Prepouch Ileitis After Ileal Pouch-anal Anastomosis: Patterns of Presentation and Risk Factors for Failure of Treatment

Prepouch Ileitis After Ileal Pouch-anal Anastomosis: Patterns of Presentation and Risk Factors... Abstract Background and Aims There is a lack in the literature about prepouch ileitis [PI], in particular regarding risk factors associated with failure of the medical treatment. Aim of the study is to analyse the characteristics of PI patients and to compare those who required surgery with those who were successfully treated with conservative therapy. Methods All cases presenting a diagnosis of PI were included and analysed. Patients eventually requiring surgery were compared with those who were managed conservatively, for symptoms of presentation, endoscopic characteristics, and rate of response to medical treatment. A sub-analysis of outcomes based on the final histology was performed. Results The overall incidence of PI among 1286 patients was 4.4% [57], after a median of 6.8 years from pouch surgery. Symptoms included increased frequency [26.4%], outlet obstruction [21%], and bleeding [15.8%]. Afferent limb stenosis affected 49.1% of patients. The comparison showed that patients requiring surgery had a higher rate of Crohn’s disease and indeterminate colitis [42.1 vs 0% and 15.8 vs 2.6%, p < 0.0001], outlet obstruction as main symptom [47.4 vs 7.9%, p = 0.0023], and afferent limb stenosis [73.7 vs 36.8%, p = 0.008] at endoscopy. Rate of failure of medical treatment at 5 years was 8.2% in patients with ulcerative colitis and 75% in the presence of both indeterminate colitis and Crohn’s disease [p < 0.0001]. Conclusions Crohn’s disease, indeterminate colitis, and stenosis with outlet obstruction are risk factors for failure of treatment after diagnosis of PI. Early aggressive therapy and surgery should be considered in these cases. Prepouch ileitis, treatment, surgery 1. Introduction Restorative proctocolectomy and ileal pouch-anal anastomosis [IPAA] is the standard treatment for ulcerative colitis [UC] that is not responsive to medical treatment or is complicated by dysplasia or cancer.1 The surgery has excellent outcomes, and most patients are satisfied with their quality of life and would recommend the procedure to others.2,3 Pouchitis is the most frequent complication after restorative proctocolectomy, with up to 50% of the patients reporting at least one flare of pouchitis within the first 10 years after surgery, which might require aggressive treatment.4–6 Much less is known about the prepouch ileitis [PI], a different inflammatory complication that occurs after the construction of an ileal pouch; this has been reported quite recently in the literature, although a universally accepted definition for PI does not exist. However, PI is generally described as an acute or chronic inflammation of the afferent limb of the pouch, which is diagnosed at pouchoscopy and confirmed at the histological examination. The symptoms are not specific, and the aetiology is unknown. The signs of prepouch ileal inflammation include friable granular mucosa, ulcers, and strictures of the afferent limb, which could extend proximally for a few tens of centimetres.7–11 A recent multicentre study reported an incidence of PI of about 5%, and almost all those patients had concurrent pouchitis, suggesting a possible similar cause.12 Other authors hypothesised a strict correlation between the picture of PI and Crohn’s disease.13,14 Only few papers have been published in recent years about PI, with small groups of patients or just case reports. Moreover, there is a lack of data regarding the effectiveness of the treatments which are administered to patients depending on the predominant clinical picture associated with the PI. For instance, it is presumable that a severe inflammation might require an escalating medical treatment, whereas a fibrotic stenosis could benefit from an endoscopic dilatation. Should those treatments fail, surgery could represent the last resort to maintain the pouch. To date, there is a paucity of evidence in the literature regarding the identification of risk factors associated with the failure of conservative treatment and, therefore, the need of surgical therapy. The aim of the present study was to identify the patients with a diagnosis of prepouch ileitis from a single large tertiary centre, and to compare those who required surgery for refractory PI with those who were successfully treated with conservative treatment, regarding patients’ characteristics, patterns of presentation, and outcomes. 2. Materials and Methods From a prospectively maintained database, all patients who had a reported diagnosis of prepouch ileitis were evaluated. The data were collected from 1989. The suspicion of PI usually arose at the follow-up endoscopy, and a confirmation of acute inflammation at the histological examination of the biopsy was required in order for the patients to be included in the study. In literature, no shared definition of PI exists. According to Shen et al., PI could be classified as an active inflammation of the afferent limb at the endoscopy, which is confirmed at the pathological examination.15 This definition was subsequently used by other authors.12 We agreed with those authors and did not require any specific symptom score in order for PI to be diagnosed. Exclusion criteria include the lack of details of the primary IPAA surgery and of PI treatment and response. Demographic and perioperative variables, including the presence of comorbidities, pre- and postoperative diagnosis, pre- and postoperative use of immunosuppressive or biologic drugs, and postoperative outcomes were evaluated. In particular, the incidence of long-term complications and the need of reoperations were accurately recorded. Postoperative complications were grouped according to the Clavien-Dindo classification.16 The date of the onset of PI was defined as the first diagnosis at endoscopy. The main symptoms associated with the endoscopic picture were recorded, and the conservative treatments were grouped into antibiotics, steroids, immunosuppressors [azathioprine, 6-mercaptopurin and methotrexate], anti-tumour necrosis factor [TNF]-alpha and endoscopic dilatations. In particular, the dilatations were performed in the presence of a symptomatic stenosis of the afferent limb extending for less than 5 cm. The success of the therapy was defined as an improvement of the symptoms and the signs of disease at the endoscopy. Failure was considered as the need to escalate to a different medical treatment or surgery due to the persistence of the symptoms. The need to repeat the same treatment was not considered a failure, as long as it eventually led to an improvement of symptoms. On the contrary, no matter if the same treatment was previously successful, should an escalation of therapy be required during the subsequent follow-up time, that treatment was marked as a failure. The retrospective nature of the study could not allow any more specific classification. When any possible conservative treatment failed, the patients could have either undergone a ‘therapeutic’ surgery [re-do pouch or pouch repair, stricturoplasty of the afferent limb, or resection and new ileal-pouch anastomosis] or experienced a pouch failure, which was defined as the need of a permanent stoma with or without the excision of the pouch. Variables were presented as median [range] or number [%]. Comparison of categorical variables was analysed with chi square or Fisher’s exact test as appropriate, and the Wilcoxon rank sum test was used for quantitative and ordinal variables. The KaplanMeier method was performed to analyse the rate of failure of the conservative treatments and the rate of pouch failure according to the final histological diagnosis. A p-value < 0.05 was considered significant. Statistical analyses were performed using JMP version 11 [SAS Institute, Cary, NC, USA]. Study data were collected and managed using REDCap [Research Electronic Data Capture] tools hosted at Alma Mater Studiorum University of Bologna.17 3. Results Between 1989 and 2016, 1286 patients underwent an IPAA formation in our centre. After review of the data and application of the exclusion criteria, 57 cases of PI were identified. Of those, eight patients had a definitive diagnosis of Crohn’s disease after the onset of PI [either confirmed at the histological examination of biopsies or after the excision of the pouch], whereas in four cases the initial diagnosis of indeterminate colitis was maintained during the follow-up. The overall incidence of PI was therefore 4.4%. The demographic characteristics and perioperative details of these patients are summarized in Table 1. Table 1. Demographic and perioperative characteristics at the time of pouch formation and follow-up.   