Melatonin Contributes to the Seasonality of Multiple Sclerosis Relapses.
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ABSTRACT:
SUBMITTER: Farez MF
PROVIDER: S-EPMC4570563 | biostudies-literature | 2015 Sep
REPOSITORIES: biostudies-literature
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Melatonin Contributes to the Seasonality of Multiple Sclerosis Relapses.
Farez Mauricio F MF Mascanfroni Ivan D ID Méndez-Huergo Santiago P SP Yeste Ada A Murugaiyan Gopal G Garo Lucien P LP Balbuena Aguirre María E ME Patel Bonny B Ysrraelit María C MC Zhu Chen C Kuchroo Vijay K VK Rabinovich Gabriel A GA Quintana Francisco J FJ Correale Jorge J
Cell 20150901 6
Seasonal changes in disease activity have been observed in multiple sclerosis, an autoimmune disorder that affects the CNS. These epidemiological observations suggest that environmental factors influence the disease course. Here, we report that melatonin levels, whose production is modulated by seasonal variations in night length, negatively correlate with multiple sclerosis activity in humans. Treatment with melatonin ameliorates disease in an experimental model of multiple sclerosis and direct ...[more]
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Project description:Multiple sclerosis (MS) is a chronic progressive inflammatory demyelinating disease affecting the central nervous system. The most common clinical type of MS tends to follow a relapsing course, affecting the vast majority of patients living with this disease. Relapses are a hallmark of MS, and are often associated with significant functional impairment and decreased quality of life. Although usually followed by a period of remission, residual symptoms after MS relapses may persist and lead to sustained disability. Adequate management of MS relapses is important, as it may help to shorten and lessen the disability associated with their course. Historically, treatment of MS relapse was the first approach (and for a period of time, the only approach) to MS treatment in general. Systemic corticosteroids and adrenocorticotropic hormone (ACTH) have broad regulatory approval and remain the most established and validated treatment options for MS relapse. Therapeutic mechanisms of ACTH were previously associated (perhaps mistakenly) with only corticotropic actions; however, recently the direct anti-inflammatory effects and immunomodulatory activity of ACTH gel acting through melanocortin pathways have been shown. Second-line treatments of steroid-unresponsive MS relapses and a possible algorithm for MS relapse management are also reviewed in this article.
| S-EPMC3557364 | biostudies-literature
Project description:High-dose short-term methylprednisolone is the recommended treatment in the management of multiple sclerosis relapses, although it has been suggested that lower doses may be equally effective. Also, glucocorticoids are associated with multiple and often dose-dependent adverse effects. This quantitative benefit-risk assessment compares high- and low-dose methylprednisolone (at least 2000 mg and less than 1000 mg, respectively, during at most 31 days) and a no treatment alternative, with the aim of determining which regimen, if any, is preferable in multiple sclerosis relapses.An overall framework of probabilistic decision analysis was applied, combining data from different sources. Effectiveness as well as risk of non-serious adverse effects were estimated from published clinical trials. However, as these trials recorded very few serious adverse effects, risk intervals for the latter were derived from individual case reports together with a range of plausible distributions. Probabilistic modelling driven by logically implied or clinically well motivated qualitative relations was used to derive utility distributions.Low-dose methylprednisolone was not a supported option in this assessment; there was, however, only limited data available for this treatment alternative. High-dose methylprednisolone and the no treatment alternative interchanged as most preferred, contingent on the risk distributions applied for serious adverse effects, the assumed level of risk aversiveness in the patient population, and the relapse severity.The data presently available do not support a change of current treatment recommendations. There are strong incentives for further clinical research to reduce the uncertainty surrounding the effectiveness and the risks associated with methylprednisolone in multiple sclerosis relapses; this would enable better informed and more precise treatment recommendations in the future.
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Project description:BackgroundIn multiple sclerosis, impact of treatment on disability progression can be confounded if treatment also reduces relapses.ObjectiveTo distinguish siponimod's direct effects on disability progression from those on relapses in the EXPAND phase 3 trial.MethodsThree estimands, one based on principal stratum and two on hypothetical scenarios (no relapses, or equal relapses in both treatment arms), were defined to determine the extent to which siponimod's effects on 3- and 6-month confirmed disability progression were independent of on-study relapses.ResultsPrincipal stratum analysis estimated that siponimod reduced the risk of 3- and 6-month confirmed disability progression by 14%-20% and 29%-33%, respectively, compared with placebo in non-relapsing patients. In the hypothetical scenarios, risk reductions independent of relapses were 14%-18% and 23% for 3- and 6-month confirmed disability progression, respectively.ConclusionBy controlling the confounding impact of on-study relapses on confirmed disability progression, these statistical approaches provide a methodological framework to assess treatment effects on disability progression in relapsing and non-relapsing patients. The analyses support that siponimod may be useful for treating secondary progressive multiple sclerosis in patients with or without relapses.
