Preventing Disability Progression Research Articles

Diagnostic MRI Score to Differentiate Susac Syndrome from Primary Angiitis of the Central Nervous System and Multiple Sclerosis.

Susac syndrome (SuS), multiple sclerosis (MS), and primary angiitis of the central nervous system (PACNS) present diagnostic challenges due to overlapping clinical features. We aimed to enhance diagnostic precision by developing the SPAMS (SuS, PACNS, MS) score, a practical radiological tool. This multicenter study included 99 patients (43 SuS, 37 MS, 19 PACNS) from South American countries. Relevant MRI features were identified through an elastic-net model determined key variables. The SPAMS score assigned 2 points for snowball lesions, 1 point for spokes-like lesions, or if there are more than 4 lesions in the corpus callosum, corpus callosum involvement, or cerebellar involvement. It subtracted 1 point if gadolinium-enhancing lesions or 4 points if Dawson's fingers are present. Bootstrapping validated the optimal cutoff at 2 points, exhibiting a diagnostic performance of area under the curve = 0.931, sensitivity = 88%, specificity = 89%, positive predictive value = 88%, negative predictive value = 89%, and accuracy = 88%. When specific MRI findings coexisted, the SPAMS score differentiated SuS from MS and PACNS. Access to MRI and standard protocol sequences makes it a valuable tool for timely diagnosis and treatment, potentially preventing disability progression and severe clinical outcomes. ANN NEUROL 2024.

Pre-Clinical Mobility Limitation (PCML) Outcomes in Rehabilitation Interventions for Middle-Aged and Older Adults: A Scoping Review

Abstract Individuals with pre-clinical mobility limitation (PCML) are at a high risk of future functional loss and progression to disability. The purpose of this scoping review was to provide a comprehensive understanding of PCML intervention studies in middle-aged and older adults. We present the interventions that have been tested or planned, describe how they have been conducted and reported, identify the knowledge gaps in current literature, and make recommendations about future research directions. An initial search of 2,291 articles resulted in 14 articles that met criteria for inclusion. Findings reveal that: (1) there is limited published work on PCML interventions, especially in middle-aged populations; and (2) the complexity and variety of PCML measures make it difficult to compare findings across PCML studies. Despite the diversity of measures, this review provides preliminary evidence that rehabilitation interventions on PCML help to delay or prevent disability progression.

Cost, efficacy and safety comparison between early intensive and escalating strategies for multiple sclerosis: a Systematic Review and Meta-analysis (P14-3.009)

<h3>Objective:</h3> Our goal was to compare the effectiveness, safety, and cost between Escalating (ESC) and Early intensive (EIT) strategies for the treatment of multiple sclerosis. <h3>Background:</h3> ESC strategy consists in starting low-to-moderate-efficacy disease modifying drugs (DMDs) in the treatment of multiple sclerosis, upscaling to high-efficacy DMDs when facing evidence of active disease. EIT strategy, on the other hand, is based on starting high-efficacy DMDs as first-line therapy. The optimal strategy is unclear in patients with multiple sclerosis. <h3>Design/Methods:</h3> We searched MEDLINE, EMBASE, and SCOPUS until September 4th, 2022 for studies comparing EIT and ESC strategies in adult patients with relapsing-remitting multiple sclerosis and a minimum follow-up of 5 years. Expanded Disability Severity Scale (EDSS), the proportion of severe adverse events, and cost in a 5-year time horizon were the main outcomes. Economic analysis followed a Markov model using previously described transition matrix, utility and costs of multiple sclerosis and DMDs. Bias assessment was performed using ROBINS-I. This review was registered with PROSPERO (CRD42022358097). <h3>Results:</h3> Seven studies involving 3,467 participants demonstrated a 30% reduction in the risk of EDSS worsening at 5 years (RR 0.7; [0.59–0.83]; p&lt;0.001) in the EIT group. Safety profile was similar between EIT and ESC strategies (RR 1.92; [0.38–9.72]; p=0.4324). EIT group showed 0.03 increase in QALY and a reduction of £1506 in a 5-year time horizon model. EIT with natalizumab in extended interval dosing, rituximab, alemtuzumab, and/or cladribine was cost-effective in our models. <h3>Conclusions:</h3> EIT presents a higher efficacy in preventing disability progression, without harnessing safety or cost in a 5-years time horizon. <b>Disclosure:</b> Mr. Pipek has nothing to disclose. Mr. Mahler Ferreira Oliveira has nothing to disclose. Miss Nascimento has nothing to disclose. Samira Luísa Apóstolos-Pereira has nothing to disclose. Dr. SILVA has nothing to disclose. Dr. Callegaro has nothing to disclose.

