Reply

Abstract

We appreciate the interest of Drs Lengeling and Schulze in our recently published article describing the association of the short-term administration of low-dose aspirin (acetylsalicylic acid [ASA]) and the occurrence of small intestinal mucosal damage.1Smecuol E. Sanchez M. Suarez A. et al.Low-dose aspirin affects the small bowel mucosa: results of a pilot study with a multidimensional assessment.Clin Gastroenterol Hepatol. 2009; 7: 524-529Abstract Full Text Full Text PDF PubMed Scopus (99) Google ScholarIt was generally believed that low-dose ASA does not cause any small-bowel damage because the drug is largely absorbed before reaching the intestine and this would limit the topical action on the intestinal mucosa.2Lanas A. Sopeña F. Nonsteroidal anti-inflammatory drugs and lower gastrointestinal complications.Gastroenterol Clin North Am. 2009; 38: 333-352Abstract Full Text Full Text PDF PubMed Scopus (135) Google Scholar Thus, until recently, it remained controversial as to whether low-dose aspirin is toxic to the small bowel.In their comment, the authors' letter highlights several important issues pertaining to this important problem. We agree with some of the points raised by our colleagues who state that in their experience with ulcerative ileitis detected in 40 patients,3Lengeling R. Mitros F. Brennan J. et al.Ulcerative enteritis encountered at ileo-colonoscopy: likely role of nonsteroidal agents.Clin Gastroenterol Hepatol. 2003; : 1160-1169Google Scholar now numbering more than 150 cases, enteric-coated formulations containing less than 325 mg/d of ASA were the single most common likely cause of the mucosal damage. In this sense, our results showed that administration of only 100 mg/d of enteric-coated ASA during 2 weeks can determine macroscopic small-bowel mucosal damage in 50% of the healthy subjects included as the study population (n = 20). Moreover, the concepts provided by both studies also were reinforced recently by contributions by Endo et al4Endo H. Hosono K. Inamori M. et al.Incidence of small bowel injury induced by low dose aspirin: a crossover study using capsule endoscopy in healthy volunteers.Digestion. 2009; 79: 44-51Crossref PubMed Scopus (78) Google Scholar and Matsumoto et al,5Matsumoto T. Kudo T. Esaki M. et al.Prevalence of non-steroidal anti-inflammatory drug-induced enteropathy determined by double-balloon endoscopy: a Japanese multicenter study.Scand J Gastroenterol. 2008; 43: 490-496Crossref PubMed Scopus (119) Google Scholar who described the enteropathy induced by short-term intake of low-dose ASA determined by different diagnostic modalities (videocapsule endoscopy and double-balloon enteroscopy study, respectively).However, as we clearly state in our study, the finding of lesions in the small bowel, as it happens with those found in the stomach after nonsteroidal anti-inflammatory drug (NSAID) or ASA use, may have little clinical relevance if they do not cause symptoms, anemia, or complications. Furthermore, a few points have been raised in Lengeling's and Schulze's Letter to the Editor that, in our opinion, also deserve further consideration.Many reports state that localization of intestinal lesions induced by NSAIDs, which occasionally can determine small-bowel bleeding, diaphragm disease, or intestinal perforation, were observed more frequently in the ileum than in the jejunum.6Allison M.C. Howatson A.G. Torrance C.J. et al.Gastrointestinal damage associated with the use of nonsteroidal anti-inflammatory drugs.N Engl J Med. 1992; 327: 749-754Crossref PubMed Scopus (970) Google Scholar, 7Matsuhashi N. Yamada A. Hiraishi M. et al.Multiple strictures of the small intestine after long-term nonsteroidal anti-inflammatory drug therapy.Am J Gastroenterol. 1992; 87: 1183-1186PubMed Google Scholar, 8Kessler W.F. Shires III, G.T. Fahey III, T.J. Surgical complications of nonsteroidal antiinflammatory drug-induced small bowel ulceration.J Am Coll Surg. 1997; 185: 250-254Abstract Full Text Full Text PDF PubMed Google Scholar, 9Yen H.H. Chen Y.Y. Soon M.S. Nonsteroidal anti-inflammatory drug-associated ileal ulcers: an evaluation by double-balloon enteroscopy.Gastrointest Endosc. 2006; 63: 328Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar On the contrary, some investigators5Matsumoto T. Kudo T. Esaki M. et al.Prevalence of non-steroidal anti-inflammatory drug-induced enteropathy determined by double-balloon endoscopy: a Japanese multicenter study.Scand J Gastroenterol. 2008; 43: 490-496Crossref PubMed Scopus (119) Google Scholar, 10Maiden L. Thjodleifsson B. Theodors A. et al.A quantitative analysis of NSAID-induced small bowel pathology by capsule enteroscopy.Gastroenterology. 