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Tailored treatment according to early post-surgery colonoscopy reduces clinical recurrence in Crohn's disease: A retrospective study

Digestive and Liver Disease, Volume 46, Issue 10, October 2014, Pages 887–892

Abstract

Background

After intestinal resection for Crohn's disease, the severity of endoscopic recurrence in the first year following surgery is predictive of clinical outcome. Aim of the study was to assess the impact on clinical recurrence of tailored therapy based on endoscopic findings in the first year following surgery for Crohn's disease.

Methods

All patients who underwent an intestinal resection for Crohn's disease between 1995 and 2005 at Saint-Louis Hospital were retrospectively included. Time-to-clinical recurrence was compared in two groups: patients who had systematic ileocolonoscopy 6–12 months after intestinal surgery with tailored treatment according to the severity of endoscopic lesions (group C) and patients without systematic endoscopic evaluation (group NC).

Results

132 patients (group C = 90, group NC = 42) were included. Probabilities of clinical recurrence were significantly lower in group C (21% and 26% at 3 and 5 years, respectively) compared with group NC (31% and 52% at 3 and 5 years respectively,p = 0.01).

Conclusion

Tailored treatment according to endoscopic assessment after ileocolonic resection is significantly associated with reduced clinical recurrence rate.

Keywords: Crohn's disease, Ileocolonoscopy, Post-operative recurrence, Prevention.

1. Introduction

Crohn's disease (CD) is a chronic, progressive, and destructive disease leading to fibrostenotic stricture or penetrating lesions of the bowel, resulting in structural bowel damage [1] . Surgical intestinal resection is frequently required to treat strictures, fistulas, or abscesses, and should be considered the ultimate manifestation of bowel damage [1] . Up to 80% of CD patients require abdominal surgery and disease recurrence is almost systematic [2] . Endoscopic recurrence, which precedes clinical recurrence, reaches 80% one year after surgery. Clinical recurrence occurs in one third of patients within one year and increases up to 80% of patients 20 years after resection[3], [4], and [5]. Almost one-half of the patients will require reoperation within 10 years of the first surgery[3] and [4]. Therefore, prevention of postoperative recurrence is a significant challenge in clinical practice.

Prophylactic postoperative therapy for clinical recurrence can be started either immediately after surgery or when endoscopic recurrence occurs[2] and [6]. The European Crohn's and Colitis Organisation consensus recommends performing ileocolonoscopy within the first year after surgery where treatment decisions may be affected [7] , but two retrospective studies have reported no clinical benefit of endoscopic tailored treatment[8] and [9]. However, in these two studies, endoscopic recurrence was defined as any lesion observed in the neo-terminal ileum or at the anastomosis (regardless of the severity of the lesions) and no Rutgeerts score was available. Furthermore, no standardised therapeutic protocol according to endoscopic findings was applied[8] and [9].

The aim of our study was to compare clinical recurrence in two groups of patients: patients who had systematic ileocolonoscopy 6–12 months after intestinal surgery with tailored treatment according to the severity of endoscopic lesions ( Fig. 1 ) [10] and patients without systematic endoscopic evaluation.

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Fig. 1 Postoperative strategy according to Rutgeerts’ score applied in Saint-Louis Hospital from 1995 to 2005. Rutgeerts endoscopic scoring system: i,0: no lesions, i,1: ≤5 aphthous ulcers, i,2: >5 aphthous ulcers with normal intervening mucosa, or lesions confined to the ileocolonic anastomosis, or skip areas of larger lesions, i,3: diffuse aphthous ileitis, i,4: diffuse inflammation with large deep ulcers or narrowing. High-risk patients: previous intestinal or extensive resection. ASA, aminosalicylates, MP, mercaptopurine.

