Objective This study was undertaken to assess the impact of immunosuppressive and immunomodulatory therapies on the severity of coronavirus disease 2019 (COVID‐19) in people with multiple sclerosis (PwMS). Methods We retrospectively collected data of PwMS with suspected or confirmed COVID‐19. All the patients had complete follow‐up to death or recovery. Severe COVID‐19 was defined by a 3‐level variable: mild disease not requiring hospitalization versus pneumonia or hospitalization versus intensive care unit (ICU) admission or death. We evaluated baseline characteristics and MS therapies associated with severe COVID‐19 by multivariate and propensity score (PS)‐weighted ordinal logistic models. Sensitivity analyses were run to confirm the results. Results Of 844 PwMS with suspected (n = 565) or confirmed (n = 279) COVID‐19, 13 (1.54%) died; 11 of them were in a progressive MS phase, and 8 were without any therapy. Thirty‐eight (4.5%) were admitted to an ICU; 99 (11.7%) had radiologically documented pneumonia; 96 (11.4%) were hospitalized. After adjusting for region, age, sex, progressive MS course, Expanded Disability Status Scale, disease duration, body mass index, comorbidities, and recent methylprednisolone use, therapy with an anti‐CD20 agent (ocrelizumab or rituximab) was significantly associated (odds ratio [OR] = 2.37, 95% confidence interval [CI] = 1.18–4.74, p = 0.015) with increased risk of severe COVID‐19. Recent use (<1 month) of methylprednisolone was also associated with a worse outcome (OR = 5.24, 95% CI = 2.20–12.53, p = 0.001). Results were confirmed by the PS‐weighted analysis and by all the sensitivity analyses. Interpretation This study showed an acceptable level of safety of therapies with a broad array of mechanisms of action. However, some specific elements of risk emerged. These will need to be considered while the COVID‐19 pandemic persists. ANN NEUROL 2021;89:780–789

See Stankoff and Louapre (doi:) for a scientific commentary on this article.Grey matter atrophy in multiple sclerosis affects certain areas preferentially. Eshaghi et al. use a data-driven computational model to predict the order in which regions atrophy, and use this sequence to stage patients. Atrophy begins in deep grey matter nuclei and posterior cortical regions, before spreading to other cortical areas.

ObjectiveTo assess whether it is feasible to establish specific cut-off values able to discriminate ‘physiological’ or ‘pathological’ brain volume rates in patients with multiple sclerosis (MS).MethodsThe study was based on the analysis of longitudinal MRI data sets of patients with MS (n=206, 87% relapsing–remitting, 7% secondary progressive and 6% primary progressive) and healthy controls (HC; n=35). Brain atrophy rates were computed over a mean follow-up of 7.5 years (range 1–12) for patients with MS and 6.3 years (range 1–12.5) for HC with the SIENA software and expressed as annualised per cent brain volume change (PBVC/y). A weighted (on the follow-up length) receiver operating characteristic analysis and the area under the curve (AUC) were used for statistics.ResultsThe weighted PBVC/y was −0.51±0.27% in patients with MS and −0.27±0.15% in HC (p<0.0001). There was a significant age-related difference in PBVC/y between HC older and younger than 35 years of age (p=0.02), but not in patients with MS (p=0.8). The cut-off of PBVC/y, as measured by SIENA that could maximise the accuracy in discriminating patients with MS from HC, was −0.37%, with 67% sensitivity and 80% specificity. According to the observed distribution, values of PBVC/y as measured by SIENA that could define a pathological range were above −0.52% with 95% specificity, above −0.46% with 90% specificity and above −0.40% with 80% specificity.ConclusionsOur evidence-based criteria provide values able to discriminate the presence or absence of ‘pathological’ brain volume loss in MS with high specificity. Such results could be of great value in a clinical setting, particularly in assessing treatment efficacy in MS.

