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What is Lupus? Peng Thim Fan, MD Clinical Professor of Medicine University of California at Los Angeles School of Medicine DEFINITION "Lupus" is the Latin word for wolf and it refers to the severe rash on the face of patients that looks like animal bites. The term "lupus" is now more often used for a disease that affects the entire body called systemic lupus erythematosus (SLE). However, there are several forms of lupus besides SLE including chronic cutaneous (discoid) lupus that does not affect other organs, drug-induced lupus that completely goes away when the offending drug is removed, neonatal lupus that affects newborns, and a relatively mild disease called subacute cutaneous lupus syndrome. TYPES OF LUPUS Discoid lupus is a skin disease that affects the face, scalp, ears and arms. It causes considerable scarring and may produce increased or decreased pigment in the central areas of the rash. It may cause permanent hair loss usually in patches. This condition exists as either an isolated skin disease or it may be one of the disease manifestations of SLE. It is more commonly seen in African-Americans than Caucasians. SLE is the classic example of a systemic autoimmune disease. It can affect every organ system but most commonly it damages the skin, joints, blood components and the kidney. No two persons with SLE will have exactly the same symptoms and there is a wide spectrum ranging from relatively mild symptoms to a severe life-threatening disease. Not all symptoms are present at the onset of the disease and it is typical for new organ systems to be affected over a period of months or years. The severity of SLE waxes and wanes and there may be periods when the disease is completely quiet (remission) and other times when the symptoms are active (flare). The disease affects women 9 times more frequently than men. It typically starts after puberty usually in the 20s and 30s. The skin is one of the most commonly affected organs in SLE and the classic sign of this disease is the butterfly or malar rash. It is a flat or slightly raised reddish rash most prominently on the cheeks but sparing the region near the crease of the nose. Sun sensitivity is common and it causes a raised red rash that typically involves the V-region of the neck and the forearms and other areas exposed to the sun. Discoid rashes (described above) are commonly seen in SLE. SLE can also cause a diffuse thinning of the scalp that is not scarring. Sometimes the blood vessels in the skin become inflamed and occluded and this causes bleeding under the skin, hives or damage to the tissue resulting in shallow ulcers or rarely gangrene of a digit. These conditions are called cutaneous vasculitis. Canker sores in the mouth and nose called aphthous ulcers are a common feature of SLE. They are typically painless and may also affect the gum margins and the tongue. Joint aching, pain, swelling and restricted movement are very common signs of SLE. The arthritis may cause deformity in the fingers that resembles rheumatoid arthritis but the bones are rarely damaged. Tendons can become inflamed and rarely they can break spontaneously. The muscles may be painful and tender when they are inflamed; prolonged inflammation can cause muscle weakness and wasting. The kidney is affected in about 50% of Caucasian and 75% of African-American SLE patients. It has the most serious impact on survival (see below). Its effects are not immediately felt by the patient but gradually with leakage of protein and blood and damage to the filtration function of the kidney the patient feels lethargic and bloated, with edema in the legs, elevated blood pressure, and marked weight gain. The lung lining can become inflamed leading to accumulation of fluid and pleuritic pain lasting days to weeks. The heart lining can also become inflamed causing chest pain and shortness of breath. Involvement of the brain commonly causes confusion, memory problems and headaches. More serious problems include stroke, seizures, bleeding in the retina and psychosis. The spinal cord and nerves can be inflamed causing numbness and tingling and weakness in the arms and legs. Mild anemia is the most common abnormality in the blood and is linked to the chronic illness of SLE. Once in a while a more severe anemia is caused by actual breakdown down of red blood cells due to an antibody against the red cell membrane (hemolytic anemia). Similarly antibodies can attack platelets reducing the platelet count and causing spontaneous bleeding. A complete shut-down of the bone marrow (aplastic anemia) is the most serious life-threatening outcome but it is fortunately rare. Table 1 lists the more common symptoms of SLE and the frequency of their occurrence. Table 1
Drug-induced lupus erythematosus affects 15,000 to 20,000 people annually in the United States. The symptoms are directly caused by certain drugs taken by the patients and they resolve completely when these drugs are stopped. The most common drugs are hydralazine, a drug used to treat high blood pressure, and procainamide, a drug used to suppress irregular heart rhythms. Many other drugs are associated with drug-induced lupus including chlorpromazine, isoniazid, methyldopa, quinidine and sulfasalazine. The symptoms include joint and muscle aches and pains, joint swelling, inflammation of the heart and lung linings with fluid accumulation, and fever. Neonatal lupus affects newborns whose mother may have SLE or may have no symptoms but carry certain antibodies that can cross the placenta and damage the fetus. These are the maternal anti-Ro (anti-SSA) antibodies and they can cause a transient rash or permanent damage to the conduction system of the infant's heart causing heart block. CAUSE Both genes and the environment play critical roles in the onset of lupus. Recent studies show that multiple genes are involved in 95% of patients with less than 5% having a single gene that play a determining role. The disease is caused by an array of antibodies that are inappropriately produced against normal tissue components. Some of these antibodies may directly damage tissue such as red cells or brain tissue. Other antibodies may