Best Practice for Therapeutic Drug Monitoring of Infliximab: Position Statement from the International Association of Therapeutic Drug Monitoring and Clinical Toxicology.

BACKGROUND: Infliximab, an anti-tumor necrosis factor monoclonal antibody, has revolutionized the pharmacological management of immune-mediated inflammatory diseases (IMIDs). This position statement critically reviews and examines existing data on therapeutic drug monitoring (TDM) of infliximab in patients with IMIDs. It provides a practical guide on implementing TDM in current clinical practices and outlines priority areas for future research. METHODS: The endorsing TDM of Biologics and Pharmacometrics Committees of the International Association of TDM and Clinical Toxicology collaborated to create this position statement. RESULTS: Accumulating data support the evidence for TDM of infliximab in the treatment of inflammatory bowel diseases, with limited investigation in other IMIDs. A universal approach to TDM may not fully realize the benefits of improving therapeutic outcomes. Patients at risk for increased infliximab clearance, particularly with a proactive strategy, stand to gain the most from TDM. Personalized exposure targets based on therapeutic goals, patient phenotype, and infliximab administration route are recommended. Rapid assays and home sampling strategies offer flexibility for point-of-care TDM. Ongoing studies on model-informed precision dosing in inflammatory bowel disease will help assess the additional value of precision dosing software tools. Patient education and empowerment, and electronic health record-integrated TDM solutions will facilitate routine TDM implementation. Although optimization of therapeutic effectiveness is a primary focus, the cost-reducing potential of TDM also merits consideration. CONCLUSIONS: Successful implementation of TDM for infliximab necessitates interdisciplinary collaboration among clinicians, hospital pharmacists, and (quantitative) clinical pharmacologists to ensure an efficient research trajectory.

Real-world Effectiveness and Safety of Risankizumab in Patients with Moderate to Severe Multirefractory Crohn's Disease: A Belgian Multicentric Cohort Study.

BACKGROUND: As real-world data on risankizumab in patients with moderate to severe Crohn's disease (CD) are scarce, we evaluated its effectiveness and safety in multirefractory Belgian patients. METHODS: Data from consecutive adult CD patients who started risankizumab before April 2023 were retrospectively collected at 6 Belgian centers. Clinical remission and response were defined using the 2-component patient-reported outcome. Endoscopic response was defined as a decrease in baseline Simple Endoscopic Score with ≥50%. Both effectiveness end points were evaluated at week 24 and/or 52, while surgery-free survival and safety were assessed throughout follow-up. RESULTS: A total of 69 patients (56.5% female, median age 37.2 years, 85.5% exposed to ≥4 different advanced therapies and 98.6% to ustekinumab, 14 with an ostomy) were included. At week 24, 61.8% (34 of 55) and 18.2% (10 of 55) of patients without an ostomy achieved steroid-free clinical response and remission, respectively. At week 52, these numbers were 58.2% (32 of 55) and 27.3% (15 of 55), respectively. Endoscopic data were available in 32 patients, of whom 50.0% (16 of 32) reached endoscopic response within the first 52 weeks. Results in patients with an ostomy were similar (steroid-free clinical response and remission, 42.9% and 14.3%, respectively). During a median follow-up of 68.3 weeks, 18.8% (13 of 69) of patients discontinued risankizumab, and 20.3% (14 of 69) of patients underwent CD-related intestinal resections. The estimated surgery-free survival at week 52 was 75.2%. No new safety issues were observed. CONCLUSIONS: In this real-world cohort of multirefractory CD patients, risankizumab was effective in inducing both clinical remission and endoscopic response. Risankizumab was well tolerated with no safety issues.

In this real-world study of multirefractory Crohn's disease patients, risankizumab was effective, with 58.2% and 27.3% achieving steroid-free clinical response and remission, respectively, at week 52. Surgery-free survival at week 52 was 75.2%, and no new safety concerns arose.

Evaluation of serum cytokines and acute phase proteins as possible pharmacodynamic biomarkers to monitor endoscopic remission during ustekinumab therapy in patients with Crohn's disease.

