MEDICAL PROGRESS

Review Article

Medical Progress I NFLAMMATORY B OWEL D ISEASE

DANIEL K. PODOLSKY, M.D.

N the decades since the major forms of idiopathic inflammatory bowel disease were defined on the basis of clinical manifestations, investigators have been challenged to identify the fundamental pathophysiologic processes underlying these enigmatic disorders, and clinicians have struggled to provide effective therapy for the often dismaying clinical manifestations. Clinical experience has led to the generally accepted notion that Crohns disease and ulcerative colitis are distinct, if not discrete, entities. However, whether these are fundamentally different diseases or part of a mechanistic continuum remains an unanswered question, with both conceptual and practical management implications.
ETIOLOGY AND PATHOPHYSIOLOGY

Inflammatory bowel disease is thought to result from inappropriate and ongoing activation of the mucosal immune system driven by the presence of normal luminal flora. This aberrant response is most likely facilitated by defects in both the barrier function of the intestinal epithelium and the mucosal immune system.
Genetic Factors

Several clinical observations suggest that genetic factors contribute to susceptibility to inflammatory bowel disease (Table 1). These include wide variations in the incidence and prevalence of Crohns disease and ulcerative colitis among different populations, cosegregation of inflammatory bowel disease in rare kindreds with a variety of uncommon genetic disorders, and more directly, familial aggregation of inflammatory bowel disease. Multiple studies have suggested that first-degree relatives of an affected patient have a risk of inflammatory bowel disease that is 4 to 20 times as high as that among the background popuFrom the Gastrointestinal Unit and the Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital and Harvard Medical School, Boston.

lation; the absolute risk of inflammatory bowel disease is approximately 7 percent among first-degree family members.1,2 A substantially higher rate of disease concordance has been observed in monozygotic twins than in dizygotic twins, especially in those with Crohns disease.1 Collectively, these findings lend compelling support to the inference that susceptibility is inherited and that the genetic contribution to the development of disease is more important in Crohns disease than in ulcerative colitis. However, the absence of simple mendelian inheritance suggests that multiple gene products contribute to a persons risk of inflammatory bowel disease. Over the past 15 years, a wide variety of candidate genes have been studied. Most associations identified between specific candidate genes, including majorhistocompatibility-complex loci, and inflammatory bowel disease have not been reproducible, have not shed new light on pathogenesis, or have not facilitated diagnosis.3-5 However, substantial progress has now been made with use of the less biased approach of genome-wide screening with microsatellite DNA markers. Screening of DNA from members of kindreds with multiple affected members identified an area of apparent linkage on chromosome 16 among kindreds with Crohns disease but not those with ulcerative colitis.6 Although the relative risk associated with this putative locus, designated IBD1, was small, the association was replicated in all but one independent study. These studies also provided evidence that inflammatory bowel disease is linked to several other genomic regions.7-10 Most of these sites are equally linked to both major forms of inflammatory bowel disease, suggesting that Crohns disease and ulcerative colitis share many common genetic and, therefore, mechanistic features. Detailed mapping of chromosome 16 has recently resulted in the identification of a gene responsible, at least in part, for this linkage.11,12 This gene encodes a cytoplasmic protein designated NOD2 (also referred to as CARD 15 [caspase activation and recruitment domain]), which is expressed in macrophages and may serve as a so-called pattern-recognition receptor for bacterial lipopolysaccharide, perhaps regulating nuclear factor-kB activation and macrophage apoptosis. European and North American patients with Crohns disease, including those without a family history of inflammatory bowel disease, are more likely to have variants of NOD2 than are persons without Crohns disease. Paradoxically, these NOD2 variants appear

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TABLE 1. EVIDENCE OF GENETICALLY DETERMINED SUSCEPTIBILITY TO INFLAMMATORY BOWEL DISEASE.

Human studies The prevalence varies among different populations. The risk is increased among first-degree relatives of affected patients. There is greater concordance among monozygotic than dizygotic twins. Syndromes resembling inflammatory bowel disease cosegregate in families with rare genetic disorders (e.g., glycogen storage disease type IB, WiskottAldrich syndrome, HermanskyPudlak syndrome). There is usually concordance in the type and site of disease among members of families with multiple affected members. Numerous candidate genes have been identified with putative allelic associations with inflammatory bowel disease, including genes that encode HLA antigens,* tumor necrosis factor (promotersequence polymorphisms), mucin, interleukin-10, interleukin-1receptor antagonist, intercellular adhesion molecule 1, kinin B1, inhibitor of kB kinase, and natural-resistanceassociated macrophage protein 2. Screening with microsatellite DNA markers has identified genomic linkage on chromosomes 16 (IBD1 locus; linkage with Crohns disease only), 3, 5, 7, 12 (linkage with ulcerative colitis only), 18, and 19 and the X chromosome. Animal studies Experiments in rodent lines with genetic alterations conferred by transgenic or gene-deletion techniques led to the heritable development of inflammatory bowel diseaselike colitis. Transgenic overexpression or deletion of a single gene by means of homologous recombination can lead to inflammatory bowel disease. The phenotype resulting from a single genetic alteration is modulated by other genetic loci (e.g., the severity and age at onset vary depending on the background strain). No single gene is uniquely associated with the development of inflammatory bowel disease; colitis results from alterations in a subgroup of genes that encode proteins involved in either the epithelial mucosal barrier or the mucosal immune response. Genetic alteration confers susceptibility but is not sufficient to result in disease (e.g., mutant murine lines maintained in a germ-free state do not manifest inflammatory bowel disease). Commensal bacteria are required for the development of inflammatory bowel disease in susceptible hosts. *Although HLA antigens have been studied extensively, the resulting associations have been variably reproducible. The IBD1 locus encodes NOD2 (also designated CARD 15).

