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491 Prediction of Clinical Response and Mucosal Healing At One Year by Faecal Calprotectin Assay After Induction With Anti-TNF Alpha Agents in IBD Patients
AGA Abstracts 491 Prediction of Clinical Response and Mucosal Healing At One Year by Faecal Calprotectin Assay After Induction With Anti-TNF Alpha Agents in IBD Patients Luisa Guidi, Manuela Marzo, Gianluca Andrisani, Carla Felice, Daniela Pugliese, Italo De Vitis, Alfredo Papa, Franca Forni, Gian Ludovico Rapaccini, Alessandro Armuzzi
Figure 1: Unadjusted 2-Propanol in Plasma Headspace (units ppb) 490
Faecal calprotectin (FC) is a protein present in the cytosol of neutrophil granulocytes and of macrophages that is released in the biological fluids under inflammatory conditions. FC levels seem to be correlated with active inflammation in inflammatory bowel diseases (IBD), Crohn's Disease (CD) and Ulcerative Colitis (UC). Non-invasive markers of response to biological therapy in IBD are needed to limit current routine investigations that are expensive and invasive. The aim of our study is to evaluate the role of FC as a non invasive marker of inflammation in order to monitor and predict the effect of therapy with TNF α-antagonists in IBD. 63 IBD patients (44 CD, 19 UC) provided samples for FC assay, before and after the induction course of anti-TNF α therapy (Infliximab n=42, Adalimumab n=18, Certolizumab Pegol n=3). Clinical activity, measured by clinical indexes (CDAI, CAI), was assessed in all patients before and after induction treatment. For mucosal healing assessment (defined as CDEIS ,3 or Mayo Endoscopic Score ≤1) all patients performed colonscopy before and after 1-year of anti-TNF α treatment. Clinical response at 1-year was obtained in 36/63 (57%, 12 UC and 24 CD) of the patients with a median FC value of 106 μg/g after induction therapy, while the 27 patients not in clinical response at 1-year had a postinduction median FC value of 300 μg/g (p=0.0002). The ROC curve analyses showed that FC levels after anti-TNFα induction have a sensitivity of 83% and a specificity of 74%, with a cut-off of 168 μg/g, for predicting clinical response at 1-year (p=0.0001). In CD we detected a sensitivity of 83% and a specificity of 75%, with a cut-off of 125 μg/g, for predicting clinical response at 1-year (p=0.0001), while in UC we detected a sensitivity of 100% and a specificity of 79%, with a cut-off of 121 μg/g, for predicting mucosal healing at 1-year (p=0.0001). Survival analysis showed for patients with FC above 168 μg/g after anti-TNF α induction course a probability of being in clinical response at 1-year significantly lower than for patients with FC less than 168 μg/g (HR 0.20, p=0.0001). The same analysis conducted in the UC patients showed a HR of 0.16 (p=0.037), while for CD patients with FC above 125 μg/g after anti-TNFα induction course the HR was 0.22 (p=0.0008). Our preliminary results suggest that faecal calprotectin can be used as a marker to estimate anti-TNF α agents's efficacy in IBD and to predict clinical response and mucosal healing at 1-year.
Prevalence of Antibodies to Adalimumab (ATA) and Correlation Between Ata and Low Serum Drug Concentration on CRP and Clinical Symptoms in a Prospective Sample of IBD Patients Fernando S. Velayos, Sarah Sheibani, Steven Lockton, Scott Hauenstein, Sharat Singh, Jonathan P. Terdiman, Uma Mahadevan BACKGROUND: Measurement of antibodies to infliximab (ATI) and the correlation observed between serum drug concentration and disease status have provided both insight into infliximab (IFX) immunogenicity and clinical utility to these markers for managing IBD patients on IFX. For adalimumab, such data are not readily available nor is clinical utility known. The prevalence of antibodies to adalimumab (ATA) in IBD patients is sparsely reported outside of one company sponsored clinical trial (2.6%). Correlation between ATA/ drug concentration and objective markers of inflammation (CRP) as well as clinical symptoms is poorly described. METHODS: An independent investigator-initiated cross-sectional study prospectively recruited 54 IBD patients on ADA (2 with ulcerative colitis) from a tertiary center to determine 1) prevalence of detectable ATA and drug concentration; 2) correlation between ATA /drug concentration and an objective measure of inflammation, C-reactive protein (CRP); and 3) whether stratified category of ATA/ drug concentration correlated with patient's self-described symptoms (remission, response, active flare). Patients were approached based on use of ADA for Crohn's or ulcerative colitis and not clinical status (remission, response, active). Questionnaire of symptoms, IBD history, ADA dosing, weight and CRP measurement were conducted within two weeks of ATA/drug concentration measurement. ATA/drug concentration blood draw was performed at trough, just prior to next ADA dose, and processed by Prometheus Laboratories. Detectable ATA was defined as .= 1U/ml and detectable drug as .=1 mcg/ml. RESULTS: The prevalence of detectable ATA was 22.2% (n=12/54) and detectable ADA concentration was 90.7% (n=49/54). Serum concentration of ,5 mcg/ml of ADA was associated with an elevated CRP (p=0.001). Detectable ATA was positively associated with an elevated CRP, and notably this correlation was independent of drug concentration (p=0.002) (Figure). Stratification of patients based on ATA/drug concentration demonstrated more active disease in patients with low drug concentration (,5 mcg/ml) and/or detectable ATA (p=0.01). CONCLUSION: Antibodies to adalimumab in ADA-treated IBD patients are more prevalent than reported in clinical trials and almost all patients on ADA have a detectable drug concentration. Both detectable ATA and ADA drug concentration ,5 mcg/ml have an important association with increased inflammation. The observation that detectable ATA correlates with elevated CRP independent of drug concentration is a novel finding and suggests preventing ATA may be the more critical of the two variables to address for maximizing clinical efficacy. That detectable ATA/ low drug concentration correlates with active disease suggests there may be clinical utility in obtaining these measurements, however longer-term data are needed.
