Systemic lupus erythematosus

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mahshid Mir, M.D. [2] Ayesha A. Khan, MD[3] Raviteja Guddeti, M.B.B.S. [4]

Systemic lupus erythematosus (SLE) is an autoimmune disease that can involve almost all body organs. Lupus may be classified into several subtypes according to the clinical features including systemic lupus erythematosus, cutaneous lupus erythematosus, drug-induced lupus, and neonatal lupus. The progression of SLE involves the immune system. Almost all of the pathological manifestations of SLE are due to antibody formation and deposition of immune complexes in different organs of the body. When the immune complexes are formed, they deposit in different body tissues and vessels, which may lead to complement activation and more organ damage. Other factors, including genetic factors, hormonal abnormalities, and environmental factors, also play a role in the pathogenesis of SLE. There are no established causes of systemic lupus erythematosus, but the most potent risk factors in the development of SLE are known to be female sex, HLA genetic mutations, African American, Asian, or non-Causcasian race, ultraviolet light exposure, and previous exposure to certain infections. SLE must be differentiated from other diseases that cause skin rash, and arthritis such as rheumatoid arthritis (RA), mixed connective tissue disease (MCTD), systemic sclerosis (SSc), dermatomyositis (DM), polymyositis (PM), and other autoimmune diseases. Worldwide, the prevalence of systemic lupus erythematosus is 60 per 100,000 persons. SLE can cause numerous flare ups. SLE usually develops in the second and third decades of life, although it can present at any age. SLE usually begins with mild symptoms such as fatigue, fever, and skin rashes. Without treatment, the patient will develop symptoms of end organ damage, which eventually leads to death in most cases. Common complications of systemic lupus erythematosus include dermatitis, nephritis, and arthritis. Most of these complications occur in chronic cases and lead to significant debilitation. The prognosis of systemic lupus erythematosus can vary. SLE can range from a benign illness to an extremely rapidly progressive disease that can lead to fulminant organ failure and death. Without treatment, systemic lupus erythematosus results in very high mortality rate. During the mid-20th century, the mortality rate of SLE was reported to be higher than 60%. SLE can be diagnosed based on SLICC criteria. The patient may have a positive history of familial lupus, skin rashes (especially photosensitive skin rashes), arthritis, and fatigue, which may be suggestive of systemic lupus erythematosus. The most common symptoms of SLE include constitutional symptoms such as fatigue, fever, myalgia, and weight changes. Other, organ-specific symptoms mostly occur with disease progression. SLE may show a variety of symptoms in different organs depending on the complications of the disease. The therapy for systemic lupus erythematosus (SLE) is targeted towards controlling disease activity and preventing organ damage. The choice of treatment for systemic lupus erythematosus (SLE) varies based on the severity of the disease and symptoms. Generally, all patients should be treated with hydroxychloroquine. Other pharmacologic medical therapies for SLE include glucocorticoids like oral prednisone or intravenous methylprednisolone, NSAIDs like celecoxib, and immunosuppressive therapy with mycophenolate, cyclophosphamide, or, particularly in severe cases, rituximab. Cutaneous lupus erythematosus (CLE), if present without the involvement of any other organ system, can be treated with topical corticosteroids. Other organ-related complications of SLE should be treated separately.

The word “lupus” means wolf in Latin, which refers to the comparison between the bites of wolves and the destructive injuries caused by SLE. The history of lupus erythematosus can be divided into three periods: classical, neoclassical, and modern.^[1] The classical period refers to the ancient history, when there was no exact definition of the disease. During the neoclassical lupus era, scientists determined the manifestations of lupus and to define the action of the disease. Modern history focuses on understanding the microscopic features and pathogenesis of SLE.

SLE may be classified into several subtypes according to clinical features, including: systemic lupus erythematosus, cutaneous lupus erythematosus, drug-induced lupus, and neonatal lupus. Systemic lupus erythematosus (SLE) itself may be classified into several subtypes based on dermatologic manifestations or glomerulonephritis. SLE may be classified according to dermatologic manifestations into 4 subtypes: acute cutaneous lupus erythematosus (ACLE), subacute cutaneous lupus erythematosus (SCLE), chronic cutaneous lupus erythematosus (CCLE), and intermittent cutaneous lupus erythematosus (ICLE). SLE may be classified according to glomerulonephritis into 6 subtypes: minimal mesangial lupus nephritis (class I), mesangial proliferative lupus nephritis (class II), focal lupus nephritis (class III), diffuse lupus nephritis (class IV), lupus membranous nephropathy (class V), and advanced sclerosing lupus nephritis (class VI).

The pathophysiology of systemic lupus erythematosus involves the immune system. Other factors such as genetic factors, hormonal abnormalities, and environmental factors also play a role. The most important environmental factors involved in the pathogenesis of SLE include ultraviolet (UV) light and certain infections. The most important genes involved in the pathogenesis of SLE include HLA-DR2, HLA-DR3, HLA class 3, C1q, and interferon (IFN) regulatory factor 5. The most prominent events involving immune abnormalities relate to persistent activation of B cells and plasma cells that make auto-antibodies during disease progression. 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 acivation, in the setting of environmental and stochastic events. Abbreviations: DC, dendritic cells; pDC, plasmacytoid dendritic cells.The disease developmental process begins with the release of microparticles and proinflammatory cytokines from the cells that are undergoing apoptosis. Due to excessive number of cells undergoing apoptosis, the body is unable to clear these microparticles entirely, and they are presented to dendritic cells as antigens. Dendritic cells process these microparticles, mature, and present these as antigens to T-cells. T-cells, microparticles, and proinflammatory cytokines themselves trigger B-cell activation and autoantibody production. As a result, body tissues lose their self-tolerance. The most prominent events involving hormonal abnormalities are due to prolactin and estrogen. On microscopic histopathological analysis, apoptotic keratinocytes, vacuolization of the basement membrane, and dermal mucin deposition are characteristic findings of SLE dermatitis, and active or inactive endocapillary or extracapillary segmental glomerulonephritis are characteristic findings of lupus nephritis.

There are no established causes for systemic lupus erythematosus. Common causes of systemic lupus erythematosus include genetic predisposition, auto-immune diseases, and use of drugs. Less common causes of systemic lupus erythematosus include environmental factors and exposure to ultraviolet (UV) light.

Systemic lupus erythematosus (SLE) must be differentiated from other diseases that cause skin rash, arthritis, positive autoimmune serology, weight loss, fevers and chronic pain, such as rheumatoid arthritis (RA), mixed connective tissue disease (MCTD), systemic sclerosis (SSc), dermatomyositis (DM), polymyositis (PM), and other autoimmune diseases.

Worldwide, the prevalence of systemic lupus erythematosus is 60 per 100,000 persons. In North America, South America, Europe, and Asia, the incidence of systemic lupus erythematosus ranges from as low as 1 per 100,000 persons to as high as 20 per 100,000 persons, with an average prevalence of 12 per 100,000 persons. The overall mortality rate of lupus is very high, estimated at approximately 50,000 deaths per 100,000. Women are more commonly affected with systemic lupus erythematosus than men. Systemic lupus erythematosus flare ups are more prevalent in women. Systemic lupus erythematosus is more prevalent in the African and Asian populations.

The most potent risk factor in the development of systemic lupus erythematosus is being female.^[2] Other risk factors include HLA genetic mutations, being African American, Asian, or non-Causcasian, and previous exposure to certain infections.

According to the United States Preventive Services Task Force, screening for systemic lupus erythematosus is not recommended.

Systemic lupus erythematosus (SLE) is an autoimmune disease. SLE involves many flare ups. SLE usually develops in the second and third decades of life, though it can present any age, beginning with mild symptoms such as fatigue, fever, and skin rashes. Without treatment, the patient will develop symptoms of end organ damage, which will eventually lead to death in most patients. The disease’s course can be divided into 4 subcategories: developmental phase, preclinical phase, clinical phase, and comorbid complication phase.

Common complications of systemic lupus erythematosus include dermatitis, nephritis, and arthritis. Most of these complications occur as part of the chronic activity of the disease, and lead to the debilitating characteristics of the disease.

The prognosis of systemic lupus erythematosus ranges from a benign illness to an extremely rapid progressive disease that can lead to fulminant organ failure and death. Without treatment, systemic lupus erythematosus will result in a very high mortality rate, with a report of higher than a 60% mortality rate during the mid-20th century. The presence of nephritis is associated with a particularly poor prognosis among patients with SLE; SLE is associated with a 10-year mortality of more than 50% among patients with nephritis. The recent increase in survival rate of patients and better prognoses may be due to increased disease recognition with more sensitive diagnostic tests, earlier diagnosis or treatment, the inclusion of milder cases, increasingly judicious therapy, and prompt treatment of complications. Although improvements in SLE diagnosis have led to better prognoses, the mortality rate among SLE patients is still 5 times higher than the normal population.

