Systemic Lupus Erythematosus
Jane E. Salmon
Robert P. Kimberly
Systemic lupus erythematosus (SLE or lupus) is a multisystem disease with a spectrum of clinical manifestations and a variable course characterized by exacerbations and remissions. It is a uniquely complex illness both clinically and immunologically and no two individuals present in the same way. Lupus is marked by both humoral and cellular immunologic abnormalities, including multiple autoantibodies [e.g., anti-C1q, anti-N-methyl-D-aspartate (NMDA)] that may directly participate in tissue injury or may indirectly lead to tissue damage by activating Fc receptors and complement. Antinuclear antibodies (ANAs), especially those to native DNA, are common immunologic abnormalities found in the disease.
Identification and characterization of abnormal autoantibodies continue to be major areas of clinical and immunochemical interest. The development of sensitive laboratory tests for autoantibodies has enabled the recognition of milder forms of SLE, with a consequent change in both reported prevalence and prognosis. The broad clinical spectrum of SLE challenges the diagnostic and therapeutic acumen of the physician.
The presence of a genetic component in SLE is supported by family studies.
Clinical disease. Family members of patients with SLE are more likely to have lupus or some other connective tissue disease.
The risk for development of SLE in a sibling of individuals affected by SLE, called the sibling risk ratio (γs), is approximately 20 times higher than that in the general population.
Concordance of disease among monozygotic twin pairs may be as high as 50%. Fraternal twins, with a concordance rate of 2% to 5%, do not have a higher frequency of SLE than do other first-degree relatives.
Asymptomatic (or healthy) family members are more likely to have a false-positive test result for syphilis, positive ANAs, antilymphocyte antibodies, and hypergammaglobulinemia.
Studies of major histocompatibility complex (MHC) genes
Lupus and lupuslike syndromes are associated with inherited abnormalities of the MHC class III genes for complement components (most commonly the C4-null allele, and also deficiencies of C2; deficiencies of other complement components are rare).
Although the strength of the association varies by ethnicity, SLE is associated with the serologically determined MHC class II allo-antigens human leukocyte antigens (HLA)-DR2 and HLA-DR3. The association with HLA-DR2 reflects the DR2 allele DRB1*1501 in whites, DRB1*1502 in Asian populations, and the unique DRB1*1503 allele in African Americans. HLA-DR3 is primarily associated with patients with lupus having a northern European ancestry.
Genetic variants of opsonins (mannose binding protein and C-reactive protein), opsonin receptors [complement receptors and immunoglobulin (Ig) receptors], lymphocyte cell surface and signaling molecules (PDCD1 and PTPN22), and cytokine genes [tumor necrosis factor-α (TNF-α) and interleukin-10] have been associated with SLE susceptibility.
Fcγ-receptors (FcγR) are important in immune complex clearance. Allelic variants of FcγR which differ in their capacities to bind IgG, alter the function of mononuclear phagocytes and thereby provide a mechanism of inherited differences in immune complex handling. The low IgG binding alleles of FcγR have been associated with increased risk for lupus nephritis.
Variants of PDCD1 and PTPN22 may be associated with lymphocyte hyperfunction.
Humoral immunity. Hyperactivity of the humoral component of immunologic responsiveness is manifested by hypergammaglobulinemia, autoantibodies, and circulating immune complexes.
Various autoantibodies may contribute to tissue injury. Attempts to correlate specific clinical patterns of the disease with specific types of autoantibodies have been partially successful. The following provide examples:
Anti-DNA antibodies have been found in renal glomerular lesions.
Sicca syndrome with SLE has been associated with La (SS-B) antibodies.
Ro (SS-A) and La antibodies have been associated with neonatal lupus, congenital complete heart block, and subacute cutaneous lupus.
Positive result of lupus anticoagulant test and anticardiolipin antibodies are associated with thrombosis, thrombocytopenia, and fetal wastage.
