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تعداد آیتم قابل مشاهده باقیمانده : -13 مورد

Systemic lupus erythematosus: Epidemiology and pathogenesis

Systemic lupus erythematosus: Epidemiology and pathogenesis
Authors:
Bevra H Hahn, MD
Insoo Kang, MD
Jinoos Yazdany, MD, MPH
Section Editor:
David S Pisetsky, MD, PhD
Deputy Editor:
Siobhan M Case, MD, MHS
Literature review current through: Apr 2025. | This topic last updated: Nov 11, 2024.

INTRODUCTION — 

Systemic lupus erythematosus (SLE) is a chronic, multisystem autoimmune disease that can have a wide array of disease manifestations, including constitutional symptoms, rashes, arthritis, hematologic abnormalities, and nephritis. It is most common in younger to middle-aged females, and certain demographic characteristics have been associated with worse disease outcomes. While the underlying disease pathogenesis is incompletely understood, it involves the development of one or more autoantibodies with the subsequent production of immune complexes and may be related to a variety of genetic, hormonal, and environmental factors. As researchers learn more about the various abnormalities in genetic and biologic pathways that cause SLE, it is possible that specific disease variants or subtypes may emerge. Indeed, studies have reported the subclassification of SLE patients into clusters with differences in clinical features based on bulk and single-cell transcriptomic analyses [1-3], although the utility of such tools in the clinical care of lupus patients is yet to be determined.

This topic explores the epidemiology and pathogenesis of SLE. The epidemiology and pathogenesis of lupus nephritis (LN) and antiphospholipid syndrome (APS) are discussed separately. (See "Lupus nephritis: Diagnosis and classification" and "Antiphospholipid syndrome: Pathogenesis".)

An overview of autoimmunity and the clinical manifestations, diagnosis, management, and prognosis of SLE in children and adults are also provided elsewhere:

●(See "Overview of autoimmunity".)

●(See "Childhood-onset systemic lupus erythematosus (cSLE): Clinical manifestations and diagnosis".)

●(See "Systemic lupus erythematosus in adults: Clinical manifestations and diagnosis".)

●(See "Systemic lupus erythematosus in adults: Overview of the management and prognosis".)

EPIDEMIOLOGY

Incidence and prevalence — Due to improved detection of mild disease, the incidence of systemic lupus erythematosus (SLE) nearly tripled in the last 40 years of the 20th century [4,5]. Estimated incidence rates are 1 to 25 per 100,000 in North America, South America, Europe, and Asia [6-9]. However, estimates in many regions are imprecise; for example, the prevalence in Africa is likely higher than previously thought [10].

The reported prevalence of SLE in the United States is 20 to 150 cases per 100,000 [11-13], with one meta-analysis reporting a prevalence of 73 out of 100,000 [11]. There is some variation based on sociodemographic factors [14]; as an example, one study found variation in prevalence rates from 164 per 100,000 in White females to 406 per 100,000 in African American females [15].

Sex — There is an increased frequency of SLE in female patients compared with male patients, with some variation across different age groups:

●In children, the female-to-male ratio is 3:1 [16].

●In adults, especially in females of childbearing years, the ratio ranges from 7:1 to 15:1 [15,16].

●In older adults, the ratio is approximately 8:1 [16].

The difference between sexes may be related to multiple factors, including the following:

●Hormones – Differences may reflect the hormonal effect of estrogen [17,18], which could explain why the sex difference is less pronounced in children. (See 'Hormonal factors' below.)

●Genetic factors – Factors related to the X chromosome may also be important in predisposing females to SLE. At least three predisposing gene variants are located on X chromosomes (IRAK1, MECP2, TLR7) [19]. There is also evidence for a gene dose effect, since the prevalence of XXY (Klinefelter syndrome) is increased 14-fold in male patients with SLE when compared with the general male population, whereas XO (Turner syndrome) is underrepresented in female patients with SLE [20]. Finally, X-chromosome inactivation might play a role in SLE susceptibility [21].

●Other factors – Sex-specific epigenetic modifications, such as deoxyribonucleic acid (DNA) methylation, and differences in gut microbiota between sexes may also play a role in SLE susceptibility [22]. Other potential explanatory factors include chronobiologic differences, intrauterine influences, pregnancy, microchimerism following pregnancies, and menstruation [23-25].

Male patients with SLE tend to have different disease manifestations than female patients, including higher rates of kidney disease, serositis, neurologic involvement, thrombosis, and cardiovascular disease [26].

Age at onset — SLE primarily occurs in female individuals of reproductive age, with 65 percent of patients with SLE experiencing disease onset between the ages of 16 and 55 [27]. Of the remaining cases, approximately 20 percent present before age 16 [28], and 15 percent present after age 55 [29,30].

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 [28,31]. By contrast, SLE tends to be milder in older adults, with a different incidence of certain clinical features (eg, higher prevalence of serositis and pulmonary involvement; lower incidence of kidney, nervous system, and hematologic involvement) and laboratory findings (eg, lower prevalence of hypocomplementemia, greater prevalence of rheumatoid factor [RF]) [31-34]. Notably, an older adult with new signs or symptoms is more likely to have drug-induced lupus than SLE. (See "Drug-induced lupus", section on 'Epidemiology'.)

Geography and race/ethnicity — Geography and race/ethnicity have been associated with variations in the prevalence of SLE, the frequency of clinical and laboratory manifestations, and the overall disease severity. When considering these reported differences, it is important to recognize that race and ethnicity are inherently imprecise, social constructs that are used to describe diverse populations [35]. Associations may therefore be related to other unmeasured factors such as genetics and social determinants of health, including access to quality health care, education level, neighborhood and physical environment, employment opportunities, environmental factors, and psychosocial stress [36-38]. (See "Use of race and ethnicity in medicine".)

With the limitations of these categories in mind, studies describing differences in the prevalence or disease manifestations of SLE based on race and ethnicity include the following:

●Prevalence – In the United States, the prevalence of SLE is higher among female individuals who are American Indian/Alaskan Native (270.6 per 100,000), followed by female individuals who are Black (230.9 per 100,000), Hispanic (120.7 per 100,000), White (84.7 per 100,000), and Asian/Pacific Islander (84.4 per 100,000) [11].

●Disease manifestations and severity – Large observational cohort studies suggest that there is an increased risk of severe disease manifestations in patients identifying with certain racial and ethnic groups.

•A cohort study of 724 patients with SLE identified differences in the prevalence and risk of developing multiple different disease manifestations; compared with White patients, the risk of developing lupus nephritis (LN) was higher for Hispanic, African American, and Asian/Pacific Islander patients (hazard ratio [HR] 2.3, 2.4, and 4.3, respectively), as was the risk of antiphospholipid syndrome (APS) in Asian/Pacific Islander and Hispanic patients (HR 2.5 and 2.6, respectively) [30].

