Systemic lupus erythematosus (pronounced /sɨˈstɛmɨk ˈluːpəs ˌɛrɨˌθiːməˈtoʊsəs/ ( listen)), often abbreviated

to SLE or lupus, is a systemic autoimmune disease (or autoimmune connective tissue disease) that can affect
any part of the body. As occurs in other autoimmune diseases, the immune system attacks the body's cells and
tissue, resulting in inflammation and tissue damage.[2] It is a Type III hypersensitivity reaction caused by
antibody-immune complex formation.

SLE most often harms the heart, joints, skin, lungs, blood vessels, liver, kidneys, and nervous system. The
course of the disease is unpredictable, with periods of illness (called flares) alternating with remissions. The
disease occurs nine times more often in women than in men, especially in women in child-bearing years ages 15
to 35, and is more common in those also of non-European descent.[3][4][5]

SLE is treatable through addressing its symptoms, mainly with cyclophosphamide, corticosteroids and
immunosuppressants; there is currently no cure. SLE can be fatal, although with recent medical advances,
fatalities are becoming increasingly rare. Survival for people with SLE in the United States, Canada, and
Europe is approximately 95% at five years, 90% at 10 years, and 78% at 20 years.[5]

Signs and symptoms

Common symptoms of SLE.[6]

SLE is one of several diseases known as "the great imitators" because it often mimics or is mistaken for other
illnesses.[7] SLE is a classical item in differential diagnosis,[3] because SLE symptoms vary widely and come and
go unpredictably. Diagnosis can thus be elusive, with some people suffering unexplained symptoms of
untreated SLE for years.

Common initial and chronic complaints include fever, malaise, joint pains, myalgias, fatigue, and temporary
loss of cognitive abilities. Because they are so often seen with other diseases, these signs and symptoms are not
part of the diagnostic criteria for SLE. When occurring in conjunction with other signs and symptoms (see
below), however, they are considered suggestive.[8]

Dermatological manifestations

As many as 30% of sufferers have some dermatological symptoms (and 65% suffer such symptoms at some
point), with 30% to 50% suffering from the classic malar rash (or butterfly rash) associated with the disease.
Some may exhibit thick, red scaly patches on the skin (referred to as discoid lupus). Alopecia; mouth, nasal, and
vaginal ulcers; and lesions on the skin are also possible manifestations.

Musculoskeletal

The most commonly sought medical attention is for joint pain, with the small joints of the hand and wrist
usually affected, although all joints are at risk. The Lupus Foundation of America estimates that more than 90
percent of those affected will experience joint and/or muscle pain at some time during the course of their illness.
[9]
Unlike rheumatoid arthritis, lupus arthritis is less disabling and usually does not cause severe destruction of
the joints. Fewer than ten percent of people with lupus arthritis will develop deformities of the hands and feet.[9]
SLE patients are at particular risk of developing osteoarticular tuberculosis.[10]

It is suggested that there might be an association between rheumatoid arthritis and SLE,[11] and that SLE is
associated with an increased risk of bone fractures in relatively young women.[12]

Hematological

Anemia may develop in up to 50% of cases. Low platelet and white blood cell counts may be due to the disease
or a side-effect of pharmacological treatment. People with SLE may have an association with antiphospholipid
antibody syndrome[13] (a thrombotic disorder), wherein autoantibodies to phospholipids are present in their
serum. Abnormalities associated with antiphospholipid antibody syndrome include a paradoxical prolonged
PTT Partial thromboplastin time (which usually occurs in hemorrhagic disorders) and a positive test for
antiphospholipid antibodies; the combination of such findings have earned the term lupus anticoagulant-
positive. Another autoantibody finding in SLE is the anticardiolipin antibody, which can cause a false positive
test for syphilis.

Cardiac

A person with SLE may have inflammation of various parts of the heart, such as pericarditis, myocarditis, and
endocarditis. The endocarditis of SLE is characteristically noninfective (Libman-Sacks endocarditis) and
involves either the mitral valve or the tricuspid valve. Atherosclerosis also tends to occur more often and
advances more rapidly than in the general population.[14][15][16]

Pulmonary

Lung and pleura inflammation can cause pleuritis, pleural effusion, lupus pneumonitis, chronic diffuse
interstitial lung disease, pulmonary hypertension, pulmonary emboli, pulmonary hemorrhage, and shrinking
lung syndrome.

