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

Adult-Onset Still's Disease (AOSD)

Adult-Onset Still's Disease is a rare systemic inflammatory disorder characterized by high spiking fevers, evanescent salmon-pink rash, arthralgia/arthritis, and elevated inflammatory markers, which represents part of a disease continuum with systemic juvenile idiopathic arthritis across different age groups. 1

Clinical Features

AOSD presents with four cardinal manifestations:

• Fever: High spiking (≥39°C), typically quotidian or double-quotidian pattern
• Rash: Evanescent, salmon-pink maculopapular rash that appears during fever spikes
• Musculoskeletal involvement: Arthralgia and/or arthritis
• Laboratory abnormalities: Marked inflammatory response

Additional common manifestations include:

• Sore throat
• Lymphadenopathy
• Splenomegaly
• Liver dysfunction
• Cardiac involvement 1

Epidemiology

• Rare disease with estimated incidence of 0.16 per 100,000 inhabitants 2
• Affects women slightly more often than men
• Typically affects younger adults, with 75% reporting onset between 16-35 years
• Bimodal age distribution with peaks at 15-25 and 36-46 years 2
• Can affect all ages, including those over 60 years

Pathogenesis

The exact etiology remains unknown, but evidence suggests:

• Genetic predisposition with various HLA associations
• Possible infectious triggers in genetically susceptible individuals
• Key role of macrophage activation leading to T helper 1 (Th1) cell cytokine activation
• Pro-inflammatory cytokines (IL-1, IL-6, IL-18) play fundamental roles in disease onset and progression 3

Diagnosis

Diagnosis is clinical and requires exclusion of infectious, neoplastic, and autoimmune diseases. The Yamaguchi criteria are most commonly used:

Yamaguchi Criteria 1

Major criteria:

• Fever ≥39°C, intermittent, ≥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 RF and ANA

Diagnosis requires:

• ≥5 criteria with at least 2 major criteria
• Exclusion of infections, malignancies, and other rheumatic diseases

Laboratory Findings

• Neutrophilic leukocytosis
• Elevated acute phase reactants (ESR, CRP)
• Markedly elevated serum ferritin (often >1000 μg/L)
• Glycosylated ferritin <20% (highly specific for AOSD) 1

Disease Course and Prognosis

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

1. Monocyclic pattern: Single episode with complete resolution within 1 year
2. Polycyclic/intermittent pattern: Recurrent flares with periods of remission
3. Chronic articular pattern: Persistent arthritis with potential joint destruction 2, 1

Prognosis is generally favorable when systemic symptoms predominate, but the chronic articular pattern carries worse outcomes with potential disability. Risk factors for chronic articular disease include rash, polyarthritis, and root joint involvement at disease onset 2.

Complications

The most serious complication is Macrophage Activation Syndrome (MAS), a life-threatening condition requiring prompt immunosuppressive treatment. Warning signs include:

• Persistent fever
• Splenomegaly
• Elevated/rising serum ferritin
• Inappropriately low cell counts
• Abnormal liver function tests
• Intravascular activation of coagulation
• Elevated/rising serum triglycerides 1

Treatment

Treatment follows a step-wise approach:

First-line therapy:

• NSAIDs (indomethacin, naproxen) - effective as monotherapy in only 7-15% of patients 2, 1

Second-line therapy:

• Corticosteroids - required in 76-95% of patients 1

Third-line therapy (for refractory cases):

• Conventional DMARDs: Methotrexate is most commonly used
• Biological agents:
  • IL-1 inhibitors (anakinra, canakinumab)
  • IL-6 inhibitors (tocilizumab)
  • TNF-α inhibitors 1, 3

Current treatment guidelines follow a treat-to-target approach with sequential goals:

• Resolution of fever and reduction of CRP by >50% by day 7
• Clinically inactive disease without glucocorticoids by month 6 1

Monitoring

Disease activity should be monitored with:

• Clinical symptoms
• Inflammatory markers
• Ferritin levels

Treatment should be adjusted based on response and complications. Screening for Still's lung disease includes monitoring for clinical symptoms and performing pulmonary function tests when indicated 1.

Clinical Pitfalls

1. Delayed diagnosis: Due to non-specific symptoms and lack of pathognomonic tests, diagnosis is often delayed while investigating fever of unknown origin
2. Misdiagnosis: Similar presentation to infections, malignancies, and other rheumatic diseases
3. Underrecognition of MAS: Failure to recognize this life-threatening complication can lead to poor outcomes
4. Overreliance on ferritin: While highly elevated ferritin is characteristic, it's not specific to AOSD and can be seen in other inflammatory conditions