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World J Gastroenterol. Oct 21, 2014; 20(39): 14393-14406
Published online Oct 21, 2014. doi: 10.3748/wjg.v20.i39.14393
Predictors of recurrence of Crohn’s disease after ileocolectomy: A review
Tara M Connelly, Evangelos Messaris, Division of Colon and Rectal Surgery, Department of Surgery, The Pennsylvania State University, College of Medicine, Hershey, PA 17033, United States
Author contributions: Both authors contributed equally to the research and writing of this manuscript as well as the final approval of the manuscript.
Correspondence to: Evangelos Messaris, MD, PhD, Division of Colon and Rectal Surgery, Department of Surgery, The Pennsylvania State University, College of Medicine, 500 University Drive, H-137, PO Box 850, Hershey, PA 17033, United States. emessaris@hmc.psu.edu
Telephone: +1-717-5315164 Fax: +1-717-5310646
Received: February 12, 2014
Revised: May 8, 2014
Accepted: June 20, 2014
Published online: October 21, 2014

Abstract

Recurrence after ileocolectomy for Crohn’s disease (CD) is common and occurs in up to 80% of patients. Such recurrence can result in repeated surgical interventions, an increased need for medical treatment and, frequently, an impaired quality of life. The aim of this overview is to provide a summary of the factors associated with disease recurrence after ileocolectomy for CD. Recurrence can be measured clinically or endoscopically using established scoring systems. Radiology and serologic tests can also be used, oftentimes in conjunction with endoscopy and/or clinical findings. Many patient and operative factors as well as pharmacologic treatments have been studied as potential predictors of recurrence. Of these, only smoking and immunomodulatory or biologic medical treatment have repeatedly been shown to effect recurrence. Genetic predictors have been studied and suggested but further evaluation in larger cohorts is necessary. This paper highlights validated, reproducible scoring systems for recurrence and the key findings of studies including patient demographics, operative techniques, various pharmacological treatments and histological findings as predictors of recurrence post ileocolectomy in CD.

Key Words: Crohn’s disease, Ileocolectomy, Recurrence, Surgical genetics, Inflammatory bowel disease

Core tip: Disease recurrence after ileocolectomy for Crohn’s disease is common. Studies have been very heterogenous in defining recurrence as it can be clinical, endoscopic, radiologic or serologic. Of the potential predictive factors studied, smoking has been consistently demonstrated to increase the risk of recurrence. While immunomodulator and biologic medical treatment have been shown to increase the time between surgery and recurrence and may decrease overall risk. Genetic predictors have been suggested but further evaluation in large groups is needed. Several other demographic and operative factors have been studied. However, none have been consistently shown to affect recurrence risk.



INTRODUCTION

Crohn’s disease (CD) is a chronic immune mediated disease of the gut that was first described as “regional ileitis” by Crohn, Ginzburg and Oppenheimer in a case series presented at American Medical Association annual meeting in 1932[1]. CD is characterized by inflammation, abscesses, fistulization and stricturing that can affect any part of the gastrointestinal tract. However, the most common distribution is the ileocolic region, the location where the small bowel and colon meet. Approximately 55% of all CD patients have an ileocolic disease distribution, followed by colonic and small bowel distributions in approximately 20%-30% and 15%-20% and of patients respectively[2].

Although not curative, surgery is commonly required for the sequelae CD (e.g., abscess, fistula, perforation, bleeding and failure of medical treatment). Up to 80% of CD patients require at least one surgical intervention in their lifetime. The most common resection is the ileocolectomy. Recurrence at the site of the anastomosis is common and challenging[3,4]. Multiple resections due to recurrent disease can lead to short gut syndrome, malabsorption and malnutrition with significant morbidity, decreased quality of life and increased hospital and outpatient costs[5]. This review highlights the patient and disease related factors that are associated with an increased risk of disease recurrence after ileocolectomy in its many forms including clinical, endoscopic and radiologic recurrence.

Defining recurrence

Recurrence can be defined in several different ways using a multitude of modalities. Such inconsistency in regard to what constitutes recurrence in conjunction with heterogeneity among patient populations and prophylactic measures against recurrence given leads to a large variance in recurrence rates between studies (Table 1)[6]. Clinical and endoscopic recurrence are most commonly reported.

Table 1 Types of postoperative recurrence and evaluation type.
Type of recurrenceEvaluation method
ClinicalQuestionnaire, CDAI, Harvey-Bradshaw Index, IBDQ
EndoscopicRutgeerts score, Crohn’s disease endoscopic index of severity
RadiographicCT or MR enterography, barium enema small bowel follow through
SerologicalMeasurement of CRP and ESR
SurgicalRequirement for repeat surgery

Clinical recurrence is loosely defined as an increase in patients’ symptoms including diarrhea, weight loss and abdominal pain. For the most appropriate investigation and reporting of clinical recurrence, established validated quality of life questionnaires such as the Inflammatory Bowel Disease Questionnaire[7] or scoring systems such as the Crohn’s disease activity score (CDAI) or Harvey-Bradshaw Index should be used[8]. The CDAI can be clinician or self-administered and contains subjective questions (on general well-being and symptoms such as abdominal pain) as well as objective measures (such as hematocrit, numbers of stools per day, weight loss, the presence of arthralgia, fistuli, fever, an abdominal mass and/or ocular, dermatological or anal manifestations) (Table 2)[9,10]. Endoscopic recurrence uses colonoscopy or ileoscopy as appropriate to determine the presence of recurrence, which is most commonly found at the site of the anastomosis. The Rutgeerts visual grading system evaluates the presence and number of aphthous ulcers and the intervening mucosa in the perianastomotic region and is the most commonly used internationally recognized endoscopic grading system for post ileocolectomy recurrence (Table 3)[11,12]. Radiographic recurrence is less commonly studied and is often utilized as an adjunct to clinical or endoscopic recurrence. CT or MR enterography, small bowel follow through and/or barium enema are the modalities currently employed[13]. Serological recurrence is defined by the elevation of serum inflammatory markers such as C reactive protein (CRP) and erythrocyte sedimentation rate (ESR). Although more novel interleukin markers have been studied, none are in clinical use to date. Surgical recurrence is determined by the requirement for repeat ileocolectomy and is often indicative of more severe disease. Oftentimes, these different classifications of recurrence are studied in conjunction with each other.

Table 2 Factors in the Crohn’s disease activity score.
General well-being
Number of stools/d
Abdominal pain
Weight loss
Presence of arthralgia, fistuli, fever and/or ocular, dermatological or anal manifestations
The need for anti-diarrheal medication
Abdominal mass
Hematocrit
Table 3 Factors in the Rutgeerts endoscopic recurrence score for postoperative recurrence of Crohn’s disease in the distal ileum.
Endoscopic appearanceScore
No aphthous ulcers0
< 5 aphthous ulcers1
> 5 aphthous ulcers with normal mucosa between the ulcers2
Diffuse aphthous ulcers throughout the ileum with intervening inflamed mucosa3
Large ulcers with diffuse inflammation, nodules or narrowing of the ileum4

Endoscopic, radiographic and serologic recurrence rates are in actuality higher than reported as frequently, only clinically symptomatic patients are investigated. Additionally, there is limited concordance between the different types of recurrence in the individual patient. For example, Bordieianou et al[14] compared endoscopic, symptomatic and surgical recurrence rates in approximately 200 ileocolectomy patients and found that while 31.2% of their cohort had documented endoscopic recurrence, only 23.1% had symptomatic and 11% had surgical recurrence. This disparity was also demonstrated in McLeod et al[15] 1997 study which included a variety of CD resections, of which 60% were ileocolectomies. Interestingly, 21% of patients with severe symptoms had minimal endoscopic or radiologic evidence of recurrence. Conversely, 28% of the asymptomatic patients studied had endoscopic or radiologic evidence of severe recurrence. Similarly, Regueiro’s study of 24 CD patients 1 year post ileocolectomy demonstrated a poor correlation between CDAI scores, serum CRP or ESR and endoscopy findings[16]. Only 87% of patients with endoscopic or radiologic recurrence had symptoms in Malireddy’s study[17].

Endoscopic recurrence generally occurs earlier than other types of recurrence with an overall mean time from surgery to endoscopic recurrence ranging from 6 mo to 4 years[14,17]. Mean time to symptomatic recurrence is approximately 5 years[14]. Mean time to repeat surgery has the longest duration, approximately 7 (range of 5-11) years[9]. Overall, rates of approximately 30% for endoscopic, 23% for symptomatic or clinical and 11%-50% for surgical recurrence are documented in the literature[3,14,18]. However, it is more clinically relevant to evaluate recurrence by time period, according to time since ileocolectomy. Overall recurrence rates by time period are shown in Table 4. The multiple factors affecting recurrence are discussed below.

Table 4 Overall recurrence rates by post ileocolectomy follow up and type of recurrence.
Time post ileocolectomyType of recurrence% of ileocolectomy PatientsRef.
1 yrClinical0%-44%McLeod et al[61], Walters et al[10], Aratari et al[27], Bordeianou et al[14], Sorrentino et al[28], Pascua et al[53]
Endoscopic0%-84%Bordeianou et al[14], Walters et al[10], McLeod et al[15,61], Regueiro et al[16,82], Rutgeerts et al[11], Pascua et al[53], Domènech et al[80], Sorrentino et al[28], Meresse et al[40], Lasson et al[89]
Surgical4%-25%Aratari et al[27], Iesalnieks et al[57]
5 yrClinical32%Aratari et al[27]
Endoscopic55%-77%Bordeianou et al[14], McLeod et al[15], Yamaoto et al[42]
Symptomatic50%Bordeianou et al[14]
Surgical4%-25%Bordeianou et al[14], Aratari et al[27], Riss et al[56], Yamamoto et al[42]
10 yrClinical52%Aratari et al[27]
Endoscopic74%Malireddy et al[17], Bordeianou et al[14]
Surgical12%-57%Stocchi et al[18], Aratari et al[27], Riss et al[56], Iesalnieks et al[57]
PATIENT FACTORS
Demographics

Although gender, age at diagnosis, age at surgery and disease duration have been studied as potential predictors of post-operative recurrence, no correlation has been consistently demonstrated[14,17,19,20].

