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.

A High Visceral-to-Skeletal Muscle Area Ratio on Cross-Sectional Imaging Is Associated With Failure of Standard Ustekinumab Doses: A Multicenter Study.

INTRODUCTION: Anti-interleukin 12/23 agents have shown greater durability in response compared with anti-tumor necrosis factor α agents. Data on the association between body composition (BC) or body mass index (BMI) and ustekinumab's therapeutic response is limited. We aimed to evaluate the impact of BC on time to failing standard doses of ustekinumab in patients with Crohn's disease (CD). METHOD: Patients with CD aged 16 years and older from 2 tertiary centers were studied retrospectively. Included patients had abdominal imaging within 6 months of ustekinumab induction and were followed until April 30, 2022. An experienced abdominal radiologist blinded to the clinical information measured the area of visceral fat area and skeletal muscle area at the mid L3 vertebral level, with values corrected for height 2 to derive respective indices (visceral fat index [VFI], skeletal muscle index [SMI]) and the VFI:SMI ratio. RESULTS: Ninety-nine patients met inclusion criteria. The mean age at ustekinumab induction was 46.6 (±1.6) years. The median BMI (interquartile range) was 26.5 (22.6-30.8). Twenty-four patients (24.2%) did not respond or lost response to standard doses of ustekinumab over the follow-up duration. A younger age (hazard ratio 0.96, 95% confidence interval 0.94-0.99, P = 0.01) and a VFI:SMI ratio >1.6 (hazard ratio 4.65, 95% confidence interval 1.73-12.45, P = 0.002) were both associated with a shorter time to failing ustekinumab at standard doses on multivariate analysis. BMI, notably, had no association with the primary outcome. DISCUSSION: A high VFI:SMI ratio is associated with an increased risk of failing standard doses of ustekinumab. BC measurements derived from cross-sectional imaging at the start of ustekinumab therapy is a useful indicator for therapeutic durability.

Upadacitinib Reduces Crohn's Disease Symptoms Within the First Week of Induction Therapy.

BACKGROUND & AIMS: Upadacitinib (UPA), an oral Janus kinase inhibitor, is approved to treat moderately to severely active Crohn's disease (CD). Because symptomatic response is an important initial treatment goal for patients, we evaluated the rapidity of symptomatic improvement in patients with CD receiving UPA 45 mg once daily (UPA45) induction therapy. METHODS: This post hoc analysis included pooled data from 2 phase 3, multicenter, double-blind, 12-week induction trials (U-EXCEL and U-EXCEED) and 1 maintenance trial (U-ENDURE). Daily diary data for the first 15 days of UPA45 or placebo (PBO) treatment were used to analyze improvement in very soft/liquid stool frequency (SF) and abdominal pain score (APS). Clinical outcomes were evaluated at every study visit. RESULTS: Overall, 1021 patients (n = 674 UPA45; n = 347 PBO) were analyzed. UPA45 demonstrated greater efficacy vs PBO for SF <3 and APS ≤1, providing rapid relief by day 5 or 6, regardless of prior biologic exposure. Mean changes in SF and APS were greater with UPA45 beginning at week 2 (-2.0 and -0.5, respectively; P < .001) and were maintained through week 12 (-3.0 and -1.0, respectively; P < .001) vs PBO. The first achievement of daily SF/APS clinical remission occurred earlier with UPA45 (median, 13 d) vs PBO (median, 32 d), and patients treated with UPA45 showed improved rates of SF/APS clinical remission (21.1% UPA45 vs 8.9% PBO) and clinical response (58.8% UPA45 vs 37.9% PBO) starting at week 2 (both P ≤ .01). CONCLUSIONS: UPA45 provided rapid relief of clinical symptoms within the first week of treatment in patients with CD. CLINICALTRIALS: gov numbers: NCT03345849, NCT03345836, and NCT03345823.

Prevalence and risk factors for early medical and surgical complications following an admission for acute severe ulcerative colitis.

