What are the diagnosis method and criteria for Systemic Lupus Erythematosus (SLE)?

Diagnosis Method and Criteria for Systemic Lupus Erythematosus (SLE)

The diagnosis of SLE relies primarily on the 2019 EULAR/ACR classification criteria, which require positive ANA testing as entry criterion, followed by a weighted scoring system of clinical and immunological manifestations, with a score ≥10 points confirming the diagnosis. 1

Diagnostic Approach

Step 1: Initial Screening

• Antinuclear antibody (ANA) testing:
  • Serves as the primary screening test with high sensitivity
  • Positive ANA at titer ≥1:160 is required as an entry criterion 2
  • Should be performed by immunofluorescence (IFI) on HEp-2 cells
  • A negative ANA test makes SLE diagnosis highly unlikely 3

Step 2: Confirmatory Testing

When ANA is positive, proceed with:

• Anti-double-stranded DNA (anti-dsDNA) antibodies:

  • Highly specific for SLE
  • Associated with renal involvement
  • Recommended testing strategy: use a sensitive screening assay first, followed by Crithidia Luciliae immunofluorescence test (CLIFT) as confirmation 2

• Anti-Smith (anti-Sm) antibodies:

  • Highly specific for SLE
  • Strong confirmatory value even in patients with low pre-test probability 4

• Complement levels (C3, C4, CH50):

  • Low levels suggest active disease
  • Useful for both diagnosis and monitoring 1

EULAR/ACR 2019 Classification Criteria

The criteria use a weighted scoring system:

Clinical Domains:

1. Constitutional: Fever (2 points)
2. Hematologic:
   • Leukopenia (3 points)
   • Thrombocytopenia (4 points)
   • Autoimmune hemolysis (4 points)
3. Neuropsychiatric: Delirium (2 points), Seizure (5 points)
4. Mucocutaneous:
   • Non-scarring alopecia (2 points)
   • Oral ulcers (2 points)
   • Subacute cutaneous OR discoid lupus (4 points each)
   • Acute cutaneous lupus (6 points)
5. Serosal:
   • Pleural or pericardial effusion (5 points)
   • Acute pericarditis (6 points)
6. Musculoskeletal: Joint involvement (6 points)
7. Renal:
   • Proteinuria >0.5g/24h (4 points)
   • Lupus nephritis class II or V (8 points)
   • Lupus nephritis class III or IV (10 points)

Immunological Domains:

1. Anti-phospholipid antibodies (2 points)
2. Complement proteins: Low C3 OR low C4 (3 points), Low C3 AND low C4 (4 points)
3. SLE-specific antibodies:
   • Anti-dsDNA (6 points)
   • Anti-Sm (6 points)

A score of ≥10 points confirms the classification of SLE 1, 5

Laboratory Testing Protocol

1. First-line tests:

   • ANA by immunofluorescence (titer ≥1:160 as cutoff in unselected populations) 2
   • Complete blood count (to detect cytopenias)
   • Urinalysis (to screen for renal involvement)
   • Serum creatinine and urine protein/creatinine ratio

2. Second-line tests (when ANA is positive):

   • Anti-dsDNA (preferably using a double-screening strategy)
   • Anti-Sm antibodies
   • Complement levels (C3, C4)
   • Anti-extractable nuclear antigens (anti-ENA)
   • Anti-phospholipid antibodies

3. Organ-specific assessment (based on clinical manifestations):

   • Skin: Biopsy with immunofluorescence for cutaneous lupus
   • Kidney: Biopsy for persistent proteinuria, active sediment, or unexplained renal dysfunction
   • Neuropsychiatric: CSF analysis, brain MRI, EEG, neuropsychological testing
   • Cardiovascular: Echocardiogram, ECG 1

Disease Activity and Damage Assessment

• Disease activity indices:

  • SLEDAI (SLE Disease Activity Index)
  • BILAG (British Isles Lupus Assessment Group)
  • SLAM (Systemic Lupus Activity Measure)

• Damage assessment:

  • SLICC/ACR Damage Index for annual evaluation 1

Common Pitfalls and Caveats

1. False-positive ANA:

   • ANA can be positive in other autoimmune diseases, infections, malignancies, and even healthy individuals
   • Always interpret in clinical context

2. Negative anti-dsDNA:

   • Up to 40% of SLE patients may have negative anti-dsDNA
   • Absence doesn't exclude diagnosis when clinical features are suggestive

3. Laboratory method variability:

   • Different testing methods yield different results
   • Laboratory reports should specify the method used 2

4. Distinguishing flare from infection:

   • Both can present with fever and organ dysfunction
   • CRP is typically elevated in infection but may be normal in SLE flares 6

5. Delayed diagnosis:

   • Often significant delay between symptom onset and diagnosis
   • Consider SLE in patients with multisystem involvement, especially young women 6

By following this systematic approach to diagnosis, clinicians can accurately identify SLE patients, assess disease activity, and monitor organ involvement, which directly impacts morbidity, mortality, and quality of life.