A Pilot Study of Intrastricture Steroid Versus Placebo Injection After Balloon Dilatation of Crohn’s Strictures
2007; Elsevier BV; Volume: 5; Issue: 9 Linguagem: Inglês
10.1016/j.cgh.2007.04.013
ISSN1542-7714
AutoresJames E. East, Jim C. Brooker, Matthew D. Rutter, Brian P. Saunders,
Tópico(s)Autoimmune and Inflammatory Disorders
ResumoBackground & Aims: Restricturing after ileocolonic resection for Crohn’s disease is common. Colonoscopic balloon dilatation is effective but repeated dilatations often are required. Intrastricture steroid injection after balloon dilatation has been reported to reduce the need for repeat dilatation in retrospective series, but no randomized data are available. Methods: We performed a pilot study comparing local quadrantic injection of triamcinolone (40 mg total dose) after endoscopic balloon dilatation of Crohn’s ileocolonic anastomotic strictures vs saline placebo. The primary end point was time to redilatation or surgery. Patients were followed up for 52 weeks. Results: Thirteen patients were randomized, 7 to steroid and 6 to placebo. Groups were well matched for baseline and dilatation characteristics. In the intention-to-treat analysis, 1 of 6 patients in the placebo group and 5 of 7 patients in the steroid group needed redilatation (log rank test P = .06; Cox regression P = .10; hazard ratio, 6.1; 95% confidence interval, 0.7–53.0). In the per-protocol analysis the differences were more significant (log rank test P = .03; Cox regression P = .07; hazard ratio, 7.7; 95% confidence interval, 0.9–67.9). Conclusions: A single treatment of intrastricture triamcinolone injection did not reduce the time to redilatation after balloon dilatation of Crohn’s ileocolonic anastomotic strictures and there was a trend toward a worse outcome. The use of this technique in clinical practice should be considered carefully until more data are available. Background & Aims: Restricturing after ileocolonic resection for Crohn’s disease is common. Colonoscopic balloon dilatation is effective but repeated dilatations often are required. Intrastricture steroid injection after balloon dilatation has been reported to reduce the need for repeat dilatation in retrospective series, but no randomized data are available. Methods: We performed a pilot study comparing local quadrantic injection of triamcinolone (40 mg total dose) after endoscopic balloon dilatation of Crohn’s ileocolonic anastomotic strictures vs saline placebo. The primary end point was time to redilatation or surgery. Patients were followed up for 52 weeks. Results: Thirteen patients were randomized, 7 to steroid and 6 to placebo. Groups were well matched for baseline and dilatation characteristics. In the intention-to-treat analysis, 1 of 6 patients in the placebo group and 5 of 7 patients in the steroid group needed redilatation (log rank test P = .06; Cox regression P = .10; hazard ratio, 6.1; 95% confidence interval, 0.7–53.0). In the per-protocol analysis the differences were more significant (log rank test P = .03; Cox regression P = .07; hazard ratio, 7.7; 95% confidence interval, 0.9–67.9). Conclusions: A single treatment of intrastricture triamcinolone injection did not reduce the time to redilatation after balloon dilatation of Crohn’s ileocolonic anastomotic strictures and there was a trend toward a worse outcome. The use of this technique in clinical practice should be considered carefully until more data are available. See Editorial on page 1027. See Editorial on page 1027. Patients who have Crohn’s disease have a 70% chance of requiring surgical resection at some time during their illness.1Sachar D.B. The problem of postoperative recurrence of Crohn’s disease.Med Clin North Am. 1990; 74: 183-188PubMed Google Scholar Most commonly this takes the form of an ileocolonic resection and anastomosis for distal small-bowel disease. There is almost invariably recurrence of the disease at the anastomosis and in a proportion of patients this is associated with stricturing at the anastomotic site, leading to symptoms.2Rutgeerts P. Geboes K. Vantrappen G. et al.Natural history of recurrent Crohn’s disease at the ileocolonic anastomosis after curative surgery.Gut. 1984; 25: 665-672Crossref PubMed Scopus (665) Google Scholar Recurrent surgery is a source of morbidity and mortality, particularly because intestinal length and function are lost permanently. Medical therapy with long courses of antibiotics can ameliorate this, but can not prevent it completely, and may be difficult to complete owing to poor compliance with medication and side effects.3Rutgeerts P. Hiele M. Geboes K. et al.Controlled trial of metronidazole treatment for prevention of Crohn’s recurrence after ileal resection.Gastroenterology. 