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Keywords:

  • Crohn's disease;
  • ileal pouch-anal anastomosis;
  • adalimumab;
  • ulcerative colitis

Abstract

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

Background:

Crohn's disease (CD) of the pouch can develop in patients with ileal pouch–anal anastomosis, resulting in significant morbidities, even pouch failure. The aim of this study was to evaluate short- and long-term outcome of adalimumab (ADA) in treating these patients.

Methods:

A total of 48 patients who received ADA for CD of the pouch from June 2006 to June 2011 were identified from our prospectively maintained Pouchitis Registry Complete clinical response was defined as the resolution of symptoms as well as the modified Pouchitis Disease Activity Index (mPDAI) score being less than 5. Partial clinical response was defined as improvement in symptoms as well as a reduction in mPDAI score of 2 or more. Endoscopic mucosal healing status before and after therapy was recorded.

Results:

At a short follow-up of median 8 weeks, 24 (50%) patients had complete response, 10 (21%) had partial response, and 14 (29%) had no response. After a median follow-up of 25.1 months, 16 (33%) patients had a complete response, 10 (21%) had a partial response, and 22 (46%) had no response. At the end of the follow-up, 13 (27%) patients achieved mucosal healing. A total of nine (19%) patients eventually developed pouch failure. Patients with a long-term response had a significantly higher mucosal healing rate (60.9% vs. 28.6%, P = 0.032) and significantly lower median mPDAI score (2.0 vs. 5.0, P = 0.004) at the first follow-up evaluation than those with no long-term response. Multivariate analysis showed concurrent endoscopic stricture dilation (hazard ratio = 5.9; 95% confidence interval: 1.6, 21.2) increased the chance for the long-term response to ADA. One patient developed multiple sclerosis during the therapy.

Conclusions:

ADA treatment, particularly in conjunction with endoscopic therapy, may help rescue a subgroup of patients with CD of the pouch from having surgery. (Inflamm Bowel Dis 2012;)

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.

PATIENTS AND METHODS

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

Patients

All patients were identified from an Institutional Review Board (IRB)-approved, prospectively maintained database of subspecialty Pouchitis Clinic from June 2006 to June 2011. Additional IRB approval was obtained for the chart review.

Inclusion and Exclusion Criteria

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

Diagnostic Criteria

CD of the pouch was diagnosed based on a combined assessment of symptoms, endoscopy, histology, radiography, and, in some cases, examination under anesthesia, with the criteria previously published by our group.5, 13 CD of the pouch was further classified into inflammatory, fibrostenotic, or fistulizing types.5, 13 These categories were modified from the Vienna Classification22 and the Montreal Classification23 for CD in nonpouch patients. Detailed diagnostic criteria for each of the three phenotypes of CD of the pouch are described in Table 1.13, 19

Table 1. Definitions of CD of the Pouch Phenotypes
CD PhenotypenDefinition
  1. CD, Crohn's disease; NSAIDs, nonsteroidal antiinflammatory drugs.

Inflammatory disease15Presence of afferent limb ulcers and presence of discrete ulcers in other parts of the small bowel (>10 cm beyond the pouch inlet) in the absence of NSAIDs use
Fibrostenotic disease8Proximal small bowel or pouch inlet stricture with associated mucosal inflammation found on contrast enema CT, MRI, or pouchoscopy
Fistulizing disease25Fistulas involving the pouch AND perineum OR proximal small intestine OR perianal or vaginal
fistulas developing more than 6 to 12 months after ileostomy take-down and the absence
of postoperative leak, abscess, and sepsis

Clinical and Surgical Characteristics

Clinical and surgical characteristics of all patients were retrieved from the database. Clinical characteristics included gender, age at diagnosis, race, diagnosis prior to and after surgery, family history of IBD or colon cancer, smoking status, extent of colitis, indication for colectomy, age at colectomy, duration of disease prior to colectomy, duration between stoma closure and development of CD of the pouch, the presence of peripheral or central arthralgia, the presence of serological markers (including ASCA [anti-Saccharomyces cerevisiae antibody] and p-ANCA [perinuclear antineutrophil cytoplasmic antibody]), duration of ADA therapy, duration of follow-up, postoperative medical therapy prior to ADA therapy, and concomitant medical and/or endoscopic therapy. Surgical characteristics included type of pouch (J-, S-, or Kock pouches) and staging of pouch surgery (1-, 2-, 3-stage or redo-pouch surgery).

