Abstract
Background
Despite the initial diagnosis of ulcerative colitis (UC), approximately 10% to 20% of patients develop Crohn’s disease–like pouch inflammation (CDLPI) after restorative proctocolectomy (RPC) with ileal pouch anal anastomosis (IPAA). The aim of this study was to evaluate whether early pouchitis, defined as pouchitis within the first year after IPAA, is a predictor of CDLPI.
Methods
This was a retrospective cohort analysis of patients with UC or IBD unclassified (IBDU) who underwent RPC with IPAA at Mount Sinai Hospital between January 2008 and December 2017. The primary outcome was development of CDLPI. Predictors of CDLPI were analyzed via univariable and multivariable Cox regression models.
Results
The analytic cohort comprised 412 patients who underwent at least 1 pouchoscopy procedure between 2009 and 2018. Crohn’s disease–like pouch inflammation developed in 57 (13.8%) patients a median interval of 2.1 (interquartile range, 1.1-4.3) years after surgery. On univariable analysis, older age at colectomy (hazard ratio [HR], 0.97; 95% CI, 0.95-0.99) was associated with a reduced risk of CDLPI; although early pouchitis (HR, 2.43; 95% CI, 1.32-4.45) and a greater number of pouchitis episodes (HR, 1.38; 95% CI, 1.17-1.63) were associated with an increased risk. On multivariable analysis, early pouchitis (HR, 2.35; 95% CI, 1.27-4.34) was significantly associated with CDLPI. Time to CDLPI was significantly less in patients who developed early pouchitis compared with those who did not (P = .003).
Conclusion
Early pouchitis is significantly associated with subsequent CDLPI development and may be the first indication of enhanced mucosal immune activation in the pouch.
Keywords: ulcerative colitis, Crohn’s disease, colectomy, pouchitis
Introduction
Up to 20% of patients with ulcerative colitis (UC) complicated by treatment refractory disease or dysplasia will require surgery, the most common of which is the staged restorative proctocolectomy (RPC) with ileal pouch anal anastomosis (IPAA).1 Pouchitis is the most common post-IPAA inflammatory complication and occurs in up to 80% of patients.2 Antibiotics induce remission in 80% of patients, yet approximately 10% to 20% proceed to develop Crohn’s disease–like pouch inflammation (CDLPI).3 Crohn’s disease–like pouch inflammation is typically characterized by inflammation of the pouch and afferent limb, stricturing of the afferent limb or small bowel, and/or fistulizing disease of the perineum or small bowel.3,4 There is no consensus regarding treatment of CDLPI, and the level of evidence to support medical therapy is relatively weak.5 Clinical response rates for CDLPI range from 20% to 60% with biologics, and pouch failure ultimately occurs in up to 45% of patients.4,6
The pathogenesis of CDLPI is not well understood; however, is postulated to involve a complex interaction between the pouch mucosal immune system and microbiome in genetically susceptible patients.7,8 The pouch undergoes a pro-inflammatory transcriptional shift after restoration of intestinal continuity, consistent with changes in the extracellular matrix and enhanced immune activation that may be permissive for subclinical inflammation.9–11 Overt clinical inflammation and the development of CDLPI are theorized to be driven by microbial dysbiosis and the exposure of the pouch to certain regional microbiota.12,13 Given this pro-inflammatory baseline, early pouchitis that occurs within the first year after ileostomy closure and restoration of intestinal continuity may be the harbinger of subsequent CDLPI development. Early pouchitis may be the first indication of the enhanced mucosal immune activation that underlies CDLPI pathogenesis.
We hypothesized that early pouchitis, defined as pouchitis within the first year after final surgical stage and restoration of intestinal continuity, may be associated with subsequent CDLPI development. We aimed to test this hypothesis by conducting a retrospective cohort analysis at a high-volume inflammatory bowel disease (IBD) center utilizing well-defined criteria for pouchitis and CDLPI.