N or median  % or range  Age  33  18–66  Male gender  36  63.1%  BMI [kg/m2]  22  13–27  Immunosuppressants at surgery  11  24.4%  Anti TNF-alpha at surgery  4  8.9%  J pouch design  56  98.2%  Hand-sewn anastomosis  9  15.8%  Postoperative complications  10  17.5%  Clavien-Dindo classification       Grade II  6  10.5%   Grade IIIb  4  7%  Length of hospital stay [days]  12  7–30  Final histopathology       Ulcerative colitis  45  79%   Indeterminate colitis  4  7%   Crohn’s disease  8  14%  Length of follow-up from IPAA[months]  222  20–354  Length of follow-up from diagnosis of PI [months]  119  8–293    N or median  % or range  Age  33  18–66  Male gender  36  63.1%  BMI [kg/m2]  22  13–27  Immunosuppressants at surgery  11  24.4%  Anti TNF-alpha at surgery  4  8.9%  J pouch design  56  98.2%  Hand-sewn anastomosis  9  15.8%  Postoperative complications  10  17.5%  Clavien-Dindo classification       Grade II  6  10.5%   Grade IIIb  4  7%  Length of hospital stay [days]  12  7–30  Final histopathology       Ulcerative colitis  45  79%   Indeterminate colitis  4  7%   Crohn’s disease  8  14%  Length of follow-up from IPAA[months]  222  20–354  Length of follow-up from diagnosis of PI [months]  119  8–293  BMI, body mass index; TNF, tumour necrosis factor; IPAA, ileal pouch-anal anastomosis; PI, prepouch ileitis. View Large The great majority of patients had a J pouch [98.2%] and a stapled anastomosis [84.2%]. A reoperation for postoperative complications was necessary in four patients [7%]. The clinical and endoscopic characteristics of presentation of PI are shown in Table 2. PI was diagnosed after a median of 6.8 years from the formation of the pouch, and a great percentage of patients did not report any specific symptom [36.8%]. At the endoscopy, pouchitis was seen in 86% of patients, and other abnormalities of the pouch [anastomotic stricture, pouch stenosis, or dilatation] were observed in 33.3% of cases. A stenosis of the afferent limb was diagnosed in 49.1% of patients. The disease of the afferent limb extended proximally for up to 30 cm [median 15 cm]. Table 2. Characteristics of disease at time of diagnosis of PI.   N or median  % or range  Interval between IPAA and diagnosis of PI [years]  6.8  0.7–21.9  Main symptom of PI   No symptoms  21  36.8%   Increased frequency  15  26.4%   Outlet obstruction  12  21%   Bleeding  9  15.8%  Endoscopic characteristics at diagnosis of PI   Anastomotic stricture  9  15.8%   Pouch stenosis  4  7%   Pouch dilatation  6  10.5%   Pouchitis  49  86%   Afferent limb stenosis  28  49.1%   Afferent limb ulcers  48  84.2%  Median length of diseased proximal bowel [cm]  15  2–30    N or median  % or range  Interval between IPAA and diagnosis of PI [years]  6.8  0.7–21.9  Main symptom of PI   No symptoms  21  36.8%   Increased frequency  15  26.4%   Outlet obstruction  12  21%   Bleeding  9  15.8%  Endoscopic characteristics at diagnosis of PI   Anastomotic stricture  9  15.8%   Pouch stenosis  4  7%   Pouch dilatation  6  10.5%   Pouchitis  49  86%   Afferent limb stenosis  28  49.1%   Afferent limb ulcers  48  84.2%  Median length of diseased proximal bowel [cm]  15  2–30  IPAA: ileal pouch-anal anastomosis; PI: prepouch ileitis. View Large Table 3 reports the distribution of the antibiotic, steroid, immunosuppressive, and biologic treatments, as well as the rate of the endoscopic dilatations and the failure rate of each of these therapies. At a median of 48.7 months for the diagnosis of PI, a total of 19 patients either experienced a pouch failure or underwent surgery in order to manage an otherwise refractory PI, either a pouch failure surgery in order to manage a otherwise refractory PI. In those cases, obviously, no conservative treatment was considered successful in the long-term. Table 3. Type of conservative treatments and percentage of failure in patient with a diagnosis of PI [excluding patients with Crohn’s disease].   Number of cases [%]  Percentage of failure [%]  Antibiotics  45 [91.8%]  54.3%  Oral or intravenous steroids  27 [56.2%]  74.1%  Immunosuppressants  9 [18.8%]  66.7%  Anti TNF-alpha  12 [25%]  76.9%  Endoscopic dilatation  7 [14.3%]  50%    Number of cases [%]  Percentage of failure [%]  Antibiotics  45 [91.8%]  54.3%  Oral or intravenous steroids  27 [56.2%]  74.1%  Immunosuppressants  9 [18.8%]  66.7%  Anti TNF-alpha  12 [25%]  76.9%  Endoscopic dilatation  7 [14.3%]  50%  View Large A pouch failure was therefore observed in eight cases [three pouch excisions and five formations of permanent ileostomy]. Of the other 11 patients, seven underwent a resection of the afferent limb, three a stricturoplasty of the limb stenosis, and one a re-do pouch with excision of the afferent limb. In total, an associated pouch repair was necessary in six cases [the already mentioned re-do pouch and five excisions of redundant cul-de-sac] [Table 4]. All patients who were diagnosed with Crohn’s disease eventually underwent surgery, and 50% of them had a pouch failure at time of surgery. Table 4. Type of surgical procedures performed for patients who failed conservative treatment.   N or median  % or range  Interval from diagnosis of PI [months]  48.7  6–161  Need of surgery for failure of treatment  19  33.3%  Pouch failure  8  14%   Pouch excision  3/8  37.5%   Permanent ileostomy  5/8  62.5%  Therapeutic surgical treatment  11  19.3%   Ileal resection and anastomosis  7/11  63.6%   Stricturoplasty  3/11  27.3%   Re-do pouch  1/11  9.1%   Associated pouch repair  6/11  54.5%    N or median  % or range  Interval from diagnosis of PI [months]  48.7  6–161  Need of surgery for failure of treatment  19  33.3%  Pouch failure  8  14%   Pouch excision  3/8  37.5%   Permanent ileostomy  5/8  62.5%  Therapeutic surgical treatment  11  19.3%   Ileal resection and anastomosis  7/11  63.6%   Stricturoplasty  3/11  27.3%   Re-do pouch  1/11  9.1%   Associated pouch repair  6/11  54.5%  View Large The univariate comparisons between patients requiring surgery and those who were managed with conservative treatment are shown in Tables 5 and 6. Patients who eventually had surgery were characterised by a significantly higher rate of American Society of Anesthesiologists [ASA] score 3 [p = 0.041], a final diagnosis of indeterminate colitis and Crohn’s disease [p < 0.0001], outlet obstruction as presenting symptom [p = 0.0023], pouch dilatation [p = 0.006], and afferent limb stenosis [p = 0.008] at the endoscopy. These patients experienced a significantly lower rate of 30-day postoperative complications after IPAA and had a lower rate of pouchitis at the time of diagnosis of PI [68.4 vs 94.8%, p = 0.0056]. Table 5. Comparison of perioperative variables and characteristics of disease between patients who underwent successful conservative treatment and those who required surgery.   Conservative treatment  Surgical treatment  p-value  Number of patients  38  19    Median age  34.5 [18–58]  24 [18–66]  0.81  Male gender  26 [68.4%]  10 [52.6%]  0.24  ASA score 3  1 [2.6%]  4 [26.7%]  0.041  Median BMI  22 [13–27]  22 [17–26]  0.5  Hand-sewn anastomosis  7 [18.4%]  2 [10.5%]  0.44  30-day complication rate  10 [26.3%]  0  0.013  Final histological diagnosis      < 0.0001  Ulcerative colitis  37 [97.4%]  8 [42.1%]    Indeterminate colitis  1 [2.6%]  3 [15.8%]    Crohn’s disease  0  8 [42.1%]    Interval between IPAA and diagnosis of PI [months]  96.2 [ ± 69.4]  86.1 [ ± 73.2]  0.68  Main symptom of PI      0.0023   No symptoms  18 [47.3%]  3 [15.8%]     Outlet obstruction  3 [7.9%]  9 [47.4%]     Increased frequency  12 [31.6%]  3 [15.8%]     Bleeding  5 [13.2%]  4 [21%]    Concurrent pouchitis  36 [94.8%]  13 [68.4%]  0.0056  IPAA stenosis  6 [15.8%]  3 [15.8%]  0.99  Pouch stenosis  2 [5.2%]  2 [15.5%]  0.46  Pouch dilatation  1 [2.6%]  5 [26.3%]  0.006  Afferent limb stenosis  14 [36.8%]  14 [73.7%]  0.008  Afferent limb ulcers  34 [89.5%]  14 [73.7%]  0.12    Conservative treatment  Surgical treatment  p-value  Number of patients  38  19    Median age  34.5 [18–58]  24 [18–66]  0.81  Male gender  26 [68.4%]  10 [52.6%]  0.24  ASA score 3  1 [2.6%]  4 [26.7%]  0.041  Median BMI  22 [13–27]  22 [17–26]  0.5  Hand-sewn anastomosis  7 [18.4%]  2 [10.5%]  0.44  30-day complication rate  10 [26.3%]  0  0.013  Final histological diagnosis      < 0.0001  Ulcerative colitis  37 [97.4%]  8 [42.1%]    Indeterminate colitis  1 [2.6%]  3 [15.8%]    Crohn’s disease  0  8 [42.1%]    Interval between IPAA and diagnosis of PI [months]  96.2 [ ± 69.4]  86.1 [ ± 73.2]  0.68  Main symptom of PI      0.0023   No symptoms  18 [47.3%]  3 [15.8%]     Outlet obstruction  3 [7.9%]  9 [47.4%]     Increased frequency  12 [31.6%]  3 [15.8%]     Bleeding  5 [13.2%]  4 [21%]    Concurrent pouchitis  36 [94.8%]  13 [68.4%]  0.0056  IPAA stenosis  6 [15.8%]  3 [15.8%]  0.99  Pouch stenosis  2 [5.2%]  2 [15.5%]  0.46  Pouch dilatation  1 [2.6%]  5 [26.3%]  0.006  Afferent limb stenosis  14 [36.8%]  14 [73.7%]  0.008  Afferent limb ulcers  34 [89.5%]  14 [73.7%]  0.12  Variables are expressed as number [%] or mean [± standard deviation]. ASA, American Society of Anesthesiologists; BMI, body mass index; IPAA, ileal pouch-anal anastomosis; PI, prepouch ileitis. View Large Table 6. Comparison of types of treatments between patients who underwent successful conservative treatment and those who required surgery.   Conservative treatment  Surgical treatment  p-value  Type of treatment   Antibiotics  35 [92.1%]  14 [73.6%]  0.05   Oral or intravenous steroids  19 [50%]  15 [83.3%]  0.017   Immunosuppressants  6 [15.8%]  7 [36.8%]  0.08   Anti TNF-alpha  7 [18.4%]  8 [44.4%]  0.040   Endoscopic dilatation  5 [13.2%]  5 [27.8%]  0.18    Conservative treatment  Surgical treatment  p-value  Type of treatment   Antibiotics  35 [92.1%]  14 [73.6%]  0.05   Oral or intravenous steroids  19 [50%]  15 [83.3%]  0.017   Immunosuppressants  6 [15.8%]  7 [36.8%]  0.08   Anti TNF-alpha  7 [18.4%]  8 [44.4%]  0.040   Endoscopic dilatation  5 [13.2%]  5 [27.8%]  0.18  TNF, tumour necrosis factor View Large After the exclusion from the analysis of patients with a diagnosis of indeterminate colitis and Crohn’s disease, the presentation with outlet obstruction [37.5 vs 8.1%, p = 0.017], the absence of pouchitis [25 vs 5.4%, p = 0.050], the presence of pouch dilatation at the endoscopy [37.5 vs 2.7%, p = 0.0017] were significantly associated with the need of surgery. A sub-comparison between cases with a diagnosis of ulcerative colitis and indeterminate colitis showed that the latter was associated with a significantly lower rate of pouchitis [50 vs 91.1%, p = 0.016], a higher rate of ulcers in the proximal limb [50% vs 4.4%], and a shorter interval between IPAA and PI diagnosis [3.2 vs 7.3 years, p = 0.011] and between PI diagnosis and surgery [2 vs 7 years, p = 0.018]. Patients with a diagnosis of Crohn’s disease were more likely to present with afferent limb stenosis [75% vs 42.2%, p = 0.041] than those who had ulcerative colitis. The analysis of the risk of failure of medical treatment after the diagnosis of PI showed an overall chance of having surgery of 5.3%, 9.3%, 24.5%, 35.3%, and 47% at 1, 2, 5, 10, and 15 years, respectively. The sub-analyses of the risk of surgery and pouch failure sorted by histological diagnosis are shown in Figures 1 and 2 and Table 7. Table 7. Comparison of risk of failure of the conservative treatment and risk of pouch failure at 1, 2, 5, and 10 years according to the final histological diagnosis, based on the Kaplan-Meier curve.   