Blackwell Science, LtdOxford, UKAJDAustralasian Journal of Dermatology0004-83802005 Blackwell Publishing Asia Pty Ltd20064711327Review Article Cutaneous lupus erythematosusJP

Callen

Australasian Journal of Dermatology (2006) 47, 1327

doi: 10.1111/j.1440-0960.2006.00217.x

GUEST REVIEW

Cutaneous lupus erythematosus: A personal approach to management

Jeffrey P Callen
Division of Dermatology, University of Louisville, Louisville, Kentucky, USA

SUMMARY
Skin disease in patients with lupus erythematosus may be subdivided into two broad categories those lesions that when biopsied demonstrate interface dermatitis and those that do not demonstrate interface dermatitis. The skin lesions that are represented by the interface dermatitis include discoid lupus erythematosus, subacute cutaneous lupus erythematosus and acute cutaneous lupus erythematosus. Patients with these specic manifestations have varying degrees of systemic involvement from rare systemic disease in patients with localized discoid lupus erythematosus to common and often severe involvement in patients with acute cutaneous lupus erythematosus. Patients who do not demonstrate interface dermatitis also may have systemic disease and in some instances the skin manifestations are linked to some of the more severe systemic manifestations. Many patients with cutaneous lesions characterized by the interface dermatitis can be controlled with standard therapies including sunscreens, protective clothing and behavioural alteration, and topical corticosteroids with or without an oral antimalarial agent. This review presents a brief summary of each common cutaneous manifestation of lupus erythematosus, its relationship to systemic involvement and treatment issues to effectively deal with the lupus erythematosus patient who has skin disease.

Key words: acute cutaneous lupus erythematosus, antiphospholipid antibody syndrome, bullous lupus erythematosus, chilblain lupus erythematosus, discoid lupus erythematosus, hypertrophic lupus erythematosus, lupus erythematosus panniculitis, lupus erythematosus tumidus, subacute cutaneous lupus erythematosus.

INTRODUCTION
The most common cutaneous lesions in patients with LE are represented histologically by an interface dermatitis, 1 and most of the problem patients who are referred to me for consultative care are those with either CCLE or SCLE. Because of the nature of my practice I also see patients with rare manifestations of LE, including chilblain LE, LET and lupus panniculitis. This review will deal with both common and uncommon cutaneous manifestations of LE, both specic and non-specic histopathological entities and conclude with a discussion of my general approach to the treatment of the common manifestations of cutaneous LE. In this review I have elected to offer references that are either classic papers or recent studies and, therefore, the reference list is not a complete listing, rather it serves as an entry into the literature from which with a proper search engine one might nd more complete listings for each entity.

Abbreviations: ACR BLE CCLE DLE EBA FDA LE LEP LET PCT SCLE SLE TNF American College of Rheumatologists bullous lupus erythematosus chronic cutaneous lupus erythematosus discoid lupus erythematosus epidermolysis bullosa acquisita Food and Drug Administration lupus erythematosus lupus erythematosus pannilucilitis lupus erythematosus tumidus porphyria cutanea tarda subacute cutaneous lupus erythematosus systemic lupus erythematosus tumour necrosis factor

Correspondence: Professor Jeffrey P Callen, Division of Dermatology, University of Louisville, 310 East Broadway, Louisville, KY 40292, USA. Email: jefca@aol.com Jeffrey P Callen, MD. Presented at the Annual Scientic Meeting of the Australasian College of Dermatologists, Perth, May 2005. Funding for colour gure publication was provided by the Edward Rosanove Grant of the Australasian College of Dermatologists. Submitted 16 May 2005; accepted 21 July 2005. 2006 The Australasian College of Dermatologists

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Table 1 Subsets of cutaneous lupus erythematosus

JP Callen

Represented by interface dermatitis on histopathological evaluation Chronic cutaneous lupus erythematosus Localized discoid lupus erythematosus (lesions on the head and neck only) Widespread discoid lupus erythematosus DLE-SLE subset (most of these patients have widespread DLE) Oral discoid lupus erythematosus (most of these patients have widespread DLE, but in rare instances patients may have isolated oral lupus erythematosus) Hypertrophic (or verrucous) lupus erythematosus Palmoplantar lupus erythematosus (approximately 50% of these patients have SLE without other cutaneous lesions in which case the diagnosis may be difcult because of a lack of appendageal structures on the palms and soles) Lupus panniculitis (half of the patients have dermal-epidermal interface dermatitis, while others have panniculitis alone without cutaneous lupus erythematosus elsewhere, in these patients it may be difcult to distinguish lupus erythematosus panniculitis from other lobular panniculitides) Subacute cutaneous lupus erythematosus Annular variant Papulosquamous variant Acute cutaneous lupus erythematosus Photosensitivity eruption Malar eruption (buttery rash) Some cutaneous lesions that are not represented by interface dermatitis on histopathological evaluation Bullous lupus erythematosus (in some cases there is an interface dermatitis, but this occurrence is rare) Tumid lupus erythematosus (in some classication systems these patients have been placed under chronic cutaneous lupus erythematosus, but they do not have interface changes and the lesions do not heal with scarring or atrophy. If this condition exists, then it belongs as a subset unto itself) Vasculopathy or vasculitis Subepidermal blistering diseases including bullous lupus erythematosus, epidermolysis bullosa acquisita, porphyria cutanea tarda and pseudoporphyria DLE, discoid erythematosus. lupus erythematosus; SLE, systemic lupus

Figure 1 Chronic cutaneous lupus erythematosus discoid, scarred lesion on the chin.

further divided into those with lesions that are only on the head and neck (localized DLE), or those with lesions on other body surfaces as well as the head and neck (widespread DLE). Other, less common forms of CCLE include hypertrophic or verrucous (wart-like) lesions, palmoplantar LE, oral DLE, LET and LEP (lupus profundus). In addition, there exists a group of patients in whom the DLE lesion is only one manifestation of SLE (DLE-SLE subset).

