Proactive Therapeutic Drug Monitoring Is Associated With Increased Drug Persistence in Patients With Inflammatory Bowel Disease Treated With Intravenous Vedolizumab.

BACKGROUND: There are limited data regarding therapeutic drug monitoring (TDM) of non-anti-tumor necrosis factor therapy in inflammatory bowel disease (IBD). This study aimed to evaluate the efficacy of proactive TDM in IBD patients treated with intravenous (iv) vedolizumab (VDZ). METHODS: This single-center retrospective cohort study included consecutive IBD patients treated with maintenance iv VDZ therapy undergoing TDM from November 2016 to March 2023. Patients were followed through June 2023 and were divided in to 2 groups: those who had at least 1 proactive TDM vs those who underwent only reactive TDM. A survival analysis was performed to evaluate drug persistence, defined as no need for drug discontinuation due to loss of response, serious adverse event, or an IBD-related surgery. RESULTS: The study population consisted of 94 patients (proactive TDM, n = 72) with IBD (ulcerative colitis, n = 53). Patients undergoing at least 1 proactive TDM compared with patients having only reactive TDM demonstrated a higher cumulative probability of drug persistence (Log-rank P < .001). In multivariable Cox proportional hazard regression analysis, at least 1 proactive TDM was the only factor associated with drug persistence (hazard ratio, 14.3; 95% confidence interval [CI], 3.8-50; P < .001). A ROC analysis identified a VDZ concentration of 12.5 µg/mL as the optimal drug concentration threshold associated with drug persistence (area under the ROC curve: 0.691; 95% CI, 0.517-0.865; P = .049). CONCLUSION: In this single-center retrospective study reflecting real-life clinical practice, proactive TDM was associated with increased drug persistence in patients with IBD treated with iv VDZ.

There are limited data regarding therapeutic drug monitoring (TDM) of non-anti-tumor necrosis factor therapy in inflammatory bowel disease (IBD). We found that proactive TDM was associated with drug persistence in patients with IBD treated with vedolizumab. Moreover, a vedolizumab concentration of 12.5 µg/mL was identified as the optimal drug concentration threshold associated with drug persistence.

Factors Associated with Delays in Initiating Biologic Therapy in Patients with Inflammatory Bowel Disease.

INTRODUCTION: Expeditious initiation of biologic therapy is important in patients with inflammatory bowel disease (IBD). However, initiation of biologics in the outpatient setting may be delayed by various clinical, social, and financial variables. AIM: To evaluate the delay in initiation of an advanced therapy in IBD and to identify factors that contributed to this delay. METHODS: This was a multi-center retrospective study. Outpatients who were initiated on a biologic therapy from 3/1/2019 to 9/30/20 were eligible for the study. Univariate and multivariate linear regression analyses were performed to identify variables associated with a delay in biologic treatment initiation. Delay was defined as the days from decision date (prescription placement) to first infusion or delivery of medication. RESULTS: In total 411 patients (Crohn's disease, n = 276; ulcerative colitis, n = 129) were included in the analysis. The median [interquartile range-(IQR)] delay for all drugs was 20 [12-37] days (infliximab, 19 [13-33] days; adalimumab, 10 [5-26] days; vedolizumab, 21 [14-42] days; and ustekinumab, 21 [14-42] days). Multivariate linear regression analysis identified that the most important variables associated with delays in biologic treatment initiation was self-identification as Black, longer distance from treatment site, and lack of initial insurance coverage approval. CONCLUSION: There may be a significant delay in biologic treatment initiation in patients with IBD. The most important variables associated with this delay included self-identification as Black, longer distance from site, and lack of initial insurance coverage approval.

When Perfect Is the Enemy of Good: Results of a RAND Appropriateness Panel on Treat to Target in Asymptomatic IBD.

