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The question of anticoagulant dosing in hospitalized patients with coronavirus disease-2019 (COVID-19) is unresolved, with randomized trials showing mixed results and heterogeneity of treatment effects for in-hospital death.To examine the association between the intensity of anticoagulation and clinical outcomes in hospitalized patients with COVID-19.Retrospective cohort study of patients with COVID-19 and respiratory impairment who were hospitalized between 3/1/2020-12/31/2020 in two Kaiser Permanente regions.We fit propensity score models using categorical regression to estimate the probability of receiving standard prophylactic, intermediate, or full-dose anticoagulation beginning on the day of admission or on the day of first respiratory deterioration. Exposure was defined by the highest dose on the day of admission or within 24 hours after deterioration. The primary outcome was in-hospital death.We included 17,130 patients in the day of admission analysis and 4,924 patients who experienced respiratory deterioration. There were no differences in propensity score-adjusted odds of in-hospital death for patients who received either intermediate (odds ratio [OR]: 1.00, 95% confidence intervals [CI] 0.89-1.12) or full anticoagulation (OR: 1.00, 95% CI: 0.85-1.17) compared with standard prophylaxis beginning on the day of admission. Similarly, there were no differences in in-hospital death for either intermediate (OR: 1.22, 95% CI: 0.82-1.82) or full anticoagulation (OR: 1.50, 95% CI: 0.90-2.51) compared with standard prophylaxis on the day of deterioration.Results of this real-world, comparative effectiveness study showed no differences in in-hospital death among newly admitted or deteriorating patients with COVID-19 who received intermediate-dose or full anticoagulation compared with standard prophylaxis.

ImportanceRacial, ethnic, and geographic differences in multiple sclerosis (MS) are important factors to assess when determining the disease burden and allocating health care resources.ObjectiveTo calculate the US prevalence of MS in Hispanic, non-Hispanic Black (hereafter referred to as Black), and non-Hispanic White individuals (hereafter referred to as White) stratified by age, sex, and region.Design, Setting, and ParticipantsA validated algorithm was applied to private, military, and public (Medicaid and Medicare) administrative health claims data sets to identify adult cases of MS between 2008 and 2010. Data analysis took place between 2019 and 2022. The 3-year cumulative prevalence overall was determined in each data set and stratified by age, sex, race, ethnicity, and geography. The insurance pools included 96 million persons from 2008 to 2010. Insurance and stratum-specific estimates were applied to the 2010 US Census data and the findings combined to calculate the 2010 prevalence of MS cumulated over 10 years. No exclusions were made if a person met the algorithm criteria.Main Outcomes and MeasurementsPrevalence of MS per 100 000 US adults stratified by demographic group and geography. The 95% CIs were approximated using a binomial distribution.ResultsA total of 744 781 persons 18 years and older were identified with MS with 564 426 cases (76%) in females and 180 355 (24%) in males. The median age group was 45 to 54 years, which included 229 216 individuals (31%), with 101 271 aged 18 to 24 years (14%), 158 997 aged 35 to 44 years (21%), 186 758 aged 55 to 64 years (25%), and 68 539 individuals (9%) who were 65 years or older. White individuals were the largest group, comprising 577 725 cases (77%), with 80 276 Black individuals (10%), 53 456 Hispanic individuals (7%), and 33 324 individuals (4%) in the non-Hispanic other category. The estimated 2010 prevalence of MS per 100 000 US adults cumulated over 10 years was 161.2 (95% CI, 159.8-162.5) for Hispanic individuals (regardless of race), 298.4 (95% CI, 296.4-300.5) for Black individuals, 374.8 (95% CI, 373.8-375.8) for White individuals, and 197.7 (95% CI, 195.6-199.9) for individuals from non-Hispanic other racial and ethnic groups. During the same time period, the female to male ratio was 2.9 overall. Age stratification in each of the racial and ethnic groups revealed the highest prevalence of MS in the 45- to 64-year-old age group, regardless of racial and ethnic classification. With each degree of latitude, MS prevalence increased by 16.3 cases per 100 000 (95% CI, 12.7-19.8; P P Conclusions and RelevanceThis study found that White individuals had the highest MS prevalence followed by Black individuals, individuals from other non-Hispanic racial and ethnic groups, and Hispanic individuals. Inconsistent racial and ethnic classifications created heterogeneity within groups. In the United States, MS affects diverse racial and ethnic groups. Prevalence of MS increases significantly and nonuniformly with latitude in the United States, even when adjusted for race, ethnicity, age, and sex. These findings are important for clinicians, researchers, and policy makers.

Objective The prevailing approaches to selecting multiple sclerosis (MS) disease modifying therapies (DMTs) have contributed to exponential increases in societal expenditures and out‐of‐pocket expenses, without compelling evidence of improved outcomes. Guidance is lacking regarding when and in whom the benefits of preventing MS‐related disability likely outweighs the risks of highly effective DMTs (HET) and when it is appropriate to consider DMT costs. Our objective was to develop a standardized approach to improve the quality, affordability and equity of MS care. Methods MS experts partnered with health plan pharmacists to develop an ethical, risk‐stratified, cost‐sensitive treatment algorithm. We developed a risk‐stratification schema to classify patients with relapsing forms of MS as high, intermediate or low risk of disability based on the best available evidence and, when the evidence was poor or lacking, by consensus. DMTs are grouped as highly, modestly or low/uncertain effectiveness and preferentially ranked within groups by safety based on pre‐specified criteria. We reviewed FDA documents and the published literature. When efficacy and safety are equivalent, the lower cost DMT is preferred. Results Assignment to the high‐risk group prompts treatment with preferred HETs early in the disease course. For persons in the intermediate‐ or low‐risk groups with cost or health care access barriers, we incorporated induction therapy with an affordable B‐cell depleting agent. Based on more favorable safety profiles, our preferred approach prioritizes use of rituximab and natalizumab among HETs and interferon‐betas or glatiramer acetate among modestly effective agents. Interpretation The risk‐stratified treatment approach we recommend provides clear, measurable guidance in whom and when to prescribe HETs, when to prioritize lower cost DMTs and how to accommodate persons with MS with cost or other barriers to DMT use. It can be adapted to other cost structures and updated quickly as new information emerges. We recommend that physician groups partner with health insurance plans to adapt our approach to their settings, particularly in the United States. Future studies are needed to resolve the considerable uncertainty about how much variability in prognosis specific risk factors explain.

