Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized by periods of remission and exacerbation.1 Despite significant advances in medical therapy in recent years, around 25%–30% of patients with UC need to undergo surgery during the course of their disease.2 Ileal pouch–anal anastomosis (IPAA) has become the surgical procedure of choice for patients with UC undergoing elective restorative proctocolectomy.3
The exact incidence of pouchitis remains uncertain and it is still very difficult to determine because it depends on the diagnostic criteria used to define the syndrome. Reported cumulative frequency rates of pouchitis 10 years after IPAA surgery range from 20%–59%, and it is estimated that ≈60% of patients who have undergone IPAA surgery for UC will develop at least one episode of pouchitis.4 Most patients experience their first episode of acute pouchitis within 12 months following surgery, but some may suffer their first exacerbation some years later.
The diagnosis is commonly made by means of clinical (increased number of liquid stools, urgency), endoscopic, and histological criteria. The Pouchitis Disease Activity Index (PDAI) is then used to ascertain the severity.5 In 2003 Shen et al6 validated the modified PDAI (mPDAI) that evaluates pouchitis without histologic items. A mPDAI value of 5 or more is considered pouchitis with activity.
The management of pouchitis is aimed at reducing bacterial overgrowth and inflammation. Many drugs have been used, such as antibiotics, mesalazine, corticosteroids, immunosuppressants, and, more recently, probiotics.7 However, refractoriness to conventional medical therapy is reported in around 25% of cases. Infliximab (IFX) is a chimeric monoclonal antibody that targets tumor necrosis factor alpha (TNF-α), and for over 5 years has proven to be effective for moderate and severe UC.8 This drug has also been successfully used for the treatment of patients with refractory Crohn's disease (CD) of the ileoanal pouch.9, 10 As high TNF-α expression occurs in the ileal mucosa during pouchitis, the use of IFX in refractory pouchitis following IPAA for UC appears to be reasonable, but actual clinical evidence for the use of IFX in refractory pouchitis is limited. Therefore, the aim of this study was to report the efficacy of IFX in patients with refractory pouchitis and evaluate potential predictors of response.
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- PATIENTS AND METHODS
The results of this multicenter, retrospective study demonstrate that IFX is an alternative treatment for patients with chronic refractory pouchitis who are not responsive to antibiotics or other conventional treatments. It is important to note that these results were observed in a well-defined set of chronic refractory pouchitis patients, because all patients suspected of having CD in colectomy or with posterior clinical data that could suggest CD were excluded from the analysis.
Antibiotics like ciprofloxacin and metronidazole have been the first-line therapy for pouchitis for years, but there are several limitations in the studies evaluating the role of these drugs. The main limitation is that there is a subset of patients who require long-term, continuous treatment with antibiotics to maintain remission (antibiotic-dependent pouchitis), due to the speed of symptomatic recurrence once antibiotics are discontinued. Long-term antibiotic use can be associated with adverse effects and bacterial resistance and maintaining remission in these patients may be challenging when considering the risk of antibiotic resistance and increased occurrence of adverse effects.14 Currently, there are no clear data about maintenance of remission of pouchitis with antibiotics.
The efficacy of IFX in the ileoanal pouch of CD patients is well established.15 More than 10 years ago, Ricart et al15 evaluated the efficacy of IFX in seven patients who developed findings compatible with CD after undergoing colectomy with IPAA for an original diagnosis of UC. They observed that after an average of 13 weeks of follow-up more than 80% of patients had achieved remission and concluded that IFX could be used successfully in CD involving an IPAA in case of refractoriness to conventional therapies. Some years later, the same group reviewed the medical records of 26 patients with similar characteristics treated with IFX and observed a high rate of complete response in the short- and mid-term.9 Efficacy of IFX was also demonstrated in a retrospective review of four pediatric patients originally diagnosed with UC, status postcolectomy and IPAA, who developed findings compatible with CD.16 Another anti-TNF-α drug (adalimumab) has also demonstrated its efficacy in the management of ileoanal pouch disease of CD patients. Shen et al17 evaluated the efficacy of adalimumab in 17 patients who developed findings compatible with CD after undergoing colectomy with IPAA. They observed that after an average of 8 weeks of follow-up, eight patients (47.1%) showed complete symptom response, while four (23.5%) showed partial response. The problem with this study was the short duration of follow-up.
