Version May 2024
EPIDEMIOLOGY — The reported prevalence of systemic lupus erythematosus (SLE) in the United States is 20 to 150 cases per 100,000 [1-5]. In one meta-analysis, the prevalence was 73 out of 100,000. In women, prevalence rates vary from 164 (White individuals) to 406 (African American individuals) per 100,000 [1]. Due to improved detection of mild disease, the incidence nearly tripled in the last 40 years of the 20th century [6]. Estimated incidence rates are 1 to 25 per 100,000 in North America, South America, Europe, and Asia [2,7-9].
Geography and race appear to affect the prevalence of SLE and the frequency and severity of clinical and laboratory manifestations:
●The disease appears to be more common in urban than rural areas [1,10].
●In the United States, the prevalence of SLE is higher among Asian, African American, African Caribbean, and Hispanic American individuals compared with White individuals [2,7,8,10]. In European countries, the prevalence of SLE is also higher among individuals from Asia and Africa [2]. By comparison, SLE occurs infrequently in Africa [2,11].
●Photosensitivity and discoid skin lesions may be more frequent clinical manifestations in patients with Northern European ancestry than those with Southern European ancestry; the former group is, however, less likely to have anticardiolipin and anti-double-stranded deoxyribonucleic acid (anti-dsDNA) antibodies [12].
Sex — The increased frequency of SLE among women has been attributed in part to an estrogen hormonal effect [13,14] (see 'Hormonal factors' below). An estrogen effect is suggested by a number of observations, including the female-to-male ratio of SLE in different age groups:
●In children, in whom sex hormonal effects are presumably minimal, the female-to-male ratio is 3:1 [15].
●In adults, especially in women of childbearing years, the ratio ranges from 7:1 to 15:1 [1,15].
●In "older" individuals, especially post-menopausal women, the ratio is approximately 8:1 [15].
Factors related to the X chromosome may also be important in predisposing women to SLE. At least three predisposing gene variants are located on X chromosomes (IRAK1, MECP2, TLR7) [16]. There is also evidence for a gene dose effect, since the prevalence of XXY (Klinefelter's syndrome) is increased 14-fold in men with SLE when compared with the general population of men, whereas XO (Turner's syndrome) is underrepresented in women with SLE [17].
Other possibilities for female predisposition include: X-inactivation, imprinting, X or Y chromosome genetic modulators, differential methylation of DNA and acetylation of histones bound to DNA, intrauterine influences, chronobiologic differences, pregnancy, microchimerism following pregnancies, and menstruation [18-20].
However, it is important to note that SLE that occurs in men is slightly different clinically from that in women, and men tend to have worse outcomes [21].
Age at onset — Sixty-five percent of patients with SLE have disease onset between the ages of 16 and 55 [22]. Of the remaining cases, 20 percent present before age 16 [23] and 15 percent after age 55 [24]. Median ages at diagnosis for White females range from 37 to 50 years, in White males from 50 to 59, in Black females from 15 to 44, and in Black males from 45 to 64 [8].
Factors affecting disease outcome — Different epidemiologic subgroups (eg, race/ethnicity, sex, and age of onset) tend to have varying degrees of disease activity and may thus affect disease outcome:
●African American and Mexican Hispanic individuals in the United States have a poorer renal prognosis than White individuals, a finding not entirely independent of socioeconomic status [25]. African American individuals are more likely to have anti-Sm, anti-RNP, discoid skin lesions, proteinuria, psychosis, and serositis [25-27].
●The clinical status is poorer in those with less education [25,28]; this effect may reflect poor compliance [29]. Clinical status is also poorer in those with lower socioeconomic status and with inadequate access to medical care [30].
●The extent and degree of activity of SLE varies in different countries and in different ethnic groups [30-32].
●Men with lupus tend to have higher frequencies of renal disease, skin manifestations, cytopenias, serositis, neurologic involvement, thrombosis, cardiovascular disease, hypertension, and vasculitis than women [33]. By contrast, Raynaud phenomenon, photosensitivity, and mucosal ulceration are less frequent manifestations in men than women. Most, but not all studies suggest that men have a higher one-year mortality rate [33-38].
●SLE in children tends to be symptomatically more severe than in adults, with a high incidence of malar rashes, nephritis, pericarditis, hepatosplenomegaly, and hematologic abnormalities [23,34].
Lupus tends to be milder in older adults, who often have a presentation more similar to that of drug-induced lupus. Clinical features of lupus in older patients include the following [34,39-41]:
●A lower ratio of affected women to men than for younger patients
●Lower incidence of malar rash, photosensitivity, purpura, alopecia, Raynaud phenomenon, renal, central nervous system, and hematologic involvement
●Lower prevalence of anti-La, anti-Sm, and anti-RNP antibodies and of hypocomplementemia
●Greater prevalence of sicca symptoms, serositis, pulmonary involvement, and musculoskeletal manifestations
●Greater prevalence of rheumatoid factor
ETIOLOGY — The etiology of systemic lupus erythematosus (SLE) remains unknown and is clearly multifactorial. This suggests that SLE may in fact be more than one disease, with many clinical symptoms and different pathophysiologic abnormalities. Thus, in the future, SLE and its variants may be classified by having the same genetic and biologic pathway abnormalities rather than based on clinical manifestations (eg, the American College of Rheumatology [ACR] criteria) and serologic abnormalities (such as the various types of antinuclear antibodies).
We present below what is known about the various genetic factors, hormonal factors, and environmental factors, and how they might interact to cause the syndrome we refer to as SLE.
To date, at least 100 susceptibility loci increase risk for polygenic multifactorial SLE, and 30 genes cause the monogenic form of SLE and SLE-like phenotype [42]. However, it is not clear how these "monogenic" defects lead to SLE. Furthermore, some of these genetic defects, such as complement deficiencies, have been found in individuals without SLE.
Etiology can be understood best if SLE is considered to be caused initially by immune pathways that lead to pathogenic autoantibodies. Some autoantibodies react with antigens such as nucleic acids, nucleosomes, phospholipids in cell membranes, and other nuclear and cytoplasmic antigens derived from dead cells, dying cells, and particles containing DNA. These autoantibodies either form immune complexes or bind directly to their antigens and subsequently cause immune/inflammatory reactions that lead to disease.