1995; 108: 1617-1621Abstract Full Text PDF PubMed Scopus (721) Google Scholar Endoscopic balloon dilatation has been used to treat Crohn’s-related anastomotic strictures since the 1970s and is effective in the long term in 41%–63% of patients, but half will require repeated dilatation to achieve this, and a significant proportion of patients will require surgery.4Thomas-Gibson S. Brooker J.C. Hayward C.M. et al.Colonoscopic balloon dilation of Crohn’s strictures: a review of long-term outcomes.Eur J Gastroenterol Hepatol. 2003; 15: 485-488PubMed Google Scholar, 5Breysem Y. Janssens J.F. Coremans G. et al.Endoscopic balloon dilation of colonic and ileo-colonic Crohn’s strictures: long-term results.Gastrointest Endosc. 1992; 38: 142-147Abstract Full Text PDF PubMed Scopus (113) Google Scholar, 6Couckuyt H. Gevers A.M. Coremans G. et al.Efficacy and safety of hydrostatic balloon dilatation of ileocolonic Crohn’s strictures: a prospective longterm analysis.Gut. 1995; 36: 577-580Crossref PubMed Scopus (226) Google Scholar, 7Dear K.L. Hunter J.O. Colonoscopic hydrostatic balloon dilatation of Crohn’s strictures.J Clin Gastroenterol. 2001; 33: 315-318Crossref PubMed Scopus (84) Google Scholar, 8Sabate J.M. Villarejo J. Bouhnik Y. et al.Hydrostatic balloon dilatation of Crohn’s strictures.Aliment Pharmacol Ther. 2003; 18: 409-413Crossref PubMed Scopus (101) Google Scholar In an effort to improve the long-term effectiveness of balloon dilatation some endoscopists have tried injecting agents locally into strictures after dilatation to try and affect the natural course of stricture healing. Agents used in the lower-gastrointestinal tract include steroids such as betamethasone and triamcinolone, and the biological agent infliximab.9Brooker J.C. Beckett C.G. Saunders B.P. et al.Long-acting steroid injection after endoscopic dilation of anastomotic Crohn’s strictures may improve the outcome: a retrospective case series.Endoscopy. 2003; 35: 333-337Crossref PubMed Scopus (135) Google Scholar, 10Biancone L. Cretella M. Tosti C. et al.Local injection of infliximab in the postoperative recurrence of Crohn’s disease.Gastrointest Endosc. 2006; 63: 486-492Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar, 11Ramboer C. Verhamme M. Dhondt E. et al.Endoscopic treatment of stenosis in recurrent Crohn’s disease with balloon dilation combined with local corticosteroid injection.Gastrointest Endosc. 1995; 42: 252-255Abstract Full Text Full Text PDF PubMed Scopus (116) Google Scholar, 12Singh V.V. Draganov P. Valentine J. Efficacy and safety of endoscopic balloon dilation of symptomatic upper and lower gastrointestinal Crohn’s disease strictures.J Clin Gastroenterol. 2005; 39: 284-290Crossref PubMed Scopus (138) Google Scholar Retrospective data in 3 small series on the use of triamcinolone suggests that it may reduce the need for repeat colonic stricture dilatation.9Brooker J.C. Beckett C.G. Saunders B.P. et al.Long-acting steroid injection after endoscopic dilation of anastomotic Crohn’s strictures may improve the outcome: a retrospective case series.Endoscopy. 2003; 35: 333-337Crossref PubMed Scopus (135) Google Scholar, 12Singh V.V. Draganov P. Valentine J. Efficacy and safety of endoscopic balloon dilation of symptomatic upper and lower gastrointestinal Crohn’s disease strictures.J Clin Gastroenterol. 2005; 39: 284-290Crossref PubMed Scopus (138) Google Scholar, 13Lavy A. Triamcinolone improves outcome in Crohn’s disease strictures.Dis Colon Rectum. 1997; 40: 184-186Crossref PubMed Scopus (69) Google Scholar This approach is suggested as an adjuvant therapy in expert reviews on the subject and anecdotally is commonplace in clinical practice in the United Kingdom and in the United States, and was routine in our unit before this study.14Saunders B.P. Brown G.J. Lemann M. et al.Balloon dilation of ileocolonic strictures in Crohn’s disease.Endoscopy. 2004; 36: 1001-1007Crossref PubMed Scopus (33) Google Scholar We aimed to test the effectiveness of triamcinolone in the prevention of recurrent stricturing in patients with Crohn’s disease after endoscopic balloon dilatation in a pilot study. Patients aged 18 years or older presenting to St. Mark’s Hospital who had symptomatic Crohn’s strictures, less than 5 cm in length as assessed by barium studies, and thought to be suitable for colonoscopic dilatation (ie, endoscopically accessible), were invited to participate in this study. Patients also had to have failed medical therapy with steroids and aminosalicylates. All patients gave written informed consent and the study was approved by the local research ethics committee. Recruitment began in April 2000, with final follow-up data in March 2004. Demographic data collected before initial dilatation included age, sex, body mass index, duration of Crohn’s disease, time since surgery for Crohn’s disease and type of surgery, medical therapy, C-reactive protein level, erythrocyte sedimentation rate, and data to allow calculation of the Crohn’s disease activity index (CDAI).15Best W.R. Becktel J.M. Singleton J.W. et al.Development of a Crohn’s disease activity index National Cooperative Crohn’s Disease Study.Gastroenterology. 