Association Between Alcohol Consumption and Disability Accumulation in Multiple Sclerosis.

BACKGROUND AND OBJECTIVES: Previous studies have indicated that alcohol consumption is associated with multiple sclerosis (MS) disease progression. We aimed to study the influence of alcohol consumption habits on disease progression and health-related quality of life in MS. METHODS: We categorized patients from 2 population-based case-control studies by alcohol consumption habits at diagnosis and followed them up to 15 years after diagnosis through the Swedish MS registry regarding changes in the Expanded Disability Status Scale (EDSS) and Multiple Sclerosis Impact Scale 29 (MSIS-29). We used Cox regression models with 95% confidence intervals (CIs) using 24-week confirmed disability worsening, EDSS 3, EDSS 4, and physical and psychological worsening from the patient's perspective as end points. RESULTS: Our study comprised 9,051 patients with MS, with a mean age of 37.5 years at baseline/diagnosis. Compared with nondrinking, low and moderate alcohol consumption was associated with reduced risk of EDSS-related unfavorable outcomes (hazard ratios between 0.81 and 0.90) and with reduced risk of physical worsening. The inverse association was confined to relapsing-remitting MS and was more pronounced among women. High alcohol consumption did not significantly affect disease progression. The inverse relationship between low-moderate alcohol consumption and disability progression became stronger when we only included those who had not changed their alcohol consumption during follow-up (hazard ratios between 0.63 and 0.71). There were no differences in measures of disability at baseline between drinkers who continued drinking alcohol after diagnosis and those who later discontinued. Our findings speak against bias due to reverse causation. DISCUSSION: Low and moderate alcohol consumption was associated with more favorable outcomes in relapsing-remitting MS, compared with nondrinking, while there was no significant influence of high alcohol consumption on disease outcomes.

The global patient-reported outcomes for multiple sclerosis initiative: bridging the gap between clinical research and care - updates at the 2023 plenary event.

Significant advancements have been achieved in delineating the progress of the Global PROMS (PROMS) Initiative. The PROMS Initiative, a collaborative endeavor by the European Charcot Foundation and the Multiple Sclerosis International Federation, strives to amplify the influence of patient input on MS care and establish a cohesive perspective on Patient-Reported Outcomes (PROs) for diverse stakeholders. This initiative has established an expansive, participatory governance framework launching four dedicated working groups that have made substantive contributions to research, clinical management, eHealth, and healthcare system reform. The initiative prioritizes the global integration of patient (For the purposes of the Global PROMS Initiative, the term "patient" refers to the people with the disease (aka People with Multiple Sclerosis - pwMS): any individual with lived experience of the disease. People affected by the disease/Multiple Sclerosis: any individual or group that is affected by the disease: E.g., family members, caregivers will be also engaged as the other stakeholders in the initiative). insights into the management of MS care. It merges subjective PROs with objective clinical metrics, thereby addressing the complex variability of disease presentation and progression. Following the completion of its second phase, the initiative aims to help increasing the uptake of eHealth tools and passive PROs within research and clinical settings, affirming its unwavering dedication to the progressive refinement of MS care. Looking forward, the initiative is poised to continue enhancing global surveys, rethinking to the relevant statistical approaches in clinical trials, and cultivating a unified stance among 'industry', regulatory bodies and health policy making regarding the application of PROs in MS healthcare strategies.

A genetic-epigenetic interplay at 1q21.1 locus underlies CHD1L-mediated vulnerability to primary progressive multiple sclerosis.

Multiple Sclerosis (MS) is a heterogeneous inflammatory and neurodegenerative disease with an unpredictable course towards progressive disability. Treating progressive MS is challenging due to limited insights into the underlying mechanisms. We examined the molecular changes associated with primary progressive MS (PPMS) using a cross-tissue (blood and post-mortem brain) and multilayered data (genetic, epigenetic, transcriptomic) from independent cohorts. In PPMS, we found hypermethylation of the 1q21.1 locus, controlled by PPMS-specific genetic variations and influencing the expression of proximal genes (CHD1L, PRKAB2) in the brain. Evidence from reporter assay and CRISPR/dCas9 experiments supports a causal link between methylation and expression and correlation network analysis further implicates these genes in PPMS brain processes. Knock-down of CHD1L in human iPSC-derived neurons and knock-out of chd1l in zebrafish led to developmental and functional deficits of neurons. Thus, several lines of evidence suggest a distinct genetic-epigenetic-transcriptional interplay in the 1q21.1 locus potentially contributing to PPMS pathogenesis.

