Switching from Dose-Intensified intravenous to SubCutaneoUS infliximab in Inflammatory Bowel Disease (DISCUS-IBD): protocol for a multicentre randomised controlled trial.

INTRODUCTION: A substantial proportion of patients with inflammatory bowel disease (IBD) on intravenous infliximab require dose intensification. Accessing additional intravenous infliximab is labour-intensive and expensive, depending on insurance and pharmaceutical reimbursement. Observational data suggest that subcutaneous infliximab may offer a convenient and safe alternative to maintain disease remission in patients requiring dose-intensified infliximab. A prospective, controlled trial is required to confirm that subcutaneous infliximab is as effective as dose-intensified intravenous infliximab, to identify predictors of disease flare and to establish the role of subcutaneous infliximab therapeutic drug monitoring. METHODS AND ANALYSIS: The DISCUS-IBD trial is an investigator-initiated, prospective, multicentre, randomised, open-label non-inferiority study comparing the rate of disease flares in participants randomised to continue dose-intensified intravenous infliximab to those switched to subcutaneous infliximab after 48 weeks. Participants are adult patients with IBD in sustained corticosteroid-free remission on any regimen of dose-intensified infliximab up to a maximum of 10 mg/kg 4-weekly intravenously. Participants allocated to intravenous infliximab will continue infliximab at the same dose-intensified regimen they were receiving at study enrolment. Subcutaneous infliximab dosing will be stratified by prior intravenous infliximab dosing. Clinical (Harvey-Bradshaw Index, partial Mayo score), biochemical (C reactive protein, faecal calprotectin), pharmacokinetic (drug-level±antidrug antibodies) and qualitative data are collected 12-weekly until study conclusion at week 48. 13 sites across Australia will participate in recruitment to reach a calculated sample size of 120 participants. ETHICS AND DISSEMINATION: Multisite ethics approval was obtained from the Health District Human Research Ethics Committee (HREC) at The Alfred Hospital under a National Mutual Acceptance (NMA) agreement (HREC/90559/Alfred-2022; Local Reference: Project 618/22, version 1.6, 2 March 2023). Findings will be reported at national and international gastroenterology meetings and published in peer-reviewed journals. DISCUS-IBD was prospectively registered with the Australian and New Zealand Clinical Trials Registry (ANZCTR) prior to commencing recruitment. TRIAL REGISTRATION NUMBER: ACTRN12622001458729.

Is the European Crohn's and Colitis organisation (ECCO) e-guide an acceptable and feasible tool for increasing gastroenterologists' guideline adherence? A mixed methods evaluation.

BACKGROUND AND AIMS: Management of inflammatory bowel disease is constantly evolving, increasing the importance for gastroenterologists to keep up to date with guidelines. Traditional implementation strategies have had only small positive impacts on clinical practice. eHealth strategies such as the European Crohn's and Colitis Organisation e-guide may be beneficial for clinician decision making in keeping with guidelines. The aim of this study was to evaluate the feasibility and acceptability of the e-guide. METHODS: A mixed methods approach was used to evaluate feasibility and acceptability. Cognitive (think-aloud) interviews were conducted with Australian gastroenterologists while using the e-guide. Two clinical scenarios were developed to allow evaluation of various aspects of the e-guide. Content analysis was applied to the qualitative interview data and descriptive analysis to the quantitative and observational data. RESULTS: Seventeen participants completed the study. Data saturation were reached. The ECCO e-guide was largely feasible and acceptable, as demonstrated by most clinical questions answered correctly, 87% reaching the answer within 3 min, and most feeling it was useful, would be beneficial to their practice and would use it again. Issues raised included difficulties with website navigation, layout of the e-guide and difficulties with access (network firewalls, paid subscription required). CONCLUSIONS: The ECCO e-guide is largely acceptable and feasible for gastroenterologists to use. Aspects of the e-guide could be modified to improve user experience. This study highlights the importance of engaging end-users in the development and evaluation of clinician educational tools.

Effects of Thiopurine Withdrawal on Vedolizumab-Treated Patients With Ulcerative Colitis: A Randomized Controlled Trial.

