Publications by authors named "Graham Radford-Smith"

90 Publications

Prospective randomised controlled trial of adults with perianal fistulising Crohn's disease and optimised therapeutic infliximab levels: PROACTIVE trial study protocol.

BMJ Open 2021 Jul 1;11(7):e043921. Epub 2021 Jul 1.

South Western Sydney Clinical School, University of New South Wales, Sydney, New South Wales, Australia

Introduction: Perianal fistulising Crohn's disease (pfCD) can be somewhat treatment refractory. Higher infliximab trough levels (TLIs) may improve fistula healing rates; however, it remains unclear whether escalating infliximab therapy to meet higher TLI targets using proactive, or routine, therapeutic drug monitoring (TDM) improves outcomes. This randomised controlled trial aimed to assess whether infliximab therapy targeting higher TLIs guided by proactive TDM improves outcomes compared with standard therapy.

Methods And Analysis: Patients with active pfCD will be randomised 1:1 to either the proactive TDM arm or standard dosing arm and followed up for 54 weeks. Patients in the proactive TDM arm will have infliximab dosing optimised to target higher TLIs. The targets will be TLI ≥ 25 µg/mL at week 2, ≥ 20 µg/mL at week 6 and ≥ 10 µg/mL during maintenance therapy. The primary objective will be fistula healing at week 32. Secondary objectives will include fistula healing, fistula closure, radiological fistula healing, patient-reported outcomes and economic costs up to 54 weeks. Patients in the standard dosing arm will receive conventional infliximab dosing not guided by TLIs (5 mg/kg at weeks 0, 2 and 6, and 5 mg/kg 8 weekly thereafter). Patients aged 18-80 years with pfCD with single or multiple externally draining complex perianal fistulas who are relatively naïve to infliximab treatment will be included. Patients with diverting ileostomies or colostomies and pregnant or breast feeding will be excluded. Fifty-eight patients per arm will be required to detect a 25% difference in the primary outcome measure, with 138 patients needed to account for an estimated 6.1% primary non-response rate and 10% dropout rate.

Ethics And Dissemination: Results will be presented in peer-reviewed journals and international conferences. Ethics approval has been granted by the South Western Sydney Local Health District Human Research Ethics Committee in Australia.

Trial Registration Number: Australian New Zealand Clinical Trials Registry (ACTRN12621000023853); Pre-results.
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http://dx.doi.org/10.1136/bmjopen-2020-043921DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8252869PMC
July 2021

Head-to-head trials in inflammatory bowel disease.

J Gastroenterol Hepatol 2021 Apr;36 Suppl 1:18-19

Integrated Gut Health Pty Ltd, QIMR Berghofer MRI, Department of Gastroenterology and Hepatology, Royal Brisbane and Women's Hospital, University of Queensland, Brisbane, Qld, Australia.

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http://dx.doi.org/10.1111/jgh.15452DOI Listing
April 2021

Randomized, Placebo Controlled Trial of Experimental Hookworm Infection for Improving Gluten Tolerance in Celiac Disease.

Clin Transl Gastroenterol 2020 12;11(12):e00274

Center for Molecular Therapeutics, Australian Institute of Tropical Health and Medicine, James Cook University, Cairns, Australia.

Introduction: Celiac disease is an autoimmune disorder where intestinal immunopathology arises after gluten consumption. Previous studies suggested that hookworm infection restores gluten tolerance; however, these studies were small (n = 12) and not placebo controlled.

Methods: We undertook a randomized, placebo-controlled trial of hookworm infection in 54 people with celiac disease. The 94-week study involved treatment with either 20 or 40 Necator americanus third-stage larvae (L3-20 or L3-40) or placebo, followed by escalating gluten consumption (50 mg/d for 12 weeks, 1 g intermittent twice weekly for 12 weeks, 2 g/d sustained for 6 weeks, liberal diet for 1 year).

Results: Successful study completion rates at week 42 (primary outcome) were similar in each group (placebo: 57%, L3-20: 37%, and L3-40: 44%; P = 0.61), however gluten-related adverse events were significantly reduced in hookworm-treated participants: Median (range) adverse events/participant were as follows: placebo, 4 (1-9); L3-20, 1 (0-9); and L3-40, 0 (0-3) (P = 0.019). Duodenal villous height:crypt depth deteriorated similarly compared with their enrolment values in each group (mean change [95% confidence interval]: placebo, -0.6 [-1.3 to 0.2]; L3-20, -0.5 [-0.8 to 0.2]; and L3-40, -1.1 [-1.8 to 0.4]; P = 0.12). A retrospective analysis revealed that 9 of the 40 L3-treated participants failed to establish hookworm infections. Although week 42 completion rates were similar in hookworm-positive vs hookworm-negative participants (48% vs 44%, P = 0.43), quality of life symptom scores were lower in hookworm-positive participants after intermittent gluten challenge (mean [95% confidence interval]: 38.9 [33.9-44] vs 45.9 [39.2-52.6]).

Discussion: Hookworm infection does not restore tolerance to sustained moderate consumption of gluten (2 g/d) but was associated with improved symptom scores after intermittent consumption of lower, intermittent gluten doses.
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http://dx.doi.org/10.14309/ctg.0000000000000274DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7678792PMC
December 2020

Letter: hidden costs in healthcare use for incident and prevalent Crohn's disease and ulcerative colitis.

Aliment Pharmacol Ther 2021 01;53(2):368-369

Department of Immunology, QIMR Berghofer Medical Research Institute, Herston, QLD, Australia.

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http://dx.doi.org/10.1111/apt.16169DOI Listing
January 2021

Intestinal Ultrasound as First-Line Investigation in Low Risk Gastrointestinal Symptoms: A New Model of Care.

Intern Med J 2020 Nov 16. Epub 2020 Nov 16.

Royal Brisbane Womens Hospital.

Background: Functional Gut Disorder's (FGD) are common. Diagnosis is symptom based, although symptoms may be indistinguishable from Inflammatory Bowel Disease. As a result of this investigations are common, diagnostic yield is low. A streamlined novel model of care may reduce costly investigations. This study aims to compare a new model of care for patients with low risk gastrointestinal symptoms to a matched historical cohort.

