Department of Medicine, Division of Allergy, Immunology and Rheumatology, University of Rochester Medical Center, 601 Elmwood Ave, Box 695, Rochester, NY 14642, United States.
Department of Biostatistics and Computational Biology, University of Rochester, Saunders Research Building, 265 Crittenden Boulevard, Box 630, Rochester, NY 14642, United States.
Semin Arthritis Rheum. 2024 Dec;69:152554. doi: 10.1016/j.semarthrit.2024.152554. Epub 2024 Sep 13.
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.
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.
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.
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.
补体级联的激活被认为在硬皮病血管病变中起作用。我们之前表明，补体因子 D 在局限性硬皮病和肺动脉高压（PAH）患者中升高。在这项研究中，我们试图评估补体级联的多个相关成分，以确定它们是否在 SSc-PAH 中发生改变，以及它们作为疾病严重程度和进展的生物标志物的潜在用途。
使用多站点存储库中的 156 例 SSc-PAH 患者的多重分析测定补体成分（n = 14），并将其与 33 例无 PAH 的 SSc 患者和 40 例健康对照进行比较。评估补体水平与右心导管检查测量值以及包括 6 分钟步行距离在内的临床终点之间的相关性。为了评估补体的纵向变化，52 例参加过先前临床试验的 SSc-PAH 患者在 0、4、12、24、36 和 48 周时检测血清补体水平。
我们发现因子 D 在 SSc-PAH 中明显高于无 PAH 的 SSc（p < 0.0001），并且对 SSc-PAH 具有高度的敏感性和特异性（AUC=0.82，p < 0.001）。在 SSc-PAH 患者中，因子 H、C4 和因子 D 的改变与 PAH 疾病严重程度的测量值相关，包括右心导管检查测量值（心输出量、右心房压和 VO2 max）、生存率和 6 分钟步行距离。在纵向临床试验研究中，补体水平或临床相关性随时间没有明显变化，也与治疗无关。
我们的工作证实了先前的研究表明补体激活在 SSc 血管疾病中起作用，因子 D 在大型 SSc-PAH 人群中升高。此外，因子 H 和其他补体因子与 PAH 的严重程度相关，包括死亡率。综上所述，这些发现表明替代补体途径在 SSc-PAH 发病机制中起作用，并可作为诊断和预后的生物标志物。
