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

Bettenworth D, Rieder F - Fibrogenesis Tissue Repair (2014)

Bottom Line: 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.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.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Gastroenterology and Hepatology, Digestive Disease Institute, Cleveland Clinic Foundation, Cleveland, OH, USA. riederf@ccf.org.

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.

No MeSH data available.


Related in: MedlinePlus

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.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
getmorefigures.php?uid=PMC4230721&req=5

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.

Mentions: Crohn’s disease (CD) is a chronic remitting and relapsing disease[1]. During acute flares, CD patients may present with mainly inflammation driven symptoms such as diarrhea, abdominal pain and weight loss[2]. However, over the long-term, the naturally progressive disease course often culminates in stricture formation. For example, around 40% of CD patients with ileal disease develop clinically apparent strictures[3]. Strictures may be subdivided into fibrotic and inflammatory as well as mixed forms[4]. Accordingly, strictures including inflammatory alterations might benefit from anti-inflammatory therapy through a reduction of the inflammation-mediated edema[5]. During the last two decades, the therapeutic armamentarium for CD has expanded significantly, especially with the use of anti-tumor necrosis factor alpha (TNF-α)-based strategies that can lead to sustained clinical response rates in a substantial proportion of CD patients[6-8]. The success of anti-TNF antibodies fueled the hope for altering the natural course of CD. Most recent epidemiological data, however, revealed that despite the establishment of early immunosuppressive therapy in CD patients with an increased risk of disabling disease, the frequency of fibrostenosing complications did not significantly change[9]. Thus, a specific anti-fibrotic therapy for stricturing complications in CD patients is needed. Despite recent advances in the pathophysiological understanding of intestinal fibrosis in CD[10,11] and in contrast to fibrotic complications in other organs, no specific anti-fibrotic drugs for intestinal strictures are currently available, and all existing therapies used in clinically apparent CD-associated stenosis are the same that are prescribed for active luminal disease. The same holds true for the treatment of penetrating CD, another inflammatory bowel disease (IBD)-associated complication that is linked to impaired intestinal remodeling and healing. Available drugs for the treatment of fibrostenosing or penetrating IBD are depicted in Figure 1. Consequently, the therapy of choice for fibrostenosing CD, in conjunction with purely anti-inflammatory therapy, comprises endoscopic dilation (ED) procedures as well as surgical approaches, with all their associated limitations and morbidity[12-14]. A significant number of patients have to undergo multiple surgeries, with the subsequent risk of developing intestinal failure. In general, isolated strictures with a length of 4 cm or less[12] which are devoid of ulcers[15] and are accessible by colonoscopy[16] or double-balloon enteroscopy[17] qualify for ED. Although ED procedures for stricturing CD are usually technically successful, more than one third of patients will still undergo surgery within the next years due to insufficient response to ED[12-14]. In addition, major complications such as bowel perforation, bleeding or infection are reported in a range of 2 to 5%[12,18]. In those CD patients where endoscopic stricture therapy is technically not feasible or not indicated, surgical approaches including resection and strictureplasty are recommended. While repeated surgical bowel resections bear the risk for induction of deficiencies in gastrointestinal functions and ultimately may manifest short bowel syndrome and intestinal failure, strictureplasty can treat intestinal obstruction without reducing intestinal length[10]. Here, the incidence of major complications including anastomotic leakage, abscess, fistula or sepsis is present in about 6%[19]. The recurrence rates differ between various forms of strictureplasty from 23 to 41%[20-22]. To date, no head to head comparison between ED and strictureplasty has been performed yet. Taken together, the insufficient therapeutic impact of currently available anti-inflammatory drugs on stricture prevention and treatment, the complications associated with ED or surgical treatment approaches associated with high socioeconomic burden[23] as well as the high recurrence rates of stricturing CD after procedures demand the development and evaluation of specific anti-fibrotic agents for stricturing CD.


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

Bettenworth D, Rieder F - Fibrogenesis Tissue Repair (2014)

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.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4230721&req=5

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.
Mentions: Crohn’s disease (CD) is a chronic remitting and relapsing disease[1]. During acute flares, CD patients may present with mainly inflammation driven symptoms such as diarrhea, abdominal pain and weight loss[2]. However, over the long-term, the naturally progressive disease course often culminates in stricture formation. For example, around 40% of CD patients with ileal disease develop clinically apparent strictures[3]. Strictures may be subdivided into fibrotic and inflammatory as well as mixed forms[4]. Accordingly, strictures including inflammatory alterations might benefit from anti-inflammatory therapy through a reduction of the inflammation-mediated edema[5]. During the last two decades, the therapeutic armamentarium for CD has expanded significantly, especially with the use of anti-tumor necrosis factor alpha (TNF-α)-based strategies that can lead to sustained clinical response rates in a substantial proportion of CD patients[6-8]. The success of anti-TNF antibodies fueled the hope for altering the natural course of CD. Most recent epidemiological data, however, revealed that despite the establishment of early immunosuppressive therapy in CD patients with an increased risk of disabling disease, the frequency of fibrostenosing complications did not significantly change[9]. Thus, a specific anti-fibrotic therapy for stricturing complications in CD patients is needed. Despite recent advances in the pathophysiological understanding of intestinal fibrosis in CD[10,11] and in contrast to fibrotic complications in other organs, no specific anti-fibrotic drugs for intestinal strictures are currently available, and all existing therapies used in clinically apparent CD-associated stenosis are the same that are prescribed for active luminal disease. The same holds true for the treatment of penetrating CD, another inflammatory bowel disease (IBD)-associated complication that is linked to impaired intestinal remodeling and healing. Available drugs for the treatment of fibrostenosing or penetrating IBD are depicted in Figure 1. Consequently, the therapy of choice for fibrostenosing CD, in conjunction with purely anti-inflammatory therapy, comprises endoscopic dilation (ED) procedures as well as surgical approaches, with all their associated limitations and morbidity[12-14]. A significant number of patients have to undergo multiple surgeries, with the subsequent risk of developing intestinal failure. In general, isolated strictures with a length of 4 cm or less[12] which are devoid of ulcers[15] and are accessible by colonoscopy[16] or double-balloon enteroscopy[17] qualify for ED. Although ED procedures for stricturing CD are usually technically successful, more than one third of patients will still undergo surgery within the next years due to insufficient response to ED[12-14]. In addition, major complications such as bowel perforation, bleeding or infection are reported in a range of 2 to 5%[12,18]. In those CD patients where endoscopic stricture therapy is technically not feasible or not indicated, surgical approaches including resection and strictureplasty are recommended. While repeated surgical bowel resections bear the risk for induction of deficiencies in gastrointestinal functions and ultimately may manifest short bowel syndrome and intestinal failure, strictureplasty can treat intestinal obstruction without reducing intestinal length[10]. Here, the incidence of major complications including anastomotic leakage, abscess, fistula or sepsis is present in about 6%[19]. The recurrence rates differ between various forms of strictureplasty from 23 to 41%[20-22]. To date, no head to head comparison between ED and strictureplasty has been performed yet. Taken together, the insufficient therapeutic impact of currently available anti-inflammatory drugs on stricture prevention and treatment, the complications associated with ED or surgical treatment approaches associated with high socioeconomic burden[23] as well as the high recurrence rates of stricturing CD after procedures demand the development and evaluation of specific anti-fibrotic agents for stricturing CD.

Bottom Line: 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.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.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Gastroenterology and Hepatology, Digestive Disease Institute, Cleveland Clinic Foundation, Cleveland, OH, USA. riederf@ccf.org.

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.

No MeSH data available.


Related in: MedlinePlus