Crafoord Laureates point to new opportunities for RA
The Royal Swedish Academy of Sciences announced in January 2013 that Peter K. Gregersen, MD, a scientist at The Feinstein Institute for Medical Research, would receive the prestigious Crafoord Prize for his genetic research in the area rheumatoid arthritis. Rheumatoid arthritis was once thought of as one disease. But researchers now discriminate between two distinct forms. The knowledge acquired by the 2013 Crafoord Laureates opens new possibilities for the prevention and better treatment of rheumatoid arthritis. Associate Web Editor Mia Burns interviewed Frank Wollheim, MD, PhD, Emeritus professor, Department of Rheumatology, Lund University Hospital.
Q: When rheumatoid arthritis was thought of as one disease, do you mean that it was considered strictly as a bone disease?
A: By no means. Rheumatoid arthritis has long been recognized as a joint disease affecting joints in a characteristic way. In addition to affecting joint structures, a number of extra-articular tissues and organs can be affected. So rheumatoid arthritis has for a long time been known as a multi-organ disease. The new observation regarding the shared epitope (Gregersen-Winchester 1987) showed that only 70 percent of rheumatoid arthritis patients had the appropriate susceptibility genes for rheumatoid arthritis and these were mainly the so called seropositive or rheumatoid factor positive patients. Rheumatoid factor was described by Waaler in 1940 and rediscovered by Marian Rose in 1948, and these discoveries allowed subdividing rheumatoid arthritis patients in seropositive and seronegative individuals, the former were more likely to have more severe disease manifestations. In 1997 another feature was discovered, the anti-citrullin antibodies, which define the same subsets but more specifically. So now one speaks of ACPA positive and ACPA negative rheumatoid arthritis. ACPA stands for anti-citrullinated protein/peptide antibodies, and ACPA testing has complemented rheumatoid factor testing as a clinical routine test.
Q: What sort of diagnostics exits to determine who carries the human leukocyte antigen risk gene?
A: This is a technical question and I am a clinician. HLA testing or tissue typing is a standard methodology used in transplantation medicine. HLA stands for human leukocyte antigen and the testing involves exposing the individual’s white cells to specific antisera. Testing can be made more detailed by using amplifying with PCR.
Q: How does smoking stimulate the formation of those proteins?
A: Smokers inhale smoke into the lungs where the smoke interacts with lung tissue, causing cellular damage (inflammation). Inflammation leads to citrullination and this gives rise to ACPA in sensitive individuals.
Q: Could you further explain more redefined treatments for these circumstances?
A: This is still in its infancy, but there are hints that patients carrying certain HLA set-up differ in their sensitivity to e.g. anti-TNF therapy and the same seem to be the case regarding ACPA status. However the major emphasis now underlines the importance of early aggressive treatment of disease activity with defined goals, this is sometimes termed “treat to target”.
Q: Was the discovery of a link between rheumatoid arthritis and the lungs surprising?
A: The link is not surprising considering the robust correlation of rheumatoid arthritis to smoking, but there may be other ways to trigger rheumatoid arthritis not involving the lung, e.g. through the gut and its microflora.
Q: How did the 2013 Crafoord Laureates come to acquire this knowledge?
A: The Klareskog group confirmed the modest overall relation of smoking to rheumatoid arthritis and using large patient materials found that the risk was augmented if the individuals were carriers of shared epitopes and were ACPA positive. It was the combinations that dramatically increase risk for rheumatoid arthritis also leading to more severe disease development.
Q: What are the two distinct forms of rheumatoid arthritis that research discriminates between?
A: ACPA positive and ACPA negative rheumatoid arthritis largely overlaps RF + (seropositive) and RF- RA but is more distinct.
Posted: October 2013