DISPATCHES FROM THE GUILD CONFERENCE, SERIES #51

A Review of the Diagnosis and Treatment of Inflammatory Pouch Conditions

April 2023 • Volume XLVII, Issue 4
Marouf Hossain,Maia Kayal

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Pouch inflammation is common after restorative proctocolectomy (RPC) with ileal pouch-anal anastomosis (IPAA) and is best described as a spectrum that includes acute and chronic pouchitis. Distinguishing between these conditions may be difficult given the extensive overlap of clinical symptoms, and treatment can be challenging due to limited evidence. The aim of this study is to review the diagnosis and treatment of inflammatory pouch disorders, focusing on acute pouchitis, chronic antibiotic dependent pouchitis, chronic antibiotic refractory pouchitis, Crohn’s disease like pouch inflammation and cuffitis.

INTRODUCTION

Despite advancements in medical therapy, ileostomy and preserves quality of life particularly surgery is still required in up to 15% of with respect to body image and social function.2-4 patients with ulcerative colitis (UC).1 Unfortunately, there are multiple inflammatory The most common surgery is the restorative proctocolectomy (RPC) with ileal pouch anal anastomosis (IPAA) which commonly involves the following three stages each separated by three months: (1) subtotal colectomy with end ileostomy, (2) proctectomy, pouch creation and proximal diverting ileostomy, and (3) ileostomy takedown and restoration of intestinal continuity. The RPC with IPAA avoids the need for a permanent ileostomy and preserves quality of life particularly with respect to body image and social function.2-4

Unfortunately, there are multiple inflammatory The most common surgery is the restorative conditions that can occur after IPAA including acute pouchitis, chronic pouchitis, and cuffitis.5 These conditions can present with a variety of overlapping clinical symptoms that include increased stool frequency, urgency, abdominal or perineal pain, and hematochezia. A thorough evaluation with history, physical exam, laboratory studies and pouchoscopy is necessary to delineate the inflammatory condition as it can impact treatment and prognosis. The Pouchitis Disease Activity Index (PDAI) is the most commonly used index to assess the severity of pouch inflammation during pouchoscopy.6 The PDAI incorporates the following: (1) clinical features: stool frequency, urgency, abdominal pain, hematochezia, fever (2) endoscopic features: edema, granularity, friability, loss of vascular pattern, mucous exudate, ulceration and (3) histologic features: polymorphonuclear leukocyte infiltration and ulceration. A PDAI score > 7 confirms the diagnosis of pouchitis, however, the severity of patient’s symptoms may not correlate to the degree of inflammation characterized by the PDAI.7

Diagnosis and treatment of inflammatory pouch conditions can be challenging given the overlapping symptoms and limited evidence. The aim of this review is to discuss acute pouchitis, chronic antibiotic dependent pouchitis, chronic antibiotic refractory pouchitis, Crohn’s disease like pouch inflammation, and cuffitis and summarize their management.

Acute pouchitis

Acute pouchitis is defined as symptoms of increased stool frequency, urgency, abdominal pain and/ or hematochezia that last less than four weeks.8 Acute pouchitis is the most common type of pouch inflammation and occurs in up to 50% of patients within 10 years of surgery.9 Risk factors for acute pouchitis include genetic polymorphisms of the IL-1 receptor antagonist and NOD2/CARD15,10 the presence of perinuclear anti-neutrophils cytoplasmic (p-ANCA) antibodies,11 smoking, and preoperative use of steroids.12

There are no approved medications for acute pouchitis, however, the mainstay of treatment is antibiotics. Although data are limited, the most commonly used antibiotics are ciprofloxacin and metronidazole. Studies have shown that a twoweek course of either antibiotic is associated with a reduction in PDAI score, however, ciprofloxacin is associated with a larger score reduction as well as fewer side effects (nausea, vomiting, peripheral neuropathy) than metronidazole.13,14 Patients with acute pouchitis who do not initially respond to a standard two week course may be treated with an additional two week course or may be transitioned to alternative antibiotics such as tinidazole, rifampin, or amoxicillin-clavulanate.8,15

Chronic pouchitis

Chronic pouchitis is defined as symptoms of increased stool frequency, urgency, abdominal pain and/or hematochezia that last greater than four weeks.16 Chronic pouchitis can be subclassified as chronic antibiotic dependent pouchitis (CADP) and chronic antibiotic refractory pouchitis (CARP). Approximately 10-20% of patients develop chronic pouchitis.5 Risk factors for chronic pouchitis include genetic polymorphisms of IL-1 and NOD2/CARD15,10 positive p-ANCA serology, an extensive UC history, and primary sclerosing cholangitis.17 Observational studies have also associated preoperative use of anti-tumor necrosis factor (TNF) agents18 and postoperative use of NSAIDs with chronic pouchitis.19

Chronic antibiotic dependent pouchitis (CADP)

CADP is defined as greater than four episodes of pouchitis per year or persistent symptoms that require long-term antibiotics to maintain remission.8 The most commonly used antibiotics for CADP are ciprofloxacin and/or metronidazole. In a cohort study of 44 patients with CADP, combined ciprofloxacin and metronidazole achieved clinical and endoscopic remission in 82% of patients.20 Given risks of resistance, and tendinopathy and neuropathy with long-term ciprofloxacin and metronidazole use, patients with CADP should be tapered to the lowest effective dose.21 Rifaximin and probiotics (VSL#3) have also been shown to be effective in the management of CADP, though evidence is limited.22-24

Chronic antibiotic resistant pouchitis (CARP)

CARP is defined as symptoms of pouchitis that fail to respond to a four-week course of antibiotics and require escalation of therapy to mesalamine, corticosteroids or biologics.8 The data to support the use of mesalamine in CARP are limited to a single case series of 16 patients that compared combined ciprofloxacin and metronidazole to oral, suppository, and enema mesalamine formulations. Approximately 50% of patients achieved clinical remission in the mesalamine group, however, clarity on which formulation was most efficacious in the case series was lacking.25 Budesonide has been studied in greater breadth than mesalamine in patients with CARP, but still data is limited by small sample sizes. In a prospective study of 20 patients with CARP, treatment with budesonide for eight weeks resulted in a significant reduction in PDAI scores and a remission rate of 75%.26 Patients with CARP who respond to budesonide may remain on the lowest effective dose or consider escalation to a biologic if the risks of maintenance budesonide are significant relative to other co-morbidities.