Although the titer of ANAs does not necessarily correlate with disease activity, the levels of anti-DNA antibodies may vary with clinical disease. Because results vary, this test cannot be used as the sole guide to therapy.
Circulating immune complexes are commonly found in active SLE and are often associated with hypocomplementemia measured as component proteins (C3 and C4) or hemolytic function (CH50). Immune complex deposits are found in many tissues. Isolated determinations of circulating complexes do not consistently correlate with disease activity. Sequential patterns of change may be of value in individual patients.
Cellular immunity. SLE is characterized by lymphopenia and often by monocytosis. The normal intricate immunoregulatory balance among cells is lost.
Anergy, evidenced by diminished delayed hypersensitivity skin testing reactions, is common.
Ig-producing B cells are hyperactive; perhaps reflecting enhanced stimulatory factors [e.g., BAFF/B-lymphocyte stimulator (BLyS)].
T-cell subsets are altered, and mononuclear phagocytes elaborate increased amounts of various cytokines. Circulating leukocytes show an mRNA expression profile suggesting interferon α stimulation, but the primary defect has not been identified.
Provocative agents. Although the etiologic agent(s) in SLE have not been identified, several factors may exacerbate the disease.
Ultraviolet light. Exposure to sunlight may precipitate either the onset or a flare of clinical disease, causing both dermatologic and systemic manifestations in about one-third of patients. Because complete avoidance of sunlight is impractical, patients should use sunscreens and should wear long-sleeved shirts, trousers rather than shorts, and wide-brimmed hats. Many effective sunscreens are available commercially; however, none of these can completely obviate the potential of significant exposure to sunlight to exacerbate SLE.
Situational stresses. Some patients may experience increased disease activity during periods of fatigue or emotional stress (e.g., when encountering school examinations or interpersonal conflict). The significance of such factors should not be overlooked, and such stress should be reduced as much as possible.
Infection. Viral infection has been suggested as an etiologic event in SLE. Although unproven as such, viral infection may provoke a flare of disease by an unknown mechanism, perhaps involving the triggering of tolllike receptors of the innate immune system and the eventual stimulation of the adaptive immune system by interferon α Although vaccination provides exposure to foreign antigen, studies with influenza and pneumococcal vaccines suggest that such
vaccination provides protection without causing increased SLE disease activity. Specific antibody responses may be lower in patients with SLE, especially those on immunosuppressive agents, than in healthy subjects.
Table 30-1 Drugs Implicated in Drug-induced Lupuslike Syndrome
a Association is well established.
Drugs. Many drugs have been associated with the development of ANAs and, in some cases, a clinical lupuslike syndrome (Table 30-1); procainamide and hydralazine were the most commonly implicated, and now, minocycline and anti-TNF medications are increasing in significance. However, the potential to induce such serologic changes in patients without SLE does not preclude the use of these drugs in patients with SLE when clinically appropriate. Although most physicians prefer to avoid them if an alternative drug is available, the use of these drugs in SLE has not been associated with documented exacerbation of disease activity.
Although no histologic feature is pathognomonic for SLE, several features are very suggestive: (a) fibrinoid necrosis and degeneration of blood vessels and connective tissue; (b) the hematoxylin body [the in vivo lupus erythematosus (LE) cell phenomenon]; (c) “onion skin” thickening of the arterioles of the spleen; and (d) Libman-Sacks verrucous endocarditis.
Routine histologic examination of tissue specimens reveals a broad range of findings.
Skin biopsy may demonstrate a leukocytoclastic angiitis, especially in palpable purpuric lesions. The typical lupus rash usually shows epidermal thinning, liquefactive degeneration of the basal layer with dermal–epidermal junction disruption, and lymphocytic infiltration of the dermis. Rheumatoidlike nodules with palisading giant cells are uncommon, and panniculitis is rare.
Synovium. Synovial biopsies may show fibrinous villous synovitis. The presence of pannus formation or bone and cartilage erosions is rare.
