Why does joint damage continue in rheumatoid arthritis patients—even during remission?
Rheumatoid arthritis (RA) affects nearly 1.5 million Americans, with almost 5% of women over 55 living with this chronic autoimmune condition. While modern treatments have improved symptom management, many patients still experience continued joint damage even during remission. Yale researchers may have discovered why.
The study, published in the Proceedings of the National Academy of Sciences, examined T lymphocytes, which are white blood cells responsible for fighting infections and cancer cells. Researchers found that certain T lymphocytes have a receptor for the immune hormone macrophage migration inhibitory factor, or MIF. Prior research showed that about 20% of people carry high-expression versions of the MIF gene, which are linked to more severe autoimmune disease.
Led by Dr. Edward Doherty and colleagues at Yale School of Medicine, the research team studied mice models with arthritis and made a surprising discovery: when they removed either MIF or its receptor CD74, the mice didn't develop arthritis at all. Researchers found that T lymphocytes with these receptors increased in mice model with induced arthritis and that simply transferring these T lymphocytes to healthy mice resulted in RA-like joint inflammation. Crucially, the team found these same MIF-sensitive T lymphocytes in the joint tissue of RA patients who needed joint replacement.
Researchers also found that these T lymphocytes stayed in an autoimmune state even after the initial inflammatory response had died down. "These cells persist in the joints and retain their autoimmune properties even when symptoms improve," explains Dr. Richard Bucala, senior author of the study. This may explain why RA flare-ups often return to previously affected joints and why gradual joint damage continues even in patients who feel well.
The findings suggest that targeting the MIF/CD74 pathway could offer new treatment options, especially for the 20% of individuals with high-expression MIF genes who experience more severe symptoms. Rather than broadly suppressing the immune system, future therapies might specifically target these disease-driving memory cells, potentially preventing both chronic inflammation and disease relapse.
Understanding the cellular mechanisms behind RA brings us closer to precision treatments that address the root causes of persistent joint damage.