1976; 70: 439-444Abstract Full Text PDF PubMed Scopus (3108) Google Scholar The primary end point was the time to repeat dilatation or surgery. The need for repeat dilatation or surgery was assessed on symptomatic (recurrence of obstructive symptoms) and clinical grounds by the physician caring for the patient. Repeat imaging was not required. Patients were followed up at 1, 4, 12, and 52 weeks. Data also were collected on maximum balloon diameter and time at maximum balloon inflation. Bowel preparation was with 1 day of dietary restriction and 2 sachets of citramag (Sanochemia, Bristol, UK) and 13 g of senna. Patients were sedated lightly with intravenous midazolam and pethidine (meperidine) and received antispasmodic, hyoscine butylbromide, unless contraindicated. Colonoscopy was performed to the stricture with position changes and hand pressure as appropriate. Once the stricture was reached it was traversed with the deflated balloon with or without a guidewire at the endoscopist’s discretion. Balloons used were through-the-scope (Microvasive Rigiflex; Boston Scientific, Natick, MA). Fluoroscopy was not used. Once the balloon was centered across the stricture it was inflated in stages, aiming for a maximal luminal diameter of 20 mm. If the patient experienced severe pain the balloon was not inflated further. The final diameter of dilation was at the discretion of the endoscopist. After inflation the balloon was held at the required inflation pressure for 1 to 2 minutes, then removed. The stricture then was assessed as to whether the colonoscope (diameter, 13 mm) could be passed and the endoscopist indicated whether the dilatation was believed to be technically a success. In severely angulated strictures, therefore, the dilatation still could be judged a success despite an inability to pass a colonoscope. Patients were randomized to triamcinolone or placebo in a 1:1 ratio in blocks of 4 using a computer-generated random number sequence. The syringe containing triamcinolone or placebo was made up by a member of the nursing staff who was not connected to the trial and was covered by opaque medical tape to obscure the contents. After dilatation the stricture was injected with 40 mg triamcinolone acetonide (Kenalog; Bristol-Myers Squibb, Middlesex, United Kingdom) in 5 mL normal saline or an identical volume of normal saline as a placebo. This was performed through a standard varix injection catheter (catheter length, 240 cm; needle length, 5 mm; Wilson-Cook Medical, Winston-Salem, NC). Another endoscopist, not involved in patient follow-up evaluation, performed the injections quadrantically deep into the mucosa at 1- to 2-cm intervals along the stricture. Neither the patient nor the physician following up the patient knew which treatment was given, although the endoscopist performing the injections may have been unblinded because triamcinolone is a milky fluid, which could be observed if leakage back into the lumen occurred during injection. Patients who became symptomatic after their first dilatation were offered repeat dilatation as part of the trial and were allocated to receive whichever treatment they had not received previously (ie, if the patient received steroid at the first dilatation they received placebo at the second). All other aspects including follow-up evaluation were as before. The original intention was to recruit approximately 50 patients with a formal power calculation performed after an initial pilot phase because no clear previous data exist on which to base such a calculation; however, after difficulties in recruitment, consideration was given to a prespecified plan to expand the study to involve another center. An unplanned interim analysis was performed at this point, with 13 patients recruited, leaving the study substantially underpowered compared with the initial plan. This analysis suggested a low probability of benefit with steroid and a possibility of harm and so the study was closed and the results are those reported here. The decision