•Similarly, in a cohort of 326 patients with SLE in the United States, the rates of nephritis, hematologic disease, and multiorgan involvement were higher in Asian and Hispanic patients compared with White patients [39].

PATHOGENESIS — 

While the pathogenesis of systemic lupus erythematosus (SLE) remains unknown and is clearly multifactorial, many clinical manifestations are directly or indirectly mediated by autoantibodies and the immune complexes they form with antigens. These and other immune system abnormalities are believed to be influenced by various genetic, hormonal, and environmental factors.

The pathogenesis of lupus nephritis (LN) and antiphospholipid syndrome (APS) are discussed in more detail elsewhere. (See "Lupus nephritis: Diagnosis and classification", section on 'Pathogenesis' and "Antiphospholipid syndrome: Pathogenesis".)

Overview — SLE is a prototypic autoimmune disease that arises from immune abnormalities influenced by the interplay of genetic, environmental, and hormonal risk factors. These abnormalities affect a variety of immune cell populations and lead ultimately to autoantibody production, immune complex formation, and aberrant cytokine expression. Immune complexes in SLE can also initiate tissue inflammation, most prominently in the kidney.

An essential feature of SLE is the production of autoantibodies to components of the cell nucleus (ie, antinuclear antibodies [ANAs]). These antibodies can bind to DNA, proteins, and complexes of proteins with nucleic acids (eg, DNA or ribonucleic acid [RNA]). ANAs can be divided into two broad classes based on reactivity to either to components of the nucleosome (a complex of DNA and histones) or to RNA-binding proteins (RBPs). Of these antibodies, antibodies to double-stranded DNA (dsDNA) and an RNA-protein complex called Smith (or Sm) are found almost exclusively in patients with SLE and represent markers for classification. While patients with SLE can also produce antibodies to other RBPs (eg, Ro/SSA and La/SSB), these ANAs are not specific for SLE.

In patients with SLE, ANA expression appears to be an antigen-driven response that arises from the presence of increased levels of the autoantigens in the blood (eg, nuclear material from dead and dying apoptotic cells) or defective clearance or removal of autoantigens. Once produced, anti-DNA antibodies can bind to DNA to form immune complexes that can mediate pathogenesis in two distinct ways. These complexes can induce local inflammation following deposition in tissue (eg, the kidney). In addition, complexes can stimulate the production of cytokines (especially type 1 interferon [IFN]) following uptake into innate immune cells and interaction with cytoplasmic nucleic acid sensors; these sensors are part of an internal host defense system that can be triggered when cell stress or infection leads to the presence of nucleic acid in the cytoplasm. Anti-RBP antibodies can also form immune complexes with their target antigens; these complexes can upregulate the production of type 1 IFN to perpetuate the cycle of autoreactivity and inflammation.

Genetic, environmental, and hormonal factors can influence the above immunologic abnormalities in multiple ways. As examples, genetic polymorphisms can lower the threshold for activation of B and T cells or interfere with the process of tolerance and thereby prevent the removal of autoreactive B cells. Environmental factors may increase exposure to autoantigens (eg, from apoptotic cells after exposure to ultraviolet light). Other social determinants of health have also been shown to affect the course and outcome of this disease [40]. (See 'Geography and race/ethnicity' above.)

Immune abnormalities — SLE is primarily a disease with abnormalities in immune regulation [41-43]. While numerous immune defects have been described in SLE, the etiology and clinical significance of these various abnormalities remains unclear. Information regarding normal function of the immune system, including antibody formation, is provided separately:

●(See "An overview of the innate immune system".)

●(See "The adaptive humoral immune response".)

●(See "The adaptive cellular immune response: T cells and cytokines".)

Autoantibodies — Autoantibodies associated with SLE are important diagnostically and are part of the underlying disease pathogenesis, although they usually precede clinical manifestations of SLE by years [44-46] and may be detected at lower levels in healthy people [47]. The clinical utility of specific autoantibodies in SLE, including ANAs (eg, Ro/SSA, La/SSB, Sm, U1 ribonucleoprotein [RNP]) and dsDNA antibodies [48-51], is discussed in more detail elsewhere. (See "Measurement and clinical significance of antinuclear antibodies" and "The anti-Ro/SSA and anti-La/SSB antigen-antibody systems" and "Antibodies to double-stranded (ds)DNA, Sm, and U1 RNP".)

Key factors in the production of autoantibodies in SLE include the following:

●Recognition of self-antigens – Autoantibodies in SLE react with a variety of self-antigens in the cell surface, nucleus, and cytoplasm, such as nucleic acids, nucleosomes, and cell membrane phospholipids. Self-antigens may be products of apoptosis, and the display of certain antigenic sites or epitopes can occur from abnormal processing [52-54] or possibly "mimicry peptides" derived from microorganisms that have sufficient structural similarity with immunodominant self-peptides [55]. They are primarily presented on cell surfaces or extracellular protein nets, particularly by cells that are activated or undergoing cell death (or NETosis in the case of neutrophils) [56,57].

●Abnormal production and regulation – Multiple processes promote an abnormal cycle of autoantibody production in SLE. When the antigen on antigen-presenting cells (eg, macrophages, B-lymphocytes, and dendritic cells [48,58]) forms a peptide-major histocompatibility complex (MHC) complex with an CD4+ autoreactive T cell, the T cell is activated and clonally expanded [55]. The autoreactive T cells then activate autoreactive B cells through direct contact and cytokine signaling (eg, interleukin 4 [IL-4], IL-6, and IL-10) [48,59]. This causes the B cells to proliferate and differentiate into antibody-producing cells that make an excess of antibodies to many nuclear antigens [48,58].

Activation of the innate immune system with release of IL-1, tumor necrosis factor (TNF)-alpha, type 1 IFN, B-cell activating factor (BAFF, also known as B lymphocyte stimulator [BLyS]), and A proliferation-inducing ligand (APRIL) promotes inflammation and survival of autoreactive B cells. Follicular helper T cells (Tfh) and IL-17-producing T cells (Th17) also promote autoantibody formation in tissue [60,61]; Tfh support high-affinity autoreactive B cells and lymphoid germinal center formation, while Th17 cells produce IL-21 that leads to tissue damage and B-cell survival. In untreated SLE, the increased autoantibody production and persistence is not downregulated appropriately by anti-idiotypic antibodies or regulatory immune cells (CD4+CD25hi-Foxp3+ regulatory T cells [Treg], Foxp3+CD8+ Tregs, Bregs, myeloid regulatory cells, and natural killer [NK] cells).

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, then finally to antibodies directed toward more limited epitopes on self-antigens [62]. Follicular helper T cells likely play a key role in this process of developing high-affinity antibodies [63,64]. The antibody idiotype (ie, the collective expression of changes in amino acids in the hypervariable region) may then stimulate and expand autoreactive T cells, thereby helping unique clones of B cells to expand [65]. The final result is the production of more specific ANAs [66].

