What antigen test is most relevant in Systemic Lupus Erythematosus (SLE)?

Antigen Testing in Systemic Lupus Erythematosus (SLE)

The most important antigen test in SLE is anti-double-stranded DNA (anti-dsDNA) antibodies, which should be performed using a dual-screening strategy: first with a solid-phase assay (SPA) such as ELISA or FEIA, followed by confirmation with Crithidia luciliae immunofluorescence test (CLIFT). 1

Primary Screening Tests

Anti-Nuclear Antibodies (ANA)

• ANA testing is the initial screening test and most sensitive test for SLE, making it the best assay for ruling out the disease 1, 2
• When ANA is positive during diagnostic work-up, proceed to specific antibody testing based on the clinical context 1
• ANA should NOT be used for monitoring disease activity after diagnosis—repeating ANA in follow-up is neither appropriate nor cost-effective 1

Anti-dsDNA Antibodies (The Gold Standard)

• Anti-dsDNA constitutes the most prominent immunological criterion in the EULAR/ACR 2019 classification criteria 1
• Anti-dsDNA testing is recommended in all ANA-positive cases with clinical suspicion of SLE 1
• When ANA is negative but clinical suspicion remains high, anti-dsDNA testing should still be performed 1, 3

Recommended Testing Algorithm for Anti-dsDNA

Dual-Screening Strategy

1. First-line: Solid-phase assay (SPA) such as FEIA, CLIA, ELISA, or multiplex assay—these offer higher sensitivity but lower specificity 1
2. Confirmation: CLIFT as the confirmatory test—considered pathognomonic with very high specificity (98%) but lower sensitivity (57%) 1, 4

Interpretation of Results

• SPA positive + CLIFT positive: SLE very likely 1
• SPA positive + CLIFT negative: Evaluate in context of clinical characteristics; neither confirms nor rules out SLE 1
• SPA negative + CLIFT negative: SLE diagnosis cannot be established at this time 1
• SPA negative + CLIFT positive: This inconsistency requires repeat testing in a new sample; if persistent, diagnosis depends on clinical characteristics 1

Additional Specific Antibody Tests

Anti-Extractable Nuclear Antigens (Anti-ENA)

When ANA is positive, confirmatory testing for anti-ENA is recommended 1. The most common targets in SLE include:

• Anti-Smith (Sm): Highly specific for SLE (99% specificity) and useful for diagnosis, especially in anti-dsDNA-negative patients 1, 5
• Anti-Ro/SSA: Associated with subacute cutaneous lupus, neonatal lupus, and congenital heart block 1
• Anti-La/SSB: Often found with anti-Ro antibodies 1
• Anti-ribosomal P: Specific for SLE, particularly associated with neuropsychiatric manifestations 1
• Anti-U1-RNP: Associated with mixed connective tissue disease overlap 1

Anti-Nucleosome Antibodies

• Show 83.33% sensitivity and 96.67% specificity for SLE 1
• May precede ANA in SLE pathogenesis 1
• Useful for monitoring disease activity in patients with lupus nephritis who remain anti-dsDNA negative 1

Antiphospholipid Antibodies

• Test for anticardiolipin, anti-β2GP1, and lupus anticoagulant 1
• Present in 30-40% of SLE patients and increase the likelihood of SLE diagnosis when clinical findings are consistent 1

Anti-C1q Antibodies

• Prevalence varies between 30-60% in SLE patients 1
• Found in almost 100% of patients with active lupus nephritis 1, 3
• Suggested as disease-activity biomarkers 1

Anti-Histone Antibodies

• More prevalent in patients with lupus nephritis than those without kidney disease 1, 6
• Can be used for monitoring disease activity in confirmed lupus nephritis when patients remain anti-dsDNA negative 1, 6
• Critical caveat: Anti-histone antibodies are more frequently found in drug-induced SLE, so they should only be used when lupus nephritis is confirmed to be not secondary to drug treatment 1, 6

Monitoring Disease Activity

Recommended Tests for Follow-Up

• Anti-dsDNA (quantitative): Use the same method and laboratory as diagnosis for consistency 1, 3
• Complement levels (C3, C4): Low levels associated with disease activity 1
• Anti-C1q antibodies: Particularly for lupus nephritis monitoring 1, 3
• Anti-nucleosome antibodies: For lupus nephritis patients who remain anti-dsDNA negative 1

Important Monitoring Caveats

• Some patients exhibit serologically active but clinically quiescent SLE—lack of correlation between serology and clinical status can persist long-term 1, 3
• Some patients with lupus nephritis (particularly membranous type) remain anti-dsDNA negative despite active disease 1

Special Clinical Scenarios

High Clinical Suspicion with Negative ANA

• Request specific antibody testing regardless of ANA result 1
• Anti-Jo-1, anti-ribosomal P, or anti-SS-A/Ro may be detected in ANA-negative patients 1
• Serology may change over time in individual patients 1

Negative ANA but Positive Anti-dsDNA

• Comprehensive evaluation for SLE is strongly recommended as this can represent true SLE 3
• Confirm anti-dsDNA result using a different method, particularly CLIFT 3
• Test for anti-nucleosome and antiphospholipid antibodies 3
• Patients require periodic clinical follow-up as anti-dsDNA may be detected before clear clinical signs develop 1, 3