Systemic Lupus Erythematosus

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Systemic Lupus Erythematosus
Luísa Abrante
Group 3
The Immune System
It is made up of various organs, cells and proteins. The immune system has a vital role: It protects your body from harmful substances, germs and cell changes that could make you ill. 
Without an immune system, we would have no way to fight harmful things that enter our body from the outside or harmful changes that occur inside our body. The main tasks of the body’s immune system are:
To fight disease-causing germs (pathogens) like bacteria, viruses, parasites or fungi, and to remove them from the body,
To recognize and neutralize harmful substances from the environment, and
To fight disease-causing changes in the body, such as cancer cells.
How the immune system is activated 
The immune system can be activated by a lot of different things that the body doesn’t recognize as its own. These are called antigens. Examples of antigens include the proteins on the surfaces of bacteria, fungi and viruses. When these antigens attach to special receptors on the immune cells (immune system cells), a whole series of processes are triggered in the body. Once the body has come into contact with a disease-causing germ for the first time, it usually stores information about the germ and how to fight it.
The immune system is made up of two parts: the innate, (non-specific) immune system and the adaptive (specific) immune system. These two systems work closely together and take on different tasks.
The Innate Immune System: Fast and general effectiveness
The innate immune system is the body's first line of defense against germs entering the body. It responds in the same way to all germs and foreign substances, which is why it is sometimes referred to as the "nonspecific" immune system. It acts very quickly: For instance, it makes sure that bacteria that have entered the skin through a small wound are detected and destroyed on the spot within a few hours. The innate immune system has only limited power to stop germs from spreading, though. The innate immune system consists of:
Protection offered by the skin and mucous membranes;
Protection offered by the immune system cells (defense cells) and proteins;
The adaptive immune system: Fighting the germs directly
The adaptive immune system takes over if the innate immune system is not able to destroy the germs. It specifically targets the type of germ that is causing the infection. But to do that it first needs to identify the germ. This means that it is slower to respond than the innate immune system, but when it does it is more accurate. It also has the advantage of being able to "remember" germs, so the next time a known germ is encountered, the adaptive immune system can respond faster.
This memory is also the reason why there are some illnesses you can only get once in your life, because afterwards your body becomes “immune.” It may take a few days for the adaptive immune system to respond the first time it comes into contact with the germ, but the next time the body can react immediately. The second infection is then usually not even noticed, or is at least milder.
The adaptive immune system is made up of:
T lymphocytes in the tissue between the body's cells
B lymphocytes, also found in the tissue between the body's cells
Antibodies in the blood and other bodily fluids
Definition
(SLE) Systemic Lupus Erythematosus, the most common lupus, is a chronic inflammatory condition caused by an autoimmune disease, is characterized by multiple, etiologically unlinked manifestations.  An autoimmune disease occurs when the body's tissues are attacked by its own immune system. Patients with lupus have unusual antibodies in their blood that are targeted against their own body tissues.
 Lupus can cause disease of the skin, heart, lungs, kidneys, joints, and nervous system. When only the skin is involved, the condition is called discoid lupus. When internal organs are involved, the condition is called systemic lupus erythematosus (SLE). Up to 10% of persons with discoid lupus (lupus limited to the skin) eventually develop the systemic form of lupus (SLE).
History:
Lupus means “wolf” in Latin.
Hippocrates (460-375 BC) was the first to describe cutaneous ulcers under the heading of herpes esthiomenos. 
 Herbernus of Tours was the first to apply the term lupus to a skin disease in 916 AD.
The first clear description of lupus erythematosus was by Biett and was reported by his student Cazenave under the term erythema centrifugum in 1833. 
In 1851 Cazenave renamed erythema centrifugum, calling it lupus erythematosus and gave a classic description of discoid lupus erythematosus. In 1872 Kaposi subdivided lupus into the discoid and systemic forms and introduced the concept of systemic disease with a potentially fatal outcome. 
Epidemiology
Gender, race, and ethnicity significantly affect SLE incidence, prevalence, damage accrual, and mortality. Systemic lupus erythematosus (SLE) is a disease distributed worldwide, which occurs in both genders, and across racial/ethnic and age groups; however, higher rates are observed in adults, in women, this female predominance is especially note-worthy during the reproductive ages, which suggests that female sex hormones may play an important role in the development of SLE and in non-Caucasians. Genetic, environmental, sociodemographic and methodological issues are responsible not only for these differences but for the variable course and outcome of the disease.
Non-Caucasians have a more severe disease with a higher risk for early mortality and damage accrual.
Males also have a more severe disease, although rare; however, a negative impact of male gender on lupus outcomes has not been firmly established.
Childhood-onset is associated with a more severe disease; moreover, it is also associated with higher damage and diminished survival; finally, late-onset lupus is mild but it is associated with higher damage accrual and a diminished survival.
