin, TNF-a is present throughout all epidermal layers and upper dermal blood vessels [22]. Through its pleiotropic actions, TNF-a is likely to be an important stimulus for the events leading to psoriasis, as summarized in Table 1. The presence of TNF-a within the dermis recruits macrophages to the area and induces secretion of other proinflammatory cytokines and chemokines. The interaction of TNF-a with the vascular endothelium leads to the enhanced expression of certain adhesion molecules and vascular endothelial growth factor, which encourages angiogenesis and facilitates migration of inflammatory cells. Finally, the increased production of proinflammatory cytokines, which is at least partially triggered by TNF-a, causes keratinocyte hyperproliferation. These actions serve to amplify, propagate, and main-
Table 1 Correlation between cellular actions of TNF-a and pathogenic mechanisms of psoriasis Cellular action of TNF-a Stimulates synthesis of proinflammatory cytokines, such as IL-1, IL-6, IL-8, and RANTES [74,75] Activates NFkB, a nuclear transcription factor [74,75,77] Stimulates transcription of keratin-6 gene promoter [79] Retards progression of keratinocyte cell cycle [85] Induces SKALP/elafin gene in keratinocytes [81] Correlation with psoriasis pathogenesis Hyperproliferative epithelium; proliferation of keratinocytes; T-cell and neutrophil activation; chemotaxis; increases ICAM-1 mRNA Decreases in the rate of apoptosis among keratinocytes Activates keratinocytes Decreases the rate of apoptosis among keratinocytes Expresses a proteinase inhibitor that the keratinocytes of normal skin do not express and that is involved in the regulation of the cutaneous inflammatory process Promotes keratinocyte proliferation and stimulates synthesis of proinflammatory cytokines. Protects cells from apoptosis Facilitates T-cell infiltration into the skin Promotes angiogenesis; with the creation of new blood vessels, T cells have increased access into the epidermis Facilitates Langerhans cell emigration and the initiation of immune responses against antigens encountered in epidermis Promotes migration of Langerhans cells from the epidermis
Increases type 1 vasoactive intestinal peptide receptor mRNA in keratinocytes [78] Increases plasminogen activator inhibitor type 2, a serine proteinase inhibitor [84] Stimulates production of ICAM-1 and other adhesion molecules [73,83] Increases VEGF directly and increases production of nitric oxide necessary for the induction of VEGF [76,86] Decreases E-cadherin expression [82]
Increases expression of CD44, a cell surface receptor for hyaluronate [80] Abbreviation: VEGF, vascular endothelial cell growth factor.
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tain the abnormal inflammatory response that is responsible for psoriasis and serve as the rationale for use of TNF-a blocking agents for the treatment of this disease.
cells could have beneficial clinical effects, but this finding has not yet been confirmed in vivo [25].
Clinical experience with infliximab Characterization of infliximab Infliximab (Remicade; Centocor, Malvern, Pennysylvania) is a TNF-a blocking agent approved for treatment of Crohns disease and rheumatoid arthritis (RA). It is a chimeric anti TNF-a monoclonal antibody made by joining the human IgG1 constant region to a murine-derived antigen-binding variable region [23]. Infliximab binds with high affinity to both soluble and transmembrane-bound forms of TNF-a and, in this manner, inhibits the ability of TNF-a to bind with its receptors and initiate the intracellular signaling that leads to gene transcription and subsequent biologic activity [24,25]. When present at molar excess over TNF-a, three infliximab molecules can bind to each molecule of soluble TNF-a, thereby blocking all receptor binding sites on the TNF. It does not bind with or inhibit the receptormediated activity of TNF-b or any other known antigen. The binding of infliximab to TNF-a is sustained, so that likelihood of dissociation and subsequent activity of TNF-a is low [26]. Because of its inhibition of TNF-a activity, infliximab also indirectly inhibits production of other proinflammatory cytokines, and its combined actions are likely to cause a reduction in proliferation of keratinocytes [19,27]. Finally, in vitro evidence indicates that the binding of infliximab to membrane-bound TNF-a results in lysis of TNF-producing cells by means of a complement- or antibody-dependent cell cytotoxicity mechanism. Reducing the population of such Randomized, controlled clinical trials An expanding literature documents the efficacy and safety of infliximab in the treatment of psoriasis. Clinical experience with infliximab in psoriasis ranges from randomized, placebo-controlled, double-blind trials to open-label studies and case series. Long-term follow-up studies and analyses of safety are also beginning to appear, providing important information about tolerability, safety, and durability of the beneficial clinical effects seen with infliximab. Three randomized, placebo-controlled trials of infliximab that evaluate improvement in psoriasis have been reported (Table 2) [28 30]. One was an investigator-initiated study of infliximab in patients with moderate to severe psoriasis (eg, !5% body surface area [BSA]) [29]. This trial assigned patients (N = 33) to receive either 5 mg/kg or 10 mg/kg of intravenous (IV) infliximab or placebo on weeks 0, 2, and 6 of the study, and these patients were evaluated initially until week 10 (eg, the induction phase). At baseline, randomized patients were clinically and demographically similar across the groups, with a mean age range of 35 to 51 years and mean Psoriasis Area and Severity Index (PASI) scores of 20 to 26. Beginning at week 2 of treatment and continuing through week 10, decreases in psoriasis severity were significantly greater with 5 mg/kg or 10 mg/kg of infliximab than with placebo. At week 10, a reduction of 75% or greater from the baseline PASI score (eg, PASI-75 response) was seen in 82% and 73% of
Table 2 Randomized, placebo-controlled trials with infliximab Study IIS phase 2 [29] Population Mod to sev plaque-type psoriasis Active PsA Mod to sev plaque-type psoriasis Treatment Infliximab, 5 mg/kg (n = 11) Infliximab, 10 mg/kg (n = 11) Placebo (n = 11) Infliximab, 5 mg/kg (n = 50) Placebo (n = 51) Infliximab, 3 mg/kg (n = 99) Infliximab, 5 mg/kg (n = 99) Placebo (n = 51) Duration of double-blind phase (wk) 10 Extension phase (wk) 10 26a
IMPACT [28] SPIRIT [30]
16 46
16 32a 10 26b
Abbreviations: IIS, investigated-initiated study; mod, moderate; sev, severe. a Open-label. b Blinded.
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patients given 5 mg/kg or 10 mg/kg doses of IV infliximab, respectively, whereas only 18% of patients treated with placebo reached this treatment goal. The results of evaluation of psoriasis from a larger investigator-initiated study, the Infliximab Multinational Psoriatic Arthritis Controlled Trial (IMPACT), support the results of the earlier study [29]. In IMPACT, 102 patients with PsA who had failed therapy with at least one traditional disease-modifying antirheumatic drug (DMARD) were randomized to either 5 mg/kg of infliximab or placebo, with infusions administered at weeks 0, 2, 6, and 14. In addition to significant improvements in joint signs and symptoms, based on American College of Rheumatology response criteria, patients exhibited significant improvements in psoriatic skin involvement. Among patients with a baseline PASI of 2.5 or greater, these scores decreased from 8.4 to 1.6 at week 16 with infliximab treatment [28]. By contrast, PASI scores worsened for those patients receiving placebo (from 8.4 to 9.3). Approximately 67% of patients randomized to infliximab infusions exhibited a 75% decrease in baseline PASI scores at week 16. Moreover, a subset of patients (n = 69) who participated in the IMPACT were receiving concomitant DMARD therapy at baseline; among these patients, 56 received concomitant methotrexate throughout the 16-week study period. PASI scores remained largely unchanged from baseline levels in those patients receiving methotrexate paired with placebo, indicating that methotrexate alone did not exert a positive effect on PASI scores. The Study of Psoriasis with Infliximab Induction Therapy (SPIRIT) trial [30] is to be fully reported at the 62nd annual meeting of the American Academy of Dermatology, but preliminary analysis noted rapid, dose-related improvements in psoriatic symptoms. The SPIRIT trial was a phase 2 multicenter, doubleblind, randomized, placebo-controlled study in patients (N = 249) with plaque psoriasis affecting 10% or more of their BSA; individuals were randomized in a 1:2:2 ratio to either placebo (n = 51), 3 mg/kg of infliximab (n = 99), or 5 mg/kg of infliximab (n = 99) infusions and treated at weeks 0, 2, and 6. Concomitant psoriasis therapy was prohibited with the exception of tar or salicylic acid containing shampoos during the study period. PASI assessments, qualityof-life questionnaires, and physician global ratings were scheduled every 2 weeks through week 10. Sustained efficacy of infliximab Results from extension phases in all three randomized trials of infliximab have been reported and
provide evidence of sustained efficacy (see Table 2). In the earlier investigator-initiated study, investigators followed up patients for an additional 16 weeks. At week 26, 33% and 67% of patients who received 5 mg/kg or 10 mg/kg, respectively, maintained a 75% improvement in PASI. Individuals were given single infusions of infliximab if a loss of response occurred (eg, <50% reduction in baseline PASI score) [31]. At week 26, 9 (41%) of 22 patients who had received infliximab during the double-blind phase exhibited a loss of response and required one or two additional infliximab infusions. This retreatment largely improved PASI scores but not to the extent seen with a full induction regimen. The 34-week (weeks 16 50) open-label extension of the IMPACT in patients with PsA showed that intermittent retreatment with infliximab effectively maintained skin and joint improvements [28]. Infusions of 5 mg/kg infliximab (at weeks 16, 18, 22, 30, 38, and 46) were administered to patients who had initially received either placebo or infliximab during double-blind infliximab treatment. Twelve (86%) of 14 patients who exhibited a PASI-75 response at week 16 sustained that level of improvement at week 50. The mean reduction in baseline PASI score was 81% at week 50. Moreover, patients who were initially given placebo and then switched to infliximab exhibited skin and joint responses of a similar magnitude to those who had received infliximab during the blinded phase of the study. The SPIRIT trial provided data during weeks 14 to 26 for 198 patients who received no further infliximab treatment after the initial three infusions at weeks 0, 2, and 6 [32]. At week 26, 14% and 30% in the 3-mg/kg and 5-mg/kg groups, respectively, maintained a 75% improvement in PASI. Collectively, the results of the extension phases of the randomized studies demonstrated that the benefit of infliximab induction treatment persists over time and is dose dependent, but is variable for individual subjects. Moreover, the data suggest that infrequent maintenance dosing may sustain clinically meaningful therapeutic responses for most patients. Uncontrolled, open-label trials Six uncontrolled trials of infliximab in patients with psoriasis or PsA have been reported (Table 3) [33 38]. These noncomparative trials examined response to infliximab therapy among small groups of patients (N = 6 to 16) with severe psoriasis or PsA refractory to other systemic therapies. Patients in these studies had undergone one or more courses of treatment with PUVA or DMARDs, such as methotrexate,
L. Winterfield, A. Menter / Dermatol Clin 22 (2004) 437447 Table 3 Noncomparative trials with infliximab First author Antoni [33] Salvarani [37] Cauza [34] Ogilvie [36] Chan [35] Schopf [38]
a
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Population All with PsA All with PsA All with PsA All with PsA 5 with psoriasis; 2 with PsA All with psoriasis
N 10 16 9 6 7 8
Treatmenta Infliximab, 5 mg/kg induction and then intermittently Infliximab, 3 mg/kg, at 0, 2, 6, 14, 22, and 30 wk Infliximab, 3 mg/kg, at 0, 2, 6, 14, and 22 wks Infliximab, 5 mg/kg, at 0, 2, and 6 wk Infliximab, 5 mg/kg, intermittently Infliximab, 5 mg/kg, at 0, 2, and 6 wk
Duration 12 mo 30 wk 22 wk 10 wk 15 mo 10 wk
Patients continued stable doses of other antiarthritis/psoriasis drugs.
but continued to exhibit PASI scores indicating substantial skin involvement. Across these studies, infliximab was administered as an induction regimen of either 3 mg/kg or 5 mg/kg at weeks 0, 2, and 6, and thereafter on an individualized basis or, in the case of longer-term studies, on an intermittent schedule. Furthermore, patients were usually maintained on a stable dose of the pre-existing treatment regimen. The magnitude and timing of improvements in psoriatic skin lesions seen in these noncomparative trials were largely comparable to those observed in the controlled trials. For example, Antoni et al [33] treated 10 patients with PsA with a 5-mg/kg infliximab induction regimen and reported an average decrease of 71% in PASI score at week 10. Likewise, Schopf et al [38] found that a 5-mg/kg infliximab induction regimen in eight patients resulted in a mean decrease of 89% in PASI at week 10. At week 14, 8 weeks following the last infliximab infusion, PASI scores were decreased by an average of 66% from baseline. Maintenance treatment over longer periods seems to preserve initial treatment response. For instance, after 44 weeks of intermittent infliximab treatment (every 8 wk), 8 of the 10 patients in the study reported by Antoni et al [33] exhibited PASI scores that decreased by an average of 71.3%. Similarly, in the largest uncontrolled trial, 16 patients with severe treatment-refractory PsA, treated with 3-mg/kg infliximab infusions at three consecutive 8-week intervals following an initial induction regimen, continued to show a robust treatment response. At week 30, PASI scores were decreased by an average of 86% from baseline [37]. Quality-of-life instruments showed that the improvement in skin involvement seen with longterm infliximab treatment can also have a significant positive effect on patients personal and health-related quality of life. Among patients repeatedly hospitalized for severe, recalcitrant psoriasis, those who received repeated intermittent infusions no longer required
hospitalization and exhibited significant improvements in quality of life, marked by the ability to return to full-time employment [35]. Thus, the results from these uncontrolled studies support those of the randomized trials, showing that infliximab is highly effective for the rapid improvement of severe psoriasis and PsA; furthermore, they suggest that prudent intermittent treatment seems to be critical for maintaining clinically relevant responses. Case series The first report of the efficacy of infliximab in treating psoriasis described the case of a 57-year-old woman who had refractory inflammatory bowel disease treated with infliximab. Infliximab infusion dramatically improved the patients psoriasis [39]. Since this observation, a growing number of case reports documenting the use of infliximab for psoriasis and PsA have appeared in the literature. They describe the treatment of patients (a total of 20 cases) who had longstanding, recalcitrant, or severe disease, affecting more than 50% of their BSA, including the face, hands, feet, and scalp [40 49]. In several instances, patients presented relatively uncommon types of psoriasis, including pustular, palmoplantar, and erythrodermic forms [41,43,47,49]. In some cases, patients had undergone prior treatment with most available topical, phototherapy, and systemic approaches, with skin lesions remaining refractory to therapy. As might be expected, many of these patients reported impaired quality of life, psychosocial difficulties, and depression [42,49]. In nearly all patients, infliximab treatment consisted of infusions of 3 to 10 mg/kg at weeks 0, 2, and 6, with intermittent maintenance treatments thereafter. Patients were maintained on pre-existing treatment regimens, often involving several agents, including methotrexate, cyclosporin and topical therapies, and
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nonsteroidal anti-inflammatory drugs for management of pain in patients with PsA. With the addition of infliximab to their treatment regimen, most patients (16 of 20) exhibited dramatic improvements in skin involvement. After 4 weeks of treatment among patients who responded well to infliximab treatment, lesions were described as reduced in area and severity, with improvements characterized by a significant reduction in redness and thickness, and healing of individual fissures. In some patients, PsArelated clinical symptoms, such as joint swelling and tenderness, also improved. Safety of infliximab More than 432,000 patients worldwide have received single or multiple doses of infliximab. Infliximab has been approved for use in moderate to severe or fistulizing Crohns disease, refractory to conventional therapies, and for combined use with methotrexate in RA, refractory to methotrexate alone. Therefore, infliximabs 10-year safety experience comprises predominantly patients with these conditions. Interpolating the adverse event profile of infliximab for patients with psoriasis from the safety database for patients with Crohns disease and RA may skew the analysis. Crohns disease and RA are chronic, debilitating systemic diseases associated with comorbidities for which patients may also be receiving other immunosuppressive therapies. Accordingly, the safety experience in these conditions may be less favorable than would be anticipated in patients receiving monotherapy with infliximab for moderate to severe psoriasis. Alternately, additional safety issues may be identified with expanded studies in a new patient population, such as in those with psoriasis alone. Safety and tolerability of infliximab in rheumatoid arthritis and Crohns disease Overall, infliximab has been well tolerated in controlled clinical trials involving patients with RA and Crohns disease. An integrated safety database is available that comprises nine open-label and placebo-controlled clinical trials involving 453 patients (Crohns disease, RA, and ulcerative colitis) who received at least one dose of infliximab [50]. The most frequent adverse events reported in 10% or more of infliximab-treated patients included headache, nausea, and upper respiratory tract infection (URI). Less frequently reported adverse events included abdominal pain, pharyngitis, fever, vomiting, coughing, rash, pain, rhinitis, sinusitis, urinary tract infection, fatigue, and pruritus. Infection was seen in 21% of patients
given infliximab compared with 11% in those given placebo. Serious adverse events associated with infliximab have been infrequent. Seven (1.5%) of 453 patients developed a lymphoproliferative disorder while undergoing infliximab therapy. A broader analysis, including 913 patients with RA or Crohns disease exposed to infliximab, showed that the rate of malignancy with infliximab was low and similar to rates expected in the general population based on the National Institutes of Health SEER database [50] Although safety statistics like these are encouraging, the long-term data still remain insufficient to answer the question of an increased risk for lymphoproliferative disorders and other malignancies [51]. Continued surveillance of all infliximabtreated patients is ongoing in an effort to conclusively define this issue. In the overall safety database analysis, infusion reactions, defined as any adverse event occurring during the infusion period or the 2-hour postinfusion observation period, were more common among infliximab-treated patients compared with those receiving placebo (16% and 6%, respectively) [50]. Among 1207 infliximab infusions, 5% (58 of 1207) were associated most commonly with nonspecific symptoms. Of these reactions, only four (0.03%) were considered serious; they were characterized by cardiopulmonary symptoms, such as chest pain, palpitations, hyper- or hypotension, and dyspnea [50]. In another report [52] documenting the frequency of infusion reactions to infliximab in 165 consecutive patients with Crohns disease, the overall incidence of infusion reactions was 6.1% (29 of 479) of infusions, affecting 9.7% (16 of 165) of patients. Mild, moderate, or severe acute reactions occurred in 3.1% (15 of 479), 1.2% (6 of 479), and 1.0% (5 of 479) of infliximab infusions, respectively. Typically, symptoms improved substantially or resolved completely after infusion rate adjustments alone or the addition of treatment with acetaminophen and antihistamines. Less commonly, steroids or epinephrine was administered. Pretreatment with these agents may also limit the reactions. Safety and tolerability of infliximab in psoriasis The safety experience for infliximab in patients with psoriasis is considerably smaller than that in the integrated analysis of safety in patients with Crohns disease and RA in clinical studies. In the investigatorinitiated study reported by Chaudhari et al [29], headache was the only adverse event that occurred more often with infliximab than with placebo. Infusion reactions were seen during the 16-week postinduction study phase in 4 (14%) of 29 patients treated
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with infliximab; these were all considered mild and transient [31]. Unlike the pattern of adverse events seen in the integrated analysis of infliximab safety data [50], the frequency of infection (including cellulitis in the placebo group and dental abscess, community-acquired pneumonia and otitis externa in the infliximab group) was similar between the placebo and infliximab groups (infliximab, n = 7; placebo, n = 6) [29]. This variance may be related to differences in the patient populations, with respect to morbidity and history of immunosuppressant use or the small patient numbers. In the SPIRIT trial, the most frequent adverse events in infliximab-treated patients were headache, pruritus, and URI [32]. The most frequently reported infections were URIs, sinusitis, and pharyngitis, the latter two occurring more frequently in the infliximab-treated groups compared with placebo. This finding may have been in part because of the shorter follow-up period in the placebo group. Similarly, in the IMPACT, the most frequent adverse events in infliximab-treated patients were URI, headache, nausea, sinusitis, and rash [53]. One patient developed an infection of the knee [28]. No opportunistic infections were reported in any of these three studies. Reactivation of latent tuberculosis Most people infected with Mycobacterium tuberculosis contain the initial infection and develop latent tuberculosis (TB). This state is characterized by evidence of an immune response against the bacterium (a positive tuberculin skin test [TST]), but no signs of active infection, including the absence of symptoms or chest radiograph evidence of disease [54]. The incidence of a positive TST without signs of active infection is approximately 1% in non-Latino individuals born in the United States, but may be higher in other ethnic groups [55]. Serious cases of reactivation of latent TB (both disseminated and nondisseminated presentations) have been reported with all TNF-a inhibitors [56 59]. Through February 2003, there were 537,000 patient years of exposure to infliximab in the United States and 109 cases of TB reported in infliximab-treated individuals. Thus, before starting TNF-a inhibitor therapy, patients should be screened for latent TB infection with a TST. Congestive heart failure Experimental evidence has suggested that TNF-a may be implicated in the pathogenesis of heart failure [60]. Three large-scale clinical trials of TNF-a inhibitors in patients with advanced congestive heart failure (CHF)one 150-patient study of infliximab [61]
and two etanercept (a fusion protein directed against TNF) trials involving a total of 2048 participants [62]were prematurely halted for lack of benefit or adverse outcomes, prompting a warning from the US Food and Drug Administration about the safety of these therapies for at-risk patients with RA. In the trial evaluating infliximab, the combined risk of death from any cause or hospitalization for heart failure was increased in the patients randomized to 10 mg/kg of infliximab relative to placebo (P = 0.043). A similar picture emerged from the two etanercept trials, which showed that the effects of the fusion protein were not different from placebo (P = 0.17 and P = 0.34, respectively). In support of the observations from these trials were reports to the MedWatch program on 47 patients who developed new or worsening CHF during TNF antagonist therapy. After TNF antagonist therapy, 38 patients developed new-onset CHF and 9 patients experienced heart failure exacerbation [63]. In contrast to the findings from these three trials and the MedWatch data, however, an abstract presented at the 2003 Annual Scientific Meeting of the American College of Rheumatology indicated that anti-TNF therapy conferred a cardioprotective effect in patients with RA [64]. The report examined medical records of 13,171 patients with RA from the National Data Bank for Rheumatic Disease over a period of 2 years and found that among those treated with anti-TNF therapies, the prevalence rate of CHF was significantly reduced. Demyelinating conditions As TNF-a antagonists have become increasingly used, there have been several reports of demyelinating and other central nervous system events in patients receiving TNF antagonists [65]. Although the causal relationship between these demyelinating events and currently available TNF-a antagonists remains unclear, it seems prudent to avoid use of TNF-a antagonists in patients with a history of demyelinating disease. Formation of anti-infliximab antibodies All biologic TNF-a inhibitors (eg, infliximab, etanercept, and adalimumab) are foreign proteins and therefore potentially immunogenic [66]. Antibody data are highly dependent on the sensitivity and specificity of the assay method used, however, so comparison of the incidence of antibodies to infliximab with the incidence of antibodies to other products may be misleading. Although the clinical relevance of antibodies to the anti TNF-a inhibitors is difficult to define, it is possible that immune responses that
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develop following treatment with foreign proteins may limit the efficacy of such treatments and increase the incidence of adverse events [67]. It has been shown that the development of antibodies to infliximab (ATI) can be reduced by several approaches, including appropriate dose selection, use of concomitant immunosuppressive agents, and administration of regular maintenance doses. The effect of dose on antibody formation and concomitant immunosuppressive therapy was demonstrated in a phase 2 RA study evaluating an infliximab induction regimen of 1 mg/kg, 3 mg/kg, or 10 mg/kg, with and without methotrexate [68]. With infliximab monotherapy, 53%, 21%, and 7% of patients with RA exhibited ATI when treated with 1 mg/kg, 3 mg/kg, and 10 mg/ kg of infliximab, respectively. Antibody titers were reduced at each dose level with concomitant methotrexate to 15%, 7%, and 0%, respectively. The data for treatment in the absence of immunosuppressant agents are similar to the results presented for the development of ATI in the SPIRIT trial. Following induction dosing at weeks 0, 2, and 6, 27.5% of patients with psoriasis receiving 3 mg/kg and 19.5% of patients receiving 5 mg/kg of infliximab were antibody positive by week 26 [69]. Furthermore, the titer of ATI was generally low, with 37 of 38 subjects positive for antibodies presenting with titers less than or equal to 1:40. Regular maintenance dosing with infliximab has been associated with a reduced incidence of antibody formation in clinical studies. In a trial in patients with active Crohns disease [70], individuals who received a single infusion of infliximab showed a 28% incidence of ATI compared with an 8% rate in those receiving induction and regular maintenance infusions of infliximab. Also, the frequency of ATI in patients with RA who were administered induction and maintenance doses of infliximab was 9%, similar to the rate in patients with Crohns disease who received maintenance infusions [71]. Additional studies are ongoing to determine the incidence of ATI in patients with psoriasis receiving long-term maintenance and intermittent treatment. ATI may influence the frequency of infusion reactions [70]. A higher incidence of these events was seen in Crohns disease and RA trials in patients with ATI compared with those who were antibody negative or inconclusive for antibodies [70,72]. Most infusion reactions were mild to moderate in nature, and there was no correlation with the presence of ATI and serious infusion reactions in the Crohns disease and RA studies. The potential for loss of response in conjunction with ATI is a concern, but regular maintenance
treatment with infliximab seems to sustain response even in the presence of ATI. For example, in patients with Crohns disease who were administered maintenance treatment, the proportion of subjects achieving a clinical response after 1 year was similar in antibody-positive and antibody-negative subjects [70]. When infliximab is administered intermittently, however, there is evidence from a cohort of 125 consecutive patients with Crohns disease who were treated as needed with infliximab that indicates efficacy may decrease in patients who develop sufficient concentrations of ATI [72]. Specifically, 36 of 53 patients initially responded well to 5 mg/kg of infliximab, but among those who developed ATI (n = 19), 11 (58%) exhibited a loss of response to infliximab treatment. Moreover, none of the patients in the trial who exhibited a continued response to infliximab (n = 21) were ATI positive.
Summary Evidence that the proinflammatory cytokine TNF-a plays a major role in the development and maintenance of psoriasis is the rationale for the use of anti TNF-a therapies. Infliximab is a chimeric human-murine antibody that selectively blocks the activity of TNF-a. Randomized, controlled clinical trials, open-label investigations, and case reports have shown that infliximab therapy leads to rapid, substantial improvements in psoriasis lesions that are among the highest seen with use of the systemic agents to date. Significant improvement in psoriatic joint involvement also has been reported. Importantly, the burden of organ toxicity with biologic therapy is lower, with no clear indication to date of hepatotoxicity, nephrotoxicity, skeletal changes, or teratogenicity that may result from traditional systemic therapies. As with other biologic agents, because of the relatively short-term (5 10 y) safety data, it is impossible to be certain at this time about the increased malignancy risk. Potential concerns and questions related to the immunosuppressive and immunogenic properties of infliximab, including increased risk of infection, infusion reactions, and waning therapeutic response in the psoriasis population, are currently being fully examined and characterized in phase 3 trials. The ongoing studies of infliximab in patients with moderate to severe psoriasis will yield a more sophisticated understanding of the benefits and risks associated with this treatment option and ultimately determine the role of this biologic agent in the psoriasis armamentarium.
