The enteric microbiota is the antigenic drive in Crohn’s disease, making microbial manipulation with faecal microbiota transplantation (FMT) a therapeutic option. However there are no data supporting its use in active Crohn’s disease. This study assessed FMT therapeutic efficacy and safety in active Crohn’s disease. This randomised, double-blind, placebo-controlled trial in patients with active Crohn’s disease (CDAI 220-450) had an initial three week “optimisation” of wholefood diet and one-week antibiotic therapy. Patients were then randomised to single-donor anaerobically-prepared FMT or placebo (2:1) for eight weeks by gastroscopy at weeks 0, 2, 6 (disease proximal to splenic flexure), or colonoscopy followed by weekly enemas (left-sided colonic disease). Primary endpoint was clinical response at week 8 defined by a CDAI decrease of ≥ 100 points or CDAI to < 150. Modified intention-to-treat (mITT) analysis included patients receiving ≥1 dose of FMT or placebo, per protocol (PP) analysis for those who completed eight weeks of treatment. Patient outcomes: Of 103 patients enrolled, 70 received FMT and 33 placebo. 95 had upper and 8 lower gastrointestinal delivery. Before FMT/placebo, the CDAI response to diet and antibiotics occurred in 21% of all patients. Primary outcome of clinical response at week eight: mITT FMT 40/70 (57.1%) vs placebo 15/33 (45.5%) (P = 0.296); PP analysis: FMT 40/63 (63.5%) vs placebo 14/30 (46.7%) (P = 0.177). Decrease in CDAI was significant only in the FMT group (P < 0.001; Image I). Endoscopic response: total SES-CD decrease of 25% or to SES-CD ≤2 was more likely with FMT 24/45 (53.3%) vs placebo 4/17 (23.5%) (P = 0.047). Significant improvement in SES-CD occurred only in the FMT group (P = 0.031). Decrease in biomarkers of inflammation CRP and faecal calprotectin did not differ between treatment groups. Donor Effect: A substantial donor effect was demonstrated, with patient clinical response rates for the 5 donors 43%, 50%, 55%, 78% and 93% (P = 0.02) and endoscopic response ranging from 31% to 70% (P = 0.27). Adverse events: Majority mild transient gut symptoms and liver function test abnormality. Faecal microbiota transplantation (FMT) for active Crohn’s disease was therapeutically more effective than placebo. Endoscopic response, a more objective parameter, significantly improved only with FMT therapy. There was a profound variation in donor therapeutic potency. The final lack of CDAI significance likely related to the large diet and antibiotics effect pre randomisation, and donor variation effect. FMT for Crohn’s disease has a promising therapeutic role. Conflict of interest: Fehily, Sasha: No conflict of interest Wright, Emily Kate: No conflict of interest Bogatic, Damjana: No conflict of interest Wilson-O’brien, Amy: No conflict of interest Basnayake, Chamara: No conflict of interest Stanley, Annalise: No conflict of interest Marks, Elise: No conflict of interest Russell, Erin: No conflict of interest Rong, Yuwei: No conflict of interest Gory, Ilana: No conflict of interest Ardalan, Zaid: Crohn’s colitis Australia Angela McAvoy Fellowship recipient 2025 GENIUS Research grant Hamilton, Amy: No conflict of interest Morrison, Mark: No conflict of interest Thompson, Alexander: No conflict of interest Bryant, Robert Venning: No conflict of interest Costello, Samuel Paul: No conflict of interest Kamm, Michael Albert: No conflict of interest

