New anti-inflammatory drugs increase risk of fungal infection

Certain new anti-inflammatory drugs increase the risk of an infection of the oral cavity, pharynx or esophagus with the fungus Candida by a factor of ten to thirty. This is evident from a large study led by researchers from the Radboudumc, published in The Lancet Regional Health Europe. The researchers base their conclusions on a worldwide epidemiological study, in which they combined four different research approaches.

In conditions such as psoriasis, ankylosing spondylitis and psoriatic arthritis, the immune system targets the own body. These are called autoimmune diseases. In recent years, new drugs have been developed and approved that inhibit the immune system in these conditions and thus alleviate the disease. These so-called biologics reduce the action of immune cells or proteins involved in inflammation, such as IL-17. The first IL-17 inhibitor came on the market in 2015, and its use has increased dramatically.

Bart-Jan Kullberg, an infectious diseases specialist at Radboudumc, followed the development of these new drugs with great interest. "We know from our expertise that IL-17 plays an important role in the defense against fungi, such as Candida. We therefore asked ourselves from the start: are patients on these medications more prone to fungal infections?" Kullberg and his team launched a global study five years ago to answer this question.

Global search

Linda Davidson, infectious diseases resident and first author, began the search in the databases of the World Health Organization (WHO) and the European Medicines Agency (EMA). These databases contain reports of adverse drug events. She investigated how often fungal infections were reported in recipients of these biologics. In a registry of pharmacies, she found out how often people who use IL-17 inhibitors are also prescribed drugs against fungal infections. In a patient group with psoriasis, she identified the number of fungal infections during IL-17 inhibitor therapy and isolated immune cells from their blood, exposed them to fungi in the laboratory and determined how the immune cells responded.

All four research approaches showed that the use of these new biologics increases the risk of a fungal infection of the oral cavity, pharynx or esophagus by a factor of ten to thirty. Davidson: "We consistently found an increased risk of Candida fungal infections during use of IL-17 inhibitors with four independent study methods. We confirmed the results from the WHO and EMA adverse event reports with drug prescription studies and a patient group with psoriasis. With data from the lab, in which we see that immune cells from patients taking IL-17 inhibitors have a decreased response to fungi, we support our findings by providing insight into the underlying mechanism of action."

Alertness desired

Twenty years ago, Kullberg read the results of a similar study with drugs that inhibit the inflammatory substance TNF-α. At the time, it was found that patients taking these drugs had a greater risk of tuberculosis. That study led to significant changes in the use of these drugs. Kullberg was impressed by the methodology and therefore used the same research method for the current study using worldwide databases, now also expanded to include independent European and Dutch data sources.

Fortunately, the consequences of the new study are less drastic. "The benefits of these biologics against IL-17 are impressive and the increased risk of fungal infection is unfortunate, but manageable," Kullberg explains. "It is especially important for physicians to be alert to this side effect and to intervene quickly if necessary, with antifungal medication. This can also be done as a maintenance dose if necessary. Only in a few cases it might be necessary to stop using the IL-17 inhibitor because of persistent fungal infections."

About the publication

The following biologics were studied:
IL-17 inhibitors: secukinumab, ixekizumab, brodalumab
IL-12/23 inhibitor: ustekinumab
IL-23 inhibitor: guselkumab

This study was published in The Lancet Regional Health Europe: Risk of Candidiasis associated with Interleukin-17 and Interleukin-12/23 inhibitors: a Real-world observational study. Linda Davidson, Juul M.P.A. van den Reek, Mariolina Bruno, Florence van Hunsel, Ron M.C. Herings, Vasiliki Matzaraki, Collins K. Boahen, Vinod Kumar, Hans M.M. Groenewoud, Frank L. van de Veerdonk, Mihai G. Netea, Elke M.G.J. de Jong, and Bart-Jan Kullberg.

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