Temporary 2-week suspension of methotrexate treatment to enhance COVID-19 vaccine response in people with immune-mediated inflammatory diseases: the VROOM RCT

Objective Methotrexate is first-line treatment for many immune-mediated inflammatory diseases. However, it inhibits vaccine-induced immunity – a major concern for this vulnerable group of patients. We evaluated if a 2-week interruption of methotrexate treatment immediately after COVID-19 booster improved antibody response against spike protein of the receptor binding domain and live virus neutralisation (ancestral Wuhan and Omicron BA.1) in patients with immune-mediated inflammatory diseases. Design Open-label, prospective, individually randomised, parallel-group, controlled superiority trial with 1 : 1 randomisation. Setting Multicentre, secondary-care rheumatology and dermatology outpatient clinics. Participants Adults with immune-mediated inflammatory diseases attending rheumatology and dermatology clinics taking methotrexate (≤ 25 mg/week) for ≥ 3 months. Intervention Suspending methotrexate treatment for 2 weeks immediately after COVID-19 booster vaccination. Main outcome(s) and measure(s) The primary outcome was spike protein of the receptor binding domain antibody level 4 weeks after COVID-19 booster vaccination. Secondary outcomes were spike protein of the receptor binding domain antibody levels 12 and 26 weeks after COVID-19 vaccine dose; live virus neutralisation (ancestral Wuhan Hu-1, Omicron BA.1) at weeks 4, 12 and 26; and self-reported inflammatory disease activity, flare-ups, quality of life, global assessment of inflammatory disease and adherence with trial allocation. Results A total of 383 participants (61% female, average age 59.0 years) were randomised to either suspend or continue methotrexate. The geometric mean (95% confidence interval) spike protein of the receptor binding domain antibody titre was 25,413 (22,227 to 29,056) and 12,326 (10,538 to 14,418) U/ml in those who suspended and continued methotrexate, respectively. The geometric mean ratio (95% confidence interval) was 2.08 (1.59 to 2.70), p < 0.0001. The intervention effect was present across prognostic subgroups, for example, age groups, methotrexate dose, methotrexate administration route, diseases and past severe acute respiratory syndrome coronavirus 2 infection. Enhanced antibody responses were sustained at 12 and 26 weeks with geometric mean ratio (95% confidence interval) 1.88 (1.44 to 2.46) and 1.50 (1.12 to 2.01), respectively. Interruption of treatment improved neutralisation of Wuhan and Omicron BA.1 at 4 weeks with geometric mean ratio (95% confidence interval) 2.56 (1.21 to 5.44) and 2.42 (1.45 to 4.05), respectively. Self-reported inflammatory disease activity initially deteriorated in the suspended methotrexate group, but the groups were comparable at week 12. Conclusion Two-week interruption of methotrexate treatment for immune-mediated inflammatory diseases enhanced antibody responses after COVID-19 vaccination that were sustained at 12 and 26 weeks. Limitations Lack of participant masking which could have affected self-reported outcomes. Condition-specific disease activity was not used as we recruited participants with a range of diseases, with many lacking validated outcome measures. We did not have data for memory B-cell and T-cell responses. Some hospitals declined to participate in the 26-week follow-up visit which was added to the study after interim analysis, due to lack of capacity, contributing to increased attrition at week 26. Future work Future research should evaluate whether interrupting other immune-suppressing treatments soon after vaccination against COVID-19 or other infectious diseases can improve immune responses. Further research should also evaluate whether a shorter hold in methotrexate would improve the immune response elicited by vaccination. Funding This synopsis presents independent research funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation programme as award number NIHR134607.