THE OFFICIAL NEWS SOURCE OF ACR CONVERGENCE 2022 • NOVEMBER 10-14



Research explores role of cytokine inhibition in treatment of a spectrum of diseases

Joerg Ermann, MD
Joerg Ermann, MD

The axis of interleukin-23 (IL-23) and interleukin-17 (IL-17), which is central to the pathogenesis of spondyloarthritis, will be part of the focus of an ACR Convergence 2020 session.

 IL-17, IL-23 and Other Cytokine Targets: Lessons from Clinical Trials for Spondyloarthritis will have its first airing, including a live question-and-answer session, from 11 a.m. – 12 p.m. EST Saturday, Nov. 7. Registered attendees can watch a replay on demand through Wednesday, March 11.

When people talk about IL-17, they are typically referring to IL-17A, said Joerg Ermann, MD, associate physician, Brigham and Women’s Hospital, and Instructor in Medicine, Harvard Medical School. However, IL-17 is a family of six different cytokines, designated from A to F. IL-17A and IL-17F are closely related and have similar functions. The role of the other IL-17 family members in spondyloarthritis is poorly understood.

“Inhibitors of IL-23 and IL-17A are part of an increasing armamentarium of medications to treat spondyloarthritis, but they don’t work for all of the disease manifestations equally,” Dr. Ermann said.

Tumor necrosis factor (TNF) inhibitors, in use longer than some newer biologics, have approval for treatment of psoriasis, psoriatic arthritis, inflammatory bowel disease, and axial spondylarthritis. In the spondyloarthritis space, interest is also growing in janus kinase (JAK) inhibitors.

“These are small molecule inhibitors of certain cytokine signaling pathways, and several phase two clinical trials that have been published suggest there’s efficacy,” Dr. Ermann said, adding that research still needs to be done to learn how they work. “Neither the TNF receptor nor the IL-17A receptor activate the JAK-signal transducer and activator of transcription (STAT) signaling pathway that’s targeted by the JAK inhibitors. The IL-23 receptor signals through a JAK-STAT pathway, but interestingly, IL-23 inhibition doesn’t work for axial disease, whereas the JAK inhibitors do.”

Both IL-23 and IL-17A inhibition have been shown to be effective in psoriasis and psoriatic arthritis. It was expected that the same would be true for axial spondyloarthritis, Dr. Ermann said. But while IL-17A inhibitors have U.S. FDA approval for axial spondyloarthritis, two clinical trials published within the past few years showed IL-23 inhibition was not effective.

Inflammatory bowel disease, including Crohn’s disease and ulcerative colitis, has responded to IL-23 inhibition. Clinical trials of IL-17A inhibitors in Crohn’s disease were stopped because of a lack of efficacy and suggestions they may actually exacerbate the disease.

Christopher T. Ritchlin, MD, MPH
Christopher T. Ritchlin, MD, MPH

Christopher T. Ritchlin, MD, MPH, chief of the Division of Allergy/Immunology and Rheumatology, University of Rochester Medical Center, will explain the basic science underlying the evidence that IL-23 and IL-17 are critical in the key pathogenic events in the skin and joints of patients with psoriatic arthritis. Animal models as well as lab work on human tissue has led to the concept that this cytokine pathway promotes inflammation and joint damage in psoriatic arthritis.

“Over the last five years, the emergence of agents that block IL-23 and IL-17 have transformed psoriasis therapy in a very dramatic way because they’re so effective,” Dr. Ritchlin said. However, he explained, the same level of effectiveness has not been observed in psoriatic arthritis.

Following IL-23’s discovery about 15 years ago, there was a major effort to develop antibodies that block these cytokines. Ixekizumab and secukinumab have been approved for the treatment of psoriasis and psoriatic arthritis, and guselkumab, an agent that blocks IL-23, has approval for treatment of psoriasis and psoriatic arthritis.

“These drugs have greatly expanded treatment options for patients with psoriatic disease,” Dr. Ritchlin said. “Clinicians are using them routinely, so understanding how they were developed and gaining insights into the science behind the molecules is of great interest to rheumatologists.”