There is increasing interest in using ≥2 advanced therapies in inflammatory bowel disease (IBD) for refractory disease, multi-organ involvement and concurrent autoimmune conditions. However, data on prescribing practices are extremely limited, and comparative efficacy and safety remain largely unknown. Prior meta-analyses have included <280 patients, primarily from small case series with heterogeneous reporting and mostly without objective outcomes [1]. We collected a comprehensive binational registry (Australia & Taiwan) of patients with IBD on combined advanced therapies (ATs)/combined immunosuppressive therapies outside of regular prescribing practice used in overlap ≥1 month. There were 307 combinations in 257 patients, median age 37 years, 146/257 (56.8%) Crohn’s disease (CD) & 110/257 (42.8%) ulcerative colitis, 111/257 (43.2%) female primarily from Australia (220/257, 85.6%; Taiwan 37/257, 14.4%). Commonest combinations were: Vedolizumab (VED) + Janus kinase inhibitor (JAK) (n = 57, 18.6%), JAK + ustekinumab (UST) (n = 52, 16.9%) & VED + tumour necrosis factor inhibitor (TNFi) (n = 44, 14.3%). Overall, via 5-point Likert scale, the combinations were deemed effective by the clinician in 66.8%. p19 inhibitors (p19i) + JAK, UST + JAK, UST + TNF had the greatest clinician-deemed efficacy rates (effective ≥70%) whereas UST + tacrolimus (TAC), JAK + TAC, & TNFi + JAK were deemed the poorest (<60%) (P=0.032). Clinical remission was achieved in 174/307 (56.7%). In 198/307 (65%), there was confirmed objective improvement (biochemically, endoscopically, and/or radiologically). The commonest adverse events (AEs) were from uncontrolled disease (n = 17, 5.5%), though there were 5/307 (1.6%) serious infections & 11/307 (3.6%) opportunistic infections. Two combinations were associated with life-threatening AEs (Common Terminology Criteria for Adverse Events (CTCAE): 4), both associated with uncontrolled IBD activity. The commonest serious AE (CTCAE 3) was from uncontrolled IBD activity (4/307, 1.3%). There were three deaths, two from uncontrolled IBD activity, one from myeloma progression in a patient with liver cirrhosis. AEs were more frequent in combinations containing JAK & tacrolimus (21/87 (24.1%) & 17/63 (27.0%) respectively, & least frequent with Th17 inhibition (p19i & UST, 16/118 (13.6%), P = 0.03). This comprehensive binational registry of combined advanced therapies in IBD, the largest to date, shows that combination use in treatment-resistant IBD is effective in the majority with acceptable safety. However, despite combination of agents, medication inefficacy remains a key area of concern. We demonstrate signals for greater efficacy & safety using several combinations that require further investigation. References: [1]Alayo QA, et al. Systematic Review With Meta-analysis: Safety and Effectiveness of Combining Biologics and Small Molecules in Inflammatory Bowel Disease. Crohns Colitis 360. 2022 Feb 10;4(1):otac002. Conflict of interest: Dr. Chetwood, John: JDC has received speaker fees from Novartis, Takeda, Johnson & Johnson, and Eli Lilly. Le, Puo-Hsien: No conflict of interest Wei, Shu Chen: Consultancy fees: AbbVie, Bristol Myers Squibb, Cornerstones, Ferring Pharmaceuticals Inc., Janssen/J & ampJ, Pfizer, Sanofi, SPYRE, Takeda, ThermoFisher. Lectures and/or speakers’ bureau payments: AbbVie, Bristol Myers Squibb, Celltrion, CornerStones, Excelisior, Ferring Pharmaceuticals Inc., Janssen/J & ampJ, Pfizer, Takeda, ThermoFisher. Wu, Hsin-Yun: No conflict of interest Corte, Crispin: Grants: Ferring, GESA Consulting: Abbvie, Ferring, Celltrion, Chiesi, Janssen, Takeda. Support for travel for meetings to support study: Pfizer, Takeda, Celltrion, Chiesi, Ferring, Falk. Lightowler, Daniel: Speaker Fees: Pfizer, DrFalk, Eli Lily Advisory Board: AbbVie, Eli Lily, Menarini, Janssen, AGPAL Travel: Pfizer, Celgene, Allergen, Janssen, AbbVie Research Support: Janssen, Ferring Education: DrFalk, AbbVie, Janssen, Pfizer Gilmore, Robert: Grant support from the Gastroenterological Society of Australia (GESA) and speaker honoraria from Johnson and Johnson, Pfizer, and education or conference support from Pfizer Chin, Simone: No conflict of interest Garg, Mayur: No conflict of interest Bahmani Kashkooli, Soleiman: Research grants from AbbVie and Janssen. Xu, Ziheng: No