Infliximab treatment of postoperative ulcers in Crohn's disease: to inject or not to inject—that is the question

Abstract

Recurrence of Crohn's disease develops within the first year after surgical resection in the majority of patients; significant endoscopic lesions may be present even without clinical symptoms.It is estimated that 75% and 90% of patients with Crohn's disease (CD) will undergo intestinal resection by 20 years and by 30 years, respectively, from the onset of their disease-related symptoms.1Becker J.M. Surgical therapy for ulcerative colitis and Crohn's disease.Gastroenterol Clin North Am. 1999; 28 (viii-ix): 371-390Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar The majority of these resections involve the terminal ileum and the cecum because of complications of CD, such as fibrostenosis, enteric fistulas, and abscesses.2Van Assche G. Rutgeerts P. Medical management of postoperative recurrence in Crohn's disease.Gastroenterol Clin North Am. 2004; 33 (x): 347-360Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar It has been clearly demonstrated that CD rapidly recurs, as evidenced by the presence of intestinal mucosal inflammation despite initial radical resection in conjunction with initial clinical remission.3Olaison G. Smedh K. Sjodahl R. Natural course of Crohn's disease after ileocolic resection: endoscopically visualised ileal ulcers preceding symptoms.Gut. 1992; 33: 331-335Crossref PubMed Scopus (409) Google Scholar New ileal inflammation on the ileal side of the anastomosis was observed in 73% of patients with CD as early as 3 months after the surgery.3Olaison G. Smedh K. Sjodahl R. Natural course of Crohn's disease after ileocolic resection: endoscopically visualised ileal ulcers preceding symptoms.Gut. 1992; 33: 331-335Crossref PubMed Scopus (409) Google Scholar It has been demonstrated that recurrence of CD develops within the first year after surgical resection in the majority of patients and that significant endoscopic lesions might be present even without clinical symptoms.4Rutgeerts P. Geboes K. Vantrappen G. Kerremans R. Coenegrachts J.L. Coremans G. Natural history of recurrent Crohn's disease at the ileocolonic anastomosis after curative surgery.Gut. 1984; 25: 665-672Crossref PubMed Scopus (638) Google Scholar Endoscopic recurrence rates reported in earlier studies ranged from 73% to 93% and 85% to 100% of patients 1 and 3 years after the surgical resection, respectively.3Olaison G. Smedh K. Sjodahl R. Natural course of Crohn's disease after ileocolic resection: endoscopically visualised ileal ulcers preceding symptoms.Gut. 1992; 33: 331-335Crossref PubMed Scopus (409) Google Scholar, 5Rutgeerts P. Geboes K. Vantrappen G. Beyls J. Kerremans R. Hiele M. Predictability of the postoperative course of Crohn's disease.Gastroenterology. 1990; 99: 956-963Abstract PubMed Google Scholar However, subsequent studies observed lower prevalence of endoscopic recurrence that occurred in 28%, 61%, and 77% of patients 1, 2, and 3 years after the intestinal resection, respectively.6McLeod R.S. Wolff B.G. Steinhart A.H. et al.Risk and significance of endoscopic/radiological evidence of recurrent Crohn's disease.Gastroenterology. 1997; 113: 1823-1827Abstract Full Text PDF PubMed Scopus (85) Google Scholar The reported rates of symptomatic recurrence after surgery were 20% after 1 year and 34% in 3 years,5Rutgeerts P. Geboes K. Vantrappen G. Beyls J. Kerremans R. Hiele M. Predictability of the postoperative course of Crohn's disease.Gastroenterology. 1990; 99: 956-963Abstract PubMed Google Scholar increasing to approximately 50% by 5 years1Becker J.M. Surgical therapy for ulcerative colitis and Crohn's disease.Gastroenterol Clin North Am. 1999; 28 (viii-ix): 371-390Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar and 59% to 79% by 15 years.7Borley N.R. Mortensen N.J. Jewell D.P. Preventing postoperative recurrence of Crohn's disease.Br J Surg. 1997; 84: 1493-1502Crossref PubMed Scopus (114) Google Scholar Moreover, it was also shown that approximately 30% of patients will undergo another intestinal resection within 10 year.8Achkar J.P. Hanauer S.B. Medical therapy to reduce postoperative Crohn's disease recurrence.Am J Gastroenterol. 2000; 95: 1139-1146Crossref PubMed Google ScholarTherefore, it is imperative to establish efficacious therapies for healing the mucosal changes in CD. Standard therapies, which include 5-aminosalicylic acid derivatives, antibiotics, and glucocorticosteroids, do not heal the intestinal mucosa.9Van Assche G. Ferrante M. Vermeire S. Rutgeerts P. The role and importance of endoscopic mucosal healing in Crohn's disease.Tech Gastrointest Endosc. 2004; 6: 138-143Abstract Full Text Full Text PDF Scopus (5) Google ScholarThe GETAID (Groupe d'Etudes Therapeutiques des Affections Inflammatoires du Tube Digestif) study evaluated endoscopic intestinal mucosal healing in patients with CD who were receiving high doses of prednisolone (1 mg/kg for 7 weeks). This study found no correlation between the endoscopic activity and clinical activity of the disease.10Modigliani R. Mary J.Y. Simon J.F. et al.Clinical, biological, and endoscopic picture of attacks of Crohn's disease. Evolution on prednisolone. Groupe d'Etude Therapeutique des Affections Inflammatoires Digestives.Gastroenterology. 1990; 98: 811-818Abstract Full Text PDF PubMed Scopus (707) Google Scholar Moreover, the GETAID study and another prospective, randomized, placebo-controlled trial demonstrated that only 29% of patients with clinical remission treated with oral prednisolone also achieved endoscopic remission.10Modigliani R. Mary J.Y. Simon J.F. et al.Clinical, biological, and endoscopic picture of attacks of Crohn's disease. Evolution on prednisolone. Groupe d'Etude Therapeutique des Affections Inflammatoires Digestives.Gastroenterology. 