bluuebunny/crossref_metadata_2025_split huggingface dataset:
DOP72 HLA-DQA1*05 associates with immunogenicity and loss of response to anti-TNF therapy in the IBD population: A meta-analysis
Authors: Bergstein S , Spencer E A 
Published: January 2023

Abstract

Background
The human leukocyte antigen (HLA) allele group HLA-DQA1*05 has been associated with the development of antidrug antibodies (ADA) to tumor necrosis factor antagonists (anti-TNF)1 in the inflammatory bowel disease (IBD) population, except in the setting of proactive optimization2. We performed a meta-analysis to determine the prevalence of HLADQA1*05 carriage, to define the association of HLA-DQA1*05 on immunogenicity and loss of response (LOR) to anti-TNF, and to explore the impact of therapeutic drug monitoring (TDM) on this association.

Methods
A systematic search of EMBASE, MEDLINE, Web of Science, and SCOPUS was conducted and identified 49 studies. Fourteen studies were included in the meta-analysis according to our inclusion and exclusion criteria. Two reviewers independently assessed eligibility and extracted data. Data extraction focused on the prevalence of HLADQA1*05 carriage, management style of the subjects (proactive TDM vs not), use of combination therapy with immunomodulators (IMM), and association of the variant with ADA and LOR. To examine the potential mitigating effect of management style, three forest plots were generated for each outcome including: 1. all studies, 2. studies using solely proactive TDM, and 3. studies where TDM was either not defined or not performed.

Results
The prevalence of HLADQA1*05 carriage was 43.3% across the 14 manuscripts (Table 1). Ten studies used data from adult populations, 2 reported on pediatrics only, and 2 reported on a mix of pediatrics and adults. Nine studies took place in Europe, and 5 occurred in North America. A little over half (57%) were abstracts. All studies included some patients on combination therapy with IMM. Data analysis confirmed that possessing the HLADQA1*05 variant leads to an increased ADA risk (OR 1.63 [95% CI: 1.35 - 1.98]). When focusing on the studies that used proactive optimization of anti-TNF therapy, the variant was no longer a risk factor for developing ADA (OR 0.37 [95% CI: 0.19 - 0.70]). Without proactive optimization, the carriage of HLADQA1*05 appears to consistently be associated with a higher risk of immunogenicity (OR 1.93 [95% CI: 1.58 - 2.36]) (Figure 1). HLADQA1*05 was also found to be a risk factor for LOR (HR 1.84 [95% CI: 1.53 - 2.22]) (Figure 2); insufficient data were available for the studies with proactive TDM on LOR.

Conclusion
Prevalence of HLADQA1*05 carriage is consistent across studies from both North America and Europe. This variant increases the risk of ADA and LOR to anti-TNF. However, in studies that used solely proactive TDM, variant carriage no longer conferred a risk for ADA.
1. Sazonovs A, et al. Gastro. 2020;158(1):189-199.
2. Spencer EA, et al. Gastro. 2022;162(6):1746-1748.e1743.
DOP76 Comparison of healing of complex perianal Crohn′s disease fistulas by advancement flap and mesenchymal stem cell therapy
Authors: Serclova Z , Tremerova A , Lengalova M , Petra Z 
Published: January 2023

Abstract

Background
The combination of surgical approach and biologic treatment is the most successful approach to achieve healing of perianal Crohn′s disease (CD) fistulas. Alongside conventional surgical methods (advancememt flap AF), a new method of fistula closure - allogeneic mesenchymal stem cell (MSC) therapy found its way to clinical practice.

Methods
The aim of a single centre prospective observational study was to compare the healing results of complex perianal CD fistulas by advancement flap and mesenchymal stem cell therapy (by darvadstrosel). 119 consecutive CD patients with complex fistula (95 with anorectal and 24 anovaginal); treated by MSC-darvastrocel in between 2018 to 3/2022. All patients had a long term loose seton drainage and optimized conventional therapy with luminal remission confirmed by colonoscopy.
Complete healing was clinically assessed (no visible external opening or a scar without secretion, no inflammation, no subsequent perianal surgery needed within 3 months post index surgery).