Despite advances in treatment, standardized mortality rates in SLE remain three times higher than in the general population. The risk of mortality is significantly increased for mortality due to renal disease, cardiovascular disease, and infection.
SLE is a risk factor for cervical neoplasia, in particular for premalignant cervical lesions. The risk is highest among patients on immunosuppressants. Treatment-wise, azathioprine was shown to increase the risk of acute myeloid leukemia or myelodysplastic syndrome 7-fold in an autoimmune population, but the study included only a small number of SLE patients.
Lupus nephritis was shown to be an important cardiovascular risk factor with a hazard ratio nine times higher compared to SLE patients without lupus nephritis. SLE doubles the risk of stroke with the highest relative risk for of stroke observed within the first year after diagnosis.
There are worldwide differences in the incidence and prevalence of SLE. In addition to genetic factors and environmental factors, the way to detect SLE patients (e.g., case definition) is an important factor, which influences the incidence and prevalence of SLE.
In addition to genetic susceptibility, hormonal and reproductive exposures (e.g., endogenous estrogens, estrogen replacement therapy), occupational and environmental exposures (e.g., silica, ultraviolet light), and infectious exposures (e.g., Epstein-Barr virus) are suggested to influence the risk of SLE. Complex interactions between genetic and environmental factors are thought to play a role in the development and progression of SLE. Estrogens enhance B cell activation (e.g., immunoglobulin production including anti-ds-DNA), while they suppress T cell activity (e.g., proliferative response to mitogens and antigens, interleukin 2 production).
INCIDENCE AND PREVALENCE OF SLE
Data from the California Lupus Surveillance Project and the Manhattan Lupus Surveillance Program allowed estimation of incidence and prevalence amongHispanics and Asians who had a higher incidence and prevalence of SLE compared to Caucasians, but lower than African Americans. In Germany, the SLE incidence rate for German women was less than half of the French rate. A decline in the annual SLE incidence of 1.8% was observed in the United Kingdom, while in contrast the prevalence increased by 50% over a period of 15 years ending with 2012.
Etiology
SLE is a multifactorial disease with unknown exact etiology, however, several genetic, immunological, endocrine, and environmental factors play a role in the etiopathogenesis of SLE. 
Familial segregation and high concordance rates in identical twins suggest a strong genetic contribution in SLE, although there is no obvious pattern of inheritance. Concordant rates for identical twins have been reported to be as high as 50%. More than 50 genes or genomic loci have been identified to be associated with SLE, most encoding proteins implicated in the function of the immune system. 
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.
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.
Numerous studies have investigated the role of infectious etiologies that may also perpetuate autoimmunity. Patients with SLE have higher titers of antibodies to Epstein-Barr virus (EBV), have increased circulating EBV viral loads, and make antibodies to retroviruses, including antibodies to protein regions homologous to nuclear antigens. In patients with SLE and EBV infection, the B cells are not primarily defective; rather, the SLE/EBV phenomenon is due to a T-cell abnormality, which causes failure in normal immunoregulation of the B-cell response. Viruses may stimulate specific cells in the immune network. Chronic infections may induce anti-DNA antibodies or even lupuslike symptoms, and acute lupus flares often follow bacterial infections.
Environmental and exposure-related causes of SLE are less clear. Possible risk factors include:
Low birthweight (< 2,500 g)
Preterm birth (≥1 month early)
Childhood exposure to agricultural pesticides
Silica dust and cigarette smoking may increase the risk of developing SLE
Estrogen use in postmenopausal women appears to increase the risk of developing SLE.
Photosensitivity is clearly a precipitant of skin disease
Ultraviolet light stimulates keratinocytes, which leads not only to overexpression of nuclear ribonucleoproteins (snRNPs) on their cell surfaces but also to the secretion of cytokines that simulate increased autoantibody production. 
Breastfeeding is associated with a decreased risk of developing SLE
Vitamin D is involved in both in both innate and acquired immunity, and vitamin D deficiency has been implicated in autoimmunity and the development of rheumatic diseases, including SLE. Young et al studied 436 individuals who reported having a relative with SLE but who did not have SLE themselves, and found that the combination of vitamin D deficiency and carriage of specific single-nucleotide polymorphisms was associated with significantly increased risk of transitioning to SLE
Drug-induced Systemic Lupus Erythematosus (SLE):
Dozens of medications have been reported to trigger Systemic Lupus Erythematosus (SLE). However, more than 90% of cases of “drug-induced lupus” occurs as a side effect of one of the following six drugs: Hydralazine (Apresoline) is used for high blood pressure.
Quinidine (Quinidine Gluconate, Quinidine Sulfate) and procainamide (Pronestyl; Procan-SR; Procanbid) are used for abnormal heart rhythms.
Phenytoin (Dilantin) is used for epilepsy.
