Introduction

Acute severe colitis (ASC) is an important cause of morbidity and mortality in Ulcerative Colitis (UC), requiring hospitalisation and, frequently, colectomy. Intravenous corticosteroids (CS) remain the first-line medical treatment. Approximately 40% of episodes of ASC do not respond to this treatment and require rescue therapy with ciclosporin (CIC) or infliximab (IFX)¹. In the past decades, these treatments and protocol-driven management algorithms led to reduced mortality and colectomy rates. A simple clinical scoring system (the Admission Model for the Intensification of Therapy in Acute Severe Colitis (ADMIT-ASC))³, based on CRP, albumin, and the Ulcerative Colitis Endoscopic Index of Severity (UCEIS) score, was recently developed to predict the steroid response on admission.

Aims & Methods

We aimed to retrospectively assess the steroid non-response during admission with ASC and the usefulness of the new prognostic clinical index ADMIT-ASC at admission to predict steroid response in a Belgian tertiary center. All patients admitted with ASC between 1^st January 2015 and 1^st April 2023 were identified from our inflammatory bowel disease database at Erasme University Hospital. Inclusion criteria were ASC patients admitted at the hospital, standard treatment with at least 3 days of intravenous CS and endoscopy evaluation upon admission. ASC was defined according to modified Truelove and Witts’ criteria as ≥6 bloody stools/day with one or more markers of systemic disturbance (tachycardia >90 beats/min, temperature >37.8°C, haemoglobin <105 g/L or CRP >30 mg/L). Steroid non-response was defined as the need for medical rescue therapy (CIC of IFX) or colectomy during the admission. ADMIT-ASC index consists of four points: CRP ≥100 mg/L (1 point), albumin ≤25 g/L (1 point) and UCEIS score ≥4 (1 point) or ≥7 (2 points).

Results

Table I Admission Demographics data (n= 84)	Steroid response (n=49)	Steroid non-response (n=35)	P value
Median disease duration (years) (IQR)	3.6 (0.3-0.9)	2.1 (0.8-5.5)	0.5
Montreal Classification	E1 : 5/49 (10%) E2 : 20/49 (41%) E3 : 24/49 (49%)	E1 : 0/35 E2 : 12/35 (34%) E3 : 23/35 (66%)	0.084
5-ASA, n (%)	22 (45%)	10 (29%)	0.13
Methotrexate or thiopurine, n (%)	6 (12%)	9 (26%)	0.11
Infliximab, n (%)	4 (8.2%)	8 (23%)	0.058
Vedolizumab, n (%)	7 (14%)	5 (14%)	>0.9
Tofacitinib, n (%)	2 (4.1%)	2 (5.7%)	>0.9
Readmission, n (%)	12 (24%)	10 (29%)	0.7
5-ASA, 5-aminosalicylate P values from Wilcoxon rank-sum test or Fisher’s exact test.

Out of 127 patients admitted with UC and treated with intravenous CS during three days, 84 (45% male, median age of 31 years old) were included in the study. Admission demographics and clinical characteristics are described in Table 1.
For 17 patients (20%), the admission was their index presentation of UC. Response to CS was seen in 49 patients (58%). Thirty-three patients (39%) received medical rescue therapy (17/33 IFX and 16/33 CIC). Colectomy rate during admission was 13% after a median duration of 18 days (IQR: 16-54). Admission C reactive protein (CRP) (p=0.036), albumin (p=0.026) and UCEIS scores (p=0.022) were significantly associated with steroid non-response. Patients scoring 0, 1, 2, 3 and 4 had steroid response rates of 90%,75%, 55%, 19% and 0%, respectively. Scoring of ≥3 was 75% (95% CI, 0.43 to 0.95) predictive of steroid failure (OR 5.08, 95%, CI 1.38 to 24.5).

Conclusion

In this tertiary referral cohort study, we confirmed that the ADMIT-ASC index is a simple clinical tool that can be used on the day of admission to predict steroid non-response in ASC with a threshold of ≥3 to identify patients who are unlikely to respond to intravenous CS and enabling timely treatment escalation or surgery.

