Publications by authors named "Daniel van Langenberg"

56 Publications

Predictive Scores in Acute Severe Ulcerative Colitis: Which, What, and When are the Decision Points We Should Target?

Clin Gastroenterol Hepatol 2021 Apr 24. Epub 2021 Apr 24.

Department of Gastroenterology, Eastern Health, Melbourne, Victoria, Australia.

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http://dx.doi.org/10.1016/j.cgh.2021.04.035DOI Listing
April 2021

Biomarker dynamics during infliximab salvage for acute severe ulcerative colitis: C-reactive protein (CRP)-lymphocyte ratio and CRP-albumin ratio are useful in predicting colectomy.

Intest Res 2021 Mar 12. Epub 2021 Mar 12.

Department of Gastroenterology, Eastern Health, Melbourne, Australia.

Background/aims: The residual risk of colectomy after infliximab salvage in steroid-refractory acute severe ulcerative colitis (ASUC) is required to inform the need for subsequent maintenance biologic therapy. The aim of this study was to determine the dynamic response of common serum biomarkers to infliximab salvage and assess their utility in predicting subsequent colectomy.

Methods: A retrospective single-center cohort study was conducted on all patients who received infliximab salvage for steroid-refractory ASUC between January 1, 2010, and July 31, 2019. Biomarkers were assessed on admission and days 1 and 3 post infliximab, and included C-reactive protein (CRP)-albumin-ratio (CAR), CRP-lymphocyte-ratio (CLR), platelet-lymphocyte-ratio (PLR) and neutrophil-lymphocyte-ratio (NLR).

Results: Of 94 patients (median age, 35 years; 67% of male), 20% required colectomy at 12 months. Biomarkers on day 3 post-infliximab best differentiated nonresponders, who had higher CRP, lower albumin and lower lymphocyte count (each P< 0.05). Day 3 predictive performance (area under the curve) for 12-month colectomy was best for CAR (0.871) and CLR (0.874), which were similar to Lindgren (0.829; P> 0.05) but superior to Mayo (0.726), partial Mayo (0.719), PLR (0.719), Ho index (0.714), NLR (0.675), Travis score (0.657) and endoscopic Mayo (0.609) (each P< 0.05). A day 3 CAR cutoff of 0.47 mg/g had 79% sensitivity, 80% specificity, 94% negative predictive value (NPV) to predict colectomy; while a day 3 CLR cutoff of 6.0 mg/109 had 84% sensitivity, 84% specificity, 96% NPV.

Conclusions: CAR and CLR measured on day 3 post infliximab salvage for steroid-refractory ASUC represent simple and routinely performed biomarkers that appear to be strong predictors of colectomy. Prospective studies are required to confirm the utility of these predictive scores.
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http://dx.doi.org/10.5217/ir.2020.00146DOI Listing
March 2021

Faecal microbiota transplantation for recurrent Clostridioides difficile infection: an Australian experience - effective, safe, yet room for improvement.

Intern Med J 2021 Jan;51(1):106-110

Department of Gastroenterology, Eastern Health, Melbourne, Victoria, Australia.

Faecal microbiota transplantation (FMT) is reportedly effective and safe for the management of recurrent or refractory Clostridioides difficile infection (CDI), yet real-world data of outcomes of FMT in Australia are limited. In this series, FMT safely resulted in resolution of CDI in 19 patients with reduced healthcare utilisation after 25 FMT, but one patient was diagnosed with an anti-nuclear antibody-positive constitutional illness and Hashimoto thyroiditis following FMT. Further prospective evaluation of the utility of FMT earlier in CDI treatment algorithms to minimise cost and morbidity, and recipient follow up for immune-mediated conditions, is required.
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http://dx.doi.org/10.1111/imj.15162DOI Listing
January 2021

Real-World Effectiveness of Ustekinumab Dose Intensification in Crohn's Disease.

Inflamm Bowel Dis 2021 May;27(6):e69

Department of Gastroenterology, Austin Health, Melbourne, Australia.

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http://dx.doi.org/10.1093/ibd/izab018DOI Listing
May 2021

Editorial: methotrexate vs azathioprine-do differential rates of discontinuation settle the debate? Authors' reply.

Aliment Pharmacol Ther 2020 11;52(9):1529-1530

Department of Gastroenterology and Hepatology, Eastern Health Clinical School, Monash University, Victoria, Australia.

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http://dx.doi.org/10.1111/apt.16095DOI Listing
November 2020

Response to: Cumulative Exposure to Infliximab, But Not Trough Concentrations, Correlate With Rate of Infection.

Clin Gastroenterol Hepatol 2021 May 26;19(5):1077. Epub 2020 Nov 26.

Department of Gastroenterology, Eastern Health, Melbourne, VIC, Australia.