was made by the principal investigator because the trial had no formal Data Safety Monitoring Board. The log rank test was used to compare the proportion in each group surviving without redilatation or surgery, the primary end point. Cox regression analysis was used to calculate the hazard ratio. Demographic data were compared with the Fisher exact test for categoric variables and the Mann–Whitney U test for continuous variables. Data were analyzed according to intention-to-treat principals with a further per-protocol analysis using additional follow-up data not collected as part of the trial. P values were considered statistically significant at less than .05 and a trend toward statistical significance was considered at less than .10. Thirteen patients were recruited, 7 were randomized to the steroid group and 6 were randomized to the placebo group. All patients in the steroid group had follow-up evaluation until week 52; 4 of 6 patients in the placebo group had follow-up evaluation until week 52. Data for the 2 patients who did not complete the follow-up evaluation were available until days 113 and 160 postdilatation, and they were censored at these points. Further follow-up data for these patients to week 52 subsequently was extracted from their clinical notes. All patients recruited had undergone a previous right hemicolectomy and all the strictures were at the ileocolonic anastomosis. The median stricture length was 2 cm (range, 1.5–4 cm) in the steroid group and 1.75 cm in the placebo group (range, 1–5 cm). Prestenotic dilatation on barium follow-through was reported in 3 patients in the placebo group and in no patients in the steroid group. There were no significant differences in baseline demographics (Table 1), or in clinical details of the dilations (Table 2) between the 2 groups. Data are expressed as medians. There were 3 episodes of mild self-limiting postdilatation bleeding that stopped during the procedure without treatment, 2 in the steroid group and 1 in the placebo group, and no other complications.Table 1Predilatation DemographicsVariableSteroid (n = 7)Placebo (n = 6)Age, y (range)44 (33–69)41 (30–52)Male:female5:23:3Body mass index22 (17–33)21 (20–29)Crohn’s duration, y22 (10–34)22 (12–34)Time since surgery, y10 (8–30)12 (11–19)aData not available for 3 patients.Immunosuppressants (%)bPrednisolone or azathioprine.3 (43%)2 (33%)Mesalamines2 (29%)3 (50%)Erythrocyte sedimentation rate (range)8 (2–36)6 (2–20)C-reactive protein level (range)2 (2–12)2 (2–8)CDAI (range)150 (89–306)151 (125–256)a Data not available for 3 patients.b Prednisolone or azathioprine. Open table in a new tab Table 2Clinical Details of DilatationVariableSteroid (n = 7)Placebo (n = 6)Balloon size, mm (range)18 (18–20)18 (15–20)Inflation duration, min (range)2 (2–3)1.75 (0.75–2)Technical success7/75/6Able to pass scope5/74/5aData were not available for 1 patient.a Data were not available for 1 patient. Open table in a new tab In the intention-to-treat analysis, 1 of 6 patients in the placebo group required redilatation, compared with 5 of 7 patients in the steroid group. No patient required surgery after their first dilatation. There was marked divergence of the survival curves by eye, and there was a statistical trend to a difference in time to repeat dilatation, which was worse in the steroid group (P = .06, log rank test; Figure 1; Cox regression, P = .10; hazard ratio, 6.1; 95% confidence interval, 0.7–53.0). Incorporation of data extracted from the clinical notes indicated that of the 2 patients lost to follow-up evaluation, 1 had no further dilatation in the 52-week follow-up period, and 1 required redilatation at 349 days (Figure 2). Statistical analysis with this additional data, the per-protocol analysis, showed a significant difference between the 2 groups (P = .03, log rank test; Cox regression, P = .07; hazard ratio, 7.7; 95% confidence interval, 0.9–67.9).Figure 2Survival curve for time to redilatation or surgery (per protocol).View Large Image Figure ViewerDownload Hi-res image Download (PPT) Five patients in the steroid group and 1 patient from the placebo group presented for redilatation during the trial follow-up period. At repeat colonoscopy there was a recurrent impassable stricture in all cases. All 5 patients in the steroid arm received placebo injection after a second dilatation (data presented in Figure 3). Follow-up data were available for 3 of the patients, with follow-up data extracted from the clinical notes for the other 2 patients in the steroid group. The time to dilatation failure after the second dilatation and placebo injection was longer than that of the same