A positive family history of IBD was demonstrated to confer a 2.2 fold increased likelihood of requiring a second ileocolectomy in Unkart’s study of 176 post ileocolectomy patients with at least one surgical recurrence. However, this result has not been replicated in the literature[21].

The most studied and most recognized risk factor for post-operative recurrence is smoking (Table 5). Several studies evaluating smoking as a predictor of recurrence do not exclusively study ileocolectomies. One such study by Kane et al[22] followed 59 CD patients post colonic resection. Sixty-nine percent of smokers vs 23% of nonsmokers had recurrence documented using a clinical symptom activity score. Odds ratio for recurrence was 2.96 in the smoking cohort and a strikingly shorter duration to clinical relapse was seen in smokers (130 vs 234 wk in nonsmokers). Cottone et al[23] similarly followed 182 surgical CD resection patients for 6 years and demonstrated that both smoking and greater disease extent were associated with worse clinical (CDAI) scores and increased risk of endoscopic recurrence. Although several variable were studied, the only significant predictor of surgical recurrence was smoking. Meta-analysis of 16 studies published between 1966-2007 inclusive of 2962 patients undergoing resection for CD demonstrated an OR of 2.2 for clinical postoperative recurrence in smokers and an increased risk of surgical recurrence particularly at 10 years (OR = 2.6, 55.5% vs 32.1% in nonsmokers)[24]. However, again, this analysis was not limited to patients who had undergone ileocolectomies only.

Table 5 Effect of smoking on postoperative recurrence.
AssociationNumber and type of patientsRef.
Recurrent clinical symptoms (OR = 2.96)59 patients post colonic resection for CD (not only ileocolectomies)Kane et al[22]
Shorter duration to clinical relapse (104 wk shorter)
Recurrent clinical symptoms (worse CDAI scores)182 post colonic resection for CD (not only ileocolectomies)Cottone et al[23]
Increased rates of endoscopic recurrence
Increased likelihood of requiring surgery
Smoking at the time of the 1st ileocolectomy conferred a 2.1 fold increased likelihood of requiring another operation176 post ileocolectomy patients with at least 1 recurrenceUnkart et al[21]
OR of 2.2 for clinical recurrenceMeta-analysis of 16 studies, 2962 patientsReese et al[24]
Increased risk of surgical recurrence particularly at 10 years (OR = 2.6)
Smokers had a lower 5 and 10-yr recurrence free likelihood (65 and 45% vs 81 and 64% in nonsmokers)141 ileocolectomy patientsYamamoto and Keighley[26]
Recurrence free rates were lower in those that smoked > 15 cigarettes per day
Patients that quit smoking are less likely to require redo ileocolectomy266Ryan et al[25]
No association with recurrence89 lap ileocolectomy patientsMalireddy et al[17]
No association with clinical or surgical recurrence83Aratari[27]
No association with clinical or endoscopic recurrence43 resections (30 = Ileocolectomies)Sorrentino[28]

Studies that focus solely on ileocolectomy recurrence include Unkart et al[21] study which demonstrated that smoking at the time of the 1st ileocolectomy confers a 2.1 fold increased likelihood of requiring another operation. http://www.ncbi.nlm.nih.gov/pubmed?term=Unkart%20JT%5BAuthor%5D&cauthor=true&cauthor_uid=18536967Repeat ileocolectomy rates of 59%-69% in smokers have been noted by Cullen et al[3] and Ryan et al[25]. Another study evaluated the relationship between the number of cigarettes smoked daily and recurrence in 141 ileocolectomy patients. Smokers had lower 5 and 10 year recurrence free likelihoods (65% and 45 % vs 81% and 64% in non-smokers). Recurrence free rates were lower in those that smoked > 15 cigarettes per day[26]. Although the majority of studies have shown an increased risk for reoperation, Maliredy, Aratari and Sorrentino did not see such an association in their studies which included approximately 195 patients combined[17,27,28].

Genetics

Since the advent of genome wide associations studies, several studies inclusive of large cohorts of both IBD patients and healthy individuals have been performed thus creating a pool of IBD-associated genes and single nucleotide polymorphisms (SNPs). To date, over 300 SNPs and 150 genetic loci have been associated with IBD[29]. With these IBD-associated genes established, a shift towards using these markers to further characterize disease behavior, including postoperative recurrence in CD, has begun[30]. Several “surgical genetics” studies have identified markers of the need for resection in their CD cohorts including mutations within the NOD2, TNFSF15 and C13ORF31 genes[31]. However, fewer studies have focused on determining a marker of recurrence.

NOD2 (nucleotide-binding oligomerization domain-containing protein 2), also known as CARD15 (caspase recruitment domain-containing protein 15), was the first gene to be associated with IBD in 2001[32]. Located on chromosome 16, the gene is expressed in several different cell types key to the pathogenesis of CD such as dendritic cells, monocytes, intestinal epithelial cells and Paneth cells. Its protein product is involved in the recognition a dipeptide found in the bacterial cell wall[33]. NOD2 has been previously associated with ileal[34] and stricturing CD[35].

An early German study evaluated the NOD2 genotypes of 51 post ileocolectomy patients. Fourteen patients required a repeat ileocolectomy. Of the 14, 12 harbored at least 1 NOD2 mutation[36]. This association may be specific to patients of German and other not yet determined ethnicities, as this increased incidence of NOD2 mutations in patients with recurrent disease was not replicated in an Italian multi-center study of 253CD patients, 42% of whom had ileocolic disease. In this study, no relation between NOD2 genotype, age at diagnosis or smoking status and recurrence was found[37]. Similarly, in a recent meta-analysis of 6 studies inclusive of 1003 patients with CD NOD2 genotype was not associated with surgical recurrence. Overall, 39% of patients with a NOD2 mutation required further resection vs 30.5% of patients without a mutation (P = 0.06). However, the included studies were very heterogenous, which may have affected results[38].

Another study of only ileocolectomy patients demonstrated the presence of a mutation in the autophagy associated IRGM (Immunity-related GTPase family, M) gene to be significantly associated with more frequent ileocolectomies and earlier time to reoperation in 66 CD patients. Ileocolectomy was performed every 6.8 +/- 1.3 years on average in patients with the at risk genotype for SNP rs4958847 vs once every 11.4 years in patients with the wild type genotype[39].

Meresse et al[40] studied G microsatellite genotype with the anti-inflammatory gene, IL10 in 36 post ileocolectomy patients. Although genotype affected IL-10 production, no association was seen with endoscopic recurrence.

Nutritional status

Poor nutritional status has been consistently associated with poor outcomes in CD surgery[41]. Thus postoperative enteral feeding has been studied as a potential way to reduce the risk of complications and recurrence. Often, such studies are technically difficult to perform, particularly after patients are discharged from the hospital, and mid-study patient exclusion due to noncompliance is common. In one such Japanese study of 40 post ileocolectomy patients followed for 5 years, 20 received nighttime continuous nasogastric feeding with an elemental diet and a low fat diet during the day. The other 20 did not receive the nighttime feed and had an unrestricted diet. No postoperative steroid, immunosuppressants or biologics treatment was given to either cohort. Thirty percent of the nighttime feeding group vs 70% of the controls had endoscopic recurrence at 1 year. Twelve months after surgery, 10% of the night feed and 45% of the control group required biologics during the follow up. Rates for surgical recurrence were 5% and 25% in the 2 groups but this was not statistically significant[42].

Much attention has been given to the gut microbiome and how it interacts with the disease process in CD[43]. However, few studied have centered on altering the gut microbiome to maintain remission in patients who have undergone resection. A meta-analysis of 10 controlled clinical trials evaluating disease recurrence, demonstrated that probiotics were not associated with either endoscopic or surgical remission. In this meta-analysis patients who had undergone surgery or medical treatment prior to the administration of probiotics were not considered separately[44]. Another systematic review of 24 manuscripts evaluating endoscopic recurrence demonstrated that enteric diets were associated with 61% reduction in endoscopic scores. However, again postoperative patients and patients in medical remission were not considered separately[45]. One multicenter randomized study by Van Gossum et al[46] focused only on post ileocolectomy patients and the effect of administration of the probiotic LAl vs placebo on early (12 wk) post ileocolectomy recurrence in 49 patients. Patients were stratified according to smoking status. There was no difference in endoscopic or clinical recurrence scores seen between the 2 groups. Twenty one percent of the placebo vs 15% of the probiotic group had recurrence scores indicative of severe recurrence but this difference was not statistically significantly different.

DISEASE BEHAVIOR
Penetrating vs non-penetrating

Disease behavior is difficult to use as a predictor of endoscopic recurrence due to the varying course of CD typically seen within the individual patient. The Montreal classification of inflammatory vs stricturing vs penetrating (fistulizing/abscessing) disease is commonly used to classify CD according to its behavior[47]; however, behavior often changes from inflammatory to stricturing or penetrating over time[48-50]. Also, at any time point a patient may have more than 1 type of disease behavior, (i.e., a stricture and a fistula) presenting challenges with classification. Additionally, penetrating disease that is initially responsive to a particular medical treatment may lose responsiveness with repeated doses and thus transform from a penetrating to inflammatory to penetrating phenotype when responsiveness ceases[51].

