Clozapine-associated systemic inflammatory reaction with adult-onset Still’s disease-like features and marked interleukin-18 elevation in a patient with schizophrenia: a case report

Clozapine can trigger early inflammatory adverse reactions ranging from transient fever to organ-dominant syndromes. It remains unclear whether this spectrum can also present as a systemic adult-onset Still’s disease (AOSD)-like phenotype.

A 54-year-old Japanese woman with long-standing treatment-resistant schizophrenia, psychogenic polydipsia with water intoxication, and overweight/obesity underwent olanzapine-to-clozapine cross-titration. Under the standard Japanese Clozaril Patient Monitoring Service procedure, clozapine was increased to 75 mg/day by day 23. Psychosis improved, but on day 27 she developed spike fever to 39.2 °C and fever-associated arthralgia. Infection was initially suspected, and empiric piperacillin/tazobactam was started while clozapine was continued because no neutropenia, marked eosinophilia, or severe organ-dominant reaction was evident. During days 27–30, no infectious focus was identified, and an evening spike-fever pattern with arthralgia and sore throat increased suspicion for clozapine-associated inflammation. Ferritin and interleukin-18 (IL-18), an autoinflammatory cytokine associated with Still’s disease, were measured after a Still-like phenotype was suspected. Clozapine was discontinued on day 35. However, the syndrome evolved with recurrent fever up to 40.2 °C, evanescent rash, edema/hypoxemia, neutrophil-predominant inflammation, hypoalbuminemia, ferritin elevation, and serial IL-18 increase from 470 pg/mL on day 33 to 1,160 pg/mL on day 49. Infection, established autoimmune disease, drug reaction with eosinophilia and systemic symptoms, and neuroleptic malignant syndrome were not favored. Overt myocarditis was not supported by normal troponin/creatine kinase and nonspecific electrocardiographic findings, but echocardiography was not performed. She fulfilled Yamaguchi and Fautrel classification criteria for AOSD-like illness. Consequently, hydrocortisone and supportive care were used, and no further spike fever occurred after day 49.

This case expands the clozapine inflammatory spectrum to a systemic AOSD-like phenotype with marked serial IL-18 elevation. When spike fever with systemic inflammation emerges during clozapine titration, early temporary interruption of clozapine should be considered, and persistent Still-like inflammation after discontinuation may warrant anti-inflammatory supportive treatment, including corticosteroids in selected cases.