bluuebunny/crossref_metadata_2025_split huggingface dataset:
P966 The intra-patient variability of adalimumab clearance during an intensive sampling study of Crohn’s disease patients receiving maintenance therapy
Authors: Strong A , Aragon-Han P , Sparrow M , Dervieux T , Ward M 
Published: January 2024

Abstract

Background
Lower adalimumab (ADA) clearance (CL) is associated with improved outcomes in Crohn’s disease (CD) and may be a superior pharmacokinetic (PK) measure than ADA concentrations. We compared intra-patient variability in ADA CL and concentrations within a 14-day treatment cycle and across two consecutive cycles under maintenance treatment.

Methods
In a previous PK study of CD patients receiving maintenance ADA 40mg fortnightly, samples were collected intensively at 3 visits (day 4-6, 7-9, and 13-14 post dose) across 2 consecutive cycles. Available sera from this cohort were subsequently used to measure ADA concentrations (lower limit quantification: &lt;1.6 µg/mL) and antibody to adalimumab (ATA) status using a drug tolerant homogeneous mobility shift assay, and albumin. Apparent ADA CL (L/day) was calculated incorporating these measure parameters in a nonlinear mixed effect model with Bayesian priors (under steady state assumption) with dose and inter-dose interval with ATA and albumin as covariate. Rates of sustained clinical and biochemical remission (Harvey Bradshaw Index (HBI) score consistently &lt;5 and CRP levels consistently &lt;3 mg/L) were estimated for each patient. Longitudinal changes in PK parameters within-and-across cycles were evaluated using intra-patient coefficient of variation and linear mixed effect models.

Results
Sera was available from 70 study visits in 12 patients (6 males, mean age 36 years). Median ADA concentrations and CL were 8 µg/mL (IQR 6.0-10.4) and 0.374 L/day (IQR 0.29-0.43), respectively, with ATA detected in one patient (#9). Estimated ADA concentrations and CL is presented in the Table. Intra-patient variability in CL was much lower across the two 14-day cycle (9% and 7%, respectively) compared to intra-patient variability in ADA concentration (15% and 13%, respectively). Linear mixed effect models confirmed these findings with no impact of sampling time on CL (intercept=0.46±0.12 L/day; slope estimate=0.002±0.002 L/day; p=0.16) as compared to significant change in ADA concentrations (intercept=10.6±1.2 µg/mL; slope estimate=-0.25±0.03 µg/mL; p&lt;0.01) over inter-dose interval sampling time. Sustained clinical and biochemical remission was achieved in 5/12 patients (42%); none presented with CL &gt;0.8 L/day (a cut-off previously associated with worse outcomes). Of 7 patients without sustained clinical and biochemical remission, two presented with optimal concentrations (&gt; 10 µg/mL), thus suggestive of mechanistic failure, and one developed ATA, lower concentration and higher ADA CL.

Conclusion
CL is subject to less intra-patient variability than ADA concentrations, supporting its assessment at any time point within a 14-day treatment cycle.
P1011 Methotrexate polyglutamates in paediatric inflammatory bowel disease: Novel tool for therapeutic drug monitoring?
Authors: Vermeer E , Struys E A , van Limbergen J E , de Boer N K , de Jonge R , de Meij T G J 
Published: January 2024

Abstract

Background
Methotrexate (MTX) is increasingly prescribed in paediatric inflammatory bowel disease (IBD), but therapeutic drug monitoring (TDM) is currently not feasible due to its characteristic pharmacokinetics and short half-life in plasma, which amounts to approximately 2.5-6.5 hours. Because of this, plasma MTX is no longer detectable shortly after administration. However, MTX-polyglutamates (PG1-5) are formed intracellularly and accumulate over time. Recently, we developed a technique for targeted erythrocyte MTX-PG analysis with the potential for TDM. Data in paediatric IBD with this technique are lacking so far. Here, we aimed to identify the potential of erythrocyte MTX-PG analysis to measure MTX levels in paediatric IBD.

Methods
In this observational cross-sectional study, we determined MTX-PG concentrations in erythrocytes retrieved from blood samples of paediatric IBD patients on low-dose MTX maintenance therapy, defined as exposure to a stable dose of MTX for at least twelve consecutive weeks. MTX-PG concentrations were determined by stable-isotope dilution liquid chromatography mass-spectrometry. Furthermore, we evaluated the effects of route of administration (oral versus subcutaneous), MTX dosage, and anthropometric data on MTX-PG concentrations.

