bluuebunny/crossref_metadata_2025_split huggingface dataset:
P368 Tofacitinib induction efficiency and intracellular cytokine dynamics in ulcerative colitis: Results from clinical practice
Authors: Kolar M , Lukas M , Malickova K , Prochazkova L , Bortlik M , Duricova D , Hruba V , Machkova N , Mitrova K , Vasatko M , Lukas M 
Published: January 2020

Abstract

Background
Tofacitinib is an oral JAK inhibitor approved for the treatment of ulcerative colitis (UC). Its efficiency was proven in registration trials; however, data from clinical practice are insufficient. Our aim was to evaluate response to tofacitinib after 8 weeks in UC patients, and to assess potential predictors of response including early cytokine production shifts.

Methods
Data from consecutive UC patients who started tofacitinib 10 mg b.i.d. were evaluated. Disease activity was assessed by Mayo score at baseline and week 8 together with C-reactive protein (CRP) and faecal calprotectin (FC). Production of IL-4, IL-10, IL-17, TNFα and IFNγ in T-helper cells was determined at baseline and week 4. At week 8, patients with total Mayo 0–5 with endoscopic subscores 0–1 were considered responders. Adverse events were registered at every visit.

Results
Twenty-four patients (41.7% males, 58.3% females), mean age 35.3 ± 11.8 years were included. Mean disease duration was 8.3 ± 5.2 years. In median, the patients were previously treated with two biologic agents; however, 25% of the patients were naive to any biologic therapy. Systemic corticosteroids were present in 41.7% patients at baseline and no patient had concomitant biologic or other immunosuppressive therapy. At week 8, 52.9% of patients responded to therapy. Total Mayo decreased in responders from mean 5.9 ± 3.5 to 1.1 ± 1.3 (p = 0.01), while in nonresponders it changed from 8.0 ± 2.5 to 8.9 ± 2.1 (p = 0.86). Endoscopic subscore decreased from 2.0 ± 1.0 to 0.6 ± 0.7 (p = 0.02) in responders, however, remained stationary in nonresponders (2.9). CRP and FC dropped significantly in responders (6.7 ± 6.2 vs. 2.0 ± 2.2 mg/l, p = 0.04; 1195 ± 1189 vs. 578 ± 654 μg/g, p = 0.05), but not in nonresponders. The responding and nonresponding groups differed significantly in baseline triglycerides, which were higher in nonresponders. Other baseline parameters were comparable. In responders, there was a significant decrease in IL-4 and no change in IL-10, while in nonresponders, there was no change in IL-4 and a significant decrease in IL-10. Tofacitinib was stopped in 23.5% of patients at week 8 due to insufficient response. Two patients reported headaches after treatment initiation and single events of CMV colitis, C. diff. colitis and oral candidiasis occurred.

Conclusion
Tofacitinib was efficient in inducing clinical response with mucosal healing in about 50% of UC patients after 8 weeks of therapy. There was no clear baseline predictor of response, however, considering limited sample, there was also no indication of even multiple biologics failure negatively affecting the response. Preliminary results of cytokine dynamics suggest early IL-4 decrease as a potential biomarker of response, warranting further investigation.
P379 Surveillance with chromoendoscopy to detect new dysplasia in inflammatory bowel disease
Authors: Villar Lucas C , Quiñones Castro R , Vaquero Ayala L , Suárez Álvarez P , Fernández Gundin M J , Sierra Ausín M 
Published: January 2020

Abstract

Background
Inflammatory Bowel Disease patients (IBD) are in a higher risk of colorectal cancer (CRC) than the general population. Studies show that surveillance with chromoendoscopy (CE) is useful for prevention as it detects a higher number of dysplastic lesions, allowing their endoscopic resection and therefore preventing CRC. We aimed to assess our endoscopic results in IBD patients with previous diagnose of dysplasia.

