Effectiveness of Disease-Modifying Treatment on Spinal Cord Lesion Formation in Relapse-Onset Multiple Sclerosis: An MSBase Registry Study.

BACKGROUND: Spinal cord lesions in multiple sclerosis (MS) have considerable impact on disability. High-efficacy disease-modifying treatments (hDMTs) are associated with greater reduction of relapses and new brain lesions compared to low-efficacy treatments (lDMTs). Knowledge on the impact of DMTs on cord lesion formation is limited as these outcome measures were not included in MS treatment trials. This study aims to investigate whether hDMTs reduce the formation of cord lesions more effectively than lDMTs. METHODS: Patients with relapse-onset MS, a cord magnetic resonance imaging (MRI) within 6 months before/after initiation of their first DMT and ≥1 cord MRI at follow-up (interval > 6 months) were extracted from the MSBase registry (ACTRN12605000455662). Patients treated with hDMTs ≥90% or lDMTs ≥90% of follow-up duration were considered the hDMT and lDMT groups, respectively. Matching was performed using propensity scores. Cox proportional hazards models were used to estimate the hazards of new cord lesions, brain lesions and relapses. RESULTS: Ninety-four and 783 satisfied hDMT and lDMT group criteria, respectively. Seventy-seven hDMT patients were matched to 184 lDMT patients. In the hDMT group there was no evidence of reduction of new cord lesions (hazard ratio [HR] 0.99 [95% CI 0.51, 1.92], p = 0.97), while there were fewer new brain lesions (HR 0.22 [95% CI 0.10, 0.49], p < 0.001) and fewer relapses (HR 0.45 [95% CI 0.28, 0.72], p = 0.004). CONCLUSION: A potential discrepancy exists in the effect of hDMTs over lDMTs in preventing spinal cord lesions versus brain lesions and relapses. While hDMTs provided a significant reduction for the latter when compared to lDMTs, there was no significant reduction in new spinal cord lesions.

Predictors of relapse risk and treatment response in AQP4-IgG positive and seronegative NMOSD: A multicentre study.

BACKGROUND: Neuromyelitis optica spectrum disorder (NMOSD) can be categorised into aquaporin-4 antibody (AQP4-IgG) NMOSD or seronegative NMOSD. While our knowledge of AQP4-IgG NMOSD has evolved significantly in the past decade, seronegative NMOSD remains less understood. This study aimed to evaluate the predictors of relapses and treatment responses in AQP4-IgG NMOSD and seronegative NMOSD. METHODS: This was a multicentre, international, retrospective cohort study using the MSBase registry. Recurrent relapse risk was assessed using an Andersen-Gill model and risk of first relapse was evaluated using a Cox proportional hazards model. Covariates that putatively influence relapse risk included demographic factors, clinical characteristics and immunosuppressive therapies; the latter was assessed as a time-varying covariate. RESULTS: A total of 398 patients (246 AQP4-IgG NMOSD and 152 seronegative NMOSD) were included. The AQP4-IgG NMOSD and seronegative NMOSD patients did not significantly differ by age at disease onset, ethnicity or annualised relapse rate. Both low-efficacy and high-efficacy immunosuppressive therapies were associated with significant reductions in recurrent relapse risk, with notably greater protection conferred by high-efficacy therapies in both AQP4-IgG NMOSD (HR 0.27, 95% CI 0.15 to 0.49, p<0.001) and seronegative NMOSD (HR 0.21, 95% CI 0.08 to 0.51, p<0.001). Longer disease duration (HR 0.97, 95% CI 0.95 to 0.99, p<0.001) and male sex (HR 0.52, 95% CI 0.34 to 0.84, p=0.007) were additional protective variables in reducing the recurrent relapse risk for the AQP4-IgG NMOSD group. CONCLUSION: Although further studies are needed to improve our understanding of seronegative NMOSD, our findings underscore the importance of aggressive treatment with high-efficacy immunotherapies in both NMOSD subtypes, regardless of serostatus.

Effectiveness of cladribine compared to fingolimod, natalizumab, ocrelizumab and alemtuzumab in relapsing-remitting multiple sclerosis.

