nature publishing group
EDITORIAL
1755
Can Stenosis in Ileal Crohn’s Disease Be Prevented by Current Therapy? Berkeley N. Limketkai, MD1 and Theodore M. Bayless, MD1
Abstract: Diagnostic delay is common with Crohn’s disease (CD), especially with ileitis. Recent data show that diagnostic delay is associated with an increased risk of bowel stenosis and intestinal surgery. It is nonetheless unclear whether early diagnosis and treatment can truly prevent CD stenosis. Available cohort studies suggest that CD stricture formation occurs over a fixed time course. Current therapies have also not been shown to reduce the risk of ileal stenosis or rates of surgery, and there are no available therapies to reverse existing fibrosis. Development of medications that target fibrosis is an important area of research. Am J Gastroenterol 2013; 108:1755–1756; doi:10.1038/ajg.2013.301
Diagnostic delay is a common phenomenon with Crohn’s disease (CD), especially with ileitis. It may take one or more years after the interaction of genetic and environmental risk factors before subtle abdominal symptoms are appreciated. Patients with colitis may also manifest troublesome symptoms, including diarrhea and rectal bleeding, earlier in the course of their disease than the subtle symptoms with ileitis (1). In this Journal, Schoepfer et al. (2) report their retrospective analysis of the Swiss Inflammatory Bowel Disease cohort to evaluate the effect of a diagnostic delay (time from symptom onset to diagnosis) on the risk of bowel stenosis, internal fistulae, perianal fistulae, and CD-related surgeries. They reviewed data of 905 CD patients and divided them into quartiles according to the length of diagnostic delay: 0–3, 4–9, 10–24, and ≥25 months. Using multivariable logistic regression, the investigators found diagnostic delay and disease duration after diagnosis to correlate with risk of bowel stenosis and need for intestinal surgery.
Importantly, the time from the first physician visit to the establishment of CD diagnosis contributed significantly to the delay. On average, it took 18 months before 75% of the patients were diagnosed. Patients with colitis, who are less likely to develop obstructive bowel stenosis, were more likely to be diagnosed within 3 months than those with ileitis. Patients with ileitis or ileocolitis, who are prone to ileal stenosis, made up the bulk of those with a diagnostic lag of over 25 months. Medication use did not differ among the four groups. Based on their interpretation of the data, the investigators conclude that stenosis and other adverse outcomes are associated with diagnostic delays. As there was a significant physician-related delay, they posit that increasing the index of suspicion for CD among primary care providers could lead to earlier diagnosis. This, in turn, would result in early implementation of anti-inflammatory or immunomodulatory therapies, which are known to be more effective in early aggressive inflammatory disease, and would hopefully lead to less bowel stenosis and surgery. However, two questions arise. First, is fixed ileal stenosis a late complication that develops over a predictable period of time? Second, and most important in evaluating the implications of this excellent study, do early diagnosis and treatment of CD prevent ileal stenosis? Currently, there are no medications to treat CD strictures, and there is no documentation that immunosuppressants or tumor necrosis factor-alpha (TNF-α) inhibitors can prevent ileal stenosis. Administration of these therapies has not decreased the long-term need for intestinal surgery (3–5). Clinical evidence indicates that stricture formation occurs over a fixed time course. In a pathologic study of 63 consecutive bowel excision specimens, performed for recurrent CD, strictures were present at a median time of 7.0 years and mean time of 7.2 years after the last excision (6). In regression analysis, strictures and large ulcers were the only pathologic findings associated with time. In another cohort of 185 CD patients who underwent a primary bowel resection for non-perforating indications, the mean time to repeat resection was 8.8 years (7), or 9.1 years specifically for obstruction (personal communication,
1 Harvey M. and Lyn P. Meyerhoff IBD Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. Correspondence: Berkeley N. Limketkai, MD, Harvey M. and Lyn P. Meyerhoff IBD Center, Johns Hopkins Hospital, 1800 Orleans Street, Zayed 7125D, Baltimore, Maryland 21287, USA. E-mail: [email protected] Received 7 July 2013; accepted 29 July 2013
© 2013 by the American College of Gastroenterology
The American Journal of GASTROENTEROLOGY
INFLAMMATORY BOWEL DISEASE
see related article on page 1744
INFLAMMATORY BOWEL DISEASE
1756
Limketkai and Bayless