Data about use of IFX in patients diagnosed with UC who develop pouchitis after colectomy are scarce. All data were obtained from case studies and open-label studies because there has not been any randomized, placebo controlled trial published in this field, mainly due to chronic refractory pouchitis patients being very heterogenic and limited in IBD Units. In 2003, an Italian group evaluated the efficacy of IFX in seven patients, showing excellent results; of the seven patients with pouchitis who received IFX, six showed a complete clinical response and one showed a partial clinical response 10 weeks after the first infusion and PDAI score had improved from 12 at baseline to 5. After a median follow-up of 11 months, all patients showed a complete clinical response.18 In a more recent study 10 patients with refractory pouchitis received an induction scheme with IFX. Ten weeks later, clinical remission was achieved in 9 out of 10 patients and it was also observed that the PDAI score dropped significantly from 13 to 5 points (P < 0.01).19 The most relevant data published to date comes from the Belgian multicenter study that included retrospectively 28 patients who received IFX for chronic refractory pouchitis and observed that after 10 weeks 88% of patients with refractory luminal inflammation showed clinical response (14 partial, 8 complete) and after a median follow-up of 20 months 56% showed sustained clinical response.13
Our short-term results are in accordance with previous studies with more than 80% of overall clinical response, but our complete response rates have been lower than previously reported.13, 19 It is difficult to find a reason for these poorer results because there were no great differences in study population and all had a similar mean time of pouchitis evolution previous to IFX treatment. Perhaps the fact that patients of our study were a bit older could have contributed to a lower short-term IFX complete response rate. Another possible explanation for these different results could be that in all these studies, including ours, subjective endpoints have been applied and this could help to explain a higher heterogeneity in results.
Mid-term results of our study are also similar to these previous studies, with more than 60% of clinical response at week 26 and 45% of any response at week 52. This is why we believe that IFX is an alternative treatment in patients with chronic pouchitis without response to conventional therapies.
One of the problems we have observed is the high rate of patients (39%) who have treatment withdrawal. Some of them, it is easy to understand why, are due to lack of response or loss of efficacy, but 15% are due to adverse events related to infusion reactions. All patients with infusion reactions had been treated with IFX in monotherapy, which is in accordance with studies that have observed lower rates of infusion reactions in patients treated with combined therapy.20, 21 With regard to the use of concomitant immunosuppressives, in our study only 54% of patients received combined therapy compared with 100% and 82% of the Italian18 and Belgian13 studies, respectively. Perhaps this difference could help to explain the lower complete response rates of our study, but we must highlight that 60% of patients had tried to treat pouchitis with azathioprine and they had failed,
We tried to find associations between potential factors and clinical response to IFX, but none of them have been associated with a better short- or mid-term response. Maybe with a higher number of patients some associations could be concluded; for example, only five patients had been treated with IFX previous to colectomy and we have not observed lower complete response rates in this subgroup of patients but in order to have stronger conclusions we need to investigate a larger prospective series.
Limitations to the current study are that it is a retrospective, descriptive, and multicenter study, with absence of a control group; all this is associated with heterogeneity in the definition of chronic refractory pouchitis. These limitations are the reason that mPDAI, CPR values, and endoscopic findings were not available in all patients; in particular, the most important limitation is that mPDAI data was only calculated in the group of patients who underwent endoscopy at each timepoint.
Another limitation is the small number of subjects, which may have also limited the analysis of demographic and clinical parameters associated with treatment response. Unfortunately, another limitation of our study is that time to relapse after IFX therapy could not be obtained for all the patients.
In conclusion, the present study shows a beneficial role of IFX in patients with chronic refractory pouchitis, but further studies, especially a prospective multicenter randomized controlled trial, are needed in order to know how and when to use this drug in this subgroup of patients.