Anastomotic Ulcers After Ileocolic Resection for Crohn’s Disease Are Common and Predict Recurrence

Abstract

Background

Crohn’s disease recurrence after ileocolic resection is common and graded with the Rutgeerts score. There is controversy whether anastomotic ulcers represent disease recurrence and should be included in the grading system. The aim of this study was to determine the impact of anastomotic ulcers on Crohn’s disease recurrence in patients with prior ileocolic resections. Secondary aims included defining the prevalence of anastomotic ulcers, risk factors for development, and their natural history.

Methods

We conducted a retrospective cohort study of patients undergoing an ileocolic resection between 2008 and 2017 at a large academic center, with a postoperative colonoscopy assessing the neoterminal ileum and ileocolic anastomosis. The primary outcome was disease recurrence defined as endoscopic recurrence (>5 ulcers in the neoterminal ileum) or need for another ileocolic resection among patients with or without an anastomotic ulcer in endoscopic remission.

Results

One hundred eighty-two subjects with Crohn’s disease and an ileocolic resection were included. Anastomotic ulcers were present in 95 (52.2%) subjects. No factors were associated with anastomotic ulcer development. One hundred eleven patients were in endoscopic remission on the first postoperative colonoscopy. On multivariable analysis, anastomotic ulcers were associated with disease recurrence (adjusted hazard ratio [aHR] 3.64; 95% CI, 1.21–10.95; P = 0.02). Sixty-six subjects with anastomotic ulcers underwent a second colonoscopy, with 31 patients (79.5%) having persistent ulcers independent of medication escalation.

Conclusion

Anastomotic ulcers occur in over half of Crohn’s disease patients after ileocolic resection. No factors are associated with their development. They are associated with Crohn’s disease recurrence and are persistent.

It is controversial whether anastomotic ulcers represent Crohn’s disease reoccurrence after ileocolic resection and should be included in the Rutgeerts score. We found anastomotic ulcers are common after ICR, are associated with increased risk of disease reoccurrence, and are persistent.

INTRODUCTION

Crohn’s disease (CD) is a chronic inflammatory disease of the gastrointestinal tract, and despite improvement in medical management, up to 60% of patients still require surgery.^1–5 Postoperative endoscopic recurrence in the neoterminal ileum occurs in approximately 70% of patients, with approximately 20% developing symptoms within 1 year of surgery.⁶ The Rutgeerts score is used to grade postoperative recurrence after ileocolic resection (ICR), with categories ≥i2 representing an increased risk of clinical recurrence.⁶ According to the original description, the i2 category portends an intermediate risk of disease progression.

However, the i2 group has a variable prognosis.⁶ Although the development of the modified Rutgeerts score has divided i2 lesions into those confined to the ileocolic anastomosis (i2a) and those with >5 ulcers in the neoterminal ileum (i2b), this classification has not been validated, and the impact of anastomotic ulcers (AUs) on disease course is poorly defined (Table 1). The combination of these 2 categories into the i2 group is controversial, with some investigators excluding AUs from the postoperative endoscopic grading system of recurrence.⁷ It has been hypothesized that AUs may represent postoperative ischemic changes with a lower likelihood of progression than true CD. Thus, further evaluation of their impact on disease course is warranted.^{8, 9} A recent technical review by the International Organization for the Study of Inflammatory Bowel Disease (IOIBD) recognized this and called for further studies to confirm that AUs reflect true disease relapse (Fig. 1).⁹

TABLE 1.

Rutgeerts Score and Description of Endoscopic Findings⁶

Rutgeerts Score		Endoscopic Findings
i0		No lesions in the neoterminal ileum
i1		≤5 ulcers in the neoterminal ileum
i2	i2a	Isolated anastomotic ulcer
	i2b	>5 ulcers in the neoterminal ileum
i3		Diffuse aphthous ileitis and a diffusely inflamed neoterminal ileum
i4		Diffuse inflammation with large ulcers, nodules, and/or narrowing in the neoterminal ileum

FIGURE 1.

Anastomotic ulcer confined to the ileocolic anastomosis of a subject with Crohn’s disease (arrow).

Greater characterization and understanding of post-ICR AUs are needed, as their etiology is poorly understood and their impact on disease recurrence is unknown. We aimed to determine the prevalence of AUs in subjects with CD who underwent ICR, identify risk factors for their development, define the impact of AUs on CD recurrence, and characterize their persistence over time.

