SYSTEMIC LUPUS ERYTHEMATOSUS

Introduction
Background

Systemic lupus erythematosus (SLE) is a chronic, multifaceted inflammatory disease that can affect every organ system of the body. SLE is protean in its manifestations and follows a relapsing and remitting course. This article addresses what is known regarding the etiology, pathophysiology, clinical features, and treatment of SLE.
Pathophysiology

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

In systemic lupus erythematosus (SLE), many genet...
In systemic lupus erythematosus (SLE), many genetic-susceptibility factors, environmental triggers, antigen-antibody responses, B-cell and T-cell interactions, and immune clearance processes interact to generate and perpetuate autoimmunity.

[ CLOSE WINDOW ]

In systemic lupus erythematosus (SLE), many genet...

In systemic lupus erythematosus (SLE), many genetic-susceptibility factors, environmental triggers, antigen-antibody responses, B-cell and T-cell interactions, and immune clearance processes interact to generate and perpetuate autoimmunity.

One proposed mechanism for the development of autoantibodies involves a defect in apoptosis that causes increased cell death and a disturbance in immune tolerance.3,4,2 The redistribution of cellular antigens during apoptosis leads to a cell-surface display of plasma and nuclear antigens in the form of nucleosomes. Thus, dysregulated (intolerant) lymphocytes begin targeting normally protected intracellular antigens.

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

According to a recent report from the National Arthritis Data Working Group, approximately 250,000 Americans have systemic lupus.5 The frequency of SLE varies by race and ethnicity, with higher rates reported among black and Hispanic people. The prevalence of SLE is approximately 40 per 100,000 whites in Rochester, Minnesota, versus 100 per 100,000 Hispanic persons in Nogales, Arizona.6,7
International

Worldwide, the prevalence of SLE varies. Although the prevalence of SLE is high in black persons in the United Kingdom, the disease is rarely reported among blacks who live in Africa.8
Mortality/Morbidity

The natural history of SLE varies from relatively benign disease to rapidly progressive and even fatal disease. SLE often waxes and wanes in affected individuals throughout life, and features of the disease vary greatly between individuals. The disease course is milder and survival rate higher among persons with isolated skin and musculoskeletal involvement than in those with renal9 and CNS disease.

SLE carries an average 10-year survival rate that now exceeds 90%.10,11 Prior to 1955, the 5-year survival rate was less than 50%. Decreased mortality rates associated with SLE can be attributed to earlier diagnosis (including milder cases), improvement in disease-specific treatments, and advances in general medical care. According to the CDC, one third of SLE-related deaths in the United States occur in patients younger than 45 years, making this a serious issue despite declining overall mortality rates. In 1976, Urowitz first reported bimodal mortality in early versus late SLE, noting that SLE-related deaths usually occur within the first 5-10 years of symptom onset.12

Infectious complications related to active SLE and immunosuppressive treatment are now the most common cause of death in early active SLE, and accelerated arteriosclerosis is a key cause of late mortality.10 The Framingham Offspring Study demonstrated that women aged 35-44 years with SLE were 50 times more likely to develop myocardial ischemia than healthy women.13 Causes of accelerated coronary artery disease (CAD) in persons with SLE are likely multifactorial, including endothelial dysfunction, inflammatory mediators, corticosteroid-induced atherogenesis, and dyslipidemia associated with renal disease.
Race

Worldwide, the prevalence of SLE appears to vary by race. However, because of different prevalence rates among people of the same race in different geographical locations, a clear conclusion cannot yet be drawn. Low reported rates of SLE in Africa in contrast to a high prevalence in black women in the United Kingdom suggests the importance of environmental influences.8 In addition, the influence of race on prognosis has been widely debated. The LUMINA study group examined SLE among black, white, and Hispanic patients in the United States (including Puerto Rico) and reported that both disease activity and poverty predicted higher mortality among racial and ethnic minorities.14
Sex

SLE frequently starts in women of childbearing age, and the use of exogenous hormones has been associated with lupus onset and flares, suggesting a role for hormonal factors in the pathogenesis of the disease.15 The risk of SLE development in men is similar to that in prepubertal or postmenopausal women. Interestingly, SLE is more common in men with Klinefelter disease than in men without the disease, also supporting a hormonal hypothesis.
Age

A correlation between age and incidence of SLE mirrors peak years of female sex hormone production. The prevalence of SLE is highest among women aged 14-64 years. SLE does not have an age predilection in males.
Clinical
History

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that can affect almost any organ system. Its presentation and course are highly variable, ranging from indolent to fulminant. The following is an overview of the multitudinous protean manifestations.16,17

