Department of Gastroenterology, University Medical Center Ljubljana, Ljubljana, Slovenia.
Alimentiv, #200, 100 Dundas Street, London, N6A 5B6, ON, Canada.
Drugs. 2021 Feb;81(3):333-347. doi: 10.1007/s40265-020-01460-3.
In Crohn's disease and ulcerative colitis, inflammation is not limited to the digestive tract. Extraintestinal manifestations (EIMs), which affect up to 50% of patients, can substantially impair quality of life. EIMs may parallel luminal disease activity or have an independent course. They most commonly involve the musculoskeletal system (e.g., peripheral or axial arthritis) and skin (e.g., erythema nodosum and pyoderma gangrenosum). Less commonly, the hepatobiliary tract (e.g., primary sclerosing cholangitis [PSC]) and the eye (e.g., episcleritis, scleritis, and uveitis) are involved. Although the pathophysiology of EIMs is poorly understood, they are likely either manifestations of a primary systemic immune disease with variable expression amongst organs, or secondary phenomena to bowel inflammation. Additional pathophysiologic mechanisms may include aberrant lymphocyte homing mediated by ectopic expression of gut-specific chemokines and adhesion molecules, cross-reactivity between microbial and self-antigens, autoantibodies against epitopes shared by the intestine and extraintestinal tissues, elevated serum concentrations of cytokines, and alterations in innate immunity. Many EIMs independent of intestinal disease activity can be successfully treated with tumor necrosis factor (TNF) antagonists. The efficacy of vedolizumab-a monoclonal antibody targeting the α4β7 integrin-for the treatment of EIMs is uncertain, but data are emerging from post hoc analyses of randomized controlled trials, prospective and retrospective cohort studies, and case series. Vedolizumab may be effective in treating EIMs related to luminal disease activity (e.g., type 1 peripheral arthritis and erythema nodosum) but has not shown biochemical improvement in PSC. Its postulated role in the development of de novo EIMs is heavily confounded by the high proportion of patients previously exposed to TNF antagonists; new EIMs could result from TNF antagonist treatment cessation rather than being caused by vedolizumab. A common limitation of clinical studies is the lack of multidisciplinary involvement in the diagnosis and monitoring of EIMs, which may lead to misdiagnosis and overreporting. Future studies should rigorously measure EIMs in parallel with objective measures of luminal disease activity to provide more robust data on the relative efficacy of new drugs, especially as increasing numbers of gut-selective compounds enter clinical development.
在克罗恩病和溃疡性结肠炎中，炎症不仅局限于消化道。肠道外表现（EIMs），影响多达 50%的患者，会显著降低生活质量。EIMs 可能与肠道疾病活动平行，也可能有独立的病程。它们最常累及肌肉骨骼系统（例如外周或轴向关节炎）和皮肤（例如结节性红斑和坏疽性脓皮病）。不太常见的是，肝胆系统（例如原发性硬化性胆管炎 [PSC]）和眼睛（例如巩膜炎、葡萄膜炎和虹膜炎）也会受到影响。尽管 EIMs 的病理生理学机制尚不清楚，但它们可能是一种主要的全身免疫性疾病的表现，其在不同器官中有不同的表达，或者是肠道炎症的继发现象。其他病理生理机制可能包括由肠道特异性趋化因子和粘附分子的异位表达介导的异常淋巴细胞归巢、微生物和自身抗原之间的交叉反应、针对肠道和肠道外组织共有的表位的自身抗体、细胞因子血清浓度升高以及先天免疫的改变。许多与肠道疾病活动无关的 EIMs 可以用肿瘤坏死因子（TNF）拮抗剂成功治疗。vedolizumab-一种针对 α4β7 整合素的单克隆抗体-治疗 EIMs 的疗效尚不确定，但来自随机对照试验、前瞻性和回顾性队列研究以及病例系列的事后分析的数据正在出现。vedolizumab 可能对与肠道疾病活动相关的 EIMs 有效（例如 1 型外周关节炎和结节性红斑），但在 PSC 中没有显示生化改善。其在新发 EIMs 中的假定作用受到先前暴露于 TNF 拮抗剂的患者比例高的严重影响；新的 EIMs 可能是由于 TNF 拮抗剂治疗的停止而不是由于 vedolizumab 引起的。临床研究的一个常见局限性是缺乏多学科参与 EIMs 的诊断和监测，这可能导致误诊和过度报告。未来的研究应该严格平行测量 EIMs 和肠道疾病活动的客观指标，以提供关于新药相对疗效的更可靠数据，特别是随着越来越多的肠道选择性化合物进入临床开发。