MATERIALS AND METHODS

Patient Population

We performed a retrospective cohort study including all patients who underwent an ICR between 2008 and 2017 at The Mount Sinai Hospital in New York. Patients were included if after index ICR there was a postoperative (index) colonoscopy which provided detailed characterization of the anastomosis and neoterminal ileum. A subgroup of patients within this cohort were included in the analyses of the impact of AUs on later outcomes if they had at least 1 follow-up visit after the index colonoscopy and were in endoscopic remission, defined as 5 or fewer ulcerations in the neoterminal ileum. This resulted in a larger cohort of all CD patients with ICR and at least 1 postoperative colonoscopy and a second smaller cohort of all CD patients with follow-up who were in endoscopic remission at index postoperative colonoscopy (Fig. 2). In this study, AUs were not considered Rutgeerts i2 disease and were evaluated independently. Therefore, Rutgeerts i2 disease only included those with >5 ulcers in the neoterminal ileum. This study was approved by the institutional review board at The Mount Sinai Hospital.

FIGURE 2.

Study design. The study cohort is derived from subjects with CD who underwent an ICR and first postoperative colonoscopy at The Mount Sinai Hospital. AU prevalence, risk factors, and persistence are derived from this group. A smaller cohort comprised of subjects in endoscopic remission with <5 neoterminal ileal ulcers on index colonoscopy is used to determine the impact of AU on CD recurrence. *i2 disease excludes AU in our cohort.

Outcomes

The primary outcome, assessed in the smaller cohort of CD patients who were in endoscopic remission at index postoperative colonoscopy, was CD recurrence defined as the development of >5 aphthous ulcers in the neoterminal ileum, diffusely inflamed mucosa, diffuse aphthous ileitis, diffuse inflammation with large ulcers, nodules and/or narrowing on future colonoscopy, or the need for a subsequent ICR after index colonoscopy. Secondary outcomes, derived from the larger cohort, were frequency of AUs on first postoperative colonoscopy, risk factors for the development of AUs, and persistence of AUs on subsequent colonoscopies, defined as the presence of AUs on the index and follow-up colonoscopy.

Variables

Our primary variable of interest for the primary outcome of CD recurrence was the presence of AUs in those in endoscopic remission on index colonoscopy. Baseline demographic data and medical and surgical history for all patients was collected through standardized extraction from the electronic medical record. Prior history of ICR was derived from the patient’s history, in addition to operative reports from the index surgery. Preoperative medications, presence of abscess at time of surgery, and need for diversion at the time of ICR were recorded. Postoperative complications including abscess, anastomotic leak, need for repeat surgery during the index hospitalization, small bowel obstruction, surgical site infection, or nonsurgical site infection were collected. Surgical technique was classified as having a stapled or sutured anastomosis and by anastomosis configuration (side-to-side, side-to-end, end-to-end) based upon operative reports. Follow-up colonoscopies were recorded. Colonoscopy findings were graded according to the Rutgeerts score, excluding AUs from the grading system.⁶ Endoscopists’ grading of the colonoscopy findings were verified by a study investigator who was blinded to the clinical course of each patient (RPH) to ensure an accurate Rutgeerts score and description of the anastomosis. Medication history and subsequent hospitalizations were recorded for all patients. Medication usage was classified as any exposure to a medication during the follow-up period, a new medication being initiated, or current use of the medication at the time of colonoscopic assessment. Smoking status was recorded as current or never/former smoker at time of index ICR.

Statistical Analysis

We performed descriptive statistics with frequencies for categorical variables, means with standard deviations (SDs) for parametric continuous variables, and medians with interquartile range (IQR) for nonparametric continuous variables. Evaluation of patient and disease characteristics associated with the formation of AUs was identified using logistic regression with reporting of odds ratios (ORs) and 95% confidence intervals (CIs). Cox regression and Kaplan-Meier methods were used to compare the risk of disease recurrence comparing patients with and without AUs. Multivariable models were constructed a priori using previously described risk factors of postoperative CD disease recurrence (internal penetrating disease, prior ICR, and smoking status) and any variables significant at the p ≤ 0.10 level in univariable analysis.^{1, 10–13} Adjusted hazard ratios (aHR) with 95% CIs are reported. The Fisher exact test was performed to evaluate the impact of medication escalation on the persistence of AUs on subsequent colonoscopies. Statistical significance was defined as a 2-sided alpha of less than 0.05. Statistical analyses were performed using SAS v9.4 (Cary, North Carolina, USA).

