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"Deep remission" of Crohn’s disease is associated with better quality of life, physical function, and cost savings.
Moreover, this composite clinical and endoscopic endpoint may be best accomplished through monitoring of the tumor necrosis factor antagonists’ plasma concentration, meaning that the pharmacokinetics of these therapies must be accounted for when optimizing drug treatment.
Those are the findings from two new analyses in the March issue of Clinical Gastroenterology and Hepatology, both by Dr. Jean-Frédéric Colombel of the Mount Sinai Hospital School of Medicine in New York.
In the first study, Dr. Colombel and his colleagues looked at 135 adults with moderate to severe ileocolonic Crohn’s enrolled in the EXTEND trial, a 52-week, randomized, double-blind placebo-controlled trial of adalimumab (doi:10.1016/j.cgh.2013.06.019).
The goal of EXTEND was to assess the effect of induction plus maintenance dosing of adalimumab, versus induction only. All patients received open-label adalimumab (160 mg and 80 mg at weeks 0 and 2, respectively) during the 4-week induction phase and were randomized at week 4 to receive adalimumab 40 mg every other week or placebo.
Overall, 19% of patients who received both adalimumab induction and maintenance therapy achieved so-called deep remission, defined as the absence of mucosal ulceration plus clinical remission (Crohn’s Disease Activity Index [CDAI], less than 150). Of the remaining responders, 8 had an absence of mucosal ulceration without clinical remission, and 19 had clinical remission with persistent mucosal ulceration.
Dr. Colombel and his coinvestigators found that patients in deep remission registered significantly fewer days absent from work, less work productivity impairment, greater work productivity, and less daily nonwork activity impairment, compared with patients who did not achieve deep remission (P less than .05 for all).
Moreover, at 1 year after therapy induction, significantly more patients in the deep remission group achieved remission according to the Inflammatory Bowel Disease Questionnaire (64% vs. 26%; P less than .05) and normal Short Form–36 Health Survey status (55% vs. 19%; P less than .05), compared with patients who were not in deep remission.
Finally, during the 40 weeks after early deep remission achievement, estimated savings among deep remission patients were $6,117 for direct medical costs and $4,243 for indirect costs related to productivity, compared with the costs for patients not in deep remission.
"This treatment target in CD [of deep remission], which combines symptom control with an objective indicator of inflammatory disease activity, still is evolving," wrote the investigators.
However, "current analysis provides preliminary evidence that early [deep remission] is achievable and may be a useful treatment target," they added.
The second analysis, also by Dr. Colombel, looked at the optimization of TNF antagonists in Crohn’s disease – specifically, at certolizumab pegol (doi:10.1016/j.cgh.2013.10.025).
In this post hoc analysis, Dr. Colombel looked at patients enrolled in the MUSIC trial, a 54-week, multicenter, single-arm open-label study assessing endoscopic improvement in patients with moderate to severe Crohn’s disease.
All patients received loading doses of certolizumab pegol 400 mg at 0, 2, and 4 weeks, followed by a maintenance dose of 400 mg every 4 weeks.
The authors found that at week 10, patients who achieved a clinical and an endoscopic response had "nominally higher" trough plasma certolizumab pegol concentrations at week 8 than those with no response or remission (16.5 mcg/mL for patients with a clinical response and 19.8 mcg/mL for patients with an endoscopic response, vs. 13.7 mcg/mL and 11.5 mcg/mL in the clinical and endoscopic nonresponders).
Similarly, patients who achieved clinical and endoscopic remission at week 10 also had nominally higher trough plasma concentrations at week 8, with clinical remission patients registering 17.6 mcg/mL (vs. 11.1 mcg/mL in patients without clinical remission) and endoscopic remission patients measuring 19.2 mcg/mL (vs. 12.6 mcg/mL in patients who did not achieve that endpoint).
"Plasma certolizumab pegol concentration is not readily measured in standard clinical practice at this time," wrote the authors.
However, "additional studies are needed to understand the relationships among clinical response, body weight, and plasma concentration of the TNF antagonist," they added.
Dr. Colombel and his colleagues disclosed numerous financial relationships with pharmaceutical companies, including the makers of adalimumab and certolizumab pegol; the EXTEND trial was funded by AbbieVie, the maker of adalimumab, and the MUSIC trial was funded by UCB Pharma, maker of certolizumab pegol.
