In addition to supporting cutting-edge basic research, the NIAMS IRP is intent on facilitating the development of new therapeutic targets through translational and clinical research. The NIAMS clinical research programs led by Daniel L. Kastner, MD, PhD, encompass a broad field of research in rheumatology, including studies in systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), periodic fever syndromes, neonatal onset multisystem inflammatory disease (NOMID), myositis, ankylosing spondylitis, and immunodeficiency. In addition, NIAMS is fortunate to have recently recruited pediatric rheumatologist Robert Colbert, MD, PhD, to lead the NIAMS’ new Pediatric Translational Research Branch.
Clinical investigators in the NIAMS IRP are studying the genetic underpinnings of several rare disorders, including Mendelian autoinflammatory diseases such as NOMID, Familial Mediterranean Fever, tumor necrosis factor (TNF)–associated periodic syndrome, and a newly identified deficiency of the interleukin-1 (IL-1) receptor antagonist (DIRA). Patients with DIRA have a genetic deficiency of the IL-1 receptor antagonist, a protein that normally regulates the actions of the inflammatory cytokine, IL-1. Children with this rare genetic disorder display a constellation of serious and potentially fatal symptoms that include swelling of bone tissue; bone pain and deformity; inflammation of the periosteum, a layer of connective tissue around the bone; and a rash that can span from small individual pustules to extensive pustulosis that covers most of the patient’s body. For most affected children, symptoms appear from birth to two weeks of age.
NIAMS IRP investigators Raphaela Goldbach-Mansky, MD, MHS, and Ivona Aksentijevich, MD, and colleagues discovered this new autoinflammatory syndrome through collaboration with clinicians with patients in Newfoundland, the United States, Puerto Rico, the Netherlands, and Sweden. Drs. Goldbach-Mansky, Aksentijevich, and colleagues discovered that DIRA was due to founder mutations in these populations.4
In the past 15 years, researchers in the NIAMS IRP have also made significant contributions to understanding the key inflammatory pathways involved in these autoinflammatory diseases, resulting in the use of medications that specifically target the IL-1 and TNF inflammatory pathways.
Genetics and Genomics Bridge the Distance Between Basic and Clinical Research
Through our extramural programs, NIAMS invests heavily in the study of the genetics and genomics of rheumatic diseases. One current focus of this investment is the support of genome-wide association studies (GWAS). These studies make use of high-throughput genotyping and large-scale genetic analyses to identify common genetic factors that influence health and disease. The full value of GWAS to the public can be realized only if the genotype and phenotype datasets are made available as rapidly as possible to a wide range of scientific investigators. In order to fulfill this promise, the NIH established the NIH Database of Genotype and Phenotype to maintain and manage the enormous amounts of data gathered through these studies. NIAMS participates in several GWAS consortia that have already contributed extensively to the body of knowledge of diseases within the NIAMS portfolio.
