BRASS Registry Enables Clinical, Genetic Research in Rheumatoid Arthritis

Because early, aggressive treatment in rheumatoid arthritis is associated with better long-term outcomes, the identification of markers of disease course and treatment response is a primary research goal. Toward this end, investigators at Brigham and Women’s Hospital in Boston have been systematically collecting detailed clinical, serologic, environmental, and genetic information on RA patients since 2003 as part of a prospective, observational cohort called the Brigham and Women’s Hospital Rheumatoid Arthritis Sequential Study (BRASS) registry.

To date, more than 1,100 RA patients from the hospital’s arthritis center with new-onset or established disease have been recruited for participation, which includes baseline and annual clinic visits to collect information on demographics, disease activity, medication use, comorbidities, functional status, disability, quality of life, and health care resource utilization; blood samples (including serum, RNA, and DNA); and hand and wrist radiographs every 2 years. Additionally, patients are asked to complete self-administered questionnaires 6 months after their annual appointments to provide information about medication use or changes, functional status, new symptoms, and health care resource use, according to the BRASS investigators (Rheumatology 2010 Sep 16. [doi: 10.1093/rheumatology/keq263]).

The registry, funded by a grant from Millenium Pharmaceuticals, Biogen Idec, and Crescendo Bioscience, “has become an important component of local, national, and international research collaborations seeking reliable scientific evidence,” according to Dr. Nancy A. Shadick, a rheumatologist at Brigham and Women’s Hospital and BRASS principal investigator. Dr. Shadick offers insight into the BRASS registry and discusses some important research that has come out of the registry as well as the challenges of clinical and genetic research in patient registries.

Question: How is the BRASS registry unique relative to other patient registries/cohort studies that collect data on rheumatic diseases and DMARD treatment?

Dr. Shadick: National and international registries of RA patients are instrumental in the collection of data regarding treatment efficacy. There are approximately 10 patient registries/cohort studies collecting data on rheumatic diseases and DMARD therapy, but not all of them collect additional laboratory tests beyond C-reactive protein, erythrocyte sedimentation rate, or additional patient clinical measures like the 28-joint DAS-CRP3 (DAS-28-CRP3). BRASS was developed to determine markers of treatment response and drug toxicity through the assessment of clinical variables and inherited genetic variants and patterns of gene expression, therefore the registry collects over 1,200 clinical variables, including lung function, periodontal health, sleep quality, mental health measures, cost effectiveness, and other patient-reported outcomes. Additionally, it collects hand radiographic data every 2 years, and it has comprehensive and complete genetic, serologic, and RNA expression capabilities on each of the cohort members. It has excellent cohort retention (more than 80% after 5 years) and very accurate medication data. The cohort offers the ability to determine biomarker and genetic predictors of drug response and toxicity and also the ability to report on the contemporary natural history of “treated RA.”

Question: In what ways has the BRASS data been used to date to gain insight into RA patients’ treatment response to DMARDs?

Dr. Shadick: Two recent papers come to mind. The first examined the association between candidate SNPS and disease activity in RA patients on methotrexate. The investigators found that patients carrying the minor allele of an ATIC single nucleotide polymorphism (SNP) were more likely to have lower disease activity after adjustment for other confounders (Rheumatology (Oxford) 2009;48:613-7). Similarly, in a multicohort study which included BRASS samples, those individuals with the protein tyrosinde phosphatase receptor type C (also known as the CD45 gene) had a better response to anti–tumor necrosis factor therapy than did those without the CD45 gene (Mol. Med. 2009;15:136-43).

Question: How have the genetic data been used in research to date?

Dr. Shadick: Our genetic researchers have analyzed the cohort using genome-wide association studies (GWAS) analyses which allow screening of a large number of genes, or SNPs, that are potentially associated with a number of RA outcomes. Pooling the results with other cohorts as well as controls without RA, the BRASS cohort data has helped determine new susceptibility genes for RA, genes that predict disease severity, nonerosive disease in RA, and earlier onset of RA.

