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Systemic lupus erythematosus (SLE) is a systemic autoimmune disease with multisystem involvement and is associated with significant morbidity and mortality. Genetic, immunological, endocrine, and environmental factors influence the loss of immunological tolerance against self-antigens leading to the formation of pathogenic autoantibodies that cause tissue damage through multiple mechanisms. This activity reviews the evaluation and management of systemic lupus erythematosus and highlights the role of the interprofessional team in caring for patients with this condition.
Systemic lupus erythematosus (SLE) is a systemic autoimmune disease with multisystemic involvement. The condition has several phenotypes, with varying clinical presentations from mild mucocutaneous manifestations to multiorgan and severe central nervous system involvement. Several immunopathogenic pathways play a role in the development of SLE. Hargraves described the lupus erythematosus (LE cell) in 1948. Several pathogenic autoantibodies have since been identified. Despite recent advances in technology and understanding of the pathological basis and risk factors for SLE, the exact pathogenesis is still not well known. Diagnosis of SLE can be challenging, and while several classification criteria have been posed, their utility in the clinical setting is still a matter of debate. Management of SLE is dictated by organ system involvement. Despite several agents shown to be efficacious in treating SLE, the disease still poses significant morbidity and mortality risk in patients.[1]
Familial segregation and high concordance rates in identical twins suggest a strong genetic contribution in SLE, although there is no obvious inheritance pattern. Concordant rates for identical twins have been reported as high as 50%. Over 100 gene loci with polymorphisms (or, rarely, copy numbers or mutations) have been identified to be associated with polygenic SLE (majority of cases), and more than 30 genes causing monogenic forms of SLE or SLE-like phenotype have been identified. These genes are associated with activation of the immune system in response to foreign antigens, self-antigen generation, and activation of innate and adaptive immune systems. Some gene mutations that are rare but are considered very high risk for the development of SLE include deficiencies of early complement components C1q, C1r, C1s (>90% risk), C4 (50%), C2 (20%), and TREX1. Some of the other genes associated include HLA-DRB1, HLA-DR2, HLA-DR3, HLA-DRX, TNFAIP3, STAT-4, STAT-1, TLR-7, IRAK1/MECP2, IRF5-TNPO3, ITGAM, etc. The most common genetic predisposition is located 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]).[2]
Several environmental triggers of SLE have been identified. Several drugs have been implicated in causing a lupus-like phenomenon by causing demethylation of DNA and alteration of self-antigens. While procainamide and hydralazine have the highest incidence of causing drug-induced lupus, more than 100 drugs have been associated with drug-induced lupus. Further, several drugs such as the sulfa-drugs are well known to cause flares in patients with SLE. Ultraviolet rays and sun exposure lead to increased cell apoptosis and are well-known triggers for SLE. Several viral infections have been implicated, and the underlying mechanism is thought to be molecular mimicry. Antibodies against Epstein-Barr virus (EBV) are more prevalent in children and adults with SLE compared to the general population. Smoking is also thought to be a risk, with a dose-response. Other potential risk factors include silica exposure, other viral infections, vitamin D deficiency, alfalfa sprouts, and foods containing canavanine.[4]
The pathogenesis of SLE is complex, and the understanding of SLE pathogenesis is constantly evolving. A break in the tolerance in genetically susceptible individuals on exposure to environmental factors leads to the activation of autoimmunity. Cell damage caused by infectious and other environmental factors exposes the immune system to self-antigens leading to activation of T and B cells, which become self-sustained by a chronic self-aimed immune response. Cytokine release, complement activation, and autoantibody production lead to organ damage.
Both innate and adaptive immune systems play a role in the pathogenesis of SLE. The innate immune system activation is either Toll-like receptor (TLR) dependent or independent. The cell membrane-bound TLRs (TLR 2, 4, 6) are activated on exposure to the extracellular DNA and RNA from dying cells, which leads to downstream activation of the interferon regulatory family (IRF-3), NF-κB, and MAP-kinases, which serve as transcription factors for the production of proinflammatory mediators such as IFN-b. The endosomal TLRs (TLR 7, 9) are activated by single-stranded RNA and demethylated DNA, leading to interferon-alpha production and RNA binding autoantibodies such as antibodies against Ro La, Sm, and RNP. The TLR-independent pathway is activated by intracytoplasmic RNA sensors (RIG-1, MDA-5) and DNA sensors (IFI16, DAI) and leads to activation of IRF3 and NF-κB. Both self DNA/RNA and foreign DNA/RNA, such as from viruses, can lead to this activation. NETosis has recently gained attention in the pathogenesis of SLE. On activation by various factors such as cytokines, activated platelets, and vascular endothelial cells, neutrophils systematically release their nuclear aggregates in the extracellular environment. These nuclear aggregates can then promote Interferon-alpha production by the dendritic cells, mediate thrombosis and vascular damage and serve as self-antigens for T-lymphocytes.
