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SARS-CoV-2 vaccines reduce the risk of COVID-19.1–3 However, some disease-modifying anti-rheumatic drugs (DMARDs), particularly glucocorticoids, methotrexate, mycophenolate mofetil and rituximab, may blunt the immunological response to COVID-19 vaccination.4 Little is known about the clinical efficacy of these vaccines at preventing COVID-19 infection in patients with systemic autoimmune rheumatic diseases (SARDs).
Mass General Brigham (MGB) is a large multicentre healthcare system in the Boston, Massachusetts, USA area. Patients with SARDs with a positive SARS-CoV-2 PCR or antigen test between 30 January 2020 and 30 July 2021 at MGB were identified using diagnostic billing codes or were referred by physicians, as previously described.5 From this cohort, we identified breakthrough infections in fully vaccinated patients, defined as a positive test ≥14 days after the final vaccine dose.6
Of 786 SARD patients with COVID-19, 340 occurred after the initial emergency use authorisation for COVID-19 vaccination in the USA. Of these, 16 (4.7%) were breakthrough infections (online supplemental figure 1). Among the breakthrough infections, 12 (75%) were female, 11 (69%) were white, the median age was 50 years and 12 (75%) had ≥1 comorbidity (table 1). The most common SARDs included rheumatoid arthritis (6, 38%), inflammatory myositis (3, 19%) and systemic lupus erythematosus (3, 19%). Rituximab (5, 31%), glucocorticoids (5, 31%), mycophenolate mofetil or mycophenolic acid (4, 25%) and methotrexate (3, 19%) were the most frequent immunosuppressives recorded prior to first vaccine dose. One (6%) patient was on no DMARD or glucocorticoid at the time of his/her vaccine.
Seven (44%) patients received the BNT162b2 (Pfizer-BioNtech) vaccine, five (31%) received the mRNA-1273 (Moderna) vaccine and four (25%) received the AD26.COV2.S (Janssen/Johnson & Johnson) vaccine. The median time from final vaccine dose to infection was 54 days (table 1). Among the 16 breakthrough infections, 15 (93%) were symptomatic and 6 (38%) patients were hospitalised, during which 4 (25%) required supplemental oxygen and 1 (6%) required mechanical ventilation (online supplemental table 1). DMARDs used prior to infection among hospitalised patients included rituximab (4, 25%) and mycophenolate mofetil or mycophenolic acid (2, 13%). Two (13%) patients died; both deceased patients had received rituximab and had interstitial lung disease.
In conclusion, a small portion of COVID-19 cases among patients with SARDs in a large US healthcare system occurred among fully vaccinated patients. However, some patients required hospitalisation that ultimately culminated in death. The most common SARD treatments at the time of vaccination included those associated with blunted antibody responses to SARS-CoV-2 vaccination.4 These findings suggest that the blunted SARS-CoV-2 antibody response following COVID-19 vaccination in certain DMARD users may be associated with an increased risk of breakthrough infections that may be severe and even fatal. Of note, the blunted response observed among glucocorticoid users is dose dependent, especially above 10 mg/day of prednisone. Some DMARD users may require alternative risk mitigation strategies, including passive immunity or booster vaccines and may need to continue shielding practices.
Our study has certain limitations. First, we did not study the risk of breakthrough infections among a cohort of vaccinated patients with a known denominator. Therefore, we cannot estimate the rate of breakthrough infections among patients with SARDs. It is possible that the observed number of cases might be expected since no vaccine will prevent every infection. Second, the proportion of asymptomatic breakthrough infections observed in our study may be an underestimate because we only included patients who presented for testing. Third, we did not have SARS-CoV-2 antibody testing available for all patients and cannot rule out the possibility that SARD manifestations (eg, interstitial lung disease) commonly treated with these medications contributed to the severity of the presentation.
In light of our findings, additional studies are urgently needed to estimate the risk of breakthrough infections among patients with SARDs and to evaluate the efficacy of booster vaccines and other strategies for DMARD users with poor immunological response to COVID-19 vaccination.
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Handling editor Josef S Smolen
Contributors All authors made substantial contributions to the conception or design of the work and in the acquisition, analysis and interpretation of the data. All authors drafted or revised the work for critically important intellectual consent. All authors provided final approval of the version to be published.
Funding NJP and KMD are supported by the National Institutes of Health Ruth L. Kirschstein Institutional National Research Service Award (T32-AR-007258). KMD is supported by the Rheumatology Research Foundation Scientist Development Award. TY-TH is supported by the National Institutes of Health Ruth L. Kirschstein Institutional National Research Service Award (T32-AR-007530). JAS is funded by NIH/NIAMS (grant numbers K23 AR069688, R03 AR075886, L30 AR066953, P30 AR070253 and P30 AR072577), the Rheumatology Research Foundation R Bridge Award, the Brigham Research Institute, and the R. Bruce and Joan M. Mickey Research Scholar Fund. ZSW is funded by NIH/NIAMS (K23AR073334 and R03AR078938).
Competing interests JAS reports research support from Bristol-Myers Squibb and consultancy fees from Bristol-Myers Squibb, Gilead and Pfizer. ZSW reports research support from Bristol-Myers Squibb and Principia/Sanofi and consulting fees from Viela Bio and MedPace. All other authors report no competing interests.
Provenance and peer review Not commissioned; externally peer reviewed.
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