Background: Since not all Crohn's disease (CD) patients respond adequately to ustekinumab therapy, biomarkers could aid to monitor treatment response and optimize therapeutic outcomes. Objectives: To explore the dynamics of serum biomarker concentrations to monitor the response to ustekinumab treatment in CD patients. Design: Retrospective, exploratory study to evaluate concentrations of serum cytokines and acute phase proteins and their relation to endoscopic remission in CD patients during ustekinumab treatment. Methods: Serum concentrations of 16 proteins including cytokines and acute phase proteins were measured using the Mesoscale Discovery Platform in serum of healthy controls (n = 13), and CD patients (n = 61) at baseline (week 0), week 8 and week 24 during ustekinumab treatment. Endoscopic remission was defined as simple endoscopic score for CD (SES-CD) <3 after 6 months of therapy. Results: Absolute concentrations of serum amyloid A protein (SAA; week 8), IL-6 (week 24), AGP (weeks 8 and 24), interferon (IFN)-γ (weeks 8 and 24), lipopolysaccharide binding protein (LBP; weeks 8 and 24) and IL-22 (weeks 8 and 24) were significantly lower in endoscopic remitters compared to non-responders (p-values ranging between <0.001 and <0.05). SAA (week 8) and AGP (week 24) were the biomarkers with the highest area under the ROC curve (AUROC; 0.761 and 0.760, respectively) for identifying patients in endoscopic remission, though their performance was not superior to C-reactive protein (CRP) or faecal calprotectin. AUROCs of the predictive probability of biomarker combinations showed superiority in discriminating endoscopic remitters from non-responders in comparison to single biomarker measurements, but not as compared to faecal calprotectin. Conclusion: Although not superior to faecal calprotectin, measurement of AGP, SAA, LBF, IFN-γ, IL-6 and IL-22 concentrations, and combinations thereof with or without CRP and faecal calprotectin, during ustekinumab therapy might contribute to adequate monitoring of treatment response in CD patients.

Utility of the Serum-Based Endoscopic Healing Index in Monitoring Therapeutic Response in Ulcerative Colitis.

INTRODUCTION: Convenient and objective noninvasive tools to monitor therapy response in patients with ulcerative colitis (UC) are needed. This study aimed to evaluate the performance of the Endoscopic Healing Index [EHI], a serum test originally developed to monitor mucosal inflammation in Crohn's disease, in patients with UC. METHODS: Serum samples paired with endoscopic data from consecutive adult patients with UC initiating advanced therapy for active disease (Mayo Endoscopic Subscore [MES] > 1) were analyzed. EHI values were compared between groups showing endoscopic improvement, remission, and nonresponse, defined, respectively, as MES of ≤1, 0 and >1. We also assessed the association of EHI with longitudinal changes of MES and compared its performance with that of fecal calprotectin (FC) and C-reactive protein. RESULTS: A total of 127 patients provided 303 samples. Median EHI increased significantly with increasing MES score ( P < 0.001). Median EHI was significantly lower in patients with endoscopic remission or improvement compared with patients with no response ( P < 0.001, P < 0.001, respectively). A 10-point decrease in EHI was associated with 89% higher odds of 1-point decrease in MES ( P < 0.001). EHI detected MES 0-1 with an area under the receiver operating curve of 77.8%, which was comparable with that of FC and C-reactive protein (85.0% [ P = 0.076] and 70.6% [ P = 0.055], respectively). DISCUSSION: EHI values are significantly responsive to changes in mucosal inflammation, also in patients with UC, and can confirm and/or rule out mucosal inflammation with an almost similar accuracy to that of FC.

Adalimumab versus ustekinumab as first-line biological in moderate-to-severe Crohn's disease: real-life cohort from a tertiary referral center.

BACKGROUND: Therapeutic options for Crohn's disease are growing, making the choice of first-line therapy relevant. Both adalimumab and ustekinumab are effective in moderate-to-severe Crohn's disease. The Safety and Efficacy of Adalimumab Versus Ustekinumab for One Year trial suggested no difference in clinical or endoscopic remission at week 52 in biological-naive Crohn's disease patients. We explored if results withstand in the real world. METHODS: We included bio-naive Crohn's disease patients starting adalimumab or ustekinumab between 2017 and 2020. Patients had endoscopy-proven moderate-to-severe disease [Simple Endoscopic Score for Crohn's disease (SES-CD) ≥3]. Clinical remission was defined as Harvey Bradshaw Index (HBI) <5 or physician global assessment. Endoscopic remission (SES-CD <3) and improvement (≥50% reduction in SES-CD from baseline) were assessed at W26-52. Propensity score matching was used. RESULTS: A total of 68 biological-naive Crohn's disease patients were included (32 adalimumab and 32 ustekinumab) and followed for median of (IQR) 60 (33-104) weeks. Patients had significantly higher odds of achieving endoscopic remission with adalimumab than ustekinumab [adjusted odds ratio (aOR), 2.73; confidence interval (CI), 1.12-7.36; P = 0.03]. Also, more adalimumab-treated patients achieved endoscopic response, clinical remission at week 26 and 52 (aOR, 2.24; CI, 0.94-5.71; P = 0.07; aOR, 1.26; CI, 0.36-4.51; P = 0.72; aOR, 1.58; CI, 0.54-4.88; P = 0.41, respectively). Treatment persistence was not different between groups (P = 0.44). The number of adverse events was similar. CONCLUSION: In a real-world cohort of biological-naive Crohn's disease patients, adalimumab was superior to ustekinumab in achieving endoscopic remission. No differences in clinical remission at W26-52 or treatment persistence were observed. Both adalimumab and ustekinumab remain good options as first-line biologicals in moderate-to-severe Crohn's disease.

