Abstract
Importance
The COVID-19 pandemic disproportionately affected patients with autoimmune and rheumatic diseases. Understanding whether certain medications affect the response to a SARS-CoV-2 supplemental dose vaccination is critical for counseling and treating patients receiving targeted immunomodulatory medications. The effect of holding these medications around the time of COVID-19 vaccination on immunogenicity and rheumatic disease outcomes has not been well studied.
Objective
To assess whether temporarily holding biologic or targeted synthetic disease-modifying antirheumatic drug therapy improves humoral immunogenicity following COVID-19 supplemental dose vaccination in patients with inflammatory arthritis as well as evaluate whether such interruption worsened disease activity.
Design, Setting, and Participants
The COVID-19 Vaccine Response (COVER) trial was a multicenter randomized clinical pragmatic trial conducted from November 2021 to May 2024 of patients with rheumatoid arthritis, psoriatic arthritis, and axial spondylarthritis who were receiving care in the Excellence Network in Rheumatology to Innovate Care and High-Impact Research (ENRICH) practice-based network. Data were analyzed from June 2024 to April 2026.
Interventions
Patients had received a primary messenger RNA COVID-19 vaccine series and were receiving stable immunomodulatory therapy with anti–tumor necrosis factor, anti–interleukin-17, abatacept, and a Janus kinase inhibitor (JAKi). Patients were randomized to continue or hold therapy for 2 weeks following their next COVID-19 supplemental dose administration.
Main Outcomes and Measures
The primary outcome was change in immunoglobulin G levels against the SARS-CoV-2 spike protein from baseline to 6-week follow-up, expressed as the geometric mean fold rise (GMFR). The primary analysis followed an intention-to-treat (ITT) principle, with missing outcomes addressed through multiple imputations. A per-protocol sensitivity analysis was also conducted. Secondary outcomes included disease flares and vaccine-related adverse events.
Results
Among 840 randomized participants (continue group: 319 female individuals [76%]; mean [SD] age, 60.0 [12.9] years; hold group: 336 female individuals [80%]; mean [SD] age, 59.1 [12.9] years), substantial increases in SARS-CoV-2 spike immunoglobulin G antibody levels were observed across all groups from baseline to the postdose visit. In the primary ITT analysis, the GMFR ratio (hold/continue) was 0.96 (95% CI, 0.36-2.56), indicating no significant difference in humoral immunogenicity between arms. Results were consistent across drug subgroups and drug half-life categories. Holding therapy significantly increased disease flare risk (odds ratio, 2.27; 95% CI, 1.41-3.65), which was most pronounced among those who used JAKi; the Outcome Measures in Rheumatology RA Flare Questionnaire corroborated this perivaccination signal (54 of 256 [21.1%] vs 23 of 253 [9.1%] with ≥10-point worsening; risk difference, 12.0%; 95% CI, 5.9%-18.1%), with full recovery in both arms by 6-week follow-up. Adverse events were comparable between medication arms and were more frequent in the hold group.
Conclusions and Relevance
This randomized clinical trial found that, among patients with inflammatory arthritis, holding select biologic or JAKi therapies for 2 weeks at the time of supplemental COVID-19 vaccine dose did not significantly enhance humoral immunogenicity and was associated with transient but clinically meaningful disease flare. Routine interruption of these therapies at the time of COVID-19 dose administration is likely not warranted.
Trial Registration
ClinicalTrials.gov Identifier:
NCT05080218