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Monocytosis as a Biomarker to Predict Relapse in Patients with Inflammatory Bowel Disease Under Maintenance Treatment with Anti-TNF Drugs: A Prospective, Longitudinal Cohort Study
AGA Abstracts
drug level monitoring could optimise anti-TNF use, it could also be associated with cost savings, but the long-term cost savings are unknown. Not only this, it is likely that it will optimise the use of anti-TNF therapy and guide on future therapies improving long-term patient outcomes. Our aim is to show that the use of therapeutic drug level and antibody monitoring is associated with cost savings by stopping unnecessary anti-TNF, or dose deescalation of therapy. Methods. By interrogating our local IBD database and searching patient records we identified all patients receiving anti-TNF therapy, the indication for performing therapeutic drug and antibody levels. We identified patients in which results of the drug levels and antibody status alone influenced the future treatment strategy, then calculated the costs and cost savings made when treatment was altered. Maintenance therapy with biosimilar Remsima costs £3510 per year, calculations were based on the assumption that all patients were receiving Remsima. Results 104 patients receiving infliximab between 2013 and 2016 had infliximab levels checked at a total cost of £7280. 26 (25%) patients were identified as having their treatment changed as a direct result of the drug levels and antibody status. 18 (69%) patients in remission with positive antibodies and undetectable trough levels had infliximab withdrawn with an annual cost saving of £63,180. 6 patients in remission had the Remsima dosing interval lengthened to 12 weeks due to high trough levels of infliximab with a cost saving of £7020 per annum 2 patients had the Remsima interval reduced to 6 weeks based on low drug trough level at an increased cost of £3510 per annum. No patient had a change in biologic drug based on drug levels alone. The total annual cost saving from the introduction of therapeutic drug level and antibody monitoring was £59,410 based on using Remsima. This cost saving would be increased to £140,920 if originator infliximab had been used. Conclusions. The use of therapeutic drug monitoring at a district general hospital leads to significant cost savings in the use of infliximab therapy.
Sa1922 MONOCYTOSIS AS A BIOMARKER TO PREDICT RELAPSE IN PATIENTS WITH INFLAMMATORY BOWEL DISEASE UNDER MAINTENANCE TREATMENT WITH ANTI-TNF DRUGS: A PROSPECTIVE, LONGITUDINAL COHORT STUDY Rocio Ferreiro, Javier Lopez-Diaz, Manuel Barreiro, J. Enrique Dominguez-Muñoz Background and aim: Monocytes play an important role in the pathogenesis of inflammatory bowel disease (IBD). These cells have been recently shown to be a biomarker of activity, but specific data in patients under biologic therapies are lacking. The aim of the study was to evaluate the accuracy of monocyte quantification in predicting flares in IBD patients under maintenance treatment with anti-TNF drugs. Methods: A prospective, longitudinal cohort study was designed. Inclusion criteria were IBD patients in clinical remission for at least six months under a continuous standard dose of 40mg/eow adalimumab therapy or 5mg/kg infliximab therapy every 8 weeks. Relapse was defined as a Harvey-Bradshaw score >4 in Crohn's disease and a partial Mayo score>3 in ulcerative colitis. Monocytes were quantified at 4-month intervals for twelve months. Monocytosis was defined as a monocyte count higher than 800 cells/µL. All patients completed a demographic and clinical questionnaire at baseline. Diagnostic accuracy of monocytosis for predicting relapse was evaluated by ROC curve analysis. Results: 95 consecutive patients were included. The median age was 44 years, 51% female and 75% with Crohn's disease. 65 (68.4%) patients remained in clinical remission and 30 (31.6%) suffered from a relapse during the follow-up period. Median monocyte concentration in the sample preceding the relapse was 500 cells/µL (range 300-1000 cells/ µL) compared to 400 cells/µL (range 0-700 cells/µL) at the end of follow-up in patients who kept in remission. Monocytosis was significantly associated with IBD relapse [OR 7.13 (95%CI 1.54-32.8)]. Specificity of monocytosis to predict relapse was 95.4%, and sensitivity 23.3%. The area under the ROC curve was 0.59, 95%CI 0.49-0.69. Conclusions: Although the specificity of the presence of monocytosis is high to predict relapse in IBD patients under anti-TNF therapy, its sensitivity is very low, thus precluding the use of this marker in clinical practice.
