Smouldering-Associated Worsening in Multiple Sclerosis: An International Consensus Statement on Definition, Biology, Clinical Implications, and Future Directions.

Despite therapeutic suppression of relapses, multiple sclerosis (MS) patients often experience subtle deterioration, which extends beyond the definition of "progression independent of relapsing activity." We propose the concept of smouldering-associated-worsening (SAW), encompassing physical and cognitive symptoms, resulting from smouldering pathological processes, which remain unmet therapeutic targets. We provide a consensus-based framework of possible pathological substrates and manifestations of smouldering MS, and we discuss clinical, radiological, and serum/cerebrospinal fluid biomarkers for potentially monitoring SAW. Finally, we share considerations for optimizing disease surveillance and implications for clinical trials to promote the integration of smouldering MS into routine practice and future research efforts. ANN NEUROL 2024.

Imaging chronic active lesions in multiple sclerosis: a consensus statement.

Chronic active lesions (CAL) are an important manifestation of chronic inflammation in multiple sclerosis and have implications for non-relapsing biological progression. In recent years, the discovery of innovative MRI and PET-derived biomarkers has made it possible to detect CAL, and to some extent quantify them, in the brain of persons with multiple sclerosis, in vivo. Paramagnetic rim lesions on susceptibility-sensitive MRI sequences, MRI-defined slowly expanding lesions on T1-weighted and T2-weighted scans, and 18-kDa translocator protein-positive lesions on PET are promising candidate biomarkers of CAL. While partially overlapping, these biomarkers do not have equivalent sensitivity and specificity to histopathological CAL. Standardization in the use of available imaging measures for CAL identification, quantification and monitoring is lacking. To fast-forward clinical translation of CAL, the North American Imaging in Multiple Sclerosis Cooperative developed a consensus statement, which provides guidance for the radiological definition and measurement of CAL. The proposed manuscript presents this consensus statement, summarizes the multistep process leading to it, and identifies the remaining major gaps in knowledge.

Limited utility of adding 3T cervical spinal cord MRI to monitor disease activity in multiple sclerosis.

BACKGROUND: Performing routine brain magnetic resonance imaging (MRI) is widely accepted as the standard of care for disease monitoring in multiple sclerosis (MS), but the utility of performing routine spinal cord (SC) MRI for this purpose is still debatable. OBJECTIVE: This study aimed to measure the frequency of new isolated cervical spinal cord lesions (CSLs) in people with MS (pwMS) undergoing routine brain and cervical SC-MRI for disease monitoring and determine the factors associated with the development of new CSLs and their prognostic value. METHODS: We retrospectively identified 1576 pwMS who underwent follow-up 3T brain and cervical SC-MRI over a 9-month period. MRI was reviewed for the presence of new brain lesions (BLs) and CSLs. Clinical records were reviewed for interval relapses between sequential scans and subsequent clinical relapse and disability worsening after the follow-up MRI. RESULTS: In 1285 pwMS (median interval: 13-14 months) who were clinically stable with respect to relapses, 73 (5.7%) had new CSLs, of which 49 (3.8%) had concomitant new BLs and 24 (1.9%) had new isolated CSLs only. New asymptomatic CSLs were associated with ⩾ 3 prior relapses (p = 0.04), no disease-modifying therapy (DMT) use (p = 0.048), and ⩾ 3 new BLs (p < 0.001); ⩾ 3 new BLs (OR: 7.11, 95% CI: 4.3-11.7, p < 0.001) remained independently associated with new CSLs on multivariable analysis. Having new asymptomatic CSLs was not independently associated with subsequent relapse or disability worsening after the follow-up MRI (median follow-up time of 26 months). CONCLUSION: Routine brain and cervical SC-MRI detected new isolated CSLs in only < 2% of clinically stable pwMS. Developing new asymptomatic CSLs was associated with concomitant new BLs and did not confer an independent increased risk of relapse or disability worsening. Performing SC-MRI may not be warranted for routine monitoring in most pwMS, and performing only brain MRI may be sufficient to capture the vast majority of clinically silent disease activity.

