儿童IBD患者高炎症负荷时的TNF sink effect

No abstract available

Background: Pharmacokinetic therapeutic failure with infliximab during induction therapy can pose a significant challenge for clinicians. The objective of this study was to conduct population pharmacokinetic and exposure–response analyses in children with inflammatory bowel disease during infliximab induction therapy. Methods: A prospective single-center observational study was conducted in anti-TNF naïve pediatric patients < 21 years of age with IBD starting infliximab according to their physicians’ clinical judgment between December 2018 and December 2020. Population pharmacokinetic analysis was conducted by nonlinear mixed-effects modeling using infliximab serum levels measured by RIDASCREEN® enzyme-linked immunosorbent assay. Infliximab serum levels were also measured by point-of-care (POC) assay using RIDA®QUICK IFX monitoring and the RIDA®QUICK SCAN II. An exposure–response analysis was conducted to evaluate the association between infliximab concentrations and efficacy outcomes at week 14. Results: The typical value of infliximab clearance in a pediatric patient with IBD weighing 51 kg was 0.252 L/day, and the Vc was 3.43 L and Vp was 2.11 L. Weight and albumin were identified to be significant covariates on clearance in the final model. Tertile analysis of infliximab exposure showed an exposure–response relationship in which higher infliximab ELISA concentrations during induction therapy were associated with clinical remission at week 14 and biochemical response at week 14, but the trend did not reach statistical significance due to the small sample size. The concordance correlation coefficient between the infliximab ELISA and the POC assay was 0.905 [0.867, 0.933]. Conclusions: We report parameter estimates during infliximab induction therapy in pediatric patients with inflammatory bowel disease. Weight and albumin were identified to be significant covariates on clearance. ELISA and POC infliximab assays showed comparable results, supporting the role of POC testing for real-time therapeutic drug monitoring.

In the last two decades, biologicals have become essential in treating children and adolescents with inflammatory bowel disease. TNF-α inhibitors (infliximab, adalimumab and golimumab) are preferentially used. Recent studies suggest that early application of TNF-α inhibitors is beneficial to inducing disease remission and preventing complications such as development of penetrating ulcers and fistulas. However, treatment failure occurs in about one third of pediatric patients. Particularly, children and adolescents differ in drug clearance, emphasizing the importance of pharmacokinetic drug monitoring in the pediatric setting. Here, current data on the choice and effectiveness of biologicals and therapeutic drug monitoring strategies are reviewed.

Objectives/Goals: Youth with IBD have preventive, psychosocial, and acute care needs beyond those of peers, yet receipt of services does not match those needs. Our objectives are to assess the feasibility of (1) an individualized care plan intervention to improve perceived and measured care quality and (2) a pragmatic trial design embedded in pediatric IBD practice. Methods/Study Population: This is a pilot rollout-design randomized trial (n = 60) at a regional academic medical center. Eligible patients are 13–19 years old with IBD for at least 3 months and scheduled for a follow-up visit during the trial. Research staff recruits from one cluster at a time until goal enrollment (14–16). Enrollees are randomized 1:1 to intervention (MyIBD now) or control (MyIBD after the trial). MyIBD combines a tabular summary of individualized acute, chronic, and preventive care needs with nurse facilitator support for patients to use the information. Surveys at baseline, 6 and 12 months measure care quality (Patient Assessment of Chronic Illness Care scale, vaccines, health services) and patient self-management skills (Partners in Health scale). Implementation outcomes are collected via chart review. Results/Anticipated Results: To date, 44 subjects have been randomized. Among subjects, the mean age is 16 years; 73% have Crohn’s disease, 77% have commercial insurance, 75% receive anti-TNF therapy, and 14% live in a rural area. Mean baseline perceived care quality (PACIC scale) is 76.9 (sd 16.3; out of 100); mean baseline perceived self-management skill (PIH scale) is 78.1 (sd 13.4; out of 96). On objective care quality measures, 59% have completed the HPV vaccine series, 32% have received an additional pneumonia vaccine; in the past year 68% have had a screening for mood disorders, 20% an emergency department visit for IBD, and 18% an IBD hospitalization. To date, the IBD clinical team has achieved 100% completion (intervention subjects receive MyIBD plus nurse facilitation) and 0% contamination (control subjects inappropriately receive MyIBD). Discussion/Significance of Impact: Study results to date support the feasibility of the pragmatic, embedded trial design and indicate opportunities for improvement in care quality as perceived by patients and as measured by common preventive and acute care quality indicators. An individualized care plan supported with nurse facilitation may improve pediatric IBD care quality.

Abstract Background Proactive therapeutic drug monitoring (TDM) for tumor necrosis factor alpha antagonist (anti-TNF) therapy in adult inflammatory bowel disease (IBD) remains controversial, with inconsistent findings from clinical trials and meta-analyses. Pediatric societal guidelines endorse the implementation of proactive TDM. However, the integration of TDM into clinical practice by pediatric gastroenterologists has not been characterized. This study was undertaken to delineate the practice patterns, attitudes, and barriers associated with anti-TNF TDM among pediatric gastroenterologists across the United States. Methods A 28-item questionnaire was developed based on prior adult surveys and current pediatric literature, undergoing 3 rounds of iteration. The survey was comprised of physician demographics, center demographics, TDM practice behavior questions and case-scenarios. The survey was deployed through the ImproveCareNow Learning Health System Network between February and June 2023. Results Among 380 invitees, 256 (77%) completed the questionnaire. Among respondents, 67% (171) were academic-affiliates, and 55% (140) were female. There was notable variability in the number of patients with IBD seen per practice. All respondents reported using TDM for infliximab, and the majority for adalimumab, and the vast majority utilizing a proactive TDM approach. The principal barriers to TDM implementation were insurance denials, cost, and logistical challenges. More respondents indicated they would initiate TDM during infliximab induction for severe ulcerative colitis than for Crohn’s disease. Conclusions In contrast to the adult literature, most pediatric gastroenterologists report undertaking proactive TDM for anti-TNF agents in IBD management. Precision dosing tools reflective of an individual’s pharmacokinetics are desired and need to be further studied.

Anti-Saccharomyces cerevisiae antibodies (ASCA) have been associated with a more aggressive Crohn’s disease (CD) phenotype. However, the effect of ASCA serology on the response to biologic therapy, specifically in children on anti-TNF therapy, is unknown. Our goal was to assess whether ASCA levels are associated with clinical outcomes in pediatric CD patients treated with anti-TNF antibodies. A single center retrospective study. Demographic, clinical and laboratory data were collected from pediatric CD patients (aged 2.2-17.9 years) treated with anti-TNF therapy, who were tested for IgG ASCA levels upon diagnosis, between 2010-2023. The cut-off value for a positive ASCA result was defined as 30 EU/mL. Clinical outcomes included durability of anti-TNF therapy, corticosteroid-free survival (CSFS) at week 52 of therapy, IBD-associated hospitalizations and IBD related surgery. One hundred seventy-two patients with CD (69 ,39% females) with a median age at diagnosis of 13.5 (11.1-15.4) years were included. Ninety-two (52%) patients had positive ASCA (> 30 EU/mL). ASCA positivity was associated with female sex (p=0.02) and ileocolonic disease location at diagnosis (p=0.02). Sixty-six (37%) patients were treated with infliximab and 111 (63%) with adalimumab. The median time of follow-up in our cohort was 115 (65-174) weeks. Time to discontinuation of anti-TNF was comparable between patients with ASCA positive and negative levels (97.8% vs. 97.4% and 89.3% vs. 87.4% at 1 and 3 years, respectively). In addition, time to IBD-associated hospitalization and surgery were also similar. Interestingly, patients with positive ASCA achieved CSFR more often, compared to patients with ASCA negative (P=0.04). Sub-analysis of patients with high ASCA values, the top 20%, (>80 EU/mL) demonstrated significantly longer durability of anti-TNF, compared to the patients with lower ASCA levels (<80 EU/mL,p= 0.02). ASCA positivity is not associated with worse outcomes in pediatric patients with CD treated with TNF antagonists.

Failure of anti-TNF therapy is a real concern in children with inflammatory bowel disease (IBD) owing to the limited therapeutic arsenal. Anti-TNF drugs modulate the immune response, a key driver of chronic inflammation in IBD. Accordingly, we analyzed changes in the frequency of T-lymphocyte and cytokine levels after 6 weeks of treatment to identify potential biomarkers of response to anti-TNF drugs. We recruited 77 patients under 18 years of age diagnosed with IBD and treated with an anti-TNF drug. Using flow cytometry and multiplex ELISA, we analyzed 31 T-lymphocyte populations and four cytokines. We identified changes in 10 populations of T lymphocytes after 6 weeks of treatment. Naïve Tregs were associated with a primary response to anti-TNF drugs, while activated Tregs were associated with long-term response. Serum INF-γ levels were decreased after anti-TNF treatment in children with Crohn’s disease (CD), but not in those with ulcerative colitis (UC). The memory CD8+ Type 2 Cytotoxic T (Tc2) subset increased in non-responders with CD and the CD4+ memory Th17 cells increased in non-responders with UC. These findings could help us to understand the cellular regulation of anti-TNF therapy, to identify children at a higher risk of treatment failure, and, potentially, to develop more personalized therapeutic strategies.

Background: The utilization of anti-tumor necrosis factor-α (anti-TNF-α) biosimilars in inflammatory bowel disease (IBD) is constantly increasing. However, pediatric data are limited. This study aimed to assess the effectiveness and safety of adalimumab biosimilar (ADL-BioS) in pediatric IBD patients. Methods: All consecutive pediatric IBD patients from the Sicilian Network for Inflammatory Bowel Disease cohort treated with ADL-BioS from 2019 to 2021 were recruited. Remission at weeks 14 and 52, treatment persistence, and adverse events were the endpoints of this study. Factors associated with clinical remission and treatment persistence were examined. Results: There were 41 patients in total. Nine (22%) patients were switched from the reference product to ADL-BioS. Two patients had multiple switches. Eleven months was the median follow-up period. Clinical remission was attained by 70.7% and 72.0% of patients on weeks 14 and 52, respectively. Four (9.8%) adverse events occurred (10.1/100 person-year). Treatment persistence was 85.4% at 1 and 2 years. Patients with a longer duration of disease had a higher probability of stopping their treatment (p = 0.036). Conclusions: This is the first real-world study that particularly addresses the use of ADL-BioS in pediatric IBD. With high rates of treatment persistence and a low frequency of non-serious side effects, ADL-BioS seems to be effective.

BACKGROUND/AIMS Changes in gene expression profiles among individuals with inflammatory bowel diseases (IBDs) could potentially influence the responsiveness to anti-TNF treatment. The aim of this study was to identify genes that could serve as predictors of early response to anti-TNF therapies in pediatric IBD patients prior to the initiation of treatment. METHODS We conducted a prospective, longitudinal, and multicenter study, enrolling 24 pediatric IBD patients aged less than 18 years who were initiating treatment with either infliximab or adalimumab. RNA-seq from blood samples was analyzed using the DESeq2 library by comparing responders and non-responders to anti-TNF drugs. RESULTS Bioinformatic analyses unveiled 102 differentially expressed genes, with 99 genes exhibiting higher expression in responders compared to non-responders prior to the initiation of anti-TNF therapy. Functional enrichment analyses highlighted defense response to Gram-negative bacteria (FDR = 2.3 ×10-7) as the most significant biological processes, and hemoglobin binding (FDR = 0.002), as the most significant molecular function. Gene Set Enrichment Analysis (GSEA) revealed notable enrichment in transcriptional misregulation in cancer (FDR = 0.016). Notably, 13 genes (CEACAM8, CEACAM6, CILP2, COL17A1, OLFM4, INHBA, LCN2, LTF, MMP8, DEFA4, PRTN3, AZU1, and ELANE) were selected for validation, and a consistent trend of increased expression in responders prior to drug administration was observed for most of these genes, with findings for 4 of them being statistically significant (CEACAM8, LCN2, LTF2, and PRTN3). CONCLUSIONS We identified 102 differentially expressed genes involved in the response to anti-TNF drugs in children with IBDs and validated CEACAM8, LCN2, LTF2, and PRTN3. Genes participating in defense response to Gram-negative bacterium, serine-type endopeptidase activity, and transcriptional misregulation in cancer are good candidates for anticipating the response to anti-TNF drugs in children with IBDs.

Combination therapy consists of both a monoclonal antibody against tumor necrosis factor (anti-TNF) (infliximab (IFX) or adalimumab (ADA)) and an immunomodulator (IMM) (thiopurines (TP) or methotrexate (MTX)). Although combination therapy improves clinical outcomes, the IMM may be discontinued to mitigate the risk of IMM-related adverse events. However, it is unknown how de-escalation impacts clinical outcomes in children with IBD. This is a retrospective review of pediatric patients with IBD (<18 years of age) initiated on combination therapy between January 2014 and December 2019. Demographic and laboratory data were recorded at initiation of combination therapy, prior to IMM discontinuation, and between 6-12 months after de-escalation. The primary objectives were to assess the impacts of de-escalation on clinical remission rates, laboratory markers, and anti-TNF trough levels, and to evaluate factors that predict a poor response to de-escalation. Linear mixed effects models with random intercepts accounting for correlated measures with a patient across time were used to compare differences between study groups (and subgroups). Chi-square and Kruskal-Wallis tests were used for comparisons between patients who did and did not require subsequent escalation. Hypothesis testing was conducted at an alpha of 0.05. We included 152 pediatric patients, of whom 126 patients had CD and 26 patients had UC/IC. The mean age of initiating combination therapy was 13.76 (± 3.1) years, and the mean duration of combination therapy was 106 (± 56) weeks. De-escalation did not increase the risk of worsening disease activity or affect laboratory values, including albumin, hemoglobin, sedimentation rate, and c-reactive protein. In patients with CD on IFX and TP, calprotectin significantly increased from 107 ug/g to 383 ug/g (p<0.05) and anti-TNF trough levels significantly decreased from 19 ug/ml to 14 ug/ml (p<0.05) after de-escalation. Eighteen percent (27 patients) of patients required subsequent escalation in therapy. Amongst these patients, anti-TNF levels were lower and CRP and ESR were higher prior to de-escalation compared to patients who did not require adjustments (p<0.05). Only patients with CD on IFX who discontinued the TP had a significant increase in fecal calprotectin and decrease in IFX levels, though the drug levels remained within therapeutic range >10 ug/ml, and there was no increased risk of worsening disease. Lower anti-TNF levels and higher inflammatory markers prior to de-escalation may be predictive of patients requiring escalation in therapy after stopping the IMM. De-escalation in children on combination therapy may be safely considered with close attention to clinical symptoms, inflammatory markers, and anti-TNF drug levels, especially in children with CD on IFX and TP combination therapy.

Although biologics are widely used in pediatric inflammatory bowel disease (IBD), the long-term durability of the biologics in children remains incompletely understood. Using the Korean Health Insurance Review and Assessment Service database (2007-2023), we identified patients aged 6-17 years with Crohn’s disease (CD) or ulcerative colitis (UC) who initiated infliximab (IFX) or adalimumab (ADA) as first biologic therapy. Persistence was evaluated using Kaplan-Meier analysis at 6 months, 1 year, and 5 years. Subgroup analyses assessed concomitant immunomodulator (IM) use and duration. Among 2542 CD patients, 1895 initiated IFX and 647 ADA; 581 UC started IFX. Among CD, IFX persistence was 97.47%. 88.0%, and 78.64%, while ADA showed 95.58%, 87.17%, and 72.79%. In UC, IFX persistence was 76.21%, 40.35% and 24.66%. In CD, IFX with IM improved durability compared with monotherapy (HR 0.67, 95% CI 0.52-0.85, p = 0.0003 at 1 year; HR 0.77, 95% CI 0.63-0.95, p = 0.0078 at 5 years), mainly when IM was continued ≥6 months, while ADA showed no clear durability benefit from the combination therapy. In UC, IFX durability improved with IM ≥ 6months at 1 year (HR 0.65, 95% CI 0.44-0.96, p = 0.023), while the effect was attenuated over time. In this nationwide, real-world study, IFX and ADA demonstrated comparable persistence in CD, while IFX durability in UC declined substantially. Sustained IM use for ≥6 months enhanced IFX durability, whereas short-term use offered limited benefit. These findings underscore the importance of IM duration in optimizing anti-TNF therapy in pediatric IBD and provide robust evidence from a nationwide population-based cohort.

