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We thank Dr Benucci et al for their comments1 on our report on fatalities of patients with inflammatory rheumatic diseases (IRDs) treated with rituximab (RTX) during the SARS-CoV-2/COVID-19 pandemic.2 The authors present a case of COVID-19 in a patient with myositis treated with RTX, who required assisted ventilation and eventually recovered after intensive care including invasive ventilation and medication with remdesivir, dexamethason and tocilizumab. While emphasising the potential of RTX to lead to severe courses of COVID-19, a particularly interesting aspect of the report is the complete absence of antibodies to SARS-CoV-2 even up to 4 weeks after discharge of the patient. The authors therefore conclude that RTX may be hazardous in the present pandemic as it may inhibit the humoral response to SARS-CoV-2 and contribute to secondary worsening of COVID-19.
The case of Dr Benucci reinforces our recommendation for caution and careful vigilance when considering treating patients with IRD with RTX in times of SARS-CoV-2. We had illustrated our concerns on two patients with RTX-treated rheumatoid arthritis who developed fatal COVID-19 and we had hypothesised that persistent B cell depletion and comedication with glucocorticoids may have resulted in severe combined cellular and humoral immunodeficiency. This assumption was based on the well-known association of RTX treatment with an increased risk for the development of viral infections, such as JC virus, hepatitis B virus or cytomegalovirus3 and the aggressive course of COVID-19 in patients with common variable immunodeficiency.4 Supporting our hypothesis is a recent publication on persistent SARS-CoV-2 viraemia in two rituximab-treated patients with severe COVID-19 pneumonia until death without any sign of viral clearance.5 It is intriguing to speculate that a defect in viral clearance may underlie also the unusual course of COVID-19 in patients with IRD treated with RTX that was recently published: Three patients with systemic sclerosis routinely treated with RTX who were affected by COVID-19 and also a patient with granulomatosis with polyangiitis treated with RTX developed atypical late clinical worsening to severe pneumonia.6 7 Whether these patients and the patients initially reported by us2 also had a defect in viral clearance or even developed viraemia,5 a rather unusual situation in viral respiratory diseases, and, if so, whether decreased viral clearance contributed to delayed clinical worsening in the reported clinical cases is unknown. These cases, however, highlight the possibility that rituximab is associated with a specific risk in SARS-CoV-2 infections and in the outcome of COVID-19. Current data from the National Registry for patients with IRD infected with SARS-CoV-2 in Germany support the contention of such a risk as in this registry, 11 out of 18 patients (61.1%) treated with RTX required hospitalisation, with 9 of the 18 patients (50%) required ventilation, whereas only 28 out of 95 patients (28.6%) treated with biological disease modifying anti-rheumatic drugs (bDMARDs) needed hospital care and only 12 (12.2%) required ventilation (Hasseli et al, submitted for publication, 2020). While further data on the risk of RTX during the SARS-CoV-2/COVID-19 pandemic and its precise mechanisms are urgently required, physicians should be aware of the potential of RTX-associated severe courses of the infection and remain to be extremely vigilant and cautious when considering RTX treatment.
Handling editor Josef S Smolen
Contributors HS-K, KK, IV, RH and AS: literature search, data analysis, data interpretation, writing.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting or dissemination plans of this research.
Patient consent for publication Not required.
Provenance and peer review Commissioned; internally peer reviewed.
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