Downloaded from gut.bmj.com on July 16, 2014 - Published by group.bmj.com
Gut Online First, published on July 16, 2014 as 10.1136/gutjnl-2014-307877
PostScript
LETTER
Importance of defining loss of response before therapeutic drug monitoring Dear Sir, I read with interest the study by Steenholdt et al1 which concluded that individualised infliximab therapy was more cost effective compared with empirical dose escalation in Crohn’s disease (CD) patients who developed secondary non-response to infliximab. The study methodology has a number of questions that require attention. First, 80% of the patients recruited for the study had non-fistulising disease, and the study entry criterion for them was having a Crohn’s Disease Activity Index (CDAI) score of ≥220. Furthermore, the endpoint for clinical response for them was defined as CDAI reduction of ≥70 points. CDAI scores are largely driven by symptom reporting2 and the lack of more objective markers for the patients with non-fistulising disease makes interpretation problematic. This leads to the second point below, as some of these patients were later found out not to have a flare of CD. Second, among the 33 patients who were randomised into the algorithm group, 25 (76%) patients were deemed to have pharmacodynamic reasons for loss of response, of which six had bile acid
malabsorption, strictures or IBS. Were the remaining 8 (24%) evaluated for possible explanations other than IBD-driven inflammation to account for their raised CDAI scores? The same can be applied for patients in the dose-intensification arm, whether they truly had IBD-related relapse. Assuming that 20% of the enrolled patients had non-IBD-related symptoms, the study would be underpowered to detect any meaningful differences in clinical response among those with CD flare. If the clinical efficacy of both methods was indeed equivalent, what is interesting is that empirical dose-intensification of infliximab seems to work even for patients who already had therapeutic levels of infliximab as defined by the study. Possible mechanisms would be higher doses of infliximab required by a subset of patients or piggy-backing the waning phase of the disease.3 What we can learn from this study is the importance of clearly defining loss of response before measuring any drug or antidrug antibody levels. Without the correct context of loss of response, interpretation of drug and antidrug antibody levels would be inappropriate, especially so when drug levels are found to be of therapeutic levels. When properly defined, customised treatment based on therapeutic drug monitoring will avoid unhelpful dose-intensification of biologics for some patients and be cost-efficient from a macro-economic level.
Nevertheless, I would like to congratulate the authors for undertaking the task of demonstrating the cost effectiveness of individualised biologic therapy for patients with complicated CD in the era of personalised medicine. Malcolm Tan Correspondence to Dr Malcolm Tan, Department of Gastroenterology and Hepatology, Changi General Hospital, 2 Simei Street 3, Singapore 529889, Singapore; [email protected] Competing interests None. Provenance and peer review Not commissioned; internally peer reviewed. To cite Tan M. Gut Published Online First: [please include Day Month Year] doi:10.1136/gutjnl-2014307877 Received 17 June 2014 Accepted 1 July 2014 Gut 2014;0:1. doi:10.1136/gutjnl-2014-307877
REFERENCES 1
2
3
Steenholdt C, Brynskov J, Thomsen OØ, et al. Individualised therapy is more cost-effective than dose intensification in patients with Crohn’s disease who lose response to anti-TNF treatment: a randomised, controlled trial. Gut 2014;63:919–27. Lahiff C, Safaie P, Awais A, et al. The Crohn’s disease activity index (CDAI) is similarly elevated in patients with Crohn’s disease and in patients with irritable bowel syndrome. Aliment Pharmacol Ther 2013;37:786–94. Solberg IC, Vatn MH, Høie O, et al.; IBSEN Study Group. Clinical course in Crohn’s disease: results of a Norwegian population-based ten-year follow-up study. Clin Gastroenterol Hepatol 2007;5:1430–8.
Gut Month 2014 Vol by 0 NoBMJ 0 1 Copyright Article author (or their employer) 2014. Produced Publishing Group Ltd (& BSG) under licence.
