Abstract Background The ability to predict failure of infliximab (IFX) in acute severe ulcerative colitis (ASUC) is crucial to identify patients who may benefit from dose-escalation, sequential rescue or early colectomy. Methods PREDICT-UC (NCT02770040) was a randomised controlled trial that compared IFX dosing strategies in ASUC.1 Clinical factors and biomarkers were collected daily between day 0 to 3 post-IFX and assessed on their ability to predict IFX failure (Lichtiger score ≥10 on day 14) and 3-month colectomy. Stepwise logistic regression was used to develop a Risk of IFX Failure (RIF) index, which was calibrated against the observed risk of IFX failure. The RIF index represents the predicted probability of IFX failure and takes on values between 0 and 1. Internal validation was performed using bootstrap validation. Results Of 138 patients, 46 received a first IFX dose of 10mg/kg and 92 received 5mg/kg; 39 (28%) experienced IFX failure and 17 (12%) required colectomy by 3 months. There was no difference in lymphocyte count (LC, ×109/L) on day 0 (prior to IFX) in patients who failed or responded to IFX (median [IQR] 1.1 [0.9–1.6] vs 1.3 [0.9–1.8], P=0.47). LC rose by day 3 in both groups, though to a lesser degree in patients who failed IFX (median [IQR] 1.9 [1.4–2.8]) compared to responders (3.3 [2.1–4.9]; P=0.004), and lower in patients requiring colectomy (median [IQR] 1.4 [1.1–1.9] vs 3.0 [2.0–4.8]; P<0.001). A lower day 3 LC was predictive of IFX failure (AUC 0.71, 95% CI 0.60–0.81) and colectomy (AUC 0.83, 95% CI 0.74–0.92). A higher CRP was predictive of both IFX failure and colectomy at all time-points from days 0 to 3 (day 3 CRP AUC 0.68, P=0.003 and 0.70, P=0.019 respectively). A lower day 3 albumin predicted IFX failure (AUC 0.63, P=0.039) while a lower day 2 albumin predicted colectomy (AUC 0.66, P=0.042). The final RIF index comprised day 3 stool frequency, rectal bleeding score, CRP and LC. The RIF index had a naïve AUC of 0.80 and an optimism-adjusted AUC of 0.73 (95% CI 0.65–0.80) for predicting IFX failure, and a naïve AUC of 0.90 and an optimism-adjusted AUC of 0.88 (95% CI 0.81–0.94) for predicting colectomy. A RIF index threshold of ≥0.15 had an 85% sensitivity and 90% negative predictive value (NPV) for IFX failure and a 94% sensitivity and 98% NPV for colectomy, while a threshold of ≥0.50 had a 92% specificity and 69% positive predictive value (PPV) for IFX failure, and an 88% specificity and 42% PPV for colectomy. Conclusion Lymphocytosis by day 3 is a novel predictor of response to IFX rescue in ASUC. The RIF index is a simple on-treatment risk index that predicts IFX failure and colectomy, and may be used to inform IFX dose-optimisation or switch to alternate therapies. References 1Choy MC, Li Wai Suen CFD, Con D, et al. Intensified versus standard dose infliximab induction therapy for steroid-refractory acute severe ulcerative colitis (PREDICT-UC): an open-label, multicentre, randomised controlled trial. Lancet Gastroenterol Hepatol 2024; 9(11): 981-96.

ABSTRACT Background Ustekinumab is an effective therapy for the management of Crohn's disease. Australia is unique, as ustekinumab can be prescribed as first‐line biologic therapy, and there is high concomitant immunomodulator use. Aim To evaluate the real‐world efficacy and safety of ustekinumab in moderate to severe Crohn's disease. Methods A multicentre prospective cohort study was conducted at 19 Australian centres between September 2019 and April 2022. Clinical assessments were performed at baseline, 3, 9 and 15 months. Logistic regression analyses were performed to identify predictors of clinical response and remission. Results 197 patients (male 45.2%) were included: 58.9% were biologic‐naïve and 50.0% were on concomitant immunomodulators. Clinical response rates were 75.4%, 75.5% and 72.3% at 3, 9 and 15 months, respectively with corresponding clinical remission rates of 45.8%, 51.6% and 55.5%. Clinical response and remission rates at 3 and 9 months were significantly higher in bio‐naïve patients compared with biologic‐exposed (p < 0.01); but no significant differences were seen with concomitant immunomodulator use. Dose escalation was required in 31.5% of patients. Ustekinumab was discontinued in 12.7% of patients. The cumulative probability of maintaining ustekinumab treatment at 15 months was 84.4%. Despite 161 adverse events reported, including 41 hospitalizations, only eight patients required treatment discontinuation due to adverse events. Conclusions This real‐world study on the use of ustekinumab in Crohn's disease showed that short‐term clinical response and remission rates are higher in bio‐naïve compared with bio‐exposed patients, with a high persistence rate at 15 months. The addition of an immunomodulator did not significantly impact outcomes. Ustekinumab was found to be safe in most patients.