Adrian Greenstein). Additionally, in our prospective pediatric CD cohort of 68 patients initially seen at the Johns Hopkins Hospital from 1960 to 1985, children who underwent resection for obstruction at least 3 years after disease onset had a mean time to surgery of 9.7 years (8). In our adult CD cohort of 32 patients who underwent surgical resection for ileal obstruction between 2002 and 2005, and previously treated with immunomodulators and/or anti-TNF agents, the mean time from CD diagnosis or last surgery to bowel resection for obstruction was 9.8 years (8,9). Laboratory studies of the pathogenesis of intestinal strictures indicate that the process once initiated by inflammation tends to be progressive and irreversible. Currently employed anti-inflammatory medications do not appear to delay this development. Fibrosis begins with mucosal inflammation and release of associated molecular mediators and growth factors that promote recruitment and proliferation of smooth muscle cells, stellate cells, and myofibroblasts (10). Fibroblasts become immortalized in their growth and collagen production, while other mechanisms, such as mechanical stiffness and continued microbial antigen exposure, promote myofibroblast activation independent of further inflammatory stimuli (11–13). There is a concomitant imbalance in extracellular matrix (ECM) turnover, followed by the accumulation of collagen and disorganization of the cytoskeletal architecture. The role of NOD2/CARD15 in the increased risk of ileal stenosis has yet to be elucidated. The resulting mucosal thickening, loss of compliance, and radial contraction of myofibroblasts consequently produce luminal stenosis (14). The outcome over several years is an irreversible, usually symmetric obstruction. While the risk of bowel stenosis in the Swiss series was associated with diagnostic delay, the time course suggests that longer overall disease duration is an important factor in the development of ileal stenosis and subsequent obstructive symptoms and surgery. Although early combination anti-TNF and immunomodulatory therapy increases remission rates and mucosal healing in patients with short duration severe CD, no therapy has yet been identified to specifically interrupt stricture pathogenesis in the susceptible patient (15). Development
The American Journal of GASTROENTEROLOGY
of medications to target discrete steps in the development of fibrosis would be an important area of research. CONFLICT OF INTEREST
Both authors wrote this editorial and are its submission guarantors. There was no financial or editorial support for preparation of this article. There are no financial or other relevant conflicts of interest to disclose. REFERENCES 1. Burbige EJ, Huang SH, Bayless TM. Clinical manifestations of Crohn’s disease in children and adolescents. Pediatrics 1975;55:866–71. 2. Schoepfer AM, Dehlavi M-A, Fournier N et al. Diagnostic delay in Crohn’s disease is associated with a complicated disease course and increased operation rate. Am J Gastroenterol 2013;108:1744–53 (this issue). 3. Cosnes J, Nion-Larmurier I, Beaugerie L et al. Impact of the increasing use of immunosuppressants in Crohn’s disease on the need for intestinal surgery. Gut 2005;54:237–41. 4. Lazarev M, Ullman T, Schraut WH et al. Small bowel resection rates in Crohn’s disease and the indication for surgery over time: experience from a large tertiary care center. Inflamm Bowel Dis 2010;16:830–5. 5. Cosnes J, Bourrier A, Laharie D et al. Early administration of Azathioprine vs conventional management of Crohn’s disease: a randomized controlled trial. Gastroenterology 2013; doi:10.1033/j.gastro.2013.04.048 (e-pub ahead of print). 6. Kelly JK, Sutherland LR. The chronological sequence in the pathology of Crohn’s disease. J Clin Gastroenterol 1988;10:28–33. 7. Greenstein AJ, Lachman P, Sachar DB et al. Perforating and nonperforating indications for repeated operations in Crohn’s disease: evidence for two clinical forms. Gut 1988;29:588–92. 8. Limketkai B, Bayless T, Ginsburg P et al. Distal ileal Crohn’s disease: the time course of the development of stenosis and obstruction. Inflamm Bowel Dis 2009;15:23–4. 9. Jacene HA, Ginsburg P, Kwon J et al. Prediction of the need for surgical intervention in obstructive Crohn’s disease by 18F-FDG PET/CT. J Nucl Med 2009;50:1751–9. 10. Rieder F, Fiocchi C. Intestinal fibrosis in inflammatory bowel disease: progress in basic and clinical science. Curr Opin Gastroenterol 2008;24:462–8. 11. Johnson LA, Rodansky ES, Sauder KL et al. Matrix stiffness corresponding to strictured bowel induces a fibrogenic response in human colonic fibroblasts. Inflamm Bowel Dis 2013;19:891–903. 12. Wells RG. The role of matrix stiffness in regulating cell behavior. Hepatology 2008;47:1394–400. 13. Otte JM, Rosenberg IM, Podolsky DK. Intestinal myofibroblasts in innate immune responses of the intestine. Gastroenterology 2003;124:1866–78. 14. Graham MF. Pathogenesis of intestinal strictures in Crohn’s disease—an update. Inflamm Bowel Dis 1995;1:220–7. 15. Alsaleh AA, Kuemmerle JF. Development and treatment of fibrosis in Crohn’s disease. Pract Gastroenterol 2013;37:32–41.