BACKGROUND: Comparisons between cladribine and other potent immunotherapies for multiple sclerosis (MS) are lacking. OBJECTIVES: To compare the effectiveness of cladribine against fingolimod, natalizumab, ocrelizumab and alemtuzumab in relapsing-remitting MS. METHODS: Patients with relapsing-remitting MS treated with cladribine, fingolimod, natalizumab, ocrelizumab or alemtuzumab were identified in the global MSBase cohort and two additional UK centres. Patients were followed for ⩾6/12 and had ⩾3 in-person disability assessments. Patients were matched using propensity score. Four pairwise analyses compared annualised relapse rates (ARRs) and disability outcomes. RESULTS: The eligible cohorts consisted of 853 (fingolimod), 464 (natalizumab), 1131 (ocrelizumab), 123 (alemtuzumab) or 493 (cladribine) patients. Cladribine was associated with a lower ARR than fingolimod (0.07 vs. 0.12, p = 0.006) and a higher ARR than natalizumab (0.10 vs. 0.06, p = 0.03), ocrelizumab (0.09 vs. 0.05, p = 0.008) and alemtuzumab (0.17 vs. 0.04, p < 0.001). Compared to cladribine, the risk of disability worsening did not differ in patients treated with fingolimod (hazard ratio (HR) 1.08, 95% confidence interval (CI) 0.47-2.47) or alemtuzumab (HR 0.73, 95% CI 0.26-2.07), but was lower for patients treated with natalizumab (HR 0.35, 95% CI 0.13-0.94) and ocrelizumab (HR 0.45, 95% CI 0.26-0.78). There was no evidence for a difference in disability improvement. CONCLUSION: Cladribine is an effective therapy that can be viewed as a step up in effectiveness from fingolimod, but is less effective than the most potent intravenous MS therapies.

Comparative analysis of cognitive and physical characteristics in late-onset, adult-onset and early-onset multiple sclerosis patients.

BACKGROUND: Late-onset multiple sclerosis (LOMS or L; MS) and early-onset MS (EOMS or E) are less common, and their prognosis can be different. To characterize the demographic and clinical features, and clinical outcomes of LOMS and EOMS patients, comparing them to adult-onset MS (AOMS or A) patients. METHODS: The study was conducted as a secondary analysis of a prospective study. The participants were divided into three groups according to age of MS onset: early onset (<18 years of age), adult-onset (20-40 years of age), and late-onset (>55 years of age). Demographic variables, oligoclonal bands, IgG index, and Expanded Disability Status Scale (EDSS) score in admission, first year, second year and current EDSS were evaluated. The Timed 25-Foot Walk Test (T25FW), Timed Up and Go (TUG), Multiple Sclerosis Walking Scale-12, Single Leg Standing Test, Activity-Specific Balance Confidence Scale, Nine-Hole Peg Test, Epworth Sleepiness Scale and Restless Legs Syndrome Severity Scale were performed. Appropriate statistical analysis was made. RESULTS: A total of 658 pwMS was included in the study and divided into three groups: EOMS (n = 117), AOMS (n = 499), and LOMS (n = 42). Statistically significant differences were determined between groups in terms of age [L (mean:59.86±5.45 years-y-)> A (36.87±9.12 y)> E(26.56±8.85 y), p < 0.001], education level, current EDSS score (L > E, p < 0.001), EDSS score in first admission, EDSS score in the first year, EDSS score in the second year (L > A > E, p < 0.001), reached an EDSS score 6 (E > L p = 0.001, E > A p = 0.015), disease duration (E > A, E > L, mean E = 11.66±9.7 y, A = 7.99±7.4 y, L = 6.31±4.67 y) time switching second-line treatment to the third line (E > L p < 0.001, A > L p = 0.002, mean E = 171.73±83.29 months-m-, A = 136.13±65.75 m, L = 65.85±45.96 m), number of relapses (A > E > L, median E = 4.0, A = 3.0, L = 2.0), distribution of MS type and oligoclonal band types. Significant differences were found in T25FW and TUG. Post-hoc analysis showed that participants in the LOMS group have longer T25FW (mean L = 7.8 ± 6.11, A = 6.25±5.09, E = 5.72±3.13, p = 0.011) and TUG (mean L = 11.01±5.53, A = 9.57±8.04, E = 8.38±5.51, p = 0.007) times than the AOMS and EOMS groups. CONCLUSION: Our result revealed that individuals with LOMS face elevated disability levels and a heightened propensity to transition from first-line treatments to more advanced therapeutic interventions. LOMS have worse lower extremity functional status than AOMS and EOMS patient. Clinical evaluations and treatment choices require more attention in LOMS. However, according to the low number of LOMS in our cohort, these results were considered cautious, and more wide and multi-center studies must be designed.

The relationship between work difficulties and physical disability, cognitive and social cognitive impairment and subcortical gray matter atrophy in persons with multiple sclerosis.

