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Postoperative Crohn’s disease, recurrence rate and risk factors
Sophie Jaspers s1646524
University of Groningen
Inflammatory Bowel Disease (IBD) Centre Department of gastroenterology
Academic Medical Centre (AMC), Amsterdam 01-07-2014 – 17-11-2014
Daily supervisors: dr. M. Duijvestein, MD/PhD, Gastroenterologist in training
Prof. Dr. G.R.A.M. D’Haens, MD/PhD, Gastroenterologist Faculty supervisor: I.M. Nijholt, PhD, Education coordinator Zwolle
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Abstract Background and aims Despite advances in medical management, many patients with Crohn’s disease (CD) require intestinal surgery during the course of the disease. Surgery is not a cure and postoperative recurrence is common in patients with CD. Ileocolonoscopy is the gold standard in the diagnosis of postoperative recurrence. There are numerous studies that report numbers of postoperative recurrence, but with varying results. Also previous studies that focus on risk factors for postoperative recurrence have given inconclusive results. The aim of this study was to retrospectively determine the endoscopic and symptomatic recurrence rate as well as to identify risk factors. Materials and methods We conducted a retrospective cohort study including 156 patients with CD who underwent an ileocecal resection between 2008 and 2013 in two referral centres. Symptomatic recurrence rates in this group were calculated. Of these, 105 patients had undergone an ileocolonoscopy within two years postoperatively and in this group endoscopic recurrence rates were calculated. To identify risk factors for endoscopic recurrence, data were compared between recurrence (modified Rutgeerts score ≥i2b) and no recurrence (modified Rutgeerts score <i2b). We also compared data to identify risk factors for symptomatic recurrence. Clinical phenotypes were classified according to the Montreal classification (age at diagnosis, location of disease and disease behaviour). Gender, family history of inflammatory bowel disease (IBD), smoking behaviour, history of previous resection(s), surgery indication, type of anastomosis, ileum length resected and postoperative use of medication were analysed as possible risk factors. Results In 105 patients, the overall endoscopic recurrence rate was 38.1%, whereas the symptomatic recurrence rate was 17.1% (in 156 patients). The endoscopic recurrence rate in patients who used postoperative biologics was 26.3%, 23.8% in patients who used immunomodulators and 51.9% in patients without postoperative medication. Only smoking the year before surgery (OR; 3.590, 95% CI 1.269-10.233, p=0.017) seemed to be a significant risk factor in the multivariate analysis for risk factors for endoscopic recurrence. Postoperative use of medication was a protective factor (not significant, but a trend), which reduced the risk with 63.1%. In the multivariate analysis for symptomatic recurrence, smoking the year before surgery (OR; 3.809, 95% CI 1.346-10.781, p=0.012) and disease behaviour (OR; 4.777, 95% CI 1.206-18.920, p=0.026) appeared to be significant risk factors. Also medication was a protective factor (OR; 0.215, 95% CI 0.071-0.658, p=0.007). Conclusion This retrospective multicentre cohort study is the first study that used the modified Rutgeerts score to evaluate endoscopic recurrence. The endoscopic as well as the symptomatic recurrence rates found were both lower than in previous studies. Prospective studies are indicated to evaluate the endoscopic recurrence rate (with the modified Rutgeerts score), to make sure every patient will undergo an ileocolonoscopy (at the same time) and thus have an even more reliable result. Based on our study, special attention should be paid in the postoperative phase to patients with smoking habits. An early start with immunomodulators or anti-tumor necrosis factor (TNF) therapy among these patients should be taken into consideration.
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Samenvatting (Nederlands) Achtergrond en doel Ondanks de vooruitgang in de medische behandeling, moeten veel patiënten met de ziekte van Crohn (ZvC) uiteindelijk toch geopereerd worden. Een operatie is niet per definitie een genezing en postoperatieve terugkeer van de ziekte komt vaak voor. Ileocolonoscopie is de gouden standaard voor het vaststellen van postoperatieve terugkeer van de ZvC. Er zijn tal van studies die aantallen van postoperatieve terugkeer van de ZvC vermelden, maar met wisselende resultaten. Ook eerdere studies die focussen op risicofactoren voor postoperatieve terugkeer geven geen eenduidige resultaten. Het doel van deze studie was om retrospectief de endoscopische en symptomatische terugkeer van de ziekte te evalueren, alsmede het identificeren van risicofactoren voor postoperatieve terugkeer van de ZvC. Materiaal en methode We voerden een retrospectieve cohort studie uit waarbij 156 patiënten met de ZvC werden geïncludeerd die een ileocecaal resectie ondergingen tussen 2008 en 2013 in twee referentiecentra. In deze groep werd de symptomatische terugkeer van de ziekte bepaald. Bij 105 patiënten was een ileocolonoscopie verricht binnen twee jaar postoperatief en in deze groep werd de endoscopische terugkeer van de ziekte bepaald. Om risicofactoren voor een endoscopisch recidief te identificeren, werden data vergeleken tussen de groep met terugkeer (‘modified Rutgeerts score’ ≥ i2b) en zonder terugkeer (‘modified Rutgeerts score’ <i2b). Ook werden data vergeleken om risicofactoren voor een symptomatisch recidief te identificeren. Klinische fenotypes werden geclassificeerd volgens de Montreal classificatie (leeftijd van diagnose, locatie van de ziekte en ziekte gedrag). Geslacht, familiegeschiedenis van inflammatoire darmziekten (IBD), rookgedrag, een voorgeschiedenis van eerdere resectie(s), operatie indicatie, soort anastomose, lengte van het gereseceerde ileum en postoperatief gebruik van medicatie werden geanalyseerd als potentiele risicofactoren. Resultaten Van de 105 patiënten had 38.1% een endoscopisch recidief, terwijl 17.1% (van de 156 patiënten) een symptomatisch recidief had. Het endoscopische recidief bij patiënten die postoperatief biologicals gebruikten was 26.3%, 23.8% bij de patiënten die immunosuppressiva gebruikten en 51.9% bij de patiënten zonder postoperatieve medicatie. Alleen roken het jaar voor de operatie (OR; 3.590, 95% CI 1.269-10.233, p=0.017) bleek een significante risicofactor in de multivariabele analyse voor risicofactoren voor een endoscopisch recidief. Het postoperatief gebruik van medicatie was een beschermende factor (niet significant, maar wel een duidelijke trend), waarbij het risico afnam met 63.1%. In de multivariabele analyse voor een symptomatisch recidief waren roken het jaar voor de operatie (OR; 3,809, 95% CI 1,346-10,781, p = 0.012) en penetrerende ziekte (OR; 4,777, 95% CI 1,206-18,920, p=0.026) beide risicofactoren. Ook medicatie was een beschermende factor (OR; 0.215, 95% CI 0,071-0,658, p=0.007). Conclusie Deze retrospectieve multicenter cohort studie is de eerste studie die de ‘modified Rutgeerts score’ gebruikt om endoscopisch recidief te evalueren. Het percentage van de patiënten met een endoscopisch en symptomatisch recidief hier gevonden, is lager dan wat is gevonden in eerdere onderzoeken. Prospectieve studies zijn geïndiceerd om het endoscopisch recidief te evalueren (met de ‘modified Rutgeerts score’) om er zeker van te zijn dat elke patiënt een ileocolonoscopie ondergaat (op hetzelfde tijdstip) en men zo nog meer betrouwbaardere resultaten krijgt. Gebaseerd op onze studie, moet er extra aandacht worden besteed in de postoperatieve fase aan patiënten die roken. Vroeg starten met immunomodulators of anti-‘tumor necrosis factor’ (TNF) medicatie onder deze patiënten zou in overweging moeten worden genomen.
