Long-term Disability Progression Research Articles

How Long-Term Disability Progression Is Different in Neuromyelitis Optica and Myelin Oligodendrocyte Glycoprotein-antibody Associated Disease

How Long-Term Disability Progression Is Different in Neuromyelitis Optica and Myelin Oligodendrocyte Glycoprotein-antibody Associated Disease

Early Clinical Predictors of Long-term Disability Progression in Patients with Multiple Sclerosis

Background: One of the unmet therapeutic needs in the treatment of multiple sclerosis (MS) is to prevent the accumulation of irreversible disability. Formulating standardized predictors of conversion in the secondary progressive phase of the relapsing-remitting MS (RRMS) should be a step toward solving this problem. Objective: To develop a reliable score, a predictor of physical disability worsening and secondary progression in patients with RRMS. Materials and Methods: Seventy-four patients with RRMS were observed retrospectively for 15 years. Clinical and demographic parameters were analyzed with respect to the time of reaching Expanded Disability Status Scale (EDSS) 4 and/or EDSS 6, as well as EDSS at the end of 15 years. Results: Almost half of the patients observed (47%) reached irreversible disability (EDSS ≥4.0) and ¼ developed secondary progression (EDSS 6.0). The statistically significant variables selected were age at onset of MS, sex, type (afferent, efferent, and combined), and number of symptoms during the first and second attacks. Based on this selection, a predictive score for the course of the disease was formed. It has a sensitivity of 86%, specificity of 89%, positive predictive value of 85%, and negative predictive value of 81%. Conclusion: The proposed predictive score can be applied as a complementary tool in the choice of appropriate therapeutic approach at the early stages of MS, which can help avoid disability overtime.

Beliefs about Medicines and the Level of Intentional Non-Adherence to Treatment among Patients with Multiple Sclerosis Treated with First-Line Drugs.

Multiple sclerosis (MS) is a chronic inflammatory, demyelinating and neurodegenerative disease of the central nervous system. MS has no curable disease but drug modifying therapy (DMT) can delay the long-term disability progression of the disease. The effectiveness of MS treatment depends on the patient's adherence to therapy. This study evaluated the level of intentional non-adherence and the relationship between beliefs about medication and the level of intentional non-adherence to treatment of patients with multiple sclerosis. A group of 146 patients with relapsing-remitting MS were included. To assess different aspect of adherence, the Intentional Non-Adherence Scale (INAS) was used. For evaluating patients' beliefs and opinions regarding medication, the Beliefs about Medicines Questionnaire (BMQ) was used. The mean total INAS score was 51.41 ± 27.83 points. Patients were most concerned about the necessity to take medication and least concerned about the harm caused by medication. The overuse and harm domains of the BMQ were significantly correlated with INAS scores (p < 0.05). Independent determinant of intentional non-adherence was overuse.

Prevalence and prognostic value of prodromal symptoms in relapsing-remitting multiple sclerosis.

Several studies have suggested the possibility that disease prodromes might occur months or even years before a multiple sclerosis diagnosis. To describe the profile of prodromal symptoms and the possible relationship between the occurrence of individual symptoms and clinical course characteristics in patients with relapsing-remitting multiple sclerosis (RRMS), and to assess their role as predictors of further disease course. The cohort included 564 patients with RRMS. Patients were stratified based on their current EDSS score, and the annual EDSS growth rate was calculated. Logistic Regression Analysis was used to study the relationship between prodromal symptoms and disease progression. The most commonly reported prodromal symptom was fatigue (42%). The following symptoms were significantly more common in women than in men: headache (39.7% vs. 26.5%, p < 0.05), excessive sleepiness (19.1% vs. 11.1%, p < 0.05) and constipation (18.0% vs. 11.1%, p < 0.05). Prodromal urinary and cognitive disturbances, fatigue and pain complaints were significantly more common in patients with the highest annual EDSS increase (p < 0.05). Multivariate analysis revealed some potential predictors of long-term disability progression: hesitancy in starting urination predicted EDSS increase by 0.6 point (p < 0.05), while deterioration in everyday functioning because of cognitive disturbances, and pain complaints, were associated with an EDSS increase of 0.5 (p < 0.05), and 0.4 (p < 0.05), respectively. Prodromal pain, urinary and cognitive complaints (especially when these lead to deterioration of everyday functioning) were associated with a higher EDSS increase rate, and may thus be regarded as possible predictors of worse clinical outcomes in RRMS patients.