1990; 98: 811-818Abstract Full Text PDF PubMed Scopus (707) Google Scholar, 11Landi B. Anh T.N. Cortot A. et al.Endoscopic monitoring of Crohn's disease treatment: a prospective, randomized clinical trial. The Groupe d'Etudes Therapeutiques des Affections Inflammatoires Digestives.Gastroenterology. 1992; 102: 1647-1653Abstract PubMed Google Scholar These data were further supported by Olaison et al12Olaison 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 (120) Google Scholar who observed persistent ileal inflammation on endoscopy in all patients, despite improvement of CD symptoms after administration of oral prednisolone for 9 to 6 weeks.Available data indicate that clinical improvement in patients with CD treated with immunomodulators is associated with regression of mucosal lesions.9Van Assche G. Ferrante M. Vermeire S. Rutgeerts P. The role and importance of endoscopic mucosal healing in Crohn's disease.Tech Gastrointest Endosc. 2004; 6: 138-143Abstract Full Text Full Text PDF Scopus (5) Google Scholar There have been several studies that evaluated the efficacy of azathioprine on mucosal healing in patients with active CD.13D'Haens G. Geboes K. Ponette E. Penninckx F. Rutgeerts P. Healing of severe recurrent ileitis with azathioprine therapy in patients with Crohn's disease.Gastroenterology. 1997; 112: 1475-1481Abstract Full Text PDF PubMed Scopus (238) Google Scholar, 14D'Haens G. Geboes K. Rutgeerts P. Endoscopic and histologic healing of Crohn's (ileo-) colitis with azathioprine.Gastrointest Endosc. 1999; 50: 667-671Abstract Full Text PDF PubMed Scopus (218) Google Scholar One study demonstrated that, among a group of patients with severe postoperative recurrence of CD who were treated with azathioprine for at least 6 months and went into clinical remission, there were 93% who had some degree of healing (40% of these patients had complete macroscopic healing, 33% by near-complete healing, 20% by partial healing, and 6.7% by absence of any healing).13D'Haens G. Geboes K. Ponette E. Penninckx F. Rutgeerts P. Healing of severe recurrent ileitis with azathioprine therapy in patients with Crohn's disease.Gastroenterology. 1997; 112: 1475-1481Abstract Full Text PDF PubMed Scopus (238) Google Scholar Similar rates of mucosal healing in patients with Crohn's colitis or ileocolitis who had clinical remission were observed in the second study. Complete endoscopic healing was observed in 70% of patients, near-complete healing in 10% of patients, partial healing in 15% of patients, and no changes in lesions in 5% of patients.14D'Haens G. Geboes K. Rutgeerts P. Endoscopic and histologic healing of Crohn's (ileo-) colitis with azathioprine.Gastrointest Endosc. 1999; 50: 667-671Abstract Full Text PDF PubMed Scopus (218) Google Scholar It should be pointed out that these studies only include the patients who entered clinical remission. We were not given the status of patients who did not achieve remission; thus, we did not know the overall rate of endoscopic remission among the entire group evaluated, ie, the responders and the nonresponders.Another immunomodulator that has recently been demonstrated to be effective for both induction of remission and maintenance of remission in patients with CD is methotrexate. There has been no prospective randomized controlled trial that has evaluated the efficacy of methotrexate for its ability in mucosal healing. There exists, however, a single, small, open-label study observed that 35% of patients with CD who were given methotrexate for 12 weeks achieved endoscopic remission of their colonic CD.15Kozarek R.A. Patterson D.J. Gelfand M.D. Botoman V.A. Ball T.J. Wilske K.R. Methotrexate induces clinical and histologic remission in patients with refractory inflammatory bowel disease.Ann Intern Med. 1989; 110: 353-356Crossref PubMed Scopus (451) Google ScholarInfliximab is a relatively new agent introduced into our armamentarium for the treatment of patients with CD. Infliximab has been evaluated for its ability to heal the mucosa in patients with active Crohn's disease. The endoscopic healing of the intestinal lesions was observed in most of 22 patients with clinically active CD treated with intravenous infliximab and none of 8 placebo recipients in a recent prospective, multicenter, randomized placebo-controlled trial.16D'Haens G. Van Deventer S. Van Hogezand R. et al.Endoscopic and histological healing with infliximab anti-tumor necrosis factor antibodies in Crohn's disease: a European multicenter trial.Gastroenterology. 1999; 116: 1029-1034Abstract Full Text Full Text PDF PubMed Scopus (696) Google Scholar Patients were randomized to receive single intravenous infusion of either placebo or infliximab at dose of 5, 10, or 20 mg/kg.16D'Haens G. Van Deventer S. Van Hogezand R. et al.Endoscopic and histological healing with infliximab anti-tumor necrosis factor antibodies in Crohn's disease: a European multicenter trial.Gastroenterology. 1999; 116: 1029-1034Abstract Full Text Full Text PDF PubMed Scopus (696) Google Scholar Intestinal lesions were scored by using Crohn's disease endoscopic index of severity (CDEIS). It was demonstrated that the endoscopic and histologic healing of the CD lesions occurred rapidly, with significant decrease in CDEIS scores in most patients treated with infliximab without an apparent dose response.16D'Haens G. Van Deventer S. Van Hogezand R. et al.Endoscopic and histological healing with infliximab anti-tumor necrosis factor antibodies in Crohn's disease: a European multicenter trial.Gastroenterology. 