Ito Hiroaki, Takazoe Masakazu, Fukuda Yoshihiro, Hibi Toshifumi, Kusugami Kazuo, Andoh Akira, Matsumoto Takayuki, Yamamura Takehira, Azuma Junichi, Nishimoto Norihiro, Yoshizaki Kazuyuki, Shimoyama Takashi, Kishimoto Tadamitsu
Department of Molecular Medicine, Graduate School of Medicine, Osaka University, Suita,
Gastroenterology. 2004 Apr;126(4):989-96; discussion 947. doi: 10.1053/j.gastro.2004.01.012.
BACKGROUND & AIMS: Interleukin-6 (IL-6) regulates immune response and inflammation. We carried out a pilot placebo-controlled study to investigate the efficacy, pharmacokinetics, and safety of MRA, a humanized monoclonal antibody to IL-6 receptor, in patients with active Crohn's disease.
Thirty-six patients with active Crohn's disease (Crohn's Disease Activity Index [CDAI] > or =150) were randomly assigned to receive biweekly intravenous infusion of either placebo, MRA, or MRA/placebo alternately for 12 weeks at a dose of 8 mg/kg. The study's primary end point was a clinical response rate that was defined as a reduction of CDAI > or =70.
At the final evaluation, 80% of the patients (8 of 10) given biweekly MRA had a clinical response as compared with 31% of the placebo-treated patients (4 of 13; P = 0.019). Twenty percent of the patients (2 of 10) on this regimen went into remission (CDAI <150), as compared with 0% of the placebo-treated patients (0 of 13). The clinical response rate of the every-4-week regimen was 42% (5 of 12). The serum concentrations of MRA were detected at 2 weeks after every infusion, at which time acute phase responses were completely suppressed; however, they were not suppressed at 4 weeks. Endoscopic and histologic examination showed no difference between MRA and placebo groups. The incidence of adverse events was similar in all the groups.
This is the first clinical trial of humanized anti-IL-6 receptor monoclonal antibody in Crohn's disease. A biweekly 8 mg/kg infusion of MRA was well tolerated, normalized the acute-phase responses, and suggests a clinical effect in active Crohn's disease.
白细胞介素-6（IL-6）调节免疫反应和炎症。我们开展了一项安慰剂对照的试点研究，以调查人源化抗IL-6受体单克隆抗体MRA治疗活动期克罗恩病患者的疗效、药代动力学及安全性。
36例活动期克罗恩病患者（克罗恩病活动指数[CDAI]≥150）被随机分配，每两周静脉输注安慰剂、MRA或MRA/安慰剂交替治疗12周，剂量为8mg/kg。该研究的主要终点是临床缓解率，定义为CDAI降低≥70。
在最终评估时，每两周接受MRA治疗的患者中80%（10例中的8例）有临床反应，而接受安慰剂治疗的患者中这一比例为31%（13例中的4例；P = 0.019）。接受该治疗方案的患者中有20%（10例中的2例）病情缓解（CDAI<150），而接受安慰剂治疗的患者中缓解率为0%（13例中的0例）。每4周治疗方案的临床缓解率为42%（12例中的5例）。每次输注后2周检测MRA的血清浓度，此时急性期反应被完全抑制；但在4周时未被抑制。内镜及组织学检查显示MRA组和安慰剂组之间无差异。所有组不良事件的发生率相似。
这是首次在克罗恩病中进行人源化抗IL-6受体单克隆抗体的临床试验。每两周输注8mg/kg的MRA耐受性良好，可使急性期反应正常化，并提示对活动期克罗恩病有临床疗效。