BACKGROUND & AIMS: The impact of thiopurine de-escalation while on vedolizumab versus continuing thiopurine therapy in ulcerative colitis (UC) is unclear. We aimed to determine the effect of thiopurine withdrawal for patients with UC in remission on vedolizumab. METHODS: This multicenter randomized controlled trial recruited UC patients on vedolizumab 300 mg intravenously every 8 weeks and a thiopurine. Patients in steroid-free clinical remission for ≥6 months and endoscopic remission/improvement (Mayo endoscopic subscore ≤1) were randomized 2:1 to withdraw or continue thiopurine. Primary outcome was comparing week 48 vedolizumab trough concentrations. Secondary outcomes were clinical relapse (partial Mayo score ≥3 and fecal calprotectin >150 µg/g or increase in Mayo endoscopic subscore ≥1 from baseline), fecal calprotectin remission (<150 µg/g), C-reactive protein remission (<5 mg/L), centrally read endoscopic remission (Mayo endoscopic subscore = 0), histologic remission (Nancy index = 0), histo-endoscopic remission, and adverse events. RESULTS: In total, 62 patients were randomized to continue (n = 20) or withdraw (n = 42) thiopurine. At week 48, vedolizumab trough concentrations were not significantly different between continue and withdrawal groups (14.7 µg/mL, interquartile rate [IQR], 12.3-18.5 µg/mL versus 15.9 µg/mL, IQR, 10.1-22.7 µg/mL, respectively, P = 0.36). The continue group had significantly higher fecal calprotectin remission (95.0%, 19/20 versus 71.4%, 30/42; P = .03), histologic remission (80.0%, 16/20 versus 48.6%, 18/37; P = .02), and histo-endoscopic remission (75.0%, 15/20 versus 32.4%, 12/37; P = .002) than the withdrawal group. Histologic activity (hazard ratio [HR], 15.5; 95% confidence interval [CI], 1.6-146.5; P = .02) and prior anti-tumor necrosis factor exposure (HR, 6.5; 95% CI, 1.3-33.8; P = .03) predicted clinical relapse after thiopurine withdrawal. CONCLUSIONS: Thiopurine withdrawal did not affect vedolizumab trough concentrations. However, it may increase fecal calprotectin, histologic, and histo-endoscopic activity. Histologic activity and prior anti-tumor necrosis factor exposure may predict disease relapse on thiopurine withdrawal for patients using vedolizumab for UC. Australian and New Zealand Trial Registry, number ACTRN12618000812291.

Dietary Emulsifier Exposure in People With Inflammatory Bowel Disease Compared With Healthy Controls: Is There a Cause for Concern?

BACKGROUND: Emulsifiers are implicated in the pathogenesis of inflammatory bowel disease (IBD). Few studies have examined emulsifier intake in people with existing IBD. We aimed to describe the frequency of exposure to 6 selected emulsifiers in a contemporary cohort of people with IBD and compare intake with healthy controls (HCs). METHODS: Baseline food records from participants in an Australian prospective cohort study examining the microbiome of IBD patients and HCs were analyzed. Exposure to inflammatory emulsifiers polysorbate-80 (P80); carboxymethylcellulose (CMC); carrageenan; xanthan gum (XG); lecithin (soy and sunflower) and mono- and diglycerides of fatty acids (MDGs) were determined by examining ingredient lists. Frequency of emulsifier exposure between groups (IBD vs HC, Crohn's disease [CD] vs ulcerative colitis [UC], IBD children vs adults, active disease vs remission) was examined after controlling for confounders. RESULTS: Records from 367 participants were analyzed (n = 176 IBD, of which there were 101 CD, 75 UC, and 191 HC patients). In total, 5022 unique food items were examined, with 18% containing 1 or more emulsifier of interest. Inflammatory bowel disease participants had significantly higher total daily emulsifier exposure compared with HCs (2.7 ±â€…1.8 vs 2.3 ±â€…1.6, P = .02). In IBD participants, emulsifiers with the highest daily exposure were MDGs (1.2 ±â€…0.93), lecithin (0.85 ±â€…0.93), and XG (0.38 ±â€…0.42). There were no recorded exposures to P80. CONCLUSIONS: Inflammatory bowel disease participants were exposed to more emulsifiers than HCs. Intake of inflammatory emulsifiers were low or nonexistent, suggesting their presence in the food supply are not as common as frequently stated.

