bluuebunny/crossref_metadata_2025_split huggingface dataset:
DOP55 Long-term outcomes after histologic-endoscopic mucosal healing: Results from the UNIFI study in Ulcerative Colitis
Authors: Leong R , Sands B , Peyrin-Biroulet L , Marano C , Miao Y , Izanec J , Feagan B , Rubin D 
Published: January 2022

Abstract

Background
In the UNIFI study of ustekinumab (UST) in ulcerative colitis (UC), patients who achieved histo-endoscopic mucosal healing (HEMH; ie, both histologic and endoscopic improvement of mucosa) after induction had higher clinical remission and corticosteroid-free clinical remission rates through 1 year than those who achieved either histologic or endoscopic improvement alone.1 Here, we report the effect of achieving HEMH after induction on long-term symptomatic outcomes through 3 years.

Methods
Patients who were in clinical response after 8 wks of IV induction with UST 130mg or ~6mg/kg (wk 8 responders) were randomized to maintenance treatment with SC UST 90mg q12w or q8w on entry into maintenance. Those who were not in clinical response to the initial UST dose at wk8 but achieved response at wk16 after receiving a single SC dose of UST 90mg at wk8 (wk16 responders) entered maintenance receiving SC 90mg q8w. After 44 wks of maintenance treatment, patients were given the option to continue in the long-term extension. HEMH was defined as achieving both endoscopic improvement (Mayo endoscopy subscore ≤1) and histologic improvement (neutrophil infiltration in &lt;5% of crypts, no crypt destruction, and no erosions, ulcerations, or granulation tissue; based on the Geboes score). Patients with insufficient data for histologic evaluation at the end of induction were excluded. Symptomatic remission was defined as a Mayo stool frequency subscore of 0 or 1 and a Mayo rectal bleeding subscore of 0.

Results
Of the 438 patients who were wk8 or wk16 responders to UST induction and received UST maintenance, 116 (26.5%) achieved HEMH after induction, 30 (6.8%) achieved endoscopic improvement without histologic improvement (EI), and 106 (24.2%) achieved histologic improvement without endoscopic improvement (HI). Patients who achieved HEMH after induction had higher symptomatic remission and corticosteroid-free symptomatic remission rates at wks92 and 152 than those with EI or HI; the differences were statistically significantly greater at wk152, while they were only numerically greater at wk92 (Table). The differences were primarily driven by patients with HEMH after induction being more likely to maintain symptomatic remission between wks92 and 152, than those with EI or HI alone. Symptomatic remission and corticosteroid-free remission rates decreased between wks92 and 152 in patients with EI or HI only.

Conclusion
Patients with UC who achieved HEMH after induction with UST were more likely to maintain symptomatic remission and corticosteroid-free symptomatic remission between 2 and 3 years of maintenance treatment than those who achieved EI or HI alone.

Reference
1. K Li, et al. Poster 1008. Presented at UEGW 2019. October 22, 2019. Barcelona, Spain.
DOP74 Comparative effectiveness of vedolizumab and ustekinumab in Crohn’s Disease patients who failed anti-TNF treatment: Interrogating 1019 patients from the UK IBD BioResource
Authors: Desoki R , Balendran K , Kapizioni C , Shawky R , Parkes M , Raine T 
Published: January 2022

Abstract

Background
Ustekinumab (UST) and vedolizumab (VDZ) are widely used to treat patients with Crohn’s disease (CD). However, limited data exist regarding comparative effectiveness of these agents for patients with CD who have failed anti-TNF treatment. We aimed to compare the efficacy of UST and VDZ utilizing the largest cohort of CD patients who failed anti-TNF in real world clinical practice.