Renal

Painless hematuria or proteinuria may often be the only presenting renal symptom. Acute or chronic renal
impairment may develop with lupus nephritis, leading to acute or end-stage renal failure. Because of early
recognition and management of SLE, end-stage renal failure occurs in less than 5% of cases.

A histological hallmark of SLE is membranous glomerulonephritis with "wire loop" abnormalities.[17] This
finding is due to immune complex deposition along the glomerular basement membrane, leading to a typical
granular appearance in immunofluorescence testing.

Neuropsychiatric
Neuropsychiatric syndromes can result when SLE affects the central or peripheral nervous system. The
American College of Rheumatology defines 19 neuropsychiatric syndromes in systemic lupus erythematosus.[18]
The diagnosis of neuropsychiatric syndromes concurrent with SLE is one of the most difficult challenges in
medicine, because it can involve so many different patterns of symptoms, some of which may be mistaken for
signs of infectious disease or stroke.[19]

The most common neuropsychiatric disorder people with SLE have is headache,[20] although the existence of a
specific lupus headache and the optimal approach to headache in SLE cases remains controversial.[21] Other
common neuropsychiatric manifestation of SLE include cognitive dysfunction, mood disorder, cerebrovascular
disease,[20] seizures, polyneuropathy,[20] anxiety disorder, and psychosis. It can rarely present with intracranial
hypertension syndrome, characterized by an elevated intracranial pressure, papilledema, and headache with
occasional abducens nerve paresis, absence of a space-occupying lesion or ventricular enlargement, and normal
cerebrospinal fluid chemical and hematological constituents.[22]

More rare manifestations are acute confusional state, Guillain-Barré syndrome, aseptic meningitis, autonomic
disorder, demyelinating syndrome, mononeuropathy (which might manifest as mononeuritis multiplex),
movement disorder (more specifically, chorea), myasthenia gravis, myelopathy, cranial neuropathy and
plexopathy.

Neurological

Neural symptoms contribute to a significant percentage of morbidity and mortality in patients with Lupus.[23] As
a result, the neural side of Lupus is being studied in hopes of reducing morbidity and mortality rates.[24] The
neural manifestation of lupus is known as Neuro Psychiatric Systematic Lupus Erythematosus (NPSLE). One
aspect of this disease is severe damage to the epithelial cells of the blood-brain barrier.

Lupus has a wide range of symptoms which span out throughout the body. The neurological symptoms include
headaches,[20] depression, seizures, cognitive dysfunction, mood disorder, cerebrovascular disease,[20]
polyneuropathy,[20] anxiety disorder, psychosis, and in some extreme cases, personality disorders.[25] In certain
regions, depression reportedly affects up to 60% of women suffering from SLE.[26]

Systemic

Fatigue in SLE is probably multifactorial and has been related to not only disease activity or complications such
as anemia or hypothyroidism but also pain; depression; poor sleep quality; poor physical fitness and perceived
lack of social support.[27][28]

Causes
There is no one specific cause of SLE. There are, however, a number of environmental triggers and a number of
genetic susceptibilities.[29][30]

Genetics

The first mechanism may arise genetically. Research indicates that SLE may have a genetic link. SLE does run
in families, but no single, causal, gene has been identified. Instead, multiple genes appear to influence a person's
chance of developing lupus when triggered by environmental factors. The most important genes are located in
the HLA region on chromosome 6, where mutations may occur randomly (de novo) or may be inherited. HLA
class I, class II, and class III are associated with SLE, but only class I and class II contribute independently to
increased risk of SLE.[31] Other genes which contain risk variants for SLE are IRF5, PTPN22, STAT4,[32]
CDKN1A,[33] ITGAM, BLK,[32] TNFSF4 and BANK1.[34] some of the susceptibility genes may be population
specific.[32]

Environmental triggers

The second mechanism may be due to environmental factors. These factors may not only exacerbate existing
SLE conditions but also trigger the initial onset.