group after their first dilatation and steroid injection, with the 2 patients who had recurrent symptoms requiring surgery. The single patient in the placebo arm did not receive treatment as part of the study at the endoscopist’s discretion. In this pilot study, quadrantic intrastricture injection of triamcinolone 40 mg after balloon dilatation of Crohn’s ileocolonic anastomotic strictures did not improve time to redilatation or surgery. In fact, there was an unexpected trend for the need for earlier redilatation with the use of triamcinolone in the intention-to-treat analysis, which was statistically significant in the per-protocol analysis. This patient group was very similar in terms of age, body mass index, Crohn’s duration, and site of stricturing to a large series reported previously at our institution, making these results likely to be generalizable to the wider Crohn’s population4Thomas-Gibson S. Brooker J.C. Hayward C.M. et al.Colonoscopic balloon dilation of Crohn’s strictures: a review of long-term outcomes.Eur J Gastroenterol Hepatol. 2003; 15: 485-488PubMed Google Scholar; however, 6 of 13 (46%) patients had a CDAI score of greater than 150, suggesting some disease activity, similar to that seen in cohorts by Breysem et al5Breysem Y. Janssens J.F. Coremans G. et al.Endoscopic balloon dilation of colonic and ileo-colonic Crohn’s strictures: long-term results.Gastrointest Endosc. 1992; 38: 142-147Abstract Full Text PDF PubMed Scopus (113) Google Scholar and Sabate et al8Sabate J.M. Villarejo J. Bouhnik Y. et al.Hydrostatic balloon dilatation of Crohn’s strictures.Aliment Pharmacol Ther. 2003; 18: 409-413Crossref PubMed Scopus (101) Google Scholar, who noted 44% and 55%, respectively, had activity based on clinical symptoms and serum markers, but less than the 82% considered to have active disease in the Couckuyt et al6Couckuyt H. Gevers A.M. Coremans G. et al.Efficacy and safety of hydrostatic balloon dilatation of ileocolonic Crohn’s strictures: a prospective longterm analysis.Gut. 1995; 36: 577-580Crossref PubMed Scopus (226) Google Scholar cohort, although activity is not defined through either systemic, endoscopic, or serum marker characteristics.15Best W.R. Becktel J.M. Singleton J.W. et al.Development of a Crohn’s disease activity index National Cooperative Crohn’s Disease Study.Gastroenterology. 1976; 70: 439-444Abstract Full Text PDF PubMed Scopus (3108) Google Scholar CDAI scores of greater than 150 in our cohort were driven principally by number of soft or liquid stools, abdominal pain, and general well being, with other components of the CDAI score contributing little. Two of 13 (15%) of our patients had active inflammation as defined by Brooker et al9Brooker J.C. Beckett C.G. Saunders B.P. et al.Long-acting steroid injection after endoscopic dilation of anastomotic Crohn’s strictures may improve the outcome: a retrospective case series.Endoscopy. 2003; 35: 333-337Crossref PubMed Scopus (135) Google Scholar using serum markers of either a C-reactive protein level greater than 10 units or an erythrocyte sedimentation rate greater than 30 mm/h, compared with 57% in their cohort. Therefore, our cohort may be somewhat underrepresentative of patients with active inflammation. These pilot data are at odds with a number of small case series using steroid injection after Crohn’s stricture dilatation that have included between 10 and 17 patients.9Brooker J.C. Beckett C.G. Saunders B.P. et al.Long-acting steroid injection after endoscopic dilation of anastomotic Crohn’s strictures may improve the outcome: a retrospective case series.Endoscopy. 2003; 35: 333-337Crossref PubMed Scopus (135) Google Scholar, 11Ramboer C. Verhamme M. Dhondt E. et al.Endoscopic treatment of stenosis in recurrent Crohn’s disease with balloon dilation combined with local corticosteroid injection.Gastrointest Endosc. 1995; 42: 252-255Abstract Full Text Full Text PDF PubMed Scopus (116) Google Scholar, 12Singh V.V. Draganov P. Valentine J. Efficacy and safety of endoscopic balloon dilation of symptomatic upper and lower gastrointestinal Crohn’s disease strictures.J Clin Gastroenterol. 2005; 39: 284-290Crossref PubMed Scopus (138) Google Scholar, 13Lavy A. Triamcinolone improves outcome in Crohn’s disease strictures.Dis Colon Rectum. 1997; 40: 184-186Crossref PubMed Scopus (69) Google Scholar These series at first glance appear to report recurrence-free rates after a single dilatation of 72%–90%; however, Singh et al12Singh V.V. Draganov P. Valentine J. Efficacy and safety of endoscopic balloon dilation of symptomatic upper and lower gastrointestinal Crohn’s disease strictures.J Clin Gastroenterol. 