What is the management of Still's disease, including signs, symptoms, evaluation, and complications?

Still's Disease: Clinical Presentation, Diagnosis, Management, and Complications

Signs and Symptoms

Still's disease presents with four cardinal features that enable rapid recognition: high spiking fever ≥39°C (102.2°F) for at least 7 days, transient salmon-pink rash coinciding with fever spikes, arthralgia or myalgia (arthritis is NOT required for diagnosis), and marked systemic inflammation with neutrophilic leukocytosis, elevated CRP, and markedly elevated ferritin. 1, 2

Core Clinical Manifestations

• Fever: Present in 95-100% of patients with characteristic quotidian or double-quotidian spiking pattern 1, 3
• Rash: Evanescent, salmon-pink (erythematous), transient, appears in 51-87% of patients, preferentially involving trunk 1, 3
• Musculoskeletal: Arthralgia/myalgia in 56-84% of patients is sufficient for diagnosis; overt arthritis appears later (median 1 month delay) and is NOT mandatory 1, 2
• Sore throat/pharyngitis: Common in 35-92% of patients 1, 3
• Lymphadenopathy: Present in 32-74% of patients 1, 3
• Splenomegaly: Occurs in 14-65% of patients (average 32%) 1, 3
• Hepatomegaly and liver dysfunction: Present in 50-75% of patients 1
• Serositis: Pericarditis in 10-37%, pleuritis in 12-53% 1, 3

Joint Involvement Patterns (When Present)

• Most commonly affected: Knees (82%), wrists (73%), ankles (55%), PIPs (47%), elbows (44%) 1
• Pattern: Typically symmetric polyarthritis associated with fever spikes 1
• Chronic articular pattern: Can lead to severe joint destruction; 67% may require joint replacement after median 28 months 1

Evaluation and Diagnosis

Use the Yamaguchi criteria for diagnosis, which requires 5 criteria with at least 2 major: Major criteria include fever ≥39°C for ≥1 week, arthralgia ≥2 weeks, typical rash, and WBC ≥10,000 with ≥80% granulocytes; Minor criteria include sore throat, lymphadenopathy/splenomegaly, liver dysfunction, and negative RF and ANA. 1, 2

Laboratory Findings

• Inflammatory markers: Neutrophilic leukocytosis (50% have WBC >15×10⁹/L, 37% have >20×10⁹/L), elevated ESR and CRP 1
• Ferritin: Very high levels (4,000-30,000 ng/mL, occasionally up to 250,000 ng/mL); fivefold increase has 80% sensitivity but only 41% specificity 1
• Glycosylated ferritin: More specific diagnostic marker when <20% 1
• IL-18 and/or S100 proteins (calprotectin): Marked elevation strongly supports diagnosis and should be measured if available 1, 2
• Serology: Negative RF and ANA are characteristic 1
• Anemia: Normocytic normochromic anemia of chronic disease 1, 4
• Thrombocytosis: Common reactive finding 1

Exclusion of Mimics

Critical pitfall: Must exclude infections, malignancies (especially lymphoma and leukemia), and other rheumatic/autoinflammatory diseases before diagnosing Still's disease. 1

Management

Initiate IL-1 inhibitors (anakinra) or IL-6 receptor inhibitors (tocilizumab) as early as possible when diagnosis is established, as these biologics show the highest level of evidence for efficacy and represent first-line therapy according to the most recent 2024 EULAR/PRES guidelines. 1, 5

Treatment Algorithm for Active Disease

High Disease Activity (fever, widespread polyarthritis, high pain, pericarditis, impending MAS)

• Start: High-dose glucocorticoids (≥1 mg/kg/day prednisone equivalent in adults, ≥2 mg/kg/day in children) IV then oral PLUS IL-1 inhibitor or IL-6 receptor inhibitor 1
• Anakinra preferred if impending MAS (use high-dose: >4 mg/kg/day in children or 100 mg twice daily in adults) 1, 5
• Begin GC tapering as soon as first intermediate target reached (no fever and 50% decrease in active joints) 1

Low or Moderate Disease Activity

• Start: IL-1 inhibitor or IL-6 receptor inhibitor with low-dose glucocorticoids (≤0.1 mg/kg/day prednisone equivalent in adults, ≤0.2 mg/kg/day in children) 1