Ulcerative colitis  Indeterminate colitis  Crohn’s disease  p-value  Failure of conservative treatment        < 0.0001   1 year  0%  25%  25%     2 years  2.5%  50%  37.5%     5 years  8.2%  75%  75%     10 years  19.7%  75%  87.5%    Pouch failure        < 0.0001   1 year  0%  0%  12.5%     2 years  0%  33%  12.5%     5 years  0%  33%  47.5%     10 years  6.3%  33%  47.5%      Ulcerative colitis  Indeterminate colitis  Crohn’s disease  p-value  Failure of conservative treatment        < 0.0001   1 year  0%  25%  25%     2 years  2.5%  50%  37.5%     5 years  8.2%  75%  75%     10 years  19.7%  75%  87.5%    Pouch failure        < 0.0001   1 year  0%  0%  12.5%     2 years  0%  33%  12.5%     5 years  0%  33%  47.5%     10 years  6.3%  33%  47.5%    View Large Figure 1. View largeDownload slide Risk of surgery for failed conservative treatment in patients with PI over a 15-year follow-up according to the final histological diagnosis. UC:,ulcerative colitis; IC, indeterminate colitis; CD, Crohn’s disease, PI: prepouch ileitis. Figure 1. View largeDownload slide Risk of surgery for failed conservative treatment in patients with PI over a 15-year follow-up according to the final histological diagnosis. UC:,ulcerative colitis; IC, indeterminate colitis; CD, Crohn’s disease, PI: prepouch ileitis. Figure 2. View largeDownload slide Rate of pouch survival in patients with PI over a 15-year follow-up according to the final histological diagnosis. UC, ulcerative colitis; IC, indeterminate colitis; CD, Crohn’s disease; PI, prepouch ileitis. Figure 2. View largeDownload slide Rate of pouch survival in patients with PI over a 15-year follow-up according to the final histological diagnosis. UC, ulcerative colitis; IC, indeterminate colitis; CD, Crohn’s disease; PI, prepouch ileitis. 4. Discussion Despite prepouch ileitis having been first described over two decades ago,18 the doubts regarding the nature of this complication, that specifically affects the afferent limb of bowel to the pouch, still outnumber the certainties. The reasons could be found in the relative low frequency and the lack of a definition of the disease, as well as of specific endoscopic or clinical scores. Moreover, as already highlighted by other authors, most of the times the endoscopy does not explore the afferent limb of bowel, and some of the symptoms could be easily associated with a concurrent pouchitis.11 Our experience confirmed that, at the moment, a generic definition of PI is necessary, as the endoscopic finding is not associated with any specific symptom in almost 40% of patients. Other symptoms, such as bleeding or an increased frequency of bowel movement, could likely make the physician suspect the presence of pouchitis. The fact that pouchitis is seen at endoscopy in the great majority of patients increases the chance of misdiagnosis. McLaughlin et al. reported the findings of 34 patients with a diagnosis of PI among 742 IPAA cases seen at St Mark’s Hospital.19 Similarly, 18% of them did not report any particular symptom, and all PI patients had pouchitis as well. The evidence that PI is likely to be associated with pouchitis led the authors to presume a common cause. However, a subsequent study compared PI and pouchitis patients and found that the former had a greater chance of undergoing steroid or immunomodulator therapy to control the symptoms, suggesting at least a more aggressive behaviour of PI. This multicentre retrospective study analysed a cohort of 546 patients who had IPAA surgery in three European centres.12 The present study includes almost 1300 IPAA procedures performed in a tertiary centre from 1989. All patients have been treated and followed by the same team of surgeons and gastroenterologists, reducing the case-mix bias and the differences in diagnosis and maintaining a similar strategy of therapy among cases. In the past, some authors assumed a correlation between Crohn’s disease and PI.14,20 In this series, eight patients had a final diagnosis of Crohn’s disease after the onset of PI, which was confirmed either through biopsies or the surgical specimen after resection. These cases, as expected, were associated with poor outcomes after both conservative and surgical treatment. The most interest finding was that indeterminate colitis had a similar trend towards the failure of treatment and, eventually, of the pouch, compared with Crohn’s disease. As shown in Figures 1 and 2, the curves are basically overlapping, especially when the outcome of the conservative treatment is analysed. Some of the characteristics of presentation are also similar between cases with indeterminate colitis and Crohn’s disease, which were both more likely to present with stricture of the afferent limb and outlet obstruction at the time of diagnosis of PI, when compared with patients with ulcerative colitis. Another interesting result was that, unlike ulcerative colitis that was associated with pouchitis in a great majority of patients [91.1%], Crohn’s disease and especially indeterminate colitis had a weaker association with inflammation of the pouch [75% and 50%, respectively], suggesting a different aetiology and confirming that, in these cases, indeterminate colitis might represent a misdiagnosed Crohn’s disease. The causes of uncertainty in IBD pathology that led to a diagnosis of indeterminate colitis at the time of colectomy included toxic colitis, the lack of pathognomonic clinical, radiological, and endoscopic pictures and, in particular, failure to recognise the classic features of Crohn’s disease or ulcerative colitis in the histological examination of the colon and rectum. The main features of Crohn’s disease include deep fissures, fistulas, the presence of segmental disease, the lack of involvement of the rectum, and the finding of transmural lymphoid aggregates and epithelioid granulomas. Concomitant upper gastrointestinal manifestations or perianal disease could also suggest a diagnosis of Crohn’s disease. The increasing finding of unusual pathological variants of IBD [UC with Crohn’s disease-like features and Crohn’s disease with UC-like features], which seem to be associated with the widespread use of biologic treatments, makes sometimes the chance of having a definite diagnosis hard even in the hands of an expert pathologist.21 The findings of the present study suggest that, in this specific subpopulation of IBD patients, indeterminate colitis behaves like Crohn’s disease, and it would be safe to assume that, despite the lack of a final diagnosis, the onset of PI in the presence of indeterminate colitis strongly suggests an underlying Crohn’s disease and should be dealt with accordingly. Consequently, it might be equally safe to conclude that, in the presence of a positive diagnosis of ulcerative colitis, PI is not the manifestation of a misdiagnosed Crohn’s disease as suggested by other authors, but it should be considered a condition per se that requires appropriate treatment and follow-up, and is associated with good long-term outcomes in terms of need of surgery and pouch failure [8.2% and 0% at 5 years, respectively]. In these cases, pouchitis is often present, suggesting a possible similar cause. However, although the majority of patients with pouchitis usually respond very well to antimicrobial therapy,22 in the present series over 50% of patients did not have a clinical remission after antibiotic treatment. In addition, immunosuppressors and anti TNF-alpha drugs were even less effective in these cases. A recent review of the literature showed a good clinical effectiveness of infliximab in the treatment of chronic refractory pouchitis, achieving up to 80% and 50% of response at short- and long-term follow-up, respectively. The review included patients who presented with Crohn’s-like complications of the pouch [stricturing or fistulising disease], confirming a good response in this subgroup as well.23 In the present study, the response to biologic drugs was less than 25%, even after exclusion of patients with a diagnosis of Crohn’s disease. Overall, in 67.7% of patients, the condition was managed through conservative treatment, but no specific therapy was proven to be more effective than others. The lack of response of PI to medical treatment, in particular antibiotics and infliximab, highlights a major difference between this condition and pouchitis. Although the frequent coexistence of the two complications might suggest a common cause, it is possible that, in susceptible patients, the inflammatory involvement of the afferent limb could at some point develop as an independent, more aggressive condition, especially when it is associated with stenosis and outlet obstruction. It is important to emphasise that the retrospective nature of the study, and the fact that several recurrences of PI might be seen during follow-up, forced a simplification of the presentation of treatment and outcomes. The need for escalation of treatment during the same presentation of disease was considered a failure, regardless of previous successful responses to the same treatment. However, many patients underwent more than one type of treatment, and the change of therapy does not necessarily reflect a failure of the previous medication. As often