to result in reduced macrophage activation of nuclear factor-kB in response to lipopolysaccharide. Persons who are homozygous for variant NOD2 may have a 20-fold or more increase in susceptibility to Crohns disease, with a particular predilection for ileal disease.13-15 Heterozygotes are also at increased risk. However, fewer than 20 percent of patients with Crohns disease are homozygous for these NOD2 variants. A putative locus associated with early-onset Crohns disease appears to be present on chromosome 5 in the vicinity of genes encoding a variety of cytokine receptors.16
Environmental Precipitants and Disease Cofactors

Whatever part genetic loci play in conferring susceptibility to inflammatory bowel disease, studies of identical twins (in which only 45 percent of pairs of identical twins are concordant for Crohns disease) make it clear that the development of disease depends on additional factors. Among myriad factors studied, the most consistent are the use of nonsteroidal anti-

inflammatory drugs, which can lead to disease flares, possibly related to an altered intestinal barrier, and early appendectomy, which is associated with a reduced incidence of ulcerative colitis.17,18 Smoking may modify the phenotype; it protects against ulcerative colitis but increases the risk of Crohns disease.19,20 Accumulating evidence suggests that the luminal flora is a requisite and perhaps central factor in the development of inflammatory bowel disease. This inference is supported by studies in murine models of colitis established through genetic manipulation and reinforced by a variety of clinical observations in patients (Table 2). For example, the development of spontaneous colitis in rats and mice appears to require the presence of luminal flora; colitis does not occur in any of several mutant strains when they are maintained in a germ-free environment, but it develops rapidly when these mice are colonized by commensal bacteria.21,22 Studies of murine models resonate with clinical experience. Broad-spectrum antibiotics and probiot-

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TABLE 2. KEY FEATURES

FEATURE

OF

MAJOR FORMS

OF INFLAMMATORY

BOWEL DISEASE.
CROHNS DISEASE

ULCERATIVE COLITIS

Clinical features Fever Abdominal pain Diarrhea Rectal bleeding Weight loss Signs of malnutrition Perianal disease Abdominal mass Growth failure in children and adolescents Site Colon Ileum Jejunum Stomach or duodenum Esophagus Intestinal complications Stricture Fistulas Toxic megacolon Perforation Cancer Endoscopic findings Friability Aphthous and linear ulcers Cobblestone appearance Pseudopolyps Rectal involvement Radiologic findings Distribution Ulceration Fissures Strictures or fistulas Ileal involvement Laboratory findings Perinuclear-staining antineutrophil cytoplasmic antibodies AntiSaccharomyces cerevisiae antibodies

Fairly common Varies Very common Very common Fairly common Fairly common Absent Absent Occasional Exclusively Never Never Never Never Unknown Absent Unknown Unknown Common Very common Absent Absent Common Very common Continuous Fine, superficial Absent Rare Dilated (backwash ileitis) 70% of patients Occasional

Common Common Fairly common Fairly common Common Common Fairly common Common Common 2/3 of patients 2/3 of patients Infrequent Infrequent Infrequent Common Fairly common Absent Uncommon Fairly common Fairly common Common Common Fairly common Fairly common Discontinuous, segmented Deep, with submucosal extension Common Common Narrowed, nodular Occasional 50% of patients

ics have proven clinical efficacy in specific subgroups of patients. Studies have demonstrated the presence of an increased number of surface-adherent and intracellular bacteria in the colonic epithelium of patients with inflammatory bowel disease.23,24 Such observations underscore the importance of further defining the mechanisms of interaction between the normal mucosa and luminal microflora and their alteration in association with inflammatory bowel disease.
Immune Response and Inflammatory Pathways