2. Materials and methods

2.1. Patients and applied strategies

Since 1995 our institution has adopted a postoperative treatment protocol based on recurrence risk and systematic ileocolonoscopy findings for CD patients who had undergone intestinal surgery ( Fig. 1 ). Patients at high risk of recurrence after surgery (i.e. previous intestinal or extensive resection) receive immunosuppressive therapy within the first month after surgery. Preventive treatment of clinical recurrence is based on ileocolonoscopy findings ( Fig. 1 ).

The medical data of all patients who underwent an intestinal resection for CD between 1995 and 2005 at Saint-Louis Hospital in Paris were retrospectively collected. Inclusion criteria were: patients with a diagnosis of CD and intestinal resection between 1995 and 2005. Exclusion criteria were: (1) postoperative management outside our department, (2) patients with clinical recurrence within 12 months of surgery, (3) anastomosis considered unreachable with standard ileocolonoscopy, (4) ileo- or colostomy.

We compared two groups: patients who had systematic ileocolonoscopy 6–12 months after intestinal surgery with tailored treatment according to the severity of endoscopic lesions (group C) and patients without systematic endoscopic evaluation (because of patient's refusal or medical omission, group NC).

Demographic and clinical characteristics, gathered from medical records, included age, sex, smoking habits, disease duration, extra-intestinal manifestations, perianal disease, family history of IBD, previous surgery, disease location and behaviour, preoperative treatment, length of resection, type of anastomosis, granulomas, Rutgeerts’ score on systematic postoperative ileocolonoscopy and postoperative treatments.

2.2. Endpoints

The primary endpoint was clinical recurrence defined as: symptomatic recurrence (Harvey–Bradshaw index >3) requiring introduction of corticosteroids and/or anti-TNF therapy; and/or surgical recurrence.

Secondary endpoints included: symptomatic recurrence (Harvey–Bradshaw index >3); time-to-introduce immunomodulatory treatments (purine analogues, methotrexate or anti-TNF) after intestinal resection and surgical recurrence (defined as the reappearance of symptoms refractory to medical treatment, or complications, leading to another intestinal resection).

2.3. Statistical analysis

Demographic and clinical characteristics of the two groups were expressed in median values and compared using the Chi-squared test and the Mann–WhitneyUtest. Probabilities of clinical recurrence, symptomatic recurrence, introduction of immunomodulatory treatments after surgery and surgical recurrence were calculated in each group using the Kaplan–Meier method and the difference between the groups was estimated using the log rank test. Probabilities were expressed at 5 years after surgery. The influence of concomitant variables on time-to-clinical recurrence was analysed using the Kaplan–Meier method. To identify independent prognostic factors, a multivariate analysis was applied via the Cox proportional hazards model, using variables with apvalue under 0.10. Apvalue under 0.05 was considered significant.

3. Results

3.1. Patients

From 1995 to 2005, 243 patients with CD underwent intestinal resection. Among them 132 were included according to the criteria of the study. There were 71 male patients (54%) and mean age at surgery was 32 years (±10). The patients’ flowchart is shown in Fig. 2 . Ninety patients (60%) had a systematic colonoscopy within the first year following surgery (median time: 7 months, 2–13; group C), and 42 patients (28%) did not undergo endoscopic evaluation during the first year (group NC) because of the patient's refusal (n = 8) or because of lack of referral (n = 34).

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Fig. 2 Patients’ flow chart.

Demographic and clinical characteristics of the patients are shown in Table 1 . At time of surgery, there was no significant difference between group C and group NC regarding gender, smoking habit, disease history and behaviour, therapies used prior to surgery and surgical procedures. Patients in group NC were younger at diagnosis and at the time of surgery; year of surgery was earlier in group NC and surgery was less often curative in group NC.

Table 1 Clinical characteristics of the patients. Group C: colonoscopy, group NC: no colonoscopy.

