Treatment of systemic lupus erythematosus: an update

Author: Michelle Petri
Date: June, 1998

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-[Rh.sub.o], 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]

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.sub.o], 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(*)Before a patient can be classified with systemiclupus erythematosus, at least four of the following11 disorders must be present:Malar rash Renal disorderDiscoid rash Neurologic disorderPhotosensitivity Hematologic disorderOral ulcers Immunologic disorderArthritis Antinuclear antibodiesSerositis

(*) -- 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.

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 CommentNSAIDs Avoid gastrotoxic NSAIDs; counter with cytoprotective therapyAntimalarials Hydroxychloroquine (Plaquenil) is the antimalarial drug used most often in the United States; ophthalmologic monitoring is recommended every six to 12 monthsGlucocorticoids 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 dailyImmunosuppressive Methotrexate (Rheumatrex) or azathioprine drugs (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 Muscoskeletal 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

[9.] Petri M, Fairbank A, Jinnah R, Hungerford D, Mont M. Progression of avascular necrosis (AVN) of the femoral head in systemic lupus erythematosus: long-term follow-up report. Arthritis Rheum 1993; 36(9 Suppl):184.

[10.] Recommendations for the prevention and treatment of glucocorticoid-induced osteoporosis. American College of Rheumatology Task Force on Osteoporosis Guidelines. Arthritis Rheum 1996; 39:1791-801.

[11.] Boumpas DT, Austin HA 3d, Vaughan EM, Klippel JH, Steinberg AD, Yarboro CH, et al. Controlled trial of pulse methylprednisolone versus two regimens of pulse cyclophosphamide in severe lupus nephritis. Lancet 1992;340:741-5.

[12.] Boumpas DT, Austin HA 3d, Vaughan EM, Yarboro CH, Klippel JH, Balow JE. Risk for sustained amenorrhea in patients with systemic lupus erythematosus receiving intermittent pulse cyclophosphamide therapy. Ann Intern Med 1993;119:366-9.

[13.] Petri M, Perez-Gutthann S, Spence D, Hochberg MC. Risk factors for coronary artery disease in patients with systemic lupus erythematosus, Am J Med 1992;93:513-9.

[14.] Petri M, Lakatta C, Magder L, Goldman D. Effect of prednisone and hydroxychloroquine on coronary artery disease risk factors in systemic lupus erythematosus: a longitudinal data analysis. Am J Med 1994;96:254-9.

[15.] Petri M, Roubenoff R, Dallal GE, Nadeau MR, Selhub J, Rosenberg IH. Plasma homocysteine as a risk factor for atherothrombotic events in systemic lupus erythematosus. Lancet 1996;348:1120-4.

[16.] Petri M, Rheinschmidt M, Whiting-O'Keefe Q, Hellmann D, Corash L. The frequency of lupus anticoagulant in systemic lupus erythematosus. A study of 60 consecutive patients by activated partial thromboplastin time, Russell viper venom time, and anticardiolipin antibody level. Ann Intern Med 1987;106:524-31.

[17.] Khamashta MA, Cuadrado MJ, Mujic F, Taub NA, Hunt BJ, Hughes GR. The management of thrombosis in the antiphospholipid-anti body syndrome. N Engl J Med 1995;332:993-7.

[18.] Cowchock FS, Reece EA, Balaban D, Branch DW, Plouffe L. Repeated fetal losses associated with anti phospholipid antibodies: a collaborative randomized trial comparing prednisone with low-dose heparin treatment. Am J Obstet Gynecol 1992; 166:1318-23.

[19.] Petri M, Howard D, Repke J, Goldman DW The Hopkins Lupus Pregnancy Center: 1987-1991 update. Am J Reprod Immunol 1992;28:188-91.

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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