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

DOI: 10.1111/j.1468-3083.2009.03363.x JEADV Blackwell Publishing Ltd REVIEW ARTICLE Enthesitis: an autoinflammatory lesion linking nail and joint involvement in psoriatic disease D McGonagle* NIHR, Leeds Biomedical Research Unit, Leeds Institute of Molecular Medicine (LIMM), Wellcome Trust Brenner Building, St James University Hospital, Leeds, LS9 7TF *Correspondence: D McGonagle. E-mail: d.g.mcgonagle@leeds.ac.uk Abstract 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. Received: 30 April 2009; Accepted: 28 May 2009 Keywords enthesitis, nail disease, psoriasis, psoriatic arthritis Conflicts of interest None declared. Introduction Traditionally, the inflammation associated with psoriasis and psoriatic arthritis (PsA) was thought to be caused by autoimmunity against a common autoantigen in the skin and joints, with the joint antigen being expressed on the synovial membrane or cartilage. However, recent studies have challenged this view, leading to greater insight into the pathogenesis of psoriasis and PsA. Indeed, a proposed new model of pathogenesis embraces the concept of autoinflammation (innate immunity related disease), which links psoriasis and PsA, as well as possible nail involvement has been developed. This presentation reviews how imaging studies have challenged the traditional model of PsA and psoriasis, the role of entheses and the relationship with the nail, and how the link between them may help to explain an alternative perspective for the pathogenesis of PsA. Central to the anatomical and microanatomical model for

10 McGonagle Figure 1 Traditional model of the pathogenesis of PsA and psoriasis. [Reprinted with permission of the BMJ Group.] 2 PsA are the entheses, the sites of insertion of tendons, ligaments or joint capsules to bone. Entheses consist of both soft tissue (tendon, ligament and their fibrocartilages) and hard tissue (calcified fibrocartilage, adjacent bone and trabecular network) components. In many sites, the enthesis is more than simply a focal attachment point, and it is intimately associated anatomically and functionally with the synovium forming a distinct organ referred to as the synovio-entheseal complex (SEC). 1 Inflammation of the entheses (enthesitis) can be studied using magnetic resonance imaging (MRI) or ultrasound. Recent highresolution MRI studies have revealed the importance of the nail in understanding the link between the skin and joints in PsA and when coupled with tissue microanatomy studies, with an eye on prevailing immunology dogma, can provide novel insights into disease mechanisms. Traditional model of pathogenesis of PsA and psoriasis The traditional model of the pathogenesis of psoriasis and PsA hypothesizes that chronic inflammation occurs as a result of T-cell directed autoimmunity against a common skin and joint autoantigen (Fig. 1). 2 However, no such common antigen has been identified to date. The anatomical basis for PsA and nail disease does not fit with this model as many articular manifestations are independent of synovitis. Characteristic features of early PsA, new bone formation, bone oedema, and periostitis, with spinal involvement and dactylitis. 3 5 These patterns of diffuse pathology often have inflammation of the enthesis as the epicenter. It is hard to conceptualise this diffuse enthesitis associated pathology in relationship to an autoantigen, but is better viewed in terms of an aberrant response to mechanical stressing, since the major function of this structure is to resist stress at insertions. 4,6 There is evidence that enthesitis is often asymptomatic in the early stages of PsA and psoriasis, without clinical signs of arthropathy, 7,8 and radiographic abnormalities are usually absent when patients first present. There are abnormalities in tendon or ligament architecture, thickening and oedema of the attachment site, bone erosion and entheseal new bone formation. 2,4 Thus, the common occurrence of subclinical enthesitis in patients with psoriasis is strong evidence for the primacy of this lesion in skeletal disease. Originally, enthesitis was only appreciated from a clinical perspective in a subgroup of patients, so its importance was not recognized. The advent of high-resolution MRI changed this view, as it revealed the extent of osteitis seen within days of presentation in patients with PsA and related seronegative disease. Although the joint structure is totally intact, osteitis is usually present in patients with PsA in the first 6 months, and it is predictive of radiographic evidence of destructive spinal involvement. MRI abnormalities are therefore likely to be highly relevant in PsA as has been found in patients with early inflammatory back pain. 9 How is synovitis in PsA linked to enthesitis? MRI studies have suggested a link between enthesitis and synovitis in swollen joints in PsA, particularly in larger joints such as the knee or heels (Achilles tendon). Enthesitis was originally thought to be a focal inflammation at insertion sites, but MRI has revealed a much more diffuse inflammation involving adjacent bone and soft tissue including the synovium. Inflammatory changes therefore are seen to occur some distance from the insertion site of the enthesis. These findings have been explained by the concept of the SEC, which is an integral component of the enthesis organ complex. 1,10 The SEC dissipates stress at bony surfaces over a wide area away from the point of insertion, and has been found in many entheses. It is made up of the enthesis, anatomically coupled by fibrocartilages to the synovial membrane. Thus, in diffuse enthesitis, pathologic changes occur adjacent to as well as at the entheses. MRI studies in patients with early PsA-related synovitis have identified osteitis in adjacent attachments, as well as subclinical enthesitis. 7,11 Enthesitis has therefore been proposed as the common denominator between psoriasis and PsA, and subclinical enthesitis may be the primary pathology that triggers secondary joint synovitis through the release of proinflammatory mediators. 6 Why is PsA so strongly associated with nail disease? Enthesitis is often difficult to recognize in many locations due to limitations in imaging, particularly in small joints. High-resolution MRI is needed to study inflammation involving the distal interphalangeal (DIP) joints and nails. 12 This technique has revealed a differing pattern of DIP joint inflammation in patients with PsA compared with osteoarthritis (Fig. 2), characterized by pronounced changes in collateral ligaments, extensor tendons and bone involvement at entheseal insertions, 13 and massive diffuse