References

1. Travis S, Satsangi J, Lémann M. Predicting the need for colectomy in severe ulcerativecolitis: a critical appraisal of clinical parameters and currently available biomarkers. Gut 2011;60:3–9.
2. Travis SP, Farrant JM, Ricketts C, et al. Predicting outcome in severe ulcerative colitis.Gut 1996;38:905–10.
3. Adams A, Gupta V, Mohsen W, et al. Gut 2023;72:433–442.

Disclosure

VB has not disclosure.
CDT has not disclosure.
CM has not disclosure.
AC has received lecture fees from Galapagos, Abbvie, Janssen, celltrion, Pfizer, Takeda.
DF has received lecture fees from Abbvie, Astrazeneca, Dr.Falk Pharma, Ferring, Janssen, Mundipharma, MSD, Pfizer, Takeda, Amgen, and advisory board fees from Abbvie, Janssen,Takeda, Celltrion, Amgen.
CL has received consultancy fees from Janssen, Abbvie, Takeda and Galapago and speaker fees from Sandoz, Janssen, Abbvie

Introduction

Endoscopic ultrasound-guided biliary drainage (EUS-BD) is reported to be useful as an alternative treatment for patients who are unable to undergo transpapillary bile duct drainage. EUS-hepaticogastrostomy (HGS), which involves a transgastric approach to the left intrahepatic bile duct, has been suggested as the first-line approach for EUS-BD because of a lower risk of bile leakage in patients with dilated intrahepatic bile ducts. However, there are few reports comparing the effectiveness and safety of EUS-BD procedures between EUS-HGS and EUS-HGS with antegrade stenting (EUS-AS+HGS).

Aims & Methods

Therefore, we compared the efficacy and safety of EUS-AS+HGS and EUS-HGS as drainage methods in EUS-BD. From April 2017 to December 2020, we retrospectively evaluated patients who underwent EUS-AS+HGS or EUS-HGS in our hospital for unresectable malignant biliary obstruction for which transpapillary biliary drainage had failed. We compared the time to recurrence of biliary obstruction (TRBO), overall survival, technical success rate, clinical success rate, adverse event rate, reintervention rate, and length of hospital stay between each procedure.

Results

A total of 68 patients, 22 in the EUS-AS+HGS group and 46 in the EUS-HGS group, were included in the study. In the EUS-HGS group, 38 patients underwent HGS only, while EUS-AS+HGS was attempted in another 8 patients who ultimately underwent EUS-HGS because of unsuccessful guidewire penetration. In the EUS-AS+HGS group, the TRBO was significantly longer, and the re-intervention rate significantly lower than in the EUS-HGS group (both p=0.03). However, there were no significant differences in technical success rate, overall survival, clinical success rate, adverse event rate, and length of hospital stay.

Conclusion

EUS-AS+HGS was superior to EUS-HGS regarding the length of biliary patency and re-intervention rate in patients with unresectable malignant biliary obstruction. The results suggest that EUS-AS+HGS is the preferred treatment when guidewire penetration of the biliary stricture is possible.

Introduction

Non-variceal upper gastrointestinal bleeding (NVUGIB) is a common gastroenterological emergency associated with significant morbidity and mortality [1-3]. Upper gastrointestinal endoscopy is currently recommended as the gold standard modality for both diagnosis and treatment [4]. As historically played a limited role in the diagnosis of acute NVUGIB, multidetector-row computed tomography angiography (MDCTA) is emerging as a promising tool in the diagnosis of NVUGIB, especially for severe cases [5-6]. However, to date, evidence concerning the role of MDCTA in the NVUGIB diagnosis is still lacking.

