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n e w e ng l a n d j o u r na l


m e dic i n e

review article
Mechanisms of Disease

Systemic Lupus Erythematosus
Anisur Rahman, Ph.D., and David A. Isenberg, M.D.


o the clinician, systemic lupus erythematosus is important because it is a potentially fatal disease that is easily confused with many other disorders. To the immunologist, lupus is intriguing because allthe key components of the immune system are involved in the underlying mechanisms of the disease. This review describes these mechanisms and shows how knowledge of the pathogenesis of lupus facilitates its treatment. The prevalence of lupus ranges from approximately 40 cases per 100,000 persons among Northern Europeans to more than 200 per 100,000 persons among blacks.1 In the United States, thenumber of patients with lupus exceeds 250,000. The life expectancy of such patients has improved from an approximate 4-year survival rate of 50% in the 1950s2 to a 15-year survival rate of 80% today.3 Even so, a patient in whom lupus is diagnosed at 20 years of age still has a 1 in 6 chance of dying by 35 years of age, most often from lupus or infection.4 Later, myocardial infarction and strokebecome important causes of death.4 This bimodal pattern of mortality in lupus was recognized more than 30 years ago.5 The diverse presentations of lupus range from rash and arthritis through anemia and thrombocytopenia to serositis, nephritis, seizures, and psychosis. Lupus should be part of the differential diagnosis in virtually any patient presenting with one of these clinical problems, especiallyin female patients between 15 and 50 years of age.

From the Centre for Rheumatology Research, Division of Medicine, University College London, London. Address reprint requests to Dr. Isenberg at the Centre for Rheumatology Research, Division of Medicine, University College London, Rm. 331, 3rd Fl., 46 Cleveland St., London W1T 4JF, United Kingdom, or at d.isenberg@ucl. N Engl J Med2008;358:929-39.
Copyright © 2008 Massachusetts Medical Society.

Gene t ic a nd Epide miol o gic Fac t or s
Since 90% of patients with lupus are female, an important role for female hormones6 seems likely, but a protective role for male hormones or an effect of genes on the X chromosome is also possible. In a blinded, randomized, controlled trial, menopausal women with lupus who receivedhormone-replacement therapy containing conjugated estrogens and progesterone had a risk of a mild-to-moderate disease flare that was 1.34 times the risk among women who received placebo (P = 0.01).7 However, trials of hormonal treatments for lupus, such as dehydroepiandrosterone, have been disappointing.8 It is unclear how sex hormones could promote lupus. Many drugs cause a variant of lupus calleddrug-induced lupus. The best known of these drugs are procainamide, hydralazine, and quinidine. Patients with druginduced lupus usually present with skin and joint manifestations; renal and neurologic features are very rare.9 An antecedent viral-like illness may occur at the onset of lupus or immediately before a flare. Identifying a particular causative virus has proved challenging. Epstein–Barr virus(EBV) may be important, since a temporal association between the onset of lupus and the occurrence of EBV infection has been reported. A case–control study involving children and young adults showed that antiEBV antibodies were present in 99% and EBV DNA was present in 100% of patients

n engl j med 358;9

february 28, 2008


Downloaded from on June 3, 2008. Copyright © 2008 Massachusetts Medical Society. All rights reserved.


n e w e ng l a n d j o u r na l


m e dic i n e

genotype determines which MHC molecules are available to the antigens that are present and thus how well the antigens can be recognized by T cells. Cytogenetic Candidate Genes Immune For this reason, particular MHC genes are associLocation with the Loci...