COVER Trial: Holding Arthritis Drugs Did Not Boost Vaccine IgG

Key Takeaways

• Among patients with inflammatory arthritis receiving supplemental COVID-19 vaccination, withholding selected targeted therapies did not provide a statistically significant spike-antibody advantage.
• Holding therapy was associated with more reported arthritis flares and interim questionnaire worsening than continuing it.
• Investigators reported recovery in both trial arms by follow-up.

Whether pausing targeted therapy changes the antibody response to supplemental coronavirus disease 2019 (COVID-19) vaccination is a clinical question for patients with rheumatoid arthritis, psoriatic arthritis, or axial spondylarthritis. Pausing treatment could also allow arthritis symptoms to worsen, including in patients whose treatment has been stable. Investigators randomized patients to continue therapy or temporarily hold it after vaccination.

Curtis and colleagues conducted the multicenter, pragmatic, randomized COVID-19 Vaccine Response (COVER) trial in the Excellence Network in Rheumatology to Innovate Care and High-Impact Research (ENRICH) practice-based network from November 2021 to May 2024. The 840 randomized patients had rheumatoid arthritis, psoriatic arthritis, or axial spondylarthritis. They had completed a primary messenger RNA (mRNA) COVID-19 vaccine series and were receiving stable tumor necrosis factor (TNF) inhibitors, interleukin-17 (IL-17) inhibitors, abatacept, or Janus kinase (JAK) inhibitors.

Patients were assigned to continue treatment or hold it for two weeks after their next supplemental vaccine dose. The primary outcome was the baseline-to-six-week geometric mean fold rise (GMFR) in spike-protein immunoglobulin G (IgG); secondary outcomes included disease flares and vaccine-related adverse events. Investigators used multiple imputation for missing primary outcomes in the intention-to-treat (ITT) analysis and conducted a per-protocol sensitivity analysis.

Spike-protein IgG rose substantially from baseline in both arms. The ITT hold-to-continue GMFR ratio was 0.96 (95% confidence interval [CI], 0.36–2.56), with no statistically significant between-arm difference.

Reported disease flares were more likely with a therapy hold: the odds ratio was 2.27 (95% CI, 1.41–3.65). Investigators described the flare signal as most pronounced among JAK-inhibitor users; this was a within-trial subgroup observation, not a randomized comparison between drug classes.

Interim worsening of at least 10 points on the Outcome Measures in Rheumatology rheumatoid arthritis Flare Questionnaire occurred in 54 of 256 patients (21.1%) aassigned to hold therapy.

In the continuation arm, 23 of 253 patients (9.1%) met that questionnaire threshold.

The absolute risk difference in interim questionnaire worsening was 12.0 percentage points (95% CI, 5.9–18.1). Investigators reported recovery in both arms by follow-up.

The wide interval around the primary antibody comparison leaves potentially meaningful differences in either direction unresolved. Binding-antibody change does not directly measure prevention of COVID-19 or other clinical protection. Missing primary outcomes were imputed, and the randomized interruption applied only to the targeted therapies studied. The JAK-inhibitor flare pattern does not establish a difference between drug classes.

The authors concluded that temporarily withholding the selected therapies did not significantly enhance the measured antibody response and was associated with transient arthritis worsening. They interpreted the findings as not supporting routine interruption of those therapies around a supplemental COVID-19 dose.

Clinician Questions

Does the two-week COVID-19 vaccination hold tested in inflammatory arthritis apply to methotrexate?

For patients with rheumatoid arthritis, psoriatic arthritis, or axial spondylarthritis receiving a supplemental COVID-19 dose, the randomized strategy held or continued stable TNF inhibitors, IL-17 inhibitors, abatacept, or JAK inhibitors. Methotrexate interruption was not the randomized strategy, so these findings do not establish its effects.

Were spike-antibody findings consistent across the targeted arthritis drugs studied around supplemental COVID-19 vaccination?

Among patients with rheumatoid arthritis, psoriatic arthritis, or axial spondylarthritis assigned to hold or continue TNF inhibitors, IL-17 inhibitors, abatacept, or JAK inhibitors after supplemental COVID-19 vaccination, investigators described the antibody comparison as consistent across drug groups and drug half-life categories. That description does not provide class-specific effect estimates.