Sa1921 ASSESSMENT OF THE USE OF THERAPEUTIC DRUG MONITORING OF ADALIMUMAB ON MAINTENANCE THERAPY IN CHILDREN WITH INFLAMMATORY BOWEL DISEASE Mallory Chavannes, France Gervais, Alexandra Verreault, Colette Deslandres, Prevost Jantchou
Sa1923 Background: Adalimumab (ADA) is effective in the induction and maintenance of remission in pediatric Crohn's disease (CD). Pharmacokinetics analysis of the IMAgINE-1 study demonstrated that a higher ADA concentration is associated with greater rates of remission. Data remains scarce in terms of which level is predictive of clinical remission in pediatric patients. Moreover, few study, have established the rate of anti-adalimumab antibody (AAA) in this population. Aims: To review our experience with therapeutic drug monitoring (TDM) in children with CD and Ulcerative colitis (UC) treated with ADA. The primary objective was to assess the serum levels of ADA in children aged 5-18 years during maintenance. We also aim to 1) establish the rate of AAA in our population and 2) correlate the levels of ADA with clinical response. Methods: This was a single-center retrospective cohort study. Patients were included if they had at least one serum level of ADA/AAA drawn between June 2014 and November 2016. ADA and AAA analysis were performed in a central lab using a classic ELISA technique. We collected biochemical inflammatory markers drawn the same day or, if missing, at a maximum of two weeks prior to the ADA level. The physician global assessment (PGA) was also recorded if it was done within 4 weeks of the ADA level. Results: In our database, we identified 95 patients treated with ADA during the study period. Fiftyeight (61%) had at least 1 ADA level drawn (47 with CD, 9 patients with UC and 2 with Indeterminate colitis). The 2 patients with indeterminate colitis were excluded. ADA was started with a median of 1.5 years from diagnosis. Eleven patients (19%), all with CD, had not received infliximab prior to initiating ADA. We collected 97 ADA levels (84% in CD). The overall median ADA level was 12 ug/mL, with a median dose of 0.74 mg/Kg/ injection and a median frequency of every 14 days. Four patients, all with CD, developed AAA (7.14%). A weekly administration was associated with a higher drug level (14.8 vs 10.1 ug/ mL, p=0.0011). At the time of ADA dosage, 47 (55.3%) levels were linked with a clinical remission. An ADA level above 10 correlated with remission according to PGA with a sensitivity of 76% and a specificity of 47.4% (p= 0.0205). AAA and previous infliximab exposure correlated with a lower ADA level (p= 0.0016 and 0.0448 respectively). Combination therapy improved ADA levels in all patients, but the median level increased more significantly in patients previously exposed to infliximab (p= 0.0369). More details are displayed in table 1. Conclusion: ADA levels are a useful tool in monitoring therapy in children with CD or UC. Aiming for levels above 10 ug/mL could be a target, as it correlates with clinical remission. Combination therapy helps to improve ADA levels. Prospective studies are required to better assess the role of TDM with ADA therapy. Summary of Results
AGA Abstracts
SERUM ADALIMUMAB LEVELS PREDICT SUCCESSFUL REMISSION AND SAFE DE-INTENSIFICATION IN INFLAMMATORY BOWEL DISEASE PATIENTS IN CLINICAL PRACTICE Mariam Aguas, Virginia Bosó, Belén Navarro, Maria Remedios Marques-Miñana, Guillermo Bastida, Belen Beltran, Marisa Iborra, Emilio Monte-Boquet, Jose Luis PovedaAndrés, Pilar Nos BACKGROUND: Little is known about the association between the pharmacokinetic features of adalimumab (ADL) and disease outcome in patients with inflammatory bowel disease (IBD). AIMS: To assess the association between random serum ADL levels and clinical and biochemical remission and between ADL levels and clinical decision making in daily practice. To determine the cut-off value for successful dose reduction in IBD patients treated with ADL. METHODS: We conducted a prospective cohort study of IBD patients who received maintenance therapy with ADL. All patients received induction with ADL (160 mg and 80 mg at weeks 