Aberrant Mucin Expression Profiles Associate With Pediatric Inflammatory Bowel Disease Presentation and Activity.

BACKGROUND: Intestinal mucosal healing is nowadays preferred as the therapeutic endpoint in inflammatory bowel disease (IBD), but objective measurements at the molecular level are lacking. Because dysregulated mucin expression is suggested to be involved in mucosal barrier dysfunction in IBD, we investigated mucin expression in association with barrier mediators and clinical characteristics in colonic tissue of a pediatric IBD population. METHODS: In this cross-sectional monocentric study, we quantified messenger RNA (mRNA) expression of mucins, intercellular junctions, and cell polarity complexes in inflamed and noninflamed colonic biopsies from pediatric IBD (n = 29) and non-IBD (n = 15) patients. We then validated mucin expression at protein level and correlated mucin mRNA expression with expression of barrier mediators and clinical data. RESULTS: The expression of MUC1, MUC3A, MUC4, and MUC13 was increased in the inflamed colon of pediatric IBD patients compared with the noninflamed colon of non-IBD control subjects. Especially MUC13 mRNA expression associated with the expression of barrier mediators, including CDH1, OCLN, and TJP2. MUC1 and MUC3B mRNA expression in combination with calprotectin levels most accurately discriminated IBD patients from non-IBD control subjects (90.6% area under the receiver-operating characteristic curve [AUCROC], 92.0% sensitivity, 73.7% specificity), whereas aberrant mRNA expression of MUC1, MUC3A, MUC4, and MUC13 was distinctive for ulcerative colitis and of MUC3B for Crohn's disease. Furthermore, expression of MUC3A, MUC3B, and MUC4 correlated with clinical disease activity (ie, Pediatric Ulcerative Colitis Activity Index and Pediatric Crohn's Disease Activity Index), and of MUC1, MUC2, MUC4, and MUC13 with endoscopic colitis severity in ulcerative colitis patients. CONCLUSIONS: Colonic mucin expression is disturbed in pediatric IBD patients and associates with disease activity and presentation, suggesting its use as molecular marker to aid in disease diagnosis and management.

Next generation point-of-care test for therapeutic drug monitoring of adalimumab in patients diagnosed with autoimmune diseases.

Therapeutic drug monitoring (TDM) of adalimumab (ADM) at the point-of-care (POC) is key to prevent loss of response but has not been accomplished to date because true POC testing solutions are still lacking. Here, we present a novel "whole blood in - result out" self-powered microfluidic chip for detecting ADM within 30 min to enable TDM at POC. Hereto, we first demonstrated on-chip plasma separation from whole blood, followed by downscaling an ADM ELISA with maintained specificity and sensitivity in plasma. This assay was then performed on a robust and easy-to-use microfluidic chip we designed based on (i)SIMPLE technology, allowing autonomous function upon single finger press activation, which was successfully validated with patient samples. Herein, we prove the potential of our technology to detect targets starting from whole blood introduced directly on-chip and to integrate various immunoassays, both for TDM and other in vitro diagnostics applications, like infectious diseases.

A Prospective Trial with Long Term Follow-up of Patients With Severe, Steroid-Resistant Ulcerative Colitis Who Received Induction Therapy With Cyclosporine and Were Maintained With Vedolizumab.

BACKGROUND: Combining vedolizumab with a rapid-onset drug such as cyclosporine is a novel combination treatment for severe steroid-resistant ulcerative colitis (UC). This prospective study describes the efficacy and safety of cyclosporine in conjunction with vedolizumab in patients with severe, steroid-resistant UC with 1 year of follow-up. METHODS: Seventeen steroid-resistant UC patients were treated with cyclosporine in combination with vedolizumab, with a follow up of 52 weeks. Clinical and endoscopic response, remission rates, and colectomy-free survival were the primary endpoints. Secondary endpoints included biochemical response and remission with C-reactive protein, erythrocyte sedimentation rate, and fecal calprotectin. RESULTS: Fifteen (88%) of 17 patients initially responded to cyclosporine and were started on vedolizumab. By week 10, 11 (73%) of 15 patients had achieved endoscopic remission with a Mayo score of ≤1. At week 26, 14 (93%) of 15 of the patients were in clinical remission and 11 (73%) were in endoscopic remission. At week 52 of follow-up, 10 (71%) of 14 of these patients continued to be in endoscopic remission and 11 (79%) of 14 were in clinical remission. Among the 10 patients in endoscopic remission, 8 (80%) reached histological remission. Colectomy-free survival rate was 82% (n = 14 of 17) at 1 year and mean C-reactive protein, erythrocyte sedimentation rate, and fecal calprotectin levels were 3.2 mg/L, 16.1 mm/h, and 168.3 µg/g, respectively. No serious adverse events were reported. CONCLUSIONS: Bridging cyclosporine to vedolizumab in severe, steroid-refractory UC patients is effective and safe at inducing and maintaining clinical, endoscopic, and biochemical response and remission up to 52 weeks of follow-up. Larger prospective studies are warranted.

