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Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Background  Crohn’s disease (CD) of the pouch can develop in patients with ileal pouch-anal anastomosis (IPAA). Scant data are available on the treatment of this disease entity.

Aim  To evaluate efficacy and safety of adalimumab in treating CD of the ileal pouch.

Methods  From June 2007 to June 2008, 17 IPAA patients with inflammatory (n = 10), fibrostenotic (n = 2) or fistulizing (n = 5) CD of the pouch treated with adalimumab were evaluated. Inclusion criteria were CD of the pouch who failed medical therapy and were otherwise qualified for permanent pouch diversion or excision. All qualified patients received the standard dosing regimen of subcutaneous injection adalimumab (160 mg at week 0, 80 mg at week 1, and 40 mg every other week thereafter). Complete clinical response was defined as resolution of symptoms. Partial clinical response was defined as improvement in symptoms. Endoscopic inflammation before and after therapy was recorded, using the Pouchitis Disease Activity Index (PDAI) endoscopy subscores.

Results  The median age was 36 years with 12 patients (70.6%) being male. At 4 weeks, seven patients (41.2%) had a complete symptom response and 6 (35.3%) had a partial response. There was also a significant improvement in the PDAI endoscopy subscores at week 4 (< 0.05). At the last follow-up (median of 8 weeks), eight patients (47.1%) had a complete symptom response and 4 (23.5%) had a partial response. Four patients (23.6%) developed adverse effects. Three patients (17.7%) eventually had pouch failure after failing to respond to adalimumab therapy.

Conclusion  Adalimumab appeared to be well-tolerated and efficacious in treating CD of the pouch in this open-labelled induction study.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Ileal pouch-anal anastomosis (IPAA) following proctocolectomy has become the surgical treatment of choice for patients with ulcerative colitis (UC) who require surgery.

Approximately 10% of patients with a preoperative diagnosis of UC or indeterminate colitis (IC) develop Crohn’s disease (CD) of the pouch after surgery.1–9 Clinically, CD of the pouch can be classified into inflammatory, fibrostenotic and fistulizing phenotypes, which are associated with different risk factors, clinical presentations and prognoses.9, 10

Crohn’s disease of the pouch can lead to fistulae, septic complications and pouch failure.9, 11–13 Reported frequency of CD-associated pouch failure ranged from 25% to 100%, depending on the duration and intensity of follow-up after IPAA, the use of medical or endoscopic therapy and the threshold for initiating pouch excision operation.2–8, 12, 14, 15 However, a majority of reported studies were performed before the era of routine use of immunomodulators and anti-TNFα therapy. There are limited published data on the treatment of CD of the pouch.16–18 A study specifically addressing pharmaceutical treatment of CD of the pouch described 26 patients with CD of the pouch who were managed with infliximab infusion. Of the 26 patients, 62% had a complete short-term response and 23% had a partial response. After a median follow-up of 22 months, 33% had pouch resection, while the pouch remained functional in 67% of patients.16

Adalimumab has been shown to be effective in treating patients with nonpouch CD and the agent has been approved by the FDA for the treatment of moderate-to-severe CD. In a recent case report, the agent was successfully used in a patient with CD of the pouch during pregnancy.19 However, adalimumab has not been systemically studied in patients with CD of the pouch.

Patients and methods

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Patients

All patients were identified from an Institutional Review Board (IRB) -approved, prospectively maintained database from June 20007 to June 2008. Informed consent was obtained from all patients before initiating adalimumab. Additional IRB approval was obtained for the chart review.

Inclusion and exclusion criteria

Patients with CD of the pouch who met all of the following criteria were included patients: (1) >15 years of age; (2) regular evaluation and follow-up in the Pouchitis Clinic; (3) CD of the pouch which failed to medial therapy with nonbiological and/or biological agents (including infliximab) and being otherwise considered for pouch diversion or excision surgery; (4) adalimumab therapy for CD of the pouch and follow-up. Exclusion criteria were pouch patients with underlying familial adenomatous polyposis (FAP) and patients with other inflammatory and non-inflammatory disorders of the pouch or surgically associated complications, such as abscess, leaks and sinuses.