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Project description:ObjectiveIntravenous methylprednisolone is the standard treatment for a multiple sclerosis relapse; however, this fails to improve symptoms in up to one quarter of patients. Immunoadsorption is an accepted treatment for refractory relapses, but prospective comparator-controlled studies are missing.MethodsIn this observational study, patients with steroid-refractory acute multiple sclerosis relapses receiving either six courses of tryptophan-immunoadsorption or double-dose methylprednisolone therapy were analysed. Outcomes were evaluated at discharge and three months later. Immune profiling of blood lymphocytes and proteomic analysis were performed by multi-parameter flow cytometry and Olink analysis, respectively (NCT04450030).Results42 patients were enrolled (methylprednisolone: 26 patients; immunoadsorption: 16 patients). For determination of the primary outcome, treatment response was stratified according to relative function system score changes ("full/best" vs. "average" vs. "worse/none"). Upon discharge, the adjusted odds ratio for any treatment response ("full/best" + "average" vs. "worse/none") was 10.697 favouring immunoadsorption (p = 0.005 compared to methylprednisolone). At follow-up, the adjusted odds ratio for the best treatment response ("full/best" vs. "average" + "worse/none") was 103.236 favouring IA patients (p = 0.001 compared to methylprednisolone). Similar results were observed regarding evoked potentials and quality of life outcomes, as well as serum neurofilament light-chain levels. Flow cytometry revealed a profound reduction of B cell subsets following immunoadsorption, which was closely correlated to clinical outcomes, whereas methylprednisolone had a minimal effect on B cell populations. Immunoadsorption treatment skewed the blood cytokine network, reduced levels of B cell-related cytokines and reduced immunoglobulin levels as well as levels of certain coagulation factors.InterpretationImmunoadsorption demonstrated favourable outcomes compared to double-dose methylprednisolone. Outcome differences were significant at discharge and follow-up. Further analyses identified modulation of B cell function as a potential mechanism of action for immunoadsorption, as reduction of B cell subsets correlated with clinical improvement.
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Project description:ObjectiveThe relationship between relapses and long-term disability in multiple sclerosis (MS) remains to be fully elucidated. Current literature is conflicting and focused on early relapses. We investigated the effects of relapses at different stages on disability progression.MethodsWe conducted a retrospective review of 2,477 patients with definite relapsing-onset MS followed until July 2003 in British Columbia, Canada. Time-dependent Cox proportional hazards models examined the effect of relapses at different time periods (0-5; >5-10; >10 years postonset) on time to cane (Expanded Disability Status Scale [EDSS]) and secondary progressive MS (SPMS). Findings were derived from hazard ratios with 95% confidence intervals (CIs), adjusted for sex, onset age, and symptoms.ResultsMean follow-up was 20.6 years; 11,722 postonset relapses were recorded. An early relapse (within 5 years postonset) was associated with an increased hazard in disease progression over the short term, by 48%; 95% CI 37%-60% for EDSS 6 and 29%; 95% CI 20%-38% for SPMS. However, this substantially lessened to 10%; 95% CI 4%-16% (EDSS 6) and 2%; 95% CI -2%-7% (SPMS) after 10 years postonset. The impact of later relapses (>5-10 years postonset) also lessened over time. Effects were modulated by age, impact being greatest in younger (<25 years at onset) and least in older (>or=35 years) patients where relapses beyond 5-years postonset typically failed to reach significance. Relapses during SPMS had no measurable impact on time to EDSS 6 from SPMS.ConclusionRelapses within the first 5 years of disease impacted on disease progression over the short term. However, the long-term impact was minimal, either for early or later relapses. Long-term disease progression was least affected by relapses in patients with an extended disease duration (>10 years) or already in the secondary progressive phase.
