Tofacitinib for ulcerative colitis: results of the prospective Dutch Initiative on Crohn and Colitis (ICC) registry.
Tofacitinib 治疗溃疡性结肠炎: 克罗恩和结肠炎 (ICC) 登记前瞻性荷兰倡议的结果。
- 作者列表："Biemans VBC","Sleutjes JAM","de Vries AC","Bodelier AGL","Dijkstra G","Oldenburg B","Löwenberg M","van Bodegraven AA","van der Meulen-de Jong AE","de Boer NKH","Srivastava N","West RL","Römkens TEH","Horjus Talabur Horje CS","Jansen JM","van der Woude CJ","Hoekstra J","Weersma RK","van Schaik FDM","Hoentjen F","Pierik MJ","Dutch Initiative on Crohn and Colitis (ICC).
BACKGROUND:Tofacitinib is a Janus kinase inhibitor approved for the treatment of ulcerative colitis (UC). AIM:To evaluate effectiveness, safety and use of tofacitinib in daily practice. METHODS:UC patients initiating tofacitinib were prospectively enrolled in 15 hospitals in the Netherlands. Corticosteroid-free clinical remission (short clinical colitis activity index [SCCAI] ≤2), biochemical remission (faecal calprotectin level ≤250 µg/g), combined corticosteroid-free clinical and biochemical remission, predictors of remission, safety outcomes, treatment dose and effect on lipids were determined at weeks 12 and 24. Endoscopic outcomes were evaluated in centres with routine endoscopic evaluation. RESULTS:In total, 123 UC patients (95% anti-TNF, 62% vedolizumab and 3% ustekinumab experienced) were followed for a median duration of 24 weeks (interquartile range 12-26). The proportion of patients in corticosteroid-free clinical, biochemical, and combined corticosteroid-free clinical and biochemical remission rate at week 24 was 29% (n: 22/77), 25% (n: 14/57), and 19% (n: 11/57) respectively. Endoscopic remission (Mayo = 0) was achieved in 21% of patients at week 12 (n: 7/33). Prior vedolizumab exposure was associated with reduced clinical remission (odds ratio 0.33, 95% confidence interval [CI] 0.11-0.94). At week 24, 33% (n: 14/42) of patients still on tofacitinib treatment used 10 mg twice daily. In total, 33 tofacitinib-related adverse events (89 per 100 patient years) occurred, 7 (6% of total cohort) resulted in discontinuation. Cholesterol, HDL and LDL levels increased during induction treatment by 18% (95% CI 9-26), 18% (95% CI 8-28) and 21% (95% CI 14-39) respectively. CONCLUSION:Tofacitinib is an effective treatment for UC after anti-TNF and vedolizumab failure. However, a relatively high rate of adverse events was observed resulting in discontinuation in 6% of patients.
背景: 托法替尼是一种 Janus 激酶抑制剂，被批准用于治疗溃疡性结肠炎 (UC)。 目的: 评价托法替尼在日常实践中的有效性、安全性和使用情况。 方法: 在荷兰 15 家医院前瞻性入组开始服用托法替尼的 UC 患者。无皮质类固醇临床缓解 (短临床结肠炎活动指数 [SCCAI] ≤ 2)，生化缓解 (粪便钙卫蛋白水平 ≤ 250 µ g/g)，无皮质类固醇联合临床和生化缓解,在第 12 周和第 24 周确定缓解的预测因子、安全性结局、治疗剂量和对血脂的影响。在常规内镜评估的中心评价内镜结果。 结果: 总共对 123 例 UC 患者 (95% 例抗 TNF 、 62% 例 vedolizumab 和 3% 例 ustekinumab 患者) 进行了中位持续时间 24 周的随访 (四分位距 12-26)。24 周无皮质激素临床、生化、联合无皮质激素临床、生化缓解率患者比例分别为 29% (n: 22/77) 、 25% (n: 14/57) 、和 19% (n: 11/57) 分别。12 周时 21% 的患者达到内镜缓解 (Mayo = 0) (n: 7/33)。先前 vedolizumab 暴露与临床缓解减少相关 (比值比 0.33，95% 置信区间 [CI] 0.11-0.94)。在 24 周时，仍接受托法替尼治疗的患者中有 33% (n: 14/42) 使用 10 mg，每日两次。总共发生了 33 例托法替尼相关不良事件 (89 例/100 患者年)，7 例 (占总队列的 6%) 导致停药。诱导治疗期间胆固醇、 HDL 和 LDL 水平分别升高 18% (95% CI 9-26) 、 18% (95% CI 8-28) 和 21% (95% CI 14-39)。 结论: 托法替尼是抗 TNF 和 vedolizumab 治疗失败后 UC 的有效治疗方法。然而，观察到相对较高的不良事件发生率，导致 6% 的患者停药。
METHODS::Chronic diseases, including inflammatory bowel disease (IBD) urgently need new biomarkers as a significant proportion of patients, do not respond to current medications. Inflammation is a common factor in these diseases and microbial sensing in the intestinal tract is critical to initiate the inflammation. We have identified ELMO1 (Engulfment and Cell Motility Protein-1) as a microbial sensor in epithelial and phagocytic cells that turns on inflammatory signals. Using a stem-cell-based "gut-in-a-dish" coculture model, we studied the interactions between microbes, epithelium and monocytes in the context of IBD. To mimic the in-vivo cell physiology, enteroid-derived monolayers (EDMs) were generated from the organoids