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Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Material and Methods
  5. Results
  6. Discussion
  7. Authorship
  8. Acknowledgements
  9. References

Background

Endoscopic balloon dilation is an efficacious and safe alternative to surgery as treatment of short intestinal strictures in Crohn's disease (CD). Factors predicting outcome of the procedure are not well described.

Aim

To evaluate whether smoking at diagnosis, treatment with azathioprine, or other clinical variables may affect clinical outcome after endoscopic dilation. The endpoint was requirement of a new intervention such as dilation or surgery with intestinal resection or strictureplasty.

Methods

Retrospective study of 83 patients with CD who underwent endoscopic balloon dilation of an intestinal stricture between 1987 and 2009.

Results

After index dilation 55/83 patients underwent a new intervention. Among current smokers, 31/32 (97%) underwent another intervention compared to 18/33 (55%) among never smokers (adjusted HR: 2.50, 95% CI: 1.14–5.50, = 0.022). After 5 years, cumulative probability of new intervention was 0.81 in smokers compared to 0.52 in never smokers; difference 0.29 (95% CI: 0.07–0.52, P = 0.01). In 16 patients, therapy with azathioprine was initiated before or shortly after the index dilation; 7/16 underwent a new intervention compared to 48/67 of those without azathioprine (HR: 0.46, 95% CI: 0.21–1.03, = 0.06). After adjustment for other variables, the association was even weaker (HR: 0.80, 95% CI: 0.29–2.18, = 0.668). Sex, age at diagnosis, age at first dilation, balloon size, location of stricture, and treatment period did not influence outcome.

Conclusions

Smoking doubles the risk of recurrent stricture formation requiring a new intervention after index dilation. Maintenance therapy with azathioprine did not influence the subsequent course and need for a new intervention.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Material and Methods
  5. Results
  6. Discussion
  7. Authorship
  8. Acknowledgements
  9. References

There is yet no cure for Crohn's disease (CD), although medical treatment has improved. Hence, surgery still remains a cornerstone in the management of CD, and in a lifelong perspective approximately 80% of patients will ultimately require surgery.[1, 2] Postoperative recurrence is common, and new endoscopic lesions will be found in a large majority of patients as early as after 1 year.[2-4] In due course, a second bowel resection will be necessary, and after 10 years 20–44% of patients have had repeated surgery. A number of clinical risk factors for postoperative recurrence have been studied, and smoking has consistently been shown to be an independent risk factor for postoperative recurrence.[1] Surgery-related factors such as type of anastomosis (end-to-end or side-to-side), laparoscopic versus open surgery, or radical versus limited resection does not influence subsequent clinical course.[1, 5]

Strictureplasty and endoscopic balloon dilation have evolved as treatment alternatives for short intestinal strictures. Although controlled data are not present, strictureplasty has been reported to be as safe and efficient as bowel resection in treatment of fibrotic strictures.[6-8] A meta-analysis found a surgical recurrence rate of 24% after a median follow-up of 46 months.[9] After endoscopic balloon dilation, repeated surgical resection has been reported in 24–36% of patients after a median follow-up of 5–5.8 years.[10, 11] However, factors influencing long-term outcome after endoscopic balloon dilation in fibrostenotic Crohn's disease are largely unknown. Technically successful dilation,[12, 13] a short stricture,[14, 15] and absence of ulcer in the stricture[16] have been found to be good prognostic factors. Disease activity, assessed by C-reactive protein (CRP) levels or endoscopic disease activity score, or medical treatment after index dilation, however, did not influence subsequent disease course.[11]

The influence of smoking in Crohn's disease in general is well known. Smoking increases the risk of developing Crohn's disease, worsens the clinical course, and increases the need for steroids, immunomodulators, and re-operations.[17] However, data on influence of smoking on the clinical course after dilation are sparse and inconsistent. An increased risk for surgery[18] or recurrent dilation[16] was reported in smokers, whereas others found no influence of smoking.[19, 20]

We have recently reported short- and long-term outcome of endoscopic dilation of intestinal strictures in a large cohort of CD patients.[10] The aim of this study was to evaluate whether smoking at diagnosis, treatment with azathioprine, or other clinical variables affected the outcome after index dilation with respect to need for new dilation or surgery with intestinal resection or strictureplasty.