492 Trough Levels and Antidrug Antibodies Predict Safety and Success of Restarting Infliximab After a Long Drug Holiday Filip J. Baert, David Drobne, Vera Ballet, Ann Gils, Niels Vande Casteele, Scott Hauenstein, Sharat Singh, Steven Lockton, Paul J. Rutgeerts, Severine Vermeire BACKGROUND AND AIMS : Pharmacokinetic monitoring enhances understanding and can improve efficacy and safety of anti-TNF therapy. Given the relative paucity of agents and frequent loss of response (LOR) to biologics, we expanded considerably our cohort that restarted infliximab(IFX) after a drug holiday of .6 months and added long term followup. We aimed to identify clinical and biologic predictors (including antibodies to IFX (ATI) and IFX trough levels (TL)) for success and safety of restarting infliximab in a ‘high immunogenic' cohort including patients with prior episodic therapy and patients restarted after LOR or infusion reactions(IR) to IFX in the past. MATERIALS AND METHODS : We identified a consecutive cohort of 128 patients (105 CD, 23 UC) in whom IFX was restarted after a median drug holiday of 15 months (range 6-125). The reasons why IFX was stopped previously included LOR and/or IR in 29 patients and remission or pregnancy in 99. Serial TL and ATI were determined using a homogenous mobility shift assay (Prometheus Labs, Inc.) enabling ATI detection in the presence of TL. We prospectively collected serum samples during first IFX therapy (t-1), at restart (t0), before the 2nd (t+1) and 3th infusion (t+2) after restart. Main outcome was treatment success (= clinical(and biological)response and safety(= absence of IR). Outcome was correlated to treatment modalities and TL and ATI at all time points. RESULTS : Overall restarting IFX was successful in 84.5% (at week 14), 70% (at year 1) and in 61% (at the end of follow-up (median . 4 years)). IR occurred in 19.5% (25/128) of whom 10 patients experienced a delayed reaction. In 12.5% (16 pts)
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AGA Abstracts
Figure 1: Unadjusted 2-Propanol in Plasma Headspace (units ppb) 490
Faecal calprotectin (FC) is a protein present in the cytosol of neutrophil granulocytes and of macrophages that is released in the biological fluids under inflammatory conditions. FC levels seem to be correlated with active inflammation in inflammatory bowel diseases (IBD), Crohn's Disease (CD) and Ulcerative Colitis (UC). Non-invasive markers of response to biological therapy in IBD are needed to limit current routine investigations that are expensive and invasive. The aim of our study is to evaluate the role of FC as a non invasive marker of inflammation in order to monitor and predict the effect of therapy with TNF α-antagonists in IBD. 63 IBD patients (44 CD, 19 UC) provided samples for FC assay, before and after the induction course of anti-TNF α therapy (Infliximab n=42, Adalimumab n=18, Certolizumab Pegol n=3). Clinical activity, measured by clinical indexes (CDAI, CAI), was assessed in all patients before and after induction treatment. For mucosal healing assessment (defined as CDEIS ,3 or Mayo Endoscopic Score ≤1) all patients performed colonscopy before and after 1-year of anti-TNF α treatment. Clinical response at 1-year was obtained in 36/63 (57%, 12 UC and 24 CD) of the patients with a median FC value of 106 μg/g after induction therapy, while the 27 patients not in clinical response at 1-year had a postinduction median FC value of 300 μg/g (p=0.0002). The ROC curve analyses showed that FC levels after anti-TNFα induction have a sensitivity of 83% and a specificity of 74%, with a cut-off of 168 μg/g, for predicting clinical response at 1-year (p=0.0001). In CD we detected a sensitivity of 83% and a specificity of 75%, with a cut-off of 125 μg/g, for predicting clinical response at 1-year (p=0.0001), while in UC we detected a sensitivity of 100% and a specificity of 79%, with a cut-off of 121 μg/g, for predicting mucosal healing at 1-year (p=0.0001). Survival analysis showed for patients with FC above 168 μg/g after anti-TNF α induction course a probability of being in clinical response at 1-year significantly lower than for patients with FC less than 168 μg/g (HR 0.20, p=0.0001). The same analysis conducted in the UC patients showed a HR of 0.16 (p=0.037), while for CD patients with FC above 125 μg/g after anti-TNFα induction course the HR was 0.22 (p=0.0008). Our preliminary results suggest that faecal calprotectin can be used as a marker to estimate anti-TNF α agents's efficacy in IBD and to predict clinical response and mucosal healing at 1-year.