Protocol

Prior to administration of ADA, all patients had been tested negative for tuberculin skin test, chest x-ray, and viral hepatitis. ADA was administered as a standard regimen: subcutaneous injection 160 mg at week 1, 80 mg at week 2, and then 40 mg every other week. Any severe adverse effects were documented. Concurrent medicine use and/or endoscopic therapy were permitted and documented accordingly. Patients were requested to have a follow-up pouchoscopy at week 8 after the initiation of ADA therapy. In addition, a yearly surveillance (for dysplasia), diagnostic, and therapeutic (for possible stricture dilations) pouchoscopy was performed in all patients. Pouchoscopy and sometimes abdominal imaging were performed on an as-needed basis in between if the patients had persistent symptoms and failed to respond to the therapy. Not all patients in the current cohort had a repeat pouchoscopy or abdominal imaging after ADA therapy, largely due to logistic reason as a majority of patients at our Pouchitis Clinic came from outside of Ohio.

Outcome Measurement

Efficacy of ADA treatment for CD of the pouch was evaluated in a comprehensive fashion, including the documentation of pouch failure; clinical response (complete, partial, or no response); and endoscopic mucosal healing. Clinical response was evaluated for different phenotypes. For inflammatory or fibrostenotic disease, complete clinical response was defined as: 1) complete resolution of pouch-associated symptoms, including reduction in frequency of bowel movements to postoperative “normal” baseline, resolution of abdominal pain and urgency, and pelvic discomfort; and 2) modified Pouchitis Disease Activity Index (mPDAI) less than 5 and with a reduction in mPDAI of 2 or more after treatment.24, 25 For fistulizing disease, complete clinical response was defined as the cessation of fistular drainage and complete closure of fistula. Partial clinical response in inflammatory/fibrostenotic disease was defined as improvement in the above pouch-associated symptoms as well as a reduction in mPDAI of 2 or more. Partial clinical response in fistulizing disease was defined as reduction in fistula drainage.

Endoscopic mucosal inflammation of different segments, i.e., the pouch, the afferent limb, and the cuff was separately scored using the PDAI endoscopy subscore.25 The PDAI endoscopy subscore for each segment ranged from 0 to 6, with 0 representing normal appearance and 6 representing the severest inflammation. The subtotal PDAI endoscopy subscores of each segment (range 0–18) was documented before ADA therapy (N = 48), at the first follow-up (N = 47), and the last follow-up (N = 48). Mucosal healing after therapy was defined as the subtotal PDAI endoscopy subscores of each segment being of 0 or 1 as well as no ulcers. For calculating the mPDAI (range 0–12) which included clinical score (range 0–6) and endoscopy score (range 0–6), the highest score among the three segments was used.

Short-term clinical response and mucosal healing were evaluated at the first follow-up after initiation of ADA therapy. Long-term clinical response and mucosal healing as well as pouch failure were evaluated at the last follow-up. Adverse effects during the therapy were documented. Pouch failure was defined as pouch excision or permanent diversion.

Statistical Analysis

The means, standard deviations, and percentiles for continuous variables and frequencies and percentages for categorical factors were calculated. Student's t-test or the nonparametric Wilcoxon rank sum tests were used to compare continuous variables. Pearson's chi-square tests were used for categorical variables. In addition, a time-to-response analysis was performed by using Cox regression analysis. P < 0.05 was considered statistically significant. Data were collected in a Microsoft Excel database (Microsoft Excel 2003; Seattle, WA) and analyzed with SAS software for Windows (v. 9.2, SAS Institute, Cary, NC).