1999; 116: 1029-1034Abstract Full Text Full Text PDF PubMed Scopus (696) Google Scholar Moreover, changes in CDEIS highly correlated with changes in the Crohn's disease activity index.16D'Haens G. Van Deventer S. Van Hogezand R. et al.Endoscopic and histological healing with infliximab anti-tumor necrosis factor antibodies in Crohn's disease: a European multicenter trial.Gastroenterology. 1999; 116: 1029-1034Abstract Full Text Full Text PDF PubMed Scopus (696) Google Scholar Evenly distributed disappearance of ulcers ranged from resolution of 74% of ulcers in the ileum to 96% in rectum.16D'Haens G. Van Deventer S. Van Hogezand R. et al.Endoscopic and histological healing with infliximab anti-tumor necrosis factor antibodies in Crohn's disease: a European multicenter trial.Gastroenterology. 1999; 116: 1029-1034Abstract Full Text Full Text PDF PubMed Scopus (696) Google Scholar Additionally, the use of infliximab on mucosal healing has been well evaluated recently in a subgroup analysis of the ACCENT I trial, which has shown significant differences between endoscopic healing in patients receiving scheduled treatment with infliximab (44%) than in patients receiving episodic treatment with this agent (18%) at week 54.17Rutgeerts P. Feagan B.G. Lichtenstein G.R. et al.Comparison of scheduled and episodic treatment strategies of infliximab in Crohn's disease.Gastroenterology. 2004; 126: 402-413Abstract Full Text Full Text PDF PubMed Scopus (858) Google Scholar Furthermore, patients achieving mucosal healing were reported to have a lower rate of hospitalization and surgery.18Rutgeerts P. Malchow H. Vatn M. Yan S. Bala M. Van Deventer S. Mucosal healing in Crohn's disease is associated with reduction in hospitalizations and surgeries [abstract].Gastroenterology. 2002; 123 (A-43)PubMed Google ScholarIn this issue of Gastrointestinal Endoscopy, Biancone et al19Biancone 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 presented results of a pilot open-label study in which 8 patients presented with endoscopic postoperative recurrence (<5 cm) and clinically inactive CD and were treated with local injections of infliximab into intestinal lesions and were followed for 14 to 21 months.19Biancone 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 endoscopic recurrence was assessed by using the Rutgeerts grading scale: grade 0, no lesions; grade 1, less than 5 aphthous lesions; grade 2, more than 5 aphthous lesions with normal mucosa between the lesions; grade 3, diffuse aphthous ileitis with diffusely inflamed mucosa; and grade 4, diffuse inflammation with already larger ulcers, nodules, and/or narrowing.5Rutgeerts P. Geboes K. Vantrappen G. Beyls J. Kerremans R. Hiele M. Predictability of the postoperative course of Crohn's disease.Gastroenterology. 1990; 99: 956-963Abstract PubMed Google Scholar There were 5 patients who received single injections and 3 patients who received 2 injections of infliximab. Among 8 patients studied, only 1 patient had clearly progressive disease at endoscopy (grade 3). The remaining patients had either very mild (grade 1; n = 2 patients) or mild lesions (grade 2; n = 5 patients). Infliximab injections did not cause significant reduction in median endoscopic score nor histologic score. However, the number or the extent of the lesions was decreased in 7 of 8 patients. The investigators claimed that local injections with infliximab are safe and feasible in patients with limited endoscopic recurrence of CD without the presence of strictures.This is the first study describing this endoscopic approach (local injection of medication in the area of recurrent disease) in patients with postoperative recurrence who have CD. A similar trial was attempted with local injection of infliximab in areas of fistulas. Local injection of infliximab adjacent to the fistula was reported only in 1 uncontrolled study to date in patients with perianal CD and showed efficacy in 10 of 15 patients.20Poggioli G. Laureti S. Pierangeli F. et al.Local injection of Infliximab for the treatment of perianal Crohn's disease.Dis Colon Rectum. 2005; 48: 768-774Crossref PubMed Scopus (85) Google Scholar The present study presents a novel, interesting approach toward patients with postoperative endoscopic recurrence of CD.The investigators are to be congratulated on the novel therapeutic approach to patients with CD. However, there are several questions that remain upon careful review of this particular report. It is unknown if this represents a prospective trial with prespecified end points. It is uncertain how the investigators chose to dose individual patients and how investigators chose to have patients undergo a second endoscopy? It is very important to know if there was a standardized measurement technique used in the evaluation of the appearance of intestinal mucosa, in particular when measuring the size of lesions, eg, ulcers. It appears that the investigators used the Rutgeerts score, which is not designed to evaluate the change in the mucosa over time, ie, the mucosal healing in endoscopic postoperative recurrence of CD. The use of validated CDEIS21Mary J.Y. Modigliani R. Development and validation of an endoscopic index of the severity for Crohn's disease: a prospective multicentre study. Groupe d'Etudes Therapeutiques des Affections Inflammatoires du Tube Digestif (GETAID).Gut. 1989; 30: 983-989Crossref PubMed Scopus (321) Google Scholar seemed to be more suitable in the present study. The investigators do not state whether the encountered ulcerations had histologic features typical for CD ulcers or whether these ulcerations were routine anastomotic ulcers without characteristic features of CD ulcers. It would be very important to know how many of the study patients had complete mucosal healing. This number is not reported. In addition, in this particular study, unblinded endoscopists represent a potential source of