bluuebunny/crossref_metadata_2025 huggingface dataset:
DOP57 Predictive modelling to examine long term treatment effectiveness of darvadstrocel in patients with complex perianal fistulas in Crohn’s Disease
Authors: Maruszczak M , Genenz K , Turkstra E , Fenu E , Hantsbarger G , Gilaberte I , Karki C , Panes J
Published: May 2021

Background

Darvadstrocel (DVS) was approved in 2018 by EMA for treatment of complex perianal fistulas in Crohn’s disease (CPF-CD)1, with evidence on long-term effectiveness still accruing. The objective of this study was to synthesize clinical trial data and real-world evidence (RWE) using robust statistical methodologies to predict absolute and relative long-term effectiveness of DVS vs. standard of care (SoC) in patients with CPF-CD.

Methods

Data was pooled from the pivotal phase 3 trial ADMIRE-CD (n=212; ≤ 2 years data), INSPECT (n=89; chart review study of patients completing ≥52 weeks in ADMIRE-CD, 2-year follow-up post-trial) and PREFACE (n=313; chart review study of patients undergoing SoC treatment, median follow-up of 4 years). Individual anonymized patient data from these studies were combined and analysed with shared covariates of interest included in regression analyses. Weighting procedures were used to adjust for bias due to differences in distribution of outcomes among patients included in INSPECT. Key outcomes were clinical remission, clinical and patient-centric remission (CPC remission), and relapse. Missing values were imputed using a multi-level Bayesian approach. Predictive statistical models extrapolated clinical outcomes beyond the observed follow-up time using parametric curves which were fitted to the defined study populations for each treatment arm and outcome. The models were then implemented within a semi-Markov model, to obtain the resultant number of patients in remission.

Results

Adult patients with CPF-CD from ADMIRE-CD and PREFACE were similar in age, number of internal and external openings of the perianal fistulas. However, the median CD disease duration was 9.5 vs 6.5 years and prior biologic exposure: 79.5% vs 46.0% for patients in ADMIRE-CD and PREFACE respectively. Patients included in INSPECT were comparable to the overall ADMIRE-CD patients for the covariates of interest. Percentage of patients in CPC remission at 24 months was 39% vs 32% for DVS and SoC respectively for ADMIRE-CD+INSPECT. However, after adding PREFACE data to the predictive model and adjusting for outcome bias, the predicted percentage of patients in CPC remission increased in DVS and SoC groups to 48% vs 35%, respectively. There were small differences by 48 months, after which the remission rates stabilized (Figure).

Conclusion

In this pooled analysis, we used predictive modelling to examine the effectiveness of DVS vs. SoC over a longer time. Inclusion of RWE to the model indicates possible maintenance of the disease-modifying effect of DVS over a longer time period.

Reference

1. Panés et al. Gastroenterology 2018;154:1334–42

Sponsor: Takeda Pharmaceuticals USA, Inc.
DOP68 Assessment of patients’ understanding of Inflammatory Bowel Diseases (IBD): Development and validation of a questionnaire (U-IBDQ)
Authors: Ostromohov G , Fiebelman M , Hirsch A , Ron Y , Aviv Cohen N , Kariv R , Deutsch L , Anbar R , Maharshak N , Fliss Isakov N
Published: May 2021

Background

Education of inflammatory bowel disease (IBD) patients regarding their disease, therapeutic aims and options, is important for patients’ empowerment and commitment to disease management. Currently, there is no standardized and validated tool for assessment patients’ knowledge of their disease. Therefore, we aimed to develop a questionnaire to evaluate IBD patients’ understanding of disease pathophysiology and treatment.

Methods

We have developed the Understanding IBD Questionnaires (U-IBDQ), consisting of multiple-choice questions in two version [for Crohn’s disease (CD) and ulcerative colitis (UC)]. U-The U-IBDQ is composed of 36 questions covering 8 IBD topics. Each question received a similar weight, and total score ranges between 0–100. Questionnaires were tested for: content validity by an independent multidisciplinary stirring committee using the content validity index, face validity, readability and responsiveness on a pilot group of IBD patients. Convergent validity was assessed by correlating scores of the U-IBDQ with physician’s subjective assessment of disease understanding and knowledge. Discriminant validity was assessed by comparison to healthy controls (HC), patients with chronic gastrointestinal (GI) conditions other than IBD, and to GI nurses. A test-retest reliability was assessed among a sub-population of IBD patients which were asked to fill-in the U-IBDQ twice. Multivariate analysis was used to determine associated factors of a high level of disease understanding.

Results

Study population consisted of IBD patients (n=106), HC (n=35), chronic GI disease patients (n=38) and GI nurses (n=19). Mean U-IBDQ score among IBD patients was 56.5±21.9, not differing between CD and UC patients (P=0.941). There was a strong correlation between the U-IBDQ score and the physician’s subjective score (r=0.747, P<0.001). The U-IBDQ showed strong discriminant validity with mean score of IBD patients significantly higher than that of HC and chronic GI disease patients, and was lower than that of GI nurses (P<0.001). The U-IBDQ is reliable as determined by Cronbach’s alpha = 0.872.

Independent factors associated with high U-IBDQ scores included academic education (OR=1.21, 95% CI 1.10–1.33, P<0.001), biologic therapy experience (OR=1.24, 95% CI 1.01–1.53, P=0.046), and IBD diagnosis before the age of 21 years (OR=2.97, 95% CI 1.05–8.87, P=0.050).