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Index
Introduction .............................................................................................................................. 5
Aim of this study ....................................................................................................................... 8
Materials and methods ............................................................................................................. 9
Patients and settings ................................................................................................................ 9
Clinical variables .................................................................................................................... 9
Defining of outcome parameters .......................................................................................... 10
Statistical analysis ................................................................................................................. 11
Results ..................................................................................................................................... 12
In and exclusion criteria ........................................................................................................ 12
Recurrence rates ................................................................................................................... 13
Clinical variables of patients ................................................................................................ 14
Risk factors for postoperative endoscopic recurrence .......................................................... 14
Risk factors for postoperative symptomatic recurrence ....................................................... 17
Discussion ................................................................................................................................ 18
Principal findings and comparison with other studies .......................................................... 18
Strengths and weaknesses ..................................................................................................... 20
Conclusion ............................................................................................................................... 21
References ............................................................................................................................... 22
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Introduction Crohn’s disease (CD) is a chronic inflammatory bowel disease (IBD) with an unpredictable clinical course. Most frequently it affects the terminal ileum, but it can affect any part of the gastrointestinal tract. Approximately 80% of the patients with CD require surgery at some point in their life(1). Indications for surgery include refractory disease, obstruction due to stenosis and perforation. In a review article published in 2004, the probability of first resective surgery ranged from 38% to 96% in the 15 years after diagnosis(2). The need for surgery remains high, although a recent meta-analysis from the IOIBD Task Force Report reported a decrease in the risk of CD surgery in population-based cohorts during the past decade (Figure 1)(3). Figure 1. Surgery rates over time. Reprinted from ‘Hospitalisations and surgery in Crohn’s disease’ by C.N. Bernstein, E.V. Loftus Jr, S.C. Ng, P.L. Lakatos and B. Moum, Gut 2012;61:622-629
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Moreover, multiple randomised controlled trials found that the use of anti-tumor necrosis factor (TNF) agents decreases the need for surgery in CD(4;5). Although surgery is effective in countering the stenosing and perforating complications of CD and surgery improves the quality of life(6), it is not curative. The overall aim of surgery is to control symptoms and restore bowel function. Even if all macroscopically involved intestine is removed, disease can recur, most commonly at or above the anastomosis(7-9). Reoperation rates reach approximately 50% during the following 10 to 20 years(10), with a definite risk of developing intestinal malabsorption and short bowel syndrome(11-14). Postoperative recurrence In 1984, Rutgeerts et al.(8) reported a recurrence rate of 72% in patients who underwent a bowel resection. These patients were endoscopically examined within one year after the operation. The recurrence rate did not differ significantly from that in patients examined one to three years or three to ten years after surgery. Similarly, in 1992 reported Olaison et al.(7) an endoscopic recurrence rate of 93% one year after terminal ileal resection. Clinical manifestation of the disease is often absent, especially in the early stages of recurring disease. The correlation between recurrence of symptoms and objective endoscopic evidence of recurrence is poor(8). Buisson et al.(15) reviewed in 2012 the natural history of postoperative CD. In randomised controlled trials, clinical recurrence in the first year after surgery occurred in 38% of the patients, whereas endoscopic recurrence in the first year was reported in 85% of the patients. In referral centres 93% of the patients showed endoscopic lesions whereas only 20% to 37% had symptoms. In population-based studies, the clinical postoperative recurrence rate ranged from 28% to 45%. The average rate of endoscopic recurrence after five years was 58%(15). Rutgeerts score Ileocolonoscopy is the gold standard for the assessment of postoperative recurrence of CD. A detailed endoscopic scoring system by Rutgeerts et al.(9) has been developed to provide prognostic information regarding the risk of clinical relapse (Table 1). Table 1. Rutgeerts score Endoscopic score Definition i0 No lesions in the distal ileum i1 <5 aphthous lesions in the distal ileum i2 ≥5 aphthous lesions with normal mucosa between the lesions or skip
areas of larger lesions or lesions confined to ileocolonic anastomosis i3 Diffuse aphthous ileitis with diffusely inflamed mucosa i4 Large ulcers with diffuse mucosal inflammation or nodules or stenosis
in the neoterminal ileum In the same article the authors show that the postoperative clinical course of CD is best predicted by the severity of endoscopic lesions of CD during the first year after resection. Patients with no or very mild lesions (Rutgeerts score i0 or i1) have a great chance of having an uneventful postoperative clinical course. Patients with diffuse recurrent lesions in the neoterminal ileum within one year of resection are more likely to have early symptoms and are prone to suffer complications. Patients with more severe endoscopic recurrence were found to have a higher risk of clinical recurrence at four years postoperatively, compared to those with less severe endoscopic mucosal lesions (Rutgeerts score ≥i2 vs. <i2; 100% vs. 9%). The presence of extensive lesions in the neoterminal ileum shown by endoscopic
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examination within some months after surgery, predicts a rapid evolution to recurrent symptoms and eventual complications. These early lesions appear to be new areas of inflammation which do not originate from microscopic inflammation prior to surgery or incomplete anastomotic healing(9). In conclusion, endoscopic recurrence precedes clinical recurrence and (early) severe endoscopic recurrence predicts a poor prognosis. The Rutgeerts’ endoscopic index has been used to define the primary endpoint in most randomised controlled trials, which functions as a surrogate for clinical recurrence. Although postoperative recurrence was initially defined as a Rutgeerts score ≥ i1, most recent randomised controlled trials use i2 as the cut-off to define endoscopic recurrence and i3 for defining ‘severe’ endoscopic recurrence. Because we know now that a Rutgeerts score of i1 is of low value to predict clinical recurrence, these changes (cut-off value i2 instead of i1) have been made. Risk factors for postoperative recurrence It is important to prevent or at least delay the postoperative recurrence as multiple surgical resections carry the risk of short-bowel syndrome(14). The identification of risk factors for postoperative recurrence is important in order to select those patients who may benefit the most from active preventive measures. The identification of risk factors can help in deciding which patients should be treated aggressively (start early with anti-TNF agents). Although multiple risk factors have been identified for postoperative recurrence, unfortunately, only a few risk factors have been consistently described in literature for predicting endoscopic, clinical or surgical recurrence.
Out of the patient related factors, only smoking has consistently been identified as a predictor of postoperative recurrence. The odds ratio for clinical recurrence for current smokers is between 2 and 3(7;16;17). Smoking has also been shown to increase the risk of endoscopic recurrence, with macroscopic lesions found in the neoterminal ileum of 70% of smokers one year after surgery compared with 35% of nonsmokers and 27% of exsmokers (18). Endoscopic recurrence rates appear to be similar, for exsmokers and non-smokers(19-21). Other patient related factors such as age, sex and age at disease onset are inconsistently reported as risk factors(22;23).
Disease related factors include the duration and severity of the disease prior to the first resection, history of previous resection(s) and penetrating disease(16;24). The duration of the disease prior to first surgery is not a consistent risk factor in the literature(25;26). Most studies show that previous surgery for CD is a risk factor for future surgery(24;27-29). Previous intestinal surgery appeared to increase the risk of postoperative recurrence (24;27;28;30;31). Perforating disease, a phenotype characterized by abcess, fistula, or free perforation, appears to be an independent risk factor for postoperative recurrence(32-36), but also previous studies have found similar recurrence rates for patients with perforating and nonperforating disease(37-39). A meta-analysis of 13 studies by Simillis et al.(36) showed that perforating disease was associated with an increased rate of both clinical and surgical recurrence compared with nonperforating indications for surgery. They also concluded that those who experienced a side-to-side anastomosis, compared to an end-to-end anastomosis, had fewer postoperative complications. However, overall patients showed a similar postoperative recurrence rate. There was a significant heterogeneity among the included studies, limiting the value of the results.