2005; 128: 1172-1178Abstract Full Text Full Text PDF PubMed Scopus (424) Google Scholar found no differences in the prevalence of NSAID-induced lesions according to small-bowel location.When considering intestinal damage related exclusively to low-doses of ASA, evidence is scarce and not as clear as suggested by Lengeling et al.3Lengeling R. Mitros F. Brennan J. et al.Ulcerative enteritis encountered at ileo-colonoscopy: likely role of nonsteroidal agents.Clin Gastroenterol Hepatol. 2003; : 1160-1169Google Scholar Thus, other studies4Endo H. Hosono K. Inamori M. et al.Incidence of small bowel injury induced by low dose aspirin: a crossover study using capsule endoscopy in healthy volunteers.Digestion. 2009; 79: 44-51Crossref PubMed Scopus (78) Google Scholar, 11Watanabe T. Sugimori S. Kameda M. et al.Small bowel injury by low-dose enteric-coated aspirin and treatment with misoprostol: a pilot study.Clin Gastroenterol Hepatol. 2008; 6: 1279-1282Abstract Full Text Full Text PDF PubMed Scopus (157) Google Scholar showed that small intestinal lesions were seen in both the jejunum and the ileum. Moreover, our study reported that mucosal lesions were more evident in the proximal small intestine (jejunum, 6; ileum, 1; and jejunum/ileum, 3).In this context, the recommendation of performing ileoscopy in all patients undergoing a colonoscopy should be discussed cautiously. In fact, the utility of routine ileoscopy as a component of screening colonoscopy is controversial. Despite many endoscopists' belief that routine intubation of the terminal ileum is a requirement for a full-screening procedure contributing significantly to quality assurance and diagnostic yield,12Cherian S. Singh P. Is routine ileoscopy useful? An observational study of procedure times, diagnostic yield, and learning curve.Am J Gastroenterol. 2004; 99: 2324-2329Crossref PubMed Scopus (77) Google Scholar others consider that the decision to perform the ileal cannulation needs to be made on a case-by-case basis13Kennedy G. Larson D. Wolff B. et al.Routine ileal intubation during screening colonoscopy: a useful maneuver?.Surg Endosc. 2008; 22: 2606-2608Crossref PubMed Scopus (20) Google Scholar because the diagnostic value of ileoscopy is not well documented. We do agree, however, that all patients with lesions found in the terminal ileum during colonoscopy should be questioned carefully concerning the use of either prescribed or over-the-counter NSAIDs or ASA, to put the findings and the clinical picture of the patient in the appropriate context.The efforts to generate safer NSAIDs, including ASA, have followed different routes, such as the development of enteric-coated, oral slow-release, or even rectal formulations.14Davies N. Sustained release and enteric coated NSAIDs: are they really GI safe?.J Pharm Pharmaceutic Sci. 1999; 2: 5-14PubMed Google Scholar It has been suggested that these types of drug delivery could shift the problem to a more distal site within the digestive tract14Davies N. Sustained release and enteric coated NSAIDs: are they really GI safe?.J Pharm Pharmaceutic Sci. 1999; 2: 5-14PubMed Google Scholar as reported in our study using enteric-coated ASA. In their Letter to the Editor, Lengeling and Schulze suggested that a chewable variety of ASA could prevent the occurrence of small intestinal lesions because of its fast absorption with the subsequent rapid dissipation of the agent, eliminating the topical requirement needed to produce enteric mucosal damage. Although this suggestion has some pathogenic basis, it should be pointed out that gastrointestinal injury by ASA therapy is the result of both local topical effects and a decrease in mucosal cyclooxygenase-1–derived prostaglandins, which until some point, could play a role in those lesions found in intestinal mucosa via systemic effect. In this sense, it should be remembered that new chewable tablet preparations determine higher plasma ASA concentrations that potentially could be part of the systemic effect.15Lücker P.W. Wetzelsberger N. Schettler T. et al.Pharmacokinetics and relative bioavailability of a new chewable, buffered acetylsalicylic acid tablet formulation in comparison to a conventional plain tablet.Methods Find Exp Clin Pharmacol. 1992; 14: 805-811PubMed Google Scholar Thus, in our opinion, further well-randomized controlled studies (not only anecdotal reports) should evaluate the intestinal toxicity of different ASA formulations (chewable, quick-release crystals, and so forth) and the clinical relevance of those findings, before any recommendations with implications for clinical practice can be made. We appreciate the interest of Drs Lengeling and Schulze in our recently published article describing the association of the short-term administration of low-dose aspirin (acetylsalicylic acid [ASA]) and the occurrence of small intestinal mucosal damage.1Smecuol E. Sanchez M. Suarez A. et al.Low-dose aspirin affects the small bowel mucosa: results of a pilot study with a multidimensional assessment.Clin Gastroenterol Hepatol. 