The Use of Disease-Modifying Therapy (DMT) to Prevent Disability Progression in Patients with Multiple Sclerosis (MS) in Thailand

Background: Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system that leads to significant disability and economic burden for patients, families, the health system, and society. Objective: To describe the demographics, natural history, and effectiveness of disease-modifying therapies (DMTs) in MS patients. Materials and Methods: The present study was a retrospective cohort study of patients diagnosed with MS at the Prasat Neurological Institute, a tertiary referral neurological center in Bangkok, Thailand, between June 1, 2010 and June 30, 2020. Demographic data, clinical characteristics, and disease course of MS patients were explored. The primary outcome of the present study was a comparison of time to events of clinical relapse, new magnetic resonance image (MRI) T2W activity, new MRI T1W with gadolinium (Gd) enhancement, and time to disability progression between patients who received DMT and patients without DMT. Results: There were 102 patients diagnosed with MS. The female-to-male ratio was 2.4-to-1. The mean age at onset was 29.61±11.62 years. The phenotypic features of these patients were classified as RRMS 80.4%, SPMS 8.8%, PPMS 3.9%, and tumefactive demyelination 6.9%. Forty-eight patients (47.1%) received DMT, 28 (58.3%) received IFN-beta, 11 (22.9%) received fingolimod, seven (14.6%) received teriflunomide, and two (4.2%) received rituximab. Results demonstrated that patients who did not received DMT had significantly more clinical disability compared to patients who received DMT (HR 2.97; 95% CI 1.01 to 8.73; p=0.048). However, the times to clinical relapse and MRI activity, including new T2W and new T1W Gd enhancing lesion, were not significantly different between the two groups. Conclusion: Patients with a relapsing-remitting phenotype tended to progress to severe disability within ten years. Treatment with DMT may delay disability progression in patients with MS. Keywords: Multiple sclerosis (MS); Disease-modifying therapy (DMT)

Cost, efficacy, and safety comparison between early intensive and escalating strategies for multiple sclerosis: A systematic review and meta-analysis.

The optimal treatment strategy of multiple sclerosis (MS) is a matter of debate. The classical approach is the escalating (ESC) strategy, which consists of starting with low- to moderate-efficacy disease-modifying drugs (DMDs) and upscale to high-efficacy DMDs when noting some evidence of active disease. Another approach, the early intensive (EIT) strategy, is starting with high-efficiency DMDs as first-line therapy. Our goal was to compare effectiveness, safety, and cost of ESC and EIT strategies. We searched MEDLINE, EMBASE and SCOPUS until September 2022, for studies comparing EIT and ESC strategies in adult participants with relapsing-remitting MS and a minimum follow-up of 5 years. We examined the Expanded Disability Severity Scale (EDSS), the proportion of severe adverse events, and cost in a 5-year period. Random-effects meta-analysis summarized the efficacy and safety and an EDSS-based Markov model estimated the cost. Seven studies with 3,467 participants showed a 30% reduction in EDSS worsening in 5 years (RR 0.7; [0.59-0.83]; p<0.001) in the EIT group vs in the ESC group. Two studies with 1,118 participants suggested a similar safety profile for these strategies (RR 1.92; [0.38-9.72]; p=0.4324). EIT with natalizumab in extended interval dosing, rituximab, alemtuzumab, and cladribine demonstrated cost-effectiveness in our model. EIT presents higher efficacy in preventing disability progression, a similar safety profile, and can be cost-effective within a 5-year timeline.