RESULTS

Patient Population

One thousand one hundred twenty-one subjects underwent an ICR at The Mount Sinai Hospital with a diagnosis of CD during the study period. We included in our study 182 patients with CD who underwent an ICR with subsequent colonoscopic postoperative assessment of the neoterminal ileum and anastomosis (Table 2). The mean age at the time of ICR was 34.8 (SD 15.0) years, and 40.7% of the cohort were women. Twenty-four (14.1%) and 96 (56.5%) subjects had perianal and internal penetrating disease, respectively. A previous ICR had been performed in 23.6% of subjects. Thirteen subjects (7.9%) in the cohort were current smokers at the time of surgery. Preoperative abscess was present in 23.6% of subjects. Twenty-six (14.3%) subjects had postoperative complications, encompassing abscess, leak, need for repeat surgery during the index hospitalization, small bowel obstruction, or a surgical or nonsurgical site infection. Most patients had a side-to-side (87%) and stapled (92.9%) anastomosis. The first postoperative colonoscopy occurred a median of 277.5 (IQR 371.5) days after the ICR. Most subjects were in endoscopic remission at their first postoperative colonoscopy, with 119 (65.4%) and 33 (18.1%) subjects with Rutgeerts scores of i0 and i1, respectively. At the time of first postoperative colonoscopy, 57.7% of subjects were on a biologic agent, with 16.6% on combination therapy (biologic agent and immunomodulator).

TABLE 2.

Characteristics of CD Patients Who Underwent an ICR With Postoperative Colonoscopy

Characteristics	Ileocolic Resection Cohort (n = 182 patients)
Female Gender, n (%)	74 (40.7)
Age at ICR, mean years (SD)	30.8 (15)
Disease Duration at ICR, median years	7.4
Time to 1st colonoscopy, median days (minimum-maximum)	277.5 (29–2897)
Ileal CD, n (%)	79 (44.6)
Ileocolonic CD, n (%)	97 (54.8)
Colonic CD, n (%)	1 (0.6)
Perianal Disease, n (%)	24 (14.1)
Internal Penetrating Disease, n (%)	96 (56.5)
Current Smoker, n (%)	13 (7.9)
Prior ICR, n (%)	43 (23.6)
Diversion at ICR, n (%)	9 (5.1)
Preoperative Abscess, n (%)	41 (23.6)
Postoperative Complications, n (%)	26 (14.3)
Abscess	3 (1.7)
Leak	3 (1.7)
Repeat Surgery	4 (2.3)
Small Bowel Obstruction	12 (7.0)
Surgical Site Infection	9 (5.3)
Nonsurgical Site Infection	4 (2.3)
Biologic Therapy at 1st Postoperative Colonoscopy, n (%)	98 (57.7)
Anti-TNF Use at 1st Postoperative Colonoscopy, n (%)	91 (53.5)
Immunomodulator at 1st Postoperative Colonoscopy, n (%)	56 (32.9)
Combination Therapy at 1st Postoperative Colonoscopy, n (%)	28 (16.6)
Anastomotic Ulcer at 1st Postoperative Colonoscopy, n (%)	95 (52.2)
Anastomosis Type, n (%)
Side to Side	120 (87.0)
End to End	5 (3.6)
End to Side	13 (9.4)
Stapled	169 (92.9)
Handsewn	13 (7.1)
Rutgeerts score at 1st Postoperative Colonoscopy, n (%)*
i0	119 (65.4)
i1	33 (18.1)
i2	19 (10.4)
i3	6 (3.3)
i4	5 (2.7)
Indication for 1st Postoperative Colonoscopy, n (%)
Follow-up/Surveillance/Screening of CD	148 (82.7)
Elevated Inflammatory Markers	1 (0.6)
Symptoms (Abdominal Pain, Diarrhea, Vomiting, Weight Loss, Tenesmus)	19 (10.6)
Blood in the Stool/Anemia	9 (5.0)
Infectious Colitis	1 (0.6)
Retained Capsule	1 (0.6)

*Rutgeerts scores exclude anastomotic ulcers as part of i2 recurrence.

