CHAPTER 274 SYSTEMICLUPUSERYTHEMATOSUS 1697

Genes that might account for increased lupus susceptibility or severity include those encoding components of the complement pathway, including C1q, C2, and C4A (Table 274-1). Impaired production of these early com-plement components may decrease the clearance of apoptotic cells, thereby augmenting the pool of available autoantigens, or decrease the solubility of immune complexes. Polymorphic variants in components of the toll-like receptor (TLR) pathways that regulate type I interferon production, includ-ing interferon regulatory factor 5 (IRF5), have been associated with a diag-nosis of SLE and increased plasma interferon activity in some populations. Association of SLE with the major histocompatibility complex (MHC) class II alleles human leukocyte antigen (HLA)-DR2 and HLA-DR3 has been documented in many studies and is most striking in patients expressing par-ticular autoantibody specificities. Polymorphisms in the Fc receptor genes FCGR2A and FCGR3A have been associated with SLE nephritis, possibly based on altered clearance of immune complexes. Variants of the PTPN22 gene, which encodes a phosphatase that regulates T-cell activation, are also associated with SLE. Genome-wide association studies have expanded the list of lupus-associated gene variants to include regulators of innate immune system activation (TNFAIP3, ITGAM, IRAK1) and signaling molecules important in lymphocyte activation (STAT4, BANK1, BLK, and LYN). Rare mutations in the TREX1 gene, encoding a DNase, have been documented in some patients with lupus-like disease and high levels of interferon. The avail-able data suggest a common theme: the genes that have been associated with lupus confer either increased activation or impaired regulation of the innate or adaptive immune responses, with increased type I interferon often observed in association with the risk genotype.

Environmental TriggersSeveral classes of potential environmental triggers for lupus have been studied. Although the female preponderance of SLE implies a role for hor-monal factors in the disease, recent concepts describe a possible contribution of epigenetic modification or dosage effects of the X chromosome as account-ing for at least some of the sex skewing. A role for microbial triggers, particu-larly virus infection, has been postulated consistent with the constitutional symptoms that often characterize the earliest stage of the disease. Epstein-Barr virus has garnered particular interest among investigators because the frequency of previous infection in SLE patients is significantly higher than in the general population (99 vs. 94%). Evidence of exposure to other viruses, including cytomegalovirus, is equivalent between SLE patients and healthy

274SYSTEMIC LUPUS ERYTHEMATOSUS MARY K. CROW

DEFINITIONSystemic lupus erythematosus (SLE) is a multisystemic autoimmune disease that results from immune systemmediated tissue damage. Manifestations of SLE can involve the skin, joints, kidney, central nervous system (CNS), car-diovascular system, serosal membranes, and the hematologic and immune systems. The disease is highly heterogeneous, with individual patients mani-festing variable combinations of clinical features. In most patients with SLE, the disease is characterized by a waxing and waning clinical course, although some demonstrate a pattern of chronic activity. The molecular triggers of the disease are not known, but the pathogenesis is understood to involve the production of autoantibodies exhibiting multiple specificities, with reactivity with nucleic acidbinding proteins being a common feature. Immune com-plexes, along with immune system cells and soluble mediators, generate inflammation and tissue damage. Therapeutic approaches generally involve immunosuppression.

EPIDEMIOLOGYA notable feature of SLE is that it occurs much more frequently in females than in males. Like Hashimotos thyroiditis and Sjgrens syndrome, the female-to-male ratio is approximately 8 : 1 to 9 : 1 in adults, and most cases are diagnosed between the ages of 15 and 44 years. In children and women older than 55, the ratio is closer to 2 : 1. The prevalence of SLE is estimated to be approximately 124 per 100,000 in the United States, and the incidence of new cases is 1.8 to 7.6 per 100,000 per year. The prevalence, severity, and characteristics of disease differ in different ethnic groups, with SLE being three to four times more frequent in African Americans than in the white population. The severity of disease is also greater in Hispanics than in whites, although data for Hispanic populations are less abundant. Asians may also have a higher prevalence of disease than whites. Recent studies of lupus in minority populations indicate that socioeconomic factors are major contrib-utors to the increased prevalence and severity of disease in African Americans and Hispanic Americans.