RESULTS

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

Demographics and Characteristics

A total of 67 patients diagnosed with CD of the pouch and being treated with ADA was identified from our database. Nineteen patients were excluded for the following reasons: ADA was initiated at outside hospitals (n = 7); the use of the agent had been started prior to colectomy (n = 4) or were started after pouch being diverted (n = 3); the agent was used for the treatment of rheumatoid arthritis (n = 1) or for endoscopic intralesional injection (n = 2); and patients were lost to regular follow-up (n = 2). Patients who did not respond to a standard dose of ADA were considered treatment failure. There was no dose escalation during ADA treatment.

The demographics and clinical characteristics of the remaining 48 patients are shown in Table 2. The mean age at colectomy was 31.3 years old with a median duration of 4.0 (interquartile range [IQR], 1.0–8.5) years from UC diagnosis to colectomy. CD of the pouch developed after a median of 12.0 (IQR 6.0–60.0) months after the ileostomy closure. The indications for proctocolectomy were medically refractory colitis (N = 47, 97.9%) or for dysplasia (N = 1, 2.1%). Forty-five (93.8%) had J-pouches, one (2.1%) had a Kock pouch, and two (4.2%) had S-pouches. After histopathological evaluation of colectomy specimens, the diagnosis of UC changed to indeterminate colitis (IC) in three (6.3%) cases and CD in two (4.2%). Based on the definitions of classifications of CD of the pouch illustrated in Table 1, 15 (31.2%) developed inflammation refractory to conventional antibiotic therapy, 8 (16.7%) had strictures, and 25 (52.1%) patients had late-onset pouch fistulae.

Table 2. Demographic and Clinical Characteristics
FactorAll (n=48)No Response (n=22)Partial/Complete Response (n=26)P-value
  1. ASCA, anti-Saccharomyces cerevisiae antibody; CD, Crohn's disease; IBD, inflammatory bowel disease; IC, indeterminate colitis; IQR, interquartile range; p-ANCA, peri-nuclear anti-neutrophil cytoplasmic antibody; PSC, primary sclerosing cholangitis; UC, ulcerative colitis.

Male (%)29 (60.4)12 (54.5)17 (65.4)0.44
Mean age at UC diagnosis25.3 ± 10.525.0 ± 10.125.5 ± 10.90.87
Mean age at colectomy31.3 ± 10.130.0 ± 10.032.4 ± 10.20.43
Median years between diagnosis and colectomy [IQR]4.0 [1.0,8.5]3.0 [1.0,7.0]4.5 [1.0,12.0]0.29
Median months between stoma taken-down and development of CD of the pouch [IQR]12.0 [6.0,60.0]12.0 [7.0,72.0]13.0 [6.0,48.0]0.63
Caucasian race (%)48 (100.0)22 (100.0)26 (100.0) 
Smoking status (%)   0.28
 Never37 (77.1)19 (86.4)18 (69.2) 
 Active smoker5 (10.4)2 (9.1)3 (11.5) 
 Ex-smoker6 (12.5)1 (4.5)5 (19.2) 
Family history of IBD (%)15 (31.3)7 (31.8)8 (30.8)0.94
Family history of colon cancer (%)7 (14.9)2 (9.5)5 (19.2)0.35
Indications for colectomy (%)   0.35
 Refractory colitis47 (97.9)22 (100.0)25 (96.2) 
 Neoplasia1 (2.1)01 (3.8) 
Pouch type (%)   0.26
 J45 (93.8)22 (100.0)23 (88.5) 
 K1 (2.1)01 (3.8) 
 S2 (4.2)02 (7.7) 
Stages of pouch surgery (%)   0.12
 14 (8.3)1 (4.5)3 (11.5) 
 234 (70.8)19 (86.4)15 (57.7) 
 36 (12.5)2 (9.1)4 (15.4) 
. Redo-pouch4 (8.3)0 (0.0)4 (15.4) 
Extent of UC (%)   0.9
 Distal2 (4.2)1 (4.5)1 (3.8) 
 Extensive colitis46 (95.8)21 (95.5)25 (96.2) 
Toxic megacolon or fulminant colitis (%)5 (10.4)2 (9.1)3 (11.5)0.78
Postoperative diagnosis (%)   0.36
 UC43 (89.6)21 (95.5)22 (84.6) 
 IC3 (6.3)1 (4.5)2 (7.7) 
 CD2 (4.2)02 (7.7) 
Phenotype   0.58
 Inflammatory15 (31.2)7 (31.8)8 (30.8) 
 Fibrostenotic8 (16.7)5 (22.7)3 (11.5) 
 Fistulizing25 (52.1)10 (45.5)15 (57.7) 
Peripheral arthralgia (%)15 (31.3)4 (18.2)11 (42.3)0.07
Central arthralgia (%)13 (27.1)3 (13.6)10 (38.5)0.05
Positive serological markers (ASCA or p-ANCA) (%)6 (12.5)3 (13.6)3 (11.5)0.83