INTRODUCTION:Several studies have demonstrated that switching stable patients with inflammatory bowel disease (IBD) from originator to biosimilar infliximab is noninferior to continuing originator infliximab. However, "real-world" data comparing long-term outcomes between switch and nonswitch cohorts is lacking. This study aimed to address this gap by comparing long-term outcomes in IBD patients across switch and nonswitch cohorts. METHODS:The SAME study was a multicenter, prospective parallel cohort noninferiority study, that enrolled Australian IBD patients in steroid-free clinical remission on maintenance originator infliximab, who either continued originator infliximab (n = 141) or switched to biosimilar (CT-P13) infliximab (n = 204). Here, we present long-term outcomes, with treatment persistence beyond 48 weeks as the primary outcome. Disease worsening, defined as any of infliximab discontinuation, dose escalation, antibody development, or adverse event, were secondary outcomes of interest. RESULTS:Of 345 patients enrolled in the SAME study, 320 (92.7%) patients were followed up beyond 48 weeks (median: 54.2 months [IQR 46.1-59.3]). There were no differences in infliximab discontinuation between switch and nonswitch cohorts (35.3% vs. 37.6%, p = 0.47). Infliximab discontinuation due to disease worsening (21.7% vs. 23.6%), dose escalation (35.2% vs. 32.4%), antibody development (5.3% vs. 11.3%), and infliximab-related adverse events (7.8% vs. 8.3%), were also comparable (all p > 0.70) between switch and nonswitch cohorts. CONCLUSIONS:Long-term infliximab persistence was similar between switch and nonswitch cohorts over 4 years of follow-up. These data represent the longest duration of "real-world" follow-up, and should provide further reassurance that nonmedical switching is safe and clinically comparable to ongoing originator infliximab in clinically stable patients with IBD.

BACKGROUND:Serum free thiols (SFTs) reflecting oxidative stress appear to correlate with inflammatory bowel disease (IBD) activity. We aimed to evaluate the performance of SFTs concentrations vs endoscopic and histological activity, compare SFTs with established biomarkers, and identify clinical and laboratory parameters independently associated with SFT levels in IBD patients. METHODS:Patients with confirmed IBD undergoing routine ileocolonoscopy for activity assessment were prospectively recruited, with serum samples obtained concurrently for SFTs and routine bloods, plus fecal calprotectin and immunochemical tests were collected ±30 days from ileocolonoscopy. Endoscopic activity was assessed via established indices and histological activity graded as inactive/mild/moderate. Receiver-operating characteristic curve analyses were utilized to assess performance of SFTs vs endoscopic activity, and multiple regression analysis was used to identify factors associated with SFT levels. RESULTS:A total of 141 (80 Crohn's disease, 61 ulcerative colitis) patients were recruited. Median SFTs were significantly lower in moderate vs inactive/mild endoscopic activity (309 µM vs 433/471 µM, respectively; P < .01). There was no significant difference in median SFTs across inactive/mild/moderate histological activity. SFTs achieved higher sensitivity than C-reactive protein in predicting moderate, endoscopically active disease (89% vs 78%; area under the curve, 0.80 each) yet was outperformed by fecal calprotectin (100%; area under the curve, 0.93). Advancing age and increasing albumin levels were independently associated with SFT levels, and thus are possible confounders. CONCLUSIONS:This prospective study has demonstrated the potential of SFTs as a serum biomarker in IBD. It was more sensitive than C-reactive protein, yet less sensitive than fecal biomarkers for prediction of endoscopically active IBD.

