Approach to Therapy for Chronic Pouchitis

Introduction

Chronic pouchitis (CP) occurs in approximately 20% of patients with ulcerative colitis (UC) after total proctocolectomy with ileal pouch anal anastomosis (IPAA). CP is categorized as antibiotic-dependent, antibiotic-refractory or Crohn’s disease-like.^{1, 2} Though CP is considered a spectrum of disease, each category has unique features. Chronic antibiotic-dependent pouchitis (CADP) involves persistent (≥4 weeks) or recurrent symptoms of pouchitis (≥4 episodes per year) that are responsive to maintenance antibiotic therapy.^{3, 4} Chronic antibiotic-refractory pouchitis (CARP) involves persistent or recurrent symptoms of pouchitis that are unresponsive to antibiotics, requiring escalation of therapy to steroids or biologic therapy.^3–6 Crohn’s disease-like pouch inflammation (CDLPI) involves inflammation of the pouch body and pre-pouch ileum, strictures of the pre-pouch ileum or proximal small bowel, and/or fistulae of the perineum or proximal small bowel.⁷ The correct delineation of CADP vs CARP vs CDLPI is imperative as it directly informs treatment.

The management of CP is challenging due to limited evidence with few randomized controlled trials. Although guidelines are available, they are largely based on expert opinion utilizing low quality data and small sample sizes.^{8, 9} In this review, we discuss the medical management of CP and its supporting data delineated by type of therapy.

Antibiotics

Antibiotics are the mainstay of therapy in CADP, of which ciprofloxacin and metronidazole are the most comprehensively studied. In a cohort study of 44 patients with CADP who received combination ciprofloxacin and metronidazole for 28 days, 36 (82%) achieved clinical and endoscopic remission, and median pouchitis disease activity index (PDAI) improved significantly even among the patients who did not achieve remission.¹⁰ In an open-label study of 51 patients with CADP who received a two-week course of ciprofloxacin or metronidazole for induction of remission followed by rifaximin for maintenance, 33 (65%) achieved clinical and endoscopic remission at three months.¹¹ Of these patients, the majority (23, 70%) received 200 mg/day of rifaximin during the maintenance period, and the remainder required rifaximin dose escalation to a maximum of 1,200 mg/day. The majority (58%) of antibiotic-responsive patients continued rifaximin as maintenance therapy for one year.

Maintenance ciprofloxacin or metronidazole at the lowest effective dose in patients may be used in patients with CADP. The tolerability of metronidazole is limited for some by nausea, metallic taste in mouth, interaction with alcohol, and potential risk of peripheral neuropathy. Ciprofloxacin has been associated with an increased risk of tendonitis and tendon rupture, particularly in individuals over 60 years old and concomitant steroids. The overall risk of complications due to chronic antibiotic therapy is low.¹² In patients who are refractory or intolerant to ciprofloxacin or metronidazole, alternative options include rifaximin, tinidazole, amoxicillin-clavulanate, doxycycline, or vancomycin, though data is limited.^{8, 13, 14}

Mesalamine

The evidence to support the use of mesalamine in CP is limited to patients with CARP and limited to a single small study. In a case series of 16 patients with CARP who received combination ciprofloxacin and tinidazole or mesalamine, 50% of patients who received mesalamine achieved clinical remission.¹³ In this study, mesalamine was administered as oral 4 gram/day, enema 8 gram/day, or suppository 1 gram/day formulation, and the superiority of the topical vs oral formulation was not evaluated. In light of the significantly limited data and given the availability of alternative therapies, the use of mesalamine is not routinely recommended in CP.

Corticosteroids

Of the available corticosteroids, only budesonide and beclomethasone have been evaluated in patients with CP. In a case series of 13 patients with CARP treated with budesonide, 60% achieved clinical response.¹⁵ In a prospective study of 20 patients with CARP treated with budesonide, 75% achieved clinical remission and the median total PDAI scores significantly decreased from 14 to 3 (p<0.001).¹⁶ In an open-label study of 10 patients with CARP treated with beclomethasone, 80% of patients achieved clinical remission and the median number of bowel movements decreased significantly from 10 to 6 (p<0.001).¹⁷

Although data is limited to the above, budesonide may be used as induction therapy in CP as a bridge to biologic or small molecule therapy. The use of budesonide as maintenance monotherapy in CP is not recommended given limited data and potential associated risks of long-term corticosteroid use.