Methods: Data were prospectively collected over 12 months. General Practitioner referrals for low risk abdominal symptoms were triaged to a new multidisciplinary clinic structure utilising Intestinal Ultrasound (IUS). Outcomes were compared to the historical model in the preceding 12 months. Duration of care (time from referral to discharge), number of contact episodes, and investigations ordered were reviewed.

Results: 37 patients meeting strict inclusion criteria completed their care. Compared with the historical cohort, colonoscopies reduced from 0.7 to 0.05 per patient (p<0.0001). Gastroenterology consults reduced from 1.5 to 1.2 (p=0.303) and dietitian review increased from 0.8 to 1.5 (p<0.0001). Total contact episodes reduced from 3.2 to 1.8 (p<0.0001). Duration of care reduced from a median of 252 days to 130 days (IQRs 287 and 69 respectively, p<0.0001). Time from first consultation to discharge reduced from 125 to 42 days (IQRs 188 and 63, p<0.0001) CONCLUSION: This multidisciplinary approach to care of low risk abdominal symptoms significantly reduced contact episodes, time in care and invasive investigations. It decreased costly gastroenterology consultation and increased allied health exposure. It demonstrates improved health service outcomes. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1111/imj.15133DOI Listing
November 2020

Crohn's Colitis Care (CCCare): bespoke cloud-based clinical management software for inflammatory bowel disease.

Scand J Gastroenterol 2020 Dec 8;55(12):1419-1426. Epub 2020 Nov 8.

Department of Gastroenterology, Royal Adelaide Hospital & University of Adelaide, Adelaide, Australia.

Background: Adherence to evidence-based management is variable in inflammatory bowel disease (IBD), which leads to worse patient outcomes and higher healthcare utilization. Solutions include electronic systems to enhance care, but these have often been limited by lack of clinician design input, poor usability, and low perceived value. A cloud-based IBD-specific clinical management software - 'Crohn's Colitis Care' (CCCare) was developed by Australia and New Zealand Inflammatory Bowel Disease Consortium clinicians and software developers to improve this.

Methods: CCCare captures patient-reported disease activity and medical assessment, medication monitoring, cancer screening, preventative health, and facilitates communication with the IBD team and referring doctor. De-identified longitudinal data are stored separately in a clinical quality registry for research. CCCare was tested for feasibility and usability in routine clinical settings at two large Australian hospitals. Users' experience was evaluated with System Usability Scale (SUS). Value to clinicians and patients was assessed by qualitative feedback. Security was assessed by penetration testing.

Results: Users ( = 13; doctors, nurses, patients) reported good usability and learnability (mean SUS score 75 (range 50-95), sub-scores were 77 (50-94) and 68 (38-100), respectively). Patients reported better communication with clinical team and greater ability to track disease. Clinicians highlighted structured management plans, medication adherence, and centralised data repository as positive features. Penetration testing was passed successfully.

Conclusions: Initial evaluation demonstrates CCCare is usable, secure, and valued in clinical use. It is designed to measure outcomes of clinical care, including efficacy, quality, cost, and complications for individuals, and to audit these at hospital and national level.
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http://dx.doi.org/10.1080/00365521.2020.1839960DOI Listing
December 2020

Telehealth in inflammatory bowel disease.

Intern Med J 2020 Sep 25. Epub 2020 Sep 25.

Department of Gastroenterology & Hepatology, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia.

Background: Inflammatory bowel disease (IBD) patients living in regional or remote Queensland are often disadvantaged by limited access to IBD specialist care. Telehealth clinics could potentially address this disparity and improve patient outcomes.

Aim: We report the impact of the Royal Brisbane and Women's Hospital (RBWH) IBD telehealth clinics from March 2011 to December 2017 including patient satisfaction and healthcare activity.

Methods: Patient satisfaction surveys were collected prospectively between March 2011 and March 2012. Healthcare activity was assessed through occasions of service (OOS), number of enrolled patients on biologics and IBD related admissions to RBWH.

Results: Overall, 3764 OOS were completed including 576 new patient and 3188 follow up visits. Mean age at first telehealth visit was 44 years (range:16-87). The IBD telehealth clinics were well accepted with 99% of the first 153 patients surveyed choosing to continue with telehealth and 94% rated the telehealth experience as very good or excellent. The net number of patients under active review increased from 125 patients in 2011 to 345 patients in 2017. Enrolled patients on biologics also increased from 9 patients in 2011 to 63 patients in 2017. There was an initial dip in annual IBD related admissions to RBWH in 2011 but these have progressively increased over time although the average length of inpatient stay annually has remained stable.

Conclusion: The RBWH IBD telehealth clinics have shown that telemedicine is well received and can be used successfully to deliver IBD specialist care to patients living in regional or remote areas. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1111/imj.15068DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7537200PMC
September 2020

Ileal pouch-anal anastomosis for ulcerative colitis: an Australian institution's experience.

Ann Coloproctol 2020 Sep 18. Epub 2020 Sep 18.

Department of Gastroenterology & Hepatology, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia.

Aim: We report outcomes and evaluate patient factors and the impact of surgical evolution on outcomes in consecutive ulcerative colitis patients who had restorative proctocolectomy with ileal pouch-anal anastomosis (IPAA) at an Australian institution over 26 years.

Methods: Data including clinical characteristics, medical therapy pre-surgery and surgical outcomes were collected. We divided eligible patients into three period arms (period 1: 1990-1999; period 2: 2000-2009; period 3: 2010-2016). Outcomes of interest were IPAA leak and pouch failure.