  Group C

n = 90
Group NC

n = 42
p value

C vs NC
Male: n (%) 51 (56) 20 (47) 0.33
Age at diagnosis, years: median (IQR) 24 (19–30) 21 (16–26) 0.03
Age at surgery, years: median (IQR) 31 (25–41) 27 (22–35) 0.04
Duration of disease before surgery, years: median (IQR) 3 (1–10) 3 (1–9) 0.59
Year of surgery: n (%)     0.001
 1995–1998 11 (12) 13 (31)  
 1999–2002 32 (35) 20 (47)  
 2003–2005 47 (52) 9 (21)  
Previous resection: n (%) 22 (24) 8 (19) 0.49
Behaviour (Montreal classification): n (%)     0.35
 B1 Non stenosing non penetrating 4 (4) 7 (16)  
 B2 Stenosing 30 (33) 14 (33)  
 B3 Penetrating 56 (62) 21 (50)  
Disease location (Montreal classification): n (%)     0.43
 L1 Small bowel 52 (57) 17 (40)  
 L2 Colon 1 (1) 4 (9)  
 L3 Small bowel + colon 32 (35) 21 (50)  
 L4 Upper gastrointestinal tract 8 (8) 8 (19)  
Perianal disease: n (%) 30 (33) 21 (50) 0.07
Extraintestinal manifestations: n (%) 20 (22) 13 (30) 0.28
Family history of IBD: n (%) 18 (20) 9 (21) 0.85
Smokers * : n (%) 33 (37) 18 (45) 0.50
Preoperative treatment: n (%)      
 Corticosteroids 81 (90) 38 (90) 0.93
 Aminosalicylates 72 (80) 35 (83) 0.65
 Immunosuppressive therapy 48 (53) 30 (71) 0.06
Anastomosis: n (%)     0.53
 Ileoileal 2 (2) 1 (2)  
 Ileocolic 83 (92) 34 (81)  
 Ileorectal 5 (5) 7 (16)  
Length of resection, cm ** : median (IQR) 30 (20–40) 20 (10–35) 0.26
Curative resection: n (%) 86 (96) 35 (83) 0.01
Granulomas *** : n (%) 45 (51) 22 (56) 0.80

* n = 127/132.

** n = 127/132.

*** n = 126/132.

IQR, interquartile range.

3.2. Systematic postoperative ileocolonoscopy according to the year of surgery

From 1995 to 2005, systematic postoperative ileocolonoscopy with tailored treatment ( Fig. 1 ) was applied in 68% of patients (90/132). This rate increases with time: 40% of patients from 1995 to 1998, 53% of patients from 1999 to 2002 and 75% from 2003 to 2005.

3.3. Endoscopic data

In group C, anastomosis could be achieved in 89 patients. Rutgeerts’ score was specified in the endoscopic report in 51 patients; for the 38 other patients, it was set retrospectively according to the detailed endoscopic description. Forty-six percent of patients (n = 41) had no or mild endoscopic recurrence (Rutgeerts’ score i0–i1): among them 78% (n = 32) had no clinical recurrence. Thirty-one percent of patients (n = 28) had moderate endoscopic recurrence (Rutgeerts’ score i2): among them 75% (n = 21) had no clinical recurrence. Twenty-two percent of patients (n = 20) had severe endoscopic recurrence (Rutgeerts’ score i3–i4): among them 45% (n = 9) had no clinical recurrence (Table S1).

3.4. Treatment modifications according to endoscopic findings

Postoperative and post-colonoscopy treatments are shown in Supplementary Figure S1. After surgery patients received MTX, thiopurines, probiotics (Lactobacillus johnsoniiLA1) or no treatment [11] . In group C, treatment was modified after ileocolonoscopy in 47% of the patients (n = 43) and treatment was correctly adjusted according to the predefined algorithm in 91% of the patients (n = 82). Rate of post-colonoscopy treatment modification varied according to the year of surgery: 27% (3/11) from 1995 to 1998, 43% (14/32) from 1999 to 2002 and 55% (26/47) from 2003 to 2005. Immunosuppressive therapy was maintained in 17% of patients (n = 15) after ileocolonoscopy and was introduced in 19% of patients (n = 17) according to the endoscopic results. Among those patients with post-colonoscopy immunosuppressive therapy, 71% (n = 23) did not have clinical recurrence.

