What is Adult-Onset Still's Disease (AOSD) and how is it assessed in adults between 20 and 40 years of age presenting with recurrent episodes of high fevers, joint pain, and rash?

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

Adult-Onset Still's Disease is a rare systemic inflammatory disorder characterized by the classic triad of high-spiking fevers exceeding 39°C, an evanescent salmon-pink rash, and arthritis/arthralgia, affecting primarily adults between 16-35 years of age. 1, 2

Core Disease Definition

AOSD is a diagnosis of exclusion requiring elimination of infectious, neoplastic, and other autoimmune diseases, and accounts for a significant proportion of fever of unknown origin cases. 2, 3 The disease has an estimated incidence of 0.16 per 100,000 inhabitants, with approximately 60% female predominance and a bimodal age distribution with peaks at 15-25 years and 36-46 years. 3

The pathogenesis involves immune dysregulation with central macrophage activation resulting in T helper 1 (Th1) cell cytokine activation, particularly IL-1, IL-6, and IL-18. 4, 5 AOSD and systemic juvenile idiopathic arthritis (sJIA) are now considered part of the same disease continuum rather than separate entities. 4, 6

Clinical Assessment: The Classic Triad

Fever Pattern

• High-spiking fevers exceeding 39°C occur in 95.7% of patients 1
• Fevers are transient, lasting typically under 4 hours 1, 2
• Follow a quotidian or double quotidian pattern with highest temperatures in late afternoon or early evening 1, 2
• Fever heralds onset of other manifestations including serositis, sore throat, myalgias, and arthralgias 1, 2

Rash Characteristics

• Evanescent, salmon-pink, maculopapular eruption occurs in 51-87% of patients (average 72.7%) 1
• Predominantly affects proximal limbs and trunk, with rare involvement of face and distal limbs 1, 2
• Often accompanied by fever and can be mildly pruritic, potentially confused with drug allergy 1
• Koebner phenomenon has been described 1
• Histology shows perivascular inflammation of superficial dermis with lymphocyte and histiocyte invasion 1

Joint Involvement

• Arthralgia and arthritis occur in 64-100% of patients 1, 2
• Most frequently affected joints: knees (69-82%), wrists (67-73%), and ankles (38-55%) 1, 2
• Pattern is typically symmetric polyarthritis with joint pain associated with fever spikes 1
• Critical distinguishing feature: carpal and pericapitate abnormalities are typically higher than in rheumatoid arthritis 1
• Wrist changes typically present 6 months after disease onset, with progressive joint space narrowing in pericapitate or carpometacarpal distribution, and ankylosis developing after 1.5-3 years 1

Additional Systemic Manifestations to Assess

Common Features

• Sore throat: 35-92% of patients 1, 2
• Myalgia: 56-84%, generalized and appearing with fever exacerbations 1, 2
• Lymphadenopathy: 32-74% 1, 2
• Splenomegaly: 14-65% 1, 2
• Hepatomegaly and liver biochemistry abnormalities: 50-75% 1, 2

Serositis

• Pleuritis: 12-53% 1, 2
• Pericarditis: 10-37% 1, 2

Laboratory Assessment Algorithm

Essential Initial Laboratory Tests

Step 1: Inflammatory Markers

• ESR: elevated in virtually all patients 1, 2
• CRP: typically raised 1, 2

Step 2: Complete Blood Count

• Leucocytosis with striking neutrophilia: 50% have counts >15×10⁹ cells/L, 37% have WBC >20×10⁹ 1, 2
• Anaemia of chronic disease: seen with active disease, normalizes with remission 1, 2
• Reactive thrombocytosis: common 1, 2
• Critical warning: Pancytopenia alerts to haemophagocytic syndrome/macrophage activation syndrome, requiring prompt immunosuppressive treatment 1

