bluuebunny/crossref_metadata_2025 huggingface dataset:
DOP23 Endoscopic evaluation at 1 month after ileocolic resection for Crohn’s disease predicts postoperative recurrence and is safe
Authors: Guo Z , Zhu Y , Cao L , Li Y , Wang Z , Zhu W
Published: January 2020

Background

Endoscopic surveillance remains the gold standard for evaluating postoperative recurrence in Crohn’ disease (CD). However, the optimal timing of the first postoperative endoscopic evaluation is unclear. The commonly used strategy, first endoscopy at 3, 6, or 12 months, demonstrates high rates of endoscopic recurrence, which means this strategy may delay the detection and treatment. The aim of this study was to determine the clinical value and safety of the endoscopy at 1 month after surgery, and define the related factors.

Methods

This was a prospective cohort study of CD patients undergoing an ileocolic resection between 2015 and 2018, with a postoperative colonoscopy at 4–5 week after surgery. The primary outcome was endoscopic recurrence at 12 months, or clinical recurrence, or surgical recurrence within 12 months after surgery. Univariate and multivariate analyses were performed to identify related factors.

Results

Eighty-four eligible CD patients were included. Among 84 colonoscopies at 4–5 week, no endoscopic complication occurred. The main endoscopic findings at the first evaluation were anastomotic ulcers (45 [10 circumferential ulcers and 35 scattered ulcers], 53.6%), ulcers in the neoterminal ileum (16, 19.0%), oedema in anastomosis (50, 59.5%), mild narrowing in anastomosis (7, 8.3%), and mild narrowing in neoterminal ileum (3, 3.6%). On univariate and multivariable analysis, anastomotic scattered ulcers were associated with forward postoperative recurrence (HR, 2.532; 95% CI, 1.019–6.318; p = 0.046). We then used the modified Rutgeerts score to define endoscopic findings: i0, 26(44.0%); i1, 4(4.8%); i2a (circumferential anastomotic ulcers were not included), 40(34.5%); i2b, 11(13.1%); i3, 0; i4, 3(7.1%). Univariate and multivariable analysis showed ≥i2a were associated with forward postoperative recurrence (HR, 3.174; 95% CI, 1.218–8.273; p = 0.018). No factor was associated with ≥i2a at the first endoscopy.

Conclusion

Endoscopic evaluation at 4–5 weeks after surgery in CD was safe, and endoscopic findings were associated with postoperative recurrence. Earlier endoscopic examination after surgery may be useful for the adjustment of medication.
DOP27 Transanal minimally invasive surgery (TAMIS): A novel approach for treatment of pouch failure
Authors: Van Praag E , Hompes R , Buskens C , Tanis P , Duijvestein M , Bemelman W
Published: January 2020

Background

Many different pouch failure (PF) indications and procedures are known. In literature, different types of PF are randomly classified and often stacked together due to complexity. Transanal minimally invasive surgery (TAMIS) is becoming increasingly popular for redo-surgery due to greater accessibility and visibility in complex pelvic surgery compared with the conventional abdominal approach. We aimed to evaluate the efficacy of TAMIS in patients with PF.

Methods

This retrospective study includes all consecutive patients over 18-year old with an ileal pouch-anal anastomosis (IPAA) and PF that were managed with TAMIS between July 2014 and July 2019. Patient characteristics, operative indications, perioperative outcomes and short-term follow-up (FU) are described using a suggested subclassification for surgical-related PF (Figure 1).

Results

Forty-six procedures were completed in 42 patients, predominantly male (66.7%) with a median age of 44.6 (range 22.0–70.8) years. Initial IPAA indications were familial adenomatous polyposis (n = 11), medical refractory ulcerative colitis (UC) (n = 29) or other (n = 2). Seven (24.1%) UC patients turned out to have Crohn’s disease (CD). Reasons for PF were septic complications (n = 18), retained rectum (n = 3), outlet problems (n = 8) (with megapouch: n = 5), inlet problems (n = 6), cuff problems (n = 8) and refractory pouchitis with unknown aetiology (n = 3). Twenty-three pouch redo’s (16 remodelling, 7 new pouches), 5 sleeve advancements, 4 cuff excisions, 1 posterior pouchpexy, and 13 pouch excisions were recorded. Five pouch excisions were performed in CD patients. Five procedures were fully completed transanally, and 41 were a combined transabdominal (with 32 open and 9 laparoscopic) and TAMIS approach. None were converted to an open procedure. Apart from the patients with a pouch excision, 9 ended up with a permanent ileostomy, although technical success was achieved in 4 of those. Six permanent ileostomies were in patients with a redo-pouch (3 remodelling, 3 new pouches), 2 after sleeve advancement and 1 after cuff excision. Major morbidity (Clavien-Dindo ≥3) occurred after 17 procedures (37.0%), 14 within 1 month after surgery with a median FU of 17.9 (0.9–41.6) months. There was no peri-operative mortality.

Conclusion

TAMIS for PF after IPAA is technically feasible with acceptable short-term outcomes. Peri-operative morbidity is high and reflects the complexity of these procedures. Success after PF procedures is difficult to interpret due to a wide range of possible outcomes such as technical success, conversion rate and number of patients with a permanent stoma. The PF subclassification makes the complex problem and surgical management of PF comprehensible.
DOP29 Elevation of a novel blood-based gene signature in a severe Crohn’s disease (CD) subtype preceding surgery defines and predicts a post-surgical decrease in pro-inflammatory pathway activation
Authors: Gonsky R , Fleshner P , Botwin G , Biener-Ramanujan E , McGovern D , Targan S
Published: January 2020

Background

CD is defined by transmural inflammation leading to inflammatory, stricturing and/or penetrating phenotypes. Identifying underlying molecular pathways and distinct disease subsets is critical for improved prognostics, therapeutics and biomarker discovery.