Genetic factors — Genome-wide association studies (GWAS) have identified over 100 gene loci with polymorphisms (or mutations or copy numbers) that predispose to polygenic SLE (the vast majority of cases) as well as more than 30 genes (mostly via mutations) causing monogenic forms of SLE or SLE-like phenotypes [16,43-46]. However, this genetic information accounts for only 30 to 40 percent of susceptibility to SLE, suggesting a large component of environmental or epigenetic influences or undiscovered gene alterations. Genetic factors that confer the highest hazard ratios (HR) of 5 to 25 are deficiencies of the complement components C1q (required to clear apoptotic cells), C4A and B, C2, or the presence of a mutated TREX1 gene (encodes the 3’ repair endonuclease 1 enzyme that degrades DNA). Each of these causes monogenic disease (defined as SLE patients who carry high-penetrance either dominantly or recessively inherited pathogenic variants in a single gene [42]); they are relatively rare in the population. A heterozygous mutation in the TREX1 gene has been associated with familial chilblain lupus [47]. Similarly, polymorphism in other DNA repair genes (ATG5, DNASE1) predispose to SLE [16,42]. Several monogenic lupus or lupus-like diseases are associated with interferonopathy and affect the levels of, or pathways in, the interferon (IFN) system, particularly type 1. These include TNFAIP3, ribonuclease (RNase) H2A-H2B, IFIH1, and several others [42].
The most common genetic predisposition is found at the major histocompatibility (MHC) locus. The MHC contains genes for antigen-presenting molecules (class I human leukocyte antigens [HLA-A, -B, and -C] and class II HLA molecules [HLA-DR, -DQ, and -DP]) (see "Human leukocyte antigens (HLA): A roadmap"). The MHC also contains genes for some complement components, cytokines, and heat shock protein.
Predisposing loci, which include HLA-DR2 and HLA-DR3, are associated with HR of approximately 1.2 to 2.4, but the region is complex and involves multiple gene linkages across the entire 120-gene region in multiple ethnic groups [48,49]. Within HLA-DRB1 loci, HLA-DRB1*0301 and HLA-DRB1*1501 predispose to SLE, whereas HLA-DRB1*1401 reduces risk. The HR for predisposing HLA-DR/DQ is approximately 2.4 and is increased in patients homozygous for predisposing alleles, indicating a gene dose effect. HR for other genes varies from 1.2 to 2.3, with additional reports of significant, but relatively low HR-conferring, genes occurring at a rapid pace.
Other genes with predisposing variants involve some associated with innate immunity (IRF5, STAT4, IRAK1, TNFAIP3, SPP1, TLR7), most of which are associated with IFN-alpha pathways. Close to half of the genetic susceptibility loci associated with polygenic SLE involve type 1 IFN production or downstream signaling [50], and several of these genes are hypomethylated [51]. Overexpression of IFN-alpha-induced genes is found in the peripheral blood and tissues of 60 to 80 percent of patients with SLE [52,53]. This is not specific for SLE. Some of the lupus-predisposing polymorphisms in STAT4, PTPN22, and IRF5 are associated with high levels of or increased sensitivity to IFN-alpha [52,54,55]. Most genetic influences are complex and depend on gene polymorphisms and gene expression, which is influenced by epigenetic modification, short-interfering ribonucleic acids (siRNAs), and gene copies. As an example, expression of TLR7 protein depends upon genetic polymorphisms, their interaction with at least one microRNA (miRNA), and the number of gene copies [56,57].
Still other predisposing genes involve lymphocyte signaling (PTPN22, OX40L, PD-1, BANK-1, LYN, BLK), each of which plays a role in activation or suppression of T- or B-cell activation or survival. Other genes influence clearance of immune complexes (complement components C1q, C4, and C2 mentioned above; FcgammaRIIA; RIIIB; CRP; and integrin alpha M [ITGAM]). In some cases, the genetic component is found in promoter regions (eg, interleukin [IL]-10) or is conferred by a variation in gene copy number rather than by different alleles (eg, FcgammaR3 and complement C4) [57-60]. Some of these genetic markers associated with SLE have differences based on their ancestral (racial) background [61].
In addition to genome-encoded susceptibility genes, epigenetic modifications are important in the pathogenesis of SLE because they regulate gene transcription (generally hypomethylation increases transcription and hypermethylation decreases it); these include hypomethylation of DNA [51,62], especially in T and B lymphocytes and monocytes. The hypomethylation affects specific genes, as does variation in acetylation of histones. The influence of miRNA, some of which control epigenetic modifications, on transcription of several SLE-predisposing genes has been identified [62-64]. There may be as many as 1850 human transcription factors (TF). These interact with specific DNA-binding elements in the promoters of certain genes to promote transcriptional initiation. Defects in TF regulation play critical roles in the immune system. In SLE, both up-regulatory and downregulatory TFs have been identified [65]. Other abnormalities in SLE patients have also been described, not only in gene transcription but also in post-transcriptional regulation, messenger RNA (mRNA) editing, alternative splicing, and protein modification (such as ubiquitination and folding) [65].
In understanding the role of genes and their modifications in SLE, it is important to remember that many of the SLE genetic studies have included all patients with SLE together. However, several have studied immunologic and clinical subsets [66-68]. There are known associations between certain gene polymorphisms and nephritis (including genes that modulate the renal disease but do not predispose to SLE per se) [69], as well as genes associated with arthritis, cytopenias, dermatitis, anti-DNA, anti-Ro/La, and anti-Sm. An additional complexity of understanding mechanisms by which genes modulate disease is variability of gene and protein expression depending upon whether the source is whole blood, isolated peripheral blood mononuclear cells, neutrophils, monocyte/macrophages, dendritic cells, or B or T cells (including different subsets of these cell types) [70].
