Systemic Lupus Erythematosus - SLE

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the presence of multiple autoantibodies, inflammatory processes, and organ system involvement.   SLE can be fatal, and early disease recognition, treatment, and monitoring can help to prevent complications.  However, diagnosis is complicated by the fact that many symptoms of SLE are nonspecific.  In addition, SLE and antiphospholipid syndrome (APS) can present similarly and the two diseases can also overlap. Antinuclear antibody (ANA) testing is useful as an initial screening approach, but is not disease specific.  In patients with positive ANA test results, additional serologic testing is generally needed to confirm a diagnosis of SLE.  Other laboratory tests are recommended at initial evaluation to help to identify organ involvement.  See Laboratory Testing below.

Quick Answers for Clinicians

When should systemic lupus erythematosus be suspected?

Presenting symptoms of systemic lupus erythematosus (SLE) are often nonspecific. In  addition to arthralgia, myalgia, fatigue, weight loss, and fever, patients may present with malar rash, photosensitivity, pleuritic chest pain, Raynaud phenomenon (new onset), and mouth sores.  SLE should be suspected in patients who demonstrate symptoms in two or more of these organ systems: cardiac, constitutional, dermal, gastrointestinal, hematologic, musculoskeletal, neuropsychiatric, pulmonary, renal, or reticuloendothelial. 

In patients with negative antinuclear antibody test results, should additional serologic testing be performed?

The American College of Rheumatology (ACR) recommends against performing “subserology” tests, or subsequent testing for autoantibodies such as anti-double-stranded DNA (dsDNA) and anti-Smith, in patients who are negative for antinuclear antibodies (ANAs) and who do not have clinical indications of autoimmune disease. 

What is neuropsychiatric systemic lupus erythematosus, and how does testing for it differ?

Neuropsychiatric systemic lupus erythematosus (NPSLE), also called neurolupus, refers to systemic lupus erythematosus (SLE) with peripheral or central nervous system (CNS) involvement and cognitive and/or psychiatric effects.  The incidence of NPSLE is not established, but some experts suggest that approximately 50% of patients with SLE develop psychiatric or neurologic symptoms at some point.  NPSLE can manifest in a variety of ways, depending on whether the CNS or peripheral nervous system is affected. Some CNS-related manifestations include aseptic meningitis, cerebrovascular disease, demyelinating syndrome, or a movement, mood, or seizure disorder, among other presentations.  Peripheral nervous system involvement can manifest with acute inflammatory demyelinating polyradiculopathy (Guillain-Barré syndrome), an autonomic disorder, myasthenia gravis, or cranial neuropathy, among other presentations.  A workup for neuropsychiatric SLE involves cerebrospinal fluid investigations and imaging studies, in addition to the serologic and nonspecific laboratory tests used in all cases of suspected SLE. 

Which testing algorithms are related to this topic?

Indications for Testing

Testing for SLE is appropriate in patients with disease manifestations in two or more organ systems (see Quick Answers above and Classification Criteria below).

Classification Criteria

The American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR) released updated, joint classification criteria for SLE in 2019 to replace the 1997 ACR criteria for SLE.  The updated criteria are intended to reflect the increased understanding of SLE as a disease and improve on the sensitivity and specificity of the previous criteria.  The Systemic Lupus International Collaborating Clinics (SLICC) has also developed widely used classification criteria.   Both the ACR-EULAR and the SLICC criteria include a combination of laboratory and clinical findings.

The criteria listed in the table below are considered applicable to SLE only when the clinical findings are not better explained by another condition. 

2019 ACR/EULAR Classification Criteria
(Overall Score of ≥10 and 1 Clinical Criterion Required)
Initial Criterion

ANAa

ANA titer of ≥1:80 on HEp-2 cells or an equivalent positive ANA test (ever)

Additional Immunologic Criteriab

 

Clinical Finding (Score)
(Only highest score in each domainc is counted)

SLE-specific antibodies

Anti-dsDNA antibodies OR

Anti-Smith antibodies (6)

Complement proteins

Decreased C3 OR decreased C4 (3)

Decreased C3 AND decreased C4 (4)

Antiphospholipid antibodies

Anticardiolipin antibodies OR

Anti-β2GP1 antibodies OR

Lupus anticoagulant (2)

