Pulles Astrid E, Mastbergen Simon C, Schutgens Roger E G, Lafeber Floris P J G, van Vulpen Lize F D
Department of Rheumatology & Clinical Immunology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands; Van Creveldkliniek, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands.
Department of Rheumatology & Clinical Immunology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands.
Pharmacol Res. 2017 Jan;115:192-199. doi: 10.1016/j.phrs.2016.11.032. Epub 2016 Nov 24.
Hemophilia is a congenital clotting factor deficiency characterized by spontaneous and trauma-related bleeding. Spontaneous bleeding shows a predilection for joints, and repeated hemarthroses lead to a disabling condition called hemophilic arthropathy. Treatment of this condition consists of preventing joint bleeding on the one hand and orthopedic surgery as a last resort on the other. Up till now, there is no disease modifying therapy available to fill the gap between these extremes. This review provides an overview of the pathogenesis of hemophilic arthropathy in order to identify potential targets for therapy. Joint bleeding induces synovial inflammation, cartilage degeneration and bone damage. These processes interact with each other and result in a vicious circle. Hemarthrosis promotes synovial hypertrophy and neoangiogenesis, increasing the susceptibility to mechanical damage and subsequent bleeding. The inflamed synovium affects the cartilage, while cartilage is also directly affected by blood via the release of cytokines and metalloproteinases, and via hydroxyl radical formation inducing chondrocyte apoptosis. Apart from the inflammatory pathways, iron plays a pivotal role in this process, as does the fibrinolytic system. Considering its pathogenesis, potential targets for disease modifying therapy in hemophilic arthropathy are iron, inflammation, vascular remodeling, hyperfibrinolysis, bone remodeling and cartilage regeneration. So far, iron chelators, anti-inflammatory therapy, anti-fibrinolytics and bone remodeling agents have demonstrated beneficial effects, predominantly in a preclinical setting. There is still a long way to go before these interventions will translate into clinical practice. The most important challenges are: establishing a universal outcome measure to predict efficacy in humans, and determination of the optimal route and timing to administer disease modifying therapy.
血友病是一种先天性凝血因子缺乏症，其特征为自发性出血和创伤相关出血。自发性出血好发于关节，反复的关节积血会导致一种致残性疾病，称为血友病性关节病。这种疾病的治疗一方面包括预防关节出血，另一方面则是在万不得已时进行骨科手术。到目前为止，尚无能够填补这两种极端治疗方法之间空白的疾病改善疗法。本综述概述了血友病性关节病的发病机制，以确定潜在的治疗靶点。关节出血会引发滑膜炎症、软骨退变和骨损伤。这些过程相互作用，形成恶性循环。关节积血会促进滑膜增生和新生血管形成，增加对机械损伤和随后出血的易感性。炎症滑膜会影响软骨，而软骨也会通过细胞因子和金属蛋白酶的释放、以及通过诱导软骨细胞凋亡的羟基自由基形成而直接受到血液的影响。除了炎症途径外，铁和纤维蛋白溶解系统在这个过程中也起着关键作用。考虑到其发病机制，血友病性关节病疾病改善治疗的潜在靶点包括铁、炎症、血管重塑、纤维蛋白溶解亢进、骨重塑和软骨再生。到目前为止，铁螯合剂、抗炎治疗、抗纤维蛋白溶解剂和骨重塑剂已显示出有益效果，主要是在临床前研究中。这些干预措施转化为临床实践仍有很长的路要走。最重要的挑战是：建立一个通用的疗效评估指标来预测对人类的疗效，以及确定疾病改善治疗的最佳给药途径和时机。
