Highlights
In a nationwide French registry spanning 98 centers, both aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder (AQP4+NMOSD) and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) showed substantial declines in annualized relapse rates between 2010 and 2024.
Time to diagnosis shortened over the study period, consistent with increasing disease recognition, wider antibody testing, and more standardized diagnostic frameworks.
Therapeutic practice evolved markedly, particularly in AQP4+NMOSD, where rituximab use increased over time and was associated with a lower risk of progressing to Expanded Disability Status Scale (EDSS) 6.
MOGAD patients had a lower risk of reaching EDSS 3 and EDSS 6 than patients with AQP4+NMOSD, reinforcing the view that these are related but clinically distinct antibody-mediated disorders with different disability trajectories.
Background and Clinical Context
AQP4+NMOSD and MOGAD are now recognized as distinct inflammatory diseases of the central nervous system, but this distinction is relatively recent in routine practice. Historically, many patients were grouped under broader inflammatory demyelinating syndromes or misclassified as atypical multiple sclerosis. Over the past 15 years, the availability of cell-based antibody assays, refinement of diagnostic criteria, and growing therapeutic experience have transformed how clinicians diagnose and treat these disorders.
AQP4+NMOSD is typically a severe astrocytopathy driven by pathogenic immunoglobulin G against aquaporin-4, often presenting with optic neuritis, longitudinally extensive transverse myelitis, area postrema syndrome, brainstem syndromes, or diencephalic and cerebral involvement. Relapses are a major determinant of cumulative disability, and prevention of attacks is a central therapeutic goal. MOGAD, in contrast, is an antibody-associated demyelinating disease with a broader age range, frequent optic neuritis and myelitis, and in some cases acute disseminated encephalomyelitis or cortical encephalitis. Although MOGAD can be highly relapsing, long-term disability is often lower than in AQP4+NMOSD, particularly when severe relapses are prevented and visual recovery is favorable.
The present analysis from the French NOMADMUS cohort is therefore clinically important because it examines how real-world care changed during a period when the field moved from diagnostic uncertainty and empiric immunosuppression toward antibody-defined disease categories and more targeted relapse prevention.
Study Design and Methods
Roux and colleagues performed a retrospective analysis of the NOMADMUS cohort, a nationwide French registry including data from 98 centers as of June 8, 2024. Patients were classified by serologic status into two groups: AQP4+NMOSD and MOGAD. The analysis included clinical characteristics, imaging data, and treatment exposure over time.
The cohort comprised 769 patients with AQP4+NMOSD and 957 with MOGAD. Across the full cohort, 68.6% were female, and the mean age at onset was 37.4 years with a standard deviation of 18.3 years. These figures reflect the known female predominance of AQP4+NMOSD and the broader age distribution seen in antibody-mediated demyelinating disease.
The principal outcomes described in the abstract were changes in annualized relapse rate over calendar time, disability outcomes measured by EDSS milestones, and treatment evolution, particularly the use of rituximab. The authors also examined the time to diagnosis and compared disability progression between AQP4+NMOSD and MOGAD.
Because this was a retrospective registry study, treatment allocation was not randomized. Accordingly, associations between therapies and outcomes should be interpreted as real-world correlates rather than proof of causal efficacy. Even so, large multicenter registries are especially valuable in rare diseases, where randomized head-to-head data are scarce and national treatment patterns can change rapidly following advances in antibody testing and regulatory approvals.
Key Results
Cohort size and demographic profile
The scale of the registry is a major strength. With 1,726 antibody-defined patients enrolled across nearly 100 French centers, NOMADMUS provides one of the more informative national snapshots of these rare disorders. The combined female proportion of 68.6% and average onset age in the late 30s are consistent with prior epidemiologic observations, though these pooled values likely mask meaningful between-disease differences, as AQP4+NMOSD is typically more female-predominant than MOGAD.
Relapse activity fell substantially over time
The most striking finding is the progressive reduction in annualized relapse rates across the observation period. In AQP4+NMOSD, the mean annualized relapse rate declined from 0.45 during 2010-2014 to 0.04 during 2022-2023, with a highly significant difference by Welch’s t test (p < 0.0001). The abstract states that similar decreases occurred in MOGAD as well, indicating that the fall in inflammatory activity was not restricted to a single antibody-defined population.
