Editor’s note: Frederick Wolfe, MD, who established the National Data Bank for Rheumatic Disease, passed away Sept. 5, 2023, in Wichita, Kans. The rheumatology community mourns his loss. Watch this site for additional information, but for now, here’s a link to his obituary in The Witchita Eagle, and we repost this story about the founding of the NDB.
Because of their focus on patient quality of life, rheumatologists have been at the forefront of research on chronic and disabling disease. With few exceptions, rheumatologic diseases are life-long, with outcomes reflecting the disease itself, the side effects of therapy, and the interplay with other comorbidities as patients age.
Not surprisingly, the study of such diseases as RA and osteoarthritis is enormously complex, expensive, and time consuming. Governmental agencies have been reluctant to sponsor studies on long-term outcomes because they prefer shorter, more focused, hypothesis-driven inquiries. Similarly, industry-sponsored studies tend to target the effects of a specific treatment in a narrow window of time rather than the whole life of a patient.
Enter Frederick Wolfe, MD, a rheumatologist in Wichita, Kan. Dr. Wolfe has maintained a patient database since the early days of desktop computers back in 1974. In 1998, he established the National Data Bank for Rheumatic Diseases (NDB). Today, this database holds information on more than 14,000 U.S. patients who have various forms of rheumatic disease. NDB is arguably the largest, most comprehensive, and most up-to-date database of its kind in the United States. “I wanted to develop something that would be an epidemiologically valid and useful resource for patients and their rheumatologists,” says Dr. Wolfe.
The NDB and other databases like it have afforded rheumatologists an in-depth view of treatment outcomes, side effects, and the overall burden that arthritis imposes on patients’ lives. They also demonstrate the invaluable contribution that large, long-term databases in general can make to knowledge of chronic illness, its natural history, and its toll on everyday life.
Birth of a Data Bank
The history of rheumatology databases began in the 1960s, when the late Donald Mitchell, MD, professor of medicine at the University of Saskatchewan, and Joseph Levinson, MD, professor emeritus of medicine and pediatrics at the University of Cincinnati, began collecting and storing patient data. Dr. Wolfe, however, was one of the first rheumatologists to computerize his records.
Shortly after he began his private database in 1974, Dr. Wolfe met James F. Fries, MD, who had started developing a large national database of patients with the rheumatic diseases. Drs. Fries, Wolfe, Mitchell, Levinson, and Thomas A. Medsger, MD, professor of medicine at the University of Pittsburgh, who was assembling a database on patients with scleroderma, combined their data to create a fledgling system that evolved into the Arthritis, Rheumatism, and Aging Medical Information System (ARAMIS).
ARAMIS was the first large-scale database system for chronic diseases. In subsequent years, other physicians contributed their data to the project. Dr. Fries and his colleagues at Stanford University administered the database and turned it into a resource available to clinicians and researchers nationwide.
Dr. Wolfe continued to amass data from his private practice and share it with ARAMIS, but this was a money-losing proposition for him, despite funding from ARAMIS and income generated from his practice. Dr. Wolfe also received funding from special research projects that he oversaw for pharmaceutical companies interested in gathering safety information and other data about their products.
Over time, Dr. Wolfe grew dissatisfied with certain aspects of ARAMIS. He believed that too few centers were involved, and that some of the data were out of date or incomplete. He also questioned the relevance in the practice setting of some of the information being collected and stored. “I wanted to collect more quality-of-life and economic measures than ARAMIS had,” he recalls. Finally, in 1998, aided by funds from one of his private research projects, he ended his official association with ARAMIS and started the NDB.
The NDB has several goals: to measure the effectiveness and adverse effects of current and future therapies; to identify factors that influence and predict outcomes—including clinical, genetic, demographic, and psychosocial predictors—and to develop new assessment tools and statistical and epidemiological methods.
Topics of Research Generated by NDB
Data Collection and Analysis
- Disease activity assessment
- Questionnaire development
- Clinically important differences
- Direct medical costs
- Indirect medical costs
- Cost effectiveness
- Income and wage losses
- Work disability
- Access to care and adequacy of care
- Quality of life
Efficacy and Effectiveness
- Effectiveness of DMARD and biologic therapy in the clinic
Complications and Drug Toxicity
- Lymphoma and other malignancies
- Joint infection
- Cardiovascular disease
- Liver disease and drug toxicity
- GI ulceration, bleeding, and perforation
- Sinus disease
Interstitial lung disease
Source: Wolfe F, Michaud K. A Brief Introduction to the National Data Bank for Rheumatic Diseases. Clin Exp Rheumato. 2005;23(Suppl 39):S168-S171).