Question: What are some of the clinical or genetic questions that the BRASS registry might help answer down the line?

Dr. Shadick: We would like to look more closely at gene/environment interactions that result in some RA comorbidities such as infection, certain cancers, RA that never erodes bone despite disease activity, and genetic predictors for RA-induced interstitial lung disease.

Question: What have been some of the challenges in the development, maintenance, and application of BRASS registry data?

Dr. Shadick: Maintaining a large patient database takes a “village.” In this case, that means a well organized team of researchers, devoted doctors who contribute information about their patients, and devoted RA patients who tirelessly remain in the study and fill out forms. However, many of the participants and the rheumatologists find participating in the BRASS registry rewarding, particularly when new scientific discovery occurs from the data. There are a few limitations in using registry data. For example, registry data (unlike randomized controlled trials) often lack the ability to evaluate drug efficacy. On the other hand, observational registries are more representative of the real-world population, and as such we are observing instead “real world effectiveness.”

This column, “Ask the Expert,” regularly appears in Rheumatology News, an Elsevier publication. Dr. Nancy A. Shadick is a clinical researcher and rheumatologist at Brigham and Women’s Hospital and an assistant professor of medicine at Harvard Medical School in Boston. She has received research grant support from Biogen Idec, Crescendo Biosciences, and Amgen.

Because early, aggressive treatment in rheumatoid arthritis is associated with better long-term outcomes, the identification of markers of disease course and treatment response is a primary research goal. Toward this end, investigators at Brigham and Women’s Hospital in Boston have been systematically collecting detailed clinical, serologic, environmental, and genetic information on RA patients since 2003 as part of a prospective, observational cohort called the Brigham and Women’s Hospital Rheumatoid Arthritis Sequential Study (BRASS) registry.

To date, more than 1,100 RA patients from the hospital’s arthritis center with new-onset or established disease have been recruited for participation, which includes baseline and annual clinic visits to collect information on demographics, disease activity, medication use, comorbidities, functional status, disability, quality of life, and health care resource utilization; blood samples (including serum, RNA, and DNA); and hand and wrist radiographs every 2 years. Additionally, patients are asked to complete self-administered questionnaires 6 months after their annual appointments to provide information about medication use or changes, functional status, new symptoms, and health care resource use, according to the BRASS investigators (Rheumatology 2010 Sep 16. [doi: 10.1093/rheumatology/keq263]).

The registry, funded by a grant from Millenium Pharmaceuticals, Biogen Idec, and Crescendo Bioscience, “has become an important component of local, national, and international research collaborations seeking reliable scientific evidence,” according to Dr. Nancy A. Shadick, a rheumatologist at Brigham and Women’s Hospital and BRASS principal investigator. Dr. Shadick offers insight into the BRASS registry and discusses some important research that has come out of the registry as well as the challenges of clinical and genetic research in patient registries.

Question: How is the BRASS registry unique relative to other patient registries/cohort studies that collect data on rheumatic diseases and DMARD treatment?

Dr. Shadick: National and international registries of RA patients are instrumental in the collection of data regarding treatment efficacy. There are approximately 10 patient registries/cohort studies collecting data on rheumatic diseases and DMARD therapy, but not all of them collect additional laboratory tests beyond C-reactive protein, erythrocyte sedimentation rate, or additional patient clinical measures like the 28-joint DAS-CRP3 (DAS-28-CRP3). BRASS was developed to determine markers of treatment response and drug toxicity through the assessment of clinical variables and inherited genetic variants and patterns of gene expression, therefore the registry collects over 1,200 clinical variables, including lung function, periodontal health, sleep quality, mental health measures, cost effectiveness, and other patient-reported outcomes. Additionally, it collects hand radiographic data every 2 years, and it has comprehensive and complete genetic, serologic, and RNA expression capabilities on each of the cohort members. It has excellent cohort retention (more than 80% after 5 years) and very accurate medication data. The cohort offers the ability to determine biomarker and genetic predictors of drug response and toxicity and also the ability to report on the contemporary natural history of “treated RA.”

