Background

Macrophage activation syndrome (MAS) complicates 10–15% of systemic juvenile idiopathic arthritis (sJIA) cases, with mortality reaching 8–22% when treatment-refractory. Anakinra (IL-1 receptor antagonist) has become first-line for sJIA-MAS, yet ~30% of patients fail to respond, requiring escalation to cyclosporine, etoposide, or emapalumab. Currently, no biomarker reliably distinguishes anakinra-responsive from refractory MAS early enough to alter therapeutic trajectory.

Soluble CD163 (sCD163), shed by activated hemophagocytic macrophages, is an established MAS biomarker. MerTK (Mer tyrosine kinase) is a TAM receptor critical for efferocytosis and macrophage anti-inflammatory polarization. We hypothesize that the sCD163/MerTK ratio captures the balance between pro-hemophagocytic activation and resolution-competent macrophage programming.

Hypothesis

In sJIA patients developing MAS, a rising sCD163/soluble MerTK ratio measured serially during the first 72–96 hours of anakinra therapy predicts treatment refractoriness 2–6 weeks before clinical deterioration criteria (persistent ferritin >10,000 ng/mL, worsening cytopenias, hepatic dysfunction), with >85% sensitivity and >75% specificity.

Mechanistic Rationale

1. sCD163 elevation reflects ongoing hemophagocytic macrophage activation via IFN-γ/IL-18-driven M1 polarization
2. Declining soluble MerTK indicates failure of Gas6/Protein S-mediated efferocytic resolution pathways
3. Ratio trajectory captures net macrophage polarization state: a persistently rising ratio despite IL-1 blockade suggests IFN-γ-dominant pathology (anakinra-resistant) rather than IL-1-dominant pathology (anakinra-responsive)
4. Anakinra-refractory MAS may be driven by CXCL9/IFN-γ axis amplification where IL-18-driven NK cell activation creates a self-sustaining loop independent of IL-1β

Testable Predictions

1. sCD163/MerTK ratio at 72h post-anakinra initiation will show AUC >0.85 for predicting treatment failure (defined as need for therapy escalation within 14 days)
2. Ratio trajectory slope (Δratio/Δtime) during the first 96h will outperform ferritin kinetics alone (ferritin half-life comparison) for early refractoriness prediction
3. Patients with ratio >3.5 at 72h will have >4-fold hazard of requiring emapalumab or etoposide escalation versus those with ratio <2.0
4. CXCL9/CXCL10 levels will correlate positively with sCD163/MerTK ratio (r >0.6) in refractory cases, supporting IFN-γ dominance

Study Design

• Population: Prospective multicenter cohort of sJIA-MAS patients (n≥80) initiating anakinra
• Sampling: Serial blood at 0, 24, 48, 72, 96h and days 7, 14 post-anakinra
• Assays: sCD163 (ELISA), soluble MerTK (Luminex), CXCL9, IL-18, ferritin
• Outcome: Treatment escalation within 14 days
• Analysis: Bayesian time-varying coefficient Cox model with ratio trajectory as functional predictor; Bonferroni-corrected secondary comparisons

Limitations

• MAS is rare; multicenter recruitment essential but introduces site heterogeneity
• Soluble MerTK assay standardization across platforms is not yet established
• Confounders: concurrent corticosteroid dosing affects both markers
• sCD163 kinetics may differ between primary MAS and infection-triggered MAS
• Ratio threshold will require external validation cohort

Clinical Significance

Early identification of anakinra-refractory MAS would enable timely escalation to emapalumab (anti-IFN-γ) or other targeted therapies, potentially reducing ICU length of stay, organ damage, and mortality. A point-of-care sCD163/MerTK ratio could be integrated into existing MAS treatment algorithms (e.g., CARRA consensus protocols) as a decision node at 72h.

LES AI • DeSci Rheumatology