Infliximab Concentrations during Induction Are Predictive for Endoscopic Remission in Pediatric Patients with Inflammatory Bowel Disease under Combination Therapy.

OBJECTIVES: To study infliximab (IFX) pharmacokinetics in children with inflammatory bowel disease (IBD) during induction therapy to predict outcome and explore if other covariates influenced outcome. STUDY DESIGN: All children with IBD starting IFX therapy (5 mg/kg at weeks 0, 2, 6, and 12) for active luminal disease from May 2017 to May 2019 were included and followed prospectively. Patients were sampled at multiple timepoints during induction (trough concentrations and peak concentration at weeks 0, 2, 6, and 12, and intermediate concentration at weeks 1-4). IFX concentrations and cumulative drug exposure were correlated with outcome at 6 months. Endoscopic remission was defined as Simple Endoscopic Score for Crohn's Disease of <3 or Mayo endoscopic subscore of 0, and deep remission as endoscopic with clinical remission (Pediatric Ulcerative Colitis Activity Index/Pediatric Crohn's Disease Activity Index of <10). RESULTS: There were 252 serum induction concentrations obtained from 32 patients (81% on concomitant thiopurines). Children in endoscopic remission (all in deep remission) at 6 months had significantly higher drug concentrations from week 4 onward. A receiver operating characteristics curve analysis identified IFX trough concentrations at week 12 of ≥5.0 µg/mL and area under the curve at weeks 0-12 of ≥4056.0 µg∗day/mL as the minimal target to achieve endoscopic remission at 6 months (area under the receiver operating characteristics curve, 0.796 [95% CI, 0.62-0.97] and area under the receiver operating characteristics curve, 0.778 [95% CI, 0.61-0.94], respectively). In addition, our findings suggest that proteomic analysis may help to understand IFX response. CONCLUSIONS: Higher IFX exposure during induction therapy in pediatric patients with IBD is associated with significantly better endoscopic and deep remission rates at 6 months. Drug concentrations differentiate remitters from nonremitters from week 4 after induction onward.

The effect of aging on infliximab exposure and response in patients with inflammatory bowel diseases.

AIMS: Controversies regarding infliximab treatment in elderly patients with inflammatory bowel diseases remain. We evaluated the effect of patient's age on infliximab exposure, efficacy and safety. METHODS: Retrospective case-control data of patients receiving infliximab induction treatment were analysed. A population pharmacokinetic model was developed to estimate individual pharmacokinetic parameters. A logistic regression model was used to investigate the effect of exposure on endoscopic remission. Repeated time-to-event models were developed to describe the hazard of safety events over time. RESULTS: A total of 104 patients (46 elderly, ≥65 years) were included. A two-compartment population pharmacokinetic model with linear elimination adequately described the data. Infliximab clearance decreased with older age, higher serum albumin, lower fat-free mass, lower C-reactive protein and absence of immunogenicity. Yet, infliximab exposure was not significantly different between elderly and nonelderly. Regardless of age, an infliximab trough concentration at week (w)14 of 15.6 mg/L was associated with a 50% probability of attaining endoscopic remission between w6 and w22. Infliximab exposure during induction treatment was not a risk factor of (severe) adverse events. The hazard of severe adverse events and malignancy increased by 2% and 7%, respectively, with increasing year of age. Concomitant immunomodulator use increased the hazard of infection by 958%, regardless of age. CONCLUSIONS: Elderly patients attained infliximab exposure and endoscopic remission similarly to nonelderly patients. Therefore, the same infliximab trough concentration target can be used in therapeutic drug monitoring. The hazards of severe adverse events and malignancy increased with age, but not with infliximab exposure.

