bluuebunny/crossref_metadata_2025_split huggingface dataset:
P0883 Proactive pharmacogenomics in azathioprine-treated pediatric inflammatory bowel disease at a Chinese tertiary hospital
Authors: Long C , Huang Y 
Published: January 2025

Abstract

Background
Despite the emergence of numerous innovative targeted therapies for the management of pediatric inflammatory bowel disease (IBD), azathioprine continues to be a pivotal first-line therapeutic agent. Nonetheless, the considerable frequency of myelotoxicity associated with its use warrants careful consideration and further investigation.

Methods
A retrospective analysis was performed on the clinical data of pediatric IBD who had undergone azathioprine pharmacogenomic testing at the Department of Gastroenterology, Children's Hospital of Fudan University, between July 2019 and May 2024. The study aimed to summarize the prevalence of metabolic gene abnormalities associated with azathioprine and to assess the incidence of myelosuppression among these patients during the subsequent follow-up period.

Results
Among the 227 patients underwent pharmacogenetic testing, abnormal genetypes occurred in 66 patients, among which 7 patients exhibited aberrant TPMT and 59 had aberrant NUDT15. Of the 58 patients who were treated with azathioprine, 23 cases experienced myelosuppression. All three children with heterozygous mutations in NUDT15 developed leukopenia following azathioprine treatment. Among patients with normal pharmacogenetic results, 20 cases (36.4%) developed myelosuppression, while 35 cases (63.6%) did not. The dose of azathioprine was below the recommended level in guidelines. The mean dose of azathioprine (mg/kg/day) in the myelosuppression group was 1.22±0.32, compared to 1.42±0.42 in the non-myelosuppression group, which represented a statistically significant difference (p&lt;0.05). However, age, gender, and the use of concomitant biologics, mesalazine, or glucocorticoids did not show significant differences between the groups (p&gt;0.05).

Conclusion
NUDT15 C415T was prevalent in China and optimal dose of azathioprine should be reconsidered in Chinese pediatric IBD.
P0886 The association of psychological factors and future exacerbation of Inflammatory activity in Crohn’s Disease: A prospective Cohort Study
Authors: Barda L , Talan Asher A , Yablecovitch D , Haj O , Haberman ziv Y , Ungar B , Eliakim R , Kopylov U , Ben-Horin S 
Published: January 2025

Abstract

Background
Recent research has highlighted the complex relationship between Inflammatory bowel disease (IBD), inflammatory activity, and psychological factors such as depression, stress, and anxiety. However, there are scant data from prospective study exploring a putative contributing role of psychological factors in promoting the inflammatory process in the gut. We aimed to explore the temporal relations between depression, stress and anxiety states with the future trajectory of inflammatory intestinal activity as assessed by video capsule endoscopy (VCE) to try to disentangle the correlation between these emotional states and inflammation.

Methods
The CORE prospective observational cohort study included patients with Crohn’s disease (CD) in clinical remission. All patients underwent six-monthly assessments by C-reactive protein (CRP), fecal calprotectin levels, VCE examination, microbiome analysis, the Crohn's disease activity score (CDAI) score and the validated Depression, Anxiety and Stress Scale - 21 Items score (DASS21) for assessment of emotional state. We compared the psychological scores' results with VCE-gauged intestinal activity from two time points: baseline and six months later.

Results
50 patients were included (median age 35.22, sex – 72% men) on a stable treatment. We observed a mild but significant increase in small bowel inflammation between baseline and the six-month follow-up, as reflected by the VCE Lewis score (median 225 vs. 360, p = 0.0002) and an increase at the depression score (p=0.029). There was no significant correlation between the baseline levels of anxiety, depression, or stress and the subsequent exacerbation of mucosal inflammation except for a weak inverse correlation observed for anxiety (p = 0.018, r = -0.33), Similarly, there was no correlation between baseline anxiety, depression or stress levels to subsequent calprotectin trajectory.

