Enthesitis: from pathophysiology to treatment

• Published in: Nature reviews. Rheumatology Vol. 13; no. 12; pp. 731 - 741
• Main Authors: Schett, Georg, Lories, Rik J., D'Agostino, Maria-Antonietta, Elewaut, Dirk, Kirkham, Bruce, Soriano, Enrique R., McGonagle, Dennis
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.12.2017; Nature Publishing Group
• Subjects: 692/4023/1670/2766; 692/420/2780; 692/700/1421; Anti-Inflammatory Agents, Non-Steroidal - therapeutic use; Antibodies, Monoclonal - pharmacology; Antibodies, Monoclonal - therapeutic use; Arthritis; Biomechanics; Bone growth; Care and treatment; Connective tissue diseases; Development and progression; Humans; Inflammation; Inflammatory diseases; Interleukin 22; Interleukin 23; Joint Diseases - diagnostic imaging; Joint Diseases - drug therapy; Joint Diseases - etiology; Ligaments; Locomotion; Medical research; Medicine & Public Health; Medicine, Experimental; Osteogenesis; Prostaglandin E2; Psoriatic arthritis; review-article; Rheumatic diseases; Rheumatology; Tendons; Tumor necrosis factor; Tumor Necrosis Factor-alpha - antagonists & inhibitors; Vasodilation
• ISSN: 1759-4790; 1759-4804
• DOI: 10.1038/nrrheum.2017.188

Key Points Entheses are predominantly extra-articularly localized structures that represent a key target of musculoskeletal inflammation in diseases such as psoriatic arthritis (PsA) and spondyloarthritis (SpA) Entheses contain a specific immune microenvironment, which is activated by a combination of factors that include mechanical stress, genetic susceptibility and microbial-triggered immune activation Enthesitis arises from robust activation of prostaglandin E2 and the IL-23–IL-17 axis, leading to the influx of innate immune cells and homing of inflammation into the entheses, which is followed by mesenchymal tissue responses and new bone formation Clinical and imaging instruments have been developed that enable the reliable detection and monitoring of enthesitis in patients with PsA and SpA Inhibition of the key effector cytokines of enthesitis — IL-17, IL-23 and TNF — has shown to be effective in supporting the resolution of enthesitis in PsA and SpA This article provides an overview of the pathophysiology of enthesitis, from induction and inflammation to tissue proliferation and bone formation. Building on these pathophysiological concepts, the clinical presentation, assessment and treatment of enthesitis are also discussed. Entheses are the insertion sites of tendons and ligaments to the bone surface and are essential structures for locomotion. Inflammation of the entheses (enthesitis) is a key feature of psoriatic arthritis and spondyloarthritis. To date, our conceptual understanding of enthesitis remains limited. This Review provides an insight into the pathophysiology of enthesitis, addressing the role of biomechanics, prostaglandin E2-mediated vasodilation and the activation of innate immune cells in the initiation phase of enthesitis, as well as the role of entheseal IL-23-responsive cells that augment inflammation by producing pro-inflammatory mediators such as IL-17A, IL-22 and TNF. In addition, the molecular steps that translate inflammation into resident tissue responses, resulting in new bone formation, are discussed. The second part of the article summarizes the clinical features of enthesitis, and the role of clinical and imaging instruments in detecting enthesitis are discussed together with their challenges and limitations. Finally, the Review summarizes the current treatment possibilities for enthesitis based on the aforementioned pathophysiological concepts, focusing on the role of cytokine-blocking agents.