Introduction

Tofacitinib is an oral JAK1 and JAK3 inhibitor approved for the treatment of ulcerative colitis (UC). Despite its proven efficacy, about 40-60% of patients fail to respond to it due to mechanisms not understood. Our aim is to identify the cellular subsets and genes involved in the response and/or resistance to tofacitinib using single-cell RNA sequencing (scRNA-seq) and in vitro functional experiments.

Aims & Methods

Colon biopsies from patients with active moderate to severe UC starting tofacitinib 10 mg bid for 8 weeks and 5 or 10 mg bid thereafter were collected at baseline and during follow-up and processed by single-cell RNA sequencing. Patients were classified as responders (R) or non-responders (NR) based in clinical, endoscopic, and histological criteria. Tofacitinib's impact on macrophages and fibroblasts was assessed using M-CSF monocyte-derived blood macrophages and primary colonic fibroblasts under various inflammatory stimuli (LPS, TNF, and IFNg).

Results

Thirteen out of thirty-one patients enrolled in this study responded to tofacitinib treatment. ScRNA-seq analysis demonstrated partial recovery of the epithelium and a decrease of plasma cells, inflammatory fibroblasts, and neutrophils in R. Importantly, the proportion of T cells remained unaltered. These findings were transcriptionally and histologically validated. Contrary to R, tofacitinib did not drive any of these changes, instead ongoing inflammation induced an increase in the proportions of neutrophils, inflammatory INHBA+ macrophages and inflammatory monocytes in NR after treatment. ScRNA-seq analysis also revealed changes in the transcriptional signature of certain resident populations, including the anti-inflammatory FOLR2+ macrophages and the lamina propria fibroblasts. In R, tofacitinib induced a more tolerogenic profile in both populations whereas in NR, both populations upregulated the expression of inflammatory genes during follow-up. In in vitro monocyte-derived macrophages tofacitinib was able to block the inflammation induced by IFNg and TNF. However, the response to LPS was intensified by tofacitinib as seen by the increased expression of genes normally associated with an inflammatory phenotype (INHBA, CLEC5A) and cytokines (CXCL1, IL6). In contrast to macrophages, fibroblasts showed an overall down regulation of inflammatory genes in response to tofacitinib regardless of the stimuli. Nonetheless, when fibroblasts were exposed to supernatants from LPS/tofacitinib-treated macrophages, they adopted a more inflammatory profile. In response to LPS stimulation monocyte-derived macrophages secrete high levels of the anti-inflammatory IL-10. The transcriptional profile of LPS-stimulated macrophages treated with a blocking anti-IL-10 antibody (Cuevas, Víctor D et al, 2022) highly correlated with the genes upregulated in FOLR2+ macrophages from tofacitinib NR patients. Cytosig analysis from scRNA-seq data confirmed significantly increased IL-10 signaling in macrophages from NR patients compared to R before starting treatment with tofacitinib.

Conclusion

Our data underscores the pivotal role of macrophages in orchestrating responses to tofacitinib and strongly suggests that IL-10 blockade in these cells in the context of ongoing inflammation may explain the exacerbated disease in those patients who become refractory. Understanding the mechanisms underlying "drug escape" may aid in ensure efficacy, limit drug failure, and potentially guide follow-up therapeutic decisions.

References

Cuevas VD, Simon-Fuentes M, Orta-Zavalza E, et al. The Gene Signature of Activated M-CSF-Primed Human Monocyte-Derived Macrophages Is IL-10-Dependent. J Innate Immun 2022;14:243-256.

Disclosure

This work was funded by Pfizer

Introduction

Response to hepatitis B vaccine (HBV) is variable in inflammatory bowel disease (IBD) patients with seroconversion rates of 34-89%. Strategies suggested to improve the seroconversion rates are double dose, accelerated schedule, or addition of booster dose with variable results. This study compared the standard (20 µg) dose and double (40 µg) dose of HBV vaccination in IBD patients.

Aims & Methods

Patients of IBD were randomized to 1:1 to receive standard or double dose of HBV at 0, 1 and 6 months. Anti-HBs titers were assessed at 1 month after the third dose. Response was defined as an adequate immune response (AIR, anti-HBs titer >10 mIU/mL) and effective immune response (EIR, anti-HBs titer >100 mIU/mL). Total mayo score and Crohn’s disease activity index (CDAI) was used to identify the active disease. IBD medications with immunosuppressive effects were categorized as immunomodulators, corticosteroids, tofacitinib and biologic group. Multivariable logistic regression analysis was done to identify the predictors of AIR and EIR.

