Shedding New Light on High-Risk Phenotypes for Pouchitis

Despite the fact that an estimated 48% of patients will develop pouchitis in the first 2 years after restorative proctocolectomy with ileal pouch-anal anastomosis (IPAA) for ulcerative colitis (UC),¹ our ability to risk stratify patients at the time of surgery based on clinical, phenotypic, or serologic factors remains limited in the current era. The paucity of actionable risk factors is even more unsettling when considering that the lifetime risk for pouchitis is over 80%,^2,3 with an estimated 17% of patients going on to develop chronic pouchitis.⁴ Although certain clinical factors such as primary sclerosing cholangitis (PSC) have been definitively linked to both pouchitis and chronic pouchitis,⁵ the study of therapies for the primary prevention of inflammatory conditions of the pouch has been limited in these high-risk populations. Similarly, the recognition of an association between pouchitis and certain serologic and/or genetic markers (eg, perinuclear anti-neutrophil cytoplasmic antibody [pANCA],^6,7 NOD2insC single nucleotide polymorphism,⁸ anti-CBir1⁶) or clinical factors (eg, extraintestinal manifestations of inflammatory bowel disease,⁹ extensive colitis¹⁰) has not led to standardized efforts to offer early interventions to those patients at the greatest risk.

In the current issue of Inflammatory Bowel Diseases, Kayal and colleagues evaluated the relationship between acute severe UC (ASUC) at the time of colectomy and subsequent development of acute pouchitis.¹¹ Given prior suggestions that pouchitis risk may be driven by a more robust immune response,^1,12 the authors compared the incidence of pouchitis among patients admitted with ASUC at the time of colectomy to those undergoing colectomy without ASUC. In their analysis, acute pouchitis occurred in 55% of the population (median 1.3 years after the final stage of surgery). In multivariable analysis, ASUC (hazard ratio [HR], 1.50; 95% CI, 1.04-2.17) and a greater number of biologics pre-colectomy (HR, 1.57; 95% CI, 1.06-2.31) were associated with an increased probability of acute pouchitis.

The authors of the current study have performed a rigorous analysis of a well-defined cohort of patients undergoing IPAA at their institution. The use of objective assessments for the identification of patients with pouchitis, including the Pouchitis Disease Activity Index (PDAI)¹³ and use of pouchoscopy in all patients, is a strength of the analysis; although the retrospective calculation of a PDAI is a potential limitation. Given that this study included only those patients who underwent a pouchoscopy during the study period, the potential exists that patients who developed pouchitis symptoms and were treated without undergoing pouchoscopy would not be accounted for in this database. This may be a nondifferential bias; however, when considering the real-world care of patients after IPAA for UC, this potential limitation must be acknowledged. Despite these limitations, this study offers new data highlighting the unique risk factors present among patients with perhaps the most severe/refractory phenotypes of UC prior to colectomy and thus creates a model to inform future research and clinical practice decisions.

Although there has been a significant expansion in our therapeutic armamentarium for the treatment of UC in recent years, an estimated 13% of patients will still require a colectomy for UC within 10 years of diagnosis.¹⁴ Given this significant proportion of patients requiring colectomy in the modern treatment era, the recently identified apparent increase in the incidence of pouchitis² is striking and warrants further evaluation of the drivers of pouchitis. In an examination of a nationwide prospective cohort from Denmark, a 15% raw and 38% relative increase in the incidence of pouchitis was demonstrated between 1996 and 2018. When considering the burden of pouchitis to individual patients and the health care system,¹⁵ identifying the etiology of pouchitis, predictors of severity, and opportunities for intervention is paramount.

The study by Kayal and colleagues is important in these efforts given the focus on the immune phenotype of patients who go on to develop pouchitis. Recent studies have evaluated the impact of anti-TNF therapy prior to colectomy as a risk factor for pouchitis.^1,12,16 A critical question regarding this relationship is whether preoperative exposure to antitumor necrosis factor (anti-TNF) therapy and potentially other advanced therapies influences the microbiome, ileal mucosal composition, or other factors to increase an individual’s risk for pouchitis, or whether these exposures represent a more refractory disease state among patients who ultimately undergo colectomy due to lack of response to these therapies. The current study extends this line of thought by demonstrating that patients with the most severe colitis (ASUC and a greater number of biologics precolectomy) were at the greatest risk for developing acute pouchitis. Specifically, the relatively early development of pouchitis in this study and the recognition by this group and other recent evaluations that patients developing pouchitis in the first year after surgery are at increased risk for chronic inflammatory conditions of the pouch^17,18 would suggest that these patients with ASUC represent a refractory population precolectomy as well as a new refractory phenotype in the early postoperative period after IPAA.

Given the potential that these patients represent a more refractory phenotype even in the post-IPAA state, new methods for risk stratification incorporating both clinical risk factors as well as novel translational approaches could inform future management strategies. Clinical information alone has limitations with regards to informing our understanding of the etiologies of pouchitis, and thus new methods of risk stratification combining the targeted clinical phenotypes employed by Kayal and colleagues with emerging multiomic approaches^19–21 and prognostic histologic factors^22,23 could significantly inform discussions with patients contemplating restorative proctocolectomy with IPAA.

Additionally, even with dedicated efforts to improve risk stratification, our current approaches to the management of pouch-related disorders are reactionary, waiting until a patient develops symptoms of pouchitis or inflammation of the pouch to initiate a new therapy postoperatively. With improved methods of risk stratification, we should also aim to investigate and ultimately employ primary and secondary prevention strategies among those patients at greatest risk for developing inflammatory conditions of the pouch, with the goal of improving patient quality of life and decreasing the probability of irreversible pouch damage and ultimately failure. Early studies of compounds such as the 8-strain probiotic combination of Lactobacillus paracasei subsp paracasei, L plantarum, L acidophilus, L delbrueckii subsp bulgaricus, Bifidobacterium longum subsp longum, B breve, B longum subsp infantis, and Streptococcus salivarius subsp thermophilus demonstrated benefit in prevention of a first episode of pouchitis and maintenance of remission after treatment for pouchitis.^24,25 However, these studies have not prompted widespread uptake of probiotics or other medications for primary or secondary prevention. In future prospective research, we must focus on taking early action to deter the development of pouchitis and other inflammatory conditions of the pouch in patients known to be at greatest risk for pouch complications.

In conclusion, Kayal and colleagues are to be congratulated for an important study that helps establish a risk profile among those patients undergoing colectomy and IPAA for UC who are at the greatest risk for developing pouchitis. Establishing these risk factors for pouchitis and identifying these at-risk phenotypes are a critical step in improving our ability to counsel patients in the perioperative state and ultimately improving outcomes in this population. These findings should serve as an important reminder of a potential emerging immune phenotype of patients undergoing colectomy for medically refractory colitis who have new risk factors for pouchitis and should promote future research in this field.

Funding

This research was supported by grants from the National Institutes of Health [K23DK127157-01 (E.L.B.).

Conflicts of Interest

E.L.B. has served as a consultant for AbbVie, Bristol-Meyers Squibb, Lilly, and Target RWE.

S.C. has served as a consultant for AbbVie, Bristol-Meyers Squibb, and Pfizer.

Data Availability

No data was presented in this commentary.