B-cell depletion with rituximab in the COVID-19 pandemic: where do we stand?

The COVID-19 pandemic has presented several challenges due to insufficient evidence to guide clinical practice. Many patients with severe, refractory rheumatic disease (including vasculitis, systemic lupus erythematosus (SLE), and rheumatoid arthritis) depend on B-cell depletion with anti-CD20 monoclonal antibodies, such as rituximab. In the current crisis, some clinicians and patients have elected to delay maintenance rituximab therapy because of perceived safety concerns. Pausing rituximab therapy carries a risk of destabilising disease control and might increase the requirement for corticosteroids, which could ironically worsen outcomes in patients with COVID-19. Initial results from the European League Against Rheumatism COVID-19 registry suggest poor outcomes in patients receiving 10 mg or more prednisolone (n=64), but not in the small numbers of patients (n=37) treated with rituximab.¹ However, clinical decision making is further complicated by other observations, such as a severe COVID-19 phenotype being reported in a single patient treated with rituximab for antineutrophil cytoplasmic antibody-associated vasculitis.² In this Correspondence, we discuss the position of B-cell-mediated adaptive immunity and rituximab therapy in the current pandemic, with regard to both potential safety concerns and, conversely, the potential for rituximab to treat specific COVID-19 complications.

The safety of rituximab in the context of COVID-19 is unclear. B-cell depletion could compromise antiviral immunity, including development of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies, increase the risk of reinfection, and impair vaccine efficacy (once a vaccine becomes available). The potential risks of hypogammaglobulinaemia secondary to rituximab also need consideration, and the results of clinical trials evaluating convalescent serum are awaited. If trials of convalescent serum show benefit, this could be a potential therapeutic option for patients with immunodeficiency (hypogammaglobulinaemia) secondary to rituximab who develop severe COVID-19.

However, we speculate that rituximab might be beneficial for some patients with severe COVID-19 with specific complications. COVID-19-associated thromboses, severe lung pathology, and hyperinflammation contribute to poor outcomes. These manifestations bear some similarities to those observed in rheumatic diseases, such as antiphospholipid syndrome,³ rheumatic-associated lung disease,⁴ and macrophage activation syndrome⁵ secondary to SLE, for which B-cell depletion with rituximab has been shown to be effective. Antiphospholipid antibodies have also been reported in COVID-19 patients with thromboses, although it is unclear whether these antibodies are pathogenic in this context,³ and lung CT features in some patients with COVID-19 resemble those of fibrotic organising pneumonia (eg, similar to anti-MDA5 anti-synthetase syndrome).⁴ It is plausible that anti-SARS-Cov-2 antibodies or immune complexes might potentially evoke monocyte or alveolar macrophage activation, thereby contributing to sustained secretion of proinflammatory cytokines and the development of pulmonary disease. Therefore, could adaptive immunity contribute to poor outcomes in COVID-19, signalling a role for rituximab?

Immunomodulation might improve outcomes in patients with COVID-19-associated hyperinflammation.⁵ Although rituximab appears to be effective in treatment of hyperinflammation or haemophagocytic lymphohistiocytosis triggered by Epstein-Barr virus, SARS-CoV-2 (unlike Epstein-Barr virus) is not known to reside in B cells. Therefore, acute B-cell depletion would not be appropriate for COVID-19-associated hyperinflammation. However, rituximab might be useful in specific scenarios in patients with COVID-19 to target chronic adaptive host immune responses. For example, when thrombotic or inflammatory lung complications persist beyond acute infection, and when viral loads are negative or low and anti-SARS-CoV-2 antibodies are positive.

In the context of COVID-19, we call for dedicated research regarding B-cell depletion to better understand the effect and timing of rituximab on patient outcomes and to explore its potential therapeutic use in the management of specific complications of COVID-19, to determine whether judicious use of rituximab might have a role in the pandemic.