Parity is associated with long-term differences in DNA methylation at genes related to neural plasticity in multiple sclerosis

BackgroundPregnancy in women with multiple sclerosis (wwMS) is associated with a reduction of long-term disability progression. The mechanism that drives this effect is unknown, but converging evidence suggests a role for epigenetic mechanisms altering immune and/or central nervous system function. In this study, we aimed to identify whole blood and immune cell-specific DNA methylation patterns associated with parity in relapse-onset MS.ResultsWe investigated the association between whole blood and immune cell-type-specific genome-wide methylation patterns and parity in 192 women with relapse-onset MS, matched for age and disease severity. The median time from last pregnancy to blood collection was 16.7 years (range = 1.5–44.4 years). We identified 2965 differentially methylated positions in whole blood, 68.5% of which were hypermethylated in parous women; together with two differentially methylated regions on Chromosomes 17 and 19 which mapped to TMC8 and ZNF577, respectively. Our findings validated 22 DMPs and 366 differentially methylated genes from existing literature on epigenetic changes associated with parity in wwMS. Differentially methylated genes in whole blood were enriched in neuronal structure and growth-related pathways. Immune cell-type-specific analysis using cell-type proportion estimates from statistical deconvolution of whole blood revealed further differential methylation in T cells specifically (four in CD4+ and eight in CD8+ T cells). We further identified reduced methylation age acceleration in parous women, demonstrating slower biological aging compared to nulligravida women.ConclusionDifferential methylation at genes related to neural plasticity offers a potential molecular mechanism driving the long-term effect of pregnancy on MS outcomes. Our results point to a potential ‘CNS signature’ of methylation in peripheral immune cells, as previously described in relation to MS progression, induced by parity. As the first epigenome-wide association study of parity in wwMS reported, validation studies are needed to confirm our findings.

HLA-DRB1*1501 influences long-term disability progression and tissue damage on MRI in relapse-onset multiple sclerosis

Background: Whether genetic factors influence the long-term course of multiple sclerosis (MS) is unresolved. Objective: To determine the influence of HLA-DRB1*1501 on long-term disease course in a homogeneous cohort of clinically isolated syndrome (CIS) patients. Methods: One hundred seven patients underwent clinical and MRI assessment at the time of CIS and after 1, 3, 5 and 15 years. HLA-DRB1*1501 status was determined using Sanger sequencing and tagging of the rs3135388 polymorphism. Linear/Poisson mixed-effects models were used to investigate rates of change in EDSS and MRI measures based on HLA-DRB1*1501 status. Results: HLA-DRB1*1501 -positive (n = 52) patients showed a faster rate of disability worsening compared with the HLA-DRB1*1501 -negative (n = 55) patients (annualised change in EDSS 0.14/year vs. 0.08/year, p < 0.025), and a greater annualised change in T2 lesion volume (adjusted difference 0.45 mL/year, p < 0.025), a higher number of gadolinium-enhancing lesions, and a faster rate of brain (adjusted difference −0.12%/year, p < 0.05) and spinal cord atrophy (adjusted difference −0.22 mm2/year, p < 0.05). Interpretation: These findings provide evidence that the HLA-DRB1*1501 allele plays a role in MS severity, as measured by long-term disability worsening and a greater extent of inflammatory disease activity and tissue loss. HLA-DRB1*1501 may provide useful information when considering prognosis and treatment decisions in early relapse-onset MS.

Association of NEDA-4 With No Long-term Disability Progression in Multiple Sclerosis and Comparison With NEDA-3: A Systematic Review and Meta-analysis.