Biologic agents such as infliximab, adalimumab, vedolizumab, and ustekinumab are commonly used for the management of CARP. A meta-analysis including 15 studies with 311 patients with CARP treated with biologics reported a pooled rate of clinical remission of 65.7% with infliximab, 47.4% with vedolizumab, and 31.0% with adalimumab.27 Vedolizumab has recently been shown to be effective in CARP in the first randomized, doubleblind, placebo-controlled trial, with superior rates of clinical and endoscopic remission and response compared to placebo.28

There is currently insufficient evidence to recommend one biologic over another for CARP, however, it is important to consider a patient’s pre-colectomy biologic use. Patients exposed to anti-TNF agents pre-colectomy and then again post-IPAA for chronic pouchitis have lower rates of clinical remission and higher rates of pouch failure.29

Crohn’s disease like pouch inflammation (CDLPI)

CDLPI is defined as inflammation of the pouch and pre-pouch ileum with or without fistulae and strictures of the proximal small bowel.8 CDLPI is a clinical diagnosis based on history, physical exam, pouchoscopy and imaging. It is important to review each patient’s surgical history as fistulae or strictures that develop within the first 12 months of ileostomy closure are not CDLPI but rather surgical complications.30,31 Histologic evidence of granulomas in the pre-pouch ileum or pouch body are suggestive of CDLPI, but are not required for diagnosis as they are typically only found in about 10% of patients.32 Risk factors for CDLPI include a family history of Crohn’s disease, pouch duration, antibodies to Saccharomyes cerevisiae and CBir1 flagellin, and early, recurrent pouchitis within the first two years of ileostomy closure.31,33,34

There is no consensus regarding the treatment of CDLPI given lack of large, randomized controlled trials. CDLPI is typically refractory to antibiotics and steroids, and biologics are firstline.35 In a meta-analysis of adalimumab and infliximab for CARP and CDLPI, adalimumab and infliximab achieved a clinical remission rate of 52% at 12 months in patients with CDLPI, superior to the rates achieved in patients with CARP.36 Ustekinumab and vedolizumab have also been shown to be effective with remission rates of approximately 80% in patients with CDLPI, though data is limited by relatively small sample sizes.37,38 Unfortunately, given the difficulties in treating CDLPI and achieving remission, up to 45% of patients will experience pouch failure and require pouch excision and transition to a permanent end ileostomy.39

Cuffitis

Cuffitis is defined as symptoms of increased stool frequency, hematochezia, tenesmus and urgency in the setting of the inflammation of the residual rectal cuff.8 Cuffitis occurs in up to 30% of patients post-IPAA, though may be underdiagnosed given the overlap of symptoms with pouchitis.40 Cuffitis can be diagnosed using the Cuffitis Activity Index, which is adapted from the PDAI, incorporating clinical, endoscopic and histologic features specifically of the rectal cuff instead of the pouch.41 Cuffitis can be characterized into classic and non-classic based on etiology. Classic cuffitis is secondary to residual ulcerative colitis in the preserved rectal tissue, while non-classic cuffitis can be due to a variety of causes such as Crohn’s disease, ischemia or prolapse. Risk factors for cuffitis include history of toxic megacolon, fulminant colitis, pre-operative use of biologic agents and increased cuff length (³ 5cm).40,42

The main stay treatment for cuffitis is topical mesalamine similar to proctitis. Treatment with mesalamine suppositories resulted in significant improvement in hematochezia as well as endoscopic and histologic inflammation of the rectal cuff.41 Patients with classic cuffitis that do not respond to topical mesalamine can consider topical corticosteroids, however, evidence is insufficient.43

Approach to delineating the inflammatory pouch conditions

The clinical, endoscopic, and histologic features of acute and chronic pouchitis overlap significantly, and it can be difficult to delineate the conditions despite laboratory studies and pouchoscopy. The key to delineating acute and chronic pouchitis is history – specifically symptom duration and response to antibiotics. Acute pouchitis is the diagnosis in patients with symptoms lasting less than four weeks while chronic pouchitis is the diagnosis in patients with symptoms lasting greater than four weeks or recurring with antibiotic course completion. CDLPI is easier to delineate from acute and chronic pouchitis as the pre-pouch ileum is typically involved and strictures and/or fistulae may be present. In patients with suspected CDLPI based on pouchoscopy or physical exam, imaging with magnetic resonance (MR) enterography and MR pelvis should be considered to fully assess for strictures or fistulae. Histology is not a reliable way to make the diagnosis of any of these conditions as biopsies typically demonstrate chronic inflammation regardless of endoscopic inflammation.44

CONCLUSION

There is a spectrum of inflammatory pouch conditions that can occur after RPC with IPAA and it is crucial to properly diagnose each in order to choose the appropriate therapy. A summary of the recommended evaluation to delineate between these conditions is presented in Figure 1, and a guide for recommended management options for each disorder is highlighted in Figure 2.  Although data are limited, the choice of therapy is directly related to the diagnosis and options range from antibiotics to biologics.

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