Inflammatory Bowel Disease Clinic, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN 55905, USA.
Dig Dis. 2010;28(3):536-42. doi: 10.1159/000320413. Epub 2010 Sep 30.
Azathioprine and 6-mercaptopurine are orally administered immunosuppressive drugs which are effective for the treatment of Crohn's disease and ulcerative colitis. Azathioprine is rapidly converted to 6-mercaptopurine after administration. 6-Mercaptopurine is then either converted to the putative active metabolites, the 6-thioguinine nucleotides, or inactivated by the enzyme xanthine oxidase to 6-thiouric acid or alternatively inactivated to 6-methylmercaptopurine by the enzyme thiopurine methyltransferase. Thiopurine methyltransferase activity is genetically determined, with one in 300 patients having low or absent enzyme activity, one in 10 patients having intermediate enzyme activity, and 9 in 10 patients having normal enzyme activity. Patients with intermediate or low thiopurine methyltransferase activity are at risk for early leukopenia. Higher erythrocyte 6-thioguinine nucleotide concentrations are associated with a greater likelihood of clinical response. Azathioprine is modestly effective for Crohn's disease and ulcerative colitis. Toxicity associated with azathioprine includes infection and lymphoma. Anti-TNF therapy with infliximab, adalimumab, and certolizumab pegol is effective for induction and maintenance treatment of Crohn's disease, and infliximab is effective for ulcerative colitis. Toxicity associated with anti-TNF therapy includes infection and lymphoma. Combination therapy with infliximab and azathioprine is more effective for inducing and maintaining steroid-free remission and mucosal healing then monotherapy with either drug alone. Strategies to reduce immunogenicity of anti-TNF agents include combination therapy with azathioprine and administration of a loading dose followed by systematic maintenance dosing. Higher serum trough concentrations of infliximab occur more frequently in patients receiving combination therapy with azathioprine and are associated with better clinical outcomes. Combination therapy is associated with an increased relative risk of opportunistic infection, but is not associated with an increased absolute risk of serious infection. Clinical practice should change such that combination therapy with an anti-TNF agent and azathioprine replace azathioprine in patients failing first line therapy with mesalamine and/or steroids.
巯嘌呤和 6-巯基嘌呤是两种口服免疫抑制剂，可有效治疗克罗恩病和溃疡性结肠炎。巯嘌呤在给药后迅速转化为 6-巯基嘌呤。6-巯基嘌呤随后要么转化为假定的活性代谢物，即 6-硫鸟嘌呤核苷酸，要么被黄嘌呤氧化酶失活为 6-硫代尿酸，或者被硫嘌呤甲基转移酶失活为 6-甲基巯基嘌呤。硫嘌呤甲基转移酶活性是由基因决定的，300 名患者中有 1 名患者酶活性低或缺失，10 名患者中有 1 名患者酶活性中等，9 名患者中有 10 名患者酶活性正常。酶活性中等或低的硫嘌呤甲基转移酶患者有早期白细胞减少的风险。红细胞 6-硫鸟嘌呤核苷酸浓度较高与临床反应的可能性更大相关。巯嘌呤对克罗恩病和溃疡性结肠炎有一定疗效。与巯嘌呤相关的毒性包括感染和淋巴瘤。英夫利昔单抗、阿达木单抗和 Certolizumab Pegol 等抗 TNF 治疗对克罗恩病的诱导和维持治疗有效，英夫利昔单抗对溃疡性结肠炎有效。与抗 TNF 治疗相关的毒性包括感染和淋巴瘤。英夫利昔单抗联合巯嘌呤治疗对诱导和维持无激素缓解和黏膜愈合的效果优于单独使用这两种药物中的任何一种。降低抗 TNF 药物免疫原性的策略包括联合巯嘌呤治疗和给予负荷剂量后系统维持剂量。接受巯嘌呤联合治疗的患者，英夫利昔单抗的血清谷浓度更高，与更好的临床结局相关。联合治疗与机会性感染的相对风险增加相关，但与严重感染的绝对风险增加无关。临床实践应改变，即在一线治疗失败时，用抗 TNF 药物和巯嘌呤联合治疗替代柳氮磺胺吡啶和/或皮质类固醇。
