A recent report from the Centers for Disease Control (CDC) in Atlanta shows that the number of deaths per year from systemic lupus erythematosus (SLE, or lupus) increased between 1979 and 1998. Death rates were more than five times higher among women than men, and more than three times higher for blacks than for whites. The most startling finding of the CDC analysis is that black women between the ages of 45 and 64 not only had the highest death rate from lupus, but the death rate in this group rose by about 70 percent over the 20-year study period.
For this analysis, published in the May 3, 2002 issue of the Morbidity and Mortality Weekly Report, CDC scientists used national mortality statistics based on information from death certificates. They found that 22,861 people died from lupus from 1979 to 1998, and the number of deaths per year increased from 879 to 1,406. Of all deaths due to lupus, 36 percent occurred in people aged 15 to 44 years.
To gather better information on the disease, including how many people it affects, and to help explain the disparities in lupus death rates among different groups, the CDC is exploring the possibility of developing a large, population-based registry for SLE. Such a registry would allow researchers to follow a large group of people over time and look at cases of lupus that develop in that population.
"The CDC report emphasizes the importance of developing improved treatments for lupus, in particular kidney and cardiovascular complications, so we can prevent excess and premature deaths," says ALR Scientific Director John H. Klippel, MD. ALR funds a broad range of medical research projects in an aggressive and concerted effort to find better treatments for lupus and, ultimately, develop ways to prevent and cure the disease. Through this newsletter, ALR will provide regular updates on the progress that researchers are making in achieving these critical goals.
One research project funded by ALR has provided new insights on what causes recurrent pregnancy loss (miscarriage) in some women with lupus, and may lead to better ways to prevent this serious problem. In many cases, miscarriages in women with lupus are due to a condition known as antiphospholipid syndrome (APS), in which abnormal antibodies known as anti-phospholipid (aPL) antibodies attack the body's own tissues and cause blood clots to form in the circulation. In pregnant women, these aPL antibodies build up in the placenta, resulting in tissue damage and miscarriage or low birth-weight babies. But exactly how these antibodies cause damage is unclear.
Until now, researchers thought the harmful effects of aPL antibodies on the unborn child occurred primarily because the antibodies cause blood clots in the blood vessels of the placenta. But ALR Investigator Jane Salmon, MD, PhD, of the Hospital for Special Surgery in New York, and her colleagues recently showed that in mice with APS, a key step in the series of events leading to pregnancy loss is activation by aPL antibodies of proteins in the bloodstream, called complement proteins, that cause tissue inflammation.
In an article in the January 21 issue of the Journal of Experimental Medicine, Dr. Salmon and her co-workers report that blocking the activation of these complement proteins prevents pregnancy loss and abnormal blood clotting in mice with APS. Because drugs that block the effects of these inflammation-causing proteins already exist, Dr. Salmon says, "this work can be translated into a treatment for women with lupus if we can demonstrate that these proteins are activated in human pregnancy loss caused by aPL antibodies, as we have shown in the mouse model of APS."
What it means for people with lupus: Even with the best available treatment, which relies on drugs that prevent blood clotting, in about one in four pregnancies women with lupus and APS still have complications, and in some cases miscarriage. APS may also cause life-threatening blood clots and strokes. If future research shows that activation of inflammation-causing complement proteins plays a critical role in pregnancy loss and abnormal blood clot formation in people with lupus and APS, then doctors should be able to more effectively prevent these problems with drugs that block the action of these proteins.
The inflammation-causing proteins that lead to the pregnancy complications of lupus studied by Dr. Salmon (see story above) are part of the "complement system," a group of 30 immune system proteins that circulate in the bloodstream. (These proteins earn their name because, among other things, they "complement" the activity of antibodies.) However, according to recent studies, some proteins in the complement system appear to protect against the development of lupus.
For some time, researchers have known that the C3 protein of the complement system plays a major role in inflammation and tissue damage, which are hallmarks of lupus. Research has also shown that people with an inherited deficiency in the C1 or C4 proteins of the complement system, which can activate C3 and trigger inflammation in a chain reaction, have a high risk of developing lupus. These latter findings led to the hypothesis that C1 and C4 "have some protective role in keeping us from developing lupus," says Michael C. Carroll, PhD, of Harvard Medical School.
To learn more about the role of complement system proteins in the development of lupus, Dr. Carroll and his colleagues are using a mouse model of lupus in which they can eliminate individual proteins through genetic engineering. "It turns out that in mice it's the same story" as in people, Dr. Carroll says. In the February 1 issue of the Journal of Immunology, he and his co-workers report that mice that are normally prone to a mild form of lupus develop a more severe form of the disease when they are deficient in C4, and that eliminating the C3 protein does not protect the C4-deficient mice from developing lupus. These studies show that C4, and not C3, plays an important role in the initial development of lupus.
In a similar research project supported by ALR, David Pisetsky, MD, PhD, of Duke University Medical Center is also using mice deficient in components of the complement system to better understand the role of complement deficiency in lupus development, and to determine whether complement proteins could be used as a treatment for the disease.
What it means for people with lupus: Learning more about the role of deficiencies in the complement system in lupus development may lead to treatments that make up for these deficiencies and prevent or reverse the course of disease.
Researchers studying children with lupus have found a new clue to the cause of immune system abnormalities in the disease. About one-quarter of all cases of lupus start before age 18, and lupus tends to be more severe in children as compared to adults.
In the November 16, 2001 issue of the journal Science, researchers from the Baylor Institute for Immunology Research and the University of Texas Southwest Medical Center in Dallas, Texas, reported that children with lupus have abnormally high blood levels of a virus-fighting substance called alpha interferon. Usually, cells in the immune system produce alpha interferon to help eliminate viral infections. But once the infection is gone, interferon normally disappears from the bloodstream.
Dr. Jacques Banchereau and his Dallas colleagues found that, in lupus patients aged 7 to 18, alpha interferon in the bloodstream triggers changes in the behavior of certain types of immune system cells. These cells are likely to play a role in the production of antibodies that react against the body's own tissues in people with lupus.
The results of this study should also apply to adults with lupus, according to the researchers. The findings are especially interesting in light of results published last September by ALR Investigator Brian Kotzin, MD, of the University of Colorado, showing that a gene that is activated by interferon plays a role in lupus susceptibility in a mouse model of the disease.
What it means for people with lupus: "Alpha interferon has long been suspected to play an important role in lupus," says ALR Scientific Director Dr. John H. Klippel. "These recent findings indicate that therapies that block the function of interferon or inhibit production of alpha interferon may be important in the disease."
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