Autoantibodies cause a pathogenic inflammatory reaction by either binding directly to their antigens or forming immune complexes (see 'Immune complexes' below). As an example, ANAs may interact with nuclear antigens expressed on cell surfaces, triggering cell injury and even death [67].

Certain SLE disease manifestations have been associated with antibodies directed towards specific cell-surface antigens [68]. A more detailed discussion of antibodies to neuronal cells in organic brain disease and antibodies to red blood cells, lymphocytes, and platelets is provided elsewhere. (See "Neurologic and neuropsychiatric manifestations of systemic lupus erythematosus", section on 'Attribution of a clinical syndrome to SLE' and "Systemic lupus erythematosus: Hematologic manifestations".).

The importance of autoantibodies in disease pathogenesis of SLE is underscored by the efficacy of various anti-B-cell therapies, such as belimumab (anti-BAFF B-cell growth factor) and probably rituximab (anti-CD20 antigen), and is also the impetus behind further testing of anti-CD19 chimeric antigen receptor (CAR) T-cell therapy. (See "Systemic lupus erythematosus in adults: Overview of the management and prognosis", section on 'Rituximab' and "Systemic lupus erythematosus in adults: Overview of the management and prognosis", section on 'Agents under investigation'.)

Immune complexes — Autoantibodies and antigens combine to form immune complexes, which persist in patients with SLE due to defective phagocytosis and clearance of immune complexes, apoptotic cells, and necrotic cell-derived material [57,69,70]. Immune complexes have been detected by immunofluorescence and/or electron microscopy in multiple areas affected by SLE and are especially important in the kidney. The pathogenic potential of immune complexes 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. As an example, different antibodies may bind to antigens at different sites in the glomerular capillary wall, leading to different histologic and clinical manifestations [71,72].

●The nature of the antigen, such as its size and charge. As an example, smaller, positively charged antigens are more able to cross the glomerular basement membrane and be deposited in the subepithelial region, where subsequent immune complex formation can lead to membranous nephropathy. (See "Lupus nephritis: Diagnosis and classification", section on 'Pathogenesis'.)

●The ability of the immune complexes 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 immune complexes are cleared from the circulation (by immunoglobulin Fc receptors on monocytes/macrophages in the liver and spleen) may be genetically impaired in SLE [73].

When cell-surface antigens form immune complexes with autoantibodies, they may cause organ damage through various mechanisms including activation of Fc receptors on macrophages of the reticuloendothelial system, complement-mediated cytotoxicity, and antibody-dependent cellular cytotoxicity (ADCC). Some antibody/antigen complexes, particularly those containing DNA or RNA/proteins, activate the innate immune system via toll-like receptor 9 (TLR9) or TLR7/TLR8, respectively. This produces cytokine patterns that favor continued autoantibody formation [74]. Specifically, dendritic cells release type 1 IFNs and TNF-alpha. Monocytes activated by immune complexes containing dsDNA or U1 RNP produce IL-1 beta via the activation of the NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome [75,76]. Additional cytosolic nucleic acid-sensing molecules such as the retinoic acid-inducible gene 1 (RIG-1)-like receptors (RLRs) and the cyclic GMP-AMP synthase (cGAS), which recognize dsRNA and DNA, respectively, may play a role in triggering innate immune cells to produce type 1 IFN and other cytokines [77].

Other immunologic abnormalities — Other types of immunologic abnormalities seen in SLE include the following:

●Cytokine abnormalities

•INF-alpha elevations – Most patients with SLE have elevated circulating levels of IFN-alpha and increased expression of IFN-alpha-inducible RNA transcripts by peripheral blood cells, especially in the setting of a disease flare [78-80]. Indeed, the type I IFN gene signature identified in peripheral blood cells of patients with SLE is observed in 60 to 85 percent of these patients [81]. These elevations may be due in part to predisposing genetic factors affecting IFN expression [82], including the SLE risk-enhancing PTPN22 C1858T allele [83]. Increased IFN production is also stimulated by immune complexes that form between ANAs and antigens that contain nucleic acid [84,85]. Recognition of these elevations led to the development of targeted treatments for SLE such as anifrolumab, which is an antibody that blocks a type 1 IFN receptor (IFNAR1). (See "Systemic lupus erythematosus in adults: Overview of the management and prognosis", section on 'Anifrolumab'.)

•BAFF elevations – BAFF (BLyS) levels are elevated in many patients with SLE and are essential for maturation and survival of post-bone marrow transitional and immature B cells into autoantibody-secreting plasmablasts and memory B cells [86]. 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 production is promoted by increased TLR activation and increased type 1 and 2 IFNs; in turn, BAFF promotes increased TLR activation. Clinical trials have demonstrated that belimumab, a monoclonal antibody to BAFF, is beneficial for the treatment of patients with SLE [86-89]. (See "Systemic lupus erythematosus in adults: Overview of the management and prognosis", section on 'Belimumab'.)

•Other cytokine abnormalities – Elevated levels of circulating TNF-alpha correlate with active disease, and TNF is expressed in kidney tissue in LN [90]. Increased levels of IL-4, IL-6, and IL-10 have also been observed [91]. However, IL-6 inhibitors have been tested for patients with SLE and are no more effective than placebo [92]; similarly, TNF-alpha inhibitors are not routinely used for treatment of SLE since there is a concern that low levels of TNF may promote certain types of autoimmunity, which could be related to the functions of TNF in altering T-cell cytokine production and inducing cell death [93]. In addition, TNF inhibitors have been associated with drug-induced lupus. (See "Drug-induced lupus".)

●Altered immune cell levels and function – An increase in circulating plasma cells (PC) and in an autoreactive subset of memory B cells is associated with disease activity in SLE [94,95]. Defects in B-cell tolerance lead to prolonged lives of autoreactive B cells [96-99]. There is also polyclonal activation of B cells and abnormal B-cell receptor signaling [100,101].

T-cell abnormalities include an increase in circulating and germinal follicular helper (CD4+) T cells and helper function by both CD4+ and CD8+ T cells [100,102,103]; a decreased number of peripheral regulatory T cells [104]; and impaired function of CD4+CD25+ Tregs [105].

SLE is also associated with increased numbers of circulating neutrophils that are undergoing NETosis (ie, a form of cell death specific for neutrophils and other myeloid cells). These cells release DNA bound to granule proteins in a mesh-like structure called NETs (neutrophil extracellular traps). NETs may stimulate anti-DNA and IFN-alpha production [46,106,107], probably involving TLR9.

Patients with SLE have dysregulation of apoptosis in various cell types, especially T lymphocytes [108], which is thought to be related to the development of autoantibodies to autoantigens derived from the apoptotic cells [109,110]. (See "Apoptosis and autoimmune disease", section on 'Systemic lupus erythematosus'.)

