Risk of Multiple Sclerosis in People Living with HIV: An International Cohort Study.

OBJECTIVE: There has been interest in a possible negative association between HIV and multiple sclerosis (MS). We aimed to compare the risk of MS in a cohort of individuals living with HIV to that in the general population. METHODS: Population-based health data were accessed for 2 cohorts of HIV-positive persons from Sweden and British Columbia, Canada. Incident MS was identified using MS registries or a validated algorithm applied to administrative data. Individuals with HIV were followed from 1 year after the first clinical evidence of HIV or the first date of complete administrative health data (Canada = April 1, 1992 and Sweden = January 1, 2001) until the earliest of incident MS, emigration, death, or study end (Canada = March 31, 2020 and Sweden = December 31, 2018). The observed MS incidence rate in the HIV-positive cohort was compared to the expected age-, sex-, calendar year-, income-specific, and region of birth-specific rates in a randomly selected sample of >20% of each general population. The standardized incidence ratio (SIR) for MS following the first antiretroviral therapy exposure ("ART-exposed") was also calculated. RESULTS: The combined Sweden-Canada cohort included 29,163 (75% men) HIV-positive persons. During 242,248 person-years of follow-up, 14 incident MS cases were observed in the HIV-positive cohort, whereas 26.19 cases were expected. The SIR for MS in the HIV-positive population was 0.53 (95% confidence interval [CI] = 0.32-0.90). The SIR for MS following the first ART exposure was 0.55 (95% CI = 0.31-0.96). INTERPRETATION: This international population-based study demonstrated a lower risk of MS among HIV-positive individuals, and HIV-positive ART-exposed individuals. These findings provide support for further exploration into the relationship among HIV, ART, and MS. ANN NEUROL 2024;95:487-494.

Incidence rate and prevalence of pediatric-onset multiple sclerosis in Sweden: A population-based register study.

BACKGROUND AND PURPOSE: Pediatric-onset multiple sclerosis (PoMS) is associated with high health care use. To plan resource allocation for this patient group, knowledge of the incidence rate and prevalence is important. However, such studies are scarce, few are population-based, and the methodology varies widely. We aimed to address this knowledge gap by performing a nationwide study of the incidence rate and prevalence of PoMS in Sweden, an area of high multiple sclerosis (MS) incidence and prevalence. METHODS: MS cases were identified by linking two nationwide registers, the National Patient Register and the Swedish MS Registry. MS cases having their first central nervous system demyelinating event or MS clinical onset before age 18 years were classified as pediatric onset. Incidence rate and prevalence were estimated annually over the study period (2006-2016) for the total population and stratified by sex and age group (<12, 12-15, and 16-17 years). Temporal trends and ratios between sexes and age groups were estimated. RESULTS: We identified 238 incident cases from 2006 to 2016, corresponding to an overall crude incidence rate of 1.12 per 100,000 person-years and an overall crude prevalence of 2.82 per 100,000 population. There was a higher incidence rate among females and the highest age category. The overall incidence rate and prevalence estimates remained stable during the study period. CONCLUSIONS: Sweden exhibits a consistently high incidence rate and prevalence of PoMS that has remained stable over time. This knowledge serves as a tool to aid in planning resource allocation and health services for this patient population.

Reduction in Cognitive Processing Speed Surrounding Multiple Sclerosis Relapse.

OBJECTIVE: The purpose of this study was to explore the longitudinal relationship between multiple sclerosis (MS) relapses and information processing efficiency among persons with relapsing-remitting MS. METHODS: We conducted a Swedish nationwide cohort study of persons with incident relapsing-remitting MS (2001-2019). Relapse information and symbol digit modalities test (SDMT) scores were obtained from the Swedish MS Registry. Follow-up was categorized into 2 periods based on relapse status: "relapse" (90 days pre-relapse to 730 days post-relapse, subdivided into 10 periods) and "remission." Linear mixed models compared SDMT scores during the relapse periods to SDMT scores recorded during remission (reference) with results reported as ß-coefficients and 95% confidence intervals (CIs), adjusted for age, sex, SDMT type (written vs oral), time-varying, disease-modifying therapy exposure and sequence of SDMT. RESULTS: Over a mean (SD) follow-up of 10.7 (4.3) years, 31,529 distinct SDMTs were recorded among 3,877 persons with MS. There was a significant decline in information processing efficiency that lasted from 30 days pre-relapse up to 550 days post-relapse, with the largest decline occurring 0 to 30 days post-relapse (ß-coefficient: -4.00 (95% CI = -4.61 to -3.39), relative to the period of remission. INTERPRETATION: We found evidence of cognitive change up to 1 month prior to relapse onset. The reduction in SDMT lasted 1.5 years and was clinically significant up to 3 months post-relapse. These results suggest that the effects of a relapse on cognition are longer than previously thought and highlight the importance of reducing relapse rates as a potential means of preserving cognitive function. ANN NEUROL 2022;91:417-423.