Downloaded from gut.bmj.com on July 16, 2014 - Published by group.bmj.com
Importance of defining loss of response before therapeutic drug monitoring Malcolm Tan Gut published online July 16, 2014
doi: 10.1136/gutjnl-2014-307877
Updated information and services can be found at: http://gut.bmj.com/content/early/2014/07/16/gutjnl-2014-307877.full.html
These include:
References
This article cites 3 articles, 1 of which can be accessed free at: http://gut.bmj.com/content/early/2014/07/16/gutjnl-2014-307877.full.html#ref-list-1
P
Gut Online First, published on July 16, 2014 as 10.1136/gutjnl-2014-307877
PostScript
LETTER
Importance of defining loss of response before therapeutic drug monitoring Dear Sir, I read with interest the study by Steenholdt et al1 which concluded that individualised infliximab therapy was more cost effective compared with empirical dose escalation in Crohn’s disease (CD) patients who developed secondary non-response to infliximab. The study methodology has a number of questions that require attention. First, 80% of the patients recruited for the study had non-fistulising disease, and the study entry criterion for them was having a Crohn’s Disease Activity Index (CDAI) score of ≥220. Furthermore, the endpoint for clinical response for them was defined as CDAI reduction of ≥70 points. CDAI scores are largely driven by symptom reporting2 and the lack of more objective markers for the patients with non-fistulising disease makes interpretation problematic. This leads to the second point below, as some of these patients were later found out not to have a flare of CD. Second, among the 33 patients who were randomised into the algorithm group, 25 (76%) patients were deemed to have pharmacodynamic reasons for loss of response, of which six had bile acid
malabsorption, strictures or IBS. Were the remaining 8 (24%) evaluated for possible explanations other than IBD-driven inflammation to account for their raised CDAI scores? The same can be applied for patients in the dose-intensification arm, whether they truly had IBD-related relapse. Assuming that 20% of the enrolled patients had non-IBD-related symptoms, the study would be underpowered to detect any meaningful differences in clinical response among those with CD flare. If the clinical efficacy of both methods was indeed equivalent, what is interesting is that empirical dose-intensification of infliximab seems to work even for patients who already had therapeutic levels of infliximab as defined by the study. Possible mechanisms would be higher doses of infliximab required by a subset of patients or piggy-backing the waning phase of the disease.3 What we can learn from this study is the importance of clearly defining loss of response before measuring any drug or antidrug antibody levels. Without the correct context of loss of response, interpretation of drug and antidrug antibody levels would be inappropriate, especially so when drug levels are found to be of therapeutic levels. When properly defined, customised treatment based on therapeutic drug monitoring will avoid unhelpful dose-intensification of biologics for some patients and be cost-efficient from a macro-economic level.
Nevertheless, I would like to congratulate the authors for undertaking the task of demonstrating the cost effectiveness of individualised biologic therapy for patients with complicated CD in the era of personalised medicine. Malcolm Tan Correspondence to Dr Malcolm Tan, Department of Gastroenterology and Hepatology, Changi General Hospital, 2 Simei Street 3, Singapore 529889, Singapore; [email protected] Competing interests None. Provenance and peer review Not commissioned; internally peer reviewed. To cite Tan M. Gut Published Online First: [please include Day Month Year] doi:10.1136/gutjnl-2014307877 Received 17 June 2014 Accepted 1 July 2014 Gut 2014;0:1. doi:10.1136/gutjnl-2014-307877
REFERENCES 1
2
3
Steenholdt C, Brynskov J, Thomsen OØ, et al. Individualised therapy is more cost-effective than dose intensification in patients with Crohn’s disease who lose response to anti-TNF treatment: a randomised, controlled trial. Gut 2014;63:919–27. Lahiff C, Safaie P, Awais A, et al. The Crohn’s disease activity index (CDAI) is similarly elevated in patients with Crohn’s disease and in patients with irritable bowel syndrome. Aliment Pharmacol Ther 2013;37:786–94. Solberg IC, Vatn MH, Høie O, et al.; IBSEN Study Group. Clinical course in Crohn’s disease: results of a Norwegian population-based ten-year follow-up study. Clin Gastroenterol Hepatol 2007;5:1430–8.
Gut Month 2014 Vol by 0 NoBMJ 0 1 Copyright Article author (or their employer) 2014. Produced Publishing Group Ltd (& BSG) under licence.
Downloaded from gut.bmj.com on July 16, 2014 - Published by group.bmj.com
Importance of defining loss of response before therapeutic drug monitoring Malcolm Tan Gut published online July 16, 2014
doi: 10.1136/gutjnl-2014-307877
Updated information and services can be found at: http://gut.bmj.com/content/early/2014/07/16/gutjnl-2014-307877.full.html
These include:
References
This article cites 3 articles, 1 of which can be accessed free at: http://gut.bmj.com/content/early/2014/07/16/gutjnl-2014-307877.full.html#ref-list-1
P