Stratification by disease phenotypes may be of benefit in genetic analyses of molecular pathogenesis. A GWAS of SLE patients stratified by ancestry and extremes of phenotype in serology and serum IFN-alpha, and using a multi-step screening approach, identified several loci of particular interest; each of these demonstrated a strong association with increased serum IFN-alpha and a particular serologic profile [71]. These included LRRC20 and PPM1H (both with anti-La), LPAR1 (with anti-Ro and –Sm), ANKS1A (with anti-Ro and anti-double-stranded DNA [anti-dsDNA]), and VSIG2 (with anti-RNP, but lacking anti-Sm). Additionally, SNPs in both PTPRM and LRRC20 were associated with increased serum IFN-alpha independent of serologic profile. The findings demonstrate heterogeneity in SLE molecular pathogenesis and indicate the potential importance of these variants for sub-phenotypes of SLE, because none of the SNPs were strongly associated with SLE in case-control analysis.
Some gene polymorphisms have also been associated with clinical subsets such as: anti-dsDNA (HLA-DR3, HLA-DQA1/DQA2, STAT4, UBE2L3, IR5, BANK1, BLK, ITGAM, ELF1, RASGRP3, PHLDB1, TMC2, NAALADL2, and NOTCH4/C6orf10), nephritis (HLASD2/DR3, STAT4, IRF5, IRF7, SLC15A4, IFIH1, TNFAIP3, TNIP1, UBE2L3, TNFSF4, IKZF1, ELF1, BLK, XKR6, ITGAM, FCGR21/3B,PDGFRA/GSX2, SLC5A11, ID4, and HAS2/SNTB1), cutaneous manifestations (IFIH1, IRF5, TNIP1, SLC15A4, TYK2, UBE2L3, RASGRP3, IKZF1, ITGAM, FCGAM, and FCGR2A), neurologic manifestations (STAT4, TNFAIP3, IL12B, ITGAM, and FCGR3A/3B), arthritis (ITGAM, MIR14GA, and IRF5), serositis (STAT4, TNIP1, and FCGR2A), oral ulcers (STAT4 and ETS1), and hematologic manifestations (TNFAIP3 and BLK) [72]. Polymorphisms in APOL1 predispose to worse kidney disease in all nondiabetic forms of nephritis, including lupus nephritis; the increased frequency of such variants in people with African ancestry may contribute to worse outcomes for these patients [73]. (See "Epidemiology of chronic kidney disease", section on 'Apolipoprotein L1 in African Americans'.)
In summary, except for the rare TREX1 mutation or deficiencies of early components of complement, there is no single gene polymorphism that creates high risk for SLE. Thus, some combination of the presence of susceptibility genes, the absence of protective genes (such as TLR5 polymorphism or loss-of-function PTPN22 variant), and the presence of variants in other genes that influence cell function is required to "achieve" enough genetic susceptibility to permit disease development [74,75]. It is highly likely that additional epigenetic changes and/or environmental triggers are also required [76,77]. While evidence describing the cumulative effect of genetic risk factors is limited, one cohort study of 1655 patients with SLE found that the combined number of genetic risk variants (as calculated by a weighted genetic risk score) was higher among patients with childhood-onset SLE versus those with disease onset in adulthood [78]. A higher weighted genetic risk score was also associated with certain disease manifestations, including types of lupus nephritis.
Hormonal factors — The immunoregulatory function of estradiol, testosterone, progesterone, dehydroepiandrosterone (DHEA), and pituitary hormones, including prolactin, has supported the hypothesis that they modulate the incidence and severity of SLE [14,15,79,80]. In support of the potential role of estrogens in predisposing to SLE, the Nurse's Health study showed that women with early menarche, or treated with estrogen-containing regimens such as oral contraceptives or postmenopausal hormone replacement therapies, have a significantly increased risk for SLE (HR of 1.5 to 2.1 ) [14,81]. However, others have either noted no effect of varied hormone levels, or treatment with hormones, on inducing lupus or flares thereof, or equivocal effects [79,81-84]. On the other hand, estrogen can stimulate the type 1 IFN pathway, while progesterone may inhibit it, suggesting that a balance between the two hormones may be important [85].
The pathogenic role of hormones in SLE may be related to their effects on immune responsiveness. Estrogen stimulates thymocytes, CD8+ and CD4+ T cells, B cells, macrophages, the release of certain cytokines (eg, IL-1), and the expression of both HLA and endothelial cell adhesion molecules (VCAM, ICAM) [86,87]. Estrogen also causes increased macrophage proto-oncogene expression and enhanced adhesion of peripheral mononuclear cells to endothelium [86]. Another potentially important effect of estradiol may be its ability to reduce apoptosis in self-reactive B cells, thus promoting selective maturation of autoreactive B cells with high affinity for anti-DNA [88]. Consequently, women are more predisposed to make autoantibodies that eventually lead to clinically apparent SLE. By comparison, androgens tend to be immunosuppressive [89]. Serum levels of DHEA, an intermediate compound in testosterone synthesis, are low in nearly all patients with SLE. Estrogen upregulates IL-21 expression in CD4+ T cells [90].
Progesterone and prolactin also affect immune activity [91,92]. Progesterone downregulates T-cell proliferation and increases the number of CD8 cells [91], while lupus flares have been associated with hyperprolactinemia [93]. In addition, both progesterone and high levels of estrogen promote a Th2 response, which favors autoantibody production [15].
Thyroid hormone may influence SLE, or vice versa. There is an increased incidence of thyroid disease in patients with SLE. In one study of 41 patients with SLE, for example, the incidence of both antithyroid antibodies (51 versus 27 percent) and elevated serum thyroid-stimulating hormone (TSH) levels (24 versus 12 percent) were higher than in controls [94].
Abnormalities of the hypothalamus-pituitary-adrenal axis may also exist among those with SLE. SLE patients appear to have an abnormal reaction to stress characterized by a heightened response to human corticotropin-releasing hormone (hCRH) [95].
Immune abnormalities — There are numerous immune defects in patients with SLE. However, the etiology of these abnormalities remains unclear; we do not know which defects are primary, genetically controlled, or secondarily induced. In certain cases, these immune defects are episodic, and some correlate with disease activity.
