Introduction

The incidental finding of terminal ileal inflammation during routine colonoscopy is not uncommon and is of unclear significance. It has been reported among asymptomatic persons undergoing non-diagnostic colonoscopy. There is limited data on long term follow-up and outcomes of such findings.(1)

Aims & Methods

This is a monocentric retrospective observational study spanning from 2018 to 2023, comparing two periods: the first period (P1) before the impact of the Covid-19 pandemic in 2020, and the second period (P2) starting 2020 reflecting the impact the pandemic left on colonoscopies. For each patient, variables were collected from medical records.

Results

Our initial database included 11200 colonoscopies, from which we randomly selected 2394 patients proportionally to the annual activity (mean of 1686/year before 2020 and 1189/year after 2020). Among indications of colonoscopy were screening and follow-up, change in bowel habits, anemia and bleeding. We excluded 287 patients (known history of inflammatory bowel disease and no ileum intubation). Then the sample was divided into P1 (681 patients) and P2 (1483 patients). Characteristics and findings are shown in Table 1. We noted better bowel preparation (77.1 vs 91.7%) and a higher ileum intubation in P2 (79.7 in P1 vs 93.8% in P2).
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N=2164			P1 (N1=681)	P2 (N2= 1483)	p
Age (years)			57.5	56.9	NS
Overall endoscopic findings n(%)	Endoscopic aspect of ileitis		0 (0)	71 (5.8)	<0.001
	Abnormal ileal findings on histology		23 (3.4)	169 (11.4)	<0.001
	Diagnosis of Crohn's disease		0 (0)	19 (0.9)	<0.001
Overall histological findings n(%)	Active ileitis		19 (2.8)	147 (9.9)	<0.001
	Focal ileitis		10 (1.5)	89 (6)	<0.001
	Ulcerative ileitis		11 (1.6)	48 (3.2)	0.031
	Erosive ileitis		3 (0.4)	31 (2.1)	0.004
	Architectural distortion		1 (0.1)	16 (1.1)	0.023

Overall ileoscopy findings showed an increased aspect of ileitis on endoscopy (0% in P1 and 5.8% in P2, with p<0.001), correlating with a significant increase in the incidence of histological findings on ileal biopsies (3.4% in P1 vs 11.4% in P2; p<0.001). These histological findings included active, focal and ulcerative ileitis, with more architectural distortion. However, these results corresponded to a less severe ileitis (0.3 vs 2.3%; p=0.001). Nineteen of these patients with positive results of ileitis were diagnosed with Crohn’s disease.

Conclusion

This study showed an increase in endoscopic and histologic ileitis on colonoscopy following the Covid-19 era. This could be the result of the direct virologic effect that the virus has on intestinal inflammation, its indirect effect on immunity triggering the onset of enteritis, or the consequence of the mass vaccination campaign held to protect from the virus. Furthermore, histology showed granulomatous inflammation similar to Crohn’s disease, which may lead to misdiagnosis and probably overtreatment.

References

1. Agrawal M, Miranda MB, Walsh S, Narula N, Colombel JF, Ungaro RC. Prevalence and Progression of Incidental Terminal Ileitis on Non-diagnostic Colonoscopy: A Systematic Review and Meta-analysis. J Crohns Colitis. 2021 Feb 14;15(9):1455–63.

Introduction

Urgency is not an IBD Patient Reported Outcome (PRO) in the STRIDE II but it has been assessed at baseline and as an outcome measure in recent pivotal RCTs with newer biologicals and targeted synthetic small molecules in both Crohn’s disease CD) and ulcerative colitis (UC). However, although it is reasonable to assume that UC patients or CD patients with rectal involvement may complain for severe urgency, urgency has been assessed even in patients with Crohn’s ileitis (iCD).

Aims & Methods

The aim of this study was to assess whether urgency is reported by iCD patients with flares or quiescent disease in a Real-World (RW) setting. This prospective, pilot, RW study included CD patients with solely L1 phenotype. L1 location was documented by ileocolonoscopy, histology and, imaging (MRE, US, or capsule endoscopy). Patients with colonic and/or rectal disease, perianal involvement and complicated ileal disease were excluded. Patients were interviewed by office visits during disease flare [HBI>5, CRP <5mg/dl, faecal calprotectin (FC)>250μg/g faecal tissue and SES-CD for terminal ileum >3 if colonoscopy was performed within a month prior to the visit) and during clinical remission (HBI<5, CRP <5mf/dl and FC <200μg/g and ileal SES-CD=0, in a recent ileocolonoscopy). The presence of and severity of urgency was recorded by a Symptom Rating Score of 0-10 (absent to very severe). The presence and severity of abdominal pain, the number and consistency of stools, nocturnal stools, blood and/or mucus in the stools, and the feeling of inadequate evacuation were sought by a structed questionnaire.

