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Treatment of Systemic Lupus Erythematosus: An Update

MICHELLE PETRI, M.D., M.P.H., Johns Hopkins University School of Medicine, Baltimore, Maryland
Systemic lupus erythematosus predominantly affects women and is more common in blacks. Although survival rates have improved, over one half of patients with systemic lupus erythematosus have permanent damage in one or more organ systems. Arthritis and cutaneous manifestations are most common, but renal, hematologic and neurologic manifestations contribute largely to morbidity and mortality. Treatment approaches emphasize using a combination of drugs to minimize chronic exposure to corticosteroids.

Systemic lupus erythematosus has fascinated physicians for almost a century and remains the prototypic autoimmune
disease. Although it is estimated to affect one out of every 1,000 white persons and one out of every 250 black women from 18 to 65 years of age, systemic lupus erythematosus is certainly not the most common example of autoimmunity encountered by physicians. Positive antinuclear antibodies are extremely common in the general population, occurring in as many as 10 to 20 percent of young women. Localized autoimmune disorders, such as autoimmune thyroid disease, are also much more common than systemic lupus erythematosus.
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Because systemic lupus erythematosus is a chronic disease, patients require extensive health education in terms of their responsibility in managing their condition. This requires compliance with office visits and medications, and lifestyle modifications to reduce or prevent associated problems such as hyperlipidemia, obesity and hypertension. An ongoing partnership between the primary care physician and the rheumatologist is essential in the long-term management of patients with systemic lupus erythematosus.

Etiology and Pathophysiology

Because of the deleterious effects of long-term The cause of systemic lupus erythematosus remains elusive. corticosteroid use, treatment of systemic lupus Predisposing factors include genetic factors (certain types of human erythematosus now increasingly emphasizes leukocyte antigens and null complement alleles), environmental factors use of steroid-sparing drugs such as azathioprine and cyclophosphamide. including sun exposure, some drugs such as sulfa antibiotics, and hormonal factors. Systemic lupus erythematosus is more common in blacks than in whites and is obviously more common in women than in men (ratio: 9:1).
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The pathophysiology of systemic lupus erythematosus is not completely understood. The production of abnormal antibodies by B cells remains the hallmark sign of lupus erythematosus. Some of the autoantibodies, such as antidoublestranded DNA and anti-Smith, are very specific for systemic lupus erythematosus. Others, including anti-RNP, antiRh and anti-La, are also present in other autoimmune diseases. Whether the B cells themselves are intrinsically abnormal is a subject of current research. One of the underlying defects in systemic lupus erythematosus may center on apoptosis, or programmed cell death. In patients with systemic lupus erythematosus, cellular antigens exposed during apoptosis incite an immune response.
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Diagnostic Considerations
The diagnosis of systemic lupus erythematosus requires a thorough history, a physical examination and laboratory tests, including a complete blood cell count, chemistry panel and urinalysis. Serologic tests such as antinuclear antibodies, anti-Rh , anti-La, anti-RNP, anti-Sm, anti-dsDNA and antiphospholipid antibodies are helpful to confirm the diagnosis. The American College of Rheumatology (ACR) has developed criteria to classify patients with a diagnosis of systemic lupus erythematosus for research studies (Table 1). Four of the 11 criteria must be met. These classification criteria are often helpful clinically, especially since they emphasize the multisystemic nature of the disease.
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TABLE 1 Classification Criteria for Systemic Lupus Erythematosus*

Before a patient can be classified with systemic lupus erythematosus, at least four of the following 11 disorders must be present: Malar rash Discoid rash Photosensitivity Oral ulcers Arthritis Serositis Renal disorder Neurologic disorder Hematologic disorder Immunologic disorder Antinuclear antibodies

Systemic lupus erythematosus is a disease that continues to evolve over time. Thus, a patient who presents with skin and joint disease remains at risk for renal disease even after having lupus erythematosus for decades. Continued monitoring, even when the disease appears to be clinically inactive, is essential. It is very important that a partnership be established between the primary care physician, the rheumatologist and any other physicians caring for the patient. This partnership has been summarized in the guidelines from the ACR.
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*--According to information from the American College of Rheumatology. Adapted with permission from Tan EM, Cohen AS, Fries JF, Masi AT, McShane DJ, Rothfield NF, et al. The 1982 revised criteria for classification of systemic lupus erythematosus. Arthritis Rheum 1982; 25:12717.

