Introduction

Th17 cells are found enriched in inflamed intestinal lesions of Crohn’s disease (CD) patients. Several evidences indicate that Th17 cells may have both a protective role in the gut but also a more pro-inflammatory function. Indeed, in response to specific polarizing cytokines and pathogenic stimuli, Th17 cells can transdifferentiate into IFNγ-producing Th17 cells acquiring a more pathogenic profile. Here, we aimed to identify the specific immunological and transcriptomic profile of intestinal-resident IFNγ-producing Th17 cells, as well as the role in the CD pathogenesis and specific gut microbiota components that induce their activation and selective increase in the gut of CD patients.

Aims & Methods

In order to define the role of IFNγ-producing Th17 cells in chronic intestinal inflammation, CD4⁺T cell subsets from CD patients and controls were phenotypically and functionally analyzed by RNA sequencing and flow cytometry. They were analyzed for responses to CD-relevant antigens with the antigen-specificity assay and monitored in CD patients before and after treatment with antibodies that neutralize TNFα (Infliximab), integrin α4β7 (Vedolizumab), or IL-23p19 (Risankizumab).

Results

Th17 cells expressing CCR5 (“pTh17”) co-produced the highest levels of IFNγ/IL-17 but were distinct from established Th1/17 cells. pTh17 cells were associated with intestinal inflammation in CD, but not with UC. Conversely, Th1/17 cells, which also co-produced IFNγ/IL-17, were not increased in inflamed compared to non-inflamed lamina propria of CD or non-IBD patients. Biological therapies differentially affected intestinal pTh17 cell frequency: whether Infliximab significantly reduced gut-infiltrating pTh17 in CD responder patients, Vedolizumab only impaired migration of cTh17 cells to the gut but did not reduce intestinal-resident pTh17 cells. Notably, pTh17 cells transdifferentiated in-vitro from conventional CCR5^-Th17 cells (“cTh17”) in the presence of IL-23. Consistently, intestinal pTh17 cells were specifically and strongly reduced after Risankizumab therapy in CD patients. Importantly, intestinal pTh17 cells were selectively activated by adherent-invasive Escherichia coli strains, but not by a commensal/probiotic E. coli strain. In contrast, Th1/17 cells were selectively activated by Cytomegalovirus.

Conclusion

We identified a previously uncharacterized subset of human intestinal IFNγ-producing Th17 cells, whose generation was promoted by IL-23 in vitro and in vivo. CCR5⁺Th17 cells (pTh17) produced high levels of pro-inflammatory cytokines, were selectively associated with intestinal inflammation in CD, and responded to CD-associated AIEC strains, suggesting a key pathogenic role in CD. Finally, besides the possibility to use pTh17 cells as a diagnostic or predictive biomarker, they also represent an important novel target for the development of new therapeutic strategies aimed at selectively blocking the harmful signalling pathways driving intestinal chronic inflammation in CD.

Disclosure

• Prof. M. Vecchi served as a consultant to Abbvie, MSD, Takeda, Janssen-Cilag, and Celgene. He received lecturer fees from Abbvie, Ferring, Takeda, MSD, Janssen-Cilag, and Zambon.
• Prof. F. Caprioli has served as consultant to Mundipharma, AbbVie, MSD, Takeda, Janssen, Roche, and Celgene; received lecture fees from AbbVie, Ferring, Takeda, Allergy Therapeutics, and Janssen; and received unrestricted research grants from Giuliani, SOFAR, MS&D, Takeda, Pfizer and AbbVie.
• All other authors have no conflicts of interest to declare.

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 Epi-IBD cohort is a prospective European population-based cohort of 1,390 patients diagnosed in 2010 and 2011 with inflammatory bowel disease (IBD) according to Copenhagen criteria in centres from Eastern and Western European countries.

Aims & Methods

The study aims at describing differences in incidence, treatment strategies, disease course and prognosis of Crohn’s disease (CD) across Eastern and Western Europe. CD patients were followed prospectively from the time of diagnosis until December 31^st, 2020, death, emigration or loss of follow-up. Clinical data on surgery, hospitalizations, and medical treatment, were captured throughout the follow-up period and entered into a validated web-database, www.epi-ibd.org. Associations between surgery and covariates were analysed by multivariate Cox regression analyses.

Results

In total, 482 CD patients aged ≥15 years from 21 centres in 5 Eastern and 11 Western European countries were included. At 10-years follow-up, 101 (21%) patients underwent first intestinal resection and 11 out of these 101 patients (11%) underwent additional resections. Furthermore, 176 (37%) patients had at least one CD related hospitalization. Cancer was diagnosed in 21 (4%) patients, including 4 gastrointestinal cancers. The use of IBD medication was comparable between Eastern and Western European centres apart from 5-aminosalicylic acid agents (Table 1).
During follow-up, 60 out of 360 patients (17%) progressed from non-stricturing-non-penetrating disease (B1) at diagnosis to stricturing or penetrating disease (B2 or B3) while 13 out of 83 patients (16%) with stricturing disease (B2) progressed to penetrating disease (B3). The median time to progression was 28 (IQR: 9-64) months from diagnosis. No patients from Eastern Europe were exposed to biological therapy prior to change in behaviour, compared to 23 out of 66 patients (35%) from Western Europe.
Multivariate Cox regression analysis showed no difference in risk of surgery according to European region (Eastern vs. Western Europe, HR: 0.54, 95%CI: 0.24-1.21). Early intervention with biological therapy (within 6 months) did not influence the risk of surgery (HR:0.75, 95%CI: 0.31-1.83), however early introduction of immunomodulators reduced the risk significantly (HR:0.54, 95%CI: 0.30-0.98). Progression in behaviour from B1 was associated with higher risk of surgery (HR:7.62, 95%CI: 3.91-14.87).

