ARTHRITIS
September 15, 2001

Systemic Lupus Erythematosus (SLE): New Treatments for Mild and Severe

Elena Peeva, M.D., M.Sc., Gisele Zandman-Goddard, M.D., and Peter Barland, M.D.
SLE sufferers should not take sulfonamide drugs.
Dr. Peeva is an Instructor of Medicine and Attending Physician at the Albert Einstein College of Medicine and Attending Physician at Montefiore Medical Center, NY, and Dr. Zandman-Goddard is an Instructor of Medicine and Attending Physician at Sheba Medical Center, Israel.


Mild SLE
Not long ago, systemic lupus erythematosus (SLE) was thought to be fatal in nearly all cases. Few SLE patients lived much longer than five years after being diagnosed. In recent decades, thankfully, the outlook for those with SLE has brightened. According to the latest figures, more than 80% of those diagnosed with SLE will survive more than ten years and many will enjoy a normal life span.

We have made dramatic progress against SLE because potent new antibiotics are available to combat and prevent the serious and unusual infections that may complicate SLE. In addition, more effective corticocosteroids and immunosuppressive drugs now enable treatments for the various kinds of organ damage that SLE can cause. A good example is end stage renal disease, a potentially fatal kidney condition, which can be managed with improved dialysis and kidney transplant techniques. Finally, better diagnostic tests are helping doctors detect SLE earlier and identify milder forms of SLE that in the past would have been missed.

Many mild SLE sufferers are young women whose symptoms are limited to arthritis-like joint pain, episodes of fatigue, sunlight-induced skin rashes, mild anemia and problems with blood platelet regulation. Mild SLE sufferers never develop the life-threatening severe form of the disease. That is the good news. The bad news is that for those with mild SLE, the side effects of conventional treatments, such as long term corticosteroid and immunosuppressive drugs, outweigh their benefits. In this article, we will look at some of the current treatment choices for those with mild SLE, with particular attention to ground-breaking, new treatments that involve manipulating the body's own hormones.


General Treatments and Precautions
While only a minority of those with mild SLE develop photosensitivity (problems tolerating sunlight), it is still a good idea for anyone with SLE to avoid excessive exposure to the sun. It is also makes good sense to use sunscreens with an SPF of at least 25. For women practicing birth control, oral contraceptives should be avoided because studies have shown that the estrogen they contain can cause SLE to flare up. These studies have not found any problem with the lower doses of estrogen used in hormone replacement therapy for menopausal women, but researchers are continuing to investigate this question.

Some people with SLE have a tendency to form blood clots. While doctors have a good test for identifying those at the greatest risk, most doctors recommend that SLE sufferers take a daily low dose aspirin, which acts as a mild blood thinner.

Another common problem associated with SLE is hypertension (high blood pressure). If you have SLE, it's especially important to control hypertension so as to avoid serious damage to kidneys and arteries. All of the standard drugs for high blood pressure have been used in patients with SLE and they seem to be equally effective and safe. An exception is sulfonamide drugs, which can cause allergic reactions in SLE sufferers and should be avoided or used with caution.
Drugs that Treat Particular SLE Symptoms
Nonsteroidal Anti-inflammatory Drugs (NSAIDs)
Joint pain and muscle pain are classic early symptoms of mild SLE. Normally, the treatment of choice for these is non-steroidal anti-inflammatory drugs (NSAIDs). Some of these drugs can cause side effects such as gastritis, ulcer and bleeding. A newer class of drugs called COX 2 selective agents has the advantage of being less likely to cause these particular side effects. Unfortunately, however, because COX 2 drugs can cause kidney problems and make high blood pressure worse, they should be used very carefully in those who have kidney or blood pressure problems.

Anti-malarial Agents
The malaria drug hydroxychloroquine (HCQ) has proven to be a good treatment for both the muscle and bone pain of SLE as well as the rashes and other sunlight-induced skin problems caused by SLE. An added benefit of HCQ is that it lowers serum cholesterol, helping those long-term SLE sufferers who might be likely to develop atherosclerosis (narrowing of the arteries). HCQ may also help control the fibromyalgia symptoms commonly seen in people with mild SLE. HCQ does have side effects, particularly affecting vision. Though other anti-malarial drugs, such as chloroquine and Atabrine®, have been used in the treatment of rheumatoid arthritis, we do not have much information on their effectiveness with SLE.

