BACKGROUND:The first Association of British Neurologists (ABN) UK multiple sclerosis (MS) pregnancy guidelines were published in 2019. Along with new disease-modifying treatments, significant new data have since become available, resulting in label changes and recognition of class effects. Alongside this, there has been increasing recognition of the importance of family planning considerations in treatment paradigms in MS. METHODS:We set out to update the ABN UK MS Pregnancy guidance with a systematic literature search, with updated guidance informed by multidisciplinary input from across neurology, obstetric medicine, pharmacy and specialist nurses.Guidance:Key updates include consideration of disease-modifying therapy mechanism and durability of action when discussing treatment approaches around pregnancy, alongside considering the impact of treatment withdrawal on relapses during pregnancy and in the postpartum period. Monoclonal antibody transfer into breast milk is generally accepted to be low, and so treatment during lactation can be considered. Active discussion around vaccination strategies during pregnancy and of the neonate is required, with vaccines generally considered safe. With active treatment strategies that take these factors into account, women can be reassured regarding disease control during pregnancy. CONCLUSION:Data sources remain limited, and further dedicated real-world studies that capture the full range of outcomes required to inform risk-benefit discussions are needed. These require collaboration and infrastructure to support the delivery of high-quality care to all women with MS considering pregnancy.

AIMS:Fatigue is a pervasive feature of multiple sclerosis (MS) and its interaction with other MS symptoms is complex. These interactions were explored over time in a large cohort of adults with MS, using a measure reflecting a patient-based definition of MS fatigue. METHODS:Participants were recruited across the UK to complete a questionnaire pack, measuring fatigue and associated demographic, clinical and symptom factors, repeated serially over up to 54 months. Following conversion to interval-level estimates, data were analysed by regression, structural equation and trajectory modelling, and Classification and Regression Tree Analysis. RESULTS:In 6356 people with MS, the prevalence of moderate/severe fatigue was 565.4/1000 (95% CI: 553.0-577.8), with no difference between sexes but significantly higher in progressive subtypes. Peak prevalence was from age 50-64. Spasticity-related pain, physical/cognitive function, anxiety, visual problems and non-restorative sleep were associated with increased fatigue. Self-efficacy had strong influences to reduce fatigue. Use of disease modifying treatment was associated with worse fatigue. Trajectory analysis showed four groups, 28.9% have ongoing severe fatigue, 66.3% fall into two worsening fatigue groups with different inception points. Only 4.9% had low, stable fatigue. These four groups varied significantly by MS subtype, EDSS, symptoms, comorbidity, and employment. The risk of fatigue worsening to moderate/severe over the ensuing 27 months could be predicted by sex, EDSS, vision and self-efficacy. CONCLUSIONS:The factors interacting with MS fatigue need consideration when managing this prevalent symptom. In addition, their effect should be accounted for in any MS trial where fatigue is an outcome.

INTRODUCTION:The social determinants of health are the conditions in which people live and the systems around them that shape these conditions. Social determinants of health may affect diagnosis and treatment for people with multiple sclerosis (MS) even in countries with universal healthcare systems. This study will investigate whether a person's age, sex and/or gender, living in a more socioeconomically deprived area and being of a minoritised ethnicity impact access to a diagnosis of MS and disease-modifying treatments (DMTs) for people living in the catchments of specialist neurology centres with a total estimated catchment population of approximately 7 million people in England and Wales. METHODS AND ANALYSIS:EQUITY-MS is a multicentre retrospective cohort study using routinely collected healthcare data. Study participants are people aged 16 and above who received a new diagnosis of MS between 1 January 2018 and 31 December 2024 while living within the catchment of five specialist neurology centres (located in Leeds, Bradford, Greater Manchester, Cardiff and East London). Data will be collected from patients' hospital records by clinical teams. The primary outcome is the length of time between MS diagnosis and prescription of any DMT. Secondary outcomes are prescriptions of a high-efficacy DMT and the duration between patient-reported symptom onset and MS diagnosis. We plan to adjust for clinical and demographic factors that could impact prescribing decisions. ETHICS AND DISSEMINATION:The study was approved by the North West-Greater Manchester East Research Ethics Committee (National Health Service) (25/NW/0184) on 14 August 2025. Results will be published in peer-reviewed journals, and summaries will be provided to local MS societies and disseminated via the study website (https://bradfordresearch.nhs.uk/bradford-centre-for-health-data-science/equity-ms/).