SLE is primarily a disease with abnormalities in immune regulation [96-98]. Anti-dsDNA antibodies are detected in the serum of all healthy individuals [99]. However, clinical assays for anti-dsDNA are calibrated in such a way that arbitrary units differentiate the levels in healthy individuals from patients with "definite" SLE. Thus, patients with SLE tend to make more anti-dsDNA antibodies than healthy individuals and most people with other diseases [99]. These abnormalities are thought to be secondary to a loss of self-tolerance; thus, affected patients (either before or during disease evolution) are no longer totally tolerant to all of their self-antigens and consequently develop an exaggerated autoimmune response [99-101].
The mediators of SLE are autoantibodies and the immune complexes they form with antigens; the autoantibodies are usually present for years before the first symptom of disease appears [102]. Self-antigens that are recognized are presented primarily on cell surfaces or extracellular protein nets, particularly by cells that are activated or undergoing apoptosis (or NETosis in the case of neutrophils), where intracellular antigens access cell surfaces where they can be recognized by the immune system [103,104].
Phagocytosis and clearing of immune complexes, of apoptotic cells, and of necrotic cell-derived material are defective in SLE, allowing persistence of antigen and immune complexes [72,104,105]. B cells/plasma cells (PC) that make autoantibodies are more persistently activated and driven to maturation by B-cell activating factor (BAFF, also known as B lymphocyte stimulator, BLyS) and by persistently activated T helper cells making B-supporting cytokines such as IL-6 and IL-10. In tissue, follicular helper T cells (Tfh) and IL-17-producing T cells (Th17) also promote autoantibody formation [106,107]. This induction of higher levels of autoantibodies than in healthy individuals reflects a defect in the mechanisms of self-tolerance [108]. Tfh support high-affinity autoreactive B cells and lymphoid germinal center formation. Th17 are enriched in renal tissue of lupus nephritis; they produce IL-21, which causes tissue damage and helps B cell survival. BAFF (BLyS), serum levels of which are elevated in many patients with SLE, is essential for maturation and survival of post-bone marrow transitional and immature B cells into autoantibody-secreting plasmablasts and memory B cells [109]. Both short- and long-lived PC make anti-DNA; targeting both might be desirable to suppress SLE; short-lived cells are more easily depleted by available approaches, such as by proteasome inhibitors. In untreated SLE, the increased autoantibody production and persistence is not downregulated appropriately by anti-idiotypic antibodies or regulatory immune cells (CD4+CD25hi-Foxp3+ Treg cells, Foxp3+CD8+ Tregs, CD4+T17regs, Bregs, myeloid regulatory cells, and natural killer [NK] cells).
Some antibody/antigen complexes, particularly those containing DNA or RNA/proteins, activate the innate immune system via TLR9 or TLR7, respectively. Thus, dendritic cells are activated and release type 1 IFNs and tumor necrosis factor (TNF)-alpha; T cells release IFN-gamma, IL-6, and IL-10; while NK and T cells fail to release adequate immunosuppressive quantities of transforming growth factor (TGF)-beta. NK cells also appear to be impaired in their regulatory function due to a subtype of NK cells that look like dendritic cells [110].These cytokine patterns favor continued autoantibody formation [111].
The innate immune system may also be activated by infections (bacterial or RNA- or DNA-containing viruses). Thus, both innate and adaptive immunity conspire to continually produce autoantibodies and to promote inflammation; if regulation of that response fails over time, clinical disease results.
There has been much interest in alterations in cellular metabolism that control differentiation, proliferation, and function of various immune cells [112]. In normal immunity, lymphocytes (and most eukaryotic cells) use oxidative phosphorylation (OXPHOS) to generate adenosine triphosphate (ATP); this occurs in mitochondria [113]. When cells are activated (effector helper T cells, plasmablast/plasmacytes), they switch to primarily a glycolytic pathway that begins in cell cytoplasm. Glucose (and some amino acids) activate energy through protein kinase pathways that include PI3K/Akt and mechanistic target of rapamycin (mTOR). mTOR, a serine/threonine protein kinase, senses nutrients, energy production, and redox potentials. It then controls additional energy activation/metabolic pathways, cell differentiation, survival, proliferation, autophagy, and protein production. In glycolysis, pyruvate is generated, which on entering mitochondria, activates the tricarboxylic acid (TCA)/Krebs cycle pathway, which generates ATP less efficiently than OXPHOS. Products of glycolysis include reactive oxygen species (ROS) that can damage cells and tissues. If, in contrast, the cells use glutaminolysis, the pentose phosphate (PPP) pathway activates and produces antioxidants; it is anabolic relative to catabolic effects of glycolysis. For example, macrophages of M1 type (pro-inflammatory) use aerobic glycolysis and generate ROS; the M2 type (healing) use the PPP pathway and have antioxidant properties. In contrast to glycolysis in activated T helper cells, the OXPHOS pathway is used by memory T, memory B, and regulatory T cells. Suppressing glycolysis results in higher numbers and function of Tregs. In patients with SLE, CD4+ T cells and CD19+ B cells have dysfunctional mitochondria and elevations in activated mTOR, resulting in depletion of ATP and increases in glycolysis, ROS production, and differentiation of naïve T cells into Th1, Tfh, and Th17 subsets. There is also abnormal cell persistence, autophagy, and cytokine production. Several investigators have suggested (and have in clinical trials) using in SLE patients inhibitors of mTOR such as rapamycin/sirolimus, inhibitors of glycolysis such as 2 deoxy-d-glucose, and inhibitors of mitochondrial transport chains such as metformin [114].
The following are some of the immune abnormalities that have been described in SLE that relate to the vicious cycle described in the preceding paragraphs:
●Elevated circulating levels of IFN-alpha and increased expression of IFN-alpha-inducible RNA transcripts by mononuclear cells, especially in patients with active disease, occur in blood and tissues of most SLE patients [115-122]. The elevated levels of IFN-alpha and increased expression of IFN-alpha-inducible transcripts may be due in part to the presence of predisposing genetic factors affecting IFN expression [123]. A similar increase in IFN-alpha-inducible transcripts occurs in synovial tissue [124]. Patients with the SLE risk-enhancing PTPN22 C1858T allele are more likely to have elevated circulating INF-alpha, which may contribute to inflammation [55].
