The Rational Use of Advanced Therapies for Inflammatory Conditions of the Pouch

With this commentary, we are excited to launch a new feature in Inflammatory Bowel Diseases, “The Pouch Corner.” The management of patients after restorative proctocolectomy with ileal pouch-anal anastomosis (IPAA) for ulcerative colitis (UC) and other indications is rapidly changing, prompting exciting new research and clinical challenges. Along with the Editorial Board, we believe that these changes offer an outstanding opportunity for critical examination of the multidisciplinary clinical and research topics that most affect the care of patients after IPAA. We will feature a discussion of these emerging topics in The Pouch Corner, allowing for in-depth discussions of both available literature and practical observations from gastroenterology and colorectal surgery that will hopefully be useful to practicing clinicians.

In this first edition of The Pouch Corner, we are focusing on the management of patients with inflammatory conditions of the pouch using advanced therapies. Following IPAA for UC, an estimated 17% of patients will develop chronic pouchitis.¹ Although many patients will respond to chronic antibiotic therapy, others will become refractory to standard antibiotic approaches and thus will require the reinstitution of immunosuppressive therapies.^2,3 Additionally, an estimated 10% of patients will develop new inflammatory complications consistent with a diagnosis of Crohn’s-like disease of the pouch (CLDP),⁴ which typically require advanced therapies. Despite the burden of these chronic inflammatory conditions of the pouch, our traditional approaches to treating these patients have relied on repurposing evidence from Crohn’s disease (CD) and UC, as there has been a paucity of dedicated randomized controlled trials (RCTs) or real-world comparative effectiveness studies in patients after IPAA. We have seen recent advances in this evidence base, however, which we will summarize here.

Vedolizumab

There were early signals regarding the potential effectiveness of vedolizumab in treating patients with chronic pouchitis.^5–7 These early observational studies set the stage for the landmark EARNEST study which was published early this year, comparing vedolizumab to placebo in the treatment of chronic pouchitis.⁸

EARNEST was a phase 4, double-blind, randomized trial in adult patients with chronic pouchitis. All patients initially received ciprofloxacin during weeks 1 to 4 and were randomized (1: 1 ratio) to receive vedolizumab 300 mg intravenously or placebo. At week 14, more patients treated with vedolizumab were in clinical remission (defined by the modified pouchitis disease activity index [mPDAI]⁹) compared with placebo (31% vs 10%, P = .01); these findings were also demonstrated at week 34 (35% vs 18%). When considering inflammatory conditions of the pouch, the rate of progression from classic chronic antibiotic-dependent pouchitis to chronic antibiotic-refractory pouchitis (CARP) is relatively unknown, and it is worth noting that all patients in EARNEST were treated with antibiotics for the first 4 weeks of the study. Additionally, over 21% of patients treated with vedolizumab continued to use antibiotic therapy at week 34 after initiation of vedolizumab compared with 12.5% of patients treated with placebo. However, given that this was among the only RCTs evaluating the use of advanced therapies in pouchitis, this is a landmark study that should prompt both discussion of the positioning of vedolizumab in this setting and future rigorous research regarding other advanced therapies for the treatment of patients with inflammatory conditions of the pouch.

Ustekinumab

Although there are no RCT data evaluating the use of ustekinumab in patients with inflammatory conditions of the pouch, multiple groups have evaluated the utility of ustekinumab in these settings in recent years. In a retrospective evaluation of ustekinumab for the treatment of CARP, 50% of patients demonstrated a clinical response at a median of 12.9 months.¹⁰ Similarly, in a multicenter evaluation of patients with both CLDP and CARP, 83% of patients demonstrated a clinical response at 6 months after induction.¹¹

These initial reports were followed by prospective evaluations, including results from a prospective registry for the study of outcomes and predictors of pouchitis and pouch-related disorders (PROP-RD), where 33% of patients with active CARP at baseline and 46% of patients with active CLDP at baseline treated with ustekinumab were in remission at 6 months after enrollment.¹² More recently, early results from a prospective, open-label study of patients with CARP indicated that the use of ustekinumab was associated with a significant decrease in the total mPDAI at both week 16 and week 48, with patients continuing ustekinumab through week 48 also demonstrating improvements in the endoscopic subscore of the mPDAI.^13,14 Interestingly, in this open-label study patients were also treated with ciprofloxacin for the first 4 weeks; however, any antibiotic use after this period was regarded as a failure of ustekinumab treatment.

