Introduction

14-day non-bismuth concomitant (with amoxicillin, clarithromycin and metronidazole) and Bismuth-based quadruple therapy are recommended first-line empirical treatment for Helicobacter pylori (H. Pylori) eradication. Systematic use of susceptibility testing and tailored first-line treatment remains to be established.

Aims & Methods

We did a multicentre, parallel group, randomised controlled trial at five French centres. Adult (≥18 years) patients with H. pylori infection were randomly assigned to verify non-inferiority of 14-day tailored PCR-guided triple therapy (tailored EAC/L14: esomeprazole 40 mg, amoxicillin 1000 mg twice daily and clarithromycin 500 mg twice daily for clarithromycin susceptible strain or levofloxacin 500 mg twice daily for clarithromycin resistant strain) compared to 14-day non-Bismuth concomitant quadruple therapy (EACM14: esomeprazole 40 mg, amoxicillin 1000 mg, clarithromycin 500 mg and metronidazole 500 mg twice daily). The primary endpoint was H. pylori eradication assessed by ¹³C urea breath test done 6 to 12 weeks after treatment. Analyses were performed in the intention-to-treat (ITT) and the per protocol (PP) populations, considering a prespecified expert-based non-inferiority margin of -5%.

Results

We screened 991 patients for eligibility and randomised 241 patients to received EACM14 or tailored EAC/L14. In the per-protocol population (excluding patients who did not performed ¹³C–urea breath test 6-12 weeks after eradication therapy and/or did not received a full 14-day regimen treatment), the eradication rate was 98.8% in the 14-day tailored PCR-guided triple therapy arm vs 96.5% in the 14-day non-Bismuth concomitant quadruple therapy arm, with the difference between the two groups being +2.35% (lower bound of CI at -3.33%). The first-line eradication rate (primary endpoint) in the ITT population was 99.2% in the tailored EAC/L14 PCR-guided group and 95.9% in the EACM14 control group, with the difference being +3.30% (lower bound of confidence interval (CI) at -0.68%). Both ITT and PP analyses demonstrated non-inferiority of EAC/L14 group, with unilateral CI95% lower bounds superior to the prespecified margin. Both first-line therapies were well tolerated, with a significant difference in favour of the tailored EAC/L14 group (any adverse events: 61.4% [EACM14] vs 41.2% [EAC/L14], p = 0.003). The most common adverse event involved the gastrointestinal tract in 107 (46.9%) patients, including 66 (57.9%) patients in the control arm and 41 (36.0%) in the experimental arm (p = 0.001).

Conclusion

In a country with high level of clarithromycin resistance, we showed the non-inferiority of 14-day tailored PCR-guided triple therapy as first-line H. pylori eradication therapy compared to 14-day non-Bismuth quadruple therapy (ClinicalTrials.gov, number NCT02576236.).

Clinical Case Summary

A female patient (born 1974) presented with chronic diarrhea (up to 16 times/day, including nocturnal episodes), bloating, periumbilical pain, fatigue, general weakness, and 10 kg weight loss. Since childhood, the patient had been under observation for chronic iron-deficiency anemia of unknown origin without prior gastrointestinal evaluation. Symptoms progressively worsened over two years due to the lack of therapeutic effect at the outpatient stage, leading to hospitalization in July 2022. Histology revealed total duodenal villous atrophy (celiac disease: Marsh 3C, Corazza-Villanacci B2; 30-40 IELs/100 epithelial cells) and lymphocytic microscopic colitis (MC) of the colon (60-70 IELs/100 epithelial cells). Other examinations (abdominal CT, enterography, stool analysis) were normal; labs showed mild iron-deficiency anemia, with protein markers within normal ranges. She was diagnosed with celiac disease combined with lymphocytic MC. A gluten-free diet, iron supplementation, and budesonide (9 mg/day for 3 months) were initiated, leading to clinical improvement. However, diarrhea recurred (up to 10 times/day) one month after stopping budesonide, despite adherence to the gluten-free diet. Duodenal histology improved (Marsh I, IELs ≤20/100 cells), confirming dietary effectiveness for celiac disease. Colonic histology showed ongoing lymphocytic MC activity (25-30 IELs/100 cells). The relapse was attributed to persistent MC. A prolonged regimen of budesonide (9 mg/day for 3 months, tapering to 6 mg/day for 6 months) was prescribed. This clinical case of celiac disease combined with lymphocytic MC demonstrates that significant improvement in small intestine structure can be achieved with a gluten-free diet and prolonged budesonide therapy. However, the recurrent diarrheal syndrome in this case was associated with the persistent course of MC. Literature emphasizes increased MC prevalence in celiac patients, reinforcing the need for timely recognition and combined therapy.