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The treatment of psoriasis and psoriatic arthritis with etanercept: practical considerations on monotherapy, combination therapy, and safety
Paul S. Yamauchi, MD, PhDa,b,*, Vivian Gindi, MDa,b, Nicholas J. Lowe, MD, FRCPa,b
b a Clinical Research Specialists, 2001 Santa Monica Boulevard, Suite 490W, Santa Monica, CA 90404, USA Division of Dermatology, University of California at Los Angeles School of Medicine, Los Angeles, CA, USA
Etanercept is a recombinant fusion protein that is currently approved by the Food and Drug Administration (FDA) for the treatment of rheumatoid arthritis, polyarticular-course juvenile rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, and in April 2004, approved for the treatment of moderate to severe plaque psoriasis. Etanercept is manufactured by Amgen under the trade name Enbrel. Etanercept is manufactured by Amgen under the trade name Enbrel. Etanercept was first used in human clinical studies in 1992, and in 1995 the rheumatoid arthritis studies were initiated. In 1998, etanercept was FDAapproved for the treatment of rheumatoid arthritis. Four years later, etanercept became the first FDAapproved drug for the treatment of psoriatic arthritis. Of all the biologic agents that are in use or potentially will be used for the treatment of psoriasis and psoriatic arthritis, etanercept has the longest track record for safety data and current evidence supports the efficacy of etanercept in the treatment of psoriasis [1,2]. Up to 42% of patients with psoriasis develop psoriatic arthritis [3]. Both diseases are immunologi-
cally driven by overproduction of an inflammatory cytokine called tumor necrosis factor-a (TNF-a) [4,5]. Etanercept is a disease-modifying drug by acting as a soluble TNF-a receptor that competitively binds to TNF-a. Once bound to etanercept, TNF-a is prevented from binding to cell surface receptors on target cells and its proinflammatory effects are thereby blocked.
Role of tumor necrosis factor-A in psoriasis and psoriatic arthritis Tumor necrosis factor-a is a proinflammatory cytokine with a molecular weight of approximately 17 kd. TNF-a is expressed in psoriatic disease mainly by activated macrophages and monocytes but is also produced by other cell types found within psoriatic plaques including dendritic cells, Langerhans cells, and T cells. TNF-a exerts a wide range of biologic activities that include antiviral properties, growth regulation of different cell types, and immunomodulation of several signal transduction cascades.
Mechanism of action
* Corresponding author. Clinical Research Specialists, 2001 Santa Monica Boulevard, Suite 490W, Santa Monica, CA 90404. E-mail address: psyamauchi@earthlink.net (P.S. Yamauchi).
One major mechanism of action of TNF-a is the induction of other inflammatory cytokines, such as interleukins-1, -2, -6, and -8; granulocyte-macrophage colony-stimulating factor; and interferon-g [4].
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Other inflammatory molecules induced by TNF-a, such as prostaglandin and leukotriene synthesis, are well known to incite bone resorption and cartilage degradation in arthritis [5,6]. In addition, TNF-a stimulates collagenase and matrix metalloproteinase production by neutrophils and fibroblasts that lead to tissue and joint damage [5,7]. Tumor necrosis factor-a also stimulates T-cell adhesion to the endothelium through the up-regulation of adhesion molecules on the surface of endothelial cells. One report demonstrated the TNF-a dependent up-regulation of intercellular adhesion molecule type 1, E-selectin, and vascular cell adhesion molecule type 1 on endothelial cells [8]. The induction of T-cell trafficking into the dermis through adhesion molecule binding in the vasculature is an important signaling event in the pathogenesis of psoriasis There are two major receptor variants for TNF-a: the p55 and p75 receptors. These high-affinity receptors are bound to the surface of the cells, such as macrophages, lymphocytes, keratinocytes, and endothelial cells, and are composed of the extracellular binding site for TNF-a, the transmembrane domain, and the cytoplasmic tail, which is responsible for signal transduction through the activation of NFkB [9]. In addition, there are soluble receptors for TNF-a that are not membrane-bound that seem to act as competitive inhibitors for TNF-a binding to cell surface receptors. The activity and levels of these soluble receptors are not sufficient enough, however, to inhibit the inflammatory cascade caused by TNF-a in disease states, such as psoriasis and psoriatic arthritis [10,11]. Levels of TNF-a receptors are up-regulated in epidermal dendritic cells and keratinocytes following treatment with TNF-a [12]. Several studies have demonstrated that TNF-a is implicated in the pathogenesis of psoriasis and psoriatic arthritis. TNF-a levels have been shown to be
increased in psoriatic plaques and in the synovial fluid of patients with active psoriatic arthritis [13,14]. TNF-a concentrations are also increased in the serum of patients with psoriasis and in suction blisters induced in psoriatic patients [15]. Furthermore, levels of TNF-a have been shown to correlate with disease severity (ie, increasing during worsening of the psoriasis and decreasing after effective therapy) [15 18]. Acute-phase reactants, which are elevated in inflammatory arthritides, correlate with the expression of TNF-a in the serum and synovial fluid [19].
Structure and function of etanercept Because there is significant correlation between disease activity of psoriasis and psoriatic arthritis and TNF-a levels, direct antagonism of TNF-a is a logical treatment modality. Etanercept is a recombinant molecule comprised of the extracellular binding domain of the TNF-a p75 receptor fused to the Fc portion of IgG1 molecule (Fig. 1). The molecular weight of etanercept is 150 kd consisting of 934 amino acids and is almost 10 times larger than insulin. Etanercept is a fully human dimeric fusion protein produced by Chinese hamster ovary cells and functions as a TNF inhibitor by binding to and inactivating both free and membrane-bound TNF-a thereby preventing interactions with its cell surface receptors. Studies have demonstrated that etanercept does not induce complement mediated TNF-a cell lysis in vitro and has very low immunogenicity. The Fc portion of IgG1 serves to stabilize etanercept and prolong the median half-life, which is 4.8 days. The dimeric form of etanercept allows binding to two TNF-a molecules at an affinity 50 to 1000 times greater than the naturally occurring soluble mono-
Fig. 1. Structure of etanercept.
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meric form of the TNF-a receptor [20]. This accounts for the greater inhibitor activity of etanercept than the natural soluble receptor [21].
tion site reactions, patients are instructed to place their injections at least an inch apart from the prior injection site or to inject at contralateral sites.
Indications, dosage, and usage of etanercept Etanercept is FDA-approved for the treatment of rheumatoid arthritis, polyarticular-course juvenile rheumatoid arthritis, ankylosing spondylitis, and psoriatic arthritis, and more recently, moderate to severe psoriasis. The dosage of etanercept for adults is 50 mg per week continuously for rheumatoid arthritis, ankylosing spondylitis, and psoriatic arthritis. For the treatment of psoriasis, the initial dosage of etanercept is 50 mg twice weekly for 12 weeks followed by stepdown dosing to 50 mg weekly continuously. For pediatric patients with juvenile rheumatoid arthritis (4 to 17 years), the dosage is 0.8 mg/kg/wk (50 mg maximum per week). The drug is self-administered by the patient subcutaneously. Etanercept is supplied as a sterile, preservativefree, lyophilized powder for subcutaneous injection after reconstitution with 1 mL of supplied bacteriostatic water. Each vial contains 25 mg of etanercept plus stabilizers including 10 mg sucrose, 40 mg mannitol, and 1.2 mg tromethamine. At the time of this writing, etanercept will be available as 50 mg doses per vial. Etanercept is stored in the refrigerator and should not be frozen. Reconstituted etanercept is stable for up to 14 days in the refrigerator. The supplied syringe does not contain any latex. The frequency of dosing is once or twice a week depending on the indication. Because etanercept is supplied as 25-mg doses per vial, for the 50-mg weekly dosing, patients are instructed to administer two shots the same day and can be given at the same time. Alternatively, etanercept can be administered 25 mg twice a week, spaced every three to four days. For psoriasis, the initial dose is 50 mg twice weekly for the first 12 weeks and patients administer etanercept as two 25-mg injections twice weekly every three to four days (four injections per week). The dosage is then stepped down to 50 mg weekly continuously (two injections per week). With the advent of the 50-mg vial, the number of injections will be reduced to half (two shots per week for 12 weeks and then one shot per week for psoriasis). Pediatric patients can administer etanercept once a week at 0.8 mg/kg or in divided doses twice a week at 0.4 mg/kg. The most common locations for subcutaneous injections are the abdomen, thighs, and upper arms. To minimize injec-
Clinical efficacy in psoriatic arthritis The safety and efficacy of etanercept were assessed in a phase III randomized, double-blinded, placebo-controlled study for 24 weeks in 205 patients with active psoriatic arthritis. Patients were randomized equally to receive either etanercept, 25 mg, twice weekly or placebo twice weekly. Patients with psoriatic arthritis were between 18 and 70 years of age and had greater than or equal to three swollen joints and greater than or equal to three tender joints with one or more of the following joint diseases: distal interphalangeal involvement, polyarticular arthritis, arthritis mutilans, asymmetric psoriatic arthritis, or ankylosing spondylitis. These patients also had plaque psoriasis with a qualifying lesion of greater than or equal to 2 cm in diameter. Patients who were on methotrexate therapy for more than 2 months could continue the methotrexate if the dose was less than 25 mg per week. The primary end point in the study for psoriatic arthritis was the American College of Rheumatology 20 definition of improvement as set forth by the FDA. These guidelines include a 20% improvement in both tender and swollen joints plus 20% improvement in three of the following: patients pain assessment, patients assessment of disability, physicians global assessment, patients global assessment, or C-reactive protein or erythrocyte sedimentation rate. In those patients with psoriatic arthritis who received etanercept, the clinical responses were evident 4 weeks into treatment and were maintained through the 24 weeks of treatment. At 12 weeks, 59% of the patients who received etanercept achieved the American College of Rheumatology 20 response compared with 15% in the placebo group. The responses were similar to patients who were or were not receiving concomitant methotrexate therapy. At week 12, 62% of patients who received concomitant etanercept plus methotrexate attained the American College of Rheumatology 20 response compared with 58% in the group who received etanercept alone. In addition, the skin lesions of psoriasis were also improved with etanercept in this trial, relative to placebo, as measured by percentages of patients achieving improvements in the Psoriasis Area and Severity Index (PASI). Responses increased over time, and at 24 weeks the proportions of patients
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achieving a 50% or 75% improvement in the PASI were 47% and 23%, respectively, in the etanercept group compared with 18% and 3% in the placebo group, respectively. Mease et al [2] showed that twice weekly subcutaneous injections of etanercept (25 mg) for 12 weeks resulted in substantial remission of both psoriasis and psoriatic arthritis. Eighty-seven percent of patients with psoriatic arthritis had a reduction in their arthritis as measured by the psoriatic arthritis response criteria versus 23% of placebo patients. The American College of Rheumatology 20 was achieved by 73% of etanercept-treated patients compared with 13% of placebo-treated patients. In addition, 26% of the etanercept-treated patients achieved a 75% improvement in the PASI compared with none in the placebo-treated group. The median PASI improvement was 46% in etanercept-treated patients versus 9% in placebo-treated patients.
Radiographic response In the phase III psoriatic arthritis study, radiographic changes were also assessed. Radiographs of the hands and wrists were obtained at baseline and at months 6 and 12. A modified total sharp score that included the distal interphalangeal joints was used to measure the degree of pencil-and-cup deformity, joint space changes, gross osteolysis, and ankylosis. More patients in the placebo group exhibited larger magnitudes of radiographic worsening compared with the etanercept-treated group. At the end of 1 year, etanercept inhibited radiographic progression of joint space narrowing and erosions compared with placebo, which led to progressive worsening [22].
Clinical efficacy in psoriasis The phase II and III trials of etanercept as monotherapy treatment for chronic plaque psoriasis have demonstrated significant clearance of psoriatic plaques. The phase II trial was a 24-week, multicentered, double-blinded, placebo-controlled study in which 112 patients with moderate to severe psoriasis (more than 10% of their body surface area) who had received prior systemic treatment were enrolled. Patients were randomized to receive 25 mg etanercept twice a week (N = 55) or placebo (N = 57). At weeks 12 and 24, 30% and 56% of patients who received etanercept achieved a 75% improvement in the PASI score, respectively, versus 2% and 5% of the placebo group at the same time intervals.
The onset of action of etanercept is of moderate rapidity. After 4 weeks of therapy, there was about an overall 28% improvement in the PASI score. Almost 40% of the patients attained a PASI 50 improvement by week 4. In addition, the Dermatology Life Quality Index (DLQI) was measured in the phase II trial. The DLQI is a reliable 10-question survey completed by the patient that analyzes the impact various skin diseases, such as psoriasis, have on a patients quality of life [23]. Physical and social elements including pain, itching, occupation and school performance, leisurely activities, and relationships are measured by the DLQI. The improvement in the DLQI scores correlated well temporally with the improvement in PASI scores. There were two phase III trials conducted for the treatment of psoriasis with etanercept: the Global phase III trial and the United States phase III trial [1]. The Global phase III trial was a 6-month, doubleblinded, multi-centered, placebo controlled study in which patients were randomized to receive either placebo (N = 204), etanercept 50 mg weekly (N = 204), or etanercept 50 mg twice-weekly (N = 203) for 3 months. Thereafter, all patients were crossed-over to receive etanercept at 50-mg weekly for the next 3 months. The data was adjusted for the intent-to-treat analysis. At 3 months, 46% of the patients attained a PASI 75 improvement in the 50-mg twice-weekly dose compared to 3% in the placebo group. When the dosage of etanercept at 50 mg twice weekly for 3 months was stepped down to 50 mg weekly for 3 additional months, the improvement was sustained with 50% of the patients attaining a PASI 75 improvement at 6 months. The phase III trial conducted in the United States was a double-blinded, multi-centered, placebocontrolled study divided into 2 parts. In the first part, patients were randomized to receive placebo (N = 168), etanercept at 25 mg weekly (N = 169), 50 mg weekly (N = 167), or 50 mg twice weekly (N = 168) for 6 months. In the placebo group, after receiving placebo for 3 months, the patients were crossed over to receive etanercept at 50 mg per week. The data was adjusted for the intent-to-treat analysis. At 3 months, 49% of the patients attained a PASI 75 improvement in the 50-mg twice-weekly dose compared to 4% in the placebo group, 34% at the 50-mg weekly dose, and 14% in the 25-mg weekly dose. There was continued improvement with longer, continuous treatment. At 6 months, 59% of the patients attained the PASI 75 improvement in the 50-mg twice-weekly dose, 44% in the 50-mg weekly dose, and 25% in the 25-mg weekly dose. Patients in
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the original placebo group who were crossed over to receive etanercept at 50-mg weekly at month 3 exhibited improvement of their psoriasis with 33% of them achieving the PASI 75 improvement a response rate consistent with that in the 50-mg once-a-week dose at 3 months (34%). In the second part of the United States phase III trial, the abrupt discontinuation and retreatment with etanercept were evaluated. For all patients who attained a PASI 75 or greater improvement at any dose (N = 409), when etanercept was abruptly discontinued, the median time to loss of response (defined as loss of half the of the PASI improvement) was 85 days. In addition, in the 409 patients observed during the discontinuation period, there was no conversion of morphology (pustular psoriasis, erythrodermic psoriasis, or unusual morphology), no serious adverse events or hospitalizations due to withdrawal, and no study discontinuation due to adverse events. Only one patient (25 mg once per week of etanercept) out of the 409 evaluated during the withdrawal phase had an episode of rebound. When patients were retreated with etanercept following loss of response, the PASI 75 response rates after 3 months of retreatment with etanercept were similar to PASI 75 response rates seen after the initial 3 months of treatment with etanercept. No significant tachyphilaxis with etanercept was evident with repeated treatments. In addition, retreatment with etanercept was not associated with increased antigenicity or formation of neutralizing antibodies. The onset of action with etanercept was rapid in the phase III trials. The improvement in the PASI scores was statistically significant over placebo for all three doses as early as 2 weeks. Higher dosages of etanercept resulted in faster clearance of the psoriasis. The DLQI was also assessed in the phase III trial and improvements in the DLQI correlated well temporally with the improvement in the PASI scores at all doses used in the study. Finally, etanercept was well tolerated at all dosages with no increased adverse events evident at the 50-mg twice-weekly dose. The results of the Global and United States phase III trials underscore several important points. There is a dose-dependent response rate with etanercept as evidenced by higher dosages of etanercept exhibiting faster response rates and higher efficacy. At 6 months, efficacy with step-down dosing from 50 mg twice weekly to 50 mg weekly was similar to 50-mg twice-weekly dosing continuously. Etanercept was not associated with rebound following abrupt discontinuation, and retreatment with etanercept resulted in comparable reestablishment of clinical response. Finally, there was no increased in-
cidence of adverse events evident with higher doses of etanercept.
Safety: frequently asked questions Between May 1, 1993, and December 31, 2001, over 121,000 patients have received etanercept in controlled clinical trials and in clinical practice. Of all the biologic agents that are currently in use or potentially will be used for the treatment of psoriasis and psoriatic arthritis, etanercept has the longest track record for safety data. Injection site reactions In clinical trials, the adverse event that occurred more frequently in patients treated with etanercept over the placebo group was transient injection site reactions. These injection site reactions typically occurred 2 to 3 weeks into treatment and consisted of erythema, pain, itching, or swelling. The mean duration of the reaction was approximately 3 to 5 days. A biopsy of an injection site reaction revealed a perivascular lymphohistiocytic reaction in the dermis but there was no evidence of a panniculitis (authors personal observations). Topical steroids, oral antihistamines, and compresses are typically used to alleviate injection site reactions. In the clinical trials, injection site reactions did not become severe enough to warrant discontinuation of etanercept. Does etanercept increase risk of malignancies? The long-term safety data in clinical trials show the incidence of malignancies was not increased in the etanercept-treated group when compared with the expected number from the National Cancer Institutes database [24]. The expected number of malignancies was 42 and the observed incidence was 41. There were no predominant types of malignancies observed and a total of five lymphomas were reported. In postmarketing surveillance (N = 127,379), the observed number of malignancies was 277 and the expected incidence was 1020. In addition, a study has demonstrated that lymphoma rates are low but increased in patients with psoriasis [25]. Patients with psoriasis had a 2.95 relative rate of developing lymphoma compared with those without psoriasis. As a TNF-a inhibitor, however, there is always the possibility that etanercept can affect the immune systems response to cancer and specific concerns and risks versus benefits should
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be discussed with the patient, especially if there is a history of malignancy. Does etanercept increase the risk of serious infections? The rates of infection that required hospitalization or parenteral antibiotic therapy were 0.04 per pt-year in the etanercept-treated group in clinical trials [24]. This rate is very similar to the total population, which was 0.03 to 0.09 per pt-year. In postmarketing surveillance, the reported rate is 0.007 per pt-year. There have been rare cases of serious infections and sepsis, which included fatalities when patients were on etanercept. Patients who are on concurrent immunosuppressants, or patients who have serious underlying medical conditions, such as diabetes, that make them predisposed to infections may be at increased risk of infection when administered etanercept and caution should be exercised when considering etanercept. Should etanercept be discontinued if an infection develops? There are no specific guidelines regarding the discontinuation of etanercept in patients who develop an infection and patient situations should be assessed individually. Patients who develop a new infection while on etanercept therapy should be closely monitored. In the authors opinion, etanercept should not be administered to patients with sepsis or active infections, including chronic or localized infections. Until the infection subsides, etanercept should be discontinued temporarily. Is laboratory testing required for patients on etanercept? There is no specific laboratory or blood testing that is required to monitor treatment with etanercept. No correlation exists with organ toxicity, such as hepatotoxicity or nephrotoxicity, with etanercept. There have been rare cases of pancytopenia reported with the usage of etanercept, however, but a cause and effect relationship has not been reported. It is up to the treating physicians discretion to determine if laboratory testing is indicated. Is tuberculin testing required before initiation of etanercept therapy? The current guideline is that no specific tuberculin testing is required before treatment with etanercept. This is in contrast to other TNF-a antagonists, such as
infliximab and adalimubab, in which tuberculosis screening is required before initiation of therapy because of the incidence of complement mediated lysis of macrophages present in tuberculous granulomas, which could release mycobacteria systemically and activate tuberculosis. The incidence of tuberculosis in 121,000 patients who have received etanercept between May 1, 1992, and December 13, 2001, was 0.02% (N = 20), which was similar to the background incidence of tuberculosis in the general population. There has not been a temporal association between the development of tuberculosis and etanercept therapy. It is up to the physicians discretion whether to initiate purified protein derivative testing for etanercept therapy. Given this regard, however, the use of purified protein derivative testing might be advisable for patients undergoing nonselective systemic therapy, such as methotrexate or cyclosporine. Can etanercept be administered to patients who test positive for tuberculosis? There are no specific recommendations regarding the use of etanercept in patients with previous positive testing for tuberculosis. In the clinical trials, there was no incidence of reactivation of tuberculosis in patients who were purified protein derivative positive. Treatment with etanercept should not be started in patients with active infections, including chronic and localized infections. If a patient is purified protein derivative positive and the chest radiograph is negative for radiographic evidence of active tuberculosis, then preventative therapy with isoniazid should be instituted before treatment with etanercept. Does etanercept cause demyelination disorders? In postmarketing surveillance, there have been rare incidences of demyelinating disorders and exacerbation of pre-existing multiple sclerosis occurring in patients treated with etanercept [26]. Cases of transverse myelitis, optic neuritis, and new onset or exacerbation of seizure disorders have been observed with etanercept. The causal relationship between these central nervous disorders and etanercept remains unclear. Caution should be exercised when considering etanercept in patients with a history or family history of multiple sclerosis. Can etanercept be administered to patients with congestive heart failure? There were two large clinical trials that evaluated the use of etanercept in the treatment of heart failure.
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These trials were terminated because of lack of efficacy. The results of one study suggested higher mortality in patients treated with etanercept compared with placebo but the second trial did not corroborate these observations. There have been reports of worsening congestive heart failure and rare instances of new onset of congestive heart failure without identifiable precipitating factors in patients treated with etanercept [27]. Caution should be exercised when using etanercept in patients who have a history of heart failure.
Practical considerations on usage of etanercept Most psoriatic patients are able to self-administer etanercept when offered to them. If self-administration by the patient is not achievable, then a family member or friend can administer the drug at home. The nursing staff easily can learn how to teach patients the technique in administering etanercept. In addition, specialty pharmacies are now available that can demonstrate to the patient how to self-inject etanercept. Because etanercept can be given once a week, it may be possible for the uncommon patient to come in weekly to the clinic for injections if home administration is not achievable. If the patient is truly needle phobic, then etanercept and other injectable agents are obviously not possible and other treatment modalities for psoriasis and psoriatic arthritis must be used. Monotherapy dosing of etanercept Most patients with moderate to severe plaque psoriasis often exhibit improvement with monotherapy step-down dosing of etanercept. Initial clearance of psoriatic plaques can be seen as early as 2 weeks at 50 mg twice weekly. The symptoms of psoriatic arthritis respond quicker than skin lesions. Frequently, patients notice a decrease in morning stiffness, pain, and swelling in their joints as soon as 2 weeks. It is not uncommon for a patient to state that the arthritis feels better after one injection. Etanercept is an ideal agent as first-line therapy in the treatment of psoriasis or psoriatic arthritis because of its high efficacy, excellent safety profile, and convenience. Once a patient has started a good treatment regime with etanercept, follow-up visits are conducted every 3 to 4 months. The maintenance dosage of etanercept for clearance of psoriasis is 50 mg weekly. Some psoriatic patients can maintain clearance of their psoriasis at decreased doses of etanercept, such as 25 mg per week, or even at longer intervals, such as every 10 to 14 days. Other patients develop remission of their psoriasis for an extended period of time when etanercept is discontinued. Should the psoriasis relapse at the lower dosages or upon discontinuation, retreatment with 50 mg weekly of etanercept is instituted without loss of efficacy as seen in the clinical trials with retreatment. Etanercept is not associated with rebound or change or morphology upon abrupt discontinuation of etanercept. In a minority of patients, the psoriasis may worsen even at 50-mg weekly dosing etanercept. This can be precipitated by known factors, which worsen psoriasis such
Does etanercept increase the risk of autoimmunity? In two trials, the percentage of patients evaluated for antinuclear antibodies who developed a positive antinuclear antibodies titer (titer ! 1:40) was higher in patients treated with etanercept (11%) than in placebo-treated patients (5%) [28,29]. The percentage of patients who developed new positive anti double stranded DNA antibodies was higher in the etanercept-treated group (15%) compared with placebo (4%) [28,29]. There have been rare cases of drug-induced systemic lupus erythematosus associated with etanercept therapy [30].
Can etanercept be given during pregnancy or breastfeeding? Etanercept is rated pregnancy category B by the FDA. No formal studies have been conducted in pregnant women who have received etanercept. It is not known if etanercept is excreted in human milk or absorbed systemically after ingestion. Because many drugs and immunoglobulins are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug.
Can immunizations be given during etanercept treatment? Most psoriatic patients receiving etanercept were able to mount effective B-cell immune responses. Patients on therapy with etanercept may receive concurrent vaccinations, except for live vaccines. There are no data available on the secondary transmission of infection by live vaccines in patients receiving etanercept.
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Table 1 Summary of six psoriatic patients treated with etanercept and combination therapy Patient 1 (M) 2 (M) 3 (M) 4 (M) 5 (M) 6 (F) Age (y) 57 51 52 33 45 55 Previous treatment UVB, cyclosporine, acitretin, etretinate, methotrexate, 6-thioguanine UVB, PUVA, methotrexate, cyclosporine Acitretin, hydroxyurea PUVA, calcipotriene cream and ointment Cyclosporine, acitretin, methotrexate Methotrexate, acitretin, UVB Arthritis None Present None Present Present None Initial combination therapy with etanercept Methotrexate, 20 mg po weekly Cyclosporine, 200 mg po qd Acitretin, 25 mg po qod Hydroxyurea, 1.5 g po qd Calcipotriene cream and ointment bid Methotrexate, 15 mg po weekly Acitretin, 25 mg po qod UVB weekly PASI score before etanercept 29 27 28 22 24 14 After etanercept 10 14 10 10 12 7 Arthritis response Improved, major Improved, moderate Improved, major
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as stress or streptococcal throat infections. In these instances where the psoriasis flares at maintenance dosages, the dose of etanercept can be increased to 50 mg twice weekly until the psoriasis improves. Then the dosage can be stepped down to 50 mg weekly for maintenance control. In contrast to psoriasis, it is recommended that patients with psoriatic arthritis be maintained at the conventional dose of 50 mg per week. Etanercept has been shown to inhibit radiographic progression of joint destruction. Any stoppage of etanercept or lowering the dose may potentially cause further osteolysis and joint space narrowing. If a patient is diagnosed with psoriatric arthritis and has moderate to severe psoriasis, step-down dosing is recommended to gain quick control of the psoriatric plaques.