PATHOBIOLOGYCurrent understanding of lupus pathogenesis incorporates roles for genetic susceptibility based on a threshold model involving multiple genes; environ-mental triggers, including microbial infection, sunlight, and certain drugs; and altered immune system function. Recent advances in immunology have focused attention on the mechanisms that account for innate immune system activation. At least some of the genetic and environmental contributions to lupus are likely to promote innate immune system activation and subsequent autoimmunity. Others may contribute to inflammation and tissue damage.Murine models have proved useful in identifying genes that could contrib-

ute to lupus susceptibility or define patterns of disease. Production of auto-antibodies characteristic of SLE and development of nephritis and accelerated death have been demonstrated in numerous murine strains in which immune system genes have been modified. In most cases, no alterations have been noted in the homologous human genes. The ease of induction of lupus-like disease in murine models suggests that there are numerous possible patho-genic paths that might lead to the clinical manifestations of lupus. It is not known which of these molecular pathways is responsible for human SLE.

GeneticsAn important role for a genetic contribution to lupus susceptibility is sug-gested by the high concordance of disease in monozygotic twins (14 to 57%).

TABLE 274-1 GENESASSOCIATEDWITHSYSTEMICLUPUSERYTHEMATOSUS

GENE* PROTEINBANK1 B-cell scaffold protein with ankyrin repeats 1BLK B-lymphocytespecific tyrosine kinaseC1QA, B, and C Complement component C1qC2 Complement component 2C4A and C4B Complement component C4CRP C-reactive proteinDRB11501 MHC class II (DR2)DRB10301 MHC class II (DR3)FCGR2A Activating FcRIIAFCGR3A Activating FcRIIIAIRF5 Interferon regulatory factor 5ITGAM Mac1/complement receptor 3IRAK1 Interleukin-1 receptorassociated kinase 1LYN Lyn tyrosine kinasePTPN22 Protein tyrosine phosphatase nonreceptor type 22STAT4 Signal transducer and activator of transcription 4TNFAIP3 A20TNFSF4 Ox40 ligandTREX1 DNase III*Genes listed have an odds ratio of 1.3.MHC = major histocompatibility complex.

CHAPTER 274 SYSTEMICLUPUSERYTHEMATOSUS1698

control subjects. Ultraviolet light exposure is a well-described trigger of lupus flares. Possible mechanisms include DNA damage and induction of apoptosis of skin cells, which result in concentration of nucleic acids and associated proteins in cell membrane blebs and increased processing by antigen-presenting cells. Data also support an association between current tobacco use and anti-double-stranded DNA antibodies and lupus disease activity. Certain drugs, including procainamide and hydralazine, can induce a lupus-like syndrome, but the symptoms usually abate after discontinuing use of the drug. These agents may promote demethylation of DNA, thereby increasing the availability of immunostimulatory DNA. Sulfa antibiotics have been reported to induce lupus flare in some patients. Administration of recombi-nant interferon- to patients with hematologic malignancies or hepatitis C infection has been associated with induction of a lupus-like syndrome. In addition, antitumor necrosis factor agents have induced lupus autoantibod-ies and occasionally clinical lupus in patients with rheumatoid arthritis.

Immunologic TriggersGenetic and environmental factors that increase the probability of develop-ment of SLE are likely to act on the immune system to induce autoimmunity and consequent tissue inflammation and damage. In addition to mechanisms that increase the availability of self-antigens, such as ultraviolet light, altered expression of gene products that mediate or regulate apoptosis, or impaired clearance of apoptotic debris, results in generalized activation of the immune system and contributes to autoimmunity in lupus. In parallel with the events that account for effective immune responses directed at exogenous microbes, the autoimmunity that occurs in SLE patients is likely to require activation of both innate and adaptive immune responses. The innate immune response is first activated by common molecular patterns expressed on the microbe and results in augmented antigen-presenting cell capacity and successful gen-eration of an antigen-specific adaptive immune response. The characteriza-tion of the TLR family of pattern recognition receptors has provided new understanding of the mechanisms through which the innate immune system is activated by exogenous and endogenous stimuli, including nucleic acidcontaining immune complexes, and promotes induction of a self-directed adaptive immune response.

