Progression to colectomy in the era of biologics: A single center experience with pediatric ulcerative colitis.
- 作者列表："Ihekweazu FD","Fofanova T","Palacios R","Ajjarapu A","Karam L","Vogel AM","Rodriguez JR","Kellermayer R
BACKGROUND/PURPOSE:Clinical outcomes in pediatric ulcerative colitis (UC) in the era of biologic agents are poorly defined. We aimed to describe risk factors for colectomy in pediatric UC in the era of infliximab therapy. METHODS:We reviewed 217 pediatric patients at Texas Children's Hospital with newly diagnosed UC between 2003 and 2015; 117 had a minimum of 5 years of follow-up. Extent of disease at diagnosis, medication exposure, the presence of extraintestinal manifestations (EIMs), and need for surgery were noted. RESULTS:Average length of follow up was 5.02 ± 2.27 years. Forty-two percent presented with pancolitis. Infliximab was used in 39%, immunomodulators in 65%, and steroids in 89% of patients. EIMs occurred in 24.9% of patients. The cumulative rate of colectomy was 12.9% at 5 years. Children presenting as E2 (Paris Classification) and children prescribed oral steroid monotherapy at diagnosis progressed to surgery faster than any other group. Of the children who received infliximab, females and children less than 5 years old were less likely to respond to therapy. CONCLUSIONS:The natural course of pediatric UC remains aggressive despite the addition of infliximab to the standard of care and suggests a need for early aggressive clinical intervention. LEVEL-OF-EVIDENCE RATING:Level IV.
背景/目的: 生物制剂时代儿童溃疡性结肠炎 (UC) 的临床结局尚不明确。我们旨在描述英夫利昔单抗治疗时代儿童 UC 结肠切除术的危险因素。 方法: 我们回顾了德克萨斯儿童医院 217 例 2003年和 2015 初诊 UC 的儿童患者; 117 例至少随访 5 年。注意到诊断时的疾病程度、药物暴露、肠外表现 (EIMs) 的存在和手术需要。 结果: 平均随访 5.02 ± 2.27 年。2% 表现为全结肠炎。39% 的患者使用了英夫利昔单抗，65% 的患者使用了免疫调节剂，89% 的患者使用了类固醇。24.9% 的患者发生 EIMs。5 年结肠切除术的累积率为 12.9%。表现为 E2 (Paris 分类) 的儿童和诊断时处方口服类固醇单药治疗的儿童进展到手术的速度比任何其他组快。在接受英夫利昔单抗治疗的儿童中，女性和小于 5 岁的儿童对治疗的反应较小。 结论: 尽管在标准护理中加入了英夫利昔单抗，但小儿 UC 的自然病程仍然具有侵袭性，提示需要早期积极的临床干预。 证据等级: IV 级。
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.