Chapter 289 SYSTEMIC LUPUS ERYTHEMATOSUS
Peter H. Schur
Systemic lupus erythematosus (SLE) is a disease of unknown cause that may produce variable combinations of fever, rash, hair loss, arthritis, pleuritis, pericarditis, nephritis, anemia, leukopenia, thrombocytopenia, and central nervous system (CNS) disease. The clinical course is characterized by periods of remissions and acute or chronic relapses. Characteristic immune abnormalities, especially antibodies to a number of nuclear and other cellular antigens, develop in patients with SLE. The diagnosis is facilitated by determining whether the patient has 4 of the 11 clinical and/or laboratory criteria developed for the classification of SLE (Table 289-1) .
EPIDEMIOLOGY.
SLE can occur at any age but has its onset primarily between ages 16 and
55. It occurs more frequently in women. In children, the female-male ratio is 1.4 to 5.8:1; in adults, it ranges from 8:1 to 13:1; and in older individuals, the ratio is 2:1. The prevalence of SLE is estimated to be between 4 and 250 cases per 100,000 population. In theUnited States, the highest incidence is among Asians inHawaii, blacks, and certain Native Americans (Sioux, Crow, Arapahoe). The risk of SLE developing in a black American female has been estimated to be 1:250. The prevalence is about the same worldwide; the disease appears to be commonin China, in Southeast Asia, and amongb lacks in the Caribbean, but is seen infrequently in blacks inAfrica. Limited observations suggest that the incidence of discoid lupus erythematosus is the same as that for SLE.
ETIOLOGY.
The cause of SLE remains unknown, although many observations suggest a role for genetic, hormonal, immune, and environmental factors. The evidence for a genetic role is summarized in    Table 289-2 . Some of these
genetic marker associations are found more frequently in SLE patients of different races a
nd ethnicities. It has been calculated that at least four genes are involved in predisposing individuals to SLE. Each gene presumably affects some aspect of immuner egulation, protein degradation, peptide transport across cell membranes, immuner esponse, complement, the reticuloendothelial system (including phagocytosis), immunoglobulins, apoptosis, and sex hormones. Thus combinations of dissimilar gene defects may result in distinct abnormal responses and produce separate pathologic processes and different clinical expression.
The evidence for hormonal abnormalities is based primarily on the observation that SLEi s much more commona mongw omenin their childbearing years. In addition, SLE has been observed in some males with Klinefelter's syndrome, and some abnormalities of estrogen metabolism have been noted in both men and women with SLE. However, the clinical expression of SLE is the same in men and women. Furthermore, a lupus-like disease ofNew Zealandmice is more common and more severe and has an earlier onset in females--and is ameliorated by oophorectomy or treatment with male hormones. However, in other strains of mice with a lupus-like disease, this gender difference is not n
oted.
Numerous immune abnormalities occur in patients with SLE, the etiology of which remains unclear; nor do we know which are primary and which are secondary. Someo f these immune defects are episodic, and some correlate with disease activity. SLE is primarilyproliferation
PATHOGENESIS.
Many manifestations are mediated by antibodies. The classic example is that of diffuse proliferative glomerulonephritis. Immune complexes, which consist of nuclear antigens (especially    DNA) and high-affinity
complement-fixing IgG (especially IgG1 and IgG3) and ANAs (especially antibodies to DNA), form in the circulation and are deposited in the glomerular basement membrane( GBM) or form in situ; histone mayf acilitate immune complex deposition. The complement system is then activated and chemotactic factors are generated. These factors induce the
attraction and infiltration of leukocytes, which then phagocytose immune complexes and cause the release of mediators (such as activators of the clotting system), which further perpetuate the glomerular inflammation. With continuing immune complex deposition, chronic inflammation may ensue, ultimately leading to fibrinoid necrosis and scarring (crescents) and loss of renal function. In lupus membranous glomerulonephritis, similar mechanisms occur, although immune complex-containing, poorly complement-fixing IgG2 and IgG4 form primarily in situ on the GBM; there is no cellular infiltrate. The mechanism for the GBM protein leakage, which results in the nephrotic syndrome, is not clear. In lupus mesangial glomerulonephritis, mesangial cells (macrophage-like PATHOLOGY.
Few unique pathologic features are associated with SLE. In patients with arthritis, the synovial histopathology tends to be non-specific, with superficial fibrin-like material and local or diffuse cell lining proliferation. Vascular changes include perivascular mononuclear cells, lumen obliteration, enlarged endothelial cells, and thrombi, but fibrinoid necrosis is uncommon.B iopsies of the malar erythema may reveal some minor basal layer abnormalities, as well as immune complex deposits at the dermal-epidermal j
unction. Discoid skin lesions are characterized by hyperkeratosis, follicular plugging, and more basal cell layer changes, including immune complexes at the dermal-epidermal junction. Pleura and pericardium are infiltrated by mononuclear cells. Lupus pneumonitis is characterized by alveolar wall injury, hemorrhage, and edema; hyaline membranef ormation; and immune complex deposits. Coronary arteries often demonstrate premature-onset atherosclerosis. Libman-Sacks endocarditis is characterized by the accumulation of immune complexes, mononuclear cells, hematoxylin bodies, and fibrin and platelet thrombi. Pathologic examination of the spleen often reveals an "onion skin" appearance of the splenic arteries, which is thought to represent healed arteritis.

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