MGB-NMOSD
Real-World Efficacy and Safety of Neuromyelitis Optica Spectrum Disorder Disease-Modifying Treatments
Bottom Line
In a real-world cohort of 176 patients with NMOSD followed for a median of 9 years, FDA-approved NMOSD-specific therapies (C5 inhibitors, inebilizumab, satralizumab) were substantially more effective and safer than rituximab, whereas MMF and azathioprine were less effective and carried higher composite risk - supporting first-line use of approved NMOSD DMTs (especially C5 inhibitors) over rituximab, MMF, or azathioprine.
Major Points
- Largest single-network real-world NMOSD comparative effectiveness cohort to date (Mass General Brigham, 2000-2024) with 176 patients (86% AQP4+, 83% female) and 331 treatment periods analyzed across 6 maintenance therapies.
- 5-year relapse-free probability was 100% for C5 inhibitors (eculizumab/ravulizumab), inebilizumab, and satralizumab, compared with 69.7% for rituximab, 51.1% for MMF, and 35.3% for azathioprine.
- Adjusted (Cox-Firth) relapse hazard ratios vs. rituximab: C5 inhibitors 0.12 (95% CI 0.07-0.24), inebilizumab 0.22 (0.12-0.65), satralizumab 0.19 (0.11-0.42).
- Annualized relapse rates: 0 for C5 inhibitors, inebilizumab, and satralizumab; 0.08 for rituximab; 0.19 for MMF; and 0.34 for azathioprine - results were similar after IPTW adjustment and when restricted to AQP4+ patients.
- C5 inhibitors had the lowest serious infection rate (incidence rate ratio 0.16 vs. rituximab, 95% CI 0.05-0.42, P=0.0002); 13% of rituximab treatment periods had hypogammaglobulinemia, 28% had serious infections, and 34% had common infections.
- Composite endpoint of relapse, SIAE, or TLAE favored C5 inhibitors (HR 0.22, 95% CI 0.05-0.67) and disfavored azathioprine (HR 2.33, 95% CI 1.08-4.86) and MMF (HR 1.75, 95% CI 1.02-2.95) compared with rituximab; inebilizumab and satralizumab were not significantly different from rituximab on the composite.
- Authors conclude clinicians should consider NMOSD-approved therapies first-line, avoid MMF and azathioprine, and caution against default first-line rituximab given cumulative relapse and adverse-event burden over time.
Design
Study Type: Retrospective real-world cohort study (comparative effectiveness)
Randomization:
Blinding: Not blinded; dual neuroimmunologist chart review with senior-author adjudication of disagreements
Enrollment Period: January 1, 2000 - June 30, 2024
Follow-up Duration: Median 9 years (IQR 5-14)
Centers: 1
Countries: USA
Sample Size: 176
Analysis: Cox proportional hazards with Firth penalized regression (frailty term for patient random effect); negative binomial relapse models with inverse probability of treatment weighting (IPTW) adjusting for age and number of prior attacks; Poisson tests for ARR; Kaplan-Meier survival curves; complete-case analysis; bootstrap (n=1,000) 95% CIs
Inclusion Criteria
- Met 2015 International Panel for NMO Diagnosis (IPND) criteria for NMOSD
- Evaluated in person by a Mass General Brigham neurologist between January 1, 2000 and June 30, 2024
- Either positive AQP4 cell-based assay in the institutional laboratory OR an NMOSD ICD code with negative AQP4 testing but meeting IPND criteria on chart review
- Received at least one maintenance NMOSD disease-modifying therapy (rituximab, eculizumab/ravulizumab, inebilizumab, satralizumab, methotrexate, mycophenolate mofetil, or azathioprine)
Exclusion Criteria
- Did not meet 2015 IPND criteria for NMOSD on chart review
- Positive serum MOG-IgG antibody (most common exclusion, n=37)
- Insufficient documentation to confirm diagnosis or treatment exposure
Arms
| Field | Control | C5 inhibitors (eculizumab/ravulizumab) | Inebilizumab | Satralizumab | Mycophenolate mofetil (MMF) | Azathioprine |
|---|---|---|---|---|---|---|
| Intervention | Anti-CD20 monoclonal antibody; off-label use for NMOSD relapse prevention | Terminal complement (C5) inhibitor; FDA-approved for AQP4+ NMOSD (eculizumab 2019, ravulizumab 2024) | Anti-CD19 monoclonal antibody (B-cell depletion); FDA-approved for AQP4+ NMOSD in 2020 | Anti-IL-6 receptor monoclonal antibody; FDA-approved for AQP4+ NMOSD in 2020 | Inosine monophosphate dehydrogenase inhibitor; off-label for NMOSD | Purine analog immunosuppressant; off-label for NMOSD |
| Duration | Median 3.4 years on treatment | Median 2.9 years on treatment | Median 1.7 years on treatment | Median 0.6 years on treatment | Median 2.1 years on treatment | Median 0.9 years on treatment |
Outcomes
| Outcome | Type | Control | Intervention | HR / OR / RR | P-value |
|---|---|---|---|---|---|
| Relapse-free survival (time to first clinically definite or probable relapse) and annualized relapse rate (ARR), compared with rituximab | Primary | Rituximab: 5-year relapse-free probability 69.7%; ARR 0.08 (95% CI 0.062-0.10) | C5 inhibitors: 100% relapse-free at 5y, ARR 0 (95% CI 0-0.062); Inebilizumab: 100% relapse-free at 3y, ARR 0 (0-0.06); Satralizumab: 100% relapse-free at 3y, ARR 0 (0-0.17); MMF: 51.1% relapse-free at 5y, ARR 0.19 (0.14-0.26); Azathioprine: 35.3% relapse-free at 5y, ARR 0.34 (0.18-0.56) | 0.12 (C5 inhibitors), 0.22 (inebilizumab), 0.19 (satralizumab) vs. rituximab | All significant; ARR comparisons by Poisson and IPTW-adjusted negative binomial models |