Modelling of the relationship between infliximab exposure, faecal calprotectin and endoscopic remission in patients with Crohn's disease.

AIMS: Evidence for the benefits of pharmacokinetic (PK) and pharmacodynamic (PD) monitoring of infliximab in patients with Crohn's disease (CD) remains scarce. We aimed to develop a population (pop)PK/PD model to characterise the infliximab dose-exposure-biomarker-response (faecal calprotectin [fCal] and endoscopic remission [ER]) relationship. METHODS: Data were obtained from 116 patients with CD in a phase 4 dose-escalation study. Three sequential models were developed: a 2-compartment popPK model linking infliximab dose to exposure; an indirect response popPK/PD model describing the inhibitory effect of infliximab exposure on fCal; and a first-order Markov popPD model linking fCal to transitions between states of ER, no ER and dropout. RESULTS: Infliximab clearance increased with increasing fCal, decreasing albumin, increasing CD activity index and presence of anti-drug antibodies. Baseline fCal increased with increasing C-reactive protein and decreasing platelet count. Lower fCal increased the probability of attaining ER and decreased the probability of losing ER. Probability of dropping out given an earlier state of absence of ER increased with time. Large interpatient PK and PD variability resulted in a flat dose-response curve. Predicted fraction of patients achieving ER was 45% [30-61] (median [interquartile range], n = 50 000) when on 5 mg/kg infliximab (~46% observed in data). Simulations with 10 mg/kg induction doses predicted an increase to 48% [32-63]. This minor benefit at the population level argues against systematic 10 mg/kg induction dosing in all patients. CONCLUSION: Model-informed infliximab dose optimisation towards a predefined fCal concentration (while accounting for PK and PD variability) may improve effectiveness of infliximab therapy.

Endoscopic remission can be predicted by golimumab concentrations in patients with ulcerative colitis treated with the changed label.

BACKGROUND: In 2018, the European Medicines Agency (EMA) replaced a fixed 50 mg every 4-week maintenance regimen of golimumab for ulcerative colitis (UC) patients weighing <80 kg with new, flexible dosing that allows reactive dose optimization to 100 mg if clinically needed. We analyzed the endoscopic remission rates and pharmacokinetics of this new dosing regimen in real-life settings. METHODS: We prospectively recruited 30 consecutive (17 with body weight <80 kg) patients with UC who received golimumab with the new EMA label. The primary endpoint was endoscopic remission (Mayo ≤1) assessed by centrally-read endoscopy at week 14 and year 1. Golimumab concentrations, measured at nine prespecified timepoints, were correlated with endoscopic remission and identified cut-offs. RESULTS: Endoscopic remission was achieved in 15/30 (50%) and 10/30 (33%) patients at week 14 and year 1, respectively. Reactive dose optimization to 100 mg maintenance was needed in 13/17 (76%) patients. Golimumab concentrations at week 6 predicted week 14 and year 1 endoscopic remission. Week 6 concentrations >10.7 µg/ml were a strong predictor for achievement and maintenance of endoscopic remission during the first year of treatment, while concentrations <5.1 µg/ml identified the opposite. CONCLUSION: One-third of the patients reached and maintained endoscopic remission during the first year of golimumab treatment, but the need for dose optimization to 100 mg every 4 weeks of maintenance was high in patients weighing <80 kg. Golimumab concentrations <5.1 µg/ml at week 6 identified patients who are unlikely to reach and maintain endoscopic remission with the new, flexible EMA label.

Tissue Exposure does not Explain Non-Response in Ulcerative Colitis Patients with Adequate Serum Vedolizumab Concentrations.

