Immunomodulators and risk for breakthrough infection after third COVID-19 mRNA vaccine among patients with rheumatoid arthritis: A cohort study

ObjectivesTo investigate COVID-19 breakthrough infection after third mRNA vaccine dose among patients with RA by immunomodulator drug class, and we hypothesized that CD20 inhibitors (CD20i) would have higher risk for breakthrough COVID-19 vs. TNF inhibitors (TNFi). MethodsWe performed a retrospective cohort study investigating breakthrough COVID-19 among RA patients at Mass General Brigham in Boston, MA, USA. Patients were followed from the date of 3rd vaccine dose until breakthrough COVID-19, death, or end of follow-up (18/Jan/2023). Covariates included demographics, lifestyle, comorbidities, and prior COVID-19. We used Cox proportional hazards models to estimate breakthrough COVID-19 risk by immunomodulator drug class. We used propensity score (PS) overlap-weighting to compare users of CD20i vs. TNFi. ResultsWe analyzed 5781 patients with RA that received 3 mRNA vaccine doses (78.8% female, mean age 64.2 years). During mean follow-up of 12.8 months, 1173 (20.2%) had breakthrough COVID_19. Use of CD20i (adjusted HR 1.74, 95%CI 1.30-2.33) and glucocorticoid monotherapy (adjusted HR 1.47, 95%CI 1.09-1.98) were each associated with breakthrough COVID-19 compared to TNFi use. In the PS overlap-weighted analysis, CD20i users also had higher breakthrough COVID-19 risk than TNFi users (HR 1.62, 95%CI 1.02-2.56). A sensitivity analysis excluding patients with cancer or interstitial lung disease yielded similar findings. ConclusionsWe identified CD20i and glucocorticoid monotherapy as risk factors for breakthrough COVID-19 among patients with RA after a 3rd vaccine dose. This contemporary study highlights the real-world impact of blunted immune responses in these subgroups and the need for effective risk mitigation strategies. What is already known about this topicO_LIPatients with RA are at increased risk for COVID-19 breakthrough infection after two vaccine doses so a third dose is recommended to complete the initial series. C_LIO_LISome immunomodulator medications, particularly CD20 inhibitors, can impact vaccine immunogenicity and waning. C_LI What this study addsO_LICD20 inhibitor use was associated with increased risk of COVID-19 breakthrough infection in people with RA who received 3 vaccine doses compared to TNF inhibitor use. C_LIO_LIGlucocorticoid monotherapy was also associated with increased risk of COVID-19 breakthrough infection. C_LI How this study might affect research, practice or policyO_LIPatients with RA who are using CD20 inhibitors or glucocorticoid monotherapy should be prioritized for risk mitigation strategies after the initial vaccine series of 3 mRNA doses. C_LIO_LIThe impact of additional vaccine doses, timing of medication dosing, and other protective measures will need further study. C_LI