Researchers have sought to find a connection between certain infectious agents (viruses and bacteria), but no
pathogen can be consistently linked to the disease. Some researchers have found that women with silicone gel-
filled breast implants have produced antibodies to their own collagen, but it is not known how often these
antibodies occur in the general population, and there is no data that show that these antibodies cause connective
tissue diseases such as SLE. There is also a small but growing body of evidence linking SLE to lipstick usage,
[35][36][37]

Drug reactions

Drug-induced lupus erythematosus is a (generally) reversible condition that usually occurs in people being
treated for a long-term illness. Drug-induced lupus mimics SLE. However, symptoms of drug-induced lupus
generally disappear once the medication that triggered the episode is stopped. There are about 400 medications
that can cause this condition, the most common of which are procainamide, hydralazine, quinidine, and
phenytoin.[3]

Non-SLE forms of lupus

Discoid (cutaneous) lupus is limited to skin symptoms and is diagnosed by biopsy of rash on the face, neck,
scalp or arms.

Pathophysiology
One manifestation of SLE is abnormalities in apoptosis, a type of programmed cell death in which aging or
damaged cells are neatly disposed of as a part of normal growth or functioning.

Transmission

In SLE, the body's immune system produces antibodies against itself, particularly against proteins in the cell
nucleus. SLE is triggered by environmental factors that are unknown.

"All the key components of the immune system are involved in the underlying mechanisms [of SLE]" according
to Rahman, and SLE is the prototypical autoimmune disease. The immune system must have a balance
(homeostasis) between being sensitive enough to protect against infection, and being too sensitive and attacking
the body's own proteins (autoimmunity). From an evolutionary perspective, according to Crow, the population
must have enough genetic diversity to protect itself against a wide range of possible infection; some genetic
combinations result in autoimmunity. The likely environmental triggers include ultraviolet light, drugs, and
viruses. These stimuli cause the destruction of cells and expose their DNA, histones, and other proteins,
particularly parts of the cell nucleus. Because of genetic variations in different components of the immune
system, in some people the immune system attacks these nuclear-related proteins and produces antibodies
against them. In the end, these antibody complexes damage blood vessels in critical areas of the body, such as
the glomeruli of the kidney; these antibody attacks are the cause of SLE. Researchers are now identifying the
individual genes, the proteins they produce, and their role in the immune system. Each protein is a link on the
autoimmune chain, and researchers are trying to find drugs to break each of those links.[3][38][39]

SLE is a chronic inflammatory disease believed to be a type III hypersensitivity response with potential type II
involvement.[40] Reticulate and stellate acral pigmentation should be considered a possible manifestation of SLE
and high titers of anticardiolipin antibodies, or a consequence of therapy.[41]

Abnormalities in apoptosis

• Apoptosis is increased in monocytes and keratinocytes

• Expression of Fas by B cells and T cells is increased
• There are correlations between the apoptotic rates of lymphocytes and disease activity.

Tingible body macrophages (TBMs) – large phagocytic cells in the germinal centers of secondary lymph
nodes – express CD68 protein. These cells normally engulf B cells that have undergone apoptosis after somatic
hypermutation. In some people with SLE, significantly fewer TBMs can be found, and these cells rarely contain
material from apoptotic B cells. Also, uningested apoptotic nuclei can be found outside of TBMs. This material
may present a threat to the tolerization of B cells and T cells. Dendritic cells in the germinal center may
endocytose such antigenic material and present it to T cells, activating them. Also, apoptotic chromatin and
nuclei may attach to the surfaces of follicular dendritic cells and make this material available for activating
other B cells that may have randomly acquired self-specificity through somatic hypermutation.[42]

Clearance deficiency

Clearance deficiency

The exact mechanisms for the development of SLE are still unclear, since the pathogenesis is a multifactorial
event. Beside discussed causations, impaired clearance of dying cells is a potential pathway for the development
of this systemic autoimmune disease. This includes deficient phagocytic activity and scant serum components in
addition to increased apoptosis.