Rubella virus seropositivity after infection or vaccination as a risk factor for multiple sclerosis.

BACKGROUND: Multiple sclerosis (MS) is a demyelinating disease affecting millions of people worldwide. Hereditary susceptibility and environmental factors contribute to disease risk. Infection with Epstein-Barr virus (EBV) and human herpesvirus 6A (HHV-6A) have previously been associated with MS risk. Other neurotropic viruses, such as rubella virus (RV), are possible candidates in MS aetiopathogenesis, but previous results are limited and conflicting. METHODS: In this nested case-control study of biobank samples in a Swedish cohort, we analysed the serological response towards RV before the clinical onset of MS with a bead-based multiplex assay in subjects vaccinated and unvaccinated towards RV. The association between RV seropositivity and MS risk was analysed with conditional logistic regression. RESULTS: Seropositivity towards RV was associated with an increased risk of MS for unvaccinated subjects, even when adjusting for plausible confounders including EBV, HHV-6A, cytomegalovirus and vitamin D (adjusted odds ratio [AOR] = 4.0, 95% confidence interval [CI] 1.8-8.8). Cases also had stronger antibody reactivity towards rubella than controls, which was not seen for other neurotropic viruses such as herpes simplex or varicella zoster. Furthermore, we observed an association between RV seropositivity and MS in vaccinated subjects. However, this association was not significant when adjusting for the aforementioned confounders (AOR = 1.7, 95% CI 1.0-2.9). CONCLUSIONS: To our knowledge, these are the first reported associations between early RV seropositivity and later MS development. This suggests a broadening of the virus hypothesis in MS aetiology, where molecular mimicry between rubella epitopes and human central nervous system molecules could be an attractive possible mechanism.

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.

COMBAT-MS: A Population-Based Observational Cohort Study Addressing the Benefit-Risk Balance of Multiple Sclerosis Therapies Compared with Rituximab.

OBJECTIVE: To assess comparative effectiveness, safety, and tolerability of off-label rituximab, compared with frequently used therapies approved for multiple sclerosis (MS). METHODS: A Swedish cohort study of persons with relapsing-remitting MS, age 18 to 75 years at inclusion and with a first therapy start or a first therapy switch between 2011 and 2018. Low-dose rituximab was compared with MS-approved therapies. Primary outcomes were proportions with 12 months confirmed disability worsening and change in MS Impact Scale-29 (MSIS-29) scores, respectively. Secondary endpoints included relapses, therapy discontinuation, and serious adverse events. Analyses used an intention-to-treat approach and were adjusted for demographics, MS features, and health characteristics. RESULTS: We included 2,449 participants as first therapy start and 2,463 as first therapy switch. Proportions with disability worsening at 3 years were 9.1% for rituximab as first therapy and 5.1% after therapy switch, with no differences to MS-approved comparators. Worsening on rituximab was mostly independent of relapses. MSIS-29 with rituximab at 3 years improved by 1.3/8.4 points (physical/psychological) for first disease-modifying therapy (DMT) and 0.4/3.6 for DMT switch, and was mostly similar across therapies. Rituximab had lower relapse rates and higher therapy persistence in both groups. The rate of hospital-treated infections was higher with rituximab after a therapy switch, but not as a first therapy. INTERPRETATION: This population-based real-world cohort study found low rates of disability progression, mostly independent of relapses, and without significant differences between rituximab and MS-approved comparators. Rituximab led to lower rates of inflammatory activity and higher treatment persistence, but was associated with an increased rate of serious infections. ANN NEUROL 2024.

Exploring the working life of people with multiple sclerosis during the COVID-19 pandemic in Sweden.