Real-world Endoscopic and Histological Outcomes Are Correlated with Ustekinumab Exposure in Patients with Ulcerative Colitis.

BACKGROUND: Histo-endoscopic outcomes are being proposed as new treatment targets in ulcerative colitis [UC]. Little is known about the pharmacokinetic-pharmacodynnamic [PK-PD] relationship of ustekinumab [UST] in UC patients or whether serum UST concentrations reflect tissue drug exposure. We aimed to study UST serum concentrations and their relation to tissue exposure and drug effectiveness in a real-world setting. METHODS: A total of 42 UC patients starting UST were prospectively followed by clinical, endoscopic and histological assessments at Week 16. Histological remission was defined as Nancy Histology Index of 0. Analogous to the UNIFI programme, histo-endoscopic mucosal improvement was defined as a combination of histological improvement [Geboes ≤3.1] and endoscopic improvement [MES ≤1]. Paired trough serum samples and colonic mucosal biopsies were collected for UST levels measurement. RESULTS: After 16 weeks [IQR 15.8-16.4] of therapy, histological remission and histo-endoscopic mucosal improvement were observed in 19 [45%] and 18 [43%] patients, respectively. Patients who achieved these outcomes had higher serum UST levels than those who did not. Patients with shorter disease duration and clinical response at Week 8 had higher odds to achieve histological remission. UST concentrations from paired serum and biopsy samples revealed a strong positive correlation [r = 0.88, p < 0.001], in both inflamed and uninflamed tissue. CONCLUSIONS: In this real-world cohort of refractory UC patients initiating UST, more than a third of the patients achieved histological remission. A drug exposure-response relationship was observed for histo-endoscopic outcomes, with no added value of measuring tissue exposure given the strong correlation with serum exposure.

Longitudinal monitoring of STAT3 phosphorylation and histologic outcome of tofacitinib therapy in patients with ulcerative colitis.

BACKGROUND: Tofacitinib is the first in class, pan-JAK inhibitor approved for ulcerative colitis (UC). Clinical efficacy has been shown, but long-term real-life endoscopic and histologic data are lacking. AIM: To investigate the effects of tofacitinib in patients with refractory UC focussing on endoscopic, histologic and molecular outcomes, including STAT3 phosphorylation (pSTAT3) detection in the spatial context of mucosal inflammation METHODS: We prospectively monitored 59 highly refractory patients (96.7% anti-TNF exposure, 91.7% vedolizumab exposure) initiating tofacitinib at two IBD referral centres and assessed outcome at the end of induction and after 48 weeks of therapy. Endoscopic improvement was defined as a Mayo endoscopic subscore ≤1, endoscopic and histologic remission as Mayo endoscopic subscore 0 and Nancy histologic score 0. Multiplex immunohistochemistry with multispectral imaging was used to assess pSTAT3. RESULTS: Endoscopic improvement was achieved by 24.4% and 30.5% of patients at weeks 8 and 48, respectively. Endoscopic and histologic remission rates were 11.1%, 23.7 and 16.7%, 21.4%, respectively. Endoscopic improvement at week 8 was significantly associated with treatment continuation in the long-term (72.7% vs 20.6%, p = 0.003). Although we observed a gradual decrease of mucosal pSTAT3 levels in both remitters and non-remitters (p < 0.05), no association with treatment outcome could be demonstrated. However, lamina propria pSTAT3 was significantly associated with the Nancy Histologic index (p = 0.004). CONCLUSION: Tofacitinib can induce and maintain endoscopic and histologic remission in up to one-quarter of highly refractory UC patients. Longitudinal monitoring of nuclear pSTAT3 in mucosal tissue compartments reflects distinctive on-target effects, independently of long-term treatment outcomes.

Biomarker discovery for personalized therapy selection in inflammatory bowel diseases: Challenges and promises.

The past decades witnessed a significant stride in deciphering the pathophysiology of inflammatory bowel disease, which further advanced drug development adding several new biologicals and small molecules to the arsenal of available therapies. Surprisingly, this wealth in therapeutic options did not yield the aspired high durable response rates. In addition, the increase in therapeutic availabilities ignited an increase in research toward biomarkers that could help assign therapies to patients with the highest probability of response. Luckily, major steps have been undertaken in this domain which resulted in the discovery of some interesting biomarkers that are still under validation. However, the pace in which this domain is progressing, the discordance between short-term endpoints in biomarker discovery studies and the ambition of the disease community in modifying disease course, and the uncertainties about the validity of discovered biomarkers highlight the need for a critical appraisal of research conduct in this domain. In this review, we shed light on areas of improvement in biomarker discovery studies that will help optimize the use of available therapies and break the current therapeutic ceiling.