Discoid lupus erythematosus

The DLE lesion is characterized by erythema, telangiectasia, adherent scale, which varies from ne to thick, follicular plugging, dyspigmentation and atrophy and scarring (Fig. 1). The lesions are usually sharply demarcated and can be round, thus giving rise to the term discoid (or disclike). The presence of scarring and/or atrophy is the characteristic that separates these lesions from those of SCLE. 3 The clinical appearance of DLE lesions is frequently so characteristic that one might consider a biopsy unnecessary. However, there is a differential diagnosis of DLE that includes other papulosquamous diseases and chronic eczema and as therapies of DLE might be associated with toxicity it seems reasonable to me to perform a biopsy for routine processing to conrm the clinical diagnosis in almost all patients. However, in my experience immunouorescence microscopy is rarely necessary. Discoid LE appears to be photo-exacerbated in most individuals, and there are reports of patients whose lesions were induced by phototesting. However, many patients are not aware that light exacerbates their disease. Patients with localized DLE have lesions located solely on the head, the neck, or both. This subset represents approximately half of the CCLE population. These patients differ from those with widespread DLE in a number of ways. They have fewer manifestations that suggest systemic disease, and they less frequently demonstrate a positive antinuclear antibody titre or leucopenia. It appears that the

Gilliam is attributed with the creation of a systematic approach to the classication of patients with cutaneous LE into a variety of subsets (Table 1).2 The purpose of classifying patients into subsets is to be able to study uniform groups of patients as well as being able to predict the prognosis for individual patients. There are still many times in a dermatologic practice that following a diagnosis of cutaneous LE a patient will become alarmed as they seek information and nd a majority of the information discusses the possibility of a poor prognosis including mortality despite ample evidence that most patients with chronic or subacute forms of cutaneous LE have a reasonable outcome.

CHRONIC CUTANEOUS LUPUS ERYTHEMATOSUS

There are a variety of clinical manifestations that patients with CCLE may demonstrate. The most common subtype of CCLE are patients with DLE. These patients may be
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Cutaneous lupus erythematosus

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Figure 3 Plantar lesions of lupus erythematosus following a vacation to Cancun, Mexico. Figure 2 Hypertrophic lupus erythematosus.

rare patient with DLE who progresses to develop more of the criteria for SLE is generally not in the localized DLE subset. Those patients with disease localized to the head and neck will have an approximately 50% chance of remission, whereas in those with widespread involvement, the disease rarely becomes clinically inactive (less than 10%). Thus, it seems that it is worthwhile to separate patients with localized DLE from those with widespread DLE.

and to date no one has reproduced the clinical lesion through phototesting. They have few systemic symptoms or abnormal laboratory ndings and only rarely do they develop enough ndings to classify them as having SLE. These patients tend to have chronic disease that is often difcult to treat; however, oral retinoids and intralesional injections of triamcinolone acetonide seem to be the most useful therapy (see the therapeutic discussion that follows).

Palmar/plantar discoid lupus erythematosus Hypertrophic lupus erythematosus

Hypertrophic or verrucous DLE (hypertrophic LE) is a unique subset in which an unusual lesion occurs. 4 The thick, adherent scale is replaced by massive hyperkeratosis (Fig. 2), and the lesions look like warts or squamous cell carcinomas. These lesions usually occur in the setting of other, more typical DLE lesions. I have seen several patients in whom an incorrect diagnosis of non-melanoma skin cancer had been made prior to the recognition of the correct diagnosis. This misinterpretation may even confound the dermatopathologist. Although the disease occurs primarily on exposed surfaces, it has not been demonstrated whether photosensitivity plays a role in the occurrence of the disease Discoid LE lesions can occur on the palms and/or soles (Fig. 3). The frequency of this subset is low, and there is no specic clinical or serologic correlation. 5 At times this type of lesion might present diagnostic problems both clinically and histopathologically as there are no appendageal structures on the palms or soles and lichen planus must be given serious consideration. These patients can have chronic disease without systemic features, or these lesions can be present in patients with SLE. There has not been any large group of such patients that have been systematically studied. I have observed plantar lesions in patients exposed to a hot sandy beach while on vacation in the Caribbean. Palmar and/or plantar lesions are reportedly difcult to
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JP Callen

treat, but there are no systematic evaluations of treatment in these patients.

Lupus erythematosus tumidus

Lupus erythematosus tumidus is characterized by erythematous to violaceous plaques or nodules, usually on sun-exposed surfaces.8 The lesions typically have no epidermal changes and when they heal they leave little if any residual changes (Fig. 5). I believe it would be preferable to classify these patients under the non-specic heading as the histology of lupus tumidus is not the interface dermatitis, but it seems that most dermatologists are content with LET appearing within this subset. Patients with lupus tumidus seem to be worsened by sunlight. These patients rarely have antibody abnormalities. The pathology reveals an increase in mucin and a periappengeal and perivascular dermal inltrate composed of lymphocytes, but there is little if any change at the dermal-epidermal interface. There is debate about whether these patients are best characterized as a variant of LE or should be recognized as a form of benign lymphocytic inltrate or an idiopathic mucinosis. Patients with LET are usually antimalarial responsive and the use of topical or intralesional corticosteroids as adjunctive therapies has been reported.

