Review article: the natural history of postoperative
Crohn's disease recurrence
A. Buisson*,†, J.-B. Chevaux‡, P. B. Allen§, G. Bommelaer*,†& L. Peyrin-Biroulet‡
*Department of
Hepato-Gastroenterology, University Hospital Estaing of Clermont-Ferrand, Auvergne University, Clermont-Ferrand, France.
†INRA, USC-2018, Clermont Université, Université d'Auvergne, Clermont-Ferrand, France. ‡Inserm U954 and Department of Hepato-Gastroenterology, University Hospital of Nancy, Université Henri Poincaré 1, Vandoeuvre-lès-Nancy, France.
§Department of Gastroenterology, Causeway Hospital, Northern Trust, N Ireland, UK.
Correspondence to:
Prof. L. Peyrin-Biroulet, Inserm U954 and Department of Hepato-Gastroenterology, University Hospital of Nancy-Brabois, Université Henri Poincaré 1, Allée du Morvan, 54511 Vandoeuvre-lès-Nancy, France. E-mail: peyrinbiroulet@gmail.com
Publication data
Submitted 14 September 2011 First decision 16 October 2011 Resubmitted 2 January 2012 Accepted 8 January 2012 EV Pub Online 7 February 2012
This uncommissioned review article was subject to full peer-review.
SUMMARY
Background
Surgical resection of the diseased bowel in Crohn's disease is unfortunately not curative, and postoperative recurrence remains a problem in these patients.
Aim
To review the rates of and risk factors for clinical and endoscopic recur-rence in population-based studies, referral centres and randomised con-trolled trials.
Methods
We searched MEDLINE (source PUBMED, 1966 to September, 2011). Results
In randomised controlled trials, clinical recurrence in thefirst year after sur-gery occurred in 10–38% of patients, whereas endoscopic recurrence in the first year was reported in 35–85% of patients. In population-based studies, approximately half of patients experienced clinical recurrence at 10 years. In referral centres, 48–93% of the patients had endoscopic lesions (Rutgeerts’ score 1) in the neoterminal ileum within 1 year after surgery, whereas 20 –37% had symptoms suggestive of clinical recurrence. Three years after sur-gery, the endoscopic postoperative recurrence rate increased to 85–100%, and symptomatic recurrence occurred in 34–86% of patients. Smoking is the strongest risk factor for postoperative recurrence, increasing by twofold, the risk of clinical recurrence. Prior intestinal resection, penetrating behaviour, perianal disease and extensive bowel disease (>50 cm) are established risk factors for postoperative recurrence. Risk factors for postoperative recur-rence remain poorly defined in population-based cohorts.
Conclusion
Endoscopic and clinical postoperative recurrence remains common in patients with Crohn's disease, and the identification of risk factors may allow targeted strategies to reduce this recurrence rate.
INTRODUCTION
Crohn's disease (CD) is a chronic disabling and destruc-tive disease.1, 2Despite increased use of immunosuppres-sive and anti-tumour necrosis factor treatments, approximately half of the patients require surgery within 10 years after diagnosis.1 Surgical resection of the dis-eased bowel is not curative, and postoperative recurrence (POR) remains a significant problem in patients with CD. There are numerous studies that report POR in CD; however, these data are heterogeneous and as such diffi-cult to interpret. This review aims to summarise our cur-rent knowledge about the incidence of and risk factors for POR in CD. Three types of study design were used for analysis, namely: randomised controlled trials, refer-ral centre studies and population-based studies.
LITERATURE SEARCH
MEDLINE (source PUBMED, 1966 to September, 2011) was employed using a combination of Medical Subject (MeSH) headings and keywords as searches, namely: ‘CD’, ‘postoperative recurrence’, ‘postoperative period’, ‘recurrence’, ‘risk factors’, ‘surgery’, ‘epidemiology’, ‘post-operative complications’, ‘operation’, ‘smoking’, ‘perforat-ing disease’, ‘penetrating disease’, ‘duration of disease’, ‘disease duration’, ‘previous resection’, ‘prior resection’, ‘family history’, ‘disease location’, ‘anastomosis’, ‘disease extent’, ‘age of onset’, ‘risk factor’, ‘sex’, ‘gender’, ‘genetic’, ‘anastomotic configuration’, ‘laparoscopic’, ‘open’, ‘length of resection’, ‘resection length’, ‘granu-loma’, ‘myenteric plexitis’, ‘NOD2’ and ‘interleukin-10’.