observed in the case of pouchitis, PI might present in several subsequent flare-ups, and new drugs could be used in order to control the symptoms even if other medications were previously administered with success. Moreover, some of these patients were diagnosis with PI before the introduction of the biologic drugs, and might have undergone those treatments only after years, in an advanced stage of the disease, when the fibrosis associated with chronic inflammation does not respond to the treatment. This study included a group of patients with specific symptoms of outlet obstruction [21%] and an endoscopic finding of stenosis or sub-stenosis of the afferent limb [49.1%]. Stenosis was found in 75% of both indeterminate colitis and Crohn’s disease patients. All these patients required surgery. Among patients with ulcerative colitis, the incidence of stenosis of the afferent limb remained high [19, 42.2%]; however, only five of these cases [26.3%] required surgery. A possible explanation for this difference might be found in the rate of patients presenting with outlet obstruction, meaning a more severe stenosis of the afferent limb, which was 13.3% among UC patients [vs 50% in Crohn’s and indeterminate colitis patients]. Outlet obstruction should be therefore considered as a strong risk factor for failure of medical treatment. Endoscopic dilatation can be attempted in order to improve the symptoms, when the stricture is shorter than 5 cm and amenable to dilation. The procedure, however, was effective in the long-term only in 37.4% of cases. The success rate increased to 50% when excluding patients with Crohn’s disease. The univariate comparison between patients requiring surgery and those who were managed conservatively, showed few important differences that might help the clinicians to predict a worse outcome at the diagnosis of PI. Apart from indeterminate colitis and Crohn’s disease, which were the strongest factors associated with a PI not responsive to medical treatment [p = 0.018], the outlet obstruction at presentation [p = 0.0085], the stenosis of the afferent limb [p = 0.035] and pouch dilatation [p = 0.0086] also played an important role in the failure of conservative treatment. Interestingly, a concurrent pouchitis was associated with a higher chance of a successful conservative treatment [p = 0.0056]. PI has an erratic pattern of presentation after IPAA. Although the median time of observation from the pouch surgery is about 7 years, some patients were diagnosed after only 8 months and others after over 20 years. The analysis of the distribution of treatment failure showed a similar trend towards a progressive, continuous incidence during follow-up after the diagnosis of PI, with a chance of having had surgery of 35.3% at 10 and 47% at 15 years. A comparison between cases who had an “early” onset [arbitrarily chosen as less than 5 years] and the others did not show any difference in outcomes. A proposed algorithm of treatment for patients diagnosed with PI is reported in Figure 3. Patients with a definitive diagnosis of UC, whose endoscopy shows ulcers, oedema, or friability of the afferent limb, without symptoms of outlet obstruction, should be treated following the European Crohn’s and Colitis Organisation guidelines for pouchitis.24 Figure 3. View largeDownload slide Proposed algorithm of treatment for patients with a diagnosis of PI [prepouch ileitis]. Figure 3. View largeDownload slide Proposed algorithm of treatment for patients with a diagnosis of PI [prepouch ileitis]. Stenosis or sub-stenosis of the afferent limb, which must be suspected in the presence of outlet obstruction symptoms, should be addressed more aggressively in consideration of the higher chance of failure of treatment. In suitable cases, when the stenosis is shorter than 5 cm, endoscopic dilatation should be attempted. However, this subgroup of patients are more likely to require surgery, which could also be proposed at an early stage in order to improve the patient’s quality of life. In the presence of Crohn’s disease, failure of the medical treatment is almost certain and therefore surgery should be considered as a primary option. The role of indeterminate colitis is still to be clarified but, taking into consideration the high risk of failure and the Crohn’s-like behaviour, early aggressive medical and surgical treatment should be considered. 5. Conclusions PI is an inflammatory complication of the pouch that occurs in a limited number of patients, but could be associated with high rate of surgery or pouch failure especially in the presence of outlet obstruction. Crohn’s disease and indeterminate colitis are associated with a greater chance of failure of treatment, and should be addressed appropriately. Funding No funding in any form was received for the study. Conflict of Interest None. Author Contributions MR: concept and design of the study; acquisition of data; analysis and interpretation of data; drafting the article; final approval of the version to be submitted. CV: acquisition of data; drafting the article; final approval of the version to be submitted. EB: acquisition of data; drafting the article; final approval of the version to be submitted, PG: concept and design of the study; revising it critically for important intellectual content; final approval of the version to be submitted. FR: concept and design of the study; revising it critically for important intellectual content; final approval of the version to be submitted. MPS: concept and design of the study; revising it critically for important intellectual content; final approval of the version to be submitted. GP: concept and design of the study; revising it critically for important intellectual content; final approval of the version to be submitted. A part of this study was presented as a digital oral presentation at the 12th congress of ECCO [European Crohn’s and Colitis Organisation], Barcelona, Spain, February 1518, 2017. Acknowledgments REDCap [Research Electronic Data Capture] is a secure, web-based application designed to support data capture for research studies, providing: 1] an intuitive interface for validated data entry; 2] audit trails for tracking data manipulation and export procedures; 3] automated export procedures for seamless data downloads to common statistical packages; and 4] procedures for importing data from external sources. RecCap is hosted at Alma Mater Studiorum University of Bologna. References 1. Øresland T, Bemelman WA, Sampietro GMet al.  ; European Crohn’s and Colitis Organisation [ECCO]. European evidence-based consensus on surgery for ulcerative colitis. J Crohns Colitis  2015; 9: 4– 25. Google Scholar PubMed  2. Lovergrove RE, Herito AG, Constantinides Vet al.   Meta-analysis of short-term and long-term outcomes of J, W and S ileal reservoirs for restorative proctocolectomy. Colorectal Dis  2007; 9: 310– 20. Google Scholar CrossRef Search ADS PubMed  3. Michelassi F, Lee J, Rubin Met al.   Long-term functional results after ileal pouch anal restorative proctocolectomy for ulcerative colitis: a prospective observational study. Ann Surg  2003; 238: 433– 41; discussion 442–5. Google Scholar PubMed  4. Gorgun E, Remzi FH. Complications of ileoanal pouches. Clin Colon Rectal Surg  2004; 17: 43– 55. Google Scholar CrossRef Search ADS PubMed  5. Shen B, Remzi FH, Lavery IC, Lashner BA, Fazio VW. A proposed classification of ileal pouch disorders and associated complications after restorative proctocolectomy. Clin Gastroenterol Hepatol  2008; 6: 145– 58; quiz 124. Google Scholar CrossRef Search ADS PubMed  6. Gionchetti P, Calafiore A, Riso Det al.   The role of antibiotics and probiotics in pouchitis. Ann Gastroenterol  2012; 25: 100– 5. Google Scholar PubMed  7. Slatter C, Girgis S, Huynh H, El-Matary W. Pre-pouch ileitis after colectomy in paediatric ulcerative colitis. Acta Paediatr  2008; 97: 381– 3. Google Scholar CrossRef Search ADS PubMed  8. Calabrese C, Fabbri A, Gionchetti Pet al.   Controlled study using wireless capsule endoscopy for the evaluation of the small intestine in chronic refractory pouchitis. Aliment Pharmacol Ther  2007; 25: 1311– 6. Google Scholar CrossRef Search ADS PubMed  9. Kuisma J, Järvinen H, Kahri A, Färkkilä M. Factors associated with disease activity of pouchitis after surgery for ulcerative colitis. Scand J Gastroenterol  2004; 39: 544– 8. Google Scholar CrossRef Search ADS PubMed  10. Iwata T, Yamamoto T, Umegae S, Matsumoto K. Pouchitis and pre-pouch ileitis developed after restorative proctocolectomy for ulcerative colitis: a case report. World J Gastroenterol  2007; 13: 643– 6. Google Scholar CrossRef Search ADS PubMed  11. Bell AJ, Price AB, Forbes A, Ciclitira PJ, Groves C, Nicholls RJ. Pre-pouch ileitis: a disease of the ileum in ulcerative colitis after restorative proctocolectomy. Colorectal Dis  2006; 8: 402– 10. Google Scholar CrossRef Search ADS PubMed  12. Samaan MA, de Jong D, Sahami Set al.   Incidence and severity of prepouch ileitis: a distinct disease entity or a manifestation of refractory pouchitis? Inflamm Bowel Dis  2016; 22: 662– 8. Google Scholar CrossRef Search ADS PubMed  13. Shen B, Fazio VW, Remzi FHet al.   Risk factors for clinical phenotypes of Crohn’s disease of the ileal pouch. Am J Gastroenterol  2006; 101: 2760– 8. Google Scholar CrossRef Search ADS PubMed  14. Wolf JM, Achkar JP, Lashner BAet al.   Afferent limb ulcers predict Crohn’s disease in patients with ileal pouch-anal anastomosis. Gastroenterology  2004; 126: 1686– 91. Google Scholar CrossRef Search ADS PubMed  15. Shen B, Bennett AE, Navaneethan Uet al.   Primary sclerosing cholangitis is associated with endoscopic and histologic inflammation of the distal afferent limb in patients with ileal pouch-anal anastomosis. Inflamm Bowel Dis  2011; 17: 1890– 900. Google Scholar CrossRef Search ADS PubMed  16. Dindo D, Demartines N, Clavien PA. Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg  2004; 240: 205– 13. Google Scholar CrossRef Search ADS PubMed  17. Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. Research electronic data capture [REDCap] - A metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform  2009; 42: 377– 81. Google Scholar CrossRef Search ADS PubMed  18. Hallak A, Baratz M, Santo Met al.   Ileitis after colectomy for ulcerative colitis or carcinoma. Gut  1994; 35: 373– 6. Google Scholar CrossRef Search ADS PubMed  19. McLaughlin SD, Clark SK, Bell AJ, Tekkis PP, Ciclitira PJ, Nicholls RJ. Incidence and short-term implications of prepouch ileitis following restorative proctocolectomy with ileal pouch-anal anastomosis for ulcerative colitis. Dis Colon Rectum  2009; 52: 879– 83. Google Scholar CrossRef Search ADS PubMed  20. Pardi DS, Sandborn WJ. Systematic review: the management of pouchitis. Aliment Pharmacol Ther  2006; 23: 1087– 96. Google Scholar CrossRef Search ADS PubMed  21. Odze RD. A contemporary and critical appraisal of ‘indeterminate colitis’. Mod Pathol  2015; 28[ Suppl 1]: S30– 46. Google Scholar CrossRef Search ADS PubMed  22. McLaughlin SD, Clark SK, Shafi Set al.   Fecal coliform testing to identify effective antibiotic therapies for patients with antibiotic-resistant pouchitis. Clin Gastroenterol Hepatol  2009; 7: 545– 8. Google Scholar CrossRef Search ADS PubMed  23. Herfarth HH, Long MD, Isaacs KL. Use of biologics in pouchitis: a systematic review. J Clin Gastroenterol  2015; 49: 647– 54. Google Scholar CrossRef Search ADS PubMed  24. Gionchetti P, Dignass A, Danese Set al.  ; ECCO. 3rd European evidence-based consensus on the diagnosis and management of Crohn’s disease 2016. Part 2: surgical management and special situations. J Crohns Colitis  2017; 11: 135– 49. Google Scholar CrossRef Search ADS PubMed  Copyright © 2017 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Crohn's and Colitis Oxford University Press

Prepouch Ileitis After Ileal Pouch-anal Anastomosis: Patterns of Presentation and Risk Factors for Failure of Treatment

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Copyright © 2017 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com
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10.1093/ecco-jcc/jjx140
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Abstract

Abstract Background and Aims There is a lack in the literature about prepouch ileitis [PI], in particular regarding risk factors associated with failure of the medical treatment. Aim of the study is to analyse the characteristics of PI patients and to compare those who required surgery with those who were successfully treated with conservative therapy. Methods All cases presenting a diagnosis of PI were included and analysed. Patients eventually requiring surgery were compared with those who were managed conservatively, for symptoms of presentation, endoscopic characteristics, and rate of response to medical treatment. A sub-analysis of outcomes based on the final histology was performed. Results The overall incidence of PI among 1286 patients was 4.4% [57], after a median of 6.8 years from pouch surgery. Symptoms included increased frequency [26.4%], outlet obstruction [21%], and bleeding [15.8%]. Afferent limb stenosis affected 49.1% of patients. The comparison showed that patients requiring surgery had a higher rate of Crohn’s disease and indeterminate colitis [42.1 vs 0% and 15.8 vs 2.6%, p < 0.0001], outlet obstruction as main symptom [47.4 vs 7.9%, p = 0.0023], and afferent limb stenosis [73.7 vs 36.8%, p = 0.008] at endoscopy. Rate of failure of medical treatment at 5 years was 8.2% in patients with ulcerative colitis and 75% in the presence of both indeterminate colitis and Crohn’s disease [p < 0.0001]. Conclusions Crohn’s disease, indeterminate colitis, and stenosis with outlet obstruction are risk factors for failure of treatment after diagnosis of PI. Early aggressive therapy and surgery should be considered in these cases. Prepouch ileitis, treatment, surgery 1. Introduction Restorative proctocolectomy and ileal pouch-anal anastomosis [IPAA] is the standard treatment for ulcerative colitis [UC] that is not responsive to medical treatment or is complicated by dysplasia or cancer.1 The surgery has excellent outcomes, and most patients are satisfied with their quality of life and would recommend the procedure to others.2,3 Pouchitis is the most frequent complication after restorative proctocolectomy, with up to 50% of the patients reporting at least one flare of pouchitis within the first 10 years after surgery, which might require aggressive treatment.4–6 Much less is known about the prepouch ileitis [PI], a different inflammatory complication that occurs after the construction of an ileal pouch; this has been reported quite recently in the literature, although a universally accepted definition for PI does not exist. However, PI is generally described as an acute or chronic inflammation of the afferent limb of the pouch, which is diagnosed at pouchoscopy and confirmed at the histological examination. The symptoms are not specific, and the aetiology is unknown. The signs of prepouch ileal inflammation include friable granular mucosa, ulcers, and strictures of the afferent limb, which could extend proximally for a few tens of centimetres.7–11 A recent multicentre study reported an incidence of PI of about 5%, and almost all those patients had concurrent pouchitis, suggesting a possible similar cause.12 Other authors hypothesised a strict correlation between the picture of PI and Crohn’s disease.13,14 Only few papers have been published in recent years about PI, with small groups of patients or just case reports. Moreover, there is a lack of data regarding the effectiveness of the treatments which are administered to patients depending on the predominant clinical picture associated with the PI. For instance, it is presumable that a severe inflammation might require an escalating medical treatment, whereas a fibrotic stenosis could benefit from an endoscopic dilatation. Should those treatments fail, surgery could represent the last resort to maintain the pouch. To date, there is a paucity of evidence in the literature regarding the identification of risk factors associated with the failure of conservative treatment and, therefore, the need of surgical therapy. The aim of the present study was to identify the patients with a diagnosis of prepouch ileitis from a single large tertiary centre, and to compare those who required surgery for refractory PI with those who were successfully treated with conservative treatment, regarding patients’ characteristics, patterns of presentation, and outcomes. 2. Materials and Methods From a prospectively maintained database, all patients who had a reported diagnosis of prepouch ileitis were evaluated. The data were collected from 1989. The suspicion of PI usually arose at the follow-up endoscopy, and a confirmation of acute inflammation at the histological examination of the biopsy was required in order for the patients to be included in the study. In literature, no shared definition of PI exists. According to Shen et al., PI could be classified as an active inflammation of the afferent limb at the endoscopy, which is confirmed at the pathological examination.15 This definition was subsequently used by other authors.12 We agreed with those authors and did not require any specific symptom score in order for PI to be diagnosed. Exclusion criteria include the lack of details of the primary IPAA surgery and of PI treatment and response. Demographic and perioperative variables, including the presence of comorbidities, pre- and postoperative diagnosis, pre- and postoperative use of immunosuppressive or biologic drugs, and postoperative outcomes were evaluated. In particular, the incidence of long-term complications and the need of reoperations were accurately recorded. Postoperative complications were grouped according to the Clavien-Dindo classification.16 The date of the onset of PI was defined as the first diagnosis at endoscopy. The main symptoms associated with the endoscopic picture were recorded, and the conservative treatments were grouped into antibiotics, steroids, immunosuppressors [azathioprine, 6-mercaptopurin and methotrexate], anti-tumour necrosis factor [TNF]-alpha and endoscopic dilatations. In particular, the dilatations were performed in the presence of a symptomatic stenosis of the afferent limb extending for less than 5 cm. The success of the therapy was defined as an improvement of the symptoms and the signs of disease at the endoscopy. Failure was considered as the need to escalate to a different medical treatment or surgery due to the persistence of the symptoms. The need to repeat the same treatment was not considered a failure, as long as it eventually led to an improvement of symptoms. On the contrary, no matter if the same treatment was previously successful, should an escalation of therapy be required during the subsequent follow-up time, that treatment was marked as a failure. The retrospective nature of the study could not allow any more specific classification. When any possible conservative treatment failed, the patients could have either undergone a ‘therapeutic’ surgery [re-do pouch or pouch repair, stricturoplasty of the afferent limb, or resection and new ileal-pouch anastomosis] or experienced a pouch failure, which was defined as the need of a permanent stoma with or without the excision of the pouch. Variables were presented as median [range] or number [%]. Comparison of categorical variables was analysed with chi square or Fisher’s exact test as appropriate, and the Wilcoxon rank sum test was used for quantitative and ordinal variables. The KaplanMeier method was performed to analyse the rate of failure of the conservative treatments and the rate of pouch failure according to the final histological diagnosis. A p-value < 0.05 was considered significant. Statistical analyses were performed using JMP version 11 [SAS Institute, Cary, NC, USA]. Study data were collected and managed using REDCap [Research Electronic Data Capture] tools hosted at Alma Mater Studiorum University of Bologna.17 3. Results Between 1989 and 2016, 1286 patients underwent an IPAA formation in our centre. After review of the data and application of the exclusion criteria, 57 cases of PI were identified. Of those, eight patients had a definitive diagnosis of Crohn’s disease after the onset of PI [either confirmed at the histological examination of biopsies or after the excision of the pouch], whereas in four cases the initial diagnosis of indeterminate colitis was maintained during the follow-up. The overall incidence of PI was therefore 4.4%. The demographic characteristics and perioperative details of these patients are summarized in Table 1. Table 1. Demographic and perioperative characteristics at the time of pouch formation and follow-up.   