Based on SLICC criteria, to be diagnosed with SLE, the patient should have either at least 4 of 17 criteria, including at least 1 of the 11 clinical criteria and one of the six immunologic criteria (for each criterion, any bullet is considered 1 clinical criteria), or a biopsy-proven nephritis compatible with SLE in the presence of antinuclear antibodies (ANA) or anti-double-stranded DNA (dsDNA) antibodies.

A positive history of familial lupus, skin rashes (especially photosensitive skin rashes), arthritis, and fatigue may be suggestive of systemic lupus erythematosus. The most common symptoms of SLE include constitutional symptoms like fatigue, fever, myalgia, and weight changes. Other organ-specific symptoms mostly occur with disease progression. SLE may show a variety of symptoms in different organs depending on its complications.

In the earlier stages of the disease, patients appear well, while in the late stages of the disease, patients are clearly ill with multi-organ involvement. The patient may show a wide range of skin manifestations including urticaria, bullous lesions, malar rash, and scarring alopecia. The patient may develop nasal and oral ulcers. Arthritis may lead to a decreased range of motion, joint effusion, and arthralgia. Neurological manifestations including psychosis, cognitive impairment, and hallucinations, may also be present. 

Laboratory findings consistent with the diagnosis of systemic lupus erythematosus include autoantibody elevation of ANA, anti-dsDNA antibody, anti-SM antibody, and antiphospholipid antibodies, and a decrease in complement levels. Nonspecific laboratory findings include mild pancytopenia, elevated levels of creatinine and proteinuria due to renal failure (secondary to nephritis), elevated levels of ESR and CRP as acute phase reactants, decreased level of complements, and positive direct Coombs test.

The most important and prevalent ECG findings associated with systemic lupus erythematosus (SLE) include sinus tachycardia, ST segment changes, and ventricular conduction disturbances. Other ECG findings are related to late complications of SLE and depend on the complication. 

On X-ray imaging, systemic lupus erythematosus (SLE) may be characterized by different features depending on the complications that have occured. The most common characteristic findings of SLE in X-ray include a thumb printing sign in abdominal graphy, blunting of the costophrenic angle due to pleural effusion, cardiomegaly, hepatomegaly, osteoprosis, tenosinovitis, and other manifestations depending on the complications. 

On abdominal CT scan, systemic lupus erythematosus (SLE) may be characterized by hepatosplenomegaly, pancreatic parenchymal enlargement, and ascites. On cardiac CT scan, SLE may be characterized by enhancement of the thickened pericardium. On brain CT scan, SLE may be characterized by brain atrophy, stroke patterns like cortical hypodensity, and increased attenuation of the cortex.

On abdominal MRI, systemic lupus erythematosus (SLE) may be characterized by hepatomegaly, pancreatic parenchymal enlargement, and hypervascularity of mesentery. On cardiac MRI, SLE may be characterized by mitral leaflet thickening, pericardial thickness, and pericardial effusions. On brain MRI, SLE may be characterized by white matter lesions, changes in blood circulation of the brain, and patchy areas of enhancement. On musculoskeletal MRI, SLE may be characterized by intramuscular edema, proliferative tenosynovitis, and bone marrow edema.

On abdominal ultrasound, systemic lupus erythematosus (SLE) may present with hepatosplenomegaly, ascites, hyperecho-kidney tissue due to nephritis, and, rarely, cholecystitis. On synovial ultrasound, SLE may present with synovial effusions and synovitis. On echocardiography, SLE may present with decreased ejection fraction, cardiac wall motion abnormality, effusion pericarditis, and valve leaflet thickening.

One other imaging modality that can be used for the diagnosis of systemic lupus erythematosus complications is the double-contrast technique for gastritis evaluation. Another imaging technique that can be helpful in the diagnosis of SLE complications, especially early manifestations, is the technetium-99m scan. The scan can be used in different ways, including bone scintigraphy and bone scans to evaluate early and late bone complications, and for early evaluation of other organ complications including cardiac, hepatobiliary, and pulmonary complications.

Other diagnostic tests that can be used for diagnosis of complications include a barium swallow for stricture diagnosis, biopsies of the kidneys and the endometrium for further diagnosis of the degree of involvement, paracentesis to evaluate body effusions, and arthrocentesis to differentiate different causes of arthritis.

The mainstay of therapy for systemic lupus erythematosus (SLE) is controlling disease activity and preventing organ damage. The treatment choice for systemic lupus erythematosus (SLE) varies based on the severity of the disease and symptoms. Generally, all patients with any type of SLE manifestation should be treated with hydroxychloroquine, regardless of the level of their disease. Other pharmacologic medical therapies for SLE include glucocorticoids like oral prednisone or intravenous methylprednisolone, NSAIDs like celecoxib, and immunosuppressive therapy with mycophenolate, cyclophosphamide, or rituximab, particularly in severe cases. Cutaneous lupus erythematosus (CLE), if presented separately without any other system involvement, can be treated with topical corticosteroids. Other organ-related complications of SLE should be treated separately.

Surgical intervention is not recommended for the management of systemic lupus erythematosus.

There is no established method for prevention of systemic lupus erythematosus.

Secondary prevention strategies following systemic lupus erythematosus include using aspirin, ACE inhibitors, and statins to reduce atherosclerotic diseases and participating in cancer screenings.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2]; Associate Editor(s)-in-Chief: Mahshid Mir, M.D. [3]

The word “lupus” means wolf in Latin, as the destructive injuries SLE causes brought to mind wolf bites. The history of lupus erythematosus can be divided into three periods: classical, neoclassical, and modern. The classical period mostly refers to ancient history, when there was no exact definition of the disease. During the neoclassical lupus era, scientists investigated the manifestations of lupus and worked to define the disease’s action. Modern history is mostly focused on a microscopical understanding of the disease and pathogenesis of SLE.

The word “lupus” means wolf in Latin, as the destructive injuries SLE causes brought to mind wolf bites. The history of lupus erythematosus can be divided into three periods: classical, neoclassical, and modern.^[1] The classical period mostly refers to ancient history, when there was no exact definition of the disease. During the neoclassical lupus era, scientists investigated the manifestations of lupus and worked to define the disease’s action. Modern history is mostly focused on a microscopical understanding of the disease and pathogenesis of SLE.

• In ancient times, it was believed that lupus patients could turn into wolves, especially when exposed to sunlight. This false belief was later found to be related to lupus photosensitivity.^[2]
• Hippocrates was the first to use the phrase “herpes esthiomenos,” which was a definition for lupus lesions. Thus, Hippocrates is considered the first to have described cutaneous ulceration of the disease.^[3][4]

• In 1230 A.D., Rogerius Frugardi was the first to describe erosive facial lesions and used the term “lupus” for the first time scientifically.^[3]
• In 1530 A.D., Giovanni Manardi used the same pattern of ulceration to describe lower extremity lesions and also called it lupus.
• In the late 18th century, Robert Willan, a British dermatologist, was the first to describe the destructive lesions of the face and nose under the heading of lupus. Lupus willani, which is cutaneous tuberculosis or lupus vulgaris, is named after him.
• In 1833, Laurent Theodore Biett was the first one to describe lupus erythematosus, although he called it “erythema centrifugum.” Later, his student Pierre Louis Alphee Cazenave published his work.^[5]
• In 1845, Ferdinand von Hebra described an aggressive skin lesion with tissue destructive characteristics. Later, in 1866, Ferdinand von Hebra used the term “butterfly” to describe what is known as malar rash. He initially named the condition “seborrhea congestiva.”^[6]
• In 1851, Cazenave was the first to complete the description of discoid lupus. He called it “lupus erythematosus.”
• In 1872, Kaposi was the first to describe the systemic signs of the disorder, including arthritis, fever, anemia, lymphadenopathy, and weight loss.
• Kaposi and Cazenave were the first ones who clearly distinguished lupus erythematosus from lupus vulgaris or cutaneous tuberculosis, though both diseases coexist in some patients.
• In the late 19th century, Sir William Osler was the first to coin the term “systemic lupus erythematosus.” He discussed systemic complications of “erythema exsudativum multiforme,” including cardiac, pulmonary, and renal problems as well as cutaneous lesions.^[6]
• In the late 19th century, Jonathan Hutchinson was the first to describe the photosensitive nature of malar rash.
• In 1902, Sequira and Balean were the first to describe acroasphyxia, or the Raynaud phenomenon, and lupus nephritis.
• In 1908, Alfred Kraus and Carl Bohac were the first to describe pulmonary involvement in lupus.
• In 1923, Emanuel Libman and Benjamin Sacks were the first to describe noninfectious endocarditis due to lupus.^[7]

