Objective In patients with Crohn’s disease (CD) on combination therapy (infliximab and immunosuppressant) and stopping infliximab (cohort from the study of infliximab diSconTinuation in CrOhn’s disease patients in stable Remission on combined therapy with Immunosuppressors (STORI)), the risk of short-term (≤6 months) and mid/long-term relapse (>6 months) was associated with distinct blood protein profiles. Our aim was to test the external validity of this finding in the SPARE cohort (A proSpective Randomized Controlled Trial comParing infliximAb-antimetabolites Combination Therapy to Anti-metabolites monotheRapy and Infliximab monothErapy in Crohn's Disease Patients in Sustained Steroid-free Remission on Combination Therapy). Design In SPARE, patients with CD in sustained steroid-free clinical remission and on combination therapy were randomly allocated to three arms: continuing combination therapy, stopping infliximab or stopping immunosuppressant. In the baseline serum of the STORI and SPARE (arm stopping infliximab) cohorts, we studied 202 immune-related proteins. The proteins associated with time to relapse (univariable Cox model) were compared between STORI and SPARE. The discriminative ability of biomarkers (individually and combined in pairs) was evaluated by the c-statistic (concordance analysis) which was compared with C-reactive protein (CRP), faecal calprotectin and a previously validated model (CEASE). Results In STORI and SPARE, distinct blood protein profiles were associated with the risk of short-term (eg, high level: CRP, haptoglobin, interleukin-6, C-type lectin domain family 4 member C) and mid/long-term relapse (eg, low level: Fms-related tyrosine kinase 3 ligand, kallistatin, fibroblast growth factor 2). At external validation, the top 10 biomarker pairs showed a higher c-statistic than the CEASE model, CRP and faecal calprotectin in predicting short-term (0.76–0.80 vs 0.74 vs 0.71 vs 0.69, respectively) and mid/long-term relapse (0.66–0.68 vs 0.61 vs 0.52 vs 0.59, respectively). Conclusion In patients with CD stopping infliximab, we confirm that the risk of short-term and mid/long-term relapse is associated with distinct blood protein profiles showing the potential to guide infliximab withdrawal. Trial registration number [NCT00571337][1] and [NCT02177071][2]. Data are available in a public, open access repository. All data relevant to the study are included in the article or uploaded as supplementary information. All the data (clinical, selected reaction monitoring (SRM) and proximity extension assay) supporting our findings are available at . For the STORI study, SRM raw data are available at (dataset identifier: PXD019434). For the SPARE study, SRM raw data are available at (dataset identifier: PXD051233). The Python codes used for data analysis are available at . [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00571337&atom=%2Fgutjnl%2F73%2F12%2F1965.atom [2]: /external-ref?link_type=ISRCTN&access_num=ISRCTNNCT02177071

中文翻译：

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预测停用英夫利昔单抗的克罗恩病患者短期和中期/长期复发的血清生物标志物的外部验证


目的 在联合治疗 （英夫利昔单抗和免疫抑制剂） 和停用英夫利昔单抗的克罗恩病 （CD） 患者中 （来自免疫抑制剂联合治疗稳定缓解的 CrOhn 病患者 （STORI） 的英夫利昔单抗 diSconTinuation 研究队列），短期 （≤6 个月） 和中/长期复发 （>6 个月） 的风险与不同的血液蛋白谱相关。我们的目的是在 SPARE 队列中测试这一发现的外部有效性 （一项前瞻性随机对照试验，比较英夫利昔单抗-抗代谢物联合治疗与抗代谢物 monotheRapy 和英夫利昔单抗 monothErapy 在联合治疗持续无类固醇缓解的克罗恩病患者中）。设计 在 SPARE 中，持续无类固醇临床缓解和联合治疗的 CD 患者被随机分配到三组： 继续联合治疗、停止英夫利昔单抗或停止免疫抑制剂。在 STORI 和 SPARE （手臂停止英夫利昔单抗） 队列的基线血清中，我们研究了 202 种免疫相关蛋白。比较 STORI 和 SARE 之间与复发时间相关的蛋白质 （单变量 Cox 模型）。通过 c 统计量 （一致性分析） 评估生物标志物 （单独和成对组合） 的鉴别能力，并与 C 反应蛋白 （CRP） 、粪便钙卫蛋白和先前验证的模型 （CEASE） 进行比较。结果 在 STORI 和 SARE 中，不同的血液蛋白谱与短期 （例如，高水平：CRP、结合珠蛋白、白细胞介素-6、C 型凝集素结构域家族 4 成员 C） 和中/长期复发 （例如，低水平：Fms 相关酪氨酸激酶 3 配体、kallistatin、成纤维细胞生长因子 2）的风险相关。 在外部验证中，前 10 对生物标志物对在预测短期 （分别为 0.76-0.80 对 0.74 对 0.71 对 0.69） 和中期/长期复发 （分别为 0.66-0.68 对 0.61 对 0.52 对 0.59） 方面显示出高于 CEASE 模型、 CRP 和粪便钙卫蛋白的 c 统计量。结论 在 CD 停用英夫利昔单抗的患者中，我们确认短期和中期/长期复发的风险与不同的血液蛋白谱相关，显示出指导英夫利昔单抗戒断的潜力。试验注册号 [NCT00571337][1] 和 [NCT02177071][2]。数据在公共、开放访问存储库中可用。与研究相关的所有数据都包含在文章中或作为补充信息上传。支持我们研究结果的所有数据（临床、选择性反应监测 （SRM） 和邻近延伸测定）均可在 上获得。对于 STORI 研究，SRM 原始数据可在（数据集标识符：PXD019434）获得。对于 SPARE 研究，SRM 原始数据可在（数据集标识符：PXD051233）获得。用于数据分析的 Python 代码可在 中找到。[1]： /lookup/external-ref？link_type=CLINTRIALGOV&access_num=NCT00571337&atom=%2Fgutjnl%2F73%2F12%2F1965.atom [2]： /external-ref？link_type=ISRCTN&access_num=ISRCTNNCT02177071