BACKGROUND: Multiple sclerosis (MS) is commonly associated with work difficulties. This study aimed to examine the relationship between work difficulties and physical disability, cognitive and social cognitive impairment, and subcortical gray matter (scGM) atrophy in pwMS. METHODS: Thirty-three employees with MS underwent assessments with Multiple Sclerosis Work Difficulties Questionnaire-23 MSWDQ-23. Physical disability was measured using EDSS, Timed 25-Foot Walk (T25FW), 2-Minute Walking Test (2-MWT), the Nine-Hole Peg test (N-HPT), and 12-item Multiple Sclerosis Walking Scale (MSWS-12). Cognitive functions were evaluated with Brief International Cognitive Assessment in MS (BICAMS), social cognition with Facial Emotion Identification (FEI), Reading the Mind in the Eyes Test (RMET), and Empathy Quotient (EQ). Anxiety and depression were assessed using Hospital Anxiety and Depression Scale (HADS). The association between variables was analysed using Spearman's correlation coefficient. GM volumes were calculated from 3T MRI data using Freesurfer, their potential relationship with work difficulties were evaluated through a linear regression model. RESULTS: MSWDQ-23 was strongly correlated with T25FW and MSWS-12 (p < 0.01), moderately correlated with EDSS, 2MWT, HAD, BICAMS, and EQ (p < 0.05). According to the linear regression model the decrease in volumes of total GM and scGM, bilateral Thalamus, bilateral Hippocampus, left Putamen, and right Caudate related with the severity of work difficulties (R²=0.815, p = 0.25). CONCLUSION: This study provides valuable insights into the multifaceted nature of work difficulties experienced by pwMS. It suggests that not only physical disability but also other factors, such as mood, cognition, empathy, and cortical and subcortical gray matter atrophy may contribute to work difficulties among pwMS.

A multi-centre longitudinal study analysing multiple sclerosis disease-modifying therapy prescribing patterns during the COVID-19 pandemic.

BACKGROUND: The COVID-19 pandemic raised concern amongst clinicians that disease-modifying therapies (DMT), particularly anti-CD20 monoclonal antibodies (mAb) and fingolimod, could worsen COVID-19 in people with multiple sclerosis (pwMS). This study aimed to examine DMT prescribing trends pre- and post-pandemic onset. METHODS: A multi-centre longitudinal study with 8,771 participants from MSBase was conducted. Two time periods were defined: pre-pandemic (March 11 2018-March 10 2020) and post-pandemic onset (March 11 2020-11 March 2022). The association between time and prescribing trends was analysed using multivariable mixed-effects logistic regression. DMT initiation refers to first initiation of any DMT, whilst DMT switches indicate changing regimen within 6 months of last use. RESULTS: Post-pandemic onset, there was a significant increase in DMT initiation/switching to natalizumab and cladribine [(Natalizumab-initiation: OR 1.72, 95% CI 1.39-2.13; switching: OR 1.66, 95% CI 1.40-1.98), (Cladribine-initiation: OR 1.43, 95% CI 1.09-1.87; switching: OR 1.67, 95% CI 1.41-1.98)]. Anti-CD20mAb initiation/switching decreased in the year of the pandemic, but recovered in the second year, such that overall odds increased slightly post-pandemic (initiation: OR 1.26, 95% CI 1.06-1.49; Switching: OR 1.15, 95% CI 1.02-1.29. Initiation/switching of fingolimod, interferon-beta, and alemtuzumab significantly decreased [(Fingolimod-initiation: OR 0.55, 95% CI 0.41-0.73; switching: OR 0.49, 95% CI 0.41-0.58), (Interferon-gamma-initiation: OR 0.48, 95% CI 0.41-0.57; switching: OR 0.78, 95% CI 0.62-0.99), (Alemtuzumab-initiation: OR 0.27, 95% CI 0.15-0.48; switching: OR 0.27, 95% CI 0.17-0.44)]. CONCLUSIONS: Post-pandemic onset, clinicians preferentially prescribed natalizumab and cladribine over anti-CD20 mAbs and fingolimod, likely to preserve efficacy but reduce perceived immunosuppressive risks. This could have implications for disease progression in pwMS. Our findings highlight the significance of equitable DMT access globally, and the importance of evidence-based decision-making in global health challenges.

Investigating the relationship of theory of mind and empathy with neuroimaging, neuropsychological, and neuropsychiatric data in persons with multiple sclerosis.

Theory of Mind (ToM) is understanding others' minds. Empathy is an insight into emotions and feelings of others. Persons with multiple sclerosis (pwMS) may experience impairment in ToM and empathy. To investigate ToM, empathy, and their relationship with neuroimaging, neuropsychological, and neuropsychiatric data. 41 pwMS and 41 HC were assessed using RMET for ToM, EQ, BICAMS, HADS. Cortical and subcortical gray matter volumes were calculated with Freesurfer from 3T MRI scans. pwMS showed lower EQ scores (44.82 ± 11.9 vs 51.29 ± 9.18, p = 0.02) and worse RMET performance (22.37 ± 4.09 vs 24,47 ± 2.93, p = 0.011). Anxiety and depression were higher in pwMS. EQ correlated with subcortical (amygdala) and cortical (anterior cingulate) volumes. RMET correlated with cortical volumes (posterior cingulate, lingual). In regression analysis, amygdala volume was the single predictor of empathy performance (p = 0.041). There were no significant correlations between social cognitive tests and general cognition. A weak negative correlation was found between EQ and the level of anxiety (r = -0.342, p = 0.038) The present study indicates that pwMS have impairment on ToM and empathy. The performance of ToM and empathy in MS is linked to the volumes of critical brain areas involved in social cognition.

