The humoral and cellular immune responses to SARS-CoV-2 vaccines were assessed among patients with rheumatoid arthritis (RA) receiving treatment with rituximab, in a study published in Lancet Rheumatology. Researchers noted that compared with individuals without RA, those with RA receiving rituximab were much less likely to mount a serologic response to a second vaccine dose; however, the administration of a third dose may boost cellular immune response in patients with an inadequate response to the first 2 doses.

Rituximab is known to impair the immunogenicity of the influenza and pneumococcal vaccines, though effect of rituximab on the SARS-CoV-2 vaccine is still unknown.

Researchers sought to examine the differential responses to 2 and 3 doses of the SARS-CoV-2 vaccines in patients with and without exposure to rituximab therapy.

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Patient data were identified using hospital records and they were invited to participate in the study in February 2021, prior to the initiation of Norway’s national vaccination program. All participants were vaccinated twice, according to the Norwegian regulations; however, patients with an inadequate serologic response to the 2 doses received a third dose.

Antibodies to the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein were measured in serum samples 2 to 4 weeks after the second and third vaccine doses. Patients with anti-RBD antibody concentrations of less than 100 arbitrary units (AU)/mL were considered to have an inadequate serologic response. The T-cell response to COVID-19 vaccination was assessed in vitro using blood samples collected before vaccination, 7 to 10 days after the second dose, and 3 weeks after third dose in a small subset of patients.

The primary study outcomes were the percentage of patients with a serologic response (anti-RBD antibody concentrations ≥70 AU/mL) and T-cell response to spike peptides after the second and third doses.

The study cohort included 87 patients receiving rituximab for RA, among whom 69 (79.3%) were women. Of the 1114 control participants enrolled, 76.7% were women. Median age was 60 years in the RA cohort and 43 years in the control cohort.

Overall, 21.8% of the RA group had an adequate serologic response after 2 doses compared with 98.4% of the control group (P <.0001). Among patients with RA, median time from last rituximab dose was significantly longer in vaccine responders compared with nonresponders (267 vs 107 days; P <.0001). Vaccine type was also significantly associated with response in the RA group, with a greater percentage of mRNA-1273 (Moderna) recipients achieving a serologic response compared with BNT162b2 (Pfizer-BioNTech) recipients (P =.016).

The T-cell responses were measured in 19 patients after the second dose, among whom 10 (53%) had a CD4+ T-cell response and 14 (74%) had a CD8+ T-cell response. A total of 49 (56.3%) patients with RA received a third dose, though only 8 (16.3%) of had a serologic response to the additional dose. However, all patients who were tested for a cellular response after the third dose mounted a robust CD4+ and CD8+ T-cell response.

Adverse events were reported by 48% of the RA cohort and 78% of the control cohort after 2 doses. No serious adverse events or deaths were observed.

These data provide further insight into the effect of rituximab on cellular and humoral immune responses to the SARS-CoV-2 vaccines. The likelihood of achieving a serologic response appeared significantly reduced with rituximab treatment, though cellular response was largely maintained in the subgroup of patients tested for a T-cell response. Administration of a third dose increased the likelihood of humoral response.

As study limitations, the researchers noted the small size of the RA cohort compared with the control cohort and the older mean age of patients with RA, which may have affected the likelihood of a serologic response. In addition, only a small percentage of individuals received a T-cell analysis.

“This study supports the provision of [3]-dose vaccination to patients with rituximab-treated [RA] to help protect this clinically vulnerable group from COVID-19, informing patients, health care providers, and decision makers on the optimal vaccination strategy,” the researchers wrote.

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


Jyssum I, Kared H, Tran TT, et al. Humoral and cellular immune responses to two and three doses of SARS-CoV-2 vaccines in rituximab-treated patients with rheumatoid arthritis: a prospective, cohort study. Lancet Rheumatol. Published online December 23, 2021. doi:10.1016/S2665-9913(21)00394-5