0 and 2) and were maintained on either 40 mg every week or every other week. All ADL samples were drawn after patients had been receiving their maintenance dose for at least 12 weeks. Serum samples were obtained between March 2014 and December 2015. The inclusion criteria were age >15 years and diagnosis of CD or UC according to internationally accepted criteria (1,2). The exclusion criteria were ulcerative proctitis, therapy with ADL for perianal disease or extra-intestinal manifestations, ileostomy, and short bowel syndrome. RESULTS: Data were available for 157 serum samples from 87 patients. Serum ADL levels were associated with clinical remission: median 9.2 µg/ml vs 6.0 µg/ml for Crohn's disease patients with active disease (p=0.009) and 14.4 µg/ml vs 5.2 µg/ml for ulcerative colitis patients with active disease (p=0.002). Serum ADL levels were 9.2 µg/ml for patients with a normal C-reactive protein (CRP) value (<5 mg/l) and 5.2 µg/ml for patients with a high CRP value (p=0.002) FIG 1. ADL levels were significantly associated with normal fecal calprotectin values (<80ng/g) (10.8 µg/ml vs 7.6, respectively, p=0.038). We analyzed the clinical decisions taken on the basis of serum ADA levels according to the cut-off values described in previous studies (8 µg/ml). Figure 2 describes patients' drug levels according to the clinical decision taken. Serum ADL levels were significantly associated with successful de-intensification compared with the group in which doses remained unchanged (AUC 0.88; 95%CI: 0.81-0.95; p<0.001). The cut-off value for successful deintensification was 12.2 µg/ml. CONCLUSIONS: Higher ADL levels were significantly associated with clinical and biochemical remission. Our results, which were obtained under conditions of daily clinical practice, suggest that an ADL cut-off of 12.2 µg/ml is appropriate for successful dose reduction in IBD patients treated with ADL.
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drug level monitoring could optimise anti-TNF use, it could also be associated with cost savings, but the long-term cost savings are unknown. Not only this, it is likely that it will optimise the use of anti-TNF therapy and guide on future therapies improving long-term patient outcomes. Our aim is to show that the use of therapeutic drug level and antibody monitoring is associated with cost savings by stopping unnecessary anti-TNF, or dose deescalation of therapy. Methods. By interrogating our local IBD database and searching patient records we identified all patients receiving anti-TNF therapy, the indication for performing therapeutic drug and antibody levels. We identified patients in which results of the drug levels and antibody status alone influenced the future treatment strategy, then calculated the costs and cost savings made when treatment was altered. Maintenance therapy with biosimilar Remsima costs £3510 per year, calculations were based on the assumption that all patients were receiving Remsima. Results 104 patients receiving infliximab between 2013 and 2016 had infliximab levels checked at a total cost of £7280. 26 (25%) patients were identified as having their treatment changed as a direct result of the drug levels and antibody status. 18 (69%) patients in remission with positive antibodies and undetectable trough levels had infliximab withdrawn with an annual cost saving of £63,180. 6 patients in remission had the Remsima dosing interval lengthened to 12 weeks due to high trough levels of infliximab with a cost saving of £7020 per annum 2 patients had the Remsima interval reduced to 6 weeks based on low drug trough level at an increased cost of £3510 per annum. No patient had a change in biologic drug based on drug levels alone. The total annual cost saving from the introduction of therapeutic drug level and antibody monitoring was £59,410 based on using Remsima. This cost saving would be increased to £140,920 if originator infliximab had been used. Conclusions. The use of therapeutic drug monitoring at a district general hospital leads to significant cost savings in the use of infliximab therapy.