The enthesis and psoriasis 11 Figure 2 Axial high-resolution MRI images of DIP joints in patients with PsA, OA and normal subjects showing extensive diffuse inflammation in PsA. [Reprinted with permission of Elsevier B.V]. 14 Indicates thickening of tissues under the nail bed. DIP, distal interphalangeal; OA, osteoarthritis; PsA, psoriatic arthritis. osteitis. 11 Indeed, perientheseal bone oedema is the most useful feature of enthesitis on MRI. Using high-resolution MRI, enthesitis has been shown to be almost always present in early DIP joint PsA. 11 The dorsal capsular enthesis may be the locus of inflammation, diffusing out to involve soft tissue adjacent to nails. 14 The inflammatory reaction around the DIP joint is sufficiently extensive that it envelops the nail matrix and it therefore appears that the inflammatory reaction around the DIP joint in arthritis and nail disease has an extensive microanatomical distribution that is best conceptualized in relationship to a network of insertions around the finger tip. Thus, anatomically, there is strong link between PsA and nail inflammation. MRI and histological studies demonstrate that the extensor tendon crossing the DIP is fused with the nail root and matrix, with tendon fibres enveloping the nail root (Fig. 3). 14 Extensor tendon fibres also split and fuse with the periosteum over the terminal phalanx, which is connected to the nail bed, thus indirectly anchoring the enthesis to the bone of the phalynx. 15 The nail plate also merges with collateral ligaments of the DIP enthesis, stabilizing the lateral margins of the nail. Thus, although the nail is developmentally related to skin and is traditionally seen as a specialized modification of it, it is in fact functionally integrated with the musculoskeletal system, anchored by entheses to the bone (Fig. 4). 15 Given this extensive level of enthesis nail interdigitation, inflammation of the extensor tendon enthesis therefore often involves the nail bed. How the enthesis might be related to nail pathology in PsA is briefly discussed. Pitting, the most common manifestation of nail involvement in PsA, is a result of lesions in the nail matrix. Inflammation of the extensor tendon and its intimate involvement with the nail matrix is likely to be implicated, and thus, it is possible that pitting is caused by sloughing of nail plate keratinocytes in the proximal nail plate as a result of local inflammation of the enthesis organ. 15 Subclinical enthesitis may also be responsible for some of the ungual pain experienced by patients with psoriasis who do not have clinical PsA, but who have nail pain. Furthermore, periostitis which is often found in patients with PsA may be explained if the nail is viewed in terms of an extended enthesis network or dermal ligaments anchored to the periosteum. This might also be relevant for understanding the underlying mechanisms associated with arthritis mutilans which usually affects the DIP joint. The possibility Figure 3 Histology sections showing extensor tendon (ET) enthesis. The superficial (SL) and deep laminae (DL) from the ET are associated with the nail root (NR) and matrix. [Reprinted with permission of Elsevier B.V]. 14

