What were the key findings of the DS-NMOSD COHORT trial?

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DS-NMOSD COHORT

Comparative Effectiveness of Disease-Modifying Treatments in Double Seronegative Neuromyelitis Optica Spectrum Disorder

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Year of Publication: 2026

Authors: Mahler JV, Vallejos GB, Mikami T, et al.

Journal: Neurology Neuroimmunology & Neuroinflammation

Citation: Neurol Neuroimmunol Neuroinflamm 2026;13(2):e200514

Link: https://doi.org/10.1212/NXI.0000000000200514

Bottom Line

In a multicenter international cohort of 103 patients with DS-NMOSD, anti-CD20 therapy (mostly rituximab) was associated with a ~98% lower relapse incidence rate ratio than the pretreatment period and substantially outperformed nonspecific immunosuppressants and MS DMTs, supporting B-cell depletion as first-line therapy.

        Major Points
        Largest reported cohort of double seronegative NMOSD (n=103) from 6 countries; median follow-up 6 years.
Anti-CD20 agents reduced relapse IRR to 0.02 (95% CI 0.01-0.04) vs pretreatment; nonspecific immunosuppressants 0.09 (0.07-0.13); MS DMTs 0.13 (0.06-0.30).
Estimated adjusted ARR: anti-CD20 0.17, NSIS 0.76, MS DMTs 1.07; Bonferroni-corrected anti-CD20 vs NSIS p=0.003 and vs MS DMTs p=0.002.
Cox HR for relapse: anti-CD20 vs MS DMTs 0.06 (95% CI 0.02-0.24, p<0.001); log-rank for anti-CD20 vs NSIS p=0.0001.
Within most-used drugs, relapse-free status: rituximab 84.6%, mycophenolate 74.1%, azathioprine 46% (chi-squared p=0.00012); azathioprine vs rituximab HR 4.95 (p=0.00016).
Traditional MS DMTs (interferon, glatiramer, fumarates, alemtuzumab) did not appear as harmful in DS-NMOSD as in AQP4+ NMOSD, but still inferior to anti-CD20.
Class IV evidence supporting anti-CD20 as preferred first-line relapse prevention in DS-NMOSD.

      

Design

Study Type: Retrospective multicenter international cohort study (Class IV evidence)

Randomization:

Blinding: Unblinded (retrospective chart review)

Enrollment Period: Data collection December 2023 - November 2024

Follow-up Duration: Median 6 years (IQR 4.1-10.9)

Centers: 10

Countries: United States, Brazil, United Kingdom, Thailand, Turkiye, China

Sample Size: 103

Analysis: Negative binomial mixed-effects regression with adjustment for covariates; Cox proportional hazards; estimated marginal means with Bonferroni correction; treatment exposure modeled as time-varying

Inclusion Criteria

Adults >=18 years at the time of data collection
Fulfilled IPND-2015 AQP4-IgG-seronegative NMOSD criteria (2 core clinical syndromes, at least one supporting neuroimaging feature, no alternative diagnosis)
Negative serum AQP4-IgG via cell-based assay at least once with subsequent consistently negative testing
Negative serum MOG-IgG via cell-based assay at least once with subsequent consistently negative testing
At least 12 months of clinical follow-up
Diagnosis of DS-NMOSD confirmed as leading diagnosis at last follow-up by senior neuroimmunologists

Exclusion Criteria

Fewer than 12 months of follow-up
Missing treatment data
Combination therapy with 2 or more concurrent DMTs
Documented medication adherence concerns
Suspicion for an alternative diagnosis such as atypical multiple sclerosis or neurosarcoidosis

