Dear Editor, Leflunomide is a nonbiological disease modifying antirheumatic agent used in the treatment of rheumatoid arthritis (RA). It acts via inhibition of dihydro-orotate dehydrogenase enzyme, which is a critical enzyme in de novo pyrimidine synthesis. This mechanism halts rapid division of cells accounting for its therapeutic efficacy as well as adverse effects. The adverse effects range from diarrhea, transaminitis, telogen effluvium, vasculitis, reversible alopecia areata, cutaneous ulceration to life threatening reactions like exfoliative dermatitis, Stevens–Johnson syndrome/toxic epidermal necrolysis.1 There are only few reported cases of leflunomide-induced cutaneous ulceration in the literature.1-3 Herein, we report a patient of RA with synovitis and secondary enthesitis, who developed leflunomide-induced cutaneous ulceration. A 66-year-old woman with a 10-year history of RA presented with a non-healing ulcer on the dorsum of her right hand for 45 days. She was on methotrexate 10 mg/week with adequate folic acid supplementation for 11 months, and leflunomide 10 mg daily for suspected secondary enthesitis for two months. The patient started developing reddish raised lesions 2 weeks after the initiation of leflunomide, initially on dorsum of right hand that progressed to involve proximal part of upper and lower limbs. The lesions ulcerated over next ten days Figure 1a. Despite treatment with topical and oral antibiotics and topical steroids, the ulcers expanded in size over the next 35 days. The patient’s general condition was stable. Differential diagnoses considered were rheumatoid vasculitis and drug-induced ulceration.Figure 1: (a) A single well-defined ulcer noted on the right fifth knuckle (b) Healed ulcer after two weeks of discontinuation of leflunomideAll routine blood investigations were within normal limits, and antinuclear antibody was negative. Serum methotrexate level was not measured as it may be an unreliable marker of toxicity in the case of low dose methotrexate therapy. The biopsy taken from the edge of the ulcer revealed a dermal hypersensitivity reaction and interface dermatitis with perivascular eosinophils without any evidence of vasculitis, suggesting a possible drug etiology Figure 2a and 2b. The absence of histopathological features like focal dermoepidermal separation with necrotic keratinocytes, cellular atypia, and dysmaturation, seen typically with methotrexate induced cutaneous ulcers4 along with predominant dermal changes favored leflunomide as culprit. This was also supported by history of recent addition of leflunomide.1Figure 2: (a) Histopathological examination depicting interface dermatitis with basal vacuolar degeneration (green asterix). (Hematoxylin and eosin, 20x), (b) Perivascular lymphocytic infiltrates mixed with few eosinophils (blue asterix) without any evidence of vasculitis (Hematoxylin and eosin, 20x)Leflunomide was discontinued and patient was administered cholestyramine 8 g thrice a day for 11 days. The ulcers healed significantly in 2 weeks despite continuing methotrexate Figure 1b. The patient did not have any new ulcer at 2 months follow up. Leflunomide undergoes nonenzymatic activation in the liver and gut into its active metabolite A77 1726 (teriflunomide), inhibiting rapidly proliferating cell lines and lymphocytes. The direct toxic effect of leflunomide on epidermal cell lines has been attributed to be the cause of ulceration.1 The combination of leflunomide and methotrexate can result in ulceration due to their synergistic effects, with methotrexate inhibiting purine metabolism and leflunomide inhibiting pyrimidine metabolism. Cutaneous ulceration can be an impending sign toward more severe toxicities, necessitating careful monitoring. Leflunomide has a half-life of 5 to 40 days (average of 15 days), but due to its extensive enterohepatic circulation, it can extend up to 2 years.1 Leflunomide induced cutaneous ulcers reportedly occur after an average latency period of 4 weeks to 13 months.1-3 These can occur irrespective of systemic manifestations of drug-induced toxicity. Discontinuation of leflunomide is therefore the most effective intervention to treat leflunomide-induced skin ulceration, as also evidenced by our case.1-3 Adjunct therapies, like cholestyramine or activated charcoal, can be added to shorten the half-life of leflunomide to 1 to 2 days. Early recognition and timely management are critical to prevent serious adverse effects that can lead to significant morbidity and mortality. Authors’ contributions We confirm that all authors have read and approved the manuscript for submission. All authors meet authorship criteria, and the manuscript represents honest work. Declaration of patient consent The authors certify that they have obtained all appropriate patient consent forms. In the form the patient has given his consent for his images and other clinical information to be reported in the journal. The patient understands that his name and initials will not be published and due efforts will be made to conceal his identity, but anonymity cannot be guaranteed. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest. Use of artificial intelligence (AI) The preparation of this manuscript was carried out entirely by the authors without the use of artificial intelligence technologies.
Subbiahmohan et al. (Tue,) studied this question.