The NDB Today
To obtain information for the NDB, Dr. Wolfe wrote to 900 rheumatologists, asking them to invite their patients to participate. Patients who agreed filled out detailed questionnaires. With updates every six months, people who have been enrolled since the beginning of the project have gone through 18 questionnaires. To date, more than 30,000 patients have completed more than 156,000 semi-annual questionnaires and Dr. Wolfe estimates that the NDB has more than 14,000 patients whose accounts are still active.
To enroll in the NDB, a patient first fills out a preliminary, two-page questionnaire with items on basic functional status. Once enrolled in the database, the patient completes the NDB Comprehensive Survey Questionnaire (CSQ) every six months. The CSQ is a large 28-page form with questions ranging from marital status to recent infectious diseases to any diagnostic tests the patient may have undergone over the previous half-year. It includes detailed questions about medications, including brand names, costs, and side effects, as well as employment questions (including income).
The key questions, which cover several pages, concern functional status. Questions ask about symptoms, joint pain, and the ability to perform basic tasks such as performing household chores, bathing, and opening car doors. “Functional status is the best predictor of a patient’s prognosis,” explains Dr. Wolfe.
The result of this mass of data is a comprehensive picture of the patient’s health and function at any given moment. Viewed over time, the questionnaires also show how patients improve or deteriorate and confirm the waxing and waning nature of many rheumatic diseases.
Should the full CSQ prove too onerous for patients, a six-page version, or Brief Survey Questionnaire is also available. Patients can mail or fax in their completed questionnaires, or they can answer them in a secure area on the Internet. The NDB makes all of its standard questionnaires available on its Web site at www.arthritis-research.org. About a third of patients complete their questionnaires on the Internet.
It takes a staff of 27 people to enter, analyze, coordinate, validate, and follow up on all of these data, often using one of the more than 1,000 software programs the NDB has developed specifically to analyze its information. The forms are scanned into the computer and verified. Whenever they detect a discrepancy or missing data, staff members must contact the patient for clarification. Patient reports of major medical events like a myocardial infarction or a bout with pneumonia are verified independently by contacting the hospital, clinic, or nursing home where the patient was treated. “Verifying patient information is responsible for our major operating cost,” says Dr. Wolfe.
Funding the Data Bank
The NDB is a nonprofit organization, and its questionnaires and findings are available to any physician or investigator who wishes to use the information in his or her research, as long as the findings are published in a peer-reviewed journal. The NDB does not sell mailing lists, and Dr. Wolfe maintains strict prohibitions against using any of the data for advertising or marketing.
The funds to support all of this work come mostly from independent research projects for private clients, including pharmaceutical company safety registries. In addition, NDB’s state-of-the-art data collection and analysis capabilities are used by its parent organization, The Arthritis Research Center Foundation, Inc. (ARCF), to perform other non–NDB-related activities.
For example, in 2004, Abbott Laboratories used ARCF-NDB technology to conduct the Humira Efficacy Response Optimization (HERO) trial. This trial evaluated the efficacy of adalimumab using patient-reported outcomes. Regardless of funding source, however, all NDB research must be published in peer-reviewed journals.
Today, the National Data Bank for Rheumatic Diseases holds information on more than 14,000 U.S. patients who have various forms of rheumatic disease.
Importance of Databases
Since its inception, the NDB has generated dozens of abstracts and publications on topics ranging from NSAID gastropathy to patients’ income and wage losses. (See “Topics of Research Generated by NDB,” above).
Some of the findings have been unexpected. “I was surprised to learn that some of the newer drugs are safer than I thought they would be, but are less effective than shown in clinical trials,” says Dr. Wolfe.
Other data have reinforced what many rheumatologists already feared regarding the risks of prednisone and other corticosteroids. “Their side effects are real and measurable—things like shingles, infection, and fractures that may develop up to 10 years after the patient stops taking the drug.”
More subtle findings have also become evident as the data are sifted and analyzed. Among patients who take leflunomide, for example, diarrhea can have a significant impact on quality of life and is frequently the reason for its discontinuation. Another example concerns the side effects of the commonly used drug prednisone. As information in the database shows, people who take prednisone may struggle with weight gain, bruising, and edema. While clinicians may not always ask about these issues and patients may not volunteer them unless they are severe, the NDB shows in stark terms how the fallout from a chronic illness can reverberate through all aspects of a patient’s life.
Information yielded by the NDB and other large databases like ARAMIS or the one started by the Consortium of Rheumatology Researchers of North America (CORRONA) is largely unobtainable through traditional randomized clinical trials of short duration.
“Rheumatologists develop lifelong relationships with their rheumatoid arthritis patients,” says Dr. Wolfe. “We take a long look at the outcomes of these illnesses. This allows us to conduct observational studies that tell us, for example, how well a drug works under real-life circumstances, unlike clinical trials, which tell you only how well a drug can work under idealized circumstances.”