Background and ObjectivesNo evidence of disease activity (NEDA)-4 has been suggested as a treatment target for disease-modifying therapy (DMT) in relapsing-remitting multiple sclerosis (RRMS). However, the ability of NEDA-4 to discriminate long-term outcomes in MS and how its performance compares with NEDA-3 remain uncertain. We conducted a systematic review and meta-analysis to evaluate (1) the association between NEDA-4 and no long-term disability progression in MS and (2) the comparative performance of NEDA-3 and NEDA-4 in predicting no long-term disability progression.MethodsEnglish-language abstracts and manuscripts were systematically searched in MEDLINE, Embase, and the Cochrane databases from January 2006 to November 2021 and reviewed independently by 2 investigators. We selected studies that assessed NEDA-4 at 1 or 2 years after DMT start and had at least 4 years of follow-up for determination of no confirmed disability progression. We conducted a meta-analysis using random-effects model to determine the pooled odds ratio (OR) for no disability progression with NEDA-4 vs EDA-4. For the comparative analysis, we selected studies that evaluated both NEDA-3 and NEDA-4 with at least 4 years of follow-up and examined the difference in the association of NEDA-3 and NEDA-4 with no disability progression.ResultsFive studies of 1,000 patients (3 interferon beta and 2 fingolimod) met inclusion criteria for both objectives. The median duration of follow-up was 6 years (interquartile range: 4–6 years). The prevalence of NEDA-4 ranged from 4.2% to 13.9% on interferon beta therapy and 24.9% to 25.1% on fingolimod therapy. The pooled OR for no long-term confirmed disability progression with NEDA-4 vs EDA-4 was 2.14 (95% confidence interval: 1.36–3.37; I2 = 0). We did not observe any significant difference between NEDA-4 and NEDA-3 in the comparative analyses.DiscussionIn patients with RRMS, NEDA-4 at 1–2 years was associated with 2 times higher odds of no long-term disability progression, at 6 years compared with EDA-4, but offered no advantage over NEDA-3.

Recurrent disability progression endpoints in multiple sclerosis clinical trials

Background: The current standard endpoint to assess disability accumulation in multiple sclerosis (MS) clinical trials is the time to the first confirmed disability progression, which excludes subsequent progression events. Including recurrent progression events may permit a more comprehensive assessment of treatment effects on disability progression. Objective: To propose a definition of recurrent disability progression events and to compare time-to-first and recurrent event analysis. Methods: Recurrent disability progression events were defined by expanding the recommended first event definition. Marginal recurrent event methods (negative binomial model, Lin–Wei–Yang–Ying model) were compared with Cox regression in data from three randomized controlled trials in relapsing multiple sclerosis (RMS) and primary progressive multiple sclerosis (PPMS), and in simulated randomized controlled trial data. Results: The recurrent event analyses included a substantially larger number of progression events compared with the time-to-first-event analyses (+7.5% and +9.9% in the RMS trials and +22.7% in the PPMS trial). The increase in the number of events resulted in more precise treatment effect estimates and a corresponding gain in statistical power. Conclusion: Our results support the use of recurrent event data analysis, especially in progressive MS trials, to improve estimates of treatment effects, increase statistical power, and better capture the clinically meaningful long-term disability progression experience.

Assessment of T2 lesion-based disease activity volume outcomes in predicting disease progression in multiple sclerosis over 10 years

BackgroundNew/enlarging T2 lesion count and T2-lesion volume (LV) are used as conventional secondary endpoints in clinical trials of patients with multiple sclerosis (PwMS). However, those outcomes may have several limitations, such as inability to account for heterogeneity of lesion formation/enlargement frequency and their dynamic volumetric behavior. Measurement of volume rather than count of new/enlarging lesions may be more representative outcome of dynamic changes over time. ObjectivesTo investigate whether new/enlarging T2-LV is more predictive of confirmed disability progression (CDP), compared to total T2-LV or new/enlarging T2 lesion count over long-term follow-up. MethodsWe studied 176 early relapsing-remitting PwMS who were followed with annual MRI examinations over 10 years. T2-LV, new/enlarging T2-LV, and new/enlarging lesion count were determined. Cumulative count/volumes were obtained. 10-year CDP was confirmed after 48-weeks. ANCOVA analysis detected MRI outcome differences in stable (n = 76) and CDP (n = 100) groups at different time points, after correction for multiple comparisons. ResultsPwMS with CDP had greater cumulative new/enlarging T2-LV at 4 years (p = 0.049), and enlarging T2-LV at 4- (p = 0.039) and 6-year follow-up (p = 0.032), compared to stable patients. PwMS with CDP did not differ from stable ones in new/enlarging T2 lesion count or total T2-LV at any of the study timepoints. PwMS with Expanded Disability Status Scale change >2.0 had significantly greater enlarging T2 lesion count (p = 0.01) and enlarging T2-LV (p = 0.038) over the 10-year follow-up. ConclusionEnlargement of T2 lesions is more strongly associated with long-term disability progression compared to other conventional T2 lesion-based outcomes.

The Effect of Smoking on Long-term Gray Matter Atrophy and Clinical Disability in Patients with Relapsing-Remitting Multiple Sclerosis.

