bluuebunny/crossref_metadata_2025_split huggingface dataset:
P539 Assessment of age as a risk factor for adverse events in patients from the tofacitinib ulcerative colitis clinical programme
Authors: Lichtenstein G R , Bressler B , Vermeire S , Francisconi C , Lawendy N , Shi H , Salese L , Judd D , Loftus E V 
Published: January 2020

Abstract

Background
Tofacitinib is an oral, small-molecule JAK inhibitor for the treatment of UC. Safety and efficacy of tofacitinib were demonstrated in Phase (P)2/3 induction studies, a 52-week, P3 maintenance study, and are being further investigated in an ongoing, open-label, long-term extension (OLE) study.1,2 Here, we provide an updated analysis of age as a risk factor for adverse events (AEs) in the tofacitinib UC clinical programme.3

Methods
Proportions of AEs and serious AEs (SAEs), and incidence rates (IRs; unique patients with events per 100 patient-years) for AEs of special interest (AESIs), were determined for two cohorts: the Maintenance Cohort (patients who received placebo or tofacitinib 5 or 10 mg twice daily [BID] in the maintenance study) and the Overall Cohort (all tofacitinib 5 or 10 mg BID-treated patients in the P2/P3/OLE studies; as of May 2019), stratified by age. Multivariable Cox proportional hazards regression analyses were performed to assess whether older age was associated with increased risk of AESIs in the Overall Cohort.

Results
In the Maintenance Cohort, IRs of AEs and SAEs were generally similar between treatment groups, with no age-related trend in the proportions of AEs in tofacitinib-treated patients. AESIs were infrequent in both treatment groups; however, herpes zoster (HZ; non-serious and serious) IRs were numerically higher in the ≥40 to &lt;50 and ≥50 years age groups for patients treated with tofacitinib 10 mg BID vs. placebo and tofacitinib 10 vs. 5 mg BID. In the Overall Cohort, IR of serious infections was generally similar between age groups, while IRs of opportunistic infections (OIs) and HZ (non-serious and serious), malignancy (excl. non-melanoma skin cancer [NMSC]), NMSC and major adverse cardiovascular events increased with increasing age. The IRs of HZ and NMSC were significantly greater in patients ≥50 years compared with patients &lt;30 years, and in patients ≥30 to &lt;40 years for NMSC. In multivariate analyses, older age was identified as a significant predictor of malignancy (excl. NMSC), NMSC and HZ.

Conclusion
In the Overall Cohort, there was a trend for an increase in the rates of OIs, HZ, malignancy (excl. NMSC) and NMSC with increasing age. In multivariate analyses, older age was associated with increased risk of malignancy (excl. NMSC), NMSC and HZ. The results of this analysis are generally consistent with previous studies suggesting older age may be associated with an increased risk of certain AESIs in patients with UC, and in some instances in the general population.4

References
P540 GB004, a novel prolyl hydroxylase inhibitor for inflammatory bowel disease, leads to gut-targeted HIF-1α pathway engagement in a multiple-dose study in healthy subjects
Authors: Levesque B , Taylor Meadows K , Buch A , Flynn M , Peters K , Olson A , Shen J , Slee D , Van Biene C , Aranda R , Vande Casteele N , Opiteck G 
Published: January 2020

Abstract

Background
GB004 is a small-molecule prolyl hydroxylase inhibitor that stabilises hypoxia-inducible factors (HIF-1α), key transcription factors involved in the protective cellular responses at the intersection of hypoxia and inflammation. GB004 was selected based on its gut-targeted profile to limit systemic on-target effects associated with HIF-1α stabilisation. GB004 is in clinical development for the treatment of inflammatory bowel disease and was shown to be safe in a single ascending dose study. The study described here evaluates the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of multiple daily doses of GB004 in plasma and colon biopsies.

Methods
This was a randomised, double-blind, placebo-controlled, multiple-dose, Phase 1a study conducted in healthy subjects at a single site in Canada. Three dose levels of GB004 or placebo formulated as a solution were administered orally once a day for 8 days; safety and PK were evaluated. Colon biopsies were obtained one day prior to the first dose and on Day 8. Colonic tissue concentrations of GB004 and HIF pathway target genes were determined.

Results
Forty-two subjects (20 male and 22 female) were dosed. No serious adverse events or deaths were recorded. The most commonly observed adverse event in GB004-treated subjects was dizziness (31%,10/32); all events were mild and did not result in study drug discontinuation. There were no identified risks of GB004. Following oral dosing, GB004 was rapidly absorbed and eliminated from the systemic circulation, with a median time to maximum concentration of 0.5 h for all dose levels. Concentrations of GB004 measured in colon biopsies were greater than in plasma at the time of the biopsy. Dose-related HIF pathway target gene engagement and PD were confirmed.