Muscle biopsies usually show a nonspecific perivascular mononuclear infiltrate, but true muscle necrosis, as seen in polymyositis, can occur.
Kidney. The kidney has been the most intensively studied organ in SLE. The entire range of glomerulonephritis (membranous, mesangial, proliferative, etc.) is seen (Table 30-2). Crescentic and necrotizing vasculitic lesions may be found. Interstitial abnormalities are often present. No single renal lesion is diagnostic of SLE. Tubuloreticular structures are not restricted to SLE.
Renal biopsy provides one indicator of prognosis, characterizing patients with diffuse membranoproliferative lesions as having the poorest 5-year kidney survival (40% to 85% depending on the studies).
Table 30-2 The International Society of Nephrology (ISN)/Renal Pathology Society (RPS) Classification of Glomerulonephritis in Systemic Lupus Erythematosus (SLE) (Revised 2003)
Minimal mesangial LN
Mesangial proliferative LN
Diffuse segmental (IV-S) or global (IV-G) LNb
Advancing sclerosing LN
Indicate the grade (mild, moderate, and severe) tubular atrophy, interstitial inflammation and fibrosis, severity of arteriosclerosis or other vascular lesions.
a Indicate the proportion of glomeruli with active and with sclerotic lesions.
b Indicate the proportion of glomeruli with fibrinoid necrosis and cellular crescents.
c Class V may occur in combination with class III or IV in which case both will be diagnosed.
LN, lupus nephritis.
Adapted from Weening JJ, D’Agati VD, Schwartz MM, et al. The classification of glomerulonephritis in systemic lupus erythematosus revisited. J Am Soc Nephrol 2004;15:241–50.
Marked chronic changes (glomerular sclerosis, fibrous crescents, interstitial fibrosis, and tubular atrophy) indicate a poor prognosis.
Recognition that the histologic class of the biopsy specimen may not be static and may either deteriorate or improve has emphasized the need for defining renal disease activity sequentially.
Central nervous system (CNS). Multifocal cerebral cortical microinfarcts associated with microvascular injury are the most common abnormalities associated with neuropsychiatric SLE. CNS lesions usually reflect vascular occlusion as a consequence of noninflammatory vasculopathy, leukoagglutination, thrombosis, vasculitis (rarely), and antibody-mediated neuronal injury.
Normal brain tissue is often present despite clinical abnormalities.
Cytoid bodies, seen as white fluffy exudates on funduscopic examination, represent superficial retinal ischemia.
Other visceral pathologic findings include Libman-Sacks verrucous endocarditis with redundant mitral valvular leaflets and lengthened chordae tendineae, pulmonary fibrosis, and nonspecific pleural thickening.
Necrotizing vasculitis may be present in the viscera and lead to secondary events, including bowel infarction, myocardial infarction, pancreatitis, and accelerated atherosclerosis.
In the spleen, the concentric periarterial fibrosis of small arteries (onion skin lesions) may be an end-stage consequence of earlier vasculitis.
Premature atherosclerosis can be found in coronary arteries and elsewhere.
Skin. Immunofluorescence shows deposits of Igs and complement at the dermal–epidermal junction (lupus band test) in 80% to 100% of lesional and 36% to 100% of nonlesional skin specimens.
Attempts to correlate a positive lupus band test result with active SLE, or the presence of lupus nephritis have given inconsistent results. Positive lupus band test results are not specific for lupus
Positive lupus band test is commonly associated with bullous pemphigoid and dermatitis herpetiformis (IgA). Dermal–epidermal immunofluorescence may also be seen in patients with rheumatoid arthritis, scleroderma, dermatomyositis, lepromatous leprosy, multiple sclerosis, cystic fibrosis, chronic active hepatitis, primary biliary cirrhosis, amyloidosis, and according to some reports, also in healthy individuals.