From bedside to bench: how existing therapies inform the relationship between Epstein-Barr virus and multiplesclerosis.

Therapy for relapsing-remitting multiple sclerosis (MS) has advanced dramatically despite incomplete understanding of the cause of the condition. Current treatment involves inducing broad effects on immune cell populations with consequent off-target side effects, and no treatment can completely prevent disability progression. Further therapeutic advancement will require a better understanding of the pathobiology of MS. Interest in the role of Epstein-Barr virus (EBV) in multiple sclerosis has intensified based on strong epidemiological evidence of an association between EBV seroprevalence and MS. Hypotheses proposed to explain the biological relationship between EBV and MS include molecular mimicry, EBV immortalised autoreactive B cells and infection of glial cells by EBV. Examining the interaction between EBV and immunotherapies that have demonstrated efficacy in MS offers clues to the validity of these hypotheses. The efficacy of B cell depleting therapies could be consistent with a hypothesis that EBV-infected B cells drive MS; however, loss of T cell control of B cells does not exacerbate MS. A number of MS therapies invoke change in EBV-specific T cell populations, but pathogenic EBV-specific T cells with cross-reactivity to CNS antigen have not been identified. Immune reconstitution therapies induce EBV viraemia and expansion of EBV-specific T cell clones, but this does not correlate with relapse. Much remains unknown regarding the role of EBV in MS pathogenesis. We discuss future translational research that could fill important knowledge gaps.

Improving the decision to switch from first- to second-line therapy in multiple sclerosis: A dynamic scoring system

Background: In relapsing-remitting multiple sclerosis (RRMS), early identification of suboptimal responders can prevent disability progression. Objective: We aimed to develop and validate a dynamic score to guide the early decision to switch from first- to second-line therapy. Methods: Using time-dependent propensity scores (PS) from a French cohort of 12,823 patients with RRMS, we constructed one training and two validation PS-matched cohorts to compare the switched patients to second-line treatment and the maintained patients. We used a frailty Cox model for predicting individual hazard ratios (iHRs). Results: From the validation PS-matched cohort of 348 independent patients with iHR ⩽ 0.69, we reported the 5-year relapse-free survival at 0.14 (95% confidence interval (CI) 0.09–0.22) for the waiting group and 0.40 (95% CI 0.32–0.51) for the switched group. From the validation PS-matched cohort of 518 independent patients with iHR > 0.69, these values were 0.37 (95% CI 0.30–0.46) and 0.44 (95% CI 0.37–0.52), respectively. Conclusions: By using the proposed dynamic score, we estimated that at least one-third of patients could benefit from an earlier switch to prevent relapse.

Humanized zebrafish as a tractable tool for in vivo evaluation of pro-myelinating drugs

Therapies that promote neuroprotection and axonal survival by enhancing myelin regeneration are an unmet need to prevent disability progression in multiple sclerosis. Numerous potentially beneficial compounds have originated from phenotypic screenings but failed in clinical trials. It is apparent that current cell- and animal-based disease models are poor predictors of positive treatment options, arguing for novel experimental approaches. Here we explore the experimental power of humanized zebrafish to foster the identification of pro-remyelination compounds via specific inhibition of GPR17. Using biochemical and imaging techniques, we visualize the expression of zebrafish (zf)-gpr17 during the distinct stages of oligodendrocyte development, thereby demonstrating species-conserved expression between zebrafish and mammals. We also demonstrate species-conserved function of zf-Gpr17 using genetic loss-of-function and rescue techniques. Finally, using GPR17-humanized zebrafish, we provide proof of principle for invivo analysis of compounds acting via targeted inhibition of human GPR17. We anticipate that GPR17-humanized zebrafish will markedly improve the search for effective pro-myelinating pharmacotherapies.