Conclusion
This study demonstrated that multiple daily doses of GB004 solution were safe and tolerable. The PK profile was consistent with its intended preferential exposure in the gut. A clinical study of GB004 is ongoing in patients with ulcerative colitis to explore safety, tolerability, PK and PD both systemically and within colonic tissue (NCT03860896). A tablet formulation is also being developed.
P541 Are we addressing the top ten research priorities in IBD?
Authors: Geldof J , LeBlanc J F , Lucaciu L , Segal J P , Lees C W , Hart A 
Published: January 2020

Abstract

Background
In 2016, the top 10 research priorities in treatment of inflammatory bowel diseases (IBD) were outlined by a group of clinicians, patients and patient-support organisations based in the UK, using the infrastructure of the James Lind Alliance (JLA) Priority Setting Partnership. Priority statements were ranked in order of perceived importance. The aim of this study was to measure the current distribution of these research priorities in European-led IBD clinical trials, ongoing or completed within the last 3 years, in light of the JLA recommendation. Pharmaceutical-led trials were excluded given the inherent bias towards drug conception and approval.

Methods
The database from Clinicaltrials.gov and European Union Clinical Trials Register were used to create an overview of non-pharmaceutical-driven European clinical studies involving adult patients with IBD. Trials posted on 09/08/2016 (publication date of the top 10 research questions) up to 16/11/2019 were included. The list was completed by trials found to be relevant, although not retrieved initially, based on author consensus.

Results
In total, 154 European non-pharmaceutical-funded clinical studies were found, of which 112 addressed one of the outlined top 10 IBD-research priorities and 8 addressed multiple topics simultaneously. Almost a third (30%) investigated the optimal treatment strategy considering efficacy, safety and cost-effectiveness (immunomodulators, biologics, surgery) in IBD (Priority 1). Development or assessment of biomarkers for stratification of patients (Priority 2) was the subject of 29 studies (24.2%). Twenty-one (17.5%) studies focused on altering gut microbiota (Priority 10). Eleven or fewer studies focused on fatigue, IBD-related pain and perianal Crohn’s disease (Priorities 4, 5 and 8). Priorities 3 and 7 concerning the role of diet in IBD management were evaluated in 9.2% studies. A minority of studies, 2.5% and 1.7%, respectively, addressed optimal timing for surgery in terminal ileal Crohn’s disease (Priority 9) and the best treatment for diarrhoea/incontinence (Priority 6). Of all 19 European countries, France, the UK and Spain accounted for almost half of all reviewed studies (49.2%).

Conclusion
Since publication of the top 10 research priorities in IBD treatment, non-pharmaceutical-funded research has mostly been focusing on development and validation of new therapeutic strategies, investigation of biomarkers and the role of gut microbiota. The latter topic has gained significant interest in IBD research, more so than higher-ranked Priority statements 3 to 9. Further research should prioritise the potential benefit of dietary interventions and patient-reported outcomes, such as management of IBD-related pain, fatigue and faecal incontinence.
P545 Deep remission assessed by endoscopy, magnetic resonance or intestinal ultrasound, in refractory Crohn’s disease patients in clinical remission with ustekinumab: a real-life single-centre experience
Authors: Calvo Moya M I , Omella Usieto I , González Lama Y , Matallana Royo V , González Partida I , Menchen Viso B , De Lucas Téllez de Meneses R , González Rodriguez M , Bella del Castillo P , Vera Mendoza M I 
Published: January 2020

Abstract

Background
Current therapeutic goals in Crohn’s disease (CD) include not only the mere absence of symptoms but also the objective resolution of macroscopic lesions, so-called deep remission (DR), which has been related to better outcomes. DR is usually acknowledged by endoscopy, although magnetic resonance (MR) or intestinal ultrasound (IUS) are also reliable, provide extramucosal information and may be more appropriate in certain clinical scenarios. Data regarding the achievement of DR with ustekinumab in real-life clinical practice is still scarce.

