Introduction

Chronic atrophic gastritis (CAG) is primarily caused by Helicobacter pylori (Hp) infection but also by autoimmune phenomena giving rise to autoimmune atrophic gastritis (AAG), whose hallmark is corpus-restricted atrophy sparing the antrum (unlike Hp infection causing extensive CAG). AAG triggered by Hp has been proposed, but diagnosis of Hp in this condition is difficult. Hp infection is one of the main risk factors for gastric cancer (GC), while the role of AAG in the onset of GC is still debated. Assessing the association of GC with AAG is thus challenging, as it requires the exclusion of Hp infection. Hence, investigating the presence of Hp-related genes in the gastric mucosa of histologically Hp negative AAG patients complicated by GC could be useful for accurately assessing the role of Hp in GC associated with AAG.

Aims & Methods

The aim was to assess the presence of Hp-related genes in corpus mucosa biopsies using Real-time and Digital PCR in AAG patients with GC and negative Hp at histology, along with Hp-positive and -negative controls.
Single-centre, experimental molecular biology study derived from 713 pts with histological diagnosis of CAG (2009-2022). Pts without corpus-restricted CAG (n=118) and with histological positivity for Hp (n=57) were excluded, resulting a source population of 538 AAG pts with negative Hp at histology. Out of these, 10 pts (80%F, age 69.5 (range 50-83) yrs) were diagnosed with gastric neoplastic lesions (GNL), including gastric cancer (GC) and high-grade intraepithelial neoplasia (HG-IEN). Real-time and Digital PCR were used to assess the presence of Hp-related genes in corpus mucosa biopsies of the 10 GNL-AAG pts and 2 Hp-positive non-atrophic gastritis pts (positive controls: 1 F,1 M, age 39, 68 yrs) and 2 subjects with a healthy stomach (negative controls: 1 F,1 M, age 22, 34 yrs). DNA was extracted from formalin-fixed, paraffin-embedded (FFPE) tissue sections of corpus mucosa biopsies and Real-time and Digital PCR were performed using specific probes for UreA, UreC, and CagA Hp-related genes. 16sRNA and Beta2 microglobulin specific probes were used as amplification ctr of bacterial and human DNA. Real-Time PCR gives a semiquantitative analysis, whereas Digital PCR measures the accurate copy numbers of Hp DNA.

Results

GNL were diagnosed in 3/10 pts at AAG diagnosis, while in 7 at follow-up (median 96, range 12-156 mos). GNL were frequently in the corpus (50%), less commonly at incisura angularis (30%) or antrum (20%), and consisted of 8 GC and 2 HG-IEN. None had family history of GC, all pts were parietal cell autoantibodies positive. ELISA Hp serology was negative in all 5/10 available sera. Hp-related genes were not detected in any of the GNL-AAG pts nor in negative controls, but UreA and UreC were found in both positive controls and CagA in one. 16sRNA gene was detected in GNL-AAG by Real-time(CT mean 26.0, SD 0.3) and Digital PCR (copies μl mean 1397,SD 348) in similar amounts as in positive controls (mean CT 25.7, SD 0.9, mean copies/μl 4977.5, SD 2185.7), indicating the detectability of bacterial genes in the extracted DNA.

Conclusion

In FFPE corpus mucosa biopsies of pts with histologically Hp negative AAG and GC, specific Hp-related genes are detectable by nor Real-time neither Digital PCR. This result supports the idea that GC development cannot be excluded a priori in primary, Hp negative AAG, suggesting that Hp-unrelated cancerogenetic mechanisms may be involved and regular surveillance should be considered in primary AAG.

References

• Lenti MV et al. Autoimmune gastritis. Nat Rev Dis Primers. 2020.
• Lahner E et al. Chronic atrophic gastritis: Natural history, diagnosis and therapeutic management. A position paper. Dig Liver Dis. 2019.
• Rugge M et al; RE.GA.IN; RE GA IN. RE.GA.IN.: the Real-world Gastritis Initiative-updating the updates. Gut. 2024.
• Neumann WL et al. Autoimmune atrophic gastritis--pathogenesis, pathology and management. Nat Rev Gastroenterol Hepatol. 2013.