Inflammatory bowel disease (IBD) in children, including Crohn’s disease (CD), ulcerative colitis (UC), and IBD-unclassified (IBD-U), requires early and effective intervention to achieve remission and prevent complications. Infliximab (IFX), an anti-TNF agent, is a mainstay of therapy, and proactive therapeutic drug monitoring (TDM) during induction may optimize outcomes, though limited pediatric data are available. A retrospective cohort study was conducted at Sidra Medicine, including pediatric IBD patients treated with IFX from 2015 to 2024. Proactive TDM involved scheduled drug level assessments before doses 2, 3, and the first maintenance dose and infliximab dose escalation were done when levels were low from target during induction. Disease activity was assessed using the Pediatric Crohn’s Disease Activity Index (PCDAI), Pediatric Ulcerative Colitis Activity Index (PUCAI), and fecal calprotectin at baseline and 12 weeks. Patients were stratified by TDM approach, and statistical analyses were performed using R software and Jamovi software. Of 148 patients included, 82.4% underwent proactive monitoring. By week 12, PCDAI and PUCAI scores significantly decreased (mean PCDAI: 42.3 to 5.93, p < 0.0001 and mean PUCAI: 42.6 to 7.19, p = 0.0044). Fecal calprotectin mean levels declined from 1544 µg/g to 425.7 µg/g (p < 0.0001). Patients with proactive monitoring demonstrated superior remission rates and lower disease activity scores. Proactive therapeutic drug monitoring during infliximab induction is associated with improved early clinical remission and biochemical response in pediatric Inflammatory bowel disease. This approach might result in early sustained remission that might modify the course of the disease. Conflict of interest: Dr. Abbas, Rasha: No conflict of interest Haidar, Omer: No conflict of interest Al Neirab, Abdallah: No conflict of interest Ibrahim, Nazira: No conflict of interest Abdelrahman, Hatim: No conflict of interest Al-Mudahka, Fatma: No conflict of interest Akobeng, Anthony k: No conflict of interest Elawad, Mamoun Abdelrahman: No conflict of interest

No abstract available

The genetic polymorphisms rs2395185 and rs2097432 in HLA genes have been associated with the response to anti-TNF treatment in inflammatory bowel disease (IBD). The aim was to analyze the association between these variants and the long-term response to anti-TNF drugs in pediatric IBD. We performed an observational, multicenter, ambispective study in which we selected 340 IBD patients under 18 years of age diagnosed with IBD and treated with anti-TNF drugs from a network of Spanish hospitals. Genotypes and failure of anti-TNF drugs were analyzed using Kaplan-Meier curves and Cox logistic regression. The homozygous G allele of rs2395185 and the C allele of rs2097432 were associated with impaired long-term response to anti-TNF drugs in children with IBD after 3 and 9 years of follow-up. Being a carrier of both polymorphisms increased the risk of anti-TNF failure. The SNP rs2395185 but not rs2097432 was associated with response to infliximab in adults with CD treated with infliximab but not in children after 3 or 9 years of follow-up. Conclusions: SNPs rs2395185 and rs2097432 were associated with a long-term response to anti-TNFs in IBD in Spanish children. Differences between adults and children were observed in patients diagnosed with CD and treated with infliximab.

Background: Up to 30% of patients with pediatric inflammatory bowel disease (IBD) do not respond to anti-Tumor Necrosis Factor (anti-TNF) therapy. The aim of this study was to identify pharmacogenomic markers that predict early response to anti-TNF drugs in pediatric patients with IBD. Methods: An observational, longitudinal, prospective cohort study was conducted. The study population comprised 38 patients with IBD aged < 18 years who started treatment with infliximab or adalimumab (29 responders and nine non-responders). Whole gene expression profiles from total RNA isolated from whole blood samples of six responders and six non-responders taken before administration of the biologic and after two weeks of therapy were analyzed using next-generation RNA sequencing. The expression of six selected genes was measured for purposes of validation in all of the 38 patients recruited using qPCR. Results: Genes were differentially expressed in non-responders and responders (32 before initiation of treatment and 44 after two weeks, Log2FC (Fold change) >0.6 or <−0.6 and p value < 0.05). After validation, FCGR1A, FCGR1B, and GBP1 were overexpressed in non-responders two weeks after initiation of anti-TNF treatment (Log2FC 1.05, 1.21, and 1.08, respectively, p value < 0.05). Conclusion: Expression of the FCGR1A, FCGR1B, and GBP1 genes is a pharmacogenomic biomarker of early response to anti-TNF agents in pediatric IBD.

Background: Biological therapy is frequently used for the treatment of inflammatory bowel disease (IBD); however, the long-term efficacy of anti-tumor necrosis factor-alpha (TNF−α) therapies, such as infliximab (IFX) and adalimumab (ADA), is often compromised by the development of antidrug antibodies (AIFX and AADA, respectively). While several individual factors are known to contribute to immunogenicity, the complex, interactive effects of various clinical variables have not been fully elucidated in a real-world setting. Methods: We conducted a hierarchical logistic regression analysis on a retrospective cohort of 153 pediatric and adult IBD patients receiving IFX or ADA therapy to identify clinical factors and their interactions associated with AIFX/AADA positivity. The analysis progressively incorporated demographic, disease-related, and treatment-related variables, culminating in a model that included two- and three-way interaction terms. Results: Our final model demonstrated modest predictive power, with a Nagelkerke R2 of 0.287, explaining less than 30% of the variance in antibody positivity using readily available clinical data (AUC of 0.806, 71.0% sensitivity and 77.6% specificity). Key predictors included the type of biological therapy (IFX vs. ADA) and the duration of treatment, with IFX therapy being a significant independent predictor (OR = 6.940, p = 0.004) for antibody positivity. Importantly, we identified novel three-way interactions, revealing that the combined effect of age at disease onset, IBD subtype, and biological therapy type significantly influences antibody formation (p = 0.042), particularly in childhood-onset ulcerative colitis patients treated with IFX. A similar interaction was found for treatment duration, IBD subtype, and therapy type (p = 0.042), where the risk of antibody positivity with IFX increased significantly with treatment length, particularly in UC patients. Conclusions: This study highlights that the combination of routine clinical variables in IBD offers a data-driven, mechanistically insightful framework, supporting the prediction of AIFX/AADA positivity to a modest extent. This framework requires prospective and external validation before clinical implementation.

Abstract Inflammatory bowel diseases (IBD) require effective therapies to prevent morbidity and maintain quality of life. The introduction of biologic agents, beginning with monoclonal antibodies targeting tumor necrosis factor (TNF) alpha, has launched a new era of advancements that have markedly improved short‐ and long‐term outcomes of Crohn's disease and ulcerative colitis. Along with these improvements, there have been challenges to address in optimizing use of biologic therapies in children with IBD. Young children may have rapid drug clearance, and growing children have changing medication needs related to changes in body size, metabolism, and development. For these and other reasons, one size (one dose) does not fit all. Therapeutic drug monitoring (TDM), which involves measurement of drug concentration in serum usually, typically at the predose trough, has emerged as a valuable tool for optimizing dosing and preventing pharmacokinetic failure. This society paper reviews the use of TDM, including target ranges during induction and maintenance therapy for anti‐TNF agents and for emerging biologics. This report has been compiled by pediatric gastroenterologists on behalf of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition IBD committee after extensive review of the current literature. The purpose of this clinical position statement is to provide guidance to clinicians in the use of TDM to optimize the treatment of children with IBD.

Highlights What are the main findings? Pharmacogenetic variants shape treatment response to azathioprine and anti-TNF agents in pediatric IBD. Genetic differences influence both efficacy and risk of adverse events. Evidence remains limited and heterogeneous. What is the implication of the main finding? Pharmacogenetics paves the way for personalized IBD therapy in children, but further clinical validation is still required. Abstract Background/Objectives: Pharmacogenetics examines genome variability and its influence on drug efficacy and toxicity, forming the foundation for personalized medicine. Patients with inflammatory bowel disease (IBD) treated with azathioprine with thiopurine S-methyltransferase (TPMT) deficiency are at an increased risk of drug-related toxic effects. Variability in the HLA-DQA1 and DQB1 alleles may lead to an inadequate therapeutic response. This study aimed to determine the significance of TPMT and HLA-DQ Allelic Variants in therapy optimization planning. Methods: A retrospective study was conducted to determine TPMT gene polymorphism and the presence of HLA-DQA1 and HLA-DQB1 alleles in children diagnosed with IBD and treated at the Institute for Child and Youth Health Care of Vojvodina in May 2023. Results: The study included 104 children with a mean age of 13.71 ± 3.1 years, with a balanced gender distribution. A TPMT mutation was identified in only one child. The most common HLA-DQA1 alleles were *01 (49%) and *05 (28.8%), while the most frequent allele at the HLA-DQB1 locus was 03 (15.4%). The presence of the HLA-DQA105 allele was associated with the development of anti-drug antibodies against anti-TNF therapy (RR: 1.23; 95% CI: 1.03–1.50), while the presence of HLA-DQA101 was significantly more frequent in children on optimized therapeutic regimens (RR: 1.63; 95% CI: 1.13–2.10). Conclusions: Prior to the initiation of azathioprine therapy, TPMT genotyping should be performed to prevent adverse effects and ensure optimal drug dosing. Identification of the HLA-DQA105 and HLA-DQA101 alleles plays an important role in the planning of biological therapy regimens, including decisions on dose escalation or interval shortening.

Introduction Recently there has been significant progress in research on the pathogenesis of inflammatory bowel diseases (IBD). Aim Our study aimed to assess selected markers of bacterial translocation in children with IBD in relationship to disease activity. Material and methods Lipopolysaccharides (LPS) – markers of bacterial translocation – and proinflammatory cytokines – interleukin (IL)-8, IL-12 and tumor necrosis factor (TNF) α – were assessed in the serum of 27 pediatric IBD patients at the outbreak of the illness and then 1 and 3 months after the introduction of the treatment. The analyzed markers were taken once in 6 healthy children in the control group. Results Serum TNF-α and LPS concentrations were significantly higher in IBD patients than in the control group (1.74 vs. 0.83 ng/ml and 21.83 vs. 10.26 pg/ml, p < 0.05). In the study group, clinical and laboratory activity mediators significantly decreased during 3 months of the treatment. All proinflammatory cytokines decreased, but significant down-regulation was observed only in relation to IL-12 (129.21 vs. 82.98 pg/ml, p < 0.05) in CD and IL-8 (32.72 vs. 20.97 pg/ml, p < 0.05) in UC patients. TNF-α levels decreased but did not reach values as in healthy children, while LPS levels increased in both groups. Conclusions IL-12 in CD and IL-8 in UC could be non-invasive markers of reduced inflammation during IBD in children. Improvements in clinical status and reductions in systemic inflammatory markers do not necessarily mean complete cessation of the inflammatory cascade. The elevated TNF-α and LPS levels found in patients in early remission may be a marker of subclinical inflammation.

The human leukocyte antigen (HLA) allele group HLA-DQA1*05 predisposes to ulcerative colitis (UC) and is associated with the development of antibodies against infliximab in patients with inflammatory bowel disease (IBD). Therefore, we hypothesized that the presence of HLA-DQA1*05 correlates with characteristics of pediatric IBD. Within a multi-center cohort in Poland, the phenotype at diagnosis and worst flare was established and HLA-DQA1*05 status was assessed enabling genotype-phenotype analyses. HLA-DQA1*05 was present in 221 (55.1%) out of 401 children with IBD (UC n = 188, Crohn’s disease n = 213). In UC, the presence of HLA-DQA1*05 was moderately associated with a large extent of colonic inflammation at diagnosis (E4 55% more frequent in HLA-DQA1*05-positive patients, p = 0.012). PUCAI at diagnosis (p = 0.078) and the time from UC diagnosis to the first administration of biologic treatment (p = 0.054) did not differ depending on HLA-DQA1*05 status. The number of days of hospitalization for exacerbation was analyzed in 98 patients for whom sufficient follow-up was available and did not differ depending on HLA-DQA1*05 carriership (p = 0.066). HLA-DQA1*05 carriers with CD were less likely to present with both stenosing and penetrating disease (B2B3, p = 0.048) and to have active disease proximal to the ligament of Treitz (L4a) at the worst flare (p = 0.046). Future research focusing on explaining and preventing anti-TNF immunogenicity should take into account that ADA may develop not only as an isolated reaction to anti-TNF exposure but also as a consequence of intrinsic differences in the early course of UC.

Background: Therapeutic drug monitoring (TDM) of infliximab (IFX) and adalimumab (ADL) mainly relies on the use of enzyme-linked immunosorbent assays (ELISA). More recently, rapid assays have been developed and validated to reduce turnaround time (TAT). Here, we compared IFX and ADL concentrations measured with both ELISA and a new fluorescence-based lateral flow immunoassay (AFIAS). Methods: In serum samples from pediatric patients, IFX and ADL drug levels, and total anti-IFX antibodies were measured using clinically validated ELISA kits (Immundiagnostik AG). Samples were further analyzed using a new rapid assay (AFIAS, Boditech Med Inc.) to measure drug levels and total anti-IFX antibodies. Results: Spearman’s correlation coefficients (rho) were 0.98 [95% confidence interval (CI) 0.97 to 0.99] for IFX (p < 0.001) and 0.83 (95% CI 0.72 to 0.90) for ADL (p < 0.001). Calculated % bias was −14.09 (95% Limits of agreement, LoA, −52.83 to 24.66) for IFX and 15.79 (LoA −37.14 to 68.73) for ADL. For the evaluation of total anti-IFX antibodies, we did not collect sufficient data to establish a statistically significant correlation between AFIAS and ELISA. The inter-rater agreement showed a “substantial” and a “moderate” agreement for IFX and ADL, respectively. Conclusions: Our results show that the AFIAS assay has an accuracy and analytical performance comparable to that of the ELISA method used for TDM of IFX and ADL. Therefore, the introduction of this device into routine clinical practice could provide results more quickly and with similar accuracy as ELISA, allowing clinicians to rapidly formulate clinical decisions.

Objectives: Limited data are currently available regarding anti-tumor necrosis factor (TNF) use and outcomes in very early onset inflammatory bowel disease (VEOIBD) patients. We aimed to assess the long-term outcomes and time to progression to anti-TNF treatment in VEOIBD patients. Methods: We retrospectively reviewed IBD patients diagnosed under 6 years of age, between January 2005 and December 2019, from the British-Columbia (BC) Pediatric IBD database. Demographic data, disease characteristics, disease location and severity were documented. Data on anti-TNF treatment at initiation and during follow up including type of biologic, dosing, and response were collected. Kaplan-Meier curves were used to assess the number of years to progression to anti-TNF treatment and the parameters influencing commencement. Results: Eighty-nine patients with VEOIBD were diagnosed during the study period. Median age at diagnosis was 3.8 years [interquartile range (IQR) 2.6–5.1], 45.3% had Crohn disease (CD) and 62.8% were males. Median duration of follow up was 6.39 years (IQR 3.71–10.55). Anti-TNF treatment was started on 39.5% of patients and 7.0% underwent surgery. Rapid progression to biologic treatment was associated with Perianal fistulizing disease or stricturing disease in CD patients (P = 0.026, P = 0.033, respectively), and disease severity (P = 0.017) in ulcerative colitis (UC) patients. The median dose of infliximab at 1 year was 10 mg/kg (IQR 7.5–11) and a median dose interval of 4.5 weeks (IQR 4–6). Clinical remission was reported in 61.8% of patients on their first biologic agent. Conclusions: The response rate was higher than previously reported and might be due to higher infliximab dosing with shorter infusion intervals than standard dosing.

Anti-drug antibodies can interfere with the activity of anti-tumor necrosis factor (TNF) agents by increasing drug clearance via direct neutralization. The presence of anti-drug antibodies is clinically relevant when trough drug concentrations are undetectable or sub-therapeutic. However, traditional immunoassay is not easily and rapidly accessible, making the translation of the results into treatment adjustment difficult. The availability of a point-of-care (POC) test for therapeutic drug monitoring (TDM) might represent an important step forward for improving the management of inflammatory bowel disease (IBD) patients in clinical practice. In this pilot study, we compared the results obtained with POC tests with those obtained by enzyme-linked immunosorbent assay (ELISA) in a group of IBD patients treated with Infliximab (IFX). We showed that POC test can reliably detect presence of antibody-to-IFX with 100% of specificity and 76% sensitivity, in strong agreement with the ELISA test (k-coefficient = 0.84).

Background: The management of pediatric inflammatory bowel disease (PIBD) has evolved significantly over the past two decades, transitioning from corticosteroids and immunomodulators to biologic and small-molecule therapies. These advances have aimed not only to control inflammation but also to promote mucosal healing, improve growth, and enhance long-term quality of life. Objectives: This narrative review summarizes current evidence on the efficacy, safety, and clinical applications of biologic and novel small-molecule therapies in PIBD, highlighting emerging trends in personalized and precision-based management. Methods: A literature search was performed across PubMed, Embase, and the Cochrane Library, focusing on studies published within the last five years. Additional data were retrieved from key guidelines and position papers issued by ECCO–ESPGHAN, SIGENP, the FDA, and the EMA. Results: Anti–tumor necrosis factor (TNF) agents such as infliximab and adalimumab remain first-line biologics with proven efficacy in remission induction and maintenance. Newer biologics—vedolizumab, ustekinumab, risankizumab, and mirikizumab—offer alternatives for anti-TNF-refractory cases, showing encouraging short-term results and favorable safety profiles. Although many are approved only for adults with limited pediatric evidence, emerging small molecules—including Janus kinase (JAK) inhibitors (tofacitinib, upadacitinib) and sphingosine-1-phosphate (S1P) modulators (etrasimod)—provide oral, rapidly acting, and non-immunogenic treatment options for refractory disease. Furthermore, the gut microbiome is increasingly recognized as an emerging therapeutic target in PIBD, with growing evidence that host–microbiome interactions can influence both the efficacy and safety of biologics and small-molecule therapies. Conclusions: While biologics and small molecules have transformed PIBD management, challenges remain, including high treatment costs, limited pediatric trial data, and variable access worldwide. Future directions include multicenter pediatric studies, integration of pharmacogenomics, and biomarker-guided precision medicine to optimize early, individualized treatment and improve long-term outcomes.