Nonetheless, several studies have attempted to correlate disease behavior with risk of post-operative recurrence. In multiple studies, including 2 large Italian multicenter studies, disease behavior was not shown to affect the risk of disease recurrence clinically, surgically or endoscopically[14,20,27,52]. Although not a primary end point of the study, a meta-analysis of 12 randomized controlled trials that evaluated medical therapies after CD resections (not exclusively ileocolectomies) from 1966 to 2005, demonstrated that fistulizing disease was significantly associated with endoscopic but not clinical recurrence in patients who had been given placebo treatment[53].

Granulomatous disease

Granulomas, or histologic areas of macrophage fusion, are a hallmark of CD but need not be present for a definitive diagnosis[54]. An association between granulomas and disease severity has been suggested but not proven[55]; however, an association between the presence of granulomas in the ileocolic resection specimen and recurrence has been consistently demonstrated. In an observational study by Malireddy et al[17] recurrence rates in 89 patients who had undergone laparoscopic ileocolectomy from April 1994-August 2006 (with a median follow up of 3.5 years) were evaluated. A 61% endoscopic, radiologic or pathologic recurrence rate was noted. The median time for recurrence was 13.1 mo (range, 1.3 mo to 8.7 years). Several potential prognosticators for recurrence including postoperative biologic and other medical treatment were also studied. The only significant predictor of recurrence found on multivariate analysis was the presence of granulomas in the initial resection specimen. An earlier Irish study of 139 patients who underwent ileocolectomy between 1980 and 2000 evaluated the presence of symptoms, endoscopic recurrence and radiological recurrence. Again, the presence of granulomas in the specimen was significantly associated with clinical and surgical recurrence[3]. In a similar early study of 114 ileocolectomy patients, 66% with granulomas vs 48% without experienced an endoscopic recurrence within the first year after an ileocolectomy[11]. In 1997, Anseline et al[20] evaluated 130 CD patients undergoing a variety of resections. After multivariate analysis, the presence of granulomas was significantly associated with recurrence.

INDEX ILEOCOLECTOMY DETAILS
Urgent vs elective resection

Several groups have hypothesized that if a patient’s first ileocolectomy is performed under emergency circumstances, this likely reflects more severe disease and thus may predict an increased likelihood of recurrence. One retrospective multicenter Italian review evaluated clinical recurrence (defined as the need for steroids in conjunction with endoscopic or radiologic findings) and surgical recurrence in 83 CD patients who underwent ileocolectomy for severe disease at the time of diagnosis vs 124 who underwent surgery later in their disease for medical refractory disease and/or complications secondary to their disease. Recurrence was evaluated at 1, 5 and 10 years. Clinical recurrence was less frequent in the early surgery group at all-time points. No difference was seen in the need for or timing of repeat surgery between the 2 groups[27]. Another retrospective study of 116 consecutive patients undergoing their first ileocolectomy at a large Austrian referral center between 1997 and 2006 demonstrated that urgent index ileocolectomy increased the risk of repeat surgery approximately 6 fold[56].

Sepsis

Another potential marker of severe disease is perioperative sepsis at the time of index ileocolectomy. However, results are conflicting and further study is warranted. Elevated white cell count was associated with endoscopic recurrence on univariate analysis in Caprilli et al[52] study of 110 ileocolectomy patients. However, an increased risk of recurrence in urgent vs elective ileocolectomy patients was not demonstrated. Iesalnieks et al[57] studied 282 patients who underwent 331 varied CD resections between 1992-2005. On multivariate analysis, postop intraabdominal septic complications and history of a previous resection were associated with increased surgical recurrence risk at all-time points studied from 1-10 years. At 1 year patients with a history of sepsis had a recurrence rate of 25% vs 4% of those without sepsis. At 10 years rates were 57% and 38% respectively.

Laparoscopic vs open approach

As laparoscopic surgery and stapled anastomosis initially gained popularity for use in the CD population in the 1980s, an interest in determining if either technique decreases the risk of recurrence post ileocolectomy led to several studies. One such retrospective review of 113 patients undergoing their index ileocolectomy between 1987-2003 (with a mean follow up of approximately 70 mo) demonstrated a slightly lower, but not significantly different, rate of postoperative medical treatment requirement in laparoscopic vs open patients (39% vs 54%). Surgical recurrence was seen in 9.5% (6/63) of laparoscopic vs 24% (12/50) of open ileocolectomy patients during a mean follow up of 81 mo. Time to recurrence was not affected. Both groups had a median time to recurrence of approximately 60 mo[58]. Similarly, Stocchi et al[18] performed a prospective randomized trial in which 77 patients underwent laparoscopic ileocolectomy and 29 underwent an open procedure. Both cohorts had a similar postoperative prophylactic medication regimen and a mean follow up of 10.5 years. Reoperation rates were the same in the 2 groups (approximately 26% in each). Endoscopic and radiologic recurrence rates were similar. Forty-eight percent of laparoscopic patients experienced endoscopic or radiologic recurrence vs open patients who demonstrated a 66% endoscopic recurrence and 52% radiologic recurrence rate. The most recent meta-analysis on laparoscopic vs open approach included 33 studies and included 2519 patients. No statistical difference was seen in surgical recurrence rates which were 25 per 1000 person years in the laparoscopic group vs 34 per 1000 person years in the open group[59].

Resection margins and type of anastomosis

Stapled anastomosis has now virtually replaced the hand sewn technique in the majority of centers performing ileocolectomies for CD. Two studies, inclusive of 199 and 89 ileocolectomy patients, evaluated resection margins and anastomotic type. In both studies, no difference in clinical recurrence was found between patients whose resection margins were affected by disease vs those who had unaffected margins. There was also no difference seen between stapled or hand sewn anastomoses[14,17]. In the only randomized study to date, Fazio et al[60] evaluated recurrence in 131 ileocolectomy patients randomized to undergo resections with proximal margins either 2 or 12 cm from the macroscopically diseased tissue followed up for median of 56 mo. The resection specimen was also studied for microscopic signs of disease. Surgical recurrence was found in 25% of patients who had undergone a limited resection vs 18% of those who had undergone the more extensive resection (P > 0.05). Clinical recurrence was demonstrated in 33% vs 29% of those with limited and extended resections respectively. No relation was seen between microscopic CD found at the resection margin and recurrence.

In Bordeianou’s study of approximately 200 ileocolectomies, stapled anastomosis although significant on univariate analysis, lost significance on multivariate analysis[14]. End-to-end vs side-to-side anastomotic techniques has also been evaluated in 2 randomised trials comparing anastomosis types in 98 and 139 CD patients respectively. Both studies failed to demonstrate a difference in symptomatic or endoscopic recurrence rates between the groups. The first study demonstrated an endoscopic recurrence rate of 42.5% in the end-end vs 37.9% in the side-side anastomosis groups and a symptomatic recurrence rate of approximately 22% in both groups[61]. The second study demonstrated that overall, on multivariate analysis, anastomosis type did not affect endoscopic recurrence. However, a 3 fold risk of recurrence was seen in a subgroup of patients with end-end anastomoses who were treated with 5 aminosalicylates (ASAs). This increased risk was not seen in those not treated with ASAs[52]. Meta-analysis of 8 studies published between 1992-2005 inclusive of 661 ileocolectomy patients compared end-to-end anastomosis vs other anastomotic configurations (stapled side-to-side, end-to-side or side-to-end, stapled circular end-to-end). No significant difference was found in clinical or surgical recurrence between the different groups[62].

Techniques to potentially minimize risk of recurrence are currently under development. The Kono-S is one such novel technique. This technique utilizes a linear stapler-cutter to transversely divide the tissue for resection. The corners of the 2 stapled lines are sutured together and antimesenteric longitudinal enterotomies are created on both sides. The enterotomies are then closed transversely in two layers resulting in an anti-mesenteric functional end-to-end anastomosis. This technique has shown promise in a small cohort of 18 patients, 43% of whom have undergone follow-up endoscopic surveillance with an average Rutgeert’s score of 0.7 (0-3) at a mean of 6.8 mo[63].

MEDICAL TREATMENT TO PREVENT DISEASE RECURRENCE

Key studies on the effect of medical treatment for the prevention of recurrence are highlighted in Table 6. Traditionally, treatment paradigms for CD followed a “bottom up” approach with initial treatment comprised of corticosteroids, antibiotics and/or 5 ASAs. Escalating treatment in the form of immunomodulators or biologics either replaced this treatment or was added to it as the disease flared or progressed. Steroids and antibiotics are rarely given as monotherapy to prevent relapse in CD currently. Thus, studies that focus on their efficacy are commonly from the 1980s and 1990s. One such double-blind, randomized trial performed in 13 European centers followed 63 patients given budesonide and 66 patients given placebo post ileocolectomy. At 1 year, no difference in endoscopic recurrence was seen between the 2 groups. However, a significantly lower endoscopic recurrence rate was seen in a subgroup of patients treated with budesonide, namely those who had undergone surgery for increased disease symptoms rather than obstruction or fistulization (32% vs 65% of the placebo group)[64].

