Surviving Immunity

An explosion of knowledge about lupus is generating change in the care of patients with this often debilitating autoimmune disease.

by Monika Guttman

If you have medical literature about lupus that is 10 years old, throw it out. Actually, make that five years old.

The information would be woefully out of date because the advances made in research, diagnosis and treatment during the last decade have been greater than those made over the past 100 years, according to the Lupus Foundation of America.

The reason, explains David A. Horwitz, M.D., professor of medicine and molecular microbiology and immunology and chief of the division of rheumatology and immunology at the Keck School of Medicine of USC, is because of breakthroughs in the understanding of the pathogenesis and genetic basis of the disease. He says, “Marked advances have been made in identifying the cellular components of the immune response, how they work, how they develop and how they are regulated. In addition, we are beginning to understand the genes that encode both the cells and their regulators.”

Chaim O. Jacob, M.D., Ph.D., associate professor of medicine and molecular microbiology and immunology at the Keck School, adds that more researchers are focused on the disease than ever before. “Lupus is in the mainstream of molecular research,” he says. “Even ten years ago, only a few people worked on the molecular aspects of this disease. Now, significant groups of people all over the world work on different aspects of lupus with sophisticated technologies.”

As a result, new information about lupus is generating a lot of change in caring for patients, with much more to come.

Therapy update

The outlook had already vastly improved since the 1950s, when the average life expectancy for a newly diagnosed lupus patient was about three years.

While lupus was lumped in with other “mysterious” diseases—otherwise known as “not well understood”—what was known was that the immune system, which normally protects the body against viruses, bacteria and other foreign materials, loses its ability to tell the difference between invaders and its own cells and tissue. The immune system makes antibodies that attack foreign cells as well as the body’s own cells. The resulting inflammation can manifest as fever, skin rashes, debilitating joint pain and extreme fatigue, as well as blood clotting problems, seizures and life-threatening attacks on major organs such as the kidneys.

These days, thanks to corticosteroids and anti-inflammatory drugs, 80 to 90 percent of lupus patients without major organ involvement can expect to live a normal lifespan. With new treatment strategies, this number could reach 100 percent.

With that increase in mind, Horwitz and William Stohl, M.D., Ph.D., professor of medicine in the division of rheumatology and immunology at the Keck School, are taking a bench-to-bedside approach to treat lupus patients. Working with patients in the division’s lupus clinic at LAC+USC Medical Center, Stohl found that they had high levels of a molecule called BLyS, an acronym for B-Lymphocyte Stimulator. B cells produce the antibodies that protect the body from infection, but they also can produce harmful autoantibodies. High levels of BLyS can contribute to autoimmune disease by increasing the number of B cells.

“If you either eliminate or neutralize BlyS, you then decrease the number of B cells that survive,” Stohl explains. “This decreases the number of B cells that fully mature into antibody-producing cells, so you reduce the levels of autoantibodies being produced, hopefully including those autoantibodies that are disease-inducing.”

Stohl is conducting Phase II trials of LymphoStat-B, an agent that can neutralize BlyS. Phase I trials, which were conducted at USC and elsewhere, determined that LymphoStat-B was safe. In addition, says Stohl, “They showed that LymphoStat-B was biologically active—the patients treated did have decreased numbers of circulating B cells.” In fact, the Phase I trials were so successful that the U.S. Food and Drug Administration (FDA) fast-tracked the drug into Phase II trials.

Current therapies for lupus try to suppress the entire immune system and reduce inflammation. LymphoStat-B and similar drugs, however, target the specific mechanisms of inflammation and autoimmunity without suppressing the whole immune system. Stohl says, “I’m cautiously optimistic that LymphoStat-B could revolutionize treatment for lupus, in particular.”

Another approach to neutralizing B cells is with Rituximab, a genetically engineered monoclonal antibody that targets a receptor called CD20, found on most B cells. The drug has already been approved by the FDA for treatment of non-Hodgkin’s B cell lymphomas. Stohl says, “Even though it is not an FDA-indicated use, there are several non-placebo-controlled trials reports about lupus patients responding to Rituximab therapy.”

Stohl says he prefers the BLyS approach, “for no other reason than Rituximab is what we call a chimeric monoclonal antibody, which means it is part human and part mouse. When you give it to a patient, there’s always a chance the body will mount an immune response against the mouse component and neutralize its therapeutic ability.”

