Hélène Zéphir

Distinguishing multiple sclerosis (MS) from myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) can be challenging because of some shared clinical and radiologic features. We aimed to describe adults with clear positive serum MOG antibodies (MOG-Abs) presenting with MS features and rethink their nosological framework. We conducted a retrospective longitudinal study within the French NOMADMUS cohort and included adults from 2015 to 2025 tested clear positive for MOG-Ab in the serum with at least 1 MS-suggestive feature: (1) biological (CSF-specific oligoclonal bands [OCBs] and/or kappa free light chain index [KFLCi] ≥5.7) or (2) radiologic (≥1 lesion among juxtacortical lesion, Dawson finger, or inferior temporal lobe lesion). All MRI scans were reviewed blindly by an expert neuroradiologist. Minimum clinical and radiologic follow-up was 6 months. We classified patients as (1) typical MS when fulfilling 2024 McDonald criteria, with OCB and/or KFLCi ≥5.7 and showing no MOGAD supporting features, or (2) equivocal in all other situations. Among the 78 included patients (65% female, median age: 35 years), 23% were classified as typical MS and 77% as equivocal; all met MOGAD criteria, and 76% met 2024 McDonald criteria, without using central veinous sign or paramagnetic rim lesion, which have been rarely assessed. Myelitis followed by optic neuritis constituted the predominant clinical presentations in the whole cohort (45% and 32%, respectively) and in both groups. For typical MS cases, half of the patients did not receive maintenance therapy after the first MOG-Ab-positive event, 28% relapsed, 55% developed new silent lesions, and none showed lesion resolution (median follow-up: 1.9 years). For equivocal patients, 84% had OCB and 88% had ≥1 MOGAD supporting feature. After the first MOG-Ab-positive event, 72% initiated a maintenance therapy-mostly rituximab-15% relapsed, 46% developed silent new lesions, and 23% showed complete resolution of ≥1 lesion (median follow-up: 3 years). Clear positive MOG-Ab may occur in patients with genuine MS, and their presence may lead to therapeutic inertia. The substantial proportion of equivocal cases highlights current diagnostic limitations and underscores the need for longitudinal clinical and radiologic reassessment.

Background Ofatumumab and ocrelizumab are widely used high-efficacy anti-CD20 therapies for relapsing-remitting multiple sclerosis (RRMS), but direct comparative evidence remains limited. We aimed to compare their effectiveness in routine clinical practice. Methods We conducted an observational cohort study emulating a target trial using data from the MSBase and Observatoire Français de la Sclérose en Plaques registries (January 2021 to December 2024). Adults with RRMS initiating ofatumumab or ocrelizumab were included. Patients were matched 1:1 using propensity scores. Primary outcomes were annualised relapse rate (ARR) and time to first relapse. Secondary outcomes included time to confirmed disability progression (CDP), progression independent of relapse activity (PIRA), confirmed disability improvement (CDI), MRI activity and treatment discontinuation. Negative binomial and Cox regression models were applied. Results A total of 5288 patients were matched with a median follow-up of 1.2 years for ofatumumab and 1.4 years for ocrelizumab. ARR was 0.07 (95% CI 0.05 to 0.08) with ofatumumab and 0.04 (0.03 to 0.05) with ocrelizumab, corresponding to an ARR ratio of 1.75 (1.43 to 2.13). Ofatumumab was associated with a lower risk of CDP (HR 0.66; 0.49 to 0.87) and PIRA (0.53; 0.39 to 0.73), but a lower probability of CDI (0.76; 0.60 to 0.96). No significant differences were observed in MRI activity or treatment discontinuation. Conclusions Both therapies were highly effective in a large cohort of patients with RRMS, with very low relapse or CDP rates. Ofatumumab was associated with slightly greater disability control, while ocrelizumab more effectively suppressed relapses. These differences were modest, and their clinical relevance requires further evidence and should be interpreted with caution.

ObjectivesAquaporin 4-immunoglobulin G-seropositive neuromyelitis optica spectrum disorder (AQP4+NMOSD) and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) are rare conditio...

