Antitumour necrosis factor therapy is associated with de novo Crohn’s disease after ileal pouch-anal anastomosis

Abstract

Aim

Tumour necrosis factor inhibitors (TNFi) have revolutionized the management of moderate to severe ulcerative colitis (UC) since their approval for UC in 2005. Still, many patients ultimately require surgery with ileal pouch-anal anastomosis (IPAA). Development of de novo Crohn’s disease (CD) following IPAA is an increasingly common and devastating complication, sometimes progressing to pouch failure. The aim of this study was to evaluate the association of preoperative TNFi exposure and the development of de novo CD after IPAA.

Method

A prospective single-center inflammatory bowel disease (IBD) registry was searched for consecutive patients with UC undergoing IPAA during a 25-year period ending July 2018. Patients with preoperative CD or IBD-unclassified were excluded. De novo CD was diagnosed upon endoscopic evidence of 5 or more mucosal ulcers proximal to the ileal pouch any time after surgery and/or pouch fistula occurring more than three months after ileostomy closure.

Results

The study cohort consisted of 400 patients with a median follow-up of 44.0 (IQR 11–113) months. Sixty-two (16%) patients developed de novo CD 28.0 (IQR 6–67) months following ileostomy closure. Survival analysis of TNFi era patients revealed a significant increase in de novo CD risk in those with preoperative TNFi exposure. Multivariable proportional hazards modeling revealed two independent predictors for de novo CD development: older age was protective (HR 0.89 per 5-year increase; P = 0.009) and preoperative TNFi exposure was hazardous (HR 2.10; P = 0.011).

Conclusion

This prospective study is the first to suggest an association between preoperative TNFi exposure and the development of de novo CD.

Introduction

Tumour necrosis factor alpha inhibitor (TNFi) agents received United States Food & Drug Administration (FDA) approval for use in ulcerative colitis (UC) in 2005. These biologic agents have since revolutionized the management of moderate to severe UC with rapid induction and maintenance of long-term remission¹. Nevertheless, up to 50% of UC patients treated with TNFi medications undergo surgery for failure of medical therapy, acute complications, or dysplasia/malignancy^1–5. Multistage restorative proctocolectomy with ileal pouch-anal anastomosis (IPAA) has become the standard operative treatment for UC. One of the most devastating complications of IPAA is the development of de novo Crohn’s disease (CD), with many patients requiring reinstitution of medical therapy or progression to pouch failure necessitating pouch excision and permanent ileostomy^6–11. Several risk factors for development of CD after IPAA have been previously identified including younger age, smoking, family history of CD, and anti-Saccharomyces cerevisiae antibody (ASCA) IgA and IgG positivity^12–15.

The proportion of patients undergoing IPAA treated with TNFi medications preoperatively appears to have risen since FDA approval of infliximab for UC¹⁶. At the same time, we have anecdotally noticed an increasing incidence of de novo CD developing in a shorter time interval after IPAA. To our knowledge, no study has identified TNFi exposure as a risk factor for de novo CD. The aim of this study was to evaluate the association of TNFi exposure and the development of de novo CD after IPAA. Given that patients with de novo CD are at increased risk of complications and pouch failure, a modifiable risk factor would be pertinent to disease management and advance our understanding of its pathophysiology.

Methods

A prospective, single-center inflammatory bowel disease registry was searched for consecutive patients with UC undergoing IPAA for medically unresponsive disease or dysplasia during a 25-year period ending July 2018. Two or three-stage IPAA with J-pouch and mucosectomy was performed in all patients. All patients had a temporary diverting ileostomy constructed at the time of pouch creation. Patients undergoing IPAA for inflammatory bowel disease-unclassified (IBD-U), indeterminate colitis (IC), and CD, those in whom the ileostomy was not closed and those using nonsteroidal anti-inflammatory drugs were excluded from analysis. All patients were seen for follow-up every 3 months following stoma closure for 1 year and then yearly thereafter, with pouchoscopy performed at all scheduled follow-up visits. All research related activities were approved by the Cedars-Sinai Medical Center Institutional Review Board (IRB # 3358).

