What is the recommended treatment for a patient with systemic juvenile idiopathic arthritis (sJIA) and intestinal lung disease?

Treatment of Systemic Juvenile Idiopathic Arthritis with Interstitial Lung Disease

For patients with systemic JIA and interstitial lung disease (sJIA-LD), avoid or discontinue IL-1 and IL-6 inhibitors immediately, as these biologics are strongly associated with this life-threatening complication, and consider JAK inhibitors or novel agents targeting both IL-1β and IL-18 simultaneously. 1, 2, 3

Critical Recognition and Risk Factors

sJIA-associated lung disease (sJIA-LD) is a highly fatal complication with mortality rates between 37-68%, requiring urgent recognition and treatment modification. 3

Key risk factors that should raise immediate concern include:

• Younger age at onset (<2 years) 1, 3
• History of macrophage activation syndrome (MAS) 1, 3
• Previous adverse reactions to tocilizumab 1
• Trisomy 21 1
• Acute digital clubbing - this is a red flag sign demanding immediate evaluation 1

Clinical presentation shows striking dissociation between mild symptoms (tachypnoea, clubbing, chronic cough) and severe pulmonary inflammation on imaging. 3

Immediate Management Strategy

Discontinue Current Biologics

Stop IL-1 inhibitors (anakinra, canakinumab) and IL-6 inhibitors (tocilizumab) immediately if sJIA-LD is suspected or confirmed, as most affected children were treated with these agents. 1, 3

The prevailing hypotheses suggest either:

• "DRESS hypothesis" - drug reaction with eosinophilia and systemic symptoms 3
• "Cytokine plasticity hypothesis" - blocking IL-1/IL-6 may unmask other inflammatory pathways 3

Glucocorticoid Therapy

Systemic glucocorticoids are recommended as part of initial treatment for sJIA with lung disease, though specific dosing was not defined in guidelines. 1

Glucocorticoids should be used at the lowest effective dose for the shortest duration, with plans for tapering as other therapies take effect. 1

Advanced Therapeutic Options

JAK Inhibitors (Emerging First-Line)

JAK inhibitors represent a promising treatment option for sJIA-LD and should be strongly considered given the contraindication to IL-1/IL-6 blockade. 3

These agents bypass the problematic cytokine-specific blockade that may contribute to lung disease development. 3

Novel Bispecific Antibodies

MAS-825 (targeting both IL-1β and IL-18 simultaneously) showed marked improvement in a case report of refractory sJIA-LD, including:

• Reduction in total and free IL-18 in serum and bronchoalveolar lavage 2
• Improved oxygen saturation and exercise tolerance 2
• Complete steroid and biologic weaning after 10 months 2
• Reduced inflammatory infiltrates (CD4, CD8 T-cells, macrophages) 2

This represents a potential breakthrough for this otherwise treatment-refractory condition. 2

Calcineurin Inhibitors

Calcineurin inhibitors are conditionally recommended as one therapeutic option, particularly if MAS features are present alongside lung disease. 1

These can be used in combination with glucocorticoids. 1

Monitoring and Diagnostic Approach

High-resolution computed tomography (HRCT) remains the gold standard for diagnosis and monitoring of sJIA-LD. 3

Emerging diagnostic tools include:

• Lung ultrasound - promising for early detection 3
• Intercellular-adhesion-molecule-5 (ICAM-5) assay - potential biomarker 3
• Elevated IL-18 levels - strongly associated with sJIA-LD risk 3

Bronchoalveolar lavage may show pulmonary alveolar proteinosis, endogenous lipoid pneumonia, or inflammatory infiltrates. 2, 3

Agents to Avoid

The following are inappropriate or uncertain in sJIA-LD:

• TNF inhibitors - inappropriate for systemic features and may worsen outcomes 1
• Abatacept - inappropriate for MAS features 1
• IVIG - inappropriate unless calcineurin inhibitor plus anakinra have failed 1
• Rituximab - generally inappropriate 1
• Conventional synthetic DMARDs alone - ineffective for systemic features 1

Common Pitfalls

The most critical error is continuing IL-1 or IL-6 blockade after sJIA-LD develops, as this increases mortality risk substantially. 1, 3

Another pitfall is delaying recognition due to mild clinical symptoms - maintain high suspicion in any sJIA patient with tachypnoea, clubbing, or chronic cough, especially those with risk factors. 3

Failure to screen for lung disease in high-risk patients (young age, MAS history, trisomy 21) before or during biologic therapy represents a missed opportunity for early intervention. 1, 3