bluuebunny/crossref_metadata_2025_split huggingface dataset:
P524 Administration and monitoring of biologic therapy in patients with inflammatory bowel disease: A national Danish survey
Authors: Volmar S , Wildt S , Munck L K 
Published: January 2020

Abstract

Background
Administration and monitoring of biologic therapy to patients with inflammatory bowel disease (IBD) is an increasing burden in gastroenterology outpatient clinics. The aim of this study was to compare the present organisation of biologic therapy to IBD patients in Denmark with the published evidence.

Methods
A national online survey using SurveyXact was send to all outpatient clinics administering biologic treatment to IBD patients in Denmark in March 2019. It focused on infusion time, post infusion observation and biochemical control of treatment with biologic drugs. A systematic literature search covering the same topics was performed on PubMed in May 2019.

Results
21 of 23 clinics completed the survey. Infusion time for infliximab induction was 2 h in all clinics and was reduced to 30 min or 1 h in 60 % and 40% of clinics respectively after ≥ 10 infusions. Vedolizumab infusion time was 30 min in 90% of clinics from start. Ustekinumab infusion time was 1 h in 90% of clinics. Observation time after intravenously administered biologics varied considerably. Only half of the clinics discharged patients on infliximab without post-infusion observation from the start of maintenance treatment increasing to 80% of clinics after ten infusions. About half of the clinics observed patient on vedolizumab maintenance for at least 30 min after 5 infusions. Ten clinics discharged patients immediately after the initial ustekinumab infusion. In 30–60% of clinics, patients were observed 20–120 min after subcutaneous injection of ustekinumab, adalimumab or golimumab. Twenty clinics controlled laboratory parameters prior to every maintenance treatment with infliximab and vedolizumab, no matter of infusion interval, while patients on injection therapy with adalimumab, golimumab and ustekinumab had biochemical tests taken every second to third months. Only two clinics measured trough values and antibodies against biologics routinely and adjusted the dose accordingly to the trough value. The systematic literature search identified 26 relevant articles. These showed that infliximab infusion time of 30 minutes is safe and questioned the necessity of post-infusion observation. There was no consensus on the frequency of biochemical control in patients on biologics.

Conclusion
Reduction and harmonisation of infusion time, post-infusion and post-injection observation time for patients on biologics could release patient and staff resources.
P527 A review of adverse events associated with immunosuppressive treatments in inflammatory bowel disease patients
Authors: Tassone D , Ding N 
Published: January 2020

Abstract

Background
Medical therapies that suppress various pathways involved in inflammation comprise the mainstay of inflammatory bowel disease (IBD) treatment. Adverse events, including the development of serious infection and malignancy, have been associated with these therapies. This study evaluates the current evidence regarding serious adverse events associated with immunosuppressive agents in the IBD patient population.

Methods
A systematic search was conducted in September 2019 by combining three key research themes: inflammatory bowel disease, immunosuppression, and adverse events. For this systematic review, adverse events are defined as either the development or recurrence of malignancy or the development of serious infection necessitating hospital admission.

Results
There is a demonstrated association between thiopurine use and increased risk of both nonmelanoma skin cancer (NMSC) or lymphoma. The length of thiopurine exposure required to increase NMSC risk is, however, unclear. Of the papers reporting on exposure length and NMSC risk, the thiopurine exposure duration required to result in a statistically significant increase in NMSC risk varied from 6 months to 5 years. Among the studies retrieved, there is a lack of consensus on malignancy risk associated with the use of anti-TNF agents. From 5 studies on malignancy risk associated with the use of anti-TNF agents, one concluded that malignancy risk is increased while three concluded that risk is unchanged from baseline. The fifth study is inconclusive on any possible association. Confounding by past or concurrent thiopurine exposure remains an issue. There is a clear association between combination therapy with both thiopurines and anti-TNF agents and increased malignancy risk when compared with exposure to either thiopurine or anti-TNF therapy alone. Anti-integrin agents were not found to be associated with an increase in adverse effects when compared with placebo, while nil studies on ustekinumab were retrieved. Individual studies on infection risk do not consistently stratify infections according to severity, limiting any analysis.

