The steady advances in the diagnosis and treatment of rheumatic diseases and the impact on clinical practice originate in part from the research enterprise supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) and other components of the National Institutes of Health (NIH). NIAMS’ programs in arthritis and rheumatic diseases cover the spectrum of basic, translational, and clinical research in a number of autoimmune and arthritis-related chronic diseases.
NIAMS and the other NIH institutes and centers are very fortunate to have the continued support of the Congress and the trust of the American public. To honor that trust, we are dedicated to conducting and supporting the best research in the most promising areas of science.
Intramural Research Program Explores the Boundaries of Rheumatic Diseases
The majority of NIAMS’ funding goes to support grants for investigators around the country and throughout the world. NIAMS also conducts research through its Intramural Research Program (IRP) on the NIH campus in Bethesda, Md.
Basic research is the backbone of NIH’s mission to acquire new knowledge to help prevent, detect, diagnose, and treat disease and disability. The IRP portfolio of basic and clinical research in rheumatology includes the study of immunity, autoimmunity, immune cell biology, and molecular immunology and inflammation. In the past few years, NIAMS investigators have made significant discoveries in the fields of autoimmunity and autoinflammatory diseases and immunodeficiency disorders.
NIAMS investigator Richard Siegel, MD, PhD, and colleagues found a potential new way to block inflammation in autoimmune diseases using a new target—a cell-surface receptor called DR3.1 Their research in mice suggests that blocking this receptor could slow or stop the damaging inflammation characteristic of autoimmune diseases, potentially without leaving the body vulnerable to serious infections, as many current therapies do.
In a study published in Nature, NIAMS Scientific Director John O’Shea, MD, and colleagues from the National Institute of Allergy and Infectious Diseases (NIAID) identified missing components in immune regulation in Job’s syndrome, a rare immunodeficiency disorder characterized by recurrent bacterial and fungal infections and bone and connective tissue abnormalities.2 They showed that Job’s sufferers lack a specific type of infection-fighting white blood cell called Th17, making them vulnerable to attacks by bacteria and fungi.
NIAMS senior investigator Juan Rivera, PhD, O’Shea, and colleagues recently showed that the protein Lyn kinase, expressed in basophils, helps control the way T helper cells differentiate in mice.3 This ability to govern cell differentiation makes basophils and their cell-signaling pathways possible targets for future therapeutic strategies in immune-mediated diseases.
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.
NIAMS has supported several significant advances in rheumatic diseases through GWAS of simple case-control design. A recent study published in Nature Genetics by the International Consortium for Systemic Lupus Erythematosus Genetics (SLEGEN) identified several susceptibility variants in women with systemic lupus erythematosus (SLE), including ITGAM, PXK, and KIAA1542.5
Other studies in SLE found an association with two novel alleles, C8orf13-BLK and ITGAM-ITGAX.6 Genetic studies of the src family tyrosine kinase BLK gene suggest that BLK tyrosine kinase contributes to B-cell tolerance mechanisms. ITGAM is a protein in the integrin alpha chain family, is expressed by several myeloid cells, and mediates interactions between immune cells.
Studies in RA through the North American Rheumatoid Arthritis Consortium continue to identify risk loci in RA.7 NIAMS-supported investigators genotyped more than 300,000 single nucleotide polymorphisms (SNPs) from 1,522 patients with RA and 1,850 matched controls and found that a common genetic variant at the TRAF-1C5 locus on chromosome 9 is associated with an increased risk of anticyclic citrullinated peptide-positive RA.
NIAMS investigators Kastner and Elaine Remmers, PhD, collaborated with NIAMS-supported investigators to explore the role of STAT4 and the risk of RA and SLE. They found a SNP haplotype in STAT4 associated with increased susceptibility to both RA and SLE. The fact that both RA and SLE share a common risk allele hints at the possibility that the two diseases share similar pathways.8
Childhood Arthritis and Rheumatology Research Alliance
These days, clinical research is predominantly a multidisciplinary, multisite endeavor. NIAMS supports several studies that utilize national networks and provide the infrastructure for pursuing large, multicenter studies—or, in the case of rarer diseases, smaller, multicenter studies.
One of these networks is the Childhood Arthritis and Rheumatology Research Alliance (CARRA), which has a mission to improve the care of children with rheumatic disease with high-quality clinical research. Through CARRA, NIAMS is supporting several large-scale clinical trials, including the Atherosclerosis Prevention in Pediatric Lupus Erythematosus (APPLE) trial, the Early Aggressive Therapy in Juvenile Idiopathic Arthritis (JIA) trial, the Safety and Effectiveness of Rilonacept for Treating Systemic Idiopathic Arthritis (RAPPORT) trial, and the Rituximab in Myositis (RIM) trial.
APPLE is studying the effects of atorvastatin (Lipitor) on lipid levels, inflammation, and the development of atherosclerosis in pediatric lupus patients. The Early Aggressive Therapy in JIA trial is comparing the effectiveness of aggressive drug regimens in treating children with poly-JIA, one of the more severe types of JIA. Specifically, the study will determine whether aggressive therapy started in the first six months of disease onset can result in inactive disease and clinical remission while patients are taking these medications.