Results

During a 15-month period, 85 iCD patients [45 males, median age (range) 33 (18-65) years, median (range) disease duration 9 (0.6-25) years] were enrolled in the study. Patients were receiving a wide range of treatments, including anti-TNF agents (n=35), ustekinumab (N=25), vedolizumab (N=5), azathioprine (n=10), budesonide (n=5) and mesalazine (n=15). Fifty patients had a flare, 65 were in remissionand 30 patients were interviewed sequentially in flare and remission of disease. All patients in disease flare reported abnormal classical PROs of CD. Moderate to severe urgency [median score 5, range 4-8] was reported by 5/50 (10%) patients with disease flare, 8/65 (12%) patients with disease remission and 2/30 (6.5%) patients who were interviewed during flare and remission of disease. 3/50 patients with urgency during a flare of CD did not report urgency during disease remission. Six of the 8 patients who were interviewed only with iCD in remission and reported urgency had concurrently typical Irritable Bowel Symptoms (IBS, abdominal pain relieved by defecation, alternating diarrhoea/constipation, inadequate bowel emptying).

Conclusion

This prospective, pilot, real-world study shows that the reliability of urgency as classical PRO in patients with iCD is questioned and raises doubts whether urgency should be included in the spectrum of PROs for patients with iCD both in RCTs and in RW studies. Validation of the terminology in different ethnic languages may also pose additional barriers in patient understanding and reporting the symptom in the presence of additional IBS-type symptoms. Large studies are needed to assess if urgency is present in patients with iCD and how reliably is reported especially in multinational RCTs.

Disclosure

Dr GJ Mantzaris: Research grants: AbbVie, Genesis, Merck Sharp & Dohme, Takeda; advisor/speaker: AbbVie, Aenorasis, Dr Falk, Ferring, Hospira, Janssen, Merck Sharp & Dohme, MYLAN, Pfizer, Takeda, Vianex.
Dr A Loukou: Nothing to declare

Introduction

Tyrosine kinase 2 (TYK2) mediates cytokine signalling in immune-mediated inflammatory diseases, including Crohn’s disease (CD). Zasocitinib (TAK-279) is a highly selective, oral, allosteric TYK2 inhibitor with efficacy and acceptable safety shown in patients with psoriasis and psoriatic arthritis.^1,2 This phase 2b study (NCT06233461) aims to assess the efficacy and safety of zasocitinib in patients with moderately to severely active CD.

Aims & Methods

This is a multicentre, randomized, double-blind induction, placebo-controlled, dose-ranging, treat-through study in patients (18–75 years) with moderately to severely active ileal, ileocolonic or colonic CD (CD Activity Index [CDAI] score 220–450 and ulcerations characteristic of CD defined by ileocolonoscopy at screening and Simple Endoscopic Score for CD [SES-CD] ≥6 or ≥4 for isolated ileitis). Eligible patients must have inadequate/loss of response or intolerance to ≥1 of oral aminosalicylates, corticosteroids, immunosuppressants, biologics, JAK inhibitors (JAKi) or sphingosine-1-phosphate (S1P) receptor modulators. Patients who have also failed <3 classes of advanced therapies will be included. After screening (30 days), approximately 268 patients will be randomized 1:1:1:1 to receive low-, medium- or high-dose zasocitinib or placebo orally once daily for 12 weeks (induction phase), followed by a 40-week maintenance period and a 4-week safety follow-up. At or after Week 12, patients receiving placebo with disease worsening based on PRO2 score will receive active zasocitinib treatment. Study doses are expected to provide ≥90% TYK2 inhibition over the 24-hour dosing interval, and were associated with efficacy in preclinical models.³ Randomization will be stratified based on previous biologic, JAKi or S1P receptor modulator therapies, and steroid use at baseline. The number of patients who received previous biologic, JAKi, S1P receptor modulator, anti-interleukin (IL)-23p19 or anti-IL-12/23p40 therapy will be capped.
Primary endpoint analysis will be conducted using a Cochran–Mantel–Haenszel (CMH) test. Binary secondary endpoints will be analysed similarly to primary endpoints. Longitudinal continuous secondary endpoints up to Week 12 will be analysed using a mixed-effects model with repeated measures. Safety data will be presented by treatment group and assessment period.