Plasma glial fibrillary acidic protein levels correlate with paramagnetic rim lesions in people with radiologically isolated syndrome.

BACKGROUND: There are no specific, evidence-based recommendations for the management of individuals with radiologically isolated syndrome. Imaging and blood biomarkers may have prognostic utility. OBJECTIVE: To determine whether plasma neurofilament light protein (NfL) or glial fibrillary acidic protein (GFAP) levels in people with radiologically isolated syndrome correlate with imaging measures that have been shown to be associated with negative clinical outcomes in people with multiple sclerosis. METHODS: Cross-sectional analysis of people with radiologically isolated syndrome. Participants underwent magnetic resonance imaging (MRI) of the brain and cervical spinal cord, and plasma was collected. Plasma NfL and GFAP levels were measured with a single-molecule array, and correlations with MRI measures were assessed, including the number of: T1-black holes, white-matter lesions demonstrating the central vein sign, paramagnetic rim lesions, cervical spinal cord lesions and infratentorial lesions. RESULTS: Plasma GFAP levels, but not NfL levels, showed correlations with the number of T1-black holes, white matter lesions demonstrating the central vein sign and paramagnetic rim lesions (all p < 0.05). CONCLUSION: We found correlations between plasma GFAP levels and imaging measures associated with poor clinical outcomes and chronic inflammation in individuals with radiologically isolated syndrome. Plasma GFAP may have prognostic utility in clinical trials and clinical practice.

Choroid plexus volume differentiates MS from its mimics.

This study aimed to determine whether choroid plexus volume (CPV) could differentiate multiple sclerosis (MS) from its mimics. A secondary analysis of two previously enrolled studies, 50 participants with MS and 64 with alternative diagnoses were included. CPV was automatically segmented from 3T magnetic resonance imaging (MRI), followed by manual review to remove misclassified tissue. Mean normalized choroid plexus volume (nCPV) to intracranial volume demonstrated relatively high specificity for MS participants in each cohort (0.80 and 0.76) with an area under the receiver-operator characteristic curve of 0.71 (95% confidence interval (CI) = 0.55-0.87) and 0.65 (95% CI = 0.52-0.77). In this preliminary study, nCPV differentiated MS from its mimics.

A multicenter pilot study evaluating simplified central vein assessment for the diagnosis of multiple sclerosis.

BACKGROUND: The central vein sign (CVS) is a proposed magnetic resonance imaging (MRI) biomarker for multiple sclerosis (MS); the optimal method for abbreviated CVS scoring is not yet established. OBJECTIVE: The aim of this study was to evaluate the performance of a simplified approach to CVS assessment in a multicenter study of patients being evaluated for suspected MS. METHODS: Adults referred for possible MS to 10 sites were recruited. A post-Gd 3D T2*-weighted MRI sequence (FLAIR*) was obtained in each subject. Trained raters at each site identified up to six CVS-positive lesions per FLAIR* scan. Diagnostic performance of CVS was evaluated for a diagnosis of MS which had been confirmed using the 2017 McDonald criteria at thresholds including three positive lesions (Select-3*) and six positive lesions (Select-6*). Inter-rater reliability assessments were performed. RESULTS: Overall, 78 participants were analyzed; 37 (47%) were diagnosed with MS, and 41 (53%) were not. The mean age of participants was 45 (range: 19-64) years, and most were female (n = 55, 71%). The area under the receiver operating characteristic curve (AUROC) for the simplified counting method was 0.83 (95% CI: 0.73-0.93). Select-3* and Select-6* had sensitivity of 81% and 65% and specificity of 68% and 98%, respectively. Inter-rater agreement was 78% for Select-3* and 83% for Select-6*. CONCLUSION: A simplified method for CVS assessment in patients referred for suspected MS demonstrated good diagnostic performance and inter-rater agreement.

Diagnostic performance of central vein sign versus oligoclonal bands for multiple sclerosis.