In the current era of treat-to-target strategies, therapeutic drug monitoring (TDM) has emerged as a potential tool in optimizing the efficacy of biologics for children diagnosed with inflammatory bowel disease (IBD). The incorporation of TDM into treatment algorithms, however, has proven to be complex. “Proactive” TDM is emerging as a therapeutic strategy due to a recently published pediatric RCT showing a clear benefit of “proactive” TDM in anti-TNF therapy. However, target therapeutic values for different biologics for different disease states [ulcerative colitis (UC) vs. Crohn's disease (CD)] and different periods of disease activity (induction vs. remission) require further definition. This is especially true in pediatrics where the therapeutic armamentarium is limited, and fixed weight-based dosing may predispose to increased clearance leading to decreased drug exposure and subsequent loss of response (pharmacokinetic and/or immunogenic). Model-based dosing for biologics offers an exciting insight into dose individualization thereby minimizing the chances of losing response. Similarly, point-of-care testing promises real-time assessment of drug levels and individualized decision-making. In the current clinical realm, TDM is being used to prolong drug durability and efficacy and prevent loss of response. Ongoing innovations may transform it into a personalized tool to achieve optimal therapeutic endpoints.

Ulcerative colitis (UC) is a disabling disease, characterized by chronic inflammation of the colon, with a rising prevalence worldwide in the pediatric age group. Although UC presents in children with varying severity, disease extent, and comorbidities, initial treatment is essentially uniform, consisting of 5-aminosalicylate drugs with corticosteroid induction for those with moderately to severely active disease. With the advent of anti-tumor necrosis factor (TNF) biologic therapy and several new biologics and small-molecule drugs for UC, precision medicine approaches to treatment are needed to more rapidly achieve sustained remission, restore quality of life, normalize development, and limit exposure to toxic corticosteroids in children with UC. Here, we review available data on clinical, biochemical, histopathologic, and molecular predictors of treatment response in UC. We also address known predictors and special treatment considerations in specific relevant scenarios such as very-early-onset UC, acute severe UC, ileal pouch anal anastomosis, and UC with concomitant primary sclerosing cholangitis. The review concludes with a prediction of how machine learning will integrate multimodal patient data to bring precision medicine to the bedside of children with UC in the future.

Introduction Personalized medicine in inflammatory bowel disease (IBD) aims to achieve maximum effectiveness through rapid induction and maintenance of remission. To achieve this goal, reliable predictors of disease course are needed. The aim of this study was to identify early markers of IBD’s poor course understood as the need for anti-tumor necrosis factor (anti-TNF-α) treatment. Material and methods We analyzed the clinical, laboratory, radiological, and endoscopic data of children with IBD. These parameters were assessed at the time of diagnosis (T0) and 8–12 weeks (T1) after the start of induction therapy. The results of patients who did not require anti-TNF-α treatment were compared to children who needed such treatment during the 2-year observation time. Results 58.14% of patients with Crohn’s disease (CD) and 31.71% of patients with ulcerative colitis (UC) required biological therapy. Patients with CD and UC receiving biological therapy, compared with those without, differed in selected clinical and laboratory parameters both at T0 and T1. In multivariate analysis, the risk of anti-TNF-α therapy in patients with CD was associated with the lack of normalization of mean corpuscular volume (MCV) and Pediatric Crohn’s Disease Activity Index (PCDAI). In patients with UC, higher albumin levels reduced this risk. Conclusions In children with IBD, disease activity and concentrations of selected biochemical parameters assessed within 3 months after diagnosis may be helpful in predicting a poor outcome of CD and UC.

Subcutaneous infliximab (SC-IFX) offers comparable efficacy and safety profiles to intravenous infliximab (IV-IFX) use in patients with inflammatory bowel disease (IBD), with relative pharmacokinetic stability demonstrated 1, 2. Minimal experience with SC-IFX use in paediatric IBD has been described3, 4. We aimed to assess the clinical tolerability of SC-IFX use in children with IBD requiring anti-tumour-necrosis factor (anti-TNF) treatment. A prospectively identified cohort of children with IBD commenced 120mg fortnightly SC-IFX dosing between February to July 2024 in an Australian tertiary paediatric centre. Treatment followed switch from stable intravenous infliximab (IV-IFX) biosimilar maintenance dosing, or as part of induction treatment. Baseline and four-weekly biochemical and clinical disease activity assessments were undertaken over a 12 week period of follow-up. Thirty-one of thirty-three patients completed the 12-week period of treatment follow-up. Median age was 15 years (IQR 14-16.5 years) and 76% (25/33) were male. Twenty-seven patients (82%) had a Crohn’s disease diagnosis. SC-IFX was prescribed as part of induction dosing in 18% (6/33). Biochemical parameters are outlined in Table 1. Median infliximab level increased by 10mg/L to 17.6mg/L at week 12, with a statistically significant increase between baseline level and all other timepoints over the follow-up period (Figure 1). Sixteen patients (48%) had a serum infliximab level greater than 20mg/L at 12 week follow-up. There was no statistically significant change in clinical disease activity indices (Paediatric Crohn’s Disease Activity Index [PCDAI] or Paediatric Ulcerative Colitis Activity Index [PUCAI]) assessed across study timepoints. No correlation between patient characteristics, including demographics, immunomodulator use and previous (if any) IV-IFX regimen, and biochemical markers at baseline or week 12 was seen. High tolerability and treatment persistence were observed in our patient group without any safety concerns. We describe the largest cohort of children with IBD prescribed SC-IFX with short-term follow-up. Serum infliximab level increased by 10mg/L over the study period, without significant change in faecal calprotectin and clinical disease activity indices. We observed high treatment persistence in our patient group. Our real-world experience suggests paediatric SC-IFX use may be a reasonable alternative to IV-IFX dosing in children in with IBD. Further large-cohort studies and long-term paediatric data is required. 1)Schreiber S, Ben-Horin S, Leszczyszyn J et al. Randomized Controlled Trial: Subcutaneous vs Intravenous Infliximab CT-P13 Maintenance in Inflammatory Bowel Disease. Gastroenterology 2021; 160: 2340-53. 2)Buisson A, Nachury M, Bazoge M et al. Long-term effectiveness and acceptability of switching from intravenous to subcutaneous infliximab in patients with inflammatory bowel disease treated with intensified doses: The REMSWITCH-LT study. Aliment Pharmacol Ther 2024; 59: 526-34. 3)Gianolio L, Armstrong K, Swann E et al. Effectiveness of Switching to Subcutaneous Infliximab in Pediatric Inflammatory Bowel Disease Patients on Intravenous Maintenance Therapy. J Pediatr Gastroenterol Nutr 2023; 77: 235-9. 4)Gianolio L, Armstrong K, Swann E et al. OC5 Effectiveness and safety of switching to subcutaneous infliximab in paediatric inflammatory bowel disease patients on established intravenous biosimilar infliximab maintenance therapy: real world data from a regional cohort. Frontline Gastroenterology 2024; 15: A4-A.

No abstract available

Identifying minimally invasive diagnostic biomarkers that predict and monitor response to TNF inhibitors would enable treatment to be personalized and increase knowledge of the biological pathways associated with response or lack thereof. Children and adolescents with Crohn’s disease who started treatment with infliximab (IFX) were enrolled in a prospective, multi-center (n=6) trial to identify biomarkers that predict response to IFX. Electronic case report forms were prepared by Studytrax (Macon, GA). Subjects <18 years of age were diagnosed with Crohn’s disease using standard clinical/pathologic criteria. Clinical evaluation and serum samples were obtained prior to initiation of IFX, after induction (dose 4), at six months, and after one year or at the time of treatment withdrawal. There were 119 subjects enrolled and 102 subjects completed induction. Non-responders (n=15) were defined prior to the 4th infusion as having a PCDAI > 10, an elevated Physician Global Assessment (PGA) or requiring dose escalation or medication change. Responders at the 4th infusions were either in remission (PUCAI ≤ 10) or were described as quiescent by PGA. Using the 7k SomaScan (SomaLogic; Boulder, CO) proteomics platform, quantitative protein profiles were generated from banked pre-treatment (V1) and after the three-dose induction (V2) to identify candidate protein biomarkers predictive of therapeutic response. Associations between the 7,310 proteins detected with SomaScan and response to IFX were assessed using t test. Response predictor models were developed using linear regression with backward selection. We report our preliminary findings from a discovery cohort of 56 subjects who completed induction. There were 15/56 (27%) non-responders and 41/56 (73%) responders at V2 after IFX induction. SomaScan analysis of the 56 individuals identified sets of differentially expressed proteins discriminating between non-responders and responders at both V1 and V2 and also defined protein signatures that changed from V1 to V2 for responders and non-responders, respectively. Strikingly, only responders demonstrated significant decreases in pro-inflammatory pathways at V2 compared to V1, thereby correlating well with anticipated reduced inflammation in responders. A 6-protein linear regression model performed with an AUC of 0.99 for predicting IFX response at pre-treatment V1. In a discovery cohort from a multicenter, prospective trial of children and adolescents treated with infliximab, a comprehensive proteomics platform was able to identify serum proteins that are highly associated with response to infliximab and accurately predict response prior to treatment.

Few genetic polymorphisms predict early response to anti-TNF drugs in inflammatory bowel disease (IBD), and even fewer have been identified in the pediatric population. However, it would be of considerable clinical interest to identify and validate genetic biomarkers of long-term response. Therefore, the aim of the study was to analyze the usefulness of biomarkers of response to anti-TNFs in pediatric IBD (pIBD) as long-term biomarkers and to find differences by type of IBD and type of anti-TNF drug. The study population comprised 340 children diagnosed with IBD who were treated with infliximab or adalimumab. Genotyping of 9 selected SNPs for their association with early response and/or immunogenicity to anti-TNFs was performed using real-time PCR. Variants C rs10508884 (CXCL12), A rs2241880 (ATG16L1), and T rs6100556 (PHACTR3) (p value 0.049; p value 0.03; p value 0.031) were associated with worse long-term response to anti-TNFs in pIBD. DNA variants specific to disease type and anti-TNF type were identified in the pediatric population. Genotyping of these genetic variants before initiation of anti-TNFs would enable, if validated in a prospective cohort, the identification of pediatric patients who are long-term responders to this therapy.

On standard dosing of infliximab (IFX), one third of patients will develop secondary loss of response (LOR) by the first year and up to 50% of initial responders will develop LOR by 5 years.1 Sustained high trough levels and dose escalation are proven to increase the durability of infliximab.2 The role of proactive therapeutic drug monitoring (TDM) to guide this remains controversial. In 2019, our unit opted for proactive TDM (at week 6, week 14 and 6 monthly thereafter) as standard therapy to guide dose escalation in maintenance. We report the outcomes of our patient cohort over 2 years from initiation of IFX. A retrospective chart review was performed between 01/01/2019 to 31/12/2021. All patients with IBD who received IFX were included. Patients with acute severe colitis were excluded as treatment protocol was different. Data on demographics, disease characteristics, immunomodifier, IFX dosing, frequency, drug and antibody levels were collected and analysed. Primary outcome was switching to different biologic as a marker of treatment failure. Standard IFX dosing is 5mg/kg IVI at 0, 2, 6 weeks for induction and 8 weekly in maintenance. The dose was escalated if week 6<15µg/mL, week 14/maintenance <5µg/mL, or <10µg/mL in stricturing/fistulising disease. 98 patients (58% male) were identified, 82% had Crohn’s disease (CD) and 18% Ulcerative Colitis (UC). Median age at diagnosis was 11 years old, and 12.5 years old at starting IFX. 81% received an immune modifier of which 64% had methotrexate and 39% azathioprine. 13% received escalated induction and 77% received escalated maintenance. The median week 6 level of standard vs escalated maintenance group was 22.8µg/mL vs 12.4µg/mL (p=0.01). 3% did not respond to induction and were discontinued. 2% developed IFX antibodies. At 1 year, 5% of CD and 22% of UC patients switched to a different biologic and at 2 years this was 13% and 44% respectively. Median time to switch was 53 weeks. Switching to alternate biologic was associated with escalated induction OR 5.2 (p<0.01) UC phenotype OR 5.6 (p<0.01) and concomitant steroid use OR 5.2 (p<0.04). Our week 6 IFX level guided clinician decision to escalate dosing in maintenance. The outcomes for our cohort show good treatment durability particularly in CD, 95% at 1 year and 87% at 2 years, which is better than what has been reported.2 Patients with severe phenotype remain poor responders and difficult to treat as evident by receiving escalated induction, i.e escalation without TDM, and steroid use being predictors. This study adds to the growing body of evidence of the role of proactive TDM in increasing durability of IFX. 1.Ding, N. S., Hart, A., & De Cruz, P. (2016). Systematic review: predicting and optimising response to anti-TNF therapy in Crohn's disease - algorithm for practical management. Alimentary pharmacology & therapeutics, 43(1), 30–51. https://doi.org/10.1111/apt.13445 2.Vahabnezhad, E., Rabizadeh, S., & Dubinsky, M. C. (2014). A 10-year, single tertiary care center experience on the durability of infliximab in pediatric inflammatory bowel disease. Inflammatory bowel diseases, 20(4), 606–613. https://doi.org/10.1097/MIB.0000000000000003

OBJECTIVES Paediatric and adult inflammatory bowel disease (pIBD, aIBD) patients may lose response to anti-TNF treatment within the first year. Adult-extrapolated weight-based dosing is incorrect in children, due to age-related pharmacokinetic differences. We investigated biomarkers for initial and maintenance of response to infliximab (IFX) or adalimumab (ADA), comparing pIBD and aIBD patients. METHODS In this prospective, observational study, pIBD (n = 24) and aIBD (n = 21) patients were included when initiating anti-TNF. Escalation from standard dosing and continued anti-TNF at 12 and 18 months were assessed. Biomarkers included clinical laboratory parameters, faecal calprotectin (FCP) and IFX trough levels (TLs). Plasma proteomics was performed in pIBD. RESULTS During our study, treatment escalation (in clinical loss of response) occurred more common in pIBD versus aIBD (p = 0.02). We established that IFX therapy escalation in pIBD patients was not due to low infliximab levels. We identified 9 pro-inflammatory proteins that were elevated in patients losing response. CONCLUSION Anti-TNF exposure-response relationship may be different in pIBD versus aIBD. No biomarkers for maintained response were identified, but 9 inflammatory proteins were of interest as potential predictors for loss of response in pIBD.

Introduction The only biologic therapy currently approved to treat moderate to severe Crohn’s disease in children (<18 years old) are those that antagonise tumour necrosis factor-alpha (anti-TNF). Therefore, it is critically important to develop novel strategies that maximise treatment effectiveness in this population. There is growing evidence that rates of sustained corticosteroid-free clinical remission, endoscopic healing and drug durability considerably improve when patients receive early anti-TNF dose optimisations guided by reactive or proactive therapeutic drug monitoring and pharmacodynamic monitoring. In response, our team has developed a personalised and scalable infliximab dosing intervention that starts with dose selection and continues throughout maintenance to optimise drug exposure. We hypothesise that a precision dosing strategy starting from induction and targeting dose-specific pharmacokinetic and pharmacodynamic endpoints throughout therapy will significantly improve outcomes compared with a conventional dosing strategy. Methods and analysis Conduct a clinical trial to assess rates of deep remission between Crohn’s disease patients receiving infliximab with precision dosing (n=90) versus conventional care (n=90). Patients (age 6–22 years) will be recruited from 10 medical centres in the USA. Each centre has been selected to provide either precision dosing or conventional care dosing. Precision dosing includes the use of a clinical decision support tool (RoadMAB) from the start of infliximab to achieve specific (personalised) trough concentrations and specific pharmacodynamic targets (at doses 3, 4 and 6). Conventional care includes the use of a modified infliximab starting dose (5 or 7.5 mg/kg based on the pretreatment serum albumin) with a goal to achieve maintenance trough concentrations of 5–10 µg/mL. The primary endpoint is year 1 deep remission defined as a combination of clinical remission (paediatric Crohn’s disease activity index<10 (child) or a Crohn’s disease activity index<150 (adults)), off prednisone>8 weeks and endoscopic remission (simple endoscopic severity-Crohn’s disease≤2). Ethics and dissemination ). The study protocol has been approved by the Cincinnati Children’s Hospital Medical Centre Institutional Review Board. Study results will be disseminated in peer-reviewed journals and presented at scientific meetings. Trial registration number NCT05660746.

Anti-tumor necrosis factor (anti-TNF) therapies have become first-line therapy for children with inflammatory bowel disease (IBD). Studies describing drug durability and loss of response to anti-TNF therapies are limited in children with IBD. This study evaluates predictors of primary non-response and long-term durability in children with IBD. This was a single-center retrospective review of patients with IBD aged 4-17 years that initiated anti-TNF therapy (infliximab or adalimumab) from January 1, 2014 - December 31, 2019. Clinical and laboratory data were recorded at time of anti-TNF initiation, at 14 weeks, 12 months, and 36 months. Kaplan-Meier analysis and log-rank tests evaluated long-term durability of anti-TNF therapy. Predictors of primary non-response (discontinuation of anti-TNF within 14 weeks) and long-term durability were assessed using Cox regression analysis and time-dependent receiver operating characteristic curves identified cut points. A total of 456 patients were initiated on anti-TNF therapy (183 adalimumab (86% CD and 14% UC/IC) and 273 infliximab (69% CD and 31% UC/IC)). Eighty one patients were lost to follow up or transferred care. Thirty seven (8%) patients were considered primary non-responders. Seven of these patients received adalimumab (3 CD, 4 UC/IC) and 30 received infliximab (7 CD, 23 UC/IC). In CD, baseline ESR >31 mm/h was predictive of primary non-response (p<0.05). In UC/IC, mono-therapy at diagnosis, baseline albumin <4 g/dL, and age at diagnosis <15.6 years were significant predictors of primary non-response. Eighty patients discontinued anti-TNF therapy between 14 weeks and 36 months. Reasons for drug discontinuation included loss of response (56%), drug reaction (24%), low therapeutic level/antibodies (19%), miscellaneous (1%). Amongst patients with CD that completed induction, week 14 lab values of albumin >3.9 g/dL, hemoglobin >11.8 g/dL, CRP <1.2 mg/dL and calprotectin <650 ug/g were associated with improved drug durability at 1 year. Patients with UC/IC had improved drug durability at 1 year if they received infliximab compared to adalimumab. The three year drug durability for both adalimumab and infliximab was slightly above 70%. Amongst patients with CD the three year drug durability was nearly 80% for both therapies. The three year drug durability with UC/IC was 37% for adalimumab and 56% for infliximab. Less than 10% of patients are primary non-responders to anti-TNF therapies; higher baseline ESR is a predictor in patients with CD, and a lower baseline albumin and younger age are predictors for patients with UC/IC. At 1 year, patients with a lesser inflammatory burden after induction appeared to have improved drug durability. Three-year durability is >75% for patients with CD on either therapy, while the durability is less for patients with UC/IC.

