bluuebunny/crossref_metadata_2025_split huggingface dataset:
DOP14 Modelling of the relationship between infliximab exposure, faecal calprotectin, and endoscopic remission in patients with Crohn’s disease
Authors: Dreesen E , Berends S , Laharie D , D’Haens G , Vermeire S , Gils A , Mathôt R 
Published: January 2020

Abstract

Background
Less than 50% of patients with Crohn’s disease (CD) starting infliximab (IFX) therapy achieve endoscopic remission (ER). Evidence for the benefits of pharmacokinetic (PK) and pharmacodynamic (PD) monitoring remains scarce. We aimed to develop a population (pop)PK/PD model to characterise the IFX dose-exposure-biomarker-response (faecal calprotectin [fCal] and ER) relationship in patients with CD.

Methods
Analyses were performed using data of a phase 4 dose-escalation study (TAILORIX). Patients started standard 5 mg/kg IFX induction therapy at weeks [w]0, 2 and 6. From w14 through w54, the IFX dose could be irreversibly doubled based on one of the three monitoring algorithms.1 Endoscopies were performed at w0, 12 and 54. Three sequential models were developed: A 2-compartment popPK model linking IFX dose to exposure, an indirect response popPK-PD model describing the inhibitory effect of IFX exposure on fCal, and a first-order Markov popPD model linking fCal to transitions between states of ER (CD endoscopic index of severity &lt;3), no ER and dropout (Figure 1). All modelling and simulation were performed using NONMEM 7.4.

Results
The study included 116/122 (95%) patients with CD enrolled in TAILORIX who had ≥1 detectable IFX serum concentration. In the developed models, it was shown that IFX clearance increased with increasing fCal, decreasing albumin, increasing CD activity index and presence of antibodies to IFX (transiently). Baseline fCal increased with increasing CRP and decreasing platelet count. Lower fCal increased probability of attaining ER and decreased probability of losing ER. Probability of dropping out given an earlier state of absence of ER increased with elapsing time. Simulations of 150 000 patients receiving 5, 7.5 or 10 mg/kg IFX (1:1:1) resulted in a flat dose–response curve due to large interindividual variability in PK and PD (Figure 2, top panels). The predicted fraction of patients achieving ER at w12 was 45.1% [30.3–60.5] (median [IQR]) when on 5 mg/kg IFX (~46.4% observed in data). However, simulations of 10 mg/kg IFX induction doses predicted only a slight increase in the fraction of patients achieving ER at w12 to 47.5% [32.0–62.6]. This minor benefit at the population level argues against systematic 10 mg/kg induction dosing in all patients. A similar observation was done during maintenance therapy, where 70.8% [62.6–75.5] of all simulated patients maintained ER at w54 (~72.2% observed in data) (Figure 2, right panels).

Conclusion
Model-informed infliximab dose optimisation towards a predefined fCal concentration—while accounting for PK and PD variability—may improve the effectiveness of infliximab therapy (eg. 64% chance of ER at w12 ~100 μg/g fCal at w6).

Reference
DOP16 An evaluation of the exposure–efficacy relationship for subcutaneous vedolizumab maintenance treatment of Crohn’s disease: Pharmacokinetic findings from VISIBLE 2
Authors: Chen C , Rosario M , Polhamus D , Dirks N , Zhang W , Sun W , Kisfalvi K , Feagan B , Sandborn W , Vermeire S , D’Haens G 
Published: January 2020

Abstract

Background
The exposure–efficacy relationship and immunogenicity rates of the new vedolizumab subcutaneous (SC) formulation have been established for maintenance treatment of ulcerative colitis (UC).1 Here, we report vedolizumab SC exposure–efficacy and immunogenicity in Crohn’s disease (CD).

Methods
VISIBLE 2 (NCT02611817; EudraCT 2015-000481-58) was a pivotal, phase 3, randomised, double-blind, placebo-controlled trial evaluating the efficacy and safety of vedolizumab SC (108 mg every 2 weeks) as maintenance treatment in patients with moderately to severely active CD. Following intravenous (IV) vedolizumab (300 mg Week 0 and 2) induction, patients with a clinical response at Week 6 (≥70-point decrease in CD activity index [CDAI] from Week 0) were randomised to blinded maintenance treatment and included in the analyses. Vedolizumab serum concentrations were measured prior to dosing using an enzyme-linked immunosorbent assay. Immunogenicity was assessed with a drug-tolerant electrochemiluminescence assay. Predicted vedolizumab trough concentrations at Week 52 were grouped by quartiles (Q), and Week 52 efficacy outcome rates calculated for each Q. Missing efficacy outcome data were imputed as failures. Efficacy outcomes were clinical remission (CDAI ≤150) and enhanced clinical response (≥100-point decrease in CDAI from Week 0 at Week 52).

