Efficacy of Medical Therapy for Stricturing CD

One of the most important goals of medical therapy for IBD is to modify its natural history and to prevent complications, such as stricture and fistula. Therefore, aggressive medical therapy, such as the top-down approach (i.e., the use of biological agents in early disease course) or combined biological agent and immunomodulator therapy, in patients at high risk for CD complications when B1 phenotype is still a predominant presentation.

Once stricture has already formed, it is not clear whether medical therapy is beneficial, effective, or harmful in treating CD stricture is controversial. Some investigators have proposed that patients with stricturing CD may have a course of treatment with corticosteroids to reduce the concurrent inflammation on stricture and above stricture. Earlier published data from the TREAT Registry and ACCENT I trial suggest a possible increased likelihood of intestinal stenosis, stricture, or obstructions after infliximab (IFX) therapy. However, multivariate analysis showed that the development of stenosis, stricture, or obstruction was associated only with severity, duration, ileal location, and corticosteroid use, but not with the use of IFX. The efficacy of IFX in treating strictures, inflammatory or noninflammatory, was reported in small case series. A study of 241 CD patients which included enterography-proven “low-risk strictures” showed that the use of immunomodulators or biological agents decreased the need for surgery in 50% of the patients during a median follow-up of 607 days, suggesting that the use of biologics may change the natural course of CD. A recent study in the correlation between response to medical therapy and MRI findings of small bowel CD reported that patients with narrowed intestine and prestenotic lumen dilation were less likely to respond to medical therapy than those with no stenosis. A recent multicenter, prospective, observational cohort study of adalimumab (ADA) in 97 patients with CD and symptomatic small bowel strictures was performed. At week 24, 62 (64%) patients had achieved success as defined as ADA continuation without prohibited treatment with other agents. After a median follow-up time of 3.8 years, 46% ± 7% of patients who were in success at week 24 (i.e., 29% of the whole cohort) were still in prolonged success at 4 years. For the whole cohort, 51% ± 5.3% of the patients did not have bowel resection surgery for 4 years. However, serious adverse events were reported in 70 of 97 (72%) patients. But whether there was an exacerbation of stricture was not specified.

Concern of Medical Therapy for Stricturing Crohn’s disease

It has been a debate whether biological therapy can trigger the formation of new stricture or worsen existing stricture. Data from the TREAT registry demonstrated that new corticosteroid use was found to be associated with stricture formation, not the use of IFX, in a multivariate analysis. The majority of previous large randomized control trials of biological agents (including IFX, ADA, certolizumab pegol, and vedolizumab) for in CD have excluded patients with underlying strictures or with obstructive symptoms, due to the concern of development of new strictures or worsening of existing strictures as well as poor response to stricturing disease. Therefore, biological agents have not been considered as a routine therapy for stricturing CD.

Clinically, we do notice that some patients on long-term therapy with biological agents were able to maintain mucosal healing, while developing spindle-shaped stricture with normal overlaying mucosa, but not traversable to pediatric colonoscope. This is consistent with some early retrospective studies in which IFX use may be associated with the development of obstruction or new stricture as a potential complication. For example, one study of 76 patients with refractory luminal CD reported seven (10%) developed bowel obstructions requiring hospitalization and surgery after IFX. Preexisting strictures were known in five of these seven patients. A separate case series of 10 patients with stricturing CD with four underlying perianal fistulae showed a progression to complete bowel obstruction resulting in surgery within 5 weeks of IFX treatment. The phenomenon has been documented in other small retrospective studies. A longitudinal study using small intestine contrast ultrasound to show new or progression of existing strictures, revealed that partial or complete obstruction developed in 3 of 36 patients treated with IFX or ADA during a mean follow-up of 23 ± 7 months. It is not clear whether the development of new stricture or worsening of existing stricture directly results from the use of anti-TNF biological agents. It is, however, prudent that CD strictures with predominantly inflammatory component may be amenable to medical therapy.