BACKGROUND: A treat-to-target strategy for inflammatory bowel disease (IBD) recommends iterative treatment adjustments to achieve clinical and endoscopic remission. In asymptomatic patients with ongoing endoscopic activity, the risk/benefit balance of this approach is unclear, particularly with prior exposure to advanced therapies. METHODS: Using the RAND/UCLA Appropriateness Method, 9 IBD specialists rated appropriateness of changing therapy in 126 scenarios of asymptomatic patients with ulcerative colitis (UC) and Crohn's disease (CD) and active endoscopic disease. Disease extent and behavior, prior treatment, prior complications, and recent disease progression were considered, as were factors that might influence decision-making, including age and pregnancy. Ratings were collected via anonymous survey, discussed at an in-person meeting, and finalized in a second anonymous survey. RESULTS: Panelists rated change in therapy as appropriate (i.e., expected benefit sufficiently outweighs potential harms from continuing therapy) in 96/126 scenarios, generally in patients with progressive, complicated, and/or extensive disease, while changing therapy was rated uncertain in 27 scenarios of mild and/or stable disease. Changing therapy was rated inappropriate in UC patients with mild and stable disease previously exposed to ≥3 therapies or with improved endoscopic activity, and in CD patients with only scattered aphthous ulcers. The validated threshold for disagreement was not crossed for any scenario. Patient age >65 years and a plan for pregnancy in the next year might influence decision-making in some settings. CONCLUSION: Appropriateness ratings can help guide clinical decision-making about changing therapy to achieve endoscopic remission in asymptomatic patients with IBD until data from ongoing randomized studies are available.

Higher Adalimumab Concentration is Associated with Complete Fistula Healing in Patients with Perianal Fistulizing Crohn's Disease.

Perianal fistulas can develop in around 30% of patients with Crohn's disease (CD) and are associated with impaired quality of life and worse outcomes including increased rates of hospitalizations and surgeries.1 The cornerstone of pharmacologic treatment for perianal fistulizing CD is anti-tumor necrosis factor therapy, mainly infliximab and adalimumab (ADM).2 Therapeutic drug monitoring (TDM) can be used to identify potential pharmacokinetic and pharmacodynamic issues and avoid or manage unwanted outcomes, such as primary nonresponse and secondary loss of response.3 There are several exposure-response relationship data demonstrating a positive correlation between serum infliximab concentrations and favorable objective therapeutic outcomes in patients with perianal fistulizing CD.4 Nevertheless, there are only limited data, which is mostly from small retrospective studies regarding the association of ADM concentration and outcomes in patients with perianal fistulizing CD.4-8 Furthermore, the optimal ADM concentration for fistula healing still remains to be elucidated. This is clinically important because drug concentration cutoffs are used in reactive and proactive TDM algorithms to define therapeutic drug concentrations. This study investigates the association of maintenance ADM concentrations with complete fistula healing (CFH) and identifies an optimal ADM concentration threshold for CFH.

Risankizumab Concentration but not IL-22 Levels are Associated With Clinical and Biochemical Remission in Patients With Crohn's Disease.

Risankizumab (RZB) is a monoclonal antibody that targets the p19 subunit of interleukin (IL)-23.1 The ADVANCE and MOTIVATE randomized controlled trials (RCTs)2 demonstrated that intravenous (IV) RZB compared with placebo led to higher rates of clinical remission and endoscopic response at week 12 in patients with active Crohn's disease (CD).2 The phase III FORTIFY RCT showed that subcutaneous (SC) RZB was significantly more effective than placebo for achieving clinical remission and endoscopic response as maintenance therapy in patients with moderate-to-severe active CD.3.

Anti-infliximab antibodies and low infliximab levels correlate with drug discontinuation in pediatric inflammatory bowel disease.