BNC210, a negative allosteric modulator of the alpha 7 nicotinic acetylcholine receptor, demonstrates anxiolytic- and antidepressant-like effects in rodents.

This work describes the characterization of BNC210 (6-[(2,3-dihydro-1H-inden-2-yl)amino]-1-ethyl-3-(4-morpholinylcarbonyl)-1,8-naphthyridin-4(1H)-one), a selective, small molecule, negative allosteric modulator (NAM) of α7 nicotinic acetylcholine receptors (α7 nAChR). With the aim to discover a non-sedating, anxiolytic compound, BNC210 was identified during phenotypic screening of a focused medicinal chemistry library using the mouse Light Dark (LD) box to evaluate anxiolytic-like activity and the mouse Open Field (OF) (dark) test to detect sedative and/or motor effects. BNC210 exhibited anxiolytic-like activity with no measurable sedative or motor effects. Electrophysiology showed that BNC210 did not induce α7 nAChR currents by itself but inhibited EC80 agonist-evoked currents in recombinant GH4C1 cell lines stably expressing the rat or human α7 nAChR. BNC210 was not active when tested on cell lines expressing other members of the cys-loop ligand-gated ion channel family. Screening over 400 other targets did not reveal any activity for BNC210 confirming its selectivity for α7 nAChR. Oral administration of BNC210 to male mice and rats in several tests of behavior related to anxiety- and stress- related disorders, demonstrated significant reduction of these behaviors over a broad therapeutic range up to 500 times the minimum effective dose. Further testing for potential adverse effects in suitable rat and mouse tests showed that BNC210 did not produce sedation, memory and motor impairment or physical dependence, symptoms associated with current anxiolytic therapeutics. These data suggest that allosteric inhibition of α7 nAChR function may represent a differentiated approach to treating anxiety- and stress- related disorders with an improved safety profile compared to current treatments.

Co-design and Consultation Ensure Consumer Needs Are Met: Building an eHealth Platform for Children with Inflammatory Bowel Disease.

BACKGROUND: Crohn's Colitis Care is an adult inflammatory bowel disease eHealth system. Crohn's Colitis Care required additional pediatric functionality to enable life-long records and mitigate transition inadequacies. AIM: This study describes and evaluates a consensus method developed to ensure consumer needs were met. METHODS: Pediatric-specific functionality and associated resources considered important for inclusion were developed by a clinician consensus group. This group was divided into thematic subgroups and underwent two voting rounds. The content validity index was used to determine items reaching consensus. Children with inflammatory bowel disease and their parents were later shown a descriptive list of non-clinical inclusion topics proposed by the consensus group, and asked to vote on whether topic-related functionality and resources should be included. RESULTS: The consensus process consulted 189 people in total (38 clinicians, 32 children with inflammatory bowel disease and 119 parents). There was agreement across all groups to incorporate functionality and resources pertaining to quality of life, mental health, self-management, and transition readiness; however, divergence was seen for general inflammatory bowel disease facts, your inflammatory bowel disease history, and satisfaction. Cost saw the greatest disparity, being less supported by consumers compared to clinicians. Over 75% of consumers agreed it would be okay for appointments to take longer for survey completion, and > 90% thought Crohn's Colitis Care should allow consumers to ask their treating team questions. CONCLUSIONS: Widespread consumer co-design and consultation were important in unveiling differing perspectives to ensure Crohn's Colitis Care was built to support both consumer and clinician perspectives. Consumers collaborate to create a list of functionality and resources to be included in software (left), influencing the final product build (right).

Adolescents and young adults communicating with gastroenterologists: variation in inflammatory bowel disease clinical communication.

