|NATIONAL INSTITUTES OF HEALTH|
|January 15, 1996||
- News Release: First Clinical Trial on the Safety of Estrogen in Lupus Erythematosus Begins
- News Release: NIAMS Establishes Lupus Registry and Repository
- Backgrounder on Systemic Lupus Erythematosus
The National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), a component of the National Institutes of Health, leads and coordinates the Federal biomedical research effort in all forms of arthritis by conducting and supporting research projects, research training, clinical trials, and epidemiological studies, and by disseminating information on research initiatives and research results.
The National Institutes of Health (NIH) has funded the first clinical trial on the safety of estrogens for women with systemic lupus erythematosus. At the present time, women with systemic lupus erythematosus (SLE, or lupus) are usually advised not to take any medications that contain estrogen in the belief that it will worsen their disease or cause problems with blood clotting.
The clinical trial, known as SELENA (Safety of Estrogen in Lupus Erythematosus National Assessment), is being funded by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), the NIH Office of Research on Women's Health and the NIH Office of Research on Minority Health.
Dr. Stephen I. Katz, Director of NIAMS, said: "Results of the trial will provide scientific evidence to support physicians' decisions about the safety of providing oral contraceptives and hormone replacement therapy (HRT) to women with SLE. Young women with lupus need options for safe, effective methods of birth control. Postmenopausal women with SLE already have a higher risk for osteoporosis and cardiovascular disease, and clearly would benefit from use of HRT."
The clinical trial will be co-directed by Dr. Jill Buyon at the Hospital for Joint Diseases in New York City, and Dr. Michelle Petri at the Johns Hopkins Hospital in Baltimore, Maryland. It will be a collaboration between five major research centers: the Hospital for Joint Diseases/Bellevue Hospital in New York City; the Johns Hopkins Hospital; the Hospital for Special Surgery/Cornell Medical Center in New York City; St. Luke's/ Roosevelt Hospital Center in New York City; and the UCLA Medical Center in Los Angeles, California. Researchers at these centers will conduct randomized, double-blind, placebo-controlled studies on the effects of oral contraceptives on disease activity in women with SLE and on the effects of hormone replacement therapy (HRT) with estrogens and cyclic low-dose progestins in postmenopausal women with SLE.
Dr. Buyon and Dr. Petri said that at the present time, the safety of estrogens in lupus is unresolved. "If these therapies become available, they are likely to have a significant impact on the health and quality of life for patients with SLE," Dr. Petri said. Dr. Buyon added: "These clinical studies will address a major concern for patients with SLE. Our patients want to know whether they can safely use these therapies."
SLE is believed to result from an interplay of genetic, environmental and hormonal factors. In SLE, the immune system is thrown out of balance and produces autoantibodies (antibodies that attack the patient's own tissues). The disease can affect many parts of the body, including the joints, skin, kidneys, lungs, heart, nervous system and blood vessels. It is characterized by periods of flares and remissions--that is, periods when disease symptoms either worsen or improve. Ninety percent of SLE victims are women, and the disease most often strikes during the childbearing years. In addition, the disease is three times more common in black women than in white women.
Dr. John Ruffin, Director of the Office of Research on Minority Health said, "Because of the disproportionate impact of lupus on the health of black women, the planned inclusion of a significant number of black women in the clinical trial is critical to its success."
For the SELENA trial, patients, many of whom are minorities, will be recruited from clinics and private practices. To participate in the study patients must have either inactive, stable disease or moderate disease, and must only require low to moderate doses of prednisone to treat their disease. In the first study, patients will receive HRT or a placebo (inactive pill) for 12 months. In the second study, each patient will receive either an oral contraceptive or a placebo for 12 months. Both studies have been designed to detect very small increases in the rate of flares in patients taking either oral contraceptives or HRT.
Both rheumatologists and gynecologists will examine and monitor all patients. Rheumatologists will measure specific outcomes by using the SLE Disease Activity Index, which measures clinical signs and symptoms in nine different organ systems, specific laboratory tests, and a physician's comprehensive assessment of each patient. Gynecologists will assess all oral contraceptive- and HRT-related symptoms or complications.
Dr. Vivian Pinn, Director of the Office of Research on Women's Health said, "We hope that results of the clinical trial will resolve some of the existing controversies about these treatments and that oral contraceptives and hormone replacement therapy will be shown to be safe options that can be utilized by women with lupus."
Johns Hopkins University
School of Medicine
Division of Rheumatology
1830 E. Monument Street
Baltimore, Maryland 21205
Contact: Dr. Michelle Petri
Hospital for Joint Diseases
301 East 17th Street
New York, New York 10003
Contact: Dr. Jill Buyon
Hospital for Special Surgery/Cornell Medical Center
535 East 70th Street
New York, New York 10021
Contact: Dr. Lisa Sammaritano
St. Luke's/Roosevelt Medical Center
432 West 58th Street
New York, New York 10019
Contact: Dr. Joan Merrill
UCLA Medical Center
Division of Rheumatology
100 Veteran Avenue
Los Angeles, California 90024-1670
Contact: Dr. Ken C. Kalunian
New York University Medical Center/Bellevue Hospital
Faculty Practice Offices
550 First Avenue, Suite 4G
New York, New York 10016
Contact: Dr. H. Michael Belmont
The National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) has established a lupus registry and repository to study not only patients but also their families in order to identify genes that determine susceptibility to the disease. The high prevalence of lupus among relatives of lupus patients suggests a genetic component for the disease. However, genetic studies of lupus to date have been incomplete.
"Our understanding of lupus and development of new treatments are sure to be aided by finding the genes that cause the disease," said Dr. Stephen I. Katz, Director of the NIAMS. "By providing an extensive source of medical information, the registry will serve as a valuable resource for researchers to advance genetic studies of this important disease," he said.
