bluuebunny/crossref_metadata_2025_split huggingface dataset:
P1018 Population pharmacokinetic and exposure-response analyses for efficacy and safety of risankizumab in subjects with moderately to severely active Ulcerative Colitis
Authors: Thakre N , Goebel A , D'Cunha R , Winzenborg I , Liu W , Pang Y 
Published: January 2024

Abstract

Background
Risankizumab (RZB) has been evaluated in subjects with moderately to severely active ulcerative colitis (UC) in the INSPIRE and COMMAND trials. Population pharmacokinetic (PPK) and exposure-response (ER) analyses were conducted at the end of Phase 2b and following Phase 3 to characterize RZB PK and its relationship with clinical efficacy and safety to support Phase 3 induction dose selection, and the final dose recommendations for induction and maintenance treatment.

Methods
PPK analyses in UC used a previously developed PPK model for Crohn’s disease with additional evaluation of covariates relevant to UC. ER relationships between RZB exposures and efficacy endpoints at the end of induction (Week 12), re-induction (Week 24; exploratory only) and maintenance (Week 52) periods were established using exploratory graphical analyses and logistic regression modeling. ER analyses for safety were performed for key variables through Weeks 12, 24 and 52 using graphical analyses.

Results
A two-compartment model with first-order absorption for SC administration and first-order elimination adequately described RZB PK. Among the various covariates assessed, body weight, baseline (BL) serum albumin, BL high-sensitivity C-reactive protein, BL fecal calprotectin, sex, advanced therapy IR status, BL pancolitis and corticosteroid use were statistically correlated with RZB clearance but their impact on exposure was not clinically relevant for efficacy.
ER analyses for efficacy using Phase 2b induction data showed that while incremental improvement in efficacy was predicted with doses increasing from 1200 to 1800 mg, the magnitude of difference in efficacy was modest especially for endoscopy-driven endpoints. Phase 3 ER analyses for efficacy showed statistically significant trends of exposure-dependent increase in efficacy following induction treatment with 1200 mg IV at Week 0, 4 and 8, with greater response rates observed with higher exposures across all evaluated endpoints at Week 12, in line with the results from Phase 2b. ER analyses for maintenance demonstrated an exposure-dependent increase in efficacy for Week 52 endpoints, with modest improvement in efficacy when increasing the dose from 180 mg to 360 mg, and largely overlapping confidence intervals. ER analyses for safety indicated no apparent exposure-dependent safety events over the induction or maintenance treatment.

Conclusion
The PPK and ER analyses of RZB in subjects with UC characterized the disposition of RZB and its relationship to efficacy and safety, as well as the lack of impact by intrinsic and extrinsic factors on PK and efficacy. Results supported the final dosing regimen recommendations for the treatment of moderately to severely active UC.
P1021 Comparison of subcutaneous and intravenous infliximab in patients with inflammatory bowel disease showed no differences in immunogenicity or treatment persistence at one year
Authors: Hancox S , Morda F , Black C , Selinger C 
Published: January 2024

Abstract

Background
The effectiveness of infliximab (IFX) in inflammatory bowel disease (IBD) can be impaired by the formation of anti-drug antibodies (ADA). Subcutaneous (SC) IFX has a different pharmacokinetic profile compared to intravenous (IV) administration. These differences may affect the risk of immunogenicity and we sought to explore this in a retrospective study.

Methods
We performed a retrospective study in Leeds, United Kingdom. Adult patients starting IFX for the first time between January 2019 and June 2022 were identified. All received standard induction with three IV doses followed by either: 1) maintenance SC IFX 2-weekly (standard practice from 2021), or 2) maintenance IV IFX (standard practice until 2021). We compared ADA levels, IFX trough levels and treatment persistence between groups after 12-months of treatment. ADA levels above 10 AU/ml were considered positive and ADA levels above 50 AU/ml as clinically relevant.