●An increase in circulating PC and in an autoreactive subset of memory B cells is associated with disease activity in SLE [125,126]. By contrast, an increase in neutrophil signature was associated with nephritis in one study of patients with pediatric lupus [53].
●A decrease in cytotoxic T cells and in functions of suppressor T cells (which would normally downregulate immune responses) occurs in most patients [127].
●Impaired generation of polyclonal T-cell cytolytic activity occurs in some [128].
●An increase in circulating and germinal follicular helper (CD4+) T cells and helper function by both CD4+ and CD8+ T cells is characteristic [129-131].
●Polyclonal activation of B cells and abnormal B-cell receptor signaling [129,132].
●Multiple signaling abnormalities of T and B lymphocytes, including cellular hyperactivity and hyperresponsiveness, which may be partially due to genetically or epigenetically determined defects occur in most patients [107,133-135].
●Metabolic abnormalities occur in lupus T and B cells associated with mitochondrial hyperpolarization and dysfunction resulting in prolonged use of glycolytic pathways (decreasing ATP, generating ROS, promoting T cell differentiation into Th1, Tfh, and Th17 that promote B cell autoantibody production, reduction of regulatory T cells and their functions), rather than the more "protective" pathways of OXPHOS and PPP, which generate ATP more efficiently and provide antioxidants, respectively.
Dysfunctional signaling in T and B cells, which is manifested by increased calcium responses to antigen stimulation; hyperphosphorylation of cytosolic protein substrates; decreased nuclear factor kB; and abnormal voltage-gated potassium (Kv1.3) channels are implicated in facilitating excessive calcium entry into T cells [136,137]. IgG directed against CD3 (perhaps TCR on CD3+ cells) upregulates expression of CREM to the IL-2 promoter, which reduces IL-2 production; this effect requires CaMKIV [138]. These changes probably account for the decreased IL-2 production of lupus T cells, which might contribute to inability to generate adequate numbers of functioning regulatory T cells.
●Defects in B-cell tolerance, perhaps related to defects in apoptosis and/or complement deficiency, lead to prolonged lives of autoreactive B cells [86,139-141].
●Increased BAFF (BLyS) expression may promote autoimmunity. B cells have three receptors for BAFF: BAFFR, B-cell maturation antigen (BCMA), and transmembrane activator and calcium-modulator and cyclophilin ligand interactor (TACI) [109,142]. BAFF, which is produced primarily by neutrophils and monocyte/macrophages, increases survival of B2 cells after their transitional T1 phase (which means the B cells have survived several deleting and anergizing tolerance mechanisms), as well as survival of resting memory B cells and plasmablasts. Stimulation by BAFF is particularly important for the survival of T-dependent B cells, the source of many autoantibodies. (See "Normal B and T lymphocyte development".)
Increased BAFF (BLyS) production is promoted by increased TLR activation and increased type 1 and 2 IFNs; in turn, BAFF promotes increased TLR activation. Thus, BAFF can contribute to sustained autoantibody production by several mechanisms. Clinical trials have demonstrated that belimumab, a monoclonal antibody to BAFF, is beneficial for the treatment of patients with SLE, including lupus nephritis, for whom its use has been approved by the US Food and Drug Administration (FDA) [109,142-144]. A proliferation-inducing ligand (APRIL), made primarily by dendritic cells, binds TACI and an additional B-cell receptor, BCMA. In some conditions, APRIL promotes B-cell survival and in others can provide a negative signal.
●BTK (Bruton's tyrosine kinase), which affects B cell function through the B cell receptor is overexpressed in B cells, which leads to overproduction of ANA and immune complex deposition in glomeruli [145].
●Increased fetal microchimerism occurs during pregnancies in women with SLE [146], providing "foreign" antigens to the immune system.
●Increased levels of microparticles (MPs) are found in SLE. Microparticles are small, membrane-bound vesicles that contain DNA, RNA, nuclear proteins, cell-adhesion molecules, growth factors, and cytokines. These MPs are shed from cells during apoptosis or activation. MPs can drive inflammation and autoimmunity, including through immune complexes [147].
●Elevated levels of circulating TNF-alpha correlate with active disease, and TNF is expressed in renal tissue in lupus nephritis [148].
●Among patients with SLE treated with antimalarials, a genotype associated with low TNF and high IL-10 levels correlated with higher serum concentrations of IFN-alpha, while those with high TNF-alpha and low IL-10 levels had increased numbers of regulatory T cells [148].
●Increased numbers of circulating neutrophils that are undergoing NETosis, a form of apoptosis specific for neutrophils; these cells release DNA bound to protein in protein nets, which stimulates anti-DNA and IFN-alpha production [149-151], probably involving TLR9.
●Abnormally high levels of erythrocyte C4-derived activation fragments (C4d) and low levels of erythrocyte complement receptor (CR1) [152].
●Abnormal TLR7 signaling in response to RNA and TLR9 signaling in response to DNA [153,154] and increased expression of TLR9 on peripheral blood B cells, PC, and dendritic cells [153,155-159]. This means that B cells can be activated to secrete autoantibody by the innate immune system, independent of T-cell help.
●Stimulation of TLR7 or TLR9 reduces the immunosuppressive activity of glucocorticoids, suggesting that nucleic acid containing immune complexes that induce TLR signaling may limit effectiveness of glucocorticoids and may account for the high doses sometimes required for therapy [160]. Correspondingly, blocking stimulation of TLR7 or TLR9 may be useful therapeutically and restore sensitivity to glucocorticoids.
●Higher expression of TLR9 on B cells as well as low CH50 levels associated with increased SLE Disease Activity Index (SLEDAI) scores [157].
●Increased serum levels of HMGB1 (high mobility group box chromosomal protein 1) in patients with SLE is associated with disease activity [161,162]. Whether this is specific for SLE is as yet not clear; antibodies to HMG have been noted in patients with juvenile idiopathic arthritis [163].
●Disrupted T effector cell differentiation involving the Wnt/beta-catenin pathway contribute to immune dysfunction in SLE [164].