bias.Additionally, the investigators note that no patients had clinical recurrence; thus, one can question why would such treatment be done in patients with quiescent disease. In other words, were the correct patients chosen for this particular pilot study? Only 1 patient in this study presented with clearly progressive endoscopic CD recurrence (Rutgeerts score, 3). It seems that one might choose patients who are inactive but who have a high potential to become active in the future (ie, those with Rutgeerts scores of 3 or 4) or those who actually have symptomatic disease (in an effort to treat their disease and thus effectively induce them into clinical remission).When a patient has endoscopic recurrence, there are usually not just 1 or 2 lesions, rather, there are often multiple lesions/ulcerations in individuals who have Rutgeerts grade 3 or grade 4 disease. The benefit of injecting 1 or 2 ulcerations in an individual with many such lesions is of uncertain significance. It should also be emphasized that those who have Rutgeerts grade 1 and 2 will have a low probability of clinical recurrence in the future.5Rutgeerts P. Geboes K. Vantrappen G. Beyls J. Kerremans R. Hiele M. Predictability of the postoperative course of Crohn's disease.Gastroenterology. 1990; 99: 956-963Abstract PubMed Google Scholar Thus, is any intervention necessary in this population with a benign course?Available data from randomized controlled trials suggest that scheduled systemic treatment with infliximab is very effective in healing established intestinal lesions in CD.16D'Haens G. Van Deventer S. Van Hogezand R. et al.Endoscopic and histological healing with infliximab anti-tumor necrosis factor antibodies in Crohn's disease: a European multicenter trial.Gastroenterology. 1999; 116: 1029-1034Abstract Full Text Full Text PDF PubMed Scopus (696) Google Scholar, 17Rutgeerts P. Feagan B.G. Lichtenstein G.R. et al.Comparison of scheduled and episodic treatment strategies of infliximab in Crohn's disease.Gastroenterology. 2004; 126: 402-413Abstract Full Text Full Text PDF PubMed Scopus (858) Google Scholar Although it has not been formally evaluated as prophylactic therapy for the treatment of patients after surgery in an effort to lessen endoscopic postoperative recurrence of CD, it would be very interesting to evaluate such patients. Moreover, scheduled systemic treatment with infliximab has been shown to be associated with lower immunogenicity of infliximab. Therefore, one may thus suggest that systemic rather than local use of infliximab should be evaluated in the treatment of postoperative endoscopic recurrence of CD, and taking into consideration the cost of local injections of infliximab and very limited evidence concerning efficacy. In the present study, investigators have not addressed the issue of whether or not local injections with infliximab are more advantageous than systemic administration of infliximab. Furthermore, it is important to realize that we attempt to avoid administration of low doses of infliximab in patients, because these low doses have the potential to immunize these patients (ie, allow them to form antibodies against infliximab) and to make patients less likely to respond to medication in the future. The investigators did not assess if these patients formed antibodies to infliximab; this could have potential implications for future risk of infusion reactions and potential influences on the duration of response to treatment.22Baert F. Noman M. Vermeire S. et al.Influence of immunogenicity on the long-term efficacy of infliximab in Crohn's disease.N Engl J Med. 2003; 348: 601-608Crossref PubMed Scopus (1844) Google ScholarMoreover, this particular study does not provide any information of whether the local treatment with infliximab may have any influence on the course of postoperative recurrence in patients with CD. The only patient with progressive endoscopic recurrence maintained the same endoscopic grade of 3 during the study period, with an increase in the histology score of 6 points from baseline, despite 2 injections of infliximab. Therefore, the efficacy of local treatment with infliximab seems to be questionable in patients with progressive endoscopic recurrence of CD.Thus, it may be of interest to perform a prospective study in which this novel therapeutic approach could be evaluated. It will be interesting to evaluate the local injections of infliximab into mucosal lesions in patients with progressive endoscopic recurrence (Rutgeerts score of 3 and 4) with the accompanying clinical recurrence of CD. In such a setting, it would be possible to assess the influence of local treatment on the natural course of postoperative recurrence of CD. It would be worth evaluating whether local injections of infliximab are more efficacious than systemic administration of infliximab in inducing both clinical and endoscopic remission in patients with postoperative recurrence of CD. Another potential therapy for this application might be to look at patients who have refractory ulceration that is causing difficulty despite maximal medical therapy, such as individuals who have had systemic infliximab with an incomplete response. The future should be of interest. It is only though carefully planned, adequately powered randomized, placebo-controlled trials that these questions can be answered with certainty. Recurrence of Crohn's disease develops within the first year after surgical resection in the majority of patients; significant endoscopic lesions may be present even without clinical symptoms.It is estimated that 75% and 90% of patients with Crohn's disease (CD) will undergo intestinal resection by 20 years and by 30 years, respectively, from the onset of their disease-related symptoms.1Becker