The authors graded the abstract of every trial identi-fied by the search to determine eligibility. If these criteria remained unclear from the abstract, the full article was retrieved for clarification. For each article of interest, both linked and cited articles were studied. Only placebo arms of RCTs were eligible for inclusion in this review article. The literature search identified 1314 articles, and of these, 83 articles were included in this review.
RATES OF CLINICAL AND ENDOSCOPIC RECURRENCE
Postoperative recurrence can be defined as endoscopic, clinical, radiological or surgical recurrence. This reviews focuses on studies that report clinical and endoscopic recurrence.
Population-based cohorts
Overall, in population-based studies, the clinical POR rate ranged from 28% to 45% and from 36% to 61% at 5 and 10 years respectively (Table S1).3–6 These studies
demonstrate a steadily rising incidence of clinical and endoscopic POR with more than half of patients experi-encing endoscopic POR at 5 years (Table S2),3–6 three-quarters at 10 years and>90% at 15 years.
Referral centre data
From referral centre data, the clinical POR rate ranged from 20% to 37% and from 34% to 47% at 1 and 5 years respectively (Table S1).7–24 In total, approximately three quarters (48–93%) and 85–100% of patients experienced endoscopic POR at 1 and 3 years respectively (Table S2).7–24 Rates of clinical POR from population-based cohort and referral centre data appear comparable; how-ever, endoscopic POR appears more frequent in referral centre-based cohorts (Figure 1). Such discrepancy may be partly explained by a biased case load in referral cen-tres.
Randomised controlled trials
Overall, approximately one quarter of patients experi-enced clinical POR, whereas more than half of patients experienced endoscopic recurrence during the first year after surgery in RCTs (Tables S1 and S2).10, 25–40 This rate of endoscopic POR is lower than that reported in referral centre-based studies (Figure 2). This apparent discrepancy could be partly explained by the inclusion of highly selected patients and clear definitions of POR in RCTs when compared with studies that may reflect real life settings. 30 58 41 89 0 10 20 30 40 50 60 % 70 80 90 100 Population-based cohorts Referral centers Clinical recurrence Endoscopic recurrence
Figure 1 | Mean rate of clinical and endoscopic postoperative recurrence in population-based cohorts and referral centres at 5 years.
RISK FACTORS FOR POSTOPERATIVE RECURRENCE
Four grades of risk factor were defined after conducting a literature search, namely: strong predictors, established predictors, non-predictive factors and no conclusive fac-tors because of lack of available data (Table 1). Possible
risk factors were obtained from population-based cohorts, referral centre data and randomised controlled trials. Tobacco
Population-based cohorts. The only population-based cohort that assessed the impact of smoking on the rate of POR was negative.6
Referral centre data. In a prospective cohort of 174 patients, a significant greater number of recurrence was
observed among smokers, especially in women
(OR= 4.2), with a dose-response relationship.41 This was confirmed 9 years later by Yamamoto et al. who found that the cumulative recurrence-free rate was lower in the heavy smokers compared with the mild smokers.42 A retrospective Italian cohort of 182 patients showed that cigarette smoking was an independent predictor for clinical [(Hazard ratio (HR) = 1.61], surgical (HR = 2) and endoscopic POR [(Odds ratio) OR= 2.2].43A meta-analysis of 16 studies that included 2962 patients reported that smokers had a twofold increased risk for clinical and a 2.5-fold increased risk for surgical POR within 10 years.44 26 75 28 54 0 10 20 30 40 % 50 60 70 80 90
Referral centers Randomised
controlled trials Clinical recurrence Endoscopic recurrence
Figure 2 | Mean rate of clinical and endoscopic postoperative recurrence in randomised controlled trials and referral centres at 1 year.
Table 1 | Risk factors for postoperative recurrence in Crohn's disease
Population-based cohorts
Referral centre studies
Randomised controlled trials Strong predictor for POR
Active smoking + +
Established predictors for POR
Penetrating behaviour + +
Perianal disease + + NA
Prior intestinal resection + + NA
Extensive small bowel resection (>50cm) + + NA
No predictive factors for POR
Type of anastomosis NA NA
Surgical procedure NA NA
Resection margins NA NA
Age at the onset of the disease + +/
Gender NA NA
Location of the disease +/ +/ NA
Duration of the disease +/ NA
Surgical complications NA NA Granuloma NA +/ NA Family history of CD NA NA CRP level NA NA Inconclusive data Myenteric plexitis NA + NA NOD2/CARD15 mutation NA +/ NA Increased TGFb NA + NA
Low Il10 mRNA level NA + NA
Randomised controlled trials. Among 152 patients fol-lowed prospectively in Canada during 48 weeks, current smokers had significantly more clinical recurrence after surgery than non-smokers (HR= 2.1).45 Interestingly, the rate of clinical POR among ex-smokers was not dif-ferent from patients who had never-smokers.45 In sum-mary, from referral centres and randomised controlled trials, current smokers have approximately a twofold increase in risk of POR in CD.