BACKGROUND: Infliximab (IFX) use is limited by loss of response often due to the development of anti-IFX antibodies and low drug levels. METHODS: We performed a single center prospective observational cohort study of pediatric and young adult subjects with inflammatory bowel disease (IBD) on IFX with over 3 years of follow-up. Infliximab levels (IFXL) and antibodies to infliximab (ATI) were measured throughout the study. Subjects were followed until IFX was discontinued. RESULTS: We enrolled 219 subjects with IBD (184: Crohn's disease; 33: Ulcerative colitis; and 2 Indeterminant colitis; 84 female, median age 14.4 years, 37% on concomitant immunomodulator). Nine hundred and nineteen serum samples (mean 4.2 ± 2.1 per patient) were tested for IFXL and ATI. During the study, 31 (14%) subjects discontinued IFX. Sixty patients had ATI. Twenty-two of those 60 patients with ATI discontinued IFX; 14 of 31 patients who discontinued IFX had detectable ATI at study onset. The combination of ATI and IFXL < 5 µg/mL at study entry was associated with the highest risk of drug discontinuation (hazard ratios [HR] ATI 4.27 [p < 0.001] and IFXL < 5 µg/mL [HR]: 3.2 p = 0.001). Patients with IFXL 5-10 µg/mL had the lowest rate of discontinuation (6%). IFX dose escalation eliminated ATI in 21 of 60 subjects. CONCLUSIONS: ATI is a strong predictor of needing to stop IFX use and inversely correlates with IFXL. Detection of ATI during therapeutic drug monitoring postinduction but also periodically during maintenance therapy identifies individuals who may benefit from IFX dose escalation and/or the addition of an immunomodulator, as these interventions may reduce or eliminate ATI.

Drug Clearance in Patients with Inflammatory Bowel Disease Treated with Biologics.

Biological therapy is very effective for treating patients with moderate to severe inflammatory bowel disease (IBD). However, up to 40% can have primary non-response, and up to 50% of the patients can experience a loss of response to anti-tumor necrosis factor therapy. These undesirable outcomes can be attributed to either a mechanistic failure or pharmacokinetic (PK) issues characterized by an inadequate drug exposure and a high drug clearance. There are several factors associated with accelerated clearance of biologics including increased body weight, low serum albumin and immunogenicity. Drug clearance has gained a lot of attention recently as cumulative data suggest that there is an association between drug clearance and therapeutic outcomes in patients with IBD. Moreover, clearance is used by model informed precision dosing (MIDP) tools, or PK dashboards, to adjust the dosing for reaching a target drug concentration threshold towards a more personalized application of TDM. However, the role of drug clearance in clinical practice is yet to be determined. This comprehensive review aims to present data regarding the variables affecting the clearance of specific biologics, the association of clearance with therapeutic outcomes and the role of clearance monitoring and MIPD in patients with IBD.

A primer on common supplements and dietary measures used by patients with inflammatory bowel disease.

Inflammatory bowel disease (IBD) is a chronic disease of the intestines. The pathophysiology of IBD, namely Crohn's disease and ulcerative colitis, is a complex interplay between environmental, genetic, and immune factors. Physicians and patients often seek complementary and alternative medicines (CAMs) as primary and supplementary treatment modalities. CAMs in IBD span a wide range of plants, herbs, pre/probiotics, and include formulations, such as cannabis, curcumin, fish oil, and De Simone Formulation. Dietary measures are also used to improve symptoms by attempting to target trigger foods and reducing inflammation. Examples include the specific carbohydrate diet, the Mediterranean diet, and a diet low in fermentable oligo-, di- and monosaccharides as well as polyols (FODMAP). We examine and review the most common complementary supplements and diets used by patients with IBD.

Development of Antibodies to Ustekinumab Is Associated with Loss of Response in Patients with Inflammatory Bowel Disease.