J.M. Surgical therapy for ulcerative colitis and Crohn's disease.Gastroenterol Clin North Am. 1999; 28 (viii-ix): 371-390Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar The majority of these resections involve the terminal ileum and the cecum because of complications of CD, such as fibrostenosis, enteric fistulas, and abscesses.2Van Assche G. Rutgeerts P. Medical management of postoperative recurrence in Crohn's disease.Gastroenterol Clin North Am. 2004; 33 (x): 347-360Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar It has been clearly demonstrated that CD rapidly recurs, as evidenced by the presence of intestinal mucosal inflammation despite initial radical resection in conjunction with initial clinical remission.3Olaison G. Smedh K. Sjodahl R. Natural course of Crohn's disease after ileocolic resection: endoscopically visualised ileal ulcers preceding symptoms.Gut. 1992; 33: 331-335Crossref PubMed Scopus (409) Google Scholar New ileal inflammation on the ileal side of the anastomosis was observed in 73% of patients with CD as early as 3 months after the surgery.3Olaison G. Smedh K. Sjodahl R. Natural course of Crohn's disease after ileocolic resection: endoscopically visualised ileal ulcers preceding symptoms.Gut. 1992; 33: 331-335Crossref PubMed Scopus (409) Google Scholar It has been demonstrated that recurrence of CD develops within the first year after surgical resection in the majority of patients and that significant endoscopic lesions might be present even without clinical symptoms.4Rutgeerts P. Geboes K. Vantrappen G. Kerremans R. Coenegrachts J.L. Coremans G. Natural history of recurrent Crohn's disease at the ileocolonic anastomosis after curative surgery.Gut. 1984; 25: 665-672Crossref PubMed Scopus (638) Google Scholar Endoscopic recurrence rates reported in earlier studies ranged from 73% to 93% and 85% to 100% of patients 1 and 3 years after the surgical resection, respectively.3Olaison G. Smedh K. Sjodahl R. Natural course of Crohn's disease after ileocolic resection: endoscopically visualised ileal ulcers preceding symptoms.Gut. 1992; 33: 331-335Crossref PubMed Scopus (409) Google Scholar, 5Rutgeerts P. Geboes K. Vantrappen G. Beyls J. Kerremans R. Hiele M. Predictability of the postoperative course of Crohn's disease.Gastroenterology. 1990; 99: 956-963Abstract PubMed Google Scholar However, subsequent studies observed lower prevalence of endoscopic recurrence that occurred in 28%, 61%, and 77% of patients 1, 2, and 3 years after the intestinal resection, respectively.6McLeod R.S. Wolff B.G. Steinhart A.H. et al.Risk and significance of endoscopic/radiological evidence of recurrent Crohn's disease.Gastroenterology. 1997; 113: 1823-1827Abstract Full Text PDF PubMed Scopus (85) Google Scholar The reported rates of symptomatic recurrence after surgery were 20% after 1 year and 34% in 3 years,5Rutgeerts P. Geboes K. Vantrappen G. Beyls J. Kerremans R. Hiele M. Predictability of the postoperative course of Crohn's disease.Gastroenterology. 1990; 99: 956-963Abstract PubMed Google Scholar increasing to approximately 50% by 5 years1Becker J.M. Surgical therapy for ulcerative colitis and Crohn's disease.Gastroenterol Clin North Am. 1999; 28 (viii-ix): 371-390Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar and 59% to 79% by 15 years.7Borley N.R. Mortensen N.J. Jewell D.P. Preventing postoperative recurrence of Crohn's disease.Br J Surg. 1997; 84: 1493-1502Crossref PubMed Scopus (114) Google Scholar Moreover, it was also shown that approximately 30% of patients will undergo another intestinal resection within 10 year.8Achkar J.P. Hanauer S.B. Medical therapy to reduce postoperative Crohn's disease recurrence.Am J Gastroenterol. 2000; 95: 1139-1146Crossref PubMed Google Scholar Recurrence of Crohn's disease develops within the first year after surgical resection in the majority of patients; significant endoscopic lesions may be present even without clinical symptoms. Recurrence of Crohn's disease develops within the first year after surgical resection in the majority of patients; significant endoscopic lesions may be present even without clinical symptoms. Therefore, it is imperative to establish efficacious therapies for healing the mucosal changes in CD. Standard therapies, which include 5-aminosalicylic acid derivatives, antibiotics, and glucocorticosteroids, do not heal the intestinal mucosa.9Van Assche G. Ferrante M. Vermeire S. Rutgeerts P. The role and importance of endoscopic mucosal healing in Crohn's disease.Tech Gastrointest Endosc. 2004; 6: 138-143Abstract Full Text Full Text PDF Scopus (5) Google Scholar The GETAID (Groupe d'Etudes Therapeutiques des Affections Inflammatoires du Tube Digestif) study evaluated endoscopic intestinal mucosal healing in patients with CD who were receiving high doses of prednisolone (1 mg/kg for 7 weeks). This study found no correlation between the endoscopic activity and clinical activity of the disease.10Modigliani R. Mary J.Y. Simon J.F. et al.Clinical, biological, and endoscopic picture of attacks of Crohn's disease. Evolution on prednisolone. Groupe d'Etude Therapeutique des Affections Inflammatoires Digestives.Gastroenterology. 1990; 98: 811-818Abstract Full Text PDF PubMed Scopus (707) Google Scholar Moreover, the GETAID study and another prospective, randomized, placebo-controlled trial demonstrated that only 29% of patients with clinical remission treated with oral prednisolone also achieved endoscopic remission.10Modigliani R. Mary J.Y. Simon J.F. et al.Clinical, biological, and endoscopic picture of attacks of Crohn's disease. Evolution on prednisolone. Groupe d'Etude Therapeutique des Affections Inflammatoires Digestives.Gastroenterology. 