Conclusion

We have developed and meticulously validated the U-IBDQ. This is a short, self-report questionnaire that has demonstrated good reliability and validity in measuring understanding of disease pathophysiology and treatment in IBD.
DOP80 Automatic detection of ulcers and erosions in PillCam™ Crohn’s capsule using a convolutional neural network
Authors: Saraiva M , Ribeiro T , Afonso J , Cardoso H , Ferreira J , Andrade P , Parente M , Jorge R , Lopes S , Macedo G
Published: May 2021

Background

Capsule endoscopy (CE) plays a central role in the management of patients with suspected or known Crohn’s disease (CD). It is indicated for the diagnosis, classification, monitoring of the response to treatment, and prognostic prediction. In 2017, PillCam™ Crohn’s Capsule (PCC) was introduced. It has demonstrated greater accuracy in detecting and evaluating the extent of lesions in these patients. However, this new tool produces thousands of images, whose revision is time-consuming and prone to errors, since lesions can be restricted to a small number of images. In the last decade, several Artificial Intelligence (AI) algorithms were developed, and demonstrated potential to mitigate some of the drawbacks of CE. Among AI tools, Convolutional Neural Networks (CNN) display the best performance for imagery analysis. This study aims to develop an AI algorithm based on an CNN for the automatic detection of ulcers and erosions of the small intestine and colon in PCC images.

Methods

A total of 8 085 PCC images were extracted from a single tertiary centre between 2017–2020. This pool of images was constituted by 2 855 images depicting ulcers, 1 975 erosions; the remaining with normal enteric and colonic mucosa. For the automatic identification of these findings, this pool of images was split into training and validation datasets. A CNN model with transfer learning using tensorflow and keras tools was constructed. The performance of the network was subsequently assessed in an independent test set.

Results

After optimizing the different layers of the CNN, our model was able to detect and distinguish small intestinal or colonic erosions or ulcers with a sensitivity and specificity of 90.0% and 96.0%, respectively. The precision and accuracy of this model were 97.1% and 92.4%, respectively (Figure 1). Particularly, the CNN detected ulcers with a sensitivity of 83% and specificity of 98%, and erosions with sensitivity and specificity of 91% and 93%, respectively.

Conclusion

Our group developed, for the first time, a CNN capable of automatically detecting ulcers and erosions of the small intestine and colon in PCC images with high sensitivity and specificity. These findings are extremely important since they pave the way for the development of systems for the automatic detection of clinically significant lesions, optimizing diagnostic performance and efficiency of monitoring CD activity.
DOP83 Efficacy and Safety of Ustekinumab for Ulcerative Colitis Through 3 Years: UNIFI Long-term Extension
Authors: Abreu M T , Danese S , Sandborn W J , Miao Y , Tikhonov I , Zhang H , Panaccione R , Hisamatsu T , Scherl E J , Leong R W , Rowbotham D S , Arasaradnam R P , Afif W , Peyrin-Biroulet L , Sands B E , Marano C
Published: May 2021

Background

Ustekinumab (UST) is an IL-12/23p40 antagonist used to treat pts with moderate-to-severe ulcerative colitis (UC). The ongoing UNIFI long-term extension (LTE) evaluates subcutaneous (SC) 90mg UST maintenance therapy, with efficacy (wk152) and safety (wk156) results reported here.

Methods

523 intravenous UST induction responders were randomized to SC maintenance therapy (175 SC placebo [PBO]; 172 UST 90mg every 12 weeks [q12w]; 176 UST 90mg q8w). 284 UST pts who completed wk44 entered the LTE. PBO pts were discontinued after wk44 unblinding. Starting at wk56, randomized pts with UC worsening could adjust to q8w. Symptomatic remission (Mayo stool frequency subscore of 0 or 1 and a rectal bleeding subscore of 0) was evaluated in randomized pts. Safety was evaluated for all 588 pts treated in the LTE, including the randomized and nonrandomized populations; 188 received PBO and 457 received UST. The nonrandomized population included responders to PBO induction and UST induction nonresponders at wk8 who received SC UST, responded 8 wks later and received UST 90mg q8w.

Results

Among all pts randomized to UST at maintenance baseline (intent-to-treat population with nonresponder imputation for missing data and treatment failure criteria), 55.2% were in symptomatic remission at wk152 (biologic naïve, 66.1%; biologic failures, 43.5%; Table 1); 96.4% (185/192) of pts in symptomatic remission at wk152 were corticosteroid-free. Overall, 20.1% (39/149 biologic failure, 16/149 biologic naïve) of pts who were randomized to UST and treated in the LTE discontinued treatment between wks44 and 156. Among randomized pts treated with UST in the LTE, 67.6% were in symptomatic remission at wk152; 76.4% of those in clinical remission at wk44 were in symptomatic remission at wk152; and 84.1% of pts with observed data at wk152 were in symptomatic remission.

From maintenance wk0-156, combined UST and PBO pts had 1281.6 and 425.0 pt-years of follow-up, respectively; and safety events per 100 pt-years of follow-up for combined UST vs PBO were AEs: 235.81 vs 204.48, SAEs: 7.73 vs 7.53, and serious infections: 2.34 vs 2.35 (Table 2). From wks96-156, there were no reported deaths or major adverse cardiovascular events. One UST-treated pt with fair skin and a prior history of basal cell carcinoma (BCC) reported 2 BCC. One 90 mg q8w UST pt receiving concomitant 6-MP reported SAEs of neutropenic sepsis and oral herpes SAE; the latter events were considered potential opportunistic infections. The dose of 6-MP was reduced, pt recovered and continued UST.

Conclusion

The efficacy of UST in pts with UC was sustained through 3 years. No new safety signals were observed.
P176 Patient preferences in steroid resistant ulcerative colitis – a discrete choice experiment survey
Authors: Wickramasekera N , Shackley P , Coates E , Barr A , Lee M , Blackwell S , Bedford H , Dames N , Sebastian S , Probert C , Lobo A
Published: May 2021

Background

Understanding patient preferences in those who are not responding to steroids for ulcerative colitis is important in informing treatment choices. This study aimed to understand the relative importance of treatment characteristics to patients by conducting a discrete choice experiment (DCE).