Results: Two hundred and twelve patients were included. Median follow up was 50 months (interquartile range [IQR]: 17-120). Rates of early and late complications were 35% and 52% respectively. Early complications included wound infection (9.4%), pelvic sepsis (8%) and small bowel obstruction (6.6%) while late complications included small bowel obstruction (19%), anal stenosis (17%) and pouch fistula (13%). Overall, IPAA leak rate was 6.1% and pouch failure rate was 4.8%. Eighty three patients (42%) experienced pouchitis. Over time, we observed an increase in patient exposure to thiopurine (p=0.0025), cyclosporin (p=0.0002) and anti-tumour necrosis factor (p<0.00001) coupled with a shift to laparoscopic technique (p<0.00001), stapled IPAA (p<0.00001), J pouch configuration (p<0.00001), a modified two-stage procedure (p=0.00012) and a decline in defunctioning ileostomy rate at time of IPAA (p=0.00002). Apart from pouchitis, there was no significant difference in surgical and chronic inflammatory pouch outcomes with time.

Conclusion: Despite greater patient exposure to immunomodulatory and biologic therapy pre surgery coupled with a significant change in surgical techniques, surgical and chronic inflammatory pouch outcome rates have remained stable.
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http://dx.doi.org/10.3393/ac.2020.08.26DOI Listing
September 2020

Editorial: obesity management and IBD-weight loss reduces IBD risk.

Aliment Pharmacol Ther 2020 08;52(4):731-732

QIMR Berghofer Medical Research Institute, Brisbane, Qld, Australia.

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http://dx.doi.org/10.1111/apt.15827DOI Listing
August 2020

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

World J Gastroenterol 2020 Aug;26(30):4428-4441

Centre for Inflammatory Bowel Diseases, St John of God Hospital, Subiaco 6008, Western Australia, Australia.

Background: Vedolizumab (VDZ), a humanised monoclonal antibody that selectively inhibits 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% = 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% 70% = 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% 40% < 0.001, 6 mo 73% 46% < 0.001, 12 mo 66% 51% = 0.03). More Australian patients achieved endoscopic remission at 6 mo compared to Oxford (69% 43% = 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 ( < 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.
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http://dx.doi.org/10.3748/wjg.v26.i30.4428DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7438197PMC
August 2020

Genome-wide association meta-analyses combining multiple risk phenotypes provide insights into the genetic architecture of cutaneous melanoma susceptibility.

Nat Genet 2020 05 27;52(5):494-504. Epub 2020 Apr 27.

Department of Dermatology, Instituto Valenciano de Oncología, Valencia, Spain.

Most genetic susceptibility to cutaneous melanoma remains to be discovered. Meta-analysis genome-wide association study (GWAS) of 36,760 cases of melanoma (67% newly genotyped) and 375,188 controls identified 54 significant (P < 5 × 10) loci with 68 independent single nucleotide polymorphisms. Analysis of risk estimates across geographical regions and host factors suggests the acral melanoma subtype is uniquely unrelated to pigmentation. Combining this meta-analysis with GWAS of nevus count and hair color, and transcriptome association approaches, uncovered 31 potential secondary loci for a total of 85 cutaneous melanoma susceptibility loci. These findings provide insights into cutaneous melanoma genetic architecture, reinforcing the importance of nevogenesis, pigmentation and telomere maintenance, together with identifying potential new pathways for cutaneous melanoma pathogenesis.
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http://dx.doi.org/10.1038/s41588-020-0611-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7255059PMC
May 2020

Multitrait analysis of glaucoma identifies new risk loci and enables polygenic prediction of disease susceptibility and progression.

Nat Genet 2020 02 20;52(2):160-166. Epub 2020 Jan 20.

Eye Department, Greenlane Clinical Centre, Auckland District Health Board, Auckland, New Zealand.

Glaucoma, a disease characterized by progressive optic nerve degeneration, can be prevented through timely diagnosis and treatment. We characterize optic nerve photographs of 67,040 UK Biobank participants and use a multitrait genetic model to identify risk loci for glaucoma. A glaucoma polygenic risk score (PRS) enables effective risk stratification in unselected glaucoma cases and modifies penetrance of the MYOC variant encoding p.Gln368Ter, the most common glaucoma-associated myocilin variant. In the unselected glaucoma population, individuals in the top PRS decile reach an absolute risk for glaucoma 10 years earlier than the bottom decile and are at 15-fold increased risk of developing advanced glaucoma (top 10% versus remaining 90%, odds ratio = 4.20). The PRS predicts glaucoma progression in prospectively monitored, early manifest glaucoma cases (P = 0.004) and surgical intervention in advanced disease (P = 3.6 × 10). This glaucoma PRS will facilitate the development of a personalized approach for earlier treatment of high-risk individuals, with less intensive monitoring and treatment being possible for lower-risk groups.
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http://dx.doi.org/10.1038/s41588-019-0556-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8056672PMC
February 2020

Co-existence of Network Architectures Supporting the Human Gut Microbiome.

iScience 2019 Dec 21;22:380-391. Epub 2019 Nov 21.

Clinical Brain Networks Group, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia; School of Biomedical Sciences, University of Queensland, Brisbane, QLD 4006, Australia.

Microbial organisms of the human gut microbiome do not exist in isolation but form complex and diverse interactions to maintain health and reduce risk of disease development. The organization of the gut microbiome is assumed to be a singular assortative network, where interactions between operational taxonomic units (OTUs) can readily be clustered into segregated and distinct communities. Here, we leverage recent methodological advances in network modeling to assess whether communities in the human microbiome exhibit a single network structure or whether co-existing mesoscale network architectures are present. We found evidence for core-periphery structures in the microbiome, supported by strong, assortative community interactions. This complex architecture, coupled with previously reported functional roles of OTUs, provides a nuanced understanding of how the microbiome simultaneously promotes high microbial diversity and maintains functional redundancy.
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http://dx.doi.org/10.1016/j.isci.2019.11.032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6911941PMC
December 2019

A validated risk stratification tool for detecting high-risk small bowel Crohn's disease.

Aliment Pharmacol Ther 2020 01 26;51(2):281-290. Epub 2019 Nov 26.

QIMR Berghofer Medical Research Institute, Brisbane, Qld, Australia.

Background: Delays in Crohn's disease (CD) diagnosis are positively associated with ileal location and an increased risk of complications.