There is little evidence on the role of diet in childhood/adolescence and multiple sclerosis (MS) in adulthood. The MS Sunshine Study recruited adults with recent-onset MS ( n = 602) and matched controls ( n = 653). Of these, 84% provided dietary recall for specific ages between childhood and young adulthood (6–10, 11–15 and 16–20 years). We used logistic regression to test associations between age-specific diet and case-control status. Consumption of fruit (all ages), yoghurt (all ages) and legumes (11–15 years) was associated with lower probability of adult-onset MS (all p

Highlights • Targeted anti-cytokine agents, tocilizumab and anakinra, used to treat COVID-19 related cytokine storm yield mixed results. • Early identification of cytokine storm using laboratory abnormalities can detect patients prior to mechanical ventilation. • Early identification and treatment of cytokine storm with anakinra and corticosteroids led to improved outcomes compared to initiating tocilizumab shortly after mechanical ventilation. • Early identification and treatment of cytokine storm may be more important than which anti-inflammatory treatment is chosen. • Our results provide additional support for the use of corticosteroid treatment of COVID19 cytokine storm., Objective To examine outcomes among patients who were treated with the targeted anti-cytokine agents, anakinra or tocilizumab, for COVID-19 -related cytokine storm (COVID19-CS). Methods We conducted a retrospective cohort study of all SARS-coV2-RNA-positive patients treated with tocilizumab or anakinra in Kaiser Permanente Southern California. Local experts developed and implemented criteria to define COVID19-CS. All variables were extracted from the electronic health record. Results At tocilizumab initiation (n = 52), 50 (96.2%) were intubated, and only 7 (13.5%) received concomitant corticosteroids. At anakinra initiation (n = 41), 23 (56.1%) were intubated, and all received concomitant corticosteroids. Fewer anakinra-treated patients died (n = 9, 22%) and more were extubated/never intubated (n = 26, 63.4%) compared to tocilizumab-treated patients (n = 24, 46.2% dead, n = 22, 42.3% extubated/never intubated). Patients who died had more severe sepsis and respiratory failure and met COVID-CS laboratory criteria longer (median = 3 days) compared to those extubated/never intubated (median = 1 day). After accounting for differences in disease severity at treatment initiation, this apparent superiority of anakinra over tocilizumab was no longer statistically significant (propensity score-adjusted hazards ratio 0.46, 95% confidence interval 0.18–1.20). Conclusions Prompt identification and treatment of COVID19-CS prior to intubation may be more important than the specific type of anti-inflammatory treatment. Randomized controlled trials of targeted anti-cytokine treatments and corticosteroids should report duration of cytokine storm in addition to clinical severity at randomization.

Background: Fatigue is a debilitating symptom of multiple sclerosis (MS), but its relation to sociodemographic and disease-related characteristics has not been investigated in larger studies. The objectives of this study were to evaluate predictors of self-reported fatigue in a Swedish nationwide register-based MS cohort.Methods: Using a repeated cross-sectional design, we included 2,165 persons with relapsing-remitting and secondary progressive MS with one or multiple Fatigue Scale for Motor and Cognitive Functions (FSMC) scores, which was modelled using multivariable linear regressions for multiple predictors.Results: Only associations to expanded disability status scale (EDSS) and Symbol Digit Modalities Test (SDMT) were considered clinically meaningful among MS-associated characteristics in our main model; compared to mild disability (EDSS 0-2.5), those with severe disability (EDSS >= 6) scored 17.6 (95% CI 13.1-22.2) FSMC points higher, while the difference was 10.7 (95% CI 8.0-13.4) points for the highest and lowest quartiles of SDMT. Differences between highest and lowest quartiles of health-related quality of life (HRQoL) instruments were even greater and considered clinically meaningful; EuroQoL Visual Analogue Scale (EQ-VAS) 31.9 (95% CI 29.9-33.8), Multiple Sclerosis Impact Scale (MSIS-29) psychological component 35.6 (95% CI 33.8-37.4) and MSIS-29 physical component 45.5 (95% CI 43.7-47.4).Conclusion: Higher self-reported fatigue is associated with higher disability level and worse cognitive processing speed, while associations to other MS-associated characteristics including MS type, line of disease modifying therapy (DMT), MS duration, relapse and new cerebral lesions are weak. Furthermore, we found a strong correlation between high fatigue rating and lower ratings on health-related quality of life instruments. Funding Agencies|Patient-Centered Outcomes Research Institute (PCORI) Award [MS-1511-33196]; Swedish Research Council [2020-02700, TF 2016-01355]; Swedish Research Council for Health, Working Life, and Welfare [2020-0115]; NEURO Sweden

This study was undertaken to evaluate a multicomponent health system intervention designed to reduce escalating disease-modifying treatment (DMT) expenditures and improve multiple sclerosis (MS) outcomes by increasing use of preferred formulary and highly effective DMTs (HETs).We conducted a trend study of treatment utilization and expenditure outcomes prior to (2009-2011) and during (2012-2018) MS Treatment Optimization Program (MSTOP) implementation in Kaiser Permanente Southern California (KPSC) compared to a Kaiser Permanente region of similar size. Annual relapse rates (ARRs) were obtained from KPSC's electronic health records.Adherence to preferred formulary DMTs increased from 25.4% in 2011 to 72.2% in 2017 following MSTOP implementation in KPSC and 22.1% to 43.8%, respectively, in the comparator. KPSC's annual DMT expenditures in 2018 were less than in 2011 despite an 11.3% increase in DMT-treated members. The decline in average per patient per year of treatment expenditures from a peak of $43.1 K in 2014 to $26.3 K in 2018 in KPSC was greater than the comparator, which peaked at $52.1 K and declined to $40.0 K in 2018. Over the 7 years following initiation of MSTOP, cumulative MS DMT expenditures were $161.6 million less than the comparator. HET use increased to 62.5% of per patient treatment-years versus 32.4% in the comparator. This corresponded to a 69% decline in adjusted ARR (95% confidence interval = 64.1-73.2%; p 0.0001) among DMT-treated patients in KPSC.A novel, expert-led health system intervention reduced MS DMT expenditures despite rising prices while simultaneously reducing MS relapse rates. Our focus on health system progress toward meaningful, measurable targets could serve as a model to improve quality and affordability of MS care in other settings. ANN NEUROL 2022;92:164-172.

