Background and Objectives People with multiple sclerosis (MS) are a vulnerable group for severe coronavirus disease 2019 (COVID-19), particularly those taking immunosuppressive disease-modifying therapies (DMTs). We examined the characteristics of COVID-19 severity in an international sample of people with MS. Methods Data from 12 data sources in 28 countries were aggregated (sources could include patients from 1–12 countries). Demographic (age, sex), clinical (MS phenotype, disability), and DMT (untreated, alemtuzumab, cladribine, dimethyl fumarate, glatiramer acetate, interferon, natalizumab, ocrelizumab, rituximab, siponimod, other DMTs) covariates were queried, along with COVID-19 severity outcomes, hospitalization, intensive care unit (ICU) admission, need for artificial ventilation, and death. Characteristics of outcomes were assessed in patients with suspected/confirmed COVID-19 using multilevel mixed-effects logistic regression adjusted for age, sex, MS phenotype, and Expanded Disability Status Scale (EDSS) score. Results Six hundred fifty-seven (28.1%) with suspected and 1,683 (61.9%) with confirmed COVID-19 were analyzed. Among suspected plus confirmed and confirmed-only COVID-19, 20.9% and 26.9% were hospitalized, 5.4% and 7.2% were admitted to ICU, 4.1% and 5.4% required artificial ventilation, and 3.2% and 3.9% died. Older age, progressive MS phenotype, and higher disability were associated with worse COVID-19 outcomes. Compared to dimethyl fumarate, ocrelizumab and rituximab were associated with hospitalization (adjusted odds ratio [aOR] 1.56, 95% confidence interval [CI] 1.01–2.41; aOR 2.43, 95% CI 1.48–4.02) and ICU admission (aOR 2.30, 95% CI 0.98–5.39; aOR 3.93, 95% CI 1.56–9.89), although only rituximab was associated with higher risk of artificial ventilation (aOR 4.00, 95% CI 1.54–10.39). Compared to pooled other DMTs, ocrelizumab and rituximab were associated with hospitalization (aOR 1.75, 95% CI 1.29–2.38; aOR 2.76, 95% CI 1.87–4.07) and ICU admission (aOR 2.55, 95% CI 1.49–4.36; aOR 4.32, 95% CI 2.27–8.23), but only rituximab was associated with artificial ventilation (aOR 6.15, 95% CI 3.09–12.27). Compared to natalizumab, ocrelizumab and rituximab were associated with hospitalization (aOR 1.86, 95% CI 1.13–3.07; aOR 2.88, 95% CI 1.68–4.92) and ICU admission (aOR 2.13, 95% CI 0.85–5.35; aOR 3.23, 95% CI 1.17–8.91), but only rituximab was associated with ventilation (aOR 5.52, 95% CI 1.71–17.84). Associations persisted on restriction to confirmed COVID-19 cases. No associations were observed between DMTs and death. Stratification by age, MS phenotype, and EDSS score found no indications that DMT associations with COVID-19 severity reflected differential DMT allocation by underlying COVID-19 severity. Discussion Using the largest cohort of people with MS and COVID-19 available, we demonstrated consistent associations of rituximab with increased risk of hospitalization, ICU admission, and need for artificial ventilation and of ocrelizumab with hospitalization and ICU admission. Despite the cross-sectional design of the study, the internal and external consistency of these results with prior studies suggests that rituximab/ocrelizumab use may be a risk factor for more severe COVID-19.

Multiple sclerosis (MS) is an autoimmune inflammatory demyelinating central nervous system disorder that is more common in women, with onset often during reproductive years. The female:male sex ratio of MS rose in several regions over the last century, suggesting a possible sex by environmental interaction increasing MS risk in women. Since many with MS are in their childbearing years, family planning, including contraceptive and disease-modifying therapy (DMT) counselling, are important aspects of MS care in women. While some DMTs are likely harmful to the developing fetus, others can be used shortly before or until pregnancy is confirmed. Overall, pregnancy decreases risk of MS relapses, whereas relapse risk may increase postpartum, although pregnancy does not appear to be harmful for long-term prognosis of MS. However, ovarian aging may contribute to disability progression in women with MS. Here, we review sex effects across the lifespan in women with MS, including the effect of sex on MS susceptibility, effects of pregnancy on MS disease activity, and management strategies around pregnancy, including risks associated with DMT use before and during pregnancy, and while breastfeeding. We also review reproductive aging and sexual dysfunction in women with MS.

Objective To investigate pregnancy-related disease activity in a contemporary multiple sclerosis (MS) cohort. Methods Using data from the MSBase Registry, we included pregnancies conceived after December 31, 2010, in women with relapsing-remitting MS or clinically isolated syndrome. Predictors of intrapartum relapse and postpartum relapse and disability progression were determined by clustered logistic regression or Cox regression analyses. Results We included 1,998 pregnancies from 1,619 women with MS. Preconception annualized relapse rate (ARR) was 0.29 (95% confidence interval 0.27–0.32), fell to 0.19 (0.14–0.24) in the third trimester, and increased to 0.59 (0.51–0.67) in early postpartum. Among women who used fingolimod or natalizumab, ARR before pregnancy was 0.37 (0.28–0.49) and 0.29 (0.22–0.37), respectively, and increased during pregnancy. Intrapartum ARR decreased with preconception dimethyl fumarate use. ARR spiked after delivery across all DMT groups. Natalizumab continuation into pregnancy reduced the odds of relapse during pregnancy (odds ratio 0.76 per month [0.60–0.95], p = 0.017). DMT reinitiation with natalizumab protected against postpartum relapse (hazard ratio [HR] 0.11 [0.04–0.32], p < 0.0001). Breastfeeding women were less likely to relapse (HR 0.61 [0.41–0.91], p = 0.016). We found that 5.6% of pregnancies were followed by confirmed disability progression, predicted by higher relapse activity in pregnancy and postpartum. Conclusion Intrapartum and postpartum relapse probabilities increased among women with MS after natalizumab or fingolimod cessation. In women considered to be at high relapse risk, use of natalizumab before pregnancy and continued up to 34 weeks gestation with early reinitiation after delivery is an effective option to minimize relapse risks. Strategies of disease-modifying therapy use have to be balanced against potential fetal/neonatal complications.

