Crohn’s Disease Like Pouch Inflammation Is Associated With Decreased Odds of Secondary Ileostomy Closure After Ileal Pouch Anal Anastomosis

Introduction

The staged total proctocolectomy (TPC) with ileal pouch anal anastomosis (IPAA) is the most common surgery performed for patients with ulcerative colitis (UC) complicated by medically refractory disease or dysplasia.¹ While the IPAA is intended to restore intestinal continuity, complications such as anastomotic leakage and Crohn’s disease–like pouch inflammation (CDLPI) may occur and necessitate the construction of a secondary ileostomy or pouch excision. Anastomotic leakage occurs in 4%-10% of patients after IPAA and has been associated with a 15-fold increased risk of pouch excision, though this risk may be decreased with early surgical management.^2-5 CDLPI develops in 10%-20% of patients as early as 1 year after IPAA and is characterized by severe inflammation of the pouch and prepouch ileum; strictures of the pouch, prepouch ileum, or proximal small bowel; or fistulae of the perineum or proximal small bowel.^6,7 Up to 45% of patients with CDLPI do not respond to medical therapy and require pouch excision.⁷

The aim of this study is to report the outcomes of patients who required a secondary ileostomy after IPAA and describe the factors associated with ileostomy closure.

Methods

Study Population and Outcome

We performed a retrospective analysis of all patients with UC or inflammatory bowel disease unclassified (IBDU) complicated by medically refractory disease or dysplasia who underwent 2- or 3-stage TPC with IPAA and subsequently required a secondary ileostomy between January 2008 and December 2017 at Mount Sinai Hospital. Patients with a baseline diagnosis of CD before colectomy were excluded. The primary outcome was secondary ileostomy closure.

Data Collection and Variables

Clinical information was abstracted from the electronic medical record using a standardized data collection sheet. Collected patient demographics and disease characteristics included sex, age at ileostomy creation, preoperative diagnosis (UC or IBDU), and pouch duration (time from final surgical stage to diverting ileostomy creation). Collected surgical characteristics included indication for colectomy, indication for secondary ileostomy after final surgical stage, number of stages, ileostomy closure, and pouch excision. Two-stage surgery was defined as (1) proctocolectomy and pouch creation with a proximal diverting ostomy and (2) ostomy closure. Three-stage surgery was defined as (1) subtotal colectomy with ileostomy, (2) completion proctectomy and pouch creation with a proximal diverting ileostomy, and (3) ostomy closure.

Anastomotic leakage was defined as a defect in the pouch-anal anastomosis identified on imaging, endoscopy, or surgery. CDLPI was defined clinically, endoscopically, and radiologically as the presence of severe inflammation of the pouch or afferent limb with ulcerations and an endoscopic Pouchitis Disease Activity Index subscore ≥5, strictures of the afferent limb or proximal small bowel, or fistulae involving the pouch, perineum, or proximal small bowel that occurred more than 6 months after final surgical stage.⁶

Statistical Analysis

Descriptive statistics were performed to describe baseline characteristics and are reported as proportions or medians (with interquartile range [IQR]) for the following categorical and continuous variables: sex, age at ileostomy creation, precolectomy disease type (UC or IBDU), colectomy indication (medically refractory disease or dysplasia), number of surgical stages, and ileostomy indication. Univariable and multivariable logistic and Cox regression for the primary outcome of secondary ileostomy closure was performed a priori with selection of the following clinically relevant variables: age, sex, ileostomy indication, and pouch duration. Adjusted odds ratios (aORs), hazard ratios, and 95% confidence intervals (CIs) are reported. All analyses were performed using SAS v9.4 (SAS Institute, Cary, NC). Two-sided P values <.05 were considered statistically significant.

Results

Among 613 patients who underwent 2- or 3-stage TPC with IPAA at Mount Sinai Hospital between 2008 and 2017, 42 (6.9%) required a secondary ileostomy after final surgical stage. Twenty-three (54.8%) patients were male, and the median age at secondary ileostomy creation was 38.2 (IQR, 25.6-48.0) years. Clinical and demographic characteristics are detailed in Table 1. The indication for secondary ileostomy was CDLPI in 24 (57.1%) patients, anastomotic leakage in 12 (28.6%), obstruction in 4 (9.5%), refractory anastomotic stricture in 1 (2.4%), and sinus tract in 1 (2.4%). The median time to ileostomy creation from final surgical stage was 14.8 (IQR, 2.5-24.8) months, and the median length of follow-up for patients after secondary ileostomy was 3.2 (IQR, 2.3-4.6) years. The primary indication for colectomy in the 24 patients who developed CDLPI and subsequently required secondary ileostomy construction was medically refractory UC. Of these, 22 (91.7%) of 24 were exposed to anti-tumor necrosis factor (anti-TNF) therapy immediately before colectomy and 2 (8.3%) of 24 were biologic naive. Only 1 (4.2%) of 24 patients who developed CDLPI had granulomas on pouch biopsy.

Anastomotic leakage was managed via exploratory laparotomy, drainage, and diversion in 5 (41.7%) of 12 patients; via small bowel resection with diversion in 3 (25.0%) of 12; via primary repair with diversion in 2 (16.7%) of 12; and via only diversion in 2 (16.7%) of 12. Biologic therapy after IPAA was prescribed for 15 (62.5%) of 24 patients with CDLPI: 12 (80%) of 15 were prescribed anti-TNF therapy and 3 (20%) of 15 were prescribed ustekinumab. Management of perianal abscesses and fistulae via incision and drainage or seton placement was required in 14 (58.3%) of 24 patients with CDLPI.

