Effect of Temporary Methotrexate Discontinuation on Vaccine Immunogenicity and Disease Flare in Rheumatoid Arthritis: A Systematic Review.

Abstract

Background: Methotrexate (MTX) is a cornerstone disease-modifying antirheumatic drug for rheumatoid arthritis (RA); however, it may attenuate vaccine-induced immune responses. Temporary MTX interruption around vaccination has been proposed to improve immunogenicity, but concerns remain regarding disease flare and safety.

Objective: To evaluate whether temporary MTX discontinuation or delayed initiation around vaccination improves vaccine immunogenicity in adults with RA, while assessing its effects on disease activity, flare risk, and safety.

Methods: PubMed/MEDLINE, Scopus, Embase, and Cochrane CENTRAL were searched for randomized controlled trials (RCTs) and observational studies comparing MTX continuation with temporary discontinuation or delayed initiation around vaccination in adults with RA. Outcomes included vaccine response rate, neutralizing antibody response, geometric mean antibody titers, disease activity, disease flare, and adverse events. Because of heterogeneity, findings were synthesized narratively.

Results: Five studies were included: 4 RCTs and 1 retrospective observational cohort. Temporary MTX interruption or delayed initiation improved vaccine immunogenicity across influenza, COVID-19, and pneumococcal vaccines. The most consistent benefit was observed when MTX was withheld during the early post-vaccination period. Improved responses included higher seroconversion rates, increased neutralizing capacity, and antibody titers. Safety findings were generally acceptable, although repeated 2-week interruptions after closely spaced COVID-19 vaccine doses increased clinical disease activity index (CDAI)-defined flare rates in 1 trial. Risk-of-bias assessment suggested generally reliable evidence, with the observational cohort rated high quality and randomized trials largely showing low overall risk of bias.

Conclusion and relevance: Temporary MTX interruption, particularly after vaccination, may enhance vaccine immunogenicity in adults with RA. These findings provide clinically relevant evidence to guide MTX management around vaccination in adults with RA. However, this strategy should be individualized according to baseline disease activity, flare risk, vaccine type, and clinical context and should not be extrapolated to pediatric patients, for whom evidence was not identified in this review.