conflict of interest Wright, Emily Kate: Speaker Fees, Consultancy and Advisory Boards: AbbVie, Celltrion, Falk, Ferring, Janssen, Pfizer. Research funding/support: AbbVie, Ferring, Janssen. Sparrow, Miles P.: Educational grants or research support – Gilead, Celltrion Speaker’s fees – Janssen, Abbvie, Ferring, Takeda, Pfizer, Celltrion, Eli Lilly, Dr. Falk Pharma Advisory boards or consultancy fees – Janssen, Takeda, Pfizer, Celgene, Abbvie, MSD, Emerge Health, Gilead, BMS, Celltrion, Eli Lilly, Alimentiv O’Donnell, Jonathan: Grants: AVANT Foundation, Medical Insurance Group of Australia (MIGA) Lewindon, Peter: No conflict of interest Subramanian, Kavitha: No conflict of interest Huang Fu, Janny: No conflict of interest Moore, Gregory Thomas: Advisory boards: AbbVie, Celltrion, Eli Lilly, Gilead, J&J, Pfizer, Takeda Speakers fees: AbbVie, Falk, Ferring, J&J, Pfizer, Roche, Sandoz, Takeda Research support: MRFF, NHMRC, CCA, GESA, Gutsy Group, AbbVie, Janssen, Pfizer, Shire, Takeda Subhaharan, Deloshaan: No conflict of interest Mohsen, Waled: No conflict of interest Tan, Zhi: No conflict of interest Thin, Lena: Pfizer- advisory board fees, research grants Takeda- research grant, advisory board fees JNJ- advisory board fees Abbvie- advisory board fees Neuroscientific - advisory committee Celltriom- advisory board fees Ghali, Mark: No conflict of interest Ghaly, Simon: Speaker fees, research grants and travel grants from Dr. Falk pharma, Janssen, Pfizer, AbbVie, Sandoz and Ferring and served on advisory boards for Pfizer and AbbVie. De Cruz, Peter: No conflict of interest Lo, Sheng Wei: No conflict of interest Paramsothy, Sudarshan: SP has served as a consultant for Vedanta Biosciences and has received speaker / advisory board fees from AbbVie, Dr Falk Pharma, Ferring, Janssen and Takeda. Leong, Rupert: advisory board: AbbVie, Aspen, BMS, Celgene, Celltrion, Chiesi, Ferring, Glutagen, Hospira, Janssen, Lilly, MSD, Novartis, Pfizer, Prometheus Biosciences, Takeda, Spyre, Roche research grants: Joanna Tiddy USYD, McCusker Charitable Foundation, Celltrion, Shire, Janssen, Takeda, Gastroenterological Society of Australia, NHMRC, Gutsy Group, Pfizer

Background:Antitumor necrosis factor (TNF) dose escalation is performed to improve therapeutic response and optimize outcomes in patients with Crohn's disease (CD). We aimed to describe the durability of anti-TNF therapy in patients with CD receiving escalated anti-TNF therapy, along with the overall durability of anti-TNF treatment between patients managed with a proactive versus reactive therapeutic drug monitoring (TDM) approach. Methods:We undertook a retrospective multicentre cohort study. One center practiced proactive TDM with a weekly virtual TDM clinic, while the other practiced reactive TDM. Patients receiving escalated infliximab or adalimumab therapy for CD from January 2015 to April 2022 were included. Durability was defined as the time from biologic start to cessation for treatment failure. Results:About 239 patients (45% female, median age 39) meeting criteria for inclusion were identified. About 165 patients were included in the proactive TDM cohort and 74 in the reactive TDM cohort.Anti-TNF naïve patients had significantly higher durability of therapy when compared with the anti-TNF exposed patients for both overall durability (P = .045) and durability postescalation (P = .017). The proactive TDM cohort had significantly higher durability when compared with the reactive cohort for both overall durability (P = .001) and durability postescalation (P = .002). Conclusions:This multicentre, retrospective cohort study illustrates the importance of dose escalation as a therapeutic strategy in IBD care. The durability of anti-TNF therapy is superior in anti-TNF naïve compared to exposed patients and can be improved further by proactive TDM to guide dose optimization.