Additional Clinical Criteriab Clinical Finding (Score)
(Only highest score in each domainc is counted)

Constitutional

Fever (2)

Hematologic

Leukopenia (3)

Thrombocytopenia (4)

Autoimmune hemolysis (4)

Neuropsychiatric

Delirium (2)

Psychosis (3)

Seizure (5)

Mucocutaneous

Nonscarring alopecia (2)

Oral ulcers (2)

Subacute cutaneous OR discoid lupus (4)

Acute cutaneous lupus (6)

Serosal

Pleural or pericardial effusion (5)

Acute pericarditis (6)

Musculoskeletal

Joint involvement (6)

Renal

Proteinuria >0.5 g/24 hrs (4)

Renal biopsy class II or V lupus nephritis (8)

Renal biopsy class III or IV lupus nephritis (10)

aPatients must have a positive ANA result (at any point in time) to be classified as having SLE, according to the 2019 ACR/EULAR criteria.

bA single occurrence of a listed condition is adequate to meet criteria; conditions do not need to occur simultaneously.

cThe term “domains” refers to the various categories, such as complement proteins, or constitutional, hematologic, or neuropsychiatric findings, etc.

Anti-β2GP1, anti-beta-2 glycoprotein 1; anti-dsDNA, anti-double-stranded DNA; C3, complement 3; C4, complement 4

Source: Aringer, 2019 

Laboratory Testing

Diagnosis

An initial evaluation for SLE involves both nonspecific and serologic testing.

Nonspecific Testing

Nonspecific laboratory tests can be helpful to identify organ involvement and assess inflammation in patients with suspected SLE. Such tests include CBC, urinalysis, a comprehensive metabolic panel, and a direct Coombs test.  Erythrocyte sedimentation rate (ESR) and/or C-reactive protein (CRP) tests are also useful: ESR levels correlate with disease activity, whereas CRP levels will often be low or normal unless infection is present. 

Serologic Testing

Serologic testing is a critical component of the assessment for SLE. A diagnosis of SLE should not be made unless at least one autoantibody or complement deficiency is determined to be present. 

Antinuclear Antibodies

ANA testing is a recommended initial screening test for SLE. However, ANAs are not specific for SLE and are seen in a variety of other connective tissue diseases, some infections, and malignancies, and are detected in elderly patients and even in some healthy individuals.  In patients with positive ANA results, SLE is unlikely unless there are accompanying features that suggest an autoimmune rheumatic disease.    Further serologic testing is indicated if titers are 1:40 or higher.  The 2019 ACR/EULAR updated classification criteria requires a positive ANA result at least once, although a small number of patients with SLE are ANA negative. 

ANA results are reported with endpoint titers and patterns. For comprehensive information on patterns and their clinical associations, refer to the International Consensus on ANA Patterns  website.

Visit the ARUP Consult Connective Tissue Disease topic for additional information about ANA testing, including a comparison of ANA testing methods, in systemic autoimmune rheumatic diseases.

Other Autoantibodies

Following a positive ANA test in patients with suspected SLE, additional serologic testing is recommended and may include tests for the autoantibodies listed below. Tests for combinations of autoantibodies are also available in panels (see ARUP Lab Tests).

Autoantibodies Comments

Anti-dsDNA and anti-Smith antibodies

In patients with clinical findings consistent with SLE, positivity is highly predictive of SLE diagnosis

Antiphospholipid antibodies:
Anticardiolipin antibodies, anti-β2GP1 antibodies, lupus anticoagulant

OR

Antibodies directed against a mixture of phosphatidylserine, phosphatidic acid, and β2GP1 antigens

Elevated levels of any of these markers increase likelihood of SLE

Presence is associated with a greater risk of arterial/venous thrombotic events and pregnancy complications in SLE

Diagnosis of APS should trigger evaluation for SLE because APS can overlap with or evolve into SLE

Anti-SSA-52, SSA-60 (Ro), anti-SSB (La)

More likely to be found in Sjögren syndrome but also associated with SLE with photosensitivity and with subacute cutaneous SLE

Anti-RNP antibodies

Presence may indicate an overlap condition like MCTD

C1q antibodies

Associated with renal involvement in SLE; helps to identify patients with increased risk for renal impairment and can be useful to guide monitoring in these patients