OBJECTIVES: This study explored the variation in emerging adults' communication with gastroenterologists around the management of inflammatory bowel disease (IBD). METHODS: Nineteen emerging adults with IBD aged 18-25 and seven gastroenterologists participated in the study. Outpatient specialist consultations of consenting participants were audio-recorded and transcribed. Transcribed consultations were analysed in terms of the linguistic structure of the consultations and the gastroenterologist-patient role relationship. RESULTS: Variations in the emerging adults' communication with their gastroenterologists stem partly from variation in their ability, opportunity, or need to contribute to the different phases of the consultation and partly from variations in the gastroenterologists' style of communication. Gastroenterologists differed in the construction of their role relationship with the patient, resulting in variations in employing empowering strategies including eliciting, exploring, and clarifying the patient's concerns, sharing clinical reasoning, and validating the patient experience. Variations were also observed in the length of appointments and the gastroenterologists' assessment and addressing of adherence issues. Techniques used by the gastroenterologist varied (1) from simply confirming adherence, to a comprehensive assessment of the patient's understanding of their management plan and their feedback, and (2) from use of persuasion to values calibration. CONCLUSIONS: Evidence-based consumer interventions and communication guidelines for clinicians are needed to address the identified variations in providing care to emerging adults living with chronic conditions.

Health Communication Research Informs Inflammatory Bowel Disease Practice and Research: A Narrative Review.

Background: In the absence of targeted empirical evidence on effective clinical communication in inflammatory bowel disease (IBD), a broad overview of existing evidence on effective communication in healthcare and available recommendations for communication in telehealth is provided and mapped onto IBD research and practice. Methods: A narrative literature review was conducted using Pubmed and Scopus databases and snowballing literature search. Results: Evidence-based relationship building strategies include communicating emotions, acknowledging and addressing patients' hesitancy, and ensuring continued support. A particular recommendation regarding telehealth interaction is to avoid long stretches of talk. Effective informational strategies include facilitating and supporting information exchange and considering patients' preferences in decision-making. In teleconsultations, clinicians should ask direct questions about patients' emotional state, clarify their understanding of patients' concerns and check patients' understanding, address at least one patient-reported outcome when discussing the recommended treatment, and shorten the consultation where possible. Strategies for maximizing effective clinical communication in the spoken communicative mode include using infographics and simple language, and assessing adherence at the beginning of the consultation. For teleconsultations, clinicians are advised to allow patients to explain the reason for their call at the beginning of the teleconsultation, probe additional concerns early and before ending the teleconsultation, and be mindful of technical issues such as voice delays. Conclusions: Use of question prompt lists, decision aids, micro-lessons, and communication training interventions for clinicians could be beneficial in IBD care. Further research into the implementation of such interventions as well as clinical communication concerns specific to IBD is warranted.

Clinician Adherence to Inflammatory Bowel Disease Guidelines: Results of a Qualitative Study of Barriers and Enablers.

Background: With the evolving inflammatory bowel disease (IBD) management landscape, it is critical that gastroenterologists keep up to date with the clinical practice guidelines (CPGs). Several studies in IBD have documented suboptimal adherence to CPGs. We aimed to gain an in-depth understanding of guideline adherence barriers reported by gastroenterologists and determine how evidence-based education can best be delivered. Methods: Interviews were conducted with a purposive sample of gastroenterologists' representative of the current workforce. Questions focused on previously identified problematic areas and shaped by the theoretical domains framework, a theory-informed approach to understanding clinician behavior, to assess all determinants of behavior. Questions explored perceived barriers to adherence and clinicians' preferred content and modes of delivery for an educational intervention. Interviews were conducted by a single interviewer and qualitative analysis performed. Results: A total of 20 interviews were conducted before data saturation was achieved (male = 12, work in a metropolitan area = 17). Five dominant subthemes for barriers to adherence emerged: negative experiences impacting future decisions, time constraints, long guidelines are impractical, unfamiliar with guideline specifics and prescribing restrictions. Adherence enablers were identified including features that improved the usability of CPGs. Computer- or smart phone-based educational interventions were preferred. Conclusions: This study identified several barriers and enablers for IBD guideline adherence and gained insight into how gastroenterologists prefer to receive evidence-based education. These results will inform the development of a targeted intervention to improve IBD guideline adherence. Improving guideline adherence is expected to facilitate standardized IBD care, ultimately leading to improved patient outcomes.