Results
Fifty-two paediatric IBD patients on MTX maintenance therapy were included. The predominant subspecies was MTX-PG3 (mean 30.5 nmol/L, SD ± 20.0) and the mean MTX-PGtotal concentration was 88.6 nmol/L (SD ± 52.6). A higher dose was linearly associated with significantly higher MTX-PG3 (r = 0.56), MTX-PG4 (r = 0.52), MTX-PG5 (r = 0.48) and MTX-PGtotal (r = 0.49) levels. When adjusted for body surface area, MTX dose was also linearly associated with significantly higher MTX-PG3 (r = 0.51), MTX-PG4 (r= 0.39), and MTX-PGtotal (r= 0.40) concentrations. A reliable comparison regarding route of administration was not possible in this cohort, due to the small number of patients receiving subcutaneous MTX (n=3).

Conclusion
We observed high inter-individual variability in the reached erythrocyte MTX-PG concentrations. Body surface adjusted or unadjusted MTX dosage showed a positive linear correlation with erythrocyte MTX-PG concentrations in children with IBD. This is a prerequisite for TDM and provides a strong basis for further research into the relation between TDM of MTX, effectivity and toxicity.
P1027 Optimizing IBD Medication and Therapy: An Interdisciplinary University Outpatient Approach
Authors: Binder B , Elger T , Huss M , Loibl J , Tews H C , Kandulski A , Kratzer A , Müller M , Fleischmann D 
Published: January 2024

Abstract

Background
A large proportion of patients with chronic inflammatory bowel disease (IBD) take a wide range of different medications, which harbor a potential risk of pharmaceutical (pharm.) interactions. Furthermore, these patients frequently seek professional advice regarding additional medications or alternative treatment options. In this study, an interdisciplinary medical-pharmaceutical team conducted a standardized survey and a pharmaceutical medication check in an IBD outpatient department. The aim was to evaluate and enhance individual therapy adherence and medication safety.

Methods
Prior to the appointment, patients were requested to provide their current medication list and to complete a standardized questionnaire regarding their general compliance and any unmet questions or concerns about their IBD therapy. A clinical pharmacist analyzed the questionnaire and carried out a thorough assessment of the list of medications for possible interactions and the potential for improvement. One day before the patient`s appointment, the pharmacist presented his findings to the treating physician, and possible interactions were discussed. After the appointment, patients were asked to complete a second questionnaire regarding their experience and possible changes in therapy, as well as their previous concerns or responses.

Results
The data from Questionnaire 1 showed two main results: (I) Overall adherence to therapy was found to be sufficiently high, as most patients reported taking their medication regularly and being aware of the main principles of their therapy. (II) Many patients expressed concerns about possible long-term side effects of their therapy and indicated that they needed additional information about their medication (Figure 1A).
Concerning the provided medication plan, 77% of all participants took more than 5 drugs and in 94% of the cases, no previous medication check had been performed. The involved clinical pharmacists suggested 1.3 interventions per patient and in 50% of all cases, at least one medication was discontinued or newly started (Table 1). In the follow-up survey, most patients stated that the interdisciplinary medical counseling had improved both their knowledge and their sense of security of their IBD treatment (Figure 1B).

Conclusion
The interdisciplinary review and monitoring of the current therapy and the individual medication of IBD patients increased patient-specific compliance and medication safety and should therefore be intensified in the future.
P1043 Immunomodulator and advanced therapies for prevention of clinical relapse and loss of response during maintenance phase in Crohn’s disease: A systematic review and network meta-analysis
Authors: Sinopoulou V , Gordon M , Vuyyuru S , Darie A M , Pavlidis P , Moran G 
Published: January 2024

Abstract

Background
Several effective advanced therapies have been approved for the treatment of Crohn’s disease (CD) in the past two decades. Given lack of adequate head-to head clinical trials it is challenging to position these therapies in the management algorithm. Therefore we performed this network meta-analysis to inform therapeutic decisions.

Methods
We searched MEDLINE, Embase, and Cochrane Central Register of Controlled Trials between inception and October 2023 for randomised controlled trials (RCTs). Outcomes assessed were clinical relapse (loss of clinical remission), loss of clinical response, adverse events (AE), withdrawal due to AE, and serious AE. We performed random-effects meta-analysis and network meta-analysis (using a frequentist approach), and estimated relative risk (RRs), 95%CI values. We used GRADE to ascertain certainty of evidence.

