Rates of serious adverse events were no different from placebo in any trial
Rates of serious adverse events were no different from placebo in any trial. or no treatment; 2. to assess the relative efficacy and safety of diseasemodifying drugs according to their benefit and safety; 3. to estimate the benefit and safety of diseasemodifying drugs that have been evaluated in all studies (randomised or nonrandomised) for treatment started after a first attack (‘early treatment’) compared with treatment started after a second attack or ALLO-2 at another later time point (‘delayed treatment’). == Search methods == We searched the Cochrane Multiple Sclerosis and Rare Diseases of the CNS Group Trials Register, MEDLINE, Embase, CINAHL, LILACS, clinicaltrials.gov, the ALLO-2 ALLO-2 WHO trials registry, and US Food and Drug Administration (FDA) reports, and searched for unpublished studies (until December 2016). == Selection criteria == We included randomised and observational studies that evaluated one or more drugs as monotherapy in adult participants with a first clinical attack suggestive of MS. We considered evidence on alemtuzumab, azathioprine, cladribine, daclizumab, dimethyl fumarate, fingolimod, glatiramer acetate, immunoglobulins, interferon beta1b, interferon beta1a (Rebif, Avonex), laquinimod, mitoxantrone, natalizumab, ocrelizumab, pegylated interferon beta1a, rituximab and teriflunomide. == Data collection and analysis == Two teams of three authors each independently selected studies and extracted data. The primary outcomes were disabilityworsening, relapses, occurrence of at least one serious adverse event (AE) and withdrawing from the study or discontinuing the drug because of AEs. Time to conversion to clinically definite MS (CDMS) defined by Poser diagnostic criteria, and probability to discontinue the treatment or dropout for any reason were recorded as secondary outcomes. We synthesized study data using randomeffects metaanalyses and performed indirect comparisons between drugs. We calculated odds ratios (OR) and hazard ratios (HR) along with relative 95% confidence intervals (CI) for all outcomes. We estimated the absolute effects only for primary outcomes. We evaluated the credibility of the evidence using the GRADE system. == Main results == We included 10 randomised trials, eight openlabel extension Mouse monoclonal antibody to ATIC. This gene encodes a bifunctional protein that catalyzes the last two steps of the de novo purinebiosynthetic pathway. The N-terminal domain has phosphoribosylaminoimidazolecarboxamideformyltransferase activity, and the C-terminal domain has IMP cyclohydrolase activity. Amutation in this gene results in AICA-ribosiduria studies (OLEs) and four cohort studies published between 2010 and 2016. The overall risk of bias was high and the reporting of AEs was scarce. The quality of the evidence associated with the results ranges from low to very low. Early treatment versus placebo during the first 24 months’ followup There was a small, nonsignificant advantage of early treatment compared with placebo in disabilityworsening (6.4% fewer (13.9 fewer to 3 more) participants with disabilityworsening with interferon beta1a (Rebif) or teriflunomide) and in relapses (10% fewer (20.3 fewer to 2.8 more) participants with relapses with teriflunomide). Early treatment was associated with 1.6% fewer participants with at least one serious AE (3 fewer to 0.2 more). Participants on early treatment were on average 4.6% times (0.3 fewer to 15.4 more) more likely to withdraw from the study due to AEs. This result was mostly driven by studies on interferon beta 1b, glatiramer acetate and cladribine that were associated with significantly more withdrawals for AEs. Early treatment decreased the hazard of conversion to CDMS (HR 0.53, 95% CI 0.47 to 0.60). Comparing active interventions during the first 24 months’ followup Indirect comparison of interferon beta1a (Rebif) with teriflunomide did not show any difference on reducing disabilityworsening (OR 0.84, 95% CI 0.43 to 1 1.66). We found no differences between the included drugs with respect to the hazard of conversion to CDMS. Interferon beta1a (Rebif) and teriflunomide were associated with fewer dropouts because of AEs compared with interferon beta1b, cladribine and glatiramer acetate ALLO-2 (ORs range between 0.03 and 0.29, with substantial uncertainty). Early versus delayed treatment We did not find evidence of differences between early and delayed treatments for disabilityworsening at a maximum of five years’ followup (3% fewer participants with early treatment (15 fewer to 11.1 more)). There was important variability across interventions; early treatment with interferon beta1b considerably reduced the odds of participants with disabilityworsening during three and five years’ followup (OR 0.52, 95% ALLO-2 CI 0.32 to 0.84 and OR 0.57, 95% CI 0.36 to 0.89). The early treatment group had 19.6% fewer participants with relapses (26.7 fewer to 12.7 fewer) compared to late treatment at a maximum of five years’ followup and early treatment decreased the hazard of conversion to CDMS at any followup up to 10 years (i.e. over five years’ followup HR 0.62, 95% CI 0.53 to 0.73). We did not draw any.