Aim: To develop a simple risk assessment tool to enable primary care physicians to recognise potential ileal CD earlier, shortening the delay to specialist investigation METHODS: Three cohorts were acquired for this study. Cohort 1 included 61 patients retrospectively identified with ileal CD between 2000 and 2010 and 78 matched controls drawn from a cohort referred for investigation of abdominal symptoms. Cohort 2 included 42 individuals diagnosed with ileal CD and 57 controls identified prospectively. Cohort 3 included an additional 84 individuals with ileal CD and 495 without CD referred for colonoscopy. Clinical symptoms and serological biomarkers were acquired and used to develop a risk prediction algorithm. The algorithm was trained independently on each of the three cohorts and tested on the latter two cohorts.

Results: Altered bowel habit with abdominal pain combined with derangements in white cell count (WCC), albumin and platelet counts were important features in predicting ileal CD (AUC = 0.92, 95% CI = 0.89-0.92). This was validated in cohorts 2 (AUC = 0.96, 95% CI = 0.95-0.98) and 3 (AUC = 0.94, 95% CI = 0.92-0.96). C-reactive protein was independently associated with ileal CD but non-signficant in a multivariate model.

Conclusion: A web-based risk stratification tool for ileal CD has been developed from objective and symptom-based criteria. This tool enables primary care physicians to more confidently request urgent specialist assessment for patients identified as at high risk for ileal CD.
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http://dx.doi.org/10.1111/apt.15550DOI Listing
January 2020

Airway Mucus Hyperconcentration in Non-Cystic Fibrosis Bronchiectasis.

Am J Respir Crit Care Med 2020 03;201(6):661-670

Inflammatory Disease Biology and Therapeutics Group, Mater Research Institute, Translational Research Institute, and.

Non-cystic fibrosis bronchiectasis is characterized by airway mucus accumulation and sputum production, but the role of mucus concentration in the pathogenesis of these abnormalities has not been characterized. This study was designed to: ) measure mucus concentration and biophysical properties of bronchiectasis mucus; ) identify the secreted mucins contained in bronchiectasis mucus; ) relate mucus properties to airway epithelial mucin RNA/protein expression; and ) explore relationships between mucus hyperconcentration and disease severity. Sputum samples were collected from subjects with bronchiectasis, with and without chronic erythromycin administration, and healthy control subjects. Sputum percent solid concentrations, total and individual mucin concentrations, osmotic pressures, rheological properties, and inflammatory mediators were measured. Intracellular mucins were measured in endobronchial biopsies by immunohistochemistry and gene expression. MUC5B (mucin 5B) polymorphisms were identified by quantitative PCR. In a replication bronchiectasis cohort, spontaneously expectorated and hypertonic saline-induced sputa were collected, and mucus/mucin concentrations were measured. Bronchiectasis sputum exhibited increased percent solids, total and individual (MUC5B and MUC5AC) mucin concentrations, osmotic pressure, and elastic and viscous moduli compared with healthy sputum. Within subjects with bronchiectasis, sputum percent solids correlated inversely with FEV and positively with bronchiectasis extent, as measured by high-resolution computed tomography, and inflammatory mediators. No difference was detected in rs35705950 SNP allele frequency between bronchiectasis and healthy individuals. Hypertonic saline inhalation acutely reduced non-cystic fibrosis bronchiectasis mucus concentration by 5%. Hyperconcentrated airway mucus is characteristic of subjects with bronchiectasis, likely contributes to disease pathophysiology, and may be a target for pharmacotherapy.
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http://dx.doi.org/10.1164/rccm.201906-1219OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7068838PMC
March 2020

Short-term colectomy is avoided in over half of regional patients failing medical therapy for acute severe ulcerative colitis with co-ordinated transfer and tertiary care.

Intern Med J 2020 07;50(7):823-829

Department of Gastroenterology and Hepatology, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia.

Background And Aims: Many patients presenting with an acute severe ulcerative colitis to a regional hospital are transferred to a metropolitan hospital for specialised care. This study aimed to evaluate the outcomes and characteristics of these patients.

Method: A retrospective observational cohort study was conducted to examine the 30-day colectomy rate using prospectively collected data on 69 consecutive index cases of acute severe ulcerative colitis transferred from regional hospitals to our metropolitan hospital meeting Truelove and Witts criteria. Those that avoided colectomy were followed out to 1 year to examine outcomes.

Results: The 30-day colectomy rate was 46.4% (32/69) in regional transfer patients. Rescue therapy was administered to 65% (45/69) of patients after transfer to our metropolitan hospital. Colectomy was avoided in 55% of these patients at 30 days. Colectomy free status was maintained in 78% (29/39) of these patients. Mortality was 0% at 30 days and 1 year.

Conclusion: Over 50% of the patients failing therapy in a regional centre and requiring transfer avoided short term colectomy with co-ordinated referral for rescue therapy in a tertiary metropolitan inflammatory bowel disease unit. These patients would have ultimately required colectomy in their regional hospital without intervention.
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http://dx.doi.org/10.1111/imj.14649DOI Listing
July 2020

Level of UV Exposure, Skin Type, and Age Are More Important than Thiopurine Use for Keratinocyte Carcinoma Development in IBD Patients.

Dig Dis Sci 2020 04 6;65(4):1172-1179. Epub 2019 Sep 6.

Centre of Inflammatory Bowel Diseases, St John of God Hospital, Subiaco, WA, Australia.

Background: Retrospective studies observe an increased risk of keratinocyte carcinomas (KCs) in patients with inflammatory bowel disease (IBD) on thiopurine (TP) medication. The role of traditional risk factors such as skin type and sun protection behavior has not been studied in this population. This study aimed to examine traditional KC risk factors and thiopurine use on skin cancer development in an IBD cohort.

Methods: Consecutive IBD patients were recruited from four specialist centers in Australia and New Zealand, each with varying UV exposure indices. Data pertaining to race, skin color, freckling and sun protection behavior, dose of TP therapy, and skin cancer development were elicited through a self-reported questionnaire.

