bluuebunny/crossref_metadata_2025_split huggingface dataset:
P361 The effect of immunomodulators and other factors on the persistence of biological agents for Crohn’s disease and ulcerative colitis: data from the Australian population-based registry
Authors: Ko Y , Paramsothy S , Leong R 
Published: January 2020

Abstract

Background
Treatment persistence (duration of medication use) provides real-world evidence on therapeutic effectiveness, tolerability and prescriber and patient preferences. Biological agent persistence in Crohn’s disease (CD) and ulcerative colitis (UC) was compared from a national population-based registry with no hierarchical prescribing order. We hypothesised immunotherapy co-therapy would increase persistence for anti-TNF agents, but not for non-anti-TNF agents due to reduced immunogenicity.

Methods
A randomly selected ten per cent subgroup of the prospectively collected population-based registry from the Australian Pharmaceutical Benefits Scheme between June 2005 and June 2019 was analysed. Treatment persistence of adalimumab (ADA), infliximab (IFX), vedolizumab (VDZ) and ustekinumab (UST) was compared. Factors affecting discontinuation were evaluated using multivariate proportional hazard regression.

Results
886 patients consisting of 1294 lines of therapy (992 CD, 302 UC, 2778 person-years of follow-up) were included. In CD, UST had the highest overall persistence rate (median persistence rate was &gt; 74.6% where 24.6 months is the maximum follow-up time recorded), followed by VDZ, IFX and ADA (p = 0.03) (Figure 1). UST had the highest persistence as first, second and third-line therapies (p &lt; 0.05). In UC, VDZ had the highest persistence rate (median persistence rate was &gt;50.3% where 47.4 months is the maximum follow-up time recorded), followed by IFX and ADA (p &lt; 0.001) (Figure 2). VDZ had the highest persistence rates as first-line therapy (p &lt; 0.001), while second and third-line therapies did not demonstrate significant differences.
Persistence of biological agents correlated with immunomodulator co-therapy in CD (R2: 0.65 p &lt; 0.001) and UC (R2: 0.50 p &lt; 0.001). Thiopurine co-therapy significantly increased persistence for IFX and ADA in CD and UC (p &lt; 0.001) (Figures 3 and 4) but was not significant for UST and VDZ. Methotrexate decreased persistence for VDZ in UC and had no effects on UST, IFX and ADA in UC and CD. In acute-severe UC, there were no significant differences between IFX as monotherapy vs. co-therapy.
On multivariate analysis, higher persistence was seen in males (HR: 0.75 95% CI: 0.59–0.94) and with immunomodulator co-therapy (HR 0.77 95% CI: 0.61–0.97, p = 0.03).

Conclusion
This real-world data reflecting treatment effectiveness, tolerability and patient and prescriber preferences supports the use of UST and VDZ over anti-TNF agents in CD and UC, respectively, to achieve high treatment persistence which is independent of immunomodulator co-therapy, possibly secondary to differing immunogenicity rates. It also highlights the substantial increase in anti-TNF therapy persistence with thiopurine co-therapy, but not with methotrexate.
P377 Risk factors of rectal amputation for Crohn’s disease with perianal lesion
Authors: Yokoo T , Yoshikawa S , Masuda T , Uchida H , Nakao T , Kashizuka H , Yamaoka K , Inagaki M , Okamoto K , Inatsugi N 
Published: January 2020

Abstract

Background
Recently, the importance of top-down therapy is emphasised for early Crohn’s Disease (CD). Especially early use of biologics after onset may prevent rectal amputation or permanent stoma concrete of CD with perianal lesion (CDp). The aim of this study was to evaluate the risk factors of permanent stoma concrete for CDp, and especially we had an interest for the relationship between permanent stoma concrete and length of time it takes for infliximab (IFX) was started to use after onset.

Methods
This is a comparative retrospective study of CDp patients who received IFX therapy at Kenseikai Nara Coloproctology Center between 2002 and 2018. We analysed risk factors of their rectal amputation using logistic regression analysis. Patients were included if they had perianal lesions and received IFX. The cases who received IFX after rectal amputation and who have missing values were excluded. Variables of interest included gender, age at onset and diagnosis, disease duration and location, disease behaviour, smoking, perianal surgical history, timing of IFX use after anoperineal lesion’s onset. Late IFX use was defined as we started to use IFX 2 years after perianal lesion’s onset.