The aggregate effect of genetic, environmental, and other processes is the sustained activation of mucosal immune responses (Fig. 1). It remains unclear whether the immune system is activated as a result of an intrin-

sic defect (either constitutive activation or the failure of down-regulatory mechanisms) or because of continued stimulation resulting from a change in the epithelial mucosal barrier.25,26 Substantial progress has been made in characterizing immune-cell populations and inflammatory mediators in patients with inflammatory bowel disease and murine models.22,27 There is reasonable consensus that the mucosa of patients with established Crohns disease is dominated by CD4+ lymphocytes with a type 1 helper-T-cell (Th1) phenotype, characterized by the production of interferon-g and interleukin-2. In contrast, the mucosa in patients with ulcerative colitis may be dominated by CD4+ lymphocytes with an atypical type 2 helper-T-cell (Th2) phenotype, char-

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Bacteria

Type 1 helper T cell Macrophage migration inhibitor factor Interleukin-12 Interleukin-18 Antigenpresenting cell

Epithelial barrier

Interferon-

Normal epithelium

Tumor necrosis factor Interleukin-1 Interleukin-6

Macrophage

Figure 1. Pathogenesis of Inflammatory Bowel Disease. Normal epithelium, with its highly evolved tight junctions and products of goblet-cell populations, most notably trefoil peptides and mucin glycoproteins, provides an effective barrier against luminal agents. The integrity of the barrier may be compromised by genetic variations in key molecular determinants, a diminished reparative response to injury, or exogenous agents, such as nonsteroidal antiinflammatory drugs. Chronic, recurrent intestinal inflammation appears to result from stimulation of the mucosal immune system by products of commensal bacteria in the lumen. Antigens from dietary sources may also contribute. Stimulation may occur as a result of the penetration of bacterial products through the mucosal barrier, leading to their direct interaction with immune cells, especially dendritic cells and lymphocyte populations, to promote a classic adaptive immune response. Alternatively, bacterial products may stimulate the surface epithelium, possibly through receptors that are components of the innate immuneresponse system; the epithelium can, in turn, produce cytokines and chemokines that recruit and activate mucosal immune cells. Activation of classic antigen-presenting cells, such as dendritic cells, or direct stimulation through pattern-recognition receptors promotes the differentiation of type 1 helper T cells (Th1) in patients with Crohns disease (shown here) or, possibly, atypical type 2 helper T cells in patients with ulcerative colitis. The stereotypical products of Th1 promote a self-sustaining cycle of activation with macrophages. In addition to producing the key cytokines that stimulate Th1 (interleukin-12, interleukin-18, and macrophage migration inhibitor factor), macrophages produce a mix of inflammatory cytokines, including interleukin-1, interleukin-6, and most notably tumor necrosis factor, which target a broad variety of other types of cells. The latter include endothelial cells, which then facilitate the recruitment of leukocytes to the mucosa from the vascular space, as well as fibroblasts and epithelium, modulating their functional properties. Most important, these functions may be altered either by genetically determined variants, as exemplified by germ-line mutations in the gene encoding NOD2, the product of the IBD1 locus, in some patients with Crohns disease, or by environmental factors.

acterized by the production of transforming growth factor b (TGF-b) and interleukin-5 but not interleukin-4.28 In murine models, the effects of the activation of Th1 cells may be enhanced by the concomitant decrease in subgroups of suppressor T cells, variously designated Th3 or Tr1, which produce the down-regulatory cytokines interleukin-10 and TGF-b.29 In-depth characterization of murine lines suggests

that the stereotypical Th1 cytokines activate macrophages, which in turn, produce interleukin-12, interleukin-18, and macrophage migration inhibitor factor and thus further stimulate Th1 in a self-sustaining cycle. Just as important, activated macrophages produce a potent mix of broadly active inflammatory cytokines, including tumor necrosis factor (TNF), interleukin-1, and interleukin-6.

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The activation of central immune-cell populations is eventually accompanied by the production of a wide variety of nonspecific mediators of inflammation (Fig. 2). These include many other cytokines, chemokines, and growth factors as well as metabolites of arachidonic acid (e.g., prostaglandins and leukotrienes) and reactive oxygen metabolites such as nitric oxide.24,27 These mediators enhance the inflammatory process itself and tissue destruction, which eventuate in the clinical manifestations of disease. Recruitment of additional leukocytes from the vascular space to sites of disease activity is especially important in maintaining inflammation and depends on the expression of adhesion molecules in the local microvasculature and counterligands on the various leukocyte populations.30,31
TREATMENT

though a full consideration is beyond the scope of this review. Notwithstanding the importance of other treatments, an expanding number and variety of drugs that target the inflammatory processes broadly or selectively are usually effective in controlling active disease in most patients and in sustaining symptomatic remission for prolonged periods in many. In general, most clinicians use a stepped approach to therapy in which more potent agents are added to the regimen if less active drugs fail to achieve an adequate response.
5-Aminosalicylic Acid