BACKGROUND: Cerebrospinal fluid (CSF) oligoclonal bands (OCB) are a diagnostic biomarker in multiple sclerosis (MS). The central vein sign (CVS) is an imaging biomarker for MS that may improve diagnostic accuracy. OBJECTIVES: The objective of the study is to examine the diagnostic performance of simplified CVS methods in comparison to OCB in participants with clinical or radiological suspicion for MS. METHODS: Participants from the CentrAl Vein Sign in MS (CAVS-MS) pilot study with CSF testing were included. Select-3 and Select-6 (counting up to three or six CVS+ lesions per scan) were rated on post-gadolinium FLAIR* images. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value for Select-3, Select-6, OCB, and combinations thereof were calculated for MS diagnosis at baseline and at 12 months. RESULTS: Of 53 participants, 25 were OCB+. At baseline, sensitivity for MS diagnosis was 0.75 for OCB, 0.83 for Select-3, and 0.71 for Select-6. Specificity for MS diagnosis was 0.76 for OCB, 0.48 for Select-3, and 0.86 for Select-6. At 12 months, PPV for MS diagnosis was 0.95 for Select-6 and 1.00 for Select-6 with OCB+ status. DISCUSSION: Results suggest similar diagnostic performance of simplified CVS methods and OCB. Ongoing studies will refine whether CVS could be used in replacement or in conjunction with OCB.

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.

Per- and Polyfluoroalkyl Substances (PFAS) in Serum of 2 to 5 year-Old Children: Temporal Trends, Determinants, and Correlations with Maternal PFAS Concentrations.

Young children may experience higher per- and polyfluoroalkyl substances (PFAS) exposure than adults due to breastfeeding, higher dust ingestion rates, and frequent hand-to-mouth activities. We explored temporal trends and determinants of child serum PFAS concentrations and their correlations with paired maternal PFAS concentrations. From 2009 to 2017, we collected one blood sample from each of 541 children aged 2-5 years participating in the Childhood Autism Risks from Genetics and Environment (CHARGE) study and quantified 14 PFAS in serum. For nine frequently detected PFAS (>65% of samples), we performed multiple regression adjusting for potential determinants to estimate mean percent concentration changes. For a subset of 327 children, we also quantified nine PFAS in their mother's serum collected at the same visit and computed Spearman correlation coefficients (rsp) between maternal and child PFAS concentrations. During 2009-2017, child serum concentrations of all nine PFAS decreased by 6-25% annually. Several PFAS concentrations were higher among non-Hispanic white children and those with highly educated parents. Most maternal and child PFAS concentrations were moderately correlated (rsp = 0.13-0.39), with a strong correlation for N-methyl perfluorooctane sulfonamido acetic acid (rsp = 0.68). Breastfeeding duration appeared to contribute to higher child and lower maternal PFAS concentrations, resulting in relatively weak correlations between maternal and child PFAS concentrations for samples collected in early childhood. Considering that more than half of our study children had neurodevelopmental concerns, the generalizability of our findings might be limited.

Prenatal exposure to per- and polyfluoroalkyl substances and child behavioral problems.

BACKGROUND: Prenatal exposure to per- and polyfluoroalkyl substances (PFAS) may adversely affect child behaviors; however, findings of epidemiologic studies are inconsistent. We examined prenatal PFAS exposure in association with child behavioral problems. METHODS: Participants were 177 mother-child pairs from MARBLES (Markers of Autism Risk in Babies - Learning Early Signs), a cohort with elevated familial likelihood of autism spectrum disorder (ASD). We quantified nine PFAS in maternal serum (1-3 samples per mother) collected from the 1st to 3rd trimesters of pregnancy. Child behavioral problems were assessed at 3 years of age using the Child Behavior Checklist (CBCL), developed to test for various behavioral problems of children. We examined associations of the CBCL scores with individual PFAS concentrations and with their mixture using negative binomial regression and weighted quantile sum regression models. RESULTS: Higher prenatal perfluorononanoate (PFNA) concentrations were associated with higher scores of externalizing problems [ß = 0.16, 95% CI (0.01, 0.32)] and aggressive behavior [ß = 0.17 (0.01, 0.32)]. Higher PFNA, perfluorooctane sulfonate (PFOS), and perfluorodecanoate (PFDA) were associated with higher scores of sleep problems [ß = 0.34 (0.15, 0.54) for PFNA, ß = 0.20 (0.02, 0.37) for PFOS, and ß = 0.19 (0.00, 0.37) for PFDA]. No significant associations observed for typically developing children, whereas PFOS, PFNA, and PFDA were associated with several behavioral problems among children diagnosed with ASD or other neurodevelopmental concerns. Exposure to a mixture of PFAS was associated with higher scores of sleep problems and aggressive behavior, mostly contributed by PFNA and PFDA. CONCLUSIONS: Our study showed that prenatal exposure to some PFAS could increase child behavioral problems at 3 years of age. However, our results should be interpreted with caution because we relied on data from a cohort with increased familial likelihood of ASD and thereby had more behavioral problems.