* Constitutional symptoms: Nonspecific fatigue, fever, arthralgia, and weight changes are the most common symptoms in new cases or recurrent active SLE flares. Fatigue, the most common constitutional symptom associated with SLE, can be due to active SLE, medications, lifestyle habits, or concomitant fibromyalgia or affective disorders. Fatigue due to active SLE generally occurs in concert with other clinical and laboratory markers. Fever, another common yet nonspecific symptom of SLE, may also result from many causes, the most common of which include active SLE, infection, and drug fever. Careful history taking may help to differentiate these. Weight loss may occur in patients with active SLE. Weight gain may also be due to corticosteroid treatment or active disease such as nephrotic syndrome anasarca.
* Musculoskeletal symptoms: Joint pain is one of the most common reasons for the initial clinical presentation in patients with SLE. Arthralgia, myalgia, and frank arthritis may involve the small joints of the hands, wrists, and knees. In contrast to rheumatoid arthritis, SLE arthritis or arthralgia may be asymmetrical, with pain that is disproportionate to swelling.
* Dermatological symptoms
o Cutaneous manifestations of SLE comprise 4 diagnostic criteria and multiple other clues to a potential diagnosis of lupus.
+ The first is malar rash, which is characterized by an erythematous rash over the cheeks and nasal bridge. It lasts from days to weeks and is occasionally painful or pruritic.
+ The second feature is photosensitivity, which may be elicited from patients who are asked if they have any unusual rash or symptom exacerbation after sun exposure.
+ The third feature may be discoid rash. Discoid lesions often also develop in sun-exposed areas but are plaquelike in character, with follicular plugging and scarring. They may be part of systemic lupus or may represent discoid lupus without organ involvement, which is a separate diagnostic entity.
+ Alopecia is the fourth and often less-specific cutaneous feature of SLE. It often affects the temporal regions or creates a patchlike pattern of hair loss.
o Other cutaneous manifestations related to but not specific to SLE include Raynaud phenomenon, livedo reticularis, panniculitis (lupus profundus), bullous lesions, vasculitic purpura, telangiectasias, and urticaria.
* Renal features: The kidney is the most commonly involved visceral organ in SLE. Although only approximately 50% of patients with SLE develop clinically evident renal disease, biopsy studies demonstrate some degree of renal involvement in almost all patients. Glomerular disease usually develops within the first few years of SLE onset and is usually asymptomatic. Acute or chronic renal failure may cause symptoms related to uremia and fluid overload. Acute nephritic disease may manifest as hypertension and hematuria. Nephrotic syndrome may cause edema, weight gain, or hyperlipidemia.
* Neuropsychiatric features
o Because of the difficulty in distinguishing causal SLE associations from certain neurological features of the disease, only seizure and psychosis are included among the diagnostic criteria. Psychosis may manifest as paranoia or hallucinations. Delirium represents a spectrum of fluctuating altered consciousness characteristic of SLE. Delirium may be caused by CNS vasculitis, encephalopathy, or the manifestations previously called organic brain syndrome. Seizures related to SLE may be generalized or partial and may precipitate status epilepticus. Aseptic meningitis, myelopathy, optic neuropathy, or other demyelinating disorders may also require urgent evaluation. Transverse myelitis with spastic paraparesis is a rare but serious complication of SLE. The CNS Lupus nomenclature has been revised to catalog many manifestations.18,19
o Cognitive disorders may be variably apparent in patients with SLE. Formal neuropsychiatric testing reveals deficits in 21-67% of patients with SLE. Whether this represents true encephalopathy, neurological damage, medication effects, depression, or some other process is unclear. Stroke and transient ischemic attack (TIA) may be related to antiphospholipid antibody syndrome or vasculitis. Migraine headaches may also be linked to antiphospholipid syndrome, although this is less clear. Headache and mood disorders may be the most commonly reported neurologic manifestation of SLE, but cause and effect may be difficult to distinguish.
o For additional information on neurologic manifestations of SLE, see the article Systemic Lupus Erythematosus in eMedicine's Neurology volume.
* Pulmonary features: Pulmonary manifestations of SLE may manifest acutely or indolently, representing many complications. Pleurisy with pleuritic chest pain with or without pleural effusions is the most common feature of acute pulmonary involvement in SLE. Shortness of breath or dyspnea may be due to many causes. Serositis due to pericardial or pulmonary effusions, pulmonary embolism, lupus pneumonitis, chronic lupus interstitial lung disease, complement-mediated pulmonary leukoaggregation, or infection may be related to lupus disease. Pulmonary hypertension without underlying parenchymal lung disease rarely occurs with symptomatic dyspnea or right-sided heart failure. Most seriously, hemoptysis may herald diffuse alveolar hemorrhage, a rare, acute, life-threatening pulmonary complication of SLE.
* Gastrointestinal features: Gastrointestinal symptoms secondary to primary SLE and adverse effects of medication are common among persons with SLE. Abdominal pain in SLE is significant because it may be directly related to active lupus, including peritonitis, pancreatitis, mesenteric vasculitis, and bowel infarction. Nausea and dyspepsia are common symptoms in patients with active SLE and are sometimes difficult to correlate with objective evidence of gastrointestinal involvement. Jaundice due to autoimmune hepatitis may also occur.
* Cardiac features: Heart failure or chest pain must be carefully examined in patients with SLE. Pericarditis that manifests as chest pain is the most common cardiac manifestation of SLE, manifesting as positional chest pain that is often relieved when the patient leans forward. Myocarditis may occur in SLE with heart failure symptomatology. Coronary vasculitis manifesting as angina or infarction is rarely reported. Libman-Sacks endocarditis is noninfectious but may manifest as symptoms similar to those of infectious endocarditis. More commonly, accelerated ischemic CAD is associated with SLE and may present indolently as atypical anginal equivalents.
* Hematologic features: A history of multiple cytopenias such as leukopenia, lymphopenia, anemia, or thrombocytopenia may suggest SLE, among other etiologies. Leukopenia and, more specifically, lymphopenia are common in SLE; this and hypocomplementemia may predispose persons with SLE to frequent infections. Anemia is occasionally overlooked in young menstruating women. Thrombocytopenia may be mild or part of a thrombotic thrombocytopenic purpura (TTP)–like syndrome or antiphospholipid antibody syndrome. History of recurrent early miscarriages or a single late pregnancy loss may be clues to lupus or isolated antiphospholipid antibody syndrome. A family history of autoimmune disease should also raise further suspicion of SLE.

Physical

As discussed above, almost any organ system can be involved in active SLE. The constellation of several physical findings may suggest a diagnosis of SLE. The American College of Rheumatology (ACR) diagnostic criteria are discussed in Lab Studies. Examination findings are discussed by system.16,17

* Constitutional/lymph findings: Fever may signal infection or an acute SLE flare. Lymphadenopathy or splenomegaly may be found.
* Cutaneous findings
o Malar rash describes an erythematous rash over the cheeks and nasal bridge, with classic nasolabial fold sparing, as seen in the image below.
o

The classic malar rash, also known as a butterfly...
The classic malar rash, also known as a butterfly rash, with distribution over the cheeks and nasal bridge. Note that the fixed erythema, sometimes with mild induration as seen here, characteristically spares the nasolabial folds.

[ CLOSE WINDOW ]

The classic malar rash, also known as a butterfly...