The major challenge for physicians managing patients with lupus erythematosus is to treat the active phase without allowing the treatment itself to cause long-term damage. This intent has led to a major change in treatment approach, with the goal of limiting corticosteroid exposure, if possible. As a result, physicians are now less reluctant to turn to immunosuppressive drugs such azathioprine (Imuran) or cyclophosphamide (Cytoxan). Treatment for active systemic lupus erythematosus differs, depending on the organ systems involved and disease severity. Current treatment often includes a combination of drugs.

Musculoskeletal Manifestations
At some point, over 90 percent of patients with systemic lupus erythematosus have polyarthralgias or polyarthritis because of the disease. Nonsteroidal anti-inflammatory drugs (NSAIDs) remain the mainstay of treatment in these patients, especially those who have mild polyarthralgias or polyarthritis (Table 2). It is preferable to avoid the more gastrotoxic NSAIDs, because patients with systemic lupus erythematosus may require NSAID treatment for years and may use NSAIDs in conjunction with other drugs such as corticosteroids, which increases the risk of gastric injury. In addition, NSAIDs may adversely affect renal function, a special concern because 50 percent of patients with systemic lupus erythematosus develop associated nephritis.

TABLE 2 Treatment of Polyarthritis in Patients with Systemic Lupus Erythematosus

Drug NSAIDs Antimalarials Comment Avoid gastrotoxic NSAIDs; counter with cytoprotective therapy Hydroxychloroquine (Plaquenil) is the antimalarial drug used most often in the United States; ophthalmologic monitoring is recommended every six to 12 months

Glucocorticoids

Individual joints may benefit from intra-articular injection of triamcinolone (Aristospan); severe polyarthritis flare-ups may be treated with intravenous "pulse therapy" consisting of 1,000 mg of methylprednisolone (Solumedrol) daily for three days; use of prednisone for maintenance therapy should be limited to 10 mg or less daily Immunosuppressive Methotrexate (Rheumatrex) or azathioprine (Imuran) can be used as steroid-sparing drugs drugs; methotrexate cannot be used during pregnancy NSAIDs=nonsteroidal anti-inflammatory drugs.

Antimalarial agents, especially hydroxychloroquine (Plaquenil), are frequently used in the treatment of polyarthritis. Hydroxychloroquine is very safe; only 1 percent of patients using it develop retinopathy. Retinopathy as a result of hydroxychloroquine use is usually reversible when the drug is discontinued. In spite of NSAID and antimalarial therapy, some patients require corticosteroids to control severe polyarthritis. An extremely severe flare-up of polyarthritis can be treated with intravenous methylprednisolone sodium succinate (AMethapred, Solu-Medrol), 1,000 mg administered over 90 minutes, given daily for three days. This therapy will usually abruptly stop the flare, allowing the patient to stay on a low-maintenance dosage of prednisone. If the maintenance dosage of prednisone is greater than 10 mg per day, additional steroid-sparing drugs can be added to the regimen. Low dosages of methotrexate (Rheumatrex), such as 7.5 mg given orally once per week, are extremely effective. It is now standard practice to use folic acid to counter some of the minor side effects of methotrexate. Patients taking methotrexate should abstain from alcohol, because combined use increases the risk of cirrhosis.
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Additional musculoskeletal complications of systemic lupus erythematosus include osteonecrosis and osteoporosis (Table 3). Osteonecrosis, also called avascular necrosis of bone, occurred in 14 percent of patients in one study.
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TABLE 3 Musculoskeletal Complications of Systemic Lupus Erythematosus

Osteonecrosis (avascular necrosis of bone) Occurs in 14 percent of patients with systemic lupus erythematosus Most commonly affects the hip joints Early detection requires MRI Core decompression of bone is an effective treatment in early stages of the disease Osteoporosis Occurs in 64 percent of patients with systemic lupus erythematosus Osteoporosis of the lumbar spine is associated with the highest dosage of prednisone and the cumulative effects of prednisone Calcium, vitamin D, calcitonin and bisphosphonates are effective treatments (even in premenopausal women with osteoporosis) MRI=magnetic resonance imaging.