Isoniazid (Nydrazid, Laniazid) is used for tuberculosis. and
d-penicillamine (used for rheumatoid arthritis)
Genetic component recognized  
Molecular biology techniques have been applied to the study of human lymphocyte antigen (HLA) Class II genes to determine specific amino acid sequences in these cell surface molecules that are involved in antigen presentation to T-helper cells in individuals with lupus. These studies have resulted in the identification of genetic-serologic subsets of systemic lupus that complement the clinico-serologic subsets. 
It is hoped by investigators working in this field that these studies will lead to the identification of etiologic factors (e.g., viral antigens/proteins) in lupus.
Over the last decade or so, we have witnessed significant advances in the understanding of the genetic basis of lupus, and of the immunological derangements which lead to the clinical manifestations of the disease. 
Advances have been made in the assessment of the impact of the disease in general, and in minority population groups, in particular and efforts are being made towards defining lupus biomarkers which may help both to predict disease outcome and to guide treatments.
Signs and Symptoms 
The following manifestations were statistically more common in childhood-onset SLE: Malar rash, fever, seizures, ulcers/mucocutaneous involvement, renal involvement, proteinuria, urinary cellular casts, thrombocytopenia, hemolytic anemia, lymphadenopathy. 
 The presentation of a triad of fever, joint pain, and rash in a woman of childbearing age should prompt investigation and may present any of the following types of manifestations: Constitutional, dermatologic, renal, musculoskeletal, neuropsychiatric, pulmonary, cardiac, hematologic and gastrointestinal.
 Constitutional 
Fatigue, fever, arthralgia, and weight changes are the most common symptoms in cases or recurrent active SLE flares. SLE-specific fatigue or fever generally occurs in concert with other clinical markers. Fever may reflect active SLE, infection, and reactions to medications (ie, drug fever).
Musculoskeletal
Joint pain is one of the most common symptoms. SLE arthritis or arthralgia may be asymmetrical, with pain that is disproportionate to swelling. SLE arthropathy is rarely erosive or deforming. Characteristic hand deformities are swan neck deformities that result from recurrent synovitis and inflammation of the joint capsule, tendons, and ligaments.
Usually, these deformities are reducible, although rarely, they may become fixed. Avascular necrosis (with or without steroid use) can occur in up to 10% of patients with SLE and is usually bilateral and involves the hip joints. Inflammatory myopathy with histopathological features similar to but less striking than polymyositis has been seen in less than 10% of SLE cases. Patients with SLE are at high risk for the development of fibromyalgia with incidences as high as 20% reported.
In general, inflammatory musculoskeletal symptoms are common in SLE, varying from inflammatory arthralgia to frank synovitis and Jaccoud arthropathy as a result of capsular laxity. With the advances of modern imaging techniques in rheumatology, ultrasound has been more and more widely used to detect musculoskeletal abnormalities, as well as to assess the disease activity. Recently, in 2019, a large observational study revealed that inflammation was detected by ultrasound in 27% of SLE patients with arthralgia, however, with no clinical arthritis. More importantly, the ultrasound-only inflammation in the joints was proved to be associated with worse clinical symptoms and serology. An interesting study comparing the ultrasound findings and clinicalassessment in reflecting the therapeutic response in SLE patients with musculoskeletal manifestations revealed that ultrasound was better than clinical assessment due to the nature of being more objective. Thus, most clinical trials based on the traditional clinical outcome measurements (SLE disease activity index [SLEDAI] and SLE responder index-4 [SRI-4]) may underestimate the efficacy of treatment in SLE. The role of sub-clinical synovitis/tendonitis on ultrasound in assessing disease activity and guiding treatment needs to be further investigated.
Gastrointestinal
Nausea and dyspepsia are common symptoms in patients with active SLE and are sometimes difficult to correlate with gastrointestinal involvement. Peptic ulcer disease is a common, especially in SLE patients treated with nonsteroidal anti-inflammatory agents (NSAIDs) and glucocorticoids.
Any part of the gastrointestinal tract may be involved in SLE and these manifestations include esophageal dysmotility (especially the upper one-third part of the esophagus), mesenteric vasculitis, lupus enteritis, peritonitis and ascites, protein-losing enteropathy, pancreatitis, and lupoid hepatitis. Further, patients with SLE and antiphospholipid antibody syndrome can develop Budd-Chiari syndrome, mesenteric vessel thrombosis, and hepatic veno-occlusive disease. 
Dermatologic
Acute cutaneous lupus erythematosus (ACLE) may be localized or generalized. The hallmark ACLE lesion is the malar rash or the butterfly rash, which is an erythematous raised pruritic rash involving the cheeks and nasal bridge. The rash may be macular or papular and spares the nasolabial folds. It usually has an acute onset, but may last several weeks, and may cause induration and scaling. The malar rash may also fluctuate with lupus disease activity. Other rashes in this location that must be differentiated from ACLE malar rash include rosacea, erysipelas, seborrheic dermatitis, and perioral dermatitis. Generalized leads to widespread maculopapular or macular rash in a photosensitivity pattern. ACLE lesions usually heal without scarring.
