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Delineating inflammatory from non-inflammatory mechanisms for therapy optimization in psoriatic arthritis

Nature Reviews Rheumatology volume 21, pages 237–248 (2025)Cite this article

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Abstract

Psoriatic arthritis (PsA) is anatomically much more heterogeneous than rheumatoid arthritis, as, beyond synovitis, it often also involves enthesitis, peritendinitis, tenosynovitis, osteitis and periostitis. This heterogeneity currently precludes a gold standard for objectively defining resolution of inflammation following treatment, with enthesitis posing a particular challenge. Despite these difficulties, we apply lessons learned from rheumatoid arthritis to describe how patients with PsA and an inadequate response to therapy can be designated within two patient subgroups, characterized by persistent inflammatory PsA (PIPsA) and non-inflammatory PsA (NIPsA), respectively. The NIPsA phenotype is defined by the lack of ongoing joint inflammation, as confirmed through clinical assessment and imaging, along with normalized inflammatory marker levels. NIPsA might be associated with obesity, biomechanical-related pain, osteoarthritis, fibromyalgia, secondary post-inflammatory damage and central pain mechanisms. In this article, we frame PsA composite outcomes measures in relationship to the PIPsA and NIPsA phenotypes and propose that this approach might help to minimize unnecessary or ineffective cycling of PsA therapy in patients who acquire dominant non-inflammatory mechanisms and might also inform future trial design.

Key points

  • For optimal management of patients with psoriatic arthritis (PsA) and an inadequate response to treatment (particularly in cases that are difficult to treat or refractory), we propose two main disease subcategories: persistent inflammatory PsA (PIPsA) and non-inflammatory PsA (NIPsA).

  • Despite the complexity of PsA in terms of the structures involved (enthesis, synovium, tendons, para-tendinous soft tissue and bone), the best clinical feature for the routine recognition of genuine inflammatory arthritis is joint swelling (synovitis or dactylitis), which can be confirmed by ultrasonography (PIPsA phenotype).

  • In symptomatic patients with persistent pain and high composite scores, but without objective clinical signs of inflammation, the absence of ‘active’ inflammation on ultrasonography suggests a NIPsA phenotype that is likely to be associated with comorbidities, such as obesity and osteoarthritis; however, distinguishing ‘pure’ and less common isolated entheseal phenotypes remains challenging for this less common clinical phenotype.

  • The exhaustion of therapeutic options define treatment-refractory PsA; however, it is recognized that non-response, as measured by composite outcomes, might involve non-inflammatory components, highlighting the need for imaging.

  • Accurate characterization of the PIPsA phenotype will facilitate clinical trials, including combinations of advanced therapies using existing composite outcomes for PsA.

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Fig. 1: The complexity of psoriatic arthritis-related joint disease.
Fig. 2: Imaging peripheral inflammation in psoriatic arthritis.
Fig. 3: Evaluating psoriatic arthritis through the perspective of composite outcomes.
Fig. 4: Stratification of patients with psoriatic arthritis who respond inadequately to therapy.

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Acknowledgements

D.M.’s work is supported by the Leeds National Institute of Health Research Biomedical Research Centre.

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Authors and Affiliations

  1. Section of Musculoskeletal Disease, NIHR Leeds Musculoskeletal Biomedical Research Centre, Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Chapel Allerton Hospital, Leeds, UK

    Alen Zabotti, Paula David, Andrea Di Matteo & Dennis McGonagle

  2. Division of Rheumatology, Azienda Sanitaria Universitaria del Friuli Centrale, Santa Maria della Misericordia Hospital, Udine, Italy

    Alen Zabotti

  3. University of Ottawa, The Ottawa Hospital Research Institute, Ottawa, Ontario, Canada

    Sibel Zehra Aydin

  4. Department of Internal Medicine B & Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Tel-Hashomer, Israel. Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel

    Paula David

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Contributions

A.Z., S.Z.A., A.D.M. and D.M. conceived the main concepts and equally described the newly suggested terminology. A.Z., S.Z.A., P.D., A.D.M. and D.M. contributed to writing. A.Z., A.D.M. and D.M. revised the final version of the manuscript.

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Correspondence to Dennis McGonagle.

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Zabotti, A., Aydin, S.Z., David, P. et al. Delineating inflammatory from non-inflammatory mechanisms for therapy optimization in psoriatic arthritis. Nat Rev Rheumatol 21, 237–248 (2025). https://doi.org/10.1038/s41584-025-01229-6

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