Treatment must begin with accurate diagnosis. The diagnosis of inflammatory bowel disease depends on the aggregate constellation of the clinical history, physical findings, and endoscopic, radiologic, and histologic features, as well as the results of routine laboratory tests (Table 2). Typically, these features permit a firm diagnosis of inflammatory bowel disease and distinction between ulcerative colitis and Crohns disease. However, in as many as 10 percent of patients with inflammatory bowel disease that is limited to the colon, it may not be possible to distinguish ulcerative colitis from Crohns disease, at least initially; thus, these patients are considered to have indeterminate colitis. Serologic markers, including perinuclear-staining antineutrophil cytoplasmic antibodies, present in up to 70 percent of patients with ulcerative colitis, and antiSaccharomyces cerevisiae antibodies, present in 50 percent or more of those with Crohns disease.32-35 Although these markers may help in the differential diagnosis of the few patients in whom the nature of colitis cannot be determined according to the usual criteria, they are not recommended for routine diagnosis. The long-term management of inflammatory bowel disease must be multidimensional and governed by the type of disease and sites involved (Table 3). Adjunctive agents, such as antidiarrheal agents, that are directed primarily at relieving symptoms rather than controlling inflammation itself can be important. Elemental diets have also been advocated as a primary treatment for Crohns disease, but patients poor compliance often limits the practicality of this approach.35,36 Proper nutrition and attention to related secondary complications such as osteoporosis resulting from malabsorption, corticosteroid therapy, or both are also important. Supplemental nutrition is especially important in the treatment of growth failure in children. Surgery can have an important role in management,

The 5-aminosalicylatebased compounds have remained mainstays of treatment for patients with mild to moderately active ulcerative colitis and Crohns disease since the recognition of the therapeutic efficacy of the prototypical agent sulfasalazine (see Supplementary Appendix 1, available with the full text of this article at http://www.nejm.org). Early studies demonstrated that 5-aminosalicylate was the functionally active moiety of this sulfapyridine congener. 5-Aminosalicylate may act by blocking the production of prostaglandins and leukotrienes, inhibiting bacterial peptideinduced neutrophil chemotaxis and adenosine-induced secretion, scavenging reactive oxygen metabolites, and perhaps inhibiting the activation of nuclear factor-kB. Over the past 15 years, a variety of newer 5-aminosalicylatebased compounds have become available.37-43 In general, a 5-aminosalicylatebased agent should be selected principally on the basis of disease location. For patients with distal colonic disease, a suppository or enema form will be most appropriate. Oral compounds in which 5-aminosalicylic acid (mesalamine) is conjugated to prevent absorption by the small bowel are appropriate for colonic disease. These include sulfasalazine, olsalazine (a 5-aminosalicylic acid dimer), and the recently approved balsalazide. Topical formulations may be used alone or in combination with oral formulations for patients with left-sided colonic disease. Oral formulations in which 5-aminosalicylic acid is in a slow-release or pH-dependent matrix can deliver therapeutic concentrations to the more proximal small bowel or distal ileum, respectively, to expand the spectrum of patients with Crohns disease who may be treated with this class of agent. Maintenance treatment with a 5-aminosalicylic acid can be effective for sustaining remission in ulcerative colitis but is of questionable value in Crohns disease.
Corticosteroids

Corticosteroids have been commonly used when 5-aminosalicylatebased compounds are inadequate. They presumably act through the same functional properties relevant to other inflammatory processes,

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Toll-like receptor

Bacterial lipopolysaccharide

NOD2 MyD88 MyD88 Interleukins Cytokines Chemokines Receptor-interacting protein 2 NIK, MEKK1, or MEKK3 TNF and receptor IKK complex Gene transcription

Interleukin-1 and receptor

IB NF-B

Antiapoptosis

Figure 2. Common Cellular Pathways of Activation in Inflammatory Bowel Disease. Activation of the protean transcriptional regulatory factor nuclear factor-kB (NF-kB) is a common pathway central to cell activation and the production of diverse inflammatory mediators, including a variety of cytokines and chemokines. It also modulates resistance to programmed cell death (apoptosis). Several inflammatory factors implicated in inflammatory bowel disease activate NF-kB by eventually stimulating an intermediate kinase such as NF-kBinducing kinase (NIK) or mitogen-activated protein kinase kinase 1 or 3 (MEKK1 or MEKK3) or by binding to receptor-interacting protein 2. These lead to phosphorylation of the inhibitor of kB kinase (IKK) and subsequent dissociation of NF-kB (itself a dimer). NF-kB then travels to the nucleus, where it can effect gene transcription. The phosphorylated constituents are subject to degradation by proteosomes after ubiquitination. The spectrum of mediators that activate this pathway includes inflammatory cytokines such as interleukin-1 and tumor necrosis factor (TNF), which bind to their respective cell-surface receptors, as well as microbial products such as lipopolysaccharide, which bind to cell-surface receptors that are members of the toll-like receptor family of pattern-recognition receptors. The pathway is also activated by NOD2 (also referred to as CARD 15), an intracytoplasmic receptor that is activated by the entry, through mechanisms yet to be defined, of bacterial lipopolysaccharide into the cytoplasm. NOD2 is the product of the IBD1 gene; germ-line mutations, which are present in many patients with Crohns disease, appear to alter the activation of the NF-kB pathway. MyD88 denotes myeloid differentiation factor 88.

