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: Timely identification of the transition from relapsing-remitting multiple sclerosis (RRMS) to secondary- progressive MS (SPMS) is of great weight for effective treatment planning. However, this transition is typically diagnosed with an average delay of three years, leading to missed opportunities for early intervention. Building on our previous artificial intelligence (AI) work with Swedish electronic health record data, we extend our approach to the global MSBase cohort. Objectives/Aims: To develop AI models that predict disease progression from RRMS to SPMS proactively in a globally heterogeneous MS population while enabling user-defined confidence levels and interpretable predictions. Methods: We utilized two large-scale MS registries: MSBase (110,000 patients; 1.3 million visits across 45 countries) and the Swedish MS registry (22,000 patients; 200,000 visits). We trained random forest classifiers to predict disease states at each clinical encounter, integrating conformal prediction to quantify predictive uncertainty and explainable AI to enhance interpretability and transparency. Results: The global model achieved an F1 score of 0.83 and outperformed country-specific models in several regions. However, in certain countries, local models were better fitted. Calibration curves revealed marked differences in RRMS and SPMS diagnoses across countries. We identified groups with aligned predictions by clustering countries based on calibration similarity. While the global model generalized well, clustered models improved local accuracy. Conclusion: We developed AI models that provide accurate and interpretable predictions of MS progression trained on registry data from 18 countries. The global model offers scalability, while localized approaches better capture regional diagnostic practices. This framework supports harmonizing diagnostic standards and can enhance clinical trial design and international data interpretation.

Introduction: The outcomes of cladribine tablets treatment (CladT) dosing in year one and two, and its longer-term treatment persistence and effectiveness in real-world MS treatment need to be better understood. Objectives/Aims: This study aimed to describe the baseline characteristics, treatment persistence, relapse rate and 24-week confirmed disability progression (CDP) or improvement (CDI) of people with MS (PwMS) treated with CladT in the MSBase registry. Methods: All PwMS recorded in MSBase on 1st February 2025 with a confirmed diagnosis of relapsing-remitting MS (RRMS) initiating CladT were included. Descriptive statistics were used to summarise demographic, clinical and treatment characteristics. Cox proportional hazard regression was used to compare clinical outcomes between treatment naive and experienced groups. Results: A total of 3834 PwMS with a confirmed diagnosis of RRMS initiated CladT since 2017. Mean (standard deviation [SD]) age at CladT initiation was 40.95 years (11.53) and 74.6% were female. Mean (SD) time from diagnosis to first CladT exposure was 7.94 years (7.21). 16.7% were treatment-naive. Mean (SD) observation time from first CladT dose was 2.19 years (1.69). Treatment switching from CladT occurred at a mean rate of 4.82% per year (95% confidence interval [CI] 4.36, 5.31). In switchers, the median (interquartile range) time to switch was 2.74 years (1.78, 3.69). The annualised relapse rate (ARR) was 0.135 (95% CI 0.13, 0.14). The rate of 24-week CDP was 0.038 per year (95% CI 0.03, 0.04) and the rate of 24-week CDI was 0.052 per year (95% CI 0.05, 0.06). In PwMS with a minimum follow-up duration of 3, 4, 5, or 6 years, annual rates for additional CladT treatment courses were 4.6, 4.8, 10.3, and 4.9%, respectively. Comparison of treatment-naive and previously treated PwMS showed no difference in time to CladT discontinuation (hazard ratio [HR] 0.99; 95% CI 0.77, 1.28), 24-week CDP (HR 0.92; 95% CI 0.67, 1.27) or 24-week CDI (HR 1.13; 95% CI 0.79, 1.61), but treatment naive PwMS had a significantly longer time to first relapse (HR 0.72; 95% CI 0.58, 0.89, p = .003). Conclusion: In the MSBase cohort of 3834 CladT-treated PwMS, treatment persistence was very high, with 4.82% of PwMS per year switching to other treatments. ARR was 0.135, and a small proportion of PwMS continued CladT treatment beyond year 4. Rates of annualised CDP were low (3.8%). CDI events were slightly more frequent (5.2%). In this real-world cohort, CladT treatment is highly effective and has very high treatment persistence.

Introduction: The study includes the latest findings from the MSBase Registry on the real-world Australian experience with Ofatumumab (OFA) in the treatment of relapsing multiple sclerosis (RMS). Here, we report the latest patient demographics, disease characteristics, and prior therapy history, providing valuable insights into the clinical efficacy and treatment persistence of OFA in both treatment-naive patients and those who have switched from prior therapies. Objectives/Aims: To continue to characterize the use of OFA in Australia through an evaluation of patient demographics, baseline characteristics and prior therapy of patients initiating OFA as recorded in MSBase. In addition, evaluations of clinical efficacy included annual relapse rate and estimates of time to first clinical event. Methods: This is the second analysis of a retrospective, secondary use of data study from the MSBase Registry, describing the baseline characteristics of RMS patients in Australia initiated on OFA treatment. Analyses included demographics, expanded disability status scale (EDSS) and treatment history with diseasemodifying therapies (DMTs). Kaplan Meier estimates were calculated for persistence, time to EDSS milestone and confirmed disability worsening. Results: As of 1st March 2025, MSBase has included 605 Australian patients who received at least one dose of ofatumumab, with a median age of 42.25 (35.86, 50.73) years and 76.7% female. The median disease duration was 8.75 (3.21, 16.43) years, and 22.3% of the participants were treatmentnaive. The most common previous DMTs included ocrelizumab (26.9%) and natalizumab (16.4%). The annualized relapse rate (ARR) during the follow-up period was significantly reduced to 0.05 (0.04, 0.07) compared to 0.34 (0.29, 0.40) in the year prior to starting ofatumumab (p<0.0001). Additionally, the change in EDSS from baseline indicated stable disability scores with median change 0 (-0.5, 0), 0 (-0.5, 0.5) and 0 (-0.5, 0.5) at 12, 18 and 24 months respectively. Kaplan Meier estimates calculated treatment persistence at 96.6% [0.9441, 0.9795] at one year and 93.3% [0.8999, 0.9553] at two years follow-up. Conclusion: The second analysis of the real-world data from the MSBase registry provides further insight into the Australian experience of relapsing MS patients initiated on OFA, with a high treatment persistence and stable disability over 24 months on treatment.