3.5. Clinical recurrence

Median duration of follow-up was 51 months (IQR 32–79). Thirty-three percent of patients (n = 44) had a clinical recurrence: 25% in group C (21/90) and 54% in group NC (23/42). Harvey–Bradshaw index could be defined for 36/44 patients. Corticosteroids and/or anti-TNF therapy was introduced in 42 and 4 patients, respectively. Time to clinical recurrence was shorter in group NC than in group C (median delay of 25 months and 31 months, respectively), with probabilities of clinical recurrence of 31% and 52% at 3 and 5 years in group NC, and of 21% and 26% in group C (p = 0.01, log rank test; Fig. 3 ) respectively. In an analysis of patients who had a curative resection (n = 121, 91%), probabilities of clinical recurrence were 31% and 55% at 3 and 5 years in group NC, compared with 19% and 21% in group C (p = 0.009, log rank test), respectively. Time to symptomatic recurrence was shorter in group NC than in group C (p = 0.02, log rank test).

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Fig. 3 Clinical recurrence-free survival.

3.6. Postoperative immunomodulatory treatments

After surgical resection, immunomodulatory treatments were introduced or maintained in 79 patients (33 patients in group NC and 46 patients in group C). Probabilities of introducing (or maintaining) immunomodulatory treatments were higher in group NC: 60% and 73% at 3 and 5 years versus 47% and 52% in group C (p = 0.04; log rank test; Figure S2) respectively. Of note one patient (in group C) received methotrexate after surgery because of previous purine analogue intolerance (Figure S1).

3.7. Surgical recurrence

Another intestinal resection was performed in 9 patients (4 in group NC and 5 in group C), with no significant difference between groups NC and C with regard to time to surgical recurrence.

3.8. Predictive risk factors of clinical recurrence

An analysis of predictive factors of clinical recurrence is given in Table 2 . In multivariate analysis, the following factors were associated with a higher risk of clinical recurrence: group NC, presence of extra-intestinal manifestations, and non-penetrating disease behaviour ( Table 3 ).

Table 2 Predictive factors of post-operative clinical recurrence univariate analysis. Group C: colonoscopy, group NC: no colonoscopy.

  Clinical recurrence
  Group C: n (%)

n = 21
Group NC: n (%)

n = 23
Male 12 (57) 11 (47)
Age at diagnosis ≤23 years 11 (52) 12 (52)
Age at surgery ≤30 years 9 (42) 14 (60)
Duration of disease before surgery ≤3 years 9 (42) 13 (56)
Year of surgery    
 1995–1998 5 (23) 9 (39)
 1999–2002 7 (33) 13 (56)
 2003–2005 9 (42) 1 (4)
Previous resection 7 (33) 5 (21)
Non penetrating behaviour # 12 (57) 13 (56)
Disease location (Montreal classification)    
 L1 Small bowel 13 (62) 9 (39)
 L2 Colon 0 2 (8)
 L3 Small bowel + colon 8 (38) 12 (52)
 L4 Upper gastrointestinal tract 2 (9) 4 (17)
Perianal disease 7 (33) 12 (52)
Extraintestinal manifestations # 8 (38) 8 (34)
Family history of IBD 5 (23) 4 (17)
Smokers * 4 (19) 11 (47)
Preoperative treatment    
 Corticosteroids 17 (80) 21 (91)
 Aminosalicylates 18 (85) 20 (86)
 Immunosuppressive therapy 6 (28) 10 (43)
Length of resection ≤30 cm ** 14 (66) 13 (56)
Curative resection 18 (85) 18 (78)
Granulomas * # 12 (57) 13 (56)
Postoperative treatments    
 None 10 (47) 2 (8)
 Aminosalicylates 8 (38) 12 (52)
 Immunosuppressive therapy 3 (14) 9 (39)

# p < 0.10, univariate analysis.

* n = 41/44.