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).

Abstract Background The utility of infliximab (IFX) therapeutic drug monitoring (TDM) in acute severe ulcerative colitis (ASUC) is unclear. We aimed to assess whether IFX levels are associated with outcomes in ASUC. Methods PREDICT-UC (NCT02770040) was a randomised controlled trial that compared dosing strategies in 138 steroid-refractory ASUC patients.1 Serum and faecal IFX levels were quantified by ELISA (MabTrack level infliximab, Essange Reagents, Netherlands) after conclusion of the trial and correlated with outcomes: IFX response by day 7 (Lichtiger score [LS]<10, with ≥3-point reduction and decrease in rectal bleeding and stool frequency ≤4/day); eventual response by day 14 (LS<10); and colectomy by month 3. Individual IFX clearance was estimated using a two-compartment pharmacokinetic model with fixed V1, V2 and Q. Results 681 serum IFX levels were available across 135 patients; 91 received an initial 5mg/kg and 44 an initial 10mg/kg IFX dose. 85 responded by day 7 and 17 required colectomy by month 3. Post-IFX serum levels were higher on days 1 and 3 (median ug/mL, IQR) in the 10mg/kg group (175.4, 137.2-202.7 and 116.3, 83.4-132.9) compared to the 5mg/kg group (91.8, 77.2-109.4 and 56.0, 46.0-67.0; each P<0.001). Day 1 and day 3 serum IFX levels were not significantly different in responders and non-responders. A higher day 3:day 1 serum IFX ratio predicted response (63.1%, IQR 56.0-72.1 vs 58.1%, IQR 51.6-62.8, P=0.006; AUC 0.67). A lower day 3 serum IFX level predicted colectomy (51.0, IQR 39.2-57.4 vs 69.0, IQR 51.1-101.7, P=0.003; AUC 0.23). IFX clearance using serum levels between days 1-7 was higher in non-responders compared to responders (0.72L/day, IQR 0.55-0.89 vs 0.56L/day, IQR 0.39-0.72, P<0.001) and in patients who had colectomy (P=0.011). Patients with high clearance (≥0.62L/day) were more likely to respond to an initial 10mg/kg vs 5mg/kg IFX dose (RR 1.50, 95%CI 1.01-2.23, P=0.046), and more likely to require colectomy if they received an initial 5mg/kg vs 10mg/kg dose (HR 4.81, 95%CI 1.09-21.37, P=0.039). In patients with high clearance who did not respond initially, response by day 14 was higher in those receiving a second 10mg/kg dose compared to 5mg/kg (10/26 [38%] vs 1/9 [11%]; RR 3.43, 95%CI 1.05-11.19, P=0.041). Day 1 and 3 faecal IFX correlated with IFX clearance (both rho=0.36, both P<0.001), CRP and the UCEIS (including bleeding and erosion/ulcer sub-scores). Conclusion Elevated day 3:day 1 serum IFX ratio was associated with IFX response by day 7. Early IFX clearance predicted IFX response and month 3 colectomy. High IFX clearance may be overcome by higher IFX dosing, resulting in improved response and reduced colectomy rates. Early IFX level quantification can help predict outcomes in ASUC. References 1.Choy MC, Li Wai Suen CFD, Con D, et al. Intensified versus standard dose infliximab induction therapy for steroid-refractory acute severe ulcerative colitis (PREDICT-UC): an open-label, multicentre, randomised controlled trial. Lancet Gastroenterol Hepatol 2024; 9(11): 981-96.

