Allan G Kermode

Background
To improve the quality and standard of care, considerable resources are invested to produce clinical guidelines for multiple sclerosis (MS) management. We aimed to investigate MS clinicians’ use of guidelines and factors that influence use.

Methods
Interview guides were developed using Fisher’s framework to assess factors that influence guideline application (categorized as personal, guideline related, and external). Nurses and neurologists experienced in MS health care were recruited through convenience sampling. Semistructured online interviews were conducted from June 2023 to October 2023, and data were analyzed using inductive and deductive methods.

Results
We interviewed 16 MS clinicians (10 nurses, 6 neurologists). Despite most clinicians believing that guidelines can improve consistency, safety, and quality of care, the application of guidelines was highly variable. Participants reported that clinical decision-making in MS management involves integrating guideline recommendations with clinical reasoning while considering patients’ circumstances and preferences, the complex nature of MS, and resource constraints. Personal barriers to guideline application included low awareness and familiarity. Guideline-related barriers included evidence, plausibility, accessibility, layout, and complexity. External barriers included a lack of resources. Facilitators were mostly guideline related, including relevance to local protocols, covering complex treatment or unfamiliar topics, and when guidelines were up to date and credible. Participants suggested various strategies to overcome barriers to guideline use.

Conclusions
Australian MS clinicians reported low awareness and high variability in the application of national and/or international MS guidelines. Clinical practice guidelines should be adaptable to local contexts, accessible, and regularly updated. Multifaceted strategies to better distribute and champion guidelines should be employed.

Introduction: Targeting progressive multiple sclerosis (MS) addresses the current single biggest unmet need in the MS therapeutic landscape and anti-Epstein-Barr virus (EBV) therapy potentially strikes at the root cause. The SpironolacTone and famciclOvir in the treatment of Progressive MS to prevent disability progression (STOP-MS) trial has been developed to assess anti-EBV therapies in the treatment of progressive MS.

Methods and analysis: STOP-MS is a multi-arm, multi-stage, randomised, double-blind, placebo-controlled trial testing spironolactone and famciclovir to prevent disability progression in MS. Australians with progressive forms of MS, aged 25 to 70 years with established disability, are eligible. Recruitment commenced in March 2025 and the first participant was enrolled on 15 April 2025. The sample size for STOP-MS is 150 in stage 1 and 300 in stage 2. In stage 1, the composite primary outcome measures will be reduction of EBV DNA in saliva and serum EBV nuclear antigen-1 antibody titres. Minimum criteria for consideration of progression to stage 2 will be a 10% reduction in the composite outcome measure. In stage 2, the primary outcome measure will be 6-month confirmed disability progression analysed using Cox-proportional hazards.

Trial registration number: The STOP-MS trial has been acknowledged by the Therapeutics Goods Administration under the Clinical Trial Notification scheme (CT-2023-CTN-03 505-1) and is registered with the Australian and New Zealand Clinical Trial Registry (ACTRN12623000849695).

Background
Multiple sclerosis (MS) diagnosis relies on identifying disease episodes disseminated in space and time, and excluding other disease explanations. MS is a genetically complex autoimmune and neurodegenerative disorder that shares features with some monogenic progressive neurological conditions. The extent to which people diagnosed with MS have an alternate diagnosis (MS mimic), or genetic multimorbidity is unknown. Additionally, the burden of rare variation associated with MS risk and severity in monogenic neurological disease genes has not been evaluated. We investigated the prevalence of disease-causing variants in progressive neurological disease genes, and their contribution to MS risk and severity, in 4,340 MS cases diagnosed in sub-speciality clinics in Australia and New Zealand, and in 2,861 local controls.

Methods
Exome sequencing and array-based genotyping data were analysed for 1,680 genes with pathogenic or likely pathogenic variants reported in ClinVar. Clinical history reviews of MS cases with putative disease-causing variants were conducted. We specifically examined the contribution of rare, likely deleterious variants in a subset of 30 hereditary spastic paraplegia (HSP) genes in 421 individuals with progressive onset MS (POMS). Gene-based association tests with MS risk and severity were performed for all genes in the cohort.

Results
We identified 166 MS cases (3.82%) with variants prompting clinical history reviews, and of 75 cases reviewed, four (0.13% of all cases) had either genetic multimorbidity in addition to MS or a potential misdiagnosis. In contrast to previous findings we observed no enrichment of likely deleterious variants in HSP genes in POMS, nor did we find significant associations between neurological disease genes and MS risk or severity.

Conclusions
Our findings suggest that rare deleterious genetic variation in progressive neurological disease genes does not play a substantive role in MS risk or severity, and that misdiagnosis is exceedingly rare in this cohort. Consequently, among individuals diagnosed with MS by a specialist, a very small proportion may benefit from clinical genomic testing to inform MS diagnosis or an alternate diagnosis, which could have implications for healthcare management.

Introduction
The MSOCR-R study evaluates the long-term effectiveness of ocrelizumab (OCR) in patients with relapsing multiple sclerosis (RMS) in real-world clinical settings.

