Treatment of Systemic Lupus Erythematosus: An Update
Am Fam Physician. 1998 Jun 1;57(11):2753-2760.
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,1 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.2 Localized autoimmune disorders, such as autoimmune thyroid disease, are also much more common than systemic lupus erythematosus.
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
The cause of systemic lupus erythematosus remains elusive. Predisposing factors include genetic factors (certain types of human leukocyte antigens and null complement alleles), environmental factors 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).3
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 anti–double-stranded DNA and anti-Smith, are very specific for systemic lupus erythematosus. Others, including anti-RNP, anti-Rho 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.4
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-Rho, 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.5 These classification criteria are often helpful clinically, especially since they emphasize the multisystemic nature of the disease.
TABLE 1 Classification Criteria for Systemic Lupus Erythematosus*
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:
*—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; 25:1271–7.
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.6
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.
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
Treatment of Polyarthritis in Patients with Systemic Lupus Erythematosus
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
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
Methotrexate (Rheumatrex) or azathioprine (Imuran) can be used as steroid-sparing 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 (A-Methapred, 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.7 Patients taking methotrexate should abstain from alcohol, because combined use increases the risk of cirrhosis.
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.8
TABLE 3 Musculoskeletal Complications of Systemic Lupus Erythematosus
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
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.8 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.9 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.
The same study reported that only 35 percent of premenopausal women with lupus erythematosus had normal bone mineral density.8 Screening for osteoporosis may be indicated in these patients because premenopausal osteoporosis can be effectively treated with calcium, vitamin D, bisphosphonates and/or calcitonin salmon (Calcimar, Miacalcin, Salmonine). Guidelines from the ACR have 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.10 Ultimately, the risk of osteoporosis can be minimized or avoided by limiting patient exposure to corticosteroids.
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
Management of Cutaneous Lupus Erythematosus
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
G6PD status should be checked
Avoid using in pregnant women
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
Methotrexate (Rheumatrex) or azathioprine (Imuran) is used as steroid-sparing drug
One of the most effective drugs for treatment of discoid lupus, but teratogenicity and 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 steroid-sparing 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.
One of the major worries for physicians and patients with systemic lupus erythematosus is lupus nephritis (Table 5). Overall, 50 percent of patients with systemic lupus erythematosus have some manifestation of lupus nephritis; this figure reached 75 percent in black patients who were followed prospectively by the author.
TABLE 5 Characteristics of Lupus Nephritis
Characteristics of Lupus Nephritis
Occurs in approximately 50 percent of patients with systemic lupus erythematosus
More common in black people
Renal biopsy can be helpful in identifying the activity of lupus nephritis and the degree of chronicity (scarring)
Cyclophosphamide (Cytoxan) is more effective than corticosteroids alone for the treatment of severe forms of lupus nephritis (diffuse proliferative glomerulonephritis)
Not all lupus nephritis is severe. Patients with milder forms, including mesangial glomerulonephritis and focal proliferative glomerulonephritis, may respond to corticosteroid therapy alone or with steroid-sparing drugs such as azathioprine. However, the patient with rapidly progressive lupus nephritis, with diffuse 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.11 Cyclophosphamide, in a dosage of 750 to 1,000 mg per m2 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.12 Even with aggressive therapy, renal lupus leads to major morbidity and is a major cause of mortality in patients with systemic lupus erythematosus.
Central Nervous System Manifestations
The central nervous system manifestations of systemic lupus erythematosus can present in many forms and are often difficult to diagnose (Table 6). No gold standard diagnostic test currently exists. Characteristic abnormalities are frequently found on brain MRI, lumbar puncture and electroencephalogram. Psychosis and seizures are usually easy to diagnose and respond well to antipsychotics or anticonvulsants, as well as to corticosteroid treatment for systemic lupus erythematosus. However, many patients with systemic lupus erythematosus present with cognitive function difficulties, making it a challenge for the physician to differentiate between what is related to active lupus erythematosus, what is related to corticosteroid treatment, and what may 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 Neurologic Manifestations of Systemic Lupus Erythematosus
Neurologic Manifestations of Systemic Lupus Erythematosus
Organic brain syndrome
Cognitive function abnormalities
One of the major complications of systemic lupus erythematosus is premature or accelerated atherosclerosis (Table 7). This complication is one of the causes of later mortality, in the perimenopausal and early postmenopausal years. It is also a major cause of morbidity. Studies conducted worldwide have suggested that somewhere between 6 and 10 percent of patients with systemic lupus erythematosus have clinically recognized premature atherosclerosis.13 When screening studies are performed, the prevalence appears to be even greater, approaching 40 percent. The pathogenesis of premature atherosclerosis is almost certainly multifactorial and includes direct effects of the disease and side effects of treatment. Longitudinal regression analyses14 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.15 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.
TABLE 7 Characteristics of Premature Atherosclerosis
Characteristics of Premature Atherosclerosis
Present in 6 to 10 percent of patients with systemic lupus erythematosus
Associated with duration of disease
Corticosteroid treatment increases the levels of cardiovascular risk factors, including weight, blood pressure, cholesterol and homocysteine levels
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 Antibody Syndrome
Characteristics of Antiphospholipid Antibody Syndrome
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.
The diagnosis of antiphospholipid antibody syndrome requires one 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,16 but high-titer anticardiolipin antibody of the IgG or IgM class is also a risk factor.
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).17 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.18 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 × 103 per mm3 (50 × 109 per L).
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 × 103 per mm3 [1.0 × 109 per L]) and rarely requires treatment. Thrombocytopenia, if stable, and if the platelet count remains above 50,000 × 103 per mm3 (50 × 109 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.
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 anti-Rho 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.
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.19 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.
TABLE 9 Pregnancy-Associated Complications in Women with Systemic Lupus Erythematosus
Pregnancy-Associated Complications in Women with Systemic Lupus Erythematosus
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-Rho 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
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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