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Background: Patients with systemic autoimmune rheumatic diseases using disease-modifying antirheumatic drugs (DMARDs) might have blunted responses to COVID-19 vaccines. The initial mRNA vaccine series is defined as three doses for this population and a fourth booster dose is recommended. The effectiveness of the fourth dose in patients with systemic autoimmune rheumatic diseases using DMARDs is not well established. We aimed to assess the effectiveness of receiving versus not receiving a fourth dose of COVID-19 mRNA vaccine using a target trial framework, in a cohort of patients with systemic autoimmune rheumatic diseases receiving DMARD therapy., Methods: We conducted an emulated target trial using observational data from the Mass General Brigham health-care system to compare receiving versus not receiving a fourth mRNA vaccine dose. Analysed patients had systemic autoimmune rheumatic diseases, were prescribed DMARDs, and were eligible for a fourth dose of BNT162b2 or mRNA-1273 vaccines between Jan 16 and June 11, 2022. To account for temporal changes, the study period was divided into 1-week intervals. Fourth-dose-exposed patients were included in a 1-week interval if they received a fourth mRNA dose in that interval; fourth-dose-unexposed patients were eligible for but had not received the fourth dose of the vaccine. The primary outcome was a SARS-CoV-2 infection; the secondary outcome was severe SARS-CoV-2 infection (ie, admission to hospital or death within -3 to +14 days of a positive test). We assessed the effectiveness of the fourth dose using time-stratified, overlap propensity score-weighted Cox regression models., Findings: We included 4305 patients, 3126 of whom received a fourth dose of vaccine and 1179 who had not. The median follow-up time was 135 days (IQR 112-154) among patients who had received a fourth dose and 65 days (30-156) among patients who had not received a fourth dose. After overlap weighting in both groups, 1863 (72·7%) of 2563 participants were women, 700 (27·3%) were men, and 2242 (87·5%) were White. Rheumatoid arthritis was present in 1392 (54·3%) of 2563 participants; the most frequent treatments were conventional synthetic DMARDs (1489 [58·1%]) or biological DMARDs (1007 [39·3%]). SARS-CoV-2 infection risk was lower among patients receiving versus not receiving a fourth dose of vaccine (HR 0·59 [95% CI 0·47-0·74]). A fourth dose reduced the risk of admission to hospital or death within -3 to +14 days of SARS-CoV-2 infection (0·35 [0·14-0·85])., Interpretation: In this emulated target trial, a fourth dose of COVID-19 mRNA vaccine reduced the risk of SARS-CoV-2 infection and severe COVID-19 among patients with systemic autoimmune rheumatic diseases using DMARDs during the Omicron era. Patients with systemic autoimmune rheumatic diseases should be encouraged to remain up-to-date with COVID-19 vaccinations., Funding: The National Institutes of Health and the National Institute of Arthritis and Musculoskeletal and Skin Diseases., Competing Interests: Declaration of interests NJP reports consulting fees from FVC Health and Alosa Health. JAS reports grant funding from Bristol Myers Squibb, the National Institute of Arthritis and Musculoskeletal and Skin Disease, the R Bruce and Joan M Mickey Research Scholar Fund, and the Llura Gund Award for Rheumatoid Arthritis Care and Research; and consulting fees from AbbVie, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Gilead, Janssen, Optum, Pfizer, ReCor, and Inova Diagnostics. ZSW reports funding from the National Institutes of Health and National Institute of Arthritis and Musculoskeletal and Skin Disease for the present manuscript; grants or contracts from Bristol Myers Squibb and Principia/Sanofi; consulting fees from Viela Bio, Zenas BioPharma, BioCryst, Horizon, Sanofi, and MedPace; and advisory board participation for Sanofi, Novartis, Shionogi, Otsuka/Visterra, and Horizon. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)