Nicolas Pierre, Vân Anh Huynh-Thu, Dominique Baiwir, Gabriel Mazzucchelli, Maximilien Fléron, Lisette Trzpiot, Gauthier Eppe, Edwin De Pauw, David Laharie, Jack Satsangi, Peter Bossuyt, Lucine Vuitton, Sophie Vieujean, Jean-Frédéric Colombel, Marie-Alice Meuwis, Edouard Louis
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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).</p><p><strong>Design: </strong>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. 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引用次数: 0
摘要
研究目的在接受联合治疗（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（英夫利昔单抗与免疫抑制剂联合治疗稳定缓解的克罗恩病患者中的英夫利昔单抗二联疗法研究（STORI）队列），短期（≤6个月）和中/长期（>6个月）复发风险与不同的血液蛋白谱相关。我们的目的是在SPARE队列（一项前瞻性随机对照试验，比较英夫利昔单抗-抗代谢药物联合疗法与抗代谢药物单一疗法和英夫利昔单抗单一疗法在接受联合疗法且无类固醇持续缓解的克罗恩病患者中的应用）中检验这一发现的外部有效性：在SPARE研究中，正在接受联合疗法并持续无类固醇临床缓解的克罗恩病患者被随机分配到三个治疗组：继续联合疗法、停用英夫利西单抗或停用免疫抑制剂。在 STORI 和 SPARE（停用英夫利昔单抗组）组别的基线血清中，我们研究了 202 种免疫相关蛋白。我们比较了 STORI 和 SPARE 两组患者中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）评估了生物标志物（单独和成对组合）的鉴别能力，并与 C 反应蛋白（CRP）、粪便钙蛋白和之前验证的模型（CEASE）进行了比较：结果：在 STORI 和 SPARE 中，不同的血液蛋白特征与短期患病风险有关（例如，高水平的 CRP、粪便钙蛋白）：结果：在 STORI 和 SPARE 中，不同的血液蛋白特征与短期（如高水平：CRP、血红蛋白、白细胞介素-6、C 型凝集素域家族 4 成员 C）和中/长期复发（如低水平：Fms 相关酪氨酸激酶）的风险有关：Fms相关酪氨酸激酶3配体、kallistatin、成纤维细胞生长因子2）。在外部验证中，前10对生物标记物在预测短期复发（分别为0.76-0.80 vs 0.74 vs 0.71 vs 0.69）和中长期复发（分别为0.66-0.68 vs 0.61 vs 0.52 vs 0.59）方面的c统计量高于CEASE模型、CRP和粪便钙蛋白：结论：在停用英夫利西单抗的CD患者中，我们证实短期和中长期复发风险与不同的血液蛋白图谱有关，显示了指导英夫利西单抗停药的潜力：试验注册号：NCT00571337 和 NCT02177071。
External validation of serum biomarkers predicting short-term and mid/long-term relapse in patients with Crohn's disease stopping infliximab.
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 and NCT02177071.
期刊介绍：
Gut is a renowned international journal specializing in gastroenterology and hepatology, known for its high-quality clinical research covering the alimentary tract, liver, biliary tree, and pancreas. It offers authoritative and current coverage across all aspects of gastroenterology and hepatology, featuring articles on emerging disease mechanisms and innovative diagnostic and therapeutic approaches authored by leading experts.
As the flagship journal of BMJ's gastroenterology portfolio, Gut is accompanied by two companion journals: Frontline Gastroenterology, focusing on education and practice-oriented papers, and BMJ Open Gastroenterology for open access original research.
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