Experimental models of spondyloarthritis: Pathophysiological insights and translational challenges

Spondyloarthritis (SpA) represents a heterogeneous group of chronic inflammatory rheumatologic diseases, including axial spondyloarthritis (axSpA), psoriatic arthritis (PsA), and SpA associated with inflammatory bowel disease (IBD). These conditions share overlapping clinical manifestations, genetic predisposition-particularly a strong association with HLA-B27-and common immunopathogenic pathways, notably the IL-23/IL-17 axis and tumor necrosis factor (TNF) signaling. Understanding SpA pathophysiology has been greatly facilitated by animal models, which have provided critical mechanistic insights and served as indispensable tools for preclinical drug testing. Among these, rodent models have been particularly informative. However, despite their contributions, no single model reproduces the full clinical spectrum of SpA, which includes axial inflammation, enthesitis, peripheral arthritis, and extra-articular manifestations such as uveitis, psoriasis, and gut involvement. This review provides a comprehensive analysis of rodent SpA models, focusing on their mechanistic underpinnings, key discoveries, and translational relevance. We first summarize the major categories of models before examining the strengths and limitations of each. We highlight how these models have advanced our understanding of the gut-joint axis, IL-23-driven entheseal inflammation, and TNF-dependent pathways, which are now major therapeutic targets. Finally, we discuss emerging strategies to enhance translational fidelity, including humanized mice, microbiome engineering, and integration of multi-omic approaches. These developments are essential to bridge the current gap between experimental findings and clinical applications in SpA.