BACKGROUND: The COVID-19 pandemic led to vast changes in working life and conditions in which we work. These changes may affect people with multiple sclerosis (PwMS) differently. We aimed to describe the working situation of PwMS during the COVID-19 pandemic and the pandemic's impact on their working lives. METHODS: All individuals aged 20-50 listed in the Swedish Multiple Sclerosis Registry were invited to participate in an online survey in 2021. Closed and open-ended responses linked to individual-level register data were used in this exploratory mixed-methods study. Differences in the proportions reporting specific impacts were assessed with chi-square tests by sex, MS severity, education, and profession. The open-ended answers were analysed through content analysis. RESULTS: Over 8500 PwMS were invited (52% response rate). We included the 3887 respondents who answered questions about the impact of the pandemic on working life. Most (93.7%) reported being in paid work. An impact of the ongoing pandemic to one's daily occupation was reported by 26.2%, with different characteristics observed across the impacts. Four categories of type of answers were identified from the open-ended answers: Direct impact on one's occupation, Disclosing or concealing MS in the workplace, Worry and uncertainty, and Broader impact to life situation. CONCLUSIONS: PwMS navigated the pandemic by interrupting as well as continuing their working lives. Many PwMS reported that the pandemic did not affect their work situation. However, the reported impacts differed among the participants and a sense of uncertainty and worry was often underlying their statements. Lessons from the pandemic may support future work participation.

Concomitant autoimmunity and risk of multiple sclerosis disability worsening.

BACKGROUND: Few studies have examined the effect of concomitant autoimmune diseases on multiple sclerosis (MS) disability worsening. We set out to examine whether concomitant Crohn's Disease (CD), Ulcerative Colitis (UC), or Type 1 Diabetes (T1D) affect MS disability worsening in a nationwide cohort of MS patients as defined by reaching expanded disability scale status (EDSS) scores 3.0, 4.0 and 6.0. METHODS: Patients with MS onset between January 2004 and January 2019 were identified from the Swedish MS registry and the Swedish National Patient Register. Kaplan-Meier analysis was used to estimate the median time to reach sustained disability milestones. Adjusted Cox proportional hazard regression models were used to calculate the risk of reaching disability milestones among persons with and without CD, UC, or T1D. RESULTS: Out of 8972 persons with MS, 88 (1.0 %) had T1D, 47 (0.8 %) had UC, and 78 (0.9 %) had CD. There was a significantly higher risk of disability progression, for persons with MS and T1D for reaching EDSS 6.0, hazard ratio (HR) = 2.21 (95 % confidence interval (CI) = 1.48 -3.31) and persons with MS and comorbid CD for reaching EDSS 3.0, HR = 2.30 (95 %CI = 1.74-3.04) and 4.0, HR = 1.59 (95 %CI = 1.09-2.32), and persons with MS and comorbid UC for reaching EDSS 3.0 HR = 1.57 (95 %CI = 1.15-2.14). As defined by Charlson's comorbidity index, the co-existence of other co-morbidities conferred a significant increase in the risk of reaching all endpoints, with HR ranging from 1.23 to 1.62. CONCLUSION: Comorbidity is associated with a significantly increased risk of reaching disability end-points, and T1D, CD, and UC increase the risk further. Thus, there appears to be a need for increased vigilance of comorbidites in persons with MS in order to optimise the long-term outcome of MS.

Genetics of immune response to Epstein-Barr virus: prospects for multiple sclerosis pathogenesis.