Prevalence of Antibodies to Adalimumab (ATA) and Correlation Between Ata and Low Serum Drug Concentration on CRP and Clinical Symptoms in a Prospective Sample of IBD Patients Fernando S. Velayos, Sarah Sheibani, Steven Lockton, Scott Hauenstein, Sharat Singh, Jonathan P. Terdiman, Uma Mahadevan BACKGROUND: Measurement of antibodies to infliximab (ATI) and the correlation observed between serum drug concentration and disease status have provided both insight into infliximab (IFX) immunogenicity and clinical utility to these markers for managing IBD patients on IFX. For adalimumab, such data are not readily available nor is clinical utility known. The prevalence of antibodies to adalimumab (ATA) in IBD patients is sparsely reported outside of one company sponsored clinical trial (2.6%). Correlation between ATA/ drug concentration and objective markers of inflammation (CRP) as well as clinical symptoms is poorly described. METHODS: An independent investigator-initiated cross-sectional study prospectively recruited 54 IBD patients on ADA (2 with ulcerative colitis) from a tertiary center to determine 1) prevalence of detectable ATA and drug concentration; 2) correlation between ATA /drug concentration and an objective measure of inflammation, C-reactive protein (CRP); and 3) whether stratified category of ATA/ drug concentration correlated with patient's self-described symptoms (remission, response, active flare). Patients were approached based on use of ADA for Crohn's or ulcerative colitis and not clinical status (remission, response, active). Questionnaire of symptoms, IBD history, ADA dosing, weight and CRP measurement were conducted within two weeks of ATA/drug concentration measurement. ATA/drug concentration blood draw was performed at trough, just prior to next ADA dose, and processed by Prometheus Laboratories. Detectable ATA was defined as .= 1U/ml and detectable drug as .=1 mcg/ml. RESULTS: The prevalence of detectable ATA was 22.2% (n=12/54) and detectable ADA concentration was 90.7% (n=49/54). Serum concentration of ,5 mcg/ml of ADA was associated with an elevated CRP (p=0.001). Detectable ATA was positively associated with an elevated CRP, and notably this correlation was independent of drug concentration (p=0.002) (Figure). Stratification of patients based on ATA/drug concentration demonstrated more active disease in patients with low drug concentration (,5 mcg/ml) and/or detectable ATA (p=0.01). CONCLUSION: Antibodies to adalimumab in ADA-treated IBD patients are more prevalent than reported in clinical trials and almost all patients on ADA have a detectable drug concentration. Both detectable ATA and ADA drug concentration ,5 mcg/ml have an important association with increased inflammation. The observation that detectable ATA correlates with elevated CRP independent of drug concentration is a novel finding and suggests preventing ATA may be the more critical of the two variables to address for maximizing clinical efficacy. That detectable ATA/ low drug concentration correlates with active disease suggests there may be clinical utility in obtaining these measurements, however longer-term data are needed.
492 Trough Levels and Antidrug Antibodies Predict Safety and Success of Restarting Infliximab After a Long Drug Holiday Filip J. Baert, David Drobne, Vera Ballet, Ann Gils, Niels Vande Casteele, Scott Hauenstein, Sharat Singh, Steven Lockton, Paul J. Rutgeerts, Severine Vermeire BACKGROUND AND AIMS : Pharmacokinetic monitoring enhances understanding and can improve efficacy and safety of anti-TNF therapy. Given the relative paucity of agents and frequent loss of response (LOR) to biologics, we expanded considerably our cohort that restarted infliximab(IFX) after a drug holiday of .6 months and added long term followup. We aimed to identify clinical and biologic predictors (including antibodies to IFX (ATI) and IFX trough levels (TL)) for success and safety of restarting infliximab in a ‘high immunogenic' cohort including patients with prior episodic therapy and patients restarted after LOR or infusion reactions(IR) to IFX in the past. MATERIALS AND METHODS : We identified a consecutive cohort of 128 patients (105 CD, 23 UC) in whom IFX was restarted after a median drug holiday of 15 months (range 6-125). The reasons why IFX was stopped previously included LOR and/or IR in 29 patients and remission or pregnancy in 99. Serial TL and ATI were determined using a homogenous mobility shift assay (Prometheus Labs, Inc.) enabling ATI detection in the presence of TL. We prospectively collected serum samples during first IFX therapy (t-1), at restart (t0), before the 2nd (t+1) and 3th infusion (t+2) after restart. Main outcome was treatment success (= clinical(and biological)response and safety(= absence of IR). Outcome was correlated to treatment modalities and TL and ATI at all time points. RESULTS : Overall restarting IFX was successful in 84.5% (at week 14), 70% (at year 1) and in 61% (at the end of follow-up (median . 4 years)). IR occurred in 19.5% (25/128) of whom 10 patients experienced a delayed reaction. In 12.5% (16 pts)
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AGA Abstracts