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VOLUME 108 NOVEMBER 2013 www.amjgastro.com
EDITORIAL
1755
Can Stenosis in Ileal Crohn’s Disease Be Prevented by Current Therapy? Berkeley N. Limketkai, MD1 and Theodore M. Bayless, MD1
Abstract: Diagnostic delay is common with Crohn’s disease (CD), especially with ileitis. Recent data show that diagnostic delay is associated with an increased risk of bowel stenosis and intestinal surgery. It is nonetheless unclear whether early diagnosis and treatment can truly prevent CD stenosis. Available cohort studies suggest that CD stricture formation occurs over a fixed time course. Current therapies have also not been shown to reduce the risk of ileal stenosis or rates of surgery, and there are no available therapies to reverse existing fibrosis. Development of medications that target fibrosis is an important area of research. Am J Gastroenterol 2013; 108:1755–1756; doi:10.1038/ajg.2013.301
Diagnostic delay is a common phenomenon with Crohn’s disease (CD), especially with ileitis. It may take one or more years after the interaction of genetic and environmental risk factors before subtle abdominal symptoms are appreciated. Patients with colitis may also manifest troublesome symptoms, including diarrhea and rectal bleeding, earlier in the course of their disease than the subtle symptoms with ileitis (1). In this Journal, Schoepfer et al. (2) report their retrospective analysis of the Swiss Inflammatory Bowel Disease cohort to evaluate the effect of a diagnostic delay (time from symptom onset to diagnosis) on the risk of bowel stenosis, internal fistulae, perianal fistulae, and CD-related surgeries. They reviewed data of 905 CD patients and divided them into quartiles according to the length of diagnostic delay: 0–3, 4–9, 10–24, and ≥25 months. Using multivariable logistic regression, the investigators found diagnostic delay and disease duration after diagnosis to correlate with risk of bowel stenosis and need for intestinal surgery.
Importantly, the time from the first physician visit to the establishment of CD diagnosis contributed significantly to the delay. On average, it took 18 months before 75% of the patients were diagnosed. Patients with colitis, who are less likely to develop obstructive bowel stenosis, were more likely to be diagnosed within 3 months than those with ileitis. Patients with ileitis or ileocolitis, who are prone to ileal stenosis, made up the bulk of those with a diagnostic lag of over 25 months. Medication use did not differ among the four groups. Based on their interpretation of the data, the investigators conclude that stenosis and other adverse outcomes are associated with diagnostic delays. As there was a significant physician-related delay, they posit that increasing the index of suspicion for CD among primary care providers could lead to earlier diagnosis. This, in turn, would result in early implementation of anti-inflammatory or immunomodulatory therapies, which are known to be more effective in early aggressive inflammatory disease, and would hopefully lead to less bowel stenosis and surgery. However, two questions arise. First, is fixed ileal stenosis a late complication that develops over a predictable period of time? Second, and most important in evaluating the implications of this excellent study, do early diagnosis and treatment of CD prevent ileal stenosis? Currently, there are no medications to treat CD strictures, and there is no documentation that immunosuppressants or tumor necrosis factor-alpha (TNF-α) inhibitors can prevent ileal stenosis. Administration of these therapies has not decreased the long-term need for intestinal surgery (3–5). Clinical evidence indicates that stricture formation occurs over a fixed time course. In a pathologic study of 63 consecutive bowel excision specimens, performed for recurrent CD, strictures were present at a median time of 7.0 years and mean time of 7.2 years after the last excision (6). In regression analysis, strictures and large ulcers were the only pathologic findings associated with time. In another cohort of 185 CD patients who underwent a primary bowel resection for non-perforating indications, the mean time to repeat resection was 8.8 years (7), or 9.1 years specifically for obstruction (personal communication,
1 Harvey M. and Lyn P. Meyerhoff IBD Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. Correspondence: Berkeley N. Limketkai, MD, Harvey M. and Lyn P. Meyerhoff IBD Center, Johns Hopkins Hospital, 1800 Orleans Street, Zayed 7125D, Baltimore, Maryland 21287, USA. E-mail: [email protected] Received 7 July 2013; accepted 29 July 2013
© 2013 by the American College of Gastroenterology
The American Journal of GASTROENTEROLOGY
INFLAMMATORY BOWEL DISEASE
see related article on page 1744
INFLAMMATORY BOWEL DISEASE
1756
Limketkai and Bayless
