Adult-onset Still disease

Adult-onset Still disease (AOSD) is a rare inflammatory disorder characterized by intermittent fever, salmon-pink rash, symmetrical polyarthritis, and arthralgia. AOSD and systemic juvenile idiopathic arthritis are increasingly viewed as the same condition with different ages of onset due to their shared clinical features and laboratory findings. The exact cause is unknown. Life-threatening complications include macrophage activation syndrome and fulminant hepatitis. In patients with suggestive clinical features and laboratory findings (e.g., leukocytosis with neutrophilia, elevated ferritin levels), a comprehensive workup is needed to exclude alternative diagnoses (e.g., infections, autoimmune diseases, malignancy). Imaging studies (e.g., echocardiography, high-resolution CT chest) may be performed to assess for organ involvement. Prompt treatment with biologic DMARDs (e.g., anakinra) can prevent disease progression. A combination of biologic DMARDs and high-dose glucocorticoids are used in severe disease.

• Prevalence (global): 1–10 per million ^[1]
• Sex: Incidence is slightly higher in female individuals than male individuals. ^[1]
• Age: typical onset 16–35 years of age but may manifest later in life ^[1]

Epidemiological data refers to the US, unless otherwise specified.

• Disease presentation: variable
  • Single or recurrent episodes
  • Chronic, progressive disease
• Main features ^[1][2]
  • Intermittent fever: ≥ 39°C (102.2°F) for > 7 days
  • Rash
    • Erythematous (salmon-pink) with macules and papules ^[2]
    • Usually intermittent, coinciding with fever
    • Typically on the trunk or proximal limbs
  • Symmetrical polyarthritis (not always present), arthralgias, and/or myalgias ^[1][2]
• Additional features ^[1][2]
  • Sore throat
  • Lymphadenopathy
  • Serositis (e.g., pleural effusion, pericarditis)
  • Splenomegaly, hepatomegaly
  • Fulminant hepatitis (in severe cases)
  • Associated interstitial lung disease: cough, dyspnea, clubbing

General principles ^[1][2]

• Early referral to a specialist (e.g., rheumatology) is required for all patients with suspected AOSD.
• Diagnosis is based on:
  • Suggestive clinical features and laboratory findings
  • Exclusion of alternative diagnoses
• The Yamaguchi classification criteria may be used to support the diagnosis.

Laboratory studies ^[1][2]

• CBC: Leukocytosis with neutrophilia and thrombocytosis support the diagnosis; leukopenia suggests macrophage activation syndrome.
• Inflammatory markers: ↑↑↑ ferritin, ↑ CRP, ↑ ESR ^[2]
• CMP: ↑ BUN, ↑ creatinine
• Liver chemistries: ↑ AST, ↑ ALT
• Coagulation studies: ↑ PT, ↑ D-dimer, ↓ fibrinogen
• Other: ↑ CK, ↑ LDH
• Additional studies may be obtained to exclude alternative diagnoses in consultation with specialists.
  • Blood culture, viral serology (e.g., EBV, HIV, CMV): to exclude infectious diseases
  • ANA, rheumatoid factor, ANCAs: to exclude autoimmune conditions (e.g., SLE, rheumatoid arthritis, polyarteritis nodosa)
  • Bone marrow or lymph node biopsy: if hematologic malignancy (e.g., non-Hodgkin lymphoma) is suspected

Macrophage activation syndrome should be suspected in patients with AOSD or systemic juvenile idiopathic arthritis and a normal or decreased WBC count, falling ESR, and/or increasing triglyceride levels.

Imaging studies ^[1][2]

• X-ray or ultrasound of affected joints: no specific findings but can help rule out seronegative rheumatoid arthritis ^[3]
• Echocardiography: if cardiopulmonary involvement (e.g., pulmonary hypertension, myocarditis) is suspected
• High-resolution CT chest: if pulmonary involvement is suspected
• CT chest, abdomen, and pelvis: if malignancy is suspected

Classification criteria ^[1][4]

The Yamaguchi criteria for AOSD are the most widely used criteria; ≥ 5 criteria must be fulfilled, including ≥ 2 major criteria.

• Major criteria
  • Fever (≥ 39°C) every day for ≥ 1 week
  • Arthralgia and/or arthritis for ≥ 2 weeks
  • Nonpruritic salmon-colored rash with macules and papules on the trunk or extremities
  • Leukocytosis ≥ 10,000/mm³ with ≥ 80% neutrophils
• Minor criteria
  • Pharyngitis and/or sore throat
  • Lymphadenopathy and/or splenomegaly
  • Elevated AST, ALT, and/or LDH
  • Negative ANA and rheumatoid factor (excludes other diagnoses)

The Yamaguchi classification criteria have high specificity but low sensitivity. They aim to standardize case definitions for enrollment in clinical trials, not to guide practice. ^[1][4]

• Infectious diseases ^[2]
  • Bacterial, e.g., endocarditis, tuberculosis
  • Viral, e.g., viral hepatitis, HIV
• Malignancy ^[2]
  • Lymphoma (Hodgkin or non-Hodgkin), e.g., angioimmunoblastic T-cell lymphoma
  • Hematologic malignancies, e.g., acute lymphoblastic leukemia, myelodysplastic syndromes
  • Solid cancers, e.g., kidney, colon, lung (including paraneoplastic syndromes)
• Systemic conditions ^[2]
  • Autoimmune and/or autoinflammatory disorders, e.g.:
    • Vasculitis, inflammatory myopathies, SLE, seronegative rheumatoid arthritis
    • Reactive arthritis or post-streptococcal arthritis
    • Sarcoidosis
    • Familial Mediterranean fever
  • Drug hypersensitivity reactions

The differential diagnoses listed here are not exhaustive.

Refer all patients to a specialist (e.g., rheumatology) early for prompt management and regular monitoring of disease activity.

• Biologic DMARD (preferred) ^[2][3]
  • IL-1 inhibitor: e.g., anakinra or canakinumab
  • OR IL-6 inhibitor: e.g., tocilizumab
• OR conventional DMARD (if biologic DMARDs are unavailable): e.g., methotrexate
• PLUS high-dose glucocorticoids for patients with severe disease (e.g., high fever, widespread polyarthritis, and/or pericarditis)

Refer patients with suspected AOSD for prompt management, as there is a narrow therapeutic window to prevent disease progression. ^[3]