No abstract available

OBJECTIVES While higher infliximab (IFX) trough concentrations (TCs) are associated with better outcomes in patients with inflammatory bowel disease (IBD), they could pose a risk for adverse events (AEs), including IFX-induced skin lesions. Therefore, we studied correlations between IFX TCs and occurrence of AEs in paediatric IBD patients. METHODS In this single-centre study, all children with Crohn's disease (CD) and ulcerative colitis (UC) receiving IFX maintenance therapy who underwent proactive drug monitoring between March 2015 and August 2022 were included. IFX doses/intervals/TCs and patient characteristics were systematically registered, as well as AEs and skin lesions appearance. RESULTS A total of 109 patients (72 CD and 37 UC) contributed 2913 IFX TCs. During a median follow-up of 3.0 [1.5-4.5] years, we observed 684 AEs in 101 patients and 49 skin lesions in 35 patients. There was no significant difference (p = .467) in median TCs between patients with and without skin lesions. However, higher median IFX doses were associated with an increased hazard rate of skin lesions [HR 1.084 (1.024-1.148), p = .005], in addition to female sex [2.210 (1.187-5.310), p = .016] and diagnosis of CD [1.695 (1.241-1.877), p = .011]. Considering IFX therapeutic TC cut-offs of 5.0 and 9.0 µg/mL, there was no significant difference in AE rate (p = .749 and p = .833, respectively). Also, no significant association between IFX doses and AE rate (p = .159). CONCLUSIONS Increasing the IFX dose to achieve therapeutic TCs may not increase the overall risk of AEs in paediatric IBD patients. However, concerns arise regarding the risk of skin lesions, especially in female CD patients.

OBJECTIVES Antibodies to infliximab (ATIs) are associated with loss of response in children with inflammatory bowel disease (IBD). We aimed to describe the effectiveness of strategies for treatment modification following ATI development in pediatric IBD: (1) treatment escalation; and (2) switching to another anti-TNF agent. METHODS This multicenter retrospective study included children with IBD (4-18 years) on infliximab. Therapeutic drug monitoring (TDM) < 6 months and corticosteroid-free remission following each strategy were evaluated for low ATI titers (≤30 AU/mL) and high ATI titers (>30 AU/mL). RESULTS Anti-infliximab antibodies were detected in 52/288 patients (18%) after a median of 15.3 months. Three of 52 ATI-positive patients were excluded due to alternative treatments. Of the remaining 49 patients, 19 had low titers and 30 had high titers. Of 19 low-ATIs, 16 (84%) underwent treatment escalation with infliximab (IFX). Of 13 patients with TDM available, seven (54%) achieved ATI suppression at subsequent TDM and 12 (92%) at any time point. Among 30 patients with high-ATIs, 17 (57%) continued with IFX; immunomodulators were started in seven patients. Of 14 patients with TDM, seven (50%) achieved ATI suppression at subsequent TDM and 10 (71%) at any time point. At 24 months of follow-up, 73% of low-ATI patients and 50% of high-ATI patients could continue with IFX without steroids. Thirteen of 30 high-ATI patients (43%) switched to another anti-TNF agent, of whom 54% and 46% had clinical response at 6 and 24 months, respectively. CONCLUSIONS Dose optimization and/or adding an immunomodulator seem effective in suppressing low ATI titers. This strategy could also be considered in high ATI titers before switching.

BACKGROUND AND AIMS We aimed to model infliximab (IFX) pharmacokinetics (PK) in pediatric acute severe ulcerative colitis (ASUC) and assess the association between PK parameters, including drug exposure, and clinical response. METHODS We studied a multicenter prospective cohort of hospitalized children initiating IFX for ASUC or IBD-unclassified. Serial IFX serum concentrations over 26 weeks were used to develop a PK model. We tested the association of PK parameter estimates with day 7 clinical response, week 8 clinical remission, week 26 corticosteroid-free clinical remission (CSF-CR) (using the Pediatric Ulcerative Colitis Activity Index) and colectomy-free survival. RESULTS 38 participants received IFX (median initial dose 9.9 mg/kg). Day 7 clinical response, week 8 clinical remission, and week 26 CSF-CR occurred in 71%, 55%, and 43%, respectively. Albumin, C-reactive protein, white blood cell count, platelets, weight, and antibodies to IFX were significant covariates incorporated into a PK model. Week 26 non-remitters exhibited faster IFX clearance than remitters (P=.013). However, cumulative IFX exposure did not differ between clinical response groups. One (2.7%) and four (10.8%) participants underwent colectomy by week 26 and two years, respectively. Day 3 IFX clearance > .02 L/h was associated with colectomy (HR 58.2, 95% CI: 6.0-568.6, P < .001). CONCLUSIONS At median higher-than-label IFX dosing for pediatric ASUC, baseline faster IFX CL was associated with colectomy and, at week 26, with lack of CSF-CR. IFX exposure was not predictive of clinical outcomes. Higher IFX dosing may sufficiently optimize early outcomes in pediatric ASUC. Larger studies are warranted to determine if sustained intensification can overcome rapid clearance and improve later outcomes.

Subcutaneous infliximab (IFX-SC) provides logistical advantages and more stable pharmacokinetics than intravenous infliximab (IFX-IV). Real-world evidence in pediatric inflammatory bowel disease (PIBD) remains limited. We assessed clinical effectiveness, pharmacokinetics, and safety after switching from IFX-IV to IFX-SC across three pediatric IBD units in the Canary Islands, Spain. Retrospective multicenter study including patients <18 years who underwent elective switch from IFX-IV to IFX-SC between 2023–2025. Clinical indices (PCDAI/PUCAI), fecal calprotectin (FC), C-reactive protein (CRP) and trough infliximab levels (TDM) were collected at baseline (last IFX-IV), 3, 6 and 12 months. Paired changes were evaluated using Wilcoxon tests. Primary endpoint: clinical remission at 6 months. Secondary endpoints: biomarker evolution, TDM stability, adverse events, hospitalizations and treatment persistence. Eleven patients were included (73% Crohn’s disease; 18% ulcerative colitis; 9% unclassified; mean age 15.4 years; 82% male). Six (54.5%) switched from optimized IFX-IV and five (45.5%) initiated IFX-SC for convenience or logistical reasons. 9/11 have completed 12 month of follow up. All were in clinical remission at baseline, which was maintained in 100% at the end of the follow up 6 or 12 months . PCDAI improved from baseline to 3 months (median 9 → 3; p = 0.042) and remained stable thereafter; PUCAI was 0 at all timepoints. CRP remained low without significant changes. FC decreased from 444 µg/g at baseline to 191 µg/g at 3 months and 180 µg/g at 6 months, although not statistically significant. TDM values were high and stable (baseline 15.5 µg/mL; 3 months 18.8 µg/mL; 6 months 18.7 µg/mL; all p > 0.2). No adverse events, hospitalizations, steroid use or discontinuations were recorded. Treatment persistence was 100% at the end of the follow up (9/11 12 month). Switching from IFX-IV to IFX-SC in this multicenter pediatric cohort was highly effective and safe, with stable therapeutic exposure and full maintenance of clinical remission. IFX-SC appears to be a practical and well-tolerated alternative to intravenous therapy in PIBD, particularly in settings where logistical burden and treatment autonomy are relevant. Larger cohorts with longer follow-up are needed Conflict of interest: Alberto, José Ramón: No conflict of interest De La Barreda Heusser, Laura: No conflict of interest Marquez Rodriguez, Juan Alberto: I have provided scientific advice/participated in medical meetings for Kern and Takeda. I am receiving a gratification for this presentation. Rodríguez Díaz, Ana Eva: No conflict of interest Carrillo Palau, Marta: No conflict of interest Fuentes Ferrer, Manuel Enrique: No conflict of interest Dr. Hernandez Camba, Alejandro: I have served as a speaker or has received research or education funding or advisory fees from Lilly, Takeda, J and J, FAES Pharma, Falk, Abbvie, Adacyte Therapeutics, Tyllots, Ferring, Kern Pharma, Alfasigma and Chiesi.

Withdrawing immunomodulators (IM) from combination therapy with infliximab (IFX) can lead to immunogenic failure due to development of antibodies to IFX (ATI). Conventional drug sensitive ELISAs detect ATI only when IFX drug levels are undetectable. We investigated whether bound ATIs detected using a novel drug tolerant ELISA taken at time of de-escalation to IFX monotherapy, predicted subsequent loss of response and unfavourable IFX pharmacokinetics in IBD patients on combination therapy. Multicentre case-control retrospective study of IBD patients treated with combination IV IFX and IM. Patients had > 6 months steroid-free clinical (Harvey Bradshaw Index ≤ 4 / Partial Mayo Score ≤ 2) and biochemical remission (C-reactive protein (CRP) <5 mg/L or faecal calprotectin (FCP) <150 µg/g). Cases (withdrew IM and continued IFX monotherapy) were compared to controls (continued combination therapy). The primary endpoint was relapse (clinically active disease with elevated FCP or CRP) over 24 months follow-up; secondary endpoints included changes in therapy and IFX drug levels. Therapeutic drug monitoring with a drug-tolerant ELISA was collected within 3 months of IM withdrawal. Bound-ATI were detected in 7/45 (15.6%) cases and 5/37 (13.5%) of controls, none of which tested positive for ATI using drug sensitive ELISA. The groups were well matched, although median duration of combination therapy was longer in cases than controls (41 vs. 20 months, p=0.045) (Table 1). Median duration of follow-up was 17 months. No patients with bound ATI at baseline met the primary endpoint of disease relapse. Higher rates of biochemical disease activity and treatment escalation in the withdrawal group were noted, however ATI status was not associated with these outcomes. When considering changes in IFX levels over subsequent 12 months, there was no significant difference between cases and controls (-0.99 and -0.84 mg/L respectively, p = 0.20). However, in all IM withdrawal patients with ATI, IFX levels reduced from baseline, with greater decreases in IFX drug levels observed in this cohort. Drug tolerant ELISA can detect bound-ATI that were previously not measureable using drug sensitive ELISA. However, presence of bound-ATI did not predict subsequent disease relapse suggesting conventional assays are suitable in this setting. In IM withdrawal, ATI positivity is associated with greater risk of reduction in IFX levels, and ultimately, potential immunogenic failure. Higher rates of disease activity were observed in IM withdrawal, suggesting that IM might be important in maintaining disease control.

OBJECTIVES Antitumor necrosis factor (anti-TNF) therapies are first-line therapies for children with inflammatory bowel disease (IBD) (Crohn's disease [CD], ulcerative colitis [UC] and IBD-unclassified [IBD-U]). Limited studies describing anti-TNFs durability and loss of response in children. This study evaluates predictors of primary Nonresponse and 3-year drug durability in children with IBD. METHODS This was a single-center retrospective review of patients with IBD less than 18 years old who initiated anti-TNF (infliximab or adalimumab) from January 1, 2014, to December 31, 2019. Clinical and laboratory data were recorded at the time of anti-TNF initiation, 14 weeks, 12 months, and 3 years. Predictors of primary nonresponse (discontinuation within 14 weeks) and durability were assessed. RESULTS A total of 456 patients initiated anti-TNF therapy (183 adalimumab and 273 infliximab). Thirty-seven (8%) patients were primary nonresponders. The 3-year drug durability for both therapies was >70%. Among patients with CD, the 3-year durability was >75% for both therapies. The 3-year durability with UC/IBD-U was 37% for adalimumab and 56% for infliximab. Predictors of primary nonresponse were an erythrocyte sedimentation rate > 55 mm/h in CD on infliximab, and baseline albumin <4 g/dL and <15.6 years at diagnosis in UC/IBD-U. CONCLUSIONS Anti-TNF therapies had a 3-year durability of >75% in patients with CD, while the durability was lower (37%-56%) for patients with UC/IBD-U. Less than 10% of patients were considered primary nonresponders, which lends support to the long-term durability of anti-TNF therapies for pediatric IBD while keeping in mind predictive factors of Nonresponse.

Abstract Objective Immunogenicity against anti-TNF antibodies usually leads to loss of response. We aimed to evaluate the efficacy of clinical strategies to improve clinical remission and pharmacokinetics upon detection of anti-drug antibodies (ADA). Methods Inflammatory bowel disease (IBD) patients with ADA against infliximab or adalimumab were identified through a single centre database search covering 2004-2022. Criteria for successful intervention upon ADA detection (baseline) were clinical remission after 1 year without further change in strategy. Results Two-hundred-and-fifty-five IBD patients (206 Crohn’s disease) were identified. At baseline, median ADA level was 77 AU/ml; 50.2% of patients were in clinical remission. Implemented strategies were: (1) 81/255 (32%) conservative management, (2) 102/255 (40%) anti-TNF optimisation, (3) 72/255 (28%) switch within or out of class. Switching was the most successful strategy for clinical remission (from 19% at baseline to 69% at 1 year, p < 0.001). Patients that continued the same dose anti-TNF or discontinued biological therapy were often in clinical remission, but deteriorated significantly (−22.7%, p = 0.004). Anti-TNF dose intensification with immunomodulator optimisation was the fastest (median 3.0 months, p = 0.009) and most effective (65% ADA suppression, p < 0.001) strategy to suppress ADA compared to solely anti-TNF or immunomodulator optimisation. Conclusions Switching therapy, within or out of class, is the most successful strategy to regain and maintain clinical remission upon immunogenicity. When switching to another anti-TNF, concomitant immunomodulatory therapy should be started or continued to prevent repeated immunogenic loss of response. Anti-TNF dose escalation with concomitant immunomodulator optimisation is the fastest and most effective strategy to suppress ADA. Summary Immunogenicity against anti-TNF antibodies is associated with loss of response in patients with inflammatory bowel diseases and remains a clinical challenge. We investigated potential therapeutic strategies in a retrospective patient cohort focusing on clinical efficacy and pharmacokinetics.

Anti-tumor necrosis factor alpha (anti-TNFα) inhibitors are used extensively for the management of moderate to severe inflammatory bowel disease (IBD) in both adult and pediatric patients. Unfortunately, not all patients show an optimal response to induction therapy, while others lose their response over time for reasons yet poorly understood. We report on a pharmacokinetic/pharmacogenetic approach to monitor the therapy with anti-TNFα in a real-world cohort of seventy-nine pediatric patients affected by IBD that was analyzed retrospectively. We evaluated plasma concentrations of infliximab, adalimumab, and related anti-drug antibodies (ADAs), and single nucleotide polymorphisms (SNPs) in genes involved in immune processes and inflammation on the anti-TNFα response. We found a significant association between the SNP in TNFα promoter (−308G>A) and clinical remission without steroids in patients on infliximab therapy. Additionally, a potential connection between HLA-DQA1*05 genetic variant carriers and a higher risk of anti-TNFα immunogenicity emerged.

