Supplementary file 2_Clinical characteristics, diagnosis, treatment, and prognosis of rituximab-induced serum sickness: a retrospective analysis of 39 reported cases.xlsx

BackgroundRituximab-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.
MethodsPubMed, 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.
Results30 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%.
ConclusionRISS 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.

背景：利妥昔单抗相关性血清病（Rituximab-induced serum sickness, RISS）是一种罕见的迟发型超敏反应，其临床特征与诊疗方案尚未完全明确。本研究旨在整合已发表的病例报告/病例系列，以阐明其临床特征、治疗策略与转归。
方法：检索PubMed、EMBASE、Web of Science、万方数据及中国知网（China National Knowledge Infrastructure, CNKI）数据库，检索时限截至2025年11月31日，采用布尔逻辑运算符组合关键词与自由文本词（如“Rituximab”“Serum Sickness”“Serum Sickness-Like Reaction”“Hypersensitivity”“Adverse Drug Reaction”“RISS”及“anti-CD20”），筛选符合纳入标准的病例报告/病例系列并采用标准化表单提取数据。采用乔安娜·布里格斯研究所（JBI）病例报告关键评价量表对研究质量进行评估。
结果：共纳入30篇符合标准的文献，涉及39例患者。患者中位年龄为33岁（范围6~86岁），女性占比71.8%，为主要受累人群。末次利妥昔单抗输注后，症状中位发作时间为7天（范围1~18天）。最常见的基础疾病指征为多发性硬化（23.1%）、肾病综合征（20.5%）及免疫性血小板减少症（20.5%）。临床症状以关节痛/关节炎（92.3%）、发热（82.1%）及皮疹（66.7%）最为多见。检测样本中，90.9%的患者抗利妥昔单抗抗体呈阳性。炎症标志物水平常升高：93.3%的患者红细胞沉降率（erythrocyte sedimentation rate, ESR）升高，91.3%的患者C反应蛋白（C-reactive protein, CRP）升高。补体消耗现象较为常见，76.5%的受检患者C3水平降低，78.6%的受检患者C4水平降低。临床治疗中，糖皮质激素为RISS的常用治疗药物，而换用其他抗CD20制剂则主要用于基础疾病的管理。总体而言，82.1%的患者实现完全康复，15.4%的患者病情改善，中位康复时间为3.0天。10例患者接受了利妥昔单抗再输注，其中60.0%出现病情复发。
结论：RISS为一种迟发型反应，通常在给药后间隔数日发作，但在重复给药方案中，可能在后续输注后短期内出现临床症状。其核心临床特征为发热、皮疹及关节痛/关节炎的经典三联征，常伴随炎症标志物升高与低补体血症。多数患者在停药、给予支持治疗及短疗程糖皮质激素治疗后可快速康复；然而，利妥昔单抗再输注存在较高的复发风险，临床应用需谨慎。