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Project description:Background: The ability to predict the spatial frequency of relapses in multiple sclerosis (MS) would enable treating physicians to decide when to intervene more aggressively and to plan clinical trials more accurately. Methods: In the current study our objective was to determine if subsets of genes can predict the time to the next acute relapse in patients with MS. Data-mining and predictive modeling tools were utilized to analyze a gene-expression dataset of 94 non-treated patients; 62 patients with definite MS and 32 patients with clinically isolated syndrome (CIS). The dataset included the expression levels of 10,594 genes and annotated sequences corresponding to 22,215 gene-transcripts that appear in the microarray. Results: We designed a two stage predictor. The first stage predictor was based on the expression level of 10 genes, and predicted the time to next relapse with a resolution of 500 days (error rate 0.079, p< 0.001). If the predicted relapse was to occur in less than 500 days, a second stage predictor based on an additional different set of 9 genes was used, resulting in a prediction with a resolution of 50 days as to the timing of the next relapse. The error rate of this predictor was 2.3 fold lower than the error rate of random predictions (error rate = 0.35, p<0.001). The predictors were further evaluated and found effective not only in untreated patients but were also valid for MS patients which subsequently received immunomodulatory treatments after the initial testing (the error rate of the first level predictor was < 0.18 with p<0.001 for all the patient groups). Conclusions: We conclude that gene expression analysis is a valuable tool that can be used in clinical practice to predict future MS disease activity. Similar approach can be also useful for dealing with other autoimmune diseases that characterized by relapsing-remitting nature Keywords: Disease prediction
2009-07-15 | GSE15245 | GEO
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Project description:BackgroundRelapsing-onset multiple sclerosis (MS) typically starts in early- to mid-adulthood, yet the trajectory of disease activity over the subsequent lifetime remains poorly defined. Previous studies have not quantified the age-specific portion of decreases in annualized relapse rates (ARR).ObjectiveThe aim of this article is to determine, under a range of disease-related assumptions, the age-specific component of decreases in ARR over time among adults with relapsing-onset MS.MethodsWe used a simulation modeling approach to examine a range of assumptions about changes in ARR due to age versus disability status. Scenarios included variations in initial ARR and rate of worsening on the Expanded Disability Status Scale. Model parameters were developed through analysis of MS patients in British Columbia, Canada, and literature review.ResultsWe found a substantial age-specific decrease in ARR in all simulated scenarios, independent of disability worsening. Under a range of clinically plausible assumptions, 88%-97% of the decrease was attributed to age and 3%-13% to disability. The age-specific decrease ranged from 22% to 37% per 5 years for a wide range of initial ARR (0.33-1.0).ConclusionDecreases in ARR were due mostly to age rather than disability status. To facilitate informed decision making in MS, it is important to quantify the dynamic relationship between relapses and age.
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Project description:High-dose biotin (HDB) is a therapy used in non-active progressive multiple sclerosis (PMS). Several reports have suggested that HDB treatment may be associated with an increased risk of relapse. We aimed to determine whether HDB increases the risk of clinical relapse in PMS and describe the characteristics of the patients who experience it. We conducted a French, multicenter, retrospective study, comparing a group of PMS patients treated with HDB to a matched control group. Poisson regression was applied to model the specific statistical distribution of the annualized relapse rate (ARR). A propensity score (PS), based on the inverse probability of treatment weighting (IPTW), was used to adjust for indication bias and included the following variables: gender, primary PMS or not, age, EDSS, time since the last relapse, and co-prescription of a DMT. Two thousand six hundred twenty-eight patients treated with HDB and 654 controls were analyzed with a follow-up of 17 ± 8 months. Among them, 148 validated relapses were observed in the group treated with biotin and 38 in the control group (p = 0.62). After adjustment based on the PS, the ARR was 0.044 ± 0.23 for the biotin-treated group and 0.028 ± 0.16 for the control group (p = 0.18). The more relapses there were before biotin, the higher the risk of relapse during treatment, independently from the use of HDB. While the number of relapses reported for patients with no previous inflammatory activity receiving biotin has gradually increased, the present retrospective study is adequately powered to exclude an elevated risk of relapse for patients with PMS treated with HDB.
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Project description:The aim of this study was to examine the impact of intravenous methylprednisolone therapy (IVMP) on the recovery of walking ability in patients experiencing multiple sclerosis (MS) relapses, to compare the responsiveness of walking-based measures, and to estimate the impact of different walking-based measures responsiveness on clinical trials.The study included 49 consecutive patients with relapsing-remitting MS who received Solu-Medrol 1000 mg/day over 3 days for relapse with difficulties in walking. The following walking-based measures were administered before and a month after IVMP: the Multiple Sclerosis Walking Scale-12 (MSWS-12), the Expanded Disability Status Scale (EDSS), the 2-minute timed walk (2-minTW), the 25-foot walk test (25FWT), the Six Spot Step Test (SSST). All patients had worn the step activity monitor accelerometer (SAM) 1 week prior to IVMP was applied and wore it again the fourth week upon the corticosteroid therapy was completed. The SAM analysis utilized the average daily step count and data regarding frequency and intensity of walking over a continuous time interval. We examined: (1) the impact of IVMP on the recovery of walking ability; (2) the responsiveness of each walking-based measure; (3) the relative responsiveness of competing walking-based measures; and (4) the impact of different walking-based measures responsiveness on clinical trials.All walking-based measures showed significant improvement of walking ability 1 month after the IVMP. The most responsive were MSWS-12 and EDSS. Different responsiveness implied a greater than 6-fold impact on sample size estimates.All applied walking-based measures showed significant improvement of walking ability 1 month after the IVMP. Responsiveness of various walking-based measures notably differ, thus affecting sample size calculations.
| S-EPMC3628135 | biostudies-other