Prevalence of Anastomotic Ulcers and Risk Factors for Anastomotic Ulcer Development

Anastomotic ulcers were present in 95 (52.2%) subjects at the first postoperative colonoscopy. Univariable analysis did not reveal any factors associated with the presence of an AU on the first postoperative colonoscopy (Table 3). Known risk factors for postoperative recurrence including internal penetrating disease (OR 0.94; 95% CI, 0.51–1.72; P = 0.83), prior ICR (OR 0.84; 95% CI, 0.42–1.66; P = 0.61), and current smoking (OR 1.05; 95% CI, 0.34–3.27; P = 0.93) were not associated with the development of AUs. Multivariable analysis incorporated male gender (univariable analysis OR 1.71; 95% CI, 0.94–3.11; P = 0.08) and the time from ICR to first postoperative colonoscopy (univariable analysis OR 1.00; 95% CI 0.99–1.00; P = 0.10), both with p ≤ 0.10 on univariable analysis, with previously specified risk factors of postoperative recurrence; we found no factors associated with AU development.

TABLE 3.

Univariable Analysis of Factors Associated With the Development of AU on the First Postoperative Colonoscopy

	No. (%)	Odds Ratio (95% confidence interval)	P
Age	—	0.99 (0.97–1.01)	0.28
Male Gender	—	1.71 (0.94–3.11)	0.08
Disease Duration (years)	—	1.00 (0.98–1.01)	0.62
Internal Fistulas	96 (56.5)	0.94 (0.51–1.72)	0.83
Ileal Crohn’s Location	79 (44.6)	0.85 (0.63–1.15)	0.30
Perianal Disease	24 (14.1)	1.32 (0.55–3.18)	0.53
Postoperative Complication	26 (14.3)	1.56 (0.67–3.65)	0.31
Current Smoker	13 (7.9)	1.05 (0.34–3.27)	0.93
Diversion at ICR	9 (5.1)	0.45 (0.11–1.88)	0.28
Preoperative Abscess	41 (23.6)	0.86 (0.42–1.73)	0.67
Side to Side Anastomosis	120 (87.0)	0.63 (0.34–1.18)	0.15
Stapled Anastomosis	169 (92.9)	0.93 (0.30–2.89)	0.90
Biologic Use at Colonoscopy	98 (57.7)	0.73 (0.39–1.33)	0.30
TNF Use at Colonoscopy	91 (53.5)	0.64 (0.35–1.18)	0.15
IM Use at Colonoscopy	56 (32.9)	1.08 (0.57–2.04)	0.82
CT Use at Colonoscopy	28 (16.6)	0.64 (0.28–1.45)	0.29
Biologic Use Prior to ICR	73 (40.1)	0.90 (0.50–1.64)	0.74
Prior ICR	43 (23.6)	0.84 (0.42–1.66)	0.61
Time from ICR-Colonoscopy	—	1.00 (0.99–1.00)	0.10

Abbreviations: IM, immunomodulatory; CT, combination therapy.

Impact of Anastomotic Ulcers on Crohn’s Disease Recurrence

One hundred eleven patients were in endoscopic remission, characterized by Rutgeerts scores of i0 or i1 on initial postoperative colonoscopy. The median time from ICR to the first postoperative colonoscopy was 253 (IQR 317) days. The duration of follow-up from the first postoperative colonoscopy until either the last encounter with the patient or the composite endpoint was reached was a mean of 774 (SD 654) days. The composite endpoint of endoscopic recurrence on subsequent colonoscopy (14 patients) or the need for subsequent ICR (6 patients) occurred in 20 patients total.

The presence of an AU at index postoperative colonoscopy significantly increased the risk of reaching the composite endpoint over time (Fig. 3). On univariable analysis, the initiation of a new biologic agent after the first postoperative colonoscopy was associated with a reduced probability of reaching the composite endpoint (aHR 0.11; 95% CI, 0.01–0.83; P = 0.03), whereas the presence of an AU trended toward an increased risk (aHR 2.70; 95% CI, 0.97–7.54; P = 0.06) (Table 4). In addition, the time between the ICR and index colonoscopy trended toward an increased risk of recurrence (aHR 1.00; 95% CI, 1.00–1.002; P = 0.05). On multivariable analysis, including known risk factors for disease recurrence, the initiation of a new biologic agent remained statistically significant (aHR 0.09; 95% CI, 0.01–0.84; P = 0.03), whereas the presence of AU was significantly associated with reaching the composite endpoint (aHR 3.64; 95% CI, 1.21–10.95; P = 0.02) (Table 5).