Abstract Background Magnetic resonance imaging (MRI) is the gold-standard for evaluating Crohn’s perianal fistulas. Multiple scoring indices to grade radiologic disease activity severity have been established, with limited comparative data and a lack of consensus regarding which index correlates most accurately with clinical findings. In a prospective MRI series, we explored the relationship between established radiologic indices and clinical healing. Methods Serial MRI scans from 60 adults with Crohn’s perianal fistulas enrolled in a prospective study were acquired. The prospective study evaluated the efficacy of a protocolised treatment strategy optimising care delivery at a single tertiary centre. Patients had ≥12 months follow-up with serial MRI performed annually. Each MRI scan had a paired physical examination, with clinical healing defined as the absence of externally draining perianal fistulas and no seton. MRI scans were reviewed by a specialist radiologist blinded to clinical findings. Radiologic disease activity severity was graded using the Van Assche Index (VAI), Magnetic Resonance Index for Assessing Fistulas in Patients with Crohn’s Disease (MAGNIFI-CD) and Fibrosis Score (FS). The primary endpoint was the relationship between radiologic indices and clinical healing. Secondary endpoints included the optimal index scores for clinical healing and the relationship between individual scoring criteria and clinical healing. Results A total of 135 MRI scans were acquired. All patients had baseline imaging, with 88% and 37% having serial imaging at 1 and 2 years, respectively. The median interval between baseline and final MRI was 16 months. Clinical healing significantly correlated with less severe radiologic disease activity, reflected by lower VAI (OR 0.70, P<0.001), lower MAGNIFI-CD (OR 0.76, P<0.001) and higher FS (OR 3.14, P<0.001). On ROC curve analysis, all radiologic indices exhibited a similarly high degree of correlation with clinical healing; AUROC of 0.91, 0.84 and 0.92, respectively (Figure 1). The optimal index scores for clinical healing were VAI ≤6 (sensitivity 83%, specificity 94%, AUROC 0.88), MAGNIFI-CD ≤8 (sensitivity 78%, specificity 73%, AUROC 0.75) and FS ≥5 (sensitivity 83%, specificity 94%, AUROC 0.88). On multivariable logistic regression analysis, increasing degree of fibrosis on FS (OR 2.68, P<0.001) and increasing fistula tract extension on VAI (OR 0.09, P<0.001) were independent positive and negative indicators of clinical healing, respectively. Conclusion Radiologic disease activity severity using established scoring indices have equally strong correlations with clinical healing of Crohn’s perianal fistulas. Further studies are needed to explore the predictive utility of individual radiologic parameters.