Methods
Retrospective cohort study carried out in a tertiary hospital between April 2017 and April 2019 including patients who had clinically active CD (Harvey–Bradshaw index [HBI] ≥ 4) objectively assessed by either endoscopy, MR or IUS; received intravenous induction with ustekinumab, had achieved clinical remission and had treatment response assessed by either endoscopy, MR or IUS. DR was deﬁned by SES-CD 0–3 or Rutgeerts index i0 if endoscopically assessed, or by complete normalisation of inﬂammatory parameters on cross-sectional imaging. Endoscopic response was deﬁned by the decrease of SES-CD of 50% compared with baseline. Radiographic response was deﬁned by improvement in bowel wall thickness, inﬂammatory fat, mural blood ﬂow and hyperenhancement compared with baseline imaging by physician global assessment. Demographics, clinical data and information regarding ustekinumab treatment were collected.

Results
90 patients treated with ustekinumab at our centre were analyzed, but only 28 met inclusion criteria (14(50%) female; median age 45 (43–50)) with a median follow-up of 19 (IQR: 15–23) months. All of them had previously failed to antiTNFα and 20 (71%) failed to ≥2 biologics. Treatment response assessment was made by endoscopy (22 cases; 79%) or cross-sectional imaging technique (6 cases; 21%) in a median time of 10 months (IQR: 7–13) from the start of treatment. Deep remission was achieved in 18 (64%) patients. Endoscopic response was achieved in 5 (18%) additional patients. Five (18%) remaining patients obtained no objective response to ustekinumab despite being in clinical remission. Patients who had received prior treatment with ≥2 biologics or those classified as B2 or B3 according to Montreal Classification were less likely to achieve deep remission, although those associations did not reach statistical significance.

Conclusion
In our experience, a majority of refractory CD patients who achieved clinical remission with ustekinumab also reached deep remission assessed by either endoscopy, MR or IUS.
P546 Ileal ulcer size significantly impacts the ability to achieve endoscopic remission: a post-hoc analysis from the SONIC trial
Authors: Narula N , Wong E , Achuthan A , Dulai P , Colombel J F , Marshall J K , Ferrante M , Reinisch W 
Published: January 2020

Abstract

Background
Endoscopic remission (ER) is an important target of treatment for Crohn’s disease (CD). However, it is unclear how individual baseline endoscopic characteristics impact the ability to achieve ER. We aimed to determine endoscopic prognostic factors that influence the likelihood of achieving ER in CD.

Methods
This was a post-hoc analysis of SONIC (NCT00094458; YODA #2019–3980), where data from 172 patients who had endoscopic scores at baseline and at week 26 were evaluated. Individual components of the Crohn’s Disease Endoscopic Index of Severity (CDEIS) and the Simple Endoscopic Score for Crohn’s disease (SES-CD) indices were used to evaluate the impact of baseline ulcer depth (CDEIS) and size (SES-CD) on likelihood of achieving ER at week 26. Ileum and colon segments were evaluated separately. Multivariate logistic regression models were used to evaluate the relationship between baseline endoscopic findings and achievement of ER in each segment at week 26, after accounting for known confounders including disease duration and treatment allocation. Results are presented as odds ratios (OR) with 95% confidence intervals (CI).

Results
The rate of ulcer improvement in the ileum was significantly lower than rates of healing throughout the colon (p &lt; 0.0001) (see figure). Patients with ulcer size &gt;2 cm in the ileum were less likely to achieve ER of the ileum compared with patients with ulcer size &lt;2 cm (OR 0.31, 95% CI 0.11–0.89, p = 0.03). Ulcer size did not consistently impact likelihood of achieving week 26 ER in colonic segments. Patients with ileal ulcer size &gt; 2 cm that were also deep were less likely to achieve ileal ER, when compared with patients with smaller or superficial ulcers (OR 0.10, 95% CI 0.02–0.68, p = 0.02). High baseline SES-CD score (&gt;16) or CDEIS score (&gt;12) did not impact the likelihood of achieving week 26 ER.

Conclusion
Ulcer size and depth, but not the overall degree of endoscopic inflammation, seem to impact likelihood of achieving week 26 ER. ER may be more difficult to achieve for patients with larger and deep ulcers in the ileum. These findings may have implications for recruitment into clinical trials and would support the importance of balancing these prognostic factors in trial arms. Further prospective data are needed to validate these findings.
P551 Combination therapy in IBD Patients: Do we need to maximise the dose of Azathioprine?
Authors: Arieira C , Dias de Castro F , Cúrdia Gonçalves T , Moreira M J , Cotter J 
Published: January 2020

Abstract

Background
The use of combination therapy of anti-TNF and thiopurines in inflammatory bowel disease (IBD) is associated with greater efficacy and lower immunogenicity. However, the dose of thiopurine in this setting remains to be elucidated. The aim of the study was to compare the trough levels, anti-TNF antibodies and the inflammatory biomarkers between two groups in combotherapy: one with low dose (LDA) and one with standard dose (SDA) of azathioprine.