Methods
MSOCR-R is an ongoing, prospective, longitudinal, observational cohort study of people with RMS newly treated with OCR, using data from the international MSBase registry. The study started in July 2018, and data collected up to October 2023 were analyzed. Outcomes were confirmed disability worsening (CDW), progression independent of relapses (PIRA), and no evidence of disease activity (NEDA-3: absence of relapse, 24-week CDW, or imaging activity).

Results
Overall, 1011 patients were enrolled (18.1% initiated OCR first-line therapy; 81.9% switched from previous treatment), with a median time of 3.4 years on OCR treatment. About 67% of patients were females. At OCR initiation, mean age was 41.9 years, median disease duration was 10.4 years, and median Expanded Disability Status Scale score was 3.0. The 4-year Kaplan–Meier probabilities of 24-week CDW or PIRA were 25.2% (95% CI 21.6–29.1) and 21.9% (95% CI 18.3–25.2), respectively. Annualized relapse rate substantially decreased from 0.58 (95% CI 0.53–0.63) before OCR to 0.05 (95% CI 0.04–0.06) after treatment initiation. NEDA-3 was assessed in 366 patients and the probability of achieving NEDA-3 was 39.7% (95% CI 36.0–43.5) at 4 years. Persistence on OCR was 88.0% (95% CI, 85.2–90.3) at 4 years. Better clinical outcomes were consistently observed among the first-line treatment cohort.

Conclusion
The MSOCR-R study provides strong real-world evidence of OCR effectiveness in people with RMS.

Background: Multiple sclerosis (MS) demonstrates a latitude gradient in prevalence and severity, implicating ultraviolet B (UVB) exposure and photoimmune mechanisms in disease risk and progression. While narrowband (NB)-UVB phototherapy has long stabilized inflammation in dermatology, its systemic immunomodulatory effects in MS remain incompletely defined. Objective To characterize the photoimmune impact of NB-UVB in clinically isolated syndrome (CIS)/MS patients, leveraging untargeted and targeted proteomic analysis including the Octave Multiple Sclerosis Disease Activity Score. Methods In the PhoCIS trial, CIS patients were randomized to NB-UVB (3 × /week for 8 weeks) or standard care. Serum samples from baseline and day 90 were analyzed using the Olink Target 96 Inflammation panel (untargeted) and the clinically validated MS Disease Activity (MSDA) test panel (targeted). Statistical analyses compared differences within and between-groups. Results Comparing the difference from baseline to day 90, the NB-UVB cohort had significant downregulation in 23 of 92 inflammatory proteins, while the Controls had no changes. Targeted MSDA scores confirmed similar differentially significant reductions in general disease activity and severity, and within the component neuroinflammation, immunomodulation, and neuroaxonal integrity scores. Conclusion NB-UVB caused broad and coordinated reductions in untargeted and targeted inflammatory proteins. These effects support NB-UVB as a promising immunomodulatory strategy in MS in both general inflammation and MS-specific activity, as well as consideration of inflammatory markers and the MS Disease Activity Score as surrogate endpoints in future trials.

Background
Patients aged ≥35 years at multiple sclerosis (MS) onset with an Expanded Disability Status Scale (EDSS) ≥3 in the first year are at highest risk of aggressive MS (EDSS ≥6 within 10 years). Those without these features are at lowest risk. We aimed to assess whether high-efficacy therapy improves outcomes in high-risk patients and whether its benefit varies by MS severity.

Methods
This longitudinal cohort study analysed MSBase and OFSEP registry data. Patients were categorized into high- or low-risk of aggressive MS. Within each risk strata, relapse and disability accumulation were compared between those receiving high-efficacy therapy (fingolimod, cladribine, monoclonal antibodies) vs. other/no therapy. Marginal structural models, adjusting for demographics, MS course, relapses, disability, and MRI activity, were used to evaluate treatment effects and interaction with aggressive MS risk.

Results
4560 patients (893 high risk, 3667 low risk) were studied. Continuous treatment with high-efficacy therapy vs other/no therapy reduced the risk of relapse and disability accumulation in patients at both high-risk and low-risk of aggressive MS.There was no evidence of an interaction between aggressive MS risk and treatment strategy. The risk of relapse was lowest in patients at low-risk of aggressive MS treated with high-efficacy therapy (HR0.58, 95%CI 0.54–0.62). High-efficacy therapy reduced the risk of disability accumulation across both aggressive MS risk strata.

Conclusion
High-efficacy therapy reduces relapse and disability accumulation in patients at both high- and low-risk of aggressive MS, with no differential treatment benefit. These findings support widespread use of high-efficacy therapy in relapsing MS.

Background/Objective
Cognitive fatigability (CF) affects many with Multiple Sclerosis (MS), yet measurement remains challenging due to poor correlation with subjective fatigue reports. MSReactor cognitive screening platform offers potential for objective CF assessment, particularly for longitudinal monitoring in clinical settings.

Objective
To determine whether changes in error rates during sustained cognitive testing provide a platform for studies investigating CF and its relationship to disease progression.

