Systemic Lupus Erythematosus - SLE

  • Diagnosis
  • Algorithms
  • Monitoring
  • Background
  • Lab Tests
  • References
  • Related Topics

Indications for Testing

  • Multisystem disease presentation

Criteria for Diagnosis

Laboratory Testing

  • Nonspecific testing – may be helpful in determining organ involvement
    • CBC – anemia, thrombocytopenia, leukopenia
    • Urinalysis – hematuria, proteinuria forecasts are indicative of renal involvement
    • Liver transaminases – may be elevated
    • Blood urea nitrogen (BUN)/creatinine – may be elevated; indicates renal involvement
    • Anti-neutrophil cytoplasmic antibody (ANCA) – rule out vasculitis
    • Complement 3 and 4 (C3, C4) – elevated levels may be predictive for glomerulonephritis in systemic lupus erythematosus (SLE)
    • C-reactive protein (CRP)
  • Anti-nuclear antibodies (ANA) – useful as initial screen (not disease-specific); positive specimens should be further tested to identify antibodies specific for SLE
    • Double-stranded DNA (dsDNA) >1:10 detected by immunofluorescence assay (IFA) – 50-60% of patients with SLE
      • Presence of high antibody titers to native dsDNA is specific and diagnostic for SLE
    • Extractable nuclear antigens
      • Smith (Sm) antibodies – highly specific for SLE but occur in only 30-35% of cases
      • Ribonucleic protein (RNP) antibodies – not specific for SLE
      • Anti-Sjögren’s syndrome antigen A (SSA, or Ro) and anti-Sjögren syndrome antigen B (SSB, or La) antibodies – not specific for SLE
    • Histone and single-stranded DNA (ssDNA) antibodies – not specific for SLE
    • Anti-ribosomal P (anti-P) – associated with neurolupus but not particularly useful in management or diagnosis of neuropsychiatric lupus
    • Chromatin antibodies
      • Primary use – diagnose drug-induced lupus
      • 50-90% of SLE patients have these antibodies
      • Associated with proteinuria, glomerulonephritis, and disease activity
      • Not specific for SLE
  • Biomarkers of lupus nephritis/disease severity
    • Anti-C1q antibodies – assess risk for SLE global activity and lupus nephritis
      • SLE
        • Presence of antibodies – predicts higher risk for developing severe manifestations of disease
      • Renal disease
        • Presence of antibodies - correlates with renal activity and flares
        • Absence of antibodies - high negative predictive value
  • Consider the following testing to rule out other diseases
  • Neurolupus
    • CSF for cell count, glucose, oligoclonal bands, culture
      • Cell count – mild elevations with mononuclear cells
      • Glucose – usually normal, but may be decreased in myelopathy
      • Oligoclonal bands
      • Interleukin 6, 8, 10 (if available) – very high; decreased with remission
  • Other testing
    • EEG – frequently abnormal
    • Collagen type VII antibody IgG by ELISA – may be positive in bullous lupus erythematosus

Imaging Studies

  • Most commonly used in suspected neuropsychiatric lupus
    • MRI/CT of brain and/or spine
    • Magnetic resonance angiography – if vascular involvement is suspected

Differential Diagnosis

  • European League Against Rheumatism (EULAR, 2010) recommendations
    • Re-evaluation of previously negative antiphospholipid antibodies prior to pregnancy, surgery, transplant, or use of estrogen-replacement therapy in the presence of new neurologic event
      • Anti-Ro and anti-La antibodies prior to pregnancy
      • Anti-dsDNA, C3, C4 to support remission
    • Other nonspecific testing every 6-12 months
      • CBC, C-reactive protein (CRP), albumin, creatinine or estimated glomerular filtration rate (EGFR), urinalysis (UA), and urine protein level
    • Other monitoring based on toxicities of prescribed therapies
    • Evaluation of cardiac risk factors
    • Osteoporosis evaluation
    • Cancer screening – follow society-specific recommendations for screening and surveillance

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the presence of several autoantibodies, formation of immune complexes, and inflammation in different organs.

Epidemiology

  • Incidence – ~1/2,000 in the U.S. (Pasoto, 2014)
  • Age – peak onset is 15-40 years
  • Sex – M<F 1:12 (ages 15-45); 1:2 other age groups
  • Ethnicity – greater incidence in African Americans, Asian Americans, and Hispanics than in Caucasians (3:1)

Risk Factors

  • Genetics – possible association with deletion of long arm of chromosome 1
  • Sun exposure
  • Drugs – hydralazine, procainamide, quinidine, penicillamine, acebutolol, and methyldopa
  • Epstein-Barr virus infection
  • Occupational exposure
    • Crystalline silica
    • Pesticides
    • Mercury