Conclusion
Understanding the relationship between IBD, inflammatory markers, and psychological factors is crucial for clinical practice. In our cohort of patients with CD in clinical remission, who were prospectively and rigorously followed with VCE, we found no evidence that anxiety, stress, or depression are associated with an increased risk of future worsening of mucosal activity. Further research is needed to explore the complex interplay and the potential mediators of relationship of stress and mucosal inflammation.
P0889 Efficacy and safety of obefazimod for the fourth and sixth year of open-label maintenance treatment in patients with moderately to severely active ulcerative colitis (UC): 2-year interim analysis after dose de-escalation to 25 mg
Authors: Danese S , Sands B E , Dulai P S , Peyrin-Biroulet L , Dubinsky M , Tilg H , Siegmund B , Hisamatsu T , Shan K , Ploncard P , Jacobstein D , Cataldi F , Rabbat C , Vermeire S 
Published: January 2025

Abstract

Background
Obefazimod is an investigational, oral, once-daily (QD), small molecule which enhances expression of microRNA-124. Obefazimod demonstrated efficacy and safety in patients with moderate to severe active UC at week-8 in two double-blind, placebo-controlled induction trials and in subsequent open-label maintenance (OLM) studies [1-3], and a randomized controlled phase 3 study, ABTECT, is ongoing.

Methods
Patients with UC on obefazimod 50mg QD with endoscopic improvement (Mayo Endoscopic subscore = 0 or 1), could enrol in an open label study in which they were administered obefazimod 25mg QD for up to an additional 54 months. This interim analysis (cut-off date: September 11, 2024) reports the findings of patients who completed Weeks 48 (W48) and 96 (W96) visit (as observed analysis).

Results
Patients with UC were treated with obefazimod 50mg QD for approximately four years in the Phase 2a OLM study and for approximately two years in the Phase 2b OLM study. Out of 174 patients who completed these studies (10 in Phase 2a OLM, 164 in Phase 2b OLM), 138 were eligible. As of the cut-off date, 130 patients rolled over in the 25 mg OLM and were dosed. Among this cohort, 16 patients (12%) discontinued prior to W48 and 6 (5%) discontinued between W48 and W96. Overall, 113 patients (87%) completed the W48 visit, 74 (57%) completed the W96 visit. After dose de-escalation, rates of clinical remission at W48 and W96 were 84% (95/113) and 87% (64/74), respectively. At W48 and W96, 91% (103/113) and 91% (68/75) of patients were in symptomatic remission, respectively. Similar trends were observed with other efficacy analyses (Table 1).
At W48, the levels of fecal calprotectin (FCP) were &lt;250 and &lt;150 µg/g for 90% (85/94) and 81% (76/94) of patients with available FCP values, respectively. At W96, 75% (49/65) of patients had FCP levels &lt;250 µg/g, and 69% (45/65) had levels &lt;150 µg/g. No new safety findings were identified over these 96 weeks.

Conclusion
Following 2-4 years of open-label treatment with obefazimod at a dose of 50 mg QD, large percentages of patients maintained efficacy measures on a lower maintenance dose of 25 mg od for two additional years. No new safety signals were observed over up to six years of obefazimod treatment, supporting a favorable long-term risk-benefit profile.

References
1.Vermeire S, et al. J Crohns Colitis 2023
2.Vermeire S, et al. Gastroenterology 2021
3.Vermeire S, et al. The Lancet Gastroenterol & Hepatol 2022.
P0891 Efficacy and safety of subcutaneous guselkumab rescue therapy in patients with moderately to severely active Crohn’s disease and inadequate response to ustekinumab: Phase 2 GALAXI 1 study long-term extension results
Authors: Afzali A , Wolf D , Leong R , Salese L , Gao L L , Busse C , Panés J 
Published: January 2025

Abstract

Background
Guselkumab (GUS) is a dual-acting IL-23p19 subunit inhibitor that is being evaluated in Crohn’s disease (CD). The GALAXI 1 study (NCT03466411) is a phase 2b study that evaluated GUS in participants (pts) with moderately to severely active CD. Pts treated with ustekinumab (UST) who met inadequate response criteria during long term extension (LTE) could cross over to GUS 200 mg q4w SC. Here, we present efficacy and safety results in pts who received GUS after experiencing an inadequate response to UST in the LTE.

Methods
Individuals with prior inadequate response or intolerance to UST were excluded from GALAXI 1; however, during the LTE, pts treated with UST ~6 mg/kg IV→UST 90 mg SC q8w who met inadequate treatment response criteria (not in clinical response [≥100-point reduction in CDAI score from baseline or CDAI&lt;150] and CDAI ≥220) between Weeks 52-80 of the LTE were eligible for a treatment switch to GUS 200 mg q4w SC, without IV induction. Clinical response and clinical remission were both assessed 16 weeks after treatment switch. Endoscopic response and endoscopic remission were assessed at Weeks 96 and 144 (definitions in Figure). Safety was assessed through Week 144.