Secondary ileostomy closure was performed a median of 4.0 (IQR, 3.1-7.9) months after creation in 18 (42.9%) patients with the following original indications: 9 (75.0%) of 12 with anastomotic leakage, 5 (20.8%) of 24 with CDLPI, 3 (75.0%) of 4 with obstruction, and 1 (100%) of 1 with sinus tract. The 5 patients with CDLPI who underwent ileostomy closure were on anti-TNF therapy at the time of surgery. The median time to secondary ileostomy closure was shorter for patients with anastomotic leakage as compared with CDLPI, 3.7 (IQR, 3.0-5.2) months vs 8.5 (IQR, 7.4-11.4) months (P=.25). On univariable and multivariable logistic and Cox regression analysis, CDLPI was significantly associated with decreased odds (aOR, 0.06; 95% CI, 0.01-0.53) and decreased probability (hazard ratio, 0.05; 95% CI, 0.01-0.41) of secondary ileostomy closure, respectively. Results of univariable and multivariable analyses are detailed in Table 2.

Eight (33.3%) patients who did not have secondary ileostomy closure ultimately underwent pouch excision: 7 (87.5%) of 8 with CDLPI and 1 (12.5%) of 8 with refractory anastomotic stricture. The median time to pouch excision from secondary ileostomy creation was 13.9 (IQR, 7.8-15.5) months. On the multivariable analysis among patients with CDLPI, age at ostomy creation (aOR, 0.99; 95% CI, 0.93-1.1), sex (aOR, 1.2; 95% CI, 0.17-8.29), and biologic use after IPAA (aOR, 0.33; 95% CI, 0.04-2.68) were not significantly associated with pouch excision.

Discussion

In this single-center study of 42 patients with UC or IBDU who underwent TPC with IPAA followed by secondary ileostomy, only 43% had restoration of intestinal continuity. CDLPI was associated with significantly decreased odds of secondary ileostomy closure and was the most common indication for pouch excision. These findings extend the current literature by providing additional insight regarding the substantial impact CDLPI has on pouch longevity, and the associated risk of permanent intestinal discontinuity after a secondary ileostomy.

There is no consensus regarding the treatment of CDLPI, and the level of evidence to support medical therapy with anti-inflammatory agents such as immunomodulators and biologics is relatively weak.⁸ Notably, biologic use for CDLPI was not associated with significantly reduced odds of pouch excision in our study, suggesting that CDLPI is a severe disease phenotype that may not respond to biologics. Pouch failure occurs in up to 45% of patients with CDLPI and necessitates pouch excision and the creation of a permanent ostomy.^7,9 The potential need for a permanent ostomy is among the top concerns for patients with IBD, and many studies have linked having a stoma to adverse psychosocial outcomes such as depression, anxiety, and low self-esteem.¹⁰ These potential psychological outcomes are particularly important in patients after IPAA who are relatively young and otherwise healthy with an anticipated long life expectancy.

In comparison with patients with CDLPI, more patients with anastomotic leakage were able to proceed with secondary ileostomy closure, and in fact, no patient with anastomotic leakage required pouch excision. This is likely due to the early, aggressive surgical management after leakage identification that occurred in our study, with the majority of patients undergoing exploratory laparotomy, washout, drainage, and diversion a median of 0.4 (IQR, 0.3-1.9) months after final surgical stage. The early management of anastomotic leakage with surgery has been shown to decrease the risk of pouch excision and negative long-term functional outcomes.⁵ Prompt management of anastomotic leakages with surgery when indicated may decrease the risk of permanent ileostomy and the associated psychological burden as previously described.

Our study had several strengths. First, all patients underwent surgery and clinical follow-up at 1 institution and all charts were systematically reviewed by 2 investigators blinded to outcomes. Second, our study had a large sample size relative to previously published data and included 100% long-term follow-up for all patients. Our study was limited by its retrospective nature and risk of selection bias.

In conclusion, patients who require a secondary ileostomy for CDLPI have a very low likelihood of having intestinal continuity restored, and currently approved therapies may not mitigate the risk of pouch excision. There is an urgent need to identify the optimal medical-surgical regimen for patients with CDLPI to decrease the burden of disease and risk of a permanent stoma.

Author Contributions

M.K.: study concept and design, acquisition of data, analysis and interpretation of data, drafting of the manuscript, critical revision of the manuscript for important intellectual content, statistical analysis; M.P.: study concept and design, acquisition of data, critical revision of the manuscript for important intellectual content, statistical analysis; Y.H.W.W.: acquisition of data, critical revision of the manuscript for important intellectual content; S.K.: critical revision of the manuscript for important intellectual contents; P.S.: critical revision of the manuscript for important intellectual contents; M.C.D.: critical revision of the manuscript for important intellectual contents; A.J.G.: study concept and design, critical revision of the manuscript for important intellectual contents. All authors provided final approval of the manuscript. M.K. is the submission’s guarantor and takes responsibility for the integrity of the work as a whole, from inception to published article.

Funding

This research did not receive grants from any funding agency in the public, commercial or not-for-profit sectors.

Conflicts of Interest

The authors have no relevant disclosures.

References