Reply.

Dear Editor:

We appreciate Calvo Elías AE et al.’s comments about our paper. As they point out, the administration of vaccines against the 2019 coronavirus disease (COVID-19) in patients with systemic autoimmune diseases (SADs) treated with rituximab (RTX) results in a decreased humoral response, which is determined by the absence or decline in the production of antibodies against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, the effect of RTX on the T-cell response (measured by an interferon-gamma release assay [IGRA]) is a matter under discussion.

It is important to note that RTX also has a significant impact on CD4+ T-cells, as it decreases their number and activation status, and increases the amount of regulatory T-cells, all of which leads to a less intense cellular response. In addition, the effect of synthetic immunosuppressive drugs as part of the treatment of these conditions also contributes to this reduced cellular response to a lesser or greater extent.

At the time of writing the special article on COVID-19 vaccines in patients with SADs, the published data on the matter were scarce; however, the results of the RituxiVac study have recently been published. This study aimed to measure the humoral and cellular response of 96 patients under treatment with anti-CD20 monoclonal antibodies (93 with RTX and three with ocrelizumab), 71 of whom had a SAD, after being vaccinated against SARS-CoV-2 (Pfizer/BioNTech and Moderna). After receiving the second dose of the vaccine, 49% of these patients developed antibodies against SARS-CoV-2 versus 100% of those of the control group. Interferon-γ production was detected in only 20% of the patients with a SAD compared with 75% of those of the control group. A decrease in the number of B- and T-cells in this group of patients with a SAD was also observed in comparison with the controls. The time elapsed since the administration of the last dose of RTX (over 7 months), as well as the number of CD19+ B-cells (greater than 27/μl) and CD4+ T-cells (greater than 653/μl), were positive predictors of a good humoral response against the SARS-CoV-2 vaccines. In contrast to our findings, in their study, Mrak D et al. observed a specific T-cell response against SARS-CoV-2 in 58% of a total of 74 patients treated with RTX, regardless of the presence or absence of B-cells and the humoral response.

As noted by Calvo Elías AE et al., the degree of protection against SARS-CoV-2 infection that this cellular response may provide in patients with a SAD treated with RTX is unknown. Furthermore, it should be recalled that RTX has been identified as a poor prognostic factor in patients with SADs and COVID-19. The available evidence indicates that RTX affects both B- and T-cells. Nevertheless, the resulting response (in the form of both antibody and interferon production) indicates that vaccination against SARS-CoV-2 is a good immunization strategy in this group of patients. The results of further studies that will be essential in determining the benefits of each type of vaccine, the number of doses required, and the timing of the vaccination in relation to the last infusion of RTX are expected to be available in the short term.