Question: In what ways has the BRASS data been used to date to gain insight into RA patients’ treatment response to DMARDs?

Dr. Shadick: Two recent papers come to mind. The first examined the association between candidate SNPS and disease activity in RA patients on methotrexate. The investigators found that patients carrying the minor allele of an ATIC single nucleotide polymorphism (SNP) were more likely to have lower disease activity after adjustment for other confounders (Rheumatology (Oxford) 2009;48:613-7). Similarly, in a multicohort study which included BRASS samples, those individuals with the protein tyrosinde phosphatase receptor type C (also known as the CD45 gene) had a better response to anti–tumor necrosis factor therapy than did those without the CD45 gene (Mol. Med. 2009;15:136-43).

Question: How have the genetic data been used in research to date?

Dr. Shadick: Our genetic researchers have analyzed the cohort using genome-wide association studies (GWAS) analyses which allow screening of a large number of genes, or SNPs, that are potentially associated with a number of RA outcomes. Pooling the results with other cohorts as well as controls without RA, the BRASS cohort data has helped determine new susceptibility genes for RA, genes that predict disease severity, nonerosive disease in RA, and earlier onset of RA.

Question: What are some of the clinical or genetic questions that the BRASS registry might help answer down the line?

Dr. Shadick: We would like to look more closely at gene/environment interactions that result in some RA comorbidities such as infection, certain cancers, RA that never erodes bone despite disease activity, and genetic predictors for RA-induced interstitial lung disease.

Question: What have been some of the challenges in the development, maintenance, and application of BRASS registry data?

Dr. Shadick: Maintaining a large patient database takes a “village.” In this case, that means a well organized team of researchers, devoted doctors who contribute information about their patients, and devoted RA patients who tirelessly remain in the study and fill out forms. However, many of the participants and the rheumatologists find participating in the BRASS registry rewarding, particularly when new scientific discovery occurs from the data. There are a few limitations in using registry data. For example, registry data (unlike randomized controlled trials) often lack the ability to evaluate drug efficacy. On the other hand, observational registries are more representative of the real-world population, and as such we are observing instead “real world effectiveness.”

This column, “Ask the Expert,” regularly appears in Rheumatology News, an Elsevier publication. Dr. Nancy A. Shadick is a clinical researcher and rheumatologist at Brigham and Women’s Hospital and an assistant professor of medicine at Harvard Medical School in Boston. She has received research grant support from Biogen Idec, Crescendo Biosciences, and Amgen.

Because early, aggressive treatment in rheumatoid arthritis is associated with better long-term outcomes, the identification of markers of disease course and treatment response is a primary research goal. Toward this end, investigators at Brigham and Women’s Hospital in Boston have been systematically collecting detailed clinical, serologic, environmental, and genetic information on RA patients since 2003 as part of a prospective, observational cohort called the Brigham and Women’s Hospital Rheumatoid Arthritis Sequential Study (BRASS) registry.

To date, more than 1,100 RA patients from the hospital’s arthritis center with new-onset or established disease have been recruited for participation, which includes baseline and annual clinic visits to collect information on demographics, disease activity, medication use, comorbidities, functional status, disability, quality of life, and health care resource utilization; blood samples (including serum, RNA, and DNA); and hand and wrist radiographs every 2 years. Additionally, patients are asked to complete self-administered questionnaires 6 months after their annual appointments to provide information about medication use or changes, functional status, new symptoms, and health care resource use, according to the BRASS investigators (Rheumatology 2010 Sep 16. [doi: 10.1093/rheumatology/keq263]).