Background and ObjectivesThe relationship between smoking, long-term brain atrophy, and clinical disability in patients with multiple sclerosis (MS) is unclear. Here, we assessed long-term effects of smoking by evaluating MRI and clinical outcome measures after 10 years in smoking and nonsmoking patients with relapsing-remitting MS (RRMS).MethodsWe included 85 treatment-naive patients with RRMS with recent inflammatory disease activity who participated in a 10-year follow-up visit after a multicenter clinical trial of 24 months. Smoking status was decided for each patient by 2 separate definitions: by serum cotinine levels measured regularly for the first 2 years of the follow-up (during the clinical trial) and by retrospective patient self-reporting. At the 10-year follow-up visit, clinical tests were repeated, and brain atrophy measures were obtained from MRI using FreeSurfer. Differences in clinical and MRI measurements at the 10-year follow-up between smokers and nonsmokers were investigated by 2-sample t tests or Mann-Whitney tests and linear mixed-effect regression models. All analyses were conducted separately for each definition of smoking status.ResultsAfter 10 years, smoking (defined by serum cotinine levels) was associated with lower total white matter volume (β = −21.74, p = 0.039) and higher logT2 lesion volume (β = 0.22, p = 0.011). When defining smoking status by patient self-reporting, the repeated analyses found an additional association with lower deep gray matter volume (β = −2.35, p = 0.049), and smoking was also associated with a higher score (higher walking impairment) on the log timed 25-foot walk test (β = 0.050, p = 0.039) after 10 years and a larger decrease in paced auditory serial addition test (attention) scores (β = −3.58, p = 0.029).DiscussionSmoking was associated with brain atrophy and disability progression 10 years later in patients with RRMS. The findings imply that patients should be advised and offered aid in smoking cessation shortly after diagnosis, to prevent long-term disability progression.

Retinal layer thinning as a biomarker of long-term disability progression in multiple sclerosis

Background: Peripapillary retinal nerve fibre layer and macular ganglion cell plus inner plexiform layer thinning are markers of neuroaxonal degeneration in multiple sclerosis. Objective: We aimed to investigate the value of peripapillary retinal nerve fibre layer and ganglion cell plus inner plexiform layer thinning for prediction of long-term disability. Methods: This is a 6-year prospective longitudinal study on 93 multiple sclerosis patients. Optical coherence tomography scans were performed at baseline, after 1, 2 and 6 years. Primary endpoint was disability progression after 6 years, defined as expanded disability status scale worsening and/or cognitive deterioration. Univariate and multivariate analysis was used to investigate the value of peripapillary retinal nerve fibre layer and ganglion cell plus inner plexiform layer to predict the primary endpoint. Results: A total of 57 (61.3%) patients had disability worsening, 40 (43.0%) expanded disability status scale worsening and 34 (36.6%) cognitive deterioration. Mean peripapillary retinal nerve fibre layer and ganglion cell plus inner plexiform layer baseline thickness were 93.0 and 75.2 µm, and mean annualised peripapillary retinal nerve fibre layer and ganglion cell plus inner plexiform layer thinning rates over 6 years were 1.3 and 1.6 µm, respectively. Univariate and multivariate analysis revealed lower peripapillary retinal nerve fibre layer and ganglion cell plus inner plexiform layer baseline thickness and higher annualised thinning rates in patients with disability progression after 6 years. Effects were more pronounced for ganglion cell plus inner plexiform layer and expanded disability status scale worsening than for peripapillary retinal nerve fibre layer models and cognitive deterioration. Conclusion: Ganglion cell plus inner plexiform layer and peripapillary retinal nerve fibre layer measurements depict neurodegeneration and predict disability progression in multiple sclerosis.

Serum neurofilament light chain levels predict long-term disability progression in patients with progressive multiple sclerosis

ObjectiveThere is a lack of sensitive and specific biomarkers for use in progressive multiple sclerosis (MS). The study aimed to assess the potential of serum neurofilament light chain (sNfL) levels...

Association of No Evidence of Disease Activity With No Long-term Disability Progression in Multiple Sclerosis: A Systematic Review and Meta-analysis.