Key Points Question Is early natalizumab cessation before or during the first trimester of pregnancy associated with multiple sclerosis relapse occurrence and relapse-related disability? Findings In this cohort study of 274 pregnancies, relapses during pregnancy and postpartum were common, with more than 10% of women retaining clinically meaningful disability from pregnancy-related natalizumab cessation relapses 1 year after delivery. Neither pregnancy itself, restarting natalizumab shortly after delivery, nor exclusive breastfeeding was associated with protection against these relapses. Meaning These findings suggest that women with multiple sclerosis need to be informed about the risks of early natalizumab cessation due to pregnancy or planned pregnancy, and treatment alternatives should be considered., This cohort study examines the associations between cessation of natalizumab therapy in women with multiple sclerosis before or during the first trimester of pregnancy with relapse occurrence and relapse-related disability., Importance The magnitude of risk of pregnancy-related multiple sclerosis relapses, particularly severe relapses, following natalizumab cessation is unclear, as is whether this risk is reduced by pregnancy or other modifiable factors. Objective To determine the association of early natalizumab withdrawal before or during pregnancy with risk of severe relapses and relapse-related disability. Design, Setting, and Participants This prospective cohort study used data from the German Multiple Sclerosis and Pregnancy Registry, which enrolled participants between November 2006 and February 2018. Data were collected through structured telephone-administered questionnaires and review of neurologists’ notes. Registry patients who stopped natalizumab treatment within the 2 years before or in the first trimester of pregnancy were included in this analysis. Data were analyzed between January and November 2021. Exposures Cessation of natalizumab before pregnancy or until the first trimester. Main Outcomes and Measures Severe and significant relapse-related disability was defined as at least a 2.0-point increase on the expanded disability status scale or new or worsening relapse-related ambulatory impairment. Multivariable models accounting for measures of disease severity and repeated events were used. Results The cohort comprised 255 women with 274 pregnancies (mean [SD] age at pregnancy onset, 31.25 [4.27] years) who stopped natalizumab before pregnancy (n = 85; median time before last menstrual period, 14.29 weeks [IQR, 3.14-42.43 weeks]) or in the first trimester (n = 189). During pregnancy and the postpartum year, relapses were reported in 183 pregnancies (66.78%), severe relapses in 44 pregnancies (16.05%), and potentially life-threatening relapses in 3 pregnancies (1.10%). One year post partum, significant relapse-related disability was accrued in 29 pregnancies (10.58%). Relapses during pregnancy (n = 109; 39.78%) and in the postpartum period (n = 135; 49.27%) were common. Pregnancy (as a time-dependent covariate) was not associated with a reduced relapse risk (adjusted HR, 0.90; 95% CI, 0.64-1.27). Neither exclusive breastfeeding (adjusted HR, 1.34; 95% CI, 0.86-2.10) nor restarting natalizumab within 4 weeks post partum (adjusted HR, 1.06; 95% CI, 0.48-2.36) were associated with a reduced risk of early postpartum relapses 6 months after delivery. However, the relapse rate ratio during 12 months post partum was lower (0.49; 95% CI, 0.28-0.86) when natalizumab was restarted in the first 4 weeks after birth. Conclusions and Relevance This cohort study’s finding suggest that 10% of women may retain clinically meaningful disability from pregnancy-related natalizumab cessation relapses 1 year post partum. This information should be shared with women on natalizumab who desire pregnancy to weigh the high risk of pregnancy-related relapses and disability to the partly uncertain risks of continuing natalizumab throughout pregnancy or switching to depleting agents before conception.

Importance There is empirical evidence that social determinants of health (SDOH) impact health outcomes in Black and Hispanic and Latinx individuals in the US. Recently, SDOH have risen to the top as essential intervention targets that could help alleviate racial and ethnic disparities. Neuromyelitis optica spectrum disorder (NMOSD) disproportionately affects Black individuals, and multiple sclerosis (MS) has seen a recent shift in select racial groups. It is unclear to what degree SDOH have been investigated and contribute to racial and ethnic health disparities and inequities. Observations This narrative review provides a contemporary synthesis of SDOH associated with racial and ethnic health disparities and inequities in MS, NMOSD, and other autoimmune disorders, such as myelin oligodendrocyte glycoprotein antibody (MOG-Ab)-associated disease. These immune-mediated neurological diseases were chosen for their capacity to be a high burden to society and because of complementary SDOH-associated challenges among minority populations. A paucity of research addressing inequities and the role of SDOH in MS and NMOSD was noted despite findings that Black individuals have a higher risk of developing MS or NMOSD and associated mortality compared with White individuals. Greater health disparities were also found for those with lower income and education, lower health literacy, and negative illness perceptions in MS. No studies in MOG-Ab disorders were found. Conclusions and relevance Increased efforts are needed to better understand the role of SDOH in racial and ethnic health disparities and inequities in MS, NMOSD, and emerging autoimmune disorders. This includes developing research frameworks aimed at understanding the magnitude and interrelationships of SDOH to better develop system-based multilevel interventions across the spectrum of care for these neurological conditions.

Objective: Novel, highly effective disease-modifying therapies have revolutionized multiple sclerosis (MS) care. However, evidence from large comparative studies on important safety outcomes, such as cancer, is still lacking. Methods: In this nationwide register-based cohort study, we linked data from the Swedish MS register to the Swedish Cancer Register and other national health care and census registers. We included 4,187 first-ever initiations of rituximab, 1,620 of fingolimod, and 1,670 of natalizumab in 6,136 MS patients matched for age, sex, and location to 37,801 non-MS general population subjects. Primary outcome was time to first invasive cancer. Results: We identified 78 invasive cancers among treated patients: rituximab 33 (incidence rate [IR] per 10,000 person-years = 34.4, 95% confidence interval [CI] = 23.7–48.3), fingolimod 28 (IR = 44.0, 95% CI = 29.2–63.5), and natalizumab 17 (IR = 26.0, 95% CI = 15.1–41.6). The general population IR was 31.0 (95% CI = 27.8–34.4). Adjusting for baseline characteristics, we found no difference in risk of invasive cancer between rituximab, natalizumab, and the general population but a possibly higher risk with fingolimod compared to the general population (hazard ratio [HR] = 1.53, 95% CI = 0.98–2.38) and rituximab (HR = 1.68, 95% CI = 1.00–2.84). Interpretation: In this first large comparative study of 3 highly effective MS disease-modifying therapies, no increased risk of invasive cancer was seen with rituximab and natalizumab, compared to the general population. However, there was a borderline-significant increased risk with fingolimod, compared to both the general population and rituximab. It was not possible to attribute this increased risk to any specific type of cancer, and further studies are warranted to validate these findings.