N or median  % or range  Age  33  18–66  Male gender  36  63.1%  BMI [kg/m2]  22  13–27  Immunosuppressants at surgery  11  24.4%  Anti TNF-alpha at surgery  4  8.9%  J pouch design  56  98.2%  Hand-sewn anastomosis  9  15.8%  Postoperative complications  10  17.5%  Clavien-Dindo classification       Grade II  6  10.5%   Grade IIIb  4  7%  Length of hospital stay [days]  12  7–30  Final histopathology       Ulcerative colitis  45  79%   Indeterminate colitis  4  7%   Crohn’s disease  8  14%  Length of follow-up from IPAA[months]  222  20–354  Length of follow-up from diagnosis of PI [months]  119  8–293    N or median  % or range  Age  33  18–66  Male gender  36  63.1%  BMI [kg/m2]  22  13–27  Immunosuppressants at surgery  11  24.4%  Anti TNF-alpha at surgery  4  8.9%  J pouch design  56  98.2%  Hand-sewn anastomosis  9  15.8%  Postoperative complications  10  17.5%  Clavien-Dindo classification       Grade II  6  10.5%   Grade IIIb  4  7%  Length of hospital stay [days]  12  7–30  Final histopathology       Ulcerative colitis  45  79%   Indeterminate colitis  4  7%   Crohn’s disease  8  14%  Length of follow-up from IPAA[months]  222  20–354  Length of follow-up from diagnosis of PI [months]  119  8–293  BMI, body mass index; TNF, tumour necrosis factor; IPAA, ileal pouch-anal anastomosis; PI, prepouch ileitis. View Large The great majority of patients had a J pouch [98.2%] and a stapled anastomosis [84.2%]. A reoperation for postoperative complications was necessary in four patients [7%]. The clinical and endoscopic characteristics of presentation of PI are shown in Table 2. PI was diagnosed after a median of 6.8 years from the formation of the pouch, and a great percentage of patients did not report any specific symptom [36.8%]. At the endoscopy, pouchitis was seen in 86% of patients, and other abnormalities of the pouch [anastomotic stricture, pouch stenosis, or dilatation] were observed in 33.3% of cases. A stenosis of the afferent limb was diagnosed in 49.1% of patients. The disease of the afferent limb extended proximally for up to 30 cm [median 15 cm]. Table 2. Characteristics of disease at time of diagnosis of PI.   N or median  % or range  Interval between IPAA and diagnosis of PI [years]  6.8  0.7–21.9  Main symptom of PI   No symptoms  21  36.8%   Increased frequency  15  26.4%   Outlet obstruction  12  21%   Bleeding  9  15.8%  Endoscopic characteristics at diagnosis of PI   Anastomotic stricture  9  15.8%   Pouch stenosis  4  7%   Pouch dilatation  6  10.5%   Pouchitis  49  86%   Afferent limb stenosis  28  49.1%   Afferent limb ulcers  48  84.2%  Median length of diseased proximal bowel [cm]  15  2–30    N or median  % or range  Interval between IPAA and diagnosis of PI [years]  6.8  0.7–21.9  Main symptom of PI   No symptoms  21  36.8%   Increased frequency  15  26.4%   Outlet obstruction  12  21%   Bleeding  9  15.8%  Endoscopic characteristics at diagnosis of PI   Anastomotic stricture  9  15.8%   Pouch stenosis  4  7%   Pouch dilatation  6  10.5%   Pouchitis  49  86%   Afferent limb stenosis  28  49.1%   Afferent limb ulcers  48  84.2%  Median length of diseased proximal bowel [cm]  15  2–30  IPAA: ileal pouch-anal anastomosis; PI: prepouch ileitis. View Large Table 3 reports the distribution of the antibiotic, steroid, immunosuppressive, and biologic treatments, as well as the rate of the endoscopic dilatations and the failure rate of each of these therapies. At a median of 48.7 months for the diagnosis of PI, a total of 19 patients either experienced a pouch failure or underwent surgery in order to manage an otherwise refractory PI, either a pouch failure surgery in order to manage a otherwise refractory PI. In those cases, obviously, no conservative treatment was considered successful in the long-term. Table 3. Type of conservative treatments and percentage of failure in patient with a diagnosis of PI [excluding patients with Crohn’s disease].   Number of cases [%]  Percentage of failure [%]  Antibiotics  45 [91.8%]  54.3%  Oral or intravenous steroids  27 [56.2%]  74.1%  Immunosuppressants  9 [18.8%]  66.7%  Anti TNF-alpha  12 [25%]  76.9%  Endoscopic dilatation  7 [14.3%]  50%    Number of cases [%]  Percentage of failure [%]  Antibiotics  45 [91.8%]  54.3%  Oral or intravenous steroids  27 [56.2%]  74.1%  Immunosuppressants  9 [18.8%]  66.7%  Anti TNF-alpha  12 [25%]  76.9%  Endoscopic dilatation  7 [14.3%]  50%  View Large A pouch failure was therefore observed in eight cases [three pouch excisions and five formations of permanent ileostomy]. Of the other 11 patients, seven underwent a resection of the afferent limb, three a stricturoplasty of the limb stenosis, and one a re-do pouch with excision of the afferent limb. In total, an associated pouch repair was necessary in six cases [the already mentioned re-do pouch and five excisions of redundant cul-de-sac] [Table 4]. All patients who were diagnosed with Crohn’s disease eventually underwent surgery, and 50% of them had a pouch failure at time of surgery. Table 4. Type of surgical procedures performed for patients who failed conservative treatment.   N or median  % or range  Interval from diagnosis of PI [months]  48.7  6–161  Need of surgery for failure of treatment  19  33.3%  Pouch failure  8  14%   Pouch excision  3/8  37.5%   Permanent ileostomy  5/8  62.5%  Therapeutic surgical treatment  11  19.3%   Ileal resection and anastomosis  7/11  63.6%   Stricturoplasty  3/11  27.3%   Re-do pouch  1/11  9.1%   Associated pouch repair  6/11  54.5%    N or median  % or range  Interval from diagnosis of PI [months]  48.7  6–161  Need of surgery for failure of treatment  19  33.3%  Pouch failure  8  14%   Pouch excision  3/8  37.5%   Permanent ileostomy  5/8  62.5%  Therapeutic surgical treatment  11  19.3%   Ileal resection and anastomosis  7/11  63.6%   Stricturoplasty  3/11  27.3%   Re-do pouch  1/11  9.1%   Associated pouch repair  6/11  54.5%  View Large The univariate comparisons between patients requiring surgery and those who were managed with conservative treatment are shown in Tables 5 and 6. Patients who eventually had surgery were characterised by a significantly higher rate of American Society of Anesthesiologists [ASA] score 3 [p = 0.041], a final diagnosis of indeterminate colitis and Crohn’s disease [p < 0.0001], outlet obstruction as presenting symptom [p = 0.0023], pouch dilatation [p = 0.006], and afferent limb stenosis [p = 0.008] at the endoscopy. These patients experienced a significantly lower rate of 30-day postoperative complications after IPAA and had a lower rate of pouchitis at the time of diagnosis of PI [68.4 vs 94.8%, p = 0.0056]. Table 5. Comparison of perioperative variables and characteristics of disease between patients who underwent successful conservative treatment and those who required surgery.   Conservative treatment  Surgical treatment  p-value  Number of patients  38  19    Median age  34.5 [18–58]  24 [18–66]  0.81  Male gender  26 [68.4%]  10 [52.6%]  0.24  ASA score 3  1 [2.6%]  4 [26.7%]  0.041  Median BMI  22 [13–27]  22 [17–26]  0.5  Hand-sewn anastomosis  7 [18.4%]  2 [10.5%]  0.44  30-day complication rate  10 [26.3%]  0  0.013  Final histological diagnosis      < 0.0001  Ulcerative colitis  37 [97.4%]  8 [42.1%]    Indeterminate colitis  1 [2.6%]  3 [15.8%]    Crohn’s disease  0  8 [42.1%]    Interval between IPAA and diagnosis of PI [months]  96.2 [ ± 69.4]  86.1 [ ± 73.2]  0.68  Main symptom of PI      0.0023   No symptoms  18 [47.3%]  3 [15.8%]     Outlet obstruction  3 [7.9%]  9 [47.4%]     Increased frequency  12 [31.6%]  3 [15.8%]     Bleeding  5 [13.2%]  4 [21%]    Concurrent pouchitis  36 [94.8%]  13 [68.4%]  0.0056  IPAA stenosis  6 [15.8%]  3 [15.8%]  0.99  Pouch stenosis  2 [5.2%]  2 [15.5%]  0.46  Pouch dilatation  1 [2.6%]  5 [26.3%]  0.006  Afferent limb stenosis  14 [36.8%]  14 [73.7%]  0.008  Afferent limb ulcers  34 [89.5%]  14 [73.7%]  0.12    Conservative treatment  Surgical treatment  p-value  Number of patients  38  19    Median age  34.5 [18–58]  24 [18–66]  0.81  Male gender  26 [68.4%]  10 [52.6%]  0.24  ASA score 3  1 [2.6%]  4 [26.7%]  0.041  Median BMI  22 [13–27]  22 [17–26]  0.5  Hand-sewn anastomosis  7 [18.4%]  2 [10.5%]  0.44  30-day complication rate  10 [26.3%]  0  0.013  Final histological diagnosis      < 0.0001  Ulcerative colitis  37 [97.4%]  8 [42.1%]    Indeterminate colitis  1 [2.6%]  3 [15.8%]    Crohn’s disease  0  8 [42.1%]    Interval between IPAA and diagnosis of PI [months]  96.2 [ ± 69.4]  86.1 [ ± 73.2]  0.68  Main symptom of PI      0.0023   No symptoms  18 [47.3%]  3 [15.8%]     Outlet obstruction  3 [7.9%]  9 [47.4%]     Increased frequency  12 [31.6%]  3 [15.8%]     Bleeding  5 [13.2%]  4 [21%]    Concurrent pouchitis  36 [94.8%]  13 [68.4%]  0.0056  IPAA stenosis  6 [15.8%]  3 [15.8%]  0.99  Pouch stenosis  2 [5.2%]  2 [15.5%]  0.46  Pouch dilatation  1 [2.6%]  5 [26.3%]  0.006  Afferent limb stenosis  14 [36.8%]  14 [73.7%]  0.008  Afferent limb ulcers  34 [89.5%]  14 [73.7%]  0.12  Variables are expressed as number [%] or mean [± standard deviation]. ASA, American Society of Anesthesiologists; BMI, body mass index; IPAA, ileal pouch-anal anastomosis; PI, prepouch ileitis. View Large Table 6. Comparison of types of treatments between patients who underwent successful conservative treatment and those who required surgery.   