Division of Gastroenterology, University of California San Diego, 9500 Gilman Dr., La Jolla, CA 92093-0956, USA.
N Engl J Med. 2012 Aug 16;367(7):616-24. doi: 10.1056/NEJMoa1112168.
Ulcerative colitis is a chronic inflammatory disease of the colon for which current treatments are not universally effective. One additional treatment may be tofacitinib (CP-690,550), an oral inhibitor of Janus kinases 1, 2, and 3 with in vitro functional specificity for kinases 1 and 3 over kinase 2, which is expected to block signaling involving gamma chain-containing cytokines including interleukins 2, 4, 7, 9, 15, and 21. These cytokines are integral to lymphocyte activation, function, and proliferation.
In a double-blind, placebo-controlled, phase 2 trial, we evaluated the efficacy of tofacitinib in 194 adults with moderately to severely active ulcerative colitis. Patients were randomly assigned to receive tofacitinib at a dose of 0.5 mg, 3 mg, 10 mg, or 15 mg or placebo twice daily for 8 weeks. The primary outcome was a clinical response at 8 weeks, defined as an absolute decrease from baseline in the score on the Mayo scoring system for assessment of ulcerative colitis activity (possible score, 0 to 12, with higher scores indicating more severe disease) of 3 or more and a relative decrease from baseline of 30% or more with an accompanying decrease in the rectal bleeding subscore of 1 point or more or an absolute rectal bleeding subscore of 0 or 1.
The primary outcome, clinical response at 8 weeks, occurred in 32%, 48%, 61%, and 78% of patients receiving tofacitinib at a dose of 0.5 mg (P=0.39), 3 mg (P=0.55), 10 mg (P=0.10), and 15 mg (P<0.001), respectively, as compared with 42% of patients receiving placebo. Clinical remission (defined as a Mayo score ≤2, with no subscore >1) at 8 weeks occurred in 13%, 33%, 48%, and 41% of patients receiving tofacitinib at a dose of 0.5 mg (P=0.76), 3 mg (P=0.01), 10 mg (P<0.001), and 15 mg (P<0.001), respectively, as compared with 10% of patients receiving placebo. There was a dose-dependent increase in both low-density and high-density lipoprotein cholesterol. Three patients treated with tofacitinib had an absolute neutrophil count of less than 1500.
Patients with moderately to severely active ulcerative colitis treated with tofacitinib were more likely to have clinical response and remission than those receiving placebo. (Funded by Pfizer; ClinicalTrials.gov number, NCT00787202.).
溃疡性结肠炎是一种慢性结肠炎症性疾病，目前的治疗方法并非对所有人都有效。一种额外的治疗方法可能是托法替尼（CP-690,550），它是一种口服 Janus 激酶 1、2 和 3 的抑制剂，体外功能特异性为激酶 1 和 3 对激酶 2，预计可阻断涉及含 γ 链细胞因子的信号传导，包括白细胞介素 2、4、7、9、15 和 21。这些细胞因子是淋巴细胞激活、功能和增殖的重要组成部分。
在一项双盲、安慰剂对照、2 期临床试验中，我们评估了托法替尼在 194 名中度至重度活动期溃疡性结肠炎患者中的疗效。患者被随机分配接受托法替尼 0.5mg、3mg、10mg 或 15mg 或安慰剂，每日两次，持续 8 周。主要终点是 8 周时的临床反应，定义为梅奥评分系统评估溃疡性结肠炎活动度（可能评分为 0 至 12，得分越高表示疾病越严重）绝对下降 3 分或以上，且相对基线下降 30%或以上，同时直肠出血亚评分下降 1 分或以上，或绝对直肠出血亚评分下降至 0 或 1。
主要终点，8 周时的临床反应，接受托法替尼 0.5mg（P=0.39）、3mg（P=0.55）、10mg（P=0.10）和 15mg（P<0.001）治疗的患者分别为 32%、48%、61%和 78%，而接受安慰剂治疗的患者为 42%。8 周时临床缓解（定义为梅奥评分≤2，无任何亚评分>1）的患者分别为 13%、33%、48%和 41%，接受托法替尼 0.5mg（P=0.76）、3mg（P=0.01）、10mg（P<0.001）和 15mg（P<0.001）治疗的患者，而接受安慰剂治疗的患者为 10%。低密度和高密度脂蛋白胆固醇均有剂量依赖性升高。3 名接受托法替尼治疗的患者的中性粒细胞绝对计数低于 1500。
与安慰剂组相比，接受托法替尼治疗的中度至重度活动期溃疡性结肠炎患者更有可能出现临床反应和缓解。（由辉瑞公司资助；临床试验.gov 编号，NCT00787202）。