Introduction: The major histocompatibility complex (MHC) locus carries a significant genetic risk burden for MS, though within the MHC the structurally diverse complement component 4 (C4) alleles remain largely understudied. Objectives/Aims: To investigate C4 genetic structural variations in MS risk and better understand how the MHC region shapes disease susceptibility. Methods: We used an established protocol to impute and analyse C4 alleles based on available genotyping data from two case-control cohorts (N1= 3252 cases and 5725 controls; N2= 8978 cases and 6976 controls), a clinical MS cohort (N3= 2387 cases) and a cohort with immune cell expression data (N4= 33 cases and 33 controls). We also performed gene-level analysis to examine the shared genetic landscape between MS onset (NGWAS= 14802 cases and 26703 controls) and plasma C4 protein (NGWAS= 68716). Results: Our data showed that C4 genetic structural variants were associated with significant changes in the risk of development of MS and the progression of MS. For instance, higher C4AL copy number burden was associated with lower risk of MS onset (fixed effect meta-analysis odds ratio= 0.89, P= 5.65×10-6) and reduced hazard of reaching MS disability milestones such as Expanded Disability Status Scale 3 (hazard ratio= 0.79, P= 9.0x10-15). In downstream gene expression analysis, we found C4 alleles may also modulate C4 expression in diseaserelevant immune cell types such as CD8+ T cells. Further, we identified that candidate genes shared between MS onset risk and plasma C4 protein level were enriched in biological pathways of immune regulation, Epstein-Barr virus infection and other autoimmune diseases such as lupus. Conclusion: These findings support future investigations of the C4 genetic structural variants as potential mechanistic and therapeutic targets in MS pathogenesis and disease progression.

Introduction: Serum neurofilament light chain (sNfL) has become a promising biomarker for acute and chronic neuroaxonal damage in relapsing and progressive multiple sclerosis (MS). Evidence is accumulating that sNfL levels have a predictive value for the risk of disability progression in MS. Objectives/Aims: To assess serum neurofilament light chain (sNfL) levels in patients with progressive MS. Methods: We analysed sNfL levels in a cross-sectional cohort study involving 181 patients with progressive MS (PMS). Additionally, we investigated the correlation between disease activity and sNfL levels in 341 patients with relapsing MS (RMS) using single molecule array technology. Results: Serum NfL levels (pg/mL) were significantly elevated in patients with RMS and PMS compared to HC (29.4 vs 12.3, p<0.05; 38.4 vs 12.3, p<0.001, respectively). Additionally, higher sNfL levels were correlated with disability. A statistically significant difference in sNfL levels was observed between relapsing and progressive disease in individuals not receiving treatment (35.2 vs 42.0, p<0.01, adjusted for age). Furthermore, treatment significantly reduced sNfL levels in RMS compared to those not receiving treatment (24.4 vs 36.9, p<0.01, adjusted for age). Notably, a statistically significant difference was observed only with natalizumab and fingolimod, but not with interferons or glatiramer acetate when compared to individuals not receiving treatment. Conclusion: The findings support the utility of sNfL measurement to monitor MS disease activity and progression alongside magnetic resonance imaging.

Introduction: Evidence from basic and clinical studies supports the role of complement activation in myelin oligodendrocyte glycoprotein antibody-related disease (MOGAD). However, the complexity of complement components hinders its clinical application. Objectives/Aims: This study aims to explore the potential of clinical practical serum complement indicators as biomarkers for MOGAD disease activity. Methods: We retrospectively included 171 records of commonly used serum complement indicators, immunoglobulin, and systemic inflammatory markers from 96 MOGAD patients and 185 records from 97 NMOSD cases. Results: MOGAD patients exhibited higher C3 (acute phase, p = 0.027; whole course, p = 0.003), C4 (acute phase, p < 0.001; whole course, p < 0.001), and CH50 (acute phase, p = 0.021) 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 at 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 peaking during the acute phase and declining during remission (C3, 81.82%, 9/11; C4, 63.64%, 7/11; CH50, 72.73%, 8/11). A positive correlation was noticed between CH50 and IgG (r = 0.317, p = 0.006). Complement levels related positively with CRP (C3, r = 0.316, p = 0.006; C4, r = 0.303, p = 0.009; CH50, r = 0.230, p = 0.050) and ESR (C3, r = 0.537, p < 0.001; C4, r = 0.280, p = 0.043; CH50, r = 0.478, p < 0.001). C4 levels were positively associated with CSF white cell count (r = 0.217, p = 0.030). Patients with higher CH50 levels tended to experience earlier recurrence than those with lower CH50 levels (log-rank p = 0.076). Conclusion: Clinically practical complement indicators can reflect disease activity, and CH50 can serve as candidate prognostic biomarkers for relapse in MOGAD.

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.