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Prophylactic medical therapy Since the late 1990s, a new class of drugs became available in the treatment of CD, the anti-TNF agents infliximab (IFX) and adalimumab (ADA). Their efficacy as induction and maintenance drugs both for adult and pediatric CD was proven in previous randomised controlled trials(40-44). Prophylactic medical therapy to reduce the rate of postoperative recurrence has been proven to be effective in randomised controlled trials and subsequent meta-analysis(45). A Cochrane review performed by Doherty et al.(46) in 2009 reported the results of 27 randomised controlled trials, which had assessed the effectiveness of medications to prevent the postoperative recurrence of CD. Here it was shown that thiopurines and anti-TNF lowered the risk of endoscopic and clinical recurrence. Azathioprine/6-mercaptopurine (6-MP) was associated with a significantly reduced risk of clinical recurrence (RR 0.59; 95% CI 0.38-0.92, NNT=7) and severe (Rutgeerts score >2) endoscopic recurrence (RR 0.64; 95% CI 0.44-0.92, NNT=4), when compared to placebo. Infliximab use was associated with an endoscopic recurrence rate of 9%, compared with 85% in patients on placebo. The clinical remission rates were 80% with infliximab and 54% with placebo. Aim of this study The varying results of recurrence rates (especially those of endoscopic recurrence) are mainly the result of different study designs, which varied in the definition of recurrence, the type of patients included and types of operation (only ileocolic resection vs. all CD-related surgery). Nevertheless, all studies show high recurrence rates. We assume that the present recurrence rate is lower than reported in literature so far, mainly due to the drug development. Also, we think the present recurrence rate is lower because of the other cut off value (Rutgeerts score i2 instead of i1). Because of the wide range of recurrence rates that is seen, it is clear that certain patient populations are at higher risk of recurrence than others. Therefore, the main aim of this study was to retrospectively observe the endoscopic and symptomatic recurrence rate of postoperative CD, as well as to identify the risk factors for postoperative recurrence.
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Materials and methods This study is a retrospective, multicentre cohort study performed in two tertiary referral centres specialized in IBD in the Netherlands: the Academic Medical Centre (AMC), Amsterdam and Leiden University Medical Centre (LUMC), Leiden. Patients and settings Patients who underwent an ileocecal resection for CD between 2008 and 2013 were included in the study. The postoperative course was retrospectively evaluated. The medical records and details of the outpatient’s clinic follow-up were reviewed. Patients without follow-up postoperatively at these institutes were excluded. Another exclusion criterion was when patients received a permanent ileostomy instead of an anastomosis. Clinical variables Gender, the presence or absence of a family history of IBD in a first, second or third degree relative and smoking behaviour were scored. Smoking behaviour was divided into one year before surgery and the first year following surgery; smoker, non-smoker or stopped smoking. Age at diagnosis, disease location and disease behaviour were categorized according to the Montreal Classification(47)(Table 2). Table 2. Montreal classification Age at diagnosis (A) A1: less than 16 years
A2: between 17 and 40 years A3: over 40 years
Disease location (L) L1: ileal disease L2: colonic disease L3: ileocolonic disease L4: upper gastrointestinal tract
Behaviour (B) B1: nonstricturing, nonpenetrating disease B2: stricturing disease B3: penetrating disease P: perianal disease
Age at diagnosis was separated into 3 groups. Disease location was defined as the maximum extent of disease involvement, any time before the first resection. Minimum involvement for a location was the presence of any aphthous lesion or ulceration. All of the patients had ileal disease, so patients were either classified as (L1) ileal disease with and without disease limited to the cecum or (L3) ileal disease with disease of the colon beyond the cecum. Disease of the upper gastrointestinal tract (L4) is scored as a disease modifier and was added to L1 or L3. None of the patients had disease limited to the colon (L2). To determine disease behaviour, also data from surgical and pathological reports were used to obtain the information about disease behaviour. Nonstricturing and nonpenetrating disease (B1) was reserved for uncomplicated inflammatory disease without signs of stricturing or penetrating disease. Stricturing disease (B2) was defined as occurrence of constant luminal narrowing combined with prestenotic dilatation and/or obstructive signs or symptoms but without evidence of penetrating disease. Penetrating disease (B3) was defined as the occurrence of intra-abdominal fistulas, inflammatory masses, and/or abcesses at any time of the course of the disease. Perianal disease (p) was added to B1-B3 when perianal disease was present. For example a perianal fistula was considered a p and not penetrating disease (B3).
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Indications for surgery were divided into refractory disease, stenosis, perforation (abcess, fistula or free perforation) and participation in the LIR!C trial(48)1. The type of anastomosis was documented; side-to-side anastomosis (SSA), end-to-end (EEA) or a side-to-end anastomosis (SEA). From the pathological reports after surgery, we noted the centimetres of ileal resection. The length of ileal resection was divided into less than 20 centimetres and 20 centimetres or more. The prescription of immunomodulators (6-mercaptopurine, azathioprine and methotrexate), or biologics (e.g., infliximab, adalimumab) during the postoperative period was recorded. Only the medication which was started within a month after the operation was used for statistical analysis. Outcomes The primary outcome of interest was endoscopic recurrence. The endoscopic findings were graded according to the modified Rutgeerts score (Table 3). We preferred to use a modification of the Rutgeerts score based on recommendations by several key opinion leaders. In the 'old' version, grade 2 represented both purely anastomotic lesions (without inflammation in the neoterminal ileum) and mild to moderate ulcers in the neoterminal ileum with normal mucosa in between. Since the anastomotic ulcers probably do not represent genuine recurrence of CD, currently a modified version of this score is being validated (though still unpublished). In this modified version, a score of i2a represents purely anastomotic lesions/ulcers, whereas a score of i2b represents ulcerations with normal mucosa in between in the neoterminal ileum. It is believed that i2a may not be associated with significant clinical recurrence later on, whereas i2b clearly is. Table 3. Modified Rutgeerts score Endoscopic score Definition i0 No lesions in the distal ileum i1 <5 aphthous lesions in the distal ileum i2a Lesions confined to the ileocolonic anastomosis (including anastomotic
stenosis) i2b ≥5 aphthous lesions or larger lesions, with normale mucosa in-between,
in the neoterminal leum (with or without anastomotic line) i3 Diffuse aphthous ileitis with diffusely inflamed mucosa i4 Large ulcers with diffuse mucosal inflammation or nodules or stenosis
in the neoterminal ileum Individuals in the cohort were diagnosed with postoperative recurrence when they had a modified Rutgeerts score of i2b or higher seen by ileocolonoscopy. All the endoscopy reports from the patients from the AMC were revisited and scored by prof. G.R.A.M. D’Haens. Those performed in LUMC were revisited and scored by dr. A.E. van der Meulen. We also documented whether there was symptomatic recurrence at the time the endoscopy was performed or one year after surgery when no ileocolonoscopy was performed. Ileocecal resection (especially in cases of extensive ileal resection) may be associated with the development of abdominal symptoms such as diarrhea or abdominal cramps secondary to bacterial overgrowth, bile salts malabsorption or short bowel syndrome, and these might be 1 LIR!C trial: the objective of this project is a comparison of the effectiveness and costs of infliximab treatment with laparoscopic ileo-colic resection in patients with recurrent Crohn’s disease of the distal ileum.
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misinterpreted as a disease recurrence(49). Thus, because diarrhea is common after ileal resection, this isolated symptom was not seen as symptomatic recurrence. An increase in diarrhea, associated with pain, fever or weight loss was regarded as symptomatic recurrence. Extra-intestinal complaints were not regarded as symptomatic recurrence. Statistical analysis Data were collected in excel and imported into the statistical SPSS program (SPSS, version 22; SPSS Inc., Chicago, IL, USA). Descriptive statistics were used to examine the baseline characteristics of the (endoscopic) postoperative recurrence (POR) group and no postoperative recurrence (no-POR) group. To evaluate the frequencies of recurrences, we defined three groups: medication use after surgery; ‘no medication’ (including 5-ASA compounds), immunomodulators or biologics. 5-ASA compounds were added to the ‘no medication’ group, as most studies don’t show a beneficial effect from 5-ASA to prevent postoperative (endoscopic) recurrence(50-52). Comparisons of frequencies of recurrence were done using the chi-squared test . To test for differences between the three groups: continuous variables were compared using Student's t-test or the Mann–Whitney U-test (for nonparametric variables). The Chi-squared test was used to evaluate distributions of categorical variables. Risk factors for the development of endoscopic or symptomatic recurrence were assessed with univariate logistic regression. The risk factors which were studied were gender, family history of IBD, surgery indication, history of previous ICR, Montreal classification, ileum length resected, type of anastomosis, smoking (the year before and after surgery) and postoperative prescription of medication. We carried out a multivariate analysis (including odds ratios) if we obtained a p-value<0.05 at univariate analysis to identify risk factors that independently predicted postoperative recurrence. Two-sided probabilities were contemplated and α values of <0.05 were considered statistically significant.
