Shehzad Ahmed Saeed

Objectives: Identifying predictors of clinical remission in pediatric ulcerative colitis (UC) will impact the therapeutic approach. We aimed to predict time to first (TFR), corticosteroid‐free (TCSFR, ≥3 months corticosteroid withdrawal), and sustained remission (TSR, ≥6 months). Methods: This retrospective study analyzed de‐identified prospectively collected data from 2383 patients enrolled in ImproveCareNow (2007–2023). We included UC patients under 18 years at diagnosis. Remission was defined as a Pediatric UC Activity Index (PUCAI; 0.05) at T0 and history of severe UC (hazard ratio [HR] = 1.142, p = 0.05) before inclusion. In patients not reaching remission at T1 (subgroup; n = 964), TFR was predicted by PUCAI (confounder; moderate HR = 0.867 or severe disease HR = 0.697, p < 0.1) at T1 and history of severe UC (HR = 1.292, p = 0.007) before T1 (mean 25 days SEM 0.7). Mean TCSFR was 569.6 days, predicted by PUCAI (only mild HR = 0.728 and moderate HR = 0.559, p < 0.001) and use of corticosteroids (HR = 0.668, p < 0.001) at T1 (mean 32 days SEM 0.9). Mean TSR was 631.0 days, predicted by PUCAI (only mild HR = 0.721 and moderate HR = 0.541, p < 0.001) and the use of oral aminosalicylates (HR = 0.793, p = 0.003) at T1 (mean 30 days SEM 0.7). Conclusions: Several clinical parameters in early disease course predict remission with increasing PUCAI as useful negative predictor.

Objectives: Identifying predictors of poor outcomes (POPO) in paediatric Crohn's disease (CD) may guide therapy. We assessed predictors of 2‐year non‐remission (primary outcome) and time to first remission (TFR), corticosteroid‐free remission (TCSFR, ≥3 months corticosteroid (CS) withdrawal and sustained remission (TSR, ≥6 months) (secondary outcomes) in paediatric CD. Methods: We retrospectively analysed prospectively collected data from 6959 paediatric CD patients (α = 0.05), using R 4.5.0 with multiple imputation, identified predictors for both outcomes (at 0, 1, 5, 6, 12, and 24 months). Results: For the primary outcome, 53/794 patients (6.7%) failed to achieve remission during 2‐year follow‐up. Female sex (odds ratio [OR] = 3.12, 95% confidence interval [CI] 1.48–6.55) and need for ustekinumab after 1 year (OR = 14.70, 95% CI 4.37–49.46) predicted non‐remission. For the secondary outcomes ( n = 3290), mean TFR, TCSFR and TSR were 4.5, 16.4, and 8.2 months, respectively. Longer TFR was predicted by female sex (hazard ratio [HR] = 0.81, 95% CI 0.71–0.92) and the need for infliximab (IFX, HR = 1.15, 95% CI 1.00–1.32) at first visit. Longer TCSFR was associated with female sex (HR = 0.85, 95% CI 0.78–0.93), race (white HR = 0.83, 95% CI 0.74–0.93 and Asian HR = 1.42, 95% CI 1.05–1.92) and type of treatment at first visit (faster if IFX, slower if CS or immunomodulators). For TSR, predictors included age at diagnosis (HR = 1.06, 95% CI 1.02–1.11) and body mass index (BMI) (HR = 0.97, 95% CI 0.94–1.00). Conclusions: Clinical parameters (female sex, younger age, and higher BMI) and therapeutic strategy (early/late use of biologicals) are POPO and associated with longer time to remission in paediatric CD.

Background: Crohn’s disease (CD) patients achieving deep remission, defined as clinical remission with endoscopic healing (EH), have a lower rate of CD-related adverse events. EH can be achieved with anti-tumor necrosis factor (TNF) dose optimizations directed by pharmacokinetic (PK) and pharmacodynamic (PD) biomarkers. The primary aim was to identify PK metrics and PD biomarker cut-points associated with EH. Methods: In this multicenter, cross-sectional study, we enrolled CD patients (age 1-22 years) who received an anti-TNF biologic (infliximab or adalimumab) for >6 months and underwent ileocolonoscopy. EH was defined as a simple endoscopic score-CD (SES-CD) < 3. Results: Eighty-seven patients were enrolled with EH found in 55.2%. Lower levels of novel biomarkers neutrophil CD64, monocyte CD64, and soluble CD64 were associated with EH with cut-points of <4.5 ratio (AUROC 0.76), <44.6 ratio (AUROC 0.67), and <15.9 ng/mL (AUROC 0.67), respectively. There was no difference in the mean trough concentrations of infliximab or adalimumab between EH and non-EH, but the median infliximab clearance was higher in non-EH (0.26 L/day) compared to EH (0.21 L/day, P = .02). In our infliximab multivariable model, slower infliximab clearance, lower platelet count, and higher serum albumin were strong predictors for EH (AUC 0.90). Conclusions: We identified novel PK and PD cut-points for biomarkers associated with EH, including infliximab clearance and the novel CD64 biomarkers. Furthermore, we developed a multivariable PK and PD model for EH that, following validation, could guide dose escalation (PK failures) or prompt a switch to an alternate advanced therapeutic for PD failures.

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. 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. 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. 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.