Results
In total, 17 pts treated with UST underwent treatment switch to continuing GUS 200 mg q4w SC therapy due to meeting inadequate treatment response criteria between Weeks 52-80 of the LTE. Pts who crossed over to GUS exhibited similar baseline demographics and disease characteristics to all GUS LTE pts (Table).
The proportions of pts achieving clinical response and clinical remission 16 weeks after treatment switch from UST to GUS 200 mg SC q4w were 58.8% and 52.9%, respectively. The proportions of pts achieving endoscopic response and endoscopic remission were 52.9% and 35.3% at study Week 96, respectively, and were maintained through Week 144 (Figure).
Key safety event rates through Week 144 were consistent with the known safety profile of GUS in approved indications.

Conclusion
Among pts who experienced inadequate response to UST in the LTE, more than half achieved clinical remission 16 weeks after treatment switch to GUS 200 mg SC q4w and &gt;50% were in endoscopic response at Week 96. These data suggest pts with an inadequate treatment response to UST may benefit from GUS treatment. Results are limited by small sample size and direct treatment switch to GUS SC maintenance dosing without IV induction.
P0895 The Prognostic Significance of Visceral Adiposity indices in conjunction with Plasma Trace Elements in Newly Diagnosed Crohn's Disease
Authors: Luo J , Li G , Hu W , Shen K , Huang X , Xu D , Wang X , Ma Y , lv M , Li S , Chen Y , Yu Q 
Published: January 2025

Abstract

Background
While imbalances in trace elements are recognized for causing dysfunction in adipose tissue and disease onset and progression of CD, the relationship between the initial status of trace elements and the risk of VAT accumulation in patients with CD remains uncertain. This study aims to investigate the prevalence of trace element deficiencies among newly diagnosed CD patients, explore how these deficiencies relate to VAT accumulation, and examine their implications for disease progression. In particular, we focus on magnesium due to its potential therapeutic effects, evaluating its role in experimental colitis models to assess its impact on inflammation and immune responses.

Methods
The analysis was based on an inception cohort of 300 patients newly diagnosed with CD between July 2019 and June 2022. Plasma trace element levels were measured at baseline. VAT was evaluated using computed tomography (CT) scans obtained at first diagnosis. Patients were followed for a period of two years to monitor outcomes. Logistic regression analyses were performed for statistical assessment. To elucidate magnesium's therapeutic mechanisms, we employed DSS-induced colitis mouse models and conducted in vitro CD4+ T cell activation experiments. Gut microbiota composition was analyzed using 16S rRNA sequencing.

Results
Deficiency in iron was most prevalent affecting 25.67% of the patients, with zinc deficiency at a rate of 3.67%. An inverse correlation was observed between magnesium levels and VAT index (β=-0.24, p&lt;0.001). Reduced levels of zinc and magnesium were predictive of adverse clinical outcomes (OR=0.51, p=0.002; OR=0.52, p=0.001) and drug outcomes (OR=0.39, p&lt;0.001; OR=0.57, p=0.004). Further stratified analysis revealed that the protecive effect of magnesium was significant exclusively in patients with a VAT-to-subcutaneous adipose tissue ratio (VAT/SAT) ≥1. Magnesium supplementation attenuated colonic inflammation in DSS-induced colitis mouse model, reduced infiltration of CD4⁺T cells, and enhanced gut microbiota diversity. Notably, there was a significant increase in beneficial bacteria, including butyrate-producing genera such as Intestinimonas, Clostridia_UCG-014, and Paludicola. In vitro studies further demonstrated magnesium's capacity to suppress inflammatory cytokine production by CD4⁺ T cells from patients with CD.