Results
AF group: Duration of luminal CD was 8,84 years (1-38) and perianal CD 4,74 years (0,5-17). Patients underwent 4,22 (1-23) previous perianal surgeries. The follow up was 11,47 months (0,5-48,9). Conservative therapy (biologics and immunosuppressants) was stable for 23,1 months (1-137). Patients did not suffer from anorectal stenosis or rectal inflammation.
MSC group: (60 pp. 36F/24M): Duration of luminal CD was 13 years (2-43 years), of perianal CD 7 years (2-23 years). Number of previous perianal surgeries was 8 (3-25). Conservative therapy was stable for 19 months (1-120). Follow up was 12,5 months (5-34). 38,3% (23) of patients had anorectal stenosis, 38,3% patients underwent advancement flap procedure prior, and 62% suffered from chronic inflammation in rectum.
Complete healing was achieved in 86,5 % pts in the AF group and 74.1% of those were healed even with vaginal fistulas.

Conclusion
There was no significant difference in the healing rate of both methods (p= 0,202).
AF procedure could be beneficial in vaginal fistulas, where MSC therapy is contraindicated.
MSC therapy is useful in the case of chronic changes of rectal mucosa, anorectal stenosis and the presence of 2 internal openings, where AF procedure is not performable.
High success rate in both groups may be conditioned by good preparation of patients (multiple previous drainages) and stable luminal disease (stable conservative treatment).
DOP83 Proactive dosing is superior to clinically based dosing in terms of endoscopic healing in paediatric patients with Crohn’s disease receiving maintenance infliximab: A randomized controlled trial
Authors: Kang B , Moon J S , Lee Y J , Kim M J , Choe B H , Ko J S , Park J H , Choe Y H 
Published: January 2023

Abstract

Background
Proactive dosing based on drug monitoring of adalimumab has been reported to be associated with higher rates of clinical remission in children with Crohn’s disease (CD). We aimed to investigate whether proactive drug monitoring of infliximab (IFX) is associated with higher rates of endoscopic healing (EH) in paediatric patients with CD.

Methods
We conducted a nonblinded, randomized controlled trial of 112 children with CD who were biologic naïve and had responded to induction treatment with IFX at 4 centers in South Korea from July 2017 to November 2020. Patients were randomly assigned to groups that received dosing based on proactive monitoring or clinically based dosing. The primary endpoint was EH at 1 year treatment.

Results
The primary endpoint was achieved in 80.0% (40/50) of the proactive dosing group and 57.1% (28/49) of the clinically based dosing group (P = 0.025). Transmural healing was achieved in 37.8% (17/45) of the proactive dosing group and 30.8% (12/39) of the clinically based dosing group (P = 0.657). Sustained corticosteroid-free clinical remission was achieved in 89.5% (51/57) of the proactive dosing group and 70.9% (39/55) of the clinically based dosing group (P = 0.025). Sustained durability of infliximab was observed in 94.7% (54/57) of the proactive dosing group and 92.7% (51/55) of the clinically based dosing group (P = 0.714).

Conclusion
Dosing based on proactive monitoring was superior to clinically based dosing in terms of endoscopic healing in a randomized controlled trial of paediatric CD.
P002 Exclusive Enteral Nutrition, the gut microbiome and corticosteroid response in patients with acute severe colitis
Authors: Bajaj A , Markandey M , Vuyyuru S , Mohta S , Singh M , Verma M , Kumar S , Kante B , Kumar P , Makharia G , Kedia S , Travis S , Ahuja V 
Published: January 2023

Abstract

Background
Supplementation with exclusive enteral nutrition (EEN) in addition to standard of care with intravenous corticosteroids (SOC) augments the steroid response in patients with acute severe ulcerative colitis (ASUC). EEN is known to alter gut microbial composition. The present study identifies changes in gut microbiota driven by EEN in patients with ASUC receiving standard steroid therapy and examines correlations between EEN-associated bacteria and response to corticosteroid therapy.

Methods
Stool samples were collected at baseline (Day0) and post-therapy (Day 7) from 44 patients with ASUC who received either SOC (n=24) or SOC supplemented with EEN (n=20) for a period of 7 days, at baseline (Day 0) and post-therapy (Day-7). Microbiome characterization was carried out using 16S rRNA gene sequencing followed by data processing using QIIME2 and R packages to analyze diversity and differentially abundant taxa.