Dr. Fries, who is now an emeritus professor of immunology and rheumatology at Stanford, concurs: “The data banks have demonstrated the importance of long-term observational studies in providing us with identifiable and verifiable information on issues like mortality, costs of the illness, and drug side effects. You can’t do randomized, clinical trials on those topics.”
Through databases, researchers have developed validated techniques to allow them to compare the effectiveness of different drugs and drug combinations used for treating rheumatologic disorders, says Dr. Fries. “Optimal treatment depends on using the best, not necessarily the newest, drugs, and for obvious reasons, drug companies won’t sponsor those studies,” he says. Private databases pick up the slack.
Long View on Chronic Disease
“Chronic diseases typically are studied for too short a time,” explains Theodore Pincus, MD, professor of medicine and microbiology at Vanderbilt University Medical Center in Nashville. “Two or three months might be sufficient to study the outcomes of an illness like acute pneumonia or myocardial infarction, but chronic conditions like rheumatoid arthritis must be studied for five to 20 years. Longitudinal databases are essential to that task.” Many of Dr. Pincus’ patients are enrolled in the NDB, and he has analyzed his own patients at Vanderbilt.
Dr. Pincus and Tuulikki Sokka, MD, PhD, a rheumatologist at Jyväskylä Central Hospital in Jyväskylä, Finland, have described several limitations of short-term clinical assessments that can be overcome by studying large numbers of patients for many years (Clin Exp Rheumatol; 23(Suppl 39):S1-S9).
Overall, the best way to assess outcomes and the functional impact of the disease is through long-term patient self-reports on issues like pain, fatigue, and global status, Drs. Pincus and Sokka write. Indeed, says Dr. Wolfe, “Loss of functional ability is the best predictor of adverse outcomes, and the only way to really assess that is through patient self-reports” such as those gathered by the NDB.
Databases are also an invaluable resource for studying rare events. Such an event might be a drug side effect, such as malignancy, which might not be picked up in a clinical trial either because too few patients were studied or because they weren’t studied long enough—or because a disorder itself might be rare.
“If you have reports from 3,000 rheumatologists, each of whom has two patients with polymyositis or scleroderma, that’s 6,000 patients and an informative database,” says Dr. Pincus.
Finally, databases provide important lessons on the fine points of data collection. Back in the early 1970s, Dr. Fries and his colleagues envisioned the project that eventually became ARAMIS as a way of maintaining objective, longitudinal data that would use then-current computer techniques to make clinical research more efficient. They quickly encountered problems, including a high dropout rate and data that were sketchy or missing altogether.
To remedy the situation they developed new ways of organizing the data and designed the Health Assessment Questionnaire (HAQ), which posed questions in a patient-friendly manner. They also realized the importance of mail and telephone follow-up and made those tasks standard parts of the data collection process.
Join the data bank!
The NDB is actively recruiting patients with all rheumatic diseases to participate in its data-gathering efforts. In fact, there is a special effort underway to enroll patients with systemic lupus erythematosus who are being treated in the community rather than in tertiary centers. Patients and rheumatologists can get more information and enroll online at www.arthritis-research.org.
Along with illustrating trends over time, databases present new questions for investigators to tackle. For example, Dr. Wolfe would like to use the data in the NDB to link to other registries, such as cancer and infectious disease registries. Such links are available in other countries, but not yet in the United States.
Information in databases must be better organized to enhance the accurate measurement of treatment efficacy, costs, and toxicity, so investigators can compare the value of different forms of therapy. “This is being done already,” says Dr. Fries, “but some improvement is necessary.”
The genetics and pathophysiology of rheumatic diseases are ripe for further research. Indeed, the NDB already gathers genetic and imaging data for outcomes research, and the developers of the CORRONA database are collecting proteomic and biomarker measures and have begun examining the relationship between single nucleotide polymorphisms and clinical outcomes.
“Large data banks are good for these types of studies, but for that they need more funding,” says Eric Matteson, MD, consultant in rheumatology and professor of medicine at the Mayo Clinic in Rochester, Minn.
The future of the NDB is another important issue. Several of the physicians interviewed for this article wonder what will happen to the NDB when Dr. Wolfe retires. This is a question that Dr. Wolfe himself has been pondering. “The NDB will continue, regardless of who directs it,” he assures TR. In fact, the NDB has just embarked on a 10-year safety-and-outcomes study.
Dr. Wolfe is committed to keeping the NDB independent of both the government and industry, and envisions it being run by younger rheumatologists and epidemiologists. Dr. Wolfe is still considering options for the NDB, perhaps turning it over in its entirety to a national organization or a university. The gift will have only one string attached, he says: “The recipient must maintain it. They must keep it alive.”
Norra MacReady is a medical journalist based in southern California.