Therapeutic drug monitoring (TDM) of infliximab (IFX) improves efficacy and treatment persistence in inflammatory bowel disease (IBD), yet strategies differ across centers. Population pharmacokinetic (PK) modeling may enable more personalized and dynamic dose adjustment. Although the optimal monitoring approach remains controversial, several studies support proactive TDM of anti-TNF agents to optimize exposure, reduce immunogenicity, and improve long-term outcomes. compare the efficacy, persistence, and safety of a proactive TDM strategy versus a PK model–based approach in IBD patients receiving IFX in real-world practice. Retrospective cohort study including IBD patients treated with IFX in a tertiary center. • Proactive TDM cohort: 2020–2022. • PK-model cohort: 2023–2025 with individualized dose predictions. Clinical, biochemical, and pharmacokinetic data were collected up to 12 months. Main endpoints: clinical and biochemical remission (PCR <5 mg/L, FC < 150 µg/g), persistence, intensification, and adverse events. A total of 159 patients were included (TDM = 114; PK = 45). Mean age was 46.3 ±16 (TDM) and 43.3 ±16 years (PK); 56.1% and 51.1% were female. Crohn’s disease: 47.7% (TDM) vs 24.5% (PK); ulcerative colitis: 46.0% vs 69.0%. Baseline inflammation differed: PCR >5 mg/L was more frequent in PK (57% vs 28%), whereas FC > 150 µg/g and global severity scores were higher in TDM (82.6% vs 72%). During follow-up, a higher proportion of PK-model patients achieved FC < 150 µg/g at week 6 (65% vs 45%, p = 0.026) and week 14 (70% vs 51%, p = 0.045). IFX >7 µg/mL at week 14 was more common in PK (70% vs 42%, p < 0.001). Intensification was required more often in PK (57.5% vs 25%, p < 0.001), while concomitant immunomodulators were more frequent in TDM (45% vs 5.6%, p < 0.001). No significant differences were observed in clinical or biochemical remission, persistence, adverse events, or HLA-DQA1*05 distribution at 12 months. Both proactive and PK-based monitoring strategies showed comparable long-term efficacy and safety. The PK-model–guided approach was associated with an earlier biochemical response and a trend toward more individualized optimization. These findings support the role of PK modeling as a complementary tool for personalized IBD management, although longer follow-up is needed to confirm whether these early advantages translate into sustained clinical benefit. References: 1. Hanauer SD; Feagan BG, Lichtensten GR et al. Maintenance infliximab for Crohńs disease: The ACCENT I randomised trial. Lancet 2002; 359:1541-15492. 2. Sand BE, Anderson FH, Berntein CN et al. Infliximab maintenance therapy for fistulizing Crohńs disease. N Engl J Med 2004; 350:876-8853. 3. Ben Horin S, Chowers Y. Review article:los of response to anti-TNF treatments in Crohńs Disease. Alimet and Pharmacol Ther 2011; 33: 987-9954. 4. Moore C, Corbett G, Moss AC. Systematic review and meta-analysis: Serum Infliximab Levels during maintenance therapy and outcomes in inflammatory bowel disease. J Crohns Colitis, 2016; 10(5): 619-25. 5. Bodini G, Giannini EG, Savarino V, Del Nero L, Pellegatta G, De Maria C, Baldissarro I, Savarino E. Adalimumab trough serum levels and anti-adalimumab antibodies in the long-term clinical outcome of patients with Crohn’s disease. Scand J Gastroenterol. 2016;51(9):1081-6. 6. Dreesen E, Van Stappen T, Ballet V, Peeters M, Compernolle G, Tops S, Van Steen K, Van Assche G, Ferrante M, Vermeire S, Gils A. Anti-infliximab antibody concentrations can guide treatment ntensification in patients with Crohn’s disease who lose clinical response. Aliment Pharmacol Ther. 2018;47(3):346-355. 7. Papamichael K, Vajravelu R, Osterman M,et al. Long-Term Outcome of Infliximab Optimization for Overcoming Immunogenicity in Patients with Inflammatory Bowel Disease. Digestive Diseases and Sciences. 2018;63(3):761-767. 8. D’Haens G, Vermeire S, Lambrecht G, et al. Increasing infliximab dose based on symptoms, biomarkers, and serum drug concentrations does not increase clinical, endoscopic, or corticosteroid-free remission in patients with active luminal Crohn’s disease. Gastroenterology. 2018 Apr; 154(5): 1343-51.e1. 9. Vande Casteele N, Ferrante M, Van Assche G, et al. Trough concentrations of infliximab guide dosing for patients with inflammatory bowel disease. Gastroenterology. 2015; 148: 1320-29. 10. Kennedy NA, Heap GA, Green HD, et al; UK Inflammatory Bowel Disease Pharmacogenetics Study Group. Predictors of anti-TNF treatment failure in anti- TNF-naive patients with active luminal Crohn’s disease: a prospective, multicentre,cohort study. Lancet Gastroenterol Hepatol. 2019;4(5):341-353. 11. Carrillo-Palau M, Alonso-Abreu I, Ramos-López L et al. Utility of infliximab serum concentration in inflammatory bowel disease treatment in real world practice at Hospital Universitario de Canarias. ECCO 2020, poster presentation. 12. Santacana Juncosa E, Rodríguez-Alonso L, Padullés Zamora A, et al. Bayes-based dosing of infliximab in inflammatory bowel diseases: Short-term efficacy [published online ahead of print, 2020 Jun 3]. Br J Clin Pharmacol. 2020;10.1111/bcp.14410. doi:10.1111/bcp.14410 13.Jamshidi A, Sabzvari A, Anjidani N, Shahpari R, Badri N. A randomized phase I pharmacokinetic trial comparing the potential biosimilar adalimumab (CinnoRA®) with the reference product (Humira®) in healthy volunteers. Expert Opin Investig Drugs. 2020;29(3):327-331. doi:10.1080/13543784.2020.1723000 14. Gorovits B, Baltrukonis DJ, Bhattacharya I, et al. Immunoassay methods used in clinical studies for the detection of anti-drug antibodies to adalimumab and infliximab. Clin Exp Immunol. 2018;192(3):348-365. doi:10.1111/cei.13112 Conflict of interest: Carrillo Palau, Marta: No conflict of interest Morant Domínguez, Andrea María: No conflict of interest Ashok Bhagchandani, Rashika: No conflict of interest Vera Santana, Belén del Carmen: No conflict of interest Medina Chico, Sergio: No conflict of interest Del Rosario García, Betel: No conflict of interest Ramos Lopez, Laura: No conflict of interest Reygosa, María Cristina: No conflict of interest Gutierrez Nicolás, Fernando: No conflict of interest Alonso, Inmaculada: No conflict of interest

Patients with very early onset inflammatory bowel disease (VEOIBD) often present with severe disease course and require escalation to biologics. Exclusion of pediatric patients from clinical trials lead to scarcity of efficacy and safety data on TNFa antagonists therapy in VEOIBD. We aimed to assess safety and efficacy of adalimumab (ADM) induction and maintenance therapy in patients with VEOIBD. This was a retrospective study involving 31 sites affiliated with the IBD Porto Group and IBD Interest Group of ESPGHAN, as well as centers in North America. Demographic, clinical and laboratory data were collected from patients diagnosed with VEOIBD who commenced ADM therapy before 6 years of age between 2014 to 2023. We identified 77 VEOIBD patients with a median age at diagnosis of 2.6 years (interquartile range [IQR] 1.3–4.1), of whom 29 (38%) were diagnosed at age <2 years (infantile-onset IBD). Thirty-seven (48%) patients were diagnosed with Crohn’s disease, 25 (32%) with ulcerative colitis and 15 (20%) with IBD-unclassified. Five (9%) from those genetically tested were diagnosed with monogenic disease. Median age at initiation of ADM was 4.2 (IQR 2.8-5.1) years. Forty-four patients (57%) were Infliximab experienced, discontinued mainly due to pharmacokinetic (20 [45%]) and pharmacodynamic (13 [30%]) failures. At initiation of ADM, concomitant corticosteroids and immunomodulators were given in 37 (48%) and 29 (37%) patients, respectively. The median wPCDAI and PUCAI scores at baseline were 45 [37.5-60] and 45 [27.5-57.5], respectively. Median follow-up time was 85.4 (IQR 40.4-139.2) weeks. While patients with CD showed significant clinical improvement after 26 and 52 weeks (PCDAI decreased to 10 [0-33.4], p<0.001, and 10 [0-25], p<0.05, respectively), No significant improvement in PUCAI score was observed among patients with UC (Figure 1). Inflammatory markers and calprotectin showed a gradual decrease over time (Figure 1). Weight and Height Z scores did not differ significantly throughout the follow-up period. ADM discontinuation rates after 1 and 3 years were 40% and 65%, respectively, mainly due to primary non-response (14, 29.8%) and loss of response (19, 40.4%). Drug discontinuation rates were not dependent on concomitant immunomodulator treatment or ADM initiation or on age (less or above 3 years). Four patients (5.2%) developed severe infections, including a patient with TTC7A mutation who died following septic shock. Adalimumab therapy was relatively safe and seemed more effective in young patients with Crohn’s disease, but not in those with ulcerative colitis. Durability was relatively low due to high rates of primary non-response and secondary loss of response.

Infliximab is an anti-TNF-α monoclonal antibody approved in chronic inflammatory bowel diseases (IBD). This study aimed at providing an in-depth description of infliximab target-mediated pharmacokinetics in 133 IBD patients treated with 5 mg/kg infliximab at weeks 0, 2, 14, and 22. A two-compartment model with double target-mediated drug disposition (TMDD) in both central and peripheral compartments was developed, using a rich database of 26 ankylosing spondylitis patients as a reference for linear elimination kinetics. Population approach and quasi-steady-state (QSS) approximation were used. Concentration-time data were satisfactorily described using the double-TMDD model. Target-mediated parameters of central and peripheral compartments were respectively baseline TNF concentrations (RC0 = 3.3 nM and RP0 = 0.46 nM), steady-stated dissociation rates (KCSS = 15.4 nM and KPSS = 0.49 nM), and first-order elimination rates of complexes (kCint = 0.17 day−1 and kPint = 0.0079 day−1). This model showed slower turnover of targets and infliximab-TNF complex elimination rate in peripheral compartment than in central compartment. This study allowed a better understanding of the multi-scale target-mediated pharmacokinetics of infliximab. This model could be useful to improve model-based therapeutic drug monitoring of infliximab in IBD patients.

Infliximab, an anti-tumor necrosis factor-alpha (TNF-α) agent, is well-established as salvage therapy in hospitalized patients with acute severe ulcerative colitis (ASUC) who do not respond to intravenous (IV) corticosteroids. Furthermore, obesity rates among patients with inflammatory bowel disease (IBD) are increasing, and it is unknown how obesity impacts treatment response in this setting. It has been postulated that obese individuals (Body Mass Index ≥30.0 kg/m²) may have decreased response to infliximab. While the exact mechanism remains unclear, it is hypothesized that excess adipose tissue increases baseline inflammatory cytokines and alters the pharmacokinetics of anti-TNF-α agents through changes in absorption and clearance. This study aimed to evaluate the impact of obesity on clinical outcomes in patients receiving infliximab for ASUC. We conducted a single-center, retrospective analysis of adult patients (>18 years old) admitted to our institution for ASUC who received inpatient infliximab salvage therapy between January 1, 2010 and October 31, 2023. Patients were categorized into two comparison groups: non-obese (BMI 18.5-29.9) and obese (BMI ≥ 30.0). Treatment response was measured by the rates of readmission (within 90-days and 1-year) and surgical intervention (during hospitalization, within 30-days, and within 1-year). Fisher exact test with alpha of 0.05 was used to compare proportions between groups. A total of 84 patients met the inclusion criteria: 64 non-obese and 20 obese. There were 4 patients (3 non-obese, 1 obese) who were lost to follow-up after 30 days and excluded from data analyses beyond that point. The 90-day readmission rate was 24.2% (15/62) for the non-obese and 32.6% (6/19) for the obese (p = 0.5567). The 1-year readmission rates were 38.7% (24/62) for non-obese and 42.1% (8/19) for obese (p = 0.7949). Surgical intervention rates during hospitalization were 3.13% (2/64) for non-obese and 10% (2/20) for obese (p = 0.2388). Within 30 days, surgical intervention rates were 4.69% (3/64) for non-obese and 5% (1/20) for obese (p = 1.0). The 1-year intervention rates were 14.6% (9/61) for non-obese and 21.1% (4/19) for obese (p = 0.4959). There was no statistically significant difference between the rates of readmissions and surgical interventions in non-obese and obese patients receiving infliximab salvage therapy for ASUC. However, it is noteworthy that obese patients exhibited higher rates of surgical intervention. Nonetheless, the impact of obesity on infliximab response in ASUC remains unknown. Further data and larger studies are needed to determine whether obesity negatively affects infliximab response in ASUC and namely to determine the optimal dosing strategy in this setting.

Improved outcomes in inflammatory bowel disease (IBD) in 2020 are due to both an increased number of effective medical therapies, and improved strategies for using these agents. These strategic advances, driven by results from well-designed prospective studies and internationally accepted guidelines, have culminated in the gradual adoption of a treat-to-target strategy as the standard of care in IBD management today. Session one of the Choosing Wisely IBD 2020 virtual symposium explored the potential treatment targets in IBD clinical practice today, first via pre-recorded video presentations from local speakers and then with a live state-of-the-art lecture and panel discussion. Dr Britt Christensen (Royal Melbourne Hospital, Melbourne, Australia) discussed the rationale for endoscopic rather than symptom-based treatment targets, before outlining data to support histological treatment targets, an area of recent interest in ulcerative colitis research in particular. Dr Antony Friedman (The Alfred Hospital, Melbourne, Australia) discussed the role of radiological treatment targets, with a focus on intestinal ultrasound, which is increasingly used in Australian IBD clinics. Dr Emily Wright (St. Vincent’s Hospital, Melbourne, Australia) then summarized the role of non-invasive biomarkers as treatment targets, including fecal calprotectin and the future potential of the recently-described serum endoscopic healing index. Dr Nick Kennedy, one of the invited international speakers, then gave a state-of-the-art lecture on integrating a treat to target approach into clinical practice in 2020. The evolution of treatment targets from symptom control to objective targets with progressively deeper levels of biomarker normalization was presented, culminating in the CALM study and STRIDE guidelines. The PANTS study, from the speaker’s institution, was then presented in detail. This was a prospective, multicentre, uncontrolled study of biologic naïve Crohn’s disease patients treated with infliximab and adalimumab, and included 1,610 patients from 120 centers in the United Kingdom. The PANTS study demonstrated the clinical and pharmacokinetic superiority of combination therapy for both infliximab and adalimumab, and showed that achieving clinical, biochemical and pharmacokinetic targets at the end of induction was associated with superior outcomes at one year. In particular, proactive therapeutic drug monitoring during induction to achieve infliximab levels >7 μg/mL or adalimumab levels >12 μg/mL was associated with improved clinical remission rates at one year, while low drug levels at week 14 were associated with the development of immunogenicity and poorer clinical outcomes at 12 months and beyond. Of great potential significance, the study identified the human leukocyte antigen (HLA) DQA1*05 haplotype (present in up to 40% of the European population) as being strongly associated with the development of immunogenicity to anti-TNFs, especially when an anti-TNF is used as monotherapy. Cost-effectiveness data from analyses from several different treat-to-target studies, including CALM, were presented, demonstrating the potential for cost-effectiveness by reducing direct and indirect costs associated with active disease and the need for hospitalization and surgery. It was acknowledged that to deliver high-quality treat-to-target IBD care a multidisciplinary approach is required. As was shown in the PANTS study, the improved outcomes associated with individualization of anti-tumor necrosis factor (TNF) dosing were presented, including the use of proactive therapeutic drug monitoring of adalimumab in the pediatric PAILOT study. A view to the future of treat-to-target medicine in IBD was presented, including the study designs of currently recruiting studies (REACT2 (NCT01698307), STARDUST (NCT03107793), VERDICT (NCT04259138)). New technologies that are starting to reach the clinic were presented, including the use of rapid testing for both anti-TNF drug levels and fecal calprotectin, and the potential for the incorporation of data from artificial intelligence analyses into treatment algorithms. A panel discussion between the invited speakers, live audience, and steering committee on the nuances of the treat-to-target strategy then followed. The concept of individualization of treatment targets by disease phenotype was discussed. For example, in Crohn’s disease, target calprotectin levels will be lower in patients with small bowel disease compared to those with colonic disease, and target anti-TNF drug levels will be higher for patients with perianal disease compared to those with luminal disease. Proactive therapeutic drug monitoring of anti-TNFs was discussed, with speakers and panelists verifying the benefits of attaining high target drug levels at the end of the treatment induction phase. Although other aspects of proactive therapeutic drug monitoring require further validation, it would appear that aiming to optimize anti-TNF dosing during the induction phase is ready for incorporation into clinical practice today. Data on therapeutic drug monitoring for vedolizumab and ustekinumab are less clear, although signals of week six vedolizumab levels >20 μg/mL and improved outcomes during maintenance are emerging. As this stage, therapeutic drug monitoring of non-anti-TNF biologics is not ready for routine ‘prime time’ use. The international speakers discussed the potential for inter-assay variability for all classes of biologics and the need to know the specifications of your assay in interpreting results. Future trends in the individualization of biologic dosing were discussed, with the hope that exciting results from recent studies, such as the HLA DQA1*05 data from PANTS, can be doi:10.1111/jgh.15445

BACKGROUND AND AIMS Accelerated infliximab (IFX) induction is often based on clinical parameters as opposed to pharmacokinetics (PK). We aimed to investigate the impact of dashboard-guided optimized induction dosing on IFX durability and immunogenicity in a real-world inflammatory bowel disease (IBD) setting. METHODS Pediatric and adult IBD patients were enrolled in a prospective single arm intervention trial. Cumulative data from each infusion (INF), weight, albumin, C-reactive protein, IFX dose, IFX trough level, and antidrug antibody presence were used to inform subsequent INF dosing. Forecasts driven by adaptive Bayesian modeling were generated to maintain trough levels for the third (INF3) and fourth (INF4) infusions of 17 μg/mL and 10 μg/mL, respectively. The primary outcome was proportion of patients prescribed accelerated dosing (AD) intervals by INF3 (<22 days) or INF4 (<49 days). Secondary outcomes included week 52 clinical and PK outcomes. Multivariate analyses and Kaplan-Meier curves compared outcomes based on adherence to dashboard forecasts. RESULTS Of the 180 per-protocol population, AD was forecast for 41% (INF3) and 69% (INF4) of patients with median intervals of 17 (INF3) and 39 (INF4) days. Baseline age >18 years, albumin >3.5 g/L, and 10-mg/kg dose were independently associated with lower rates of AD by INF4. Nonadherence with the INF4 forecast (n = 39) was an independent predictor of antidrug antibody (P < .0001) and IFX discontinuation (P = .0006). A total of 119 of 123 patients on IFX at week 52 were in steroid-free remission. CONCLUSIONS The application of a PK dashboard during induction can optimize dosing early to improve IFX durability and immunogenicity.