Introduction The enteric microbiota drives inflammation in Crohn’s disease. Yet, there are no placebo controlled trials evaluating the efficacy and safety of faecal microbiota transplantation (FMT) in inducing and maintaining remission in patients with active Crohn’s disease. The Microbial Restoration (MIRO) study aims to establish this evidence.Methods and analysis At two specialist inflammatory bowel disease centres, 120 enrolled patients will have a 3-week period of diet optimisation (removal of ultra-processed foods) together with a 7-day course of antibiotics (to facilitate subsequent FMT engraftment). Patients will then be stratified to upper gut (for disease proximal to the splenic flexure) or lower gut (distal to the splenic flexure) disease. Patients will then be randomised in a 2:1 ratio to receive anaerobically prepared stool or placebo for 8 weeks either by gastroscopy, or colonoscopy and enemas. Clinical response at 8 weeks (Crohn’s Disease Activity Index (CDAI) reduction ≥100 points or to <150 points) is the primary outcome measure. Non-responders to placebo and partial responders to FMT (CDAI decrease <100 but >70) receive FMT for weeks 8–16.Patients achieving clinical response from FMT after 8 or 16 weeks will be randomised in a 1:1 ratio to either a 44-week maintenance phase of FMT or placebo. Patients will receive FMT from one donor throughout the study.The MIRO study will establish whether FMT is an effective and safe therapy to induce and maintain remission in patients with active Crohn’s disease.Ethics and dissemination Ethical approval has been received by the St Vincent’s Hospital Melbourne Human Research Ethics Committee (HREC-A 084/21). The results will be disseminated in peer-reviewed journals and presented at international conferences.Trial registration number ClinicalTrials.gov: NCT04970446; Registered on 20 July 2021.

Abstract Background Fibrostenotic strictures are common in Crohn’s disease, have limited treatment options and lack validated biomarkers to predict treatment response. Fourier-transform infra-red (FTIR) spectroscopy provides reproducible biochemical information from biospecimens using a rapid, label-free, non-destructive technique via molecular vibrations. We previously completed a proof-of-concept study that identified spectral biomarkers for inflammation in a model of colitis.1 The aim of this study was to investigate whether the tissue biochemical "fingerprint" using FTIR spectroscopy can predict patient clinical response to anti-tumour necrosis-factor-α (anti-TNFα) therapy, and identify spectral biomarkers for treatment response. Methods Hyperspectral images were acquired using the Agilent Cary 670 FPA-IR coupled with the Agilent Cary 620 microscope in transflection mode in the wavenumber region 1800 – 800 cm-1 from fixed ileo-colonoscopic biopsies from 62 patients with Crohn’s disease and 12 healthy controls. A subset of patients (n = 24) were included from STRIDENT2, a randomised study assessing adalimumab therapy for intestinal Crohn’s strictures. Thousands of spectra were obtained per sample, pre-processed via transformation to the second derivative, normalised and reduced to 25 spectra per sample prior to analysis using partial least squares discriminant analysis (PLSDA) with internal cross-validation. Spectral biomarkers were identified by the most contributive infra-red bands from the latent variables (LV) and significant variable importance in projection (VIP) scores of >1. Adjacent histological sections were stained with H&E, Masson’s trichrome and α-smooth muscle actin with inflammation and fibrosis scored by a clinical pathologist. Results Spectra from baseline biopsies from the 24 patients in the STRIDENT study demonstrated excellent performance using PLSDA in discriminating between responders and non-responders in relation to the 12 month clinical outcomes, defined by area under the receiver operating characteristic curve (AUC) >0.9 for MRI and IUS responses, normalisation of faecal calprotectin and CRP, CDAI and pain responses (Table 1). Spectral biomarkers of interest for stricture response to anti-TNFα are shown in Figure 1 and include the amide I and II protein bands (peaks at 1651 and 1543 cm-1, respectively), the carboxylate group of proteins (1454 cm-1), lipid bands (1750 and 1395 cm-1), collagen band (1236 cm-1), glycoprotein bands (1081 and 1030 cm-1), and nucleic acid bands (1236, 1081 and 966 cm-1). Conclusion The novel technique of FTIR spectroscopy detects tissue biochemical "fingerprints" in fibrostenotic Crohn’s disease that demonstrate excellent discrimination for predicting clinical response to adalimumab therapy. References 1.Keung C, Heraud P, Kuk N, et al. Fourier-Transform Infra-Red Microspectroscopy Can Accurately Diagnose Colitis and Assess Severity of Inflammation. Int J Mol Sci. 2022;23(5). 2.Schulberg JD, Wright EK, Holt BA, et al. Intensive drug therapy versus standard drug therapy for symptomatic intestinal Crohn's disease strictures (STRIDENT): an open-label, single-centre, randomised controlled trial. Lancet Gastroenterol Hepatol. 2022;7(4):318-331. 3.Rimola J, Ordas I, Rodriguez S, et al. Magnetic resonance imaging for evaluation of Crohn's disease: validation of parameters of severity and quantitative index of activity. Inflamm Bowel Dis. 2011;17(8):1759-1768.