• In the early 20th century, George Belote and H.S. Ratner were the first to describe endocarditis of Libman-Sacks as a manifestation of lupus, even without concurrent cutaneous involvement. They changed the common idea of the necessity of cutaneous involvement for the diagnosis of lupus.
• In 1935, Paul Klemperer, George Baehr, and A.D. Pollack were the first to describe wire loop nephritis.
• In 1959, Leonardt, Arnett, and Schulman were the first to describe the familial aggregation of lupus and concordance in monozygotic twins.
• In 1906, Wasserman, while trying to develop a serologic test for syphilis, was the first to describe a complement-fixing antibody that reacted with extracts from bovine hearts. The corresponding antigen was later identified as cardiolipin.^[7]
• In 1948, Malcolm Hargraves discovered the lupus erythematosus (LE) cell. He observed two unusual phenomena in several bone marrow preparations while adding serum from patients with lupus erythematosus to bone marrow preparations from normal subjects.^[8]
• In 1954, Miescher and Fauconnet observed that absorption of lupus serum with nuclei prevented its ability to induce the LE cell phenomenon, suggesting that a globulin in the serum was reacting with, or destroying, the nuclei.^[8]
• In 1954, researchers at the Cleveland Clinic were the first to describe drug-induced lupus erythematosus, which was induced by the antihypertensive drug hydralazine.^[9]
• in 1958, George Friou discovered that the substance in the serum of patients with lupus erythematosus that reacted to the nuclei of cells was gamma globulin. He also discovered that the target in the nucleus was the complex of DNA and histones. He described the indirect immunoflourescence test to detect antinuclear antibodies. Autoantibodies like nuclear ribonucleoprotein (nRNP), Smith, Ro, La, and anticardiolipin antibodies were discovered based on his primary work.^[9]
• In 1959, the discovery of a lethal kidney disease in Otago Medical School in New Zealand represented a breakthrough in the understanding of lupus. The discovery provided many insights into disease mechanisms in immunopathogenesis of auto-antibody formation, immunologic tolerance, and the development of glomerulonephritis in lupus. The discovery also led to better evaluation of newer therapeutic agents in lupus erythematosus.^[4]
• In 1971, the first classification criteria for lupus was established.
• In 1982, the criteria were revised by the American College of Rheumatology (ACR) to incorporate new advances in serologic testing (ANA and anti-dsDNA) and improved biostatistical techniques.^[4][7]
• In 2012, the Systemic Lupus Collaborating Clinics (SLICC) revised and validated the American College of Rheumatology (ACR) SLE classification criteria in order to improve clinical relevance, meet stringent methodology requirements, and incorporate new knowledge in SLE immunology.^[4]

• Michael Jackson, had both SLE and vitiligo; diagnosed in 1986, and confirmed by his dermatologist, Arnold Klein, who presented legal documents during court depositions.^[10][11]
• Lady Gaga, has been tested borderline positive for SLE;^[12] says she hopes to avoid symptoms by maintaining a healthy lifestyle.^[13][14][11]
• Selena Gomez, American actress and singer was diagnosed with lupus.^[15][11]
• Toni Braxton, hospitalized in Los Angeles in December 2012 because of “minor health issues” related to lupus.^[16][11]
• Louisa May Alcott, American author best known for her novel Little Women; has been suggested to have had SLE.^[17][11]
• Ferdinand Marcos, former Philippine president; died of SLE complications in 1989.^[18][11]
• Hugh Gaitskell, British politician; died of SLE complications in 1963 aged 56.^[19][11]
• Donald Byrne, American chess player; died from SLE complications in 1976.^[20]
• Lauren Shuler Donner, American movie producer was diagnosed with lupus.^[21][11]
• Caroline Dorough-Cochran, died of SLE complications. She was the sister of Howie D. of the Backstreet Boys, who founded the Dorough Lupus Foundation in her memory.^[11]
• Pumpuang Duangjan, “queen of Thai country music”, was diagnosed with lupus.^[11]
• Juli Furtado, champion professional mountain biker was diagnosed with lupus.^[22][11]
• Sophie Howard, British glamour model was diagnosed with lupus.^[23][11]
• J Dilla (also known as Jay Dee), hip-hop producer and beat maker; died of SLE complications in 2006.^[24][11]
• Teddi King, American singer; died of SLE complications in 1977.^[25][11]
• Charles Kuralt, former anchor of CBS Sunday Morning; died of SLE complications in 1997.^[26][11]
• Inday Ba (also known as N’Deaye Ba), Swedish-born actress; died from SLE complications at age 32.^[27][11]
• Mary Elizabeth McDonough, American actress; believes her SLE to be due to silicone breast implants.^[28][11]
• Flannery O’Connor, American fiction writer; died of SLE complications in 1964.^[29][11]
• Tim Raines, former major league baseball player was diagnosed with lupus.^[30][11]
• Ray Walston, character actor who died of SLE complications in 2001 after a six-year battle with the disease.^[31][11]
• Michael Wayne, Hollywood director and producer; part owner of Batjac Productions; son of John Wayne, died of heart failure resulting from SLE complications in 2003.^[32][11]

Template:WH Template:WS

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mahshid Mir, M.D. [2], Raviteja Guddeti, M.B.B.S. [3], Kiran Singh, M.D. [4]

Lupus may be classified into several subtypes according to clinical features, including systemic lupus erythematosus, cutaneous lupus erythematosus, drug-induced lupus, and neonatal lupus. Systemic lupus erythematosus (SLE) itself may be classified into several subtypes based on dermatologic manifestations or glomerulonephritis. SLE may be classified according to dermatologic manifestations into 4 subtypes: acute cutaneous lupus erythematosus (ACLE), subacute cutaneous lupus erythematosus (SCLE), chronic cutaneous lupus erythematosus (CCLE), and intermittent cutaneous lupus erythematosus (ICLE). SLE may be classified according to glomerulonephritis into 6 subtypes: minimal mesangial lupus nephritis (class I), mesangial proliferative lupus nephritis (class II), focal lupus nephritis (class III), diffuse lupus nephritis (class IV), lupus membranous nephropathy (class V), and advanced sclerosing lupus nephritis (class VI).

Lupus may be classified into the following types based on clinical characteristics:^[1]

• Systemic lupus erythematosus (SLE)
• Cutaneous lupus erythematosus (CLE)
• Drug-induced lupus
• Neonatal lupus

SLE may be further classified according to dermatologic manifestations into 4 subtypes:^[1][2][3]

• Acute cutaneous lupus erythematosus (ACLE)
• Subacute cutaneous lupus erythematosus (SCLE)
• Chronic cutaneous lupus erythematosus (CCLE)
• Intermittent cutaneous lupus erythematosus (ICLE)

Subtypes	Manifestation/subclass
Acute cutaneous lupus erythematosus (ACLE)	Localized ACLE (i.e., malar rash, butterfly rash) Generalized ACLE Toxic epidermal necrolysis-like ACLE
Subacute cutaneous lupus erythematosus (SCLE)	Annular SCLE Papulosquamous SCLE Drug-induced SCLE Neonatal lupus (dermatitis manifestations) Less common subtypes: Erythrodermic Poikilodermatous Erythema multiforme-like (Rowell syndrome) Vesiculobullous annular SCLE
Chronic cutaneous lupus erythematosus (CCLE)	Discoid lupus erythematosus (DLE) Localized DLE Generalized DLE Hypertrophic DLE Lupus erythematosus tumidus (LE tumidus) Lupus profundus (also known as lupus panniculitis) Chilblain lupus erythematosus (chilblain LE) Lichenoid cutaneous lupus erythematosus-lichen planus overlap syndrome (LE-LP overlap syndrome)
Intermittent cutaneous lupus erythematosus (ICLE)	A consistent histopathologic feature of ACLE, SCLE, and discoid lupus erythematosus

SLE may be classified according to the degree of glomerulonephritis into 6 subtypes:^[4][5][6]

• Minimal mesangial lupus nephritis (class I)
• Mesangial proliferative lupus nephritis (class II)
• Focal lupus nephritis (class III)
• Diffuse lupus nephritis (class IV)
• Lupus membranous nephropathy (class V)
• Advanced sclerosing lupus nephritis (class VI)

Subtype	Manifestation/subclass
Minimal mesangial lupus nephritis (class I)	The earliest and mildest form of glomerular involvement Normal urinalysis, no or minimal proteinuria, and a normal serum creatinine
Mesangial proliferative lupus nephritis (class II)	Microscopic hematuria and/or proteinuria
Focal lupus nephritis (class III)	Hematuria and proteinuria May also have hypertension, a decreased glomerular filtration rate, and/or nephrotic syndrome
Diffuse lupus nephritis (class IV)	Most common and most severe form Hematuria and proteinuria Nephrotic syndrome, hypertension, and reduced glomerular filtration rate Hypocomplementemia (especially C3) and elevated anti-DNA levels, especially during active disease[7]
Lupus membranous nephropathy (class V)	Hematuria and proteinuria Nephrotic syndrome, hypertension, and reduced glomerular filtration rate Hypocomplementemia
Advanced sclerosing lupus nephritis (class VI)	Slowly progressive renal dysfunction Proteinuria

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mahshid Mir, M.D. [2], Cafer Zorkun, M.D., Ph.D. [3], Raviteja Guddeti, M.B.B.S. [4]

The pathophysiology of systemic lupus erythematosus involves the immune system. Other factors such as genetic factors, hormonal abnormalities, and environmental factors also play a role. The most important environmental factors involved in the pathogenesis of SLE include ultraviolet (UV) light and some infections. The most important genes involved in the pathogenesis of SLE include HLA-DR2, HLA-DR3, HLA class 3, C1q, and interferon (IFN) regulatory factor 5. The most prominent events involving immune abnormalities are related to persistent activation of B cells and plasma cells that make auto-antibodies during disease progression. The disease developmental process begins with the release of microparticles and proinflammatory cytokines from the cells that are undergoing apoptosis. Due to excess amount of apoptosis, the body is unable to clear these microparticles entirely, and these microparticles are presented to dendritic cells as antigens. Dendritic cells process these microparticles and mature, and present these as antigens to T-cells. T-cells, microparticles, and proinflammatory cytokines themselves trigger B-cell activation and autoantibody production. As a result, body tissues lose their self-tolerance. The most prominent events involving hormonal abnormalities are due to prolactin and estrogen. On microscopic histopathological analysis, apoptotic keratinocytes, vacuolization of the basement membrane, and dermal mucin deposition are characteristic findings of SLE dermatitis, and active or inactive endocapillary or extracapillary segmental glomerulonephritis are characteristic findings of lupus nephritis.

