Etanercept‐induced subacute cutaneous lupus erythematosus

Sir, Etanercept (Enbrel®) is a human tumour necrosis factor (TNF) receptor p75 Fc fusion protein which is used for the treatment of active rheumatoid arthritis if the response to disease‐modifying anti‐rheumatic drugs has proved insufficient. TNF is the product of macrophages and exerts powerful effects on the immune system, including the induction of proinflammatory mediators (e.g. interleukin‐1, nitric oxide and prostaglandins), metalloproteinases and adhesion molecules [1]. Etanercept acts as a competitive inhibitor of TNF and prevents binding of TNF to the cell surface TNF‐R, thereby reducing the biological activity of TNF [2]. Adverse effects are usually limited to injection‐site reactions and upper respiratory tract reactions [2–5]. Recently, the European Agency for the Evaluation of Medicinal Products issued a statement regarding serious blood dyscrasias associated with etanercept [6]. Formation of antibodies to double‐stranded DNA (dsDNA) has been noted in patients treated with etanercept, but lupus‐like syndrome is not mentioned in the product information. We report on a 54‐yr‐old female who developed subacute cutaneous lupus erythematosus (SCLE) during treatment with etanercept. A 54‐yr‐old woman received etanercept 25 mg subcutaneously twice a week since 7 September 1999 for the treatment of active seropositive nodular rheumatoid arthritis. Other medications included methotrexate 15 mg intramuscularly per week, prednisolone 2×5 mg, ibuprofen 2×400 mg, omeprazole 1×40 mg, alfacalcidol 2×0.25 μg, folic acid 1×0.5 mg, calcium carbonate/calcium lactogluconate 1×500 mg, losartan 2×50 mg, amitriptyline 1×25 mg, and paracetamol 4×500 mg. She responded well to etanercept therapy. In December 1999, she presented with annular polycyclic erythematosquamous lesions mainly located on the back and front of the trunk, and some solitary lesions on the upper arms and legs. She experienced an itching, burning feeling from these skin lesions, which were initially interpreted as compatible with seborrhoeal dermatitis. After topical treatment with a corticosteroid‐containing ointment, the skin rapidly cleared, but after discontinuation the lesions soon recurred (Fig. 1). Further examination of the skin revealed signs of periungual telangiectasia on the fingers. Biopsies for histology and direct immunofluorescence were taken from skin lesions on the trunk after the patient had abstained from local therapy for several weeks. Microscopic examination of the skin showed a thin horny layer with no follicular plugging and an epidermis with local liquefactive degeneration of the basal layer. Some colloid bodies were observed in the basal area of the epidermis. In the upper part of the dermis a perivascular mononuclear infiltrate was present. There were no signs of small vessel vasculitis. Direct immunofluorescence showed some granules of immunoglobulin (Ig)M and C3c alongside the epidermal–dermal conjunction. No deposits of IgG, IgA or C1q and C4 were observed. It was concluded that the morphology of the skin lesions and the periungual telangiectasia, together with the microscopy of the skin lesions, were suggestive of SCLE. The patient was treated with betamethasone cream. Laboratory tests showed a titre of anti‐dsDNA of 48 IU/ml (normally <10 IU/ml, Farr assay), C3 143 mg/dl (normal range 80–160 mg/dl), C4 19 mg/dl (normal range 15–40 mg/dl), CH50 117% (normal range 75–125%) and anti‐nuclear antibodies (ANA) 1:40 (normally <1:40); she was negative for extractable nuclear antibodies. At the time of her last follow‐up in May 2000, her rash had resolved; etanercept had not been discontinued. Clinically, SCLE has to be differentiated from chronic discoid lupus erythematosus (LE) and skin diseases with a psoriasiform or pityriasiform presentation. In our patient, the skin lesions were initially interpreted as compatible with seborrhoeal‐like dermatitis. The liquefactive degeneration of the basal cells seen in the microscopic examination of the skin, however, is not in accordance with the histology observed in seborrhoeal dermatitis. In contrast with skin lesions in chronic discoid LE, the skin lesions in this patient cleared without atrophy after topical treatment. The results of the immunohistology were inconclusive, possibly as a result of the long‐term immunosuppressive therapy with methotrexate and low‐dose prednisolone. In view of their close time relationship, it seems very plausible that the administration of etanercept was causally related to the onset of SCLE. None of the other drugs which our patient used has been associated with SCLE. Although anti‐dsDNA antibodies are not specific for SCLE [7], the rise in anti‐dsDNA titre in our patient may have contributed to the onset of SCLE. The fact that the rash resolved despite continuation of etanercept may be explained partly by the concomitant therapy with prednisolone and methotrexate. SCLE could also be a transient adverse effect of etanercept. Many drugs are known for their transient immunological adverse effects, including the formation of anti‐dsDNA antibodies [8, 9]. Although approximately 15% of patients treated with etanercept develop anti‐dsDNA antibodies and 11% develop ANA, lupus‐like syndromes have not been reported in the premarketing phase [4, 5, 10]. Recently, the history was described of a 78‐yr‐old patient with rheumatoid arthritis who developed acute discoid LE 4 days after her fourth injection of etanercept [11]. She had no history of skin rashes or other manifestations of lupus and was negative for antinuclear and anti‐dsDNA antibodies. The rash resolved after discontinuation of etanercept and initiation of corticosteroid treatment. Furthermore, the Dutch Inspectorate for Healthcare received three other reports of etanercept‐induced cutaneous LE (Table 1). In all three cases, the skin lesions resolved after discontinuing administration of etanercept and corticosteroid. These cases also support a potential causal relationship between the administration of etanercept and the onset of autoimmune skin disease. In conclusion, this case report suggests that, apart from the induction of autoantibodies, etanercept can cause SCLE. Etanercept‐induced SCLE appears to be highly responsive to local corticosteroid treatment, even without withdrawal of therapy. Skin lesions on the back of the patient. Reports of the Dutch Inspectorate for Healthcare ssDNA, single‐stranded DNA; SSA, antibodies to RO. aEnbrel. Reports of the Dutch Inspectorate for Healthcare ssDNA, single‐stranded DNA; SSA, antibodies to RO. aEnbrel. Correspondence to: B. H. Ch. Stricker, Drug Safety Unit, Inspectorate for Healthcare, PO Box 16119, 2500 BC The Hague, The Netherlands.