Lifestyle factors in multiple sclerosis disability progression and silent brain damage: A cross-sectional study

ObjectiveTo determine the association between lifestyle risk factors with 1/ the Multiple Sclerosis Severity Score (MSSS) and 2/ ongoing subclinical brain damage in non-active MS patients on high-efficacy treatment. MethodsCross-sectional study in persons with Multiple Sclerosis (PwMS) investigating lifestyle factors including cognitive reserve (CR), physical activity (PA), smoking status, alcohol use, dietary habits, body mass index (BMI), blood pressure (BP) and cholesterol ratio. Data were collected through validated questionnaires, clinical and laboratory examination. Serum Neurofilament light chain (sNfL) levels were used as a proxy for ongoing brain damage in a subgroup of persons with non-active MS on high-efficacy treatment. Multiple regression analysis (MRA) models explored the relationship between lifestyle factors with the MSSS score and sNfL. Results351 PwMS were included (43.04 ± 11.77 years, 69.8% female). Higher CR and PA were associated with a lower MSSS; overweight or obesity and higher systolic BP with a higher MSSS. The MRA model explained 22.2% of the variance for MSSS (R².255, adjusted R².222). Higher BMI and BP were related to lower sNfL. Twenty-3% (R².279, adjusted R².230) of the variance was explained in the MRA model for sNfL. ConclusionOur study suggests an association between a ‘brain healthy lifestyle’ with disability progression in MS. A cognitive and physical active lifestyle alongside a normal body weight and blood pressure may help to prevent future disability in MS. Longitudinal and interventional research is necessary to gain insight in the causal pathway of these risk factors in preventing disability progression in MS.

Preferences Toward Attributes of Disease-Modifying Therapies: The Role of Nurses in Multiple Sclerosis Care.

ABSTRACTBACKGROUND: Nurses play an essential role in coordinating the care of patients with multiple sclerosis (MS) throughout their disease trajectory in a complex treatment landscape. The aim of this study was to assess nurses' preferences toward different disease-modifying therapy attributes. METHODS: We conducted a multicenter, noninterventional, cross-sectional study in collaboration with the Sociedad Española de Enfermería Neurológica. Nurses actively involved in MS care were invited to participate in the study. Prevention of disability progression, preservation of cognitive function, side effect profile and safety monitoring, and method of administration were the treatment attributes tested. Conjoint analysis was used to assess preferences in 8 simulated treatment options and rank them from most to least preferred. RESULTS: A total of 98 nurses were included in the study. The mean (SD) age was 44.7 (9.8) years, and 91.8% were female with a mean (SD) time of experience in MS care of 7.5 (5.4) years. Participants prioritized preservation of cognition (38.6%), followed by preventing disability progression (35.2%) and side effect risk and safety monitoring (13.5%). Route and frequency of administration were the least preferred attributes (7.4% and 5.3%, respectively). Estimated utilities were consistent across the sample according to sociodemographic and professional practice characteristics. CONCLUSIONS: Nurses' preferences toward treatments were mainly driven by efficacy attributes. This information may support the role of nurses in the multidisciplinary management of MS facilitating shared decision making.

Disability Progression in SPMS Despite Therapeutic Intervention: Current Status and Perspectives of Treatment with Disease-Modifying Drugs

Currently, siponimod is the only disease-modifying drugs (DMDs) with proven efficacy and safety in clinical trials for secondary progressive multiple sclerosis (SPMS). However, the efficacy of siponimod in preventing disability progression is insufficient and it has not yet been able to deter disability progression. Therefore, it is considered necessary to use DMDs with a high relapse-preventive effect at a relatively early stage of SPMS, while disease activity remains evident. Bruton's tyrosine kinase inhibitors have the potential to prevent progression of all MS disease types and are expected to be the cornerstone of the next generation of treatment. The results of these clinical trials are awaited.

