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Publication Date: May 2001
Revised September 2006
Lupus: A Patient Care Guide for Nurses and Other Health Professionals
Chapter 2: Advances in Lupus Research
- Treatment and Health Maintenance
- Role of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Scientists know that systemic lupus erythematosus (SLE) is an autoimmune disease, and recent studies have begun to unravel some of the elements involved. Genetic, environmental, and hormonal factors are all believed to play roles in causing lupus. Much research is being conducted to understand these factors and how they work together.
Epidemiological studies may yield further clues about the cause of lupus. For example, SLE is more prevalent in women, especially those in the reproductive years, than in men. And while people of all ethnicities get lupus, the incidence rate for Asian women (particularly those of Chinese and Filipino descent) and African American women is three to four times higher than it is for Caucasian women. African American women also tend to develop the disease at a younger age, develop more serious complications, and have a higher mortality rate from the disease than do Caucasian women. Researchers are trying to find out why lupus is more common in these populations.
Health professionals continue to search for better ways to care for people with lupus. Understanding what causes the disease and why certain people are more likely to develop it may one day lead to promising new treatments for, or even prevention of, lupus. In the meantime, researchers continue to look for new treatments and ways to modify existing ones so they can diminish or eliminate side effects and improve the quality of life for people who have lupus.
During the last 15 years, researchers have made a tremendous amount of progress in lupus research. The number of studies on this disease has increased exponentially, and most researchers believe that answers to some of the key questions are close at hand. This chapter highlights some of the recent research advances in lupus and provides an overview of the direction of current research.
Investigators have found evidence to support several likely possibilities in the etiology of SLE. Some believe there may be more than one type of SLE and that its etiology may vary from one person to the next. Current studies are focusing on the following elements:
- immune system dysfunction
- environmental influences
In lupus research, as in many areas of research, animal models have played an important role. This discussion of the etiology of lupus includes examples of research conducted in animal models that illustrate how these factors might influence the development of SLE in humans.
Immune System Dysfunction
Lupus is known as an autoimmune disease because a person’s immune system attacks the body’s own tissues. In lupus, the signs and symptoms of the disease can be attributed to damage caused directly by autoantibodies, the deposition of immune complexes (the combination of antigen and autoantibody), or cell-mediated immune mechanisms. Various steps are involved in these mechanisms, and scientists hope to reveal the cause of lupus by examining each step. In the process of doing so, they also may find new ways to treat lupus.
One of the hallmarks of lupus is the formation of autoantibodies, which are antibodies that react with a person’s own tissue. Autoantibodies occasionally can be present in healthy people, but they are typically found in low concentrations. Essentially all patients with lupus have autoantibodies, generally in high concentrations. The most characteristic autoantibodies are antinuclear antibodies. They are so called because they generally target the nucleic acids, proteins, and ribonucleoprotein complexes inside a cell’s nucleus. Other autoantibodies in people with lupus also can bind to cell surface membranes and destroy cells directly or bind to circulating proteins.
Research studies have shown an association between the presence of certain autoantibodies and particular manifestations of lupus, such as kidney or skin disease. Scientists are now trying to establish whether these autoantibodies actually cause signs or symptoms of lupus. However, most people with lupus test positive for many different autoantibodies, so it is often very difficult to identify which autoantibodies are responsible for a specific type of tissue damage in human subjects.
In lupus, the immune system produces too many autoantibodies and forms too many immune complexes. Normally, antigen-antibody immune complexes are joined by complement, a substance in the blood that aids in the breakup and removal of immune complexes from the body. Scientists have found that SLE patients have both inherited and acquired abnormalities in complement and complement receptors. These deficiencies in complement may decrease the body’s ability to get rid of immune complexes. Immune complexes that are not broken up may be deposited in various body tissues, leading to the inflammation that results in tissue damage. Scientists continue to study:
- the nature of immune complexes and what happens to them once they are formed
- the nature of the autoantibodies that make up the immune complexes
- the reason for increased production of autoantibodies.