2005; 39: 284-290Crossref PubMed Scopus (138) Google Scholar reported restricturing rates that included data from the upper-gastrointestinal tract, which, when excluded, makes the redilatation rates of the lower-gastrointestinal cases dilated without steroid similar to those rates with steroid. Lavy13Lavy A. Triamcinolone improves outcome in Crohn’s disease strictures.Dis Colon Rectum. 1997; 40: 184-186Crossref PubMed Scopus (69) Google Scholar used a precut needle knife to incise the stricture radially rather than balloon dilatation. Ramboer et al11Ramboer C. Verhamme M. Dhondt E. et al.Endoscopic treatment of stenosis in recurrent Crohn’s disease with balloon dilation combined with local corticosteroid injection.Gastrointest Endosc. 1995; 42: 252-255Abstract Full Text Full Text PDF PubMed Scopus (116) Google Scholar performed multiple dilatations in 13 patients, the majority at less than 1-year intervals, although their cohort did avoid surgery. The best retrospective evidence was from a subgroup of 3 patients in the Brooker et al9Brooker J.C. Beckett C.G. Saunders B.P. et al.Long-acting steroid injection after endoscopic dilation of anastomotic Crohn’s strictures may improve the outcome: a retrospective case series.Endoscopy. 2003; 35: 333-337Crossref PubMed Scopus (135) Google Scholar series. They found prolonged dilation-free periods with steroid injection and short periods without. These case series data should therefore be viewed with care. This study had several limitations, primarily the small sample size. However, the groups do appear well matched for standard criteria for Crohn’s severity and therapy performed at baseline. The difference seen did not reach a conventional level of statistical significance in the intention-to-treat analysis, but the rapid divergence of curves suggesting possible harm would make it ethically challenging to justify further recruitment to our study after this analysis, and the per-protocol analysis adds further weight to this. Therefore, although not confirming statistically that triamcinolone at this dose is detrimental in this situation, the study suggests it is at least of no benefit and clinicians should weigh the risks and benefits for individual patients carefully before using steroid injection postdilatation in clinical practice until further data are available from a larger randomized controlled trial. This does not preclude the use of steroid injection in other areas of the gastrointestinal tract, in particular the upper-gastrointestinal tract, where the retrospective data look stronger and the mechanism of restricturing may be different.12Singh V.V. Draganov P. Valentine J. Efficacy and safety of endoscopic balloon dilation of symptomatic upper and lower gastrointestinal Crohn’s disease strictures.J Clin Gastroenterol. 2005; 39: 284-290Crossref PubMed Scopus (138) Google Scholar The possibility of a type II error as a result of the small sample size exists, with the possibility that the steroid group was more likely to fail from the start of the trial by chance owing to unknown confounders, despite the well-matched demographics of the 2 groups. Therefore, the data probably should be regarded as hypothesis-generating; however, the comparison of the paired survival curves in Figure 3 in patients who received both treatments support the suggestion from the main data set that placebo was at least no worse than steroid in terms of time to redilatation. The chance of finding a positive result in favor of triamcinolone in a larger study is small; however, to confirm the unexpected result of this pilot study, a larger randomized controlled trial will be required. The hazard ratio in our intention-to-treat analysis was approximately 6, and the median time to redilatation was 170 days in the steroid group. For 80% power (1−β) to detect half this difference (ie, a hazard ratio of 3) seen here with a probability (α) of .05, the trial would need to recruit 25 subjects. Ideally, such a trial would be considerably larger than this to allow detection of subgroups who might benefit. Strictures were assessed only with barium, and other modalities such as ultrasound or white cell scanning might have identified a subgroup of strictures, such as those where there was transmural inflammation, which might be more likely to respond to steroids. These should be included as prespecified subgroups in a future randomized controlled trial. Because fluoroscopy was not used, it remains possible that in very fibrotic strictures the diameters aimed for were not achieved owing to waisting of the balloon, although relatively high inflation pressures were used, up to 8 atmospheres. Smoking data also were not collected prospectively, a factor that is known to increase recurrence rates in Crohn’s disease, but in an analysis of 2 large series of patients with Crohn’s disease strictures treated with balloon dilatation smoking was not a factor in dilatation failure in the medium term.4Thomas-Gibson S. Brooker J.C. Hayward C.M. et al.Colonoscopic balloon dilation of Crohn’s strictures: a review of long-term outcomes.Eur J Gastroenterol Hepatol. 