Subacute cutaneous lupus erythematosus

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[level-membership-for-dermatology-category]

Subacute cutaneous lupus erythematosus

Jeffrey P. Callen and Courtney R. Schadt

Evidence Levels:  A Double-blind study  B Clinical trial ≥ 20 subjects  C Clinical trial < 20 subjects  D Series ≥ 5 subjects  E Anecdotal case reports

image

Subacute cutaneous lupus erythematosus (SCLE) is a non-scarring, non-atrophic variant of lupus erythematosus (LE) that was first distinguished from other cutaneous variants in 1979. At least half of the patients with SCLE have or develop four or more of the features that allow classification as systemic LE using the criteria of the American College of Rheumatology. In general, however, their prognosis is better than that of unselected patients with systemic LE and these patients have less likelihood of having renal or neurologic disease (Black, D.R., et al, 2002. Arch Dermatol 138 (9),1175–1178).

Management strategy

Therapy of cutaneous lesions in patients with LE involves both an empiric and a scientific approach. Unfortunately, there are few double-blind, placebo-controlled trials of drugs used in the treatment of cutaneous LE.

The goals of management of SCLE are to improve the patient’s appearance, relieve the symptomatology, and prevent the development of dyspigmentation. Cosmetic problems are often of major importance to the patient with cutaneous LE. Dyspigmentation may follow SCLE, and may be effectively hidden by agents such as Covermark™ or Dermablend™.

Once a diagnosis of subcutaneous LE has been made, management must involve sun avoidance and sun protection, and elimination of medications that might be responsible for the skin lesions. Treatment with the most benign drugs possible should be stressed. Topical corticosteroids and oral antimalarials are the most commonly prescribed medications. Although systemic corticosteroids may be highly effective, attempts should be made to reduce their dosage and use other medications in their place to avoid corticosteroid-associated side effects.

Specific investigations

The cornerstone of the management of SCLE is correct diagnosis and thorough evaluation. The patient should have a careful history, physical examination, and laboratory studies directed at uncovering systemic manifestations that might occur in LE. The risk of serious systemic involvement (renal, central nervous system, or cardiopulmonary involvement) in patients with SCLE is probably around 10%, though many patients with SCLE – more than 50% – have sufficient criteria to classify them as having systemic lupus erythematosus (SLE).

Subacute cutaneous lupus erythematosus and its association to drugs: a population-based matched case-control study of 234 patients in Sweden.

Grönhagen CM, Fored CM, Linder M, Granath F, Nyberg F. Br J Dermatol 2012; 167: 296–305.

This study is a first in which population-based data for diagnosis of cutaneous LE were compared with a national database on prescription drug use. In this study, the authors linked SCLE to terbinafine (OR [odds ratio]=38.5, 95% CI 6.6–∞), tumor necrosis factor-α (TNF-α) inhibitors (OR=8.0, 95% CI 1.6–37.2), antiepileptics (OR=3.4, 95% CI 1.9–5.8) and proton pump inhibitors (OR=2.9, 95% CI 2.0–4.0). They did not find a significant OR for thiazides, or other antihypertensive agents, which they speculated might be due to a longer latency between the time of prescription and the onset of disease.

A complete list of the patient’s medications will assist in the exclusion of drug-induced cutaneous LE. Drugs that have been linked as causes of SCLE primarily include antihypertensive agents such as hydrochlorothiazide, calcium channel blockers, statins, proton pump inhibitors, terbinafine, tumor necrosis factor-α antagonists, and angiotensin-converting enzyme inhibitors. Because of the growing list of agents linked to SCLE development or exacerbation, any newly introduced drug should be considered as a possible trigger.

First-line therapies

image Cosmetics E
image Sunscreens and protective clothing C
image Corticosteroids E
image Antimalarials B
image Topical retinoids E
image Topical tacrolimus or pimecrolimus B

Intralesional triamcinolone is effective for discoid lupus erythematosus of the palms and soles.

Callen JP. J Rheumatol 1985; 12: 630–3.

Intralesional injections of corticosteroids are often effective in patients with lesions that are refractory to topical corticosteroids. 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. Alternative agents for intralesional injection have not been well tested.

The association of the two antimalarials chloroquine and quinacrine for treatment-resistent chronic and subacute cutaneous lupus erythematosus.

Feldmann R, Salomon D, Saurat JH. Dermatology 1994; 189: 425–7.