2009; 7: 524-529Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar It was generally believed that low-dose ASA does not cause any small-bowel damage because the drug is largely absorbed before reaching the intestine and this would limit the topical action on the intestinal mucosa.2Lanas A. Sopeña F. Nonsteroidal anti-inflammatory drugs and lower gastrointestinal complications.Gastroenterol Clin North Am. 2009; 38: 333-352Abstract Full Text Full Text PDF PubMed Scopus (135) Google Scholar Thus, until recently, it remained controversial as to whether low-dose aspirin is toxic to the small bowel. In their comment, the authors' letter highlights several important issues pertaining to this important problem. We agree with some of the points raised by our colleagues who state that in their experience with ulcerative ileitis detected in 40 patients,3Lengeling R. Mitros F. Brennan J. et al.Ulcerative enteritis encountered at ileo-colonoscopy: likely role of nonsteroidal agents.Clin Gastroenterol Hepatol. 2003; : 1160-1169Google Scholar now numbering more than 150 cases, enteric-coated formulations containing less than 325 mg/d of ASA were the single most common likely cause of the mucosal damage. In this sense, our results showed that administration of only 100 mg/d of enteric-coated ASA during 2 weeks can determine macroscopic small-bowel mucosal damage in 50% of the healthy subjects included as the study population (n = 20). Moreover, the concepts provided by both studies also were reinforced recently by contributions by Endo et al4Endo H. Hosono K. Inamori M. et al.Incidence of small bowel injury induced by low dose aspirin: a crossover study using capsule endoscopy in healthy volunteers.Digestion. 2009; 79: 44-51Crossref PubMed Scopus (78) Google Scholar and Matsumoto et al,5Matsumoto T. Kudo T. Esaki M. et al.Prevalence of non-steroidal anti-inflammatory drug-induced enteropathy determined by double-balloon endoscopy: a Japanese multicenter study.Scand J Gastroenterol. 2008; 43: 490-496Crossref PubMed Scopus (119) Google Scholar who described the enteropathy induced by short-term intake of low-dose ASA determined by different diagnostic modalities (videocapsule endoscopy and double-balloon enteroscopy study, respectively). However, as we clearly state in our study, the finding of lesions in the small bowel, as it happens with those found in the stomach after nonsteroidal anti-inflammatory drug (NSAID) or ASA use, may have little clinical relevance if they do not cause symptoms, anemia, or complications. Furthermore, a few points have been raised in Lengeling's and Schulze's Letter to the Editor that, in our opinion, also deserve further consideration. Many reports state that localization of intestinal lesions induced by NSAIDs, which occasionally can determine small-bowel bleeding, diaphragm disease, or intestinal perforation, were observed more frequently in the ileum than in the jejunum.6Allison M.C. Howatson A.G. Torrance C.J. et al.Gastrointestinal damage associated with the use of nonsteroidal anti-inflammatory drugs.N Engl J Med. 1992; 327: 749-754Crossref PubMed Scopus (970) Google Scholar, 7Matsuhashi N. Yamada A. Hiraishi M. et al.Multiple strictures of the small intestine after long-term nonsteroidal anti-inflammatory drug therapy.Am J Gastroenterol. 1992; 87: 1183-1186PubMed Google Scholar, 8Kessler W.F. Shires III, G.T. Fahey III, T.J. Surgical complications of nonsteroidal antiinflammatory drug-induced small bowel ulceration.J Am Coll Surg. 1997; 185: 250-254Abstract Full Text Full Text PDF PubMed Google Scholar, 9Yen H.H. Chen Y.Y. Soon M.S. Nonsteroidal anti-inflammatory drug-associated ileal ulcers: an evaluation by double-balloon enteroscopy.Gastrointest Endosc. 2006; 63: 328Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar On the contrary, some investigators5Matsumoto T. Kudo T. Esaki M. et al.Prevalence of non-steroidal anti-inflammatory drug-induced enteropathy determined by double-balloon endoscopy: a Japanese multicenter study.Scand J Gastroenterol. 2008; 43: 490-496Crossref PubMed Scopus (119) Google Scholar, 10Maiden L. Thjodleifsson B. Theodors A. et al.A quantitative analysis of NSAID-induced small bowel pathology by capsule enteroscopy.Gastroenterology. 