What is the diagnosis and treatment approach for Adult Still's disease, a rare inflammatory disorder characterized by chronic inflammation and unknown etiology?

Adult Still's Disease: Diagnosis and Management

Adult Still's Disease (AOSD) is a rare systemic inflammatory disorder of unknown etiology characterized by high spiking fevers, evanescent rash, arthritis, and multiorgan involvement that requires a clinical diagnosis and stepwise treatment approach with NSAIDs, corticosteroids, and biological agents. 1

Clinical Manifestations

AOSD presents with a classic triad of symptoms:

• Fever: Quotidian or double-quotidian spiking fevers (>39°C), typically occurring in the evening
• Rash: Evanescent, salmon-colored maculopapular rash that appears during fever spikes
• Arthritis/Arthralgia: Affects multiple joints, commonly knees, wrists, and ankles

Additional common manifestations include:

• Sore throat: Present in 35-92% of patients
• Myalgia: Occurs in 56-84% of patients, often during fever exacerbations
• Lymphadenopathy: Seen in 32-74% of patients
• Hepatosplenomegaly: Liver abnormalities in 50-75% of patients
• Serositis: Pleuritis and pericarditis in 10-53% of patients 1

Diagnostic Approach

AOSD is a diagnosis of exclusion that requires ruling out infectious, neoplastic, and other autoimmune diseases. Several diagnostic criteria exist, with Yamaguchi criteria being the most widely used 1, 2:

Yamaguchi Criteria

Major criteria:

• Fever ≥39°C for ≥1 week
• Arthralgia ≥2 weeks
• Typical rash
• Leukocytosis (≥10,000/mm³ with ≥80% neutrophils)

Minor criteria:

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

Diagnosis requires ≥5 criteria with at least 2 major criteria 1

Laboratory Findings

• Elevated inflammatory markers: ESR and CRP nearly always elevated
• Leukocytosis: Often >15,000/mm³ with neutrophil predominance
• Hyperferritinemia: Extremely high levels (4,000-30,000 ng/mL) are characteristic
• Glycosylated ferritin: Levels <20% are highly specific for AOSD
• Negative serologies: RF and ANA typically negative
• Liver enzyme abnormalities: Common but usually mild 1, 3

Treatment Algorithm

Treatment should follow a stepwise approach based on disease severity and response:

1. First-line therapy:

   • NSAIDs: Only effective as monotherapy in 7-15% of patients
   • Preferred agents: Indomethacin and naproxen (more effective than aspirin) 1

2. Second-line therapy:

   • Corticosteroids: Required in 76-95% of patients
   • Prednisone 0.5-1 mg/kg/day for systemic symptoms
   • Higher doses may be needed for severe disease
   • IV pulse methylprednisolone for refractory cases 1, 3

3. Third-line therapy (steroid-sparing agents):

   • Conventional DMARDs: Methotrexate is first choice
   • Other options: Leflunomide, azathioprine, cyclosporine, gold salts 1, 3, 2

4. Biological agents (for refractory cases):

   • IL-1 inhibitors: Anakinra and canakinumab (canakinumab is FDA-approved for AOSD) 2
   • IL-6 inhibitors: Tocilizumab
   • TNF-α inhibitors: Less effective than IL-1 or IL-6 inhibitors 3, 4, 2

Disease Course and Prognosis

AOSD typically follows one of three patterns:

1. Monocyclic: Single episode with complete resolution (30%)
2. Polycyclic/Intermittent: Recurrent episodes with periods of remission (30%)
3. Chronic articular: Persistent arthritis with potential joint destruction (40%) 1, 5

Prognosis is generally favorable when systemic symptoms predominate. The chronic articular pattern carries worse long-term outcomes with potential joint destruction and disability 3.

Complications and Monitoring

• Macrophage activation syndrome (MAS): Life-threatening complication requiring prompt immunosuppressive treatment
• Cardiac involvement: Myocarditis and pericarditis
• Respiratory failure: Rare but serious complication
• Amyloidosis: Long-term complication of chronic inflammation 1, 6

Monitor disease activity with clinical symptoms, inflammatory markers, and ferritin levels. Adjust treatment based on response and complications.

Important Considerations

• Early diagnosis is crucial: Delay in diagnosis is common due to nonspecific presentation
• Hyperferritinemia: Extremely high ferritin levels are highly suggestive of AOSD
• Treatment resistance: Most patients require corticosteroids and often immunosuppressive agents
• Window of opportunity: Earlier treatment with biologics may lead to better outcomes 4
• Treat-to-target approach: Currently lacking standardized guidelines 2

AOSD remains a diagnostic challenge requiring a high index of suspicion and exclusion of other conditions. The emergence of biological therapies has significantly improved outcomes for patients with refractory disease.