What are the guidelines for diagnosing and managing Adult-Onset Still's Disease (AOSD) in a patient with suspected systemic inflammation and no prior medical history?

Guidelines for Diagnosis and Management of Adult-Onset Still's Disease (AOSD)

Diagnosis

AOSD diagnosis requires operational criteria focusing on four cardinal features: spiking fever ≥39°C for at least 7 days, transient salmon-pink rash coinciding with fever spikes, musculoskeletal involvement (arthralgia/myalgia with or without overt arthritis), and high inflammation markers (neutrophilic leukocytosis, elevated CRP and ferritin). 1

Key Diagnostic Features

• Fever pattern: Temperature must reach ≥39°C (102.2°F) with characteristic spiking pattern lasting at least 7 days 1
• Rash characteristics: Transient, erythematous (salmon pink), preferentially on trunk, often coinciding with fever spikes; urticarial variants may occur 1
• Musculoskeletal involvement: Arthralgia/myalgia is usually present; overt arthritis is supportive but not necessary for initial diagnosis and may appear later 1
• Laboratory markers: Neutrophilic leukocytosis, elevated CRP, and markedly elevated serum ferritin are typical 1, 2

Advanced Diagnostic Testing

• Measure serum IL-18 and/or S100 proteins (calprotectin) if available, as marked elevation strongly supports the diagnosis 1
• Ferritin levels are typically higher than in other autoimmune, inflammatory, infectious, or neoplastic diseases 3
• Glycosylated ferritin determination can help differentiate AOSD from other conditions 4

Critical Exclusions

Alternative diagnoses must be carefully excluded, including malignancies, infectious diseases, other immune-mediated inflammatory diseases, and monogenic autoinflammatory disorders. 1 The Yamaguchi and Fautrel criteria are the most widely used diagnostic tools in clinical practice, though diagnosis is often reached by exclusion when investigating fever of unknown origin 2.

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Management Strategy

IL-1 inhibitors (anakinra) or IL-6 receptor inhibitors (tocilizumab) should be initiated as early as possible when the diagnosis is established, as these biologics show the highest level of evidence for efficacy and represent first-line treatment. 1, 5

Treatment Algorithm

For active AOSD with high disease activity:

• Start with IL-1 inhibitor (anakinra) or IL-6 receptor inhibitor (tocilizumab) immediately 1, 5
• Anakinra is preferred if macrophage activation syndrome (MAS) is impending 5
• Early initiation improves outcomes due to a "window of opportunity" before 3 months of symptom onset 6

For moderate disease activity:

• IL-1 or IL-6 inhibitors with low-dose glucocorticoids (≤0.1 mg/kg/day prednisone equivalent) 5

Traditional Therapies (Now Secondary Options)

• NSAIDs as monotherapy are effective in only 7-15% of patients and should not be relied upon as definitive treatment 1, 5
• Glucocorticoids have 76-95% response rates but most patients require long-term maintenance with significant side effects 1, 5
• High-dose prednisone should be limited to 6 months for NSAID-refractory systemic disease with persistent anemia, pericarditis, serositis, or elevated liver enzymes 1, 6
• Methotrexate (11.5 mg/week) achieves 88% response and 78% complete remission as a steroid-sparing agent, allowing 69% reduction in daily prednisone and complete discontinuation in 42% of patients 1, 6

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Treatment Targets and Monitoring

The ultimate goal is drug-free remission, defined as at least 6 months of clinically inactive disease (CID) without medications. 1, 5

Sequential Treatment Targets

• Day 7: Resolution of fever and CRP reduction >50% 1
• Week 4: No fever, active joint count reduction >50%, normal CRP, and physician/patient global assessment <20 on 0-100 VAS 1
• Month 3: CID with glucocorticoids <0.1-0.2 mg/kg/day 1
• Month 6: CID without glucocorticoids 1

Maintain CID for 3-6 months without glucocorticoids before initiating biologic DMARD tapering. 1, 5, 6

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Management of Refractory Disease

If no response to initial biologic therapy, rotate between IL-1 and IL-6 inhibitors. 5 For difficult-to-treat cases, consult specialized Still's disease expert centers 1, 5.

Second-Line Options

• Conventional DMARDs (methotrexate, cyclosporin A, azathioprine) show approximately 40% overall response 1
• TNF inhibitors (infliximab > etanercept) may be considered but show lower efficacy than IL-1/IL-6 blockade 1
• Experimental therapies (JAK inhibitors, IFN-γ inhibitors) for refractory cases 5

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Life-Threatening Complications

Macrophage Activation Syndrome (MAS)

MAS should be detected promptly and treated rapidly, as it occurs in 15-23% of AOSD patients with high mortality. 1, 2, 3

Suspect MAS with:

• Persistent fever, splenomegaly, elevated or rising serum ferritin 1
• Inappropriately low cell counts, abnormal liver function tests 1
• Intravascular coagulation activation, elevated or rising triglycerides 1

MAS treatment must include:

• High-dose glucocorticoids (intravenous methylprednisolone 15-30 mg/kg/day, maximum 1 g/infusion) 6
• Anakinra (>4 mg/kg/day in children or 100 mg twice daily in adults) 5, 6
• Consider adding cyclosporin A and/or IFN-γ inhibitors as part of initial therapy 1

Lung Disease

Actively screen for lung disease with clinical symptoms (clubbing, persistent cough, shortness of breath) and pulmonary function tests (pulse oximetry, DLCO measurement). 1

• Investigate with high-resolution CT scan in any patient with clinical symptoms 1
• IL-1 or IL-6 inhibitors are NOT contraindicated in patients with lung disease 1

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Disease Patterns and Prognosis

AOSD follows three clinical patterns, each affecting approximately one-third of patients 5:

• Monocyclic/self-limited: Systemic symptoms with remission within 1 year (median 9 months) 5, 3
• Polycyclic/intermittent: Recurrent flares with complete remission between episodes 5, 3
• Chronic articular: Dominated by joint manifestations; erosions occur in one-third of patients; worst prognosis requiring more aggressive therapy 5, 3, 4

Prednisone requirements increase with disease pattern: 57% for self-limited, 67% for intermittent, and 77% for chronic articular AOSD. 1

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Critical Pitfalls to Avoid

• Never rely solely on NSAIDs or glucocorticoids as long-term therapy, as 85-93% of patients will require more advanced treatment 1, 5
• Avoid maintenance prednisone 10-15 mg/day for arthritis, as eight patients developed severe joint destruction despite this treatment 1, 6
• Do not delay biologic therapy beyond 3 months of symptom onset, as early initiation prevents persistent chronic course 6
• Maintain high suspicion for MAS throughout disease course, as it can develop at any time, even during remission or on biologic therapy 1, 6
• Do not withhold IL-1/IL-6 inhibitors in patients with lung disease, as they are not contraindicated 1