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Controversies and challenges in the clinical care of patients with IBD:You cant always get what you want!Stephen B. Hanauer, MDUniversity of Chicago Medicine
Conflicts of InterestAbbottJanssenUCBPrometheusWhat I want for Hanukkah/ChristmasCost-effective therapeutic drug monitoring for biologicsAbility to dose-adjust biologicsA reliable surrogate for mucosal healing
Therapeutic Drug MonitoringClinical Gastroenterology and HepatologyVolume 10, Issue 10 , Pages 1079-1087, October 2012Therapeutic Drug Monitoring of Tumor Necrosis Factor Antagonists in Inflammatory Bowel DiseaseIngridOrds, Brian G.Feagan, William J.Sandborn
Effects of absent blood levels Disease recurs (or no primary response)Development of antibodies (immunogenicity)Secondary loss of responseFactors Affecting the Pharmacokinetics of Monoclonal AntibodiesIMPACT on PK Presence of ADAs Decreases serum [mAbs] Three fold-increased clearanceWorse clinical outcomesConcomitant use of ISReduces formationIncreases serum [mAbs]Decreases mAbs clearanceBetter clinical outcomesHigh Baseline [TNF-]May decrease [mAbs] by increasing clearanceLow AlbuminIncreases clearanceWorse clinical outcomesHigh Baseline CRPIncreases clearanceBody size High BMI may increase clearanceGenderMales have higher clearanceOrdas I, Feagan B, Mould D, Sandborn WJ. Clin Pharmacol Ther 2012Effect of Trough Serum Infliximab Concentrations on Clinical Outcome at >52 Weeks
Trough serum infliximab Detectable UndetectableMaser et al. Clin Gastroenterol Hepatol. 2006; 4:1248-54Patients in remission (%)Patients with endoscopic improvement >75% (%)Patients with complete endoscopic remission (%)Patients with CRP 300 mg/kg). Two consecutive calprotectin levels of >300 mg/kg predict a flare 27 CRP > 5mg/l and Calpro >250g/g were associated with relapse in short term
After discontinuation of IFX in CD patients, elevated levels of CRP and calpro were associated with increased risk of short term relapse, even with high variability of markers during follow-upClose monitoring of CRP and fecal calprotectin levels to predict relapse in Crohn's disease patients. A sub-analysis of the STORI studyN= 113 CD patients in corticosteroid-free remission for 6mos on IFX and immunosuppressants (IS) . IFX discontinued , CRP and calprotectin measured every 2 mos through 18 mos or clinical relapse.
de Suray, et al. ECCO 2012, abstract P274
P = 0.07P = 0.001P274. Close monitoring of CRP and fecal calprotectin levels to predict relapse in Crohn's disease patients. A sub-analysis of the STORI studyN. de Suray, J. Salleron, G. Vernier-Massouille, J.C. Grimaud, Y. Bouhnik, D. Laharie, J.-L. Dupas, H. Pillant, L. Picon, M. Veyrac, M. Flamant, G. Savoye, R. Jian, M. De Vos, E. Piver, J.Y. Mary, J.-F. Colombel, E. Louis
Background: In Crohn's disease (CD), predicting relapse by measuring non-invasive biomarkers could allow early treatment adaptation. Several studies have shown a correlation between intestinal inflammation and serum C-reactive protein (CRP) or fecal calprotectin (Calpro) levels. However, few data exists about the usefulness of close monitoring of these two biomarkers to predict relapse of CD in the short term. The aim of our study was to assess the value of close monitoring of CRP and Calpro levels to predict relapse of CD after infliximab (IFX) discontinuation.
Methods: Luminal CD patients treated for at least one year with scheduled IFX combined with immunosuppressant (IS) and in stable remission without steroids for at least 6 months were prospectively recruited into the STORI study. IFX was discontinued at baseline and IS treatment was kept at a stable dose over the study period. CRP and Calpro levels were measured every 2 months until 18 months of follow-up or until clinical relapse. For each patient, median values of CRP and Calpro were computed and compared between relapsers and non-relapsers by a Mann-Whitney test. Relapse rate was analysed using the Cox model (time dependent) for CRP and Calpro.