Diagnostic criteria

Patients with CD of the pouch were diagnosed based on a combined assessment of symptoms, endoscopy, histology, radiography and, in some cases, examination under anaesthesia, using the criteria previously published by our group.20 CD of the pouch belonged to either of the three clinical phenotypes modified for the Vienna Classification21 and Montreal Classification:22 inflammatory, fibrostenotic and fistulizing CD.20 Detailed diagnostic criteria for each of the three phenotypes of CD of the pouch were described elsewhere.20

Clinical practice

In our routine clinical practice, the candidacy for adalimumab included failure or intolerance to conventional medical therapy with 5-aminosalicylates (5-ASAs), corticosteroids or immunomodulators. A history of adverse effects to infliximab and a history of failure to respond to infliximab were not contraindications for adalimumab. Patients with pregnancy or intention for pregnancy and patients with pouchitis or cuffitis were not considered candidates for adalimumab. As a part of our routine clinical practice, an outpatient evaluation with a combined assessment of demographic, clinical, endoscopic, histological and radiographic data was conducted. The data were entered into our prospectively maintained Pouchitis Database. All patients underwent outpatient pouch endoscopy with biopsy. Segmental evaluation and biopsy of the afferent limb, pouch and rectal columnar cuff were performed during pouch endoscopy. The endoscopic features of the afferent limb and pouch body were documented and biopsies were separately labelled. The Pouchitis Disease Activity Index (PDAI)23 endoscopy scores (ranging from 0 to 6, with 6 being the most severe inflammation) were measured to grade inflammation of the afferent limb, pouch and cuff respectively. Examination under general anaesthesia, retrograde radiographic pouchography, CT enterography, MRI of the pelvis or small bowel capsule endoscopy were performed, if the diagnosis of CD of the pouch was not conclusive by routine clinical, endoscopic and histological examination. Routine laboratory tests were performed for patients with persistent symptoms, including complete blood cell counts, basic metabolic panel, hepatic function panel, serum cytomegalovirus DNA and, in a few cases, C-reactive protein.

Prior to administration of adalimumab, all patients were negative for tuberculin skin tests and chest X-ray for tuberculosis and negative for viral hepatitis. The standard dosing regimen was given: 160 mg subcutaneous injection for week 1, 80 mg subcutaneous injection for week 2, then 40 mg subcutaneous injection every other week. A repeat pouch endoscopy was routinely performed 4 weeks after the initiation of therapy. Like all other patients with symptomatic CD of the pouch, patients under adalimumab therapy were followed up at the Pouchitis Clinic every 1–3 months. Repeat endoscopy and radiographic examination were performed as needed. Patients who responded continued to receive therapy with a dose of 40 mg every other week, while nonresponders patients sought surgical consultation.

Concurrent medicine use was permitted and documented. However, no concurrent immunomodulator was given at and during the adalimumab therapy.

Outcome measurement

Clinical complete response was defined as complete resolution of pouch-associated symptoms, including reduction in frequency of bowel movements to post-operative ‘normal’ baseline, resolution of abdominal pain and urgency and pelvic discomfort, as well as cessation of fistular drainage in fistulizing CD of the pouch. Clinical partial response was defined as improvement in the above pouch-associated symptoms, including the reduction in fistular drainage. Endoscopic mucosal inflammation of the pouch and afferent limb before and after the therapy was calculated, using the PDAI endoscopy subscores,23 for those who underwent follow-up pouch endoscopy. Physician Global Assessment Score [ranging from 1 (complete relief of symptoms) to 6 (worsening of symptoms)] was calculated before and after therapy.24 Pouch failure was defined as pouch excision or permanent diversion. Any adverse effects were documented.

The role of medical therapy for fibrostenotic CD has been debatable. Medical therapy including biological therapy, has a minimal impact on fibrostenotic strictures in-patients with CD of the pouch. Therefore, endoscopic stricture scores before and after adalimumab therapy were not listed as a treatment outcome. The goal for using biologics in fibrostenotic CD of the pouch was not to improve strictures; rather, it was for the concurrent mucosal inflammation.

Statistical analysis

Descriptive statistics were computed for all variables. These included medians, 25th and 75th percentiles for continuous factors and frequencies for categorical variables. Wilcoxon signed rank tests were used to assess changes in pre and post symptom and endoscopy scores. A P < 0.05 was considered statistically significant. SAS version 9.1 software (The SAS Institute, Cary, NC, USA) was used to carry out all analyses.