Combination therapy with etanercept Iyer et al [31] reported six cases of patients with severe recalcitrant psoriasis that was partially resistant to other ongoing systemic agents or phototherapy whose disease activity showed marked improvement with the addition of etanercept to the treatment regime. Three of the patients also had severe psoriatic arthritis. Table 1 illustrates the improvement in the disease activity for each of the six patients following the addition of etanercept to their treatment regime. When etanercept was combined with other agents, each of the patients psoriasis and those with psoriatic arthritis became more responsive to treatment and allowed lower doses of other systemic agents to be used to limit their side effects. For example, patient 2 demonstrated a response to cyclosporine, but the dosage was limited by the development of medication-related hypertension. In addition, no additional toxicity was found with etanercept when added to such agents as methotrexate, hydroxyurea, acitretin, or cyclosporine. None of these patients developed any serious or opportunistic infections. Addition of etanercept did not potentiate any type of organ toxicity, myelosuppression, metabolic or lipid abnormalities, hypertension, or malignancies. No drug interactions with etanercept were evident. These case reports underscore two important points. First, etanercept can be added safely to some other systemic and topical agents to augment efficacy and develop more potent combination regimens in severe recalcitrant cases of psoriasis, at least over a short-term crisis period. Second, etanercept can play a role in diminishing the short- and long-term toxicities of other systemic medications by allowing
lower doses of these agents to be used while maintaining disease control. Etanercept is an excellent choice that can be used in combination therapy for the treatment of psoriasis. Etanercept offers a good method to wean and transition psoriatic patients off of systemic agents. One prevalent problem with these systemic agents, such as cyclosporine and methotrexate, is the occurrence of rebound and flare-ups on abrupt cessation. For example, a patient with psoriasis who has attained good clearance with cyclosporine at 5 mg/kg most likely rebounds with sudden discontinuation. The addition of etanercept at 50 mg per week prevents this from occurring. Because the onset of action for etanercept is typically evident in about 4 weeks, the dose of cyclosporine should be held constant for that period of time. After 4 weeks, the dosage of cyclosporine can slowly be lowered by 50 to 100 mg every 2 to 4 weeks while maintaining the etanercept. Laboratory monitoring and blood pressure checks should be performed while on cyclosporine. With methotrexate, the dosage can be lowered by 2.5 mg every 2 to 4 weeks after instituting therapy with etanercept for 4 weeks. There are no specific guidelines for transitioning off of systemic agents while on etanercept but these are some of the methods that the authors have used.
Summary It is quite evident the pathogenesis of psoriasis is modulated by immune-mediated mechanisms that invoke activated T cells and inflammatory cytokines, such as TNF-a. Current immunosuppressive systemic treatments may be effective in controlling psoriasis to a certain degree but have significant drawbacks, such as toxicity and relapse of the disease on discontinuation. The advantages of biologic agents are their greater selectivity in targeting specific pathways in the inflammatory cascade of psoriasis with a much higher safety profile. With specific antagonism directed against TNF-a, etanercept has demonstrated remarkable efficacy in the treatment of psoriasis and psoriatic arthritis.
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[2] Mease PJ, Goffe BS, Metz J, VanderStoep A, Finck B, Burge DJ. Etanercept in the treatment of psoriatic arthritis and psoriasis: a randomized trial. Lancet 2000;29:385 90. [3] Gladman DD, Brockbank J. Psoriatic arthritis. Expert Opin Investig Drugs 2000;9:1511 22. [4] Aggarwal BB, Natarajan K. Tumor necrosis factors: developments during the last decade. Eur Cytokine Netw 1996;7:93 124. [5] Dayer JM, Beutler B, Cerami A. Cachectin/tumor necrosis factor stimulates collagenase and prostaglandin E2 production by human synovial cells and dermal fibroblasts. J Exp Med 1985;162:2163 8. [6] Bertolini DR, Nedwin GE, Bringman TS, Smith DD, Mundy GR. Stimulation of bone resorption and inhibition of bone formation in vitro by human tumour necrosis factors. Nature 1986;319:516 8. [7] Catrina AI, Lampa J, Ernestam S, Klint E, Bratt J, Klareskog L, et al. Anti-tumour necrosis factor (TNF)alpha therapy (etanercept) down-regulates serum matrix metalloproteinase (MMP)-3 and MMP-1 in rheumatoid arthritis. Rheumatology (Oxford) 2002; 41:484 9. [8] Mackay F, Loetscher H, Stueber D, Gehr G, Lesslauer W. Tumor necrosis factor alpha (TNF-alpha)-induced cell adhesion to human endothelial cells is under dominant control of one TNF receptor type, TNF-R55. J Exp Med 1993;177:1277 86. [9] Hohmann HP, Remy R, Poschl B, van Loon AP. Tumor necrosis factors-alpha and beta bind to the same two types of tumor necrosis factor receptors and maximally activate the transcription factor NF-kappa B at low receptor occupancy and within minutes after receptor binding. J Biol Chem 1990;265:15183 8. [10] Aderka D, Engelmann H, Maor Y, Brakebusch C, Wallach D. Stabilization of the bioactivity of tumor necrosis factor by its soluble receptors. J Exp Med 1992; 175:323 9. [11] Baugh JA, Bucala R. Mechanisms for modulating TNF alpha in immune and inflammatory disease. Curr Opin Drug Discov Devel 2001;4:635 50. [12] Gilhar A, David M, Kalish RS, Weisinger G. In vivo effects of cytokines on psoriatic skin grafted on nude mice: involvement of the tumour necrosis factor (TNF) receptor. Clin Exp Immunol 1996;106:134 42. [13] Ettehadi P, Greaves MW, Wallach D, Aderka D, Camp RDR. Elevated tumour necrosis factor-alpha biological activity in psoriatic skin lesions. Clin Exp Immunol 1994;96:146 51. [14] Partsch G, Steiner G, Leeb BF, Dunky A, Broll H, Smolen JS. Highly increased levels of tumor necrosis factor-alpha and other proinflammatory cytokines in psoriatic arthritis synovial fluid. J Rheumatol 1997; 24:518 23. [15] Bonifati C, Carducci M, Cordiali Fei P, Trento E, Sacerdoti G, Fazio M, et al. Correlated increases of tumour necrosis factor-alpha, interleukin-6 and granulocyte monocyte-colony stimulating factor levels in suction blister fluids and sera of psoriatic patients relation-
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induced systemic lupus erythematosus associated with etanercept therapy. Lancet 2002;359:579 80. [31] Iyer S, Yamauchi P, Lowe NJ. Etanercept for severe psoriasis and psoriatic arthritis: observations on combination therapy. Br J Dermatol 2002;146:118 21.
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Current concepts and review of pimecrolimus in the treatment of psoriasis

Klaus Wolff, MD, FRCP
Department of Dermatology, University of Vienna, Vienna General Hospital, Waehringer Guertel 18 20, Vienna A-1090, Austria
The ascomycine macrolactam derivative pimecrolimus is a novel inflammatory cytokine-release inhibitor [1 6] that has a high degree of cytokine selectivity. The first ascomycine derivative to show efficacy in a disease was SDZ 281-240, which a proof-of-concept study showed cleared psoriasis as effectively as the high-potency corticosteroid clobetasol-17-proprionate when applied topically under occlusive conditions [7]. Pimecrolimus has been shown to suppress atopic dermatitis [8,9] and contact dermatitis [10] when applied topically and psoriasis when delivered topically under occlusion [11]. A large-scale experience with pimecrolimus cream has now accumulated in atopic dermatitis where multicenter studies proved high efficacy and safety. Studies in more than 2000 patients confirm that topical pimecrolimus is suitable for short-and long-term treatment of atopic dermatitis in adults, children, and infants older than 3 months [7]. After topical application, the levels of pimecrolimus in blood remain consistently low and no clinically relevant, drug-related, systemic adverse events have been reported [12]. When given systemically in animal models with inflammatory skin disease, pimecrolimus exhibits high anti-inflammatory activity [1] and a low potential for systemic immunosuppression [7]. Pimecrolimus therefore has been considered for use in the
systemic treatment of patients with psoriasis. A randomized, double-blind, placebo-controlled proofof-concept phase 1/2 study has confirmed the efficacy, safety, and tolerability of this drug as an oral treatment in psoriasis [13]. Although pimecrolimus is not yet approved as a systemic drug, the experience available to date suggests that it might be a novel, highly effective systemic drug for psoriasis and other inflammatory skin diseases.
Preclinical profile Pimecrolimus is a calcineurin inhibitor that selectively targets T cells and mast cell activation in vitro. It blocks the release of helper T-cell (Th1 and Th2) cytokines [14] and inhibits the induction of coreceptors involved in the accessory cell-dependent activation of inflammation-mediating T cells [15]. In addition, it prevents the production of cytokines and the release of proinflammatory mediators from mast cells [14,16,17]. In animal models, pimecrolimus is highly active against skin inflammation after systemic application. In contrast to cyclosporin and tacrolimus, pimecrolimus has only a low potential to impair systemic immune responses [1,6,18,19]. In rats, oral pimecrolimus is superior to cyclosporin by a factor of 4 and superior to tacrolimus by a factor of more than 2 in the down-regulation of allergic contact dermatitis; in mice, oral pimecrolimus is superior to cyclopsorin and equal to tacrolimus in inhibiting allergic contact dermatitis [19]. Although in these animal models pimecrolimus is highly effective in suppressing the inflammatory response in the elicitation phase of allergic contact dermatitis, it has no effect on the
Part of this work was supported by a grant from Novartis AG, Basel, Switzerland. The author has served as a consultant to Novartis Research Institute, Vienna, Austria; however, he has no direct financial interest in this subject matter, neither with Novartis nor with any companies making competing products. E-mail address: klaus.wolff@akh-wien.ac
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induction phase, which is in contrast to oral cyclosporin or tacrolimus [18]. Also, although the inhibition of the primary immune response with tacrolimus and cyclosporin is associated with a decrease in lymph node weight and cellularity, this effect is not observed with pimecrolimus [18,19]. Also in contrast to cyclosporin and tacrolimus, pimecrolimus has a low immunosuppressive effect in animal models when given systemically. For instance, the potential of pimecrolimus to suppress a graftversus-host reaction is 8 and 66 times less than tacrolimus and cyclosporin, respectively. This finding also holds for allogeneic kidney transplantation and antibody production models [1,6,19]. In summary, it seems that pimecrolimus has a different profile than other calcineurin inhibitors such as tacrolimus and cyclosporin. It is equal to or even more potent than tacrolimus and cyclosporin in suppressing cutaneous inflammatory responses; in addition, it interferes only with the elicitation phase and not with the initiation phase of an immune response and is far less effective in suppressing a systemic immune response than tacrolimus or cyclosporin. These findings suggest that oral treatment with pimecrolimus in humans with inflammatory skin disease should leave systemic immune surveillance intact as a natural defense system.
Oral pimecrolimus in patients with psoriasis Clinical efficacy Pimecrolimus is highly effective in suppressing psoriasis. In a randomized, double-blind, placebocontrolled, multiple-rising-dose study, it was shown that pimecrolimus was highly effective in downregulating psoriatic disease activity [13]. Although there was no change in Psoriasis Area and Severity Index (PASI) scores in patients taking the placebo or in patients receiving low doses of pimecrolimus daily (5 mg, 10 mg, and 20 mg, respectively), there was clear efficacy in patients receiving 40 mg (20 mg twice daily) and 60 mg (30 mg twice daily) of pimecrolimus per day. This improvement involved a reduction of scaling, erythema, and infiltration of lesions (Fig. 1), and led to a significant reduction of patients PASI score to an almost complete clearing of lesions after 4 weeks of treatment. This response was clearly dose-dependent (Fig. 2). The mean reduction of PASI (change from baseline at day 28) was 60% for the 40-mg/day and 75% for the 60-mg/day patient groups [13]. These results now have been confirmed by a multicenter study, which reported on 143 patients with moderate to severe chronic plaque psoriasis and extending over 12 weeks of treatment;
Fig. 1. The clinical efficacy of pimecrolimus is shown for a patient receiving 30 mg twice daily on day 0 (left) and day 28 (right).
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Fig. 2. The clinical efficacy of pimecrolimus as assessed by percentage of PASI change from baseline for the different dose levels. (From Rappersberger K, Komar M, Ebelin ME, Scott G, Burtin P, Creig G, et al. Pimecrolimus identifies a common genomic anti-inflammatory profile, is clinically highly effective in psoriasis and is well tolerated. J Invest Dermatol 2002;119: 876 87; with permission.)
the median change in PASI from baseline showed a clear dose-dependent effect and again was greatest for the 40-mg/day and 60-mg/day groups [20]. At 12 weeks, the median reduction in PASI was 80% and 58% in the 60-mg and 40-mg groups, respectively, and 43% of patients were clear or almost clear of disease following 12 weeks of treatment with 60-mg/day dosages [20]. Follow-up and recurrences In the original study [13], follow-up evaluation showed recurrence of psoriasis after 8 weeks but no rebound. In the two highest-dose (40-mg and 60-mg) patient groups in the multicenter study [20], more than half of the patients had not experienced disease relapse 10 weeks after stopping treatment. Pharmacokinetics Pharmacokinetics of pimecrolimus reveal rapid absorption, attainment of steady state after 5 to 10 days, and a linear dose dependency at steady state [13]. Both Cmax and AUC0 24 increased broadly in proportion to the dose. Steady state was reached after days 5 to 10 at daily administrations of 30 mg of pimecrolimus twice daily, and Cmax and AUC0 24 reached 54.5 ng/mL and 589.9 ng h/mL at steady state, respectively [13]. Pharmacogenomics Gene expression analysis identified a common genomic profile for pimecrolimus in blood cells of
patients with psoriasis [13]. Blood samples subjected to a gene expression analysis using gene chips for the survey of more than 7000 genes permitted the identification of a common genomic profile of pimecrolimus consisting of approximately 150 genes. Pimecrolimus strongly down-regulated the expression of genes associated with the macrolactam target pathway, cellular activation and proliferation, antigen presentation and genes related to cellular metabolism, signal transduction, transcription factors, and inflammatory mediators. Genes related to lymphocyte recruitment, chemotaxis, and cellular migration were also down-regulated, but no significant changes in T-lymphocyte markers could be detected at the RNA expression level, suggesting an absence of a systemic T-cell suppressive effect of the drug. There was also no change of expression for transforming growth factor b1 3 and for interleukin 1 (IL-1), IL-2, IL-8, and IL-10. None of the expression changes in genes that showed change were clearly related to side effects or toxicity, and genes associated with apoptosis, stress, and enzymatic induction did not change expression [13]. Tolerability Pimecrolimus is well tolerated and lacks notable clinical and laboratory side effects. In the previously described study [13], there were no clinically notable and significant changes in physical examination, blood pressure, heart rate, and ECG throughout the study. The only consistent side effect recorded was a transient feeling of warmth on the upper chest occurring about 40 minutes after ingestion of the drug and
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lasting approximately 90 minutes. It did not occur every time after drug intake, and in 75% of all patients it did not occur more than 3 times during 28 days of treatment. Furthermore, the sensation of warmth was not a matter of concern for the patients. Hematology and blood chemistry analyses revealed no significant changes throughout the study, and there were no notable changes of kidney function, such as glomerular filtration rate or renal plasma flow, and glucose tolerance tests were normal [13]. Tolerability of pimecrolimus has been confirmed in a multicenter study comprising 243 adult patients with psoriasis and atopic dermatitis over a treatment period of 12 weeks [21]. The only adverse effect that showed a clear dose effect relationship was the transient mild to moderate feeling of warmth described previously. Headache and common gastrointestinal symptoms, such as nausea and dyspepsia, were the most commonly observed adverse effects, but these were not significantly increased as compared with placebo-treated patients; this finding was also true for skin and systemic infections. These data indicate that pimecrolimus has an excellent safety profile in short-term treatment (4 wk and 12 wk, respectively) of patients and is also in line with the pharmacogenomic profile of pimecrolimus examined in the original study on this drug [13]. Immunology Pimecrolimus leaves immunologic parameters unaffected. Intradermal testing for delayed hypersensitivity reactions to recall antigens showed no significant changes from pre-to post-treatment testing for the pimecrolimus-and placebo-treated patients [13]. Flow cytometry analysis of blood lymphocyte subpopulations revealed no significant differences between treatment groups and patients taking placebo. In addition, no consistent or significant changes or patterns were seen in the proliferation of lymphocytes or in the patterns of cytokine release before and after 4 weeks of treatment [13]. The absent suppressive effect on circulating lymphocytes is of considerable importance because, as discussed later, pimecrolimus down-regulates T cells in the skin. Histopathology Histopathologically and immunopathologically, pimecrolimus reverses the psoriatic phenotype to normal [13]. After 4 weeks of treatment, pimecrolimus induces an almost complete reversion of psoriatic epidermal hyperplasia and a marked reduction of the inflammatory infiltrate. In addition, it induces the
expression of proliferation-associated keratin-16 and the proliferating Ki-67+ keratinocytes. Staining patterns of involucrin and filaggrin reverted from that typical for psoriasis to near that of normal epidermis, and keratinocyte activation was significantly reduced or abolished. In contrast to pimecrolimus absence of effect on circulating lymphocytes [13], there was a significant reduction of CD3+, CD4+, and CD8+ dermal lymphocytes and of CD3+ and CD4+ epidermal lymphocytes; importantly, there was no significant change in the CD1a+ subpopulation in the epidermis and dermis, indicating that pimecrolimus leaves Langerhans cells unchanged [13].
Summary Although pimecrolimus is approved as a topical treatment for atopic dermatitis in the United States, the European Union, and most other Western countries, it is not yet approved for use as a systemic drug because phase 2 studies are still ongoing. Nonetheless, evidence accumulated to date indicates the following: it has a genomic profile of broad antiinflammatory activity without evidence of toxicity as evaluated in blood cells, it exhibits excellent clinical tolerability after 4 and 12 weeks of oral treatment, and it is highly effective in a concentration-dependent manner in patients with moderate to severe plaque psoriasis. The impressive clinical efficacy of pimecrolimus compares favorably with that of established systemic treatments for psoriasis, such as psoralen with ultraviolet A (PUVA), retinoic acid PUVA combinations, and cyclosporin [13]. No impairment of organ function, as assessed by clinical and laboratory examinations, and no systemic immune suppression have been noted in the studies performed thus far. In addition, no viral infections and increase of skin infections were seen throughout the time patients were observed [13,21]. These findings harmonize with the observed gene profiling of the drug, which showed down-regulation of genes responsible for the target pathway, inflammation, activation, proliferation, chemotaxis, and migration of leukocytes but did not reveal changes in gene expression that might be linked to treatment-related immune suppression and toxicity [13]. The findings also seem to verify the observation in animal models in which pimecrolimus had high skin-selective, anti-inflammatory activity and a very low potential for effective systemic immune responses [6]. The efficacy of pimecrolimus in psoriasis and its short-term safety are encouraging, but it will have to be determined whether the safety profile of this novel
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drug continues to be as favorable when it is administered over longer periods of time. Multicenter trials are underway to answer these and other questions. The experience available with this drug to date is unique, however, and supports the notion that pimecrolimus may also be effective for other T-cell mediated skin diseases. The efficacy of oral pimecrolimus already has been shown in atopic dermatitis [22].
[12]
[13]
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[1] Meingassner JG, Grassberger M, Fahrngruber H, Moore HD, Schuuman H, Stuetz A. A novel antiinflammory drug, SDZ ASM 981, for the topical and oral treatment of skin diseases: in vivo pharmacology. Br J Dermatol 1997;137:568 76. [2] Grassberger M, Baumruker T, Enz A, Hiestand P, Hultsch T, Kalthoff F, et al. A novel anti-inflammatory drug, SDZ ASM 981, for the treatment of skin diseases: in vitro pharmacology. Br J Dermatol 1999; 141:264 73. [3] Neckermann G, Bavandi A, Meingassner JG. Atopic dermatitis-like symptoms in hypomagnesaemic hairless rats are prevented and inhibited by systemic or topical SDZ ASM 981. Br J Dermatol 2000;142: 669 79. [4] Paul C, Graeber M, Stuetz A. Ascomycins, promising agents for the treatment of inflammatory skin diseases. Expert Opin Invest Drugs 2000;9:69 77. [5] Wellington K, Spencer CM. Adis new drug profile: ASM 981. BioDrugs 2000;74:409 16. [6] Stuetz A, Grassberger M, Meingassner JG. Pimecrolimus (Elidel, SDZ ASM 981)preclinical pharmacologic profile and skin selectivity. Semin Cutan Med Surg 2001;20:233 41. [7] Rappersberger K, Meingassner JG, Fialla R, Foedinger D, Sterniczky B, Rauch S, et al. Clearing of psoriasis by a novel immunosuppressive macrolide. J Invest Dermatol 1996;106:701 10. [8] Van Leent EJM, Gra ber M, Thurston M, Wagenaar A, Spuls PI, Bos J. Effectiveness of the ascomycin macrolactam SDZ in the topical treatment of atopic dermatitis. Arch Dermatol 1998;134:805 9. [9] Harper J, Green A, Scott G, Gruendl E, Dorobek B, Cardno M, et al. First experience of topical SDZ ASM 981 in children with atopic dermatitis. Br J Dermatol 2001;144:781 9. [10] Queille-Roussel C, Graeber M, Thurston M, Lachapelle JM, Decroix J, DeCuyper C, et al. SDZ ASM 981 is the first non-steroid that suppresses established nickel contact dermatitis elicited by allergen challenge. Contact Dermatitis 2000;42:149 50. [11] Mrowietz U, Gra ber M, Brautigam M, Thurston M, Wagenaar A, Weidinger G, et al. The novel ascomycin derivative SDZ ASM 981 is effective for psoriasis
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when used topically under occlusion. Br J Dermatol 1998;139:992 6. Van Leent EJM, Ebelin ME, Burtin P, Spuls PI, Bos JD. Low systemic concentrations of SDZ ASM 981 after topical treatment of extensive atopic dermatitis lesions. Eur Acad Dermatol Venereol 1998;11:S133 4. Rappersberger K, Komar M, Ebelin ME, Scott G, Burtin P, Creig G, et al. Pimecrolimus identifies a common genomic anti-inflammatory profile, is clinically highly effective in psoriasis and is well tolerated. J Invest Dermatol 2002;119:876 87. Grassberger M, Baumruker T, Enz A, Hiestand P, Hultsch T, Kalthoff F, et al. A novel anti-inflammatory drug, SDZ ASM 981, for the treatment of skin diseases: in vitro pharmacology. Br J Dermatol 1999; 141:264 73. Kalthoff FS, Chung J, Grassberger M, Stuetz A. SDZ ASM 981 potently inhibits the induction of coreceptors involved in the accessory cell-dependent activation of inflammation-mediating T cells [abstract]. J Invest Dermatol 2001;117:440. Hultsch T, Mu ller KD, Meingassner JG, Grassberger M, Schopf RE, Knop J. Ascomycin macrolactam derivative SDZ ASM 981 inhibits the release of granule-associated mediators and of newly synthesized cytokines in RBL 2H3 mast cells in an immunophilindependent manner. Arch Dermatol Res 1998;290: 501 7. Zuberbier T, Chong SU, Grunow K, Guhl S, Welker P, Grassberger M, et al. The ascomycin macrolactam pimecrolimus (ElidelandR, SDZ ASM 981) is a potent inhibitor of mediator release from human dermal mast cells and peripheral blood basophils. J Allergy Clin Immunol 2001;108: 275 80. Meingassner JG, Fahrngruber H, Barandi A. SDZ ASM 981, in contrast to CyA and FK 506, does not suppress the primary immune response in murine allergic contact dermatitis [abstract]. J Invest Dermatol 2000;114:832. Meingassner JG, Hiestand P, Bigaud M, Grassberger M, Schuurman H, Tanner M, et al. SDZ ASM 981 is highly effective in animal models of skin inflammation, but has only low activity in models indicating immunosuppressive potential, in contrast to cyclosporin A and FK 506. J Invest Dermatol 2001;117:532. Griffiths C, Dubertret L, Gottlieb A. Treatment with oral pimecrolimus significantly improves psoriasis with a clear dose-response effect [abstract]. J Invest Dermatol 2003;121:301. Wolff K, Caro I, Murrell D, Ortonne JP. Safety profile of oral pimecrolimus in atopic eczema and psoriasis: a pooled analysis from two dose-finding studies [abstract]. J Invest Dermatol 2003;121:1245. Hanifin J, Fleming C, Korman N, Reitamo S. Treatment with oral pimecrolimus significantly improves atopic dermatitis (AD) with a clear dose-response effect [abstract]. J Invest Dermatol 2003;121:1240.
Dermatol Clin 22 (2004) 467 476
Retinoid therapy for psoriasis

Paul S. Yamauchi, MD, PhDa,b, Dalia Rizk, MDa, Nicholas J. Lowe, MDa,b,*
b a Clinical Research Specialists, 2001 Santa Monica Boulevard, Suite 490W, Santa Monica, CA 90404, USA Division of Dermatology, University of California at Los Angeles School of Medicine, Los Angeles, CA 90095-1750, USA
The systemic retinoids possess a remarkable range of activities and clinical applications. They are an important form of therapy for patients with more severe and resistant types of psoriasis. In general, with plaque psoriasis, systemic retinoids are used most effectively in combination with other forms of therapy, such as phototherapy or other systemic agents. With generalized pustular psoriasis, they are effective as monotherapy and are frequently helpful for the control of exfoliative psoriasis. The Food and Drug and Administration (FDA) in the United States has approved four derivatives of systemic retinoids. Isotretinoin, whose main indication is for cystic acne, has been found to be ineffective for plaque-type psoriasis as monotherapy treatment [1]. Clinical responses, however, were observed with isotretinoin for pustular psoriasis [1] and in conjunction with phototherapy for psoriasis [2,3]. Bexarotene is approved for the treatment of cutaneous T-cell lymphoma. One report showed that bexarotene at 0.5 to 2 mg/kg/d reduced lesions in patients with moderate to severe psoriasis [4]. Topical retinoids for the treatment of psoriasis was introduced in the United States in 1997 for the treatment of plaque-type psoriasis. The only FDA-approved topical retinoid for psoriasis is tazarotene gel and cream. Topical tazarotene has remained one of the mainstay treatments for psoriasis. This article focuses on the treatment of psoriasis with acitretin, the only systemic retinoid approved for psoriasis, and also briefly discusses its predecessor, etretinate, which was replaced by acitretin in 1997
and is no longer available. The use of topical tazarotene is also discussed in detail. Combination therapy of retinoids, both topical and systemic, with phototherapy and other therapeutic agents is described. In addition, new retinoid analogues that are currently undergoing clinical investigation at the time of preparation of this article are mentioned. Finally, potential toxicities and adverse effects associated with retinoids are discussed.
