Cheong Fei-Ying, Gower Adam C, Farber Harrison W
Department of Medicine, Arthritis Center, Boston University School of Medicine, Boston, MA.
Clinical & Translational Science Institute, Boston University, Boston, MA.
Semin Arthritis Rheum. 2017 Feb;46(4):465-472. doi: 10.1016/j.semarthrit.2016.05.015. Epub 2016 Jun 7.
Pulmonary arterial hypertension (PAH) is one of the most devastating complications in scleroderma (SSc) patients and has a poorer outcome than other PAH subgroups. Tadalafil (Adcirca) is a phosphodiesterase-5 inhibitor (PDE5-I) approved by the FDA for treatment of PAH; however, its effectiveness specifically in SSc-PAH patients is unclear. We investigated whether there were differences in gene expression associated with 16 weeks of treatment with tadalafil and, if so, whether these changes differed with respect to treatment outcome.
We enrolled 10 SSc-PAH subjects who were naïve to PDE5-I treatment, profiled gene expression in whole blood prior to and following treatment with tadalafil, measured changes in genomic profiles before and after treatment with tadalafil, and correlated them with changes in clinical outcomes, such as cardiopulmonary hemodynamics, six-min walk distance (6MWD), Borg Dyspnea Index (BDI), NYHA/WHO functional class (FC), B-type natriuretic peptide (BNP), and cardiac magnetic resonance imaging (cMRI).
Genes associated with IL-12 signaling and extracellular matrix maintenance were coordinately up- or down-regulated with treatment, respectively, across all subjects. Interestingly, we found that genes encoding voltage-gated potassium channels and genes related to innate immunity were coordinately up-regulated in subjects who improved with tadalafil treatment compared to those patients who did not. In contrast, up-regulation of Golgi-related gene sets was associated with clinical worsening during the treatment period.
The results of this pilot study suggest that outcomes of SSc-PAH patients treated with tadalafil are associated with specific changes in gene expression and biological pathways.
肺动脉高压（PAH）是硬皮病（SSc）患者最具破坏性的并发症之一，其预后比其他PAH亚组更差。他达拉非（Adcirca）是一种经美国食品药品监督管理局（FDA）批准用于治疗PAH的磷酸二酯酶-5抑制剂（PDE5-I）；然而，其在SSc-PAH患者中的具体疗效尚不清楚。我们研究了接受他达拉非治疗16周后基因表达是否存在差异，如果存在差异，这些变化在治疗结果方面是否有所不同。
我们纳入了10名未接受过PDE5-I治疗的SSc-PAH受试者，在接受他达拉非治疗前后对全血中的基因表达进行分析，测量他达拉非治疗前后基因组图谱的变化，并将其与心肺血流动力学、六分钟步行距离（6MWD）、博格呼吸困难指数（BDI）、纽约心脏协会/世界卫生组织功能分级（FC）、B型利钠肽（BNP）和心脏磁共振成像（cMRI）等临床结果的变化进行关联分析。
在所有受试者中，与白细胞介素-12信号传导和细胞外基质维持相关的基因分别在治疗过程中协同上调或下调。有趣的是，我们发现与未改善的患者相比，在接受他达拉非治疗后病情改善的受试者中，编码电压门控钾通道的基因和与先天免疫相关的基因协同上调。相反，高尔基体相关基因集的上调与治疗期间的临床病情恶化有关。
这项初步研究的结果表明，接受他达拉非治疗的SSc-PAH患者的治疗结果与基因表达和生物学途径的特定变化有关。
