Background: People with multiple sclerosis (MS) are a vulnerable group for severe 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. Demographic and clinical covariates were queried, alongside COVID-19 clinical severity outcomes, hospitalisation, admission to ICU, requiring artificial ventilation, and death. Characteristics of outcomes were assessed in patients with suspected/confirmed COVID-19 using multilevel mixed-effects logistic regression. Results: 657 (28.1%) with suspected and 1,683 (61.9%) with confirmed COVID-19 were analysed. 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 hospitalisation (aOR=1.56,95%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), though 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 hospitalisation (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 with artificial ventilation (aOR=6.15,95%CI=3.09-12.27). Compared to natalizumab, ocrelizumab and rituximab were associated with hospitalisation (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 with ventilation (aOR=5.52,95%CI=1.71-17.84). Importantly, associations persisted on restriction to confirmed COVID-19 cases. No associations were observed between DMTs and death. Conclusions: Using the largest cohort of people with MS and COVID-19 available, we demonstrated consistent associations of rituximab with increased risk of hospitalisation, ICU admission, and requiring artificial ventilation, and ocrelizumab with hospitalisation and ICU admission, suggesting their use may be a risk factor for more severe COVID-19.

Background: People with multiple sclerosis face significant employment-related challenges, with little known of the drivers of these outcomes. Objective: We examined prospective trajectories of employment-related outcomes up to 11 years following a first episode of central nervous system (CNS) demyelination (FCD). Methods: Participants were aged 18–59 years, at FCD, with at least two observations and were employed at study entry or anytime during follow-up ( n = 207). Outcomes were employment status (full-time, part-time and unemployed), average workhours per week and disability support pension (DSP; receiving/not receiving). We used group-based trajectory modelling to identify groups with common trajectories. Factors associated with trajectory membership were explored using log-multinomial regression. Results: Distinct trajectories were identified for employment (4), workhours (4) and DSP (2). Compared with stable full-time, female sex was strongly associated with being in the stable part-time trajectory (risk ratio (RR): 5.35; 95% confidence interval (CI) = 2.56–11.20; p < 0.001). A greater level of disability at 5-year review (RR: 1.35; 95% CI = 1.19–1.53) and having more than two comorbidities at baseline (RR: 2.77; 95% CI = 1.37–5.64) were associated with being in early and late deteriorated employment trajectories, respectively. Compared with the increased part-time trajectory, every additional relapse during the 5 years post-FCD was associated with a 10% increased risk of being in the reduced part-time trajectory (RR = 1.10; 95%CI = 1.00–1.22). For every additional EDSS point at 5-year review, the risk of being in the DSP trajectory increased (RR = 1.21; 95% CI = 1.05–1.41). Conclusion: These trajectories indicate substantial heterogeneity and the complex impact of MS on employment from its earliest timepoints. Understanding these trends could enable better targeting of interventions to facilitate workforce retention, particularly for females, those with a higher number of comorbidities, more frequent relapses and greater rate of disability accrual.

Background People with multiple sclerosis (MS) are a vulnerable group for severe 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) covariates were queried, alongside COVID-19 hospitalisation, admission to ICU, requiring 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 EDSS. Results 657 (28.1%) with suspected and 1,683 (61.9%) with confirmed COVID-19 were analysed. Among suspected+confirmed/confirmed-only COVID-19, 20.9%/26.9% were hospitalised, 5.4%/7.2% were admitted to ICU, 4.1%/5.4% required artificial ventilation, and 3.2%/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 hospitalisation (aOR=1.56,95%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), though only rituximab was associated with higher risk of artificial ventilation (aOR=4.00,95%CI=1.54-10.39). Importantly, associations persisted on restriction to confirmed COVID-19 cases. No associations were observed between DMTs and death. Conclusions Despite the cross-sectional design of this study, the internal and external consistency of these results with prior studies suggests their use may be a risk factor for more severe COVID-19. Key messages Anti-CD20 DMTs may be associated with worse COVID-19 severity amongst people with multiple sclerosis.

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Limited studies have been conducted to identify and validate multiple sclerosis (MS) genetic loci associated with disability progression. We aimed to identify MS genetic loci associated with worsening of disability over time, and to develop and validate ensemble genetic learning model(s) to identify people with MS (PwMS) at risk of future worsening. We examined associations of 208 previously established MS genetic loci with the risk of worsening of disability; we learned ensemble genetic decision rules and validated the predictions in an external dataset. We found 7 genetic loci (rs7731626: HR 0.92, P = 2.4 × 10–5; rs12211604: HR 1.16, P = 3.2 × 10–7; rs55858457: HR 0.93, P = 3.7 × 10–7; rs10271373: HR 0.90, P = 1.1 × 10–7; rs11256593: HR 1.13, P = 5.1 × 10–57; rs12588969: HR = 1.10, P = 2.1 × 10–10; rs1465697: HR 1.09, P = 1.7 × 10–128) associated with risk worsening of disability; most of which were located near or tagged to 13 genomic regions enriched in peptide hormones and steroids biosynthesis pathways by positional and eQTL mapping. The derived ensembles produced a set of genetic decision rules that can be translated to provide additional prognostic values to existing clinical predictions, with the additional benefit of incorporating relevant genetic information into clinical decision making for PwMS. The present study extends our knowledge of MS progression genetics and provides the basis of future studies regarding the functional significance of the identified loci.