Background:The role of omega-3 fatty acid in multiple sclerosis (MS) susceptibility is unclear.Objective:To determine whether fish/seafood intake or genetic factors that regulate omega-3 fatty acids levels are associated with MS risk.Methods:We examined the association of fish and shrimp consumption and 13 tag single nucleotide polymorphisms (SNPs) in FADS1, FADS2, and ELOV2 with risk of MS in 1153 individuals from the MS Sunshine Study, a case-control study of incident MS or clinically isolated syndrome (CIS), recruited from Kaiser Permanente Southern California.Results:Consuming fish/seafood at least once a week or at least once a month with regular fish oil use was associated with 44% reduced odds of MS/CIS (adjusted OR = 0.56; 95% CI = 0.41–0.76; p = 0.0002) compared with consuming fish/seafood less than once a month and no fish oil supplementation. Two FADS2 SNPs (rs174611 and rs174618) were independently associated with a lower risk of MS (adjusted ORs = 0.74, 0.79, p = 0.0056, 0.0090, respectively). Association of FADS2 SNPs with MS risk was confirmed in an independent dataset.Conclusion:These findings suggest that omega-3 fatty acid intake may be an important modifiable risk factor for MS. This is consistent with the other known health benefits of fish consumption and complementary genetic studies supporting a key role for omega-3 regulation.

ImportanceRituximab and other B-cell–depleting therapies blunt humoral responses to SARS-CoV-2 vaccines, particularly when the vaccine is administered within 6 months of an infusion. Whether this translates into an increased risk of hospitalization or death from COVID-19 is unclear.ObjectivesTo examine whether rituximab treatment is associated with an increased risk of hospitalization for COVID-19 among SARS-CoV-2–vaccinated persons with multiple sclerosis (MS) and whether delaying vaccination more than 6 months after rituximab treatment is associated with decreased risk.Design, Setting, and ParticipantsThis retrospective cohort study used Kaiser Permanente Southern California’s electronic health record to identify individuals from January 1, 2020, to February 15, 2022, who had MS and who had been vaccinated against SARS-CoV-2.ExposuresRituximab treatment compared with disease-modifying therapies (DMTs) that do not interfere with vaccine efficacy or being untreated (no or other DMT group). Among rituximab-treated patients, the exposure was receiving at least 1 vaccine dose more than 6 months after their last infusion compared with receiving all vaccine doses 6 months or less since their last infusion.Main Outcomes and MeasuresThe main outcome was hospitalization due to COVID-19 infection. The odds of infection resulting in hospitalization following SARS-CoV-2 vaccination were adjusted for race and ethnicity, advanced MS-related disability; vaccine type; booster dose; and, among rituximab-treated only analyses, cumulative rituximab dose and dose at last infusion. Exposures, outcomes, and covariates were collected from the electronic health record.ResultsAmong 3974 SARS-CoV-2–vaccinated people with MS (mean [SD] age, 55.3 [15] years; 2982 [75.0%] female; 103 [2.6%] Asian or Pacific Islander; 634 [16.0%] Black; 953 [24.0%] Hispanic; 2269 [57.1%] White; and 15 [0.3%] other race or ethnicity), rituximab-treated patients (n = 1516) were more likely to be hospitalized (n = 27) but not die (n = 0) compared with the 2458 individuals with MS receiving no or other DMTs (n = 7 and n = 0, respectively; adjusted odds ratio [aOR] for hospitalization, 7.33; 95% CI, 3.05-17.63). Receiving messenger RNA (mRNA) SARS-CoV-2 vaccine (aOR, 0.36; 95% CI, 0.15-0.90; P = .03) and receiving a booster vaccination (aOR, 0.31; 95% CI, 0.15-0.64; P = .002) were independently associated with a decreased risk of hospitalization for COVID-19. Among vaccinated rituximab-treated individuals with MS, receiving any vaccination dose more than 6 months after the last rituximab infusion was associated with a reduced risk of COVID-19 hospitalization (aOR, 0.22; 95% CI, 0.10-0.49).Conclusions and RelevanceThis cohort study’s findings suggest that rituximab-treated people with MS should be strongly encouraged to receive mRNA SARS-CoV-2 vaccines and boosters more than 6 months after their last rituximab infusion whenever possible. The low absolute risk of hospitalization for COVID-19 among mRNA-vaccinated individuals with MS should not preclude use of rituximab, which has marked efficacy, cost, and convenience advantages over other DMTs.

I read the article by Miyasaki et al.1 with interest. Keys to academic success include publications, grants, and professional society leadership positions—keys that have been traditionally controlled by White men. This has had the predictable effects of primarily men advancing in academic careers. The American Academy of Neurology has taken conscious steps toward reducing sex disparities. The data presented by Miyasaki et al.1 indicate relative improvements in the metrics where the AAN has most influence: bestowing awards, serving on committees, and contributing the first and last authorship in Neurology ®. Proportionally, these metrics were similar among men and women AAN members by 2017. However, despite equal numbers of women and men completing neurology residencies, the number of AAN members remains mostly men. The discrepancy is greatest when comparing the number of female neurologists, or those with a membership designation of senior, researcher, or honorary (n = 4,992), with males (n = 10,877). When students, interns, junior, and physician affiliates are added, this difference is smaller. This implies that lower-level positions are overrepresented among female AAN members, and female neurologists see less value in AAN membership. Retrofitting a system designed for White men to accommodate the rest of us is a messy process. There is much work to be done. I admire the AAN for trying.

The open access publishing model provides readers of all backgrounds access to articles free of charge. To cover the costs of open access, however, many journals now charge substantial article processing fees. This has inadvertently created yet another barrier for trainees to engage in scholarly activity. Herein, we describe the issue, review the literature, and provide suggestions for addressing this barrier with the focus on the neurology specialty.

ObjectiveTo develop a valid algorithm for identifying multiple sclerosis (MS) cases in administrative health claims (AHC) datasets.MethodsWe used 4 AHC datasets from the Veterans Administration (VA), Kaiser Permanente Southern California (KPSC), Manitoba (Canada), and Saskatchewan (Canada). In the VA, KPSC, and Manitoba, we tested the performance of candidate algorithms based on inpatient, outpatient, and disease-modifying therapy (DMT) claims compared to medical records review using sensitivity, specificity, positive and negative predictive values, and interrater reliability (Youden J statistic) both overall and stratified by sex and age. In Saskatchewan, we tested the algorithms in a cohort randomly selected from the general population.ResultsThe preferred algorithm required ≥3 MS-related claims from any combination of inpatient, outpatient, or DMT claims within a 1-year time period; a 2-year time period provided little gain in performance. Algorithms including DMT claims performed better than those that did not. Sensitivity (86.6%–96.0%), specificity (66.7%–99.0%), positive predictive value (95.4%–99.0%), and interrater reliability (Youden J = 0.60–0.92) were generally stable across datasets and across strata. Some variation in performance in the stratified analyses was observed but largely reflected changes in the composition of the strata. In Saskatchewan, the preferred algorithm had a sensitivity of 96%, specificity of 99%, positive predictive value of 99%, and negative predictive value of 96%.ConclusionsThe performance of each algorithm was remarkably consistent across datasets. The preferred algorithm required ≥3 MS-related claims from any combination of inpatient, outpatient, or DMT use within 1 year. We recommend this algorithm as the standard AHC case definition for MS.