Abstract Background Faecal calprotectin (FCP) is routinely used in the management of inflammatory bowel disease; however, its role in acute severe ulcerative colitis (ASUC) is unclear. We aimed to evaluate the relationship between FCP and outcomes in ASUC. Methods We included ASUC patients who were screened/randomised as part of PREDICT-UC (NCT02770040), a randomised controlled trial that evaluated escalated infliximab (IFX) dosing strategies in steroid-refractory ASUC.1 Stool was collected at screening, and in steroid-refractory patients at day 0 (pre-IFX), and days 1, 3, 5, 7, 14, 30 and 42 and months 3, 6, 9 and 12 post-IFX. FCP was quantified by Liaison® XL (Diasorin) and correlated with outcomes. Outcomes included initial IFX response by day 7 (Lichtiger score<10, with ≥3-point reduction and decrease in rectal bleeding and stool frequency ≤4/day), month 3 colectomy and month 3 Mayo remission (partial Mayo ≤1 & Mayo endoscopic score ≤1). Results Of 185 patients with ASUC, 49 were steroid responders while 136 were steroid-refractory and received IFX. Of 136, 85 were initial IFX responders and 17 required colectomy by month 3. Screening FCP was higher in steroid-refractory compared to steroid responsive patients (median [IQR] 3745 [1753-6175] ug/g vs 2305 [826-4400] ug/g, P=0.020). In steroid-refractory patients, day 0 FCP did not correlate with the Mayo endoscopic score or Ulcerative Colitis Endoscopic Index of Severity (UCEIS) but correlated with CRP (rho=0.251, P=0.031) and the erosion/ulcer sub-score of the UCEIS (rho=0.298, P=0.010). In linear mixed modelling, FCP dynamics in the first 3 days differed between IFX responders and non-responders (daily 22% decrease [95% CI 13 to 31%] vs 3% decrease [95% CI -12 to 16%], P=0.018). A higher day 3:day 0 FCP ratio predicted initial IFX non-response (median [IQR] 109 [51-158] % vs 57 [21-92] %, P=0.006, Area under receiver operator characteristic curve [AUROC]=0.72). FCP dynamics in the first 2 weeks after IFX differed in patients who avoided vs required colectomy (weekly 59% decrease, 95% CI 52 to 65% vs 6% decrease, 95% CI -76 to 50%; P=0.012). Month 3 colectomy was predicted by a higher day 7 FCP (AUROC 0.71, 95% CI 0.49-0.92, P=0.044) and a higher day 3:day 0 FCP ratio (AUROC 0.75, 95% CI 0.58-0.91, P=0.018). Mayo remission at 3 months was predicted by lower day 14 FCP (AUROC 0.31, P=0.004) and day 14:day 0 ratio (AUROC 0.27, P=0.006). Conclusion FCP level and dynamics are novel predictors of outcomes in ASUC. Decrease in FCP by day 3 after IFX predicts initial response. Absolute day 7 FCP and early dynamics predict colectomy. Absolute day 14 FCP and FCP dynamics by day 14 predict month 3 Mayo remission and may help identify patients who may benefit from treatment optimisation. References 1.Choy MC, Li Wai Suen CFD, Con D, et al. Intensified versus standard dose infliximab induction therapy for steroid-refractory acute severe ulcerative colitis (PREDICT-UC): an open-label, multicentre, randomised controlled trial. Lancet Gastroenterol Hepatol 2024; 9(11): 981-96.

The optimal infliximab dose intensification strategy to address loss of response associated with subtherapeutic infliximab trough levels remains uncertain, as does whether post-intensification trough and treatment targets should influence this decision. This pharmacokinetic simulation study aimed to identify infliximab dose intensification strategies capable of achieving post-intensification infliximab trough thresholds associated with clinical and objective treatment targets in Crohn’s disease and ulcerative colitis. A validated pharmacokinetic infliximab model, applied to 200 simulated patients, identified those with subtherapeutic (< 3.00 mg/L) trough levels after 30 weeks of standard (5 mg/kg 8-weekly) dosing, and subsequently applied 10 dose intensification strategies over a further 32 weeks. The proportion of simulations achieving 32-week post-intensification infliximab trough levels associated with endoscopic remission (ulcerative colitis > 7.50 mg/L, Crohn’s disease > 9.70 mg/L) was the primary outcome, with perianal fistula healing (Crohn’s disease > 10.10 mg/L) and clinical improvement (ulcerative colitis > 3.70 mg/L, Crohn’s disease > 7.00mg/L) evaluated as secondary outcomes. All outcomes were stratified by intensity of dose intensification, with standard (≤ 10 mg/kg 8-weekly or 5 mg/kg 4-weekly; n = 5) and intensive (> 10 mg/kg 8-weekly or 5 mg/kg 4-weekly; n = 5) dosing strategies defined, respectively. The median pre-intensification infliximab trough level was 0.91 mg/L (interquartile range 1.37). Intensive dosing strategies were more likely to achieve infliximab trough concentrations associated with endoscopic remission (ulcerative colitis 36.48

