1 Rheumatology Department and2 Dermatology Department, University Hospital of Rouen, 3 Inserm U519, Rouen, 4 Rheumatology Department, University Hospital of Nantes, Nantes and5 Dermatology Department, Hospital of Noirmoutier, Noirmoutier, France
Correspondence to: V. Goëb, Service de Rhumatologie, Centre Hospitalier Universitaire de Rouen, 76031 Rouen Cedex, France. E-mail: goebvince{at}yahoo.fr
SIR, Leflunomide is a disease-modifying anti-rheumatic drug (DMARD). It is effective in monotherapy and/or in combination with TNF- blockers in the treatment of RA. Leflunomide inhibits pyrimidine metabolic pathways in lymphocytes and other rapidly proliferating cells. Its active metabolite, A771726, inhibits dihydroorotate dehydrogenase, a key enzyme of de novo pyrimidine synthesis.
Variable leflunomide-related adverse events have been reported. Diarrhoea is the most frequent one. It usually occurs within the first 3 months of treatment and resolves in most cases after symptomatic treatment or after decreasing the leflunomide dose [1]. Pancytopenia [2] and liver dysfunction with elevated serum levels of transaminases [3] have also been described, necessitating the monitoring of blood cell count and liver function.
Adverse cutaneous reactions due to leflunomide have also been reported, including alopecia and skin ulceration [4]. A case of leflunomide-induced subacute cutaneous lupus erythematosus (SCLE) has been reported [5]. Here we report two other cases of SCLE occurring in RA patients treated with leflunomide.
Patient 1 was a 59-yr-old woman who had had RA since 1987, with progressive joint destruction despite successive treatments with gold salts, sulphasalazine and methotrexate (MTX). MTX was subsequently combined with infliximab in September 2000. In January 2002, MTX and infliximab were stopped because of persistent active RA. The patient was then treated with leflunomide (20 mg daily after a 100 mg daily loading dose for the first 3 days) associated with prednisone (5 mg daily), ketoprofen and tramadol. In December 2002, the patient presented an annular eruption on the back, neck and face suggestive of SCLE (Fig. 1). Neither arthritis nor other systemic involvement was observed. A blood test showed an inflammatory state (ESR 84 mm in 1st h, CRP 121 mg/l), antinuclear antibodies (ANA) 1/1000 with homogeneous fluorescence, and anti-Ro antibodies 43 UI/ml (n<30). Anti-double-stranded DNA antibodies were negative. Histological examination of a skin biopsy demonstrated vacuolar degeneration of basal keratinocytes with sparse keratinocyte necrosis and a perivascular inflammatory infiltrate of lymphocytes in the superficial dermis. Direct immunofluorescence showed IgM and C3 deposits along the dermalepidermal junction. Leflunomide was stopped without washout procedure. The patient was treated for 1 month with topical corticosteroids. Cutaneous eruption totally cleared within 3 weeks and anti-Ro antibodies reverted to normal (21 UI/ml in December 2004).
|
Clinical, biological and immunohistological features of the two patients were suggestive of SCLE. These two patients with leflunomide-induced SCLE had no history of cutaneous eruption or clinical features of lupus erythematosus. These two cases of SCLE were most likely due to leflunomide since the eruption completely cleared after stopping leflunomide while other concomitant drugs were continued. In both cases, leflunomide was used as monotherapy without combination with MTX or biological agents. These two cases are reminiscent of a previous similar observation reported by Kerr et al. [5]. SCLE appeared 6 weeks after the introduction of leflunomide. Biological abnormalities were detectable as Ro (>100 µ/ml) and antihistone antibodies. Histological examination of a biopsy of the rash showed marked basal cell liquefaction and a moderate dermal perivascular chronic infiltrate. Direct immunofluorescence revealed IgG in the papillary dermis. Cutaneous features completely healed 5 months after stopping the drug.
Clinicians should be aware of this rare side effect of leflunomide since it requires stoppage of the drug and may thus interfere with the treatment of RA. Leflunomide may now be listed among gold salts and sulphasalazine [6] as DMARDs that could potentially induce cutaneous lupus.
|
X.L.L. has worked as a consultant for Aventis. The other authors have declared no conflicts of interest.
References
|