Enthesitis is a central feature of spondyloarthritis (SpA). Advanced imaging and pathologic findings suggest that enthesitis is a diffuse process with effects on adjacent bone and soft tissue. As a result of repeated biomechanical stress, it appears that microdamage at the enthesis triggers an inflammatory response in the synovium, leading to synovitis.
Along with mechanical stress, exogenous bacteria may play a role in activating the immune response, especially in genetically predisposed individuals whose major histocompatibility locus encodes the class I molecule HLA–B27. Recent studies in animal models suggest that autoimmunity against versican and fibrocartilage proteins, and bone morphogenetic protein (BMP) signaling play roles in enthesitis development.
Finally, interleukin-23 (IL-23) has been implicated in enthesitis with inflammatory effects mediated through IL-17 and tumor necrosis factor (TNF), and new bone formation driven by IL-22.
Whether enthesitis is a primary central lesion or a secondary process remains a matter of debate. Studies that have implicated enthesitis as the primary process include studies of TNF-transgenic mice, in which the earliest lesion appears to be in the enthesis. However, this may be model specific, and a number of reports have challenged the idea of enthesitis as the primary inflammatory lesion. (Note: See the full study for the study sources referred to here.)
This review article summarizes the substantial progress that has been made in addressing the pathophysiology, molecular mechanisms, genetic associations, clinical features, diagnostic modalities and treatment of enthesitis.
The spine itself (the clinical hallmark of SpA) remains inaccessible to traditional enthesitis-focused research methodologies thus far. However, newer imaging techniques are on the horizon.
Investigations and clinical observations uniformly point out with increasing clarity that the enthesis is much more than a simple attachment site. A number of studies have shown that it functions as a unit comprising adjacent tissues, including bone and fibrocartilage linked to synovium, and serves as a way of dissipating stress over a wide area.
Inflammation at the enthesis manifests in the adjacent synovium presumably via immunity to common antigens or via release of proinflammatory cytokines at the enthesis.
Although work by Benjamin and McGonagle suggest that the enthesis is the primary SpA lesion, the precise role of the enthesis in early stages of disease, especially regarding issues of cause or effect, remains an area of continued debate and discovery.
Further examination into the role of the inflammatory mediators, including IL-17, IL-22, and IL-23 as well as potentially others, in driving enthesitis and bone formation will be important to direct our attention toward future therapeutic targeted pathways in patients with SpA.
