Introduction

Crohn's disease is characterized by patchy, transmural inflammation predominantly affecting the ileum and colon. Ileo-colonoscopy remains the gold standard for assessing mucosal inflammatory activity in clinical trials, and can be quantified using the Simple Endoscopic Score for Crohn’s Disease (SES-CD). However, ileo-colonoscopy is invasive, therefore there has been growing interest in non-invasive imaging modalities such as magnetic resonance imaging (MRI). The Simplified Magnetic Resonance Index of Activity (sMaRIA) is an MRI-based score which provides a standardised approach for evaluating disease activity. Most previous studies investigating the correlation between sMaRIA and SES-CD have been single centre studies with limited numbers of readers and performed only in patients with longstanding disease. While MRI is superior to colonoscopy for assessment of transmural penetrating and stricturing disease, the performance of sMaRIA for assessment of mucosal activity in the post-treatment setting remains unanswered.

Aims & Methods

To evaluate the performance of sMaRIA for detection of mucosal inflammation in patients with recently diagnosed Crohn’s disease using ileo-colonoscopy and SES-CD as the reference standard. We conducted a post-hoc analysis of the PROFILE trial, in which patients had undergone paired ileo-colonoscopy and small bowel MRI at end of trial (week 48). Central reading was performed by validated pools of consultant radiologists (MRI) and gastroenterologists (ileo-colonoscopy), blinded to clinical data. Correlations between SES-CD and sMaRIA scores were assessed, alongside classification performance and remission rates by treatment arm. For this study endoscopic and MRI remission were respectively defined as SES-CD ulcer subscore <1 and sMaRIA ulcer subscore of 0.

Results

253 patients had paired ileo-colonoscopy and MRI at end of trial with a median time gap of 22 days between investigations and no treatment change over this period. The overall correlation between SES-CD and sMaRIA scores at week 48 was poor (Spearman’s rank=0.196). [KS(UHNFT1] Overall sMaRIA had low sensitivity (27%) [NN2] for identifying active inflammation evident on ileo-colonoscopy. On segmental analysis MRI detected only 4/146 ulcerated segments (SES-CD ulcer subscore >0). Focusing on patients with ileal involvement, terminal ileal ulcer subscores also showed low correlation (Spearman’s rank=0.11). When using the mucosal component of MRI / sMaRIA to assess ulcer-free remission, no difference in end of trial outcomes was observed for “top-down” vs “accelerated step-up” treatment groups (95% vs 96% remission, p=0.728). Rates of ulcer-free remission assessed by SES-CD were different between treatment groups (86% vs 71% remission, p=0.004).

Conclusion

In this cohort of recently-diagnosed patients with Crohn’s disease and predominantly inflammatory disease phenotype, sMaRIA showed low sensitivity for detecting mucosal inflammation / ulceration. Had sMaRIA been used instead of SES-CD in the PROFILE trial it would have failed to identify the benefit of the “top-down” treatment strategy. These findings suggest that sMaRIA on MRI should not replace SES-CD scoring on ileo-colonoscopy for assessing mucosal inflammatory activity in Crohn’s disease.

References

A biomarker-stratified comparison of top-down versus accelerated step-up treatment strategies for patients with newly diagnosed Crohn's disease (PROFILE): a multicentre, open-label randomised controlled trialNoor, Nurulamin MNoor, Nurulamin et al.
The Lancet Gastroenterology & Hepatology, Volume 9, Issue 5, 415 - 427

Introduction

Immune checkpoint inhibitors (ICIs) have marked a breakthrough in the management of a wide range of cancer types, leading to increased overall survival. However, this treatment is frequently associated with the onset of various immune-related adverse events (irAEs), including ICI-related diarrhea and colitis.¹ Current recommendations for patients with diarrhea or colitis grade 2 or higher (graded via CTCAE)² include the discontinuation of ICI and administration of immune suppressants (e.g. steroids or biologics), which may lead to worse outcomes in these patients.³ Therefore, alternative therapeutic strategies to manage irAEs are needed. The gut microbiota plays a pivotal role in the onset of gastrointestinal irAEs, but the role of its therapeutic modulation on these disorders is mostly unknown. ^4,5

Aims & Methods

Our aim was to evaluate the efficacy and safety of therapeutic microbiome modulation for gastrointestinal irAEs in cancer patients. We enrolled cancer patients affected by ICI-related diarrhea/colitis referred to our Microbiome Clinic from January 2023 to March 2025. After clinical evaluation, patients were stratified according to severity of diarrhea (graded via CTCAE)² and then received a microbiome-modulating therapy. Patients were followed-up for at least 8 week after the initiation of therapy. We collected data about patient demographics (age and gender), patient’s overall health status as assessed by the the Charlson Comorbidity Index (CCI)⁶, type of cancer, oncological therapy and its suspension, time in weeks from initiation of cancer therapy to onset of diarrhea, severity of diarrhea (graded via CTCAE)², time in weeks until resolution of diarrhea and resumption of oncological therapy