Comparative effectiveness of dimethyl fumarate versus non-specific immunosuppressants: Real-world evidence from MSBase.

Background: The use of non-specific immunosuppressants (NSIS) to treat multiple sclerosis (MS) remains prevalent in certain geographies despite safety concerns, likely due to resource limitations. Objective: To use MSBase registry data to compare real-world outcomes in adults with relapsing-remitting MS (RRMS) treated with dimethyl fumarate (DMF) or NSIS (azathioprine, cyclosporine, cyclophosphamide, methotrexate, mitoxantrone or mycophenolate mofetil) between January 1, 2014 and April 1, 2022. Methods: Treatment outcomes were compared using inverse probability of treatment weighting (IPTW) Cox regression. Outcomes were annualized relapse rates (ARRs), time to discontinuation, time to first relapse (TTFR) and time to 24-week confirmed disability progression (CDP) or 24-week confirmed disability improvement (CDI; in patients with baseline Expanded Disability Status Scale [EDSS] score ≥2). Results: After IPTW, ARR was similar for DMF (0.13) and NSIS (0.16; p = 0.29). There was no difference in TTFR between cohorts (hazard ratio [HR]: 0.98; p = 0.84). The DMF cohort experienced longer times to discontinuation (HR: 0.75; p = 0.001) and CDP (HR: 0.53; p = 0.001), and shorter time to CDI (HR: 1.99; p < 0.008), versus the NSIS cohort. Conclusion: This analysis supports the use of DMF to treat patients with relapsing forms of MS, and may have implications for MS practices in countries where NSIS are commonly used to treat RRMS.

Risk of hepatitis B virus reactivation in people with multiple sclerosis treated with ocrelizumab: an observational study from Turkey.

BACKGROUND: The risk of hepatitis B virus (HBV) reactivation remains unclear in people with multiple sclerosis (MS) receiving ocrelizumab. We aimed to assess HBV seroprevalence and reactivation risk in MS patients on ocrelizumab and to evaluate the effectiveness of antiviral prophylaxis against HBV reactivation. METHODS: In this single-center, cross-sectional study, 400 people with MS receiving ocrelizumab were screened for HBV at baseline and antiviral prophylaxis was implemented based on serological results. Patients were monitored for HBV reactivation, and outcomes were analyzed. RESULTS: Among 56 (14%) patients who had serology compatible with occult or resolved HBV infection, 49 (85.7%) received antiviral prophylaxis regularly and had no HBV reactivation during the follow-up. Reactivation of HBV occurred in 2 out of 7 (28.6%) patients who did not receive antiviral prophylaxis and in one patient who did not adhere to the prophylaxis regimen. All patients with reactivation had anti-HBs levels below 100 mIU/mL and the median titer was significantly lower than the patients with no HBV reactivation (p = 0.034). CONCLUSION: This study highlights a 14% anti-HBc positivity, indicating a potential risk for HBV reactivation in people with MS receiving ocrelizumab. This suggests the importance of vigilant monitoring and the implementation of prophylactic measures. Our recommendation emphasizes antiviral prophylaxis, particularly for patients with low anti-HBs, and a pre-emptive strategy for others.

Discriminative ability of the original and short form of the Activities-specific Balance Confidence scale and its individual items for falls in people with multiple sclerosis.

BACKGROUND: Balance confidence is an essential component of fall risk assessment in persons with multiple sclerosis (pwMS). AIMS: The aims of this cross-sectional study were to 1) investigate the ability of the 16-item Activities-specific Balance Confidence scale (ABC-16), 6-item Activities-specific Balance Confidence scale (ABC-6), and each item of the ABC-16 for distinguishing fallers and 2) determine cutoff scores for these scales to discriminate fallers and non-fallers in pwMS. METHODS: One hundred and fifty-six participants [fallers/non-fallers: 60 (38.5%)/96 (61.5%), median EDSS: 1.5] were enrolled. Balance confidence was assessed using the ABC-16 and ABC-6. The self-reported number of falls in the past three months was recorded. Descriptive assessments, including walking, balance, and cognition were performed. Logistic regression and receiver operating characteristic analyses were conducted to estimate the sensitivities and specificities of the ABC-16 and ABC-6. RESULTS: Both the ABC-16 (AUC: 0.85) and ABC-6 (AUC: 0.84) had the discriminative ability for falls. Each item of the ABC-16 scale was a significantly related to falls [odds ratio (OR) range: 1.38 to 1.89]. Items 8 and 10 had the highest odds ratio (OR: 1.85; 95%CI: 1.47-2.33, OR: 1.89; 95%CI: 1.49-2.40; respectively). We found cutoff scores of ≤ 70 of 100 (sensitivity: 71.67, specificity: 86.46) and ≤ 65/100 (sensitivity: 76.67, specificity: 79.17) in discrimination between fallers and non-fallers for the ABC-16 and ABC-6, respectively. CONCLUSION: Both original and short forms of the ABC scale are an efficient tool for discriminating fallers and non-fallers in pwMS. Although all items are related to falls, outdoor walking activities have the strongest associations with falls than other items.

