COVID-19 Booster May Enhance T-cell Immune Response in Rituximab-Treated Patients With RA

While patients with rheumatoid arthritis on rituximab therapy have been reported to have insufficient serological responses to the COVID-19 vaccine, T cells, which protect against severe COVID-19, may be elevated after a third dose.

A third dose of the COVID-19 vaccine given to rituximab-treated patients with rheumatoid arthritis (RA) 6 to 9 months after infusion may boost cellular immune response, even though it may not produce a serological response, according to a study published in The Lancet.1

“Patients with rheumatoid arthritis on rituximab therapy have been reported to be at increased risk of severe outcomes from COVID-19, and it is crucially important to evaluate their response to SARS-CoV-2 vaccination,” investigators stated. “Previous reports have suggested that T cells are necessary for protection against severe COVID-19 in settings of low antibody titres, for rapid and efficient resolution of COVID-19, and for protection against fatal outcomes in patients treated with anti-CD therapies for hematological malignancies.”

Patients with RA currently treated with rituximab and healthy controls who have received the COVID-19 vaccines were enrolled in this Norwegian prospective, cohort study (Nor-vaC; NCT04798625) between February 9, 2021 and May 27, 2021. Eligible patients were recruited from 2 Norwegian hospitals. Controls were healthcare workers and blood doners from associated hospitals in Oslo, Norway. Participants were given 2 doses based on Norwegian vaccination protocol.

Patients without sufficient concentrations of anti-receptor-binding domain (RBD) after 2 doses of the vaccine were then enrolled in a separate study and were able to receive a third dose. RBD antibodies were measured 2 to 4 weeks after both second and third doses. T-cell responses were analyzed before vaccination, 7 to 10 days after the second dose, and 3 weeks following the third dose. During this time, patients with RA paused any disease-modifying antirheumatic drug (DMARD) treatment 1 week prior to vaccination and 2 weeks post-vaccination. At baseline and 2 weeks after vaccination, patients completed questionnaires including demographic data, medication usage, disease activity, COVID-related issues, and adverse events. Additional information about rituximab infusions, disease duration, and DMARDs was collected via medical records. Disease activity assessments were also performed 2 to 4 weeks after the second dose. Controls answered questionnaires about demographic data, adverse events, sex, age, and vaccine date and type.

The primary endpoint was to compare the percentage of patients with humoral and T-cell responses to spike peptides after receiving 2 and 3 doses of the vaccine with healthy controls. Safety of 2 and 3 doses and potential predictors of serological response was also assessed.

A total of 87 patients and 1114 healthy controls donated serum. Of patients with RA, 79.3% (n = 69) were women and the median age was 60 years. In the control group, 76.7% were women and the median age was 43 years. Concomitant DMARDs were used in 56 (64.4%) patients. Most patients received the BNT162b2 (Pfizer-BioNtech;72·4%) or mRNA1273 (Moderna; 24·1%).

The median time since the last rituximab infusion was 267 days for those with serological response and 107 days for non-responders.

Of the 49 patients that were given a third vaccine dose, approximately 70 days after the second vaccine, only 21.8% (n = 19) had a serological response after 2 vaccine doses, compared with 98.4% (n = 1096) of controls. After the third vaccine dose, 16.3% (n = 8) had a serological response, with an average of 250 since the last rituximab infusion.

After adjusting for sex and age, vaccine type (mRNA-1273 or BNT162b2) was also significantly associated with serological response.

After the second dose, 53% (n = 10/19) patients showed CD4 T-cell responses and 74% (n = 14/19) had CD8 T-cell responses. The third dose produced CD4 and CD8 T-cell responses in all patients (n = 12), including for the delta variant. Unlike serological responses, rituximab infusion time was not correlated with T-cell response.

Adverse events were observed in 48% (n = 32/67) patients with RA and 78% (n = 191/244) of controls after the second vaccine dose. Among patients who received all 3 doses, disease flares were reported in 14% after the first dose, 8% after the second dose, and 16% after the third dose. There were no serious adverse events.

Strengths included the broad inclusion criteria, assessment of both humoral and cellular vaccine response, and assessment of adverse events. However, the median age difference between the patients (60 years) and healthy controls (43 years) limits the study. Investigators mitigated this by adjusting for age in the analyses. While the small sample size of patients further limits the study, the safety data is encouraging. Lastly, since only patients were able to receive a third dose, responses could not be compared with controls.

“If possible, patients should be vaccinated against COVID-19 before the initiation of rituximab therapy. For an optimal response, the interval between rituximab infusion and vaccination should be as long as possible, preferably at least 9 months,” investigators concluded. “The clinical significance of the cellular immune response in the absence of virus-specific antibodies remains to be elucidated. Alternative anti-rheumatic therapies might be considered in individual patients if repeated rituximab infusions preclude the development of protective anti-SARS-CoV-2 antibodies.”


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 [published online ahead of print, 2021 Dec 23]. Lancet Rheumatol. 2021;10.1016/S2665-9913(21)00394-5. doi:10.1016/S2665-9913(21)00394-5