Downside of Holding Methotrexate with COVID-19 Vaccination Save

A recent prospective, randomized, blinded clinical trial has shown that a 2 week hold of methotrexate (MTX) following COVID-19 (Sinovac-CoronaVac) vaccination resulted in greater anti-SARS-CoV-2 immunogenicity; but there was an increase in flare rates after the second dose of vaccine.

The ACR task force on COVID-19 vaccination has recommended temporary cessation of MTX with COVID-19 vaccination, largely based on data accrued with influenza vaccination where holding MTX improved the overall immunogenicity of the vaccine.

In this study, 139 adult rheumatoid arthritis (RA) patients with stable disease activity (CDAI ≤10) and taking prednisone ≤7.5 mg/day) were either randomised (1:1) to withdraw MTX (MTX-hold) for 2 weeks after each vaccine dose or maintain MTX (MTX-maintain), with evaluations at day 28 (D28) and D69. Coprimary outcomes were anti-SARS-CoV-2 S1/S2 IgG seroconversion (SC) and neutralising antibody (NAb) positivity at D69. 

Nine patients were excluded (5 COVID-19, 4 protocol violations). Safety evaluation included 60 patients in the MTX-hold and 69 patients in the MTX-maintain group. Further exclusions included 27 patients (13 (21.7%) vs 14 (20.3%), p=0.848) with positive baseline IgG/NAb and 10 patients (21.3%) in MTX-hold with CDAI >10 at D28.

At D69, the MTX-hold group (n=37) had a higher rate of seroconversions than the MTX-maintain group (n=55) (78% vs 55%; p=0.019). There were no differences in neutralizing Ab positivity (62% vs 49%; p=0.217).

At D28 flare, the rates were comparable in both groups (p=0.576), whereas RA flares (CDAI >10) were more frequent in MTX-hold at D69 (p=0.024).  Interestingly they excluded another 37 patients after randomization and vaccination - including 10 patients (21.3%) in MTX-hold who flared (CDAI >10) at D28. Another 27 patients were excluded for high baseline neutralizing antibodies.

While seroconversion rates were better with holding MTX, increased flare rates after the first and second MTX withdrawal questions the marginal benefit of seroconversion (78% vs 55%). Shared decision making and discussion of the possibility of flares is advised.