Eva Petrow , Changyong Feng , Ashley Frazer-Abel , Roberta Goncalves Marangoni , Katie Lutz , William C. Nichols , V. Michael Holers , Christopher Ritchlin , R. James White III , Benjamin D. Korman
{"title":"D因子和其他替代性补体因子作为系统性硬化症相关性肺动脉高压（SSc-PAH）生物标志物的效用","authors":"Eva Petrow , Changyong Feng , Ashley Frazer-Abel , Roberta Goncalves Marangoni , Katie Lutz , William C. Nichols , V. Michael Holers , Christopher Ritchlin , R. James White III , Benjamin D. Korman","doi":"10.1016/j.semarthrit.2024.152554","DOIUrl":null,"url":null,"abstract":"<div><h3>Background</h3><p>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.</p></div><div><h3>Methods</h3><p>Complement components (<em>n</em> = 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.</p></div><div><h3>Results</h3><p>We found that factor D was significantly elevated in SSc-PAH compared to SSc without PAH (<em>p</em> < 0.0001) and was highly sensitive and specific for SSc-PAH (AUC=0.82, <em>p</em> < 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.</p></div><div><h3>Conclusion</h3><p>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.</p></div>","PeriodicalId":21715,"journal":{"name":"Seminars in arthritis and rheumatism","volume":null,"pages":null},"PeriodicalIF":4.6000,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Utility of factor D and other alternative complement factors as biomarkers in systemic sclerosis-associated pulmonary arterial hypertension (SSc-PAH)\",\"authors\":\"Eva Petrow , Changyong Feng , Ashley Frazer-Abel , Roberta Goncalves Marangoni , Katie Lutz , William C. Nichols , V. Michael Holers , Christopher Ritchlin , R. James White III , Benjamin D. Korman\",\"doi\":\"10.1016/j.semarthrit.2024.152554\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><h3>Background</h3><p>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.</p></div><div><h3>Methods</h3><p>Complement components (<em>n</em> = 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.</p></div><div><h3>Results</h3><p>We found that factor D was significantly elevated in SSc-PAH compared to SSc without PAH (<em>p</em> < 0.0001) and was highly sensitive and specific for SSc-PAH (AUC=0.82, <em>p</em> < 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.</p></div><div><h3>Conclusion</h3><p>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.</p></div>\",\"PeriodicalId\":21715,\"journal\":{\"name\":\"Seminars in arthritis and rheumatism\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":4.6000,\"publicationDate\":\"2024-09-13\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Seminars in arthritis and rheumatism\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S004901722400194X\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"RHEUMATOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Seminars in arthritis and rheumatism","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S004901722400194X","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"RHEUMATOLOGY","Score":null,"Total":0}
Utility of factor D and other alternative complement factors as biomarkers in systemic sclerosis-associated pulmonary arterial hypertension (SSc-PAH)
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.
期刊介绍：
Seminars in Arthritis and Rheumatism provides access to the highest-quality clinical, therapeutic and translational research about arthritis, rheumatology and musculoskeletal disorders that affect the joints and connective tissue. Each bimonthly issue includes articles giving you the latest diagnostic criteria, consensus statements, systematic reviews and meta-analyses as well as clinical and translational research studies. Read this journal for the latest groundbreaking research and to gain insights from scientists and clinicians on the management and treatment of musculoskeletal and autoimmune rheumatologic diseases. The journal is of interest to rheumatologists, orthopedic surgeons, internal medicine physicians, immunologists and specialists in bone and mineral metabolism.
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