Martyanov Viktor, Kim Grace-Hyun J, Hayes Wendy, Du Shuyan, Ganguly Bishu J, Sy Oumar, Lee Sun Ku, Bogatkevich Galina S, Schieven Gary L, Schiopu Elena, Marangoni Roberta Gonçalves, Goldin Jonathan, Whitfield Michael L, Varga John
Geisel School of Medicine at Dartmouth, Hanover, NH, United States of America.
David Geffen School of Medicine at UCLA, University of California, Los Angeles, CA, United States of America.
PLoS One. 2017 Nov 9;12(11):e0187580. doi: 10.1371/journal.pone.0187580. eCollection 2017.
There are no effective treatments or validated clinical response markers in systemic sclerosis (SSc). We assessed imaging biomarkers and performed gene expression profiling in a single-arm open-label clinical trial of tyrosine kinase inhibitor dasatinib in patients with SSc-associated interstitial lung disease (SSc-ILD).
Primary objectives were safety and pharmacokinetics. Secondary outcomes included clinical assessments, quantitative high-resolution computed tomography (HRCT) of the chest, serum biomarker assays and skin biopsy-based gene expression subset assignments. Clinical response was defined as decrease of >5 or >20% from baseline in the modified Rodnan Skin Score (MRSS). Pulmonary function was assessed at baseline and day 169.
Dasatinib was well-tolerated in 31 patients receiving drug for a median of nine months. No significant changes in clinical assessments or serum biomarkers were seen at six months. By quantitative HRCT, 65% of patients showed no progression of lung fibrosis, and 39% showed no progression of total ILD. Among 12 subjects with available baseline and post-treatment skin biopsies, three were improvers and nine were non-improvers. Improvers mapped to the fibroproliferative or normal-like subsets, while seven out of nine non-improvers were in the inflammatory subset (p = 0.0455). Improvers showed stability in forced vital capacity (FVC) and diffusing capacity for carbon monoxide (DLCO), while both measures showed a decline in non-improvers (p = 0.1289 and p = 0.0195, respectively). Inflammatory gene expression subset was associated with higher baseline HRCT score (p = 0.0556). Non-improvers showed significant increase in lung fibrosis (p = 0.0313).
In patients with SSc-ILD dasatinib treatment was associated with acceptable safety profile but no significant clinical efficacy. Patients in the inflammatory gene expression subset showed increase in skin fibrosis, decreasing pulmonary function and worsening lung fibrosis during the study. These findings suggest that target tissue-specific gene expression analyses can help match patients and therapeutic interventions in heterogeneous diseases such as SSc, and quantitative HRCT is useful for assessing clinical outcomes.
Clinicaltrials.gov NCT00764309.
系统性硬化症（SSc）尚无有效的治疗方法或经过验证的临床反应标志物。我们在一项关于酪氨酸激酶抑制剂达沙替尼治疗系统性硬化症相关间质性肺病（SSc-ILD）患者的单臂开放标签临床试验中评估了影像学生物标志物并进行了基因表达谱分析。
主要目标是安全性和药代动力学。次要结局包括临床评估、胸部定量高分辨率计算机断层扫描（HRCT）、血清生物标志物检测以及基于皮肤活检的基因表达亚组分类。临床反应定义为改良罗丹皮肤评分（MRSS）较基线下降>5%或>20%。在基线和第169天评估肺功能。
31例接受药物治疗的患者中，达沙替尼耐受性良好，中位治疗时间为9个月。6个月时临床评估或血清生物标志物未见显著变化。通过定量HRCT，65%的患者肺纤维化无进展，39%的患者总ILD无进展。在12例有可用基线和治疗后皮肤活检的受试者中，3例病情改善，9例未改善。改善者归入纤维增生性或正常样亚组，而9例未改善者中有7例属于炎症亚组（p = 0.0455）。改善者的用力肺活量（FVC）和一氧化碳弥散量（DLCO）保持稳定，而未改善者这两项指标均下降（分别为p = 0.1289和p = 0.0195）。炎症基因表达亚组与较高的基线HRCT评分相关（p = 0.0556）。未改善者的肺纤维化显著增加（p = 0.0313）。
在SSc-ILD患者中达沙替尼治疗具有可接受的安全性，但无显著临床疗效。在研究期间，炎症基因表达亚组的患者皮肤纤维化增加、肺功能下降且肺纤维化恶化。这些发现表明，靶组织特异性基因表达分析有助于在SSc等异质性疾病中匹配患者和治疗干预措施，定量HRCT有助于评估临床结局。
Clinicaltrials.gov NCT00764309。