Results: A total of 691 IBD patients were included with 62 reporting KC development. Thiopurine usage was similar among patients who developed skin cancer compared with those who did not (92% vs. 89%, p = 0.3). There was no statistically significant association between KC development and TP dose or 6-thioguanine nucleotide levels. In multivariate modeling, four factors were independently and significantly associated with KC: age over 61 years old versus less than 30 years old (OR 6.76; 95% CI 2.38-19.18), residing in Brisbane versus Christchurch (OR 3.3; 95% CI 1.6-6.8), never staying in the shade versus staying in the shade ≥ 50% of the time (OR 3.8; 95% CI 1.4-10.5), and having a skin type that never tanned versus other skin types (OR 6.9; 95% CI 2.9-16.0).

Conclusion: Skin type, age, and sun protection behavior are more important risk factors for KC development than thiopurine medication use in this IBD population.
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http://dx.doi.org/10.1007/s10620-019-05818-wDOI Listing
April 2020

Crohn's disease is facilitated by a disturbance of programmed death-1 ligand 2 on blood dendritic cells.

Clin Transl Immunology 2019 25;8(7):e01071. Epub 2019 Jul 25.

Molecular Immunology Laboratory QIMR Berghofer Medical Research Institute Herston QLD Australia.

Objective: Crohn's disease (CD) is characterised by inflammation, predominantly associated with ilea. To investigate the basis for this inflammation in patients with CD, we examined dendritic cells (DC) which are pivotal for maintenance of immunological tolerance in the gut.

Methods: Ileal biopsies and blood DCs from CD patients and controls were examined by microscopy and flow cytometry for PD-L1 and PD-L2 expression, as PD-L1 has been implicated in colitis but the contribution of PD-L2 is less clear. studies, of blood samples from CD patients, were used to demonstrate a functional role for PD-L2 in disease pathogenesis.

Results: Quantitative microscopy of CD11c DCs in inflamed and noninflamed ilea from CD patient showed > 75% loss of these cells from the villi, lamina propria and Peyer's patches compared with non-CD controls. Given this loss of DCs from ilia of CD patients, we hypothesised DCs may have migrated to the blood as these patients can have extra-intestinal symptoms. We thus examined blood DCs from CD patients by flow cytometry and found significant increases in PD-L1 and PD-L2 expression compared with control samples. Microscopy revealed an aggregated form of PD-L2 expression, known to drive Th1 immunity, in CD patients but not in controls. functional studies with PD-L2 blockade confirmed PD-L2 contributes significantly to the secretion of pro-inflammatory cytokines known to cause disease pathogenesis.

Conclusion: Taken together, this study shows that PD-L2 can influence the progression of CD and blockade of PD-L2 may have therapeutic potential.
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http://dx.doi.org/10.1002/cti2.1071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6657371PMC
July 2019

Anti-TNF Therapy in Pregnant Women With Inflammatory Bowel Disease: Effects of Therapeutic Strategies on Disease Behavior and Birth Outcomes.

Inflamm Bowel Dis 2020 01;26(1):93-102

Department of Gastroenterology, St Vincent's Hospital, and University of Melbourne, Melbourne, Australia.

Background: Active inflammatory bowel disease (IBD) adversely affects pregnancy outcomes. Little is known about the risk of relapse after stopping anti-tumor necrosis factor (anti-TNF) treatment during pregnancy. We assessed the risk of relapse before delivery in women who discontinued anti-TNF treatment before gestational week (GW) 30, predictors of reduced infant birth weight, a marker associated with long-term adverse outcomes, and rates and satisfaction with counseling.

Methods: Pregnant women with IBD receiving anti-TNF treatment were prospectively invited to participate in an electronic questionnaire carried out in 22 hospitals in Denmark, Australia, and New Zealand from 2011 to 2015. Risk estimates were calculated, and birth weight was investigated using t tests and linear regression.

Results: Of 175 women invited, 153 (87%) responded. In women in remission, the relapse rate did not differ significantly between those who discontinued anti-TNF before GW 30 (1/46, 2%) compared with those who continued treatment (8/74, 11%; relative risk, 0.20; 95% confidence interval [CI], 0.02 to 1.56; P = 0.08). Relapse (P = 0.001) and continuation of anti-TNF therapy after GW 30 (P = 0.007) were independently associated with reduced mean birth weight by 367 g (95% CI, 145 to 589 g; relapse) and 274 g (95% CI, 77 to 471 g; anti-TNF exposure after GW 30). Of 134 (88%) women who received counseling, 116 (87%) were satisfied with the information provided.

Conclusions: To minimize fetal exposure in women in remission, discontinuation of anti-TNF before GW 30 seems safe. Relapse and continuation of anti-TNF therapy after GW 30 were each independently associated with lower birth weight, although without an increased risk for birth weight <2500 g. Most women received and were satisfied with counseling.
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http://dx.doi.org/10.1093/ibd/izz110DOI Listing
January 2020

Food avoidance in outpatients with Inflammatory Bowel Disease - Who, what and why.

Clin Nutr ESPEN 2019 06 9;31:10-16. Epub 2019 Apr 9.

The University of Queensland, Brisbane, Australia; QIMR Berghofer Medical Research Institute, Brisbane, Australia; Department of Gastroenterology and Hepatology, Royal Brisbane and Women's Hospital, Brisbane, Australia. Electronic address:

Background And Aims: Food avoidance is common with Inflammatory Bowel Disease (IBD) and adherence to dietary guidelines is poor, contributing to under and over nutrition. Reasons for food avoidance have not been previously explored in detail. This study of IBD outpatients aimed to describe food avoidance patterns and rationale behind this, and describe source and confidence with dietary advice.

Methods: A prospective cross-sectional study using structured interview, nutritional assessment and medical record review was conducted in patients with confirmed diagnosis of IBD (n = 117) attending outpatient clinics over a six-month period. Participants were interviewed on foods avoided, rationale for food avoidance and previous dietary advice (source and confidence). Means ± SD or medians (IQR), percentages and counts were used to describe participant characteristics, food avoidance, and source and confidence in dietary advice. Bivariate analysis was used to explore relationships between food avoidance and disease factors (IBD subtype; disease activity: active disease vs remission), and between confidence in dietary advice and disease activity.

