Research Spotlight: New Study Reveals Potential Ways Rheumatoid Arthritis Can Resist Even the Best Treatments

Kevin Wei, MD, PhD, and Kartik Bhamidipati, PhD, of the Division of Rheumatology Inflammation and Immunity in the Mass General Brigham Department of Medicine, are the corresponding and lead authors of a paper published in Nature Immunology, “Spatial patterning of fibroblast TGFβ signaling underlies treatment resistance in rheumatoid arthritis.”

Q: What challenges or unmet needs make this study important?

Rheumatoid arthritis (RA) is a common autoimmune disease where the body's immune system mistakenly attacks the lining of its own joints, causing chronic pain, swelling and stiffness.

While there have been remarkable advancements in the treatment of RA with an array of therapies that target inflammation, a large subset of patients (approximately 6-28%) continue to experience difficult-to-manage symptoms of disease even after receiving multiple lines of treatment. There is a critical need to identify new therapeutic approaches for patients who are refractory to existing treatment options.

Q: What central question(s) were you investigating?

Our research focused on discovering why some people with rheumatoid arthritis don't respond well to standard treatments, by looking closely at the biology of their joint tissue.

Q: What methods or approach did you use?

We leveraged cutting-edge spatial transcriptomics to profile over 30 joint biopsies from patients before and after they received treatment, providing us with a highly detailed “map” of joint tissues. We then asked which features within these joint tissue “maps” corresponded to a lack of adequate treatment response.

Q: What did you find?

We observed an exaggerated wound healing response (fibrogenesis) in the joints of patients who failed to achieve remission. Though the treatments were effective in depleting immune populations and reducing joint swelling, they were not adequately effective at alleviating joint pain in non-remitting patients, which was linked to increased tissue scarring.

We also discovered that the buildup of scar tissue in joints happens because the normal communication between blood vessels and endothelial cells with nearby support cells, called fibroblasts, gets disrupted. If we can find ways to help these cells talk to each other properly again, we might be able to stop or even reverse the harmful scarring that leads to ongoing joint problems.

Q: What are the real-world implications, particularly for patients?

Our study identifies this type of tissue scarring as a key driver of treatment-refractory RA. This mechanism remains unaddressed by the current therapeutic landscape and offers a novel, targetable pathway for patients resistant to existing treatments.

Q: What emerging trends in this field excite you right now?

Advances in technology are speeding up the deep molecular profiling of patient samples, ushering in an exciting era of precision medicine for autoimmune diseases where treatment is tailored to a patient's unique molecular characteristics (such as protein levels, enzyme activity, and more). This targeted approach promises to replace the current trial-and-error treatment methods with more effective interventions, significantly improving patient outcomes and quality of life.

Authorship: In addition to Bhamidipati and Wei, Mass General Brigham authors include Alexa McIntytre, Shideh Kazerounian, Gao Ce, Miles Tran, Sean Prell, Vikram Khedgikar, Roopa Madhu, Sonia Presti, Ksenia Anufrieva, Philip Blazar, Jeffrey Lange, Ellen Gravallese, Michael Brenner, and Ilya Korsunsky.

Paper cited: Bhamidipati, K., et al. “Spatial patterning of fibroblast TGFβ signaling underlies treatment resistance in rheumatoid arthritis.” Nature Immunology. DOI: 10.1038/s41590-025-02386-2

Funding: This work was supported by grants from the National Institutes of Health (NIH-NIAMS K08AR077037, NIH-NIAMS T32AR007530-36) and the Burroughs Wellcome Fund Career Awards for Medical Scientists.

Disclosures: Wei has a sponsored-research agreement from Merck Pharmaceuticals, BMS, Anaptys Bio and 10x Genomics.