Stevens-Johnson syndrome-like exanthema secondary to methotrexate histologically simulating acute graft-versus-host disease

ARTICLE

In 1951 MTX was introduced for the therapy of severe psoriasis vulgaris. MTX is an antimetabolite which competitively inhibits dihydrofolatereductase, and thus the synthesis of purines and thymidine acid [1]. Its major effect on the cell cycle is a potentially reversible inhibition of proliferation in the late G1-phase and lethal cytotoxity in the S-phase. The antipsoriatic effect is based on its antiproliferative, anti-inflammatory and possibly immunosuppressive properties. MTX is recommended in severe cases of psoriasis vulgaris, or psoriasis with peripheral joint disease. Due to its spectrum of side effects, regular clinical and laboratory follow up is necessary. Furthermore pharmacological interactions with diuretics and non-steroidal anti-inflammatory agents (NSAIDS) like acetylic salicylic acid (ASA), are a problem [2, 3]. The treatment of psoriasis with methotrexate (MTX) may cause skin reactions such as urticaria, exanthemata, ulcers and even lead to toxic epidermal necrolysis [2]. However, skin lesions resembling Stevens-Johnson-syndrome imitating a graft-versus-host reaction histologically have not been reported so far.

Case report

For treatment of severe psoriasis vulgaris the 61 year old male patient initially took an unusually high dose of MTX (10 mg/day), because he misinterpreted the dose instructions of his dermatologist. After three months therapy was interrupted because of oral mucosal ulceration. Following a myocardial infarction the patient had started an angiotensin-converting-enzyme (ACE)-inhibitor (2.5 mg Lisinopril per day) and reinfarct prophylaxis in the form of 100 mg ASA per day. He also received 10 mg of levostatin for treatment of his concomitant hypercholesterolaemia. Because of worsening psoriasis, MTX therapy was reinstituted one month later at a dosage of 20 mg/week. Three days after the first dose very painful ulceration of the oral mucosa occurred, together with widely scattered burning skin lesions. The patient was referred to our hospital with a presumed diagnosis of Stevens-Johnson syndrome; as possible trigger the ACE-inhibitor or levostatin was considered.

Clinical examination revealed an erythema multiforme-like exanthema with dark brown to purple lesions similar to target lesions on the back, trunk and proximal inner legs (Fig. 1 a, b) and multiple buccal ulcerations. Laboratory investigation revealed pancytopenia, with a leucopenia of 2.4 x 10⁹/l leucocytes, thrombocytopenia at 51 x 10⁹/l, which decreased during the following days to 10 x 10⁹/l, and anaemia at a haemoglobin of 11.1 g/l. The MTX administration was stopped and calcium folinate at a dosage of 7.5 mg four times a day for 24 days was given. The ACE-inhibitor and the lipid lowering agent, both of which could have caused a Stevens-Johnson reaction, were replaced. Systemic high dose steroid therapy was started at a daily dosage of 80 mg prednisolone (1 mg/kg body weight) and reduced to a maintenance dose of 20 mg per day after four weeks. After symptomatic therapy with thrombocyte concentrates, the platelet count normalized. At discharge all haematological parameters were normal. Oral and skin lesions were treated with local steroids.The combined local and systemic therapy led to a complete remission of skin lesions and residual psoriatic plaques.

Histology of the right upper leg showed an atrophic epidermis with focal parakeratosis and subcorneal spongiform pustules representing residual psoriatic changes. Several necrotic keratinocytes in all portions of the epidermis, with satellite cell necrosis and suprabasal ballooning keratinocytes could be demonstrated. In the upper dermis a sparse, perivascular lymphocytic infiltrate without eosinophils was seen (Fig. 2). Single dermal and epidermal lymphocytes expressed T cell markers, but B-cells and cytotoxic T cells were completely absent. The histology of the epidermis was consistent with an acute graft-versus-host reaction [4, 5].

Discussion

MTX is indicated for severe psoriasis or psoriatic arthritis [1]. Severe side effects can occur during treatment with MTX. Besides the toxic reaction on the bone marrow, skin reactions can occur in up to five percent of treated patients ranging from urticarial exanthemata to toxic epidermal necrolysis [2, 6]. Burning sensations within the psoriatic plaques are considered as a warning symptom for the beginning of MTX intoxication. Our patient had complained about such sensations before the skin lesions resembling a Stevens-Johnson syndrome occurred. It is presumed that a toxic effect of MTX on keratinocytes is the reason for the severe skin reaction. Therefore, Reed and Sober introduced the term of "MTX-induced necrolysis" [6]. Two types of MTX-induced necrolysis can be distinguished clinically [7]. While type I shows damage within the psoriatic plaques, as in our patient, type II additionally evokes skin alterations in skin affected by other pathology as e.g. stasis dermatitis. Oral ulcers together with burning sensations within the psoriatic plaques, leucopenia and thrombocytopenia, as in our patient, are interpreted as early symptoms of an MTX-intoxication [2].

The clinical appearances were those of Stevens-Johnson syndrome. Furthermore, the typical histological alterations with vacuolic degeneration between epidermis and the dermis as described for an EEM [8], were not found, whereas toxic changes of the epidermis with atrophy and numerous necrotic keratinocytes in different portions of the epidermis, resembling acute phase GvHD were seen [4]. Similar graft-versus-host like skin reactions have been described for Carbamazepine and Allopurinol, but not for MTX [9]. The lack of epidermal CD-8 positive cells in the case presented indicates a toxic reaction rather than a real GvHD. Epidermal atrophy and necrotic keratinocytes are other clues to MTX-toxicity, as has been reported following intradermal injection of MTX [10]. The toxic side effects of MTX can be enhanced by impaired renal function as well as concommittant use of other drugs which influence the pharmakokinetics of MTX [2]. Hence severe skin reactions during simultaneous administration of trimethoprim, amiloride, indomethacin, and frusemide have been described in the literature [2]. Kremer et al. demonstrated that NSAID drugs, e.g. acetylsalicylic acid (ASA), decrease the clearance of MTX [3] . The degree of inhibition of renal MTX-excretion depends on the weekly MTX dose rather than the dosage or kind of NSAID. Further evidence for the crucial role of ASA in our case in increasing MTX toxicity was the exacerbation of skin rash and pancytopenia occurring only during the concomittant intake of ASA.

This case emphasizes the risk of severe side effects affecting the skin during simultaneous therapy with MTX and NSAIDS. Furthermore, MTX can induce an unusual histological reaction pattern resembling acute graft-versus-host disease, which is a clue to MTX induced skin toxicity.

Article accepted on 26/6/00

REFERENCES

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