Oral discoid lupus erythematosus

Oral DLE is histopathologically and clinically similar to cutaneous DLE (Fig. 4). These lesions are different from the oral and nasal ulcerations that occur in SLE. 6 Those occurring in the patient with SLE are associated with active systemic disease and are histopathologically non-specic. Patients with lesions that look like those of DLE in the oral mucosa have systemic associations that are similar to those observed in patients with localized or widespread DLE lesions on the skin. It appears that dark-skinned individuals, including Australian Aboriginals, are prone to development of squamous cell carcinoma in chronic lesions of the lips.7

Lupus erythematosus panniculitis

Lupus erythematosus panniculitis, also known as lupus profundus. is a lobular panniculitis that occurs rarely in patients with DLE or with SLE. It is often chronic, and it can lead to cutaneous and subcutaneous atrophy (Fig. 6) and occasional ulceration.9 Twice as many patients with LEP do not have systemic disease as have systemic disease; however, in the most recent series only three of 12 patients with LEP had SLE.10 Lupus erythematosus panniculitis must be differentiated from other forms of panniculitis. Several reports of patients who were presumed to have LEP, but eventually were diagnosed with subcutaneous panniculitis-like T-cell lymphoma have been published recently.11,12 Patients with LEP do not appear to be photosensitive. They are a challenging group to treat, and although there are no

Figure 4 Oral discoid lupus erythematosus.

Figure 5 Lupus erythematosus tumidus. 2006 The Australasian College of Dermatologists

Figure 6 Lupus erythematosus panniculitis.

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Figure 8 Papulosquamous erythematosus. Figure 7 Annular subacute cutaneous lupus erythematosus.

subacute

cutaneous

lupus

large series of patients reported, most reports suggest that LEP is responsive to antimalarial therapy.

Discoid lupus erythematosus-systemic lupus erythematosus subset13

The DLE-SLE subset denes a small group of patients (approximately 510%) who, by the nature of their selection, have systemic disease in association with scarring cutaneous disease. Patients whose disease progresses from purely cutaneous disease into this group are characterized by widespread DLE, the presence of clinically appreciable periungual telangiectasias, persistent elevated erythrocyte sedimentation rates, leucopenia and positive antinuclear antibody titres. Patients in this group may have DLE alone at the onset, DLE with other symptoms or signs, or systemic disease without cutaneous lesions. The time frame is variable for the development of SLE in these patients, but most of the patients in this group develop the criteria for SLE within 13 years following diagnosis. These patients with DLE-SLE rarely have renal disease, and even when they do, it is most often transient and mild. Discoid LE-SLE is a distinct LE subset because of its relatively benign, albeit chronic, course. These patients are more difcult to treat, but are approached in the same manner as others with DLE (see later).

is thus worthwhile to separate SCLE as a distinct subset. 15 Annular SCLE (Fig. 7) often needs to be differentiated from gurate erythemas, while papulosquamous SCLE (Fig. 8) must be differentiated from psoriasis and lichen planus, and in both instances a supercial dermatophyte infection should be considered. Diagnosis is based upon clinical pathological correlation. Immunouorescence microscopy and serological tests may be supportive, but neither the presence of specic antibodies is diagnostic nor is their absence exclusionary. Dermatomyositis can mimic SCLE and in the past several years I have seen at least two patients whom I had diagnosed with SCLE whose features eventually clearly represented dermatomyositis. Patients with SCLE have been described in association with other conditions. They may have Sjgrens syndrome, idiopathic thrombocytopenic purpura, urticarial vasculitis, other cutaneous vasculitic syndromes, and/or deciency of the second component of complement (C2d). Anti-Ro (SSA)-positive SCLE has been induced or exacerbated by a variety of drugs, particularly antihypertensive agents. 1619 Treatment of SCLE follows a similar paradigm as for DLE (see later).

ACUTE CUTANEOUS LUPUS ERYTHEMATOSUS

Acute cutaneous LE produces malar erythema, the classic buttery rash from which the term lupus erythematosus (wolf-like redness) was coined. The rash is induced by sun exposure, or by exposure to other sources of UV light. Patients with a buttery rash usually have active systemic disease, but there is no specic organ system involved. Several cutaneous abnormalities had been part of the ACR criteria but have been found to be less specic than photosensitivity. Diffuse hair loss (alopecia) was one of the original criteria. Patients with SLE can develop a diffuse hair thinning, but this is most likely related to the presence of a severe episode of systemic illness. Photosensitivity is a major feature of almost all subsets of cutaneous LE, as well as being one of the 11 ACR criteria for the classication of SLE.20,21 Photosensitivity is dened
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SUBACUTE CUTANEOUS LUPUS ERYTHEMATOSUS

This subset is dened by the presence of skin lesions in which neither scarring nor atrophy occurs. 1416 In addition, follicular plugging is rarely observed in the lesions of SCLE. It is important to understand, however, that the patient in the SCLE subset can also have some scarring lesions of DLE, but these are not the predominant lesion. At least 50% of the patients with SCLE will have four or more features that classify them for a diagnosis of SLE. However, patients with SCLE differ from unselected patients with SLE and it

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JP Callen that are frequently used by LE patients. Bullous pemphigoid and EBA are immunological disorders and it appears that LE patients are more likely to have additional autoimmune diseases than might be predicted in the general population.

as an abnormal reaction to sunlight that is observed by the patient or by the medical practitioner. Patients with DLE and SCLE have been tested and in many instances their lesions are experimentally reproducible by UVB light (290 320 nm) and/or UVA light (320360 nm).22

Vasculitis NON-INTERFACE DERMATITIS MANIFESTATIONS OF LUPUS ERYTHEMATOSUS Bullous lupus erythematosus