Background Behçet’s disease (BD) is a persistent inflammatory vasculitis affecting various vessel types across multiple organ systems. It clinically presents recurrent oral and genital ulcers, ocular inflammation, and various skin manifestations. Etiology remains multifactorial, involving genetic susceptibility, immune system dysregulation, and environmental triggers such as infections. Intestinal involvement represents a rare but particularly severe form of BD, whose clinical features frequently resemble those of inflammatory bowel diseases (IBD), complicating differential diagnosis and management. Case presentation We report a case of a 23-year-old male with progressive postprandial abdominal pain, diarrhea, and marked weight loss. His clinical history was notable for recurrent oral aphthae, genital ulcers, and perianal infections. Colonoscopic examination revealed circumferential ulceration, mucosal edema, contact bleeding, and significant narrowing of the ileocecal lumen. Histopathological analysis indicated chronic active inflammation in the absence of granulomas or definitive vasculitis. Infectious and neoplastic causes were systematically excluded. The patient was diagnosed with intestinal BD. Although initial therapy with infliximab yielded partial clinical improvement, drug-level monitoring revealed suboptimal trough levels, indicating secondary loss of response. Subsequently, treatment was transitioned to the Janus kinase (JAK) inhibitor upadacitinib, which led to full symptom resolution and mucosal healing on follow-up endoscopy. Conclusion This case underscores the diagnostic and therapeutic challenges associated with intestinal BD, especially in distinguishing it from Crohn’s disease and addressing resistance to anti-TNF agents. Our findings suggest that JAK inhibitors like upadacitinib may offer a promising alternative for patients with refractory intestinal BD. Incorporating therapeutic drug monitoring into clinical practice allows for personalized, adaptive treatment adjustments, potentially improving long-term outcomes in complex cases.

Abstract Objectives Deficiency of serum 25‐hydroxyvitamin D [25(OH)D] was associated with decreased short‐term response to anti‐tumor necrosis factor‐alpha (TNF‐α) agents in adults with inflammatory bowel disease (IBD). The aim of this study was to evaluate the association between serum 25(OH)D levels and the outcome of children with IBD undergoing anti‐TNF‐α therapy. Methods Children with IBD who were treated with anti‐TNF‐α agents and whose 25(OH)D levels had been measured at the initiation of therapy were included. Demographic, clinical, and laboratory data were collected retrospectively between 1/2012 and 1/2022. 25(OH)D levels above 30 ng/mL were considered sufficient. Results A total of 150 children with IBD were treated with anti‐TNF‐α agents, and 84 of them (58 Crohn's disease, 26 ulcerative colitis, median [interquartile range] age 15.2 [12.8–16.5] years) met the inclusion criteria. Sixty‐five (77%) patients were 25(OH)D‐deficient. Adequate 25(OH)D levels were associated with clinical response (hazard ratio [HR] = 4, 95% confidence interval [CI] 1.43–11.11, p = 0.008), and clinical remission (HR = 4.62, 95% CI 2.56–8.33, p < 0.001). While anti‐TNF‐α trough levels were comparable between 25(OH)d‐deficient and non‐deficient children, intensification of anti‐TNF‐α therapy was more prevalent among children with 25(OH)D deficiency (65% vs. 21%, p < 0.001). Conclusions Adequate serum 25(OH)D is an independent predictor of a favorable outcome of pediatric IBD under anti‐TNF‐α therapy.

BACKGROUND & AIMS The evolution of complicated pediatric Crohn's disease (CD) in the era of anti-tumor necrosis factor (aTNF) therapy continues to be described. Since CD progresses from inflammatory to stricturing (B2) and penetrating (B3) disease behaviors in a subset of patients, we aimed to understand the risk of developing complicated disease behavior or undergoing surgery in relation to aTNF timing and BMI z-score (BMIz) normalization. METHODS Multi-center, 5-year longitudinal data from 1075 newly-diagnosed CD patients were analyzed. Descriptive statistics, univariate and stepwise multivariate Cox proportional hazard regression (CPHR), and log-rank analyses were performed for risk of surgery and complicated disease behaviors. Differential gene expression from ileal bulk RNA sequencing were correlated with outcomes. RESULTS Stricturing complications had the largest increase from 2.98% to 10.60% over 5 years. Multivariate CPHR revealed aTNF exposure within 3 months from diagnosis (HR 0.33; 95%CI 0.15-0.71) and baseline L2 disease (HR 0.29; 95%CI 0.09-0.92) to be associated with reduced B1 to B2 progression. For children with low BMIz at diagnosis (n=294), multivariate CPHR showed BMIz normalization within 6 months of diagnosis (HR 0.47; 95%CI 0.26-0.85) and 5-aminosalicyclic acid exposure (HR 0.32; 95%CI 0.13-0.81) were associated with decreased risk for surgery while B2 (HR 4.20; 95%CI 1.66-10.65) and B2+B3 (HR 8.24; 95%CI 1.08-62.83) at diagnosis increased surgery risk. Patients without BMIz normalization were enriched for genes in cytokine production and inflammation. CONCLUSIONS Anti-TNF exposure up to 3 months from diagnosis may reduce B2 progression. Additionally, lack of BMIz normalization within 6 months of diagnosis is associated with increased surgery risk and a pro-inflammatory transcriptomic profile.

Observational data has reported anti-TNF related dermatological complications in patients with IBD at 20-22%1,2. Previous histological assessment of some of these lesions have identified skin infiltrates rich in IL-12, IL-17 and IL-233. Underlying aetiology is currently unclear. We aimed to characterise the clinical and inflammatory cytokine profile of patients with IBD who develop dermatological complications of anti-TNF treatment. Patients who were receiving anti-TNF therapy and developed dermatological complications were prospectively recruited from IBD outpatient clinics in a tertiary referral centre. Age and disease matched controls were identified. All patients were reviewed by dermatology to confirm diagnosis. Serum samples and disease phenotype were collected at time of recruitment. Serum cytokine concentrations were quantified using cytometric bead array (IL-8, IL-1, IL-6, IL-10, TNF, IL-12p70)(BD Biosciences) and enzyme linked immunosorbent assays (IL-17 and IL-23) (DuoSet R&D Systems). Thirty-three patients were recruited. 51.5% (n = 17) were diagnosed as having a dermatological complication of anti-TNF therapy. The majority developed psoriasiform dermatitis (47%). The mean time to diagnosis was 18 months (IQR 2- 48). Seventeen (55%) patients had CD. Twenty-five (76%) patients had serum samples for cytokine analysis. Pancolitis (n = 8; 72.7%) and small bowel disease (n = 3; 50%) were the most frequent distribution of disease in patients who developed dermatological complications with UC and CD respectively. A trend toward lower mean concentrations of TNF and higher mean concentrations of IL-8, IL-17 & IL-23 was noted in those who developed cutaneous complication compared to controls. However, in those who developed skin complications, patients with CD had significantly higher IL-23 serum levels in comparison to those patients with UC (Mann-Whitney p  =  0.026). Although not statistically significant, patients who developed dermatological complications had higher mean anti-TNF trough levels (15.1mcg/ml vs.6.6mcg/ml p  =  0.051). No statistical correlation between anti-TNF antibodies or disease response and development of skin complications was identified. Patients with CD who develop skin complications secondary to anti-TNF therapy have higher serum levels of IL-23. Lower serum TNF and higher serum IL-17 and IL-23 concentrations is consistent with previous hypothesis related to paradoxical psoriasis4. However, our data suggests that this may be a mechanism more prominent in patients with CD. These findings support further investigation in larger, more representative samples. References: 1. Cleynen I, Vermeire S. Paradoxical inflammation induced by anti-TNF agents in patients with IBD. Nat Rev Gastroenterol Hepatol. Sep 2012;9(9):496-503. doi:10.1038/nrgastro.2012.125 2. Freling E, Baumann C, Cuny JF, et al. Cumulative incidence of, risk factors for, and outcome of dermatological complications of anti-TNF therapy in inflammatory bowel disease: a 14-year experience. Am J Gastroenterol. Aug 2015;110(8):1186-96. doi:10.1038/ajg.2015.205 3. Tillack C, Ehmann LM, Friedrich M, et al. Anti-TNF antibody-induced psoriasiform skin lesions in patients with inflammatory bowel disease are characterised by interferon-gamma-expressing Th1 cells and IL-17A/IL-22-expressing Th17 cells and respond to anti-IL-12/IL-23 antibody treatment. Gut. Apr 2014;63(4):567-77. doi:10.1136/gutjnl-2012-302853 4. Toussirot E, Aubin F. Paradoxical reactions under TNF-alpha blocking agents and other biological agents given for chronic immune-mediated diseases: an analytical and comprehensive overview. RMD Open. 2016;2(2):e000239. doi:10.1136/rmdopen-2015-000239 Conflict of interest: Dr. Mchale, Ciarán: No conflict of interest Mc Gettigan, Neasa: No conflict of interest Beatty, Paula: No conflict of interest O’Sullivan, David: No conflict of interest McKenna-Barry, Matthew: No conflict of interest Schilling, Carole: No conflict of interest Dowling, Jennifer: No conflict of interest Roche, Muireann: No conflict of interest Boland, Karen: No conflict of interest

Supplemental Digital Content is available in the text ABSTRACT Objectives: Experimental studies have shown that vitamin D has an immunomodulatory effect on the innate and adaptive immune systems. Associations between vitamin D deficiency and development or progression of inflammatory bowel diseases (IBDs) are reported, but a cause-and-effect relationship between pretreatment 25 hydroxyvitamin D [25(OH)D] levels and response to anti-tumor necrosis factor-α (anti-TNF) therapy is not established. Methods: This retrospective study evaluated pediatric IBD patients who had 25(OH)D levels drawn within 3 months of initiating infliximab and/or adalimumab treatment. Demographic features, Paris classification, baseline 25(OH)D levels, disease activity, and laboratory results before and after 3 months of anti-TNF therapy were collected. The interaction between vitamin D insufficiency at induction and lack of response to anti-TNF therapy at 3 months was determined. Results: Of the 383 patients, 76 met inclusion criteria. Sixty-five patients (85.5%) had Crohn disease (CD) and 11 (14.5%) had ulcerative colitis. Seven patients had 25(OH)D levels obtained during both infliximab and adalimumab induction; hence 83 subjects were evaluated (infliximab: 70 patients, adalimumab: 13 patients). 25(OH)D <30 ng/mL was found in 55 of 83 (66.3%) subjects. There were no differences in gender, IBD type, disease activity scores between vitamin D-sufficient and vitamin D-insufficient groups. In CD, proximal gastrointestinal tract inflammation was associated with vitamin D insufficiency (P = 0.019), but other Paris classification parameters and laboratory results were similar in 2 groups. Early termination of anti-TNF therapy was significantly higher in patients who had vitamin D insufficiency (14.5% vs 0%, P = 0.034). Conclusions: Vitamin D insufficiency before anti-TNF treatment may result in poor response to induction therapy.

BACKGROUND The aim of the present study was to investigate outcomes of anti-TNF-alpha (ATA) withdrawal in selected pediatric patients with inflammatory bowel disease who achieved clinical remission and mucosal and histological healing (MH and HH). METHODS A retrospective analysis was performed on children and adolescents affected by Crohn disease (CD) and ulcerative colitis (UC) who were followed up at 2 tertiary referral centers from 2008 through 2018. The main outcome measure was clinical relapse rates after ATA withdrawal. RESULTS One hundred seventy patients received scheduled ATA treatment; 78 patients with CD and 56 patients with UC underwent endoscopic reassessment. We found that MH was achieved by 32 patients with CD (41%) and 30 patients with UC (53.6%); 26 patients with CD (33.3%) and 22 patients with UC (39.3%) achieved HH. The ATA treatment was suspended in 45 patients, 24 affected by CD and 21 by UC, who all achieved concurrently complete MH (Simplified Endoscopic Score for CD, 0; Mayo score, 0, respectively) and HH. All the patients who suspended ATA shifted to an immunomodulatory agent or mesalazine. In contrast, 17 patients, 8 with CD and 9 with UC, continued ATA because of growth needs, the persistence of slight endoscopic lesions, and/or microscopic inflammation. Thirteen out of 24 patients with CD who suspended ATA experienced disease relapse after a median follow-up time of 29 months, whereas no recurrence was observed among the 9 patients with CD who continued treatment (P = 0.05). Among the patients with UC, there were no significant differences in relapse-free survival among those who discontinued ATA and those who did not suspend treatment (P = 0.718). CONCLUSIONS Despite the application of rigid selection criteria, ATA cessation remains inadvisable in CD. In contrast, in UC, the concurrent achievement of MH and HH may represent promising selection criteria to identify patients in whom treatment withdrawal is feasible.

The use of biologic therapy is increasing in pediatric patients with inflammatory bowel disease (IBD). However, efficacy may be compromised by increased drug clearance and anti‐drug antibodies (ADAs). Historically, concomitant immunomodulator therapy (CIT) has been used to prevent ADA formation. Pediatric studies evaluating CIT have focused largely on white, non‐Hispanic patients and have demonstrated variable benefits. This study evaluated the utility of CIT in preventing ADAs in a pediatric IBD population with high Hispanic representation.

Infliximab (IFX) is widely used for treating pediatric inflammatory bowel disease (pIBD). Development of anti-infliximab antibodies (AbIFX) reduces treatment efficacy, accelerating drug clearance. This study evaluated factors impacting serum IFX levels, AbIFX positivity in pIBD, and aimed to identify the most appropriate IFX threshold for antibody testing. Clinical and biochemical data, including inflammatory and disease-activity indices, were collected from pIBD patients followed at a tertiary referral center who underwent IFX and AbIFX measurements between May 2019 and September 2024. IFX and AbIFX were quantified by ELISA. AbIFX positivity was defined as > 3 U/mL. A total of 374 paired IFX–AbIFX determinations from 55 patients (26 males; Crohn’s disease n = 41, ulcerative colitis n = 14) were analyzed. AbIFX were detected in at least one determination in 29% of patients, more frequently in Crohn’s disease (34%) than in ulcerative colitis (14%). At univariate analysis, IFX concentrations were significantly associated with BMI (r = 0.1425, p = 0.0058), ESR (r=-0.1673, p = 0.0028), CRP (r=-0.2801, p < 0.0001) and albumin (r = 0.1309, p = 0.0156). In the multivariate linear regression model, adjusted for days since last infusion and dose (mg/kg), only ESR remained independently associated with IFX levels (B = –0.095, p = 0.011). At univariate analysis, AbIFX positivity correlated with disease activity (p = 0.036) and infusion reactions (p < 0.0001). In the multivariate logistic regression, only infusion reactions remained an independent predictor of antibody positivity (OR = 22.8, p = 0.002). A moderate inverse correlation was observed between IFX and AbIFX levels (p < 0.0001). ROC analysis (AUC = 0.790) identified a 3 µg/mL IFX threshold as the most accurate cut-off for predicting AbIFX positivity (sensitivity 77,6%, specificity 70,1%), outperforming the conventional 5 µg/mL threshold (sensitivity 79,6%, specificity 51,6%). Systemic inflammation, reflected by elevated ESR, emerged as the main determinant of reduced IFX through levels. Antibody development was strongly associated with infusion-related reactions, likely representing the clinical expression of infliximab immunogenicity. A serum IFX threshold of 3 µg/mL appears to be a more accurate and clinically useful trigger for reflex antibody testing, supporting a personalized and cost-effective therapeutic drug-monitoring strategy in pediatric IBD. Conflict of interest: Dr. Gagliano, Chiara: No conflict of interest Carciofi, Annalisa: No conflict of interest Borgiani, Francesca: No conflicts of interest Olivetti, Linda: No conflict of interest Morelli, Renato: No conflict of interest Babini, Lucia: No conflict of interest Baldassari, Michela: No conflict of interest Calcinari, Alessandra: No conflict of interest Brusco, Mario: No conflict of interest Franceschini, Elisa: No conflict of interest Moretti, Marco: No conflict of interest Lionetti, Maria Elena: No conflict of interest Gatti, Simona: No conflict of interest

Background Inadequate systemic exposure to infliximab (IFX) is associated with treatment failure. This work evaluated factors associated with reduced IFX exposure in children with autoimmune disorders requiring IFX therapy. Methods In this single-center cross-sectional prospective study IFX trough concentrations and anti-drug antibodies (ADAs) were measured in serum from children diagnosed with inflammatory bowel disease (IBD) ( n  = 73), juvenile idiopathic arthritis (JIA) ( n  = 16), or uveitis ( n  = 8) receiving maintenance IFX infusions at an outpatient infusion clinic in a tertiary academic pediatric hospital. IFX concentrations in combination with population pharmacokinetic modeling were used to estimate IFX clearance. Patient demographic and clinical data were collected by chart review and evaluated for their relationship with IFX clearance. Results IFX trough concentrations ranged from 0 to > 40 μg/mL and were 3-fold lower in children with IBD compared to children with JIA ( p  = 0.0002) or uveitis ( p  = 0.001). Children with IBD were found to receive lower IFX doses with longer dosing intervals, resulting in dose intensities (mg/kg/day) that were 2-fold lower compared to children with JIA ( p  = 0.0002) or uveitis ( p  = 0.02). Use of population pharmacokinetic analysis to normalize for variation in dosing practices demonstrated that increased IFX clearance was associated with ADA positivity ( p  = 0.004), male gender ( p  = 0.02), elevated erythrocyte sedimentation rate (ESR) (p = 0.02), elevated c-reactive protein (CRP) ( p  = 0.001), reduced serum albumin concentrations ( p  = 0.0005), and increased disease activity in JIA ( p  = 0.009) and IBD ( p  ≤ 0.08). No significant relationship between diagnosis and underlying differences in IFX clearance was observed. Multivariable analysis by covariate population pharmacokinetic modeling confirmed increased IFX clearance to be associated with anti-IFX antibody positivity, increased ESR, and reduced serum albumin concentrations. Conclusions Enhanced IFX clearance is associated with immunogenicity and inflammatory burden across autoimmune disorders. Higher systemic IFX exposures observed in children with rheumatologic disorders are driven primarily by provider drug dose and interval selection, rather than differences in IFX pharmacokinetics across diagnoses. Despite maintenance IFX dosing at or above the standard recommended range for IBD (i.e., 5 mg/kg every 8 weeks), the dosing intensity used in the treatment of IBD is notably lower than dosing intensities used to treat JIA and uveitis, and may place some children with IBD at risk for suboptimal maintenance IFX exposures necessary for treatment response.