Background: Faecal biomarkers are increasingly utilized for disease assessment in inflammatory bowel disease (IBD). Objectives: To characterize the relative and combined accuracy of faecal calprotectin (FC) and faecal immunochemical testing (FIT) for detecting endoscopic and histologically active disease in Crohn’s disease (CD) and ulcerative colitis (UC), subdivided by disease location. Design: A prospective cohort study. Methods: Patients with confirmed IBD undergoing routine ileocolonoscopy for activity assessment were prospectively recruited and performed both FC and FIT ±30 days of ileocolonoscopy. Endoscopic activity was assessed via the simplified endoscopic score for CD, Mayo endoscopic score for UC and histological activity graded as nil/mild/moderate. Receiver-operator curve analyses were utilized to assess the performance of FC and FIT per disease subtype and location. Results: In all, 137 (79 CD, 57 UC) patients were recruited. FC was more sensitive than FIT in detecting active endoscopic (CD: 91% versus 69%, UC: 94% versus 82%) and histological (CD: 86% versus 55%, UC 88% versus 56%) disease. However, FIT was more specific than FC in detecting active endoscopic (CD: 94% versus 56%, UC: 85% versus 69%) and histological (CD: 93% versus 55%, UC: 96% versus 70%) diseases. FIT was more sensitive and specific than FC in detecting active colonic CD (endoscopic activity: 94% versus 93%, histological activity: 92% versus 77%, respectively); however, it was poorly sensitive for active ileal CD (43% versus 89%). Conclusion: FC demonstrated higher sensitivity and FIT higher specificity for active IBD. Hence, dual testing was synergistic, displaying excellent performance characteristics across most IBD locations and subtypes, holding promise for future clinical application. Trial registration: Not applicable.

BACKGROUND:Thiopurine co-therapy with anti-tumour necrosis factor-alpha (anti-TNFα) agents is associated with higher anti-TNFα drug levels and reduced immunogenicity in inflammatory bowel disease (IBD). AIMS:We aimed to evaluate the association between 6-thioguanine nucleotide (6-TGN) and anti-TNFα levels and the optimal 6-TGN threshold level associated with higher anti-TNFα levels in combination therapy. METHODS:We performed a retrospective cross-sectional multicentre study of patients with IBD on combination anti-TNFα and thiopurine maintenance therapy between January 2015 and August 2021. Primary outcomes were infliximab and adalimumab levels. Secondary outcomes were antibodies to infliximab (ATI) or adalimumab (ATA). Univariable and multivariable linear regression were performed to identify variables associated with anti-TNFα levels. Receiver operator characteristic curves were used to define the optimal 6-TGN cut-off levels associated with therapeutic anti-TNFα levels. RESULTS:The study included 743 paired 6-TGN and anti-TNFα levels (640 infliximab and 103 adalimumab). 6-TGN levels were associated with infliximab levels, but not adalimumab levels, on univariable and multivariable regression. The optimal 6-TGN cut-off associated with therapeutic infliximab levels (≥5 mcg/mL) was 261 pmol/8 × 108 red blood cell (RBC) (area under the curve (AUC) = 0.57) for standard infliximab dosing and 227.5 pmol/8 × 108 RBC (AUC = 0.58) for escalated dosing. For therapeutic adalimumab levels (≥7.5 mcg/mL), the 6-TGN cut-off was 218.5 pmol/8 × 108 RBC (AUC = 0.59) for standard adalimumab dosing and 237.5 pmol/8 × 108 RBC (AUC = 0.63) for escalated dosing. CONCLUSION:6-TGN levels were weakly associated with infliximab but not adalimumab levels in combination therapy. 6-TGN levels in the lower end of the therapeutic range (230-260 pmol/8 × 108 RBC) may be adequate to maintain higher infliximab levels, particularly with escalated infliximab dosing.