Objectives To use automated coding to identify broad neurological diagnoses and link to sociodemographic data.Design Retrospective observational study.Setting Tertiary outpatient neurology services covering Greater Manchester and East Cheshire.Participants All adult patients attending neurology appointments between 1 January 2018 and 1 November 2024, covering a population of 3.3 million.Outcome measures To extract and correctly code outpatient neurological diagnoses from semistructured clinical letters and to identify sociodemographic differences.Results Successfully extracted diagnostic data were coded and linked to sociodemographic data for 125 273 unique neurology outpatients. Headache (16.1%, n=26 631) and epilepsy (14.3%, n=24 880) were the most common diagnoses observed. Higher rates were seen from the highest social deprivation for females with functional neurological disorder (age-standardised rate ratio (ASRR) (95% CI) 1.78 (1.73 to 1.83)), headache (ASRR (95% CI) 1.64 (1.61 to 1.68)) and males with epilepsy (ASRR (95% CI) 1.36 (1.32 to 1.39)). Females from lower social deprivation were observed at higher rates with demyelination/inflammation (ASRR (95% CI) 1.34 (1.23 to 1.45)). Ethnicity was missing for 16.5% (n=17 523), but Asian, black and mixed ethnicities had lower rates of clinic attendance compared with white.Conclusions Automated coding of outpatient neurology data can reveal diagnostic patterns and health disparities, providing insights not previously available at scale. These data offer a powerful tool to support service planning, resource allocation and population-level research.

Background:Despite the relative success of immuno-modulatory disease-modifying therapy in relapsing remitting multiple sclerosis, progressive worsening of disability remains a major problem, particularly for those with secondary progressive multiple sclerosis. Various underlying mechanisms are likely to contribute, augmented by comorbidities (such as vascular risk) and ageing. In the phase 2b MS-STAT trial, simvastatin (80 mg) (Sandoz Ltd, Camberley, UK) reduced the mean annualised whole brain atrophy rate by 43% compared to placebo in patients with secondary progressive multiple sclerosis (p = 0.003). We now report the phase 3, MS-STAT2 trial, with confirmed progression of disability as the primary outcome. Methods:A multicentre, phase 3, randomised, double-blind, placebo-controlled clinical trial was conducted at 31 UK neuroscience centres and district general hospitals. Secondary progressive multiple sclerosis participants aged 18-65 years were randomised 1 : 1 to oral simvastatin (80 mg), or matched placebo, based on a minimisation algorithm that incorporated the following factors: sex (male/female); age (< or ≥ 45 years); Expanded Disability Status Scale baseline score (≤ 5.5 or ≥ 6); whether participants were taking newly licensed (2017 onward) disease-modifying treatments for secondary progressive multiple sclerosis; and trial site. An independent and secure online randomisation service was used. All participants, site investigators and the trial co-ordinating team were blinded to treatment allocation. The Expanded Disability Status Scale was measured every 6 months and was compared to baseline scores, with remote data collection used when enforced by the COVID-19 pandemic. The primary outcome was time to Expanded Disability Status Scale-confirmed disability progression. Progression of disability was defined as an increase of at least one point on the Expanded Disability Status Scale if the baseline score was < 6, or an increase of 0.5 point if the baseline score was ≥ 6. The initial disability progression event was finalised as confirmed if the increase in Expanded Disability Status Scale score persisted at the next assessments ≥ 6 months later. Follow-up was for 36 months, or 54 months, for those without confirmed disability progression at 36 months who agreed to enter an optional blinded extension. An intention-to-treat analysis was carried out. Findings:The study was conducted between 10 May 2018 and 26 July 2024. There were 964 participants randomised, with 482 in the placebo group and 482 in the simvastatin group. 173 (35.9%) participants in the placebo group and 192 (39.8%) participants in the simvastatin group experienced Expanded Disability Status Scale-confirmed disability progression (adjusted hazard ratio = 1.13, 95% confidence interval 0.91 to 1.39, p = 0.263). No material differences in the secondary outcomes were observed. No major safety issues were seen. Interpretation:The MS-STAT2 trial did not demonstrate a treatment effect of simvastatin in slowing disability progression in participants with secondary progressive multiple sclerosis. Despite the favourable outcomes of the previous phase 2b trial, simvastatin use in secondary progressive multiple sclerosis should be confined to existing vascular indications. Funding:This synopsis presents independent research funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme as award number 15/57/143.