Results
Following vedolizumab IV induction (N = 644), patients with a clinical response were randomised and received vedolizumab SC (N = 275) or placebo (N = 134) as maintenance treatment. At Week 52, patients on vedolizumab SC maintenance had a positive exposure–efficacy relationship for clinical remission (Q1: 37.7%; Q4: 50.7%) and enhanced clinical response (Q1: 37.7%; Q4: 53.6%; Figures 1 and 2). Overall, 7/275 (2.5%) patients on vedolizumab SC (following vedolizumab IV induction) developed anti-vedolizumab antibodies (AVAs): 3/7 patients were persistently AVA positive and 4/7 had neutralising antibodies. Five of 7 AVA-positive patients on vedolizumab SC did not achieve clinical remission and enhanced clinical response at Week 52; 2 of those patients were persistently AVA-positive. Immunogenicity was not associated with injection-site reactions or hypersensitivity reactions.

Conclusion
These preliminary results suggest a trend for higher vedolizumab SC serum concentrations with greater efficacy in CD, but the association was less pronounced than was reported in UC. (1) The AVA rate was similar to what was observed in prior vedolizumab IV studies. (2) In this study, vedolizumab immunogenicity appeared to be associated with clinical outcome.

References
DOP18 Impact of adherence to anti-tumour necrosis factor therapy on clinical outcomes in Crohn’s disease: A nationwide population-based study
Authors: Park J J , Koo H , Park Y , Park S J , Kim T I , Kim W H , Cheon J H , Han E H 
Published: January 2020

Abstract

Background
The impact of compliance with anti-tumour necrosis factor (TNF) on the clinical outcomes of Crohn’s disease (CD) is not well unknown. We performed a nationwide population-based study to investigate the impact of adherence to anti-TNF therapy on clinical outcomes in CD patients.

Methods
Using the National Health Insurance claims data, we collected data on newly diagnosed patients with CD between 2004 and 2015. Given that infliximab was listed in the National Health Insurance Service in 2006 and adalimumab in 2010, data only after the listing date were extracted. A total of 2784 patients were included according to inclusion criteria. Medication adherence was measured based on the following three criteria, including the ratio of delayed visit, the ratio of the number of visits, and the ratio of actual administration, and was assessed at four-point in time from the initial administration: 14, 22, 39, and 48 weeks.

Results
A total of 2179 patients received infliximab, and 605 patients received adalimumab. The mean cumulative actual to predetermined prescription ratio (CAPPR) at 14 and 48 weeks was 1.07 and 1.17, respectively. CAPPRs of infliximab users were higher than those of adalimumab users (1.06 and 1.21 vs. 1.02 and 1.04 at 14 and 48 weeks, respectively). As hospital visits were delayed one more day, risk of perianal surgery (odds ratio [OR] 1.21, 95% confidence interval [CI] 1.089–1.333), corticosteroid use (OR = 1.008, 95% CI 1–1.016), and hospitalisation (OR = 1.05,95% CI 1.002–1.108) at 48 weeks were significantly increased. Moreover, as CAPPR decreased by 1 percent point, risk of bowel resection (OR = 1.589, 95% CI 0.713–3.542), perianal surgery (OR = 1.246, 95% CI 0.868–1.79), and hospitalisation (OR = 1.128, 95% CI 0.998–1.276) at 14 weeks were significantly increased.

Conclusion
Our data indicate that adherence to anti-TNF therapy affects major clinical outcomes of CD in the short- and mid-term period. Intervention to improving adherence to anti-TNF therapy is highly needed for better clinical outcomes in CD.
DOP21 Time to first treatment with biologic agents for ulcerative colitis and Crohn’s disease across four Nordic countries: Results from the TRINordic study
Authors: Høivik M , Lördal M , Burisch J , Langholz E , Knudsen T , Voutilainen M , Moum B , Anisdahl K , Saebo B , Haiko P , Malmgren C , Coskun M , Melberg H O 
Published: January 2020

Abstract

Background
Real-world data on time from diagnosis to first biologic treatment is limited for ulcerative colitis (UC) and Crohn’s disease (CD) patient populations.

