bluuebunny/crossref_metadata_2025_split huggingface dataset:
P517 Re-treatment with filgotinib in patients with Ulcerative Colitis following treatment interruption: Analysis of the SELECTION and SELECTIONLTE studies
Authors: Vermeire S , Feagan B , Peyrin-Biroulet L , Oortwijn A , Faes M , de Haas A , Rogler G 
Published: January 2022

Abstract

Background
Long-term treatment regimens for ulcerative colitis (UC) present challenges for patients who may need to interrupt therapy for various reasons.1 Filgotinib (FIL) is an oral Janus kinase 1 preferential inhibitor. We performed a post hoc analysis of data collected from patients with UC treated with FIL in the phase 2b/3 SELECTION programme to assess the efficacy and safety of re-treatment following treatment interruption.

Methods
The SELECTION programme comprises two Induction Studies and a Maintenance Study (NCT02914522) and a long-term extension (LTE) study (NCT02914535). Adults aged 18–75 years with moderately to severely active UC, who had clinical remission or Mayo Clinic Score (MCS) response to FIL 200 mg or 100 mg at week 10 of SELECTION were re-randomized 2:1 to continue assigned FIL treatment or placebo (PBO) from week 11 to week 58. Patients with disease worsening (DW) in the Maintenance Study could enter the LTE study to receive open-label FIL 200 mg once daily. We assessed the efficacy of FIL in patients treated with induction FIL 200 mg or 100 mg who were randomized to PBO in the Maintenance Study and were re-treated with open-label FIL in the LTE study. Efficacy endpoints included partial MCS (pMCS) response and remission at LTE baseline and weeks 2, 4, 12 and 24. Non-responder imputation was used to analyse efficacy results.

Results
This analysis evaluated 50 patients treated with FIL 200 mg and 35 treated with FIL 100 mg in the Induction Study, who were withdrawn and re-treated upon DW. Baseline characteristics were similar among patients in the 200 mg and 100 mg treatment groups, with a median time to DW of 16.9 and 13.3 weeks, respectively. Mean pMCS declined rapidly in both groups from LTE baseline to week 2, reaching pMCS &lt;2 at week 24 (Figure 1). By as early as week 2 of re-treatment, over 60% of patients in both groups had achieved pMCS response (Figure 2). By week 12, 78% of the 200 mg group and 94% of the 100 mg group achieved a pMCS response. Median time to response was 2.4 and 2.1 weeks in the 200 mg and 100 mg groups, respectively. Figure 3 shows that pMCS remission was achieved in 42% of the 200 mg group and 45% of the 100 mg group by week 24. Median time to pMCS remission was 23.6 and 12.1 weeks in the 200 mg and 100 mg groups, respectively. The number of adverse events upon re-treatment in the LTE was consistent with that reported in SELECTION (Table 1).

Conclusion
The majority of patients re-treated with FIL achieved pMCS response and remission within 12 weeks, with onset as early as week 2. Good disease control was maintained over the course of 24 weeks. Re-treatment was well tolerated, with no new safety signals observed among these patients.

Reference
1. Rubin DT. Gastroenterol Hepatol 2019;15:612–5.
P543 Point-of-care testing in therapeutic drug monitoring of infliximab
Authors: Šahinović I , Orsic Fric V , Konjik V , Pavela J , Borzan V , Šerić V 
Published: January 2022

Abstract

Background
Within the past 20 years infliximab (IFX), a monoclonal antibody targeting tumor necrosis factor-alpha, has become an established therapy for inducing and maintaining remission in inflammatory bowel disease (IBD). IFX therapeutic drug monitoring (TDM) using the point-of-care (POC) methods showed to be able to produce results fast enough to allow IFX dose adjustments before drug infusion. This study aimed to compare IFX quantification using two POC tests, Procise IFX (Procise Dx) and Quantum Blue Infliximab assay (Bühlmann Laboratories AG).

Methods
Serum samples from 22 IBD patients (M=64%) on IFX maintenance therapy were collected immediately before drug infusion. Capillary blood was also collected from 6 IBD patients by finger prick using whole blood pipettes (Procise Dx). Crohn’s disease (CD) was diagnosed in 12 patients and ulcerative colitis (UC) in 10 patients. For method comparison, a Passing Bablok regression was used and for qualitative comparison weighted kappa statistic was obtained after stratification of results by therapeutic range (&lt;3 mg/l, ≥3 to 7 mg/L, and ≥7 mg/L).

