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A proactive approach to therapeutic drug monitoring during maintenance therapy with infliximab in the treatment of inflammatory bowel diseases (IBDs) and other chronic immune-mediated inflammatory diseases significantly improves sustained disease control, compared with standard care, which was defined as no therapeutic drug monitoring, new research shows.
“This trial showed that therapeutic drug monitoring improved infliximab [maintenance] treatment by preventing disease flares without increasing drug consumption,” reported the authors of the study published in JAMA.
Infliximab and other tumor necrosis factor (TNF)–inhibitor drugs offer significant benefits in the treatment of IBDs and other chronic inflammatory diseases; however, up to 50% of patients become nonresponsive to the therapy within the first years of treatment, posing risks of disease worsening and possible organ damage.
To address the problem, therapeutic drug monitoring has been recommended, more so with IBD guidelines than rheumatoid arthritis; these have included measures such as dose adjustment or drug switching when there is evidence that disease control is not being maintained.
However, with low serum drug concentrations and the development of antidrug antibodies believed to be key indicators of a waning response, there is growing interest in a more proactive monitoring approach, involving scheduled assessments of serum and antibody levels, performed regardless of any signs of disease activity changes, and the provision of dosing adjustments, if needed.
In the earlier Norwegian Drug Monitoring (NORDRUM) A trial, first author Silje Watterdal Syversen, MD, PhD, of the division of rheumatology and research, Diakonhjemmet Hospital, Oslo, Norway, and colleagues evaluated the effects of the proactive drug monitoring approach during the initiation phase of infliximab treatment, but found no significant improvement in the study of 411 patients in terms of the primary outcome of remission rates.
For the current NORDRUM B trial, they sought to instead determine if benefits of the proactive therapeutic drug monitoring may be more apparent during the maintenance phase of infliximab treatment.
The trial involved 458 adults at 20 hospitals in Norway who had immune-mediated inflammatory diseases (IMIDs), including rheumatoid arthritis (n = 80), spondyloarthritis (n = 138), psoriatic arthritis (n = 54), ulcerative colitis (n = 81), Crohn’s disease (n = 68), or psoriasis (n = 37), and who were undergoing maintenance therapy with infliximab.
The patients, who had a median of about 40 weeks’ prior infliximab therapy, were randomized 1:1 to receive either proactive therapeutic drug monitoring, consisting of scheduled monitoring of serum drug levels and antidrug antibodies and adjustments in dose and intervals as needed according to a trial algorithm (n = 228), or standard infliximab therapy, without the regular drug and antibody level monitoring (n = 230).
Over a 52-week follow-up, the primary outcome of sustained disease control without disease worsening was significantly higher in the proactive therapeutic drug monitoring group (73.6%; n = 167) versus standard care (55.9%; n = 127; P < .001). The risk of disease worsening was meanwhile significantly greater with standard care versus proactive drug monitoring (hazard ratio, 2.1).
Serum infliximab levels remained within the therapeutic range throughout the study period in 30% of patients receiving proactive therapeutic drug monitoring, compared with 17% in the standard care group, and low serum infliximab levels (≤2 mg/L) occurred at least once during the study period among 19% and 27% of the two groups, respectively.
Clinically significant levels of antidrug antibodies (≥50 mcg/L) occurred in 9.2% of the therapeutic drug monitoring patients and 15.0% of the standard care group.
About 55% of patients were also using concomitant immunosuppressive therapy, and the findings were consistent among those who did and did not use the drugs. There no significant differences in adverse events between the therapeutic drug-monitoring (60%) and standard care groups (63%).
Importantly, while the mean dose of infliximab during the trial was 4.8 mg/kg in both groups, an increase in dosage after disease worsening was more common in the standard therapy group (51%) than in the therapeutic drug monitoring group (31.6%), underscoring the improved dose control provided with the proactive therapeutic drug monitoring, the authors note.
The findings suggest “proactive therapeutic drug monitoring might be more important during maintenance therapy, a period during which low drug levels could be an important risk factor for therapeutic failure,” the authors conclude.