BACKGROUND AND AIMS: Some patients with ulcerative colitis [UC] do not respond to vedolizumab treatment despite adequate drug exposure in serum. This study aimed to investigate vedolizumab in tissue and questioned whether insufficient tissue exposure could explain non-response in UC patients with adequate serum vedolizumab concentrations. METHODS: A paired serum sample and colonic mucosal biopsy was collected from 40 UC patients [20 endoscopic responders, 20 non-responders] at week 14 of vedolizumab treatment. Vedolizumab, soluble [s]-mucosal addressin cell adhesion molecule-1 [MAdCAM-1], s-vascular cell adhesion molecule-1 [VCAM-1] and s-intercellular adhesion molecule-1 [ICAM-1] were measured in serum and/or tissue. Endoscopic response was defined as Mayo endoscopic sub-score ≤1. RESULTS: A significant positive correlation was observed between vedolizumab serum and colonic tissue concentrations [ρ = 0.84, p < 0.0001], regardless of the macroscopic inflammatory state of the tissue. Vedolizumab tissue concentrations were lower in non-responders than in responders [0.07 vs 0.11 µg/mg, p = 0.04]. In the subgroup of patients with adequate vedolizumab serum concentrations [>14.6 µg/mL], tissue vedolizumab was not significantly different between responders and non-responders [0.15 vs 0.13 µg/mg; p = 0.92]. Serum sMAdCAM-1 concentrations, but not serum sICAM-1 or sVCAM-1 concentrations, were significantly higher in responders than in non-responders with adequate vedolizumab serum concentrations [1.04 vs 0.83 ng/mL, p = 0.03]. CONCLUSIONS: Vedolizumab concentrations in colonic mucosal tissue of UC patients reflect the concentration in serum regardless of the macroscopic inflammatory state of the tissue. Our data show that insufficient tissue exposure does not explain non-response in UC patients with adequate serum vedolizumab concentrations.

Development and validation of immunoassays for monitoring of guselkumab and anti-guselkumab antibodies in patients with moderate-to-severe psoriasis.

Therapeutic drug monitoring, which is the measurement of drug concentrations in the blood, is a useful tool to guide clinical decision-making and treatment adjustments, on the condition that drug concentrations are correlated with treatment response. For guselkumab, an anti-IL-23 monoclonal antibody for the treatment of moderate-to-severe psoriasis, such a concentration-response relationship could not yet be determined as no commercial assays for the quantification of this drug or antibodies against this drug are available. Therefore, the aim of this study was to develop and validate immunoassays for the quantification of guselkumab and anti-guselkumab antibodies according to the guidelines of the European Medicines Agency (EMA). A diverse panel of 20 highly specific anti-guselkumab monoclonal antibodies (MA-GUS) was generated of which eight revealed a neutralizing capacity of ≥65 %. At least seven different antibody clusters were identified based on their epitope binning profile. Using MA-GUS9F6 as the capture antibody and MA-GUS12G12 as the detection antibody, an ELISA was developed with a dose-response curve ranging from 0.08 to 5 ng/mL. The assay was specific, selective and could accurately and precisely quantify guselkumab concentrations in spiked healthy control serum and serum from guselkumab-treated psoriasis patients with a cut-off for quantification of 0.014 µg/mL. The presence of IL-23 in physiological concentrations or of non-neutralizing antibodies did not impact the quantification of guselkumab, while the presence of neutralizing antibodies did. Using MA-GUS12A9 as a calibrator, two anti-guselkumab antibody assays were developed to detect anti-guselkumab antibodies, which differ in the threshold for detection and quantification and the tolerance to the presence of guselkumab. Together, these validated immunoassays are essential to establish a concentration-response relationship and will allow the future implementation of therapeutic drug monitoring in moderate-to-severe psoriasis patients receiving guselkumab treatment.

Evaluating an easy sampling method using dried blood spots to determine vedolizumab concentrations.

An association between vedolizumab (VDZ) trough concentrations and therapeutic outcome has been observed in patients with inflammatory bowel diseases. VDZ samples are typically collected via venous sampling for therapeutic drug monitoring (TDM), but can alternatively be collected via dried blood spot (DBS) samples, which can be used for intensive sampling to investigate pharmacokinetic profiles. Therefore, we have developed a DBS method for determining VDZ concentrations and validated this method by comparing VDZ measurements in paired DBS and venous patient samples. First, VDZ was spiked in citrated whole blood and spotted on filter paper. After drying, DBS were extracted and VDZ concentrations were determined in the extracts using ELISA. For clinical validation, 41 paired DBS and serum samples were collected from 19 VDZ-treated patients. VDZ concentrations measured in DBS extracts strongly correlated with serum concentrations (Pearson r = 0.978, p < 0.0001). No significant impact of the hematocrit value was observed on the VDZ DBS/serum concentration ratios. Additionally, the VDZ DBS/serum ratio was calculated in nine individual patients, which was, in general, shown to be stable over time. VDZ DBS sampling is a robust method that can be used as an alternative to venous blood collection for TDM of VDZ. VDZ concentrations in DBS highly correlated with VDZ serum concentrations over a broad concentration range, allowing DBS to be used for intensive sampling to gain more insight in VDZ pharmacokinetics.