This month's issue of Clinical Gastroenterology and Hepatology contains two articles that explore important, novel concepts in the management of patients with Crohn's disease - that of mucosal healing as a potential therapeutic endpoint and that of therapeutic drug monitoring of tumor necrosis factor antagonists.
New endpoints are required because the currently accepted endpoint of a Crohn's Disease Activity Index score of less than 150 points does not optimally track with endoscopic healing, which appears to correlate with favorable longer-term outcomes such as reduced need for corticosteroids, hospitalizations, and major abdominal surgeries.
In a secondary analysis of the EXTEND trial (a study of endoscopic healing of Crohn's disease with adalimumab), the authors were able to show that patients who had achieved the endpoint of "deep remission" (that is, clinical remission and absence of ulcerations on endoscopy) by week 12 had fewer hospitalizations and surgeries than those who had not achieved deep remission.
Interestingly, those patients achieving deep remission had better outcomes than those who achieved endoscopic but not clinical remission, whereas there didn't appear to be an incremental benefit of achieving deep remission over clinical remission alone.
One should consider this a proof of concept study of the potential utility of deep remission as an endpoint, and we need to see prospective trials before concluding that deep remission is an endpoint to strive for in all of our patients.
The second article was a secondary analysis of the MUSIC trial (a study of endoscopic improvement of Crohn's disease with certolizumab pegol) and attempted to correlate certolizumab pegol concentrations with endoscopic response or remission.
The authors found that levels at week 8 were significantly associated with rates of endoscopic response and remission at week 10. They also found that higher body weight and serum C-reactive protein levels were associated with lower certolizumab levels.
This study corroborates evidence from other studies that concentrations of infliximab and adalimumab can be correlated to clinical outcomes.
Furthermore, the relationship between certolizumab plasma levels and other factors such as body weight and C-reactive protein levels highlights the complex pharmacokinetics of these biologic agents and underscores the potential need for therapeutic drug monitoring.
Dr. Edward V. Loftus Jr., AGAF, is professor of medicine and director, inflammatory bowel disease clinic, division of gastroenterology and hepatology, Mayo Clinic, Rochester, Minn. He is a consultant for AbbVie, UCB, Janssen, Takeda-Millennium, and Immune Pharmaceuticals and receives research support from AbbVie, UCB, Janssen, Takeda-Millennium, Pfizer, Amgen, Santarus, Robarts Clinical Trials, Bristol-Myers Squibb, GlaxoSmithKline, Genentech, Shire, and Braintree Labs.
This month's issue of Clinical Gastroenterology and Hepatology contains two articles that explore important, novel concepts in the management of patients with Crohn's disease - that of mucosal healing as a potential therapeutic endpoint and that of therapeutic drug monitoring of tumor necrosis factor antagonists.
New endpoints are required because the currently accepted endpoint of a Crohn's Disease Activity Index score of less than 150 points does not optimally track with endoscopic healing, which appears to correlate with favorable longer-term outcomes such as reduced need for corticosteroids, hospitalizations, and major abdominal surgeries.
In a secondary analysis of the EXTEND trial (a study of endoscopic healing of Crohn's disease with adalimumab), the authors were able to show that patients who had achieved the endpoint of "deep remission" (that is, clinical remission and absence of ulcerations on endoscopy) by week 12 had fewer hospitalizations and surgeries than those who had not achieved deep remission.
Interestingly, those patients achieving deep remission had better outcomes than those who achieved endoscopic but not clinical remission, whereas there didn't appear to be an incremental benefit of achieving deep remission over clinical remission alone.
One should consider this a proof of concept study of the potential utility of deep remission as an endpoint, and we need to see prospective trials before concluding that deep remission is an endpoint to strive for in all of our patients.
The second article was a secondary analysis of the MUSIC trial (a study of endoscopic improvement of Crohn's disease with certolizumab pegol) and attempted to correlate certolizumab pegol concentrations with endoscopic response or remission.
The authors found that levels at week 8 were significantly associated with rates of endoscopic response and remission at week 10. They also found that higher body weight and serum C-reactive protein levels were associated with lower certolizumab levels.