ObjectiveConsiderable gaps exist in knowledge regarding the prevalence of neurologic diseases, such as multiple sclerosis (MS), in the United States. Therefore, the MS Prevalence Working Group sought to review and evaluate alternative methods for obtaining a scientifically valid estimate of national MS prevalence in the current health care era.MethodsWe carried out a strengths, weaknesses, opportunities, and threats (SWOT) analysis for 3 approaches to estimate MS prevalence: population-based MS registries, national probability health surveys, and analysis of administrative health claims databases. We reviewed MS prevalence studies conducted in the United States and critically examined possible methods for estimating national MS prevalence.ResultsWe developed a new 4-step approach for estimating MS prevalence in the United States. First, identify administrative health claim databases covering publicly and privately insured populations in the United States. Second, develop and validate a highly accurate MS case-finding algorithm that can be standardly applied in all databases. Third, apply a case definition algorithm to estimate MS prevalence in each population. Fourth, combine MS prevalence estimates into a single estimate of US prevalence, weighted according to the number of insured persons in each health insurance segment.ConclusionsBy addressing methodologic challenges and proposing a new approach for measuring the prevalence of MS in the United States, we hope that our work will benefit scientists who study neurologic and other chronic conditions for which national prevalence estimates do not exist.

ObjectiveTo describe the safety and efficacy of rituximab (RTX) in MS and pregnancy, we conducted a retrospective cohort study of 74 pregnancies among 55 women treated with RTX for MS and their offspring.MethodsWe used prospectively collected information from the electronic health record at Kaiser Permanente Southern California between 2012 and 2019 of mother and baby to identify treatment history, pregnancy outcomes, and relapses.ResultsLast RTX exposure before conception occurred between 1.8 and 5.2 months in 32 (49%) of 65 pregnancies and accidentally during the first trimester in 9 (12%). Among 38 live births, adverse pregnancy outcomes were as follows: 3 preterm deliveries (including 1 set of twins), 1 neonatal death (preterm twin), and 1 perinatal stroke (full-term). No stillbirths, chorioamnionitis, or major malformations were found. Fifteen (27%) women had at least one first-trimester miscarriage, of whom 8 (53%) had a history of infertility. Cumulative dose or timing of last RTX infusion was not associated with an increased risk of miscarriage. Only 2 (5.4%) women experienced relapses, one during pregnancy and the other postpartum.ConclusionWe observed no increase in adverse pregnancy outcomes compared with expected national incidence rates and remarkably little disease activity in RTX-treated women with MS, particularly when compared with periconceptional natalizumab-treated cohorts. However, larger studies are needed to fully assess the safety of RTX use before pregnancy, especially risks associated with prolonged B-cell depletion and hypogammaglobulinemia. Until these data are available, we recommend restricting RTX use before pregnancy to women who require highly effective MS treatments.Classification of evidenceThis study provides Class IV evidence that for pregnant women with MS, RTX controls disease activity and does not increase adverse pregnancy outcomes.

ObjectiveTo assess possible adverse effects on breastfed infants of mothers receiving monoclonal antibodies (MAbs) during pregnancy and/or lactation.MethodsWe identified 23 patients from the German Multiple Sclerosis and Pregnancy Registry (DMSKW) who received MAbs (17 natalizumab and 6 anti-CD20) during lactation. Thirteen were already exposed to natalizumab during the third trimester of pregnancy, and 1 received ocrelizumab during pregnancy. Data were obtained from standardized, telephone-administered questionnaires completed by the mother during pregnancy and at 1, 3, 6, and 12 months postpartum. Natalizumab concentration in mother’s milk was analyzed in 3 patients and natalizumab serum concentration in 2 of these patients and their breastfed infants.ResultsWe did not observe a negative impact on infant health and development attributable to breast milk exposure after a median follow-up of 1 year. Infants exposed to natalizumab during the third trimester had a lower birth weight and more hospitalizations in the first year of life. The concentration of natalizumab in breast milk and serum of infants was low; B cells normal in infants breastfed under anti-CD20.ConclusionMore data on the effect of Mab exposure during pregnancy are needed. Otherwise, our data suggest that treatment with natalizumab, ocrelizumab, or rituximab during lactation might be safe for breastfed infants.

Background Our multiple sclerosis (MS) stakeholder groups expressed concerns about whether MS disease-modifying therapies (DMTs) increase the risk of specific outpatient infections. Validated methods for identifying the risk of these selected outpatient infections in the general population either do not exist, exclude the clinically important possibility of recurrent infections, or are inaccurate, largely because existing studies relied primarily on International Classification of Diseases (ICD) codes to identify infectious outcomes. Additionally, no studies have validated methods among the MS population, where some MS symptoms can be mistaken for infections (e.g., urinary tract infections (UTIs)). Objective To utilize multiple data elements in the electronic health record (EHR) to improve accurate identification of selected outpatient infections in an MS cohort and general population controls. Methods We searched Kaiser Permanente Southern California's EHR based on ICD-9/10 codes for specified outpatient infections from 1/1/2008-12/31/2018 among our MS cohort (n=6000) and 5:1 general population controls matched on age, sex, and race/ethnicity (n=30,010). Random sample chart abstractions from each group were used to identify common coding errors for outpatient pneumonia, upper and lower respiratory tract infection, UTIs, herpetic infections (herpes zoster (HZ), herpes simplex virus (HSV)), fungal infections, otitis media, cellulitis, and influenza. This information was used to define discrete infectious episodes and to identify the algorithm with the highest positive predictive value (PPV) after supplementing the ICD-coded episodes with radiology, laboratory and/or pharmacy data. Results PPVs relying on ICD codes alone were inaccurate, particularly for identifying recurrent herpetic infections (HZ (42%) and HSV (60%)), UTIs (42%) and outpatient pneumonia (20%) in MS patients. Defining and validating episodes improved the PPVs for all the selected infections. The final algorithms' PPVs were 80-100% in MS and 75-100% in the general population, after including dispensed treatments (UTI, herpetic infections and yeast vaginitis), timing of dispensed treatments (UTI, herpetic infections and yeast vaginitis), removal of prophylactic antiviral use (herpetic infections), and inclusion of selected laboratory (UTIs) and imaging results (pneumonia). The only exception was outpatient pneumonia, where PPVs improved but remained ≤70%. There were no significant differences in the PPVs for the final algorithms between the MS and general population. Conclusions Provided herein are accurate and validated algorithms that can be used to improve our understanding of how the risk of recurrent outpatient infections are influenced by MS treatments, MS-related disability, and co-morbidities. Findings from such studies will be important in helping patients and clinicians engage in shared decision-making and in developing strategies to mitigate risks of recurrent infections.