Results

We enrolled 42 patients in the study period (8 males, 34 females, mean age 58,3 years-old, mean CCI-index 5.8). All patients were treated with ICI (Pembrolizumab: n=25 , Dostarlimab: n=4, Nivolumab: n=4; Atezolizumab: n=3; Novulumab and Ipilumab: n=2, Cemiplimab: n=2; Mogamulizumab: n=1; Pertuzumab: n=1). Ten patients experienced G1 diarrhea (23,8%), 16 (38,1) G2, 15 (35,7%) G3 and one G4 (2,4%). As indicated by current European Guidelines³, 30 patients (71,4%) had to interrupt ICI due to diarrhea. Multi-strain probiotics were administered to 27 (64.3% ) patients, rifaximin to 22 (52,4%). Overall, 21 patients (50%) needed therapy with systemic steroids. Seven patients who experienced ICI-related colitis refractory to steroids and biologics were successfully treated with FMT. Twenty-eight patients (66.7% ) had a resolution of the diarrhea (G0) and 11 patients (26.2%) had diarrhea G1 at a mean time of 8 weeks. Upon resolution of diarrhea, nine of the 30 patients who had interrupted ICI (30%) were able to resume the treatment. None of the patients experienced any adverse event related to gut microbiota modulation as defined by CTCAE².

Conclusion

Therapeutic modulation of gut microbiota appears to be a promising safe and effective approach for treating ICI-related diarrhea and colitis. However, these preliminary findings need confirmation through more consolidated and well-designed studies.

References

1. Dougan M, Wang Y, Rubio-Tapia A, Lim JK. AGA Clinical Practice Update on Diagnosis and Management of Immune Checkpoint Inhibitor Colitis and Hepatitis: Expert Review. Gastroenterology. 2021;160(4):1384-1393. doi:10.1053/j.gastro.2020.08.063
2. Freites-Martinez A, Santana N, Arias-Santiago S, Viera A. Using the Common Terminology Criteria for Adverse Events (CTCAE - Version 5.0) to Evaluate the Severity of Adverse Events of Anticancer Therapies. Actas Dermosifiliogr. 2021;112(1):90-92. doi:10.1016/j.ad.2019.05.009
3. Haanen J, Obeid M, Spain L, et al. Management of toxicities from immunotherapy: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol. 2022;33(12):1217-1238. doi:10.1016/j.annonc.2022.10.001
4. Wang Y, Wiesnoski DH, Helmink BA, et al. Fecal microbiota transplantation for refractory immune checkpoint inhibitor-associated colitis. Nat Med. 2018;24(12):1804-1808. doi:10.1038/s41591-018-0238-9
5. Wang T, Zheng N, Luo Q, et al. Probiotics Lactobacillus reuteri Abrogates Immune Checkpoint Blockade-Associated Colitis by Inhibiting Group 3 Innate Lymphoid Cells. Front Immunol. 2019;10. doi:10.3389/fimmu.2019.01235
6. Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: Development and validation. J Chronic Dis. 1987;40(5):373-383. doi:10.1016/0021-9681(87)90171-8

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.

Introduction

Colorectal cancer (CRC) often develops from precancerous lesions such as tubular adenomas (TA) and sessile serrated lesions (SSL). The gut microbiome has been implicated in colorectal carcinogenesis, but specific microbial signatures associated with different adenoma subtypes remain incompletely characterized. This study aimed to identify microbial biomarkers associated with TA and SSL, and explore their correlations with dietary macronutrients.

Aims & Methods

Stool samples were collected from 801 patients prior to colonoscopy from National University Hospital and Tan Tock Seng Hospital, Singapore. After colonoscopy, the patients were classified as having TA (n=315), SSL (n=24), both (n=8), or neither (controls, n=454). Shotgun metagenomic sequencing was performed using Novaseq6000, and microbial taxonomy was annotated with MetaPhlAn4. Multivariate linear regression adjusted for age, gender, and BMI was used to identify species associated with polyp subtypes. A subset of 172 participants completed a validated food frequency questionnaire (FFQ) assessing 19 macronutrients, enabling correlation analysis between diet and adenoma-associated microbes.