The Lupus Registry and Repository will be assembled and administered at the Oklahoma Medical Research Foundation in Oklahoma City, Oklahoma. The project will be directed by Dr. John Harley, Professor of Immunology at the University of Oklahoma Health Sciences Center and staff physician at the Oklahoma City Veterans Medical Center. They are seeking lupus patients who have two or more family members who have also been diagnosed with the disease. Patients, many of whom are minorities, will be recruited from clinics, private practices and voluntary organizations. Families who qualify for the study will be sent a sample collection kit, a consent form and a questionnaire. A blood sample will be collected and the completed materials will be sent to Dr. Harley and his associates for evaluation.
Dr. Harley and his associates will collect and update clinical, demographic and laboratory data on all patients with lupus and their families for the Lupus Registry. They will store blood, cells and DNA from these individuals in the Lupus Repository. The researchers will also analyze each DNA sample in the repository for the presence of a standard set of genetic markers. A centralized database will provide this genetic information along with clinical and laboratory information from the registry. Together, these data can be used as the starting point for genetic analysis to identify possible lupus genes. Ultimately the repository will contain data on more than 125 fully characterized lupus families, and be available to other researchers.
Systemic lupus erythematosus (SLE, or lupus) is believed to result from an interplay of genetic, environmental and hormonal factors. In lupus, the immune system is thrown out of balance and produces autoantibodies (antibodies that attack the patient's own tissues). The disease can affect many parts of the body, including the joints, skin, kidney, lungs, heart, nervous system and blood vessels. It is characterized by period of flares and remissions--that is, periods when disease symptoms either worsen or improve. Ninety percent of lupus patients are women, and the disease most often strikes during the childbearing years. In addition, lupus is three times more common in black women than in white women.
Dr. Harley said that solving the problem of lupus is especially difficult because features of the illness vary from patient to patient. "We plan to use the utmost care in categorizing each patient. Hopefully, investigators will find this information useful and dependable as they attempt to understand the mysteries of this disease."
Lupus Registry and Repository
Patients or physicians interested in participating should contact:
Ms. Ida Adams
Ms. Gail Bruner
Oklahoma Medical Research Foundation
Oklahoma City, Oklahoma
1-800-522-0211 Extension 7479
# # #
Systemic lupus erythematosus (SLE, or lupus) is an autoimmune disease, in which autoantibodies attack the body's own tissues. This results in inflammation that causes redness, swelling, pain and tissue injury in affected parts of the body. Most often the joints, skin, kidneys, lungs, heart, nervous system and blood vessels are involved. The signs and symptoms of lupus differ from one person to another, and the disease can range from mild to life-threatening. It is characterized by periods of flares and remissions-that is, periods when disease symptoms either worsen or improve.
At present, rheumatologists and other physicians who treat women with systemic lupus erythematosus (SLE, or lupus) generally do not prescribe oral contraceptives or estrogen replacement therapy for women with lupus because of the widely-held view that estrogens can aggravate the disease. This view is based on a number of observations, including the following:
- Lupus is more common among women than men.
- Lupus is sometimes associated with Klinefelter's syndrome, a condition associated with infertility and other abnormalities of sexual development. Men with this syndrome usually have an extra X chromosome (i.e., they have two X chromosomes and one Y chromosome).
- Both women and men with lupus have abnormal estrogen metabolism.
- Studies in mice with lupus-like disease have shown that removing the ovaries is beneficial for the course of the disease.
- Some physicians have reported (anecdotal evidence) that lupus patients experience onset of disease or disease flares while taking estrogens.
In contrast, results of small retrospective studies suggest that disease flares do not increase significantly in patients taking newer oral contraceptives, which contain less estrogen than in the past, or estrogen replacement therapy. And until now there have been no controlled clinical trials to determine whether estrogens in the form of either oral contraceptives or hormone replacement therapy aggravate disease in women with lupus.
Thus, the available data are not sufficient to dismiss the use of a highly effective method of birth control and an effective way to prevent osteoporosis and cardiovascular disease for women with lupus. Postmenopausal women with lupus have an increased risk for osteoporosis and cardiovascular disease because (1) patients with lupus are often treated with corticosteroids such as prednisone, which increase the risk of osteoporosis; (2) cardiovascular disease is a known complication of SLE; and (3) prednisone therapy increases the level of many known risk factors for cardiovascular disease, including weight, blood pressure, and cholesterol.
- Current scientific evidence indicates that SLE is caused by a combination of genetic and environmental factors.
- Studies showing that lupus runs in families support the idea that a person's genetic makeup affects their susceptibility to developing lupus. Particularly striking evidence that genes play a significant role in lupus is provided by studies of twins. Lupus is much more likely to affect both members of a pair of identical twins, who share the same set of genes, than two nonidentical twins or other siblings.
- Research suggests that multiple genes contribute to disease susceptibility in lupus, and that no single genetic abnormality can by itself cause the disease.
- It is much more difficult for researchers to identify disease genes in genetically complex diseases such as lupus than in diseases caused by a single gene defect (such as cystic fibrosis or Huntington disease).
- Continued development of new, better, and faster technologies for analyzing genetic material (DNA) and the great progress being made in the Human Genome Project are enabling researchers to tackle genetically complex diseases such as lupus or diabetes, allowing them to begin to identify genes that may cause these diseases.
- Researchers predict that they will need to study a large number of families (more than a hundred, and perhaps several hundred) affected by SLE in order to identify the genes that determine disease susceptibility. In particular, they need to study families in which at least two members, and preferably more, are affected by the disease.
- Identifying the genes that contribute to development of lupus should open the door to better understanding of the disease and, ultimately, new and better ways to treat, or even prevent, the disease.
-Elia Ben-Ari, Office of Scientific and Health Communications