The major risk factors for osteonecrosis include a prednisone dosage greater than 20 mg per day for one month or longer, and the presence of Raynaud's disease or vasculitis. Avascular necrosis of bone, if detected early by magnetic resonance imaging (MRI), can often be effectively treated with core decompression of bone, an orthopedic procedure. Patients with osteonecrosis who present at later stages usually require a total joint replacement. The early detection of avascular necrosis of bone usually requires an MRI scan of the hip.
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The same study reported that only 35 percent of premenopausal women Sun block, topical steroids and antimalarials are used to alleviate the cutaneous with lupus erythematosus had normal bone mineral density. Screening manifestations of systemic lupus for osteoporosis may be indicated in these patients because erythematosus. premenopausal osteoporosis can be effectively treated with calcium, vitamin D, bisphosphonates and/or calcitonin salmon (Calcimar, Miacalcin, Salmonine). Guidelines from the ACR have
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suggested the use of estrogen supplementation in premenopausal women with corticosteroid-induced osteoporosis, but this therapy has not yet been shown to be safe in patients with systemic lupus erythematosus. Ultimately, the risk of osteoporosis can be minimized or avoided by limiting patient exposure to corticosteroids.
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Cutaneous Manifestations
Over 90 percent of patients with systemic lupus erythematosus eventually have a cutaneous manifestation of the disease, including malar rash, discoid lupus erythematosus, alopecia or aphthous stomatitis. The usual therapy for cutaneous lupus erythematosus is strict use of sun block, judicious use of topical steroids (although fluorinated topical steroids should not be used on the face) and antimalarial therapy (Table 4). Some patients with very severe cases of discoid lupus erythematosus may not respond adequately to the usual dosage of hydroxychloroquine, which is 400 mg per day for a normal-sized adult. Quinacrine, in a dosage of 100 mg per day, can be added without increasing the risk of retinopathy, or the patient can be switched to chloroquine HCl (Aralen), in a dosage of 250 mg per day.

TABLE 4 Management of Cutaneous Lupus Erythematosus

Treatment agent Sun block Antimalarials Comment

Blocks both UVA and UVB radiation Use of combination antimalarial therapy (hydroxychloroquine [Plaquenil] and quinacrine) or chloroquine (Aralen), which has more risk of retinopathy, is sometimes necessary Dapsone G6PD status should be checked Retinoids Avoid using in pregnant women Corticosteroids Use of corticosteroids may be necessary as part of initial therapy for severe discoid lupus or for lupus vasculitis; intradermal corticosteroids are helpful for individual discoid lesions, especially in the scalp Immunosuppressive Methotrexate (Rheumatrex) or azathioprine (Imuran) is used as steroid-sparing drug drugs Thalidomide One of the most effective drugs for treatment of discoid lupus, but teratogenicity and (Synovir) neuropathy will limit its acceptance and use UVA=ultraviolet A; UVB=ultraviolet B; G6PD=glucose-6-phosphate dehydrogenase.

Because chloroquine therapy carries an increased risk of retinopathy compared with hydroxychloroquine therapy, patients taking it should undergo ophthalmologic monitoring every three months. In patients who cannot tolerate antimalarials, dapsone or retinoids are additional therapeutic choices. It is important that glucose-6-phosphate dehydrogenase status be checked in black patients before they begin dapsone therapy. Retinoids should not be used in patients who may become pregnant. Patients with very severe cutaneous lupus erythematosus, including lupus vasculitis, may require high dosages of corticosteroids. If the maintenance dosage of corticosteroids is greater than 10 mg per day, the addition of steroidsparing agents, such as methotrexate or azathioprine, should be considered. One of the most effective drugs in the treatment of cutaneous lupus erythematosus, including discoid lupus erythematosus, is thalidomide (Synovir); however, because of its teratogenic effects and the increased risk of peripheral neuropathy in patients taking it, this agent will probably never have widespread use.

Renal Manifestations TABLE 5 Characteristics of Lupus Nephritis

Occurs in approximately 50 percent of patients with

One of the major worries for physicians and patients with systemic systemic lupus erythematosus lupus erythematosus is lupus nephritis (Table 5). Overall, 50 percent of patients with systemic lupus erythematosus have some More common in black people manifestation of lupus nephritis; this figure reached 75 percent in Renal biopsy can be helpful in identifying the activity black patients who were followed prospectively by the author. Not all lupus nephritis is severe. Patients with milder forms, including mesangial glomerulonephritis and focal proliferative Cyclophosphamide (Cytoxan) is more effective than glomerulonephritis, may respond to corticosteroid therapy alone or corticosteroids alone for the treatment of severe with steroid-sparing drugs such as azathioprine. However, the forms of lupus nephritis (diffuse proliferative patient with rapidly progressive lupus nephritis, with diffuse glomerulonephritis) proliferative glomerulonephritis on biopsy, or severe proteinuria and active urine sediment, will initially need high-dose corticosteroid therapy and should be a candidate for cyclophosphamide therapy. Clinical trials at the National Institutes of Health have been instructive in the development of protocols for the administration of cyclophosphamide with minimal long-term toxicity. Cyclophosphamide, in a dosage of 750 to 1,000 mg per m body surface area, is well tolerated when given in conjunction with prehydration, mesna ([Mesnex injection], which binds acrolein, a toxic cyclophosphamide metabolite) to avoid hemorrhagic cystitis, and antiemetics. Patients receiving this therapy may later be at risk for the development of malignancies, but the risk of leukemia and lymphoma appears to be very small. Premature ovarian failure is a significant complication and occurs in up to 60 percent of women over 30 years of age. Even with aggressive therapy, renal lupus leads to major morbidity and is a major cause of mortality in patients with systemic lupus erythematosus.
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of lupus nephritis and the degree of chronicity (scarring)

