bluuebunny/crossref_metadata_2025_split huggingface dataset:
P347 Undetectable levels of adalimumab in clinical practice: Should we say goodbye to the drug?
Authors: Bejar S , Bastida Paz G , Aguas M , Garrido Marín A , Marques R , Valero Pérez E , del Hoyo Francisco J , Tortosa Seguí L , Muñoz Gómez D , Poveda J L , Nos Mateu P 
Published: January 2020

Abstract

Background
Therapeutic drug monitoring (TDM) is used in inflammatory bowel disease to guide dosing of biologics to individualise drug exposure and optimise outcomes. In case of undetectable levels of Adalimumab (levels &lt;1.6 μg/ml) some authors recommend to discontinue the treatment, although this strategy is not universally accepted. The aim of this study was to describe the evolution (recovery of levels and persistence of treatment) of patients with undetectable levels of ADA and its relationship with the different treatment strategies (dose escalation and/or addition of an immunosuppressant)

Methods
Since October 13 to August 19, 758 TDM were performed in 260 patients treated with ADA. We selected the patients who had at least a level &lt;1.6 μg / ml. Patients with follow-up fewer than 90 days after level detection and those in whom the drug was withdrawn at that time were excluded

Results
We identified 46 patients with undetectable levels; 12 were excluded. Thirty-four patients were included, 29 (85.3%) with Crohn’s disease and 5 (14.7%) with ulcerative colitis. Ten (29.4%) patients had combined treatment and 17 (50%) had previously received another anti-TNF. In 24 (70.6%) TDM was performed proactively. After detection of levels &lt;1.6 μg /ml, ADA was intensified in 20 patients (58.8%) either shortening the interval in 18 (90%), increasing the dose in 8 (40%) or with both interventions in 6 (30%). In 5 (14.7%) patients an immunomodulator was added and in 14 (41.2%) the treatment was not modified. At the end of the follow-up (mean 1101 days; SD 510) 61.8% (21/34) of the patients continued with ADA: 75% (15/20) in the intensified group and 42.9% (6/14) in the group of those who did not receive changes in treatment. Fourteen patients (41. 2%) recovered therapeutic levels (&gt;5 μg/ml), 12 (60%) in the intensified-patient group and 2 (14.3%) in the group in whom the treatment was not modified. ADA was withdrawn in 13 patients (32.8%) after a mean time of 358 days (SD 258). The ADA maintenance rate (HR=3.88; 95% CI 1.2–12.4; p = 0.02) and the recovery ratio of ADA levels (HR = 6.75; 95% CI 1.1–39, 8; p = 0.03) was higher in the intensified group. Hypoalbuminemia was associated with an earlier withdrawal of ADA (p = 0.03)

Conclusion
The intensification of ADA in patients with IBD and undetectable plasma concentrations allows recovery of levels and maintenance of the drug in a high percentage of patients. The decision to withdraw treatment in patients with undetectable levels should be individualised.
P362 Prospective study of phArmaCokinetics of InFliximab during induction in patients with Crohn’s disease and ulcerative colitis (PACIFIC)
Authors: Liefferinckx C , Bossuyt P , Thomas D , Rahier J F , Louis E , Baert F , Dewint P , Pouillon L , Lambrecht G , Vermeire S , Franchimont D 
Published: January 2020

Abstract

Background
Loss of response (LOR) to infliximab (IFX) remains a challenge in routine management of IBD patients. We evaluated IFX high-resolution pharmacokinetics (PK) during induction with intermediate and peak PK levels.

Methods
This is a prospective, multicentre (n = 9), interventional study approved by EC (P2017/484). Fourteen blood samples were collected per patient from baseline to week 30. All patients were IFX naïve with active disease according to clinical, biological and endoscopy criteria. The primary outcome evaluated the inter-individual variability of IFX PK during induction and correlation with remission at week 30. In addition to trough levels (TLs), intermediate (ILs) and peak levels (PLs) were also measured and defined as drug level between two infusions and drug level early on after infusion (+2h), respectively. Remission was defined as having a Harvey Bradshaw Index (HBI) ≤ 4 and C-Reactive Protein (CRP) ≤5 for Crohn’s disease (CD), and as a clinical Mayo score ≤2 and faecal calprotectin &lt;250 µg/g for ulcerative colitis (UC). IFX samples were measured by ELISA (Apdia) while a drug-tolerant affinity capture elution anti-infliximab assay was used to measure anti-infliximab antibodies (ATI) at weeks 6, 22 and 30.