Medication use and risk of amyotrophic lateral sclerosis-a systematic review.

BACKGROUND: Studying whether medications act as potential risk factors for amyotrophic lateral sclerosis (ALS) can contribute to the understanding of disease etiology as well as the identification of novel therapeutic targets. Therefore, we conducted a systematic review to summarize the existing evidence on the association between medication use and the subsequent ALS risk. METHODS: A systematic review was conducted in Medline, Embase, and Web of Science from the date of database establishment to December 10, 2021. References of identified articles were further searched for additional relevant articles. Studies were included if (1) published in English, (2) explored medication use as exposure and development of ALS as outcome, and (3) the design was a human observational study. Clinical trials, reviews, comments, editorials, and case reports were excluded. Quality assessment was performed using a pre-validated tool for non-randomized studies, the Newcastle-Ottawa Assessment Scale (NOS). RESULTS: Of the 4760 studies identified, 25 articles, including 13 case-control studies, five nested case-control studies, six cohort studies, and one retrospective chart review, were included in the review. Among these studies, there were 22 distinct study populations that included 171,407 patients with ALS, seven classes of medication examined, and 23 studies with a NOS ≥ 5. There was a general lack of agreement between studies on the associations of cholesterol-lowering drugs, anti-inflammatory drugs, immunosuppressants, antibiotics, oral contraceptives (OCs) or hormone replacement therapy (HRT), antihypertensive drugs, antidiabetics, and drugs for psychiatric and neurological disorders with the subsequent risk of ALS. However, it appeared that statins, aspirin, OCs/HRT, antihypertensives, and antidiabetics were unlikely related to a higher risk of ALS. The positive associations noted for antibiotics, antidepressants, and skeletal muscle relaxants might be attributable to prodromal symptoms of ALS. CONCLUSIONS: There is currently no strong evidence to link any medication use with ALS risk.

Military service and related risk factors for amyotrophic lateral sclerosis.

BACKGROUND: The cause of amyotrophic lateral sclerosis (ALS) is unknown, but occupations have been explored as a potential proxy measure of risk. There is a substantial body of literature connecting military service to ALS. We aimed to summarize and assess the quality of this evidence. METHODS: Systematic review of the literature, including observational studies which explored one of the following exposures: general military service (army, air force, marines, or navy); or specific exposures associated with military service measured among military personnel. The outcome of interest was ALS incidence, which could include onset, diagnosis, or death from ALS. RESULTS: A total of 2642 articles were screened. Following exclusion, 19 articles remained for inclusion in the systematic review, including 1 meta-analysis and 18 original observational studies. Most studies were of moderate quality. In general, the relationship between military service was suggestive of an increased risk, particularly among Gulf War and WWII veterans. Exposure to pesticides (including Agent Orange) certain chemicals (exhaust, burning agents), heavy metals, and head trauma appeared to increase the risk of ALS among military personnel. CONCLUSIONS: There is a possible association between military service and the subsequent development of ALS; however, the evidence was limited. Studies were generally hindered by small sample sizes and inadequate follow-up time. Future studies should endeavor to objectively measure specific exposures, or combinations thereof, associated with military service, as this will be of vital importance in implementing preventative strategies into military organizations.

Validating the diagnosis of multiple sclerosis using Swedish administrative data in Värmland County.