though which among these may be especially important in inflammatory bowel disease has not been determined. Topical corticosteroids (hydrocortisone enemas or foam) can be used as an alternative to 5-aminosalicylatebased compounds for patients with ulcerative

proctitis or distal ulcerative colitis. Oral prednisone or prednisolone is used for moderately severe ulcerative colitis or Crohns disease, in doses ranging up to 60 mg per day for patients with the most severe disease. Intravenous administration is warranted for patients who are sufficiently ill to require hospital-

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TABLE 3. THERAPEUTIC OPTIONS

VARIABLE DISTAL ULCERATIVE COLITIS

FOR

ULCERATIVE COLITIS

AND

CROHNS DISEASE.
CROHNS DISEASE

EXTENSIVE ULCERATIVE COLITIS

Mild disease

Oral or rectal aminosalicylates Rectal corticosteroids Oral or rectal aminosalicylates Rectal corticosteroids Oral or parenteral corticosteroids Rectal corticosteroids

Oral aminosalicylates

Moderate disease

Oral aminosalicylates

Severe disease

Oral or parenteral corticosteroids Intravenous cyclosporine Oral or intravenous corticosteroids, in addition to oral azathioprine or mercaptopurine

Refractory disease Oral or intravenous corticosteroids, in addition to oral azathioprine or mercaptopurine Perianal disease

Oral aminosalicylates Oral metronidazole Possibly oral budesonide or ciprofloxacin Oral corticosteroids (budesonide for ileal or right-sided colonic disease) Oral azathioprine or mercaptopurine Oral or parenteral corticosteroids Subcutaneous or intravenous methotrexate Intravenous infliximab Intravenous infliximab

Remission

Oral antibiotic (metronidazole or ciprofloxacin) Intravenous infliximab Oral azathioprine or mercaptopurine Oral or rectal aminosalicylates Oral aminosalicylates Possibly oral azathioprine or mercaptopurOral azathioprine or mercaptopurine Oral azathioprine or mercaptopurine ine, mesalamine, metronidazole Oral azathioprine or mercaptopurine

ization; the majority of such patients, even those with fulminant ulcerative colitis, will have a response within 7 to 10 days. Optimal administration schedules for either oral or intravenous corticosteroids have not been defined. Corticosteroids, irrespective of the route of administration, should be continued only as long as needed to control acute inflammatory activity, since they have no proven maintenance benefit in the treatment of either ulcerative colitis or Crohns disease. Optimal tapering schedules have not been defined and are generally guided by clinical experience.44 Although corticosteroids are frequently, though not invariably, effective, these effects must be balanced against their many and often serious side effects. In general, side effects correlate with the dose and duration of treatment. Some side effects may be partially offset by careful management (e.g., early administration of supplemental calcium, vitamin D, and bisphosphonates to reduce corticosteroid-induced osteoporosis and careful monitoring of blood pressure and blood glucose for corticosteroid-induced hypertension and diabetes). For some patients, the side effects may be partially circumvented by the use of budesonide, which has recently become available in the United States in a controlled-ileal-release formulation; an enema form is also available elsewhere.45-47 However, concern persists that patients who take budesonide for prolonged periods remain at risk for systemic side effects; although first-pass metabolism may eliminate more than 90 percent of the drug, budesonide has an affinity for the glucocorticoid receptor that is 50 to 100 times that of prednisone. Moreover, its use is limited primarily to patients with distal ileal and right-sided colonic

disease, and its efficacy somewhat less than that of conventional corticosteroids.
Immunosuppressive and Immunoregulatory Agents

There is an expanding role for immunomodulatory drugs in the care of patients with inflammatory bowel disease. These agents are generally appropriate for patients in whom the dose of corticosteroids cannot be tapered or discontinued. All these agents (as well as corticosteroids) put patients at risk for opportunistic infections. Azathioprine and its active metabolite mercaptopurine have been the most extensively used immunosuppressive agents, despite early hesitation arising from concern about an increased risk of lymphoma and other side effects. Indeed, this issue remains unresolved, in part owing to uncertainty about the possibility of a small, underlying increase in the risk of lymphoma in patients with inflammatory bowel disease.48-50 The actual mechanisms of action responsible for the therapeutic effect of these drugs remain largely unknown but may include suppressing the generation of a specific and long-lived subgroup of T cells, which might account for the prolonged time needed to achieve a therapeutic response. Clinical studies have shown that these agents are efficacious when they are given in adequate doses in patients with ulcerative colitis or Crohns disease, allowing a gradual decrease in the corticosteroids and prolonging remission.51-53 The onset of benefit typically takes several weeks and may require up to six months, so that these drugs are not useful in the control of acute disease activity and, conversely, should