Methods

CD3+ T cells were purified from paired blood and mucosal tissue from 101 CD and 17 non-IBD subjects requiring surgery. Longitudinal samples (n = 30) were collected 4–13 mo. post-surgery. Expression profiles were generated by RNAseq, T-cell subset deconvolution by xCell and transcriptome-wide associations (TWAS) using TWAS-hub.

Results

Unsupervised clustering of peripheral T-cell gene expression at surgery revealed 2 CD profiles: Expression from cluster1, labelled CD-PBT (63%), clustered tightly with the non-IBD group. In cluster2, expression shifted from a peripheral toward a mucosal profile, labelled CD-PBmu(cosal) (37%). CD-PBmu was defined by differentially expressed genes (DEG) (1944 DEG, p < 0.001) regulating cell migration and adhesion pathways and a distinct T-cell subset composition associated with stricturing disease (p = 0.03), increased resected bowel length (p = 0.036) and post-op recurrence (p = 0.01). There were no significant differences in disease location/behaviour. Independent validation (5 public datasets) confirmed the CD-PBmu signature in data from whole blood (CD patients failing anti-TNF therapy, n = 204) and the mucosal-like expression profile in data from ileal tissue (paediatric CD patients, studies n = 751). A defining feature of CD-PBmu, validated in a separate CD cohort (n = 19), was decreased pro-inflammatory cytokine/chemokine and adhesion molecule expression following surgery (900 DEG, p < 0.001). No post-surgery change in expression was detected in CD-PBT. A 44-gene classifier was identified to enable clinical application. The classifier accurately detected the CD-PBmu patient subtype, correlated with the altered composition of peripheral T-cell subsets and overlapped with IBD associated TWAS signals (>60%). Recently, another group posed a blood-based 17 gene panel as predictive for aggressive IBD. These genes were not predictive for either the CD-PBmu or CD-PBT subtype (<50% DEG).

Conclusion

Severe CD can be stratified into 2 subtypes based on peripheral T-cell gene expression. Circulating T cells from CD-PBmu exhibit a mucosal-like gene signature, altered T-cell subset composition, clinical features of severity and decreased pro-inflammatory gene expression post-surgery. These findings hold potential to identify targets for CD subtype-specific therapeutic development. The 44-gene classifier overlapped with multiple paediatric CD datasets, suggesting the potential application of these findings for treatment stratification early in the disease process.
DOP35 Monitoring of mucosal T cells subsets under biotherapies in IBD: responders exhibit a phenotype similar to healthy controls
Authors: Hammoudi N , Perez K , Hassid D , Tran Minh M L , Gornet J M , Baudry C , Lourenco N , Gergaud B , Chardiny V , Bonnet J , Le Bourhis L , Allez M
Published: January 2020

Background

A dysregulated T-cell response is involved in the pathophysiology of inflammatory bowel diseases (IBD). T cells expressing the NKG2D activation receptor are implicated. Here, we investigated changes in intestinal T lymphocyte subsets overtime in patients treated by biotherapy for active disease.

Methods

In this prospective single-centre study, patients with IBD who have started a biotherapy (Infliximab, Adalimumab, Golimumab, Vedolizumab, Ustekinumab) for active disease were included. Mucosal biopsies in the inflamed segment were taken during endoscopies before treatment initiation (W0) and in the same location 14 weeks (W14) and 52 weeks (W52) after inclusion. Control biopsies were taken from 16 patients without IBD (7 ileal and 9 colonic). Immunophenotyping of isolated lymphocytes was performed by flow cytometry at each timepoint. Correlation with endoscopic response was evaluated. For Crohn’s disease (CD), the response was defined by a 50% decrease of the CDEIS score. For ulcerative colitis (UC), the response was defined by a 2 points decrease of the UCEIS

Results

Between February 2016 and November 2018, 85 patients were included. Forty-four were male (52%). Forty had an active CD with the most inflamed segment located for 28 in the colon and 12 in the ileum. Thirty-nine patients had active UC and 6 pouchitis. An anti-TNF was started for 51 patients (60%), Vedolizumab for 16 patients (19%) and Ustekinumab for 18 (21%). Lymphocytes phenotyping was performed at inclusion for the whole cohort, at W14 for 67 patients (79%) and at W52 for 49 patients (58%). Data concerning endoscopic response was available for all patients.

At W0, IBD patients displayed higher rates of CD4 T cells and lower rates of CD8 T cells than controls (medians: 31% vs. 48% for CD4, p < 0.001 and 52% vs. 37% for CD8, p < 0.001 respectively). Endoscopic responders experienced a normalisation of these mucosal populations as compared with non-responders (W14: 58% vs. 45% for CD4, p = 0.005 and 40% vs. 28% for CD8, p = 0.03; W52 56% vs. 43% for CD4, p = 0.01 and 27 vs. 43% for CD8, p = 0.003). Results remained significant when splitting the cohort in CD and UC patients. Before treatment initiation, IBD patients displayed lower expression of NKG2D on CD8 T cells (78% vs. 94%, p < 0.001). At W52, endoscopic responders presented significantly higher expression of this marker on CD8 T cells compared with non-responders (85% vs. 68%, p < 0.001). Results remained significant in UC and CD patients.