Results
Both methods measured lower IFX concentrations in CD patients (4,95 (0,65 – 5,80) mg/L) than in UC patients (8,50 (4,80 – 12,20) mg/L). In two patients with confirmed IFX antibodies, both methods showed immeasurably low IFX concentrations. Passing Bablok regression analysis of IFX concentration in serum sample has showed a proportional deviation between two POC methods (y=0.416 (-0.654 to 1.279) + 0.753 (0.648 to 0.923)x). A good comparison has been observed for capillary blood measured using Procise IFX test and serum samples measured using Quantum Blue Infliximab assay (y=-2.732 (-4.315 to 1,867) + 1.263 (0.278 to 1.566)x), although IFX concentration was lower in capillary blood. Classification of results according to therapeutic interval showed good agreement for serum samples and serum and whole capillary blood measurements (κ=0.79 (0.59–0.999 and κ=0.80 (0.45–1.00), respectively).

Conclusion
Because of proportional differences, two POC tests can’t be used interchangeably for longitudinal TDM of IFX in IBD patients. There is a need for caution in the interpretation of IFX in whole blood, due to its possibly lower concentration.
P556 The effect of multiple doses of upadacitinib 45 mg on the pharmacokinetics of cytochrome P450 substrates in healthy adult subjects
Authors: Ibrahim M , Pangan A , Feng T , Mohamed M E 
Published: January 2022

Abstract

Background
Upadacitinib is a selective Janus kinase 1 inhibitor, which is approved for treatment of several inflammatory diseases. Upadacitinib 45 mg QD dose was evaluated for induction treatment in ulcerative colitis Phase 3 studies and is currently being evaluated in Crohn’s disease Phase 3 studies. A prior clinical study demonstrated that upadacitinib 30 mg QD dose resulted in no clinically relevant effects on plasma exposures of sensitive probe substrates for cytochrome P450 (CYP) enzymes. The objective of this study was to evaluate the effect of repeated doses of upadacitinib 45 mg on the pharmacokinetics of sensitive probe substrates of CYP enzymes in healthy adult subjects.

Methods
This was an open-label, multiple-dose, two-period study using the modified Cooperstown 5 + 1 cocktail drugs (midazolam [CYP3A], caffeine [CYP1A2], warfarin + vitamin K [CYP2C9], omeprazole [CYP2C19], and dextromethorphan [CYP2D6]). Twenty healthy adults received single oral doses of the cocktail drugs without upadacitinib in Period 1, followed by daily dosing of upadacitinib 45 mg for 16 days and administration of the cocktail drugs on Day 11 (for midazolam) and Day 12 (rest of substrates) in Period 2. A washout period of 6 days separated each Period. Serial blood samples and 12-hour urine samples (for dextromethorphan and dextrorphan) were collected. Pharmacokinetic parameters were estimated using noncompartmental analysis and repeated-measures analyses were performed for the natural logarithms of Cmax and AUC to assess the effect of upadacitinib on the probe substrates.

Results
The ratio (90% confidence interval) of area under the plasma concentration-time curve from time 0 to infinity (AUCinf) central values when the cocktail drugs were administered with upadacitinib 45 mg relative to when administered alone were 0.76 (0.69–0.83) for midazolam, 1.04 (0.95–1.13) for caffeine, 1.12 (1.05–1.20) for S-warfarin, 1.35 (1.18–1.54) for dextromethorphan, and 0.98 (0.85–1.13) for omeprazole. The 5-hydroxy-omeprazole to omeprazole plasma AUC ratio was unchanged (90% confidence interval within the no effect limits of 0.8 to 1.25).

Conclusion
Administration of daily upadacitinib 45 mg doses resulted in a limited effect on midazolam (CYP3A) and dextromethorphan (CYP2D6) exposures and had no relevant effects on the sensitive probe substrates for CYP1A2, CYP2C9 and CYP2C19. These limited effects are not expected to be clinically relevant or necessitate dose adjustment of CYP3A or CYP2D6 substrates. These results are consistent with a previous drug interaction evaluation for upadacitinib 30 mg and support lack of relevant effects of upadacitinib on drugs metabolized by CYP enzymes.
P579 Rates, predictive factors and effectiveness of ustekinumab intensification to 4- or 6-weekly intervals in Crohns’s disease
Authors: Derikx L , Plevris N , Su S , Gros B , Lyons M , Siakavellas S , Constantine-Cook N , Jenkinson P , O’Hare C , Merchant L , Noble C , Arnott I , Jones G , Lees C 
Published: January 2022