Methods
Study Population and Outcome
We performed a retrospective cohort analysis of all patients with UC or IBD unclassified (IBDU) complicated by medically refractory disease or dysplasia who underwent RPC with IPAA at Mount Sinai Hospital between January 2008 and December 2017 and at least one subsequent pouchoscopy 12 months after final surgical stage. Patients younger than 18 years old or with a baseline diagnosis of CD were excluded. The primary outcome was development of CDLPI. This study was approved by the Mount Sinai Hospital Institutional Review Board.
Definitions
Crohn’s disease–like pouch inflammation was defined clinically, endoscopically, and radiologically as one of the following: (1) severe inflammation of the pouch and afferent limb, (2) strictures of the afferent limb or proximal small bowel, and (3) fistulae involving the pouch, perineum, or proximal small bowel that occurred more than 6 months after ostomy closure.3 Pouch duration was defined as time from final surgical stage. Pouchitis was defined as a total Pouchitis Disease Activity Index (PDAI) score ≥7 with symptoms of increased stool frequency from postoperative baseline, rectal bleeding, fecal urgency, abdominal pain, or fever (temperature ≥37.8) in the setting of an abnormal pouchoscopy with mucosal edema, granularity, friability, loss of vascular pattern, mucosal exudate, and/or ulceration and histologic inflammation.14 Pouchitis was defined as a modified PDAI score ≥5 using clinical and endoscopic subscores only if there was no histology associated with the pouchoscopy or if the histology was reported in a manner that did not permit histologic PDAI subscore calculation. Patients who received antibiotics empirically for a presumed diagnosis of pouchitis and did not have an accompanying confirmatory pouchoscopy were not included. Early pouchitis was defined as pouchitis that occurred within the first year after final surgical stage and restoration of intestinal continuity. The diagnoses of CDLPI and pouchitis were made in the absence of postoperative complications.
Data Collection and Variables
Clinical information was reviewed from the electronic medical record by 2 reviewers using a standardized instrument. Collected patient demographics and disease characteristics included age, sex, precolectomy diagnosis (UC or IBDU), precolectomy biologic use, family history of CD, colectomy indication, C-reactive protein at the time of colectomy, tobacco use at the time of IPAA construction, body mass index at the time of IPAA construction, postoperative complications (anastomotic leaks and abscesses), and pouch duration. The presence of backwash ileitis at the time of colectomy was extracted from pathology reports. All postoperative pouchoscopy procedure notes were reviewed, and collected data included indication, endoscopic findings, and histologic results. The PDAI was retrospectively calculated for each patient at the time of their pouchoscopy. The clinical PDAI subscore was calculated based on the symptoms noted in the “indication” section of the pouchoscopy report; the endoscopic PDAI subscore was calculated using the findings noted in the “results” section of the pouchoscopy; and the histologic PDAI subscore was calculated using the associated pathology report. In instances where there were no symptoms detailed in the “indication” section of the pouchoscopy report, clinical notes within 1 week of the pouchoscopy were reviewed, and the documented symptoms were used to calculate the clinical PDAI subscore. The number and timing of pouchitis episodes that occurred before CDLPI diagnosis were documented.
Analytic Approach
Descriptive statistics were performed to describe baseline characteristics and are reported as proportions or medians (with interquartile range [IQR]) for categorical and continuous variables, respectively. A univariable Cox regression model was used to assess unadjusted relationships between hypothesized risk factors and CDLPI. A multivariable Cox regression model was used for the primary outcome of CDLPI and was performed a priori with selection of the following clinically relevant variables: age, sex, early pouchitis, and number of pouchitis episodes. Hazard ratios (HRs) and 95% confidence intervals (CIs) are reported. All analyses were performed using SAS v9.4 (SAS Institute, Cary, NC).