This case-control study examines the risk of severe COVID-19 infection in individuals with multiple sclerosis who were receiving rituximab.

Objective:To determine whether Epstein-Barr virus (EBV) or cytomegalovirus (CMV) seropositivity is associated with multiple sclerosis (MS) in blacks and Hispanics and to what extent measures of the hygiene hypothesis or breastfeeding could explain these findings. EBV and CMV have been associated with MS risk in whites, and the timing and frequency of both viruses vary by factors implicated in the hygiene hypothesis.Methods:Incident cases of MS or its precursor, clinically isolated syndrome (CIS), and matched controls (blacks, 111 cases/128 controls; Hispanics, 173/187; whites, 235/256) were recruited from the membership of Kaiser Permanente Southern California. Logistic regression models accounted for HLA-DRB1*1501 status, smoking, socioeconomic status, age, sex, genetic ancestry, and country of birth.Results:Epstein-Barr nuclear antigen-1 (EBNA-1) seropositivity was independently associated with an increased odds of MS/CIS in all 3 racial/ethnic groups (p < 0.001 for blacks and whites, p = 0.02 for Hispanics). In contrast, CMV seropositivity was associated with a lower risk of MS/CIS in Hispanics (p = 0.004) but not in blacks (p = 0.95) or whites (p = 0.96). Being born in a low/middle-income country was associated with a lower risk of MS in Hispanics (p = 0.02) but not after accounting for EBNA-1 seropositivity. Accounting for breastfeeding did not diminish the association between CMV and MS in Hispanics.Conclusions:The consistency of EBNA-1 seropositivity with MS across racial/ethnic groups and between studies points to a strong biological link between EBV infection and MS risk. The association between past CMV infection and MS risk supports the broader hygiene hypothesis, but the inconsistency of this association across racial/ethnic groups implies noncausal associations.

Background: Illness perceptions have been reported to be important determinants of multiple sclerosis (MS)–related well-being. Hispanic culture is defined by strong cultural beliefs in which illness is often perceived to arise from strong emotions. Understanding the perceptions of MS in Hispanic Americans may provide a better understanding of cultural barriers that may exist. The purpose of this study was to describe Hispanic American perceptions of MS. Methods: We gathered information from semistructured interviews, focus groups, and participant responses from the University of Southern California Hispanic MS Registry. This information was then stratified into a matrix of environmental, biological, and sociocultural determinants. Differences were examined by place of birth, treatment preference, and ambulatory difficulty. Logistic regression was used to investigate the relationship between sociocultural perceptions, place of birth, and ambulation. Results: Most participants were female (n = 64, 61%), US born (n = 64, 61%), and receiving treatment for MS. Participants cited environmental and sociocultural perceptions, with significant differences noted by place of birth. Sociocultural factors such as strong emotions were almost four times more commonly perceived in immigrants compared with US-born participants (adjusted odds ratio, 3.66; 95% confidence interval, 1.12–11.90; P = .03). Male, low-education, and low-income participants were also more likely to perceive MS to be a result of strong emotions, but these differences were not statistically significant. Conclusions: Hispanic American perceptions of MS differ by place of birth, with reports of cultural idioms more common among immigrants, which could affect disease management. These findings may be useful in designing educational interventions to improve MS-related well-being in Hispanic populations.

ObjectiveTo use the case-only gene-environment (G E) interaction study design to estimate interaction between pregnancy before onset of MS symptoms and established genetic risk factors for MS among White adult females.MethodsWe studied 2,497 female MS cases from 4 cohorts in the United States, Sweden, and Norway with clinical, reproductive, and genetic data. Pregnancy exposure was defined in 2 ways: (1) live birth pregnancy before onset of MS symptoms and (2) parity before onset of MS symptoms. We estimated interaction between pregnancy exposure and established genetic risk variants, including a weighted genetic risk score and both HLA and non-HLA variants, using logistic regression and proportional odds regression within each cohort. Within-cohort associations were combined using inverse variance meta-analyses with random effects. The case-only G × E independence assumption was tested in 7,067 individuals without MS.ResultsEvidence for interaction between pregnancy exposure and established genetic risk variants, including the strongly associated HLA-DRB1*15:01 allele and a weighted genetic risk score, was not observed. Results from sensitivity analyses were consistent with observed results.ConclusionOur findings indicate that pregnancy before symptom onset does not modify the risk of MS in genetically susceptible White females.

Background Obesity is common in the United States and is associated with a higher risk of relapse and comorbidities, and increased disease progression, in people with MS. Methods We examined the prevalence of overweight and obesity in the MS Sunshine Study, a matched case-control study of multiple sclerosis in Southern California (470 cases, 519 controls). We reported the proportion of participants who adopted a specific diet for nutrition or weight loss purposes, and identified independent predictors of dieting. Results In the total population, 32% and 37% were overweight and obese, respectively. Case participants were no more likely to adopt a specific diet for nutrition or weight loss purposes than control participants (10% and 11%, respectively). Being obese, younger, female or non-Hispanic were independently associated with dieting. Conclusion Despite the evidence that obesity can worsen MS prognosis, and the high prevalence of overweight/obesity, case participants were no more likely to adopt a specific diet than control participants. Improved nutrition education may help people with MS make healthy dietary changes for nutrition or weight loss purposes.