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http://dx.doi.org/10.1016/j.cgh.2020.05.057DOI Listing
May 2021

Assessing adherence to infusion-based biologic therapies in patients with inflammatory bowel disease.

Res Social Adm Pharm 2021 Aug 22;17(8):1420-1425. Epub 2020 Oct 22.

Department of Gastroenterology, Eastern Health, Melbourne, VIC, Australia; Eastern Health Clinical School, Monash University, Melbourne, VIC, Australia.

Background: The intravenous biologics infliximab and vedolizumab are effective long-term therapies for inflammatory bowel disease (IBD). Though highly effective, suboptimal adherence may result in loss of response and adverse sequelae. The extent and outcomes of suboptimal adherence with intravenous biologics, including in IBD, requires further evaluation.

Objectives: To ascertain adherence to infliximab and vedolizumab infusions, and determine factors associated with poorer adherence within an IBD cohort.

Methods: A retrospective single-centre cohort study of IBD patients, assessing adherence to infliximab and vedolizumab over 2 years (July 1, 2017 to June 30, 2019) was conducted. Medical and pharmacy dispensing records were used to determine date of infusion. Adherence was assessed using the continuous, multiple interval measure of medication gaps (CMG). Objectively measured disease remission was achieved if one or more of endoscopic remission, faecal calprotectin <100 μg/mL and/or CRP <5 mg/mL occurred within 3 months of end of follow-up. Bivariate analysis and multiple linear regression elucidated factors associated with poorer adherence.

Results: Of 193 IBD patients, 132 (68.4%) had Crohn's disease. One hundred and thirty six (70.5%) patients received infliximab and 57 (29.5%) received vedolizumab with a median 13 [IQR 11-14] doses administered per patient over 2 years. Adherence according to CMG was similar between infliximab and vedolizumab groups (median 1.5% vs 1.2%, p = 0.31). In multiple linear regression analysis male sex, shorter IBD duration and clinic non-attendances were each associated with poorer adherence (Beta 4.69, 3.90, 3.56 respectively, p < 0.05) and objective disease remission was inversely associated with poorer adherence (Beta -3.27, p < 0.05).

Conclusion: There was a wide range of adherence to biologic infusions in this IBD cohort with poorer adherence associated with patient related factors. Conversely, objectively measured remission was strongly associated with adherence. This emphasises the need for targeted interventions to improve adherence and monitoring, and mitigate treatment delays.
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http://dx.doi.org/10.1016/j.sapharm.2020.10.011DOI Listing
August 2021

Letter: rationalising aminosalicylates in inflammatory bowel disease.

Aliment Pharmacol Ther 2020 11;52(10):1619-1620

Department of Gastroenterology, Box Hill Hospital, Eastern Health, Box Hill, Vic., Australia.

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http://dx.doi.org/10.1111/apt.16107DOI Listing
November 2020

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

Med J Aust 2021 02 17;214(3):128-133. Epub 2020 Oct 17.

Fiona Stanley Hospital, Perth, WA.

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.
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http://dx.doi.org/10.5694/mja2.50824DOI Listing
February 2021

The impact of tobacco smoking on treatment choice and efficacy in inflammatory bowel disease.

Intest Res 2021 Apr 13;19(2):158-170. Epub 2020 Oct 13.

Department of Gastroenterology, Eastern Health, Box Hill Hospital, Box Hill, Australia.

Smoking significantly increases the risk of developing and worsens Crohn's disease (CD), yet protects against the development and reduces the severity of ulcerative colitis. It is less clear whether smoking impacts the efficacy of therapeutics in inflammatory bowel disease (IBD). We review the literature regarding the relationship between smoking and the efficacy of medical and surgical therapy in IBD. Smoking is associated with alterations in thiopurine metabolism and may affect time to disease relapse. The outcomes of anti-tumor necrosis factor therapy in active smokers appear neutral with data lacking for newer biologics. Smoking increases the risk of postoperative recurrence in those requiring resection for CD, likely attributable to perturbations of the gut microbiota although further implications of these for disease onset/progression and treatment efficacy remain unclear. Multiple lifestyle and psychosocial confounders are likely under-recognized cofactors in the association between smoking and IBD. Despite the widely promulgated risks associated with cigarette smoking in CD, more incisive data are required to further elucidate the actual relationship between smoking and disease pathways, while accounting for the several negative cofactors prevalent in smokers which cast uncertainty on the magnitude of the direct effect of smoking on disease pathophysiology and the efficacy of therapy.
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http://dx.doi.org/10.5217/ir.2020.00008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8100381PMC
April 2021

Transitioning patients with inflammatory bowel disease from hospital-based to rapid home-based infliximab: A stepwise, safety and patient-orientated process towards sustainability.

World J Gastroenterol 2020 Sep;26(36):5437-5449

Department of Gastroenterology, Eastern Health, Box Hill 3128, Victoria, Australia.