Epstein-Barr virus (EBV) infection has been advocated as a prerequisite for developing multiple sclerosis (MS) and possibly the propagation of the disease. However, the precise mechanisms for such influences are still unclear. A large-scale study investigating the host genetics of EBV serology and related clinical manifestations, such as infectious mononucleosis (IM), may help us better understand the role of EBV in MS pathogenesis. This study evaluates the host genetic factors that influence serological response against EBV and history of IM and cross-evaluates them with MS risk and genetic susceptibility in the Swedish population. Plasma IgG antibody levels against EBV nuclear antigen-1 (EBNA-1, truncated=aa[325-641], peptide=aa[385-420]) and viral capsid antigen p18 (VCAp18) were measured using bead-based multiplex serology for 8744 MS cases and 7229 population-matched controls. The MS risk association for high/low EBV antibody levels and history of IM was compared to relevant clinical measures along with sex, age at sampling, and associated HLA allele variants. Genome-wide and HLA allele association analyses were also performed to identify genetic risk factors for EBV antibody response and IM history. Higher antibody levels against VCAp18 (OR=1.74, 95% CI=1.60-1.88) and EBNA-1, particularly the peptide (OR=3.13, 95% CI=2.93-3.35), were associated with an increased risk for MS. The risk increased with higher anti-EBNA-1 IgG levels up to twelve times the reference risk. We also identified several independent HLA haplotypes associated with EBV serology overlapping with known MS risk alleles (e.g., DRB1*15:01). Although there were several candidates, no variants outside the HLA region reached genome-wide significance. Cumulative HLA risk for anti-EBNA-1 IgG levels, particularly the peptide fragment, was strongly associated with MS. In contrast, the genetic risk for high anti-VCAp18 IgG levels was not as strongly associated with MS risk. IM history was not associated with class II HLA genes but negatively associated with A*02:01, which is protective against MS. Our findings emphasize that the risk association between anti-EBNA-1 IgG levels and MS may be partly due to overlapping HLA associations. Additionally, the increasing MS risk with increasing anti-EBNA-1 levels would be consistent with a pathogenic role of the EBNA-1 immune response, perhaps through molecular mimicry. Given that high anti-EBNA-1 antibodies may reflect a poorly controlled T-cell defense against the virus, our findings would be consistent with DRB1*15:01 being a poor class II antigen in the immune defense against EBV. Lastly, the difference in genetic control of IM supports the independent roles of EBNA-1 and IM in MS susceptibility.

Coronavirus disease 2019 infection among working-aged people with multiple sclerosis and the impact of disease-modifying therapies.

Background: The risk of coronavirus disease 2019 among people with multiple sclerosis with different disease-modifying therapies is not well established. Objective: To investigate the occurrence of coronavirus disease 2019 and the remaining symptoms among people with multiple sclerosis and the associations with different disease-modifying therapies. Methods: Individuals aged 20-50 listed in the Swedish Multiple Sclerosis Registry were invited to participate in a survey in 2021. Information on reported coronavirus disease 2019 infection and remaining symptoms were linked to individual-level register data. The risks by disease-modifying therapy of having coronavirus disease 2019 or having remaining symptoms were estimated with logistic regression. Results: Of the 4393 participants, 1030 (23.4%) self-reported coronavirus disease 2019 (749 confirmed and 281 suspected). The observed odds for coronavirus disease 2019 did not differ by disease-modifying therapy (p-values <0.05). The majority reporting coronavirus disease 2019 had fully recovered (68.5%), 4.2% were currently/recently sick, and 27.0% had symptoms remaining after 2 months. The most frequently reported remaining symptoms involved one's sense of smell or taste (37.0%), fatigue (20.0%), and breathing (12.0%). No statistically significant associations were observed between having remaining symptoms and the disease-modifying therapy. Conclusion: Despite the initial concerns of differing infection risks by MS treatments, we observed no differences in coronavirus disease 2019 occurrence or remaining symptoms among those who had coronavirus disease 2019. Nonetheless, exercising caution in interpreting our findings, it remains implicit that people with multiple sclerosis are particularly susceptible to infection and that lingering symptoms may persist beyond the initial infection.

Big Multiple Sclerosis Data network: an international registry research network.

BACKGROUND: The Big Multiple Sclerosis Data (BMSD) network ( https://bigmsdata.org ) was initiated in 2014 and includes the national multiple sclerosis (MS) registries of the Czech Republic, Denmark, France, Italy, and Sweden as well as the international MSBase registry. BMSD has addressed the ethical, legal, technical, and governance-related challenges for data sharing and so far, published three scientific papers on pooled datasets as proof of concept for its collaborative design. DATA COLLECTION: Although BMSD registries operate independently on different platforms, similarities in variables, definitions and data structure allow joint analysis of data. Certain coordinated modifications in how the registries collect adverse event data have been implemented after BMSD consensus decisions, showing the ability to develop together. DATA MANAGEMENT: Scientific projects can be proposed by external sponsors via the coordinating centre and each registry decides independently on participation, respecting its governance structure. Research datasets are established in a project-to-project fashion and a project-specific data model is developed, based on a unifying core data model. To overcome challenges in data sharing, BMSD has developed procedures for federated data analysis. FUTURE PERSPECTIVES: Presently, BMSD is seeking a qualification opinion from the European Medicines Agency (EMA) to conduct post-authorization safety studies (PASS) and aims to pursue a qualification opinion also for post-authorization effectiveness studies (PAES). BMSD aspires to promote the advancement of real-world evidence research in the MS field.