There is considerable evidence showing that genes play a role in the etiology of lupus. The extremely high occurrence of lupus in both members of a pair of identical twins and the increased prevalence of lupus among first- and second-degree relatives of people with lupus suggests a genetic component. In addition, when researchers look at autoantibodies typically found in a lupus patient and her or his siblings and compare them with clinical manifestations of the disease in the individuals, they find that the individuals have the autoantibodies in common more often than they have the clinical manifestations in common. This finding indicates a genetic basis for the formation of autoantibodies that play a role in lupus.
Studies to date suggest that many different genes contribute to lupus susceptibility and that no single genetic abnormality causes the disease. It also appears that genes may be influential in determining the type or severity of lupus. Genes that have been associated with lupus in humans include:
- the immune system genes human leukocyte antigen (HLA)-DR3 (and B8 in older data), HLA-DR2, and complement C4 genes; other HLA-DR alleles; and alleles at HLA-DQ
- genes that control immune complex deposition and programmed cell death.
Researchers studying lupus in animals have discovered a single gene that causes a lupus-like illness in mice.
In these mice, the fas gene, one of the genes that controls apoptosis (programmed cell death), is defective. When the defective fas gene is replaced with a normal gene, the mice no longer develop signs of the disease.
Scientists continue to study the genetics of lupus in humans and in animals. If the genes that create a predisposition for lupus can be identified, it may be feasible to correct genetic defects through gene therapy or other treatments. At this time, researchers are studying:
- genes associated with the clearance of immune complexes
- genes associated with immune abnormalities in lupus
- genes associated with apoptosis.
Researchers believe that genetic predisposition is just one piece of the puzzle of lupus etiology. Studies have shown that the occurrence of lupus is high among both members of a pair of identical twins and much lower among nonidentical twins and other full siblings. The fact that this concordance is not 100 percent among identical twins, however, suggests that environmental agents probably trigger lupus in individuals with a genetic predisposition. Environmental factors that scientists are considering include sunlight, stress, certain chemical substances, toxic exposures, and infectious agents such as viruses.
Exposure to the ultraviolet (UV) rays of sunlight can lead to a skin rash and exacerbate systemic manifestations of lupus. Exposure to UVA or UVB light causes certain cellular proteins to accumulate in abnormally large amounts on the cell’s surface. These proteins react with autoantibodies commonly found in people with SLE, leading to a local or systemic inflammatory response.
Doctors suspect stress is a possible trigger for lupus flares. Frequently, patients ascribe their first symptoms or worsening symptoms to a stressful event, such as divorce, death of a loved one, or job loss. Scientists do not have a clear explanation for this phenomenon, but research is being done to find out whether stress hormones such as adrenaline or cortisone may influence the development or course of the disease.
A number of drugs cause a lupus-like illness in susceptible individuals. These include chlorpromazine, hydralazine, isoniazid, methyldopa, and procainamide, as well as TNF (tumor necrosis factor) inhibitors such as etanercept (Enbrel®) and infliximab (Remicade®), which are used for rheumatoid arthritis. When the offending drug is stopped, the lupus symptoms resolve. When researchers determine how these drugs cause lupus, they may be able to provide further answers on the etiology of SLE. Some drugs can precipitate flares of SLE, including sulfonamides, sulfonamide antibiotics, and echinacea.
Several toxic exposures have been associated with SLE. These include silica and mercury.
Environmental crystalline silica exposure has been associated with the formation of autoantibodies and the development of SLE and other autoimmune disease.
A National Institutes of Health (NIH)-funded epidemiological study published in 2002 by the American College of Rheumatology found that silica exposure “may promote the development of SLE in some individuals.” In a 2005 study funded partly by the NIH, researchers found that autoimmune-prone New Zealand mice that were exposed to silica experienced increases in autoantibodies and glomerulonephritis.
Animal studies have established a connection between exposure to mercury and lupus-like autoimmune disease. Additionally, case studies in humans have demonstrated a correlation between accidental mercury exposure and the onset or increased severity of autoimmune disease symptoms. Two ongoing studies funded by the National Institute of Environmental Health Sciences are examining the biochemical, molecular, and genetic mechanisms underlying mercury-induced autoimmunity.