Background: Infliximab and other intravenous biologic infusions are increasingly used for chronic disorders like inflammatory bowel disease (IBD). Rapid infliximab and home-based infusions are attractive solutions to address resource and capacity issues for infusion centres, yet infliximab infusion reactions reportedly occur in up to 25% of patients with IBD, even at the manufacturers' recommended infusion duration of 2 h.

Aim: To evaluate the safety, cost and patient satisfaction of transitioning from hospital-based, standard 2 h to rapid home-based, 30-min infliximab infusions.

Methods: All patients receiving rapid infliximab infusions for IBD between 2014 to 2017 (39 mo) were compared with those who received standard two-hour IFX infusions between 2005-2013 (96 mo) at a single IBD centre. Data (per-infusion and per-individual) including adverse drug reactions (ADR), duration (based on needle-departure time) and other clinical data were extracted from electronic medical records. Multivariable logistical regression analysis assessed factors potentially associated with increased risk of ADRs to rapid infusions. The primary outcome was the safety [as per relative risk (RR) of ADR] of (1) rapid 30 m infusions (both hospital- and home-based) standard 2 h infliximab infusions. Also, relative cost per infusion and patient satisfaction and productivity were evaluated in rapid infusion recipients who transitioned to home-based infusions.

Results: Of 129 patients who received 1461 rapid IFX infusions (2014-2017) were compared with 169 patients who received 2214 standard IFX infusions (2005-2013). Within the rapid cohort, 55 (42.6%) were males, median age 42 years (range 18, 86), 114 (84%) had Crohn's disease (CD) with a median disease duration 5 years (0, 36). Median needle to departure time was higher in the standard than the rapid protocol group, 108 (70, 253) 50 (33, 90) min, < 0.001), with a per infusion cost of $AUD 107.50 $49.77, respectively (both < 0.001). There was no difference in median infusion duration or costs between rapid home hospital-based infusions ( = 0.21). 8 patients in the rapid infliximab cohort had an ADR compared with 23 standard infliximab recipients (RR 0.55% 1.04% respectively), hence a higher likelihood of ADR with standard compared to rapid infusions [RR 3.0, 95%CI (1.2, 7.7), = 0.02]. No ADRs were observed in 405 rapid home-based infusions. A lower body mass index (< 22 kg/m), presence of one or more extra intestinal manifestations, longer disease duration (> 3 years) and previous exposure to another biologic were each independently associated with a higher likelihood of reaction (s) to rapid infusions. All (100%) survey respondents preferred the rapid standard infusions, however within rapid infusion recipients, 61.3% found home based infusions more inconvenient than hospital-based infusions despite a median of 0 h per week missed from paid work and no self-reported loss of work productivity.

Conclusion: Transitioning to rapid infliximab infusions appears very safe with significant cost benefit, patient satisfaction and avails the provision of safe, efficient, home-based infliximab infusions by IBD centres worldwide.
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http://dx.doi.org/10.3748/wjg.v26.i36.5437DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7520608PMC
September 2020

Development of a Simple, Serum Biomarker-based Model Predictive of the Need for Early Biologic Therapy in Crohn's Disease.

J Crohns Colitis 2021 Apr;15(4):583-593

Department of Gastroenterology, Eastern Health, Melbourne, VIC, Australia.

Background: Early or first-line treatment with biologics, as opposed to conventional immunomodulators, is not always necessary to achieve remission in Crohn's disease [CD] and may not be cost-effective. This study aimed to develop a simple model to predict the need for early biologic therapy, in order to risk-stratify CD patients and guide initial treatment selection.

Methods: A model-building study using supervised statistical learning methods was conducted using a retrospective cohort across two tertiary centres. All biologic-naïve CD patients who commenced an immunomodulator between January 1, 2004 and December 31, 2016, were included. A predictive score was derived using Cox regression modelling of immunomodulator failure, and was internally validated using bootstrap resampling.

Results: Of 410 patients [median age 37 years, 47% male, median disease duration 4.7 years], 229 [56%] experienced immunomodulator failure [39 required surgery, 24 experienced a new stricture, 44 experienced a new fistula/abscess, 122 required biologic escalation] with a median time to failure of 16 months. Independent predictors of treatment failure included raised C-reactive protein [CRP], low albumin, complex disease behaviour, younger age, and baseline steroids. Highest CRP and lowest albumin measured within the 3 months preceding immunomodulator initiation outperformed baseline measurements. After model selection, only highest CRP and lowest albumin remained and the resultant Crohn's Immunomodulator CRP-Albumin [CICA] index demonstrated robust optimism-corrected discriminative performance at 12, 24, and 36 months (area under the curve [AUC] 0.84, 0.83, 0.81, respectively).