Methods
A retrospective study was performed, selecting all patients with an established diagnosis of IBD, who were on combined maintenance treatment (at least 6 months of therapy) with azathioprine and anti-TNF. We divided the population into two groups according to the azathioprine dose: LDA &lt;2 mg/kg and SDA: ≥ 2 mg/kg).

Results
We included 99 patients, 52.5% female with a median age of 33 (17–61) years. Eighty patients (80.8%) were diagnosed with Crohn’s Disease and 19 (19.2%) with ulcerative colitis. Seventy-one (71.8%) patients were on infliximab (IFX) and 28 (28.3%) were on adalimumab (ADA). In the IFX group, there were no differences between trough levels (6.86 vs. 6.70 mg/ml, p = 0.892) or formation of antibodies anti-IFX (6.3% vs. 5.1%; p = 0.838) in SDA vs. LDA. Moreover, there were no differences between inflammatory biomarkers: CRP (p = 0.315) and faecal calprotectin (p = 0.48) among the two groups. Regarding ADA group, there were no differences in trough levels of ADA (10.15 vs. 10.65 mg/ml, p = 0.836), the formation of antibodies anti-ADA (7.7% vs. 6.7%; p = 0.916) and in inflammatory biomarkers: CRP (p = 0.525) and faecal calprotectin (p = 0.496) among the two groups.

Conclusion
In our cohort, there were no differences between anti-TNF trough levels, formation of antibodies anti-TNF and in inflammatory biomarkers among patients in combotherapy with azathioprine in a standard dose vs. lower dose. In terms of immunogenicity, lower doses of azathioprine seem sufficient to inhibit the formation of antibodies, with better tolerance and better safety profile.
P557 Increased risk of anastomotic leak in Crohn’s disease patients unable to complete preoperative mechanical bowel preparation
Authors: Iesalnieks I , Marek F , Kala Z , Kunovsky L 
Published: January 2020

Abstract

Background
To assess the risk of postoperative anastomotic leak in Crohn’s disease patients unable to complete the preoperative mechanical bowel preparation (MBP): a prospective observational study from two referral centres in Germany and the Czech Republic.

Methods
Preoperative MBP was used routinely in all Crohn’s disease patients undergoing elective ileocolic or colorectal resections completed by the formation of an anastomosis since 6/2016. The MBP consisted of 2 L Polyethyleneglycol (PEG) solution combined with two doses of oral antibiotics Metronidazole and Paromomycin. The MBP was defined as incomplete when patients were not able to drink the whole amount of PEG solution due to side effects or complications. The primary endpoint was occurrence of anastomotic leak. The secondary endpoint was the incidence of postoperative intraabdominal septic complications (IASC) which were defined as an anastomotic leak, intraabdominal abscess or fistula and peritonitis.

Results
Between 6/2016 and 11/2019, 96 Crohn’s disease patients underwent elective ileocolic or colorectal resections after receiving preoperative MBP and oral antibiotics. Twenty-four (25%) developed complications of MBP, mostly vomiting; 17 patients (18%) were not able to complete MBP. The presence of extraintestinal disease manifestations (Hazard Ratio 4.8, p = 0.029), preoperative weight loss (HR 5.7, p = 0.019) and female sex (HR 13.3, p = 0.005) were associated with an increased probability not to be able to complete MBP. Postoperative anastomotic leak occurred in 2 patients (2%). The risk of anastomotic leak was significantly higher in patients unable to complete MBP (12%) as compared with patients with complete MBP (0%, p = 0.03). Postoperative IASC occurred in 7 patients (7%). Patient unable to complete preoperative MBP were at higher risk to develop IASC; however, the difference was not statistically significant (18% vs. 5%, p = 0.10)

Conclusion
The anastomotic leak rate is very low when preoperative mechanical bowel preparation and oral antibiotics have been used. However, patients not able to complete MBP might be at an increased risk.
P558 Validation of the ‘IBD Disk’ in clinical practice
Authors: FERGUSON A , Ding N , Connell W , Williams J , Wright E , Kamm M , Thompson A , Lust M , Flanagan E , Basnayake C 
Published: January 2020

Abstract

Background
The inflammatory bowel disease (IBD) Disk is a tool that has been developed from the IBD Disability Index in order to objectively measure the degree of disability in patients suffering from IBD. It provides a visual representation of disability state, thereby increasing the ease of application in a clinical setting. Currently, it has not yet been validated in any population. Our primary aim was to hence validate the IBD Disk in a clinical setting.