Results
Seven-day EEN supplementation of SOC in patients with ASUC resulted in enhanced proportions of Methylobacterium, Sphingomonas, Limosilactobacillus, Megamonas, Thermus, Viellonella, with a reduction in Ruminococcus gnavus, Gemmiger, Pseudomonas, and Enterococcus. EEN-mediated enhancement in specific taxa correlated positively with patients’ day-7 serum albumin levels and negatively with day-3 faecal calprotectin levels (FCal) (Fig.1). Gut microbial composition of patients who responded to EEN-augmented SOC showed an enhanced abundance of Coprococcus, Megamonas, Oribacterium, Sediminibacterium, Acidibacter, and Thermus, and reduction in Sutterella, R. gnavus, Collinsella, Dorea, and Morganella, when compared to non-responders (Fig.2). Baseline gut microbiome signature in patients with ASUC predicts a potential response to both SOC and EEN-supplemented SOC in patients with ASUC (Fig.3).

Conclusion
Augmentation of clinical response by EEN-conjugated corticosteroid therapy is accompanied by specific gut microbial changes in patients with ASUC.
P038 Notch pathway in fibrosis: a new anti-fibrotic therapy in Crohn's disease?
Authors: Marti-Chafer S , Jimenez-Mallen E , Mendoza T , Macias-Ceja D C , Bauset C , Seco-Cervera M , Calatayud S , Cosin-Roger J , Barrachina M D , Ortiz-Masiá D 
Published: January 2023

Abstract

Background
Fibrosis represent the main complications related to Crohn's disease (CD). Notch signalling mediate fibrogenic process, including epithelial-mesenchymal transition (EMT) and fibroblast senescence but its role in CD fibrosis is currently unknown. Previous studies have shown a high expression of NOTCH4, NOTCH3, DLL3 and DLL4 in CD fibrotic tissue. DLL4 mainly activates transcription factors involved in EMT, and macrophages could act as a possible source of DLL4 (Edo, et al., 2022. JCC (i200)).The general aim of the present study is to determine the possible potential of Notch pathway as a therapeutic target in intestinal fibrosis associated with CD. Specifically, we pretend: to analyze the localization of NOTCH3/4 receptors in the intestinal tissue of patients with CD complicated; to study the relevance of NOTCH3/4 receptors in the EMT; to study the relevance of Notch pathway in the senescence of intestinal fibroblast.

Methods
We have analyzed in intestinal samples from CD patients with complicated lesions: the localization of NOTCH3/4 receptors by IH and the protein expression of senescence markers (BCL2 and P53) by WB. We carry out in vitro studies and analyze: the protein expression of HES1 (effector Notch pathway) and EMT markers in DLL4-HT29 treated cells transfected with miNOTCH3 or miNOTCH4; and the protein expression of senescence proteins in HSIF fibroblasts treated with DLL4 or DLL3.

Results
NOTCH3 was located preferentially in muscular areas -muscularis mucosa, endothelium and muscularis externa- with a striking staining of infiltrated cells in the mucosa of the unaffected area. NOTCH4 is found more specifically in the crypts of the mucosa, as well as in cells of the lamina propria of the unaffected mucosa. The expression of senescence proteins in the tissue showed elevated levels of BCL2 and P53, compared to the unaffected tissue of the same patient. DLL4 increased the protein expression of EMT markers in HT29 cells, and NOTCH4 silencing significantly reverted the expression of these EMT markers. NOTCH3 silencing produced no significant changes after DLL4-HT29 treatment. DLL3, and not DLL4, produced in intestinal fibroblasts a significant increase in the protein expression levels of BCL2, and P53, compared to the vehicle (Figure).