Results
Demographic and baseline data of the study population are presented in Table 1.

Among the 62 patients enrolled, 33.9% of patients (n = 21/62) were in remission at week 30. Eight patients dropped out due to disease worsening. Median TLs at week 6 were higher among patients in clinical remission at week 30 (p = 0.02) confirming previous observations. However, ILs at day 3 as well as PLs after the third infusion were also significantly higher in patients in clinical remission at week 30 (Figure 1a–c).

ATI were detected as soon as week 6. At week 2, infliximab levels were significantly lower among patients in which ATI developed at a later time point (p = 0.006) and this observation was confirmed when measuring ILs at day 17 (p = 0.002), TLs at week 6 (p = 0.002) and ILs at week 10 (p = 0.001).

Conclusion
This multicentre prospective study demonstrates that intermediate levels as early as day 3 predict remission at week 30 in IBD patients. Low IFX levels during induction were correlated to future ATI development. PK modelling may allow to better select patients early on for sustained remission with infliximab.
P366 CRP levels and PMS as early predictors of clinical and endoscopic outcomes in adult patients with moderately-to-severely active UC treated with tofacitinib: a post hoc analysis of OCTAVE Induction 1 and 2
Authors: Dubinsky M C , Hudesman D P , Steinwurz F , Kulisek N , Salese L , Paulissen J , Su C , Ponce de Leon D , Magro F 
Published: January 2020

Abstract

Background
Tofacitinib is an oral, small-molecule JAK inhibitor for the treatment of ulcerative colitis (UC). In a Phase 2 study, changes from baseline in C-reactive protein (CRP) levels as early as Week 4 and partial Mayo scores (PMS) as early as Week 2 were shown to correlate with clinical and endoscopic outcomes at Week 8 in patients with UC receiving tofacitinib.1 We aimed to determine whether CRP levels and/or PMS can be early predictors of clinical or endoscopic outcomes at Week 8 in OCTAVE Induction 1 and 2 (NCT01465763; NCT01458951).2

Methods
In OCTAVE Induction 1 and 2, patients received placebo or tofacitinib 10 mg twice daily (BID) for 8 weeks. Mean CRP levels at baseline and Week 4, and PMS at baseline and Weeks 2 and 4, were analysed by secondary endpoint (clinical response, clinical remission, mucosal healing and endoscopic remission) status at Week 8. Univariate logistic regression analyses were performed to evaluate if CRP levels (log-transformed) or PMS were associated with these endpoints.

Results
In patients treated with tofacitinib 10 mg BID, numerically greater decreases from baseline were observed in CRP levels at Week 4 in patients who achieved a clinical response at Week 8 vs. those who did not achieve a clinical response (Table). Similarly, numerically greater decreases from baseline were observed in PMS at Weeks 2 and 4 in patients who achieved clinical response, clinical remission, mucosal healing and endoscopic remission at Week 8 vs. those who did not achieve these endpoints (Table). Logistic regression results showed that PMS at Weeks 2 and 4, and CRP levels at Week 4, were significantly (p &lt; 0.001) associated with a clinical response at Week 8 (odds ratio [95% confidence interval] 0.578 [0.529, 0.631]; 0.483 [0.437, 0.533]; 0.631 [0.572, 0.695], respectively). This was also true for clinical remission (0.523 [0.467, 0.587]; 0.426 [0.367, 0.495]; 0.582 [0.508, 0.666]), mucosal healing (0.650 [0.600, 0.705]; 0.599 [0.548, 0.655]; 0.576 [0.515, 0.643]) and endoscopic remission (0.659 [0.574, 0.756]; 0.604 [0.513, 0.712]; 0.663 [0.549, 0.802]) at Week 8.

Conclusion
These post hoc analyses showed that PMS as early as Week 2 and CRP levels as early as Week 4 may be predictors of improved clinical and endoscopic outcomes in patients with moderately to severely active UC treated with tofacitinib 10 mg BID. These results are in alignment with the findings reported from the Phase 2 trial.1

References
P370 Endoscopic balloon dilatation in paediatric stricturing Crohn’s disease: A retrospective collaborative study of the paediatric IBD Porto group of ESPGHAN
Authors: Ledder O , Viala J , Urlep D , Serban D , De Ridder L , Martinelli M , Romano C , Oliva S , Sharma S , Thomson M , Turner D 
Published: January 2020

Abstract

Background
Endoscopic balloon dilatation (EBD) is an effective management strategy in stricturing Crohn’s disease (CD). While adult studies showed a high success rate of improved symptoms and avoiding surgical intervention, very little has been published in children. We thus present a multi-centre retrospective cohort study of EBD in paediatric CD from 9 centres affiliated with the Paediatric IBD Porto group of ESPGHAN.