Material and Methods

  1. Top of page
  2. Summary
  3. Introduction
  4. Material and Methods
  5. Results
  6. Discussion
  7. Authorship
  8. Acknowledgements
  9. References

Patients

The original cohort consisted of 178 patients with CD that underwent endoscopic balloon dilation during the period 1987–2009 due to an intestinal stricture causing symptoms of bowel obstruction at index dilation.[10] In the present study, we excluded 53 referral cases to avoid selection bias, and 42 cases that after index dilation had repeated dilations performed due to an asymptomatic intestinal stricture. In the early study period, these 42 patients underwent subsequent dilations without clinical symptoms of bowel obstruction due to a belief that this practice might reduce the risk of recurrence of symptomatic stricture or surgery. Hence, they are excluded as they will not reflect the true long-term outcome of the procedure. Thus, the current cohort consisted of 83 (39 female) patients with CD. Demographic data, clinical characteristics, and endoscopic and surgical procedures were searched for in the medical records at the Departments of Medicine and Surgery.

Definitions

The diagnosis of CD was based on Lennard-Jones criteria.[21] Disease location and behaviour were classified according to Montreal classification.[22] A bowel stricture was defined as a persistent narrowing that could not be passed by a standard colonoscope. A symptomatic stricture refers to a stricture associated with clinical symptoms of bowel obstruction such as postprandial abdominal pain, vomiting, and nausea.

Smoking habits at diagnosis, based on data in medical records, were classified as never smokers, ex-smokers, or active smokers. Smoking was defined as daily consumption of tobacco for at least 6 months. Maintenance therapy with azathioprine was defined as continuous use in an appropriate dosage for at least 6 months after index dilation. Outcome was defined as need of new intervention, referring to either a new dilation or surgical treatment with an intestinal resection or strictureplasty, during follow-up after index dilation.

Endoscopic dilation

Endoscopic dilation was generally done as an outpatient procedure using conscious sedation with benzodiazepines and/or opioids. Standard colonoscope (Olympus, Hamburg, Germany; Pentax Europe GmbH, Hamburg, Germany) and through-the-scope dilation balloons with a maximal diameter of 12–25 mm (Boston Scientific, Cork, Ireland; Cook Medical Europe Ltd, Limerick, Ireland) were used. The balloon was positioned under visual control in the stricture and inflated with water stepwise, with a gradually increasing diameter. Inflation time varied between 1 and 3 min. The procedure was repeated until the colonoscope could pass through the stricture. Fluoroscopy was not used.

Anastomotic strictures have been considered most appropriate for endoscopic dilation, and the authors have generally been restrictive in treating de novo strictures, especially colonic strictures. Concomitant fistula or abscesses have been exclusion criteria. In most cases the stricture was documented by a small bowel follow-through or enteroclysis, or in recent years by magnetic resonance tomography.[23] To assess influence of improved endoscopic technique and change of treatment strategies over time, we analysed two time periods separately, 1987–1998 and 1999–2009.

Statistics

Continuous variables are summarized with median and interquartile range (IQR). Patients are followed from the date of first dilation to the second intervention (new dilation, bowel resection or strictureplasty) or until 31 December 2009 if no second intervention occurred. Cumulative risks of second intervention are illustrated with Kaplan-Meier plot. Cox regression was used to evaluate the association to smoking and other clinical variables. All explanatory variables were analyzed as categorical in Cox regression. Measures of association are Hazard ratios (HR) with 95% confidence intervals (95% CI). A P-value less than 0.05 was regarded as statistically significant. All statistical analyses were performed in stata release 11 (StataCorp LP, College Station, TX, USA).

Ethics

The study was approved by the Regional Ethics Review Board in Uppsala.

Results

  1. Top of page
  2. Summary
  3. Introduction
  4. Material and Methods
  5. Results
  6. Discussion
  7. Authorship
  8. Acknowledgements
  9. References

Patients

At index dilation, the median (IQR) age at diagnosis of the 83 patients with CD was 32 (22–43) years, and at first dilation 48 (39–59) years. The median duration from diagnosis to first dilation was 16 (7–22) years. Thirty-seven patients were dilated in the first period of the study (1987–1998), and 46 in the latter (1999–2009). Demographic and clinical characteristics of the patients are shown in Table 1.

Table 1. Demographic and clinical characteristics of patients and data on stricture characteristics and dilation procedures
 Patients = 83
Gender: male/female44/39
Age at diagnosis, median (IQR)32 (22–43) years
Age at first dilation, median (IQR)48 (39–59) years
Disease duration at first dilation, median (IQR)16 (7–22) years
Disease location at diagnosis
Ileal (L1)45 (54%)
Colonic (L2)6 (7%)
Ileocolonic (L3)31 (37%)
Data missing1
Behaviour at diagnosis
Non-stricturing, non-penetrating (B1)37 (45%)
Stricturing (B2)37 (45%)
Fistulating (B3)6 (7%)
Data missing3
Previous surgery71 (86%)
Location of stricture
Ileum18 (22%)
Ileocolonic anastomosis57 (69%)
Other location8 (10%)
Diameter of dilation balloon
12–18 mm38 (46%)
20 mm18 (22%)
25 mm20 (24%)
Data missing7
Follow-up time, median (IQR) years10 (5–16)

At diagnosis, patients were classified as smokers (= 32), never smokers (= 33) and ex-smokers (= 13). Data was missing in 5 patients. During follow-up 10 patients gave up smoking.

