What is Still's disease?

What is Still's Disease?

Still's disease is a rare systemic autoinflammatory disorder that encompasses both systemic juvenile idiopathic arthritis (sJIA) in children and adult-onset Still's disease (AOSD) in adults, representing a continuum of the same disease entity characterized by high spiking fevers, evanescent rash, arthralgia/arthritis, and marked systemic inflammation. 1, 2

Disease Definition and Classification

Still's disease should be understood as a unified disease spectrum affecting both children and adults, with the age of onset being the primary distinguishing factor. 1, 3

• The disease affects approximately 0.16 per 100,000 inhabitants, with women affected slightly more often than men (approximately 60% female). 1, 2
• Three-quarters of patients develop disease onset between ages 16-35 years, with a bimodal age distribution showing peaks at 15-25 years and 36-46 years. 1, 2
• The disease is considered a complex multigenic autoinflammatory syndrome where genetic susceptibility combined with environmental triggers leads to pathologic inflammation. 4

Core Clinical Features for Rapid Recognition

The diagnosis of Still's disease relies on recognizing four cardinal features, and critically, arthritis is NOT required for diagnosis. 1

1. Fever Pattern

• Temperature ≥39°C (102.2°F) with characteristic spiking pattern (quotidian or double-quotidian) for at least 7 days. 1
• Fever spikes are typically daily and predictable in timing. 3

2. Skin Manifestations

• Evanescent salmon-pink (erythematous) rash that is transient and often coincides with fever spikes. 1
• Rash preferentially involves the trunk and may be challenging to identify on darker skin. 1
• Other rash patterns (urticarial) may be consistent with diagnosis. 1

3. Musculoskeletal 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
• Requiring arthritis for diagnosis leads to unnecessary and potentially dangerous diagnostic delays. 1

4. Laboratory Markers of Inflammation

• Neutrophilic leukocytosis with high neutrophil count. 1
• Elevated ESR, CRP, and markedly elevated serum ferritin (often extremely high). 1, 5
• Additional markers include increased platelet count, fibrinogen, and D-dimers. 1

Pathophysiology

Still's disease is driven by macrophage and neutrophil activation with key roles for IL-1β, IL-18, and IL-6 in disease pathogenesis. 6, 4, 7

• IL-18 and IL-1β are processed through inflammasome machinery and drive downstream inflammation. 1, 4
• These cytokines cause IL-6 and Th1 cytokine secretion, leading to the systemic inflammatory cascade. 4, 7
• Natural killer cell cytotoxic function is decreased in active disease. 4
• Alarmins such as S100 proteins (calprotectin, S100 A12) amplify inflammation as danger-associated molecular patterns. 1

Diagnostic Approach

Still's disease is a diagnosis of exclusion requiring elimination of infectious, neoplastic, and other autoimmune diseases. 1, 2, 3

Classification Criteria

• The Yamaguchi criteria are most widely used and validated in both children and adults with high sensitivity. 1, 3
• Notably, arthritis is not mandatory in Yamaguchi criteria, aligning with current understanding. 1

Supportive Biomarkers

• Marked elevation of serum IL-18 and/or S100 proteins (calprotectin) strongly supports diagnosis and should be measured if available. 1
• These biomarkers identify Still's disease with high sensitivity and specificity, though validated thresholds are lacking. 1
• Hyperferritinemia with collapsed glycosylated ferritin (<20%) is characteristic. 4

Common Pitfall

• Do not delay diagnosis waiting for arthritis to develop—arthralgia alone with other features is sufficient. 1
• Still's disease is responsible for a significant proportion of fever of unknown origin cases. 1, 2

Disease Patterns and Prognosis

Still's disease follows three distinct clinical patterns, each affecting approximately one-third of patients. 8, 4

1. Self-limited/monocyclic pattern: Systemic symptoms with remission within 1 year (median 9 months). 8
2. Intermittent/polycyclic pattern: Recurrent flares with complete remission between episodes. 8
3. Chronic articular pattern: Dominated by joint manifestations that can lead to severe joint destruction and generally has worse prognosis. 8, 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, 3

• MAS can occur at disease onset, during treatment, or even when disease is in remission, especially in the context of infection. 1
• MAS is more frequent in children under age 2 but can occur at any age. 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
• Candidate biomarkers for MAS include CXCL-9, IL-18, ADA2 activity, and soluble IL-2 receptor. 1

Treatment Goals

The ultimate goal of Still's disease management is drug-free remission, which is realistic for a substantial proportion of patients with modern biologic therapies. 1, 2

• Treatment follows a treat-to-target approach with regular disease activity assessment. 1, 2, 8
• Primary target is clinically inactive disease (CID) off glucocorticoids, defined as absence of Still's disease-related symptoms and normal ESR or CRP. 1, 8
• Remission is defined as at least 6 months with CID. 1