An increasing number of patients in clinical practice are transitioning from intravenous (IV) to subcutaneous (SC) dosing of infliximab. In this simulation study, we evaluated hypothetical dosing scenarios both for typical adults and adults with obesity and for children switching from steady-state IV to SC infliximab, as well as those initiating SC infliximab therapy. By combining two previous published infliximab models, we were able to simulate both IV and SC dosing in adults and children. Various dosing regimens were simulated using a large virtual population. In each scenario, the distribution of trough concentrations and area under the plasma concentration–time curve (AUC) was calculated. Peak levels were higher after IV dosing compared with SC dosing, while trough levels were higher after SC dosing, leading to more stable infliximab levels over time. Overall exposure remained largely similar when switching from a standard IV to SC dosing regimen. Patients with a high body mass index and those on high-frequency IV dosing regimens of infliximab demonstrated reduced exposure when transitioned to the fixed SC dose. Paediatric patients exhibited higher exposure on the fixed SC dose. Simulation of SC induction schemes demonstrated early achievement of steady-state plasma levels. Infliximab exposure (AUC) remains largely similar when transitioning from standard IV to SC dosing. Current dosing regimens may not be optimal for patients with severe obesity, paediatric patients and patients on high-frequency infliximab regimens. These findings provide a foundation for future clinical research to refine SC infliximab dosing in these populations.

Efficacy of infliximab in children with inflammatory bowel disease can be enhanced when serum concentrations are measured and further dosing is adjusted to achieve and maintain a target concentration. Use of a population pharmacokinetic model may help to predict an individual’s infliximab dose requirement. The aim of this study was to evaluate the predictive performance of available infliximab population pharmacokinetic models in an independent cohort of Dutch children with inflammatory bowel disease. In this retrospective study, we used data of 70 children with inflammatory bowel disease (443 infliximab concentrations) to evaluate eight models that focused on infliximab pharmacokinetic models in individuals with inflammatory bowel disease, preferably aged ≤ 18 years. Predictive performance was evaluated with prior predictions (based solely on patient-specific covariates) and posterior predictions (based on covariates and infliximab trough concentrations). Model accuracy and precision were calculated with relative bias and relative root mean square error and we determined the classification accuracy at the trough concentration target of ≥ 5 mg/L. The population pharmacokinetic model by Fasanmade was identified to be most appropriate for the total dataset (relative bias before/after therapeutic drug monitoring: −20.7%/11.2% and relative root mean square error before/after therapeutic drug monitoring: 84.1%/51.6%), although differences between models were small and several were deemed suitable for clinical use. For the Fasanmade model, sensitivity and specificity for maximum posterior predictions for the next infliximab trough concentration to be ≥ 5 mg/L were respectively 83.5% and 80% with an area under the receiver operating characteristic curve of 0.870. In our paediatric cohort, various models provided acceptable predictive performance, with the Fasanmade model deemed most suitable for clinical use. Model-informed precision dosing can therefore be expected to help to maintain infliximab trough concentrations in the target range.

INTRODUCTION: In patients with inflammatory bowel diseases (IBDs), high visceral adipose tissue (VAT) burden is associated with a lower response to infliximab, potentially through alterations in volume distribution and/or clearance. Differences in VAT may also explain the heterogeneity in target trough levels of infliximab associated with favorable outcomes. The aim of this study was to assess whether VAT burden may be associated with infliximab cutoffs associated with efficacy in patients with IBD. METHODS: We conducted a prospective cross-sectional study of patients with IBD receiving maintenance infliximab therapy. We measured baseline body composition parameters (Lunar iDXA), disease activity, trough levels of infliximab, and biomarkers. The primary outcome was steroid-free deep remission. The secondary outcome was endoscopic remission within 8 weeks of infliximab level measurement. RESULTS: Overall, 142 patients were enrolled. The optimal trough levels of infliximab cutoffs associated with steroid-free deep remission and endoscopic remission were 3.9 mcg/mL (Youden Index [J]: 0.52) for patients in the lowest 2 VAT % quartiles (<1.2%) while optimal infliximab level cutoffs associated with steroid-free deep remission for those patients in the highest 2 VAT % quartiles was 15.3 mcg/mL (J: 0.63). In a multivariable analysis, only VAT % and infliximab level remained independently associated with steroid-free deep remission (odds ratio per % of VAT: 0.3 [95% confidence interval: 0.17–0.64], P < 0.001 and odds ratio per μg/mL: 1.11 [95% confidence interval: 1.05–1.19], P < 0.001). DISCUSSION: The results may suggest that patients with higher visceral adipose tissue burden may benefit from achieving higher infliximab levels to achieve remission.

Abstract Objectives Payer mandates have resulted in children with inflammatory bowel disease (IBD) switching from originator Remicade® (O‐Rem) to an infliximab biosimilar (B‐IFX). Patients and families are fearful of switching because disease has been well controlled on O‐Rem. Real‐world data documenting clinical outcomes after such switches in pediatric patients are limited. The aim of this project was to examine 1 year of follow‐up in a large adolescent/young adult IBD cohort who changed from O‐Rem to B‐IFX. Methods We identified patients with IBD at Connecticut Children's receiving O‐Rem for at least 1 year, who were either in clinical remission or had low disease activity, and who were subsequently switched to B‐IFX. An age, gender, IBD‐subtype, and duration since diagnosis cohort that continued on O‐Rem was then matched to the switch cohort and served as a comparator group (1: switch vs. 2: no‐switch). B‐IFX was Inflectra® in all cases. Results Two hundred and seventy‐nine patients (mean age 18.7 years, Crohn's disease = 243, ulcerative colitis = 36) were studied (switch, n = 93, no‐switch, n = 186). Mean time since diagnosis was >6 years in both groups, and mean duration of anti‐tumor necrosis factor use was >5 years. There were no significant changes in hemoglobin, albumin, C‐reactive protein, erythrocyte sedimentation rate, or disease activity in either group over 1 year. Dosing modifications as well as the frequency of low‐level antibodies to infliximab were similar in both groups over the study period. Conclusion Switching from O‐Rem to B‐IFX has no impact on clinical or laboratory parameters over the subsequent year. Clinicians can reliably reassure patients and families that switching is safe.

No abstract available

BACKGROUND AND AIMS Adequate infliximab concentrations during induction treatment are predictive for deep remission (corticosteroid-free clinical and endoscopic remission) at six months in children with inflammatory bowel diseases (IBD). Under standard infliximab induction dosing, children often have low infliximab trough concentrations. Model-informed precision dosing (MIPD) (i.e., model-based therapeutic drug monitoring) is advocated as a promising infliximab dosing strategy. We aimed to develop and validate an MIPD framework for guiding paediatric infliximab induction treatment. METHODS Data from 31 children with IBD (4-18years) receiving standard infliximab induction dosing (5mg/kg at week [w]0, w2, and w6) were repurposed. Eight paediatric population pharmacokinetic models were evaluated. Modelling and simulation were used to identify exposure targets, an optimal sampling strategy, and develop a multi-model prediction algorithm for implementation into an MIPD software tool. A role for infliximab clearance monitoring was evaluated. RESULTS A 7.5mg/L infliximab concentration target at w12 was associated with 64% probability of deep remission at six months. With standard dosing, less than 80% of simulated children <40kg attained this target. The w12 target was most accurately and precisely achieved by implementing MIPD at w6 using the w6 infliximab concentration (rapid assay required). The multi-model algorithm outperformed single models when optimising the w6 dose based on both w2 and w4 concentrations. MIPD using only the w2 concentration resulted in biased and imprecise predictions. Infliximab clearances at w6 and w12 were predictive for deep remission. CONCLUSIONS A freely available, multi-model MIPD tool facilitates infliximab induction dosing and improves deep remission rates in children with IBD.

No abstract available

Background and Aims Children with very early onset inflammatory bowel disease (VEO-IBD) are uniquely at risk of inadequate infliximab (IFX) exposure. We studied the association between standard body weight (BW)-based and body surface area (BSA)-based dosing strategies and outcomes. Methods We identified VEO-IBD patients treated with IFX before 9 years at a single center. Patients were separated into those that received a BSA-based dose (200 mg/m2) and standard BW dosing (5 mg/kg). IFX drug levels, dose intensification, time on steroids, and long-term outcomes were compared. Receiver operator characteristic curves determined the optimal BW- and BSA-based dose to achieve a trough ≥10 μg/ml at dose 4 (IFX#4). Results Forty-three children with VEO-IBD were identified. Receiver operator characteristic curves demonstrated optimal BW- and BSA-based doses to achieve IFX trough ≥10 μg/ml at IFX#4 were 7.5 mg/kg and 180mg/m2. Children were classified to standard BW dosing (22/43) and BSA dosing (10/43). IFX#4 trough was significantly higher in those who received BSA dosing (BSA 18.6 μg/ml [interquartile range 10.8–28.1] vs BW 5.1 μg/ml [interquartile range 2.6–10.7], P = .04). BSA dosing was more likely to achieve a target drug level >10 μg/ml at IFX#4 (BSA 70% vs BW 18%, P = .02). BW dosing was associated with a greater likelihood of dose escalation (BW 82% vs BSA 30%, P < .01) and a shorter time to first escalation. BSA dosing was associated with shorter time spent on steroids (P = .02). Conclusion Young children require higher IFX dosing to achieve adequate drug exposure. Our data support the use of a BSA-based dose of 200 mg/m2 or, if a BW-based approach is used, 7.5 mg/kg. BSA dosing allows the use of a consistent dose over the age and weight spectrum.

Objectives: In patients with inflammatory bowel diseases (IBD), data on trough concentration (TC) response to adjustments of anti-tumor necrosis factor (TNFα) are scarce. Methods: We included pediatric patients with IBD who were treated with anti-TNFα agents and had sequential monitoring of TC pre- and post-adjustment. Patients with positive anti-drug-antibodies or with concomitant change in immunomodulatory treatment were excluded. Results: For the entire cohort (86 patients), median age at diagnosis was 13.2 (interquartile range, 10.7–14.9) years [females, 48%; Crohn disease (CD), 72%]. For infliximab, 58 patients had 201 interval changes and 26 had dose increase. Increase in TC following dose increase could not be predicted due to significant variability (P = 0.9). For every 10% decrease in interval, TC was increased by 1.6 µg/mL or by 57.2% (P = 0.014). Perianal disease was associated with attenuated response. For every 10% increase in interval, TC was decreased by 0.66 µg/mL or by 4.2%. The diagnosis of CD was associated with reduced response to interval increase. For adalimumab, 28 patients had 31 and 12 events of interval decrease or increase, respectively. Interval decrease resulted in increased median TC from 4.5 (3.5–5.3) µg/mL to 8.1 (6.5–10.5) µg/mL (X1.8) while interval increase resulted in TC change from 15.5 (12.8–18.6) µg/mL to 9.7 (6.5–14.6) µg/mL (:1.6) (P < 0.001 for both). Increase in delta TC was associated with younger age, and with absence of perianal disease (P = 0.001). Conclusion: Changes in TC following treatment adjustment can be almost linearly predicted for adalimumab while response to infliximab adjustment are more variable.

In pediatric inflammatory bowel disease (IBD), proactive therapeutic drug monitoring (TDM) involves measuring infliximab (IFX) trough levels at pre-specified time points or intervals. Existing literature suggests that optimizing IFX dosing in response to levels at week 14, prior to the start of maintenance infusions, offers clinical benefit at 52 weeks. There has been growing interest in beginning proactive TDM earlier, prior to the 3rd and final induction infusion. We hypothesize that early proactive TDM prior to the 3rd versus 4th IFX infusion improves clinical outcomes in children with IBD. A retrospective cohort analysis included children with IBD receiving IFX treatment between January 1, 2020 and December 31, 2023. This study compared patients who underwent proactive TDM of IFX prior to the 3rd infusion (early group) versus those whose levels were first measured prior to the 4th infusion (later group). Propensity score matching was used to match patients based on gender, disease, and age at IFX start. Clinical and laboratory data, along with Physician Global Assessment (PGA), were collected at baseline and for one year following initiation of IFX and compared between the early and later groups. The primary outcomes were time to clinical remission based on PGA and therapeutic maintenance IFX levels (>5 μg/ml), IBD-related hospitalizations and surgeries, and discontinuation of IFX. Secondary outcomes evaluated clinical outcomes at 6- and 12-months post-IFX initiation in both groups. Time to event analysis including Kaplan Meier plots and log-rank tests were used to compare time to therapeutic maintenance between study groups. In total, 68 patients from each group were matched. Patients from the early group experienced a faster median time to clinical remission of 140 days (95% CI: 108, 167) versus 203 days (95% CI: 167, 232) in patients from the later group (p < 0.05). While time to therapeutic maintenance IFX levels did not significantly differ across the entirety of both groups, 75% of patients from the early group achieved therapeutic levels in a median of 134 days (95% CI: 114, 182) versus 183 days (95% CI: 153, 224) in the later group. There were no significant differences in IFX discontinuation, hospitalizations, IBD-surgeries, or clinical outcomes at 6- and 12-months post-IFX initiation between the groups. Early proactive TDM of IFX prior to the 3rd infusion may significantly accelerate time to clinical remission compared to later proactive TDM. It is suspected that measuring IFX trough levels earlier prior to the third infusion enables timely dose adjustments and promoted faster clinical improvement. Given its potential to enhance outcomes, early proactive TDM prior to the third infusion should be considered a valuable strategy in the clinical management of children with IBD.

Transmural healing (TH) is an emerging treatment target for IBD and is associated with superior outcomes compared to clinical or endoscopic healing. However, current paediatric proactive infliximab (IFX) therapeutic drug monitoring (pTDM) guidelines are based on clinical and biochemical outcomes. This study aimed to identify IFX trough concentration (cTrough) targets associated with TH assessed by intestinal ultrasound (IUS). This cohort study included paediatric IBD patients, <18 years of age, who started IFX and underwent IUS as part of routine clinical care. Patients with isolated upper GI disease, proctitis or no IUS follow-up were excluded. The primary outcome was the IFX induction cTrough associated with TH, defined as a maximum bowel wall thickness (BWT) <2.5mm per paediatric consensus and compared with the adult <3.0mm definition (+/- colour doppler signal). IUS was conducted following the International Bowel UltraSound (IBUS) acquisition consensus by two IBUS-certified paediatric gastroenterologists. IFX cTrough and antibodies (ATIs) were measured at the 3rd and 4th infusion and at maintenance intervals following pTDM guidelines. IFX and ATIs were measured by LC-MS/MS and ECLIA, respectively (Mayo Clinic Laboratories). Area under the receiver operating characteristics (AUROC) analyses were used to evaluate IFX cTrough cutoffs associated with TH. The cohort included 66 children with IBD, 45 of whom met inclusion criteria (67 IFX cTrough-IUS pairs). Mean age 10 (IQR: 9-13) years of age, 53% (24) Crohn’s disease, and 58% (26) female. Patients with the paediatric TH target (BWT <2.5mm) had a higher median IFX induction cTroughs 39.5 μg/mL (24.5-50) compared to ≥ 2.5mm, 14 μg/mL (7.6-26.5; P=0.04). Patients with a maximum BWT <3.0 mm had higher IFX induction cTroughs 32 μg/mL (25-49) compared to ≥ 3.0mm, 14 μg/mL (7.6-23; P=0.03). At infusion-3, an IFX ≥22 μg/mL cutoff predicted TH (AUROC 0.74; sensitivity 0.80, specificity 0.80) for <2.5mm and (AUROC 0.78; sens 0.83, spec 0.89) for <3.0mm. At infusion-4, a cutoff of IFX ≥17 μg/mL (AUROC 0.75; sens 1.00, spec 0.71) predicted the paediatric TH target at < 2.5mm, while a cutoff of IFX ≥14 μg/mL (AUROC 0.82; sens 1.00, spec 0.75) predicted TH at the adult <3.0mm definition. Addition of colour doppler signal to BWT did not improve AUROC predictions. Moreover, maintenance IFX concentrations beyond infusion-4 did not predict TH. This study identified IFX cTroughs that predict paediatric transmural healing by intestinal ultrasound. Maintenance concentrations did not predict healing. Future intervention studies should evaluate if prospective optimized dosing results in enhanced transmural healing outcomes. Conflict of interest: Toroslu, Ertug: NOTHING TO DECLARE Patel, Perseus: None Colman, Ruben: No conflicts

Monitoring infliximab (IFX) concentrations is crucial for optimizing IFX therapy in children with inflammatory bowel diseases (IBDs) who show low response rates due to inadequate drug exposure. Substantial variation occurs in IFX trough concentrations in paediatric patients. Objectives: This study aimed to investigate IFX pharmacokinetics (PK) in children with IBD during both the induction phase and maintenance phases and to identify covariates associated with IFX PK. Methods: This single-centre retrospective cohort study was conducted at an academic children’s hospital. Data was extracted from paediatric IBD patients receiving IFX between January 2018 and October 2023 and included demographic-, clinical- and laboratory parameters collected from electronic health records. Linear mixed model analysis was performed to investigate associations between these parameters and IFX trough concentrations. Target attainment [≥15 μg/mL in induction or 5–10 μg/mL in maintenance phase] of the IFX dosing regimens was evaluated. Results and Conclusions: A total of 115 children (417 unique IFX concentrations) were included. Multivariate analysis revealed significant positive associations between IFX and albumin concentrations (β = 0.388, p = 0.010) and IFX concentrations with dose (β = 6.534, p < 0.001), and an inversion association between IFX concentrations and treatment phase (β = −4.922, p < 0.001). During the induction and maintenance phases, 57.2% and 30.6% of IFX concentrations were subtherapeutic, respectively. A systematic search of studies investigating factors influencing IFX concentrations was concurrently performed. Our findings were critically compared against existing literature to assess relevant clinical and biochemical determinants of IFX PK in children with IBD. Our findings highlight the need for personalized dosing strategies in pediatric IBD patients, particularly during the induction phase. By implementing therapeutic drug monitoring (TDM) and considering clinical and biochemical factors, clinicians can implement more personalized strategies, potentially improving treatment efficacy and reducing the risk of treatment failure or adverse effects. This approach could lead to better target attainment, potentially enhancing clinical outcomes and minimizing premature switching to other therapies.