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Results Between 2008 and 2013, there were 156 patients with CD who underwent an ileocecal resection in AMC or LUMC. Of these, 129 patients underwent an ileocolonoscopy postoperatively, of which 105 patients within two years (Figure 2). The minimum time between surgery and ileocolonoscopy was 30 days and the maximum was 702 days with a mean of 304 days. Figure 2. Flow chart of total numbers of patients, number of ileocolonoscopies performed.
167 patients with ICR
11 excluded • Follow-up other hospital • Continent ileostoma
156 patients included in our study
27 patients without an ileocolonoscopy
129 patients with an ileocolonoscopy
105 patients with ileocolonoscopy within two years
24 patients with ileocolonoscopy after two years
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Further analysis for endoscopic recurrence was performed on these 105 patients, which consisted of 39 male (37.1%) and 66 (62.9%) female patients. In the majority of the patients, stenosis was the indication for surgery (49.5%). 16.2% had a perforation as indication, 15.2% refractory disease and 19.0% participated in the LIR!C trial (Table 4). Table 4. Indications for surgery n (%) Stenosis 52 (49.5) Perforation 17 (16.2) Refractory disease 16 (15.2) LIR!C trial 20 (19.0) To evaluate if there is endoscopic recurrence or not, we took a cut off value of the modified Rutgeerts score of 12b or higher. 40 out of 105 (38.1%) patients developed endoscopic recurrence. The symptomatic rate was lower; 24 of 156 patients (17.1%) developed symptoms. Noticeable, the symptomatic recurrence rate was not higher comparing severe recurrence (Rutgeerts score i3 and i4) to less severe recurrence (Rutgeerts i2b), with a p-value of 0.630. As mentioned earlier, we defined three groups regarding medication use to further evaluate the frequencies of postoperative recurrence (Table 5). Table 5. Percent of Rutgeerts score in three groups Medication use Rutgeerts score
i0 i1 i2a i2b i3 i4 Biologics 47.4 5.3 21.1 5.3 10.5 10.5 Immunomodulators 28.6 19.0 28.6 14.3 4.8 4.8 No medication 17.5 15.8 15.8 21.1 15.8 14.0 In the group which used biologics, there was a postoperative recurrence rate (modified Rutgeerts score ≥i2b) of 26.3%, in the group who used immunomodulators 23.8% and in the group without medication 51.9% (Figure 3). There was a significant difference (p=0.037) in postoperative recurrence by comparing those three groups. By comparing biologics with no medication we did not find a significant difference but a trend (p=0.062) and by comparing immunomodulators with no medication we found a significant difference (p=0.032). By comparing biologics and immunomodulators we did not find a significant difference (p=0.855). With regard to patient characteristics, there was no significant difference in gender, family history of IBD, age at diagnosis, disease behaviour, smoking behaviour (before and after resection), disease location (p=0.051), surgery indication and ileum length resected between those three groups. Though, we found a significant difference in type of anastomosis (p=0.018) and a history of previous ICRs (p=0.043). This significant difference was only seen when we compared the biologics with no medication; for type of anastomosis (p=0.018) and previous ICR (=0.014). In the biologics group there were significantly more patients who had one or more previous resections and less patients with a side-to-side anastomosis.
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Figure 3. Recurrence rates between three groups
Recurrence= modified Rutgeerts score i2b, i3 and i4. No recurrence= modified Rutgeerts score i0, i1 and i2a. Risk factors for postoperative recurrence To identify risk factors for endoscopic recurrence, we defined a group with recurrence (modified Rutgeerts score ≥ i2b) and no recurrence (modified Rutgeerts score <i2b). From the 105 patients who underwent an ileocolonoscopy within two years after surgery, 40 patients had recurrence and 65 patients had no recurrence. Clinical variables of patients In both groups there were more female than male patients (Table 6). In the no recurrence group, 20% of the patients smoked the year before surgery, against 46.9% in the recurrence group. The majority of the patients were diagnosed between the age of 17 and 40 years and had stricturing disease. In the no recurrence group 36.9% had penetrating disease, against 20% with penetrating disease in the recurrence group. When classifying the location according to the Montreal classification, in the no recurrence group 56.9% exhibited disease in the ileum and in the recurrence group this was 77.5%. In both groups, the most used type of anastomosis was SSA. The percentage of patients who had one or more previous ICRs and the ileum length resected was approximately equal in both groups. 20% of the patients without recurrence smoked the year following surgery. In the patients without recurrence this was 42.4%. With regard to medication, in the no recurrence group 29.2% used postoperative biologics, 27.7% used immunomodulators and 43.1% did not use medication. In the recurrence group, 12.5% used postoperative biologics, 15% used immunomodulators and 72.5% used no medication for CD (Table 6).
0
10
20
30
40
50
60
70
80
90
100
Biologics Immunosuppressiva No medication
Recurrence
No recurrence
%
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Table 6. Clinical variables Clinical variables No recurrence
(i0, i1, i2a) n=65
Recurrence (i2b, i3, i4) n=40
Gender, % Male Female Family history IBD, % Yes No History of previous ICR,% 0 1 or more Smoker, 1 year before surgery,% Yes No Stopped Age at diagnosis, % A1 A2 A3 Disease behaviour, % B1 B2 B3 Perianal disease Disease location, % L1 L2 L3 L4 (Upper GI) modifier Anastomosis, % SSA ESA EEA Surgery indication, % Perforation Stenosis Refractory disease LIRIC trial Ileum length resected, % <20 centimetres ≥20 centimetres Medication, started within a month after ICR, % Biologics Immunomodulators No medication Smoking, first year following surgery, % Yes No Stopped
24/65 (36.9) 41/65 (63.1) 10/38 (26.3) 28/38 (73.7) 40/62 (64.5) 22/62 (35.5) 10/50 (20.0) 36/50 (72.0) 4/50 (8.0) 10/65 (15.4) 52/65 (80.0) 3/65 (4.6) 10/65 (15.4) 31/65 (47.7) 24/65 (36.9) 15/65 (23.1) 37/65 (56.9) 0 28/65 (43.1) 5/65 (7.9) 43/59 (72.9) 5/59 (8.5) 11/59 (18.6) 9/65 (13.8) 30/65 (46.2) 11/65 (16.9) 15/65 (23.1) 39/60 (65) 21/60 (35) 19/65 (29.2) 18/65 (27.7) 28/65 (43.1) 10/48 (20.8) 37/48 (77.1) 1/48 (2.1)
15/40 (37.5) 25/40 (62.5) 9/24 (37.5) 15/24 (62.5) 24/40 (60) 16/40 (40) 15/32 (46.9) 17/32 (53.1) 0 9/40 (22.5) 23/40 (57.5) 8/40 (20.0) 9/40 (22.5) 23/40 (57.5) 8/40 (22.5) 7/40 (17.5) 31/40 (77.5) 0 9/40 (22.5) 3/40 (7.5) 26/35 (74.3) 1/35 (2.9) 8/35 (22.9) 8/40 (20.0) 22/40 (55.0) 5/40 (12.5) 5/40 (12.5) 22/36 (61.1) 14/36 (38.9) 5/40 (12.5) 6/40 (15) 29/40 (72.5) 14/33 (42.4) 18/33 (54.5) 1/33 (3.0)
IBD, inflammatory bowel disease; ICR, ileocecal resection; SSA, side-to-side anastomosis; ESA, end-to-side anastomosis; EEA, end-to-end-anastomosis.
