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Fecal Infliximab Loss
December 2015 Unit for the Clinical Management of Digestive Diseases Virgen del Rocio University Hospital University of Seville Seville, Spain Institute of Biomedicine of Seville (IBIS) Seville, Spain SCOTT L. FRIEDMAN Division of Liver Diseases Icahn School of Medicine at Mount Sinai New York, New York MANUEL ROMERO-GOMEZ Unit for the Clinical Management of Digestive Diseases Virgen del Rocio University Hospital University of Seville Seville, Spain Institute of Biomedicine of Seville (IBIS) Seville, Spain
References 1. 2. 3. 4. 5. 6. 7.
Vilar-Gomez E, et al. Gastroenterology 2015;149: 367–378 e5. Jensen MD, et al. Circulation 2014;129:S102–S138. Hall KD, et al. Cell Metab 2015;22:427–436. Sacks FM, et al. N Engl J Med 2009;360:859–873. Foster GD, et al. Ann Intern Med 2010;153:147–157. Haufe S, et al. Hepatology 2011;53:1504–1514. Lazo M, et al. Diabetes Care 2010;33:2156–2163.
Conflicts of interest The authors disclose no conflicts.
Correspondence 1989
observed in hospitalized patients (only one-third of this study group) with severe colitis and systemic inflammatory response. We suggest that future prospective studies might usefully focus on this patient cohort and evaluate whether measurement of fecal IFX loss “adds value” to the traditional measurement of inflammatory burden and disease severity by markers such as C-reactive protein and serum albumin.3 It would be useful to know if detection of early fecal IFX loss shows utility in guiding accelerated IFX dosing to improve the likelihood of mucosal healing (perhaps assessed at a later time point than in this study) and ultimately, therefore, decrease the requirement for colectomy. DAVID. J. GIBSON GLEN. A. DOHERTY Centre for Colorectal Disease St Vincent’s University Hospital & School of Medicine University College Dublin Dublin, Ireland
References 1. 2. 3.
Brandse JF, et al. Gastroenterology 2015;149:350–355. Gibson DJ, et al. Clin Gastroenterol Hepatol 2015;13: 330–335 e331. Sjoberg M, et al. Aliment Pharmacol Ther 2013;38: 377–387.
Conflicts of interest The authors disclose no conflicts. Most current article
Most current article http://dx.doi.org/10.1053/j.gastro.2015.07.071 http://dx.doi.org/10.1053/j.gastro.2015.10.040
Fecal Infliximab Loss Dear Editor: We read with great interest the article by Brandse et al1 reporting fecal infliximab (IFX) loss in the setting of severe colitis. This is an important study and the data are impressive, suggesting that the peak rate of fecal drug loss is in the initial days after induction, when colonic inflammation is at its highest, and when patients are at greatest risk of treatment failure and need for colectomy. The definition of antitumor necrosis factor failure in ulcerative colitis has been evolving recently, and it is increasingly recognized that treatment failure more often reflects inadequate dosing of anti-tumor necrosis factor agent than true primary therapeutic nonresponse. We would therefore challenge the decision of the authors to define patients who required either escalation of IFX dose or infusion intervals as nonresponders in their study. As our group have highlighted, an accelerated IFX induction in patients with severe ulcerative colitis may overcome the combined impact of high inflammatory burden and increased drug loss to decrease the need for colectomy.2 It seems from this study that fecal loss of IFX is primarily
Reply. We thank Drs Gibson and Doherty for their interest in our article on fecal loss of infliximab (IFX) in severe ulcerative colitis and the challenge to define the population that may benefit from an accelerated IFX dosing.1 The abundant presence of proteases, such as matrix metalloproteinases 3 and 12, in the feces of inflammatory bowel disease patients have been shown to degrade IFX into F(ab’)2 fragments.2 In our study, we did not use protease inhibitors to prevent this proteolytic degradation of IFX. Our results may thereby be an underestimation of the actual IFX concentrations that are present in feces of these patients. With respect to the observation that fecal loss of IFX is observed primarily in hospitalized patients with severe colitis and systemic inflammatory response, we wish to add the following remark. Criteria for hospitalization are very strict in The Netherlands, including in both hospitals that participated in this manuscript. This means that only patients with acute severe ulcerative colitis who also suffer from additional complications such as toxic megacolon, sepsis, or malnutrition, are hospitalized; most other patients receive IFX induction in the ambulatory setting, even when they are every sick. Overall, however, hospitalization reflects more severe disease because hospitalized patients had
References 1. 2. 3. 4. 5. 6. 7.