In commenting to this news organizatin, Dr. Syversen noted that, despite the variety of IMIDs, there were no significant differences with IBDs or other disorders.
“Our data show consistent findings across all diseases included,” she said.
Furthermore, “in the present study, and [prior research] using the same definition of disease worsening, IBD patients in general had a comparable flare rate as compared to inflammatory arthritis.”
Caveats include severe illness, potential cost challenges
Commenting on the research, Stephen B. Hanauer, MD, noted that a potential exception to the lack of benefit previously observed during treatment induction could be patients with severe illness.
“In patients with more severe disease and in particular with low albumin, [which is] more common in IBD than other immune-mediated inflammatory diseases, there is rapid metabolism and clearance of monoclonal antibodies early that limit efficacy of standard induction dosing,” said Dr. Hanauer, a professor of medicine and medical director of the Digestive Health Center at Northwestern University, Chicago. 
Noting that the average duration of treatment in the study prior to randomization was nearly a year (about 40 weeks), he added that a key question is “How to initiate therapeutic drug monitoring earlier in course to further optimize induction and prevent loss of response in maintenance.”
Dr. Hanauer shared that, “in our practice, we use a combination of proactive and reactive therapeutic drug monitoring based on individual patients and their history with prior biologics.”
Findings may usher in ‘new era’ in immune-mediated inflammatory disease treatment
In an editorial published in JAMA with the study, Zachary S. Wallace, MD, and Jeffrey A. Sparks, MD, both of Harvard Medical School in Boston, further commented that “maintaining disease control in nearly 3 of 4 patients represents a meaningful improvement over standard care.”
However, key challenges with the approach include the potential need for additional nurses and others to help monitor patients, and associated costs, which insurance providers may not always cover, they noted.
Another consideration is a lack of effective tools for monitoring measures including antidrug antibodies, they added, and “additional clinical trials within specific disease subgroups are needed.”
However, addressing such barriers “may help introduce a new era in treatment approach to maintenance therapy for patients with immune-mediated inflammatory diseases,” the editorialists write.
Niels Vande Casteele, PharmD, PhD, an associate professor at the department of medicine, University of California, San Diego, and affiliate faculty, Skaggs School of Pharmacy & Pharmaceutical Sciences, commented that the study is “an important milestone in the field of therapeutic drug monitoring of biologics for immunoinflammatory diseases.”
“The ability of proactive therapeutic drug monitoring to achieve sustained disease control without increased drug consumption is [a] notable finding,” he said in an interview.
Noting a limitation, Dr. Casteele suggested the inclusion of more specific measures of disease activity could have provided clearer insights.
“In particular for gastrointestinal diseases, we know that symptoms do not correlate well with inflammatory disease activity,” he said. “As such, I would have preferred to see clinical symptoms being complemented with endoscopic and histologic finds to confirm disease activity.”
Ultimately, he said that the results suggest “proactive therapeutic drug monitoring is not required for all patients, but it is beneficial in some to achieve sustained disease control over a prolonged period of time.”
This study received funding by grants from the Norwegian Regional Health Authorities (interregional KLINBEFORSK grants) and the South-Eastern Norway Regional Health Authorities; study authors reported relationships with various pharmaceutical companies, including Pfizer, which makes infliximab. Dr. Wallace reported research support from Bristol Myers Squibb and Principia/Sanofi and consulting fees from Viela Bio, Zenas Biopharma, and MedPace. Dr. Sparks reported consultancy fees from AbbVie, Bristol Myers Squibb, Gilead, Inova Diagnostics, Janssen, Optum, and Pfizer. Dr. Hanauer is a consultant and lecturer for Abbvie, Janssen, and Takeda and consultant for Pfizer, Celltrion, Amgen, Samsung Bioepis. Dr. Casteele has received research grants and personal fees from R-Biopharm, Takeda and UCB; and personal fees from AcelaBio, Alimentiv, Celltrion, Prometheus, Procise DX, and Vividion for activities that were all outside of the reviewed study.
Help your patients better understand their IBD treatment options by sharing AGA’s patient education, “Living with IBD,” in the AGA GI Patient Center at www.gastro.org/IBD.