Methods
This retrospective observational study collected data from the National Patient Registries and National Prescription Registries in Sweden (data on biologic use was only available for Stockholm [STK], Norway [NOR], Denmark [DEN]) and one university hospital database (Turku, Finland [FIN]) during 2010–2017 to investigate time from diagnosis to first biologic treatment for UC and CD. Patients with ≥2 ICD-10 diagnosis codes for UC (K51) or CD (K50) from 2010 or later were included; patients were classified according to their last code. The look-back period for SWE was until 2000, for NOR until 2008, for DEN until 1995, and for FIN until 2004. Time to first biologic was defined as the period from the first UC or CD code to first biologic record. In FIN, it was only possible to investigate infliximab (IFX).

Results
A total of 47,568 patients were included (STK n = 5594, NOR n = 20,761, FIN n = 2118, DEN n = 19,095). Of them, 30 397 patients had UC and 17 171 CD diagnosed during 2010–2017. Time to first biologic following diagnosis of UC or CD was decreased over time. For patients diagnosed with CD in 2015, in STK, NOR, FIN, and DEN, 30%, 35%, 25%, and 26%, respectively, received a biologic within 2 years; in 2010, the proportions were less than 10%, 20%, 5%, and 22%, respectively. FIN results may be attributed to only IFX use captured in the data sources. NOR had in most cohorts the shortest time between diagnosis and first treatment with a biologic agent, e.g. 33%, 35%, 36%, 34% and 33% of patients diagnosed with CD in 2011, 2012, 2013, 2014 and 2015, respectively, received a biologic already one month after diagnosis compared with 2%, 1%, 3%, 4% and 6%, respectively, in STK, 7%, 5%, 9%, 4% and 5%, respectively, in FIN and 3%, 10%, 28%, 12% and 23%, respectively, in DEN. Fewer UC than CD patients received biologics, but the time to first biologic was shortened to the same extent (Figure 1 and 2, respectively). In NOR, FIN and DEN, the most common biologic used was IFX for UC and CD, e.g. 18%, 14% and 15%, respectively, of UC and 35%, 17% and 35%, respectively, of CD patients diagnosed in 2015 had received IFX; in STK it was IFX for UC (8% of patients diagnosed in 2015) and adalimumab for CD (20% of patients diagnosed in 2015).

Conclusion
This retrospective observational study of &gt;45 000 patients with inflammatory bowel disease in four Nordic countries showed reduced time between diagnosis and first biologic from 2010 to 2017, with the shortest time between diagnosis and first biologic in Norway. IFX was most commonly used.
DOP26 Real-life dosing patterns and concomitant drug use among ustekinumab-treated patients with Crohn’s disease
Authors: af Björkesten C G , Ilus T , Hallinen T , Soini E , Eberl A , Hakala K , Heikura M , Hirsi E , Jussila A , Kellokumpu M , Koskela R , Koskinen I , Moilanen V , Nielsen C , Nieminen U , Nuutinen H , Heikkinen M , Suhonen U M , Tillonen J , Utriainen K , Vihriälä I , Wennerström C , Borsi A , Nissinen R , Koivunen M , Sipponen T 
Published: January 2020

Abstract

Background
Real-life long-term evidence on ustekinumab treatment in patients with Crohn’s disease (CD) is limited. We performed a retrospective non-interventional nation-wide chart review study of dosing and long-term clinical outcomes in Finnish CD patients treated with ustekinumab (FINUSTE2, EUPAS30920).

Methods
FINUSTE2 was carried out in 17 Finnish centres. Eligible patients were adults with CD, receiving an intravenous (IV) first dose of ustekinumab during 2017 or 2018. Data on disease activity, dosage, and concomitant medications were collected at baseline, 16 weeks, and 1 year from treatment initiation. All measurements on ustekinumab trough concentrations (TC) were recorded.

Results
The study included 155 patients (48% female) with a mean age of 44 and disease duration of 14 years. The disease was stricturing or penetrating in 69% of patients, 59% had prior CD-related surgeries, and 96% had a treatment history of at least one biologic agent. After one IV dose and one to two subcutaneous (SC) doses at 8 to 16 weeks, 140 patients (93%) continued to maintenance treatment with SC ustekinumab, of which nearly three-quarters with a dosage interval of 8 weeks (Figure 1). Of 93 patients with a follow-up of at least 1 year, 77 were still on ustekinumab. During follow-up, 55 patients (39%) had their ustekinumab dose adjusted, mostly (n = 44, 31.4%) as a shortening of the dosage interval. Forty-nine patients had in total 65 ustekinumab TC measurements performed, with a mean of 2.2 µg/ml at 16 weeks (n = 23) and 2.7 µg/ml at 1 year (n = 25). In 67% of cases, the reason for measuring TC was lack of or insufficient response. No anti-drug antibodies appeared at any time point. The proportion of patients on ustekinumab monotherapy increased significantly, from 34% (n = 52) at baseline to 54% (n = 79/146; p &lt; 0.001) at 16 weeks and 64% (n = 49/77; p &lt; 0.01) at 1 year. Correspondingly, corticosteroid use decreased significantly, and a trend towards reduced use of immunomodulators was observed (Figure 2).

