B-cell depleting therapies such as rituximab have become ‘therapeutic pariahs’ during the pandemic because of their associations with poor COVID outcomes, Australian clinicians say.
Two recent studies have found that B-cell depleting therapies stand out as the only immunosuppressive drugs that appear to increase the risk of adverse outcomes in patients with COVID-19 disease.
One review published in Neurology investigated the associations of immunosuppressive disease-modifying therapies (DMTs) with COVID outcomes in 1,683 MS patients with confirmed COVID infection and 657 people with suspected infection.
Compared to other DMTs, ocrelizumab and rituximab were associated with hospitalisation (adjusted odds ratio 1.75 and 2.76, respectively) and ICU admission (aOR 2.55 and 4.32, respectively), and rituximab was also associated with artificial ventilation (aOR 6.15).
The authors of the international study – including Professor Kalincik of Melbourne University Department of Neurology – noted that these increased risks of COVID-19 severity were in addition to the risks associated with older age, progressive MS phenotype, and higher disability.
Similarly, another retrospective analysis of outcomes for 16,494 patients taking long term immunosuppressive therapy hospitalised for COVID-19 disease found that the only significant increases for any immunosuppressant were for in-hospital death with rituximab for rheumatological disease (Hazard Ratio 1·72, 95% CI 1·10–2·69) and for cancer (HR 2·57, 1·86–3·56).
Writing in Lancet Rheumatology, the study authors said their findings confirmed those of other studies suggesting that rituximab may have a deleterious effect on COVID outcomes by impairing antiviral humoral response.
“Rituximab is a chimeric monoclonal antibody that binds to the cell surface protein CD20 and induces B-cell apoptosis. This mechanism of action powerfully interferes with antibody response to infection, and it can lead to prolonged viral replication. Therefore, the null effect for ventilation and an increased risk of death are plausible,” they wrote.
In an accompanying commentary, Dr David Liew, a rheumatologist at Austin Health, Melbourne and Associate Professor Robinson of the Royal Brisbane & Women’s Hospital, said the concerns raised about poor COVID-19 outcomes in patients treated with rituximab were now “beyond doubt”.
They said it was unfortunate this had become apparent when rituximab was being found to have clinical applications across multiple diseases, including MS.
“At a time in which much of the world is benefiting from more affordable rituximab biosimilars, we might ordinarily be heralding this as rituximab’s golden era. The persistence of COVID-19 as an issue has instead dampened enthusiasm for rituximab in contemporary practice,” they wrote.
Nevertheless, they suggested there may be ways to mitigate the risks of COVID for patients in whom B-cell depleting therapies such as rituximab may still be the best therapeutic option, by providing vaccination and boosters.
“If vaccination can induce sufficient and sustained humoral immunity before rituximab is needed, rituximab could plausibly be far less risky, particularly if B-cell repertoire diversity can combat subtle spike protein mutations,” they said.
“However, questions about the optimal strategy for individual patients remain unanswered. When should rituximab be timed relative to vaccine administration? What improvements will additional vaccine boosters confer? How important is having some cell-mediated immunity in patients treated with rituximab?”
Other therapeutic strategies to enable safer use of rituximab could include post-exposure prophylaxis with neutralising monoclonal antibodies such as casirivimab and imdevimab.
And pre-exposure prophylaxis with long-acting monoclonal antibodies might be appropriate for patients at the highest risk, they added.
But for some patients the way forward may only be to avoid using rituximab, and instead opt for therapeutic alternatives even if inferior in efficacy, they concluded.