OBJECTIVES: Multiple sclerosis (MS) is a chronic neurodegenerative disease of the central nervous system. Identifying MS at the population level is important for disease surveillance and allocation of resources. The Swedish National Patient Registry (NPR) has been used to study the epidemiology of MS, but the accuracy of this resource is not known. We aimed to validate a definition of MS using the Swedish NPR in Värmland County using a longitudinal cohort design. MATERIALS AND METHODS: Data were extracted from the NPR, the Total Population Register, the Swedish MS Register, and medical records for the years 2001-2013. Fifteen algorithms of hospitalizations and clinic visits for MS were developed and compared with findings in medical records, which acted as the "gold standard" definition. Sensitivity, specificity, and positive and negative predictive values (PPV, NPV) were estimated. RESULTS: Of 805 eligible persons identified in the NPR, 763 had MS (94.8%) according to medical records. Of these, 544 (71.3%) were also registered in the SMSreg. The case definition that had a well-balanced sensitivity and specificity required three or more clinic or hospital visits for MS (sensitivity of 85.3% (95% CI: 82.6-87.8) and specificity of 81.0% (95%CI: 65.9-91.4). CONCLUSIONS: Multiple case definitions with high sensitivity and moderate specificity were found, suggesting that the NPR can be used to accurately identify persons with MS.

Comorbidities Are Associated with Altered Health Services Use in Multiple Sclerosis: A Prospective Cohort Study.

BACKGROUND: Persons with multiple sclerosis (MS) use health resources with greater frequency than the general population. However, little is known regarding which patient characteristics might contribute. OBJECTIVE: The study aimed to evaluate characteristics associated with healthcare use in MS patients. METHODS: Consecutive MS clinic attendees were recruited (September-November 2010), with clinical, demographic, and patient-completed questionnaires collected at 3 visits over 2 years. Linkage with administrative data (hospital, physician, and pharmacy records) provided healthcare use outcomes until December 31, 2013. Findings were reported as adjusted rate ratios (adjRRs) using negative binomial regression. RESULTS: A total of 340 MS patients with a mean (SD) age of 48.4 (12.0) years and subsequent follow-up of 3.1 (0.34) years were included. Fatigue and high physical comorbidity count (≥3 vs. none) were significantly associated with higher rates of physician encounters (adjRRs: 1.37 and 1.52, respectively), prescriptions filled (adjRRs: 1.25 and 1.40), and hospitalizations (adjRRs: 4.02 and 3.45). In addition, anxiety, disruptive pain, and perceived functional cognitive difficulties were associated with higher rates of physician encounters and prescriptions dispensed (adjRR ranged from 1.28 to 1.48). DISCUSSION: The presence of fatigue and higher physical comorbidity burden were associated with higher rates of health services use. Findings have implications for those examining healthcare burden or organizing health services for persons with MS.

Drug exposure and the risk of multiple sclerosis: A systematic review.

BACKGROUND: Several environmental and lifestyle factors have been associated with multiple sclerosis (MS) risk, including some pharmacological treatments. We systematically reviewed the literature on prescription drug exposure and MS risk. METHODS: Six databases were searched for original observational studies reporting drug exposure and MS risk published before 2017. RESULTS: Thirteen articles fulfilled inclusion criteria. Exposure to neither amiloride nor valproic acid was associated with MS (adjusted hazard ratio (adj.HR = 1.34;95% CI:0.81-2.20; adj.HR = 1.30;95%CI:0.44-3.80, respectively). Four studies explored oral contraceptive exposure and reported no association with MS; while a single study found an increased risk (odds ratio [adj.OR] = 1.52;95%CI:1.21-1.91). While penicillin exposure was associated with reduced risk of developing MS (adj.OR = 0.5;95%CI:0.3-0.9), a later study observed an elevated risk for penicillin (adj.OR = 1.21;95%CI:1.10-1.27) and all antibiotics (adj.OR = 1.41;95%CI:1.29-1.53), which was potentially attributed to underlying infection. Anti-tumor necrosis factor-alpha (TNFα) was not associated with MS risk in persons with inflammatory bowel disease (standard morbidity ratio = 4.2;95%CI:0.1-23.0) and arthritis (standardized incidence ratio = 1.38;95%CI:0.69-2.77); however, men exposed to anti-TNFα who also had arthritis and individuals with ankylosing spondylitis were at an increased risk (standardized incidence ratios = 3.91;95%CI:1.47-10.42 and 3.48;95%CI:1.45-8.37, respectively). A reduced risk of MS was observed with exposure to the beta2-adrenergic agonist fenoterol (adj.OR = 0.58;95%CI:0.45-0.76), and the sedating histamine 1-receptor antagonists (adj.OR = 0.2;95%CI:0.1-0.8), but not the non-sedating equivalent (adj.OR = 0.8;95%CI:0.4-1.6). CONCLUSIONS: The suggestion that some drugs may prevent MS is intriguing and warrants further study. In addition, further pharmacovigilance is needed to assess the safety of anti-TNFα drugs in specific populations in the context of MS risk.