Objective: This study assessed a sizable cohort of patients with amyotrophic lateral sclerosis (ALS) in a relatively deprived and ethnically diverse area in the northwest of England. We aimed to evaluate the interaction of relative deprivation and ethnicity with the incidence of ALS. Methods: Six hundred and ninety-three adults from Greater Manchester who were diagnosed with ALS between 1 January 2011 and 31 December 2021 were included in this study. Data were collected from electronic patient records. Relative deprivation was estimated using the Index of Multiple Deprivation 2019 and patients were divided into quartiles of deprivation in England. Ethnicity was sub-grouped into White, Southeast Asian, Black, and Other. Poisson's regression analysis was used to calculate the incidence rate and its interactions with deprivation and ethnicity. Results: 55.4% of patients were male, 95.4% were White, 57.4% were in the two most deprived quartiles, and 87.2% had died by the end of the observation period. The crude incidence rate was 2.21 cases per 100,000 (95% CI 2.00-2.40) per year. There was no difference in the adjusted incidence rates among the quartiles of deprivation, even when considering ethnicity as a confounding variable. The risk of ALS in the White population was 2.08 (95% CI 1.47-3.04) times greater than that in the non-White population. Conclusion: In our cohort, relative deprivation was not an independent risk factor for ALS. A stronger association between White ethnicity and ALS was noted. The reason for this association remains unclear, highlighting the need for more research in this field.