Assessment of Clinical Characteristics

Detailed preoperative clinical profiles assessing demographic information, disease characteristics and treatment regimens were prospectively collected using chart review and patient interviews immediately after IPAA and during routine postoperative visits. Disease duration was calculated as the number of months between the diagnosis of UC to initial surgery date. Patients who smoked in the past or at the time of surgery were considered to be smokers. Family history of both IBD and CD specifically were recorded. Extraintestinal manifestations noted before colectomy including primary sclerosing cholangitis (PSC), skin lesions (pyoderma gangrenosum, erythema nodosum, leukocytoclastic vasculitis), bone/joint disease (arthritis, ankylosing spondylitis, sacroiliitis), or eye disease (uveitis, episcleritis) considered by the investigators and patient’s physicians to be manifestations of IBD were tabulated. The diagnosis of PSC was based on clinical findings and confirmed in all cases using magnetic resonance cholangiopancreatography. Backwash ileitis was defined as macroscopic or histological inflammation within the most distal 3 cm of the terminal ileum, not thought to be CD. Disease extent was classified as left-sided colitis or pancolitis based on preoperative endoscopic findings. Preoperative treatment with TNFi medications (infliximab, adalimumab, golimumab, or certolizumab) and number of different TNFi therapies prior to surgery was recorded. In patients who did not receive TNFi medication, cyclosporine was used as salvage therapy.

Diagnosis of UC, IBD-U, and CD

Preoperative clinical, endoscopic, and pathological criteria were reviewed in all patients to determine whether they had UC, IBD-U or CD. All patients underwent radiological small bowel evaluation or wireless capsule endoscopy prior to IPAA to exclude small bowel disease. Clinically, UC patients had endoscopic and histological features consistent with continuous inflammation extending proximally from the dentate line but no perianal disease. Patients were classified as having preoperative IBD-U or postoperative IC when they had clinical features of UC with some features suggestive but not diagnostic of CD, according to the Montreal classification¹⁷. Preoperative features of IBD-U included skip lesions possibly related to medical therapy, remote history of anal fistula or ulcer, or small bowel inflammation more than 3 cm proximal to the ileocaecal valve. Postoperative features of IC included gross or microscopic transmural colonic inflammation or discontinuous histological involvement of the colon possibly related to medical therapy.

CD was diagnosed by discontinuous inflammation at the time of index colonoscopy and prior to medical therapy, active proximal small bowel or perianal disease, or non-ruptured crypt granulomatous inflammation on histopathological examination.

Serological Analysis

Serological analysis for ASCA IgA and IgG on serum collected within 7 days of surgery was performed by Prometheus Laboratories (San Diego, California). Serum antibody levels were measured by enzyme-linked immunosorbent assay (ELISA), expressed as ELISA units (EU/mL) and analyzed according to laboratory standards for positivity (greater than 2 standard deviations above the mean control titer). Serological assays were performed blindly without knowledge of patient clinical characteristics. Similarly, clinical course after IPAA was assessed without knowledge of the patient’s seromarker profile. Perinuclear antineutrophil cytoplasmic, outer membrane porin C, Cbir1 flagellin, and glycoprotein 2 antibody levels were not routinely collected.

De novo CD

De novo CD after IPAA was diagnosed by endoscopy and histopathological evaluation of biopsy specimens when mucosal inflammation (5 or more ulcers) involved the small-bowel mucosa proximal to the ileal pouch any time after surgery and/or when a pouch fistula developed more than three months after ileostomy closure. Follow-up small bowel imaging and endoscopy was used to confirm the presence or continued presence of CD in those patients with small bowel involvement. There is no accepted definition of when a pouch fistula after IPAA is considered CD or a surgical complication, however our institution has traditionally used 3 months as a cutoff¹². Stool studies were obtained in all cases to exclude infection. All findings and diagnoses were reviewed with experienced gastroenterologists and pathologists. Time to diagnosis of de novo CD was defined as the interval from ileostomy closure to diagnosis.

TNFi Era Analysis

In order to investigate the association of TNFi exposure with de novo CD development, patients undergoing surgery after the introduction of TNFi were analyzed separately. The entire cohort was also divided into 2 study periods chronologically based on date of stoma closure: pre-TNFi era (1993 to 1998) and TNFi era (1999 to 2018). The year 1998 was selected as infliximab was approved by the FDA for Crohn’s disease in 1998 and was being used off-label for ulcerative colitis at that time. Infliximab was approved by the FDA for UC in 2005. Additional analysis was conducted using 2005 as a cutoff comparing patients from the pre-UC TNFi era (1993–2005) and UC TNFi era (2006–2018).

