What are the latest guidelines for diagnosing Adult-Onset Still's Disease (AOSD)?

Diagnosing Still's Disease: Latest Guidelines

Primary Diagnostic Approach

The 2024 EULAR/PReS guidelines establish that Still's disease diagnosis requires recognition of four cardinal features using operational definitions, and critically, arthritis is NOT mandatory for diagnosis—arthralgia alone is sufficient. 1

Core Diagnostic Criteria (Operational Definitions)

The following four features should be systematically assessed 1:

1. Fever Pattern

• Temperature ≥39°C (102.2°F) for at least 7 days 1
• Characteristic spiking pattern (quotidian or double-quotidian) 1
• This is the most consistent feature and should raise immediate suspicion 1

2. Skin Manifestations

• Salmon-pink (erythematous) rash that is transient and evanescent 1
• Typically coincides with fever spikes 1
• Preferentially involves the trunk 1
• Other rash patterns (urticarial) may be consistent with diagnosis 1
• Important caveat: The rash may be challenging to identify on darker skin tones 1

3. Musculoskeletal Involvement

• Arthralgia or myalgia is sufficient for diagnosis 1
• Overt arthritis is supportive but NOT necessary 1
• Arthritis typically appears later with a median delay of 1 month after disease onset (range 0 to several months) 1
• The 2024 guidelines explicitly state that requiring arthritis leads to unnecessary and potentially deleterious diagnostic delays 1

4. Laboratory Evidence of High Inflammation

• Neutrophilic leukocytosis 1
• Elevated ESR and serum CRP 1
• Elevated ferritin (typically markedly elevated) 1
• Additional supportive findings: increased platelet count, fibrinogen, and D-dimers 1

Classification Criteria to Guide Diagnosis

The Yamaguchi criteria remain the most validated tool, tested in both children and adults with high sensitivity 1:

• These criteria do NOT require arthritis for diagnosis, aligning with current understanding 1
• While not specifically developed for diagnostic ascertainment, classification criteria help clinicians identify the disease 1
• The diagnosis remains one of exclusion after ruling out infectious, neoplastic, and autoimmune disorders 1, 2

Advanced Biomarkers (When Available)

Marked elevation of serum IL-18 and/or S100 proteins (e.g., calprotectin) strongly supports the diagnosis and should be measured if available 1:

• These biomarkers are not yet universally available but represent the strongest supportive evidence when present 1
• IL-18 and S100 proteins show superior diagnostic accuracy compared to traditional markers 1
• The 2024 guidelines specifically recommend their measurement when accessible 1

Critical Differential Diagnoses to Exclude

Before confirming Still's disease, systematically rule out 1:

Infectious Causes

• Viral syndromes (rubella, CMV, EBV, mumps, Coxsackievirus, adenovirus) 1
• If symptoms persist beyond 3 months, viral causes become less likely 1
• Bacterial infections including mycobacteria 1

Neoplastic Disorders

• Leukemia, lymphoma, angioblastic lymphadenopathy 1
• These may present with atypical rashes or isolated lymphadenopathy 1
• Bone marrow or lymph node biopsy may be needed in unclear cases 1

Autoinflammatory Syndromes

• Familial Mediterranean fever (FMF) 1
• TNF receptor-associated periodic syndrome (TRAPS) 1
• Other periodic fever syndromes 1

Other Rheumatic Diseases

• Reactive arthritis and spondyloarthropathies 1
• Systemic lupus erythematosus 1
• Vasculitides 1

Diagnostic Algorithm

1. Identify the four cardinal features using operational definitions above 1
2. Apply Yamaguchi criteria to support clinical diagnosis 1
3. Measure IL-18 and S100 proteins if available for strong supportive evidence 1
4. Systematically exclude infectious, neoplastic, and other autoimmune causes 1, 2
5. Do NOT delay diagnosis waiting for arthritis to develop 1

Common Diagnostic Pitfalls

• Waiting for arthritis to appear: This causes unnecessary diagnostic delays and is explicitly discouraged by the 2024 guidelines 1
• Missing the rash on darker skin: Requires heightened clinical awareness 1
• Performing unnecessary exploratory laparotomy: The constellation of fever, abdominal pain, and mesenteric lymphadenopathy can mimic surgical emergencies 1
• Overlooking periodic fever syndromes: These can closely mimic Still's disease, particularly in younger patients 1

Disease Activity and Remission Definitions

Once diagnosed, use these standardized definitions 1:

• Clinically inactive disease (CID): Absence of Still's disease-related symptoms AND normal ESR or CRP 1
• Remission: Period of at least 6 months with CID 1

Life-Threatening Complication Requiring Vigilance

Macrophage activation syndrome (MAS) occurs in up to 23% of patients and represents the most severe complication with high mortality 3, 4:

• Can occur at disease onset, during treatment, or even in remission 3
• Requires immediate recognition and treatment 3, 4
• Maintain high vigilance with adequate laboratory monitoring 1, 3