SEARCH

SEARCH BY CITATION

Keywords:

  • infliximab;
  • rescue therapy;
  • chronic refractory pouchitis

Abstract

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Background:

Despite medical therapy, 30% of patients with ulcerative colitis (UC) need to undergo surgery. Around 50% of patients with proctocolectomy with ileal pouch–anal anastomosis (IPAA) develop complications of the pouch. Clinical evidence for the use of infliximab (IFX) in refractory pouchitis is limited. The aim of this study was to report efficacy of IFX in these patients.

Methods:

A retrospective, multicenter study was designed. Patients older than 18 years with chronic refractory pouchitis treated with IFX (5 mg/kg) were included. Short-term IFX efficacy was evaluated at week 8 and mid-term efficacy at weeks 26 and 52. Complete response was defined as cessation of diarrhea and urgency and partial response as marked clinical improvement but persisting symptoms. The modified Pouchitis Disease Activity Index (mPDAI) without endoscopy was calculated when available.

Results:

Thirty-three consecutive UC patients with chronic refractory pouchitis were included (18 male, mean age 45 years, range 21–67). At week 8, 21% patients achieved complete response and 63% showed partial clinical response. At weeks 26 and 52, 33% and 27% achieved complete response and 33% and 18% showed partial clinical response, respectively. Thirteen patients (39%) withdrew treatment (four for lack of efficacy, four for loss of response and five for adverse events). None of the potential factors analyzed had an influence on response to IFX.

Conclusions:

IFX was effective in the short- and mid-term in patients with chronic refractory pouchitis. However, medication had to be discontinued in a high number of patients. (Inflamm Bowel Dis 2011;)

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.

PATIENTS AND METHODS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Study Patients

A retrospective, open-label, multicenter study was designed. The study population comprised chronic refractory pouchitis patients attending 13 Spanish inflammatory bowel disease (IBD) referral centers belonging to the Spanish Working Group on Crohn's Disease and Ulcerative Colitis (GETECCU).

Inclusion criteria were patients older than 18 years with chronic refractory pouchitis treated with IFX (5 mg/kg). The diagnosis of chronic refractory pouchitis included all patients with clinical and endoscopic findings of pouchitis who had previously failed when given therapy with antibiotics for at least 4 consecutive weeks and probiotics or immunosuppressive drugs. CD was at first excluded using a careful reexamination of the colonic surgical and histological specimens. Patients with histological features of CD such as epithelioid granulomas, discontinuous crypt distortion and discontinuous inflammation, or transmural inflammation after review of the colectomy specimen were excluded. The study was approved by the local Ethics Committee.

Clinical characteristics of all patients were reviewed including gender, age at diagnosis, presence of extraintestinal manifestations, family history of IBD, smoking behavior, extent of disease according the Montreal Classification prior to colectomy,11 time (in months) of disease prior to IPAA, age at primary surgery, time (in months) after surgery prior to pouchitis, fistulae associated with the pouch, and type of primary surgery.

Study Treatment and Assessments

Patients were treated with standard infusions of IFX (5 mg/kg body weight). All patients were evaluated according to the following: the use of an induction scheme (IFX at weeks 0, 2, and 6), the use of a maintenance scheme (IFX every 8 weeks after the induction period), time (in weeks) of IFX treatment, number of doses received, need and type of dose escalation, use of IFX treatment previous to colectomy, drugs including nonsteroidal antiinflammatory drugs (NSAIDs), drugs used for treatment of pouchitis before IFX, and concomitant treatment used with IFX. In case of discontinuation of treatment the reasons were recorded and all adverse events that were a cause of drug withdrawal were notified. In accordance with Spanish GETECCU guidelines,12 those patients who had received IFX previously were treated with hydrocortisone and dexclorpheniramine in order to prevent infusion reactions and delayed hypersensitivity reactions.