We conducted a systematic review and meta-analysis to evaluate the relationship between no evidence of disease activity (NEDA) and no long-term disability progression on low- and high-efficacy therapy in relapsing-remitting multiple sclerosis (RRMS). MEDLINE, Embase, and the Cochrane Database were searched from January 1, 2006, to January 26, 2021. We selected studies that evaluated NEDA-3 (no relapse, new MRI lesion, or confirmed disability progression) at 1 or 2 years and had a minimum of 4 years of follow-up for determination of disability progression. Data were extracted by 2 independent reviewers and were meta-analyzed with a random-effects model. Primary outcome of no disability progression was defined as no confirmed progression on the Expanded Disability Status Scale during follow-up. We assessed the odds ratio (OR) for no disability progression with NEDA vs evidence of disease activity (EDA). Positive predictive value (PPV) of NEDA for no disability progression was summarized for studies with prevalence of no progression >80% vs ≤80% separately. We included 29 studies in our qualitative synthesis, of which 27 (16 low efficacy, 11 high efficacy) were included in the meta-analysis (N = 10,935 participants). Median follow-up was 5.6 years (interquartile range 4.3-8.0 years). The pooled ORs for no progression with NEDA-3 vs EDA were 2.32 (95% CI 1.58-3.42; I 2 = 73%) for low-efficacy therapy and 3.19 (95% CI 1.86-5.47; I 2 = 86%) for high-efficacy therapy. Among studies with prevalence of no progression at follow-up >80%, the pooled PPV for low efficacy therapy was 91% (95% CI 89%-93%) and for high-efficacy therapy was 92% (95% CI 88%-94%). Among studies with prevalence of no progression ≤80%, the pooled PPV for low-efficacy therapy was 81% (95% CI 75%-86%) and for high-efficacy therapy was 86% (95% CI 80%-90%). NEDA-3 is associated with no long-term disability progression in RRMS on both low- and high-efficacy therapies. Further studies of early composite outcome measures incorporating easily measurable biomarkers and longer follow-up may help to improve the prognostic value of NEDA-3 in RRMS. International Prospective Register of Systematic Reviews Identifier: CRD42020189316.

Slowly Expanding Lesions Predict 9-Year Multiple Sclerosis Disease Progression.

Background and ObjectivesChronic active lesions contribute to multiple sclerosis (MS) severity, but their association with long-term disease progression has not been evaluated yet. White matter (WM) lesions showing linear expansion over time on serial T1- and T2-weighted scans (i.e., slowly expanding lesions [SELs]) have been proposed as a marker of chronic inflammation. In this study, we assessed whether SEL burden and microstructural abnormalities were associated with Expanded Disability Status Scale (EDSS) score worsening and secondary progressive (SP) conversion at 9.1-year follow-up in patients with relapsing-remitting (RR) MS.MethodsIn 52 patients with RRMS, SELs were identified among WM lesions by linearly fitting the Jacobian of the nonlinear deformation field between time points obtained combining 3T brain T1- and T2-weighted scans acquired at baseline and months 6, 12, and 24. Logistic regression analysis was applied to investigate the associations of SEL number, volume, magnetization transfer ratio (MTR), and T1-weighted signal intensity with disability worsening (i.e., EDSS score increase) and SP conversion after a median follow-up of 9.1 years.ResultsAt follow-up, 20/52 (38%) patients with MS showed EDSS score worsening; 13/52 (25%) showed SP conversion. A higher baseline EDSS score (for each point higher: OR = 3.15 [95% CI = 1.61; 8.38], p = 0.003), a higher proportion of SELs among baseline lesions (for each % increase: OR = 1.22 [1.04; 1.58], p = 0.04), and lower baseline MTR values of SELs (for each % higher: OR = 0.66 [0.41; 0.92], p = 0.033) were significant independent predictors of EDSS score worsening at follow-up (C-index = 0.892). A higher baseline EDSS score (for each point higher: OR = 6.37 [1.98; 20.53], p = 0.002) and lower baseline MTR values of SELs (for each % higher: OR = 0.48 [0.25; 0.89], p = 0.02) independently predicted SPMS conversion (C-index = 0.947).DiscussionThe proportion of SELs is associated with MS progression after 9 years. More severe SEL microstructural abnormalities independently predict EDSS score worsening and SPMS conversion. The quantification of SEL burden and damage using T1-, T2-weighted, and MTR sequences may identify patients with RRMS at a higher risk of long-term disability progression and SPMS conversion.Classification of EvidenceThis study provides Class III evidence that in patients with RRMS starting treatment with natalizumab or fingolimod, the proportion of SELs on brain MRI was associated with EDSS score worsening and SPMS conversion at 9-year follow-up.

