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Utility of factor D and other alternative complement factors as biomarkers in systemic sclerosis-associated pulmonary
Eva Petrow1, Changyong Feng2, Ashley Frazer-Abel3
1Department of Medicine, Division of Allergy, Immunology and Rheumatology, University of Rochester Medical Center, 601 Elmwood Ave, Box 695, Rochester, NY 14642, United States.
Insights
Complement factor D is elevated in scleroderma (SSc) with pulmonary arterial hypertension (PAH), indicating its role in disease severity. Other complement factors like H and C4 also correlate with PAH severity and mortality, suggesting potential as biomarkers.
Area of Science:
- Immunology
- Rheumatology
- Cardiology
Background:
- Complement cascade activation is implicated in scleroderma (SSc) vasculopathy.
- Previous research identified elevated complement factor D in limited cutaneous SSc and pulmonary arterial hypertension (PAH).
Purpose of the Study:
- To assess alterations in complement cascade components in SSc-PAH.
- To evaluate the utility of complement components as biomarkers for SSc-PAH disease severity and progression.
Main Methods:
- Multiplex assays measured 14 complement components in 156 SSc-PAH patients, 33 SSc without PAH patients, and 40 healthy controls.
- Correlations were analyzed between complement levels, right heart catheterization measures, and clinical endpoints (e.g., 6-minute walk distance).
- Longitudinal serum complement levels were monitored over 48 weeks in 52 SSc-PAH patients from a clinical trial.
Main Results:
- Factor D was significantly elevated in SSc-PAH versus SSc without PAH (p < 0.0001), showing high sensitivity and specificity (AUC=0.82).
- In SSc-PAH, altered factor H, C4, and factor D correlated with PAH severity markers (cardiac output, right atrial pressure, VO2 max), survival, and 6-minute walk distance.
- No significant longitudinal changes in complement levels or clinical associations were observed, nor were they linked to treatment in the trial.
Conclusions:
- Findings confirm the role of complement activation in SSc vascular disease and elevated factor D in SSc-PAH.
- Factor H and other complement factors are associated with PAH severity and mortality in SSc-PAH patients.
- The alternative complement pathway is implicated in SSc-PAH pathogenesis and may serve as a diagnostic and prognostic biomarker.
Background:
Activation of the complement cascade is thought to play a role in scleroderma vasculopathy. We previously showed that complement factor D was elevated in patients with limited cutaneous SSc and pulmonary arterial hypertension (PAH). In this study, we sought to assess multiple relevant components of the complement cascade to determine if they are altered in SSc-PAH, as well as their potential utility as biomarkers of disease severity and progression.
Methods:
Complement components (n = 14) were measured using multiplex assays in 156 patients with SSc-PAH from a multi-site repository and were compared to 33 patients with SSc without PAH, and 40 healthy controls. Data were evaluated for correlations between complement levels, right heart catheterization measures, and clinical endpoints including 6-minute walk distance. To assess complement longitudinally, serum complement levels were assayed at 0, 4, 12, 24, 36 and 48 weeks in 52 SSc-PAH patients who participated in a prior clinical trial.
Results:
We found that factor D was significantly elevated in SSc-PAH compared to SSc without PAH (p < 0.0001) and was highly sensitive and specific for SSc-PAH (AUC=0.82, p < 0.001). In SSc-PAH patients, alterations in factor H, C4, and factor D were associated with measures of PAH disease severity including right heart catheterization measurements (cardiac output, right atrial pressure, and VO2 max), survival, and 6-minute walk distance. No significant changes in complement levels or clinical associations were seen over time or associated with treatment in the longitudinal clinical trial study.
Conclusion:
Our work confirms prior studies demonstrating a role for complement activation in SSc vascular disease and elevations of factor D in a large SSc-PAH population. Further, factor H and other complement factors are associated with severity of PAH including mortality. Taken together, these findings suggest that the alternative complement pathway plays a role in SSc-PAH pathogenesis and may serve as a biomarker to inform diagnosis and prognosis.