Monitoring of anti-drug antibodies in patients on ustekinumab is not routinely recommended in patients with inflammatory bowel disease (IBD) due to low rates of immunogenicity. AIM OF STUDY: The purpose of this study was to investigate the relationship between anti-drug antibodies detected by a drug-tolerant assay and loss of response (LOR) to therapy in a cohort of patients with IBD being treated with ustekinumab. PATIENTS AND METHODS: This retrospective study consecutively enrolled all adult patients with moderate to severe active IBD who had at least 2 years of follow-up after ustekinumab was initiated. LOR was defined as CDAI > 220 or HBI > 4 for Crohn's disease (CD) and partial Mayo subscore > 3 for ulcerative colitis (UC) and with a modification in disease management. RESULTS: Ninety patients were included (78 CD and 12 UC; mean age 37 years). Median levels of anti-ustekinumab antibodies (ATU) were significantly higher in patients with LOR compared to those with ongoing clinical response (15.2 µg/mL-eq CI (7.9-21.5) and 4.7 µg/mL-eq CI (2.1-10.5), respectively; p = 0.04). The area under the ROC curve (AUROC) for ATU in predicting LOR was 0.76. The optimal cut-off point for identifying patients with LOR was 9.5 µg/mL-eq with a sensitivity of 80% and specificity of 85%. Uni- and multivariate analyses showed that serum ATU ≥ 9.5 µg/mL-eq (hazard ratio (HR) 2.54, 95%CI (1.80-5.93)), p = 0.022, prior vedolizumab (HR 2.78, 95%CI (1.09-3.34), p = 0.019) and prior azathioprine (HR 0.54, 95%CI (0.20-0.76), p = 0.014) exposures were the only factors independently associated with LOR to UST. CONCLUSION: In our real-life cohort, ATU was identified as an independent predictor of LOR to ustekinumab in patients with IBD.

Higher Postinduction Infliximab Concentrations Are Associated With Favorable Clinical Outcomes in Pediatric Crohn's Disease: A Post Hoc Analysis of the REACH Trial.

INTRODUCTION: Exposure-outcome relationship data show that higher infliximab concentrations are associated with better outcomes in patients with Crohn's disease (CD). However, most of these data were derived from adult patients on maintenance therapy. We aimed to investigate the association of infliximab concentrations during and early after induction therapy of infliximab with short-term and long-term clinical outcomes in a pediatric CD population. METHODS: We conducted a post hoc analysis of the REACH trial which included pediatric patients with moderate-to-severe CD treated with infliximab (n = 103). The investigated outcomes were early clinical remission (CR) defined as a pediatric CD activity index score of ≤ 10, assessed at week 10, and long-term clinical response (LTCR) defined as a decrease from baseline in the pediatric CD activity index score of at least 15 points, with a total score of ≤ 30 and no need for drug discontinuation, assessed at weeks 30 and 54. RESULTS: Based on multivariable logistic regression analysis, higher week 10 infliximab concentrations were independently associated with CR at week 10 (odds ratio: 1.54; 95% confidence interval: 1.06-2.22; P = 0.022) and LTCR at week 30 (odds ratio: 1.62; 95% confidence interval: 1.12-2.36; P = 0.010). Receiver operating characteristic analysis identified week 10 infliximab concentration thresholds of ≥7.1 µg/mL and ≥6.5 µg/mL to be associated with CR at week 10 and LTCR at week 30, respectively. DISCUSSION: Higher postinduction infliximab concentrations are associated with both short-term and long-term favorable clinical outcomes in pediatric patients with CD. Tailoring dosing during induction to achieve higher infliximab exposure may lead to better outcomes in pediatric patients with CD.

Validating the Simplified Endoscopic Mucosal Assessment for Crohn's Disease: A Novel Method for Assessing Disease Activity.

BACKGROUND: To demonstrate treatment efficacy in Crohn's disease (CD), regulatory authorities require that trials include an endoscopic remission/response end point; however, standardized endoscopic assessment of disease activity, such as the Simple Endoscopic Score for Crohn's Disease (SES-CD), is not typically recorded by clinicians in practice or outside of clinical trials. The novel Simplified Endoscopic Mucosal Assessment for Crohn's Disease (SEMA-CD) was developed to be easy to use in routine clinical practice and as a trial end point. We conducted a study to assess and validate the reliability and feasibility of SEMA-CD as a measure of endoscopic disease activity. METHODS: Pre- and post-treatment ileocolonoscopy videos of pediatric (n = 36) and adult (n = 74) CD patients from 2 ustekinumab clinical trials were each scored with SEMA-CD by 2 to 3 professional central readers, blinded to clinical history and other video scorings; the correlation between SEMA-CD and SES-CD previously completed during the trials was assessed. Sensitivity to change, inter- and intrarater reliability, and comparative ease of scoring were also assessed. RESULTS: The SEMA-CD strongly correlated with SES-CD (Spearman ρ = 0.89; 95% confidence interval, 0.86-0.92). Pre- to post-treatment changes in SEMA-CD vs in SES-CD were strongly correlated, and the correlation remained strong between the scores when compared by study population (pediatric, adult), disease severity, and video quality. Intra- and inter-rater reliability were good, and SEMA-CD was rated easier than SES-CD to score 63.0% of the time, although slightly more difficult than SES-CD to score <1.0% of the time. CONCLUSIONS: The SEMA-CD is reliable, reproducible, sensitive to change, and easy to use in both pediatric and adult patients with CD.