Blisters may occur in patients with LE and can represent another disease process occurring in conjuction with LE, or they may be a specic LE-related phenomenon known as BLE (Fig. 9).23 Bullous LE lesions are often seen in patients with active SLE, may either be grouped lesions or be lesions that are triggered by trauma. The lesions of BLE have simulated dermatitis herpetiformis and EBA. Many of the patients with BLE have antibodies to type VII collagen. Recently a patient was reported with disease that mimicked toxic epidermal necrolysis, but was histologically represented by apoptosis.24 The difculties in the classication of bullous lesions in patients with LE were discussed. Bullous LE is said to respond particularly well to oral dapsone. However, many of the patients that I have treated have required oral corticosteroids because of active systemic disease. Other blistering skin conditions in LE patients include PCT, pseudoporphyria, bullous pemphigoid and EBA. Porphyria cutanea tarda may be more common in patients with LE and its presence impacts the therapy of both conditions. Specically, patients with LE are regularly treated with antimalarial agents, but patients with PCT often develop a toxic response to antimalarial agents and the doses should be lowered to avoid this toxicity. In addition, phlebotomy is a usual therapy for PCT, but it may worsen LE or may be contraindicated in patients who are anaemic. Pseudoporphyria is often drug-induced and the most common drugs that cause it are non-steroidal anti-inammatory agents Vasculitis may complicate LE and is perhaps more frequent in patients with systemic disease than in LE subsets without systemic involvement. Vessels of all sizes might be affected. Small vessel vasculitis is probably more often seen in patients with SCLE who possess anti-Ro/SS-A antibodies and have coexisting Sjgrens syndrome.25 However, I have observed what appears to be palpable purpura on the legs of SCLE patients (Fig. 10) that mimics vasculitis, but that represents SCLE and responds to therapy directed at SCLE. It is therefore helpful to biopsy these patients as the choice of therapy will be affected.

Antiphospholipid antibody syndrome

Antiphospholipid antibody syndrome can accompany LE or may occur as a primary disease. 26 There does not appear to be a specic subset of LE patients who might be associated with antiphospholipid antibodies. Cutaneous manifestations include necrosis of the skin, pyoderma gangrenosumlike ulcerations and livedo reticularis. Therapy of antiphospholipid antibody syndrome is independent of that of cutaneous LE; however, antimalarial therapy is of benet for both processes.

Chilblain lupus erythematosus27

Rare patients will have tumid lesions on acral surfaces that are worsened by cold, moist weather (Fig. 11). These patients have been termed to have chilblain LE. Not all patients with chilblains (also known as perniosis) have LE or will develop LE. The histopathological features include

Figure 9 Bullous lupus erythematosus. 2006 The Australasian College of Dermatologists

Figure 10 Subacute cutaneous lupus erythematosus simulating small vessel vasculitis.

Cutaneous lupus erythematosus

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TREATMENT OF CUTANEOUS LUPUS ERYTHEMATOSUS

A cornerstone in the treatment of DLE and SCLE involves correct diagnosis and thorough evaluation. The patient should have a careful history, physical examination and laboratory studies that are directed at uncovering systemic manifestations that might occur in patients with LE. Absence of manifestations such as renal disease or involvement of the nervous system is indicative of a benign prognosis. In this case the patient may be cautiously reassured that they are unlikely to develop serious systemic involvement. However, periodic reassessment historically as well as with simple tests such as complete blood counts and urinalysis will usually be sufcient to identify the patient who is developing more serious disease. The risk of serious systemic involvement in patients with DLE is under 5%, whereas that in patients with SCLE is probably approximately 10%, even though many patients, roughly 50%, with SCLE have sufcient criteria to classify them as SLE. The goals of treatment of the patient with DLE or SCLE are to improve the patients appearance and to prevent the development of deforming scars, atrophy or dyspigmentation. Although many patients with cutaneous LE have some systemic ndings (Fig. 12), the majority of patients with CCLE or SCLE have disease that primarily affects their skin and may be reassured that their prognosis is relatively benign. Therapy of cutaneous lesions in patients with LE involves both an empirical as well as a scientic approach (Table 2).29,30 Unfortunately, there are few double-blind, placebo-controlled trials of drugs utilized in the treatment of cutaneous LE. I generally approach patients with specic lesions of LE in a similar manner, when they have the relatively xed lesions of SCLE or CCLE manifest by DLE lesions.

Figure 11 Chilblain lupus erythematosus.

a lymphocytic inltrate, but interface dermatitis is not present. Patients with LE-associated chilblains seem to have more severe and more persistent disease, and they may have either SLE or cutaneous LE. The disease is more common in women. Therapy involves prevention of exacerbating factors, smoking cessation and antimalarial agents.

LABORATORY PHENOMENA IN PATIENTS WITH CUTANEOUS LUPUS ERYTHEMATOSUS

The full gamut of systemic disease manifestations of SLE can occur in patients with cutaneous disease, and thus these individuals can have any or all of the laboratory associations of the disorder. Serological abnormalities are common in SLE. They are rarer in patients with pure cutaneous disease, such as DLE or hypertrophic LE. The presence of abnormalities in these patients correlates with progressive disease or with the ACR criteria for SLE. The use of direct cutaneous immunouorescence testing led to a better understanding of the pathogenesis of cutaneous LE; however, its use in the clinic as a diagnostic and prognostic tool is discouraged except under very selective situations. Lesional immunouorescence may be helpful when the clinical and histopathological diagnosis is in question. This is most often useful when dealing with patients who have lesions of the scalp, palms or soles when the biopsy for routine processing is not characteristic. However, normal facial skin can demonstrate false positive lupus band immunouorescence microscopy reactions in 1020% of cases when using Michels transport media as opposed to the utilization of fresh frozen tissue. 28 This is meaningful because outside of very few medical centres the common method for direct immunouorescence testing is to use Michels medium. The use of non-involved, nonexposed skin in the lupus band test is believed to correlate with active renal disease; however, it is cumbersome and its use has become unnecessary with widely available serological testing.