Central Nervous System Manifestations

The central nervous system manifestations of systemic lupus erythematosus Neurologic Manifestations of can present in many forms and are often difficult to diagnose (Table 6). No Systemic Lupus gold standard diagnostic test currently exists. Characteristic abnormalities are Erythematosus frequently found on brain MRI, lumbar puncture and electroencephalogram. Psychosis and seizures are usually easy to diagnose and respond well to Psychosis antipsychotics or anticonvulsants, as well as to corticosteroid treatment for Seizures Organic brain syndrome systemic lupus erythematosus. However, many patients with systemic lupus Stroke erythematosus present with cognitive function difficulties, making it a Cognitive function abnormalities challenge for the physician to differentiate between what is related to active Transverse myelopathy lupus erythematosus, what is related to corticosteroid treatment, and what may Mononeuritis multiplex be related to depression or chronic fatigue syndrome. Fibromyalgia, a musculoskeletal syndrome characterized by generalized pain, fatigue and a variety of associated symptoms, is found in as many as 30 percent of patients with systemic lupus erythematosus and is frequently associated with chronic fatigue. Patients with central nervous system manifestations of lupus erythematosus who present with status epilepticus, organic brain syndrome or coma can be treated with intravenous methylprednisolone pulse therapy. Patients with severe or resistant symptoms may also require treatment with intravenous cyclophosphamide and/or plasmapheresis. However, it is usually necessary to rule out other conditions that may mimic central nervous system manifestations of systemic lupus erythematosus, including infection and toxic metabolic states.

TABLE 6

Cardiovascular Manifestations TABLE 7

One of the major complications of systemic lupus erythematosus Characteristics of Premature is premature or accelerated atherosclerosis (Table 7). This Atherosclerosis complication is one of the causes of later mortality, in the perimenopausal and early postmenopausal years. It is also a major Present in 6 to 10 percent of patients with systemic lupus erythematosus cause of morbidity. Studies conducted worldwide have suggested that somewhere between 6 and 10 percent of patients with Associated with duration of disease systemic lupus erythematosus have clinically recognized premature atherosclerosis. When screening studies are performed, Corticosteroid treatment increases the levels of the prevalence appears to be even greater, approaching 40 percent. cardiovascular risk factors, including weight, blood The pathogenesis of premature atherosclerosis is almost certainly pressure, cholesterol and homocysteine levels multifactorial and includes direct effects of the disease and side effects of treatment. Longitudinal regression analyses have shown that increasing the dosage of prednisone increases serum cholesterol, weight and blood pressure. Patients with systemic lupus erythematosus have higher levels of homocysteine, a known risk factor for atherosclerosis. Intervention, in the form of both lifestyle modifications and pharmacologic therapy, may be appropriate in young women with systemic lupus erythematosus and these risk factors for atherosclerosis.
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Antiphospholipid antibody syndrome is one of the most common causes of acquired hypercoagulability in the general population and is much more common in patients with systemic lupus erythematosus (Table 8). About one half of patients with systemic lupus erythematosus make antiphospholipid antibodies, including anticardiolipin antibody and lupus anticoagulant. These antibodies often fluctuate over time, as does disease activity in general. Patients who have antiphospholipid antibodies have an increased risk of antiphospholipid antibody syndrome, a hypercoagulable state that can present with venous thrombosis, arterial thrombosis, recurrent pregnancy loss or thrombocytopenia.

TABLE 8 Characteristics of Antiphospholipid The diagnosis of antiphospholipid antibody syndrome requires one Antibody Syndrome of the four clinical presentations mentioned previously and the
presence of either lupus anticoagulant or moderate- or high-titer anticardiolipin antibody. In patients with systemic lupus erythematosus, the presence of lupus anticoagulant appears to be more specific for the syndrome than the presence of anticardiolipin antibodies, but high-titer anticardiolipin antibody of the IgG or IgM class is also a risk factor.
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50 percent of patients with systemic lupus erythematosus manufacture antiphospholipid antibodies but often do so intermittently and at low titer The two clinically important antiphospholipid antibodies are lupus anticoagulant and anticardiolipin antibody Presentations of antiphospholipid antibody syndrome include thrombosis, recurrent or late pregnancy loss, and thrombocytopenia Long-term management of patients who have had a thrombotic event resulting from antiphospholipid antibody syndrome includes high-intensity warfarin (Coumadin) therapy (INR of 3 to 4) INR=International Normalized Ratio.