Conclusion
NOTCH pathway is involved in the regulation of key cellular functions and processes essential for the pathogenesis of intestinal fibrosis in CD patients. DLL4-NOTCH4 interaction triggers transcription factors involved in mesenchymal epithelial transition in colonic epithelial cells, while DLL3 seems to have a more relevant role in activation of senescence in fibroblasts.
P066 ON104, a novel bioengineered antibody targeting oxidized Macrophage Migration Inhibitory Factor (oxMIF) shows efficacy in two distinct models of experimental colitis
Authors: Ferhat M , Mangano K , Nicoletti F , Landlinger C , Michael T 
Published: January 2023

Abstract

Background
Macrophage Migration Inhibitory Factor (MIF) is a pleiotropic inflammatory cytokine and a primary counter-regulator of glucocorticoids (GCs) that emerged as a pivotal regulator of chronic inflammation including inflammatory bowel diseases (IBD). MIF occurs in two immunologically distinct, conformational isoforms: reduced MIF, ubiquitously present in various tissues and the circulation of healthy subjects, and oxidized MIF (oxMIF), described as the pathogenic and druggable isoform of MIF. In this study we evaluated the anti-inflammatory effects of the anti-oxMIF antibody ON104 in two different mouse models of colitis.

Methods
The fully human antibody ON104, which specifically targets oxMIF, was generated by advanced antibody engineering technology. The therapeutic potential of the Fc-silenced ON104 antibody was tested in two different models of colitis in mice: the acute model of DSS-induced colitis in C57BL/6 mice and the chronic model of adoptive T-cell transfer in SCID mice. At disease induction, ON104 was given twice a week for 8 weeks (chronic colitis) or three times for 1 week (acute colitis). Body weight, stool consistency, and rectal bleeding were assessed to evaluate colitis severity. At the end of the DSS-induced colitis model, colons were dissected for immuno-histological examinations.

Results
ON104 antibody, specifically directed against oxMIF, was completely devoid of Fcγ receptors binding and cytokine triggering in the presence of immune cells. Treatment with ON104 in the chronic colitis model substantially attenuated clinical signs of colitis by thwarting body weight loss and restoring stool consistency. In the acute DSS colitis model, oxMIF neutralization was able to reduce mucosal thickness and colonic immune cell infiltration compared to vehicle-treated mice.

Conclusion
Our findings substantiate the role of oxMIF in the pathogenesis of experimental colitis. Thus, targeting oxMIF may represent a new and promising treatment option for IBD.
P086 Sirtuin 7 inhibitor attenuates colonic mucosal immune activation in mice–potential therapeutic target in Inflammatory Bowel Disease
Authors: Kim S H , Jeen Y T , Jeon H J , Kim E S , Keum B , Chun H J 
Published: January 2023

Abstract

Background
Accumulating evidence has shown that sirtuin 7 (SIRT7), a mediator of various cellular activities, plays an important role in the pathogenesis of various immune-mediated inflammatory disorders. However, information remains limited regarding the role of SIRT7 in intestinal inflammation. We used a murine colitis model to investigate the role of SIRT7 in intestinal immunity and whether SIRT7 inhibitors could attenuate the intestinal inflammatory response.

Methods
Mice were divided into three groups: control, colitis-induced, and SIRT7 inhibitor-treated. A colitis mouse model was established by intraperitoneal injection and nasal challenge with ovalbumin, as in our previous study. Quantitative analyses of inflammatory cytokines and SIRT7 levels in the colonic mucosa were performed to compare the changes in inflammatory responses between the three groups.

Results
The colitis group showed increased levels of inflammatory cytokines and SIRT7 in the colonic mucosa. The inflammatory reaction was suppressed in colitis-induced mice administered SIRT7 inhibitor. The qRT-PCR results showed normalization of inflammatory cytokines in the SIRT7 inhibitor-treated group. Histologic study revealed a decrease in the extent of inflammation after SIRT7 treatment. We also observed that the degree of clinical inflammation was improved in SIRT7-treated mice.

Conclusion
Our study demonstrated that SIRT7 inhibition attenuated the inflammatory response in the colon of mice, suggesting a possible role for SIRT7 in the pathogenesis of immune-mediated intestinal inflammation.
P090 Low-density neutrophils are higher in individuals with active ulcerative colitis
Authors: Mendieta Escalante E A , Barrera-Vargas A , Torres-Ruiz J J , Merayo-Chalico F , Dijkstra G , Faber K N , Yamamoto Furusho J K 
Published: January 2023

Abstract

Background
Introduction: Neutrophils and neutrophil extracellular traps (NETs) play a significant role in the pathogenesis of ulcerative colitis (UC), a chronic and relapsing inflammatory disease of the colon. Low-density neutrophils (LDNs) are a recently identified subset of neutrophils that are more prone to develop NETs and produce more pro-inflammatory cytokines and calprotectin than neutrophils of normal density. Moreover, LDNs show reduced phagocytotic activity towards bacteria. LDNs are subclassified as mature (CD15+CD14-CD10+) and immature (CD15+CD14-CD10-) based on CD10 expression, of which the immature LDNs are most pro-inflammatory. LDNs have been identified in a number of autoimmune diseases, including systemic lupus erythematosus, psoriasis, antineutrophil cytoplasmic antibody-associated vasculitis, and rheumatoid arthritis, but not yet studied in UC.