Abstract

Background
The efficacy and safety of ustekinumab (UST) intravenous induction followed by 8- and 12- weekly maintenance was established in the UNITI controlled trial. These data report dose intensification for 12- to 8-weekly but not 4-weekly. The effectiveness of this strategy is an important, unanswered real-world question. We aimed 1) to assess the cumulative incidence of UST dose intensification to 4- or 6-weekly in patients with Crohn’s disease (CD), 2) to identify factors associated with dose intensification, and 3) to assess the effectiveness and safety of this strategy.

Methods
We performed a retrospective, observational cohort study in a tertiary IBD referral centre. All CD patients treated with UST between 22 January 2015 and 28 October 2020 were identified from a prospective biologic prescription database. Subsequently, data on IBD phenotype, UST interval, drug survival, and corticosteroid-free remission were collected. Dose intensification and drug survival were established with (one minus) Kaplan Meier curves. Logistic regression models were used to identify factors independently associated with dose intensification.

Results
163 CD patients (male: 71/163 [43.6%]; median disease duration 9.5 years [IQR 4.8–17.1]) were treated with UST, with median follow-up time of 20.3 months (13.4–38.4). 21/163 patients (12.9%) were biologic naïve, whereas 142 patients (87.1%) were previously treated with one (n=100, 61.3%) or two biologic therapies (n=42, 25.8%). During follow-up, 55/163 patients (33.7%) underwent dose intensification to a 4-weekly (n=50, 30.7%) or 6-weekly (n=5, 3.1%) interval. Median time to dose intensification was 6.1 months (3.9–11.0); after 1 year 29.9% were escalated to 4- or 6-weekly UST. Prior exposure to both anti-TNF and vedolizumab (HR 9.5; 1.3–70.9) as well as concomitant steroid use at start of UST (HR 1.8; 1.0–3.1) were independently associated with dose intensification (Figure 1; non-significant: age, CD behaviour, perianal disease activity and UST start dose).
Following dose intensification 62.6% patients (29/55) remained on UST beyond 1 year (median time to discontinuation 5.2 months; Figure 2). No licensed treatment options remained in 12/29 patients. At the end of follow-up, (median 8.9 months [4.3–14.8] following dose intensification) 27.8% (15/54) were in corticosteroid-free and clinical remission.

Figure 1

Conclusion
One third of CD patients treated with UST will undergo dose intensification to a 4- or 6-weekly interval within the first year. Patients who failed two or more biologics were more likely to dose intensify. These are a very refractory group of CD patients, the majority of whom have no licensed treatment options available.
P581 Transmural remission improves clinical outcomes up to 5 years in patients with Crohn’s Disease
Authors: Pedro J , Botto I , Fernandes S , Lemos J , Neves J , Campelo P , Carvalho D , Bernardo S , Gonçalves A R , Valente A , Moura Santos P , Rosa I , Tavares de Sousa H , Ramos J , Venâncio J , Leitão J , Claro I , Correia L , Tato Marinho R 
Published: January 2022

Abstract

Background
Endoscopic remission (ER) is currently endorsed as one of the main treatment targets in Crohn’s Disease (CD). In a previous study, we have shown that transmural remission (TR) is associated with better clinical outcomes up to 1-year. It is unknown if these results still hold over a longer follow-up

Methods
This was a multicenter study, including 333 CD patients with magnetic resonance enterography (MRE) and colonoscopy evaluation performed within a 6-month interval and at least 5-years of follow-up. Patients were classified as having TR (inactive MRE and colonoscopy), ER (active MRE and inactive colonoscopy), and no remission (NR) (active colonoscopy). The need for surgery, hospitalization, steroids, and biologics was evaluated at 5-years of follow-up.

