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By Michelle Meadows
Arletha Manlove, 41, of Kansas City, Mo., first noticed feeling different after having her first child. She experienced unusual fatigue, but thought maybe it was the adjustment of taking care of a new baby.
Everything was a struggle, she says. "It was a chore to take a shower and a chore to get dressed." She also had unexplained fevers, recurrent upper respiratory infections, and swelling and aching in her hands. "I would wake up in the morning with swollen fingers, and by the time I got dressed, the swelling would go down."
She had six miscarriages in five years and repeated bouts of uterine pain. "I had been to gynecologists, psychiatrists, psychologists, and general practitioners," she says. "I started to think maybe they were right; maybe it was all in my head."
After a devastating miscarriage in the second trimester of pregnancy, Manlove's uterine pain became even worse and her other symptoms continued. At her mother's urging, she agreed to try one more doctor, a fertility specialist. He diagnosed her with both endometriosis and lupus in 1990 and referred her to a rheumatologist, a doctor who has additional training in diagnosing and treating arthritis and other diseases of the joints, muscles, and bones.
Manlove recalls feeling better right away after taking a combination of three medicines: prednisone, Imuran (azathioprine), and Plaquenil (hydroxychloroquine). "I remember thinking: 'I'm back! This is what it's like to feel good,'" she says. "But then the side effects kicked in. I had horrible mood swings, and within a very short time, I went from 121 pounds to 200 pounds."
Under close monitoring from her doctor, Manlove went on to have a successful pregnancy and had a second child 12 years ago. She says she's learned that good communication between patients and doctors is essential for coping with chronic illness. "I was very good about letting him know about side effects and asking questions, and we have been able to cut back on some of the medications over time," she says. She's also made important lifestyle changes. "You can't expect your doctor to give you a pill and then everything will be OK," she adds.
Lupus experts recommend that people with lupus have regular medical appointments and take their medication as prescribed. Other recommendations include sunscreen use and limiting sun exposure to prevent flares, regular exercise to improve joint flexibility and muscle strength, good eating habits, and plenty of rest.
"I've learned to stop when I need to, and sometimes I take three short naps in a day," says Manlove, who works full time and is active with the Lupus Foundation of America (LFA) as a support group facilitator. A chronic illness can take a toll on family and friends, too, so it's important to seek out support.
"My husband believes me when I say I feel bad," she says. "Without his support, the stress of this journey would have been much harder. Not everyone is so lucky."
The body's natural defenses, called the immune system, protect us from viruses, bacteria, and other foreign invaders. But in people with systemic lupus erythematosus (SLE), the immune system can't tell the difference between foreign substances and the healthy cells and tissues.
"Instead of fighting infection, the immune system attacks 'self,' the person's normal tissues," says Michelle Petri, M.D., a professor of medicine and director of the Lupus Center at The Johns Hopkins University School of Medicine in Baltimore. Immune complexes then build up in the tissues, causing inflammation, tissue injury, and pain. "SLE can affect any organ system," Petri says, "but especially causes skin rashes after sun exposure, swollen joints, and kidney disease."
SLE, also commonly called lupus, is a chronic autoimmune disease that affects 1.5 million to 2 million Americans, according to the LFA. Nine out of 10 people who have it are women, and it mostly affects women of childbearing age, those between ages 15 and 44. But men, children younger than 15, and older people also get lupus. People of any race or ethnicity can develop lupus, but blacks, Hispanics, Asians, and American Indians are at increased risk.
There is no cure for lupus, but, in most cases, the disease can be managed. Because of better detection and early treatment, between 80 percent and 90 percent of people with lupus can look forward to a normal lifespan, according to the LFA.
"Although the overall outlook has improved, it is a disease that must be monitored very carefully," says David Isenberg, M.D., academic director of rheumatology at University College London. "It has a major effect on quality of lives, and a smaller, but significant, number of people still die from it."
Maribel Ramirez, 43, was diagnosed with lupus in 1989 and started a support group in the Houston area in 1995 for Spanish speakers who have the disease. "I see people dying, and it's very difficult," she says. "We are desperate for better treatments." Ramirez has suffered damage to her lungs, kidneys, and heart. In 1994, she had a stroke due to vasculitis, a condition in which blood vessels become inflamed. "I worry about the disease and all the medications that I've been taking for so long," she says.
There are effective drugs that decrease inflammation and suppress the immune system in people with lupus, but these drugs also can lead to damaging side effects. Doctors and patients have to weigh carefully the benefits and risks of treatment. Isenberg likens treating patients with lupus to putting them on a fence between two fields.
"One side represents the effects of the disease, and the other represents the side effects of treatment," he says. For example, people with lupus are at increased risk for developing hardening of the arteries that can cause a heart attack or stroke. The risk is due partly to having lupus and partly to taking corticosteroids, which decrease inflammation caused by the disease.
