What is Adult-Onset Still's Disease (AOSD)?

What is Adult-Onset Still's Disease (AOSD)?

Adult-Onset Still's Disease (AOSD) is a rare systemic inflammatory disorder of unknown cause, characterized by the classic triad of high spiking fevers (quotidian or double-quotidian pattern), evanescent salmon-colored rash, and arthritis with potential multiorgan involvement. 1

Disease Definition and Historical Context

• AOSD is named after George Still, who described the pediatric form in 1897, though Eric Bywaters first established it as a distinct adult disease entity in 1971. 1
• The disease represents a continuum with systemic juvenile idiopathic arthritis (sJIA), sharing overlapping clinical and biological features across age groups. 2, 3
• AOSD sits at the crossroad between auto-inflammatory syndromes and autoimmune diseases, driven primarily by macrophage activation and pro-inflammatory cytokines (IL-1, IL-6, IL-18). 4, 5

Epidemiology

• AOSD is rare with an estimated incidence of 0.16 per 100,000 inhabitants. 1
• The disease affects women slightly more often than men (approximately 60% female). 1
• Three-quarters of patients develop disease onset between ages 16-35 years, though it can occur at any age including after 60. 1
• A bimodal age distribution exists with peaks at 15-25 years and 36-46 years. 1

Clinical Manifestations

Classic Triad Features:

• High spiking fevers: Quotidian (once daily) or double-quotidian (twice daily) pattern with temperatures typically exceeding 39°C (102°F), often occurring in late afternoon or evening. 1, 2
• Evanescent rash: Salmon-pink colored, maculopapular, non-pruritic rash that appears with fever spikes and disappears within hours. 1, 4
• Arthritis/Arthralgia: Joint involvement ranging from arthralgias to frank arthritis, potentially leading to severe joint destruction in chronic cases. 1, 2

Additional Manifestations:

• Multiorgan involvement can include hepatosplenomegaly, lymphadenopathy, serositis (pleuritis, pericarditis), and pharyngitis. 1, 4
• Liver function test abnormalities are common. 4

Disease Patterns and Prognosis

AOSD follows three distinct clinical patterns, each affecting approximately one-third of patients: 6

1. Self-limited/monocyclic pattern: Systemic symptoms with remission within 1 year (median 9 months). 6
2. Intermittent/polycyclic pattern: Recurrent flares with complete remission between episodes. 6
3. Chronic articular pattern: Dominated by persistent joint manifestations that can lead to severe joint destruction and generally carries worse prognosis. 6

Diagnostic Approach

• AOSD is a diagnosis of exclusion requiring elimination of infectious, neoplastic, and other autoimmune diseases. 1
• No single diagnostic test exists; diagnosis relies on clinical criteria, most commonly the Yamaguchi and Fautrel criteria. 2
• Laboratory findings are nonspecific but include leukocytosis, markedly elevated acute phase reactants (ESR, CRP), and characteristically extremely elevated serum ferritin levels (usually >1000 μg/L). 4, 5
• Rheumatoid factor and antinuclear antibodies are typically absent, though positive ANA can occur and adds diagnostic complexity. 4, 7
• AOSD is responsible for a significant proportion of fever of unknown origin cases. 1, 8

Life-Threatening Complications

• Macrophage activation syndrome (MAS) is the most severe complication, reported in up to 23% of AOSD patients with high mortality rates. 2
• MAS requires urgent treatment with high-dose glucocorticoids and high-dose anakinra (>100 mg twice daily in adults). 6
• Lung disease can develop and requires screening with pulmonary function tests and high-resolution CT when indicated. 6

Treatment Overview

The American College of Rheumatology recommends IL-1 inhibitors (anakinra) or IL-6 receptor inhibitors (tocilizumab) as first-line treatment for AOSD, as these biologics demonstrate the highest level of evidence for efficacy and safety. 6

Treatment Hierarchy:

• NSAIDs are effective as monotherapy in only 7-15% of patients. 6
• Glucocorticoids achieve 76-95% response rates but most patients require long-term maintenance with significant side effects. 6
• Conventional DMARDs (particularly methotrexate) serve as steroid-sparing agents with modest efficacy (~40% response). 6
• Canakinumab is the only FDA-approved biologic specifically for AOSD treatment. 2

Treatment Targets:

• The primary goal is achieving clinically inactive disease (CID) off glucocorticoids. 6
• Early initiation of biologic therapy improves outcomes through a "window of opportunity" effect. 6, 3
• A treat-to-target approach with regular disease activity assessment is recommended. 6

Critical Clinical Pitfalls

• Do not rely solely on NSAIDs or glucocorticoids for long-term management, as most patients require more advanced treatment. 6
• Always screen for and promptly treat MAS, which represents the most life-threatening complication. 6
• Avoid empiric steroids in undiagnosed fever cases, as they mask inflammatory findings on subsequent imaging and can be harmful if malignancy or certain infections are present. 8, 9
• Consider AOSD in the differential diagnosis of fever of unknown origin, particularly when accompanied by the classic triad and markedly elevated ferritin. 8, 2