Disease behaviour
Population-based cohorts. In the Olmsted County
cohort, the medical records of 310 incident cases of CD diagnosed between 1970 and 2004, were reviewed through March 2009.6 Of these, 117 patients underwent ileal or ileocecal resection. Surprisingly, a penetrating phenotype as opposed to a non-penetrating/non-strictur-ing patient was significantly associated with a decreased risk of endoscopic recurrence of the small bowel (HR= 0.57).6This needs to be confirmed in other popu-lation-based cohorts.
Referral centre data. A meta-analysis including 13 stud-ies and 3044 patients found that patients with a pene-trating phenotype (B3 according to the Montreal classification) had more POR (defined as the need for surgery) than non-penetrating phenotype (OR = 1.5; P= 0.002).46 In a large referral centre-based cohort enrolling 770 patients, patients with a penetrating pheno-type had a twofold increased risk for POR.47In a referral centre-based study that included 101 patients followed during 15 years, the median interval between the first and second intestinal operation was 1.7 years for the penetrating group compared with 13 years for the non-penetrating group (P= 0.005). The median time between two operations during the study period was 2 years for the penetrating group vs. 9.9 years for the non-penetrating group (P= 0.0002).48 In another referral centre-based cohort that included 91 patients, the average interval
between the first surgery and the second surgery
was 5.3± 7.4 years for the penetrating group compared with 7.9 ± 8.5 years for the non-penetrating group (P< 0.05).49 More recently, in a referral centre-based cohort that enrolled 34 subjects, patients with a penetrat-ing behaviour also experienced significantly more recur-rence-defined as appearance of symptoms confirmed by endoscopic, radiological or histological investigations than non-penetrating behaviour.50 In 287 CD operated-patients who had surgical resection performed, the recurrence-free interval of patients with penetrating
phenotype, after a mean follow-up of 4 years, was signif-icantly shorter.51
However, there are some conflicting data about the association of penetrating phenotype with the risk of POR. Of the 100 patients extracted from a database of a referral centre, penetrating disease did not influence postoperative outcome [Relative risk (RR) = 0.825; P= 0.553].52
In summary, despite some conflicting data52
especially in the only population-based cohort interesting in dis-ease behaviour,6 a penetrating phenotype appears to increase the risk of POR in CD, and was thus considered as a risk factor in the ECCO consensus.53
Perianal disease
Population-based cohorts. In a Swedish population-based cohort of 907 patients with primary ileocaecal CD, there was a higher associated POR rate in patients with perianal lesions (RR= 1.6; P = 0.003).4
Referral centre data. In an Italian referral centre-based cohort, among 127 CD patients monitored after surgery for a median follow-up of 41 months, only a history of perianal disease (HR= 16.9) strongly increased the risk of recurrence.54In a Chinese referral centre-based cohort (2003–2009), of 44 patients who had bowel resection, multivariate analyses showed that perianal disease was the only independent risk factor for clinical recurrence (P< 0.05).24
In summary, despite a wide variation on reported risk of recurrence, the presence of perianal disease is thus considered to be a risk factor for POR.53
Age of patient at time of resection
Population-based cohorts. In Olmsted County, Minne-sota, recurrence was more frequent in patients who were less than 40 years of age at the time of definitive resec-tion, when compared with patients >40 years old (57% vs. 25% respectively).5 Hellers et al. reported that in the younger age-group (under 25 years), the middle group (25–40 years) and the highest age-group (over 40 years), the cumulative clinical recurrence rate at 5 years were 58%, 43% and 39% respectively. The difference between the youngest and the oldest age-group reached statistical significance (P < 0.05).3
Referral centre data. Among 154 patients (77 with recurrence) from a referral centre in Oslo, Norway, the risk of recurrence was higher in patients under 20 years both at diagnosis (OR= 2.2) and at time of their
operation (OR = 2.7).55 In Heidelberg, Germany, among 689 individuals, who underwent resection and/or strictu-roplasty and who were followed for a mean period of 50 months (range, 5–166 months), the risk for POR decreased with increasing age at time of first operation (2% risk reduction per year of age) as well as with age at diagnosis (4% risk reduction per year of age).56 In the cohort from the General Infirmary at Leeds from 1939 to 1968, of 168 patients with primary resection, POR was more common in patients who came to surgery below the age of 20 years (53%), whereas recurrence decreased in the third, fourth and fifth decades.57 Above the age of 50 years, recurrence rates dropped sharply (7%).57 From the surgical database of Stanford, Califor-nia, patients aged 19 years and under at the time of their first ileocecal operation had an increased risk of one re-operation for recurrent ileocecal CD (RR= 1.98, 95% CI 1.6–2.4).58
