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.
In October, the Brigham and Women's Hospital Rheumatoid Arthritis Sequential Study (BRASS) enrolled patient number 1,000 in its longitudinal cohort. For four years, the data from RA patients in our hospital-based practice of 33 rheumatologists have:
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enabled scientific discovery and verification in a wide range of studies seeking to understand the natural history of the disease;
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track treatment response;
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reveal new genes important for disease etiology, optimal outcomes, and new therapies;
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and many other aspects of RA.
This program is funded by a grant from Millennium Pharmaceuticals and Biogen/Idec. "There are a number of registries around the world - we probably have the most extensive repository of genetic, laboratory, and clinical data for RA," said Michael E. Weinblatt, MD, Co-director of Clinical Rheumatology, Associate Director of the Center for Arthritis and Joint Diseases, and BRASS principal investigator. "The biggest surprise is how many patients were interested in the program and how invested the patients are in helping us learn about their disease."
"The registry has become an important component of local, national, and international research collaborations seeking reliable scientific evidence," said Nancy A. Shadick, MD, MPH, BWH rheumatologist and BRASS principal investigator.
Latest BRASS Findings
Here is a sample of the most recent findings, prepared for the Novem-ber 2007 American College of Rheumatology meeting in Boston:
Rapid clinical tool.
A quicker shorter way to assess RA disease activity may be nearly as good as the gold-standard long-form and may be easier to use in non-academic settings, reports Kerri Batra, MD, Clinical Fellow in the Division of Rheumatology, Imm-unology, and Allergy at BWH, and her colleagues. In a study of 961 BRASS patient records, two tools, the Clinical Disease Activity Index (CDAI) and the Routine Assessment of Patient Index Data (RAPID), correlated moderately well with the more complex Disease Activity Score (DAS) at baseline and the change in scores one year later. The RAPID and CDAI can be more easily used in the office setting, because they do not require a blood test to measure an inflammatory marker, the researchers said.
Disease improvement.
Analysis of data from 591 patients showed a two-year trend of reduction in rheumatoid arthritis disease by standard clinical and laboratory measures. Over the same time, use of TNF inhibitors increased, and NSAID and steroid use decreased, found Dr. Batra and her colleagues. "While it is difficult to correlate these observations in a non-trial setting," the abstract authors wrote, "the trends are compelling and consistent with findings in large clinical trials of biologic therapies."
Genetic markers for disease severity.
Researchers have begun to tease out the genome region associated with anti-cyclic citrullinated peptide (anti-CCP) antibodies. The anti-CCP titer is more specific than rheumatoid factor and just as sensitive in RA. More importantly, it correlates better with disease progression as tracked by X-rays. Jing Cui, MD, PhD, statistical geneticist in the Division of Rheumatology, Immunology, and Allergy, and her colleagues analyzed 116,204 single-nucleotide polymorphisms (SNPs) in a sample of 561 BRASS patients. The researchers found several genetic variations within the major histocompatibility complex region, as well as several outside the MHC region which may influence the anti-CCP titer.
Exploring genes for RA pain.
A study to confirm potential pain perception genetic markers identified by others last year in a healthy population failed to find an association in RA patients. Roberta Glass, Senior Program-mer/Analyst in the Division's Section of Clinical Sciences, and her colleagues sought to replicate a report of several genetic variations that seem to influence pain perception. They tested samples of 420 patients on an Affymetrix gene chip with three of the 15 reported variations associated with pain. "Further research is needed to see whether the other SNPs can be replicated in RA patients," the team concluded.
Found: new gene for RA.
A new gene associated with RA susceptibility is likely in the TNF pathway and may contribute to the disease etiology, according to a study led by Robert M. Plenge, MD, PhD, rheumatologist and leader of the genome-wide association component of BRASS. He and his colleagues first discovered the gene in a study of 397 BRASS patients and then confirmed it in two other major international patient databases (see pp. 10-11).
To learn more about BRASS, visit www.brassstudy.org
Case Study
Patients Advise Doctors on Living with RA and Better Communication Ideas Include "Health Passport," Buddy System
The emphasis on the patient perspective is a paradigm shift among rheumatologists and is part of a bigger trend in medicine to integrate patient priorities into the clinical encounter and into research outcomes assessment, Nancy A. Shadick, MD, MPH, BWH, a Director of BRASS, and principal investigator of Patient-centered Outcomes initiative (PACO), and senior research assistant Jenny Heller, wrote in an article in the March 2007 Current Opinion in Rheumatology.
Like many other people with RA, Patricia has felt all alone with her disease at times. First, a painfully swollen right foot mystified numerous doctors for eight months until a friend referred her to the Brigham and Women's Orthopedic and Arthritis Center. She was diagnosed and treated, ultimately participating in a clinical trial of a new TNF-alpha inhibitor that has greatly slowed progression and relieved pain.
Then Patricia had to work out for herself how to adapt her life to her weakening joints over the last 12 years. She knew no one else with RA, either to commiserate or share helpful tips - until BWH researchers invited her to a focus group designed to tap the first-hand expertise of people living with the disease.
The focus group kicked off the opening phase of a new PACO project for RA. The four-year patient project began in 2006 and includes some of the 1,000 participants in BRASS. The project, funded by a grant by the Bristol-Myers Squibb Foundation, aims to identify patients' concerns about living with RA, improve patient-doctor communication, and ease patient self-management, said Dr. Shadick.
"We're trying to incorporate the patient perspective into the treatment of RA," Dr. Shadick said. "Doctors and patients are interested in a patient's overall improvement, but doctors tend to evaluate improvement that incorporates objective findings such as swollen joints and improved blood tests, while patients will mark their improvement in terms of day-to-day impact, including how they can care for their children and if they feel a sense of normalcy and can maintain their job and social independence."
The research team will publish a more formal assessment of the focus group findings.
"Patients and physicians often have different assessments of the patient's health state," Heller and Dr. Shadick wrote. "Fatigue, pain, and return to normalcy are, for patients, the highest priorities in achieving wellness, but patients often fail to discuss these issues with their rheumatologists or feel their rheumatologists do not accord them adequate importance when they are discussed."
A patient advisory committee of 18, including Patricia, now meets several times a year to discuss ways to improve the dialogue between doctors and patients in the Orthopedic and Arthritis Center. They provide insights and ideas for new tools, educational materials, and services. The new approaches will be piloted in the BWH Orthopedic and Arthritis Center within the next few months as part of a model for patient-centered care that can be expanded to other hospitals.
New Tools for Patients
The first new tool, now in the prototype stage, is a "Health Passport" to help patients manage health information and support communication with their doctors. The carry-along log offers space to record health concerns, keep a list of nurses and other contacts, jot down questions to ask the rheumatologist, and track medications and surgeries.
The project team is developing an educational packet for newly diagnosed RA patients. The brochure will summarize basic information, list additional resources, and include success stories to help new patients learn how others manage their disease. PACO is developing a "buddy system" to match newly diagnosed patients with those with more disease experience to answer questions and share tips on continuing with accustomed activities, which can relieve some of a new patient's apprehension.
In June, Dr. Shadick and Dr. Weinblatt held a mini-workshop on RA medications to educate patients and provide a forum for interaction with other people with RA. Video segments of the presentation are available online at the project website at www.pacostudy.org
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