IL-33 in Spondyloarthritis, the missing key

Interleukin-33 (IL-33), an alarmin released upon tissue stress or damage, has gained increasing interest in the pathophysiology of inflammatory diseases such as spondyloarthritis (SpA). Acting through its receptor ST2, IL-33 contributes to the activation of type 2 innate lymphoid cells, Th17 responses, and macrophage polarization. It is involved in key musculoskeletal features of SpA, including enthesitis, synovitis, and axial inflammation, and may also play a role in associated extra-articular manifestations such as gut, skin, eyes inflammation. Preclinical studies targeting the IL-33/ST2 axis have shown promising results, with a reduction of arthritis severity, structural joint damage, and inflammation. The dual role of IL-33 in inflammation and bone metabolism further supports its relevance in SpA. Depending on the cellular context, IL-33 can inhibit osteoclast differentiation or promote pathological bone formation, particularly through the induction of pro-osteogenic macrophages. These findings open the possibility of targeting IL-33 not only to control inflammation but also to modulate structural outcomes, including new bone formation. As current biologics such as anti-TNFα or anti-IL-17 therapies do not fully prevent structural progression in all patients, IL-33 represents an attractive complementary target. This review discusses the emerging role of the IL-33/ST2 pathway in SpA and its potential therapeutic implications.