Introduction

Microscopic colitis (MC) refers to two pathologies – Collagenous colitis (CC) and Lymphocytic colitis (LC) that cause chronic watery diarrhoea, urgency, incontinence leading to significantly decreased quality of life¹. It is thought that MC develops due to a pathological immune response to intestinal luminal antigens in genetically predisposed individuals, with microbiota playing an important role^{2, 3}. However, the pathogenesis of MC is still unclear.

Aims & Methods

The aim of this study was to identify and characterize changes in bacterial composition of MC patients in terminal ileum and different colonic segments and determine its relation to the clinical course of disease. Biopsies from terminal ileum and six segments of the colon were collected during diagnostic colonoscopies. DNA extraction was performed using AllPrep DNA/RNA Micro Kit (Qiagen) following the manufacturer’s instructions. To determine bacterial composition, sequencing of the 16S rRNA variable region V3-V4 was conducted using the 27F and 338R polymerase chain reaction primers and sequenced on a MiSeq (2×250 bp; Illumina, Hayward, CA). Bioinformatic analysis was performed using DADA2, and taxonomic classification was carried out with the RDP classifier.

Results

Biopsy samples from 20 active CC patients, 20 active LC patients, and 50 controls demonstrated distinct microbial profiles across different intestinal segments, as revealed by beta-diversity and differential compositional analyses. Compared with controls, CC patients had consistent alterations in three bacterial families throughout the entire colon, with Erysipelatoclostridiaceae and Coriobacteriaceae decreased and Pasteurellaceae increased. Additionally, 35 families had segment-specific changes, and 25 families displayed altered abundance in the terminal ileum.
LC patients exhibited a consistent increase in Erisypelotrichaceae across the entire colon, with 38 other families showing segmental changes, and 12 families displaying altered abundance in the terminal ileum. Comparing LC and CC revealed a significantly different bacterial profile. LC showed lower abundance across many families, particularly in the right colon and terminal ileum. After sample collection, 15 CC patients and 12 LC patients received budesonide, with 3 CC and 2 LC patients having incomplete response. Beta diversity analysis revealed significant differences in the ascending colon and left side of the colon of CC patients based on response to budesonide. Patients with incomplete response to budesonide had an increased abundance of the genus Paucibacter. Similar tendencies were not observed in LC.
1 CC patient exhibited a quiescent disease course, 6 reached a sustained remission after treatment, 7 had a relapsing and 6 had a chronic active disease. Significant differences in beta diversity were observed in transverse, descending colon and rectum. Beta diversity of the descending colon had a medium correlation with disease behaviour. In the LC group 6 patients had a quiescent disease, 8 had a sustained remission after treatment, 3 exhibited a relapsing and 4 had a chronic active disease. No significant correlation between microbiota and disease behaviour was observed in LC.

Conclusion

This study showed significant differences in bacterial composition between CC, LC and controls in the terminal ileum and colon. In both CC and LC, bacterial alterations were not consistent throughout the entire colon but varied between different colonic segments. Microbiome differences based on response to budesonide and disease behaviour were observed in CC, but not LC.

References

1. Verhaegh BPM, Münch A, Guagnozzi D, et al. Course of Disease in Patients with Microscopic Colitis: A European Prospective Incident Cohort Study. J Crohns Colitis. 2021;15(7):1174-1183.
2. Miehlke S, Guagnozzi D, Zabana Y, et al. European guidelines on microscopic colitis: United European Gastroenterology (UEG) and European Microscopic Colitis Group (EMCG) statements and recommendations. United European Gastroenterol J. Published online 2020.
3. Burke KE, D’Amato M, Ng SC, Pardi DS, Ludvigsson JF, Khalili H. Microscopic colitis. Nat Rev Dis Primers. 2021;7(1).

Introduction

Owing to the multiplication of therapeutic options in ulcerative colitis (UC), how sequencing the drugs is a burning question. For chosing the best treatment, efficacy is a key point. However, only one head-to-head randomized controlled trial is available (VARSITY) and network meta-analyses are difficult to interpret. Then, real-world data are necessary to help ranking the treatment in UC.