Results
A total of 32 RCTs comprising 10,924 patients were included in the analysis. On network meta-analysis of 15 interventions based on prevention of clinical relapse, combination of infliximab (IFX) and azathioprine (AZA) (RR 0.31, 95%CI [0.17-0.56]), IFX (RR 0.62, 95%CI [0.5-0.76], moderate certainty), and adalimumab (RR 0.68, 95%CI [0.55-0.84], moderate certainty) were the only agents that were effective compared to placebo (Figure 1). Methotrexate (RR 0.57, 95%CI [0.32-1.03], low certainty) and azathioprine (RR 0.82, 95%CI [0.62-1.1]), very low certainty) were not effective. On analysis based on prevention of clinical response for nine interventions, there was high certainty evidence for ustekinumab (RR 0.73, 95%CI [0.61-0.86]), upadacitinib (RR 0.64, 95%CI [0.57-0.72]), and moderate certainty of evidence for infliximab (RR 0.71, 95%CI [0.59-0.84]), adalimumab (RR 0.68, 95%CI [0.61-0.75]), certolizumab (RR 0.57, 95%CI [0.47-0.7]), CTP13 (RR 0.46, 95%CI [0.38-0.57]), vedolizumab (RR 0.82, 95%CI [0.68-0.99]), natalizumab (RR 0.54, 95%CI [0.43-0.68]). Tofacitinib was not effective and there was no data available for immunomodulators and combination therapies for this outcome. On analysis of serious adverse events advanced therapies were of no difference to placebo (very low certainty).

Conclusion
On network meta-analysis immunomodulators and advanced therapies for maintenance phase, combination of anti-TNFs and immunomodulators followed by anti-TNF monotherapy had large effect size with moderate certainty for prevention of clinical relapse. There was moderate to high certainty evidence to suggest newer advanced therapies are effective in prevention of loss of clinical response.
P1058 Safety and effectiveness of subcutaneous infliximab formulation in difficult-to-treat Crohn’s Disease patients with previous exposure to intravenous infliximab: A case-series
Authors: Mulinacci G , Pirola L , Piazza O Sed N , Laffusa A , Fichera M , Massironi S , Invernizzi P , Caprioli F A , Viganò C 
Published: January 2024

Abstract

Background
Despite the increased therapeutic armamentarium for Crohn’s Disease (CD), a relevant proportion of patients fail to respond to multiple therapies and ultimately require surgery. Intravenous (IV) infliximab (IFX) reinduction after a drug holiday is associated with reduced drug efficacy and both acute and delayed infusion reactions, due to immunological mechanisms and development of antidrug antibodies, and is currently contraindicated. Recently, a subcutaneous (SC) formulation of IFX has been developed, demonstrating equal efficacy and safety with a better immunogenicity profile (i.e. biobetter). This study evaluated the safety and effectiveness of retreatment with SC IFX in CD patients previously exposed to IV IFX.

Methods
Data were retrospectively collected through the Electronic Medical Record. Patients included were IV IFX-experienced and subsequently treated with SC formulation after a period of drug holiday ≥ 1 year. Collected data included demographics, disease characteristics and activity, current and previous treatment, adverse events, and reasons for previous anti-TNFα discontinuation.

Results
12 patients with CD were included. Mean age at diagnosis and disease duration were 16.2 (±6.7 SD) and 15.6 years (±7.4 SD) respectively. All patients had failed at least three biologics, and 7 patients underwent previous surgery. The main reason for IV IFX discontinuation was secondary failure (4 patients, 33%). Median time from IV suspension to SC treatment start was 106.5 months (IQR=98.5) with median treatment duration of 24 (IQR=37.5) and 7.5 (IQR=4.5) months for IV and SC IFX respectively. SC IFX was introduced as an add-on dual biologic therapy in 5 patients (3 treated with Ustekinumab, 2 with Vedolizumab).
Overall, one adverse event with SC IFX was reported: a grade 2 serum sickness reaction, which led to treatment discontinuation. No immediate allergic reactions were reported. 10 patients had at least 6 months of follow-up. Median HBI reduction at 6 months from SC IFX begin was significant (p&lt;0.05), varying from 7.5 (IQR=3.5) to 3.5 (IQR=4).
C-Reactive Protein levels normalized in 3 (38%) patients, reduced in 2 (25%), and remained stable in 3 (38%). Faecal calprotectin normalized in 2 (29%) patients, reduced in 1 (14%), remained stable in 2 (29%), and increased in 2 (29%). At 6 months steroid free remission rate (HBI≤4) was 66%.