Another challenge, says Petri, is that there are no treatments for two common complaints of lupus patients--fatigue and memory loss. Ramirez says she once had to pull off the freeway and call a friend for help because she was lost, even though she was very close to home.
Researchers are looking for lupus treatments that are safer and more targeted, but the uniqueness of the disease poses challenges for drug development. The exact cause of lupus is unknown. The disease varies in intensity. And the symptoms are wide-ranging, sometimes involving multiple organs. Symptoms also tend to come and go, with active periods, called flares, and quiet periods when the disease is in remission.
In March 2005, the Food and Drug Administration released a draft guidance for industry on testing drugs for lupus in clinical trials. The guidance includes a general discussion of outcomes and measurements of disease activity, as well as claims that the agency may be willing to approve if they are supported by substantial evidence. "This guidance is an important step in stimulating new drug development for lupus treatment," says Acting FDA Commissioner Dr. Lester M. Crawford. "We are intensely interested in this area."
The most common symptoms of lupus are skin rashes, extreme fatigue, arthritis, unexplained fevers, and kidney problems. According to the LFA, about 40 percent of people with lupus have a rash that spreads across the nose and over the cheeks in the shape of a butterfly, called the malar rash.
"Because lupus can affect any organ, the disease can look different in different people," says David Wofsy, M.D., chief of rheumatology at the San Francisco Veterans Affairs Medical Center and professor of medicine at the University of California, San Francisco. Inflammation in one person might lead to multiple organ damage, whereas another person might have just occasional joint pain. "There are many people who never encounter the life-threatening manifestations of the disease," Wofsy says.
When lupus is severe, such as with serious kidney damage, the symptoms are more obvious to a physician. But, in most cases, people experience mild symptoms, which can make the illness hard to diagnose. Lupus also may develop gradually. "In the hands of someone knowledgeable about lupus, it can be easy to diagnose," Wofsy says. "But it's not uncommon to hear that someone with lupus went to several doctors before being diagnosed or was misdiagnosed." Experts say that sometimes, it can take a couple of years to figure out what's going on.
"In mild forms of the disease, symptoms usually present in a confusing manner," Wofsy says. "Somebody comes in who is young with a variety of nonspecific symptoms, and a doctor may not be thinking about lupus. The person might complain about feeling tired in the afternoons or about feeling achy. A doctor could think that these symptoms might be due to stress or depression, or a virus."
One of the most frustrating things for someone with lupus is being sick, but feeling like nobody believes you, Ramirez says. "People think you're lazy or crazy, or both," she says. "You can also look nice and healthy, even though you feel very bad."
Before she was diagnosed with lupus, Ramirez battled mysterious symptoms for 10 years. She had five miscarriages, and later found out that women with lupus have higher rates of pregnancy loss. She also had unexplained skin rashes, anemia, pain in her legs and arms, urinary tract infections, kidney infections, fevers, mouth sores, and overwhelming fatigue.
In an unpublished study done in 1999, Isenberg and his colleagues asked 100 lupus patients what they were most worried about regarding their illness. "Their biggest concern was fatigue," Isenberg says. "They were worried about sleeping all night and still being exhausted in the morning or about feeling too tired to pick their children up from school or to do other things that they want to do."
As a former police officer and member of the military, Tony Chisholm, 46, of Fall City, Wash., was used to being active. Feeling wiped out from lupus sent him into a deep depression. "I just couldn't get out of bed," he says. "But nothing would show up on a physical exam."
He also has had bouts of flu symptoms, swelling around the eyes, joint pain, and chest pain. "Sometimes, the symptoms last for four months, and then I might go four more months without any problems," he says.
It was a photograph that finally helped Chisholm get some answers. In 1997, he and his family went to Great Britain for vacation and met another couple. The couple mailed Chisholm a photo from the trip. "The red butterfly rash across my face was plain as day," he says. "My wife insisted that I go to the doctor." After looking at the photo, the doctor ran tests for lupus. "Before that, I hadn't been diagnosed with anything else, except maybe hypochondria."
Early detection of lupus is important to lower the chance of organ damage and other complications. Doctors rely on a patient's report of symptoms, a medical history and exam, and blood and urine tests. "Lupus can lower blood counts and affect kidneys, causing protein and blood in the urine," Petri says. Doctors also may do skin or kidney biopsies, in which tissue is removed and examined for signs of autoimmune disease.