Aims & Methods

We aimed to compare the effectiveness of tofacitinib and ustekinumab in patients with ulcerative colitis (UC) previously exposed to at least one anti-TNF agent.
In this multicenter study, we retrospectively included consecutive UC adult patients previously exposed to at least one anti-TNF agent, with partial Mayo score (pMS) > 2, having who started tofacitinib or ustekinumab between January 2019 and June 2022.
The primary endpoint was steroid-free clinical remission (pMS ≤ 2) (CFREM) at week 16 (W16). Secondary endpoints were endoscopic remission (CFREM + Mayo endoscopic score (MES) ≤ 1), and histological remission (CFREM + MES ≤ 1 + Nancy index ≤ 1).
Comparisons were performed using propensity score analyses adjusted on potential confounders.

Results

Overall, 289 patients were included (tofacitinib = 124 patients, ustekinumab = 165 patients). The groups were comparable (tofacitinib vs vedolizumab) for male gender (50.8% vs 43.3%), mean age (40.7 vs 42.9 years), median UC duration (8.6 vs 9.3 years), concomitant use of 5-ASA (13.7% vs 9.7%), steroids (25.0% vs 29.7%), immunosuppressants (7.3% vs 5.5%), and ≥ 2 prior biologics (85.5% vs 82.4%). Tofacitinib group had more pancolitis (55.6% vs 42.4%, p = 0.026) and UC with pMS > 6 (64.5% vs 50.3%, p = 0.016). In our study, 42.1 % of the patients treated with tofacitinib continued using a dose of 10 mgx2/day until W16 while 47.3% of the patients on ustekinumab required dose escalation to 90 mg/4 weeks before W16.
After propensity score analysis, the rate of CFREM at W16 was 37.8% and 35.6% in the tofacitinib and ustekinumab arms, respectively arm (p=0.75). CFREM at W16 was achieved in 43.3% vs 57.1% (p = 0.48) after failure of one biologic, 20.7% vs 37.9% (p=0.16) two biologics and 46.7% vs 23.2% (p=0.047) if ≥ 3 biologics, in tofacitinib and ustekinumab arms, respectively. After primary failure to at least one biologic, the rate of CFREM at W16 was 46.3% on tofacitinib vs 25.9% on ustekinumab (p = 0.13). CFREM at W16 was similar with tofacitinib and ustekinumab in case of more severe UC such as pMS ≥ 6 (40.6% vs 41.5%) and CRP > 30 (27.2% vs 33.0%).
No predictor of tofacitinib effectiveness has been identified. Factors associated with no CFREM at W16 on ustekinumab were male gender (p=0.035), ≥ 3 prior biologics (p=0.013), prior use of tofacitinib (p=0.03), primary failure to at least one biologic (p=0.013).
After propensity score analysis, endoscopic remission was achieved in 17.0% vs 11.7% (p =0.47) and histological remission in 4.4% vs 7.8% (p=0.32) of the patients treated with tofacitinib and ustekinumab, respectively.
At last follow-up, we did not observe any difference between the two groups regarding the time to drug discontinuation, time to hospitalization and time to colectomy.

Conclusion

Tofacitinib and ustekinumab have similar effectiveness at short and long-term in UC after anti-TNF failure. However, the efficacy of ustekinumab could be more impacted by prior therapeutic failures but not by UC severity.

Disclosure

Anthony Buisson: Consulting fees for Abbvie, Amgen, Arena, Biogen, Celtrion, CTMA, Fresenius-Kabi, Galapagos, Janssen, MSD, Nexbiome, Pfizer, Roche, Takeda and Tillotts. Lecture fees for Abbvie, Amgen, Biogen, Fresenius-Kabi Galapagos, Janssen, Mayoli-Spindler, MSD, Norgine, Pfizer, Roche, Takeda, Tillotts and Vifor Pharma. Research grants from Abbvie, Celltrion, Janssen, Pfizer, Takeda.
Maria Nachury: MN received board membership, consultancy, or lecture fees from Abbvie, Adacyte, Amgen, Arena, Biogen, CTMA, Celltrion, Ferring, Fresenius-Kabi, Janssen, Mayoli-Spindler, MSD, Pfizer, Takeda
Thomas Guilmoteau: None
Romain Altwegg: Received lecture and consulting fees from Abbvie, Janssen, MSD, Pfizer, Takeda.
Xavier Treton: Received honoraria from Abbvie, MSD, Takeda, Ferring, Norgine and Janssen.
Mathurin Fumery: Consulting/lecture fees for Abbvie, Amgen, Arena, Biogen, Celtrion, CTMA, Galapagos, Janssen, MSD, Pfizer, Takeda, Tillotts. MSD, Gilead, Celgene, Sandoz and Ferring.
Mélanie Serrero: Declared fees from Pfizer, Abbvie, Takeda, Janssen, MSD, Amgen, Ferring, Tillotts, Celltrion
Ludovic Caillo: Declared fees from Janssen, abbvie, Takeda, amgen, Pfizer, norgine
Bruno Pereira: None
Aurélien Amiot: Has served as a consultant, served on the advisory board, received lecture fees, and received travel fees from AbbVie, Hospira, Takeda, Gilead, Biocodex, Janssen, Ferring, and MSD.
Guillaume Bouguen: Received lecture fees from Abbvie, Ferring, MSD, Takeda and Pfizer and consultant fees from Takeda, Janssen.