Methods

Patients completed a two-part online survey. Participants were shown 12 DCE tasks – a series of side by side comparison of competing, hypothetical treatment characteristics describing effectiveness, remission, speed of response, route of administration and safety and asked to select a preferred treatment. Disease control was assessed by the IBD-control-8 questionnaire (poor control < 13). Participants also completed a ranking exercise where patients were asked to rank four commonly used treatments (Adalimumab, Infliximab, Tofacitinib, and Vedolizumab,) in order of preference. Survey responses were analysed using descriptive statistics and regression analyses.

Results

115 patients completed the survey (mean age 45 years; 52% female; median time since diagnosis 10 years). 107 (93%) had previously received steroids; 81 (70%) thiopurines and 81 (70%) biological therapies or tofacitinib. 51 (45%) reported poor control of ulcerative colitis. Figure 1 shows the results of the regression analyses where all treatment characteristics had a significant influence on patients’ treatment choice. Patient preferences were strongest for lower side effects, for example, compared to a treatment that had very common side effects, patients were more likely to take a treatment that had very rare side effects (ß 2.937, p<0.01) even if very rare side effects are usually more severe. Patients preferred a treatment with higher likelihood of induction of response, but they were unable to differentiate between 50% success rate and 60% success rate. Higher levels of remission (ß 0.065, p<0.01) and faster acting treatments were preferred (ß -0.145, p<0.01). Taking a pill daily at home (ß 0.848, p<0.01) or injections at home every 8 weeks (ß0.541, p<0.01) were preferable compared to infusions every 8 weeks. Notably, there was no significant difference between infusion, every 8 weeks at hospital compared to injection, every 2 weeks, at home (ß -0.029, p= 0.85). When asked to rank four commonly used biologics, the most preferred treatment was Infliximab (38%) and Tofacitinib (38%), followed by Vedolizumab (17%) and Adalimumab (6%).

Conclusion

Quantifying preferences through DCEs helps to identify and prioritise treatment characteristics that are important to patients. The results could be used to improve discussions between patients and clinicians when reviewing treatment options.
P181 Patient-led remote intracapillary pharmacokinetic sampling (fingerPRICKS) for therapeutic drug monitoring in patients with Inflammatory Bowel Disease
Authors: Chee D , Nice R , Hamilton B , Jones E , Hawkins S , Redstone C , Cairnes V , Pohl K , Chanchlani N , Lin S , Kennedy N , Ahmad T , Goodhand J , McDonald T
Published: May 2021

Background

Because of COVID-19 public health restrictions, telemedicine has replaced conventional outpatient follow up for most patients with chronic immune-mediated inflammatory disorders treated with biologic drugs. Innovative solutions to facilitate remote therapeutic drug monitoring are therefore required. Low-volume intracapillary blood sampling can be undertaken by patients at home and samples returned by post to central laboratories.

Methods

We sought to report the effect of the COVID-19 pandemic on requests for therapeutic drug monitoring and the equivalence, acceptability and effectiveness of low-volume intracapillary fingerprick sampling compared to conventional venepuncture. Drug and antidrug antibody levels were measured using standard ELISAs.

Results

Therapeutic drug monitoring requests for adalimumab (96.5 [70.5 - 106] per week to 52 [33.5 - 57.0], p < 0.001) but not infliximab (184.5 [161.2 - 214.2] to 161 [135 - 197.5], p = 0.34) reduced during the first UK stay-at-home lockdown compared with the preceding six months.

Fingerprick sampling was equivalent to conventional venepuncture for adalimumab (Figure 1), infliximab, vedolizumab, and ustekinumab drug and anti-adalimumab and -infliximab antibody levels. The median (IQR) volume of serum obtained using intracapillary sampling was 195µL (130–210). More than 87% (90/103) patients agreed that intracapillary testing was easy and 69% (71/103) preferred it to conventional venepuncture (Figure 2).

In routine care, 75.3% (58/77) patients returned two blood samples within 14 days to permit remote assessment of biologic therapeutic drug monitoring.

Conclusion

Therapeutic drug monitoring can be undertaken using patient-led remote intracapillary blood sampling and has the potential to be a key adjunct to telemedicine in patients with immune-mediated inflammatory diseases.
P193 Assessement of cumulative bowel damage using Lemann index and MaRIA score in surgically naive patients with Crohn’s disease
Authors: Domislović V , Hrabric Sonje K , Brinar M , Cukovic-Cavka S , Turk N , Grgic D , Sjekavica I , Krznaric Z
Published: May 2021

Background

The Lémann index (LI) is a unique tool that measures cumulative bowel damage in Crohn’s disease (CD) using data on surgical procedures and severity and extent of bowel lesions. Magnetic resonance index of activity (MaRIA) is composed of features independently associated with endoscopic disease activity. Primary aim was to investigate differences in factors associated with elevated LI in total population and surgically naive patients. Secondary aim was to compare diagnostic accuracy of gMARIA and LI in determing active disease in surgically naive patients.

Methods

In this cross-sectional study on 251 CD patients LI was calculated evaluating 20 small bowel, 7 large bowel and 3 upper GI segments. For each segment bowel resections, inflammatory, stricturing or penetrating lesions were taken into account. Global MaRIA (gMaRIA) index was calculated using following parameters on 6 bowel segments: bowel wall thickness, ulcers, edema and relative contrast enhancement. Longstanding disease was defined as ≥10 year disease duration. Disease activity was defined as combination of clinical and biochemical disease activity (CRP>5 or HBI≥5).