ObjectiveTo determine whether black or Hispanic patients with newly diagnosed multiple sclerosis (MS) are more likely to have cognitive impairment than white patients when compared to controls matched on age, sex, and race/ethnicity. Whether black or Hispanic patients have a more aggressive MS disease course than white patients remains unclear. No prior studies have examined differences in early cognitive impairment. The oral Symbol Digit Modalities Test (SDMT) is sensitive to early cognitive impairment in MS but normative data in nonwhite patients are limited.MethodsWe studied 1,174 adults who enrolled in the MS Sunshine Study. SDMT and verbal fluency were measured in 554 incident cases of MS or clinically isolated syndrome (CIS) and 620 matched controls. Multivariable regression was used to examine correlates of abnormal SDMT in the entire cohort.ResultsThe strongest independent predictors of lower oral SDMT scores in rank order were having MS/CIS, lower educational attainment, and being black or Hispanic. Black and Hispanic patients and controls had lower SDMT scores than white participants even after controlling for age, sex, and education. However, no interaction between race/ethnicity and MS case status on SDMT scores was detected. Easy-to-use reference scores stratified by age and educational attainment for black and Hispanic patients are provided.ConclusionPersons with newly diagnosed MS/CIS are more likely to have subtly impaired cognitive function than controls regardless of race/ethnicity. Lower absolute SDMT scores among black and Hispanic patients compared to white patients highlight underlying US population differences rather than differences in MS disease severity.

ObjectiveTo determine whether women with multiple sclerosis (MS) diagnosed according to current criteria are at an increased risk of postpartum relapses and to assess whether this risk is modified by breastfeeding or MS disease-modifying therapies (DMTs), we examined the electronic health records (EHRs) of 466 pregnancies among 375 women with MS and their infants.MethodsWe used prospectively collected information from the EHR at Kaiser Permanente Southern and Northern California between 2008 and 2016 of the mother and infant to identify treatment history, breastfeeding, and relapses. Multivariable models accounting for measures of disease severity were used.ResultsIn the postpartum year, 26.4% relapsed, 87% breastfed, 36% breastfed exclusively for at least 2 months, and 58.8% did not use DMTs. At pregnancy onset, 67.2% had suboptimally controlled disease. Annualized relapse rates (ARRs) declined from 0.37 before pregnancy to 0.14–0.07 (p < 0.0001) during pregnancy, but in the postpartum period, we did not observe any rebound disease activity. The ARR was 0.27 in the first 3 months postpartum, returning to prepregnancy rates at 4–6 months (0.37). Exclusive breastfeeding reduced the risk of early postpartum relapses (adjusted hazard ratio = 0.37, p = 0.009), measures of disease severity increased the risk, and resuming modestly effective DMTs had no effect (time-dependent covariate, p = 0.62).ConclusionMost women diagnosed with MS today can have children without incurring an increased risk of relapses. Women with suboptimal disease control before pregnancy may benefit from highly effective DMTs that are compatible with pregnancy and lactation. Women with MS should be encouraged to breastfeed exclusively.

ObjectiveTo determine whether MS disease-modifying therapies (DMTs) can be safely discontinued in patients aged 50 years or older with suspected benign/burnt-out MS and to define criteria to identify such patients.MethodsWe conducted a retrospective cohort study of 136 patients with suspected benign/burnt-out MS who discontinued DMTs from the electronic health record (EHR) at Kaiser Permanente Southern California.ResultsThe majority discontinued an injectable DMT (n = 131, 96%). At the time of DMT discontinuation, mean and SD for age was 60.6 (6.2) years, disease duration 19.5 (10.7) years, and time since last relapse 11.0 (7.2) years. After a mean duration of follow-up of 5.0 years post-DMT discontinuation, 5 (3.7%) patients had a relapse, 2 (1.5%) had mild residual deficits, and 3 (2.2%) had asymptomatic MRI disease activity. Patients with MS disease activity following DMT discontinuation were younger (median = 53.6 years) than those who remained disease activity free. Fifty patients (36.8%) had only 1 lifetime relapse, of whom 1 relapsed post-DMT discontinuation. Sixty (56.6%) of 106 patients with spinal cord MRIs before discontinuation showed demyelinating lesions.ConclusionsDMT discontinuation in older patients with suspected benign/burnt-out MS appears safe. Our findings suggest that MRI evidence of spinal cord involvement does not preclude the possibility of benign/burnt-out MS, and for those with 2 or more lifetime relapses, a benign/burn-out classification is best reserved for those aged 55 years and older. Future studies to determine whether DMT discontinuation is safe at a younger age in patients with a single lifetime relapse are needed.Classification of EvidenceThe study provides Class IV evidence that DMTs can be safely discontinued in older patients with suspected benign/burnt-out MS.

Multiple sclerosis (MS) is an autoimmune disease with high prevalence among populations of northern European ancestry. Past studies have shown that exposure to ultraviolet radiation could explain the difference in MS prevalence across the globe. In this study, we investigate whether the difference in MS prevalence could be explained by European genetic risk factors. We characterized the ancestry of MS-associated alleles using RFMix, a conditional random field parameterized by random forests, to estimate their local ancestry in the largest assembled admixed population to date, with 3,692 African Americans, 4,915 Asian Americans, and 3,777 Hispanics. The majority of MS-associated human leukocyte antigen (HLA) alleles, including the prominent HLA-DRB1*15:01 risk allele, exhibited cosmopolitan ancestry. Ancestry-specific MS-associated HLA alleles were also identified. Analysis of the HLA-DRB1*15:01 risk allele in African Americans revealed that alleles on the European haplotype conferred three times the disease risk compared to those on the African haplotype. Furthermore, we found evidence that the European and African HLA-DRB1*15:01 alleles exhibit single nucleotide polymorphism (SNP) differences in regions encoding the HLA-DRB1 antigen-binding heterodimer. Additional evidence for increased risk of MS conferred by the European haplotype were found for HLA-B*07:02 and HLA-A*03:01 in African Americans. Most of the 200 non-HLA MS SNPs previously established in European populations were not significantly associated with MS in admixed populations, nor were they ancestrally more European in cases compared to controls. Lastly, a genome-wide search of association between European ancestry and MS revealed a region of interest close to the ZNF596 gene on chromosome 8 in Hispanics; cases had a significantly higher proportion of European ancestry compared to controls. In conclusion, our study established that the genetic ancestry of MS-associated alleles is complex and implicated that difference in MS prevalence could be explained by the ancestry of MS-associated alleles., Author summary Multiple sclerosis (MS) is an autoimmune disease that is mostly found in populations with northern European ancestry. Our study investigates whether there is evidence that the difference in MS prevalence around the globe could be explained by European MS genetic risk factors in African Americans, Hispanics, or Asian Americans. Our work first established that most alleles associated with MS are not necessarily European, but are in fact, cosmopolitan. However, we also observed in African Americans that European HLA-DRB1*15:01 conferred three times the odds of MS compared to the African allele. The allele HLA-DRB1*15:01 has been shown to be a major genetic risk factor in Europeans and other admixed populations. In addition, we observed genetic variations between European and African HLA-DRB1*15:01 alleles that, based on location, could influence the function of antigen-binding proteins involved in MS. Consequently, it is plausible that ancestry could explain the risk or protective effects of other MS-associated alleles. Additionally, our study found on chromosome 8 in Hispanics a region where MS cases have more European ancestry than controls, implicating there may be new MS risk alleles to be discovered in Hispanics. In conclusion, our study found evidence that the difference in MS prevalence could be explained by European ancestry and established that the ancestry of MS genetic risk factors is complex.