Methods
We performed a retrospective data collection from IBD patients who have had dysplastic lesions in screening chromoendoscopy, performed in our hospital from January 2013 to June 2019. Demographic and clinical data at basal time were collected, as well as endoscopic and histological findings in basal chromoendoscopy and in the first follow-up

Results
353 chromoendoscopies were performed in our Endoscopy Unit in this period and 50 patients showed dysplastic lesions. 14 (28%) of them had already had dysplasia in previous colonoscopies, which were performed with white light and aleatory biopsies. Basal characteristics are shown in the following table.
In the initial chromoendoscopy, an average of 2.57 dysplastic lesions with an average size of 7.59 mm was detected. 70.8% were flat lesions (0-IIa/0-IIb Paris classification) and 53% were located distal to the splenic flexure. 85.7% were tubular adenomas low-grade dysplasia (LGD), 2 cases of high-grade dysplasia (HGD), one serrated polyp and one adenocarcinoma. Twenty-nine follow-up chromoendoscopy have been performed and new dysplasia lesions were found in 41.37% (average of 1.86 lesions, median 8 mm). 55.6% of the lesions were tubular adenomas LGD and 11.1% serrated adenomas LGD. Our analysis shows that patients with new lesions in the second chromoendoscopy had had worse bowel preparation on the first one (7.5 vs. 8.9, p = 0,006). We also found that these patients with new lesions had more flat lesions than sessile ones (70.6% Paris IIa, 23.5% IIb, 5.9% Is, p &lt; 0,005).

Conclusion
Surveillance with chromoendoscopy in IBD patients with previous dysplastic lesions detects new dysplasia in 28% of them and LGD is the most frequent histology. In our sample, finding flat lesions or worse bowel cleaning in the first chromoendoscopy predicts having a higher number of lesions on the follow-up.
P385 A mucosal marker predicting tofacitinib induced an endoscopic response in ulcerative colitis
Authors: Verstockt B , Verstockt S , Alsaoud D , Sabino J , Ferrante M , Vermeire S 
Published: January 2020

Abstract

Background
The pan-Janus kinase (JAK) inhibitor tofacitinib (TFC) has recently been approved for and added to the treatment armamentarium of patients with moderate-to-severe ulcerative colitis (UC). With increasing choices and absence of predictive biomarkers generated from pivotal trials, real-world data are needed to stratify patients based on their molecular fingerprint in order to improve likelihood of response.

Methods
We obtained inflamed colonic biopsies from 52 consecutive patients initiating biological therapy (anti-TNF [n = 16], vedolizumab [VDZ, n = 20]) or TFC [n = 16] for active UC (Mayo endoscopic sub-score ≥2). Treatment choices were made in agreement between patient and physician, but all included patients were naïve for the mode of action initiated. All patients were treated with standard dosage according to the label. The response was defined as a Mayo endoscopic sub-score ≤1 and assessed by weeks 8–14. RNA was extracted and single-end RNA sequencing performed using Illumina HiSeq4000. Sequencing data were analysed through differential gene expression (DESeq2) and an unbiased network biology approach (Weighted Gene Coexpression Network Analysis).

Results
Response was observed in 5 (31.2%) anti-TNF, 13 (65.0%) VDZ, and 5 (31.2%) TFC-treated patients. Previously reported markers for anti-TNF response, including oncostatin M (p = 0.62), TREM1 (p = 0.70) and IL13RA2 (p = 1.0) could not differentiate TFC responders from non-responders. Similarly, the 4-gene vedolizumab signature [MAATS1, PIWIL1, RGS13 and DCHS2] could not discriminate TFC responders from non-responders (p = 0.13). No baseline differences in JAK/STAT-signalling could be identified either. Hence, we performed an unbiased network analysis of all TFC samples which identified 1 cluster of 65 genes, significantly correlating with response (p = 0.006). The hub gene within this network turned out to be the most differentially expressed gene (p = 1.5E−9, fold change [FC] 2.3), with a predictive accuracy for response of 100% (p &lt; 0.001). In contrast, this gene could not predict anti-TNF or vedolizumab induced response (p = 0.13; p = 0.10, respectively). Of interest, baseline expression of the identified marker did not correlate with C-reactive protein, faecal calprotectin, Mayo endoscopic sub-score and other inflammatory markers including IL-6, IL-1B or epithelial markers. In TFC responders, the identified biomarker was significantly reduced by week 8, as compared with baseline (fold change [FC] -3.1, p = 0.0004), but not in non-responders (FC 1.2, p = 0.2) (Figure 1).

