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The brain antigen-specific B cell response correlates with glatiramer acetate responsiveness in relapsing-remitting multiple sclerosis patients.

ABSTRACT: B cells have only recently begun to attract attention in the immunopathology of multiple sclerosis (MS). Suitable markers for the prediction of treatment success with immunomodulatory drugs are still missing. Here we evaluated the B cell response to brain antigens in n = 34 relapsing-remitting MS (RRMS) patients treated with glatiramer acetate (GA) using the enzyme-linked immunospot technique (ELISPOT). Our data demonstrate that patients can be subdivided into responders that show brain-specific B cell reactivity in the blood and patients without this reactivity. Only in patients that classified as B cell responders, there was a significant positive correlation between treatment duration and the time since last relapse in our study. This correlation was GA-specific because it was absent in a control group that consisted of interferon-ß (IFN-β)-treated RRMS patients (n = 23). These data suggest that GA has an effect on brain-reactive B cells in a subset of patients and that only this subset benefits from treatment. The detection of brain-reactive B cells is likely to be a suitable tool to identify drug responders.

SUBMITTER: Rovituso DM

PROVIDER: S-EPMC4585696 | biostudies-other | 2015

REPOSITORIES: biostudies-other

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Project description:Doses of fingolimod lower than 0.5 mg per day were not investigated during the fingolimod clinical development program. Whether lower doses of fingolimod might retain efficacy with fewer safety risks remains unknown. To evaluate the efficacy and safety of fingolimod, 0.5 mg, and fingolimod, 0.25 mg, compared with glatiramer acetate and to assess whether these doses of fingolimod show superior efficacy to glatiramer acetate in adult patients with relapsing-remitting multiple sclerosis. Fingolimod, 0.5 mg, or fingolimod, 0.25 mg, orally once per day or glatiramer acetate, 20 mg, subcutaneously once per day. The Multiple Sclerosis Study Evaluating Safety and Efficacy of Two Doses of Fingolimod Versus Copaxone (ASSESS) was a phase 3b multicenter randomized rater-blinded and dose-blinded 12-month clinical trial conducted between August 9, 2012, and April 30, 2018 (including the time required to recruit participants). A total of 1461 patients aged 18 to 65 years with relapsing-remitting multiple sclerosis were screened, and 1064 participants were randomized. These participants had at least 1 documented relapse during the previous year or 2 documented relapses during the previous 2 years and an Expanded Disability Status Scale score of 0 to 6 at screening. Data were analyzed between September and November 2018. The superiority of the fingolimod doses was tested hierarchically, with fingolimod, 0.5 mg, vs glatiramer acetate, 20 mg, tested first, followed by fingolimod, 0.25 mg, vs glatiramer acetate, 20 mg. The primary end point was the reduction in annualized relapse rate (ARR). Magnetic resonance imaging parameters, safety, and tolerability were also assessed. Of 1461 adult patients screened, 1064 participants (72.8%) were randomized (mean [SD] age, 39.6 [11.0] years; 792 women [74.4%]) to 3 treatment groups: 352 participants received fingolimod, 0.5 mg, 370 participants received fingolimod, 0.25 mg, and 342 participants received glatiramer acetate, 20 mg. In total, 859 participants (80.7%) completed the study. Treatment with fingolimod, 0.5 mg, was superior to treatment with glatiramer acetate, 20 mg, in reducing ARR (40.7% relative reduction); the relative reduction with fingolimod, 0.25 mg, was 14.6%, which was not statistically significant (for fingolimod, 0.5 mg, ARR, 0.15; 95% CI, 0.11-0.21; for fingolimod, 0.25 mg, ARR, 0.22; 95% CI, 0.17-0.29; for glatiramer acetate, 20 mg, ARR, 0.26; 95% CI, 0.20-0.34). Treatment with both fingolimod doses (0.5 mg and 0.25 mg) significantly reduced new or newly enlarging T2 and gadolinium-enhancing T1 lesions compared with treatment with glatiramer acetate. Adverse events were reported in similar proportions across treatment groups (312 participants [90.4%] in the fingolimod, 0.5 mg, group, 323 participants [88.3%] in the fingolimod, 0.25 mg, group, and 283 participants [87.3%] in the glatiramer acetate group). Fingolimod, 0.5 mg, demonstrated superior clinical efficacy compared with glatiramer acetate, 20 mg, and had a superior benefit-risk profile compared with fingolimod, 0.25 mg, in adult participants with relapsing-remitting multiple sclerosis. ClinicalTrials.gov Identifier: NCT01633112.