** n = 42/44.

Table 3 Predictive factors of postoperative clinical recurrence multivariate analysis.

  Odds ratio 95% IC p value
Group NC 1.9 1.07–3.57 0.02
Non penetrating disease behaviour 2.4 1.29–4.47 0.005
Extraintestinal manifestations 2.9 1.51–5.55 0.001

Group NC, no colonoscopy; OR, odds ratio.

4. Discussion

We here report the first study showing a positive impact of postoperative management based on systematic ileocolonoscopy within the first year after ileocolonic resection for CD. Our main result is a significant decrease in clinical recurrence by 50% when treatment is tailored to the severity of endoscopic recurrence. This strategy was applied in the majority of our patients and led to a postoperative treatment modification after systematic ileocolonoscopy in about half of the patients.

To our knowledge, two other retrospective studies have evaluated the impact of postoperative endoscopic monitoring with tailored treatment according to the endoscopic findings, but did not report any benefit of this strategy. Bordeianou et al. [8] compared three strategies tested in 199 patients: immediate postoperative treatment, tailored treatment after ileocolonoscopy and no treatment. At 5 years, the global rate of endoscopic recurrence was 56% and the global rate of symptomatic recurrence was 49%, with no significant difference in time to symptomatic recurrence among the three groups of patients. Similarly, De Cruz et al. [9] reported no clinical benefit from postoperative colonoscopy with adjusted treatment in 70 patients versus no postoperative colonoscopy in 66 patients. By contrast, we here report a significant difference in probabilities of clinical recurrence after surgery: 26% at 5 years in patients with systematic colonoscopy compared with 52% in patients without endoscopic evaluation. Some differences may partly explain these conflicting conclusions. Our definition of endoscopic recurrence was more precise, according to Rutgeerts’ score, whereas it was a binary definition in the other studies. Moreover, we had a predefined and standardised algorithm of treatment according to endoscopic findings that was correctly adjusted in 91% of patients and resulted in the introduction of immunomodulatory treatment in 23% of patients. By contrast, there was no standardised response to endoscopic results in the other studies and only 9% of the patients received immunomodulatory treatment after colonoscopy in De Cruz et al.’s study. However, one recent prospective study, only published in abstract form so far, found that endoscopic monitoring at six months with treatment step-up for recurrence was superior to standard care in reducing postoperative endoscopic recurrence at 18 months: 49% versus 67%, respectively [11] .

We identified three predictive risk factors of clinical recurrence: patients without endoscopic evaluation, the presence of extra-intestinal manifestations and non-penetrating disease behaviour. In previous publications, smoking status has emerged as an independent risk factor for postoperative recurrence [12] . In our retrospective study, this factor could not be studied correctly because of the lack of data and variations of smoking behaviour over time. Penetrating disease behaviour was also previously reported to predict postoperative recurrence. The fact that we did not observe this in our study could be explained by an early postoperative treatment of patients with penetrating disease behaviour.

We found that among those patients with post-colonoscopy immunosuppressive therapy, 71% (n = 23) did not have clinical recurrence, which is much higher than the protection rate afforded by thiopurines in previous studies. First, in the three randomised controlled trials comparing thiopurines with placebo or mesalamine[13], [14], and [15], clinical recurrence was defined as Crohn's Disease Activity Index (CDAI) above 200 or 250 (or a clinical score defined by the authors). In our study, we added to clinical symptoms the introduction of corticosteroids and/or anti-TNF therapy. This restriction may avoid overestimation of clinical recurrence because of postoperative diarrhoea. Second, we excluded patients with clinical recurrence within 12 months of surgery (thinking that colonoscopy could not have been performed in time instead of wrongfully penalising group NC). This point may also have contributed to the minor clinical recurrence rate.

