Temporary Methotrexate Withdrawal Improves COVID-19 Immunogenicity

Results indicated that a brief methotrexate withdrawal after COVID-19 vaccine doses may improve immunogenicity in patients with rheumatoid arthritis.

A 2-week methotrexate (MTX) withdrawal after COVID-19 vaccine doses improves immune response in patients with rheumatoid arthritis (RA), according to a study published in the Annals of Rheumatic Diseases.1 Increased flares after the second MTX withdrawal may be linked to a shorter interval between doses.

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“Temporary immunosuppressant withdrawal is suggested as a possible strategy to enhance vaccine immunogenicity in patients with autoimmune rheumatic diseases (ARD),” investigators stated. “In this context, Park et al demonstrated that the discontinuation of MTX improved immunogenicity of the annual influenza vaccines in patients with RA, concluding that the interruption of 2 MTX doses after vaccination was safe and equally effective as holding 4 MTX doses. Due to these results, recommendations have emerged favoring the withdrawal of MTX for 1–2 weeks after COVID-19 vaccines.”

The single-center, prospective, randomized, intervention study evaluated patients with RA (≥18 years old) who were randomized to withdraw MTX (MTX-hold) for 2 weeks after each dose of the vaccine or maintain MTX (MTX-maintain). Patients were analyzed at day 0 (D0), day 28 (D28), and day 69 (D69). Those involved in the study were in remission or in a state of low disease activity (Clinical Disease Activity Index [CDAI] score of ≤10) on D0 and were receiving a maximum 7.5 mg/day of oral prednisone.

Excluded patients included any person with a history of anaphylaxis to vaccine components, symptoms of COVID-19 at vaccination, hospitalization, previous COVID-19 vaccinations, demyelinating disease, decompensated heart failure (class III/IV), and blood transfusion ≤6 months.

Primary outcomes evaluated the anti-SARS-CoV-2 S1/S2 IgG seroconversion (SC) and neutralizing antibody (NAb) positivity at D69. Secondary outcomes were the geometric mean titers (GMT) as well as flare rates.

A total of 138 patients were included in the study, with 60 patients in the MTX-hold group and 69 patients in the MTX-maintain group. Exclusions included 27 patients with a positive baseline IgG/NAb and 10 patients with CDAI >10 at D28. Of the remaining 47 patients in the MTX-hold cohort, 21.3% (n = 20) reported a flare on D28 and did not stop MTX the second time. Demographics, comorbidities, disease duration, disease activity, and current therapies were comparable between both groups. However, prednisone was more frequent in the MTX-hold group.

At D69, the MTX-hold group (n = 37) had higher rates of SC (p=0.019) when compared with the MTX-maintain group (n =55) (78.4% vs 54.5%, respectively). Differences in NAb positivity were not significant (p=0.217).

Further analysis indicated age (≥60 years) and leflunomide combination were negatively associated with SC. Adhering to the MTX withdrawal protocol was positively linked to SC.

Rates of flare at D28 were comparable in both groups (p>0.05). While CDAI >10 was more prevalent in the MTX-hold group at D69 (p=0.011), flares were similar in both groups based on the Disease Activity Score-28 (DAS28) (p=0.188). Throughout the study, the same pattern of flares was reported. While groups were similar in DAS28 variation, a higher number of flares was observed in patients with higher CDAI scores and those who reported disease worsening.

A strength of the study was including patients who were in remission or had low disease activity, as well as those receiving low prednisone doses, which indicates safer conditions for MTX withdrawal. A precise analysis of flares was accounted for using the randomized, clinical design of the study in addition to the evaluation of disease activity status and validated RA scores. Vaccine immunogenicity and flares were analyzed alongside disease features, treatment, and demographic information. However, the small sample size and exclusion criteria limited and underpowered the trial.

“This study provides novel data that 2-week MTX withdrawal after each vaccine dose improves anti-SARS-CoV-2 IgG response to the Sinovac-CoronaVac vaccine,” investigators concluded. “This strategy requires close surveillance and shared decision making due to the possibility of disease activity worsening.”


Araujo CSR, Medeiros-Ribeiro AC, Saad CGS, et al. Two-week methotrexate discontinuation in patients with rheumatoid arthritis vaccinated with inactivated SARS-CoV-2 vaccine: a randomised clinical trial [published online ahead of print, 2022 Feb 22]. Ann Rheum Dis. 2022;annrheumdis-2021-221916. doi:10.1136/annrheumdis-2021-221916