Conclusion

The intestinal T cells of IBD patients with active disease present an increase of the CD4 to CD8 T-cell ratio and lower expression of NKG2D on CD8 T cells reflecting engagement of this receptor in inflammation. These T-cell parameters are normalised in endoscopic responders but not in non-responders
DOP39 The first prospective, multicentre, randomised controlled trial on discontinuation of infliximab in ulcerative colitis in remission; endoscopic normalisation does not guarantee successful withdrawal
Authors: Kobayashi T , Motoya S , Nakamura S , Yamamoto T , Nagahori M , Tanaka S , Hisamatsu T , Hirai F , Nakase H , Watanabe K , Matsumoto T , Tanaka M , Abe T , Suzuki Y , Watanabe M , Hibi T
Published: January 2020

Background

Anti-tumour necrosis factor (TNF)-α agents are the mainstay of the long-term treatments for refractory ulcerative colitis (UC). However, there is no prospective randomised controlled trial evaluating if anti-TNF-α agents can be discontinued in UC patients in remission.

Methods

Patients with UC maintained in clinical remission with infliximab (IFX) were prospectively enrolled from 23 specialist centres. Patients confirmed to be in (1) clinical remission for > 6 months, (2) steroid-free and (3) Mayo endoscopic subscore (MES) of 0 or 1 were randomised with stratified factors (MES and use of immunomodulators) into two groups (continue or discontinue IFX) in 1:1. The biopsy was taken from the rectum and Nancy histological Index (NI) was centrally scored at randomisation. The primary endpoint was remission rate at week 48 in full analysis set (FAS). Factors associated with remission at Week 48 were evaluated by logistic regression adjusted for the treatment group. Efficacy and safety of retreatment with IFX after relapse were also evaluated.

Results

A total of 92 patients were included in the FAS and the remission rates at week 48 were 80.4% (95% CI: 66.1–90.6) and 54.3% (95% CI: 39.0–69.1) in IFX-continued and IFX-discontinued groups, respectively (p = 0.008). Although the duration of IFX, use of concomitant immunomodulators, IFX concentration, and MES of 0 at randomisation were not predictive, C-reactive protein and NI were associated with remission at week 48 in FAS (p = 0.039 and 0.019, respectively). Retreatment with IFX lead to remission in 8 out of 12 patients (66.7%) in 8 weeks and was well-tolerated.

Conclusion

This first prospective multicentre randomised controlled trial confirmed that discontinuation of maintenance IFX resulted in the increased risk of relapse but retreatment was effective in UC. Endoscopic normalisation was not sufficient for the successful discontinuation of IFX.
DOP42 Impact of discontinuing thiopurines at anti-TNF initiation in inflammatory bowel disease: A nationwide Danish cohort study
Authors: Bohn Thomsen S , Ungaro R , Allin K , Poulsen G , Mikael A , Colombel J F , Jess T
Published: January 2020

Background

The impact of discontinuing vs. continuing thiopurines at anti-TNF initiation in thiopurine experienced patients with inflammatory bowel disease (IBD) is unclear.

Methods

We used the nationwide Danish registers to establish a national cohort of patients with IBD who received thiopurines prior to initiating anti-TNF during 2003–2014. We compared patients who discontinued vs. continued thiopurine within 90 days of anti-TNF initiation. Our primary outcome was a composite of any clinical event: corticosteroids, hospitalisation, surgery, or death. We used Cox regression models to calculate adjusted hazard ratios (aHR) with 95% confidence intervals (CI). Analyses were adjusted for sex, diagnosis-age, IBD-subtype, disease duration, calendar year, pre-anti-TNF thiopurine duration, and past disease severity including hospitalisations the past year, surgery past 5 years, and corticosteroid use the past year.

Results

Of 6998 anti-TNF exposed, 1602 patients (Crohn’s disease, n = 1000, ulcerative colitis, n = 602) received thiopurines prior to anti-TNF. Of these, 489 (44%) received thiopurines for more than 180 days. At anti-TNF initiation, 503 patients discontinued thiopurines and were followed for a median 3.54 years and 1099 continued thiopurines with a median follow-up of 3.92 years. Discontinuing thiopurines at anti-TNF initiation statistically significantly increased the risk of the composite outcome (aHR 1.25; 95% CI 1.09 to 1.45). Analyses of the individual outcomes revealed a statistically significantly increased risk of later corticosteroid use in thiopurine discontinuers (aHR 1.31; 95% CI 1.11 to 1.56), but no increased risk of the remaining outcomes.

IR; incidence rate, HR; hazard ratio, CI; confidence interval, IBD; inflammatory bowel disease. P-value is the test of interaction between the variable and the treatment groups.

Conclusion

In our nationwide cohort study of patients with IBD, we found that continuing thiopurines after anti-TNF initiation impacted the outcome favourably, especially regarding corticosteroid use. Further studies are warranted to investigate this central clinical question.
DOP57 Vedolizumab has similar efficacy rates in young and elderly patients: A binational, multicentre, retrospective case–control study
Authors: Cohen N A , Plevris N , Kopylov U , Grinman A , Ungar B , Yanai H , Leibovitzh H , Fliss N , Hirsch A , Ritter E , Ron Y , Bar-Gil Shitrit A , Goldin E , Dotan I , Ben-Horin S , Lees C , Maharshak N
Published: January 2020

Background

Treatment of inflammatory bowel diseases (IBD) is associated with multiple side effects, such as malignancies and infections, that may be more common in the elderly population. The aim of this study was to compare the safety and efficacy of vedolizumab (VDZ) in young and elderly patients.

Methods

This is a binational, multicentre, retrospective, case–control study consisting of patients from multiple centres in Israel and from Edinburgh, UK. IBD patients in whom VDZ treatment was initiated during 2015–2019, and were followed for at least 14 weeks, were included in the study according to their age groups: ≤40 years or ≥60 years. Patients were matched for disease duration, classification and severity.