Introduction

The 52-week, phase 3 True North (TN) study (NCT02435992) demonstrated the efficacy and safety of ozanimod (OZA), a highly selective sphingosine 1-phosphate receptor 1 and 5 modulator, in patients (pts) with moderately to severely active ulcerative colitis (UC). A prior analysis reported the long-term safety of OZA up to ~4 y from TN baseline through Week (W) 142 of the ongoing TN open-label extension (OLE; NCT02531126).

Aims & Methods

This analysis assessed the cumulative long-term safety of OZA with an additional year of exposure (pt disposition available until OLE W190 [up to ~5 y of OZA]). All pts who entered the OLE from TN (ie, clinical nonresponders at W10 and those who lost response during maintenance or completed maintenance at W52) were included in this analysis. Treatment-emergent adverse events (TEAEs) were monitored from the first dose of OZA in TN or the OLE through data cutoff; exposure-adjusted incidence rates (EAIRs) per 100 patient-years (PY) are presented. Lab abnormalities, including absolute lymphocyte count (ALC) reductions, were assessed during the OLE through data cutoff.

Results

A total of 823 pts entered the TN OLE. At data cutoff, 43.0% of pts had completed OLE W190 and total OZA exposure was 2681 PY. Overall, the cumulative safety assessments did not meaningfully change with an additional year of OZA exposure (Table). EAIRs of TEAEs, serious TEAEs, and TEAEs leading to treatment discontinuation remained consistent, and there were no new cases of malignancy, bradycardia, third-degree atrioventricular (AV) block, myocardial ischemia, ischemic stroke, pulmonary embolism, deep vein thrombosis, or macular edema with an additional year of OZA exposure. Three pts newly developed infections; however, only 1 pt had a serious infection (keratouveitis), which was not related to treatment. Two additional pts experienced mild hypertension. Reductions in ALC <500 cells/µl were common in the OLE (57.2%), but few pts had ALC <200 cells/µl(6.6%). Occurrence of ALC <200 cells/µl was not temporally associated with serious or opportunistic infections. Most alanine aminotransferase and aspartate aminotransferase elevations were transient and resolved without treatment interruption, and no serious hepatic events occurred.

Table. Cumulative safety assessments during TN and the TN OLE in all pts who entered the OLE	Up to ~4 y of OZA exposurea (n=823) Total PYc = 2536 n (%) EAIRd		Up to ~5 y of OZA exposureb (n=823) Total PYc = 2681 n (%)e n (%)			Up to ~4 y of OZA exposurea (n=823) Total PYc = 2536 n (%) EAIRd		Up to ~5 y of OZA exposureb (n=823) Total PYc = 2681 n (%)e n (%)
TEAEs	685 (83.2)	85.5	687 (83.5)	85.1	Third-degree AV block	1 (0.1)	0.04	1 (0.1)	0.04
Serious TEAEs	158 (19.2)	7.0	163 (19.8)f	6.8	Hypertension	55 (6.7)	2.3	56 (6.8)	2.2
TEAEs leading to treatment discontinuation	64 (7.8)	2.5	66 (8.0)	2.5	Myocardial ischemia	3 (0.4)	0.12	3 (0.4)	0.11
Infection	378 (45.9)	22.7	381 (46.3)	22.1	Ischemic stroke	3 (0.4)	0.12	3 (0.4)	0.11
Herpes zoster	30 (3.6)	1.2	31 (3.8)	1.2	Pulmonary embolism	3 (0.4)	0.12	3 (0.4)	0.11
COVID-19	103 (12.5)	4.3	103 (12.5)	4.1	Deep vein thrombosis	3 (0.4)	0.12	3 (0.4)	0.11
Serious infection	44 (5.3)	1.8	45 (5.5)	1.7	Macular edema	3 (0.4)	0.12	3 (0.4)	0.11
Malignancy	18 (2.2)	0.71	17 (2.1)	0.63	Cystoid macular edema	3 (0.4)	0.12	3 (0.4)	0.11
Bradycardia	3 (0.4)	0.12	3 (0.4)	0.11