Transmural healing is emerging as a key treatment target in Crohn's disease. This study aimed to determine the role of magnetic resonance imaging (MRI) and intestinal ultrasound (IUS) in the assessment of the radiologic response of Crohn's disease strictures to treatment. The STRIDENT (Stricture Definition and Treatment) study was a randomized controlled trial of (2:1) intensive high-dose adalimumab combined with a thiopurine vs standard dose monotherapy adalimumab in patients with stricturing Crohn's disease. Clinical response was defined as a reduction in the Obstructive Symptom Score at 12 months. Intestinal ultrasound was performed at baseline, 4, 8, and 12 months and MRI at baseline and 12 months. This study examines secondary outcomes of stricture resolution and changes in stricture morphology with treatment. Of 77 patients, 52 were in the intensive treatment group and 25 in the standard therapy group. Clinical response was achieved in 56 of 77 patients (73%). Complete stricture resolution occurred in 17 patients on IUS (29%) and 16 patients on MRI (22%). Stricture improvement occurred in 23 of 59 patients on IUS (39%) and 24 of 72 patients on MRI (33%). Bowel wall thickness improved at 12 months on both IUS (P < .0001) and MRI (P < .001) and was significantly lower in clinical responders (IUS P = .003) and those with fecal calprotectin < 100 µg/g (IUS P < .001; MRI P = .001). Radiologic severity of Crohn's disease strictures can improve with drug treatment, with complete stricture resolution observed in some. Intestinal ultrasound and MRI are effective modalities for monitoring the treatment response in patients with stricturing Crohn's disease (STRIDENT Drug Therapy Study: NCT03220841).

BACKGROUND AND AIMS:Inflammatory bowel disease (IBD) therapeutics and pregnancy itself are known to impact immune cell populations, but a detailed understanding of the effect of specific therapies is lacking, particularly for infants exposed in utero. With comprehensive flow cytometric assessment, we aimed to explore how IBD and its treatment impact both maternal and infant immunophenotypes and cytokine production. METHODS:Peripheral blood was taken for flow cytometry immunophenotyping and quantification of cytokine responses to stimulation from women with IBD and healthy controls throughout pregnancy, at delivery, and postpartum. Blood samples were also taken from the umbilical cord and peripherally from the resultant offspring at the age of 6 weeks. RESULTS:Eighteen participants (16 with IBD and 2 healthy controls) were recruited to this single-center prospective cohort study. Basal T regulatory cell population proportions were 46% lower (0.21% vs 0.39%, P = .027) in those participants exposed to ustekinumab (n = 4). No other significant differences were noted in immunophenotype according to drug therapy exposure. Basal (1.75% vs 0.47%, P = .036) and lipopolysaccharide-stimulated (72.2% vs 64.7%, P = .028) production of tumour necrosis factor by classical dendritic cells were increased 3.7- and 1.1-fold, respectively, in those with an elevated fecal calprotectin (n = 6). Basal CD4+α4β7+ (41.4% to 66.5%, P = .0043) and CD8+α4β7+ (81.2% to 93.6%, P = .007) population proportions increased 1.6- and 1.2-fold, respectively, in infants from birth to 6 weeks. CONCLUSIONS:This study provides the foundation for ongoing investigation to more definitively extricate the impact of maternal IBD activity, drug exposures, and disease phenotype on infant immune system development and function. These novel data suggest that IBD pharmacotherapies may not significantly impact maternal or infant immune regulation.

