Leflunomide in subacute cutaneous lupus erythematosus – two sides of a coin

Authors

  • Anke Suess MD,

    1. From the Department of Dermatology, University of Leipzig, Leipzig, Germany, and Department of Dermatology, University of Erlangen, Erlangen, Germany
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  • Michael Sticherling Prof.

    1. From the Department of Dermatology, University of Leipzig, Leipzig, Germany, and Department of Dermatology, University of Erlangen, Erlangen, Germany
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Anke Suess, md Department of Dermatology Phillip-Rosenthal-Str. 23–25 University of Leipzig D-04103 Leipzig Germany
E-mail: anke.suess@medizin.uni-leipzig.de

Abstract

Background  Subacute cutaneous lupus erythematosus (SCLE), a distinct clinical subset of lupus erythematosus, remains a therapeutic challenge, especially in cases resistant to topical and standard systemic therapy. Leflunomide, a novel antirheumatic drug, has shown efficacy in the treatment of systemic lupus erythematosus in pilot studies.

Methods  We report two patients with SCLE who demonstrated the spectrum of possible clinical responses to leflunomide therapy.

Results  One patient experienced a complete clinical remission of symptoms, whereas the other developed a massive skin reaction which was distinctly related to the commencement of leflunomide therapy.

Conclusion  To our knowledge, this is the first time that remission and deterioration of SCLE by leflunomide therapy have been described.

Introduction

Subacute cutaneous lupus erythematosus (SCLE) is a subset of lupus erythematosus (LE), first described in 1979 by Sontheimer et al.,1 and clinically characterized by annular and/or psoriasiform lesions, photosensitivity, and frequently by anti-Ro (SSA) and anti-La (SSB) antibodies and milder systemic disease than in patients with systemic lupus erythematosus (SLE).2–4

The management of SCLE remains a challenge, especially in cases resistant to topical and standard systemic therapy.5

Recently published reports have indicated that the novel antirheumatic drug leflunomide is effective and safe in patients with SLE.6,7

In this paper, we report two patients with recalcitrant SCLE who were treated with leflunomide with contrasting results.

Case Reports

Case 1

A 78-year-old patient presented with acute-onset erythematosquamous lesions on the upper part of the body.

Since 1980, he had suffered from arthralgia, intermittently accompanied by joint swelling. This was diagnosed as rheumatoid arthritis (RA), and he was treated for several years with oral low-dose prednisolone. In 1998, the patient was diagnosed with incomplete SLE by a rheumatologist, fulfilling only part of the diagnostic criteria (polyarthralgia without erosive lesions, positive serologic tests for anti-DNS antibodies, low C3 and C4 complement), and was treated with azathioprine in combination with low-dose prednisolone; however, azathioprine had to be stopped because of exacerbated arthralgia and chills.

In 2001, symmetric and partially confluent, nonitching erythematosquamous papules and plaques appeared on the hairline, neck, shoulders, back, and chest (Fig. 1).

Figure 1.

Patient 1: nonitching erythematosquamous papules and plaques before leflunomide therapy

Standard laboratory investigations were normal, except for an increase in serum creatinine (128 µmol/L; normal, 45–105 µmol/L), erythrocyte sedimentation rate (ESR) (21 mm/h), and C-reactive protein (CRP) (12.8 mg/L; normal, < 5 mg/L). Rheumatic factor was negative. The antinuclear antibody (ANA) titer before therapy was 1 : 2560 (normal, < 1 : 80), Ro/SSA antibody ratio 3.6 (normal, < 1.0–1.4), and La/SSB antibody ratio 2.8 (normal, < 1.0–1.4). The creatinine clearance was decreased (44.8 mL/min; normal, 85–170 mL/min), but there was no significant proteinuria. Lung function tests revealed a reduced membrane function in combination with a low-grade obstruction and emphysema. Cardiologic, neurologic, ophthalmologic, and radiologic findings were normal. Immunohistochemical examinations revealed focal and granular deposits of immunoglobulin M (IgM) and C3c at the dermoepidermal junction in lesional and sun-exposed skin. In unaffected and sun-protected skin, linear deposits of IgA, IgG, and IgM, as well as intermittent granular deposits of C3c, were found at the dermoepidermal junction.

On the basis of all of these findings, SCLE was diagnosed.

In addition to his long-term oral prednisolone at 7 mg/day, treatment with leflunomide was started with 100 mg/day for 3 days, followed by 10 mg/day. After 3 months, the skin lesions and arthralgia had clearly improved. After 5 months of treatment, the patient was free of skin lesions and arthralgia. During the entire course, the treatment was well tolerated. A slight elevation of γ-glutamyl transferase (γ-GT) (1.31–1.88 µmol/L; normal, 0.13–1.02 µmol/L) was noticed after starting leflunomide, and returned to normal values after 1 year of therapy. ANA dropped to a titer of 1 : 640 after 1.5 years of therapy. Compared with baseline, the Ro/SSA antibody ratio increased slightly (4.5) and the La/SSB antibody ratio decreased to 1.8.

On clinical improvement, the leflunomide dose was slowly tapered and finally discontinued after a total course of 1.5 years. Skin lesions and arthralgia remained absent for up to 12 months after stopping leflunomide (Fig. 2).

Figure 2.

Patient 1: complete clinical remission 1 year after stopping leflunomide

Case 2

A 42-year-old woman presented with an acute deterioration of her skin disease after 3 months of arthritis treatment with leflunomide. RA had been diagnosed in 1989, and SCLE in 1999. The skin lesions were treated with topical glucocorticosteroids; however, different immunomodulatory drugs, such as gold, Metalcaptase, methotrexate, cyclosporin, and oral glucocorticosteroids, were ineffective, and the patient experienced deteriorating erosive arthritis. Consequently, in April 2000, leflunomide was initiated at 100 mg/day, and subsequently 20 mg/day, in addition to long-term oral prednisolone at 5 mg/day. Rapid improvement of arthritis was noticed in the first 3 months of treatment, until her skin symptoms massively deteriorated and she had to be referred to hospital.