NIAMS is also sponsoring two placebo-phased studies to address unmet needs in patients with rare diseases. The unique designs used seek to minimize patient exposure to placebo because all patients receive the intervention while maintaining the statistical rigor of a well-controlled, randomized clinical trial. RIM is an international, multicenter clinical trial examining the effectiveness of rituximab for treating myositis in adults and children. The RAPPORT trial is evaluating Rilonacept, an IL-1 blocker/trap, in the systemic form of JIA. More information about these trials and other NIAMS-supported efforts is available through the NIH’s ClinicalTrials.gov Web site (www.clinicaltrials.gov).
Basic research is the backbone of NIH’s mission to acquire new knowledge to help prevent, detect, diagnose, and treat disease and disability.
The Osteoarthritis Initiative
Osteoarthritis (OA) is the most common form of arthritis, affecting an estimated 27 million adults in the United States. Today, 35 million people—13% of the U.S. population—are 65 or older. By 2030, 20% of Americans (approximately 70 million people) will have passed their 65th birthday and will be at risk for OA. One of the barriers to the development of drugs that block joint degradation, the underlying cause of painful and disabling OA symptoms, is the lack of objective and measurable standards for disease progression by which new drugs can be evaluated. To overcome this problem, the NIH—with input from the U.S. Food and Drug Administration—has partnered with private sponsors to create the Osteoarthritis Initiative (OAI) that is delivering a publicly available research resource that investigators can use to identify and evaluate OA biomarkers. In this case, the biomarker would be a physical sign, biological substance, or imaging finding that could be used in clinical studies to monitor changes in joint health.
The OAI is currently collecting OA patient data, radiological information, and biospecimens and will make these data widely available so that investigators around the world can utilize the information. The study, which uses a prospective, natural history cohort, tracks nearly 5,000 subjects over time. It aims to increase understanding and ultimately improve treatment of a major cause of disability among Americans. So far, the initiative has released baseline clinical data on all participants, as well as 12- and 18-month follow-up data and images on many. When the study is complete, the information will document the natural progression of the disease and help identify biomarkers associated with it, ideally hastening research and therapies. All OAI data and images are available to researchers worldwide through the initiative’s Web site (www.oai.ucsf.edu/datarelease), along with tools to interpret them.
New Standards for Patient-Reported Outcomes
The NIAMS continues to help lead the paradigm-shifting NIH Roadmap initiative. The Patient-Reported Outcomes Measurement Information System (PROMIS) seeks to advance the science of patient-reported outcomes in clinical research and care by applying state-of-the-art item response theory (IRT) approaches. Calibration of items and questions by IRT methods improves the precision, lessens the patient burden to gather this information, and allows comparisons of these clinically important outcomes not possible to date. Long term, PROMIS offers unique opportunities to learn more about how interventions, biologic or behavioral, affect individual patients either from an efficacy or adverse event perspective. Much more is available about PROMIS, including a demonstration of computerized-adaptive testing, through its Web site (www.nihpromis.org).
I have provided just a few examples of the NIAMS support of outstanding research in rheumatic diseases. These investments will help alleviate the suffering that these patients currently endure. At NIAMS, we are dedicated to the continued support of this basic and clinical research.
Dr. Katz is director of NIAMS at the NIH.
References
- Meylan F, Davidson TS, Kahle E, et al. The TNF-family receptor DR3 is essential for diverse T cell-mediated inflammatory diseases. Immunity. 2008;29:79-89.
- Milner JD, Brenchley JM, Laurence A, et al. Impaired TH17 cell differentiation in subjects with autosomal dominant hyper-IgE syndrome. Nature. 2008;452:773-776.
- Charles N, Watford WT, Ramos HL, et al. Lyn kinase controls basophil GATA-3 transcription factor expression and induction of Th2 cell differentiation. Immunity. 2009;30:533-543.
- Aksentijevich I, Masters SL, Ferguson PJ, et al. An autoinflammatory disease with deficiency of the interleukin-1 receptor antagonist. N Engl J Med. 2009;360:2416-2427.
- The International Consortium for Systemic Lupus Erythematosus Genetics (SLEGEN), Harley JB, Alarcón-Riquelme ME, et al. Genome-wide association scan in women with systemic lupus erythematosus identifies susceptibility variants in ITGAM, PXK, KIAA1542 and other loci. Nat Genet. 2008;40:204-210.
- Hom G, Graham RR, Modrek B, et al. Association of systemic lupus erythematosus with C8orf13-BLK and ITGAM-ITGAX. N Engl J Med. 2008;358:900-909.
- Plenge RM, Seielstad M, Padyukov L, et al. TRAF-C5 as a risk locus for rheumatoid arthritis—a genomewide study. N Engl J Med. 2007; 357:1199-1209.
- Remmers EF, Plenge RM, Lee AT, et al. STAT4 and the risk of rheumatoid arthritis and systemic lupus erythematosus. N Engl J Med. 2007;357:977-986.