Methods
Adults with relapsing-remitting and secondary-progressive MS were recruited from seven Australian tertiary MS clinics. Participants completed MSReactor cognitive testing battery: a simple reaction time, a choice reaction time, and a One back test (OBK, which is a measure of working memory). Each test required participants to make 32–35 responses to stimuli appearing on screen. CF was quantified as a sustained doubling of incorrect responses in the last third compared to first third of OBK test. Expanded Disability Status Scale (EDSS) was assessed as part of standard care.

Results
Among 836 participants, 113 (13.5%) demonstrated a sustained doubling of errors in OBK task over follow-up period (median 890 days, IQR: 1070). Of these, 7 participants with sustained increases in intra-test error rates subsequently had a 6-month confirmed disability progression event.

Conclusion
This study explores MSReactor as an objective measure of CF in MS. We identified a group of participants who consistently made more errors in latter third of a sustained working memory test, which appeared independent of future disability progression. Further research is needed to validate this finding against clinical correlates and work productivity.

Background
Managing multiple sclerosis (MS) in cancer survivors is complex due to immune system interactions and the impact of treatment. Limited guidance exists on disease-modifying therapy (DMT) use during and after chemotherapy. This study examined how DMT decisions in breast cancer influence MS outcomes and whether chemotherapy itself affects MS disease activity.

Methods
Data were obtained from the MSBase registry, including 172 individuals with MS and breast cancer who received chemotherapy, and 229 for whom chemotherapy data were not available. Survival analyses assessed time to first relapse and confirmed disability progression (CDP) after cancer diagnosis, with DMT modelled as a time-varying covariate. Propensity score matching compared outcomes between those who received cancer chemotherapy adjuvant to their MS treatment and matched controls receiving standard MS treatment alone.

Results
Post-chemotherapy MS management varied, with most clinicians de-escalating or withholding DMTs. Older age was associated with lower relapse risk (HR = 0.90, 95% CI: 0.93–0.97, p = 0.001). Chemotherapy had a protective effect on time to first relapse (HR 0.58, 95% robust CI: 0.37 to 0.95, p = 0.03) compared to matched controls receiving standard MS treatment. Chemotherapy was not associated with a significant effect on CDP (HR 0.68, 95% robust CI: 0.38–1.23, p=0.06).

Conclusion
Chemotherapy was associated with better relapse outcomes compared to standard therapy in matched controls, supporting withholding or de-escalating DMTs during cancer treatment. DMT reinitiation should be guided by individual risk assessment and may be less indicated in older individuals, who demonstrated a lower relapse risk following chemotherapy.

Family planning is an important aspect of multiple sclerosis (MS), and neuromyelitis optica spectrum disorder (NMOSD) management. Knowledge gaps remain, including optimal perinatal management strategies, and fetal risks associated with disease-modifying therapy (DMT) exposure.
To describe perinatal DMT use, together with pregnancy and neonatal outcomes prospectively recorded in the International MSBase Pregnancy and Women's Health Registry.
We report summary statistics for data collected between May 2020 and August 2024.
A total of 1887 relapsing-remitting MS (RRMS), 12 primary-progressive MS (PPMS), 2 radiologically isolated syndrome (RIS) and 21 NMOSD completed pregnancies were recorded, including 1644 (85.5%) live births, 208 (10.8%) miscarriages, and 6 (0.3%) neonatal deaths. Most women had unassisted (53.8%) or assisted (7.4%) vaginal births. Seventy five percent of pregnancies had DMT exposures within 6 months preconception; 19% of NMOSD, and 62% of MS pregnancies were DMT-exposed during gestation; 18.1% of pregnancies reported in-pregnancy monoclonal antibody DMT exposure. No overt safety signals were seen.
This first report from the newly launched MSBase pregnancy registry, establishes an increasing number of pregnancies being conceived on monoclonal antibody therapies. Although no safety signals were observed, it is important to continue monitoring for safety signals in real-world databases as the use of highly effective therapies continues to increase perinatally.

Early prediction of disability progression in multiple sclerosis (MS) remains challenging despite its critical importance for therapeutic decision-making. We present the first systematic evaluation of personalized federated learning (PFL) for 2-year MS disability progression prediction, leveraging multi-center real-world data from over 26,000 patients. While conventional federated learning (FL) enables privacy-aware collaborative modeling, it remains vulnerable to institutional data heterogeneity. PFL overcomes this challenge by adapting shared models to local data distributions without compromising privacy. We evaluated two personalization strategies: a novel AdaptiveDualBranchNet architecture with selective parameter sharing, and personalized fine-tuning of global models, benchmarked against centralized and client-specific approaches. Baseline FL underperformed relative to personalized methods, whereas personalization significantly improved performance, with personalized FedProx and FedAVG achieving ROC-AUC scores of 0.8398 ± 0.0019 and 0.8384 ± 0.0014, respectively. These findings establish personalization as critical for scalable, privacy-aware clinical prediction models and highlight its potential to inform earlier intervention strategies in MS and beyond.