Alimentary Pharmacology and Therapeutics Letters to the Editors
Letter: tumour necrosis factor alpha blocker switching – a not so simple pharmacokinetic R. Licinio, G. Losurdo, E. Ierardi, A. Di Leo & M. Principi Section of Gastroenterology, Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy. E-mail: [email protected] doi:10.1111/apt.13212
SIRS, We read with interest the meta-analysis by Gisbert et al., which demonstrates that the efficacy of switching from one to another anti-tumour necrosis factor (TNF) alpha agent, in the therapy of inflammatory bowel disease, depends on the rationale of the change in the drug. In fact, the patients switching for intolerance experienced disease remission in 61% of cases, whereas those classified as secondary and primary non-responders achieved remission in 45% and 30% of cases, respectively.1 These proportions of response after switching the type of anti-TNF alpha in the different categories are not unexpected. Indeed, primary non-responder patients are probably carriers of alternative inflammatory pathways, while patients with secondary non-response could be experiencing a reduction in drug levels, due to the formation of antibodies against the drug itself.2 Finally, patients intolerant to anti-TNF alpha are only the ‘victim’ of an adverse effect, but the drug itself is still efficacious to inhibit the inflammation. Therefore, we believe that the remission rate of 30% in primary non-response is surprising, taking into account the molecular reason of non-response in this particular subset of patients. We emphasise that in the short term (6–8 weeks) even second-line anti-TNF alpha has a small remission rate that, successively, increases reaching the 30% of remission rate in the medium-long term.1 This could lead us to hypothesise that other factors and mechanisms may be involved in primary
Letter: tumour necrosis factor alpha blocker switching – a not so simple pharmacokinetic. Authors’ reply J. P. Gisbert & M. Chaparro Gastroenterology Unit, Hospital Universitario de La Princesa, IIS-IP and CIBEREHD, Madrid, Spain. E-mail: [email protected] doi:10.1111/apt.13222 1302
non-response - for example, high levels of TNF alpha at baseline.3, 4 In these cases, the second-line anti-TNF alpha shows a low remission rate (18%) in the first 2 months and only after additional administrations is it able to block the large amount of the cytokine in both serum and tissue to obtain remission. Consequently, we presume that the 70% of persistent non-responders are represented by the subgroup of patients whose inflammation is driven by other mediators and TNF alpha is irrelevant for the inflammatory process. Finally, switching to another TNF alpha is the best management for secondary non-response and for intolerant patients. However, it is not efficacious in primary non-response where TNF alpha is not the major cytokine mediating the inflammation. In this setting, the subgroup which obtain remission with switching presumably benefits by the blocking of a hypothetically major amount of TNF alpha, which could be also achieved by continuing the first-line drug for a longer time.
ACKNOWLEDGEMENT Declaration of personal and funding interests: None. REFERENCES 1. Gisbert JP, Marın AC, McNicholl AG, Chaparro M. Systematic review with meta-analysis: the efficacy of a second anti-TNF in patients with inflammatory bowel disease whose previous antiTNF treatment has failed. Aliment Pharmacol Ther 2015; 41: 613–23. 2. Ainsworth MA, Bendtzen K, Brynskov J. Tumor necrosis factoralpha binding capacity and anti-infliximab antibodies measured by fluid-phase radioimmunoassay as predictors of clinical efficacy of infliximab in Crohn’s disease. Am J Gastroenterol 2008; 103: 944–8. 3. Ordas I, Mould DR, Feagan BG, et al. Anti-TNF monoclonal antibodies in inflammatory bowel disease: pharmacokineticsbased dosing paradigms. Clin Pharmacol Ther 2012; 91: 635–46. 4. Olsen T, Goll R, Cui G, et al. TNF-alpha gene expression in colorectal mucosa as a predictor of remission after induction therapy with infliximab in ulcerative colitis. Cytokine 2009; 46: 222–7.