Results
After excluding 41 patients (16 stopped IFX after IV induction, 24 moved to SC after &gt;4 IV doses, and 1 lost to follow-up), 101 patients receiving maintenance SC IFX were compared to 108 patients continuing with maintenance IV IFX. At 12-months, prevalence of ADA positivity was similar in both groups (48.1% SC vs 50.6%; p=0.775). Clinically relevant ADA levels (&gt;50 AU/ml) were also similar (21.1% SC vs 26.5% IV; p=0.481). Additionally, there were no statistically significant differences in terms of detectable IFX trough levels and treatment persistence after 12-months of treatment between the two groups. Patients receiving combination therapy with IFX and immunomodulators showed a significant reduction in ADA formation irrespective of the route of IFX administration. 34.8% of patients receiving combination therapy had detectable ADA compared to 65.2% receiving IFX monotherapy (OR 0.28 (95% CI 0.13-0.58; p=0.001)). Treatment persistence was also significantly higher in those receiving combination therapy compared with monotherapy at 12-months (73.3% vs. 51.9%; p=0.004). The proportion of patients with detectable drug levels at 12-months was also higher with combination therapy (91.3% vs. 72.7%; p=0.005).

Conclusion
There were no significant differences in ADA levels, IFX levels, and treatment persistence between the SC and IV routes of IFX administration after 12 months of treatment. Concurrent use of immunomodulators was associated with reduced immunogenicity and better treatment persistence regardless of the route of maintenance IFX. Clinicians should advise patients on the benefits of immunomodulator combination therapy when initiating IFX regardless of route of administration.
P1029 Prevalance and risk factors of thromboembolism in Inflammatory Bowel Disease
Authors: Katı O , Bakkaloglu O K , Hatemi I , Celik A F , Seyahi E , Erzin Y 
Published: January 2024

Abstract

Background
Inflammatory bowel disease (IBD), as a chronic inflammatory condition, can affect atherosclerotic process, arterial events, and increase the formation of venous thromboembolism. The aim of this study was to determine the frequency of thromboembolism and the risk factors associated with acute thromboembolism in our IBD cohort.

Methods
A total of 3133 patients with 1414 Crohn's Disease (CD), 1667 Ulcerative Colitis (UC) and 52 Indeterminate Colitis who were admitted between 1999 and 2021 were retrospectively analyzed. Patients with acute arterial events and venous thromboembolism (n=39) during the follow-up period were compared with a control group (n=78) of the same gender and same diagnosis. Patients with Behçet's syndrome (n=126),systemic vasculitis (n=16) and hereditary thrombophilia (n=5) were excluded.

Results
Among 3133 IBD patients, number of patients with arterial events or venous thromboembolism at any time was 124, and the frequency was 3,95%. A total of 132 thromboembolic events, 86 arterial (65,2%) and 46 venous (34,8%) were recorded.Coronary artery disease was significantly higher in the UC group (2,3% vs. 1,2%; p=0.028). During follow-up, 40 acute thromboembolic events, 25 arterial and 15 venous, were seen in 39 patients (frequency 1,24%). There was no significant difference between the CD and UC groups in terms of acute thromboembolism (p=0.871). The presence of exacerbation, the presence of hospitalization, the number of priot hospitalizations and clinical activity at the last visit were associated with both arterial and venous thromboembolism; smoking history, age at diagnosis, body-mass index, non-mucosal CD (Montreal B2-B3) and higher basal CRP were associated with arterial thromboembolism only; higher CRP at the last visit, annual exacerbation frequency, presence of an additional inflammatory disease, presence of complications (surgery, abcess), longer total steroid traetment duration and also recent steroid therapy were associated only with venous thromboembolism. In regression analysis, recent steroid therapy and additional inflammatory disease were considered as independent risk factors for venous thromboembolism whereas age at diagnosis of IBD was considered as an independent risk factor for arterial events.