●Abnormal TLR signaling and expression – TLR7/TLR8 (recognizes RNA) and TLR9 (recognizes DNA) are involved in the IFN-alpha response [81,111] and monocyte activation [75,76]. Studies of SLE have identified abnormal TLR7 signaling in response to RNA and TLR9 signaling in response to DNA [112-114] as well as increased expression of TLR9 on peripheral blood B cells, PC, and dendritic cells [112,114-118]. This may mean that the innate immune system can activate B cells to secrete autoantibodies, 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 the effectiveness of glucocorticoids and account for the high doses sometimes required for therapy [119]. Antimalarial drugs (eg, hydroxychloroquine) used to treat some manifestations of SLE may block TLR7, TLR8, and TLR9 signaling. (See "Antimalarial drugs in the treatment of rheumatic disease", section on 'Mechanism of action'.)

●Abnormal cellular metabolism – Alterations in cellular metabolism control immune cell differentiation, proliferation, and function [120]. In normal immunity, mitochondria in lymphocytes use oxidative phosphorylation (OXPHOS) to generate adenosine triphosphate (ATP) [121]. In patients with SLE, CD4+ T cells and CD19+ B cells have dysfunctional mitochondria and elevations in activated mechanistic target of rapamycin (mTOR), resulting in depletion of ATP and increases in glycolysis, production of reactive oxygen species (ROS), and differentiation of naïve T cells into Th1, Tfh, and Th17 subsets.

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 [19,122-125]. Some of the single-nucleotide polymorphisms (SNPs) in SLE risk genes predispose to particular clinical subsets of SLE. However, except for the rare monogenic mutations, there is no single gene polymorphism that creates a high risk for SLE. Thus, it is highly likely that some combination of the presence of susceptibility genes, the absence of protective genes, and the presence of variants in other genes that influence cell function is required to "achieve" enough genetic susceptibility to permit disease development [126-128]. Moreover, genetic information accounts for only 30 to 40 percent of susceptibility to SLE, suggesting that additional epigenetic changes and/or environmental triggers are also required [129,130].

Stratification by disease phenotypes may be beneficial in genetic analyses of molecular pathogenesis, especially since there may be variants or subtypes of SLE. While most genetic studies in SLE have grouped all patients together, several have examined immunologic and clinical patient subsets [131-133]. As an example, in a GWAS study that stratified SLE patients by ancestry and extremes of phenotype in serology and serum IFN-alpha, a multistep 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 [134].

More information on genetic factors implicated in the development of SLE is provided below:

●Monogenic mutations – 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 exonuclease which degrades single-stranded DNA) [135]. Each of these mutations causes monogenic disease (defined as SLE patients who carry high penetrance either dominantly or recessively inherited pathogenic variants in a single gene [136]); they are relatively rare in the population. A heterozygous mutation in the TREX1 gene has been associated with familial chilblain lupus [137]. Similarly, polymorphisms in other DNA repair genes (ATG5, DNASE1) predispose to SLE [19,136]. Several monogenic lupus or lupus-like diseases are associated with interferonopathy and affect the levels of, or pathways in, the IFN system, particularly type 1. These include TNFAIP3, ribonuclease (RNase) H2A-H2B, IFIH1, and several others [136].

●MHC associations – The most common genetic predisposition for SLE 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 [138,139]. 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 predisposing genetic variants – 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 [140], and several of these genes are hypomethylated [141]. Overexpression of IFN-alpha-induced genes is found in the peripheral blood and tissues of 60 to 80 percent of patients with SLE [1,142]. 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 [83,142,143]. Most genetic influences are complex and depend on gene polymorphisms and gene expression, which is influenced by epigenetic modification, short-interfering RNAs (siRNAs), and gene copies. As an example, the expression of TLR7 protein depends upon genetic polymorphisms, their interaction with at least one microRNA (miRNA), and the number of gene copies [144,145].

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; C-reactive protein (CRP); and integrin alpha M [ITGAM]). In some cases, the genetic component is found in promoter regions (eg, IL-10) or is conferred by a variation in gene copy number rather than by different alleles (eg, FcgammaR3 and complement C4) [145-148]. Some of these genetic markers associated with SLE have differences based on their ancestral (racial) background [149].

There are known also associations between certain gene polymorphisms and specific clinical manifestations or laboratory findings in SLE (eg, arthritis, cytopenias, dermatitis, anti-DNA, anti-Ro/La, and anti-Sm) [70]. Genetic factors in the pathogenesis of LN are discussed in detail separately. (See "Lupus nephritis: Diagnosis and classification", section on 'Pathogenesis'.)

●Combined genetic risk – 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 [150]. A higher weighted genetic risk score was also associated with certain disease manifestations, including types of LN.

●Epigenetic changes – Epigenetic modifications (eg, hypo- or hypermethylation, histone acetylation) are important in the pathogenesis of SLE because they regulate gene transcription [141,151]. Some miRNA may influence these epigenetic modifications [152].

●Other changes – Other abnormalities in gene regulation and processing in patients with SLE include alterations in transcription factors, posttranscriptional regulation, messenger RNA (mRNA) editing, alternative splicing, and protein modification (eg, ubiquitination and folding) [153].

Hormonal factors — Multiple hormones have immunoregulatory function and may modulate the incidence and severity of SLE:

●Estrogen – Data to implicate estrogen in the pathogenesis of SLE are mixed. In the Nurse's Health study, females with more cumulative exposure to estrogen (eg, early menarche, treatment with estrogen-containing oral contraceptives or postmenopausal hormone replacement therapies) had an increased risk for SLE (HR of 1.5 to 2.1) [18,154]. However, other studies have not found a clear relationship between the incidence of SLE or SLE flares with varied estrogen levels or hormonal therapies [154-158]. Some researchers have noted that the balance between estrogen and progesterone may be important, as estrogen can stimulate the type 1 IFN pathway while progesterone may inhibit it [159].

Estrogen may predispose to the development of SLE through various pathways. 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 (vascular cell adhesion molecule [VCAM], intercellular adhesion molecule [ICAM]) [96,160]. In addition, estrogen reduces apoptosis in self-reactive B cells, thus promoting selective maturation of autoreactive B cells with high affinity for anti-DNA [161]. Other factors related to estrogen may include its role in upregulating IL-21 expression in CD4+ T cells [162], increasing macrophage proto-oncogene expression, and enhancing adhesion of peripheral mononuclear cells to endothelium [96].

●Progesterone and prolactin – Progesterone and prolactin also affect immune activity [163,164]. Progesterone downregulates T-cell proliferation and increases the number of CD8 T cells [163], while hyperprolactinemia has been associated with SLE flares [165]. In addition, both progesterone and high levels of estrogen promote a Th2 response, which favors autoantibody production [16].

●Androgens – Androgens tend to be immunosuppressive [166]. Serum levels of dehydroepiandrosterone (DHEA), an intermediate compound in testosterone synthesis, are low in nearly all patients with SLE.