Results

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Demographic and clinical characteristics

From June 2007 to June 2008, 17 IPAA patients with CD of the pouch treated with adalimumab were identified from our Pouchitis Clinic database. One patient with chronic NSAID use was also included in the study as the diagnosis of CD of the pouch had been made when she was not taking NSAIDs. The median age was 36 years and 12 patients were male (70.6%). Four patients were active smokers or ex-smokers. The median duration of the pouch was 8 years. The cohort of 17 patients consisted of 10 inflammatory (58.8%), 2 fibrostenotic (11.8%) and 5 fistulizing (29.4%) CD of the pouch. Of the five patients with fistulizing CD of the pouch, five had complex perianal fistulae and one had a pouch-vaginal fistula. All five patients had developed fistulae more than 12 months later after ileostomy take-down. They had received long-term single or combination of antibiotic therapy. Two patients with complex perianal fistulae had been treated with incision and drainage, and mushroom catheter or seton placement.

While nine patients (52.9%) had peripheral or central arthralgia and three patients (17.7%) had a history of thromboembolic events, none of the 17 patients had ocular, cutaneous or hepatobiliary manifestations of IBD. Five patients had used infliximab before colectomy and one patient used infliximab for CD of the pouch. None of the patients had used adalimumab before the surgery. Fifteen patients had a J pouch, one had an S pouch and one had a continent ileostomy (Table 1).

Table 1.   Demographic and clinical characteristics of study patients
FactorAll (n = 17)
  1. Values presented are n (%) or median (25th, 75th percentiles).

Current age (years)36.0 (28.0, 49.0)
Male gender12 (70.6)
Race17 (100.0)
Smoking
 Never13 (76.5)
 Ex-smoker2 (11.8)
 Active smoker2 (11.8)
Regular alcohol consumption1 (5.9)
Married9 (52.9)
Duration of inflammatory bowel disease, years18.0 (8.0, 22.0)
Duration of pouch, years8.0 (4.0, 14.0)
Duration of follow-up at pouchitis clinic, years2.0 (1.0, 3.0)
Phenotype of Crohn’s disease
 Inflammatory10 (58.8)
 Fibrostenotic2 (11.8)
 Fistulizing5 (29.4)
Regular NSAID use1 (5.9)
History of immumodulator use for Crohn’s disease of the pouch5 (29.4)
History of infliximab use for Crohn’s disease of pouch1 (5.9)
History of Clostridium difficile pouchitis3 (17.7)
Family history of inflammatory bowel disease
 Crohn’s disease2 (11.8)
 Ulcerative colitis2 (11.8)
Family history of colon cancer1 (5.9)
J Pouch15 (88.2)
Stage of pouch surgery
 214 (82.4)
 31 (5.9)
 42 (11.8)
Colectomy for refractory colitis16 (94.1)
Pancolitis16 (94.1)
Fulminant colitis2 (11.8)
Pre-operative diagnosis
 Ulcerative colitis11 (64.7)
 Indeterminate colitis5 (29.4)
 Crohn’s colitis1 (5.9)
Pre-operative use of infliximab5 (29.4)
Peripheral arthralgia5 (29.4)
Central arthralgia4 (23.5)
Thromboembolic events3 (17.7)
Current weight loss in pounds0.0 (0.0, 15.0)
Granuloma on pouch biopsy1 (5.9)
Routine antidepressant use4 (23.5)
Routine antianxiety agent use1 (5.9)
Routine use of narcotics4 (23.5)

Efficacy

The median follow-up after the initiation of adalimumab therapy was 8 weeks. At 4 weeks, seven patients had a complete symptom response and six had a partial response; at a median of 8 weeks, eight patients had a complete symptom response and four had a partial response. All six patients who had arthralgia responded to the therapy, with five having partial response and one having a complete response. Of five patients with fistulizing CD of the pouch, two responded (Table 2). It appears that clinical response was not associated with smoking status, as four current or ex- smokers all had partial or complete clinical response.

Table 2.   Treatment efficacy and concurrent medical and surgical therapy
FactorAll (n = 17)
  1. Values presented are n (%) or median (25th, 75th percentiles).

Total duration of adalimumab therapy (weeks)8.0 (6.0, 26.0)
Indication for adalimumab therapy
 Failed other medical therapy16 (94.1)
 Intolerance to other medicines1 (5.9)
Efficacy in symptom improvement at 4 weeks
 None4 (23.5)
 Partial6 (35.3)
 Complete7 (41.2)
Improved arthralgia post treatment at 4 weeks (n = 6)
 Partial5 (83.3)
 Complete1 (16.7)
Efficacy in symptom improvement at last follow-up
 None5 (29.4)
 Partial4 (23.5)
 Complete8 (47.1)
General endoscopic inflammation improvement
 None3 (21.4)
 Partial4 (28.6)
 Complete7 (50.0)
Fistular response at 4 weeks (n = 5)
 None3 (60.0)
 Partial1 (20.0)
 Complete1 (20.0)
Concurrent antibiotics13 (76.5)
Concurrent oral budesonide7 (41.2)
Concurrent oral or topical 5ASAs4 (23.5)
Concurrent immunomodulators0 (0)
Concurrent endoscopic therapy5 (29.4)
History pouch-preserving surgical therapy2 (11.8)
Adverse effects
 None13 (76.5)
 Headache3 (17.7)
 Injection site reaction1 (5.9)
Pouch failure3 (17.7)