Vilar-Gomez E, et al. Gastroenterology 2015;149: 367–378 e5. Jensen MD, et al. Circulation 2014;129:S102–S138. Hall KD, et al. Cell Metab 2015;22:427–436. Sacks FM, et al. N Engl J Med 2009;360:859–873. Foster GD, et al. Ann Intern Med 2010;153:147–157. Haufe S, et al. Hepatology 2011;53:1504–1514. Lazo M, et al. Diabetes Care 2010;33:2156–2163.
Conflicts of interest The authors disclose no conflicts.
Correspondence 1989
observed in hospitalized patients (only one-third of this study group) with severe colitis and systemic inflammatory response. We suggest that future prospective studies might usefully focus on this patient cohort and evaluate whether measurement of fecal IFX loss “adds value” to the traditional measurement of inflammatory burden and disease severity by markers such as C-reactive protein and serum albumin.3 It would be useful to know if detection of early fecal IFX loss shows utility in guiding accelerated IFX dosing to improve the likelihood of mucosal healing (perhaps assessed at a later time point than in this study) and ultimately, therefore, decrease the requirement for colectomy. DAVID. J. GIBSON GLEN. A. DOHERTY Centre for Colorectal Disease St Vincent’s University Hospital & School of Medicine University College Dublin Dublin, Ireland
References 1. 2. 3.
Brandse JF, et al. Gastroenterology 2015;149:350–355. Gibson DJ, et al. Clin Gastroenterol Hepatol 2015;13: 330–335 e331. Sjoberg M, et al. Aliment Pharmacol Ther 2013;38: 377–387.
Conflicts of interest The authors disclose no conflicts. Most current article
Most current article http://dx.doi.org/10.1053/j.gastro.2015.07.071 http://dx.doi.org/10.1053/j.gastro.2015.10.040
Fecal Infliximab Loss Dear Editor: We read with great interest the article by Brandse et al1 reporting fecal infliximab (IFX) loss in the setting of severe colitis. This is an important study and the data are impressive, suggesting that the peak rate of fecal drug loss is in the initial days after induction, when colonic inflammation is at its highest, and when patients are at greatest risk of treatment failure and need for colectomy. The definition of antitumor necrosis factor failure in ulcerative colitis has been evolving recently, and it is increasingly recognized that treatment failure more often reflects inadequate dosing of anti-tumor necrosis factor agent than true primary therapeutic nonresponse. We would therefore challenge the decision of the authors to define patients who required either escalation of IFX dose or infusion intervals as nonresponders in their study. As our group have highlighted, an accelerated IFX induction in patients with severe ulcerative colitis may overcome the combined impact of high inflammatory burden and increased drug loss to decrease the need for colectomy.2 It seems from this study that fecal loss of IFX is primarily
Reply. We thank Drs Gibson and Doherty for their interest in our article on fecal loss of infliximab (IFX) in severe ulcerative colitis and the challenge to define the population that may benefit from an accelerated IFX dosing.1 The abundant presence of proteases, such as matrix metalloproteinases 3 and 12, in the feces of inflammatory bowel disease patients have been shown to degrade IFX into F(ab’)2 fragments.2 In our study, we did not use protease inhibitors to prevent this proteolytic degradation of IFX. Our results may thereby be an underestimation of the actual IFX concentrations that are present in feces of these patients. With respect to the observation that fecal loss of IFX is observed primarily in hospitalized patients with severe colitis and systemic inflammatory response, we wish to add the following remark. Criteria for hospitalization are very strict in The Netherlands, including in both hospitals that participated in this manuscript. This means that only patients with acute severe ulcerative colitis who also suffer from additional complications such as toxic megacolon, sepsis, or malnutrition, are hospitalized; most other patients receive IFX induction in the ambulatory setting, even when they are every sick. Overall, however, hospitalization reflects more severe disease because hospitalized patients had