Systemic lupus erythematosus overview

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Overview
Historical Perspective
Classification
Pathophysiology
Causes
Differentiating Systemic lupus erythematosus from other Diseases
Epidemiology and Demographics
Risk Factors
Screening
Natural History, Complications and Prognosis
Diagnosis
Diagnostic Criteria
History and Symptoms
Physical Examination
Laboratory Findings
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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] Ayesha A. Khan, MD[3] Raviteja Guddeti, M.B.B.S. [4]

Overview

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.

Historical perspective

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. 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.

Classification

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).

Pathophysiology

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.

Causes

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.

Differentiating Systemic lupus erythematosus from other 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.

Epidemiology and Demographics

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.

Risk Factors

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

Screening

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

Natural history, complications and prognosis

Natural History

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.

Complications

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.

Prognosis

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.

Diagnosis

Diagnostic criteria

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.

History and Symptoms

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.

Physical Examination

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

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.

Imaging Findings

Electrocardiographic findings

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. 

X-ray

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. 

CT scan

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.

MRI

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.

Ultrasound and echocardiography

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.

Other imaging findings

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 studies

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.

Treatment

Medical Therapy

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.

Surgery

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

Prevention

Primary Prevention

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

Secondary Prevention

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

References

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