Results

Patients with TA were older (mean age 64.0±7.8 vs 62.3±7.5 years in controls, p=0.02) and more likely to be male (69.5% vs 52.4%, p<0.01). After adjustment for confounders, we identified 38 microbial species significantly associated with polyp subtypes; 20 were associated with SSL and 18 with TA, with minimal overlap between the two polyp subtypes. Only two species showed associations with both polyp types: Holdemanella biformis and GGB3277_SGB4327, with the latter showing opposing directional relationships (negative for TA, positive for SSL). Of note, SSL were associated with increased abundance of Faecalibacterium SGB15346 and Bifidobacterium adolescentis. In the dietary analysis, we identified significant correlations between SSL-associated microbes and sugar intake, particularly Faecalibacterium SGB15346 (r=0.170, p=0.03) and Clostridium sp_AM49_4BH (r=0.156, p=0.04). E. hominis, positively associated with SSL, showed the strongest dietary associations overall, correlating positively with carbohydrate intake (r=0.243, p<0.01) and starch consumption (r=0.246, p<0.01).

Conclusion

Our study identified distinct microbial signatures associated with TA and SSL, with minimal overlap, suggesting separate host-microbial biological pathways in their development. The positive correlation between SSL-associated microbes and sugar intake provides a potential mechanistic link between dietary habits and SSL formation, which may be particularly relevant given the increasing incidence of early-onset colorectal neoplasia. These findings offer potential microbial biomarkers for early detection of colorectal polyps and suggest targeted dietary interventions as a strategy for precision chemoprevention.

Introduction

Anti-tumor necrosis factor (TNF)-α are the first target therapies approved for the treatment of steroid-dependent or -refractory ulcerative colitis (UC). Drugs with different mechanisms of action have recently entered the market, but data on the optimal management of UC after failure of first-line anti-TNF-α are lacking.

Aims & Methods

The PODIUM study is a multicentre, retrospective, observational study that aims to compare the real-life effectiveness and safety of second-line vedolizumab (VDZ), ustekinumab (UST) and tofacitinib (TOF) in patients with UC. Consecutive patients with UC who had failed at least one anti-TNF-α and were never exposed to other target therapies were enrolled from 12 centres across Europe. Sociodemographic data, data on clinical activity and adverse events of interest (AEIs, defined as AE requiring temporary/permanent drug discontinuation or medical intervention) were retrospectively extracted from medical records, from the initiation of second-line therapy until one year of observation/drug discontinuation/last available follow-up. The primary outcome was the cumulative probability of achieving steroid-free clinical remission (SFCR), defined as stool frequency=0-1 and rectal bleeding=0 and no concomitant steroids, over the first year of treatment; inverse probability of treatment weighting (IPTW), calculated as the inverse of the probability of receiving each drug (IPTW=1/Propensity Score), was applied to the primary outcome to account for imbalances in cohorts’ characteristics. We performed an interim analysis including all data collected up to March 15^th 2024; data collection is still ongoing at the submission of this Abstract.

Results

Data on 303 patients (172 VDZ, 63 UST, 68 TOF) were included in the analysis. The main baseline characteristics are presented in Table 1. After IPTW, the cumulative probability of achieving SFCR during the first year was 51.0%, 59.1% and 64.1% for VDZ, UST and TOF, respectively; both UST and TOF were superior to VDZ at Log-rank test (p<0.001), with no differences between the two. At weighted logistic regression, female sex (adjusted Odds Ratio, aOR, 0.06, Confidence Interval, CI, 95% 0.41-0.73, p<0.001) and higher Charlosn Comorbidity Index calculated without considering age (aOR 0.73, 95% CI 95% 0.60-0.88, p=0.001) were independently associated with a lower probability of achieving SFCR during the first year. Recorded AEIs were 16 (4 infections) in the VDZ group (9.3% of VDZ-treated patients), 6 (1 infection) in the UST group (9.5% of UST-treated patients), and 15 (5 infections, including 1 Zoster reactivation) in the TOF group (22.1% of TOF-treated patients).
Table 1

Conclusion

This preliminary analysis suggests that both UST and TOF might have superior effectiveness, compared to VDZ, as second-line agents in patients with UC after anti-TNF-α. Confirmatory analysis with a larger sample size will be performed. A slightly higher rate of AEIs was observed in the TOF group.