Results: Almost all participants reported food avoidance (90%), with more foods avoided during active disease (5.2 ± 3.6 foods/food categories, versus remission 2.9 ± 2.5, p < 0.001). Lactose-containing foods were avoided by 40% of patients in active disease and 33% in remission. Pain/cramping, increased bowel motions and diarrhea were the most common reasons for avoiding foods/food categories during both active disease and remission. Participants were most confident in advice received from the internet (3.3 ± 1.2; dietitian: 2.8 ± 1.5) in active disease; in remission participants had greatest confidence in advice received from gastroenterologists (4.1 ± 0.8; dietitian: 3.5 ± 1.2).

Conclusion: High prevalence of avoidance of nutritious foods and low confidence in dietetic advice amongst people with IBD is of concern. Further work is needed to build trust and ensure patients are provided with evidence-based nutrition recommendations to manage their symptoms whilst optimizing nutritional quality of their diet.
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http://dx.doi.org/10.1016/j.clnesp.2019.03.018DOI Listing
June 2019

Evaluating a risk assessment tool to improve triaging of patients to colonoscopies.

Intern Med J 2019 10;49(10):1292-1299

QIMR Berghofer Medical Research Institute, Population Health Department, Brisbane, Queensland, Australia.

Background: Colonoscopy is the gold standard in the diagnosis of significant bowel disease (SBD), including colorectal cancer, high-risk adenoma and inflammatory bowel disease. As the demand for colonoscopy services is placing significant pressure on hospital resources, new solutions are needed to manage patients more efficiently and effectively.

Aim: We investigated the impact of using a risk assessment tool (RAT) to improve selection of patients for colonoscopy procedures to detect SBD.

Methods: A hybrid simulation model was constructed to replicate the current patient triage bookings and waiting times in a large metropolitan hospital. The model used data on 327 patients who were retrospectively assessed for risk of SBD. Risk assessment incorporated blood and faecal immunochemical test results, gender and age in addition to patient symptoms. The model was calibrated over 12 months to current outcomes and was compared with the RAT and a third scenario where low-risk patients did not proceed to a colonoscopy. One-way sensitivity analyses were undertaken.

Results: Using the RAT was expected to shorten waiting times by 153 days for moderately-urgent patients and 138 days for non-urgent patients. If low-risk patients did not proceed to colonoscopy, waiting times were expected to reduce for patients with SBD by 17 days producing cost-savings of AU$373 824 through avoided colonoscopies.

Conclusions: A hybrid model that combines patient-level characteristics with hospital-level resource constraints can demonstrate improved efficiency in a hospital clinic. Further research on risk assessment is required to improve quality patient care and reduce low-value service delivery.
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http://dx.doi.org/10.1111/imj.14267DOI Listing
October 2019

Systematic Review and Meta-analysis: Optimal Salvage Therapy in Acute Severe Ulcerative Colitis.

Inflamm Bowel Dis 2019 06;25(7):1169-1186

Department of Gastroenterology, Austin Hospital, Melbourne, Australia.

Background: Infliximab is an effective salvage therapy in acute severe ulcerative colitis; however, the optimal dosing strategy is unknown. We performed a systematic review and meta-analysis to examine the impact of infliximab dosage and intensification on colectomy-free survival in acute severe ulcerative colitis.

Methods: Studies reporting outcomes of hospitalized steroid-refractory acute severe ulcerative colitis treated with infliximab salvage were identified. Infliximab use was categorized by dose, dose number, and schedule. The primary outcome was colectomy-free survival at 3 months. Pooled proportions and odds ratios with 95% confidence intervals were reported.

Results: Forty-one cohorts (n = 2158 cases) were included. Overall colectomy-free survival with infliximab salvage was 79.7% (95% confidence interval [CI], 75.48% to 83.6%) at 3 months and 69.8% (95% CI, 65.7% to 73.7%) at 12 months. Colectomy-free survival at 3 months was superior with 5-mg/kg multiple (≥2) doses compared with single-dose induction (odds ratio [OR], 4.24; 95% CI, 2.44 to 7.36; P < 0.001). However, dose intensification with either high-dose or accelerated strategies was not significantly different to 5-mg/kg standard induction at 3 months (OR, 0.70; 95% CI, 0.39 to 1.27; P = 0.24) despite being utilized in patients with a significantly higher mean C-reactive protein and lower albumin levels.

Conclusions: In acute severe ulcerative colitis, multiple 5-mg/kg infliximab doses are superior to single-dose salvage. Dose-intensified induction outcomes were not significantly different compared to standard induction and were more often used in patients with increased disease severity, which may have confounded the results. This meta-analysis highlights the marked variability in the management of infliximab salvage therapy and the need for further studies to determine the optimal dose strategy.
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http://dx.doi.org/10.1093/ibd/izy383DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6783899PMC
June 2019

Detectable Laboratory Abnormality Is Present up to 12 Months Prior to Diagnosis in Patients with Crohn's Disease.

Dig Dis Sci 2019 02 26;64(2):503-517. Epub 2018 Nov 26.

Inflammatory Bowel Diseases Research Group, QIMR Berghofer Medical Research Institute, Brisbane, Australia.

Background And Aims: Patients with inflammatory bowel disease (IBD) often have subjective symptoms for months or years prior to their diagnosis. Blood tests taken prior to diagnosis may provide objective evidence of duration of pre-diagnosis disease. We aim to describe the pre-diagnosis laboratory pattern of patients with IBD.

Methods: A total of 838 patients diagnosed with IBD between 01/01/1996 and 01/03/2014, with pre-diagnosis laboratory testing available, contributed data for analysis. C-reactive protein, erythrocyte sedimentation rate, hemoglobin level, mean cell volume (MCV) platelet count, white blood cell count, neutrophil count, albumin level, ferritin level, serum iron level, alanine transaminase level, and fecal calprotectin were examined in the 24 months leading up to diagnosis and compared to baseline data taken between 24 and 36 months prior to diagnosis.