Subacute cutaneous lupus erythematosus (SCLE) rash is a photosensitive, widespread, nonscarring, nonindurated rash. It 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. This rash is seen in patients with a positive Anti-Ro (SSA) antibody in up to 90% of the cases. It can also be caused by some drugs such as hydrochlorothiazide. It has also been reported in patients with Sjogren syndrome and rheumatoid arthritis. 
Discoid lupus erythematosus (DLE) is the most common form of chronic cutaneous lupus erythematosus (CCLE). DLE may occur with or without SLE, and can be either localized (only head and neck) or generalized (above and below the neck). The lesions are disk-shaped erythematous papules or plaques with adherent scaling and central clearing. DLE heals with scarring, and when present on the scalp, can be associated with permanent alopecia.
Several other skin manifestations are seen in SLE that are not specific for SLE. These include cutaneous vasculitis (leukocytoclastic or urticarial), vasculopathy (livedo reticularis, superficial thrombophlebitis, Raynaud's phenomenon, erythromelalgia, periungual telangiectasia), sclerodactyly, rheumatoid nodules, calcinosis cutis, bullous lesions, urticaria, erythema multiforme, acanthosis nigricans and leg ulcers.
Renal
The kidney is the most commonly involved visceral organ in SLE. Although approximately 50% of patients with SLE develop evident renal disease, biopsy studies demonstrate some degree of renal involvement in most patients. Glomerular disease usually develops within the first few years of SLE onset and is often asymptomatic. Lupus nephritis can cause leakage of protein into the urine, fluid retention, high blood pressure, and even kidney failure. This can lead to further fatigue and swelling (edema) of the legs and feet. With kidney failure, machines are needed to cleanse the blood of accumulated waste products in a process called dialysis.
Lupus pneumonitis can be seen in up to 10% of lupus patients. Interstitial pneumonitis, alveolitis, alveolar wall injury, and edema and hemorrhage are commonly seen in these patients. Immunoglobulin and complement deposition is seen in the vessel wall. Chronic interstitial lung disease can occur in up to 50% of these patients and is characterized by interstitial lymphoid aggregates and fibrosis, septal thickening and type-2 pneumocyte hyperplasia. Medial hypertrophy and intimal fibrosis involving the branches of the pulmonary artery lead to pulmonary hypertension in SLE. Again, immunoglobulin and complement deposition can be seen in the vessel wall.
Lupus nephritis can involve the glomeruli, interstitium, tubules and the vessels with immune complex deposition in all four compartments. The World Health Organization classification criteria for lupus nephritis describes 6 classes of lupus nephritis all with distinct pathological features and significant differences in clinical outcomes. This has lead to a different treatment approach for each class and knowing the class of lupus nephritis before initiating treatment is vital. 
Class I: Minimal mesangial lupus nephritis
Class II: Mesangial proliferative lupus nephritis
Class III: Focal lupus nephritis
Class IV: Diffuse segmental or Diffuse global lupus nephritis
Class V: Membranous lupus nephritis
Class VI: Advanced sclerosing lupus nephritis
The involvement may range from mild subnephrotic proteinuria to diffuse progressive glomerulonephritis leading to chronic kidney damage. Lupus nephritis usually occurs early in the course of SLE. New-onset hypertension, hematuria, proteinuria, lower extremity edema, and elevation in creatinine shall raise suspicion for lupus nephritis. A biopsy is crucial in staging the lupus nephritis and ruling out other causes. The treatment of lupus nephritis is dictated by the biopsy findings and prognosis varies for each class with an excellent prognosis for classes I and II, and poor outcomes with classes III and IV. Class V usually carries a favorable prognosis except for complications of nephritis syndrome such as thromboembolism which are common in this class.
Neuropsychiatric 
NP-SLE, collectively referred to as neurologic and psychiatric involvement in SLE, is highly diverse with a broad spectrum of presentations (range from subtle cognitive dysfunction to acute confusion states, psychosis, stoke). A comprehensive review published in Nat Rev Rheumatology 2019 summarized the frequencies of 19 neuropsychiatric manifestations that can occur in SLE (12 relating to central nervous system, seven to peripheral nervous system). There has been a large body of work on central nervous system (CNS) involvement in SLE patients, but involvement of peripheral nervous system in 7.6% of SLE patients reported from a multi-ethnic, prospective inception cohort study, also reduced patients’ health-related quality of life. Although research interest in NP-SLE has been growing, the diagnosis of NP-SLE remains full of challenges. Autoantibodies would be the most promising biomarkers for the diagnosis. The Swiss SLE Cohort Study Group demonstrated that antibodies against components of nervous system were found in 13% (23/174) of total SLE populations, and anti-myelin oligodendrocyte glycoprotein antibody was significantly associated with NP-SLE. Besides, some classic antibodies, such as anti-phospholipid, anti-ribosomal P, and anti-aquaporin 4 antibodies are implicated in NP-SLE.