Conclusion
This is the first report showing that SC IFX reinduction in CD patients previously exposed to IV IFX is safe, even after a long drug holiday. It might be regarded as a rescue option in difficult-to-treat patients, either alone or combined with other immunosuppressants.
P1071 Patient preferences for adalimumab in inflammatory bowel disease: a nationwide study from the GETAID
Authors: Caron B , Seksik P , Buisson A , Wils P , Savoye G , Stefanescu C , Laharie D , Guillo L , Abitbol V , Bonnet J , Altwegg R , Vuitton L , Moussata D , Bourreille A , Biron A , Gilletta C , Fumery M , Nahon S , Nancey S , Camara H , Peyrin-Biroulet L 
Published: January 2024

Abstract

Background
Several adalimumab preparations are now available on the market for patients with inflammatory bowel disease. Comparative satisfaction and tolerability are unknown. The aim of this study was to investigate inflammatory bowel disease patient satisfaction with approved adalimumab biosimilars and their originator.

Methods
In this cross-sectional study, we included 941 consecutive adalimumab-treated patients with inflammatory bowel disease across 45 centres affiliated with the GETAID who completed a satisfaction questionnaire comprising four items each rated by a 10 points-scale. The differences in responses were performed using one-way analysis of variance followed by Tukey's Honest Significant Difference test.

Results
The most commonly used drugs at inclusion were Humira® (436/941, 46.3%), Amgevita® (177/941, 18.8%), and Hulio® (105/941, 11.2%). Mean overall satisfaction rate with adalimumab was 8.5 [standard deviation 1.8]. Overall satisfaction was significantly higher in patients treated with Humira® (8.6 [1.5]), Hulio® (8.6 [1.8]) or Amgevita® (8.5 [1.4]) (p&lt;0.05). Satisfaction with the subcutaneous injection form was higher for patients treated with Yuflyma® (9.0 [1.4]), Humira® (8.9 [1.3]) and Hulio® (8.9 [1.7]) (p&lt;0.05). A total of 299 patients (31.8%) described injection site reactions. Two hundred twenty-three patients (23.7%) reported that they were previously treated with another adalimumab of which (32/223, 14.3%) discontinued treatment due to side effects.

Conclusion
In this real-world setting, patients with inflammatory bowel disease had a high level of satisfaction with adalimumab treatment, with some differences in terms of overall satisfaction and satisfaction with the injection device.
P1072 Upadacitinib appears effective in inducing clinical, biochemical, endoscopic and histologic improvements in previously treatment refractory Ulcerative Colitis
Authors: Choon X Y , Patel C , White C , Centritto A , Lal N , Sharma E , Chester D , Dart R , Anderson S , Ray S , Mawdsley J , Irving P , Samaan M 
Published: January 2024

Abstract

Background
Upadacitinib is a novel, oral agent which acts by inhibition of JAK signaling. It has proven efficacy in large-scale, randomised trials for the treatment of UC. We report our real-world experience of upadacitinib as induction therapy in a single centre study of UC patients, including patients who were refractory or intolerant of other advanced therapies.

Methods
We performed a retrospective analysis of outcomes in patients who were commenced on upadacitinib for UC at a tertiary IBD centre between October 2022 to October 2023. The parameters used to assess disease activity were the Simple Clinical Colitis Activity Index (SCCAI), faecal calprotectin (FCP), Ulcerative Colitis Endoscopic Index of Severity (UCEIS) and Nancy Histological Index (NHI). Clinical response was defined as a reduction of SCCAI of ≥3 points, clinical remission as SCCAI of ≤2, biochemical remission as FC&lt;150ug/g. Endoscopic remission was defined as UCEIS 0-1 and histological remission as NHI 0-1. Medical records were reviewed for patient-reported adverse events.
Wilcoxon matched-pairs signed rank test was used to compare pre- and post-treatment continuous variables.