Methods
We conducted a retrospective cohort analysis using data retrieved from the UK IBD BioResource, capturing 34,148 subjects. We identified patients with CD, who failed anti-TNF and were subsequently treated with UST or VDZ as second or third-line therapy. Inverse probability of treatment weighting (IPTW) was used to balance groups using a propensity score-weighting approach accounting for baseline patient or disease related characteristics. Persistence on therapy with clinician assessment of treatment success, without the need for treatment change or surgery was used to estimate the response to treatment. We compared treatment survival curves before and after IPTW and used a log rank test for differences between groups

Results
654 CD patients received VDZ, either as second line (51%) or third line (49%) therapy. 365 patients received UST, 52% as a second line and 48% as a third line therapy. All patients received either infliximab or adalimumab as first and/or second biologic therapy. Baseline characteristics are detailed in table 1. Following IPTW, variables were well balanced. Patients receiving VDZ showed similar rates of treatment success compared to UST as second- and third-line biologic agent after anti TNF failure (before IPTW adjustment, log rank p 0.241; after IPTW, log rank p 0.154). Outcomes for UST were similar between 2nd and 3rd line usage (p 0.81), but outcomes for VDZ were significantly worse when used 3rd line compared to 2nd line (p &lt;0.0001).Subgroup analysis of unadjusted survival data showed significantly better outcomes for patients with ileal disease distributiontreated with UST compared to VDZ (p=0.043) but no significant differences in outcomes for subgroups with colonic or ileocolonic disease.We estimate persistence on UST and VDZ to be 67%, 54%, 49% and 49% at 1, 2, 3 and 5 years respectively.

Conclusion
Using data from a multi-institutional cohort of patients with CD with larger number of participants and longer follow-up than previous cohorts, we demonstrate no difference between UST and VDZ used as second and/or third line biologic therapy, after anti-TNF failure. Subgroup analysis reveals some patient characteristics predictive of differential treatment response.
DOP76 Real-world multicenter comparison of effectiveness between tofacitinib and vedolizumab in patients with Ulcerative Colitis after failure to at least one anti-TNF agent
Authors: Buisson A , Nachury M , Fumery M , Guilmoteau T , Leclerc E , Altwegg R , Serrero M , Mathieu N , Treton X , Vuitton L , Pereira B , Amiot A , Bouguen G 
Published: January 2022

Abstract

Background
Several therapeutic options are now available in ulcerative colitis after anti-TNF failure, but no data compared hitherto tofacitinib and vedolizumab.
We compared the effectiveness of tofacitinib and vedolizumab in UC patients with prior exposure ≥ 1 anti-TNF.

Methods
In this multicentre retrospective study, we consecutively included all adult UC patients with partial Mayo score &gt; 2, with ≥ 1 prior anti-TNF agent and started either tofacitinib (10mg b.i.d ± decreased to 5 mg b.i.d from week 8 (W8)) or vedolizumab (300 mg IV at W0-W2-W6 -W14 [± additional W10]) between January 2019 and June 2021.
The primary endpoint was corticosteroid-free clinical remission or CFREM (partial Mayo score ≤ 2) at W16. Secondary endpoints were endoscopic improvement (CFREM + endoscopic Mayo score ≤ 1) and mucosal healing (CFREM + endoscopic and histological remission defined as Nancy index ≤ 1).
All the comparisons were performed using propensity score analyses (inverse probability of treatment weighting) adjusted on gender, smoking, UC duration and extent, number of prior biologics or prior primary failure to biologics, concomitant 5-ASA, steroids or immunosuppressive agents, and disease severity.

Results
Overall, 400 patients will be included. Among the 200 first patients, 87 and 112 received tofacitinib and vedolizumab, respectively (one missing patient). Except for more pancolitis (54.0% vs 38.4%, p=0.028), less immunosuppressive therapies (4.6% vs 27.7%, p &lt; 0.001), and higher rate of prior exposure ≥ 2 biologics (87.4% vs 37.5%, p &lt; 0.001) in tofacitinib arm, baseline characteristics were similar across the two groups including concomitant 5-ASA (10.3% vs 18.8%) and steroids (23.0% vs 31.2%). Vedolizumab infusion at W10 was performed in 34.3% while 42.5% received tofacitinib 10 mg b.i.d until W16.
CFREM was achieved in 54.2% and 42.5% in tofacitinib and vedolizumab, respectively p=0.089). The rate of CFREM at W16 was 57.4% vs 51.1% (p=0.77) after one biologic, 55.4% vs 41.8% (p=0.61) after 2 biologics, 56.9% vs 6.3% (p=0.007) after at least 3 biologics, and 59.0% vs 33.3% (p=0.17) in the subgroup with partial Mayo score ≥ 6, in tofacitinib and vedolizumab groups, respectively.
Tofacitinib was more effective than vedolizumab to achieve CFREM at W16 in patients with primary failure to at least biologic (71.6% vs 30.8%, p=0.049).
Among 177 patients, endoscopic improvement was higher in patients treated with tofacitinib (33.6 % vs 7.1%, p=0.048). Mucosal healing was observed in 6.4% vs 3.8% in tofacitinib and vedolizumab arms, respectively (p=0.27).

