Systemic Lupus Erythematosus
Male Osteoporosis: New trends in diagnosis and therapy
Genetics of susceptibility and severity in systemic lupus erythematosus
Genetic Risk Factor Found for Lupus in African American Women
Systemic Lupus Erythematosus
U.S. Department of Health and Human Services
National Institutes of Health
National Institute of Arthritis and Musculoskeletal and Skin Diseases
Lupus is the focus of intense research as scientists try to determine what causes the disease and
how it can best be treated. Some of the questions they are working to answer include: Why are
women more likely than men to have the disease? Why are there more cases of lupus in some
racial and ethnic groups? What goes wrong in the immune system, and why? How can we correct the way the immune system functions once something goes wrong? What treatment approaches will
work best to lessen lupus symptoms? How do we cure lupus?
To help answer these questions, scientists are devel-oping new and better ways to study the disease. They are doing laboratory studies that compare various aspects of the immune systems of people with lupus with those of other people both with and with-out
lupus. They also use mice with disorders resembling lupus to better understand the abnormalities of the immune system that occur in lupus and to identify possible new therapies.
The National Institute of Arthritis and Musculoskeletal Skin Diseases (NIAMS), a component
of the Department of Health and Human Services’ National Institutes of Health (NIH), has a
major focus on lupus research in its on campus program in Bethesda, Maryland. By evaluating
patients with lupus and their relatives, researchers on campus are learning more about how lupus develops and changes over time. The NIAMS also funds many lupus researchers across the United States. Some of these researchers are studying the genetic factors that increase a person’s risk for developing lupus. To help scientists gain new knowledge, the NIAMS also has established Specialized Centers of Research devoted specifically to lupus research. In addition, the NIAMS is funding lupus registries that gather medical information as well as blood and tissue samples from patients and their relatives. This gives researchers across the country access to information and materials they can use to help identify genes that determine susceptibility to the disease.
Identifying genes that play a role in the development of lupus is an active area of research. For
example, researchers suspect that a genetic defect in a cellular process called apoptosis,
or “programmed cell death,” exists in people with lupus. Apoptosis is similar to the process that causes leaves to turn color in autumn and fall from trees; it allows the body to eliminate cells that have fulfilled their function and typically need to be replaced. If there is a problem in the apoptosis process, harmful cells may stay around and do damage to the body’s own tissues. For example, in a mutant mouse strain that develops a lupus-like illness, one of the genes that controls apoptosis is defective. When it is replaced by a normal gene, the mice no longer develop signs of the disease. Scientists are studying what role genes involved in
apoptosis may play in human disease development.
Studying genes for complement, a series of proteins in the blood that play an important part in the immune system, is another active area of lupus research. Complement acts as a backup for antibod-ies, helping them destroy foreign substances that invade the body. If there is a decrease in complement, the body is less able to fight or destroy foreign substances. If these substances are not removed from the body, the immune system may become
overactive and begin to make autoantibodies.
Recent large studies of families with lupus have identified a number of genetic regions that appear to be associated with risk of SLE. Although the specific genes and their function remain unknown, intensive work in mapping the entire human genome offers promise that these genes will be
identified in the near future. This should provide knowledge of the complex factors that contribute to lupus susceptibility.
NIAMS-funded researchers are uncovering the impact of genetic, socioeconomic and
cultural factors on the course and outcome of lupus in Hispanics, African Americans
and Caucasians. Preliminary data show that African American and Hispanic lupus
patients typically have more kidney damage compared with Caucasians.
In addition, NIAMS-funded researchers found that African American lupus patients have more
skin damage compared with Hispanics and Caucasians, and that the death rate from lupus is higher in African Americans and Hispanics compared with Caucasians. It is thought that autoimmune diseases, such as lupus, occur when a genetically susceptible individual encounters an unknown environmental agent or trigger. In this circumstance, an abnormal immune response can be initiated that leads to the signs and symptoms of lupus. Research has focused on both the genetic susceptibility and the environmental trigger. Although the environmental trigger remains unknown, microbial agents such
as Epstein-Barr virus and others have been considered. Researchers also are studying other factors that may affect a person’s susceptibility to lupus. For example, because lupus is more common in women than in men, some researchers are investigating the role of hormones and other male-female differences in the development and course of the disease. A current study funded by the NIH is focusing on the safety and effectiveness of oral contraceptives (birth-control pills) and hormone replacement therapy in women with lupus. Doctors have worried about the wisdom of prescribing
oral contraceptives or estrogen replacement therapy for women with lupus because of a widely held view that estrogens can make the disease worse. Oral contraceptives and estrogen replacement therapy do not, as once feared, appear to intensify lupus symptoms. Scientists do not know the
effects of oral contraceptives on women with antiphospholipid antibody syndrome.
Patients with lupus are at risk of developing atherosclerotic vascular disease (hardening of the blood vessels that can cause heart attack, angina or stroke). The increased risk is due partly to having lupus and partly to steroid therapy. Preventing atheroscle-rotic vascular disease in lupus patients is a new area of study. NIAMS-funded researchers are studying the most effective ways to manage cardiovascular risk factors and prevent cardiovascular disease in adult lupus patients. In childhood lupus, researchers are evaluating the safety and effectiveness of drugs called statins that lower LDL
(or bad) cholesterol levels as a method of preventing fat buildup in the blood vessels.