General measures
A complete list of the patients medications will assist in the exclusion of drug-induced cutaneous LE. Drugs that have been linked as causes of cutaneous LE, primarily SCLE, include hydrochlorothiazide, calcium channel blockers and terbinane1719 (Table 3). Also, patients who smoke may have more severe clinical disease than non-smokers. 70 Thus, it is critical that patients with cutaneous LE who smoke be placed in programmes to alter this behaviour. It is not known whether nicotine patches or gum exacerbate cutaneous LE; however, it has been my policy to try to avoid them in a smoking cessation programme. Cosmetic problems are often of major importance to the patient with cutaneous LE. Dyspigmentation may follow both DLE and SCLE and may be effectively hidden by agents such as Covermark or Dermablend. Scarred lesions may be excised if they are inactive; however, the possibility of reactivation resulting from manipulation exists because the Kbner phenomenon has been reported to occur in some patients with LE.
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JP Callen

Figure 12 Schematic illustrating the relative risk of SLE for the various subsets of cutaneous lupus erythematosus. ACLE, acute cutaneous lupus erythematosus; BLE, bullous lupus erythematosus; CCLE, chronic cutaneous lupus erythematosus; HLE, hypertrophic lupus erythematosus; LEP, lupus erythematosus pannilucilitis; LET, lupus erythematosus tumidus; NLE, neonatal lupus erythematosus; SCLE, subacute cutaneous lupus erythematosus; SLE, systemic lupus erythematosus.

Sun protective measures

Photosensitivity is generally prevalent in patients with cutaneous LE. Patients with SLE have a history of photosensitivity in 5773%, whereas those with SCLE report photosensitivity in 7090%; those patients with DLE are estimated at 50% and almost 100% of patients with tumid LE are photosensitive. The action spectrum has been dened by photoprovocation testing and includes UVA, UVB and occasionally visible light. Phototesting does not reproduce lesions in all or even a majority of patients and should be reserved for investigative studies or for individual patients with workers compensation or medicolegal issues. Sunscreens are a cornerstone of therapy, but their importance is often forgotten as the medical practitioner manipulates the topical or systemic therapies that the patient is using. The ideal sunscreen would be broad in its spectrum and water-resistant. Unfortunately, no sunscreen is able to block all UVR that might exacerbate cutaneous LE in any patient and, therefore, patients should also be encouraged to alter their sun-related behaviour and to utilize sun-protective measures including sun-protective clothing. A recent study examined the capacity of three sunscreens to prevent the development of skin lesions by provocative phototesting.71 Although each of the three sunscreens tested prevented lesions, the extent to which they did so varied greatly. The sunscreen that was most effective contained octocrylene as the UVB protectant, mexoryl SX, mexoryl XL and parsol 1789 as UVA protectants and titanium oxide, which is a physical blocker, and thus blocks the entire UV and visible light spectrum. Their
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study was of only 11 patients (nine men and two women) of whom eight had SCLE and three had DLE. These ndings have been extended in a recently published report. 72 There are hundreds of sunscreens that are available. Care must be taken to locate a sunscreen that has the characteristics that are most efcacious in patients with LE, specically the sunscreen should have a high SPF and be broad spectrum. The product studied in LE, Anthelios, contains mexoryl SX, mexoryl XL, parsol 1789 and ocotcrylene, and it is unavailable and not yet approved in the USA by the FDA. It is not available in Australia at the time of writing.

Topical and local therapies

Topical corticosteroids are usually prescribed for patients with cutaneous LE. An appropriate topical corticosteroid is selected for the area of the body being treated as well as the type of lesions that are present. Facial lesions should be treated with low- to mid-potency topical agents such as 2.5% hydrocortisone, desonide, aclomethasone, or hydrocortisone valerate. Lesions on the trunk and arms may be treated with mid-potency agents such as triamcinolone acetonide, or betamethasone valerate. Lesions on the palms or soles and hypertrophic lesions often require superpotent corticosteroids such as clobetasol or halobetasol. Patients prefer creams over ointments; however, the ointments may be more potent and possibly are more effective. For lesions on hairy areas, most patients prefer a lotion or foam. Although topical corticosteroids are effective in study settings, in the ofce setting they do not appear to be as effec-

Cutaneous lupus erythematosus

Table 2 Therapy for cutaneous lupus erythematosus Standard therapy: Thorough evaluation Is the patient on any drugs that might exacerbate the disease? (B, III) Is the patient a smoker? (B, II-iii) Reassurance and education Sunscreens (A, I-i), sun-protective clothing and lifestyle alterations Topical corticosteroids (A, I-i) Intralesional corticosteroids (B, III) Antimalarial agents: hydroxychloroquine, chloroquine, quinacrine (A, II-ii) When standard therapy fails: Is the patient using the therapy appropriately? Topical agents and local therapies: Retinoids: tretinoin, tazarotene (C, III) Pimecrolimus (B, II-iii) Tacrolimus (B, II-iii) Imiquimod (C, IV) Laser (pulse dye or argon: C, IV) Cryotherapy (C, IV) Systemic therapies Dapsone (C, III) Auranon (C, III) Clofazimine (B, I) Thalidomide (B, II-iii) Retinoids: isotretinoin (B, III), acitretin (A, I) Immunosuppressive/cytotoxic agents (C, III): azathioprine, methotrexate, mycophenolate mofetil, cyclosporin, other Intravenous immune globulin (C, II-iii) Cytokines: -interferon, chimeric CD4 monoclonal antibody, etanercept, iniximab, adlumimab (C, IV) Systemic corticosteroids (C, III) Strength of recommendations: A, there is good evidence to support the use of the procedure/agent; B, there is fair evidence to support the use of the procedure/agent; C, there is poor evidence to support the use of the procedure/agent. Quality of evidence: I, evidence obtained from at least one designed, randomized-controlled trial; II-i, evidence obtained from well-designed controlled trials without randomization; II-ii, evidence obtained from well-designed cohort of case-control analytical studies, preferably from more than one centre or research group; II-iii, evidence obtained from multiple time series with or without intervention. Dramatic results in uncontrolled experiments (such as results of the introduction of penicillin treatment in the 1940s could be regarded as this type of evidence); III, opinions of respected authorities based on clinical experience, descriptive studies or reports of expert committees; IV, evidence inadequate due to problems of methodology, for example sample size, or length of comprehensiveness of follow up or conicts in the evidence.