Results
The analytic cohort comprised 412 patients who met full inclusion criteria and underwent at least 1 pouchoscopy procedure between 2009 and 2018. Of these, 224 (54.4%) were male, and the median age at the time of colectomy was 35.6 years (IQR, 26.9-48.6). The median pouch duration was 3.9 (IQR, 2.6-6.7) years. Pouchitis occurred in 225 (54.6%) patients, with more than 2 episodes of pouchitis occurring in 89 (21.6%) patients. The median time to pouchitis was 1.3 (IQR, 0.6-2.8) years, and 94 (22.8%) patients developed early pouchitis. Full clinical and demographic characteristics of the analytic cohort are provided in Table 1. Serology results were available for 24 patients: 1 of 24 (4.2%) had positive ASCA (anti-saccharomyces cerevisiae antibodies) IgG, 2 of 24 (8.3%) positive ASCA IgA, 4 of 24 (16.7%) positive ANCA (antineutrophil cytoplasmic antibodies), 4 of 24 (16.7%) positive anti-OmpC (outer-membrane porin C), and 3 of 24 (12.5%) positive anti-CBir1.
Table 1.
Clinical and demographic characteristics of patients who underwent RPC with IPAA.
| Characteristics | N = 412 (%) |
|---|---|
| Age at colectomy, yearsa | 35.6 (26.9-48.6) |
| Precolectomy disease duration, yearsa | 5.0 (1.98-12.0) |
| Male | 224 (54.4) |
| Disease type | |
| Ulcerative colitis | 353 (85.7) |
| IBDU | 59 (14.3) |
| Colectomy indication | |
| Medically refractory disease | 363 (88.1) |
| Dysplasia | 49 (11.9) |
| Backwash ileitisat colectomy | 51 (12.4) |
| C-reactive protein at colectomy, mg/La | 34 (7.4-81.5) |
| Family history of Crohn’s disease | 90 (21.9) |
| Active tobacco use at IPAA construction | 17 (4.1) |
| BMI at IPAA construction, kg/m2a | 23.2 (20.7-26.5) |
| Early pouchitis | 94 (22.8) |
Median (interquartile range).
Crohn’s disease–like pouch inflammation developed in 57 (13.8%) patients in a median interval of 2.1 (IQR, 1.1-4.3) years following final surgical stage. Of these, 21 (36.8%) had isolated pouch and afferent limb inflammation and 13 (22.8%) had isolated fistulizing disease. A subset of patients had the following combined disease phenotypes: 8 (14.0%) inflammatory/stricturing and 15 (26.3%) inflammatory/fistulizing. No patient had isolated stricturing disease or combined structuring/fistulizing disease in the absence of inflammation. Among the 8 patients with stricturing disease, all strictures were located in the afferent limb. Of the 28 patients with fistulizing disease, fistulae were classified as pouch-perianal in 19 (67.9%), pouch-vaginal in 6 (21.4%), entero-enteric in 2 (7.1%), and pouch-prostate in 1 (3.6%). Among the 52 patients who had at least 2 pouchoscopy procedures (separately diagnosing pouchitis and CDLPI), 2 (3.9%) had no prior episodes of pouchitis, and 22 (42.3%) had early pouchitis. Colectomy pathology for patients who developed CDLPI was confirmed to lack features of CD. Four (7.0%) patients who developed CDLPI had PSC.
On univariable analysis, older age at the time of colectomy (HR, 0.97; 95% CI, 0.95-0.99) was associated with a reduced risk of CDLPI, although early pouchitis (HR, 2.43; 95% CI, 1.32-4.45) and a greater number of pouchitis episodes (HR, 1.38; 95% CI, 1.17-1.63) were associated with an increased risk. On multivariable analysis, older age at the time of colectomy (HR, 0.97; 95% CI, 0.5-0.99) was associated with a reduced risk of CDLPI, and early pouchitis (HR, 2.35; 95% CI, 1.27-4.34) was significantly associated with an increased probability of CDLPI. Notably, preoperative IBDU, family history of CD, and backwash ileitis were not associated with CDLPI development. Full univariable and multivariable results for the outcome of CDLPI are provided in Table 2. Time to CDLPI was significantly less in patients who developed early pouchitis compared with those who did not (P = .003; Figure 1). When restricting the analysis to patients with the outcome of fistulizing CDLPI, early pouchitis remained a significant risk factor (HR, 2.12; 95% CI, 1.10-4.43). Full univariable and multivariable results for the outcome of fistulizing CDLPI are provided in Table 3.