Statistical Analysis

Numerical variables are summarized as mean ± standard deviation and compared using Student’s t-test unless otherwise stated. Categorical variables are summarized as n (%) and compared using χ² or Fisher’s exact test unless otherwise stated. Freedom from de novo CD was estimated by Kaplan-Meier analysis and compared across groups by log-rank test. Given the inclusion of TNFi exposure as a predictor variable, univariable and multivariable analysis of associations with de novo CD were conducted only on TNFi era patients. Cox proportional hazards analysis was used to determine hazard ratios and confidence intervals for associations with the development of de novo CD. Descriptive summaries between those who developed or did not develop de novo CD are included as a supplement (supplementary appendix: Table S1). Multivariable analysis was done using Cox proportional hazards modeling using forward stepwise analysis with an entry level of 0.15 for potential predictor variables. Variables “age at disease onset” and “disease duration” were excluded from multivariable analysis because of significant collinearity with “age at surgery”.

A two-sided p - value of less than 0.05 was considered statistically significant. Statistical analysis was performed using IBM SPSS Software (Version 20). Kaplan-Meier curves and figures were created using SAS software (University Edition, December 2018 release).

Results

The study cohort of 400 UC patients included 205 (51%) males and had a mean age of 38.5 ± 15.9 years (Table 1). Most patients underwent a 2-stage (56%) IPAA for medically refractory disease and exhibited pancolitis at the time of surgery. Eighty-three patients (21%) had EIMs associated with their disease, including arthritis (n = 60), skin disease (n = 12), PSC (n = 9) or uveitis (n = 5). Three patients had more than one EIM. Although about one-third (29%) of patients had a family history of IBD, only 10% of the cohort had a family history of CD. Twenty-eight of the 318 (9%) patients with ASCA serology measured before surgery were considered to be ASCA positive. Fifteen (4%) patients were ASCA IgA+, 10 (3%) patients were ASCA IgG+ and 3 (1%) patients expressed both forms of ASCA. Approximately 21% of our cohort received cyclosporine. Sixty-two (16%) patients developed de novo CD predominantly diagnosed endoscopically by afferent limb ulceration (77%) with a median time to diagnosis of 28.0 (interquartile range (IQR) 11 – 113) months following ileostomy closure.

Table 1:

Clinical Characteristics of Pre-TNFi Era and TNFi Era Patients

	Study Cohort (n=400)	Pre-TNFi Era (n=55)	TNFi Era (n=345)	P-value
Male gender	205 (51)	31 (56)	174 (50)	0.47
Age at surgery (years)	38.5 (16)	38.5 (15)	38.5 (16)	0.99
Age at disease onset (years)	29.5 (14)	30.5 (13)	29.3 (14)	0.58
Disease duration (months)	105.4 (107)	101.0 (109)	106.1 (107)	0.74
Smoking history	102 (26)	18 (33)	84 (24)	0.19
Family history of IBD	117 (29)	17 (31)	100 (29)	0.75
Family history of CD	39 (10)	6 (11)	33 (10)	0.81
Extraintestinal disease	83 (21)	8 (15)	75 (22)	0.28
Backwash ileitis	47 (12)	5 (9)	42 (12)	0.65
Disease extent				0.15
Left-sided colitis	79 (20)	15 (27)	64 (19)
Pancolitis	321 (80)	40 (73)	281 (81)
Indication for surgery				0.57
Disease activity	328 (82)	47 (86)	281 (81)
Cancer / dysplasia	72 (18)	8 (15)	64 (19)
Preoperative ASCA expression *	28/318 (9)	8/55 (15)	20/263 (8)	0.12
Cyclosporine	85 (21)	22 (40)	63 (18)	0.001
Follow-up time (months) a	44.0 (11–113)	141.0 (52–190)	35.0 (10–94)	< 0.001
De novo CD	62 (16)	8 (15)	54 (16)	NA**
De novo CD diagnosis method				> 0.99
Afferent limb disease	48 (77)	6 (75)	42 (78)
Pouch fistula	14 (23)	2 (25)	12 (22)

Data represented as mean (SD) or n (%).

^aMedian (IQR).

TNFi tumour necrosis factor inhibitor; IBD inflammatory bowel disease; CD Crohn’s disease; ASCA anti-Saccharomyces cerevisiae antibody; NA not applicable.

^*Those with preoperative ASCA testing represented by denominator.

^**Refer to Figure 1: Kaplan-Meier analysis.

Our cohort included 55 patients (14%) from the pre-TNFi era (years 1993 – 1998) and 345 patients (86%) from the TNFi era (years 1999 – 2018). Between the two TNFi eras, there was no significant difference in clinical characteristics (Table 1). The usage of cyclosporine decreased from 40% to 18% between TNFi eras (P = 0.001). The development of de novo CD was significantly faster following FDA approval of infliximab (Figure 1, P = 0.018). The faster development of de novo CD was similarly appreciated after changing the chronological cutoff between groups to 2005, the year infliximab was approved for UC (supplementary appendix: Figure S1, P = 0.028).