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Analysis of clinical variables for endoscopic recurrence Univariate analysis (Table 7) did not support that gender, family history of IBD, age at diagnosis, disease behaviour, anastomosis, surgery indication, ileum length resected, history of previous ICR and smoking the first year following surgery were associated with endoscopic recurrence. In the univariate analysis, smoking the year before surgery and ileal disease location (L1) emerged to be significant risk factors for endoscopic recurrence. Regarding the impact of medical therapy on postoperative course, we identified a protective effect from medication (biologics or immunomodulators) regarding endoscopic recurrence. Table 7. Univariate analysis of clinical variables for endoscopic recurrence Patient characteristics OR (95% CI) P value Gender Family history IBD History of previous ICR Smoking, 1 year before surgery (yes vs. no and stopped) Age at diagnosis (A1 vs A2 vs A3) Disease behaviour (B1 vs B2 vs B3) Disease location (L1 vs L3) L4 (Upper GI) modifier Anastomosis (SSA vs ESA vs EEA) Surgery indication Ileum length resected Postoperative use of medication (Biologics and immunomodulators vs. no medication) Smoking, first year following surgery (yes vs. no vs. stopped)
0.976 (0.432-2.203) 0.595 (0.199-1.784) 1.212 (0.534-2.749) 3.529 (1.323-9.413) 1.347 (0.634-2.861) 0.595 (0.330-1.073) 2.607 (1.071-6.346) 0.619 (0.397-0.966) 1.044 (0.624-1.746) 1.044 (0.624-1.746) 0.703 (0.459-1.079) 0.322 (0.141-0.734) 0.528 (0.226-1.232)
0.953 0.354 0.645 0.012 0.438 0.085 0.035 0.936 0.871 0.107 0.702 0.007 0.139
Values in bold are significant. BD, inflammatory bowel disease; ICR, ileocecal resection; SSA, side-to-side anastomosis; ESA, end-to-side anastomosis; EEA, end-to-end-anastomosis. In the multivariate logistic regression (Table 8) which included only factors that seemed to have a significant impact on the risk of postoperative endoscopic recurrence in the univariate analysis, smoking remained a significant risk factor. When patients smoked the year before surgery they had a 3.6-fold increased risk for recurrence compared to patients who did not smoke or stopped smoking. Postoperative prescription of medication is not a significant protective factor, but there seems to be a trend (p=0.054). The use of biologics or immunomodulators reduced the risk of endoscopic recurrence with 61.9%.
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Table 8. Risk factors in the multivariate analysis for endoscopic recurrence Patient characteristics
OR (95% CI)
P value
Smoking, 1 year before surgery Disease location Postoperative use of medication
3.590 (1.260-10.233) 1.958 (0.665-5.766) 0.381 (0.142-1.018)
0.017 0.223 0.054
Values in bold are significant. Analysis of clinical variables for symptomatic recurrence We also performed a univariate analysis for symptomatic recurrence (Table 9). Only smoking the year before surgery and disease behaviour were found to be significant risk factors. The prescription of medication was a significant protective factor. Table 9. Univariate analysis of clinical variables for symptomatic recurrence Patient characteristics OR (95% CI) P value Gender Family history IBD History of previous ICR Smoker, 1 year before surgery Age at diagnosis Disease behaviour (Penetrating vs. non penetrating) Perianal disease Disease location L4 Anastomosis Surgery indication Ileum length resected Postoperative use of medication Smoking, first year following surgery
0.489 (0.189- 1.269) 2.981 (0.881-10.089) 0.887 (0.363-2.168) 3.652 (1.382- 9.654) 0.933 (0.412-2.112) 3.788 (1.218-11.781) 0.471 (0.130-1.701) 1.085 (0.682-1.727) 2.378 (0.667-8.474) 0.868 (0.509-1.482) 0.691 (0.430-1.110) 1.176 (0.443-3.116) 0.285 (0.114-0.710) 1.291 (0.575-2.897)
0.142 0.079 0.793 0.009 0.868 0.021 0.250 0.729 0.182 0.604 0.126 0.745 0.007 0.536
Values in bold are significant. In the multivariate analysis, smoking (OR; 3.809, 95% CI 1.346-10.781, p=0.012), as well as disease behaviour (OR; 4.777, 95% CI 1.206-18.920, p=0.026) were both confirmed to be independent risk factors for symptomatic recurrence. For disease behaviour there is 4,5-fold increased risk when comparing penetrating with non-penetrating disease. Patients who smoked the year before surgery have a 3.8-fold increased risk of symptomatic recurrence. The prescription of postoperative medication lowered the risk to become symptomatic with (1-0.215=) 78.5% (OR; 0.215, 95% CI 0,071-0,658, p=0.007)
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Discussion The aim of this multi-centre retrospective cohort study was to determine the postoperative recurrence rate of CD as well as to identify risk factors. Recurrence rates and risk factors related to recurrence in postoperative CD have varied in previously published studies. In our study endoscopic recurrence was the primary outcome of interest. Besides that, we focused on symptomatic recurrence. Because of the wide range of recurrence rates that are seen in literature, it is clear that certain patient populations are at higher risk of recurrence than others. Given the fact that many, but not all patients will suffer relapse, identifying those at greatest risk, and thus most likely to incur greatest benefits from treatment, is of great importance. Principal findings and comparison with other studies Recurrence rate In the present study we found an overall endoscopic recurrence rate of 38.1%. This recurrence rate is lower than found in most previous studies. In a review in 2012 performed by Buisson et al.(15), an endoscopic recurrence rate of 85% in randomised controlled trials and 93% in referral centres was found. Importantly, some of the previous studies took another cut off value (Rutgeerts score ≥1), instead of the modified Rutgeerts score >i2a to define postoperative recurrence. Recently, Orlando et al.(53) showed a recurrence rate of 61.7% at 6 months postoperatively. They defined recurrence with a Rutgeerts score ≥i1. This differs from our definition of recurrence; when there were endoscopic lesions in the anastomotic line we called it no recurrence (modified Rutgeerts score i2a). This might explain the difference in recurrence rates. When we made a subdivision in groups of medication we found in the patients who used biologics a recurrence rate of 26.3% and in patients who used immunomodulators a recurrence rate of 23.8%. Patients who did not use medication postoperatively had a recurrence rate of 51.9%. There was a significant difference when we compared patients who used immunomodulators to those without postoperative medication (p=0.037). When we compared the biologics group to the group without medication there was a trend (p=0.062) in favour of biologics. We found a symptomatic recurrence rate of 17.4% after 1 year (or at the time the endoscopy was performed). In the same review mentioned above by Buisson et al., 38% of the patients in randomised controlled trials had symptomatic recurrence in the first year after surgery and in referral centres this was between 34% and 86%. Risk factors for postoperative recurrence The findings of previous studies focusing on possible risk factors for postoperative recurrence of CD have been inconsistent and the varying results may be due to different study designs and (too) small study designs. In the current study, smoking before surgery and ileal disease location were both associated with an increased risk of postoperative endoscopic recurrence when using univariate analysis. Only smoking was confirmed by multivariate analysis. In a meta-analysis by Reese et al.(17), which included 16 studies, smoking was found to almost double the risk of clinical and surgical recurrence. Smoking has also been shown to be a risk factor for endoscopic recurrence. Cottone et al.(18) showed a recurrence rate of 70% in smokers compared to 35% of non-smokers (OR 2.2, p<0.05). Our data only partly support that smoking is associated with an increased risk of endoscopic recurrence; only smoking before surgery appears to be a significant risk factor, both in endoscopic and symptomatic recurrence. Smoking the year following surgery appears not to be a risk factor for postoperative recurrence.