form complexes with their targets (antigens) and these antibody-antigen complexes, called immune complexes, circulate in the blood stream and deposit in various tissues such as the kidney and the lining of various organs such as the joints, lungs and heart. Once deposited the immune complexes cause inflammation and damage to the organ. Some antibodies may cause abnormal clotting resulting in occluded vessels that can cause strokes, deep vein thrombosis and phlebitis, and miscarriages due to blocked blood supply to the placenta. Some genes that are linked to lupus are important in the clearance of immune complexes from the blood stream and others with the regulation of the immune system and the inflammatory response. However the environment also plays a critical role since only 25% of identical twins of patients with lupus develop the disease. The incidence in fraternal twins who do not share an identical genetic make-up is only 9%, similar to the 10% seen in first-degree relatives of lupus patients. African-Americans and African-Caribbeans are affected more often than Caucasians (1/250 versus 1/400). Asians and Hispanics may also have a higher incidence but incidence rates have not been done. African-Americans, Asians and Hispanics appear to have more severe disease. The striking female predominance of lupus may be related to the stimulatory effect of estrogen on the immune system. Many environmental factors have been identified. The best established risk factor is ultraviolet light exposure. Both UV-B and UV-A rays are implicated. The damage to skin cells triggers more antibody production. Increasing estrogen exposure may be the reason why oral contraceptives and estrogen replacement at menopause have been linked to the onset of lupus. Earlier pregnancies may be a potential trigger for the same reason. The effect of smoking on the immune response is complex and current studies give conflicting results. Hair dyes and hair straighteners have been linked to the onset of SLE but two recent studies fail to show any association. Penicillin and Sulfa drugs are implicated in causing lupus flares while a drug called minocycline, used to treat acne, may induce the onset of lupus. In a monkey model, alfalfa sprouts provoked a lupus-like illness but no foods have been implicated in human studies. A number of viral infections are thought to trigger lupus including Parvovirus B19, Hepatitis C, Epstein-Barr Virus, and cytomegalovirus. Vaccinations are safe and effective in lupus patients and routine immunization is encouraged. However, there are several recent reports linking Hepatitis B vaccination to the onset of SLE. More studies need to be done in this area. DIAGNOSIS In 1997 the American College of Rheumatology (ACR) formulated the current classification criteria for SLE. Eleven clinical and laboratory criteria are selected and four criteria are required for the classification of SLE. Even though these are not diagnostic criteria but are meant for investigators doing studies on SLE to have a uniform database they have been widely adopted for diagnosis. These criteria are shown on Table 2. Table 2
The ANA or antinuclear antibody is the most sensitive test for the diagnosis of lupus. If it is absent then there is a less than 1% chance that a patient has SLE. Patients with isolated discoid lupus may have a negative ANA but they seldom go on to develop symptoms in other organs. A positive ANA however does not automatically imply that lupus is present. The test is only meaningful when interpreted in the context of the presence of the clinical features that suggest SLE. It should never be interpreted in isolation since many other conditions may be associated with a positive ANA including autoimmune thyroid disease, hepatitis of any cause, parasitic infections such as malaria and viral infections such as infectious mononucleosis. Elderly people have a high incidence of positive ANA (8%) and even young healthy blood donors may have a positive ANA. Some patients with fibromyalgia and chronic fatigue syndrome have symptoms that superficially resemble lupus and the reported incidence of ANA is 12-23% in these patients. The majority of these patients do not develop lupus when followed for several years. Several other auto-antibodies are highly suggestive of SLE. These include anti-DNA and anti-Sm. Low serum complement components C3 and C4 are also useful tests both to diagnose lupus and to follow patients since the levels often go up during remission and go down during a flare. Complement is consumed in a state of immune activation and the level therefore drops with increased disease activity. TREATMENT SLE is a disease that evolves over time. There are periods of remission and exacerbation and organ damage can occur early or late. Kidney disease is particularly silent and insidious and the damage may progress over time. Treatment is directed at stopping inflammation and it needs to be aggressively pursued to stop organ damage. However the current drugs that we use to treat lupus have significant toxicity and we need to use them wisely so as not to over-treat or under-treat. Lupus patients need to be taught to get adequate rest during periods of increased disease activity since fatigue is a prominent feature of disease flares. However a regular exercise program is also important since it improves muscle and cardiac conditioning and actually reduces fatigue. All patients should avoid unnecessary sun exposure and use sunscreens with an SPF of greater than 15. Wearing long sleeves and broad-brimmed hats helps. A well-balanced nutritious diet is important. Avoid food fads that may cause nutritional deficiencies. Calcium intake of 1500mg daily is important in patients taking prednisone since this drug causes osteoporosis. While fish oils are reported to lower disease activity the large amount needed to accomplish this effect is unrealistic. DRUG TREATMENT Non-steroidal anti-inflammatory drugs (NSAIDs) are useful for relieving pain and reducing fever and inflammation. They are used for treating fever and for the joint aches and pains and swelling. They may also relieve pleuritic pain and pericarditis. The main toxicity is stomach distress and a risk