The progression of systemic lupus erythematosus (SLE) involves the immune system. Nearly all of the pathological manifestations of SLE occur due to antibody formation and the creation and deposition of immune complexes in different organs of the body. When the immune complexes are formed, they deposit on different body tissues and vessels, which may lead to complement activation and more organ damage. There are other factors such as genetic factors, hormonal abnormalities, and environmental factors that also play a role in the pathogenesis of SLE.

The environmental factors and genetic factors are the most important risk factors for developing SLE because they may jump-start the disinhibited cellular apoptosis chain. This apoptosis step is the first step in the pathogenesis of lupus.

• Infections
  • May stimulate some antigen specific cells and increase apoptosis
  • May induce anti-DNA antibodies
  • May mimic lupus-like symptoms
  • Associated with higher risk of SLE
  • Associated with triggering the active courses and flare ups of disease in children
  • Include:
    • Parvovirus B19
    • Epstein-Barr virus (EBV)
    • Trypanosomiasis
    • Mycobacterial infections
    • SLE flares may follow bacterial infections
• Ultraviolet (UV) light:
  • Can stimulate B-cells to produce more antibodies
  • May activate macrophages, interfere with antigen processing, and therefore increase the degree of autoimmunity

The development of systemic lupus erythematosus (SLE) is due to the activation of different mechanisms that may result in auto-immunity. The disease developmental process begins with the release of microparticles and proinflammatory cytokines from the cells that are undergoing apoptosis. Due to excess amount of apoptosis, the body is unable to clear these microparticles entirely, and these microparticles are presented to dendritic cells as antigens. Dendritic cells process these microparticles and mature, and present these as antigens to T-cells. T-cells, microparticles, and proinflammatory cytokines themselves trigger B-cell activation and autoantibody production. As a result, body tissues lose their self-tolerance. Affected patients are no longer entirely tolerant to all of their self-antigens, leading to development of an autoimmune disease and producing autoantibodies as a response. During disease progression, B cells and plasma cells that make autoantibodies are more persistently activated due to signaling abnormalities, causing them to make more autoantibodies. These autoantibodies are targeted predominantly to intracellular nucleoprotein particles.^[1][2] This increase in autoantibody production and persistence is supposed to be downregulated by anti-idiotypic antibodies or regulatory immune cells, but the massive immunologic response in SLE prevents this downregulation from taking place. After formation of immune complexes, the classical complement pathway is activated, which leads to the deposition of immune complexes in different organs and is responsible for flare ups and long term complications. The most important immune abnormalities that are related to SLE development and progression are: 

Increased level of microparticles (MPs):^[3]

• Microparticles are small, membrane-bound vesicles enclosing DNA, RNA, nuclear proteins, cell adhesion molecules, growth factors, and cytokines
• They are shed from cells during apoptosis or activation
• Microparticles can drive inflammation and autoimmunity by their derivatives

Increased expression of specific genetic factors may be associated with promoting autoimmunity. The most important cytokine changes include:^[4][3]

• Increased expression of interferon alpha (IFN-α) inducible RNA transcripts by mononuclear cells 
• Increased IFN-I production due to increased availability of stimulatory nucleic acids
  • May be responsible for SLE chronic characteristics
• Elevated levels of circulating TNF-alpha (expressed by renal tissue in lupus nephritis) correlate with active disease

Protein kinases are responsible for intracellular cytokine signals. Intracellular signaling leads to various types of cell response, such as:

• Cell migration
• Cell proliferation
• Inflammatory response

Cell signaling abnormalities leads to:

• T and B lymphocytes cellular hyperactivity
• T and B lymphocytes hyper responsiveness
• Persistence of auto-reactive T cells that would otherwise have been deleted

Signaling abnormalities of T and B lymphocytes, may be due to:

• Abnormal voltage-gated potassium channels, these channels facilitate excessive calcium entry into T cells and lead to increased calcium responses to antigen stimulation
• Hyperphosphorylation of cytosolic protein substrates
• Decreased nuclear factor kB

• Increase in circulating plasma cells and memory B cells that are associated with SLE activity
• Polyclonal activation of B cells and abnormal B-cell receptor signaling
• Increase in B cells’ life span

• Decrease in cytotoxic T cells, decrease in suppressor T cell function, and impaired generation of polyclonal T-cell cytolytic activity
• Increased number and activity of helper T cells

• Increased number of circulating neutrophils undergoing NETosis (NET=neutrophil extracellular traps), a form of apoptosis specific for neutrophils, releases DNA bound to protein in protein nets, which stimulates anti-DNA and IFN-alpha production
• Increased neutrophil extracellular trap leads to: ^[5]
  • Thrombus formation
  • Increased disease activity and renal disease and thus can be used even as a disease activity marker
  • Endothelial cell damage and inflammation in atherosclerotic plaques, which may contribute to accelerated atherosclerosis in systemic lupus erythematosus

The following evidence is suggestive of the hormonal predisposition to SLE:

• Predilection of the disease for females shows the relationship between female hormones and the onset of SLE
• Significantly increased risk for SLE in:^[6]
  • Early age of menarche
  • Early age at menopause or surgical menopause
  • Women that are treated with estrogen-containing regimens such as oral contraceptives or postmenopausal hormone replacement therapies

Hormones that are related to disease progression include:^[7]

• Stimulates the immune system and is elevated in SLE

• Including oral contraceptive use and postmenopausal hormone replacement therapy: ^[7][8]
  • Stimulates the type 1 IFN pathway
  • Stimulates thymocytes, CD8+ and CD4+ T cells, B cells, macrophages, and causes the release of certain cytokines (eg, IL-1)
  • Prompt maturation of B cells, especially those that have a high affinity to anti-DNA antibodies by decreasing the apoptosis of self-reactive B-cells^[9]
  • Stimulate expression of HLA and endothelial cell adhesion molecules (VCAM, ICAM)
  • Increases macrophage proto-oncogene expression
  • Enhanced adhesion of peripheral mononuclear cells to endothelium

• May inhibit the type 1 interferon pathway, suggesting that a balance between estrogen and progesterone may be critical for the body to remain healthy
  • Down-regulates T-cell proliferation and increases the number of CD8 cells
  • Act mainly as a protective agent
• Both progesterone and high levels of estrogen promote a Th2 response, which favors auto-antibody production

Systemic lupus erythematosus is transmitted in a polygenic inheritance pattern. Genes involved in the pathogenesis of systemic lupus erythematosus include HLA class 2 (especially DR2 and DR3), HLA class 3 (especially complement genes including C2 and C4 genes), IFNRF5 gene, and other genes related to the immunologic system. The following evidence is also suggestive of the genetic predisposition of SLE:^[10]

• Increase occurrence of disease in identical twins
• Increased disease frequency among first degree relatives
• The increased occurrence of the disease in siblings of SLE patients