In 16/83 patients, azathioprine was given as maintenance therapy, which was introduced before (= 13) or shortly after the index dilation (= 3). None were treated with anti-TNF agents.

Outcome

In total, 55/83 (66%) patients underwent a new intervention during follow-up. Smoking habits influenced the subsequent risk for new intervention after index dilation. In the group of current smokers, 31/32 (97%) underwent another intervention compared to 18/33 (55%) of never smokers (HR: 2.18, 95% CI: 1.22–3.93, = 0.009). The increased risk remained after adjustment for other variables (HR: 2.50, 95% CI: 1.14–5.50, = 0.022) (Table 2). After 5 years follow-up, the cumulative probability for new intervention among smokers, ex-smokers and never smokers was 0.81, 0.32 and 0.52, respectively (Figure 1). Smokers had statistically significantly higher cumulative probability compared to never smokers, difference 0.29 (95% CI: 0.07–0.52, = 0.01). There was no significant difference between ex-smokers at diagnosis and never smokers (Table 2). However, in 10 patients that stopped smoking during follow-up, the risk for a new intervention remained increased [unadjusted HR: 2.68 (95% CI: 1.22–5.91), = 0.014, adjusted HR: 2.48 (95% CI: 0.95–8.48) = 0.064].

Table 2. Cox regression analyses of risk of new intervention (repeated dilation, surgical bowel resection, or strictureplasty) during follow-up after index dilation
 No. of eventsRateaUnadjusted (= 83) HR (95% CI)P-valueAdjustedb (= 70) HR (95% CI)P-value
  1. a

     Rate is number of events per person year.

  2. b

     Adjusted for all variables in the table. Analyses were restricted to 70 patients where information of all variables was available.

Sex
Men, = 44250.14Reference Reference 
Women, = 39300.181.38 (0.81–2.36)0.2330.74 (0.38–1.44)0.379
Age at diagnosis
10–31 years, = 42290.18Reference   
32–73 years, = 41260.140.83 (0.49–1.42)0.500  
Smoking habits at diagnosis
Never smoked, n = 33180.12Reference Reference 
Current smoker, n = 32310.342.18 (1.22–3.93)0.0092.50 (1.14–5.50)0.022
Ex-smoker, = 1350.050.50 (0.18–1.34)0.1660.60 (0.20–1.83)0.371
Missing, = 5      
Year of index dilatation
1987–1998, = 37310.17Reference Reference 
1999–2009, = 46240.150.63 (0.37–1.07)0.0880.89 (0.40–1.96)0.772
Azathioprine treatment after index dilation
No, = 67480.19Reference Reference 
Yes, = 1670.070.46 (0.21–1.03)0.0600.80 (0.29–2.18)0.668
Age at index dilation
20–46 years, = 38280.16Reference Reference 
47–88 years, = 42250.140.74 (0.43–1.27)0.2760.86 (0.46–1.61)0.647
Missing, = 3      
Years from diagnosis to index dilatation
0–5 years, = 17140.21Reference Reference 
6–54 years, = 66410.140.66 (0.36–1.21)0.1770.90 (0.43–1.91)0.788
Size of balloon
12–18 mm, = 38230.120.65 (0.32–1.32)0.2380.71 (0.28–1.79)0.466
20 mm, = 18120.26Reference Reference 
25 mm, = 20150.170.94 (0.44–2.02)0.8700.67 (0.25–1.80)0.431
Missing, = 7      
Location of stricture
Ileocolonic, = 57380.15Reference Reference 
Ileal, = 18130.201.11 (0.59–2.09)0.7381.45 (0.68–3.13)0.338
Other, = 840.120.70 (0.25–1.97)0.4990.93 (0.25–3.39)0.909
image

Figure 1. Kaplan-Meier plot showing probability of intervention-free survival after index dilation in relation to smoking habits at diagnosis of Crohn's disease.

