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• Highlights
• Introduction
• Causes
• Risk Factors
• Symptoms
• Complications
• Diagnosis
• Treatment
• Treatment for Cutaneous and Mild SLE
• Treatment for Severe SLE
• Lifestyle Changes
• Resources
• References

Systemic lupus erythematosus

Description

An in-depth report on the causes, diagnosis, treatment, and prevention of lupus.

Alternative Names

Lupus

Treatment for Severe SLE

Severe SLE is treated with corticosteroids, also called steroids, which suppress the inflammatory process. Steroids can help relieve many of the complications and symptoms, including anemia and kidney involvement.

Oral prednisone (Deltasone, Orasone) is usually prescribed. Other drugs include methylprednisolone (Medrol, Solumedrol), hydrocortisone, and dexamethasone (Decadron).

Some people need to take oral prednisone for only a short time; others may require it for a long duration. An intravenous administration of methylprednisolone using "pulse" therapy for 3 days is proving useful for flare-ups in the joints. Combinations with other drugs, particularly immunosuppressants, may be beneficial.

Regimens vary widely depending on the severity and location of the disease. Most patients with SLE can eventually function without prednisone, although some may have to choose between the long-term toxicity of corticosteroids and the complications of active disease.

Side Effects of Long-Term Oral Corticosteroids. Unfortunately, serious and even life-threatening complications have been associated with long-term steroid use. The bone-thinning condition osteoporosis is a common and particularly severe long-term side effect of prolonged steroid use. Medications that can prevent osteoporosis include calcium supplements, parathyroid hormone, alendronate etidronate, risedronate, or hormone replacement therapy in post-menopausal women. Vitamin C and E may help reduce the risk of cataracts.

Other side effects associated with prolonged use of oral steroids include:

• Cataracts
• Glaucoma
• Diabetes
• Fluid retention
• Susceptibility to infections
• Weight gain
• High blood pressure
• Acne
• Excess hair growth
• Wasting of the muscles
• Menstrual irregularities
• Irritability
• Insomnia
• Psychosis

Withdrawal from Long-Term Use of Oral Corticosteroids. Long-term use of oral steroid medications suppresses secretion of natural steroid hormones by the adrenal glands. After withdrawal from these drugs, this so-called adrenal suppression persists and it can take the body a while (sometimes up to a year) to regain its ability to produce natural steroids again. There have been a few cases of severe adrenal insufficiency that occurred when switching from oral to inhaled steroids, which, in rare cases, has resulted in death.

No one should stop taking any steroids without consulting a doctor first, and if steroids are withdrawn, regular follow-up monitoring is necessary. Patients should discuss with their doctors measures for preventing adrenal insufficiency during withdrawal, particularly during stressful times, when the risk increases.

Immunosuppressant Drugs

Drugs known as immunosuppressants are often used, either alone or with corticosteroids for very active SLE, particularly when kidney or neurologic involvement or acute blood vessel inflammation is present. These drugs suppress the immune system by damaging cells that grow rapidly, including those that produce antibodies. About a third of patients take immunosuppressants at some point in the course of the disease.

Specific Immunosuppressants. The most common immunosuppressants are:

• Cyclophosphamide (Cytoxan) used to be considered the gold standard of treatment for lupus kidney disease (lupus nephritis). Cyclophosphamide is given intravenously and is sometimes used in combination with corticosteroids or other drugs. It has been used for lupus since the 1970s. Side effects are very severe and include nausea, vomiting, hair loss, infertility, and infections.
• Mycophenolate mofetil (CellCept) is now becoming the new standard. Many recent studies have shown that CellCept works better than cyclophosphamide and causes far fewer severe side effects (diarrhea is the main side effect). Unlike cyclophosphamide, it is taken by mouth. A 2005 study reported that 23% of patients treated with CellCept for lupus kidney disease went into remission after 6 months, compared with 6% of patients treated with cyclophosphamide. Experts are now recommending CellCept as a first-line treatment for newly diagnosed patients with mild or moderate lupus kidney disease. It may not be appropriate for patients with kidney failure or rapidly progressing kidney disease.
• Azathioprine (Imuran) has the lowest toxicity, but is also less effective than others.
• Methotrexate (Rheumatrex) may be helpful for patients with moderate SLE who do not have kidney insufficiency or very severe complications of SLE.
• Cyclosporine (Sandimmune) has been used for years, mostly for SLE associated with kidney involvement. High blood pressure is common, however, with this drug.

The most frequent side effects of immunosuppressants include:

• Stomach and intestinal problems
• Skin rash
• Mouth sores
• Hair loss

Serious side effects of immunosuppressants include:

• Low blood cell counts
• Anemia
• Menstrual irregularity
• Early menopause
• Ovarian failure
• Infertility
• Herpes zoster (shingles)
• Liver and bladder toxicity
• Increased risk of cancer

A 2005 study suggested that short-term hormone replacement therapy is safe for women with SLE and does not increase the risk of disease flares. Sterility in female patients may be avoided by administering pulsed doses at the time of menstruation. In general, immunosuppressants should not be used alone unless corticosteroids are ineffective or inappropriate. Grapefruit juice has an enzyme that may enhance the effects of some immunosuppressants

Hormone Treatments

Dehydroepiandrosterone (DHEA). Dehydroepiandrosterone (DHEA) is a natural steroid hormone that is produced by the adrenal glands and converted into estrogen and androgen. Some evidence suggests that DHEA deficiencies may play a role in SLE. Although DHEA is sold as a dietary supplement, and has been proclaimed as a cure for a wide variety of ailments, there is little scientific evidence to support most of these claims. In addition, because natural supplements are unregulated, there is no guarantee of quality control.

However, the synthetic equivalent of DHEA, prasterone, is being investigated as a potential treatment for SLE, and several clinical trials have indicated promising, although mixed, results. In a 2004 randomized, double-blind, placebo-controlled trial of women with active lupus, prasterone significantly improved or stabilized lupus symptoms and reduced disease flare-ups. Women who received prasterone also experienced reductions in total cholesterol and triglyceride levels. A 2005 trial of women with SLE found that prasterone prevented bone loss and increased spinal and hip BMD, but additional trials have failed to confirm the benefit. Women in both trials were also taking other SLE drug treatments, such as prednisone. Prasterone is still in the drug development stage and it is not clear when, or if, it will be commercially available.

Danazol. Researchers are also investigating the use of danazol (Danocrine), a male hormone. One study reported long-term remission of thrombocytopenia when it was used with the corticosteroid prednisone. As with DHEA, side effects include male characteristics such as acne and hair growth.

Plasmapheresis

Plasmapheresis is a process in which the fluid part of the blood, called plasma, is removed from blood cells. The procedure involves first taking blood from the patient. The plasma, which contains the inflammatory antibodies and other immunologically active substances, is discarded and replaced with other fluids. The blood is then returned. Plasmapheresis is not useful for routine management of patients but may have some benefits for patients who do not respond to standard treatments or in specific cases, such as lupus patients with hemolytic anemia.

Investigational Treatments

Monoclonal Antibodies (MAbs). A MAb is a laboratory-made protein that targets specific immune cells, such as B cells. B cell over-activation has been identified as a key component of the lupus disease process.

• Epratuzumab is being investigated for treatment of moderate to severe lupus. The FDA granted the drug Fast Track status (a designation that speeds up the approval process for promising drugs that address an unmet need). Phase III trials began in 2005.
• Belimumab (Lymphostat-B) has also received Fast Track status. Phase II trial data has shown promising results, and the drug is entering Phase III trials.
• Rituximab (Rituxan), a lymphoma cancer and rheumatoid arthritis drug, has shown good results in reducing B cells and improving lupus symptoms. It is currently in Phase II/III trials. However, in December 2006 the FDA warned of several cases of progressive multifocal leukoencephalopathy (PML) in patients with lupus who took this drug. PML is a life-threatening brain infection. Some patients developed PML as late as 12 months after their last dose of rituximab. Two patients with lupus died from PML.

Leflunomide. Leflunomide (Arava), a disease-modifying anti-rheumatic drug, blocks autoimmune antibodies and reduces inflammation in patients with rheumatoid arthritis. The drug is now being used for lupus with good results, but requires further study.

Abetimus . Abetimus (Riquent) is being developed to treat lupus patients with kidney disease (lupus nephritis). It is currently in Phase III trials.

Autologous Stem Cell Transplantation. Some patients with severe lupus have achieved at least short-term remission after undergoing autologous transplantation of stem cells and high-dose drug therapy to suppress the damaging immune factors. Stem cells are the early forms for all blood cells in the body. An autologous transplant is one in which marrow or blood cells used are the patient's own. (The advantage to an autologous transplant is that the patient's own cells are not at risk for rejection by the immune system.)

The procedure first removes the cells from the patient, who then receives high-dose immunotherapy. The stem cells are then reintroduced. Early results of small studies are encouraging, especially for treatment of antiphospholipid syndrome. Evidence suggests that these re-introduced stem cells do not repeat the original autoimmune errors. A 2006 study in the Journal of the American Medical Association indicated that autologous stem cell transplantation can help boost the immune system and lead to remission. Patients in the study had severe lupus that was resistant to standard treatments. Results were long-lasting. Researchers calculated that patients had a 50% chance of remaining disease-free after 5 years.