Short-term IFX efficacy was evaluated at week 8 and mid-term efficacy at weeks 26 and 52. Clinical response was classified into three categories: complete response, partial response, and no response. These definitions were similar to those previously used elsewhere.9, 13 Complete response was defined as cessation of diarrhea, urgency, and blood loss and partial response as marked clinical improvement but persisting symptoms. We applied the mPDAI when it was available.

Evolution of C-reactive protein (CRP) levels and endoscopic changes after treatment were evaluated in patients when these were possible.

Predictors of Response

The potential influence of gender, smoking habits, family history of IBD, extent of the disease according to Montreal Classification, extraintestinal manifestations, IFX treatment previous to colectomy, presence of fistulae, type of primary surgery, and concomitant treatment including immunosuppressives on the efficacy of IFX therapy for pouchitis were also analyzed.

Statistics

Demographic and clinical parameters were compiled and summary statistics calculated. Results are presented as percentages. Univariate analysis was performed by the chi-squared test and Fisher's exact test as appropriate. Multivariate analysis was based on unconditional logistic regression, on which clinical response was considered the dependent variable and the demographic and clinical data were considered independent variables. P values less than 0.05 were considered statistically significant. All statistical tests were performed with the SPSS 13.0 statistical software package (Chicago, IL).

RESULTS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Population Characteristics

By way of GETECCU, 35 patients were evaluated. Two patients (5.7%) were excluded because they had presented CD characteristics after colectomy. A total of 33 confirmed UC patients (15 female) who received IFX for chronic refractory pouchitis were finally included. Demographic characteristics are shown in Table 1. Prior to IFX all patients had been treated for at least 4 consecutive weeks with antibiotics (metronidazole, ciprofloxacine, a combination of both, or rifaximine) for pouchitis. As well as with antibiotics, 20 patients (60.6%) had failed with azathioprine treatment, 11 (33%) with probiotics, 20 (60.6%) with topic aminosalicylates, 16 (48.5%) with oral aminosalicylates, 14 (42.4%) with topic steroids, and 12 (36.4%) with oral steroids. No patients had received methotrexate or cyclosporine for treatment of pouchitis. No patients had been treated with NSAIDs.

Table 1. Demographic Characteristics of Patients
Gender (%)15 female (45.5%)
 18 male (54.5%)
Mean age (range)45.4 years (21–67)
Years since UC diagnosis (range)14.7 years (2–30)
Tobacco habits at surgery (%) 
 Nonsmokers22 (66.7%)
 Former smokers6 (18.2%)
 Smokers5 (15.2%)
Family history of IBD (%) 
 Yes1 (3%)
 No32 (97%)
Extension of colitis (%) 
 Proctitis (E1)0 (0%)
 Left-side colitis (E2)2 (6.1%)
 Extensive Colitis (E2)31 (93.9%)
Extraintestinal manifestations (%) 
 Yes12 (36.4%)
 No21 (63.6%)
Type of primary surgery (%) 
 Proctocolectomy without ileostomy13 (39.4%)
 Proctocolectomy with ileostomy12 (36.4%)
 Total colectomy with ileostomy8 (24.2%)
IFX treatment before colectomy 
 Yes5 (15.2%)
 No28 (84.8%)
Fistulae associated to pouch 
 Yes10 (30.3%)
 No23 (69.7%)

The mean time of pouchitis evolution previous to IFX treatment was 47 months (range, 2–252). All patients received an induction scheme (IFX at weeks 0, 2, and 6) at doses of 5 mg/body weight and 25 (75.8%) continued with a maintenance scheme (IFX every 8 weeks). Among these 25 patients, nine (36%) needed dose escalation (five of them to 10 mg/body weight and the other four with a shorter interval of time between infusions). Median time of IFX follow-up was 60 weeks. During IFX treatment some patients received concomitant treatments, shown in Table 2.

