Pausing Methotrexate Improves Antibody Response Following COVID-19 Vaccination

methotrexate syringe
Researchers evaluated the effect of methotrexate and its discontinuation on the humoral immune response following COVID-19 vaccination in patients with autoimmune rheumatic diseases.

Older adult patients with autoimmune rheumatic diseases (AIRDs) treated with methotrexate (MTX) should temporarily discontinue the drug for at least 10 days after receiving COVID-19 vaccination, according to study findings published in Annals of the Rheumatic Diseases

A retrospective subanalysis of an observational cohort study of patients with AIRDs at the Charité Department for Rheumatology and Clinical Immunology in Berlin, Germanywas was conducted between April 2021 and September 2021. The researchers sought to evaluate the effect of MTX and its discontinuation on humoral response following COVID-19 vaccination in patients with AIRDs. The secondary objective was to establish additional influencing factors on the antibody response among these patients. 

A total of 73 patients were enrolled in the study. All study participants were at least 18 years of age, had an AIRD diagnosis, and had received a COVID-19 vaccine that is authorized for use in Germany. Neutralizing SARS-CoV-2 antibodies were measured following a second COVID-19 vaccine in 64 patients (70.3% women; mean age of 61 years) with AIRDs who received MTX therapy. Thirty-one of these patients temporarily paused treatment with MTX. An additional 21 patients (90.5% women; mean age of 61 years) with AIRDs who were not receiving any type of immunosuppressive therapy served as the control group.

Antibody response was measured at approximately 2 weeks following the second vaccination, with a maximum range of 11 to 112 days. Neutralizing antibody levels were evaluated via use of a surrogate virus neutralization test. Patients who achieved inhibition rates of at least 30% were considered to have demonstrated a SARS-CoV-2-specific humoral response and were defined as responders, whereas individuals with inhibition rates of less than 30% were defined as nonresponders.

Patients who received MTX therapy exhibited a significantly lower mean antibody response compared with those with AIRDs who were not receiving immunosuppressive therapy (71.8% vs 92.4%, respectively; P <.001). Among participants treated with MTX, age correlated negatively with immune response (r= –0.49; P <.001).

All of the 9 patients who had antibody levels below the cutoff were older than age 60 years. Patients who paused MTX treatment during their first vaccination had significantly higher mean neutralizing antibody levels following their second vaccination compared with patients who continued MTX treatment during both vaccinations (83.1% vs 61.2%, respectively; P =.001). This finding was particularly apparent in patients who were older than age 60 years (80.8% vs 51.9%, respectively; P =.001). The effect of the time period following vaccination was greater than that of the time period prior to vaccination, with the critical cutoff being 10 days.

A major limitation of the study was the fact that because data regarding the MTX intake schedule during vaccination were evaluated retrospectively, recall bias could not be excluded. Due to the small sample size, factors in the multivariable logistic regression modeling were limited, which could lead to bias and residual confounding.

The study authors concluded that age (≥60 years), short vaccine interval, and MTX continuation were key factors associated with an inadequate antibody response among patients with an AIRD receiving COVID-19 vaccination.

Disclosure: One of the study authors has declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of the author’s disclosures. 


Arumahandi de Silva AN, Frommert LM, Albach FN, et al. Pausing methotrexate improves immunogenicity of COVID-19 vaccination in elderly patients with rheumatic diseases. Ann Rheum Dis. 2022;81(6):881-888. doi:10.1136/annrheumdis-2021-221876

This article originally appeared on Rheumatology Advisor