Multiple sclerosis (MS) is a neurodegenerative and inflammatory disease presenting most commonly in its relapsing and remitting form, whereby a relapse is defined as an acute exacerbation of disease activity associated with worsening disability. Relapse diagnosis is impeded by its heterogeneous presentation, limited detectability on magnetic resonance imaging and ‘pseudo-relapse’ which occurs due to factors unrelated to MS itself such as infection. Currently, we do not have easily accessible biomarkers that can distinguish relapse from remission. The diagnosis is generally made on clinical grounds as per the discretion of a neurologist and relapse treatment constitutes usage of high dose corticosteroids which may not provide long term benefit. Additionally, the recurrent usage of high dose corticosteroids is associated with a myriad of side effects and their mechanism of action is not targeted. To improve diagnostic and treatment strategies for MS relapse, we must first understand the underlying biology involved. Most literature in this field focuses on lymphocytes, overlooking innate immunity. Indeed, all the current disease modifying therapies in MS target lymphocytes. However, there is increasing evidence for the role of innate immune cells in MS disease activity. This review will discuss MS disease, relapse presentation, treatment strategies, the cellular composition of different lesion types and consider current biomarkers of disease activity versus disease stability. With a focus on innate immunity, we hope to provide new insight into future novel biomarkers to capture MS disease activity.

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

BackgroundThe role of rituximab in the treatment of myasthenia gravis (MG) remains uncertain due to limited randomized controlled evidence and heterogeneous observational data. While rituximab is often used in refractory MG, its comparative effectiveness against other non-steroidal immunosuppressive therapies (NSISTs) has yet to be fully clarified.ObjectiveTo evaluate the effectiveness of rituximab compared to a second NSIST in achieving a composite clinical outcome in acetylcholine-receptor-antibody (AChR-Ab) positive MG patients using causal inference methods to adjust for confounding.MethodsWe conducted a retrospective cohort study of AChR-Ab positive MG patients treated with rituximab or a second NSIST. The primary outcome was time to achieving a composite clinical endpoint representing a patient acceptable symptom state (PASS): Myasthenia Gravis Composite (MGC) score ≤ 3, daily corticosteroid dose ≤ 5 mg prednisolone equivalent, and no rescue therapy use in the preceding month. To reduce confounding by indication and improve causal comparability between treatment groups, inverse probability of treatment weighting (IPTW) based on propensity scores was used to balance baseline covariates. Cox proportional hazards models were applied to estimate the effect of treatment on time to outcome.Results169 patients entered into the time-to-event analysis, and after IPTW adjustment, baseline characteristics between treatment groups were balanced. There was no statistical difference in the hazard ratio between Rituximab compared to a second NSIST in achieving the composite clinical outcome (HR = 1.27, 95% CI 0.66–2.45, p = 0.48).ConclusionIn this IPTW-adjusted analysis, rituximab did not improve the time-to-improvement compared to a second NSIST in AChR-Ab-positive MG.

Chimeric antigen receptor T-cell (CAR-T) therapy is associated with immune effector cell-associated neurotoxicity syndrome (ICANS), which can manifest as acute and sub-acute cognitive dysfunction. Few studies have investigated cognitive recovery post-CAR-T therapy. In this prospective longitudinal study, patients treated with CAR-T therapy at The Alfred Hospital, Melbourne, underwent cognitive testing at preinfusion and 3- and 6-months postinfusion. Psychometric tests measured attention, processing speed, visuospatial function, language, memory, and executive function. 197 cognitive evaluations were conducted on 91 participants (62% male, mean age at infusion was 66.1 yr [SD = 10.6 yr]). Thirty-two (35%) patients developed ICANS. General linear mixed-effects models found no evidence for an interaction between time and ICANS group for most psychometric test Z-scores, except for a single test of visuospatial function (P = .007). Patients in the ICANS group demonstrated a decline on this test relative to the non-ICANS group, but the magnitude of this effect was small. Patients who develop ICANS demonstrate no strong evidence of significant cognitive decline in 6 months post-CAR-T therapy. Our data are reassuring, revealing that ICANS-related cognitive impairment resolves sometime in the first 3 months post-CAR-T therapy in most cases.