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In patients treated with azathioprine after index dilation, 7/16 (44%) underwent a new intervention compared to 48/67 (72%) of those without this treatment (HR: 0.46, 95% CI: 0.21–1.03, = 0.06) (Table 2). However, use of azathioprine was different in smokers (1/32; 3%) compared to never smokers (9/33; 27%) and after adjustment for smoking and other clinical variables, the association was even weaker (HR: 0.80, 95% CI: 0.29–2.18), = 0.668). No other clinical variable such as sex, age at diagnosis, age at first dilation, balloon size, location of stricture, or treatment period showed a statistically significant association to outcome (Table 2).

Discussion

  1. Top of page
  2. Summary
  3. Introduction
  4. Material and Methods
  5. Results
  6. Discussion
  7. Authorship
  8. Acknowledgements
  9. References

This study confirms that smoking has a detrimental effect on the clinical course of CD and increases the risk for surgery or new balloon dilation after index dilation of an intestinal stricture. This is consistent with other well-known consequences of smoking, being the most important environmental factor in the pathogenesis of CD. It is well known that smokers have an increased risk of developing CD. In a meta-analysis, current smoking was associated with CD with an odds ratio of 1.76 (95% CI: 1.40–2.22) compared to non-smoking.[24] Furthermore, smoking has a deleterious effect on the clinical course of CD. Smoking increases complication frequency and the need for steroids, immunomodulators, and re-operations.[2, 17, 25] and may also increase the risk of loss of response to anti-TNFs.[26] The effect of smoking on postoperative recurrence in CD was studied in a meta-analysis of 16 studies encompassing 2962 patients.[8] A two-fold increased risk of clinical recurrence, and a 2.5-fold increased risk of surgical recurrence at 10 years were seen in smokers compared to non-smokers.

Data on influence of smoking after endoscopic balloon dilation are limited and conflicting. An increased risk for surgery[18] or recurrent dilation[16] was reported in smokers, whereas two other studies found no significant influence of smoking on outcome.[19, 20] In the present study, we show that smoking is associated with a twofold increased risk of new intervention with HR of 2.18 in unadjusted analysis and of 2.50 when adjusted for other variables. In ex-smokers at diagnosis, however, no increased risk of a new intervention was seen (HR: 0.5, 95% CI: 0.18–1.34, = 0.166), whereas in 10 patients quitting smoking at any time after diagnosis, the risk remained increased, as in active smokers. This is consistent with other reports and might be caused by a carryover effect after stopping smoking, which seems to be reduced over time.[27] In this study we used smoking data at the time of diagnosis of Crohn's disease, as smoking data at index dilation were not generally available in medical records. We consider smoking data reliable, since our clinic has kept records of smoking habits for a long time. Since this is a retrospective study, it has not been possible to differentiate between moderate and heavy smokers, and assess a dose-response relationship of smoking.[25] Smoking has been shown to be an important risk factor, especially in ileal disease compared to other disease locations. Most of our patients had an ileal location, since 77/83 had a de novo stricture in ileum or a stricture in an ileocolic anastomosis. Consequently, there were too small numbers of patients with strictures in other locations to address whether smoking influenced recurrence rates differently in ileal and colonic disease.

The mechanisms on the molecular and cellular level by which smoking influences the pathogenesis of CD are incompletely known. Several potential mechanisms have been proposed, such as alterations in gut permeability or intestinal cytokine and eicosanoid production or modulation of mucosal immune responses. None of these hypotheses, however, have given a satisfying explanation.[28]

There are limited data on efficacy of medical therapy after balloon dilation. In their retrospective study of 138 patients, Thienpont et al. reported that treatment with 5-ASA, azathioprine or anti-TNF at first dilation did not influence the long-term outcome after the procedure, and the need for new dilation or surgery was not affected by medical therapy.[11] In a randomised, placebo-controlled trial, so far only reported as abstract at DDW 1997, 30 patients with CD were randomised to receive either azathioprine 100 mg/day together with budesonide 9 mg/day (= 15) or placebo (= 15) after endoscopic dilation of intestinal strictures. After 6 and 12 months, placebo-treated patients had recurrence of obstructive symptoms significantly more often compared to those given anti-inflammatory treatment. Furthermore, surgical treatment for restenosis was necessary in 8/15 patients given placebo compared to 3/15 patients receiving azathioprine and budesonide (P = 0.021).[29] The anti-fibrotic properties of Tranilast, inhibiting TGF-β expression and action,[30] was assessed in a pilot study of 24 patients with quiescent CD and non-symptomatic intestinal strictures.[31] Patients were allocated to treatment with tranilast 200 mg t.d.s. or no therapy. Balloon dilation due to symptomatic stricture was required in 1/12 versus 5/12 patients during follow-up (P = 0.0034). No further publications on use of this agent in Crohn's disease have been found ever since. There are limited data on biologics in treatment of strictures or after dilation. No randomised controlled trial has been conducted hitherto, and only uncontrolled case series have been published.[32-35] In a small series of three patients, dilation of colonic strictures was achieved by intralesional injection of infliximab.[36]