Comparative Effectiveness of Natalizumab, Fingolimod, and Injectable Therapies in Pediatric-Onset Multiple Sclerosis: A Registry-Based Study.

BACKGROUND AND OBJECTIVES: Patients with pediatric-onset multiple sclerosis (POMS) typically experience higher levels of inflammation with more frequent relapses, and though patients with POMS usually recover from relapses better than adults, patients with POMS reach irreversible disability at a younger age than adult-onset patients. There have been few randomized, placebo-controlled clinical trials of multiple sclerosis (MS) disease-modifying therapies (DMTs) in patients with POMS, and most available data are based on observational studies of off-label use of DMTs approved for adults. We assessed the effectiveness of natalizumab compared with fingolimod using injectable platform therapies as a reference in pediatric patients in the global MSBase registry. METHODS: This retrospective study included patients with POMS who initiated treatment with an injectable DMT, natalizumab, or fingolimod between January 1, 2006, and May 3, 2021. Patients were matched using inverse probability treatment weighting. The primary outcome was time to first relapse from index therapy initiation. Secondary study outcomes included annualized relapse rate; proportions of relapse-free patients at 1, 2, and 5 years; time to treatment discontinuation; and times to 24-week confirmed disability worsening and confirmed disability improvement. RESULTS: A total of 1,218 patients with POMS were included in this analysis. Patients treated with fingolimod had a significantly lower risk of relapse than patients treated with injectable DMTs (hazard ratio [HR], 0.49; 95% confidence interval [CI], 0.29-0.83; p = 0.008). After adjustment for prior DMT experience in the unmatched sample, patients treated with natalizumab had a significantly lower risk of relapse than patients treated either with injectable DMTs (HR, 0.15; 95% CI 0.07-0.31; p < 0.001) or fingolimod (HR, 0.37; 95% CI 0.14-1.00; p = 0.049). The adjusted secondary study outcomes were generally consistent with the primary outcome or with previous observations. The findings in the inverse probability treatment weighting-adjusted patient populations were confirmed in multiple sensitivity analyses. DISCUSSION: Our analyses of relapse risk suggest that natalizumab is more effective than fingolimod in the control of relapses in this population with high rates of new inflammatory activity, consistent with previous studies of natalizumab and fingolimod in adult-onset patients and POMS. In addition, both fingolimod and natalizumab were more effective than first-line injectable therapies. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that patients with POMS treated with natalizumab had a lower risk of relapse than those with fingolimod.

Comparing ocrelizumab to interferon/glatiramer acetate in people with multiple sclerosis over age 60.

BACKGROUND: Ongoing controversy exists regarding optimal management of disease modifying therapy (DMT) in older people with multiple sclerosis (pwMS). There is concern that the lower relapse rate, combined with a higher risk of DMT-related infections and side effects, may alter the risk-benefit balance in older pwMS. Given the lack of pwMS above age 60 in randomised controlled trials, the comparative efficacy of high-efficacy DMTs such as ocrelizumab has not been shown in older pwMS. We aimed to evaluate the comparative effectiveness of ocrelizumab, a high-efficacy DMT, versus interferon/glatiramer acetate (IFN/GA) in pwMS over the age of 60. METHODS: Using data from MSBase registry, this multicentre cohort study included pwMS above 60 who switched to or started on ocrelizumab or IFN/GA. We analysed relapse and disability outcomes after balancing covariates using an inverse probability treatment weighting (IPTW) method. Propensity scores were obtained based on age, country, disease duration, sex, baseline Expanded Disability Status Scale, prior relapses (all-time, 12 months and 24 months) and prior DMT exposure (overall number and high-efficacy DMTs). After weighting, all covariates were balanced. Primary outcomes were time to first relapse and annualised relapse rate (ARR). Secondary outcomes were 6-month confirmed disability progression (CDP) and confirmed disability improvement (CDI). RESULTS: A total of 248 participants received ocrelizumab, while 427 received IFN/GA. The IPTW-weighted ARR for ocrelizumab was 0.01 and 0.08 for IFN/GA. The IPTW-weighted ARR ratio was 0.15 (95% CI 0.06 to 0.33, p<0.001) for ocrelizumab compared with IFN/GA. On IPTW-weighted Cox regression models, HR for time to first relapse was 0.13 (95% CI 0.05 to 0.26, p<0.001). The hazard of first relapse was significantly reduced in ocrelizumab users after 5 months compared with IFN/GA users. However, the two groups did not differ in CDP or CDI over 3.57 years. CONCLUSION: In older pwMS, ocrelizumab effectively reduced relapses compared with IFN/GA. Overall relapse activity was low. This study adds valuable real-world data for informed DMT decision making with older pwMS. Our study also confirms that there is a treatment benefit in older people with MS, given the existence of a clear differential treatment effect between ocrelizumab and IFN/GA in the over 60 age group.

