Ferraccioli G, Tolusso B, De Santis M
Division of Rheumatology, Catholic University of the Sacred Heart-Catholic University of Rome, Rome, Italy.
Pharmacogenomics J. 2007 Feb;7(1):2-9. doi: 10.1038/sj.tpj.6500396. Epub 2006 May 9.
Preliminary pharmacogenetic data suggest that germline genetic informations might be of value in individualizing disease-modifying antirheumatic drugs (DMARDs) therapy in various autoimmune chronic inflammatory diseases. Either DMARDs small molecules (DMARDs-SM) or DMARDs biological therapies (DMARDs-BT) might be selected for their lower toxicity or better efficacy based on single-nucleotide polymorphisms (SNPs) of genes governing the metabolism of drugs, or the response of immune cells to proinflammatory molecules, or the proinflammatory molecular activity of immune cells. Data available for one DMARDs-SM, methotrexate, suggest that a careful assessment of the SNPs of four enzymes involved in the folate metabolism allow one to construct a genetic index of toxicity (toxicogenetic index) that might be employed in daily practice to find the patient's most at risk. Only the full knowledge of the various gene polymorphisms controlling the phenotypic manifestations of the inflammatory-immunological milieu of each rheumatic disease will allow one to obtain the clear definition of a personalized medicine. Few different cytokine gene SNPs seem to be of importance in determining the susceptibility to diseases, or the aggressiveness of diseases. The role of genetics in affecting a possible clinical response to DMARDs-BT targeting specific inflammatory molecules or their receptors still has to be defined. However, the available data suggest that cytokine (and/or receptors) gene SNPs might indeed play a role in determining the biological effects, hence the clinical effectiveness of DMARDs-BT. Crucial to this aim will be the prospective analysis of clinical benefits and safety on the basis of the at baseline stratification of gene SNPs in each chronic inflammatory rheumatic disease before starting any new DMARDs-SM or DMARDs-BT.
初步的药物遗传学数据表明，种系遗传信息可能有助于在各种自身免疫性慢性炎症性疾病中实现改善病情抗风湿药（DMARDs）治疗的个体化。基于药物代谢相关基因的单核苷酸多态性（SNP）、免疫细胞对促炎分子的反应或免疫细胞的促炎分子活性，可以选择毒性较低或疗效较好的DMARDs小分子药物（DMARDs-SM）或DMARDs生物疗法（DMARDs-BT）。关于一种DMARDs-SM即甲氨蝶呤的现有数据表明，仔细评估参与叶酸代谢的四种酶的SNP能够构建一个毒性遗传指数，该指数可用于日常实践中找出风险最高的患者。只有全面了解控制每种风湿性疾病炎症免疫环境表型表现的各种基因多态性，才能明确个性化医疗的定义。少数不同的细胞因子基因SNP在决定疾病易感性或疾病侵袭性方面似乎具有重要意义。遗传学在影响针对特定炎症分子或其受体的DMARDs-BT可能的临床反应中的作用仍有待确定。然而，现有数据表明，细胞因子（和/或受体）基因SNP可能确实在决定生物学效应，进而决定DMARDs-BT的临床疗效方面发挥作用。在开始任何新的DMARDs-SM或DMARDs-BT之前，基于每种慢性炎症性风湿性疾病基因SNP的基线分层对临床益处和安全性进行前瞻性分析对于实现这一目标至关重要。