Class	Gene subtype	Function	Pathological effect and Molecular mechanisms
Autoantigen presentation	HLA class 2[11]	Contains genes encoding glycoproteins that process and present peptides for recognition by T cells (antigen presenting cells) The most important related genes: HLA-DR2 HLA-DR3	Associated with an overall 2- to 3-fold increase in the risk of SLE More common in European and Asian people HLA-DQ and HLA-DR alleles: Strong association with SLE autoantibodies
Immune complex dependent response	HLA class 3[12]	Contains important immune genes including: C2 gene C4 gene Encode complement proteins The complement system acts through opsonization: Facilitates the clearance of apoptotic debris and cellular fragments The fragments may contain nuclear antigens, which are targets for SLE-associated autoantibodies Complement C4-A has a higher affinity for immune complexes Circulating complement C4 proteins clear immune complexes	Complete C2 and C4 deficiencies: Rare Associated with a mild form of SLE that affects mostly the joints and skin Stronger genetic evidence for an association with SLE in C4A than C4-B Circulating complement C4 proteins deficiency will promote autoimmunity
	C1q genes[12]	The complement system acts through opsonization: Facilitates the clearance of apoptotic debris and cellular fragments The fragments may contain nuclear antigens, which are targets for SLE-associated autoantibodies	Homozygous deficiency of C1q: Rare Develop a severe and early onset form of SLE Associated with severe glomerulonephritis and skin manifestations
Innate response	Interferon (IFN) regulatory factor 5[13]	Codes a transcription factor in the type 1 interferon pathway Regulates: Expression of IFN-dependent genes Inflammatory cytokines Genes involved in apoptosis	The most strongly and consistently SLE-associated loci outside the MHC region Upon activation, IRF5 activates transcription of type I IFN and proinflammatory cytokines such as TNFα, IL-12 and IL-6 Specific combinations of several polymorphisms in the IRF5 region interact to increase disease risk
	STAT4[14][15][16][17]	Encodes the signal transducer and activator of transcription 4 protein	Associated with a more severe SLE phenotype: Disease-onset at a young age (<30 years) High frequency of nephritis Associated with the presence of antibodies towards double-stranded DNA Mutation lead to an increased sensitivity to IFN-α signaling in peripheral blood mononuclear cells
	The IRAK1–MECP2 region	Encodes a protein kinase: Regulates multiple pathways in both innate and adaptive immune responses by linking several immune-receptor-complexes to TNF receptor-associated factor 6 Critical role in the transcriptional suppression of methylation-sensitive genes	The exact pathogenetics is not completely known
	FcγR genes[18]	Encode proteins that: Recognize immune complexes Are involved in antibody-dependent responses	Mutation associated with: Low affinity for IgG2-opsonized particles Reduced clearance of immune complexes
Cell apoptosis regulators	TREX1	Encodes a major exonuclease: Proofreads DNA polymerase Functions also as a DNA-degrading enzyme in granzyme-A-mediated apoptosis Act as a cytosolic DNA sensor	Mutation lead to impairs DNA damage repair, that lead to: Accumulation of endogenous retroelement-derived DNA Defective clearance of this DNA induces IFN production An immune-mediated inflammatory response Systemic autoimmunity
	IL-10	Encodes IL-10 An important regulatory cytokine with both immunosuppressive and immunostimulatory properties	Increased IL-10 production by B cells and monocytes from patients with SLE is known to correlate with disease activity
IFNα regulators	TNFAIP3 and TNIP1	Encode key regulators of the NFκB signaling pathway Modulate cell activation, cytokine signaling and apoptosis	The exact pathogenetics is not completely known
	PHRF1	Encodes an elongation factor	Related to SLE-associated autoantibodies and elevated IFN-α activity
Regulators of Lymphocytes	TNFSF4	The genes in this loci produce interaction induces the production of co-stimulatory signals to activate T cells	Inhibits the generation and function of IL-10 producing CD4+ T cells Induces B-cell activation and differentiation Induces IL-17 production Mutation lead to predisposition to SLE: Augmenting the interaction between T cells and antigen-presenting cells Influencing the functional consequences of T-cell activation
	BLK[19]	Encodes a protein kinase: Mediates intracellular signaling Influences B cells proliferation and differentiation Influences tolerance of B cells	More common in Chinese and Japanese populations
	PTPN22[20]	Encodes a lymphoid-specific phosphatase that inhibits T-cell activation	Associated with a higher risk of developing multiple autoimmune diseases More seen in European populations Mutation increases the intrinsic lymphoid-specific phosphatase activity that lead to: Reduction of T-cell receptor (TCR) signaling threshold Promotion of autoimmunity
	BANK1[21][22]	Encodes a B-cell adaptor protein Facilitates the release of intracellular calcium Alters the B-cell activation threshold	Mutations lead to hyperctivation of B-cell receptors and the subsequent B-cell hyperactivity that is commonly observed in SLE
	LYN[23]	Mediates B-cell activation Mediates B-cell inhibition
	ETS1[24][25]	Negatively regulates the differentiation of B cells and type 17 T-helper cells Regulates lymphocytes by inhibiting the function of an important transcription factor in plasma cells	The exact pathogenetics is not completely known
	IKZF1[26]	Encodes a lymphoid-restricted transcription factor Regulates: Lymphocyte differentiation and proliferation Self-tolerance through regulation of B-cell-receptor signaling	A novel SLE susceptibility locus in a Chinese population A strong candidate locus in European-derived populations
Genes involved in immune complex clearance	ITGAM[25]	Encodes a protein that binds the complement cleavage fragment of C3b	Contributes to SLE susceptibility

• Homozygous deficiencies of the components of complement, especially C1q, are associated with developing immunologic diseases, particularly SLE or a lupus-like disease.^[27]
• The FcγRIIA polymorphism has been associated with nephritis in African Americans, Koreans, and Hispanics. Both FcgammaRIIa and FcgammaRIIIa have low binding alleles that confer risk for SLE and may act in the pathogenesis of disease. ^[28]
• Women treated with estrogen-containing regimens such as oral contraceptives or postmenopausal hormone replacement therapies are more predisposed to SLE.
• Annular or psoriasiform skin lesions are associated with anti-Ro (SS-A) and anti-La (SS-B) antibodies.
• Anti-Ro, anti-La, anti sm, and anti RNP antibodies have been associated with mucocutaneous involvement and less severe nephropathy.

On gross pathology the most important characteristic findings are:

• Kidney: Bilateral pallor and hypertrophy
• Brain: Infarct regions and hemorrhages
• Heart: Cardiomegaly and valvular vegetation
• Lung: Peural fibrosis and pleural effusion

On microscopic histopathological analysis, lupus erythematosus (LE) cells can be seen in SLE. LE cells are neutrophils that have engulfed an intact nucleus. LE cells are also known as LE bodies.

On microscopic histopathological analysis, apoptotic keratinocytes, vacuolization of the basement membrane, and dermal mucin deposition are characteristic findings of SLE dermatitis, and active or inactive endocapillary or extracapillary segmental glomerulonephritis are characteristic findings of SLE nephritis. Microscopic findings in systemic lupus erythematosus are based on the involved organ system.

Common shared histopathologic features among all different subtypes of cutaneous lupus include:

• Hyperkeratosis
• Epidermal atrophy
• Dermal mucin deposition
• Liquefactive degeneration of the basal layer of the epidermis and vacuolization
• Thickening of the basement membrane
• Pigment incontinence
• Mononuclear cell infiltration at dermo-epidermal junction
• Superficial, perivascular, and perifollicular areas (due to mononuclear cell inflammatory infiltrate)

SLE dermatitis subtype	Specific microscopic findings	Preview
Acute cutaneous lupus erythematosus	Lymphohistiocytic infiltrate in the superficial dermis [29]
Subacute cutaneous lupus erythematosus	Less follicular plugging and hyperkeratosis in comparison with dischoid lupus erythematosus Superficial appendageal and perivascular lymphocytic infiltration Absence or minimal change of basement membrane thickening
Chronic cutaneous lupus erythematosus	Discoid lupus erythematosus : Follicular plugging Mononuclear cell infiltration near the dermal-epidermal junction, dermal blood vessels, and appendages Lupus erythematosus tumidus: Consists of predominately CD3+/CD4+ lymphocytes Focal interface changes Lupus profundus (lupus panniculitis): Perivascular infiltrates of mononuclear cells plus panniculitis Hyaline fat necrosis Direct immunofluorescence: immune deposits in the dermal-epidermal junction

Class	SLE nephritis subtype	Light microscopy findings	Light microscopy previews	Electron microscopy/Immunofluorescence findings
I	Minimal mesangial lupus nephritis	–		Mesangial immune deposits
II	Mesangial proliferative lupus nephritis	Mesangial hyper cellularity (of any degree) Mesangial matrix expansion		Isolated subepithelial or subendothelial deposits
III	Focal lupus nephritis	Active or inactive endocapillary or extracapillary segmental glomerulonephritis Involvement of glomeruli < 50%		Immune deposits in the subendothelial space of the glomerular capillary and mesangium Fibrinoid necrosis and crescents in glomeruli Tubulointerstitial or vascular abnormalities
IV	Diffuse lupus nephritis	Endocapillary glomerulonephritis Extracapillary glomerulonephritis Mesangial abnormalities Involvement of glomeruli > 50%		Subendothelial deposits specially during the active phase Diffuse wire loop deposits with little or no glomerular proliferation
V	Lupus membranous nephropathy	Diffuse thickening of the glomerular capillary wall Immunofluorescence or electron microscopy		Global or segmental subepithelial immune deposits
VI	Advanced sclerosing lupus nephritis	Global sclerosis Involvement of glomeruli > 90%		Global or segmental subepithelial immune deposits

• Nonspecific histopathologic findings
• Superficial fibrin-like material
• Local or diffuse synovial cell lining proliferation
• Vascular changes:
  • Perivascular mononuclear cells
  • Lumen obliteration
  • Enlarged endothelial cells
  • Thrombi

• Hyperkeratosis
• Atrophy of rete processes
• Superficial and deep inflammatory infiltrates
• Edema in the lamina propria
• Continuous or patchy periodic acid-Schiff (PAS)-positive deposits in the basement membrane zone
• Deposition of intercellular mucin
• Deposition of immunoglobulin and complement at the dermal-epidermal junction

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mahshid Mir, M.D. [2] Raviteja Guddeti, M.B.B.S. [3]

There are no established direct causes of systemic lupus erythematosus. Common contributory factors in the development of systemic lupus erythematosus include genetic predisposition, auto-immune diseases, and use of drugs. Less common factors include environmental factors and exposure to ultraviolet (UV) light.