Antihistone antibodies

Reportedly detected in all cases of drug-induced SLE

Also associated with a small percentage of rheumatoid arthritis, primary biliary cholangitis, and systemic sclerosis cases

Anti-P antibodies

Once considered useful to assess patients with possible neuropsychiatric SLE; now believed to have limited diagnostic value

anti-P, antiribosomal P; anti-RNP, antiribonucleic protein; MCTD, mixed connective tissue disease

Sources: Gordon, 2017 ; Lam, 2016 ; Joseph, 2010 ; Karimifar, 2013 

Complement Components

Increased complement consumption is typical in active SLE, and complement testing is routinely performed as part of the serologic workup.  Tests for total complement as well as C3 and C4 are useful to support an SLE diagnosis and for disease monitoring (see Monitoring).  Because C3 and C4 levels correlate with disease activity, results can help to rule out active disease, particularly renal disease.  Decreased C3 and C4 levels may be associated with glomerulonephritis in SLE.

Circulating Immune Complexes

Immune complexes (antigen-antibody complexes) that form in tissue or circulate in the bloodstream are involved in SLE pathogenesis.  Circulating immune complexes can deposit in tissues and induce inflammatory processes, and those that bind to C1q have known associations with SLE, particularly SLE with lupus nephritis.  Tests to detect these immune complexes are considered useful to assess disease activity in patients with SLE. 

Cerebrospinal Fluid Analysis

Cerebrospinal fluid (CSF) investigations are indicated to assess patients for suspected neuropsychiatric systemic lupus erythematosus (NPSLE), also called neurolupus.  Recommended CSF analysis includes cell count, glucose, protein, culture, and oligoclonal band assessment. 

Other Testing

Imaging studies are useful in patients with suspected NPSLE,  and may include magnetic resonance imaging (MRI) or computed tomography (CT) scanning of the brain and/or spine, as well as magnetic resonance angiography if vascular involvement is suspected. Other testing is indicated for patients with manifestations of specific organ involvement; eg, patients with suspected renal involvement may need assessment with renal biopsy. 

Monitoring

The American Academy of Family Physicians (AAFP) recommends that patients with SLE be monitored with the following tests every 3-6 months: C3 and C4, serum creatinine, anti-dsDNA antibody, CBC, and urinalysis.  Other tests that may be useful include a CRP or ESR test; antiphospholipid, anti-SSA (Ro), anti-SSB (La), and anti-RNP antibody, immunoglobulin, and direct Coombs tests; renal, liver, and thyroid function tests; and other tests as clinically indicated.  Tests to detect circulating immune complexes (C1q binding and anti-C1q IgG antibody assays) are also considered helpful in monitoring patients with SLE.  Additional or more frequent testing is indicated in patients receiving specific treatments and in those who develop particular complications of SLE, such as hemolytic anemia or lupus nephritis. 

The British Society of Rheumatology (BSR) recommends monitoring as often as every 1-3 months for active disease and after a disease flare, and monitoring every 6-12 months in patients with low or no disease activity, or stable disease after treatment.  In addition, because antiphospholipid antibodies are linked to pregnancy complications and thrombotic events, the BSR recommends that patients with SLE who previously tested negative for antiphospholipid antibodies be retested before pregnancy or surgery or if a vascular event has occurred.  The BSR also recommends testing for anti-SSA (Ro) and anti-SSB (La) antibodies before pregnancy because of the association between these antibodies and neonatal lupus. 

SLE is linked to an increased risk for cardiovascular disease, including myocardial infarction and rapidly progressive atherosclerosis. Patients with an established diagnosis of SLE should be periodically assessed for cardiovascular disease, hypertension, dyslipidemia, and diabetes mellitus.  Other complications of SLE include circulatory disease, infections, renal disease, non-Hodgkin lymphoma, lung cancer, and osteoporosis, and monitoring for these conditions is recommended.  Yearly evaluation for organ damage is also recommended. 

