When should Adult-Onset Still's Disease (AOSD) be suspected in adults with persistent high fevers, joint pain, and a salmon-colored rash, particularly those between 20 and 40 years old?

When to Suspect Adult-Onset Still's Disease

Suspect AOSD immediately when a patient presents with high-spiking fevers ≥39°C lasting at least 7 days, accompanied by a transient salmon-pink rash and arthralgia/myalgia, particularly when standard infectious workup is negative and inflammatory markers are markedly elevated. 1

Core Diagnostic Features

The 2024 EULAR/PRES guidelines provide operational definitions to facilitate rapid identification 1:

Fever Pattern (Present in 95.7% of cases)

• Temperature ≥39°C (102.2°F) for at least 7 days 1
• Spiking pattern lasting typically under 4 hours, following quotidian or double quotidian pattern 2
• Highest temperatures occur in late afternoon or early evening 2
• Fever heralds onset of other manifestations including serositis, sore throat, myalgias, and arthralgias 2

Rash Characteristics (Present in 51-87% of cases)

• Transient, erythematous (salmon-pink) eruption that often coincides with fever spikes 1
• Preferentially involves trunk and proximal limbs, rarely affecting face and distal limbs 2
• Other rash patterns (urticarial, pruritic) may be consistent with diagnosis 1, 3
• Critical pitfall: Do not dismiss the rash as drug allergy—it is pathognomonic and often accompanies fever 4

Musculoskeletal Involvement (Present in 64-100% of cases)

• Arthralgia/myalgia is usually present; overt arthritis is supportive but NOT necessary for diagnosis 1
• Arthritis may appear later with median delay of 1 month after disease onset (range 0 to several months) 1
• Most frequently affected joints: knees (69-82%), wrists (67-73%), ankles (38-55%) 2
• Critical pitfall: Do not overlook wrist involvement—carpal and pericapitate abnormalities distinguish AOSD from rheumatoid arthritis 4

Laboratory Red Flags

Inflammatory Markers (Present in virtually all cases)

• Neutrophilic leukocytosis with high levels of ESR, CRP, and ferritin 1
• 50% of patients have WBC >15×10⁹ cells/L; 37% have WBC >20×10⁹ 2, 4
• Very high ferritin levels (4,000-30,000 ng/mL, with extreme levels up to 250,000 ng/mL reported) 2, 4
• Elevated platelet count, fibrinogen, and D-dimers 1

Additional Laboratory Features

• Anaemia of chronic disease (normalizes with remission) 2, 4
• Hepatomegaly and liver biochemistry abnormalities in 50-75% of patients 2, 4
• Critical pitfall: Do not attribute liver dysfunction solely to NSAIDs—it is an intrinsic disease feature 4

Additional Clinical Clues

Systemic Manifestations

• Sore throat (35-92% of patients) 2
• Myalgia (56-84%), generalized and appearing with fever exacerbations 2
• Lymphadenopathy (32-74%) and splenomegaly (14-65%) 2
• Pleuritis (12-53%) and pericarditis (10-37%) 2
• Dermatographism (92% in one series) 5

Patient Demographics

• Primarily affects adults between 16-35 years of age, with bimodal peaks at 15-25 years and 36-46 years 4
• Approximately 60% female predominance 4

Critical Life-Threatening Complication to Monitor

Macrophage Activation Syndrome (MAS) is the main challenging and life-threatening complication 1:

• Can occur at disease onset, during treatment, or even during remission 1
• May present as relapse of Still's disease directly as MAS, especially with concurrent infection 1
• Critical pitfall: Do not miss pancytopenia—it signals potentially fatal MAS requiring urgent intervention 4
• Requires immediate recognition and immunosuppressive treatment 4

Diagnostic Approach

When to Strongly Suspect AOSD

Suspect AOSD when the following constellation is present:

1. High-spiking fevers ≥39°C for ≥7 days 1
2. Transient salmon-pink rash (even if urticarial or atypical) 1, 3
3. Arthralgia/myalgia (arthritis not required) 1
4. Markedly elevated inflammatory markers with very high ferritin 1, 2
5. Negative infectious workup and negative ANA/RF 1, 4

Classification Criteria as Diagnostic Aids

While not developed for diagnosis, the Yamaguchi criteria (most sensitive at 93.5%) can help identify disease 1:

• Requires 5 criteria with at least 2 major
• Major criteria: fever, arthralgia, typical rash, WBC >10,000
• Negative ANA and RF required 4

Differential Diagnosis to Exclude

AOSD is a diagnosis of exclusion requiring elimination of 1, 4:

• Infectious disorders (viral syndromes, bacterial infections)
• Neoplastic disorders (leukemia, lymphoma)
• Other autoimmune diseases (reactive arthritis, vasculitides)
• Periodic fever syndromes (familial Mediterranean fever, TRAPS)
• Hemophagocytic syndrome

Atypical Presentations

Be aware that AOSD can present atypically with 6:

• Delayed onset of fever, leukocytosis, and transaminitis
• Seizures and myocarditis
• Pruritic, hyperpigmented, scaly rash rather than classic salmon-pink eruption
• Right heart failure due to lymphocytic myocarditis

The key is maintaining high clinical suspicion when the classic triad is present with markedly elevated inflammatory markers and negative infectious/autoimmune workup, even if arthritis has not yet developed. 1