Holding Methotrexate After Second COVID-19 Vaccine Dose May Be Best in Psoriatic, Rheumatoid Arthritis

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Holding methotrexate after the second COVID-19 vaccine dose is associated with similar immunogenicity and a lower risk of disease flare compared with withholding methotrexate after both vaccine doses.

In patients with psoriatic arthritis (PsA) or rheumatoid arthritis (RA), withholding methotrexate for 2 weeks after vaccination with ChAdOx1 nCov-19 (AstraZeneca) for COVID-19 led to a higher antibody response compared with the continuation of methotrexate, although this was accompanied by an increased risk of disease flare. This is according to research published in The Lancet Rheumatology,1 which found withholding methotrexate only after the second vaccine dose may carry a lower risk for disease flare, with no considerable difference in the antibody response.

“This finding remained despite the wide gap between the 2 doses of the ChAdOX1 n COV-19 vaccine (12–16 weeks) and could be translated into practice by withholding methotrexate only during the second dose of vaccine to achieve an optimal trade-off between immunogenicity and risk of flare,” Padmanabha Shenoy, DM, of the Centre for Arthritis and Rheumatism in Cochin, India, and colleagues, noted.

An optimal COVID-19 vaccination strategy is essential for vulnerable population groups, including people with autoimmune inflammatory arthritis on immunosuppressants such as methotrexate, which inhibit vaccine-induced immunity against SARS-CoV-2. However, the evidence supporting methotrexate withdrawal at the time of COVID-19 vaccination is scarce, especially for the ChAdOx1 nCoV-19 vaccine.

Between July 6 and December 15, 2021, participants were recruited to 2 parallel, randomized trials, dubbed MIVAC I and MIVAC II. Researchers assessed the post-vaccination antibody titers and disease flare rates that resulted from withholding methotrexate for 2 weeks after each dose of the ChAdOx1 nCov-19 vaccine (MIVAC I) or only after the second dose of vaccine (MIVAC II) compared with continuation of methotrexate. The trials, which were undertaken at a single center in India, included people with either PsA or RA with stable disease activity, who had been on a fixed dose of methotrexate for the preceding 6 weeks. People with previous COVID-19 or who were positive for anti-SARS-CoV-2 nucleocapsid antibodies were excluded, as were those on high-dose corticosteroids and rituximab. The primary outcome for both trials was the titer of anti-receptor binding domain (RBD) antibody measured 4 weeks after the second vaccine dose.

In MIVAC I, a total of 158 participants (94% women) completed the study. The median post-vaccination antibody titers in the methotrexate hold group (n=80, 14% PsA) were significantly higher compared with the control group (n=78, 8% PsA) (2484.0 IU/mL, IQR 1050.0–4388.8 vs 1147.5 IU/mL, 433.5–2360.3; p=0.0014). Meanwhile, 25% of the methotrexate hold group and 8% of the methotrexate continuation group had a disease flare after the first vaccine dose (p=0.0050). After the second vaccine dose, the respective rates were 24% and 13% (p=0.10).

In MIVAC II, a total of 157 participants (86% women) completed the study. The methotrexate hold group (n=76, 8% PsA) had higher post-vaccination antibody titers compared with the control group (n=81, 1% PsA) (2553.5 IU/ml, IQR 1792.5–4823.8 vs 990.5, 356.1–2252.5; p<0.0001). However, no significant difference was found in the proportion of participants with a disease flare between the groups (12% of the methotrexate hold group vs 5% of the methotrexate continuation group; p=0.15).

No serious adverse events were reported during the trial period.

“Interruption of methotrexate during the second dose of ChAdOx1 nCov-19 vaccine appears to be a safe and effective strategy to improve the antibody response in patients with rheumatoid or psoriatic arthritis,” investigators concluded.


Skaria TG, Sreeprakash A, Umesh R, et al. Withholding methotrexate after vaccination with ChAdOx1 nCov19 in patients with rheumatoid or psoriatic arthritis in India (MIVAC I and II): results of two, parallel, assessor-masked, randomised controlled trialsLancet Rheumatol. 2022;4(11):e755-e764. doi:10.1016/S2665-9913(22)00228-4