• Genetic predisposition:^[1]
  • HLA class polymorphism
  • Complement genes
  • Female sexual gene due to high levels of estrogen and prolactin
• Auto-immune disease^[2]

• Infections
  • Parvovirus B19
  • Epstein-Barr virus (EBV)
  • Trypanosomiasis
  • Mycobacterial infections 

• Exposure to ultraviolet (UV) light^[3]
  • Can exacerbate or induce systemic manifestations of SLE 
• Drug-induced lupus

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mahshid Mir, M.D. [2]

Systemic lupus erythematosus (SLE) must be differentiated from other diseases that cause skin rash, arthritis, positive autoimmune serology, weight loss, fevers and chronic pain, such as rheumatoid arthritis (RA), mixed connective tissue disease (MCTD), systemic sclerosis (SSc), dermatomyositis (DM), polymyositis (PM), and other autoimmune diseases.

Systemic lupus erythematosus (SLE) must be differentiated from other diseases that cause skin rash, arthritis, positive autoimmune serology, weight loss, fevers and chronic pain, such as rheumatoid arthritis (RA), mixed connective tissue disease (MCTD), systemic sclerosis (SSc), dermatomyositis (DM), polymyositis (PM), and other autoimmune diseases.

Abbreviations: ANA: Antinuclear antibody, RF: Rheumatoid factor, Anti-CCp: Anti-cyclic citrullinated protein antibody, Anti U1RNP: Anti-U1 ribonucleoprotein antibodies, Anti Sm: Anti-Sm antibodies, Anti Ro: Anti Ro antibody also called anti-Sjögren’s-syndrome-related antigen A antibody, Anti-dsDNA: Anti-double stranded DNA.
(Up arrows represent higher amounts and down arrows represent lower amounts)

Disease		Arthritis					Auto-antibodies							Raynaud phenomenon	Rash pattern	Distinguishing/specific features
		Polyarthritis	Tenderness	Edema	Deformity /Erosion	Pattern	ANA	RF	Anti-CCp	Anti U1RNP	Anti Sm	Anti Ro	Anti-dsDNA
Systemic lupus erythematosus[1]		+	+	+	–	Small joints	↑	–	–	–	↑	↑	–	+	Malar rash and photosensitivity
Rheumatoid arthritis (RA)[2]		+	+	+	+	Small and large joints	–	↑↑	↑↑	–	–	–	–	+	Subcutaneous nodules	Erosive arthropathy
Rhupus[3]		+	+	+	+	Small and large joints	↑	↑	↑	↑	↑	–	↑	+	Malar rash and photosensitivity	Erosive arthropathy
Mixed connective tissue disease (MCTD)[4]		–	–	–	+	Small and large joints	–	↑↑	↑	–	–	–	–	+	Cutaneous eruptions, Gottron’s papules, photodistributed erythema, poikiloderma, and calcinosis cutis	Overlapping features of SLE, systemic sclerosis (SSc), and polymyositis (PM) that lead to more than one diagnosis
Undifferentiated connective tissue disease (UCTD)[5]		+	–	–	–	Lower extremity	↑	↑	–	–	↑	–	–	+	Erythematous macules, patches, or papules with delicate scale	Multiple connective tissue diseases with no enough criteria for a single diagnosis
Systemic sclerosis (SSc)[6]		+/-	+	+	+/-	Lower extremity	↑↑	–	–	–	↑	–	↑	+	Hyperkeratosis, edema, and erythema	Sclerodactyly, Telangiectasias, Calcinosis, Malignant hypertension, acute renal failure
Sjögren’s syndrome[7]		+/-	+/-	–	–	Lower extremity, axiallary creases	↑	–	–	–	↑	↑	–	–	Xerosis, scaly skin, annular erythema	Keratoconjunctivitis sicca
Vasculitis	Temporal arteritis[8]	–	+	+	–	Distal extremity	–	–	–	–	–	–	–	–	Rare	Involvement of cranial branches of arteries, visual loss
	Takayasu[9]	–	+/-	+/-	–	Transient extremity	–	–	–	–	–	–	–		Erythema nodosum, pyoderma gangrenosum	Absent or weak peripheral pulse
	Poly-arteritis nodosa[10]	–	+/-	–	–	General and mild	–	–	–	–	–	–	–		Tender erythematous nodules, purpura, livedo reticularis, bullous or vesicular eruption	Testicular pain or tenderness and neuropathies
Behçet’s syndrome[11]		+/-	+/-	+/-	–	medium and large joints	–	–	–	–	–	–	–	–	Recurrent and usually painful mucocutaneous ulcers, acneiform lesions, papulo-vesiculo-pustular eruptions, superficial thrombophlebitis	Male dominancy
Kikuchi’s disease[12]		–	+/-	–	–	medium and large joints	↑/↓	–	–	–	–	–	–	–	Transient skin rashes, malar rash, erythematous macules, patches, papules, or plaques	May be associated with SLE
Serum sickness[13]		+	+	+/-	–	General	–	–	–	–	–	–	–	–	Pruritic rash, urticaria and/or serpiginous macular rash	Self-limited
Psoriatic arthritis[14]		–	–	–	–	Small and large joints	–	–	–	–	–	–	–	–	Psoriasis and onychodystrophy	Dactylitis (sausage digits)
Human parvovirus B19 infection[15]		+	+	–	–	Small joints	–	–	–	–	–	–	–	–	Erythematous rashes	Rare in adults, fifth’s disease in children

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mahshid Mir, M.D. [2], Cafer Zorkun, M.D., Ph.D. [3], Raviteja Guddeti, M.B.B.S. [4]

Worldwide, the prevalence of systemic lupus erythematosus is 60 per 100,000 persons. In North America, South America, Europe, and Asia, the incidence of systemic lupus erythematosus ranges from as low as 1 per 100,000 persons to as high as 20 per 100,000 persons, with an average prevalence of 12 per 100,000 persons. The overall mortality rate of lupus is very high, estimated at approximately 50,000 deaths per 100,000. Women are more commonly affected with systemic lupus erythematosus than men. Systemic lupus erythematosus flare-ups are more prevalent in women. Systemic lupus erythematosus is more prevalent in people of the African and Asian races.

• Worldwide, the prevalence of systemic lupus erythematosus is 60 per 100,000 persons.^[1]
• Worldwide, a conservative estimate suggests that over 5 million people have lupus.
• Throughout the United States, the prevalence of systemic lupus erythematosus ranges from a low of 20 per 100,000 persons to a high of 150 per 100,000 persons with an average prevalence of 25 per 100,000 persons.^[1]

• In North America, South America, Europe, and Asia, the incidence of systemic lupus erythematosus ranges from as low as 1 per 100,000 persons to as high as 20 per 100,000 persons, with an average prevalence of 12 per 100,000 persons.^[1]
• Systemic lupus erythematosus incidence has approximately tripled during the past 3-4 decades. The increase in incidence is mainly attributed to improvement in diagnostic tests that have led to SLE diagnosis in earlier stages of the disease.

• The overall mortality rate of lupus is very high, estimated to have approximately 50,000 deaths per 100,000 cases.^[1]
• Approximately one third of deaths from SLE occur among persons aged <45 years.
• Non-Causcasian race is a risk factor for death from SLE.

• SLE mortality is mainly due to associated organ failures related to long term or more severe disease manifestations include, secondary infection, end stage renal disease due to lupus nephritis, and cardiovascular disease from accelerated atherosclerosis.

• The disease is more common in the young patient population even though it can occur at any age.
• Sixty-five percent of patients with SLE have disease onset between the ages of 16 and 55.

• Women are more commonly affected with systemic lupus erythematosus than men. Systemic lupus erythematosus flare ups are more prevalent in women.
  • The female to male ratio is approximately 5 to 1.
• Men are more commonly affected with cutaneous lupus erythematosus than women.
  • The male to female ratio is approximately 3 to 1.^[2]
• Complications of SLE such as renal disease, skin manifestations, cytopenias, serositis, neurologic involvement, thrombosis, cardiovascular disease, hypertension, and vasculitis are more common in men than in women.

• Systemic lupus erythematosus is more prevalent in Africans and Asians.
• The disease appears to be more common in urban than rural areas.
• Non-Caucasian race is a risk factor for death due to SLE.