Results
Fifty-four patients were recruited. Mean age was 37 years old, the ratio of males to females was 3.5. Forty-one patients’ disease was located in the small and large intestine, and thirteen patients’ were located in the large intestine. Median follow-up duration was 149 months. Among 54 patients, 10 patients were received rectal amputation or permanent stoma concrete. The univariate analysis revealed that the risk factors for rectal amputation were smoking habit (OR 7.56, 95% CI 1.41–53.88, p-value = 0.007), penetrating type (OR 6.44, 95% CI 1.21–39.22, p-value = 0.013) and Late IFX use (OR 12.47, 95% CI 1.50–589.26, p = 0.011). A multivariate analysis revealed that smoking habit (OR 21.5, 95% CI 1.92–239, p = 0.013) smoking behaviour (OR 21.5, 95% CI 1.92–239.00, p = 0.013) and Late IFX use (OR 16.0, 95% CI 1.01–254, p = 0.049) were independent risk factor for rectal amputation (Table 1).

Conclusion
Smoking and late IFX use may be a significant risk factor of rectal amputation for CDp. Early use of biologics may prevent permanent stoma concrete for CDp.
P390 New features of molecular diagnostics of the regulation of molecular apoptotic pathway in ulcerative colitis
Authors: Iakovlev A A , Volkov A , Shcherbakova I , Tarasova G , Malakhanov S , Bashtovaya O 
Published: January 2020

Abstract

Background
The incidence rate of ulcerative colitis (UC) in Russia is 5–30 cases per 100,000 per year. Molecular pathways of the UC development are not clear. The purpose of the work was to study the molecular interactions of the apoptotic pathway in patients with UC.

Methods
The clinical trial included 92 patients with UC. The clinical presentation of UC depends on the extent of involvement: distal colitis, extensive colitis; the severity of the disease. Criteria of the diagnosis of UC corresponded to ECCO Consensus. Mucosal specimens were graded according to grades 0, 1, 2, 3. The separation of proteins of colon mucosa was based on technologies of IEF, SDS-PAGE, 2DPAGE, by standard sets (MB-HIC C8 Kit, MB-IMAC Cu, MB-Wax Kit, Bruker, USA). The getting of mass-spectrogram was determined by matrix-assisted laser desorption-ionisation time-of-flight mass spectrometry (MALDI-TOF-MS/MS, Ultraflex II, Bruker, USA). Statistical analysis was performed using the software Statistica 10.0 (Statsoft).

Results
HSP2 controls the apoptosis of colonocytes and immune response in damaged colon mucosa by Bcl-2 and IL-17, and is also responsible for the resistance to therapeutic strategies. Anti-apoptotic functions of HSP27 is possible through the interaction with DAXX7, the activation of Akt and the inhibition of the apoptosis. HSP47 interacts with collagen I, II, III, IV and V types, that contributes to the launch of autoimmune process in UC. Caspase 8 protects colonocytes from TNFα-induced cell death through necroptosis mechanism via the blockade of the expression of RIP3. Significant decrease of the expression of PPARγ promotes the activation of STAT and AP-1 signalling pathways, that promotes the increase of the synthesis of IL-2, -6, -8, -12, TNFα, matrix metalloproteinases, the activity of immune and inflammation processes in the colon mucosa.
Results of qualitative proteomic analysis in patients with UC (Tab.)

Conclusion
Proteomic analysis has demonstrated the cascade with caspases 8, 9, 10, the release of cytochrome C from mitochondria, which interacts with Apaf-1, causing activation of caspase-9 in UC colon mucosa. TNF-α activates of initiator caspase-2, -8, and -10 in the apoptotic pathway. The NF-kB pathway induces cellular inhibitors of apoptosis, which function as specific caspase inhibitors in UC colonic mucosa.
P392 Initial experience with fibrin glue combined with infliximab treatment of postoperative anastomotic fistula in patients with Crohn’s disease
Authors: YAO D 
Published: January 2020

Abstract

Background
Postoperative anastomotic fistula is one of the most frequent and potentially life-threatening complications following gastrointestinal resections in patients with Crohn’s disease. The purpose of this study was to report the results of using infliximab to treat postoperative anastomotic fistula in patients with Crohn’s disease.

Methods
A prospective parallel study of fibrin glue combined with infliximab vs. fibrin glue treatment was conducted. Demographic and clinical characteristics and outcomes were compared between the groups.

Results
Thirty-five patients with postoperative anastomotic fistula were evaluated; 14 received fibrin glue combined with infliximab treatment and 21 received fibrin glue treatment. No significant differences in demographic or clinical characteristics were found between the two groups (all p &gt; 0.05). There were two recurrences in the fibrin glue group, and no recurrences in the fibrin glue combined with infliximab group(p = 0.506). No complications occurred in either group.