| Composite: relapse, serious infectious AE (SIAE), or treatment-limiting AE (TLAE) - C5 inhibitors vs. rituximab | Secondary | Rituximab 5-y event-free 55% | C5 inhibitors 5-y event-free 91% | HR 0.22 | 95% CI 0.05-0.67 |
| Composite endpoint - Azathioprine vs. rituximab | Secondary | Rituximab 5-y event-free 55% | Azathioprine 5-y event-free 19% | HR 2.33 | 95% CI 1.08-4.86 |
| Composite endpoint - MMF vs. rituximab | Secondary | Rituximab 5-y event-free 55% | MMF 5-y event-free 35% | HR 1.75 | 95% CI 1.02-2.95 |
| Composite endpoint - Inebilizumab vs. rituximab | Secondary | Rituximab | Inebilizumab 3-y event-free 38% | HR 1.23 | 95% CI 0.24-3.12 (NS) |
| Composite endpoint - Satralizumab vs. rituximab | Secondary | Rituximab | Satralizumab 3-y event-free 79% | HR 1.01 | 95% CI 0.16-2.68 (NS) |
| Serious infectious adverse event (hospitalization for infection) - C5 inhibitors vs. rituximab | Secondary | Rituximab serious infections 28% of treatment periods | C5 inhibitors lowest IRR | Incidence rate ratio 0.16 (alt analysis 0.17) | 95% CI 0.05-0.42; P=0.0002 |
| Rituximab - Hypogammaglobulinemia | Adverse | 13% (25/192) | |||
| Rituximab - Common infections (UTI, URI) | Adverse | 34% | |||
| Rituximab - Serious infections (e.g., bacterial pneumonia, IV antibiotic-requiring) | Adverse | 28% | |||
| Rituximab - Hypersensitivity/infusion reactions | Adverse | 6.3% | |||
| Rituximab - Opportunistic infections | Adverse | 28% | |||
| C5 inhibitors - Common infections | Adverse | 9.5% | |||
| C5 inhibitors - Opportunistic infections | Adverse | 9.5% | |||
| C5 inhibitors - Hypogammaglobulinemia | Adverse | 0% | |||
| C5 inhibitors - Hypersensitivity | Adverse | 0% | |||
| Inebilizumab - Common infections | Adverse | 9.1% | |||
| Inebilizumab - Opportunistic infections | Adverse | 18% | |||
| Inebilizumab - Hypogammaglobulinemia | Adverse | 9.1% | |||
| Satralizumab - Common infections | Adverse | 11% | |||
| Satralizumab - Opportunistic infections | Adverse | 16% | |||
| Satralizumab - Hypersensitivity | Adverse | 5.3% | |||
| MMF - Common infections | Adverse | 31% | |||
| MMF - Opportunistic infections | Adverse | 25% | |||
| Azathioprine - Common infections | Adverse | 17% | |||
| Azathioprine - Opportunistic infections | Adverse | 17% | |||
| Serious infection incidence rate ratio vs. rituximab - C5 inhibitors | Adverse | 0.16 (95% CI 0.05-0.42) | |||
Subgroup Analysis
Restricting to AQP4-IgG seropositive patients produced similar results for relapse-free survival, ARR, and composite endpoint (eFigure 4); sensitivity analysis restricted to imaging-confirmed relapses also concordant (eFigure 3); inebilizumab and satralizumab were used exclusively in AQP4+ seropositive patients, while 1 seronegative patient received a C5 inhibitor.
Criticisms
- Retrospective single-network (Mass General Brigham) design with non-randomized treatment assignment; despite IPTW adjustment for age and prior attacks, residual confounding is likely (e.g., disease severity, comorbidities, calendar-era of treatment).
- Tertiary referral ascertainment bias - cohort may overrepresent refractory or severe NMOSD, limiting generalizability.
- Marked differences in time on treatment by drug (rituximab median 3.4 y vs. satralizumab 0.6 y, inebilizumab 1.7 y) and small per-arm sample sizes (inebilizumab n=11, satralizumab n=19, C5 inhibitors n=21) limit statistical power and may underestimate late adverse events for newer drugs.
- Zero-event arms (C5 inhibitors, inebilizumab, satralizumab) required Firth penalized regression and exact Poisson methods; the composite endpoint can mask differential effects across efficacy vs. toxicity.
- Retrospective relapse assessment is subjective despite dual-reviewer adjudication; MRI confirmation availability varied (94% in definite, 9.5% confirmed in 'unlikely' events), and historical inconsistent monitoring limited longitudinal CD19/CD20 and IgG data.
- Inebilizumab and rituximab share B-cell depletion mechanisms - expected similar long-term safety profiles may emerge with longer follow-up; selection bias toward rituximab for patients ineligible for trials may also affect comparisons.
- Cost-effectiveness was not formally evaluated despite large price differences (C5 inhibitors >$500,000/year first year vs. rituximab biosimilars $10,000-$20,000/year); authors call for dedicated cost-effectiveness studies.
Funding
Not explicitly stated in the abstract or available full text; institutional Mass General Brigham study with IRB approval. No commercial sponsor reported.
Based on: MGB-NMOSD (Neurology: Neuroimmunology & Neuroinflammation, 2026)
Authors: Bilodeau PA, Wruble Clark M, Ganguly A, ..., Bhattacharyya S
Citation: Neurol Neuroimmunol Neuroinflamm 2026;13(2):e200536
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