Background: Risk factors for colectomy following an episode of acute severe ulcerative colitis (ASUC) have been well studied, but data examining the early complications following an episode is limited. Objectives: We aimed to evaluate the prevalence and risk factors for medical and surgical complications within 90 days of an ASUC admission and determine if a high-intensity induction infliximab dose is associated with these complications. Design: Retrospective analysis. Methods: We conducted a retrospective study of ASUC admissions between January 2015 and July 2021 at a tertiary hospital. The primary outcome was the prevalence of total, medical and surgical complications within 90 days following an ASUC admission. Multivariate linear regression analysis assessed for factors associated with the prevalence of complications. Results: A total of 150 patients had 186 hospital admissions for ASUC. In total, 101/186 (54.3%) admissions required rescue medical therapy. Standard infliximab induction occurred in 65/100 admissions, accelerated infliximab induction in 35/100 and cyclosporine in 1/100 of admissions. In total, 117 complications, including 74/117 (63.2%) medical and 43/117 (36.8%) surgical complications, arose. Low serum albumin was independently associated with a higher incidence of total [ß = -0.08 (95% confidence interval (CI): -0.15, -0.01), p = 0.03] and surgical complications [ß = -0.1 (95% CI: -0.18, -0.001), p = 0.047], while an increased age was associated with increased incidence of surgical complications [ß = 0.06 (95% CI: 0.01, 0.12), p = 0.02]. A higher Charlson score was associated with increased medical complications [ß = 0.12 (95% CI: 0.01, 0.24), p = 0.03]. Infliximab induction dose intensity was not associated with an increased incidence of any complications. Conclusion: Early complications following an ASUC admission is prevalent although the majority are not serious. Risk factors associated with complications include low serum albumin, older age and a higher comorbidity score. Induction infliximab dose intensity, however, is not a risk factor.

The yield of dysplasia and serrated lesions in a single-centre tertiary inflammatory bowel disease cohort.

Background: Chromoendoscopy is preferred over high-definition white light endoscopy (HDWLE) for dysplasia surveillance in inflammatory bowel disease (IBD) patients, but is more time-consuming to perform and real-world evidence is limited. The prevalence of sessile serrated lesions (SSLs) in IBD patients is also unknown. Objective: To determine the yield of polypoid and non-polypoid dysplasia and SSLs in IBD patients undergoing dysplasia surveillance and the associations for these lesions. Design: A retrospective cohort study from a tertiary IBD centre. Methods: A keyword search of the colonoscopy reporting system was performed. IBD patients with colonic disease that underwent colonoscopy for surveillance between 1 February 2015 and 1 February 2018 were included. Clinical, endoscopic and histopathological outcomes were extracted for the analysis. Results: Of 2114 patients identified, 276 eligible colonoscopies in 126 patients were analysed. The median age at colonoscopy was 51 years (interquartile range: 42-58 years). 71/126 (56%) of colonoscopies were performed in male patients, with 57/126 (45%) having ulcerative colitis, 68/126 (54%) Crohn's colitis and 1/126 (0.79%) IBD-unspecified. The prevalence for any neoplasia was 75/276 (27%). The prevalence for all serrated lesions was 43/276 (16%). Increased age was a risk factor for finding a neoplastic lesion on both univariate and multivariate analyses. Chromoendoscopy was associated with twice the odds of finding a neoplastic lesion (odds ratio: 1.99, 95% confidence interval: 1.13-3.51, p = 0.02), on multivariate analysis. No factor was associated with an increased risk of finding a serrated lesion. Conclusion: Significant neoplastic lesions and serrated lesions were detected in 27% and 16% of colonoscopies performed in IBD patients, respectively, with the highest yield in older patients. Chromoendoscopy significantly increased neoplasia yield compared to HDWLE and still has a robust utility in this pragmatic real-world study.