Monocytes isolated from whole blood of SLE sufferers show reduced expression of CD44 surface molecules
involved in the uptake of apoptotic cells. Most of the monocytes and tingible body macrophages (TBM), which
are found in the germinal centres of lymph nodes, even show a definitely different morphology; they are smaller
or scarce and die earlier. Serum components like complement factors, CRP, and some glycoproteins are,
furthermore, decisively important for an efficiently operating phagocytosis. With SLE, these components are
often missing, diminished, or inefficient.
Recent research has found an association between certain lupus patients (especially those with lupus nephritis)
and an impairment in degrading Neutrophil extracellular traps (NETs). These were due to DNAse1 inhibiting
factors, or NET protecting factors in patient serum, rather than abnormalities in the DNAse1 itself.[43] DNAse1
mutations in lupus have so far only been found in some Japanese cohorts.[44]

The clearance of early apoptotic cells is an important function in multicellular organisms. It leads to a
progression of the apoptosis process and finally to secondary necrosis of the cells if this ability is disturbed.
Necrotic cells release nuclear fragments as potential autoantigens as well as internal danger signals, inducing
maturation of dendritic cells (DC), since they have lost their membranes' integrity. Increased appearance of
apoptotic cells also simulates inefficient clearance. That leads to maturation of DC and also to the presentation
of intracellular antigens of late apoptotic or secondary necrotic cells, via MHC molecules. Autoimmunity
possibly results by the extended exposure to nuclear and intracellular autoantigens derived from late apoptotic
and secondary necrotic cells. B and T cell tolerance for apoptotic cells is abrogated, and the lymphocytes get
activated by these autoantigens; inflammation and the production of autoantibodies by plasma cells is initiated.
A clearance deficiency in the skin for apoptotic cells has also been observed in people with cutaneous lupus
erythematosus (CLE).[45]

Germinal centres

Accumulation in germinal centres (GC)

In healthy conditions, apoptotic lymphocytes are removed in germinal centres by specialized phagocytes, the
tingible body macrophages (TBM), which is why no free apoptotic and potential autoantigenic material can be
seen. In some people with SLE, accumulation of apoptotic debris can be observed in GC because of an
ineffective clearance of apoptotic cells. In close proximity to TBM, follicular dendritic cells (FDC) are localised
in GC, which attach antigen material to their surface and, in contrast to bone marrow-derived DC, neither take it
up nor present it via MHC molecules.

Autoreactive B cells can accidentally emerge during somatic hypermutation and migrate into the GC light zone.
Autoreactive B cells, maturated coincidentally, normally do not receive survival signals by antigen planted on
follicular dendritic cells, and perish by apoptosis. In the case of clearance deficiency, apoptotic nuclear debris
accumulates in the light zone of GC and gets attached to FDC. This serves as a germinal centre survival signal
for autoreactive B-cells. After migration into the mantle zone, autoreactive B cells require further survival
signals from autoreactive helper T cells, which promote the maturation of autoantibody-producing plasma cells
and B memory cells. In the presence of autoreactive T cells, a chronic autoimmune disease may be the
consequence.

Anti-nRNP autoimmunity

Autoantibodies to nRNP A and nRNP C initially targeted restricted, proline-rich motifs. Antibody binding
subsequently spread to other epitopes. The similarity and cross-reactivity between the initial targets of nRNP
and Sm autoantibodies identifies a likely commonality in cause and a focal point for intermolecular epitope
spreading.[46]

Others

Elevated expression of HMGB1 was found in the sera of patients and mice with systemic lupus erythematosus,
High Mobility Group Box 1 (HMGB1) is a nuclear protein participating in chromatin architecture and
transcriptional regulation. Recently, there is increasing evidence that HMGB1 contributes to the pathogenesis of
chronic inflammatory and autoimmune diseases due to its pro-inflammatory and immunostimulatory properties.
[47]

Criteria

The American College of Rheumatology established eleven criteria in 1982,[50] which were revised in 1997[51] as
a classificatory instrument to operationalise the definition of SLE in clinical trials. They were not intended to be
used to diagnose individuals and do not do well in that capacity. For the purpose of identifying patients for
clinical studies, a person has SLE if any 4 out of 11 symptoms are present simultaneously or serially on two
separate occasions.