Determinants of non-adherence to disease-modifying therapies in multiple sclerosis: A cross-Canada prospective study.

BACKGROUND: Poor adherence to the disease-modifying therapies (DMTs) for multiple sclerosis (MS) may attenuate clinical benefit. A better understanding of characteristics associated with non-adherence could improve outcomes. OBJECTIVE: To evaluate characteristics associated with non-adherence to injectable DMTs. METHODS: Consecutive patients from four Canadian MS Clinics were assessed at three time points over two years. Clinical and demographic information included self-reported DMT use, missed doses in the previous 30 days, health behaviors, and comorbidities. Non-adherence was defined as <80% of expected doses taken. We employed generalized estimating equations to examine characteristics associated with non-adherence at all time points with findings reported as adjusted odds ratios (OR). RESULTS: In all, 485 participants reported use of an injectable DMT, of whom 107 (22.1%) were non-adherent over the study period. Non-adherence was associated with a lower Expanded Disability Status Scale score (0-2.5 vs 3.0-5.5, OR: 1.80; 95% confidence interval (CI): 1.06-3.04), disease duration (⩽5 vs <5 years, OR: 2.23; 95% CI: 1.10-4.52), alcohol dependence (OR: 2.14; 95% CI: 1.23-3.75), and self-reported cognitive difficulties, measured by the Health Utilities Index-3 (OR: 1.55; 95% CI: 1.08-2.22). CONCLUSIONS: Nearly one-quarter of participants were non-adherent during the study. Alcohol dependence, perceived cognitive difficulties, longer disease duration, and mild disability status were associated with non-adherence. These characteristics may help healthcare professionals identify patients at greatest risk of poor adherence.

Disease-Modifying Therapies and Adherence in Multiple Sclerosis: Comparing Patient Self-Report with Pharmacy Records.

BACKGROUND: Self-report and pharmacy records are often used to measure adherence rates to disease-modifying therapies (DMTs) in multiple sclerosis (MS), but little is known about how the sources compare. OBJECTIVE: Compare self-report and pharmacy records for assessing DMT use and adherence rates. METHODS: Demographic information, self-reported DMT use, and missed DMT doses in the previous 30 days were obtained from consecutive MS patients attending an MS clinic and linked to pharmacy records. A medication possession ratio (MPR) was calculated using pharmacy records for the year before and after the visit; MPR <80% defined nonadherence. Agreement between self-report and pharmacy records was assessed using Cohen's kappa (κ). RESULTS: Of 326 participants, 135 reported using an injectable DMT. There was near-perfect and perfect agreement between self-report and pharmacy records for DMT use (κ = 0.95; 95% CI 0.91-0.98) and DMT agent (κ = 1.00). Nonadherence was estimated at 13% (17/128) from the 30-days self-report compared to 30% (34/113) and 43% (53/123) in the year pre- and post-clinic visit from pharmacy records, indicating moderate to fair agreement (year prior: κ = 0.41; 95% CI 0.22-0.59; year post: κ = 0.22; 95% CI 0.09-0.36). CONCLUSIONS: Patients self-reports closely reflected pharmacy records when assessing DMT use and product. Moderate to fair agreement was found when comparing adherence rates between sources.

Adverse health behaviours are associated with depression and anxiety in multiple sclerosis: A prospective multisite study.