The first-line therapy is the use of an antimalarial drug. The antimalarial preferred by the authors is hydroxychloroquine sulfate (Plaquenil). This drug is used in doses of 200 mg orally once or twice daily, or in a dose of less than 6.5 mg/kg daily. The onset of action of the antimalarial agents is roughly 4 to 8 weeks, and for this reason some physicians have advocated higher initial loading doses. Hydroxychloroquine is also of benefit for the joint symptoms and malaise that may accompany SCLE. Hydroxychloroquine is less toxic, but also less effective than chloroquine phosphate (Aralen), which is used in doses of 250–500 mg daily. Thus patients who fail to respond fully to hydroxychloroquine may be switched to chloroquine, but the two should not be used together because of the concern that ophthalmologic toxicity may be enhanced. Another antimalarial, quinacrine hydrochloride (Atabrine), may add benefit to either hydroxychloroquine or chloroquine, and is not associated with ophthalmologic toxicity. This agent is not readily available, but several compounding pharmacies in the USA have it.

Hydroxychloroquine sulfate treatment is associated with later onset of systemic lupus erythematosus.

James JA, Kim-Howard XR, Bruner BF, Jonsson MK, McClain MT, Arbuckle MR, et al. Lupus 2007; 16: 401–9.

This is a retrospective analysis of a prior cohort of 130 US military personnel who later met ACR criteria for classification of SLE. Patients treated with hydroxychloroquine prior to a diagnosis of SLE had a significantly longer time between the onset of the first clinical symptom (often cutaneous disease) and the development of SLE criteria (median: 1.08 vs 0.29 years). Patients treated with prednisone before diagnosis also more slowly satisfied the classification criteria. The difference in median times between patients who received NSAIDs before diagnosis, as opposed to those who did not, was not statistically different. Patients treated with hydroxychloroquine also had a lower rate of autoantibody accumulation and fewer autoantibody specificities both at and after diagnosis. These findings suggest that early hydroxychloroquine use is associated with delayed onset of SLE.

This is an important observation by which dermatologists might justify the use of antimalarials early in the course of disease, even for localized lesions.

Second-line therapies

image Dapsone E
image Gold B
image Thalidomide B
image Retinoids C
image Immunosuppressive agents: methotrexate, azathioprine, mycophenolate mofetil C

Long-term thalidomide use in refractory cutaneous lesions of lupus erythematosus: a series of 65 Brazilian patients.

Coelho A, Souto MI, Cardoso CR, Salgado DR, Schmal TR, Waddington Cruz M, et al. Lupus 2005; 14: 434–9.

Sixty-three patients (98.9%) presented complete or partial improvement with thalidomide therapy. Drowsiness occurred in 50 patients (77%). Twenty-eight (43.2%) presented with neuropathy symptoms. Nerve conduction studies were done in 21 (75%) of them and were abnormal in 12 (57%). With the interruption of thalidomide, 24 (82.5%) had complete or partial improvement of neuropathy symptoms and 23 (82%) had cutaneous relapse. There were no significant differences in treatment duration, age, total dose, and systemic versus cutaneous LE between those who did or did not develop neuropathy.

Thalidomide in cutaneous lupus erythematosus.

Pelle MT, Werth VP. Am J Clin Dermatol 2003; 4: 379–87.

This is an excellent compilation of reports of the use of thalidomide for cutaneous lupus erythematosus.

Thalidomide has recently become more available and is being used with some regularity for patients with cutaneous LE. Its mechanism of action is believed to involve a reduction in inflammatory mediators, particularly TNF-α and Fas ligand. Open-label trials suggest that it is highly effective, and may result in an increase in the lymphocyte count and a reduction in C-reactive protein level. Induction with 100–300 mg daily at bedtime results in improvement in 90% of patients who are able to tolerate the drug. Toxicity commonly associated with thalidomide use includes drowsiness, headache, weight gain, amenorrhea, 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. 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, but in their recent summary paper Pelle and Werth suggest this study at baseline and every 6 months while on therapy. The author chooses not to perform nerve conduction studies unless symptoms develop.

Thalidomide is a potent teratogen, and accordingly the company has developed a program to prevent the chance of pregnancy in patients exposed to the drug. This requires that the prescribing physician and the pharmacy be registered with the company, and that the patient use extra precautions in taking the drug. No more than a 1-month supply may be prescribed 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.

Mechanism-oriented assessment of isotretinoin in chronic or subacute cutaneous lupus erythematosus.

Newton RC, Jorizzo JL, Solomon AR, Sanchez RL, Daniels JC, Bell JD, et al. Arch Dermatol 1986; 122: 180–6.

Eight of 10 patients with cutaneous LE had an excellent response to oral isotretinoin 80 mg daily for 16 weeks.

Oral retinoids are effective in many patients who have failed to respond to previous less toxic therapies. Isotretinoin and acitretin (formerly etretinate was used) have both been used in doses similar to those used for acne vulgaris or psoriasis, respectively. 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 of chronic cutaneous LE. Experience in SCLE is limited.

