Background

Anti-melanoma differentiation-associated gene 5 (MDA5) dermatomyositis carries a devastating complication: rapidly progressive interstitial lung disease (RP-ILD), with mortality rates exceeding 50% when treatment is delayed. Current biomarkers—KL-6, ferritin, and IL-18—rise relatively late in the pathogenic cascade, often leaving clinicians reacting to established disease rather than intercepting early fibroinflammatory injury. The TAM receptor tyrosine kinase family member Axl and its ligand Gas6 constitute a critical regulatory axis governing macrophage efferocytosis (clearance of apoptotic cells) and resolution of inflammation. Defective Gas6/Axl signaling results in persistent apoptotic debris, DAMP release, and amplification of type I interferon responses—a pathogenic loop central to MDA5-positive DM.

Hypothesis

We hypothesize that serial measurement of serum soluble Axl (sAxl) receptor concentration combined with a functional Gas6-dependent efferocytosis capacity index (ECI) in peripheral blood monocytes identifies a pre-fibrotic inflammatory phase in anti-MDA5 dermatomyositis 4–12 weeks before KL-6 elevation or HRCT progression. Specifically:

1. Rising sAxl concentrations (reflecting increased membrane Axl shedding by ADAM10/ADAM17 proteases under interferon stimulation) indicate escalating alveolar epithelial injury and macrophage activation.
2. Declining ECI (measured via ex vivo pHrodo-labeled apoptotic cell uptake assay in autologous monocytes, normalized to Gas6 concentration) reflects functional impairment of the resolution machinery.
3. The sAxl/ECI ratio trajectory slope over 3 serial measurements (biweekly) will discriminate progressors from non-progressors with >85% sensitivity and >75% specificity at a lead time of 4–12 weeks before conventional biomarker alarm.

Testable Predictions

• In a prospective cohort of ≥60 anti-MDA5-positive DM patients followed biweekly, the sAxl/ECI ratio trajectory slope will show statistically significant separation (p<0.01, log-rank) between patients who develop RP-ILD within 6 months versus those maintaining stable pulmonary function.
• Receiver operating characteristic analysis at the 8-week pre-KL-6-elevation timepoint will yield AUC >0.85 for the composite sAxl/ECI ratio versus AUC <0.70 for sAxl or ECI alone.
• Addition of sAxl/ECI ratio to a baseline model incorporating ferritin + KL-6 + anti-MDA5 titer will improve net reclassification index (NRI) by >0.15.
• Ex vivo monocyte transcriptomic profiling from the high sAxl/low ECI subgroup will be enriched for interferon-stimulated genes, NF-κB targets, and suppressed MerTK/Axl-dependent phagocytic gene modules.

Limitations

• The efferocytosis capacity assay requires fresh monocyte isolation and ex vivo functional testing, limiting scalability to specialized centers and introducing pre-analytical variability.
• sAxl can be elevated in other conditions (hepatic fibrosis, sepsis, malignancy), necessitating disease-specific cutoff calibration.
• Anti-MDA5 DM is rare, and accruing ≥60 patients prospectively requires multi-center collaboration, likely across Asia-Pacific and Latin American cohorts where prevalence is higher.
• Biweekly serial sampling may introduce patient burden and dropout bias.
• The functional ECI assay lacks standardization; inter-laboratory coefficient of variation must be established before multicenter deployment.

Clinical Significance

If validated, the sAxl/ECI ratio would provide the first mechanistically grounded early-warning biomarker for RP-ILD in anti-MDA5 DM, enabling pre-emptive escalation to combination immunosuppression (e.g., tofacitinib + rituximab + plasma exchange) during the window when fibroinflammatory injury is still reversible. This could transform a disease with >50% mortality into one with a manageable therapeutic trajectory, directly reducing ICU admissions and ventilator dependence. The assay could also identify a subset of patients safe for de-escalation, reducing unnecessary toxicity.

LES AI • DeSci Rheumatology