Many researchers suspect that infectious agents such as viruses may trigger lupus by somehow disrupting cellular immune function in susceptible individuals. It is possible that a virus can infect B cells (cells programmed to produce antibodies in response to specific antigens) and cause them to produce autoantibodies. Research provides evidence that antibodies produced to fight viruses such as the Epstein-Barr virus crossreact with bodily proteins in genetically susceptible people. Researchers are continuing to study various mechanisms by which viruses could result in autoimmunity.
SLE is more prevalent in women during their reproductive years. In addition, disease activity sometimes flares during pregnancy or during the postpartum period. For these reasons, researchers have long considered that hormones may influence lupus. Some research in animals also supports this supposition. Lupus-like illnesses in animals are exacerbated when they receive female hormones.
A recent study showed that oral contraceptives do not increase flares in SLE, but hormone therapy does cause an increase in mild-to-moderate (though not severe) flares.
Improving current treatments for people with lupus and improving the reproductive health of women with lupus are also important elements of ongoing lupus research. Specifically, investigators are studying ways to:
- optimize the use of immunosuppressives, such as corticosteroids and cyclophosphamide, and decrease unwanted side effects
- develop new therapies with fewer side effects
- correct underlying immune abnormalities
- improve reproductive health in women with lupus.
Optimize the Use of Immunosuppressives
Corticosteroids, such as prednisone, are a mainstay of lupus therapy because they suppress the immune system and reduce inflammation. Unfortunately, they also cause some serious side effects, including weight gain, hypertension, diabetes, cataracts, glaucoma, infections, osteonecrosis, steoporosis, and coronary artery disease. Other, less serious, side effects can also take a toll on thepatient’s quality of life. Scientists are investigating how corticosteroid use can be minimized in such a way that the benefits are retained while the side effects are reduced.
Cyclophosphamide also suppresses the immune system and has antiinflammatory properties. Treatment with cyclophosphamide improves many severe manifestations of lupus. Unfortunately, cyclophosphamide can produce serious toxicities. Patients using this drug may experience nausea and vomiting, alopecia, and an increased risk for infections. In the long term, cyclophosphamide also may damage gonadal tissue and lead to ovarian or testicular failure. Other potential long-term complications include hemorrhagic cystitis, bladder fibrosis, bladder cancer, and other cancers such as lymphoma. At this time, scientists are conducting studies to better understand the long-term effects of cyclophosphamide therapy. In addition, they are exploring the use of additional drugs that might counteract some of the negative side effects of cyclophosphamide. For example, they have found that giving leuprolide (Lupron®) to a woman 2 weeks before each cyclophosphamide infusion can reduce the risk of premature ovarian failure resulting in infertility. They are also trying to determine the dose regimen of cyclophosphamide that is most effective and causes the fewest severe side effects.
Mycophenolate mofetil (CellCept®) is another immunosuppressant used to treat severe lupus; however, it is not approved by the Food and Drug Administration (FDA) for people with lupus. (It is FDA-approved for preventing rejection of kidneys by patients receiving transplants.) Several clinical trials have proven the benefit of mycophenolate mofetil for lupus nephritis.
Mycophenolate acts through the inhibition of T and B cell function. Possible side effects include diarrhea, low white blood cell counts, and certain viral infections. There is also concern that long-term use will increase the risk of malignant cancers later in life.
Scientists are also trying to identify combination therapies that may be more effective than single-treatment approaches. For example, in lupus nephritis patients with moderate kidney scarring, a combination of cyclophosphamide and prednisone is more effective in preserving renal function than is treatment with prednisone alone. In these patients, the combination therapy reduces the likelihood of end-stage renal failure.
Develop New Therapies
While some researchers are examining existing drug and treatment practices, other researchers are developing new treatment regimens. Promising areas of treatment research include biologic agents and hormones.
On the basis of new information about the SLE disease process, scientists are using novel biologic agents to selectively block parts of the immune system.
Developing and testing these new drugs, which are based on compounds that occur naturally in the body, is an exciting and promising new area of lupus research. One such agent is rituximab, a monoclonal antibody that lowers B cell counts and is approved for lymphoma treatment. In several series of patients with clinically active lupus, a single injection of the agent brought significant improvement in symptoms. Epratuzumab, another monoclonal antibody that may work by modulating B cell function, is in phase III clinical trials for moderate-to-severe lupus.
