Fixed drug eruption induced by mycophenolate mofetil, a rare entity with significant consequences

Mycophenolate mofetil (MMF) is an immunosuppressive agent widely used in solid organ transplantation and autoimmune diseases, particularly lupus nephritis. Its mechanism involves inhibition of T- and B-lymphocyte proliferation.1 Common adverse drug reactions (ADRs) include gastrointestinal symptoms, haematological abnormalities and infections. Immediate hypersensitivity reactions are rare, with an estimated anaphylaxis rate of 0.98 per 100 000 patient-years but have recently led to updated postmarketing warnings.2 Delayed HRs are even less described and uncommon with nonspecific skin-ADR including rash or pruritus.1 Fixed drug eruption (FDE) is a delayed-HR characterized by recurrent, well-demarcated erythematous or violaceous lesions that reappear at the same sites upon re-exposure to the culprit drug.3 MMF is very rarely implicated in FDE. We report the case of a 52-year-old woman with systemic lupus erythematosus complicated by class IV lupus nephritis. She had been intermittently treated with mycophenolate mofetil (CellCept®), with poor adherence. On two occasions, a few minutes after oral intake, she developed generalized pruritus with facial, eyelid and lip angioedema, without systemic involvement. Symptoms resolved spontaneously within days. Several years later, similar symptoms occurred following intake of mycophenolate sodium (Myfortic®), this time associated with oval violaceous macules on the trunk, which resolved spontaneously after treatment discontinuation. Given the suspicion of immediate hypersensitivity to MMF, skin prick testing with CellCept® was performed and was negative. It was followed by an oral provocation test (OPT), in two steps. During OPT, the patient reported diffuse pruritus without objective skin lesions. One day later, she developed multiple well-demarcated, nonbullous violaceous macules on the shoulders, clavicular areas and cheeks, highly suggestive of FDE (Figure 1). Skin biopsy revealed necrotic keratinocytes and a dermal inflammatory infiltrate containing lymphocytes, histiocytes, and eosinophils, consistent with FDE (see Figure 2). No systemic involvement was identified. The diagnosis of MMF-induced FDE was supported by lesion recurrence at identical sites after OPT, delayed onset, and compatible histology. MMF was permanently discontinued and replaced by an mTOR inhibitor, with no recurrence during follow-up. MMF-induced FDE appears extremely rare. In collaboration with the pharmacovigilance department, only two cases (including ours) were identified in the French Pharmacovigilance Database; the second case was not retained due to confounding drugs and a fatal outcome unrelated to MMF. In the World Health Organization global database, only seven cases have been reported, including two published cases.4, 5 In these reports, MMF was prescribed for connective tissue diseases, with eruptions occurring after re-introduction, and characterized by recurrent violaceous hyperpigmented lesions, sometimes with mucosal involvement but no systemic symptoms. FDE is most commonly associated with nonsteroidal anti-inflammatory drugs, tetracyclines, fluoroquinolones, trimethoprim, pseudoephedrine, cetirizine and phenytoin.3 The pathophysiology involves a delayed type IV hypersensitivity reaction mediated by resident memory CD8+ T cells persisting in previously affected skin sites, explaining the recurrence of lesions at identical locations upon re-exposure. This diagnosis is of major clinical importance, as FDE may evolve into generalized bullous forms that can mimic toxic epidermal necrolysis, leading to potentially life-threatening consequences and requiring permanent discontinuation of MMF. This may significantly impact long-term therapeutic strategies, including eligibility for renal transplantation. This case highlights the importance of considering FDE in the differential diagnosis of cutaneous reactions to MMF since it can be life threatening, especially in generalized bullous forms. Therapeutic alternatives may be limited, especially in a transplantation project. Prompt recognition is essential to avoid repeated drug exposure and potential progression of cutaneous reactions. None. None declared. The data that support the findings of this study are available from the corresponding author upon reasonable request.