Conclusions: The derived CICA index based on simple, widely available markers is feasible, internally valid, and has a high utility in predicting immunomodulator failure. This requires external, prospective validation.
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http://dx.doi.org/10.1093/ecco-jcc/jjaa194DOI Listing
April 2021

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

Editorial: direct costs are only the tip of the iceberg in inflammatory bowel disease.

Aliment Pharmacol Ther 2020 09;52(5):879-880

Department of Gastroenterology, Eastern Health, Box Hill, Vic, Australia.

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http://dx.doi.org/10.1111/apt.15990DOI Listing
September 2020

Thiopurines vs methotrexate: Comparing tolerability and discontinuation rates in the treatment of inflammatory bowel disease.

Aliment Pharmacol Ther 2020 10 14;52(7):1174-1184. Epub 2020 Aug 14.

Department of Gastroenterology and Hepatology, Monash University, Eastern Health Clinical School, Victoria, Australia.

Background: There are safety concerns regarding immunomodulators (thiopurines and methotrexate) for treatment of inflammatory bowel disease (IBD).

Aim: To compare the long-term tolerability, and persistence of thiopurine and methotrexate therapy in IBD.

Methods: A retrospective cohort study was performed at two hospitals between 1 January 2004 and 31 December 2016 for patients commenced on thiopurines or methotrexate for IBD. Treatment discontinuation rates, intolerances and disease activity were obtained from medical records.

Results: There were 782 patients commenced on immunomodulator therapy; 244 (31%) on methotrexate with folate (67% subcutaneous therapy) and 538 (69%) on thiopurine (73% azathioprine). Median follow-up was 42 vs 47 months (P = 0.09). In patients on thiopurines, median 6-TGN was 298 pmol/8 x 10 RBCs, while the median dose of methotrexate was 25 mg weekly. Methotrexate recipients had a higher rate of prior immunomodulator intolerance, were typically older and had a longer disease duration (54% vs 3%, median 43 vs 36 years, 6 vs 5 years, respectively, each P < 0.05). Overall, 208 (27%) discontinued therapy due to adverse events, (40% on methotrexate vs 19% on thiopurines, P < 0.001), including nausea (18% vs 4%), fatigue (7% vs 2%) and hepatotoxicity (8% vs 2%, each P < 0.001). Hospitalisations from adverse events (0.8% vs 0.9%) and serious infections (9% vs 12%), and deaths (1% vs 0%) were comparable between groups (all P > 0.05). Discontinuation due to adverse events occurred later in patients on methotrexate than on thiopurines (median 7 vs 5 months, P = 0.08).

Conclusion: Discontinuation of methotrexate occurred at rates twice that of dose-optimised thiopurine therapy.
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http://dx.doi.org/10.1111/apt.16039DOI Listing
October 2020

Anti-TNF-associated immunogenicity: use a retroactive drug but a proactive approach.

Gut 2021 Apr 17;70(4):812-813. Epub 2020 Jul 17.

Department of Gastroenterology, Eastern Health, Box Hill, Victoria, Australia.

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http://dx.doi.org/10.1136/gutjnl-2020-322302DOI Listing
April 2021

Letter: ustekinumab dose intensification for loss of response-should we re-induce before shortening the dose interval?

Aliment Pharmacol Ther 2020 08;52(3):564-565

Department of Gastroenterology, Eastern Health, Melbourne, Vic., Australia.

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http://dx.doi.org/10.1111/apt.15883DOI Listing
August 2020

Letter: choosing between ustekinumab and vedolizumab in anti-TNF refractory Crohn's disease-the devil is in the detail.

Aliment Pharmacol Ther 2020 08;52(3):561-562

Department of Gastroenterology, Eastern Health, Melbourne, Vic., Australia.

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http://dx.doi.org/10.1111/apt.15862DOI Listing
August 2020

A virtual clinic increases anti-TNF dose intensification success via a treat-to-target approach compared with standard outpatient care in Crohn's disease.

Aliment Pharmacol Ther 2020 06 7;51(12):1342-1352. Epub 2020 May 7.

Department of Medicine, Monash University, Melbourne, Vic., Australia.

Background: Virtual clinics represent a novel model of care in inflammatory bowel disease. Their effectiveness in promoting high quality use of biologic therapy and facilitating a treat-to-target approach is unknown.

Aim: To evaluate clinical and process-driven outcomes in a virtual clinic compared to standard outpatient care amongst patients receiving intensified anti-TNF therapy for secondary loss of response.

Methods: We performed a retrospective multi-centre, parallel, observational cohort study of Crohn's disease patients receiving intensified anti-TNF therapy for secondary loss of response. Objective assessments of disease activity and anti-TNF trough levels at secondary loss of response and during subsequent 6-month semesters, were compared longitudinally between virtual clinic and standard outpatient care cohorts. The primary endpoint was treatment success, with appropriateness of dose intensification, tight disease monitoring and treatment de-escalation representing secondary outcomes.