Results
Patients with TR presented lower rates of surgery (1.9% vs 17.9% vs 23.7%, P&lt;0.001 and P=0.008), hospitalization (13.2% vs 30.4% vs 37.9%, P=0.001 and P=0.038), steroids (11.3% vs 21.4% vs 33.0%, P=0.001 and P=0.2), biologics (18.9% vs 51.8% vs 66.5%, P&lt;0.001 and P=0.001), and any adverse outcome (26.4% vs 64.3% vs 78.6%, P&lt;0.001) compared to ER and NR. Comparisons between ER and NR were mostly non-significant in respect to surgery (P=0.474), hospitalization (P=0.352), steroids (P=0.106), biologics (P=0.045), and any adverse outcome (P=0.036). The time until reaching any individual outcome was also significantly longer for TR. In multivariate analysis, endoscopic remission (OR 0.234 95%CI 0.135–0.405, P&lt;0.001) and MRE remission (OR 0.316 95%CI 0.187–0.536, P&lt;0.001) were independently associated with a lower likelihood of reaching any adverse outcome.

Conclusion
TR was associated with improved clinical outcomes over 5-years of follow-up. Going beyond ER appears to provide significant clinical benefits in the short and long-term.
P584 Systematic Review and Meta-analysis Evaluating the Real-World Effectiveness and Safety of Ustekinumab in Crohn’s Disease
Authors: Hosack T , Gadhok R , Lindsay J O 
Published: January 2022

Abstract

Background
The landmark UNITI trials 1 of Ustekinumab (UST, an anti-p40IL12/23 mAb) in treating Crohn’s disease (CD) demonstrated 6-week clinical response and 44-week clinical remission rates of 38% and 41% in TNF experienced and 52% and 62.5% in TNF naive patients. Clinical trials may not however reflect real world experience.

Methods
A systematic review and meta-analysis was conducted according to PRISMA guidelines to assess the real-world effectiveness and safety of UST in luminal CD based on current licensing approvals. A systematic literature search was performed using MEDLINE, EMBASE and conference proceedings from inception to 17 March 2021. Random-effects meta-analysis was used to assess clinical response, clinical remission, corticosteroid-free clinical remission (CFCR), biochemical remission and mucosal healing (MH) at weeks 8, 14, 26 and 52. Safety profile as well as rates of primary non-response (NR), secondary loss of response (LOR) and dose-intensification were also evaluated.

Results
4,957 studies were screened with 36 studies (22 full text articles and 14 abstracts) meeting inclusion criteria, comprising 3,821 patients in total. Pooled outcome measures for clinical response, clinical remission, CFCR and biochemical remission at weeks 8, 14, 26 and 52 as well as MH at weeks 26 and 52 are reported in Table 1. UST was discontinued in 12.0% (95%CI, 7.3%-17.8%) during the follow-up period with over half attributable to failure of response. The overall safety profile was favourable compared to clinical trials, with a pooled adverse events rate of 14.6% (95%CI, 9.8%-20.2%). Primary NR and LOR were observed in 10.7% (95%CI, 6.6%-15.6%) and 12.7% (95%CI, 3.5%-26.5%), respectively. UST dose was intensified in 25.6% (95%CI, 11.3%-43.4%) of patients during follow-up.

Conclusion
This systematic review and meta-analysis of real-world studies demonstrates clinical effectiveness and safety of UST for CD comparable to that observed in clinical trials, supporting the use of UST in CD.

Reference
1. Feagan BG et al. N Engl J Med 2016; 375:1946–1960 DOI: 10.1056/NEJMoa1602773
P595 Validation of a predictive algorithm for thiopurine induced hepatotoxicity in IBD patients
Authors: Van Moorsel F , Deben D , Creemers R , Winkens B , Pierik M , Bus P , Simsek M , de Boer N , van Bodegraven A , Wong D 
Published: January 2022

Abstract

Background
The thiopurines, azathioprine (AZA) and mercaptopurine (MP), are effective and remain standard treatment options in steroid sparing and maintaining remission in patients with inflammatory bowel disease (IBD). Approximately 25% of patients discontinue within three months after treatment initiation due to adverse events, of which about half due to hepatotoxicity. We hypothesise that identification of patients with an increased risk of adverse events and timely treatment optimisation (e.g. dose adjustment, adjuvant allopurinol) can prevent treatment failure due to adverse events.
The primary objective of this prospective observational multicentre study was to optimise and validate a proposed hepatotoxicity predictive algorithm in IBD patients starting AZA or MP therapy.