Multiple sclerosis (MS) relapse diagnosis is impeded by 'pseudo-relapses' whilst relapse treatment lacks specificity. Before we can improve clinical care, we must first improve our understanding of relapse pathogenesis. Currently, the circulatory immune mechanisms underpinning relapse are poorly understood. We aimed to determine changes in circulatory cell counts from people with MS during relapse versus remission and their association with clinical outcomes. Data was collected retrospectively by screening 2316 patient files through which we identified 78 episodes of MS relapse and remission. From these participants full blood examination data, we calculated immune cell counts and ratios. In participants with contrast enhancing lesions on magnetic resonance imaging (MRI, n = 38), total neutrophil count (p = 0.04) and neutrophils/total white cell count (N%) was higher (p = 0.04) in relapse versus remission. Similarly, in participants with a new lesion on MRI (n = 51), total neutrophil count (p = 0.01) was significantly higher during relapse versus remission. Univariable regression analyses demonstrated that lymphocytes, the neutrophil to lymphocyte ratio, monocytes/total white cell count (M%) and N% were all associated with changes in disability scores whilst multivariable regression analyses demonstrated that M% was associated with the presence of contrast enhancing lesions. This study determined that neutrophils are elevated in the circulation of people with MS during relapse compared to remission. Additionally, neutrophils, monocytes and lymphocytes were found to be associated with clinical outcomes of relapse. These findings support the notion that alterations in circulating immune cells may play a role in MS relapse pathogenesis and may inform future biomarker studies.

BACKGROUND:Pregnancy does not adversely affect disability outcomes in women with multiple sclerosis (MS). However, it remains uncertain whether pregnancy is associated with slower disability accumulation, and whether this association differs according to the timing of pregnancy during the disease course. METHODS:This observational cohort study used prospectively ascertained data in the international MSBase Registry (1991-2022), supplemented with retrospective surveys detailing participants' complete pregnancy histories. The study included women with mild relapse-onset MS, defined as an Expanded Disability Status Scale (EDSS) score of 2.5 or below. A flexible parametric survival model was used to assess the time-varying effect of live-birth pregnancy on reaching sustained EDSS 3. RESULTS:We included 2079 women, of whom 571 had a live-birth pregnancy after baseline. Live-birth pregnancies occurring within the first 4.42 years of follow-up were associated with longer time to sustained EDSS 3. At 10 years, live birth was associated with an absolute cumulative difference of 0.51 years in time to this disability milestone (95% confidence interval (CI): 0.23, 0.79). Among women with live births, postpartum relapses were associated with shorter time to sustained EDSS 3 (hazard ratio (HR): 1.61; 95% CI: 1.02, 2.55). CONCLUSION:Live-birth pregnancy occurring earlier in follow-up was associated with a longer time to disability accrual.

Predicting relapses in myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) when disability is relapse-dependent is crucial to guide treatment decisions including whether to treat from onset. MOG-AR, a relapse risk score, was recently developed in a Chinese cohort from disease onset. This study aimed to externally validate the MOG-AR score. MOGAD patients seen through the Oxford National NMO Service with ≥ 1-year disease duration and available data for MOG-AR score calculation (variables of age, sex, onset attack phenotype, treatment) were included. MOG-AR score and grade were calculated. Relapse occurrence at 3 years from onset was used as the primary outcome. MOG-AR performance was assessed by measures of discrimination and calibration. We included 284 MOGAD patients with a 4.7-year median disease duration. Relapse occurred in 38

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:Chronic lesion tissue expansion (CLTE) reflects slow, concentric growth of established multiple sclerosis (MS) lesions and is linked to central brain atrophy and disability progression. Whether existing MS disease-modifying therapies (DMTs) differentially influence this aspect of progressive MS biology remains unclear. OBJECTIVES:To compare the effect of current DMTs on CLTE in a multicentre, real-world MS cohort. METHODS:We conducted a retrospective, observational study using linked clinical data from MSBase and the MSBase Imaging Repository. Data from patients aged ⩾18 years with ⩾3 longitudinal MRI scans, and 7 therapies with ⩾100 stable treatment epochs were included. Therapy effects on CLTE, new T2 lesions, and brain atrophy were assessed using epoch-based covariate-adjusted generalised estimating equation models, with fingolimod as a comparator. RESULT:The cohort included 564 patients contributing 1648 stable treatment epochs. After adjustment for demographic, clinical, and imaging covariates, B-cell depleting therapy was the only DMT associated with significantly lower CLTE (β = -4.03, p = 0.017) relative to fingolimod. CLTE was independently associated with age, baseline lesion volume, and centre effects. CONCLUSIONS:B-cell depletion is associated with reduced CLTE, a promising biomarker of progressive MS biology.