Aims & Methods

The purpose of this study was to retrospectively investigate the diagnostic performance of emergent MDCTA performed prior to any diagnostic modality or following urgent upper endoscopy to identify the status, the site and the underlying etiology of severe NVUGIB. Institutional databases were reviewed in order to identify severe acute NVUGIB patients who were admitted to our bleeding unit and were referred for emergent MDCTA prior to any hemostatic treatment (<3 hours) or following (<3 hours) endoscopy, between December 2019 and October 2022. The study aim was to evaluate the diagnostic performance of MDCTA to detect the status, the site and the etiology of severe NVUGIB with endoscopy, digital subtraction angiography, surgery, pathology or a combination of them as reference standards.

Results

A total of 68 patients (38 men, median age 69 years [range 25–96]) were enrolled. The overall MDCTA sensitivity, specificity, and accuracy to diagnose bleeding status were 77.8% (95% CI: 65.5-87.3), 40% (95% CI: 5.3-85.3), and 75% (95% CI: 63.0-84.7), respectively (Table 1). Finally, the overall MDCTA sensitivity to identify the bleeding site and the bleeding etiology were 92.4% (95% CI: 83.2-97.5) and 79% (95% CI: 66.8-88.3), respectively.

Table 1. The diagnostic performance of MDCTA in detecting bleeding status.

	Active (n = 40)	Recent (n = 26)	Non-active and non-recent (n = 2)	Total (n = 68)
TP	29	20	-	49
TN	-	-	2	2
FP	0	3	-	3
FN	11	3	0	14
Sensitivity (95% CI)	72.5 (56.1-85.4)	87.0 (66.4-97.2)	-	77.8 (65.5-87.3)
Specificity (95% CI)	-	-	100 (15.81-100)	40.0 (5.3-85.3)
PPV (95% CI)	100 (88.1-100)	87.0 (66.4-97.2)	-	94.2 (84.1-98.8)
NPV (95% CI)	-	-	100 (15.81-100)	12.5 (1.55-38.4)
Accuracy (95% CI)	-	-	-	75 (63.0-84.7)

TP, true positive; TN, true negative; FP, false positive; FN, false negative; CI, confidence interval; PPV, positive predictive value; NPV, negative predictive value.

Conclusion

MDCTA seems to be a feasible and effective modality in detecting the site, the status and the etiology of severe acute NVUGIB. It may play a crucial role in the management of selected cases of NVUGIB, especially those clinically severe and/or secondary to rare and extraordinary rare sources, effectively guiding timing and type of treatment. However, further large prospective studies are needed to clarify the role of MDCTA in the diagnostic process of acute NVUGIB.

References

1. Wuerth BA, Rockey DC. Changing Epidemiology of Upper Gastrointestinal Hemorrhage in the Last Decade: A Nationwide Analysis. Dig Dis Sci 2018; 63: 1286–1293.
2. Laine L, Yang H, Chang S-C, et al. Trends for incidence of hospitalization and death due to GI complications in the United States from 2001 to 2009. Am J Gastroenterol 2012; 107: 1190–1195; quiz 1196.
3. Sanders DS, Perry MJ, Jones SGW, et al. Effectiveness of an upper-gastrointestinal haemorrhage unit: a prospective analysis of 900 consecutive cases using the Rockall score as a method of risk standardisation. Eur J Gastroenterol Hepatol 2004; 16: 487–494.
4. Gralnek IM, Stanley AJ, Morris AJ, et al. Endoscopic diagnosis and management of nonvariceal upper gastrointestinal hemorrhage (NVUGIH): European Society of Gastrointestinal Endoscopy (ESGE) Guideline - Update 2021. Endoscopy 2021; 53: 300–332.
5. Napoli A, Fleischmann D, Chan FP, et al. Computed tomography angiography: state-of-the-art imaging using multidetector-row technology. J Comput Assist Tomogr 2004; 28 Suppl 1: S32-45.
6. Wu L-M, Xu J-R, Yin Y, et al. Usefulness of CT angiography in diagnosing acute gastrointestinal bleeding: a meta-analysis. World J Gastroenterol 2010; 16: 3957–3963.

