Fibrostenotic strictures in Crohn's disease

Abstract

The use of biologic agents including anti-tumor necrosis factor monoclonal antibodies followed by anti-integrins and anti-interleukins has drastically changed the treatment paradigm of Crohn's disease (CD) by improving clinical symptoms and mucosal healing. However, up to 70% of CD patients still eventually undergo surgery mainly due to fibrostenotic strictures. There are no specific anti-fibrotic drugs yet. This review comprehensively addresses the mechanism, prediction, diagnosis and treatment of the fibrostenotic strictures in CD. We also introduce promising anti-fibrotic agents which may be available in the near future and summarize challenges in developing novel therapies to treat fibrostenotic strictures in CD.

Keywords: Crohn disease; Endoscopic balloon dilatation; Fibrostenosis; Intestinal fibrosis; Stricture.

Fig. 1.

Pathophysiological process to fibrotic strictures. APCs, antigen presenting cells; ILs, interleukins; Th0, naïve T cells; Th, T helper cells; IFN-γ, interferon-γ; TNF-α, tumor necrosis factor α; ROS, reactive oxygen species; TGF-β1, transforming growth factor-β1; CTGF, connective tissue growth factor; PDGF, platelet-derived growth factor; FGF, fibroblast growth factor; IGF, insulin-like growth factor; MMP9, matrix metalloproteinase 9; SMCs, smooth muscle cells; SEMFs, subepithelial myofibroblasts; ICC, interstitial cells of Cajal; EMT, epithelial mesenchymal transition; Endo-MT, endothelial mesenchymal transition; BM-MSCs, bone marrow derived mesenchymal stem cells; ECM, extracellular matrix.

Fig. 2.

Overview of Smad-dependent and Smad-independent transforming growth factor-β (TGF-β) signaling in intestinal fibrosis. ERK, extracellular signal regulated kinase; JNK, c-Jun N-terminal kinase; p38 MAPK, p38 mitogen-activated protein kinase; Rho, Ras homolog family member; ROCK, Rho kinase; MLC, myosin light chain; F-actin, filamentous actin; G-actin, globular actin; MRTF, myocardin-related transcription factor; SRF, serum response factor; ECM, extracellular matrix; α-SMA, α-smooth muscle actin; MYLK, myosin light-chain kinase.

Fig. 3.

Suggested treatment algorithm for stricturing Crohn’s disease. ^a Concurrent complications include: fistula, abscess, phlegmon, dysplasia, or malignancy. ^b Contraindications include: outside reach of endoscopy, stricture type (angulated, spindle-shaped, or asymmetric), or stricture location at proximity of the penetrating complication. NG, nasogastric; US, ultrasound; CTE, computed tomography; enterography; MRE, magnetic resonance enterography; IV, intravenous; CRP, C-reactive protein; EBD, endoscopic balloon dilatation.