Crohn's Disease Complicated by Strictures
Crohn's Disease Complicated by Strictures
Up to 80% of CD patients require at least one surgical resection within 10 years of diagnosis. A large portion of these interventions are due to stricturing disease. To avoid surgery, medical as well as endoscopic treatment options have been described. In addition, stricturoplasties are employed to preserve bowel length.
Traditionally, intestinal strictures in CD have been treated by oral and intravenous corticosteroids, bowel rest, and in the case of intractable symptoms, bowel resection. With the emergence of immunosuppressants, such as azathioprine/6-mercaptopurine and biological agents (anti-tumour necrosis factor α (TNF)) additional medical therapy options are available. In spite of this evolution, to date no specific intestinal antifibrotic therapy exists. Strikingly, the incidence of stricture formation and rate of surgery in CD did not decrease in past decades, despite the use of azathioprine. Data are emerging that earlier and prolonged use of immunosuppressive medication, including anti-TNF agents, can reduce the need for surgical interventions and hospitalisations. These results are encouraging, but have either been retrospective or in the case of prospective studies follow-up times were short. Nevertheless, these investigations suggest that our current ability to control inflammation is not sufficient consistently to prevent stricture formation. Whether earlier intervention with combination therapy with azathioprine and an anti-TNF agent would be more effective in the prevention of stricture formation is unknown.
At the current time a variety of modalities are used to try and discriminate medically responsive strictures from those that will require surgery, such as imaging (CTE, MRE), laboratory biomarkers (C-reactive protein, erythrocyte sedimentation rate) and stool biomarkers (fecal calprotectin). Yaffe and colleagues reported their experience with non-operative management of acute small bowel obstruction in 26 CD patients. In all but one patient the obstruction was relieved within 72 h using a regimen that included clear liquid diet, small bowel tube, total parenteral nutrition, prednisone, intravenous fluids and intravenous crystalline adrenocorticotrophic hormone. Seventy-five per cent of patients experienced at least a second episode during a mean follow-up of 52 months, all of which again responded to medical management. Forty-six per cent of patients eventually underwent elective surgery. If the patients remained free of obstruction after the initial episode for at least 8 months the risk of surgery thereafter was only 17%, indicating that medical therapy can ultimately prevent surgery in a clinically meaningful proportion of patients. A theoretical example of an oedematous bowel before and after medical therapy is illustrated in figure 2.
(Enlarge Image)
Figure 2.
Reduction of transmural oedema significantly affects the luminal cross-sectional area (adapted from Yaffe et al).
There was initially some concern regarding the use of infliximab in patients with established strictures, based on two retrospective reports. Subsequently, this idea was challenged by a study of 20 CD patients, 15 of whom had obstructive symptoms, treated with infliximab. Small intestinal contrast ultrasound was performed. In no case was progression of strictures or the occurrence of new strictures seen. In 80% of the patients responding to infliximab the stenosis completely regressed. Most importantly, data in large numbers of patients from the TREAT registry and the ACCENT I infliximab maintenance trial did not show an increased risk of the clinical occurrence of strictures. A recent review on this topic came to the same conclusion.
Currently, no specific medical therapy exists to treat fibrotic intestinal strictures. The dogma is that once fibrosis exists, it cannot be reversed. Data from hepatic cirrhosis and pulmonary fibrosis challenge this notion. Finding a specific antifibrotic therapy is an intense area of investigation in pharmaceutical companies and academic centres. A wide variety of mechanisms and platforms are being explored. Our hope is that in the next iteration of this or similar reviews, promising medical therapies for the treatment of fibrotic intestinal strictures will have emerged.
If medical therapy fails to improve obstructive symptoms, endoscopic dilation (ED) has become an accepted modality for the treatment of selected CD strictures. Main applications are short and isolated strictures within reach of a standard colonoscope, with many amenable strictures localised at the site of the ileocecal anastomosis after ileocecal resection. Most commonly through-the-scope balloons (TTS) are used to reach and pneumatically dilate strictures (figure 3). In general, the available reports are highly heterogeneous in respect of techniques used, follow-up times and endpoints applied.
(Enlarge Image)
Figure 3.
Through-the-scope endoscopic pneumatic balloon dilation of an anastomotic ileocecal stricture.