Abstract Background The optimal dosing strategy of infliximab (IFX) in Acute Severe Ulcerative Colitis (ASUC) is unknown. We compared intensified and standard dose IFX strategies in ASUC. Methods In this open-label randomised trial (NCT02770040), patients from 13 Australian centres with intravenous steroid-refractory ASUC were randomised to receive a first dose of 10mg/kg or 5mg/kg IFX in a 1:2 ratio. Patients in the 10mg/kg group (intensified induction [II]) received a second dose at day 7 or earlier at time of non-response; all 5mg/kg patients were re-randomised 1:1 to standard (SI) or accelerated induction (AI), which produced three induction groups: II, SI and AI. SI patients received 5mg/kg at week 0, 2 and 6, with an extra 5mg/kg dose before day 7 if non-response. AI patients received 5mg/kg at week 0, 1 and 3, with the week 1 dose increased to 10mg/kg and given earlier if non-response. Primary outcome: clinical response by day 7 (reduction in Lichtiger score to <10, with decrease of ≥3 points and improvement in rectal bleeding and stool frequency to ≤4/day). Secondary outcomes compared induction regimens until month 3. Analysis was by intention to treat. Results Between July 2016 & September 2021, 138 patients were randomised; 46 received a first IFX dose of 10mg/kg and 92 received 5mg/kg. Primary outcome: day 7 clinical response was observed in 65% (30/46) of 10mg/kg vs 61% (56/92) of 5mg/kg patients (P=0.76). In the 5mg/kg group, the rate of day 7 response was numerically lower in those with albumin <25g/L vs ≥25g/L [47% (15/32) vs 68% (41/60), P=0.07]. No difference in clinical response was observed in the 10mg/kg group when stratified by albumin [64% (9/14) vs 66% (21/32) P>0.99]. There was no difference in time to clinical response, change in Lichtiger score or CRP from baseline to day 7. Two patients who received 10mg/kg IFX underwent colectomy in the first 7 days vs 0 in the 5mg/kg group (P=0.21). Comparison of induction regimens (II, SI & AI): no difference in clinical remission rates between weeks 2 and 6 were observed. AI and II groups had higher rates of combined clinical and biochemical remission compared to SI between weeks 2 and 6 (P=0.042). At 3 months, there was no difference in rates of endoscopic and steroid-free remission, as well as rates of colectomy (II 7%; SI 12%; AI 19%, P=0.20). Conclusion In steroid-refractory ASUC, a first dose of 10mg/kg or 5mg/kg IFX achieved similar clinical response rates by day 7. Patients receiving intensified or accelerated induction achieved clinical and biochemical remission earlier compared to standard induction; however, outcomes at three months were similar. Patients with a lower albumin may benefit from proactive intensified dosing strategies.

Background/Aims Assessment of quality of magnetic resonance enterography (MRE) in small bowel Crohn’s disease (CD) activity evaluation has received little attention. We assessed the impact of bowel distention and motion artifact on MRE activity indices in ileal CD. Methods A cohort of patients who underwent contemporaneous MRE and colonoscopy for ileal CD assessment between 2014 and 2021 at 2 centers were audited. An abdominal radiologist blinded to clinical data reviewed each MRE, graded bowel distention and motion artifact upon a pre-specified 3-point scale and calculated the original magnetic resonance index of activity (MaRIA) and simplified MaRIA (sMaRIA), London index and CD MRE index (CDMI). Ileal endoscopic activity was graded via the Simplified Endoscopy Score for CD (SES-CD). The performance of MRE indices in discriminating active disease (SES-CD ≥3) stratified by MRE quality was measured by receiver operator characteristic analyses. Results One hundred and thirty-seven patients had MRE and colonoscopy within a median of 16 days (range, 0–30 days) with 63 (46%) exhibiting active disease (SES-CD ≥3). Forty-four MREs (32%) were deemed low quality due to motion artifact and/or moderate to poor distention. Low-quality MREs demonstrated reduced discriminative performance between ileal SES-CD ≥3 and MRE indices (MaRIA 0.838 vs. 0.634, sMaRIA 0.834 vs. 0.527, CDMI 0.850 vs. 0.595, London 0.748 vs. 0.511, P<0.05 for all). Individually the presence of any motion artifact markedly impacted the discriminative performance (e.g., sMaRIA area under the curve 0.544 vs. 0.814, P<0.05). Conclusions Image quality parameters can significantly impact MRE disease activity interpretation. Quality metrics should be reported, enabling cautious interpretation in lower-quality studies.