Understanding the predictors of progression from a first to a second demyelinating event (and formerly, a diagnosis of clinically definite multiple sclerosis) is important clinically. Previous studies have focused on predictors within a single domain, e.g. radiological, lacking prospective data across multiple domains. We tested a comprehensive set of personal, environmental, neurological, MRI and genetic characteristics, considered together, as predictors of progression from first demyelinating event to clinically definite multiple sclerosis. Participants were aged 18-59 years and had a first demyelinating event during the study recruitment period (1 November 2003-31 December 2006) for the Ausimmune Study (n = 216) and had follow-up data to 2-3 years post-initial interview. Detailed baseline data were available on a broad range of demographic and environmental factors, MRI, and genetic and viral studies. Follow-up data included confirmation of clinically definite multiple sclerosis (or not) and changes in environmental exposures during the follow-up period. We used multivariable logistic regression and Cox proportional hazards regression modelling to test predictors of, and time to, conversion to clinically definite multiple sclerosis. On review, one participant had had an undiagnosed event prior to study recruitment and was excluded (n = 215). Data on progression to clinically definite multiple sclerosis were available for 91.2% (n = 196); 77% were diagnosed as clinically definite multiple sclerosis at follow-up. Mean (SD) duration of follow-up was 2.7 (0.7) years. The set of predictors retained in the best predictive model for progression from a first demyelinating event to clinically definite multiple sclerosis were: younger age at first demyelinating event (adjusted odds ratio (aOR) = 0.92, 95%CI = 0.87-0.97, per additional year of age); being a smoker at baseline (vs not), (aOR = 2.55, 95%CI 0.85-7.69); lower sun exposure at age 6-18 years (aOR = 0.86, 95%CI 0.74-1.00, per 100KJ/m2 increment in ultraviolet radiation dose), presence (vs. absence) of infratentorial lesions on baseline magnetic resonance imaging (aOR = 7.41, 95%CI 2.08, 26.41); and single nucleotide polymorphisms in HLA-B (rs2523393, aOR = 0.25, 95%CI 0.09-0.68, for any G vs. A:A), TNFRSF1A (rs1800693, aOR = 5.82, 95%CI 2.10-16.12, for any C vs. T:T), and a vitamin D binding protein gene (rs7041, aOR = 3.76, 95%CI 1.41-9.99, for any A vs. C:C). The final model explained 36% of the variance. Predictors of more rapid progression to clinically definite multiple sclerosis (Cox proportional hazards regression) were similar. Genetic and magnetic resonance imaging characteristics as well as demographic and environmental factors predicted progression, and more rapid progression, from a first demyelinating event to a second event and clinically definite multiple sclerosis.

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Background: A comprehensive understanding of factors associated with multiple sclerosis (MS)-related work productivity loss will inform targeted interventions. We have previously shown the strong impact of symptom severity on MS-related work productivity loss. However, the effect of work difficulties, work self-efficacy and work psychological safety is yet to be well evaluated in this context. Objectives: This study evaluates the association between work difficulties, work self-efficacy and work psychological safety, and MS-related presenteeism, absenteeism and total work productivity loss. Methods: We analysed data from employed participants of the Australian MS Longitudinal Study (AMSLS) who took part in both the 2015 Medication and Disease Course survey, and 2015 Employment survey ( n = 744). Data were analysed using Cragg Hurdle regression models. Results: We found that low workplace self-esteem, interpersonal difficulties at work and work self-efficacy were associated with total work productivity loss. In a multivariable model, a 10-unit decrease in workplace self-esteem, increase in interpersonal difficulties at work and 5-unit increase in work self-efficacy were independently associated with a 3.75% increase, 2.89% increase and 3.36% reduction in total work productivity loss, respectively. When separating total work productivity loss in presenteeism and absenteeism, stronger effects were seen for presenteeism than absenteeism. Surprisingly, work psychological safety was not associated with MS-related work productivity loss. Conclusion: Work psychosocial well-being such as self-confidence at work, work self-efficacy and interpersonal difficulties at work are crucial factors governing work productivity in people with MS (PwMS). Multidisciplinary support team assistance of PwMS in symptom self-care, skills around effective communication about MS in the workplace, the psychological impact of work and the modification of work demands may positively influence the employment outcomes.