In a systematic review and descriptive pooled data analysis of 13 retrospective studies from 1990 to 2007, including 347 CD patients, the mean time from diagnosis of CD to occurrence of stricture was 13 years and the mean stricture length 2.7 cm (0.5–20 cm). This analysis mainly included postsurgical strictures and all were dilated with TTS. ED was technically successful in 86% of cases; 89% of the unsuccessful attempts had to undergo surgery. Long-term clinical efficacy (mean follow-up was 33 months), defined as being free of surgery was achieved in 58% of the patients. The mean interval between ED and surgery was 15 months in the remaining 42% of CD patients. A stricture length of 4 cm or less was associated with a surgery-free outcome in a multivariate analysis (OR 4, 95% CI 1.16 to 13.8). In subsequent dilations the estimation of clinical efficacy remained unchanged. In a single-centre study assessing 776 dilations in 178 CD patients (80% anastomotic) at 5-year follow-up 52% of patients had no further intervention or one dilation only and 36% of patients had surgery. Thienpont and colleagues reported the need for repeated dilation in 46% and surgery in 24% of CD patients during a mean follow-up of 5.8 years.
Factors influencing outcome after endoscopic balloon dilation in fibrostenotic CD are largely unknown. Technically successful dilation, stricture length of 4 cm or less and the absence of ulcer in the stricture are positively associated with successful dilatation. The data on smoking are inconsistent. In contrast, neither C-reactive protein concentrations, endoscopic disease activity nor medical treatment after dilation influenced the subsequent disease course in a different study. The majority of the observations were made with anastomotic strictures. No difference was noted when comparing the dilation efficacy or the probability of surgery-free survival of native versus postsurgical strictures. Small bowel adenocarcinoma is rare, but if overlooked can be fatal. In the CD-affected colon malignancy is more frequent and the incidence is comparable to ulcerative colitis. The endoscopist should therefore have a low threshold for taking a biopsy before ED. There is no convincing evidence that such mucosal biopsies increase the risk of perforation with subsequent balloon dilatation. The availability of deep enteroscopy, including double-balloon endoscopy makes dilatations in the more proximal upper small bowel feasible.
When mechanically dilating the intestine, perforation is a valid concern. Only few studies with low patient numbers addressed the safety of this procedure. In a randomised controlled trial with 29 paediatric patients with ED and intralesional steroid injection no complications were reported. A systematic review including 13 studies reported a major complication rate (defined as bleeding, perforation, infection or other event leading to hospitalisation) of 2%, with this value being up to 11% and 18% in two series. In 776 dilations in 178 patients a complication rate of 5.3% has been reported, which included bowel perforation, major bleeding, minor bleeding and abdominal pain or fever. To our knowledge no death related to the procedure has ever been reported.
Intralesional injection of steroids has been successfully used in other stricturing gastrointestinal conditions, such as peptic, corrosive or anastomotic strictures or fibrosis post-radiotherapy. Triamcinolone is considered an appropriate agent given its prolonged local effect, believed to last for 3–4 weeks.
In CD strictures most available evidence is retrospective and uncontrolled. Intralesional steroid injection in 13 CD patients led to a 100% immediate success rate. However, no follow-up data were provided. In a small retrospective series assessing anastomotic strictures, steroid injection delayed re-stricturing and reduced re-dilation rate. Singh et al found a lower stricture recurrence rate in the steroid group compared to placebo. In a systematic review the use of steroid injection appeared to be related to dilatation efficacy. In a single-centre prospective randomised controlled trial with 29 paediatric CD subjects intralesional triamcinolone injections after ED, led to a longer time to re-dilation and to surgery in the steroid group compared to placebo. However, sample size was small and follow-up time short. It should be noted that a prospective study in 13 adult CD patients was terminated early after reporting that triamcinolone injection led to an earlier need for re-dilation compared to placebo. In this series, however, only anastomotic strictures were examined, the strictures were possibly long-standing (8–30 years after surgery) and the multicentre design could have influenced different endoscopic procedures among different centres. Small, non-controlled, case reports and series assessed the use of intralesional TNF inhibitor therapy with encouraging results.
Endoscopic metallic stent insertion has been tried in a few patients. The initial success rate was reported to be 100%, but major complications, such as migration, perforation or fistulisation were frequent (67% of patients). In a prospective cohort study with 11 patients the authors concluded that the complication rate is too high to make this a routine treatment option, even when extractable stents are used. Biodegradable stents might be an emerging alternative. Finally, carving the stricture with a sphincterotome supplementing ED has been reported in one study with no increase in complications, and this technique has been successfully combined with steroid injections. A preliminary report indicates that patients receiving budesonide after dilation as opposed to dilation alone have a better outcome.
