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The incidence of multiple sclerosis (MS) is rising in women. To determine whether the use of combined oral contraceptives (COCs) are associated with MS risk and whether this varies by progestin content. We conducted a nested case-control study of females ages 14-48 years with incident MS or clinically isolated syndrome (CIS) 2008-2011 from the membership of Kaiser Permanente Southern California. Controls were matched on age, race/ethnicity and membership characteristics. COC use up to ten years prior to symptom onset was obtained from the complete electronic health record. We identified 400 women with incident MS/CIS and 3904 matched controls. Forty- percent of cases and 32% of controls had used COCs prior to symptom onset. The use of COCs was associated with a slightly increased risk of MS/CIS (adjusted OR = 1.52, 95%CI = 1.21-1.91; p<0.001). This risk did not vary by duration of COC use. The association varied by progestin content being more pronounced for levenorgestrol (adjusted OR = 1.75, 95%CI = 1.29-2.37; p<0.001) than norethindrone (adjusted OR = 1.57, 95%CI = 1.16-2.12; p = 0.003) and absent for the newest progestin, drospirenone (p = 0.95). Our findings should be interpreted cautiously. While the use of some combination oral contraceptives may contribute to the rising incidence of MS in women, an unmeasured confounder associated with the modern woman's lifestyle is a more likely explanation for this weak association.

Vitamin D has been associated with multiple sclerosis (MS) and several markers of disease state in whites. There are limited reports of vitamin D’s influence in MS in ethnic groups, such as in Hispanics. In this study, we compared vitamin D levels in Hispanics and whites with MS and tried to determine whether season or increasing disability influence hypovitaminosis D in Hispanics with MS. Serum 25-hydroxyvitamin D [25(OH)D] levels and clinical characteristics were compared in a cross-sectional sample of Hispanics ( n  = 80) and whites ( n  = 80) with MS recruited from the University of Southern California. Serum 25(OH)D levels were significantly lower in Hispanics than whites with MS (mean and standard deviation 25.1 ± 9.4 and 37.3 ± 19.8 ng/ml, respectively; p  < 0.001). Hispanics were significantly more likely than whites to be vitamin D insufficient (≤30 ng/ml; 70 vs. 41 %, respectively; p  < 0.001) and deficient (≤20 ng/ml; 40 vs. 14 %, respectively, p  < 0.001). In Hispanics, serum 25(OH)D levels were not influenced by season ( p  = 0.8) or higher physical disability (EDSS ≥6, p  = 0.7). We found that the relationship between vitamin D and MS differs by Hispanic ethnicity. Hypovitaminosis D was significantly more common among Hispanics than among whites with MS, and the majority of Hispanics were vitamin D insufficient. Interestingly, there was no association between vitamin D levels and season or increasing disability in the Hispanics. Our findings imply that factors influencing vitamin D levels and possibly vitamin D requirements may vary by ethnicity in patients with MS. These results should be confirmed in larger, prospective multi-ethnic cohort studies.

BackgroundWe analysed the COMparison Between All immunoTherapies for Multiple Sclerosis (NCT03193866), a Swedish nationwide observational study in relapsing-remitting multiple sclerosis (RRMS), to identify trajectories of processing speed and physical disability after disease-modulating therapy (DMT) start.MethodsUsing a group-modelling approach, we assessed trajectories of processing speed with oral Symbol Digit Modalities Test (SDMT) and physical disability with Expanded Disability Status Scale, from first DMT start among 1645 patients with RRMS followed during 2011–2022. We investigated predictors of trajectories using group membership as a multinomial outcome and calculated conditional probabilities linking membership across the trajectories.ResultsWe identified 5 stable trajectories of processing speed: low SDMT scores (mean starting values=29.9; 5.4% of population), low/medium (44.3; 25.3%), medium (52.6; 37.9%), medium/high (63.1; 25.8%) and high (72.4; 5.6%). We identified 3 physical disability trajectories: no disability/stable (0.8; 26.8%), minimal disability/stable (1.6; 58.1%) and moderate disability (3.2; 15.1%), which increased to severe disability. Older patients starting interferons were more likely than younger patients starting rituximab to be on low processing speed trajectories. Older patients starting teriflunomide, with more than one comorbidity, and a history of pain treatment were more likely to belong to the moderate/severe physical disability trajectory, relative to the no disability one. There was a strong association between processing speed and physical disability trajectories.ConclusionsIn this cohort of actively treated RRMS, patients’ processing speed remained stable over the years following DMT start, whereas patients with moderate physical disability deteriorated in physical function. Nevertheless, there was a strong link between processing speed and disability after DMT start.

