What are the clinical features, diagnostic workup, and management of adult‑onset Still’s disease?

Adult-Onset Still's Disease: Clinical Features, Diagnosis, and Management

Clinical Features

Adult-onset Still's disease (AOSD) presents with a classic triad of high-spiking fevers exceeding 39°C, an evanescent salmon-pink rash, and arthritis/arthralgia, occurring in over 95% of patients for fever and 64-100% for joint involvement. 1, 2, 3

Cardinal Manifestations

Fever Pattern:

• High-spiking fevers exceeding 39°C occur in 95.7% of patients, are transient (lasting typically under 4 hours), and follow a quotidian or double quotidian pattern with highest temperatures in late afternoon or early evening 2, 3
• Fever heralds the onset of other manifestations including serositis, sore throat, myalgias, and arthralgias 3

Characteristic Rash:

• The evanescent, salmon-pink, maculopapular eruption occurs in 51-87% of patients, predominantly affecting proximal limbs and trunk, with rare involvement of face and distal limbs 2, 3
• The rash is often accompanied by fever and can be mildly pruritic 2
• Critical pitfall: Do not dismiss this rash as a drug allergy, as it is pathognomonic and often accompanies fever 2

Musculoskeletal Involvement:

• Arthralgia and arthritis occur in 64-100% of patients, most frequently affecting knees (69-82%), wrists (67-73%), and ankles (38-55%) 2, 3
• Arthritis is not mandatory for diagnosis and may appear later, with a median delay of 1 month after disease onset 2
• Critical pitfall: Do not overlook wrist involvement, as carpal and pericapitate abnormalities distinguish AOSD from rheumatoid arthritis 2

Additional Systemic Features

• Sore throat occurs in 35-92% of patients, while myalgia has an incidence of 56-84% 3
• Lymphadenopathy is seen in 32-74% of patients, and splenomegaly in 14-65% 3
• Pleuritis affects 12-53% of patients, and pericarditis affects 10-37% 3
• Hepatomegaly and liver biochemistry abnormalities are present in approximately 50-75% of patients 3
• Critical pitfall: Do not attribute liver dysfunction solely to NSAIDs, as hepatomegaly and abnormal liver biochemistry are intrinsic disease features 2

Diagnostic Workup

AOSD is a diagnosis of exclusion requiring systematic elimination of infectious, neoplastic, and other autoimmune diseases, with documentation of the four cardinal features followed by application of validated diagnostic criteria. 1, 2

Laboratory Assessment

Essential Laboratory Tests:

• ESR is elevated in virtually all patients, and CRP is typically raised 2, 3
• Leucocytosis with striking neutrophilia is common, with 50% of patients having counts >15×10⁹ cells/L, and 37% having WBC >20×10⁹ 2, 3
• Anaemia of chronic disease is seen with active disease and normalizes with remission 2, 3
• Very high ferritin levels (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, 3
• Measurement of glycosylated ferritin fraction is crucial, as values <20% strongly support AOSD diagnosis and are included in the Fautrel criteria 2
• Rheumatoid factor and antinuclear antibodies are typically absent 3, 4
• Abnormal liver function tests (AST/ALT) are observed in 89% of patients 5

Novel Biomarkers:

• IL-18 levels are significantly higher in AOSD than in bacterial infections and correlate positively with ferritin, with a diagnostic accuracy of 97.67% when combined with ferritin 3
• S100 proteins (S100A8/A9 and A12) show diagnostic value in AOSD 3

Diagnostic Criteria

Yamaguchi Criteria (Most Widely Used):

• Requires 5 criteria with at least 2 major, including fever, arthralgia, typical rash, WBC >10,000, and negative ANA and RF 2

Fautrel Criteria (Incorporates Ferritin):

• Major criteria include spiking fever, arthralgia, transient erythema, pharyngitis, PMN >80%, and glycosylated ferritin <20% 2
• Minor criteria include maculopapular rash and leukocytes >10×10⁹/L 2