The efficacy of adalimumab was further delineated by the calculation of the PDAI symptom and endoscopy subscores and PGA before and after the therapy at week 4. Four-week post treatment PDAI symptom and endoscopic subscores were significantly lower than pre-treatment scores (< 0.05) (Figures 1 and 2). There was also a significant improvement in PGA at week 4 (< 0.05) (Table 3).

image

Figure 1.  Endoscopy of the afferent limb before (a) and after (b) adalimumab injection.

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image

Figure 2.  Histology of the afferent limb before (a) and after (b) adalimumab injection.

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Table 3.   Pre and Post treatment pouchitis disease activity (PDAI) symptom and endoscopic scores and physician global assessment scores at Week 4
FactorAll (n = 17)P-value
  1. Values presented are median (25th, 75th percentiles). P-values correspond to Wilcoxon singed rank tests.

PDAI Symptom score (range 0–6)
 Pre-treatment4 (4, 4)<0.001
 Post-treatment1 (1, 2)
 Pre-Post PDAI score3 (2, 3)
PDAI Pouch Endoscopy Score (range 0–6)
 Pre-treatment3 (2, 4)<0.001
 Post-treatment0 (0, 2)
 Pre-Post pouch-endoscopy score2 (1, 3)
PDAI Afferent Limb Endoscopy Score (range 0–6)
 Pre-treatment2 (1, 3)0.004
 Post-treatment0 (0, 1)
 Pre-Post A-limb endoscopy score1 (0, 2)
PDAI Cuff Endoscopy Score (range 0–6)
 Pre-treatment2.5 (0, 4)0.016
 Post-treatment0 (0, 1)
 Pre-Post cuff endoscopy score1 (0, 4)
Physician Global Assessment Score (range 1–6)
 Pre-treatment scores5 (4, 6)<0.001
 Post-treatment scores1 (1, 2)
 Pre-Post scores3 (3, 4)

None of the patients was on immunomodulators during the trial. A majority of patients had concurrent use of antibiotics before and during the trial with ciprofloxacin, metronidazole, rifaximin and tinidazole. Five patients received endoscopic therapy at the entry into the trial or at the follow-up pouch endoscopy, with endoscopic balloon stricture dilations or polypectomy. Two patients had a history of incision and drainage of abscesses prior to the trial (Table 2).

Three patients (17.7%) had pouch failure with permanent surgical diversion or pouch excision after failure to respond to adalimumab therapy. The three patients elected not to try other biological therapy (Table 2).

Adverse effects

Four patients developed adverse effects, which were probably attributed to adalimumab administration: three had transient headache and one had injection site reaction. None of the patients had to discontinue use of the agent (Table 2).

Discussion

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Crohn’s disease of the pouch has been increasingly recognized and diagnosed in patients with IPAA and is one of the leading causes for pouch failure. Adalimumab has not been systematically evaluated for the treatment of CD of the pouch, while it is routinely used in treating CD in nonpouch patients since its approval by the FDA in 2005. In this open-labelled induction study, subcutaneous administration of adalimumab was shown to be effective in a majority of these patients, as evidenced by the improvement in subjective symptoms and objective endoscopy inflammation scores. These patients had otherwise been considered for surgical diversion or pouch excision. It appears that the response to adalimumab therapy was not affected by prior infliximab treatment before or after colectomy and IPAA or smoking status. The response rate of adalimumab was comparable with that of infliximab from the historical data published in literature.16 Although minor adverse effects occurred in 25% of the patients, the agent was generally well-tolerated.

Patients with CD of the pouch can present with low-grade fever, weight loss, nausea, fistular drainage and failure to thrive, in addition to common symptoms of diarrhoea, abdominal pain, and pelvic discomfort.25 Pouch endoscopy is typically the first-line diagnostic modality. Ulcerated lesions in the afferent limb proximal to the pouch26 and ulcerated strictures at the pouch inlet, afferent limb or mid-pouch27 in the absence of current NSAID use are suggestive of CD. The diagnosis of CD of the pouch typically necessitates long-term medical therapy. While antibiotic therapy is often used in fistulizing CD of the pouch, its efficacy in inflammatory and fibrostenotic CD appeared to be limited, according to the authors’ experience. In clinical practice, topical and oral mesalazine (mesalamine) and corticosteroids (particularly budesonide) are frequently used to treat CD of the pouch and these agents may be useful in reducing mucosal inflammation. However, there were no published data in the literature on these agents in treating CD of the pouch.