Higher Anti-tumor Necrosis Factor-α Levels Correlate With Improved Radiologic Outcomes in Crohn's Perianal Fistulas.

BACKGROUND & AIMS: Higher anti-tumor necrosis factor-α (TNF) drug levels are associated with improved clinical healing of Crohn's perianal fistulas. It is unclear whether this leads to improved healing on radiologic assessment. We aimed to evaluate the association between anti-TNF drug levels and radiologic outcomes in perianal fistulising Crohn's disease. METHODS: A cross-sectional retrospective multicenter study was undertaken. Patients with perianal fistulising Crohn's disease on maintenance infliximab or adalimumab, with drug levels within 6 months of perianal magnetic resonance imaging were included. Patients receiving dose changes or fistula surgery between drug level and imaging were excluded. Radiologic disease activity was scored using the Van Assche Index, with an inflammatory subscore calculated using indices: T2-weighted imaging hyperintensity, collections >3 mm diameter, rectal wall involvement. Primary endpoint was radiologic healing (inflammatory subscore ≤6). Secondary endpoint was radiologic remission (inflammatory subscore = 0). RESULTS: Of 193 patients (infliximab, n = 117; adalimumab, n = 76), patients with radiologic healing had higher median drug levels compared with those with active disease (infliximab 6.0 vs 3.9 µg/mL; adalimumab 9.1 vs 6.2 µg/mL; both P < .05). Patients with radiologic remission also had higher median drug levels compared with those with active disease (infliximab 7.4 vs 3.9 µg/mL; P < .05; adalimumab 9.8 vs 6.2 µg/mL; P = .07). There was a significant incremental reduction in median inflammatory subscores with higher anti-TNF drug level tertiles. CONCLUSIONS: Higher anti-TNF drug levels were associated with improved radiologic outcomes on magnetic resonance imaging in perianal fistulising Crohn's disease, with an incremental improvement at higher drug level tertiles for both infliximab and adalimumab.

Switching Australian patients with moderate to severe inflammatory bowel disease from originator to biosimilar infliximab: a multicentre, parallel cohort study.

OBJECTIVE: To examine whether non-medical switching of patients with inflammatory bowel disease (IBD) from originator infliximab to a biosimilar (CT-P13, Inflectra) is safe and clinically non-inferior to continued treatment with originator infliximab. DESIGN: Prospective, open label, multicentre, parallel cohort, non-inferiority study in seven Australian hospitals over 48 weeks, May 2017 - October 2019. PARTICIPANTS: Adults (18 years or older) with IBD receiving maintenance originator infliximab (Remicade) who had been in steroid-free clinical remission for at least 12 weeks. INTERVENTION: Managed program for switching patients in four hospitals from originator to biosimilar infliximab (CT-P13); patients in three other hospitals continued to receive originator infliximab (control). MAIN OUTCOME MEASURES: Clinical disease worsening requiring infliximab dose escalation or change in therapy. RESULTS: The switch group included 204 patients, the control group 141 patients with IBD. Ten patients in the control group (7%) and 16 patients switched to CT-P13 (8%) experienced clinical deterioration; the adjusted risk difference (control v switch group) was -1.1 percentage points (95% CI, -6.1 to 8.2 percentage points), within our pre-specified non-inferiority margin of 15 percentage points. Serious adverse events leading to infliximab discontinuation were infrequent in both the switch (six, 3%) and control (six, 4%) groups. CONCLUSION: Switching patients with IBD from originator to biosimilar infliximab is safe and non-inferior to continuing treatment with originator infliximab. Moreover, the introduction of biosimilar infliximab, by increasing market competition, has resulted in substantial cost savings for the Pharmaceutical Benefits Scheme.

Ileocolonic End-to-End Anastomoses in Crohn's Disease Increase the Risk of Early Post-operative Endoscopic Recurrence in Those Undergoing an Emergency Resection.