The genetic architecture of Multiple Sclerosis (MS) susceptibility has been extensively assessed in populations of European ancestry. Greater ancestral diversity in genetic analyses of MS susceptibility is needed to improve the utility of Multiple Sclerosis genetic risk scores, fine map causal variants underlying established associations, and thereby enhance the identification of drug targets. Here we report findings from a genetic study of Multiple Sclerosis susceptibility in an ancestrally-diverse United Kingdom-based cohort. Participants with Multiple Sclerosis were recruited via clinical sites, an online platform, and through the United Kingdom Multiple Sclerosis Register. Phenotype data were gathered using a standardised questionnaire. DNA was extracted from saliva samples obtained remotely or in person, and participants were genotyped using a commercial genotyping array. Following imputation, cases were combined with controls from the United Kingdom Biobank and subjected to stringent quality control and genetic ancestry inference. We defined two broad ancestral groups of South Asian and African ancestry. We performed within-ancestry case-control genome-wide association studies of Multiple Sclerosis susceptibility using logistic models accounting for population structure and sex. We examined both single nucleotide variants and imputed classical Human Leukocyte Antigen alleles. We curated two ancestrally-matched case-control genetic datasets (South Asian ancestry: NCase=175, NControl=6744; African ancestry: NCase=113, NControl=5177). In both ancestries, we found genetic variants within the Major Histocompatibility Complex associated with Multiple Sclerosis susceptibility (South Asian ancestry: lead variant chr6:32600515:G:A on hg38 co-ordinates, Odds Ratio=1.84, nearest gene HLA-DRB1, P=4.6x10-6; African ancestry: lead variant chr6:29919337:A:G, Odds Ratio=2.24, nearest gene HLA-A P=4.3x10-5). European-ancestry susceptibility alleles were over-represented in cases from both ancestries, with the degree of concordance stronger for the South Asian (ρ=0.31, P=8.1x10-6) than African (ρ=0.1, P=0.3) ancestry cohort. European-derived genetic risk scores performed better than chance but less well than in European ancestry cohorts, explaining 1.6% (South Asian, P=1.0x10-4) and 0.5% (African, P=0.08) of the liability to MS. The genetic architecture of MS susceptibility shows strong concordance across ancestral groups suggesting shared disease mechanisms. Larger studies in diverse populations are likely to enhance our understanding of how genetic variation contributes to MS susceptibility in people of all ancestral backgrounds. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was supported by a Medical Research Council (MRC) Clinical Research Training Fellowship (CRTF) jointly funded by the UK MS Society (BMJ; grant reference: MR/V028766/1), by AIMS2CURE, and Barts Charity. BMJ is currently funded by a Guarantors of Brain post-doctoral fellowship. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The London South East Research Ethics Committee has approved this study and its amendments. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Code used to perform these analyses is provided on Github at https://github.com/benjacobs123456/ms\_geno\_diversity. Genetic association summary statistics will be made available via the GWAS catalogue on publication.

BACKGROUND:Despite the success of immune modulation in the treatment of relapsing multiple sclerosis, disability progression is a major problem driven by multiple mechanisms. Comorbidities (eg, vascular risk) and ageing are thought to augment these neurodegenerative pathologies. In the phase 2b MS-STAT trial of simvastatin (80 mg) versus placebo in secondary progressive multiple sclerosis (SPMS), the adjusted difference in brain atrophy rate between groups was -0·254% per year: a 43% reduction. In this phase 3 MS-STAT2 trial, we aimed to assess the efficacy of simvastatin versus placebo in slowing the progression of disability in SPMS. METHODS:This phase 3, randomised, double-blind, parallel group, placebo-controlled clinical trial was conducted at 31 neuroscience centres and district general hospitals in the UK. Participants aged 18-65 years with a diagnosis of SPMS and an Expanded Disability Status Scale (EDSS) of between 4·0 and 6·5 were eligible and randomly assigned (1:1) to oral simvastatin (80 mg) or matched placebo for up to 4·5 years, based on a minimisation algorithm within an independent and secure online randomisation service. All participants, site investigators, and the trial coordinating team were masked to treatment allocation. The primary outcome was time to 6-month EDSS confirmed disability progression (an increase of at least 1 point if EDSS score at baseline visit was less than 6·0 or an increase of 0·5 point if EDSS score at baseline visit was 6·0 or more) assessed in all randomly assigned participants (intention-to-treat analysis) without imputation. This study is registered with ClinicalTrials.gov (NCT03387670) and is on the ISRCTN registry (ISRCTN82598726). The study is completed. FINDINGS:Between May 10, 2018, and July 26, 2024, 1079 patients were screened for eligibility and 964 participants were randomly assigned, with 482 (50%) in the placebo group and 482 (50%) in the simvastatin group. Of all 964 participants, 704 (73%) were female and 260 (27%) were male, with a mean age of 54 years (SD 7). 173 (36%) of 482 participants in the placebo group and 192 (40%) of 482 participants in the simvastatin group had 6-month confirmed disability progression (adjusted hazard ratio 1·13 [95% CI 0·91 to 1·39], p=0·26). Although no emergent safety issues were seen, there was one serious adverse reaction (rhabdomyolysis) in the simvastatin group. 12 (2%) of 482 participants in the placebo group and five (1%) of 482 participants in the simvastatin group had a cardiovascular serious adverse event. INTERPRETATION:The MS-STAT2 trial did not show a treatment effect of simvastatin in slowing disability progression in SPMS. Simvastatin use in multiple sclerosis should be confined to existing vascular indications. FUNDING:National Institute for Health and Care Research Health Technology Assessment Programme, UK Multiple Sclerosis Society, and the US National Multiple Sclerosis Society.