Therapy
Up to 80% of CD patients require at least one surgical resection within 10 years of diagnosis. A large portion of these interventions are due to stricturing disease. To avoid surgery, medical as well as endoscopic treatment options have been described. In addition, stricturoplasties are employed to preserve bowel length.
Medical Therapy
Traditionally, intestinal strictures in CD have been treated by oral and intravenous corticosteroids, bowel rest, and in the case of intractable symptoms, bowel resection. With the emergence of immunosuppressants, such as azathioprine/6-mercaptopurine and biological agents (anti-tumour necrosis factor α (TNF)) additional medical therapy options are available. In spite of this evolution, to date no specific intestinal antifibrotic therapy exists. Strikingly, the incidence of stricture formation and rate of surgery in CD did not decrease in past decades, despite the use of azathioprine. Data are emerging that earlier and prolonged use of immunosuppressive medication, including anti-TNF agents, can reduce the need for surgical interventions and hospitalisations. These results are encouraging, but have either been retrospective or in the case of prospective studies follow-up times were short. Nevertheless, these investigations suggest that our current ability to control inflammation is not sufficient consistently to prevent stricture formation. Whether earlier intervention with combination therapy with azathioprine and an anti-TNF agent would be more effective in the prevention of stricture formation is unknown.
At the current time a variety of modalities are used to try and discriminate medically responsive strictures from those that will require surgery, such as imaging (CTE, MRE), laboratory biomarkers (C-reactive protein, erythrocyte sedimentation rate) and stool biomarkers (fecal calprotectin). Yaffe and colleagues reported their experience with non-operative management of acute small bowel obstruction in 26 CD patients. In all but one patient the obstruction was relieved within 72 h using a regimen that included clear liquid diet, small bowel tube, total parenteral nutrition, prednisone, intravenous fluids and intravenous crystalline adrenocorticotrophic hormone. Seventy-five per cent of patients experienced at least a second episode during a mean follow-up of 52 months, all of which again responded to medical management. Forty-six per cent of patients eventually underwent elective surgery. If the patients remained free of obstruction after the initial episode for at least 8 months the risk of surgery thereafter was only 17%, indicating that medical therapy can ultimately prevent surgery in a clinically meaningful proportion of patients. A theoretical example of an oedematous bowel before and after medical therapy is illustrated in figure 2.
(Enlarge Image)
Figure 2.
Reduction of transmural oedema significantly affects the luminal cross-sectional area (adapted from Yaffe et al).
There was initially some concern regarding the use of infliximab in patients with established strictures, based on two retrospective reports. Subsequently, this idea was challenged by a study of 20 CD patients, 15 of whom had obstructive symptoms, treated with infliximab. Small intestinal contrast ultrasound was performed. In no case was progression of strictures or the occurrence of new strictures seen. In 80% of the patients responding to infliximab the stenosis completely regressed. Most importantly, data in large numbers of patients from the TREAT registry and the ACCENT I infliximab maintenance trial did not show an increased risk of the clinical occurrence of strictures. A recent review on this topic came to the same conclusion.
Currently, no specific medical therapy exists to treat fibrotic intestinal strictures. The dogma is that once fibrosis exists, it cannot be reversed. Data from hepatic cirrhosis and pulmonary fibrosis challenge this notion. Finding a specific antifibrotic therapy is an intense area of investigation in pharmaceutical companies and academic centres. A wide variety of mechanisms and platforms are being explored. Our hope is that in the next iteration of this or similar reviews, promising medical therapies for the treatment of fibrotic intestinal strictures will have emerged.
Endoscopic Dilation
If medical therapy fails to improve obstructive symptoms, endoscopic dilation (ED) has become an accepted modality for the treatment of selected CD strictures. Main applications are short and isolated strictures within reach of a standard colonoscope, with many amenable strictures localised at the site of the ileocecal anastomosis after ileocecal resection. Most commonly through-the-scope balloons (TTS) are used to reach and pneumatically dilate strictures (figure 3). In general, the available reports are highly heterogeneous in respect of techniques used, follow-up times and endpoints applied.
(Enlarge Image)
Figure 3.
Through-the-scope endoscopic pneumatic balloon dilation of an anastomotic ileocecal stricture.
