Abstract：
OBJECTIVE: The impact of thiopurine de-escalation while on vedolizumab versus continuing thiopurine therapy in ulcerative colitis (UC) is unclear. We aimed to determine the effect of thiopurine withdrawal for patients with UC in remission on vedolizumab.
METHODS: This multicenter randomized controlled trial recruited UC patients on vedolizumab 300 mg intravenously every 8 weeks and a thiopurine. Patients in steroid-free clinical remission for ≥6 months and endoscopic remission/improvement (Mayo endoscopic subscore ≤1) were randomized 2:1 to withdraw or continue thiopurine. Primary outcome was comparing week 48 vedolizumab trough concentrations. Secondary outcomes were clinical relapse (partial Mayo score ≥3 and fecal calprotectin >150 μg/g or increase in Mayo endoscopic subscore ≥1 from baseline), fecal calprotectin remission (<150 μg/g), C-reactive protein remission (<5 mg/L), centrally read endoscopic remission (Mayo endoscopic subscore = 0), histologic remission (Nancy index = 0), histo-endoscopic remission, and adverse events.
RESULTS: In total, 62 patients were randomized to continue (n = 20) or withdraw (n = 42) thiopurine. At week 48, vedolizumab trough concentrations were not significantly different between continue and withdrawal groups (14.7 μg/mL, interquartile rate [IQR], 12.3-18.5 μg/mL versus 15.9 μg/mL, IQR, 10.1-22.7 μg/mL, respectively, P = 0.36). The continue group had significantly higher fecal calprotectin remission (95.0%, 19/20 versus 71.4%, 30/42; P = .03), histologic remission (80.0%, 16/20 versus 48.6%, 18/37; P = .02), and histo-endoscopic remission (75.0%, 15/20 versus 32.4%, 12/37; P = .002) than the withdrawal group. Histologic activity (hazard ratio [HR], 15.5; 95% confidence interval [CI], 1.6-146.5; P = .02) and prior anti-tumor necrosis factor exposure (HR, 6.5; 95% CI, 1.3-33.8; P = .03) predicted clinical relapse after thiopurine withdrawal.
CONCLUSIONS: Thiopurine withdrawal did not affect vedolizumab trough concentrations. However, it may increase fecal calprotectin, histologic, and histo-endoscopic activity. Histologic activity and prior anti-tumor necrosis factor exposure may predict disease relapse on thiopurine withdrawal for patients using vedolizumab for UC. Australian and New Zealand Trial Registry, number ACTRN12618000812291.
METHODS: This multicenter randomized controlled trial recruited UC patients on vedolizumab 300 mg intravenously every 8 weeks and a thiopurine. Patients in steroid-free clinical remission for ≥6 months and endoscopic remission/improvement (Mayo endoscopic subscore ≤1) were randomized 2:1 to withdraw or continue thiopurine. Primary outcome was comparing week 48 vedolizumab trough concentrations. Secondary outcomes were clinical relapse (partial Mayo score ≥3 and fecal calprotectin >150 μg/g or increase in Mayo endoscopic subscore ≥1 from baseline), fecal calprotectin remission (<150 μg/g), C-reactive protein remission (<5 mg/L), centrally read endoscopic remission (Mayo endoscopic subscore = 0), histologic remission (Nancy index = 0), histo-endoscopic remission, and adverse events.
RESULTS: In total, 62 patients were randomized to continue (n = 20) or withdraw (n = 42) thiopurine. At week 48, vedolizumab trough concentrations were not significantly different between continue and withdrawal groups (14.7 μg/mL, interquartile rate [IQR], 12.3-18.5 μg/mL versus 15.9 μg/mL, IQR, 10.1-22.7 μg/mL, respectively, P = 0.36). The continue group had significantly higher fecal calprotectin remission (95.0%, 19/20 versus 71.4%, 30/42; P = .03), histologic remission (80.0%, 16/20 versus 48.6%, 18/37; P = .02), and histo-endoscopic remission (75.0%, 15/20 versus 32.4%, 12/37; P = .002) than the withdrawal group. Histologic activity (hazard ratio [HR], 15.5; 95% confidence interval [CI], 1.6-146.5; P = .02) and prior anti-tumor necrosis factor exposure (HR, 6.5; 95% CI, 1.3-33.8; P = .03) predicted clinical relapse after thiopurine withdrawal.
