O'Brien Jayden A, Lesnak Joseph B, Price Theodore J
Department of Neuroscience and Center for Advanced Pain Studies, University of Texas at Dallas, 800 W Campbell Rd, Richardson, TX, 75080, USA.
Curr Rheumatol Rep. 2025 Jul 16;27(1):30. doi: 10.1007/s11926-025-01198-5.
Pain is one of the most debilitating sequelae of rheumatoid arthritis. Established and emerging therapies offer effective disease control for many patients, though they often have underwhelming efficacy for pain relief. The uncoupling of pain intensity from disease activity and inflammation presents an ongoing challenge in both our understanding of the pathophysiology and our ability to treat joint pain. The generation of high-parameter, unbiased -omic data sets generated from patient-derived tissues is changing how we think about rheumatoid arthritis pain. In this review, we discuss the peripheral drivers of pain in rheumatoid arthritis-affected joints and their innervating primary afferents. We evaluate how human molecular immunology and neuroscience approaches are helping us unravel the heterogeneity of pain in rheumatoid arthritis and propose future directions to clarify how pain is maintained in the absence of inflammation.
Synovial fibroblasts have emerged as key pronociceptive drivers within the rheumatic joint. Further to the classical proinflammatory mediators known to drive pain, such as cytokines and prostaglandins, bone morphogenetic proteins, ephrin signaling, and netrins appear to be upregulated in both rheumatoid arthritis-affected synovium and the innervating sensory neurons. Resulting adaptations to innervating primary afferents such as synaptogenesis and neurite outgrowth may occur in a sensory neuron subtype-specific manner causing pain that is disproportionate to inflammation. Nociceptor sprouting in the joint may explain why pain tends to persist despite adequate disease control. Future mechanistic work exploring the conditions under which these nociceptors sprout into the joint will provide new therapeutic avenues for ensuring that pain resolves alongside the inflammation associated with rheumatoid arthritis.
疼痛是类风湿关节炎最使人衰弱的后遗症之一。已有的和新出现的疗法能为许多患者有效控制疾病，不过它们对缓解疼痛的效果往往不尽人意。疼痛强度与疾病活动及炎症的脱钩，在我们对病理生理学的理解以及治疗关节疼痛的能力方面，都是持续存在的挑战。从患者来源的组织生成的高参数、无偏倚的组学数据集正在改变我们对类风湿关节炎疼痛的看法。在本综述中，我们讨论类风湿关节炎受累关节疼痛的外周驱动因素及其支配的初级传入神经。我们评估人类分子免疫学和神经科学方法如何帮助我们揭示类风湿关节炎疼痛的异质性，并提出未来的方向，以阐明在无炎症情况下疼痛是如何维持的。
滑膜成纤维细胞已成为风湿性关节内关键的伤害感受驱动因素。除了已知驱动疼痛的经典促炎介质，如细胞因子和前列腺素外，骨形态发生蛋白、 Ephrin 信号传导和网蛋白在类风湿关节炎受累的滑膜和支配的感觉神经元中似乎都上调。由此导致的对支配初级传入神经的适应性变化，如突触形成和神经突生长，可能以感觉神经元亚型特异性的方式发生，导致与炎症不成比例 的疼痛。关节中伤害感受器的芽生可能解释了为什么尽管疾病得到了充分控制，疼痛仍倾向于持续存在。未来探索这些伤害感受器在何种条件下芽生进入关节的机制研究，将为确保疼痛与类风湿关节炎相关炎症一并消退提供新的治疗途径。