Nevertheless, no gold standard has been established for the diagnosis of NP-SLE so far. With the rapid development of neuroimmunology, an emerging number of biomarkers in the field of NP-SLE will come out. In clinical practice, discrimination between NP-SLE and CNS infections in SLE patients is always important and sometimes challengeable.A simplified scoring system integrated with eight key factors was proposed by the Peking Union Medical College Hospital to assist distinguishing CNS infections from NP-SLE. Fulfilling four or more criteria showed a superior ability in predicting CNS infection with sensitivity of 85% and specificity of 84.2%. Of note, the proposed scoring system still needs to be further validated in large prospective cohorts and is worthy of expectation.
Brain involvement is referred to as lupus cerebritis. Other CNS manifestations include aseptic meningitis, demyelinating syndrome including optic neuritis and myelitis, movement disorders such as chorea and cognitive dysfunction. Patients with SLE are also at high risk for ischemic strokes. Cranial and peripheral (sensorimotor, axonal) neuropathies, mononeuritis multiplex, autonomic neuropathies, and syndromes mimicking Guillain-Barré syndrome and Myasthenia gravis are the peripheral nervous system manifestations. Psychiatric manifestations are especially difficult to diagnose and manage and may range from depression and anxiety to frank psychosis.
Cardiac and Pulmonary
Vasculitis is characterized by inflammation with damage to the walls of various blood vessels. The damage blocks the circulation of blood through the vessels and can cause injury to the tissues that are supplied with oxygen by these vessels. Inflammation of the lining of the lungs (pleuritis) with pain aggravated by deep breathing (pleurisy) and of the heart (pericarditis) can cause sharp chest pain. The chest pain is aggravated by coughing, deep breathing, and certain changes in body position. The heart muscle itself rarely can become inflamed (carditis). It has also been shown that young women with SLE have a significantly increased risk of heart attacks due to coronary artery disease.
Hematologic
 White blood cells can be decreased in SLE (referred to as leukopenia). Also, low blood-clotting factors called platelets (thrombocytopenia) can be caused by lupus. Leukopenia can increase the risk of infection, and thrombocytopenia can increase the risk of bleeding. Low red blood cell counts (hemolytic anemia) can occur. Inflammation of muscles (myositis) can cause muscle pain and weakness. This can lead to elevations of muscle enzyme levels in the blood.
Pathogenesis
 In individuals with lupus, both B cells and T cells become overactive. The two main consequences of this increased activity are the production of autoantibodies (antibodies that recognize and destroy the body’s own cells) and inflammation that can lead to long-term, irreversible scarring. 
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 increases mononuclear cell production while increased IL-17 and IL-21 leads to increased T-cell production. Increased Interferon-γ leads to defective T-cell production. 
T-cells lead to the activation of autoreactive B-cells by CD40L and cytokine production, which leads to autoantibody production, which is 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-cell activation. These autoantibodies are pathogenic and cause organ damage by immune complex deposition, complement, and neutrophil activation, and altering cell function leading to apoptosis and cytokine production.
 Further, the autoreactive B-cells in SLE which are stimulated by self-antigens, are not readily eliminated due to a deficiency of the process involved in the functional neutralization of autoreactive B cells. 
Novel Insights, 2019.
The type I interferon (IFN) family of innate immune cytokines contributes to the aberrant immune functions of SLE. Recent work on Science revealed a novel mechanism between mitochondrial DNA (mtDNA) and autoimmunity. Short mtDNA fragments released by oxidative stressed mitochondria could enter the cytosol via the pores formed by oligomerization of the mitochondrial voltage-dependent anion channel, and then induce type I IFN production and promote lupus-like disease. Type I IFN genes were also highly expressed in neutrophils. The emerging roles of neutrophils and neutrophil extracellular traps in SLE inflammation and autoimmunity were well summarized by clinical scientists. In a paper published in Nature Medicine, Caielli et al identified a novel T cell subset in SLE, CXCR5−CXCR3+PD1hiCD4+ T peripheral helper cells, which could activate B cells in a unique manner and promote autoantibody development. In 2019, an excellent research conducted by Chinese scientists was published on Cell. In SLE patients, augmented protein kinase phosphorylation and circular RNAs (circRNAs) reduction were observed. Functional study showed that endogenous circRNAs tended to form imperfect RNA duplexes and acted as inhibitors of double-stranded RNA-activated protein kinase related to innate immunity, thus providing a connection between circRNAs and SLE.