• SLE is more severe among African-American women than others with a higher mortality rate.^[1][3]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mahshid Mir, M.D. [2], Raviteja Guddeti, M.B.B.S. [3]

The most potent risk factor in the development of systemic lupus erythematosus is gender; females are more likely to develop SLE.^[1] Other risk factors include HLA genetic mutations; being African American, Asian, or non-Causcasian; and previous exposure to certain infections.

The underlying cause of this autoimmune disease is not clear. Clinical data suggests that the onset of systemic lupus erythematosus is associated with the following factors:

• Female gender: SLE affects women nine times more than men^[2][3]
• Age: Occurs more commonly in people younger than 50
• Race: African Americans, Asians, and other non-Causcasians are affected more often than people of other races^[4]
• Drugs: The following drugs carry the greatest risk of developing drug-induced lupus erythematosus
  • Chlorpromazine
  • Hydralazine
  • Isoniazid
  • Methyldopa
  • Penicillamine
  • Procainamide
  • Quinidine
  • Sulfasalazine
• Familial history of:
  • SLE
  • Rheumatoid arthritis
  • Thrombotic thrombocytopenic purpura

• Infections can stimulate some antigen specific cells and lead to SLE disease:
  • Epstein-Barr virus (EBV) may induce anti-DNA antibodies or even lupus-like symptoms. It is associated with higher risk of SLE and also triggering the active course of disease in children^[5]
  • Trypanosomiasis or mycobacterial infections may have the same effect as EBV
• Ultraviolet (UV) light
• Cigarette smoking^[6]
• Crystalline silica exposure in work environment (e.g. cleaning powders, soil, pottery materials, cement, etc.)^[7]
• Drug allergy^[8]
• Caring for a pet (especially a dog)

• This table must include the cardinal manifestations of differential diagnosis and the list of diseases must be prioritize based on mortality rate and prevalences of the diseases. For example, if you want to write a differential diagnosis table for heat stroke, sepsis, malignant hyperthermia, neuroleptic malignant syndrome, and serotonin syndrome first, you need to mention the cardinal manifestations for these conditions as, hyperthermia and altered mental status. Second, prioritize your list based on disease mortality or prevalence then, create the table. You can find the example here.

Differential Diagnosis	Similar Features	Differentiating Features
Differential 1	On [physical exam; history; diagnostic test; imaging], [Differential 1] {has; demonstrates} [feature 1], [feature 2], [feature 3] also observed in [disease name].	On [physical exam; history; diagnostic test; imaging], [Differential 1] {has; demonstrates} [feature 1], [feature 2], [feature 3] that distinguish it from [disease name].
Differential 2	On [physical exam; history; diagnostic test; imaging], [Differential 1] {has; demonstrates} [feature 1], [feature 2], [feature 3] also observed in [disease name].	On [physical exam; history; diagnostic test; imaging], [Differential 1] {has; demonstrates} [feature 1], [feature 2], [feature 3] that distinguish it from [disease name].
Differential 3	On [physical exam; history; diagnostic test; imaging], [Differential 1] {has; demonstrates} [feature 1], [feature 2], [feature 3] also observed in [disease name].	On [physical exam; history; diagnostic test; imaging], [Differential 1] {has; demonstrates} [feature 1], [feature 2], [feature 3] that distinguish it from [disease name].
Differential 4	On [physical exam; history; diagnostic test; imaging], [Differential 1] {has; demonstrates} [feature 1], [feature 2], [feature 3] also observed in [disease name].	On [physical exam; history; diagnostic test; imaging], [Differential 1] {has; demonstrates} [feature 1], [feature 2], [feature 3] that distinguish it from [disease name].
Differential 5	On [physical exam; history; diagnostic test; imaging], [Differential 1] {has; demonstrates} [feature 1], [feature 2], [feature 3] also observed in [disease name].	On [physical exam; history; diagnostic test; imaging], [Differential 1] {has; demonstrates} [feature 1], [feature 2], [feature 3] that distinguish it from [disease name].

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Mahshid Mir, M.D. [2]

According to the United States Preventive Services Task Force, screening for systemic lupus erythematosus is not recommended.

According to the United States Preventive Services Task Force, screening for systemic lupus erythematosus is not recommended.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mahshid Mir, M.D. [2]

Common complications of systemic lupus erythematosus include dermatitis, nephritis, and arthritis. Prognosis is generally poor, and the 10-year mortality rate of patients with systemic lupus erythematosus is approximately 40%. The disease’s course can be divided into 4 subcategories: developmental phase, preclinical phase, clinical phase, and comorbid complication phase.

Systemic lupus erythematosus (SLE) is an autoimmune disease. Several flare-ups may happen in the course of the disease. SLE usually develops in the second and third decades of life, although it can present at any age. It usually starts with mild symptoms such as fatigue, fever, and skin rashes. Without treatment, the patient will develop symptoms of end organ damage, which will eventually lead to death in most patients.

The disease course can be divided into 4 subcategories based on the course of the disease:^[1][2][3]

• Genetic mutations
• UV radiation exposure
• Smoking

• Mostly associated with auto-immune antibody production
• Autoantibodies common to other systemic autoimmune diseases
• Proceeds with a more disease-specific clinically overt autoimmune phase

• The phase due to damages of the autoantibodies to the body tissues (mostly related to disease itself)
• Inflammation
• Involvement of first organs
• Flares
• Involvement of additional organs
• Early damages (e.g. alopecia, fixed erythema, cognitive dysfunction, valvular heart disease, avascular necrosis, tendon rupture, Jaccoud’s arthropathy, and osteoporosis)

The phase of damages due to complications of longstanding disease, immunosuppressive therapy, and end organ damage (irreversible damages and complications)

• Infections
• Atherosclerosis
• Malignancies

• Stress (emotional, etc.)
• Sunlight
• Ultraviolet light
• Infection
• Injuries
• Surgery
• Pregnancy
• Abrupt discontinuation of medications
• Treatment noncompliance
• Medications
• Immunizations
• Lupus nephritis
• Presence of neurologic complications
• Presence of vasculitis
• Elevated anti-dsDNA
• Low C3 level

Complications that can develop as a result of prolonged activation of systemic lupus erythematosus or the SLE therapy are:^{[6][7][8][9][10][11][12][13][14][15][16]}

(Up arrows represent higher frequencies and down arrows represent lower frequencies)

Organ	Disease	Description	Frequency
Gastrointestinal	Dysphagia	Usually due to an underlying esophageal motility disorder Concomitant gastroesophageal reflux disease	↑↑↑
	Peptic ulcer disease	Due to: The disease itself The adverse effect of SLE treatment	↑
	Intestinal pseudo-obstruction	May lead to mechanical obstruction of the small or large bowel in the absence of an anatomic lesion Obstructing the flow of intestinal contents	↓↓
	Protein-losing enteropathy	Occurs in patients with clinically severe SLE with multi-organ involvement Characterized by: Profound edema Hypoalbuminemia The absence of nephrotic range proteinuria	↓↓
	Hepatitis	May be due to: Drug-induced damage Steatosis Viral hepatitis (concomitant with SLE) Vascular thrombosis Overlap with autoimmune hepatitis due to SLE itself	↑
	Acute pancreatitis	Occurs usually in the setting of active SLE	↓
	Mesenteric vasculitis	Mostly involve: Medium-sized branches of the celiac artery Superior mesenteric artery Inferior mesenteric artery Features of mesenteric vasculitis include: Abdominal pain Gastrointestinal bleeding Intestinal ischemia, infarction, perforation Pancreatitis Primary spontaneous peritonitis: An infection that develops in the peritoneum mainly due to lupus vasculitis	↓↓
	Acute cholecystitis	Due to periarterial fibrosis and acute vasculitis May progress to gangrene, perforation, and sepsis	↓↓
Pulmonary	Pleural disease	May lead to: Pleuritic chest pain with or without radiographic evidence of a pleural effusion Inflammation of the pleura, the lining of the pleural cavity, surrounding the lungs Pneumothorax: a collection of air within the pleural cavity	↑
	Acute pneumonitis	Fulminant form of diffuse lung injury Characterized by rapid onset with fever, cough, and shortness of breath	↓↓
	Pulmonary hemorrhage	Pulmonary alveolar hemorrhage: Acutely ill patients with hemoptysis, fever, cough, and hypoxemia Extensive blood loss Associated with high mortality rates of 70%–90%	↓↓
	Pulmonary hypertension	Increased pressure in the pulmonary artery or lung vasculature Characterized by shortness of breath, dizziness, and faint	↑
	Thromboembolic disease	Chronic inflammation that increase the risk of thromboembolic events	↑
	Shrinking lung syndrome	Characterized by dyspnea and shortness of breath (estimated prevalence approximately 0.5%)	↓↓
Cardiac	Cardiomegaly	Due to: Myocarditis Libman-Sacks endocarditis Subacute bacterial endocarditis Uremia Pulmonary arterial hypertension with right-sided heart failure Corticosteroid-related cardiomyopathy	↑↑
	Valvular disease	Different valvular complications include: Libman-Sacks vegetations Valve thickening Valve regurgitation Mainly due to immunoglobulin and complement deposition in valvular structure Affect the mitral valve more frequently	↑↑
	Pericardial disease	Acute pericarditis Pericardial effusion	↓
	Myocarditis	Characterized by: Chest pain ST segment elevation Elevated biomarkers of myonecrosis Heart failure Sudden death Myonecrosis may happen as a consequence of autoimmune reaction	↓
	Coronary artery disease	Mainly as a result of increased risk of atheromatous plaques due to autoimmune status of SLE	↑↑
Neurological	Cognitive dysfunction	May be temporarily affected by multiple, transient metabolic and systemic processes	↑
	Stroke	Increase risk of thrombotic stroke due to small vessel vasculopathy	↓
	Seizures	May happen secondary to increased intracranial pressure: Hypercoagulability state (due to inflammation) Thrombosis within the cerebral venous	↑
	Psychosis	Can indirectly influence cognitive performance Mostly accompanied by hallucinations in SLE	↑↑
	Neuropathies	Peripheral neuropathy Mostly related to disease activity Central nervous system involvement association A predilection for asymmetric and lower extremities involvement, especially peroneal and sural nerves	↑↑
Musculoskeletal	Arthritis	Mostly symmetrical and non-erosive arthritis Arthralgias Effusions Decreased range of motion of both small and large joints Morning stiffness	↑↑↑↑
	Osteonecrosis (Avascular necrosis)	Most common in the femoral head Can involve humeral head, tibial plateau, and scaphoid navicular Usually bilateral Often asymptomatic Glucocorticoids treatment is associated with the greatest risk of developing the disease	↓
	Subcutaneous nodules	Associated with active disease and flare ups	↑
	Osteoporosis	Mostly due to glucocorticoid usage Loss of height Sudden back pain	↑
Skin	Cutaneous lupus erythematosus	Erythema in a malar distribution over the cheeks and nose (but sparing the nasolabial folds), which appears after sun exposure	↑
	Photosensitivity	Common theme for skin lesions associated with SLE	↑↑↑
	Non-scarring alopecia	May occur at some point during the course of their disease	↑
	Oral and nasal ulcers	Usually painless	↑↑
	Discoid lesions	More inflammatory Have a tendency to scar	↑
Very rare disorders	Malignancy	Non-Hodgkin’s lymphoma Lung cancer Liver cancer Vulvar/vaginal cancer Thyroid cancer	↓↓↓
	Diabetes mellitus	Increase predisposition to: Lupus nephritis Peripheral neuropathy Retinal disease	↓