The therapeutic strategy for late-onset multiple sclerosis (LOMS) with a relapsing-remitting onset remains unclear, potentially leading to underexposure to disease-modifying therapies (DMTs) compared with adult-onset multiple sclerosis (AOMS). We investigated the differences in DMT use between LOMS and AOMS within the French MS registry at comparable levels of disease severity. This retrospective cohort study used data extracted in December 2024 from the French MS registry on patients with relapsing-remitting onset MS between 1997 and 2023. The primary outcome was the annual probability of receiving a DMT according to age at MS onset, adjusted for disease severity. Secondary outcomes included the annual probability of receiving a highly effective DMT (HEDMT), each DMT separately, having ≥1 EDSS measurement, having ≥1 brain MRI, and DMT initiations and discontinuations. We used a longitudinal logistic model with generalized estimating equations and an inverse-probability-of-censoring weighting. A total of 36,148 were included patients; 26,540 (73.4%) were female, mean age was 33.5 years (SD, 9.7), and 2,308 (6.4%) were aged ≥50 at disease onset. Median follow-up was 10.8 years (interquartile range, 5.6-17.0). Patients with LOMS had a lower annual probability of receiving a DMT compared with patients with AOMS (73.7% vs 83.1%; odds ratio [OR], 0.57 [95% CI 0.52-0.62]). The difference was greater for HEDMT (24.6% vs 44.4%; OR, 0.41 [95% CI 0.36-0.46]). Patients with LOMS were more likely to receive teriflunomide and less likely to receive fumarates, S1PR modulators, natalizumab, or anti-CD20. Clinical and radiologic follow-up did not differ significantly between patients with LOMS and AOMS. The rate of DMT initiation was lower in patients with LOMS (0.13 vs 0.17 initiation per patient-year). Although the proportions of DMT discontinuation were similar (59.7% vs 60.4%, excluding pregnancy-related discontinuations), these discontinuations were more often attributed to a complete discontinuation strategy (27.9% vs 22.3%) and less often to an escalation strategy (9.2% vs 13.8%) in patients with LOMS. At comparable levels of disease severity, patients with LOMS were less likely to be treated with DMTs, particularly HEDMT, than patients with AOMS. This gap was driven both by fewer DMT initiations and more frequent complete discontinuations.

Background: Limited evidence exists on how to use kappa free light chains (κFLCs) and oligoclonal bands (OCBs) in diagnosing intrathecal immunoglobulin synthesis (IgS). Objective: To compare different algorithms to define IgS. Methods: A retrospective analysis of the 2022 French cohort study was conducted. Patients were considered to have IgS if (1) the κFLC index was ⩾6.1, (2) OCB was positive, (3) the κFLC index was ⩾6.1 or OCB was positive, (4) the κFLC index was ⩾20 or OCB was positive, regardless of the κFLC index value, or (5) the κFLC index was ⩾20 or OCB was positive (with OCB tested only when the κFLC index was between 3.5 and 20). People with multiple sclerosis (MS) were compared with controls and with a subgroup of age- and sex-matched MS-mimicking disorders. Results: Of 1531 patients, 675 had MS and 856 were controls (133 MS mimics). Agreement between OCB and κFLC index (⩾6.1) was high (89%). All tested algorithms demonstrated high accuracy in separating groups. Using the sequential approach (5) achieves higher specificity and a significant reduction in OCB testing. Conclusion: Using a simple cut-off point of 6.1 for routine screening is accurate, but testing for OCB when the κFLC index is between 3.5 and 20 increases specificity and should be prospectively studied in challenging cases.

The differential diagnosis between aquaporin-4-immunoglobulin G-positive neuromyelitis optica spectrum disorder (AQP4-NMOSD), myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD), and multiple sclerosis (MS) can be complex. Kappa free light chain index (KFLC-Index) emerged as an effective biomarker for distinguishing patients with MS from patients with other conditions. The main aim of this study was to assess the diagnostic performance of KFLC-Index in differentiating MOGAD, AQP4-NMOSD, and MS and to compare it with CSF-restricted oligoclonal bands (OCB) performance. We conducted a retrospective case-control study involving 18 French centers through our national NOMADMUS database. Patients were eligible if they received MOGAD or AQP4-NMOSD diagnosis and if OCB status and KFLC-Index levels were available or could be measured retrospectively. As a comparator, we included a group of patients with MS from the Lyon center. We included 303 patients with 140 MOGAD, 37 AQP4-NMOSD, and 126 MS. The sex ratio F/M was 1/1 in the MOGAD group, 5/1 in the NMOSD group, and 4/1 in the MS group. The median age was 38 years in the MOGAD group, 52 in the NMOSD group, and 32 in the MS group. The median KFLC-Index (interquartile range) was the lowest in the MOGAD group (0.60 [0.33-2.09]) with 71% of undetectable CSF-KFLC, intermediate in the NMOSD group (8.85 [3.04-16.78]), and the highest in the MS group (49.90 [16.31-113.39]). KFLC-Index had very good diagnostic performance in differentiating MOGAD from MS (area under the curve [AUC] 0.93, 95% CI 0.9-0.96) with an optimal threshold of 5.7 (95% CI 4.74-6.85), a sensitivity of 0.89 (0.83-0.94), and a specificity of 0.89 (0.83-0.94). KFLC-Index had good performance in differentiating NMOSD from MS (AUC 0.82, 95% CI 0.74-0.88) and MOGAD from NMOSD (AUC 0.77, 95% CI 0.69-0.86). KFLC-Index did not significantly outperformed OCB in separating MOGAD from MS and NMOSD from MS; however, the combination of the 2 tests was more performant than used separately. KFLC-Index is a valuable tool in distinguishing MS from AQP4-NMOSD and MOGAD and provides additional information to that given by OCB. We suggest that KFLC-Index as an additional supporting criterion for the differential diagnosis between MOGAD and MS.