A commonly used test for lupus is the anti-nuclear antibody (ANA) test, which looks for autoantibodies that are reacting against the nucleus, also known as the command center, of the body's cells. "Most people with lupus have an elevated ANA, though a few rare patients have a negative ANA," Petri says. But a positive ANA isn't enough to confirm lupus. "Twenty percent of healthy women can have a positive ANA," she says. The ANA also detects other autoimmune diseases, including Sjögren's syndrome, scleroderma, and rheumatoid arthritis.
So if the ANA test is positive, more specific testing is used to confirm a lupus diagnosis. Doctors test for complement components, a group of proteins in the blood that help destroy bacteria. Low complement levels can be associated with lupus. Doctors also do blood tests for antibodies to DNA and for other cell nuclear components. Two specific tests for lupus are the anti-double-stranded DNA (anti-dsDNA) antibody test and the Smith antibody (anti-Sm) test.
"Lupus is an unpredictable disease, but certain antibodies help to make some predictions," Petri says. For example, people with anti-dsDNA or low complement are more likely to develop kidney disease, she says. And some women with lupus have a syndrome in which antiphospholipid antibodies cause blood clots. This syndrome is associated with miscarriages, strokes, and deep vein thrombosis.
The American College of Rheumatology says that to be diagnosed as having lupus, a person should meet at least four of the following clinical and laboratory criteria:
How and why lupus develops is not understood. Experts say the illness probably results from a complex mix of hormonal, genetic, and environmental factors. The hormone estrogen likely plays some role, which may explain why more women than men have the disease. And lupus involvement may worsen before menstruation and during pregnancy.
Genetics may partly explain racial and ethnic differences in the incidence and severity of lupus. Blacks not only have a higher incidence of lupus, but they tend to develop it earlier and experience more severe disease.
To look for patterns, researchers are studying families in which one or more members have lupus. Lupus sometimes runs in families. About 5 percent of children develop lupus if a parent had the disease, according to the LFA. Research shows that if an identical twin has lupus, the other twin is more likely to have or develop the disease than a non-identical twin would be.
Petri says the environmental factors that may trigger lupus in genetically susceptible people include ultraviolet light, infections such as the Epstein-Barr virus, some drugs such as antibiotics in the sulfa group (Bactrim, Gantrisin, and Septra), and echinacea. Some people experience drug-induced lupus caused by extensive use of medications. The symptoms are similar to SLE but usually go away when the medications are stopped. Drugs most commonly connected with drug-induced lupus are hydralazine for hypertension and procainamide for irregular heart rhythms.
"It's believed that somehow the wrong immune system meets the wrong insult," says Joan Merrill, M.D, medical director of the LFA and head of the Clinical Pharmacology Research Program at the Oklahoma Medical Research Foundation. "Healthy people may inherit protective genes," Merrill says. "It's as if you shuffle a deck of cards and lupus patients get the bum deal."
In 2003, the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) announced that scientists had discovered a genetic "signature" in some people with SLE who develop life-threatening complications, such as blood disorders, central nervous system damage, and kidney failure. Fourteen of the thousands of genes studied were linked to a subset of SLE patients with severe disease. The 14 genes are known as the interferon (IFN) expression signature. The genes are turned on by IFN, a family of proteins that have a role in regulating immune responses.
The Alliance for Lupus Research created the International SLE Genetics Consortium, a group of researchers who are working to find the genes that put people at risk of lupus. Consortium members will contribute genetic material from all over the world in the hope of finding more targeted treatment.
Scientists have also recently discovered that people with lupus may have a genetic defect in a cellular process called apoptosis. Normally, special white blood cells work to clear dying cells from the body. But if there is an abnormality in this process, the lingering cell debris may trigger the production of autoantibodies that attack healthy tissue.
Researchers continue to investigate abnormalities in T cells and B cells of mice and humans with lupus. These white blood cells control immune response.
Doctors take an individualized approach to treatment, depending on the nature and severity of the disease. Sometimes, a combination of drugs is needed. Through early treatment, doctors want to prevent flares, to treat them when they occur, and to lower the risk of organ damage. At the same time, a key goal is minimizing the side effects of medication.
Many people with lupus need only Tylenol (acetaminophen) or non-steroidal anti-inflammatory medications (NSAIDs), such as aspirin, Advil, and Aleve. These medications control pain, fever, and inflammation. Risks of NSAIDs include stomach or bowel irritation. And when prescription NSAIDs are used chronically, there appears to be a possibility of an increased risk of heart attacks and strokes.
For serious problems such as kidney inflammation, corticosteroids may be needed. Examples are prednisone, prednisolone, and cortisone. These are either applied to the skin or taken by pill or injection. Side effects include weight gain, puffy cheeks, thinning hair, acne, mood swings, and trouble with concentration.
Taken over long periods, corticosteroids also can raise blood pressure and cholesterol levels, as well as increase the risk of infections, diabetes, cataracts, and osteoporosis. "As many as 90 percent of SLE patients require prednisone, which has side effects even at low doses," says Petri. These drugs shouldn't be stopped suddenly.
