Management strategies and clinical outcomes vary substantially in patients newly diagnosed with Crohn's disease. We evaluated the use of a putative prognostic biomarker to guide therapy by assessing outcomes in patients randomised to either top-down (ie, early combined immunosuppression with infliximab and immunomodulator) or accelerated step-up (conventional) treatment strategies. PROFILE (PRedicting Outcomes For Crohn's disease using a moLecular biomarker) was a multicentre, open-label, biomarker-stratified, randomised controlled trial that enrolled adults with newly diagnosed active Crohn's disease (Harvey-Bradshaw Index ≥7, either elevated C-reactive protein or faecal calprotectin or both, and endoscopic evidence of active inflammation). Potential participants had blood drawn to be tested for a prognostic biomarker derived from T-cell transcriptional signatures (PredictSURE-IBD assay). Following testing, patients were randomly assigned, via a secure online platform, to top-down or accelerated step-up treatment stratified by biomarker subgroup (IBDhi or IBDlo), endoscopic inflammation (mild, moderate, or severe), and extent (colonic or other). Blinding to biomarker status was maintained throughout the trial. The primary endpoint was sustained steroid-free and surgery-free remission to week 48. Remission was defined by a composite of symptoms and inflammatory markers at all visits. Flare required active symptoms (HBI ≥5) plus raised inflammatory markers (CRP >upper limit of normal or faecal calprotectin ≥200 μg/g, or both), while remission was the converse—ie, quiescent symptoms (HBI <5) or resolved inflammatory markers (both CRP ≤ the upper limit of normal and calprotectin <200 μg/g) or both. Analyses were done in the full analysis (intention-to-treat) population. The trial has completed and is registered (ISRCTN11808228). Between Dec 29, 2017, and Jan 5, 2022, 386 patients (mean age 33·6 years [SD 13·2]; 179 [46%] female, 207 [54%] male) were randomised: 193 to the top-down group and 193 to the accelerated step-up group. Median time from diagnosis to trial enrolment was 12 days (range 0–191). Primary outcome data were available for 379 participants (189 in the top-down group; 190 in the accelerated step-up group). There was no biomarker–treatment interaction effect (absolute difference 1 percentage points, 95% CI –15 to 15; p=0·944). Sustained steroid-free and surgery-free remission was significantly more frequent in the top-down group than in the accelerated step-up group (149 [79%] of 189 patients 29 [15%] of 190 patients, absolute difference 64 percentage points, 95% CI 57 to 72; p<0·0001). There were fewer adverse events (including disease flares) and serious adverse events in the top-down group than in the accelerated step-up group (adverse events: 168 315; serious adverse events: 15 42), with fewer complications requiring abdominal surgery (one ten) and no difference in serious infections (three eight). Top-down treatment with combination infliximab plus immunomodulator achieved substantially better outcomes at 1 year than accelerated step-up treatment. The biomarker did not show clinical utility. Top-down treatment should be considered standard of care for patients with newly diagnosed active Crohn's disease. Wellcome and PredictImmune Ltd.

中文翻译：

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新诊断克罗恩病患者自上而下与加速逐步治疗策略的生物标志物分层比较（PROFILE）：一项多中心、开放标签随机对照试验

新诊断克罗恩病患者的治疗策略和临床结果差异很大。我们通过评估随机接受自上而下（即早期联合英夫利昔单抗和免疫调节剂的免疫抑制）或加速逐步（传统）治疗策略的患者的结果，评估了使用假定的预后生物标志物来指导治疗。 PROFILE（使用分子生物标志物预测克罗恩病的结果）是一项多中心、开放标签、生物标志物分层、随机对照试验，纳入了新诊断的活动性克罗恩病成人（哈维-布拉德肖指数≥7，或者 C 反应蛋白升高）或粪便钙卫蛋白或两者，以及活动性炎症的内镜证据）。潜在参与者被抽血以测试源自 T 细胞转录特征的预后生物标志物（PredictSURE-IBD 测定）。测试后，通过安全的在线平台将患者随机分配至按生物标志物亚组（IBDhi 或 IBDlo）、内镜炎症（轻度、中度或重度）和程度（结肠或结肠）分层的自上而下或加速升级治疗。其他）。在整个试验过程中保持对生物标志物状态的盲法。主要终点是持续无类固醇和无手术缓解至第 48 周。缓解是通过所有就诊时的症状和炎症标志物的综合来定义的。耀斑需要活动症状 (HBI ≥5) 加上升高的炎症标志物（CRP > 正常上限或粪便钙卫蛋白 ≥200 μg/g，或两者兼而有之），而缓解则相反，即静止症状 (HBI <5) 或得到缓解炎症标志物（CRP ≤正常上限且钙卫蛋白<200 μg/g）或两者。分析是在全面分析（意向治疗）人群中进行的。试验已完成并已注册 (ISRCTN11808228)。 2017年12月29日至2022年1月5日期间，386名患者（平均年龄33·6岁[SD 13·2]；179名[46%]女性，207名[54%]男性）被随机分组​​：顶部193名患者下降组和193加速升压组。从诊断到试验入组的中位时间为 12 天（范围 0-191）。 379 名参与者的主要结果数据可用（自上而下组 189 人；加速升级组 190 人）。不存在生物标志物-治疗相互作用效应（绝对差异1个百分点，95% CI –15至15；p=0·944）。自上而下组中持续无类固醇和免手术缓解的频率显着高于加速升压组（189 名患者中的 149 [79%] 190 名患者中的 29 [15%]，绝对差异 64 个百分点，95% CI 57 至 72；p<0·0001)。自上而下组的不良事件（包括疾病发作）和严重不良事件少于加速升压组（不良事件：168 315；严重不良事件：15 42），需要腹部手术的并发症也更少。一十分）和严重感染（三八）没有区别。英夫利昔单抗联合免疫调节剂的自上而下治疗在 1 年时取得的结果明显优于加速升级治疗。该生物标志物没有显示出临床实用性。自上而下的治疗应被视为新诊断的活动性克罗恩病患者的护理标准。 Wellcome 和 PredictImmune 有限公司