According to researchers, there is a group of genes that are responsible for the discrepancy between the diagnosis of rheumatoid arthritis and the symptoms experienced by patients. Treatment for rheumatoid arthritis has advanced significantly in recent years, with many medications now effectively preventing the inflammation that causes pain and swelling in the joints. However, approximately 20% of patients with visibly swollen and painful joints do not experience relief from even the strongest anti-inflammatory drugs, despite multiple rounds of treatment. Additionally, surgical interventions intended to remove the inflammation do not always provide the expected relief.In a recent study published in Science Translational Medicine, researchers have discovered the reason behind the excessive tissue growth in some patients with joint pain. Co-senior author Dana Orange, from Rockefeller’s Laboratory of Molecular Neuro-oncology, explains, “In some cases, their joints aren’t actually inflamed. With these patients, if you press on the joint, it feels mushy and thick to the touch, but it’s not caused by the infiltrating immune cells. They have excessive tissue growth, but without inflammation. So why are they experiencing pain?”
According to the study, these patients have a suite of 815 genes that activate abnormal growth of tissue without causing inflammation.
Research has found that there are 815 genes involved in rewiring the sensory nerves in tissues that protect the affected joints. This discovery helps explain why traditional anti-inflammatory drugs are not effective in reducing pain for these patients, according to Orange. The results of this study could potentially lead to the development of new treatments for these individuals.
Challenging Nature of Rheumatoid Arthritis
Rheumatoid arthritis is a complex chronic condition that manifests with symptoms such as stiffness, tenderness, swelling, limited motion, and pain in the hands, wrists, feet, and other joints. It typically affects both sides of the body symmetrically and presents with unpredictable flare-ups.of these patients to a near-constant state of NSAID overuse,” Wollaeger says. “many of these patients are getting increasing doses or being switched from one NSAID to another. The idea behind NSAID overuse is that inflammation causes pain,” Wollaeger says. “But if it were that simple, we wouldn’t have the problem of treating people who are still in pain despite multiple drugs. “It’s likely that cytokines and other immune mediators play a role in the pain sensation, but it is a complex, poorly understood relationship. Traditional NSAIDs may not be targeting the right receptors or the pain-sensing synovium.” This is where we need to have a better understanding and better interventions for the future.”
patients often take numerous medications that result in weakening their immune system but offer little relief for their symptoms,” Orange explains. The team of researchers, including Orange, decided to explore the genes expressed in the joint tissue of these patients to find some answers. They studied tissue samples and pain reports from 39 individuals with RA who experienced pain but showed minimal signs of inflammation. In addition, they developed a machine-learning analysis called graph-based gene expression module identification (GbGMI) to examine all potential gene combinations in the dataset and identify the most effective ones.A group of genes has been identified to be linked to a specific clinical symptom, such as pain. Through RNA sequencing, researchers found that out of 15,000 genes expressed in tissue samples, around 2,200 had increased expression in 39 patients. By using GbGMI, they pinpointed 815 genes associated with patient reports of pain, despite the challenge of having a large number of genes and a limited number of patients, according to co-senior author Fei Wang, professor of population health sciences and founding director of the Institute of Artificial Intelligence for Digital Health.al Health at Weill Cornell Medicine. “Our approach using graphs effectively examined the connections between a group of genes and patient-reported pain.”
Analysis of single cell sequencing discovered that among the four types of fibroblasts in synovial tissue, CD55+ fibroblasts showed the highest level of expression of genes associated with pain. CD55+ cells, located in the outer synovial lining, produce synovial fluid, enabling smooth joint movement. These cells also showed expression of the NTN4 gene, which produces a protein called Netrin-4. Netrin proteins play a role in guiding the growth of axons and promoting new vascular growth.
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Researchers made an unexpected discovery about pain pathways. They found that certain genes are heavily involved in the growth of neuron axons, which are crucial for sensory perception and transmitting information to the central nervous system. Fibroblasts may be producing substances that impact the growth of sensory nerves, leading to hypotheses about their role in pain sensation. To investigate further, neurons were grown in a lab and treated with Netrin-4 to see how it affected them.
Netrin-4 has been found to have an impact on the growth of pain receptors, specifically CGRP+ (gene-related peptide) receptors, for the first time.
Imaging of RA synovial tissue showed an abundance of blood vessels, surrounded by CGRP+ sensory nerve fibers, growing towards the lining fibroblasts in areas of excessive tissue growth, or hyperplasia. This process likely contributes to the soft swelling mistaken for inflammation.
Improved Medications
In the future, the researchers anticipate the development of better drugs.The focus is on identifying additional products produced by fibroblasts that could impact the growth of pain-sensitive neurons. Researchers will also explore how other types of sensory nerves may be impacted.
“We looked at one type, but there are around twelve. We are unsure if all nerves are equally affected. And we do not want to eliminate all sensation. Sensory nerves play a crucial role in recognizing the need to avoid certain movements and understanding the position of your joint in space, for example,” Orange explains.
“We aim to thoroughly investigate these specifics in the hopes of developing alternative treatments for patients with minimal inflammation.”The current situation is that patients are receiving expensive medications that cost $70,000 a year, even though there is no chance of them working. It is important for us to improve the process of matching the right drug with the right patient.
