Adverse effects of immunotherapies for multiple sclerosis: a network meta-analysis

• Published in: Cochrane database of systematic reviews 2023-11, Vol.11 (11), p.CD012186
• Main Authors: Tramacere, Irene, Virgili, Gianni, Perduca, Vittorio, Lucenteforte, Ersilia, Benedetti, Maria Donata, Capobussi, Matteo, Castellini, Greta, Frau, Serena, Gonzalez-Lorenzo, Marien, Featherstone, Robin, Filippini, Graziella
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Alemtuzumab; Azathioprine; Cladribine; Daclizumab; Dimethyl Fumarate; Female; Fingolimod Hydrochloride; Glatiramer Acetate; Humans; Immunosuppressive Agents - adverse effects; Immunotherapy; Interferon beta-1a - adverse effects; Interferon beta-1b; Male; Multiple Sclerosis - drug therapy; Natalizumab; Network Meta-Analysis; Neurology; Pharmacological interventions for Multiple Sclerosis; Rituximab; Young Adult
• ISSN: 1469-493X; 1469-493X
• DOI: 10.1002/14651858.CD012186.pub2

Multiple sclerosis (MS) is a chronic disease of the central nervous system that affects mainly young adults (two to three times more frequently in women than in men) and causes significant disability after onset. Although it is accepted that immunotherapies for people with MS decrease disease activity, uncertainty regarding their relative safety remains. To compare adverse effects of immunotherapies for people with MS or clinically isolated syndrome (CIS), and to rank these treatments according to their relative risks of adverse effects through network meta-analyses (NMAs). We searched CENTRAL, PubMed, Embase, two other databases and trials registers up to March 2022, together with reference checking and citation searching to identify additional studies. We included participants 18 years of age or older with a diagnosis of MS or CIS, according to any accepted diagnostic criteria, who were included in randomized controlled trials (RCTs) that examined one or more of the agents used in MS or CIS, and compared them versus placebo or another active agent. We excluded RCTs in which a drug regimen was compared with a different regimen of the same drug without another active agent or placebo as a control arm. We used standard Cochrane methods for data extraction and pairwise meta-analyses. For NMAs, we used the netmeta suite of commands in R to fit random-effects NMAs assuming a common between-study variance. We used the CINeMA platform to GRADE the certainty of the body of evidence in NMAs. We considered a relative risk (RR) of 1.5 as a non-inferiority safety threshold compared to placebo. We assessed the certainty of evidence for primary outcomes within the NMA according to GRADE, as very low, low, moderate or high. This NMA included 123 trials with 57,682 participants Serious adverse events (SAEs) Reporting of SAEs was available from 84 studies including 5696 (11%) events in 51,833 (89.9%) participants out of 57,682 participants in all studies. Based on the absolute frequency of SAEs, our non-inferiority threshold (up to a 50% increased risk) meant that no more than 1 in 18 additional people would have a SAE compared to placebo. Low-certainty evidence suggested that three drugs may decrease SAEs compared to placebo (relative risk [RR], 95% confidence interval [CI]): interferon beta-1a (Avonex) (0.78, 0.66 to 0.94); dimethyl fumarate (0.79, 0.67 to 0.93), and glatiramer acetate (0.84, 0.72 to 0.98). Several drugs met our non-inferiority criterion versus placebo: