Sandborn William J, Colombel Jean Frédéric, Enns Roberts, Feagan Brian G, Hanauer Stephen B, Lawrance Ian C, Panaccione Remo, Sanders Martin, Schreiber Stefan, Targan Stephan, van Deventer Sander, Goldblum Ronald, Despain Darrin, Hogge Gary S, Rutgeerts Paul
Mayo Clinic, Rochester, Minn 55905, USA.
N Engl J Med. 2005 Nov 3;353(18):1912-25. doi: 10.1056/NEJMoa043335.
Natalizumab, a humanized monoclonal antibody against alpha4 integrin, inhibits leukocyte adhesion and migration into inflamed tissue.
We conducted two controlled trials to evaluate natalizumab as induction and maintenance therapy in patients with active Crohn's disease. In the first trial, 905 patients were randomly assigned to receive 300 mg of natalizumab or placebo at weeks 0, 4, and 8. The primary outcome was response, defined by a decrease in the Crohn's Disease Activity Index (CDAI) score of at least 70 points, at week 10. In the second trial, 339 patients who had a response to natalizumab in the first trial were randomly reassigned to receive 300 mg of natalizumab or placebo every four weeks through week 56. The primary outcome was a sustained response through week 36. A secondary outcome in both trials was disease remission (a CDAI score of less than 150).
In the first trial, the natalizumab and placebo groups had similar rates of response (56 percent and 49 percent, respectively; P=0.05) and remission (37 percent and 30 percent, respectively; P=0.12) at 10 weeks. Continuing natalizumab in the second trial resulted in higher rates of sustained response (61 percent vs. 28 percent, P<0.001) and remission (44 percent vs. 26 percent, P=0.003) through week 36 than did switching to placebo. Serious adverse events occurred in 7 percent of each group in the first trial and in 10 percent of the placebo group and 8 percent of the natalizumab group in the second trial. In an open-label extension study, a patient treated with natalizumab died from progressive multifocal leukoencephalopathy, associated with the JC virus, a human polyomavirus.
Induction therapy with natalizumab for Crohn's disease resulted in small, nonsignificant improvements in response and remission rates. Patients who had a response had significantly increased rates of sustained response and remission if natalizumab was continued every four weeks. The benefit of natalizumab will need to be weighed against the risk of serious adverse events, including progressive multifocal leukoencephalopathy. (ClinicalTrials.gov numbers, NCT00032786 and NCT00032799.)
那他珠单抗是一种抗α4整合素的人源化单克隆抗体，可抑制白细胞黏附和向炎症组织的迁移。
我们进行了两项对照试验，以评估那他珠单抗作为活动性克罗恩病患者的诱导和维持治疗。在第一项试验中，905例患者在第0、4和8周被随机分配接受300mg那他珠单抗或安慰剂。主要结局是在第10周时的缓解，定义为克罗恩病活动指数（CDAI）评分至少降低70分。在第二项试验中，339例在第一项试验中对那他珠单抗有反应的患者被随机重新分配，在第56周前每四周接受300mg那他珠单抗或安慰剂。主要结局是至第36周的持续缓解。两项试验的次要结局均为疾病缓解（CDAI评分小于150）。
在第一项试验中，那他珠单抗组和安慰剂组在10周时的缓解率（分别为56%和49%；P=0.05）和缓解率（分别为37%和30%；P=0.12）相似。在第二项试验中，持续使用那他珠单抗至第36周的持续缓解率（61%对28%，P<0.001）和缓解率（44%对26%，P=0.003）高于改用安慰剂组。在第一项试验中，每组7%的患者发生严重不良事件，在第二项试验中，安慰剂组10%的患者和那他珠单抗组8%的患者发生严重不良事件。在一项开放标签扩展研究中，一名接受那他珠单抗治疗的患者死于进行性多灶性白质脑病，与人类多瘤病毒JC病毒有关。
那他珠单抗用于克罗恩病的诱导治疗在缓解率和缓解率方面有微小但无显著意义的改善。有反应的患者如果每四周持续使用那他珠单抗，持续缓解率和缓解率会显著提高。那他珠单抗的益处需要与包括进行性多灶性白质脑病在内的严重不良事件风险相权衡。（ClinicalTrials.gov编号，NCT00032786和NCT00032799。）