The classic malar rash, also known as a butterfly rash, with distribution over the cheeks and nasal bridge. Note that the fixed erythema, sometimes with mild induration as seen here, characteristically spares the nasolabial folds.
o Photosensitive rash is often macular or diffusely erythematous in sun-exposed areas of the face, arms, or hands, as in the image below.
o

Photosensitive systemic lupus erythematosus (SLE)...
Photosensitive systemic lupus erythematosus (SLE) rashes typically occur on the face or extremities, which are sun-exposed regions. Photo courtesy of Dr. Erik Stratman, Marshfield Clinic.

[ CLOSE WINDOW ]

Photosensitive systemic lupus erythematosus (SLE)...

Photosensitive systemic lupus erythematosus (SLE) rashes typically occur on the face or extremities, which are sun-exposed regions. Photo courtesy of Dr. Erik Stratman, Marshfield Clinic.
o Discoid lesions are plaquelike in character, with follicular plugging, which may create scarring. Again, these may represent limited discoid lupus or SLE.
o Alopecia in SLE often affects the temporal regions or creates a patchy pattern.
o Oral ulcers may be noted, with palatal ulcers being most specific for SLE.
o Many other cutaneous findings are not explicitly diagnostic features of SLE. Livedo reticularis is characterized by a lacy, mottled, erythematous skin pattern that develops in some patients with SLE or antiphospholipid antibody syndrome. Raynaud phenomenon may be observed with blue, white, and red color change at the distal digital tips. Capillaroscopy can be performed with an ophthalmoscope to search for dilated capillary nailfold loops. Panniculitis, bullous lesions, vasculitic purpura, and urticaria are other skin lesions that are sometimes seen in SLE.
* Musculoskeletal findings: Small-joint arthritis of the hands and wrists is the most common musculoskeletal finding in SLE, followed by arthritis of the knees. Pain reports may be out of proportion to synovitis or swelling upon examination. Jaccoud arthropathy is the term used to describe the nonerosive hand deformities due to chronic arthritis and tendonitis that develop in 10% of patients with SLE. Myositis that may manifest as weakness rarely occurs and is more commonly related to overlap syndromes or corticosteroid-induced myopathy. Fibromyalgia, which should be distinguished by myofascial tenderness without weakness, is commonly concomitant with SLE, causing generalized widespread pain, arthralgia, and myalgia.
* Renal findings: Hypertension or hematuria may signal nephritic SLE. Edema of periorbital or peripheral regions and anasarca are common physical findings related to nephrotic syndrome or volume overload with renal failure.
* Neuropsychiatric findings: Altered mental status in SLE may be secondary to aseptic meningitis, seizures, psychosis, or organic brain syndrome. Focal neurological deficits may represent stroke, TIA, or mononeuritis. Mononeuritis may manifest as the functional loss of one or a few isolated peripheral nerves and is observed in some patients with SLE vasculitis or antiphospholipid disease.
* Cardiopulmonary findings: Pleuropericardial friction rubs and signs of effusions may be found. Hypoxia, tachypnea, crackles, or gross hemoptysis may be signs of pneumonitis or diffuse intrapulmonary hemorrhage. Hemodynamic instability and hypoxia may suggest pulmonary embolism. Heart failure signs or arrhythmias may point to ischemia or inflammatory myocarditis. Murmurs may represent Libman-Sacks endocarditis, superimposed infectious endocarditis, or thromboembolic disease.
* Gastrointestinal findings: Abdominal tenderness and pain may be observed in peritonitis, pancreatitis, mesenteric vasculitis, or non–lupus-related processes. Lupus peritonitis is a less-common serositis that may be present, even in the absence of ascites.

Causes

Although the specific cause of SLE is unknown, immune-system dysregulation and immune-complex tissue damage at sites such as the skin and kidneys, as well as direct antibody-mediated cytotoxicity that causes thrombocytopenia and hemolytic anemia, are suspected causes. Multiple immune disturbances may predispose to SLE (see chart below).

In systemic lupus erythematosus (SLE), many genet...
In systemic lupus erythematosus (SLE), many genetic-susceptibility factors, environmental triggers, antigen-antibody responses, B-cell and T-cell interactions, and immune clearance processes interact to generate and perpetuate autoimmunity.

[ CLOSE WINDOW ]

In systemic lupus erythematosus (SLE), many genet...

In systemic lupus erythematosus (SLE), many genetic-susceptibility factors, environmental triggers, antigen-antibody responses, B-cell and T-cell interactions, and immune clearance processes interact to generate and perpetuate autoimmunity.

Recent reports have synthesized what is known about the mechanisms of SLE disease and genetic associations.2,20 More than 10 gene loci are known to increase the risk of SLE. A genetic predisposition is supported by the 25% concordance among monozygotic twins versus 2% in dizygotic twins. Studies of the human leukocyte antigens (HLA) reveal that HLA-A1, B8, and DR3 are more common in persons with SLE than in the general population. The presence of the null complement alleles and congenital deficiencies of complement (especially C4, C2, and other early components) are also associated with an increased risk of SLE.

Numerous studies have also investigated the role of infectious etiologies such as Epstein-Barr virus (EBV) that may also perpetuate autoimmunity. The multitudinous distinct genetic associations suggest complex genetic predisposition and gene environment interactions, perhaps explaining the variable clinical manifestations in persons with SLE.Differential Diagnoses
Antiphospholipid Syndrome
Polyarteritis Nodosa
Fibromyalgia
Preeclampsia
Hepatitis C
Rheumatic Fever
Infectious Mononucleosis
Rheumatoid Arthritis
Infective Endocarditis
Scleroderma
Lyme Disease
Serum Sickness
Lymphoma, B-Cell
Thrombotic Thrombocytopenic Purpura
Mixed Connective-Tissue Disease
Undifferentiated Connective-Tissue Disease
Other Problems to Be Considered

Drug-induced lupus erythematosus
Vasculitis
Leukemia
Neoplasia
HIV infection
Multiple sclerosis
Parvovirus or other viral infections
Workup
Laboratory Studies

Systemic lupus erythematosus (SLE) is a diagnosis that must be based on the proper constellation of clinical findings and laboratory evidence. Familiarity with the diagnostic criteria helps clinicians to recognize SLE and to subclassify this complex disease based on the pattern of target-organ manifestations.

