Total proctocolectomy with ileal pouch–anal anastomosis (IPAA) has become the surgical treatment of choice for the majority of patients with ulcerative colitis (UC) who require surgery. The surgical procedure maintains the intestinal continuity, avoids the need for a permanent stoma, and improves patients' health-related quality of life.1 However, short-term and long-term complications after surgery are common. Crohn's disease (CD) or “CD-like” condition of the pouch, along with pouchitis, are among the most common long-term inflammatory complications of IPAA and among the leading causes for pouch failure.2–6
It is reported that cumulative frequencies of CD of the pouch ranged from 2.7%–13%.3, 7–12 Patients with CD of the pouch can present with inflammatory, fibrostenotic, and fistulizing forms.13 Currently, there is no general consensus on the treatment algorithm of CD of the pouch. A combined medical, endoscopic, and surgical therapy for fibrostenotic or fistulizing CD of the pouch has been advocated.5 To date, there were several case series on successful use of tumor necrosis factor-alpha (TNF-α) antagonists in treating this group of patients. Short- and long-term efficacy and safety of infliximab for CD of the pouch have been reported.14–20 We have previously reported short-term (a median follow-up of 8 weeks) outcome of induction therapy with adalimumab (ADA) in 17 patients with CD of the pouch. The agent appeared to be well-tolerated, efficacious, and safe in treating the cohort.20 We have now accumulated a larger number of patients with a longer follow-up who were treated with the agent. On the other hand, the measurement of mucosal healing has recently been advocated for being a marker of clinical outcome in IBD trials.21 The mucosal healing related to anti-TNF use in CD of the pouch has not been investigated. The aim of this open-labeled study was to evaluate the clinical outcome of induction and maintenance therapy of ADA in patients with CD of the pouch.
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- PATIENTS AND METHODS
CD of the pouch has been increasingly recognized in patients with IPAA and remains very difficult to treat. There are limited data on management in the literature. Our previous open-label study indicated the induction efficacy of ADA in patients with CD of the pouch.20 In the present study with a larger sample size and longer duration of treatment and follow-up, ADA was shown to be effective in both short-term induction therapy (complete response 50.0%; partial response 20.8%) and long-term maintenance therapy (complete response 33.3%; partial response 20.8%) in a subset of patients. In addition, the need for concurrent medical therapies including antibiotics, corticosteroids, and immunomodulators might decrease after the initiation of ADA treatment. Patients who achieved mucosal healing or had a lower mPDAI after induction therapy appeared to have a better long-term outcome.
Several studies have shown some efficacy of biologics including infliximab and ADA in treating CD of the pouch.14–20 In a case series of 26 patients with CD of the pouch reported by Colombel et al,15 58% had a long-term (median follow-up 21.5 months) response to infliximab. Viscido et al16 reported the efficacy of infliximab in seven patients with refractory fistulizing pouchitis. After a median follow-up 11 months, all seven patients showed a complete clinical response, four had a complete fistula response. In the third series of 10 cases reported by Calabrese et al,17 infliximab was shown to be effective in treating chronic refractory pouchitis and ileitis. After 10 weeks of treatment, clinical remission was observed in 90% of patients and an endoscopic/histological healing of lesions was documented in 80% of patients. This was the first study that evaluated the mucosal healing in infliximab treatment for CD-like complications of the pouch. Recently, a Belgian case series of 28 patients with refractory pouchitis or CD-related complications of the pouch was reported by Ferrante et al.18 After a median follow-up of 20 months, 56% of patients with refractory luminal inflammation showed a sustained clinical response and three out of seven fistula patients showed a sustained fistula response. Most recently, Haveran et al19 studied the efficacy of infliximab and/or azathioprine (AZA) in the treatment of 21 patients with CD-like complications after IPAA. Pouch failure occurred most commonly in the fistula group treated with infliximab and AZA/6-MP (6/13, 46%). None of the above studies was able to identify the predictors for response to biological therapy in treating CD of the pouch, which might have been due to the small sample sizes.