Conclusion
In addition to risk factors such as age, smoking and obesity, parameters indicating disease activity, inflammatory comorbidities and recent steroid therapy appear to be associated with acute thromboembolism in IBD patients.
P1036 Persistence of biologics and advanced small molecules in 4th, 5th and 6th line of therapy for inflammatory bowel disease: a cross-sectional retrospective study
Authors: Parigi T L , Massimino L , Carini A , Allocca M , D'Amico F , Furfaro F , Zilli A , Cagliani S , Errico C , Facoetti A , Nicolò S , Peyrin-Biroulet L , Danese S 
Published: January 2024

Abstract

Background
The choice of treatment for inflammatory bowel disease (IBD) with multiple prior drug failures, also known as difficult-to-treat (D2T) IBD, is an increasing challenge. We assessed the persistence of biologics and advanced small molecules, a surrogate for their efficacy, in patients with Crohn's disease (CD) and ulcerative colitis (UC) overall and in 4th, 5th and 6th lines of advanced treatment.

Methods
We retrospectively searched the electronic medical records of patients with IBD followed at the San Raffaele Hospital (Milan, Italy) up to 1 October 2023. Patients enrolled in clinical trials that changed disease management or receiving experimental drugs were excluded. Drug persistence was defined as the time from initiation to discontinuation of each treatment. Welch's ANOVA and Games-Howell's method for multiple comparisons were used.

Results
A total of 679 patients with moderate to severe IBD were included. 350 had CD, 326 UC, and 3 IBD-U. The mean disease duration was 11 years and 452 (66%) had received 5-aminosalicylates or antimetabolites as first maintenance treatment. Escalation to and changes between advanced treatments over time is summarised in Figure 1A. A greater use of anti-TNF agents was observed in the first lines of treatment whereas newer medications were proportionally more prescribed in refractory patients.
In the overall analysis, regardless of the line of treatment, there was no difference in drug persistence between agents at 12 months (p=0.62), with approximately half of the patients having discontinued the drug. Figure 1B
In subsequent lines of treatment, drug persistence decreased significantly in patients with CD (p=0.002). The trend was particularly pronounced from line 2, with a mean duration of 31 months, to line 7, with a mean duration of 11 months.
In UC, the reduction was less evident and borderline non-significant (p=0.05), although it suggests a decrease in drug efficacy as the disease progresses. Figure 2 A, B
In patients with D2T IBD, drug persistence in 4th, 5th and 6th line advanced treatment was similar for all agents (all p&gt;0.05), indicating no clear advantage of one drug over the others. Figure 2 C, D, E

Conclusion
In CD, and possibly in UC, the persistence of patients on any advanced drug decreases with subsequent lines of treatment. None of the advanced agents showed a longer persistence time when used as a 4th, 5th or 6th line of treatment.
P1060 Diverting Ostomy for Crohn’s Pancolitis in Pediatric Patients
Authors: Kwon H 
Published: January 2024

Abstract

Background
Childhood-onset Crohn’s disease (CD) is characterized by extensive anatomic involvement, with high rates of panenteric CD. Given the fact that total colectomy for these patients result in permanent loss of colonic absorption of nutrients, ostomy can be a good surgical option for children with Crohn’s pancolitis requiring surgical intervention. The purpose of this study was to retrospectively review the outcome of diverting ostomy for Crohn’s pancolitis in children.

Methods
Children with Crohn’s disease involving total colon with or without small intestine who underwent surgery were included. Preoperative patient features including extent of disease using Paris classification, nutritional status and medications were recorded. Outcomes analyzed included postoperative medication changes, nutrition and growth changes, postoperative complications and need for further operative interventions.

Results
We identified 13 patients with a median age of 11 years (range 5 months-15 years), all of whom had pancolitis at the time of surgery. All 13 patients underwent stoma formation, initially. Three patients received colectomy after median 24 months. Takedown rate was 38% (n=5) and the time from stoma formation to takedown was median 13 months (range 10-34 months). Weight and height z-score have been improved after ostomy.