SIRS, Licinio et al.1 have nicely commented on our metaanalysis on the efficacy of a second anti-tumour necrosis factor (TNF) therapy in patients with inflammatory bowel disease whose previous anti-TNF treatment has failed, in which we concluded that this efficacy largely depended on the cause for switching.2 We showed that the remission rate was higher when the reason to withdraw the first anti-TNF was intolerance (61%), compared with secondary (45%) or primary Aliment Pharmacol Ther 2015; 41: 1301–1305 ª 2015 John Wiley & Sons Ltd
Letters to the Editors failure (30%). Thus, our sub-analysis revealed some – albeit quite limited – benefit for switching even after primary failure. As Licinio et al. rightly state, our meta-analysis showed that, for primary failure, the short-term (4–8 weeks) remission rate (18%) was lower than that obtained in the medium term (9–40 weeks) (30%) and long term (41–52 weeks) (28%). In this respect, data from the openlabel extension cohort of the GAIN trial3 showed that among initial nonresponders to adalimumab at week 4, 67% achieved a response and 25% entered remission by week 12. Those data suggest that 4 weeks may be too early to assess the response to the induction doses, mainly in infliximab-experienced Crohn’s disease patients. Licinio et al.1 hypothesise that this delay in response may be explained by the existence of high levels of TNF alpha (at either serum or tissue) at baseline, and that could be a reason. However, in the Spanish multicenter PREDICROHN GETECCU study, we assessed the usefulness of measuring TNF serum levels to predict remission (at week 14) with anti-TNF treatment (either infliximab or adalimumab) in 117 patients with Crohn’s disease.4 TNF serum levels were measured using a highly sensitive modified ELISA, Collaborative enzyme enhanced reactive immunoassay (CEER), at baseline and at weeks 4, 8 and 14. We found that although, overall, basal TNF levels seemed to be lower among patients that reached
Letter: low muscle mass and disordered eating as causes of osteopenia in inflammatory bowel disease E. M. DeFilippis, C. Webb, R. U. Warren, S. Tabani, B. P. Bosworth & E. J. Scherl Jill Roberts Center for Inflammatory Bowel Disease, New York Presbyterian-Weill Cornell Medical College, New York, NY, USA. E-mail: [email protected] doi:10.1111/apt.13213
SIRS, We read with interest the article by Bryant et al.,1 which studied the prevalence of low lean mass and sarcopenia in patients with inflammatory bowel disease (IBD). They briefly mention that this population may be at risk for accelerated sarcopenia due to chronic inflammation and malnutrition. They attribute malnutrition to causes including malabsorption, dietary restriction and surgery.1 Malnutrition may also be secondary to disordered eating behaviors. Previous studies have suggested that Aliment Pharmacol Ther 2015; 41: 1301–1305 ª 2015 John Wiley & Sons Ltd
remission under infliximab treatment, the concentration of soluble TNF was not useful for predicting response to the anti-TNF treatment during the induction phase. Nevertheless, these are still preliminary results and these analyses will need to be repeated at the end of the study, to confirm whether measuring soluble TNF serum levels may be useful to predict medium long-term remission.
ACKNOWLEDGEMENT The authors’ declarations of personal and financial interests are unchanged from those in the original article.2 REFERENCES 1. Licinio R, Losurdo G, Ierardi E, Di Leo A, Principi M. Tumor necrosis factor alpha blocker switching – a not so simple pharmacokinetic. Aliment Pharmacol Ther 2015; 41: 1302. 2. Gisbert JP, Marin AC, McNicholl AG, Chaparro M. Systematic review with meta-analysis: the efficacy of a second anti-TNF in patients with inflammatory bowel disease whose previous antiTNF treatment has failed. Aliment Pharmacol Ther 2015; 41: 613–23. 3. Sandborn WJ, Rutgeerts P, Enns R, et al. Adalimumab induction therapy for Crohn disease previously treated with infliximab: a randomized trial. Ann Intern Med 2007; 146: 829–38. 4. Chaparro M, Guerra I, Iborra M, et al.; on behalf of the PREDICROHN GETECCU study group. Soluble TNF serum levels during the induction phase in Crohn’s disease patients with anti-TNF treatment. J Crohn Colitis 2015; 9(Suppl.1): S302.