●Hypothalamic-pituitary-adrenal axis – SLE patients appear to have an abnormal reaction to stress characterized by a heightened response to human corticotropin-releasing hormone (hCRH) [167].

●Thyroid hormones – Thyroid hormone may influence SLE, or vice versa. There is an increased incidence of thyroid disease in patients with SLE [168,169].

Environmental factors — The environment probably has a role in the etiology of SLE via its effects on the immune system. SLE has been associated with the following environmental factors:

●Infection – Various viral pathogens have been associated with the development of SLE, especially Epstein-Barr virus (EBV) [170-172]. Patients with SLE have higher circulating EBV viral loads and titers of EBV antibodies [173,174]. Some antibodies to EBV may target protein regions that homologous to human nuclear antigens [175]; antibodies to these molecular mimicry molecules, and to endogenous retroviruses, may contribute to the development of autoimmunity [176,177]. Viruses can also stimulate antigen-specific cells in the immune network [48,178,179].

There is also limited evidence to suggest that bacterial infections may increase immune activation and inflammation, which can activate autoreactive lymphocytes and therefore exacerbate SLE symptoms [180].

●Microbiome alterations – The balance of the microbiome of various organs likely contributes to autoimmunity [181]. Metagenome studies reported alterations in the gut bacteria such as Streptococcus and Clostridium species in patients with SLE, especially untreated ones [182,183]. In GWAS data of patients with SLE, some biological pathways of the genes with altered expression in the gut metagenome overlapped with SLE-specific biological pathways [182], suggesting the possible interaction between the gut microbiome and the host.

The relationship between SLE and the microbiome may be mediated in part by similarities between peptides in the microorganism and self-peptides, which could lead to autoantibody formation [55]. As an example, a study in SLE patients compared with healthy controls showed a fivefold increase of Ruminococcus gnavus (RG) in the intestinal microbiota, which 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]. In addition, cross-reactive responses between human Ro60 and human gut, oral, and skin microbiota have been found, and colonization of germ-free mice with only one Ro60 expressing commensal bacterium can induce the production of anti-human Ro60 IgG antibodies [184].

●Ultraviolet light exposure – The relationship between ultraviolet (UV) light exposure and SLE manifestations is likely related to multiple pathways. UV exposure can damage DNA and increase keratinocyte apoptosis, which can subsequently lead to the formation of anti-DNA antibodies, especially in the setting of abnormal clearance of apoptotic cells [185]. It may also stimulate keratinocytes to express more small nuclear RNPs (snRNPs) on their cell surface [186,187] and to secrete certain cytokines (eg, IL-1, IL-3, IL-6, granulocyte-macrophage colony-stimulating factor [GM-CSF], and TNF-alpha) that activate antibody-producing B cells. Other proposed mechanisms include increased binding of anti-Ro, anti-La, and anti-RNP antibodies to UV-activated keratinocytes [188]; altered cellular membrane phospholipid metabolism; increased IL-1 release from cutaneous keratinocytes and Langerhans cells; and increased inducible nitrogen oxide synthase (iNOS) expression and nitric oxide production in keratinocytes [189].

In addition to the local effects in skin, UV light may increase systemic autoimmunity through interference with macrophage activation and antigen processing, as well as promotion of autoreactive T cells, which is related to decreased DNA methylation and subsequent overexpression of lymphocyte function-associated antigen 1 (LFA-1) [190].

●Psychosocial stress and trauma – Psychosocial stress, specifically trauma and posttraumatic stress disorder (PTSD), is associated with both the onset and severity of SLE [191-194]. As an example, findings from the Nurses' Health Study II indicate that females with PTSD had almost a threefold increased risk of developing SLE compared with others in the cohort [191]. This may be related to some of the hormonal changes observed in patients with SLE, especially in the hypothalamic-pituitary-adrenal (HPA) axis [195]. (See 'Hormonal factors' above.)

●Tobacco use – Past and present cigarette smoking appears to be a risk factor for the development of SLE [196].

●Other factors – The risk of developing SLE may also be elevated after exposure to other factors, including silica dust (eg, found in cleaning powders), soil, and pottery materials [17,197-202]. Allergies to medications, particularly to antibiotics, are reported more frequently in patients with newly diagnosed SLE than healthy controls [179]. Finally, the role of unidentified environmental factors in the development of SLE is supported by the slightly higher prevalence of SLE in pet dogs of patients with SLE versus those without SLE [203].

There is not clear evidence of associations between SLE and the use of hair dyes, lipstick, occupational solvents, pesticides, or alcohol [199,204].

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.)

●Basics topics (see "Patient education: Lupus (The Basics)")

●Beyond the Basics topics (see "Patient education: Systemic lupus erythematosus (Beyond the Basics)")

SUMMARY

●Epidemiology – The estimated incidence of systemic lupus erythematosus (SLE) is 1 to 25 per 100,000 in North America, South America, Europe, and Asia. The prevalence of SLE in the United States is 20 to 150 cases per 100,000. (See 'Incidence and prevalence' above.)

•Sex – There is an increased frequency of SLE in female individuals compared with male individuals, with the female-to-male ratio ranging from 3:1 in children to up to 7:1 to 15:1 in adults. This may be related to differences in hormones (eg, estrogen) and genetic factors on the X-chromosome. (See 'Sex' above.)

•Age at onset – Approximately 65 percent of patients experience disease onset between the ages of 16 and 55, while 20 percent present before age 16 and 15 percent present after age 55. The disease course tends to be more severe in children and milder in older adults. (See 'Age at onset' above.)

•Geography and race/ethnicity – Geography and race/ethnicity have been associated with variations in the prevalence, manifestations, severity, and outcome of SLE. However, these associations are likely related to unmeasured factors, such as genetic variations and social determinants of health. (See 'Geography and race/ethnicity' above.)

●Pathogenesis – While the multifactorial pathogenesis of SLE remains unknown, many clinical manifestations are directly or indirectly mediated by autoantibodies and the immune complexes they form with antigens. These and other immune system abnormalities are believed to be influenced by various genetic, hormonal, and environmental factors. (See 'Overview' above.)

•Immune abnormalities – While there are numerous immune defects in patients with SLE, it is unclear which defects are primary and which are secondarily induced. (See 'Immune abnormalities' above.)

-Autoantibodies – Autoantibodies in SLE react with a variety of self-antigens in the cell surface, nucleus, and cytoplasm, such as nucleic acids, nucleosomes, and cell membrane phospholipids. These antibodies may cause an inflammatory reaction by either binding directly to their antigens or forming immune complexes. As an example, antinuclear antibodies (ANAs) target autoantigens within the cell nucleus; they may interact with nuclear antigens expressed on cell surfaces, triggering cell injury and even death, either by activating complement and/or by cell penetration. (See 'Autoantibodies' above.)