BACKGROUND & AIMS:Recent controlled data from the STRIDENT study suggest that, in the short-term, drug treatment effectively relieves symptoms and improves bowel wall morphology. Here, we present the long-term results of this clinical trial, identifying predictors of treatment outcomes. METHODS:Patients with symptomatic Crohn's disease strictures were randomized 2:1 to high-dose adalimumab induction followed by 40 mg fortnightly plus thiopurine, with dose increase at 4 and/or 8 months if evidence of persisting inflammation, or standard dose adalimumab monotherapy. Baseline stricture magnetic resonance imaging risk score was assessed: prestenotic dilation ≥30 mm, stricture length >50 mm, and bowel wall thickness ≥10 mm (each factor assigned a score of 1). Patients were assessed at 12 months for clinical response (reduction in the 14-day obstructive symptom score). Follow-up interviews were performed at a minimum of 4 years. RESULTS:In the initial 12-month study, 52 patients were randomized to the intensive and 25 to the standard treatment arm, with 64 of 77 (83%) completing at least 12 months of therapy, whereas 13 patients (17%) withdrew: 8 for surgical treatment and 5 for other reasons. Following study completion at 12 months, 12 of 77 patients (16%) required endoscopic dilation, and 22 of 77 patients (29%) required surgery. Clinical responders had a lower rate of surgical resection compared with nonresponders (20% vs 52%; P < .001). The stricture magnetic resonance imaging risk score predicted surgery-free survival (odds ratio, 2.34; 95% confidence interval, 1.32-4.16; P = .004). CONCLUSIONS:The clinical response to adalimumab is durable in a majority of patients beyond 4 years of therapy. In patients with symptomatic Crohn's disease strictures, drug treatment is a viable initial treatment. Stricture Definition and Treatment (STRIDENT) Drug Therapy Study: Clinicaltrials.gov, Number: NCT03220841.

BACKGROUND & AIMS:The role of infliximab therapeutic drug monitoring in acute severe ulcerative colitis (ASUC) management is unknown. We aimed to identify whether infliximab therapeutic drug monitoring is associated with ASUC outcomes. METHODS:Serum and stool samples were collected from patients enrolled in the PREDICT-UC randomized controlled trial (NCT02770040), which compared intensified and standard infliximab rescue in steroid-refractory ASUC. Infliximab levels measured after trial conclusion and clearance derived using pharmacokinetic modelling were correlated with outcomes. RESULTS:Infliximab levels were measured in 681 serum and 198 fecal samples from 135 patients. Lower day 3 serum infliximab levels predicted infliximab failure on day 14 (area under the receiver operator characteristic curve = 0.63; P = .043) and colectomy by 3 months (area under the receiver operator characteristic curve = 0.77; P = .0027); a threshold of ≤57.9 μg/mL had 83% sensitivity, 67% specificity, 24% positive predictive value, and 97% negative predictive value for colectomy. Patients with high clearance between day 1 and 7 (≥0.62 L/d) were more likely to respond to an initial 10 mg/kg vs 5 mg/kg infliximab dose (risk ratio, 1.50; 95% confidence interval [CI], 1.01-2.23), and had a higher risk of colectomy if they received an initial 5 mg/kg vs 10 mg/kg dose (HR, 4.81; 95% CI, 1.09-21.37). In patients with high clearance who did not respond to the first infliximab dose, day 14 response rate was higher with a second 10 mg/kg vs 5 mg/kg dose (38% vs 11%; risk ratio, 3.43; 95% CI, 1.05-11.19). Day 3 fecal infliximab levels correlated with endoscopic severity and was associated with day 7 nonresponse (P = .016). CONCLUSIONS:Early infliximab levels and clearance calculation can predict outcomes in ASUC. This is the first study to demonstrate that high infliximab clearance may be overcome by intensified infliximab dosing. (NCT02770040; Optimizing Infliximab Induction Therapy for Acute Severe Ulcerative Colitis).