We conducted a retrospective cohort study in Kaiser Permanente Southern California from 1 January 2020 to 30 September 2020. We found that rituximab‐treated persons with multiple sclerosis (pwMS, n = 1895) were more likely be hospitalized (n = 8, 33.3%), but not die (n = 0) from COVID‐19, compared to the 4.81 million non‐MS population (5.8% and 1.4%, respectively). Time in months (adjusted OR = 0.32, 95% CI = 0.15–0.69, p = 0.0033) and receiving 1000 mg compared to lower doses at last infusion (adjusted OR = 6.28, 95% CI = 1.38–28.5, p = 0.0173) were independent predictors of COVID‐19 severity. Rituximab‐treated pwMS should be counseled to take extra precautions in the 5 months following each infusion. Using extended dosing intervals and lower doses could be considered.

In this phase 2 trial involving 104 patients with relapsing–remitting multiple sclerosis, patients who received rituximab on days 1 and 15 had fewer gadolinium-enhancing lesions on magnetic resonance imaging and fewer relapses during 48 weeks of follow-up than patients who received placebo. Rituximab was associated with more adverse events within 24 hours after the first infusion. The study was too small and short to assess uncommon adverse events or long-term safety. Patients with relapsing–remitting multiple sclerosis who received rituximab on days 1 and 15 had fewer gadolinium-enhancing lesions on MRI and fewer relapses during 48 weeks of follow-up than patients who received placebo. Multiple sclerosis, the prototypical inflammatory demyelinating disease of the central nervous system, is second only to trauma as a cause of acquired neurologic disability in young adults. 1 Multiple sclerosis usually begins as a relapsing, episodic disorder (relapsing–remitting multiple sclerosis), evolving into a chronic neurodegenerative condition characterized by progressive neurologic disability. 2 The traditional view of the pathophysiology of multiple sclerosis has held that inflammation is principally mediated by CD4+ type 1 helper T cells. Therapies (e.g., interferon beta and glatiramer acetate) developed on the basis of this theory decrease the relapse rate by approximately one third 3 , 4 but do not fully . . .

Objective To estimate risks for all‐cause mortality and for severe COVID‐19 in multiple sclerosis patients and across relapsing–remitting multiple sclerosis patients exposed to disease‐modifying therapies. Methods We conducted a Swedish nationwide population‐based multi‐register linkage cohort study and followed all multiple sclerosis patients (n = 17,692 in March 2020), individually age‐, sex‐, and region‐matched to five population‐based controls (n = 86,176 in March 2020) during March 2020–June 2021. We compared annual all‐cause mortality within and across cohorts, and assessed incidence rates and relative risks for hospitalization, intensive care admission, and death due to COVID‐19 in relation to disease‐modifying therapy use, using Cox regression. Results Absolute all‐cause mortality among multiple sclerosis patients was higher from March to December 2020 than in previous years, but relative risks versus the population‐based controls were similar to preceding years. Incidence rates of hospitalization, intensive care admission, and death due to COVID‐19 remained in line with those for all‐cause hospitalization, intensive care admission, and mortality. Among relapsing–remitting patients on rituximab, trends for differences in risk of hospitalization due to COVID‐19 remained in the demographics‐, socioeconomic status‐, comorbidity‐, and multiple sclerosis severity‐adjusted model. Interpretation Risks of severe COVID‐19‐related outcomes were increased among multiple sclerosis patients as a whole compared to population controls, but risk increases were also seen for non‐COVID‐19 hospitalization, intensive care admission, and mortality, and did not significantly differ during the pandemic compared to pre‐pandemic years. The risk conveyed by disease‐modifying therapies was smaller than previously assumed, likely as a consequence of the possibility to better control for confounders.

