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Psoriatic arthritis from a mechanistic perspective

Nature Reviews Rheumatology volume 18, pages 311–325 (2022)Cite this article

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Abstract

Psoriatic arthritis (PsA) is part of a group of closely related clinical phenotypes (‘psoriatic disease’) that is defined by shared molecular pathogenesis resulting in excessive, prolonged inflammation in the various tissues affected, such as the skin, the entheses or the joints. Psoriatic disease comprises a set of specific drivers that promote an aberrant immune response and the consequent development of chronic disease that necessitates therapeutic intervention. These drivers include genetic, biomechanical, metabolic and microbial factors that facilitate a robust and continuous mobilization, trafficking and homing of immune cells into the target tissues. The role of genetic variants involved in the immune response, the contribution of mechanical factors triggering an exaggerated inflammatory response (mechanoinflammation), the impact of adipose tissue and altered lipid metabolism and the influence of intestinal dysbiosis in the disease process are discussed. Furthermore, the role of key cytokines, such as IL-23, IL-17 and TNF, in orchestrating the various phases of the inflammatory disease process and as therapeutic targets in PsA is reviewed. Finally, the nature and the mechanisms of inflammatory tissue responses inherent to PsA are summarized.

Key points

  • Genetic associations with psoriatic arthritis (PsA), which involve both HLA and non-HLA genes, partially overlap with those observed in psoriatic skin disease.

  • Microbial dysbiosis and alteration of microbiota-produced metabolic factors precede the onset of PsA and are associated with changes in epithelial barrier function, precipitating inflammation in PsA.

  • Metabolic changes related to PsA are linked to obesity and changes in free fatty acid levels, and cardiovascular risk is increased in PsA owing to inflammation and metabolic alterations.

  • Mechanoinflammation is pathognomonic for psoriatic skin as well as musculoskeletal disease, and leads to enthesitis and bony spur formation at entheseal sites.

  • Inducer, enhancer and effector cytokines, such as IL-23, IL-17 and TNF, respectively, orchestrate the inflammatory disease process in PsA and are the main therapeutic targets.

  • Structural changes in PsA include the formation of enthesophytes, triggered by periosteal responses, and bone erosions, resulting from chronic synovitis and osteoclast activation.

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Fig. 1: Drivers, manifestations and consequences of PsA.
Fig. 2: Mechanistic model of PsA.
Fig. 3: Mechanoinflammation affecting tendons in PsA.
Fig. 4: Structural changes in the context of PsA.

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Authors and Affiliations

  1. Department of Medicine 3, Friedrich Alexander University Erlangen-Nuremberg and Universitaets-klinikum Erlangen, Erlangen, Germany

    Georg Schett

  2. Deutsches Zentrum Immuntherapie DZI, Friedrich Alexander University Erlangen-Nuremberg and Universitaets-klinikum Erlangen, Erlangen, Germany

    Georg Schett

  3. St. Clare’s Mercy Hospital, St. John’s, Newfoundland, Canada

    Proton Rahman

  4. Division of Allergy, Immunology and Rheumatology, University of Rochester Medical Center Rochester, Rochester, NY, USA

    Christopher Ritchlin

  5. College of Medical Veterinary and Life Sciences, University of Glasgow, Glasgow, UK

    Iain B. McInnes

  6. VIB-UGent Center for Inflammation Research and Ghent University Hospital, Ghent, Belgium

    Dirk Elewaut

  7. Department of Medicine, Division of Rheumatology, NYU Grossman School of Medicine, New York, NY, USA

    Jose U. Scher

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  1. Georg Schett
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Schett, G., Rahman, P., Ritchlin, C. et al. Psoriatic arthritis from a mechanistic perspective. Nat Rev Rheumatol 18, 311–325 (2022). https://doi.org/10.1038/s41584-022-00776-6

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