Unfavorable impact of anti-rituximab antibodies on clinical outcomes in children with complicated steroid-dependent neph

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Unfavorable impact of anti-rituximab antibodies on clinical outcomes in children with complicated steroid-dependent nephrotic syndrome Shuichiro Fujinaga 1 Mayu Nakagawa 1

&

Tomohiko Nishino 1 & Shota Endo 1 & Chisato Umeda 1 & Yoshitaka Watanabe 1 &

Received: 3 April 2020 / Revised: 22 May 2020 / Accepted: 27 May 2020 # IPNA 2020

Abstract Background Anti-rituximab antibodies (ARA) are associated not only with adverse events, such as infusion reactions (IR) and serum sickness, but also with rituximab efficacy. However, the clinical relevance of ARA in children with steroid-dependent nephrotic syndrome (SDNS) remains unknown. Methods We retrospectively reviewed clinical outcomes of 13 children with complicated SDNS receiving repeated single-dose rituximab treatments at 375 mg/m2 to assess whether ARA formation could impact toxicity and efficacy of additional rituximab. Pre-rituximab 22 samples collected from patients who developed IR during the second or subsequent rituximab doses were measured by electrochemiluminescence analysis. Results ARA were identified in 5 of 13 patients (9 of 22 samples). Median time to recovery of CD19+ B cells to > 1% of total lymphocytes and median relapse-free time after rituximab treatment were significantly shorter in the 9 ARA-positive samples than the 13 ARA-negative samples (41 vs. 100 days, p < 0.01 and 119 vs. 308 days, p < 0.05, respectively). Kaplan–Meier analysis showed that time to CD19+ B cell recovery after rituximab was significantly shorter in ARA-positive samples than in ARA-negative samples (p < 0.005). Severe IR developed in two ARA-positive patients and serum sickness in one ARA-positive patient. Conclusions The incidence of ARA formation was high in the pre-rituximab samples of patients with complicated SDNS who developed IR during the second or subsequent rituximab doses, suggesting that ARA formation might have an unfavorable impact on the toxicity and efficacy of additional rituximab doses in these patients. Keywords Steroid-dependent nephrotic syndrome . Rituximab . Anti-rituximab antibody . Infusion reactions . Serum sickness . Electrochemiluminescence analysis

Introduction Rituximab, a mouse–human chimeric monoclonal anti-CD20 antibody, is used to prevent relapse in children with complicated steroid-dependent nephrotic syndrome (SDNS) [1, 2]. The immunogenicity of rituximab, which presents with the formation of anti-rituximab antibodies (ARA), is a wellrecognized phenomenon in several other diseases treated with rituximab, such as non-Hodgkin lymphoma, rheumatoid arthritis, and systemic lupus erythematosus (SLE) [3–5]. Although the presence of ARA may affect the * Shuichiro Fujinaga [email protected] 1

Division of Nephrology, Saitama Children’s Medical Center, 1-2 Shintoshin, Chuo-ku, Saitama 330-8777, Japan

pharmacokinetics, efficacy, and toxicity of rituximab, there is scarce information regarding the incidence and clinical outcomes of children with SDNS who are ARA-positive. Infusion reactions (IR), one of the most frequently encoun