Anti-infliximab antibodies: How to compare old and new data?

BACKGROUND: Anti-drug-antibodies (ADA) against infliximab are frequently measured in patients receiving infliximab treatment with loss of response and undetectable infliximab concentrations. Different ADA bridging assays (1st generation, 2nd generation and ready-to-use kit) have been developed successively and were applied over the last 10 years, making comparison between ADA concentrations very challenging. A cutoff of 8 µg/ml was established to discriminate low from high ADA concentrations using the 1st generation ADA bridging assay. The objective of this study was to enable comparison of ADA concentrations determined with the different assays that were developed over the years. METHODS: 166 serum samples were collected from patients with inflammatory bowel disease treated with infliximab. 98 samples were measured simultaneously with the 1st and 2nd generation ADA assay, 67 serum samples were measured with the 2nd generation assay and the ready-to-use kit. RESULTS: From our ADA concentration comparison experiments, we deduced that the previously established cutoff of 8 µg/ml with the 1st generation ELISA has a similar impact as the cutoff of 374 ng/ml with the 2nd generation ELISA and a cutoff of 119 ng/ml in the ready-to-use ELISA kit. CONCLUSION: ADA concentrations measured with the different assays were compared and a cutoff concentration was determined for each of them to distinguish between low and high ADA concentrations. These cutoff concentrations may serve as a tool for clinicians to make treatment decisions for patients with a loss of response to infliximab and undetectable infliximab serum concentrations.

Influence of Drug Exposure on Vedolizumab-Induced Endoscopic Remission in Anti-Tumour Necrosis Factor [TNF] Naïve and Anti-TNF Exposed IBD Patients.

BACKGROUND AND OBJECTIVES: Vedolizumab has demonstrated efficacy and safety in patients with Crohn's disease [CD] and ulcerative colitis [UC]. Endoscopic outcome data are limited, especially in anti-tumour necrosis factor [TNF] naïve patients. The present study compared endoscopic outcome in anti-TNF naïve and exposed patients, and explored if this was affected by drug exposure. METHODS: We retrospectively analysed all patients initiating vedolizumab at our tertiary referral centre since 2015. For UC, endoscopic improvement was defined as a Mayo endoscopic subscore ≤1 at week 14. For CD, endoscopic remission was defined as absence of ulcerations at week 22. Vedolizumab trough concentrations were measured at week 6, week 14 and during maintenance. RESULTS: A total of 336 patients were identified [53.3% CD], 20% of them being anti-TNF naïve. Endoscopic improvement was achieved by 56.1% of UC patients and endoscopic remission by 39.1% of CD patients. Endoscopic outcomes were significantly better in anti-TNF naïve vs exposed patients [all: 67.2% vs 42.0%, p = 0.0002; UC: 74.4% vs 50.0%, p = 0.02; CD: 57.1% vs 35.8%, p = 0.03]. Achievement of endoscopic end points significantly impacted long-term treatment continuation [p = 9.7 × 10-13]. A better endoscopic outcome was associated with significantly higher drug exposure in both CD and UC. CONCLUSIONS: The results of this observational, single-centre real-life study suggest that vedolizumab may induce endoscopic remission in both CD and UC. Although anti-TNF naïve patients had a significantly better outcome, 42% of anti-TNF exposed patients still benefited endoscopically. A clear exposure-endoscopic response relationship exists, but not all patients will benefit from treatment intensification. Hence, predictive biomarkers remain necessary. PODCAST: This article has an associated podcast which can be accessed at https://academic.oup.com/ecco-jcc/pages/podcast.

Monitoring a Combination of Calprotectin and Infliximab Identifies Patients With Mucosal Healing of Crohn's Disease.

