<h3>Background</h3> Although many studies have been conducted on COVID-19 in recent years, there are still unanswered questions regarding breakthrough infections (BTIs), particularly in patients with systemic lupus erythematosus (SLE). <h3>Objectives</h3> This study aimed to determine the occurrence of breakthrough COVID-19 infections in patients with SLE versus other autoimmune rheumatic diseases (AIRDs), non-rheumatic autoimmune diseases (nrAIDs), and healthy controls (HCs). <h3>Methods</h3> The study was based on data from the COVAD questionnaire which amassed a total of 10,783 complete responses from patients with SLE, AIRD, or nrAIRD, and HCs. After exclusion of individuals who were unvaccinated, those who received one vaccine dose only, and those with uncertain responses regarding the vaccine doses, a total of 9,595 patients formed the study population of the present investigation. If a COVID-19 infection occurred after the initial two vaccine doses and at least one booster dose (at least three doses in total, herein termed full vaccination), it was considered a BTI. Data were analysed using multivariable regression models. Statistically significant results were denoted by <i>p</i> values &lt;0.05. <h3>Results</h3> A total of 7,016/9,595 (73.1%) individuals were fully vaccinated. Among those, 1,002 (14.2%) reported at least one BTI, and 166 (2.3%) reported at least two BTIs. Among SLE patients, 867/1,218 (71.2%) were fully vaccinated. Among fully vaccinated SLE patients, 137 (15.8%) reported at least one BTI while 28 (3.2%) reported at least two BTIs. BTI frequencies in fully vaccinated SLE patients were comparable to those of other AIRDs (OR: 1.0; 95% CI: 0.8–1.3; <i>p</i>=0.447) and nrAIDS (OR: 0.9; 95% CI: 0.6–1.3; <i>p</i>=0.856) but higher compared with HCs (OR: 1.2; 95% CI: 1.0–1.6; <i>p</i>=0.022). For SLE patients with three vaccine doses, 113/137 (82.5%) reported at least one BTI while the corresponding number for four vaccine doses was 24/137 (17.5%). Compared with HCs (OR: 10.6; 95% CI: 1.2–93.0; <i>p</i>=0.032) and other AIRDs (OR: 3.5; 95% CI: 1.08–11.5; <i>p</i>=0.036), SLE patients showed higher frequencies of hospitalisation. AID multimorbidity was associated with a 15-fold increased risk for a need of advanced treatment for COVID-19 (OR: 15.3; 95% CI: 2.6–88.2; <i>p</i>=0.002). <h3>Conclusion</h3> COVID-19 BTIs occurred in nearly 1 every 6^th fully vaccinated patient with SLE, and 20% more frequently in this patient population compared with fully vaccinated HCs. Moreover, BTIs in SLE patients were more severe compared with BTIs in HCs or patients with AIRDs other than SLE, resulting in a greater need for hospitalisation. AID multimorbidity contributed to a more severe COVID-19 BTI requiring advanced management. These insights call for greater attention to vaccination in the vulnerable group of SLE patients, with appropriate risk stratification towards optimised vaccination strategies. <h3>Acknowledgements</h3> The authors thank all survey respondents, as well as patient associations and all members of the COVAD study group for their invaluable role in the data collection. <h3>Disclosure of Interests</h3> Emelie Kihlgren Olsson: None declared, Naveen Ravichandran: None declared, Elena Nikiphorou Speakers bureau: EN has received speaker honoraria/participated in advisory boards for Celltrion, Pfizer, Sanofi, Gilead, Galapagos, AbbVie, and Lilly., Consultant of: EN has received speaker honoraria/participated in advisory boards for Celltrion, Pfizer, Sanofi, Gilead, Galapagos, AbbVie, and Lilly., Grant/research support from: EN holds research grants from Pfizer and Lilly., Julius Lindblom: None declared, Sreoshy Saha: None declared, Syahrul Sazliyana Shaharir: None declared, Wanruchada Katchamart: None declared, Phonpen Akarawatcharangura Goo: None declared, Lisa Traboco: None declared, Yi-Ming Chen: None declared, Kshitij Jagtap: None declared, James B. Lilleker Speakers bureau: JBL has received speaker honoraria for Sanofi Genzyme, Roche, and Biogen. None is related to this manuscript. Consultant of: JBL has participated in advisory boards for Sanofi Genzyme, Roche, and Biogen. None is related to this manuscript. Arvind Nune: None declared, John Pauling: None declared, Chris Wincup: None declared, Vishwesh Agarwal: None declared, Dey Dzifa: None declared, Carlos Enrique Toro Gutierrez: None declared, Carlo Vinicio Caballero: None declared, Hector Chinoy Speakers bureau: HC has been a speaker for UCB, and Biogen., Consultant of: HC has received consulting fees from Novartis, Eli Lilly, Orphazyme, Astra Zeneca., Grant/research support from: HC was supported by the National Institution for Health Research Manchester Biomedical Research Centre Funding Scheme. The views expressed in this publication are those of the authors and not necessarily those of the NHS, National Institute for Health Research, or Department of Health. HC has received grant support from Eli Lilly and UCB., Vikas Agarwal: None declared, Rohit Aggarwal Consultant of: RA has a consultancy relationship with and/or has received research funding from the following companies: Bristol Myers-Squibb, Pfizer, Genentech, Octapharma, CSL Behring, Mallinckrodt, AstraZeneca, Corbus, Kezar, Abbvie, Janssen, Kyverna Alexion, Argenx, Q32, EMD-Serono, Boehringer Ingelheim, Roivant, Merck, Galapagos, Actigraph, Scipher, Horizon Therapeutics, Teva, Beigene, ANI Pharmaceuticals, Biogen, Nuvig, Capella Bioscience, and CabalettaBio., Grant/research support from: RA has a consultancy relationship with and/or has received research funding from the following companies: Bristol Myers-Squibb, Pfizer, Genentech, Octapharma, CSL Behring, Mallinckrodt, AstraZeneca, Corbus, Kezar, Abbvie, Janssen, Kyverna Alexion, Argenx, Q32, EMD-Serono, Boehringer Ingelheim, Roivant, Merck, Galapagos, Actigraph, Scipher, Horizon Therapeutics, Teva, Beigene, ANI Pharmaceuticals, Biogen, Nuvig, Capella Bioscience, and CabalettaBio., Latika Gupta: None declared, Ioannis Parodis Grant/research support from: IP has received research funding and/or honoraria from Amgen, AstraZeneca, Aurinia Pharmaceuticals, Elli Lilly and Company, Gilead Sciences, GlaxoSmithKline, Janssen Pharmaceuticals, Novartis and F. Hoffmann-La Roche AG.