A proactive approach to therapeutic drug monitoring during maintenance therapy with infliximab in the treatment of inflammatory bowel diseases (IBDs) and other chronic immune-mediated inflammatory diseases significantly improves sustained disease control, compared with standard care, which was defined as no therapeutic drug monitoring, new research shows.
“This trial showed that therapeutic drug monitoring improved infliximab [maintenance] treatment by preventing disease flares without increasing drug consumption,” reported the authors of the study published in JAMA.
Infliximab and other tumor necrosis factor (TNF)–inhibitor drugs offer significant benefits in the treatment of IBDs and other chronic inflammatory diseases; however, up to 50% of patients become nonresponsive to the therapy within the first years of treatment, posing risks of disease worsening and possible organ damage.
To address the problem, therapeutic drug monitoring has been recommended, more so with IBD guidelines than rheumatoid arthritis; these have included measures such as dose adjustment or drug switching when there is evidence that disease control is not being maintained.
However, with low serum drug concentrations and the development of antidrug antibodies believed to be key indicators of a waning response, there is growing interest in a more proactive monitoring approach, involving scheduled assessments of serum and antibody levels, performed regardless of any signs of disease activity changes, and the provision of dosing adjustments, if needed.
In the earlier Norwegian Drug Monitoring (NORDRUM) A trial, first author Silje Watterdal Syversen, MD, PhD, of the division of rheumatology and research, Diakonhjemmet Hospital, Oslo, Norway, and colleagues evaluated the effects of the proactive drug monitoring approach during the initiation phase of infliximab treatment, but found no significant improvement in the study of 411 patients in terms of the primary outcome of remission rates.
For the current NORDRUM B trial, they sought to instead determine if benefits of the proactive therapeutic drug monitoring may be more apparent during the maintenance phase of infliximab treatment.
The trial involved 458 adults at 20 hospitals in Norway who had immune-mediated inflammatory diseases (IMIDs), including rheumatoid arthritis (n = 80), spondyloarthritis (n = 138), psoriatic arthritis (n = 54), ulcerative colitis (n = 81), Crohn’s disease (n = 68), or psoriasis (n = 37), and who were undergoing maintenance therapy with infliximab.
The patients, who had a median of about 40 weeks’ prior infliximab therapy, were randomized 1:1 to receive either proactive therapeutic drug monitoring, consisting of scheduled monitoring of serum drug levels and antidrug antibodies and adjustments in dose and intervals as needed according to a trial algorithm (n = 228), or standard infliximab therapy, without the regular drug and antibody level monitoring (n = 230).
Over a 52-week follow-up, the primary outcome of sustained disease control without disease worsening was significantly higher in the proactive therapeutic drug monitoring group (73.6%; n = 167) versus standard care (55.9%; n = 127; P < .001). The risk of disease worsening was meanwhile significantly greater with standard care versus proactive drug monitoring (hazard ratio, 2.1).
Serum infliximab levels remained within the therapeutic range throughout the study period in 30% of patients receiving proactive therapeutic drug monitoring, compared with 17% in the standard care group, and low serum infliximab levels (≤2 mg/L) occurred at least once during the study period among 19% and 27% of the two groups, respectively.
Clinically significant levels of antidrug antibodies (≥50 mcg/L) occurred in 9.2% of the therapeutic drug monitoring patients and 15.0% of the standard care group.
About 55% of patients were also using concomitant immunosuppressive therapy, and the findings were consistent among those who did and did not use the drugs. There no significant differences in adverse events between the therapeutic drug-monitoring (60%) and standard care groups (63%).
Importantly, while the mean dose of infliximab during the trial was 4.8 mg/kg in both groups, an increase in dosage after disease worsening was more common in the standard therapy group (51%) than in the therapeutic drug monitoring group (31.6%), underscoring the improved dose control provided with the proactive therapeutic drug monitoring, the authors note.
The findings suggest “proactive therapeutic drug monitoring might be more important during maintenance therapy, a period during which low drug levels could be an important risk factor for therapeutic failure,” the authors conclude.