Conclusion
We identified a TFC-specific biomarker unrelated to disease severity, increasing the potency of a robust predictive marker based on its underlying mode-of-action. Validation in independent larger datasets is warranted.
P420 A randomised, observer-blinded phase Ib multiple, ascending dose study of UTTR1147A, an IL-22Fc fusion protein, in healthy volunteers and ulcerative colitis patients
Authors: Wagner F , Mansfield J , Geier C , Dash A , Wang Y , Li C , Lekkerkerker A , Lu T 
Published: January 2020

Abstract

Background
Inflammatory bowel disease (IBD) is characterised by gut dysbiosis, weakened epithelial barrier, and a dysregulated immune system. Interleukin-22 (IL-22), an IL-10 family cytokine, has demonstrated efficacy in animal IBD models by promoting intestinal epithelial repair, increasing antimicrobial peptide production, and increasing mucin production via goblet cells1. UTTR1147A is a fusion protein in which IL-22 is linked with the Fc portion of IgG4 to improve the pharmacokinetic (PK) characteristics.

Methods
A phase I study (NCT02749630) was conducted to evaluate the safety, tolerability, PK, and pharmacodynamics (PD) of repeat IV dosing of UTTR1147A in healthy volunteers (HV) and UC patients with centrally read Mayo endoscopic score ≥ 2. 38 HVs and 24 UC patients were given UTTR1147A or placebo at doses ranging from 30 to 90 µg/kg either biweekly or monthly (6:2 UTTR1147A: placebo per cohort). PK and serum PD (REG3A and CRP) were studied across multiple time points and the Mayo Clinic Score was evaluated at baseline, day 30 and day 85.

Results
Overall, UTTR1147A was safe and adequately tolerated in HV and UC patients. The most common adverse events were on-target dermatological effects (dry skin, erythema, and pruritus) that were manageable, monitorable and reversible. Dose-limiting non-serious dermatological toxicities (severe dry skin, erythema, exfoliation, and discomfort) were seen in two HVs and 1 UC patient dosed with 90ug/kg Q2wk. There were 2 unrelated serious adverse events (ankle fracture and cytomegalovirus infection) that eventually resolved. PK analyses showed that UTTR1147A exposures were, in general, dose proportional within HVs and within UC patients, with a mean elimination half-life of ~16 days and ~12 days, respectively. At the same dose level, UC patients showed relatively lower drug exposures than HVs, possibly due to faster drug clearance. Consistent with the Phase Ia2, UTTR1147A directly induced production of serum PD biomarkers REG3A and CRP at all dose cohorts tested compared with placebo. Notably, UC patients appear to have attenuated serum PD responses compared with HV. Clinical response was observed in 7/18 patients, and clinical remission in 5/18 patients treated with UTTR1147A compared with 1/6 and 0/6 placebo patients, respectively.

Conclusion
UTTR1147A demonstrated adequate safety and PK profile in healthy volunteers and UC patients. PD biomarker data demonstrated pharmacological activity of UTTR1147A providing evidence of IL-22R pathway activation. Together with the preliminary signals of efficacy, these data support further investigation of this potential, novel non-immunosuppressive therapy in IBD.
P425 SPOSIB SB2: a Sicilian prospective observational study of patients with inflammatory bowel disease treated with infliximab biosimilar SB2
Authors: Macaluso F S , Fries W , Viola A , Centritto A , Cappello M , Giuffrida E , Privitera A C , Piccillo G , Magnano A , Vinci E , Vassallo R , Trovatello A , Belluardo N , Giangreco E , Camilleri S , Garufi S , Bertolami C , Ventimiglia M , Renna S , Orlando R , Rizzuto G , Grova M , Orlando A 
Published: January 2020

Abstract

Background
Few data on Infliximab (IFX) biosimilar SB2 in inflammatory bowel disease (IBD) are available.

Methods
SPOSIB SB2 is a multicentre, observational, prospective study performed among the cohort of the Sicilian Network for Inflammatory Bowel Disease (SN-IBD). All consecutive patients with Crohn’s disease (CD) or Ulcerative Colitis (UC) starting IFX biosimilar SB2 from the introduction of the drug in Sicily (March 2018) to September 2019 (18 months) were enrolled. Patients were divided into five groups (group A: naive to IFX, naive to anti-TNFs; group B: naive to IFX, previously exposed to other anti-TNFs; group C: switch from IFX originator to SB2; group D: switch from CT-P13 to SB2; group E: multiple switches: from IFX originator to CT-P13 to SB2). The primary end-point was the assessment of safety, in terms of the rate of serious adverse events (SAEs). Secondary end-point was the evaluation of effectiveness, in terms of steroid-free clinical remission and clinical response at 8 weeks and at the end of follow-up, and as treatment persistency.