Conclusion
Disruptions in baseline trace elements correlate with poor outcomes in CD patients. The interaction between trace elements and VAT may impact disease progression. Magnesium's therapeutic effects, mediated through immunomodulation and microbiota regulation, highlight its potential as a therapeutic target for personalized treatment approaches in inflammatory bowel disease.
P0897 Association of HLA Genotypes with Anti-Drug Antibody Development in Taiwanese Inflammatory Bowel Disease Patients Undergoing Biologic Therapies
Authors: Weng M T , Yao C Y , Lin W C , Lai S K , Chen P L , Tung C C , Wong J M , Wei S C 
Published: January 2025

Abstract

Background
Anti-drug antibodies (ADAs) are a primary factor in the loss of response to infliximab and other adverse drug reactions. The genetic variant HLA-DQA1*05 has been associated with infliximab antibody development in Crohn’s disease (CD) among European populations. This study aims to assess the relationship between HLA genotypes and ADA formation in non-European inflammatory bowel disease (IBD) patients receiving anti-tumor necrosis factor (TNF), anti-integrin, or anti-IL-12/23 therapies.

Methods
This prospective cohort study enrolled patients with IBD receiving anti-TNF, anti-integrin, or anti-IL-12/23 therapy between January 2022 and March 2024. NGS-based HLA genotyping was performed for all participants. The occurrence of ADAs was assessed, and the frequencies of specific HLA alleles were compared between patients who developed ADAs and those who did not. Additionally, HLA allele frequencies in ADA-positive patients were analyzed against the general population in Taiwan.

Results
A total of 95 patients with IBD were included in the study, along with HLA genotype data from 1,097 control individuals obtained from the Taiwan Biobank. Among the IBD patients, 58 received anti-TNF therapy, 27 underwent anti-integrin therapy, and 10 were treated with anti-IL-12/23 therapy. According to the reimbursement criteria in Taiwan, all patients have to be treated with conventional therapy and when with inadequate response or with adverse effects, then biologics would be reimbursed. Therefore, all the 95 patients were under the biologics and immunosuppressive agents (either thiopurine or methotrexate) combination therapy. No ADA development was observed in patients treated with anti-integrin or anti-IL-12/23 therapies. However, among the 58 patients treated with anti-TNF therapy (38 with infliximab and 20 with adalimumab), 21 developed ADAs (18 infliximab-related and 3 adalimumab-related). A comparison of patients with and without ADAs revealed a significant association between the HLA-C*03:04:01 allele and ADA development (33.3% vs. 10.8%, p=0.035), whereas the HLA-DQA1*05 allele showed no association (52.3% vs. 51.4%, p=0.940). The frequency of the HLA-C*03:04:01 allele was comparable between IBD patients and the broader Taiwanese population (16.8% vs. 11.2%, p=0.0915).

Conclusion
This study demonstrated that the different HLA locus associated with ADA development among different ethnics. While HLA-DQA1*05 was found in European cohort, our data showed that HLA-C*03:04:01 was significantly associated with an increased risk of anti-TNF antibodies formation in Taiwanese IBD patients.

References
1.Sazonovs A, Kennedy NA, Moutsianas L, et al. HLA-DQA1*05 Carriage Associated WithDevelopment of Anti-Drug Antibodies to Infliximab and Adalimumab in Patients WithCrohn's Disease. Gastroenterology 2020;158:189-199.
P0899 Previous extended colectomy is associated with particularly high risk of postoperative small bowel fistula in Crohn’s disease patients
Authors: Iesalnieks I , Bercher M , Schmitz A 
Published: January 2025

Abstract

Background
Postoperative small bowel fistula is one of the most detrimental complications in abdominal surgery. Patients with Crohn’s disease seem to be at higher risk. Performing small bowel surgery in patients with previous extended colectomy, surgeons face diffuse small bowel adhesions. Moreover, patients with small bowel disease after previous (total) colectomy pose one of the most vulnerable populations. Present analysis was conducted in order to analyze the incidence of small bowel fistula following abdominal surgery in Crohn’s disease patients.

Methods
Consecutive patients with Crohn’s disease undergoing intestinal resection between 1992 and 2024 were included in current analysis using a prospectively maintained database. “Small bowel fistula” was defined as any small bowel perforation away from any anastomoses, strictureplasties or any other kind of small bowel sutures. “Previous extended colectomies” were total abdominal colectomies or proctocolectomies in patients’ history prior to the current surgery.