The registry, funded by a grant from Millenium Pharmaceuticals, Biogen Idec, and Crescendo Bioscience, “has become an important component of local, national, and international research collaborations seeking reliable scientific evidence,” according to Dr. Nancy A. Shadick, a rheumatologist at Brigham and Women’s Hospital and BRASS principal investigator. Dr. Shadick offers insight into the BRASS registry and discusses some important research that has come out of the registry as well as the challenges of clinical and genetic research in patient registries.

Question: How is the BRASS registry unique relative to other patient registries/cohort studies that collect data on rheumatic diseases and DMARD treatment?

Dr. Shadick: National and international registries of RA patients are instrumental in the collection of data regarding treatment efficacy. There are approximately 10 patient registries/cohort studies collecting data on rheumatic diseases and DMARD therapy, but not all of them collect additional laboratory tests beyond C-reactive protein, erythrocyte sedimentation rate, or additional patient clinical measures like the 28-joint DAS-CRP3 (DAS-28-CRP3). BRASS was developed to determine markers of treatment response and drug toxicity through the assessment of clinical variables and inherited genetic variants and patterns of gene expression, therefore the registry collects over 1,200 clinical variables, including lung function, periodontal health, sleep quality, mental health measures, cost effectiveness, and other patient-reported outcomes. Additionally, it collects hand radiographic data every 2 years, and it has comprehensive and complete genetic, serologic, and RNA expression capabilities on each of the cohort members. It has excellent cohort retention (more than 80% after 5 years) and very accurate medication data. The cohort offers the ability to determine biomarker and genetic predictors of drug response and toxicity and also the ability to report on the contemporary natural history of “treated RA.”

Question: In what ways has the BRASS data been used to date to gain insight into RA patients’ treatment response to DMARDs?

Dr. Shadick: Two recent papers come to mind. The first examined the association between candidate SNPS and disease activity in RA patients on methotrexate. The investigators found that patients carrying the minor allele of an ATIC single nucleotide polymorphism (SNP) were more likely to have lower disease activity after adjustment for other confounders (Rheumatology (Oxford) 2009;48:613-7). Similarly, in a multicohort study which included BRASS samples, those individuals with the protein tyrosinde phosphatase receptor type C (also known as the CD45 gene) had a better response to anti–tumor necrosis factor therapy than did those without the CD45 gene (Mol. Med. 2009;15:136-43).

Question: How have the genetic data been used in research to date?

Dr. Shadick: Our genetic researchers have analyzed the cohort using genome-wide association studies (GWAS) analyses which allow screening of a large number of genes, or SNPs, that are potentially associated with a number of RA outcomes. Pooling the results with other cohorts as well as controls without RA, the BRASS cohort data has helped determine new susceptibility genes for RA, genes that predict disease severity, nonerosive disease in RA, and earlier onset of RA.

Question: What are some of the clinical or genetic questions that the BRASS registry might help answer down the line?

Dr. Shadick: We would like to look more closely at gene/environment interactions that result in some RA comorbidities such as infection, certain cancers, RA that never erodes bone despite disease activity, and genetic predictors for RA-induced interstitial lung disease.

Question: What have been some of the challenges in the development, maintenance, and application of BRASS registry data?

Dr. Shadick: Maintaining a large patient database takes a “village.” In this case, that means a well organized team of researchers, devoted doctors who contribute information about their patients, and devoted RA patients who tirelessly remain in the study and fill out forms. However, many of the participants and the rheumatologists find participating in the BRASS registry rewarding, particularly when new scientific discovery occurs from the data. There are a few limitations in using registry data. For example, registry data (unlike randomized controlled trials) often lack the ability to evaluate drug efficacy. On the other hand, observational registries are more representative of the real-world population, and as such we are observing instead “real world effectiveness.”

This column, “Ask the Expert,” regularly appears in Rheumatology News, an Elsevier publication. Dr. Nancy A. Shadick is a clinical researcher and rheumatologist at Brigham and Women’s Hospital and an assistant professor of medicine at Harvard Medical School in Boston. She has received research grant support from Biogen Idec, Crescendo Biosciences, and Amgen.