Conclusion
Tofacitinib and vedolizumab are effective after failure to anti-TNF agents. Tofacitinib seems to be more effective in case of primary failure to biologics and multiple therapeutic failure.
DOP81 Baseline whole-blood gene expression of TREM1 does not predict clinical or endoscopic outcomes following adalimumab treatment in patients with Ulcerative Colitis or Crohn’s Disease in the SERENE studies
Authors: Verstockt B , Al Mahi N , Pivorunas V , Smaoui N , Guay H , Kennedy N A , Hanauer S B , Ferrante M , Panés J , Vermeire S 
Published: January 2022

Abstract

Background
Conflicting evidence exists regarding whether low baseline Triggering Receptor Expressed on Myeloid cells (TREM)1 whole-blood gene expression predicts response or non-response to anti-tumour necrosis factor agents in patients with Ulcerative Colitis (UC) or Crohn’s Disease (CD). This study investigated whether baseline TREM1 expression predicted outcomes following adalimumab treatment in patients with UC or CD in the SERENE Phase 3 studies.

Methods
The SERENE studies (SERENE-UC, NCT02065622; and SERENE-CD, NCT02065570) compared a higher adalimumab induction dosing regimen versus the standard regimen in patients with UC or CD. Whole-blood TREM1 expression was analysed by RNA sequencing in patients who received standard-dose adalimumab and had clinical and endoscopic outcomes at Week 8 or 52 in SERENE-UC (n=95 for Week 8 and n=70 for Week 52 outcomes), or Week 12 or 56 in SERENE-CD (n=106 for all Week 12 outcomes; n=48 for clinical and n=50 for endoscopic outcomes at Week 56). Outcome definitions are summarised in Table 1. A 2-sample t-test was used to compare baseline TREM1 gene expression (log2 counts per million) in clinical or endoscopic remitters or responders versus non-remitters or non-responders at Weeks 8 and 52 (SERENE-UC) or Weeks 12 and 56 (SERENE-CD).

Results
In SERENE-UC, baseline TREM1 expression did not predict clinical remission at Week 8 (Figure 1a; p=0.7942) and was only weakly predictive of clinical remission at Week 52 (Figure 1b; p=0.04997). Further, it was not predictive of clinical response at Week 8 or Week 52, nor of endoscopic remission or endoscopic response (Figure 1c) at Week 8 (p&gt;0.05 in all cases), although a weak correlation was observed with both endoscopic remission (p=0.0484) and endoscopic response (p=0.01162; Figure 1d) at Week 52. In SERENE-CD, baseline TREM1 expression was not linked to endoscopic or clinical outcomes at either Week 12 or Week 56 (p&gt;0.05 in all cases; Figure 2a–d). Stratification by adalimumab quartiles did not increase the ability of baseline TREM1 expression to predict clinical outcomes in either study. Of note, a highly positive correlation was observed between baseline TREM1 expression and neutrophils in endoscopic responders and non-responders in both studies. Regardless of clinical or endoscopic response or non-response, TREM1 expression decreased over time following adalimumab treatment. All results obtained with standard-dose adalimumab were replicated with the higher dose (data not shown).

