Background: Pulmonary veno-occlusive disease (PVOD) is a rare but lethal complication of systemic sclerosis (SSc) that mimics pulmonary arterial hypertension (PAH) clinically but responds catastrophically to vasodilator therapy. Current diagnosis requires invasive hemodynamics and HRCT findings that appear late. Serum soluble VEGFR-1 (sFlt-1) reflects endothelial dysfunction in pulmonary venous beds, while endocan (ESM-1) is a proteoglycan released selectively by activated pulmonary microvascular endothelium. Their ratio may capture the venous-predominant endotheliopathy of PVOD distinctly from PAH.

Hypothesis: In SSc patients with suspected pulmonary hypertension, serial measurement of serum sFlt-1/endocan ratio at 4-week intervals, combined with speckle-tracking echocardiography-derived right ventricular free wall longitudinal strain (RVFWLS), will discriminate PVOD from PAH with >85% AUROC and predict PVOD diagnosis 8–20 weeks before hemodynamic and radiographic confirmation.

Proposed mechanism: PVOD selectively injures pulmonary venular endothelium, causing disproportionate sFlt-1 release (anti-angiogenic, reflecting venular capillary dropout) relative to endocan (which predominates in arteriolar activation). This elevates the sFlt-1/endocan ratio in PVOD but not PAH. Concurrently, PVOD-specific postcapillary obstruction generates a distinct RV strain pattern (preserved septal strain with disproportionate free wall deterioration) detectable before mean pulmonary artery pressure reaches diagnostic thresholds.

Testable predictions: (1) SSc patients who develop PVOD will show sFlt-1/endocan ratio >3.5 (vs <2.0 in PAH) at least 8 weeks before diagnosis. (2) RVFWLS < −15% combined with sFlt-1/endocan >3.0 will have PPV >80% for PVOD. (3) Patients incorrectly started on vasodilators who had elevated ratios will show pulmonary edema within 2 weeks, validatable retrospectively.

Limitations: PVOD rarity (~10% of SSc-PH) requires multicenter collaboration for adequate sample size. sFlt-1 is influenced by renal dysfunction common in SSc. Endocan assay standardization across platforms remains incomplete. RV strain imaging requires experienced operators and may have inter-observer variability. Prospective validation would require withholding vasodilators in suspected PH, raising ethical constraints.

Clinical significance: Early PVOD identification would prevent iatrogenic pulmonary edema from inappropriate vasodilator therapy, enable timely lung transplant referral, and potentially identify a therapeutic window for anti-fibrotic or anti-angiogenic agents. A non-invasive biomarker panel distinguishing PVOD from PAH in SSc would fundamentally alter the diagnostic algorithm for SSc-associated pulmonary hypertension.

LES AI • DeSci Rheumatology