Chemistry and pharmacology Fig. 1 shows the chemical structures of acitretin and etretinate. Acitretin is the principle active metabolite of the prodrug, etretinate. They are very similar to each other except that etretinate is the ethylester form of acitretin. Because of this modification, however, under physiologic conditions etretinate is in an uncharged state and is 50 times more lipophilic than acitretin, which carries a negative charge [5]. Consequently, etretinate is accumulated in adipose tissue because of its high lipophilicity as opposed to acitretin, which is not stored in fat. This is the main pharmacokinetic reason why acitretin has a much shorter half-life (approximately 50 hours) than etretinate (approximately 120 days). In light of the highly teratogenic effects associated with systemic retinoids (discussed later) and because of its long half-life and detection in the serum up to 2 years after discontinuing treatment, etretinate was withdrawn from the market in 1997 following the introduction of acitretin. Studies have demonstrated that the concurrent ingestion of ethanol with acitretin results in the transesterification conversion of acitretin to etretinate [6,7]. Furthermore, higher alcohol consumption was linked to higher etretinate concentrations. This is clinically significant because the ingestion of alcohol extends the
* Corresponding author. Clinical Research Specialists, 2001 Santa Monica Boulevard, Suite 490W, Santa Monica, CA 90404. E-mail address: nlowe@crs.com (N.J. Lowe).
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Fig. 1. Chemical structures of etretinate (A) and acitretin (B).
half-life of acitretin to the same as that of etretinate because of the enzymatic conversion. There are no data documenting the spontaneous formation of acitretin to etretinate in the absence of alcohol consumption. It is also important to instruct patients that systemic retinoids, including acitretin, have higher absorption and improved bioavailability when ingested with food [8]. Fig. 2 illustrates the structure of tazarotene. Minimal systemic absorption of tazarotene occurs because of rapid metabolism in the skin to the active metabolite, tazarotenic acid, which is systemically absorbed and further metabolized. Tazarotenic acid is hydrophilic and is rapidly metabolized causing no apparent accumulation within body tissues. More than 99% of tazarotenic acid is bound to plasma proteins. The metabolism of tazarotene to tazarotenic acid occurs through esterase hydrolysis in skin. On conversion, tazarotenic acid exhibits a half-life of approximately 18 hours in both normal and psoriatic patients.
Mechanism of action The exact molecular mechanism by which retinoids are able to exert their effects on psoriasis is unknown. It has been demonstrated that acitretin modulates the cellular differentiation of the epidermis, which results in deceased scaling, erythema, and thickness of the plaques. There is also histologic evidence that acitretin decreases the thickness of the stratum corneum and the inflammation in the epidermis and dermis that is associated with psoriasis. Tazarotene has multiple effects on keratinocyte differentiation and proliferation, and inflammation processes that contribute to psoriasis. In animal models, topical tazarotene blocks induction of ornithine
decarboxylase activity, which is associated with cell proliferation and expression. In vitro skin models and cell cultures have demonstrated tazarotene suppresses expression of MRP8, a marker of inflammation present in high levels in the epidermis of psoriasis patients and inhibits the formation of hyperkeratotic plaques. Tazarotene also induces the expression of tazaroteneinduced gene 3, a suppressor gene that may inhibit epidermal hyperproliferation in treated plaques. There are two classes of nuclear retinoid receptors that have been identified: the retinoic acid receptor and retinoid X receptor. The retinoic acid receptors and retinoid X receptors are each composed of three different subtypes, labeled a, b, and g [9]. Nuclear retinoid receptors exist as dimers, and retinoic acid receptors are known to form heterodimers with retinoid X receptors [10]. Acitretin has been shown to activate all three subtypes of retinoic acid receptor, despite the absence of measurable binding to any of the subtypes [10]. Tazarotenic acid selectively binds to retinoic acid receptors and exhibits little affinity for retinoid X receptors [11]. The function of these retinoic acid receptor retinoid X receptor heterodimers is unknown in the skin. Such data indicate that further studies are necessary to understand the interaction of acitretin with nuclear receptors.
Monotherapy with systemic retinoids Several studies have confirmed the efficacy of acitretin treatment for different types of psoriasis [12 19]. Pustular forms of psoriasis are more responsive to systemic retinoid monotherapy than plaque-type psoriasis, which responds more slowly. With plaque-type psoriasis, it is possible to enhance the response to therapy by combining retinoids with other treatments. Pustular psoriasis When acitretin is used as monotherapy for generalized pustular psoriasis, the initial dose is 25 to 50 mg per day, but higher doses may be required in some patients. A rapid resolution of generalized pustular psoriasis is achieved usually within 10 days
Fig. 2. Chemical structure of tazarotene.
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of initiating acitretin, which is probably the drug of first choice for the treatment of this condition. One advantage with acitretin for pustular psoriasis over methotrexate is the absence of acute effects on the peripheral blood count. Methotrexate may occasionally produce acute leukopenia in patients with generalized pustular psoriasis, which can lead to a major toxicity risk in these patients. Pustular psoriasis leads to rapid proliferation of monocytes in the S-phase of the cell cycle. Methotrexate, which blocks DNA synthesis in these cells, may lead to failure of maturation of cells beyond mitosis that leads to myelosuppression [20]. This phenomena is not clinically evident with acitretin, After the clearance of pustulation, the psoriasis can continue to be controlled by reducing the dose of acitretin (eg, decreasing acitretin at 25 mg per day to 25 mg every other day or to 10 mg per day). Some patients, however, relapse and develop plaque-type psoriasis. In such patients, alternative forms of therapy, such as phototherapy, can gradually be instituted in combination with acitretin. When the psoriasis improves, the retinoid then can be tapered down. In women of childbearing age, acitretin should probably be avoided whenever possible, even for pustular psoriasis. If acitretin is required, strict birth control practices must be adhered to and alcohol must be avoided. In such situations, oral isotretinoin with its shorter half-life of 10 to 20 hours may be used as an alternative to control the pustulation. Starting doses range from 1 to 1.5 mg/kg/d. If necessary, phototherapy may be initiated to control the psoriasis. Another situation in which acitretin is effective is in the treatment of palmoplantar pustular psoriasis, particularly where there is significant hyperkeratosis or severe pustulation. Isotretinoin may be used as an alternative in women who are fertile. Retinoid therapy reduces the degree of hyperkeratosis and pustulation. If monotherapy with acitretin is not achieving the desired results, then combination with psoralen plus UVA (PUVA) phototherapy is extremely useful. Alternatively, hydroxyurea at 500 mg twice a day in conjunction with acitretin is another way of controlling palmoplantar pustular psoriasis. Exfoliative erythrodermic psoriasis In exfoliative erythrodermic psoriasis, acitretin is useful at starting doses of 25 to 50 mg per day. It is advantageous to use emollients liberally along with the application of mild topical corticosteroids (eg, triamcinolone acetonide [0.025% cream or ointment]) under occlusion to achieve more rapid resolution of psoriasis.
Rarely, patients with severe exfoliative erythrodermic psoriasis may need to use a combination of acitretin with methotrexate. This combination should only be used rarely and, when it is, only with careful monitoring of the peripheral blood count and liver function tests. Another option for the treatment of exfoliative psoriasis is to use methotrexate or cyclosporine therapy to achieve a rapid improvement after which the methotrexate or cyclosporine dosage is reduced and low doses of acitretin (10 to 25 mg per day) are introduced.
Combination therapy for moderate to severe plaque psoriasis In patients with severe plaque psoriasis, especially if the condition is extensive with hyperkeratosis, the use of a retinoid plus other forms of treatment, particularly phototherapy, has been shown to be highly effective. The dose of the retinoid or the amount of alternative therapy required when used separately can be reduced if used in combination with each other. Acitretin and psoralen plus UVA phototherapy For combination therapy, the optimum dose for acitretin is 0.3 mg/kg/d, either 2 weeks before starting phototherapy or at the same time. The increases in ultraviolet radiation should be more gradual and cautious than in patients not taking systemic retinoids because of an increased risk of ultraviolet radiationinduced erythema. This is not a true photosensitivity, but probably represents increased epidermal transmission of the ultraviolet radiation because of altered optical properties of the stratum corneum caused by the retinoid. The concomitant use of PUVA with acitretin has been studied by several investigators [21 27]. Most patients receiving the combination improve more quickly than with PUVA or acitretin alone. In addition, the total number of ultraviolet radiation exposures can be reduced. Following clearance of psoriasis, various maintenance regimens may be used. Acitretin administered in low maintenance doses can be effective, or acitretin therapy can be stopped and maintenance therapy is undertaken solely with PUVA. In a double-blinded comparative study, patients with severe, widespread psoriasis were randomized to receive either PUVA alone or PUVA in combination with acitretin [21]. Eighty percent of patients with PUVA alone demonstrated marked or complete clearing of psoriasis, whereas 96% of patients who re-
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ceived adjunctive therapy with PUVA plus acitretin exhibited the same degree of improvement. The mean cumulative UVA dose given to patients who received combination therapy was 42% less than that required for patients who received PUVA alone. When patients with psoriasis were initially treated with acitretin at 50 mg per day for 2 weeks followed by decreasing the amount to 25 mg per day in conjunction with PUVA for up to 10 weeks, there was a 40.5% reduction in the total cumulative UVA dose, a decrease of the overall duration of treatment by almost 18 days, and a reduction in the number of PUVA treatments by nearly six sessions, when compared with treatment with PUVA alone [22]. Bath PUVA together with acitretin is another option for treatment of patents with pustular, plaquetype, or erythrodermic psoriasis [24]. After 4 weeks of treatment, patients had greater than a 90% response rate with no relapse after 3 months. The safety of PUVA is now of concern because of the risk of melanoma and nonmelanoma skin cancer. Whether or not acitretin alters this risk is unknown at this stage. Acitretin and UVB phototherapy Acitretin plus UVB therapy is another combination form of therapy to treat psoriasis and has been investigated [28 30]. This option can be used for those patients who are intolerant of side effects associated with oral psoralens, such as gastrointestinal toxicity. Treatment with UVB combined with acitretin at 50 mg per day or placebo resulted in greater clearance with fewer treatments and smaller amounts of UVB radiation when acitretin was used compared with placebo [29]. A 74% improvement in the psoriasis score was noted in patients treated with acitretin plus UVB compared with 35% with UVB only. In addition, in the same study, when only acitretin was used, there was a 42% reduction in psoriasis. There was a decrease in the total number of hours of exposure time to UVB therapy by approximately 6 hours when acitretin was used to attain clearance compared with light treatment alone. Another study demonstrated that when patients with psoriasis were initially treated with 35 mg per day of acitretin during the first 4 weeks of therapy followed by concomitant therapy with UVB radiation plus 25 mg per day of acitretin and compared with the placebo group, there was a 79% decrease in the psoriasis severity index in the acitretin and UVB group and 35% reduction in the UVB-only group [28]. In addition, the medium cumulative dose to achieve 75% clinical improvement
was 41.5% lower when acitretin was combined. Finally, the number of treatments to attain 80% to 100% clearance of psoriatic plaques was decreased by 5.6 sessions with UVB plus acitretin versus UVB only [30]. The total UVB dose and minimal erythema dose was reduced by approximately 20%. In summary, reasons for combining PUVA or UVB with systemic retinoids include the following: 1. Better clearance 2. Decreased cumulative ultraviolet doses 3. The number of treatments and duration of PUVA therapy is reduced 4. The possibility of reduction or cessation of acitretin therapy before the occurrence of side effects, such as hyperlipidemia or alopecia Combination therapy with other agents Combination therapy of acitretin with other modalities other than light therapy can be used to control psoriasis. Concomitant treatment with acitretin and topical calcipotriene may help reduce psoriatic plaques better than with either alone [31,32]. In addition, acitretin at 25 mg per day together with hydroxyurea, 500 mg twice daily, has been effective for some patients with chronic plaque psoriasis and pustular psoriasis. When using combination therapy with acitretin and hydroxyurea, the complete blood count should be carefully monitored. Combination therapy with immunomodulatory agents New-generation drugs are being developed that selectively target key cytokines and receptor molecules on T cells and antigen-presenting cells that are involved in the pathogenesis of psoriasis. These immunomodulators are in the form of monoclonal antibodies or fusion proteins that are administered as injections either subcutaneously, intramuscularly, or intravenously. One biologic agent that is currently on the market and is FDA-approved for rheumatoid arthritis and psoriatic arthritis is etanercept. Etanercept is currently undergoing clinical trials as monotherapy treatment for psoriasis. Etanercept is a fusion protein that acts as a soluble tumor necrosis factor and competitively binds to tumor necrosis factor thereby preventing tumor necrosis factor from binding to cell surface receptors on target cells. Because tumor necrosis factor is involved in the pathogenesis of psoriasis, through such inhibition, etanercept serves as an antiinflammatory agent that is beneficial in the treatment
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Fig. 3. Patient with recalcitrant plaque-type psoriasis (A) before and (B) after treatment with 25 mg acitretin each day plus etanercept, 25 mg twice a week subcutaneously for 8 weeks.
of psoriasis. A recent report demonstrated that combination therapy with etanercept together with various systemic agents, such as cyclosporine, methotrexate, acitretin, or hydroxyurea, in patients with severe recalcitrant psoriasis resulted in marked improvement and reduction in the PASI score [33]. More importantly, no added toxicity was seen in these patients when etanercept was combined with a systemic agent. Fig. 3 shows a patient with refractory psoriasis who responded well to combination therapy with 25 mg per day of acitretin plus twice-weekly 25-mg subcutaneous injections of etanercept. Combination treatment with systemic agents and immunomodulators underscores the significance of treating psoriasis in the future. With the advent of new biologic agents and the existing systemics, this new approach to combination therapy may provide an impetus in controlling psoriasis that previously was difficult to treat.
In a dose escalation study, 181 patients with moderate to severe plaque psoriasis received daily doses of oral tazarotene (0.4 to 6.3 mg) or placebo (Lowe et al, submitted for publication). Optimal efficacy was seen with the 4.2-mg dose. At this dosage, the body surface area involvement was reduced by 17% at week 12 and 82% of patients were satisfied or very satisfied with oral tazarotene. Fig. 4 shows a patient who had good clearance of psoriatic plaques with oral tazarotene at 4.2 mg per day by week 12. The only significant adverse effect noted was cheilitis at doses of 2.8 mg or higher. There were no other dose-related adverse events, such as increased liver function enzymes, hyperlipidemia, or changes in the hematologic profile. The shorter half-life of oral tazarotene may potentially be a useful alternative for systemic retinoid treatment in women of childbearing age with psoriasis.
Other systemic retinoids Oral tazarotene An oral form of tazarotene (a topical retinoid approved for plaque psoriasis and acne) has recently been developed that is currently not available on the market during the preparation of this article. Tazarotene is converted to its active metabolite, tazarotenic acid, which has a short elimination half-life of 7 to 12 hours (Allergan, unpublished data).
Toxicities and adverse reactions associated with systemic retinoids Teratogenicity All systemic retinoids are highly teratogenic with a pregnancy category of X rated by the FDA. Major human fetal abnormalities associated with retinoids include meningomyelocele, meningoencephalocele, multiple bony malformations, facial dysmorphia, lowset ears, high palate, decreased cranial volume alterations, and cardiovascular malformations.
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Fig. 4. Patient with plaque psoriasis (A) before and (B) after treatment with oral tazarotene, 4.2 mg each day for 12 weeks.
In light of its teratogenicity, acitretin must not be used by women who are pregnant or who intend to become pregnant during therapy or at any time for at least 3 years following discontinuation of therapy. In addition, acitretin must not be used by women who may not use reliable contraception while taking acitretin or for at least 3 years following cessation of treatment. In addition, the current guideline states that ethanol must not be ingested by female patients either during treatment with acitretin or for 2 months after discontinuing acitretin to avoid conversion into etretinate, which carries a much longer elimination half-life. This is caused by the transesterification of acitretin to etretinate by ethanol as previously discussed. Mucocutaneous toxicity Mucocutaneous toxicity occurs with all of the systemic retinoids [34]. The common mucocutaneous side-effects in order of frequency are cheilitis, skin peeling, alopecia, xerosis, rhinitis, nail dystrophy, epistaxis, sticky skin, retinoid dermatitis, and xerophthalmia. Hair loss may occur a few weeks after initiation of treatment and ceases 6 to 8 weeks after discontinuation of therapy. In rare cases, chronic hair loss has occurred. Patients frequently find these symptoms extremely difficult to accept. Rapid reduction in retinoid therapy is desirable to reduce the impact on patients of these toxicity problems. Some studies have suggested that 800 IU of vitamin E daily may reduce some of the mucocutaneous effects of systemic retinoids [35]. Arthralgias and myalgias Some patients develop muscle pain and myalgias with or without an elevation of creatine phosphokinase. In general, it is wise for patients to avoid
excessive muscle exercising, particularly excessive weight lifting and contact sports, because these forms of activity may increase such risks. Arthralgias occur in a small percentage of patients and disappear on discontinuation of therapy. Pseudotumor cerebri Acitretin and other systemic retinoids have been associated with cases of pseudotumor cerebri (benign intracranial hypertension). Such symptoms and signs include papilledema, severe headaches, nausea and vomiting, and visual disturbances. If pseudotumor cerebri is suspected, ophthalmologic evaluation for papilledema should be conducted and if present, the retinoid should be discontinued immediately. Oral retinoids should not be taken with tetracycline or tetracycline derivatives because of increased risk of pseudotumor cerebri. Ophthalmologic effects Ocular toxicity does not seem to be a major problem with acitretin, although rare cases of disturbances of color vision have been recorded. Most of the ocular symptoms have been mucocutaneous in nature, such as dry eyes, irritation of eyes, and loss of brow and lashes. Other side effects, such as blurred vision, cataracts, decreased night vision, and diplopia, are much less common. Skeletal toxicity There is some concern that long-term high-dose acitretin therapy is associated with changes that resemble diffuse idiopathic skeletal hyperostosis, which include anterior spinal ligamentous calcification and the formation of osteophytes and bony bridges. Disk space narrowing is not evident in diffuse idiopathic
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skeletal hyperostosis. There seems to be a cumulative threshold dose of 25 to 30 g etretinate below which skeletal toxicity is not seen radiographically. Psychiatric effects There are no recorded incidents of suicide or depression linked to patients on systemic retinoid therapy for the treatment of psoriasis. There is clearly a background of depression with some psoriasis patients but this has not been noted to be aggravated by acitretin (Lowe NJ, unpublished observations, 2002). Hyperlipidemia Hyperlipidemia occurs in approximately 25% to 50% of patients. Occasionally, severe levels reaching five to eight times the normal value occur, but usually levels are increased two to three times the normal. The incidence of pancreatitis or eruptive xanthomas with increased triglyceride levels is uncommon. In addition, levels of high-density lipoproteins decrease with oral retinoids. These abnormal levels are reversible on cessation of therapy. Patients with an increased tendency to develop hypertriglyceridemia include those with diabetes mellitus, obesity, increased alcohol intake, or a familial history of these conditions. There are a number of ways to manage hyperlipidemia including low-fat diets, reduced alcohol intake, physical activity, the use of polyunsaturated fish-oil supplements, and prescribing lipid-lowering drugs. Hepatotoxicity All the systemic retinoids have the potential for liver toxicity. Elevations of aspartate transaminase (serum glutamic-oxaloacetic transaminase), alanine transaminase (serum glutamate pyruvate transaminase), g-glutamyltransferase (GGTP), low-density lipoproteins, and alkaline phosphatase have occurred in 33% of patients treated with acitretin. During the clinical trials in the United States for acitretin, 3.8% of patients had sufficient elevation of liver function tests that they were discontinued from further treatment. If hepatotoxicity is suspected with acitretin, the drug should be discontinued and a liver work-up should be conducted.
enzymes; renal function tests; creatine phosphokinase; and a lipid panel including triglycerides, cholesterol, and high-density lipoproteins. In all women of childbearing age, a monthly pregnancy test must be conducted. These investigations should be performed initially every 2 weeks while on clearance doses, reducing to monthly or 2-monthly assessments depending on the maintenance dose required. There is presently no requirement for liver biopsy.
Guidelines for the use of systemic retinoids in psoriasis The following guidelines apply for the use of systemic retinoids in psoriasis: 1. Acitretin can be prescribed for male patients or postmenopausal female patients. It is up to the clinicians discretion to prescribe acitretin in women of childbearing age keeping in mind the strict guidelines associated with acitretins teratogenicity. If there is any suggestion that a woman desires pregnancy, or suspicion that adequate birth control methods will not be practiced, or abstinence from alcohol cannot be avoided, then acitretin should not be prescribed to that woman. 2. Careful pretreatment and screening should be performed to exclude the possibility of hyperlipidemia and hepatotoxicity. Risk factors for hyperlipidemia (diabetes mellitus, obesity) should be looked for and a history of alcohol use and hepatitis should be screened in every patient. 3. Retinoids should be considered as monotherapy in generalized pustular psoriasis. 4. Combination therapy of acitretin with PUVA or UVB is advised in patients with severe plaque psoriasis and localized palmoplantar psoriasis, including local pustular psoriasis of the palms and soles. 5. Combination therapy of acitretin with hydroxyurea may be beneficial in some patients with plaque or pustular psoriasis. In addition, combination therapy with the retinoids and the new immunomodulatory biologic agents may play pivotal roles in the future treatment of psoriasis. 6. New retinoids, such as oral tazarotene, seem to have a good safety profile. Longer-term studies and combination studies with this drug are eagerly awaited.
Frequency of follow-up Blood investigations should include a full blood count; a complete metabolic panel including liver
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Topical tazarotene There are four formulations for topical tazarotene: (1) 0.05% gel, (2) 0.1% gel, (3) 0.05% cream, and (4) 0.1% cream. All four vehicles and strengths can be used for plaque psoriasis. In general, gels and the more concentrated strengths tend to have a higher incidence of irritation, pruritus, erythema, stinging, and desquamation. These side effects are most apparent on initial applications but alleviate with continuous usage. In two multicentered, double-blinded, randomized, placebo-controlled studies involving 660 patients, tazarotene gels 0.05% and 0.1% applied once a day for 3 months were found to be efficacious and safe for the treatment of plaque psoriasis. The most profound effect with tazarotene gel was the improvement of plaque elevation [36]. Results of two multicenter studies showed that topical therapy once daily with tazarotene in a cream formulation at concentrations of 0.05% or 0.1% was effective in the treatment of plaque psoriasis [37]. A total of 1303 patients participated in these randomized, double-blinded, placebo-controlled trails in which tazarotene creams 0.1% and 0.05% or vehicle were applied daily to all psoriatic lesions for 12 weeks followed by a 12-week posttreatment period. Tazarotene creams 0.05% and 0.1% were significantly more effective than vehicle in terms of clinical success rates and in reducing the severity of the clinical signs of plaque psoriasis. Tazarotene cream 0.1% was generally more effective, although slightly less well tolerated, than the 0.05% cream. Both tazarotene concentrations showed good maintenance of therapeutic effect during a 12-week posttreatment period. Tazarotene creams 0.05% and 0.1% for the treatment of psoriasis were found to be safe with acceptable tolerability. To counteract potential irritation from tazarotene, topical corticosteroids may be combined to the lesions. A study showed that application of tazarotene in the evening and a mid- to high-potency topical corticosteroids in the morning achieved significantly greater reductions in scaling, erythema, and overall lesional severity, and a decreased incidence of adverse events [38]. Combination therapy by alternating tazarotene and high-potency steroids each day significantly increased the treatment success rate and lowered incidence of treatment-related adverse effects [39]. Short contact with tazarotene minimizes the local irritation on the skin. For patients who are beginning therapy with tazarotene, initial application times of 15 minutes in the evenings and then washing off the tazarotene decreases the incidence of stinging, burning, and erythema. As the patient becomes accus-
tomed and more tolerant to tazarotene, application times are prolonged incrementally until patients can leave it on overnight. Combination treatment using tazarotene with ultraviolet therapy has become very popular for the treatment of plaque psoriasis [40 43].The efficacy of tazarotene reported in clinical trials suggests that this drug may help to improve the efficacy of phototherapy, and perhaps reduce the ultraviolet light exposure required without introducing additional, clinically significant problems. Broad or narrow band UVB plus tazarotene combination achieves greater reductions in the elevation and scaling of difficult-totreat psoriatic plaques than UVB phototherapy alone. The tazarotene combination therapy also achieved initial treatment success in less than half the time needed with phototherapy alone. Combining UVB phototherapy with tazarotene treatment seems to offer a valuable therapeutic option that is more efficacious and faster than UVB phototherapy alone.
Summary Both systemic and topical retinoids provide an excellent alternative for the treatment of psoriasis. Retinoids are generally used as combination therapy with other treatment modalities, such as phototherapy or other topical or systemic agents, and can be combined with the newer biologic agents, such as etanercept. Newer retinoids are being developed to treat psoriasis with the hope of a less toxic side effect profile. For now, retinoids remain a mainstay for the treatment of psoriasis.
