In patients with inflammatory arthritis, temporary interruption of biologic or Janus kinase inhibitor (JAKi) therapies during supplemental COVID-19 vaccination does not help improve humoral immunogenicity and even increases flare risk, as shown in the pragmatic COVER trial.
In the intention-to-treat analysis, the primary outcome of immunoglobulin G (IgG) levels against the SARS-CoV-2 spike protein increased over 6 weeks of follow-up after a COVID-19 booster vaccination, with no significant difference seen between patients who paused their immunomodulatory medications for 2 weeks after receiving their booster dose (interruption group) and those who continued taking their immunomodulatory medications without interruption (continuation group) (adjusted geometric mean fold rise [GMFR], 4.69 vs 4.86; GMFR ratio, 0.96, 95 percent confidence interval [CI], 0.36–2.56). [JAMA Intern Med 2026;doi:10.1001/jamainternmed.2026.4894]
“Results were consistent across drug subgroups and drug half-life categories,” according to lead investigator Dr Jeffrey Curtis from the University of Alabama at Birmingham, Birmingham, Alabama, US, and colleagues.
Meanwhile, patients in the interruption group were more likely to report flare or disease worsening following a booster dose as compared with those in the continuation group (odds ratio [OR], 2.27, 95 percent CI, 1.41–3.65). The flare signal associated with pausing immunomodulatory treatment was most pronounced among JAKi users (OR, 3.65, 95 percent CI, 1.69–7.87) and did not differ significantly among users of abatacept, anti–IL-17, or TNFi, although point estimates consistently favoured continuation.
Data from the Outcome Measures in Rheumatology (OMERACT) Rheumatoid Arthritis Flare Questionnaire (RA-FQ) showed that at a median of 10 days after booster vaccination, patients in the interruption group experienced a clinically meaningful increase in disease activity (2.63 points from baseline), while those in the continuation group remained stable (0.15 points), with 21.1 percent and 9.1 percent of patients in the respective groups meeting the ≥10-point worsening threshold (risk difference, 12 percent, 95 percent CI, 5.9–18.1). By week 6 post-vaccination, both groups showed modest improvements in disease activity, with similar worsening rates (11.2 percent in each group).
The OMERACT RA-FQ data validated the disease activity worsening associated with pausing immunomodulatory medications, with worsening “concentrated during the first 1 to 2 weeks following vaccination and being self-limited,” Curtis and colleagues said.
Furthermore, while abatacept and JAKi use were associated with attenuated antibody responses compared with anti–IL-17 and TNFi, which was consistent with prior data, pausing these treatments for 2 weeks did not improve COVID-19 vaccine immunogenicity, “demonstrating that a medication’s attenuation of vaccine response does not mean brief interruption can restore it,” they continued.
Together, “these findings suggest that vaccination status should ideally be optimized before initiating biologic therapy when feasible, and agents with less sustained immunosuppressive effects on vaccine response, such as TNFi and ixekizumab, may be preferable to abatacept or JAKi in patients expected to require repeated COVID-19 vaccination,” according to Curtis and colleagues.
Individualizing perivaccination care
In an invited commentary, Drs Jin Kyun Park and Eun Bong Lee from Seoul National University College of Medicine, Seoul, Korea, said: “These findings [from COVER] reinforce an emerging principle that the perivaccination management of immunosuppressive therapy should not follow a one-size-fits-all approach. Rather, decisions should be guided by the mechanism of action of the individual agent, the underlying disease, the type of vaccine, and the need to balance optimal vaccine immunogenicity against maintenance of disease control.” [JAMA Intern Med 2026;doi:10.1001/jamainternmed.2026.4891]
Park and Lee, however, cautioned against generalizing the results, noting several considerations in the trial methodology.
“First, the study enrolled patients with inflammatory arthritis but excluded those with connective tissue diseases, such as systemic lupus erythematosus and idiopathic inflammatory myopathies, which have distinct immunopathogenic mechanisms and are commonly treated with different immunosuppressive agents, including mycophenolate mofetil and calcineurin inhibitors,” Park and Lee noted.
“Second, booster responses are driven predominantly by antigen-experienced memory lymphocytes, which may be less susceptible to interruption of specific immunomodulatory pathways than the activation of naive lymphocytes during primary immunization. Third, the primary outcome focused on humoral immunogenicity,” they added.
Park and Lee called for additional high-quality trials evaluating individual immunosuppressive agents across different autoimmune diseases, vaccine platforms, and both humoral and cellular immune responses.
“Ultimately, the data [from those additional research] should inform the development of practical, agent- and vaccine-specific recommendations by professional societies, clearly identifying which immunosuppressive therapies should be temporarily withheld, for which vaccines, and in which clinical settings. Such guidance would be particularly valuable for general internists and other clinicians who routinely administer vaccines to patients receiving immunosuppressive therapy,” they concluded.
COVER trial
COVER included 840 patients with rheumatoid arthritis, psoriatic arthritis, or axial spondylarthritis who were receiving care in the Excellence Network in Rheumatology to Innovate Care and High-Impact Research (ENRICH) practice-based network.
All 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, or JAKi. These patients were randomly assigned to pause (n=420) or continue (n=420) therapy for 2 weeks following their next COVID-19 booster dose administration.
In the interruption group, the mean age of the patients was 59.1 years, 80 percent were female, 92 percent were White, 16 percent were currently smoking, and the mean BMI was 31.6 kg/m2. In the continuation group, the mean age of the patients was 60 years, 76 percent were female, 88 percent were White, 12 percent were currently smoking, and the mean BMI was 31.8 kg/m2.
In terms of adverse events, general symptoms were more frequent in the interruption vs continuation group (61 percent vs 49 percent), which was driven by new or worsened fatigue (30 percent vs 19 percent) and consistent with perivaccination disease worsening in the interruption group. Nausea was more frequent in the continuation group (25 percent vs 16 percent), while injection site reactions did not significantly differ between the two treatment groups.