The Brigham and Women’s Hospital Rheumatoid Arthritis Sequential Study (BRASS) is a landmark study making significant contributions to understanding the genetic basis of rheumatoid arthritis, to identifying potential targets for new drug development, and to defining the most effective clinical management strategies for each patient.
The Brigham and Women’s Hospital Rheumatoid Arthritis Sequential Study (BRASS), under the direction of Michael E. Weinblatt, MD, and Nancy A. Shadick, MD, will provide a large-scale observation of the natural history of rheumatoid arthritis (RA). Since March 2003, investigators have enrolled almost 1,000 patients and are collecting a wealth of demographic, clinical, and genetic data to create a panoramic view of how rheumatoid arthritis affects patients’ lives. Researchers are collecting information on more than 1,000 variables including X-rays, blood samples for immunophenotyping and DNA/RNA testing, environmental risk factors, and disease activity scoring. At six-month intervals patients are administered a questionnaire to collect information on disease severity, emotional status, functional status, employment status, medications, side effects, and intercurrent health events.
Genome-wide genetic association study
In addition, researchers are conducting a genome-wide analysis that could reveal genes not previously understood to be involved in RA. BWH researchers, in collaboration with the Broad Institute of Massachusetts Institute of Technology and Harvard University, use high-throughput genomic technology to create a “genetic fingerprint” of each patient. This technology has only recently become available, and has been applied to very few common human diseases.
Robert M. Plenge, MD, PhD, a BWH rheumatologist leading the genome-wide association component of BRASS, says, “Genomic medicine – translating genetic information into prediction of disease susceptibility, characterization of gene-environment interactions, identification of new therapeutic targets, and development of novel gene-based diagnostics – has, to date, had very little impact on the clinical management of patients with RA. Through the BRASS Registry, we hope to change that.”
Inherited genetic variation within two genes has been unequivocally associated with risk of developing RA. One gene, HLA-DRB1, has been known for nearly 30 years; the other, PTPN22, has only recently been identified. Together, they explain only a fraction of the genetic risk of RA, suggesting that variation within other genes is likely important. To identify additional risk genes, the BRASS Registry is conducting a genome-wide genetic association study with approximately 100,000 single nucleotide polymorphism (SNP) markers in over 500 RA patients.
As part of this ongoing effort, BRASS researchers including Drs. Plenge, Shadick, and Weinblatt recently contributed to an article published in Nature Genetics describing how geographic ancestry affects the identification of genes that influence common diseases such as RA. The article describes a novel methodology to evaluate population stratification that helps exclude biologically irrelevant geography-based genetic differences from consideration as susceptibility genes for specific diseases. This method appears to be more effective than previous corrective measures in a genome-wide context.
Dr. Plenge says, “We hope this methodology will help in our quest to identify new genes that shed light on disease pathogenesis – and ultimately lead to improved patient care.”
Tailoring clinical care
In anticipation of identifying such genes, the BRASS researchers have established an infrastructure to test how these genetic variants, or alleles, may affect the course and clinical management of disease. As an example, the BRASS research group has tested whether the HLA-DRB1 or PTPN22 variants are relevant predictors of response to TNF-alpha inhibitors or methotrexate.
Inherited variation is just one way to classify risk of disease. Another powerful genomic approach is to study how genes are turned on and off during the course of disease, and whether these gene expression patterns predict disease outcome or response to therapy. BRASS researchers including
Drs. Shadick and Weinblatt, along with Jonathan S. Coblyn, MD, Director of Clinical Rheumatology at BWH, have examined gene expression patterns in over 50 patients before and after treatment with TNF-alpha inhibitors and methotrexate. Preliminary results suggest the possibility that an NFkB gene expression pathway “signature” at two weeks post therapy may predict treatment response at three months.
Dr. Shadick says, “Identifying markers that will better predict each patient’s likely prognosis and response to specific therapeutic agents will be critical to improving clinical care for RA patients. Currently, treatment choices are empirically based. It can take several months of trial and error to identify the best drug or combination of drugs for an individual patient, and in the meantime, irreversible joint damage is occurring. Our goal is to tailor treatment to individual patients’ genetic profiles.”
A resource for research to shape clinical care
Michael B. Brenner, MD, Chief of BWH’s Division of Rheumatology, Immunology, and Allergy, says, “The BRASS registry, by far the most detailed of the existing handful of rheumatoid arthritis patient registries throughout the country, represents an important resource for our own researchers as well as other experts studying autoimmune diseases and inflammation.”
BWH researchers have collaborated with Millennium Pharmaceuticals, which supports BRASS, in the following studies that will be presented this month at the American College of Rheumatology meetings.
- Expression of NFkB-regulated Genes Associated With RA Disease Activity and is Altered by Anti-TNFa Treatment – But Not by Methotrexate
- Biomarkers of Rheumatoid Arthritis Disease Activity in Mouse and Man: A Translational Approach
- Protein Biomarkers that Predict Changes in Rheumatoid Arthritis (RA) Disease Activity
- The Anti-cyclic Citrullinated Antibody Titer Does Not Predict Disease Activity in Rheumatoid Arthritis
- Whole Genome Association Study Using 116,204 SNPs in Rheumatoid Arthritis
- Association Between Disease Activity, Attitudes Toward Exercise and Exercise in Patients With Rheumatoid Arthritis
- PTPN22 and HLA SE Are Not Associated With Discontinuation of TNF – Inhibitors or Methotrexate in a Large RA Cohort
For more information on the BRASS Registry and current research, call 1-800-638-6294 or e-mail bwhrheumatology@partners.org.
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