Project description:BACKGROUND:We systematically reviewed the comparative effectiveness of injectable beta-interferons (IFN-?) and glatiramer acetate (GA) on annualised relapse rate (ARR), progression and discontinuation due to adverse events (AEs) in RRMS, using evidence from within the drugs' recommended dosages. METHODS:We updated prior comprehensive reviews, checked references of included studies, contacted experts in the field, and screened websites for relevant publications to locate randomised trials of IFN-? and GA with recommended dosages in RRMS populations, compared against placebo or other recommended dosages. Abstracts were screened and assessed for inclusion in duplicate and independently. Studies were appraised using the Cochrane risk of bias tool. Rate ratios for ARR, hazard ratios for time to progression, and risk ratios for discontinuation due to AEs were synthesised in separate models using random effects network meta-analysis. RESULTS:We identified 24 studies reported in 42 publications. Most studies were at high risk of bias in at least one domain. All drugs had a beneficial effect on ARR as compared to placebo, but not compared to each other, and findings were robust to sensitivity analysis. We considered time to progression confirmed at 3 months and confirmed at 6 months in separate models; while both models suggested that the included drugs were effective, findings were not consistent between models. Discontinuation due to AEs did not appear to be different between drugs. CONCLUSIONS:Meta-analyses confirmed that IFN-? and GA reduce ARR and generally delay progression as defined in these trials, though there was no clear 'winner' across outcomes. Findings are additionally tempered by the high risk of bias across studies, and the use of an impairment/mobility scale to measure disease progression. Future research should consider more relevant measures of disability and, given that most trials have been short-term, consider a longitudinal approach to comparative effectiveness. REVIEW REGISTRATION:PROSPERO CRD42016043278 .

Project description:BackgroundThe aim of this study was to evaluate the safety, tolerability, and efficacy of a brand-generic glatiramer acetate product in patients with relapsing-remitting multiple sclerosis over a 12-month period. A noninterventional cohort study was conducted on 185 patients. The patients had a confirmed and documented diagnosis of relapsing-remitting multiple sclerosis as defined by the Revised McDonald Criteria (2010), were ambulatory with a Kurtzke Expanded Disability Status Scale score of 0 to 5.5, and their treatment by glatiramer acetate 40 mg/mL was just started.MethodsAdverse drug reactions, relapse rate, magnetic resonance imaging parameters, and Expanded Disability Status Scale score were evaluated over 1 year.ResultsOf 185 enrolled patients from 21 different cities, 170 completed the study. The mean (SD) Expanded Disability Status Scale score was 1.97 (0.75) at the time of screening. The mean age was 33 years with an average of 4-year multiple sclerosis history, and 83% were women. Hepatic disorder and depression were the most frequent medical history. The most common adverse drug reactions were local pain (45.4%) and erythema (38.9%). The immediate postinjection reactions included dyspnea (10.3%), anxiety (9.7%), palpitation (8.1%), urticaria (5.4%), flushing (3.24%), chest pain (2.16%), and throat constriction (0.54%). The percentage of relapse-free patients at Month 12 was 87%, and the annual relapse rate was 0.134. An increase in the Expanded Disability Status Scale score was observed in 20% of patients, and new T2 and gadolinium-enhancing lesions were found in 34.7% and 9.4%, respectively. The rate of treatment failure was 1.6% and 4.3% according to the Modified Rio and Rio scores, respectively.ConclusionsThe 40 mg brand-generic glatiramer acetate product was well tolerated in this selected group of Iranian patients with relapsing-remitting multiple sclerosis, and patient adherence was favorable over 1 year. (Curr Ther Res Clin Exp. 2018; 79:XXX-XXX).

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The brain antigen-specific B cell response correlates with glatiramer acetate responsiveness in relapsing-remitting multiple sclerosis patients.

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