Pathophysiology

  • Pathophysiology of SLE is not completely understood; however, the following have been implicated
    • Apoptosis (programmed cell death) leading to loss of immune tolerance
    • Interferon-alpha (IFN-α) and plasmacytoid dendritic cells (PDCs)
    • Toll-like receptors through the induction of IFN-α by PDCs
  • Hallmark of disease is polyclonal B-cell activation with production of multiple pathogenic antibodies
    • Double-stranded DNA (dsDNA)
    • Smith (Sm)
    • Anti-Sjögren syndrome antigen A (SSA, or Ro) (anti-SSA)
    • Antiphospholipid antibodies (anticardiolipin and beta-2 glycoprotein 1)
    • Lupus anticoagulant
    • C1q
    • Nucleosome
    • Anti-Sjögren syndrome antigen B (SSB, or La) (anti-SSB)
    • Ribosomal P protein

Clinical Presentation

  • Dermatologic – malar discoid rash, photosensitivity, skin eruptions, alopecia
  • Musculoskeletal – arthritis, arthralgia, myalgia
  • Serositis – pleuritis, pericarditis
  • Renal – nephritis
  • Neurologic
    • Central nervous system – meningitis, demyelinating disease, seizures, psychosis, mood disorder, stroke, chorea, myelopathy, headache, transient ischemic attack
    • Peripheral nervous system – autonomic disorder, mononeuropathy, myasthenia gravis, cranial neuropathy, plexopathy, polyneuropathy
  • Hematologic – hemolytic anemia, leukopenia, thrombocytopenia, antiphospholipid syndrome symptoms
  • Cardiovascular – vasculitis, Libman-Sachs endocarditis
  • Ocular – sicca syndrome
  • Complications

Tests generally appear in the order most useful for common clinical situations. Click on number for test-specific information in the ARUP Laboratory Test Directory.

Anti-Nuclear Antibodies (ANA), IgG by ELISA with Reflex to ANA, IgG by IFA 0050080
Method: Qualitative Enzyme-Linked Immunosorbent Assay/Semi-Quantitative Indirect Fluorescent Antibody

Limitations

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

ANA ELISA assays have lower sensitivities for antibodies associated with nucleolar and specked ANA-IFA patterns

Follow Up

Recommend cutaneous direct immunofluorescence testing of active edge of new lesion (lesional biopsy) if dermatologic manifestations are present

Connective Tissue Diseases Profile 0051668
Method: Semi-Quantitative Multiplex Bead Assay

Double-Stranded DNA (dsDNA) Antibody, IgG by ELISA with Reflex to dsDNA Antibody, IgG by IFA 0050215
Method: Qualitative Enzyme-Linked Immunosorbent Assay/Semi-Quantitative Indirect Fluorescent Antibody

Limitations

Some patients with early or inactive SLE may be positive for anti-dsDNA IgG by ELISA but negative by CLIFT

Follow Up

If the patient is negative by CLIFT but positive by ELISA and clinical suspicion remains, consider antinuclear antibody (ANA) testing by IFA

Chromatin Antibody, IgG 2005287
Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay

Anti-C1q Antibody, IgG 2007601
Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay

Limitations

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

C1q antibodies are not specific for lupus

Complement Components 3 and 4 0050149
Method: Quantitative Immunoturbidimetry

Complement Component 4 0050155
Method: Quantitative Immunoturbidimetry

C-Reactive Protein 0050180
Method: Quantitative Immunoturbidimetry

Related Tests

Guidelines

Agmon-Levin N, Damoiseaux J, Kallenberg C, Sack U, Witte T, Herold M, Bossuyt X, Musset L, Cervera R, Plaza-Lopez A, Dias C, Sousa MJosé, Radice A, Eriksson C, Hultgren O, Viander M, Khamashta M, Regenass S, Andrade LEduardo Co, Wiik A, Tincani A, Rönnelid J, Bloch DB, Fritzler MJ, Chan EK L, De La Torre G, Konstantinov KN, Lahita R, Wilson M, Vainio O, Fabien N, Sinico RAlberto, Meroni P, Shoenfeld Y. International recommendations for the assessment of autoantibodies to cellular antigens referred to as anti-nuclear antibodies. Ann Rheum Dis. 2014; 73(1): 17-23. PubMed

Albrecht J, Berlin JA, Braverman IM, Callen JP, Connolly MK, Costner MI, Dutz J, Fivenson D, Franks AG, Jorizzo JL, Lee LA, McCauliffe DP, Sontheimer RD, Werth VP. Dermatology position paper on the revision of the 1982 ACR criteria for systemic lupus erythematosus. Lupus. 2004; 13(11): 839-49. PubMed

Aletaha D, Neogi T, Silman AJ, Funovits J, Felson DT, Bingham CO, Birnbaum NS, Burmester GR, Bykerk VP, Cohen MD, Combe B, Costenbader KH, Dougados M, Emery P, Ferraccioli G, Hazes JM W, Hobbs K, Huizinga TW J, Kavanaugh A, Kay J, Kvien TK, Laing T, Mease P, Ménard HA, Moreland LW, Naden RL, Pincus T, Smolen JS, Stanislawska-Biernat E, Symmons D, Tak PP, Upchurch KS, Vencovský J, Wolfe F, Hawker G. 2010 Rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheum. 2010; 62(9): 2569-81. PubMed