Clinically, a drop of this magnitude is meaningful. In AQP4+NMOSD, each relapse can leave permanent visual, motor, sensory, bowel-bladder, or brainstem disability. Therefore, even modest reductions in relapse frequency can translate into important long-term benefits. The observed decline likely reflects several converging developments: earlier diagnosis, more widespread use of relapse-preventive immunotherapy, improved clinician recognition of relapse phenotypes, and perhaps better avoidance of treatments known to be ineffective or potentially harmful in NMOSD.
Diagnosis became faster
The registry also documented a reduction in time to diagnosis over the 15-year period. Although the abstract does not provide the exact interval data, this trend is highly plausible and clinically significant. Delayed diagnosis historically exposed patients to repeated attacks before a clear disease label was established. The improved diagnostic timeline likely reflects broader availability of serum antibody testing, implementation of international criteria, and growing familiarity among neurologists, ophthalmologists, neuroradiologists, and emergency clinicians with opticospinal and area postrema presentations.
This point is especially relevant for MOGAD, whose recognition as a disease distinct from both multiple sclerosis and AQP4-NMOSD matured later than the recognition of AQP4+NMOSD. Faster diagnosis can reduce diagnostic drift, limit inappropriate use of multiple sclerosis disease-modifying therapies, and support earlier risk stratification for relapse prevention.
Treatment patterns evolved, especially rituximab use in AQP4+NMOSD
Therapeutic strategy shifted considerably over the study period. In AQP4+NMOSD, rituximab use increased over time and was associated with a lower risk of reaching EDSS 6, with a hazard ratio of 0.38 and a statistically significant p value below 0.001; the reported interval was 0.21 to 0.68. This suggests a substantial relative reduction in the risk of severe ambulatory disability among treated patients.
From a practical standpoint, EDSS 6 corresponds to the need for unilateral assistance, such as a cane or crutch, to walk about 100 meters. Preventing progression to this level is a meaningful patient-centered outcome. The association observed here aligns with long-standing clinical experience supporting B-cell depletion in AQP4+NMOSD and is biologically plausible given the central role of antibody-mediated humoral immunity in the disease.
The abstract does not detail treatment trends in MOGAD to the same extent, which likely reflects the absence of a universally accepted standard long-term maintenance strategy and the more heterogeneous relapse course in that disorder. Real-world treatment in MOGAD often includes corticosteroid tapering, intravenous immunoglobulin, rituximab, mycophenolate mofetil, azathioprine, or observation after a monophasic event, depending on relapse pattern and phenotype. The French registry’s broad timeframe should eventually help clarify which maintenance strategies are associated with the best balance of relapse control and functional outcome in different MOGAD subgroups.
Disability accumulation was lower in MOGAD than in AQP4+NMOSD
The study found that the risk of reaching EDSS 3 or EDSS 6 was lower in MOGAD than in AQP4+NMOSD. This is an important comparative result because it reinforces a consistent clinical message: while MOGAD can cause severe acute attacks, its long-term disability trajectory is often less aggressive than that of AQP4+NMOSD, particularly when assessed at the population level.
EDSS 3 generally reflects moderate disability but preserved ambulation, whereas EDSS 6 marks substantial mobility impairment. Lower risk at both thresholds suggests that MOGAD not only progresses more slowly to severe disability but also accumulates moderate neurologic deficits less frequently than AQP4+NMOSD. That said, this group-level observation should not obscure the fact that some MOGAD patients experience recurrent optic neuritis with cumulative visual loss or relapsing myelitis with significant residual deficits.
Clinical Interpretation
This report captures a broader transition in neuroimmunology: antibody-defined diagnosis has changed both prognosis and management. The reduction in relapse activity across time is likely not merely a secular trend but a reflection of improved systems of care. French clinicians increasingly recognized disease-specific presentations, accessed more reliable cell-based assays, and escalated maintenance therapy more effectively in high-risk patients.
For AQP4+NMOSD, the rituximab finding is particularly relevant in countries and health systems where access to newer biologics may vary. Although randomized trials have since established efficacy for agents such as eculizumab, satralizumab, and inebilizumab in AQP4-IgG-positive NMOSD, rituximab has remained a widely used off-label standard in many centers because of clinician familiarity, comparatively broad availability, and generally strong real-world performance. The NOMADMUS data support the idea that broader rituximab adoption has likely contributed to better long-term disease control in routine practice.