Another biologic agent is LymphoStat-B® (belimumab), a human monoclonal antibody that recognizes and inhibits the biological activity of B-lymphocyte stimulator or BLyS. Laboratory and observational studies have indicated that higher than normal levels of BLyS may play a role in autoimmune diseases, such as SLE and rheumatoid arthritis. LymphoStat-B® is being studied as potential treatment for these diseases.
Because hormones are believed to influence the course and perhaps even the etiology of lupus, many researchers are interested in testing the effects of hormones on people with lupus. For example, animal and human studies have shown benefits associated with dehydroepiandrosterone (DHEA) therapy. DHEA is a naturally occurring hormone present in unusually low concentrations in women with lupus. In clinical trials, DHEA reduced the prednisone requirements for patients and reduced flares.1
Other research is showing that other hormone preparations that were once thought to worsen lupus—such as hormone replacement therapy and oral contraceptives—may be safe for some women with the disease.
1 DHEA is not approved by the U.S. Food and Drug administration for treatment of lupus.
Correct Underlying Immune Abnormalities
Researchers predict that one day it may be possible to correct the underlying immune abnormalities in people with lupus. Studies are underway to explore the dimensions, risks, and benefits of reconstructing the immune system by high-dose cyclophosphamide with or without stem cell rescue.
Improve Reproductive Health in Women with Lupus
Because of recent improvements in diagnostic tools for lupus and a better understanding of the disease, doctors can now predict the likelihood of a lupus-related miscarriage and identify women at risk for giving birth to babies with neonatal lupus. Doctors and people with lupus can now take measures to prevent miscarriages, and doctors can prepare to treat those babies born with neonatal heart block, the most serious complication of neonatal lupus.
Progress is also being made in another important area of reproductive health. In the past, women with lupus have not been able to use oral contraceptives or take advantage of hormone replacement therapy because of concerns that estrogens exacerbate lupus. However, recent results of a major study, Safety of Estrogen in Lupus Erythematosus National Assessment (SELENA), funded by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), the NIH Office of Research on Women’s Health, and the National Center on Minority Health and Health Disparities, suggest that oral contraceptives do not increase flares in women with SLE. Women with antiphospholipid antibodies cannot take oral contraceptives, however, because of the increased risk of blood clots.
NIAMS leads and coordinates the Federal biomedical research effort in lupus by conducting and supporting research projects, research training, clinical trials, and epidemiologic studies and by disseminating information on research results.
NIAMS funds many scientists across the United States who are studying the causes and mechanisms of tissue injury in SLE and the reasons why lupus strikes women and certain minority populations more frequently.
In addition, NIAMS has established the first Specialized Centers of Research (SCORs) devoted to lupus. These centers enable basic scientists and clinicians to collaborate closely on lupus research.
To further the study of the genetics of lupus and to provide a resource for all researchers in this field, NIAMS has established a lupus registry and repository. Researchers who study families in which two or more members have been diagnosed with lupus collect and continually update clinical, demographic, and laboratory data on these individuals and submit the data to the lupus registry. Blood, cell, and tissue samples and DNA from these individuals will be stored in the lupus repository.
The registry and repository will allow all lupus researchers access to an enormously valuable database of information on people with lupus. For example, researchers will be able to analyze each DNA sample in the repository for the presence of a standard set of genetic markers. A centralized database will maintain 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. Finding the genes that cause the disease may help researchers develop new treatments. In addition, this research will help identify which people with lupus will develop the most severe manifestations of the disease. This will help doctors decide who needs the most aggressive treatment.
In February 2003, Congress called on the Office of the Secretary of the Department of Health and Human Services (DHHS) to establish a Federal working group on lupus to exchange information and coordinate Federal efforts regarding lupus research and education initiatives. As the lead institute at the NIH for lupus research, NIAMS was asked to direct this Federal working group. The group is composed of representatives from all relevant DHHS agencies and other Federal departments having an interest in lupus.
Research advances of the past have led to significant improvements in the prognosis for patients with lupus. As current research efforts unfold, there is continued hope for new treatments, further improvements in patient quality of life, and ultimately, for ways in which to prevent or cure the disease.