Allan G Kermode

The authors regret an error in the CRediT Authorship Contribution Statement. The updated statement is as follows:

The authors had full editorial control of the manuscript and provided their final approval of all content. H. Butzkueven: conceptualization; funding acquisition; investigation; resources; methodology; supervision; validation; writing – original draft preparation; writing – review & editing. P. Farr: project administration; data curation; writing – original draft preparation; writing – review & editing. S. Ozakbas: investigation; resources; writing – review & editing. C. Boz: investigation; resources; writing – review & editing. T. Kalincik: investigation; resources; writing – review & editing. L. Taylor: investigation; resources; writing – review & editing. A. Van Der Walt: investigation; resources; writing – review & editing. R. Alroughani: investigation; resources; writing – review & editing. K. Buzzard: investigation; resources; writing – review & editing. O. Skibina: investigation; resources; writing – review & editing. J. Lechner-Scott: investigation; resources; writing – review & editing. G. Laureys: investigation; resources; writing – review & editing. M. Terzi: investigation; resources; writing – review & editing. V. Van Pesch: investigation; resources; writing – review & editing. F. Grand-Maison: investigation; resources; writing – review & editing. M. Barnett: investigation; resources; writing – review & editing. A. Kermode: investigation; resources; writing – review & editing. J.L. Sanchez Menoyo: investigation; resources; writing – review & editing. J. Rojas: investigation; resources; writing – review & editing. B. Willekens: investigation; resources; writing – review & editing. M. Foschi: investigation; resources; writing – review & editing. C. Ramo-Tello: investigation; resources; writing – review & editing. E. Skromne: investigation; resources; writing – review & editing. P. Dirks: conceptualization; methodology; writing – original draft preparation; writing – review & editing. E. Muros-Le Rouzic: conceptualization; methodology; supervision; writing – original draft preparation; writing – review & editing. T. Spelman: conceptualization; data curation; formal analysis; methodology; resources; supervision; validation; writing – original draft preparation; writing – review & editing.

The authors would like to apologise for any inconvenience caused.

Introduction: People with multiple sclerosis (MS) engage in less physical activity and experience higher rates of osteoporosis, falls and fractures than the general population, contributing to reduced health-related quality of life (HRQoL) and increased healthcare costs. High-intensity resistance and impact training (HiRIT) has beneficial effects on bone, muscle and physical function in other populations, but its effectiveness in people with MS is unclear.

Methods and analysis: STRONG-MS is a codesigned, clinician-led, single-blind, randomised controlled trial evaluating the effect of a HiRIT programme, ONERO, on HRQoL for people with MS. Secondary aims include assessing changes in bone mineral density, body composition, physical function, fatigue, mood as well as intervention safety, feasibility, acceptability, sustainability and cost-effectiveness. One hundred and eighty participants will be randomised (2:1) to ONERO or usual care for 12 months. The intervention comprises two times weekly, supervised, small-group sessions delivered by accredited allied health professionals. Outcomes will be assessed at 12 and 24 months using intention-to-treat analyses. Sustainability will be evaluated during a second 12-month period, during which participants fund ongoing participation privately or through support schemes.

Ethics and dissemination: The study has approval from a Health Human Research Ethics Committee. All participants will provide written informed consent. Findings will be disseminated through peer-reviewed publications, conference presentations and summaries for participants, consumer representatives and community organisations. This study will provide novel evidence on the ability of the ONERO to improve HRQoL and musculoskeletal health in people with MS as well as its feasibility, acceptability and sustainability, to inform poststudy implementation.

Background
We aim to elucidate the differences in complement activation between myelin oligodendrocyte glycoprotein antibody-related disease (MOGAD) and neuromyelitis optic spectrum diseases (NMOSD), and explore the relationship between complement levels and disease activity in MOGAD.

Methods
We retrospectively included 171 records of commonly used serum complement indicators, immunoglobulin, and systemic inflammatory markers from 96 MOGAD patients, 185 records from 97 anti - Aquaporins - 4 IgG (AQP4 - IgG) seropositive NMOSD cases, and 15 records from 11 AQP4 - IgG seronegative NMOSD cases.