References
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Dermatol Clin 22 (2004) 477 486
Psoriatic arthritis: prevalence, diagnosis, and review of therapy for the dermatologist
Eric M. Ruderman, MD*, Siddharth Tambar, MD
Department of Medicine, Northwestern University Feinberg School of Medicine, 240 East Huron Street, McGaw 2300, Chicago, IL 60611, USA
Psoriatic arthritis (PsA) is an inflammatory arthritis that is commonly associated with psoriasis. Characteristic symptoms of any inflammatory arthritis include pain and stiffness in affected joints, morning stiffness lasting longer than 30 minutes, and stiffness that is accentuated by prolonged rest and relieved with activity.
and Wright [4] have described five different clinical patterns of joint involvement: 1. Asymmetric oligoarthritis, where fewer than five joints are affected in an asymmetric distribution. 2. Symmetric polyarthritis, in which more than five joints in a symmetric pattern are involved. This pattern is almost indistinguishable from RA. 3. Distal arthritis, characterized by distal interphalangeal joint involvement. 4. Arthritis mutilans, a destructive arthritis that results in severe deformities. 5. Spondyloarthropathy, disease affecting the spine (spondylitis), sacrum-sacroiliac joints (sacroiliitis), and hip-shoulder joints with or without peripheral arthritis. Studies done since Moll and Wright [4] published their classification scheme have not found the same distribution in all patient populations [5]. Furthermore, some patients present with more than one pattern, and many undergo a change in the pattern of their arthritis during follow-up [6,7]. One proposed disease classification is limited to just three patterns: (1) asymmetric oligoarthritis, (2) symmetric polyarthritis, and (3) spondyloarthropathy. Other series have suggested that nearly all patients fit into the second pattern [8,9]. Another group has suggested that the disease is best divided into just two subsets: peripheral arthritis, and axial (spinal) disease with or without peripheral arthritis [7]. Oligoarthritis has been considered the most common initial presentation, although recent series have questioned this
Prevalence and presentation of disease Although psoriasis affects 1% to 3% of the United States population, it has been reported that 7% to 31% of patients with psoriasis also have PsA [1]. The wide range may relate to the variability in the populations studied, from community-based cohorts to referral clinics or hospitalized patients. There is an equal gender distribution, onset of joint complaints is typically in the 30s to 50s, and whites have a greater incidence as compared with African Americans and Asians. In the United States, the incidence of new cases is approximately 6 per 100,000, and the prevalence is 100 per 100,000 [2,3]. Although previously believed to be a less severe variant of rheumatoid arthritis (RA), PsA is now considered a distinct disease process as first described by Moll and Wright [4]. When compared with RA, patients with PsA tend to have less tender joints and less prominent joint effusions. Significant joint destruction and pain, however, are still possible. Moll
* Corresponding author. E-mail address: e-ruderman@northwestern.edu (E.M. Ruderman).
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presumption [7,10]. Although rare, isolated distal interphalangeal (DIP) synovitis and arthritis mutilans are considered the most specific joint findings in PsA. The pattern of severity of the joint disease is not related to the pattern or severity of the skin disease. In the majoriy of patients, however, skin findings develop years before the arthritis [11]. At present, most information on disease patterns is observational. Current efforts to develop better outcomes measurements in PsA may ultimately produce characterizations of disease patterns that are more clearly related to pathogenesis or response to specific therapies.
Box 2. Radiographic features of PsA Peripheral Asymmetric distribution Distal interphalyngeal joint involvement Periostitis Preservation of bone density Bony ankylosis Pencil-in-cup deformities
Axial Diagnosis Psoriatic arthritis is considered a seronegative spondyloarthropathy, a group of diseases that includes ankylosing spondylitis, reactive arthritis or Reiters syndrome, and the arthritis associated with inflammatory bowel disease. These diseases share a predilection for asymmetric peripheral arthritis and axial or spinal involvement. As with other spondyloarthropathies, musculoskeletal manifestations of PsA may also include inflammation at the site of attachment of tendons and ligaments (enthesitis), especially at the Achilles tendon insertion and the insertion of the plantar fascia into the calcaneus. Dactylitis, also described as a sausage digit, may also be seen. These digits develop swelling and tenderness of the entire finger or toe because of inflammation of the tendons along with the involved joints. Inflammatory eye involvement has been observed in up to one third of patients with PsA [11]. The diagnosis of PsA is based on the clinical presentation of joint complaints, a history of psoriasis, radiographic changes, and a possible family history of psoriasis. The presence of other arthritis conditions makes the diagnosis of PsA difficult at times; a diagnosis of PsA requires the exclusion of other possible causes of joint symptoms (Box 1). Confounders include the coexistence of gout and Box 1. Differential diagnosis of PsA Osteoarthritis Gout Rheumatoid arthritis Reactive arthritis Ankylosing spondylitis Inflammatory bowel disease related arthritis Sacroiliitis (may be asymmetrical) Vertebral syndesmophytes Intervertebral ankylosis Paravertebral ossification
osteoarthritis in some patients. Gouty arthritis is commonly seen in association with psoriasis, presumably related to the hyperuricemia resulting from rapid skin cell turnover [12]. Osteoarthritis is a common disease, and in women DIP involvement with Heberdens nodes may be mistaken for the DIP synovitis seen in PsA. The presence of soft tissue swelling and erythema around the joint may help to distinguish PsA changes from osteoarthritis. Finally, RA or another arthritic condition may be present in a patient who also happens to have unrelated skin psoriasis. There are no specific laboratory studies used in making the diagnosis of PsA. An elevated erythrocyte sedimentation rate, C-reactive protein, or leukocytosis is seen in one third of patients, consistent with a nonspecific inflammatory state [13]. The common finding of normal acute-phase reactants may help to distinguish PsA from RA. Although PsA is classically considered a rheumatoid factor negative disease, both antinuclear antibodies and rheumatoid factor may be present in 10% of patients [5]. There are common and distinct radiographic changes in PsA (Box 2). In one study, radiographic damage was found in two thirds of patients at initial presentation [14]. Bone changes in PsA may be distinct from the findings in other inflammatory arthropathies, and may include a combination of erosion and new bone formation in distal joints. Distinctive radiographic features of PsA include asymmetric oligoarticular distribution, relative absence of periarticular osteopenia, involvement of
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the DIP joints, and involvement of the sacroiliac joints [15]. Other changes include joint space loss with or without ankylosis; destruction of isolated joints; fluffy periostitis; and lysis of the terminal phalanges (acro-osteolysis). Pencil-in-cup appearance of phalanges is also described, and is a combination of tapering of the middle phalanx and bony proliferation at the base of the distal phalanx. In contrast to RA, bone density in PsA is usually preserved [16]. Findings in the axial skeleton include paravertebral ossification, vertebral syndesmophytes, asymmetric sacroiliitis, apophyseal sclerosis, and calcification of the interspinous or anterior ligaments [15]. Cervical spine findings include intervertebral disk-space narrowing and ankylosis; both atlantoaxial fusion and subluxation may be found in the upper cervical spine. Temporomandibular joint involvement, with condylar erosions and condylar osteolysis, may occur [17]. MRI may be more sensitive than plain radiographs in documenting the articular, periarticular, and soft tissue inflammation in PsA [18]. MRI seems to be especially useful in demonstrating entheseal changes, such as inflammation and new bone formation, and may be useful in differentiating an early spondyloarthropathy from early RA [19,20].
Damage and disability Opinions differ as to the extent of joint damage and subsequent disability in PsA. Some population studies suggest a disease with a relatively benign course. An evaluation of psoriasis in Olmsted County, Minnesota, from 1982 through 1991 identified 66 cases of PsA among 1056 confirmed cases of psoriasis [3]. During the 10-year follow-up period, only 3% and 8% of the patients developed erosive changes on foot and hand radiographs, respectively [3]. Only 25 patients developed extra-articular manifestations of disease, including enthesitis, inflammatory eye disease, and urethritis. A population study in Finland showed a similar incidence rate of PsA, but found that 46% of the patients developed erosive joint disease [21]. The difference may relate to an ascertainment bias in the Finnish study that limited its cohort to patients receiving medication for their PsA. Cohort analyses of referral populations also suggest that PsA is frequently associated with a significant amount of erosive arthritis [10,14]. In a study of 220 patients with PsA seen at a Canadian referral center, Gladman et al [14] found that 67% of the patients had erosive disease. The presence of DIP joint involvement and symmetrical polyarthri-
tis were associated with the most advanced radiologic changes in this study. Similarly, Torre Alonso et al [10] reported on a Spanish cohort of 180 patients with PsA, 57% of whom had erosive disease on radiographs. Although PsA has traditionally been viewed as a disease with a benign prognosis, radiographic evidence, such as that described previously, indicates that the disease is more progressive and destructive than previously thought. In a comparison of radiographic changes in PsA and RA, there was no significant difference in the severity of damage seen in hands and feet [22]. Furthermore, both groups had similar numbers of joints affected by significant radiologic damage. Although the highest rate of peripheral joint involvement in PsA seems to be within 12 months of disease onset, the disease has been shown to be progressive in terms of the number of joints affected and the damage to those joints [23]. It has been suggested that possible indicators of poor prognosis include younger age at onset, extensive skin involvement, and certain HLA antigens [24]. Although the degree of skin involvement and HLA type do not demonstrate a consistent impact between studies, the most reliable factor in determining a poor prognosis is polyarticular onset of disease. In fact, in a recent prospective study the only independent risk factor predictive of erosive and deforming disease over time was a polyarticular onset of disease [25]. Disability and reduced quality of life in psoriatic arthritis may be caused by factors other than joint damage alone. In a recent study comparing 47 patients with RA and PsA of equivalent duration, the patients with RA seemed to have greater disease severity, as suggested both by radiographic damage and the medication they were taking [26]. Function and quality of life scores were similar for both groups, however, leading the authors to suggest that this finding may have resulted from the additional burden of skin disease in the PsA patients [26]. In a separate study, PsA patients reported more limitations because of emotional problems than a comparison group of RA patients [27]. This finding is consistent with the psychosocial disability that has been reported in connection with psoriasis [28]. In most patients (70%), arthritis symptoms develop years after skin changes present. In 10% to 15%, arthritis precedes psoriasis, yet a significant family history of psoriasis may help in making the diagnosis. In 15% of patients the initial presentation includes arthritis and psoriasis together [11,14]. The correlation between skin disease and arthritis is limited; only 35% of patients with PsA note a relationship between the severity of their skin disease
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and joint activity [14]. With respect to predictors of future arthritis in patients with isolated psoriasis, nail involvement is the only clinical feature that identifies patients with psoriasis who are likely to develop arthritis [15]. In fact, nail involvement is found in 80% of patients with PsA [29]. Moreover, the only significant relationship shown between severity of arthritis and psoriasis has been DIP joint activity and nail involvement [30].
Disease pathogenesis The pathogenesis of PsA is unknown, but genetic, environmental, and immunologic factors all seem to influence disease susceptibility. Forty percent of patients with psoriasis or PsA have a first-degree relative with disease [29]. Individual HLA antigens, found on the short arm of chromosome 6, have been associated with PsA, and may be involved in antigen presentation, or they may be in linkage disequilibrium with another disease susceptibility gene. HLA antigens B13, B17, B38, B39, B27, Cw*0602, DR4, and DR7 have been implicated [29,31,32]. HLA-B7 and HLA-B27 are found more commonly in patients with PsA compared with patients with isolated skin psoriasis [29]. HLA-B27 itself is actually more common in the other seronegative spondyloarthropathies, however, and is only found in approximately 40% of patients with PsA. HLA-DR4, which is strongly associated with RA, is also associated with the polyarticular form of PsA [29]. HLA-B39, -B27, and -DQw3 have been reported to be associated with disease progression [33]. Genetic inheritance of genes other than HLA antigens also may be important. A separate gene locus on chromosome 16 has also been associated with PsA, with inheritance from the father being more strongly associated with developing the condition when compared with inheritance from the mother of the same allele [34]. Just as with the inflammatory response seen in psoriatic skin lesions, immunologic factors have been implicated within the joint spaces in PsA. T cells found in plasma and synovium are predominantly CD8+ cells and are activated, expressing HLA-DR molecules and interleukin (IL)-2 receptors [35]. These activated cells also secrete multiple proinflammatory cytokines and within the synovium there are elevated levels of tumor necrosis factor (TNF)-a, IL-1, IL-2, and the anti-inflammatory cytokine IL-10 [36]. The overall milieu results in proliferation and activation of synovial and epidermal fibroblasts. At the same time there are increased numbers of
osteoclast precursors, resulting in osteoclastogenesis and bony erosions [37]. Environmental factors are also believed to play a role in pathogenesis of PsA. An infectious etiology has been proposed. Elevated levels of IgG antibody to the C-terminal of Streptococcus pyogenes M protein have been found compared with patients with only skin psoriasis, RA, and controls [38]. Exacerbations of both psoriasis and PsA have been reported in the context of HIV infection; however, the viral role in this situation is not clear [39]. Trauma may also be involved, similar to the Koebner phenomenon in which patients may develop psoriasis at site of previous trauma. Some patients with PsA have reported a history of trauma before the onset of their disease [40].
Treatment Treatment of PsA has generally been similar to treatment of other types of inflammatory arthritis, including RA. Physical therapy and other nonmedical treatments may be useful. Nonsteroidal anti-inflammatory drugs have been shown to be effective in PsA [41,42]. Some authors have raised concern that nonsteroidal anti-inflammatory drugs may exacerbate the associated skin disease [43,44]. Corticosteroids are also used, although again there is some concern over exacerbation of skin disease, particularly after withdrawal of relatively short courses, and concern that corticosteroids may cause the skin disease to become resistant to other therapies [2,44]. Other authors have suggested that the use of corticosteroids may be an important risk for the development of PsA in a patient with psoriasis [45]. Historically, the management of PsA unresponsive to anti-inflammatory therapy has borrowed from the disease-modifying antirheumatic drugs commonly used to treat RA. Injectable gold salts, although infrequently used at the present time, were one of the earliest second-line therapies for RA, and clinical benefit from the use of these agents in PsA has been reported [46 48]. Similar to the experience in RA, auranofin, the oral form of gold, seems to be less effective than the parenteral forms, although it may be better tolerated [48,49]. Hydroxychloroquine and other antimalarials have been reported to be effective in PsA in uncontrolled series, although hydroxychloroquine has been reported to exacerbate skin disease in some cases [50]. A meta-analysis of 12 clinical trials of various medications for PsA found statistical benefit relative to placebo only for intravenous methotrexate, sulfa-
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salazine, azathioprine, and etretinate, although studyrelated issues limited the interpretation of the results of the last two [51]. The authors noted a significant placebo response in all 12 trials, and suggested that this limits the ability of uncontrolled trials to guide treatment decisions in PsA. Despite the issue of placebo response, anecdotal reports and open series may provide a clue to the value of a particular therapy by using a variety of measurements of disease activity. Controlled clinical trials, however, require predetermined end points, generally including defined response criteria. The Psoriatic Arthritis Response Criteria (PsARC) (Box 3), developed for use in clinical trials of sulfasalazine, includes measurements of tender and swollen joints, and patient and physician assessments of disease activity [52]. The American College of Rheumatology (ACR) response criteria includes these same measurements, and adds the elements of pain, functional assessment, and acute-phase reactant levels (Box 4) [53]. An ACR-20 response indicates 20% improvement in these measurements of disease activity. ACR-50 and ACR-70 responses, respectively, indicate 50% and 70% improvement. Although the ACR response criteria have been used to evaluate treatment response in PsA, some have raised concern that these response criteria may be less reliable in this disease because of the generally lower sedimentation rates and lower joint counts. Efforts are currently underway to develop and validate disease-specific response criteria in PsA. Sulfasalazine, originally developed some 50 years ago for use in treating RA, has been demonstrated in controlled trials to be effective in PsA. Using the PsARC, sulfasalazine, 2 g/d, was shown to be statistically more effective than placebo in a multicenter
Box 4. American College of Rheumatology response criteria Both 20% improvement in tender-joint count 20% improvement in swollen-joint count
Plus 20% improvement in three of five of the following criteria Patient pain assessment (100 mm visual analog scale) Patient global assessment (100 mm visual analog scale) Physician global assessment (100 mm visual analog scale) Patient self-assessed function (Health Assessment Questionnaire or similar instrument) Acute-phase reactant value (erythrocyte sedimentation rate or C-reactive protein)
Box 3. Psoriatic arthritis response criteria Improvement in at least two of four criteria, one of which must be tender- or swollen-joint score Physician global assessment (! 1 unit on a scale of 0 to 5) Patient global assessment (! 1 unit on a scale of 0 to 5) Tender-joint score (! 30%) Swollen-joint score (! 30%) Plus No worsening in any criterion
trial in 221 patients [52]. In this same group of patients, the drug was shown to be more effective for the management of peripheral arthritis than for axial disease [54]. In a separate placebo-controlled study of sulfasalazine, 3 g/d, in 351 patients with spondyloarthropathies, the drug was found to be particularly effective in the subset of patients with PsA [55]. Cyclosporine, frequently used in the treatment of psoriasis, has been evaluated in the treatment of PsA, although there are no published double-blind studies with this agent. Early series described the use of relatively high doses of cyclosporine, up to 6 mg/kg/d [56,57]. More recent studies have used lower doses to reduce toxicity [58,59]. In a prospective, open study of cyclosporine for psoriasis and PsA, the drug was clearly more effective for skin disease than for joint symptoms [58]. A 50% reduction in skin involvement was achieved within 5 to 6 weeks of initiation of therapy, whereas a 50% reduction in joint symptoms took 24 weeks. A prospective, open 1-year comparison of cyclosporine and methotrexate for the treatment of PsA demonstrated improvement in multiple measurements of joint disease activity for both compounds [60]. Cyclosporine was initially dosed at 3 mg/kg/d in this trial, then raised as necessary to a maximum of 5 mg/kg/d; the comparable dose range
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for methotrexate was 7.5 to 15 mg/wk. In a 24-week prospective, open study, cyclosporine, 3 mg/kg/d, was statistically more effective than sulfasalazine, 2 g/d, in reducing pain, the primary end point [59]. Methotrexate, another drug frequently used to treat psoriasis, was reported to be effective as a parenteral therapy for PsA as early as 1964 [61]. A retrospective analysis of 59 patients treated for up to 11 years with weekly low-dose methotrexate (initially 15 mg/wk) reported response in 43 patients that was unrelated to the initial severity of disease [62]. The only placebo-controlled, blinded study of low-dose, oral methotrexate for the treatment of PsA was published in 1984, and included 37 patients with active arthritis that could not be treated successfully with aspirin or nonsteroidal anti-inflammatory drugs [63]. Although a variety of arthritis assessments were evaluated, including grip strength, morning stiffness, and joint counts, the only variable that statistically improved compared with placebo was the physician global assessment [63]. Etretinate, also used to treat psoriatic skin disease, has been investigated as a therapy for PsA [64,65]. One open-label trial treated 40 patients for up to 24 weeks with etretinate, 50 mg/d, reducing the dose to 25 mg daily when necessary because of side effects [65]. Significant improvements were seen in all measurements of PsA disease activity. Thirty-nine of the 40 patients had mucocutaneous side effects, however, including nine in whom these side effects resulted in discontinuation of therapy. Such toxicity has limited the acceptance of etretinate as a therapy for PsA. Finally, leflunomide, the most recently introduced antimetabolite for the treatment of RA, has been examined in PsA [66,67]. This drug, a pyrimidine synthesis inhibitor, is believed to work by selectively reducing activated inflammatory cells, particularly T cells, in inflamed joints. A placebo-controlled study demonstrated a modest response rate of 58% in the leflunomide group compared with 38.5% in the placebo group (again highlighting the placebo response in this disease) [67]. There was also a statistically significant improvement in skin lesions in the leflunomide group. The discontinuation rate was quite high for both groups in this 24-week study. In addition to potential differences in efficacy, there are potential differences in toxicity that must be evaluated before applying RA therapy to PsA. This is highlighted in a recently published review that examined and compared disease-modifying antirheumatic drugs treatment courses in disease-modifying antirheumatic drugs in 104 patients with PsA and 102 patients with RA [68]. Agents used included
parenteral gold, methotrexate, and sulfasalazine. Patients were treated longer for RA with both gold and methotrexate (35 versus 12 months and 72 versus 12 months, respectively), whereas the treatment course for sulfasalazine in PsA was slightly longer (17 versus 12 months). Although the results did not show a difference in efficacy for the three drugs in these two diseases, toxicity was seen more frequently among the PsA patients. Rash and hematologic disorders were the most common toxicities leading to discontinuation of therapy in PsA patients treated with gold, whereas elevated serum transaminases, hematologic disorders, and infections were the most common reasons in the methotrexate-treated patients. The authors comment that these differences in toxicity may limit the applicability of RA therapies to patients with PsA [68].
Biologic response modifiers The perceived imbalance between efficacy and toxicity may be one of the factors that have limited the widespread use of second-line agents in PsA. Biologic response modifiers may hold the key to reversing this imbalance. Recent studies have demonstrated both clinical and radiographic improvement in RA with compounds that block the biologic activity of TNF-a [69 72]. Experimental evidence has suggested that TNF-a also may play an important role in the pathogenesis of PsA [36,73]. These findings, coupled with the clinical experience in RA, have led to trials of TNF-a antagonists in PsA. Infliximab, a chimeric monoclonal antibody directed against TNF-a, has been studied as a therapy for PsA in several small open-label treatment studies [74 76], and in a larger placebo-controlled trial [77]. A placebo-controlled study of infliximab in 40 patients with spondyloarthropathies included 13 with PsA [78]. Regimens studied with this intravenously administered agent have included loading doses at 0, 2, and 6 weeks, followed by repeated doses every 8 weeks. Doses have ranged from the 3 mg/kg dose commonly used as the initial dose in RA to 5 mg/kg, the dose used for the treatment of Crohns disease and ankylosing spondylitis [74,76,78]. Results in all of these studies have been encouraging. More than half of the patients in two of the open-label trials achieved an ACR-70 response after the loading doses and maintained this response with ongoing treatment [75,76]. In the spondyloarthropathy trial, the primary end points of patient and physician assessment on a visual analog scale improved significantly in the treatment group, where-
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as the placebo group remained unchanged [78]. Results were seen as early as 2 weeks, and maintained through 12 weeks in this short study. A recently reported double-blind, placebo-controlled trial of infliximab in PsA included 102 patients with active disease (more than five actively inflamed joints) [77]. Patients were randomized to receive 5 mg/kg of infliximab or placebo at 0, 2, and 6 weeks, and then every 8 weeks thereafter. Background therapy with second-line agents, including methotrexate, was allowed, as was therapy with nonsteroidal antiinflammatory drugs and less than 10 mg of prednisone, but the doses were to remain stable. At 16 weeks, the percentage of patients achieving an ACR-20, -50, and -70 was 69%, 49%, and 29%, respectively. Only 8% of the placebo-treated patients achieved an ACR-20, and none reached a higher level of response. The presence or type of background therapy did not influence response. Infliximab is typically used in combination with methotrexate in the therapy of RA; the addition of methotrexate seems both to increase efficacy and decrease toxicity [79,80]. The necessity of combination therapy with methotrexate in PsA has yet to be determined. Etanercept is a recombinant fusion protein combining the extracellular portions of two p75 TNF receptors with the Fc fragment of a human IgG1. This TNF-a antagonist has been studied for the treatment of PsA in two placebo-controlled trials [81]. In a small, single center trial, 60 patients with PsA were randomized to receive etanercept, 25 mg twiceweekly (N = 30), or placebo (N = 30) [81]. End points included the PsARC and the ACR20. After 12 weeks of treatment, 87% of the patients in the etanercept group met the PsARC compared with 23% of the patients in the placebo group. An ACR20 was achieved by 73% of the patients in the etanercept group compared with 13% in the placebo group. The results of the single center trial were corroborated in a large, multicenter trial of etanercept, which enrolled 205 patients with PsA. In this study, 59% of etanercept-treated patients achieved an ACR-20 at 12 weeks compared with 15% of placebo-treated patients. An ACR-50 was achieved by 38% of the etanercept-treated patients and an ACR-70 by 11% [82]. This trial also demonstrated that radiographic progression in the treated group was significantly reduced when compared with placebo [83]. As in treatment for RA, the most common treatment-related adverse events seen with etanercept therapy for PsA have been injection site reactions. On the basis of these data, etanercept has become the first biologic agent approved in the United States for the treatment of PsA. Registry trials for infliximab
and adalimumab, a fully human anti-TNF antibody approved for treatment of RA, are currently underway. Concern has been raised in clinical practice about the potential increased risk for infection that may accompany TNF inhibition, including bacterial infections and opportunistic and atypical infections, such as tuberculosis [84 86]. PPD screening before the initiation of treatment and appropriate vigilance during treatment are important elements of therapy with these agents. Other biologic response modifiers are being studied in psoriasis and PsA. Alefacept, which modulates T-cell response by blockade of the IL-2 receptor, has shown promising results in the treatment of plaque psoriasis. A small pilot study in PsA has shown that alefacept improves clinical joint score along with skin disease [87].
Summary Psoriatic arthritis is increasingly perceived as a common disease that causes progressive joint damage and disability. With earlier recognition and diagnosis, clinicians have the chance to intervene before significant permanent damage has occurred, reducing longterm disability and enhancing quality of life. With skin disease typically developing much earlier than joint disease, dermatologists can play a key role in identifying the onset of PsA. Dermatologists will frequently be the first physicians to recognize a diagnosis of PsA and will need to work closely with rheumatologists to establish the diagnosis and select treatments that will address both the skin and the joint disease. Cooperative management, with input from both specialties, will result in the most efficient and effective care for both the skin and joint manifestations of this disease. Newer therapeutic agents, such as the TNF-a antagonists and other biologic response modifiers, offer the potential for improved efficacy without some of the toxicities that have limited traditional therapies. However, these agents are not for all patients. As with the use of these agents in psoriatic skin disease, the financial cost of these agents is high. Patients with mild joint symptoms or only a few involved joints may not require biologic agents to manage their arthritis, sparing them both the cost and the potential toxicity. On the other hand, those with aggressive, destructive disease would benefit from effective treatment before they develop permanent joint damage. Ongoing research into the epidemiology and outcomes of PsA can provide insight into the patient characteristics, such as multiple involved
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E.M. Ruderman, S. Tambar / Dermatol Clin 22 (2004) 477486 imaging techniques. Baillieres Clin Rheumatol 1994;8: 465 82. Kononen M. Radiographic changes in the condyle of the temporomandibular joint in psoriatic arthritis. Acta Radiol 1987;28:185 8. Offidani A, Cellini A, Valeri G, Giovagnoni A. Subclinical joint involvement in psoriasis: magnetic resonance imaging and X-ray findings. Acta Derm Venereol 1998;78:463 5. McGonagle D, Gibbon W, OConnor P, Green M, Pease C, Emery P. Characteristic magnetic resonance imaging entheseal changes of knee synovitis in spondylarthropathy. Arthritis Rheum 1998;41:694 700. Jevtic V, Watt I, Rozman B, Kos-Golja M, Demsar F, Jarh O. Distinctive radiological features of small hand joints in rheumatoid arthritis and seronegative spondyloarthritis demonstrated by contrast-enhanced (Gd-DTPA) magnetic resonance imaging. Skeletal Radiol 1995;24:351 5. Kaipiainen-Seppanen O. Incidence of psoriatic arthritis in Finland. Br J Rheumatol 1996;35:1289 91. Rahman P, Nguyen E, Cheung C, Schentag CT, Gladman DD. Comparison of radiological severity in psoriatic arthritis and rheumatoid arthritis. J Rheumatol 2001;28:1041 4. McHugh NJ, Balachrishnan C, Jones SM. Progression of peripheral joint disease in psoriatic arthritis: a 5-yr prospective study. Rheumatology (Oxford) 2003;42: 778 83. Espinoza LR, Cuellar ML. Psoriatic arthritis: management. In: Hochberg MC, Silman AJ, Smolen JS, Weinblatt ME, Weisman MH, editors. Rheumatology. 3rd edition. London: Mosby; 1998. p. 1259 65. Queiro-Silva R, Torre-Alonso JC, Tinture-Eguren T, Lopez-Lagunas I. A polyarticular onset predicts erosive and deforming disease in psoriatic arthritis. Ann Rheum Dis 2003;62:68 70. Sokoll KB, Helliwell PS. Comparison of disability and quality of life in rheumatoid and psoriatic arthritis. J Rheumatol 2001;28:1842 6. Husted JA, Gladman DD, Farewell VT, Cook RJ. Health-related quality of life of patients with psoriatic arthritis: a comparison with patients with rheumatoid arthritis. Arthritis Rheum 2001;45:151 8. Rapp SR, Feldman SR, Exum ML, Fleischer Jr AB, Reboussin DM. Psoriasis causes as much disability as other major medical diseases. J Am Acad Dermatol 1999;41(3 pt 1):401 7. Gladman DD, Anhorn KA, Schachter RK, Mervart H. HLA antigens in psoriatic arthritis. J Rheumatol 1986; 13:586 92. Cohen MR, Reda DJ, Clegg DO. Baseline relationships between psoriasis and psoriatic arthritis: analysis of 221 patients with active psoriatic arthritis. Department of Veterans Affairs Cooperative Study Group on Seronegative Spondyloarthropathies. J Rheumatol 1999;26:1752 6. Eastmond CJ. Psoriatic arthritis: genetics and HLA antigens. Baillieres Clin Rheumatol 1994;8:263 76.
joints, that may be indicators of poor outcomes. Appropriate patient selection will be critical to ensure that resources are used wisely on patients who will benefit, and that those who would benefit the most are treated appropriately.