Table 2. Concomitant Treatment Received with IFX
DrugsN (%)
Azathioprine18 (54.5%)
Antibiotics11 (33.3%)
Topical aminosalicylates9 (27.3%)
Oral aminosalicylates7 (21.2%)
Probiotics5 (15.2%)
Topical steroids3 (9.1%)
Oral steroids3 (9.1%)
Loperamide1 (3%)
Methotrexate0 (0%)

Short-term Efficacy

At week 8, seven patients (21.2%) with chronic refractory pouchitis achieved complete response and 21 (63.6%) showed partial clinical response. Only five of the patients (15.2%) did not show any response (Fig. 1). The evolution of mPDAI is shown in Figure 2 at weeks 8, 26, and 52. CRP was available in 25 patients; the evolution of CRP is shown in Figure 3 at weeks 8, 26, and 52. Unfortunately, endoscopy was only performed in six patients at week 8. In one patient (16.7%) complete mucosal healing was observed. None of the potential factors analyzed (gender, smoking habits, extent of the disease, extraintestinal manifestations, IFX treatment previous to colectomy, presence of fistulae, type of primary surgery, and concomitant treatment including immunosuppressives) had an influence on short-term response to IFX.

thumbnail image

Figure 1. Short (week 8) and mid term (weeks 26 and 52) response to IFX.

Download figure to PowerPoint

thumbnail image

Figure 2. Evolution of mPDAI at weeks 0, 8, 26, and 52.

Download figure to PowerPoint

thumbnail image

Figure 3. Evolution of CRP at weeks 0, 8, 26, and 52.

Download figure to PowerPoint

Mid-term Efficacy

At week 26, after an intention to treat (ITT) analysis, 11 patients (33.3%) were in complete response and another 11 (33.3%) had shown partial clinical response (Fig. 1). After analyzing only the patients who continued treatment at week 26, a complete response rate of 44% and a similar partial response rate of 44% were observed. A CRP value was obtained in 17 patients (51.5%) (Fig. 3). Five patients had endoscopy evaluation at that week and two (40%) of them presented complete healing of the mucosa of the pouch.

At week 52, after an ITT analysis, nine patients (27.3%) were in complete clinical response and another six (18.2%) had shown partial clinical response (Fig. 1). After analyzing only the patients who continued at week 52 with treatment, we observed a remission rate of 56.3% and a response rate of 37.5%. A CRP value was obtained in eight patients (Fig. 3). After 1 year endoscopy evaluation was performed in seven patients and four (57.1%) presented complete healing of the mucosa of the pouch. Among the nine patients who needed dose escalation, at week 52 four (44.4%) had achieved complete response and only one (11.1%) did not present any clinical response.

Time to relapse after IFX treatment is shown in Figure 4. Neither at week 26 nor at week 52 did any of the potential factors analyzed (gender, smoking habits, extent of the disease, extraintestinal manifestations, presence of fistulae, type of primary surgery, and concomitant treatment including immunosuppressives) have an influence on response to IFX.

thumbnail image

Figure 4. Kaplan–Meier curve for time to relapse (weeks) in patients treated with IFX.

Download figure to PowerPoint

Drug Withdrawal and Adverse Events

Overall, 13 patients (39.3%) had to withdraw IFX treatment, five (15.1%) due to severe adverse events, four (12.1%) for lack of efficacy of IFX, and four (12.1%) for loss of primary response. Figure 5 shows a flow chart with patient recruitment and evolution. Among the five patients (15.1%) who had presented major adverse events that forced discontinuation of the treatment, four patients presented infusion reactions (none of them were treated with concomitant immunomodulators) and another patient presented a lupus-like syndrome. Two of these five patients had been treated with IFX previously to colectomy. Three other patients presented mild adverse events (two dermatologic reactions and an acute hypertensive emergency) that did not force them to discontinue treatment.

thumbnail image

Figure 5. Flow chart with patient recruitment and evolution.

Download figure to PowerPoint

DISCUSSION

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

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.

REFERENCES

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES