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Systemic Lupus Erythematosus

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Description

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

Alternative Names

Corticosteroids; Immunosuppressant Drugs

Treatment for Severe SLE

Severe SLE is treated with corticosteroids, also called steroids, which suppress the inflammatory process, and help relieve many of the complications and symptoms, including anemia and kidney involvement. Oral prednisone (Deltasone, Orasone) is usually prescribed. Other agents 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 three 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 SLE patients 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. Adverse effects of prolonged use of oral steroids include cataracts, glaucoma, osteoporosis, diabetes, fluid retention, susceptibility to infections, weight gain, hypertension, capillary fragility, acne, excess hair growth, wasting of the muscles, menstrual irregularities, irritability, insomnia, and psychosis. 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.

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. It should be noted that 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 physician first, and if steroids are withdrawn, regular follow-up monitoring is necessary. Patients should discuss with their physician 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 the following:

Azathioprine (Imuran). Azathioprine has the lowest toxicity but is also less effective than others.
Methotrexate (Rheumatrex). This agent is helpful for patients with moderate SLE who do not have kidney insufficiency or very severe complications of SLE.
Cyclophosphamide (Cytoxan). Pulsed administration of cyclophosphamide is effective in improving long-term outcome in patients with kidney involvement. A combination with a pulsed corticosteroid may prove to be even better without posing a risk of additional side effects. High-dose cyclophosphamide can achieve remission in certain patients with severe SLE who are not improving with prednisone or other agents. Regimens using oral or low-dose IV cyclophosphamide in combination with other agents, notably azathioprine, are also reporting good results.Until recently, many physicians considered cyclophosphamide the gold standard of treatment.
Mycophenolate mofetil (CellCept) is now becoming the new gold standard. This immunosuppressant shows particular effectiveness for complications in the kidney causes less infection and diarrhea than other agents. Studies in 2003 and 2004 have shown that in patients with severe lupus nephritis, CellCept is as effective as daily cyclophosphamide and superior to monthly cyclphosphamide therapy. Patients may receive CellCept as an initial treatment, or may be given it once remission has been achieved by another drug first. One particularly effective approach entails initial treatment with cyclophosphamide followed by maintenance with CellCept.
Cyclosporine (Sandimmune) has been used for years, mostly for SLE associated with kidney involvement. High blood pressure is common, however, with this drug.

Other drugs commonly used include chlorambucil (Leukeran) and nitrogen mustard (Mustargen). One center reported that the use of these drugs reduced disease activity overall by 33%. Combining them with corticosteroids may allow the steroid to be withdrawn more quickly.

General Side Effects. The most frequent side effects of immunosuppressants are stomach and intestinal distress, skin rash, and mouth sores. Hair loss can occur. Over-suppression of the immune system can cause low blood cell counts and serious side effects, including anemia, menstrual irregularity, possible ovarian failure and permanent infertility, herpes zoster (shingles), liver and bladder toxicity, and an increased risk of cancer. Sterility in female patients may be averted 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). SLE patients have very low levels of dehydroepiandrosterone (DHEA). This is a mild male hormone that is produced in the fetus and stops at birth. Production then resumes at age seven, peaks at 30, and then declines slowly throughout life. Some evidence suggests that DHEA deficiencies may play a role in SLE. A few studies have now reported that DHEA supplements (e.g., prasterone) may reduce flare-ups and allow lower doses of corticosteroids in some patients. Although it does not appear to have benefits for severe SLE.

Note: DHEA is available over the counter and as with all so-called natural substances is not presently regulated.

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.

Warnings on Alternative and So-Called Natural Remedies

It should be strongly noted that alternative or natural remedies are not regulated and their quality is not publicly controlled. In addition, any substance that can affect the body's chemistry can, like any drug, produce side effects that may be harmful. Even if studies report positive benefits from herbal remedies, the compounds used in such studies are, in most cases, not what are being marketed to the public.

There have been a number of reported cases of serious and even lethal side effects from herbal products. In addition, some so-called natural remedies were found to contain standard prescription medication. Of specific concern are studies suggesting that up to 30% of herbal patent remedies imported from China having been laced with potent pharmaceuticals such as phenacetin and steroids. Most problems reported occur in herbal remedies imported from Asia, with one study reporting a significant percentage of such remedies containing toxic metals.

The following web site is building a database of natural remedy brands that it tests and rates. Not all are available yet (www.consumerlab.com).

The Food and Drug Administration has a program called MEDWATCH for people to report adverse reactions to untested substances, such as herbal remedies and vitamins (800-332-1088).

Blood Exchange Procedures

Plasmapheresis is a process in which the fluid part of the blood, called plasma, is removed from blood cells. The procedure involves first withdrawing 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.

Experimental Treatments

Leflunomide. Leflunomide (Arava) 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.