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Table 3 Drugs reported in the literature to cause subacute cutaneous lupus erythematosus Drug Thiazides Chlorothiazide Hydrochlorothiazide Hydrochlorothiazide and triamterene Terbinane Biologic therapy Etanercept Iniximab Calcium channel blocker Diltiazem Nifedipine Nitrendipine Verapamil ACE inhibitors Captopril Captopril and cilazapril Enalapril Lisinopril Griseouvin PUVA therapy Cinnarizine Cinnarizine and thiethylperazine Interferon- Statins Pravastatin Simvastatin Leunomide Docetaxel Phenytoin COL-3 Gold Naproxen Aldactone Fertilizer and pesticide containing hay Ranitidine Bupropion No. of patients 2 12 3 16 4 1 10 3 1 4 1 1 2 1 3 2 1 1 3 1 1 2 4 1 3 1 1 1 1 5 1 Reference no. 31 16, 32, 33, 34 35 17, 3641 4245 46 16, 4748 16, 47, 49 50 47 51 52 16 16 53, 54 55, 56 57 58 16, 59 16 16 60, 61 62 63 64 65 66 67 68 69 18

tive, probably because of their expense and messiness. The prescribing doctor should consider the total amount of corticosteroid that the patient applies, as it is possible to cause hypothalamic-pituitary-adrenal axis suppression. Several other topical agents might be of use in individual patients with cutaneous LE. However, none of these agents have been tested in any systematic manner. Retinoids, specically tretinoin, might be effective and have primarily been used in patients with DLE and hypertrophic LE. Tazarotene, another retinoid approved for use in acne and

psoriasis, has been reported to be effective in a limited number of patients. Recently, several case series have reported that topical immunomodulators including tacrolimus ointment 0.1% and pimecrolimus cream are effective for DLE or SCLE.73,74 These agents are approved for use in patients with atopic eczema. Their use is associated with possible irritation and absorption is possible through diseased skin. Patients in whom these agents have been used have not had elevated blood levels observed, but as with other topical agents their use could result in absorption and medical practitioners should consider blood chemistry and blood pressure assessment in patients using large quantities of these agents. One theoretical concern with the chronic use of immunomodulators is the possibility of developing non-melanoma skin cancer and thus patients should be carefully monitored. Individual case reports have documented improvement or control of LE skin lesions following application of calcipotriene (FDA-approved for psoriasis) or imiquimod75 (FDA-approved for warts, solar keratoses and basal cell carcinoma).
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JP Callen tions have also been reported with antimalarial drugs, as well as hyperpigmentation, generalized or localized pruritus, lichenoid drug eruption, or hypopigmentation of the hair, nails and mucous membranes. Haematological toxicity may occur and may be manifest late in the course of therapy. Haematological toxicity appears to be more common with quinacrine than the other antimalarials. Fortunately, the frequency of these side-effects with antimalarials is relatively uncommon with the exception of the gastrointestinal side-effects. Ocular toxicity, including irreversible retinopathy has been reported with chloroquine and hydroxychloroquine, but not with quinacrine. The risk of ocular changes is greater with chloroquine. Ophthalmological toxicity is probably related to the daily dose as well as the duration of therapy. Daily doses of hydroxychloroquine below 6.5 mg/ kg appear to be quite safe even when used for long periods. If detected early, these changes often do not progress if the drug is stopped. However, there are rare patients in whom the drug is stopped, but the retinopathy continues. Although there are other ocular changes, including blurring of vision and corneal deposition of the antimalarial, these are reversible upon cessation of the drug. Ophthalmological evaluation, preferably by an ophthalmologist who is aware of these agents, should be performed at baseline or shortly after initiation of therapy and periodically, every 612 months.84

Intralesional injections of corticosteroids are often effective in patients with lesions that are refractory to topical corticosteroids.76 Small amounts of triamcinolone acetonide (3 mg/mL) may be injected with a 30-gauge needle into multiple areas. These injections are often very effective in control of the lesions but do not prevent the development of new lesions. The potential for cutaneous atrophy and/or dyspigmentation similar to that seen with the disease should be discussed with the patient; however, in most cases an experienced dermatologist is able to inject without a great risk. Also, as with topical corticosteroids, the total dose of intralesional corticosteroids should be noted. Alternative agents for intralesional injection have not been well tested. Interferon- has been successfully used when given subcutaneously, and it would be interesting to see if lower doses injected into individual lesions would be effective, without systemic ill effects. Interferon- injections for LE are not an approved use, and there are some cases of development or exacerbation of SLE in patients treated with this agent.77 Individual cases of responses to other types of local therapy with liquid nitrogen78 or various vascular lasers79,80 have suggested that in selected patients benets might occur. The pulse dye laser has been used in 14 patients with cutaneous LE.80 Responses were described in more than 60% of the lesions treated, but often involved only a decrease in erythema. The effect was observed to last up to a year in some of the patients and they suggested that resumption of usual therapy was possible in some of the patients whose disease was previously poorly controlled.

Systemic corticosteroids
In difcult cases, multiple other approaches have been advocated for the treatment of cutaneous LE. In general, low-dose systemic corticosteroids ( <1 mg of prednisone per day or its equivalent) are rarely effective for DLE, and only partially effective for SCLE lesions. Corticosteroids are effective for the acute lesions of photosensitivity, the malar rash, or for vasculitic lesions that may complicate LE. Chronic use of oral or intramuscular corticosteroids should be avoided unless required for systemic disease.