2003; 15: 485-488PubMed Google Scholar, 8Sabate J.M. Villarejo J. Bouhnik Y. et al.Hydrostatic balloon dilatation of Crohn’s strictures.Aliment Pharmacol Ther. 2003; 18: 409-413Crossref PubMed Scopus (101) Google Scholar The failure of steroids to improve time to redilatation was unexpected from retrospective data on lower-gastrointestinal Crohn’s strictures and other strictures in the gastrointestinal tract treated with steroid injection successfully (eg, corrosive, radiation-induced, or postsurgical strictures).16Lucha P.A. Fticsar J.E. Francis M.J. The strictured anastomosis: successful treatment by corticosteroid injections—report of three cases and review of the literature.Dis Colon Rectum. 2005; 48: 862-865Crossref PubMed Scopus (45) Google Scholar, 17Kochhar R. Makharia G.K. Usefulness of intralesional triamcinolone in treatment of benign esophageal strictures.Gastrointest Endosc. 2002; 56: 829-834Abstract Full Text Full Text PDF PubMed Scopus (177) Google Scholar In vivo data also suggest that triamcinolone is effective in breaking down mature collagen and therefore theoretically should reduce fibrosis.18Ketchum L.D. Robinson D.W. Masters F.W. The degradation of mature collagen: a laboratory study.Plast Reconstr Surg. 1967; 40: 89-91Crossref PubMed Scopus (38) Google Scholar Data on the pathophysiology of Crohn’s strictures are limited, with some evidence for the role of smooth muscle cells, mast cells, tumor necrosis factor-α, vascular endothelial growth factor, connective tissue growth factor, and ischemia.19Gelbmann C.M. Mestermann S. Gross V. et al.Strictures in Crohn’s disease are characterised by an accumulation of mast cells colocalised with laminin but not with fibronectin or vitronectin.Gut. 1999; 45: 210-217Crossref PubMed Scopus (149) Google Scholar, 20Sorrentino D. Avellini C. Beltrami C. et al.Selective effect of infliximab on the inflammatory component of a colonic stricture in Crohns disease.Int J Colorectal Dis. 2006; 21: 276-281Crossref PubMed Scopus (42) Google Scholar, 21Graham M.F. Diegelmann R.F. Elson C.O. et al.Collagen content and types in the intestinal strictures of Crohn’s disease.Gastroenterology. 1988; 94: 257-265Abstract PubMed Google Scholar, 22Beddy D. Mulsow J. Watson R.W. et al.Expression and regulation of connective tissue growth factor by transforming growth factor beta and tumour necrosis factor alpha in fibroblasts isolated from strictures in patients with Crohn’s disease.Br J Surg. 2006; 93: 1290-1296Crossref PubMed Scopus (67) Google Scholar, 23Beddy D. Watson R.W. Fitzpatrick J.M. et al.Increased vascular endothelial growth factor production in fibroblasts isolated from strictures in patients with Crohn’s disease.Br J Surg. 2004; 91: 72-77Crossref PubMed Scopus (63) Google Scholar, 24Osborne M.J. Hudson M. Piasecki C. et al.Crohn’s disease and anastomotic recurrence: microvascular ischaemia and anastomotic healing in an animal model.Br J Surg. 1993; 80: 226-229Crossref PubMed Scopus (36) Google Scholar Added to this must be the effects of surgical resection and anastomosis. Multiple mechanisms may lead to restenosis including inflammation, fibrosis, ischemia, local immune responses, and interactions with luminal contents. Metronidazole has been shown to reduce the rate of inflammation at Crohn’s anastomotic strictures 1 year after surgery, possibly through altering luminal bacterial flora or via an immunomodulatory effect.3Rutgeerts P. Hiele M. Geboes K. et al.Controlled trial of metronidazole treatment for prevention of Crohn’s recurrence after ileal resection.Gastroenterology. 1995; 108: 1617-1621Abstract Full Text PDF PubMed Scopus (721) Google Scholar Although a reduction in the recurrence of Crohn’s symptoms was seen in this study it is not clear whether this equated with reduced stenosis. A combination of budesonide and azathioprine is reported to reduce recurrence of stenosis after endoscopic dilatation of ileocolonic anastomotic strictures compared with placebo, but this report remains in abstract form only.25Raedler A. Peters I. Schreiber S. Treatment with azathioprine and budesonide prevents reoccurrence of ileocolonic stenoses after endoscopic dilatation in Crohn’s disease.Gastroenterology. 