Rheumatoid arthritis patients using medications that are interleukin-1β (IL-1β) receptor antagonists, like Kineret (anakinra), may be at much higher risk of infections with Group A Streptococcal bacteria, a flesh-eating bacteria that is the cause of such illnesses as strep throat, according to a recent study from the University of California San Diego.
The study, “IL-1β is an innate immune sensor of microbial proteolysis,” published in Science Immunology, shows that IL-1β is critical for the immune system to recognize and respond to bacterial infections.
“The more we know about each step in the body’s immune response to bacterial infections, the better equipped we are to design more personalized, targeted therapies for autoimmune diseases — therapies that are effective, but minimize risk of infection,” Victor Nizet, MD, professor of pediatrics and pharmacy at UC San Diego School of Medicine and Skaggs School of Pharmacy and Pharmaceutical Sciences, and the study’s senior author, said in a press release.
IL-1β is an important mediator of the immune response, promoting the activation of specific subsets of immune cells that engulf and clear invading pathogens. This molecule is first produced as an inactive precursor, and needs to be cleaved to become activated.
Until now, researchers believed that the only body could mediate the cleavage of the IL-1β precursor through a cellular structure known as the inflammasome. But this study found that Streptococcal bacteria could secrete an enzyme, called SpeB, that also cleaves and activates IL-1β, inducing a protective immune response.
Although this may seem odd, researchers believe that this action provides a competitive advantage to less invasive Streptococcal strains, such as those that cause strep throat. Activation of the immune system clears up competing bacteria, allowing Strep bacteria to get established in the body.
The findings may also explain why some of the more invasive, flesh-eating bacteria have a mutation in the SpeB gene that impairs its production. “It helps them avoid tripping the alarm and setting off an immune response,” said the study’s first author, Christopher LaRock, a postdoctoral researcher in Nizet’s lab.
In autoimmune diseases such as rheumatoid arthritis, the immune system starts attacking the body’s own healthy cells instead of only attacking foreign pathogens. For this reason, patients with these diseases are given drugs that hamper the immune system, including those that inhibit IL-1β-derived signaling.
Based on these new observations, the authors hypothesized that IL-1β inhibition could increase the incidence of severe bacterial infections. Thy examined a U.S. Food and Drug Administration (FDA) database for adverse effects of the IL-1β antagonist Kineret in patients with rheumatoid arthritis. Their findings revealed that patients on Kineret were 300 times more likely to experience invasive, flesh-eating Streptococcal infections than those not using this medication.
“A likely explanation for this increased risk is that with IL-1beta out of the picture, as is the case with patients taking anakinra [Kineret], strep strains can progress to invasive infection even while producing SpeB, which goes unnoticed by the immune system,” LaRock said.
The findings support a role for IL-1β as an early warning system that is triggered upon bacterial infection.
“Inhibiting the body’s bacterial sensor can put a person at risk for invasive infection,” Nizet said, “but just the fact that we now know that this patient population is at higher risk and why means we can take simple steps — such as close monitoring and prophylactic antibiotics — to prevent it from happening. “