Methods
40 patients were recruited from an outpatient setting in a tertiary centre in Australia. All patients completed four surveys, the IBD Disk, the IBD Disability Index (IBD-DI), the Hospital Anxiety and Depression Score (HADS) and the Shortened IBD Questionnaire (SIBDQ). Nineteen of these patients then elaborated on their answers in a semi-structured narrative interview based on the IBD Disk. After a consultation with a gastroenterologist, the treating doctors were also asked to fill out an IBD Disk based on their own perceptions of the participant’s degree of disability. The IBD Disk was assessed for its internal consistency, construct validity and factor structure. The qualitative data were analysed and coded using NVIVO and then associated to IBD Disk scores.

Results
Of the patients recruited 48% were female, 30% had ulcerative colitis and 52% were in clinical remission. Average IBD Disk score was 40.75. Our results suggest the IBD Disk is an internally consistent tool for clinical use when assessing disability (Cronbach’s Α = 0.888). This is supported by statistically significant differences in IBD Disk scores between patients in clinical remission and patients with active disease (p = 0.002). There is also a good correlation between the Patient-Reported IBD Disk scores and the IBD-DI scores (r = 0.864), Doctor Perceived IBD Disk scores (r = 0.794) and the HADS Depression score (r = 0.759). IBD Disk scores also negatively correlated with the Shortened IBD Questionnaire (r = −0.864). Qualitative data also correlate well thematically with IBD Disk scores. These results suggest an appropriate system for grading disability status via the IBD Disk is: 0–24 = no disability; 25–49 = mild disability; 50–74 = moderate disability; and, 75–100 = severe disability.

Conclusion
This study supports the use of the IBD Disk as a reliable and valid self-reporting tool in clinical situations. There is strong internal consistency, construct validity, factor structure and qualitative thematic association. However, more data are needed to further validate the IBD Disk. Most significantly though, the IBD Disk is likely to become a valuable tool for the practical assessment of disability in patients with IBD in the near future.
P569 The role of multidrug-resistant infections in IBD patients undergoing surgery
Authors: Colombo F , Lamperti G M B , Antinori S , Corbellino M , Maconi G , Ardizzone S , Foschi D , Sampietro G 
Published: January 2020

Abstract

Background
Inflammatory bowel diseases (IBD) patients are particularly vulnerable to an increased incidence of infections, due to both innate characteristics and prolonged pharmacological therapies as steroids, biologics and antibiotics. Very few data are available in the literature about multidrug-resistant (MDR) infections and previous studies have not taken into account the impact of the surgical treatment on infections. We focused on the identification of risk factors for the development of MDR infections in IBD patients undergoing surgical procedures, we investigated the involved microorganisms, and finally, we proceeded to a costs/complications analysis of the treatment.

Methods
472 consecutive, unselected IBD patients (285 Crohn’s disease and 187 ulcerative colitis) undergoing surgery from 2016 to 2018 in our Tertiary Care Centre were divided into three groups: MDR infections, antibiotics sensitive infections (no-MDR) and no infections.

Results
In 37 CD patients nutritional status (p &lt; 0.0008), preoperative biologics (p &lt; 0.008) and antibiotic therapy (p &lt; 0.001), duration of surgical procedure (p &lt; 0.0001) and preoperative hospitalisation length (p &lt; 0.0001) were risks factors for MDR infection development. In 14 UC patients multidrug-resistant infection was related to age at surgery (p &lt; 0.003), disease duration (p &lt; 0.008), inflammatory/nutritional status (p &lt; 0.04), preoperative antibiotic therapy (p &lt; 0.04), and suture leakage (p &lt; 0,01). In the MDR CD group Gram + cocci (54%) were the most implicated pathogens, with a prevalence of 19% of Enterococcus faecium; while in MDR UC patients Gram – bacilli (59%) were the most involved pathogens, with prevalence of Escherichia coli ESBL+ (47%). The antibiotic therapy cost for the CD group was higher in MDR (3249 €) and no-MDR (924 €) groups vs. non-infected patients (41€). In UC we found higher cost only in the MDR group (1408€ vs. 33€).

Conclusion
Preoperative risk factors involved in the development of MDR infections in IBD patients undergoing surgery were identified. Some factors, such as nutritional status or preoperative antibiotic therapy, were found to be common between CD and UC patients, while some others were found to be specific for UC or CD. Some of these elements appear to be non-modifiable, while some others are part of the multidisciplinary approach, for which further studies are needed to improve the preoperative ‘patient optimisation’ in order to reduce surgical complications.