^aData cutoff of June 30, 2023. ^bData cutoff of January 10, 2024. ^cTotal PY was calculated as the sum of the number of years on study contributed by each pt from time of first dose to last date on study. ^dEAIRs were calculated as number of pts/PY × 100. ^eTN OLE is an ongoing study. Individual TEAE terms may not add up as harmonization of final data is pending. ^fFor the 5 pts who newly reported a serious TEAE, events included 1 pt each with UC exacerbation, colitis, pancreatitis, and umbilical hernia, and 1 pt with ulcerative keratitis and keratouveitis.

Conclusion

The ongoing safety profile of OZA is consistent with previous analyses, with no new safety concerns identified. Long-term OZA use representing 2681 PY of exposure continues to be well tolerated in pts with moderately to severely active UC.

Disclosure

Acknowledgment: This study was sponsored by Bristol Myers Squibb. Writing and editorial assistance was provided by Traci Stuve, MA, and Alexandra Stafford, PhD, of Peloton Advantage, LLC, an OPEN Health company, and was funded by Bristol Myers Squibb.

JT: received grants from AbbVie and Janssen; received advisory board or speaker fees from AbbVie, Bristol Myers Squibb, Janssen, Pfizer, and Sandoz.
RL: consulted for Bristol Myers Squibb and Pfizer.
KK: received lecture honoraria from Gore.
SL: consulted for AbbVie, Bristol Myers Squibb, Eli Lilly, and Janssen.
TK: served as an advisory board member, consultant, or speaker for AbbVie, Alfresa Pharma, Alimentiv, Astellas, Bristol Myers Squibb, Celltrion, Covidien, EA Pharma, Eli Lilly, Ferring, Galapagos, Gilead Sciences, Janssen, JIMRO, JMDC, Kissei Pharmaceutical, Kyorin Pharmaceutical, Mitsubishi Tanabe Pharma, Mochida Pharmaceutical, Nippon Kayaku, Pfizer, Takeda, ThermoFisher Scientific, and Zeria Pharmaceutical; received research funding from AbbVie, Alfresa Pharma, EA Pharma, Gilead, Kyorin Pharmaceutical, Mochida Pharmaceutical, Nippon Kayaku, Otsuka Holdings, Pfizer, Sekisui Medical, Takeda, ThermoFisher Scientific, and Zeria Pharmaceutical.
DB: served as advisory board member or consultant for AbbVie, Amgen, Arena, Atheneum, BNG Service GmbH, Bristol Myers Squibb, CED Service GmbH, Celltrion, DGVS, Diaplan, Doctorflix, Eli Lilly, Else Kröner-Fresenius-Stiftung, Falk Foundation, Ferring, Galapagos, Gastroenterology Today, GlaxoSmithKline, Guidepoint, Impulze, Janssen-Cilag, Medical Tribune, MedTrix, MSD, Mylan, Onkowissen, Pfizer, Pharmacosmos, Roche, Sandoz, Streamed Up, Takeda, Tetrameros, Thieme, Tillotts, UCB, Viatris, and Vifor Pharma.
LK: reported no conflicts of interest.
DM, NRS, AP, MD, HW, DW, MTO, and AJ: employees and/or shareholders of Bristol Myers Squibb.
BPA: consulted for AbbVie, Bristol Myers Squibb, Celltrion, Eli Lilly, Janssen, Medtronic, Pfizer, Prometheus, Samsung Bioepis, and Takeda; lectured for AbbVie, Bristol Myers Squibb, Eli Lilly, Janssen, Pfizer, and Takeda.