Endoscopic Balloon Dilation

The use EBD to treat fibrous strictures in IBD stems from its efficacy with benign strictures other than IBD, such as peptic strictures, biliary stricture, and nonsteroidal antiinflammatory drug–induced strictures. The efficacy of EBD therapy for the primary and secondary in CD strictures has been well documented. A metaanalysis of 13 studies including a total of 347 patients with mainly anastomotic strictures, technical success rate, and long-term efficacy were achieved in 86% and 58%, respectively, during a mean follow-up period of 33 months. In multivariate analysis, only stricture length ≤ 4 cm was found to be associated with a better surgery-free outcome. It is interesting that the comparison of outcome of EBD from periods 1987–1998 versus 1999–2009 showed no significant difference in the need for repeat dilation or surgery, suggesting that recent advances in medical and surgical therapy did not influence the long-term outcomes of the endoscopic therapy.

It is speculated that the pathogenesis of the primary and anastomotic strictures in CD is different, with inflammation and surgical factors being the contributing factors. In various studies, reported short-term technical success of EBD ranged from 71% to 100% and long-term success rate ranged from 50% to 100%. It is believed that the reported discrepancy in EBD may be explained by heterogeneity of included patient population, especially composition of primary and anastomotic strictures. It is still not clear whether primary or anastomotic strictures in CD patients respond to EBD therapy. In a study of 55 patients with EBD for 74 symptomatic strictures (69% being the primary), the rates of technical success were comparable for the primary and secondary strictures. However, the long-term outcome appeared to be worse in the primary stricture group with in nearly half of the patients requiring surgery during a mean follow-up of 44 months. Our earlier study of 128 patients and a total of 430 EBD 169 strictures (88 primary, 81 secondary) showed no statistical difference between primary or anastomotic strictures in the need for surgery (34% vs. 30%), redilation (59% vs. 58%), or total interventions (surgery + redilations, 72% vs. 73%), in a mean follow-up of 33 months. However, a study of 30 patients showed a better surgical-free survival with the secondary strictures than that of the primary strictures.

Attempts have been made to make the head-to-head comparison, comparison between endoscopic and surgical therapy for CD stricture. We recently conducted a study comparing EBD (N = 176) versus surgery (N = 130) for the secondary strictures at ICA in CD patients and found that the surgical treatment was more effective than EBD but carried a higher risk for complications. Upfront surgery for ICA stricture (hazard ratio [HR], 0.49; 95% confidence interval [CI]: 0.32–0.76) was found to be associated with a lower risk for subsequent surgery. However, one or more EBD delayed the need for surgery by an average of 6.5 years. Our recent study of comparison of EBD and surgical resection of primary strictures of the ileum or ileocolon showed the sustained response of EBD is not as good as that of EBD in the secondary stricture of from a published historic cohort from our Center. Furthermore, EBD for the primary strictures appears to more prone to procedure-associated perforation in this author’s experience.

It is believed that the response to EBD therapy is comparable between CD stricture and non-CD benign strictures ; and between the primary and CD anastomotic strictures. It is important to identify the factors to predict the response to EBD therapy. The presence of long stricture (>4–5 cm) or prestenotic lumen dilation may be the main predictors for poor response to EBD. Therefore, EBD may not be the best initial approach for those patients. Attempt has been made to create a predictor model for the responder or poor responder to EBD therapy. Our group created a nomogram in study of 185 patients with CD-associated ICA anastomotic strictures with a total of 462 EBD. During a mean follow-up of 3.9 years, 27 patients (15%) required hospitalization without surgery for strictures, and 66 (36%) required subsequent surgery. Factors associated with the need for surgery on multivariable analysis were symptomatic disease (HR, 3.54; 95% CI: 1.41–8.93), longer time interval from last surgery (HR, 1.05; 95% CI: 1.01–1.10), and radiographic prestenotic dilation (HR, 2.36; 95% CI: 1.38–4.03). The nomogram was created based on those factors, to estimate the need for surgery with a good concordance index of 0.67. For patients with those risk factors, EBD alone may not be effective. Alternative approaches may be attempted, including modification of endoscopy therapy, such as use of ES or surgical intervention. Our group is currently working on a nomogram for EBD and ES in the treatment of CD primary strictures.