Conclusion
Children with CD pancolitis could benefit from diverting ostomy which offers an opportunity to spare the large intestine partially or completely which could improve nutrition and growth. Outcome comparison between diverting ostomy and colectomy should be discussed with larger study populations.
P1066 The real-life use of the Crohn's disease exclusion diet (CDED) in adults with mild-to-moderate Crohn's disease activity: an interim analysis of an open-label randomized controlled trial
Authors: Bodini G , Pasta A , Formisano E , Calabrese F , Apollonio M , Pisciotta L , Giannini E G 
Published: January 2024

Abstract

Background
The Crohn's Disease Exclusion Diet (CDED) is a validated dietary intervention characterized by a specific highly restrictive food regime which aim to induce remission and reducing inflammation in Crohn's disease (CD). In a previously randomized control trial (RCT), clinical remission was achieved in a range of 75-85% of patients after 6 and 12-weeks of CDED. We aim to provide an additional real-world evidence-based validation.

Methods
Interim analysis of an open-label randomized controlled trial of CD patients with mild-to-moderate clinical activity assessed by Harvey-Bradshaw Index (HBI) was performed. Demographical characteristics and medical history were collected at enrollment, while weight, body mass index (BMI), HBI, fecal calprotectin and serum inflammatory indices were assessed at baseline and after 12 and 24 weeks. Bioelectrical impedance analysis (BIA) was performed every 12-weeks in CDED group to test the safety. The primary endpoint was clinical remission (HBI&lt;5) and was assessed in the intention-to-treat population.

Results
Twenty-four patients were randomized to receive CDED diet, while 21 were in control group. No significant differences among all parameters considered were observed at baseline. Five patients in CDED group discontinued diet because of intolerance at median of 5 weeks. At week 12, the median HBI was lower in CDED patients than in control patients (3, IQR 1-5 vs 5, IQR 4-6, respectively; p=0.001) resulting in more patients achieving clinical remission (17/24, 70,8% vs 8/21, 38,1%, respectively; p=0.027). No differences in fecal calprotectin and serum inflammatory indices were observed. The administration of CDED was associated with weight loss (72 to 69 kg, p=0.003), although BIA analysis showed a decrease in fat mass (18.2% to 15.5%, p&lt;0.0001), while fat-free mass significantly increased (81.9% to 83.7%, p=0.001). No difference in body cellular mass was observed after 12-weeks of CDED.

Conclusion
The CDED is effective in inducing remission in mild-to-moderate clinical activity CD patients and seems to be safe and well-accepted.
P1068 Limited long-term efficacy of corticosteroids in microscopic colitis emphasizing the need for advanced therapies
Authors: Taelman T , Vermeire S , Ferrante M , Sabino J , Verstockt B 
Published: January 2024

Abstract

Background
Microscopic colitis (MC) is a chronic inflammatory bowel disease, characterized by chronic watery diarrhea, and consisting of 2 subtypes: collagenous (CC) and lymphocytic (LC) colitis. It mainly affects middle-aged adults, although it can occur at any age. The only approved therapy is budesonide, preferably administered in a tapering regimen given the high relapse rates. However, little is known about the long-term natural history of the disease.

Methods
All adult patients diagnosed with MC after clinical and histological assessment at our referral center between 2014 and 2022 were reviewed. Patients with follow-up less than 3 months or in whom no clear description of initiated therapy could be identified by retrospective chart review, were excluded for evaluation of long-term outcomes. Clinical remission was defined according to the Hjortswang criteria as &lt; 3 stools/day or &lt; 1 watery stool/day. Data on relapse rates, subsequent therapies and surgery were collected.