Results: 113 patients were included and analyzed. Among them, 51 presented a relapse after a median follow-up of 10 months. 721 CRP and 675 Calpro measurements were performed with a median of 6 measurements/patient for both markers. During follow-up, we found a high variability of CRP and Calpro, regardless of the occurrence of relapse. However, the medians of median concentrations of CRP and Calpro per patient were higher in relapsers than in non-relapsers (3.9 vs 2.8 mg/l, P = 0.07; 151 vs 52 g/g, P = 0.001). Using time-dependent Cox model, values of CRP >5 mg/l and Calpro >250 g/g were associated with relapse in the short term with a HR of relapse (95% confidence interval) of 4.2 (1.9 to 9.2), p = 0.001 and 6.5 (2.7 to 15.6), p < 0.001, respectively.
Conclusions: After discontinuation of IFX in CD patients, elevated levels of CRP and Calpro were associated with an increased risk of short term relapse, even if there was a high variability of both markers during follow-up. Other models taking into account the relative and sustained changes of these markers should improve the accuracy for prediction of relapse.28Fecal lactoferrin level is an indicator of mucosal healing85pts monitored for the complete 12-months49pts experienced sustained remission defined by CAI44 achieved mucosal healing based on Endoscopy Score 0141 did not show any signs of acute histological activity (Riley Score)FLA was the only biomarker to show a median level above cut-off for active disease defined by endoscopy as well as histology for pts in sustained clinical remission
29Langhorst J., et al. ECCO 2012. Abstract P095.Fecal lactoferrin level is an indicator of mucosal healingFecal lactoferrin (FLA) level is an indicator of mucosal healing in patients with ulcerative colitis: Aprospective 12-month monitoring study85pts monitored for the complete 12-months36pts suffered a flare49pts experienced sustained remission defined by CAI. 30Langhorst J., et al. ECCO 2012. Abstract P095.FlareRemissionP-valueMedian FLA levels (g/g)405150g/g9%31%TibbleUC1-4 mos.>50g/g10%*85%*TibbleCD1-4 mos.>50g/g15%85%CostaUC1-12 mos.>150g/g10%81%CostaCD1-12 mos.>150g/g57%87%DIncaUC3-36 mos.>130g/g30%79%SipponenUC+CD> 3mos (51% >12 months)>100g/g25%39%WalkiewiczCDNot stated>400g/g11%56%Lewis JD. Gastroenterology 2011;13* NPV 100% at 12 weeks33Monitoring InflammationCan Fecal Calprotectin detect subclinical inflammation? predict future flares?
Gisbert, IBD 2009; 15: 1190.CD and UC in clinical remissionCutoff of 167Prediction of future flaresYou Cant Always Get What you Want.
David RubinSBH Magic Bus cutDavid RubinDavid Rubin's AlbumGarageBand 6.0.52012Chart1826
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East
Sheet1Anti-TNF changed (11/12)Infliximab increased (1/6)East9217
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Sheet1Anti-TNF changed (2/6)Infliximab increased (25/29)East4086
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83/11330/11328/1131 year outcome1y outcome
Sheet11 year outcomeRemission73.5DR26.5Discontinued25To resize chart data range, drag lower right corner of range.
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Reason for D/C
Sheet1Reason for D/CFlare7Safety5Withdrew consent16To resize chart data range, drag lower right corner of range.
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3.92.8RelapsersNon-relapsers
Sheet1RelapsersNon-relapsersSeries 3CRP (mg/l)3.92.82Category 22.54.42Category 33.51.83Category 44.52.85To resize chart data range, drag lower right corner of range.
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15152RelapsersNon-relapsers
Sheet1RelapsersNon-relapsersSeries 3Calpro (g/g)151522Category 22.54.42Category 33.51.83Category 44.52.85To resize chart data range, drag lower right corner of range.
David RubinSBH You Can't Always Get What you Want cutDavid RubinDavid Rubin's AlbumGarageBand 6.0.52012