The treatment landscape for rheumatoid arthritis (RA) has witnessed significant advancements in recent times. In many instances, a range of medications can now effectively suppress the inflammatory cells responsible for inducing swelling and discomfort as they invade tissues surrounding the joints.

However, approximately 20% of patients with visibly swollen and painful joints find little to no relief from multiple rounds of even the most potent anti-inflammatory drugs available.

Through surgical interventions aimed at removing inflamed tissue, researchers have uncovered a key insight: “In certain cases, the joints aren’t actually inflamed,” explains co-senior author Dana Orange, an associate professor at Rockefeller’s Laboratory of Molecular Neuro-oncology. “These patients exhibit excessive tissue growth, which gives the joint a mushy and thick feel upon touch, but without the presence of infiltrating immune cells. So why do they still experience pain?”

In a recent study published in Science Translational Medicine, Orange and her team propose a potential explanation. These patients possess a set of 815 genes that trigger abnormal growth of sensory neurons within the tissues surrounding the affected joints.

“These 815 genes essentially rewire the sensory nerves, elucidating why traditional anti-inflammatory medications fail to alleviate pain in these patients,” explains Orange. These findings hold promise for the development of novel treatments tailored to address the needs of these individuals.

A perplexing dissociation

Rheumatoid arthritis poses a complex challenge as a chronic condition. Its hallmark symptoms – stiffness, tenderness, swelling, restricted motion, and pain – gradually manifest in various joints such as the hands, wrists, and feet. The condition typically progresses symmetrically across the body and follows an unpredictable pattern of flare-ups. Extreme fatigue and depression often accompany these symptoms.

While most cases of RA stem from immune cell byproducts like cytokines, bradykinins, or prostanoids infiltrating the synovium (the soft tissue lining the joints) and binding to pain receptors, medications targeting these immune mediators have significantly improved the management of RA for the majority. However, individuals grappling with the disconnect between inflammation and pain have not experienced similar benefits.

In a futile attempt to alleviate symptoms, doctors frequently prescribe successive rounds of anti-inflammatory drugs to these patients. As Orange notes, “We are subjecting some patients to a lot of medications that cause immunosuppression and yet have little chance of making their symptoms better.”

In pursuit of answers, Orange and her team scrutinized the gene expression profiles in joint tissue samples obtained from these patients.

Identifying genetic contributors

Analyzing tissue samples and pain reports from 39 RA patients exhibiting pain with minimal inflammation, the researchers employed a machine-learning approach known as graph-based gene expression module identification (GbGMI).

GbGMI systematically explores potential gene combinations within a dataset to identify the optimal gene set associated with a specific clinical feature – in this case, pain.

Using RNA sequencing, the team identified approximately 2,200 genes with heightened expression in the 39 patients out of the 15,000 genes evaluated. Through GbGMI, they pinpointed 815 genes strongly associated with patient-reported pain.

“This presents a challenging problem, given the large number of genes and limited patient data,” explains co-senior author Fei Wang, professor at Weill Cornell Medicine. “The graph-based approach effectively elucidated the collective associations between gene sets and patient-reported pain.”

Further analysis using single-cell sequencing revealed that among the four types of fibroblasts present in synovial tissue, CD55+ fibroblasts exhibited the highest expression of pain-associated genes. Positioned in the outer synovial lining, CD55+ cells secrete synovial fluid, facilitating smooth joint movement. Additionally, they expressed the NTN4 gene, encoding a protein called Netrin-4. Netrin family proteins play crucial roles in guiding axon growth paths and promoting vascular growth.

Unexpected pain mechanisms

Remarkably, these genes were found to be enriched in pathways critical for neuron axon growth. Sensory neurons, responsible for transmitting information to the central nervous system, play a pivotal role in sensation. Axons, their branching extensions, project into tissues.

“This led us to speculate that fibroblasts may produce substances influencing the growth of sensory nerves,” suggests Orange.

To investigate further, the researchers cultured neurons in vitro and treated them with Netrin-4, observing significant sprouting and branching of CGRP+ (calcitonin gene-related peptide) pain receptors. This marked the first instance of Netrin-4 influencing the growth of pain-sensitive neurons, Orange notes.

Imaging of RA synovial tissue unveiled an abundance of blood vessels surrounded by CGRP+ sensory nerve fibers, extending toward the lining fibroblasts in areas of excessive tissue growth or hyperplasia. This process likely contributes to the soft swelling often mistaken for inflammation by rheumatologists and surgeons.

Future therapeutic avenues

Moving forward, the researchers aim to explore additional substances produced by fibroblasts that might influence the growth of pain-sensitive neurons. They also intend to investigate other types of sensory nerves that could be affected.

“While we focused on one type, there are approximately a dozen sensory nerve varieties. We’re uncertain if all nerves are equally affected, and we don’t want to completely block sensation,” emphasizes Orange. “Sensory nerves play a crucial role in alerting individuals to avoid certain movements and in determining joint position. We aim to delve deeper into these nuances to develop alternative treatments for patients experiencing minimal inflammation. Currently, they’re prescribed medications costing up to $70,000 annually, with little prospect of efficacy. We must improve our ability to match the right drug with the right patient.”

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