Baseline Characteristics

Characteristic	Overall (N=103)	Treatment Distribution
Female	76 (73.7%)
Male	27 (26.2%)
Median Age at Onset (y)	35 (IQR 24-44)
Median Follow-up (y)	6.0 (IQR 4.1-10.9)
Race - White	48 (46.6%)
Race - Black/African American	12 (11.7%)
Race - Asian	22 (21.4%)
Race - Other	19 (18.4%)
Ethnicity - Latino	28 (27.1%)
Relapsing Disease	82 (79.6%)
MOGAD-like Features	7 (6.7%)
Onset - Optic Neuritis	55 (53.3%)
Onset - Transverse Myelitis	60 (58.2%)
Onset - Simultaneous ON+TM	21 (20.3%)
Onset - Area Postrema Syndrome	12 (11.6%)
Onset - Brainstem Syndrome	12 (11.6%)
Onset - Cerebral Syndrome	4 (3.9%)
Positive Oligoclonal Bands	13/75 (17.3%)
Longitudinally Extensive Myelitis (>=3 segments)	76 (73.8%)
Longitudinally Extensive Optic Neuritis	53 (51.4%)
Periependymal Brainstem Lesions	25 (24.3%)
Autoimmune Comorbidities	13 (12.6%)
Median MOG-IgG Tests per Patient	2 (IQR 1-3)
Tested with Live CBA for MOG-IgG	74 (72%)
Tested with Fixed CBA for MOG-IgG	24 (23%)
Tested Before First DMT	28 (27%)
Any DMT		97 (94.1%)
Anti-CD20 (rituximab/ocrelizumab)		53 (51.4%)
Rituximab		52 (50.4%)
Ocrelizumab		2 (1.9%)
Nonspecific Immunosuppressants (any)		66 (64%)
Azathioprine		50 (48.5%)
Mycophenolate		27 (26.2%)
Cyclophosphamide		8 (7.8%)
Methotrexate		3 (2.9%)
Mitoxantrone		1 (0.9%)
Traditional MS DMTs		7 (6.8%)
IVIg		3 (2.9%)
Tocilizumab		2 (1.9%)
Eculizumab		1 (1.0%)

Arms

Field	Anti-CD20	Nonspecific Immunosuppressants (NSIS)	MS DMTs	Control
Intervention	Rituximab or ocrelizumab (B-cell depletion)	Azathioprine, mycophenolate, methotrexate, cyclophosphamide, or mitoxantrone	Interferon-beta, glatiramer, fumarates, or alemtuzumab	No chronic DMT (time from disease onset to first DMT or full follow-up for untreated patients)
Duration	Variable, time-varying exposure modeled per patient	Variable, time-varying exposure modeled per patient	Variable, time-varying exposure modeled per patient	Variable

Outcomes

Outcome	Type	Control	HR / OR / RR	P-value
Incidence rate ratio (IRR) of relapses on each DMT class compared with the pretreatment period (negative binomial mixed-effects regression, adjusted for covariates)	Primary			<0.001 for all DMT groups vs pretreatment
Adjusted annualized relapse rate (ARR) - Anti-CD20	Secondary	Value: 0.17 (95% CI 0.07-0.40)
Adjusted ARR - NSIS	Secondary	Value: 0.76 (95% CI 0.40-1.43)
Adjusted ARR - MS DMTs	Secondary	Value: 1.07 (95% CI 0.39-2.93)
Pairwise ARR anti-CD20 vs NSIS (Bonferroni-corrected)	Secondary			0.003
Pairwise ARR anti-CD20 vs MS DMTs (Bonferroni-corrected)	Secondary			0.002
Pairwise ARR NSIS vs MS DMTs	Secondary			Not significant
Cox HR for relapse - anti-CD20 vs MS DMTs	Secondary		0.06 (95% CI 0.02-0.24)	<0.001
Cox HR for relapse - NSIS vs MS DMTs	Secondary		0.35 (95% CI 0.12-1.04)	0.059
Kaplan-Meier anti-CD20 vs NSIS log-rank	Secondary			0.0001
Relapse-free status during rituximab treatment periods	Secondary	Value: 84.6% (44/52)
Relapse-free status during mycophenolate treatment periods	Secondary	Value: 74.1% (20/27)
Relapse-free status during azathioprine treatment periods	Secondary	Value: 46% (23/50)
Azathioprine vs rituximab (univariate Cox)	Secondary		4.95 (95% CI 2.16-11.38)	0.00016
Mycophenolate vs rituximab (univariate Cox)	Secondary		2.03 (95% CI 0.71-5.79)	0.18
Mycophenolate vs azathioprine (univariate Cox)	Secondary		0.41 (95% CI 0.18-0.94)	0.03
Early (first-line) vs late rituximab	Secondary		1.28 (95% CI 0.3-5.4)	0.73
Pretreatment duration (each additional month)	Secondary			<0.001
NSIS discontinuation - driven by relapses	Adverse	46% of NSIS discontinuations
NSIS discontinuation - adverse events	Adverse	29% of NSIS discontinuations
NSIS discontinuation - pregnancy planning	Adverse	14% of NSIS discontinuations
Anti-CD20 discontinuation	Adverse	Rare; too few events for class-level rate comparison
Note	Adverse	Detailed adverse event tables (e.g., infusion reactions, infections) were not reported in this retrospective cohort; safety data were limited to discontinuation reasons recorded in charts