In commenting to this news organizatin, Dr. Syversen noted that, despite the variety of IMIDs, there were no significant differences with IBDs or other disorders.
“Our data show consistent findings across all diseases included,” she said.
Furthermore, “in the present study, and [prior research] using the same definition of disease worsening, IBD patients in general had a comparable flare rate as compared to inflammatory arthritis.”
Caveats include severe illness, potential cost challenges
Commenting on the research, Stephen B. Hanauer, MD, noted that a potential exception to the lack of benefit previously observed during treatment induction could be patients with severe illness.
“In patients with more severe disease and in particular with low albumin, [which is] more common in IBD than other immune-mediated inflammatory diseases, there is rapid metabolism and clearance of monoclonal antibodies early that limit efficacy of standard induction dosing,” said Dr. Hanauer, a professor of medicine and medical director of the Digestive Health Center at Northwestern University, Chicago.
Noting that the average duration of treatment in the study prior to randomization was nearly a year (about 40 weeks), he added that a key question is “How to initiate therapeutic drug monitoring earlier in course to further optimize induction and prevent loss of response in maintenance.”
Dr. Hanauer shared that, “in our practice, we use a combination of proactive and reactive therapeutic drug monitoring based on individual patients and their history with prior biologics.”
Findings may usher in ‘new era’ in immune-mediated inflammatory disease treatment
In an editorial published in JAMA with the study, Zachary S. Wallace, MD, and Jeffrey A. Sparks, MD, both of Harvard Medical School in Boston, further commented that “maintaining disease control in nearly 3 of 4 patients represents a meaningful improvement over standard care.”
However, key challenges with the approach include the potential need for additional nurses and others to help monitor patients, and associated costs, which insurance providers may not always cover, they noted.
Another consideration is a lack of effective tools for monitoring measures including antidrug antibodies, they added, and “additional clinical trials within specific disease subgroups are needed.”
However, addressing such barriers “may help introduce a new era in treatment approach to maintenance therapy for patients with immune-mediated inflammatory diseases,” the editorialists write.
Niels Vande Casteele, PharmD, PhD, an associate professor at the department of medicine, University of California, San Diego, and affiliate faculty, Skaggs School of Pharmacy & Pharmaceutical Sciences, commented that the study is “an important milestone in the field of therapeutic drug monitoring of biologics for immunoinflammatory diseases.”
“The ability of proactive therapeutic drug monitoring to achieve sustained disease control without increased drug consumption is [a] notable finding,” he said in an interview.
Noting a limitation, Dr. Casteele suggested the inclusion of more specific measures of disease activity could have provided clearer insights.
“In particular for gastrointestinal diseases, we know that symptoms do not correlate well with inflammatory disease activity,” he said. “As such, I would have preferred to see clinical symptoms being complemented with endoscopic and histologic finds to confirm disease activity.”
Ultimately, he said that the results suggest “proactive therapeutic drug monitoring is not required for all patients, but it is beneficial in some to achieve sustained disease control over a prolonged period of time.”
This study received funding by grants from the Norwegian Regional Health Authorities (interregional KLINBEFORSK grants) and the South-Eastern Norway Regional Health Authorities; study authors reported relationships with various pharmaceutical companies, including Pfizer, which makes infliximab. Dr. Wallace reported research support from Bristol Myers Squibb and Principia/Sanofi and consulting fees from Viela Bio, Zenas Biopharma, and MedPace. Dr. Sparks reported consultancy fees from AbbVie, Bristol Myers Squibb, Gilead, Inova Diagnostics, Janssen, Optum, and Pfizer. Dr. Hanauer is a consultant and lecturer for Abbvie, Janssen, and Takeda and consultant for Pfizer, Celltrion, Amgen, Samsung Bioepis. Dr. Casteele has received research grants and personal fees from R-Biopharm, Takeda and UCB; and personal fees from AcelaBio, Alimentiv, Celltrion, Prometheus, Procise DX, and Vividion for activities that were all outside of the reviewed study.
Help your patients better understand their IBD treatment options by sharing AGA’s patient education, “Living with IBD,” in the AGA GI Patient Center at www.gastro.org/IBD.