The B-cells can also serve as antigen-presenting cells and can activate T-cells by presenting internalized soluble antigens to T-cells. This creates a loop where both B and T cells activate each other, both leading to more autoimmunity.
Mechanism of autoantibody production and tissue injury in lupus: Self-antigen dependent activation of autoreactive B cells and CD4 T cells in secondary lymphoid organs, leads to production of pathogenic autoantibodies that, along with inflammatory cytokines, promotes tissue injury in lupus. Antigen-presenting dendritic cells are necessary for adaptive immune cell activation, and contribute to inflammatory cytokine production. Autoantibodies in complexes with autoantibodies contribute to innate immune cell activation and cytokine production. Genetic predisposition is a requisite for aberrant immune system activation, in the setting of environmental and stochastic events. Abbreviations: DC, dendritic cells; pDC, plasmacytoid dendritic cells.
Role of Innate Cells (Neutrophils, Macrophages and Dendritic Cells) in SLE Pathogenesis. Altered properties in neutrophils, including decreased clearance of apoptotic material and increased synthesis and release of various proteins including oxidants, hydrolytic enzymes, and inflammatory cytokines which contribute to tissue damage. Myeloid dendritic cells (DCs) and plasmacytoid dendritic cells (pDCs) represent two major DC subsets derived from different developmental pathways from their precursors. pDCs are a specialized type of interferon (IFN)-producing cells capable of producing massive amounts of type-I IFNs upon stimulation. Type I IFNs can induce the formation of neutrophil extracellular traps (NETs), which are a source of self-stimuli and reciprocally enhance production of type I IFNs. Based on their function, myeloid DCs can be further divided into tolerogenic and immunogenic DCs. In SLE patients, immunogenic DCs/macrophages acquire activated phenotypes with increased production of inflammatory cytokines or enhanced self-antigen processing and presentation. Tolerogenic DC/macrophages are responsible for the rapid removal of apoptotic cells, and, coupled with their ability to produce anti-inflammatory cytokines, efficiently suppress autoimmunity. A significant reduction in both the number and function of these cells is observed. (NCBI, 2017).
Abbreviations: BDCA2–DTR, blood dendritic cell antigen 2–diphtheria toxin receptor transgene; CAMKIV, calcium/calmodulin-dependent protein kinase type IV; DNMT, DNA methyl transferase; HDAC, histone deacetylase; ICOS, inducible T cell costimulatory; IRF, interferon regulatory factor; PD-1, programmeddeath receptor; LAP, microtubule-associated protein 1A/1B-light chain 3 (LC3)-associated phagocytosis; mTOR, mechanistic target of rapamycin; NET, neutrophil extracellular trap; PP2A, protein phosphatase 2A; PTPN22, protein tyrosine phosphatase, non-receptor type 22; ROCK, Rho-associated protein kinase; SLAM, signaling lymphocyte activation molecule family of receptors; STAT, signal transducer and activator of transcription; Tfh, T follicular helper cell; TLR, Toll-like receptor.
T-cell signaling alteration in systemic lupus erythematosus (SLE). TCR T cell receptor, Lck lymphocyte-specific protein tyrosine kinase, ZAP-70 zeta-chain-associated protein kinase 70, FcRγ Fc receptor common gamma subunit chain, Syk Spleen tyrosine kinase, NFAT nuclear factor of activated T cells, CaMKIV activated calmodulin kinase IV, CREM cAMP responsive element modulator, IL interleukin, PIP2 phosphatidylinositol-4, 5-bisphosphate, PIP3 phosphatidylinositol-3, 4, 5-triphosphate, PI3K phosphoinositide-3 kinase, Akt protein kinase B, mTORC mammalian target of rapamycin complex, ERM ezrin/radixin/moesin, ROCK Rho-associated protein kinase.
Diagnosis
Classification criteria – Theory Based
American College of Rheumatology (ACR) first developed the SLE classification criteria in 1971 and revised them in 1982 and 1997. The 1997 ACR criteria were further revised by the Systemic Lupus International Collaborating Clinics (SLICC) group in 2012.
The 1997 ACR criteria required the presence of 4 out of 11 criteria for the classification of SLE. The 11 criteria included were malar rash, discoid rash, photosensitivity, alopecia, Raynaud phenomenon, oral/nasal ulcers, arthritis (non-erosive arthritis involving 2 or more peripheral joints), serositis (pleurisy or pericarditis), renal disease (proteinuria greater than 500 mg daily or cellular RBC, granular, tubular, or mixed casts), hematologic disease (Hemolytic anemia with reticulocytosis, or leukopenia less than 4000/mm3 on 2 or more occasions or lymphopenia less than 1500/mm3 on 2 or more occasions, or thrombocytopenia less than 100,000/mm3 in the absence of medications known to decrease platelets).
