Fw: Progress on lupus: New clarity for a baffling disease

[Guest guest]

----- Original Message ----- From: Kathi

Sent: Monday, September 30, 2002 1:36 AM

Subject: Progress on lupus: New clarity for a baffling disease

Progress on lupus: New clarity for a baffling disease Although lupus patients continue to face a difficult path, physicians who treat them see reasons for hope. By Kathleen F. Phalen, AMNews correspondent. Oct. 7, 2002. The Latin root of the word "lupus" means wolf. That makes it an appropriate name for this mysterious disease. For those who have it, it means that their body's own killer instinct has turned inward, mistaking their own organs and tissues for prey -- attacking and devouring them. Formally known as systemic lupus erythematosis, lupus is an inflammatory autoimmune roller coaster of flares and remissions. It is a disease of more questions than answers; of veiled origins and misdiagnoses; and of less than ideal treatments. "There was no fundamental treatment change in 30 years," says Israeli Jaffe, MD, a rheumatologist at Columbia Presbyterian Eastside in New York. Even so, there's a possibility. "There may be new things on the horizon," Dr. Jaffe says. "Today patients are diagnosed earlier. That's good. It used to be routine to end up on dialysis. The quality and duration of life have improved." Still, the Centers for Disease Control and Prevention recently reported a 60% increase in lupus deaths since 1979 -- a statistic scientists discuss cautiously, fearing its misinterpretation. "Outcomes tend to be worse for minority populations. I caution that what they've documented needs to be confirmed," says Manzi, MD, MPH, associate professor of medicine and epidemiology at the University of Pittsburgh School of Medicine and co-director of the Lupus Center of Excellence at the University of Pittsburgh Medical Center. "Are there other confounding factors such as socioeconomic or genetic differences?" Most agree that lupus presents a baffling riddle with hidden answers and no cure. But with the completion of the human genome, new treatments in trial, identification of new markers and earlier diagnosis, the lupus puzzle now has some promising pieces. "We certainly never want to give false hope, but we are at an all-time peak for lupus research. There is cause for great optimism on a variety of fronts," says ph Ahearn, MD, associate professor of medicine at the University of Pittsburgh School of Medicine and co-director of the Lupus Center of Excellence at the University of Pittsburgh Medical Center. "Ultimately a vaccine. ... Never getting the disease -- that would be the Holy Grail here." Unraveling threads Here's a quick review of what is known. Lupus is a chronic, multisystemic inflammatory autoimmune disease often affecting the skin, joints, blood and kidneys. About 90% of patients are young women between 15 and 45. About 70% of lupus cases are SLE, the most severe and potentially fatal form of the disease. Other types include pediatric, discoid and drug-induced. It's not clear how many people have lupus, but estimates range from 500,000 to 4 million. Women are five times more likely to die of the disease than are men. And according to the CDC, in the past 20 years, there has been a 70% increase in the number of African-American women dying from complications of lupus. First identified by its characteristic raised red facial blotches, some say lupus got its name because the rash resembled a wolf bite. Doctors have known about lupus for centuries, but it was not until the 1950s that autoimmunity was associated with the disease. For those with lupus, the immune system is not able to distinguish antigens from its own cells. As a result, the system begins making autoantibodies. There is speculation that environmental factors -- viral or bacterial infections, UV light, prescription heart medication, antipsychotic drugs, some antibiotics, stress and certain hormones -- may be the cause. Some researchers have even fingered the Epstein-Barr virus, mononucleosis, Lyme disease and anti-DNA antibodies. In August, researchers at the University of Florida, Gainesville, published findings in the journal of Arthritis and Rheumatism, identifying pristane, a hydrocarbon oil, as an environmental trigger in mice. Some investigators point to a genetic predisposition. Several areas of chromosome 1 and the Fas gene have been linked with lupus. "There are human families with a Fas mutation and autoimmune disease like lupus," says Ralph C. Budd, MD, a rheumatologist and director of the immunology program at the University of Vermont, College of Medicine in Burlington. How does that relate to lupus? "Cell death of autoreactive lymphocytes may not occur normally in the absence of one or more death receptors. In the case of Fas, in its absence or with a nonfunctional mutant, both humans and mice accumulate such autoreactive lymphocytes," he says. "Fas triggers a signal pathway that ultimately leads to degradation of many cell components, essentially autodigestion." Dozens of other genes are currently under investigation, but scientists still do not know which genes are associated with a greater likelihood of getting the disease. Clarifying a chameleon Lupus symptoms are often unpredictable and transient, differing from patient to patient. They can change, mimic and confuse. Many patients endure chronic pain and fragile health for years before knowing why. In a study by the Lupus Foundation of America, more than half of lupus patients went at least four years and saw three or more doctors before obtaining