Disease-modifying therapies in managing disability worsening in paediatric-onset multiple sclerosis: a longitudinal analysis of global and national registries.

BACKGROUND: High-efficacy disease-modifying therapies have been proven to slow disability accrual in adults with relapsing-remitting multiple sclerosis. However, their impact on disability worsening in paediatric-onset multiple sclerosis, particularly during the early phases, is not well understood. We evaluated how high-efficacy therapies influence transitions across five disability states, ranging from minimal disability to gait impairment and secondary progressive multiple sclerosis, in people with paediatric-onset multiple sclerosis. METHODS: Longitudinal data were obtained from the international MSBase registry, containing data from people with multiple sclerosis from 151 centres across 41 countries, and the Italian Multiple Sclerosis and Related Disorders Register, containing data from people with multiple sclerosis from 178 Italian multiple sclerosis centres. People younger than 18 years at the onset of multiple sclerosis symptoms were included, provided they had a confirmed diagnosis of relapsing-remitting multiple sclerosis and at least four Expanded Disability Status Scale (EDSS) scores recorded within 12-month intervals. The primary outcome was the time to change in disability state: minimal disability (EDSS scores 0, 1·0, and 1·5), mild disability (EDSS scores 2·0 and 2·5), moderate disability (EDSS scores 3·0 and 3·5), gait impairment (EDSS scores ≥4·0), and clinician diagnosed secondary progressive multiple sclerosis. A multi-state model was constructed to simulate the natural course of multiple sclerosis, modelling the probabilities of both disability worsening and improvement simultaneously. The impact of high-efficacy disease-modifying therapies (alemtuzumab, cladribine, daclizumab, fingolimod, mitoxantrone, natalizumab, ocrelizumab, rituximab, or autologous haematopoietic stem cell transplantation) and low-efficacy disease-modifying therapies (dimethyl fumarate, glatiramer acetate, interferon beta, or teriflunomide), compared with no treatment, on the course of disability was assessed. Apart from recruitment, individuals with lived experience of multiple sclerosis were not involved in the design and conduct of this study. FINDINGS: A total of 5224 people (3686 [70·6%] female and 1538 [29·4%] male) with mean age at onset of multiple sclerosis 15·24 years (SD 2·52) were included. High-efficacy therapies reduced the hazard of disability worsening across the disability states. The largest reduction (hazard ratio 0·41 [95% CI 0·31-0·53]) was observed in participants who were treated with high-efficacy therapies while in the minimal disability state, compared with those remained untreated. The benefit of high-efficacy therapies declined with increasing disability. Young people with minimal disability who received low-efficacy therapy also experienced a reduced hazard (hazard ratio 0·65 [95% CI 0·54-0·77]) of transitioning to mild disability, in contrast to those who remained untreated. INTERPRETATION: Treatment of paediatric-onset relapsing-remitting multiple sclerosis with high-efficacy therapy substantially reduces the risk of reaching key disability milestones. This reduction in risk is most pronounced among young people with minimal or mild disability when treatment began. Children with relapsing-remitting multiple sclerosis should be treated early with high-efficacy therapy, before developing significant neurological impairments, to better preserve their neurological capacity. FUNDING: National Health and Medical Research Council, Australia; MSBase Foundation Fellowship; MS Australia Postdoctoral Fellowship.

COVID-19 vaccine response in Neuromyelitis Optica Spectrum Disorder.

OBJECTIVES AND AIMS: Neuromyelitis Optica Spectrum Disorder (NMOSD) is a disabling autoimmune disease of the central nervous system that requires immunosuppressants to control the relapses. The latter puts them at risk for more severe COVID-19 infection. Vaccines are an effective way to control the pandemic. However, we do not know how effective they are in immunologically compromised patients. We aimed to evaluate and compare antibody levels in NMOSD patients treated with disease-modifying therapies after two doses of inactivated and mRNA COVID-19 vaccines. METHODS: Patients with NMOSD diagnosis and age-sex matched healthy controls who received two doses of either inactivated and mRNA COVID-19 vaccine were recruited in the study. Serum samples were collected at least two weeks after the second dose. RESULTS: Serum samples from 24 NMOSD patients (Mean age-36.58, Female-70.83%) and 24 healthy controls (Mean age-36.71, Female-70.83%) were evaluated. Mean antibody titer was lower in the NMOSD group (Mean; SD (2.43 ± 1.51) than in healthy controls (Mean; SD 3.23 ± 0.80). Seronegativity was only seen in the rituximab group, there were no such cases in the azathioprine group. (9 vs 0). CONCLUSIONS: The study shows that NMOSD patients treated with rituximab may still be susceptible to severe COVID-19 infection even after both inactivated and mRNA vaccines.

Emulating randomised clinical trials in relapsing-remitting multiple sclerosis with non-randomised real-world evidence: an application using data from the MSBase Registry.