These changes promote the production of antinuclear antibodies (ANAs, see below). In addition, certain strains of mice (eg, those with the lpr, also known as Fas-/FasL- mutation) have a genetic defect in apoptosis, resulting in abnormal programmed cell death that allows the development of autoreactivity and the dramatic increase in an aberrant lymphoid population. Humans with a comparable mutation (ie, autoimmune lymphoproliferative syndrome) display abnormal lymphoproliferation in association with cytopenias and autoimmunity. In humans with lupus, dysregulation of apoptosis has been demonstrated among different cell types, particularly T lymphocytes and the Fas/Fas ligand pathway [133]; some SLE patients also have defective clearing of apoptotic cells [165]. (See "Apoptosis and autoimmune disease", section on 'Autoimmune lymphoproliferative syndrome'.)
C1q and antiphospholipid antibodies enhance opsonization and clearance [166-169]; thus, depressed levels of C1q and C4 may impair phagocytosis and delay clearance [170,171]. The act of phagocytosis results in a stimulation of the immune response to autoantigens derived from the apoptotic cells [172,173]. In addition, protein cleavage by caspases and granzyme B may promote the antigenicity of the contents of apoptotic cells [104].
Cleavage of complement with production of breakdown products is characteristic of most patients with active SLE. In fact, hypocomplementemia (especially in addition to rising serum levels of anti-DNA) is a fairly good predictor of disease flare. Measurement of C4d (a breakdown product) bound to erythrocytes and/or to B cells has been reported to distinguish SLE from similar diseases and perhaps to be useful in predicting flares [174].
As noted above, TLR7 and TLR9 may play a role in promoting autoimmunity. TLR7 and TLR9 are involved in the IFN-alpha response [175], and immune complexes containing DNA/autoantibody activate dendritic cells through cooperation of CD32 and TLR9 [158]; similarly, RNA-containing self-antigens can activate dendritic cells through TLR7 [159], both by innate immune stimulation via TLR7 (recognizes RNA) and TLR9 (recognizes DNA), which can directly stimulate B cells to make autoantibodies, and by T-cell stimulation of B cells via adaptive immunity as well as activating the INF-alpha response (see below) [151]. Antimalarial drugs (eg, hydroxychloroquine) used to treat some manifestations of SLE block TLR7 and TLR9 signaling.
These multiple defects cause a cascade of events that begins with abnormal cellular breakdown and ends with the production of autoantibodies. As cells break down abnormally, certain (especially nuclear and cryptic self peptides [176]) antigens are processed (perhaps abnormally [177,178]) into peptides by antigen-presenting cells such as macrophages, B lymphocytes, and dendritic cells [100,179]. Alternatively, microorganisms may be broken down within antigen-presenting cells into "mimicry peptides" that have sufficient structural similarity with immunodominant self peptides [180]. It is likely that the microbiome of many organs provides additional antigens to stimulate antibody formation. A study in SLE patients compared with healthy controls showed in the intestinal microbiota a fivefold increase in Ruminococcus gnavus (RG) of the Lachnospiraceae family, whereas other taxonomic microbial groups were decreased. In addition, the increase correlated with high SLE disease activity; antibodies to cell wall lipoglycans from RG correlated with active nephritis, high disease activity, high anti-dsDNA, and low C3 and C4 levels [181].
With any of these mechanisms, a peptide-MHC complex forms and stimulates the activation and clonal expansion of CD4+ autoreactive T cells [180]. These cells, via contact plus release of cytokines (eg, IL-4, IL-6, and IL-10) [100,182], cause autoreactive B cells to become activated, proliferate, and differentiate into antibody-producing cells that make an excess of antibodies to many nuclear antigens [100,179]. At the same time, activation of the innate immune system with release of IL-1, TNF-alpha, type 1 IFNs, BAFF (BLyS), and APRIL promotes inflammation and survival of autoreactive B cells. Thus, a specific immune profile develops that is characterized by the development of elevated levels of ANAs, especially to DNA, Sm, RNP, Ro, La, nucleosomes, and other nuclear antigens [100,183-185]. Several of these autoantibodies are important clinically. ANAs appear at some time during the course of disease in >95 percent of patients with SLE, so its absence on multiple testings suggests SLE is not the correct diagnosis. Anti-dsDNA is associated with higher risks for nephritis; anticardiolipins are associated with higher risk for clotting and fetal loss. Anti-Ro/SSA is associated with a chronic form of lupus dermatitis as well as with higher risk for neonatal lupus in babies of mothers with SLE.
ANAs are made to antigens from active sites on molecules involved in essential cellular functions (such as RNA splicing) [185]. With continued pressure over time from self-antigens, the immune response switches, via somatic hypermutation, from low-affinity, highly cross-reactive immunoglobulin M (IgM) antibodies; to high-affinity IgG antibodies; and then finally to antibodies directed toward more limited epitopes on self-antigens [186]. Idiotypes of antibodies may then stimulate autoreactive T cells to expand, thereby helping unique clones of B cells to expand [187]. The final result is the production of more specific ANAs [188], which may precede clinical manifestations by years [102,151,189].
Not all autoantibodies cause disease. In fact, all normal individuals make autoantibodies, although in small quantities. The variability in clinical disease that exists among different patients may therefore reflect the variability in the quality and quantity of the immune response, including regulatory networks.
Environmental factors — The environment probably has a role in the etiology of SLE via its effects on the immune system.
●Viruses, for example, may stimulate antigen-specific cells in the immune network [100,190,191]. In addition, trypanosomiasis or mycobacterial or Epstein-Barr virus (EBV) infections may induce anti-DNA antibodies or even lupus-like symptoms, and lupus flares may follow bacterial infections (perhaps related to bacterial CpG motifs) [136,192]. Patients with SLE also have higher titers of antibodies to EBV, have increased circulating EBV viral loads, and make antibodies to retroviruses, including to protein regions homologous to nuclear antigens [193,194]. In fact, studies in children with SLE suggest that EBV infection may be a triggering event resulting in clinical SLE [193]. Antibodies to these molecular mimicry molecules, and to endogenous retroviruses, may contribute to the development of autoimmunity [195,196]. The balance of the microbiome of various organs probably contributes to autoimmunity [181].
●There is limited evidence to suggest that bacterial infections may trigger increased immune activation and inflammation, thereby playing a role in potentially stimulating activation of autoreactive lymphocytes resulting in worsening lupus symptoms [197].
