Medical therapy of stricturing Crohn's disease: what the gut can learn from other organs - a systematic review

Abstract

Crohn's disease (CD) is a chronic remitting and relapsing disease. Fibrostenosing complications such as intestinal strictures, stenosis and ultimately obstruction are some of its most common long-term complications. Despite recent advances in the pathophysiological understanding of CD and a significant improvement of anti-inflammatory therapeutics, medical therapy for stricturing CD is still inadequate. No specific anti-fibrotic therapy exists and the incidence rate of strictures has essentially remained unchanged. Therefore, the current therapy of established fibrotic strictures comprises mainly endoscopic dilation as well as surgical approaches. However, these treatment options are associated with major complications as well as high recurrence rates. Thus, a specific anti-fibrotic therapy for CD is urgently needed. Importantly, there is now a growing body of evidence for prevention as well as effective medical treatment of fibrotic diseases of other organs such as the skin, lung, kidney and liver. In face of the similarity of molecular mechanisms of fibrogenesis across these organs, translation of therapeutic approaches from other fibrotic diseases to the intestine appears to be a promising treatment strategy. In particular transforming growth factor beta (TGF-β) neutralization, selective tyrosine kinase inhibitors, blockade of components of the renin-angiotensin system, IL-13 inhibitors and mammalian target of rapamycin (mTOR) inhibitors have emerged as potential drug candidates for anti-fibrotic therapy and may retard progression or even reverse established intestinal fibrosis. However, major challenges have to be overcome in the translation of novel anti-fibrotics into intestinal fibrosis therapy, such as the development of appropriate biomarkers that predict the development and accurately monitor therapeutic responses. Future clinical studies are a prerequisite to evaluate the optimal timing for anti-fibrotic treatment approaches, to elucidate the best routes of application, and to evaluate the potential of drug candidates to reach the ultimate goal: the prevention or reversal of established fibrosis and strictures in CD patients.

Figure 1

Therapeutic strategies to modify wound healing in Crohn’s disease. Currently available therapies for stricturing or fistulizing CD are depicted. Data derived from Embase, Medline and ClinicalTrials.gov. 6-MP, 6-mercaptopurine; AZA, azathioprine; CD, Crohn’s disease; ECM, extracellular matrix; IL, interleukin; mAb, monoclonal antibody; TNF, tumor necrosis factor.

Figure 2

Pipeline for therapeutic strategies to alter and improve fibrosis in organs other than the intestine. Each color represents a particular organ. Agents are classified based on their mode of action. Data derived from Embase, Medline and ClinicalTrials.gov. CCL2, chemokine ligand 2; CTGF, connective tissue growth factor; ECM, extracellular matrix; HIF, hypoxia inducible factor; IL, interleukin; JAK, janus kinase; JNK, c-Jun N-terminal kinase; mAb, monoclonal antibody; SAP, serum amyloid P component; TGF-β, transforming growth factor beta; VIP, vasoactive intestinal peptide.

Figure 3

Compounds used as anti-fibrotic therapies in other organs and their mode of action. The blue boxes represent a major profibrotic pathway. Compounds are depicted in red, indicating their mechanism of action. Abs, antibodies; ALK, activin receptor-like kinase; AT, angiotensin; CTGF, connective tissue growth factor; ECM, extracellular matrix; HGF, hepatocyte growth factor; HMG-CoA, 3-hydroxy-3-methylglutaryl-coenzyme A; Inh, Inhibitor; IL, interleukin; MAPK, mitogen-activated protein kinase; mTOR, mammalian target of rapamycin; PPAR, peroxisome proliferator-activated receptor; SMAD, small mothers against decapentaplegic; TGF, transforming growth factor.

Figure 4

A suggested path to more efficient translation of new discoveries to Crohn’s disease-associated fibrosis. Adapted from Friedman et al. [24]. IBD, inflammatory bowel disease.