12 McGonagle Figure 4 The link between the nail, enthesis and periosteum. [Reprinted with permission of Karger AG.] 15 Figure 5 Alternative model of the pathogenesis of PsA and psoriasis. 15 that psoriatic nail disease phenotypic expression may relate to the enthesis network or mechanical stressing of skeletal tissues awaits confirmation using high-resolution imaging. Alternative model for the pathogenesis of PsA and psoriasis The above findings are important for a better understanding of immunological diseases such as PsA and psoriasis, and we have proposed an alternative classification to the prevailing classical autoimmune dogma to explain the underlying pathophysiology. 16 This model differentiates between autoimmune reactions in which an adaptive immune response is the main mechanism behind the clinical manifestations of the disease, and an autoinflammatory reaction in which local factors at sites predisposed to the disease cause a primary innate immune response, resulting in tissue damage and inflammation independent of adaptive immune responses. This new classification recognizes tissue-specific factors as being important in the phenotypic expression of diseases previously regarded as autoimmune. Normal enthesis attachment sites in healthy joints show histological evidence of subclinical microdamage and tissue repair, 17, 18 probably as a result of continuous mechanical wear and tear. This microdamage and inflammation extends to fibrocartilage adjacent to insertion points close to synovium (i.e. in the SEC), again as a result of high mechanical stress. 19 Similarly, microdamage or trauma may be responsible for skin lesions in psoriasis, which is a classic example of the Koebner response phenomenon in dermatology. 2 Koebner responses may also contribute to nail involvement in psoriatic disease. 15 In support of this general Koebner response it has been proposed that entheses and skin share microanatomical features, with both sites having large surface areas between two different types of tissue and these assist in dissipating stress during regional compressive and shear force applications. 2 We recently reviewed the genetic disparities between psoriasis and PsA and nail disease. 20 Recognising that the immunogenetic features of psoriatic arthritis and nail disease, in particular, do not conform to the prevailing dogma of autoimmunity, and recognizing that tissue specific factors at disease prone sites may be key players in some types of inflammation against self, as outlined above, we developed a new translationally relevant classification for non infectious inflammatory disorders. 16,21 Whilst classical autoantibody associated autoimmune diseases are critically dependent on primary and secondary lymphoid organs, the seronegative arthropathies, including PsA, crucially rely on intrinsic dysregulation of the enthesis mesenchymal derived target tissue for disease expression. 16 To facilitate classification and to link into existing nomenclature in translational immunology we termed these tissue specific factors that lead to inflammation as autoinflammatory (or factors capable of triggering regional innate immune responses). When this knowledge is integrated with the genetics of psoriatic disease, the pathogenesis of PsA and nail disease, both of which appear to lack the HLA Cw0602 association, appears to have a primary autoinflammatory rather than an autoimmune basis (Fig. 5). Since this concept was originally formulated it has derived powerful support from TNF transgenic mouse models of arthritis with a PsA like phenotype that includes sacroiliitis and enthesitis. 22 The initiation of arthritis in TNF transgenic mice is at the enthesis and its expression is critically dependent on enthesis stromal cells and not on cells of the immune system. 22 This proof of concept work shows how tissue specific factors or autoinflammatory factors may lead to disease phenotypes hitherto regarded as autoimmune. It is however clear that type 1 psoriasis has a prominent adaptive immune component driving the disease. This HLA-Cw0602 associated psoriasis appears to be intermediate between the two boundaries of autoimmunity and innate immune driven disease, and is thus distinct from classical autoimmunity. 16,21 This distinction may reside in the fact that intrinsic dysregulation of keratinocyte or skin barrier function may lead to regional

The enthesis and psoriasis 13 microscopic inflammation that triggers secondary T cell driven responses by as yet poorly defined mechanisms. 21 This model therefore captures the interplay between T cells and keratinocytes in the immunopathogenesis of psoriasis. Conclusion Although developmentally related to skin, the nail is functionally integrated to skeletal appendages with linking to the enthesis. The enthesis is more than just a focal point of insertion of tendons and ligaments to bone, and encompasses soft tissue and structures such as the nail, to form the SEC or enthesis organ around the DIP joint. The close functional integration of the joint and the nail likely underscores the propensity for nail disease and osteolysis that is strongly associated with PsA. The sites of disease prone to inflammation in psoriasis related diseases appear to be prone to subclinical microdamage which is key to understanding disease. To conclude, this perspective provides a unifying clinical concept and immunological model that links the skin and joint in PsA, and offers a new way of looking at the spectrum of disease related to psoriasis. Acknowledgments I would like to thank Dr Ai Lyn Tan and Professor Mike Benjamin, and all my colleagues at the Academic unit of Musculoskeletal Diseases in Leeds for their contribution to the research included in this review. References 1 McGonagle D, Lories RJU, Tan AL, Benjamin M. The concept of a synovio-entheseal complex and its implications for understanding joint inflammation and damage in psoriatic arthritis and beyond. Arthritis Rheum 2007; 56: 2482 2491. 2 McGonagle D, Tan AL, Benjamin M. The biomechanical link between skin and joint disease in psoriasis and psoriatic arthritis: what every dermatologist needs to know. Ann Rheum Dis 2008; 67: 1 4. 3 Gladman DD, Antoni C, Mease P et al. Psoriatic arthritis: epidemiology, clinical features, course, and outcome. 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