Results

The study is actively enrolling with the first patient randomized in March 2024. An open-label extension is planned for zasocitinib responders. The primary efficacy endpoint is the achievement of endoscopic response at Week 12 (>50% decrease in SES-CD from baseline [for patients with isolated ileal disease: SES-CD ≤4 or ≥2-point reduction]). Secondary efficacy endpoints at Week 12 include: clinical remission (CDAI <150), clinical response (CDAI reduction from baseline of ≥100), endoscopic remission (SES-CD ≤4 or ≤2 for patients with ileal disease, no subscore >1), patient-reported symptoms and disease-specific health-related quality of life (HRQoL). Safety and tolerability will be assessed by treatment-emergent adverse events (AEs), serious AEs and AEs of special interest throughout the study. Intestinal ultrasound measurements, using the International Bowel Ultrasound Segmental Activity Score (IBUS-SAS), will be assessed at Weeks 4, 12 and 52 in a subset of patients.

Conclusion

Alongside evaluating the efficacy and safety of zasocitinib in patients with moderately to severely active CD, this unique 52-week treat-through study design will assess the impact of treatment on HRQoL, an area of significant unmet need in this population.

References

1. Armstrong A et al. AAD 2023.
2. Kivitz A et al. Arthritis Rheumatol 2023;75(Suppl 9).
3. Kong KF et al. J Crohns Colitis 2024;18(Suppl 18).

Disclosure

VJ has received: consulting/advisory board fees from AbbVie, Alimentiv, Arena Pharmaceuticals, Asahi Kasei Pharma, Asieris, AstraZeneca, Avoro Capital, Bristol Myers Squibb, Celltrion, Eli Lilly, Endpoint Health, Enthera, Ferring, Flagship Pioneering, Fresenius Kabi, Galapagos, Genentech, Gilde Healthcare, Gilead, GlaxoSmithKline, Innomar, JAMP, Janssen, Merck, Metacrine, Mylan, Pandion, Pendopharm, Pfizer, Prometheus Biosciences, Protagonist, Reistone Biopharma, Roche, Roivant, Sandoz, Second Genome, Sorriso, Synedgen, Takeda, TD Securities, Teva, Topivert, Ventyx and Vividion; and speaker fees from AbbVie, Bristol Myers Squibb, Ferring, Fresenius Kabi, Galapagos, Janssen, Pfizer, Shire and Takeda. VG, LZ, VN, OA, AND, FN, TF, LS and NS are employees and equity holders of Takeda.

Introduction

Cirrhosis is a chronic condition with a high mortality. Cirrhotic patients with portal hypertension frequently present with large esophageal varices with bleeding or need for endoscopic intervention. The choice of treatment for variceal hemorrhage is endoscopic ligation and beta-blockers, which can be used as secondary prophylaxis. The pleiotropic effects of statins have been reported for the treatment of cardiovascular diseases, but at the liver level they favor the reduction of the hepatic venous pressure gradient (HVPG), with a decrease in the number of variceal hemorrhage events; however, their use had been restricted in cirrhotic patients due to their association with elevations in liver biochemistries.

Aims & Methods

To evaluate the safety statins in cirrhotic patients with an indication for high cardiovascular risk. And as a secondary aim, determine the presence of variceal hemorrhage during follow-up. This retrospective cohort study was carried out by the "Centro Médico Nacional 20 de Noviembre" between 2018 to 2022. Child Pugh A and B cirrhotic patients with a history of variceal hemorrhage or large varices with endoscopic ligation intervention without active hemorrhage were included and observed over a period of 4 years. To determine adverse events, compatible clinical data and biochemical examinations were searched in the electronic record, and pharmacovigilance committee records were reviewed.

Results

A total of 106 patients were included, of which 53 with statin use and 53 without statins. The characteristics were 41.5% men (n=44), 58.5% women (n=62). The average age was 62 ± 10 years. In order of frequency, the causes were: cryptogenic 25.5% (n=27), hepatitis C virus (HCV) 21.7% (n=23), primary biliary cholangitis (PBC) 14.2% (n=15), metabolic dysfunction-associated fatty liver disease (MAFLD) 13.2% (n=14), alcohol 12.3% (n=13), autoimmune hepatitis (AIH) 11.3% (n=12), hepatitis B virus (HBV) 1.9% (n= 2). With Child Pugh A 67% (n=71) Child Pugh B 35% (n=33). In the statin and non-statin group, the average values of the following variables were PT 12.7 ±1.9 vs 14 ±2.2, AST 39.6 ±24 vs 61 ±40, ALT 37.6 ±28 vs 51 ±38, albumin 3.8 ±0.6 vs 3.6 ±0.5, total cholesterol 157.6 ±35 vs 179.4 ±68, INR 1.06 ±0.17 vs 1.1 ±0.18 (p=< 0.05) (Table 1). In the group of patients with statin use in 18.4% (n=10) Variceal ligation was performed, and in the group without statins, 24.5% (n=13), with a RR of 1.075, 95% CI (0.8-1.3). In the group of patients with statin use, 9.5% (n=5) had a bleeding event, and in the group without statins, 7.5% (n=4) had a bleeding event, with an RR of 1.25, CI 95% (0.3-4.4). None of the participants had clinical adverse effects.