Table 2.
Univariable and multivariable analysis of the outcome of CDLPI
| Variable | Univariable Model | Multivariable Model | ||
|---|---|---|---|---|
| HR (95% CI) | P | HR (95% CI) | P | |
| Age | 0.97 (0.95-0.99) | <0.001 | 0.97 (0.94-0.98) | 0.02 |
| Male | 1.05 (0.62-1.77) | 0.87 | 1.06 (0.58-1.92) | 0.85 |
| IBDU | 0.95(0.30-3.05) | 0.93 | NAa | NAa |
| Family history of Crohn’s disease | 1.38 (0.68-2.77) | 0.37 | NAa | NAa |
| Backwash ileitis | 1.27 (0.62-2.59) | 0.51 | NAa | NAa |
| BMI at IPAA construction | 0.99 (0.92-1.05) | 0.94 | NAa | NAa |
| Number of pouchitis episodes | 1.38 (1.17-1.63) | <0.001 | 1.08 (0.85-1.37) | 0.52 |
| Early pouchitis | 2.43 (1.32-4.45) | 0.004 | 2.35 (1.27-4.34) | 0.01 |
Variable was not applied in multivariable model.
Figure 1.
Kaplan-Meier estimates of developing CDLPI in patients with vs without early pouchitis.
Table 3.
Univariable and multivariable analysis of the outcome of fistulizing CDLPI
| Variable | Univariable Model | Multivariable Model | ||
|---|---|---|---|---|
| HR (95% CI) | P | HR (95% CI) | P | |
| Age | 0.97 (0.94-0.99) | 0.01 | 0.99 (0.95-1.00) | 0.07 |
| Male | 1.60 (0.84-3.04) | 0.16 | 1.70 (0.80-362) | 0.17 |
| IBDU | 0.44 (0.06-3.22) | 0.42 | NAa | NAa |
| Family history of Crohn’s disease | 1.28 (0.55-2.98) | 0.57 | NAa | NAa |
| Backwash ileitis | 1.19 (0.50-2.82) | 0.70 | NAa | NAa |
| BMI at IPAA construction | 0.98 (0.91-1.07) | 0.69 | NAa | NAa |
| Number of pouchitis episodes | 1.37 (1.13-1.66) | 0.002 | 1.07 (0.82-1.41) | 0.61 |
| Early pouchitis | 2.08 (1.01-4.31) | 0.04 | 2.12 (1.01-4.43) | 0.04 |
Variable was not applied in multivariable model.
Discussion
To date, there are no reliable predictors that can be used to inform the risk of CDLPI in patients with UC. In this single-center study of 412 patients with UC or IBDU who underwent RPC with IPAA, approximately 14% developed CDLPI within a median interval of 2 years following the final surgical stage. Crohn’s disease–like pouch inflammation development was significantly associated with early pouchitis, and time to CDLPI development was significantly less in patients with early pouchitis compared with those without. These findings provide additional insight into early pouchitis as a potential marker of subsequent CDLPI development. Similar to previous studies, we did not find IBDU or backwash ileitis to be significant risk factors for CDLPI.15–19
Purported risk factors for CDLPI reported in small studies include longer pouch duration, family history of CD, presence of IgA and IgG antibodies to Saccharomyces cerevisiae, and antibodies to CBir1 flagellin.4,19–21 Pouchitis is the most common post-IPAA inflammatory complication and occurs in 50% of patients within the first 2 years after surgery.22 Previous studies have noted that patients with chronic pouchitis, compared with those without, have a significantly shorter mean time to the first episode of pouchitis.22,23 Yet, pouchitis has not been comprehensively investigated as a risk factor or predictor for subsequent CDLPI development.22 Given the predisposition to inflammation that patients who develop CDLPI may manifest at baseline, early pouchitis within the first year after final surgical stage and restoration of intestinal continuity may be the harbinger to subsequent disease. In our study, early pouchitis was significantly associated with subsequent CDLPI development and may be the first indication of the underlying enhanced mucosal immune activation and microbial dysbiosis that precedes CDLPI. This association remained significant when sensitivity analysis restricted the outcome to fistulizing CDLPI and patients with inflammation limited to the pouch and/or prepouch ileum were excluded; this eliminated the possibility that our results were indicative of an increased risk of chronic pouchitis rather than true CDLPI.