In patients with fibrostenotic CD of the pouch, endoscopic treatment (i.e. balloon stricture dilations) was often used. Fibrostenotic CD can be treated with combined medical, endoscopic27 and surgical28 therapy. Pouch-preserving surgical treatment modalities, such as incision and drainage and seton or mushroom catheter placement for abscess, were performed. Despite the limited duration of follow-up in most studies, some of patients appeared to be able to retain their pouches with aggressive medical or endoscopic therapy, even before the era of the wide use of biological therapy.9, 10, 12, 16

There are some issues in outcome measurements for the clinical trials in CD of the pouch. One of the major advantages of the trials is the utilization of the easy-to-perform pouch endoscopy as part of an objective measurement of outcome. However, there have been hurdles in running clinical trials in CD of the pouch. The commonly used instruments for measuring outcomes in CD such as Crohn’s Disease Activity Index and Harvey-Bradshaw Index could not be directly applied to the patients with IPAA,29 as some of symptoms listed in these instruments, such as bowel frequency, may reflect true disease activity or a post-operative norm in the patients with an altered bowel anatomy. Similarly, the PDAI score was designed for as a research tool for pouchitis. The PDAI does not cover mucosal inflammation of the small bowel and cuff, nor structuring or fistulizing lesions. Therefore, a new diagnostic instrument specifically for CD of the pouch is needed for diagnosis, quantification of disease activity and measurement of outcomes.

Despite the limitations to the current study, i.e. a noncontrolled, open-labelled study design and a short duration of the follow-up, the findings from the study may provide some answers as well as raise questions with regard to the treatment of CD of the pouch. It should be emphasized that randomized trials in this patient population are difficult to conduct, in part due to the lack of a large sample size, heterogeneity in clinical phenotypes and a limited interest from industry sponsors. Nonetheless, it appears that adalimumab was well-tolerated and effective in inducing symptom remission in the majority of patients who would otherwise require surgical therapy. However, it should be pointed out that the current study only assessed short-term response and efficacy and safety of adalimumab in long-term maintenance therapy for CD of the pouch need further investigation. Whether a top-down strategy, i.e. the use of adalimumab at the beginning of the course of CD of the pouch, improves treatment outcome and alters natural history, remains to be seen. In addition, there are no guidelines or consensus on choice among the four available biological agents approved by the FDA for the treatment of CD (infliximab, adalimumab, certalimumab, and natalimumab) as the first-line agent for CD of the pouch. Finally, whether the addition of immunomodulators to the biological therapy improves outcomes in CD of the pouch remains to be investigated.

In conclusion, this open-label induction study indicates that adalimumab appears to be well-tolerated and, in conjunction with other medical and endoscopic therapy, is effective in induction therapy in a majority of patients with CD of the pouch. Adalumimab may not be a first-line agent for CD of the pouch. Rather, it may be considered as a last-resort, rescuing agent for these patients before pouch excision or permanent diversion. Randomized trials with a longer follow-up are needed for the further evaluation of the safety and efficacy of the agent in both induction and maintenance in this patient population.

Acknowledgements

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Declaration of personal and funding interests: The Cleveland Clinic maintains policies requiring that certain disclosures of financial interests accompany manuscripts submitted for publication. These financial interests with companies must be disclosed by co-authors from Cleveland Clinic whose research is sponsored by the companies or whose products (or direct and primary competitor’s products) are discussed in the manuscript.

In accordance with this Cleveland Clinic, we are disclosing that we have served within the past year or will serve in the coming year in the following roles in connection with the companies listed below.

 RoleCompany
  1. This study was supported by an internal Fund of the Digestive Disease Institute of Cleveland Clinic.

Bo Shen, MDHonorariaUCB, Centocor, Salix, Abbott
Research GrantOcera, Salix, P & G
Elaine Queener, LPNResearch SupportOcera
Feza Remzi, MDNoneNone
Zan Lavety, MDNoneNone
Bocio Lopez, MSNoneNone
Ling ShenNoneNone
John Goldblum, MDNoneNone
Victor Fazio, MDNoneNone

References

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References
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