BACKGROUND: Depression and anxiety are common among people with multiple sclerosis (MS), as are adverse health behaviours, but the associations between these factors are unclear. OBJECTIVE: To evaluate the associations between cigarette smoking, alcohol use, and depression and anxiety in MS in a cross-Canada prospective study. METHODS: From July 2010 to March 2011 we recruited consecutive MS patients from four MS clinics. At three visits over two years, clinical and demographic information was collected, and participants completed questionnaires regarding health behaviours and mental health. RESULTS: Of 949 participants, 75.2% were women, with a mean age of 48.6 years; most had a relapsing-remitting course (72.4%). Alcohol dependence was associated with increased odds of anxiety (OR: 1.84; 95% CI: 1.32-2.58) and depression (OR: 1.53; 95% CI: 1.05-2.23) adjusting for age, sex, Expanded Disability Status Scale (EDSS), and smoking status. Smoking was associated with increased odds of anxiety (OR: 1.29; 95% CI: 1.02-1.63) and depression (OR: 1.37; 95% CI: 1.04-1.78) adjusting for age, sex, EDSS, and alcohol dependence. Alcohol dependence was associated with an increased incidence of depression but not anxiety. Depression was associated with an increased incidence of alcohol dependence. CONCLUSION: Alcohol dependence and smoking were associated with anxiety and depression. Awareness of the effects of adverse health behaviours on mental health in MS might help target counselling and support for those 'at risk'.

Disclosing or concealing multiple sclerosis in the workplace: two sides of the same coin-insights from a Swedish population-based survey.

Background: People with multiple sclerosis (PwMS) face health and social challenges of living with a chronic and potentially disabling condition. To disclose or conceal MS at work may critically affect individuals' work situation, career opportunities, and health. PwMS may experience a dilemma when assessing if the possible benefits of disclosing the diagnosis outweigh the possible risks. However, concealing in the long-term may have health implications and prevent opportunities for support and work adjustments. Few studies have examined what drives PwMS to disclose or conceal MS at work and the consequences of these ways of managing MS. Objectives: To explore the reasons PwMS report for disclosing and/or concealing their MS diagnosis in the workplace, as well as the consequences they have experienced. Methods: A web-based survey of PwMS was conducted in 2021. All individuals aged 20-50 listed in the Swedish MS registry were invited to participate. The response rate was 52% and among these participants, 3,810 (86%) completed questions regarding workplace disclosure and/or concealment of MS. Free-text responses on these topics were analyzed using inductive content analysis. Results: It was common to disclose MS in the workplace (85%). Identified drivers for disclosure and concealment related to four categories: Work-related, Social, Personal and Circumstantial. Work-related drivers focused on employment or protecting one's career, and changing one's work situation versus maintaining it. Social drivers included the need for support, addressing or preventing stigma, and being considerate of others. Personal drivers were linked to moral values/personal beliefs and processing of the diagnosis. Circumstantial drivers related to involuntary or unforeseen events, timing factors, one's medical condition and external opinion/advice. Identified consequences for disclosure and concealment related to three categories: Work-life, Social, and Personal. Work-life consequences included work arrangements, and career opportunities. Social consequences were linked to MS awareness, stigma, interactions and social support, as well as dynamics of work relationships. Personal consequences involved levels of disease acceptance, and attitudes toward managing MS. Conclusion: PwMS often described the question of disclosure as challenging and navigated it with caution, as both disclosure and concealment can yield favorable and unfavorable outcomes.

Socioeconomic status and quality of multiple sclerosis care in Sweden.

In Sweden's universal healthcare system, it is unknown whether people of higher socioeconomic status receive higher quality multiple sclerosis (MS) care. Using linked clinical and administrative data, we investigated the quality of care received by 4426 adults aged 23-60 with relapsing-remitting MS. In adjusted analyses, we demonstrated that higher premorbid educational attainment is associated with 4-12 % more frequent neurologist visits and MRI scans in the first four years post diagnosis, while higher premorbid income was associated with faster diagnosis-to-treatment times by 34-64 days. Neither education nor income were associated with time to diagnosis. This suggests that the more favourable MS outcomes observed for people of higher socioeconomic status may in part be related to higher quality care.