1990; 98: 811-818Abstract Full Text PDF PubMed Scopus (707) Google Scholar, 11Landi B. Anh T.N. Cortot A. et al.Endoscopic monitoring of Crohn's disease treatment: a prospective, randomized clinical trial. The Groupe d'Etudes Therapeutiques des Affections Inflammatoires Digestives.Gastroenterology. 1992; 102: 1647-1653Abstract PubMed Google Scholar These data were further supported by Olaison et al12Olaison 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 (120) Google Scholar who observed persistent ileal inflammation on endoscopy in all patients, despite improvement of CD symptoms after administration of oral prednisolone for 9 to 6 weeks. Available data indicate that clinical improvement in patients with CD treated with immunomodulators is associated with regression of mucosal lesions.9Van Assche G. Ferrante M. Vermeire S. Rutgeerts P. The role and importance of endoscopic mucosal healing in Crohn's disease.Tech Gastrointest Endosc. 2004; 6: 138-143Abstract Full Text Full Text PDF Scopus (5) Google Scholar There have been several studies that evaluated the efficacy of azathioprine on mucosal healing in patients with active CD.13D'Haens G. Geboes K. Ponette E. Penninckx F. Rutgeerts P. Healing of severe recurrent ileitis with azathioprine therapy in patients with Crohn's disease.Gastroenterology. 1997; 112: 1475-1481Abstract Full Text PDF PubMed Scopus (238) Google Scholar, 14D'Haens G. Geboes K. Rutgeerts P. Endoscopic and histologic healing of Crohn's (ileo-) colitis with azathioprine.Gastrointest Endosc. 1999; 50: 667-671Abstract Full Text PDF PubMed Scopus (218) Google Scholar One study demonstrated that, among a group of patients with severe postoperative recurrence of CD who were treated with azathioprine for at least 6 months and went into clinical remission, there were 93% who had some degree of healing (40% of these patients had complete macroscopic healing, 33% by near-complete healing, 20% by partial healing, and 6.7% by absence of any healing).13D'Haens G. Geboes K. Ponette E. Penninckx F. Rutgeerts P. Healing of severe recurrent ileitis with azathioprine therapy in patients with Crohn's disease.Gastroenterology. 1997; 112: 1475-1481Abstract Full Text PDF PubMed Scopus (238) Google Scholar Similar rates of mucosal healing in patients with Crohn's colitis or ileocolitis who had clinical remission were observed in the second study. Complete endoscopic healing was observed in 70% of patients, near-complete healing in 10% of patients, partial healing in 15% of patients, and no changes in lesions in 5% of patients.14D'Haens G. Geboes K. Rutgeerts P. Endoscopic and histologic healing of Crohn's (ileo-) colitis with azathioprine.Gastrointest Endosc. 1999; 50: 667-671Abstract Full Text PDF PubMed Scopus (218) Google Scholar It should be pointed out that these studies only include the patients who entered clinical remission. We were not given the status of patients who did not achieve remission; thus, we did not know the overall rate of endoscopic remission among the entire group evaluated, ie, the responders and the nonresponders. Another immunomodulator that has recently been demonstrated to be effective for both induction of remission and maintenance of remission in patients with CD is methotrexate. There has been no prospective randomized controlled trial that has evaluated the efficacy of methotrexate for its ability in mucosal healing. There exists, however, a single, small, open-label study observed that 35% of patients with CD who were given methotrexate for 12 weeks achieved endoscopic remission of their colonic CD.15Kozarek R.A. Patterson D.J. Gelfand M.D. Botoman V.A. Ball T.J. Wilske K.R. Methotrexate induces clinical and histologic remission in patients with refractory inflammatory bowel disease.Ann Intern Med. 1989; 110: 353-356Crossref PubMed Scopus (451) Google Scholar Infliximab is a relatively new agent introduced into our armamentarium for the treatment of patients with CD. Infliximab has been evaluated for its ability to heal the mucosa in patients with active Crohn's disease. The endoscopic healing of the intestinal lesions was observed in most of 22 patients with clinically active CD treated with intravenous infliximab and none of 8 placebo recipients in a recent prospective, multicenter, randomized placebo-controlled trial.16D'Haens G. Van Deventer S. Van Hogezand R. et al.Endoscopic and histological healing with infliximab anti-tumor necrosis factor antibodies in Crohn's disease: a European multicenter trial.Gastroenterology. 1999; 116: 1029-1034Abstract Full Text Full Text PDF PubMed Scopus (696) Google Scholar Patients were randomized to receive single intravenous infusion of either placebo or infliximab at dose of 5, 10, or 20 mg/kg.16D'Haens G. Van Deventer S. Van Hogezand R. et al.Endoscopic and histological healing with infliximab anti-tumor necrosis factor antibodies in Crohn's disease: a European multicenter trial.Gastroenterology. 1999; 116: 1029-1034Abstract Full Text Full Text PDF PubMed Scopus (696) Google Scholar Intestinal lesions were scored by using Crohn's disease endoscopic index of severity (CDEIS). It was demonstrated that the endoscopic and histologic healing of the CD lesions occurred rapidly, with significant decrease in CDEIS scores in most patients treated with infliximab without an apparent dose response.16D'Haens G. Van Deventer S. Van Hogezand R. et al.Endoscopic and histological healing with infliximab anti-tumor necrosis factor antibodies in Crohn's disease: a European multicenter trial.Gastroenterology. 1999; 116: 1029-1034Abstract Full Text Full Text PDF PubMed Scopus (696) Google Scholar Moreover, changes in CDEIS highly correlated with changes in the Crohn's disease activity index.16D'Haens G. Van Deventer S. Van Hogezand R. et al.Endoscopic and histological healing with infliximab anti-tumor necrosis factor antibodies in Crohn's disease: a European multicenter trial.Gastroenterology. 