The 1982 American College of Rheumatology (ACR) criteria summarize features necessary to diagnose SLE.21,22 They are summarized below with a useful mnemonic. The presence of 4 of the 11 criteria yields a sensitivity of 85% and a specificity of 95% for SLE. Keep in mind that individual features are variably sensitive and specific. Patients with SLE may present with any combination of clinical features and serologic evidence of lupus. The following is the ACR diagnostic criteria in SLE, presented in the "SOAP BRAIN MD" acronym:

* Serositis - Pleurisy, pericarditis on examination or diagnostic ECG or imaging
* Oral ulcers - Oral or nasopharyngeal, usually painless; palate is most specific
* Arthritis - Nonerosive, two or more peripheral joints with tenderness or swelling
* Photosensitivity - Unusual skin reaction to light exposure
* Blood disorders - Leukopenia (<4 X 103 cells/µL on more than one occasion), lymphopenia (<1500 cells/µL on more than one occasion), thrombocytopenia (<100 X 103 cells/µL in the absence of offending medications), hemolytic anemia * Renal involvement - Proteinuria (>0.5 g/d or 3+ positive on dipstick testing) or cellular casts
* ANAs - Higher titers generally more specific (>1:160); must be in the absence of medications associated with drug-induced lupus
* Immunologic phenomena - dsDNA; anti-Smith (Sm) antibodies; antiphospholipid antibodies (anticardiolipin immunoglobulin G [IgG] or immunoglobulin M [IgM] or lupus anticoagulant); biologic false-positive serologic test results for syphilis, lupus erythematosus (LE) cells (omitted in 1997)
* Neurologic disorder - Seizures or psychosis in the absence of other causes
* Malar rash - Fixed erythema over the cheeks and nasal bridge, flat or raised
* Discoid rash - Erythematous raised-rimmed lesions with keratotic scaling and follicular plugging, often scarring

In patients with high clinical suspicion or high ANA titers, additional testing is indicated. This commonly includes evaluation of antibodies to dsDNA, complement, and ANA subtypes such as Sm, SSA, SSB, and ribonucleoprotein (RNP) (often called the ENA panel). Screening laboratory studies to diagnose possible SLE should include a CBC count with differential, serum creatinine, urinalysis with microscopy, ANA, and, perhaps, basic inflammatory markers. The following are autoantibody tests used in the diagnosis of SLE:23

* ANA - Screening test; sensitivity 95%; not diagnostic without clinical features
* Anti-dsDNA - High specificity; sensitivity only 70%; level variable based on disease activity
* Anti-Sm - Most specific antibody for SLE; only 30-40% sensitivity
* Anti-SSA (Ro) or Anti-SSB (La) - Present in 15% of patients with SLE and other connective-tissue diseases such as Sjögren syndrome; associated with neonatal lupus
* Anti-ribosomal P - Uncommon antibodies that may correlate with lupus cerebritis
* Anti-RNP - Included with anti-Sm, SSA, and SSB in the ENA profile; may indicate mixed connective-tissue disease with overlap SLE, scleroderma, and myositis
* Anticardiolipin - IgG/IgM variants measured with enzyme-linked immunoassay (ELISA) among the antiphospholipid antibodies used to screen for antiphospholipid antibody syndrome
* Lupus anticoagulant - Multiple tests (eg, Direct Russell Viper Venom test) to screen for inhibitors in the clotting cascade in antiphospholipid antibody syndrome
* Coombs test - Coombs test–positive anemia to denote antibodies on RBCs
* Anti-histone - Drug-induced lupus ANA antibodies often this type (eg, with procainamide or hydralazine; perinuclear antineutrophil cytoplasmic antibody [p-ANCA]–positive in minocycline-induced drug-induced lupus)

Other laboratory tests used in the diagnosis of SLE include the following:

* Inflammatory markers: Levels of inflammatory markers, including the erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP), may be elevated in any inflammatory condition, including SLE. CRP levels change more acutely, and the ESR lags behind disease changes.
* Complement levels: C3 and C4 levels are often depressed in patients with active SLE because of consumption by immune complex–induced inflammation. In addition, some patients have congenital complement deficiency that predisposes them to SLE.
* A CBC count may help to screen for leukopenia, lymphopenia, anemia, and thrombocytopenia, and urinalysis and creatinine studies may be useful to screen for kidney disease.
* Liver test results may be mildly elevated in acute SLE or in response to therapies such as azathioprine or nonsteroidal anti-inflammatory drugs (NSAIDS).
* Creatinine kinase levels may be elevated in myositis or overlap syndromes.

Imaging Studies

* Joint radiography often provides little evidence of SLE given the absence of erosions, even in the presence of Jaccoud arthropathy with deformity or subluxations. The most common radiographic changes in SLE include periarticular osteopenia and soft-tissue swelling.
* Chest radiography and chest CT scanning can be used to monitor interstitial lung disease and to assess for pneumonitis, pulmonary emboli, and alveolar hemorrhage.
* Brain MRI/magnetic resonance angiography (MRA) is used to evaluate CNS lupus for white-matter changes, vasculitis, or stroke, although findings are often nonspecific.
* Echocardiography is used to assess for pericardial effusion, pulmonary hypertension, or verrucous Libman-Sacks endocarditis.

Procedures

* Lumbar puncture may be performed to exclude infection with fever or neurologic symptoms. Nonspecific elevations in cell count and protein level and decrease in glucose level may be found in the cerebrospinal fluid of patients with CNS lupus.
* Renal biopsy is used to identify the specific type of glomerulonephritis, to aid in prognosis, and to guide treatment. Another benefit of renal biopsy is in distinguishing renal lupus from renal thrombosis, which may complicate antiphospholipid antibody syndrome and require anticoagulation rather than immunomodulatory therapy.
* Skin biopsy can help to diagnose SLE or unusual rashes in patients with SLE. Many different rashes may herald SLE, making review by a dermatopathologist important.

Histologic Findings

Renal biopsy is used to confirm the presence of lupus nephritis, to aid in classification of SLE nephritis, and to guide therapeutic decisions. The World Health Organization classification for lupus nephritis is based on light microscopy, electron microscopy, and immunofluorescence findings.

