What are the diagnostic criteria and treatment options for a patient suspected of having Still's disease, characterized by high fever, joint pain or swelling, and elevated inflammatory markers, such as elevated erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP)?

Diagnosis of Still's Disease

Still's disease diagnosis requires a combination of characteristic clinical features (high spiking fever, evanescent salmon-pink rash, arthritis/arthralgia, sore throat) with marked elevation of inflammatory markers and hyperferritinaemia, while systematically excluding malignancies, infections, and other immune-mediated diseases. 1

Clinical Diagnostic Features

The diagnosis is primarily clinical and based on recognizing the characteristic constellation of symptoms:

Major Clinical Features

• Fever pattern: Daily high spiking fevers (≥39°C), typically quotidian with return to baseline between spikes 1, 2
• Rash: Salmon-pink, evanescent, maculopapular rash that appears with fever spikes and disappears between episodes, occurring in 51-87% of patients 1, 2
• Arthritis/Arthralgia: Joint involvement ranging from arthralgias to frank arthritis, though arthritis is NOT mandatory for diagnosis 1
• Sore throat: Pharyngitis present in 35-92% of patients 2

Additional Systemic Features

• Hepatosplenomegaly: Splenomegaly in 14-65% (average 32%), hepatomegaly with liver dysfunction in 50-75% 1, 2
• Lymphadenopathy: Present in 32-74% of patients 2
• Serositis: Pericarditis (10-37%), pleuritis (12-53%) 2
• Myalgia: Occurs in 56-84% of patients 2

Essential Laboratory Investigations

Standard Laboratory Tests

• Complete blood count: Neutrophilic leukocytosis (often >15,000/μL) with elevated neutrophils 1
• Inflammatory markers: Markedly elevated ESR and CRP 1
• Serum ferritin: Extremely elevated levels (often 4,000-30,000 ng/mL, sometimes up to 250,000 ng/mL) with 80% sensitivity when ≥5× upper limit of normal 1
• Glycosylated ferritin fraction: <20% is highly specific (93% specificity when combined with 5× ferritin elevation), though it remains low for months after remission and cannot monitor disease activity 1
• Liver function tests: Elevated transaminases, alkaline phosphatase in 50-75% 1
• Autoantibodies: Negative rheumatoid factor and antinuclear antibodies 1

Advanced Biomarkers (When Available)

• Serum IL-18: Marked elevation strongly supports diagnosis with high sensitivity and specificity, though validated cut-off values are not yet established 1
• S100 proteins (calprotectin, S100A8/A9, S100A12): Highly elevated levels identify Still's disease with high sensitivity and specificity, though consensual thresholds need validation 1

These biomarkers should be measured if available, as marked elevation strongly supports the diagnosis. 1

Critical Differential Diagnoses to Exclude

Alternative diagnoses must be carefully considered before initiating immunosuppressive therapy, as glucocorticoids or immunomodulating agents can be deleterious if Still's disease is misdiagnosed, particularly with underlying malignancies. 1

Priority Exclusions

• Malignancies: Lymphomas, leukemias, solid tumors 1
• Infections: Bacterial endocarditis, tuberculosis, viral infections (EBV, CMV, parvovirus B19), disseminated fungal infections 1
• Other immune-mediated diseases: Systemic lupus erythematosus, vasculitis, reactive arthritis 1
• Monogenic autoinflammatory disorders: Familial Mediterranean fever, TNF receptor-associated periodic syndrome, cryopyrin-associated periodic syndromes 1
• In adults specifically: VEXAS syndrome and clonal hematopoiesis of indeterminate potential (CHIP) 1

Diagnostic Algorithm

Step 1: Recognize Clinical Pattern

Identify the characteristic triad: high spiking fever + evanescent rash + arthritis/arthralgia with sore throat 1

Step 2: Confirm Laboratory Abnormalities

Document neutrophilic leukocytosis, markedly elevated ESR/CRP, hyperferritinaemia (≥5× normal), and negative RF/ANA 1

Step 3: Measure Advanced Biomarkers

Obtain IL-18 and S100 proteins (calprotectin) if available—marked elevation strongly supports diagnosis 1

Step 4: Systematically Exclude Mimics

Perform targeted investigations based on clinical suspicion: blood cultures, imaging for malignancy, infectious disease serologies, bone marrow biopsy if cytopenias present 1

Step 5: Apply Clinical Criteria

The Yamaguchi criteria remain widely used: requires ≥5 criteria including ≥2 major criteria (fever ≥39°C for ≥1 week, arthralgia ≥2 weeks, typical rash, leukocytosis ≥10,000/μL with ≥80% neutrophils) 1

Imaging Considerations

• Initial radiographs: Usually normal or show soft tissue swelling, joint effusion, periarticular demineralization 1
• Advanced imaging: MRI with gadolinium or bone scan may be more sensitive for early diagnosis 1
• Characteristic late findings: Intercarpal and carpometacarpal joint space narrowing (bilateral in 69%), pericapitate ankylosis (25%), distal interphalangeal, intertarsal, and cervical zygapophyseal ankylosis 1

Common Diagnostic Pitfalls

The median duration of fever before diagnosis is 6 weeks, as Still's disease typically presents as fever of unknown origin requiring extensive workup. 3

• Premature diagnosis: Initiating immunosuppression before adequately excluding infections and malignancies can be catastrophic 1
• Over-reliance on ferritin alone: While highly elevated ferritin is suggestive, it has only 41% specificity when used alone 1
• Missing MAS: Inappropriate cytopenias, rising ferritin, elevated liver enzymes, and triglycerides signal macrophage activation syndrome—a life-threatening complication requiring immediate recognition 4, 5
• Ignoring pulmonary involvement: Active surveillance for lung disease with clinical assessment, pulse oximetry, and DLCO is essential, as pulmonary complications significantly impact mortality 4, 5

Disease Course Patterns

Still's disease follows three distinct patterns, each affecting approximately one-third of patients:

• Self-limited/monocyclic: Systemic symptoms with remission within 1 year (median 9 months) 5, 2
• Intermittent/polycyclic: Recurrent flares with complete remission between episodes 5, 2
• Chronic articular: Dominated by joint manifestations that can lead to severe joint destruction and worse prognosis 5, 2

Definition of Remission

Clinically inactive disease (CID) is defined as absence of Still's disease-related symptoms with normal ESR or CRP; remission requires maintaining CID for at least 6 months. 1