Disclosure

No conflict of interest to declare.

Introduction

Therapeutic progress in inflammatory bowel disease (IBD) is limited by the lack of understanding of the pathophysiology and the mechanisms involved in response or lack/loss of response to treatments. IBD patients are treated with anti-inflammatory drugs, including biologics such as anti-tumor necrosis factor (TNF) agents, which have been crucial in achieving steroid-free remission and prevention of long-term complications. However, a significant subgroup of patients becomes refractory to these biologicals due to the development of immunogenicity, characterized by the presence of anti-drug antibodies (ADAs). The antibody production and peripheral tolerance are initiated and maintained within lymphoid organs, such as the peripheral lymph nodes, but the exact role of immune cells in these lymphoid structures and whether they are involved in anti-drug antibody (ADA) formation is unknown.

Aims & Methods

We aimed to unravel the pathophysiology behind the development of anti-drug antibodies. Therefore, we performed ultrasound-guided inguinal lymph node needle biopsies from which we isolated leukocytes along with PBMCs from the same patients. Leukocyte populations were analyzed at single cell level via high dimensional phenotyping through mass cytometry (CyTOF).

Results

Using this unique approach, we have so far results from 4 Crohn’s Disease (CD) patients with ADAs (75% females, 50% active disease) and 4 without ADAs (50% females, 75% active disease). Active disease was defined, as an observation of an elevated CRP (c-reactive protein) (>5 mg/L) and/or calprotectin >250 (mg/kg), including symptoms (Harvey-Bradshaw index score > 4 or disease activity index score-CDAI >150).
The proportion of CD4⁺ TEMRA (terminally differentiated effector memory T-cells), CD4⁺ effector and central memory T-cells were increased in the peripheral lymph nodes of patients that developed immunogenicity. Mature NK cells, classical and non-classical monocytes were also increased. Furthermore, the levels of the alpha-4 integrin expression were higher in the lymph node T-lymphocytes, as well as, in the lymph node naïve and memory B-cell subsets in the patient group with ADAs.

Table: Cytometry and Biochemical Characteristics.

Parameters	ADAs (n=4)	no ADAs (n=4)	p-value
Proportion of Lymph Node CD4+ TEMRA T-Cells; median (Range)	5.3 (1.05-16.5)	0.16 (0.1-0.39)	0.02
Proportion of Lymph Node CD4+ Effector Memory T-Cells; median (Range)	3.2 (0.64-7.2)	0.5 (0.14-1.37)	0.049
Proportion of Lymph Node Mature NK-Cells; median (Range)	4.04 (0.49-5.17)	0.08 (0.05-0.2)	0.029
Proportion of Lymph Node Classical Monocytes; median (Range)	4.8 (1.47-16.9)	0.8 (0.91-1.1)	0.027
Proportion of Lymph Node Non Classical Monocytes; median (Range)	6.9 (0.99-9.4)	0.9 (0.68- 0.99)	0.026
Mean alpha-4 Integrin Expression Levels (Effector T-cells)	1.61	0.87	0.03
Mean alpha-4 Integrin Expression Levels (Memory B-cells)	1.58	0.94	0.03
CRP (c-reactive protein) (mg/l); median (Range)	2.85 (0.5-8.5)	3.90 (0.7-14.75)	0.396
Calprotectin (mg/kg); median (Range)	650 (228-1130)	1007 (476-2037)	0.17

Conclusion

Lymph node T-helper cells, monocytes and NK cells potentially play a role in the development ADAs in IBD patients treated with biologics. Although, there was no significant difference in the proportion of naïve and memory B-cells, our findings concerning the alpha-4 integrin expression levels also indicate that both lymph node T and B-lymphocytes, are possibly characterized by a higher migratory potential during immunogenicity conditions.