The Swedish Multiple Sclerosis Register is a national register monitoring treatment and clinical course for all Swedish multiple sclerosis (MS) patients, with high coverage and close integration with the clinic. Despite its great value for epidemiologic research, it has not previously been validated. In this brief report, we summarize a large validation of >3,000 patients in the register using clinical chart review in the context of the COMBAT-MS study. While further improving the data quality for a central cohort of patients available for future epidemiologic research, this study also allowed us to estimate the accuracy and completeness of the register data.

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.

Background Cognitive impairment and dementia are frequently under-recognized. Health system strategies anchored in primary care are essential to address gaps in timely, comprehensive diagnosis. The goal of this paper is to describe the adaptation of a tablet-based brain health assessment (TabCAT-BHA) intervention and the study protocol to test its effectiveness in improving the detection of cognitive impairment, including dementia. Methods This mixed-methods, pragmatic, cluster randomized, hybrid effectiveness-implementation trial is being conducted in two 18-month waves with 26 Kaiser Permanente Southern California primary care clinics, with 13 serving as intervention clinics and 13 as usual care clinics. Patients 65 years and older with memory concerns ( n  ~ 180,000) receiving care at the 26 clinics will be included in the analyses. Primary care clinics are provided the following practice supports as part of the TabCAT-BHA intervention: brief education and training on neurocognitive disorders and study workflows; digital tools to assess cognitive function and support clinician decision making and documentation; and registered nurse support during the work-up and post-diagnosis periods for primary care providers, patients, and families. The intervention was adapted based on engagement with multiple levels of clinical and operational leaders in the healthcare system. Effectiveness outcomes include rates of cognitive impairment diagnosis in primary care and rates of completed standardized cognitive assessments and specialist referrals with incident diagnoses. Implementation outcomes include acceptability-appropriateness-feasibility, adoption, and fidelity. Results We identified seven themes organized by system-, provider-, and patient-level domains that were used to adapt the TabCAT-BHA intervention. Accordingly, changes were made to the provider education, diagnostic work-up, and post-diagnostic support. Results will be reported in fall of 2027. Conclusions Our engagement with multiple primary and specialty care clinical and operational leaders to adapt the TabCAT-BHA intervention to these primary care clinics has informed the protocol to evaluate the intervention’s effectiveness for improving the detection of cognitive impairment, including dementia, in an integrated healthcare system. Trial Registation Clinicaltrials.gov: NCT06090578 (registered 10/24/23).

The purpose of this study was to determine the incidence of clinically isolated syndrome (CIS), a potential precursor of multiple sclerosis (MS), and whether it varies by race/ethnicity in a multi-ethnic, population-based cohort. We conducted a retrospective cohort study of over 9 million person-years of observation from the multi-ethnic, community-dwelling members of Kaiser Permanente Southern California Health Plan from January 1, 2008 to December 31, 2010. Incidence of CIS and risk ratios comparing incidence rates between racial/ethnic groups were calculated using Poisson regression. We identified 468 newly diagnosed CIS cases that did not meet McDonald criteria for MS. The average age at diagnosis was 39.0 years (range 2.7–85.8) and 68.8 % were women. The female preponderance was more pronounced among black (75.7 %) and Hispanics (70.5 %) than in white and Asian individuals with CIS (66.5 and 54.5 %, respectively; P  = 0.14). The most common presenting symptom in Hispanics was optic neuritis ( P  = 0.008), and in blacks, transverse myelitis ( P  = 0.07). Incidence of CIS was lower in Hispanics (3.8, 95 % CI 3.2–4.4, P  < 0.0001) and Asians (2.4, 95 % CI 1.5–3.6, P  < 0.0001) and similar in blacks (6.8, 95 % CI 5.3–8.5, P  = 0.30) compared with whites (5.9, 95 % CI 5.1–6.7). The incidence of CIS varies by race/ethnicity and sex in a similar pattern to MS. In addition, the clinical presentation of CIS varies by race/ethnicity. These findings strengthen the probability that the old belief that blacks have a decreased risk of MS is no longer true. These findings highlight that studies that include minorities are likely to lead to important insights into the etiology and prognosis of CIS and MS.