Results

We recruited 144 patients (82 CD and 62 UC) to the elderly cohort and 140 patients (83 CD and 57 UC) to the young cohort. The respective average age was 70.2 ± 7.3 years and 29.6 ± 5.7 years. Elderly patients had significantly more cardiovascular, metabolic and respiratory co-morbidities and had less prior exposure to anti-TNF agents compared with the young cohort (CD: 51% vs. 88%, p < 0.001; UC: 47% vs. 70%, p = 0.03). Clinical and endoscopic responses were comparable between the groups at Weeks 14 and 52 among elderly and young (Week 52 remission: CD: 40% vs. 35%, p = 0.7; UC: 48% vs. 51%, p = 0.84) (Figure 1). However, the use of more than one anti-TNF agent was an independent predictor of poor response and remission rates to VDZ at all time points among the elderly (OR 0.13; 95% CI 0.03–0.69). A total of 49 adverse events were documented, 23 (16%) in the young cohort and 26 (18%) in the elderly cohort (p = 0.5). Overall there were significantly more infections in the elderly cohort (3 (2%) vs. 17 (12%), p = 0.002) and included nasopharyngeal, urinary, skin and Clostridium difficile infections. None of them was fatal but one patient stopped treatment due to urinary sepsis. There were significantly more non-specific adverse events such as headache and myalgia in the young cohort (8% vs. 2%, p = 0.03). Six patients (4%) in the young cohort required drug discontinuation due to adverse events compared with 4 patients (3%) in the elderly cohort (p = 0.5). The reasons for discontinuation were similar between the groups.

Conclusion

VDZ is equally effective in elderly and young IBD patients. This study shows an increased risk of overall infections in the elderly cohort, it is unclear whether these are related to VDZ treatment or the age and background diseases of these patients. In elderly patients, the use of VDZ before anti-TNF therapy may improve response and remission rates.
DOP60 Vedolizumab treatment persistence and safety in an extended access program (XAP)
Authors: Danese S , Subramanian K , Van Zyl J , Adsul S , Lindner D , Roth J , Vermeire S
Published: January 2020

Background

Vedolizumab, a gut-selective, α 4β 7 integrin antagonist, has been established as an effective and safe treatment for patients with UC or CD in the GEMINI phase 3 program and long-term safety (LTS) study. An extended access program (XAP) was initiated to provide continued access to patients who were benefiting from vedolizumab in GEMINI LTS and to monitor safety. We now report persistence and safety results from a 2-year data analysis.

Methods

Vedolizumab XAP (NCT02743806) is a phase 3b/4 prospective, open-label, multinational interventional study. A rollover from GEMINI LTS (NCT00790933) to the XAP, patients reduced dosing frequency from vedolizumab 300 mg IV every 4 weeks (Q4W) to every 8 weeks (Q8W) or remained on vedolizumab 300 mg IV Q4W if medically indicated. This 2-year data analysis assessed persistence on Q8W dosing after dosing frequency reduction, need for escalation to Q4W dosing, incidence of relapse (defined as dose escalation, study withdrawal due to adverse event, loss of adequate benefit from vedolizumab, or increased corticosteroid [CS] or immunomodulator dose), and safety 2 years after rollover from GEMINI LTS.

Results

A total of 311 patients (142 UC, 169 CD) from GEMINI LTS enrolled in the XAP. Median (range) duration of exposure to vedolizumab prior to the XAP was 8.0 years (5.2–10.0) for patients with UC and 7.5 years (5.4–9.9) for patients with CD. Of patients with UC and CD, 93.0% and 84.6%, respectively, reduced dosing frequency to Q8W at XAP start, and 87.3% and 77.5%, respectively, remained on Q8W after 2 years. At baseline, 93.0% of all patients with UC and 88.2% of all patients with CD were in CS-free remission; patients who maintained Q4W dosing at baseline had lower CS-free remission rates (62.5% in UC and 69.2% in CD). Of patients who initiated Q8W dosing at enrolment in the XAP, 95% had no relapse for ≥6 months (97.0% UC, 93.7% CD; Table 1). Only 7.3% of patients required dose escalation to Q4W, and 11.6% experienced relapse during the 2-year follow-up. Times to dose escalation and relapse were similar in patients with UC and CD (Figures 1 and 2). At 2 years, 4 of 8 patients with UC and 4 of 12 patients with CD who required dose escalation to Q4W discontinued vedolizumab early due to loss of benefit or adverse events. Adverse events related to vedolizumab were infrequent; no new or serious events attributed to vedolizumab were reported.

Conclusion

High patient persistence on Q8W vedolizumab was observed in the first 2 years after reduction of dosing frequency in the XAP. Overall, there were low rates of Q4W dose escalation and CD or UC disease relapse. The safety profile was consistent with previous reports with no new signals observed.
N25 Outcomes of a GP outreach programme to offer colonoscopic surveillance for IBD patients being managed in primary care
Authors: Windak H , Cairnes V , Chanchlani N , Desmond C , Hamilton B , Heerasing N , Hendy P , Simeng L , Kennedy N A , Goodhand J , Ahmad T , Gordon C
Published: January 2020

Background

Colonoscopic surveillance in IBD patients can reduce the development of colorectal cancer (CRC) and the rate of CRC-associated death. We recently reported that 27% of IBD patients living in East Devon are managed exclusively in primary care of whom about 23% maybe eligible for colonoscopic surveillance. We devised an outreach programme, whereby we invited primary care physicians to enrol these patients in a colonoscopic surveillance programme.

Methods

In December 2017, we contacted 37 general practices, where 161 patients with UC who were eligible for surveillance had been identified. Each practice was sent a letter explaining the goals of the project, a link to the National Institute for Healthcare and Clinical Excellence (NICE) guidance for CRC surveillance in IBD patients and patient information booklets. We informed the practices of their eligible patients and asked them to refer patients for secondary care IBD consults if appropriate. We included an outcome form that captured whether the patient was referred, was deemed inappropriate for surveillance, had surveillance elsewhere, had declined surveillance, or was no longer registered at the practice.

