Withholding methotrexate after COVID-19 vaccination: different strategies, same results? – The Lancet

We read with great interest the Article by Teny Grace Skaria and colleagues

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  • 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 trials.

about the strategy of withdrawing methotrexate after the ChAdOx1 nCov-19 (Oxford–AstraZeneca) vaccine in patients with rheumatoid arthritis and psoriatic arthritis. Their study confirmed the benefit of 2-week methotrexate interruption after vaccination in a population of patients predominantly younger than 60 years (MIVAC I and MIVAC II), and further demonstrated the benefit of methotrexate interruption only after the second vaccine dose (MIVAC II)—a strategy that might lead to a lower incidence of flares.

1

  • 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 trials.

Levels of antibodies against the spike receptor binding domain (anti-RBD) were comparable at the end of MIVAC I and MIVAC II, suggesting that withdrawing methotrexate after the second vaccine might be equivalent to withdrawing it after both vaccine doses. However, structural differences between the studies might preclude a definitive conclusion about the equivalence of the strategies regarding immunogenicity. MIVAC I excluded patients who were positive for anti-RBD or anti-nucleocapsid antibodies before the first vaccine dose; whereas MIVAC II only excluded patients with anti-nucleocapsid antibodies detectable after the first dose. This distinct baseline criterion most likely resulted in a greater number of patients with previous SARS-CoV-2 infection (ie, anti-RBD antibody positive or formerly anti-nucleocapsid antibody-positive patients who became negative before enrolment) in MIVAC II. Patients with previous SARS-CoV-2 infection are known to respond better to vaccines compared with patients who are naive to SARS-CoV-2.

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  • Aikawa NE
  • Kupa LVK
  • Pasoto SG
  • et al.
Immunogenicity and safety of two doses of the CoronaVac SARS-CoV-2 vaccine in SARS-CoV-2 seropositive and seronegative patients with autoimmune rheumatic diseases in Brazil: a subgroup analysis of a phase 4 prospective study.

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  • Boekel L
  • Steenhuis M
  • Hooijberg F
  • et al.
Antibody development after COVID-19 vaccination in patients with autoimmune diseases in the Netherlands: a substudy of data from two prospective cohort studies.

In addition, studies have shown that post-infection longevity for anti-nucleocapsid antibodies was lower than anti-RBD antibodies and waned rapidly in immunosuppressed patients.

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  • Søfteland JM
  • Gisslén M
  • Liljeqvist JÅ
  • et al.
Longevity of anti-spike and anti-nucleocapsid antibodies after COVID-19 in solid organ transplant recipients compared to immunocompetent controls.

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  • Caballero-Marcos A
  • Salcedo M
  • Alonso-Fernández R
  • et al.
Changes in humoral immune response after SARS-CoV-2 infection in liver transplant recipients compared to immunocompetent patients.

Therefore, MIVAC II might have included some patients with previous SARS-CoV-2 infection at baseline who were prone to a more robust vaccine response. Supporting this notion, a comparison (using χ2 test) of overall MIVAC I and II patients’ seroconversion rates after the first dose, as depicted in table 2,

1

  • 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 trials.

showed that pooled MIVAC I patients had lower seroconversion rates (n=104 [66%]) than did pooled MIVAC II patients (n=126 [80%]; p=0·0039), regardless of the methotrexate holding strategy. Even among patients in methotrexate-hold groups, those who withdrew methotrexate after the first dose had lower seroconversion rates (MIVAC I n=50 [63%]) than patients who did not (MIVAC II n=63 [83%]; p=0·0044). In summary, MIVAC I and II populations are probably different regarding previous exposure to SARS-CoV-2, which might account for the comparable immunogenicity observed with different methotrexate discontinuation schemes. Stopping methotrexate solely after the second vaccine dose instead of after both doses in the primary vaccine schedule might be safer, but further studies are necessary to compare the immune benefit of these strategies. Source