What are the symptoms and treatment options for Adult-Onset Still's Disease (AOSD)?

Adult-Onset Still's Disease: Clinical Manifestations

Adult-Onset Still's Disease (AOSD) presents with a classic triad of high spiking fevers (>39°C), evanescent salmon-pink rash, and arthritis/arthralgias, occurring in over 95% of patients. 1

Cardinal Symptoms

Fever Pattern

• High spiking fevers exceeding 39°C (102.2°F) occurring daily for at least 7 days 1
• Quotidian or double-quotidian pattern with peak temperatures in late afternoon or early evening 1
• Transient duration, typically lasting under 4 hours per spike 1
• Fever heralds onset of other manifestations including serositis, sore throat, myalgias, and arthralgias 1
• Present in 95.7% of patients across major retrospective studies 1

Characteristic Rash

• Evanescent, salmon-pink, maculopapular eruption predominantly on proximal limbs and trunk 1
• Rare involvement of face and distal limbs 1
• Often accompanies fever spikes and may be mildly pruritic, frequently confused with drug allergy 1
• Koebner phenomenon can be demonstrated 1
• Present in 51-87% of patients (average 72.7%) 1

Musculoskeletal Manifestations

• Arthralgia and arthritis occur in 64-100% of patients 1
• Most frequently affected joints: knees, wrists, and ankles 1
• Symmetric polyarthritis pattern with joint pain associated with fever spikes 1
• Distinctive carpal and pericapitate abnormalities that differentiate AOSD from rheumatoid arthritis 1
• Wrist changes typically appear 6 months after disease onset, with progressive joint space narrowing in pericapitate or carpometacarpal distribution 1
• Ankylosis develops after 1.5-3 years in chronic cases 1

Additional Clinical Features

Systemic Manifestations

• Sore throat: 35-92% of patients 1
• Myalgias: 56-84% of patients 1
• Lymphadenopathy: 32-74% of patients 1
• Splenomegaly: 14-65% of patients 1
• Hepatomegaly with abnormal liver function tests 1, 2

Serositis

• Pleuritis: 12-53% of patients 1
• Pericarditis: 10-37% of patients 1

Laboratory Findings

Hematologic Abnormalities

• Striking neutrophilic leukocytosis with 50% of patients having WBC >15×10⁹/L and 37% having WBC >20×10⁹/L 1
• Elevated ESR in virtually all patients 1
• Elevated CRP reflecting active inflammation 1
• Anemia of chronic disease during active disease 1
• Reactive thrombocytosis is common 1

Specific Biomarkers

• Extremely elevated serum ferritin levels with collapsed glycosylated ferritin (<20%) 3
• Marked elevation of serum IL-18 and/or S100 proteins (calprotectin) strongly supports diagnosis 1
• Rheumatoid factor and antinuclear antibodies typically absent 1, 4

Disease Patterns and Prognosis

AOSD follows three distinct clinical patterns, each affecting approximately one-third of patients: 5, 3

• Self-limited/monocyclic pattern: Systemic symptoms with remission within 1 year (median 9 months) 5
• Intermittent/polycyclic pattern: Recurrent flares with complete remission between episodes 5
• Chronic articular pattern: Dominated by joint manifestations that can lead to severe joint destruction and worse prognosis 5, 3

Critical Diagnostic Considerations

AOSD is a diagnosis of exclusion requiring elimination of infectious, neoplastic, and other autoimmune diseases. 1, 2

Key Differential Diagnoses to Exclude

• Viral syndromes (rubella, CMV, EBV, mumps, Coxsackievirus, adenovirus) if symptoms persist beyond 3 months 1
• Neoplastic disorders including leukemia, lymphoma, and angioblastic lymphadenopathy 1
• Periodic fever syndromes including familial Mediterranean fever and TRAPS 1
• Other autoimmune conditions including reactive arthritis, spondyloarthropathies, dermatomyositis, and vasculitides 1
• Hemophagocytic syndrome, Kikuchi's syndrome, Sweet's syndrome 1

Life-Threatening Complications

Macrophage activation syndrome (MAS) occurs in up to 23% of AOSD patients and represents the most severe complication with high mortality. 1, 6

• MAS should be detected promptly and treated rapidly with high-dose glucocorticoids and high-dose anakinra 1, 5
• Other life-threatening complications include fulminant hepatitis, myocarditis, and disseminated intravascular coagulation 1
• Severe lung disease is an emerging concern requiring screening for clubbing, persistent cough, and shortness of breath 5

Common Pitfalls

• Confusing the evanescent rash with drug allergy, leading to unnecessary medication changes 1
• Failing to recognize the quotidian fever pattern, which is highly characteristic 1
• Overlooking wrist involvement, which provides key diagnostic differentiation from rheumatoid arthritis 1
• Delaying diagnosis while pursuing extensive infectious or malignancy workup beyond what is clinically indicated 1

Treatment Approach

IL-1 inhibitors (anakinra) or IL-6 receptor inhibitors (tocilizumab) should be initiated as first-line treatment as early as possible when diagnosis is established, as they demonstrate the highest level of evidence for efficacy and safety. 1, 5, 2

Treatment Targets

The ultimate goal is drug-free remission, defined as clinically inactive disease (CID) maintained for at least 6 months. 1, 5

Intermediate Treatment Targets

• Day 7: Resolution of fever and reduction of CRP by >50% 1
• Week 4: No fever, reduction of active joint count by >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

First-Line Biologic Therapy

Early initiation of biologic therapy improves outcomes through a "window of opportunity" effect. 5, 2

• Anakinra is preferred for patients with impending MAS 5
• Tocilizumab at 8 mg/kg every 4 weeks is effective, with some patients requiring every 2-week dosing for symptom control 7
• Short-duration glucocorticoids should be used in combination with biologics, not as monotherapy 1

Traditional Therapies (Limited Role)

• NSAIDs are effective as monotherapy in only 7-15% of patients and should not be relied upon for long-term management 5
• Glucocorticoids alone have 76-95% response rates but most patients require long-term maintenance with significant side effects 5
• Methotrexate as a steroid-sparing agent has modest efficacy (approximately 40% overall response) 5

Refractory Disease Management

• Rotating between IL-1 and IL-6 inhibitors may be considered if no response to initial biologic 5
• Consulting specialized centers is recommended for difficult-to-treat cases 1, 5
• JAK inhibitors and IFN-γ inhibitors may be considered as experimental therapies 5

MAS Treatment Protocol

High-dose glucocorticoids and high-dose anakinra (>4 mg/kg/day in children or 100 mg twice daily in adults) are first-line for MAS. 5

• Cyclosporine A and/or IFN-γ inhibitors may be added for refractory MAS 5
• Prompt recognition and rapid treatment are essential given high mortality 1