1999; 116: 1029-1034Abstract Full Text Full Text PDF PubMed Scopus (696) Google Scholar Evenly distributed disappearance of ulcers ranged from resolution of 74% of ulcers in the ileum to 96% in rectum.16D'Haens G. Van Deventer S. Van Hogezand R. et al.Endoscopic and histological healing with infliximab anti-tumor necrosis factor antibodies in Crohn's disease: a European multicenter trial.Gastroenterology. 1999; 116: 1029-1034Abstract Full Text Full Text PDF PubMed Scopus (696) Google Scholar Additionally, the use of infliximab on mucosal healing has been well evaluated recently in a subgroup analysis of the ACCENT I trial, which has shown significant differences between endoscopic healing in patients receiving scheduled treatment with infliximab (44%) than in patients receiving episodic treatment with this agent (18%) at week 54.17Rutgeerts P. Feagan B.G. Lichtenstein G.R. et al.Comparison of scheduled and episodic treatment strategies of infliximab in Crohn's disease.Gastroenterology. 2004; 126: 402-413Abstract Full Text Full Text PDF PubMed Scopus (858) Google Scholar Furthermore, patients achieving mucosal healing were reported to have a lower rate of hospitalization and surgery.18Rutgeerts P. Malchow H. Vatn M. Yan S. Bala M. Van Deventer S. Mucosal healing in Crohn's disease is associated with reduction in hospitalizations and surgeries [abstract].Gastroenterology. 2002; 123 (A-43)PubMed Google Scholar In this issue of Gastrointestinal Endoscopy, Biancone et al19Biancone 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 presented results of a pilot open-label study in which 8 patients presented with endoscopic postoperative recurrence (<5 cm) and clinically inactive CD and were treated with local injections of infliximab into intestinal lesions and were followed for 14 to 21 months.19Biancone 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 endoscopic recurrence was assessed by using the Rutgeerts grading scale: grade 0, no lesions; grade 1, less than 5 aphthous lesions; grade 2, more than 5 aphthous lesions with normal mucosa between the lesions; grade 3, diffuse aphthous ileitis with diffusely inflamed mucosa; and grade 4, diffuse inflammation with already larger ulcers, nodules, and/or narrowing.5Rutgeerts P. Geboes K. Vantrappen G. Beyls J. Kerremans R. Hiele M. Predictability of the postoperative course of Crohn's disease.Gastroenterology. 1990; 99: 956-963Abstract PubMed Google Scholar There were 5 patients who received single injections and 3 patients who received 2 injections of infliximab. Among 8 patients studied, only 1 patient had clearly progressive disease at endoscopy (grade 3). The remaining patients had either very mild (grade 1; n = 2 patients) or mild lesions (grade 2; n = 5 patients). Infliximab injections did not cause significant reduction in median endoscopic score nor histologic score. However, the number or the extent of the lesions was decreased in 7 of 8 patients. The investigators claimed that local injections with infliximab are safe and feasible in patients with limited endoscopic recurrence of CD without the presence of strictures. This is the first study describing this endoscopic approach (local injection of medication in the area of recurrent disease) in patients with postoperative recurrence who have CD. A similar trial was attempted with local injection of infliximab in areas of fistulas. Local injection of infliximab adjacent to the fistula was reported only in 1 uncontrolled study to date in patients with perianal CD and showed efficacy in 10 of 15 patients.20Poggioli G. Laureti S. Pierangeli F. et al.Local injection of Infliximab for the treatment of perianal Crohn's disease.Dis Colon Rectum. 2005; 48: 768-774Crossref PubMed Scopus (85) Google Scholar The present study presents a novel, interesting approach toward patients with postoperative endoscopic recurrence of CD. The investigators are to be congratulated on the novel therapeutic approach to patients with CD. However, there are several questions that remain upon careful review of this particular report. It is unknown if this represents a prospective trial with prespecified end points. It is uncertain how the investigators chose to dose individual patients and how investigators chose to have patients undergo a second endoscopy? It is very important to know if there was a standardized measurement technique used in the evaluation of the appearance of intestinal mucosa, in particular when measuring the size of lesions, eg, ulcers. It appears that the investigators used the Rutgeerts score, which is not designed to evaluate the change in the mucosa over time, ie, the mucosal healing in endoscopic postoperative recurrence of CD. The use of validated CDEIS21Mary J.Y. Modigliani R. Development and validation of an endoscopic index of the severity for Crohn's disease: a prospective multicentre study. Groupe d'Etudes Therapeutiques des Affections Inflammatoires du Tube Digestif (GETAID).Gut. 1989; 30: 983-989Crossref PubMed Scopus (321) Google Scholar seemed to be more suitable in the present study. The investigators do not state whether the encountered ulcerations had histologic features typical for CD ulcers or whether these ulcerations were routine anastomotic ulcers without characteristic features of CD ulcers. It would be very important to know how many of the study patients had complete mucosal healing. This number is not reported. In addition, in this particular study, unblinded endoscopists represent a potential source of bias. Additionally, the investigators note that no patients had clinical recurrence; thus, one can question why would such