Participation in Social Activities and Relationship between Walking Habits and Disability Incidence

Identifying the relationship between physical and social activity and disability among community-dwelling older adults may provide important information for implementing tailored interventions to prevent disability progression. The aim of this study was to determine the effect of the number of social activities on the relationship between walking habits and disability incidence in older adults. We included 2873 older adults (mean age, 73.1 years; SD, ±5.9 years) from the National Center for Geriatrics and Gerontology—Study of Geriatric Syndromes. Baseline measurements, including frequencies of physical and social activities, health conditions, physical function, cognitive function, metabolic parameters, and other potential disability risk factors (for example, the number of years of education); monthly assessment for disability was monitored through long-term care insurance certification for at least 2 years from baseline. During a mean follow-up of 35.1 months (SD, 6.4 months), 133 participants developed disability. The disability incidence was 19.0 and 27.9 per 1000 person-years for participants who walked more (≥3 times per week) and less (≤3 times per week) frequently, respectively. The potential confounding factor-adjusted disability hazard ratio was 0.67 (95% confidence interval, 0.46 to 0.96; p = 0.030). The relationship between habitual walking and the number of social activities was statistically significant (p = 0.004). The reduction of disability risk by walking was greater among participants with fewer social activities. Habitual walking was associated with disability incidence, with a more pronounced effect among older adults who were less likely to engage in social activities.

Successful Management of Natalizumab-Associated Primary Central Nervous System Lymphoma through Autologous Stem Cell Transplant

Natalizumab is used as a second-line treatment for multiple sclerosis (MS). Some reports have linked natalizumab to primary central nervous system lymphoma (PCNSL), although few have described its management. A 45-year-old woman with Balo’s Concentric Sclerosis presented dizziness, vertigo accompanied by dysarthria, weakness on the left side and blurred vision to the right eye after the fourth dose of natalizumab. Magnetic resonance imaging (MRI) and a brain biopsy confirmed the diagnosis of PCNSL. The patient received modified PCNSL chemotherapy (MATRix protocol) followed by high-dose chemotherapy (HDC) supported by an autologous hematopoietic stem cell transplant (ASCT) as a consolidation therapy. Thirty months later, she is still in complete remission of her PCNSL and MS. In this case, whole brain radiotherapy was excluded because it may be associated with an increased risk of neurotoxicity in MS. ASCT was preferred because it has been shown to prevent disability progression in less advanced MS stages. Our patient is the second to receive an ASCT in this context and this option of treatment should be the preferred if the patient is eligible.

Disability progression in relapse-free multiple sclerosis patients on fingolimod versus interferon-beta/glatiramer acetate

Background: Disability progression independent of relapses (PIRA) has been described as a frequent phenomenon in relapsing-remitting multiple sclerosis (RRMS). Objective: To compare the occurrence of disability progression in relapse-free RRMS patients on interferon-beta/glatiramer acetate (IFN/GA) versus fingolimod. Methods: This study is based on data from the Swiss association for joint tasks of health insurers. Time to relapse and 12-month confirmed disability progression were compared between treatment groups using multivariable Cox regression analysis with confounder adjustment. Inverse-probability weighting was applied to correct for the bias that patients on fingolimod have a higher chance to remain relapse-free than patients on IFN/GA. Results: We included 1640 patients (64% IFN/GA, 36% fingolimod, median total follow-up time = 4–5 years). Disease-modifying treatment (DMT) groups were well balanced with regard to potential confounders. Disability progression was observed in 155 patients (8.8%) on IFN/GA and 51 (7.6%) on fingolimod, of which 44 and 23 were relapse-free during the initial DMT, respectively. Adjusted standard regression analysis on all patients indicated that those on fingolimod experience less frequently disability progression compared with IFN/GA (hazard ratio = 0.53 (95% confidence interval = 0.37–0.76)). After bias correction, this was also true for patients without relapses (hazard ratio=0.56 (95% confidence interval = 0.32–0.98). Conclusion: Our analysis indicates that fingolimod is superior to IFN/GA in preventing disability progression in both relapsing and relapse-free, young, newly diagnosed RRMS patients.

Efficacy and safety of alemtuzumab treatment in a real-world cohort of patients with multiple sclerosis.

