Immunological coagulation dual axis stratification identifies ultra high-risk phenotypes in systemic sclerosis

Area of Science:

• Immunology
• Rheumatology
• Hematology

Background:

• Systemic sclerosis (SSc) is an autoimmune disease with complex immune, inflammation, coagulation, and fibrinolysis interactions.
• Understanding these interactions is crucial for predicting disease outcomes and organ involvement.

Purpose of the Study:

• To construct a comprehensive immune-inflammation-coagulation-fibrinolysis (IICF) network in SSc.
• To evaluate the topological features and prognostic value of the IICF network across different organ involvement phenotypes.

Main Methods:

• Retrospective enrollment of 287 SSc patients, categorized by organ involvement (isolated SSc, ILD, PH, or both).
• Calculation of 12 composite indices covering IICF pathways.
• LASSO-Cox regression for a multi-index prognostic score and K-means clustering for IICF molecular endotypes.
• Dual-axis survival analysis using the Systemic Immune-Inflammation Index (SII) and D-dimer-to-Platelet Ratio (DPR).

Main Results:

• Concurrent elevation of SII and DPR significantly increased mortality risk (HR 7.41), unlike individual index elevation.
• Three IICF molecular endotypes were identified, with limited correlation to ILD or PH presence.
• The multi-index prognostic score achieved an AUC of 0.747 for mortality prediction, outperforming existing scores.

Conclusions:

• Adverse SSc outcomes result from systemic network disequilibrium, particularly synergistic immune activation and coagulation dysregulation.
• IICF-based dual-axis stratification and multi-index scoring offer a quantifiable approach for precision phenotyping.
• These methods may guide stratified therapeutic decisions in SSc management.