References

1. Miehlke S., Guagnozzi D., Zabana Y., Tontini G.E., Kanstrup Fiehn A.M., Wildt S., Bohr J., Bonderup O., Bouma G., D’Amato M., Heiberg Engel P.J., Fernandez-Banares F., Macaigne G., Hjortswang H., Hultgren-Hörnquist E., Koulaouzidis A., Kupcinskas J., Landolfi S., Latella G., Lucendo A., Lyutakov I., Madisch A., Magro F., Marlicz W., Mihaly E., Munck L.K., Ostvik A.E., Patai Á.V., Penchev P., Skonieczna-Żydecka K., Verhaegh B., Münch A. European guidelines on microscopic colitis: United European Gastroenterology and European Microscopic Colitis Group statements and recommendations. United European Gastroenterol J. 2021 Feb 22;9(1):13–37. doi: 10.1177/2050640620951905. Epub ahead of print. PMID: 33619914; PMCID: PMC8259259.

2. Calabrese C., Gionchetti P., Liguori G., Areni A., Fornarini G.S., Campieri M., Rizzello F. Clinical course of microscopic colitis in a single-center cohort study. J Crohns Colitis. 2011 Jun;5(3):218-21. doi: 10.1016/j.crohns.2011.01.004. Epub 2011 Feb 18. PMID: 21575884.

3. Microscopic Colitis: A Concise Review for Clinicians. June Tome MD, Amrit K. Kamboj MD, Darrell S. Pardi MD MS. DOI: https://doi.org/10.1016/j.mayocp.2021.03.022.

4. Tome M.D., Kamboj A.K., Pardi D.S. Microscopic Colitis: A Concise Review for Clinicians. Mayo Clinic Proceedings. 2021;96(5):1212-1222. DOI: https://doi.org/10.1016/j.mayocp.2021.03.022.

Introduction

Primary sclerosing cholangitis (PSC) is known to present characteristic cholangiographic findings; however, detailed observations using peroral cholangioscopy (POCS) have rarely been reported. We previously reported that POCS findings in PSC can be classified into three types: active (inflammatory), chronic (scarring), and tumorous (tumor-like). These findings may aid in the differential diagnosis of PSC and may be useful in predicting prognosis.

Aims & Methods

We aimed to analyze POCS findings in PSC in detail based on this classification and to clarify their characteristics by evaluating the frequency of each finding, their temporal changes, and comparisons with other biliary diseases.
We retrospectively reviewed 22 patients with PSC who underwent POCS between February 2018 and February 2023. For comparison, we included 19 cases of hepatolithiasis, 25 cases of cholangiocarcinoma, and 3 cases of IgG4-related sclerosing cholangitis (IgG4-SC). Twelve POCS findings were categorized into three types: active (mucosal erythema, ulcers, fibrous white exudates, irregular surface), chronic (longitudinal scarring, annular scarring, pseudodiverticula, stenosis), and tumorous (dilated vessels, tortuous vessels, friability, mass formation). In addition, we included “punched-out lesion (POL)” as an original finding. Each finding was graded on a 5-point scale (0–4) based on the extent or number of lesions, and scores were calculated for each type. We conducted three analyses: (1) correlation between cholangiographic and POCS findings in PSC, (2) temporal changes in POCS findings in PSC, and (3) comparison of POCS findings between PSC and other biliary diseases.

Results

In the first analysis, annular scarring (100%), stenosis (89%), POL (89%), and longitudinal scarring (86%) were frequently observed in PSC. Annular scarring was identified in all cases with a shaggy appearance on cholangiography, and stenosis were present in all ducts with band-like stricture. In ducts showing diverticulum-like outpouchings, longitudinal and annular scarring, pseudodiverticula, and POL were consistently seen, whereas other findings were absent. In the second analysis, active and tumorous scores varied over time even within the same case, whereas chronic scores remained stable or showed a progressive increase. A negative correlation was observed between active and chronic scores (p-value <0.001, r =-0.702). In the third analysis, chronic findings and POL were significantly more common in PSC compared to other diseases (p-value <0.001). Pseudodiverticula were seen exclusively in PSC, while dilated and tortuous vessels and friability were significantly more frequent in cholangiocarcinoma and IgG4-SC (p-value <0.001).