Conservative treatment  Surgical treatment  p-value  Type of treatment   Antibiotics  35 [92.1%]  14 [73.6%]  0.05   Oral or intravenous steroids  19 [50%]  15 [83.3%]  0.017   Immunosuppressants  6 [15.8%]  7 [36.8%]  0.08   Anti TNF-alpha  7 [18.4%]  8 [44.4%]  0.040   Endoscopic dilatation  5 [13.2%]  5 [27.8%]  0.18    Conservative treatment  Surgical treatment  p-value  Type of treatment   Antibiotics  35 [92.1%]  14 [73.6%]  0.05   Oral or intravenous steroids  19 [50%]  15 [83.3%]  0.017   Immunosuppressants  6 [15.8%]  7 [36.8%]  0.08   Anti TNF-alpha  7 [18.4%]  8 [44.4%]  0.040   Endoscopic dilatation  5 [13.2%]  5 [27.8%]  0.18  TNF, tumour necrosis factor View Large After the exclusion from the analysis of patients with a diagnosis of indeterminate colitis and Crohn’s disease, the presentation with outlet obstruction [37.5 vs 8.1%, p = 0.017], the absence of pouchitis [25 vs 5.4%, p = 0.050], the presence of pouch dilatation at the endoscopy [37.5 vs 2.7%, p = 0.0017] were significantly associated with the need of surgery. A sub-comparison between cases with a diagnosis of ulcerative colitis and indeterminate colitis showed that the latter was associated with a significantly lower rate of pouchitis [50 vs 91.1%, p = 0.016], a higher rate of ulcers in the proximal limb [50% vs 4.4%], and a shorter interval between IPAA and PI diagnosis [3.2 vs 7.3 years, p = 0.011] and between PI diagnosis and surgery [2 vs 7 years, p = 0.018]. Patients with a diagnosis of Crohn’s disease were more likely to present with afferent limb stenosis [75% vs 42.2%, p = 0.041] than those who had ulcerative colitis. The analysis of the risk of failure of medical treatment after the diagnosis of PI showed an overall chance of having surgery of 5.3%, 9.3%, 24.5%, 35.3%, and 47% at 1, 2, 5, 10, and 15 years, respectively. The sub-analyses of the risk of surgery and pouch failure sorted by histological diagnosis are shown in Figures 1 and 2 and Table 7. Table 7. Comparison of risk of failure of the conservative treatment and risk of pouch failure at 1, 2, 5, and 10 years according to the final histological diagnosis, based on the Kaplan-Meier curve.   Ulcerative colitis  Indeterminate colitis  Crohn’s disease  p-value  Failure of conservative treatment        < 0.0001   1 year  0%  25%  25%     2 years  2.5%  50%  37.5%     5 years  8.2%  75%  75%     10 years  19.7%  75%  87.5%    Pouch failure        < 0.0001   1 year  0%  0%  12.5%     2 years  0%  33%  12.5%     5 years  0%  33%  47.5%     10 years  6.3%  33%  47.5%      Ulcerative colitis  Indeterminate colitis  Crohn’s disease  p-value  Failure of conservative treatment        < 0.0001   1 year  0%  25%  25%     2 years  2.5%  50%  37.5%     5 years  8.2%  75%  75%     10 years  19.7%  75%  87.5%    Pouch failure        < 0.0001   1 year  0%  0%  12.5%     2 years  0%  33%  12.5%     5 years  0%  33%  47.5%     10 years  6.3%  33%  47.5%    View Large Figure 1. View largeDownload slide Risk of surgery for failed conservative treatment in patients with PI over a 15-year follow-up according to the final histological diagnosis. UC:,ulcerative colitis; IC, indeterminate colitis; CD, Crohn’s disease, PI: prepouch ileitis. Figure 1. View largeDownload slide Risk of surgery for failed conservative treatment in patients with PI over a 15-year follow-up according to the final histological diagnosis. UC:,ulcerative colitis; IC, indeterminate colitis; CD, Crohn’s disease, PI: prepouch ileitis. Figure 2. View largeDownload slide Rate of pouch survival in patients with PI over a 15-year follow-up according to the final histological diagnosis. UC, ulcerative colitis; IC, indeterminate colitis; CD, Crohn’s disease; PI, prepouch ileitis. Figure 2. View largeDownload slide Rate of pouch survival in patients with PI over a 15-year follow-up according to the final histological diagnosis. UC, ulcerative colitis; IC, indeterminate colitis; CD, Crohn’s disease; PI, prepouch ileitis. 4. Discussion Despite prepouch ileitis having been first described over two decades ago,18 the doubts regarding the nature of this complication, that specifically affects the afferent limb of bowel to the pouch, still outnumber the certainties. The reasons could be found in the relative low frequency and the lack of a definition of the disease, as well as of specific endoscopic or clinical scores. Moreover, as already highlighted by other authors, most of the times the endoscopy does not explore the afferent limb of bowel, and some of the symptoms could be easily associated with a concurrent pouchitis.11 Our experience confirmed that, at the moment, a generic definition of PI is necessary, as the endoscopic finding is not associated with any specific symptom in almost 40% of patients. Other symptoms, such as bleeding or an increased frequency of bowel movement, could likely make the physician suspect the presence of pouchitis. The fact that pouchitis is seen at endoscopy in the great majority of patients increases the chance of misdiagnosis. McLaughlin et al. reported the findings of 34 patients with a diagnosis of PI among 742 IPAA cases seen at St Mark’s Hospital.19 Similarly, 18% of them did not report any particular symptom, and all PI patients had pouchitis as well. The evidence that PI is likely to be associated with pouchitis led the authors to presume a common cause. However, a subsequent study compared PI and pouchitis patients and found that the former had a greater chance of undergoing steroid or immunomodulator therapy to control the symptoms, suggesting at least a more aggressive behaviour of PI. This multicentre retrospective study analysed a cohort of 546 patients who had IPAA surgery in three European centres.12 The present study includes almost 1300 IPAA procedures performed in a tertiary centre from 1989. All patients have been treated and followed by the same team of surgeons and gastroenterologists, reducing the case-mix bias and the differences in diagnosis and maintaining a similar strategy of therapy among cases. In the past, some authors assumed a correlation between Crohn’s disease and PI.14,20 In this series, eight patients had a final diagnosis of Crohn’s disease after the onset of PI, which was confirmed either through biopsies or the surgical specimen after resection. These cases, as expected, were associated with poor outcomes after both conservative and surgical treatment. The most interest finding was that indeterminate colitis had a similar trend towards the failure of treatment and, eventually, of the pouch, compared with Crohn’s disease. As shown in Figures 1 and 2, the curves are basically overlapping, especially when the outcome of the conservative treatment is analysed. Some of the characteristics of presentation are also similar between cases with indeterminate colitis and Crohn’s disease, which were both more likely to present with stricture of the afferent limb and outlet obstruction at the time of diagnosis of PI, when compared with patients with ulcerative colitis. Another interesting result was that, unlike ulcerative colitis that was associated with pouchitis in a great majority of patients [91.1%], Crohn’s disease and especially indeterminate colitis had a weaker association with inflammation of the pouch [75% and 50%, respectively], suggesting a different aetiology and confirming that, in these cases, indeterminate colitis might represent a misdiagnosed Crohn’s disease. The causes of uncertainty in IBD pathology that led to a diagnosis of indeterminate colitis at the time of colectomy included toxic colitis, the lack of pathognomonic clinical, radiological, and endoscopic pictures and, in particular, failure to recognise the classic features of Crohn’s disease or ulcerative colitis in the histological examination of the colon and rectum. The main features of Crohn’s disease include deep fissures, fistulas, the presence of segmental disease, the lack of involvement of the rectum, and the finding of transmural lymphoid aggregates and epithelioid granulomas. Concomitant upper gastrointestinal manifestations or perianal disease could also suggest a diagnosis of Crohn’s disease. The increasing finding of unusual pathological variants of IBD [UC with Crohn’s disease-like features and Crohn’s disease with UC-like features], which seem to be associated with the widespread use of biologic treatments, makes sometimes the chance of having a definite diagnosis hard even in the hands of an expert pathologist.21 The findings of the present study suggest that, in this specific subpopulation of IBD patients, indeterminate colitis behaves like Crohn’s disease, and it would be safe to assume that, despite the lack of a final diagnosis, the onset of PI in the presence of indeterminate colitis strongly suggests an underlying Crohn’s disease and should be dealt with accordingly. Consequently, it might be equally safe to conclude that, in the presence of a positive diagnosis of ulcerative colitis, PI is not the manifestation of a misdiagnosed Crohn’s disease as suggested by other authors, but it should be considered a condition per se that requires appropriate treatment and follow-up, and is associated with good long-term outcomes in terms of need of surgery and pouch failure [8.2% and 0% at 5 