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be used only when prolonged therapy is planned. Although no firm guidelines for initiating the use of these agents have been established, many clinicians consider their use if it has not been possible to wean patients from corticosteroids after six weeks. Toxic effects, some quite serious, frequently limit the use of azathioprine and mercaptopurine. Dose-related suppression of bone marrow is uniformly observed, and the white-cell count must be monitored closely when therapy is initiated and periodically thereafter (typically every two to three months). Considerable progress has been made in delineating the pathways of metabolism of mercaptopurine, and these findings have highlighted the importance of genetic variants of the key enzyme thiopurine S-methyltransferase in determining susceptibility to life-threatening bone marrow suppression.54-56 Approximately 0.1 percent of patients are homozygous for a functionally null allele that leads to the accumulation of toxic metabolites derived from alternative degradative pathways. Neither blood counts nor metabolite concentrations reliably predict other toxic effects, which include pancreatitis and drug-induced hepatotoxicity. In both instances, these initially asymptomatic effects are usually reversible with discontinuation of the medication and rapidly recur with greater severity if treatment is resumed. Methotrexate is effective in the treatment of corticosteroid-dependent active Crohns disease and in maintaining remission.57-59 Typically, the drug is administered as a weekly injection, either intramuscular (15 mg per week) or subcutaneous (25 mg per week), and the response becomes evident over a period of several weeks. The mechanism of action of this agent also remains mostly uncertain. Aside from the generic risks of immunosuppression, methotrexate may lead to interstitial pneumonitis, which is first manifested by nonproductive cough and dyspnea, and there is a dose-related risk of hepatic fibrosis. Cyclosporine can be effective in the treatment of patients with severe ulcerative colitis who are hospitalized and otherwise in need of urgent proctocolectomy.60-62 This agent is presumed to work by blocking lymphocyte activation. High doses can achieve at least short-term control of disease sufficient to allow up to 80 percent of hospitalized patients who have been unresponsive to corticosteroids to be switched to a tapering oral regimen of cyclosporine. Cyclosporine is usually added after an initial 7-to-10-day trial of intravenous high-dose corticosteroids. A recent study has shown essentially equivalent response rates in patients given either cyclosporine or corticosteroids as initial intravenous therapy after hospitalization.62 Although, as noted above, short-term control of disease will result from the addition of cyclosporine in a substantial number of patients, approximately 50 percent will undergo proctocolectomy within a

year as a result of either the inability to taper medications or recurrent disease activity. Azathioprine or mercaptopurine may help sustain the cyclosporineinduced response. In general, cyclosporine should not be used in the treatment of patients with Crohns disease, with the possible exception of patients with symptomatic and severe perianal or cutaneous fistulas.63 Recent trials have suggested that the related compound tacrolimus, as well as mycophenolate mofetil, is also effective in the treatment of patients with inflammatory bowel disease, though direct comparative studies with cyclosporine have not been carried out.
Anti-TNF Therapy

The availability of the prototypical anti-TNF agent infliximab has offered an important advance in therapy for patients with Crohns disease.64 Infliximabs mechanism of action is incompletely understood. Its effectiveness suggests that TNF, a product of activated macrophages, may have a pivotal role among the many regulatory peptides with altered expression in association with inflammatory bowel disease.65,66 This chimeric monoclonal antibody, composed of a complement-fixing human IgG1 constant region and a murine-derived antigen-binding variable region, binds soluble TNF; however, its action is thought to depend in part on its ability to bind precursor cell-surface TNF, perhaps leading to monocyte apoptosis. Two pivotal trials demonstrated the efficacy of infliximab in patients with Crohns disease.67,68 In the first, approximately two thirds of patients with moderately active Crohns disease who received a single infusion of infliximab had a significant reduction in their score on a standard Crohns Disease Activity Index; of these, approximately half (one third of the total) achieved actual clinical remission. The response was generally quite prompt (usually within two weeks). However, the durability of the response ranged from a few weeks to six months or more. This pattern of response was mirrored in the second reported study in which patients with perianal and cutaneous fistulas received three infusions over a period of six weeks. Since this drug was approved for use in the United States, the experience in treating patients in routine practice has largely resembled that observed in controlled studies.69-71 Important questions remain to be addressed to define the most appropriate use of infliximab. Recently completed trials suggest the effectiveness of serial administration of the drug to maintain the initial response, but this indication is not yet approved.72 Furthermore, although responses have been reported in small numbers of patients with a variety of other intestinal inflammatory conditions (e.g., Behets syndrome), the usefulness of infliximab in patients with ulcerative colitis remains uncertain.

