Vaccine Response On/off Methotrexate (VROOM): does temporarily suspending methotrexate treatment for two weeks enhance COVID-19 vaccine response?- A Randomised Controlled Trial

Question: Does interrupting low-dose methotrexate treatment for two weeks after SARS-CoV-2 vaccine booster improve the immune response to it, and what are the underlying mechanisms? Background: Low-dose methotrexate has emerged as the first line systemic therapy for chronic inflammatory conditions such as rheumatoid arthritis and psoriasis. However, its inhibitory effects on lymphocyte function causes suboptimal vaccine immunogenicity. A brief two-week treatment interruption after vaccination with the influenza vaccine protected 46% participants against all included strains compared to 22% participants with continued treatment. It is unknown if such a treatment interruption would improve immunity to vaccines against the SARS-CoV-2. This uncertainty resulted in conflicting advice from specialist societies, anxiety among patients, and may be addressed during the booster vaccinations in winter 2021. Aim: To examine the effects of a two-week interruption in low-dose methotrexate treatment (upto 25 mg/week) after SARS-CoV-2 vaccine booster on vaccine immunogenicity in people with inflammatory conditions. Study design: Prospective, parallel group, randomised controlled trial with internal feasibility assessment, and nested mechanistic study. Setting: Secondary care Population: Adults (age 18 years or more) with stable inflammatory disease, on low-dose weekly methotrexate, able to interrupt treatment for two weeks according to their consultant. Randomisation: 1:1 individual randomisation. Minimised by inflammatory conditions, age (40 year or less, 41-64 year, 65 year or more), SARS-CoV-2 vaccine received in current vaccination cycle (mRNA vs. other). Intervention: Advice to withhold methotrexate for two weeks post SARS-Cov-2 vaccine booster. Comparator: To continue with methotrexate as usual. Outcomes: Primary: Anti-spike receptor binding domain (RBD) antibody at week 4. Secondary: Anti-spike-RBD antibody at week 12; disease flare up, disease activity, treatment changes, quality of life at weeks 4 and 12. Mechanistic: Antibody neutralisation titres at weeks 4 and 12; effects of methotrexate adherence using validated bioassay on immunological outcomes. Research contact: 1] Pre-booster: consent, research assessments, blood collection. 2] Randomisation (phone): reconfirm eligibility, assess global disease activity. 3] Weeks 1, 2 (SMS): adherence to intervention, global disease activity (only week 2). 4] Weeks 4, 12: research assessment, blood collection. Analysis: Multi-level mixed effects models adjusted for randomisation factors and important prognostic factors using the as randomised population. Sample size: 560 participants (280 in each arm) will allow detection of an absolute difference of 25% anti-spike-RBD antibody, using 90%, 2-sided a=5% and 10% loss to follow up. 100 participants (50 in each arm) will participate in the mechanistic sub-study and provide additional blood samples for methotrexate adherence biomarker and neutralisation assay. Timeline: Set-up: months 1-3; Recruitment: months 4-16; Laboratory analysis: months 6 to 21; Data analysis: months 15-24. Write-up: months 21-24. Impact and dissemination: The findings will be disseminated to patients, the public, policy makers including the Joint Committee on Vaccinations and Immunisation, and Rheumatology and Dermatology societies where they will influence clinical practice.