Nucleoside Analogues. Nucleoside analogs, including fludarabine (Fludara) and cladribine (Leustatin), target white blood cells and have been used to treat cancer and various autoimmune diseases. They are now under investigation for SLE and may prove to be very beneficial, particularly in combination with other agents, such as cyclophosphamide.

Biologic Agents. A number of biologic agents are under investigation that target molecules or compounds involved in the autoimmune inflammatory process. Because these agents affect very specific parts of the immune process, they cause far fewer adverse systemic effects than immunosuppressants do. An enormous effort in research and drug development is now focused on bringing biological agents to lupus patients.

Genetically designed antibodies, called monoclonal antibodies (MAbs.), are being investigated that target specific factors in the immune system believed to be important in the disease process. Rituximab (Rituxan), for example, blocks a receptor on B-cells, which helps to reduce autoantibodies. Very small early studies are promising. Other MAbs under investigation include IDEC-131 (which blocks a receptor called CD154), eculizumab (Alexion) (which blocks complement--immune factors critical for disease in the kidney), monoclonal antibodies that target the potent immune factor interleukin-10 (IL-10).

The most promising biologic agent, LJP 394, targets double stranded DNA (dsDNA) antibodies, which are important in the SLE disease process. It is not useful in all patients, but may be very effective in reducing flare-ups, including in the kidneys, in selective patients. One 2002 review reported that out of 12 biologic agent studied since 1999, this was the only drug that was showing clear-cut effectiveness. A decision regarding FDA approval of this drug is expected in 2004.

CD 40 is a receptor on a helper T-cell, an immune factor important in SLE. Initial research appeared promising, but drugs targeting CD40 ultimately failed in later stages.

Intravenous Immunoglobulin. Intravenous immunoglobulin (also called gamma globulin) is used against antiphospholipid antibodies. This treatment has helped improve fever, arthritis, and thrombocytopenia (reduction in blood platelets). It does not appear to relieve skin problems. In some cases SLE has worsened with this treatment.

Autologous Stem Cell Transplantation. Some patients with severe SLE 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 itself 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. Evidence suggests that these re-introduced stem cells do not repeat the original autoimmune errors. In some cases, SLE has remained inactive for more than two years. The procedure is still experimental, however, and has some serious risk.

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. A small study suggested it may have some benefits for lower 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 SLE patients at high risk for infection. Treating Infections. Lung infections need to be treated aggressively with antibiotics. (Note: Antibiotic drugs such as penicillin or the sulfa drugs may cause sensitivity rashes that can be confused with SLE rash.) Treating Lung Inflammation. It should be noted that 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 physician 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 agents. Bosentan (Tracleer) is the first oral agent approved for pulmonary hypertension. Sildenafil (Viagara) is also be used for this condition. Lung transplantation may be required.
Bleeding and Clotting Disorders	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.) 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 agent may be needed life long.
Kidney Disease	Drugs. Steroids are the most effective and rapid drugs for treating active kidney disease and for managing milder forms of nephritis. They also might be useful for initial treatment of proliferative nephritis in some cases, particularly women who want to become pregnant, although this is under debate. Pulsed administration of cyclophosphamide is the most effective drug at this time for proliferative lupus nephritis, and, in combination with a steroid, has been shown to control proliferative nephritis in between 60% and 90% of patients. Because of its effect on fertility, however, some physicians prefer avoiding cyclophosphamide and use a steroid alone as long as possible. Others are concerned, however, that delaying cyclophosphamide in severe nephritis can cause permanent kidney scarring. Regimens using oral or low-dose IV administration plus prednisone followed by azathioprine are show promise.High-dose cyclophosphamide is showing promise for achieving remission in patients with severe SLE. Mycophenolate mofetil, a newer agent, is proving to be helpful in treating kidney disease associated with SLE. It may have fewer side effects than other immunosuppressants. A 2002 study suggested it may be more effective than cyclophosphamide pulse therapy. Procedures. Kidney transplant or dialysis should be considered for SLE patients 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. Whether plasmapheresis is beneficial for SLE kidney disease is not yet clear.
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. Animal studies suggest that they may even have some protective effects on the SLE disease process itself, although one study reported no benefits on SLE patients, and some patients even deteriorated.
Heart Disease	The need for aggressive treatment of high blood pressure often accompanies kidney disease. SLE is also accompanied by high cholesterol levels, which also require diet and usually drug therapies. [See Well-Connected Reports #3 Angina and Coronary Artery Disease, #14 High Blood Pressure, Report #23 Cholesterol, and Report #43 Heart Healthy Diet.]

The spleen is an organ involved in the production and maintenance of red blood cells, the production of certain circulating white blood cells, as a part of the lymph system, and as a part of the immune system.