The previous study from our group showed short-term (median follow-up of 8 weeks) efficacy of ADA: 47% (8/17) had a complete symptom response and 23% (4/17) had a partial response.20 From this study, it appeared that ADA was efficacious in induction therapy of CD of the pouch and was well tolerated. Our current study for the first time shed some light on the factors that predicted good response to ADA in patients with CD of the pouch. Review of current literature showed that clinical efficacy at week 12 (early deep clinical remission) was associated with medium-term clinical efficacy and mucosal healing during ADA therapy for CD, whereas the need for combined immunosuppressants at induction and smoking status were the predictors for nonresponse.26 Our current study also confirmed that early deep clinical remission with symptom response and endoscopic mucosal healing was associated with good response in CD of the pouch. On the other hand, we were not able to find any association between concomitant immunosuppressive as well as smoking status with the treatment efficacy of ADA. That might have been due to a type II error, as there were only five patients that had immunosuppressive along with ADA. Additionally, patients with central arthralgia were more prevalent in treatment responders (P = 0.054). This might strengthen the indication for biologics use in CD of the pouch complicated with arthritis or arthropathy.
In the present study the use of preoperative biologics was found to be associated with the treatment response to ADA in Cox regression analysis. In total there were nine (18.8%) patients who had been treated with infliximab before surgery. The indications for colectomy in those patients were primary failure to respond to infliximab in four patients, infusion reaction in two, and secondary failure in three. Of the nine patients, three had primary failure to ADA and six had primary response to ADA. The three patients who failed to respond to ADA also had failed infliximab before surgery. In contrast, of the six patients with primary response to ADA, one had primary failure to preoperative infliximab treatment, two had infusion reactions to the infliximab treatment, and three had secondary treatment failure to infliximab. While the preoperative use of infliximab was statistically associated with post-IPAA treatment response to ADA, we could not definitively conclude that the use of infliximab treatment before surgery predicted the response to ADA therapy in CD of the pouch, due to possible type I error. On the other hand, the majority of patients were treated with ADA, despite the fact that some of the patients had a preoperative use of infliximab. Although a recent randomized controlled trial of CD showed loss of tolerance and efficacy when infliximab electively switched to ADA,27 there are currently no published studies on the efficacy and safety of either continuing or switching of biologic agents before and after colectomy and IPAA. The reasons that we routinely used ADA for this cohort of CD of the pouch were based on several factors, including personal experience of the treating physician, reluctance from patients in receiving intravenous infusion for logistic reasons, and the failure or infusion reaction to preoperative infliximab therapy.
The Cox analysis also revealed that concurrent endoscopic treatment was associated with the treatment response of ADA. Various endoscopic treatments for pouch diseases such as balloon dilation, topical corticosteroid injection, and needle knife therapy have been previously reported by our team.28, 29 The findings of the present study support the notion that concurrent endoscopic treatments for fibrostenotic CD of the pouch may be beneficial.
There are several limitations to our study. First, there might have been referral bias, due to the nature of our subspecialty clinic. Second, the mPDAI score was originally introduced as a research tool for pouchitis. Inherently, it does not cover the specific symptoms related to fistulizing diseases. Therefore, in the present study mPDAI was only measured in patients with inflammatory/fibrostenotic lesions. For patients with fistulizing subtype, we evaluated clinical response based on specific symptoms associated with fistula. Third, the clinical response of fistulizing disease was assessed by symptoms related to fistula. The use of abdominal imaging such as pelvic MRI might have added more value. Finally, there might have been an impact of concurrent immunosuppressives contributing to the response to ADA. As reported in the literature, concurrent immunosuppressive use was associated with higher rates and longer duration of response to infliximab in CD.30 However, as mentioned above, we were not able to show that immunosuppressive use provided additional therapeutic benefits. In addition, inflammation of the pouch body or pouchitis can be a part of CD of the pouch. It has been hard to separate CD of the pouch versus isolated conventional pouchitis superimposed on CD of the pouch. In patients with fistular CD of the pouch, however, we routinely continue single or double antibiotic therapy. In addition, oral budesonide was routinely used in the patients with current primary sclerosing cholangitis. Oral prednisone has not been a part of our standard care for CD of the pouch.
In conclusion, ADA was generally well tolerated and appeared to be effective for induction and maintenance in managing IPAA patients complicated with CD of the pouch. Short-term response with mucosal healing and low mPDAI scores may predict a better long-term outcome.