Neurologic disease (seizures or psychosis in the absence of an alternative explanation), immunologic criteria (Antiphospholipid antibodies present based on either an abnormal serum level of IgM or IgG anticardiolipin antibodies or a tested positive result for lupus anticoagulant or anti-DNA antibody or anti-Sm antibody or false-positive syphilis test with VDRL or RPR) and antinuclear antibody positivity in the absence of drugs known to cause drug-induced lupus.
It requires at least one of the 4 criteria to be clinical and at least one of the 4 criteria to be immunologic. Neurologic and immunologic criteria were expanded to include new information about the SLE immunology. Further, patients with biopsy-proven nephritis and positive ANA or anti-double-stranded DNA could be directly classified as SLE even if they lacked any other criteria. Compared to the 1997 ACR criteria, the SLICC criteria have an improvement in the sensitivity and are considered to be more valid and clinically relevant.
Updated criteria and management (2019).
Unlike with ACR-1997 and Systemic Lupus International Collaborating Clinics-2012 classification criteria, EULAR/ACR-2019 criteria are a score-based system. There are ten hierarchical domains (seven clinical and three immunological) consisting of a total of 22 criteria with distinct weights in this new classification criteria. Positivity of anti-nuclear antibodies (ANA) is the entry criterion, and then an individual patient with a total score of 10 or higher would be classified as SLE. Of note, in this situation, the patients with negative ANA would not be allowed for classification of SLE. Thus, high-quality ANA testing is extremely important and it calls for more efforts to standardize the test.
An updated recommendation for the management of SLE was proposed in 2019. Over a decade has passed since the previous version was published in 2008. Notably, the recommendation 2019 strongly emphasizes to minimize disease activity with remission or low disease activity as a principle goal of therapy. This reflects the art of treat-to-target strategy in SLE. 
Correspondingly, a number of studies demonstrated that achieving remission or low disease activity would significantly reduce damage accrual and improve health-related quality of life in SLE. In addition, belimumab, the first approved biological drug for SLE, was newly recommended to patients with extra-renal disease, inadequate control by first-line treatments, and inability to taper glucocorticoids daily dose to acceptable levels (ie, prednisone 7.5 mg/d). Efficacy of hydroxychloroquine (HCQ) in lupus has been very well established. Last year there were also abundant discussions regarding the recommended dosage of HCQ (no more than 5 mg/kg daily) in the new recommendations. Whether the lower dose HCQ processes comparable clinical effects to the previously recommended 6.5 mg/kg daily still needs to be confirmed. Measuring HCQ concentration in serum can be helpful to detect patient's adherence, but the concentration-adjusted dosing therapy has not been proven superiority yet. 
Further studies are urgently required. Screening for HCQ retinopathy should be done before administration, repeated at 5 years, and then every year during HCQ treatment, according to the recommendation.
Laboratory tests
Complete blood count. This test measures the number of red blood cells, white blood cells and platelets as well as the amount of hemoglobin, a protein in red blood cells. Results may indicate if you have anemia, a low white blood cell or platelet count may occur in lupus as well.
Erythrocyte sedimentation rate. This blood test determines the rate at which red blood cells settle to the bottom of a tube in an hour. A faster than normal rate may indicate a systemic disease, such as lupus, or an infection, another inflammatory condition or cancer.
Kidney and liver assessment. Blood tests can assess how well your kidneys and liver are functioning. Lupus can affect these organs.
Urinalysis. An examination of a sample of your urine may show an increased protein level or red blood cells in the urine, which may occur if lupus has affected your kidneys.
Antinuclear antibody (ANA) test. A positive test for the presence of these antibodies — produced by your immune system — indicates a stimulated immune system. While most people with lupus have a positive ANA test, most people with a positive ANA do not have lupus. If positive for ANA, more-specific antibody testing should be done.
Imaging tests
Chest X-ray. An image of your chest may reveal abnormal shadows that suggest fluid or inflammation in your lungs.
Echocardiogram. This test uses sound waves to produce real-time images of your beating heart. It can check for problems with your valves and other portions of your heart.
Biopsy: A sample of kidney tissue or skin obtained with needle or through a small incision.
Treatment and Outcomes
Management of systemic lupus erythematosus (SLE) often depends on disease severity and disease manifestations, although hydroxychloroquine has a central role for long-term treatment in all SLE patients. The LUMINA (Lupus in Minorities: Nature versus Nurture) study and other trials have offered evidence of a decrease in flares and prolonged life in patients given hydroxychloroquine, making it the cornerstone of SLE management. 
Types of medicines commonly used to treat lupus include:
Nonsteroidal anti-inflammatory drugs (NSAIDs). Over-the-counter NSAIDs, such as ibuprofen and naproxen, help reduce mild pain and swelling in joints and muscles. 