Therapy Prior to or Concomitant with ADA Treatment

As illustrated in Table 3, all patients with CD of the pouch had been treated with conventional antibiotics, including ciprofloxacin, metronidazole, tinidazole, rifaximin, or a combination of them prior to ADA. Six (12.5%) patients with CD of the pouch had been treated with infliximab prior to ADA therapy, with three having infusion reaction and the other three having either no response or loss of response to infliximab. Other types of therapy prior to ADA are listed in Table 3.

Table 3. Treatment of Ulcerative Colitis and/or Pouch Diseases Prior to and Concomitant with Adalimumab
FactorAll (n=48)No Response (n=22)Partial/Complete Response (n=26)P-value
  • AZA, azathioprine; 5-ASA, 5-aminosalicylic acid; IPAA, ileal pouch-anal anastomosis; IQR, interquartile range; mPDAI, modified Pouchitis Disease Activity Index; 6-MP, 6-mercaptopurine.

  • *

    P = 0.006;

  • #

    P = 0.024;

  • P = 0.022;

  • P = 0.085 (vs. postoperative treatment prior to adalimumab).

Median follow-up months since 1st clinic visit25.1 [5.3,44.2]25.0 [3.5,56.9]25.9 [7.6,43.6]0.93
Mean follow-up months since IPAA127.9 ± 72.8132.8 ± 73.1123.8 ± 73.70.67
Median [IQR] weeks on adalimumab41.0 [30.0,64.0]32.0 [14.5,47.0]55.5 [38.0,87.5]0.001
Median [IQR] weeks from 1st adalimumab to the 1st follow-up8.0 [5.0,10.0]6.0 [4.0,8.0]8.0 [6.0,10.0]0.33
Indications for adalimumab0.51
 Failed other therapy (%)42 (87.5)20 (90.9)22 (84.6) 
 Intolerance to other therapy (%)6 (12.5)2 (9.1)4 (15.4) 
Preoperative use of biologics (%)9 (18.8)3 (13.6)6 (23.1)0.40
Postoperative treatment prior to adalimumab 
 Antibiotics (%)48 (100.0)22 (100.0)26 (100.0) 
 Corticosteroids (%)30 (65.2)13 (59.1)17 (70.8)0.4
 AZA/6-MP (%)15 (32.6)9 (40.9)6 (25.0)0.25
 5-ASAs (%)21 (45.7)7 (31.8)14 (58.3)0.07
 Infliximab (%)6 (12.5)3 (13.6)3 (12.5)0.91
Concomitant treatment during adalimumab treatment 
 Antibiotics (%)40 (83.3)*17 (77.3)23 (88.5)0.27
 Corticosteroids (%)18 (37.5)#7 (31.8)11 (42.3)0.46
 AZA/6-MP (%)5 (10.4)2 (9.1)3 (11.5)0.79
 5-ASAs (%)12 (25.0)3 (13.6)9 (35.0)0.10
 Intravenous immunoglobulin (%)1 (2.1)0 (0.0)1 (3.8)0.35
Endoscopic treatments (%)22 (45.8)9 (41.0)13 (50.0)0.63
 Balloon dilation (%)20 (41.7)8 (36.4)12 (46.2)0.58
 Needle knife (%)5 (10.4)4 (18.2)1 (3.8)0.09
 Topical corticosteroid injection (%)7 (14.6)3 (13.6)4 (15.4)0.92
Median mPDAI [IQR] before adalimumab6.0 [6.0,8.0]7.0 [6.0,8.0]6.0 [5.5,8.0]0.72