Objective
Examine the existence of LDNs in UC patients and their possible association to disease severity.

Methods
A total of 13 healthy controls and 20 patients with UC were included. Their clinical activity was evaluated with the Truelove-Witts score. LDNs and subtypes were quantified by flow cytometry in the peripheral blood mononuclear cells (PBMC).

Results
The relative abundance of LDNs was significantly higher in UC patients compared to healthy controls (1.55±1.14 vs. 0.62±0.36 respectively, P&lt;0.05). Moreover, LDNs numbers were higher in UC patients with active disease compared to those in remission (2.67±1.36 vs. 1.09±0.55; P&lt;0.05) (Figure 1). The abundance of immature (CD15+CD14-CD10-) LDNs positively correlated with the Truelove-Witts index (rho=.530, P&lt;0.05) and fecal calprotectin levels (OR=1.2, P&lt;0.05, CI=1-1.36) as illustrated in Figure 2.
Figure 1

Figure 2

Conclusion
LDNs levels are elevated in PBMCs of patients with UC and pro-inflammatory immature LDNs are associated with disease activity.
P107 Decreased epithelial keratinization contributes to defective wound healing in Crohn's disease fistula
Authors: Becker drs. M , Koelink P , Bemelman W , D'Haens G , Buskens C , Wildenberg M 
Published: January 2023

Abstract

Background
Up to 30% of Crohn's Disease (CD) patients suffer from perianal fistula creating a high disease burden. Treating CD fistula is challenging compared to cryptoglandular fistula, which have a significantly better wound healing response. Previous studies suggested epithelial to mesenchymal transition as an inducer of fistula formation, as markers were observed in fistula tracts. However, most studies compared CD fistula to normal mucosa, thus disregarding whether any observed difference was in fact a sign of healing (as CD fistula will have more active healing than uninjured mucosa) or a sign of pathology (as healing is not occurring effectively). Therefore, in this study we evaluated CD fistula, as well as both healthy mucosa (no active healing) and cryptoglandular fistula (effective healing) in order to determine the role of differences found.

Methods
Biopsies from the internal opening (n=20) of perianal fistula of CD patients were collected and compared to two publicly available datasets obtained from un-inflamed rectum (RISK cohort and GSE83245). In addition, curettage material of CD (n=54) and cryptoglandular fistula (n=15) was obtained. Expression profiling was performed using RNASeq.

Results
Comparing the mucosa at the internal opening of CD fistula to publicly available datasets of healthy rectum, 770 genes were differentially expressed. Pathway analysis revealed upregulation of proliferative and inflammatory processes, consistent with expected immune and wound healing responses. Interestingly, strongest upregulation was seen for processes of cornification and keratinization, including expression of IVL (involucrin) and FLGR2 (fillagrin2), involved in keratinocyte differentiation.
To evaluate whether this was contributing to active wound healing or rather to persistent disease, we analyzed the actual tract in CD and cryptoglandular fistula. Strikingly, cornification and keratinization processes were more pronounced in cryptoglandular fistula, suggesting a role in effective healing rather than the persistent pathology seen in CD. Similar data was observed for TGFb, previously detected in CD fistula and thus considered a pathological contributor. While we confirm increased TGFb activity in CD fistula compared to normal mucosa, activity in cryptoglandular fistula tracts was higher than in CD fistula tracts. Again, this would suggest TGFb signaling as part of the wound healing response rather than part of the pathogenic mechanism.

Conclusion
Perianal fistulas show upregulation of keratinization and cornification pathways compared to healthy mucosa. Comparing CD and cryptoglandular fistula, we saw more cornification in the better healing cryptoglandular fistula, suggesting involvement in effective healing rather than pathology.