Since 2021, CDC guidelines have defined the primary COVID-19 vaccine series for moderately or severely immunosuppressed adults as two doses of mRNA vaccine, three to four weeks apart, plus a third dose at least four weeks later. The CDC also recommends additional booster doses after completing the primary vaccine series.
American College of Rheumatology guidelines recommend holding certain disease-modifying anti-rheumatic drugs (DMARDs; interrupting therapy) around the time of COVID-19 vaccination to improve immunogenicity. That guidance is based on a randomized, controlled trial of methotrexate interruption by patients with rheumatoid arthritis (RA) around the time of seasonal influenza vaccination.
In an observational study in “real-world” practice, researchers at Brigham and Women’s Hospital did not identify significant differences in the antibody response to COVID-19 vaccination among RA patients who held versus continued DMARDs around the last dose of their primary series. Sara K. Tedeschi, MD, MPH, director of the Fast Track Clinic for Giant Cell Arteritis and head of Crystal-Induced Arthritic Diseases in the Division of Rheumatology, Inflammation, and Immunity, Anna H. Jonsson, MD, PhD, rheumatologist in the Division, Duane R. Wesemann, MD, PhD, allergist and immunologist in the Division of Allergy and Clinical Immunology, and colleagues report the results in Seminars in Arthritis and Rheumatism.
The study included 60 adults with RA who had received two doses of mRNA COVID-19 vaccine before enrollment between July and December 2021. At enrollment and two days after the third dose, participants were asked to report which DMARDs they used and whether they held DMARDs around each dose of vaccine. 57% held at least one DMARD around the third dose.
Blood samples were collected before and four weeks after the third dose of COVID-19 vaccine (the final dose in the RA patients’ primary vaccination series).
For the RA patients, the antibody response was considered “normal” four weeks after the third dose if it was within one standard deviation of the response in 50 healthy controls four to eight weeks after their second dose of COVID-19 vaccine (the final in their primary series):
- 43% of RA patients had a normal anti-S response to the SARS-CoV-2 spike protein
- 62% of RA patients had a normal anti-RBD response to the receptor binding domain of the spike protein
Achievement of a normal antibody response wasn’t significantly different between patients who held DMARDs and those who continued them or between patients who used methotrexate versus other DMARDs.
The researchers assessed the activation of T cells by stimulating peripheral blood mononuclear cells with commercially available SARS-CoV-2 peptide pool (Miltenyi Biotec). The peptide pool includes lyophilized peptides covering the complete protein coding sequence of the SARS-CoV-2 spike glycoprotein. The primary outcome was the frequency of stimulated CD4 T cells expressing ≥2 activation markers (IFN-γ, TNF, IL-2, 4–1BB, CD40L, CD69) minus the frequency of unstimulated CD4 T cells expressing ≥2 activation markers:
- Frequency of activated T cells was significantly increased in RA patients after the third dose of the COVID-19 vaccine (fold-change, 1.52; P<0.0001)
- The increase was significant both in subjects who held DMARDs and those who continued DMARDs
- The frequency of activated T cells was lower in RA patients (median, 0.30%) than in vaccinated controls (0.62%), although this difference was not statistically significant
Changes in T-cell responses did not correlate with changes in antibody levels.
It’s reassuring that COVID-19 vaccination generated anti-viral antibody and T cell responses even for RA patients who did not hold DMARDs around vaccination. However, only about half of the patients had normal titers of anti-S and anti-RBD antibodies even after a third dose of the vaccine. This finding highlights the vulnerability of these patients and supports the need for vaccination schedules specifically designed to optimize their responses.