Conclusion
Infliximab strategy with combining fibrin glue is a simple and effective treatment alternative in the management of postoperative anastomotic fistula in Crohn’s disease.
P396 Pharmacokinetics and circulating total lymphocyte count pharmacodynamic response from single and multiple oral doses of etrasimod in Japanese and Caucasian healthy male subjects
Authors: Lee C A , Acevedo L , Oh D A , Baweja P , Gilder K , Han D , Jhee S , Komori K , Mullin S , Nguyen-Cleary T , Schmelzer K , Tang Y , Zhang J , Grundy J 
Published: January 2020

Abstract

Background
Etrasimod is a selective, sphingosine 1-phosphate receptor modulator in development for chronic immune-mediated inflammatory disorders. We evaluated etrasimod pharmacokinetics (PK) and its pharmacodynamic (PD) effect (lymphocyte count) in Japanese and Caucasian healthy male subjects.

Methods
This phase 1 study comprised 12 men (10 etrasimod; 2 placebo) in each of 4 groups (Japanese, 1 and 2 mg; Caucasian, 1 and 2 mg). Etrasimod or matching placebo was administered once daily (QD) from Days 1 to 7, followed by a 7-day washout and a single dose on Day 15. Blood was intensively sampled on Days 1 and 7 for plasma PK and collected each morning on Days 1 to 15 to measure lymphocyte counts and calculate lymphocyte PD parameters, including Rmin, Rmax, and AUECNet.

Results
Etrasimod peak (Cmax) and total (AUC0-τ) plasma exposure values in Japanese and Caucasian subjects were dose-dependent and showed low-to-moderate inter-subject variability for each dose. Following single and multiple doses, geometric least squares (LS) mean etrasimod exposure values were slightly-to-moderately higher in Japanese subjects compared with Caucasian subjects; however, corresponding dose-body weight normalised etrasimod exposure values were similar indicating the exposure differences appear mainly attributable to bodyweight differences rather than ethnicity. Dose-dependent decreases in median lymphocyte counts were observed in both ethnicities from Days 2 to 8 and increased back to near baseline levels during the washout period. As expected, only LS mean Rmin and AUECNet values were dose-dependent in both ethnicities (table), with none of the evaluated lymphocyte PD parameters being statistically different between Japanese and Caucasian male subjects.

Conclusion
These results demonstrate the lack of clinically meaningful PK or PD (lymphocyte response) ethnic differences between Japanese and Caucasian healthy male subjects and support the potential inclusion of Japanese patients with moderately to severely active ulcerative colitis in global phase 3 clinical trials evaluating an etrasimod 2 mg QD dosing regimen.
P402 Prediction of emergency department re-visit among Crohn’s disease patients: a retrospective study
Authors: Mahajna H , Barash Y , Ungar B , Soffer S , Ben-Horin S , Klang E , Kopylov U 
Published: January 2020

Abstract

Background
Patients with Crohn’s disease are frequently subject to symptoms causing them to seek medical care in emergency departments (ED). Recurrent ED visits are common after initial discharge. The burden of recurrent ED visits of Crohn’s patients is high for the patient and the health care system. We aimed to identify the characteristics of patients with Crohn’s disease who return to the ED within 30 days from discharge.

Methods
We created an electronic data repository of all IBD patients admitted to our tertiary medical centre in the time frame 2012 – 2018. Data included tabular demographic and clinical variables, as well as free-text physician records. For this study, we retrieved consecutive Crohn’s patients who were discharged from the ED. We included only patients with complains that can be attributed to Crohn’s disease exacerbation or complication. Patients without available blood test results were excluded, as well as pregnant women and patients under 18. Patients who returned to the ED in 30 days were compared with those who did not.

Results
Overall, 2148 patients visited our ED with complaints related to Crohn’s disease exacerbation or complication. 1435 (67%) were admitted for hospitalisation. Six hundred and ninety-five (33%) were discharged, of them, 110 (15.8%) returned to the ED within 30 days. Male gender, tachycardia (&gt;100 bpm), pain score &gt;4 (using numerical pain rating scale of 0–10), Albumin &lt;3.5 gr/dl, elevated alkaline phosphatase (&gt;120 IU/l), hyponatremia (&lt;135 meq/l), and anaemia (defined as less than 13.5 gr/dl for males and less than 12.0 gr/dl for females) were found to be associated with ED returns. On multivariate analysis, anaemia (OR 2.44 [95% CI 1.24–4.8]), tachycardia (OR 2.88 [95% CI 1.33–6.2]), and elevated alkaline phosphatase (OR 2.68 [95% CI 1.25–5.78]) were independently associated with ED returns. Of patients with 0, 1, 2, and 3 risk factors for ED re-visits 10%, 17%, 30%, and 33% revisited the ED within 30 days from discharge, respectively.