Results

This study included 251 CD patients [age 35 (25–47), 55.3% males, disease duration 7 (2–15) years]. There were 103 (40%) surgically naïve and 112 (44.6%) patients with longstanding disease. In total population, higher LI values were observed in patients with longstanding disease (10.47 vs 5.41, p<0.001), patients treated with biological therapy (9.6 vs. 6.3, p=0.005) and with prior surgery (11.92 vs. 1.57, p<0.005). There was no difference in LI according to activity (7.53 vs. 7.66, p=0.911) and smoking status (6.9 vs. 7.3, p=0.336). In multivariate analysis adjusted for age, gender and BMI, independent predictors of elevated LI in total population was prior surgery (β=9.26, p<0.001) and disease duration (β=0.20, p<0.003). Independent predictors in surgically naive patients were current or ex smoking status (β=1.69, p<0.001) and gMARIA (β=0.10, p<0.001). Biological therapy, disease duration and clinical and biochemical disease activity were not significant predictors (p>0.05). Diagnostic accuracy of LI in surgically naive patients in defining active disease was lower [AUC 0.75 (95%CI 0.65–0.84)] compared to gMaRIA [AUC 0.82 (95%CI 0.73–0.89)].

Conclusion

Since surgical procedures contribute significantly to the LI, it is important to determine predictors of cumulative bowel damage in surgically naive patients. CD patients should be strongly advised to stop smoking and to regularly monitor disease activity using radiological methods. gMaRIA is superior to LI in detecting active disease in surgically naive patients.
P228 Prehabilitation strategies prior to ileocolonic resection in Crohn’s disease in a prospective cohort study: a missed window of opportunity?
Authors: Ruiterkamp M , Arkenbosch J , van Ruler O , van der Marel S , van Dongen K , Maljaars P W J , Hoentjen F , West R , Jharap B , Dijkstra G , Campmans-Kuijpers M , Jansen S , Romberg-Camps M , Stassen L , van der Woude C J , de Vries A
Published: May 2021

Background

Prehabilitation strategies to improve the postoperative course after intestinal resections in Crohn’s disease (CD) are mostly non-evidence-based. Prehabilitation strategies may include preoperative nutritional, physical and psychological management and optimization of medical treatment prior to surgery. In this study, we explore whether and to what extent prehabilitation strategies are currently used in a real-world prospective cohort.

Methods

In this multicenter prospective cohort study, data were collected in three secondary and two tertiary Dutch hospitals. CD patients (pts) aged ≥ 18 years who underwent ileocecal or ileocolonic (re)resection were included between November 2017 and January 2021. Data were collected on disease severity, IBD medication at time of surgery, preoperative BMI, weight loss within a year prior to resection, assessment of sarcopenia and hand grip strength (HGS), laboratory assessment, including albumin and micronutrients, and preoperative visits to a dietician, physiotherapist and psychologist. In addition, the 30-day postoperative complication rate was recorded.

Results

To date, 90 pts were included (38% male, median age 35.6 years) (Table 1). The main indications for ileocolonic resection were stenosis (55 (61%)), therapy refractory inflammation (15 (17%)) and penetrating disease (14 (18.9%)). At time of surgery, 60 pts (67%) were on IBD medication (immunomodulator n=16; biological n=22; combination therapy n=11, corticosteroids n=19). Median preoperative BMI was 23.7 kg/m2 (IQR 20.9–27.2). Sarcopenia and HGS were not assessed. Preoperative weight within a year prior to resection was recorded in only 31/90 (34%) pts. During the preoperative period, 32/90 pts (36%) visited a dietician, of whom 25/32 (78%) received a nutritional intervention (enteral support 16 (64%), parenteral support 0, exclusive enteral nutrition (EEN) 7 (28%), total parenteral nutrition (TPN) 2 (8%)). 4/90 pts (4%) visited a physiotherapist and 6/90 (7%) a psychologist. Albumin was assessed in 52/90 (58%) pts (median 38 (IQR 32–45); ferritin, vitamin B12 and D in 9/90 (10%), 10/90 (11%), 6/90 (7%) patients. Postoperative complication occurred in 32/90 (36%) pts, most often infections (68%) (Table 2). Four pts underwent a re-intervention for abdominal infection (2/4), anastomotic leakage (1/4) or ileus (1/4). Five pts (16%) were readmitted for anastomotic leakage (2/5), ileus (1/5), abdominal pain (1/5) and infection (1/5).

Conclusion

Prehabilitation strategies are not routinely applied in CD patients scheduled for ileocolonic resection and, since postoperative complications occur in more than a third of patients, further research into the yield of implementing multimodal prehabilitation is indicated.
P272 Tofacitinib as salvage therapy for patients hospitalized with refractory severe active ulcerative colitis: a GETAID multicenter prospective/retrospective cohort
Authors: Uzzan M , Bresteau C , Laharie D , Stefanescu C , Carbonnel F , Serrero M , Viennot S , Nachury M , Amiot A , Altwegg R , Picon L , Nahon S , Vuitton L , Ah Soune P , Kirchgesner J , Peyrin-Biroulet L , Bouhnik Y
Published: May 2021

Background

Up to 25% of patients with ulcerative colitis (UC) will require hospitalization for severe flare. In UC patients admitted who have already experienced multiple drug failures, including steroids and anti-TNF agents, new quick-acting medical options are needed. Tofacitinib is effective in refractory UC and has a rapid mechanism of action. It could be considered in this setting.

We aimed to evaluate the efficacy and safety of tofacitinib in patients hospitalized for an acute UC flare.

Methods

We conducted an observational and multicenter study with both retrospective and prospective collections in 14 GETAID tertiary IBD centers. The primary objective was to assess the survival without colectomy following tofacitinib initiation. We determined rates of clinical response, clinical remission, and clinical steroid-free remission at week 6 and week 14 and safety.