Assessing the Relationship between the Gut Microbiota and Inflammatory Bowel Disease Therapeutics: A Systematic Review.

Current inflammatory bowel disease (IBD) treatments including non-biological, biological, and nutritional therapies aim to achieve remission and mucosal healing. Treatment efficacy, however, is highly variable, and there is growing evidence that the gut microbiota influences therapeutic efficacy. The aim of this study was to conduct a systematic review and meta-analysis to define changes in the gut microbiota following IBD treatment and to identify microbial predictors of treatment response. A systematic search using MEDLINE/Embase and PubMed was performed in July 2022. The review was conducted based on the Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines. Studies were included if they reported longitudinal microbiota analysis (>2 weeks) using next-generation sequencing or high-throughput sequencing of faecal/mucosal samples from IBD patients commencing treatment. Meta-analysis on alpha-diversity changes following infliximab treatment was conducted. Thirty-nine studies met the inclusion criteria, and four studies were included in the meta-analysis. An increase in alpha diversity was observed following treatment with 5-aminosalicylates, corticosteroids, and biological therapies in most studies. Characteristic signatures involving the enrichment of short-chain-fatty-acid-producing bacteria including Faecalibacterium prausnitzii and a reduction of pathogenic bacteria including various Proteobacteria were demonstrated following treatment with specific signatures identified based on treatment outcome. The meta-analysis demonstrated a statistically significant increase in bacterial richness following infliximab treatment (standardised mean difference -1.16 (-1.50, -0.83), p < 0.00001). Conclusion: Distinct microbial signatures are seen following treatment and are associated with treatment response. The interrogation of large longitudinal studies is needed to establish the link between the gut microbiota and IBD therapeutic outcomes.

Colonic Epstein-Barr Virus-Associated Mucocutaneous Ulcer Associated With Ulcerative Colitis.

Epstein-Barr virus-associated mucocutaneous ulcer is a rare lymphoproliferative disorder that occurs in immunosuppressed states that can develop in the gastrointestinal tract and mimic inflammatory bowel disease or other malignancies. We present the case of a 61-year-old man who presented with concurrent acute severe ulcerative colitis and colonic Epstein-Barr virus-associated mucocutaneous ulcer requiring rituximab therapy and a subtotal colectomy.

Integration of mental health and quality of life screening tools in an inflammatory bowel disease-specific electronic medical record (Crohn Colitis Care): process and early outcomes.

Psychological problems are prevalent in people with inflammatory bowel diseases but are not routinely addressed. To improve recognition, three psychological screening tools were integrated into clinical management software (Crohn Colitis Care). In the first 6 months, completion rates varied between participating sites, and approximately 23-34% of respondents scored in moderate or higher ranges for psychological distress. Evaluation of the clinical utility of the module to improve patient outcomes is recommended.

Correlates of Hypertensive-Level BP in African American Adolescents.

OBJECTIVE: Adult cardiovascular disease has its roots in childhood and adolescence. Risks for pediatric hypertension include obesity, male sex, and minority race. We identified risk factors associated with hypertension specifically among African American adolescents ages 13-18. METHODS: We analyzed data from the US National Health and Nutrition Examination Surveys from 2011 to 2018, defining BP consistent with hypertension as average systolic or diastolic BP ≥ 130/80 mmHg or taking medication for a clinical diagnosis of hypertension. Univariate analyses compared characteristics of adolescents with and without hypertensive-level BP. Logistic regression was completed to more precisely identify risk factors. RESULTS: Among 838 African American adolescents, 48 met criteria for hypertensive-level BP, for a population prevalence of 5.8%. Due to low rates of hypertensive-level BP in girls (2.7%), our analysis focused on the subset of boys, who had an 8.9% prevalence rate, increasing to 26.1% for boys with obesity and 35.3% for boys with severe obesity. Boys with hypertensive-level BP had significantly lower family incomes, higher rates of being in single-parent families, more frequent consumption of fast food, were more likely to be taking prescription medications for psychiatric diagnoses, and had higher A1c and cholesterol values. CONCLUSIONS: Our study confirms the much higher risk for hypertensive-level BP in African American boys and emphasizes the important role of social determinants of health in this common illness.