BACKGROUND: To mimic as closely as possible a randomised controlled trial (RCT) and calibrate the real-world evidence (RWE) studies against a known treatment effect would be helpful to understand if RWE can support causal conclusions in selected circumstances. The aim was to emulate the TRANSFORMS trial comparing Fingolimod (FTY) versus intramuscular interferon ß-1a (IFN) using observational data. METHODS: We extracted from the MSBase registry all the patients with relapsing-remitting multiple sclerosis (RRMS) collected in the period 2011-2021 who received IFN or FTY (0.5 mg) and with the same inclusion and exclusion criteria of the TRANSFORMS RCT. The primary endpoint was the annualised relapse rate (ARR) over 12 months. Patients were 1:1 propensity-score (PS) matched. Relapse-rate ratio (RR) was calculated by mean of a negative binomial regression. RESULTS: A total of 4376 patients with RRMS (1140 in IFN and 3236 in FTY) were selected. After PS, 856 patients in each group were matched. The ARR was 0.45 in IFN and 0.25 in FTY with a significant difference between the two groups (RR: 0.55, 95% CI: 0.45 to 0.68; p<0.001). The result of the emulation was very similar and fell within the 95% CI of that observed in the RCT (RR: 0.49, 95% CI: 0.37 to 0.64; p<0.001) with a standardised difference of 0.66 (p=0.51). CONCLUSIONS: By applying the same inclusion and exclusion criteria used in the RCT and employing appropriate methodology, we successfully replicated the RCT results with only minor discrepancies. Also, even if the confounding bias cannot be fully eliminated, conducting a rigorous target trial emulation could still yield valuable insights for comparative effectiveness research.

Investigation of the Relationship Between Coping With the Disease and Affecting Cognitive, Physical, and Psychosocial Factors in People with Multiple Sclerosis.

OBJECTIVE: To investigate the relationship between coping mechanisms in people with multiple sclerosis (MS, pwMS) and cognitive, physical, and psychosocial factors such as socio-demographic characteristics, disability, personality, stigma, quality of life, depression, and anxiety. METHOD: One hundred and two pwMS were enrolled in this cross-sectional study. Demographics and clinical characteristics were recorded. Coping with the MS Scale (CMSS), including seven subscales, which are problem-solving, physical assistance, acceptance, avoidance, personal health control, energy conservation, and emotional release, was used to measure coping. Anxiety and depression levels, stigma, neuropsychological symptoms, and personality were measured by the Hospital Anxiety and Depression Scale (HAD), EuroQol-5D Quality of Life Scale (EQ-5D), Quality of Life in Neurological Diseases (NeuroQoL) -Stigma Scale, Multiple Sclerosis Neuropsychological Questionnaire (MSNQ), and Revised Eysenck Personality Questionnaire-Abbreviated Form (EKA-GGK), respectively. RESULTS: There was a weak statistically significant positive correlation between the physical support subscale and age and the disease duration and a strong positive correlation with EDSS (r = .214, p = .035; r = .213, p = .036; r = .582, p ≤ .0001, respectively). There was a moderate negative relationship between the physical support subscale and the EQ-5D mobility, self-care, pain, and health subscales (r = -.434, p = .000; r = -.482, p = .000; r = -.526, p ≤ .001, respectively), a weak negative correlation with anxiety, and a strong negative relationship with usual activities (r = -.379, p ≤ .001; r = -.243, p = .017; r = -.384, p ≤ .001, respectively). CONCLUSION: It has been shown that coping with MS can be affected by cognitive, physical, and psychosocial factors.

Predictors of relapse severity in multiple sclerosis.

BACKGROUND: The severity of relapses is one of the determinants of residual disability in multiple sclerosis (MS), contributing to the final progressive state. However, the factors that predict the severity of relapses are not fully understood. AIM: To predict relapse severity in MS and investigate the relationship between relapse severity and the degree of improvement in physical, cognitive, and social tests. METHODS: This observational single-center study prospectively assesses relapse severity in patients with MS. Relapses were classified as mild, moderate, and severe. Before relapse treatment and 1 month into remission four physical tests, four cognitive tests, and six surveys were performed. Multinomial regression analyses were applied to predict relapse severity. RESULTS: A total of 126 relapses were studied prospectively. Twenty-two were lost to follow-up. Multiple sclerosis International Quality of Life (MusiQol) questionnaire (r = 0.28, p = 0.006) and Symbol Digit Modalities Test (SDMT, r = 0.23, p = 0.022) improvement statuses were correlated with the severity of the relapse. Higher cases with improvement were observed in the severe relapse group on both MusiQol and SDMT, but no difference for those with a mild relapse. In the predictive model, only disease duration [Odds Ratio (OR) 0.808 95% confidence interval (CI) 0.691 to 0.945; p = 0.008] and Body Mass Index (BMI, OR 1.148 95% CI 1.018 to 1.294; p = 0.024) were associated with relapse severity. CONCLUSION: Only disease duration was found to be predictive of relapse severity among disease-related variables. On the other hand, BMI may be a modifiable patient-related factor to consider in the management of exacerbations in MS.