For MOGAD, the registry underscores a more nuanced reality. Outcomes are generally better than in AQP4+NMOSD, but management remains less standardized. The disease can be monophasic or relapsing, pediatric or adult-onset, optic nerve-predominant or multifocal. This heterogeneity complicates treatment decisions and makes real-world longitudinal data especially valuable. The current study therefore advances understanding even without establishing a single preferred MOGAD maintenance regimen.
Strengths and Limitations
Strengths
The main strengths are scale, national coverage, and clinical relevance. Rare-disease registries are indispensable when randomized evidence is incomplete, especially for long-term outcomes such as disability accumulation and evolving treatment patterns. The inclusion of 98 centers improves representativeness and reduces the chance that observed trends simply reflect the practice style of a few tertiary referral hospitals.
The long observation window from 2010 to 2024 is another major asset. It spans key periods in the field, including the establishment of the 2015 International Panel criteria for NMOSD and the later formalization of MOGAD as a distinct entity. This allows the registry to function not just as a cohort description but as a record of how scientific advances translated into practice.
Limitations
As a retrospective observational study, the analysis is vulnerable to confounding by indication, survivorship bias, and changes in referral patterns. Patients treated with rituximab may differ systematically from those not receiving it, and calendar-time improvements may partly reflect better ascertainment of milder cases or earlier entry into specialist care.
The abstract provides limited granularity regarding subgroup composition, treatment sequencing, relapse definitions, antibody assay harmonization, and handling of missing data. It also does not specify adjusted covariates for the reported hazard ratio. These details will matter when readers interpret the magnitude and robustness of the treatment-outcome associations.
Another important issue is generalizability. France has a mature referral network for rare neuroinflammatory disease, and outcomes may differ in settings with less consistent antibody access, fewer specialty centers, or different reimbursement structures for immunotherapy.
Relation to Current Evidence and Guidelines
The NOMADMUS findings fit well with contemporary knowledge. The 2015 International Panel criteria helped standardize diagnosis of NMOSD, particularly for AQP4-IgG-positive patients. More recently, international MOGAD diagnostic criteria have provided a framework for classifying this increasingly recognized disorder. Parallel therapeutic advances have reshaped AQP4+NMOSD care, with randomized controlled trials supporting complement inhibition, interleukin-6 receptor blockade, and CD19-directed B-cell depletion in selected patients. Even before and alongside these approvals, rituximab accumulated a substantial real-world evidence base.
What this French registry adds is not proof that one agent is universally superior, but a real-world demonstration that systems-level progress matters: earlier diagnosis, more coherent disease labeling, and greater uptake of effective relapse prevention are associated with better outcomes over time. For clinicians, this is a reminder that rare-disease care improves not only through new drugs but also through diagnostic pathways, referral networks, laboratory access, and longitudinal follow-up.
Implications for Practice
Several practical implications emerge. First, rapid antibody testing remains crucial in patients with optic neuritis, longitudinally extensive transverse myelitis, area postrema syndrome, or steroid-responsive demyelinating syndromes that do not fit typical multiple sclerosis. Second, preventing relapses should remain the central management objective in AQP4+NMOSD, given the high disability cost of each attack. Third, MOGAD should be approached as a distinct disease with individualized relapse-risk assessment rather than as a variant of multiple sclerosis or NMOSD.
For health systems, the findings support continued investment in national registries and specialist referral pathways. In rare neuroimmunologic diseases, practice variation can be substantial, and registries provide an efficient way to monitor outcomes, identify effective treatment strategies, and inform policy where conventional trials are difficult to conduct.
Conclusion
The French NOMADMUS cohort offers a compelling longitudinal view of how AQP4+NMOSD and MOGAD care has evolved from 2010 to 2024. Across a large national registry, time to diagnosis decreased, relapse activity fell substantially, and treatment strategies shifted toward more active long-term prevention. In AQP4+NMOSD, increasing rituximab use was associated with a lower risk of reaching EDSS 6, while MOGAD showed a more favorable disability trajectory than AQP4+NMOSD overall.
These results illustrate the clinical value of earlier recognition and sustained relapse prevention in antibody-mediated central nervous system disease. They also highlight an important next step for the field: translating registry insights into more precise, phenotype-specific treatment algorithms, especially for MOGAD, where long-term management remains less standardized.
Funding and Trial Registration
The abstract provided does not report funding details or a ClinicalTrials.gov registration number. NOMADMUS is described as a nationwide French cohort analysis.
References
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