An interdisciplinary perspective on peripheral drivers of pain in rheumatoid arthritis

• Published in: Nature reviews. Rheumatology 2024-11, Vol.20 (11), p.671-682
• Main Authors: Rutter-Locher, Zoe, Kirkham, Bruce W., Bannister, Kirsty, Bennett, David L., Buckley, Christopher D., Taams, Leonie S., Denk, Franziska
• Format: Article
• Language: English
• Subjects: 692/1807/410; 692/4023/1670/498; Analgesics; Arthralgia; Autoantibodies; Central nervous system; Chronic pain; Drug development; Interdisciplinary aspects; Medicine; Medicine & Public Health; Mesenchyme; Pain; Review Article; Rheumatoid arthritis; Rheumatology; Sensory neurons; Synovitis
• ISSN: 1759-4790; 1759-4804; 1759-4804
• DOI: 10.1038/s41584-024-01155-z

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. Emerging data suggest that resident cells and locally produced mediators interact with nerves in the joint to promote pain in rheumatoid arthritis. This Review discusses the potential neuro–immune–stromal interactions promoting joint pain and highlights the need for an interdisciplinary approach to therapeutic 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.