Epidemiology

The reported prevalence of SLE in children and adolescents (1-6/100,000) is lower than that in adults (20-70/100,000). Prevalence of SLE is highest among African-Americans, Asians, Hispanics, Native Americans, and Pacific Islanders. SLE predominantly affects females, with reported 5 : 1 ratio prior to puberty, a 9 : 1 ratio during reproductive years, and near prepubertal ratios in the postmenopausal period. Childhood SLE is rare before 5 yr of age and is usually diagnosed in adolescence. Up to 20% of all individuals with SLE are diagnosed prior to age 16 yr.

Pathology

Histologic features most suggestive of SLE include findings in the kidney and skin, especially the discoid rash. Renal manifestations of SLE are classified histologically according to the criteria of the International Society of Nephrology (Chapter 508). The finding of diffuse proliferative glomerulonephritis (class IV) significantly increases risk for renal morbidity. Renal biopsies are very helpful to establish the diagnosis of SLE and to stage disease. Immune complexes are commonly found with “full house” deposition of immunoglobulin and complement. The characteristic discoid rash depicted in Figure 152-1D is characterized on biopsy by hyperkeratosis, follicular plugging, and infiltration of mononuclear cells into the dermal-epidermal junction. The histopathology of photosensitive rashes can be nonspecific, but immunofluorescence examination of both affected and nonaffected skin may reveal deposition of immune complexes within the dermal-epidermal junction. This finding is called the lupus band test, which is specific for SLE.

Figure 152-1 Mucocutaneous manifestations of SLE. A, Malar rash; B, vasculitic rash on toes; C, oral mucosal ulcers; D, discoid rash in malar distribution.

Pathogenesis

Developing a model of SLE pathogenesis is challenging, given the need to account for tremendous heterogeneity in disease expression and fluctuations of disease activity over time. It is clear that autoantibodies, cytokines, and aberrant lymphocyte function have important roles in SLE pathogenesis.

A hallmark of SLE is the generation of autoantibodies directed against self-antigens, particularly nucleic acids. These intracellular antigens are ubiquitously expressed but are usually inaccessible and cloistered within the cell. During cell necrosis or apoptosis, the antigens are released. SLE skin cells are highly susceptible to damage from ultraviolet light, and the resulting cell demise results in release of cell contents, including nucleic antigens. Individuals with SLE may have markedly increased levels of apoptosis or significantly impaired ability to clear cell debris, causing prolonged exposure to these nucleic antigens in the bloodstream and ample opportunity for their recognition by immune cells, leading to production of autoantibodies by B cells. Circulating autoantibodies may form immune complexes and deposit in tissues, leading to local complement activation, initiation of a proinflammatory cascade, and, ultimately, tissue damage. Antibodies to double-stranded DNA can form immune complexes, deposit in glomeruli, and initiate inflammation leading to glomerulonephritis. Many individuals with SLE have circulating antibodies to double-stranded DNA yet do not have nephritis, suggesting that autoantibodies alone are not sufficient to cause disease.

Individuals with SLE frequently demonstrate abnormal cytokine levels. In particular, peripheral blood mononuclear cells from patients with SLE exhibit patterns of gene expression suggestive of stimulation by interferon-α (IFN-α). IFN-α production by dendritic cells can be stimulated in vivo by immune complexes. Excess levels of interferon can promote expression of other proinflammatory cytokines and chemokines, maturation of monocytes into dendritic dells, promotion of autoreactive B and T cells, and loss of self-tolerance. Many, but not all, patients with SLE exhibit this interferon signature. Other cytokines with increased expression in SLE include interleukin-2 (IL)-2, IL-6, IL-10, IL-12, B-lymphocyte stimulator (BlyS), and anti–tumor necrosis factor-α (TNF-α).

Both B and T cells demonstrate functional impairments in SLE. In active SLE, B-cell populations have impaired tolerance and increased autoreactivity, enhancing B cells’ ability to produce autoantibodies following exposure to self-antigen. In addition, cytokines such as BlyS may promote abnormal B-cell number and function. T-cell abnormalities in SLE include increased numbers of memory T cells and decreased number and function of T-regulatory cells. SLE T cells display aberrant signaling and increased autoreactivity. As a result, they are resistant to attrition by normal apoptosis pathways.

Clinical Manifestations

Any organ system can be involved in SLE, so the potential clinical manifestations are protean (Table 152-1). The presentation of SLE in childhood or adolescence differs from that in adults. The most common presenting complaints of children with SLE include fever, fatigue, hematologic abnormalities, arthralgia, and arthritis. Renal disease in SLE is often asymptomatic; thus careful monitoring of blood pressure and urinalyses is critical. SLE is often characterized by periods of flare and disease quiescence or may follow a more smoldering disease course. The neuropsychiatric complications of SLE may occur with or without apparently active SLE and are particularly difficult to detect in adolescents, who are already at high risk for mood disorders. Long-term complications of SLE and its therapy, including accelerated atherosclerosis and osteoporosis, become clinically evident in young to middle adulthood. SLE is a disease that evolves over time in each affected individual, and new manifestations may arise even many years after diagnosis.

Table 152-1 POTENTIAL CLINICAL MANIFESTATIONS OF SYSTEMIC LUPUS ERYTHEMATOSUS

Diagnosis

The diagnosis of SLE requires a comprehensive clinical and laboratory assessment revealing characteristic multisystem disease and excluding other etiologies, including infection and malignancy. Presence of 4 of the 11 American College of Rheumatology 1997 Revised Classification Criteria for SLE (Table 152-2) simultaneously or cumulatively establishes the diagnosis of SLE. Of note, although a positive antinuclear antibody (ANA) test result is not required for the diagnosis of SLE, ANA-negative lupus is extremely rare. Hypocomplementemia, although common in SLE, is not represented among the classification criteria.