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E.M. Ruderman, S. Tambar / Dermatol Clin 22 (2004) 477486 ized, double-blind, placebo controlled trial of low-dose pulse methotrexate in psoriatic arthritis. Arthritis Rheum 1984;27:376 81. Ciompi ML, Bazzichi L, Marotta G, Pasero G. Tigason (etretinate) treatment in psoriatic arthritis. Int J Tissue React 1988;10:25 7. Klinkhoff AV, Gertner E, Chalmers A, et al. Pilot study of etretinate in psoriatic arthritis. J Rheumatol 1989;16: 789 91. Liang GC, Barr WG. Open trial of leflunomide for refractory psoriasis and psoriatic arthritis. J Clin Rheumatol 2001;7:366 70. Kaltwasser P, Nash P, Gladman D, Mease PJ. Efficacy and safety of leflunomide in the treatment of psoriatic arthritis: results from the TOPAS study [abstract LB04]. Presented at the 66th Annual Scientific Meeting of the American College of Rheumatology. New Orleans, October 24 29, 2002. Ujfalussy I, Koo E, Sesztak M, Gergely P. Termination of disease-modifying antirheumatic drugs in rheumatoid arthritis and in psoriatic arthritis: a comparative study of 270 cases. Z Rheumatol 2003;62:155 60. Moreland LW, Schiff MH, Baumgartner SW, et al. Etanercept therapy in rheumatoid arthritis: a randomized, controlled trial. Ann Intern Med 1999;130: 478 86. Lipsky PE, van der Heijde DM, St Clair EW, et al. Infliximab and methotrexate in the treatment of rheumatoid arthritis. Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy Study Group. N Engl J Med 2000;343:1594 602. Genovese MC, Bathon JM, Martin RW, et al. Etanercept versus methotrexate in patients with early rheumatoid arthritis: two-year radiographic and clinical outcomes. Arthritis Rheum 2002;46:1443 50. Bathon JM, Martin RW, Fleischmann RM, et al. A comparison of etanercept and methotrexate in patients with early rheumatoid arthritis. N Engl J Med 2000; 343:1586 93. Partsch G, Wagner E, Leeb BF, Broll H, Dunky A, Smolen JS. T cell derived cytokines in psoriatic arthritis synovial fluids. Ann Rheum Dis 1998;57:691 3. Cauza E, Spak M, Cauza K, Hanusch-Enserer U, Dunky A, Wagner E. Treatment of psoriatic arthritis and psoriasis vulgaris with the tumor necrosis factor inhibitor infliximab. Rheumatol Int 2002;22:227 32. Antoni C, Dechant C, Hanns-Martin Lorenz PD, et al. Open-label study of infliximab treatment for psoriatic arthritis: clinical and magnetic resonance imaging measurements of reduction of inflammation. Arthritis Rheum 2002;47:506 12. Salvarani C, Cantini F, Olivieri I, et al. Efficacy of infliximab in resistant psoriatic arthritis. Arthritis Rheum 2003;49:541 5. Antoni C, Kavanaugh A, Kirkham B, et al. The Infliximab Multinational Psoriatic Arthritis Controlled Trial (IMPACT) [abstract 985]. Arthritis Rheum 2002; 46(suppl 9):S381. Van Den Bosch F, Kruithof E, Baeten D, et al. Randomized double-blind comparison of chimeric monoclonal antibody to tumor necrosis factor alpha (infliximab) versus placebo in active spondylarthropathy. Arthritis Rheum 2002;46:755 65. Maini RN, Breedveld FC, Kalden JR, et al. Therapeutic efficacy of multiple intravenous infusions of anti-tumor necrosis factor alpha monoclonal antibody combined with low-dose weekly methotrexate in rheumatoid arthritis. Arthritis Rheum 1998;41: 1552 63. Baert F, Noman M, Vermeire S, et al. Influence of immunogenicity on the long-term efficacy of infliximab in Crohns disease. N Engl J Med 2003;348: 601 8. Mease PJ, Goffe BS, Metz J, VanderStoep A, Finck B, Burge DJ. Etanercept in the treatment of psoriatic arthritis and psoriasis: a randomised trial. Lancet 2000;356:385 90. Mease PJ, Kivitz AJ, Burch F, Siegel E, Cohen S, Burge DJ. Improvement in disease activity in patients with psoriatic arthritis receiving etanercept (ENBREL): results of a phase 3 multicenter clinical trial [abstract 226]. Arthritis Rheum 2001; 44(suppl 9):S90. Ory P, Sharp JT, Salonen D, et al. Etanercept (ENBREL) inhibits radiographic progression in patients with psoriatic arthritis [abstract 442]. Arthritis Rheum 2002;46(suppl 9):S196. Keane J, Gershon S, Wise RP, et al. Tuberculosis associated with infliximab, a tumor necrosis factor alpha-neutralizing agent. N Engl J Med 2001;345: 1098 104. Gomez-Reino JJ, Carmona L, Valverde VR, Mola EM, Montero MD. Treatment of rheumatoid arthritis with tumor necrosis factor inhibitors may predispose to significant increase in tuberculosis risk: a multicenter active-surveillance report. Arthritis Rheum 2003;48: 2122 7. Hamilton CD. Tuberculosis in the cytokine era: what rheumatologists need to know. Arthritis Rheum 2003; 48:2085 91. Kraan MC, van Kuijk AW, Dinant HJ, et al. Alefacept treatment in psoriatic arthritis: reduction of the effector T cell population in peripheral blood and synovial tissue is associated with improvement of clinical signs of arthritis. Arthritis Rheum 2002;46:2776 84.
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Dermatol Clin 22 (2004) 487 492
Practical considerations in future psoriasis therapies

Christy Riddle, MDa, Melodie Young, MSN, RNb,c,*, Alan Menter, MDa,c
a
Department of Internal Medicine, Baylor University Medical Center, 3500 Gaston Avenue, Dallas, TX 75246, USA b Graduate School of Nursing, The University of Texas at Arlington, Arlington, TX, USA c Texas Dermatology Associates, 5310 Harvest Hill Road, Suite 260, Dallas, TX 75230, USA
Revolutionary new therapies for psoriasis are likely to allow dermatologists, even those who consider themselves nonpsoriasis experts, the ability to provide more targeted treatments that can offer a significant number of patients the ability to reclaim their lives. This new frontier in therapy significantly broadens the choices dermatologists and their patients have available from which to choose. For decades, psoriasis therapy has been limited to Goeckerman treatment, phototherapy, and several systemic drugs that although effective are limited by toxicities that frequently precluded long-term maintenance therapy. It is hoped that the introduction of these new biologic drugs allows dermatologists to share in the excitement and enter the psoriasis therapy arena. For the patient, this means wider access and potentially fewer risks. As discussed elsewhere in this issue, psoriasis researchers, pharmaceutical companies, and front-line
Alan Menter has the following conflicts of interest: (1) research: Abbott, Allergan, Allermed, Amgen, Astralis, Biogen, Centocor, Connetics, Corixa, Dermik, Dow, Ferndale, Fujisawa, Galderma, Genzyme, GlaxoSmithKline, Inamed, Lumenis, Medicis, Novartis, Otsuka, Photocure, Regeneratio, Pharma AG, Scirex, Serono, Thermosurgery; and (2) consultancies and honoraria: Allergan, Amgen, Biogen, Centocor, Genentech, ICN, Novartis, Serono, Thermosurgery, Warner-Chilcott. No stock ownership. Melodie Young has the following conflicts of interest: Nurse Advisory Boards for Biogen, Fujisawa, and Genentech. Presentations for Allergan, Amgen, Biogen, Fujisawa, Genentech, Healthpoint, and ICN. * Corresponding author. Texas Dermatology Associates, 5310 Harvest Hill Road, Suite 260, Dallas, TX 75230. E-mail address: melodieyoung@aol.com (M. Young).
psoriasis experts have collaborated to develop biologic therapies that directly target specific steps in the immunopathologic process of psoriasis and other immune-mediated diseases. Fortuitously, the side effects and cumulative toxicities in the short-term at least seem to be less burdensome than those of the traditional workhorses of psoriasis (ie, methotrexate, cyclosporine, retinoids, and psoralen plus UVA). Critical in this revolution is the recognition by the dermatologist of the value in assisting the psoriasis sufferer in assessing the impact of this disease on his or her quality of life. Pain and suffering are obviously subjective characteristics of any chronic debilitating disease that do not always correlate with the objective severity gauged by the treating physician. There are now validated tools for psoriasis patients to measure their deficiencies, both physical and emotional [1]. Improvement in individualizing therapy depends on having the clinician evaluate the impact of psoriasis on the patients quality of life and the value of having the patient also recognize the physical and emotional impact or damage sustained from living with psoriasis. The Koo-Menter Psoriasis Index (KMPI) is a tool requiring the input of both the patient and the clinician and encourages changing the paradigm whereby a clinician alone decides what is best or having a patient deny the quality of life issues inherent in psoriasis and its treatment. This index provides guidance in deciding on a patients eligibility for a systemic treatment. It legitimizes the patients quality of life concerns, their joint symptomatology, and degree of psoriasis involvement, thereby allowing the clinician to determine if more aggressive therapies are warranted. Like rheumatologists, gastroenterologists, and neurologists who have had access to new technologic therapies over the past
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10 years, dermatologists now have the opportunity to offer psoriasis patients the hope of clearer skin and the encouragement of looking forward to a brighter outlook on life. This article discusses practical issues that allow dermatologists the ability to implement the expanding psoriasis armamentarium into their practices. Individual dermatologists are faced with an internet-savvy patient population who will no doubt have many questions about the new therapies. The increasing use of direct-to-consumer marketing tools by pharmaceutical companies also increases patient awareness and interest in biologics. Because the authors earnestly believe the correct therapy can help psoriasis patients reclaim their lives, they outline the steps necessary to integrate these new therapies into busy dermatology practices. Each practice must decide the extent to which it will offer currently available and future systemic and biologic therapies based on patient demand, support staff, available space, and the economic considerations unique to that office.
The available armamentarium Now and over the next few years, more and more biologics will be introduced for moderate to severe plaque psoriasis. The science, clinical efficacy, and side effect profiles of each of these drugs have been discussed in detail elsewhere in this issue. This article addresses information related to the practical aspects of their use. Already approved is alefacept (Amevive), which is administered in-office only by the intramuscular injection (IM) route. Efalizumab (Raptiva) given by subcutaneous weekly injection was approved at the end of 2003 for treatment of moderate to severe psoriasis. Biologics available for other indications but not yet approved for psoriasis are the tumor necrosis factor-a (TNF-a) antagonist drugs etanercept (Enbrel), infliximab (Remicade), and adalimumab (Humira). Enbrel is a subcutaneously self-administered biologic, currently approved for psoriatic arthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, and ankylosing spondylitis, but ex-
Table 1 Biologics pending approval or currently available for moderate to severe plaque psoriasis Product Alefacept Approval status Approved for moderate to severe psoriasis Administration IM 15 mg each week for 12 doses, in-office Short-term efficacy data Monitoring and side effects 33% obtained PASI 75 at 14 weeks CD4+ counts weekly while dosing; chills
Efalizumab
Approved for moderate to severe plaque psoriasis
1 mg/kg weekly 28% obtained PASI subcutaneous injections 75 at wk 12 by the patient
Monitor platelets, flu-like symptoms, rebound
Etanercept
25 50 mg Approved for juvenile subcutaneous by the and adult rheumatoid patient twice weekly and psoriatic arthritis and ankylosing spondylitis, approval for moderate to severe plaque psoriasis imminent Approved for Crohns 5 mg/kg IV infusion disease and rheumatoid in-office at weeks arthritis 0, 2, 6, and q 8 weeks thereafter
34% obtained PASI 75 at 12 wk
Optional laboratory monitoring, injection site reactions, CNS symptoms and infections
Infliximab
88% obtained PASI 75 at wk 10
TB testing; VS and infection monitoring pre-, during, and postinjection; premedication: acetaminophen, diphenhydramine, and prednisone As for above 2 TNF-a agents
Adalimumab Approved for rheumatoid arthritis
40 mg every other week subcutaneous
53% obtained PASI 75 at week 12
Abbreviations: CNS, central nervous system; PASI, Psoriasis Area and Severity Index; TB, tuberculosis; VS, vital signs. Data from Psoriasis for the clinician: a new therapeutics era (the biologics) beckons. J Am Acad Dermatol 2003;49.
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pecting an indication for plaque psoriasis in 2004. Infliximab (Remicade) is currently indicated in the treatment of Crohns disease and rheumatoid arthritis and is administered as an in-office intravenous (IV) infusion. Adalimumab (Humira) is another subcutaneously self-administered TNF-a monoclonal antibody approved for rheumatoid arthritis. Both of these latter drugs are in phase two and three development for psoriasis and psoriatic arthritis. Table 1 provides a summary of the available injectable biologics. Other systemic therapies under development for psoriasis include oral pimecrolimus (Elidel) and oral tazarotene (Tazorac), both familiar to dermatologists as topical agents used for atopic dermatitis, acne, and psoriasis.
Staffing requirements Dermatology nurses in most dermatologic practices already are familiar with injectable medications, such as triamcinolone and methotrexate. The addition of subcutaneously and intramuscularly administered biologics, such as alefacept, efalizumab, etanercept, and adalimumab, necessitates only a small amount of change in the nursing role. Because etanercept, efalizumab, and adalimumab may be self-injected each week by the patient, the nurse provides counseling and instruction at the beginning of treatment and then assists in managing patients between office visits. The technique for reconstituting and self-injecting medications is precise and requires all staff interacting with patients to have extensive training in these procedures. Thereafter, the nurse is available to answer questions and dispense medications on subse-
quent office visits. For IM alefacept, the patient requires weekly visits with the nurse for drawing laboratories and drug administration. Registered nurses (RNs), licensed vocational nurses, and some medical assistants are trained in IM administration techniques and can inject IM alefacept. The nurse or allied health professional monitors the alefacept inventory, procures the drugs from the pharmaceutical company or contracted pharmacy, and schedules patients accordingly. Coding and billing for subcutaneous and IM injectables is consistent with 99,211 level visits ($20 to $25) if the patient only interacts with a nurse. The actual injection procedure is billed as Current Procedural Terminology (CPT) code 90,782 ($5 to $7). Reimbursement for medication obtained from contracted pharmacies or distributors is billed by the appropriate J-code [2]. Phlebotomy and laboratory codes may also apply 36,415 ($4 to $5) for venipuncture and 86361 ($20 to $30) for CD4+ evaluation. Refer to Table 2 for the recommended code use. Because most dermatology practices do not employee RNs, starting an infusion center to administer IV therapies requires the greatest amount of change in the practice. Qualified staff has to be hired and trained. Other changes include developing space, obtaining necessary equipment, and safety considerations. A RN with infusion therapy experience and fully trained in the management of potential side effects becomes a central and irreplaceable part of the team. His or her role includes procurement of the drug, patient education, obtaining informed consent, IV access, documentation, laboratory review, drug administration, and multiple patient assessments. Fortunately, codes for reimbursement of these RN ser-
Table 2 Suggested codes for biologic therapy Function Nurse only Subcutaneous or intramuscular injection Venipuncture CD4+ evaluation IV push IV infusion up to 1 h IV infusion for each additional h Infliximab Unclassified drugs for Medicare Unclassified drugs non-Medicare Code CPT 99211 CPT 90782 CPT 36415 Lab code 83681 CPT 90784 CPT code 90780 CPT code 90781 J1745 J3490 J3590 Allowable $20 $25 per visit $5 $7 per injection $4 $5 $20 $30 $23 $45 $23 $65.70 per unit $875 per vial Variable Description Evaluation and teaching If administered by nursing staff Blood draw Laboratories obtained and billed from practice IV administration of a drug, may include access IV access and administration of a drug Continuous infusion beyond the first hour 10 units per vial Total per dose Reimbursed per third-party contract with each practice
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vices are available, but the degree to which they are covered differs between third-party payers and from state to state. Billing for IV infusion uses E, M, J, and CPT codes. CPT level 90,784 level ($21) IV push or the 90,780 level ($45) up to 1 hour and 90,781 for each additional hour depending on time requirements for the procedure. When billing for infliximab, use code J1745 with a Medicare reimbursement allowable rate of $65.70 per unit. For alefacept or other unclassified drugs, code J3490 with a Medicare reimbursement allowable of $875 per vial. For non-Medicare claims for alefacept, code J34590 with reimbursement varying dependent on the third-party contract (see Table 2). Space considerations depend on the individual office, but a private area with an infusion chair, writing and work surface, and stool are essential. If an extra examination room is available it may be converted easily to an infusion room for daily or perhaps only once-weekly use, depending on patient volume. A licensed medical doctor must always be present when performing infusions. Infliximab infusions mandate additional changes. The infusion time for this particular biologic runs from 1.5 to 3 hours. The patient must also be monitored for an hour afterward for postinfusion reactions. At least one RN must be present to infuse and monitor the patients, but a medical assistant or licensed vocational nurse can assist with preparation and monitoring of more than one patient. Also necessary is a
medical doctor immediately available for evaluation and management. Advanced cardiac life-support training is not mandatory, but is encouraged, and each physician must weigh risks and benefits and malpractice-related issues of advanced cardiac life-support training. At a minimum, the office must be able to provide oxygen therapy, diphenhydramine, epinephrine, and steroids to patients having an infusion reaction. In this regard, other medicine and surgical subspecialties have readily embraced these issues and offer dermatologists a great deal of published data to simplify this process [3 5]. Several options are recommended for infusion space configuration. The best arrangement depends on the level of psoriasis care each practice wishes to provide. If feasibility and volume dictate, additional office space adjacent to the main office can be leased and remodeled into a freestanding infusion center. Space dedicated for waiting, reception, charts, and infusion cubicles requires about 500 to 1000 sq ft. Fortunately, most committed dermatologists and other specialists have been able to work within the framework of their existing space or otherwise using a much smaller amount of space. An 8-ft by 8-ft stall with one wall curtained satisfies the Health Information Portability and Accountability Act guidelines for patient privacy and allows easy nursing access. Furniture, a telephone system, computer and monitoring equipment, crash cart, oxygen, and pulse oximeter are the necessary equipment. Besides the RN with
Fig. 1. Tiers of psoriasis care providers.
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Advanced Cardiac Life Support Qualifications, a receptionist and an infusion billing specialist comprise the staff [2]. Again, depending on the volume of patients treated, they may be either full time with the infusion center or shared with the general dermatology practice. Because so many options are becoming available, dermatologists have choices to make about the level of psoriasis care to provide. Many of these newly indicated drugs can be integrated easily into already busy practices with only minimal changes in staff and space. The authors foresee several tiers of psoriasis care based on services offered (Fig. 1). The highest level is a psoriasis center of excellence similar to the dedicated psoriasis day care centers of the 80s and 90s. Currently, there are only a handful of centers in the United States that truly offer expert medical and nursing care, cutting edge therapy, clinical research, and the full spectrum of traditional modalities of systemic agents and phototherapy. At these centers, psoriasis patients have been receiving psoralen plus UVA or narrow-band phototherapy; systemics, such as methotrexate, cyclosporine, and etretinate; second-tier drugs, such as hydroxyurea, 6-thioguanine, and mycophenolate mofetil; and the new biologics. These centers are likewise involved in clinical trials with biologics seeking psoriasis and psoriatic arthritis indications. They also may be in trials for oral pimecrolimus, tazarotene, or other psoriasis therapies, and are intimately involved with patient education and advocacy with the National Psoriasis Foundation and the American Academy of Dermatology in physician education. Reaching this level of excellence requires time, staff, and space dedication for phototherapy units, an infusion center, patient education areas, and clinical research. The next tier, with a lesser expenditure of resources than the center of excellence, is known as a psoriasis specialty clinic. This resource allows for some UV and systemic therapy and biologics, but not necessarily at the comprehensive scope of the top tier centers. This is very feasible for medically oriented dermatologists who wish to take more initiative in treating their psoriasis patients with moderate to severe disease. In some areas, they are the referral center for physicians with limited expertise and interest. The medical dermatologist who does not wish routinely to tackle the treatment of severe or moderately affected psoriatic patients makes up the next tier of care. This level of service provides limited treatment options and does not invest resources in phototherapy or extensive offering of all available therapies. For example, in this third tier, patients may receive the
option of methotrexate or a self-administered biologic, which requires very little change in practice. It is hoped that patients will be made aware of the new sophisticated biologic therapies and provided appropriate information, such as literature, web sites, and National Psoriasis Foundation referrals. Education and training of staff on the use, effects, provision, and billing of the new medication is, as in the prior two tiers, undertaken at this level. The final tier and the one least likely to provide a range of therapeutic options for moderate to severe psoriasis is the general community dermatologist or surgically oriented dermatologist whose interests lie elsewhere within dermatology. These physicians likely refer to a colleague who has the interest, staff, and facilities to offer more options, expertise, and quality of care to their patients.
Summary This is an exciting time to be in dermatology, both medical and nursing, especially for those interested in helping to change the lives of psoriasis patients. For too long the pace of new treatment modalities has crept along with few breakthroughs and minimal industry support. Now, as biologic therapy becomes a major focus of research and approval of new drugs gathers speed, dermatology is challenged to maintain and even regain its standing in the medical subspecialty arena. For a significant number of psoriasis patients with recalcitrant disease (not just a tiny minority) this means fresh hope that sophisticated new therapies will provide a better quality of life with potentially fewer side effects than the traditional weapons. Dermatologists who previously did not consider themselves psoriasis experts but who care about making a significant difference in patients lives now have the opportunity to treat patients they once referred effectively and safely in their own offices. This revolution in psoriasis therapy is a challenging one for the specialty but it is hoped it is one in which both patients and physicians win qualitatively and intellectually.
References
[1] Koo J, Menter A. The Koo-Menter psoriasis instrument for identifying candidate patients for systemic therapy. Psoriasis Forum, Summer 2003. p. 6 9. [2] Craze M, Young M. Integrating biologic therapies into a dermatology practice: practical and economic considerations. J Am Acad Dermatol 2003;49:S139 42.
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C. Riddle et al / Dermatol Clin 22 (2004) 487492 trexate in the treatment of rheumatoid arthritis. N Engl J Med 2000;343:1594 602. [5] Cheifetz A, Smedley M, Martin S, Reiter M, Leone G, Mayer L, et al. The incidence and management of infusion reactions to infliximab: a large center experience. Am J Gastroenterol 2003;98:1315 24.
[3] Chaudhari U, Romano P, Mulcahy LD, Dooley LT, Baker DG, Gottlieb AB. Efficacy and safety of infliximab monotherapy for plaque-type psoriasis: a randomized trial. Lancet 2001;357:1842 7. [4] Lipsky PE, Van der Heijde D, St. Clair W, Furst DE, Breedveld FC, Kalden JR, et al. Infliximab and metho-
Dermatol Clin 22 (2004) 493 499
Psoriasis: future research needs and goals for the twenty-first century
Christopher E.M. Griffiths, MD, FRCP
The Dermatology Centre, Hope Hospital, Irving Building, Salford, Manchester M6 8HD, UK
Most dermatologists are still involved with the management of patients with psoriasis. Despite its ubiquitous presence in outpatient clinics and monopoly of dwindling inpatient resources, psoriasis remains an enigma. Few studies have accurately addressed the prevalence and epidemiology of psoriasis outside secondary care. Molecular genetics indicate what has been suspected for some time in that clinicians are dealing with a continuum of psoriasis with similar phenotypes. Although no genes that are specific for psoriasis have been identified it is only a matter of time before a gene mutation is identified, perhaps leading to development of an animal model faithful to the histologic, immunologic, and clinical features of the disease. The explosion in new therapies under trial for psoriasis is a direct consequence of advances in the understanding of the key pathogenic pathways in psoriasis. Components of these pathways can be targeted selectively by biologic agents. Despite such progress clinicians are held back by lack of a good evidence base for efficacy in that many of the therapies for psoriasis are hindered by paucity of consensus on clinically relevant outcome measures. This article, inevitably speculative, part philosophic, discusses what I believe are the future needs in psoriasis research and how achievement of these goals should lead to a greater understanding of, and better therapy for, this disease (Table 1).