This study corroborates evidence from other studies that concentrations of infliximab and adalimumab can be correlated to clinical outcomes.
Furthermore, the relationship between certolizumab plasma levels and other factors such as body weight and C-reactive protein levels highlights the complex pharmacokinetics of these biologic agents and underscores the potential need for therapeutic drug monitoring.
Dr. Edward V. Loftus Jr., AGAF, is professor of medicine and director, inflammatory bowel disease clinic, division of gastroenterology and hepatology, Mayo Clinic, Rochester, Minn. He is a consultant for AbbVie, UCB, Janssen, Takeda-Millennium, and Immune Pharmaceuticals and receives research support from AbbVie, UCB, Janssen, Takeda-Millennium, Pfizer, Amgen, Santarus, Robarts Clinical Trials, Bristol-Myers Squibb, GlaxoSmithKline, Genentech, Shire, and Braintree Labs.
This month's issue of Clinical Gastroenterology and Hepatology contains two articles that explore important, novel concepts in the management of patients with Crohn's disease - that of mucosal healing as a potential therapeutic endpoint and that of therapeutic drug monitoring of tumor necrosis factor antagonists.
New endpoints are required because the currently accepted endpoint of a Crohn's Disease Activity Index score of less than 150 points does not optimally track with endoscopic healing, which appears to correlate with favorable longer-term outcomes such as reduced need for corticosteroids, hospitalizations, and major abdominal surgeries.
In a secondary analysis of the EXTEND trial (a study of endoscopic healing of Crohn's disease with adalimumab), the authors were able to show that patients who had achieved the endpoint of "deep remission" (that is, clinical remission and absence of ulcerations on endoscopy) by week 12 had fewer hospitalizations and surgeries than those who had not achieved deep remission.
Interestingly, those patients achieving deep remission had better outcomes than those who achieved endoscopic but not clinical remission, whereas there didn't appear to be an incremental benefit of achieving deep remission over clinical remission alone.
One should consider this a proof of concept study of the potential utility of deep remission as an endpoint, and we need to see prospective trials before concluding that deep remission is an endpoint to strive for in all of our patients.
The second article was a secondary analysis of the MUSIC trial (a study of endoscopic improvement of Crohn's disease with certolizumab pegol) and attempted to correlate certolizumab pegol concentrations with endoscopic response or remission.
The authors found that levels at week 8 were significantly associated with rates of endoscopic response and remission at week 10. They also found that higher body weight and serum C-reactive protein levels were associated with lower certolizumab levels.
This study corroborates evidence from other studies that concentrations of infliximab and adalimumab can be correlated to clinical outcomes.
Furthermore, the relationship between certolizumab plasma levels and other factors such as body weight and C-reactive protein levels highlights the complex pharmacokinetics of these biologic agents and underscores the potential need for therapeutic drug monitoring.
Dr. Edward V. Loftus Jr., AGAF, is professor of medicine and director, inflammatory bowel disease clinic, division of gastroenterology and hepatology, Mayo Clinic, Rochester, Minn. He is a consultant for AbbVie, UCB, Janssen, Takeda-Millennium, and Immune Pharmaceuticals and receives research support from AbbVie, UCB, Janssen, Takeda-Millennium, Pfizer, Amgen, Santarus, Robarts Clinical Trials, Bristol-Myers Squibb, GlaxoSmithKline, Genentech, Shire, and Braintree Labs.
"Deep remission" of Crohn’s disease is associated with better quality of life, physical function, and cost savings.
Moreover, this composite clinical and endoscopic endpoint may be best accomplished through monitoring of the tumor necrosis factor antagonists’ plasma concentration, meaning that the pharmacokinetics of these therapies must be accounted for when optimizing drug treatment.
Those are the findings from two new analyses in the March issue of Clinical Gastroenterology and Hepatology, both by Dr. Jean-Frédéric Colombel of the Mount Sinai Hospital School of Medicine in New York.
In the first study, Dr. Colombel and his colleagues looked at 135 adults with moderate to severe ileocolonic Crohn’s enrolled in the EXTEND trial, a 52-week, randomized, double-blind placebo-controlled trial of adalimumab (doi:10.1016/j.cgh.2013.06.019).