Endoscopic Stricturotomy

In our Interventional IBD unit, ES is increasingly performed, for the first choice or rescuing procedure for strictures refractory EBD therapy. We recently performed a case-control study, comparing efficacy and safety of CD strictures at ileocolonic anastomosis (ICA), colo-colonic anastomosis (CCA), and ileorectal anastomosis (IRA). A total of 185 patients were studied, including 21 treated with ES and 164 treated with EBD. The immediate success with passage of the scope through the stricture after therapy was achieved in 100% of patients treated with ES and 90% patients with EBD. Subsequent surgery for stricture was required in 2 (10%) patients with ES and 55 (33%) with EBD ( P = .03), during a median of 0.8 (interquartile range: 0.1–1.6) year and 4.0 (interquartile: 0.8–6.9) years, respectively (Lan L and Shen B. Inflamm Bowel Dis accepted for publication).

It appears that ES is more effective than EBD for the treatment of CD-associated anastomotic stricture. ES may carry a higher risk for bleeding and lower risk for perforation than EBD. Further studies are needed to compare the efficacy and safety between ES and EBD in the treatment of primary strictures of CD and between ES and surgery in the treatment primary and secondary strictures of CD.

Other Endoscopic Treatment Modalities

Investigators have explored self-expanding metal stents in the treatment of refractory strictures. The use of biodegradable stents in patients with CD strictures has also been reported. Detailed information on the stent treatment is discussed in a separate chapter ( Chapter 15 ). It appears that securing the stent and preventing stent migration are the main challenges. The short and long efficacy and adverse effects, particularly stent migration and bowel perforation, of stents need to be further evaluated.

Endoscopy-Associated Complications

The efficacy and safety should be carefully balanced between medical versus endoscopic versus surgical therapy and between different modalities of endoscopy therapy. The main complications of endoscopic therapy are perforation and excessive bleeding. Reported EBD-associated complication rates ranged from 0% to 15%. A metaanalysis of 13 studies in a total of 347 CD patients with stricture, reported complication rate showed the complications rate ranging from 2% to 10%. In a separate review of 23 studies with sample size of 5 to 59 patients, the major complication rate was 3% during a median follow-up of 21 months. The discrepancy in the frequency of complications is due to multiple factors, including the sample size, number of dilation per session, balloon pressure, balloon size, lesions, patients included, definition of complications, and technical expertise.

Question has been whether (1) IBD is a risk factor for procedure-associated perforation of diagnostic and therapeutic endoscopy; or (2) underlying IBD is associated with severe complications after endoscopy-associated perforation or “complication’s complication,” that is, intensive care unit admission, the requirement for bowel resection or construction of diverting stoma, or mortality.

Our group has conducted a series of investigation in the concern. We studied the risk of colonic perforation (spontaneous or iatrogenic) using the Nationwide Inpatient Sample and found that patients in the IBD group had a higher risk than the control group, with adjusted odds ratio (aOR) of 1.83 (95% CI: 1.40, 2.38). In addition, EBD was independent risk factor for perforation in both IBD and non-IBD patients with aOR = 6.63 (95% CI: 3.95, 11.11). When therapeutic endoscopy was performed, however, patients with underlying IBD may not have a higher risk for complication than the non-IBD controls. In our case-control study in comparison of EBD between CD stricture and non-CD–related benign stricture, the complication (perforation and bleeding) rate was comparable. We would like to know the risk factors for endoscopy-related complications within the group of IBD patients. We performed a study of IBD patients with lower GI endoscopy using electronic medical records of the Cleveland Clinic Health System and found that severe active disease on endoscopy (aOR, 3.82; 95% CI: 1.03–15.24) and concurrent use of systemic corticosteroids use (aOR, 7.68; 95% CI: 1.48, 39.81) to be associated with an increased risk for perforation.

Not all complications can lead to life-threatening consequence. But when it happens, the complication can be detrimental. The complication’s complication ranges from hospital admission, blood transfusion, surgical intervention, bowel resection, diverting ostomy, intensive care unit stay, organ failure, or even mortality. We performed a study of 9518 IBD and 207,816 non-IBD patients from Cleveland Clinic Health System and confirmed that underlying diagnosis of IBD is a risk factor for diagnostic or therapeutic endoscopy-associated complications. In addition, the use of systemic corticosteroids at the time of endoscopy to be associated with greater risk for the detrimental adverse outcomes postperforation (OR, 13.5; 95% CI: 1.3–18.4).

