Adult-Onset Still's Disease (AOSD)
Diagnosis
Adult-Onset Still's Disease should be diagnosed based on the clinical triad of high spiking fevers (≥39°C), evanescent salmon-pink rash, and arthritis/arthralgia, combined with markedly elevated ferritin (typically >1000 ng/mL, often >10,000 ng/mL) and exclusion of mimicking conditions. 1, 2
Cardinal Clinical Features
- Daily high spiking fevers ≥39°C (102.2°F) with a characteristic quotidian pattern (fever spikes once or twice daily, returning to baseline between episodes) 1, 2
- Evanescent salmon-pink maculopapular rash predominantly on trunk and proximal limbs, typically appearing with fever spikes and often mildly pruritic; may demonstrate Koebner phenomenon 1, 3
- Arthritis or arthralgia affecting knees, wrists, and ankles most commonly; symmetric polyarthritis pattern typical, though arthritis may appear later in disease course 1, 3
- Sore throat reported in 35-92% of cases, though this is a symptom difficult for children to report and may represent reporting bias 1
Essential Laboratory Work-Up
Obtain the following tests immediately when AOSD is suspected:
Serum ferritin with glycosylated ferritin fraction (if available): Extremely elevated ferritin >1000 ng/mL (often >10,000 ng/mL) with glycosylated fraction <20% strongly supports diagnosis 1, 2, 4
- Ferritin cut-offs for diagnosis: 273-2500 ng/mL depending on control population, with higher cut-offs (≥5000 ng/mL) providing 92% specificity 1
IL-18 and/or S100 proteins (calprotectin): Marked elevation strongly supports diagnosis 1, 2, 4
Complete blood count with differential: Neutrophilic leukocytosis (>10,000-15,000/mm³) present in 52-79% of cases; thrombocytosis common 1, 2, 4
Inflammatory markers: ESR and CRP markedly elevated in 95-98% of cases 1, 3
Liver function tests: Elevated transaminases in 31-56% of cases 1, 2, 4
Rheumatoid factor and ANA: Typically negative (positive in only 4-9% of cases) 1
Critical Differential Diagnoses to Exclude
The following must be systematically ruled out before confirming AOSD diagnosis:
Infections: Sepsis, endocarditis, viral hepatitis, tuberculosis, EBV 1, 2
- Ferritin levels can distinguish AOSD from sepsis with 74-97% sensitivity and 50-94% specificity using cut-offs of 1086-1120 ng/mL 1
Malignancies: Lymphoma, leukemia, solid tumors 1, 2
- IL-18 >40,600 ng/mL distinguishes AOSD from acute lymphoblastic leukemia with 95% sensitivity and 100% specificity 1
Other autoimmune diseases: Systemic lupus erythematosus, rheumatoid arthritis, vasculitis 1, 2
Monogenic autoinflammatory disorders: TRAPS, CAPS, FMF 1
Life-Threatening Complications Requiring Immediate Recognition
Macrophage Activation Syndrome (MAS)
MAS occurs in 11.9-36% of AOSD patients and is the leading cause of mortality—screen actively at presentation and throughout disease course. 3, 2, 4
Suspect MAS when the following features develop:
- Persistent fever despite treatment 1
- Splenomegaly 1
- Elevated or rising serum ferritin (often >10,000 ng/mL) 1
- Inappropriately low cell counts (cytopenias including anemia, thrombocytopenia, leukopenia) 1, 3
- Abnormal liver function tests 1
- Intravascular coagulation activation (elevated D-dimer, prolonged PT/PTT) 1
- Elevated or rising serum triglycerides 1, 4
MAS treatment must include high-dose glucocorticoids plus anakinra, ciclosporin, and/or IFNγ inhibitors as part of initial therapy. 1
Other Severe Complications
- Fulminant hepatitis with potential for liver failure 3
- Myocarditis with risk of heart failure 3
- Lung disease: Screen with pulse oximetry, DLCO measurement, and high-resolution CT scan if clinical symptoms present (clubbing, persistent cough, shortness of breath) 1
Recommended Treatment
Initiate an IL-1 inhibitor (anakinra) or IL-6 inhibitor (tocilizumab) as early as possible when diagnosis is established to avoid prolonged systemic glucocorticoid use. 1, 2
Treatment Algorithm
Initial therapy (Day 0):
- Start IL-1 inhibitor (anakinra preferred) or IL-6 inhibitor (tocilizumab) 1, 2, 5
- Glucocorticoids may be added initially but should not be used as monotherapy for prolonged periods 1, 2
Treatment targets with specific timelines:
- Day 7: Resolution of fever and reduction of CRP by >50% 1, 2
- Week 4: No fever, reduction of active joint count by >50%, normal CRP, and physician/patient global assessment <20 on 0-100 VAS 1
- Month 3: Clinically inactive disease (CID) with glucocorticoids <0.1-0.2 mg/kg/day 1
- Month 6: CID without glucocorticoids 1
Ultimate goal: Drug-free remission (defined as ≥6 months with CID) 1
Biologic DMARD Tapering
- Maintain CID for 3-6 months without glucocorticoids before initiating biologic DMARD tapering 1
Evidence Supporting Early Biologic Use
The 2023 EULAR/PReS guidelines prioritize IL-1 and IL-6 inhibitors due to high evidence of efficacy, with earlier initiation associated with faster achievement of clinical inactivity 1, 5. This represents a paradigm shift from historical reliance on glucocorticoids and conventional synthetic DMARDs 5, 6.
Management of Difficult Cases
Patients with severe MAS, lung disease, or refractory disease should be managed in collaboration with Still's disease expert centers. 1
Important caveat: The presence of risk factors for Still's lung disease or development of lung disease should NOT be considered a contraindication to IL-1 or IL-6 inhibitors 1
Disease Recognition: AOSD and sJIA Are the Same Entity
EULAR and PReS now recognize systemic juvenile idiopathic arthritis (sJIA) and adult-onset Still's disease as the same disease continuum, termed "Still's disease." 1, 3 This is supported by overlapping clinical manifestations, identical cytokine profiles, and similar treatment responses across age groups 1, 7.