Underexposure to infliximab often leads to loss of response in patients with inflammatory bowel disease (IBD). Model‐informed precision dosing (MIPD) offers a superior approach to maintaining target infliximab concentrations compared to empirical dosage adjustment. This study aims to externally validate the population pharmacokinetic (PK) models implemented in TDMx, an online MIPD dashboard system, for adult and pediatric Korean IBD patients before clinical use. This retrospective study included 199 IBD patients (142 adults, 57 children) treated with intravenous infliximab at Seoul National University Hospital (Seoul, Republic of Korea) from 2019 to 2023. Three adult and seven pediatric models were evaluated based on accuracy, precision, goodness of fit plots, prediction‐corrected visual predictive checks, and normalized prediction distribution errors. For adults, the Passot model showed the best fit (mean percentage error (MPE) 26.4%, mean absolute error (MAE) 1.1 mg/L, relative root‐mean square error (rRMSE) 159.0%), whereas all pediatric models were unsuitable for clinical use (MPE 30.4%–143.4%, MAE 1.4–2.6 mg/L, rRMSE 96.3%–564.0%). Predictive performance was compared between datasets with or without accurate information on antibodies‐toward‐infliximab (ATI), as well as with and without previous concentrations. Assuming all patients were ATI positive improved predictive performance, likely due to the inherent positive bias of the population PK models. Incorporating previous concentrations improved predictions for adult models, achieving acceptable accuracy and precision (Passot model: MPE 17.5%, MAE 1.8 mg/L, rRMSE 80.3% with one concentration). However, pediatric models remained clinically unacceptable, highlighting the need to develop models specifically tailored for this population.

Abstract Background VEO-IBD patients defined as children with IBD diagnosed before 6rys of age, account for approximately 10% of pediatric IBD patients. They are uniquely at risk of inadequate infliximab (IFX) exposure. We report the dosing patterns, efficacy and safety of IFX use in a cohort of patients with VEO-IBD. Aims To study the response rate and outcome of IFX in VEOIBD patients with active therapeutic drug monitoring. Our primary aim was to study the rate of clinical remission and outcome of patients with VEOIBD on IFX. Our secondary aim was to study the IFX failure rate in VEOIBD children and also to study the association of body weight (BW) and body surface area (BSA) dosing. Methods A retrospective chart review was conducted for all children with VEOIBD diagnosed between 1st January 2013 to 31st December 2022 with a minimum follow up of one year at a single centre. The patients were identified from the British Columbia paediatric IBD database. Clinical data, including IBD medication use and response were collected from the medical record. REB approval was obtained for this study. Results A total of 77 patients were identified and reviewed in our study with 28 (34.1%) exposed to infliximab, with a mean follow up of 65.6 months (±31.7mo). The mean age at diagnosis was 45.9 months (SD±18.5m). Among them, 14 (50%) were diagnosed with Crohn’s disease and 11 (39%) and 3 (11%) with ulcerative colitis and IBD-U respectively. 19/28 (67.8%) patients were started on IFX below 6yrs of age. The median time from diagnosis to IFX commencement was 11.9 months (IQR 3.9-11.9mo). The median pre dose 3 and pre dose 4 infliximab trough levels were 4.35 μg/mL and 5.2 μg /mL respectively with a mean IFX induction dose of 6.7 mg/kg (SD ±2.14mg/kg) and 160.6 mg/m2 body surface area. 18/28 (64.3%) patients needed a dose change after induction with the rest needing dose optimization at follow up. 12/28 (42.8%) were on concomitant therapy with methotrexate or azathioprine. 17/28 (60.7%) continued on IFX as their therapy, with a mean IFX dose of 300mg/m2 and 10.25 mg/kg to achieve clinical remission at last follow. The median drug level for these patients was 7.15 μg/mL. Clinical remission at last follow up on IFX was achieved in all 17/28 patients with 7/17 in biochemical remission, defined at fecal calprotectin <250μg/g. Infliximab failure occurred in 11/28 (39.3%) of patients with 10/11 due to secondary loss of response. Among those 11, 7 were exposed to a 2nd biologic and 4 to a 3rd biologic with response in 7. Three patients required a colectomy and 1 underwent a bone marrow transplant. Conclusions Infliximab trough levels pre dose 3 and 4 are often low in VEO-IBD patients and dose optimization is very common. Funding Agencies None

There is controversy about whether levels of anti-tumor necrosis factor (TNF) and antidrug antibodies (ADAs) are accurate determinants of loss of response to therapy. We analyzed the association between trough levels of anti-TNF agents or ADAs and outcomes of interventions for patients with loss of response to infliximab or adalimumab. We performed a retrospective study of pediatric and adult patients with inflammatory bowel disease and suspected loss of response to anti-TNF agents treated at medical centers throughout Israel from October 2009 through February 2013. We examined the correlation between outcomes of different interventions and trough levels of drug or ADAs during loss of response. An additional subanalysis was performed including only patients with a definite inflammatory loss of response (clinical worsening associated with increased levels of C-reactive protein or fecal calprotectin, or detection of inflammation by endoscopy, fistula discharge, or imaging studies). Among 247 patients (42 with ulcerative colitis), there were 330 loss-of-response events (188 to infliximab and 142 to adalimumab). Trough levels of adalimumab greater than 4.5 mcg/mL and infliximab greater than 3.8 mcg/mL identified patients who failed to respond to an increase in drug dosage or a switch to another anti-TNF agent with 90% specificity; these were set as adequate trough levels. Adequate trough levels identified patients who responded to expectant management or out-of-class interventions with more than 75% specificity. Levels of antibodies against adalimumab >4 microgram per mL equivalent (mcg/mL-eq) or antibodies against infliximab >9 mcg/mL-eq identified patients who did not respond to an increased drug dosage with 90% specificity. Patients with high titers of ADAs had longer durations of response when anti-TNF agents were switched than when dosage was increased (P = .03; log-rank test), although dosage increases were more effective for patients with no or low titers of ADAs (P = .02). An analysis of definite inflammatory loss-of-response events (n = 244) produced similar results; patients with adequate trough levels had a longer duration of response when they switched to a different class of agent than when anti-TNF was optimized by either a dosage increase or by a switch within the anti-TNF class (P = .002; log-rank test). The results of this retrospective analysis suggest that trough levels of drug or ADAs may guide therapeutic decisions for more than two-thirds of inflammatory bowel disease patients with either clinically suspected or definite inflammatory loss of response to therapy.

To individualize timing of infliximab (IFX) treatment in children and adolescents with inflammatory bowel disease (IBD) using a patient-managed eHealth program. Patients with IBD, 10 to 17 years old, treated with IFX were prospectively included. Starting 4 weeks after their last infusion, patients reported a weekly symptom score and provided a stool sample for fecal calprotectin analysis. Based on symptom scores and fecal calprotectin results, the eHealth program calculated a total inflammation burden score that determined the timing of the next IFX infusion (4-12 wk after the previous infusion). Quality of Life was scored by IMPACT III. A control group was included to compare trough levels of IFX antibodies and concentrations and treatment intervals. Patients and their parents evaluated the eHealth program. There were 29 patients with IBD in the eHealth group and 21 patients with IBD in the control group. During the control period, 94 infusions were provided in the eHealth group (mean interval 9.5 wk; SD 2.3) versus 105 infusions in the control group (mean interval 6.9 wk; SD 1.4). Treatment intervals were longer in the eHealth group (P < 0.001). Quality of Life did not change during the study. Appearance of IFX antibodies did not differ between the 2 groups. Eighty percent of patients reported increased disease control and 63% (86% of parents) reported an improved knowledge of the disease. Self-managed, eHealth-individualized timing of IFX treatments, with treatment intervals of 4 to 12 weeks, was accompanied by no significant development of IFX antibodies. Patients reported better control and improved knowledge of their IBD.

The aim of the study was to evaluate infliximab (IFX) dosing and treatment durability relative to luminal disease burden in patients with inflammatory bowel disease. Records from 98 pediatric patients treated with IFX between 2012 and 2014 were reviewed. Disease extent was classified as "limited," "moderate," or "extensive" based on cumulative assessment of mucosal involvement. Patients started taking standard 5 mg/kg dosing were compared with those initiated taking 10 mg/kg with regard to treatment durability. Overall, 26.4%, 58.3%, and 70% with limited, moderate, or extensive disease, respectively, started taking a standard IFX dose of 5 mg/kg required therapy escalation. Patients with moderate and extensive disease, started taking the 5 mg/kg per dose, showed statistically significant shorter times to escalation than those with limited disease. The percentage of patients remaining on their initial 5 mg/kg per dose at 12 months was 80.1%, 56.9%, and 40.0% for limited, moderate, and extensive disease, respectively. Among patients started taking 10 mg/kg, 100% remained on this dose. All the patients with limited disease who required dose escalation continued on the higher dose at the time of analysis; however, among those with the most extensive disease, 43% failed escalation because of nonresponse or infusion reaction. Patients with extensive disease started taking 5 mg/kg of IFX were more likely to require dose escalation compared to those with limited or moderate disease. All of the patients with moderate and extensive disease started taking 10 mg/kg of IFX remained on this dose. These results suggest that patients with more extensive disease may benefit from higher initial IFX dosing as it relates to durability of the treatment.

A pilot study investigated the cytokine profile (IL-6, TNF-α, IL-17 A, and IL-10) at diagnosis, affecting infliximab (IFX) trough levels (TLs) in pediatric patients with Crohn's disease (CD). In this follow-up study, we evaluated the changes in cytokine level changes after Crohn's disease treatment. Cytokines were re-measured after 1 year of treatment. infliximab trough levels and total anti-infliximab antibodies were also measured in patients who had started infliximab treatment. In total, 29 patients followed up for a year after moderate to severe Crohn's disease diagnosis from June 2020 to June 2021 were enrolled. The mean concentrations of all cytokines at one year were significantly lower than those at the time of diagnosis. IL-6, IL-17 A, and IL-10 concentrations at 1 year maintained their correlation with each other observed at diagnosis, unlike TNF-α following infliximab treatment. At 1 year, TNF-α concentration exhibited a negative correlation with infliximab trough levels (Pearson coefficient = -0.500, p = 0.009), and a positive correlation with anti-infliximab antibody titre (Pearson coefficient = 0.510, p = 0.018). The diagnostic capability of 1-year TNF-α concentration to predict achievement of deep remission had an area under the ROC of 0.802 (p = 0.008), with a TNF-α cut-off concentration set at 9.40 pg/mL. Decreased cytokine concentrations following Crohn's disease treatment reflected reduced inflammatory burden. Targeted medical intervention (infliximab) aimed at specific cytokines, such as TNF-α, led to the reduction of the corresponding cytokines. High TNF-α level post-treatment, combined with suboptimal infliximab trough levels and increased antibody formation, may contribute to deep remission failure in patients.

Background: Substantial inter-and intra-individual variability of Infliximab (IFX) pharmacokinetics necessitates tailored dosing approaches. Here, we evaluated the performances of a Model Informed Precision Dosing (MIPD) Tool in forecasting trough Infliximab (IFX) levels in association with disease status and circulating TNF-α in patients with Inflammatory Bowel Diseases (IBD). Methods: Consented patients undergoing every 8-week maintenance therapy with IFX were enrolled. Midcycle specimens were collected, IFX, antibodies to IFX, albumin were determined and analyzed with weight using nonlinear mixed effect models coupled with Bayesian data assimilation to forecast trough levels. Accuracy of forecasted as compared to observed trough IFX levels were evaluated using Demings’s regression. Association between IFX levels, CRP-based clinical remission and TNF-α levels were analyzed using logistic regression and linear mixed effect models. Results: In 41 patients receiving IFX (median dose = 5.3 mg/Kg), median IFX levels decreased from 13.0 to 3.9 µg/mL from mid to end of cycle time points, respectively. Midcycle IFX levels forecasted trough with Deming’s slope = 0.90 and R2 = 0.87. Observed end cycle and forecasted trough levels above 5 µg/mL associated with CRP-based clinical remission (OR = 7.2 CI95%: 1.7−30.2; OR = 21.0 CI95%: 3.4−127.9, respectively) (p < 0.01). Median TNF-α levels increased from 4.6 to 8.0 pg/mL from mid to end of cycle time points, respectively (p < 0.01). CRP and TNF-α levels associated independently and additively to decreased IFX levels (p < 0.01). Conclusions: These data establish the value of our MIPD tool in forecasting trough IFX levels in patients with IBD. Serum TNF-α and CRP are reflective of inflammatory burden which impacts exposure.

Biologic agents with various mechanisms against Crohn's disease (CD) have been released and are widely used in clinical practice. However, two anti-tumor necrosis factor (TNF) agents, infliximab (IFX) and adalimumab (ADL), are the only biologic agents approved by the Food and Drug Administration for pediatric CD currently. Therefore, in pediatric CD, the choice of biologic agents should be made more carefully to achieve the therapeutic goal. There are currently no head-to-head trials of biologic agents in pediatric or adult CD. There is a lack of accumulated data for pediatric CD, which requires the extrapolation of adult data for the positioning of biologics in pediatric CD. From a pharmacokinetic point of view, IFX is more advantageous than ADL when the inflammatory burden is high, and ADL is expected to be advantageous over IFX in sustaining remission in the maintenance phase. Additionally, we reviewed the safety profile, immunogenicity, preference, and compliance between IFX and ADL and provide practical insights into the choice of anti-TNF therapy in pediatric CD. Careful evaluation of clinical indications and disease behavior is essential when prescribing anti-TNF agents. In addition, factors such as the efficacy of induction and maintenance of remission, safety profile, immunogenicity, patient preference, and compliance play an important role in evaluating and selecting treatment options.

The escalating worldwide prevalence of Crohn's disease (CD) among children and adolescents, coupled with a trend toward earlier onset, presents significant challenges for healthcare systems. Moreover, the chronicity of this condition imposes substantial individual burdens. Consequently, the principal objective of CD treatment revolves around rapid inducing remission. This study scrutinizes the impact of age, gender, initial disease localization, and therapy on the duration to achieve disease activity amelioration. Data from the Saxon Pediatric IBD Registry in Germany were analyzed over a period of 15 years. In addition to descriptive methods, logistic and linear regression analyses were conducted to identify correlations. Furthermore, survival analyses and Cox regressions were utilized to identify factors influencing the time to improvement in disease activity. These effects were expressed as Hazard Ratios (HR) with 95% confidence intervals. Data on the clinical course of 338 children and adolescents with CD were available in the registry. The analyses showed a significant correlation between a young age of onset and the severity of disease activity. It was evident that treatment with anti-TNF (Infliximab) was associated with a more favorable prognosis in terms of the time required for improvement in disease activity. Similarly, favorable outcomes were observed with the combination therapies of infliximab with enteral nutrition therapy and Infliximab with immunosuppressants.Conclusion: Our analysis of data from the Saxon Pediatric IBD Registry revealed that the timeframe for improvement of disease activity in pediatric Crohn's disease is influenced by several factors. Specifically, patient age, treatment modality, and initial site of inflammation were found to be significant factors. The study provides important findings that underline the need for individualized treatment.

Standard outpatient induction dosing of infliximab (IFX) may not be effective in hospitalized ulcerative colitis (UC) patients with higher inflammatory burden and colectomy risk. Our aim was to determine whether initial IFX induction dose affects 30-day colectomy rate and other disease-related outcomes. IFX-naive hospitalized UC patients receiving at least 1 inpatient 5 mg/kg (SD) or 10 mg/kg (HD) IFX induction dose were included. Baseline demographics and admission-related characteristics were documented. Propensity score based matching was used to control for provider bias introduced due to nonprotocolized choice of IFX dose. The primary outcome was 30-day colectomy; secondary outcomes included the need for an accelerated induction IFX (AD), length of stay (LOS), 90-day and 1-year colectomy, and complications. Of 146 (120 SD/26 HD) patients included, 25 (17.1%) underwent colectomy by 30 days, 33 (22.6%) by 90 days, and 41 (28.1%) by 1 year. In 21 propensity score matched dyads (n = 42) treated with SD or HD, colectomy rates and LOS were similar. SD patients more often needed AD (23.8% vs. 0%, P = 0.048) and AD patients progressed to colectomy more rapidly within 30 days compared to non-AD (P = 0.001). Female sex and hypoalbuminemia were associated with significantly increased odds of needing AD on both univariate and multivariate analyses. In our propensity score based analysis, receiving accelerated IFX dosing after an initial SD infusion was associated with significantly higher 30-day colectomy rates in hospitalized acute UC patients. The most effective dosing strategy in this population remains unclear and prospective randomized studies are needed.