ES is a novel approach for IBD-associated stricture, and there are limited published data on its safety in comparison with conditional EBD. In the study of 164 patients with EBD and 21 patients with ES for ICA, CCA, and IRA anastomotic strictures from CD, we recorded five procedure-associated perforations (1.1% per procedure) in the EBD group and none in the ES group. We also documented four procedure-associated, transfusion-required bleeding (8.8% per procedure) occurred in the ES group and none in the EBD group (Lan N and Shen B. manuscript submitted). It appears that ES carries a higher risk for bleeding and lower risk for perforation, than EBD.

Surgical Bowel Resection and Anastomosis

The most common modality of bowel resection surgery for CD is ileal or ileocolonic resection (ICR) with ICA for B1 and B3 disease based on the Montreal Classification. It appears that a wide versus narrow margin of resection or anastomosis type has no impact on the postoperative disease recurrence. However, anastomosis type may affect endoscopist’s recognition and treatment, if stricture recurs.

Stricturoplasty

Bowel-sparing procedures, such as STX, have gained popularity. It is intriguing that the bowel lumen of STX place is often spared with recurrent disease. Another study of 52 patients reported regression of serositis, and fat wrapping at previous STX sites. A separate study of 21 patients undergoing isoperistaltic STX which showed radiographic, endoscopic, and histopathological evidence of regression in 20 patients during a median follow-up period of 8 years. STX has also been shown to normalize inflammatory indices, ameliorate anemia and hypoalbuminemia, facilitate weight gain, and reduce in the need for medications. STX is considered as a preferred procedure to surgical resection.

The main indications for STX include: (1) diffuse jejunoileitis with single or multiple short fibrotic strictures; (2) strictures with a prior history of multiple small bowel resections; (3) recurrent strictures within 1 year of previous resection; (4) isolated ICA, IRA, or ileal pouch strictures; (5) strictures at the pouch inlet; and (6) selected duodenal strictures. STX may not be performed as an initial treatment of primary CD strictures, due to the concern of concurrent malignancy in the area.

Various types of STX configurations have been described for the management of CD and non-CD strictures. The most common STX are Heineke–Mikulicz (H-M) STX (for strictures length ≤ 10 cm), Finney STX (for stricture length between 10 and 20 cm), and Michelassi’s STX (for strictures > 20 cm). Others include ileoileal side-to-side isopersitaltic STX, ileocolonic side-to-side isopersitaltic STX, and ileocecal side-to-side isopersitaltic STX. The efficacy of STX in treating the primary and secondary/anastomotic CD strictures is detailed in a separate chapter ( Chapter 21 ).

Disease recurrence after STX is common in patients with CD. The location of recurrent disease can be distal or proximal to the STX site or at the inlet and or outlet of STX. Ozuner et al. from the Cleveland Clinic, reported a postoperative disease recurrence rate of 28% in 162 patients undergoing STX with a median follow-up of 4 years. A separate study of 314 patients from the same institution showed a disease recurrence rate of 34% post-STX during a median follow-up of 8 years. A metaanalysis of 15 retrospective studies of a 506 patients with a total of 1825 STX procedures showed a recurrence rate of 26% during a mean follow-up of 33 months. A metaanalysis of 32 studies with 1616 patients who underwent 4538 STX was conducted to compare disease recurrence and other outcomes between the conventional STX (the H-M and Finney techniques) and nonconventional STX (including the modified Finney, combined Heineke–Mikulicz and Finney, modified Heineke–Mikuliczs, and modified Michelassi). The study showed that early (3% [39/1157] vs. 1% [4/459]) and late (28% [329/1157] vs. 17% [77/459]) postoperative recurrent small bowel obstruction in the conventional and nonconventional STX groups, respectively, are common, with a mean disease duration before STX was 94.6 months with a mean follow-up of 50.1 months. The results suggest that the postoperative recurrence of disease and/or stricture is common. Although recurrent mucosal or luminal CD can be treated with various medications, the recurrent strictures need to be treated with endoscopy and/or surgery.