T-lymphocytes and B-lymphocytes play a significant role in the pathogenesis of SLE. Apoptotic and damaged cell-derived antigens are presented to T-cells by antigen-presenting cells. T-cells in SLE display a distorted gene expression leading to the production of several cytokines. These T-cells produce less IL-2, which leads to altered regulatory T-cell production. Increased IL-6, IL-10, IL-12, and IL-23 increase mononuclear cell production while increased IL-17 and IL-21 lead to increased T-cel production. Increased Interfern-γ leads to defective T-cell production. T-cells lead to the activation of autoreactive B-cells by CD40L and cytokine production, leading to autoantibody production, a hallmark of SLE. Toll-like receptors on interaction with DNA and RNA lead to activation of these B-cells, and the nucleic acid and protein-containing intranuclear complexes are the most prominent antigens leading to B-cel activation. These autoantibodies are pathogenic and cause organ damage by immune complex deposition, complement, and neutrophil activation, altering cell function leading to apoptosis and cytokine production.[4][6]
Further, the autoreactive B-cells in SLE, stimulated by self-antigens, are not readily eliminated due to a deficiency of the process involved in the functional neutralization of autoreactive B cells. The B-cells can also serve as antigen-presenting cells and activate T-cells by presenting internalized soluble antigens to T-cells. This creates a loop where both B and T cells activate each other, leading to more autoimmunity.[7]
Vasculitis is common in SLE, and vascular lesions may demonstrate various pathologies. Immune complex deposition with an inflammatory response is the most common lesion, although it may be seen without a significant inflammatory response. Small and large vessel necrotizing vasculitis with fibrinoid necrosis is less common but can be seen and differentiated from other vasculitides by immune complex deposition in the vessel wall. Thrombotic microangiopathy can present in patients with SLE and antiphospholipid antibody syndrome.[8]
SLE is a multisystem disease with several phenotypes. Clinical features may vary from a very mild disease with only mucocutaneous involvement to severe life-threatening disease with multiorgan involvement. All organ systems can be involved in SLE. An autoantibody profile can sometimes help predict the disease course and clinical features. Several studies have indicated the development of serological abnormalities several years before the onset of clinical lupus. This is termed pre-clinical lupus, where a patient may have serological abnormalities consistent with SLE and may have some clinical features but still does not meet the criteria for SLE. There is evidence that a significant percentage of these patients with pre-clinical lupus, including those with incomplete lupus or undifferentiated connective tissue disease, may transition to clinical lupus and fulfill the SLE criteria later in life.
Subacute cutaneous lupus erythematosus (SCLE) rash is a photosensitive, widespread, nonscarring, nonindurated rash. SCLE may be either papulosquamous resembling psoriasis or an annular/polycystic lesion with central clearing and peripheral scaling. SCLE lesions may last several months but usually, heal without scarring. SCLE rash is seen in patients with a positive Anti-Ro (SSA) antibody in up to 90% of the cases. SCLE can also be caused by some drugs such as hydrochlorothiazide.[3] It has also been reported in patients with Sjogren syndrome and rheumatoid arthritis.[4]
Anemia is present in more than 50 % of patients with SLE and most commonly is anemia of chronic disease. Other causes of anemia in SLE may include iron deficiency anemia, coomb's positive autoimmune hemolytic anemia, red blood cell aplasia, and microangiopathic hemolytic anemia, which may be associated with antiphospholipid antibody syndrome. Leukopenia secondary to neutropenia or lymphopenia is also very frequent and severe. Thrombocytopenia can be mild or severe and may be associated with antiphospholipid antibody syndrome and autoantibodies against platelets, glycoprotein IIb/IIIa, or thrombopoietin receptor. Pancytopenia is not infrequent and may occasionally be associated with myelofibrosis. Soft non-tender lymphadenopathy is common in SLE, although rare cases of histiocytic necrotizing lymphadenitis have been reported (Kikuchi-Fujimoto disease). Splenomegaly is common in SLE, while splenic atrophy and asplenism have been reported. 2ff7e9595c
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