Results

Sixty-five percent of practices (24/37) responded and we received responses for 57 of 161 (35%) potentially eligible patients. Thirty-five (61%) patients were referred to our IBD service; 7 (12%) patients declined surveillance; 7 (12%) patients were deemed by their GP to be unfit for surveillance and 5 (10%) were no longer registered at the identified GP practice; 2 (4%) had surveillance arranged elsewhere and 1 (2%) patient had died. Amongst the 35 patients referred to secondary care; 22 (63%) underwent surveillance colonoscopy, 12 (34%) declined surveillance after discussion or did not attend their booked appointments and one is awaiting colonoscopy. Half of patients who had a colonoscopy had active inflammation. We diagnosed one CRC He was an elderly man with a locally invasive signet ring caecal tumour, without distant metastases, who went onto to have a curative right hemicolectomy without complication.

Conclusion

Patients with longstanding IBD are frequently managed exclusively in primary care and maybe overlooked for colonoscopic CRC surveillance. There is a need to implement processes to facilitate identification and recall of patients eligible for surveillance across primary and secondary care.
N28 Effectiveness of pre-biologic screening for viral hepatitis and HIV
Authors: Clarke M , Goodhand J , Ahmad T , Cairnes V , Kennedy N A
Published: January 2020

Background

Biologic treatments can reactivate viral hepatitis and HIV. Prior to starting biologic therapy, the ECCO guidelines recommend patients are screened for chronic viral infection. We recently diagnosed a patient treated with adalimumab with HIV. As a consequence we sought to assess the effectiveness of our screening process for viral infections and to identify factors linked to non-testing

Methods

We screened our pharmacy dispensing records and IBD database for all patients currently treated with biologic therapies. We then cross-referenced our virology records for HIV, Hepatitis B (HBV) and Hepatitis C (HCV) screening. We used our IBD database and clinical records to record demographic and clinical factors associated with non-testing.

Results

As of September 2019 we were treating 453 patients with a biopharmaceutical drug in whom pre-treatment testing for viral hepatitis and HIV is recommended. Amongst whom, 50 (11%), 22 (5%) and 24 (5%) patients had not been tested for HIV, HBV or HCV, respectively.

Our patient with HIV had inflammatory ileocolonic Crohn’s disease and been treated with combination azathioprine and adalimumab since October 2016. He was in clinical remission at the time of HIV diagnosis (July 2018). We stopped his azathioprine and adalimumab and he was commenced on antiretroviral therapy. After 13 months’ follow-up, he had not developed immune reconstitution syndrome or had a flare of his Crohn’s disease. Moving forwards, the identified unscreened patients currently on biologic treatment are being tested at the earliest opportunity. Patients receiving infusions of biopharmaceuticals are being screened with their verbal consent at the time of their next infusion. Patients receiving subcutaneous treatments are being screened at their next appointment.

Conclusion

Comprehensive review of our biologic-treated patients revealed that 11% had not been screened for HIV and/or chronic viral hepatitis.
DOP75 Efficacy of tofacitinib dose escalation to 10 mg BID in patients with UC after completing maintenance therapy in remission and losing response: Data from OCTAVE open-label, long-term extension study
Authors: Rubin D T , Dubinsky M C , Panés J , Wu D C , Lawendy N , Guo X , Lai C , Kwok K , Su C , Salese L
Published: January 2020

Background

Tofacitinib is an oral, small-molecule JAK inhibitor for the treatment of ulcerative colitis (UC). The efficacy and safety of tofacitinib were demonstrated in patients with moderate to severe UC in three Phase 3 studies.1 Here, we investigated outcomes in a subpopulation of the ongoing, open-label, long-term extension study (OLE) (OCTAVE Open; NCT01470612; May 2019; database not locked), including maintenance of remission patients receiving tofacitinib 5 mg twice daily (BID) who were dose-escalated to 10 mg BID due to flare.

Methods

Analysis included the maintenance remission–dose-escalation subpopulation: patients who achieved remission at Week 52 in OCTAVE Sustain (tofacitinib 5 or 10 mg BID, or placebo), entered OLE (5 mg BID), but were dose-escalated to 10 mg BID due to flare (based on total Mayo score [MS]; local read endoscopy). Remission: total MS ≤2 with no subscore >1, and rectal bleeding (RB) subscore 0. Dose escalation during OLE was permitted if patients experienced a flare, defined as ≥3 increase from maintenance study baseline total MS and ≥1 increase in RB and endoscopic subscore (ES; unless ES=3 at baseline and remained 3) after ≥8 weeks of treatment in OLE. Kaplan–Meier for estimation of time to dose escalation was assessed in all OLE maintenance remission population relative to OLE baseline. Partial MS remission (≤2 with no subscore >1; no ES) assessed at Months (M)3, 6, 9 and 12 post-dose-escalation; mucosal healing (MH; ES ≤1) and remission assessed at M12 post-dose-escalation. Adverse events (AEs) also assessed.

Results

Of the 944 patients enrolled in OLE, 162 were in remission at baseline and received tofacitinib 5 mg BID, and 41 were dose-escalated to 10 mg BID due to flare (22 had prior TNFi failure). The cumulative proportion of patients with dose escalation was 4.3%, 10.6%, 12.6% and 13.2% at M3, 6, 9 and 12 of OLE, respectively. Partial MS remission was 75.0% at M3, and partial MS remission, MH and remission were 95.0%, 63.6% and 57.6%, respectively, at M12 post-dose escalation (Table). One case each of serious infection, herpes zoster (non-serious; opportunistic infection) and malignancy were reported (see Table).