isolated from WT and ELMO1-/- mice and colonic biopsies of IBD patients. The EDMs were infected with the IBD-associated microbes to monitor the inflammatory responses. ELMO1-depleted EDMs displayed a significant reduction in bacterial internalization, a decrease in pro-inflammatory cytokine productions and monocyte recruitment. The expression of ELMO1 is elevated in the colonic epithelium and in the inflammatory infiltrates within the lamina propria of IBD patients where the higher expression is positively correlated with the elevated expression of pro-inflammatory cytokines, MCP-1 and TNF-α. MCP-1 is released from the epithelium and recruits monocytes to the site of inflammation. Once recruited, monocytes require ELMO1 to engulf the bacteria and propagate a robust TNF-α storm. These findings highlight that the dysregulated epithelial ELMO1→MCP-1 axis can serve as an early biomarker in the diagnostics of IBD and other inflammatory disorders.
METHODS:BACKGROUND:Peripheral blood eosinophilia (PBE) is a biomarker of an aggressive multiyear natural history in adults with inflammatory bowel diseases (IBDs). Additionally, PBE at diagnosis is associated with higher disease activity in pediatric-onset IBD. We sought to determine if PBE can function as a biomarker of long-term disease severity in pediatric-onset IBD patients who are followed into adulthood. METHODS:We analyzed a consented, prospective, natural history IBD registry at an adult tertiary center from 2009 to 2018. Prevalence of PBE was evaluated in both pediatric- and adult-onset IBD patients. Demographics, clinical characteristics, and health care utilization data were compared in patients with and without PBE. RESULTS:Among 2800 adult IBD patients, 23.4% had pediatric-onset disease. PBE was found in 34% of the pediatric-onset patients compared with 26.8% of the adult-onset IBD patients (P < 0.001). In the pediatric-onset IBD cohort, PBE was associated with higher rates of allergies (P < 0.0001), but not of asthma, allergic rhinitis, or primary sclerosing cholangitis. In the adult IBD patients with pediatric-onset disease, PBE was associated with higher rates of C-reactive protein elevation (P < 0.0001), erythrocyte sedimentation rate elevation (P < 0.0001), higher health care utilization, and higher average health care charges per year (P < 0.00001). CONCLUSIONS:Peripheral blood eosinophilia was more prevalent in adult IBD patients with pediatric-onset compared with adult-onset disease. Among all IBD patients with long-term follow-up, PBE defined a subgroup with more severe illness. These data suggest that PBE may be a biomarker for a high-risk subgroup with high cost trajectory and long-term severity in pediatric-onset IBD that persists into adulthood.
METHODS::Inflammatory bowel diseases (IBDs) are chronic inflammatory disorders with a complex pathogenesis, affecting people of all ages. They are characterized by alternating phases of clinical relapse and remission, depending on the fine balance between immune cells and the gut microbiota. The cross talk between cells of the immune system and the gut microbiota can result in either tolerance or inflammation, according to multifactorial triggers, ranging from environmental factors to genetic susceptibility. Glucocorticoid (GC) administration remains the first-line treatment for IBDs, although long-term use is limited by development of serious adverse effects. Recently, new alternative pharmacological therapies have been developed, although these are not always effective in IBD patients. There is a constant demand for effective new drug targets to guarantee total remission and improve the quality of life for IBD patients. The glucocorticoid-induced leucine zipper (GILZ) has been implicated as a promising candidate for this purpose, in view of its powerful anti-inflammatory effects that mimic those of GCs while avoiding their unwanted adverse reactions. Here we present and discuss the latest findings about the involvement of GILZ in IBDs.