One out of five lupus patients experiences symptoms such as headaches, dizziness, memory disturbances, stroke, or changes in behavior that result from changes in the brain or other parts of
the central nervous system. Such lupus patients have what is called “neuropsychiatric” lupus. NIAMS-funded scientists are applying new tools such as brain imaging techniques to discover cellular activity and specific genes that may cause neuropsychiatric lupus. By uncovering the mechanisms
responsible for central nervous system damage in lupus patients, researchers hope to move closer
to improved diagnosis and treatment for patients with neuropsychiatric lupus.
Researchers are focusing on finding better treatments for lupus. A primary goal of this research is to develop treatments that can effectively minimize the use of corticosteroids. Scientists are trying to identify combination therapies that may be more effective than single
treatment approaches. Another goal is to improve the treatment and management of lupus in the kidneys and central nervous system. For example, a 20-year study supported by the NIAMS and the NIH found that combining cyclophosphamide with prednisone helped
delay or prevent kidney failure, a serious complication of lupus.
On the basis of new information about the disease process, scientists are using novel “biologic agents” to selectively block parts of the immune system. Development and testing of these new
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drugs, which are based on compounds that occur naturally in the body, comprise an exciting and promising new area of lupus research. The hope is that these treatments not only will be effective,
but also will have fewer side effects. Preliminary research suggest that white blood cells known as B cells may play a key role in the development of lupus. Biologics that interfere with B cell function or block the interactionsof immune cells are active areas of research. These targeted treat-ments hold promise because they have the advantage of reduced side effects and adverse reactions compared with conventional therapies. Clinical trials are testing the safety and effectiveness of rituximab (also called anti-CD20) in treating people with lupus. Rituximab is a genetically engineered antibody that blocks the production of B cells. Other treatment options currently being explored include reconstructing the immune system by bone marrow transplantation. In the future, gene therapy also may play an important role in lupus treatment.
Hope for the Future
With research advances and a better understanding of lupus, the prog-nosis for people with lupus today is far brighter than it was even 20 years ago. It is possible to have lupus and remain active and involved with life, family and work. As current research efforts unfold, there is continued hope for
new treatments; improvements in quality of life; and ultimately, a way to prevent or cure the disease. The research efforts of today may yield the answers for tomorrow, as scientists continue to unravel the mysteries of lupus.Pregabalin for the treatment of fibromyalgia syndrome: results of a
randomized, double-blind, placebo-controlled trial
Fibromyalgia syndrome (FMS) is characterized by widespread musculoskeletal pain and lowered pain threshold. Other prominent symptoms include disordered sleep and fatigue. FMS affects an estimated 2% of the population, predominantly women. This trial
at the University of Michigan Ann Arbor was designed to evaluate the efficacy and safety of pregabalin,
a novel alpha(2)-delta ligand, for treatment of symptoms associated with FMS. A multicenter, double-blind, 8-week, randomized clinical trial compared the
effects of placebo with those of 150, 300, and 450 mg/day prega-balin on pain, sleep, fatigue and health-related quality of life in 529 patients with FMS. The primary outcome variable was the comparison of
end point mean pain scores, derived from daily diary ratings of pain intensity, between each of the pregabalin treatment groups and the placebo group. Pregabalin at 450 mg/day significantly reduced the average severity of pain in the primary analysis compared with placebo, and significantly more patients in this group had improvement in pain at the end point. Pregabalin at 300 and 450 mg/day was
associated with significant improvements in sleep quality, fatigue, and global measures of change. Pregabalin at 450 mg/day improved several domains of health-related quality of life. Dizziness and somnolence were the most frequent adverse events. Rates of discontinuation due to adverse events were similar across all 4 treatment groups.
CONCLUSION:
Pregabalin at 450 mg/day was efficacious for the treatment of FMS, reducing symptoms of
pain, disturbed sleep and fatigue compared with placebo. Pregabalin was well tolerated and improved global measures and health-related quality of life.
Source: Arthritis Rheum. 2005 Apr;52(4):1264-73
Male Osteoporosis: New trends in diagnosis and therapy
Osteoporosis is a common condition in men affecting approxi-mately 2 million males in the U.S. Compared with women, osteoporosis develops later in life and the incidence of osteoporosis related fractures is lower in men. The morbidity and mortality associated with osteoporotic fractures are much greater in men compared with women, and secondary causes of osteoporosis are more frequently (in approximately 50% of cases) identified in men compared with women with osteoporosis. Excessive alcohol
consumption, glucocorticoid excess and hypogonadism are the most commonly identified causes. Primary osteoporosis in men has been linked to changes in sex steroid secretion, the growth hormone-insulin-like growth factor and the vitamin D-parathy-roid
hormone. Diagnosing osteoporosis in men is complicated by an ongoing debate on whether to use sex-specific reference val-ues for bone mineral density (BMD) or female reference values. The International Society for Clinical Densitometry recommended
using a T score of –2.5 or less of male reference values to diag-nose osteoporosis in men who are >/=65 years of age. However, this definition is yet to be validated in terms of fracture incidence and prevalence. Ensuring adequate calcium and vitamin D intake
is the cornerstone of any regimen aimed at preventing or treating osteoporosis in men. Bisphosphonates are currently the therapy of choice for treatment of male osteoporosis. A short course of parathyroid hormone (1-34) [teriparatide] may be indicated for
men with very low BMD or in those in whom bisphosphonate therapy is unsuccessful. The use of testosterone-replacement therapy for the prevention and treatment of male osteoporosis remains controversial but likely to benefit osteoporotic men with
evident hypogonadism.
Source: Drugs Aging. 2005;22(9):741-8