Conclusion
An established association between thiopurine use and increased risk of both lymphoma or NMSC exists. However, the duration of thiopurine exposure necessary to increase NMSC risk is uncertain. There is a lack of consensus on whether anti-TNF agents increase malignancy risk due to confounding from past or concurrent thiopurine exposure. Combination therapy increases malignancy risk when compared with exposure to either thiopurine or anti-TNF therapy alone. Limited studies on the newer biologic therapies were retrieved. Finally, evidence which stratifies infections according to severity is lacking.
P529 Natural history and management strategies of ulcerative colitis (UC) in a paediatric population: A 10-year review in a tertiary paediatric gastroenterology centre
Authors: Sonnino M , Ocholi A , ElZein A , Saliakellis E , Pensabene L , Borrelli O , Kiparissi F 
Published: January 2020

Abstract

Background
Paediatric UC can be severe with high colectomy rates. We describe clinical practice, management strategies and determine whether an accelerated approach can influence the natural history of UC.

Methods
Retrospective study reviewing paediatric UC patient’s records diagnosed January 2009–June 2019. Demographics, diagnosis, auxology, extra-intestinal manifestations, medical/surgical treatment and therapeutic drug monitoring (TDM) data were recorded.

Results
Fifty-two patients were diagnosed with UC, 23 females. Median age at diagnosis 10 years (range: 1–15). Median follow-up: 40.5 months (range: 1–125). At diagnosis, 85% received 5-aminosalicylates (5ASA), 82% steroids, 51% azathioprine. Within 1 year, 94% received steroids, 90% azathioprine and 69% biologics (Infliximab (IFX) and Adalimumab (ADA)), mean months after diagnosis: 18.4 ± 16.8. Seventy-six per cent were monitored with a proactive approach (TDM). Seventy-one per cent developed antibodies towards IFX after an average of 9.2 months (concomitant treatment with immunomodulators), 27% to ADA after an average of 15.2 months. Treatment at 1 year: 80% 5ASA, 70% AZA, 8% MTX, 13% IFX, 13% ADA and 4% sirolimus. At 1-year follow-up, steroid treatment dropped from 82% to 24% (p &lt; 0.001), steroid-free remission rate 76%. Rate of first relapse 19% within 3 months, 38% within 6 months and 61.5% within 12 months. The latest endoscopy available (mean: 41.6 ± 25.2 months): 19% mucosal remission, disease limited to rectum: 15%. Disease regression 40%, stable 23% and progression 6%. Extra-intestinal manifestations 27%; three cerebrovascular events. No patients manifested lymphoproliferative disease. Only three patients underwent surgery, colectomy rate 6%. We compared patients who initiated azathioprine at diagnosis (51%, early group) and after 1 month (44%, late group). No surgery in the early group, two in the late group. Steroid use was higher in the early group (95% vs. 61%, p = 0.013). There were no differences in the mean number of steroid courses, PUCAI, treatment escalation, flares, family history, UCEIS, blood exams at diagnosis and growth parameters. At 1-year follow-up, the mean PUCAI was double in the late group, CRP was double in the early group (18.3 ± 24.9 vs. 7.3 ± 10.0, p = 0.2). The need to escalate treatment at 2 years was correlated to ESR (p = 0.05) and PUCAI at 1 year (p = 0.04), steroid courses (p = 0.049) and AZA dose at 1 year (p = 0.04). We found a significant difference in patients receiving adalimumab (0 vs. 6, p = 0.005). AZA doses were similar in both groups.