A proactive approach to therapeutic drug monitoring during maintenance therapy with infliximab in the treatment of inflammatory bowel diseases (IBDs) and other chronic immune-mediated inflammatory diseases significantly improves sustained disease control, compared with standard care, which was defined as no therapeutic drug monitoring, new research shows.
“This trial showed that therapeutic drug monitoring improved infliximab [maintenance] treatment by preventing disease flares without increasing drug consumption,” reported the authors of the study published in JAMA.
Infliximab and other tumor necrosis factor (TNF)–inhibitor drugs offer significant benefits in the treatment of IBDs and other chronic inflammatory diseases; however, up to 50% of patients become nonresponsive to the therapy within the first years of treatment, posing risks of disease worsening and possible organ damage.
To address the problem, therapeutic drug monitoring has been recommended, more so with IBD guidelines than rheumatoid arthritis; these have included measures such as dose adjustment or drug switching when there is evidence that disease control is not being maintained.
However, with low serum drug concentrations and the development of antidrug antibodies believed to be key indicators of a waning response, there is growing interest in a more proactive monitoring approach, involving scheduled assessments of serum and antibody levels, performed regardless of any signs of disease activity changes, and the provision of dosing adjustments, if needed.
In the earlier Norwegian Drug Monitoring (NORDRUM) A trial, first author Silje Watterdal Syversen, MD, PhD, of the division of rheumatology and research, Diakonhjemmet Hospital, Oslo, Norway, and colleagues evaluated the effects of the proactive drug monitoring approach during the initiation phase of infliximab treatment, but found no significant improvement in the study of 411 patients in terms of the primary outcome of remission rates.
For the current NORDRUM B trial, they sought to instead determine if benefits of the proactive therapeutic drug monitoring may be more apparent during the maintenance phase of infliximab treatment.
The trial involved 458 adults at 20 hospitals in Norway who had immune-mediated inflammatory diseases (IMIDs), including rheumatoid arthritis (n = 80), spondyloarthritis (n = 138), psoriatic arthritis (n = 54), ulcerative colitis (n = 81), Crohn’s disease (n = 68), or psoriasis (n = 37), and who were undergoing maintenance therapy with infliximab.
The patients, who had a median of about 40 weeks’ prior infliximab therapy, were randomized 1:1 to receive either proactive therapeutic drug monitoring, consisting of scheduled monitoring of serum drug levels and antidrug antibodies and adjustments in dose and intervals as needed according to a trial algorithm (n = 228), or standard infliximab therapy, without the regular drug and antibody level monitoring (n = 230).
Over a 52-week follow-up, the primary outcome of sustained disease control without disease worsening was significantly higher in the proactive therapeutic drug monitoring group (73.6%; n = 167) versus standard care (55.9%; n = 127; P < .001). The risk of disease worsening was meanwhile significantly greater with standard care versus proactive drug monitoring (hazard ratio, 2.1).
Serum infliximab levels remained within the therapeutic range throughout the study period in 30% of patients receiving proactive therapeutic drug monitoring, compared with 17% in the standard care group, and low serum infliximab levels (≤2 mg/L) occurred at least once during the study period among 19% and 27% of the two groups, respectively.
Clinically significant levels of antidrug antibodies (≥50 mcg/L) occurred in 9.2% of the therapeutic drug monitoring patients and 15.0% of the standard care group.
About 55% of patients were also using concomitant immunosuppressive therapy, and the findings were consistent among those who did and did not use the drugs. There no significant differences in adverse events between the therapeutic drug-monitoring (60%) and standard care groups (63%).
Importantly, while the mean dose of infliximab during the trial was 4.8 mg/kg in both groups, an increase in dosage after disease worsening was more common in the standard therapy group (51%) than in the therapeutic drug monitoring group (31.6%), underscoring the improved dose control provided with the proactive therapeutic drug monitoring, the authors note.
The findings suggest “proactive therapeutic drug monitoring might be more important during maintenance therapy, a period during which low drug levels could be an important risk factor for therapeutic failure,” the authors conclude.