Alemtuzumab is a monoclonal anti-CD52 antibody prescribed to treat relapsing-remitting multiple sclerosis (RRMS). Alemtuzumab affects the balance of the immune system by depleting circulating lymphocytes, leading to the formation of a new immune repertoire less likely to induce autoimmune attack against CNS myelin. We collected real-world data of RRMS patients treated with alemtuzumab. We assessed relapse rate, disability progression, and MRI-related disease activity over a 24month period. Our study included 35 RRMS patients (19 female and 16 male) with a mean age of 37.3years (SD = 10.5). The patient cohort had a mean disease duration of 10.4years, median previous disease modifying treatments (DMTs) of 3.0, and a median expanded disability status scale (EDSS) score of 4.0 (IQR 2.5-6.0). Neurological disability remained stable during treatment and there was no statistically significant change in EDSS score. Prior to treatment, the median relapse rate was 2.0 (IQR 1.0-3.0); after treatment the median relapse rate was 0.0. This 2.0 decrease in relapse rate is statistically significant (p < 0.0001). Moreover, the treated patients exhibited a statistically significant decrease in gadolinium (GD) enhancing lesions on MRI [both in number (p < 0.005) and volume (p < 0.005)]. Thirty-three percent of patients reached NEDA-3 (no evidence of disease activity) status by the end of treatment. In a real-world setting, alemtuzumab treatment significantly decreased relapse rate and GD-enhancing lesions while preventing disability progression. Tolerability of treatment was high, with patients experiencing only minor adverse events.

P204 Effect of baricitinib on functional impairment in RA patients with moderate disease activity and an inadequate response to conventional DMARDs

Abstract Background In RA, disease activity correlates with physical function and there is a link between joint damage and functional disability. In many countries, RA patients with inadequate response (IR) to MTX or other conventional DMARDs (cDMARDs) are not eligible for potentially more effective treatments, such as biologic or targeted synthetic DMARDs (tsDMARDs), unless they have high disease activity (HDA). Thus, managing RA patients with persistent moderate disease activity (MDA) despite cDMARD treatment poses a problem. Baricitinib (BARI) is a tsDMARD approved for the treatment of moderate to severe RA in adults. This post-hoc analysis assessed if RA patients with MDA benefit from improved physical function with BARI treatment to the same extent as patients with HDA. Methods Patients analysed were from the modified intention-to-treat populations in the BARI phase 3 studies RA-BEAM (MTX-IR) and RA-BUILD (cDMARD-IR) with moderate to severe disability (HAQ-Disability Index [HAQ-DI] score ≥1), MDA (Simplified Disease Activity Index [SDAI] score 11.1-26.0) or HDA (SDAI score&amp;gt;26.0) and non-missing SDAI data at baseline. All patients fulfilled ACR criteria for RA. Patients from RA-BEAM received BARI 4 mg + MTX once daily (n = 396), adalimumab 40 mg every 2 weeks + MTX (n = 270) or placebo (PBO) + MTX (n = 390); patients from RA-BUILD received BARI 4 mg (n = 189) or 2 mg (n = 186) or PBO (n = 185). Multivariable linear regression (MLR) models were used to estimate mean HAQ-DI scores at baseline and week 24 (W24) for the treatment arms stratified by baseline disease activity (MDA or HDA SDAI). Age, RA duration, BMI, high-sensitivity CRP, baseline SDAI disease activity (MDA/HDA), treatment and treatment-by-baseline SDAI interaction were included as covariates. The MLR model for HAQ-DI at (W24) was further adjusted by baseline HAQ-DI. Results In patients from RA-BEAM with MDA at baseline, the mean adjusted HAQ-DI score at W24 was greater in PBO (1.314) than in BARI 4 mg (0.843) patients (Δ = 0.472; p = 0.001). A similar pattern of improved physical function with BARI was seen in RA-BUILD, but the adjusted mean difference in HAQ-DI score between PBO (1.376) and BARI 4 mg (1.113) was not statistically significant (Δ = 0.263; p = 0.109). In patients with HDA at baseline, the W24 mean adjusted HAQ-DI score was 0.443 points greater (p &amp;lt; 0.001) with PBO (1.387) than with BARI 4 mg (0.944) in RA-BEAM, and 0.257 points greater (p &amp;lt; 0.001) in RA-BUILD. Conclusion MTX-IR and/or cDMARD-IR RA patients with MDA and moderate to severe disability at baseline treated with BARI showed a similar pattern of improvement in physical function vs. PBO-treated patients to that seen in patients with HDA, supporting early use of BARI in MDA patients. As for those with HDA, patients with persistent MDA despite MTX and/or other cDMARD treatment could benefit from access to biologic and tsDMARDs to prevent disability progression. Disclosures B. Kirkham: Consultancies; AbbVie, Eli Lilly, Gilead, Janssen, Novartis, Pfizer. Grants/research support; Eli Lilly, Novartis. E. Nikiphorou: Honoraria; Pfizer, Sanofi, Gilead, Celltrion, Eli Lilly. P. López-Romero: Shareholder/stock ownership; Eli Lilly. Other; Full time employee of Eli Lilly. I. Kouris: Shareholder/stock ownership; Eli Lilly. Other; Full time employee of Eli Lilly. T. Holzkaemper: Shareholder/stock ownership; Eli Lilly. Other; Full time employee of Eli Lilly. L. Zaremba-Pechmann: Other; contractor for Eli Lilly and Company. I. de la Torre: Shareholder/stock ownership; Eli Lilly. Other; Full time employee of Eli Lilly. P.C. Taylor: Consultancies; AbbVie, Biogen, Galapagos, Gilead, GlaxoSmithKline, Janssen, Eli Lilly, Pfizer, Roche, Sanofi, Nordic Pharma, Fresenius, UCB. Grants/research support; Celgene, Galapagos, Janssen, Eli Lilly.