BACKGROUND:It has long been accepted that multiple sclerosis (MS) is heterogenous regarding presentation and disease course, so that outcomes are diverse; however, there is less data on variation in the immediate period after diagnosis. METHODS:Our objective was to identify the clinical and demographic factors present at diagnosis. Two cohorts were compared from the Trajectories of Outcome in Neurological Conditions-MS study: those joining within one year of diagnosis (inception cohort) compared to 9-11 years following diagnosis (decade cohort). Patient reported outcome data were fitted to the Rasch model to yield interval estimates, longitudinal data were analysed by group-based trajectory models. RESULTS:The inception cohort (n = 813) showed impact on fatigue, disability, health status and quality of life (QOL), although as expected, less than the decade cohort (n = 679), who also had more depressive symptoms. The average trajectory of health status was deceptive, as analysis showed two distinct groups, 13.8 % having much poorer health status, sustained for at least 3 years from diagnosis. Similarly, there were distinct groups with different trajectories identified for disability and QOL. These groups varied for depression, anxiety, sleep problems, employment, comorbidities, smoking history, and deprivation indices, highlighting influences prior to diagnosis. CONCLUSIONS:MS care must be personalised from diagnosis; service design should account for those people with MS experiencing poor health status from diagnosis. Basing capacity planning on average trajectories would be misleading. Furthermore, this evidence shows that service provision to support symptom management and disability clearly needs to be resourced from the diagnostic year.

Aim In a large UK multiple sclerosis (MS) cohort, we examined work status and how it changed over follow-up, identifying demographic, clinical and other factors associated with these transitions. Methods Participants of the Trajectories of Outcome in Neurological Conditions-MS study completed questionnaires on demographics, work instability, disability, fatigue, mood and quality of life at baseline and follow-up to explore work disability (stopping), discontinuity (retiring early) and drift (downgrading). Regression and Classification and Regression Tree (CART) analysis examined predictive factors. Results Among 1035 subjects aged 20-60 years in paid work at baseline with mean follow-up 22.7 months, net annual increases were 4.0% for work disability, 3.1% for discontinuity and 1.8% for drift. Risk of work disability was increased by age, work instability and for part-time work, female sex. The risk of drift was 3.9 times higher for females; work instability increased drift for all subjects. Reverse work disability and drift were also observed, i.e. returning to employment or upgrading work. Discontinuity was influenced by secondary progressive subtype, impaired cognition, more comorbidities, and reduced by disease modifying therapy use. CART analysis showed that risk of job loss could be predicted using age, EDSS and sickness absence information, and of medical retirement using the above three factors and MS subtype. Conclusions Screening for people with MS at greater risk of losing employment could be readily done in clinical practice, facilitating further discussion with the multidisciplinary team and referral to support services as appropriate.