Conclusion

For patients with moderate to severe UC who entered OLE in remission, received tofacitinib 5 mg BID but flared and were dose-escalated to 10 mg BID, response was recaptured for most by M3 post-dose-escalation and remission was recaptured in the majority by M12. Safety in this subpopulation was generally consistent with that observed in the overall tofacitinib UC programme.2 Due to the small sample size and open-label nature, results should be interpreted with caution.

References
DOP79 Dose escalation of upadacitinib in Crohn’s disease patients with an inadequate response: Data from the randomised CELEST study
Authors: Sandborn W , Panés J , Peyrin-Biroulet L , Louis E , Greenbloom S , Zhou W , Zhou Q , Liu J , Lacerda A P
Published: January 2020

Background

Patients with Crohn’s disease (CD) may lose response to treatment, requiring dose adjustments. This analysis from the CELEST study evaluated efficacy and safety in patients with CD who required an escalated dose of upadacitinib (UPA), an oral selective JAK1 inhibitor.

Methods

CELEST (NCT02365649) was a placebo-controlled phase 2 study of adults with moderate-to-severe CD refractory to immunosuppressants/biologics. Patients were randomised to placebo or UPA 3, 6, 12, or 24 mg twice daily (BID) or 24mg once daily (QD) for 16 weeks (weeks), followed by a 36-week double-blind maintenance period to receive 3, 6 or 12mg BID or 24mg QD (Figure 1). Patients who met criteria for inadequate response (average daily liquid/soft stool frequency [SF] >2.2 or average daily abdominal pain score >1.8, and increase in hs-CRP >1 mg/l from baseline [BL] or hs-CRP ≥5 mg/l at previous or current visit) at or after week 20 were eligible to receive open-label (OL) therapy with UPA 12mg BID. Patients with inadequate response at or after 4 weeks of OL 12 mg BID could further escalate to OL 24 mg BID. Data were analysed using descriptive statistics of clinical/endoscopic improvement, change from BL in hs-CRP and faecal calprotectin (FC), and AEs at week 52.

Results

Among 220 randomised patients, 180 were re-randomised into the maintenance period; 60 had inadequate response and received OL 12 mg BID. Of the 60 patients, 25 (42%) were in clinical response at week 16. After receiving OL 12 mg, 27 patients (45%) required escalation to OL 24 mg BID. A higher proportion of patients who received OL 24 mg received 2 or more prior TNF antagonists, and had higher BL FC, SF, and Simplified Endoscopic Score for CD (SES-CD) compared with patients who remained on OL 12 mg BID (Table 1). At week 52, 15% of patients who received OL 12 mg achieved clinical remission and 10% achieved endoscopic response. Of the patients who escalated to OL 24 mg, 39% achieved clinical remission and 41% were in endoscopic response at week 52 (Table 2). At week 52, change from BL in FC and hs-CRP was −2123 ± 2475 µg/g and −5.1 mg/l, respectively, for patients who received OL 24 mg vs. −423 ± 2953 and −6.4 mg/l for OL 12 mg. Serious infection was reported in 3 patients (2 receiving OL 12 mg and 1 receiving OL 24 mg). Two nonserious herpes zoster events were reported (1 on each dose), but neither event led to discontinuation of UPA. No malignancies, cardiovascular events, thromboembolic events, intestinal perforations, tuberculosis, or deaths were reported for patients who dose-escalated.

Conclusion

Patients with non-response or loss of response during CELEST gained clinical remission and endoscopic response with UPA 12 mg BID or further escalation to 24 mg BID. No new safety risks were observed for either dose of UPA, consistent with double-blind CELEST results.
DOP80 Effectiveness of ustekinumab and vedolizumab in patients with Crohn’s disease refractory to anti-tumour necrosis factor: A multi-centre comparative study
Authors: Alric H , Amiot A , Kirchgesner J , Tréton X , Allez M , Bouhnik Y , Beaugerie L , Carbonnel F , Meyer A
Published: January 2020

Background

There is no head-to-head trial comparing ustekinumab and vedolizumab in patients with Crohn’s disease (CD) refractory to anti-TNF. In France between May 2014 and November 2016, vedolizumab (and not ustekinumab) was reimbursed for patients who had failed anti-TNF. Then, between December 2016 and August 2018, ustekinumab (and not vedolizumab) was reimbursed for this category of patients. Since September 2018, both ustekinumab and vedolizumab are reimbursed in patients who are refractory to anti-TNF. The aim of this study was to compare effectiveness and safety of ustekinumab and vedolizumab in patients with CD refractory to anti-TNF.

Methods

We studied all consecutive patients with active CD who were refractory to at least one anti-TNF, and were treated either with vedolizumab or ustekinumab, in five university hospitals of the Paris area, between May 2014 and August 2018. The primary endpoint was clinical remission rate at week 48. Adjustment according to propensity scores with inverse probability of treatment weighting was performed.

Results

239 patients were included, 107 received ustekinumab and 132 received vedolizumab. After propensity scoring with IPTW, there was no difference between the two groups (Figure 1). At week 48, the clinical remission rate was higher with ustekinumab than with vedolizumab (54.4% vs. 38.3%; OR =1.92, 95% CI [1.09–3.39]). At week 48, corticosteroid-free remission rate tended to be numerically higher with ustekinumab than with vedolizumab (44.7% vs. 34.0%; OR = 1.57, 95% CI [0.88–2.79]). Treatment persistence was significantly more frequent in the ustekinumab group (71.5% vs. 49.7%; OR = 2.54, 95% CI [1.40–4.62]). The dose optimisation rate at week 48 was higher with vedolizumab than with ustekinumab (53.5% vs. 30.1%; OR = 0.37, 95% Cl [0.21–0.67]). Subgroup analyses showed that ustekinumab was associated with higher clinical remission rates at week 48 in patients with ileal CD (OR = 3.49; 95% CI [1.33–9.17]), a penetrating phenotype (OR = 6.58; 95% CI [1.91–22.68]) and a history of perianal disease (OR = 2.48; 95% CI [1.04–5.93]). Regardless of treatment group, combotherapy was associated with a higher clinical remission rate at week 48 (OR = 1.93; 95% CI [1.09–3.43]).