Table 6 Key studies on medical treatment for the prevention of postoperative recurrence in post ileocolectomy patients.
Interventions ComparedStudy DesignStudy Numbers (end of follow-up)Follow-upClinical ImprovementEndoscopic ImprovementOtherRef.
Mesalamine vs PlaceboDouble Blind, Multicenter8712 mo59% of placebo vs 41% of mesalamine had a clinical relapseSignificantly less severe and less frequent lesions in mesalamine group (P < 0.008)Severe endoscopic or radiologic was 24% in mesalamine vs 56% of placebo (P = 0.004)Brignola et al[68]
Budesonide vs placeboDouble-blind, randomized trial12912 moNo difference in CDAI at any time point in the studyOnly patients who underwent surgery for increased disease symptoms (not fibrostenotic or fistulizing disease) had a significantly lower endoscopic recurrence rate (32% vs 65% of the placebo group)AT 12 mo the ESR value was 13.3 mm/h in the budesonide group vs 20.2 mm/h in the placebo group (P = 0.017). Mean CRP values after decreased from 19.0 to 6.2 mg/L in the budesonide group and from 12.7 to 12.2 mg/L in the placebo group (P = 0.018)Hellers et al[64]
Mesalamine vs placeboDouble-blind, placebo controlled1224648 wk25% of the mesalamine vs 36% of the placebo had a relapse [(per CDAI) P = 0.06] On subgroup analysis ileocolonic patients had fewer relapses on mesalamine (21% vs 41%) P = 0.00310% vs 23% surgical recurrence (P = 0.13)Sutherland et al[67]
Mesalamine vs placeboRandomized163 post-surgical patients1 109 were post ileocolectomyMaximum 72 moEndoscopic and radiological recurrence was significantly decreased in the mesalamine group with relative risks of 0.6 (P = 0.016)31% symptomatic recurrence rate (symptoms plus endoscopic and/or radiological confirmation of disease) vs 41% in the control group, P = 0.03McLeod et al[69]
6 MP, mesalamine or placeboMulti (5) center, double blind, randomized13124 moClinical recurrence was improved by mesalamine or 6 MP. Clinical recurrence rates at 24 mo were 50% for 6 MP, 58% for mesalamine and 77% for placebo (P = 0.04)Only 6 MP, not mesalamine was superior to placebo to prevent endoscopic and radiographic recurrence at 24 mo. Relapse was 43% with 6 MP, 63% with mesalamine, 64% with placebo (P = 0.03)Radiographic recurrence rates were 33% for 6 MP, 46% for mesalamine and 49% for placebo (P > 0.05)Hanauer et al[76]
Infliximab vs mesalamine (control)Prospective, multicenter pilot study to determine if giving infliximab after diagnosis of postoperative endoscopic ileocolic CD recurrence at 6 mo can induce endoscopic remission at 54 wk24 (19 had ileocaecal disease)54 wkNo clinical recurrence in the infliximab group at 6 moNo endoscopic remission at 54 wk in the mesalamine group vs the infliximab group 54% had endoscopic remission at 54 wk (P = 0.01)Sorrentino et al[28]
18% of mesalamine who had clinical relapse by 9 mo
Adalizumab vs AZA vs mesalamineRandomized512 yrThe ADA treated patients had the lowest incidence of endoscopic recurrence (6.3% vs 64.7% of the AZA group and 83.3% of the mesalamine group)Savarino et al[83]
Infliximab vs placeboRandomized241 yrClinical remission was higher in the IFX group (80% vs 54%) but P = 0.38)Endoscopic and histologic recurrence was significantly lower at 1 yr in the patients treated with infliximab (1 of 11; 9.1% and) vs placebo (11 of 13 patients; 84.6%). P = 0.0006Lower histologic recurrence in the IFX group (3 of 11/27% vs 11 of 13/85% of placebo) P = 0.01Regueiro et al[82]
Metronidazole +AZA or placebo62Randomized12 moEndoscopic recurrence was observed in 14 of 32 (43.7%) patients in the AZA group and in 20 of 29 (69.0%) patients in the placebo group at 12 mo post-surgery (P = 0.048. At 1 yr 21% of the AZA group were lesion free vs 3% of the placebo (P = 0.04)D'Haens et al[77]
Metronidazole vs placeboDouble-blind controlled513 yrClinical recurrence rates at 1 yr were 4% in the metronidazole vs 25% of placebo) NSD P = 0.04. Reductions at 2 yr (26% vs 43%) and 3 yr (30% vs 50%) both NSDAt 12 wk, 21 of 28 patients (75%) in the placebo group had recurrent lesions in the neoterminal ileum vs 12 of 23 patients (52%) in the metronidazole group (P = 0.09)Rutgeerts et al[65]
Immunosuppressants (AZA/6 MP or MTX) vs control (5 ASAs or no treatment)26 patients undergoing their 2nd ileocolectomy3 yrClinical recurrence was lower in the immmunosuppressant group vs the control group (3/12, 25% vs 6/10, 60%; P < 0.05)The control group required a 3rd resection more commonly. (7/12, 58% vs 2/14, 17% P < 0.02)Alves et al[79]
(range 17-178 mo)No difference in time to recurrence was seen (approximately 27 mo in both groups)
AZA therapy commenced immediatiely post resectionProspective, observational56 consecutive patients 15 or 27% had ileocolectomiesMean 12-84 moNo clinical recurrence at 12 mo recurrence70% had endoscopic recurrence at 12 mo. The cumulative probability of endoscopic recurrence was 82% at 5 yrDomènech[90]

Studies on antibiotic monotherapy have been limited to metronidazole. In a double-blind controlled trial evaluating the use of metronidazole as monotherapy post ileal resection in 51 patients, recurrent lesions were seen in 75% of the placebo group vs 52% of the metronidazole group at 12 wk (P = 0.09). At 1 year, clinical recurrence rates were much lower in the metronidazole group (4% vs 25%); however significance was lost at 2 years (26% vs 43%)[65].

The commonly used aminosalicylate based drugs, including mesalamine, generally have low side effect profiles and have been shown by meta-analysis to prevent relapse in inactive CD[66]. However, results from studies evaluating their long term efficacy in the prevention of post ileocolectomy recurrence are not impressive, particularly in regard to clinical recurrence. One large double blind, placebo controlled study by Sutherland et al[67] compared clinical recurrence as defined by CDAI scores in medical and surgical CD patients (who had undergone a variety of resections) treated with either mesalamine or placebo. At 48 wk, 25% of the mesalamine vs 36% of the placebo had a clinical recurrence. However, disease recurrence was only 10 d later in the mesalamine treated patients. Interestingly, ileocolonic patients had fewer relapses on mesalamine (21% vs 41% given placebo) on subgroup analysis. In another double-blind, multicenter clinical trial published in 1995, 87 patients were treated with mesalamine or placebo within 1 mo after undergoing ileocolectomy. At 12 mo, 41% of the 17 patients who relapsed clinically had been given mesalamine. Using endoscopic and radiological evaluation with scoring systems, the mesalamine group had significantly less frequent and less severe lesions and milder disease. Disease was classified as “severe” in 24% of the mesalamine treated patients vs 56% of those given placebo[68]. In another study published the same year, 163 post resection patients (of whom 109 had undergone ileocolectomy) were randomized to receive either mesalamine twice a day or placebo. During a maximum follow up of 72 mo, 31% of those given mesalamine experienced a symptomatic recurrence defined as symptoms plus endoscopic and/or radiological confirmation of disease vs 41% in the control group[69].

A new paradigm of a “top down” approach to the treatment of CD in which surgery and early institution of immunomodulatory and/or biologic drug therapy has been suggested by large trials such as the SONIC trial. This approach has demonstrated improved mucosal healing, a reduction in steroid use, longer remission times and faster clinical response than the traditional bottom up approach[70,71]. Additionally, multidrug therapy has been proven to increase drug serum levels, address multiple disease mechanisms and potentially reduce the production of anti-drug antibodies[70,72,73]. The immunomodulatory drugs azathioprine (AZA) and 6 mercaptopurine (6 MP) are two drugs commonly used in the top down approach. Used on their own or in conjunction with other IBD medications, these drugs have a high success rate in treating flares, reducing the steroid requirement and increasing remission rates in medically treated disease and[74,75] have been suggested to be effective at reducing recurrence and increasing duration from surgery to recurrence. In a 5 center, double blind study inclusive of 131 post ileocolectomy patients randomized to receive 6 MP, mesalamine or placebo, only 6 MP was superior to placebo for the prevention of endoscopic and radiographic recurrence at the study endpoint of 24 mo. Clinical recurrence rates were improved by mesalamine or 6 MP administration with recurrence rates of 50% for 6 MP, 58% for mesalamine and 77% for placebo at 24 mo demonstrated. Endoscopic and radiologic recurrence rates were 43% and 33% for 6 MP, 63% and 46% for mesalamine and 64% and 49% for placebo[76].

The utility of immunomodulatory drugs has been studied in subgroups of patients who are at increased risk for recurrence. D’Haens et al[77] studied 62 patients who were aged < 30, had a history of multiple ileocolectomies and/or had penetrating disease. Post ileocolectomy, all patients were given metronidazole for 3 mo with either azathioprine or placebo for 12 mo. At 12 mo, a significant difference in endoscopic recurrence was observed with 43.7% of patients in the AZA group experiencing recurrence vs 69.0% of those in the placebo group. Endoscopically, 21% of the AZA group were lesion free vs 3% of the placebo (P = 0.04). Mañosa et al[78] virtually reversed this study and administered AZA to 50 ileocolectomy patients postoperatively. At 3 mo, patients were randomized to receive either metronidazole or placebo. At 12 mo, endoscopic recurrence was seen in 36% of the metronidazole and 56% of the placebo group. However, this difference was not significant, suggesting that AZA on its own may be sufficient. In another high risk group, those undergoing their 2nd ileocolectomy for anastomotic recurrence, immunosuppressant drugs were shown to decrease clinical and surgical recurrence. Twenty-six patients were randomized to receive an immunosuppressant drug (6 MP, AZA, Methotrexate, n = 14) or a control treatment (5 ASAs, n = 5 or no treatment, n = 7). Clinical recurrence rates were lower in the immunosuppressant treated group vs the control group (3/12, 25% vs 6/10, 60%; P < 0.05). No difference in time to recurrence was demonstrated between the groups (approximately 27 mo in both groups). The control group required a 3rd resection more commonly (7/12, 58% vs 2/14, 17%, P < 0.02)[79]. Other evidence suggests that AZA/6 MP treatment may delay but not prevent recurrence. Fifty-six consecutive patients commenced on AZA treatment immediately after resection were studied in Domènech et al[80] observational study. Fifteen (27%) had ileocolectomies. Seventy percent of the cohort had endoscopic recurrence at 12 mo. However, no clinical recurrence was observed. At approximately 3 years’ follow up, 30% of patients maintained endoscopic remission. At 5 years, the cumulative probability of endoscopic remission dropped to 18%. Due such evidence, the American Gastrological Association has recommended that as 6 MPs likely reduce the risk of clinical and endoscopic recurrence, they should be used in those at “high risk” for recurrence or ‘in whom postoperative recurrence would have deleterious effects[81].