The patient presented with generalized annular erythemata with hemorrhagic and partly bullous centres and wheal-like borders. The skin eruption was focused on the face (Fig. 3a), low neckline, back of the trunk, and the extensor surfaces of the extremities (Fig. 3b). In addition, multiple ulcerations and crusts were found on the oral and genital mucosa.

Figure 3.

Patient 2: erythematosquamous lesions after 3 months of leflunomide therapy

Laboratory investigations showed an elevated CRP (17 mg/L; normal, < 5 mg/L), a slightly increased ESR (14 mm/h), and a leukopenia of 2.5 × 109/L [normal, (4.0–9.0) × 109/L]. The ANA titer was distinctly elevated at 1 : 2560, with anti-Ro/SSA antibodies at 170 U/mL; however, these findings were unchanged to previous examinations. Complement factors C3 and C4 were decreased, as was complement activity (CH50).

In skin biopsies, focal vacuole degeneration in the basal cell layer, with scattered necrotic keratinocytes, was detected (Fig. 4a). Within the upper dermal plexus, perivascular lymphohistiocytic infiltrates, single neutrophilic granulocytes, and leukocytoclasia were found. Direct immunofluorescence examination exhibited focal fine to coarse granular deposits of immunoglobulin M (IgM) at the basement membrane zone (Fig. 4b).

Figure 4.

Patient 2. (a) Focal vacuole degeneration in the basal cell layer with scattered necrotic keratinocytes in affected skin (hematoxylin and eosin stain; magnification, ×40). (b) Focal fine to coarse granular deposits of immunoglobulin M (IgM) at the basement membrane zone in a skin biopsy (direct immunofluorescence; magnification, ×40)

Because of the close relationship between drug intake and the deterioration of skin disease, leflunomide was stopped and washed out with colestyramine. The skin and mucous membrane condition rapidly improved. At the same time, however, the arthralgia deteriorated, and treatment with intravenous methotrexate at 15 mg/week and oral hydroxychloroquine at 200 mg/day was initiated.

Discussion

The novel anti-inflammatory and immunomodulatory agent leflunomide has no structural or functional relation to any other known immunomodulatory drug.8 The inhibition of pyrimidine synthesis mainly affects the proliferation of B and T lymphocytes.9 Additional anti-inflammatory effects of leflunomide have been described, and include blocking of CD43-mediated T-lymphocyte aggregation in vitro.10

Common side-effects of leflunomide include elevation of liver enzymes and anemia.8,9 Exfoliative dermatitis has also been described.11

Leflunomide has been licensed for RA as well as psoriatic arthritis. Similar beneficial effects were seen in both of our patients. In retrospect, however, our patients’ relapsing arthritis may be regarded as part of SCLE rather than classical RA. Arthritis is described in up to 90% of SLE patients, whereas erosive arthritis is found in only 5%.12 In both of our patients, the arthritic symptoms improved significantly, which indicates that there is a different pathogenesis of joint and skin symptoms in lupus arthritis. Our first patient with SCLE was successfully treated with leflunomide for both arthralgia and skin manifestations. This is the first case of a patient with SCLE successfully treated with leflunomide at 10 mg/day, which is a low dose compared with those used in the treatment of RA. Our second patient, however, experienced a deterioration of her skin lesions in relation to the initiation of leflunomide. It is difficult to distinguish whether the skin lesions were caused by the drug itself – corresponding to a drug-induced skin eruption – or to a deterioration of SCLE by the drug.

The skin eruption was found at classical predilection sites of SCLE (face, low neckline, extensor surfaces of the arms), and thus indicated aggravation of the pre-existing skin disease; however, both histologic and immunohistologic symptoms were indicative of a drug-induced skin eruption of the erythema multiforme type.

Classical drug-induced SLE is characterized by systemic disease with a low incidence of nephritis, lack of cutaneous involvement, and the presence of antihistone antibodies. A limited number of drugs have been associated with this phenomenon.13 With regard to the serologic testing in our patient, with both negative antihistone and anti-ssDNA antibodies, as well as the clinical appearance, classical drug-induced antihistone LE sensu stricto seems unlikely. More recently, however, a new subset of drug-induced LE, characterized primarily by cutaneous disease and the presence of anti-Ro/SSA antibodies, has been described,14 which could apply to our patient.

To our knowledge, this is the first report of a deterioration of pre-existing SCLE in association with leflunomide treatment; however, five cases of new-onset SCLE associated with leflunomide therapy have been described.15–18 Although these patients received leflunomide for severe arthritis and none had a history of SCLE, in two of the cases, as in our patient, anti-Ro antibodies were present before leflunomide was initiated, whereas, in the other patients, they had not been found previously. In four of the five patients, anti-Ro antibodies were detected at the time of occurrence of the skin eruption.

Patients in whom SCLE lesions precipitate or deteriorate after the initiation of leflunomide may represent a subset with a pre-existing autoimmune diathesis. With regard to the five other cases described in the literature, this subset of patients is characterized by severe arthritis and the presence of anti-Ro/SSA antibodies. This should be taken into account when prescribing this novel drug. Nevertheless, based on the therapeutically successful case, further investigations and controlled trials of the treatment of SCLE with leflunomide should be performed. This new treatment option could be of particular benefit for those patients in whom standard therapies with corticosteroids, antimalarials, and other immunosuppressive drugs are contraindicated or of limited clinical effect.

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