BACKGROUND: Although several disease-modifying treatments are available for relapsing multiple sclerosis, treatment effects have been more modest in progressive multiple sclerosis and have been observed particularly in actively relapsing subgroups or those with lesion activity on imaging. We sought to assess whether natalizumab slows disease progression in secondary progressive multiple sclerosis, independent of relapses.METHODS: ASCEND was a phase 3, randomised, double-blind, placebo-controlled trial (part 1) with an optional 2 year open-label extension (part 2). Enrolled patients aged 18-58 years were natalizumab-naive and had secondary progressive multiple sclerosis for 2 years or more, disability progression unrelated to relapses in the previous year, and Expanded Disability Status Scale (EDSS) scores of 3·0-6·5. In part 1, patients from 163 sites in 17 countries were randomly assigned (1:1) to receive 300 mg intravenous natalizumab or placebo every 4 weeks for 2 years. Patients were stratified by site and by EDSS score (3·0-5·5 vs 6·0-6·5). Patients completing part 1 could enrol in part 2, in which all patients received natalizumab every 4 weeks until the end of the study. Throughout both parts, patients and staff were masked to the treatment received in part 1. The primary outcome in part 1 was the proportion of patients with sustained disability progression, assessed by one or more of three measures: the EDSS, Timed 25-Foot Walk (T25FW), and 9-Hole Peg Test (9HPT). The primary outcome in part 2 was the incidence of adverse events and serious adverse events. Efficacy and safety analyses were done in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT01416181.FINDINGS: Between Sept 13, 2011, and July 16, 2015, 889 patients were randomly assigned (n=440 to the natalizumab group, n=449 to the placebo group). In part 1, 195 (44%) of 439 natalizumab-treated patients and 214 (48%) of 448 placebo-treated patients had confirmed disability progression (odds ratio [OR] 0·86; 95% CI 0·66-1·13; p=0·287). No treatment effect was observed on the EDSS (OR 1·06, 95% CI 0·74-1·53; nominal p=0·753) or the T25FW (0·98, 0·74-1·30; nominal p=0·914) components of the primary outcome. However, natalizumab treatment reduced 9HPT progression (OR 0·56, 95% CI 0·40-0·80; nominal p=0·001). In part 1, 100 (22%) placebo-treated and 90 (20%) natalizumab-treated patients had serious adverse events. In part 2, 291 natalizumab-continuing patients and 274 natalizumab-naive patients received natalizumab (median follow-up 160 weeks [range 108-221]). Serious adverse events occurred in 39 (13%) patients continuing natalizumab and in 24 (9%) patients initiating natalizumab. Two deaths occurred in part 1, neither of which was considered related to study treatment. No progressive multifocal leukoencephalopathy occurred.INTERPRETATION: Natalizumab treatment for secondary progressive multiple sclerosis did not reduce progression on the primary multicomponent disability endpoint in part 1, but it did reduce progression on its upper-limb component. Longer-term trials are needed to assess whether treatment of secondary progressive multiple sclerosis might produce benefits on additional disability components.FUNDING: Biogen.

Background: Only limited data are available on whether glatiramer acetate exposure during pregnancy has an effect on perinatal outcome. Objective: To determine the effect of glatiramer acetate exposure during pregnancy on pregnancy outcomes in women with multiple sclerosis. Methods: We compared the outcome of pregnancies of women with multiple sclerosis exposed to glatiramer acetate with pregnancies unexposed to disease-modifying therapies. Women were enrolled into the German Multiple Sclerosis and Pregnancy registry. A standardized questionnaire was administered during pregnancy and postpartum. Detailed information on course of multiple sclerosis and pregnancy, concomitant medications, labor, delivery, and outcome of pregnancy was obtained. Results: We collected data on 246 multiple sclerosis pregnancies, 151 exposed to glatiramer acetate and 95 unexposed to disease-modifying therapies during pregnancy. Three (2.2%) congenital anomalies occurred in the exposed and 6 (6.7%) in the control group. We did not observe an increase in other adverse pregnancy or delivery outcomes including spontaneous abortions, preterm birth, Cesarean sections, or reduced birth weight in the exposed group. Conclusion: Our data provide further evidence that glatiramer acetate exposure during the first trimester of pregnancy appears safe and without teratogenic effect. These findings provide important additive knowledge to better counsel women with multiple sclerosis in planning a pregnancy.

Multiple sclerosis (MS) incidence and serum 25-hydroxyvitamin D (25OHD) levels vary by race/ethnicity. We examined the consistency of beneficial effects of 25OHD and/or sun exposure for MS risk across multiple racial/ethnic groups. We recruited incident MS cases and controls (blacks 116 cases/131 controls; Hispanics 183/197; whites 247/267) from the membership of Kaiser Permanente Southern California into the MS Sunshine Study to simultaneously examine sun exposure and 25OHD, accounting for genetic ancestry and other factors. Higher lifetime ultraviolet radiation exposure (a rigorous measure of sun exposure) was associated with a lower risk of MS independent of serum 25OHD levels in blacks (adjusted OR = 0.53, 95% CI = 0.31-0.83; p = 0.007) and whites (OR = 0.68, 95% CI = 0.48-0.94; p = 0.020) with a similar magnitude of effect that did not reach statistical significance in Hispanics (OR = 0.66, 95% CI = 0.42-1.04; p = 0.071). Higher serum 25OHD levels were associated with a lower risk of MS only in whites. No association was found in Hispanics or blacks regardless of how 25OHD was modeled. Lifetime sun exposure appears to reduce the risk of MS regardless of race/ethnicity. In contrast, serum 25OHD levels are not associated with MS risk in blacks or Hispanics. Our findings challenge the biological plausibility of vitamin D deficiency as causal for MS and call into question the targeting of specific serum 25OHD levels to achieve health benefits, particularly in blacks and Hispanics.