Results
42 patients were started on 45mg once daily upadacitinib over this period. 20 were female, the mean age was 39. 31 had left sided disease, 8 had pancolitis. 39 (93%) patients had prior experience of advanced therapy and 22 (52%) had ≥2 prior therapies.
At baseline, mean SCCAI was 7 (1-15), and mean FCP 1328 (42-6810) μg/g. Baseline endoscopy demonstrated a mean UCEIS of 5 (3-7) and baseline histology a mean NHI of 3 (1-4).
At the 6-week follow up, paired data on clinical and biochemical responses were available in 23 and 27 patients respectively, showing an improvement to a mean SCCAI of 3 (p=0.0004) and mean FCP of 491 μg/g (p=0.002). 16 (70%) achieved clinical response, 14 (61%) were in clinical remission. 15 (56%) had a reduction in FCP to &lt;150 μg/g.
Endoscopic reevaluation took place after a minimum of 12 weeks on treatment. Paired endoscopic outcomes in 20 patients demonstrated an improvement of UCEIS to a mean of 1 (p&lt;0.0001), with 16 (80%) patients in endoscopic remission. Week 12 histology showed improvement to a mean NHI of 2 (p&lt;0.0001, n=19), with 9 (47%) patients achieving histological remission.
6 (14%) patients were non-responders. 3 required a colectomy, 2 necessitated a switch in medical therapy, 1 remained on extended induction.
3 patients (7%) reported facial acne as an adverse event, no others were reported.

Conclusion
Upadacitinib appears effective at inducing significant clinical, biochemical, endoscopic and histological improvements within 12 weeks, amongst a real-world cohort of patients with moderate-to-severe UC that has proved refractory to other advanced therapies.
P1081 Pharmacokinetics and immunogenicity of the ustekinumab biosimilar candidate ABP 654 in patients with moderate-to-severe plaque psoriasis
Authors: Chow V , Mytych D T , Blauvelt A , Papp K , Barragan C , Yamauchi P , Crowley J , Franklin J 
Published: January 2024

Abstract

Background
ABP 654 is being developed as a biosimilar candidate to ustekinumab reference product (RP), a biologic agent used in the treatment of certain chronic, immune-mediated, inflammatory diseases. Previously, we reported no clinically meaningful differences in efficacy or safety between ABP 654 and ustekinumab RP in a 52-week randomised, double-blinded, active-controlled study in patients with moderate-to-severe plaque psoriasis. Here, we describe the pharmacokinetics (PK) and anti-drug antibody (ADA) results from the same study.

Methods
A total of 563 patients were randomised in a 1:1 ratio to receive ABP 654 or ustekinumab RP at a subcutaneous dose of 45 mg (baseline body weight [BW] ≤ 100 kg) or 90 mg (baseline BW &gt; 100 kg) (Fig. 1). Serum samples for PK and ADA evaluations were collected at various timepoints. Concentrations of ABP 654 and ustekinumab RP were measured using an electrochemiluminescent (ECL) assay based on the Meso Scale Discovery platform. All ADA samples were tested in a validated binding, acid-dissociation ECL assay. Samples testing positive for binding antibodies were evaluated for neutralising ADA in a validated ECL-based affinity capture elution assay.

Results
From baseline to Week 52, the geometric least-squares (LS) means of trough serum concentrations were similar between the ABP 654 and ustekinumab RP groups. In addition, the geometric LS means of serum concentrations were similar post Week 28 for patients (ABP 654, n=25 and ustekinumab RP, n=34) who received dose intensification. Of patients with a post-baseline ADA result through Week 28, 52 (18.6%) patients in the ABP 654 group and 104 (37.1%) patients in the ustekinumab RP group tested positive for binding ADAs. Of these, 24 (8.6%) patients in the ABP 654 group and 50 (17.9%) patients in the ustekinumab RP group tested positive for neutralising ADAs. For dose intensification patients with a post-baseline result post Week 28, no patients in the ABP 654 group tested positive for binding or neutralising ADAs, and 2 (5.9%) patients in the ustekinumab RP group tested positive for binding and neutralising ADAs.

Conclusion
Throughout the study, serum trough concentrations remained comparable between ABP 654 and ustekinumab RP. While the percentages of binding and neutralising ADAs were numerically lower for the ABP 654 group compared with the ustekinumab RP group through Week 28 (and in patients who received dose intensification), the available clinical efficacy, safety, and PK data suggest that these differences were not clinically impactful. Overall, the results support a conclusion of no clinically meaningful differences between ABP 654 and ustekinumab RP.