Results
MOGAD patients exhibited higher C3 (acute phase, p = 0.003) and C4 (acute phase, p < 0.001; whole course, p < 0.001) levels than NMOSD patients. In the MOGAD cohort, elevated CH50 levels were found in 76.47 % (130/170) cases, with higher frequencies during the acute phase 80.82 % (59/73). In the acute phase, MOGAD patients showed increased C4 (p = 0.022), CH50 (p = 0.021), and IgG (p = 0.031) levels. We also observed the dynamic fluctuations in complement concentrations after clinical attacks in MOGAD, with complement concentrations peaked during the acute phase and declined during remission (C3, 81.82 %, 9/11; C4, 63.64 %, 7/11; CH50, 72.73 %, 8/11). Positive correlations were observed between complement levels (p < 0.05) and IgG, CRP, ESR, and cerebrospinal fluid white blood cell count in MOGAD patients. Patients with higher CH50 levels tended to experience earlier recurrence than those with lower CH50 levels (log-rank p = 0.076).

Conclusions
Clinically practical complement indicators can reflect disease activity, and CH50 can serve as prognostic candidate biomarkers for relapse in MOGAD.

Background
Predicting disease progression at the individual level is essential for personalized medicine. We previously developed machine-learning tools to estimate 5-year progression risk in people with multiple sclerosis (PwMS). Such models should account for disease-modifying therapy (DMT) and objective outcome definitions.

Methods
In a retrospective multicenter case–control study, we evaluated adults with relapsing–remitting multiple sclerosis (RRMS) at baseline. Using machine-learning, we developed two complementary tools for individualized 5-year risk estimation: DAAE-M, optimized for transparency, software-neutral use, and mitigation of indication bias, and ELIE, optimized for dynamic landmark-based modeling, complex treatment histories, and mitigation of immortal-time bias. Disease progression was defined using both a clinical outcome (RRMS-to-progressive MS) and an objective outcome (late-stage confirmed progression independent of relapse activity).

Results
Among 34,510 people with RRMS (72.6% female, mean age = 37.1, mean disease duration = 5.8), 9.8% and 21% met clinical and objective progression criteria, respectively, over five years. Both models demonstrated good calibration across risk-groups (Brier scores 0.06–0.16). DAAE-M provided patient-level risk estimates with monotonic risk escalation across risk-groups for clinical (3.1%/11.2%/22.6%/33.0%) and objective (8.4%/14.5%/23.3%/38.8%) progression. For DAAE-M, high-efficacy DMT was associated with approximately half the progression risk compared with low-efficacy DMT (risk-ratios: 0.42–0.59; p < 0.01). ELIE also showed good calibration across risk deciles with increasing incidence for both clinical (0.3%/1.2%/1.7%/2.5%/3.7%/5.5%/7.2%/10.2%/14.3%/21.5%) and objective (0.9%/1.6%/2.5%/4.0%/5.8%/7.8%/10.2%/15.3%/20.9%/32.5%) outcomes.

Conclusion
We developed two well-calibrated machine-learning-based tools for individualized 5-year prediction of clinically- and objectively-defined MS progression, each with distinct strengths in usability, bias handling, and treatment modeling. These findings support future tool use in personalized risk stratification and secondary prevention.

Patients aged ≥ 35 years at multiple sclerosis (MS) symptom onset with an Expanded Disability Status Scale (EDSS) score ≥ 3 within the first year are at highest risk of developing aggressive MS (EDSS ≥ 6 within 10 years). Patients without these features are at lowest risk. This study aimed to evaluate whether high-efficacy disease-modifying therapy (HE-DMT) reduced the risk of relapse and disability accumulation in individuals at high risk of aggressive MS, and whether treatment benefit varied by MS severity.
This observational cohort study used longitudinal data from two registries: MSBase (international) and OFSEP (France). Adults with relapse-onset MS and an EDSS score recorded within 12 months of symptom onset were included. Patients were classified into high-risk or low-risk groups for aggressive MS based on the above strata; those at intermediate risk were excluded. A pseudo-cohort framework compared periods of continuous HE-DMT (fingolimod, cladribine, monoclonal antibodies) with periods of non-HE-DMT states (on lower-efficacy DMTs or untreated) within each aggressive MS risk stratum. Marginal structural models with repeated adjustment for time-varying confounders of treatment and censoring were used to estimate counterfactual cumulative hazards of relapses and 6-month confirmed disability worsening and improvement. An interaction between MS risk stratum and treatment strategy was tested. A secondary analysis evaluated patients who received an HE-DMT during the study period.
In total, 10,405 people (2021 high risk, 8384 low risk) were included. Continuous HE-DMT reduced the risk of relapse in both high-risk and low-risk groups. There was no evidence of a difference in disability outcomes between treatment approaches. There was no evidence of an interaction between aggressive MS risk and treatment effect. In stratified analyses, lowest relapse risk was observed in the low-risk group treated with HE-DMT (hazard ratio [HR] 0.75, 95% CI 0.69-0.80). Treatment with HE-DMT was associated with relapse risk comparable to that observed in the low-risk group not treated with HE-DMT (HR 0.99, 0.87-1.13). In a secondary analysis restricted to patients who receive HE-DMT during the study timeframe, treatment with HE-DMT reduced the risk of disability worsening in the high-risk group (HR 0.75, 0.58-0.99), to the level observed in the low-risk group (HR 0.80, 0.70-0.92).
HE-DMTs reduced the risk of relapse in people at both high and low risk of aggressive MS, with no evidence of differential treatment benefit. In the overall population, no evidence of a difference in disability outcomes between HE-DMT-treated and HE-DMT-untreated time was observed. However, among patients ever exposed to HE-DMT, disability worsening was less common while treated with HE-DMT.