●Ultraviolet (UV) light may stimulate keratinocytes to express more snRNPs on their cell surface [198,199] and to secrete more IL-1, IL-3, IL-6, granulocyte macrophage colony-stimulating factor (GM-CSF), and TNF-alpha, thereby stimulating B cells to make more antibodies. In addition to the local effects in skin, UV light may also increase the degree of systemic autoimmunity by interfering with antigen processing by and activation of macrophages. UV light decreases T-cell DNA methylation, which may lead to overexpression of lymphocyte function-associated antigen (LFA)-1 [200]. These T cells may then become autoreactive, resulting in autoantibody formation.
●Silica dust, found in cleaning powders, soil, pottery materials, cement, and cigarette smoke, may increase the risk of developing SLE, especially in African American women [13,201-206].
●Allergies to medications, particularly to antibiotics, are reported more frequently in patients with newly diagnosed SLE than healthy controls [191].
●There is a slight, but significantly higher prevalence of lupus in pet dogs of patients with SLE (three cases among 59 pet dogs owned by 37 SLE patients, versus none among 187 dogs in non-SLE households) [207]. These observations suggest a possible common environmental factor for both human and dog systemic lupus.
●There is no apparent association between SLE and the use of hair dyes, lipstick, occupational solvent exposure, the use of pesticides, or alcohol consumption [203,208].
●Past and present cigarette smoking appears to be a risk factor for the development of SLE [209].
PATHOGENESIS OF CLINICAL MANIFESTATIONS — Although the exact etiology of systemic lupus erythematosus (SLE) remains obscure, it is clear that many of the clinical manifestations of SLE are mediated directly or indirectly by antibody formation and the creation of immune complexes (IC). As an example, IC deposition and subsequent complement activation in the kidney is responsible for much of the tissue damage of lupus nephritis (see "Lupus nephritis: Diagnosis and classification"). IC have also been detected (by immunofluorescence and/or electron microscopy) at the dermal-epidermal junction in both skin lesions and normal skin, as well as in the choroid plexus, the pericardium, and the pleural cavity.
The pathogenic potential of IC varies, depending on the following:
●The characteristics of the antibody, such as its specificity, affinity, charge, and ability to activate complement or other mediators of inflammation. In the glomerulus, for example, different antibodies may bind to antigens at different sites in the glomerular capillary wall, leading to different histologic and clinical manifestations [210,211].
●The nature of the antigen, such as its size and charge. Smaller cationic antigens, for example, are more able to cross the glomerular basement membrane and be deposited in the subepithelial region. The ensuing formation of IC should lead to membranous nephropathy rather than a proliferative glomerulonephritis. (See "Lupus nephritis: Diagnosis and classification", section on 'Pathogenesis'.)
●The ability of the IC to be solubilized by complement and bound to the complement receptor (CR1) on red blood cells (both systems may be defective in SLE).
●The rate at which the IC are cleared by immunoglobulin Fc receptors on monocytes/macrophages in the liver and spleen from the circulation may be genetically impaired in SLE [212].
Kidney disease — Initiation of kidney disease in SLE is likely due to the deposition or formation of immune complexes in the mesangium, subendothelial, or subepithelial spaces, with subsequent activation of complement.
IC in this disease consist of nuclear antigens (especially DNA), and high-affinity, complement-fixing immunoglobulin G (IgG) antinuclear antibodies (ANAs) [213] (especially IgG1 and IgG3 [214]), and antibodies to DNA [215]. These complexes either form in the circulation, where they are poorly cleared [216] or form in situ as free antibody binds to free antigen that has already deposited in the glomerulus or is an intrinsic glomerular antigen [217]. Histones have high affinity for the glomerular basement membrane (GBM) and may facilitate IC deposition [218]. Antibody reactivities in the serum that best correlate with active nephritis in human SLE are directed against DNA/chromatin or laminin/myosin/vimentin/heparan sulfate [219], suggesting the importance of these reactivities to pathogenesis.
Elevated levels of anti-DNA antibodies commonly precede development of clinical lupus nephritis. This was illustrated in a study of serum samples collected from military recruits. Among those who developed SLE and renal disease, 92 percent had elevated levels of anti-double-stranded DNA (anti-dsDNA) antibodies present before diagnosis [189]. In addition, the combination of a rising level (titer) of anti-DNA and evidence of increased complement activation (eg, rising C3a), if detected, may allow preemptive treatment and avoid lupus flares [220].
Once deposited in the mesangial or subendothelial aspect of the GBM, IC activate the complement system, thereby generating chemotactic factors that attract the infiltration of leukocytes and mononuclear cells. These cells phagocytose IC and release mediators (such as cytokines and activators of the clotting system) that perpetuate glomerular inflammation. With continuing IC deposition, chronic inflammation may ensue, ultimately leading to fibrinoid necrosis, scarring, and reduced renal function.
In addition, in situ antibody deposition occurring in the subepithelial space in lupus membranous nephropathy is not associated with cell damage. In this setting, complement is activated at a site that is separated from circulating inflammatory cells by the GBM [221]. As a result, these patients develop epithelial cell injury and proteinuria but not active inflammation and proliferative glomerulonephritis.
An important consideration for likelihood of developing chronic renal disease, or end-stage kidney disease, is the influence of immune deposition and complement activation on non-immune cells in the target tissue. When lupus nephritis begins, there is activation of endothelial cells, mesangial cells, podocytes, renal tubular epithelial cells, and tissue-fixed macrophages. It is possible that injury to any of these cells, or their combinations, activates pathways that can lead to glomerulosclerosis, interstitial nephritis, and interstitial fibrosis even if the initial offending immune attack subsides.
Cell-surface antibodies — SLE patients make antibodies to a number of cell-surface antigens. Antibodies to a 66-kDa membrane antigen have been implicated in lupus nephritis, vasculitis, and hypocomplementemia, as well as antibodies to a 55-kDa antigen and to an 18-kDa protein in thrombocytopenia [222], and antibodies to neuronal cells in organic brain disease (see "Neurologic and neuropsychiatric manifestations of systemic lupus erythematosus", section on 'Attribution of a clinical syndrome to SLE'). Cell-surface antibodies also attach to red blood cells, lymphocytes, and platelets (see "Hematologic manifestations of systemic lupus erythematosus"). In addition, ANAs may interact with nuclear antigens expressed on cell surfaces, triggering cell injury and even death, either by activating complement and/or by cell penetration [223].
