Toxic epidermal necrosis-like dermatosis induced by the first course of methotrexate

ARTICLE

Auteur(s) : Yu Sawada, Chika Kawakami, Motonobu Nakamura, Yoshiki Tokura, Ryutaro Yoshiki

Department of Dermatology, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu, Fukuoka, 807-8555, Japan

Toxic epidermal necrolysis (TEN) is the most severe cutaneous reaction for drugs [1]. Methotrexate is a widely used immunosuppressant, and cutaneous side effects are reported [2, 3]. Here, we report a case of TEN-like dermatosis (pseudo-TEN) following the first administration of methotrexate.

A 64-year-old man underwent hemodialysis because of chronic renal failure caused by diabetes mellitus type 2. He had been treated for psoriasis with narrowband ultraviolet B light for 10 years. Because of exacerbation of the psoriatic eruption, he visited a dermatology clinic and received a course of methotrexate (6 mg weekly). Five days later, he developed a widespread skin eruption with a high fever and diarrhea. He had no history of medication and allergy to medicines. He was referred to our department for evaluation of the eruption.

Erosions and scaly crusts spread widely on the back (figure 1A), buttocks (figure 1B), and extremities. These changes occurred on a diffusely erythematous background. The oral mucosa was not affected, and no Nikolsky sign was observed. His psoriatic lesions had disappeared after the intake of methotrexate. Laboratory examination revealed pancytopenia: leukocyte count, 1500/μL; platelet count, 6.0 × 10⁴/μL; and hemoglobin level, 12.2 g/dL. C-reactive protein was elevated to 26.09 mg/dl (normal, < 0.2 mg/dL) and fasting serum glucose was 443 mg/dL. The renal function deteriorated: serum creatinine, 9.37 mg/dL (normal, 0.6-1.1 mg/dL); blood urea nitrogen, 64 mg/dL (normal, 8-22 mg/dL); and hyperkalemia, 5.8 mEq/L (normal, 3.6-4.9 mEq/L). His SCORTEN score was 4 points (Age > 40 years, serum BUN > 27 mg/dL, blistering body surface > 10%, serum glucose > 250 mg/dL). A skin biopsy taken from his back showed necrotic epidermis (figure 1C). A vacuolar alteration of basal cells was found with lymphocytes infiltrating into the epidermis and upper dermis. Dyskeratotic keratinocytes in the epidermis might indicate epidermal regeneration (figure 1D). Since the mucous membranes were spared and the duration was short between the initiation of the drug intake and the appearance of the eruption, we diagnosed it as pseudo-TEN caused by methotrexate.

The patient was admitted to hospital, and methotrexate was discontinued. Despite the systemic administration of granulocyte-colony stimulating factor, pancytopenia still persisted on the 14 day after the therapy. Bone marrow examination revealed presumably hemophagocytic syndrome caused by methotrexate, and a steroid half pulse therapy (methylpredonisolone 500 mg daily for 3 days) was performed. Five days later, the neutropenia improved. The renal dysfunction was gradually alleviated by dialysis. The erosive lesions were epithelized with disappearance of erythema in 3 weeks. On the 41st day of hospitalization, however, his blood pressure fell with deterioration of renal function. He died of heart and renal failure. An autopsy disclosed cardiac tamponade secondary to renal failure.

Methotrexate is a choice for severe psoriasis. About 90% of methotrexate is excreted as an unchanged form through the kidney within 24 hours [4]. The toxicity of methotrexate is dose-dependent and may be augumented by renal dysfunction. Several adverse effects of methotrexate have been reported, including TEN, Stevens-Johnson syndrome and acral erythema [3, 5]. In these cases, the skin eruptions occurred after several courses of methotrexate. Our patient is the first case of pseudo-TEN evoked by the first course of methotrexate therapy. Although a T-cell mediated cytotoxic mechanism underlies the pathogenesis of TEN [5], the TEN-like eruption due to methotrexate seems to be induced by its own cytotoxicity [6]. Our case supports this concept and suggests sensitization for the development of methotrexate-induced pseudo-TEN is not necessary. The early appearance of the cumulative toxicity of methotrexate and resultant pseudo-TEN are presumably exaggerated by the renal failure.

Acknowledgements

References

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