Effect of a 2-week interruption in methotrexate treatment versus continued treatment on COVID-19 booster vaccine immunity in adults with inflammatory conditions (VROOM study): a randomised, open label, superiority trial

Abstract

Background: Immunosuppressive treatments inhibit vaccine-induced immunity against SARS-CoV-2. We evaluated whether a 2-week interruption of methotrexate treatment immediately after the COVID-19 vaccine booster improved antibody responses against the S1 receptor-binding domain (S1-RBD) of the SARS-CoV-2 spike protein compared with uninterrupted treatment in patients with immune-mediated inflammatory diseases.

Methods: We did an open-label, prospective, two-arm, parallel-group, multicentre, randomised, controlled, superiority trial in 26 hospitals in the UK. We recruited adults from rheumatology and dermatology clinics who had been diagnosed with an immune-mediated inflammatory disease (eg, rheumatoid arthritis, psoriasis with or without arthritis, axial spondyloarthritis, atopic dermatitis, polymyalgia rheumatica, and systemic lupus erythematosus) and who were taking low-dose weekly methotrexate (≤25 mg per week) for at least 3 months. Participants also had to have received two primary vaccine doses from the UK COVID-19 vaccination programme. We randomly assigned the participants (1:1), using a centralised validated computer randomisation program, to suspend methotrexate treatment for 2 weeks immediately after their COVID-19 booster (suspend methotrexate group) or to continue treatment as usual (continue methotrexate group). Participants, investigators, clinical research staff, and data analysts were unmasked, while researchers doing the laboratory analyses were masked to group assignment. The primary outcome was S1-RBD antibody titres 4 weeks after receiving the COVID-19 booster vaccine dose, assessed in the intention-to-treat population. This trial is registered with ISRCT, ISRCTN11442263; following the pre-planned interim analysis, recruitment was stopped early.

Findings: Between Sept 30, 2021 and March 3, 2022, we recruited 340 participants, of whom 254 were included in the interim analysis and had been randomly assigned to one of the two groups: 127 in the continue methotrexate group and 127 in the suspend methotrexate group. Their mean age was 59·1 years, 155 (61%) were female, 130 (51%) had rheumatoid arthritis, and 86 (34%) had psoriasis with or without arthritis. After 4 weeks, the geometric mean S1-RBD antibody titre was 22 750 U/mL (95% CI 19 314-26 796) in the suspend methotrexate group and 10 798 U/mL (8970-12 997) in the continue methotrexate group, with a geometric mean ratio (GMR) of 2·19 (95% CI 1·57-3·04; p<0·0001; mixed-effects model). The increased antibody response in the suspend methotrexate group was consistent across methotrexate dose, administration route, type of immune-mediated inflammatory disease, age, primary vaccination platform, and history of SARS-CoV-2 infection. There were no intervention-related serious adverse events.

Interpretation: A 2-week interruption of methotrexate treatment for people with immune-mediated inflammatory diseases resulted in enhanced boosting of antibody responses after COVID-19 vaccination. This intervention is simple, low-cost, and easy to implement, and could potentially translate to increased vaccine efficacy and duration of protection for susceptible groups.

Funding: National Institute for Health and Care Research.

Conflict of interest statement

Declaration of interests The institutions of the authors received funding from the NIHR-MRC-EME programme (award number NIHR 134607) towards conducting this research. LC reports research grants from Abbvie, Amgen, Celgene, Eli Lilly, Janssen, Novartis, Pfizer, and UCB, and personal consulting fees or lecture fees from AbbVie, Amgen, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Eli Lilly, Gilead, Galapagos, GlaxoSmithKline, Janssen, Medac, Moonlake, Novartis, Pfizer, and UCB in the past 36 months. JB reports research grants from Pfizer and travel or conference fees from UCB, Pfizer, and Eli Lilly. AA reports institutional research grants from AstraZeneca and Oxford Immunotec, personal author royalties from UpTodate and Springer, personal consulting fees from Inflazome and NGM Biopharmaceuticals, and personal payments for lectures from Menarini Pharmaceuticals and Cadilla Pharmaceuticals, in the past 36 months and unrelated to the current work. AA is also co-chair of the OMERACT CPPD Working Group and co-chair of the ACR/EULAR CPPD Classification Criteria Working Group. JSN-V-T was seconded to the Department of Health and Social Care in England until March 31, 2022.

Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.

Figures

Figure 1

Trial profile Anti-S1-RBD=antibody for S1 subunit of SARS-CoV-2 spike protein receptor-binding domain. *Some patients had more than one stated reason for ineligibility.

Figure 2

Treatment effects (geometric mean ratio) for different subgroups at 4 weeks Vertical black line indicates no effect. Dotted grey line indicates the overall effect.

Figure 3

Treatment effects (geometric mean ratio) for different subgroups at 12 weeks Vertical black line indicates no effect. Dotted grey line indicates the overall effect.