References

1. Stein RE, Lee DY, Leonard MB, et al. The association between drug levels, anti-drug antibodies, and therapeutic response during infliximab therapy in pediatric Crohn’s disease. J Crohns Colitis 2014; 8: S434.
2. Bodini G, Savarino V, Dulbecco P, et al. The influence of anti-adalimumab antibodies on adalimumab trough levels, TNF-alpha levels and clinical outcome. J Crohns Colitis 2014; 8: S42
3. Stefan S, Sandborn WJ, Choi J, et al. Anti-drug antibodies separate responses of markers of inflammation (c-reactive protein, fecal calprotectin) in Crohn’s disease patients treated with certolizumab pegol. Inflamm Bowel Dis 2014; 20: S68.
4. Strand V, Balsa A, Al-Saleh J, et al. Immunogenicity of Biologics in Chronic Inflammatory Diseases: A Systematic Review. BioDrugs. 2017;31(4):299-316. doi:10.1007/s40259-017-0231-8.
5. Brun MK, Goll GL, Jørgensen KK, et al. Risk factors for anti-drug antibody formation to infliximab: Secondary analyses of a randomised controlled trial. J Intern Med. 2022;292(3):477-491. doi:10.1111/joim.13495.

Disclosure

The authors state no conflict of interest.

Introduction

Inflammatory Bowel Diseases (IBD) are chronic inflammatory disorders characterised by alterations of acute relapses and remission. The past decades have brought substantial advances in the pharmacological management of IBD by the introduction of immunosuppressive agents, biologics and lately small molecules. Although, the sustained efficacy of the currently available anti-inflammatory therapies is still far from optimal. Therefore, the development of novel therapies represents a major unmet clinical need in this field. Recently the enrichment of the coagulation pathway genes and among these, plasminogen activator inhibitor 1 (PAI-1) was described in IBD, whereas PAI-1 emerged as a link between the epithelium and inflammation. Moreover, the genetic deletion of PAI-1 impaired the severity of experimental colitis in mice.

Aims & Methods

Based on these, our aim was to develop and test novel PAI-1 inhibitors for the treatment of IBD. Novel, peptide-based PAI-1 inhibitors were designed and screened in silico, then the selected ones were synthetized using the ixPeptide® platform. The inhibitory potential of the peptides was determined by an in vitro PAI-1 activity assay. Cytotoxicity was monitored in vitro in Hela cells with the CellTiter Glo assay. Based on the in vitro results LDN-071 was selected for further analysis. Experimental colitis was induced in mice with 3% DSS and after the induction of colitis 10 mg/bwkg LDN-071 was administrated per os for four consecutive days. The changes of body weight, spleen weight and colon length were measured. Haematoxylin eosin (HE) and Periodic acid-Schiff (PAS) staining were performed for histology. ELISA and qRT-PCR measurements were applied to analyse the mucosal cytokine expressions. In vivo toxicity of LDN-071 was determined in mice.

Results

LDN-071 significantly inhibited PAI-1 in vitro without decreasing the cell viability in a concentration range of 1µM-1mM. The administration of 10 mg/bwkg LDN-071 in the DSS-treated mice prevented the body weight loss, the development of bloody diarrhoea, the decrease of colon length and increase of the spleen weight, which were displayed by the DSS+vehicle-treated animals. The histological analysis of the colon revealed that DSS treatment induced a severe transmural inflammation, ulceration, loss of crypt structures and goblet cell depletion. Importantly, all of these parameters were significantly impaired by the administration of 10 mg/bwkg LDN-071. Additionally, mucosal gene and protein expressions of TNF-α, IL-1β and IL-6 were significantly impaired by PAI-1 inhibition. Importantly, no signs of toxicity were LDN-071 observed in mice exposed to 100 mg/bwkg LDN-071 for 7 days.

Conclusion

Our results showed that LDN-071, a novel peptide-based inhibitor of PAI-1. It significantly reduces the severity of experimental colitis in mice. We propose that the inhibition of PAI-1 could be a potential novel therapeutic strategy in IBD.

Disclosure

LDN-071 PAI-1 inhibitor is owned by Ladon Therapeutics Ltd.