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Observational Study
. 2025 Jul;39(7):693-705.
doi: 10.1007/s40263-025-01191-7. Epub 2025 May 29.

Long-Term Effectiveness and Safety of Rituximab in Neuromyelitis Optica Spectrum Disorder: A 5-Year Observational Study

Giovanni Novi #  1 , Francesca Bovis #  2 , Chiara Sciolla  3 , Jessica Frau  4 , Matteo Minetti  5 , Francesca Napoli  6 , Marika Vianello  7 , Giacomo Greco  8   9 , Elia Sechi  10 , Andrea Bellomo  11 , Paola Garelli  12   13 , Antonio Luca Spiezia  14 , Roberta Fantozzi  15 , Giuseppe Schirò  16 , Laura Ghezzi  17   18 , Chiara Zecca  19   20 , Elisabetta Signoriello  21 , Laura Brambilla  22 , Matteo Lucchini  23   24 , Simona Bonavita  25 , Irene Schiavetti  26   2 , Maria Malentacchi  3 , Eleonora Cocco  4   27 , Alessandro Franceschini  5 , Giorgia Mataluni  6 , Matteo Gastaldi  28 , Anna Rolando  12 , Paolo Solla  10 , Maria Cellerino  29 , Gianmarco Abbadessa  25 , Roberta Lanzillo  13 , Alessia Di Sapio  30 , Antonio Uccelli  26   29 , Maria Pia Sormani  26   2
Affiliations
Observational Study

Long-Term Effectiveness and Safety of Rituximab in Neuromyelitis Optica Spectrum Disorder: A 5-Year Observational Study

Giovanni Novi et al. CNS Drugs. 2025 Jul.

Abstract

Background: Neuromyelitis optica spectrum disorder (NMOSD) is a severely disabling autoimmune disease that predominantly impacts the optic nerves and spinal cord. It is often linked to immunoglobulin G (IgG) antibodies targeting the aquaporin-4 water channel (AQP4-IgG). Rituximab, which depletes CD20-positive B cells, is effective in reducing the frequency of NMOSD relapses. The objective of this retrospective, 5-year observational study was to evaluate the effectiveness and safety of rituximab in patients with AQP4-IgG-positive NMOSD.

Methods: We conducted a multicenter, retrospective study using prospectively collected data from 23 multiple sclerosis (MS) and NMOSD centers (22 in Italy, 1 in Switzerland). The study cohort included patients with AQP4-IgG-positive NMOSD who had completed rituximab induction therapy, with data collected up to May 2024. Two maintenance strategies were used-fixed 6-monthly infusions or reinfusions guided by flow cytometry-on the basis of CD19+ or CD27+ memory B-cell repopulation thresholds. Clinical outcomes included annualized relapse rate (ARR), time to first relapse (TTFR), and Expanded Disability Status Scale (EDSS) worsening, which was assessed both overall and between relapses to indirectly evaluate the possibility of inter-attack disability progression. Safety outcomes encompassed infusion-related reactions and adverse events.

Results: A total of 138 patients were analyzed. ARR significantly decreased from 1.54 (95% confidence interval (CI) 1.34-1.75) before rituximab to 0.15 (95% CI 0.12-0.19) over the 5-year follow-up. Approximately 33% of patients experienced at least one relapse during treatment, after a median time of 5.21 months. Higher pre-rituximab relapse rates were associated with shorter TTFR. Subtle increases of 0.5-1 points in EDSS between relapses were observed in one third of patients. Mild infections were common, and 21% of patients experienced infusion-related reactions. In addition, six patients developed malignancies.

Conclusions: Over 5 years, rituximab consistently reduced the incidence of relapses in patients with NMOSD, though 33% of them still experienced a relapse during this period, generally within the first 6 months of treatment. No unexpected adverse events were identified. While safety monitoring remains crucial, further studies are needed to better understand rituximab's impact on NMOSD management.

