What is the recommended workup for a suspected case of adult-onset Still's disease (AOSD)?

Workup for Adult-Onset Still's Disease

The workup for suspected AOSD requires documenting the four cardinal features—spiking fever ≥39°C for ≥7 days, transient salmon-pink rash, musculoskeletal involvement (arthralgia/myalgia), and markedly elevated inflammatory markers—followed by systematic exclusion of infections, malignancies, and other rheumatic diseases, with measurement of serum ferritin (particularly glycosylated fraction) and IL-18 if available to support the diagnosis. 1

Clinical Assessment

Cardinal Features to Document

• Fever pattern: Document temperature spikes ≥39°C (102.2°F) lasting at least 7 days, typically following a quotidian or double-quotidian pattern with peaks in late afternoon or early evening 1, 2

• Characteristic rash: Look for transient, evanescent, salmon-pink maculopapular eruption that preferentially involves the trunk and proximal limbs, often coinciding with fever spikes 1, 2

  • The rash may be mildly pruritic and can be urticarial in some cases 1
  • Critical pitfall: Do not dismiss this as a drug allergy—it is pathognomonic for AOSD 2

• Musculoskeletal involvement: Document arthralgia or frank arthritis, most commonly affecting knees (69-82%), wrists (67-73%), and ankles (38-55%) 2, 3

  • Important: Arthritis is NOT mandatory for diagnosis and may appear later (median delay of 1 month after disease onset) 1
  • Specifically examine wrists for carpal and pericapitate abnormalities that distinguish AOSD from rheumatoid arthritis 2

• Additional systemic features: Document sore throat (35-92%), lymphadenopathy (32-74%), splenomegaly (14-65%), hepatomegaly (50-75%), pleuritis (12-53%), and pericarditis (10-37%) 2, 3

Laboratory Workup

Essential Inflammatory Markers

• Complete blood count: Look for leukocytosis with striking neutrophilia (>80% PMN), with 50% of patients having WBC >15×10⁹/L and 37% having WBC >20×10⁹/L 1, 2, 3

  • Anemia of chronic disease is common and normalizes with remission 2, 3
  • Reactive thrombocytosis is frequently present 3

• Acute phase reactants: ESR is elevated in virtually all patients, and CRP is typically markedly raised 1, 2, 3

• Serum ferritin: Measure total ferritin levels, which are characteristically very high (4,000-30,000 ng/mL, with extreme levels up to 250,000 ng/mL reported) and correlate with disease activity 2, 3, 4

  • Measure glycosylated ferritin fraction: Values <20% strongly support AOSD diagnosis and are included in the Fautrel criteria 1, 4

Novel Biomarkers (If Available)

• Serum IL-18: Marked elevation strongly supports the diagnosis (diagnostic accuracy 97.67% when combined with ferritin) 1, 3, 5

  • IL-18 levels are significantly higher in AOSD than in bacterial infections and correlate positively with ferritin 3

• S100 proteins: S100A8/A9 (calprotectin) and S100A12 show diagnostic value in AOSD 1, 3

Liver Function Tests

• Measure AST, ALT, alkaline phosphatase, and bilirubin, as hepatomegaly and abnormal liver biochemistry occur in 50-75% of patients 2, 3
  • Critical pitfall: Do not attribute liver dysfunction solely to NSAIDs—it is an intrinsic disease feature 2

Autoantibody Testing

• Rheumatoid factor (RF): Should be negative 1
• Antinuclear antibodies (ANA): Should be negative 1
  • These are required as exclusion criteria in the Yamaguchi classification criteria 1

Exclusion of Differential Diagnoses

Mandatory Exclusions

AOSD is a diagnosis of exclusion requiring systematic elimination of three categories 1:

1. Infectious diseases: Blood cultures (multiple sets), viral serologies (EBV, CMV, parvovirus B19, HIV), tuberculosis testing (PPD or IGRA, chest imaging), and other infections based on clinical suspicion 1, 6

2. Malignancies: Age-appropriate cancer screening, with particular attention to lymphoproliferative disorders given the lymphadenopathy and systemic symptoms 1

3. Other rheumatic diseases: Testing for systemic lupus erythematosus, rheumatoid arthritis, vasculitis, and other connective tissue diseases 1

Application of Diagnostic Criteria

Yamaguchi Criteria (Most Widely Used)

Requires 5 criteria with at least 2 major 1:

Major criteria:

• Fever ≥39°C, intermittent, >1 week
• Arthralgia ≥2 weeks
• Typical rash
• WBC ≥10,000 (≥80% granulocytes)

Minor criteria:

• Sore throat
• Lymphadenopathy and/or splenomegaly
• Liver function test abnormalities
• Negative ANA and RF

Fautrel Criteria (Includes Ferritin)

Offers the advantage of incorporating ferritin and glycosylated ferritin values 1, 4, 7:

Major criteria (2 points each):

• Spiking fever >39°C
• Arthralgia
• Transient erythema
• Pharyngitis
• PMN >80%
• Glycosylated ferritin <20%

Minor criteria (1 point each):

• Maculopapular rash
• Leukocytes >10×10⁹/L

Requires specific point combinations for diagnosis 1

Screening for Life-Threatening Complications

Macrophage Activation Syndrome (MAS)

• Monitor for pancytopenia, as this signals potentially fatal MAS requiring urgent intervention 2, 8
• Measure fibrinogen, D-dimers, triglycerides, and ferritin (paradoxically may decrease in MAS) 1
• Consider measuring CXCL-9, soluble IL-2 receptor, and activated CD8 T cells if available 1
• Critical pitfall: Do not miss pancytopenia—it requires immediate high-dose glucocorticoids and anakinra 2, 8

Cardiopulmonary Complications

• Echocardiogram to assess for pericarditis and pericardial effusion (10-37% of patients) 3
• Chest imaging and pulmonary function tests to screen for lung disease 8

Algorithmic Approach to Workup

1. Document cardinal features: Fever pattern, rash characteristics, joint involvement, systemic symptoms
2. Obtain inflammatory markers: CBC with differential, ESR, CRP, ferritin (total and glycosylated fraction)
3. Check autoantibodies: RF and ANA (should be negative)
4. Measure liver function tests: AST, ALT, alkaline phosphatase
5. Obtain IL-18 and S100 proteins if available to strongly support diagnosis 1
6. Systematically exclude infections: Blood cultures, viral serologies, tuberculosis testing
7. Exclude malignancies: Age-appropriate screening, imaging as indicated
8. Exclude other rheumatic diseases: Additional autoantibody testing as clinically indicated
9. Apply Yamaguchi or Fautrel criteria once exclusions are complete 1
10. Screen for MAS: Monitor for pancytopenia, hypofibrinogenemia, hypertriglyceridemia 1, 8