Conclusion
The findings of this study suggest that baseline whole-blood TREM1 gene expression is not a robust predictor of clinical or endoscopic outcomes following adalimumab treatment in patients with UC or CD.
DOP83 Normalisation of biomarkers and improvement in clinical outcomes in patients with Crohn’s Disease treated with risankizumab in the phase 3 ADVANCE, MOTIVATE, and FORTIFY studies
Authors: Atreya R , Feagan B , Shchukina O , Jairath V , Rieder F , Hisamatsu T , Siegmund B , Rizzo J , Kligys K , Neimark E , Song A , Zambrano J , Mallick M , Cheng E , Armuzzi A 
Published: January 2022

Abstract

Background
The efficacy of risankizumab (RZB), an interleukin 23 p19 inhibitor, in patients with Crohn’s disease (CD) has been reported. Normalisation of high-sensitivity C-reactive protein (hs-CRP) and faecal calprotectin (FCP) are intermediate treatment targets in CD. Here, we evaluated changes in these objective inflammatory biomarkers and clinical outcomes with RZB treatment.

Methods
In 2 phase 3, randomised, double-blind studies (ADVANCE, NCT03105128; MOTIVATE, NCT03104413), patients with moderately to severely active CD received 12-week intravenous (IV) RZB induction therapy or placebo (PBO). Patients with clinical response to RZB IV induction were rerandomised in a 52-week maintenance study (FORTIFY, NCT03105102) to receive subcutaneous (SC) RZB or PBO (ie, RZB withdrawal). Induction analyses included patients who received either 600 mg RZB IV or PBO for 12 weeks. Maintenance analyses included patients who received 360 mg RZB SC every 8 weeks or withdrawal (PBO SC) for 52 weeks. Outcomes assessed were normalisation of hs-CRP and FCP concentrations at week 12 of induction and at week 52 of maintenance in patients with elevated biomarkers at baseline (hs-CRP &gt; 5 mg/L and/or FCP &gt; 250 μg/g), clinical biomarker response (defined as enhanced clinical response [≥ 60% average daily stool frequency (SF) decrease and/or ≥ 35% average daily abdominal pain score (APS) decrease] and ≥ 50% reduction in hs-CRP or FCP), and clinical biomarker remission (defined as clinical remission per CD Activity Index or SF/APS criteria and normal hs-CRP or FCP) during maintenance treatment. Nonresponder imputation was used for missing data.

Results
Greater proportions of patients receiving RZB vs PBO achieved normalisation of hs-CRP and FCP at the end of the 12-week induction period and the 52-week maintenance period (P &lt; .0001 for all; Table). Among patients with clinical response to RZB IV induction and entered maintenance, rates of clinical biomarker response were maintained through week 52 in patients receiving 360 mg RZB SC and declined over time among patients in the withdrawal (PBO SC) arm (Figure A). Rates of clinical biomarker remission increased over time in patients receiving 360 mg RZB SC. At week 52, clinical remission and normalisation of hs-CRP or FCP was achieved by 41% of patients receiving RZB vs 28%–29% of patients in the withdrawal (PBO SC) arm (Figure B-C). The safety profile of RZB in CD was previously reported.

Conclusion
Normalisation of objective biomarkers of inflammation in CD was achieved with RZB induction and maintenance therapy. Improvements in both clinical outcomes and biomarker levels were sustained with continuous RZB maintenance therapy and decreased over time in patients discontinuing RZB.
DOP84 Risankizumab maintenance therapy results in sustained improvements in endoscopic outcomes in patients with moderate to severe Crohn’s Disease: Post-hoc analysis from the phase 3 study FORTIFY
Authors: Irving P M , Abreu M , Axler J , Gao X , Torres J , Neimark E , Song A , Wallace K , Kligys K , Berg S , Liao X , Panaccione R 
Published: January 2022

Abstract

Background
Data from Phase 3 studies in Crohn’s disease (CD) demonstrated significant improvements in endoscopic outcomes with risankizumab (RZB) versus placebo (PBO) following 12-weeks (wks) induction therapy. Continued maintenance therapy with 360mg RZB SC led to significantly higher rates of endoscopic response and remission at Wk52 compared to withdrawal/placebo. This post-hoc analysis examined the durability of SC RZB maintenance therapy for endoscopic outcomes among patients achieving these endpoints at the end of induction

Methods
Patients achieving clinical response with 12-wks IV RZB induction therapy in ADVANCE or MOTIVATE entered the maintenance study, FORTIFY, and received either RZB SC or had RZB withdrawn and received placebo for 52 wks. For this analysis, endoscopic outcomes in the RZB 360 mg SC (N=141) and withdrawal/placebo (N=164) arms are reported. Maintenance of endoscopic response, endoscopic remission, and/or an SES-CD score of 0–2 were assessed at Wk52 in patients who achieved these endpoints at Wk0 of maintenance (Wk12 of induction). Safety was assessed throughout the study.