Background/Objectives: Infliximab biosimilars entered the United States (US) market in November 2016. Uptake of infliximab biosimilars has been slow in adult studies. We aimed to assess variation in the initiation of infliximab biosimilars in a large pediatric cohort. Methods: We performed a retrospective cohort study using data from 2016 to 2023 prospectively collected by the ImproveCareNow (ICN) Network, a multicenter pediatric inflammatory bowel disease (IBD) quality improvement collaborative. Pediatric patients with IBD who started any infliximab therapy were included. Descriptive statistics were used to summarize patient characteristics and changes in the use of infliximab agents. Chi-square or Fisher’s exact tests were used to evaluate differences in infliximab biosimilar initiation over time by race, age, ethnicity, and region. Results: In total, 4602 patients from 73 ICN centers started an infliximab agent. Infliximab biosimilar initiation rose steadily from 1% in 2018 to nearly 42% in 2023, with 88% of centers using biosimilars in 2023. Overall, from 2016 to 2023, the total percentage of patients who were started on an infliximab biosimilar was 17.3%. There were no differences in infliximab biosimilar initiation by age, race, or ethnicity, except in 2020 for age and race. The Midwest, West, and Southwest regions had higher initiation rates of infliximab biosimilars than the rest of the US. Conclusions: The percentage of patients with IBD initiating an infliximab biosimilar rose slowly to nearly 42% by 2023, and eight (12%) centers never recorded prescribing an infliximab biosimilar in the ICN Network. There were no differences in biosimilar initiation based on race or ethnicity.

INTRODUCTION: Human leukocyte antigen (HLA) DQA1*05 has been associated with the development of anti-drug antibodies (ADA) to tumor necrosis factor antagonists (anti-TNFα) and treatment failure among adults with Crohn's disease (CD). However, findings from other studies have been inconsistent with limited pediatric data. METHODS: We analyzed banked serum from patients with CD aged P = 0.08). After stratification by HLA DQA1*05 and by methotrexate vs placebo, patients who were HLA DQA1*05 negative and assigned to methotrexate experienced less treatment failures than HLA DQA1*05-positive patients on placebo (hazard ratio 0.31, 95% CI 0.13–0.70; P = 0.005). A trend toward increased ADA development among HLA DQA1*05-positive participants was not significant (odds ratio 1.96, 95% CI 0.90–4.31, P = 0.09). After further stratification, HLA DQA1*05-negative participants assigned to methotrexate were less likely to develop ADA relative to HLA DQA1*05-positive patients on placebo (odds ratio 0.12, 95% CI 0.03–0.55; P = 0.008). DISCUSSION: In a randomized trial of children with CD initiating anti-TNFα, 40% were HLA DQ-A1*05 positive, which was associated with a trend toward increased risk of both treatment failure and ADA. These risks were mitigated, but not eliminated, by adding oral methotrexate. HLA DQ-A1*05 is an important biomarker for prognosis and risk stratification.

INTRODUCTION: Obesity is common among patients with pediatric Crohn's disease (PCD). Some adult studies suggest obese patients respond less well to anti-tumor necrosis factor (TNF) treatment. This study sought compares anti-TNF response and anti-TNF levels between pediatric patients with normal and high body mass index (BMI). METHODS: The COMBINE trial compared anti-TNF monotherapy with combination therapy with methotrexate in patients with PCD. In this secondary analysis, a comparison of time-to-treatment failure among patients with normal BMI vs BMI Z-score >1, adjusting for prescribed anti-TNF (infliximab [IFX] or adalimumab [ADA]), trial treatment assignment (combination vs monotherapy), and relevant covariates. Median anti-TNF levels across BMI category was also examined. RESULTS: Of 224 participants (162 IFX initiators and 62 ADA initiators), 111 (81%) had a normal BMI and 43 (19%) had a high BMI. High BMI was associated with treatment failure among ADA initiators (7/10 [70%] vs 12/52 [23%], hazard ratio 0.29, P = 0.007) but not IFX initiators. In addition, ADA-treated patients with a high BMI had lower ADA levels compared with those with normal BMI (median 5.8 vs 12.8 μg/mL, P = 0.02). IFX trough levels did not differ between BMI groups. DISCUSSION: Overweight and obese patients with PCD are more likely to experience ADA treatment failure than those with normal BMI. Higher BMI was associated with lower drug trough levels. Standard ADA dosing may be insufficient for overweight children with PCD. Among IFX initiators, there was no observed difference in clinical outcomes or drug levels, perhaps due to weight-based dosing and/or greater use of proactive drug monitoring.

Aim: To evaluate the performance of the multiple imputation (MI) method for estimating clinical effectiveness in pediatric Crohn's disease in the ImproveCareNow registry; to address the analytical challenge of missing data. Materials & methods: Simulation studies were performed by creating missing datasets based on fully observed data from patients with moderate-to-severe Crohn's disease treated with non-ustekinumab biologics. MI was used to impute sPCDAI remission statuses in each simulated dataset. Results: The true remission rate (75.1% [95% CI: 72.6%, 77.5%]) was underestimated without imputation (72.6% [71.8%, 73.3%]). With MI, the estimate was 74.8% (74.4%, 75.2%). Conclusion: MI reduced nonresponse bias and improved the validity, reliability, and efficiency of real-world registry data to estimate remission rate in pediatric patients with Crohn's disease.