Conclusion
In this nationwide real-life study, treatment with ustekinumab in patients with longstanding and complicated CD was persistent and allowed for significant corticosteroid tapering. A vast majority started the maintenance treatment with an 8-week dosage interval and nearly one-third of all patients required a dose increase, suggesting a highly refractory disease phenotype. The lack of detected antidrug antibodies during follow-up indicates low immunogenicity for ustekinumab.
DOP32 Clinical and molecular characterisation of patients with durable response to ustekinumab induction therapy: Results from the UNIFI phase 3 studies in moderate-to-severe ulcerative colitis
Authors: Li K , Yang F , Hayden K , Strawn D , Wadman E , Bhagat S , Marano C , Friednman J R 
Published: January 2020

Abstract

Background
Ustekinumab (UST) is an effective therapy for moderate-to-severe ulcerative colitis (UC).1 A subset of patients responded to the induction dose of UST and achieved clinical remission at maintenance Week 44 (M-Week 44) following placebo (PBO) maintenance. The clinical and molecular characteristics of this group are unknown.

Methods
Three subsets of patients in the UNIFI phase 3 studies were compared: (1) UST induction Week 8 (I-Week 8) responders who achieved clinical remission at M-Week 44 following PBO maintenance (n = 32; referred to as 1UST-R); (2) UST I-Week 8 responders who did not achieve clinical remission at M-Week 44 following PBO maintenance (n = 87; 1UST-NR); (3) patients who had no clinical response following two doses of UST induction (n = 93; 2UST-NR). Clinical characteristics, histologic activity, inflammation burden, and genetic risk were compared among the three groups at induction baseline. Serum biomarkers related to the IL-12 and IL-23 pathways and/or UC in general (IFNg, IL-17A, IL-22, MMPs, SAA, and NGAL) were analysed in ~60% of patients within the three groups and compared with patients who achieved M-Week 44 clinical remission following UST maintenance and normal controls.

Results
1UST-R had lower disease activity and inflammation burden (CRP, faecal calprotectin, and faecal lactoferrin) at induction baseline than 1UST-NR and 2UST-NR. They had shorter disease duration, a lower frequency of biologic therapy failure, and a trend of lower polygenic genetic risk scores. Disease (MMPs and NGAL) and pathway-related biomarkers (IL17A and IL22) for this group were comparatively less elevated at induction baseline. Histologic measures of architectural change and chronic inflammation were higher in 2UST-NR than in 1UST-R or 1UST-NR at induction baseline. IFNg, IL17A, IL22, MMPs, and SAA in UC were partially normalised by UST induction and further improved with UST maintenance therapy. In contrast, there was no further improvement in these serum markers among the 1UST-R patients during the maintenance phase.

Conclusion
Patients with a durable response to UST induction had lower disease activity, serum biomarkers indicative of inflammation, and IL-12 and IL-23 pathway activity. Although the molecular effects of UST induction were retained through M-Week 44 in this group, the lack of further improvement suggests a molecular benefit of UST maintenance therapy.

Reference
DOP33 Stratification of patients for treatment with adalimumab by a combination of immune-profiling and in vivo efficacy studies in a novel mouse model of ulcerative colitis
Authors: Gropp R , Jodeleit H , Caesar J , Villarroel Aguilera C , Sterz S , Holdt L , Beigel F , Breiteneicher S , Stallhofer J , Siebeck M 
Published: January 2020

Abstract

Background
The Holy Grail in chronic inflammatory diseases is the identification of biological markers which might explain the heterogeneity of disease manifestations and predict responses to treatment. The aim of this study was to identify immunological subgroups of patients with UC and to test responsiveness to adalimumab in these subgroups in the mouse model of ulcerative colitis (UC), which is based on NOD/scid IL-2Rγ null (NSG) mice reconstituted with peripheral blood mononuclear cells (PBMCs; NSG-UC).