The anti-tumor necrosis factor (TNF) drugs, including infliximab and adalimumab are among the newest IBD drugs and have rapidly gained popularity over the past 10 years. A role for these drugs in the prolongation of postoperative remission has been suggested by preliminary studies. In one such study, significantly lower 1 year postoperative endoscopic and histologic recurrence rates were demonstrated in patients who had undergone ileal resection who were treated with infliximab. 9.1% (1 of 11) of these patients had endoscopic recurrence vs 27% (3 of 11) that were given placebo. Clinical remission rates were also higher in the infliximab group (80% vs 54% of the placebo group) but this difference wasn’t significant[82]. One prospective, multicenter but also small Italian study, aimed to determine if the administration of infliximab after diagnosis of postoperative endoscopic recurrence of ileocolic CD can induce endoscopic remission at 54 wk. Mesalamine was used as the control. In the mesalamine group (n = 11), no endoscopic remission was seen at 54 wk. Two patients had clinical recurrences at 8 and 9 mo. In the infliximab group (n = 23), 54% had endoscopic remission at 54 wk. None had clinical recurrence[28].

Infliximab is the most commonly used and studied anti-TNF drug. However, a recent randomized control trial evaluated the efficacy of adalimumab for the prevention of post ileocolectomy recurrence[83]. Fifty-one patients were randomized to receive adalizumab, AZA or mesalamine postoperatively. At 2 years, the adalizumab treated patients had the lowest incidence of endoscopic recurrence (6.3% vs 64.7% of the AZA group and 83.3% of the mesalamine group). Similarly clinical recurrence was lower in the adalizumab treated patients (12.5% vs 65% in both the AZA and mesalamine groups).

The timing of postoperative treatment has sparked a great interest due to the side effects of many IBD medications. The use of a “tailored treatment approach” to determine the effect of the timing of drug commencement on symptomatic recurrence after ileocolectomy was studied by Bordeianou et al[14]. In their cohort of 199 ileocolectomy patients, 35% were given immediate post ileocolectomy prophylaxis in the form of antibiotics, 5 ASAs, immunomodulators (6 MP/AZA) and/or anti-TNFs. Sixteen percent were commenced on a drug regimen at the time of endoscopic recurrence and 49% percent did not receive any treatment. Symptomatic recurrence occurred in 29% of those treated immediately postoperatively vs 44% of those who were treated after recurrence. After multivariate analysis, the significant difference between the 2 groups was lost and the only remaining significant prognostic factor recurrence was Charlson Comorbidity Index[84]. Malireddy et al[17] studied pre vs postoperative administration of anti-TNFs and immunomodulators in 89 laparoscopic ileocolectomies. Timing of treatment did not affect recurrence rates. Postoperative medical treatment lengthened the time to recurrence with a median time to recurrence of 25 mo demonstrated in the group given pharmacoprophylaxis vs 16 mo in the control group. However, this difference was not statistically significant.

SERUM MARKERS

Serum markers such as CRP and ESR are relatively noninvasive to obtain and have been demonstrated to reflect disease activity. Thus such markers may be potential prognosticators for post ileocolectomy recurrence. ESR and CRP were studied in a randomized controlled multicenter Italian trial of 98 patients undergoing their first ileocolectomy. When evaluating endoscopic recurrence at 6, 12, 24, and 36 mo post operatively, ESR and CRP were not correlated with endoscopic recurrence[52].

Pro and anti-inflammatory cytokines are not measured in clinical practice. However, they offer the potential to be used as markers of disease activity and, possibly, disease recurrence. Yamamoto et al[85] evaluated levels of the proinflammatory cytokines IL-6 (interleukin 6), IL1B and TNFα in blood, ileal biopsies and rectal biopsies at enrollment and 1 year after ileocolectomy in 36 patients. On univariate analysis, the 16 patients who experienced a clinical relapse (determined by CDAI scores) demonstrated significantly higher IL1B, IL-6 and TNFα levels in their ileal mucosa compared to the 20 patients who did not experience clinical relapse. There was no association with these markers in either the blood or rectal mucosa and relapse demonstrated. On multivariate analysis, IL-6 remained as an independent predictor of clinical relapse. IL-6 has also been demonstrated to be increased in the serum of CD patients with previously quiescent CD experiencing a disease flare[86]. IL10 is a well-known anti-inflammatory cytokine. Meresse et al[40] studied IL-10 levels and endoscopic recurrence in 36 patients 3 mo post ileocolectomy. Recurrence rate was 53%. Patients with recurrence had significantly lower IL-10 production. When ileal mRNA expression levels were compared with the patients’ individual genotypes, varying IL10 production based on IL-10. G microsatellite genotype was seen. However, there was no correlation between genotype and endoscopic recurrence.

Faecal calprotectin (FC) and lactoferrin have been widely studied as noninvasive markers of gut inflammation. Recently, several groups have attempted to correlate levels of these markers with risk of postoperative recurrence in CD. Lamb et al[87] were among the first to study a potential correlation. In their cohort of 13 post-surgical CD patients followed for 1 year (3 of whom had ileocolic disease) and a separate cohort of 104 patients who gave a single stool sample at a median of 24 mo postoperatively (28 of whom had ileocolic disease) both FC and lactoferrin correlated with clinical symptoms as evaluated by Harvey Bradshaw Index. Both markers were found to be more accurate at predicting clinical recurrence than CRP, platelet count and endoscopic appearance. Patients with Harvey Bradshaw scores indicative of severe disease activity (n = 28) had FC and lactoferrin levels of 661 μg/g and 116.6 μg/g vs 70.2 μg/g and 5.9 μg/g in those with clinically inactive disease (n = 43) (P < 0.001). Although levels of both markers were slightly higher in those with endoscopic recurrence, this difference was not statistically significantly different between the groups. Subsequently, FC levels of 29 ileocolectomy patients were studied by Lobatón et al[88] Levels correlated more closely with clinical recurrence than CRP, white cell count and platelet count. Endoscopic recurrence scores also correlated with levels. Lasson et al[89] in a study published in Jan 2014, evaluated FC levels in 30 ileocolectomy patients in specimens collected monthly postoperatively for 1 year. Fifty-eight percent had endoscopic remission at one year. FC levels fluctuated over time and were mainly affected by diarrhea. Although median calprotectin levels were not significantly different between patients in remission and patients with recurrence, the majority of patients with high values had recurrence. This may have been influenced by diarrhea at the time of sampling.

CONCLUSION

Crohn’s disease cannot be cured. Surgical resection offers an opportunity for “resetting” the disease into a state of temporary remission. It is known that after surgical resection recurrence rates range from 20 to over 60 percent. Identifying modifiable risk factors for postoperative disease recurrence can assist the clinician in implementing more aggressive prophylactic treatment to prevent recurrence and to sustain remission. The application of an optimal strategy for preventing postoperative recurrence is a multidisciplinary task that includes the gastroenterologist and the colorectal surgeon, as well as all the supporting staff that can ensure preoperative optimization, detailed and timely surgical intervention and early implementation of appropriate treatment to keep the patient in remission.