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Conflict of interest statement

Declarations. Funding: No funding was received for conducting this study. F.B. received the 2022 Biostatistic/Informatics Junior Faculty Award (grant code BI-2107-38160) awarded by the National MS Society. Conflicts of Interest: G.N. received speaker honoraria from Alexion, Roche, and Novartis; J.F. reports a relationship with Biogen, Bristol, Novartis, Genzyme, Merck, Teva, and Alexion that includes: board membership, consulting or advisory, and speaking and lecture fees; M.V. received compensation for travel grants or speaking activities from Biogen, Merck Serono, Roche, BMS Cellgene, Janssen, and Novartis; E.S.e. has received speaker honoraria and support for attending scientific meetings from Alexion. He serves as an editorial board member for BMC Neurology and Frontiers in Neurology and is a member of the Medical Advisory Board of the MOG project; R.F. received honoraria for advisory boards and consulting from Bristol MS, Roche, Merck, and Novartis; C.Z. reports that the Ente Ospedaliero Cantonale (employer) received compensation for speaking activities, consulting fees, or research grants from Almirall, Biogen Idec, Bristol Meyer Squibb, Lundbeck, Merck, Novartis, Sanofi, Teva Pharma, and Roche; E.S.i. reports a relationship with Almirall, Biogen, Genzyme, Novartis, and Teva that includes: board membership and travel reimbursement; L.B. received honoraria for speaking from Novartis, Roche, and Horizon and for traveling from Sanofi-Genzyme, Merck-Serono, Novartis, Horizon, and Roche; she acted as an Advisory Board Member of Sanofi-Genzyme, Novartis, and Merck-Serono, and she is involved as principal investigator in clinical trials for Roche and Merck-Serono; M.L. has received honoraria from Biogen, Merck Serono, Novartis, Roche, Sanofi-Genzyme, Almirall, and Bayer for consulting services, speaking, and/or travel support; S.B. reports a relationship with Novartis, Merck-Serono, Alexion, BMS, Biogen, Roche, Janssen-Cilag, and Horizon that includes: speaking and lecture fees and travel reimbursement; I.S. reports a relationship with Roche, Biogen, Horizon, Novartis, Hoya, Hippocrates Research, D.M.G Italia, Eyepharma, and DreamsLab that includes: consulting or advising; M.Ma. received fees from Novartis and Biogen Idec for speaking in scientific meetings; E.C. has received honoraria for consultancy or speaking from Bayer Biogen, Novartis, Sanofi, Merck, TEVA, Roche, Bristol, Janssen, and Alexion; M.G. received honoraria for the participation in advisory boards from Roche and UCB; P.S. has received speaker honoraria from Bayer and Zambon; M.C. received personal compensations from Novartis, Genzyme, and Teva and consulting fees from Zambon; A.d.S. received compensation for speaking and consulting by Biogen, Novartis, Roche, Sanofi, Alexion, and Sandoz and reimbursement by Merck, Biogen, Genzyme, and Roche for attending conferences; A.U. received grants (for his institution) from FISM, Biogen, Roche, Alexion, and Merck Serono; participated on a Data Safety Monitoring Board or Advisory Board (at his institution) for BD, Biogen, Iqvia, Sanofi, Roche, Alexion, and Bristol Myers Squibb; M.P.S. reports a relationship with Biogen Idec, Merck Serono, Teva, Genzyme, Roche, Novartis, GeNeuro, and Medday that includes: consulting or advising. M.P.S. is also an Editorial Board Member of CNS Drugs. M.P.S. was not involved in the selection of peer reviewers for the manuscript nor any of the subsequent editorial decisions. F.B., C.S., M.M.i., F.N., G.G., A.B., P.G., A.L.S., G.S., L.G., A.F., G.M., A.R., G.A., and R.L. have no relevant financial interests to disclose. Availability of Data and Material: Data are available upon reasonable request from the authors. Ethics Approval: The study was approved by the Ethics Committee of IRCCS Ospedale Policlinico San Martino, Genova, protocol 067REG2017. Consent to Participate: Patients provided written consent to participate in the study. Consent for Publication: Not applicable. Code Availability: Not applicable. Author Contributions: G.N.—drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data; study concept or design; analysis or interpretation of data; FB—drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data; study concept or design; analysis or interpretation of data; additional contributions: graphic presentation. C.S., J.F., M.M., F.N., M.V., G.G., A.B., P.G., A.L.S., R.F., G.S., L.G., E.S., L.B., M.L., S.B., I.S., M.M., E.C., A.F., G.M., A.R., P.S., M.C., G.A., R.L., A.d.S., and A.U.—drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data; E.S., M.G., M.P.S.—drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data; study concept or design; analysis or interpretation of data. All authors read and approved the final submitted paper and agree to be accountable for this work.

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