Background/Purpose: In August 2021, the CDC recommended a third SARS-CoV-2 mRNA vaccine dose to complete the initial vaccine series for immunosuppressed patients who had previously received 2 mRNA doses. Despite this, some rheumatoid arthritis (RA) patients may remain at increased risk for breakthrough COVID-19 infection, due to use of immunomodulators which lead to blunted immune responses to vaccination and infection. Identifying patients at highest risk for breakthrough infection despite 3 vaccines can prioritize resources for prevention. Therefore, we investigated the risk of breakthrough COVID-19 among RA patients with at least 3 vaccine doses using disease-modifying antirheumatic drugs (DMARDs), especially TNF inhibitors (TNFi) and CD20 inhibitors (CD20i), during the Omicron wave.

Methods: We performed a retrospective cohort study investigating DMARDs and risk for breakthrough COVID-19 among RA patients who had received 3 mRNA vaccines at a large health care system. A previously validated algorithm was used to identify RA patients using a combination of diagnosis codes and DMARD/glucocorticoid prescription (PPV 90%). COVID-19 was identified systematically from positive PCR tests or patient reports to the hospital/clinic of home rapid antigen tests. Patients were followed from the date of 3rd vaccine (index date) until breakthrough COVID-19, non-COVID death, or end of follow-up (January 18, 2023). A previously defined hierarchical algorithm was used to categorize DMARD exposures. Covariates included demographics, lifestyle, comorbidities, and prior COVID-19. We used Cox proportional hazards models to estimate the risk of COVID-19 among different DMARD users. We then used propensity scores and overlap-weighting to further account for confounding when comparing the risk among users of CD20i vs. TNFi.

Results: We identified 5781 patients with RA who used DMARDs/glucocorticoids and 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 a SARS-CoV-2 infection (incidence rate 15.7 per 1000 person-months) (Table 1). Users of CD20i were more likely than TNFi users to have COVID-19 after the index date (adjusted HR 1.74, 95%CI 1.30-2.33), as were users of steroid monotherapy (adjusted HR 1.47, 95%CI 1.09-1.98) (Figure 1). After using propensity scores for overlap weighting to account for baseline differences, CD20i users remained at higher risk for COVID-19 than TNFi users (HR 1.62, 95%CI 1.02-2.56; Figure 2). In a sensitivity analysis excluding patients with cancer or interstitial lung disease, the findings were similar.

Conclusion: In this RA-specific study evaluating the impact of DMARD use on the risk of COVID-19 during the Omicron phase of the pandemic, we identified CD20i and steroid monotherapy use as risk factors for breakthrough COVID-19. This contemporary study highlights the excess risk associated with glucocorticoid monotherapy or CD20 inhibitor use for RA treatment and identifies important subgroups for counseling and additional risk mitigation strategies.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/immunomodulators-and-risk-for-breakthrough-covid-19-after-a-third-sars-cov-2-mrna-vaccine-among-patients-with-rheumatoid-arthritis-a-cohort-study/