Tailoring Multi-omics to Inflammatory Bowel Diseases: All for One and One for All.

Inflammatory bowel disease [IBD] has a multifactorial origin and originates from a complex interplay of environmental factors with the innate immune system at the intestinal epithelial interface in a genetically susceptible individual. All these factors make its aetiology intricate and largely unknown. Multi-omic datasets obtained from IBD patients are required to gain further insights into IBD biology. We here review the landscape of multi-omic data availability in IBD and identify barriers and gaps for future research. We also outline the various technical and non-technical factors that influence the utility and interpretability of multi-omic datasets and thereby the study design of any research project generating such datasets. Coordinated generation of multi-omic datasets and their systemic integration with clinical phenotypes and environmental exposures will not only enhance understanding of the fundamental mechanisms of IBD but also improve therapeutic strategies. Finally, we provide recommendations to enable and facilitate generation of multi-omic datasets.

Translating Results from VARSITY to Real World: Adalimumab vs Vedolizumab as First-line Biological in Moderate to Severe IBD.

BACKGROUND: Selecting a first-line therapy remains challenging in IBD. Adalimumab (ADM) and vedolizumab (VDZ) effectively lead to endoscopic remission in moderate to severe IBD. The VARSITY trial showed superiority of VDZ over ADM in ulcerative colitis (UC) regarding clinical remission and endoscopic improvement at week 52. We explored these results in a real-world setting of UC and Crohn's disease (CD). METHODS: This retrospective study followed a cohort of biologic-naïve patients starting ADM or VDZ from 2015-2019. Patients had moderate to severe disease (endoscopic Mayo score ≥2 for UC, presence of ulcerations for CD) prior to therapy initiation. For UC, endoscopic remission (endoscopic Mayo score 0) and improvement (endoscopic Mayo score ≤1) at week 52 were assessed. For CD, endoscopic remission (absence of ulcerations) and improvement (markedly better endoscopy despite ulcerations) at weeks 26-52 were studied. Treatment persistence was also evaluated. RESULTS: In total, 195 biologic-naïve patients (109 UC; 86 CD) were included. In UC, VDZ was superior to ADM regarding endoscopic remission (29% vs 11%, P = .03), endoscopic improvement (51% vs 26%, P = .01) at week 52, and treatment persistence (P = .04). In CD, no differences in endoscopic remission (VDZ 48% vs ADM 60%; P=0.37), improvement (VDZ 76% vs ADM 77%; P = 1.00), or treatment persistence (P=0.43) at weeks 26-52 were seen. Safety profiles were similar in UC and CD. CONCLUSIONS: This real-world cohort study of biologic-naïve IBD patients found VDZ to be superior to ADM as first-line treatment for patients with UC-but not CD-regarding endoscopic remission at week 52 and treatment persistence.

Breaking the therapeutic ceiling in drug development in ulcerative colitis.

Increased knowledge of the intricate pathogenesis of ulcerative colitis has triggered an advance in drug development during the past two decades, resulting in the advent of several biological agents and small-molecule therapies. Although the increase in therapeutic options is positive, remission rates of patients with ulcerative colitis given new therapeutic agents in induction trials remain at a modest 20-30%, seemingly facing a so-called therapeutic ceiling. This therapeutic ceiling requires a critical appraisal and highlights the need for alternative strategies for drug development. In this Review, we objectively itemise the boundaries of therapeutic efficacy in ulcerative colitis, provide possible explanations for the shortcomings of current strategies, and propose solutions to achieve better therapeutic outcomes in ulcerative colitis.

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.

Monitoring vedolizumab and ustekinumab drug levels in patients with inflammatory bowel disease: hype or hope?

Therapeutic drug monitoring (TDM) plays a vital role in implementing precision medicine in inflammatory bowel disease (IBD), and may contribute to increased effectiveness, lower rates of drug toxicity and cost savings. While expert panels advocate the use of reactive TDM for anti-tumor necrosis factor (anti-TNF) agents, TDM is not yet widely recommended for non-anti TNF biologicals. We provide an overview of the observational evidence of the value of TDM in case of vedolizumab and ustekinumab. We also shed light on obstacles that need to be addressed before establishing wide acceptance of TDM in the field of IBD. In this respect, new analytical techniques and modelling approaches are being developed to further optimize efficacy of TDM and to facilitate general acceptance of this tool in personalizing IBD management.