Results

Fifty-eight patients were included. All but one patient with active lupus were exposed to antiTNF. 50 (86.2%) patients have received infliximab and 18 (31%) to ciclosporin. Patients were previously exposed to a median of 2.5 lines of biologic treatment before tofacitinib.Median Lichtiger at inclusion was 11.5 (interquartile range IQR[9 - 13]), median CRP was 17 mg/l (IQR[6.5 - 67]) and total Mayo score was 10 (IQR[9.3 - 11]). Deep ulcerations were observed in 10 patients (17.2%).With a median follow-up of 6.5 months (IQR [2.9-12.4]), colectomy-free survival rates were estimated at 80.1% (95CI [70.1-91.4]) at 3 months and at 75.1% (95CI[64.1-88.1]) at 6 months. Rates of clinical response, clinical remission and clinical steroid-free remission were 60.3%, 46.6% and 37.9% at week 6 an, 48.1%, 37% and 35.2% at week 14, respectively. At the end of follow-up, 29 patients (50%) were still treated with tofacitinib. The survival without tofacitinib discontinuation was estimated at 82.8% (95CI[73.6-93.1), 67.8% (95CI[56.6-81.4]) and 46.2% (95CI[34.2-62.4]) at 1, 3, and 6 months (Figure 3).Regarding safety, no death was observed, three patients withdrew tofacitinib due to adverse events. Two herpes zosters occurred in patients aged over 60 years old. No thrombotic event occurred.

Conclusion

Tofacitinib appears as a promising option in patients hospitalized with a severe UC flare that needs further validation in prospective and controlled trials.
P273 The duration of clinical remission in patients with Crohn’s disease depends on the frequency of administration of mesenchymal stromal cells of the bone marrow
Authors: Knyazev O , Kagramanova A V , Lishchinskaya A , Li I , Shkurko T , Veselov A , Fadeeva N , Zhulina E , Parfenov A
Published: May 2021

Background

Anti-cytokine therapy with anti-TNF-α drugs contributes to the achievement of persistent remission of Crohn’s disease (CD). Allogeneic mesenchymal stromal cells (MSC) of the bone marrow are also used for the treatment of CD.

Objective

to evaluate the duration of remission of CD in the context of mesenchymal stromal cells (MSC) therapy of the bone marrow, depending on the frequency of MSC administration.

Methods

76 patients with CD with luminal form of CD (terminal ileitis, colitis, and ileocolitis) were divided into two groups. The first group of patients aged 19 to 58 years (Me-29) (n=34) received culture of MCS according to the scheme: 0-1-2-12-26-52 weeks, then annually 2 times a year. The second group of patients with CD (n=42) aged 20 to 62 years (Me-28) received culture of MCS according to the scheme: 0-1-2-12-26-52 weeks to achieve remission within one year. The effectiveness of therapy was evaluated 12, 24, 36, 48 and 60 months after the start of therapy using the Harvey-Bradshaw index.

Results

During 12 months of follow-up, 4/34 patients (11.76%) relapsed among patients in 1-st group. In 2-nd group, relapse occurred in 5/42 (11.9%) (HR-0.63; 95% CI 0.288-3.397; p=0.84).

After 24 months, 6/34 patients (17.6%) relapsed in 1-st group. In the 2-nd group of patients, the disease relapsed in 11/42 (26.2%) (HR-0.674; 95% CI 0.278-1.634; p=0.37).

After 36 months, the disease relapsed in 7/34 patients in 1-st group (20.6%). In the 2-nd group, relapse was in 18/42 (42.8%) (HR-0.48; 95% CI 0.228-1.014; p=0.038).

After 48 months, in the 1-st group receiving MSCS, a relapse occurred in 9/34 (26.5%). In the 2-nd group, relapse occurred in 22/42 (52.4%) (HR-0.5; 95% CI 0.269-0.949; p=0.021).

After 60 months, 10/34 (29.4%) relapsed in 1-st group. In the 2-nd group, relapse occurred in 24/42 (57.1%) (HR-0.463; 95% CI 0.250-0.860; p=0.007).

Conclusion

The duration of clinical remission in patients with luminal Crohn’s disease depends on the frequency of administration of mesenchymal stromal cells.
P294 AMT-101, a gut selective oral IL-10 fusion: results from a Phase 1b study in patients with active Ulcerative Colitis
Authors: Posch M , Tanase R , Maisaia K , Jucov A , Geier C , Hotson D , Hamdy O , Whitney J A , Garovoy M , Kanwar B , Schreiber S
Published: May 2021

Background

IL-10 is a pleiotropic anti-inflammatory cytokine that restores mucosal homeostasis. Genetic deficiencies in IL-10 cause intestinal inflammation in mice and are associated with early onset IBD in humans. In mice, this can be reversed by addition of exogenous IL-10. Subcutaneous use of recombinant human IL-10 treatment in patients with Crohn’s Disease led to symptomatic and endoscopic improvement, but dose limiting systemic toxicity including anemia and thrombocytopenia was observed and appeared to be mediated by induction of gamma-interferon. AMT-101 is an oral, gut selective, fusion protein of IL-10 and a carrier protein that mediates transcytosis through intestinal enterocytes into the lamina propria (LP). Pre-clinical studies demonstrated that AMT-101 efficiently transits the epithelial cell barrier, targets mucosal immune cells in the LP, and results in improved colitis disease severity without systemic exposure.

Methods

A multiple ascending dose Ph1b POC trial was conducted in 16 patients with active UC where patients were randomized 3:1 to receive AMT-101 at doses of 1, 3, 10, or 30 mg or PBO, orally, once daily for 14 days. Primary and secondary outcome measures included safety and PK. Exploratory endpoints included changes in fecal calprotectin, histology, and stool microbiome.

Results

AMT-101 was safe and well tolerated; all AEs were mild to moderate and self limiting. No systemic toxicities associated with prior administration of IL-10 (e.g.anemia or thrombocytopenia) were observed. Systemic levels of AMT-101 were below limit of quantitation, given the GI restricted design. 1 mg and 3 mg AMT-101 led to placebo-adjusted mean reductions of FCP of 44% and 27%, respectively, in patients with baseline FCP>150 μg/g. Paired biopsy samples were centrally read in a blinded manner using the Geboes scoring system. Improvements were observed in 60% (6/10) of patients on AMT-101, compared with 0% (0/2) patients treated with placebo. Microbiome analyses revealed changes in phyla abundance in the 1mg and 3mg treatment cohorts (Bacteroidetes: 28.3% ± 31.4 to 51.3% ± 21.6; Firmicutes: 21.8% ± 12.7 to 30% ± 7.3), including Roseburia hominis and Faecalibacterium prausnitzii species.

