Background/Purpose: Immunosuppressive treatments inhibit vaccine-induced immunity. We evaluated if a two-week interruption of methotrexate treatment immediately after COVID-19 booster improved antibody response against spike protein of the receptor binding domain (S1-RBD) and live virus neutralization (ancestral Wuhan and Omicron BA.1) in patients with immune mediated inflammatory diseases (IMIDs).

Methods: We conducted an open-label, prospective, parallel-group, randomized controlled, superiority trial in 26 UK hospitals. Adults attending Rheumatology and Dermatology clinics taking methotrexate (≤25mg/week) for ≥3 month for inflammatory conditions were randomly assigned 1:1 using minimization to suspend or continue methotrexate treatment for two-weeks immediately after their COVID-19 booster. Data were analyzed using an intention to treat approach.

Results: 383 participants (mean age 59.0 years, 61% female) were randomized to either suspend or continue methotrexate arms. 61.4% (n=235) were female, 54.3% (n=208) had RA, 31.9% (n=122) psoriasis with/without arthritis. The median methotrexate dose was 20 mg/week. 94.5% (n=362) received a mRNA vaccine booster, mean 178 days after the second dose of the primary vaccination. Adherence to the intervention was high with 96.3% (n=184) and 97.4% (n=187) self-reported adherence with allocation in the suspend and continue methotrexate groups respectively.

At four-weeks, the geometric mean (95% confidence interval (CI)) S1-RBD antibody level was 25,413(22,227-29,056) and 12,326(10,538-14418) U/mL in suspend and continue treatment groups respectively, with geometric mean ratio (GMR)(95%CI) 2.08(1.59-2.70), p< 0.0001, mixed-effects model. The increase in antibody response was consistent across age-groups, methotrexate doses, route, IMIDs, primary vaccination platform, and prior SARS-CoV-2 infection. Enhanced antibody responses were sustained at 12 and 26 weeks with GMR(95%CI) 1.88(1.44-2.46) and 1.50(1.12-2.01) respectively. Planned exploratory subgroup analyses suggested a greater treatment effect at higher methotrexate dose (Interaction GMR effect (95% CI) 0.67(0.47, 0.96) at 4-weeks and 0.64(0.420.96) at 12-weeks).

The Wuhan Hu-1 IC50 neutralizing antibody titer was higher in the methotrexate suspend group compared to the continue treatment group at four and 26-weeks. In a mixed-effect model, the GMR (95% CI) for Wuhan Hu-1 IC50 neutralizing antibody titer on suspending methotrexate for two-weeks was 2.56 (1.21-5.44) at 4 weeks, and 3.50 (1.34-9.18) at 26-weeks. The Omicron BA.1 IC50 cross neutralizing antibody titer was higher in the methotrexate suspend group compared to the continue treatment group at 4-weeks with GMR (95% CI) 2.42 (1.45-4.05).

There were no differences in quality of life. Self-reported disease activity deteriorated slightly at 4-weeks in the suspend methotrexate group, but normalized by week-12.

Conclusion: Two-week interruption of methotrexate treatment for IMIDs enhanced boosting of antibody responses after COVID-19 vaccination that were sustained at 12 and 26 weeks. (Trial registration: ISRCTN11442263)

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/two-week-break-in-methotrexate-treatment-and-covid-19-vaccine-response-results-of-the-vaccine-response-on-off-methotrexate-vroom-study-an-open-label-prospective-two-arm-parallel-group-multi-cen/