Clinical Characteristics and Long-Term Outcomes of Late-Onset Multiple Sclerosis: A Swedish Nationwide Study.

BACKGROUND AND OBJECTIVES: Clinical onset of multiple sclerosis (MS) after the age of 50 years is uncommon and associated with a less favorable natural history. The differences in long-term outcomes in patients with late-onset MS (LOMS, onset 50 years or older) and adult-onset MS (AOMS, onset 18 years or older and younger than 50 years) during the disease-modifying therapy (DMT) era have been less studied. This study aimed to compare patient characteristics, DMT exposure, and disability progression in Swedish patients with LOMS and AOMS over 2 decades (2001-2022). METHODS: The nationwide Swedish MS registry was searched for patients with an onset of MS between January 1, 2001, and December 31, 2018, with symptom onset at age 18 years or older and ≥2 recorded Expanded Disability Status Scale (EDSS) scores. Clinical and demographic parameters and exposure to DMT were compared between LOMS and AOMS. Time to disability milestones (EDSS 4 and 6) was assessed using Kaplan-Meier curves and Cox proportional hazards regression models adjusted for sex, disease course, calendar year at onset, and DMT exposure. RESULTS: Among 8739 patients with MS who met inclusion criteria, 1,028 (11.8%) were LOMS. Primary progressive MS was more frequently diagnosed in LOMS compared with that in AOMS (25.2% vs 4.5%; p < 0.001). Most of the patients had been prescribed DMT, but more rarely in LOMS compared with AOMS (74.7% vs 95.6%; p < 0.001). Less than half of patients with LOMS had been exposed to a high-efficacy DMT (45.8%) compared with 73.5% of AOMS (p < 0.001). The risk of reaching disability milestones was greater for LOMS compared with that for AOMS (EDSS 4; adjusted hazard ratio [aHR] 2.71; 95% CI 2.22-3.30; p < 0.001, and EDSS 6; aHR 2.67; 95% CI 2.12-3.36; p < 0.001). DISCUSSION: This study distinguishes LOMS as a particularly vulnerable group and clinically supports close vigilance of these patients. Further studies are needed to assess and clarify the benefit of DMT usage in older adults with MS.

Association of pre-existing maternal cardiovascular diseases with neurodevelopmental disorders in offspring: a cohort study in Sweden and British Columbia, Canada.

BACKGROUND: We aimed to investigate the associations of pre-existing maternal cardiovascular disease (CVD) with attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD) and intellectual disability (ID) in offspring. METHODS: This population-based cohort study included singletons live-born without major malformations in Sweden (n = 2 699 675) and British Columbia (BC), Canada (n = 887 582) during 1990-2019, with follow-up from age 1 year until the outcome, death, emigration or December 2020, whichever came first. The primary exposure was defined as a composite CVD diagnosed prior to conception: cerebrovascular disease, arrhythmia, heart failure, valvular and congenital heart diseases. The incidences of ADHD, ASD and ID, comparing offspring of mothers with versus without CVD, were calculated as adjusted hazard ratios (aHRs). These results were compared with models using paternal CVD as negative control exposure. RESULTS: Compared with offspring of mothers without CVD, offspring of mothers with CVD had 1.15-fold higher aHRs of ADHD [95% confidence interval (CI): 1.10-1.20] and ASD (95% CI 1.07-1.22). No association was found between maternal CVD and ID. Stratification by maternal CVD subtypes showed increased hazards of ADHD for maternal heart failure (HR 1.31, 95% CI 1.02-1.61), cerebrovascular disease (HR 1.20, 95% CI 1.08-1.32), congenital heart disease (HR 1.18, 95% CI 1.08-1.27), arrhythmia (HR 1.13, 95% CI 1.08-1.19) and valvular heart disease (HR 1.12, 95% CI 1.00-1.24). Increased hazards of ASD were observed for maternal cerebrovascular disease (HR 1.25, 95% CI 1.04-1.46), congenital heart disease (HR 1.17, 95% CI 1.01-1.33) and arrythmia (HR 1.12, 95% CI 1.01-1.21). Paternal CVD did not show associations with ADHD, ASD or ID, except for cerebrovascular disease which showed associations with ADHD and ASD. CONCLUSIONS: In this large cohort study, pre-existing maternal CVD was associated with increased risk of ADHD and ASD in offspring.

