Methotrexate May Lower Vaccine Response in Patients With RA

Methotrexate (MTX) treatment may lead to lower antibody responses after vaccination in people with rheumatoid arthritis (RA), according to a recent study that found reduced vaccine-induced CD4 T cell activation after treatment.¹

“MTX is considered the gold standard for treating RA and is also often used in the treatment of other immune-mediated inflammatory diseases (IMID) such as psoriatic arthritis (PsA) and spondyloarthritis (SpA). MTX is primarily known for its inhibitory effect on purine and pyrimidine synthesis required for cell division, making it a key anticancer treatment. While the exact anti-inflammatory mechanism of MTX in IMID treatment is still unknown, proposed modes of action include increased adenosine release, inhibition of nuclear factor-κB (NF-κB) signaling, increased expression of long intergenic non-coding RNA regulating inflammatory processes and promotion of nitric oxide synthase uncoupling leading to T cell apoptosis²,” lead investigator Laura YL Kummer, Doctorate Student / Research Assistant. Department of Immunopathology, Sanquin Research, and colleagues wrote.¹

Kummer and colleagues analyzed data in 59 patients with rheumatic disease, including 18 with RA and 2 with PsA on MTX monotherapy, 10 patients with RA without immunosuppressive treatment, and 29 healthy controls. The investigators analyzed CD4 T and B cell responses 7 days and 3–6 months after 2 SARS-CoV-2 messenger RNA vaccinations. They used high-dimensional flow cytometry analysis to analyze fresh whole blood, an activation-induced marker assay to measure antigen-specific CD4 T cells, and spike probes to study antigen-specific B cells.¹

The investigators found that 7 days after 2 SARS-CoV-2 vaccinations, total B and T cell counts were similar between MTX-treated patients and controls. Spike-specific B cell frequencies were unaffected.

Notably, the frequency of antigen-specific CD4 T cells was reduced in patients using MTX and correlated strongly with anti-RBD IgG antibodies, but not in healthy controls, suggesting that decreased CD4 T cell activity may result in slower vaccination antibody responses in MTX-treated patients. Specifically, patients treated with MTX had a median induction IQR of 0.17 (95% CI, 0.12-0.21) compared with 0.29 (95% CI, 0.18-0.39) in patients not on MTX (P = .017). The total number of CD4 T cells were not affected by MTX treatment.¹

“Overall, these data present evidence of reduced vaccine-specific CD4 T cell responses in MTX-treated patients with RA, which is associated with slower antibody kinetics in these patients. Although it remains unclear to what extent lower CD4 T cell responses impact clinical outcomes in these patients, it is wise to consider that CD4 T cell immunity may be less robust in these patients during future vaccinations or emerging infections. Furthermore, these data potentially contribute to elucidating the anti-inflammatory mechanism of action of MTX in Immunomodulatory drugs,” Kummer and colleagues concluded.¹

The investigators noted that study limitations included a relatively small number of participants, the spread in sample timing, and the rare population of control patients with RA without systemic immunosuppressive treatment, which may have skewed the study group to have lower disease activity. They were also unable to characterize spike-specific cTfh cells due to technical constraints.

REFERENCES

1. Kummer LYL, Fernández Blanco L, Kreher C On behalf of the T2B! Immunity Against SARS-CoV-2 Study Group, et al. Methotrexate treatment hampers induction of vaccine-specific CD4 T cell responses in patients with IMID. RMD Open 2024;10:e004664. doi: 10.1136/rmdopen-2024-004664

2. Freeman ML, Clagett BM, Moisi D, et al. Methotrexate Inhibits T Cell Proliferation but Not Inflammatory Cytokine Expression to Modulate Immunity in People Living With HIV. Front Immunol 2022;13:924718. doi:10.3389/fimmu.2022.92471