Two hands viewed in X-ray format showing red areas of inflammation around the joints to indicate arthritis or rheumatic disease
Credit: Puwadol Jaturawutthichai/Shutterstock

Researchers part of a public-private partnership have identified new targets for the treatment of autoimmune diseases, including lupus and rheumatoid arthritis. That’s according to a trio of new studies published in the 18 June 2019 issue of Nature Immunologythat provide new details about how tissue damage occurs in these diseases.

No effective targeted therapy currently existsfor systemic lupus erythematosus (lupus) and most people only have partial responses to rheumatoid arthritis (RA) drugs in large part because the basic biology of these autoimmune diseases has been poorly understood. In 2014, the National Institutes of Health (NIH) created the Accelerating Medicines Partnership (AMP) to address some of the most intractable diseases.

The current studies suggest that investigators are within reach of developing novel targeted therapies, said NIH Director Francis S. Collins, M.D., Ph.D. in a press release. “AMP is laying the foundation for precision medicine in rheumatoid arthritis and lupus,” Collins said. The organizations within AMP that focus on RA and Lupus include seven biopharmaceutical companies and five non-profit organizations.

The NIH estimates that 1.5 Americans have RA. The number of people with lupus in the U.S., however, is difficult to estimate because symptoms vary and it can be hard to tell exactly when the disease starts. Still, the Lupus Foundation of America estimates 1.5 million Americans have the disease. Half of the people with lupus will go on to develop lupus nephritis, a potentially fatal kidney disease, according to the Centers for Disease Control and Prevention.

Each of the three studies made novel discoveries about the biology of the diseases, identified new potential targets and, in some cases, suggested potential future diagnostics.

Kidney and skin cells in lupus nephritis.Until now, researchers assumed that inflammatory cells were the primary cause of tissue damage in this kind of lupus. But, by analyzingkidney and skin cells using single-cell RNA sequencing, researchers led by Jill Buyon, M.D., at New York University found molecular signatures that suggestimmune system signaling and genes responsible for scar formation play important roles in the disease process. “In this study, scRNA-seq applied to renal and skin biopsies from patients with LN and healthy control subjects identified clinically relevant signatures associated with disease,” the authors wrote. Their findings suggest that a future diagnostic that utilizes skin cells might replace invasive kidney biopsies.

Immune cell role in lupus nephritis. In the second study, AMP investigators analyzed kidney, blood and urine samples from people with and without lupus nephritis to learn more about how immune cells cause progressive damage in the kidneys. The study was led by led by Betty Diamond, M.D., at The Feinstein Institute for Medical Research, Manhasset, New York. “We analyzed kidney samples from patients with lupus nephritis and from healthy control subjects using single-cell RNA sequencing. Our analysis revealed 21 subsets of leukocytes active in disease,” the authors wrote. They also found that Ssngle-cell analysis of immune cells in urine yielded similar results, suggesting that a urine-based diagnostic may be a way to easily track disease progression.

Inflammatory cell states in RA tissue. RA is characterized by chronic inflammation of the synovium—a thin tissue that lines joints. AMP investigators led by Soumya Raychaudhuri, M.D., Ph.D., at Brigham and Women’s Hospital, Boston, used single-cell profiling technologies to analyze synovial biopsies. They identified subsets of cells—including a kind of fibroblast cell, called subling fibroblasts, which are involved in producing cellular scaffolding, specific white blood cells and others – that appear more often in people with rheumatoid arthritis. Further studies are needed to define molecular mechanisms that regulate fibroblasts in RA, the researchers wrote.

“These AMP rheumatoid arthritis and lupus findings offer insights into intriguing immune system targets that are worthy of more investigation,” said Robert Carter, M.D., acting director of the National Institute of Arthritis and Musculoskeletal and Skin Diseases.

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