1997; 112: A1067Google Scholar Another series looking at concomitant steroids or immunosuppressive therapy after dilatation found no relationship with the need for redilatation in a multivariate analysis.8Sabate J.M. Villarejo J. Bouhnik Y. et al.Hydrostatic balloon dilatation of Crohn’s strictures.Aliment Pharmacol Ther. 2003; 18: 409-413Crossref PubMed Scopus (101) Google Scholar Prednisolone improves symptoms but not endoscopic inflammation in ileal Crohn’s disease.26Olaison G. Sjodahl R. Tagesson C. Glucocorticoid treatment in ileal Crohn’s disease: relief of symptoms but not of endoscopically viewed inflammation.Gut. 1990; 31: 325-328Crossref PubMed Scopus (121) Google Scholar Local steroids therefore also may not suppress mucosal inflammation to decrease restricturing and may have other unhelpful effects. In an animal model of wound healing, local triamcinolone significantly impaired neovascularization compared with systemic triamcinolone, suggesting that local steroids might lead to postdilatation stricture ischemia.27Hashimoto I. Nakanishi H. Shono Y. et al.Angiostatic effects of corticosteroid on wound healing of the rabbit ear.J Med Invest. 2002; 49: 61-66PubMed Google Scholar The benefits of anti-inflammatory therapy also have been questioned recently, with studies suggesting that one of the disease mechanisms in Crohn’s disease is impaired neutrophil migration and therefore steroids may exacerbate this problem.28Marks D.J. Harbord M.W. MacAllister R. et al.Defective acute inflammation in Crohn’s disease: a clinical investigation.Lancet. 2006; 367: 668-678Abstract Full Text Full Text PDF PubMed Scopus (341) Google Scholar Finally, underdosing should be considered. The single dose used here, 40 mg, is lower than in other series in which the doses of triamcinolone injected has been up to 160 mg.12Singh V.V. Draganov P. Valentine J. Efficacy and safety of endoscopic balloon dilation of symptomatic upper and lower gastrointestinal Crohn’s disease strictures.J Clin Gastroenterol. 2005; 39: 284-290Crossref PubMed Scopus (138) Google Scholar Other reported case series have shown improved outcomes with multiple dilatations with steroid injections, leading to a cumulative dose, a possibility that was not tested because of our trial design. Future research in this area should focus on elucidating some of the basic mechanisms behind restricturing to allow a more logical choice of therapeutic agent for future trials as well as imaging modalities that might predict which strictures are likely to achieve long-term benefit with balloon dilatation. More aggressive medical therapy, including the use of metronidazole, might improve outcome. Groups already are assessing locally injected infliximab to reduce inflammation, but results are as yet preliminary, with other promising biological agents becoming available.10Biancone L. Cretella M. Tosti C. et al.Local injection of infliximab in the postoperative recurrence of Crohn’s disease.Gastrointest Endosc. 2006; 63: 486-492Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar The use of biodegradable or drug-eluting stents postdilatation also holds promise for long-term remission. In summary, in our pilot study, intrastricture injection of triamcinolone failed to improve time to repeat dilatation after balloon dilatation of Crohn’s ileocolonic anastomotic strictures, with a trend toward worse outcomes. Clinical use of this and other agents should be reconsidered until further controlled data are available from large randomized studies. The authors thank Professor D. S. Rampton, Royal Free Hospital, London, United Kingdom, for contributing a patient to this study, and Paul Bassett, Statsconsultancy, United Kingdom, for statistical advice. Intramural Steroid Injection and Endoscopic Dilation for Crohn’s DiseaseClinical Gastroenterology and HepatologyVol. 5Issue 9PreviewThe surgical dictum is: “A chance to cut, is a chance to cure.” Every clinician involved in caring for patients with Crohn’s disease (CD) is facing this dilemma. Although resection of stenotic or perforated intestinal segments often is unavoidable, remission after surgery for CD is only temporary. Endoscopically, more than 70% of patients will have new lesions within a year, and 40% will be symptomatic within 4 years.1 Because repeated bowel resections may result in short-bowel syndrome, the quest for bowel-conserving strategies over the past 25 years resulted in the introduction in clinical practice of both endoscopic and surgical strictureplasty. Full-Text PDF
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