Antimalarial agents
When existing lesions are not controlled with topical agents or intralesional corticosteroids, systemic therapy is often indicated. The rst-line therapy is the use of an oral antimalarial drug. Antimalarials seem to work less well in patients who smoke.81,82 The antimalarial that I prefer is hydroxychloroquine sulphate. This drug is used in doses of 200 mg orally once or twice per day, or in a dose of <6.5 mg/ kg/day. The onset of action of the antimalarial agents is roughly 48 weeks and for this reason some doctors have advocated higher initial loading doses. Hydroxychloroquine is also of benet to the joint symptoms and malaise that may accompany cutaneous LE. Hydroxychloroquine is associated with less ocular toxicity, but also appears to be less effective than chloroquine phosphate that is used in doses of 250500 mg per day. Thus patients who fail to fully respond to hydroxychloroquine may be switched to chloroquine; however, I believe that these two antimalarial agents should not be used together because of the potential that ophthalmological toxicity may be enhanced. Another antimalarial, quinacrine HCl, may add benet to either hydroxychloroquine or chloroquine and is not associated with ophthalmological toxicity.83 This agent is not readily available, but several compounding pharmacies in the USA have it available. Antimalarial drugs may cause nausea, diarrhoea, myopathy, cardiomyopathy, and/or psychosis. Cutaneous erup 2006 The Australasian College of Dermatologists

Antibiotics
Dapsone, given in doses of 25200 mg daily, has been useful for patients with vasculitic lesions that may accompany LE, SCLE lesions, bullous LE and oral ulcerations. 85 In openlabel clinical trials, dapsone has resulted in improvement in some patients with DLE or SCLE; however, the level of benet has been judged as excellent in only approximately 25% of patients. In contradistinction, clofazimine failed to demonstrate efcacy in all but one report.86 There are several special circumstances in which dapsone may be useful. The rst is bullous LE. In addition, those patients with urticarial vasculitis in combination with SCLE lesions may be beneted by the use of dapsone. In my practice I have only observed one patient who seemed to benet from dapsone therapy, and therefore it is only the rst line of therapy for a minority of patients. A variety of other antibiotics have been used for the treatment of cutaneous LE. The antibiotic cefuroxime axetil resulted in the clearing of skin lesions in three patients with

Cutaneous lupus erythematosus SCLE at a dose of 500 mg daily.87 Cefuroxime axetil is a second-generation -lactamase oral cephalosporin. Others must replicate this observation before it can be recommended for widespread use; however, it is a relatively benign form of treatment. Another group has reported the successful use of sulphasalazine 2 g per day in eight of 11 patients.88 Sulphasalazine is used for inammatory bowel disease and various arthritides. The eight patients who responded were all rapid acetylators, while the three who fail to respond were all slow acetylators. No serious toxicity was noted in this small open-label case series. In contrast, a drug eruption was noted in ve of six patients treated with sulphasalazine and in only two patients did they feel that there was a benecial effect.89 Although this drug might be effective in some patients, there are multiple reports of drug-induced SLE and cutaneous LE in patients with inammatory bowel disease and rheumatoid arthritis. Therefore, I would not consider this agent in view of the multitude of agents that are potentially as effective and appear to be safer. A recent report of 33 patients with active cutaneous lesions of LE, including discoid LE, subacute cutaneous LE and acute cutaneous LE (malar rash) who were on stable doses of prednisone compared clofazimine 100 mg/day with chloroquine 250 mg/day for a period of 6 months. Twenty-seven patients completed the trial, including 11 treated with clofazimine and 16 treated with chloroquine. The reasons for dropping out of the study appear to be related to the activity of the systemic component of LE. A good response occurred in 75.0% of the clofazimine group and 82.4% of the chloroquine group. Complete response occurred in 18.8% and 41.2%, respectively. There were too few patients for the authors to note differential response between subsets of cutaneous LE. Drug-related toxicity was mild and in the clofazimine group consisted of a red-brown discolouration in six of the patients and xerosis in ve patients. Gastrointestinal toxicity occurred in roughly the same proportion of patients with either agent. The authors concluded that clofazimine and chloroquine were equally effective for cutaneous lesions of LE, but that clofazimine was poorer at preventing ares of systemic LE and should therefore be reserved for patients with exclusively cutaneous lesions in whom chloroquine was contraindicated.

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eruption presumed to be due to the auranon. She had been treated with the auranon for antimalarial-resistant SCLE, and the dose had been raised when the eruption occurred. Cessation of the drug led to a resolution of the eruption and control of her SCLE was achieved with aggressive sunprotection measures and chloroquine.

Thalidomide
Thalidomide has recently become more available in the USA, but is still restricted. Medical practitioners, pharmacies and patients all have to register with the companys pregnancy prevention programme and each prescription is limited to no more than a 1-month supply. Thalidomide is being used for patients with cutaneous LE with some regularity in the USA and Europe. Its mechanism of action is believed to involve decrease in inammatory mediators, particularly TNF- and Fas-ligand. It has been recently demonstrated in a murine system that thalidomide inhibits UVB-induced keratinocytes apoptosis. 92 These observations were extended to humans in a study of photoprotective effects of thalidomide.93 Open-label trials suggest that it is highly effective94 and may result in an increase in the lymphocyte count and a decrease in the C-reactive protein level. I usually begin therapy with a conservative dosing schedule of 50 mg nightly, but others have reported that with an initial dose of 100300 mg nightly, 90% of patients who are able to tolerate the drug will improve. As my patients have responded I lower the dose to the lowest effective dose, often 50 mg two or three nights per week is sufcient to maintain control of the patients lesions. Toxicity commonly associated with thalidomide use includes drowsiness, headache, weight gain, amenorrhoea and dizziness. Drowsiness and dizziness may persist during the following day. Neuropathy, usually sensory, may limit the ability of patients to continue thalidomide on a long-term basis. The risk of neuropathy is dose-dependent and it appears that doses of less than 25 mg per day are rarely, if ever, associated with the development of neuropathy.95 Neuropathy may be reversible, but there are patients whose neuropathy has progressed despite stopping the drug. Whether nerve conduction studies should be performed at the onset of therapy and periodically is not known. Thalidomide is a potent teratogen and accordingly the company has developed a programme to prevent the chance of pregnancy in patients exposed to the drug. The programme requires that the prescribing doctor and the pharmacy be registered with the company and that the patient take extra precautions in taking the drug. No more than a 1-month supply may be written for at any one time. Unfortunately the response to thalidomide is not durable in most patients; therefore long-term, low-dose maintenance therapy may be necessary. Thalidomide has been associated with an increased potential for thromboses and, therefore, it is probably useful to assess patients for a history of venous or arterial hypercoagulability prior to initiating therapy and in addition the thalidomide-treated patient should probably be maintained on an antimalarial agent upon initiation of therapy.96 Ovarian failure is possible following thalidomide therapy.96
2006 The Australasian College of Dermatologists

