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Medical Therapy of Stricturing Crohn's Disease

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Medical Therapy of Stricturing Crohn's Disease Bettenworth and Rieder Fibrogenesis & Tissue Repair 2014, 7:5 http://www.fibrogenesis.com/content/7/1/5 REVIEW Open Access Medical therapy of stricturing Crohn’s disease: what the gut can learn from other organs - asystematicreview Dominik Bettenworth1† and Florian Rieder2,3*† 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. Keywords: Crohn’s disease, Intestinal fibrosis, Organ fibrosis, Anti-fibrotic agents Methods OR ‘skin’ OR ‘lung’ OR ‘systemic nephrogenic’ AND ‘fibro- Literature search and data selection sis’ OR ‘anti-fibrotic therapy’). Additionally, references of A comprehensive literature search was performed to assess cited original articles and reviews were further assessed for all relevant citations found in Embase, Medline (service of relevant work. The search included studies between 1960 the US National Library of Medicine (NLM) and the Na- and 2013. These data together with the authors’ personal tional Institutes of Health (NIH)) and the Cochrane Library experience in the field represent the basis of this review. for the following key words: (‘Crohn’sdisease(CD’)OR ‘Crohn’s’ AND (‘stricture’ OR ‘fibrosis’), (‘kidney’ OR ‘liver’ Introduction Crohn’s disease (CD) is a chronic remitting and relaps- * Correspondence: [email protected] †Equal contributors ing disease [1]. During acute flares, CD patients may 2Department of Gastroenterology and Hepatology, Digestive Disease present with mainly inflammation driven symptoms Institute, Cleveland Clinic Foundation, Cleveland, OH, USA such as diarrhea, abdominal pain and weight loss [2]. 3Department of Pathobiology, Lerner Research Institute, NC22, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA However, over the long-term, the naturally progressive Full list of author information is available at the end of the article disease course often culminates in stricture formation. © 2014 Bettenworth and Rieder; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Bettenworth and Rieder Fibrogenesis & Tissue Repair 2014, 7:5 Page 2 of 16 http://www.fibrogenesis.com/content/7/1/5 For example, around 40% of CD patients with ileal healing. Available drugs for the treatment of fibroste- disease develop clinically apparent strictures [3]. Stric- nosing or penetrating IBD are depicted in Figure 1. tures may be subdivided into fibrotic and inflammatory Consequently, the therapy of choice for fibrostenosing as well as mixed forms [4]. Accordingly, strictures in- CD, in conjunction with purely anti-inflammatory ther- cluding inflammatory alterations might benefit from apy, comprises endoscopic dilation (ED) procedures as anti-inflammatory therapy through a reduction of the well as surgical approaches, with all their associated inflammation-mediated edema [5]. During the last two limitations and morbidity [12-14]. A significant number decades, the therapeutic armamentarium for CD has of patients have to undergo multiple surgeries, with the expanded significantly, especially with the use of anti- subsequent risk of developing intestinal failure. In gen- tumor necrosis factor alpha (TNF-α)-based strategies eral, isolated strictures with a length of 4 cm or less [12] that can lead to sustained clinical response rates in a which are devoid of ulcers [15] and are accessible by substantial proportion of CD patients [6-8]. The suc- colonoscopy [16] or double-balloon enteroscopy [17] cess of anti-TNF antibodies fueled the hope for altering qualify for ED. Although ED procedures for stricturing the natural course of CD. Most recent epidemiological CD are usually technically successful, more than one data, however, revealed that despite the establishment third of patients will still undergo surgery within the of early immunosuppressive therapy in CD patients next years due to insufficient response to ED [12-14]. In with an increased risk of disabling disease, the fre- addition, major complications such as bowel perfor- quency of fibrostenosing complications did not signifi- ation, bleeding or infection are reported in a range of 2 cantly change [9]. Thus, a specific anti-fibrotic therapy to 5% [12,18]. In those CD patients where endoscopic for stricturing complications in CD patients is needed. stricture therapy is technically not feasible or not indicated, Despite recent advances in the pathophysiological un- surgical approaches including resection and strictureplasty derstanding of intestinal fibrosis in CD [10,11] and in are recommended. While repeated surgical bowel resec- contrast to fibrotic complications in other organs, no tions bear the risk for induction of deficiencies in gastro- specific anti-fibrotic drugs for intestinal strictures are intestinal functions and ultimately may manifest short currently available, and all existing therapies used in bowel syndrome and intestinal failure, strictureplasty can clinically apparent CD-associated stenosis are the same treat intestinal obstruction without reducing intestinal that are prescribed for active luminal disease. The same length [10]. Here, the incidence of major complications in- holdstrueforthetreatmentof penetrating CD, another cluding anastomotic leakage, abscess, fistula or sepsis is inflammatory bowel disease (IBD)-associated complica- present in about 6% [19]. The recurrence rates differ be- tion that is linked to impaired intestinal remodeling and tween various forms of strictureplasty from 23 to 41% 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, extra- cellular matrix; IL, interleukin; mAb, monoclonal antibody; TNF, tumor necrosis factor. Bettenworth and Rieder Fibrogenesis & Tissue Repair 2014, 7:5 Page 3 of 16 http://www.fibrogenesis.com/content/7/1/5 [20-22]. To date, no head to head comparison between ED IL-17A was found to possess pro-fibrotic activity in and strictureplasty has been performed yet. Taken together, various cell types including cardiac fibroblasts [37], hepatic the insufficient therapeutic impact of currently available stellate cells [38], skin fibroblasts [39] and lung epithelial anti-inflammatory drugs on stricture prevention and cells [40]. In addition, IL-17E was shown to increase colla- treatment, the complications associated with ED or sur- genproductioninlungfibroblasts [41]. Consistent with a gical treatment approaches associated with high socio- role of IL-17 in fibrosis IL-17 tissue levels were increased in economic burden [23] as well as the high recurrence a murine model of intestinal fibrosis [26]. In human fibrotic rates of stricturing CD after procedures demand the de- CD, IL-17A, but not IL-17E, was overexpressed within velopment and evaluation of specific anti-fibrotic agents tissue samples from CD strictures as compared to non- for stricturing CD. strictured CD areas and healthygut.IL-17secretionfrom cultured intestinal
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