Increasing age has not been associated with adverse short- or long-term outcomes after IPAA despite concerns otherwise.24 Multiple small studies and systematic reviews with meta-analysis have concluded that there are no differences in rates of anastomotic leaks, pouchitis, incontinence, or pouch failure in older patients.24–27 Our study further provides reassurance by noting that increasing age was significantly associated with a decreased risk of CDLPI, albeit the hazard ratio of 0.97 may be rounded up and interpreted as null. Regardless, our data serve as further evidence that increasing age is not a risk factor for adverse pouch outcomes and likely has no impact on pouch longevity. The American Society of Colon and Rectal Surgeons recommends against using age as a factor in the decision to proceed with RPC.28
There are no consensus treatment guidelines for CDLPI, and up to 45% of patients with CDLPI require pouch excision and transition to a permanent ileostomy.4,6 The risk of a permanent ostomy is a significant concern for patients with IBD and has been associated with depression and anxiety.29 For this reason, there is an urgent need to improve risk stratification and CDLPI prognostication. Our study is an important first step in this direction because it identifies early pouchitis as a potential marker of subsequent CDLPI development. Our results need to be validated in a multicenter study, as they have the potential to significantly impact post-IPAA surveillance and care. Consideration should be given for proactive monitoring in patients who develop early pouchitis with regular clinic visits, labs, calprotectin, and pouchoscopy surveillance to rapidly diagnose CDLPI should it occur.
Our study had several strengths. First, all patients underwent surgery and long-term clinical follow-up at one institution. Second, all charts were systematically reviewed by 2 investigators blinded to outcomes. Third, strict clinical, endoscopic, and radiologic definitions for pouchitis and CDLPI were utilized. Our study also had a number of limitations. First, the study was retrospective and performed at a single center and thus subject to selection bias. Second, we were not powered to evaluate serologies as predictors of CDLPI development, specifically antibodies to ASCA IgA/IgG and CBir1, which have previously been shown to be associated with the development of CDLPI.19–21
In conclusion, early pouchitis was associated with subsequent CDLPI development in patients originally diagnosed with UC in this single-center study. Postoperative risk ratification is a large unmet need for patients with UC who undergo RPC with IPAA, and there are no well-established risk factors that can be used to meaningfully counsel patients. Patients with early pouchitis may represent an at-risk group for CDLPI, and these findings should prompt larger studies into appropriate postoperative surveillance strategies.
Acknowledgments
None.
Glossary
Abbreviations
- UC
ulcerative colitis
- CD
Crohn’s disease
- CDLPI
Crohn’s disease–like pouch inflammation
- IBDU
inflammatory bowel disease unclassified
- RPC
restorative proctocolectomy
- IPAA
ileal pouch anal anastomosis
Contributor Information
Maia Kayal, Department of Medicine, Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
David Kohler, Department of Medicine, Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Michael Plietz, Department of Surgery, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Sergey Khaitov, Department of Surgery, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Patricia Sylla, Department of Surgery, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Alexander Greenstein, Department of Surgery, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Marla C Dubinsky, Department of Medicine, Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Author Contributions
M.K.: study concept and design, data collection, data analysis, and drafting of the manuscript; D.K. and M.P.: data collection and critical revision of the manuscript; S.K., A.G. and P.S.: critical revision of the manuscript; M.D.: study concept and design and critical revision of the manuscript. All authors reviewed and approved the final version of the manuscript.
Conflicts of Interest
The authors have no other relevant conflicts of interest or disclosures. The authors declare no funding support for this project.
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