ARUP Lab Tests

Antinuclear Antibodies

Preferred ANA screening test for connective tissue diseases

Patterns reported include homogeneous, speckled, centromere, nucleolar, nuclear dots, or cytoplasmic; all positive results are reported with endpoint titers

Aid in initial diagnosis of connective tissue disease

Low-titer ANAs common with advancing age; certain drugs may also cause low-titer ANAs

ANA ELISA assays have been reported to have lower sensitivities than ANA IFA for systemic autoimmune rheumatic diseases

Detects antibodies against double-stranded DNA (dsDNA), histones, SS-A (Ro), SS-B (La), Smith, Smith/RNP, Scl-70, Jo-1, centromere proteins, and other antigens extracted from the HEp-2 cell nucleus

Aid in initial diagnosis of connective tissue disease

Recommend if high suspicion for SLE or Sjögren syndrome

Other Autoantibodies

Recommended for the evaluation of SLE

Initial testing includes rheumatoid factor (RF), C3, C4, and ANAs; specimens are screened for ANAs using enzyme-linked immunosorbent assay (ELISA)

Method

Quantitative Immunoturbidimetry/Semi-Quantitative Enzyme-Linked Immunosorbent Assay/Semi-Quantitative Indirect Fluorescent Antibody/Quantitative Chemiluminescent Immunoassay/Semi-Quantitative Multiplex Bead Assay

Secondary screening for SLE based on ANA results

Confirmatory test for SLE based on ANA results

Confirmatory test for a diagnosis of SLE or MCTD following a positive ANA result

Useful in the differential diagnosis of connective tissue disease with or without myopathy

Primarily associated with a diagnosis of MCTD but may be seen with patients with SLE, SSc, and inflammatory myopathies

Recommended for the differential diagnosis of SLE and Sjögren syndrome

Preferred initial panel when APS is strongly suspected

Panel includes anti-β2GP1 IgG and IgM antibodies and cardiolipin IgG and IgM antibodies (see Lab Test Directory for full components list)

Acceptable initial test when APS is strongly suspected

More specific than cardiolipin IgG and IgM antibodies in the diagnosis of APS

Acceptable initial test when APS is strongly suspected

Order with Lupus Anticoagulant Reflexive Panel  and Cardiolipin Antibodies, IgG and IgM

May also be useful in estimating risk of thrombosis and/or pregnancy-related morbidity in patients with SLE

Use for patients with a significant probability of having APS

Order with Cardiolipin Antibodies, IgG and IgM, and Beta-2 Glycoprotein 1 Antibodies, IgG and IgM

Acceptable initial test when APS is strongly suspected

Order with Lupus Anticoagulant Reflexive Panel and Beta-2 Glycoprotein 1 Antibodies, IgG and IgM

Order as secondary screen based on results of ANA test or if ANA IFA is negative and Sjögren syndrome, SLE, systemic sclerosis, or myositis is strongly suspected

Recommended for the differential diagnosis of SLE and Sjögren syndrome

Preferred panel contains SSA 52, SSA 60, and SSB; refer to Extractable Nuclear Antigen Antibodies (SSA 52, SSA 60, and SSB) test

Use for differential evaluation of patients with SLE, Sjögren syndrome, polymyositis/ dermatomyositis, and/or other tissue diseases or overlapping syndromes

First-line testing for connective tissue disease

Panel includes dsDNA, IgG; Smith/RNP, IgG; Smith (ENA), IgG; SSA 52 and 60, IgG; SSB, IgG; Jo-1, IgG; Scl-70, IgG

Confirmatory test for specific connective tissue disease

Panel includes Smith (ENA), Smith/RNP, SSA, SSB, Jo-1, RPP, centromere and Scl-70 antibodies

Assess risk for lupus nephritis and global SLE disease activity
 

Not all patients with lupus nephritis will be positive for C1q antibodies
 

C1q antibodies are not specific for SLE

Evaluate suspected drug-induced lupus

Negative results do not rule out drug-induced lupus

May be useful to detect central nervous system SLE (somewhat rare) or renal involvement in SLE

Complements

Initial screening for suspected deficiency in the classical complement pathway

Monitor rheumatologic disease

Circulating Immune Complexes

Detect circulating immune complexes

Cerebrospinal Fluid Analysis

Medical Experts

Contributor

References

  1. Nuclear Patterns ICAP

    International Consensus on Antinuclear Antibody Patterns. Nuclear patterns. International Consensus on ANA Patterns. Gainesville, FL. [Updated: 2019; Accessed: Jun 2020]

    Online
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