Results: Of 149 patients with similar baseline characteristics, 69 were managed via a virtual clinic and 80 via standard outpatient care. There were higher rates of treatment success in the virtual clinic cohort (60.9 vs 35.0%, P < 0.002). Rates of appropriate dose intensification (82.6% vs 40.0%, P < 0.001), biomarker remission (faecal calprotectin P = 0.002), tight-disease monitoring (84.1% vs 28.8%, P < 0.001) and treatment de-escalation (21.3% vs 10.0%, P = 0.027) also favoured the virtual clinic cohort.

Conclusion: This study favoured a virtual clinic-led model-of-care over standard outpatient care in facilitating treatment success as part of an effective treat-to-target approach in Crohn's disease. A virtual clinic model-of-care also improved treatment outcomes and quality of use of intensified anti-TNF therapy through processes that promoted appropriate dose intensification and tight-disease monitoring, while encouraging more frequent dose de-escalation.
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http://dx.doi.org/10.1111/apt.15742DOI Listing
June 2020

Outcomes of a drug shortage requiring switching in patients with ulcerative colitis.

World J Gastrointest Pathophysiol 2020 Apr;11(2):32-42

Department of Gastroenterology, Eastern Health, Box Hill, Victoria 3128, Australia.

Background: Drug shortages are common yet their impact on patient care and their commercial ramifications has not been adequately researched. In Australia a shortage of balsalazide (2012-2013) necessitated substitution with alternative 5-aminosalicylate (5-ASA) formulations for ulcerative colitis (UC).

Aim: To assess and compare the clinical and commercial sequelae of non-medical switching from balsalazide to another 5-ASA and/or return to balsalazide once supply resumed.

Methods: A prospective cohort study of patients on balsalazide for mild-moderate UC was conducted where, strictly due to the national shortage (November 2012- January 2013), were switched to alternative 5-ASA and/or then returned to balsalazide once supply resumed. Clinical (Partial Mayo), endoscopic (Mayo score) activity, adverse effects (to alternative 5-ASA) and percentage market share (of continuous 5-ASA users) from baseline (., time of switching due to shortage) through to five years were assessed.

Results: Of 31 patients switched due to the shortage, 12 (38.7%) resumed balsalazide immediately once supply resumed, 8 (25.8%) prompted by adverse effects to the alternative 5-ASA used. Three patients (9.7%) had documented symptomatic improvement, 15 (48.4%) were unchanged and 13 (41.9%) had symptomatic worsening baseline ( < 0.01), after switching to an alternative 5-ASA. At 3 and 5y post switch, overall 26/31 (83.9%) and 23/31 (74.2%) had remained continuously on any 5-ASA therapy respectively. Twelve (38.7%) and 11 (35.5%) patients remained on balsalazide continuously at three and five years respectively after drug supply returned, equating to a loss of market share (within 5-ASA class) of 45.2% and 38.7% respectively.

Conclusion: This study of a balsalazide shortage in UC patients exemplifies the detrimental impact of a drug shortage on long term patient, disease and commercial outcomes.
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http://dx.doi.org/10.4291/wjgp.v11.i2.32DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7156848PMC
April 2020

Retrospective study of idiosyncratic drug-induced liver injury from infliximab in an inflammatory bowel disease cohort: the IDLE study.

Ann Gastroenterol 2020 Mar-Apr;33(2):162-169. Epub 2020 Feb 12.

Department of Gastroenterology, Eastern Health (Thomas Worland, Daniel van Langenberg, Muyur Garg, Amanda Nicoll).

Background: Infliximab therapy may be associated with drug-induced liver injury (DILI), often resembling a drug-induced autoimmune hepatitis. However, the prevalence of DILI in patients receiving infliximab is unclear. Abnormal liver biochemistry is common in patients with inflammatory bowel disease (IBD) and definitive diagnosis may be difficult. The aim of this study was to describe the patterns of abnormal liver biochemistry in an IBD cohort.

Methods: In a retrospective cohort study of adult patients with IBD treated with infliximab through a single institution we used the Roussel Uclaf Causality Assessment Method (RUCAM) to evaluate liver biochemistry and possible DILI. All cases of abnormal liver biochemistry were ascribed a presumptive diagnosis from the electronic medical record.

Results: Fifty-seven of the 175 patients (149 Crohn's disease, 26 ulcerative colitis) had abnormal liver biochemistry. Of the 57 cases, one had highly probable, and 10 possible DILI due to infliximab. There were no significant differences regarding demographics, concomitant therapy/disease, indication for infliximab or outcomes between patients with normal and abnormal liver biochemistry, except for higher baseline alanine transaminase and alkaline phosphatase in the abnormal biochemistry group (P<0.001). Multivariate logistic regression showed male sex (odds ratio [OR] 2.49, 95% confidence interval [CI] 1.22-5.09; P=0.01) and background liver disease (OR 15.09, 95%CI 4.09-55.69; P<0.001) to be associated with the abnormal liver biochemistry group.