Patients with systemic lupus erythematosus who have already had a manifestation of antiphospholipid antibody syndrome require treatment. Patients who have had venous or arterial thrombosis appear to benefit from maintenance therapy with high-intensity (International Normalized Ratio of 3 to 4) warfarin (Coumadin). Women who have had recurrent pregnancy loss in the first trimester, or even one second- or third-trimester loss, have a greater chance of a successful pregnancy if given heparin and low-dose aspirin therapy. Patients with antiphospholipid antibody syndrome who also have thrombocytopenia cannot be safely treated with either heparin or warfarin, unless their platelet count remains above 50,000 3 10 per mm (50 3 10 per L).
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Hematologic Lupus

Anemia in patients with systemic lupus erythematosus is most often associated with chronic disease or is related to iron deficiency. Classic autoimmune hemolytic anemia can present acutely (and severely) or as a chronic condition. Severe hemolytic anemia is treated initially with intravenous methylprednisolone, 1,000 mg per day for three days. Leukopenia, which frequently occurs in patients with systemic lupus erythematosus, is usually not severe (i.e., white blood cell count of less than 1,000 3 10 per mm [1.0 3 10 per L]) and rarely requires treatment. Thrombocytopenia, if stable, and if the platelet count remains above 50,000 3 10 per mm (50 3 10 per L), should not be associated with bleeding unless the patient has an additional coagulation defect. Severe, life-threatening thrombocytopenia is treated with high-dose intravenous methylprednisolone but may also require intravenous immunoglobulin therapy. The long-term management of patients with severe thrombocytopenia may also include danazol (Danocrine), vincristine (Oncovin), immunosuppressive drugs and, in rare instances, splenectomy.
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Pregnancy in Women with Systemic Lupus Erythematosus

Twenty years ago, women with systemic lupus erythematosus were often told not to become pregnant. Today, most women with lupus erythematosus can have a successful pregnancy, although the potential for maternal and fetal complications does exist (Table 9).Patients who require warfarin or cyclophosphamide therapy should not become pregnant because of the teratogenic potential of these drugs. Some patients with lupus erythematosus who have the antiRh and anti-La antibodies do have a higher risk of congenital heart block in the fetus. Patients with antiphospholipid antibody syndrome have an increased risk of pregnancy loss and may require heparin and low-dose aspirin therapy to have a successful pregnancy.
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TABLE 9 Pregnancy-Associated Complications in Women with Systemic Lupus Erythematosus

Pregnancy loss Early losses are usually due to active lupus erythematosus or unknown factors Second- or third-trimester losses are usually due to antiphospholipid antibody syndrome Congenital heart block Mother usually has both anti-Rh and anti-La antibodies Most babies survive, but some have important morbidity Monitoring the next pregnancy with serial four-chamber fetal echocardiograms may allow early detection of fetal heart block Preterm birth Risk factors include active lupus erythematosus, maintenance therapy using prednisone dosages of more than 20 mg daily, renal disease and hypertension Increased risk of premature rupture of the membranes Pre-eclampsia may be difficult to differentiate from renal flare caused by systemic lupus erythematosus
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Patients with active lupus erythematosus and renal disease, or those who require higher dosages of prednisone (greater than 20 mg per day) have an increased risk of preterm birth. In spite of these obstacles, prenatal management that is based on a partnership between a rheumatologist and an obstetrician who has experience with high-risk pregnancies usually results in a successful outcome.
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The Author
Michelle Petri, M.D., M.P.H., is an associate professor of medicine at Johns Hopkins University School of Medicine, Baltimore, where she is also the director of the Lupus Center and the Hopkins Lupus Cohort Study. Dr. Petri received a medical degree from Harvard Medical School, Boston. After training in internal medicine at Massachusetts General Hospital, Boston, she completed

fellowships in rheumatology, and allergy and immunology at the University of California, San Francisco, School of Medicine.
Address correspondence to Michelle Petri, M.D., M.P.H., Division of Rheumatology, Johns Hopkins University School of Medicine, 1830 E. Monument St., Suite 7500, Baltimore, MD 21205. Reprints are not available from the author.

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