Rheumatoid arthritis (RA) is usually treated with strong anti-inflammatory drugs that help reduce swelling and pain in the joints.
But for about 20% of patients, these medications don’t work, even after multiple rounds. Until now, the reason has remained unclear.
A new study published in Science Translational Medicine reveals that some patients may not actually have joint inflammation, even though their joints appear swollen and feel painful. Instead, these patients may have abnormal nerve growth in the tissues around their joints, which causes pain without inflammation.
Researchers led by Dana Orange at Rockefeller University and Fei Wang at Weill Cornell Medicine discovered that a group of 815 genes may be causing this unusual nerve growth.
These genes appear to rewire sensory nerves in the joints, leading to ongoing pain even in the absence of inflammation. This explains why standard RA medications, which target inflammation, are not effective for these patients.
Rheumatoid arthritis is a long-term disease that causes joint stiffness, swelling, and pain. It affects both sides of the body and often appears in the hands and feet. Fatigue and depression are also common. While most cases are caused by the immune system attacking joint tissues, this study shows that some pain may have a completely different cause.
Doctors often assume these patients still have inflammation and continue prescribing powerful anti-inflammatory drugs. But this may be exposing patients to unnecessary treatments, high costs, and potential side effects without any benefit.
To better understand what’s happening, the researchers examined joint tissue samples from 39 patients with RA who had pain but low inflammation. They used a computer model called GbGMI to find which genes were most closely linked to patient-reported pain. Out of 15,000 genes, they found that 815 were highly active in these patients.
They also found that one type of cell in the joint tissue — CD55+ fibroblasts — was producing a protein called Netrin-4. This protein is known to help grow nerve fibers and blood vessels.
When they added Netrin-4 to neurons in the lab, it caused pain-sensing nerve cells to grow and branch out. This suggests that the fibroblasts in the joints may be encouraging the growth of nerves that send pain signals.
Images of joint tissues showed too many blood vessels and nerves in the outer layers of the joints, where the swelling occurs. These nerve fibers were growing toward the same fibroblast cells that were producing Netrin-4, leading to a kind of swelling that feels similar to inflammation — but isn’t.
In the future, the researchers want to explore other proteins made by fibroblasts and how they affect different types of sensory nerves. They hope this work will lead to better treatments that target nerve-related pain, not just inflammation.
Right now, some patients are taking expensive medications — up to $70,000 a year — that don’t help them. With this new understanding, doctors might be able to give them more effective treatments based on the true cause of their pain.
If you care about pain, please read studies about vitamin K deficiency linked to hip fractures in old people, and these vitamins could help reduce bone fracture risk.
For more health information, please see recent studies that Krill oil could improve muscle health in older people, and eating yogurt linked to lower frailty in older people.
The study is published in Science Translational Medicine.
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