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An interdisciplinary perspective on peripheral drivers of pain in rheumatoid arthritis

Nature Reviews Rheumatology (2024)Cite this article

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Abstract

Pain is one of the most debilitating symptoms of rheumatoid arthritis (RA), and yet remains poorly understood, especially when pain occurs in the absence of synovitis. Without active inflammation, experts most often attribute joint pain to central nervous system dysfunction. However, advances in the past 5 years in both immunology and neuroscience research suggest that chronic pain in RA is also driven by a variety of abnormal interactions between peripheral neurons and mediators produced by resident cells in the local joint environment. In this Review, we discuss these novel insights from an interdisciplinary neuro-immune perspective. We outline a potential working model for the peripheral drivers of pain in RA, which includes autoantibodies, resident immune and mesenchymal cells and their interactions with different subtypes of peripheral sensory neurons. We also offer suggestions for how future collaborative research could be designed to accelerate analgesic drug development.

Key points

  • With the advent of biologic drugs bringing ever-improving disease control, pain is emerging as one of the most important remaining symptoms in rheumatoid arthritis.

  • Pain mechanisms in rheumatoid arthritis are still not fully understood, especially when pain is uncoupled from joint inflammation.

  • Emerging evidence implicates not only immune cells and cytokines but also autoantibodies and mesenchymal cells in arthritis-induced neuronal hyperactivity.

  • Efforts towards large collaborative and interdisciplinary consortia to address specific questions are promising and valuable in accelerating our understanding of pain in rheumatoid arthritis.

  • Recognizing pain as a distinct and essential clinical outcome in addition to disease activity and tissue damage is vital.

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Fig. 1: Peripheral innervation of joints.
Fig. 2: Examples of prototypical diagrams of reviews on peripheral neuron sensitization.
Fig. 3: Emerging mechanistic model of rheumatoid arthritis pain.

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Acknowledgements

The authors acknowledge the following funding support: a National Institute for Health Research (NIHR) Doctoral Fellowship (NIHR301674 to Z.R.-L.) and a Wellcome Trust Collaborative Award (224257/Z/21/Z to B.W.K., D.L.B., C.D.B., F.D. and L.S.T.).

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Author notes

  1. These authors contributed equally: Leonie S. Taams, Franziska Denk.

Authors and Affiliations

  1. Department of Rheumatology, Guy’s Hospital, London, UK

    Zoe Rutter-Locher & Bruce W. Kirkham

  2. Centre for Inflammation Biology & Cancer Immunology, Department of Inflammation Biology, School of Immunology & Microbial Sciences, King’s College London, London, UK

    Zoe Rutter-Locher & Leonie S. Taams

  3. Wolfson Sensory Pain and Regeneration Centre (SPaRC), King’s College London, London, UK

    Kirsty Bannister & Franziska Denk

  4. Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK

    David L. Bennett

  5. Kennedy Institute for Rheumatology, University of Oxford, Oxford, UK

    Christopher D. Buckley

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Contributions

All authors reviewed and/or edited the manuscript before submission and contributed substantially to discussion of the content, L.S.T., Z.R.-L., B.W.K. and F.D. researched data for the article, and L.S.T., Z.R.-L. and F.D. wrote the article.

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Correspondence to Leonie S. Taams or Franziska Denk.

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Competing interests

D.L.B. has received research grant funding from Eli Lilly and AstraZeneca. B.W.K. has been an adviser or speaker for AbbVie, Eli-Lilly, Galapagos, Janssen, Novartis, Pfizer and UCB. F.D. receives funding from Ono Pharmaceuticals, is a Scientific Advisor for Cellectricon and is consulting for GSK. L.S.T. has received research funding, speaker or consultancy fees from Sanofi, CESAS Medical, UCB, GSK and AbbVie. C.D.B. has received research grant funding from Janssen, Roche and is an adviser for GSK and AbbVie. He is a founder of Mestag Therapeutics. None of the other authors declares any competing interests relevant to this Review.

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Nature Reviews Rheumatology thanks Neil Basu, who co-reviewed with Flavia Sunzini; Dana Orange; and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Rutter-Locher, Z., Kirkham, B.W., Bannister, K. et al. An interdisciplinary perspective on peripheral drivers of pain in rheumatoid arthritis. Nat Rev Rheumatol (2024). https://doi.org/10.1038/s41584-024-01155-z

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