The prognosis of systemic lupus erythematosus ranges from a benign illness to an extremely rapid progressive disease that can lead to a fulminant organ failure and death. Without treatment, systemic lupus eryhtematosus will result in a very high mortality rate, with a report of higher than a 60% mortality rate during the mid-20th century. The presence of nephritis is associated with a particularly poor prognosis among patients with SLE; SLE is associated with a 10-year mortality of more than 50% among patients with nephritis. The increase in survival rate of patients and better prognosis may be due to increased disease recognition with more sensitive diagnostic tests, earlier diagnosis or treatment, the inclusion of milder cases, increasingly judicious therapy, and prompt treatment of complications. Although improvements in SLE diagnosis have led to better prognosis, the mortality rate among SLE patients is still 5 times higher than the normal population.^{[17][18][19][20]}

• Presence of nephritis (especially diffuse proliferative glomerulonephritis)
• Hypertension
• Male sex
• Young age
• Older age at presentation
• Low socioeconomic status
• Black race: Higher rate of nephritis
• Presence of antiphospholipid antibodies
• High overall disease activity

• Lupus nephritis
• Progression to end-stage renal disease
• Increased disease severity
• Damage or poor survival

• Features of the antiphospholipid syndrome (APS)
• CNS involvement
• Severe lupus nephritis
• Increase in mortality rate

• Less photosensitivity
• More serositis
• Older age at diagnosis
• Higher 1 year mortality compared to women

• Lower incidence of:
  • Malar rash
  • Photosensitivity
  • Purpura
  • Alopecia
  • Raynaud’s phenomenon
  • Nephritis
  • Central nervous system involvement
• Greater prevalence of:
  • Serositis
  • Pulmonary involvement
  • Sicca syndrome
  • Musculoskeletal manifestations

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mahshid Mir, M.D. [2]

Based on SLICC criteria, for an SLE diagnosis, the patient should have either at least 4 of 17 criteria, including at least 1 of the 11 clinical criteria and one of the six immunologic criteria (for each criterion, any bullet is considered as 1 clinical criteria), or a biopsy-proven nephritis compatible with SLE in the presence of antinuclear antibodies (ANA) or anti-double-stranded DNA (dsDNA) antibodies.

In 2012, Systemic Lupus International Collaboration Criteria (SLICC) developed a new criteria for SLE diagnosis. SLICC criteria for the classification of systemic lupus erythematosus was developed based on the old ACR criteria for the classification of systemic lupus erythematosus to address a more sensitive diagnostic criteria and also to cover weaknesses of the previous ACR criteria.^[1][2]

Based on SLICC criteria, diagnosis of SLE is defined as:^[3]

• Meeting at least 4 of 17 criteria, including at least 1 of the 11 clinical criteria and one of the six immunologic criteria 

OR

• Biopsy-proven nephritis compatible with SLE in the presence of antinuclear antibodies (ANA) or anti-double-stranded DNA (dsDNA) antibodies

A criterion is considered positive if one or more of the observations listed in the definition for the criterion are present in the patient. A criterion should only be counted once, regardless of the number of observations in the definition that the patient presents with.

Category	Criterion	Definition
Clinical	Acute cutaneous lupus	Lupus malar rash Fixed erythema, flat or raised, over the malar eminences, tending to spare the nasolabial folds Bullous lupus Toxic epidermal necrolysis variant of SLE Maculopapular lupus rash Photosensitive lupus rash (in the absence of dermatomyositis); Skin rash as a result of unusual reaction to sunlight, by patient history or physician observation   Subacute cutaneous lupus Nonindurated psoriaform and/or annular polycyclic lesions that resolve without scarring, although occasionally with postinflammatory dyspigmentation or telangiectasias
	Chronic cutaneous lupus	Classic discoid rash Localized (above the neck) Generalized (above and below the neck) Hypertrophic (verrucous) lupus Lupus panniculitis (profundus) Mucosal lupus Lupus erythematosus tumidus Chilblains lupus OR Discoid lupus/lichen planus overlap
	Nonscarring alopecia	Diffuse thinning or hair fragility with visible broken hairs (in the absence of other causes, such as alopecia areata, drugs, iron deficiency, and androgenic alopecia)
	Oral or nasal ulcers	Palate, buccal, tongue, or nasal ulcers (in the absence of other causes, such as vasculitis, Behçet’s disease, infection, inflammatory bowel disease, reactive arthritis, and acidic foods)
	Joint disease	Synovitis involving two or more joints, characterized by swelling or effusion Tenderness in two or more joints and at least 30 minutes of morning stiffness
	Serositis	Typical pleurisy for more than one day, pleural effusions, or pleural rub Typical pericardial pain (pain with recumbency improved by sitting forward) for more than one day, pericardial effusion, pericardial rub, or pericarditis by electrocardiography in the absence of other causes, such as infection, uremia, and Dressler’s syndrome
	Renal	Urine protein-to-creatinine ratio (or 24-hour urine protein) representing 500 mg protein/24 hours Red blood cell casts
	Neurologic	Seizures Psychosis Mononeuritis multiplex (in the absence of other known causes, such as primary vasculitis) Myelitis Peripheral or cranial neuropathy (in the absence of other known causes, such as primary vasculitis, infection, and diabetes mellitus)  Acute confusional state (in the absence of other causes, including toxic/metabolic, uremia, drugs)
Hematologic	Hemolytic anemia	Hemoglobin less than 12 g/dL in females and 13 g/dL in males
	Leukopenia or lymphopenia	Leukopenia (<4000/mm3 at least once) (in the absence of other known causes, such as Felty’s syndrome, drugs, and portal hypertension) Lymphopenia (<1000/mm3 at least once) (in the absence of other known causes, such as glucocorticoids, drugs, and infection)
	Thrombocytopenia	Thrombocytopenia (<100,000/mm3) at least once in the absence of other known causes, such as drugs, portal hypertension, and thrombotic thrombocytopenic purpura
Immunologic	ANA	ANA level above laboratory reference range
	Anti-dsDNA	Anti-dsDNA antibody level above laboratory reference range (or >twofold the reference range if tested by ELISA)
	Anit-SM	Presence of antibody to Sm nuclear antigen
	Antiphospholipid	Antiphospholipid antibody positivity as determined by any of the following: Positive test result for lupus anticoagulant False-positive test result for rapid plasma reagin Medium- or high-titer anticardiolipin antibody level (IgA, IgG, or IgM) Positive test result for anti-beta 2-glycoprotein I (IgA, IgG, or IgM)
	Low complement	Low C3 Low C4 Low CH50
	Direct Coombs’ test	Direct Coombs’ test in the absence of hemolytic anemia