Research Overview in RA
Current developments and trends in RA research
Basic research in immunology and biology conducted over the past several decades has greatly expanded our understanding of how the immune system functions and has given us insights into the many pathologic mechanisms involved in RA.
This research has led to the development of exciting new treatments for RA. We are now able, more than ever before, to control disease activity and inflammation and prevent or reduce the damage that can occur to joints and other structures.
Additionally, research in genetics is providing clues about why some individuals may be susceptible to development of RA and others are not. These clues may eventually lead to a better understanding of the cause or causes of RA.
Where is research in RA being conducted?
RA research is going on throughout the world at major universities and medical centers. Much of the basic research being conducted in RA is being funded by government agencies. For instance, in the US the National Institutes of Health (NIH) funds a range of medical research programs throughout the US. The National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), a part of the NIH, is a major supporter of research in RA.1
Research in developing treatments for RA is being conducted by pharmaceutical and biotechnology companies. Even as new treatments for RA are entering the marketplace, many other experimental approaches to RA are in earlier stages of development and will be the next generation of treatments in the decades to come.
Key areas of research in RA
Ongoing research in RA is focused in several areas, including:
- Immunology and biology
- Drug treatments
- Complementary and alternative therapies, and other treatments
- Impact of RA on patients and society
Researchers are examining a range of genetic factors that may play a role in increasing risk for developing RA and increasing the severity of the disease in certain groups of patients. Since research has shown that there are distinct types of RA, RA in which auto-antibodies are present in plasma and other bodily fluids (such as anti-citrullinated protein antibodies [ACPA]) and RA in which these antibodies are not found, genetics research has tried to clarify the genetic basis for these distinct types of disease.2
One ongoing area of genetics research is focused on identifying variations in key immune system genes that may increase risk for developing RA. To date some 30 gene variants have been linked to increased risk for RA. More gene variants have been linked to ACPA-positive RA than to ACPA-negative disease. The most important genetic contributor to RA risk seems to be a group of genes located on chromosome 6p called the human leukocyte antigen (HLA) genes.2
Recent research has also identified non-HLA genes that are linked to increased RA risk. These include a variation in the gene that encodes for (“encodes” is the technical term for a gene that carries instructions used to create something) an enzyme called PTPN22 involved in the control of T-cell activation (T-cells are white blood cells that play an important role in the immune response). People who have a particular variation in this gene (called single nucleotide polymorphism [SNP]) are twice as likely to develop RA as those who do not have the variation. The same variation in the PTPN22 gene has been linked to other autoimmune diseases and explains why such diseases appear to run in families.2
Other immune system gene variants that appear to be linked to RA (as well as other autoimmune disorders) include the STAT4 gene which encodes a protein that regulates and activates immune system cells, the TNFAIP3 gene which encodes the protein tumor necrosis factor (TNF), and the PTPRC gene which encodes the protein tyrosine phosphatase, receptor type C, a signaling molecule involved in a variety of basic cell functions.2
Twin studies using microarray technology are able to examine large numbers of genes in discordant twin pairs (where one twin has RA and one does not) to detect genetic differences that might explain the presence of RA in only one twin. This research has led to the identification of hundreds of genetic variants that may possibly be linked to increased RA risk.1
Recent epidemiologic research has examined trends in the prevalence of RA, showing a possible decline of rates of RA in the US, from 2.1 million cases in 1995 to 1.29 million in 2005. Studies have also shown differences in prevalence by region in the US, with the highest rates among certain Native American populations and the lowest rates among people of Asian descent (Chinese and Japanese). These differences in prevalence suggest the importance of genetic factors in increasing risk for RA. However, since studies estimate that genetic factors account for about 50% to 60% of the risk for developing RA, ongoing research projects are examining the causal role of a number of environmental factors, including viruses, bacteria, stress, and exposures to chemicals and pollutants.3
A disability and societal impacts
Another area of ongoing research in RA is disability and the social impacts related to the disease. Dramatic advances in the treatment of RA over the past 20 years have significantly changed long-term outcomes for patients, reducing disability and allowing many patients to lead full and productive lives. Using data from large RA patient registries and databases designed to capture information about treatment and disability, researchers have been able to document steady declines in disability of about 2% per year since the late 1970s. Despite this trend, researchers have found that disability associated with RA still results in many individuals eventually leaving the workforce. This is especially true among women. One study compared rates at which women left the workforce in the late 1980s and the late 1990s. The study found no significant differences between these two periods, with over a quarter of women from both periods leaving the workforce within four years of being diagnosed with RA.1
Immunology and biology
Research in immunology and biology conducted over recent decades has advanced our understanding of the factors involved in activation of the immune system and progression of damage to joints and other structures in RA. This research continues to provide new insights into the complex interactions between immune system cells and the chemicals and antigens that trigger the immune response and a deeper understanding of the interactions between genes and the environment that alter the immune response and result in the RA disease process. Recent research in selected intracellular signaling pathways involved in immune system function, including the Janus kinase (JAK) and mitogen-activated protein kinase (MAPK) pathways, have led to the development of molecularly targeted treatments for RA. Ongoing basic research in immunology holds the promise of further breakthroughs in the identification of molecular targets for future generations of RA treatments.3
Other research is advancing our understanding of the processes involved in RA-related joint destruction. For example, one NIAMS-sponsored study is examining the role that the adhesion molecule cadherin-11 plays in destruction of cells in the synovium. Normally, cadherin-11 allows cells to adhere or stick together to form the layer lining the synovium. However, when this lining becomes overgrown and thickened during inflammation (synovitis), cadherin-11 can promote the destruction of the synovium. In animal studies, researchers are testing whether blocking the effects of cadherin-11 can prevent RA-related joint destruction. Other studies have found abnormalities or variations in genes associated with RA that encode certain immune system proteins. These abnormal proteins make immune system cells resistant to the normal process of cell death, called apoptosis, allowing them to build up in the joint lining where they promote the autoimmune response characteristic of RA. Scientists hope that blocking the action of these proteins can help control the disease process in RA.1
Ongoing research, some of it at a very basic level and some of it in advanced clinical stages, is evaluating the potential of emerging disease-modifying anti-rheumatic drug (DMARD) treatments for RA. Pharmaceutical and biotechnology companies are spear-heading efforts to discover and test the newest generations of these treatments for RA and the pipeline of products in advanced stages of research is rich.
Other research efforts are examining the role of complementary and alternative medicine (CAM) treatments in the management of RA. These therapies include a broad range of interventions, including vitamins, minerals, herbal and other supplements, exercise, alternative systems of medicine (e.g. acupuncture, Traditional Chinese Medicine [TCM]), and mind-body interventions (e.g. meditation, yoga, Tai Chi).