Results
Following 12-wks of IV RZB induction therapy (FORTIFY Wk0), 141 patients were randomized to RZB 360 mg (patients achieving endoscopic response, 55/141; endoscopic remission, 39/141; SES-CD score of 0–2, 29/141) and 164 were randomized to withdrawal (PBO SC) (patients achieving endoscopic response, 73/164; endoscopic remission, 46/164; SES-CD 0–2, 32/164). Maintenance of endoscopic response at Wk52 was demonstrated in 70.2% (39/55) of patients receiving RZB 360 mg SC versus 38.4% (28/73) of patients in the withdrawal (PBO SC) arm (P&lt;0.001). Maintenance of endoscopic remission at Wk52 was demonstrated in 74.4% (29/39) of patients receiving RZB 360 mg versus 23.9% (11/46) of patients in the withdrawal (PBO SC) arm (P&lt;0.001). Maintenance of an SES-CD score from 0–2 at Wk52 was demonstrated in 65.5% (19/29) of patients receiving RZB 360 mg versus 21.9% (7/32) of patients in the withdrawal (PBO SC) arm (P&lt;0.001).RZB maintenance treatment was well-tolerated and no new safety signals were observed. The safety profile of RZB has been reported previously.1–5

Conclusion
RZB IV induction followed by SC maintenance therapy led to sustained improvements in endoscopic outcomes, demonstrating the durability of efficacy with continued RZB treatment in patients with moderate to severe CD.

Reference
1. Feagan, B. G. et al. Lancet 389, 1699–1709 (2017) 2 Feagan, B. G. et al. Lancet Gastroenterol Hepatol 3, 671–680 (2018) 3 Ferrante, M. et al. Journal of Crohn’s and Colitis jjab093 (2021) 4 Ferrante, M. et al. in UEGW 2021 5 D’Haens, G. et al. in DDW 2021
P014 Impact of experimental ileitis and Toll-Like Receptor 4 signaling on enteric inhibitory neurotransmission
Authors: Faggin S , Cerantola S , Dal Prà A , Caldana G , Bosi A , Banfi D , Giaroni C , Savarino E , Giron M C 
Published: January 2022

Abstract

Background
Alterations in Toll-like receptor 4 (TLR4) expression and changes in enteric neurotransmissions influence the onset and severity of inflammatory bowel disease (IBD). We aimed to assess the interaction between the enteric inhibitory pathways and TLR4 signaling in a mouse model of dinitrobenzene sulfonic acid (DNBS)-induced small intestine inflammation.

Methods
Male TLR4-/- mice (9±2 weeks old) were intrarectally treated with 2.5% DNBS. Pro-inflammatory cytokines (IL-6 and TNF-α) were measured in ileal samples. Changes in ileal muscle tension were recorded following exposure to: i) 10-Hz electric field stimulation in non-adrenergic-non-cholinergic (NANC) conditions (1 μM guanethidine + 1 μM atropine) with or without 10 µM 1400W (a inducible nitric oxide synthase (iNOS) inhibitor), or 0.1 µM Nω-nitro-L-arginine methyl ester (L-NAME; a pan-NOS inhibitor); ii) 30 μM dopamine or 30 μM SKF38393 (a dopamine 1 receptor (D1R) agonist) or bromocriptine (a D2R agonist). Immunoreactivity of neuronal (HuC/D) and glial (S100β) markers as well as nitrergic chemical coding (i.e. nNOS and iNOS) were determined in longitudinal muscle-myenteric plexus whole-mount preparations (LMMPs) by confocal microscopy.

