What is Adult-Onset Still's Disease?

What is Adult-Onset Still's Disease?

Adult-Onset Still's Disease (AOSD) is a rare systemic autoinflammatory disorder characterized by the classic triad of high spiking fevers (>39°C), evanescent salmon-pink rash, and arthralgia/arthritis, representing the same disease continuum as systemic juvenile idiopathic arthritis but occurring in adults. 1, 2

Epidemiology and Demographics

• AOSD affects approximately 0.16 per 100,000 people, making it a rare condition 1, 3
• Women are affected slightly more often than men (approximately 60% female) 1, 3
• Three-quarters of patients develop disease between ages 16-35 years, with a bimodal age distribution showing peaks at 15-25 years and 36-46 years 1, 3
• The disease represents a continuum with systemic juvenile idiopathic arthritis (sJIA), sharing similar clinical features, cytokine patterns (IL-6, IL-18, TNF-α), and pathogenic mechanisms 4, 5

Cardinal Clinical Features

The diagnosis relies on recognizing four cardinal features, and critically, arthritis is NOT required for diagnosis: 1

Fever Pattern

• Temperature ≥39°C (102.2°F) with characteristic spiking pattern (quotidian or double-quotidian) lasting at least 7 days 1
• Fevers are transient, typically lasting under 4 hours, with highest temperatures in late afternoon or early evening 2
• Fever heralds the onset of other manifestations including serositis, sore throat, myalgias, and arthralgias, occurring in 95.7% of patients 2

Rash Characteristics

• Evanescent salmon-pink (erythematous) maculopapular eruption that is transient and often coincides with fever spikes 1, 2
• Predominantly affects proximal limbs and trunk, with rare involvement of face and distal limbs 2

Joint Involvement

• Arthralgia or myalgia is usually present and sufficient for diagnosis 1
• Overt arthritis is supportive but NOT necessary for diagnosis and typically appears later (median delay of 1 month after disease onset, range 0 to several months) 1
• When arthritis develops, the most frequently affected joints are knees (69-82%), wrists (67-73%), and ankles (38-55%) 2
• A distinctive pattern of intercarpal and carpometacarpal joint space narrowing can occur (bilateral in 69%), leading to pericapitate ankylosis in 25% of cases 4

Additional Systemic Manifestations

• Sore throat occurs in 35-92% of patients 2
• Myalgia has an incidence of 56-84%, appearing generalized with fever exacerbations 2
• Lymphadenopathy is seen in 32-74% of patients, and splenomegaly in 14-65% 2
• Pleuritis affects 12-53% of patients, and pericarditis affects 10-37% 2
• Hepatomegaly and liver biochemistry abnormalities are present in approximately 50-75% of patients 2

Laboratory Abnormalities

• ESR is elevated in virtually all patients, and CRP is typically raised 2
• Leucocytosis with striking neutrophilia is seen in 50% of patients, with counts >15×10⁹ cells/L, and 37% have WBC >20×10⁹ 2
• Very high ferritin levels, ranging from 4,000-30,000 ng/mL, are common, with extreme levels up to 250,000 ng/mL reported, and serum ferritin correlates with disease activity 2
• Marked elevation of serum IL-18 and/or S100 proteins (calprotectin) strongly supports diagnosis 1
• Rheumatoid factor and antinuclear antibodies are usually absent 6

Disease Patterns and Prognosis

AOSD follows three distinct clinical patterns, each affecting approximately one-third of patients: 2

• Self-limited/monocyclic pattern: Single episode with resolution
• Intermittent/polycyclic pattern: Recurrent flares with periods of remission
• Chronic articular pattern: Persistent joint involvement, often with joint erosions and potential for severe hip involvement requiring total hip replacement 4

Diagnostic Approach

• AOSD is a diagnosis of exclusion requiring elimination of infectious, neoplastic, and other autoimmune diseases 2, 3
• The disease is responsible for a significant proportion of fever of unknown origin cases 2, 3
• The Yamaguchi criteria are most widely used and validated in both children and adults with high sensitivity, and notably, arthritis is not mandatory in these criteria 1, 5

Differential Diagnoses to Exclude

The spectrum of differential diagnoses is wide and includes: 4

• Infectious: Viral syndromes (rubella, cytomegalovirus, Epstein-Barr virus, mumps, Coxsackievirus, adenovirus) can be excluded if symptoms persist beyond 3 months 4
• Neoplastic: Leukemia, lymphoma, and angioblastic lymphadenopathy 4
• Autoimmune: Reactive arthritis, spondyloarthropathies, dermatomyositis, vasculitides 4
• Other inflammatory: Haemophagocytic syndrome, Kikuchi's syndrome, Sweet's syndrome, granulomatous disorders 4
• Periodic fever syndromes: Familial Mediterranean fever and TNF receptor associated periodic syndrome (TRAPS) 4

Life-Threatening Complications

Macrophage activation syndrome (MAS) is the most severe and life-threatening complication, occurring in up to 23% of patients and requiring immediate recognition and treatment. 1, 5

• MAS can occur at disease onset, during treatment, or even when disease is in remission, especially in the context of infection 1
• Physicians managing Still's disease must always maintain high vigilance for MAS, monitor with adequate laboratory workups, and be prepared to rapidly adjust treatment 1

Pathogenesis

• The pathogenesis involves central macrophage activation resulting in T helper 1 (Th1) cell cytokine activation 7
• Pro-inflammatory cytokines such as IL-1, IL-6, IL-18, interferon-gamma, and TNF-α are elevated and play a fundamental role in disease onset and progression 6, 7, 8
• AOSD is at the crossroad of auto-inflammatory syndromes and autoimmune diseases 9

Treatment Goals

• The ultimate goal of AOSD management is drug-free remission, which is realistic for a substantial proportion of patients with modern biologic therapies 1
• Treatment follows a treat-to-target approach with regular disease activity assessment 1
• Primary target is clinically inactive disease (CID) off glucocorticoids, defined as absence of Still's disease-related symptoms and normal ESR or CRP 1
• Early initiation of biologic therapy improves outcomes through a "window of opportunity" effect 3, 7