Rituximab exposure is associated with serum sickness in patients with multiple sclerosis, nephrotic syndrome, or immune thrombocytopenia.

Rituximab-induced serum sickness (RISS) is an uncommon delayed hypersensitivity reaction with incompletely characterized clinical features and management. We aimed to synthesize published case reports/series to delineate clinical patterns, therapeutic strategies, and outcomes. PubMed, EMBASE, Web of Science, WanFang Data, and China National Knowledge Infrastructure (CNKI) were searched for rituximab-induced serum sickness reports published up to Nov 31, 2025, using keywords and free-text terms (e.g., “Rituximab,” “Serum Sickness,” “Serum Sickness-Like Reaction,” “Hypersensitivity,” “Adverse Drug Reaction,” “RISS,” and “anti-CD20”) with Boolean operators. Eligible case reports/series were screened and data were extracted with a standardized form. Study quality was evaluated using the JBI Critical Appraisal Checklist for Case Reports. 30 eligible articles identified 39 patients. The median age was 33 years (range 6, 86), with a female predominance (71.8%). The median symptom onset time was 7 days (range 1, 18) after last rituximab exposure. The most common indications were multiple sclerosis (23.1%), nephrotic syndrome (20.5%), and immune thrombocytopenia (20.5%). Clinically, arthralgia/arthritis (92.3%), fever (82.1%), and rash (66.7%) predominated. Anti-rituximab antibodies were positive in 90.9% of tested cases. Inflammatory markers were frequently elevated, with 93.3% of patients showing elevated erythrocyte sedimentation rate (ESR) and 91.3% showing elevated C-reactive protein (CRP). Complement consumption were frequent, with decreased C3 and C4 levels observed in 76.5% and 78.6% of tested patients, respectively. Corticosteroids were commonly used as the treatment for RISS, while switching to another anti-CD20 agent was primarily a strategy for managing the underlying disease. Overall, 82.1% achieved complete recovery and 15.4% improved, with a median recovery time of 3.0 days. Rechallenge was reported in 10 patients, with recurrence in 60.0%. RISS is a delayed reaction occurring after a free interval of several days, but it may clinically present shortly after a subsequent infusion in repeated dosing regimens. Its main features include the classic triad of fever, rash, and arthralgia or arthritis, commonly accompanied by elevated inflammatory markers and hypocomplementemia. Most patients improve rapidly after drug withdrawal, supportive care, and short-course corticosteroid therapy; however, rechallenge carries a substantial risk of recurrence and should be approached cautiously.