Biologics

Anti-tumor necrosis factor (TNF), anti-integrin and anti-interleukin agents have demonstrated efficacy and safety in CARP and CDLPI. In a meta-analysis of 311 patients with CARP, the pooled rate of clinical remission was 31%, 47.4%, and 65.7% with adalimumab, vedolizumab, and infliximab, respectively.¹⁸ Although data regarding choice and positioning of biologics in CARP and CDLPI is unavailable, patients exposed to anti-TNF therapy pre-colectomy and post-IPAA may be less likely to achieve clinical remission and more likely to have pouch failure.¹⁹

Small Molecules

In a retrospective study of 13 patients with CP treated with tofacitinib, 46% achieved clinical response during follow-up; however, 64% ultimately discontinued therapy due to primary or secondary loss of response.³³ In a multicenter study of 15 patients with CARP treated with different JAK inhibitors, including tofacitinib, filgotinib and upadacitinib, steroid-free and antibiotics-free clinical response and remission were achieved in 53% and 40%, respectively.³⁴ There are additional case reports of using small molecules in CP with variable success.

There is insufficient data to recommend tofacitinib or other JAK Inhibitors prior to adalimumab, infliximab, vedolizumab, and ustekinumab in CP; however, it may be considered in CP patients with previous exposure to these biologics as novel mechanisms of action.

Fecal Microbiota Transplant

Given the causal association between the microbiome and pouchitis, fecal microbiota transplantation (FMT) for CP has been examined; however, a number of studies have shown no benefit and poor engraftment.³⁵ In a placebo-controlled, double blinded trial of 6 patients with CP who received FMT, only one patient achieved remission, and the study was stopped early due to perceived futility.³⁶ In two pilot studies with 27 cumulative patients with CARP treated with FMT, there were minor reductions in disease activity and bowel movement frequency, but none of the patients achieved clinical remission.^{37, 38} Similarly, in a recent randomized, placebo-controlled trial of 26 patients with CARP, FMT was not efficacious and was associated with earlier disease relapse as compared to placebo.³⁹ Furthermore, five patients in the FMT group relapsed within the first four weeks following FMT, while no patient in the placebo group relapsed during this time period. In light of the limited data and significant differences in method of administration and source, FMT is not recommended for the management of CP at this time though a microbial-based strategy with better engraftment may have a role in the future.

Discussion

Management of chronic pouchitis is a clinical challenge, particularly among those patients with CARP and CDLPI where biologics or small molecules are needed. The existing data predominantly comes from small retrospective cohorts of patients with CP and reflect significant variation in practices. In addition, most studies combine outcomes from patients with CARP and CDLPI even though these represent distinct entities within the spectrum of CP. Although each may respond differently to medications, differences in response rate and relative efficacy are difficult to ascertain in existing studies.

Medication selection, particularly beyond antibiotics, remains difficult in the absence of distinct clinical predictors or biomarkers of response to therapy. Use of biologics and small molecules with a novel mechanism of action to which a patient has not been exposed is appealing mechanistically in the management of CP. Pre-colectomy exposure and response to a given class of medications may influence the likelihood of reusing a medication post colectomy but does not necessarily preclude its use for CP. Specific disease behavior, such as fistulizing disease or perianal fistula in CDLPI, may influence medication selection, favoring the use of TNF antagonists in the absence of contraindications. TNF inhibitors have higher rates of immunogenicity and reuse of this class of medications has been associated with more infusion reactions and delayed hypersensitivity reactions related to antibody formation which can lead to discontinuation of therapy in a subset of patients.³¹ Combinations of therapies may be needed to manage CP though even less data is available to guide these therapeutic decisions.

Further complicating the management of CP is the lack of a defined “treat to target” strategy. Treatment targets in CP are distinct from those in UC or CD, and predominantly focus on improvement of clinical symptoms and quality of life and avoidance of pouch failure. Endoscopic remission is not a universally recognized treatment target, and in fact, may not be attainable in CP. The utility of additional treatment targets such as C-reactive protein (CRP) or calprotectin has not been elucidated in patients with an IPAA. CRP levels have not been shown to differ significantly in patients with pouchitis vs those without, and calprotectin thresholds have not been established in this setting.⁴⁰

In conclusion, a number of therapies are available for the management of CP with variable success. The choice of therapy should be individualized and take into account pre-colectomy medications, disease behavior, and extra-intestinal manifestations while balancing efficacy and safety. Additional RCTs are needed to better inform this area of significant unmet need.