Corticosteroids
Low dose corticosteroids are often effective in treating the musculoskeletal inflammation, fatigue, occasional low-grade fever and other symptoms of mild SLE. The problem with these drugs is that their continued use over many years is likely to cause osteopenia, or loss of bone mass. For this reason, most SLE sufferers on corticosteroids are also given calcium and vitamin D.

Emerging Therapies: Hormone Manipulation
There is a growing body of scientific evidence linking female hormones (for example, estrogen) to lupus and other autoimmune disorders. In lupus, the ratio of females to males with the disease is about 9:1 during childbearing age. At menopause, the numbers drop markedly. Menopause, of course, involves changes in the amount of estrogen produced by the female body. This has led some to speculate that estrogen levels within the body may have something to do with lupus. Further supporting the idea that female hormones play a role in SLE is the fact that female patients with SLE often have abnormal estrogen levels, while male lupus patients tend to have decreased serum testosterone levels.

Sixteen to 26% of women with SLE have increased levels of the hormone prolactin which stimulates milk production in the breast. Studies of lupus, using animals, have shown that increasing estrogen and prolactin levels worsens lupus, while many male hormones seem to have beneficial effects. This suggests that controlling prolactin production through drugs may be a promising new treatment for SLE. As for male hormones, decreased levels of testosterone and dehydroepiandrosterone (DHEA) have been observed in male lupus patients and there is some evidence that increasing the levels of these hormones may slow down the disease.


Severe SLE
Someone is said to have severe or life-threatening SLE when the disease has damaged or destroyed one of the body's organ systems. Typical examples include severe kidney disease; neuropsychiatric symptoms such as personality change, epilepsy and psychosis; major blood disorders; and problems with the lung, heart and pancreas. The standard treatment for these patients has been high doses of corticosteroids, sometimes together with immunosuppressive drugs (such as azathioprine or cyclophosphamide). These drugs are often effective, but there is a down side. Long-term use of these powerful chemotherapy drugs can cause side effects such as high blood pressure, hyperglycemia (elevated blood sugar), osteoporosis, cataracts, weight gain and emotional instability. The immune system suppressant, cyclophosphamide, has further side effects such as infertility and birth defects.

The shortcomings of these conventional therapies for severe SLE have led researchers to look for new drugs that zero in on particular aspects of the immune system, rather than suppressing the entire immune response, which, for obvious reasons, can be very dangerous. Because explanations of how these new therapies work is very technical, patients with severe SLE should discuss these therapies with their doctor. Here are the names of the therapies and the new drugs.


New Cytotoxic Agents
Cytotoxic agents such as cyclophosphamide, azathioprine and cyclosporine are only used for severe SLE, as they can cause many serious side effects. Other new drugs in this class are mycophenolate mofetil (MMF), fludarabine and cladribine.

Stem Cell Restoration
The immune system is generated from cells in the bone marrow known as stem cells. Many researchers believe that dysfunctional stem cells may be the cause of SLE. If they are right, then destroying these disease-producing stem cells and replacing them with healthy stem cells might be a way to stop or eliminate SLE. With stem cell therapy, doctors target bone marrow with radiation or various drugs and then transplant healthy stem cells. While few of these procedures have been done, the early results appear promising.

Inhibition of the Idiotypic Network
Intravenous immunoglobulin (IVIg) is a substance that has the ability to regulate lupus activity. IVIg has also been reported to be an effective treatment for arthritis, thrombocytopenia and the neuropsychiatric mainifestations of lupus.

Other new experimental therapies target various stages of the immunoinflammatory response. Therapies you may hear about include inhibition of costimulatory pathways, manipulation of the complement system27 and manipulation of cytokines.


Summary
Systemic lupus erythematosus, whether mild or severe, is a disease that varies greatly from person to person. No two patients present with the identical picture. Any treatment, therefore, must be tailored to the individual.

It should be remembered that people who have a mild form of the disease may experience flare-ups or even develop severe SLE, for which treatments may be quite different. The key to treating mild SLE is detecting these flare-ups before they have caused irreversible organ damage and while they are still treatable. This means careful and close monitoring. Fortunately, there are emerging forms of treatment for mild SLE, such as hormonal therapy, which are likely to further improve the lives of those with this chronic disease.

Conventional therapies for severe SLE, such as corticosteroids and immunosuppressants, have serious side effects and are far too broad in their effects on the body. As we have obtained a better understanding of the regulation of the immune system, however, we have been able to develop new, more targeted therapies for SLE, likely to be more effective and less toxic than the conventional treatments. However, they represent only the first steps on a journey that promises to lead to safer and more effective SLE treatments.
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