FIGURE 3.

Kaplan-Meier curve for CD recurrence comparing patients in endoscopic remission with and without anastomotic ulcers (log-rank P = 0.048).

TABLE 4.

Univariable Analysis of Factors Associated With Composite Endpoint of CD Recurrence (Endoscopic Recurrence or Need for Repeat ICR) After Index Postoperative Colonoscopy

	No. (%)	Adjusted Hazard Ratio (95% Confidence Interval)	P
Male Gender	62 (55.9)	1.06 (0.43–2.65)	0.90
Anastomotic ulcer	59 (53.2)	2.70 (0.97–7.54)	0.06
Age	—	0.97 (0.93–1.01)	0.13
Time from ICR-Colonoscopy	—	1.00 (1.00–1.002)	0.05
Stapled Anastomosis	106 (95.5)	0.75 (0.10–5.70)	0.78
Side to Side Anastomosis	76 (68.5)	0.97 (0.38–2.49)	0.94
Internal Fistulas	58 (52.3)	0.79 (0.32–1.97)	0.62
Ileal Crohn’s Location	47 (42.3)	0.85 (0.33–2.20)	0.74
Perianal Disease	16 (14.4)	1.22 (0.39–3.76)	0.73
Current Smoker	7 (6.3)	1.54 (0.44–5.42)	0.50
Post Colonoscopy Biologic Exposure	79 (71.2)	1.07 (0.38–2.98)	0.90
Post Colonoscopy IM Exposure	51 (46.0)	0.77 (0.31–1.93)	0.59
Post Colonoscopy CT Exposure	27 (24.3)	1.16 (0.41–3.26)	0.78
Post ICR Biologic Exposure	79 (71.2)	1.07 (0.38–2.98)	0.90
Post ICR IM Exposure	51 (46.0)	0.77 (0.31–1.93)	0.58
Post Colonoscopy New Biologic	23 (20.7)	0.11 (0.01–0.83)	0.03
Post Colonoscopy New IM	15 (13.5)	0.30 (0.04–2.23)	0.24
Post Colonoscopy New CT	12 (10.8)	0.36 (0.05–2.74)	0.33
Prior ICR	25 (22.5)	1.73 (0.65–4.58)	0.27

Abbreviations: IM, immunomodulatory; CT, combination therapy.

TABLE 5.

Multivariable Analysis of Factors Associated With Composite Endpoint of CD Recurrence (Endoscopic Recurrence or Need for Repeat ICR) After Index Postoperative Colonoscopy

	Adjusted Hazard Ratio (95% Confidence Interval)	P
Anastomotic Ulcer	3.64 (1.21–10.95)	0.02
Prior ICR	1.51 (0.54–4.20)	0.43
Current Smoker	0.53 (0.11–2.66)	0.44
Internal Fistulas	0.99 (0.34–2.84)	0.98
Time from ICR-Colonoscopy	1.00 (1.00–1.00)	0.20
Post Colonoscopy New Biologic	0.09 (0.01–0.84)	0.03

Persistence of Anastomotic Ulcers Over Time

Sixty-six of the 182 subjects undergoing an ICR had a second colonoscopy at a median of 529 (IQR 649) days. Thirty-nine of these subjects (59.1%) had an AU present on the first postoperative colonoscopy. Thirty-one of the 39 patients (79.5%) had a persistent AU present on the second colonoscopy. Escalation of medical therapy, defined as the initiation of a new biologic or immunomodulator after the index colonoscopy, occurred in 10 patients with an AU on the first postoperative colonoscopy. The AU resolved in 30% of these subjects, which was not statistically significant (P = 0.55). Nine subjects (33.3%) without an AU on the first postoperative colonoscopy developed one on the second colonoscopy.