Subgroup Analysis

Sex, race, ethnicity, age at onset, suspicion for MOGAD, and clinical onset syndrome (ON, TM, simultaneous ON+TM, area postrema, brainstem, or cerebral) were not significantly associated with relapse rate after adjustment. Longer interval from disease onset to first DMT was associated with a slightly lower IRR (0.98 per month, p<0.001), interpreted as confounding by indication (milder disease delays DMT).

Criticisms

Retrospective observational design with potential residual confounding and confounding by indication despite multivariable adjustment.
Class IV evidence; no randomization or blinding.
Roughly 23% of patients tested with fixed (rather than live) cell-based assays, which have lower sensitivity for MOG-IgG and AQP4-IgG; cannot fully exclude misclassified MOGAD or AQP4+ cases.
Median time from onset to antibody testing was long (33.6 months for AQP4-IgG and 47.1 months for MOG-IgG), and only 27% were tested before any DMT; immunotherapy can cause MOG-IgG sero-reversion.
Neuroimaging was not required for attack definition and MRI was available in only ~60% of attacks; possible inclusion of pseudorelapses.
Corticosteroid maintenance regimens excluded from exposure modeling due to inconsistent documentation; acute rescue therapy data also incompletely captured.
Patients on combination DMTs excluded, possibly skewing the cohort toward milder phenotypes; selection bias from IPND-2015 diagnostic requirement of 2 core syndromes biases toward relapsing disease.
Small number of patients on MS DMTs (n=7), eculizumab (n=1), tocilizumab (n=2), and IVIg (n=3) limits inference for these classes.
Adverse event reporting was limited to documented discontinuation reasons rather than systematic safety capture.

Funding

Not specified in the available full text

Based on: DS-NMOSD COHORT (Neurology Neuroimmunology & Neuroinflammation, 2026)

Authors: Mahler JV, Vallejos GB, Mikami T, et al.

Citation: Neurol Neuroimmunol Neuroinflamm 2026;13(2):e200514

Content summarized and formatted by NeuroTrials.ai.

DS-NMOSD COHORT

(2026)

Objective

Compare the real-world effectiveness of anti-CD20 agents vs nonspecific immunosuppressants for relapse prevention in double seronegative NMOSD (AQP4-IgG and MOG-IgG negative).

Study Summary

• Anti-CD20 therapy markedly lowered relapse incidence rate ratio (IRR 0.02, 95% CI 0.01-0.04) vs pretreatment, outperforming nonspecific immunosuppressants (IRR 0.09, 95% CI 0.07-0.13) and MS DMTs (IRR 0.13, 95% CI 0.06-0.30)
• Adjusted annualized relapse rate was lowest with anti-CD20 (ARR 0.17, 95% CI 0.07-0.40) vs NSIS (0.76, 95% CI 0.40-1.43) and MS DMTs (1.07, 95% CI 0.39-2.93); Bonferroni-corrected pairwise p=0.003 vs NSIS, p=0.002 vs MS DMTs
• Cox model: anti-CD20 HR 0.06 (95% CI 0.02-0.24, p<0.001) vs MS DMTs; relapse-free status with rituximab 84.6%, mycophenolate 74.1%, azathioprine 46% (p=0.00012)

Intervention

Anti-CD20 B-cell depletion (rituximab, ocrelizumab) compared with nonspecific immunosuppressants (azathioprine, mycophenolate, methotrexate, cyclophosphamide, mitoxantrone) and MS DMTs.

Inclusion Criteria

Adults meeting IPND-2015 AQP4-IgG-seronegative NMOSD criteria with persistently negative serum AQP4-IgG and MOG-IgG via cell-based assays and >=12 months of follow-up.

Study Design

Arms: Anti-CD20 (n=53) vs Nonspecific immunosuppressants (n=66) vs MS DMTs (n=7); pretreatment period served as reference.

