Alberta Children's Hospital Research Institute, University of Calgary, Heritage Medical Research Building, Room 293, 3330 Hospital Drive, NW, Calgary, AB T2N 4N1, Canada.
Centre of General Paediatrics and Neonatology, Department of Paediatrics, Asklepios Clinics, Arnold-Janssen Strasse 29, 537, Sankt Augustin D-53757, Germany.
Nat Rev Rheumatol. 2014 Nov;10(11):682-90. doi: 10.1038/nrrheum.2014.140. Epub 2014 Aug 12.
Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic condition in childhood, with many children requiring immunomodulatory therapies for many years following diagnosis. A considerable proportion of children experience therapeutic inefficacy or substantial adverse effects, or both, but a lack of reliable clinical indicators and biomarkers to predict treatment response prevents optimization of existing therapies. The identification of valid candidate gene variants involved in the pathways of methotrexate and etanercept, the most commonly used medications in JIA, has seen little success to date. The limited success of these studies is possibly due to the presence of confounding variables in the study populations, the heterogeneity of outcome parameters used to determine treatment response and the small number of candidate gene variants analysed. The first genome-wide pharmacogenetic study in JIA has identified gene regions of particular biological interest, but these findings require validation. Moreover, epigenetic mechanisms as well as ontogeny processes might be additional factors influencing drug responses. Access to large, well-documented JIA cohorts and the rapid development of advanced genome analytics is ushering in a personalized approach to treatment. The discovery of new pharmacogenomic biomarkers and systems pathways can provide new drug targets and predictive tools for improved drug response and fewer adverse drug reactions in JIA.
幼年特发性关节炎（JIA）是儿童中最常见的慢性风湿性疾病，许多儿童在确诊后需要多年接受免疫调节治疗。相当一部分儿童存在治疗无效或严重不良反应，或两者兼而有之，但缺乏可靠的临床指标和生物标志物来预测治疗反应，从而无法优化现有的治疗方法。迄今为止，在甲氨蝶呤和依那西普（JIA 最常用的药物）相关通路中涉及的有效候选基因变异的鉴定工作收效甚微。这些研究的有限成功可能是由于研究人群中存在混杂变量、用于确定治疗反应的结果参数的异质性以及分析的候选基因变异数量较少。JIA 的第一项全基因组药物遗传学研究已经确定了具有特殊生物学意义的基因区域，但这些发现尚需验证。此外，表观遗传机制以及个体发育过程可能是影响药物反应的其他因素。获得大型、记录良好的 JIA 队列以及先进基因组分析技术的快速发展，为治疗带来了个性化方法。发现新的药物基因组生物标志物和系统途径可为改善 JIA 的药物反应和减少不良反应提供新的药物靶点和预测工具。