American Society for Clinical Pathology. Choosing Wisely - Five Things Physicians and Patients Should Question. An initiative of the ABIM Foundation. [Last revision Feb 2015; Accessed: Jan 2016]

Pasoto SGofinet, Viana VSantos Tri, Bonfa E. The clinical utility of anti-ribosomal P autoantibodies in systemic lupus erythematosus. Expert Rev Clin Immunol. 2014; 10(11): 1493-503. PubMed

Petri M, Orbai A, Alarcón GS, Gordon C, Merrill JT, Fortin PR, Bruce IN, Isenberg D, Wallace DJ, Nived O, Sturfelt G, Ramsey-Goldman R, Bae S, Hanly JG, Sánchez-Guerrero J, Clarke A, Aranow C, Manzi S, Urowitz M, Gladman D, Kalunian K, Costner M, Werth VP, Zoma A, Bernatsky S, Ruiz-Irastorza G, Khamashta MA, Jacobsen S, Buyon JP, Maddison P, Dooley MAnne, van Vollenhoven RF, Ginzler E, Stoll T, Peschken C, Jorizzo JL, Callen JP, Lim S, Fessler BJ, Inanc M, Kamen DL, Rahman A, Steinsson K, Franks AG, Sigler L, Hameed S, Fang H, Pham N, Brey R, Weisman MH, McGwin G, Magder LS. Derivation and validation of the Systemic Lupus International Collaborating Clinics classification criteria for systemic lupus erythematosus. Arthritis Rheum. 2012; 64(8): 2677-86. PubMed

Saag KG., Teng GGee, Patkar NM., Anuntiyo J, Finney C, Curtis JR., Paulus HE., Mudano A, Pisu M, Elkins-Melton M, Outman R, Allison JJ., Almazor MSuarez, Bridges L, Cha W. American College of Rheumatology 2008 Recommendations for the Use of nonbiologic and biologic Therapies in Rheumatoid Arthritis. In Arthritis Care & Research, American College of Rheu: 2008.

General References

D'Cruz DP, Khamashta MA, Hughes GR V. Systemic lupus erythematosus. Lancet. 2007; 369(9561): 587-96. PubMed

Joseph FG, Scolding NJ. Neurolupus. Pract Neurol. 2010; 10(1): 4-15. PubMed

Levy DM, Kamphuis S. Systemic lupus erythematosus in children and adolescents. Pediatr Clin North Am. 2012; 59(2): 345-64. PubMed

Lisnevskaia L, Murphy G, Isenberg D. Systemic lupus erythematosus. Lancet. 2014; 384(9957): 1878-88. PubMed

Mackillop LH, Germain SJ, Nelson-Piercy C. Systemic lupus erythematosus. BMJ. 2007; 335(7626): 933-6. PubMed

Madhok R, Wu O. Systemic lupus erythematosus. Am Fam Physician. 2007; 76(9): 1351-3. PubMed

Mok CChiu. Biomarkers for lupus nephritis: a critical appraisal. J Biomed Biotechnol. 2010; 2010: 638413. PubMed

Rahman A, Isenberg DA. Systemic lupus erythematosus. N Engl J Med. 2008; 358(9): 929-39. PubMed

Rekvig OPetter, van der Vlag J, Seredkina N. Review: antinucleosome antibodies: a critical reflection on their specificities and diagnostic impact. Arthritis Rheumatol. 2014; 66(5): 1061-9. PubMed

Self SE. Autoantibody testing for autoimmune disease. Clin Chest Med. 2010; 31(3): 415-22. PubMed

Smith PP, Gordon C. Systemic lupus erythematosus: clinical presentations. Autoimmun Rev. 2010; 10(1): 43-5. PubMed

Tucker LB. Making the diagnosis of systemic lupus erythematosus in children and adolescents. Lupus. 2007; 16(8): 546-9. PubMed

References from the ARUP Institute for Clinical and Experimental Pathology®

Copple SS, Giles R, Jaskowski TD, Gardiner AE, Wilson AM, Hill HR. Screening for IgG antinuclear autoantibodies by HEp-2 indirect fluorescent antibody assays and the need for standardization. Am J Clin Pathol. 2012; 137(5): 825-30. PubMed

Copple SS, Martins TB, Masterson C, Joly E, Hill HR. Comparison of three multiplex immunoassays for detection of antibodies to extractable nuclear antibodies using clinically defined sera. Ann N Y Acad Sci. 2007; 1109: 464-72. PubMed

Martins TB, Burlingame R, von Mühlen CA, Jaskowski TD, Litwin CM, Hill HR. Evaluation of multiplexed fluorescent microsphere immunoassay for detection of autoantibodies to nuclear antigens. Clin Diagn Lab Immunol. 2004; 11(6): 1054-9. PubMed

Medical Reviewers

Last Update: July 2016