Mahler J.V.Vallejos G.B.Mikami T.Bilodeau P.A.Anderson M.Drosu N.Bobrowski-Khoury N.Silva G.D.Solti M.Apóstolos-Pereira S.L.Callegaro D.Leles Vieira de Souza B.Manzano G.S.Vishnevetsky A.Gillani R.Pasquale O.Kim A.Vij R.Kister I.Gibbons E.L.Jacob A.Huda S.Said Y.Krett J.D.Sotirchos E.S.Ramprasad M.Abboud H.Crelier V.T.C.Dos Santos G.Uawithya E.Siritho S.Sezen A.Altintas A.Gai F.Guo Y.Bhattacharyya S.Levy M.Matiello M.Mahidol University2026-02-152026-02-152026-03-01Neurology R Neuroimmunology Neuroinflammation Vol.13 No.2 (2026) , e200514https://repository.li.mahidol.ac.th/handle/123456789/115062BACKGROUND AND OBJECTIVES: Double seronegative NMOSD (DS-NMOSD) lacks approved disease-modifying treatments, and limited data exist on optimal relapse-prevention strategies. In this multicenter, international, retrospective cohort study, we sought to compare the real-world effectiveness of anti-CD20 agents vs nonspecific immunosuppressants as disease-modifying strategies for relapse prevention in DS-NMOSD. METHODS: A retrospective cohort database was constructed using standardized data collection from medical records across collaborating centers in the United States, Brazil, the United Kingdom, Thailand, Turkiye, and China. Patients meeting IPND-2015 NMOSD criteria with negative serum aquaporin-4 and myelin oligodendrocyte glycoprotein antibody testing via cell-based assays and at least 12 months of follow-up were reviewed. The primary outcome was the incidence rate ratio (IRR) of relapses; secondary outcomes included the annualized relapse rate (ARR) and time to relapse. RESULTS: A total of 103 patients with DS-NMOSD met study criteria, with a median follow-up of 6 years. Anti-CD20 therapy was associated with a significantly lower IRR (0.02, 95% CI 0.01-0.04) and ARR (0.17, 95% CI 0.07-0.40) compared with nonspecific immunosuppressants (0.76, 95% CI 0.40-1.43) after adjusting for covariates. Survival analysis demonstrated a prolonged relapse-free interval with anti-CD20 agents. DISCUSSION: Our findings support the use of B-cell depletion as a potentially superior relapse-prevention strategy in DS-NMOSD, highlighting its potential as a first-line therapy. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that, in patients with DS-NMOSD, treatment with a DMT reduces relapse incidence rate ratio compared with no treatment and anti-CD20 DMTs are associated with a lower relapse incidence rate ratio compared with nonspecific immunosuppressants.NeuroscienceMedicineArticleSCOPUS10.1212/NXI.00000000002005142-s2.0-1050295252722332781241637688