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TABLE 4. POTENTIAL THERAPEUTIC AGENTS

AGENT RATIONALE
OR

FOR INFLAMMATORY

BOWEL DISEASE.
STATUS

TARGET

Growth hormone

Heparin

Fish oil

Stimulates production of insulin-like growth factor 1; trophic for the intestinal mucosa Binds relevant growth factors (e.g., fibroblast growth factor); blocks prothrombotic state; has antithrombotic activity Modulates metabolism of arachidonic acid and its products Agent in tobacco that may account for the protective effect of smoking in patients with ulcerative colitis Inhibits intracellular processing of tumor necrosis factor Presumptive optimal metabolic fuel for colonic epithelium Modulates antigenic load either directly or through altered flora Inhibits pathogenic T cells

Superior to placebo in patients with active Crohns disease in a single trial Some activity in suppressing active ulcerative colitis in multiple trials

Nicotine patch

Thalidomide Short-chain fatty acids Elemental diet Mycophenolate mofetil Tacrolimus

Interleukin-11 Interleukin-10 Antiinterferon-g Antiinterleukin-12 Keratinocyte growth factor p38 Inhibitor Antia4 integrin Antia4b7 integrin Bactericidalpermeability-increasing protein Rosiglitazone Probiotic mixture

Inhibits activation pathways in lymphocytes and other cell populations Enhances epithelial integrity Down-regulates lymphocyte activation Antagonizes activation of macrophages by interferon-g Antagonizes interleukin-12 activation of type 1 helper T cells Stimulates epithelial proliferation and repair Inhibits signal pathway leading to nuclear factor-kB Inhibits leukocyte recruitment Inhibits leukocyte recruitment Inhibits bacterial stimulation

Reduced postoperative recurrence of Crohns disease over a 2-year period in a controlled trial Reduced some symptoms of ulcerative colitis but caused no objective changes in a controlled trial Response in patients with active Crohns disease in two pilot trials Enema formulation improved distal ulcerative colitis; results vary Improvement in active Crohns disease in multiple studies Response in patients with Crohns disease, but not ulcerative colitis, in small series and controlled trials Benefit similar to that afforded by cyclosporine in small series; healing of fistulas Phase 23 studies in patients with Crohns disease Minimal activity in patients with Crohns disease in phase 3 trials Phase 2 trial in patients with Crohns disease Phase 2 studies in patients with Crohns disease Phase 2 studies in patients with ulcerative colitis Phase 12 studies in patients with Crohns disease Variable activity in patients with Crohns disease in phase 3 studies Phase 3 studies in patients with ulcerative colitis and Crohns disease Phase 2 studies in patients with Crohns disease Phase 2 trial in patients with ulcerative colitis Prevented pouchitis in studies of patients with ulcerative colitis; reduced activity in Crohns disease

Inhibits peroxisome-proliferator activated receptor-g Replaces pathogenic endogenous flora

The optimal timing of infliximab administration and the value of maintenance therapy must be determined in rigorous studies, for several reasons. First, patients may not remain responsive to infliximab therapy indefinitely, and in some, the duration of response after an infusion becomes progressively shorter. Second, some patients who received infliximab during trials and who resumed treatment after a prolonged hiatus had a serum sicknesslike reaction, suggesting that

the drug should not be used intermittently. Collectively, these two observations necessitate judicious use of this agent in patients with a lifelong condition. Third, the therapy is quite costly in terms of both the cost of the drug itself and the logistics of infusing it (the average third-party reimbursement per dose administered to a 70-kg patient is more than $5,200). Fourth, though it is generally safe, serious complications can ensue. In addition to occasional hypersensi-

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tivity and infusion reactions, a number of deaths have been reported as a result of tuberculosis or sepsis. Complications have included the reactivation of tuberculosis with atypical features; thus, all patients should be screened for tuberculosis before beginning therapy. Although a lupus-like syndrome has been reported infrequently after treatment with infliximab, the clinical significance of the more frequently detected antinuclear antibodies and antichimeric monoclonal antibodies is uncertain. Finally, lymphoma has developed in a small number of patients receiving infliximab, though a causal relation has not been established. A number of other agents that target TNF are in advanced stages of clinical evaluation. These include CDP571, a humanized monoclonal antibody in which only the small number of residues necessary to confer antigen specificity remain from the original murine antibody. The overall usefulness of CDP571 in clinical trials involving patients with active Crohns disease appears to be generally similar to that observed with infliximab.73,74 These results contrast with the very limited efficacy of etanercept, a fusion protein composed of the ligand-binding domain of the soluble receptor for TNF and an IgG common region, in patients with Crohns disease.75 There has been recent interest in the use of thalidomide in the treatment of Crohns disease, because of its presumptive action in blocking the production of TNF through the inhibition of intracellular pathways.76 Two small pilot trials have suggested therapeutic effectiveness.77,78 However, given the infamous history of this agent as a teratogen, its use requires rigorous supervision, including confirmation of adequate contraception in patients of childbearing age.
Antibiotics and Probiotics

