Enthesitis: an autoinflammatory lesion linking nail and joint involvement in psoriatic disease

The traditional model for psoriasis and psoriatic arthritis (PsA) is that autoimmunity directed against a common skin and joint autoantigen leads to chronic autoreactive T cell driven inflammation. However, recent imaging, histological and genetic studies have challenged this view, especially with respect to joint and nail disease, and provide a broader insight into the pathogenesis of PsA and associated nail involvement. Clinically unrecognized enthesitis (inflammation at tendon and ligament attachments) is commonly seen in early PsA at all sites of the disease. Specifically, enthesitis is associated with adjacent osteitis or bone and synovial inflammation. Even in normal joints, normal insertions are associated with microdamage and inflammatory change, strongly suggesting that local tissue specific, or what has been described as autoinflammatory factors, may dictate disease expression. Distal interphalangeal (DIP) joint disease in PsA is associated with diffuse inflammation that envelops the nail root and adjacent bone. In fact, the nail is intimately linked to entheses, with the extension tendon of the DIP joint sending fibres from bone that envelop the nail root in an interdigitating fashion. Furthermore, the joint collateral ligament enthesis has fibres that merge with the lateral borders of the nail. Other anchorage mechanisms include fibres that directly tether the nail plate to the underlying periosteum, which itself is closely anchored to the extension tendon. The frequent microdamage and tissue repair at normal enthesis attachment sites in healthy joints has resulted in a proposed new model of PsA pathogenesis embracing the concept of autoinflammation, whereby tissue specific factors, including microtrauma, lead to regional innate immune activation and persistent inflammation, as an alternative to primary immunopathology driven by T and B cell abnormalities. Unlike the classical autoimmune diseases, which may attack a completely normal organ, autoimmunity in psoriatic disease is likely to involve tissues where there is intrinsic dysregulation of the target tissues. These tissue specific factors related to the enthesis appear to be key to the phenotypic expression of diseases hitherto regarded as autoimmune. The pathogenesis of PsA, nail disease and to a lesser extent psoriasis therefore appear to have an autoinflammatory (innate immune driven) rather than autoimmune basis. Taken together, these findings are important for better understanding PsA, nail disease and psoriasis, and for conceptualizing the immunopathogenic basis of these diseases and further exploring the role of enthesitis in their pathophysiology.