Conclusions: Abnormal liver biochemistry is common in IBD patients on infliximab. Patients who are male, or have abnormal pre-therapy liver biochemistry or background liver disease, are more likely to develop worsening liver biochemistry during infliximab therapy. RUCAM scoring may help identify true cases of DILI.
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http://dx.doi.org/10.20524/aog.2020.0453DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7049241PMC
February 2020

Medical Management of Infliximab Failure in Acute Severe Ulcerative Colitis.

J Crohns Colitis 2020 07;14(7):1029

Department of Gastroenterology, Box Hill Hospital, Eastern Health, Box Hill, Australia.

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http://dx.doi.org/10.1093/ecco-jcc/jjaa006DOI Listing
July 2020

The Cost-effectiveness of Initial Immunomodulators or Infliximab Using Modern Optimization Strategies for Crohn's Disease in the Biosimilar Era.

Inflamm Bowel Dis 2020 02;26(3):369-379

Department of Gastroenterology and Hepatology, Eastern Health, Monash University, Eastern Health Clinical School, Box Hill, Victoria, Australia.

Background: Treatment cost, efficacy, and safety are integral considerations when optimizing management of Crohn's disease (CD). This study assessed the cost-effectiveness of initial immunomodulator and anti-tumor necrosis factor (anti-TNF) agents for the treatment of CD from a US third-party perspective, incorporating current treatment algorithms, optimization strategies, and reduced costs availed by biosimilars.

Method: A 1-year Markov model was developed to simulate the cost and quality-adjusted life-years (QALYs) of initial azathioprine, infliximab, and combination therapy for moderate to severe CD. Treatment was changed based on tolerability and clinical disease activity at 3-monthly intervals. Efficacy data were based on published literature.

Results: Initial azathioprine had the lowest cost and utility ($35,337 and 0.63 QALYs), whereas combination therapy was the costliest yet conferred the highest health benefits ($57,638 and 0.67 QALYs). The incremental cost-effectiveness of infliximab and combination therapy compared with azathioprine were both in excess of $500,000 per QALY gained. Initial azathioprine remained the most cost-effective treatment on sensitivity analysis compared with infliximab and combination therapy, with 90% reductions in anti-TNF therapy costs and a 5-year time horizon, although combination therapy had an acceptable cost-effectiveness when costs were reduced in the extended model. Initial infliximab, ustekinumab, and vedolizumab were dominated by combination therapy.

Conclusions: In the biosimilar era, initial azathioprine with escalation to infliximab appeared more cost-effective in the short term compared with infliximab or combination therapy, although initial combination therapy yields acceptable ICERs in the long term with continued reductions in anti-TNF therapy costs and will likely be the preferred treatment strategy in the future.
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http://dx.doi.org/10.1093/ibd/izz159DOI Listing
February 2020

Endocuff Vision is safe to use for dysplasia surveillance in patients with ulcerative colitis: a feasibility study.

Endosc Int Open 2019 Sep 28;7(9):E1044-E1048. Epub 2019 Aug 28.

Department of Gastroenterology, Eastern Health, Melbourne, Australia.

Endocuff Vision improves adenoma detection rates in patients without inflammatory bowel disease. This study aimed to investigate the safety and feasibility of Endocuff Vision-assisted high-definition white light endoscopy (HDWLE) with dye-spray chromoendoscopy for detection of dysplasia in patients with ulcerative colitis. Patients with clinically inactive ulcerative colitis due for dysplasia surveillance were recruited. Procedural endpoints included safety, cecal intubation rate (CIR), terminal ileum intubation rate (TIR), withdrawal time, polyp detection rate, dysplasia detection rate (DDR), and sessile serrated lesion detection rate. Twenty-five patients (9 female, median age 57 [range 28 - 82] years) were studied. Endocuff Vision-assisted HDWLE was completed in all participants, with a CIR of 100 %, in a median 4 minutes (range 2 - 16), and a TIR of 88% in a median of 6.5 minutes (range 3 - 19). Median withdrawal time was 18 minutes (range 10 - 55), including application of dye-spray, biopsies and polypectomy. The Mayo Endoscopic subscore was 0 in 11, 1 in 9, and 2 in 5 patients. The DDR was 24 % (6 patients had a total of 12 dysplastic lesions) and sessile serrated lesion detection rate was 12 % (3 patients had a total of 4 sessile serrated polyps). No serious adverse events occurred, with one patient developing clinically insignificant minor mucosal bleeding. Endocuff Vision-assisted HDWLE is feasible and safe in patients with ulcerative colitis undergoing dysplasia surveillance. Further studies are required to assess superiority of this technique compared with standard high-definition white light endoscopy with chromoendoscopy.
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http://dx.doi.org/10.1055/a-0886-6421DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6713553PMC
September 2019

Inflammatory bowel disease and superior mesenteric artery thromboembolism.