Exploring the relationship between Endothelin-1 and peripheral inflammation in multiple sclerosis

BackgroundIdentifying pathways linking neuroinflammation and neurodegeneration is essential to help prevent disability progression in people with multiple sclerosis (MS). Endothelin-1 (ET-1) is a potent vasoconstrictor thought to contribute to cerebral hypoperfusion and tissue damage in MS. Its link with the neuroinflammatory process remains poorly investigated. ObjectivesTo determine plasma ET-1 levels in treatment-naïve people with MS and controls, and the relationship between ET-1 and other peripheral immune mediator levels as potential markers of the disease process. MethodsThis is a retrospective study that included specimens previously collected from 35 treatment-naïve patients with clinically isolated syndrome highly suggestive of MS or definite MS and 35 sex- and age-matched controls. ET-1 plasma levels were measured by enzyme-linked immunosorbent assay (ELISA), and plasma cytokine levels [interleukin (IL)-1beta, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12(p70), IL-13, interferon (IFN)-γ and tumor necrosis factor (TNF)-α] were simultaneously measured by Multiplex assay. ResultsET-1 levels were significantly increased in MS patients compared to controls. No significant difference in cytokine levels between the groups were found. However, a significant increase in IFN-γ/IL-4 ratio was observed in patients with MS in comparison with controls, suggestive of Th1 skewed response. Binary logistic regression was performed to ascertain the effects of age, sex, ET-1 and cytokine levels on the likelihood of MS diagnosis. In the final model, ET-1, IL-4 and IFN-γ levels remained as predictors of MS. There was no significant correlation between ET-1 and cytokine levels. ConclusionsPatients with MS presented increased levels of ET-1 and an immune response biased towards a Th1 profile. Although both ET-1 and Th1 cytokine profile were predictors of MS diagnosis, ET-1 levels were not associated with peripheral immune markers, suggesting that these changes may occur independently.