The goal of EXTEND was to assess the effect of induction plus maintenance dosing of adalimumab, versus induction only. All patients received open-label adalimumab (160 mg and 80 mg at weeks 0 and 2, respectively) during the 4-week induction phase and were randomized at week 4 to receive adalimumab 40 mg every other week or placebo.
Overall, 19% of patients who received both adalimumab induction and maintenance therapy achieved so-called deep remission, defined as the absence of mucosal ulceration plus clinical remission (Crohn’s Disease Activity Index [CDAI], less than 150). Of the remaining responders, 8 had an absence of mucosal ulceration without clinical remission, and 19 had clinical remission with persistent mucosal ulceration.
Dr. Colombel and his coinvestigators found that patients in deep remission registered significantly fewer days absent from work, less work productivity impairment, greater work productivity, and less daily nonwork activity impairment, compared with patients who did not achieve deep remission (P less than .05 for all).
Moreover, at 1 year after therapy induction, significantly more patients in the deep remission group achieved remission according to the Inflammatory Bowel Disease Questionnaire (64% vs. 26%; P less than .05) and normal Short Form–36 Health Survey status (55% vs. 19%; P less than .05), compared with patients who were not in deep remission.
Finally, during the 40 weeks after early deep remission achievement, estimated savings among deep remission patients were $6,117 for direct medical costs and $4,243 for indirect costs related to productivity, compared with the costs for patients not in deep remission.
"This treatment target in CD [of deep remission], which combines symptom control with an objective indicator of inflammatory disease activity, still is evolving," wrote the investigators.
However, "current analysis provides preliminary evidence that early [deep remission] is achievable and may be a useful treatment target," they added.
The second analysis, also by Dr. Colombel, looked at the optimization of TNF antagonists in Crohn’s disease – specifically, at certolizumab pegol (doi:10.1016/j.cgh.2013.10.025).
In this post hoc analysis, Dr. Colombel looked at patients enrolled in the MUSIC trial, a 54-week, multicenter, single-arm open-label study assessing endoscopic improvement in patients with moderate to severe Crohn’s disease.
All patients received loading doses of certolizumab pegol 400 mg at 0, 2, and 4 weeks, followed by a maintenance dose of 400 mg every 4 weeks.
The authors found that at week 10, patients who achieved a clinical and an endoscopic response had "nominally higher" trough plasma certolizumab pegol concentrations at week 8 than those with no response or remission (16.5 mcg/mL for patients with a clinical response and 19.8 mcg/mL for patients with an endoscopic response, vs. 13.7 mcg/mL and 11.5 mcg/mL in the clinical and endoscopic nonresponders).
Similarly, patients who achieved clinical and endoscopic remission at week 10 also had nominally higher trough plasma concentrations at week 8, with clinical remission patients registering 17.6 mcg/mL (vs. 11.1 mcg/mL in patients without clinical remission) and endoscopic remission patients measuring 19.2 mcg/mL (vs. 12.6 mcg/mL in patients who did not achieve that endpoint).
"Plasma certolizumab pegol concentration is not readily measured in standard clinical practice at this time," wrote the authors.
However, "additional studies are needed to understand the relationships among clinical response, body weight, and plasma concentration of the TNF antagonist," they added.
Dr. Colombel and his colleagues disclosed numerous financial relationships with pharmaceutical companies, including the makers of adalimumab and certolizumab pegol; the EXTEND trial was funded by AbbieVie, the maker of adalimumab, and the MUSIC trial was funded by UCB Pharma, maker of certolizumab pegol.
"Deep remission" of Crohn’s disease is associated with better quality of life, physical function, and cost savings.
Moreover, this composite clinical and endoscopic endpoint may be best accomplished through monitoring of the tumor necrosis factor antagonists’ plasma concentration, meaning that the pharmacokinetics of these therapies must be accounted for when optimizing drug treatment.
Those are the findings from two new analyses in the March issue of Clinical Gastroenterology and Hepatology, both by Dr. Jean-Frédéric Colombel of the Mount Sinai Hospital School of Medicine in New York.
In the first study, Dr. Colombel and his colleagues looked at 135 adults with moderate to severe ileocolonic Crohn’s enrolled in the EXTEND trial, a 52-week, randomized, double-blind placebo-controlled trial of adalimumab (doi:10.1016/j.cgh.2013.06.019).