Intest Res 2020 Jan 3;18(1):130-133. Epub 2019 Sep 3.

Department of Gastroenterology, Eastern Health, Box Hill Hospital, VIC, Australia.

While patients with inflammatory bowel disease are known to be at increased risk of venous thromboembolism, the risk of arterial thrombosis is less well recognized. Here, we describe the case of a middle-aged female with a recent diagnosis of Crohn's disease who presented to her local emergency department with acute abdominal pain. Subsequent investigations revealed a thrombus in the superior mesenteric artery resulting in multi-organ infarction requiring major intra-abdominal surgery and extensive resection of segments of small and large bowel.
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http://dx.doi.org/10.5217/ir.2019.00068DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7000650PMC
January 2020

Inflammatory Bowel Disease Helpline Reduces Subsequent Inpatient Admission Rates.

J Crohns Colitis 2020 Feb;14(2):281

Department of Gastroenterology, Box Hill Hospital, Melbourne, VIC, Australia.

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http://dx.doi.org/10.1093/ecco-jcc/jjz141DOI Listing
February 2020

A comparison of long-term healthcare utilization and costs in patients with acute severe ulcerative colitis receiving infliximab early colectomy.

Ther Adv Chronic Dis 2019 29;10:2040622319825595. Epub 2019 Jan 29.

Department of Gastroenterology and Hepatology, Eastern Health, Victoria, Australia Monash University, Eastern Health Clinical School, Victoria, Australia.

Background: Early intervention for acute severe ulcerative colitis (ASUC) improves outcomes. Outcomes and healthcare costs for an infliximab-first and colectomy-first approach were compared.

Methods: This single-center retrospective cohort study of inpatients with steroid-refractory ASUC who received infliximab 5 mg/kg (1-3 doses without maintenance) or initial colectomy between 2004 and 2014 assessed long-term healthcare utilization and direct costs following infliximab or colectomy, using admission coding data until 31 December 2016.

Results: A total of 118 patients received either infliximab ( = 85, 72%) or colectomy ( = 33, 28%) as initial therapy, with 35(41%) patients eventually requiring colectomy post-infliximab (median 213 days, range [6, 3739]). Median follow up was 7 years [0, 14]. Following infliximab for ASUC, 44% of patients then received antitumor necrosis factor maintenance. After ASUC therapy, length of stay and number of admissions did not significantly differ between groups but higher numbers of complications prompting readmission occurred in the colectomy group (median 4 1, < 0.001). There were no differences in admissions or total length of stay for patients who had received infliximab first then colectomy those treated with colectomy first (median 7.0 4.0, 41.5 days 29 days, respectively, each > 0.05). Total costs were lower at 6 months (mean AUD17,662 AUD24,852, = 0.003), yet were similar at 7 years following an infliximab compared with colectomy approach (AUD72,834 AUD59,557, = 0.23). After infliximab, costs were significantly higher at 7 years with biologic rather than immunomodulator-only maintenance therapy (AUD109,365 AUD47,842, < 0.01).

Conclusions: In support of current practice, infliximab salvage in steroid-refractory ASUC achieved reduced short-term healthcare costs compared with initial colectomy, though long-term costs were not significantly different.
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http://dx.doi.org/10.1177/2040622319825595DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6354298PMC
January 2019

Systematic Review: Cost-effective Strategies of Optimizing Anti-tumor Necrosis and Immunomodulators in Inflammatory Bowel Disease.

Inflamm Bowel Dis 2019 08;25(9):1462-1473

Department of Gastroenterology and Hepatology, Eastern Health, Monash University, Eastern Health Clinical School, Box Hill, Victoria, Australia.

Background: Medication costs in inflammatory bowel disease (IBD) are now the principal driver of health care costs. Cost-effective strategies to optimize and rationalize treatment are therefore necessary.

Methods: A systematic review until April 30, 2018, was performed to identify economic evaluations of strategies to optimize infliximab, adalimumab, and immunomodulators for the treatment of IBD in adults. A qualitative synthesis of the identified studies was performed.

Results: Seventy articles were identified that met the inclusion criteria. Adalimumab seems cost-effective compared with infliximab as maintenance therapy for moderate to severe Crohn's disease (CD). Infusion costs are a significant additional treatment cost with infliximab. However, other studies found biosimilar infliximab more cost-effective than alternative biologics in fistulizing and moderate-severe luminal CD-although the latter did not reach a willingness-to-pay threshold of <$50,000. In moderate-severe ulcerative colitis, infliximab seems more cost-effective than adalimumab. Multiple tailored approaches to treatment based on objective markers of disease activity or efficacy have been shown to be cost-effective in CD, including following secondary loss of response to anti-TNF therapy for postoperative recurrence and in escalating treatment. For immunomodulator treatment, both thiopurine methyltransferase (TPMT) testing before commencing thiopurines and thiopurine metabolite testing for dose optimization seem cost-effective.