Adrian Greenstein). Additionally, in our prospective pediatric CD cohort of 68 patients initially seen at the Johns Hopkins Hospital from 1960 to 1985, children who underwent resection for obstruction at least 3 years after disease onset had a mean time to surgery of 9.7 years (8). In our adult CD cohort of 32 patients who underwent surgical resection for ileal obstruction between 2002 and 2005, and previously treated with immunomodulators and/or anti-TNF agents, the mean time from CD diagnosis or last surgery to bowel resection for obstruction was 9.8 years (8,9). Laboratory studies of the pathogenesis of intestinal strictures indicate that the process once initiated by inflammation tends to be progressive and irreversible. Currently employed anti-inflammatory medications do not appear to delay this development. Fibrosis begins with mucosal inflammation and release of associated molecular mediators and growth factors that promote recruitment and proliferation of smooth muscle cells, stellate cells, and myofibroblasts (10). Fibroblasts become immortalized in their growth and collagen production, while other mechanisms, such as mechanical stiffness and continued microbial antigen exposure, promote myofibroblast activation independent of further inflammatory stimuli (11–13). There is a concomitant imbalance in extracellular matrix (ECM) turnover, followed by the accumulation of collagen and disorganization of the cytoskeletal architecture. The role of NOD2/CARD15 in the increased risk of ileal stenosis has yet to be elucidated. The resulting mucosal thickening, loss of compliance, and radial contraction of myofibroblasts consequently produce luminal stenosis (14). The outcome over several years is an irreversible, usually symmetric obstruction. While the risk of bowel stenosis in the Swiss series was associated with diagnostic delay, the time course suggests that longer overall disease duration is an important factor in the development of ileal stenosis and subsequent obstructive symptoms and surgery. Although early combination anti-TNF and immunomodulatory therapy increases remission rates and mucosal healing in patients with short duration severe CD, no therapy has yet been identified to specifically interrupt stricture pathogenesis in the susceptible patient (15). Development
The American Journal of GASTROENTEROLOGY
of medications to target discrete steps in the development of fibrosis would be an important area of research. CONFLICT OF INTEREST
Both authors wrote this editorial and are its submission guarantors. There was no financial or editorial support for preparation of this article. There are no financial or other relevant conflicts of interest to disclose. REFERENCES 1. Burbige EJ, Huang SH, Bayless TM. Clinical manifestations of Crohn’s disease in children and adolescents. Pediatrics 1975;55:866–71. 2. Schoepfer AM, Dehlavi M-A, Fournier N et al. Diagnostic delay in Crohn’s disease is associated with a complicated disease course and increased operation rate. Am J Gastroenterol 2013;108:1744–53 (this issue). 3. Cosnes J, Nion-Larmurier I, Beaugerie L et al. Impact of the increasing use of immunosuppressants in Crohn’s disease on the need for intestinal surgery. Gut 2005;54:237–41. 4. Lazarev M, Ullman T, Schraut WH et al. Small bowel resection rates in Crohn’s disease and the indication for surgery over time: experience from a large tertiary care center. Inflamm Bowel Dis 2010;16:830–5. 5. Cosnes J, Bourrier A, Laharie D et al. Early administration of Azathioprine vs conventional management of Crohn’s disease: a randomized controlled trial. Gastroenterology 2013; doi:10.1033/j.gastro.2013.04.048 (e-pub ahead of print). 6. Kelly JK, Sutherland LR. The chronological sequence in the pathology of Crohn’s disease. J Clin Gastroenterol 1988;10:28–33. 7. Greenstein AJ, Lachman P, Sachar DB et al. Perforating and nonperforating indications for repeated operations in Crohn’s disease: evidence for two clinical forms. Gut 1988;29:588–92. 8. Limketkai B, Bayless T, Ginsburg P et al. Distal ileal Crohn’s disease: the time course of the development of stenosis and obstruction. Inflamm Bowel Dis 2009;15:23–4. 9. Jacene HA, Ginsburg P, Kwon J et al. Prediction of the need for surgical intervention in obstructive Crohn’s disease by 18F-FDG PET/CT. J Nucl Med 2009;50:1751–9. 10. Rieder F, Fiocchi C. Intestinal fibrosis in inflammatory bowel disease: progress in basic and clinical science. Curr Opin Gastroenterol 2008;24:462–8. 11. Johnson LA, Rodansky ES, Sauder KL et al. Matrix stiffness corresponding to strictured bowel induces a fibrogenic response in human colonic fibroblasts. Inflamm Bowel Dis 2013;19:891–903. 12. Wells RG. The role of matrix stiffness in regulating cell behavior. Hepatology 2008;47:1394–400. 13. Otte JM, Rosenberg IM, Podolsky DK. Intestinal myofibroblasts in innate immune responses of the intestine. Gastroenterology 2003;124:1866–78. 14. Graham MF. Pathogenesis of intestinal strictures in Crohn’s disease—an update. Inflamm Bowel Dis 1995;1:220–7. 15. Alsaleh AA, Kuemmerle JF. Development and treatment of fibrosis in Crohn’s disease. Pract Gastroenterol 2013;37:32–41.
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VOLUME 108 NOVEMBER 2013 www.amjgastro.com