The goal of EXTEND was to assess the effect of induction plus maintenance dosing of adalimumab, versus induction only. All patients received open-label adalimumab (160 mg and 80 mg at weeks 0 and 2, respectively) during the 4-week induction phase and were randomized at week 4 to receive adalimumab 40 mg every other week or placebo.
Overall, 19% of patients who received both adalimumab induction and maintenance therapy achieved so-called deep remission, defined as the absence of mucosal ulceration plus clinical remission (Crohn’s Disease Activity Index [CDAI], less than 150). Of the remaining responders, 8 had an absence of mucosal ulceration without clinical remission, and 19 had clinical remission with persistent mucosal ulceration.
Dr. Colombel and his coinvestigators found that patients in deep remission registered significantly fewer days absent from work, less work productivity impairment, greater work productivity, and less daily nonwork activity impairment, compared with patients who did not achieve deep remission (P less than .05 for all).
Moreover, at 1 year after therapy induction, significantly more patients in the deep remission group achieved remission according to the Inflammatory Bowel Disease Questionnaire (64% vs. 26%; P less than .05) and normal Short Form–36 Health Survey status (55% vs. 19%; P less than .05), compared with patients who were not in deep remission.
Finally, during the 40 weeks after early deep remission achievement, estimated savings among deep remission patients were $6,117 for direct medical costs and $4,243 for indirect costs related to productivity, compared with the costs for patients not in deep remission.
"This treatment target in CD [of deep remission], which combines symptom control with an objective indicator of inflammatory disease activity, still is evolving," wrote the investigators.
However, "current analysis provides preliminary evidence that early [deep remission] is achievable and may be a useful treatment target," they added.
The second analysis, also by Dr. Colombel, looked at the optimization of TNF antagonists in Crohn’s disease – specifically, at certolizumab pegol (doi:10.1016/j.cgh.2013.10.025).
In this post hoc analysis, Dr. Colombel looked at patients enrolled in the MUSIC trial, a 54-week, multicenter, single-arm open-label study assessing endoscopic improvement in patients with moderate to severe Crohn’s disease.
All patients received loading doses of certolizumab pegol 400 mg at 0, 2, and 4 weeks, followed by a maintenance dose of 400 mg every 4 weeks.
The authors found that at week 10, patients who achieved a clinical and an endoscopic response had "nominally higher" trough plasma certolizumab pegol concentrations at week 8 than those with no response or remission (16.5 mcg/mL for patients with a clinical response and 19.8 mcg/mL for patients with an endoscopic response, vs. 13.7 mcg/mL and 11.5 mcg/mL in the clinical and endoscopic nonresponders).
Similarly, patients who achieved clinical and endoscopic remission at week 10 also had nominally higher trough plasma concentrations at week 8, with clinical remission patients registering 17.6 mcg/mL (vs. 11.1 mcg/mL in patients without clinical remission) and endoscopic remission patients measuring 19.2 mcg/mL (vs. 12.6 mcg/mL in patients who did not achieve that endpoint).
"Plasma certolizumab pegol concentration is not readily measured in standard clinical practice at this time," wrote the authors.
However, "additional studies are needed to understand the relationships among clinical response, body weight, and plasma concentration of the TNF antagonist," they added.
Dr. Colombel and his colleagues disclosed numerous financial relationships with pharmaceutical companies, including the makers of adalimumab and certolizumab pegol; the EXTEND trial was funded by AbbieVie, the maker of adalimumab, and the MUSIC trial was funded by UCB Pharma, maker of certolizumab pegol.
FROM CLINICAL GASTROENTEROLOGY AND HEPATOLOGY
Major finding: Deep remission in Crohn’s disease is a novel and useful treatment target; reaching it may depend on monitoring blood levels of the drugs used to treat the disease.
Data source: Analyses of the EXTEND and MUSIC trials.
Disclosures: Dr. Colombel and his colleagues disclosed numerous financial relationships with pharmaceutical companies, including the makers of adalimumab and certolizumab pegol; the EXTEND trial was funded by AbbieVie, the maker of adalimumab, and the MUSIC trial was funded by UCB Pharma, maker of certolizumab pegol.