Conclusion

These findings suggest that the characteristic cholangiographic findings of PSC are mainly formed by chronic scarring. Diverticulum-like outpouchings reflect only fibrotic changes. Furthermore, the coexistence of inflammation and fibrosis, along with the time-dependent progression of fibrosis, is a unique feature of PSC, although active inflammation may obscure chronic findings. Finally, longitudinal scarring and POL were particularly prominent in PSC, and pseudodiverticula were highly specific to this disease, suggesting their usefulness in differential diagnosis. In conclusion, chronic findings on POCS are characteristic of PSC and may serve as a helpful tool in its diagnosis and differentiation from other biliary diseases.

References

T Fujisawa, M Ushio, S Takahashi, et al., Role of Peroral Cholangioscopy in the Diagnosis of Primary Sclerosing Cholangitis. Diagnostics (Basel), 2020. 10(5).
T Itoi, T Kamisawa, Y Igarashi, et al., The role of peroral video cholangioscopy in patients with IgG4-related sclerosing cholangitis. J Gastroenterol, 2013. 48(4): p. 504-14.
T H Karlsen, T Folseraas, D Thorburn, et al., Primary sclerosing cholangitis - a comprehensive review. J Hepatol, 2017. 67(6): p. 1298-1323.
T Nakazawa, K Notohara, S Tazuma, et al., The 2016 diagnostic criteria for primary sclerosing cholangitis. J Gastroenterol, 2017. 52(7): p. 838-844.
T Nakazawa, H Ohara, H Sano, et al., Cholangiography can discriminate sclerosing cholangitis with autoimmune pancreatitis from primary sclerosing cholangitis. Gastrointest Endosc, 2004. 60(6): p. 937-44.
H Isayama, S Tazuma, N Kokudo, et al., Clinical guidelines for primary sclerosing cholangitis 2017. J Gastroenterol, 2018. 53(9): p. 1006-1034.
W L Campbell, M S Peterson, M P Federle, et al., Using CT and cholangiography to diagnose biliary tract carcinoma complicating primary sclerosing cholangitis. AJR Am J Roentgenol, 2001. 177(5): p. 1095-100.

Introduction

There is currently lack of published data on the use of ustekinumab (UST) in routine care setting in Greece. REASSURE study aimed to generate real-world evidence (RWE) on treatment persistence, and patient-reported outcomes (PROs) in patients with Crohn’s Disease (CD).

Aims & Methods

This was an observational, prospective study of adult (18-80 years old) patients with confirmed diagnosis of CD, who commenced therapy with UST as 1^st, 2^nd, or 3rd line biologic treatment, according to physician’s decision, local standards of clinical practice and as per label indication. Data were collected by routine assessments, including Harvey-Bradshaw Index (HBI), and PROs at baseline (start of UST) and follow-up visits every 6-months. Last visit was done at month 24 (±2 months) or at treatment discontinuation (whichever occurred first). Drug persistence, disease activity and safety outcomes over the 24-month observation period are presented herein.

Results

A total of 169 eligible patients were enrolled in 19 Gastroenterology Clinics in Greece between April 2019 and February 2021. At baseline, median age was 45.0 years, 50.9% (86/169) of patients were females, 43.4% (72/166) were employed, and 68.5% (113/165) were former or current smokers. UST was the 1st, 2^nd, and 3rd biologic treatment in 35.5% (60/169), 35.5% (60/169), and 29.0% (49/169) of patients, respectively. The median duration of study participation was 23.9 months (median number of injections received: 13.0). At 24 months, 21.9% (37/169) of patients had discontinued UST after a mean of 10.2 months due to lack/loss of response (15/37), safety issues (10/37), lost at follow-up (6/37), patient’s wish (2/37), death (2/37; both unrelated to UST), pregnancy (1/37) and patient issues (1/37). The Kaplan-Meier (KM)-estimated median drug survival (i.e., time to treatment discontinuation) was not reached in the overall population or subgroups by treatment line, with no statistically significant differences in the risk of UST discontinuation between subgroups of interest [2L vs 1L: hazard ratio (HR)=1.07, 95% confidence interval (CI)=0.48-2.39; 3L vs 1L: HR=1.54, 95% CI=0.70-3.40; 3L vs 2L: HR=1.42, 95% CI=0.65-3.11). The KM-estimated UST treatment-persistence rates for the overall population s were 86.7%, 80.5%, and 78.0%, at 12-, 18-, and 24-months, respectively. The baseline median total ΗΒΙ (8.0) significantly improved (P<0.001) at 12, 18, and 24 months, with a median 4-point reduction at each timepoint, among paired observations. Significant improvements were also noted based on imputed data and in the subgroups per treatment line. The adverse event (AE), serious AE, and UST-related AE rates were 63.9% (108/169), 18.9% (32/169), and 19.5% (33/169), respectively. Each UST-related AE was reported in <4.0% of the patients. Further details on baseline characteristics, 12/18/24-month outcomes, and UST-related AEs are presented in Table 1.