Results
No changes in IL-6 and TNF-α ileal mRNA transcripts were found after DNBS administration. The development of ileitis did not affect the NANC-inhibitory response, that was partially reduced in presence of 1400W or L-NAME, suggesting that TLR4 signaling influences NO-mediated inhibitory responses. DNBS-treated mice showed a significant increase in dopamine-induced relaxation (+31%) and in D1R- and D2R-mediated inhibitory responses (by +57% and +75%, respectively). A significant reduction of the total number of HuC/D+ neurons (-25%), with a proportional increase in nNOS+ neurons (+11%) was found in LMMPs of DNBS mice, associated with a significant reduction of S100β immunofluorescence (-12%) and no changes in iNOS immunoreactivity, highlighting a potential involvement of TLR4 signaling in the development of neuroplasticity and reactive gliosis.

Conclusion
The present data suggest that the severity of small intestine ileitis and neuronal dysfunction depend on the interplay occurring between TLR4 signaling and enteric inhibitory pathways. This evidence further strengthens the importance of characterizing neuroimmune interactions to identify potential molecular mechanism(s) representing putative pharmacological targets for the development of efficacious IBD therapies.
P027 Effects of anti-TNF and anti-α4β7 drugs on circulating monocytes migratory capacity in inflammatory bowel disease
Authors: Soleto I , Fernández-Tomé S , Mora-Gutiérrez I , Baldan-Martin M , Ramirez C , Santander C , Moreno-Monteagudo J A , Casanova M J , Casals F , Casabona S , Becerro I , Chaparro M , Bernardo D , Gisbert J P 
Published: January 2022

Abstract

Background
Inflammatory bowel disease (IBD) is an idiopathic and chronic disorder that include ulcerative colitis (UC) and Crohn’s disease (CD). Both diseases are different but show an uncontrolled intestinal immune response that generate tissue inflammation. Monocytes (Φ) play a key role in the tolerogenic maintenance in the gastrointestinal mucosa. These cells are antigen presenting cells highly specialized to control immune response against gut microbiota and food antigens. It has been previously reported that circulating Φ are recruited by intestinal mucosa in a CCR2 dependent manner. Also, in IBD patients this Φ recruitment is more prominent than in healthy controls (HC) but the specific migration mechanism is still unknown.

Methods
This is a cross-sectional observational postmarketing study where the modulatory effect of different biologic treatments on samples from patients with endoscopic diagnosis of IBD and HC was studied ex vivo. Peripheral blood mononuclear cells (PBMC) were obtained from 15 patients per group, and were cultured in presence of anti-TNF or vedolizumab. Following culture, surface markers expression was determined hence assessing the differential effect of biological drugs (if any) over the Φ subset in the different groups. After that, the migratory capacity of circulating Φ toward CCL2, CCL25 and MadCam1 from the different study groups was determined. Finally, we evaluated the Φ migratory capacities in presence of biological drugs or with culture media alone.

Results
Our data showed that within CD14+ population, CD patients presented a higher percentage of CCR5+ and CCR9+ and the surface expression level of CCR2 and CCR9 was increased. In addition, anti-TNF reduced the number of CCR9+ Φ subset in HC. In HC an UC patients vedolizumab reduced the percentage of β7+ Φ (Figure 1). According to the circulating Φ migratory capacity as expected, the migration towards CCL2 was higher than toward culture media (Figure 2). When the effect of biological drugs was evaluated, surprisingly anti-TNF increased the Φ migration. Also, vedolizumab showed a clear tendency to decrease the Φ migration towards CCL2 and MadCam1 in HC and in UC (Figures 3 and 4).

Conclusion
Circulating Φ from IBD patients express a different migration pattern than HC, being the expression of these molecules modulated by anti-TNF drugs. The capacity of circulating Φ to migrate towards CCL2 is higher than towards culture media. Unexpectedly, anti-TNF increases the migratory capacity of Φ. On other hand, treatment of Φ from HC and UC patients with vedolizumab, induces a clear downward trend of their migratory capacity towards CCL2 and MadCam1