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Treatment for rheumatoid arthritis (RA) has advanced significantly in recent years, with medications that can effectively combat inflammation in the tissues surrounding joints. However, about 20% of patients with painful and swollen joints do not experience relief from even the strongest anti-inflammatory drugs. Surgical interventions have revealed that these patients have excessive tissue growth without inflammation, leading to pain. In a new study published in Science Translational Medicine, researchers have identified a set of 815 genes that activate abnormal growth of sensory neurons in tissues surrounding affected joints, leading to pain that is not alleviated by anti-inflammatory drugs.

Rheumatoid arthritis is a chronic disease characterized by symptoms such as stiffness, tenderness, swelling, limited motion, and pain in various joints. The condition occurs symmetrically and sporadically, with irregular flare-ups. Immune cells invade the synovium, leading to inflammation and pain. While most cases of RA respond well to drugs that target immune mediators, patients with excessive tissue growth without inflammation do not benefit from these treatments. As a result, these patients often receive multiple rounds of anti-inflammatory drugs that do not provide relief, exposing them to unnecessary medications that suppress the immune system.

Researchers examined tissue samples and pain reports from 39 RA patients with pain but little inflammation to identify genes associated with pain. Using a machine-learning analysis called graph-based gene expression module identification (GbGMI), they identified 815 genes that were associated with patient reports of pain. Single cell sequencing analysis revealed that CD55+ fibroblasts in synovial tissue expressed the highest levels of pain-associated genes. These fibroblasts secreted synovial fluid and expressed the NTN4 gene, which codes for a protein called Netrin-4 that promotes axon growth and new vascular growth in tissues.

The researchers found that the identified genes were enriched in pathways important for neuron axon growth, leading to the hypothesis that fibroblasts produced substances that altered sensory nerve growth. In vitro experiments showed that Netrin-4 promoted the sprouting and branching of CGRP+ pain receptors in neurons. Imaging of RA synovial tissue revealed an abundance of blood vessels surrounded by CGRP+ sensory nerve fibers growing towards lining fibroblasts, causing squishy swelling mistaken for inflammation. The researchers aim to identify other fibroblast-produced substances that affect the growth of pain-sensitive neurons and explore the impact on different types of sensory nerves to develop targeted treatments for patients with little inflammation.

The findings from this study offer insight into the mechanisms underlying pain in patients with excessive tissue growth without inflammation in RA. By identifying genes associated with pain and understanding how fibroblasts alter sensory nerve growth, researchers hope to develop new treatments for these patients. The ultimate goal is to match the right treatment with the right patient to improve outcomes and avoid unnecessary exposure to ineffective medications. Through further research, researchers aim to uncover additional substances produced by fibroblasts that affect pain-sensitive neuron growth and explore the impact on different sensory nerve types to develop more targeted therapies for patients with little inflammation in RA.

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