-Immune complexes – Autoantibodies and antigens combine to form immune complexes, which persist in patients with SLE due to defective phagocytosis and clearing of immune complexes, apoptotic cells, and necrotic cell-derived material. The immune complexes may cause organ damage through various mechanisms including activation of Fc receptors on macrophages of the reticuloendothelial system, complement-mediated cytotoxicity, and antibody-dependent cellular cytotoxicity (ADCC). (See 'Immune complexes' above.)

-Other immunologic abnormalities – Multiple other immunologic abnormalities have been identified in SLE, which have sometimes provided opportunities for the development of targeted therapies. As examples, most patients with SLE have elevated circulating levels of interferon (IFN)-alpha and B-cell activating factor (BAFF, also known as B lymphocyte stimulator [BLyS]); recognition of these elevations led to the development of anifrolumab (an antibody that blocks a type 1 IFN receptor) and belimumab (a monoclonal antibody to BAFF), respectively. (See 'Other immunologic abnormalities' 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 'Genetic factors' above.)

•Hormonal factors – Multiple hormones have immunoregulatory function and may modulate the incidence and severity of SLE, including estradiol, progesterone, and prolactin. (See 'Hormonal factors' above.)

•Environmental factors – The environment probably plays a role in the etiology of SLE via its effects on epigenetic changes and the immune system. Potential factors may include infection (eg, Epstein-Barr virus [EBV]), microbiome alterations, ultraviolet (UV) light exposure, psychosocial stress and trauma, and tobacco use. (See 'Environmental factors' above.)

ACKNOWLEDGMENT — 

The UpToDate editorial staff acknowledges Peter H Schur, MD, who contributed to earlier versions of this topic review.

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Topic 4669 Version 41.0

References

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14 : Update on prevalence of diagnosed systemic lupus erythematosus (SLE) by major health insurance types in the US in 2016.

15 : Prevalence of adult systemic lupus erythematosus in California and Pennsylvania in 2000: estimates obtained using hospitalization data.

16 : The role of sex hormones in systemic lupus erythematosus.

17 : Hormonal, environmental, and infectious risk factors for developing systemic lupus erythematosus.

18 : Reproductive and menopausal factors and risk of systemic lupus erythematosus in women.

19 : Recent insights into the genetic basis of systemic lupus erythematosus.

20 : Klinefelter's syndrome (47,XXY) in male systemic lupus erythematosus patients: support for the notion of a gene-dose effect from the X chromosome.

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25 : Overexpression of X-linked genes in T cells from women with lupus.

26 : Review: Male systemic lupus erythematosus: a review of sex disparities in this disease.

27 : Review: Male systemic lupus erythematosus: a review of sex disparities in this disease.

28 : Lupus in childhood.

29 : Clinical features of systemic lupus erythematosus: differences related to race and age of onset.

30 : Racial and Ethnic Differences in the Prevalence and Time to Onset of Manifestations of Systemic Lupus Erythematosus: The California Lupus Surveillance Project.

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34 : Clinical features and prognosis of late-onset systemic lupus erythematosus: results from the 1000 faces of lupus study.

35 : Reframing health disparities in SLE: A critical reassessment of racial and ethnic differences in lupus disease outcomes.

36 : A multiethnic, multicenter cohort of patients with systemic lupus erythematosus (SLE) as a model for the study of ethnic disparities in SLE.

37 : Prognosis in proliferative lupus nephritis: the role of socio-economic status and race/ethnicity.

38 : Epidemiology and sociodemographics of systemic lupus erythematosus and lupus nephritis among US adults with Medicaid coverage, 2000-2004.

39 : Race, Ethnicity, and Disparities in the Risk of End-Organ Lupus Manifestations Following a Systemic Lupus Erythematosus Diagnosis in a Multiethnic Cohort.

40 : Multiplicative Impact of Adverse Social Determinants of Health on Outcomes in Lupus Nephritis: A Meta-analysis and Systematic Review.

41 : Systemic lupus erythematosus.

42 : The basis of autoimmunity: Part I. Mechanisms of aberrant self-recognition.

43 : Cellular and molecular mechanisms of regulation of autoantibody production in lupus.

44 : Development of autoantibodies before the clinical onset of systemic lupus erythematosus.

45 : Clinical criteria for systemic lupus erythematosus precede diagnosis, and associated autoantibodies are present before clinical symptoms.

46 : Update on the cellular pathogenesis of lupus.

47 : Laboratory testing for the diagnosis, evaluation, and management of systemic lupus erythematosus: Still more questions for the next generations: A Tribute and Thanks and in Memory of my mentor: Henry G. Kunkel.

48 : Autoantibodies in systemic lupus erythematosus.

49 : Antinuclear antibodies: diagnostic markers for autoimmune diseases and probes for cell biology.

50 : Presence of nucleosome-restricted antibodies in patients with systemic lupus erythematosus.

51 : Autoantibodies and their significance.

52 : Lupus autoimmunity: from peptides to particles.

53 : Defective antigen-presenting cell function in patients with systemic lupus erythematosus.

54 : Serum amyloid P component controls chromatin degradation and prevents antinuclear autoimmunity.

55 : Selective binding of self peptides to disease-associated major histocompatibility complex (MHC) molecules: a mechanism for MHC-linked susceptibility to human autoimmune diseases.

56 : Autoimmune disease. A problem of defective apoptosis.

57 : Sources of autoantigens in systemic lupus erythematosus.

58 : B cells process and present lupus autoantigens that initiate autoimmune T cell responses.

59 : Immune cells and cytokines in systemic lupus erythematosus: an update.

60 : Follicular Helper T Cells in Systemic Lupus Erythematosus.

61 : Aberrant T Cell Signaling and Subsets in Systemic Lupus Erythematosus.

62 : Self antigens and epitope spreading in systemic autoimmunity.

63 : T follicular helper cell differentiation, function, and roles in disease.

64 : T Follicular Helper Cell Heterogeneity.

65 : Immune tolerance to autoantibody-derived peptides delays development of autoimmunity in murine lupus.

66 : Idiotypic induction of autoimmunity: a new aspect of the idiotypic network.

67 : Cell injury mediated by autoantibodies to intracellular antigens.

68 : Characterization of anti-endothelial cell antibodies in the patients with systemic lupus erythematosus: a potential marker for disease activity.

69 : Remnants of secondarily necrotic cells fuel inflammation in systemic lupus erythematosus.

70 : Remnants of secondarily necrotic cells fuel inflammation in systemic lupus erythematosus.

71 : Anti-DNA antibodies form immune deposits at distinct glomerular and vascular sites.

72 : Lupus autoantibodies interact directly with distinct glomerular and vascular cell surface antigens.

73 : Variant genotypes of the low-affinity Fcgamma receptors in two control populations and a review of low-affinity Fcgamma receptor polymorphisms in control and disease populations.

74 : Blood dendritic cells in systemic lupus erythematosus exhibit altered activation state and chemokine receptor function.