BACKGROUND AND AIM: Several risk factors affecting post-operative recurrence in Crohn's disease patients have been studied, and of these, the role of the anastomosis remains contentious. We aimed to compare the risk of developing early post-operative endoscopic recurrence (EPER), in resections that had an end-to-end anastomosis (ETEA) to a side-to-side anastomosis (STSA). METHODS: All Crohn's disease patients that underwent an ileocolic or small bowel resection between January 2012 and June 2017 at two tertiary IBD centres were reviewed retrospectively. Included patients had a minimum of 12-month clinical follow-up and a colonoscopy within 12 months of the resection or stoma reversal. Univariate and multivariate binary logistic regression analyses determined the independent risk factors for early post-operative endoscopic recurrence, defined as a Rutgeerts score of ≥ i2b. RESULTS: Ninety-two resections associated with an ETEA or a STSA were included for analysis. The ETEA was the most common anastomosis, constructed in 55 patients (59.8%). Forty-nine operations (53.3%) resulted in a ≥ i2b recurrence at the first surveillance colonoscopy. The multivariate analysis showed that there was no difference between the ETEA and STSA in determining the odds ratio (OR) for developing EPER (OR = 2.41 (0.95-6.05), P = 0.06). In those that underwent a resection emergently however, the significant determinants of EPER were as follows: having an ETEA (OR = 38.12 (2.44-595.87), P = 0.01), failing to commence a biologic and/or an immunosuppressant early (OR = 24.21 (1.69, 347.81), P = 0.02), and active smoking (OR = 7.19 (1.12-46.21), P = 0.04). CONCLUSION: The ETEA is best avoided in those undergoing an emergency resection. The early commencement of a biologic and/or an immunosuppressant and smoking cessation is imperative this high-risk group of patients.

The Effect of Adiposity on Anti-Tumor Necrosis Factor-Alpha Levels and Loss of Response in Crohn's Disease Patients.

INTRODUCTION: A high body mass index is known to adversely affect antitumor necrosis factor-alpha trough levels and secondary loss of response (SLOR) in patients with Crohn's disease. We hypothesize that high levels of adiposity negatively affect these outcomes and aimed to determine if this relationship exists. METHODS: We performed a retrospective cross-sectional study of 69 patients with Crohn's disease from two tertiary inflammatory bowel disease centers between February 1, 2015, and June 30, 2018. Primary responders to infliximab (IFX) or adalimumab (ADA) who had a trough level performed within 6 months of CT or MRI scan and at least 12 months of clinical follow-up were eligible for inclusion. Body composition as measured on CT/MRI scans were correlated with trough concentration and time SLOR. Multivariate adjustments were made for established risk factors known to affect trough levels and SLOR. RESULTS: Of 69 included patients, 44 (63.8%) and 25 (36.2%) patients received IFX and ADA, respectively. Multivariate analysis revealed that IFX trough concentrations were inversely correlated with visceral fat area (-0.02 [-0.04, -0.003], P = 0.03), visceral fat index (-0.07 [-0.12, -0.01], P = 0.02) and visceral fat: skeletal muscle area ratio (-3.81 [-7.13, -0.50], P = 0.03), but not body mass index (-0.23 [-0.52, 0.06], P = 0.11). No predictive factors were found for ADA. Increased total adipose area was associated with an increased risk of SLOR in ADA-treated patients, but not IFX-treated patients (hazard ratio = 1.01 [1.002, 1.016], P = 0.011). DISCUSSION: Visceral adiposity is an important predictor of IFX trough levels, and high total adiposity predicts for SLOR to ADA.

Vedolizumab for ulcerative colitis: Real world outcomes from a multicenter observational cohort of Australia and Oxford.