BACKGROUND & AIMS: In the TAILORIX trial, no benefit could be shown by infliximab dose escalation based on pharmacokinetic (infliximab serum concentrations) and pharmacodynamic (biomarkers and symptoms) monitoring compared with dose escalation based on symptoms alone in patients with Crohn's disease (CD). We investigated whether integration of pharmacokinetic and pharmacodynamic monitoring can be used to evaluate responses to infliximab induction and maintenance therapy, based on findings from endoscopy. METHODS: We performed a post hoc analysis of patients with CD included in a trial to test the effects of infliximab dose escalation, based on biomarkers and serum concentrations of infliximab, on symptoms (the Study Investigating Tailored Treatment With Infliximab for Active Crohn's Disease trial; n = 122). We analyzed data from this study to determine whether concentrations of biomarkers and serum concentrations of infliximab were associated with endoscopic outcomes (n = 116). The primary end points were endoscopic response (CD endoscopic index of severity decrease ≥50% from baseline), endoscopic remission (CD endoscopic index of severity, <3), and absence of ulcers at weeks 12 and 54 of infliximab treatment. RESULTS: Infliximab trough concentrations greater than 23.1 mg/L at week 2 and greater than 10.0 mg/L at week 6 were associated with endoscopic remission at week 12 (positive predictive values, 72% and 76%; negative predictive values, 65% and 59%, respectively). During maintenance therapy, we found evidence for an exposure-response relationship only after dose escalation; trough concentrations greater than 10.6 mg/L were associated with the absence of ulcers at week 54 (positive predictive value, 49%; negative predictive value, 92%). Low fecal concentrations of calprotectin during therapy were associated with endoscopic response and remission (P < .05). Dose escalations increased trough concentrations of infliximab; persistent increase in fecal concentration of calprotectin, despite dose escalation, was associated with a lack of endoscopic response and remission. A significantly higher proportion of patients with antibodies to infliximab, identified by a drug-tolerant assay, dropped out of the study compared with patients without antibodies (P < .0001). CONCLUSIONS: In a post hoc analysis of data from a trial to test the effects of infliximab dose escalation on symptoms, we found that during maintenance therapy, the combination of fecal concentration of calprotectin and trough concentration of infliximab can guide dose adjustment and increase the chances for endoscopic response and remission. ClinicalTrialsRegister.eu EudraCT no: 2011-003038-14.

Evaluating Efficacy, Safety, and Pharmacokinetics After Switching From Infliximab Originator to Biosimilar CT-P13: Experience From a Large Tertiary Referral Center.

BACKGROUND: The use of infliximab biosimilar CT-P13 has increased in patients with inflammatory bowel disease. Nevertheless, doubts about switching from infliximab originator to biosimilar still exist among patients and health care professionals. METHODS: Our tertiary referral center underwent a mandatory switch from infliximab originator to CT-P13 in 2017. We investigated pharmacokinetics, efficacy, and safety of this switch. The primary endpoint was infliximab discontinuation within 6 months of switching. Secondary endpoints included loss of clinical remission, need for treatment optimization, adverse events, evolution of patient-reported outcome, C-reactive protein, infliximab trough levels, and antidrug-antibodies. RESULTS: A total of 361 patients (54.0% male, 70.0% Crohn's disease, 55.6% in clinical remission) were enrolled. Infliximab discontinuation within 6 months was observed in 4%. Loss of clinical remission, adverse events, and antidrug-antibodies were identified in only 2.0%, 2.2%, and 1.1% of patients, respectively. C-reactive protein concentrations and infliximab trough levels remained stable. Independent factors associated with remission at 6 months were lower PRO2 at switch (HR 6.024; 95% CI, 4.878-8.000; P < 0.0001) and higher hemoglobin levels (HR 1.383; 95% CI, 1.044-2.299; P = 0.018). CONCLUSIONS: Switching from infliximab originator to CT-P13 was not associated with an increased risk of treatment discontinuation, loss of clinical remission, or adverse events. No significant changes in infliximab trough levels or immunogenicity could be identified.

A Population Pharmacokinetic and Exposure-Response Model of Golimumab for Targeting Endoscopic Remission in Patients With Ulcerative Colitis.