Methods
We adapted an algorithm from a previous study to predict the risk of developing hepatotoxicity in thiopurine drug treatment using multivariable logistic regression and a receiver operating characteristic curve. The determinants age, BMI and 6-MMPR-concentration one week after start of treatment (T=1) were inserted as continuous variables in this algorithm. Sex was inserted as a dichotomous variable.
Inclusion criteria were adult thiopurine-naive IBD patients initiating AZA or MP treatment. Subjects were treated according to guidelines and followed for 12 weeks. The primary study outcome was hepatotoxicity within 12 weeks, defined as ALAT &gt; 2x ULN or an R value ((ALAT / ULN ALAT)/(AP / ULN ALP)) ≥ 5. The hepatotoxicity- and no-hepatotoxicity groups were compared using the Mann-Whitney U-test.

Results
In total, 255 patients were included from Dec 2015 to June 2019, of whom 26 were excluded because of no actual start with AZA or MP (n=18), loss to follow up (n=7) or no IBD diagnosis (n=1). Out of 229 patients 21 (9%) developed hepatotoxicity. Five out of 21 patients (24%) in the hepatotoxicity-group and 123 out of 208 patients (59%) in the no-hepatotoxicity-group had to be excluded for analysis (see Figure 1).
Ninety-three % of patients received MP with a median dose of 0.7 mg/kg (95%CI 0.3–1.4 mg/kg). Median dose of AZA (7%) was 2.0 mg/kg (95%CI 1.1 - 2.6 mg/kg).

There was a difference between the hepatotoxicity and no-hepatotoxicity group in BMI (28 versus 24, p=0.022) and 6-MMPR/6-TGN ratio at T=1 (16 versus 9, p=0.027). In Table 1, the number of true positives, true negatives, false positives and false negatives are presented. The diagnostic values are shown in Table 2. A specificity of 77% (95%CI 66–85%) and a sensitivity of 50% (95%CI 26–75%) was obtained.

Conclusion
In conclusion, the adapted algorithm does not accurately predict hepatotoxicity in this cohort of patients on relatively low-dose thiopurine treatment.
P598 Indicators for inadequate response among patients with Ulcerative Colitis treated with advanced therapies in German clinical practice
Authors: Bokemeyer B , Picker N , Kromer D , Rosin L , Patel H 
Published: January 2022

Abstract

Background
Management of Ulcerative Colitis (UC) is challenging, and clinicians are often obliged to attempt a variety of therapies in sequence until an adequate clinical response is achieved. This study examined the rates of inadequate response to advanced therapies among UC patients in clinical practice in Germany.

Methods
Using a retrospective chart review, patients with UC treated with an advanced therapy (adalimumab, infliximab, golimumab, vedolizumab, and tofacitinib) between 01/2017 through 09/2019 were selected from 18 outpatient gastroenterology practices across Germany. Patients with at least 12 months of data before (baseline) and after initiating an advanced therapy (Index Date) were included. Data was collected up to 24 months after index date. Inadequate response was defined as at least one of the following events: index therapy discontinuation due to lack of response, therapy escalation, augmentation with newly prescribed conventional therapies, corticosteroid (CS) dependency (use for ≥12 weeks), CS use during the maintenance phase, UC-related hospitalisations, surgery or emergency visit. Subgroups included patients with prior exposure to biologics, with and without remission (clinical remission defined as partial Mayo Score ≤1) at one year, and concurrent use of CS at the index date. Kaplan-Meier analysis was used to examine the rates over time. Patients were censored at the end of the study period.

Results
Among 149 patients (females: 50.3%; median age: 40 years; median follow-up: 25.9 months), 96 (64.4%) patients were biologic-naïve. Nearly half of the patients (45.5%) had ≥1 indicator for an inadequate response within two years after the index date (Figure 1). Among those who discontinued (N=43), 82.0% had switched to another advanced therapy. Therapy escalation was observed in 20 (16.3%) patients, and augmentation with conventional therapies was observed in 19 (15.6%) patients. 14 patients (11.3%) received CS during the maintenance phase of the index therapy, and 14 patients (10.1%) were CS dependent for ≥12 weeks. Inadequate response rates were significantly higher in patients without (n=80) vs. with remission (n=54) after one year (53.4% vs. 35.5%; p&lt;0.05, Figure 2) and in patients with (n=42) vs. without concurrent CS (n=107) at the index date (67.0% vs. 36.9%; p&lt;0.05). There was no significant difference between biologic-naïve and biologic-experienced patients.

Conclusion
Nearly half of the patients with UC experienced an inadequate response to their advanced therapy within two years. Higher rates of inadequate response were observed in patients without remission and in those with concurrent use of CS at baseline. More effective therapies are needed to achieve better outcomes in UC.