individuals with gastrointestinal (GI) disorders may be at increased risk for disordered eating.2 It is postulated that these individuals may begin to associate certain GI symptoms with particular foods, leading to conditioned food aversions, and ultimately the development of disordered eating.2–5 Yet, there is limited research in this area. From March to October of 2013, we conducted a prospective study of 250 IBD patients who were surveyed about eating patterns, medical history and IBD symptoms. Patients were also asked to complete an EAT-26 survey, a standardised and validated tool to identify atrisk patients.6 A score greater than 20 is suggestive of an eating disorder; the patient should see a qualified mental health professional.7 Disordered eating was defined as a score greater than 15. Two hundred and twenty-six subjects completed the EAT-26 portion: 196 patients scored 20. Patient characteristics are described in Table 1. Notably, 63 patients 1303
Copyright of Alimentary Pharmacology & Therapeutics is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
Letter: tumour necrosis factor alpha blocker switching – a not so simple pharmacokinetic R. Licinio, G. Losurdo, E. Ierardi, A. Di Leo & M. Principi Section of Gastroenterology, Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy. E-mail: [email protected] doi:10.1111/apt.13212
SIRS, We read with interest the meta-analysis by Gisbert et al., which demonstrates that the efficacy of switching from one to another anti-tumour necrosis factor (TNF) alpha agent, in the therapy of inflammatory bowel disease, depends on the rationale of the change in the drug. In fact, the patients switching for intolerance experienced disease remission in 61% of cases, whereas those classified as secondary and primary non-responders achieved remission in 45% and 30% of cases, respectively.1 These proportions of response after switching the type of anti-TNF alpha in the different categories are not unexpected. Indeed, primary non-responder patients are probably carriers of alternative inflammatory pathways, while patients with secondary non-response could be experiencing a reduction in drug levels, due to the formation of antibodies against the drug itself.2 Finally, patients intolerant to anti-TNF alpha are only the ‘victim’ of an adverse effect, but the drug itself is still efficacious to inhibit the inflammation. Therefore, we believe that the remission rate of 30% in primary non-response is surprising, taking into account the molecular reason of non-response in this particular subset of patients. We emphasise that in the short term (6–8 weeks) even second-line anti-TNF alpha has a small remission rate that, successively, increases reaching the 30% of remission rate in the medium-long term.1 This could lead us to hypothesise that other factors and mechanisms may be involved in primary
Letter: tumour necrosis factor alpha blocker switching – a not so simple pharmacokinetic. Authors’ reply J. P. Gisbert & M. Chaparro Gastroenterology Unit, Hospital Universitario de La Princesa, IIS-IP and CIBEREHD, Madrid, Spain. E-mail: [email protected] doi:10.1111/apt.13222 1302
non-response - for example, high levels of TNF alpha at baseline.3, 4 In these cases, the second-line anti-TNF alpha shows a low remission rate (18%) in the first 2 months and only after additional administrations is it able to block the large amount of the cytokine in both serum and tissue to obtain remission. Consequently, we presume that the 70% of persistent non-responders are represented by the subgroup of patients whose inflammation is driven by other mediators and TNF alpha is irrelevant for the inflammatory process. Finally, switching to another TNF alpha is the best management for secondary non-response and for intolerant patients. However, it is not efficacious in primary non-response where TNF alpha is not the major cytokine mediating the inflammation. In this setting, the subgroup which obtain remission with switching presumably benefits by the blocking of a hypothetically major amount of TNF alpha, which could be also achieved by continuing the first-line drug for a longer time.
ACKNOWLEDGEMENT Declaration of personal and funding interests: None. REFERENCES 1. Gisbert JP, Marın AC, McNicholl AG, Chaparro M. Systematic review with meta-analysis: the efficacy of a second anti-TNF in patients with inflammatory bowel disease whose previous antiTNF treatment has failed. Aliment Pharmacol Ther 2015; 41: 613–23. 2. Ainsworth MA, Bendtzen K, Brynskov J. Tumor necrosis factoralpha binding capacity and anti-infliximab antibodies measured by fluid-phase radioimmunoassay as predictors of clinical efficacy of infliximab in Crohn’s disease. Am J Gastroenterol 2008; 103: 944–8. 3. Ordas I, Mould DR, Feagan BG, et al. Anti-TNF monoclonal antibodies in inflammatory bowel disease: pharmacokineticsbased dosing paradigms. Clin Pharmacol Ther 2012; 91: 635–46. 4. Olsen T, Goll R, Cui G, et al. TNF-alpha gene expression in colorectal mucosa as a predictor of remission after induction therapy with infliximab in ulcerative colitis. Cytokine 2009; 46: 222–7.