Sa1922 MONOCYTOSIS AS A BIOMARKER TO PREDICT RELAPSE IN PATIENTS WITH INFLAMMATORY BOWEL DISEASE UNDER MAINTENANCE TREATMENT WITH ANTI-TNF DRUGS: A PROSPECTIVE, LONGITUDINAL COHORT STUDY Rocio Ferreiro, Javier Lopez-Diaz, Manuel Barreiro, J. Enrique Dominguez-Muñoz Background and aim: Monocytes play an important role in the pathogenesis of inflammatory bowel disease (IBD). These cells have been recently shown to be a biomarker of activity, but specific data in patients under biologic therapies are lacking. The aim of the study was to evaluate the accuracy of monocyte quantification in predicting flares in IBD patients under maintenance treatment with anti-TNF drugs. Methods: A prospective, longitudinal cohort study was designed. Inclusion criteria were IBD patients in clinical remission for at least six months under a continuous standard dose of 40mg/eow adalimumab therapy or 5mg/kg infliximab therapy every 8 weeks. Relapse was defined as a Harvey-Bradshaw score >4 in Crohn's disease and a partial Mayo score>3 in ulcerative colitis. Monocytes were quantified at 4-month intervals for twelve months. Monocytosis was defined as a monocyte count higher than 800 cells/µL. All patients completed a demographic and clinical questionnaire at baseline. Diagnostic accuracy of monocytosis for predicting relapse was evaluated by ROC curve analysis. Results: 95 consecutive patients were included. The median age was 44 years, 51% female and 75% with Crohn's disease. 65 (68.4%) patients remained in clinical remission and 30 (31.6%) suffered from a relapse during the follow-up period. Median monocyte concentration in the sample preceding the relapse was 500 cells/µL (range 300-1000 cells/ µL) compared to 400 cells/µL (range 0-700 cells/µL) at the end of follow-up in patients who kept in remission. Monocytosis was significantly associated with IBD relapse [OR 7.13 (95%CI 1.54-32.8)]. Specificity of monocytosis to predict relapse was 95.4%, and sensitivity 23.3%. The area under the ROC curve was 0.59, 95%CI 0.49-0.69. Conclusions: Although the specificity of the presence of monocytosis is high to predict relapse in IBD patients under anti-TNF therapy, its sensitivity is very low, thus precluding the use of this marker in clinical practice.
Sa1921 ASSESSMENT OF THE USE OF THERAPEUTIC DRUG MONITORING OF ADALIMUMAB ON MAINTENANCE THERAPY IN CHILDREN WITH INFLAMMATORY BOWEL DISEASE Mallory Chavannes, France Gervais, Alexandra Verreault, Colette Deslandres, Prevost Jantchou
Sa1923 Background: Adalimumab (ADA) is effective in the induction and maintenance of remission in pediatric Crohn's disease (CD). Pharmacokinetics analysis of the IMAgINE-1 study demonstrated that a higher ADA concentration is associated with greater rates of remission. Data remains scarce in terms of which level is predictive of clinical remission in pediatric patients. Moreover, few study, have established the rate of anti-adalimumab antibody (AAA) in this population. Aims: To review our experience with therapeutic drug monitoring (TDM) in children with CD and Ulcerative colitis (UC) treated with ADA. The primary objective was to assess the serum levels of ADA in children aged 5-18 years during maintenance. We also aim to 1) establish the rate of AAA in our population and 2) correlate the levels of ADA with clinical response. Methods: This was a single-center retrospective cohort study. Patients were included if they had at least one serum level of ADA/AAA drawn between June 2014 and November 2016. ADA and AAA analysis were performed in a central lab using a classic ELISA technique. We collected biochemical inflammatory markers drawn the same day or, if missing, at a maximum of two weeks prior to the ADA level. The physician global assessment (PGA) was also recorded if it was done within 4 weeks of the ADA level. Results: In our database, we identified 95 patients treated with ADA during the study period. Fiftyeight (61%) had at least 1 ADA level drawn (47 with CD, 9 patients with UC and 2 with Indeterminate colitis). The 2 patients with indeterminate colitis were excluded. ADA was started with a median of 1.5 years from