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

What is Adult-Onset Still's Disease?

Adult-Onset Still's Disease (AOSD) is a rare systemic autoinflammatory disorder characterized by the classic triad of high-spiking fevers (>39°C), evanescent salmon-pink rash, and arthritis/arthralgia, though arthritis is NOT required for diagnosis. 1, 2

Disease Definition and Classification

AOSD represents the adult manifestation of a disease continuum that includes systemic juvenile idiopathic arthritis (sJIA) in children—they are now considered the same disease entity affecting different age groups. 2, 3 The disease was first convincingly described by Eric Bywaters in 1971 when he identified adults presenting similarly to pediatric Still's disease. 4

Epidemiology

• Incidence: Approximately 0.16 per 100,000 inhabitants, making this a rare condition. 5, 2
• Age distribution: Bimodal peaks at 15-25 years and 36-46 years, with three-quarters of patients developing disease between ages 16-35. 5, 2
• Sex distribution: Women are affected slightly more often than men (approximately 60% female). 5, 2
• Clinical significance: AOSD accounts for a significant proportion of fever of unknown origin (FUO) cases. 1, 5

Cardinal Clinical Features

The Classic Triad (Critical for Recognition)

High-spiking fevers:

• Temperature ≥39°C (102.2°F) occurring in over 95% of patients. 1
• Characteristic quotidian or double-quotidian pattern with peaks in late afternoon or early evening. 1, 2
• Fever episodes are transient, typically lasting under 4 hours. 1
• Fever heralds the onset of other manifestations including serositis, sore throat, myalgias, and arthralgias. 1

Evanescent salmon-pink rash:

• Occurs in 64-100% of patients. 1
• Maculopapular eruption predominantly affecting proximal limbs and trunk, with rare involvement of face and distal extremities. 1
• Rash is transient and often coincides with fever spikes. 2

Arthralgia/Arthritis:

• Present in 64-100% of patients, but arthritis is NOT mandatory for diagnosis—arthralgia or myalgia alone is sufficient. 1, 2
• Most frequently affected joints: knees (69-82%), wrists (67-73%), and ankles (38-55%). 1
• Overt arthritis typically appears later (median delay of 1 month after disease onset, range 0 to several months). 2

Additional Systemic Manifestations

Common features:

• Sore throat: 35-92% of patients. 1
• Myalgia: 56-84%, generalized and appearing with fever exacerbations. 1
• Lymphadenopathy: 32-74% of patients. 1
• Splenomegaly: 14-65% of patients. 1
• Hepatomegaly and liver biochemistry abnormalities: 50-75% of patients. 1

Serositis:

• Pleuritis: 12-53% of patients. 1
• Pericarditis: 10-37% of patients. 1

Laboratory Abnormalities (Highly Characteristic)

Inflammatory markers:

• ESR elevated in virtually all patients. 1
• CRP typically raised. 1

Hematologic findings:

• Leukocytosis with striking neutrophilia in 50% of patients (counts >15×10⁹ cells/L), with 37% having WBC >20×10⁹. 1
• Anemia of chronic disease during active disease, often normalizing with remission. 1
• Reactive thrombocytosis is common. 1

Ferritin (Highly Suggestive):

• Very high ferritin levels ranging from 4,000-30,000 ng/mL are common, with extreme levels up to 250,000 ng/mL reported. 1
• Serum ferritin correlates with disease activity. 1

Autoantibodies:

• Rheumatoid factor and antinuclear antibodies are usually absent. 6

Diagnostic Approach

AOSD is a diagnosis of exclusion requiring elimination of infectious, neoplastic, and other autoimmune diseases. 1, 5 The Yamaguchi criteria are the most widely used and validated diagnostic tools in both children and adults with high sensitivity. 2, 7

Key diagnostic considerations:

• No single diagnostic test exists for AOSD. 6
• Marked elevation of serum IL-18 and/or S100 proteins (calprotectin) strongly supports diagnosis and should be measured if available. 2
• Clinical diagnosis is generally reached by exclusion while investigating a patient with FUO. 3

Disease Patterns and Prognosis

AOSD follows three distinct clinical patterns, each affecting approximately one-third of patients: 1

1. Self-limited/monocyclic pattern
2. Intermittent/polycyclic pattern
3. Chronic articular pattern

Recent evidence suggests classification into two distinct categories: "systemic" and "articular" phenotypes. 3

Life-Threatening Complications

Macrophage Activation Syndrome (MAS):

• The most severe and life-threatening complication, occurring in up to 23% of AOSD patients. 2, 3
• Characterized by high mortality rate. 3
• Can occur at disease onset, during treatment, or even when disease is in remission, especially in the context of infection. 2
• Physicians managing AOSD must always maintain high vigilance for MAS, monitor with adequate laboratory workups, and be prepared to rapidly adjust treatment. 2

Pathogenesis

The etiology remains unknown, but immune dysregulation plays a central role. 8 Key pathogenic features include:

• Central role of macrophage activation resulting in T helper 1 (Th1) cell cytokine activation. 9
• Pro-inflammatory cytokines IL-1, IL-6, and IL-18 play fundamental roles in disease onset and progression. 9, 6
• Genetic component suggested with associations to various HLA antigens (HLA-B17, B18, B35, DR2), though findings are inconsistent across studies. 4
• Hypothesis that various infectious agents may act as disease triggers in genetically predisposed hosts, similar to reactive arthritis. 4