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In recent years, great progress has been made in the treatment of rheumatoid arthritis (RA). In many conditions, a combination of drugs can now effectively suppress the inflammatory cells that cause swelling and discomfort when they enter the tissues around the joints.
Yet, for some reason, about 20 percent of patients with painful, obviously swollen joints get no relief even from several rounds of these strongest anti-inflammatory drugs.
Surgical interventions aimed at removing the inflamed tissues revealed that, “in some cases, their joints are not actually inflamed,” according to clinical investigations at Rockefeller’s Laboratory of Molecular Neuro-Oncology. says co-senior author Dana Orange, associate professor. “With these patients, if you put pressure on the joint, it feels pulpy and thick to the touch, but that’s not due to infiltrating immune cells. They have excessive tissue growth, but no inflammation. So why are they experiencing pain?”
Also Read: Good Life with Arthritis: Strategies for a Pain-Free Life
In a new paper in Science Translational Medicine, Dana and colleagues suggest an explanation. These patients have a cluster 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 the pain in these patients,” says Orange. The findings could lead to new treatments for these outliers.
a shocking separation
Rheumatoid arthritis is a complex chronic disease. Its symptoms – stiffness, tenderness, swelling, limited movement and pain – gradually emerge in the hands, wrists, feet and other joints. It occurs symmetrically (not just in one arm, but in both, for example) and sporadically, with irregular flare-ups. Extreme fatigue and depression are also common.
Most cases of RA are caused by products of immune cells such as cytokines, bradykinin or prostanoids that attack the synovium – a soft tissue lining the joints – where they attach 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 been of no benefit to sufferers.
Doctors often prescribe drug after anti-inflammatory drug in an ultimately futile attempt to provide relief to these patients. As a result, “we’re giving some patients lots of drugs that cause immunosuppression and yet have little chance of improving their symptoms,” Orange says.
He and his colleagues sought answers in genes expressed in joint tissue samples from these patients.
genetic culprit
Researchers looked at tissue samples and self-reported pain reports from 39 RA patients who had pain but little inflammation. He also developed a machine-learning analysis, which he coined graph-based gene expression module identification (GBGMI).
GbGMI tests every possible combination of genes in the dataset to determine the optimal set of genes that associate with a target clinical trait – in this case, pain.
Using RNA sequencing, the researchers found that about 2,200 of the 15,000 genes expressed in the tissue samples had increased expression in the 39 patients. Using GbGMI, they identified 815 genes that were simultaneously associated with patient reports of pain.
“This is a challenging problem, because we 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 of Artificial Intelligence for Digital Health at Weill. . Cornell Medicine. “The graph-based approach we used effectively explored collective relationships 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-associated genes. Located in the outer synovial lining, CD55 cells secrete synovial fluid, allowing friction-free joint movement. They also express the NTN4 gene, which codes for a protein called netrin-4. Netrin family proteins guide axon growth pathways and promote new vascular growth.
Amazing Pain Paths
The researchers discovered that these genes were enriched in pathways that are important for neuron axon growth. Key to sensation, sensory neurons receive and transmit information to the central nervous system. Axons are the tendrils that extend from them and spread through the tissues.
“This led us to hypothesize that perhaps fibroblasts are producing things that alter the development of sensory nerves,” says Orange.
But what role did proteins play in pain perception?
To find out, they grew neurons in vitro and then injected netrin-4 into them, which triggered the sprouting and branching of CGRP (gene-related peptide) pain receptors. She says this is the first time that netrin-4 has been shown to alter the development of pain-sensitive neurons.
Imaging of RA synovial tissue also revealed an abundance of blood vessels, which feed and nourish new cells. These vessels were innervated by CGRP sensory nerve fibers and growing toward the lining fibroblasts in areas of excessive tissue growth, or hyperplasia. This process potentially causes squishy swelling that many rheumatologists and surgeons mistake for inflammation.
better medicine
In the future, the researchers aim to explore other products produced by fibroblasts that may influence the development of pain-sensitive neurons. They will also check for 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 sensations. Sensory nerves are important for knowing when you need something.” Activities to avoid and, for example, the position of your joint in space,” says Orange.
“We want to delve deeper into those details so that hopefully we can come up with other treatments for patients who don’t have a lot of inflammation. Right now, he’s taking medications that can cost $70,000 a year but have no chance of working. “We must do a better job of getting the right medicine to the right patient.”
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