BACKGROUND:The optimal dosing strategy for infliximab in steroid-refractory acute severe ulcerative colitis (ASUC) is unknown. We compared intensified and standard dose infliximab rescue strategies and explored maintenance therapies following infliximab induction in ASUC. METHODS:In this open-label, multicentre, randomised controlled trial, patients aged 18 years or older from 13 Australian tertiary hospitals with intravenous steroid-refractory ASUC were randomly assigned (1:2) to receive a first dose of 10 mg/kg infliximab or 5 mg/kg infliximab (randomisation 1). Block randomisation was used and stratified by history of thiopurine exposure and study site, with allocation concealment maintained via computer-generated randomisation. Patients in the 10 mg/kg group (intensified induction strategy [IIS]) received a second dose at day 7 or earlier at the time of non-response; all patients in the 5 mg/kg group were re-randomised between day 3 and day 7 (1:1; randomisation 2) to a standard induction strategy (SIS) or accelerated induction strategy (AIS), resulting in three induction groups. Patients in the SIS group received 5 mg/kg infliximab at weeks 0, 2, and 6, with an extra 5 mg/kg dose between day 3 and day 7 if no response. Patients in the AIS group received 5 mg/kg infliximab at weeks 0, 1, and 3, with the week 1 dose increased to 10 mg/kg and given between day 3 and day 7 if no response. The primary outcome was clinical response by day 7 (reduction in Lichtiger score to <10 with a decrease of ≥3 points from baseline, improvement in rectal bleeding, and decreased stool frequency to ≤4 per day). Secondary endpoints assessed outcomes to day 7 and exploratory outcomes compared induction regimens until month 3. From month 3, maintenance therapy was selected based on treatment experience, with use of thiopurine monotherapy, combination infliximab and thiopurine, or infliximab monotherapy, with follow-up as a cohort study up to month 12. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, NCT02770040, and is completed. FINDINGS:Between July 20, 2016, and Sept 24, 2021, 138 patients were randomly assigned (63 [46%] female and 75 [54%] male); 46 received a first dose of 10 mg/kg infliximab and 92 received 5 mg/kg infliximab. After randomisation 1, we observed no significant difference in the proportion of patients who had a clinical response by day 7 between the 10 mg/kg and 5 mg/kg groups (30 [65%] of 46 vs 56 [61%] of 92, p=0·62; risk ratio adjusted for thiopurine treatment history, 1·06 [95% CI 0·94-1·20], p=0·32). We found no significant differences in secondary endpoints including time to clinical response or change in Lichtiger score from baseline to day 7. Two patients who received 10 mg/kg infliximab underwent colectomy in the first 7 days compared with no patients in the 5 mg/kg group (p=0·21). Three serious adverse events occurred in three patients in both the 10 mg/kg group and 5 mg/kg group. After randomisation 2, the proportions of patients with clinical response at day 14 (34 [74%] of 46 in the IIS group, 35 [73%] of 48 in the AIS group, and 30 [68%] of 44 in the SIS group, p=0·81), clinical remission at month 3 (23 [50%], 25 [52%], 21 [48%], p=0·92), steroid-free remission at month 3 (19 [41%], 20 [42%], 18 [41%], p=1·0), endoscopic remission at month 3 (21 [46%], 22 [46%], 21 [48%], p=0·98), and colectomy at month 3 (three [7%] of 45, nine [19%] of 47, five [12%] of 43, p=0·20) were not significantly different between groups. Between day 8 and month 3, the proportion of patients with at least one infectious adverse event possibly related to infliximab was two (4%) of 46 in the IIS group, eight (17%) of 48 in the AIS group, and eight (18%) of 44 in the SIS group (p=0·082). No deaths occurred in the study. INTERPRETATION:Infliximab is a safe and effective rescue therapy in ASUC. In steroid-refractory ASUC, a first dose of 10 mg/kg infliximab was not superior to 5 mg/kg infliximab in achieving clinical response by day 7. Intensified, accelerated, and standard induction regimens did not result in a significant difference in clinical response by day 14 or in remission or colectomy rates by month 3. FUNDING:Australian National Health and Medical Research Council, Gastroenterology Society of Australia, Gandel Philanthropy, Australian Postgraduate Award, Janssen-Cilag.