Systematic Exclusion Process

The European League Against Rheumatism recommends systematically excluding:

• Infectious diseases: viral syndromes (rubella, cytomegalovirus, Epstein-Barr virus, mumps, Coxsackievirus, adenovirus) can be excluded if symptoms persist beyond 3 months 6
• Neoplastic disorders: leukaemia, lymphoma, and angioblastic lymphadenopathy 6
• Other rheumatic diseases: systemic lupus erythematosus, rheumatoid arthritis, vasculitis, and other connective tissue diseases 2
• Periodic fever syndromes: familial Mediterranean fever and TNF receptor associated periodic syndrome (TRAPS) 6

Screening for Life-Threatening Complications

Macrophage Activation Syndrome (MAS):

• Critical pitfall: Do not miss pancytopenia, as it signals potentially fatal macrophage activation syndrome requiring urgent intervention 2
• MAS has been reported in up to 23% of AOSD patients and is considered the most severe complication with high mortality 7, 8
• Monitor for pancytopenia and measure fibrinogen, D-dimers, triglycerides, and ferritin (paradoxically may decrease in MAS) 2
• Consider measuring CXCL-9, soluble IL-2 receptor, and activated CD8 T cells if available 2

Other Serious Complications:

• Pericarditis, cardiac tamponade, disseminated intravascular coagulation, amyloidosis, hepatic disease, and respiratory failure 2

Disease Patterns and Prognosis

Three distinct clinical patterns exist, each affecting approximately one-third of patients: 2, 3

1. Self-limited/monocyclic pattern: Characterized by a systemic single episode with favorable prognosis 2, 8
2. Intermittent/polycyclic pattern: Characterized by multiple flares (≤1 year lasting) alternating with remissions 2, 8
3. Chronic articular pattern: Dominated by persistently active disease with associated polyarthritis that can lead to joint destruction 2, 8

Distinctive radiographic findings include intercarpal and carpometacarpal joint space narrowing (bilateral in 69%) that can lead to pericapitate ankylosis in 25% of cases. 6

Management

The American College of Rheumatology recommends IL-1 inhibitors (anakinra) or IL-6 receptor inhibitors (tocilizumab) as first-line treatment for AOSD, with the primary goal of achieving clinically inactive disease off glucocorticoids. 1

Treatment Algorithm

First-Line Therapy:

• IL-1 inhibitors (anakinra) or IL-6 receptor inhibitors (tocilizumab) are recommended as first-line treatment 1
• Canakinumab is the only FDA-approved biologic for the treatment of AOSD 7
• Early initiation of biologic therapy improves outcomes through a "window of opportunity" effect 1

Corticosteroids:

• High dosages of corticosteroids are usually the first line therapy when systemic symptoms predominate 8
• Despite corticosteroid treatment, a large percentage of patients experiences several flares with evolution toward chronic disease course 8

Conventional Synthetic DMARDs:

• Used in steroid-refractory patients, including methotrexate, gold, azathioprine, leflunomide, tacrolimus, ciclosporin, and cyclophosphamide 4

Biologics for Refractory Cases:

• Anti-TNFα, anti-IL-1, and anti-IL-6 agents have been successfully used in refractory cases 4, 8
• Intravenous immunoglobulin has also been used 4

Treatment Targets

• A treat-to-target approach with regular disease activity assessment is recommended 1
• The primary goal is achieving clinically inactive disease (CID) off glucocorticoids 1

Prognosis

• Up to 16% of patients die during follow-up due to AOSD-related complications 8
• Prognosis depends on the disease course and tends to be more favorable when systemic symptoms predominate 4

Epidemiology

• AOSD is a rare disease with an estimated incidence of 0.16 per 100,000 inhabitants 6, 1
• The disease affects women slightly more often than men (approximately 60% female) 6, 1
• Three-quarters of patients develop disease onset between ages 16-35 years, with a bimodal age distribution with peaks at 15-25 years and 36-46 years 6, 1, 2
• AOSD is responsible for a significant proportion of fever of unknown origin cases 1, 3