Background In patients with Multiple Sclerosis (pwMS) disease-modifying therapies (DMTs) affects immune response to antigens. Therefore, post-vaccination serological assessments are needed to evaluate the effect of the vaccine on SARS-CoV-2 antibody response. Methods We designed a prospective multicenter cohort study enrolling pwMS who were scheduled for SARS-Cov-2 vaccination with mRNA vaccines (BNT162b2, Pfizer/BioNTech,Inc or mRNA-1273, Moderna Tx,Inc). A blood collection before the first vaccine dose and 4 weeks after the second dose was planned, with a centralized serological assessment (electrochemiluminescence immunoassay, ECLIA, Roche-Diagnostics). The log-transform of the antibody levels was analyzed by multivariable linear regression. Findings 780 pwMS (76% BNT162b2 and 24% mRNA-1273) had pre- and 4-week post-vaccination blood assessments. 87 (11·2%) were untreated, 154 (19·7%) on ocrelizumab, 25 (3·2%) on rituximab, 85 (10·9%) on fingolimod, 25 (3·2%) on cladribine and 404 (51·7%) on other DMTs. 677 patients (86·8%) had detectable post-vaccination SARS-CoV-2 antibodies. At multivariable analysis, the antibody levels of patients on ocrelizumab (201-fold decrease (95%CI=128–317), p < 0·001), fingolimod (26-fold decrease (95%CI=16–42), p < 0·001) and rituximab (20-fold decrease (95%CI=10–43), p < 0·001) were significantly reduced as compared to untreated patients. Vaccination with mRNA-1273 resulted in a systematically 3·25-fold higher antibody level (95%CI=2·46–4·27) than with the BNT162b2 vaccine ( p < 0·001). The antibody levels on anti-CD20 therapies correlated to the time since last infusion, and rituximab had longer intervals (mean=386 days) than ocrelizumab patients (mean=129 days). Interpretation In pwMS, anti-CD20 treatment and fingolimod led to a reduced humoral response to mRNA-based SARS-CoV-2 vaccines. As mRNA-1273 elicits 3·25-higher antibody levels than BNT162b2, this vaccine may be preferentially considered for patients under anti-CD20 treatment or fingolimod. Combining our data with those on the cellular immune response to vaccines, and including clinical follow-up, will contribute to better define the most appropriate SARS-CoV-2 vaccine strategies in the context of DMTs and MS. Funding FISM[2021/Special-Multi/001]; Italian Ministry of Health‘Progetto Z844A 5 × 1000′.

Background : We previously reported selective decreases of neocortical volumes in patients with early relapsing-remitting (RR) multiple sclerosis (MS) with mild cognitive impairment, with a good correlation between cortical volumes and cognitive measures.Objective: To assess the relevance of gray matter changes over time to changes in cognition in RRMS.Design: A longitudinal survey after 2.5 years. Each patient underwent a magnetic resonance imaging (MRI) protocol identical to that performed at baseline; cognitive performance was reassessed with the Rao Brief Repeatable Battery of Neuropsychological Tests in Multiple Sclerosis. Setting: Two university MS clinics.Patients: Of 41 patients with RRMS who participated in the original cross-sectional study, 28 were available for the follow-up evaluation (18 women; mean±SD age, 37.1±8.9 years; mean±SD MS duration, 7.3±2.9 years; mean±SD Expanded Disability Status Scale score, 1.8±1.5). Main Outcome Measures:We measured the percentage of brain volume changes, normalized cortical volume (NCV) changes, and normalized deep gray matter volume changes on conventional T1-weighted MRIs and changes in lesion load on T2-weighted MRIs. The number of tests failed on the Rao Brief Repeatable Battery were used to classify the patients as cognitively deteriorating or stable or improving.Results: We identified 12 of 28 cognitively deteriorating and 16 of 28 stable or improving patients. These subgroups did not differ in the mean±SD percentage of brain volume changes (−2.1%±1.2% vs −1.3%±1.3%; P=.11), normalized deep gray matter volume changes (−2.1±2.8 mL vs −0.6±3.1 mL; P=.60), and changes in lesion load on T2-weighted MRIs (1.9±2.6 mL vs 1.6±2.3 mL; P=.73). However, NCV changes were significantly higher in deteriorating than in stable or improving patients (−43.0±18.9 mL vs −17.8 ± 26.6 mL; P = .007). In deteriorating patients, NCV changes were correlated with performance in a verbal fluency test (r=0.73; PϽ.001). In a regression model, only NCV changes were significantly associated with deteriorating cognitive performance (odds ratio, 0.8; 95% confidence interval, 0.7-0.9). Conclusion:Progressive neocortical gray matter loss is relevant to MS-associated cognitive impairment and may represent a sensitive marker of deteriorating cognitive performance in RRMS.