Fresolimumab treatment decreases biomarkers and improves clinical symptoms in systemic sclerosis patients
Fresolimumab treatment decreases biomarkers and improves clinical symptoms in systemic sclerosis patients
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DOI：
10.1172/jci77958
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发表时间：
2015-07-01
影响因子：
15.9
通讯作者：
Lafyatis, Robert
中科院分区：
文献类型：
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作者：
Rice, Lisa M.;Padilla, Cristina M.;Lafyatis, Robert
背景。 TGF-β 在体外具有有效的促纤维化活性，长期以来一直与系统性硬化症 (SSc) 有关，因为 TGF-β 调节的基因在 SSc 患者的皮肤和肺部表达增加。因此，抑制TGF-β可能使这些患者受益。方法。患有早期弥漫性皮肤 SSc 的患者参加了 fresolimumab 的开放标签试验，fresolimumab 是一种针对所有 3 种 TGF-β 亚型的高亲和力中和抗体。 7 名患者接受了 2 次 1 mg/kg 剂量的 fresolimumab，8 名患者接受了 1 次 5 mg/kg 剂量的 fresolimumab。在治疗前后进行连续中前臂皮肤活检，分析 TGF-β 调节的生物标志物基因血小板反应蛋白-1 (THBS1) 和软骨寡聚蛋白 (COMP) 的表达，并对肌成纤维细胞进行染色。使用改良的 Rodnan 皮肤评分 (MRSS) 评估临床皮肤病。结果。在患者皮肤中，两组患者接受fresolimumab治疗后THBS1表达均迅速下降（第7周时P = 0.0313，第3周时P = 0.0156），并且两组皮肤COMP表达均呈现强烈下降趋势。临床皮肤病显着且迅速减少（所有时间点 P < 0.001）。其他 TGF-β 调节基因（包括 SERPINE1 和 CTGF）的表达水平下降（分别为 P = 0.049 和 P.0.012），并且在 fresolimumab 治疗后，SSc 皮肤病的 2 基因纵向药效生物标志物下降（P = 0.0067）。使用 fresolimumab 后，患者皮肤的真皮肌成纤维细胞浸润也有所下降（P < 0.05）。 THBS1 的基线水平可预测 fresolimumab 治疗后 THBS1 表达的降低和 MRSS 的改善。结论。 fresolimumab 对 TGF-β 调节基因表达的快速抑制强烈表明 TGF-β 与 SSc 纤维化的发病机制有关。 MRSS 的平行改善表明 fresolimumab 可以快速逆转皮肤纤维化标志物。
BACKGROUND. TGF-beta has potent profibrotic activity in vitro and has long been implicated in systemic sclerosis (SSc), as expression of TGF-beta-regulated genes is increased in the skin and lungs of patients with SSc. Therefore, inhibition of TGF-beta may benefit these patients.METHODS. Patients with early, diffuse cutaneous SSc were enrolled in an open-label trial of fresolimumab, a high-affinity neutralizing antibody that targets all 3 TGF-beta isoforms. Seven patients received two 1 mg/kg doses of fresolimumab, and eight patients received one 5 mg/kg dose of fresolimumab. Serial mid-forearm skin biopsies, performed before and after treatment, were analyzed for expression of the TGF-beta-regulated biomarker genes thrombospondin-1 (THBS1) and cartilage oligomeric protein (COMP) and stained for myofibroblasts. Clinical skin disease was assessed using the modified Rodnan skin score (MRSS).RESULTS. In patient skin, THBS1 expression rapidly declined after fresolimumab treatment in both groups (P = 0.0313 at 7 weeks and P = 0.0156 at 3 weeks), and skin expression of COMP exhibited a strong downward trend in both groups. Clinical skin disease dramatically and rapidly decreased (P < 0.001 at all time points). Expression levels of other TGF-beta-regulated genes, including SERPINE1 and CTGF, declined (P = 0.049 and P. 0.012, respectively), and a 2-gene, longitudinal pharmacodynamic biomarker of SSc skin disease decreased after fresolimumab treatment (P = 0.0067). Dermal myofibroblast infiltration also declined in patient skin after fresolimumab (P < 0.05). Baseline levels of THBS1 were predictive of reduced THBS1 expression and improved MRSS after fresolimumab treatment.CONCLUSION. The rapid inhibition of TGF-beta-regulated gene expression in response to fresolimumab strongly implicates TGF-beta in the pathogenesis of fibrosis in SSc. Parallel improvement in the MRSS indicates that fresolimumab rapidly reverses markers of skin fibrosis.