years, respectively]. In these cases, pouchitis is often present, suggesting a possible similar cause. However, although the majority of patients with pouchitis usually respond very well to antimicrobial therapy,22 in the present series over 50% of patients did not have a clinical remission after antibiotic treatment. In addition, immunosuppressors and anti TNF-alpha drugs were even less effective in these cases. A recent review of the literature showed a good clinical effectiveness of infliximab in the treatment of chronic refractory pouchitis, achieving up to 80% and 50% of response at short- and long-term follow-up, respectively. The review included patients who presented with Crohn’s-like complications of the pouch [stricturing or fistulising disease], confirming a good response in this subgroup as well.23 In the present study, the response to biologic drugs was less than 25%, even after exclusion of patients with a diagnosis of Crohn’s disease. Overall, in 67.7% of patients, the condition was managed through conservative treatment, but no specific therapy was proven to be more effective than others. The lack of response of PI to medical treatment, in particular antibiotics and infliximab, highlights a major difference between this condition and pouchitis. Although the frequent coexistence of the two complications might suggest a common cause, it is possible that, in susceptible patients, the inflammatory involvement of the afferent limb could at some point develop as an independent, more aggressive condition, especially when it is associated with stenosis and outlet obstruction. It is important to emphasise that the retrospective nature of the study, and the fact that several recurrences of PI might be seen during follow-up, forced a simplification of the presentation of treatment and outcomes. The need for escalation of treatment during the same presentation of disease was considered a failure, regardless of previous successful responses to the same treatment. However, many patients underwent more than one type of treatment, and the change of therapy does not necessarily reflect a failure of the previous medication. As often observed in the case of pouchitis, PI might present in several subsequent flare-ups, and new drugs could be used in order to control the symptoms even if other medications were previously administered with success. Moreover, some of these patients were diagnosis with PI before the introduction of the biologic drugs, and might have undergone those treatments only after years, in an advanced stage of the disease, when the fibrosis associated with chronic inflammation does not respond to the treatment. This study included a group of patients with specific symptoms of outlet obstruction [21%] and an endoscopic finding of stenosis or sub-stenosis of the afferent limb [49.1%]. Stenosis was found in 75% of both indeterminate colitis and Crohn’s disease patients. All these patients required surgery. Among patients with ulcerative colitis, the incidence of stenosis of the afferent limb remained high [19, 42.2%]; however, only five of these cases [26.3%] required surgery. A possible explanation for this difference might be found in the rate of patients presenting with outlet obstruction, meaning a more severe stenosis of the afferent limb, which was 13.3% among UC patients [vs 50% in Crohn’s and indeterminate colitis patients]. Outlet obstruction should be therefore considered as a strong risk factor for failure of medical treatment. Endoscopic dilatation can be attempted in order to improve the symptoms, when the stricture is shorter than 5 cm and amenable to dilation. The procedure, however, was effective in the long-term only in 37.4% of cases. The success rate increased to 50% when excluding patients with Crohn’s disease. The univariate comparison between patients requiring surgery and those who were managed conservatively, showed few important differences that might help the clinicians to predict a worse outcome at the diagnosis of PI. Apart from indeterminate colitis and Crohn’s disease, which were the strongest factors associated with a PI not responsive to medical treatment [p = 0.018], the outlet obstruction at presentation [p = 0.0085], the stenosis of the afferent limb [p = 0.035] and pouch dilatation [p = 0.0086] also played an important role in the failure of conservative treatment. Interestingly, a concurrent pouchitis was associated with a higher chance of a successful conservative treatment [p = 0.0056]. PI has an erratic pattern of presentation after IPAA. Although the median time of observation from the pouch surgery is about 7 years, some patients were diagnosed after only 8 months and others after over 20 years. The analysis of the distribution of treatment failure showed a similar trend towards a progressive, continuous incidence during follow-up after the diagnosis of PI, with a chance of having had surgery of 35.3% at 10 and 47% at 15 years. A comparison between cases who had an “early” onset [arbitrarily chosen as less than 5 years] and the others did not show any difference in outcomes. A proposed algorithm of treatment for patients diagnosed with PI is reported in Figure 3. Patients with a definitive diagnosis of UC, whose endoscopy shows ulcers, oedema, or friability of the afferent limb, without symptoms of outlet obstruction, should be treated following the European Crohn’s and Colitis Organisation guidelines for pouchitis.24 Figure 3. View largeDownload slide Proposed algorithm of treatment for patients with a diagnosis of PI [prepouch ileitis]. Figure 3. View largeDownload slide Proposed algorithm of treatment for patients with a diagnosis of PI [prepouch ileitis]. Stenosis or sub-stenosis of the afferent limb, which must be suspected in the presence of outlet obstruction symptoms, should be addressed more aggressively in consideration of the higher chance of failure of treatment. In suitable cases, when the stenosis is shorter than 5 cm, endoscopic dilatation should be attempted. However, this subgroup of patients are more likely to require surgery, which could also be proposed at an early stage in order to improve the patient’s quality of life. In the presence of Crohn’s disease, failure of the medical treatment is almost certain and therefore surgery should be considered as a primary option. The role of indeterminate colitis is still to be clarified but, taking into consideration the high risk of failure and the Crohn’s-like behaviour, early aggressive medical and surgical treatment should be considered. 5. Conclusions PI is an inflammatory complication of the pouch that occurs in a limited number of patients, but could be associated with high rate of surgery or pouch failure especially in the presence of outlet obstruction. Crohn’s disease and indeterminate colitis are associated with a greater chance of failure of treatment, and should be addressed appropriately. Funding No funding in any form was received for the study. Conflict of Interest None. Author Contributions MR: concept and design of the study; acquisition of data; analysis and interpretation of data; drafting the article; final approval of the version to be submitted. CV: acquisition of data; drafting the article; final approval of the version to be submitted. EB: acquisition of data; drafting the article; final approval of the version to be submitted, PG: concept and design of the study; revising it critically for important intellectual content; final approval of the version to be submitted. FR: concept and design of the study; revising it critically for important intellectual content; final approval of the version to be submitted. MPS: concept and design of the study; revising it critically for important intellectual content; final approval of the version to be submitted. GP: concept and design of the study; revising it critically for important intellectual content; final approval of the version to be submitted. A part of this study was presented as a digital oral presentation at the 12th congress of ECCO [European Crohn’s and Colitis Organisation], Barcelona, Spain, February 1518, 2017. Acknowledgments REDCap [Research Electronic Data Capture] is a secure, web-based application designed to support data capture for research studies, providing: 1] an intuitive interface for validated data entry; 2] audit trails for tracking data manipulation and export procedures; 3] automated export procedures for seamless data downloads to common statistical packages; and 4] procedures for importing data from external sources. RecCap is hosted at Alma Mater Studiorum University of Bologna. References 1. 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A proposed classification of ileal pouch disorders and associated complications after restorative proctocolectomy. Clin Gastroenterol Hepatol  2008; 6: 145– 58; quiz 124. Google Scholar CrossRef Search ADS PubMed  6. Gionchetti P, Calafiore A, Riso Det al.   The role of antibiotics and probiotics in pouchitis. Ann Gastroenterol  2012; 25: 100– 5. Google Scholar PubMed  7. Slatter C, Girgis S, Huynh H, El-Matary W. Pre-pouch ileitis after colectomy in paediatric ulcerative colitis. Acta Paediatr  2008; 97: 381– 3. Google Scholar CrossRef Search ADS PubMed  8. Calabrese C, Fabbri A, Gionchetti Pet al.   Controlled study using wireless capsule endoscopy for the evaluation of the small intestine in chronic refractory pouchitis. Aliment Pharmacol Ther  2007; 25: 1311– 6. Google Scholar CrossRef Search ADS PubMed  9. Kuisma J, Järvinen H, Kahri A, Färkkilä M. Factors associated with disease activity of pouchitis after surgery for ulcerative colitis. Scand J Gastroenterol  2004; 39: 544– 8. 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Journal of Crohn's and ColitisOxford University Press

Published: Mar 1, 2018

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