Conclusion

This study suggests that, after 1 year of follow-up, ustekinumab is associated with a higher rate of clinical remission than vedolizumab in CD patients refractory to anti-TNF, particularly in those with ileal and penetrating disease.
DOP81 Time to loss of efficacy among patients in remission following induction treatment with tofacitinib 10 mg BID who reduced tofacitinib dose or discontinued tofacitinib in OCTAVE sustain
Authors: Dubinsky M C , Chou J W , Su C , Wang W , Modesto I , Guo X , Vermeire S
Published: January 2020

Background

Tofacitinib is an oral, small-molecule JAK inhibitor for the treatment of ulcerative colitis (UC). Safety and efficacy of tofacitinib were evaluated in two Phase 3 induction studies (OCTAVE Induction 1 and 2; NCT01465763, NCT01458951), a 52-week, Phase 3 maintenance study (OCTAVE Sustain, NCT01458574) and an ongoing, open-label, long-term extension study (NCT01470612).1,2 Here, we assess time to treatment failure among patients in remission at the end of OCTAVE Induction 1 and 2 who enrolled in OCTAVE Sustain.

Methods

In OCTAVE Induction 1 and 2, patients received placebo or tofacitinib 10 mg twice daily (BID) for 8 weeks; clinical responders were re-randomised to placebo, tofacitinib 5 or 10 mg BID in OCTAVE Sustain for 52 weeks. Kaplan–Meier method was used to estimate median time to treatment failure (withdrawal due to insufficient clinical response) in patients who received 10 mg BID in induction studies and entered OCTAVE Sustain in remission (total Mayo score ≤2 with no subscore >1, and rectal bleeding subscore [RB] 0). Treatment failure: ≥3-point increase from baseline total Mayo score, plus ≥1-point increase in RB and endoscopic subscore (ES; centrally read) and absolute ES ≥2 after ≥8 weeks of maintenance therapy.

Results

Following induction, 156 patients in remission entered OCTAVE Sustain and received tofacitinib 5 mg BID (N = 57) or 10 mg BID (N = 50), or placebo (N = 49). Estimated treatment failure rates are reported in the table. At Week 52, Kaplan–Meier rates of treatment failure were higher in patients who switched to placebo (81.8% [95% confidence interval 67.0, 90.4]) vs. those who continued to receive tofacitinib 10 mg BID (25.6% [14.2, 38.6]) or reduced their dose to 5 mg BID (34.4% [21.8, 47.3]). Median time to treatment failure was 169 days for placebo and >52 weeks for tofacitinib 5 and 10 mg BID (due to the low number of treatment failure events, exact median time to treatment failure was not available for tofacitinib 5 or 10 mg BID).

Conclusion

For patients in remission following 8 weeks of induction treatment with tofacitinib 10 mg BID, median time to treatment failure for those who continued tofacitinib treatment (5 or 10 mg BID) was >52 weeks. After treatment interruption (remission patients who were re-randomised to placebo), median time to treatment failure was 169 days; this was similar to previously published time-to-treatment-failure data for patients with clinical response (including remission) following 8 weeks of induction treatment with tofacitinib who were re-randomised to placebo.3.

References
DOP86 An IFN-STAT1-MLKL axis drives programmed necrosis of Paneth cells in Crohn’s ileitis
Authors: HARTMANN L , Siegmund B , Weidinger C , Becker C , Neurath M F , Günther C
Published: January 2020

Background

Interferons (IFNs) are immune-modulatory cytokines expressed by epithelial and mucosal cells in response to viral and bacterial infection. Just recently, we discovered a correlation between IFN-λ expression and disease activity, including small intestinal inflammation and Paneth cell dysfunction, in human Crohn’s disease patients. On a molecular level, we uncovered that IFN-λ mediates epithelial cell death, in particular, Paneth cell death by a programmed necrosis, dependent on STAT1 activation and controlled by caspase-8. These results suggested that IFN-λ can be considered as a pathogenic cytokine in Crohn′s ileitis and should be considered as a new and promising target for future therapeutic intervention for this particular subtype of IBD. Our central question is now by which pathways interferon-regulated programmed necrosis of epithelial cells contributes to intestinal inflammation and how these mechanisms could be targeted for future therapeutic intervention.

Methods

We use a mouse model for Crohn’s Disease like inflammation and Paneth cell death that has a specific deletion of Caspase-8 in intestinal epithelial cells (Casp8∆IEC). We stimulate small intestinal organoids derived from Casp8∆IEC mice with IFNs in vitro and we overexpress IFN-λ in these mice in vivo by hydrodynamic tail vein injection of an IFN-λ expression vector. Furthermore, we use JAK-inhibitors to impede pharmacologically cell death pathways in the pathogenesis of intestinal inflammation in vitro and in vivo.

Results

We uncovered that gene expression of the cell death mediators Mlkl and Caspase-8 is dependent on IFN-λ-mediated JAK-STAT1 signalling. The non-specific pan JAK-inhibitor Tofacitinib is able to attenuate gene expression of Mlkl and Caspase-8 in vitro as well as in vivo. It prevents non-apoptotic as well as apoptotic cell death of small intestinal organoids stimulated with IFN-λ and is sufficient to prevent small intestinal tissue destruction in Casp8∆IEC mice challenged with IFN-λ. Additionally, we use the selective JAK1-inhibitor Filgotinib to limit the targeted JAK-STAT signalling pathways to only JAK1-STAT1 signalling and thus reduce side effects of the inhibitor on other signalling pathways. This had a similar effect as Tofacitinib suggesting that IFN controls MLKL-mediated cell death via JAK1.