DISCUSSION

To our knowledge, this study is the first to characterize in depth the prevalence and significance of AUs in subjects with CD who undergo an ICR. Our main findings were that they occurred in approximately half (52.2%) of patients. There are no risk factors predicting their development, and they significantly increase the risk of disease progression in subjects in endoscopic remission. We also found that AUs were persistent in approximately 80% of patients when present on the first postoperative colonoscopy and did not appear to be affected by medication escalation.

The prevalence of AUs in subjects with CD is not clearly defined in postoperative studies, which often do not describe the number of subjects with AUs.^{13, 14} Strikingly however, AUs after ICR in subjects without CD are rarely present, though the literature is generally limited to case reports and series.¹⁵ One of the larger published series found that 0 of 28 subjects without inflammatory bowel disease developed post-ICR AUs.¹⁶ This is supported by our experience where we found that 0 of 7 subjects who underwent an ICR for non-CD related indications at Mount Sinai had an AU on a postoperative colonoscopy that included a description of the anastomosis (unpublished). Although better determination of the rates of AUs in subjects without CD is needed to draw firm conclusions, the high prevalence of AUs in those with CD supports a relationship to the disease as opposed to postoperative ischemic sequela.

Further supporting that AUs represent a CD-related factor, it is our finding that they independently predict objective disease progression (aHR 3.64, CI 1.21–10.95; P = 0.02). Two prior studies by Bayart et al and Riviere et al attempted to evaluate the impact of AUs on clinical disease recurrence.^{17, 18} Bayart et al evaluated postoperative symptoms attributed to CD in 50 patients who underwent an ICR with either i2a or i2b disease on index colonoscopy, finding no difference in the rate of clinical recurrence between the 2 groups. Riviere et al recently followed 365 subjects who underwent an ICR, finding no difference in clinical recurrence rates in those with i2a and i2b disease. Both studies demonstrate that the presence of an isolated AU portends the same risk of symptomatic recurrence as the presence of >5 ulcers in the neoterminal ileum. Yet, the reliance on symptoms to define disease progression in both studies is a significant limitation, given the frequency of symptoms after ICR and the poor correlation between symptoms and inflammation in inflammatory bowel disease.¹⁹ However, these results support our finding that AUs impact disease course and that there is an association between AU and CD.

The natural history of AUs is unknown, with no prior studies evaluating their progression over time or the impact that CD-related medications have on their course. We demonstrated that AUs persist in most patients if present on the index postoperative colonoscopy. Once present, approximately 80% of subjects will have them on the second endoscopic evaluation. Medication escalation did not affect which subjects would continue to have AUs present on subsequent colonoscopies, though only 10 of the 31 subjects with AUs in our cohort underwent therapeutic escalation, likely underpowering this analysis. Given the recalcitrant nature of AUs, further studies are needed to understand the impact of CD-related therapies on these ulcers and which patients are at risk for having them persistently. Furthermore, additional evaluation is needed to determine if medication escalation based solely on the presence of an AU at the index colonoscopy will alter the disease course.

The unique association of AUs with CD and their impact on disease course provokes the question of their origin. Several hypotheses can be formed. A common assertion is that they represent postoperative ischemic changes either from reduced blood flow at the anastomosis or a reaction to sutures or staples at the surgical site. We contend that this is less likely given the high relative prevalence of AUs in subjects with CD and their impact on disease recurrence. The absence of perioperative factors or complications associated with their development argues against AUs representing the sequela of a surgical insult. The claim that AUs represent unresected inflammatory disease has been refuted by multiple studies demonstrating that their development after complete macroscopic removal of the disease at the time of surgery and that residual microscopic inflammation does not influence outcomes.^{6, 16, 20, 21} A potential role of the microbiome in their development may be supported by mouse models demonstrating altered immune microbial interactions after ICR, with recruited innate immune cells demonstrating decreased microbial responsiveness. Given the innate immune dysfunction in CD, this modulation of immune function via intestinal resection may underpin the disease reoccurrence that usually occurs at the anastomotic region and may lead to ulceration at the anastomotic site.²² Lastly, the lymphatic system warrants further evaluation given the relationship between altered lymphatics and CD, in addition to an association between decreased intestinal lymphatic density and postoperative endoscopic reoccurrence of CD after ICR.^{23, 24}