Proactive Metabolite Testing in Patients on Thiopurine May Yield Long-Term Clinical Benefits in Inflammatory Bowel Disease.

BACKGROUND: The thiopurine medications are well established in the treatment of inflammatory bowel disease (IBD). There is significant variation in levels of toxic and therapeutic metabolites. Current data from small or short-term studies support therapeutic drug monitoring (TDM) in assessing azathioprine (AZA) and 6-mercaptopurine (6MP). TDM of thiopurines involves measurement and interpretation of metabolites 6-TGN and 6-MMPR. AIMS: This study aimed to assess long-cterm outcomes of patients on thiopurines following therapeutic drug monitoring. METHODS: A multicenter retrospective observational study of outcomes post thiopurine TDM was conducted. Demographics, disease characteristics, physician global assessment, IBD therapy at baseline TDM and again at 12 months were collected. Clinical outcomes were analyzed according to TDM result, and indication for TDM including proactive and other indications. RESULTS: The study included 541 patients. Only 39% of patients had appropriate dosing of thiopurines. AZA/6MP TDM informed a management change in 61.9%, and enabled 88.8% of the cohort to continue AZA/6MP following TDM. At 12 months following TDM the majority (74.1%) of the cohort remained on AZA/6MP. Clinical remission was higher at 12-months following thiopurines TDM (68%) compared to baseline (37%), including proactive TDM. Post TDM, 13.0% of patients were identified as shunters and commenced on thiopurine-allopurinol co-therapy. CONCLUSION: Thiopurine TDM resulted in a change in management for the majority of patients. Post TDM significantly more patients were in remission. TDM allowed the identification of non-adherence and shunters who, without intervention, would not reach therapeutic drug levels. Proactive TDM allowed identification and management of inappropriate dosing, and was associated with increased levels of clinical remission.

An Extremes of Phenotype Approach Confirms Significant Genetic Heterogeneity in Patients with Ulcerative Colitis.

BACKGROUND AND AIMS: Ulcerative colitis [UC] is a major form of inflammatory bowel disease globally. Phenotypic heterogeneity is defined by several variables including age of onset and disease extent. The genetics of disease severity remains poorly understood. To further investigate this, we performed a genome wide association [GWA] study using an extremes of phenotype strategy. METHODS: We conducted GWA analyses in 311 patients with medically refractory UC [MRUC], 287 with non-medically refractory UC [non-MRUC] and 583 controls. Odds ratios [ORs] were calculated for known risk variants comparing MRUC and non-MRUC, and controls. RESULTS: MRUC-control analysis had the greatest yield of genome-wide significant single nucleotide polymorphisms [SNPs] [2018], including lead SNP = rs111838972 [OR = 1.82, p = 6.28 × 10-9] near MMEL1 and a locus in the human leukocyte antigen [HLA] region [lead SNP = rs144717024, OR = 12.23, p = 1.7 × 10-19]. ORs for the lead SNPs were significantly higher in MRUC compared to non-MRUC [p < 9.0 × 10-6]. No SNPs reached significance in the non-MRUC-control analysis (top SNP, rs7680780 [OR 2.70, p = 5.56 × 10-8). We replicate findings for rs4151651 in the Complement Factor B [CFB] gene and demonstrate significant changes in CFB gene expression in active UC. Detailed HLA analyses support the strong associations with MHC II genes, particularly HLA-DQA1, HLA-DQB1 and HLA-DRB1 in MRUC. CONCLUSIONS: Our MRUC subgroup replicates multiple known UC risk variants in contrast to non-MRUC and demonstrates significant differences in effect sizes compared to those published. Non-MRUC cases demonstrate lower ORs similar to those published. Additional risk and prognostic loci may be identified by targeted recruitment of individuals with severe disease.

Higher infliximab and adalimumab trough levels are associated with fistula healing in patients with fistulising perianal Crohn's disease.

