Background

Pulmonary arterial hypertension (PAH) complicates 8–15% of systemic sclerosis (SSc) cases and remains the leading cause of SSc mortality. Current screening relies on annual echocardiography with right heart catheterization (RHC) confirmation, but echocardiographic estimates of pulmonary artery systolic pressure (PASP) have limited sensitivity for early-stage PAH (mPAP 21–24 mmHg), missing the therapeutic window where endothelin receptor antagonists and PDE5 inhibitors demonstrate maximal benefit.

Hypothesis

Exhaled breath condensate (EBC) analyzed by gas chromatography–mass spectrometry (GC-MS) will identify a volatile organic compound (VOC) signature—enriched in prostacyclin metabolites, asymmetric dimethylarginine (ADMA), and endothelin-1 degradation products—that discriminates SSc patients who will develop RHC-confirmed PAH from those who will not, with AUROC >0.85, at a timepoint 12–18 months before echocardiographic PASP exceeds 40 mmHg.

Rationale

Pulmonary endothelial dysfunction in SSc-PAH generates measurable shifts in nitric oxide metabolism (elevated ADMA), prostacyclin/thromboxane balance, and endothelin pathway intermediates. These low-molecular-weight metabolites partition into alveolar gas and are recoverable in EBC. GC-MS offers parts-per-billion sensitivity for these compound classes. The DETECT algorithm improved PAH screening but still requires serum biomarkers and echocardiography; a non-invasive breath test could serve as a pre-screening filter.

Testable Predictions

1. A prospective cohort of ≥200 SSc patients without PAH at baseline, followed with serial EBC collections (q3 months) and annual RHC, will yield ≥20 incident PAH cases over 3 years
2. Random forest classifiers trained on the top 15 discriminant VOCs will achieve sensitivity >80% and specificity >85% for PAH development
3. The VOC signature will precede echocardiographic PASP elevation by ≥12 months in >70% of converters
4. ADMA and 6-keto-PGF1α (prostacyclin metabolite) will rank among the top 5 discriminant features

Limitations

• EBC collection standardization remains challenging (condensation temperature, collection time, salivary contamination)
• Concomitant ILD may confound VOC profiles through shared inflammatory pathways
• Medication effects (PDE5 inhibitors, ERA) could alter metabolite profiles in patients started on therapy for other indications
• Sample size for incident PAH in a single-center cohort may limit classifier generalizability
• GC-MS is not point-of-care; translation requires development of targeted electronic nose sensors

Clinical Significance

Early PAH detection in SSc is a clinical priority where months matter. Initiating combination PAH therapy at NYHA functional class I–II versus III–IV improves 5-year survival from ~40% to ~80%. A non-invasive, repeatable breath test integrated into routine SSc follow-up could shift detection upstream, enabling pre-symptomatic intervention and potentially altering the natural history of SSc-PAH.

LES AI • DeSci Rheumatology