Conclusion
We suggest that an accelerated step-up approach may reduce colectomy rates in paediatric UC patients. Further multi-centre studies are needed to confirm our findings.
P530 Cost-effectiveness of vedolizumab SC vs. adalimumab for moderately to severely active ulcerative colitis
Authors: Diakite I , Schultz B , Carter J , Snedecor S , Turpin R 
Published: January 2020

Abstract

Background
Intravenous vedolizumab (VDZ IV) is approved for the treatment of moderately to severely active ulcerative colitis (UC). Subcutaneous VDZ (VDZ SC) was studied in the VISIBLE 1 trial (NCT02611830) and is under review by the US Food and Drug Administration for maintenance treatment. VARSITY (NCT02497469) is the first head-to-head trial to compare 2 biologics (VDZ IV vs. adalimumab SC [ADA]) in UC. We evaluated the cost-effectiveness of VDZ SC vs. ADA from a US payor perspective using efficacy data from these trials.

Methods
We used a cohort decision tree model with a time horizon up to 2 years. Simulated cohorts included patients with and without prior biologic therapy who initiated treatment with VDZ IV (300 mg in weeks 0, 2, and 6) or ADA (day 1: 160 mg; day 15: 80 mg) for a 6 week induction period. Initial responders went on to maintenance treatment with VDZ SC (108 mg every 2 weeks) or ADA (40 mg every 2 weeks); maintenance remitters continued treatment for 2 years. Patients with inadequate response to induction, or serious adverse drug reaction (ADR) switched to treatment with biologics (tofacitinib, infliximab, or golimumab). Patients who were intolerant to biologics received corticosteroids with or without curative surgery. The relative effectiveness of VDZ IV vs. ADA was derived from network meta-analyses of published randomised controlled trials. Model outcomes included total direct medical costs associated with drug acquisition, administration, routine monitoring, toxicity management, ADRs, and cost per remission achieved. Costs (eg, drug, monitoring, healthcare resource utilisation, administration) are expressed in 2019 US$.

Results
Based on our model, VDZ SC was associated with greater clinical response (52.92% vs. 45.07%) and remission at year 2 (22.49% vs. 14.36%) compared with ADA. Total direct medical costs per patient over 2 years were $98,034 for VDZ SC and $137,007 for ADA. After 2 years of treatment, more patients were in remission with VDZ SC than ADA for lower overall costs.

Conclusion
The clinical foundation for this model is built primarily on evidence from clinical trials of adults with moderately to severely active UC. This allowed us to extrapolate clinical outcomes out to 2 years and estimate direct medical costs over that time. These modelled outcomes indicated that treatment with VDZ IV followed by VDZ SC is more effective and less costly for remission compared with initiation with ADA.
P535 Effects of the Janus Kinase 1 (JAK1)-selective inhibitor filgotinib on circulating cytokines and whole-blood genes/pathways of patients with moderately to severely active Crohn’s disease (CD)
Authors: Roblin X , Serone A , Yoon O K , Zhuo L , Grant E , Woo J , Liu J , Galien R , D’Haens G 
Published: January 2020

Abstract

Background
A Phase 2 study of the JAK1-selective inhibitor filgotinib (FIL) dosed at 200 mg once daily for 10 weeks in moderately to severely active CD (FITZROY, ClinicalTrial.gov #NCT02048618) demonstrated significantly higher clinical remission rates compared with placebo,1 and early decrease in systemic and mucosal inflammation biomarkers that was more pronounced in endoscopic responders.2 We investigated baseline (BL) correlation of whole-blood transcriptome pathway activities with clinical disease indexes and circulating cytokines. The effect of FIL on changes in disease-related pathways in responders and nonresponders was also explored.

Methods
PAXgene blood samples were collected from 104 CD patients at BL and Week 10 (W10). RNA was sequenced (Illumina HiSeq 2500) after globin depletion (ThermoFisher GlobinClear). Differential gene expression analysis was performed using the limma R package,3 and Hallmark pathway4 activity scores were calculated using a single-sample Gene Set Enrichment Analysis (ssGSEA).5 All correlations were performed using the Spearman method.