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We also investigated in our study the impact of Montreal classification on endoscopic and symptomatic recurrence. Ileal disease was found to be significant in the univariate analysis, but is not an independent risk factor for endoscopic recurrence. This has been evaluated in a number of studies, with varying results; ileal disease(26;54) and ileocolonic disease(55;56) have both been reported to be associated with an increased risk of recurrence. Penetrating disease behaviour, which seemed to be a significant risk factor for symptomatic recurrence in the univariate analysis, was confirmed in the multivariate analysis. We couldn’t confirm this for endoscopic recurrence. These data are consistent with previous studies. A meta-analysis in 2008 performed by Simillis et al.(36) showed a hazard ratio of 1.5 when comparing penetrating with non-penetrating disease for recurrence. Although endoscopic and clinical recurrence rates were not evaluated as separate endpoints in this meta-analysis, non-penetrating disease (compared to penetrating disease) reduced the risk of surgical recurrence. In a review performed by Buisson et al.(15) they concluded that despite some conflicting data, penetrating disease is an important risk factor for postoperative recurrence in CD. A problem with establish disease behaviour is that penetrating and stricturing disease are not always based on clinical grounds, sometimes it’s established during surgery or from the pathological reports afterwards. We found in our study similar recurrence rates when we compared type of anastomosis. This is in line with a meta-analysis by Simillis et al.(36), who found no difference in recurrence rates when comparing SSA to EEA. Moreover, a randomised controlled trial performed in 2009 showed no difference in endoscopic or symptomatic recurrence rates between those who underwent SSA compared to ESA(24). Our data do not support the view that recurrence is more common in patients who underwent more than 20 cm. ileal resection. In a German referral centre, they found that those with bowel resection longer than 20 cm. had a higher risk of endoscopic recurrence(57). In a study performed in 2000 they found significant more clinical recurrences in patients with long resected segments (more than 50 cm.)(58). In the literature, there is conflicting evidence about the impact of age at onset disease on recurrence. In some studies, onset of disease at low age has been correlated to a higher recurrence rate(59;60). We found no such correlation in our patients. This is in accordance with several other studies that report no relationship between age at onset and recurrence(9;10;25;55). Subclinical endoscopic lesions precede the development of clinical symptoms and patients with severe recurrence are more likely to become symptomatic(9;61). Yamamoto et al.(61) showed that the endoscopic severity at 6 months is predictive for clinical recurrence during the next 5 years. We did not find in our analysis that patients with more severe endoscopic recurrence have significant more symptomatic recurrences. This could be due to the fact that we only evaluated symptomatic recurrence in the short term (with a mean of one year) and not in the long term. Prevention of postoperative recurrence In our study there was a significant difference in endoscopic recurrence rate when comparing the immunomodulator group with the no medication group, but there was no significant difference between the biologics group compared to the patients without postoperative medication. This may be due to the fact that significantly more patients in the biologics group had one or more previous resection(s). Previous resection appeared to be a significant risk factor in previous studies(24;27;28;30;31). However in our study, previous ICR was not found to be a significant risk factor for postoperative recurrence. Postoperative use of medication, which had seemed to be a significant protective factor for endoscopic recurrence in the univariate analysis, still showed a trend but not significance in
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the multivariate analysis (OR, 0.381 95% CI, 0.142-1.018, P=0.054). Postoperative use of medication (biologics or immunomodulators) was associated with a decreased risk of symptomatic recurrence (in both univariate and multivariate analysis). This observation supports the fact that postoperative preventive therapy with these drugs has an impact on postoperative recurrence of CD after ICR(62). Our numbers were too small to use medication as a categorical variable in the univariate and multivariate analysis. Therefore we merged biologics and immunomodulators and couldn’t calculate a p-value and odds ratio per medication group. This could be the reason that medication was not an independent protective factor for endoscopic recurrence. Although not significant we found a risk reduction of 61.9% when we compared patients who used medication to the group without medication. And when we compared the three groups in frequencies of recurrences, we saw significant less recurrence in patients who used immunomodulators compared to patients without postoperative medication. Only one study compared the effect of thiopurines (alone) to placebo on postoperative recurrence. They showed a decrease of endoscopic recurrence in the thiopurine group(51). There have been two randomised controlled trials comparing infliximab with placebo. Reguerio et al.(63) demonstrated that endoscopic lesions were significantly lower at one year in the infliximab group compared to controls. They found no significant difference in symptomatic recurrence. Yoshida et al.(64) did demonstrate a decrease in clinical recurrence at one year comparing infliximab with the control group. There are several studies that compared biologics with thiopurines. In an open label pilot study performed by Armuzzi et al.(65), there was found that infliximab was more effective than azathioprine in reducing histological, but not endoscopic and clinical recurrence after ICR in ‘high risk’ patients. Patients were considered at ‘high risk’ if they had 2 or more of the following factors: young age ate diagnosis (≤ 30 years), penetrating disease behavior, active smoking, perianal disease at diagnosis of CD, previous surgery and less than 3 years from previous surgery. In a prospective pilot study, performed by Yamamota et al.(66), they showed significant less symptomatic and endoscopic recurrence in the infliximab group compared to the azathioprine group. Savarino et al.(67) showed in a randomised controlled trial that the rate of endoscopic and symptomatic recurrence was significantly lower in patients who were prescribed adalimumab compared to azathioprine. The latter is in concordance with our study, in which we did not find a significant difference for endoscopic recurrence rates when we compared the biologics group with the immunomodulators group.
Strengths and weaknesses This is the first study using the modified Rutgeerts score to evaluate the endoscopic recurrence rate. The gastroenterologists who revisited the scores of the endoscopies have both lots of experience and there was per hospital one gastroenterologist who did it, concluding that the scores are reliable. A weakness is that every endoscopy is only scored and revisited by one gastroenterologist and not both, which had made the scores even more reliable. There are several other limitations to our study. Potential weakness of our study includes a relatively small population size. This is a common problem in retrospective studies, in which researchers are unable to directly influence the number of patients. Because the study is retrospective and we only used the medical records of patients, some variables are incomplete. Our primary outcome of interest was endoscopic recurrence and not every patient had undergone an ileocolonoscopy. And as with any retrospective study, data may be the subject of bias. The medical centres where the study took place are both tertiary centres with a lot of experience in IBD. The patients referred to these hospitals have in general more complex
21
disease presentation with greater need for surgery and possibly also higher rates of postoperative recurrence. Thus the recurrence rate found here could be higher than in population-based studies. Smoking is reported as a strong predictor of postoperative recurrence in previous studies. The fact that we only found this for smoking before surgery and not after surgery may be due to the lack of data regarding smoking the year before surgery (21% missing) and smoking the year following surgery (17.4% missing). Another weakness in our study is the outcome symptomatic recurrence. When patients develop clinical symptoms, it is often difficult to decide whether they are related to CD itself or not (49;68;69). Because a lot of people have abdominal discomfort after surgery it’s not always clear if the patient has complaints because of CD recurrence or because of another reason (for example irritable bowel syndrome (IBS) complaints or adhesions due to surgery). In addition, most of the patients become symptomatic later than a year after surgery. In our study we evaluated symptoms one year after resection, but this might be too short. However this was not our primary outcome of interest. Finally, it is possible that the endoscopic recurrence rate is overestimated because there were 27 patients without an ileocolonoscopy. The reason that those patients did not have an ileocolonoscopy could be due to the fact that those patients were at low risk for recurrence. They definitely did not have symptoms otherwise there was a real possibility they had an ileocolonoscopy. Conclusion In conclusion, this retrospective multicentre cohort study is the first study which used the modified Rutgeerts score to evaluate endoscopic recurrence. We found an overall endoscopic recurrence rate of 38.1% and a symptomatic recurrence rate of 17.1%. The endoscopic recurrence rate for patients without postoperative medication was 51.9%. The endoscopic as well as the symptomatic recurrence rates found were both lower than in previous studies. Only smoking the year before surgery was an independent risk factor for endoscopic recurrence. Smoking the year before surgery and penetrating disease appeared to be significant risk factors for symptomatic recurrence. Postoperative prescription of biologics or immunomodulators lowered the risk of both endoscopic and symptomatic recurrence. Prospective studies are indicated to evaluate the endoscopic recurrence rate (with the modified Rutgeerts score), to make sure every patient will undergo an ileocolonoscopy (at the same time) and thus have an even more reliable result. Based on our study, special attention should be paid in the postoperative phase to patients with smoking habits. An early start with immunomodulators or anti-TNF therapy among these patients should be taken into consideration.