Abstract Background The optimal maintenance regimen after rescue therapy for Acute Severe Ulcerative Colitis (ASUC) is unknown. We aimed to evaluate prospectively the impact of different maintenance regimens after successful infliximab (IFX) rescue, along with factors associated with Month 12 remission. Methods Clinical responders at 3 months from PREDICT UC, a randomised trial (NCT02770040) comparing standard and intensified IFX rescue strategies, were evaluated in this prospective cohort study up to Month 12. Maintenance therapies were as follows: (1) Thiopurine monotherapy (azathioprine or mercaptopurine) for thiopurine naïve patients or prior suboptimal thiopurine therapy (TP); (2) Combination thiopurine and IFX therapy 5mg/kg 8-weekly for thiopurine-experienced patients (IFX+TP combo); (3) IFX monotherapy 5mg/kg 8-weekly for thiopurine-intolerant patients (IFX mono). All patients received oral 5-aminosalicylates. Clinical and endoscopic assessments were performed at baseline (Month 3) and Month 12. Clinical remission was defined as a partial Mayo score of 0-1 and endoscopic remission as Mayo Endoscopic Score (MES) of 0-1. Results Of 138 patients randomised, 79 entered the maintenance phase. Of these, 56 (71%) received TP, 16 (20%) received IFX+TP combo and 7 (9%) received IFX mono. Baseline characteristics were similar across the 3 maintenance groups. At 12 months, 42 patients (53%) were in clinical remission, 44 patients (56%) were in endoscopic remission, and one patient underwent colectomy. The 3 maintenance groups had similar rates of clinical remission (TP 55%, IFX+TP combo 56%, IFX mono 29%; P=0.39) and endoscopic remission (TP 55%, IFX+TP combo 56%, IFX mono 57%; P=0.99) at 12 months. Clinical Remission On univariable and multivariable analysis, no factors were associated with clinical remission at 12 months, including baseline CRP, albumin, partial Mayo score, MES, UCEIS or maintenance strategy. Endoscopic Remission Factors associated with endoscopic remission at 12 months included baseline partial Mayo score of 0 (OR 3.36, 95% CI 1.24-9.10, P=0.017), MES of 0-1 (OR 3.48, 95% CI 1.08-11.27, P=0.037) and UCEIS of 0-1 (OR 3.30, 95% CI 1.24-8.76, P=0.016). However, a partial Mayo score cut-off of 0-1 did not reach significance (OR 3.46, P=0.09). No factors associated with endoscopic remission were identified on multivariable analysis. Conclusion In steroid-refractory ASUC patients who received IFX rescue, clinical and endoscopic remission at Month 3 were associated with endoscopic remission at Month 12, particularly among patients with greater depth of remission. Month 3 assessment helps identify patients at higher risk of disease progression for whom more intensive treatment may be required.

Background: Endoscopic balloon dilatation (EBD) is an alternative therapy to avoid or delay surgery in stricturing Crohn’s disease (CD); however, certain factors determining outcomes remain poorly defined, and conflicting evidence exists in current studies. In one of the largest cohorts to date, we assess outcomes following EBD for stricturing CD for both anastomotic and de novo strictures.Methods: A retrospective cohort study of CD patients undergoing EBD was conducted at 12 hospitals across Australia and New Zealand. Local databases were used to identify cases from February 1999 to November 2019. Data from patient endoscopy reports and medical records were used to determine patient medical details and EBD outcomes. Multivariable analysis was undertaken to identify factors associated with technical and long‐term success.Results: A total of 273 patients with stricturing CD were identified (48% female; 49.6% Montreal L3 disease). Of 695 EBD procedures (355 anastomotic, 340 de novo strictures), the majority (80.1% of strictures with identified length) was performed on short strictures (< 4 cm). Technical success, defined as the ability to traverse the stricture with a colonoscope after dilation, was achieved in 577 (83%) of endoscopic procedures, with success more likely with de novo strictures compared with anastomotic strictures (aOR: 3.21, P = 0.010). A significantly higher failure rate was noted with long strictures (aOR: 0.09, P < 0.001). A total of 74 patients (27%) required surgery within 5 years with stricture length, the only significant factor associated with increased surgery risk (aHR: 2.37, P < 0.01).Conclusion: EBD is a highly effective and safe procedure in both de novo and anastomotic strictures < 4 cm that can prevent or delay the need for surgical treatment.