Zhan Zhi-Qing, Li Jia-Xin, Chen Ying-Xuan, Fang Jing-Yuan
Division of Gastroenterology and Hepatology, NHC Key Laboratory of Digestive Diseases, State Key Laboratory for Oncogenes and Related Genes, School of Medicine, Shanghai Institute of Digestive Disease, Renji Hospital, Shanghai Jiao Tong University, Shanghai, China.
Department of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu, China.
United European Gastroenterol J. 2025 May;13(4):531-541. doi: 10.1002/ueg2.12719. Epub 2024 Dec 16.
With limited evidence connecting paradoxical inflammatory bowel disease (paradoxical IBD) to the newest biologics and Janus kinase inhibitors, our study aims to investigate the occurrence of paradoxical IBD induced by these agents in treating other immune-mediated inflammatory diseases (IMIDs). We aim to identify associated risk signals, the primary affected population, and the risk profile changes over time.
We performed disproportionality analysis to evaluate paradoxical IBD risk signals using data from the FDA Adverse Event Reporting System. Stratification analyses according to IBD subtype, age, gender, and agents' indications were performed. Weibull shape parameter (WSP) test was conducted to assess paradoxical IBD risk changes over time. Linkage disequilibrium score regression and Mendelian Randomization were employed to evaluate genetic correlations and causality between these agents' indications (i.e., non-IBD IMIDs) and IBD.
This study included 3296 patients reporting 3407 occurrences of paradoxical IBD following using these agents as primary suspects. Among TNF blockers, consistent positive signals for paradoxical IBD were noted: Adalimumab (n = 1983, ROR [95%CI] = 1.55 [1.47-1.63]), Infliximab (n = 545, ROR [95%CI] = 2.12 [1.95-2.32]), Certolizumab Pegol (n = 342, ROR [95%CI] = 1.9 [1.71-2.12]), and Golimumab (n = 154, ROR [95%CI] = 1.64 [1.4-1.93]). Ustekinumab, an IL-12 and IL-23 antagonist, also showed a strong positive signal (n = 155, ROR [95%CI] = 2.03 [1.73-2.39]). Conversely, Upadacitinib, Tofacitinib (Janus kinase inhibitors), and Risankizumab (IL-23 antagonist) exhibited insignificant associations with paradoxical IBD. Crohn's disease (CD) is the mainly developing form. WSP analysis identified two temporal patterns of paradoxical IBD: early failure and random failure types. Significant genetic correlations between three IMIDs and IBD were uncovered, with psoriasis specifically found to causally elevate CD risk.
This study identifies paradoxical IBD as a consistent positive signal across multiple IMID agents, predominantly manifesting as CD, potentially aiding in timely detection and therapeutic decision-making.
由于将反常性炎症性肠病（paradoxical IBD）与最新生物制剂和 Janus 激酶抑制剂联系起来的证据有限，我们的研究旨在调查这些药物在治疗其他免疫介导的炎症性疾病（IMIDs）时诱发反常性 IBD 的情况。我们旨在识别相关风险信号、主要受影响人群以及风险特征随时间的变化。
我们使用美国食品药品监督管理局不良事件报告系统的数据进行不成比例分析，以评估反常性 IBD 的风险信号。根据 IBD 亚型、年龄、性别和药物适应症进行分层分析。进行威布尔形状参数（WSP）测试以评估反常性 IBD 风险随时间的变化。采用连锁不平衡评分回归和孟德尔随机化来评估这些药物的适应症（即非 IBD 的 IMIDs）与 IBD 之间的遗传相关性和因果关系。
本研究纳入了 3296 名患者，这些患者报告了 3407 例将这些药物作为主要可疑药物后发生的反常性 IBD 事件。在肿瘤坏死因子阻滞剂中，发现了一致的反常性 IBD 阳性信号：阿达木单抗（n = 1983，风险比 [95%置信区间] = 1.55 [1.47 - 1.63]）、英夫利昔单抗（n = 545，风险比 [95%置信区间] = 2.12 [1.95 - 2.32]）、赛妥珠单抗（n = 342，风险比 [95%置信区间] = 1.9 [1.71 - 2.12]）和戈利木单抗（n = 154，风险比 [95%置信区间] = 1.64 [1.4 - 1.93]）。乌司奴单抗，一种白细胞介素 - 12 和白细胞介素 - 23 拮抗剂，也显示出强烈的阳性信号（n = 155，风险比 [95%置信区间] = 2.03 [1.73 - 2.39]）。相反，乌帕替尼、托法替布（Janus 激酶抑制剂）和司库奇尤单抗（白细胞介素 - 23 拮抗剂）与反常性 IBD 的关联不显著。克罗恩病（CD）是主要的发病形式。WSP 分析确定了反常性 IBD 的两种时间模式：早期失效型和随机失效型。发现三种 IMIDs 与 IBD 之间存在显著的遗传相关性，具体发现银屑病会因果性地增加 CD 风险。
本研究将反常性 IBD 确定为多种 IMID 药物中一致的阳性信号，主要表现为 CD，这可能有助于及时检测和进行治疗决策。