Cognitive dysfunction is a common manifestation of immune effector cell-associated neurotoxicity syndrome (ICANS) following chimeric antigen receptor (CAR) T-cell therapy. ICANS may be life-threatening and so necessitates rapid recognition and intervention. This study investigated the utility of a computerized test of attention and processing speed (CARTcog) for monitoring ICANS. In this prospective pilot study, 89 CAR-T patients (71% male, mean age at infusion = 67.18 yr) completed 1149 CARTcog tests and 5347 ICE scores during their inpatient stay. Of the 89 participants, 30 (34%) developed ICANS. Receiver operating characteristic analysis demonstrated that five of six CARTcog scores had moderate discriminatory power in identifying patients who develop ICANS in the following 12 hours (area under the curve = 0.77 to 0.79). Cutoffs were derived, and Bayesian generalized linear mixed models demonstrated that the reaction times above the cutoff on the choice reaction task were associated with an almost 20-fold increase in the odds of developing ICANS (OR = 19.64 [95% credible interval 5.14 to 96.20]). Three case studies illustrate the practical utility of CARTcog. CARTcog may facilitate early detection of ICANS and thereby enhance patient safety and treatment outcomes.

Background: Late-onset multiple sclerosis (LOMS), defined by symptom onset after age 50, is increasingly recognised as a distinct clinical entity. Evidence comparing disease-modifying therapies (DMTs) in this subgroup remains limited. Objectives: To compare clinical outcomes of anti-CD20 monoclonal antibodies and sphingosine-1-phosphate receptor modulators (S1PRMs) in LOMS. Design: Multicentre, observational cohort study based on real-world data from an international multiple sclerosis registry. Methods: We analysed data from the MSBase registry, including relapsing–remitting LOMS patients treated with anti-CD20 therapies (ocrelizumab, ofatumumab, rituximab) or S1PRMs (fingolimod, ozanimod, siponimod, ponesimod) for ⩾6 months. Primary outcomes were annualised relapse rate (ARR), Expanded Disability Status Scale (EDSS) change, confirmed disability worsening (CDW), progression independent of relapse activity (PIRA), and PIRA without MRI activity (PIRMA). Analyses used inverse probability of treatment weighting (IPTW). Causal forest and best linear projector (BLP) models explored effect modification. Results: After weighting, 347 patients (median age 53.7 years; 69% female; median follow-up 6.9 years) were included. No significant differences were found for ARR, EDSS change, CDW, PIRA, or PIRMA. Exploratory analyses suggested greater anti-CD20 benefit in patients with earlier onset (⩽55 years), shorter disease duration (⩽2 years from diagnosis), and lower disability (EDSS < 3). Conclusions: In this real-world LOMS cohort, no statistically significant differences were observed between anti-CD20 and S1PRM therapies. Exploratory analyses suggested anti-CD20 may be associated with better outcomes in selected subgroups; these findings are hypothesis-generating. Trial Registration: Not applicable.

BACKGROUND:Ocrelizumab, a monoclonal antibody targeting CD20+ B cells, is a high-efficacy therapy for multiple sclerosis (MS). METHODS:Patients with relapse-onset MS treated with ocrelizumab, fingolimod, natalizumab or alemtuzumab for ≥6 months were identified from three registries: MSBase, OFSEP and Danish MS Registry. Pairwise comparisons were performed in the overall cohort and 14 predefined clinicodemographic subgroups based on sex, disease activity, MS duration, Expanded Disability Status Scale, prior therapy and reason for prior treatment cessation. Relapses, progression independent of relapse activity (PIRA) and relapse-associated worsening (RAW) were compared in pairwise-censored groups. RESULTS:Fingolimod was associated with a higher annualised relapse rate (ARR) (0.14 vs 0.06, p<0.001), relapse risk (HR 2.26, 95% CI 1.98 to 2.58), RAW (1.62, 1.08 to 2.43) and lower risk of disability improvement (0.78, 0.63 to 0.96) than ocrelizumab. Superiority of ocrelizumab over fingolimod on relapses was maintained in all subgroups. Natalizumab was associated with marginally higher ARR (0.10 vs 0.07, p<0.001), relapse risk (1.35, 1.16 to 1.57) and RAW (1.77, 1.07 to 2.94) than ocrelizumab. Alemtuzumab was associated with higher ARR (0.18 vs 0.12, p<0.001) and relapse risk (1.48, 1.25 to 1.76) than ocrelizumab, but there was no evidence for a difference in risk of RAW. There was no evidence for a difference on PIRA in any comparisons. Ocrelizumab was superior to natalizumab and alemtuzumab on relapses in patients who were not treatment-naïve, experienced disease activity on the prior therapy or stopped prior therapy due to lack of efficacy. CONCLUSIONS:Ocrelizumab provides superior control of relapses and RAW, especially among patients with prior on-treatment disease activity. Treatment of PIRA remains an unmet need.