Methotrexate hampers immunogenicity to BNT162b2 mRNA COVID-19 vaccine in immune-mediated inflammatory disease

Abstract

Objective: To investigate the humoral and cellular immune response to messenger RNA (mRNA) COVID-19 vaccines in patients with immune-mediated inflammatory diseases (IMIDs) on immunomodulatory treatment.

Methods: Established patients at New York University Langone Health with IMID (n=51) receiving the BNT162b2 mRNA vaccination were assessed at baseline and after second immunisation. Healthy subjects served as controls (n=26). IgG antibody responses to the spike protein were analysed for humoral response. Cellular immune response to SARS-CoV-2 was further analysed using high-parameter spectral flow cytometry. A second independent, validation cohort of controls (n=182) and patients with IMID (n=31) from Erlangen, Germany, were also analysed for humoral immune response.

Results: Although healthy subjects (n=208) and patients with IMID on biologic treatments (mostly on tumour necrosis factor blockers, n=37) demonstrate robust antibody responses (over 90%), those patients with IMID on background methotrexate (n=45) achieve an adequate response in only 62.2% of cases. Similarly, patients with IMID on methotrexate do not demonstrate an increase in CD8+ T-cell activation after vaccination.

Conclusions: In two independent cohorts of patients with IMID, methotrexate, a widely used immunomodulator for the treatment of several IMIDs, adversely affected humoral and cellular immune response to COVID-19 mRNA vaccines. Although precise cut-offs for immunogenicity that correlate with vaccine efficacy are yet to be established, our findings suggest that different strategies may need to be explored in patients with IMID taking methotrexate to increase the chances of immunisation efficacy against SARS-CoV-2 as has been demonstrated for augmenting immunogenicity to other viral vaccines.

Keywords: Covid-19; arthritis; methotrexate; psoriatic; rheumatoid; vaccination.

Figure 1

Anti-SARS-CoV-2 IgG levels in cohorts from New York City (A) and Erlangen (B) in healthy participants without IMID (blue), patients with IMID not receiving MTX (green) and patients with IMID treated with MTX (yellow). Solid lines represent mean titre of each group. For the New York City cohort (A), adequate response is defined as greater than 5000 units, and for the Erlangen cohort (B), adequate response is defined as greater than 5.7 (OD, 450 nm), 2 SDs of the mean of controls. Percentages and group comparisons using χ² test of independence reflect proportion of those achieving an adequate response within each group. * indicates p value less than .05 and ** indicates p value less than .001. IMID, immune-mediated inflammatory disease; MTX, methotrexate.

Figure 2

Immune cell populations from the New York City cohort by high spectral flow in healthy controls (blue, n=20), patients with immune-mediated inflammatory disease (IMID) not on methotrexate (MTX; green, n=24) and patients with IMID on MTX (yellow, n=18), at baseline and after the second dose of BNT162b2 mRNA vaccine. Prevaccination and postvaccination comparisons were performed using Wilcoxon signed-rank tests. Y-axes presented as a logarithmic scale. NS indicates no statistical significance. * indicates p value less than .05. ** indicates p value less than .01. *** indicates p value less than .0001. Tfh, T follicular helper.