Results
At BL, pathways with activity scores positively correlated with Simple Endoscopic Score for Crohn’s Disease (SES-CD) were immune (IL6/JAK/STAT3, inflammatory response), metabolic, and reactive oxygen species (ROS). These were also positively correlated with systemic inflammation (CRP, SAA, IL6, and OSM) and epithelial turnover (IL22, C4M2, and C3M) markers. Ten weeks of FIL treatment led to significant decreases in these pathways in endoscopic responders (50% reduction in SES-CD) (Figure), whereas there were no significant changes by placebo treatment. While interferon (IFN) response pathway scores showed a weak correlation (rho &lt; 0.2) with SES-CD at BL, they are significantly reduced by FIL treatment, particularly in FIL responders.

Conclusion
In whole blood, inflammation, metabolic, and ROS pathways are reduced by FIL in endoscopic responders at W10, while a reduction in IFN response pathways was observed in all patients regardless of endoscopic response.

References
P536 Early prediction of intravenous corticosteroid therapy failure in moderate–severe ulcerative colitis
Authors: Croft A , Lord A , Radford-Smith G 
Published: January 2020

Abstract

Background
An episode of acute severe ulcerative colitis (UC) is a watershed event during the disease course with a heightened risk of colectomy during and following these episodes.1 The prompt identification of these events followed by the early implementation of appropriate treatment is essential to obtaining the best clinical outcomes for these unwell patients. The majority of published risk scores predicting the important clinical outcomes of intravenous corticosteroid therapy failure and colectomy-by-discharge rely on clinical data from days 1–3 of therapy.2 There is a paucity of tools that allow for a simple and individualised prediction of risk of corticosteroid therapy failure during the earliest stages of admission.

Methods
Data were prospectively obtained from 349 presentations of moderate–severe UC requiring hospital admission to a tertiary referral hospital. The failure of intravenous corticosteroid therapy was strictly defined by the (Oxford) Day 3 and Day 7 criteria.3 Seventeen clinical, laboratory and endoscopic variables all available within 24 h of hospital presentation were assessed for their ability to differentiate intravenous corticosteroid therapy responders from non-responders. A stepwise generalised linear model was formulated based on the results of the initial univariate analyses.

Results
Intravenous corticosteroid therapy failure occurred in 208/349 (60%) of presentations. The formulated risk score included the variables of oral corticosteroid therapy failure, bowel frequency and serum albumin concentration with or without the Mayo endoscopic subscore (MES). With the addition of the MES, the area under the curve (AUC) of the risk score was 0.758. When the positive predictive value of the score (threshold) for correctly predicting intravenous corticosteroid therapy failure was set at 85%, 105/275 (38%) of presentations with available data were identified as high risk for corticosteroid therapy failure (Figure 1).

Conclusion
This practical risk assessment tool provides clinicians with a personalised prediction of the likelihood of success of a course of intravenous corticosteroid therapy in moderate–severe UC. It enables the identification of individuals at high risk of treatment failure who may be suitable for consideration of early treatment escalation or screening for appropriate clinical trials.

References
P549 A virtual clinic enhances the quality use of anti-TNF dose intensification and rates of treatment success using a treat-to-target approach compared with standard outpatient care in Crohn’s disease
Authors: Srinivasan A , van Langenberg D R , Little R , Sparrow M P , De Cruz P , Ward M G 
Published: January 2020

Abstract

Background
Virtual clinics (VC) represent a novel model-of-care which promote quality use of biologics and facilitate a treat-to-target (T2T) approach. We aimed to evaluate the clinical and process-driven outcomes of intensified anti-TNF therapy for secondary loss of response (SLoR) in a VC compared with standard outpatient care (SoC).

Methods
A retrospective multicenter, parallel observational cohort study of patients with Crohn’s disease (CD) who underwent anti-TNF dose intensification to address SLoR with up to 2-years of follow-up was undertaken. Objective assessments of disease activity and anti-TNF trough levels at SLoR then during subsequent 6-month semesters were compared longitudinally between VC and SoC groups. ‘Anti-TNF escalation success’ was the primary endpoint, defined as achieved when two consecutive 6-month semesters of objective assessment demonstrated inactive disease. Dose intensification was defined as ‘appropriate’ if there was both objective evidence of disease activity, plus anti-TNF trough levels at or below the lower limit of the therapeutic range prior to intensification. ‘Treatment escalation failure’ was defined by the occurrence of one or more of biologic switching, discontinuation or further intensification; recommencement of corticosteroids, or IBD-related surgery.

