Systemic Lupus Erythematosus

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Chapter 152 Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by multisystem inflammation and the presence of circulating autoantibodies directed against self-antigens. SLE occurs in children and adults, disproportionately affecting women of reproductive age. Although nearly every organ may be affected, the most commonly involved are the skin, joints, kidneys, blood-forming cells, blood vessels, and central nervous system. Compared with adults, children and adolescents with SLE have more severe disease and more widespread organ involvement.

Etiology

The pathogenesis of SLE remains unknown, but several factors likely influence risk and severity of disease, including genetics, hormonal milieu, and environmental exposures.

A genetic predisposition to SLE is suggested by the association with specific genetic abnormalities, including congenital deficiencies of C1q, C2, and C4 and the finding that individuals with SLE frequently have a family history of SLE or other autoimmune disease. In addition, certain HLA types (including HLA-B8, HLA-DR2, and HLA-DR3) occur with increased frequency in SLE. Although SLE has a clear genetic component, its occurrence is sporadic in families and concordance is incomplete, even among identical twins, suggesting that multiple genes are involved and that nongenetic factors are also important in disease expression.

Because SLE preferentially affects women, especially during their reproductive years, it is suspected that hormonal factors are important in pathogenesis. Ninety percent of individuals with SLE are female, making gender the strongest risk factor for SLE. Estrogens are likely to play a role in SLE, and in vitro and animal model studies suggest that estrogen exposure promotes B-cell autoreactivity. Results of studies on the impact of exogenous estrogen on women with SLE are conflicting. Estrogen-containing oral contraceptives do not appear to induce flares in quiescent SLE, but the risk of flares may be increased in postmenopausal women receiving hormone replacement.

The environmental exposures that may trigger the development of SLE remain unknown; however, certain viral infections (including Epstein-Barr virus) may play a role in susceptible individuals, and ultraviolet light exposure is known to aggravate SLE disease activity. Environmental influences also may induce epigenetic modifications to DNA, which increase the risk of SLE and drug-induced lupus. For example, in mouse models, drugs such as procainamide and hydralazine can promote lymphocyte hypomethylation and a lupus-like syndrome.

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.

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

TARGET ORGAN POTENTIAL CLINICAL MANIFESTATIONS
Constitutional Fatigue, anorexia, weight loss, fever, lymphadenopathy
Musculoskeletal Arthritis, myositis, tendonitis, arthralgias, myalgias, avascular necrosis, osteoporosis
Skin Malar rash, discoid rash, photosensitive rash, cutaneous vasculitis, livedo reticularis, periungual capillary abnormalities, Raynaud’s phenomenon, alopecia, oral and nasal ulcers
Renal Hypertension, proteinuria, hematuria, edema, nephrotic syndrome, renal failure
Cardiovascular Pericarditis, myocarditis, conduction system abnormalities, Libman-Sacks endocarditis
Neurologic Seizures, psychosis, cerebritis, stroke, transverse myelitis, depression, cognitive impairment, headaches, pseudotumor, peripheral neuropathy, chorea, optic neuritis, cranial nerve palsies
Pulmonary Pleuritis, interstitial lung disease, pulmonary hemorrhage, pulmonary hypertension, pulmonary embolism
Hematologic Immune-mediated cytopenias (hemolytic anemia, thrombocytopenia or leukopenia), anemia of chronic inflammation, hypercoaguability, thrombocytopenic thrombotic microangiopathy
Gastroenterology Hepatosplenomegaly, pancreatitis, vasculitis affecting bowel, protein-losing enteropathy
Ocular Retinal vasculitis, scleritis, episcleritis, papilledema

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.