Results: For patients with Crohn's disease, a significant drop in serum albumin and MCV levels and a significant rise in platelet count were observed between 115 and 385 days prior to diagnosis (p < 0.01, two-tailed t test). For patients with ulcerative colitis, a significant change in albumin level, MCV, hemoglobin level, platelet count, and serum iron level was observed at diagnosis (p < 0.01, two-tailed t test) but was not detectable before.

Conclusions: These data provide objective evidence of duration of delay between disease onset and diagnosis in a cohort of patients with IBD. Expediting diagnostic testing in patients presenting with symptoms consistent with IBD, who also have abnormal laboratory results, may reduce diagnostic delay, speed access to therapy, and improve clinical outcomes.
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http://dx.doi.org/10.1007/s10620-018-5357-0DOI Listing
February 2019

The effect of pre-admission immunosuppression on colectomy rates in acute severe ulcerative colitis.

Therap Adv Gastroenterol 2018 13;11:1756284818809789. Epub 2018 Nov 13.

Department of Gastroenterology and Hepatology, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia.

Background: Patients on immunosuppression at the time of acute severe ulcerative colitis have been suggested to be at a higher risk of colectomy than those who are treatment-naïve. The aim of this study was to examine the effect of immunosuppressive therapy on the risk of colectomy.

Method: We conducted a retrospective observational cohort study using prospective data examining the 30 day and 1 year colectomy rates of 200 consecutive patients with an index episode of acute severe ulcerative colitis as defined by the Truelove and Witts criteria.

Results: Immunosuppression on admission was shown not to increase colectomy rate at 30 days post-admission (immunomodulator: = 0.422, oral steroids: = 0.555). A total of 24 patients underwent colectomy between 30 days and 1 year. A three-fold higher risk of colectomy at 1 year was seen in those requiring an immunomodulator prior to the index admission compared with those started during the index admission [41% 14% odds ratio (OR): 2.93 (1.19-7.24 = 0.016)]. Factors most predictive of colectomy at 30 days were abdominal radiographic colonic dilation ⩾5.5 cm, first presentation of ulcerative colitis, C-reactive protein ⩾ 45 mg/l on day 3 of therapy and bowel frequency ⩾8 on day 3.

Conclusion: The need for an immunomodulator prior to admission with acute severe ulcerative colitis increases the medium-term colectomy rate by three-fold at 1 year. Prospective studies are needed to confirm these findings and develop strategies to reduce the high risk in this subgroup of patients.
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http://dx.doi.org/10.1177/1756284818809789DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6236856PMC
November 2018

IL23R-Protective Coding Variant Promotes Beneficial Bacteria and Diversity in the Ileal Microbiome in Healthy Individuals Without Inflammatory Bowel Disease.

J Crohns Colitis 2019 Mar;13(4):451-461

Gut Health, QIMR Berghofer Medical Research Institute, Herston, Brisbane 4006, Australia.

Background And Aims: This study aimed to characterize the mucosa-associated microbiota in ileal Crohn's disease [CD] patients and in healthy controls in terms of host genotype and inflammation status.

Methods: The mucosa-associated microbiotas of intestinal pinch biopsies from 15 ileal CD patients with mild and moderate disease and from 58 healthy controls were analysed based on 16S ribosomal sequencing to determine microbial profile differences between [1] IL23R, NOD2 and ATG16L1 genotypes in healthy subjects, [2] ileal CD patients and control subjects, and [3] inflamed and non-inflamed mucosal tissue in CD patients.

Results: The protective variant of the IL23R gene [rs11209026] significantly impacted the microbial composition in the ileum of healthy subjects and was associated with an increased abundance of phylotypes within the family Christensenellaceae as well as increases in diversity and richness. Comparative analysis of healthy and non-inflamed CD microbiome samples indicated a notable decrease in the abundance of Faecalibacterium prausnitzii as well as Shannon diversity and richness. Inflamed and non-inflamed ileal samples of CD subjects had high intra-individual stability and inter-individual variability, but no significant alterations in diversity, richness or taxa were identified. Calprotectin correlated positively with the abundance of Proteobacteria and negatively with diversity in the samples from healthy subjects.

Conclusions: The observation of low diversity and low abundance of beneficial bacteria in healthy control subjects carrying the IL23R [rs11209026] wild-type GG genotype indicates that the gut microbiome is influenced by host genetics and is altered prior to disease diagnosis. Faecal calprotectin may be a potential non-invasive screening tool for dysbiosis in subjects without disorders of intestinal inflammation.
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http://dx.doi.org/10.1093/ecco-jcc/jjy188DOI Listing
March 2019

NLRP1 restricts butyrate producing commensals to exacerbate inflammatory bowel disease.

Nat Commun 2018 09 13;9(1):3728. Epub 2018 Sep 13.

Inflammation Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia.

Anti-microbial signaling pathways are normally triggered by innate immune receptors when detecting pathogenic microbes to provide protective immunity. Here we show that the inflammasome sensor Nlrp1 aggravates DSS-induced experimental mouse colitis by limiting beneficial, butyrate-producing Clostridiales in the gut. The colitis-protective effects of Nlrp1 deficiency are thus reversed by vancomycin treatment, but recapitulated with butyrate supplementation in wild-type mice. Moreover, an activating mutation in Nlrp1a increases IL-18 and IFNγ production, and decreases colonic butyrate to exacerbate colitis. We also show that, in patients with ulcerative colitis, increased NLRP1 in inflamed regions of the colon is associated with increased IFN-γ. In this context, NLRP1, IL-18 or IFN-γ expression negatively correlates with the abundance of Clostridiales in human rectal mucosal biopsies. Our data identify the NLRP1 inflammasome to be a key negative regulator of protective, butyrate-producing commensals, which therefore promotes inflammatory bowel disease.
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http://dx.doi.org/10.1038/s41467-018-06125-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6137172PMC
September 2018

Genome-wide association study of intraocular pressure uncovers new pathways to glaucoma.