Footnotes

P- Reviewer: Miki K, Takumi K S- Editor: Qi Y L- Editor: A E- Editor: Liu XM

References
1.  Crohn BB, Ginzburg L, Oppenheimer GD. Landmark article Oct 15, 1932. Regional ileitis. A pathological and clinical entity. By Burril B. Crohn, Leon Ginzburg, and Gordon D. Oppenheimer. JAMA. 1984;251:73-79.  [PubMed]  [DOI]  [Cited in This Article: ]
2.  Baumgart DC, Sandborn WJ. Crohn’s disease. Lancet. 2012;380:1590-1605.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 1347]  [Cited by in F6Publishing: 1376]  [Article Influence: 114.7]  [Reference Citation Analysis (0)]
3.  Cullen G, O’toole A, Keegan D, Sheahan K, Hyland JM, O’donoghue DP. Long-term clinical results of ileocecal resection for Crohn’s disease. Inflamm Bowel Dis. 2007;13:1369-1373.  [PubMed]  [DOI]  [Cited in This Article: ]
4.  Whelan G, Farmer RG, Fazio VW, Goormastic M. Recurrence after surgery in Crohn’s disease. Relationship to location of disease (clinical pattern) and surgical indication. Gastroenterology. 1985;88:1826-1833.  [PubMed]  [DOI]  [Cited in This Article: ]
5.  Thompson JS, Iyer KR, DiBaise JK, Young RL, Brown CR, Langnas AN. Short bowel syndrome and Crohn’s disease. J Gastrointest Surg. 2003;7:1069-1072.  [PubMed]  [DOI]  [Cited in This Article: ]
6.  Cunningham MF, Docherty NG, Coffey JC, Burke JP, O’Connell PR. Postsurgical recurrence of ileal Crohn’s disease: an update on risk factors and intervention points to a central role for impaired host-microflora homeostasis. World J Surg. 2010;34:1615-1626.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 33]  [Cited by in F6Publishing: 35]  [Article Influence: 2.7]  [Reference Citation Analysis (0)]
7.  Irvine EJ. Quality of life of patients with ulcerative colitis: past, present, and future. Inflamm Bowel Dis. 2008;14:554-565.  [PubMed]  [DOI]  [Cited in This Article: ]
8.  Harvey RF, Bradshaw JM. A simple index of Crohn’s-disease activity. Lancet. 1980;1:514.  [PubMed]  [DOI]  [Cited in This Article: ]
9.  Best WR, Becktel JM, Singleton JW, Kern F. Development of a Crohn’s disease activity index. National Cooperative Crohn’s Disease Study. Gastroenterology. 1976;70:439-444.  [PubMed]  [DOI]  [Cited in This Article: ]
10.  Walters TD, Steinhart AH, Bernstein CN, Tremaine W, McKenzie M, Wolff BG, McLeod RS. Validating Crohn‘s disease activity indices for use in assessing postoperative recurrence. Inflamm Bowel Dis. 2011;17:1547-1556.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 37]  [Cited by in F6Publishing: 38]  [Article Influence: 2.9]  [Reference Citation Analysis (0)]
11.  Rutgeerts P, Geboes K, Vantrappen G, Kerremans R, Coenegrachts JL, Coremans G. Natural history of recurrent Crohn’s disease at the ileocolonic anastomosis after curative surgery. Gut. 1984;25:665-672.  [PubMed]  [DOI]  [Cited in This Article: ]
12.  Marshall JK. Reporting ileocolonoscopy in inflammatory bowel disease. Can J Gastroenterol. 2006;20:399-400.  [PubMed]  [DOI]  [Cited in This Article: ]
13.  Sailer J, Peloschek P, Reinisch W, Vogelsang H, Turetschek K, Schima W. Anastomotic recurrence of Crohn’s disease after ileocolic resection: comparison of MR enteroclysis with endoscopy. Eur Radiol. 2008;18:2512-2521.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 95]  [Cited by in F6Publishing: 101]  [Article Influence: 6.3]  [Reference Citation Analysis (0)]
14.  Bordeianou L, Stein SL, Ho VP, Dursun A, Sands BE, Korzenik JR, Hodin RA. Immediate versus tailored prophylaxis to prevent symptomatic recurrences after surgery for ileocecal Crohn’s disease? Surgery. 2011;149:72-78.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 33]  [Cited by in F6Publishing: 36]  [Article Influence: 2.8]  [Reference Citation Analysis (0)]
15.  McLeod RS, Wolff BG, Steinhart AH, Carryer PW, O’Rourke K, Andrews DF, Blair JE, Cangemi JR, Cohen Z, Cullen JB. Risk and significance of endoscopic/radiological evidence of recurrent Crohn’s disease. Gastroenterology. 1997;113:1823-1827.  [PubMed]  [DOI]  [Cited in This Article: ]
16.  Regueiro M, Kip KE, Schraut W, Baidoo L, Sepulveda AR, Pesci M, El-Hachem S, Harrison J, Binion D. Crohn’s disease activity index does not correlate with endoscopic recurrence one year after ileocolonic resection. Inflamm Bowel Dis. 2011;17:118-126.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 108]  [Cited by in F6Publishing: 83]  [Article Influence: 6.4]  [Reference Citation Analysis (0)]
17.  Malireddy K, Larson DW, Sandborn WJ, Loftus EV, Faubion WA, Pardi DS, Qin R, Gullerud RE, Cima RR, Wolff B. Recurrence and impact of postoperative prophylaxis in laparoscopically treated primary ileocolic Crohn disease. Arch Surg. 2010;145:42-47.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 20]  [Cited by in F6Publishing: 21]  [Article Influence: 1.5]  [Reference Citation Analysis (0)]
18.  Stocchi L, Milsom JW, Fazio VW. Long-term outcomes of laparoscopic versus open ileocolic resection for Crohn’s disease: follow-up of a prospective randomized trial. Surgery. 2008;144:622-627; discussion 627-628.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 101]  [Cited by in F6Publishing: 80]  [Article Influence: 5.0]  [Reference Citation Analysis (0)]
19.  Ellis L, Calhoun P, Kaiser DL, Rudolf LE, Hanks JB. Postoperative recurrence in Crohn’s disease. The effect of the initial length of bowel resection and operative procedure. Ann Surg. 1984;199:340-347.  [PubMed]  [DOI]  [Cited in This Article: ]
20.  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;84:78-82.  [PubMed]  [DOI]  [Cited in This Article: ]
21.  Unkart JT, Anderson L, Li E, Miller C, Yan Y, Gu CC, Chen J, Stone CD, Hunt S, Dietz DW. Risk factors for surgical recurrence after ileocolic resection of Crohn’s disease. Dis Colon Rectum. 2008;51:1211-1216.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 61]  [Cited by in F6Publishing: 63]  [Article Influence: 3.9]  [Reference Citation Analysis (0)]
22.  Kane SV, Flicker M, Katz-Nelson F. Tobacco use is associated with accelerated clinical recurrence of Crohn’s disease after surgically induced remission. J Clin Gastroenterol. 2005;39:32-35.  [PubMed]  [DOI]  [Cited in This Article: ]
23.  Cottone M, Rosselli M, Orlando A, Oliva L, Puleo A, Cappello M, Traina M, Tonelli F, Pagliaro L. Smoking habits and recurrence in Crohn’s disease. Gastroenterology. 1994;106:643-648.  [PubMed]  [DOI]  [Cited in This Article: ]
24.  Reese GE, Nanidis T, Borysiewicz C, Yamamoto T, Orchard T, Tekkis PP. The effect of smoking after surgery for Crohn’s disease: a meta-analysis of observational studies. Int J Colorectal Dis. 2008;23:1213-1221.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 181]  [Cited by in F6Publishing: 199]  [Article Influence: 12.4]  [Reference Citation Analysis (0)]
25.  Ryan WR, Allan RN, Yamamoto T, Keighley MR. Crohn’s disease patients who quit smoking have a reduced risk of reoperation for recurrence. Am J Surg. 2004;187:219-225.  [PubMed]  [DOI]  [Cited in This Article: ]
26.  Yamamoto T, Keighley MR. The association of cigarette smoking with a high risk of recurrence after ileocolonic resection for ileocecal Crohn’s disease. Surg Today. 1999;29:579-580.  [PubMed]  [DOI]  [Cited in This Article: ]
27.  Aratari A, Papi C, Leandro G, Viscido A, Capurso L, Caprilli R. Early versus late surgery for ileo-caecal Crohn’s disease. Aliment Pharmacol Ther. 2007;26:1303-1312.  [PubMed]  [DOI]  [Cited in This Article: ]
28.  Sorrentino D, Terrosu G, Paviotti A, Geraci M, Avellini C, Zoli G, Fries W, Danese S, Occhipinti P, Croatto T. Early diagnosis and treatment of postoperative endoscopic recurrence of Crohn’s disease: partial benefit by infliximab--a pilot study. Dig Dis Sci. 2012;57:1341-1348.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 59]  [Cited by in F6Publishing: 60]  [Article Influence: 5.0]  [Reference Citation Analysis (0)]
29.  Jostins L, Ripke S, Weersma RK, Duerr RH, McGovern DP, Hui KY, Lee JC, Schumm LP, Sharma Y, Anderson CA. Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature. 2012;491:119-124.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 3465]  [Cited by in F6Publishing: 3309]  [Article Influence: 275.8]  [Reference Citation Analysis (0)]
30.  Koltun WA. The future of surgical management of inflammatory bowel disease. Dis Colon Rectum. 2008;51:813-817.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 3]  [Cited by in F6Publishing: 3]  [Article Influence: 0.2]  [Reference Citation Analysis (0)]
31.  Cleynen I, González JR, Figueroa C, Franke A, McGovern D, Bortlík M, Crusius BJ, Vecchi M, Artieda M, Szczypiorska M. Genetic factors conferring an increased susceptibility to develop Crohn’s disease also influence disease phenotype: results from the IBDchip European Project. Gut. 2013;62:1556-1565.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 190]  [Cited by in F6Publishing: 197]  [Article Influence: 17.9]  [Reference Citation Analysis (0)]
32.  Hugot JP, Chamaillard M, Zouali H, Lesage S, Cézard JP, Belaiche J, Almer S, Tysk C, O’Morain CA, Gassull M. Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn’s disease. Nature. 2001;411:599-603.  [PubMed]  [DOI]  [Cited in This Article: ]