Methods
Demographics, imaging, serological data, clinical indices (including the newly-developed modified CD obstructive score (mCDOS)), post-EBD complications and need for surgical intervention were recorded on electronic case report forms.

Results
Thirty-nine balloon dilatations were performed on 34 children (20 (59%) male, mean age 14.3 ± 3.4 years, median disease duration 3.5 years (IQR 1.1–5.8)). Successful avoidance of surgical intervention was recorded in 26 (76%) children, during a median follow-up period of 24 weeks (IQR 8–24). There was an increase in number of patients in clinical remission (wPCDAI &lt; 12.5) following EBD from 20% pre-dilation to 36% (ns), 53% (p = 0.017) and 57% (p = 0.015) at weeks 2, 8 and 24, respectively. There was a trend to reduced mCDOS, from 5 (IQR 0–15) at baseline to 5 (0–6.25) (ns), 5 (0–5) (p = 0.04), and 0 (0–7.5) (ns), respectively. The stricture was primary in 31 (79%) children (17 in the ileocecal valve (ICV) region, 3 in the terminal ileum, 9 in the colon and 1 in the duodenum), 7 of whom had multiple strictures. Eight (21%) children had an anastomotic stricture. Median stricture length was 3 cm (IQR 2–4.7), bowel wall thickness 7 mm (IQR 5–8) and median pre-stenotic dilatation of 4.5 cm (IQR 4–5). Median maximal dilatation diameter was 15 mm (IQR 12–18) with the successful passage of the colonoscope in 26/39 (67%). There were 3 (8%) post-dilatation complications including one bleed following rectal dilatation (with spontaneous resolution) and 2 perforations (1 duodenal perforation managed conservatively and 1 ICV perforation requiring surgical resection).

Conclusion
EBD is an effective and safe technique in paediatric stricturing CD with over 75% avoiding surgery by one year and 8% complications. Further data are required to better identify optimal stricture features and dilatation diameter in children.
P371 Self-medication with analgesics in ulcerative colitis: Results of a patient survey
Authors: Rodríguez-Lago I , Mesonero Gismeno F , Cañas M , Savini C , Saldaña R , Feo-Lucas L , Fernandez S , Cea-Calvo L , Juliá B 
Published: January 2020

Abstract

Background
Ulcerative colitis (UC) is a debilitating chronic condition that affects the large intestine and courses with episodes of flare and remission, being steroid-free remission the main treatment goal. Our aim was to assess the prevalence of self-medication with analgesics, and its associated factors in a Spanish cohort of UC patients.

Methods
An anonymous cross-sectional survey was developed by 3 IBD experts from the Spanish working group on Crohn’s disease (CD) and Ulcerative Colitis (GETECCU), one nurse of the Spanish nursing working group on inflammatory bowel disease (GETEII) and two patients from the Spanish confederation of associations of patients with CD and UC (ACCU). A link to the online survey was distributed to the ACCU affiliates and to other adult patients with UC through 50 inflammatory bowel disease (IBD) units from Spain. Participants voluntarily answered to the survey based on their own experiences during the last year.

Results
We collected data from 546 patients, 61% women, mean age 40 years old. Of these, 51% patients were followed-up by IBD specialists and 47% by a general gastroenterologist. Patients’ self-reported disease activity during the last year was: 125 (23%) inactive, 188 (34%) mild, 170 (31%) moderate and 63 (12%) severe. Visits to the emergency room (24%), urgent telephone calls (43%) and hospital admissions (10%) were reported by patients during the last year. A total of 320 (59%) patients declared to have self-medicated with analgesics during the past year, mostly with paracetamol [n = 247 (45%)] and metamizole [118 (22%)], followed by ibuprofen [26 (5%)] and codeine [23 (4%)]. The frequency of self-medication was higher in those patients who declared having a moderate (57%) to severe (65%) disease activity, compared with those who felt their disease was mild (45%) or inactive (39%), (p &lt; 0.001). In addition, patients who needed urgent telephone assistance showed a higher frequency of self-medication (n = 139, 59%) [OR 2 (95% CI:1–3), p &lt; 0.001]. Multivariate analysis revealed that self-medication with analgesics was associated to female gender [OR 2 (95% CI: 1–3), p &lt; 0.001], intravenous (IV) biological therapy [OR 3 (95% CI: 2–5), p &lt; 0.001] and visits to the emergency room [OR 3 (95% CI: 2–4), p &lt; 0.001].