Nat Genet 2018 08 27;50(8):1067-1071. Epub 2018 Jul 27.

QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.

Intraocular pressure (IOP) is currently the sole modifiable risk factor for primary open-angle glaucoma (POAG), one of the leading causes of blindness worldwide. Both IOP and POAG are highly heritable. We report a combined analysis of participants from the UK Biobank (n = 103,914) and previously published data from the International Glaucoma Genetic Consortium (n = 29,578) that identified 101 statistically independent genome-wide-significant SNPs for IOP, 85 of which have not been previously reported. We examined these SNPs in 11,018 glaucoma cases and 126,069 controls, and 53 SNPs showed evidence of association. Gene-based tests implicated an additional 22 independent genes associated with IOP. We derived an allele score based on the IOP loci and loci influencing optic nerve head morphology. In 1,734 people with advanced glaucoma and 2,938 controls, participants in the top decile of the allele score were at increased risk (odds ratio (OR) = 5.6; 95% confidence interval (CI): 4.1-7.6) of glaucoma relative to the bottom decile.
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http://dx.doi.org/10.1038/s41588-018-0176-yDOI Listing
August 2018

Nonsynonymous Polymorphism in Guanine Monophosphate Synthetase Is a Risk Factor for Unfavorable Thiopurine Metabolite Ratios in Patients With Inflammatory Bowel Disease.

Inflamm Bowel Dis 2018 11;24(12):2606-2612

Department of Gastroenterology, Christchurch Hospital, Christchurch, New Zealand.

Background: Up to 20% of patients with inflammatory bowel disease (IBD) who are refractory to thiopurine therapy preferentially produce 6-methylmercaptopurine (6-MMP) at the expense of 6-thioguanine nucleotides (6-TGN), resulting in a high 6-MMP:6-TGN ratio (>20). The objective of this study was to evaluate whether genetic variability in guanine monophosphate synthetase (GMPS) contributes to preferential 6-MMP metabolizer phenotype.

Methods: Exome sequencing was performed in a cohort of IBD patients with 6-MMP:6-TGN ratios of >100 to identify nonsynonymous single nucleotide polymorphisms (nsSNPs). In vitro assays were performed to measure GMPS activity associated with these nsSNPs. Frequency of the nsSNPs was measured in a cohort of 530 Caucasian IBD patients.

Results: Two nsSNPs in GMPS (rs747629729, rs61750370) were detected in 11 patients with very high 6-MMP:6-TGN ratios. The 2 nsSNPs were predicted to be damaging by in silico analysis. In vitro assays demonstrated that both nsSNPs resulted in a significant reduction in GMPS activity (P < 0.05). The SNP rs61750370 was significantly associated with 6-MMP:6-TGN ratios ≥100 (odds ratio, 5.64; 95% confidence interval, 1.01-25.12; P < 0.031) in a subset of 264 Caucasian IBD patients.

Conclusions: The GMPS SNP rs61750370 may be a reliable risk factor for extreme 6MMP preferential metabolism.
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http://dx.doi.org/10.1093/ibd/izy163DOI Listing
November 2018

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

Eur J Gastroenterol Hepatol 2018 07;30(7):735-740

Gastroenterology and Liver Services, Concord Repatriation General Hospital.

Background: Vedolizumab (VDZ), an α4β7 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.
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http://dx.doi.org/10.1097/MEG.0000000000001150DOI Listing
July 2018

Development and evaluation of a risk assessment tool to improve clinical triage accuracy for colonoscopic investigations.

BMC Cancer 2018 02 27;18(1):229. Epub 2018 Feb 27.

Inflammatory Bowel Diseases, QIMR Berghofer Medical Research Institute, Brisbane, Australia.

Background: Gastroenterology Departments at hospitals within Australia receive thousands of General Practitioner (GP)-referral letters for gastrointestinal investigations every month. Many of these requests are for colonoscopy. This study aims to evaluate the performance of the current symptoms-based triage system compared to a novel risk score using objective markers.

Methods: Patients with lower abdominal symptoms referred by their GPs and triaged by a Gastroenterology consultant to a colonoscopy consent clinic were recruited into the study. A risk assessment tool (RAT) was developed using objective data (clinical, demographic, pathology (stool test, FIT), standard blood tests and colonoscopy outcome). Colonoscopy and histology results were scored and then stratified as either significant bowel disease (SBD) or non-significant bowel disease (non-SBD).

Results: Of the 467 patients in our study, 45.1% were male, the mean age was 54.3 ± 13.8 years and mean BMI was 27.8 ± 6.2. Overall, 26% had SBD compared to 74% with non-SBD (42% of the cohort had a normal colonoscopy). Increasing severity of referral symptoms was related to a higher triage category, (rectal bleeding, P = 2.86*10; diarrhoea, P = 0.026; abdominal pain, P = 5.67*10). However, there was no significant difference in the prevalence of rectal bleeding (P = 0.991) or diarrhoea (P = 0.843) for SBD. Abdominal pain significantly reduced the risk of SBD (P = 0.0344, OR = 0.52, CI = 0.27-0.95). Conversely, the RAT had a very high specificity of 98% with PPV and NPV of SBD prediction, 74% and 77%, respectively. The RAT provided an odds ratio (OR) of 9.0, 95%CI 4.29-18.75, p = 2.32*10), higher than the FIT test (OR = 5.3, 95%CI 2.44-11.69, p = 4.88*10), blood score (OR = 2.8, 95%CI 1.72- 4.38, p = 1.47*10) or age (OR = 2.5, 95%CI 1.61-4.00, 5.12*10) independently. Notably, the ORs of these individual objective measures were higher than the current practice of symptoms-based triaging (OR = 1.4, 95%CI 0.88-2.11, p = 0.153).

Conclusions: It is critical that individuals with high risk of having SBD are triaged to the appropriate category with the shortest wait time. Here we provide evidence that a combination of blood markers, demographic markers and the FIT test have a higher diagnostic accuracy for SBD than FIT alone.
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http://dx.doi.org/10.1186/s12885-018-4140-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6389276PMC
February 2018
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