The IL-17 pathway is now firmly established to play a central role in the pathogenesis of axial and peripheral SpA. The evidence from genetics, functional studies, experimental models, and human expression analysis has been confirmed by phase III clinical trials with anti-IL17A antibodies in ankylosing spondylitis (AS) and psoriatic arthritis (PsA) showing a profound suppression of signs and symptoms of inflammation. Interestingly, these trials also showed a suppression of articular destruction in PsA and low mSASSS progression rates in AS. A key scientific and clinical question is thus how and to what extend the IL-17 pathway contributes to structural damage in SpA.
The role of IL-17A in driving osteoclast maturation and activation is well understood. Its potential role in new bone formation, however, remains much more controversial. Recent animal experiments indicate that IL-17A may suppress osteoblast activity and new bone formation by inhibition of Wnt signaling. In contrast, however, work in the HLA-B27 tg rat model showed that IL-17A inhibition halts pathological axial and peripheral osteoproliferation. Albeit this may be an indirect effect related to suppression of inflammation, bone formation experiments with human cells indicate a direct osteoblast-promoting effect of IL-17A. This concept is further supported by recent studies in bone fracture models.
The differential effects of IL-17 family members on bone formation illustrates well that the functional outcome of cytokine signaling is highly dependent on the exact cellular and immunological context in which it is occurring, with important difference between mice and humans. Further translational studies in human patients are needed to establish whether IL-17 blockade may not only suppress inflammation but also halt both catabolic and anabolic aspects of structural damage in human SpA.
Disclosure of Interest None declared
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