Step 3: Ferritin and Glycosylated Fraction

• Very high ferritin levels: 4,000-30,000 ng/mL common, with extreme levels up to 250,000 ng/mL reported 1, 2
• Ferritin correlates with disease activity and normalizes with remission 1, 2
• Fivefold increase in serum ferritin has 80% sensitivity and 41% specificity 1
• Glycosylated ferritin <20% is highly specific: when combined with fivefold serum ferritin rise, sensitivity is 43% but specificity rises to 93% 1

Step 4: Autoantibodies (Typically Negative)

• Rheumatoid factor: usually absent 1
• Antinuclear antibodies: usually absent 1

Step 5: Liver Function Tests

• Abnormal in approximately 50-75% of patients 1, 2

Emerging Biomarkers

• IL-18 levels are significantly higher in AOSD than bacterial infections, with diagnostic accuracy of 97.67% when combined with ferritin 2
• S100 proteins (S100A8/A9 and A12) show diagnostic value 2

Diagnostic Criteria Application

Yamaguchi Criteria (Most Sensitive at 93.5%) 1

Requires 5 criteria with at least 2 major:

Major Criteria:

• Fever >39°C, intermittent, >1 week
• Arthralgia >2 weeks
• Typical rash
• WBC >10,000 (>80% granulocytes)

Minor Criteria:

• Sore throat
• Lymphadenopathy and/or splenomegaly
• Liver function test abnormalities
• Negative ANA and RF

Exclusion criteria: Infections, malignancies, rheumatic diseases 1

Fautrel Criteria (Highest Specificity at 98.5%) 1

Major Criteria (4 points each):

• Spiking fever >39°C
• Arthralgia
• Transient erythema
• Pharyngitis
• PMN >80%
• Glycosylated ferritin <20%

Minor Criteria (1 point each):

• Maculopapular rash
• Leucocytes >10×10⁹/L

Requires total score with specific major criteria combinations. 1

Disease Pattern Recognition for Prognosis

Three distinct clinical patterns exist, each affecting approximately one-third of patients: 1

Self-Limited/Monocyclic Pattern

• Characterized by systemic symptoms (fever, rash, serositis, organomegaly) 1
• Most patients achieve remission within 1 year (median 9 months) from first and only episode 1
• Favorable prognosis with rare serious complications 1

Intermittent/Polycyclic Systemic Pattern

• Recurrent flares with or without articular symptoms 1
• Complete remission between flares, which may be years apart 1
• Flares tend to be milder than initial episode 1

Chronic Articular Pattern

• Dominated by articular manifestations that can be severe and lead to joint destruction 1
• 67% of patients in this group required at least one total joint replacement after median of 28 months from disease onset 1
• Predictors at disease onset: rash, polyarthritis, and root joint (shoulder, hip) involvement 1
• Generally more disability and worse prognosis than systemic disease 1

Life-Threatening Complications to Monitor

Macrophage Activation Syndrome (MAS):

• Reported in up to 23% of AOSD patients 6
• Most severe complication with high mortality rate 6
• Presents with pancytopenia, requiring immediate recognition and immunosuppressive treatment 1

Other Serious Complications:

• Pericarditis and cardiac tamponade 1
• Disseminated intravascular coagulation (can lead to death) 1
• Amyloidosis 1
• Hepatic disease and hepatic failure (exceedingly rare) 1
• Respiratory failure 1

Critical Pitfalls to Avoid

• Do not dismiss the rash as drug allergy - the evanescent salmon-pink rash is pathognomonic and often accompanies fever 1
• Do not overlook wrist involvement - carpal and pericapitate abnormalities distinguish AOSD from rheumatoid arthritis 1
• Do not attribute liver dysfunction solely to NSAIDs - hepatomegaly and abnormal liver biochemistry are intrinsic disease features in 50-75% 1
• Do not miss pancytopenia - this signals potentially fatal macrophage activation syndrome requiring urgent intervention 1
• Do not rely on a single diagnostic criterion - AOSD is a diagnosis of exclusion requiring systematic elimination of infections, malignancies, and other autoimmune diseases 2, 3