Conclusion: In a win-win for patients and payers, several potential avenues to achieve cost-effectiveness-but also therapeutic optimization of anti-TNF therapies-were elucidated in this review with comparatively sparse data for immunomodulators. Optimizing immunomodulator and anti-tumor necrosis factor alpha therapy to achieve objective disease control seems to be cost-effective at conventional willingness-to-pay thresholds in a number of clinical settings.
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http://dx.doi.org/10.1093/ibd/izy399DOI Listing
August 2019

Higher Mucosal Healing with Tumor Necrosis Factor Inhibitors in Combination with Thiopurines Compared to Methotrexate in Crohn's Disease.

Dig Dis Sci 2019 06 17;64(6):1622-1631. Epub 2018 Dec 17.

Department of Gastroenterology and Hepatology, Eastern Health, Box Hill Hospital, Level 2, 5 Arnold Street, Box Hill, VIC, 3128, Australia.

Background: The differential impact of anti-tumor necrosis factor (anti-TNF) therapy with methotrexate versus thiopurine co-therapy on endoscopic remission remains uncertain.

Aims: To compare rates of endoscopic remission based on methotrexate or thiopurine co-therapy used with anti-TNF therapy in Crohn's disease.

Methods: A retrospective observational study at two tertiary centers between 2010 and 2016 compared endoscopic remission rates and persistence on anti-TNF therapy in combination with methotrexate versus thiopurines for at least 3 months.

Results: Of 412 patients on anti-TNF therapy, 278 (67%) received immunomodulator co-therapy for ≥ 3 months and 269 (65%) had complete data for analysis. Methotrexate was used in 77 (29%) and thiopurines in 192 (71%) patients plus either infliximab (156, 58%) or adalimumab (113, 42%), with median follow-up of 2.8 years. The methotrexate group had greater prior immunomodulator intolerance (62% vs 20%, p < 0.01). Endoscopic remission rates were higher in those treated with thiopurine compared to methotrexate co-therapy at 12 m (58% vs 17%, p < 0.01) and at last review (59% vs 40%, p = 0.03). Endoscopic remission rates were higher with thiopurines than methotrexate when combined with adalimumab (49% vs 6%, p < 0.01) but not with infliximab (65% vs 54%, p = 0.09). In multivariate analysis, thiopurine co-therapy, elevated baseline CRP, and therapeutic anti-TNF drug levels were each associated with longer persistence of co-therapy (each p < 0.05). There were no significant differences in adverse events, malignancy or infection rates.

Conclusion: In this cohort, anti-TNF and thiopurine co-therapy resulted in higher rates of mucosal healing than methotrexate, the difference is most pronounced with adalimumab and conversely with low-dose methotrexate.
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http://dx.doi.org/10.1007/s10620-018-5422-8DOI Listing
June 2019

Characterization of ulcerative colitis-associated constipation syndrome (proximal constipation).

JGH Open 2018 Oct 5;2(5):217-222. Epub 2018 Aug 5.

Department of Gastroenterology Alfred Hospital and Monash University Melbourne Victoria Australia.

Background: The syndrome of constipation with other abdominal symptoms ("proximal constipation") in ulcerative colitis (UC) is commonly recognized by practitioners but is poorly described, with no recognized definition and little understanding with regard to prevalence and effect of therapies on disease outcomes. This study aimed to address these issues in a cross-sectional, consecutive series of patients with UC.

Methods: A working definition of proximal constipation was established. Consecutive patients were recruited, and their disease activity, recent medications, and investigations plus abdominal symptoms were assessed at a study visit. Relevant clinical data were also extracted from medical records.

Results: Of 125 patients with UC, (mean age 47, range 14-84 years, 61 male), 58 (46%) fulfilled the definition of proximal constipation. The main symptoms were reduced stool frequency (69%), hard stools (43%), abdominal pain (40%), excessive flatus (29%), straining (24%), and sensation of incomplete emptying (14%). Proximal constipation was associated with female gender (OR 3.45 [1.45-8.24]), left-sided (OR 2.84 [1.14-7.11]) and concurrently active disease (OR 5.56 [1.96-16.67]), but not age, disease duration or therapy. A total of 88% had an increase in anti-inflammatory therapy, with the use of laxatives or fiber supplements in 63% compared with 1.4% of those without proximal constipation.

Conclusions: Proximal constipation is common, and its risk increases in active and distal disease, especially in women. Validation of its definition and evaluation of therapeutic strategies are needed. A new term "ulcerative colitis-associated constipation syndrome" is proposed to more accurately depict its nature.
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http://dx.doi.org/10.1002/jgh3.12076DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6207018PMC
October 2018
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