Mycophenolate sodium for subacute cutaneous lupus erythematosus resistant to standard therapy.

Kreuter A, Tomi NS, Weiner SM, Huger M, Altmeyer P, Gambichler T. Br J Dermatol 2007; 156: 1321–7.

This was a prospective, non-randomized, open-label pilot study to evaluate the efficacy of mycophenolate sodium monotherapy in patients with recalcitrant subacute SCLE. Monotherapy with oral enteric-coated mycophenolate sodium 1440 mg daily was given for a total of 3 months. Treatment outcome was evaluated by means of the Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI). Assessment included the monitoring of adverse effects and clinical laboratory parameters. Ten patients with active SCLE resistant to at least one standard therapy were included in the trial. Mycophenolate sodium led to a remarkable improvement of skin lesions, resulting in a significant reduction in the mean CLASI from the beginning to the end of therapy. Clinical improvement was confirmed by ultrasonographic assessments and colorimetry. No serious side effects were noted.

This report used measures of response that are validated. In addition, photodocumentation was provided for two patients and is convincing. A double-blind, placebo-controlled trial needs to be performed.

The author has patients who have seemed to have some response to MMF, but ability to manage patients with this agent as a sole therapy is mixed, just as the reports in the literature suggest.

Efficacy and safety of methotrexate in recalcitrant cutaneous lupus erythematosus: results of a retrospective study in 43 patients.

Wenzel J, Brähler S, Bauer R, Bieber T, Tüting T. Br J Dermatol 2005; 153: 157–762.

Among 139 patients with cutaneous LE seen between 2001 and 2003, 43 were treated with low-dose methotrexate. This led to a highly significant (p<0.01) decline in disease activity. An improvement of the cutaneous lesions was recorded in nearly all patients treated with MTX (42 of 43; 98%). Severe side effects necessitating discontinuation of treatment were recorded in seven patients (16%), which quickly resolved when MTX was discontinued. Life-threatening complications were not observed. Intravenous administration was better tolerated than the oral route. Interestingly, they observed a significant increase in circulating lymphocyte numbers in patients with lymphocytopenia prior to MTX treatment.

This is a large number of patients with excellent improvement. This agent has not been as successful in the patients the author has treated.

Third-line therapies

image Clofazimine A
image Phenytoin B
image High-dose intravenous immunoglobulin C
image Cytokine therapy D
image Rituximab E
image Ustekinumab E
image Leflunomide E

Double-blind, randomized, controlled clinical trial of clofazimine compared with chloroquine in patients with systemic lupus erythematosus.

Bezerra EL, Vilar MJ, da Trindade Neto PB, Sato EI. Arthritis Rheum 2005; 52: 3073–8.

This is a randomized controlled trial comparing clofazimine to chloroquine. Twenty-seven of 33 patients who were randomized completed 6 months of treatment. The groups were homogeneous and comparable in terms of demographic and clinical characteristics. Five CFZ-treated patients and one CDP-treated patient (p=0.15) dropped out because of the development of severe lupus flare. At the end of the study, 12 CFZ-treated patients (75%) and 14 CDP-treated patients (82.4%) had complete or near-complete remission of skin lesions; intention-to-treat analysis showed no significant difference in the response rates between groups. Side effects, mainly skin and gastrointestinal events, were frequent in both groups, but no patients had to discontinue their treatment.

In the author’s opinion, careful analysis of this report does not justify the conclusion rendered above. More patients treated with clofazimine had LE flares, and the responses were not comparable. In addition, the numbers of patients is quite small. The results of this study do not warrant the use of clofazimine.

Intravenous immunoglobulin (IVIg) for therapy-resistant cutaneous lupus erythematosus.

Goodfield M, Davison K, Bowden K. J Dermatol Treat 2004; 15: 46–50.

This is an open-label study of 12 patients with various forms of cutaneous LE, all of whom had SLE. Three of the patients had SCLE. Of the 10 evaluable patients, five had excellent responses, two had partial responses, and three had limited or no responses. One patient developed an acute cutaneous vasculitis; otherwise, there were no significant adverse reactions.

High-dose intravenous immuneglobulin has been used successfully; 1 g/kg daily for 2 consecutive days monthly was administered to these patients who had failed to respond to multiple previous therapies. Although there might be an excellent response in some patients, the response is often short-lived. Toxicity is minimal, but this therapy is extremely expensive.

Regression of subacute cutaneous lupus erythematosus in a patient with rheumatoid arthritis treated with a biologic tumor necrosis factor alpha-blocking agent: comment on the article by Pisetsky and the letter from Aringer et al.

