• biological therapy
• COVID-19
• rituximab

We appreciate the comments by Shanoj et al1 in response to our letter regarding the SARS-CoV-2 antibody response after COVID-19 in patients with rheumatic disease.2 Examining whether patients treated with CD20 inhibitors have antibody responses to SARS-CoV-2 is a question of great clinical importance in the management and vaccination of patients taking these medications during the COVID-19 pandemic.

Shanoj et al describe anti-spike and anti-nucleocapsid antibody test results among five patients with PCR-confirmed COVID-19 and prior exposure to rituximab.1 Among these patients, one patient developed neither anti-spike nor anti-nucleocapsid antibodies.1 This patient had been treated with rituximab for several years and had no detectable CD19+ B cells shortly before the onset of COVID-19.1 One patient developed anti-spike but not anti-nucleocapsid antibodies; although the duration of rituximab treatment is not provided, this patient did have circulating CD19+ B cells near the time of infection.1

In our study, three patients were exposed to rituximab prior to COVID-19.2 Two of these patients had been treated with rituximab for many years and had undetectable circulating CD19+ B cells, and these patients had negative or variable antibody responses to SARS-CoV-2.2 Both of these patients had more severe and chronic COVID-19 courses, with one patient death and one patient with sustained respiratory symptoms 8 months after COVID-19 infection.2 In contrast, one patient had recently started rituximab within 3 months prior to COVID-19 infection (CD19 flow cytometry unavailable), and this patient was positive for SARS-CoV-2 antibodies and had an uncomplicated clinical course.2 We agree that the lower doses of rituximab in most of the patients in the cases series by Shanoj et al (500 mg in four patients and 1000 mg in one patient) may also in part explain the differences between their findings and ours.1

The findings in our study and that by Shanoj et al suggest that the dose and duration of therapy with CD20 inhibitors may influence the ability to mount an antibody response to COVID-19. In addition to case reports, case series and multicentre comparative cohort studies suggesting higher risk of severe COVID-19 associated with rituximab exposure,3–5 rheumatic disease patients exposed to rituximab prior to infection who were reported in the COVID-19 Global Rheumatology Alliance had higher risk of COVID-19-related death than users of methotrexate monotherapy (HR 4.04, 95% CI 2.32 to 7.03).6 Further studies are needed to determine the factors, such as duration, dose, timing of therapy and degree of CD19+ B cell depletion, that influence whether patients treated with CD20 inhibitors develop robust and durable neutralising antibody responses to COVID-19.