Low levels of anti-SARS-CoV-2 antibodies after vaccination in rituximab-treated patients: comment on the article by Simon et al.

To the Editor:

We read with great interest the report of the study by Dr. Simon and colleagues, in which impaired humoral immune responses, but not T cell immune responses, were observed after vaccination against SARS–CoV‐2 in patients with immune‐mediated inflammatory diseases (IMIDs) treated with rituximab (RTX) (1). The authors reported that none of the 8 vaccinated RTX‐treated patients developed IgG antibodies against the spike S1 and nucleocapsid proteins of SARS–CoV‐2. Moreover, Boyarsky et al recently reported increased rates of undetectable titers of anti–SARS–CoV‐2 antibodies in patients treated with RTX (P = 0.04) (2). In patients with hematologic malignancies treated with RTX, only 0–14% developed a serologic response to the BNT162b2 messenger RNA (mRNA) vaccine when RTX was administered within the 12 months before vaccination (3).

On this basis, we examined antibody responses after 2 doses of the SARS–CoV‐2 vaccine in 11 patients treated with RTX. Seven patients (63.6%) were female, 9 had a diagnosis of rheumatoid arthritis, 1 had a diagnosis of dermatomyositis, and 1 had a diagnosis of cryoglobulinemic vasculitis. Patients with a history of SARS–CoV‐2 infection or low IgG levels were excluded. Patients had received a mean ± SD of 5.5 ± 3.9 RTX cycles before SARS–CoV‐2 vaccination, and the first dose of the vaccine was administered a mean ± SD of 20.4 ± 13.4 weeks after the last RTX cycle. All patients except 1 were vaccinated with the BNT162b2 mRNA SARS–CoV‐2 vaccine. We used a quantitative chemiluminescence microparticle immunoassay (Abbott) to detect IgG antibodies against the SARS–CoV‐2 spike protein. Consistent with the aforementioned studies, only 2 (18.2%) of 11 patients had antibody levels above the cutoff value of 50 arbitrary units (AU)/ml; the median level of anti–SARS–CoV‐2 antibodies was 21.3 AU/ml (interquartile range 4–28).

Our results confirm those from earlier studies showing reduced antibody response after COVID‐19 vaccination in patients with IMIDs receiving RTX therapy (1, 2, 4). RTX treatment has been associated with worse COVID‐19 outcomes, such as more severe disease and increased duration of hospitalization (5). Given that vaccination against SARS–CoV‐2 has been highly effective in preventing the development of pneumonia associated with COVID‐19 (6), it is considered essential for patients treated with RTX to be vaccinated. Nevertheless, RTX treatment has been associated with reduced antibody response after flu and pneumococcal vaccination (7). Based on these data, the American College of Rheumatology recommended that patients being treated with RTX should optimally be vaccinated against COVID‐19 4 weeks before the next scheduled cycle, and RTX administration should be withheld for 2–4 weeks after the second vaccine dose (8).

However, we observed low levels of anti–SARS–CoV‐2 antibodies even though the first vaccine dose was administered a mean of 5 months after the last RTX cycle. Mrak et al also reported inadequate antibody development when the first vaccine dose was administered ~6.9 months after the last RTX cycle (4). Indeed, the time from last RTX cycle correlated with peripheral B cell counts and anti–SARS–CoV‐2 antibody levels, and the percentage of peripheral B cells was associated with antibody development in vaccinated patients (4). These data imply that the time interval between last RTX administration and first vaccine dose should possibly be reconsidered. As RTX‐treated patients seem to exhibit T cell immune responses to SARS–CoV‐2 vaccination (1,4), the clinical significance of impaired humoral responses after vaccination in these patients remains unclear.

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