Median mPDAI [IQR] at the 1st follow-up3.0 [2.0,5.0]5.0 [3.0,8.0]2.0 [1.5,3.0]0.004
Median mPDAI [IQR] at the last follow-up2.0 [2.0,5.0]5.5 [4.0,7.0]2.0 [1.5,4.0]0.02
Subtotal PDAI endoscopy score of each segment before adalimumab, median [IQR]4.0 [3.0,6.0]4.0 [3.0,8.0]3.5 [2.75,5.0]0.15
Subtotal PDAI endoscopy score of each segment at the 1st follow-up, median [IQR]2.0 [0.0,5.0]3.0 [1.0,8.0]1.0 [0.0,3.25]0.03
Subtotal PDAI endoscopy score of each segment at the last follow-up, median [IQR]2.0 [1.0,4.0]3.0 [2.0,6.5]1.5 [0.0,4.0]0.002
Mucosal healing at the 1st follow-up (%)20 (41.7)6 (27.3)14 (53.8)0.03
Mucosal healing at the last follow-up (%)13 (27.1)0 (0.0)13 (50.0)<0.001
Adverse effects (%)6 (12.5)2 (9.1)4 (15.4) 

The majority (n = 42, 87.5%) of patients were treated with ADA for refractory CD, with the remaining patients (n = 6, 12.5%) for intolerance to other therapy. In our clinical practice, ADA had routinely been used as a rescue therapy before patients were considered for surgery. Three patients had had a history of adverse reaction to infliximab administration; two developed acute pancreatitis while on 6-mercaptopurine (6-MP) and one had abnormal liver function tests from 6-MP.

In addition to ADA treatment, concurrent medical therapies were used in the majority of patients, including the use of antibiotics, immunomodulators, oral budesonide, and 5-aminosalicylates (5-ASA) (Table 3). Furthermore, endoscopic treatments were performed in nearly half of the patients (22/48, 45.8%). Multiple sessions of endoscopic balloon dilation were performed in 20 (41.7%) patients; endoscopic needle knife therapy for strictures was done in 5 (10.4%) patients; and topical corticosteroid injection of balloon-dilated strictures was performed in 7 (14.6%) patients (Table 3).

Short-term and Long-term Efficacy of ADA

The median total duration of ADA therapy was 41 (interquartile range (IQR), 30–64) weeks. At the short-term follow-up after induction therapy with a median of 8 (IQR, 5.0–10.0) weeks, 24 (50.0%) patients had a complete response, 10 (20.8%) had a partial response, and 14 (29.2%) had no response (Table 4). Of the 23 patients with either inflammatory or fibrostenotic CD, 10 (43.5%) had a complete response and 6 (26.1%) had a partial response. Of the 25 patients with fistulizing CD, 14 (56.0%) had a complete symptom response and 4 (16.0%) had a partial symptom response.