SIRS, Licinio et al.1 have nicely commented on our metaanalysis on the efficacy of a second anti-tumour necrosis factor (TNF) therapy in patients with inflammatory bowel disease whose previous anti-TNF treatment has failed, in which we concluded that this efficacy largely depended on the cause for switching.2 We showed that the remission rate was higher when the reason to withdraw the first anti-TNF was intolerance (61%), compared with secondary (45%) or primary Aliment Pharmacol Ther 2015; 41: 1301–1305 ª 2015 John Wiley & Sons Ltd
Letters to the Editors failure (30%). Thus, our sub-analysis revealed some – albeit quite limited – benefit for switching even after primary failure. As Licinio et al. rightly state, our meta-analysis showed that, for primary failure, the short-term (4–8 weeks) remission rate (18%) was lower than that obtained in the medium term (9–40 weeks) (30%) and long term (41–52 weeks) (28%). In this respect, data from the openlabel extension cohort of the GAIN trial3 showed that among initial nonresponders to adalimumab at week 4, 67% achieved a response and 25% entered remission by week 12. Those data suggest that 4 weeks may be too early to assess the response to the induction doses, mainly in infliximab-experienced Crohn’s disease patients. Licinio et al.1 hypothesise that this delay in response may be explained by the existence of high levels of TNF alpha (at either serum or tissue) at baseline, and that could be a reason. However, in the Spanish multicenter PREDICROHN GETECCU study, we assessed the usefulness of measuring TNF serum levels to predict remission (at week 14) with anti-TNF treatment (either infliximab or adalimumab) in 117 patients with Crohn’s disease.4 TNF serum levels were measured using a highly sensitive modified ELISA, Collaborative enzyme enhanced reactive immunoassay (CEER), at baseline and at weeks 4, 8 and 14. We found that although, overall, basal TNF levels seemed to be lower among patients that reached
Letter: low muscle mass and disordered eating as causes of osteopenia in inflammatory bowel disease E. M. DeFilippis, C. Webb, R. U. Warren, S. Tabani, B. P. Bosworth & E. J. Scherl Jill Roberts Center for Inflammatory Bowel Disease, New York Presbyterian-Weill Cornell Medical College, New York, NY, USA. E-mail: [email protected] doi:10.1111/apt.13213
SIRS, We read with interest the article by Bryant et al.,1 which studied the prevalence of low lean mass and sarcopenia in patients with inflammatory bowel disease (IBD). They briefly mention that this population may be at risk for accelerated sarcopenia due to chronic inflammation and malnutrition. They attribute malnutrition to causes including malabsorption, dietary restriction and surgery.1 Malnutrition may also be secondary to disordered eating behaviors. Previous studies have suggested that Aliment Pharmacol Ther 2015; 41: 1301–1305 ª 2015 John Wiley & Sons Ltd
remission under infliximab treatment, the concentration of soluble TNF was not useful for predicting response to the anti-TNF treatment during the induction phase. Nevertheless, these are still preliminary results and these analyses will need to be repeated at the end of the study, to confirm whether measuring soluble TNF serum levels may be useful to predict medium long-term remission.
ACKNOWLEDGEMENT The authors’ declarations of personal and financial interests are unchanged from those in the original article.2 REFERENCES 1. Licinio R, Losurdo G, Ierardi E, Di Leo A, Principi M. Tumor necrosis factor alpha blocker switching – a not so simple pharmacokinetic. Aliment Pharmacol Ther 2015; 41: 1302. 2. Gisbert JP, Marin AC, McNicholl AG, Chaparro M. Systematic review with meta-analysis: the efficacy of a second anti-TNF in patients with inflammatory bowel disease whose previous antiTNF treatment has failed. Aliment Pharmacol Ther 2015; 41: 613–23. 3. Sandborn WJ, Rutgeerts P, Enns R, et al. Adalimumab induction therapy for Crohn disease previously treated with infliximab: a randomized trial. Ann Intern Med 2007; 146: 829–38. 4. Chaparro M, Guerra I, Iborra M, et al.; on behalf of the PREDICROHN GETECCU study group. Soluble TNF serum levels during the induction phase in Crohn’s disease patients with anti-TNF treatment. J Crohn Colitis 2015; 9(Suppl.1): S302.
individuals with gastrointestinal (GI) disorders may be at increased risk for disordered eating.2 It is postulated that these individuals may begin to associate certain GI symptoms with particular foods, leading to conditioned food aversions, and ultimately the development of disordered eating.2–5 Yet, there is limited research in this area. From March to October of 2013, we conducted a prospective study of 250 IBD patients who were surveyed about eating patterns, medical history and IBD symptoms. Patients were also asked to complete an EAT-26 survey, a standardised and validated tool to identify atrisk patients.6 A score greater than 20 is suggestive of an eating disorder; the patient should see a qualified mental health professional.7 Disordered eating was defined as a score greater than 15. Two hundred and twenty-six subjects completed the EAT-26 portion: 196 patients scored 20. Patient characteristics are described in Table 1. Notably, 63 patients 1303
Copyright of Alimentary Pharmacology & Therapeutics is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