Fautrel B, Foltz V, Frances C, Bourgeois P, Rozenberg S. Arthritis Rheum 2002; 46: 1408–9.

This is a single case report. There have been multiple reports linking TNF-α antagonists to the development of cutaneous as well as systemic LE.

There are many new biologic agents that might prove to be useful for cutaneous LE. Caution should be used with the TNF antagonists, however, because, although an individual case of benefit has been reported, there are many patients in whom these drugs have resulted in development of the disease. Properly conducted observational studies followed by placebo-controlled trials will be helpful.

[/level-membership-for-dermatology-category][not-level-membership-for-dermatology-category]

Subacute cutaneous lupus erythematosus

Jeffrey P. Callen and Courtney R. Schadt

Evidence Levels:  A Double-blind study  B Clinical trial ≥ 20 subjects  C Clinical trial < 20 subjects  D Series ≥ 5 subjects  E Anecdotal case reports

image

Subacute cutaneous lupus erythematosus (SCLE) is a non-scarring, non-atrophic variant of lupus erythematosus (LE) that was first distinguished from other cutaneous variants in 1979. At least half of the patients with SCLE have or develop four or more of the features that allow classification as systemic LE using the criteria of the American College of Rheumatology. In general, however, their prognosis is better than that of unselected patients with systemic LE and these patients have less likelihood of having renal or neurologic disease (Black, D.R., et al, 2002. Arch Dermatol 138 (9),1175–1178).

Management strategy

Therapy of cutaneous lesions in patients with LE involves both an empiric and a scientific approach. Unfortunately, there are few double-blind, placebo-controlled trials of drugs used in the treatment of cutaneous LE.

The goals of management of SCLE are to improve the patient’s appearance, relieve the symptomatology, and prevent the development of dyspigmentation. Cosmetic problems are often of major importance to the patient with cutaneous LE. Dyspigmentation may follow SCLE, and may be effectively hidden by agents such as Covermark™ or Dermablend™.

Once a diagnosis of subcutaneous LE has been made, management must involve sun avoidance and sun protection, and elimination of medications that might be responsible for the skin lesions. Treatment with the most benign drugs possible should be stressed. Topical corticosteroids and oral antimalarials are the most commonly prescribed medications. Although systemic corticosteroids may be highly effective, attempts should be made to reduce their dosage and use other medications in their place to avoid corticosteroid-associated side effects.

Specific investigations

The cornerstone of the management of SCLE is correct diagnosis and thorough evaluation. The patient should have a careful history, physical examination, and laboratory studies directed at uncovering systemic manifestations that might occur in LE. The risk of serious systemic involvement (renal, central nervous system, or cardiopulmonary involvement) in patients with SCLE is probably around 10%, though many patients with SCLE – more than 50% – have sufficient criteria to classify them as having systemic lupus erythematosus (SLE).

Subacute cutaneous lupus erythematosus and its association to drugs: a population-based matched case-control study of 234 patients in Sweden.

Grönhagen CM, Fored CM, Linder M, Granath F, Nyberg F. Br J Dermatol 2012; 167: 296–305.

This study is a first in which population-based data for diagnosis of cutaneous LE were compared with a national database on prescription drug use. In this study, the authors linked SCLE to terbinafine (OR [odds ratio]=38.5, 95% CI 6.6–∞), tumor necrosis factor-α (TNF-α) inhibitors (OR=8.0, 95% CI 1.6–37.2), antiepileptics (OR=3.4, 95% CI 1.9–5.8) and proton pump inhibitors (OR=2.9, 95% CI 2.0–4.0). They did not find a significant OR for thiazides, or other antihypertensive agents, which they speculated might be due to a longer latency between the time of prescription and the onset of disease.

A complete list of the patient’s medications will assist in the exclusion of drug-induced cutaneous LE. Drugs that have been linked as causes of SCLE primarily include antihypertensive agents such as hydrochlorothiazide, calcium channel blockers, statins, proton pump inhibitors, terbinafine, tumor necrosis factor-α antagonists, and angiotensin-converting enzyme inhibitors. Because of the growing list of agents linked to SCLE development or exacerbation, any newly introduced drug should be considered as a possible trigger.

First-line therapies

image Cosmetics E
image Sunscreens and protective clothing C
image Corticosteroids E
image Antimalarials B
image Topical retinoids E
image Topical tacrolimus or pimecrolimus B

Intralesional triamcinolone is effective for discoid lupus erythematosus of the palms and soles.

Callen JP. J Rheumatol 1985; 12: 630–3.

Intralesional injections of corticosteroids are often effective in patients with lesions that are refractory to topical corticosteroids. 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. Alternative agents for intralesional injection have not been well tested.