BACKGROUND: Vedolizumab (VDZ), a humanised monoclonal antibody that selectively inhibits alpha4-beta7 integrins is approved for use in adult moderate to severe ulcerative colitis (UC) patients. AIM: To assess the efficacy and safety of VDZ in the real-world management of UC in a large multicenter cohort involving two countries and to identify predictors of achieving remission. METHODS: A retrospective review of Australian and Oxford, United Kingdom data for UC patients. Clinical response at 3 mo, endoscopic remission at 6 mo and clinical remission at 3, 6 and 12 mo were assessed. Cox regression models and Kaplan Meier curves were performed to assess the time to remission, time to failure and the covariates influencing them. Safety outcomes were recorded. RESULTS: Three hundred and three UC patients from 14 centres in Australia and United Kingdom, [60% n = 182, anti-TNF naïve] were included. The clinical response was 79% at 3 mo with more Australian patients achieving clinical response compared to Oxford (83% vs 70% P = 0.01). Clinical remission for all patients was 56%, 62% and 60% at 3, 6 and 12 mo respectively. Anti-TNF naive patients were more likely to achieve remission than exposed patients at all the time points (3 mo 66% vs 40% P < 0.001, 6 mo 73% vs 46% P < 0.001, 12 mo 66% vs 51% P = 0.03). More Australian patients achieved endoscopic remission at 6 mo compared to Oxford (69% vs 43% P = 0.01). On multi-variate analysis, anti-TNF naïve patients were 1.8 (95%CI: 1.3-2.3) times more likely to achieve remission than anti-TNF exposed (P < 0.001). 32 patients (11%) had colectomy by 12 mo. CONCLUSION: VDZ was safe and effective with 60% of UC patients achieving clinical remission at 12 mo and prior anti-TNF exposure influenced this outcome.

Entyvio lengthen dose-interval study: lengthening vedolizumab dose interval and the risk of clinical relapse in inflammatory bowel disease.

BACKGROUND: Vedolizumab (VDZ), an α4ß7 anti-integrin antibody, is efficacious in the induction and maintenance of remission in ulcerative colitis (UC) and Crohn's disease (CD). In the GEMINI long-term safety study, enrolled patients received 4-weekly VDZ. Upon completion, patients were switched to 8-weekly VDZ in Australia. The clinical success rate of treatment de-escalation for patients in remission on VDZ has not been described previously. AIM: To determine the proportion of patients who relapsed after switching from 4 to 8-weekly VDZ, the mean time to relapse, and the recapture rate when switching back to 8-weekly dosing. MATERIALS AND METHODS: This was a retrospective, observational, multicenter study of patients previously recruited into GEMINI long-term safety in Australia. Data on the demographics and biochemical findings were collected. RESULTS: There were 34 patients [23 men, mean age 49.1 (±13.1) years] and their mean disease duration was 17.6 (±8.5) years. The mean 4-weekly VDZ infusion duration was 286.5 (±48.8) weeks. A total of five (15%) patients relapsed on dose-interval increase (4/17 UC, 1/17 CD) at a median duration from dose interval lengthening to flare of 14 weeks (interquartile range=6-25). Eighty percent (4/5) of patients re-entered remission following dose-interval decrease back to 4-weekly. No clinical predictors of relapse could be determined because of the small cohort size. CONCLUSION: The risk of patients relapsing when switching from 4 to 8-weekly VDZ ∼15% and is similar between CD and UC. Dose-interval decrease recaptures 80% of patients who relapsed. Therapeutic drug monitoring of VDZ may be of clinical relevance.

Oral tacrolimus for the treatment of refractory inflammatory bowel disease in the biologic era.

