Scientists identify new target to battle rheumatoid arthritis

A new study led by researchers at Hospital for Special Surgery identifies the mechanism by which a cell signaling pathway contributes to the development of rheumatoid arthritis (RA). In addition, the study provides evidence that drugs under development for diseases such as cancer could potentially be used to treat RA. Rheumatoid arthritis, a systemic inflammatory autoimmune disease that can be crippling, impacts over a million adults in the United States.

"We uncovered a novel mechanism by which the Notch pathway could contribute to RA, said Xiaoyu Hu, M.D., Ph.D., a research scientist at Hospital for Special Surgery in New York City and principal investigator of the study. The study appears online in advance of print in Nature Immunology.

Prior to this study, researchers knew that an intracellular molecular pathway called Notch is involved in diseases such as cancer. In the last year, other scientists conducted a genome wide association study to identify genes that were linked to the development of rheumatoid arthritis. They discovered that a certain mutation in a gene involved in the Notch pathway puts patients at risk for RA, but nobody knew just how it was involved.

"We were intrigued. Nothing has been known about how the Notch pathway is important to RA," said Dr. Hu. Working with researchers at other institutions in the United States and abroad, HSS investigators started putting two and two together and noted that Notch might be involved in a misfiring of the immune system that is commonly seen in RA.

The researchers designed experiments to test whether the Notch pathway had an influence on macrophages, a type of white blood cell that is most commonly known for gobbling up pathogens but which can also cause inflammation. Macrophages that have gone awry possess widespread pro-inflammatory and destructive capabilities that can critically contribute to acute and chronic rheumatoid arthritis. "In the case of RA, inflammatory macrophages attack joints and they produce inflammatory mediators that basically sustain inflammation in joints," said Dr. Hu.

In experiments, researchers found that knockout mice that lack the Notch pathway in macrophages were unable to produce certain type of macrophages and exhibited a lesser inflammatory phenotype.

Risk factors for the development of rheumatoid arthritis There is increasing interest in attempting to understand what the risk factors are that lead to the development of rheumatoid arthritis (RA). Twin studies have proved a genetic role but also quantified the non-genetic risk. There is thus scope for identifying environmental predictors that might offer a strategy to prevent the disease. Changes in the female hormonal environment such as in pregnancy, breastfeeding and the use of the oral contraceptive (OC) pill appear to have a role. Of the traditional lifestyle exposures, cigarette smoking has been associated with a consistently increased risk that might also apply to the passive inhalation of smoke. Occupation probably has a minor influence, although exposure to silica dust is of aetiological importance. Recent studies have highlighted a role for diet, with suggestions that diets high in caffeine, low in antioxidants and high in red meat may contribute to an increased risk. The most plausible environmental exposure is infection and although several decades of study have produced few definitive candidate organisms, Epstein-Barr virus (EBV) remains an interesting target.