Oral gold
Auranon, an oral form of gold, has been used for cutaneous LE.91 Complete remission occurs in a minority of patients, about 15%, whereas a partial response has been noted in about two-thirds of those treated. My personal experience has been encouraging in a small number of patients. Auranon is begun at a dose of 3 mg per day and after 1 week the dose may be raised to twice daily if the patient experiences no problem with nausea, diarrhoea or headache. I have treated patients with as high as 3 mg three times per day without difculty. Monitoring with regular complete blood counts and urinalysis is suggested. Responsiveness may be best in patients with non-scarring forms of cutaneous LE. I have seen one patient with a lichenoid drug

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JP Callen The use of cytokine therapy has been reported. I predict that there will be additional reports of newer agents that are available and are just beginning to be tested for some dermatological indications, as well as others that are not currently on the market. As thalidomide may be effective through its effects on TNF-, it might be possible that iniximab, adalimumab or etanercept 109 might also prove to be of benet to patients with cutaneous LE. However, these agents have been associated with the development of druginduced SLE and SCLE in rare individuals and, therefore, I have been unwilling to use them until large case series or randomized controlled studies demonstrate their safety and effectiveness. Alefacept causes apoptosis of activated Tcells and efalizumab alters the ability of T-cells to migrate into inammatory diseases. Both of these agents are FDAapproved for psoriasis and their use might be of benet for patients with cutaneous LE by altering the inammatory reaction; however, thus far neither agent has been reported to be effective. Recently interest in the use of rituximab (FDA-approved for B-cell lymphoma) has been used for treatment of rheumatoid arthritis and systemic LE. However, it appears that the pathogenesis of cutaneous LE is different than SLE and the use of this agent may or may not affect cutaneous lesions. Interferon- has been used successfully;110 however, all patients on this regimen develop toxicity and long-term remission is rarely achieved. In addition, there are reports of induction or exacerbation of SLE in patients treated with interferon- (see earlier). Chimeric CD4 monoclonal antibody infusions for ve patients with severe, refractory cutaneous LE and long-lasting improvement was noted, with a restoration of responsiveness to conventional treatments.111 If other cytokines can be administered and result in the restoration of response to less toxic therapy, then perhaps we will be able to induce remission with one agent and maintain it with another.

Phenytoin
Phenytoin was studied in 93 patients with cutaneous LE and excellent results in 90% were observed. 97 Oral phenytoin 300 mg per day was prescribed to their patients for up to 6 months. Relapse occurred in at least one-third of the patients in whom follow-up data were available, but prolonged remission of 612 months was noted in 33 patients. Toxicity was minimal in prevalence and severity, although there have been reports of drug-induced lupus due to phenytoin in the past. There have been no further reports of the use of this agent and I have not personally used it.

Retinoids
Oral retinoids are effective in many patients who have failed previous less toxic therapies. Isotretinoin and acitretin have both been used in doses similar to those used for acne vulgaris or psoriasis, respectively.98 The response is not durable and after short courses the patient will still need further suppressive therapy. These agents are particularly helpful in patients with hypertrophic lesions, or those with lesions on the palms/soles. The usual form of monitoring for these agents includes careful assessment of potential for pregnancy and pregnancy prevention programmes. In addition, each of these drugs is associated with possible hepatotoxcity, hyperlipidaemia, depression and pseudotumour cerebri. Therefore, patients are regularly assessed with hepatic function tests, lipid proles and a careful review of systems.

Immunosuppressive and cytotoxic agents

Several cytotoxic agents have been reported to be benecial for the control of cutaneous LE lesions. Azathioprine has perhaps had the greatest number of reports, 99 but methotrexate100,101 and mycophenolate mofetil102 have also been reported to benet patients with recalcitrant disease. A recent study of methotrexate demonstrated a high degree of efcacy with 42 of 43 patients responding, and limited toxicity that was quickly reversible upon cessation of the therapy. Doses of methotrexate varied between 15 and 25 mg/week. In addition to its effects on skin disease, these authors also noted improvement in accompanying lymphopenia.102 Continued therapy is required to maintain the remission. Small case series, or individual reports have suggested that cytarabine, cyclophosphamide and cyclosporin may be effective.103105

CONCLUSION
In summary, patients should be treated with sunscreens, protective clothing, behavioural alteration, topical corticosteroids, intralesional corticosteroids and oral antimalarials as standard therapy. Attempts to reduce or stop smoking may aid in the control of cutaneous LE. The choice of alternative therapy is personal and discussions of the risks and benets should be carefully documented. Successful therapy for cutaneous LE is possible in almost all wellmotivated, cooperative patients.

ACKNOWLEDGEMENT
I am grateful to Dr Cassis for the preparation of Table 3.

Biological agents
High-dose intravenous immune globulin has been used in 14 patients.106108 One gram/kg/day for two consecutive days monthly was administered to these patients who had failed multiple previous therapies. There was an excellent result in seven of 14 patients, and a partial response in ve others but response is short-lived. Toxicity is minimal, but one patient developed a small vessel vasculitis.
2006 The Australasian College of Dermatologists

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