Table 1. Demographics, selected clinical characteristics, and outcomes of patients

Characteristics	Statin treatment, % (n=53)	Without statin treatment, % (n= 53)	p
Sex Female Male	58.5 (31) 41.5 (22)	58.5 (31) 41.5 (22)
Etiology MAFLD PBC AIH HCV HBV ALCOHOL CRYPTOGENIC	11.3 (6) 11.3 (6) 9.4 (5) 22.6 (12) 1.9 (1) 13.2 (7) 30.2 (16)	15.1 (8) 17 (9) 13.2 (7) 20.8 (11) 1.9 (1) 11.3 (6) 20.8 (11)
Age (years)	63	61	0.320
Aspartate aminotransferase(U/L)	39.6	61	0.001
Alanine aminotransferase(U/L)	37.6	51.2	0.041
Albumin	3.8	3.6	0.045
Prothrombin time	12.7	14	0.002
Total cholesterol (mmol/L)	157.6	179.4	0.042
International normalized ratio	1.06	1.1	0.004

Conclusion

The use of statins in cirrhosis compensated with portal hypertension was safe. In this study we could not demonstrate the pleiotropic effect of statins, probably due to the sample size. Therefore, it is necessary to generate subsequent studies including a larger number of patients.

Disclosure

The authors declare that they have no conflict of interest.

Introduction

Gut microbiome alterations are known to be one of the pathogenic pathways of irritable bowel syndrome (IBS), mainly in its post-infectious form (PI-IBS) ¹. To date, untargeted therapeutic approaches have obtained conflicting results in patients with PI-IBS ^2,3
Gut microbiome testing are emerging as a promising diagnostic tool to target microbiota and offer a personalized therapeutic strategy, but their real value is still unknown.

Aims & Methods

Our aim is to evaluate whether a personalized approach based on gut microbiome testing is an effective strategy for PI-IBS.
In this pilot study, we included consecutive patients with PI-IBS, diagnosed according to the Rome IV guidelines⁴, referring at our outpatient microbiome clinic in 2022.
All patients underwent a commercially available stool microbiome testing (XMICROGem from XBIOGem) based on 16S rRNA analysis and performed as already described⁵. Then, patients received a targeted therapy based on results of the gut microbiome testing, with the aim of restoring balance among the bacterial subpopulations of the gut microbiota. Non-adsorbable antibiotics were used to downregulate the abundance of pathobionts, while prebiotics and probiotics were given to boost the abundance of specific taxa and/or to compete with gut pathobionts. Patients were followed up to 12 weeks after the end of therapy.
We collected the following data of patients: age, gender, presence of gastrointestinal (GI) symptoms (assessed with the GSRS); specific characteristics of gut microbiome (alpha diversity, abundance of Proteobacteria, Firmicutes, Bacteroidetes, Bifidobacteria, Lactobacilli, Akkermansia, and short-chain fatty acid producers including Lachnospiraceae, Faecalibacterium, Roseburia, Butyrivibrio); specific therapy given after testing, including non-adsorbable antibiotics, prebiotics, and probiotic strains. The primary outcome was the resolution of at list one symptom, while secondary outcomes were the resolution of more than one (if present) and all of them at 12 weeks.

Results

Thirteen patients were enrolled in the study period (8 males, 5 females, mean age 31 years-old). Of them, 9 (69%) had IBS-D and 4 (31%) IBS-C. Nine patients (69%) had bloating, and 10 (71%) had abdominal pain at baseline. At gut microbiome testing: three (23%) patients presented with low alpha diversity, three (23%) with high abundance of Proteobacteria, five (38%) of Firmicutes. Seven (54%) patients presented with low abundance of SCFA-producing bacteria, eight (62%) of Akkermansia and nine (69%) of Bifidobacteria.
Patients were treated with the following non-adsorbable antibiotics: rifaximin in nine (69%) patients, and paromomicin in four (31%) patients. The following prebiotics and probiotic strains were used after antibiotics: multispecies probiotics in five patients (38%), Bifidobacterium-based probiotics in five patients (38%), Lactobacillus-based probiotics in eight patients (54%), and Escherichia coli Nissle 1917 in 2 (15%) patients; inulin and psyllium were used in nine (69%) patients.
At 12-week follow-up, 12 patients (93%) experienced an improvement of symptoms, with five of them (38%) experiencing a total remission of symptoms.