Conclusion
Self-medication with analgesics is a common practice in patients with UC from Spain. Factors like being a woman, treatment with IV biological drugs, needing urgent telephone assistance and attending to the emergency room, were associated with self-medication with analgesics.
This project was endorsed by GETECCU, GETEII, ACCU and funded by MSD Spain.
P374 Disease course and fate of Crohn’s perianal fistula patients following failure of initial biologic therapy: real-world lessons on the impact of refractory disease from a tertiary centre cohort
Authors: Adegbola S , Mak W Y , Sahnan K , Hiles S , Bassett P , Lung P , Warusavitarne J , Faiz O , Phillips R , Tozer P , Hart A 
Published: January 2020

Abstract

Background
Current evidence demonstrates that anti-TNF therapies lead to clinical response rates &gt;50% have been reported in the short-term. These remission rates decrease to about a third of patients who initially achieved remission, after three years. Options are limited in cases refractory to biologic therapy, and there is limited knowledge of disease course in these cases, in part due to limited disease states characterised for Crohn’s perianal fistula in the absence of cure. This study applies recently described disease states within the context of Crohn’s perianal fistula to determine the fate of patients refractory to initial biologic therapy and quantitatively evaluate the health resource impact of the loss of response to treatment in this cohort.

Methods
Retrospective review of records from patients undergoing anti-TNF treatment for Crohn’s perianal fistula at St Mark’s Hospital between January 2007–December 2016, identified those refractory to treatment. We applied disease states defined from a recent vignette study of the general public and CD patients in the UK, and also obtained data on length of time patients spent in each disease state and subsequent disease states they transitioned to and created a Markov model to assess transition probabilities. We also collected data on healthcare resource utilisation (MRI, hospital interactions, surgical/medical therapy) within each disease state.

Results
Eight fistula disease states (including proctectomy, defunctioning surgery, remission and symptomatic states) were retrospectively ascribed to all clinical records/visits where documentation was available. The majority of refractory patients were switched on to alternate anti-TNF therapy and most reside in a ‘mild chronic symptomatic fistula’ disease state with a minority of patients subsequently transitioning into a severe disease state or remission state. Successful proctectomy disease state accounted for the longest period of continuous length of time in any one disease state (mean 4.4 years). The overall remission rate (of any duration) for our study cohort of 78 patients was 46%; however, sustained (1year or more) remission rate was 27%. Some 19% patients underwent proctectomy. There was considerable healthcare resource utilisation amongst all disease states particularly with biologic therapy (most expensive healthcare resource).

Conclusion
Whereas most patients reside in a mild chronic state following failure of at least one biologic therapy, a fifth of patients refractory to treatment undergo proctectomy which, when successful, accounts for the longest continuous length of time patients spend in a single disease state. There remains considerable healthcare resource utilisation and better treatment options are needed in refractory patients.
P375 Feasibility of the first paediatric randomised controlled pilot trial of faecal microbiota transplant for ulcerative colitis
Authors: PAI N , Popov J , Hartung E , Hill L , Grzywacz K , Godin D , Thabane L , Lee C , Surette M , Moayyedi P 
Published: January 2020

Abstract

Background
The first multicentre paediatric randomised-controlled trial (RCT) of faecal microbiota transplant (FMT) in ulcerative colitis (UC) was recently completed in Ontario and Quebec, Canada. The use of FMT in paediatric UC treatment has been limited to small, open-label case series. Unique clinical and patient factors necessitated a paediatric-specific pilot RCT. Our aim was to assess key feasibility measures of conducting an FMT trial in paediatric patients to inform design, and feasibility of larger, future multicentre studies.