Table 1. International Society of Nephrology 2003 Revised Classification of SLE Nephritis24

Open table in new window
[ CLOSE WINDOW ]
Table
Class Classification Features

Class I


Minimal mesangial


Normal light microscopy findings; abnormal electron microscopy findings

Class II


Mesangial proliferative


Hypercellular on light microscopy

Class III


Focal proliferative


<50% of glomeruli involved Class IV Diffuse proliferative >50% of glomeruli involved; classified segmental or global; treated aggressively

Class V


Membranous


Predominantly nephrotic disease

Class VI


Advanced sclerosing


Chronic lesions and sclerosis
Class Classification Features

Class I


Minimal mesangial


Normal light microscopy findings; abnormal electron microscopy findings

Class II


Mesangial proliferative


Hypercellular on light microscopy

Class III


Focal proliferative


<50% of glomeruli involved Class IV Diffuse proliferative >50% of glomeruli involved; classified segmental or global; treated aggressively

Class V


Membranous


Predominantly nephrotic disease

Class VI


Advanced sclerosing


Chronic lesions and sclerosis

Lupus skin rash often demonstrates inflammatory infiltrates at the dermoepidermal junction and vacuolar change in the basal columnar cells. Discoid lesions demonstrate more-significant skin inflammation, with hyperkeratosis, follicular plugging, edema, and mononuclear cell infiltration at the dermoepidermal junction. In many SLE rashes, immunofluorescent stains demonstrate immunoglobulin and complement deposits at the dermoepidermal basement membrane.Treatment
Medical Care

Management for systemic lupus erythematosus (SLE) depends on disease severity. Periodic follow-up and laboratory testing, including urinalyses, CBC count with differential, and creatinine, are imperative to detect signs and symptoms of new organ-system involvement and to monitor the response or adverse reactions to therapies. At least quarterly visits are recommended in most cases. The European League Against Rheumatism (EULAR) has released recommendations for the treatment of SLE, and a US American College of Rheumatology Task Force has generated a quality indicator set.25,26

Treatment recommendations for SLE depend on disease manifestations.27 In general, fever, cutaneous manifestations, musculoskeletal manifestations, and serositis represent milder disease, which may wax and wane with disease activity. These are often controlled with low-potency medications or short steroid courses. CNS involvement and renal disease must be recognized as more severe disease manifestations and are often treated with more aggressive immunosuppression.

Acute emergencies in SLE include severe neurologic involvement, systemic vasculitis, profound thrombocytopenia with a TTP-like syndrome, rapidly progressive glomerulonephritis, and diffuse alveolar hemorrhage. These may be treated with high-dose intravenous steroids and cytotoxic therapy such as cyclophosphamide. In rare cases, TTP, diffuse alveolar hemorrhage, or profound steroid-refractory thrombocytopenia may require plasma exchange or therapy with intravenous immunoglobulin (IVIG), respectively. Catastrophic antiphospholipid antibody syndrome also requires aggressive acute management. (See the article Antiphospholipid Syndrome in eMedicine’s Rheumatology volume for more details.)

Preventative care measures for patient with SLE are necessary to minimize the risks of steroid-induced osteoporosis and accelerated atherosclerotic disease. The ACR Guidelines for the prevention of glucocorticoid-induced osteoporosis suggest traditional steps and the consideration of prophylactic bisphosphonate therapy. Recently, numerous authors have also advocated drafting cardiovascular prevention guidelines that equate SLE as a "CAD risk-equivalent" similar to diabetes mellitus. This is based on a 10-year coronary event rate of 13-15% in patients with active SLE that is comparable to a 10-year event rate of 18.8% in patients with known CAD.28 Recent work points out that African American patients may be particularly vulnerable to premature cardiovascular disease (CVD) and CVD-related death.29
Consultations

The multisystemic nature of SLE often requires involvement of consultants, depending on the organ system involved. Consultation with any of the following specialists may be necessary:

* Rheumatologist
* Infectious disease specialist
* Neurologist
* Pulmonologist
* Cardiologist
* Gastroenterologist
* Nephrologist
* Dermatologist
* Hematologist

Diet

No diet-based treatment of SLE has been proven effective.
Activity

Patients with SLE should be reminded that activity may need to be modified as tolerated. Specifically, stress such as physical illness may precipitate SLE flares. Additionally, persons with SLE should wear sunscreen and protective clothing or avoid sun exposure to limit photosensitive rash or disease flares.
Medication

Treatment of systemic lupus erythematosus (SLE) is guided by the individual patient's manifestations. Fever, rash, musculoskeletal manifestations, and serositis generally respond to treatment with hydroxychloroquine, NSAIDS, and low-to-moderate–dose steroids, as necessary, for acute flares. Medications such as methotrexate may be useful in chronic lupus arthritis, and azathioprine and mycophenolate have been widely used in moderate severity lupus.

CNS involvement and renal disease constitute more serious disease and often require high-dose steroids and other immunosuppression agents such as cyclophosphamide, azathioprine, or mycophenolate. Class IV diffuse proliferative lupus nephritis has also been treated with aggressive cyclophosphamide induction therapy, and recent trials of mycophenolate have not demonstrated superiority.30 New investigations are in progress to examine the role of rituximab and other biological therapies in SLE. Recent observational evidence suggests that hydroxychloroquine may have protective benefits in patients with SLE, including improved survival.31
Nonsteroidal Anti-inflammatory Drugs (NSAIDs)

These agents provide symptomatic relief for arthralgias, fever, and mild serositis.

NSAIDs may cause elevated liver function test results in patients with active SLE. Additionally, concomitant administration with prednisone may increase risk of GI ulceration.