BACKGROUND: Unlike other anti-tumor necrosis factor alpha antibodies, golimumab does not deliver on its promise of effectiveness for treating patients with ulcerative colitis. We investigated the value of therapeutic drug monitoring for optimizing golimumab therapy. METHODS: We analyzed the golimumab pharmacokinetics data of 56 patients with moderate to severe ulcerative colitis. Induction and maintenance golimumab concentrations (296 venipuncture, 414 serum) were used to develop a population pharmacokinetic model. Exposure-response relationships were analyzed using the data of 40/56 patients with available endoscopy data. Receiver operating characteristic curve analysis was performed, and an exposure-response Markov model was developed, linking golimumab exposure to probabilities of transitioning between Mayo endoscopic subscore (MES) states from baseline to week (w)14. RESULTS: Golimumab pharmacokinetics was best described by a 2-compartment model with linear absorption and elimination. Antibodies to golimumab and previous biological therapy reduced golimumab exposure. Still, interindividual pharmacokinetic variability (IIVPK) remained largely unexplained. Endoscopic remission (ER; MESw14 ≤ 1) was achieved in 14/40 (35%) patients. Golimumab serum trough concentration thresholds of 7.4 mg/L (w6) and 3.2 mg/L (w14) predicted ER at w14 (positive predictive values [pv+] 83% and 91%, pv- 82% and 67%, respectively). The 3.2-mg/L target predicted 38% and 44% chances of achieving ER in patients with MESbaseline of 3 and 2, respectively. CONCLUSIONS: Personalized, model-based induction dosing aiming at here-established target concentrations may account for IIVPK and thus provide patients with more equal chances of achieving ER. As <50% of patients attained the exposure targets, higher golimumab induction dosing requires investigation to secure its future in clinical practice.

Successful Infliximab Treatment is Associated With Reversal of Clotting Abnormalities in Inflammatory Bowel Disease Patients.

BACKGROUND AND GOALS: Active inflammatory bowel diseases (IBD) represent an independent risk factor for venous thromboembolism. The authors investigated the hemostatic profile of IBD patients before and after induction treatment with infliximab, vedolizumab, and methylprednisolone. STUDY: This prospective study included 62 patients with active IBD starting infliximab, vedolizumab, and/or methylprednisolone, and 22 healthy controls (HC). Plasma was collected before (w0) and after induction therapy (w14). Using a clot lysis assay, amplitude (marker for clot intensity), time to peak (Tmax; marker for clot formation rate), area under the curve (AUC; global marker for coagulation/fibrinolysis), and 50% clot lysis time (50%CLT; marker for fibrinolytic capacity) were determined. Plasminogen activator inhibitor-1 (PAI-1) and fibronectin were measured by ELISA. Clinical remission was evaluated at w14. RESULTS: At baseline, AUC, amplitude, and 50%CLT were significantly higher in IBD patients as compared with HC. In 34 remitters, AUC [165 (103-229)% vs. 97 (78-147)%, P=0.001], amplitude [119 (99-163)% vs. 95 (82-117)%, P=0.002], and 50%CLT [122 (94-146)% vs. 100 (87-129)%, P=0.001] decreased significantly and even normalized to the HC level. Vedolizumab trough concentration correlated inversely to fibronectin concentration (r, -0.732; P=0.002). The increase in Tmax for infliximab-treated remitters was significantly different from the decrease in Tmax for vedolizumab-treated remitters (P=0.028). The 50%CLT increased (P=0.038) when remitters were concomitantly treated with methylprednisolone. CONCLUSIONS: Control of inflammation using infliximab most strongly reduced those parameters that are associated with a higher risk of venous thromboembolism.

Achieving Mucosal Healing in Inflammatory Bowel Diseases: Which Drug Concentrations Need to Be Targeted?

Biologicals introduced a major shift in the treatment of patients suffering from inflammatory bowel diseases. Despite providing a tight disease control for many patients, a considerable proportion of patients will fail to respond favorably to treatment or will lose response over time. Therapeutic drug monitoring emerged as a valuable tool to guide clinical decision making as serum drug concentrations have been linked to outcomes. Focusing on mucosal healing as the ultimate treatment goal, different drug concentration thresholds to achieve this outcome have been identified in the literature and are summarized in this review. For therapeutic drug monitoring to be successful in guiding clinical decision making, the used assay, the sampling time point, and the outcome that is aimed for should be taken into account when interpreting drug concentration thresholds. Awareness of these essential aspects among clinicians will improve the implementation of therapeutic drug monitoring and aid in making an evidence-based decision.