Breakthrough developments in rheumatoid arthritis reported

Peter K. Gregersen, MD, stares at x-rays of hands, searching out the telltale signs of inflamed joints and wrists from his research subjects with rheumatoid arthritis. With these clinical features at his side, he turns to the basic building blocks of life – the human genome – to figure out what makes these people susceptible to the disabling inflammatory condition.

Dr. Gregersen has finally closed the circle between key genes identified in his laboratory at the Robert S. Boas Center for Genomics and Human Genetics at The Feinstein Institute for Medical Research in Manhasset, NY and more than a 1,000 patients with rheumatoid arthritis. The genes will help tell the story of how the immune system works to create specific antibodies that in turn increase a person’s risk for this crippling disease.

On Monday at the Federation of Clinical Immunology Services’ (FOCIS) meetings in San Diego, CA, Dr. Gregersen and his colleagues will be presenting the lab’s latest genetic findings. The group conducted genome-wide scans to identify polymorphisms, or genetic variants, that are associated with the inflammatory condition and can be used to understand the triggers of the disease. This will provide key insights into the pathways underlying rheumatoid arthritis and other autoimmune diseases. It may ultimately provide tests to predict who will respond to the available new treatments. Franak Batliwalla, PhD, also of The Feinstein Institute, will be presenting related studies on biomarkers and genetic influences on drug response at the same meeting.

Identifying Immune System Mediators

About one percent of the US population will develop rheumatoid arthritis, an autoimmune disease that leads to painful joint swelling. Scientists are cracking the genetic code that makes the immune system wage an attack on a person’s joints. Over the last decade, Dr. Gregersen and his colleagues have been amassing a genetic database complete with siblings with rheumatoid arthritis (and some family members without it) in an attempt to single out those genes that are involved in the autoimmune process. In fact, in 2004, they identified a gene called PTPN2 that confers a two-fold risk for rheumatoid arthritis and a number of other autoimmune diseases. The Feinstein now holds the largest collection from rheumatoid arthritis patients in the world.

Following the cellular pathway, it has been shown that PTPN22 influences the “trigger point” for activation of T-cells, immune cells that are normally called on to wage battle against infection. In autoimmune diseases like rheumatoid arthritis, PTPN22 appears to put people at higher risk of a wayward T-cell response.

The group has since gone on to use modern genetic methods to search for single nucleotide polymorphisms, or SNPs, to identify players that have fallen under the radar of older methods. The group has discovered another signaling molecule that seems to increase a person’s risk for rheumatoid arthritis by 30 percent. (The paper reporting the gene is in press.)