Conclusion

In summary, our results indicate that targeting IFN-λ-mediated JAK-STAT1 signalling by the small-molecules Tofacitinib and Filgotinib impedes induction of Mlkl and Caspase-8-mediated cell death pathways. Therefore, JAK1 inhibitors such as Filgotinib might represent a promising novel therapy that may be sufficient to achieve efficacy particularly in Crohn′s ileitis patients who display elevated IFN-l serum levels.
DOP90 The role of Nlrp9b, a novel NLR member in regulating experimental colitis
Authors: Zheng D , Levy M , Elinav E
Published: January 2020

Background

The NOD-like receptors (NLR) are important family members of the intracellular pathogen recognition receptors, which recognise pathogen- or danger-associated molecular patterns in the cell. The NLR signalling pathways are increasingly recognised to play critical roles in the pathogenesis of inflammatory bowel diseases. We have identified an NLR member, Nlrp9b, whose expression is restricted to the epithelium of the gastrointestinal tract. However, the role of Nlrp9b in regulating intestinal inflammation and the underlying mechanism remains to be clarified.

Methods

We generated constitutive Nlrp9b-deficient (Nlrp9b−/−) mice to study the function of Nlrp9b. We induced experimental colonic inflammation by using dextran sulphate sodium (DSS). Bone marrow transfer experiments were conducted to clarify the cell type in which Nlrp9b exerts its function. We then performed RNA-sequencing of intestinal tissues from Nlrp9b−/− mice and WT controls to investigate the potential mechanisms.

Results

Nlrp9b−/− mice were more susceptible to DSS-induced colitis compared with cohousing wild-type (WT) mice, manifesting as exacerbated weight loss, more severe inflammation in colonoscopy and histopathology. Non-haematopoietic expression of Nlrp9b was responsible for protection against intestinal inflammation. Inflammasome activation was not impaired in Nlrp9b−/− mice, as we detected no defects in both cleavage of caspase 1 and secretion of IL18 in Nlrp9b−/− mice. Through RNA sequencing, we identified 300 differentially expressed genes in the intestinal tissue between Nlrp9b−/− and the co-housed WT controls, which primarily belongs to pathways involved in intestinal IgA production, as well as antigen processing and presentation. Indeed, IgA levels were globally reduced in Nlrp9b−/− mice, on the levels of mRNA expression, secreted antibodies measured in the intestinal lumen, and serum IgA. Furthermore, the total numbers of immune cells in the Peyer's patches were significantly reduced in Nlrp9b−/− mice, including leukocytes, B cells and B cells in the germinal centres, where they class switch to IgA producing cells.

Conclusions

Nlrp9b functions in the non-haematopoietic compartments of intestine and is protective against experimental intestinal inflammation, through potential mechanisms involving intestinal IgA production.
P002 Specific genome editing to model hypermethylation of the SP140 gene that associates to Crohn’s disease
Authors: Hageman I , Li Yim A , Joustra V , Ghiboub M , Gecse K , Te Velde A , D’Haens G , Paulusma C , Henneman P , De Jonge W
Published: January 2020

Background

SP140 (Speckled 140 KDa) encodes an epigenetic reader protein with an immune restricted expression, that binds to epigenetically modified (acetylated and methylated) histones and thereby regulates expression of large gene sets, including pro-inflammatory cytokines, in innate immune cells. SP140 is implicated in CD because single nucleotide polymorphisms, as well as defective protein function are associated with CD and marks anti-TNF response. Through a genome-wide methylation screen of Crohn’s disease (CD) patients peripheral blood, we identified two hypermethylated positions in SP140 locus associated with CD patients. We hypothesise that this DNA hypermethylation at the SP140 locus controls SP140 expression in CD patients contributing to their colitis development.

Methods

To address the role of SP140 DNA methylation, we used CRISPR ‘dead’ Cas9 (dCas9) epigenome-editing for specifically adding methyl groups (dCas9-DNMT) or removing methyl groups (dCas9-TET) in monocyte cell line THP1. We developed guide RNAs complementary to the gene expression regulatory region of the SP140 gene. With lentiviral delivery, we transduced THP-1 cells with guide RNA-lentiviruses, and with dCas9-DNMT or dCas9-TET lentiviruses. We assessed the level of SP140 methylation using bisulphite Sanger sequencing and the effect of methylation intervention of SP140 using qPCR and ELISA for SP140, IL-6, TNFα, IL-1β.

Results

We observed that SP140 gene in THP-1 cells under control conditions contained little methylated CpG sites. We induced sp140 hypermethylation through transduction of dCas9-DNMT. We validated hypermethylation of the two SP140 CpGs in transduced THP1 cells, thus mimicking the observed hypermethylation in CD patients cells. SP140 hypermethylation in THP1 cells polarised into M1 macrophages and stimulated with lipoteichoic acid (TLR-2 ligand), displayed a decrease of TNFα and (p = 0.042) protein levels. Similarly, we showed a decrease of TNFα (p = 0.02) and IL-6 (p = 0.03) protein release after transduction dCas9-DNMT and stimulation with LPS or Zymosan (TLR-2/4 ligand).

Conclusion

In this study, we demonstrated that editing SP140 gene methylation through CRISPR-dCAS9 technology allows modelling of the relevance of epigenetic marks for CD aetiology. Through methylome editing, we could affect the expression of CD-associated pro-inflammatory genes. Our dCas9 technique will allow us to investigate the role of DNA-methylation in the aetiology of CD.