Introduction: Ocrelizumab (OCR), a CD20+ B-cell depleting monoclonal antibody, is a highly effective therapy for Multiple Sclerosis (MS). However, safety concerns may lead to treatment discontinuation, raising questions about the clinical consequences of such decisions.

Materials and Methods: This propensity score-matched study utilized data from the MSBase registry to compare outcomes between patients discontinuing OCR due to safety concerns ("Switchers") and those continuing treatment ("Continuers"). Matching was performed using inverse probability of treatment weighting (IPTW) to balance treatment duration and baseline characteristics. Primary outcomes included annualized relapse rate (ARR), time to first relapse, 24-48 weeks confirmed disability worsening (CDW), and progression independent of relapse activity (PIRA).

Results: From an initial cohort of 310 Switchers and 1,315 Continuers, 66 patients who experienced at least one safety event and switched from OCR were matched with 66 Continuers. PS-IPTW analyses revealed higher ARR in Switchers (0.08, 95% CI: 0.05-0.14) versus Continuers (0.038, 95% CI: 0.02-0.07; p=0.040). Time to first relapse showed no significant difference (HR=2.23, 95% CI: 0.68-7.28; p=0.183). Trends toward increased CDW24 weeks risk (PS-IPTW HR=2.11, 95% CI: 0.93-4.75; p=0.073), while no significant difference was found at 48 weeks (HR=1.81, 95% CI: 0.83-3.30; p=0.201). PIRA risk showed a trend toward an increase in Switchers (HR=2.45, 95% CI: 0.95-6.29; p=0.063).

Discussion: In this propensity-score-matched analysis, OCR discontinuation due to safety concerns was associated with increased relapse activity and trends toward greater disability progression. These findings highlight the importance of maintaining therapeutic intensity and systematic monitoring during treatment transitions to mitigate safety risks

Conclusion: Further research is needed to develop strategies for effectively managing adverse events to optimize patient outcomes.

How two main treatments for late-onset multiple sclerosis compare in real life Multiple sclerosis (MS) is a disease where the immune system attacks the brain and spinal cord. When MS begins after the age of 50, it is called late-onset multiple sclerosis (LOMS). This form of MS can progress faster and respond differently to treatment compared to cases that start earlier in life. In this study, we compared two important groups of modern MS treatments: - Anti-CD20 therapies, which target specific immune cells, and - S1P receptor modulators, which prevent immune cells from reaching the brain. We analysed real-world data from an international MS registry called MSBase, including people with relapsing LOMS who had used one of these therapies for at least six months. We looked at how often relapses occurred, how disability changed over time, and whether disability increased independently of relapses. The results showed that, overall, both treatment types worked similarly in preventing relapses and disability worsening. However, in some patients—especially those younger than 55, with early disease and lower disability—anti-CD20 therapies appeared to have a small advantage. These findings suggest that both therapies are effective for most people with late-onset MS, but that starting anti-CD20 treatment early may be beneficial for selected patients. This information can help doctors personalise treatment plans for older adults living with MS.