Disclosure

Giuseppe Privitera received consultancy fees from Alphasigma and Janssen. Cristina Bezzio received lecture fees and served as a consultant for Takeda, MSD, Ferring, Abbvie, Galapagos and Janssen. Edoardo Vincenzo Savarino has served as speaker for Abbvie, Agave, AGPharma, Alfasigma, Aurora Pharma, CaDiGroup, Celltrion, Dr. Falk, EG Stada Group, Fenix Pharma, Fresenius Kabi, Galapagos, Janssen, JB Pharmaceuticals, Innovamedica/Adacyte, Malesci, MayolyBiohealth, Omega Pharma, Pfizer, Reckitt Benckiser, Sandoz, SILA, Sofar, Takeda, Tillots, and Unifarco; has served as a consultant for Abbvie, Agave, Alfasigma, Biogen, Bristol-Myers Squibb, Celltrion, DiademaFarmaceutici, Dr. Falk, Fenix Pharma, Fresenius Kabi, Janssen, JB Pharmaceuticals, Merck & Co, Nestlè, Reckitt Benckiser, Regeneron, Sanofi, SILA, Sofar, Synformulas GmbH, Takeda, and Unifarco; he has received research support from Pfizer, Reckitt Benckiser, SILA, Sofar, Unifarco, Zeta Farmaceutici. Daniela Pugliese received speaker fees and/or advisory board from AbbVie, Galapagos, MSD, Takeda and Janssen, Pfizer. Iago Rodriguez-Lago has received financial support for traveling and educational activities from or has served as an advisory board member for Abbvie, Adacyte, Celltrion, Chiesi, Danone, Ferring, Faes Farma, Janssen, Galapagos, MSD, Pfizer, Roche, Takeda, and Tillotts Pharma. Financial support for research: Tillotts Pharma. Manuel Barreiro-de Acosta has served as a speaker, consultant and advisory member for and has received research funding from MSD, AbbVie, Janssen, Kern Pharma, Celltrion, Takeda, Gilead, Celgene, Pfizer, Sandoz, Biogen, Fresenius, Ferring, Faes Farma, Dr. Falk Pharma, Chiesi, Gebro Pharma, Adacyte and Vifor Pharma. Sara Onali has received speaker fees from AbbVie, Takeda, Janssen, Amgen, Galapagos and Norgine. Massimo Claudio Fantini has received speaker and consultancy fees from AbbVie, Takeda, Janssen-Cilag, Pfizer, Sandoz, Biogen, Galapagos, Bristol-Myers Squibb, and MSD; and research grants from Pfizer and Janssen-Cilag. Karmiris K has served as speaker, consultant, and advisory member for Abbvie, Amgen, Enorasis, Ferring, Galenica, Genesis, Janssen, MSD, Pfizer, Takeda and Vianex. Henit Yanai has received consulting fees Abbvie, Ferring, Janssen, Neopharm Ltd., Pfizer, Takeda; Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events Abbvie, Janssen, Pfizer, Takeda, Neopharm Ltd.; Participation on a Data Safety Monitoring Board or Advisory Board Abbvie, Neopharm Ltd., Pfizer, Takeda. Ana Gutierrez has served as speaker, consultant and advisory member for or has received research funding from MSD, Abbvie, Pfizer, Kern Pharma, Takeda, Janssen, Ferring, Faes Farma, Shire Pharmaceuticals, Tillotts Pharma, Chiesi and Otsuka Pharmaceutical. Luca Pastorelli has received consultant and/or speaker fees from Giuliani, Ferring, Janssen, Takeda. María Chaparro has served as a speaker and consultant for and has received research or education funding from MSD, AbbVie, Hospira, Pfizer, Takeda, Janssen, Ferring, Shire Pharmaceuticals, Dr. Falk Pharma, Tillotts Pharma, Biogen, Gilead and Lilly. Yamile Zabana has received speaker and/or consultant fees from AbbVie, Adacyte, Almirall, Amgen, Dr Falk Pharma, FAES Pharma, Ferring, Janssen, MSD, Otsuka, Pfizer, Shire, Takeda, Galapagos, Boehringer Ingelheim and Tillots. Alessandro Armuzzi: consulting and/or advisory board fees from AbbVie, Amgen, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Celltrion, Eli-Lilly, Ferring, Galapagos, Gilead, Janssen, MSD, Mylan, Pfizer, Protagonist Therapeutics, Roche, Samsung Bioepis, Sandoz, Takeda; lecture and/or speaker bureau fees from AbbVie, Amgen, Arena, Biogen, Bristol-Myers Squibb, Eli-Lilly, Ferring, Galapagos, Gilead, Janssen, MSD, Mitsubishi-Tanabe, Novartis, Pfizer, Roche, Sandoz, Samsung Bioepis, Takeda; and research grants from MSD, Pfizer, Takeda and Biogen. The remaining authors declare no competing interests. The remaining Authors declare no competing interests.