Methods
The immunological profiles of 40 UC patients and 16 non-UC donors were determined by flow cytometric analysis of PBMCs in a snapshot and longitudinal study and analysed by principal component (PCA), orthogonal partial least square discrimination (oPLS-DA)- and hierarchical clustering analysis. NSG mice were reconstituted five times at consecutive time points with PBMCs from a single donor and were analysed for frequencies of human leukocytes, histological phenotype and levels of calprotectin (CRP) and transforming growth factor (TGF)-β. The response to adalimumab was tested in the NSG-UC model reconstituted with PBMC from patients clustering in group I (n = 2) or II (n = 2). Readout were the clinical, colon and histological scores, serum levels of glutamic and aspartic acid and interleukin (IL)-6 and IL-1β. The response was analysed by PCA.

Results
Hierarchical clustering identified two major subgroups in UC patients. Group I was characterised by TH17 and M1 monocytes, group II by TH2/TH1 and switched B cells. O-PLS-DA revealed significant discrimination between the two groups.

Patients analysed in longitudinal studies switched from one group to the other. Thus, these subgroups reflected the dynamics of inflammation in patients. Mice reconstituted five times at consecutive time points with PBMC from one donor achieved an immunological phenotype reflecting the one of the Patient at that time point. Like the patient, mice switched from a pro-inflammatory phenotype (group II) to an M1 monocyte driven inflammation (group I).

In mice, group II was characterised by a severe influx of inflammatory cells and oedema whereas group I was signified by extensive fibrosis. This observation was corroborated by colonic CRP and TGFß levels. CRP levels were significantly higher in group II, whereas TGFβ levels were increased in group I. PCA analysis revealed that mice reconstituted with PBMC from group II responded better to treatment with adalimumab than mice from group I.

Conclusion
The combination of profiling and testing of therapeutics in the NSG-UC model may ultimately lead to individualised and phase-dependent therapies.
DOP48 Gene expression landscape of epithelial monolayer in inflammatory bowel disease
Authors: Sæterstad S , Østvik A E , Sandvik A K , Granlund Van Beelen A 
Published: January 2020

Abstract

Background
Gene expression analyses on IBD tissue are dominated by analyses of biopsy homogenates that are highly heterogeneous due to a difference in cell populations when contrasting inflamed vs. healthy mucosa. We wished to characterise the inflammatory activity of the isolated epithelial monolayer (EM), avoiding the infiltrating inflammatory cells, thereby form a comprehensive understanding of the epithelium’s role in IBD pathobiology.

Methods
Total RNA was isolated from laser capture microdissected (LCM) colon EM, and sequencing libraries were prepared using TruSeq RNA access kit (Illumina, CA, USA). Gene cluster analysis (WGCNA) was used to stratify the expression data in genetic modules. Following this, we characterised the modules correlated to IBD status, using Metacore pathway analysis, in order to suggest what underlying biological processes contribute to the observed correlation of expression data. Finally, we used immunohistochemistry to verify the protein expression pattern of key players in the suggested pathways, thereby confirming EM involvement in these processes during inflammation.

Results
Biopsies from active (a) IBD (7 UCa, 5 CDa) and from un-inflamed (u) IBD and healthy control (7 UCu, 5 CDu and 6 HC) were included in the analysis. 6386 genes were differentially expressed (adjusted p-value (pval.) &lt;0.05) in EM from active inflamed colon vs. un-inflamed (Figure 1). Six gene modules showed a significant correlation between inflammatory status and gene expression (Figure 2). Of note was a broad, significant up-regulation of MHC class II presentation machinery, e.g. STAT1 (log2 fold change (lfc) 0.93, p &lt; 0.001), CIITA (lfc 2.57, p &lt; 0.001) and HLA-DRB1 (lfc 3.69, p &lt; 0.001), and a down-regulation unique to epithelial cells of the retinoic acid receptors RARA (lfc −0.79, p &lt; 0.001) and RXRA (log fc −0.56, p &lt; 0.001). The most significantly up-regulated pathway was ‘Immune Response’, induction of antigen presentation machinery by IFN-γ (FDR 2.5 × 10–18), while ‘RXR-dependent regulation of lipid metabolism’ (FDR 2.6 × 10–8) was the most significantly down-regulated pathway.

Conclusion
Our analyses suggest that the involvement of the EM in IBD inflammation goes far beyond acting as a barrier. The largest genetic modules are dominated by genes important for inflammatory regulation, suggesting that the EM is much more involved in these processes than what is commonly understood. This study lends support to further analyses of interplay between epithelial cells and immune cells, particularly in a pro-inflammatory environment.