Gestational exposure to organophosphate esters and autism spectrum disorder and other non-typical development in a cohort with elevated familial likelihood.

BACKGROUND: Gestational exposure to organophosphate esters (OPEs) is known to affect offspring neurodevelopment in animal studies. However, epidemiological evidence is inconsistent. METHODS: Participants were 277 mother-child pairs from MARBLES (Markers of Autism Risk in Babies - Learning Early Signs), a cohort with elevated familial likelihood of autism spectrum disorder (ASD). Nine OPE biomarker concentrations were quantified in maternal urine collected during the 2nd or 3rd trimesters of pregnancy. At age 3 years, children underwent clinical assessment for ASD and were classified into ASD, other non-typical development (non-TD), or typical development (TD). Multinomial logistic regression was used to estimate associations between each OPE biomarker and relative risk ratios for ASD and non-TD compared to TD. We examined effect modification by child sex and socioeconomic status. We also conducted a secondary analysis by using a continuous measure of ASD symptom severity as an outcome. Quantile-based g-computation was performed to examine the associations for an OPE mixture. RESULTS: Overall, no significant association was observed between the concentrations of each OPE biomarker or their mixture and relative risk for either ASD or non-TD. Effect modifications by child sex and maternal education were not observed. When the analysis was stratified by homeownership, among non-homeowners, ASD likelihood was increased with increased levels of bis(1-chloro-2-propyl) phosphate, bis(butoxyethyl) phosphate, and sum of di-n-butyl phosphate and di-iso-butyl phosphate (DBUP/DIBP) (pint < 0.10). Higher DBUP/DIBP were associated with increased ASD symptom severity scores. CONCLUSION: There was no clear evidence of gestational OPE exposure in association with relative risk for ASD; however, potential effect modification by homeownership was observed. Although our cohort includes children with elevated familial likelihood of ASD, this is the first study investigating the association between gestational OPE exposure and clinically-diagnosed ASD. Further research is needed to confirm our findings in the general population.

Early childhood exposure to environmental phenols and parabens, phthalates, organophosphate pesticides, and trace elements in association with attention deficit hyperactivity disorder (ADHD) symptoms in the CHARGE study.

BACKGROUND: A growing body of literature investigated childhood exposure to environmental chemicals in association with attention-deficit/hyperactivity disorder (ADHD) symptoms, but limited studies considered urinary mixtures of multiple chemical classes. This study examined associations of concurrent exposure to non-persistent chemicals with ADHD symptoms in children diagnosed with autism spectrum disorder (ASD), developmental delay (DD), and typical development (TD). METHODS: A total of 549 children aged 2-5 years from the Childhood Autism Risks from Genetics and Environment (CHARGE) case-control study were administered the Aberrant Behavior Checklist (ABC). This study focused on the ADHD/noncompliance subscale and its two subdomains (hyperactivity/impulsivity, inattention). Sixty-two chemicals from four classes (phenols/parabens, phthalates, organophosphate pesticides, trace elements) were quantified in child urine samples, and 43 chemicals detected in > 70% samples were used to investigate their associations with ADHD symptoms. Negative binomial regression was used for single-chemical analysis, and weighted quantile sum regression with repeated holdout validation was applied for mixture analysis for each chemical class and all chemicals. The mixture analyses were further stratified by diagnostic group. RESULTS: A phthalate metabolite mixture was associated with higher ADHD/noncompliance scores (median count ratio [CR] = 1.10; 2.5th, 97.5th percentile: 1.00, 1.21), especially hyperactivity/impulsivity (median CR = 1.09; 2.5th, 97.5th percentile: 1.00, 1.25). The possible contributors to these mixture effects were di-2-ethylhexyl phthalate (DEHP) metabolites and mono-2-heptyl phthalate (MHPP). These associations were likely driven by children with ASD as these were observed among children with ASD, but not among TD or those with DD. Additionally, among children with ASD, a mixture of all chemicals was associated with ADHD/noncompliance and hyperactivity/impulsivity, and possible contributors were 3,4-dihydroxy benzoic acid, DEHP metabolites, MHPP, mono-n-butyl phthalate, and cadmium. CONCLUSIONS: Early childhood exposure to a phthalate mixture was associated with ADHD symptoms, particularly among children with ASD. While the diverse diagnostic profiles limited generalizability, our findings suggest a potential link between phthalate exposure and the comorbidity of ASD and ADHD.