Another category of drugs that has worked in some lupus patients is called anti-malarials. They work to prevent flares, new kidney disease, and blood clots, Petri says. Experts say that Plaquenil (hydroxychloroquine sulfate) is the one most commonly used. The risk of side effects is low, but, in very rare cases, anti-malarials can cause changes in the retina. People who take anti-malarials are advised to get regular eye exams. More common side effects include nausea, diarrhea, and blurry vision.
Some people who experience severe flares also may need immunosuppressive or chemotherapy drugs, which are given by mouth or infusion. Examples are Imuran (azathioprine), Cytoxan (cyclophosphamide), and Sandimmune and Neoral (both cyclosporines). These drugs suppress the immune system and help limit organ damage. But they also make it harder to fight off infection, and all raise the risk of anemia and cancer. Other side effects are nausea, vomiting, hair loss, osteoporosis, and ovarian failure.
"Our biggest challenge is the toxicity of the drugs--trying to control the pathological immune response without doing considerable harm," says Wofsy. "In some cases, the treatment is worse than the disease. We always have to ask: "Are we making the person susceptible to infection? Are we causing osteoporosis? What other harm are we doing?"
Progress has been made in preventing and treating some of the secondary problems related to lupus, Wofsy says. For example, people taking corticosteroids may also require other medications to help prevent bone loss.
"We do a much better job of controlling hypertension, preventing osteoporosis, and treating infections with antibiotics in patients with lupus than we used to do," Wofsy says. "But the advances with lupus have not yet come in the form of treatments that reverse the immunologic problems that are at the heart of the disease."
The FDA hasn't approved any drugs specifically for lupus in nearly 40 years. Lupus experts say that the disease has not attracted enough of an investment from drug companies. It also can be difficult to develop data that prove a drug's safety and effectiveness because lupus is such a highly variable disease. And the FDA can approve a drug only after determining that the benefits outweigh the risks in a comparative study.
One concern in drug development is that a drug may prove beneficial for one organ but may turn out to damage another. There are also challenges with assessing effectiveness in a disease in which symptoms come and go in cycles. And because lupus develops gradually, a patient may develop a new symptom that could be due to the disease. Or it could be a side effect of medication.
According to the FDA, creative trial design is needed to overcome these challenges. The agency's recently released guidance discusses the need for clear clinical endpoints to show what's being measured in trials and what the outcome means for both short- and long-term results.
Promising approaches under investigation for lupus include hormone modification drugs, immunosuppressive drugs that are more selective, and new biologics. Researchers are especially looking for lupus treatments that can minimize the use of corticosteroids.
In people with lupus who have severe kidney disease, CellCept (mycophenolate mofetil), a drug approved for organ transplants, has helped some of them. Of the biologics under study for lupus treatment, some block B cells and other parts of the immune system to both increase effectiveness and lower side effects. Examples include Rituxan (rituximab), made by Genentech Inc. of South San Francisco, Calif., and Lymphostat-B (belimumab), made by Human Genome Sciences Inc. of Rockville, Md.
Researchers are also investigating stem cell transplantation. In this process, stem cells are selected from the person's blood or bone marrow through a procedure known as leukopheresis. The stem cells are stored outside of the body. The individual receives potent systemic drugs or biologicals in an attempt to destroy the immune system cells that are attacking normal tissue, and is then reinfused with his or her stored stem cells. The goal is to destroy the cells that may be responsible for initiating inflammation, and to stimulate new cells that will no longer be programmed to attack normal tissues.
According to the National Institutes of Health (NIH), participating in clinical trials for new treatments can give people a more active role in their health care, access to new treatments before they are widely available, and a sense of making an important contribution to medical research. The NIH recommends that people find out about the benefits and risks of any clinical trial they are considering, including information on why researchers believe that an experimental treatment holds promise. In order to achieve the most reliable results, clinical trials have inclusion and exclusion criteria to determine who can participate.
Wofsy calls this an exciting time for lupus research. "There are more active clinical trials for lupus than ever before, and there are a number of promising ideas," he says. "They won't all work, but there is reason to hope that we will find treatments for lupus that are safer and more effective."
For more information about clinical trials studying lupus treatments, talk with your doctor or contact www.clinicaltrials.gov
Lupus Foundation of America
2000 L St., N.W., Suite 710
Washington, DC 20036
(202) 349-1155
National Institute of Arthritis and Musculoskeletal and Skin Diseases
1 AMS Circle
Bethesda, MD 20892
(877) 226-4267
American College of Rheumatology
1800 Century Place, Suite 250
Atlanta, GA 30345
(404) 633-3777