Epidemiology Surprisingly, there are few comprehensive epidemiologic studies of chronic plaque psoriasis. In Europe and the United States the oft-quoted prevalence is 2% of the population [1] with caveats that Northern Europe (ie, Scandinavia [2]) has a higher prevalence than Southern Europe and that in China psoriasis is rarer [3]. In the United Kingdom epidemiologic surveys are confounded by the fact that not all people with psoriasis seek medical help and that only a minority of cases is seen by dermatologists. A national survey, perhaps along the lines of a census, is required to examine accurately the prevalence, preferably on a regional basis, but this is dependent on clinical examination of alleged sufferers. Often people who are told they have psoriasis are shown subsequently to have other skin disorders, such as discoid eczema, dermatitis, and seborrheic dermatitis. It is my view that the prevalence of chronic plaque psoriasis is a good deal higher than 2%. In the United Kingdom newer, better treatments and the promotional awareness campaigns associated with them probably bring more psoriasis sufferers to the attention of primary care practitioners. This promotional bias may mask any real changes that have occurred in prevalence. As far as can be ascertained there has been no significant change in prevalence of psoriasis over the past 20 years unlike atopic dermatitis where cases have doubled. Prevalence figures for psoriasis are important for planning of resources for management. One of the drawbacks to achieving accurate prevalence figures is the lack of reliable diagnostic criteria for psoriasis (diagnosis is made purely on clinical examination). Clinical diagnosis is acceptable
E-mail address: christopher.griffiths@man.ac.uk
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Table 1 Research needs and goals of psoriasis Research needs Enhanced public awareness of psoriasis Health economics studies Identification of genes Goals Increased funds available for research Make case for burden of disease and economic impact Animal model Understanding of pathomechanisms Gene therapy Understanding of pathomechanisms Prevention and vaccination strategies Targets of therapy Identification of patients who would benefit from behavioural therapy and who are at risk of stress-induced relapse Prediction of prognosis and response to therapy Studies relevant to real life management of psoriasis Strategic application of research and development
Identification of autoantigen Investigation of innate immune responses angiogenesis and Koebner phenomenon Interrogation of the brain-skin axis and psychosocial disability Classification of clinical phenotypes Outcome measures and trial design Academia-industry collaboration
for dermatologists but not necessarily for other health care personnel. There is no test, other than skin biopsy, to aid diagnosis for the disease that is analogous to rheumatoid factor for rheumatoid arthritis or antinuclear antibodies for systemic lupus erythematosus. Clinical research is entering a new era, one that has direct relevance to psoriasis. Modern day clinicians are becoming overreliant on diagnostic tests and as a consequence are starting to lose or place less value on clinical examination. Chronic plaque psoriasis is referred to as a single disease entity but those working in psoriasis clinics and who see large numbers of psoriasis patients know that within this umbrella definition are subsets of disease with relatively distinct clinical patterns, such as small plaque, follicular, thin plaque, seborrheic, and so forth [4]. These patterns may relate to prognosis. It is my view that these patterns are relevant. As an analogy, penguins as a genus are birds that are instantly recognizable to most people. Within the generic definition of penguin, however, there are different, distinct species of penguins (Emperor, King, Rockhopper, and so forth). What is required is for careful phenotype classification of psoriasis predicated on clinical pattern. A diligent clinical research fellow is capable of performing such an important task. Our dermatologic forefathers, such as Willan [5], had only clinical observation at their disposal and were able to classify and subclassify dermatologic disease on pattern; it is beholden on us to recapture these skills. Quite possibly this phenotype mapping possesses fidelity with
genotype and allows clinic-based prediction of response to therapy, prognosis, and so forth.
Genetics Indubitably most research funding in psoriasis is spent on immunogenetics: the search for the psoriasis genes. There are at least eight psoriasis susceptibility loci located on different chromosomes. Psoriasis susceptibility locus-1 [6] close to HLACw6 [7] is a key determinant of early onset psoriasis beginning on or before 40 years of age [8] but of itself is not the psoriasis gene. A combination of genes is undoubtedly required to reveal the psoriasis phenotype after exposure to an environmental trigger, such as streptococcal pharyngitis or tonsillitis [9]. It is possible that different families have different permutations of genes and triggers leading to the skin reaction pattern typical of psoriasis. The elucidation of genes and gene products in psoriasis is of vital importance if targeted therapies are to be designed that may cure or even prevent the disease. Heterogeneity of disease probably precludes gene therapy for the time being. Perhaps the most important consequence of identifying psoriasis genes is the ability to develop a transgenic animal model for psoriasis. No such model exists; the nearest is a severe combined immunodeficient mouse xenografted with biopsies of human psoriasis [10]. An animal model allows rapid and economic screening of potential therapeutic agents. Diseases associated with psoriasis are impor-
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tant clinical signposts to candidate gene approaches; a good example is Crohns disease with its fivefold increased prevalence of psoriasis [11]. Genes close to caspase response domain-15 on chromosome 16 (a mutation that confers a 48-fold increased risk to Crohns disease [12]) are attractive candidates for psoriasis [13] as are other genes of the innate immune response.
Pathomechanisms The three classic histologic features of psoriasis are the main subjects of research into pathomechanisms: (1) abnormal epidermal keratinocyte proliferation and differentiation, (2) inflammation, and (3) angiogenesis. Current research into epidermal components is in abeyance but if psoriasis is to be considered an autoimmune disease then the putative autoantigen is most likely a component of the epidermis, probably an epitope of keratin. Investigations into this, particularly keratin cross-reactivity with streptococcal M protein, are important [14]. The inflammatory response whether cellular or cytokine is a critical focus of current research. The past decade has witnessed detailed investigation of the acquired immune responses in psoriasis: CD4-CD8 T [15] cells and the Th1-Th2 cytokine pattern [16]. The pendulum is starting to swing away from research into the acquired immune response toward investigation of the role of the innate immune response in psoriasis [17]. This is in line with research on other autoimmune inflammatory diseases, such as Crohns disease and multiple sclerosis. Severe combined immunodeficiency mouse xenotransplantation studies have identified natural killer [18] cells as important in promulgating the natural killer cell and T-cell activity and keratinocyte proliferation, [19], and tumor necrosis factor-a (TNF-a) [20] indicates the importance of this immune pathway in psoriasis. The role of this pathway seems increasingly important with the discovery of different natural killer cell receptors [21], abnormalities or deficiencies in which may promote the inflammatory response. The central role that TNF-a plays in this inflammatory response is underscored by the efficacy of TNF-a blocking biologics, such as infliximab [22] and etanercept [23], in psoriasis. On this basis an inappropriate innate immune response in the skin of patients with psoriasis seems to be an attractive research hypothesis. Perhaps the most underresearched area of psoriasis pathogenesis has been in the field of vascular biology. Studies 20 years ago showed that changes in the dermal capillary bed are among the earliest
in the evolution from uninvolved skin to plaque [24]. Research work on angiogenic factors derived from epidermal keratinocytes, specifically vascular endothelial growth factor (VEGF), have reawakened interest in the vascular component of psoriasis [25]. A single nucleotide polymorphism of the 405 CC genotype of the VEGF gene confers susceptibility to severe psoriasis of early onset [26] and a mouse transgenic for overexpression of VEGF has a psoriasiform phenotype [27]. The roles of VEGF isoforms in psoriasis and their reciprocal relationship with antiangiogenic factors (eg, thrombospondin-1) are a further area for research, as are receptor-targeted therapies (ie, anti-VEGF and VEGF-receptor).
Quality of life There is little doubt that one of the hindrances to obtaining significant research funding for psoriasis is the view (nondermatologic) that the disease is of low priority, particularly because it has no appreciable mortality. The specialty of dermatology has only recently, and belatedly, awoken to this misconception. Although dermatologists and patients are well aware of the psychosocial [28,29] and financial consequences of psoriasis, comparatively little work has specifically addressed these in an objective, structured manner. Studies have shown that psoriasis produces significant impairment in quality of life, indeed to a level lower than that produced by diabetes [30]. The psychosocial disability suffered by psoriasis patients is immense. Stress caused by living with psoriasis is the greatest stressor in patients lives [28], so much so that most patients practice avoidancecoping and automatic vigilance [31]. It is these elements of psoriasis morbidity that require further study, particularly the roles that stress and worry may have on compliance with, and efficacy of, treatment [32]. Major areas of research are whether self-help and cognitive behavioral therapy can significantly improve quality of life and enhance the efficacy of traditional pharmacologic approaches to treatment. Few dermatologists have received any form of training in how to recognize psychologic distress, particularly depression and anxiety in their patients. This is highly relevant for physicians who deal with chronic adult medical dermatoses, such as psoriasis, that have a significant impact on quality of life. Work is required to assess strategies to improve compliance and adherence with prescribed therapy coupled with in-depth assessment of the health economics of psoriasis care. What is the true burden of disease to individual, family member, taxpayer, health care
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system, and government? Such information is vital to facilitate informed debate on the economics of treating these patients, particularly with the seemingly expensive biologics. Such studies by necessity should be performed on a country-by-country basis.
from the standpoint of psychoneuroimmunology and hypothalamic-pituitary-adrenal axis responses to stress and the roles of neuropeptides in facilitating skin inflammation.
Evidence base Triggers Revelation of the psoriatic phenotype is the consequence of a confluence of genetic predisposition and environmental trigger. The triggers are as important, and probably as protean, as the putative genetic mutations; however, comparatively little funding or endeavor is aimed at elucidating the nature of these environmental triggers. A few triggers are recognized, such as streptococcal infection, lithium, Koebners phenomenon, and stress, but there is no clear understanding as to how and in whom such an exposure eventuates in psoriasis. Take Koebners phenomenon, for example. First described in 1878, the Koebner or isomorphic response is a characteristic feature of active psoriasis [33]. There is no understanding as to how trauma to the epidermis results in psoriasis; indeed, few researchers have specifically addressed this issue. The appearance of psoriasis at sites of skin trauma or pressure is probably indicative of epidermal signaling leading to up-regulation or induction of vascular adhesion molecules allowing primed T cells to egress into the dermis. Lithium [34], prescribed for manic depression, and HIV infection [35] also trigger or exacerbate psoriasis and are clinical clues to pathogenesis. Stress is another purported trigger. A study performed in Manchester [36] showed that 60% of psoriasis patients believed that stress was either a trigger or an exacerbator of their disease, an observation familiar to any dermatologist dealing with psoriasis patients. Somewhat surprisingly, despite strong circumstantial evidence, there has not been a detailed prospective study of whether exacerbations of psoriasis are linked to stressful life events. The ability of neuroendocrine responses to impact on physiology is an area of increasing scientific interest, and already under intense investigation in inflammatory bowel disease, rheumatoid arthritis, and multiple sclerosis [37]. Evidence exists that experimental psychosocial stress and the real life stress of final examinations for medical students can impact significantly on skin physiology, particularly on the barrier function of the stratum corneum [38,39]. The brain-skin axis or neuroscience of the skin, particularly as it pertains to psoriasis, is an exciting and relatively untrodden area of research both An important component of managing a patient with psoriasis is knowledge of how various treatments compare with each other in terms of efficacy, side effects, and patient acceptability. Current practice has not been subject to rigorous evaluation; the evidence-base movement is only beginning to stimulate reflection on how and why clinicians use the medicines they do for psoriasis management. A recent survey [40] by the European Dermato-Epidemiology Network of 226 randomized controlled trials for psoriasis produced some important information: only two randomized controlled trials had compared two or more different systemic therapies (although to some extent rectified by the recent comparative study of methotrexate with cyclosporin) [41]; median study duration was only on the order of 7 weeks (woefully inadequate in a chronic, life-long disease); less than 4% of studies considered maintenance of remission or relapse rates; less than 10% reported patient preferences; and amazingly 43 different scoring systems were used to assess outcome. There is a need to improve the quality of design and reporting of future psoriasis studies; many of these issues are addressed in the CONSORT statement [42] about good practice in designing, analyzing, and reporting clinical trials. In particular, placebo-controlled trials should be confined mainly to early development of new therapies; comparator studies with standard practice should be performed before acceptance of new treatments; and more longterm studies are required to assess remission, relapse, side-effects, and patient preference. In order that the results of studies are directly relevant and important to patients, patients themselves should be consulted during the design stage [43]. Consensus is desperately needed as to the best way to assess response of psoriasis to treatment. The most commonly used measure of psoriasis severity, the Psoriasis Area and Severity Index [44], a composition of surface area affected by psoriasis, scaling, erythema, and plaque thickness, is unwieldy, requires training in its use, and is poor at revealing or identifying changes in mild-moderate disease. Furthermore, current determinants of disease severity, such as Psoriasis Area and Severity Index, physicians global assessment, and body surface area, are
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physical and take no account of psychosocial disability (the two do not correlate) [45]. Agreement is urgently needed to reach consensus on relevant measures of psoriasis severity, and as a consequence, relevant outcomes for treatment. For instance, these should incorporate, in a holistic manner, the other determinants of psoriasis severity, namely psychosocial disability and resistance to therapy as exemplified by the Salford Psoriasis Index [46].
New therapies Research into new therapies needs to be collaboration between academia and industry [47]. The era of biologic therapies is exciting, not only because there are new selective therapies for psoriasis, but because the success or failure of such targeted approaches allows valuable insights into the biologic pathways critical to the psoriatic process. This is nothing new. The observation that cyclosporin is a highly effective therapy for severe psoriasis [48] finally paved the way to an acceptance that T cells are central to the psoriatic process and subsequently the development of a plethora of biologics for this disease. Two observations from biologics illustrate the yin and yang of this argument. Anti TNF-a approaches, such as infliximab [22] and etanercept [23], have highlighted the central proinflammatory role of TNF-a in psoriasis, whereas the nonefficacy of an anti E-selectin approach [49] demonstrates that E-selectin and cutaneous lymphocyte-associated antigen binding may be redundant in psoriasis. The latter observation of nonefficacy of blocking T-cell trafficking in psoriasis implies that biologics, probably those targeting T-cell activation and trafficking, may be used more effectively and appropriately in preventing relapse of psoriasis following clearance with some other entity (ie, cyclosporin). The goal is to place new therapies strategically and not to judge solely on ability to induce clearance or remission; a two-step approach is required. In all the excitement over systemic biologics that target T cells and cytokines one must not overlook other targets and other drugs. Angiogenesis is an attractive and highly pertinent target in psoriasis; the field is well developed in cancer and new therapies for cancer reliant on antiangiogenic approaches (eg, anti-VEGF) are a logical choice for trials in psoriasis. Nonbiologics, such as retinoids (eg, tazarotene [50]), and retinoid-like drugs, such as liarozole [51], an inhibitor of retinoic acid 4-hydroxylase without the long-term risks of acitretin, are certainly worth pur-
suing. Other drugs, such as oral pimecrolimus, which has cyclosporin-like efficacy seemingly without toxicity, are promising [52]. In the rush to use more systemics, the place of effective, cosmetically acceptable topicals should not be ignored. The inexorable rise of appearance- and procedurebased dermatology may produce some benefit for those still involved in adult medical dermatology. Development of new lasers and application of old lasers for psoriasis shows some promise in that the excimer 308-mm UVB laser is effective for small recalcitrant plaques [53], and pulse dye laser treatment of plaques can result in long-term remission [54]. This, coupled with photodynamic therapy, may be an opportunity for procedure-based treatment but not prevention of psoriasis particularly if stable.
Summary The research needs and goals for therapy of psoriasis should be consonant. The research should identify targets for treatment, may produce an animal model, and conceivably gene therapy. Therapies should embrace these observations but need to undergo trials in a way that is relevant to real life (ie, in comparison with current clinical practice); with longterm objectives; and with realistic outcome measures. Research goals should, in no small way, be determined by the patients themselves working in close collaboration with scientists, clinicians, and industry. It is only by this concerted approach that progress can be made. It should be borne in mind, however, that serendipity and not reductionism has perhaps been the greatest driver of change.
References
[1] Nevitt GJ, Hutchinson PE. Psoriasis in the community: prevalence, severity and patients beliefs and attitudes towards the disease. Br J Dermatol 1996;135:533 7. [2] Lomholt G, editor. Psoriasis: prevalence, spontaneous course and genetics. A census study on the prevalence of skin disease on the Faroe Islands. Copenhagen: GEC Gad; 1963. [3] Yip SY. The prevalence of psoriasis in the mongoloid race. J Am Acad Dermatol 1984;10:965 8. [4] Camp RDR. Psoriasis. In: Champion R, Burton J, Burns A, Breathnach S, editors. Textbook of dermatology. Oxford: Blackwell Science; 1998. p. 1589 1650. [5] Willan R. On cutaneous diseases. London: J. Johnson; 1808. [6] Nair RP, Stuart P, Henseler T, Jenisch S, Chia NV,
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C.E.M. Griffiths / Dermatol Clin 22 (2004) 493499 Westphal E, et al. Localization of psoriasis-susceptibility locus PSORS1 to a 60-kb interval telomeric to HLA-C. Am J Hum Genet 2000;66:1833 44. Enerback C, Martinsson T, Inerot A, Wahlstrom J, Enlund F, Yhr M, et al. Evidence that HLA-Cw6 determines early onset of psoriasis, obtained using sequence-specific primers (PCR-SSP). Acta Derm Venereol 1997;77:273 6. Henseler T, Christophers E. Psoriasis of early and late onset: characterization of two types of psoriasis vulgaris. J Am Acad Dermatol 1985;13:450 6. Telfer NR, Chalmers RJ, Whale K, Colman G. The role of streptococcal infection in the initiation of guttate psoriasis. Arch Dermatol 1992;128:39 42. Nickoloff BJ, Kunkel SL, Burdick M, Strieter RM. Severe combined immunodeficiency mouse and human psoriatic skin chimera: validation of a new animal model. Am J Pathol 1995;146:580 8. Yates VM, Watkinson G, Kelman A. Further evidence for an association between psoriasis, Crohns disease and ulcerative colitis. Br J Dermatol 1982;106: 323 30. Ogura Y, Bonen DK, Inohara N, Nicolae DL, Chen FF, Ramos R, et al. A frameshift mutation in NOD2 associated with susceptibility to Crohns disease. Nature 2001;411:603 6. Young C, Allen MH, Cuthbert A, Ameen M, Veal C, Leman J, et al. A Crohns disease-associated insertion polymorphism (3020insC) in the NOD2 gene is not associated with psoriasis vulgaris, palmo-plantar pustular psoriasis or guttate psoriasis. Exp Dermatol 2003; 12:506 9. Baker BS, Brown DW, Fischetti VA, Ovigne JM, Porter W, Powles A, et al. Skin T cell proliferative response to M protein and other cell wall and membrane proteins of group A streptococci in chronic plaque psoriasis. Clin Exp Immunol 2001;124:516 21. Baker BS, Swain AF, Fry L, Valdimarsson H. Epidermal T lymphocytes and HLA-DR expression in psoriasis. Br J Dermatol 1984;110:555 64. Schlaak JF, Buslau M, Jochum W, Hermann E, Girndt M, Gallati H, et al. T cells involved in psoriasis vulgaris belong to the Th1 subset. J Invest Dermatol 1994; 102:145 9. Nickoloff BJ, Bonish B, Huang BB, Porcellia SA. Characterization of a T cell line bearing natural killer receptors and capable of creating psoriasis in a SCID mouse model system. J Dermatol Sci 2000;24: 212 25. Gilhar A, Ullmann Y, Kerner H, Assy B, Shalaginov R, Serafimovich S, et al. Psoriasis is mediated by a cutaneous defect triggered by activated immunocytes: induction of psoriasis by cells with natural killer receptors. J Invest Dermatol 2002;119:384 91. Ruckert R, Asadullah K, Seifert M, Budagian VM, Arnold R, Trombotto C, et al. Inhibition of keratinocyte apoptosis by IL-15: a new parameter in the pathogenesis of psoriasis? Immunology 2000;165: 2240 50. [20] Ettehadi P, Greaves MW, Wallach D, Aderka D, Camp RD. Elevated tumour necrosis factor-alpha (TNFalpha) biological activity in psoriatic skin lesions. Clin Exp Immunol 1994;96:146 51. [21] Cameron AL, Kirby B, Fei W, Griffiths CEM. Natural killer and natural killer-T cells in psoriasis. Arch Dermatol 2002;294:363 9. [22] Chaudhari U, Romano P, Mulcahy LD, Dooley LT, Baker DG, Gottlieb AB. Efficacy and safety of infliximab monotherapy for plaque-type psoriasis: a randomised trial. Lancet 2001;9:1842 7. [23] Mease PJ, Goffe BS, Metz J, VanderSteop A, Finck B, Burge DJ. Etanercept in the treatment of psoriatic arthritis and psoriasis: a randomised trial. Lancet 2000; 356:385 90. [24] Braverman IM, Sibley J. Role of the microcirculation in the treatment and pathogenesis of psoriasis. J Invest Dermatol 1982;78:12 7. [25] Detmar M, Brown LF, Claffey KP, Yeo KT, Kocher O, Jackman RW. Overexpression of vascular permeability factor/vascular endothelial growth factor and its receptors in psoriasis. J Exp Med 1994;180:1141 6. [26] Young HS, Summers AM, Bhushan M, Brenchley PEC, Griffiths CEM. Single nucleotide polymorphisms of vascular endothelial growth factor (VEGF) in psoriasis of early onset. J Invest Dermatol, 2004; 122:209 215. [27] Xia YP, Li B, Hylton D, Detmar M, Yancopoulos GD, Rudge JS. Transgenic delivery of VEGF to mouse skin leads to an inflammatory condition resembling human psoriasis. Blood 2003;102:161 8. [28] Fortune DG, Main CJ, OSullivan TM, Griffiths CEM. Quality of life in psoriasis: the contribution of clinical variables and psoriasis-specific stress. Br J Dermatol 1997;137:755 60. [29] Zachariae R, Zachariae H, Blomqvist K, Davidsson S, Molin L, Mork C, et al. Quality of life in 6497 Nordic patients with psoriasis. Br J Dermatol 2002;146: 1006 16. [30] Finlay AY, Coles EC. The effect of severe psoriasis on the quality of life of 369 patients. Br J Dermatol 1995; 132:236 44. [31] Fortune DG, Richards HL, Corrin A, Taylor RJ, Griffiths CEM, Main CJ. Attentional bias for psoriasisspecific and psychosocial threat in patients with psoriasis. J Behav Med 2003;26:211 24. [32] Fortune DG, Richards HL, Kirby B, McElhone K, Markham T, Roger S, et al. Psychological distress impairs clearance of psoriasis in patients treated with photochemotherapy (PUVA). Arch Dermatol 2003; 139:752 6. [33] Eyre RW, Krueger GG. The Koebner response in psoriasis. In: Roenigk HH, Maibach HI, editors. Psoriasis. New York: Marcel Dekker; 1984. p. 105 16. [34] Abel EA, DiCicco LM, Orenberg EK, Fraki JE, Farber EM. Drugs in exacerbation of psoriasis. J Am Acad Dermatol 1986;15:1007 22. [35] Johnson TM, Duvic M, Rapini RP, Rios A. AIDS exacerbates psoriasis. N Engl J Med 1985;313:1415.
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Dermatol Clin 22 (2004) 501 508
Sclerotherapy basics
Margaret E. Parsons, MDa,b,*
a
Dermatology Consultants of Sacramento, 5340 Elvas Avenue, Suite 600, Sacramento, CA 95819, USA b Department of Dermatology, University of California at Davis, Davis, CA, USA
Every day dermatologists see patients with varicosities of the legs. Treatment of these vessels can be rewarding to both the physician and the patient. Sclerotherapy can improve the cosmetic appearance of aberrant blood vessels and greatly benefit symptomatic veins by decreasing pain, burning, and cramps that many patients describe. Resolution of larger varicosities can improve the risk of further venous disease sequelae. Sclerotherapy continues to be the gold standard in the treatment of lower extremity small vessel disease. An understanding of the indications, mechanisms, and treatment management is essential. This article reviews the basics of sclerotherapeutic treatment of the smaller vessels. Varicose and telangiectatic veins affect both men and women. In the United States, 8.65% of men and 12.9% of women have varicose veins. Telangiectatic veins are reported at a higher rate of 28.9% of men and 40.9% of women in the United States [1]. These vessels can be visually unattractive and may also be symptomatic. Venous disease contributes to the changes of stasis dermatitis, pigmentary alteration, and edema of the lower legs. Even mild venous disease can cause restless legs syndrome and pain [2]. Sometimes a patient will complain of a single cluster of veins causing pain [3]. Sclerotherapy can be very effective in decreasing the pain of varicose and telangiectatic leg veins [4,5]. Many factors can affect an individuals predisposition to develop varicose veins. Genetics is believed to play a major role in the development of leg veins, and familial incidence has been reported in 15% to
40% of cases [4]. Leg veins occur less often in the nonwhite population. Pregnancy also affects the incidence of leg veins, and varicosities increase with multiple pregnancies. The distensibility of the vessel wall and increased blood volume during pregnancy can also increase the formation of new blood vessels and increase the diameter of existing blood vessels. Similarly, occupations that require significant walking, standing, or long periods of sitting can contribute to blood vessel pooling in the lower extremities and therefore an increase in varicosities. Nurses, grocery clerks, and teachers, therefore, are among some of the patients often presenting with vessels for treatment. Leg-crossing also can cause development of vessels in the area of pressure of one leg on another. Instructing patients about this causal factor can help decrease further vessels in the area.
Anatomy It is important to have an understanding of the vasculature and anatomy of the lower extremities when doing sclerotherapy. Although this article focuses on the smaller vessels, it is important to understand general circulatory patterns. For example, it has been demonstrated that telangiectasias can communicate with the deep venous system [6]. The volume of sclerosant at a treatment session should therefore be limited to decrease the chance of the sclerosing solution entering the deeper system where it may potentially cause deep vein thrombosis [6]. When treating larger vessels, a thorough knowledge of anatomy is essential. The deeper venous system includes the femoral and popliteal veins, which are affected by muscular compression. The channels of connection between the deep and super-
* Dermatology Consultants of Sacramento, 5340 Elvas Avenue, Suite 600, Sacramento, CA 95819. E-mail address: mepmd@ix.netcom.com
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ficial systems are called the perforating veins. They provide the junction between the saphenous, femoral, and popliteal systems. These perforating veins allow for the return flow to the subcutaneous systems [7]. The superficial venous system includes the great saphenous vein, the accessory saphenous vein, and the lesser saphenous vein. The reticular and connecting branch veins provide for further connection
Box 1. Duffy system of classification Type 1telangiectasia spider veins 0.1 to 1.0 mm in diameter Red to cyanotic in color Type 1Atelangiectatic matting Less than 0.2 mm in diameter Red color Type 1Bcommunicating telangiectasia Type 1 veins in direct communication with varicose veins of the saphenous system Type 2mixed telangiectatic/varicose veins No direct communication with the saphenous system Type 3nonsaphenous varicose veins (reticular) 2 to 8 mm in size Blue to blue-green Type 4saphenous varicose viens Usually over 8 mm in diameter Blue to blue-green From Goldman M. Sclerotherapy: treatment of varicose and telangiectatic. Leg veins. 2nd edition. St. Louis, MO: Mosby; 1995. Modified from Duffy D. Small vessel sclerotherapy: an overview. In: Callen, et al, editors. Advances in dermatology, vol. 3. Chicago: Yearbook; 1988; with permission.
throughout the system. When treating larger vessels, it is important to identify specific flow patterns occurring in the patient by Doppler or Duplex studies. It is helpful to understand the different types of vessels that can be seen with visual examination. This understanding facilitates knowledge of and planning of treatment with sclerotherapy, and documenting this treatment in the chart. A simple description of the vessels with color and size can be sufficient. The Duffy classification is also useful for describing vessels (Box 1). The diameter of the vessel also helps determine which solution can be used for injection.