Methods
Patients were randomised (1:1) to receive rectal enemas 2×/week for 6 weeks, followed by a 6-month follow-up period. Enemas contained normal saline (placebo), or RBX2660 (Rebiotix; Roseville, USA), a faecal microbiota preparation of stool from healthy adult donors (active). Patients were eligible for the open-label extension following completion or withdrawal from the placebo arm. Study feasibility was assessed through patient eligibility, recruitment, completion of sample collections, adverse events, and hospitalisations.

Results
Over 36 months across two tertiary IBD clinics, 48 paediatric patients were screened for participation. 75.0% (36) met eligibility criteria for enrolment and 69.4% (25) participated in the randomised trial. 53.8% (7) of patients randomised to the placebo arm entered the open-label arm. We stratified completion of sample collections by intervention (Weeks 0–6), and follow-up phases of the trial (Weeks 6–30). 75.3% of required bloodwork was obtained during both phases; patient-provided stool samples declined from 76.0% (intervention) to 45% (follow-up). 83.0% (10) reported adverse events in the active arm, and 38.4% (5) in placebo; these were all minor and self-limited (muscle pain, cough, fatigue, etc.). No patients experienced adverse events related to enemas. Five patients experienced serious adverse events: IBD flare (2 active, 1 placebo), and reactivation of C. difficile infection (2 active) (Table 1).

Conclusion
In this first paediatric RCT of FMT for UC, we established important feasibility data regarding the design of FMT trials in children. Patient acceptance of FMT was high, and well-tolerated with minor, self-limited adverse events, and few serious adverse events. Return-rates of stool samples were low during follow-up; strategies to improve uptake are needed, particularly given the value of microbiome data for analyses. Overall, our study demonstrates strong interest and tolerance among paediatric patients for FMT-based trials. Future studies will build upon our protocol to enhance clinical data on the effects of microbiota-based therapeutics in children.
P388 Prediction model to safely CEASE anti-TNF therapy in Crohn’s disease: validation of a predictive diagnostic tool for the cessation of anti-TNF treatment in CD in a Dutch population
Authors: Ten Bokkel Huinink S , de Jong D , van der Woude J , Nieboer D , Steyerberg E , Wolfhagen F , van Tuyl B , West R , Romkens T , Tan A , Hoentjen F , Mares W , Bodelier A , Dijkstra G , Mallant R , de Boer N , Reinders J , van Boeckel P , Tack G , Duijvestein M , D’Haens G , de Vries A 
Published: January 2020

Abstract

Background
Tools for patient identification to safely cease anti-TNF therapy in Crohn’s disease (CD) patients are urgently needed. After an individual participant data meta-analysis (IPD-MA) a predictive diagnostic tool has been developed for cessation of anti-TNF therapy in CD. This study aims to validate this tool.

Methods
A retrospective study was conducted, in 16 Dutch Hospitals, of CD patients in whom anti-TNF therapy was ceased. Inclusion criteria were anti-TNF therapy use &gt;6 months, start of anti-TNF therapy due to luminal CD and remission as an indication for cessation. Collected baseline demographic, clinical, biochemical, treatment and imaging data were included; age, gender, smoking, Montreal classification, disease- and remission duration, history of surgery, type of anti-TNF medication, previous or concomitant immunosuppressant, thiopurines level, previous anti-TNF therapy, anti-TNF therapy duration, haemoglobin, leukocytes, thrombocytes, albumin, C-reactive protein, anti-TNF serum concentration, anti-infliximab/adalimumab antibodies, remission at MRI/endoscopy, additional stop reason other than remission. The primary outcome was documented relapse of CD that necessitated (re)introduction of biologicals, corticosteroids or immune-suppressants or surgery.

Results
A total of 523 CD patients (333 females (63%), median age 40 years (IQR 32 – 53)) were included. 293 (56%) patients experienced a relapse after anti-TNF cessation after a median follow-up of 30.2 months (IQR 15–51). The relapse rate was 33% (95% CI 31–34) and 53% (95% CI 52–53) after 1 and 2 years, respectively. The discriminative ability of the prediction model in this external validation cohort (Table 1) equalled that of a previous IPD-MA with a C-statistic of 0.59. An update of the model with faecal calprotectin resulted in a C-statistic of 0.60 [0.55–0.63] and a reported calibration slope of 0.69.

Conclusion
A previously developed predictive diagnostic tool to safely cease anti-TNF therapy in CD has been validated, however, showed moderate performance in this external cohort. A further update of the model with biochemical and histological data is necessary to improve our ability to adequately select patients for cessation of anti-TNF therapy and is currently being performed.