Table 4. Short- and Long-term Efficacy of Adalimumab Treatment
FactorShort-termLong-term
Clinical response (N=48)  
 None (%)14 (29.2)22 (45.8)
 Partial (%)10 (20.8)10 (20.8)
 Complete (%)24 (50.0)16 (33.3)
Clinical response in patient with inflammatory or fibrostenotic disease (N=23)  
 None (%)7 (30.4)12 (52.2)
 Partial (%)6 (26.1)4 (17.4)
 Complete (%)10 (43.5)7 (30.4)
Clinical response in patients with fistulizing disease (N=25)  
 None (%)7 (28.0)10 (40.0)
 Partial (%)4 (16.0)6 (24.0)
 Complete (%)14 (56.0)9 (36.0)
Mucosal healing (%)20 (41.7)13 (27.1)
Pouch failure (%)NA9 (18.8)

The efficacy of ADA in maintenance therapy was also evaluated. After a median follow-up of 25.1 (IQR, 5.3–44.2) months, 16 (33.3%) patients maintained remission, 10 (20.8%) had a partial response, and 22 (45.8%) had no response. At the end of follow-up, 13 (50%) patients among 26 who still remained in response achieved mucosal healing of the pouch. The PDAI endoscopy subscore of each segment did not differ at the baseline between patients who achieved final mucosal healing with those who did not (median [IQR], 3.0 [3.0, 4.0] vs. 4.0 [3.0, 8.0], P = 0.134). In total, nine patients (18.8%) had their pouches excised or had a permanent diverting ileostomy.

On the other hand, the need of concomitant CD-related medicines appeared to decrease at the end of the follow-up. The number of patients requiring concomitant antibiotic, corticosteroid, or immunomodulator therapies after ADA treatment declined compared with the numbers before administration therapy (P = 0.006, 0.024 and 0.022, respectively) (Table 3). The treatment sessions per patient per year in those patients who were treated endoscopically did not differ significantly before and after ADA therapy (median 1.75 [IQR 1.0, 2.0] vs. 1.0 [1.0, 1.6], P = 0.112).

Factors Predicting Good Response for ADA Therapy

Based on univariate analysis by comparing patients with long-term complete/partial response (n = 26) to patients with no response (n = 22), several factors were found to be more prevalent in treatment responders (Tables 2, 3). Patients with long-term response had a significantly higher mucosal healing rate (60.9% vs. 28.6%, P = 0.032) and a significantly lower median mPDAI (2.0 [IQR, 1.5-3.0] vs. 5.0 [IQR, 3.0-8.0], P = 0.004) at the first follow-up evaluation than those with no long-term response. Long-term responders had a numerically higher prevalence of central arthralgia (38.5% vs. 13.6%; P = 0.054) than nonresponders. There were no differences in smoking status, family history of IBD, postoperative diagnosis, disease phenotype, and positive serological markers between long-term responders and nonresponders.

The long-term time-to-response analysis was performed by a Cox regression model. After adjusting for endoscopic treatment with injection, use of preoperative biologics increased the risk of response 3.8 times (hazard ratio [HR] = 3.8, 95% confidence interval [CI] 1.2, 11.7, P = 0.02). In addition, subjects who had endoscopic balloon dilation of strictures with topical corticosteroid injection had 5.9 times (HR = 5.9, 95% CI 1.6, 21.2, P = 0.007) higher hazard of clinical response.

Adverse Effects

Administration of ADA was generally well tolerated. Six patients (12.5%) developed adverse events that were probably attributed to ADA administration. Three patients had transient headache and one had injection site reaction; and none of the four patients had to discontinue use of the agent. Treatment was discontinued in the remaining two patients. One patient was a 36-year-old male who developed symptomatic multiple sclerosis diagnosed with both magnetic resonance imaging (MRI) and spinal tap 81 weeks after the treatment of ADA. This patient was treated with ADA for refractory inflammatory CD and was in partial response. His neurological symptoms resolved after discontinuation of the therapy. However, he developed pouch failure with permanent diverting ileostomy after discontinuation of ADA. The other patient had to stop the therapy due to low-grade fever with unknown origin after 41 week's treatment with ADA. This patient had inflammatory CD of the pouch who had achieved a complete remission at the time of discontinuation of the therapy.

DISCUSSION

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

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.

Acknowledgements

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

Potential conflict of interest: B.S. has received honoraria from Abbott Laboratories, Axcan, Optimer, and Prometheus Laboratories.

REFERENCES

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