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Reference List
(1) Caprilli R, Gassull MA, Escher JC et al. European evidence based consensus on the diagnosis and management of Crohn's disease: special situations. Gut 2006;55 Suppl 1:i36-‐i58.
(2) Wolters FL, Russel MG, Stockbrugger RW. Systematic review: has disease outcome in Crohn's disease changed during the last four decades? Aliment Pharmacol Ther 2004;20(5):483-‐96.
(3) Bernstein CN, Loftus EV, Jr., Ng SC et al. Hospitalisations and surgery in Crohn's disease. Gut 2012;61(4):622-‐9.
(4) Panaccione R, Colombel JF, Sandborn WJ et al. Adalimumab sustains clinical remission and overall clinical benefit after 2 years of therapy for Crohn's disease. Aliment Pharmacol Ther 2010;31(12):1296-‐309.
(5) Rutgeerts P, Feagan BG, Lichtenstein GR et al. Comparison of scheduled and episodic treatment strategies of infliximab in Crohn's disease. Gastroenterology 2004;126(2):402-‐13.
(6) Delaney CP, Kiran RP, Senagore AJ et al. Quality of life improves within 30 days of surgery for Crohn's disease. J Am Coll Surg 2003;196(5):714-‐21.
(7) Olaison G, Smedh K, Sjodahl R. Natural course of Crohn's disease after ileocolic resection: endoscopically visualised ileal ulcers preceding symptoms. Gut 1992;33(3):331-‐5.
(8) Rutgeerts P, Geboes K, Vantrappen G et al. Natural history of recurrent Crohn's disease at the ileocolonic anastomosis after curative surgery. Gut 1984;25(6):665-‐72.
(9) Rutgeerts P, Geboes K, Vantrappen G et al. Predictability of the postoperative course of Crohn's disease. Gastroenterology 1990;99(4):956-‐63.
(10) Yamamoto T. Factors affecting recurrence after surgery for Crohn's disease. World J Gastroenterol 2005;11(26):3971-‐9.
(11) Dietz DW, Fazio VW, Laureti S et al. Strictureplasty in diffuse Crohn's jejunoileitis: safe and durable. Dis Colon Rectum 2002;45(6):764-‐70.
(12) Hellers G. Crohn's disease in Stockholm county 1955-‐1974. A study of epidemiology, results of surgical treatment and long-‐term prognosis. Acta Chir Scand Suppl 1979;490:1-‐84.
(13) Romagnuolo J, Fedorak RN, Dias VC et al. Hyperhomocysteinemia and inflammatory bowel disease: prevalence and predictors in a cross-‐sectional study. Am J Gastroenterol 2001;96(7):2143-‐9.
(14) Thompson JS. Strategies for preserving intestinal length in the short-‐bowel syndrome. Dis Colon Rectum 1987;30(3):208-‐13.
(15) Buisson A, Chevaux JB, Allen PB et al. Review article: the natural history of postoperative Crohn's disease recurrence. Aliment Pharmacol Ther 2012;35(6):625-‐33.
23
(16) Moss AC. Prevention of postoperative recurrence of Crohn's disease: what does the evidence support? Inflamm Bowel Dis 2013;19(4):856-‐9.
(17) Reese GE, Nanidis T, Borysiewicz C et al. The effect of smoking after surgery for Crohn's disease: a meta-‐analysis of observational studies. Int J Colorectal Dis 2008;23(12):1213-‐21.
(18) Cottone M, Rosselli M, Orlando A et al. Smoking habits and recurrence in Crohn's disease. Gastroenterology 1994;106(3):643-‐8.
(19) Martin G, Heyen F, Dube S. [Factors of recurrence in Crohn disease]. Ann Chir 1994;48(8):685-‐90.
(20) Medina C, Vergara M, Casellas F et al. Influence of the smoking habit in the surgery of inflammatory bowel disease. Rev Esp Enferm Dig 1998;90(11):771-‐8.
(21) Timmer A, Sutherland LR, Martin F. Oral contraceptive use and smoking are risk factors for relapse in Crohn's disease. The Canadian Mesalamine for Remission of Crohn's Disease Study Group. Gastroenterology 1998;114(6):1143-‐50.
(22) Borowiec AM, Fedorak RN. Predicting, treating and preventing postoperative recurrence of Crohn's disease: the state of the field. Can J Gastroenterol 2011;25(3):140-‐6.
(23) Moskovitz D, McLeod RS, Greenberg GR et al. Operative and environmental risk factors for recurrence of Crohn's disease. Int J Colorectal Dis 1999;14(4-‐5):224-‐6.
(24) McLeod RS, Wolff BG, Ross S et al. Recurrence of Crohn's disease after ileocolic resection is not affected by anastomotic type: results of a multicenter, randomized, controlled trial. Dis Colon Rectum 2009;52(5):919-‐27.
(25) Poggioli G, Laureti S, Selleri S et al. Factors affecting recurrence in Crohn's disease. Results of a prospective audit. Int J Colorectal Dis 1996;11(6):294-‐8.
(26) Wolff BG. Factors determining recurrence following surgery for Crohn's disease. World J Surg 1998;22(4):364-‐9.
(27) Ng SC, Lied GA, Arebi N et al. Clinical and surgical recurrence of Crohn's disease after ileocolonic resection in a specialist unit. Eur J Gastroenterol Hepatol 2009;21(5):551-‐7.
(28) Onali S, Petruzziello C, Calabrese E et al. Frequency, pattern, and risk factors of postoperative recurrence of Crohn's disease after resection different from ileo-‐colonic. J Gastrointest Surg 2009;13(2):246-‐52.
(29) Riss S, Schuster I, Papay P et al. Repeat intestinal resections increase the risk of recurrence of Crohn's disease. Dis Colon Rectum 2013;56(7):881-‐7.
(30) Binder V, Hendriksen C, Kreiner S. Prognosis in Crohn's disease-‐-‐based on results from a regional patient group from the county of Copenhagen. Gut 1985;26(2):146-‐50.
(31) Goldberg PA, Wright JP, Gerber M et al. Incidence of surgical resection for Crohn's disease. Dis Colon Rectum 1993;36(8):736-‐9.
24
(32) Aeberhard P, Berchtold W, Riedtmann HJ et al. Surgical recurrence of perforating and nonperforating Crohn's disease. A study of 101 surgically treated Patients. Dis Colon Rectum 1996;39(1):80-‐7.
(33) Hofer B, Bottger T, Hernandez-‐Richter T et al. The impact of clinical types of disease manifestation on the risk of early postoperative recurrence in Crohn's disease. Hepatogastroenterology 2001;48(37):152-‐5.
(34) Lautenbach E, Berlin JA, Lichtenstein GR. Risk factors for early postoperative recurrence of Crohn's disease. Gastroenterology 1998;115(2):259-‐67.
(35) Sachar DB, Lemmer E, Ibrahim C et al. Recurrence patterns after first resection for stricturing or penetrating Crohn's disease. Inflamm Bowel Dis 2009;15(7):1071-‐5.
