What is the appropriate diagnostic workup and management strategy for adult‑onset Still’s disease?

Adult-Onset Still's Disease: Diagnostic Workup and Management

Immediate Diagnostic Approach

Adult-onset Still's disease is a clinical diagnosis of exclusion requiring systematic elimination of infectious, neoplastic, and other autoimmune diseases, with diagnosis based on the presence of the classic triad: high-spiking fevers >39°C, evanescent salmon-pink rash, and arthritis/arthralgia. 1, 2

Key Clinical Features to Identify

• Fever pattern: High-spiking fevers exceeding 39°C that are transient (lasting <4 hours), following quotidian or double-quotidian patterns with peaks in late afternoon or early evening 1
• Rash characteristics: Evanescent, salmon-pink, maculopapular eruption predominantly on proximal limbs and trunk, typically appearing with fever episodes 1
• Joint involvement: Arthralgia/arthritis in 64-100% of patients, most commonly affecting knees (69-82%), wrists (67-73%), and ankles (38-55%) 1
• Associated symptoms: Sore throat (35-92%), myalgias (56-84%), lymphadenopathy (32-74%), splenomegaly (14-65%), and serositis (pleuritis 12-53%, pericarditis 10-37%) 1

Essential Laboratory Workup

Diagnostic laboratories should include:

• Inflammatory markers: ESR (elevated in virtually all patients) and CRP (typically raised) 1
• Complete blood count: Leukocytosis with neutrophilia >15×10⁹ cells/L in 50% of patients, with 37% having WBC >20×10⁹; anemia of chronic disease and reactive thrombocytosis are common 1
• Ferritin levels: Very high levels (4,000-30,000 ng/mL, occasionally up to 250,000 ng/mL) that correlate with disease activity 1
• Liver function tests: Hepatomegaly and abnormal liver biochemistry in approximately 50-75% of patients 1
• Negative serologies: Rheumatoid factor and antinuclear antibodies are typically absent 3, 4

Advanced biomarkers for diagnostic support:

• IL-18 levels: Significantly elevated in AOSD compared to bacterial infections, with diagnostic accuracy of 97.67% when combined with ferritin 1
• Glycosylated ferritin fraction: Low fraction is useful as both diagnostic and disease activity marker 5

Exclusion of Differential Diagnoses

The diagnosis requires systematic exclusion of:

• Infectious diseases (particularly bacterial infections, endocarditis, viral infections)
• Malignancies (lymphomas, leukemias)
• Other autoimmune diseases (systemic lupus erythematosus, vasculitis)
• AOSD is responsible for a significant proportion of fever of unknown origin cases 3, 2

First-Line Treatment Strategy

The American College of Rheumatology recommends IL-1 inhibitors (anakinra) or IL-6 receptor inhibitors (tocilizumab) as first-line treatment for AOSD, representing a paradigm shift from traditional corticosteroid-based therapy. 6, 2

Treatment Algorithm by Disease Activity

For active AOSD with high disease activity:

• Start with IL-1 inhibitors (anakinra) or IL-6 receptor inhibitors (tocilizumab) 6
• Anakinra is specifically preferred for patients with impending macrophage activation syndrome 6

For moderate disease activity:

• IL-1 or IL-6 inhibitors combined with low-dose glucocorticoids (≤0.1 mg/kg/day prednisone equivalent) 6

Critical timing consideration:

• Early initiation of biologic therapy improves outcomes through a "window of opportunity" effect 6, 2

Traditional Therapies: Limited Role

NSAIDs have minimal efficacy:

• Effective as monotherapy in only 7-15% of patients 6
• Should not be relied upon as long-term therapy 6

Glucocorticoids:

• Historically the mainstay with 76-95% response rates, but most patients require long-term maintenance with significant side effects 6
• Should be used at low doses in combination with biologics rather than as primary therapy 6

Conventional DMARDs (particularly methotrexate):

• Used as steroid-sparing agents with modest efficacy (approximately 40% overall response) 6
• Secondary role in the biologic era 6

Treatment Targets and Monitoring

Primary treatment goal:

• Achieve clinically inactive disease (CID) off glucocorticoids 6, 2

Intermediate targets:

• Decrease active joints by 50% 6

Monitoring strategy:

• Regular assessment of disease activity with treatment adjustment using a treat-to-target approach 6, 2
• Maintain clinically inactive disease for at least 6 months off glucocorticoids before considering tapering biologic therapy 6

Management of Refractory Disease

If no response to initial biologic therapy:

• Rotate between IL-1 and IL-6 inhibitors 6
• For difficult-to-treat cases, consult with specialized centers 6
• Experimental therapies (JAK inhibitors, IFN-γ inhibitors) may be considered 6

Recognition and Management of Disease Patterns

AOSD follows three distinct clinical patterns, each affecting approximately one-third of patients 6, 1:

• Self-limited/monocyclic pattern: Systemic symptoms with remission within 1 year (median 9 months) 6
• Intermittent/polycyclic pattern: Recurrent flares with complete remission between episodes 6
• Chronic articular pattern: Dominated by joint manifestations that can lead to severe joint destruction; generally worse prognosis requiring more aggressive therapy 6

Life-Threatening Complications

Macrophage Activation Syndrome (MAS)

MAS is the most severe complication with high mortality, occurring in up to 23% of AOSD patients: 7

• Treatment: High-dose glucocorticoids and high-dose anakinra (>4 mg/kg/day in children or 100 mg twice daily in adults) 6
• Additional options: Cyclosporine A and/or IFN-γ inhibitors 6
• Prevention: Anakinra is preferred when MAS is impending 6

Pulmonary Complications

• Screen for lung disease symptoms (clubbing, persistent cough, shortness of breath) 6
• Monitor with pulmonary function tests and high-resolution CT when indicated 6
• IL-1 or IL-6 inhibitors are not contraindicated in patients with lung disease 6

Critical Pitfalls to Avoid

• Do not rely solely on NSAIDs or glucocorticoids as long-term therapy, as most patients will require more advanced treatment 6
• Do not delay biologic therapy, as early initiation improves outcomes 6, 2
• Do not fail to screen for and promptly treat MAS, which is life-threatening 6
• Do not overlook regular monitoring of disease activity and treatment response 6
• Do not use TNF inhibitors as first-line therapy; they should be reserved for patients with purely chronic articular manifestations 8