Transport Mechanism for Nuclear Localization of Irradiation-Activated EGFR Measured by Single-Molecule Pull-Down Assay.

Nuclear transport of epidermal growth factor receptor (EGFR) is considered to be a key cause of radiation resistance in cancer therapy. Here, we showed that irradiation-activated EGFR binds to the nuclear transport protein karyopherin alpha (KPNA) rather than karyopherin subunit beta 1 (KPNB1), through a single-molecule pull-down assay, which allows measurement of the binding affinity by single proteins in cell lysate without an additional purification step. We also obtained kinetic parameters for the binding between the phosphorylated nuclear localization signal (NLS) peptide of EGFR (645RRRHIVRKRpTLRR657) and KPNA. This observation may help developing small molecules to modulate nuclear transport, which potentially reduces the radiation resistance during irradiation therapy.

Prenatal Exposure to Per- and Polyfluoroalkyl Substances and Childhood Autism-related Outcomes.

BACKGROUND: Epidemiologic evidence linking prenatal exposure to per- and polyfluoroalkyl substances (PFAS) with altered neurodevelopment is inconclusive, and few large studies have focused on autism-related outcomes. We investigated whether blood concentrations of PFAS in pregnancy are associated with child autism-related outcomes. METHODS: We included 10 cohorts from the National Institutes of Health (NIH)-funded Environmental influences on Child Health Outcomes (ECHO) program (n = 1,429). We measured 14 PFAS analytes in maternal blood collected during pregnancy; eight analytes met detection criteria for analysis. We assessed quantitative autism-related traits in children via parent report on the Social Responsiveness Scale (SRS). In multivariable linear models, we examined relationships of each PFAS (natural log-transformed) with SRS scores. We further modeled PFAS as a complex mixture using Bayesian methods and examined modification of these relationships by child sex. RESULTS: Most PFAS in maternal blood were not associated with child SRS T-scores. Perfluorononanoic acid (PFNA) showed the strongest and most consistent association: each 1-unit increase in ln-transformed PFNA was associated with greater autism-related traits (adjusted ß [95% confidence interval (CI)] = 1.5 [-0.1, 3.0]). The summed mixture, which included six PFAS detected in >70% of participants, was not associated with SRS T-scores (adjusted ß [95% highest posterior density interval] = 0.7 [-1.4, 3.0]). We did not observe consistent evidence of sex differences. CONCLUSIONS: Prenatal blood concentrations of PFNA may be associated with modest increases in child autism-related traits. Future work should continue to examine the relationship between exposures to both legacy and emerging PFAS and additional dimensional, quantitative measures of childhood autism-related outcomes.

Incidence and predictors of demyelinating disease in spondyloarthritis: data from a longitudinal cohort study.