In an Italian referral centre, patients under 30 years referred had significantly higher cumulative recurrence rate after a 5-year follow-up than patients over 50 years (25% vs. 0% respectively, P< 0.01).59
In contrast, several studies10, 60, 61have found no rela-tionship between age and POR in CD. From Bologna, Italy, among 233 patients who underwent resection for both primary and recurrent CD during a 15-year period with a minimum follow-up of 18 months, there was no difference in POR rates in patients who were under or over 34 years age at first operation.62 Among 100 con-secutive patients undergoing ileocaecal resection in the German referral centre of Heidelberg, age at the onset of the disease was not associated with POR.52
Randomised controlled trials. In an Italian multicentre, randomised, controlled trial, 110 patients were enrolled, and age at operation was not associated with an increased risk of endoscopic POR.63 In summary, con-flicting evidence exists regarding the effect of age on the risk of POR, and therefore cannot be used as a definite risk factor for POR at present.53
Disease location
Population-based cohorts. A Swedish population-based study reported a rising cumulative clinical recurrence rate of approximately 30% after 5 years, 50% after 10 years and 60% after 15 years in the case of pure ileal disease.3 In the case of ileocolonic disease, the cumula-tive clinical recurrence rates were similar (30% after 5 years, 50% after 10 years and 55% after 15 years).3
Recurrence rates of colonic CD seemed to be lower, being approximately 20% after 5 years and 35% after 10 years.3
In the Olmsted County cohort of patients with CD who had a resection, the authors reported that after resection, whether the site of disease was small bowel, colonic or both, there was no difference in the risk for recurrence.5
Referral centre data. Several studies have reported an association between POR and disease location.61, 64 Ileal disease65 and jejunal involvement56 have been associated with an increased risk of POR. In an Italian retrospective study, ileo-colonic resection was associated with higher rates of endoscopic recurrence than in patients with other types of resection (88% vs. 42%, P< 0.001).23 However, the frequency of symptomatic recurrence was lower in patients with ileo-colonic resection than in those with other resections (37% vs. 100%; P< 0.001).23
In 233 patients followed in Bologna, Italy, prospec-tively for 15-years after surgery, the recurrence rates for primary ileocolic, jejuno-ileal and colonic involvement were similar.62 Although not significant in the overall analysis, recurrence (within 36 months) was significantly greater for colonic involvement (24%) compared with 8% and 13% for ileocolic and jejuno-ileal disease respec-tively (P< 0.05).62
Other studies have not reported an association between disease location and POR.66, 67, 68 In summary, there is wide variation in reported risk of post-operative recurrence for disease site, and therefore this cannot reli-ably predict risk of POR at present.53
Disease duration at the time for surgery
Population-based cohorts. In Stockholm County, disease duration before surgery did not influence the rate of clinical recurrence.3
Referral centre data. There is conflicting data regarding the association of disease duration with the risk of POR.57, 61, 63 At Mount Sinai Hospital in patients who had small bowel surgical resections between 1964 and 1973, the risk of symptomatic recurrence was lower for
those with disease duration exceeding 10 years
(P= 0.01).66 Among 233 Italian patients, there was a correlation between clinical POR and a shorter duration of the disease prior to initial surgery (P= 0.0009).62
However, in several studies, preoperative disease dura-tion had no significant effect on the need for further sur-gery.10, 52, 60, 68 In summary, disease duration at the
time of surgery has not been shown to be a reliable as a risk factor for risk of POR.53
Others clinical factors
Other criteria were examined for POR such as gender63 and family history,69 but these have not been shown to predict POR.53
Prior intestinal resection
Population-based cohorts. Of the 244 patients in whom the disease recurred after the first curative operation, in a Swedish cohort, 197 had reoperation, and the rate of clinical POR was significantly higher than after the first operation (P< 0.05).3 Of the 97 patients in whom the disease recurred after a second curative operation, 78 were submitted to a third curative operation.3 The cumulative rate was approximately 40% after 5 years and 60% after 10 years, which was slightly less than after the second operation.3
Referral centre data. Among 99 patients with surgical resection in St Mark's hospital in London, symptomatic POR was more frequent in those who had previous sur-gery (P= 0.06).22 In summary, prior intestinal resection does appear to be a risk factor for POR in CD.53