Results
149 patients (69 VC vs. 80 SoC) underwent infliximab (n = 94) or adalimumab (n = 55) dose intensification with similar baseline patient, disease and treatment characteristics between cohorts. The median duration of follow-up post dose-intensification was 1.9 and 1.5 years for the SoC and VC cohorts respectively (p = 0.37). There were higher rates of appropriate dose intensification (82.6 vs. 40.0%, p &lt; 0.01) across the VC cohort. Higher proportions of anti-TNF escalation success (60.9 v 35.0%, p &lt; 0.01), biomarker remission (i.e., C-Reactive Protein (&lt;5mg/l) and faecal calprotectin (&lt;150 μg/ml) normalisation, log-rank tests, p = 0.06 and p &lt; 0.01 respectively), tight disease monitoring (84.1 vs. 28.8%, p &lt; 0.01) and de-escalation of intensified therapy (21.3 vs. 10.0%, p = 0.03) were also achieved by the VC cohort following dose-intensification.

Conclusion
This study favoured a VC-led model of care over standard outpatient-based IBD care in facilitating an effective T2T approach to CD management. A VC model of care improved quality use of intensified anti-TNF therapy through processes that promoted appropriate dose intensification and encouraged more frequent anti-TNF dose de-escalation. Moreover, tight semester-based monitoring using a T2T-based strategy facilitated by the VC was associated with improved treatment outcomes.
P553 Safety of the sequential use of biological therapy in inflammatory bowel disease: Results from a tertiary referral centre
Authors: Moens A , Ballet V , Sabino J , Vermeire S , Ferrante M 
Published: January 2020

Abstract

Background
Switching between biological therapies is frequently observed in the routine management of inflammatory bowel disease (IBD). Yet, it is unknown whether sequential use of biologicals affects safety such as serious infections and malignancies. We aimed to compare the occurrence of serious infections and malignancies in regards to the number and classes of biologicals to which patients were exposed.

Methods
This retrospective cohort study included all IBD patients exposed to commercially available biologicals from 1999 to 2019 in a tertiary referral centre. Follow-up started at initiation of first biological. Exclusion criteria included: patients &lt;18 years, episodic administration of biologicals or administration for another indication than IBD and loss to follow-up &lt;2 years after initiation of first biological. Via review of full electronic medical records, we studied the development of serious infections (defined as any infection leading to hospitalisation or treatment change) and malignancies. Poisson and Cox regression models were used.

Results
In total 1374 patients were included (Figure 1). During a median (IQR) follow-up of 8 (4–13) years, 373 serious infections and 127 malignancies were reported in 245 (19%) and 92 (7%) patients, leading to an incidence rate of 2.2 and 0.8 per 100.000 patients per year, respectively. The number of serious infections was dependent on prior exposure to immunomodulators (IM, p = 0.001), the number of biologicals (p = 0.042) and the number of biological classes to which the patient was exposed (p = 0.004, overall test Poisson model p = 0.0001). The risk of serious infections increased when a patient was exposed to three or more different biologicals or two or more different classes of biologicals. The number of malignancies was also affected by the number of biologicals (p = 0.028) to which the patient was exposed, with a higher risk of developing a malignancy with exposure to an increasing number of biologicals (Figure 2 and 3). Cox regression for the time to develop a first or second malignancy was independent of exposure to IM, number of biologicals as well as number of different biological classes to which the patient was exposed. Median (IQR) time to develop a first or second malignancy after the start of the first biological was 6 (3–9) and 6 (4–12) years.

Conclusion
In this large single-centre cohort study spanning 20 years, the overall risk of serious infections and malignancies in patients exposed to biologicals remains low, yet the risk increased with more and sequential use of biologicals so close vigilance is needed.