Expert opinion on the use of contraception in people with multiple sclerosis.

BACKGROUND: Current guidance on the selection of appropriate contraception for people with multiple sclerosis (PwMS) is lacking. OBJECTIVE: To address this gap, an expert-led consensus program developed recommendations to support clinicians in discussing family planning and contraception with women and men with multiple sclerosis (MS). METHODS: A multidisciplinary steering committee (SC) of 13 international clinical experts led the program, supported by an extended faculty of 32 experts representing 18 countries. A modified Delphi methodology was used for decision-making and consensus-building. The SC drafted 15 clinical questions focused on patient-centered care, selection of contraception, and timing of stopping/starting contraception and disease-modifying therapies (DMTs). Statements addressing each question were drafted based on evaluation of published evidence and the experts' clinical experience. Consensus was reached if ⩾75% of respondents agreed (scoring 7-9 on a 9-point scale) with each recommendation. RESULTS: Consensus was reached on 24 of 25 proposed recommendations, including how and when to discuss contraception, types and safety of contraceptives, and how to evaluate the most appropriate contraceptive options for specific patient groups, including those with significant disability or being treated with DMTs. CONCLUSION: These expert recommendations provide the first practical, relevant, and comprehensive guidance for clinicians on the selection of contraception in PwMS.

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.

Recent trends in disease-modifying therapy use and associated sickness absence and disability pension among people with multiple sclerosis in Sweden.

BACKGROUND: Disease-modifying therapies (DMTs) have led to improved health and work productivity among people with multiple sclerosis (PwMS). OBJECTIVES: To describe trajectories of recent DMT use and their association with sickness absence and/or disability pension (SADP) among PwMS in Sweden. METHODS: A longitudinal register-based study was conducted among 1395 PwMS with treatment start in 2014/2015. While DMT use over 5 years was assessed using sequence analysis resulting in four clusters, a 7-year (Y-2 toY4) trend of SADP was analyzed using zero-inflated negative binomial regression. RESULTS: Four clusters of DMT use trajectories were identified: long-term non-high-efficacy (483, 34.6%), long-term high-efficacy (572, 41%), escalation (221, 15.8%), and discontinuation (119, 8.5%). Progressive MS and higher expanded disability status scale scores were associated with the escalation, long-term high-efficacy, or discontinuation clusters. PwMS in the long-term high-efficacy and escalation clusters had higher likelihood of being on SADP. However, PwMS initiating high-efficacy DMTs demonstrated steeper decline in SADP than others. CONCLUSION: Using sequence analysis, this study showed recent DMT use trajectories among PwMS where initiation of high-efficacy DMTs has become more common. The trend of SADP was stable and lower in those using non-high-efficacy DMTs and larger improvements were shown in those initiating high-efficacy DMTs.

Trajectories of cognitive processing speed and physical disability over 11 years following initiation of a first multiple sclerosis disease-modulating therapy.

BACKGROUND: We 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. METHODS: Using 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. RESULTS: We 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. CONCLUSIONS: In 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.

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.

Introducing a core dataset for real-world data in multiple sclerosis registries and cohorts: Recommendations from a global task force.

BACKGROUND: As of September 2022, there was no globally recommended set of core data elements for use in multiple sclerosis (MS) healthcare and research. As a result, data harmonisation across observational data sources and scientific collaboration is limited. OBJECTIVES: To define and agree upon a core dataset for real-world data (RWD) in MS from observational registries and cohorts. METHODS: A three-phase process approach was conducted combining a landscaping exercise with dedicated discussions within a global multi-stakeholder task force consisting of 20 experts in the field of MS and its RWD to define the Core Dataset. RESULTS: A core dataset for MS consisting of 44 variables in eight categories was translated into a data dictionary that has been published and disseminated for emerging and existing registries and cohorts to use. Categories include variables on demographics and comorbidities (patient-specific data), disease history, disease status, relapses, magnetic resonance imaging (MRI) and treatment data (disease-specific data). CONCLUSION: The MS Data Alliance Core Dataset guides emerging registries in their dataset definitions and speeds up and supports harmonisation across registries and initiatives. The straight-forward, time-efficient process using a dedicated global multi-stakeholder task force has proven to be effective to define a concise core dataset.