diagnosis. Eleven patients (19%), all with CD, had not received infliximab prior to initiating ADA. We collected 97 ADA levels (84% in CD). The overall median ADA level was 12 ug/mL, with a median dose of 0.74 mg/Kg/ injection and a median frequency of every 14 days. Four patients, all with CD, developed AAA (7.14%). A weekly administration was associated with a higher drug level (14.8 vs 10.1 ug/ mL, p=0.0011). At the time of ADA dosage, 47 (55.3%) levels were linked with a clinical remission. An ADA level above 10 correlated with remission according to PGA with a sensitivity of 76% and a specificity of 47.4% (p= 0.0205). AAA and previous infliximab exposure correlated with a lower ADA level (p= 0.0016 and 0.0448 respectively). Combination therapy improved ADA levels in all patients, but the median level increased more significantly in patients previously exposed to infliximab (p= 0.0369). More details are displayed in table 1. Conclusion: ADA levels are a useful tool in monitoring therapy in children with CD or UC. Aiming for levels above 10 ug/mL could be a target, as it correlates with clinical remission. Combination therapy helps to improve ADA levels. Prospective studies are required to better assess the role of TDM with ADA therapy. Summary of Results
AGA Abstracts
SERUM ADALIMUMAB LEVELS PREDICT SUCCESSFUL REMISSION AND SAFE DE-INTENSIFICATION IN INFLAMMATORY BOWEL DISEASE PATIENTS IN CLINICAL PRACTICE Mariam Aguas, Virginia Bosó, Belén Navarro, Maria Remedios Marques-Miñana, Guillermo Bastida, Belen Beltran, Marisa Iborra, Emilio Monte-Boquet, Jose Luis PovedaAndrés, Pilar Nos BACKGROUND: Little is known about the association between the pharmacokinetic features of adalimumab (ADL) and disease outcome in patients with inflammatory bowel disease (IBD). AIMS: To assess the association between random serum ADL levels and clinical and biochemical remission and between ADL levels and clinical decision making in daily practice. To determine the cut-off value for successful dose reduction in IBD patients treated with ADL. METHODS: We conducted a prospective cohort study of IBD patients who received maintenance therapy with ADL. All patients received induction with ADL (160 mg and 80 mg at weeks 0 and 2) and were maintained on either 40 mg every week or every other week. All ADL samples were drawn after patients had been receiving their maintenance dose for at least 12 weeks. Serum samples were obtained between March 2014 and December 2015. The inclusion criteria were age >15 years and diagnosis of CD or UC according to internationally accepted criteria (1,2). The exclusion criteria were ulcerative proctitis, therapy with ADL for perianal disease or extra-intestinal manifestations, ileostomy, and short bowel syndrome. RESULTS: Data were available for 157 serum samples from 87 patients. Serum ADL levels were associated with clinical remission: median 9.2 µg/ml vs 6.0 µg/ml for Crohn's disease patients with active disease (p=0.009) and 14.4 µg/ml vs 5.2 µg/ml for ulcerative colitis patients with active disease (p=0.002). Serum ADL levels were 9.2 µg/ml for patients with a normal C-reactive protein (CRP) value (<5 mg/l) and 5.2 µg/ml for patients with a high CRP value (p=0.002) FIG 1. ADL levels were significantly associated with normal fecal calprotectin values (<80ng/g) (10.8 µg/ml vs 7.6, respectively, p=0.038). We analyzed the clinical decisions taken on the basis of serum ADA levels according to the cut-off values described in previous studies (8 µg/ml). Figure 2 describes patients' drug levels according to the clinical decision taken. Serum ADL levels were significantly associated with successful de-intensification compared with the group in which doses remained unchanged (AUC 0.88; 95%CI: 0.81-0.95; p<0.001). The cut-off value for successful deintensification was 12.2 µg/ml. CONCLUSIONS: Higher ADL levels were significantly associated with clinical and biochemical remission. Our results, which were obtained under conditions of daily clinical practice, suggest that an ADL cut-off of 12.2 µg/ml is appropriate for successful dose reduction in IBD patients treated with ADL.
S-394