Conclusion

After 10 years of follow-up, 21% underwent intestinal resection and 10% required additional resections. Despite the widespread use of immunomodulators and biological therapy, 16% of the patients had disease behavioural progression, which was associated with higher risk of surgery. Early introduction of immunomodulators was found to be beneficial.

Introduction

Fecal microbiota transplantation (FMT) is the most effective therapy in the treatment of recurrent Clostridioides difficile infection (rCDI), and can be offered in fresh, frozen or lyophilized formulation with similar efficacy. Microbial engraftment is thought to be one of the mechanisms mediating its efficacy. However, the importance of microbes has been questioned by two small preliminary clinical studies that showed sterile fecal filtrate could prevent C. difficile recurrence.

Aims & Methods

Aims: 1) determine if lyophilized sterile fecal filtrate (LSFF) is non-inferior to lyophilized FMT (LFMT) in efficacy; 2) evaluate changes in patient reported health related quality of life (HRQOL); 3) understand patient preferences for different attributes of FMT.
Methods: This double-blind, non-inferiority (margin= 10%) study in 4 academic centers in Canada randomized rCDI patients with > 3 CDI episodes to either LSFF or LFMT (1:1) between 2019 and 2023. Each treatment consisted of 15 oral capsules. Primary outcome was proportion of participants without CDI recurrence at 8 week. Secondary outcomes included 1) proportion of participants without CDI recurrence at week 24 weeks, 2) serious adverse events (mortality, hospitalization and infections related to treatments), and 3) minor adverse events (nausea, vomiting, abdominal pain and fever). Exploratory outcomes included changes in HRQOL and relative importance of different attributes of FMT.

Results

137 participants were randomized (mean [SD] age, 61.2 [18.6] years; 89 women [65.4%]; mean CDI episodes 3.8) to LFMT group (66 participants) and LSFF (71 participants) group. In per-protocol analysis, prevention of rCDI 8 weeks after assigned treatment was achieved in 63.8% of participants in LSFF group and 86.9% in LFMT group (difference, -23.1%), resulting in trial termination. Serious adverse events were infrequent: 4 hospitalizations deemed not related and 1 hospitalization possibly related, and 1 death from COVID deemed not related to assigned treatment. Minor adverse events were self-limited and infrequent: nausea (6), vomiting (2), abdominal discomfort (15) and fever (2). Following treatment, participants had significant increases in EQ-5D-5L (n=99) VAS (median change: 10; p <0.001) and index value (median change: 0.04; p<0.001), and Cdiff32 (n=94) physical domain (median change: 16.07; p <0.001), mental domain (median change: 29.46; p<0.001), and social relationships domain (median change: 7.37; p<0.001). Work impairment decreased (n=21; median change: -10%; p<0.001) and activity impairment decreased (n=101; median change: -20%; p<0.001). Participants (n=103) indicated the 3 most important attributes of FMT were: treatment effectiveness, unknown risks of treatment and known risks of treatment.
Table 1. Participant baseline characteristics

Conclusion

Among adults with rCDI, LSFF was inferior to LFMT by oral capsules in preventing recurrent infection over 8 weeks. The result emphasizes the importance of microbes in mediating FMT efficacy. Preserving microbial viability in future development of microbial therapeutics is paramount.

Disclosure

none

Introduction

Emerging evidence indicates an immunomodulatory role of the appendix in ulcerative colitis (UC). Previous studies suggest a beneficiary effect for appendectomy in inducing and maintaining remission. Therefore, appendectomy might be considered as an alternative treatment in these patients.

Aims & Methods

Aim: To evaluate the efficacy of appendectomy in maintaining remission in UC patients.
Methods: Adult patients with established UC in complete clinical and endoscopic remission (defined as Mayo score <3 with endoscopic subscore of 0 or 1) after being medically treated for disease relapse within 12 months prior to randomization were enrolled in the Netherlands and United Kingdom. Patients were randomized (1:1) to undergo additional appendectomy (intervention group) or continue current medical therapy (control group). The primary outcome was the one-year UC relapse rate, defined as a total Mayo-score score ≥5 with endoscopic subscore of 2 or 3. To detect a clinically relevant decrease in relapse rate from 40% to 20%, 82 patients per study arm were needed. Trial progress and safety reports with accumulated number of (serious) adverse events in both groups were presented to the Data Safety Monitoring Board (DSMB) annually, and therefore data are available. Last patient was included in August 2022, so the final analyses will commence in September 2023.

Results

Between September 2012 and September 2022, 198 patients were randomized. A total of 99 patients were included in the intervention group and 99 patients in the control group. The one-year follow-up data were complete for 183 patients in April 2023.
There were 86 males and 112 females, with a median age of 41 years (IQR 33-52). Baseline characteristics were comparable in both groups, with the majority of patients having been treated for either proctitis (38.9%) or left sided colitis (35.9%) (Table 1). A total of three serious adverse events (SAE) were reported in the appendectomy group, of which two were related to the surgical procedure (reintervention for mechanical ileus and postoperative hematoma) and one hospitalisation for clostridium infection. One SAE was reported within the first year in the control group (appendicitis). During follow up there were no colectomies in the appendectomy group, whereas three patients underwent colectomy for therapy-refractory disease in the control group. In addition, the one-year reported colitis-associated adverse event rate was significantly lower in the appendectomy group when compared to the control group (43.4% vs. 62.7%, P=0.01).

Conclusion

Appendectomy in patients with UC has the possibility to decrease the rate of colitis-associated (serious) adverse events significantly. This suggests that the final analysis of the primary outcome parameter (relapse rate) in September 2023 could demonstrate that appendectomy is superior to standard medical therapy alone in maintaining remission in these patients.