The upside to sulfasalazine’s covid risk

2 minute read

Discovering more about its mechanism of action could allow us to repurpose the mainstay rheumatoid arthritis drug.

A common drug for rheumatoid arthritis could have an exciting future, if explanations for its harmful link to covid are vindicated.

In a thought-provoking editorial piece in The Lancet Rheumatology, authors from Johns Hopkins University and the University of Queensland’s Associate Professor Phillip Robinson have proposed that sulfasalazine may be a risk factor for severe covid based on its action as a type 1 interferon inhibitor.

This, in turn, suggests it could be a useful treatment for autoimmune diseases where type 1 interferon production plays a role in immunopathogenesis. This includes systemic lupus erythematosus (SLE), dermatomyositis and Sjögren’s syndrome – conditions in need of effective and affordable therapeutics.

The link between sulfasalazine and increased risk of severe covid and covid deaths has been recorded in several studies. These findings appear to be at odds with sulfasalazine’s presumed mechanism as an inhibitor of TNF and prostaglandin synthesis – patients on TNF inhibitors had a reduced risk of severe covid or death.

The authors referred to recent testing of drugs that target plasmacytoid dendritic cells which found that sulfasalazine had a strong inhibitory effect on type 1 interferon production.

In addition to supporting its use as a relatively cheap oral treatment for type 1 interferon-driven autoimmune and autoinflammatory diseases, the observation also provides a possible explanation for sulfasalazine’s link with increased covid severity.

The authors pointed to data linking type 1 interferon with resistance to covid and other viruses – including herpes zoster, for which there is an increased risk among RA patients taking sulfasalazine. In inhibiting type 1 interferon, sulfasalazine is impairing effective early immune responses to viral infection.

“These interesting trends in registry data have been hard to explain, and in reality we need other data to explore covid risk,” Professor Robinson said.

“But in trying to explain these trends and how they might plausibly happen, we might actually have given ourselves preliminary insights into an old drug, and something to test in SLE, starting with animal models.”

Lancet Rheumatol 2022, online 15 March

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