What are the classification criteria and initial management for suspected adult‑onset Still’s disease or systemic juvenile idiopathic arthritis?

Treatment and Classification Criteria for Still's Disease

Classification Criteria

Use the Yamaguchi criteria to diagnose Still's disease—arthritis is NOT required, and waiting for arthritis to develop is a dangerous error that delays treatment. 1

Core Diagnostic Features (Yamaguchi Criteria)

The Yamaguchi criteria achieve 96.2% sensitivity and 92.1% specificity and are validated in both children and adults. 2 Apply these criteria only after systematically excluding infections, malignancies (especially lymphomas and leukemias), other rheumatic diseases, and monogenic autoinflammatory disorders. 2, 3

Major criteria (need ≥5 total with ≥2 major):

• Fever ≥39°C (102.2°F) for ≥7 days with characteristic spiking pattern (quotidian or double-quotidian) 1, 2
• Arthralgia lasting ≥2 weeks (NOT arthritis—this is critical because arthritis typically appears later with median delay of 1 month after disease onset) 1, 2
• Evanescent salmon-pink rash that is transient and often coincides with fever spikes 1, 2
• Leukocytosis ≥10,000/mm³ with ≥80% neutrophils 1

Minor criteria:

• Sore throat 1
• Lymphadenopathy and/or splenomegaly 1
• Liver dysfunction (elevated transaminases or LDH) 1
• Negative rheumatoid factor and ANA 1

Supportive Biomarkers (Measure When Available)

Marked elevation of IL-18 and/or S100 proteins (calprotectin) strongly supports the diagnosis and should be measured if available. 1, 3

• Serum ferritin: Markedly elevated (4,000–30,000 ng/mL or ≥5× upper normal limit) provides strong supportive evidence 1, 2
• IL-18: Levels ≥1,000 pg/mL help differentiate from other inflammatory conditions (sensitivity 70-95%, specificity 82-100% depending on cutoff) 1
• S100A8/A9 (calprotectin): Elevated levels (cutoffs 9,160-30,650 ng/mL) show 72-84% sensitivity and 80-90% specificity 1

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Initial Management Algorithm

Start IL-1 or IL-6 inhibitors as first-line therapy at disease onset or during flares—do not wait to see if the disease becomes chronic. 1

Step 1: Assess Disease Severity at Presentation

High disease activity includes: 1

• High spiking fever
• Widespread polyarthritis
• High pain levels (VAS >6-7/10)
• Pericarditis
• Impending macrophage activation syndrome (elevated LFT and/or very high ferritin)

Step 2: Initial Treatment Based on Severity

For HIGH disease activity: 1

• High-dose glucocorticoids: ≥1 mg/kg/day prednisone equivalent in adults or ≥2 mg/kg/day in children (IV initially, then oral) 1
• PLUS IL-1 or IL-6 inhibitor immediately 1
• Prefer anakinra (IL-1 blocker) if bacterial infection remains in differential diagnosis due to short half-life and reassuring safety profile 1
• Use high-dose anakinra (>4 mg/kg/day in children or 100 mg twice daily in adults) if impending MAS 1

For MILD-MODERATE disease activity: 1

• IL-1 or IL-6 inhibitor (first-line biologic therapy regardless of severity) 1
• Low or intermediate-dose glucocorticoids (≤0.1 mg/kg/day prednisone equivalent in adults or ≤0.2 mg/kg/day in children) are optional but not mandatory 1

Step 3: Treatment Targets and Timeline

Primary target: Clinically inactive disease (CID) defined as absence of Still's disease-related symptoms and normal ESR or CRP. 1, 2

Mandatory treatment milestones: 1

• At 3 months: Achieve CID on low-dose glucocorticoids
• At 6 months: Achieve CID off glucocorticoids
• Remission: Maintain CID off glucocorticoids for ≥6 months 1

Begin progressive glucocorticoid tapering as soon as first intermediate target is reached. 1

Step 4: Management of Treatment Failure

If CID on low-dose glucocorticoids NOT achieved at 3 months OR CID off glucocorticoids NOT achieved at 6 months: 1

• Rotate between IL-1 and IL-6 inhibitors (switch from one class to the other) 1
• Continue slow progressive glucocorticoid tapering during rotation 1

If CID off glucocorticoids NOT achieved after IL-1/IL-6 inhibitor rotation: 1

• Consider patient as difficult-to-treat (D2T) 1
• Discuss in multidisciplinary rounds with Still's disease expert (in Europe through ERN-RITA) 1
• Consider less-established options: JAK inhibitors, hematopoietic stem cell transplantation, or immunosuppressants 1

Step 5: Maintenance and Tapering After Remission

Once CID off glucocorticoids is achieved: 1

• Maintain IL-1 or IL-6 inhibitor for 3-6 months until remission (≥6 months CID off glucocorticoids) 1
• Maintain at least 6 months of CID off glucocorticoids before initiating biologic tapering 1

If major flare occurs while in CID off glucocorticoids: 1

• Re-induce with same algorithm as initial presentation 1

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Critical Complications Requiring Immediate Recognition

Macrophage Activation Syndrome (MAS)

MAS occurs in up to 23% of patients and represents the most severe, life-threatening complication with high mortality. 2, 3

MAS can occur: 2, 4

• At disease onset
• During treatment
• Even when disease is in remission, especially with concurrent infection

Clinical features of MAS: 1

• Persistent high fever (loss of quotidian pattern)
• Hepatosplenomegaly
• Cytopenias (especially thrombocytopenia, anemia)
• Elevated LFT
• Very high ferritin (often >10,000 ng/mL)
• Elevated triglycerides
• Low fibrinogen
• Hemophagocytosis on bone marrow (not always present early)

Candidate biomarkers for MAS (if available): 1

• CXCL-9
• IL-18
• Soluble IL-2 receptor
• Activated CD8 T cells

Treatment of MAS: 1

• High-dose anakinra (>4 mg/kg/day in children or 100 mg twice daily in adults) is preferred 1
• High-dose glucocorticoids 1
• Rule out concurrent infection 1

Other Severe Manifestations

Still's lung disease: Parenchymal lung involvement can occur and requires aggressive management 1, 5

Maintain high vigilance, monitor with adequate laboratory workups, and be prepared to rapidly adjust treatment at all times. 2

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Common Pitfalls to Avoid

1. Delaying diagnosis while waiting for arthritis to develop—arthralgia alone is sufficient and arthritis typically appears 1 month later 1, 4

2. Using NSAIDs or waiting to see disease course before starting biologics—IL-1/IL-6 inhibitors should be first-line regardless of severity 1

3. Failing to recognize impending or early MAS—maintain constant vigilance for fever pattern change, cytopenias, and rising ferritin 2, 4

4. Not tapering glucocorticoids aggressively enough—begin tapering as soon as intermediate targets are met to minimize toxicity 1

5. Inadequate exclusion of mimics—systematically rule out infections, malignancies, and other rheumatic diseases before confirming diagnosis 3