Figure 1:

Time to de novo Crohn’s disease development was significantly faster during the tumor necrosis factor inhibitor (TNFi) era compared to the pre-TNFi era, shown in this Kaplan-Meier analysis (P = 0.018). Number of patients at risk are shown below the curves.

Amongst the 345 patients in the TNFi era, nearly half (n=166, 48%) were treated preoperatively with TNFi medication (Table 2). The majority of patients with preoperative TNFi exposure received only 1 medication (71%), 28% received 2 medications and 1% received 3 or more medications. Including those treated with more than one TNFi medications, 152 (44%) patients received infliximab, 56 (16%) patients received adalimumab, 3 (1%) patients received certolizumab and 2 (1%) patients received golimumab. Compared to TNFi naïve patients, those with TNFi exposure were younger with a shorter duration of disease. Patients with TNFi exposure exhibited significantly more backwash ileitis, pancolitis, underwent surgery more often for medically refractory disease, and were less often prescribed cyclosporine. Finally, TNFi exposed patients had a shorter follow-up time (median 18.0 (IQR 6 – 56) months) compared to TNFi naïve patients (median 64.0 (IQR 19 – 128) months) (P < 0.001). Survival analysis of TNFi era patients revealed a significant increase in de novo CD risk in those with preoperative TNFi exposure (Figure 2, P = 0.003).

Table 2:

Clinical Characteristics of TNFi Naïve and TNFi Exposed Patients During the TNFi Era

	TNFi Naïve (n=179)	TNFi Exposed (n=166)	P-value
Male gender	99 (55)	75 (45)	0.067
Age at surgery (years)	41.6 (15)	35.1 (16)	< 0.001
Age at disease onset (years)	30.6 (13)	28.0 (15)	0.10
Disease duration (months)	125.7 (120)	84.9 (87)	< 0.001
Smoking history	52 (29)	32 (19)	0.044
Family history of IBD	47 (26)	53 (32)	0.29
Family history of CD	12 (7)	21 (13)	0.068
Extraintestinal disease	39 (22)	36 (22)	> 0.99
Backwash ileitis	11 (6)	31 (19)	< 0.001
Disease extent			0.018
Left-sided colitis	42 (24)	22 (13)
Pancolitis	137 (77)	144 (87)
Indication for surgery			< 0.001
Disease activity	126 (70)	155 (93)
Cancer / dysplasia	53 (30)	11 (7)
Preoperative ASCA expression *	14/166 (8)	6/97 (6)	0.63
Cyclosporine	44 (25)	19 (11)	0.002
Follow-up time (months) a	64.0 (19–128)	18.0 (6–56)	< 0.001
De novo CD	26 (15)	28 (17)	NA**
De novo CD diagnosis method			> 0.99
Afferent limb disease	20 (78)	22 (79)
Pouch fistula	6 (23)	6 (21)

Data represented as mean (SD) or n (%).

^aMedian (IQR).

TNFi tumour necrosis factor inhibitor; IBD inflammatory bowel disease; CD Crohn’s disease; ASCA anti-Saccharomyces cerevisiae antibody; NA not applicable.

^*Those with preoperative ASCA testing represented by denominator.

^**Refer to Figure 2: Kaplan-Meier analysis.

Figure 2:

Patients with preoperative tumor necrosis factor inhibitor (TNFi) exposure were at significantly increased risk of de novo Crohn’s disease compared to those who were TNFi naïve, shown in this Kaplan-Meier analysis (P = 0.003). Number of patients at risk are shown below the curves.

Univariable Cox proportional hazards analysis revealed several significant clinical risk factors for the development of de novo CD including younger age at surgery and preoperative TNFi exposure (Table 3). Neither family history of IBD nor CD was significantly associated with the development of de novo CD with hazard ratios of 1.70 (95% CI 0.99 – 2.92, P = 0.057) and 1.77 (95% CI 0.80 – 3.94, P = 0.16) respectively. Patient age at disease onset and disease duration were not included in multivariable analysis as they exhibited significant collinearity (P < 0.001) with age at surgery. Multivariable forward stepwise Cox proportional hazards modeling revealed two independent predictors for de novo CD development: older age was protective (HR 0.89 per 5-year increase, 95% CI 0.81 – 0.97, P = 0.009) and preoperative TNFi exposure was hazardous (HR 2.1, 95% CI 1.19 – 3.71, P = 0.011).