Examining the environmental risk factors of progressive-onset and relapsing-onset multiple sclerosis: recruitment challenges, potential bias, and statistical strategies.

It is unknown whether the currently known risk factors of multiple sclerosis reflect the etiology of progressive-onset multiple sclerosis (POMS) as observational studies rarely included analysis by type of onset. We designed a case-control study to examine associations between environmental factors and POMS and compared effect sizes to relapse-onset MS (ROMS), which will offer insights into the etiology of POMS and potentially contribute to prevention and intervention practice. This study utilizes data from the Primary Progressive Multiple Sclerosis (PPMS) Study and the Australian Multi-center Study of Environment and Immune Function (the AusImmune Study). This report outlines the conduct of the PPMS Study, whether the POMS sample is representative, and the planned analysis methods. The study includes 155 POMS, 204 ROMS, and 558 controls. The distributions of the POMS were largely similar to Australian POMS patients in the MSBase Study, with 54.8% female, 85.8% POMS born before 1970, mean age of onset of 41.44 ± 8.38 years old, and 67.1% living between 28.9 and 39.4° S. The POMS were representative of the Australian POMS population. There are some differences between POMS and ROMS/controls (mean age at interview: POMS 55 years vs. controls 40 years; sex: POMS 53% female vs. controls 78% female; location of residence: 14.3% of POMS at a latitude ≤ 28.9°S vs. 32.8% in controls), which will be taken into account in the analysis. We discuss the methodological issues considered in the study design, including prevalence-incidence bias, cohort effects, interview bias and recall bias, and present strategies to account for it. Associations between exposures of interest and POMS/ROMS will be presented in subsequent publications.

Sedentary behaviour and related factors in people with multiple sclerosis.

BACKGROUND: Sedentary behaviour is a major problem in persons with multiple sclerosis (pwMS). However, little is known about the related factors of sedentary behaviour in MS. Our study aimed to examine the association between sedentary behaviour and physical activity level, fear of falling, and fatigue. METHOD: Demographic and clinical data have been recorded. Sedentary behaviour was assessed with the Marshall Sitting Questionnaire, physical activity level was evaluated with the Godin Leisure Time Exercise Questionnaire, fear of falling was evaluated with the Fall Efficacy Scale International, and fatigue was evaluated with the modified fatigue impact scale (MFIS). The Timed 25-Foot Walk, 6-Minute Walk Test, Timed Up and Go Test, and 12-Item Multiple Sclerosis Walking Scale were also used to assess walking and perceived walking disability. RESULTS: We recruited 71 pwMS [49 were female (69 %), mean age:38.08 years, median EDSS:1.5]. The mean daily sitting time was 593.54 min (∼10 h). No significant correlation was found between sitting times and demographics, leisure time physical activity, fear of falling, walking, perceived walking disability, and neurological disability level (p > 0.05). Logistic regression analysis indicated that being male increased the risk of sedentary behaviour by 3.08 times, being employed increased the risk of sitting by 4.65 times, and each point increase in MFIS scores resulted in a 1.03-fold elevation in the odds of prolonged sitting. CONCLUSION: The fact that pwMS, even with a mild disability spend almost 10 h sitting highlights the significance of sedentary behaviour in this population. Developing strategies to address modifiable factors, such as fatigue, may be effective in reducing sedentary behaviour.

Dual-task difficulties as a risk factor for unemployment in people with multiple sclerosis.

BACKGROUND: No study has investigated the impact of dual-tasking difficulties as a risk factor for unemployment in people with multiple sclerosis (pwMS). The aim was to examine the influence of dual-task performance on employment status and work difficulties and to identify the predictors of employment status in pwMS. METHODS: Eighty-four pwMS, including 42 employed and 42 unemployed, participated in the study. Dual-task difficulties were assessed using the Dual-task Impact on Daily-living Activities-Questionnaire (DIDA-Q), while dual-task performance was evaluated through the 30-second Walk Test and Nine-Hole Peg Test, incorporating a cognitive task. Walking and cognitive function were also measured. RESULTS: Employed pwMS had better scores in walking, cognitive function, single and dual-task performance than unemployed pwMS (p < .05). Lower scores in walking (odds ratio [OR] = 1.81, p < .001) and upper extremity-related (OR = 1.44, p = .019) dual-task performance and higher scores in the cognitive subscale of the DIDA-Q questionnaire (OR = 1.20, p = .037) were significantly associated with higher odds of being unemployed. Among employed pwMS, DIDA-Q subscales showed moderate-to-strong correlations with MSWSDQ-23 scores. The other variables showed weak-to-moderate correlations with subscale and total scores of MSWSDQ-23. CONCLUSION: Cognitive function, as opposed to motor function, has been found to be a significant predictor of unemployment in pwMS.