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.

Pathogenesis of Intestinal Fibrosis in Inflammatory Bowel Disease and Perspectives for Therapeutic Implication

“…Some of the most promising therapeutic strategies are directed at a specific blockade of TGF-β signaling, inhibition of tyrosine kinases, components of the renin-angiotensin systems, IL-13 and mammalian target of rapamycin [6] .…”

“…Determination of key molecular regulators of fibrogenesis could lead to the identification of potential anti-fibrotic agents. The potential to stop or even reverse organ fibrosis has been shown in other organs of the human body [6] , for instance, in liver fibrosis through cure of hepatitis C virus infection [7] .…”

Intestinal Fibrosis and Liver Fibrosis: Consequences of Chronic Inflammation or Independent Pathophysiology?

“…Activating subpopulations of macrophages to increase MMP expression and the induction of myofibroblast apoptosis may be suitable and may serve as an antifibrotic therapeutic armamentarium [107]. Another approach could be the stimulation of MMP production, which has been successfully performed in animal studies [5,108,109]. …”

“…The imbalance between the production and degradation of ECM is observed commonly in various fibrotic diseases and represents a promising target for antifibrotic approaches [5]. Degradation of the ECM components is regulated by the enzymatic activity of MMPs [80], which is affected by the expression of tissue inhibitors of metalloproteinase (TIMPs).…”

“…While inflammatory strictures may respond to anti-inflammatory medical treatment, fibrostenotic strictures do not resolve upon immunosuppressive therapy. Due to the paucity of antifibrotic drugs for intestinal fibrosis [5], CD-associated fibrotic strictures are a major reason why approximately 75% of CD patients have to undergo surgery at least once during their lifetime [6]. …”