Results
973 patients undergoing 1096 bowel resections were included. There were 804 ileocolic resections, 254 colonic resections and 38 other resections (small bowel resection, ileostomy resections, pouch excisions and abdominoperineal resections). Postoperative intraabdominal septic complications occurred in 162 patients (15%), 8 patients died (0.7%). Postoperative small bowel fistula occurred in 9 patients (0.8%). 52 patients attended current surgery with a history of previous (procto-)colectomy. Current surgery consisted of 13 resections of ileosigmoid or ileorectal anastomoses, 12 ileostomy resections, 10 abdominoperineal resections, 9 small bowel resections, 5 J-Pouch excisions, 1 Kock pouch excisions, 1 Redo-Pouch and 1 IPAA in the study population. 10 of 52 patients (19%) with a history of previous extended colectomy underwent laparoscopic surgery with one patient converted to open. The history of previous extended colectomy was the only factor associated with an increased risk of postoperative small bowel fistula by a multivariate analysis (7.7% vs. 0.5%, Hazard ratio 7.1, p&lt;0.001) but not for all intraabdominal septic complications (15% in both groups). The risk of postoperative small bowel fistula was not increased in patients with a history of any other previous intestinal resection than extended colectomy.

Conclusion
Crohn’s disease patients with a history of previous total colectomy or proctocolectomy are at a particularly high risk of postoperative small bowel fistula when they undergo further surgeries. Surgeons must be aware of this complication in cases of unexpected postoperative symptoms.
P0900 Hyperbaric oxygen therapy downstages refractory perianal fistulizing Crohn’s disease and allows for surgical closure
Authors: Mulders L , Beek K , Becker M , Koelink P , Zwart M , van der Bilt J , Vlug M , Tielbeek J , Rietdijk S , Jansen J , Ridderikhof M , de Jonge W , Bemelman W , Stoker J , D'Haens G , van Hulst R , Wildenberg M , Buskens C , Gecse K ,   AMFIBIO study group
Published: January 2025

Abstract

Background
Hyperbaric Oxygen Therapy (HBOT) has previously shown benefit in treatment-refractory perianal fistulizing Crohn’s disease (PFCD). However, the biological mechanisms underlying therapy response remain poorly understood. In this prospective study, we aimed to assess the feasibility, efficacy, and safety of HBOT followed by surgical closure, while also investigating translational changes associated with HBOT.

Methods
Patients with active PFCD refractory to 6 months of optimized medical therapy were included. After receiving a seton, patients started HBOT (40 sessions, 110 minutes each with 5-minute air breaks, 100% oxygen at 2.4 atmosphere). Half-way, at week 4, the seton was removed and surgical closure of the internal fistula opening was attempted. All patients continued stable dose of medical treatment during the study. Response was assessed clinically, by pelvic MRI and by patient-reported QoL. RNAseq data of surgical biopsies of the internal fistula opening were explored between patients after completion of HBOT and matched non-HBOT patients.

Results
Sixteen patients completed HBOT and all of them could undergo a technically successful surgical procedure at week 4 (See Table 1). Clinical remission (no draining fistula openings) was achieved in 43% (W9), 42% (W26) and 70% (W52), and PDAI remission (≤4) was achieved by 31% (W9), 58% (W26) and 70% (W52) (Figure 1). MRI remission (MAGNIFI-CD ≤6) was achieved by 42% (W26) and 57% (W52), and MRI healing (MAGNIFI-CD = 0) was achieved by 8% (W26) and 40% (W52). Quality of Life (CAFQOL) improved significantly with a mean improvement of 10.7 (SE 3.9) by W26 and 22.7 (SE 6.0) by W52. (S)AEs included one patient with a potential oxygen toxicity seizure without long term effects, and one patient reported claustrophobia, no new AEs were reported.
Surgical biopsies obtained after HBOT displayed increased expression of cornification markers including CRNN, KRT4, KRT13 and SPRR2B. Pathway analysis confirmed biological activity of ‘keratinization’ and ‘dermal development’ in post-HBOT samples. This is similar to those observed previously in cryptoglandular fistulas. In contrast, patients without HBOT on stable medical treatment mainly showed general immune activation.

Conclusion
HBOT resulted in downstaging of active PFCD, which became amenable to surgical closure. The combined treatment approach resulted in sustained clinical and MRI remission in patients with refractory disease. HBOT resulted in enhanced activity of pathways associated with keratinization and dermal development. These data support a model where HBOT shifts an active Crohn’s disease fistula towards a more manageable cryptoglandular-like phenotype.