BACKGROUND & AIMS: Clinically active inflammatory bowel disease (IBD) is associated with an increased risk of adverse pregnancy outcomes. However, the validity of clinical scores to assess antenatal disease activity is questionable. We aimed to assess whether active disease defined by intestinal ultrasound (IUS) may predict adverse pregnancy outcomes. METHODS: This international prospective cohort study recruited pregnant individuals with IBD from 2017 to 2023 from 3 specialist IBD pregnancy services. Participants underwent clinical assessments and fecal calprotectin (FCP) testing in the first (T1), second (T2), and third (T3) trimesters, and 6 weeks postpartum. IUS was performed in T1 or T2 when referral timing allowed. Univariable and multivariable log-binomial regression analyses were used to estimate the impact of IUS activity on pregnancy outcomes. Cohen's k coefficients were used to determine agreement between FCP, IUS, and clinical disease activity. RESULTS: The study recruited 377 participants, 198 with Crohn's disease (CD), and 234 women underwent an IUS during pregnancy. A maximal bowel wall thickness (BWT) >6 mm in T2 was associated with a 4-fold increased risk of prematurity (relative risk [RR], 4.01; 95% confidence interval [CI], 1.26-12.72; P =.018) and 2-fold increased risk of lowbirth-weight delivery (RR, 2.19; 95% CI. 1.01-4.72; P =.046). Hyperemia on IUS in T2 was associated with a 3-fold increase in preeclampsia risk (RR, 3.46; 95% CI, 1.03-11.12; P =.046). Each 1-mm increase in BWT in T2 was estimated to increase the risk of gestational diabetes (RR, 1.08; 95% CI, 1.088-1.089; P <.001) Agreement between clinical (Harvey Bradshaw index or Simple Clinical Colitis Activity Index) and IUS/FCP activity during pregnancy was weak, particularly for CD. CONCLUSIONS: Active IBD on IUS in pregnancy is associated with an increased risk of adverse pregnancy outcomes, independent of clinical activity and FCP. Use of IUS monitoring antenatally should be considered to guide therapeutic decision-making.

Background and Aims Crohn's perianal fistula healing rates remain low. We evaluated the efficacy of a protocolized multidisciplinary treatment strategy optimizing care in adults with Crohn's perianal fistulas.Methods A new treatment strategy was established at a single tertiary center. The strategy comprised 3 dynamic stages of care directed toward achieving and maintaining fistula healing. Stage A, active disease, focused on early commencement and proactive escalation of biologic therapies and structured surgical reviews ensuring adequate fistula drainage and conditioning. Stage B, optimized disease with a seton in situ, focused on consideration for seton removal and appropriateness of definitive surgical closure and/or ablative techniques. Stage C, healed disease, focused on proactive care maintenance. Sixty patients were sequentially enrolled and prospectively followed for >= 12 months. Endpoints included clinical healing and radiologic remission in those with clinically active fistulas, and relapse in those with healed fistulas.Results At baseline, 52% (n = 31) and 48% (n = 29) had clinically active and healed fistulas, respectively. For patients with clinically active fistulas, 71% achieved clinical healing after 22 months, with estimated healing rates of 39% and 84% at 1 and 2 years, respectively. Radiologic remission was achieved in 25%, significantly higher than baseline inclusion rates of 6%. For patients with healed fistulas, 7% experienced clinical relapse after 23 months, with no significant change in radiologic remission, 80% versus 86% at baseline.Conclusions A protocolized treatment strategy proactively optimizing care resulted in high rates of clinical healing and improved radiologic remission of Crohn's perianal fistulas. Controlled-matched studies are needed.