The Pathophysiological Significance of Dual Inhibition of IL-17A and IL-17F in Psoriatic Arthritis and Axial Spondyloarthritis

Objective: Spondylarthritides (SpA), including psoriatic arthritis (PsA) and axial spondyloarthritis (axSpA) are immune-mediated diseases in which the IL-23/IL-17 axis plays a central role. IL-17A inhibition is already a well-established and effective treatment strategy. Emerging evidence suggests that IL-17F, a cytokine closely related to IL-17A but less potent, is not a passive bystander but a key participant in chronic sustained inflammation and therapeutic escape, offering a compelling concept for dual inhibition. This review aims to examine the pathophysiological significance of dual inhibition of IL-17A and IL-17F in psoriatic arthritis and axial spondyloarthritis. Methods: Conducting a search through PubMed/MEDLINE, Scopus, and Web of Science, using keywords and Medical Subject Headings (MeSH) terms such as "spondyloarthritis", "psoriatic arthritis", "IL-17A", "IL-17F", "IL-23", "IL-23 independent mechanisms", "dual inhibition", "pathogenesis", "gut-joint axis", "secukinumab", "ixekizumab", "bimekizumab", "sonelokimab", we select the relevant literature for this comprehensive pathophysiological narrative. Results: This review examines the distinct and synergistic functions of IL-17A and IL-17F in key tissues, including the synovium, enthesis, skin, gut, and eye, and their contribution to the paradoxical imbalance of bone remodelling. The advent of dual IL-17A/F inhibitors, particularly bimekizumab has revolutionised our therapeutic approach, offering a promising option for patients with difficult-to-treat SpA. We also discuss emerging technology agents, such as sonelokimab and izokibep. Conclusion: Inhibiting both IL-17A and IL-17F signifies not only a significant therapeutic advancement but also a vital strategy towards overcoming the limitations of our current armamentarium in achieving deeper and more sustained remission in SpA. Future studies and long-term data will be essential in determining the position of dual IL-17A/F inhibitors within treatment guidelines.