(36) Simillis C, Yamamoto T, Reese GE et al. A meta-‐analysis comparing incidence of recurrence and indication for reoperation after surgery for perforating versus nonperforating Crohn's disease. Am J Gastroenterol 2008;103(1):196-‐205.
(37) Avidan B, Sakhnini E, Lahat A et al. Risk factors regarding the need for a second operation in patients with Crohn's disease. Digestion 2005;72(4):248-‐53.
(38) De Dombal FT, Burton I, Goligher JC. Recurrence of Crohn's disease after primary excisional surgery. Gut 1971;12(7):519-‐27.
(39) Yamamoto T, Allan RN, Keighley MR. Perforating ileocecal Crohn's disease does not carry a high risk of recurrence but usually re-‐presents as perforating disease. Dis Colon Rectum 1999;42(4):519-‐24.
(40) Hanauer SB, Feagan BG, Lichtenstein GR et al. Maintenance infliximab for Crohn's disease: the ACCENT I randomised trial. Lancet 2002;359(9317):1541-‐9.
(41) Sands BE, Anderson FH, Bernstein CN et al. Infliximab maintenance therapy for fistulizing Crohn's disease. N Engl J Med 2004;350(9):876-‐85.
(42) Hanauer SB, Sandborn WJ, Rutgeerts P et al. Human anti-‐tumor necrosis factor monoclonal antibody (adalimumab) in Crohn's disease: the CLASSIC-‐I trial. Gastroenterology 2006;130(2):323-‐33.
(43) Sandborn WJ, Hanauer SB, Rutgeerts P et al. Adalimumab for maintenance treatment of Crohn's disease: results of the CLASSIC II trial. Gut 2007;56(9):1232-‐9.
(44) Colombel JF, Sandborn WJ, Rutgeerts P et al. Adalimumab for maintenance of clinical response and remission in patients with Crohn's disease: the CHARM trial. Gastroenterology 2007;132(1):52-‐65.
(45) Van AG, Dignass A, Reinisch W et al. The second European evidence-‐based Consensus on the diagnosis and management of Crohn's disease: Special situations. J Crohns Colitis 2010;4(1):63-‐101.
(46) Doherty G, Bennett G, Patil S et al. Interventions for prevention of post-‐operative recurrence of Crohn's disease. Cochrane Database Syst Rev 2009;(4):CD006873.
25
(47) Satsangi J, Silverberg MS, Vermeire S et al. The Montreal classification of inflammatory bowel disease: controversies, consensus, and implications. Gut 2006;55(6):749-‐53.
(48) Eshuis EJ, Bemelman WA, van Bodegraven AA et al. Laparoscopic ileocolic resection versus infliximab treatment of distal ileitis in Crohn's disease: a randomized multicenter trial (LIR!C-‐trial). BMC Surg 2008;8:15.
(49) Meihoff WE, Kern F, Jr. Bile salt malabsorption in regional ileitis, ileal resection and mannitol-‐induced diarrhea. J Clin Invest 1968;47(2):261-‐7.
(50) Florent C, Cortot A, Quandale P et al. Placebo-‐controlled clinical trial of mesalazine in the prevention of early endoscopic recurrences after resection for Crohn's disease. Groupe d'Etudes Therapeutiques des Affections Inflammatoires Digestives (GETAID). Eur J Gastroenterol Hepatol 1996;8(3):229-‐33.
(51) Hanauer SB, Korelitz BI, Rutgeerts P et al. Postoperative maintenance of Crohn's disease remission with 6-‐mercaptopurine, mesalamine, or placebo: a 2-‐year trial. Gastroenterology 2004;127(3):723-‐9.
(52) Papi C, Aratari A, Tornatore V et al. Long-‐term prevention of post-‐operative recurrence in Crohn's disease cannot be affected by mesalazine. J Crohns Colitis 2009;3(2):109-‐14.
(53) Orlando A, Mocciaro F, Renna S et al. Early post-‐operative endoscopic recurrence in Crohn's disease patients: Data from an Italian Group for the study of inflammatory bowel disease (IG-‐IBD) study on a large prospective multicenter cohort. J Crohns Colitis 2014;8(10):1217-‐21.
(54) Post S, Herfarth C, Bohm E et al. The impact of disease pattern, surgical management, and individual surgeons on the risk for relaparotomy for recurrent Crohn's disease. Ann Surg 1996;223(3):253-‐60.
(55) Anseline PF, Wlodarczyk J, Murugasu R. Presence of granulomas is associated with recurrence after surgery for Crohn's disease: experience of a surgical unit. Br J Surg 1997;84(1):78-‐82.
(56) Raab Y, Bergstrom R, Ejerblad S et al. Factors influencing recurrence in Crohn's disease. An analysis of a consecutive series of 353 patients treated with primary surgery. Dis Colon Rectum 1996;39(8):918-‐25.
(57) Welsch T, Hinz U, Loffler T et al. Early re-‐laparotomy for post-‐operative complications is a significant risk factor for recurrence after ileocaecal resection for Crohn's disease. Int J Colorectal Dis 2007;22(9):1043-‐9.
(58) Bernell O, Lapidus A, Hellers G. Risk factors for surgery and recurrence in 907 patients with primary ileocaecal Crohn's disease. Br J Surg 2000;87(12):1697-‐701.
(59) Scarpa M, Angriman I, Barollo M et al. Risk factors for recurrence of stenosis in Crohn's disease. Acta Biomed 2003;74 Suppl 2:80-‐3.
(60) Softley A, Myren J, Clamp SE et al. Factors affecting recurrence after surgery for Crohn's disease. Scand J Gastroenterol Suppl 1988;144:31-‐4.
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(61) Yamamoto T, Bamba T, Umegae S et al. The impact of early endoscopic lesions on the clinical course of patients following ileocolonic resection for Crohn's disease: A 5-‐year prospective cohort study. United European Gastroenterol J 2013;1(4):294-‐8.
(62) Gao X, Yang RP, Chen MH et al. Risk factors for surgery and postoperative recurrence: analysis of a south China cohort with Crohn's disease. Scand J Gastroenterol 2012;47(10):1181-‐91.
(63) Regueiro M, Schraut W, Baidoo L et al. Infliximab prevents Crohn's disease recurrence after ileal resection. Gastroenterology 2009;136(2):441-‐50.
(64) Yoshida K, Fukunaga K, Ikeuchi H et al. Scheduled infliximab monotherapy to prevent recurrence of Crohn's disease following ileocolic or ileal resection: a 3-‐year prospective randomized open trial. Inflamm Bowel Dis 2012;18(9):1617-‐23.
(65) Armuzzi A, Felice C, Papa A et al. Prevention of postoperative recurrence with azathioprine or infliximab in patients with Crohn's disease: an open-‐label pilot study. J Crohns Colitis 2013;7(12):e623-‐e629.
(66) Yamamoto T, Umegae S, Matsumoto K. Impact of infliximab therapy after early endoscopic recurrence following ileocolonic resection of Crohn's disease: a prospective pilot study. Inflamm Bowel Dis 2009;15(10):1460-‐6.
(67) Savarino E, Bodini G, Dulbecco P et al. Adalimumab is more effective than azathioprine and mesalamine at preventing postoperative recurrence of Crohn's disease: a randomized controlled trial. Am J Gastroenterol 2013;108(11):1731-‐42.
(68) Kurien M, Evans KE, Leeds JS et al. Bile acid malabsorption: an under-‐investigated differential diagnosis in patients presenting with diarrhea predominant irritable bowel syndrome type symptoms. Scand J Gastroenterol 2011;46(7-‐8):818-‐22.
(69) Parker MC, Ellis H, Moran BJ et al. Postoperative adhesions: ten-‐year follow-‐up of 12,584 patients undergoing lower abdominal surgery. Dis Colon Rectum 2001;44(6):822-‐9.