Conclusion

Our data provide RWE for high persistence rate of treatment with UST in our series with Greek patients with CD. Treatment with UST demonstrated a highly favorable effect on disease activity, in combination with a predictable safety profile.

Disclosure

Disclosure: This study was sponsored by Janssen - Cilag, Greece.

Giorgos Bamias Advisor/lecturer for Janssen, Pfizer, Takeda, Abbvie, MSD, Mylan, Genesis Pharma, Adacyte Therapeutics, Amgen, Ferring, Cooper, BMS; Funding (Grants/Honoraria): Pfizer, Takeda, Abbvie, Aenorasis; Research/Clinical Trials: Abbvie, Takeda, Janssen.
Gerassimos J. Mantzaris has received consultant and/or speaker fees from AbbVie, MSD, Celtrion,Ferring, Aenorasis, Janssen, Pfizer, Takeda, Falk Pharma, and Vianex and research support from AbbVie, Ferring, MSD, and Vianex
Maria Tzouvala has received clinical research funding from Janssen-Cilag Pharmaceuticals SACI, Takeda HELLAS SA, AbbVie Pharmaceuticals S.A. Consulting and/or speaking fees MSD Sharp& Dohme, Janssen-Cilag Pharmaceuticals SACI, Takeda, AbbVie Pharmaceuticals S.A, Pfizer, Amgen. Advisory boards: Janssen-Cilag Pharmaceuticals SACI, Takeda, AbbVie Pharmaceuticals S.A, Pfizer, Amgen
Dimitrios Christodoulou has received consulting and speaking fees for Janssen, MSD, Galenica. Advisory Board for Galenica
Ioannis Koutroubakis has received clinical research funding: Abbvie, Faran, Ferring, Pfizer, Viatris, Vianex, Vifor, Unipharma. Consulting and/or speaking fees Abbvie, Genesis, Janssen, MSD, Takeda, Vianex. Advisory boards: Abbvie, Janssen, MSD, Pfizer, Takeda, Vianex
Christos Liatsos has received clinical research funding from: Janssen, and consulting and/or speaking fees from: MSD, Pfizer, Boston SCI, Amgen, Galenica.
Georgios Papatheodoridis Clinical research funding: Abbvie, Gilead, Takeda, Vianex. Consulting and/or speaking fees: Abbvie, Astra-Zeneca, BioARS Therapeutics, Elpen, Genesis, Gilead, GlaxoSmithKline, Ipsen, Novo Nordisk, Roche, Sobi. Advisory boards: Abbvie, Astra-Zeneca, Albireo, Amgen, Galenica, Genesis, Gilead, GlaxoSmithKline, Ipsen, Janssen, Novo Nordisk, Roche, Takeda
Dr Katsanos Konstantinos received honoraria for consulting services (educational services, scientific articles, participation in Advisory Boards, clinical trials, lecture fees, other) from the companies as follows:AbbVie, AMGEN, ENORASIS, Epsilon Health, Ferring, Genesis, Grifols S.A., JANSSEN, MSD, Mylan, Shire and Takeda.
Evanthia Zampeli has received clinical research funding: Janssen, TAKEDA, ABBVIE. Consulting and/or speaking fees: Janssen, TAKEDA, BMS, AMGEN, MYLAN. Advisory boards: BMS, GALENICA
Georgios Germanidis has received clinical research funding from Janssen.
Konstantinos Soufleris Consulting and/or speaking fees: AbbVie, Janssen, MSD, Pfizer, Takeda. Clinical research funding:Pfizer. Advisory board: BMS, Galenica.
Matina-Lydia Chatzinikolaou has received consulting fees from Abbvie, Takeda, Amgen, Ferring, Janssen
George Kokkonis has received clinical Research funding from Janssen and speaking fees from Janssen and Amgen
Alexandros Boubonaris has served as advisory board member for Amgen, Takeda
Marios Giakoumis has received clinical research funding from Janssen
Artemis Trikola has received clinical research funding from Janssen
George Michalopoulos has received speaker fees : Takeda, MSD, , Abbvie, Jannsen, Pfizer, Amgen
Vasileios Delis, Konstantina Paraskeva, Theodosios Sdonas, Athanasia Tasovasili, Evgenia Papathanasiou, Maria Palatianou, Andreaddds Nakos, Nikoletta Mathou, George Kalopitas, Panagiotis Giannelis, Kalliopi Foteinogiannopoulou, Konstantina Chalakatevaki, Eleni Beka, Chara Lamouri, Eleftheria Giannakoulopoulou have no conflicts to disclose.
Konstantinos Thomopoulos, Stergios Vradelis, Andreas Protopapas, Ioannis Pachiadakis, Ioannis Goulis, Pantelis Karatzas, George Theocharis, George Tribonias, Angeliki Machaira, Nikolaos Kyriakos, Adonis Protopapas, Konstantinos Fasoulas, Eleni Orfanoudaki and Charilaos Taloumtzis have not disclosed any conflicts.
Spyridon Michopoulos has received clinical research funding from Janssen, Takeda, BMS, consulting and/or speaking fees from Takeda, and has served as advisory board member for Takeda.
Christos Gkamaloutsos, Ioannis Kanistras and Aikaterini Mpartsea are employees of Janssen - Cilag, Greece.