Other clinical approaches now in trials hold significant hope as well. For instance, Horwitz has been working with a type of immune cell called the regulatory T cell, which plays a key role in controlling the activity of the immune system. He and his colleagues have devised a method to take T cells that have not yet differentiated into any specific type and biochemically persuade them to become regulatory T cells. In an article recently published in the Journal of Immunology, Horwitz and his group reported that a single injection of these induced regulatory T cells doubled the survival of mice that had developed a lupus-like syndrome. In addition, he reported that these same regulatory T cells can markedly prolong the survival of heart transplants from genetically mismatched mice who would otherwise tend to reject the hearts immediately. A summary of this work was reported in the online version of the journal Science.

The next step, Horwitz says, is a first-of-its-kind Phase I study of these induced regulatory T cells in human patients. Horwitz will be directing this study at the Clinical Center of the National Institutes of Health in Bethesda, Md. Immune cells will be collected from the patients’ blood, given the chemical cocktail that will turn them into regulatory T cells, and then returned to the patients in the hope that they will restore normal immune function and control lupus and possibly other autoimmune conditions.

“I think we’re on the threshold of a significant advance that, if it works, will certainly be much safer than the drugs available now,” Horwitz says.

Combined research

Through increased research into the immunogenetics of lupus, scientists are adding to their knowledge of the disease. “We and others have identified several chromosomal locations where genes that predispose to lupus are located,” says Jacob. What they have discovered is that there are multiple genes involved in the disease, but that no single gene is more important than the other genes. Jacob says, “Identifying all the genes will be tough, because there’s no single gene that is sufficient for development of lupus.”

Because of the highly complicated nature of the disease, he says, lupus researchers have realized that to speed the genetic understanding, “we need to collaborate more, rather than working in relatively small groups.” Jacob and other lupus scientists recently met to put together a realistic plan for collaboration with colleagues around the world. The good news, he says, is that investigators have come up with many new ways of finding the lupus genes, and “the technological developments in the last couple of years are just enormous. We’re using all of them to try to understand this specific disease.”

For example, by looking at the genes, “we already can say, in principle, what your chances are of developing kidney disease, one of the most devastating consequences of lupus,” notes Jacob. “For a new patient, knowing what is ahead gives you the option of possibly taking some precautionary measures.”
Jacob expects the genetic indications for progression of lupus will be even better defined in the next few years. Patients will be diagnosed differently, based on the genetic profile of their disease, he says. “It is clear that lupus is not one disease—that one form affects the skin, another affects the blood, and so forth,” he says. “We will be able to subdivide the disease into clinical subgroups with somewhat different etiologies and different genes and different treatment requirements.” As a result, he adds, “We are not going to talk about ‘lupus’ but ‘SLE-1’ and ‘SLE-2,’ subdivisions that will have specific consequences in terms of pathogenesis and prognosis.”

It also is clear that the genes themselves will not be the only pathways to curing this disease. “Even if we identify all the genes involved in lupus, it’s already clear that each gene is only moderately involved and has to interact with the environment. So there are questions about what triggers the genes to express lupus,” says Jacob. Environmental causes could range from sex hormones—it is thought estrogen plays a role in the development of lupus, which might explain why 80 percent of lupus patients are women—to ultraviolet light. “There may be viruses and bacteria, there may be a food component,” Jacob speculates. “We don’t know yet, and the gene-environment interaction will be an important factor in understanding the disease.”
Genetics also will have an important role in future lupus therapy planning. Pharmacogenomics—the understanding of how a person’s genes predisposes their reactions to certain medications—will make it easier to design optimal medical therapies. “The effect of the drugs will not be the same in every person,” he says. “It depends on their metabolism of the medications, which depends on certain genetic components of their liver or kidney.” For example, if someone metabolizes a drug quickly and efficiently, the medication is in the body for a much shorter time. “So we would have a case where we think a drug doesn’t work, but it may be that an increase in the dosage is needed for that specific person. In another person, the same dose may cause side effects.” This area is generating more interest among researchers, who hope to see clinical applications not far in the future.

If the past five to 10 years are any indication, the future has never been brighter for lupus patients. “The breakthrough really will come from the combined effort of all these research projects, which will give us a better understanding of what the disease is and how it can be treated,” Jacob says. Stohl and Horwitz agree: “We have never been more optimistic.”

For more information about lupus research at the Keck School of Medicine of USC, or to learn more about any of The Doctors of USC, call 1-800-USC-CARE (1-800-872-2273). For a free brochure, call the Lupus Foundation of America at 1-888-38-LUPUS, or visit their Web site at www.lupus.org.