BACKGROUND: Patients with inflammatory bowel disease who are refractory to standard therapies frequently require surgery. The long-term efficacy of tacrolimus in patients who fail standard immunosuppressive and antitumor necrosis factor α therapy is unknown. METHODS: Thirty-five patients (11 Crohn's disease and 24 ulcerative colitis) with medication-resistant disease were treated with oral tacrolimus and reviewed retrospectively. Patients were commenced on tacrolimus 0.1 mg/kg/day, with a trough level targeted between 8 and 12 ng/mL. Clinical response or remission at 30 days, 90 days, and 1 year was assessed. The overall risk of requiring surgery and predictive factors were also assessed. RESULTS: All patients had failed a thiopurine, 5 (14%) had also failed methotrexate, while 90% had a primary or secondary nonresponse, or an incomplete response, to an antitumor necrosis factor α agent. The proportions that achieved a clinical response at 30 days, 90 days, and 1 year was 65.7%, 60%, and 31.4%, respectively, whereas the corresponding proportions in remission were 40%, 37.1%, and 22.9%. The cumulative risk of requiring surgery was 40.4% at 1 year and 59.3% at 2 years with a median time to surgery of 22 months (range, 0.5-84 months). Patients who were steroid refractory, or dependent, before starting tacrolimus were more likely to have surgery (P = 0.006), whereas patients who were able to achieve or maintain a clinical response with tacrolimus by 90 days were less likely (P = 0.004). CONCLUSIONS: Tacrolimus is able to induce a clinical response in a third and remission in a fifth of medically refractory patients with inflammatory bowel disease at 1 year. A 90-day therapeutic trial is worthwhile in difficult to treat patients.

IgG4-related sclerosing disease of the small bowel presenting as necrotizing mesenteric arteritis and a solitary jejunal ulcer.

Since first described in the mid 1990s, there has been burgeoning literature on IgG4-related sclerosing disease. The number of sites that may be involved is ever increasing, with the pancreas, salivary glands, and lymph nodes being the most commonly affected organs. There are no well-documented cases arising in the gastrointestinal tract. In this report, we present the first case to our knowledge of IgG4-related sclerosing disease involving the small bowel with a distinctly unusual clinicopathologic presentation. A previously well 46-year-old woman presented with a 2-year history of intermittent abdominal pain with recent worsening due to small bowel obstruction. Following imaging, which showed jejunitis with surrounding mesenteric inflammatory changes, she proceeded to a segmental small bowel resection. The resected jejunum revealed an isolated, stenosing chronic ulcer associated with a necrotizing mesenteric arteritis. A transmural inflammatory infiltrate rich in IgG4 plasma cells was seen in the wall of the bowel and mesenteric artery. Abundant IgG4 interfollicular plasma cells were also identified in a mesenteric lymph node. The serum IgG4 level was elevated at >800 mg/dL (reference range 8 to 140 mg/dL). Although phlebitis is an almost constant feature of this disease, arteritis is not described other than in the lung and aorta. In this report, we also discuss the diagnostic pitfalls and the differential diagnoses that should be considered when this condition arises in the gastrointestinal tract.

Acute graft-versus-host disease after liver transplant: novel use of etanercept and the role of tumor necrosis factor alpha inhibitors.

Acute graft-versus-host disease following orthotopic liver transplantation is a rare but feared complication arising in 1% to 2% of cases with a dismal prognosis. It most often presents as fever, rash, and diarrhea with or without pancytopenia. Patients die from complications of marrow failure such as sepsis or bleeding. Because of its low incidence, there is no clear treatment protocol for this complication. Both increasing and withdrawing immunosuppression have been attempted with variable success. Although anti-tumor necrosis factor alpha therapy has been widely used for the treatment of steroid-resistant acute graft-versus-host disease in the hematopoietic stem cell transplant setting, there previously have been no reported cases of its use in liver transplantation. The aim of this report is to review a case of acute graft-versus-host disease and the use of etanercept to manage this complication. Etanercept has never previously been used in liver transplantation complicated by acute graft-versus-host disease. In the hematology literature, the success of its use is offset by significant rates of serious infectious (especially fungal) complications. However, preliminary results are encouraging and offer insight into its use as a potentially viable therapeutic option. We report the first successful use of etanercept in liver transplantation-associated graft-versus-host disease, albeit complicated by invasive aspergillosis, and recommend concurrent antifungal prophylaxis when the drug is used in this setting.