Results
276 patients (median age 39 years; CD 49.3%, UC 50.7%) were included [group A: 127 (46.0%); group B: 65 (23.6%); group C: 17 (6.2%); group D: 43 (15.6%); group E: 24 (8.7%)]. The cumulative number of infusions of SB2 was 1798, the median follow-up was 8 months (IQR: 4–12 months), and the total follow-up time was 182.7 patient-years (PY). Sixty-seven SAEs occurred in 57 patients (20.7%), with an incidence rate of 36.7 per 100 PY, and 26 of them caused the withdrawal of the drug. The incidence rate ratio (IRR) of SAEs was higher among patients in group B compared with group A (57.7 vs. 30.2 per 100 PY; IRr = 1.91; p = 0.026) and group C (57.7 vs. 18.9 per 100 PY; IRr = 2.93; p = 0.045). The effectiveness of IFX biosimilar SB2 after 8 weeks of treatment was evaluated in patients naïve to IFX (group A + B; n = 192): 110 patients (57.3%) had steroid-free remission, 26 patients (13.5%) achieved a partial response, while 56 patients had no response (29.2%). At the end of follow-up, 72 patients (26.1%) interrupted the treatment, without significant differences in treatment persistency estimations between the five groups (log-rank p = 0.15).

Conclusion
This is the first prospective study on the use of IFX biosimilar SB2 in IBD. Safety and efficacy of SB2 seem to be overall similar to those reported for IFX originator and IFX biosimilar CT-P13. A higher incidence of SAEs was observed among patients naive to IFX and previously exposed to other anti-TNFs.
P429 Clinical utility of thiopurine metabolite monitoring in inflammatory bowel disease and its impact on healthcare utilisation in Singapore
Authors: Yeo J Q , Wee H L , Cheen H H , WONG A , Lim T G , Leong W F , Chowbay B , Salazar E , Shim H H , Chan W P W , Kong S C , Ong W C 
Published: January 2020

Abstract

Background
Thiopurines are recommended for maintenance of steroid-free remission in inflammatory bowel disease (IBD). Thiopurine metabolite monitoring (MM) is increasingly used in the Western population. However, it remains a new strategy in Singapore with limited information on its therapeutic and economic benefits. Hence, this study aims to investigate the clinical utility of MM and its impact on healthcare resource utilisation in Singaporean IBD patients.

Methods
A retrospective observational study was conducted at the Singapore General Hospital outpatient IBD Centre. Patients with IBD, baseline MM during 2014–2017 and weight-based thiopurine doses for ≥4 weeks were followed up for 1 year. Actions taken to optimise therapy, metabolite levels before and after the first action were documented. Outcomes assessed included steroid-free remission (SFR), clinical remission (defined as SFR, CRP &lt;9.1mg/l and stool calprotectin &lt;250ug/g), no escalation to anti-tumour necrosis factor or surgery, clinical healthcare resource utilisation and direct healthcare costs.

Results
Ninety IBD patients (50 CD, 40 UC) were included. Among them, 40% had baseline metabolite levels within therapeutic range, 31.1% sub-therapeutic, 21.1% supra-therapeutic and 7.8% shunters. Repeated MM with subsequent dose optimisation helped 67.2% of patients achieve therapeutic levels after 1 year. In particular, dose optimisation and reinforcement of adherence in the sub-therapeutic group recaptured clinical remission in almost 50% of the patients. Overall, 86.7% of patients achieved steroid-free remission and 90% had no therapy escalation or surgery (Table 1). Despite greater outpatient visits and laboratory investigations with MM, the median total healthcare costs at 1 year only increased marginally (S$6,407.66 [shunters] vs. S$5,215.20 [supra-therapeutic] vs. S$4,970.80 [sub-therapeutic] vs. S$4,370.48 [control (within therapeutic range)], p = 0.592) (Table 2).