2005; 128: 1172-1178Abstract Full Text Full Text PDF PubMed Scopus (424) Google Scholar found no differences in the prevalence of NSAID-induced lesions according to small-bowel location. When considering intestinal damage related exclusively to low-doses of ASA, evidence is scarce and not as clear as suggested by Lengeling et al.3Lengeling R. Mitros F. Brennan J. et al.Ulcerative enteritis encountered at ileo-colonoscopy: likely role of nonsteroidal agents.Clin Gastroenterol Hepatol. 2003; : 1160-1169Google Scholar Thus, other studies4Endo H. Hosono K. Inamori M. et al.Incidence of small bowel injury induced by low dose aspirin: a crossover study using capsule endoscopy in healthy volunteers.Digestion. 2009; 79: 44-51Crossref PubMed Scopus (78) Google Scholar, 11Watanabe T. Sugimori S. Kameda M. et al.Small bowel injury by low-dose enteric-coated aspirin and treatment with misoprostol: a pilot study.Clin Gastroenterol Hepatol. 2008; 6: 1279-1282Abstract Full Text Full Text PDF PubMed Scopus (157) Google Scholar showed that small intestinal lesions were seen in both the jejunum and the ileum. Moreover, our study reported that mucosal lesions were more evident in the proximal small intestine (jejunum, 6; ileum, 1; and jejunum/ileum, 3). In this context, the recommendation of performing ileoscopy in all patients undergoing a colonoscopy should be discussed cautiously. In fact, the utility of routine ileoscopy as a component of screening colonoscopy is controversial. Despite many endoscopists' belief that routine intubation of the terminal ileum is a requirement for a full-screening procedure contributing significantly to quality assurance and diagnostic yield,12Cherian S. Singh P. Is routine ileoscopy useful? An observational study of procedure times, diagnostic yield, and learning curve.Am J Gastroenterol. 2004; 99: 2324-2329Crossref PubMed Scopus (77) Google Scholar others consider that the decision to perform the ileal cannulation needs to be made on a case-by-case basis13Kennedy G. Larson D. Wolff B. et al.Routine ileal intubation during screening colonoscopy: a useful maneuver?.Surg Endosc. 2008; 22: 2606-2608Crossref PubMed Scopus (20) Google Scholar because the diagnostic value of ileoscopy is not well documented. We do agree, however, that all patients with lesions found in the terminal ileum during colonoscopy should be questioned carefully concerning the use of either prescribed or over-the-counter NSAIDs or ASA, to put the findings and the clinical picture of the patient in the appropriate context. The efforts to generate safer NSAIDs, including ASA, have followed different routes, such as the development of enteric-coated, oral slow-release, or even rectal formulations.14Davies N. Sustained release and enteric coated NSAIDs: are they really GI safe?.J Pharm Pharmaceutic Sci. 1999; 2: 5-14PubMed Google Scholar It has been suggested that these types of drug delivery could shift the problem to a more distal site within the digestive tract14Davies N. Sustained release and enteric coated NSAIDs: are they really GI safe?.J Pharm Pharmaceutic Sci. 1999; 2: 5-14PubMed Google Scholar as reported in our study using enteric-coated ASA. In their Letter to the Editor, Lengeling and Schulze suggested that a chewable variety of ASA could prevent the occurrence of small intestinal lesions because of its fast absorption with the subsequent rapid dissipation of the agent, eliminating the topical requirement needed to produce enteric mucosal damage. Although this suggestion has some pathogenic basis, it should be pointed out that gastrointestinal injury by ASA therapy is the result of both local topical effects and a decrease in mucosal cyclooxygenase-1–derived prostaglandins, which until some point, could play a role in those lesions found in intestinal mucosa via systemic effect. In this sense, it should be remembered that new chewable tablet preparations determine higher plasma ASA concentrations that potentially could be part of the systemic effect.15Lücker P.W. Wetzelsberger N. Schettler T. et al.Pharmacokinetics and relative bioavailability of a new chewable, buffered acetylsalicylic acid tablet formulation in comparison to a conventional plain tablet.Methods Find Exp Clin Pharmacol. 1992; 14: 805-811PubMed Google Scholar Thus, in our opinion, further well-randomized controlled studies (not only anecdotal reports) should evaluate the intestinal toxicity of different ASA formulations (chewable, quick-release crystals, and so forth) and the clinical relevance of those findings, before any recommendations with implications for clinical practice can be made. Comments on Nonsteroidal Anti-Inflammatory Drug EnteropathyClinical Gastroenterology and HepatologyVol. 8Issue 2PreviewDear Editor: Full-Text PDF