New York [US], In recent years, considerable progress has been made in the treatment of rheumatoid arthritis (RA). In many conditions, a combination of medications cannot effectively suppress the inflammatory cells that cause swelling and discomfort when they enter the tissue surrounding the joint, yet for some reason, become painful, markedly swollen. About 20 percent of patients with damaged joints do not get any sustained relief. Even multiple rounds of the strongest anti-inflammatory drugs, plus surgical interventions aimed at removing inflamed tissue, have revealed why, "in some cases, their joints are actually not inflamed," says co-senior author and associate professor of clinical medicine Dan Orange. Investigations at Rockefeller's Molecular Neuro-Oncology Laboratory. “With these patients, if you press on the joint, it feels pulpy and thickened to the touch, but this is not due to infiltration of immune cells.They involve excessive tissue growth, but no inflammation. So why are they experiencing pain? In a new paper in Science Translational Medicine, Dana and colleagues suggest an explanation. These patients have a set of 815 genes that activate abnormal growth of sensory neurons in the tissues that support the affected joints. "These 815 genes are reactivating sensory nerves, which explains why anti-inflammatory drugs don't work to reduce pain in these patients," Orange says. These outliers from the findings are new. There may be treatments.A tricky disconnectio Rheumatoid arthritis is a tricky chronic disease. Its symptoms – stiffness, tenderness, swelling, limited motion, and pain – gradually emerge in the hands, wrists, feet, and other joints. It occurs symmetrically (for example, not in just one arm but in both) and sporadically, also accompanied by extreme fatigue and depression. Most cases of typical RA are caused by products of immune cells such as cytokines, bradykinin, or prostanoids. They are caused to invade the synovium – a soft tissue lining the joints – where they connect to damage-sensing pain receptors. Drugs targeting immune mediators have made RA a far more tolerable condition for most people, but the disconnect between inflammation and pain has not benefited sufferers. Doctors often prescribe anti-inflammatory drugs to these patients, ultimately in a futile attempt to provide relief.As a result, "we're giving some patients lots of drugs that cause immunosuppression and yet have very little chance of improving their symptoms," Orange says, adding that he and his colleagues used joint tissue samples from these patients. The answer sought in the genes expressed in. Genetic culprit Researchers looked at tissue samples and self-reported pain reports from 3 RA patients who had pain but little inflammation. He has also developed a machine-learning analysis that he coined Graph-Based Gene Expression Module Identification (GBGMI). GBGMI tests every possible combination of genes in a dataset to determine the optimal set of genes that associate with a targeted clinical feature – in this case using RNA sequencing, researchers found that tissue samples Of the 15,000 genes differentially expressed, approximately 2,200 had increased expression in 39 patients. Using GBGMI, they identified 815 genes that were simultaneously associated with patient reports of pain. “This is a challenging problem, because our have a large number of genes but a limited number of patients," says co-senior author Fei Wang, professor of population health sciences and founding director of the Institute for Artificial Intelligence for Digital Health at Weill Cornell Medicine. "The graph-base The approach we used effectively detected collective associations between gene sets and patient-reported pain.Single cell sequencing analysis found that of the four types of fibroblasts in synovial tissue, CD55+ fibroblasts displayed the highest expression of pain-related genes Located in the outer synovial lining, CD55+ cells secrete synovial fluid, which facilitates friction-free joint movement. Allows. They also express the NTN4 gene, which codes for a protein called netrin-4 in the NET family and directs axon growth pathways. Developmentally, it turned out that these genes were enriched in pathways that regulate axon growth. Axons are important for development, the researchers found, where sensory, sensor neurons receive and transmit information to the central nervous system. "This helped us speculate that maybe fibroblasts were producing something like this," says Orange. that alter the development of sensory nerves." But to find out what role the protein played in pain sensation, they grew neurons in vitro. And then added Netrin-4 to them which triggered the sprouting and branching of CGRP+ (gene-related peptide) Pi receptors. This is the first time that netrin-4 has been shown to alter the growth of pain-sensitive neurons, they noted, noting that imaging of RA synovial tissue also revealed an abundance of blood vessels that feed and nourish the new cells. Are.These vessels were surrounded by CGRP+ sensor nerve fibers and growing toward lining fibroblasts in areas of excessive tissue growth, or hyperplasia. This process potentially leads to squishy swelling, which many rheumatologists and surgeons consider a better medicine for swelling. In the future, the researchers aim to focus on other products that can influence the development of pain-sensitive neurons that fibroblasts produce. They will also examine other types of sensory nerves that may be affected "We studied one type, but there are about a dozen. We don't know if all nerves are affected equally.And we don't want to block all of the sensory nerves that are important for knowing when you should avoid certain activities and positioning of your joint in space," Orange says. "We want to take a deeper look at those details so that hopefully." So that we can find other treatments for patients. Those who do not have much swelling. Right now he's on drugs that can cost $70,000 a year, but they have no chance of working. We must do a better job of getting the right medicine to the right patient."