The failure of relapses and white matter lesions to properly explain long-term disability and progression in multiple sclerosis is compounded by its artificial separation into relapsing remitting, secondary progressive, and primary progressive pigeonholes. The well-known epidemiological disconnection between relapses and long-term disability progression has been rediscovered as "progression independent of relapse activity", i.e. smouldering multiple sclerosis. This smouldering associated worsening proceeds despite early and prolonged use of disease modification therapies, even those that are highly effective at preventing relapses and new/enhancing white matter lesions on MRI. We recognise that smouldering associated worsening and relapse/lesion associated worsening coexist, to varying extents. The extent of cortical demyelination has been shown to correlate significantly with the severity of diffuse injury in normal appearing white matter (post mortem histopathologically (r = 0.55; P = 0.001), and in vivo with MRI (r = -0.6874; P = 0.0006)) and does so independently of white matter lesion burden. Axon loss in the normal appearing white matter explains disability in multiple sclerosis better than focal white matter lesions do. Smouldering associated worsening typically manifests as a length-dependent central axonopathy. We propose a unifying model for multiple sclerosis pathogenesis, wherein accumulation of cortical lesion burden predisposes associated normal appearing white matter to diffuse injury, whilst also intensifying damage within white matter lesions. Our novel two-hit hypothesis implicates cortical disease as a culprit for smouldering multiple sclerosis, abetted by active focal inflammation in the white matter (and vice versa). Substantiation of the two-hit hypothesis would advance the importance of specific therapeutic intervention for (and monitoring of) cortical/meningeal inflammation in people with multiple sclerosis.

BackgroundThe prevalence of depression in Multiple Sclerosis (MS) is often assessed by administering patient reported outcome measures (PROMs) examining depressive symptomatology to population cohorts; a recent review summarised 12 such studies, eight of which used the Hospital Anxiety and Depression Scale-Depression (HADS-D). In clinical practice, depression is diagnosed by an individual structured clinical interview; diagnosis often leads to treatment options including antidepressant medication. It follows that an MS population will include those whose current depressive symptoms meet threshold for depression diagnosis, plus those who previously met diagnostic criteria for depression and have been treated such that depressive symptoms have improved below that threshold. We examined a large MS population to establish a multi-attribute estimate of depression, taking into account probable depression on HADS-D, as well as anti-depressant medication use and co-morbidity data reporting current treatment for depression. We then studied associations with demographic and health status measures and the trajectories of depressive symptoms over time.MethodsParticipants were recruited into the UK-wide Trajectories of Outcome in Neurological Conditions-MS (TONiC-MS) study, with demographic and disease data from clinical records, PROMs collected at intervals of at least 9 months, as well as co-morbidities and medication. Interval level conversions of PROM data followed Rasch analysis. Logistic regression examined associations of demographic characteristics and symptoms with depression. Finally, a group-based trajectory model was applied to those with depression.ResultsBaseline data in 5633 participants showed the prevalence of depression to be 25.3% (CI: 24.2-26.5). There were significant differences in prevalence by MS subtype: relapsing 23.2% (CI: 21.8- 24.5), primary progressive 25.8% (CI: 22.5-29.3), secondary progressive 31.5% (CI: 29.0-34.0); disability: EDSS 0-4 19.2% (CI: 17.8-20.6), EDSS ≥4.5 31.9% (CI: 30.2-33.6); and age: 42-57 years 27.7% (CI: 26.0-29.3), above or below this range 23.1% (CI: 21.6-24.7). Fatigue, disability, self-efficacy and self esteem correlated with depression with a large effect size (>.8) whereas sleep, spasticity pain, vision and bladder had an effect size >.5. The logistic regression model (N=4938) correctly classified 80% with 93% specificity: risk of depression was increased with disability, fatigue, anxiety, more comorbidities or current smoking. Higher self-efficacy or self esteem and marriage reduced depression. Trajectory analysis of depressive symptoms over 40 months in those with depression (N=1096) showed three groups: 19.1% with low symptoms, 49.2% with greater symptoms between the threshold of possible and probable depression, and 31.7% with high depressive symptoms. 29.9% (CI: 27.6-32.3) of depressed subjects were untreated, conversely of those treated, 26.1% still had a symptom level consistent with a probable case (CI: 23.5-28.9).ConclusionA multi-attribute estimate of depression in MS is essential because using only screening questionnaires, diagnoses or antidepressant medication all under-estimate the true prevalence.Depression affects 25.3% of those with MS, almost half of those with depression were either untreated or still had symptoms indicating probable depression despite treatment. Services for depression in MS must be pro-active and flexible, recognising the heterogeneity of outcomes and reaching out to those with ongoing symptoms.