In commenting to this news organizatin, Dr. Syversen noted that, despite the variety of IMIDs, there were no significant differences with IBDs or other disorders.
“Our data show consistent findings across all diseases included,” she said.
Furthermore, “in the present study, and [prior research] using the same definition of disease worsening, IBD patients in general had a comparable flare rate as compared to inflammatory arthritis.”
Caveats include severe illness, potential cost challenges
Commenting on the research, Stephen B. Hanauer, MD, noted that a potential exception to the lack of benefit previously observed during treatment induction could be patients with severe illness.
“In patients with more severe disease and in particular with low albumin, [which is] more common in IBD than other immune-mediated inflammatory diseases, there is rapid metabolism and clearance of monoclonal antibodies early that limit efficacy of standard induction dosing,” said Dr. Hanauer, a professor of medicine and medical director of the Digestive Health Center at Northwestern University, Chicago.
Noting that the average duration of treatment in the study prior to randomization was nearly a year (about 40 weeks), he added that a key question is “How to initiate therapeutic drug monitoring earlier in course to further optimize induction and prevent loss of response in maintenance.”
Dr. Hanauer shared that, “in our practice, we use a combination of proactive and reactive therapeutic drug monitoring based on individual patients and their history with prior biologics.”
Findings may usher in ‘new era’ in immune-mediated inflammatory disease treatment
In an editorial published in JAMA with the study, Zachary S. Wallace, MD, and Jeffrey A. Sparks, MD, both of Harvard Medical School in Boston, further commented that “maintaining disease control in nearly 3 of 4 patients represents a meaningful improvement over standard care.”
However, key challenges with the approach include the potential need for additional nurses and others to help monitor patients, and associated costs, which insurance providers may not always cover, they noted.
Another consideration is a lack of effective tools for monitoring measures including antidrug antibodies, they added, and “additional clinical trials within specific disease subgroups are needed.”
However, addressing such barriers “may help introduce a new era in treatment approach to maintenance therapy for patients with immune-mediated inflammatory diseases,” the editorialists write.
Niels Vande Casteele, PharmD, PhD, an associate professor at the department of medicine, University of California, San Diego, and affiliate faculty, Skaggs School of Pharmacy & Pharmaceutical Sciences, commented that the study is “an important milestone in the field of therapeutic drug monitoring of biologics for immunoinflammatory diseases.”
“The ability of proactive therapeutic drug monitoring to achieve sustained disease control without increased drug consumption is [a] notable finding,” he said in an interview.
Noting a limitation, Dr. Casteele suggested the inclusion of more specific measures of disease activity could have provided clearer insights.
“In particular for gastrointestinal diseases, we know that symptoms do not correlate well with inflammatory disease activity,” he said. “As such, I would have preferred to see clinical symptoms being complemented with endoscopic and histologic finds to confirm disease activity.”
Ultimately, he said that the results suggest “proactive therapeutic drug monitoring is not required for all patients, but it is beneficial in some to achieve sustained disease control over a prolonged period of time.”
This study received funding by grants from the Norwegian Regional Health Authorities (interregional KLINBEFORSK grants) and the South-Eastern Norway Regional Health Authorities; study authors reported relationships with various pharmaceutical companies, including Pfizer, which makes infliximab. Dr. Wallace reported research support from Bristol Myers Squibb and Principia/Sanofi and consulting fees from Viela Bio, Zenas Biopharma, and MedPace. Dr. Sparks reported consultancy fees from AbbVie, Bristol Myers Squibb, Gilead, Inova Diagnostics, Janssen, Optum, and Pfizer. Dr. Hanauer is a consultant and lecturer for Abbvie, Janssen, and Takeda and consultant for Pfizer, Celltrion, Amgen, Samsung Bioepis. Dr. Casteele has received research grants and personal fees from R-Biopharm, Takeda and UCB; and personal fees from AcelaBio, Alimentiv, Celltrion, Prometheus, Procise DX, and Vividion for activities that were all outside of the reviewed study.
Help your patients better understand their IBD treatment options by sharing AGA’s patient education, “Living with IBD,” in the AGA GI Patient Center at www.gastro.org/IBD.
FROM JAMA