BACKGROUND: Tumor necrosis factor-alpha inhibitors, including infliximab and adalimumab, are effective medical treatments for perianal fistulising Crohn's disease (CD), but not all patients achieve fistula healing. AIM: To determine the correlation between perianal fistula healing and closure with infliximab and adalimumab trough levels. METHODS: In this multicentre retrospective study conducted across four tertiary inflammatory bowel disease centres in Australia, we identified CD patients with perianal fistulae on maintenance infliximab or adalimumab who had a trough level within twelve weeks of clinical assessment. Data collected included demographics, serum infliximab and adalimumab trough levels (mg/L) within 12 wk before or after their most recent clinical assessment and concomitant medical or surgical therapy. The primary outcome was fistula healing, defined as cessation in fistula drainage. The secondary outcome was fistula closure, defined as healing and closure of all external fistula openings. Differences between patients who did or did not achieve fistula healing were compared using the chi-square test, t test or Mann-Whitney U test. RESULTS: One hundred and fourteen patients (66 infliximab, 48 adalimumab) were included. Forty-eight (72.7%) patients on maintenance infliximab achieved fistula healing and 18 (27.3%) achieved fistula closure. Thirty-seven (77%) patients on maintenance adalimumab achieved fistula healing and 17 (35.4%) achieved fistula closure. Patients who achieved fistula healing had significantly higher infliximab and adalimumab trough levels than patients who did not [infliximab: 6.4 (3.8-9.5) vs 3.0 (0.3-6.2) mg/L, P = 0.003; adalimumab: 9.2 (6.5-12.0) vs 5.4 (2.5-8.3) mg/L, P = 0.004]. For patients on infliximab, fistula healing was associated with lower rates of detectable anti-infliximab antibodies and younger age. For patients on adalimumab, fistula healing was associated with higher rates of combination therapy with an immunomodulator. Serum trough levels for patients with and without fistula closure were not significantly different for infliximab [6.9 (4.3-10.2) vs 5.5 (2.5-8.3) mg/L, P = 0.105] or adalimumab [10.0 (6.6-12.0) vs 7.8 (4.2-10.0) mg/L, P = 0.083]. CONCLUSION: Higher maintenance infliximab and adalimumab trough levels are associated with perianal fistula healing in CD.

Timing of Live Attenuated Vaccination in Infants Exposed to Infliximab or Adalimumab in Utero: A Prospective Cohort Study in 107 Children.

BACKGROUND AND AIMS: For infants exposed in utero to anti-tumour necrosis factor-α [TNF] medications, it is advised that live-attenuated vaccinations be postponed until the drug is cleared, but little is known about time to clearance. To minimize delays before live-attenuated vaccination can be given, we aimed to develop a pharmacokinetic model to predict time-to-clearance in infants exposed during pregnancy. METHODS: We prospectively followed in utero infliximab/adalimumab-exposed infants of mothers with inflammatory bowel disease across four countries between 2011 and 2018. Infants with a detectable anti-TNF umbilical-cord level and at least one other blood sample during the first year of life were included. RESULTS: Overall, 107 infants were enrolled, including 166 blood samples from 71 infliximab-exposed infants and 77 samples from 36 adalimumab-exposed infants. Anti-TNF was detectable in 23% [n = 25] of infants at 6 months. At 12 months, adalimumab was not detected but 4% [n = 3] had detectable infliximab. A Bayesian forecasting method was developed using a one-compartment pharmacokinetic model. Model validation showed that the predicted clearing time was in accordance with the measured observations. A clinician-friendly online calculator was developed for calculating full anti-TNF clearing time: https://xiaozhu.shinyapps.io/antiTNFcalculator2/. CONCLUSIONS: Almost one-quarter of infants born to mothers receiving anti-TNF during pregnancy have detectable anti-TNF at 6 months. To limit the time to live-attenuated vaccination in infants of mothers receiving anti-TNF during pregnancy, the results of a cord drug level at birth and a second sample ≥ 1 month thereafter can be used to estimate the time for full anti-TNF clearance in these children.