UVA-1 Phototherapy. A promising treatment uses ultraviolet A-1 (UVA-1) radiation, which are long UVA wave lengths that do not promote sunburn and may actually block inflammatory immune factors. Small studies have suggested that UVA-1 phototherapy may have some benefits for lowering disease activity in SLE.

Treatments for Some Complications of Systemic Lupus Erythematosus
Infections, Inflammation, or Hypertension in the Lungs	Preventive Measures. Immunizations with inactive viruses and preventive antibiotics should be considered for patients with SLE at high risk for infection. Treating Infections. Lung infections need to be treated aggressively with antibiotics. However, antibiotic drugs such as penicillin or the sulfa drugs may cause sensitivity rashes that can be confused with SLE rash. Treating Lung Inflammation. While inflammation of the lung (pneumonitis) resembles pneumonia, it is not an infection but is a result of the autoimmune process. This condition needs to be treated with corticosteroids or immunosuppressants, but only if the doctor is sure infection is not present. Treating Pulmonary Hypertension. Pulmonary hypertension is very serious. Drugs known as prostacylins -- which include epoprostenol, iloprost, and treprostinil -- are standard drugs. Bosentan (Tracleer) is the first oral drug approved for pulmonary hypertension. An inhaled iloprost formulation (Ventavis) was approved in 2004. Sildenafil (Viagra) is also be used for this condition. Lung transplantation may be required.
Bleeding and Clotting Disorders	Antiphospholipid Syndrome and Clotting Disorders. Hydroxychloroquine or aspirin may help prevent blood clots in women with antiphospholipid syndrome (APS). (Aspirin does not appear to be protective in men with who carry the autoantibodies responsible for APS.) In patients who have experienced blood clots, treatment with the anticoagulant warfarin (Coumadin) is advisable. This blood-thinning drug may be needed life long. Scientists are investigating other treatment options including autologous stem cell transplantation. This procedure involves removing stem cells from a patient’s blood or bone marrow and then introducing them back into the patient. The procedure has shown promise in studies for treating lupus-associated APS, but it is still experimental. Excess Bleeding from Thrombocytopenia (Drop in Blood Platelets). Treatments that may be effective for thrombocytopenia include combinations of a corticosteroid and either danazol (a male hormone) or the antimalarial hydroxychloroquine. Immunosuppressants or intravenous immunoglobulin IgG may be helpful in some patients. Surgical removal of the spleen may be advisable if bleeding disorders are a serious problem, but this option should be considered carefully, because the spleen provides one line of defense against infection. (Abnormal spleen function, in any case, appears to be fairly common in SLE.)

Kidney Disease

Drugs. Mycophenolate mofetil (CellCept), a newer drug, is proving to be helpful in treating kidney disease associated with SLE and has fewer side effects than other immunosuppressants. It is taken by mouth. Recent studies suggest that it works better than cyclophosphamide. CellCept may be best for patients with mild-to-moderate lupus kidney disease and may not be appropriate for patients with advanced kidney disease. Intravenous cyclophosphamide is the most effective drug at this time for proliferative lupus nephritis, and, in combination with a steroid, has been shown to control advanced kidney disease in between 60 - 90% of patients. It has severe side effects including nausea, vomiting, hair loss, and infertility. Steroids are also useful for treating active kidney disease and for managing milder forms of nephritis. Procedures. Kidney transplant or dialysis should be considered for patients with SLE with severe kidney damage. For unknown reasons, SLE does not generally recur in the transplanted kidneys. Studies are conflicting, however, over whether SLE transplant patients have higher organ-rejection rates than other kidney-transplant recipients. Both transplantation and dialysis have potentially serious complications. Plasmapheresis. It is not clear if plasmapheresis is beneficial for SLE kidney disease.

Osteoporosis

Treatments for osteoporosis include calcium, vitamin D, bisphosphonates, parathyroid hormone, and selective estrogen-receptor modulators (SERM). SERMs, such as tamoxifen (Nolvadex), raloxifene (Evista), and tibolone (Livial), are of particular interest in SLE because they have been designed to produce the benefits of estrogen without some of its adverse effects, such as hormone-related breast cancer. [See In-Depth Report #18: Osteoporosis.]

Heart Disease

The need for aggressive treatment of high blood pressure often accompanies kidney disease. SLE is also accompanied by high cholesterol levels, which requires diet changes and drug therapies. [See In-Depth Reports #3: Coronary artery disease; #14: High blood pressure; #23: Cholesterol; #43: Heart healthy diet.]

• Review Date: 1/2/2007
• Reviewed By: Harvey Simon, MD, Associate Professor of Medicine, Harvard Medical School; Physician, Massachusetts General Hospital.

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