1. Malar rash (rash on cheeks); sensitivity = 57%; specificity = 96%.[52]

2. Discoid rash (red, scaly patches on skin that cause scarring); sensitivity = 18%; specificity
= 99%.[52]
3. Serositis: Pleurisy (inflammation of the membrane around the lungs) or pericarditis
(inflammation of the membrane around the heart); sensitivity = 56%; specificity = 86%
(pleural is more sensitive; cardiac is more specific).[52]
4. Oral ulcers (includes oral or nasopharyngeal ulcers); sensitivity = 27%; specificity = 96%.
[52]

5. Arthritis: nonerosive arthritis of two or more peripheral joints, with tenderness, swelling, or
effusion; sensitivity = 86%; specificity = 37%.[52]
6. Photosensitivity (exposure to ultraviolet light causes rash, or other symptoms of SLE
flareups); sensitivity = 43%; specificity = 96%.[52]
7. Blood—hematologic disorder—hemolytic anemia (low red blood cell count) or leukopenia
(white blood cell count<4000/µl), lymphopenia (<1500/µl) or thrombocytopenia
(<100000/µl) in the absence of offending drug; sensitivity = 59%; specificity = 89%.[52]
Hypocomplementemia is also seen, due to either consumption of C3 and C4 by immune
complex-induced inflammation or to congenitally complement deficiency, which may
predispose to SLE.
8. Renal disorder: More than 0.5 g per day protein in urine or cellular casts seen in urine
under a microscope; sensitivity = 51%; specificity = 94%.[52]
9. Antinuclear antibody test positive; sensitivity = 99%; specificity = 49%.[52]
10.Immunologic disorder: Positive anti-Smith, anti-ds DNA, antiphospholipid antibody, and/or
false positive serological test for syphilis; sensitivity = 85%; specificity = 93%.[52] Presence
of anti-ss DNA in 70% of cases (though also positive with rheumatic disease and healthy
persons).[53]
 11.Neurologic disorder: Seizures or psychosis; sensitivity = 20%; specificity = 98%.[52]

The mnemonic to remember the 11 symptoms is 'MD SOAP BRAIN' or 'DOPAMIN(E) RASH'.[54]

Pregnancy

While most infants born to mothers who have SLE are healthy, pregnant mothers with SLE should remain under
medical care until delivery. Neonatal lupus is rare, but identification of mothers at highest risk for complications
allows for prompt treatment before or after birth. In addition, SLE can flare up during pregnancy, and proper
treatment can maintain the health of the mother longer. Women pregnant and known to have the antibodies for
anti-Ro (SSA) or anti-La (SSB) often have echocardiograms during the 16th and 30th weeks of pregnancy to
monitor the health of the heart and surrounding vasculature.[59]

Contraception and other reliable forms of pregnancy prevention is routinely advised for women with SLE, since
getting pregnant during active disease was found to be harmful. Lupus nephritis was the most common
manifestation. Overall live-birth was 72.7%; the most common causes of pregnancy loss were spontaneous
abortion (miscarriage) and fetal death in utero. Pregnancy outcome was worse in SLE patients whose disease
flared up during pregnancy.[61]

Prognosis
SLE is considered incurable, but highly treatable.

In the 1950s, most people diagnosed with SLE lived fewer than five years. Advances in diagnosis and treatment
have improved survival to the point where over 90% now survive for more than ten years, and many can live
relatively asymptomatically. (It is important to note that "ten years" in this statistic does not indicate an average
survival rate, but is merely the length of the referenced study. According to the Lupus Foundation of America,
"the majority of people with lupus today can expect to live a normal lifespan."[72])

Prognosis is normally worse for men and children than for women; however, if symptoms are present after age
60, the disease tends to run a more benign course. Early mortality, within 5 years, is due to organ failure or
overwhelming infections, both of which can be modified by early diagnosis and treatment. The mortality risk is
fivefold when compared to the normal population in the late stages, which can be attributed to cardiovascular
diseases acquired from corticosteroid therapy, the leading cause of death for people with SLE.[62]