Employment and absenteeism in working-age persons with multiple sclerosis

Aims: To better understand the impact of the clinical course of multiple sclerosis (MS) and disability on employment, absenteeism, and related factors.Materials and methods: This study included respondents to the North American Research Committee on Multiple Sclerosis Registry spring 2015 update survey who were US or Canadian residents, aged 18–65 years and reported having relapsing-remitting MS (RRMS), secondary progressive MS (SPMS), or primary progressive MS (PPMS). The RRMS and SPMS participants were combined to form the relapsing-onset MS (RMS) group and compared with the PPMS group regarding employment status, absenteeism, and disability. Multivariable logistic regression was used to examine the relationship between employment-related outcomes and factors that may affect these relationships.Results: Of the 8004 survey respondents, 5887 (73.6%) were 18–65 years of age. The PPMS group (n = 344) had a higher proportion of males and older mean age at the time of the survey and at time of diagnosis than the RMS group (n = 4829). Female sex, age, age at diagnosis, cognitive and hand function impairment, fatigue, higher disability levels, ≥3 comorbidities, and a diagnosis of PPMS were associated with not working. After adjustment for disability, the employed PPMS sub-group reported similar levels of absenteeism to the employed RMS sub-group.Limitations: Limitations of the study include self-report of information and the possibility that participants may not fully represent the working-age MS population.Conclusions: In MS, employment status and absenteeism are negatively affected by disability, cognitive impairment, and fatigue. These findings underscore the need for therapies that prevent disability progression and other symptoms that negatively affect productivity in persons with MS to enable them to persist in the workforce.

Progressive multiple sclerosis: from pathogenic mechanisms to treatment.

During the past decades, better understanding of relapsing-remitting multiple sclerosis disease mechanisms have led to the development of several disease-modifying therapies, reducing relapse rates and severity, through immune system modulation or suppression. In contrast, current therapeutic options for progressive multiple sclerosis remain comparatively disappointing and challenging. One possible explanation is a lack of understanding of pathogenic mechanisms driving progressive multiple sclerosis. Furthermore, diagnosis is usually retrospective, based on history of gradual neurological worsening with or without occasional relapses, minor remissions or plateaus. In addition, imaging methods as well as biomarkers are not well established. Magnetic resonance imaging studies in progressive multiple sclerosis show decreased blood-brain barrier permeability, probably reflecting compartmentalization of inflammation behind a relatively intact blood-brain barrier. Interestingly, a spectrum of inflammatory cell types infiltrates the leptomeninges during subpial cortical demyelination. Indeed, recent magnetic resonance imaging studies show leptomeningeal contrast enhancement in subjects with progressive multiple sclerosis, possibly representing an in vivo marker of inflammation associated to subpial demyelination. Treatments for progressive disease depend on underlying mechanisms causing central nervous system damage. Immunity sheltered behind an intact blood-brain barrier, energy failure, and membrane channel dysfunction may be key processes in progressive disease. Interfering with these mechanisms may provide neuroprotection and prevent disability progression, while potentially restoring activity and conduction along damaged axons by repairing myelin. Although most previous clinical trials in progressive multiple sclerosis have yielded disappointing results, important lessons have been learnt, improving the design of novel ones. This review discusses mechanisms involved in progressive multiple sclerosis, correlations between histopathology and magnetic resonance imaging studies, along with possible new therapeutic approaches.

Repair strategies for multiple sclerosis: challenges, achievements and perspectives.

Despite major progress in multiple sclerosis (MS) treatment, to date, accumulation of irreversible clinical disability is not sufficiently prevented with immunotherapies. In this context, repair strategies aimed at reducing axonal damage are becoming a very active field of preclinical and clinical research. Improved understanding of the cellular and molecular mechanisms of myelin repair, together with the emergence of new therapeutic candidates are paving the way for novel therapeutic strategies in MS. In parallel, there is a very active development of imaging methods to assess lesions ongoing remyelination that are crucially needed to evaluate therapeutic efficacy. The current development of a very dynamic and multidisciplinary research on remyelination should accelerate the development of myelin repair strategies in MS, to prevent disability progression.