Other Advanced Therapies and Positioning of Advanced Therapies

Recent guidelines on the management of pouchitis and inflammatory pouch disorders from the American Gastroenterological Association (AGA) can improve our understanding of the clinical effectiveness of these novel advanced therapies and other advanced therapies for the treatment of pouch-related disorders.¹⁵ Prior systematic reviews and meta-analyses have demonstrated the potential effectiveness of antitumor necrosis factor alpha (anti-TNF) therapies in the treatment of inflammatory conditions of the pouch.^16,17 While informative, similar to our understanding of the utility of most advanced therapies in the treatment of inflammatory conditions of the pouch, these data were largely based on retrospective or observational studies. Thus, while the AGA suggested the use of advanced immunosuppressive therapies for the treatment of both recurrent pouchitis with inadequate response to antibiotics (commonly referred to as CARP) and CLDP, both recommendations were made with a very low certainty of evidence (with the exception of vedolizumab in the setting of CARP, which had a low certainty of evidence). The available data for JAK-inhibitors such as tofacitinib would suggest a potential role in inflammatory conditions of the pouch.^12,18–20 However, the volume of evidence is lacking even in comparison to other mechanisms of action, and this remains an opportunity for future research.

In reality, only 2 RCTs have been performed in this field (the previously mentioned EARNEST study⁸ and one study of adalimumab²¹). Based on encouraging results from retrospective evaluations and prospective open-label studies or registries,^12,13 questions remain as to whether RCTs of other advanced therapies would yield similar findings to those of the EARNEST study. Similarly, future prospective studies will be informative regarding the appropriate positioning or sequencing of therapies in patients with chronic inflammatory conditions of the pouch. In particular, the comparative effectiveness of advanced therapies in the treatment of pouch-related disorders is an unknown at this time.

When considering the appropriate sequencing of advanced therapies after IPAA, one must also consider the impact of prior advanced therapy exposure. In EARNEST, 29% of patients treated with vedolizumab had received an anti-TNF therapy after colectomy. However, therapy exposure prior to colectomy may also play an important role in future treatment success. There are some indications that exposure prior to colectomy can influence the natural history after IPAA.^22,23 Additionally, given the expanding treatment armamentarium for UC, we must understand the potential influence of precolectomy treatment failure on post-IPAA therapy choices. In one retrospective study, Kayal and colleagues found patients who received anti-TNF therapy prior to colectomy and after IPAA were less likely to achieve clinical remission compared with those patients who were anti-TNF-naïve or were treated with a different class of therapy post-IPAA.²⁴ However, these patterns have not been definitively demonstrated to date.²⁵

Current Practice, Future Directions

Although the most robust data for the management of inflammatory conditions of the pouch have been generated from EARNEST, decision-making regarding advanced therapy use for inflammatory conditions of the pouch remains individualized in most cases. Considering the presentation of the patient’s inflammatory condition of the pouch (refractory pouchitis, prepouch ileitis, perianal complications, etc.), prior treatment, comorbidities, and any extraintestinal manifestations of IBD may aid in decision-making in the current era.

All of these emerging data offer great promise but also prompt considerations of future areas of research and unmet clinical needs in the current era. To offer informed decision-making for patients with inflammatory conditions of the pouch, we must have robust prospective data. These may be generated from traditional RCTs but may also come in the form of novel trial designs including pragmatic clinical trials²⁶ and real-world comparative efficacy and effectiveness studies.²⁷ Such rigorous study designs will allow for more informed decision-making regarding treatment sequencing and future decisions of earlier risk stratification.

Improving our understanding of the risk factors for chronic inflammatory conditions of the pouch would also potentially inform decision-making surrounding the initiation of advanced therapies after IPAA, including potential surgical complications that would necessitate intervention from a pouch surgeon rather than medical therapy. In both UC and CD, the early introduction of appropriate therapy to patients with a severe prognosis is favored. However, in patients after IPAA, we often are reactionary, waiting until after a patient develops debilitating symptoms or complications of chronic inflammatory disease. Understanding the drivers of inflammatory conditions of the pouch may lead to earlier identification of high-risk phenotypes and tailored interventions for those individuals, thus changing their overall disease course after IPAA.

Conclusion

In summary, the data supporting the use of advanced therapies in the treatment of inflammatory conditions of the pouch suggest several treatment options for patients with refractory presentations after IPAA. Although there are many unmet needs including improved understanding of treatment sequencing and comparative effectiveness, recent advances including new RCTs and new mechanisms of action in the treatment of inflammatory conditions of the pouch offer great promise for patients with chronic pouch-related disorders.

Funding

This research was supported by grants from the National Institutes of Health [K23DK127157].

Conflicts of Interest

E.B. has served as a consultant for Target RWE.

M.K. has served as a consultant for Pfizer, AbbVie, Bristol Meyers Squibb, Fresenius.

D.S. has nothing to disclose.