To reduce potential for cardiovascular issues, high blood pressure and high cholesterol should be prevented or
treated aggressively. Steroids should be used at the lowest dose for the shortest possible period, and other drugs
that can reduce symptoms should be used whenever possible.[62] High serum creatinine, hypertension, nephrotic
syndrome, anemia and hypoalbuminemia are poor prognostic factors.[73]

The ANA is the most sensitive screening test for evaluation, whereas anti-Sm (anti-Smith) is the most specific.
The dsDNA (double-stranded DNA) antibody is also fairly specific and often fluctuates with disease activity; as
such, the dsDNA titre is sometimes useful to monitor disease flares or response to treatment.[74]

Epidemiology
The rate of SLE varies considerably between countries, ethnicity, gender, and changes over time.[75] In the
United States the prevalence of SLE is estimated to be about 53 per 100,000, translating to about 159,000 out of
300 million people in the US being affected.[75][76] In Northern Europe the rate is about 40 per 100,000 people.[77]
SLE occurs more frequently and with greater severity among those of non-European descent.[76] That rate has
been found to be as high as 159 per 100,000 among those of Afro-Caribbean descent.[75]

SLE, like many autoimmune diseases, affects females more frequently than males, at a rate of almost 9 to 1.[75]

The incidence of SLE in the United States increased from 1.0 in 1955 to 7.6 in 1974. Whether the increase is
due to better diagnosis or to increasing frequency of the disease is unknown.[75]

History

The history of SLE can be divided into three periods: classical, neoclassical, and modern. The classical period
began when the disease was first recognized in the Middle Ages and saw the description of the dermatological
manifestation of the disorder. The term lupus is attributed to 12th-century physician Rogerius, who used it to
describe the classic malar rash. The neoclassical period was heralded by Móric Kaposi's recognition in 1872 of
the systemic manifestations of the disease. The modern period began in 1948 with the discovery of the LE cell
(the lupus erythematosus cell—a misnomer, as it occurs with other diseases as well) and is characterised by
advances in our knowledge of the pathophysiology and clinical-laboratory features of the disease, as well as
advances in treatment.[79]

Medical historians have theorized that people with porphyria (a disease that shares many symptoms with SLE)
generated folklore stories of vampires and werewolves, due to the photosensitivity, scarring, hair growth, and
porphyrin brownish-red stained teeth in severe recessive forms of porphyria (or combinations of the disorder,
known as dual, homozygous, or compound heterozygous porphyrias).[79]

Useful medication for the disease was first found in 1894, when quinine was first reported as an effective
therapy. Four years later, the use of salicylates in conjunction with quinine was noted to be of still greater
benefit. This was the best available treatment until the middle of the twentieth century, when Hench discovered
the efficacy of corticosteroids in the treatment of SLE.[79]

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Pathophysiology

SLE is an autoimmune disorder characterized by multisystem microvascular inflammation with the generation
of autoantibodies. Although the specific cause of SLE is unknown, multiple factors are associated with the
development of the disease, including genetic, racial, hormonal, and environmental factors.1,2 Many immune
disturbances, both innate and acquired, occur in SLE, as illustrated in below.

In systemic lupus erythematosus (SLE), many genetic-susceptibility factors,

environmental triggers, antigen-antibody responses, B-cell and T-cell
interactions, and immune clearance processes interact to generate and
perpetuate autoimmunity.
One proposed mechanism for the development of autoantibodies involves a defect in apoptosis that causes
increased cell death and a disturbance in immune tolerance.3,4,2 The redistribution of cellular antigens during
apoptosis leads to a cell-surface display of plasma and nuclear antigens in the form of nucleosomes. Thus,
dysregulated (intolerant) lymphocytes begin targeting normally protected intracellular antigens.

Immune complexes form in the microvasculature, leading to complement activation and inflammation.
Moreover, antibody-antigen complexes deposit on the basement membranes of skin and kidneys. In active SLE,
this process has been confirmed based on the presence of complexes of nuclear antigens such as DNA,
immunoglobulins, and complement proteins at these sites. Serum antinuclear antibodies (ANAs) are found in
virtually all individuals with active SLE, and antibodies to native double-stranded DNA (dsDNA) are relatively
specific for the diagnosis of SLE.