Conclusion
MM guided timely dose optimisation or therapy escalation for non-responders, identification of non-adherence and reversal of shunting. Therefore, it is a useful clinical tool to optimise thiopurines without significantly increasing healthcare resource costs.
P433 A real-world observational study assessing treatment persistence in ulcerative colitis patients receiving anti-TNF treatment (golimumab or adalimumab)
Authors: Hoque S , Boccaletti S , Puenpatom A , Brown C , Black C , Roberts J , Rajkovic I , Milligan G 
Published: January 2020

Abstract

Background
There are limited published observational data describing both clinical outcomes and treatment persistence rates for anti-TNFs used to treat ulcerative colitis (UC), particularly for golimumab. Based on published literature the outcomes demonstrated in clinical trials do not necessarily translate into clinical practice, highlighting the importance of real-world studies. In this study, we evaluated treatment persistence, switching patterns, and colectomy outcomes between golimumab and adalimumab in the real-world setting.

Methods
A retrospective chart review was conducted across 16 NHS sites in the UK. Data describing demographics, treatment history and colectomy were collected for UC patients treated with either golimumab or adalimumab. Patients were receiving golimumab or adalimumab as first or second-line therapy and initiating treatment between 1 March 2016 and 30 September 2017. Patients enrolled were required to have at least 6 months of data for analyses, and were followed within 12 months where the data were available. Kaplan–Meier analysis was conducted to assess time to discontinuation and also time to colectomy; log-rank tests were used to compare the two treatment arms.

Results
A total of 183 patients, (87 golimumab, 96 adalimumab), mean age was 45.6 years (46.8 years golimumab; 44.4 years adalimumab) and 59.6% were male (71.3% golimumab; 49.0% adalimumab), were included. Overall, 79.8% (78.2% golimumab; 81.3% adalimumab) of patients were receiving their first-line biologic. Treatment persistence with golimumab or adalimumab were relatively similar; 64.4% of golimumab and 64.6% of adalimumab patients remaining on treatment at 12 months (p = 0.7, Figure 1). Of the 65 patients who discontinued treatment within 12 months, 48.4% golimumab and 64.7% adalimumab switched to another biologic. Of those patients who switched, vedolizumab was the most commonly prescribed drug (56.8%), followed by infliximab biosimilar (Inflectra/Remsima) (29.7%) and infliximab (Remicade) (13.5%). Colectomy-free survival was demonstrated by 92.0% golimumab and 91.7% of adalimumab patients 12 months post-treatment initiation (p = 0.7).

Conclusion
The real-world data collected in this study demonstrate comparable treatment persistence for golimumab compared with adalimumab 12 months following treatment initiation. Colectomy-free survival was relatively similar within 1 year.
P451 Short-and long-term effectiveness of ustekinumab in patients with Crohn’s disease: real-world data from a German IBD cohort
Authors: Kubesch A , Rueter L , Farrag K , Krause T , Stienecker K , Hausmann J , Filmann N , Dignass A , Stein J , Blumenstein I 
Published: January 2020

Abstract

Background
The IL-12/23 inhibitor ustekinumab (UST) opened up new treatment options for patients with Crohn’s disease (CD). Due to the recent approval, Real-World German data on long-term efficacy and safety are lacking. This study aimed to assess the clinical course of CD patients under UST therapy and to identify potential predictive markers.

Methods
Patients with CD receiving UST treatment in three hospitals and two outpatient centres were included and retrospectively analysed. Rates for short- and long-term remission and response were analysed with the help of clinical (Harvey–Bradshaw Index [HBI]) and biochemical (C-reactive protein [CRP], faecal calprotectin [fCal]) parameters for disease activity.

Results
Data from 180 patients were evaluated. One hundred six patients had a follow-up of at least 8 weeks and were included. 96.2% of the patients were pre-exposed to anti- TNFα agents and 34.4% to both anti-TNFα and anti-integrin. The median follow-up was 49.1 weeks (95% CI 42.03–56.25). At week 8, 51 patients (54.8%) showed response to UST, and 24 (24.7%) were in remission. At week 48, 39 (41.9%) responded to UST, and 20 patients (21.5%) were in remission. Steroid-free response and remission at week eight were achieved by 30.1%, and 19.3% of patients. At week 48, 26.9% showed steroid-free response to UST, and 15.1% of the initial patient population was in steroid-free remission. Clinical response at week 16 was independently associated with remission at week 48.

Conclusion
Our study confirms short- and long-term UST effectiveness and tolerability in a cohort of multi-treatment exposed patients.