Ibuprofen (Advil, Motrin, Ibuprin)

DOC for patients with mild-to-moderate pain. Inhibits inflammatory reactions and pain by decreasing prostaglandin synthesis

* Dosing
* Interactions
* Contraindications
* Precautions

Adult

400 mg PO q4-6h, 600 mg q6h, or 800 mg q8h while symptoms persist; not to exceed 2.4 g/d
Pediatric

20-70 mg/kg/d PO divided tid/qid, start at lower end of dosing range and titrate; not to exceed 2.4 g/d

* Dosing
* Interactions
* Contraindications
* Precautions

Coadministration with aspirin increases risk of inducing serious NSAID-related adverse effects; probenecid may increase concentrations and, possibly, toxicity of NSAIDs; may decrease effect of hydralazine, captopril, and beta-blockers; may decrease diuretic effects of furosemide and thiazides; may increase PT when taking anticoagulants (instruct patients to watch for signs of bleeding); may increase risk of methotrexate toxicity; phenytoin levels may be increased when administered concurrently

* Dosing
* Interactions
* Contraindications
* Precautions

Documented hypersensitivity; peptic ulcer disease; recent GI bleeding or perforation; renal insufficiency; high risk of bleeding

* Dosing
* Interactions
* Contraindications
* Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions

Caution in congestive heart failure, hypertension, and decreased renal and hepatic function; caution in anticoagulation abnormalities or during anticoagulant therapy; can cause aseptic meningitis in SLE
Antimalarials

Antimalarials may work through numerous proposed mechanisms in SLE, mediating subtle immunomodulation without overt immunosuppression. They are useful in preventing and treating lupus skin rashes, constitutional symptoms, arthralgias, and arthritis. They also help to prevent lupus flares and have been associated with reduced morbidity and mortality in SLE.

Hydroxychloroquine (Plaquenil)

Inhibits chemotaxis of eosinophils and locomotion of neutrophils and impairs complement-dependent antigen-antibody reactions. Hydroxychloroquine sulfate 200 mg is equivalent to 155 mg hydroxychloroquine base and 250 mg chloroquine phosphate.

* Dosing
* Interactions
* Contraindications
* Precautions

Adult

200 mg PO qd/bid; if BW <130 lb, may be candidate for dose reduction to qd to minimize retinal toxicity
Pediatric

3-5 mg/kg/d (base) PO qd or divided bid; not to exceed 6.5 mg/kg/d adult dose

* Dosing
* Interactions
* Contraindications
* Precautions

Serum levels increase with cimetidine; magnesium trisilicate may decrease absorption

* Dosing
* Interactions
* Contraindications
* Precautions

Documented hypersensitivity; psoriasis; retinal and visual field changes that limit monitoring

* Dosing
* Interactions
* Contraindications
* Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions

Caution in hepatic disease, G-6-PD deficiency, psoriasis, and porphyria; not recommended for long-term use in children; refer for maintenance ophthalmologic examinations32 ; test periodically for muscle weakness
Immunosuppressant Agents

These agents act as immunosuppressives and cytotoxic and anti-inflammatory agents.

Griffiths et al (2010) compared the corticosteroid-sparing effect of cyclosporine with azathioprine in patients with severe SLE. Reduction of the corticosteroid dose from baseline was achieved with either cyclosporine or azathioprine. No significant difference in corticosteroid-sparing effect was observed with either treatment. The authors concluded that azathioprine may be considered first-line therapy since cyclosporine requires close monitoring of blood pressure and serum creatinine.33

Methotrexate (Folex PFS, Rheumatrex)

For managing arthritis, serositis, cutaneous, and constitutional symptoms. Blocks purine synthesis and AICAR, thus increasing anti-inflammatory adenosine concentration at sites of inflammation. Ameliorates symptoms of inflammation.

* Dosing
* Interactions
* Contraindications
* Precautions

Adult

7.5-25 mg PO/IM qwk
Pediatric

Not established

* Dosing
* Interactions
* Contraindications
* Precautions

Oral aminoglycosides may decrease absorption and blood levels of concurrent oral methotrexate (MTX); charcoal lowers MTX levels; coadministration with etretinate may increase hepatotoxicity of MTX; folic acid or its derivatives contained in some vitamins may decrease response to MTX; coadministration with NSAIDs may (rarely) be fatal only in high-dose MTX; indomethacin and phenylbutazone can increase MTX plasma levels; may decrease phenytoin serum levels; probenecid, salicylates, procarbazine, and sulfonamides, including TMP-SMZ, may increase effects and toxicity of MTX; may increase plasma levels of thiopurines

* Dosing
* Interactions
* Contraindications
* Precautions

Documented hypersensitivity; alcoholism; hepatic insufficiency; documented immunodeficiency syndromes; preexisting blood dyscrasias (eg, bone marrow hypoplasia, leukopenia, thrombocytopenia, significant anemia); renal insufficiency

* Dosing
* Interactions
* Contraindications
* Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions

Monitor CBC counts monthly and liver and renal function q2mo during therapy (monitor monthly during initial 6 mo, with dose adjustments, or upon risk of elevated MTX levels); MTX has toxic effects on hematologic, renal, GI, pulmonary, and neurologic systems; discontinue if blood counts drop significantly; aspirin, NSAIDs, or low-dose steroids may be administered concomitantly with MTX (possibility of increased toxicity with NSAIDs, including salicylates, has not been noted at rheumatologic dosing levels)

Cyclophosphamide (Cytoxan)

Used for immunosuppression in cases of serious SLE organ involvement, especially severe CNS involvement, vasculitis, and lupus nephritis. Chemically related to nitrogen mustards. As an alkylating agent, the mechanism of action of the active metabolites may involve cross-linking of DNA, which may interfere with growth of normal and neoplastic cells.