of disease in the susceptible host have provided an impetus to the development of alternative strategies to manipulate the intestinal flora for therapeutic benefit. Probiotics, the administration of healthy bacteria, appears to be one promising approach.81 Patients with pouchitis or active Crohns disease who were treated with a mixture of commensal bacteria had a positive therapeutic response; these findings should prompt increased efforts to define the value of this approach, which could be free of systemic side effects.82
Investigational Agents

Empirical clinical experience has led to the recognition that antibiotics are useful in the treatment of subgroups of patients with Crohns disease.79 In contrast, antibiotics have very limited use in patients with ulcerative colitis, suggesting a differential role of the luminal flora in the two forms of inflammatory bowel disease.80 Metronidazole can be effective in the treatment of patients with Crohns disease who have perianal fistulas. However, high doses are usually necessary (up to 750 mg three times daily), and the side effects may be limiting, most notably neurotoxicity. Despite its lack of effectiveness in the treatment of ulcerative colitis, metronidazole can control colonic (but not small-bowel) Crohns disease. Ciprofloxacin and clarithromycin have been advocated as alternatives to metronidazole, but only small trials have been reported. The effectiveness of nonspecific antibiotics and experimental evidence of the central role of the luminal flora as an essential cofactor for the development

Advances in the understanding of the pathophysiology of inflammatory bowel disease, even if they are still incomplete, have led to great interest in the evaluation of a variety of new therapeutic agents with novel actions (Table 4). The explication of the cytokine network in inflammatory bowel disease and the seemingly central role of macrophage-produced interleukin-12, as described above, have led to ongoing trials with antibodies against interleukin-12. Interleukin-10, a cytokine that generally down-regulates the activation of Th1 cells, was found to have minimal activity in Crohns disease.83-85 Preliminary studies of interleukin-11, a cytokine that is thought to act by enhancing the epithelial barrier as well as through the inhibition of inflammatory cytokines, showed an apparent benefit. Larger trials of interleukin-11 in patients with ulcerative colitis and Crohns disease are in progress.86 Strategies that block the recruitment of leukocytes to the sites of mucosal inflammation have produced promising results for example, a large-scale study of patients with Crohns disease who were treated with a monoclonal antibody directed against the a4 integrin subunit. This integrin is part of a heterodimer that functions as a homing molecule for mucosal lymphocytes.87 Studies in both patients with ulcerative colitis and those with Crohns disease are also under way after the demonstration, in pilot studies, that a chimeric antibody specific for the a4b7 integrin heterodimer reduced disease activity in patients with moderate-to-severe ulcerative colitis.88 Increasing attention is being directed at efforts to block the intracellular signaling pathways central to the activation of lymphocytes and macrophages with the use of p38 antagonists and agents that target the transcription factor nuclear factor-kB. A few patients have already received a p38-blocking small molecule, with apparent benefit. However, most of these agents are in a relatively early stage of development,89 and the overall safety of disrupting ubiquitous signaling mechanisms remains to be determined. In addition, a variety of more conventional agents, including growth hormone,90 transdermal nicotine,91 fish oil,92

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and rosiglitazone,93 have been found to have some effect in trials of variable sizes (Table 4). Finally, several patients with Crohns disease had a prolonged remission after undergoing allogeneic bone marrow transplantation for unrelated reasons; this effect was presumably the result of reconstitution with nonpathogenic T cells.94 However, this approach cannot be considered established therapy.
CONCLUSIONS

Considerable progress has been made recently in both defining the mechanisms underlying the development of inflammatory bowel disease and expanding the spectrum of effective therapies. It is reasonable to expect that, as the spectrum of genes that confer susceptibility to inflammatory bowel disease is identified, attention will be focused on the mechanisms through which they lead to ulcerative colitis and Crohns disease. A definitive understanding will require the delineation of the nature of the interactions with environmental factors, especially microflora. Progress in achieving these goals should lead to more precise genetic-based diagnosis, including presymptomatic risk assessment in family members of affected patients. In the interim, progress in our understanding of facets of the pathophysiology of inflammatory bowel disease has led to the development of useful new therapies.
The Center for the Study of Inflammatory Bowel Disease is supported by funds from the National Institutes of Health (P30 DK43351).

I am indebted to Drs. Lawrence Friedman, Stephen Goldfinger, and Bruce Sands for comments and suggestions.

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