Conclusion
In our large tertiary centre cohort, recurrent ED visits within 30 days occurred in 16% of the patients. Tachycardia, anaemia and elevated alkaline phosphatase were found to be independently associated with recurrent visits. This model, if validated in prospective studies, may be implemented in order to minimise the burden of recurrent ED visits.
P415 The anti-IL-23/IL-12 agent Ustekinumab is an effective and safe induction therapy in patients with Crohn’s disease refractory or intolerant to anti-TNF: a multicentre Italian study
Authors: Gubbiotti A , Barberio B , Zingone F , D’Incà R , Bertani L , Ferronato A , Urbano M T , Sablich R , Savarino E V 
Published: January 2020

Abstract

Background
There are limited real-life studies in medical literature evaluating the efficacy and safety of Ustekinumab, an Anti-IL-23/Anti IL-12 agent, in patients with Crohn’s disease (CD) who required treatment because of refractoriness or intolerance to previous biological treatments. Thus, the aim of this study was to assess the effectiveness and tolerability of Ustekinumab in anti-TNF refractory or intolerant CD patients.

Methods
All CD patients who completed induction with Ustekinumab in three Italian IBD Units (Padua, Santorso, and Pisa) were enrolled. Patients were evaluated after induction (first intravenous dose followed by a subcutaneous dose at 8 weeks) and clinical (Harvey- Bradshaw-Index) and biochemical data, including faecal calprotectin (FC) and C-reactive protein (CRP) were collected. Information on the need of optimisation (every 12 or 8 weeks) and adverse events were also collected. Continuous and categorical variables were expressed as mean with standard deviation (sd) and frequency with percentages, respectively. Comparisons between variables were conducted using paired t-test and chi-square test. Data were analysed using STATA11.1 software.

Results
Sixty-three patients were included (41 males, mean age 43 ± sd 13.2 years). All of them had previously been treated with at least one biologic agent and 95.2% with oral steroids. The main indications for starting therapy were: previous treatment failure (77.2%) and pharmacological intolerance (17.5%). At the time of the induction, 28.6% patients were under steroid treatment. Post induction, clinical remission was obtained in 63.5% patients, while steroid-free clinical remission in 52.4%. Moreover, a statistically significant reduction of FC (from 916 μg/l to 444 μ/l, p &lt; 0.001) and normalisation of CRP (n = 14, 33.3%; p &lt; 0.001) were observed. After induction, 3 adverse effects were reported, and in two treatment discontinuations was necessary (i.e. 1 case of pyelonephritis and 1 case of a re-activation of entero-cutaneous fistula). Finally, among 63 patients enrolled, 51 (80.9%) were optimised with a maintenance regimen of 8 weeks sub-cutaneous doses.

Conclusion
Our study shows that Ustekinumab seemed is effective in achieving clinical remission and steroid-free clinical remission after induction in the majority of CD patient despite the refractoriness to anti-TNF treatment. Moreover, the drug appeared safe and well tolerated. On the other hand, treatment optimisation to 8 weeks was adopted in most of the patients, in order to guarantee a better outcome.
P418 Filgotinib decreases molecular markers of JAK1 signal transduction in Crohn’s disease: concordance with endoscopy and histopathology
Authors: Reinisch W , Brodbeck J , Galien R , Grant E , Hébuterne X , Kłopocka M , Petryka R , Roblin X , Serone A , Tasset C , Yoon O K , Zaboli S , Vermeire S 
Published: January 2020

Abstract

Background
Filgotinib (FIL) is a JAK1 inhibitor under phase 3 clinical evaluation for treatment of IBD. We conducted a post hoc analysis in a subset of patients with moderately to severely active CD from FITZROY (NCT02048618) to assess the effect of FIL (200 mg QD) on molecular markers of JAK1-related signalling (STAT1 and STAT3 phosphorylation) within epithelium (Ep) and non-Ep regions of intestinal mucosa and explore their correlation to histologic and endoscopic indices.

Methods
Biopsies were collected at baseline (BL) and week 10 (W10) from the most affected area of each predefined bowel segment (ileum, ascending, transverse, descending colon, and rectum). Within-subject matched biopsies for all segments from FIL (n = 42) and placebo (PBO; n = 18) treated patients were scored for histologic (GHAS) and endoscopic (SES-CD) disease activity totalling to 300 segments. Using specific antibodies and IHC, %pSTAT1 and %pSTAT3 positive nuclei within Ep and non-Ep regions of each biopsy were quantified using machine learning (Visiopharm v.2019.06). Basal pSTAT levels assessed from 182 nondiseased (SES-CD = 0 and GHAS = 0) segments were used to determine a threshold for categorising segments as either low or high molecular disease activity (MDA). Agreement between endoscopy or histology and MDA was evaluated by κ and % agreement by segment and all segments combined.