OBJECTIVES: To investigate the incidence of demyelinating disease (DD) among spondyloarthritis (SpA) patients and identify risk factors that predict DD in this patient population. METHODS: Axial SpA (axSpA) and psoriatic arthritis (PsA) patients were identified from a longitudinal cohort database. Each group was analysed according to the presence or absence of DD. Incidence rates (IR) of DD were obtained with competing risk analysis. Cox regression analysis with Fine and Grey's method was used to evaluate predictors of DD development. RESULTS: Among 2260 patients with follow-up data, we identified 18 DD events corresponding to an average IR of 31 per 100 000 persons per year for SpA. The IR of DD at 20 years was higher in axSpA than in PsA (1.30% vs 0.13%, p= 0.01). The risk factors retained in the best predictive model for DD development included ever- (versus never-) smoking (HR 2.918, 95% CI 1.037-8.214, p= 0.0426), axSpA (versus PsA) (HR 8.790, 95% CI 1.242-62.182, p= 0.0294), and presence (versus absence) of IBD (HR 5.698, 95% CI 2.083-15.589, p= 0.0007). History of TNFi therapy was not a predictor of DD. CONCLUSION: The overall incidence of DD in this SpA cohort was low. Incident DD was higher in axSpA than in PsA. A diagnosis of axSpA, the presence of IBD, and ever-smoking predicted the development of DD. History of TNFi use was not found to be a predictor of DD in this cohort.

Employment status, productivity loss, and associated factors among people with multiple sclerosis.

BACKGROUND: Multiple Sclerosis (MS) affects people in their most productive years of life. Consequently, MS can substantially affect employment and work-related outcomes. OBJECTIVES: This study characterizes productivity loss and employment status of people with multiple sclerosis (pwMS) and investigates associated factors. METHODS: We used baseline data collected as part of the Canadian Prospective Cohort Study to Understand Progression in Multiple Sclerosis (CanProCo). Using the Valuation of Lost Productivity questionnaire, we measured MS-related paid work productivity loss for those employed, productivity losses incurred by those unemployed (i.e. lost employment time), and unpaid work productivity losses for all. A set of sociodemographic, disease, and performance-related factors were investigated using a two-part regression model for productivity loss and a multinomial logistic model for employment status. RESULTS: From the cohort of 888 pwMS enrolled at baseline (mostly showing mild to moderate disability), 75% were employed, and of those unemployed, 69% attributed their unemployment to health-related issues. Total productivity loss over a 3-month period averaged 64 and 395 hours for those employed and unemployed, respectively. Some factors that affected productivity loss and employment status included use of disease-modifying therapies, fatigue, and performance indicators such as cognitive processing speed. CONCLUSION: Productivity loss experienced by employed and unemployed pwMS is substantial. Targeting the identified modifiable factors is likely to improve work productivity and permanence of MS patients in the workforce.

Should trigeminal neuralgia be considered a clinically isolated syndrome?

The association between trigeminal neuralgia (TN) and multiple sclerosis (MS) is well established. Many MS patients with TN have magnetic resonance imaging (MRI) evidence of a symptomatic demyelinating lesion. Although infratentorial presentations are included in the diagnostic criteria for MS, there remains confusion in clinical practice as to whether TN should be considered a clinically isolated syndrome for the application of McDonald criteria. In this case series, we discuss this diagnostic quandary in patients presenting with TN and additional MRI findings suggestive of MS and highlight the unmet need for data in such patients to optimally guide their care.

Prediction of relapse activity when switching to cladribine for multiple sclerosis.

BACKGROUND: Patients with relapsing-remitting multiple sclerosis commonly switch between disease-modifying therapies (DMTs). Identifying predictors of relapse when switching could improve outcomes. OBJECTIVE: To determine predictors of relapse hazard when switching to cladribine. METHODS: Data of patients who switched to cladribine, grouped by prior disease-modifying therapy (pDMT; interferon-ß/glatiramer acetate, dimethyl fumarate, teriflunomide, fingolimod or natalizumab (NTZ)), were extracted from the MSBase Registry. Predictors of relapse hazard during the treatment gap and the first year of cladribine therapy were determined. RESULTS: Of 513 patients, 22 relapsed during the treatment gap, and 38 within 1 year of starting cladribine. Relapse in the year before pDMT cessation predicted treatment gap relapse hazard (hazard ratio (HR) = 2.43, 95% confidence interval (CI) = 1.03-5.71). After multivariable adjustment, relapse hazard on cladribine was predicted by relapse before pDMT cessation (HR = 2.00, 95% CI = 1.01-4.02), treatment gap relapse (HR = 6.18, 95% confidence interval (CI) = 2.65-14.41), switch from NTZ (HR compared to injectable therapies 4.08, 95% CI = 1.35-12.33) and age at cladribine start (HR = 0.96, 95% CI = 0.91-0.99). CONCLUSION: Relapse during or prior to the treatment gap, and younger age, are of prognostic relevance in the year after switching to cladribine. Switching from NTZ is also independently associated with greater relapse hazard.