Long-term disability progression in childhood and adolescent onset multiple sclerosis patients

Early onset pediatric multiple sclerosis (MS) is extremely rare, occurring in 0.2–0.6% of all MS cases. The aim of this study is to describe and compare disease course and prognosis of early and late (ie, disease onset before and after age 11 years) onset pediatric MS.

CSF Chitinase 3-Like 2 Is Associated With Long-term Disability Progression in Patients With Progressive Multiple Sclerosis.

ObjectiveThis study aimed to identify long-term prognostic protein biomarkers associated with disease progression in patients with progressive multiple sclerosis (MS).MethodsCSF samples were collected from a discovery cohort of 28 patients with progressive MS who participated in a clinical trial with interferon beta. Patients were classified into high and low disability progression phenotypes according to numeric progression rates (NPR) and step-based progression rates (SPR) after a mean follow-up time of 12 years. Protein abundance was measured by shotgun proteomics. Selected proteins from the discovery cohort were quantified by parallel reaction monitoring in CSF samples from an independent validation cohort of 41 patients with progressive MS classified also into high and low disability progression phenotypes after a mean follow-up time of 7 years.ResultsOf 2,548 CSF proteins identified in the discovery cohort, 10 were selected for validation based on their association with long-term disability progression: SPATS2-like protein, chitinase 3–like 2 (CHI3L2), plasma serine protease inhibitor, metallothionein-3, phospholipase D4, beta-hexosaminidase, neurexophilin-1, adipocyte enhancer-binding protein 1, cathepsin L1, and lipopolysaccharide-binding protein. Only CHI3L2 was validated, and patients with high disability progression exhibited significantly higher CSF protein levels compared with patients with low disability progression (p = 0.03 for NPR and p = 0.02 for SPR). CHI3L2 levels showed good performance to discriminate between high and low disability progression in patients with progressive MS (area under the curve 0.73; sensitivity 90% and specificity 63%).ConclusionsAlthough further confirmatory studies are needed, we propose CSF CHI3L2 as a prognostic protein biomarker associated with long-term disability progression in patients with progressive MS.Classification of EvidenceThis study provides Class II evidence that high CSF CHI3L2 levels identified higher disability progression in patients with progressive MS.

Cerebrospinal fluid oligoclonal immunoglobulin gamma bands and long-term disability progression in multiple sclerosis: a retrospective cohort study

Multiple sclerosis (MS) patients with immunoglobulin gamma (IgG) oligoclonal bands (OCB) in the cerebrospinal fluid (CSF) have different genetic backgrounds and brain MRI features compared to those without. In this study, we aimed to determine whether CSF-OCB status is associated with long-term disability outcomes. We used Swedish MS register data on clinically definite MS patients with known OCB status. Date of birth, age at MS onset, and time to sustained Expanded Disability Status Scale (EDSS) milestones 3, 4, and 6; time to conversion to secondary progressive (SP) MS, sex, and immunomodulatory treatment (IMTs) duration were collected. Multivariate Cox regression models were used to investigate the association between OCB status and risk of reaching each milestone. The OCB-positive group reached disability milestones at an earlier time and younger age. OCB-positivity significantly increased the risk of reaching EDSS 3.0 (HR = 1.29, 95% CI 1.12 to 1.48, P < 0.001) and 4.0 (HR = 1.38, 95% CI 1.17 to 1.63, P < 0.001). The OCB-positive group had a 20% higher risk of conversion to SPMS. CSF-OCB presence is associated with higher risk of reaching EDSS milestones and conversion to SPMS. Our findings suggest higher disease modifying effect of OCB presence in the early inflammatory stages of MS.

Characterizing Long-term Disability Progression and Employment in NARCOMS Registry Participants with Multiple Sclerosis Taking Dimethyl Fumarate.