33.  McCauley JL, Abreu MT. Genetics in diagnosing and managing inflammatory bowel disease. Gastroenterol Clin North Am. 2012;41:513-522.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 9]  [Cited by in F6Publishing: 9]  [Article Influence: 0.8]  [Reference Citation Analysis (0)]
34.  Roberts RL, Hollis-Moffatt JE, Gearry RB, Kennedy MA, Barclay ML, Merriman TR. Confirmation of association of IRGM and NCF4 with ileal Crohn’s disease in a population-based cohort. Genes Immun. 2008;9:561-565.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 107]  [Cited by in F6Publishing: 110]  [Article Influence: 6.9]  [Reference Citation Analysis (0)]
35.  Ahmad T, Armuzzi A, Bunce M, Mulcahy-Hawes K, Marshall SE, Orchard TR, Crawshaw J, Large O, de Silva A, Cook JT. The molecular classification of the clinical manifestations of Crohn’s disease. Gastroenterology. 2002;122:854-866.  [PubMed]  [DOI]  [Cited in This Article: ]
36.  Büning C, Genschel J, Bühner S, Krüger S, Kling K, Dignass A, Baier P, Bochow B, Ockenga J, Schmidt HH. Mutations in the NOD2/CARD15 gene in Crohn’s disease are associated with ileocecal resection and are a risk factor for reoperation. Aliment Pharmacol Ther. 2004;19:1073-1078.  [PubMed]  [DOI]  [Cited in This Article: ]
37.  Maconi G, Colombo E, Sampietro GM, Lamboglia F, D’Incà R, Daperno M, Cassinotti A, Sturniolo GC, Ardizzone S, Duca P. CARD15 gene variants and risk of reoperation in Crohn’s disease patients. Am J Gastroenterol. 2009;104:2483-2491.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 27]  [Cited by in F6Publishing: 28]  [Article Influence: 1.9]  [Reference Citation Analysis (0)]
38.  Solon JG, Burke JP, Walsh SR, Coffey JC. The effect of NOD2 polymorphism on postsurgical recurrence in Crohn’s disease: a systematic review and meta-analysis of available literature. Inflamm Bowel Dis. 2013;19:1099-1105.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 20]  [Cited by in F6Publishing: 20]  [Article Influence: 1.8]  [Reference Citation Analysis (0)]
39.  Sehgal R, Berg A, Polinski JI, Hegarty JP, Lin Z, McKenna KJ, Stewart DB, Poritz LS, Koltun WA. Mutations in IRGM are associated with more frequent need for surgery in patients with ileocolonic Crohn’s disease. Dis Colon Rectum. 2012;55:115-121.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 41]  [Cited by in F6Publishing: 44]  [Article Influence: 3.7]  [Reference Citation Analysis (0)]
40.  Meresse B, Rutgeerts P, Malchow H, Dubucquoi S, Dessaint JP, Cohard M, Colombel JF, Desreumaux P. Low ileal interleukin 10 concentrations are predictive of endoscopic recurrence in patients with Crohn’s disease. Gut. 2002;50:25-28.  [PubMed]  [DOI]  [Cited in This Article: ]
41.  Wagner IJ, Rombeau JL. Nutritional support of surgical patients with inflammatory bowel disease. Surg Clin North Am. 2011;91:787-803, viii.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 24]  [Cited by in F6Publishing: 27]  [Article Influence: 2.1]  [Reference Citation Analysis (0)]
42.  Yamamoto T, Shiraki M, Nakahigashi M, Umegae S, Matsumoto K. Enteral nutrition to suppress postoperative Crohn’s disease recurrence: a five-year prospective cohort study. Int J Colorectal Dis. 2013;28:335-340.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 70]  [Cited by in F6Publishing: 67]  [Article Influence: 6.1]  [Reference Citation Analysis (0)]
43.  Manichanh C, Borruel N, Casellas F, Guarner F. The gut microbiota in IBD. Nat Rev Gastroenterol Hepatol. 2012;9:599-608.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 771]  [Cited by in F6Publishing: 830]  [Article Influence: 69.2]  [Reference Citation Analysis (0)]
44.  Rahimi R, Nikfar S, Rahimi F, Elahi B, Derakhshani S, Vafaie M, Abdollahi M. A meta-analysis on the efficacy of probiotics for maintenance of remission and prevention of clinical and endoscopic relapse in Crohn’s disease. Dig Dis Sci. 2008;53:2524-2531.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 121]  [Cited by in F6Publishing: 124]  [Article Influence: 7.8]  [Reference Citation Analysis (0)]
45.  Pimentel-Nunes P, Dinis-Ribeiro M, Magro F. Systematic review on drug and diet-induced endoscopic remission in Crohn’s disease. Eur J Gastroenterol Hepatol. 2009;21:491-503.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 4]  [Cited by in F6Publishing: 5]  [Article Influence: 0.3]  [Reference Citation Analysis (0)]
46.  Van Gossum A, Dewit O, Louis E, de Hertogh G, Baert F, Fontaine F, DeVos M, Enslen M, Paintin M, Franchimont D. Multicenter randomized-controlled clinical trial of probiotics (Lactobacillus johnsonii, LA1) on early endoscopic recurrence of Crohn’s disease after lleo-caecal resection. Inflamm Bowel Dis. 2007;13:135-142.  [PubMed]  [DOI]  [Cited in This Article: ]
47.  Satsangi J, Silverberg MS, Vermeire S, Colombel JF. The Montreal classification of inflammatory bowel disease: controversies, consensus, and implications. Gut. 2006;55:749-753.  [PubMed]  [DOI]  [Cited in This Article: ]
48.  Pariente B, Cosnes J, Danese S, Sandborn WJ, Lewin M, Fletcher JG, Chowers Y, D’Haens G, Feagan BG, Hibi T. Development of the Crohn’s disease digestive damage score, the Lémann score. Inflamm Bowel Dis. 2011;17:1415-1422.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 412]  [Cited by in F6Publishing: 419]  [Article Influence: 32.2]  [Reference Citation Analysis (1)]
49.  Cosnes J, Cattan S, Blain A, Beaugerie L, Carbonnel F, Parc R, Gendre JP. Long-term evolution of disease behavior of Crohn’s disease. Inflamm Bowel Dis. 2002;8:244-250.  [PubMed]  [DOI]  [Cited in This Article: ]
50.  Louis E, Collard A, Oger AF, Degroote E, Aboul Nasr El Yafi FA, Belaiche J. Behaviour of Crohn’s disease according to the Vienna classification: changing pattern over the course of the disease. Gut. 2001;49:777-782.  [PubMed]  [DOI]  [Cited in This Article: ]
51.  Reinisch W. “How to manage loss of response to anti-TNF in Crohn’s disease?“. Curr Drug Targets. 2010;11:152-155.  [PubMed]  [DOI]  [Cited in This Article: ]
52.  Caprilli R, Corrao G, Taddei G, Tonelli F, Torchio P, Viscido A. Prognostic factors for postoperative recurrence of Crohn’s disease. Gruppo Italiano per lo Studio del Colon e del Retto (GISC). Dis Colon Rectum. 1996;39:335-341.  [PubMed]  [DOI]  [Cited in This Article: ]
53.  Pascua M, Su C, Lewis JD, Brensinger C, Lichtenstein GR. Meta-analysis: factors predicting post-operative recurrence with placebo therapy in patients with Crohn‘s disease. Aliment Pharmacol Ther. 2008;28:545-556.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 64]  [Cited by in F6Publishing: 64]  [Article Influence: 4.0]  [Reference Citation Analysis (0)]
54.  Geboes K. What histologic features best differentiate Crohn’s disease from ulcerative colitis? Inflamm Bowel Dis. 2008;14 Suppl 2:S168-S169.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 13]  [Cited by in F6Publishing: 13]  [Article Influence: 0.8]  [Reference Citation Analysis (0)]
55.  Ramzan NN, Leighton JA, Heigh RI, Shapiro MS. Clinical significance of granuloma in Crohn’s disease. Inflamm Bowel Dis. 2002;8:168-173.  [PubMed]  [DOI]  [Cited in This Article: ]
56.  Riss S, Schuster I, Papay P, Herbst F, Mittlböck M, Chitsabesan P, Stift A. Surgical recurrence after primary ileocolic resection for Crohn’s disease. Tech Coloproctol. 2014;18:365-371.  [PubMed]  [DOI]  [Cited in This Article: ]
57.  Iesalnieks I, Kilger A, Glass H, Müller-Wille R, Klebl F, Ott C, Strauch U, Piso P, Schlitt HJ, Agha A. Intraabdominal septic complications following bowel resection for Crohn’s disease: detrimental influence on long-term outcome. Int J Colorectal Dis. 2008;23:1167-1174.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 76]  [Cited by in F6Publishing: 76]  [Article Influence: 4.8]  [Reference Citation Analysis (0)]
58.  Lowney JK, Dietz DW, Birnbaum EH, Kodner IJ, Mutch MG, Fleshman JW. Is there any difference in recurrence rates in laparoscopic ileocolic resection for Crohn’s disease compared with conventional surgery? A long-term, follow-up study. Dis Colon Rectum. 2006;49:58-63.  [PubMed]  [DOI]  [Cited in This Article: ]
59.  Patel SV, Patel SV, Ramagopalan SV, Ott MC. Laparoscopic surgery for Crohn’s disease: a meta-analysis of perioperative complications and long term outcomes compared with open surgery. BMC Surg. 2013;13:14.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 67]  [Cited by in F6Publishing: 73]  [Article Influence: 6.6]  [Reference Citation Analysis (0)]
60.  Fazio VW, Marchetti F, Church M, Goldblum JR, Lavery C, Hull TL, Milsom JW, Strong SA, Oakley JR, Secic M. Effect of resection margins on the recurrence of Crohn’s disease in the small bowel. A randomized controlled trial. Ann Surg. 1996;224:563-571; discussion 571-573.  [PubMed]  [DOI]  [Cited in This Article: ]
61.  McLeod RS, Wolff BG, Ross S, Parkes R, McKenzie M. 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;52:919-927.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 181]  [Cited by in F6Publishing: 173]  [Article Influence: 11.5]  [Reference Citation Analysis (0)]
62.  Simillis C, Purkayastha S, Yamamoto T, Strong SA, Darzi AW, Tekkis PP. A meta-analysis comparing conventional end-to-end anastomosis vs. other anastomotic configurations after resection in Crohn’s disease. Dis Colon Rectum. 2007;50:1674-1687.  [PubMed]  [DOI]  [Cited in This Article: ]