Table 3:

Univariable and Multivariable Analysis of Factors Associated with Development of De novo CD in the TNFi era

Variable	Univariable HR	95% CI	P	Multivariable HR	95% CI	P
Male gender	0.85	0.50 – 1.46	0.56
Age at surgery (years) a	0.87	0.80 – 0.96	0.003	0.89	0.81 – 0.97	0.009
Age at disease onset (years) *	0.98	0.96 – 1.00	0.068a
Disease duration (months) *	1.00	0.99 – 1.00	0.066a
Smoking history	0.58	0.29 – 1.17	0.13
TNFi exposure	2.29	1.31 – 4.01	0.004	2.10	1.19 – 3.71	0.011
Family history of IBD	1.70	0.99 – 2.92	0.057
Family history of CD	1.77	0.80 – 3.94	0.16
Extraintestinal disease	1.30	0.69 – 2.43	0.42
Backwash ileitis	1.11	0.47 – 2.60	0.81
Disease extent			0.058
Left-sided colitis	ref	ref
Pancolitis	2.17	0.97 – 4.81
Indication for surgery			0.086
Disease activity	ref	ref
Cancer / dysplasia	0.50	0.22 – 1.10
Preoperative ASCA expression	1.50	0.54 – 4.20	0.44
Cyclosporine	0.84	0.45 – 1.58	0.59

^aPer 5-year increase

^*Excluded from multivariable analysis for collinearity with “age at surgery” (P < 0.001).

HR hazard ratio; CI confidence interval; TNFi tumour necrosis factor inhibitor; IBD inflammatory bowel disease; CD Crohn’s disease; ASCA anti-Saccharomyces cerevisiae antibody; ref reference.

Discussion

Identifying risk factors for the development of de novo CD would provide insights into both the understanding of disease pathophysiology and management. In this analysis of 400 consecutive UC patients undergoing IPAA, we found that 16% of patients developed de novo CD, more than double the incidence (7%) cited in a 2008 study¹² from our center. This high incidence of de novo CD may be a result of referral center bias and/or longer follow-up. An alternative explanation may be that preoperative TNFi use before IPAA surgery has steadily increased, with a new subpopulation coming to surgery exposed to chronic maintenance dosing of TNFi medication¹⁸. As our data showed preoperative anti-TNF therapy to be an independent risk factor for development of de novo CD following IPAA, it is plausible that use of TNFi agents may be partly responsible for the increasing incidence of de novo CD.

No previous studies have identified preoperative TNFi exposure as a potential risk factor, likely because of an insufficient volume of TNFi exposed patients. In two of the largest prospective studies of outcomes following IPAA, Shen and coworkers either made no mention¹³ or included only a very small proportion of patients (3.2%)¹⁵ with pre-colectomy TNFi or biologic medication exposure. Similarly, analysis of a prospectively maintained database of over 2800 patients by Melton et al. included only 91 (9%) patients with preoperative infliximab exposure¹⁴. A 2009 study from our center included 30 (13%) patients with preoperative infliximab use, however IPAA outcomes in patients were not analyzed separately from other immunomodulators¹². Patients with pre-colectomy TNFi exposure comprised a substantial proportion (48%) of our cohort and likely supplied the necessary power to detect the association with de novo CD development. Furthermore, high TNFi exposure may account for our study not validating previously identified preoperative risk factors for de novo CD after IPAA such as smoking, family history of CD, and ASCA positivity^12,13,15.

In addition to preoperative TNFi exposure, we identified younger age as an independent risk factor for de novo CD development, itself interesting on a number of levels. Clinically, the only factor associated with the development of de novo CD after IPAA in IBD-U is younger age at disease onset¹⁹. Biologically, patients diagnosed at a younger age or in childhood may be exposed or respond differently to various microbial antigens as compared to adults, resulting in a more persistent immune reactivity²⁰. Alternatively, this may simply represent a function of time, as the longer duration of microbial antigen exposure may increase eventual rate of conversion to another form of mucosal inflammation.