Diroximel fumarate in patients with relapsing-remitting multiple sclerosis: Final safety and efficacy results from the phase 3 EVOLVE-MS-1 study.

BACKGROUND: Diroximel fumarate (DRF) is approved for adults with relapsing-remitting multiple sclerosis (RRMS) in Europe and for relapsing forms of MS in the United States. DRF and dimethyl fumarate (DMF) yield bioequivalent exposure of the active metabolite monomethyl fumarate. Prior studies indicated fewer gastrointestinal (GI)-related adverse events (AEs) with DRF compared with DMF. OBJECTIVE: To report final outcomes from EVOLVE-MS-1. METHODS: EVOLVE-MS-1 was an open-label, 96-week, phase 3 study assessing DRF safety, tolerability, and efficacy in patients with RRMS. The primary endpoint was safety and tolerability; efficacy endpoints were exploratory. RESULTS: Overall, 75.7% (800/1057) of patients completed the study; median exposure was 1.8 (range: 0.0-2.0) years. AEs occurred in 938 (88.7%) patients, mostly of mild (28.9%) or moderate (50.3%) severity. DRF was discontinued due to AEs in 85 (8.0%) patients, with < 2% discontinuing due to GI or flushing/flushing-related AEs. At Week 96, mean number of gadolinium-enhancing lesions was significantly reduced from baseline (72.7%; p < 0.0001); adjusted annualized relapse rate was 0.13 (95% confidence interval: 0.11-0.15). CONCLUSION: DRF was generally well tolerated over 2 years, with few discontinuations due to AEs; radiological measures indicated decreased disease activity from baseline. These outcomes support DRF as a treatment option in patients with RRMS.

Comparative effectiveness of cladribine tablets versus other oral disease-modifying treatments for multiple sclerosis: Results from MSBase registry.

BACKGROUND: Effectiveness of cladribine tablets, an oral disease-modifying treatment (DMT) for multiple sclerosis (MS), was established in clinical trials and confirmed with real-world experience. OBJECTIVES: Use real-world data to compare treatment patterns and clinical outcomes in people with MS (pwMS) treated with cladribine tablets versus other oral DMTs. METHODS: Retrospective treatment comparisons were based on data from the international MSBase registry. Eligible pwMS started treatment with cladribine, fingolimod, dimethyl fumarate, or teriflunomide tablets from 2018 to mid-2021 and were censored at treatment discontinuation/switch, death, loss to follow-up, pregnancy, or study period end. Treatment persistence was evaluated as time to discontinuation/switch; relapse outcomes included time to first relapse and annualized relapse rate (ARR). RESULTS: Cohorts included 633 pwMS receiving cladribine tablets, 1195 receiving fingolimod, 912 receiving dimethyl fumarate, and 735 receiving teriflunomide. Individuals treated with fingolimod, dimethyl fumarate, or teriflunomide switched treatment significantly more quickly than matched cladribine tablet cohorts (adjusted hazard ratio (95% confidence interval): 4.00 (2.54-6.32), 7.04 (4.16-11.93), and 6.52 (3.79-11.22), respectively). Cladribine tablet cohorts had significantly longer time-to-treatment discontinuation, time to first relapse, and lower ARR, compared with other oral DMT cohorts. CONCLUSION: Cladribine tablets were associated with a significantly greater real-world treatment persistence and more favorable relapse outcomes than all oral DMT comparators.