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  • Review Article
  • Published:

Enthesitis: from pathophysiology to treatment

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

Abstract

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.

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Figure 1: Enthesitis versus synovitis.
Figure 2: Functional model of enthesitis.
Figure 3: Microanatomical changes in enthesitis.

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Acknowledgements

This work is supported by the Collaborative Research Center (CRC) 1181 of the German Research Council (Deutsche Forschungsgemeinschaft-DFG). D.M.'s work is funded by the Leeds NIHR Biomedical Research Centre.

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Schett, G., Lories, R., D'Agostino, MA. et al. Enthesitis: from pathophysiology to treatment. Nat Rev Rheumatol 13, 731–741 (2017). https://doi.org/10.1038/nrrheum.2017.188

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