Methotrexate Impairs COVID Vax Response

One-third of patients with immune-mediated inflammatory diseases being treated with methotrexate showed attenuated responses to the COVID-19 vaccine, researchers reported.

In two independent cohorts, robust antibody responses were observed in 98.1% of healthy controls and in 91.9% of patients with immune-mediated diseases not on methotrexate, but in only 62.2% of patients receiving methotrexate (P<0.001), reported Jose U. Scher, MD, of NYU Langone Health in New York City, and colleagues.

“Our results suggest that the optimal protection of patients with immune-mediated inflammatory diseases against COVID-19 will require further studies to determine whether additional doses of vaccine, dose modification of methotrexate, or even temporary discontinuation of this drug can boost immune response as has been demonstrated for other viral vaccines in this patient population,” they wrote in Annals of the Rheumatic Diseases.

Patients with immune-mediated diseases have an increased susceptibility to viral infections both because of the underlying disease and the medications used to control it. Previous experience, particularly with the influenza vaccine, has suggested that vaccine responses were less robust among patients receiving certain conventional disease-modifying antirheumatic drugs (DMARDs).

To explore this question, researchers from New York City and Erlangen, Germany, obtained peripheral blood monocyte cells and sera from patients at their local centers, analyzing pre- and post-immunization SARS-CoV-2 spike-specific antibody titers. Participants were given two doses of the Pfizer/BioNTech mRNA vaccine. In the New York cohort, cellular immune responses were also measured using high-dimensional spectral flow cytometry.

The New York cohort recruited 25 patients with immune-mediated inflammatory diseases on methotrexate alone or in combination with other drugs, 26 on anti-cytokine therapy such as tumor necrosis factor (TNF) inhibitors and/or oral immunomodulators (other than methotrexate), and 26 healthy controls.

The Erlangen cohort included 20 patients on methotrexate monotherapy, 11 on TNF inhibitors alone, and 182 healthy controls.

The majority of patients in both groups had rheumatoid arthritis or psoriasis/psoriatic arthritis. More than two-thirds were women. Patients receiving methotrexate were older than patients on other medications or healthy controls (54.5 vs 45 vs 40.8 years, respectively).

In the New York cohort, 96.1% of healthy controls had an adequate humoral response, as did 92.3% of those on medications other than methotrexate, compared with 72% of those receiving methotrexate. Similar results were seen for the minority of patients who had experienced COVID-19 before receiving the vaccine.

Median antibody titers were 104,354 in the healthy group and 113,608 in the non-methotrexate group, but only 46,901 in the methotrexate group.

In the Erlangen cohort, adequate immunogenicity was observed in 98.3% of healthy controls and in 90.9% of the non-methotrexate group compared with 50% of those in the methotrexate group. IgG antibodies to the S1 domain of the virus’s spike protein were measured on a commercial enzyme-linked immunosorbent assay, with an adequate response being defined as higher than 5.7 nm optical density.

Median optical densities in the Erlangen cohort were 9.4 nm among healthy controls, 7.8 nm in the non-methotrexate group, and 5.9 nm in the methotrexate group.

Because immunogenicity can be influenced by age and patients in the methotrexate group tended to be older, the researchers also considered the immune response only for patients younger than 55 and found that there was still an attenuated antibody response in the methotrexate group.

A subset of the New York group also underwent phenotyping of immune cells before and after immunization, with all groups showing increased proportions of spike-specific B cells, T follicular helper cells, activated CD4+ T cells, and HLA-DR+ CD8+ T cells. However, in the methotrexate group, activated CD8+ T cells (CD8+ T cells that express Ki67 and CD38 and the CD8+ T cells that produce granzyme B) were not expressed.

“Reduced induction of cytotoxic CD8+ T cell responses, combined with inconsistent induction of antibody responses, may further impair effectiveness of COVID-19 vaccines and render immune-mediated inflammatory disease patients on methotrexate more at risk of inadequate vaccine response,” the researchers explained.

Limitations of the study included its small numbers and the fact that the specific levels of immunogenicity necessary for protection have not been fully established.