The CLARION study: first report on safety findings in patients newly initiating treatment with cladribine tablets or fingolimod for multiple sclerosis.

OBJECTIVES: As part of the CLARION study: (1) characterize the incidence of severe infections, herpes zoster, and malignancies in patients newly initiating cladribine or fingolimod for relapsing multiple sclerosis (MS); (2) estimate the incidence of severe lymphopenia among cladribine users; and (3) describe prior/subsequent disease-modifying therapy (DMT) in both cohorts. METHODS: Patients were identified from seven participating MS registries/data sources. The incidence rate (IR) of each outcome per 1000 patient-years and its 95% confidence interval (95%CI) were estimated for cohorts using Poisson regression. RESULTS: By cut-off date (01-April-2020), 742 cladribine and 867 fingolimod users were included. Mean follow-up was ∼1 year. The IR for severe infections from all contributing sources (except Denmark) was: cladribine, 7.37 (2.76,19.6); fingolimod, 6.55 (2.46,17.4). The corresponding IR for herpes zoster was 5.51 (1.78,17.1) and 3.27 (0.82,13.1), respectively, while values for opportunistic infections were 0 (0,6.76) and 1.63 (0.23,11.6), respectively. There were no events of progressive multifocal leukoencephalopathy in either cohort. The IR of severe lymphopenia was 63.9 (40.7,100.1) in 349 cladribine users from contributing sources. The IR of malignancies (cut-off date 01-April-2022) was 3.55 (1.59,7.90) for the cladribine cohort (n = 1035) and 3.55 (1.48,8.52) for the fingolimod cohort (n = 843) from three MS registries/data sources. In the combined data sources, 36.8% of cladribine and 27.4% of fingolimod users were DMT-naïve; after initiation of study treatment, 2.5% and 20.2% switched to another DMT, respectively. CONCLUSION: No new safety signal was observed in patients treated with cladribine tablets, although results are limited by a relatively short duration of follow-up.

The impact of healthcare systems on the clinical diagnosis and disease-modifying treatment usage in relapse-onset multiple sclerosis: a real-world perspective in five registries across Europe.

Introduction: Prescribing guidance for disease-modifying treatment (DMT) in multiple sclerosis (MS) is centred on a clinical diagnosis of relapsing-remitting MS (RRMS). DMT prescription guidelines and monitoring vary across countries. Standardising the approach to diagnosis of disease course, for example, assigning RRMS or secondary progressive MS (SPMS) diagnoses, allows examination of the impact of health system characteristics on the stated clinical diagnosis and treatment access. Methods: We analysed registry data from six cohorts in five countries (Czech Republic, Denmark, Germany, Sweden and United Kingdom) on patients with an initial diagnosis of RRMS. We standardised our approach utilising a pre-existing algorithm (DecisionTree, DT) to determine patient diagnoses of RRMS or secondary progressive MS (SPMS). We identified five global drivers of DMT prescribing: Provision, Availability, Funding, Monitoring and Audit, data were analysed against these concepts using meta-analysis and univariate meta-regression. Results: In 64,235 patients, we found variations in DMT use between countries, with higher usage in RRMS and lower usage in SPMS, with correspondingly lower usage in the UK compared to other registers. Factors such as female gender (p = 0.041), increasing disability via Expanded Disability Status Scale (EDSS) score (p = 0.004), and the presence of monitoring (p = 0.029) in SPMS influenced the likelihood of receiving DMTs. Standardising the diagnosis revealed differences in reclassification rates from clinical RRMS to DT-SPMS, with Sweden having the lowest rate Sweden (Sweden 0.009, range: Denmark 0.103 - UK portal 0.311). Those with higher EDSS at index (p < 0.03) and female gender (p < 0.049) were more likely to be reclassified from RRMS to DT-SPMS. The study also explored the impact of diagnosis on DMT usage in clinical SPMS, finding that the prescribing environment and auditing practices affected access to treatment. Discussion: This highlights the importance of a healthcare system's approach to verifying the clinical label of MS course in facilitating appropriate prescribing, with some flexibility allowed in uncertain cases to ensure continued access to treatment.

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.