Conclusion

The results of this Phase 1b study confirm that once daily, oral AMT-101 was safe and well tolerated without SAEs previously observed with systemic IL-10 and without systemic exposure, by design. Doses at 10 mg or less suggest potential clinical efficacy paired with an enhancement of favorable enteric commensal bacteria after only 14 days of treatment. These findings support AMT-101 as actively exerting an immunomodulatory effect in the intestinal lamina propria and support ongoing Ph2 trials of AMT-101.
P298 Budesonide MMX versus Prednisolone for Ulcerative Colitis: Comparative outcomes from a British retrospective multi-centre study
Authors: Rosiou K , Ong Ming San E , Kumar A , Esquivel K , Almas S , Stokes D , Ng T , Jayasooriya N , Ranasinghe I , Pollok R , Brookes M , Selinger C P
Published: May 2021

Background

Budesonide MMX (Cortiment) is superior to placebo for mild to moderate UC flares and has a favourable side effect profile. However, no head-to-head data with Prednisolone exist. During the COVID-19 pandemic many IBD units chose Cortiment as first line treatment for outpatients’ flares of UC. The aim of this retrospective study was to compare outcomes of Cortiment vs Prednisolone treatment for UC.

Methods

Hospital based prescriptions from of 3 UK IBD units were extracted from computerized pharmacy records for the time periods between 1/3/2019 – 30/6/2019 and 1/3/2020 – 30/6/2020. All adult outpatients treated with oral steroids for a flare of UC were included.

Baseline data included age, sex, phenotype, IBD medications, symptoms and changes to medication at time of steroid prescription. Follow up data included need for hospital admission for acute severe ulcerative colitis, symptoms at 4 weeks and end of treatment, need for rescue Prednisolone (Cortiment group only). Primary outcome was symptomatic improvement at 4 weeks.

Results

The 2019 (94 patients) and 2020 (127 patients) cohorts did not differ significantly with regards to age, sex, phenotype and baseline characteristics. The proportion of Cortiment prescriptions rose significantly from 24.5% in 2019 to 70.1% in 2020 (p<0.001). At week 4 of treatment there were statistically significant differences in mean bowel frequency (3.49 in 2019 vs 5.85 in 2020, p=0.001), rectal bleeding <50% (89.7% of patients in 2019 vs 73.1% in 2020, p=0.039) and physician global assessment (39.2% of patients in remission in 2019 compared to 19.8% in 2020, p=0.045).There was no significant difference in hospital admissions, rectal bleeding and physician global assessment at end of treatment.

Patients prescribed Cortiment in 2019 had similar baseline characteristics to those prescribed Cortiment in 2020. Mean bowel frequency at four weeks was significantly higher in 2020 (6.18) compared to 2019 (3.69, p=0.034), but rectal bleeding (p=0.388) and physician global assessment at week four did not differ between 2019 and 2020 (p=0.422). Rescue Prednisolone was required in 10% of Cortiment patients in 2019 vs 31.3% in 2020 (p=0.058).

Conclusion

Cortiment was used as the main first line steroid for UC during the pandemic to reduce the risk of adverse COVID-19 outcomes. This change in treatment was, however, associated with worse UC outcomes at 4 weeks and 31% needed rescue Prednisolone. As active IBD is associated with worse COVID-19 outcomes clinicians should carefully evaluate the choice of steroid to achieve optimal disease control and COVID-19 risk minimization.
P299 Loss-of-response to anti-tumour necrosis factor-α critically depends on treatment duration in patients with Inflammatory Bowel Disease
Authors: Schultheiss J , Mahmoud R , Louwers J , van der Kaaij M , van Hellemondt B , van Boeckel P , Mahmmod N , Jharap B , Fidder H , Oldenburg B
Published: May 2021

Background

Inflammatory bowel disease (IBD) is often managed with anti-tumour necrosis factor-α (anti-TNFα) compounds, but only few studies have reported on long-term outcomes. We aimed to determine whether the incidence of loss-of-response decreases with longer treatment duration.

Methods

In a multicentre, retrospective cohort study of patients with IBD who received anti-TNFα for at least 4 months between 2011-2019, we compared incidence rates of loss-of-response between different intervals of treatment duration and performed parametric survival modelling to assess changes with longer treatment duration. Cox regression analysis was performed to identify predictors of loss-of-response. Secondary outcomes included overall anti-TNFα discontinuation and dose escalation.

Results

We included 900 anti-TNFα treatment episodes in 746 individual patients, with up to 9 years of follow-up. During follow-up, the most frequently observed reason for anti-TNFα discontinuation was loss-of-response (Figure 1), which occurred in 231 (25.7%) episodes, with presence of anti-drug antibodies in 67/231 (29%). Within the first year, the incidence of loss-of-response was threefold higher than after four years of treatment (17.3% versus 4.7% per patient-year, p<0.001). The incidence of overall drug discontinuation (28.6% versus 14.0% per patient-year, p<0.001) and dose escalations (36.5% versus 6.4% per patient-year, p<0.001) also decreased significantly from the first year to after four years, respectively. Risk factors for loss-of-response included stricturing or penetrating Crohn’s disease (adjusted hazard ratio [aHR] 1.67, 95% CI 1.14 – 2.44), while male sex (aHR 0.74, 95% CI 0.56 – 0.98) and concomitant immunomodulators (aHR 0.73, 95% CI 0.54 – 0.98) were protective.

