What are the Yamaguchi criteria for diagnosing adult‑onset Still’s disease?

Yamaguchi Criteria for Adult-Onset Still's Disease

The Yamaguchi criteria are the most validated and widely used diagnostic criteria for adult-onset Still's disease, requiring 5 or more criteria (including at least 2 major criteria) after exclusion of infections, malignancies, and other rheumatic diseases. 1

Major Criteria (Need at least 2 of these)

• Fever ≥39°C lasting ≥1 week with a characteristic spiking pattern (quotidian or double-quotidian) 2, 3

• Arthralgia lasting ≥2 weeks - notably, frank arthritis is NOT required for diagnosis, as joint inflammation often appears later with a median delay of 1 month after disease onset 1, 4

• Typical evanescent salmon-pink rash that is transient, maculopapular, predominantly affecting proximal limbs and trunk, often coinciding with fever spikes 2, 3

• Leukocytosis ≥10,000/mm³ with ≥80% polymorphonuclear neutrophils - this threshold provides optimal diagnostic accuracy in validation studies 2, 3

Minor Criteria (Need remaining criteria to total ≥5)

• Sore throat - occurs in 35-92% of patients and has good specificity when present 2, 3

• Lymphadenopathy and/or splenomegaly - seen in 32-74% and 14-65% of patients respectively 2

• Liver dysfunction (elevated transaminases or bilirubin) - present in 50-75% of patients 2

• Negative rheumatoid factor AND negative antinuclear antibodies - both must be negative to fulfill this criterion 2, 3

Critical Performance Characteristics

The Yamaguchi criteria demonstrate 96.2% sensitivity, 92.1% specificity, and 87.14% overall accuracy, making them superior to other proposed criteria sets (Calabro, Cush, Reginato) in validation studies 1, 5, 2, 3

Essential Exclusion Requirements

You must systematically exclude the following before applying Yamaguchi criteria, as AOSD remains fundamentally a diagnosis of exclusion despite having classification criteria 1, 5:

• Infections - particularly bacterial infections, as fever patterns can overlap 5
• Malignancies - especially lymphomas and leukemias that can mimic systemic features 1
• Other rheumatic diseases - systemic lupus erythematosus, vasculitis, reactive arthritis, dermatomyositis 1, 6
• Monogenic autoinflammatory disorders - familial Mediterranean fever, TRAPS, VEXAS syndrome in adults 1

Diagnostic Augmentation with Biomarkers

While not part of the original Yamaguchi criteria, markedly elevated serum ferritin (typically 4,000-30,000 ng/mL or ≥5-fold upper normal limit) and IL-18 strongly support the diagnosis and should be measured when available 1, 7, 3

• Glycosylated ferritin <20% has high specificity for AOSD and is incorporated into the newer Fautrel criteria 7
• Extremely elevated IL-18 (>1,000 pg/mL) helps distinguish AOSD from other inflammatory conditions and infections 8, 6

Common Diagnostic Pitfalls to Avoid

• Do not require arthritis for diagnosis - the Yamaguchi criteria intentionally use "arthralgia" as the major criterion because overt arthritis often develops later, and requiring it causes dangerous diagnostic delays 1, 4

• Do not dismiss cases with positive autoantibodies - while negative RF and ANA are part of the minor criteria, rare overlap cases with other rheumatic diseases can occur, and extremely high IL-18 may help confirm AOSD in these situations 6

• Do not apply criteria without thorough exclusion workup - in fever of unknown origin cohorts, the Yamaguchi criteria maintain 95%+ sensitivity and specificity only when proper exclusions are performed 5

• Do not use clinical scoring systems alone - newer clinical scales lack sensitivity (55%) compared to Yamaguchi criteria (95%) and should only be used to "rule in" rather than "rule out" AOSD 5