To our knowledge, this is the first study identifying preoperative TNFi exposure as a risk factor for development of de novo CD following IPAA. Indeed, this study raises far more questions than it answers, particularly because the potential mechanism of this new association is unexplored. It is possible that TNF inhibitors are masking preoperative manifestations of CD or perhaps modifying their inflammatory phenotype. Even more intriguing is the possible relationship between the gut microbiome and TNFi agents and how this interaction may predispose patients to developing de novo CD^21,22. Perhaps TNFi therapy induces a subclinical state of continued pathogenic microbial exposure that may have otherwise been prevented following colectomy for medically refractory disease. Busquets and coworkers describe a rapid change in intestinal microbiota composition, specifically E. coli prevalence, towards eubiosis within 1 month of adalimumab treatment²². While this study of 19 patients argues in favour of the restorative potential of TNFi agents, their study was limited to 3 months of observation.

Although TNFi are associated with the development of de novo CD in UC, the treatment of de novo CD following IPAA with TNFi is still effective. A recent study of 350 UC and IBD-U patients who developed de novo CD showed that TNF inhibitors may prevent pouch failure, even in those who previously failed TNFi therapy²³. A fundamental lack of pathophysiological understanding of de novo CD underscores why we cannot explain why preoperative TNFi exposure is associated with the development of de novo CD yet effectively treats de novo CD as well.

Despite the knowledge gained by this study, we were bound by several limitations. Our study may not be generalizable to patients with IBD-U as these patients were excluded. Family history of IBD and CD were recorded, but degree or history of family lineage was not collected. Furthermore, we recorded the number and type of immunomodulators these patients received, however we did not obtain sufficient dosing data to extrapolate a dose dependent relationship between TNFi exposure and de novo CD development.

Ultimately, randomization will be instrumental to defining a causal relationship between preoperative TNFi exposure and development of de novo CD, however this would require a robust protocol and multi-center collaboration to confer the statistical power required to detect a meaningful result. As such, we advocate for a randomized controlled trial that may illuminate a target for the treatment or prevention of de novo CD. Finally, because we were unable to rigorously assess disease activity, the relationship between TNFi exposure and de novo CD may be tempered and may solely be a reflection of disease activity.

Lastly, given its growing incidence and recognition, we find it important to discuss the diagnostic challenges of de novo CD, particularly its distinction from non-pouch CD. The phenomenon of post-ileal pouch CD-like inflammatory complications in patients with UC, IBD-U, or IC has been described in the literature by many names including denovo or de novo CD, Crohn’s disease of the pouch, Crohn’s pouchitis, or Crohn’s disease-like inflammation of the pouch. Although CD is included within the name, de novo CD is a unique entity separate from non-pouch CD and should not be considered a “missed” diagnosis especially in our well-differentiated study population excluding IBD-U and IC. Hallmarks of non-pouch CD include granulomas on histology, transmural inflammation, and involvement of multiple areas of intestine, however these are rarely seen in de novo CD²⁴. In fact, none of our biopsies on de novo CD patients exhibited a granuloma on pathology.

The most controversial aspect of de novo CD is the absence of an agreed definition. While most institutions subscribe to a core definition of “Crohn’s-like ulcerative inflammation in the pre-pouch afferent limb and/or non-anastomotic strictures or fistulas unrelated to surgery or infection”, there are discrepancies in criteria and timing. As mentioned above, our criteria include endoscopic evidence of 5 or more ulcers in the afferent limb proximal to the ileal pouch any time after surgery or when a pouch fistula developed more than three months after ileostomy closure following exclusion of pelvic sepsis. We, with others, use 3 months as our cutoff before a surgical complication or sepsis can be excluded²⁵, while some use 6 months²⁶, and a minority advocate for a year. Despite these variations, most institutions remain consistent in their definitions allowing comparisons to be made across time. Though heterogeneity exists between institutional definitions, there exist unifying features which bolsters the possibility of a standardized definition for de novo CD in the future.

Conclusion

In summary, the incidence of de novo CD appears to have increased to 16% from 7% in 2008 mirroring a rise in the proportion of patients with preoperative TNFi exposure before IPAA. This prospective study is the first to show that preoperative TNFi exposure is an independent risk factor for the development of de novo CD. Although the potential mechanism of this new association is unclear, the interaction between the gut microbiome and TNFi agents may be important. Given that patients with de novo CD are at increased risk of complications and pouch failure, a modifiable risk factor would be pertinent to both disease management and our understanding of this pathophysiology.

What does this paper add to the literature?

The pathophysiological development of de novo Crohn’s disease following ileal pouch-anal anastomosis is still not understood. We uncover a novel link between pre-colectomy exposure to anti-tumour necrosis factor alpha inhibitor medications and the development of de novo Crohn’s disease. This finding offers insight into potential immunological or microbiological mechanisms for this disease.