Conclusion

Long-term use of anti-TNFα maintenance treatment is associated with a reduced risk of loss-of-response in patients with IBD.
P304 Rational infliximab induction dosing to achieve long-term deep remission in children with Inflammatory Bowel Diseases
Authors: Kantasiripitak W , van Hoeve K , Sabino J , Vermeire S , Hoffman I , Declerck P , Thomas D , Ferrante M , Dreesen E
Published: May 2021

Background

Adequate infliximab (IFX) trough concentrations (TCs) during induction treatment are predictive for long-term clinical and endoscopic remission in paediatric patients with inflammatory bowel diseases (IBD). However, under the approved weight-based dosing (5 mg/kg), children often have low IFX TCs, since the relationship between bodyweight and the IFX pharmacokinetic (PK) parameters is nonlinear. Therefore, there is a need to optimise paediatric dosing to engage optimal IFX TCs during induction treatment.

Methods

Fifty-two paediatric patients with IBD (34 Crohn’s disease (CD), 18 ulcerative colitis (UC)) contributed IFX samples (246 intermediate and 150 trough samples) during either induction treatment (n=32) or maintenance treatment (n=20). A population PK (popPK) model was developed to describe the relationship between IFX dose and exposure. The previously published IFX popPK model based on data of 112 children with CD in the Phase 3 REACH trial was used as a frequentist prior to inform parameter estimation using NONMEM. Our popPK model was used to simulate IFX TCs during induction treatment under different induction dosing regimens (5 mg/kg, 7.5 mg/kg, and 10 mg/kg IFX at weeks 0, 2, and 6). Probabilities of TC target attainment (PTA) were compared. The TC target, associated with a 75% probability of achieving deep remission (DR) at six months after initiating IFX treatment, was identified using a logistic regression model and a ROC analysis. DR was defined as combined endoscopic remission (Simple Endoscopic Score for CD <3 or Mayo endoscopic sub-score 0) and corticosteroid-free clinical remission (Paediatric CD or UC Activity Index <10).

Results

The median boyweight was 44 kg (range 15-92 kg). A 2-compartment popPK model with first-order elimination described IFX concentrations well (Table 1). The IFX clearance by weight increased with decreasing bodyweight, decreasing serum albumin and absence of immunomodulator combo-therapy. Also, the IFX volume of distribution in the central and peripheral compartment by weight increased with decreasing bodyweight. A total of 18/32 (56%) patients in the induction treatment achieved DR at six months. An IFX TC of 23.0 mg/L at week 6 was identified as the TC target (100% sen, 33% spe, 100% npv, and 50% ppv). Children with a bodyweight less than 30 kg could only reach a 50% PTA when receiving 10 mg/kg IFX combo-therapy during induction (Figure 1). While children with a bodyweight above 30 kg had more than 50% PTA when receiving either 10 mg/kg IFX monotherapy or 7.5 mg/kg IFX combo-therapy (Table 2).

Conclusion

IFX doses higher than 5 mg/kg are needed during induction in children with IBD to facilitate the attainment of the TC target, thereby increasing the chance of long-term DR.
P311 Intensive dried blood spot sampling shows a higher drug exposure throughout the first 24 weeks of therapy in ustekinumab-treated Crohn’s disease patients achieving endoscopic remission
Authors: Van den Berghe N , Verstockt B , Ballet V , Gils A , Sabino J , Ferrante M , Vermeire S , Declerck P , Thomas D
Published: May 2021

Background

Various studies have shown an association between ustekinumab serum concentrations and treatment response in patients with Crohn’s disease (CD). However, the time point at which this concentration is most informative for long-term outcome is unknown. Dried blood spot (DBS) sampling allows remote collection of blood for measurements at various time points. By use of this sampling method, the current study aimed to evaluate the exposure-response relationship of ustekinumab throughout the first 24 weeks of treatment and to investigate the time points at which ustekinumab levels could identify patients achieving endoscopic remission.

Methods

This interim-analysis included DBS (n = 332) and serum (n = 60) samples collected from 13 ustekinumab-treated CD patients at 25 time points during the first 6 months of therapy. All patients received an intravenous infusion of ~6 mg/kg ustekinumab followed by subcutaneous dosing of 90 mg every 8 weeks. Ustekinumab concentrations were measured in serum and DBS extracts using an ustekinumab ELISA (apDia, Turnhout, Belgium). Endoscopic remission was defined as simple endoscopic score for CD (SES-CD) ≤3 after 6 months of therapy. The Mann-Whitney U-test was used to compare unpaired data.

Results

Three out of 13 patients (23.1%) achieved endoscopic remission. Ustekinumab concentrations in serum correlated with those in DBS extracts (Spearman r = 0.97, p <0.0001). Measurement of the ustekinumab concentration in 38 simultaneously collected DBS and serum samples showed an average DBS-to-serum conversion factor of 2.5±0.7 (mean±SD) with an acceptable interpatient variability (CV ≤29%). Concentration-time profiles showed that patients in remission have a higher area under the curve (AUC), hence a higher drug exposure, than patients not achieving remission (906 vs 466 μg*day/mL, p=0.007, Figure). A negative correlation was observed between the AUC and SES-CD at week 24 (Spearman r = -0.74, p=0.0048). Ustekinumab concentrations in DBS extracts at the intermediate time points week 6, week 11 and week 12 after treatment start exhibited the most significant difference between remitters and non-remitters (Table). In contrast, no significant difference was observed in ustekinumab levels in DBS extracts at week 8, week 16 and week 24 between remitters and non-remitters.