a correct diagnosis. For some it's worse: 12, 13 or 14 doctors before a diagnosis of lupus is made. Misdiagnosis is less likely for patients with the classic rash and joint pain, Dr. Jaffe says. "The disease can hit any one of a number of organ systems, and that can determine how it presents," he says. "It is a complicated diagnosis." Some common symptoms include persistent profound fatigue, joint pain and inflammation, skin rashes, extreme sensitivity to sunlight, mental confusion, chronic low-grade fever, Reynaud's-like extremities, mouth ulcers and hair loss. "Patients can be arthritic, psychotic, have low white blood cell count, low platelets. Sometimes they have profound malaise," Dr. Jaffe says. There is no single test for lupus, although the FDA just approved a new screening tool projected to identify about 20% of those missed with older methods. The color-coded test -- anti-SR protein antibody assay -- identifies SR proteins, a helpful biomarker for lupus since a majority of patients produce antibodies to SR. According to the FDA, this test can identify 50% to 70% of lupus patients who react positively to SR proteins. Scientists at the University of Pittsburgh are in the process of licensing a complement-based assay for diagnosis and monitoring. "In pilot testing, it performed significantly better than current gold standard tests such as ANA, serum C3, serum C4, and anti-double-stranded DNA," says Dr. Manzi. "In preliminary studies, the sensitivity, specificity, positive predictive value and negative predictive value of this assay ranged from 86% to 96% for a diagnosis of SLE versus healthy controls and patients with other autoimmune and inflammatory diseases." According to the National Institutes of Health, initial screening includes a complete blood count, liver and kidney screening panels, laboratory tests for specific auto-antibodies -- antinuclear antibodies, ANA -- a syphilis test, urinalysis, blood chemistries and erythrocyte sedimentation rate. But using the ANA alone is not adequate, says Terry MD, director of the division of rheumatology at Saint Louis University School of Medicine. "It is nonspecific, and about 20% to 30% of healthy females are positive for ANA." In addition to a medical history, lab work and a positive ANA, a high-titer anti-DNA antibody or anti-Sm antibody are important indications of lupus. "The anti-DNA, double-stranded nuclear protein is a more refined test," Dr. Jaffe says. At times, biopsies of the skin or kidney can support a diagnosis of SLE. A sanguine future? Right now, treatments are not ideal. "Patients could die from the side effects," Dr. says. Most common are NSAIDS, antimalarials such as Plaquenil (hydroxychloroquine sulfate) or chloroquine, steroids, or cytotoxic agents such as Imuran (azathioprine) or Cytoxan (cyclophosphamide). Until recently there has not been a specific drug for lupus. But a handful of pharmaceutical companies are beginning to file new drug applications with the FDA, says Klippel, MD, scientific director of the Alliance for Lupus Research. "We're hopeful that within the next decade we'll see lupus drugs." Some drugs in the pipeline include LJP 394, an investigational drug in phase III trials under development by La Jolla Pharmaceutical Co., San Diego. It is a selective B lymphocyte immunomodulator for the treatment of lupus renal disease. Genelabs' Prestara, formerly Aslera, was approved in September by the FDA contingent on an additional clinical trial. Studies observed a positive effect on bone mineral density for women with mild to moderate SLE. ion Pharmaceuticals Inc. is in phase II trials with the drug Eculizumab (5G1.1), a C5 inhibitor, for the treatment of lupus nephritis. Human Genome Sciences is initiating a phase I clinical trial for LymphoStat-B, which works by binding to BLyS, a B Lymphocyte Stimulator that may be a sensitive marker of lupus disease activity. The drug will inhibit BLyS stimulation of B cell development and proliferation. Although it's gotten some negative press, stem cell transplant shows great promise for lupus patients, says Ann E. Traynor, MD, associate professor of medicine at Northwestern Memorial University Hospital in Chicago. "I am really frustrated. The information is not getting to rheumatologists," she says. "There is a misunderstanding about its safety. ... There is no question of the natural incidence of death in the population we are treating. But no one has died, with the exception of one patient who relapsed." Northwestern Memorial Hospital performed the country's first stem cell transplant for lupus about five years ago. Since then, it has performed more than 22. In the procedure, a patient's own stem cells are removed, and the immune system is deliberately destroyed with chemotherapy. Immediately after an escalated Cytoxan dose, patients are infused with stem cells, Dr. Traynor says. When the aberrant lupus lymphocytes are out of the picture, stem cells multiply and rebuild a healthy immune system. Only available for patients who have failed other treatments, stem cell transplants are now entering phase III, multicenter trials. "Patients have gone from critically ill on 20 to 30 meds a day to nothing," Dr. Traynor says. "One point I would like to make -- doctors who have had a patient die of lupus since the protocol was available need to strongly examine if they referred, and if not, why not. "My feeling now is there is no reason to die of lupus anymore." Back to top. ADDITIONAL INFORMATION: SLE diagnostic criteria At least four criteria should be present either simultaneously