Polygenic liability for anxiety in association with comorbid anxiety in multiple sclerosis.

OBJECTIVE: Comorbid anxiety occurs often in MS and is associated with disability progression. Polygenic scores offer a possible means of anxiety risk prediction but often have not been validated outside the original discovery population. We aimed to investigate the association between the Generalized Anxiety Disorder 2-item scale polygenic score with anxiety in MS. METHODS: Using a case-control design, participants from Canadian, UK Biobank, and United States cohorts were grouped into cases (MS/comorbid anxiety) or controls (MS/no anxiety, anxiety/no immune disease or healthy). We used multiple anxiety measures: current symptoms, lifetime interview-diagnosed, and lifetime self-report physician-diagnosed. The polygenic score was computed for current anxiety symptoms using summary statistics from a previous genome-wide association study and was tested using regression. RESULTS: A total of 71,343 individuals of European genetic ancestry were used: Canada (n = 334; 212 MS), UK Biobank (n = 70,431; 1,390 MS), and the USA (n = 578 MS). Meta-analyses identified that in MS, each 1-SD increase in the polygenic score was associated with ~50% increased odds of comorbid moderate anxious symptoms compared to those with less than moderate anxious symptoms (OR: 1.47, 95% CI: 1.09-1.99). We found a similar direction of effects in the other measures. MS had a similar anxiety genetic burden compared to people with anxiety as the index disease. INTERPRETATION: Higher genetic burden for anxiety was associated with significantly increased odds of moderate anxious symptoms in MS of European genetic ancestry which did not differ from those with anxiety and no comorbid immune disease. This study suggests a genetic basis for anxiety in MS.

Premorbid Sociodemographic Status and Multiple Sclerosis Outcomes in a Universal Health Care Context.

Importance: Multiple sclerosis (MS) severity may be informed by premorbid sociodemographic factors. Objective: To determine whether premorbid education, income, and marital status are associated with future MS disability and symptom severity, independent of treatment, in a universal health care context. Design, Setting, and Participants: This nationwide observational cohort study examined data from the Swedish MS Registry linked to national population registries from 2000 to 2020. Participants included people with MS onset from 2005 to 2015 and of working age (aged 23 to 59 years) 1 year and 5 years preceding disease onset. Exposures: Income quartile, educational attainment, and marital status measured at 1 and 5 years preceding disease onset. Main Outcome and Measures: Repeated measures of Expanded Disability Status Scale (EDSS) scores and patient-reported Multiple Sclerosis Impact Scale (MSIS-29) scores. Models were adjusted for age, sex, relapses, disease duration, and treatment exposure. Secondary analyses further adjusted for comorbidity. All analyses were stratified by disease course (relapse onset and progressive onset). Results: There were 4557 patients (mean [SD] age, 37.5 [9.3] years; 3136 [68.8%] female, 4195 [92.1%] relapse-onset MS) with sociodemographic data from 1-year preonset of MS. In relapse-onset MS, higher premorbid income and education correlated with lower disability (EDSS, -0.16 [95% CI, -0.12 to -0.20] points) per income quartile; EDSS, -0.47 [95% CI, -0.59 to -0.35] points if tertiary educated), physical symptoms (MSIS-29 physical subscore, -14% [95% CI, -11% to -18%] per income quartile; MSIS-29 physical subscore, -43% [95% CI, -35% to -50%] if tertiary educated), and psychological symptoms (MSIS-29 psychological subscore, -12% [95% CI, -9% to -16%] per income quartile; MSIS-29 psychological subscore, -25% [95% CI, -17% to -33%] if tertiary educated). Marital separation was associated with adverse outcomes (EDSS, 0.34 [95% CI, 0.18 to 0.51]; MSIS-29 physical subscore, 35% [95% CI, 12% to 62%]; MSIS-29 psychological subscore, 25% [95% CI, 8% to 46%]). In progressive-onset MS, higher income correlated with lower EDSS (-0.30 [95% CI, -0.48 to -0.11] points per income quartile) whereas education correlated with lower physical (-34% [95% CI, -53% to -7%]) and psychological symptoms (-33% [95% CI, -54% to -1%]). Estimates for 5-years preonset were comparable with 1-year preonset, as were the comorbidity-adjusted findings. Conclusions and relevance: In this cohort study of working-age adults with MS, premorbid income, education, and marital status correlated with disability and symptom severity in relapse-onset and progressive-onset MS, independent of treatment. These findings suggest that socioeconomic status may reflect both structural and individual determinants of health in MS.

