ACR CONVERGENCE 2020—In recent years, a pathophysiological role for the interleukin (IL) 17/IL-23 axis in the development of psoriasis, enthesitis and inflammatory arthritis has been investigated in both rodent and human models. Clinical trials have demonstrated differential benefits for skin disease and joint disease in patients with psoriatic arthritis, axial spondyloarthritis (axSpA) and ankylosing spondylitis (AS).
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Explore This IssueMarch 2021
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During the session IL-17, IL-23 and Other Cytokine Targets: Lessons from Clinical Trials for Spondyloarthritis, two investigators reviewed the recent literature and shared emerging insights regarding cytokine-targeting therapies for various disease manifestations in spondyloarthritis.
Christopher Ritchlin, MD, MPH, professor and chief of the Allergy/Immunology and Rheumatology Division, University of Rochester Medical Center, New York, discussed the genetic basis for susceptibility to the development of spondyloarthritis and shared current research insights on the clinical benefits of blocking IL-17/IL-23 axis pathways to treat patients with psoriatic arthritis.
Joerg Ermann, MD, an instructor in medicine at Harvard Medical School, Boston, and a researcher and rheumatologist at Brigham and Women’s Hospital, Boston, discussed the development and current trajectory for cytokine-targeting therapies used to treat axSpA.
Cytokine Targets in Psoriatic Arthritis
Dr. Ritchlin, a principal investigator for several clinical trials testing the efficacy of agents in the treatment of psoriatic and rheumatoid arthritis and AS, explained that the IL-17/IL-23 axis has both IL-17-dependent and IL-17-independent pathways. In the IL-17-dependent pathway, IL-23 released by dendritic cell macrophages can activate the differentiation of T helper 17 (Th-17) cells through retinoid-related orphan receptor γt, releasing a variety of important cytokines, including IL-17A and IL-17F, as well as IL-22, that can influence a number of other cell types.
In the IL-17-independent pathway, IL-23 interacts with its receptor on a variety of cell sites. These interactions can promote a number of critical events in these cells, including angiogenesis, recruitment of cells and infiltration of activated Th-17 and IL-2 cells. Dr. Ritchlin noted, “These pathways really make a difference, particularly when you are looking at therapeutics.”
It’s important to recognize that IL-17 molecules in a number of isoforms, Dr. Ritchlin stated. These isoforms include a homodimer (IL-17A) and a heterodimer (IL-17F) that bind to specific receptors. Receptor engagement results in downstream activation of P38, and subsequent transcription of NF-κB and activator protein 1 activation (AP-1). These transcription factors promote the production of a variety of pro- and anti-inflammatory molecules. He also emphasized that Th-17 cells can be proinflammatory, anti-inflammatory or regulatory, and the microenvironment they are found in can help drive a cell in a certain direction, “so just seeing that a cell expresses the signature of an IL-17 helper cell does not necessarily tell you the function of that cell.”
In a brief review of the genetic basis of psoriatic arthritis from the perspective of IL-23, Dr. Ritchlin shared work by Stuart et al. comparing genetic SNPs of patients with psoriatic arthritis.1 He highlighted the potential associations of genetic snips with abnormalities in the IL-17/IL-23 axis.