Conclusion

A precision medicine approach based on gut microbiome testing may be a promising strategy to treat PI-IBS. Well designed, randomized and larger studies are needed to confirm our preliminary findings.

References

1. Downs, I. A., Aroniadis, O. C., Kelly, L. & Brandt, L. J. Postinfection Irritable Bowel Syndrome: The Links Between Gastroenteritis, Inflammation, the Microbiome, and Functional Disease. J Clin Gastroenterol 51, 869–877 (2017).
2. Lee, Y. Y., Annamalai, C. & Rao, S. S. C. Post-Infectious Irritable Bowel Syndrome. Curr Gastroenterol Rep 19, 56 (2017).
3. Jin, Y. et al. Beneficial effects of Rifaximin in post-infectious irritable bowel syndrome mouse model beyond gut microbiota. J Gastroenterol Hepatol 33, 443–452 (2018).
4. Drossman, D. A. Functional Gastrointestinal Disorders: History, Pathophysiology, Clinical Features, and Rome IV. Gastroenterology 150, 1262-1279.e2 (2016).
5. De Maio, F. et al. Characterization of gut microbiota in patients with metabolic syndrome candidates for bariatric/metabolic surgery: Preliminary findings of a multi-center prospective study. Diabetes Res Clin Pract 180, 109079 (2021).

Disclosure

G.I. has received personal fees for acting as speaker for Biocodex, Danone, Sofar, Malesci, Metagenics and Tillotts Pharma, and for acting as consultant and/or advisor for Ferring Therapeutics, Giuliani, Malesci and Tillotts Pharma.
A.G. reports personal fees for consultancy from Eisai Srl, 3PSolutions, Real Time Meeting, Fondazione Istituto Danone, SinergieSrl, Board MRGE and Sanofi SpA personal fees for acting as a speaker for Takeda SpA, AbbVie and Sandoz SpA and personal fees for acting on advisory boards for VSL3 and Eisai.
G.C. has received personal fees for acting as advisor for Ferring Therapeutics.
All other authors have no conflicts of interest to disclose.

Clinical Case Summary

EUS-BD is an alternative therapeutic approach in case of unsuccessful biliary drainage by ERCP (1,2). Our aim is to report another possible indication of EUS-BD as a salvage treatment in a case of post-ERCP perforation around the papilla.
This is a case-report of a 79-years-old woman admitted for obstructive jaundice with bilirubin levels of 18 mg/dL. A MRI displayed marked dilation of intrahepatic bile ducts, gallbladder and choledochus (18-mm) until its distal part where and abrupt stop and a regular stricture was observed. An ERCP failed to cannulate the common bile duct. After a precut procedure, retroperitoneal extravasation of the contrast was observed. After consultation with the surgical team and fully information to the family of the patient about therapeutic alternatives, an EUS-BD was performed immediately after the ERCP as a therapeutic approach aiming to treat simultaneously the perforation and the obstructive jaundice without delay.
EUS-BD was performed according to the standardized technique with a transgastric approach. The intrahepatic bile duct was puncture with a 19-gauge needle. A 0.025” guide-wire was inserted and the fistula was created using a 6French cystostome with pure current. After exchanging the guide-wire for another of 0.035” and passing it to the duodenum, a 6-cm long, fully-covered metal stent was deployed at the stricture as antegrade fashion.
A further CT-scan displayed no collections with decreasing of the bile duct dilation. The clinical outcome of the patient was uneventful, being discharged one-week after the EUS-BD.
One month later, a scheduled pancreaticoduodenectomy was performed. The surgical specimen showed a 4-mm wide distal cholangiocarcinoma.
EUS-BD with fully-covered metal stenting was effective to both drainage and covering perforation site. EUS-BD could be deemed as another potential indication in selected cases as an immediate rescue therapy after ERCP adverse events such as perforation.

References

Nakai Y, Isayama H, Wang HP, Rerknimitr R, Khor C, Yasuda I, et al. International consensus statements for endoscopic management of distal biliary stricture. J Gastroenterol Hepatol. 2020;35(6):967-79.
Huh G, Park DH. EUS-guided transhepatic biliary drainage for next-generation ERCPists. Gastrointest Endosc. 2022;95(3):452-4.

Disclosure

Rafael Romero-Castro is consultant to Cook Medical since February 28th, 2023.