Polygenicity of Comorbid Depression in Multiple Sclerosis.

BACKGROUND AND OBJECTIVES: Depression is common in multiple sclerosis (MS) and is associated with faster disability progression. The etiology of comorbid depression in MS remains poorly understood. Identification of individuals with a high risk of depression, through polygenic scores (PGS), may facilitate earlier identification. Previous genetic studies of depression considered depression as a primary disorder, not a comorbidity, and thus, findings may not generalize to MS. Body mass index (BMI) is a risk factor of both MS and depression, and its association may highlight differences in depression in MS. To improve the understanding of comorbid depression in MS, we will investigate PGS in people with MS, with the hypothesis that a higher depression PGS is associated with increased odds for comorbid depression in MS. METHODS: Samples from 3 sources (Canada, UK Biobank, and the United States) were used. Individuals were grouped into cases (MS/comorbid depression) and compared with 3 control groups: MS/no depression, depression/no immune disease, and healthy persons. We used 3 depression definitions: lifetime clinical diagnoses, self-reported diagnoses, and depressive symptoms. The PGS were tested in association with depression using regression. RESULTS: A total of 106,682 individuals of European genetic ancestry were used: Canada (n = 370; 213 with MS), UK Biobank (n = 105,734; 1,390 with MS), and the United States (n = 578 with MS). Meta-analyses revealed individuals with MS and depression had a higher depression PGS compared with both individuals with MS without depression (odds ratio range per SD 1.29-1.38, p < 0.05) and healthy controls (odds ratio range per SD 1.49-1.53, p < 0.025), regardless of the definition applied and when sex stratified. The BMI PGS was associated with depressive symptoms (p ≤ 0.001). The depression PGS did not differ between depression occurring as a comorbid condition with MS or as the primary condition (odds ratio range per SD 1.03-1.13, all p > 0.05). DISCUSSION: A higher depression genetic burden was associated with approximately 30%-40% increased odds of depression in European genetic ancestry participants with MS compared with those without depression and was no different compared with those with depression and no comorbid immune disease. This study paves the way for further investigations into the possible use of PGS for assessing psychiatric disorder risk in MS and its application to non-European genetic ancestries.

Association between brain volume and disability over time in multiple sclerosis.

Background: Most previous multiple sclerosis (MS) brain atrophy studies using MS impact scale 29 (MSIS-29) or symbol digit modalities test (SDMT) have been cross-sectional with limited sets of clinical outcomes. Objectives: To investigate which brain and lesion volume metrics show the strongest long-term associations with the expanded disability status scale (EDSS), SDMT, and MSIS-29, and whether MRI-clinical associations vary with age. Methods: We acquired MRI and clinical data from a real-world Swedish MS cohort. FreeSurfer and SPM Lesion Segmentation Tool were used to obtain brain parenchymal, cortical and subcortical grey matter, thalamic and white matter fractions as well as T1- and T2-lesion volumes. Mixed-effects and rolling regression models were used in the statistical analyses. Results: We included 989 persons with MS followed for a median of 9.3 (EDSS), 10.1 (SDMT), and 9.3 (MSIS-29) years, respectively. In a cross-sectional analysis, the strength of the associations of the MRI metrics with the EDSS and MSIS-29 was found to drastically increase after 40-50 years of age. Low baseline regional grey matter fractions were associated with longitudinal increase of EDSS and physical MSIS-29 scores and decrease in SDMT scores and these atrophy measures were stronger predictors than the lesion volumes. Conclusions: The strength of MRI-clinical associations increase with age. Grey matter volume fractions are stronger predictors of long-term disability measures than lesion volumes.

COVID-19 clinical outcomes and DMT of MS patients and population-based controls.

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.