CONCLUSIONS: Thiopurine withdrawal did not affect vedolizumab trough concentrations. However, it may increase fecal calprotectin, histologic, and histo-endoscopic activity. Histologic activity and prior anti-tumor necrosis factor exposure may predict disease relapse on thiopurine withdrawal for patients using vedolizumab for UC. Australian and New Zealand Trial Registry, number ACTRN12618000812291.
摘要：
目的：在溃疡性结肠炎（UC）中，对维多珠单抗与继续噻嘌呤治疗的影响尚不清楚。我们的目的是确定噻嘌呤戒断对缓解期UC患者维多珠单抗的影响。
方法：这项多中心随机对照试验招募了UC患者，每8周静脉注射维多珠单抗300mg和硫嘌呤。无类固醇临床缓解≥6个月且内镜下缓解/改善（Mayo内镜下评分[MES]≤1）的患者以2：1的比例随机分配退出或继续接受硫嘌呤。主要结果是比较第48周的维多珠单抗谷浓度。次要结果为临床复发（部分Mayo评分≥3，粪便钙卫蛋白>150μg/g或MES较基线增加≥1），粪便钙卫蛋白缓解（<150μg/g），C反应蛋白缓解（<5mg/L），中央阅读内镜缓解（MES=0），组织学缓解（南希指数=0），组织内镜缓解和不良事件。
结果：总计，62例患者被随机分为继续（n=20）或撤回（n=42）硫嘌呤。在第48周，维多珠单抗谷浓度在继续组和停药组之间没有显着差异（分别为14.7μg/mL[IQR：12.3-18.5μg/mL]与15.9μg/mL[IQR：10.1-22.7μg/mL]，P=0.36）。继续组的粪便钙卫蛋白缓解率明显高于对照组（95.0%[19/20]和71.4%[30/42]，P=0.03),组织学缓解（80.0%[16/20]对48.6%[18/37]，P=0.02）和组织内镜缓解（75.0%[15/20]对32.4%[12/37]，P=0.002)比戒断组。组织学活性（HR：15.5[95CI：1.6-146.5]，P=0.02）和先前的抗TNF暴露（HR：6.5[95CI：1.3-33.8]，P=0.03）预测噻嘌呤戒断后的临床复发。
结论：停用硫嘌呤并不影响维多珠单抗谷浓度。然而,它可能会增加粪便钙卫蛋白，组织学和组织内镜活动。组织学活性和先前的抗TNF暴露可能预测使用维多珠单抗治疗UC的患者停用硫嘌呤后的疾病复发;澳大利亚和新西兰试验注册,编号ACTRN12618000812291。
方法：这项多中心随机对照试验招募了UC患者，每8周静脉注射维多珠单抗300mg和硫嘌呤。无类固醇临床缓解≥6个月且内镜下缓解/改善（Mayo内镜下评分[MES]≤1）的患者以2：1的比例随机分配退出或继续接受硫嘌呤。主要结果是比较第48周的维多珠单抗谷浓度。次要结果为临床复发（部分Mayo评分≥3，粪便钙卫蛋白>150μg/g或MES较基线增加≥1），粪便钙卫蛋白缓解（<150μg/g），C反应蛋白缓解（<5mg/L），中央阅读内镜缓解（MES=0），组织学缓解（南希指数=0），组织内镜缓解和不良事件。
结果：总计，62例患者被随机分为继续（n=20）或撤回（n=42）硫嘌呤。在第48周，维多珠单抗谷浓度在继续组和停药组之间没有显着差异（分别为14.7μg/mL[IQR：12.3-18.5μg/mL]与15.9μg/mL[IQR：10.1-22.7μg/mL]，P=0.36）。继续组的粪便钙卫蛋白缓解率明显高于对照组（95.0%[19/20]和71.4%[30/42]，P=0.03),组织学缓解（80.0%[16/20]对48.6%[18/37]，P=0.02）和组织内镜缓解（75.0%[15/20]对32.4%[12/37]，P=0.002)比戒断组。组织学活性（HR：15.5[95CI：1.6-146.5]，P=0.02）和先前的抗TNF暴露（HR：6.5[95CI：1.3-33.8]，P=0.03）预测噻嘌呤戒断后的临床复发。
结论：停用硫嘌呤并不影响维多珠单抗谷浓度。然而,它可能会增加粪便钙卫蛋白，组织学和组织内镜活动。组织学活性和先前的抗TNF暴露可能预测使用维多珠单抗治疗UC的患者停用硫嘌呤后的疾病复发;澳大利亚和新西兰试验注册,编号ACTRN12618000812291。