Results
Median basal pSTAT1 was similar between colonic Ep and non-Ep regions (1%–2%), but higher in ileal Ep (5%). Median basal pSTAT3 was higher in non-Ep (3%–5%) vs. Ep (1%–2%) regions across all segments. At BL, MDA was elevated in segments with ulceration (~10%, pSTAT1 and pSTAT3). In segments with GHAS activity subscore ≥2 at BL, both Ep MDA (10%–30%) and non-Ep MDA were elevated (25%–35%) and correlated to histologic activity. In segments with low BL MDA, significantly fewer segments with FIL showed MDA worsening at W10 compared with PBO (both pSTAT1 and pSTAT3). In segments with high BL MDA, FIL treatment improved significantly more segments than PBO; this was evident for pSTAT3 only (table). Concordance between MDA and endoscopy was mostly fair to moderate (κ 0.3–0.5), whereas MDA and histology showed moderate to good concordance (κ 0.4–0.8).

Conclusion
Filgotinib treatment improved JAK1-related MDA within the mucosa of CD patients. Concordance between MDA and clinical indices was highest with histology.
P419 Clinical effectiveness and safety of first-line biologic vedolizumab as a monotherapy or combination therapy in ulcerative colitis and Crohn’s disease patients: results from the EVOLVE study
Authors: Bressler B , Yarur A , Kopylov U , Bassel M , Brett N , Colby C , Lopez C , Saha S , Kifnidi C , Agboton C , Adsul S , Demuth D , Luo M , Wang S , Mantzaris G J 
Published: January 2020

Abstract

Background
There is little long-term research (≥12 months) in ulcerative colitis (UC) and Crohn’s disease (CD) patients investigating the impact on clinical effectiveness of combined (combo) therapy of vedolizumab (VDZ) plus immunomodulators/immunosuppressants (IMMs) compared with VDZ monotherapy. Research suggests the use of concomitant aminosalicylates [5-ASAs] in UC may not bolster effectiveness. Finally, it is unclear if the safety profile differs between VDZ monotherapy and combo therapy. This study described clinical effectiveness and safety outcomes in patients with UC or CD treated with first-line biologic VDZ as monotherapy or combo therapy with IMMs or 5-ASAs (UC only).

Methods
This was a real-world, multi-country (Canada, Greece and the USA), retrospective chart review study of biologic-naïve UC and CD patients (≥18 years old) treated with VDZ (initiated Tx May 2014–March 2018). Data were collected from Tx initiation to the earliest of death and chart abstraction date. Cumulative rates of clinical effectiveness outcomes over 24 months (Tx persistence, clinical response and clinical remission) were estimated using the Kaplan-Meier method with unadjusted comparisons conducted using the log-rank test. Clinical response and remission were assessed from standard disease measures reported in medical records. Analyses of unadjusted incidence rates (per 100 person-years [PYs]) of disease exacerbations, disease-related surgeries, serious adverse events (SAEs) and serious infections (SIs) were performed. For these analyses in monotherapy vs. VDZ+IMMs, UC and CD patients were combined due to restrictions of sample size and a number of events.

Results
This analysis included 318 patients treated with VDZ (monotherapy: UC = 53, CD = 108; VDZ+IMMs: UC = 22, CD = 24; VDZ+5-ASAs: UC = 111). There were no observed differences in age, sex or disease duration between patients on monotherapy vs. VDZ+IMMs or vs. VDZ+5-ASAs. Data trends in effectiveness outcomes were similar in monotherapy vs. VDZ+IMMs over 24 months (Figure 1). Tx persistence (monotherapy: 71.6%; VDZ+5-ASAs: 82.7%; p = 0.40), clinical remission (monotherapy: 54.3%; VDZ+5-ASAs: 87.7%; p = 0.37) and clinical response (monotherapy: 81.7%; VDZ+5-ASAs: 92.2%; p = 0.54) were also similar between monotherapy and VDZ+5-ASAs over 24 months. Safety outcomes were similar between groups (Figure 2).

Conclusion
Though sample sizes were small, the unadjusted trends in the results of this long-term real-world study suggest that biologic-naïve UC or CD patients treated with VDZ alone may have similar clinical effectiveness outcomes to patients receiving VDZ+IMMs. Trends in data also suggest that in patients with UC, VDZ+5-ASAs may not be more effective than VDZ alone.