75 : Self double-stranded (ds)DNA induces IL-1βproduction from human monocytes by activating NLRP3 inflammasome in the presence of anti-dsDNA antibodies.

76 : U1-small nuclear ribonucleoprotein activates the NLRP3 inflammasome in human monocytes.

77 : The central role of nucleic acids in the pathogenesis of systemic lupus erythematosus.

78 : Interferon regulatory factors: critical mediators of human lupus.

79 : Deciphering systemic lupus erythematosus-associated serum biomarkers reflecting apoptosis and disease activity.

80 : Emerging concepts of type I interferons in SLE pathogenesis and therapy.

81 : Pathogenesis of systemic lupus erythematosus: risks, mechanisms and therapeutic targets.

82 : A common haplotype of interferon regulatory factor 5 (IRF5) regulates splicing and expression and is associated with increased risk of systemic lupus erythematosus.

83 : The PTPN22 C1858T polymorphism is associated with skewing of cytokine profiles toward high interferon-alpha activity and low tumor necrosis factor alpha levels in patients with lupus.

84 : Functional assay of type I interferon in systemic lupus erythematosus plasma and association with anti-RNA binding protein autoantibodies.

85 : Unique Interplay Between Antinuclear Antibodies and Nuclear Molecules in the Pathogenesis of Systemic Lupus Erythematosus.

86 : Belimumab for systemic lupus erythematosus.

87 : BAFF blockade for systemic lupus erythematosus: will the promise be fulfilled?

88 : A phase II, randomized, double-blind, placebo-controlled, dose-ranging study of belimumab in patients with active systemic lupus erythematosus.

89 : Efficacy and safety of belimumab in patients with active systemic lupus erythematosus: a randomised, placebo-controlled, phase 3 trial.

90 : Influence of functional interleukin 10/tumor necrosis factor-alpha polymorphisms on interferon-alpha, IL-10, and regulatory T cell population in patients with systemic lupus erythematosus receiving antimalarial treatment.

91 : New insights into the immunopathogenesis of systemic lupus erythematosus.

92 : Efficacy and safety of an interleukin 6 monoclonal antibody for the treatment of systemic lupus erythematosus: a phase II dose-ranging randomised controlled trial.

93 : Anti-Tumor Necrosis Factor-αInduced Systemic Lupus Erythematosus().

94 : Correlation between circulating CD27high plasma cells and disease activity in patients with systemic lupus erythematosus.

95 : Activated memory B cell subsets correlate with disease activity in systemic lupus erythematosus: delineation by expression of CD27, IgD, and CD95.

96 : Estrogens, the immune response and autoimmunity.

97 : Lupus: key pathogenic mechanisms and contributing factors.

98 : A critical role for complement in maintenance of self-tolerance.

99 : Defective B cell tolerance checkpoints in systemic lupus erythematosus.

100 : Systemic lupus erythematosus.

101 : B cell receptor signaling in human systemic lupus erythematosus.

102 : CD8+ lymphocytes from patients with systemic lupus erythematosus sustain, rather than suppress, spontaneous polyclonal IgG production and synergize with CD4+ cells to support autoantibody synthesis.

103 : Interleukin 21 correlates with T cell and B cell subset alterations in systemic lupus erythematosus.

104 : The Regulatory T Cell in Active Systemic Lupus Erythematosus Patients: A Systemic Review and Meta-Analysis.

105 : Deficient CD4+CD25high T regulatory cell function in patients with active systemic lupus erythematosus.

106 : The Role of Cell Death in the Pathogenesis of SLE: Is Pyroptosis the Missing Link?

107 : At the Bedside: Neutrophil extracellular traps (NETs) as targets for biomarkers and therapies in autoimmune diseases.

108 : Emerging and critical issues in the pathogenesis of lupus.

109 : Proteins phosphorylated during stress-induced apoptosis are common targets for autoantibody production in patients with systemic lupus erythematosus.

110 : Autoantigens in systemic autoimmunity: critical partner in pathogenesis.

111 : Nucleic acids of mammalian origin can act as endogenous ligands for Toll-like receptors and may promote systemic lupus erythematosus.

112 : The role of innate immunity in autoimmune tissue injury.

113 : Immunology. Discriminating microbe from self suffers a double toll.

114 : Role of pathogenic auto-antibody production by Toll-like receptor 9 of B cells in active systemic lupus erythematosus.

115 : Expansion of toll-like receptor 9-expressing B cells in active systemic lupus erythematosus: implications for the induction and maintenance of the autoimmune process.

116 : Toll-like receptor expression in lupus peripheral blood mononuclear cells.

117 : Human lupus autoantibody-DNA complexes activate DCs through cooperation of CD32 and TLR9.

118 : Regulation of lupus-related autoantibody production and clinical disease by Toll-like receptors.

119 : TLR recognition of self nucleic acids hampers glucocorticoid activity in lupus.

120 : Immune cell metabolism in autoimmunity.

121 : Immunometabolism in the pathogenesis of systemic lupus erythematosus: an update.

122 : Association of systemic lupus erythematosus with C8orf13-BLK and ITGAM-ITGAX.

123 : Review of recent genome-wide association scans in lupus.

124 : A nonsynonymous functional variant in integrin-alpha(M) (encoded by ITGAM) is associated with systemic lupus erythematosus.

125 : Advances in lupus genetics.

126 : A stop codon polymorphism of Toll-like receptor 5 is associated with resistance to systemic lupus erythematosus.

127 : A loss-of-function variant of PTPN22 is associated with reduced risk of systemic lupus erythematosus.

128 : Systemic lupus erythematosus genetics: insights into pathogenesis and implications for therapy.

129 : Genes, epigenetic regulation and environmental factors: which is the most relevant in developing autoimmune diseases?

130 : Epigenetics in the pathogenesis of systemic lupus erythematosus.

131 : Phenotypic associations of genetic susceptibility loci in systemic lupus erythematosus.

132 : Risk alleles for systemic lupus erythematosus in a large case-control collection and associations with clinical subphenotypes.

133 : Genetic Factors in Systemic Lupus Erythematosus: Contribution to Disease Phenotype.

134 : Genetic analysis of the pathogenic molecular sub-phenotype interferon-alpha identifies multiple novel loci involved in systemic lupus erythematosus.

135 : Genetics of SLE: mechanistic insights from monogenic disease and disease-associated variants.

136 : New Horizons in the Genetic Etiology of Systemic Lupus Erythematosus and Lupus-Like Disease: Monogenic Lupus and Beyond.

137 : Familial chilblain lupus--a monogenic form of cutaneous lupus erythematosus due to a heterozygous mutation in TREX1.

138 : High-density SNP screening of the major histocompatibility complex in systemic lupus erythematosus demonstrates strong evidence for independent susceptibility regions.