Introduction

Budesonide orodispersible tablet (BOT) is the only approved topical steroid available in Europe for the induction and maintenance of remission in patients with eosinophilic esophagitis (EoE). Available randomized controlled trials have demonstrated that, following induction of histological remission with BOT 1mg twice daily (bid), patients can be maintained in remission with BOT 0.5mg bid. It is currently unknown whether a dose of 1mg once daily (od) has comparable efficacy to 0.5mg bid.

Aims & Methods

In this prospective study conducted at two tertiary referral centers for EoE, we enrolled consecutive patients with EoE undergoing clinical, endoscopic, and histologic re-assessment while on maintenance treatment for EoE with BOT 0.5mg bid or BOT 1mg od. All included patients had achieved histological remission (i.e., <15 eosinophils/high-power field, eos/HPF) following induction of remission with BOT 1mg bid. At the end of the induction of remission period (T0), all patients were assessed using the dysphagia symptom questionnaire (DSQ), the EoE endoscopic reference score (EREFS), and peak eosinophil counts (PEC). At re-assessment while on maintenance treatment (T1), all patients underwent 1) assessment of dysphagia and adaptive behaviors with the DSQ and the Pisa EoE Adaptation Questionnaire v1.0 (PiEAQ). Clinical remission was defined as DSQ not increasing >30% compared to T0. 2) upper endoscopy (EGDS) with assessment of EREFS score and at least six esophageal biopsies, and 3) histological assessment using the EoE Histology Scoring System (EoEHSS). In addition, a comprehensive global assessment of clinical, endoscopic, and histologic findings was performed using the validated index of severity for EoE (I-SEE score). Kruskal-Wallis Rank Sum Test and Pearson’s Chi-squared were used for comparisons. Significance threshold was p<0.05.

Results

Fifty-six patients were included (46 males and 10 females). Following histological remission with BOT 1mg bid, 28 (50%) initiated maintenance treatment with BOT 1mg od and 28 (50%) with BOT 0.5 bid. At the end of induction of remission (T0), the two groups had achieved similar outcomes, with comparable median DSQ [0 (0-28) vs 0 (0-28)], EREFS [1 (0-2) vs 1 (0-1)], and PEC [1 (0-7) vs 1.5 (0-4)] (all p>0.3) (Table 1). At the end of the maintenance treatment (T1), the two groups had been taking maintenance treatment for a comparable duration [20 weeks (12 – 36) vs 20 weeks (12 – 32; p=0.7). Persistent histological and clinical remission at T1 was present in 86% of BOT 1mg od versus 93% of BOT 0.5 bid (p=0.7). In addition, EREFS scores were comparable between groups at T1 [1 (0-2) vs 1 (0-2), p=0.8]. Similarly, the EoEHSS stage and grade was comparable between groups, as was the PiEAQ score [1.5 (0.75-2) vs 0.5 (0-2); p=0.06], and the I-SEE score [ 3 (2-4) vs 3 (2-4); p=0.5] (Table 2).

Conclusion

Persistent clinical endoscopic, and histological remission was maintained in most patients treated either with BOT 1mg od or BOT 0.5mg bid for a median of 20 weeks, indicating that the total daily dose of BOT 1mg may be more important that the frequency of administration, at least in the short term.

Disclosure

Speaker or Consultancy for Apogee Therapeutics, Alfasigma, Dr Falk Pharma, Sanofi, Malesci, JB Pharmaceuticals