In a systematic review and descriptive pooled data analysis of 13 retrospective studies from 1990 to 2007, including 347 CD patients, the mean time from diagnosis of CD to occurrence of stricture was 13 years and the mean stricture length 2.7 cm (0.5–20 cm). This analysis mainly included postsurgical strictures and all were dilated with TTS. ED was technically successful in 86% of cases; 89% of the unsuccessful attempts had to undergo surgery. Long-term clinical efficacy (mean follow-up was 33 months), defined as being free of surgery was achieved in 58% of the patients. The mean interval between ED and surgery was 15 months in the remaining 42% of CD patients. A stricture length of 4 cm or less was associated with a surgery-free outcome in a multivariate analysis (OR 4, 95% CI 1.16 to 13.8). In subsequent dilations the estimation of clinical efficacy remained unchanged. In a single-centre study assessing 776 dilations in 178 CD patients (80% anastomotic) at 5-year follow-up 52% of patients had no further intervention or one dilation only and 36% of patients had surgery. Thienpont and colleagues reported the need for repeated dilation in 46% and surgery in 24% of CD patients during a mean follow-up of 5.8 years.
Factors influencing outcome after endoscopic balloon dilation in fibrostenotic CD are largely unknown. Technically successful dilation, stricture length of 4 cm or less and the absence of ulcer in the stricture are positively associated with successful dilatation. The data on smoking are inconsistent. In contrast, neither C-reactive protein concentrations, endoscopic disease activity nor medical treatment after dilation influenced the subsequent disease course in a different study. The majority of the observations were made with anastomotic strictures. No difference was noted when comparing the dilation efficacy or the probability of surgery-free survival of native versus postsurgical strictures. Small bowel adenocarcinoma is rare, but if overlooked can be fatal. In the CD-affected colon malignancy is more frequent and the incidence is comparable to ulcerative colitis. The endoscopist should therefore have a low threshold for taking a biopsy before ED. There is no convincing evidence that such mucosal biopsies increase the risk of perforation with subsequent balloon dilatation. The availability of deep enteroscopy, including double-balloon endoscopy makes dilatations in the more proximal upper small bowel feasible.
When mechanically dilating the intestine, perforation is a valid concern. Only few studies with low patient numbers addressed the safety of this procedure. In a randomised controlled trial with 29 paediatric patients with ED and intralesional steroid injection no complications were reported. A systematic review including 13 studies reported a major complication rate (defined as bleeding, perforation, infection or other event leading to hospitalisation) of 2%, with this value being up to 11% and 18% in two series. In 776 dilations in 178 patients a complication rate of 5.3% has been reported, which included bowel perforation, major bleeding, minor bleeding and abdominal pain or fever. To our knowledge no death related to the procedure has ever been reported.
Adjuvant Techniques to Endoscopic Dilation
Intralesional injection of steroids has been successfully used in other stricturing gastrointestinal conditions, such as peptic, corrosive or anastomotic strictures or fibrosis post-radiotherapy. Triamcinolone is considered an appropriate agent given its prolonged local effect, believed to last for 3–4 weeks.
In CD strictures most available evidence is retrospective and uncontrolled. Intralesional steroid injection in 13 CD patients led to a 100% immediate success rate. However, no follow-up data were provided. In a small retrospective series assessing anastomotic strictures, steroid injection delayed re-stricturing and reduced re-dilation rate. Singh et al found a lower stricture recurrence rate in the steroid group compared to placebo. In a systematic review the use of steroid injection appeared to be related to dilatation efficacy. In a single-centre prospective randomised controlled trial with 29 paediatric CD subjects intralesional triamcinolone injections after ED, led to a longer time to re-dilation and to surgery in the steroid group compared to placebo. However, sample size was small and follow-up time short. It should be noted that a prospective study in 13 adult CD patients was terminated early after reporting that triamcinolone injection led to an earlier need for re-dilation compared to placebo. In this series, however, only anastomotic strictures were examined, the strictures were possibly long-standing (8–30 years after surgery) and the multicentre design could have influenced different endoscopic procedures among different centres. Small, non-controlled, case reports and series assessed the use of intralesional TNF inhibitor therapy with encouraging results.
Endoscopic metallic stent insertion has been tried in a few patients. The initial success rate was reported to be 100%, but major complications, such as migration, perforation or fistulisation were frequent (67% of patients). In a prospective cohort study with 11 patients the authors concluded that the complication rate is too high to make this a routine treatment option, even when extractable stents are used. Biodegradable stents might be an emerging alternative. Finally, carving the stricture with a sphincterotome supplementing ED has been reported in one study with no increase in complications, and this technique has been successfully combined with steroid injections. A preliminary report indicates that patients receiving budesonide after dilation as opposed to dilation alone have a better outcome.
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