These complexes are cleared from the circulation, and may cause organ damage, through one of the following mechanisms:
●Fc receptors on macrophages of the reticuloendothelial system
●Complement-mediated cytotoxicity
●Antibody-dependent cellular cytotoxicity (ADCC) resulting in hemolytic anemia, leukopenia, and thrombocytopenia
Antiphospholipid antibodies — Patients with SLE may form antibodies to a phospholipid-beta-2-glycoprotein I complex. Beta-2-glycoprotein I normally has an anticoagulant effect that is diminished by blocking effects of the antibody. This may explain why antiphospholipid antibodies are implicated in the etiology of the arterial and venous thromboses (causing strokes and thrombophlebitis), and in placental infarcts (causing miscarriages). Most antibodies that bind cardiolipin also bind beta-2-glycoprotein I; lupus anticoagulants are more likely to bind proteins required for thrombosis or clot lysis, such as thrombin. (See "Pathogenesis of antiphospholipid syndrome".)
Antiphospholipid antibodies, like ANAs, may be present prior to the diagnosis of SLE. This was illustrated in a study of a cohort of 130 patients for whom stored serum samples that preceded the SLE diagnosis were available [224]. The presence of anticardiolipin antibodies (ACA) was noted in 24 patients who later developed SLE. ACA were detected an average of three years prior to the diagnosis of SLE. In addition, the patients with anticardiolipin antibodies tended to develop more severe lupus than those without these antiphospholipid antibodies. Eleven patients with anticardiolipin antibodies developed thrombotic events prior to the diagnosis of SLE.
Skin lesions — Skin lesions are thought to be multifactorial in origin [225] (see "Overview of cutaneous lupus erythematosus"). In particular, exposure to ultraviolet (UV) light has a number of local effects in the skin:
●It damages DNA. The patient can then make antibodies to DNA, IC form, complement is activated, and a local inflammatory response ensues.
●It increases binding of anti-Ro, anti-La, and anti-RNP antibodies to UV-activated keratinocytes, which express those antigens in apoptotic blebs on the cell surface [226].
●It alters cellular membrane phospholipid metabolism. Portions of cell membranes may be rearranged so the usually cytoplasmic-facing surfaces (and potentially antigenic molecules) flip onto the extracellular surface.
●It increases interleukin (IL)-1 release from cutaneous keratinocytes and Langerhans cells.
●It increases apoptosis of keratinocytes in patients with SLE and in healthy persons, but clearance of apoptotic cells by phagocytes is abnormal [227].
●It induces inducible nitrogen oxide synthase (iNOS) expression and increased nitric oxide production in keratinocytes [228].
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Beyond the Basics topics (see "Patient education: Systemic lupus erythematosus (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●Epidemiology – The prevalence of systemic lupus erythematosus (SLE) in the United States is 20 to 150 cases per 100,000. The estimated incidence is 1 to 25 per 100,000 in North America, South America, Europe, and Asia. Both geography and race affect the prevalence of SLE and the frequency and severity of clinical and laboratory manifestations. The increased frequency of SLE among women has been attributed in part to an estrogen hormonal effect. (See 'Epidemiology' above and 'Sex' above.)
•Age at onset – Disease onset is between the ages of 16 and 55 in 65 percent of patients, but disease also occurs in both children and older individuals.
•Factors affecting disease outcome – Different epidemiologic subgroups, including those based upon race/ethnicity, sex, and age of onset, tend to have varying degrees of disease activity and may differ in their prevalence of given clinical manifestations, which may affect disease outcome. (See 'Age at onset' above and 'Factors affecting disease outcome' above.)
●Etiology – The etiology of SLE remains unknown and is clearly multifactorial. Many observations suggest a role for genetic, hormonal, immunologic, and environmental factors. (See 'Etiology' above.)
•Genetic factors – There is no single gene polymorphism that creates high risk for SLE, except for the rare TREX1 mutation or deficiencies of early components of complement. A combination of factors is likely required to achieve sufficient genetic susceptibility to permit disease development, which may include the presence of susceptibility genes, the absence of protective genes, and the presence of other genes that permit tissue injury after any type of insult. Additionally, some of the single-nucleotide polymorphisms (SNPs) in SLE risk genes predispose to particular clinical subsets of SLE. (See 'Etiology' above and 'Genetic factors' above.)
•Hormonal factors – Substantial evidence of the immunoregulatory function of estradiol, testosterone, progesterone, dehydroepiandrosterone (DHEA), and pituitary hormones, including prolactin, has supported the hypothesis that these hormones modulate the incidence and severity of SLE. (See 'Hormonal factors' above.)
•Immune abnormalities – There are numerous immune defects in patients with SLE. However, the etiology of these abnormalities remains unclear; we do not know which defects are primary and which are secondarily induced. In certain cases, these immune defects are episodic, and some correlate with disease activity. (See 'Immune abnormalities' above.)
•Environmental factors – The environment probably has a role in the etiology of SLE via its effects on epigenetic changes and the immune system. (See 'Environmental factors' above.)
●Pathogenesis of clinical manifestations – It is clear that many of the clinical manifestations are mediated directly or indirectly by antibody formation and the creation of immune complexes (IC). Initiation of renal disease in SLE is likely due to the deposition or formation of IC in the mesangium, subendothelial, or subepithelial spaces, with subsequent activation of complement. Activated fixed tissue macrophages in the kidney also play a major role in tissue damage. SLE patients make antibodies to a number of cell-surface antigens, such as those to a phospholipid-beta-2 glycoprotein I complex; these antibodies are involved in thromboembolic events and obstetric complications. Skin lesions are thought to be multifactorial in origin; ultraviolet (UV) light has local effects in skin and may increase the degree of autoimmunity. (See 'Pathogenesis of clinical manifestations' above.)
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