* Dosing
* Interactions
* Contraindications
* Precautions

Adult

500-750 mg/m2 IV qmo
Pediatric

Administer as in adults

* Dosing
* Interactions
* Contraindications
* Precautions

Allopurinol may increase risk of bleeding or infection and enhance myelosuppressive effects; may potentiate doxorubicin-induced cardiotoxicity; may reduce digoxin serum levels and antimicrobial effects of quinolones; chloramphenicol may increase half-life while decreasing metabolite concentrations; may increase effect of anticoagulants; coadministration with high doses of phenobarbital may increase rate of metabolism and leukopenic activity; thiazide diuretics may prolong cyclophosphamide-induced leukopenia and neuromuscular blockade by inhibiting cholinesterase activity

* Dosing
* Interactions
* Contraindications
* Precautions

Documented hypersensitivity; severely depressed bone marrow function

* Dosing
* Interactions
* Contraindications
* Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions

Regularly examine hematologic profile (particularly neutrophils and platelets) to monitor for hematopoietic suppression; regularly examine urine for RBCs, which may precede hemorrhagic cystitis, monitoring should continue at least annually indefinitely after treatment; infertility is a common complication that should be disclosed (ovulatory suppression or egg/sperm harvest may be discussed prior to treatment)

Azathioprine (Imuran)

Immunosuppressant and less toxic alternative to cyclophosphamide and as steroid-sparing agent in nonrenal disease. Antagonizes purine metabolism and inhibits synthesis of DNA, RNA, and proteins. May decrease proliferation of immune cells, which results in lower autoimmune activity.

* Dosing
* Interactions
* Contraindications
* Precautions

Adult

1 mg/kg/d PO for 6-8 wk, increase by 0.5 mg/kg q4wk until response or until dose reaches 2.5 mg/kg/d
Pediatric

Not established

* Dosing
* Interactions
* Contraindications
* Precautions

Allopurinol inhibits xanthine oxidase and raises levels of azathioprine to potentiate toxicity; concurrent use with ACE inhibitors may induce severe leukopenia; may increase levels of methotrexate metabolites and decrease effects of anticoagulants, neuromuscular blockers, and cyclosporine

* Dosing
* Interactions
* Contraindications
* Precautions

Documented hypersensitivity; low levels of serum thiopurine methyl transferase (TPMT)

* Dosing
* Interactions
* Contraindications
* Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions

Increases risk of neoplasia; caution with liver disease and renal impairment; hematologic toxicities may occur; consider assessing TPMT level prior to therapy; monitor liver, renal, and hematologic function monthly; pancreatitis rarely associated

Immune globulin intravenous (Gamimune, Gammagard, Sandoglobulin)

Used for immunosuppression in serious SLE flares. Neutralizes circulating myelin antibodies through anti-idiotypic antibodies. Down-regulates proinflammatory cytokines, including INF-gamma. Blocks Fc receptors on macrophages, suppresses inducer T and B cells, and augments suppressor T cells. Blocks complement cascade, promotes remyelination, and may increase CSF IgG (10%).

* Dosing
* Interactions
* Contraindications
* Precautions

Adult

2 g/kg IV over 2-5 d
Pediatric

Not established

* Dosing
* Interactions
* Contraindications
* Precautions

Increases toxicity of live virus vaccine (MMR); do not administer within 3 mo of vaccine

* Dosing
* Interactions
* Contraindications
* Precautions

Documented hypersensitivity; IgA deficiency; anti-IgE/IgG antibodies

* Dosing
* Interactions
* Contraindications
* Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions

Check serum IgA before IVIG (use an IgA-depleted product, eg, Gammagard S/D); infusions may increase serum viscosity and thromboembolic events; infusions may increase risk of migraine attacks, aseptic meningitis (10%), urticaria, pruritus, or petechiae (2-30 d postinfusion); increases risk of renal tubular necrosis in elderly patients and in patients with diabetes, volume depletion, and preexisting kidney disease; laboratory result changes associated with infusions include elevated antiviral or antibacterial antibody titers for 1 mo, 6-fold increase in ESR for 2-3 wk, and apparent hyponatremia

Mycophenolate (CellCept)

Useful for maintenance in lupus nephritis and other serious lupus cases. Inhibits inosine monophosphate dehydrogenase (IMPDH) and suppresses de novo purine synthesis by lymphocytes, thereby inhibiting their proliferation. Inhibits antibody production.

* Dosing
* Interactions
* Contraindications
* Precautions

Adult

Titrate to 1 g PO bid
Pediatric

Not established; 15-23 mg/kg PO bid suggested

* Dosing
* Interactions
* Contraindications
* Precautions

In combination with either acyclovir or ganciclovir, may result in higher levels for both interacting drugs because of competition for renal tubular excretion; aluminum/magnesium in some antacids and cholestyramine-containing products may decrease absorption, reducing levels (do not administer together); probenecid may increase levels of mycophenolate; salicylates and azathioprine may increase toxicity; may decrease levonorgestrel AUC; may decrease live virus vaccine immune response; may increase free fraction levels of theophylline when administered with theophylline

* Dosing
* Interactions
* Contraindications
* Precautions

Documented hypersensitivity

* Dosing
* Interactions
* Contraindications
* Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions

Increases risk for infection (monitor blood count); severe renal impairment (CrCl <25 mL/min) may have increased adverse effects due to increase free MPA; caution in active peptic ulcer disease; incidence of malignancies and lymphoma consistent with that reported for other immunosuppressants (0.9%); commonly causes constipation, nausea, diarrhea, urinary tract infection, and nasopharyngitis; rare reports include interstitial lung disorders, colitis, pancreatitis, intestinal perforation, GI hemorrhage, gastric ulcers, duodenal ulcers, and ileus; do not chew, crush, or cut Myfortic tab
Corticosteroids

These agents are used predominately for anti-inflammatory activity and as immunosuppressants. Preparations include oral, intravenous, topical, and intraarticular injections.

Methylprednisolone (Adlone, Medrol, Solu-Medrol, Depopred)

Used for acute organ-threatening exacerbations. Decreases inflammation by suppressing migration of polymorphonuclear leukocytes and reversing increased capillary permeability.