A Systematic Review on the Interest of Drug-tolerant Assay in the Monitoring of Inflammatory Bowel Disease.

Many patients with inflammatory bowel disease [IBD] are treated with anti-tumour necrosis factor [TNF] therapies, of which infliximab [IFX] is most commonly used. Loss of response [LOR] to anti-TNF therapy due to immunogenic failure accounts for 20% of subsequent medical intervention and is defined, using a drug-sensitive assay, as low or undetectable concentration of drug with high titres of anti-drug antibodies [ADAb]. We performed a systematic review to investigate the use of a drug-tolerant assay during both induction and maintenance, to monitor patients treated with anti-TNFs. After the search on PubMed, 90 publications were reviewed. Most ADAb detection methods are drug-sensitive, cannot detect ADAb in the presence of drug, and therefore cannot be used close to drug administration when the drug concentration is too high. To overcome this major limitation, several drug-tolerant techniques have been developed and will be discussed in this review. Using drug-tolerant assays, ADAb against IFX or adalimumab [ADM] can be detected during induction and predict primary non-response or LOR. Drug-sensitive assays do not allow detection of ADAb during the induction phase when IFX or ADM concentration is typically high.

Blockade of PGK1 and ALDOA enhances bilirubin control of Th17 cells in Crohn's disease.

Unconjugated bilirubin (UCB) confers Th17-cells immunosuppressive features by activating aryl-hydrocarbon-receptor, a modulator of toxin and adaptive immune responses. In Crohn's disease, Th17-cells fail to acquire regulatory properties in response to UCB, remaining at an inflammatory/pathogenic state. Here we show that UCB modulates Th17-cell metabolism by limiting glycolysis and through downregulation of glycolysis-related genes, namely phosphoglycerate-kinase-1 (PGK1) and aldolase-A (ALDOA). Th17-cells of Crohn's disease patients display heightened PGK1 and ALDOA and defective response to UCB. Silencing of PGK1 or ALDOA restores Th17-cell response to UCB, as reflected by increase in immunoregulatory markers like FOXP3, IL-10 and CD39. In vivo, PGK1 and ALDOA silencing enhances UCB salutary effects in trinitro-benzene-sulfonic-acid-induced colitis in NOD/scid/gamma humanized mice where control over disease activity and enhanced immunoregulatory phenotypes are achieved. PGK1 and/or ALDOA blockade might have therapeutic effects in Crohn's disease by favoring acquisition of regulatory properties by Th17-cells along with control over their pathogenic potential.

Therapeutic Drug Monitoring of Biologics in Crohn's Disease.

Reactive therapeutic drug monitoring (TDM) is considered the standard of care for optimizing biologics in inflammatory bowel disease (IBD) including Crohn's disease (CD). Preliminary data show that proactive TDM is associated with positive outcomes in IBD and can be also used to efficiently guide therapeutic decisions in specific clinical scenarios. Higher biological drug concentrations are associated with favorable therapeutic outcomes in specific IBD populations or phenotypes including pediatric CD, perianal fistulizing CD, small bowel CD, and following an ileocolonic resection for CD. Future perspectives of TDM include the use of rapid testing, pharmacogenomics, and pharmacokinetic dashboards toward individualized therapy.