The strengths of our study include its large size and long follow-up period. Our objective definition of CD recurrence, defined by endoscopic findings or the need for subsequent ICR and the incorporation of postoperative CD risk factors into our modelling, strengthens our results compared with prior studies. One limitation is the single-center retrospective study design. Our center serves as a referral center, limiting the endoscopic and follow-up data available for some patients, which may bias our cohort to include sicker subjects and result in the exclusion of subjects with limited follow-up data or who are less severe and cared for in the community. Limited data are available for many subjects who underwent an ICR at our institution and who did not follow up our center, precluding comparison of the clinical characteristics of those included and excluded from our cohort. Furthermore, the retrospective study design limits our ability to assess the impact that duration of medication exposure has on study outcomes. Lastly, interobserver reproducibility of the Rutgeerts score has been shown to be moderate. To address this concern, each colonoscopy was reviewed by 1 investigator (RPH).²⁵

In conclusion, further prospective evaluation is needed to confirm our findings and delineate the impact that medications have on AUs over time. Studies aimed at evaluating the etiology of AUs, and therefore a cause of disease progression, may be helpful in expanding our understanding of this phenomena and the pathophysiology of CD. Furthermore, differences in interpretation of AUs could impact the results of clinical trials evaluating prevention of postoperative recurrence, highlighting the importance of greater understanding of their influence. Anastomotic ulcers are common after ICR, are associated with an increased risk of disease recurrence, and should be considered a possible risk factor for postoperative progression.

Further studies are needed to verify our conclusions and evaluate the impact of therapeutic escalation on the risk of disease progression when AUs are present. In light of our findings and other recent publications demonstrating the impact of AUs on clinical disease recurrence, we recommend the close observation of subjects with AUs who are otherwise in endoscopic remission characterized by Rutgeerts scores i0 and i1. Our results support the claim that AUs are not inconsequential postoperative findings and portend an increased risk of disease progression, thereby necessitating closer monitoring.

Glossary

Abbreviations

aHR

adjusted hazard ratio

AU

anastomotic ulcers

CD

Crohn’s disease

ICR

ileocolic resection

IQR

interquartile range

OR

Odds ratio

SD

standard deviation

Author Contribution: RPH, BLC, and JFC contributed to the conception and design of the study. RPH, BLC, and RCU performed the data analysis. RPH, RCU, DC, SL, BES, JFC, and BLC interpreted the analysis and contributed substantially to revising the manuscript critically for important intellectual content. RPH drafted the final version of the manuscript. All authors approve the final version of the article, including the authorship list.

Conflicts of interest: RPH has served as a speaker, a consultant, or an advisory board member for Takeda and Janssen and has received research support from Intralytix, Inc. and a Career Development Award from the Crohn’s and Colitis Foundation. RCU has served as a speaker, a consultant, or an advisory board member for Takeda, Pfizer, and Janssen and has received research support from Abbvie, Pfizer, and Boehringer Ingelheim and a Career Development Award from the Crohn’s and Colitis Foundation. BES has served as a speaker, a consultant, or an advisory board member for AbbVie, Allergan, Arena Pharmaceuticals, Boehringer-Ingelheim, Celgene, Ferring, Gilead, Janssen, Lilly, Otsuka, Pfizer, Synergy Pharmaceuticals, Takeda, Therevance Biopharma R&D, and TiGenix and has received research support from Celgene. JFC has served as a speaker, a consultant, or an advisory board member for AbbVie, Amgen, Boehringer-Ingelheim, Arena Pharmaceuticals, Celgene Corporation, Celltrion, Enterome, Eli Lilly, Ferring Pharmaceuticals, Genentech, Janssen and Janssen, Medimmune, Merck & Co., Nextbiotix, Novartis Pharmaceuticals Corporation, Otsuka Pharmaceutical Development & Commercialization, Inc., Pfizer, Protagonist, Second Genome, Gilead, Seres Therapeutics, Shire, Takeda, Theradiag, and Zealand Pharma; he has served as a speaker for AbbVie, Ferring, Takeda, Celgene and Corporation and has stock options with Intestinal Biotech Development, Genefit; he has received research support from AbbVie, Takeda, and Janssen and Janssen. BLC has served as a speaker, a consultant or, an advisory board member for Abbvie, Alfasigma, Allergan, Celltrion, Ferring, Grifols, Janssen, and Sublimity Therapeutics. DC and SL had no conflicts to report.