What is the diagnostic approach for adult-onset Still's disease?

Diagnosis of Adult-Onset Still's Disease

Adult-onset Still's disease should be diagnosed using operational clinical criteria combined with specific biomarkers when available, while systematically excluding alternative diagnoses—particularly infections, malignancies, and other immune-mediated diseases. 1

Core Diagnostic Criteria

The 2024 EULAR/PReS guidelines establish that Still's disease (encompassing both systemic juvenile idiopathic arthritis and adult-onset Still's disease) should be identified using four key operational definitions 1:

Essential Clinical Features

• Fever: Spiking pattern with temperature ≥39°C (102.2°F) for at least 7 days
• Rash: Transient, salmon-pink (erythematous), coinciding with fever spikes, predominantly on trunk (though urticarial variants are acceptable)
• Musculoskeletal involvement: Arthralgia or myalgia is sufficient; arthritis is NOT mandatory for diagnosis and often appears later (median 1 month delay)
• Inflammatory markers: Neutrophilic leukocytosis, elevated CRP, ESR, and ferritin

Critical caveat: The requirement for arthritis has been explicitly removed from diagnostic criteria because it causes unnecessary and potentially harmful diagnostic delays. Arthralgia alone is sufficient when other features are present. 1

Supportive Biomarkers

Marked elevation of serum IL-18 and/or S100 proteins (particularly calprotectin) strongly supports the diagnosis and should be measured if available. 1 These biomarkers demonstrate high sensitivity and specificity for Still's disease, though validated cut-off values are still being established. 1

Additional supportive laboratory findings include:

• Elevated platelet count
• Increased fibrinogen and D-dimers
• Hyperferritinemia (often extremely elevated)
• Glycosylated ferritin ≤20% (when available) 2

Algorithmic Diagnostic Approach

Step 1: Identify Suspected Cases

Look for patients presenting with:

• Fever of unknown origin with spiking pattern
• At least two major clinical features from the operational definitions above
• Marked systemic inflammation (neutrophilia, elevated CRP/ferritin)

Step 2: Measure Specific Biomarkers (if available)

• Serum IL-18 levels
• S100 proteins (calprotectin, S100A12)
• Glycosylated ferritin percentage

Step 3: Systematic Exclusion of Mimics

This is mandatory. Alternative diagnoses to carefully exclude include 1:

• Infections: Bacterial endocarditis, viral infections, tuberculosis
• Malignancies: Lymphomas, leukemias, solid tumors
• Other immune-mediated diseases: Systemic lupus erythematosus, vasculitis, other connective tissue diseases
• Monogenic autoinflammatory disorders: Familial Mediterranean fever, TRAPS, other periodic fever syndromes

Step 4: Apply Classification Criteria

While the Yamaguchi criteria remain the most validated (tested in both children and adults with high sensitivity) 1, newer scoring systems show promise. A 2023 points-based algorithm demonstrated superior accuracy (92.8% vs 78.8% for Yamaguchi) using: typical rash (3 points), fever ≥39°C (3 points), pharyngitis (2 points), arthritis (2 points), neutrophil-to-lymphocyte ratio ≥4 (2 points), and glycosylated ferritin ≤20% (1 point), with diagnosis at ≥7 points. 2

Common Diagnostic Pitfalls

1. Waiting for arthritis to develop: This delays diagnosis unnecessarily; arthralgia is sufficient 1
2. Dismissing atypical rash patterns: While salmon-pink is classic, urticarial rashes can occur 1
3. Inadequate exclusion of mimics: Still's disease remains a diagnosis of exclusion; infections and malignancies must be systematically ruled out 1
4. Missing early macrophage activation syndrome (MAS): Monitor for persistent fever, splenomegaly, rising ferritin, cytopenias, abnormal liver function, and elevated triglycerides—MAS can present at disease onset 1

Practical Diagnostic Workflow

When you suspect Still's disease based on fever pattern and rash:

• Obtain complete blood count with differential (looking for neutrophilia)
• Measure CRP, ESR, ferritin (and glycosylated ferritin if available)
• Order IL-18 and S100 proteins if accessible
• Perform comprehensive infectious workup (blood cultures, viral serologies, tuberculosis screening)
• Screen for malignancy (age-appropriate cancer screening, consider bone marrow if cytopenias present)
• Check autoimmune serologies (ANA, RF, ANCA) to exclude other rheumatologic conditions
• Assess for monogenic disorders if family history or atypical features present

The diagnosis can be established when operational criteria are met, supportive biomarkers are elevated, and alternative diagnoses have been systematically excluded. Early diagnosis is critical because prompt initiation of IL-1 or IL-6 inhibitors significantly improves outcomes and reduces glucocorticoid exposure. 1