* Dosing
* Interactions
* Contraindications
* Precautions

Adult

1 g/d IV for 3 d
Pediatric

Not established

* Dosing
* Interactions
* Contraindications
* Precautions

Coadministration with digoxin may increase digitalis toxicity secondary to hypokalemia; estrogens may increase levels of methylprednisolone; phenobarbital, phenytoin, and rifampin may decrease levels of methylprednisolone (adjust dose); monitor patients for hypokalemia when taking medication concurrently with diuretics

* Dosing
* Interactions
* Contraindications
* Precautions

Documented hypersensitivity; viral, fungal, or tubercular skin infections

* Dosing
* Interactions
* Contraindications
* Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions

Hyperglycemia, edema, osteonecrosis, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, growth suppression, myopathy, and infections are possible complications of glucocorticoid use

Prednisone (Deltasone, Orasone, Meticorten)

Immunosuppressant for treatment of autoimmune disorders. May decrease inflammation by reversing increased capillary permeability and suppressing PMN activity. Stabilizes lysosomal membranes and suppresses lymphocytes and antibody production. Low-dose oral prednisone can be used for milder SLE, but more severe involvement necessitates high doses of oral or intravenous therapy

* Dosing
* Interactions
* Contraindications
* Precautions

Adult

5-60 mg/d PO qd or divided bid/qid; taper over week(s) as symptoms resolve
Pediatric

4-5 mg/m2/d PO; alternatively, 0.05-2 mg/kg PO divided bid/qid; taper over 2 wk as symptoms resolveFollow-up
Further Inpatient Care

Fever in patients with systemic lupus erythematosus (SLE) is grounds for inpatient admission because of the difficulty of distinguishing a disease flare from infection in these immunocompromised hosts. Patients with SLE are often complement deficient and at particular risk for infections with encapsulated organisms. For example, meningococcemia in young females with lupus may be catastrophic. Additionally, stress-dose steroid protocols should be used in patients who are receiving maintenance corticosteroids when they are admitted with infectious or perioperative stress.
Further Outpatient Care

Periodic follow-up and laboratory testing, including CBC counts, creatinine, and urinalyses, are imperative for detecting signs and symptoms of new organ-system involvement and for monitoring response and adverse reactions to therapies. Periodic complement levels and dsDNA titers may be used as adjuncts to clinical evaluation for detecting lupus flares. The EULAR recently released key recommendations for the management of SLE.

Preventative care should include prophylactic immunization against encapsulated organisms: meningococcal vaccination, Pneumovax, and routine Haemophilus influenzae childhood vaccination. Annual influenza vaccine is also encouraged.
Transfer

CNS lupus with depressed consciousness may prompt ICU transfer and consideration of protective intubation. TTP and catastrophic antiphospholipid antibody syndrome should prompt transfer to a center capable of offering plasma exchange therapy.

Deterrence/Prevention

* Avoid ultraviolet light and sun exposure to minimize worsening symptoms due to photosensitivity.
* Estrogen therapies have typically been avoided to prevent disease flares; progesterone contraception has been encouraged. However, recent studies have suggested that oral contraceptives may not be associated with disease flares or thrombosis risk in patients with mild lupus without antiphospholipid antibodies.15,34
* High rates of sulfa allergy and anecdotal reports of disease flares have also led to avoidance of sulfa-based medications in patients with SLE.
* Aggressive blood pressure and lipid goals may help to prevent CAD or renal disease progression.28
* Antimalarial therapy (hydroxychloroquine) has been shown to prevent relapses and to improve mortality.31
* Angiotensin-converting enzyme (ACE) inhibitors and/or angiotensin receptor blockers may be useful in patients with renal disease.
* Calcium, vitamin D, and prophylactic bisphosphonates may reduce the risk of glucocorticoid-induced osteoporosis.

Complications

Opportunistic infections can develop, most often in patients receiving chronic immunosuppressive therapy. Another less-common complication is osteonecrosis, especially of the hips and knees after prolonged high-dose corticosteroid usage. More commonly, premature atherosclerotic disease and myocardial infarction are indolent complications of chronic inflammation.
Prognosis

SLE carries a highly variable prognosis, largely predicted by individual patient manifestations and disease course. Renal and CNS involvement tend to be associated with a worse prognosis.11
Patient Education

* Photosensitivity: Instruct patients with SLE to avoid exposure to sunlight and ultraviolet light.
* Medication toxicity: Monitor the use of NSAIDs and salicylates because of increased renal and hepatic toxicity. Additionally, monitoring should include surveillance for cytopenias or toxicities specific to individual immunosuppressive agents.
* Opportunistic infections: Instruct patients with SLE to seek medical care for evaluation of new symptoms, including fever.
* CAD: Educate patients with SLE regarding aggressive lipid and blood pressure goals to minimize the risk of CAD. In addition, teach patients to recognize the signs and symptoms of myocardial infarction.
* For excellent patient education resources, visit eMedicine's Blood and Lymphatic System Center, Arthritis Center, and Muscle Disorders Center. Also, see eMedicine's patient education articles Lupus (Systemic Lupus Erythematosus), Chronic Fatigue Syndrome, and Chronic Pain.

Miscellaneous
Medicolegal Pitfalls

* Failure to monitor for systemic lupus erythematosus (SLE) or failure to recognize progression or complications of disease: New organ-system involvement and infectious or thromboembolic complications, especially those that may lead to irreversible CNS disease, renal disease, or death, must be recognized.
* Failure to counsel patients on medication risks: Medication toxicity, risks of discontinuing therapy, and noncompliance should all be included in the discussion.
* Discussion of contraception and potential pregnancy planning: Disclosing potential teratogenicity and planning contraception, as well as carefully planning and monitoring pregnancy, may be key in female patients of reproductive age.

Special Concerns

* Pregnancy
o Fertility rates in women with SLE are similar to those in the general population. However, the incidences of spontaneous abortion, premature labor, and intrauterine death are somewhat higher in women with SLE, especially in those with SSA(Ro)/SSB(La) antibodies, antiphospholipid antibodies, or lupus nephritis.
o Ideally, SLE should be well controlled for at least 4 months prior to conception to minimize complications.
o SLE can also flare during or after pregnancy. Additionally, neonatal lupus can develop in the babies of mothers with antibodies to SSA/Ro, causing skin rashes and congenital heart block.
o Obstetricians who handle high-risk pregnancies should monitor all pregnancies in patients with SLE.
o Suggestions for treatment of SLE during pregnancy are also included in the recent EULAR recommendations.
o For additional information, see the article Systemic Lupus Erythematosus and Pregnancy in eMedicine's Rheumatology volume.