Extent of the disease
Population-based cohorts. Among 476 patients of a Swedish population-based cohort, resection of longer segments of ileum (>50 cm) appeared to increase the risk of relapse (RR= 1.4).4
Referral centre data. In a German referral centre, among 100 consecutive patients undergoing isolated ileo-caecal resection for CD, those with bowel resection longer than 20 cm, had a higher risk of endoscopic POR (RR= 0.42; P = 0.0116).52 Among 127 Italian CD patients, the length of bowel resection did not influence postoperative course of the disease (RR= 1 and 1.25 respectively).54 Nevertheless, such groups did not con-sider extension of disease as risk factors.57, 67, 70, 71 In summary, extensive small bowel resection, defined as from between 20 cm and 50 cm of resected bowel, is considered as an established risk factor for POR.53 Other surgical parameters
In a meta-analysis, there was a trend to a lower number of POR rates in the laparoscopy group, but this tech-nique requires further study in CD to assess whether it
may reduce post-operative recurrence.72 Scarpa et al. reported that side-to-side anastomosis decreases the clin-ical POR when compared with end-to-side anastomo-sis.73 This may be explained by the wider lumen in the former technique with advantages of delayed anasto-motic stenosis, decreased faecal stasis and reduced sec-ondary ischaemia.73
Histology
Plexitis. From Leuven, Belgium, among 59 patients oper-ated for CD, those with myenteric plexitis of the
proxi-mal resection margin, had a higher endoscopic
recurrence rate at 3 months (P = 0.008) and at 1 year (P = 0.041). Sokol et al.74 reported that in 171 patients submucosal plexitis were predictive for clinical POR (HR = 1.87).74
In contrast at St Mark's Hospital, London, from 99 patients operated, the difference of clinical POR between patients with or without plexitis in the proximal resec-tion margin did not reach clinical significance.75
Appearance of granulomas. In a German referral centre of 100 consecutive patients undergoing isolated ileocaecal resection for CD, granulomas showed no significant influence on the POR rates,52 whereas, among 130 patients operated on for CD in Australia, the association of granulomas with recurrence remained significant (P= 0.03).61 Overall, these findings await replication by independent groups.
The significance of the association of plexitis with the proximal resection margin and the appearance of granu-lomas with risk of POR in CD is not fully understood, and requires further prospective studies.
Genetics
There is conflicting evidence with regard to the genetic mutations and the risk of post-operative CD recurrence. Two studies have reported an increased risk of POR and need for re-operation with the NOD2/CARD15 muta-tions,76, 77 whereas further studies have reported no correlation with NOD2/CARD15 mutations and risk for re-operation.78, 79 Therefore, although of academic inter-est, the genetic association of NOD2/CARD15 status can-not be recommended to predict POR risk in clinical practice.
Biology and immunology
There have been reports of an association with an increase in ileal tumour growth factor beta,80 or low Interleukin 10-mRNA levels20 and POR in CD; however,
with small sample sizes it is not possible to provide definite associations. The level of C-reactive protein before surgery could not predict the risk of postoperative recurrence.12, 63
CONCLUSION
This is the first article reviewing the natural history (clinical and endoscopic recurrence, and risk factors) of POR using data from population-based studies, referral centre data and randomised controlled trials.
The strongest risk factor for POR in CD appears to be active smoking. Other important risk factors include perianal lesions, penetrating behaviour, prior intestinal resection and extensive bowel resection. However, large prospective studies are required to accurately predict moderate to high-risk patients. This information could be used in future disease modification trials to formulate accurate risk stratification models to better target aggres-sive therapies in high-risk individuals. Future work in POR may include non-invasive biomarkers and the
iden-tification of genetic mutations that may accurately pre-dict future risk.
ACKNOWLEDGEMENTS
Declaration of personal interests: L. Peyrin-Biroulet has served as a speaker, a consultant and an advisory board member for Abbott and Merck. Declaration of funding interests: None.
SUPPORTING INFORMATION
Additional Supporting Information may be found in the online version of this article:
Table S1. Rates of clinical postoperative recurrence. Table S2. Rates of endoscopic postoperative recurrence. Please note: Wiley-Blackwell are not responsible for the content or functionality of any supporting materials supplied by the authors. Any queries (other than missing material) should be directed to the corresponding author for the article.
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