There is a greater prevalence of multiple sclerosis (MS), a neurological autoimmune condition, in populations living further from the equator, hypothesised to be due to reduced sunlight exposure. There exists a proven sunlight surrogate therapy for dermatological inflammatory conditions, in the form of narrowband (NB; 311-312 nm)-UVB phototherapy. Yet, there is a paucity of randomized trials of the therapeutic delivery of NB-UVB beyond dermatology for conditions with a systemic inflammatory component. To investigate the potential for use in MS, the PhoCIS trial (narrowband UVB phototherapy for Clinically Isolated Syndrome)(ACTRN 12614000185662), was established. Participants with Clinically Isolated Syndrome, the earliest symptomatic form of MS, were given NB-UVB (24 sessions over 8 weeks) and followed for 12 months. The published clinical, immunological, and quality of life results from the PhoCIS trial have uncovered new evidence of systemic immune stabilisation by NB-UVB. This perspective provides the first unified overview of these results to inspire future randomised trials of NB-UVB across other autoimmune diseases which share both prevalence that follows UVB exposure, and systemic immune dysregulation.

Background and Objectives
Previous studies have reported inconsistent findings regarding the impact of age at onset on relapse risk in aquaporin-4 antibody–positive neuromyelitis optica spectrum disorder (AQP4-IgG NMOSD), although older disease onset has been linked to more rapid disability accrual. This is in contrast to multiple sclerosis, where advancing age and older onset are associated with reduced relapse activity, allowing for treatment de-escalation or discontinuation in some older patients. The aim of this study was to clarify the influence of age at onset on relapse risk as well as disability accrual in a large, international cohort of patients with NMOSD.

Methods
We conducted a retrospective, multicenter cohort study using the MSBase data registry to evaluate annualized relapse rates (ARRs), time to first relapse, and time to Expanded Disability Status Scale (EDSS) scores of 4 and 6. For inclusion, a diagnosis of AQP4-IgG NMOSD according to the latest iteration of the criteria and availability of the minimum data set were required. Patients were stratified as pediatric onset (<18 years of age), early onset (18–55 years inclusive) or late onset (>55 years of age). Analyses included patients on high-efficacy therapy (HET), those on low-efficacy therapy (LET), and an incident cohort with the first clinical visit within 12 months from disease onset. Predictors of first relapse and EDSS 4/6 thresholds were analyzed using Cox proportional models.

Results
Data from 539 patients (42 pediatric, 421 with early onset, 76 with late onset; 85.2% female) with a median age at onset of 35 years (Q1 25.10, Q3 47.60) and a disease duration of 7.42 years (Q1 3.23, Q3 13.10) were analyzed. ARR and time to first relapse were not influenced by age at disease onset. Patients on HET had fewer relapses than those on LET (p < 0.001). Older age was linked to faster disability accumulation. In addition, higher baseline EDSS scores and delayed treatment were independent predictors of future disability.

Discussion
Our study demonstrates that while age at onset does not affect relapse risk, older patients experience more rapid disability accrual. These findings underscore the importance of early initiation of effective preventive immunotherapy in all age groups. The primary limitations of this study pertain to its retrospective design and the sole reliance on EDSS for disability assessment.

Background
Multiple Sclerosis (MS) severity is influenced by several factors. Understanding the impact of age at disease onset may help to better characterize clinical and disease features across age groups. This study aimed to characterize the clinical features and disability outcomes of late-onset MS (LOMS) and very late-onset MS (vLOMS), compared to adult-onset MS (AOMS).

Methods
We conducted an observational study using data from the MSBase registry and categorized patients based on age at MS onset: AOMS (18–39 years), transition onset (40–49 years), LOMS (50–59 years), and vLOMS (≥ 60 years). Disease progression was assessed using the 24 week confirmed disability progression, EDSS4 and 6 milestones, conversion to secondary progressive MS(SPMS), and the first progression independent of relapse activity (PIRA) event. Cox proportional hazard regression models were used to determine unadjusted hazard ratios(HR), and propensity score inverse probability of treatment weighting(PS-IPTW) balanced covariate distributions.

Results
Among 81,236 patients, 5.2% had LOMS and 1% had vLOMS. Primary progressive MS was more frequent in LOMS and vLOMS (21.7 and 24%, respectively). Patients with LOMS and vLOMS had a significantly increased risk of 24 week confirmed disability progression (HR:LOMS = 1.39, vLOMS = 1.80), EDSS 4 (HR:LOMS = 2.14, vLOMS = 2.95), EDSS 6 (HR:LOMS = 2.33, vLOMS = 6.33), SPMS (HR:LOMS = 1.62, vLOMS = 2.38), and first PIRA event (HR:LOMS = 2.12, vLOMS = 2.93).

Conclusion
LOMS and vLOMS exhibited a more progressive disease onset and higher disability milestones compared with AOMS.