or serially during any period to sustain a diagnosis of systemic lupus erythematosus. Malar rash, often in a butterfly configuration, across nose and cheeks Discoid rash A reaction to sunlight more severe than sunburn Frequent development of mouth or nose ulcers Pain, tenderness or swelling in two or more joints Pleurisy or pericarditis Kidney disorder marked by excessive protein or cellular casts in the urine Nervous system disorders such as seizures or psychotic behavior not attributed to drugs or metabolic dysfunction Blood disorders such as hemolytic anemia, leukopenia, thrombocytopenia Immunologic disorder marked by positive anti-double-stranded DNA test, positive anti-Sm test, positive antiphospholipid antibody such as anticardiolipin or false-positive syphilis test (about 70% of lupus patients have a false-positive) Positive antinuclear antibody test Source: Alliance for Lupus Research, American College of Rheumatology, Lupus Foundation of America Back to top. Death toll 1,406 deaths from lupus reported in 1998, up 61% from 1979. 22,861 lupus deaths documented between 1979 and 1998. 14.5% of arthritis deaths are from systemic lupus erythematosus. 70% increase in death rates from SLE reported between 1979 and 1998 among black women 45 to 64. 36.4% of SLE deaths are among people between 15 and 44. 5 times higher death rate reported for women than men; three times higher for blacks than for whites. Source: Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention Back to top. In the pipeline A range of promising new lupus treatments and research findings are bringing hope to physicians and patients who face this disease. Among the highlights: In late August, the Food and Drug Administration cleared a new screening test for lupus -- the first significant diagnostic breakthrough in more than four decades. It is expected to pick up 20% of systemic lupus erythematosus cases that previously fell through the cracks. LJP 394, a selective B lymphocyte immunomodulator developed by La Jolla Pharmaceutical Co. for the treatment of lupus renal disease, is now in phase III trials. The pharmaceutical preparation of the hormone DHEA (GL701, Aslera) by Genelabs Technologies was stalled by the FDA in 2001 because of interpretation of efficacy and safety data. But on August 28, the FDA approved Genelabs' new drug application for Prestara (prasterone), formerly Aslera, contingent on the successful completion of an additional clinical trial. Studies observed a positive effect on bone mineral density for women with mild to moderate SLE. Northwestern Memorial Hospital in Chicago performed the country's first stem cell transplant to treat lupus five years ago. Multicenter trials are now entering phase III. Early findings show promise with some patients in total remission. ion Pharmaceuticals Inc. is in phase II trials with the drug Eculizumab (5G1.1), a C5 inhibitor, for the treatment of lupus nephritis. Studies show that the B Lymphocyte Stimulator (BLyS) may be a sensitive marker of lupus disease activity. Human Genome Sciences is initiating a phase I clinical trial for LymphoStat-B, which works by binding to BLyS and inhibiting its stimulation of B cell development and proliferation. Researchers at University of Vermont, Burlington, are examining the signal pathways of the Fas gene and its inhibitor cFLIP in murine models of autoimmunity. Scientists have identified new information about BAFF (B cell activating factor), a key protein for B lymphocyte development and the receptor protein (BAFF-r) -- a key target associated with abnormal B lymphocyte activity. Researchers are studying the role of cytokines in lupus. Researchers are looking at the role of bacteria and viruses. Back to top. Holding the line on lupus flares For Sherry Barber, symptoms started when she was 24. She'd fall asleep at her desk; she couldn't walk a mile to her Clarendon, Va., Metro stop; her hands ached and she was plagued by chronic pain. Still, she blamed her busy life and two jobs. "It was easy at the time to dismiss the symptoms," says Barber, now 29. "I thought I had carpal tunnel, and I was tired because I was working so much." But the pain intensified, and even simple tasks were impossible. Within four months she was in the hospital. That's when Barber was diagnosed with lupus. "Women my age are frequently dismissed as hypochondriacs," she says. "It takes so long and so much work to get a doctor to believe us." After a couple of flares and treatments that depressed her, made her hair fall out and caused her to become bloated, she is now participating in a clinical trial. The drug, LJP 394, was developed by La Jolla Pharmaceutical Co. and is designed to target B cells and reduce renal flares. Patients get an IV injection once a week. "It seems to have the ability to suppress B cells," says Wiseman, PhD, La Jolla Pharmaceutical founder. "And results show a 70% reduction in lupus flares. ... We hope to finish phase III this year and with good data go to the FDA." Right now Barber is stable, but because the trial is blinded she does not know if she's actually getting the drug. Why did she participate? "I hope we can get more people to understand the disease," she said. Present treatments are like trying to kill a fly with a nuclear bomb, says Mahesh Krishnan, MD, MPH, a nephrologist with Virginia Nephrology Group in Fairfax, Va., which is involved in the LJP 394 trial. "The advantage of LJP is that it is like a cruise missile strike targeting the B cell, which produces antibodies." http://www.ama-assn.org/sci-pubs/amnews/pick_02/hlsa1007.htm