139 : Mapping of multiple susceptibility variants within the MHC region for 7 immune-mediated diseases.

140 : The genetics of type I interferon in systemic lupus erythematosus.

141 : Genome-Wide DNA Methylation Analysis of Chinese Patients with Systemic Lupus Erythematosus Identified Hypomethylation in Genes Related to the Type I Interferon Pathway.

142 : Cutting edge: autoimmune disease risk variant of STAT4 confers increased sensitivity to IFN-alpha in lupus patients in vivo.

143 : Association of the IRF5 risk haplotype with high serum interferon-alpha activity in systemic lupus erythematosus patients.

144 : MicroRNA-3148 modulates allelic expression of toll-like receptor 7 variant associated with systemic lupus erythematosus.

145 : TLR7 ligands induce higher IFN-alpha production in females.

146 : STAT4 associates with systemic lupus erythematosus through two independent effects that correlate with gene expression and act additively with IRF5 to increase risk.

147 : Copy number polymorphism in Fcgr3 predisposes to glomerulonephritis in rats and humans.

148 : Gene copy-number variation and associated polymorphisms of complement component C4 in human systemic lupus erythematosus (SLE): low copy number is a risk factor for and high copy number is a protective factor against SLE susceptibility in European Americans.

149 : The genetics and molecular pathogenesis of systemic lupus erythematosus (SLE) in populations of different ancestry.

150 : Higher Genetic Risk Loads Confer More Diverse Manifestations and Higher Risk of Lupus Nephritis in Systemic Lupus Erythematosus.

151 : Dissecting complex epigenetic alterations in human lupus.

152 : MicroRNAs--novel regulators of systemic lupus erythematosus pathogenesis.

153 : The applied basic research of systemic lupus erythematosus based on the biological omics.

154 : The effect of combined estrogen and progesterone hormone replacement therapy on disease activity in systemic lupus erythematosus: a randomized trial.

155 : Sex hormones and systemic lupus erythematosus: review and meta-analysis.

156 : Combined oral contraceptives in women with systemic lupus erythematosus.

157 : A trial of contraceptive methods in women with systemic lupus erythematosus.

158 : Menopause hormonal therapy in women with systemic lupus erythematosus.

159 : Modulation of autoimmune rheumatic diseases by oestrogen and progesterone.

160 : Hormonal regulation of B-cell function and systemic lupus erythematosus.

161 : Sex hormones and SLE: influencing the fate of autoreactive B cells.

162 : Oestrogen up-regulates interleukin-21 production by CD4(+) T lymphocytes in patients with systemic lupus erythematosus.

163 : Mechanism of immunosuppression of progesterone on maternal lymphocyte activation during pregnancy.

164 : The possible role of prolactin in autoimmunity.

165 : Association between prolactin and disease activity in systemic lupus erythematosus. Influence of statistical power.

166 : Sex hormones and the immune system--Part 1. Human data.

167 : Altered function of the hypothalamic stress axes in patients with moderately active systemic lupus erythematosus. I. The hypothalamus-autonomic nervous system axis.

168 : The association of autoimmune thyroiditis with systemic lupus erythematosus.

169 : Thyroid Disease in Lupus: An Updated Review.

170 : Viruses as potential pathogenic agents in systemic lupus erythematosus.

171 : An increased prevalence of Epstein-Barr virus infection in young patients suggests a possible etiology for systemic lupus erythematosus.

172 : Epstein-Barr virus as a potentiator of autoimmune diseases.

173 : Lupus and Epstein-Barr.

174 : Defective control of latent Epstein-Barr virus infection in systemic lupus erythematosus.

175 : Epstein Barr Virus and Autoimmune Responses in Systemic Lupus Erythematosus.

176 : Endogenous retroviral pathogenesis in lupus.

177 : Antibodies against human endogenous retrovirus K102 envelope activate neutrophils in systemic lupus erythematosus.

178 : Increased antiretroviral antibody reactivity in sera from a defined population of patients with systemic lupus erythematosus. Correlation with autoantibodies and clinical manifestations.

179 : Risk factors for development of systemic lupus erythematosus: allergies, infections, and family history.

180 : Bacterial infections in lupus: Roles in promoting immune activation and in pathogenesis of the disease.

181 : Lupus nephritis is linked to disease-activity associated expansions and immunity to a gut commensal.

182 : Metagenome-wide association study revealed disease-specific landscape of the gut microbiome of systemic lupus erythematosus in Japanese.

183 : An Autoimmunogenic and Proinflammatory Profile Defined by the Gut Microbiota of Patients With Untreated Systemic Lupus Erythematosus.

184 : Commensal orthologs of the human autoantigen Ro60 as triggers of autoimmunity in lupus.

185 : Skin sensitivity to UVB irradiation in systemic lupus erythematosus is not related to the level of apoptosis induction in keratinocytes.

186 : Experimental reproduction of skin lesions in lupus erythematosus by UVA and UVB radiation.

187 : Autoantigens targeted in systemic lupus erythematosus are clustered in two populations of surface structures on apoptotic keratinocytes.

188 : Enhanced membrane binding of autoantibodies to cultured keratinocytes of systemic lupus erythematosus patients after ultraviolet B/ultraviolet A irradiation.

189 : Chance, genetics, and the heterogeneity of disease and pathogenesis in systemic lupus erythematosus.

190 : Mechanisms of drug-induced lupus. II. T cells overexpressing lymphocyte function-associated antigen 1 become autoreactive and cause a lupuslike disease in syngeneic mice.

191 : Association of Trauma and Posttraumatic Stress Disorder With Incident Systemic Lupus Erythematosus in a Longitudinal Cohort of Women.

192 : The association of trauma with self-reported flares and disease activity in systemic lupus erythematosus (SLE).

193 : Relationships Between Adverse Childhood Experiences and Health Status in Systemic Lupus Erythematosus.

194 : Posttraumatic Stress Disorder and Risk of Systemic Lupus Erythematosus Among Medicaid Recipients.

195 : The link between post-traumatic stress disorder and systemic lupus erythematosus.

196 : The link between post-traumatic stress disorder and systemic lupus erythematosus.

197 : Cigarette smoking, alcohol consumption, and the risk of systemic lupus erythematosus: a case-control study.

198 : Occupational exposure to crystalline silica and risk of systemic lupus erythematosus: a population-based, case-control study in the southeastern United States.

199 : Occupational exposures and risk of systemic lupus erythematosus: a review of the evidence and exposure assessment methods in population- and clinic-based studies.

200 : Association of smoking with dsDNA autoantibody production in systemic lupus erythematosus.

201 : Occupational silica and solvent exposures and risk of systemic lupus erythematosus in urban women.

202 : Cigarette smoking and the risk of systemic lupus erythematosus: a meta-analysis.

203 : Pet dogs owned by lupus patients are at a higher risk of developing lupus.

204 : Alcohol consumption is not protective for systemic lupus erythematosus.