The risk factors for conversion from relapsing-remitting to secondary progressive multiple sclerosis remain highly contested. The aim of this study was to determine the demographic, clinical and paraclinical features that influence the risk of conversion to secondary progressive multiple sclerosis. Patients with adult-onset relapsing–remitting multiple sclerosis and at least four recorded disability scores were selected from MSBase, a global observational cohort. The risk of conversion to objectively defined secondary progressive multiple sclerosis was evaluated at multiple time points per patient using multivariable marginal Cox regression models. Sensitivity analyses were performed. A total of 15,717 patients were included in the primary analysis. Older age (hazard ratio (HR) = 1.02, p < 0.001), longer disease duration (HR = 1.01, p = 0.038), a higher Expanded Disability Status Scale score (HR = 1.30, p < 0.001), more rapid disability trajectory (HR = 2.82, p < 0.001) and greater number of relapses in the previous year (HR = 1.07, p = 0.010) were independently associated with an increased risk of secondary progressive multiple sclerosis. Improving disability (HR = 0.62, p = 0.039) and disease-modifying therapy exposure (HR = 0.71, p = 0.007) were associated with a lower risk. Recent cerebral magnetic resonance imaging activity, evidence of spinal cord lesions and oligoclonal bands in the cerebrospinal fluid were not associated with the risk of conversion. Risk of secondary progressive multiple sclerosis increases with age, duration of illness and worsening disability and decreases with improving disability. Therapy may delay the onset of secondary progression.

Background: We sought to identify an optimal oral corticosteroid regimen at the onset of myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), which would delay time to first relapse while minimising cumulative corticosteroid exposure.Methods: In a retrospective multicentre cohort study, Cox proportional hazards models examined the relationship between corticosteroid course as a time-varying covariate and time to first relapse. Simon-Makuch and Kaplan-Meier plots identified an optimal dosing strategy.Results: We evaluated 109 patients (62 female, 57%; 41 paediatric, 38%; median age at onset 26 years, (IQR 8–38); median follow-up 6.2 years (IQR 2.6–9.6)). 76/109 (70%) experienced a relapse (median time to first relapse 13.7 months; 95% CI 8.2 to 37.9). In a multivariable model, higher doses of oral prednisone delayed time to first relapse with an effect estimate of 3.7% (95% CI 0.8% to 6.6%; p=0.014) reduced hazard of relapse for every 1 mg/day dose increment. There was evidence of reduced hazard of relapse for patients dosed ≥12.5 mg/day (HR 0.21, 95% CI 0.07 to 0.6; p=0.0036), corresponding to a 79% reduction in relapse risk. There was evidence of reduced hazard of relapse for those dosed ≥12.5 mg/day for at least 3 months (HR 0.12, 95% CI 0.03 to 0.44; p=0.0012), corresponding to an 88% reduction in relapse risk compared with those never treated in this range. No patient with this recommended dosing at onset experienced a Common Terminology Criteria for Adverse Events grade >3 adverse effect.Conclusions: The optimal dose of 12.5 mg of prednisone daily in adults (0.16 mg/kg/day for children) for a minimum of 3 months at the onset of MOGAD delays time to first relapse.

The visual system offers unparalleled precision in the assessment of neuroaxonal damage. With the majority of patients with multiple sclerosis (MS) experiencing afferent and efferent visual dysfunction, outcome measures capturing these deficits provide insight into neuroaxonal injury, even in those with minimal disability. Ideal for use in clinical trials, visual measures are generally inexpensive, accessible, and reproducible. Quantification of visual acuity, visual fields, visual quality of life, and electrophysiologic parameters allows assessment of function, whereas optical coherence tomography (OCT) provides reliable measures of the structural integrity of the anterior afferent visual pathway. The technology of oculomotor biometrics continues to advance, and discrete measures of fixation, smooth pursuit, and saccadic eye movement abnormalities are ready for inclusion in future trials of MS progression. Visual outcomes allow tracking of neuroaxonal injury and aid in distinguishing MS from diseases such as neuromyelitis optica spectrum disorder (NMOSD) or myelin oligodendrocyte glycoprotein antibody–associated diseases (MOGAD). OCT has also provided unique insights into pathophysiology, including the identification of foveal pitting in NMOSD, possibly from damage to Müller cells, which carry an abundance of aquaporin-4 channels. For some study designs, the cost-benefit ratio favors visual outcomes over more expensive MRI outcomes. With the next frontier of therapeutics focused on remyelination and neuroprotection, visual outcomes are likely to take center stage. As an international community of collaborative, committed, vision scientists, this review by the International MS Visual System Consortium (IMSVISUAL) outlines the quality standards, informatics, and framework needed to routinely incorporate vision outcomes into MS and NMOSD trials.