Delayed-release dimethyl fumarate (DMF) is effective in relapsing-remitting multiple sclerosis (RRMS), but long-term effects of DMF on disability and disease progression in clinical settings are unknown. We evaluated disability and employment outcomes in persons with RRMS treated with DMF for up to 5 years. This longitudinal study included US North American Research Committee on Multiple Sclerosis (NARCOMS) Registry participants with RRMS reporting DMF initiation in fall 2013 through spring 2018 with 1 year or more of follow-up. Time to 6-month confirmed disability progression (≥1-point increase in Patient-Determined Disease Steps [PDDS] score) and change in employment status were evaluated using Kaplan-Meier analysis. Participants were censored at last follow-up or at DMF discontinuation, whichever came first. During the study, 725 US participants with RRMS had at least 1 year of DMF follow-up data, of whom most were female and White. At year 5, 69.9% (95% CI, 65.4%-73.9%) of these participants were free from 6-month confirmed disability progression, and 84.7% (95% CI, 78.6%-89.2%) were free from conversion to secondary progressive MS. Of 116 participants with data at baseline and year 5, most had stable or improved PDDS and Performance Scales scores over 5 years. Of 322 participants 62 years and younger and employed at the index survey, 66.0% (95% CI, 57.6%-73.1%) were free from a negative change in employment type over 5 years. Most US NARCOMS Registry participants treated up to 5 years with DMF remained free from 6-month confirmed disability progression and conversion to secondary progressive MS and had stable disability and employment status. These results support the long-term stability of disability and work-related outcomes with disease-modifying therapy.

Clinical effects associated with five-year retinal nerve fiber layer thinning in multiple sclerosis

BackgroundNeurodegenerative changes in multiple sclerosis (MS) are associated with long-term disability progression (DP). Optical coherence tomography (OCT) measures may be used to monitor DP. ObjectiveTo determine significant effects driving the changes in OCT-based peripapillary retinal nerve fiber layer (pRNFL) in heterogeneous group of MS patients. MethodsTotal of 144 MS patients (109 relapsing-remitting MS and 35 progressive MS (PMS) with mean age at baseline of 47.6 and 56.5 years old, respectively) underwent clinical and OCT examination over 5-year follow-up. All OCT exams were reviewed using the OSCAR-IB criteria. The 5-year DP was determined based on Expanded Disability Status Scale (EDSS) changes and MS clinical trial criteria. Data regarding previous history of MS optic neuritis (MSON) and use of disease modifying treatment (DMT) was derived by in-person interview and review of electronic medical records. Mixed model-type of repeated measure analysis determined effects driving pRNFL change for analysis which utilized all eyes separately. ResultsOver an average of 5.3-years follow-up, the MS population demonstrated significant pRNFL thinning (F = 16.108, p < 0.001). The pRNFL thinning was greater due to progressive MS subtype (F = 5.102, p = 0.025), greater age at baseline (F = 4.554, p = 0.034), occurrence of DP (F = 6.583, p = 0.011), and previous history of MSON (F = 7.053, p = 0.008). Use of any or highly potent DMT (natalizumab versus first-line injectable treatments versus no DMT) significantly reduced the pRNFL thinning (F = 8.367, p = 0.004) over the follow-up. Lastly, occurrence of DP in PMS patients older than 50 years old was associated with greater pRNFL thinning (F = 6.667, p = 0.013). ConclusionLongitudinal pRNFL changes are modified by age, disease subtype, disabiltiy progression, history of MSON, DMT use and their interactions.

Serum contactin-1 as a biomarker of long-term disease progression in natalizumab-treated multiple sclerosis

Background: Natalizumab treatment provides a model for non-inflammation-induced disease progression in multiple sclerosis (MS). Objective: To study serum contactin-1 (sCNTN1) as a novel biomarker for disease progression in natalizumab-treated relapsing-remitting MS (RRMS) patients. Methods: Eighty-nine natalizumab-treated RRMS patients with minimum follow-up of 3 years were included. sCNTN1 was analyzed at baseline (before natalizumab initiation), 3, 12, 24 months (M) and last follow-up (median 5.2 years) and compared to 222 healthy controls (HC) and 15 primary progressive MS patients (PPMS). Results were compared between patients with progressive, stable, or improved disability according to EDSS-plus criteria. Results: Median sCNTN1 levels (ng/mL,) in RRMS (baseline: 10.7, 3M: 9.7, 12M: 10.4, 24M: 10.8; last follow-up: 9.7) were significantly lower compared to HC (12.5; p ⩽ 0.001). It was observed that 48% of patients showed progression during follow-up, 11% improved, and 40% remained stable. sCNTN1 levels were significantly lower in progressors both at baseline and at 12M compared to non-progressors. A 1 ng/mL decrease in baseline sCNTN1 was consistent with an odds ratio of 1.23 (95% confidence interval 1.04–1.45) (p = 0.017) for progression during follow-up. Conclusion: Lower baseline sCNTN1 concentrations were associated with long-term disability progression during natalizumab treatment, making it a possible blood-based prognostic biomarker for RRMS.