Type I InterferonRecent studies of gene expression in peripheral blood mononuclear cells of SLE patients using microarray technology have demonstrated that activation of genes regulated by type I interferon is a common feature in patients with active disease and may represent innate immune system activation. Interferon- is gaining attention as a soluble mediator that may be respon-sible for many of the immunologic alterations that have been observed in SLE and is identified as a potential therapeutic target. Immune complexes con-taining DNA or RNA are postulated to contribute to the production of type I interferon in SLE. Demethylated CpG-rich DNA or RNA associated with nucleic acidbinding proteins can activate plasmacytoid dendritic cells and other immune system cells through TLRs and thereby result in the produc-tion of type I interferon (interferon- or -) and other proinflammatory cytokines (E-Fig. 274-1). Diverse effects of type I interferon on immune system function are consistent with the altered immune responses observed in SLE patients, including maturation of dendritic cells, increased immuno-globulin (Ig) class switching to mature immunoglobulin isotypes (IgG and IgA), and induction of soluble mediators that increase B-cell differentiation and inflammatory responses, such as B-lymphocyte stimulator (BLyS) and interferon-. Induction of an immunostimulatory microenvironment by interferon- may support the development of a humoral immune response directed at self-antigens, particularly intracellular particles that contain nucleic acids and nucleic acidbinding proteins. It is not known why some individuals initiate immune system activation directed at self-antigens and others do not.

AutoantibodiesThe most characteristic lupus autoantibodies target intracellular particles containing both nucleic acid and nucleic acidbinding proteins. Understand-ing the significance of induction of these particular autoantibody specificities may provide clues to the etiology of SLE. A recent analysis of the spectrum of autoantibodies present in the sera of individuals in whom SLE is later diagnosed has suggested that autoantibodies reactive with certain RNA-binding proteins, including the Ro protein, occur early in the preclinical stage of the disease, along with a positive antinuclear antibody (ANA) test. These are often followed by anti-DNA antibodies and, finally, by the development

of antibodies specific for the spliceosomal proteins Smith (Sm) and ribonu-cleoprotein (RNP) at approximately the time of diagnosis (Fig. 274-1). These observations suggest that individuals who demonstrate progression from a narrow focus of humoral immunity to proteins associated with RNA to anti-bodies that bind DNA and other specificities are those in whom sufficient autoimmunity develops to manifest clinical symptoms. Approximately one third of SLE patients have autoantibodies reactive with phospholipids or the proteins associated with them, particularly 2-glycoprotein I (2GPI). These autoantibody specificities can also be present independently of SLE in primary antiphospholipid antibody syndrome (Chapter 177).

Immune Complexes and ComplementTissue and organ damage in SLE is mediated by the deposition or in situ formation of immune complexes and subsequent complement activation and inflammation. The complement system (Chapter 49), composed of more than 30 proteins that act in concert to protect the host against invading organ-isms, initiates inflammation and tissue injury. Complement activation pro-motes chemotaxis of inflammatory cells and generates proteolytic fragments that enhance phagocytosis by neutrophils and monocytes. The classic pathway is activated when antibodies bind to antigen and generate potent effectors. Alternative pathway activation mechanisms differ in that they are initiated by the binding of spontaneously activated complement components to the surfaces of pathogens or self-tissues. C3a, an anaphylatoxin that binds to receptors on leukocytes and other cells, causes activation and release of inflammatory mediators. C5a is a potent soluble inflammatory, anaphyla-toxic, and chemotactic molecule that promotes recruitment and activation of neutrophils and monocytes and mediates endothelial cell activation through its receptor. The release of reactive oxygen and nitrogen intermediates is an additional mechanism that contributes to tissue damage.Tissues targeted by immune system activity in lupus include the skin,

where immune complexes and complement are deposited in a linear pattern (as demonstrated in the lupus band test, in which deposited antibodies are identified by a fluorescent tag), the glomeruli, and heart valves. Recent data also suggest that antibodies reactive with hippocampal neurons in the brain can mediate excitotoxic death. Immune and inflammatory mechanisms responsible for the vasculopathy of lupus are multifactorial and not clearly defined. Microvascular damage is observed in splenic arteries and is charac-terized by the typical onion-skin pattern of concentric connective tissue deposition. In addition to vascular damage mediated by inflammation, thrombosis, including microthrombi, contributes to ischemia and cell necro-sis in the brain and other organs.

Time (yr)

Patie

nts

with

pos

itive

test

ANAAnti-RoAnti-LaAPLAnti-ds DNAAnti-SmAnti-nRNP

Diagnosis

2345 1 0 1 2 3 4 5

20

40

60

80

100

0

FIGURE 274-1. Proportionofpatientswithpositiveantibodytestsrelativetothetimeofdiagnosisorappearanceofthefirstclinicalmanifestationofsystemiclupuserythe-matosus(SLE).Foreachautoantibody,theproportionofpatientstestingpositiverelativeto the time of diagnosis or to the time of appearance of the first clinical criterion wasassessed.InanalysesofthetimefromantibodydevelopmenttothediagnosisofSLE,anti-nuclearantibodies(ANAs)appearedsignificantlyearlierthananti-Smantibodies(Z=3.22,P