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  • Review Article
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Phenotypic heterogeneity in psoriatic arthritis: towards tissue pathology-based therapy

Nature Reviews Rheumatology volume 19, pages 153–165 (2023)Cite this article

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Abstract

Psoriatic arthritis (PsA) is a heterogeneous disease involving multiple potential tissue domains. Most outcome measures used so far in randomized clinical trials do not sufficiently reflect this domain heterogeneity. The concept that pathogenetic mechanisms might vary across tissues within a single disease, underpinning such phenotype diversity, could explain tissue-distinct levels of response to different therapies. In this Review, we discuss the tissue, cellular and molecular mechanisms that drive clinical heterogeneity in PsA phenotypes, and detail existing tissue-based research, including data generated using sophisticated interrogative technologies with single-cell precision. Finally, we discuss how these elements support the need for tissue-based therapy in PsA in the context of existing and new therapeutic modes of action, and the implications for future PsA trial outcomes and design.

Key points

  • Outcome measures used in psoriatic arthritis clinical trials do not sufficiently reflect phenotypical heterogeneity related to disease domains in a tissue-specific fashion.

  • Distinct pathogenetic mechanisms can explain tissue-distinct responses to different therapies in psoriatic disease.

  • Discrete tissue environments leading to specific tissue-based signatures should be approached in a distinct and complementary manner; this concept supports a paradigm shift in clinical trial design and clinical practice.

  • Understanding tissue-driven responses to therapies will help to facilitate a move towards a tissue-based precision medicine approach in psoriatic arthritis.

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Fig. 1: Clinical spectrum of PsA with phenotypes and genetic and/or environmental triggers.
Fig. 2: Different tissue and prominent pathogenetic mechanisms and response to current drug mechanisms of action.
Fig. 3: A new cell-based therapeutic concept and emerging targets in PsA.

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  1. These authors jointly supervised this work: Iain B. McInnes, Stefan Siebert.

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  1. School of Infection and Immunity, College of Medical Veterinary and Life Sciences, University of Glasgow, Glasgow, UK

    Aurelie Najm, Carl S. Goodyear, Iain B. McInnes & Stefan Siebert

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Najm, A., Goodyear, C.S., McInnes, I.B. et al. Phenotypic heterogeneity in psoriatic arthritis: towards tissue pathology-based therapy. Nat Rev Rheumatol 19, 153–165 (2023). https://doi.org/10.1038/s41584-022-00874-5

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