Rituximab’s ‘golden era’ brought down by COVID

By Michael Woodhead

22 Nov 2021

Australian rheumatologists says the COVID-19 pandemic has dampened enthusiasm for rituximab during what should have been a ‘golden era’ for the B-cell depleting therapy in rheumatological disease

With new data again linking it to poor outcomes in patients with COVID-19, the drug has unfortunately become something of a “therapeutic pariah” according to Dr David Liew and Associate Professor Philip Robinson .

In a commentary article for Lancet Rheumatology, they note that a retrospective analysis of outcomes for 16,494 patients taking long term immunosuppressive therapy hospitalised for COVID-19 disease found no increased risk of mechanical ventilation or in-hospital death for rheumatological, antineoplastic, or antimetabolite immunosuppressants, with the exception of rituximab.

The US data for 2020-2021 showed that after propensity score matching the only significant increases for any immunosuppressant were found 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).

Overall, the long term use of immunosuppressants was associated with a reduced risk of invasive ventilation (8% vs 9%; 0·89, 0·83–0·96), and there was a significant decrease in risk of in-hospital mortality associated with JAK inhibitors (HR 0.42; 0·24–0·73)

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 their commentary, Dr Liew from 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 the potential utility of rituximab has been shown across multiple diseases, including in the maintenance of … ANCA-associated vasculitis, in primary Sjögren’s syndrome, and even as proof-of-concept in diseases such as systemic sclerosis and polymyalgia rheumatica.”

Nevertheless, they suggested there may be ways to mitigate the risks of COVID for patients in whom 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 wrote.

“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, they suggested.

And pre-exposure prophylaxis with long-acting monoclonal antibodies might be appropriate for patients at the highest risk, they added.

But for many patients the way forward may be to avoid using rituximab, the commentary concluded. While this may not be such a problem for patients with RA, there are some for whom rituximab is the first line or only option, they noted.

“The detriment from choosing an inferior option, such as azathioprine for the maintenance of ANCA-associated vasculitis, will need to be balanced against potentially improved outcomes with COVID-19,” they wrote.

Already a member?

Login to keep reading.

OR
Email me a login link