Kidney. Glomerular immunofluorescence to determine the distribution, pattern, and density of Ig, Ig class, and complement components does not appear to have prognostic or therapeutic significance. The presence of immunofluorescence for Ig or complement is not restricted to SLE; however, it is compatible with immune complex-mediated disease and its presence differentiates between SLE and ANCA-related disorders that do not demonstrate glomerular immunofluorescence and are therefore designated as “pauci-immune” nephritides.
A female-to-male ratio of 9:1 is seen in most series of adult patients. The female predominance is less striking in SLE that occurs in childhood (disease onset preceding puberty) and in elderly patients with SLE.
First symptoms usually occur between the second and fourth decades of life, but may be seen in any age group. The presentation of SLE in the elderly (as much as 10% of the total population with lupus in some series) may differ from that in younger patients.
III. ETHNIC DISTRIBUTION
Although lupus occurs in all races, its prevalence is not equally distributed among all groups. SLE occurs more commonly in blacks than in whites, and Hispanic and black patients have been noted to have more severe disease. The average annual incidence in the United States is approximately 27.5 in 1 million for white women and 75.4 in 1 million for black women. The reported prevalence figures for women vary widely, from 1 in 100 to 1 in 10,000.
I. SLE is a multisystem disease
in which the diagnosis rests on the recognition of a constellation of clinical and laboratory findings. No single finding makes the diagnosis, although some findings, such as antibodies to double-stranded DNA or a characteristic malar rash, are more suggestive than others.
II. American College of Rheumatology (ACR) criteria for classification
of SLE have been devised to ensure at least minimum uniformity for disease classification in clinical studies (see Appendix A). The presence of four criteria (not necessarily occurring simultaneously) is required to classify a patient as presenting with SLE.
is a common manifestation of active SLE. Although above 103°F at times, sustained fever of such magnitude is not common and should stimulate a search for infection. Acute severe disease (“lupus crisis”) may be accompanied by fever of up to 106°F.
Facial erythema is more common than the classic “butterfly” eruption as an acute cutaneous manifestation; photosensitivity dermatitis and bullous lesions may also occur. Subacute cutaneous LE includes both annular and papulosquamous lesions.
Chronic discoid lesions with central atrophy, depigmentation, and scarring or nonscarring alopecia are common occurrences in 20% to 30% of patients.
Mucous membrane lesions with ulcers of the hard palate and nasal septal perforations may be present.
Raynaud’s phenomenon may be associated with acrosclerosis and, rarely, with digital ulceration.
Purpura and ecchymosis may occur as a result of either the disease (e.g., thrombocytopenia) or the corticosteroid treatment.
V. MUSCULOSKELETAL SYSTEM
Arthritis is common and affects both small and large joints in a symmetric pattern. The axial spine is not involved. Even in the face of longstanding arthritis, bony erosions are uncommon. Reducible joint deformity is caused by capsular laxity and by both tendinous and ligamentous involvement, which lead to partial subluxation. Tendon ruptures may occur.
Septic arthritis can occur due to the immunosuppressed state of the patient and the presence of joint damage due to osteonecrosis.
Osteonecrosis, an important cause of disability in late lupus, presents with acute pain, most commonly in the hip, but more than 50% of patients have involvement of multiple joints.
Inflammatory myositis may occur in 5% to 10% of patients. Muscle weakness may also reflect corticosteroid-induced myopathy, chloroquine-induced myopathy as a rare occurrence, or a myasthenia gravislike syndrome associated with SLE.
VI. CARDIOVASCULAR SYSTEM
The major cardiovascular morbidity associated with SLE appears to be accelerated coronary artherosclerosis and ischemic coronary disease.
Atherosclerotic cardiovascular disease occurs in excess of that predicted by conventional cardiovascular risk factors and is considered to be related to systemic inflammation associated with SLE.
Pericarditis is the most common cardiovascular manifestation. Pericardial effusions demonstrable by echocardiogram may be present in up to 60% of patients. Symptomatic pericarditis occurs in approximately 25% of patients. Tamponade is rare.
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