Machine Learning Study Offers Clues to Why Some People Have Rheumatoid Arthritis Pain Without Inflammation
Posted on by Dr. Monica M. Bertagnolli
About 1.5 million adults in the U.S. are living with rheumatoid arthritis (RA), an autoimmune disease in which the immune system attacks joint tissue, causing inflammation, swelling, and pain. Treatments often do a good job fighting inflammation to slow or even stop joint damage and ease pain. But this doesn’t work for everyone. Many people with RA don’t find pain relief, even with the strongest anti-inflammatory, disease-modifying therapies now available.
Why is that? A new study supported in part by NIH and reported in Science Translational Medicine has an intriguing answer.1 The findings suggest that in some people with RA, the joint lining may direct the growth of pain-sensing neurons to cause pain in the absence of inflammation. This discovery, made possible with the help of machine learning, suggests potential new ways to treat this painful disease.
The findings come from a team led by Fei Wang, Weill Cornell Medicine, New York City, and Dana E. Orange, Rockefeller University, New York City. They were inspired by recent studies showing that RA pain and inflammation don’t always go together. In fact, people with RA who have limited inflammation in some cases report just as much pain as those who have extreme inflammation. As a result, they also tend to get less benefit from anti-inflammatory drugs.
To find out why, the researchers studied the soft tissue, or synovium, lining the spaces of the joints from people with this less common form of RA. They were in search of underlying differences in gene activity to explain the pain without inflammation. They knew it wouldn’t be easy, given the variation in the way people experience and report pain and the limited availability of surgically removed tissue samples. To overcome those roadblocks, they developed a machine learning approach that could pinpoint pain-associated patterns of gene activity in the complex data that would otherwise be too difficult to discern.
Their RNA sequencing analysis turned up 815 genes that were expressed at unusually high levels in the joint tissue of 22 people who had RA pain with low inflammation. They also confirmed this same pattern of gene activity in a second group of patients with early untreated RA and little inflammation.
The researchers went on to find that this pattern was clearest in fibroblast cells (a major cell type of the synovium) which provide the structural framework of the joint space, but become a key driver of inflammation and joint damage in RA. Those fibroblasts also expressed a gene that encodes a protein called netrin-4, which is related to a family of proteins that play a role in the growth of neurons. It led them to wonder whether the joint tissue might be producing substances that could alter pain-sensing nerves to cause pain.
To learn more, they turned to studies in mice. They found that fluid collected from joint fibroblast cell cultures and netrin-4 made mouse neurons sprout new branches carrying pain receptors in the lab. The findings suggested that the RA joint lining was indeed producing substances that could lead to the growth of pain-sensing neurons.
To see if this might play a role in people with RA and little inflammation, they looked closely at the joints. Those images revealed an abundance of blood vessels that could nurture tissue growth. Those vessels were also surrounded by pain-sensing nerve fibers extending toward the joint lining in places where there was an abnormal amount of tissue growth.
The researchers think this process explains why painful, arthritic joints sometimes feel squishy and swollen even when they aren’t inflamed. In future studies, they want to learn more about which sensory neurons are specifically affected, noting that there are about a dozen different types. While much more study is needed, their goal is to find promising new ways to treat RA by targeting this underlying process, giving more people with RA much needed pain relief.
Reference:
[1] Bai Z, et al. Synovial fibroblast gene expression is associated with sensory nerve growth and pain in rheumatoid arthritis. Science Translational Medicine. DOI: 10.1126/scitranslmed.adk3506 (2024).
NIH Support: National Institute of Arthritis and Musculoskeletal and Skin Diseases
We need research on Polymyalgia Rheumatica (PMR). No new studies or research in years.
Now what, I am interested in this because I feel I have a different form of RA, diagnosed when I was 35 with multiple blood tests findings over several months. But my progression has been really slow with little to know seen joint damage. That once had a doctor tell me I didn’t have RA because I had no damage to my hands. I have little inflammation but severe pains but it is not constant. I would love to have something that gave me relief when anti-inflammatories are not doing anything for me.
My older sister and I both have abnormal joint development that has increased as we age causing pain and infringement on surrounding tissues/nerve function that has led to surgery. Our mother had extreme RA that caused a need for numerous joint replacements, 30+ while she was alive. We both have had numerically close rheumatoid factor test results, however, were never diagnosed with RA. My sister recently had surgery to remove an ulcer over a prominent bony overgrowth and to have the excess bone reduced. After reading this article about RA without the usual inflammation that occurs with this malady, I wonder how many people with RA are undiagnosed, because blood tests for rheumatoid factor, sedimentary rate, etc., don’t fall in the range for a RA diagnosis. Due to the opiate addiction crisis in this country, many professional health care folks are very reluctant to prescribe substances that could adequately reduce pain for these individuals with undiagnosed RA. due to the test’s numerical values. My sister and I have both experienced the assumption of ‘drug seeking’ by specialists when we search for relief so we might resume normal activities no matter what the suggestions may be. Drugs are not the quest. We both agree that other forms of therapy are of more value in the ‘big picture’ in maintaining health and ability to possibly function in some comfort. As we age out of this life, we both have witnessed people dismissing needed surgeries/procedures due to the fear of inadequate pain relief following this type of necessity. Thank you for this forum to extrapolate on the thoughts that arise after reading this article.
Many of the preclinical research studies have a rather primitive way of assessing ADME based on what is known about small molecules. Ever since the introduction of biologics in the repertoire of FDA approved drugs, the assessment of ADME is not quite the same. Formulations can affect the uptake of macro-molecules by a variety of cells. Something for consideration not just for biologics such as mAb to treat chronic conditions, but also vaccines while priming the immune system to pathogens. Hence why a good understanding of MOA is much more crucial than small molecules. It’s usually a big leap across “the valley of death” to go from preclinical animal and in-vitro studies to an approved product without a black-box warning.