Patients per Arm: 103 patients overall, 214 treatment periods (anti-CD20 53, NSIS 66, MS DMTs 7, others 6)

Outcome

• Primary: IRR of relapses lowest with anti-CD20 (0.02, 95% CI 0.01-0.04) vs NSIS (0.09) vs MS DMTs (0.13), all p<0.001 vs pretreatment
• Secondary: Adjusted ARR 0.17 (anti-CD20) vs 0.76 (NSIS) vs 1.07 (MS DMTs); time-to-relapse HR 0.06 anti-CD20 vs MS DMTs (95% CI 0.02-0.24, p<0.001)
• Sensitivity: rituximab vs azathioprine HR 4.95 (95% CI 2.16-11.38, p=0.00016); mycophenolate vs azathioprine HR 0.41 (95% CI 0.18-0.94, p=0.03)

Clinical Question

In patients with double seronegative NMOSD (AQP4-IgG and MOG-IgG negative), are anti-CD20 agents more effective than nonspecific immunosuppressants for relapse prevention?

Bottom Line

Major Points

Largest reported cohort of double seronegative NMOSD (n=103) from 6 countries; median follow-up 6 years.
Anti-CD20 agents reduced relapse IRR to 0.02 (95% CI 0.01-0.04) vs pretreatment; nonspecific immunosuppressants 0.09 (0.07-0.13); MS DMTs 0.13 (0.06-0.30).
Estimated adjusted ARR: anti-CD20 0.17, NSIS 0.76, MS DMTs 1.07; Bonferroni-corrected anti-CD20 vs NSIS p=0.003 and vs MS DMTs p=0.002.
Cox HR for relapse: anti-CD20 vs MS DMTs 0.06 (95% CI 0.02-0.24, p<0.001); log-rank for anti-CD20 vs NSIS p=0.0001.
Within most-used drugs, relapse-free status: rituximab 84.6%, mycophenolate 74.1%, azathioprine 46% (chi-squared p=0.00012); azathioprine vs rituximab HR 4.95 (p=0.00016).
Traditional MS DMTs (interferon, glatiramer, fumarates, alemtuzumab) did not appear as harmful in DS-NMOSD as in AQP4+ NMOSD, but still inferior to anti-CD20.
Class IV evidence supporting anti-CD20 as preferred first-line relapse prevention in DS-NMOSD.

Study Design

Study Type: Retrospective multicenter international cohort study (Class IV evidence)
Randomization: No
Blinding: Unblinded (retrospective chart review)
Sample Size: 103
Follow-up: Median 6 years (IQR 4.1-10.9)
Centers: 10
Countries: United States, Brazil, United Kingdom, Thailand, Turkiye, China

Primary Outcome

Definition: Incidence rate ratio (IRR) of relapses on each DMT class compared with the pretreatment period (negative binomial mixed-effects regression, adjusted for covariates)

Control	Intervention	HR/OR	P-value
-	-	-	<0.001 for all DMT groups vs pretreatment

Limitations & Criticisms

Retrospective observational design with potential residual confounding and confounding by indication despite multivariable adjustment.
Class IV evidence; no randomization or blinding.
Roughly 23% of patients tested with fixed (rather than live) cell-based assays, which have lower sensitivity for MOG-IgG and AQP4-IgG; cannot fully exclude misclassified MOGAD or AQP4+ cases.
Median time from onset to antibody testing was long (33.6 months for AQP4-IgG and 47.1 months for MOG-IgG), and only 27% were tested before any DMT; immunotherapy can cause MOG-IgG sero-reversion.
Neuroimaging was not required for attack definition and MRI was available in only ~60% of attacks; possible inclusion of pseudorelapses.
Corticosteroid maintenance regimens excluded from exposure modeling due to inconsistent documentation; acute rescue therapy data also incompletely captured.
Patients on combination DMTs excluded, possibly skewing the cohort toward milder phenotypes; selection bias from IPND-2015 diagnostic requirement of 2 core syndromes biases toward relapsing disease.
Small number of patients on MS DMTs (n=7), eculizumab (n=1), tocilizumab (n=2), and IVIg (n=3) limits inference for these classes.
Adverse event reporting was limited to documented discontinuation reasons rather than systematic safety capture.

Citation

Neurol Neuroimmunol Neuroinflamm 2026;13(2):e200514

View Original Publication →

DS-NMOSD COHORT

Comparative Effectiveness of Disease-Modifying Treatments in Double Seronegative Neuromyelitis Optica Spectrum Disorder

Bottom Line

Major Points

Design

Inclusion Criteria

Exclusion Criteria

Baseline Characteristics

Arms

Outcomes

Subgroup Analysis

Criticisms

Funding

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