Comparative effectiveness of inebilizumab versus conventional immunotherapies in AQP4-IgG-positive NMOSD: a prospective cohort study with time-varying treatment effects

Background To compare relapse and disability outcomes of inebilizumab, azathioprine (AZA), mycophenolate mofetil (MMF) and rituximab (RTX) in maintenance-therapy-naive patients with aquaporin-4 IgG-positive neuromyelitis optica spectrum disorder. Methods We prospectively enrolled 566 patients (inebilizumab n=72, AZA n=196, MMF n=170, RTX n=128). Primary effectiveness analyses were conducted in the per-protocol cohort (n=528), with supportive analyses in the full cohort. Both used inverse probability of treatment weighting to estimate the average treatment effect on the treated, with inebilizumab as reference. Primary outcomes were annualised relapse rate (ARR) and time to first relapse; disability progression was secondary. Adverse events (AEs) were assessed in the full cohort. Results In the per-protocol cohort, median age was 37 years, 477 (90.3%) were female and median follow-up was 21.5 months. Compared with inebilizumab, ARR was higher with AZA (incidence rate ratio (IRR) 4.78), MMF (IRR 4.33) and RTX (IRR 2.26; all p<0.05). Average relapse hazards were higher with AZA (HR 3.77; p=0.006) and MMF (HR 4.05; p=0.003), but not significantly different with RTX (hazard ratio (HR) 2.08; p=0.178). Time-varying analysis suggested a higher relapse hazard with RTX only during the first 6 months. Supportive analyses in the full cohort yielded consistent results. AZA and MMF were associated with greater disability progression than inebilizumab, whereas RTX was not. Severe AEs did not differ across groups. Conclusions Inebilizumab was associated with better relapse and disability outcomes than AZA or MMF. Compared with RTX, inebilizumab was associated with lower ARR, whereas no significant differences were detected in time to first relapse or disability progression.