Corticosteroids. (prednisone) may help reduce swelling, tenderness, and pain. In high doses, they can calm the immune system. Lupus symptoms usually respond very quickly to these powerful drugs. Once this has happened, your doctor will lower your dose slowly until you nolonger need it. The longer a person uses these drugs, the harder it becomes to lower the dose. Stopping this medicine suddenly can harm your body.
Antimalarial drugs. It also treat joint pain, skin rashes, fatigue, and lung inflammation. Two common antimalarial medicines are hydroxychloroquine (Plaquenil) and chloroquine phosphate (Aralen). Studies found that taking antimalarial medicine can stop lupus flares and may help people with lupus live longer.
BLyS-specific inhibitors. These drugs limit the amount of abnormal B cells (cells in the immune system that create antibodies) found in people with lupus. A common type of BLyS-specific inhibitor that treats lupus symptoms, belimumab, blocks the action of a specific protein in the body that is important in immune response.
Immunosuppressive agents/chemotherapy. These medicines may be used in severe cases of lupus, when lupus affects major organs. These medicines can cause serious side effects because they lower the body’s ability to fight off infections. 
Other medicines. To treat diseases that are linked to lupus — such as high blood pressure or osteoporosis. Many people with lupus are also at risk for blood clots, which can cause a stroke or heart attack. Anticoagulants (“blood thinners”) might be prescribed, such as warfarin or heparin, to prevent your blood from clotting too easily. Do not take warfarin during pregnancy.
Therapeutic advances in SLE (2019).
Belimumab, the first drug approved for SLE following assessment in a randomized clinical trial (RCT), put an end to the dilemma of unavailability of new medication for SLE for more than half a century. In 2019, a study based on 13-years’ safety and efficacy data of belimumab plus standard therapy demonstrated that belimumab was well tolerated with no new safety concerns, and efficacy was further improved. A propensity score-matched comparative analysis conducted by Urowitz et al revealed that belimumab-treated group experienced significantly less progression of organ damage compared with patients receiving standard therapy (harzard ratio 0.391; 95% CI 0.253–0.605; P < 0.001). These results highlighted the efficacy and tolerability of belimumab as a novel therapeutic agent for SLE. Undoubtedly, the approval of belimumab for the treatment of SLE and the recognition that clinical trial design can be improved, have kindled hopes for the exploration of novel medications for SLE. Several new approaches targeting B cells, cytokines, or intracellular signaling pathways, are fiercely under investigation.
Other promising therapies
Immune imbalance between effector and regulatory CD4+ T cells was observed in SLE. Low doses of interleukin-2 (IL-2) can regulate CD4+ T cell subsets and subsequently was used to treat SLE, as described in a previous publication in Nature Medicine. Recently, a randomized, double-blind, placebo-controlled study performed by the team of the Peking University People's Hospital demonstrated that low-dose IL-2 treatment resulted in a higher SRI-4 response rate with no more adverse events in active SLE patients compared with placebo group. The promising data warrant further multicenter large-scale RCT studies. The preliminary data from a small RCT published in 2019 indicated that omalizumab, a monoclonal antibody against IgE, was associated with improvement in disease activity in SLE patients, with good tolerance. It was gratifying that traditional Chinese medicine, artemisinin may be a potential alternative for SLE treatment. A multi-center phase I RCT showed a significantly more favorable response to artemisinin than placebo in mild/moderate SLE patients. Further investigations of these exciting new agents are extremely encouraged and to be expected. A number of aforementioned new drugs clearly offer hope for the SLE treatment. It may not take too long to have a range of biological options to treat SLE patients, which matches the choices we have for rheumatoid arthritis patients.
Most recent and promising phase II-III clinical trials of new drugs in SLE from ClinicalTrial.gov. Data from March 14, 2020.
New understanding of Prognosis in SLE (2019).
Although prognosis of SLE patients has been improved substantially from 5-year survival rate of approximately 50% in 1950s to over 90% in the early 2000s, SLE is still life-threatening and a major cause of premature death. In 2019, a large, long-term follow-up cohort study revealed that patients with SLE were three times more likely to die from any cause compared with patients without lupus. Of note, standardized mortality ratio (SMR) was particularly higher in patients younger than 40 years old, which underlined more attention needs to be paid in this sub-population. In addition, a huge racial disparity in mortality associated with SLE was demonstrated by Lim et al. Compared with Caucasian SLE patients, cumulative SLE mortality was significantly higher among blacks (SMR 3.34 vs. 2.43, respectively). This high burden of mortality in SLE may be partially interpreted by increased risks of multiple comorbidities. In a latest study, UK scholars noticed that SLE was associated with greater risk of any comorbidity at and after diagnosis. 
Furthermore, comorbidities at SLE diagnosis accounted for 27.6% of the apparent difference in mortality between SLE patients and matched controls, which calls for a thorough search for comorbidities in SLE patients. The unchanged trend of premature mortality in SLE highlights critical unmet need for improved and optimized management of SLE, especially for new treatments.
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