Division of Gastroenterology, University of California San Diego, La Jolla, California 92093-0956, USA.
N Engl J Med. 2012 Oct 18;367(16):1519-28. doi: 10.1056/NEJMoa1203572.
In patients with Crohn's disease, the efficacy of ustekinumab, a human monoclonal antibody against interleukin-12 and interleukin-23, is unknown.
We evaluated ustekinumab in adults with moderate-to-severe Crohn's disease that was resistant to anti-tumor necrosis factor (TNF) treatment. During induction, 526 patients were randomly assigned to receive intravenous ustekinumab (at a dose of 1, 3, or 6 mg per kilogram of body weight) or placebo at week 0. During the maintenance phase, 145 patients who had a response to ustekinumab at 6 weeks underwent a second randomization to receive subcutaneous injections of ustekinumab (90 mg) or placebo at weeks 8 and 16. The primary end point was a clinical response at 6 weeks.
The proportions of patients who reached the primary end point were 36.6%, 34.1%, and 39.7% for 1, 3, and 6 mg of ustekinumab per kilogram, respectively, as compared with 23.5% for placebo (P=0.005 for the comparison with the 6-mg group). The rate of clinical remission with the 6-mg dose did not differ significantly from the rate with placebo at 6 weeks. Maintenance therapy with ustekinumab, as compared with placebo, resulted in significantly increased rates of clinical remission (41.7% vs. 27.4%, P=0.03) and response (69.4% vs. 42.5%, P<0.001) at 22 weeks. Serious infections occurred in 7 patients (6 receiving ustekinumab) during induction and 11 patients (4 receiving ustekinumab) during maintenance. Basal-cell carcinoma developed in 1 patient receiving ustekinumab.
Patients with moderate-to-severe Crohn's disease that was resistant to TNF antagonists had an increased rate of response to induction with ustekinumab, as compared with placebo. Patients with an initial response to ustekinumab had significantly increased rates of response and remission with ustekinumab as maintenance therapy. (Funded by Janssen Research and Development; CERTIFI ClinicalTrials.gov number, NCT00771667.).
在患有克罗恩病的患者中，人源化单克隆抗体乌司奴单抗（一种针对白细胞介素-12 和白细胞介素-23 的药物）的疗效尚不清楚。
我们评估了乌司奴单抗在对肿瘤坏死因子（TNF）治疗耐药的中重度克罗恩病成年患者中的疗效。在诱导期，526 名患者被随机分配接受静脉注射乌司奴单抗（剂量为 1、3 或 6mg/每千克体重）或安慰剂，分别于第 0 周给药。在维持期，对在第 6 周时对乌司奴单抗有应答的 145 名患者进行第二次随机分组，分别接受乌司奴单抗（90mg）或安慰剂皮下注射，分别于第 8 周和第 16 周给药。主要终点是 6 周时的临床应答。
达到主要终点的患者比例分别为：每千克体重 1mg、3mg 和 6mg 乌司奴单抗组为 36.6%、34.1%和 39.7%，而安慰剂组为 23.5%（与 6mg 组相比，P=0.005）。6mg 剂量的乌司奴单抗与安慰剂在第 6 周时的临床缓解率无显著差异。与安慰剂相比，乌司奴单抗维持治疗可显著提高第 22 周时的临床缓解率（41.7%比 27.4%，P=0.03）和应答率（69.4%比 42.5%，P<0.001）。诱导期有 7 名患者（6 名接受乌司奴单抗）和维持期有 11 名患者（4 名接受乌司奴单抗）发生严重感染。1 名接受乌司奴单抗治疗的患者发生基底细胞癌。
与安慰剂相比，对 TNF 拮抗剂耐药的中重度克罗恩病患者对乌司奴单抗诱导治疗的应答率增加。对乌司奴单抗初始有应答的患者，乌司奴单抗维持治疗的应答率和缓解率显著提高。（由 Janssen Research and Development 资助；CERTIFI ClinicalTrials.gov 编号，NCT00771667）。