Etiology Various factors contribute to the pathophysiology of the development of varicosities. Aging of vessels plays a major role in the cause of these conditions, where many of the same factors as in the aging of the skin are seen. The intima of a blood vessel becomes thickened, the elastic lamina atrophies, and the adventitia becomes more fibrous. Because varicosities usually have endothelial damage as part of their development, they are therefore susceptible to sclerosing. In addition, the varicosities have a fibrosed adventitia and an atrophic elastic layer accessible to the sclerosant. Chronic hypertension can lead to valvular insufficiency and dilatation of the vessels. Hormonal effects of increased estrogen during pregnancy also contribute to distensibility of the blood vessel wall. Patient history should also include the patients use of hormonal replacement therapy or oral contraceptive agents, but these are usually a low and stable dose with minimal, if any, notable effects on distensibility. Vin et al [8] showed that the effects of estroprogestogen treatment on superficial venous system is dose-dependent. Tamoxifen can also cause an increase in hypercoaguability and should be noted during the consultation appointment and reviewed with the patient. The physical factors of leg-crossing and tight clothing can play a role by causing focused pressure in areas, and obesity or pelvic obstruction from a tumor or lymph node can also cause stress on the lower extremity vasculature. Valvular incompetence can be caused by a genetic dysfunction or even a decreased number of valves. Thrombophlebitis is also related to valvular dysfunction.
Sclerosing agents The concept and purpose of a sclerosing agent in the treatment of varicosities is straightforward. Scle-
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rosants are injected into the vessel and affect the vessel wall by initiating a vein wall injury. If the injury causes sufficient damage to the vessel wall, the vessel will be resorbed and fibrosed. The agents cause some damage to the endothelial cell wall and also to some of the deeper layers of the vessel wall. This deeper damage is important to the success of sclerotherapy and in decreasing the incidence of recanalization [9]. There are three types of sclerosants: detergents, osmotic agents, and chemical irritants (Box 2). Detergents interact with the surface lipids of cellular membranes and cause disruption of the endothelial cells. Detergents are chemicals with polar (hydrophilic) and nonpolar (hydrophobic) groups. The nonpolar group of the detergent molecule aligns itself with the cell membrane of the endothelial cell because the internal space of the plasma membrane is also nonpolar. This placement reduces surface tension of the cell membrane, which leads to the disruption of the endothelial layer. Similarly, detergents can disrupt the deeper layers of the vessel wall as well. Osmotic agents cause cellular dehydration by disrupting the water balance of a cell and thereby causing damage to the cells of the endothelial level. Osmotic agents also disrupt the noncellular mural layers of the vessel, decreasing the chance of recanalization [9]. There is a relation between the concentration of the sclerosant and the depth of the vessel wall damage. Chemical irritants, the last class of sclerosants, have their effect through various mechanisms to damage the vessel wall. An ideal sclerosant would clear all veins that were injected, have no side effects, and be painless to the
Box 2. Sclerosing agent classification Detergents Sodium tetradecyl sulfate (Sotradecol) Polidocanol (Aethoxysclerol) Sodium morruhate (Scleromate) Ethanolamine oleate (Ethamolin) Osmotic agents Hypertonic saline Saline/dextrose (Sclerodex) Chemical irritants Chromated glycerin (Sclermo) Polyiodinated iodine
patient; however, a perfectly ideal sclerosant does not exist. Therefore, it is important to understand the good and bad points of each sclerosing agent. There are three sclerosing agents most commonly used in the treatment of small vessels: hypertonic saline, sodium tetradecyl sulfate, and polidocanol. Other agents are used for some of the larger vessels, some agents that are no longer used, and there are other agents that are used outside the United States. Hypertonic saline comes as a 23.4% solution of sodium chloride. It is approved by the US Food and Drug Administration (FDA) for use as an abortificant, so its use in sclerotherapy is considered off-label. It provides for a fast-fade of vessels and has a very low risk of allergenicity. It does sting and cause discomfort to the patient, however. As a salt solution, it can cause fluid overload if significant volumes are used or if many very distal vessels are treated. Hypertonic saline is caustic enough to cause skin sloughing at the site of injection in some cases. If it extravasates, ulceration can occur. If used appropriately, however, it works very well in the treatment of vessels. Appropriate dilution minimizes the risk of ulceration and telangiectatic matting. For treating smaller vessels, dilution of the 23.4% sodium chloride solution with normal saline to an 11.7% solution is important. In very fine vessels or in vessels in the ankle area, a solution of approximately 6% sodium chloride may be appropriate. The 23.4% solution can be used directly in reticular and larger vessels [10]. Over the years, dilutions with lidocaine and heparin have been used. A solution of two parts 23.4% saline and one part 1% lidocaine with epinephrine (resulting in a 15.6% saline/0.33% lidocaine) solution has been used. This solution introduces a possible allergen and another agent that causes stinging, however. Normal saline can be used for dilution. Heparin also has been used because it is believed to decrease the risk of clotting. Its inclusion, however, again introduces another agent with its own particular complexities to the mixture, including the risk of allergenicity [11]. Sodium tetradecyl (Sotradecol) has been widely used in the United States. In recent years no major manufacturer has been producing it. It is FDA approved if a manufacturer meets production guidelines. Some smaller companies are currently preparing the solution. Negative effects include possible ulceration, pigmentation, and necrosis, and this agent can be painful in patients with thrombophlebitis. It also has the potential to induce anaphylaxis. The following appropriate dilutions for vessel size will minimize the potential for side effects: telangiectatic veins
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less than 2 mm in diameter (0.1% 0.3% concentration); varicose veins, 2 to 4 mm (0.5% 1% concentration); and larger ( > 4 mm) varicose veins (1.5% 3% concentration.) Polidocanol (also known as Aethoxysclerol) is currently not FDA approved for use in the United States, although it has been submitted for such approval for some years. There is extensive experience with polidocanol in Australia [12,13], and it is used in Europe as well. Because it is pain free (ie, without the stinging caused by saline or Sotradecol), it is well liked by patients. It also has decreased risk of skin sloughing and pigmentation. The agents negative features are the slower fading of treated vessels and risk of allergic reaction. Because of this latter risk, a test dose of 0.5% solution should be injected into a vessel before a treatment session. The solutions should be diluted appropriately as follows: 0.25% to 0.75% for telangiectasias, 1% for vessels of 1 to 2 mm, and 2% solution for vessels of 2 to 4 mm. There are total daily dose limitations with polidocanol based on body weight (2 mg/kg/d) and detailed in the manufacturers guidelines [11,14]. Sadick [15] has shown comparable results between hypertonic saline and polidocanol. A solution that is composed of saline (10%), dextrose (5%), propylene glycol, and phenethyl alcohol is manufactured under the brand name Sclerodex. This substance is not FDA approved, although it is approved in Canada. It has limited use because it can only be used in very small vessels, those smaller than 1 mm in diameter. It has the risk of pigmentation, allergenicity, and necrosis. Because there is a decreased percentage of saline, there may be decreased cramping during treatment. The manufacturer recommends a maximum volume of 1 cc at any injection site, with a total per session of no more than 10 cc [16]. Sodium morrhuate (Scleromate) is an FDA-approved substance that is currently infrequently used and is not indicated for use in telangiectasias. It must be diluted to appropriate concentration. Its many potential side effects limit its use (eg, necrosis, hyperpigmentation, pain, risk of pulmonary embolus, allergenicity, and risk of anaphylaxis) [16]. Ethanolamine oleate (Ethamolin) is of historical significance in sclerotherapy as one of the first FDAapproved sclerosing agents. It is not used much now, however, because it is a viscous solution with a risk of a hemolytic reaction [11]. Chromated glycerin (Sclermo) has been used in Europe but is not approved for use by the FDA. It can be used for telangiectasias and has a low potential of hyperpigmentation. Only a total of a 0.1-cc prediluted solution can be used in a single session, and it can be
diluted with lidocaine. Chromated glycerin can be painful to patients upon injection [11]. Polyiodinated iodine is the most powerful of all sclerosants and is used in treatment of the saphenofemoral junction, a treatment beyond the scope of this article. It is not FDA approved and can cause necrosis. Therefore, it is not appropriate for use in small vessel sclerotherapy.
Patient history and physical examination As with all medical and surgical treatments, it is important to obtain a thorough patient history [17]. There are some contraindications for sclerotherapy. Pregnancy, a history of hypercoaguability, and allergy to any agents are very specific contraindications. A patient with a history of hypercoaguability may be revealed by history of thrombophlebitis, pulmonary embolus, deep vein thrombosis, or having a positive lupus anticoagulant status. Allergy to aspirin, heparin, and anesthetics can also be important, depending on the choice of sclerosant. Those patients who have a history of easy bruising or bleeding, or those patients who are on aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), or vitamin E therapy, have increased chances of bruising and bleeding with sclerotherapy. Smokers and those on hormone replacement therapy or oral contraceptive pills may have an increased risk of clotting, although these factors are not specific contraindications. Hormonal therapy has been shown to have an association with increased telangiectatic matting [18]. Systemic disease status must be reviewed and include discussion of the following conditions: hypertension, congestive heart failure, diabetes, asthma, and infectious disease. Some of these conditions can be relative contraindications because of poor healing and risk of infection. A good candidate for sclerotherapy is an active patient. Activity status is also important in posttreatment counseling because some high-impact activities must be avoided immediately following sclerotherapy. The status and results of other leg vein treatments, including sclerotherapy, stripping, other surgical treatments, or laser treatments should be reviewed with the patient. The dermatologist should also know the patients family history in relation to predisposition to varicosity development. It is important to examine the patient from hip to toe, rather than just a patients calf or a similarly focused area. Examination of the extent of the disease with which the patient is presenting is important so that the patient is treated appropriately and so that any significant underlying venous disease is not over-
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looked. Underlying venous or arterial disease can result in risks such as emboli or ulceration and lead to poor results with sclerotherapy treatment. During examination, it is important to assess if there are just a few scattered vessels or vessels throughout both legs. Similarly, the physician should determine if there are just spider telangiectasias and a few reticular veins visible or if there are large varicosities visible. The physician should examine the patient at the inner upper thigh for any saphenous visibility. Examination of the patients skin for evidence of venous disease, such as pigmentation, stasis changes, and actinic damage, may indicate the possibility of poor healing. As appropriate, an examination for hernias and fascial defects should be performed. Palpation of arterial pulses and veins can also assist in examination. Valsalva maneuvers can assist in checking for poor venous flow in the groin area. Other physical maneuvers include the Perthes test, Brodie-Trendelenburg test, and the percussion/Schwartz test. These modalities are outlined in some of the textbooks on sclerotherapy and in an article by Fronek [19]. Lab work to evaluate hypercoaguability or bleeding risks may be appropriate if something in the patient history suggests further evaluation is warranted. If the vessels are larger than 4 mm in diameter or if there are significant signs of venous damage, further evaluation by Doppler (unidirectional or bidirectional), Duplex Ultrasound, or photoplethysmography is indicated. These tests evaluate the extent of venous disease and may indicate that larger vessels need to be addressed. Excellent discussions of these modalities are available in textbooks on sclerotherapy, and training is available at the meetings of the North American Society of Phlebology.
irritating, is preferred) are used after injecting for immediate compression and to cover the bleeding point of injection. Gloves are to be used as a universal precaution. The current author was trained to use a mid-to high-potency topical corticosteroid cream after injection and before applying the cotton ball and tape. Although there has not been a study to evaluate the use of topical corticosteroid cream, patients seem to find it soothing and it seems to decrease the slight urticarial focal reaction some get at the site of injection. Also, it may decrease skin sloughing at the site of injection by decreasing local inflammatory reaction.
Injection techniques When injecting the patient with the sclerosant, it is important to have good lighting and, if needed, magnification. Injecting the patient with the needle bevel angled up and with a slight bend at the hub seems to be the most comfortable for the physician. Also, with the bevel up, the physician can best judge where the solution is going. It is important to inject slowly. Rapid injection can cause extravasation and increase the risk of telangiectatic matting. If the needle moves, there is risk of scleroscent getting out of the vessel, and extravasation is more likely. Therefore it is important to inject slowly, stop when there is resistance, and not rush while doing the procedure. The amount of sclerosant per site ranges from 0.1 to 0.5 cc. It is recommended to proceed from proximal to distal sites in larger vessels [20], but the reality is that, for small vessel sclerotherapy, the dermatologist usually addresses the vessels that bother the patient the most. The shin, distal lower leg near the ankle, and popliteal areas cause more discomfort and have a somewhat higher risk of ulceration. Therefore these locations are not a good place to start a sclerotherapy treatment plan. If a patient has significant reticular disease, it is usually recommended that the reticular vessels be treated first. Dr. David Green has shown some excellent results in which patients just wanted to treat the spider telangiectasias and not reticular veins (American Academy of Dermatology session, 1999 annual meeting). Subsequently, the current author has found that to be true for her patients. As with all treatments, documentation is important. Some physicians find that stamps or predrawn sheets are helpful in documenting leg vein treatment. If a patient describes burning pain, it is likely that extravasation is occurring. There is a small group of patients, however, who have significant pain with
Materials A basic sclerotherapeutic set-up can be simple. The solutions a kit should include are as follows: the sclerosing agent, normal saline, dilutant in case of extravasation, and possibly nitroglycerin paste. The choice between 3-cc syringes and 1-cc syringes is a personal preference, but locking syringes are recommended. The physician should try both sizes and decide which is preferable. All syringes should be well labeled as to what solution they contain and its percentage strength. Disposable 30-gauge needles are used for injection, with a larger-gauge needle used for drawing up solutions. Alcohol wipes are used for cleansing the area before treatment. It is often easier to visualize veins in the area after wiping with alcohol. Cotton balls and tape (paper tape, which is less
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accurate sclerotherapy. If extravasation occurs, the sclerosant should be diluted with normal saline or 1% lidocaine to decrease the risk of ulceration. Hyaluronidase has been shown to decrease the risk of extravasation-related ulceration. A dose of 75 units of hyaluronidase injected into the extravasated area can be effective in decreasing ulceration [21,22]. Therefore, it is important to have a syringe filled and ready with your choice of a countertreatment agent. If a patient has cramping while the physician is in the process of injecting, the physician should knead or massage the area or go on to the other leg for a while. As discussed, the ankle area has a higher risk of ulceration and should never be first in a patients treatment plan. It is important to use diluted solution in this region and only do a small amount of treatment in the ankle area in a session. Reticular veins are rewarding to treat. The treatment of reticular veins usually causes less stinging to the patient. For these vessels, a smaller amount of sclerosant in each syringe is preferred (eg, 0.5 cc). This is because when treating reticular vessels, the physician should draw back on the needle to get a flash of blood to ensure that he or she is in the vessel. Once there is flashback, inject slowly. Resistance is felt when the solution is reaching a valve or tortuosity and is an indication to stop injecting. Compression with cotton and tape is done immediately after removing the needle.
compression hose use is appropriate. For reticular vein treatment, 2 to 3 weeks is preferred. Patients are advised to be ambulatory, because inactivity can increase the risk of clotting. They are also advised to avoid high-impact activity, such as jogging, aerobics, and kick-boxing. Patients are also advised that wearing some level of daily support hose should improve their lower extremity vessel status. Some patients find that their legs are less tired at the end of the day and prefer to wear the hose on a regular basis, which is especially important in occupations where the patient stands all day [26].
Side effects/complications Overall, sclerotherapy is a safe and well-tolerated procedure. There are some areas to be aware of, however, and it is important to caution patients about these areas in your consultation appointment and informed consent. Bruising at the site of injection can occur and is more likely if the patient takes aspirin or NSAIDs. This effect clears with time. Localized urticaria can occur at the site of injection and seems to be relieved by the use of topical corticosteroids applied before the application of dressings and compression hose. The urticaria is transient and can occur with most agents. The theory is that it is caused by the irritation of the endothelial wall of the injected vessel [11]. Many patients complain of some pain at the time of procedure. Hyperpigmentation can occur in up to 10% to 30% of vessels but is more likely to occur in vessels larger than 2 mm [25]. Compression therapy and the avoidance of tanning decrease this likelihood. Hyperpigmentation clears with time or can be managed with topical tretinoin or hydroquinones, or the physicians hyperpigmentation treatment of choice. Crusting at the site of injection has been reported up to 10% of the time and is caused by out-leak of sclerosant. Telangiectatic matting can also occur, especially if the sclerosant is injected too quickly and possibly if the concentration percentage is too strong. Matting has been shown to occur in up to 15% to 20% of patients [25,27]. Management with treatment at a future visit is usually appropriate. Laser or light therapy may play a role in treatment of vessels that are too small to inject. Edema can also occur with sclerotherapy. The lower part of the leg, particularly the ankle area, is prone to this side effect. Compression therapy and caution regarding the volume of sclerosant used in a session can minimize edema.
Compression Compression improves the results of sclerotherapy and decreases the risk of recanalization, hyperpigmentation, phlebitic reactions, and telangiectatic matting [23,24]. Compression is normally accomplished with hose stockings. These stockings are rated in terms of their compressive ability, with the common ranges of 12 to 40 mm Hg. Support hose have a more even and graduated compression than bandaging or wrapping. Patients who only undergo spider vessel treatment can wear lighter compression hose, in the range of 12 to 20 mm Hg. Patients with reticular vein treatments should wear hose in the 20 to 30 mm Hg range. Hose in the 30 to 40 mm Hg range may be too strongly compressive if the patient is lying down much of the day. Overcompression could be a risk factor for ulceration [25]. Patients are instructed to put their hose on just after therapy and ideally before standing at all. They wear the hose overnight the first night after treatment and then during the day as well. For spider and small vein treatment, approximately 5 to 7 days of wearing
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Superficial thrombophlebitis can occur with vessels of 3 to 5 mm and can be managed with compression, NSAIDs, heat, and sometimes intramuscular corticosteroids. Nodular fibrosis can occur with the larger vessels and needs to be minimized with compression and managed with reassurance and time. Necrosis can be caused by out-leaks of the sclerosant, and needle placement issues warrant patience and caution when sclerosing vessels. Sometimes dilution with lidocaine, normal saline, or hyaluronidase can minimize necrosis. Ulcers can occur with injection of sclerosants. Extravasation or injection into an arteriole can also lead to ulceration. If extravasation is suspected, dilution with normal saline, lidocaine, or hyaluronidase can help as previously discussed. Also, if the physician sees a white blanching suggestive of arteriole infiltration, application of topical nitroglycerin paste at the site may decrease the potential for ulceration by increasing the microcirculation, which can flush the sclerosant from the arteriole [28]. If an ulcer occurs, patience, frequent visits, and good ulcer care management are important.
A follow-up examination with the patient after sclerotherapy usually occurs at approximately 1 month, unless they have any problems or questions and need to be seen sooner. Patients are usually advised that some vessels may take up to a month to fully clear after therapy, and further treatment, if needed, can be planned at that time.
New developments New areas of discussion in sclerotherapy include the use of foam sclerosant. Foam is formed by mixing air with the sclerosant [29,30]. Sclerotherapy is also being used on vessels of the face, hand, and chest [31]. These areas are more complex and should be reviewed with someone experienced in treating these areas. Laser therapy continues to evolve with new modalities. Currently, however, laser and light therapies should be considered in patients who do not tolerate sclerotherapy because of a fear of needles or failure of previous therapy, or in those who are prone to telangiectatic matting [32].
Summary Patient management Before performing sclerotherapy on a patient, it is important to have a thorough consultation appointment. During this appointment, details of the patients history are obtained. A standardized form for patients for sclerotherapy can simplify the history-taking. A complete examination as previously discussed should be performed. Risks, benefits, and side effects should be reviewed with the patient as appropriate for an informed consent. The patients treatment plan can be reviewed with the patient, helping to ensure realistic outcomes. It is important to advise patients that vessels may take up to a month to fade after treatment. The number of sessions will vary with the extent of the disease, amount of therapy done in each session, and the rate of success of treatment. Additional sessions are usually not scheduled until 4 to 6 weeks after therapy. Appropriate compression hose should be discussed, because the patient will need these with them at the time of treatment. Patients are advised that they may need to modify exercise programs to avoid high-impact activities from 1 to 3 weeks after therapy (1 wk for telangiectasias and up to 3 wks for reticular veins). Patients are also advised at consultation to avoid shaving or moisturizing the 24 hours before (or day of) procedure. Sclerotherapy is a good procedure to include in dermatology practice. As with all procedures, the dermatologist should proctor with a colleague and learn further details about the procedure before beginning independent practice. Sclerotherapy of small vessels requires minimal equipment and has a high satisfaction for both the patient and physician.
References
[1] Engel A, Johnson M, Haynes S. Health effects of sunlight exposure in the United States: results from the First National Health and Nutrition Examination Survey 1971 1974. Arch Dermatol 1988;124:72. [2] Kanter A. The effect of sclerotherapy on restless legs syndrome. Dermatol Surg 1992;21:328 32. [3] Isaacs M. Symptomatology of vein disease. Dermatol Surg 1995;21:321 3. [4] Sadick N. Predisoposing factors of varicose and telangiectatic leg veins. J Dermatol Surg Oncol 1992;18: 883 6. [5] Weiss R, Weiss M. Resolution of pain associated with varicose and telangiectatic leg veins after compression sclerotherapy. J Dermatol Surg Oncol 1990;16: 333 6. [6] Bohler-Sommeregger K, Karnel F, Schuller-Petrovic S, Santler R. Do telangiectases commmunicate with the
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M.E. Parsons / Dermatol Clin 22 (2004) 501508 deep venous system? J Dermatol Surg Oncol 1992;18: 403 6. Green D. Sclerotherapy for the permanent eradication of varicose veins: theroretical and practical considerations. J Am Acad Dermatol 1998;38:461 75. Vin F, Allaert F, Levardon M. Influence of estrogens and progesterone on the venous system of the lower limbs in women. J Dermatol Surg Oncol 1992;18: 888 92. Green D. Mechanism of action of sclerotherapy. Semin Dermatol 1993;12(2):88 97. Sadick N. Sclerotherapy of varicose and telangiectatic leg veins: minimal sclerosant concentration of hypertonic saline and its relationship to vessel diameter. J Dermatol Surg Oncol 1991;65 70. Goldman M. Sclerotherapy: treatment of varicose and telangiectatic leg veins. St. Louis, MO: Mosby; 1995. Conrad P, Malouf G, Stacey M. The Australian Polidocanol (Aethosysklerol) Study: results at 2 years. Dermatol Surg 1995;21:334 6. McCoy S, Evans A, Spurrier N. Sclerotherapy for leg telangiectasiaa blinded comparative trial of polidocanol and hypertonic saline. Dermatol Surg 1999;25: 381 6. Goldman M. Treatment of varicose and telangiectatic leg veins: double blind prospective comparative trial between Aethoxyskerol and Sotradecol. Dermatol Surg 2002;28:52 5. Sadick N. Hyperosmolar versus detergent sclerosing agents in sclerotherapy: effect on distal vessel obliteration. J Dermatol Surg Oncol 1994;20:313 6. Goldman M. A comparison of sclerosing agents: clinical and histological effects of intravascular sodium morrhuate, ethanolamine oleate, hypertonic saline (11.7%) and sclerodex in the dorsal rabbit ear vein. J Derm Surg Oncol 1991;17:354 62. Drake L, Dinehart S, Goltz R, Graham G, Kordinsky M, Lewis C, et al. Guidelines of care of sclerotherapy treatment of varicose and telangiectatic leg veins. J Am Acad Dermatol 1996;34:523 8. Davis L, Duffy D. Determination of incidence and risk factors for postsclerotherapy telangiectatic matting of the lower extremity: a retrospective analysis. J Dermatol Surg Oncol 1990;16:327 30. Fronek H. Noninvasive examination of the venous system in the leg. presclerotherapy evaluation. J Dermatol Surg Oncol 1989;15:170 3. DeGroot W. Practical phleboloby: sclerotherapy of large veins. J Dermatol Surg Oncol 1991;17:589 95. Zimmet S. The prevention of cutaneous necrosis following extravasaton of hypertonic saline and sodium tetadecyl sulfate. J Dermatol Surg Oncol 1993;19:641 6. Zimmet S. Hyaluronidase in the prevention of sclerotherapy-induced extravasation necrosis: a doseresponse study. Dermatol Surg 1996;22:73 6. Goldman M, Beaudoing D, Marley W, Lopez L, Butie A. Compression in the treatment of leg telangiectasia: a preliminary report. J Dermatol Surg Oncol 1990;16:322 5. Weiss R, Sadick N, Goldman M, Weiss M. Postsclerotherapy compression: controlled comparative study of duration of compression and its effects on clinical outcome. Dermatol Surg 1995;25:105 8. Goldman M, Sadick N, Weiss R. Cutaneous necrosis, telangiectatic matting, and hyperpigmentation following sclerotherapy: etiology, prevention, and treatment. Dermatol Surg 1995;21:19 29. Ramelet A-A. Compression therapy. Dermatol Surg 2002;28:6 10. Weiss R, Weiss M. Incidence of side effects in the treatment of telangiectasias by compression sclerotherapy: hypertonic saline vs. policocanol. J Dermatol Surg Oncol 1990;16:800 4. Bihari I, Magyar E. Reasons for ulceration after injection treatment of telangiectasia. Dermatol Surg 2001; 27:133 6. Frullini A, Cavezzi A. Sclerosing foam in the treatment of varicose veins and telangiectases: history and analysis of safety and complications. Dermatol Surg 2002; 28:11 5. Tessari L, Cavezzi A, Frullini A. Preliminary experience with a new sclerosing foam in the treatment of varicose veins. Dermatol Surg 2001;27:58 60. Bowes L, Goldman M. Sclerotherapy of tericular and telangiectatic veins of the face, hands, and chest. Dermatol Surg 2002;28:46 51. Dover J, Sadick N, Goleman M. The role of lasers and light sources n the treatment of leg veins. Dermatol Surg 1999;25:328 36.
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Alan Menter, MD Jennifer Cather, MD Guest Editors

A. Menter, J. Cather / Dermatol Clin 22 (2004) xiiixiv

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An update on the genetics of psoriasis

* Corresponding author. E-mail address: fc29@le.ac.uk (F. Capon).

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to disentangle the contribution of individual psoriasis-susceptibility genes.

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Current concepts in the immunopathogenesis of psoriasis

* Corresponding author. E-mail address: jgk@rockefeller.edu (J.G. Krueger).

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M.A. Lowes et al / Dermatol Clin 22 (2004) 349369

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D.S. Aaronson, M. Lebwohl / Dermatol Clin 22 (2004) 379388

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Phototherapy arsenal in the treatment of psoriasis