In addition to primary strictures, STX has also been used to treat secondary or anastomotic stricture or recurrent stricture at the previous STX site. However, there are scant data in the experience of STX in the treatment of anastomotic strictures. STX for the treatment of anastomotic strictures faces the same issue of recurrent disease and/or stricture. One study of 24 patients with symptomatic ICA strictures post-STX showed that 23% required addition surgery for recurrent CD. A separate study of 22 patients showed a recurrence rate of 5% during a median follow-up of 24 months. A study of larger sample size of 42 patients undergoing STX for anastomotic strictures showed a recurrence rate of 50% during a median follow-up of 99 months.

There are limited data on direct comparison of endoscopic therapy versus STX in the treatment of IBD strictures. We have performed a historical cohort study comparing EBD and STX in the treatment of ileal pouch strictures. A total of 167 patients met the inclusion criteria, including 151 (90%) patients with EBD and 16 (10%) with STX. Fifty-one patients (31%) had multiple pouch strictures and 100 (60%) patients had strictures at the pouch inlet. There were no significant differences found between the two groups, except for the severity of strictures, with STX being more severe. Patients in the two groups had similar overall pouch survival rates and stricture-free survival rates. It is not clear whether the results can be extrapolated in primary or secondary CD strictures without the history of restorative proctocolectomy. In addition, a comparison of ES and STX in the treatment CD stricture is required.

Risk Factors for Postoperative Recurrence of Bowel Resection or Stricturoplasty

Postoperative disease recurrence is common in patients with bowel resection for CD. A number of risk factors have been described for postoperative recurrence, including young age at the onset of disease, female gender, the presence of family history of CD, smoking, penetrating CD, long disease duration, the lack of prophylactic medical treatment, ileal site of involvement, indication for surgery, length of resected bowel, anastomotic technique, presence of noncaseating granulomas or neuronal plexitis on surgical resected specimens, disease involvement at the site of resection, and perioperative blood transfusions.

There are few published studies in risk factors for postoperative recurrence of CD undergoing STX. It appears that STX type may have an impact on the disease recurrence. A metaanalysis of 15 studies reported a higher reoperative rates for H-M STX than Finney. Additionally, a separate metaanalysis of 23 studies reported that 90% of recurrences occurred at non-STX site and 3% had site-specific recurrence. Short disease duration, younger age (<35 years), and short interval after previous resection may be factors for recurrence.

The risk factors for postoperative recurrence of CD are described in a separate chapter ( Chapter 25 ). The detailed techniques of endoscopic therapy for surgery-altered bowel in IBD patients are described in a separate chapter ( Chapter 12 ).

Surgery-Associated Complications

The reported frequency of postoperative complications after bowel resection and anastomosis has ranged from 5% to 30%. The complications include wound infection, anastomotic leak, abdominal or pelvic abscess or sepsis, and enterocutaneous fistula. The reported risk factors for the complications include preoperative low albumin level (<30 g/L), corticosteroid use, and the presence of abscess or fistula at the time of laparotomy. It is controversial whether a preoperative use of anti-TNF or anti-integrin biologics is associated with postoperative infectious complications. In a metaanalysis of eight studies comparing stapled side-to-side anastomosis (N = 396) and handsewn end-to-end anastomosis (N = 425) at ICR for CD patients found that stapled side-to-side anastomosis to have lower overall postoperative complications.

The common postoperative complications after STX are GI bleeding, ileus, bowel obstructions, and wound infection anastomotic leak, fistula, abscess, and sepsis. In a metaanalysis of 15 studies involving 506 patients undergoing 1825 STX, the overall complication rate was 13%. Complication rates after conventional and nonconventional STX have been reported to be 8% and 15%, respectively. Older age, the presence of weight loss, and hypoalbuminemia, the need for perioperative parenteral nutrition, the presence of intraabdominal abscess, and emergency surgery were found to related to postoperative complications. Interestingly, one study found that immunomodulators and IFX may help to reduce postoperative infectious complications following STX as well as bowel resection in CD patients.