Treatment Targets and Timeline (Treat-to-Target Approach)

The ultimate goal is drug-free remission, achievable in a substantial proportion of patients with modern biologic therapy. 1, 2

• Day 7: Resolution of fever and CRP reduction >50% 1
• Week 4: No fever, active joint count reduction >50%, normal CRP, physician and patient global assessment <20/100 1
• Month 3: Clinically inactive disease (CID) with glucocorticoids <0.1-0.2 mg/kg/day 1
• Month 6: CID without glucocorticoids 1
• Remission: CID maintained for ≥6 months 1
• Before biologic tapering: Maintain CID for 3-6 months without glucocorticoids 1, 5

Refractory Disease Management

• If no response to initial biologic: Rotate between IL-1 and IL-6 inhibitors 1
• Difficult-to-treat cases: Consult Still's disease expert centers 1, 5
• Experimental therapies: JAK inhibitors, IFN-γ inhibitors (emapalumab), bispecific antibodies to IL-1/IL-18 1, 5

Traditional Therapies (Now Second-Line)

Critical pitfall: NSAIDs are effective as monotherapy in only 7-15% of patients and should not be relied upon as long-term therapy. 1, 5

• NSAIDs: Indomethacin and naproxen preferred over salicylates; 88% require prednisone addition 1
• Glucocorticoids alone: 76-95% response rates but most require long-term maintenance with significant side effects 5
• Methotrexate: Used as steroid-sparing agent with modest efficacy (~40% response) 5

Complications

Macrophage Activation Syndrome (MAS)

MAS is the most severe and life-threatening complication, occurring in up to 23% of patients, and requires immediate recognition and aggressive treatment with high-dose glucocorticoids plus anakinra, ciclosporin, and/or IFN-γ inhibitors. 1, 2

Recognition of MAS

• Clinical features: Persistent fever, splenomegaly 1
• Laboratory findings: Elevated or rising serum ferritin, inappropriately low cell counts (pancytopenia), abnormal LFTs, intravascular coagulation activation, elevated or rising triglycerides 1
• Timing: Can occur at disease onset, during treatment, or even during remission (especially with infection) 1, 2

MAS Treatment

• Mandatory: High-dose glucocorticoids 1
• Add: Anakinra (high-dose preferred), ciclosporin, and/or IFN-γ inhibitors as part of initial therapy 1, 5

Lung Disease

Actively screen for lung disease with clinical symptoms (clubbing, persistent cough, shortness of breath) and pulmonary function tests (pulse oximetry, DLCO measurement); investigate with high-resolution CT if symptoms present. 1, 5

• Important: IL-1 or IL-6 inhibitors are NOT contraindicated in patients with lung disease 1, 5

Other Serious Complications

• Cardiac: Pericarditis, tamponade 1, 3
• Hematologic: Disseminated intravascular coagulation (rare but life-threatening) 1, 4
• Hepatic: Hepatic failure (exceedingly rare) 1
• Renal: Amyloidosis 1
• Respiratory: Respiratory failure 1

Disease Patterns and Prognosis

Three clinical patterns each affect approximately one-third of patients: self-limited/monocyclic (remission within 1 year, median 9 months), intermittent/polycyclic (recurrent flares with complete remission between episodes), and chronic articular (dominated by joint manifestations with potential severe destruction). 1, 5, 3

Prognostic Factors

• Poor prognosis predictors: Rash, polyarthritis, and root joint (shoulder, hip) involvement at disease onset predict chronic articular pattern 1
• Chronic articular disease: More disability and worse prognosis than systemic-only disease; 67% may require joint replacement 1
• Systemic disease: Generally favorable prognosis with rare serious complications 1, 3

Critical Pitfalls to Avoid

• Never rely on NSAIDs or glucocorticoids alone as long-term therapy—most patients require biologic therapy 1, 5
• Always maintain high vigilance for MAS with regular laboratory monitoring, as it can occur at any time including during remission 1, 2
• Do not delay biologic therapy—early initiation improves outcomes (window of opportunity) 5
• Do not assume arthritis is required for diagnosis—arthralgia alone is sufficient 1, 2
• Do not withhold IL-1 or IL-6 inhibitors in patients with lung disease—they are not contraindicated 1, 5