63.  Fichera A, Zoccali M, Kono T. Antimesenteric functional end-to-end handsewn (Kono-S) anastomosis. J Gastrointest Surg. 2012;16:1412-1416.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 43]  [Cited by in F6Publishing: 38]  [Article Influence: 3.2]  [Reference Citation Analysis (0)]
64.  Hellers G, Cortot A, Jewell D, Leijonmarck CE, Löfberg R, Malchow H, Nilsson LG, Pallone F, Pena S, Persson T. Oral budesonide for prevention of postsurgical recurrence in Crohn’s disease. The IOIBD Budesonide Study Group. Gastroenterology. 1999;116:294-300.  [PubMed]  [DOI]  [Cited in This Article: ]
65.  Rutgeerts P, Hiele M, Geboes K, Peeters M, Penninckx F, Aerts R, Kerremans R. Controlled trial of metronidazole treatment for prevention of Crohn’s recurrence after ileal resection. Gastroenterology. 1995;108:1617-1621.  [PubMed]  [DOI]  [Cited in This Article: ]
66.  Messori A, Brignola C, Trallori G, Rampazzo R, Bardazzi G, Belloli C, d’Albasio G, De Simone G, Martini N. Effectiveness of 5-aminosalicylic acid for maintaining remission in patients with Crohn’s disease: a meta-analysis. Am J Gastroenterol. 1994;89:692-698.  [PubMed]  [DOI]  [Cited in This Article: ]
67.  Sutherland LR, Martin F, Bailey RJ, Fedorak RN, Poleski M, Dallaire C, Rossman R, Saibil F, Lariviere L. A randomized, placebo-controlled, double-blind trial of mesalamine in the maintenance of remission of Crohn’s disease. The Canadian Mesalamine for Remission of Crohn’s Disease Study Group. Gastroenterology. 1997;112:1069-1077.  [PubMed]  [DOI]  [Cited in This Article: ]
68.  Brignola C, Cottone M, Pera A, Ardizzone S, Scribano ML, De Franchis R, D’Arienzo A, D’Albasio G, Pennestri D. Mesalamine in the prevention of endoscopic recurrence after intestinal resection for Crohn’s disease. Italian Cooperative Study Group. Gastroenterology. 1995;108:345-349.  [PubMed]  [DOI]  [Cited in This Article: ]
69.  McLeod RS, Wolff BG, Steinhart AH, Carryer PW, O’Rourke K, Andrews DF, Blair JE, Cangemi JR, Cohen Z, Cullen JB. Prophylactic mesalamine treatment decreases postoperative recurrence of Crohn’s disease. Gastroenterology. 1995;109:404-413.  [PubMed]  [DOI]  [Cited in This Article: ]
70.  Colombel JF, Sandborn WJ, Reinisch W, Mantzaris GJ, Kornbluth A, Rachmilewitz D, Lichtiger S, D’Haens G, Diamond RH, Broussard DL. Infliximab, azathioprine, or combination therapy for Crohn’s disease. N Engl J Med. 2010;362:1383-1395.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 2221]  [Cited by in F6Publishing: 2205]  [Article Influence: 157.5]  [Reference Citation Analysis (0)]
71.  Baert F, Moortgat L, Van Assche G, Caenepeel P, Vergauwe P, De Vos M, Stokkers P, Hommes D, Rutgeerts P, Vermeire S. Mucosal healing predicts sustained clinical remission in patients with early-stage Crohn’s disease. Gastroenterology. 2010;138:463-468; quiz e10-e11.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 603]  [Cited by in F6Publishing: 599]  [Article Influence: 42.8]  [Reference Citation Analysis (0)]
72.  Cammà C, Giunta M, Rosselli M, Cottone M. Mesalamine in the maintenance treatment of Crohn’s disease: a meta-analysis adjusted for confounding variables. Gastroenterology. 1997;113:1465-1473.  [PubMed]  [DOI]  [Cited in This Article: ]
73.  Pearson DC, May GR, Fick GH, Sutherland LR. Azathioprine and 6-mercaptopurine in Crohn disease. A meta-analysis. Ann Intern Med. 1995;123:132-142.  [PubMed]  [DOI]  [Cited in This Article: ]
74.  Ewe K, Press AG, Singe CC, Stufler M, Ueberschaer B, Hommel G, Meyer zum Büschenfelde KH. Azathioprine combined with prednisolone or monotherapy with prednisolone in active Crohn‘s disease. Gastroenterology. 1993;105:367-372.  [PubMed]  [DOI]  [Cited in This Article: ]
75.  Candy S, Wright J, Gerber M, Adams G, Gerig M, Goodman R. A controlled double blind study of azathioprine in the management of Crohn’s disease. Gut. 1995;37:674-678.  [PubMed]  [DOI]  [Cited in This Article: ]
76.  Hanauer SB, Korelitz BI, Rutgeerts P, Peppercorn MA, Thisted RA, Cohen RD, Present DH. Postoperative maintenance of Crohn’s disease remission with 6-mercaptopurine, mesalamine, or placebo: a 2-year trial. Gastroenterology. 2004;127:723-729.  [PubMed]  [DOI]  [Cited in This Article: ]
77.  D’Haens GR, Vermeire S, Van Assche G, Noman M, Aerden I, Van Olmen G, Rutgeerts P. Therapy of metronidazole with azathioprine to prevent postoperative recurrence of Crohn’s disease: a controlled randomized trial. Gastroenterology. 2008;135:1123-1129.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 221]  [Cited by in F6Publishing: 220]  [Article Influence: 13.8]  [Reference Citation Analysis (0)]
78.  Mañosa M, Cabré E, Bernal I, Esteve M, Garcia-Planella E, Ricart E, Peñalva M, Cortes X, Boix J, Piñol M. Addition of metronidazole to azathioprine for the prevention of postoperative recurrence of Crohn’s disease: a randomized, double-blind, placebo-controlled trial. Inflamm Bowel Dis. 2013;19:1889-1895.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 3]  [Cited by in F6Publishing: 16]  [Article Influence: 1.5]  [Reference Citation Analysis (0)]
79.  Alves A, Panis Y, Joly F, Pocard M, Lavergne-Slove A, Bouhnik Y, Valleur P. Could immunosuppressive drugs reduce recurrence rate after second resection for Crohn disease? Inflamm Bowel Dis. 2004;10:491-495.  [PubMed]  [DOI]  [Cited in This Article: ]
80.  Domènech E, Mañosa M, Bernal I, Garcia-Planella E, Cabré E, Piñol M, Lorenzo-Zúñiga V, Boix J, Gassull MA. Impact of azathioprine on the prevention of postoperative Crohn’s disease recurrence: results of a prospective, observational, long-term follow-up study. Inflamm Bowel Dis. 2008;14:508-513.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 71]  [Cited by in F6Publishing: 77]  [Article Influence: 4.8]  [Reference Citation Analysis (0)]
81.  Lichtenstein GR, Abreu MT, Cohen R, Tremaine W. American Gastroenterological Association Institute medical position statement on corticosteroids, immunomodulators, and infliximab in inflammatory bowel disease. Gastroenterology. 2006;130:935-939.  [PubMed]  [DOI]  [Cited in This Article: ]
82.  Regueiro M, Schraut W, Baidoo L, Kip KE, Sepulveda AR, Pesci M, Harrison J, Plevy SE. Infliximab prevents Crohn’s disease recurrence after ileal resection. Gastroenterology. 2009;136:441-450.e1; quiz 716.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 443]  [Cited by in F6Publishing: 406]  [Article Influence: 27.1]  [Reference Citation Analysis (0)]
83.  Savarino E, Bodini G, Dulbecco P, Assandri L, Bruzzone L, Mazza F, Frigo AC, Fazio V, Marabotto E, Savarino V. Adalimumab is more effective than azathioprine and mesalamine at preventing postoperative recurrence of Crohn’s disease: a randomized controlled trial. Am J Gastroenterol. 2013;108:1731-1742.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 148]  [Cited by in F6Publishing: 158]  [Article Influence: 14.4]  [Reference Citation Analysis (0)]
84.  Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis. 1987;40:373-383.  [PubMed]  [DOI]  [Cited in This Article: ]
85.  Yamamoto T, Umegae S, Kitagawa T, Matsumoto K. Mucosal cytokine production during remission after resection for Crohn’s disease and its relationship to future relapse. Aliment Pharmacol Ther. 2004;19:671-678.  [PubMed]  [DOI]  [Cited in This Article: ]
86.  Louis E, Belaiche J, van Kemseke C, Franchimont D, de Groote D, Gueenen V, Mary JY. A high serum concentration of interleukin-6 is predictive of relapse in quiescent Crohn’s disease. Eur J Gastroenterol Hepatol. 1997;9:939-944.  [PubMed]  [DOI]  [Cited in This Article: ]
87.  Lamb CA, Mohiuddin MK, Gicquel J, Neely D, Bergin FG, Hanson JM, Mansfield JC. Faecal calprotectin or lactoferrin can identify postoperative recurrence in Crohn’s disease. Br J Surg. 2009;96:663-674.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 106]  [Cited by in F6Publishing: 111]  [Article Influence: 7.4]  [Reference Citation Analysis (0)]
88.  Lobatón T, López-García A, Rodríguez-Moranta F, Ruiz A, Rodríguez L, Guardiola J. A new rapid test for fecal calprotectin predicts endoscopic remission and postoperative recurrence in Crohn’s disease. J Crohns Colitis. 2013;7:e641-e651.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 113]  [Cited by in F6Publishing: 116]  [Article Influence: 10.5]  [Reference Citation Analysis (0)]
89.  Lasson A, Strid H, Ohman L, Isaksson S, Olsson M, Rydström B, Ung KA, Stotzer PO. Fecal calprotectin one year after ileocaecal resection for Crohn’s disease--a comparison with findings at ileocolonoscopy. J Crohns Colitis. 2014;8:789-795.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 43]  [Cited by in F6Publishing: 44]  [Article Influence: 4.4]  [Reference Citation Analysis (0)]
90.  Domènech E, Zabana Y, Garcia-Planella E, López San Román A, Nos P, Ginard D, Gordillo J, Martínez-Silva F, Beltrán B, Mañosa M. Clinical outcome of newly diagnosed Crohn’s disease: a comparative, retrospective study before and after infliximab availability. Aliment Pharmacol Ther. 2010;31:233-239.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 5]  [Cited by in F6Publishing: 10]  [Article Influence: 0.7]  [Reference Citation Analysis (0)]