In our study we could not observe any effect of azathioprine on the subsequent need for new intervention. In the unadjusted analysis there was no statistically significant difference in azathioprine-treated patients compared to those not using the drug. After adjustment for other variables including smoking the difference became even less. However, it must be pointed out that most patients were treated with azathioprine before index dilation and were in fact failing azathioprine already at first dilation. Furthermore, there is a potential risk of a type II error as the number of patients in the study is limited. Moreover, the indication for introducing azathioprine may reflect a more aggressive disease course, and there is accordingly a risk of bias by indication. Hence, there is a need to perform a prospective randomised, controlled trial to evaluate the best possible treatment after endoscopic dilation to reduce recurrence risk.

Consistent with other studies,[11, 16, 18, 19, 37] clinical variables, such as sex, age at diagnosis, age at index dilation, size of the balloon, and localisation of the stricture, did not influence outcome after dilation. Furthermore, comparison of two time periods, 1987–1998 versus 1999–2009, showed no significant differences in outcome. This supports the position that changes in the medical or surgical treatment or increasing experience of the endoscopic technique by the endoscopists has not significantly influenced our data. Several endoscopists with different endoscopic skills were involved in the procedures. This, however, reflects a day-to-day clinical situation, which makes the results even more relevant. Varying skills of endoscopists may unquestionably affect the immediate success rate and outcome of dilation, but likely not the long-term recurrence rate analysed herein. Biochemical markers of inflammation, stricture width and length, and severity of endoscopic lesions have not been evaluated due to incomplete data. Thienpont et al. reported that disease activity, assessed by CRP levels, did not influence subsequent disease course.[11] Moreover, they found that severity of endoscopic lesions did not influence recurrent dilation or surgery, and patients with Rutgeerts postoperative recurrence score i0-i1 had a similar long-term outcome compared to those with score i2-i4.[11] In view of these data, we believe that absence of information on systemic or mucosal inflammation does not interfere with our major results and conclusions. As a proxy marker for clinical disease severity, we analysed time from diagnosis to index dilation and there was no difference in patients with a short time period (≤5 years) compared to those with a longer time period (>5 years).

In conclusion, this study, although it has the inherent limitations of a retrospective, observational study without a control group, shows that smoking increases twofold the risk of a new intervention after endoscopic balloon dilation of intestinal stricture in CD. Maintenance therapy with azathioprine did not reduce the risk for a new intervention. The data reinforce the view that patients with CD should strongly be advised to quit smoking.[38]

Authorship

  1. Top of page
  2. Summary
  3. Introduction
  4. Material and Methods
  5. Results
  6. Discussion
  7. Authorship
  8. Acknowledgements
  9. References

Guarantor of the article: Curt Tysk.

Author contributions: Anders Gustavsson contributed to the study concept and design, acquisition of data, analysis and interpretation of data, drafting of manuscript, and critical revision of the manuscript. Anders Magnuson contributed to the statistical analysis, interpretation of data and critical revision of the manuscript. Björn Blomberg contributed to the interpretation of data and critical revision of the manuscript. Magnus Andersson contributed to the interpretation of data and critical revision of the manuscript. Jonas Halfvarson contributed to the study concept and design, interpretation of data, and critical revision of the manuscript. Curt Tysk contributed to the study concept and design, interpretation of data, and critical revision of the manuscript. All authors have approved the final version of the manuscript.

Acknowledgements

  1. Top of page
  2. Summary
  3. Introduction
  4. Material and Methods
  5. Results
  6. Discussion
  7. Authorship
  8. Acknowledgements
  9. References

Declaration of personal interests: Anders Gustavsson has served as a speaker for MSD. Jonas Halfvarson has served as a speaker for MSD, Abbott and Renapharma Vifor. Curt Tysk has served as a speaker for Tillotts Pharma, Falk Pharma, Ferring, MSD and AstraZeneca.

Declaration of funding interests: This study was funded in part by The Foundation for Clinical Research in Inflammatory Bowel Disease, United States, and Uppsala-Örebro Regional Research Council, Sweden. Research nurse Kerstin Eriksson, Clinical Research Support, Örebro assisted in collecting the data. This is gratefully acknowledged. No writing support was provided.

References

  1. Top of page
  2. Summary
  3. Introduction
  4. Material and Methods
  5. Results
  6. Discussion
  7. Authorship
  8. Acknowledgements
  9. References