Conclusion

Intensive DBS sampling showed that ustekinumab-treated CD patients in endoscopic remission have a higher drug exposure throughout the first 24 weeks of treatment than patients not in remission. DBS is an easy sampling method that allows accurate monitoring of ustekinumab exposure over time and could help to identify underexposed patients which might benefit from treatment optimization.
P329 Comparative Assessment of Adalimumab Trough Levels between Point-of-Care Testing and current Standard of Care (enzyme linked immunosorbent assay) in patients with Inflammatory Bowel Disease
Authors: Marsilio I , Maniero D , Lorenzon G , Rigo A , Cardin R , Facchin S , Barberio B , D’Incà R , Zingone F , Bahur B , Bray K B , Savarino E V
Published: May 2021

Background

Adalimumab (ADL) is a therapeutic monoclonal antibody that targets the proinflammatory cytokine tumor necrosis factor-alpha (TNF-α) and has been shown to effectively induce and maintain disease remission in patients with Inflammatory Bowel Disease (IBD). However, some patients fail to respond to this treatment, experiencing primary failure (no response to induction therapy), while others initially respond but lose efficacy over time (secondary failure). Therapeutic Drug Monitoring (TDM), in clinical practice, may lead to maintain therapeutic drug concentration thereby optimizing individual dosage regimen and improving treatment response. Recently, a point of care testing (POCT) has been developed to rapidly measure trough levels in patients taking ADL. Comparative data with current gold standard are lacking.

Aim

To determine the degree of analytical correlation between a recently developed POCT (ProciseDx) ADL assay which analyze capillary whole blood and the comparative enzyme linked immunosorbent assays (ELISA) from serum samples.

Methods

From December 2020 to February 2021, consecutive patients (aged ≥ 18 years) taking ADA (Humira, Amgevita, Imraldi) were recruited at Gastroenterology Unit, Padua University Hospital, during outpatient visits. In each patient, ADL levels from capillary whole blood collected by finger stick were performed using the ProciseDx ADL assay with reportable range between 1.3 µg/mL - 51.5 µg/mL; at the same time, a serum sample from venous blood was collected to carry out Grifols’ Promonitor ELISA test (range ≤ 0.024 – 12 µg/mL). A Deming regression test was used to identify the correlation between the two methods.

Results

Sixty patients were enrolled (67% males with mean age of 3±14), with 80% of them having CD, 17% UC and 3% an undetermined-Inflammatory Bowel Disease (IBD-U). The assessment with ProciseDx POCT was feasible and required a turnaround time of 3±0.2 minutes while serum ELISA analysis required the collection of at least 40 samples (around three weeks at our centre) and 3 hours to be performed. Thirty patients (63% males with mean age of 41±14) had therapeutic levels as assessed by ProciseDx ADL assay lower than 1.3 or greater than 12 µg/mL, in accordance with ELISA assessment. Among the remaining 30 patients (70% males with mean age of 43±15), the correlation between the two tests was high (r of 0.858 (95% CI 0.720 – 0.930)).

Conclusion

The ProciseDx POCT has similar accuracy but was more rapid and easy to be performed in providing the results of TDM in outpatients taking ADL. This could lead to a more rapid and effective optimization of the biological drug, thus avoiding treatment failure.
P334 Tofacitinib for the treatment of Ulcerative Colitis: Analysis of malignancy rates from the Ulcerative Colitis clinical programme
Authors: Ungaro R C , Ciorba M A , Rogler G , Sharara A I , Sunna N , Connelly S B , Mundayat R , Lawendy N , Panés J
Published: May 2021

Background

Tofacitinib is an oral, small molecule JAK inhibitor for the treatment of ulcerative colitis (UC). We present an updated analysis of adjudicated malignancies in the tofacitinib UC clinical programme, including final data from the open-label, long-term extension (OLE) study (as of 24 Aug 2020).

Methods

Malignancies were evaluated from 3 randomised, placebo-controlled studies (2 Phase [P]3 induction studies [NCT01465763; NCT01458951]; 1 P3 maintenance study [NCT01458574]) and an OLE study (NCT01470612). Three cohorts were analysed: Induction (P3 induction studies), Maintenance (P3 maintenance study) and Overall (patients receiving tofacitinib 5 or 10 mg twice daily [BID] in P3 or OLE studies; data from the previous data cut [May 2019] are also reported for comparison). Analysis was by predominant dose (PD) 5 or 10 mg BID, based on average daily dose <15 mg or ≥15 mg, respectively (82.1% of patients received PD 10 mg BID). An independent adjudication committee reviewed potential malignancies. Proportions and incidence rates (IRs; unique patients with events per 100 patient-years of exposure) were evaluated for malignancies (excluding non-melanoma skin cancer [NMSC]) and NMSC.

Results

1124 patients were evaluated for malignancies (2809.4 patient-years of tofacitinib exposure; up to 7.8 years of treatment; median duration of 685.5 days). No malignancies (excluding NMSC) occurred in Induction Cohort patients. Malignancies (excluding NMSC) occurred in 1 Maintenance Cohort patient (who was receiving placebo) and in 25 Overall Cohort patients (IR 0.86 [95% confidence interval (CI) 0.56, 1.27]: PD tofacitinib 5 mg BID n=5, IR 0.63 [95% CI 0.20, 1.47]; PD tofacitinib 10 mg BID n=20, IR 0.95 [95% CI 0.58, 1.46]); 5 new cases since May 2019 (Table).1 NMSC events in the Induction and Maintenance Cohorts were previously reported (Table).1 NMSC events occurred in 21 Overall Cohort patients (IR 0.73 [95% CI 0.45, 1.12]): PD tofacitinib 5 mg BID n=5, IR 0.63 (95% CI 0.21, 1.48); PD tofacitinib 10 mg BID n=16, IR 0.77 (95% CI 0.44, 1.25); 2 new cases since May 2019 (Table).1

Conclusion

There was no apparent clustering of types of malignancy, excluding NMSC. Malignancies (excluding NMSC) and NMSC IRs remained stable over time, being comparable to those previously reported in the tofacitinib UC clinical programme.1 In this analysis, malignancies (excluding NMSC) and NMSC IRs were similar to those in patients with UC treated with tumour necrosis factor inhibitors, as reported from claims data (IRs of 0.63 and 1.69, respectively).2

References