Background: The revised McDonald criteria shifted toward the recognition of the radiologically isolated syndrome (RIS) as the first phase of the multiple sclerosis (MS) spectrum. Objectives: To characterize differences between RIS individuals, early MS patients, and healthy controls (HCs) using a high-precision clinical assessment tool based on digital technology. Methods: We performed a multicentric, cross-sectional study involving RIS, early MS patients, and HC. Subjects were assessed using Neuraccure, an iPad application capable of detecting subtle abnormalities in four neurological functions: hand coordination, low-contrast vision, reaction time, and eye movements. Results: In total, 565 individuals were included (MS: 255, RIS: 146, HC: 164). HC performed better than RIS and MS across all digital measures ( p < 0.0001 to 0.03). There was no statistical difference between RIS and MS patients, except for the coordination test, which was slightly worse in MS patients ( p = 0.03). The receiver operating characteristic (ROC) analysis indicated that the presence of at least two impaired functions could detect RIS and MS from HC with 83.2% sensitivity and 84.3% specificity. A higher number of impaired functions were associated with lower brain magnetic resonance imaging (MRI) volumes. Conclusion: High-precision neurological evaluation can distinguish HC from RIS and MS at an individual scale with a good performance.

In women with multiple sclerosis (MS), the therapeutic strategy may be influenced by the anticipation of future pregnancies, leading to underexposure to disease-modifying therapies (DMTs) and highly effective DMTs (HEDMTs) compared with men. We aimed to evaluate potential therapeutic inertia in women with MS and explore its causes. We performed a retrospective cohort study based on data extracted on June 2023 from the Observatoire Français de la Sclérose en Plaques for all patients with a relapsing-remitting MS onset between 18 and 40 years. The primary outcome was the annual probability of receiving a DMT, accounting for sex, disease severity, and pregnancy/postpartum periods. Secondary outcomes were the annual probability of receiving a HEDMT, each DMT separately, and interaction of the effect of sex with calendar year, patient age, and disease duration. We used a longitudinal logistic model with generalized estimating equations and an inverse-probability-of-censoring weighting. We included 22,657 patients with MS; 16,857 (74.4%) were female, mean (SD) age at onset was 29.0 (6.0) years, and median (interquartile range) follow-up duration was 11.6 (6.6-17.3) years. Women were significantly less likely to receive a DMT (odds ratio [OR] 0.92, 95% CI 0.87-0.97) or a HEDMT (OR 0.80, 95% CI 0.74-0.86). This difference appeared 2 years after disease onset for DMTs and 1 year for HEDMTs, and did not differ significantly according to patient's age. Teriflunomide, sphingosine-1-phosphate receptor modulators, and anti-CD20s were significantly underused in women throughout their entire period of availability; interferons β (IFN-β) and natalizumab were initially less used and then equally after some time; glatiramer acetate and fumarates were first used equally, then more frequently in women. The proportion of treated women, analyzed from the first childbirth of 5,268 women, began to decline 18 months before childbirth, from 42.6% to 27.9% at the estimated time of conception. Women with MS were significantly less exposed to DMTs compared with men. Anticipation of pregnancy was probably an important factor underlying this difference, but also sex-specific therapeutic inertia. Neurologists and patients should be educated on the most recent recommendations on the use of DMTs in the context of pregnancy to avoid deleterious therapeutic inertia.