for ulcers and bleeding. Conventional NSAIDs like ibuprofen, naproxen and diclofenac are fairly well tolerated. Antimalarial drugs include hydroxychloroquine, chloroquine and quinacrine. These drugs are effective for cutaneous lupus and for the joint symptoms. Recent long-term studies show that they may prevent major disease flares. They also lower cholesterol. These drugs need to be taken for several months to show a beneficial effect. They are well tolerated except for mild nausea, bloating and diarrhea. Dizziness, skin rashes and discoloration are less common side effects. The most important complication is the deposit of the drug in the retina causing blind spots and diminished night vision. Fortunately these complications are rare when the doses used are kept low. An ophthalmologist should be consulted after a patient has taken an antimalarial drug for 6 months and visits twice a year are recommended during long-term therapy. Current recommendation is to continue these drugs during pregnancy. Corticosteroids are the most important drugs used in the treatment of SLE. They are very effective in stopping inflammation and suppressing the abnormal immune response. High doses (prednisone 60mg daily) may be needed to suppress severe disease manifestations such as kidney and brain involvement. The dose is then tapered as clinical and laboratory improvement occurs. Alternate day corticosteroid treatment is not effective when the disease is still active but may be useful to maintain a state of remission since it lowers the risk of side effects. Certain complications are particularly distressing to patients such as weight gain, facial swelling, increased bruising and a "buffalo hump." They add to the depression that may be part of the disease or a complication of corticosteroids. Major long-term complications include osteoporosis with an increased risk for hip and vertebral fracture and lipid deposits in the blood vessels due to elevated cholesterol leading to an increased risk for heart attacks. High dose prednisone kept for prolonged periods causes hypertension, cataracts and diabetes and may lead to an interruption of blood supply to the hips causing a collapse of the hip bone (avascular necrosis). Methotrexate is helpful in treating skin and joint symptoms of lupus and allows the more rapid reduction of prednisone to reduce side effects. It is not effective for kidney disease. Methotrexate may cause oral ulcers and stomach distress. It has considerable potential for liver toxicity so that liver function tests need to be performed every 4 weeks and alcohol use should be curtailed. Rarely methotrexate may cause inflammation and scarring of the lungs. Immunosuppressive Agents. These include azathioprine, cyclophosphamide, cyclosporine and mycophenolate mofetil. They all work by suppressing the immune response. Cyclophosphamide is the best documented for efficacy but also the most toxic of the alternatives. It is less toxic given as a monthly intravenous infusion rather than daily as an oral drug. Nevertheless it increases the risk for lymphoma, leukemia and bladder cancer and when combined with high-dose prednisone it increases the risk for life-threatening infections. Ovarian failure is another well-recognized complication. Cyclosporine may reduce disease activity and protein leak from the kidneys. It is difficult to use since it can also cause kidney damage and hypertension and may even precipitate a gout attack. Azathioprine has been used less and less since its benefit for kidney disease is hard to prove. We now use it occasionally after a course of successful treatment with cyclophosphamide since it may stabilize the disease with long-term use and it is much less toxic than cyclophosphamide. Mycophenolate mofetil has been shown to suppress kidney disease in SLE and it is a useful alternative to cyclophosphamide since it does not cause ovarian failure and has overall fewer side effects. It may still cause nausea and vomiting and oral herpes. Hormonal Treatment. Dehydroxyepiandrosterone sulfate (DHEA) is a weak male hormone that is effective in improving the sense of well-being and reducing fatigue. It allows less prednisone to be used and thereby protects against osteoporosis. Danazol is a synthetic steroid that is helpful for treating low platelet count and hemolytic anemia. Experimental drugs include bromocriptine, dapsone, thalidomide and clofazimine. Biologic agents that have a potential for altering the body's reaction to DNA and other stimuli that trigger lupus include anti-CD40 ligand and LJP 394. Recently two drugs, etanercept and infliximab, have been shown to be dramatically effective in treating rheumatoid arthritis. There are theoretical reasons for caution in their use in SLE since they may potentially make the disease worse. Some of the most severe cases of lupus are now treated with bone marrow transplantation and reconstitution. The hope is that the immune cells that cause the disease will be eliminated and the newly reconstituted bone marrow will not sustain the disease activity. Results to date are conflicting.  PROGNOSIS The outcome of SLE has improved in reports from different parts of the world. Five-year survival was 51% in 1954 and 97% in 1981. Recent 10-year survival exceeded 90% in some centers. Part of the improved statistics may be related to the larger number of cases of mild lupus that are now recognized sooner. Physicians are more judicious in their use of corticosteroids and immunosuppressive medications and infections are detected sooner and treated more aggressively. We are learning to prevent and treat corticosteroid-induced osteoporosis and to lower cholesterol and other lipids and manage blood pressure elevation better. Kidney damage is still a leading cause of reduced survival. A large study from Europe shows that survival at 5 years has reached 95% for all lupus patients but kidney disease is the main cause of reduced survival in that study. It is hoped that better patient education and compliance and the development of new, more effective and less toxic drugs will lead to steady improvement in survival and the quality of life.  |
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