Colonoscopy could be performed in 98% of patients (89/90, one colonoscopy was incomplete because of a loop) with no complications. However, this invasive procedure requires bowel preparation, sedation and it can bring complications. Biomarkers such as faecal calprotectin and faecal lactoferrin could be used but showed conflicting results in this setting [10] . One recent study [16] reported no significant difference in calprotectin concentrations between patients in endoscopic remission and patients with recurrent disease one year after ileocaecal resection for CD. Furthermore, there was a significant variation in calprotectin concentrations over time, which affects usefulness of calprotectin in clinical practice [16] . By contrast, some authors found that both calprotectin and lactoferrin could be clinically relevant biomarkers for predicting postoperative recurrence[17] and [18]. Lamb et al., [17] considered >50 μg/g and >7.25 μg/g as good cutoff values for calprotectin and lactoferrin to diagnose clinical postoperative recurrence. In addition, another recent study showed that these biomarkers correlated positively with endoscopic scores [18] . A cutoff value of 170 μg/g for calprotectin showed 83%sensitivity and 93%specificity in predicting a risk of clinical recurrence [18] .

Our study was undertaken prior the publication of European Crohn's and Colitis Organisation (ECCO) guidelines, [7] which recommended performing ileocolonoscopy within the first year of surgery where treatment decisions may be affected. Thus, the preventive strategy was applied in only 60% of patients; 28% did not have colonoscopy mainly because of medical omission. Our results emphasise the validity of the ECCO recommendation. Nevertheless, our work shows daily clinical practice and it is of note that the application of the strategy increased based on year of surgery, reaching 75% in the 2003–2005 period. Our study promotes systematic ileocolonoscopy after intestinal resection to guide treatment strategy, leading to an appropriate use of immunosuppressive therapy in patients at risk of clinical relapse and to a reduction of clinical recurrence. Moreover, this tailored strategy did not excessively increase immunosuppressive use; indeed, time to immunomodulatory treatment prescription was significantly shorter in patients without than in patients with endoscopic evaluation. Several limitations need to be acknowledged. First, it is a retrospective and monocentric study. Second, 8% of patients had no curative resection (n = 11), which means that they had residual postoperative disease. Nevertheless, after exclusion of these patients from the analysis, probabilities of clinical recurrence were still significantly different between group C and NC. Third, none of the patients received preventive anti-TNF therapy either after surgery or after colonoscopy. Indeed, the first data showing the great efficacy of anti-TNF therapy to prevent endoscopic and clinical recurrence or to treat early endoscopic recurrence were published after the time of our study[19], [20], and [21]. Alongside this, considering the low efficacy of purine analogues at preventing postoperative recurrence [22] we could discuss ( Fig. 1 ) the introduction of anti-TNF therapy into our strategy instead of purine analogues [21] .

In conclusion, we report that tailored treatment according to ileocolonoscopic assessment after ileocolonic resection is significantly associated with a reduced clinical recurrence rate. In the era of mucosal healing as a major objective, and given the excellent results of anti-TNF antibodies in the prevention and treatment of postoperative endoscopic recurrence, tailored treatment according to risk factors and endoscopic findings should be essential in the postoperative management of CD patients[19], [20], [23], and [24].

Conflict of interest

None declared.

Appendix A. Supplementary data

The following are the supplementary data to this article:

mmc2

Figure S1 The treatments given after surgery are shown, as well as the changes in the therapy after endoscopic assessment. AZA, azathioprine; 6-MP, 6-mercaptopurine; MTX, methotrexate.

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Figure S2 Immunomodulatory treatment-free survival.

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Footnotes

a Department of Gastroenterology, University Hospital of Saint-Louis, Paris, France

b Department of Digestive Surgery, University Hospital of Saint-Louis, Paris, France

lowast Corresponding author at: Service de Gastroentérologie, Hôpital Saint-Louis, 1, avenue Claude Vellefaux, 75010 Paris, France. Tel.: +33 1 42 49 95 46; fax: +33 1 42 49 91 68.