treatment be done in patients with quiescent disease. In other words, were the correct patients chosen for this particular pilot study? Only 1 patient in this study presented with clearly progressive endoscopic CD recurrence (Rutgeerts score, 3). It seems that one might choose patients who are inactive but who have a high potential to become active in the future (ie, those with Rutgeerts scores of 3 or 4) or those who actually have symptomatic disease (in an effort to treat their disease and thus effectively induce them into clinical remission). When a patient has endoscopic recurrence, there are usually not just 1 or 2 lesions, rather, there are often multiple lesions/ulcerations in individuals who have Rutgeerts grade 3 or grade 4 disease. The benefit of injecting 1 or 2 ulcerations in an individual with many such lesions is of uncertain significance. It should also be emphasized that those who have Rutgeerts grade 1 and 2 will have a low probability of clinical recurrence in the future.5Rutgeerts P. Geboes K. Vantrappen G. Beyls J. Kerremans R. Hiele M. Predictability of the postoperative course of Crohn's disease.Gastroenterology. 1990; 99: 956-963Abstract PubMed Google Scholar Thus, is any intervention necessary in this population with a benign course? Available data from randomized controlled trials suggest that scheduled systemic treatment with infliximab is very effective in healing established intestinal lesions in CD.16D'Haens G. Van Deventer S. Van Hogezand R. et al.Endoscopic and histological healing with infliximab anti-tumor necrosis factor antibodies in Crohn's disease: a European multicenter trial.Gastroenterology. 1999; 116: 1029-1034Abstract Full Text Full Text PDF PubMed Scopus (696) Google Scholar, 17Rutgeerts P. Feagan B.G. Lichtenstein G.R. et al.Comparison of scheduled and episodic treatment strategies of infliximab in Crohn's disease.Gastroenterology. 2004; 126: 402-413Abstract Full Text Full Text PDF PubMed Scopus (858) Google Scholar Although it has not been formally evaluated as prophylactic therapy for the treatment of patients after surgery in an effort to lessen endoscopic postoperative recurrence of CD, it would be very interesting to evaluate such patients. Moreover, scheduled systemic treatment with infliximab has been shown to be associated with lower immunogenicity of infliximab. Therefore, one may thus suggest that systemic rather than local use of infliximab should be evaluated in the treatment of postoperative endoscopic recurrence of CD, and taking into consideration the cost of local injections of infliximab and very limited evidence concerning efficacy. In the present study, investigators have not addressed the issue of whether or not local injections with infliximab are more advantageous than systemic administration of infliximab. Furthermore, it is important to realize that we attempt to avoid administration of low doses of infliximab in patients, because these low doses have the potential to immunize these patients (ie, allow them to form antibodies against infliximab) and to make patients less likely to respond to medication in the future. The investigators did not assess if these patients formed antibodies to infliximab; this could have potential implications for future risk of infusion reactions and potential influences on the duration of response to treatment.22Baert F. Noman M. Vermeire S. et al.Influence of immunogenicity on the long-term efficacy of infliximab in Crohn's disease.N Engl J Med. 2003; 348: 601-608Crossref PubMed Scopus (1844) Google Scholar Moreover, this particular study does not provide any information of whether the local treatment with infliximab may have any influence on the course of postoperative recurrence in patients with CD. The only patient with progressive endoscopic recurrence maintained the same endoscopic grade of 3 during the study period, with an increase in the histology score of 6 points from baseline, despite 2 injections of infliximab. Therefore, the efficacy of local treatment with infliximab seems to be questionable in patients with progressive endoscopic recurrence of CD. Thus, it may be of interest to perform a prospective study in which this novel therapeutic approach could be evaluated. It will be interesting to evaluate the local injections of infliximab into mucosal lesions in patients with progressive endoscopic recurrence (Rutgeerts score of 3 and 4) with the accompanying clinical recurrence of CD. In such a setting, it would be possible to assess the influence of local treatment on the natural course of postoperative recurrence of CD. It would be worth evaluating whether local injections of infliximab are more efficacious than systemic administration of infliximab in inducing both clinical and endoscopic remission in patients with postoperative recurrence of CD. Another potential therapy for this application might be to look at patients who have refractory ulceration that is causing difficulty despite maximal medical therapy, such as individuals who have had systemic infliximab with an incomplete response. The future should be of interest. It is only though carefully planned, adequately powered randomized, placebo-controlled trials that these questions can be answered with certainty. DisclosureG. Lichtenstein, MD, has received honorarium and has performed research with Centocor, the manufacturer of infliximab, and has also performed research and received honorarium from Prometheus Laboratories and Salix Corp, manufacturers of azathioprine. G. Lichtenstein, MD, has received honorarium and has performed research with Centocor, the manufacturer of infliximab, and has also performed research and received honorarium from Prometheus Laboratories and Salix Corp, manufacturers of azathioprine.