Results
Three-hundred twenty-four patients were included, of whom 198 (CC 38.3%, LC 61.7%) were eligible for long-term assessment (Table 1) with a median follow-up of 3.7 [1.1 – 6.3] years. Median age at diagnosis was 63.4 [51.6-74.7] years. Concomitant diseases occurring in 3% or more included thyroid dysfunction (11.6%), coeliac disease (3.5%) and Parkinson’s disease (5.1%), which numerically was more prevalent in the LC (7.4%) than CC (1.3%) population (p=0.09). A minority of patients had a family predisposition of IBD (5.6%). Spontaneous clinical remission occurred in 37 (18.6%) patients, while 4 (2.0%) patients were treated with 5ASA. Most patients (79.3%) were treated with corticosteroids, resulting in 81.1% clinical remission within 3 months. Eighty-six patients (54.8%) flared upon steroid tapering and/or withdrawal requiring corticotherapy reinitiation, prolongation or dose intensification. Due to steroid resistance or dependency, subsequent treatment options included 5ASA (n=14), cholestyramine (n=11), methotrexate (n=6) and azathioprine (n=8), all with limited effect. More advanced therapies are being used, including anti-TNF agents (n=25), vedolizumab (n=9) and JAK inhibitors (n=8). Eighteen patients (9.2%) are currently on maintenance advanced therapies for MC. Two treatment-refractory patients underwent colectomy.

Conclusion
In this large single-center retrospective analysis, steroids confirmed their first line position to induce clinical remission in MC. However, more than 50% of patients relapsed upon steroid tapering and/or withdrawal, resulting in a substantial need for advanced therapy in this patient population. The long-term efficacy and safety of these advanced IBD therapies in MC should therefore be further investigated.
P1080 Real-world Study on Early Predictors of Infliximab Treatment Efficacy in Crohn's disease
Authors: Lv C , Chen Y , Yan F , Pi S , Liu Y , Chen R , Tang W , Zhang H 
Published: January 2024

Abstract

Background
Infliximab (IFX) can effectively induce and maintain the clinical remission of Crohn's disease (CD). However, a substantial number of CD patients experience primary or secondary nonresponse to IFX during treatment. Therefore, it is essential to identify early predictors of IFX treatment efficacy.

Methods
This study included 147 CD patients. Based on clinical outcomes, patients were categorized into IFX nonresponse and response group. We collected and compared laboratory data on blood routine examination, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), fecal calprotectin and post-induction IFX drug concentration and antibody levels in both groups. Logistic regression models were employed to identify potential factors associated with the risk of IFX nonresponse. Machine learning using random forest analysis was utilized to quantitatively assess the predictive features for IFX treatment efficacy and ROC curves was used to evaluate the model’s accuracy. Additionally, we performed HE staining and double immunofluorescence staining for CD64 and CD206 on intestinal biopsy tissues obtained before IFX treatment to compare the difference of macrophage subtypes between the nonresponse and response groups.

Results
Data from both cohorts revealed that patients in the IFX nonresponse group had lower drug concentration (P &lt; 0.001), higher antibody levels (P &lt; 0.001), and increasing ESR during the induction therapy (P &lt; 0.001). Univariate and multivariate Logistic regression models demonstrated that IFX drug concentration and the ratio of ESR before and after induction therapy were associated with the risk of nonresponse. After the induction period, for each unit increase in drug concentration (1 μg/ml), the risk of IFX nonresponse decreased by 23% (RR= 0.77, 95% CI = 0.68-0.89), while each doubling of the ESR ratio after induction was associated with a 1.43-fold increase in the risk of nonresponse (RR= 2.43, 95% CI = 1.48-4.00). After combining data from the two cohorts, random forest machine learning analysis revealed that drug concentration below 1.5 μg/ml and an increase in ESR during induction could predict IFX nonresponse, with ROC curve areas of 0.740 and 0.651, respectively. Furthermore, immunofluorescence staining of intestinal mucosal biopsy tissues before IFX treatment showed a higher proportion of M1-type macrophages in the nonresponse group compared to the response group (P &lt; 0.05).

Conclusion
Our study suggests that lower post-induction IFX drug concentrations and an increase in ESR during the induction phase are predictive of IFX nonresponse. Additionally, a higher proportion of M1-type macrophages in the intestinal mucosa before IFX treatment is associated with IFX nonresponse.