Results

Eighty-eight patients of IBD were randomized to receive standard (45, 51.1%) or double (43, 48.9%) dose of HBV. 79 of 88 patients had ulcerative colitis (UC) and 9 had Crohn’s disease (CD). 49 (55.7%) patients had active disease while 39 (44.3%) were in remission. At the end of the study, total 63 (71.61%) patients achieved AIR and 51 (60%) achieved EIR. AIR (88.4 % vs. 55.6 %, p 0.001) and EIR (69.8% vs. 46.7%, p = 0.028) rates were significantly higher with double dose compared to standard dose of HBV. Patients with active IBD had higher AIR (87.5% vs. 44%, p = 0.001) and EIR (70.8% vs. 32%, p = 0.007) rates with double dose of HBV. Patients with IBD in remission also had higher AIR (89.5% vs. 70%) and EIR (78.4% vs. 65%) rates with double dose of HBV, though statistically non-significant.
Multivariable analysis identified the use of double dose of HBV {odds ratio (OR) 10.865, 95% confidence interval (CI): 2.418-48.817} and biologic (OR 0.022, 95% CI: 0.001-0.421) as predictors to achieve AIR. Similarly, double dose of HBV (OR 3.0, 95% CI: 1.087-8.280) and use of biologic (OR 0.074, 95% CI: 0.006-0.931) also predicted the EIR.

Conclusion

Double dose of HBV vaccine demonstrated a superiority over standard dose of vaccine for achieving both AIR and EIR. Use of biologic impaired the response. Double dose of HBV should be used in IBD patients to improve the seroconversion rates.

Disclosure

No conflict of Interest

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 36-week (W) POWER trial evaluated the efficacy and safety of a single intravenous (IV) re-induction ustekinumab (UST) dose vs continued UST subcutaneous (SC) treatment in Crohn’s disease (CD) patients with secondary loss of response (LoR) to standard UST maintenance therapy. Here, we report subgroup analysis of the primary endpoint by baseline characteristics.

Aims & Methods

Adults with moderately–severely active CD who initially responded to UST IV induction therapy per label and later experienced LoR were included. LoR was defined as CD Activity Index (CDAI) score of ≥220 and ≤450, plus either elevated C-reactive protein (CRP; >3mg/L), faecal calprotectin (fCal; >250mg/kg), or endoscopy performed ≤3 months before W0 with ≥1 ulcerations in ileum and/or colon (active CD). At baseline (W0), randomised patients received ~6mg/kg IV UST/SC placebo (IV arm) or IV placebo/SC UST 90mg (SC arm), followed by SC UST 90mg dosing at W8/16. Descriptive statistics were used to summarise baseline characteristics. Clinical assessments occurred at W0/8/16. Primary endpoint: clinical response (CRes; decrease of ≥100 points from W0 or CDAI <150) at W16. Odds ratios (ORs), confidence intervals (CIs) and p-values were estimated with a logistic regression model.

Results

The full analysis set comprised 215 patients at W0 (SC, n=107; IV, n=108). At W16, 86.0% (SC) and 92.6% (IV) of patients completed treatment. At W16, 37.4% (SC) and 49.1% (IV) of patients achieved CRes (p=0.089). Of all baseline characteristics, disease location and duration, inflammatory biomarkers, and prior biologic failures were of particular interest (Table). A greater proportion of patients from the IV vs SC arm achieved CRes at W16 (OR 3.6; 95%CI 1.6–8.1; p=0.002) of those with ileum and colon involvement. Patients with disease duration of <5 years in the IV (n=22) vs SC (n=20) arm were more likely to achieve W16 CRes (OR 4.5; 95%CI 1.2–17.4; p=0.029). A greater proportion of patients in the IV vs SC arm with elevated baseline CRP (OR 2.1; 95%CI 1.1–4.0; p=0.029) or fCal (OR 2.0; 95%CI 1.0–4.0; p=0.045) achieved W16 CRes as did patients with 1 prior biologic failure (OR 2.8; 95%CI 1.0–7.6; p=0.042).

Conclusion

POWER assessed the efficacy and safety of UST IV re-induction in patients with LoR during UST maintenance therapy. This analysis suggests that patients with fewer prior biologic exposures and shorter disease duration but a higher disease burden at baseline including greater disease extent involving ileum and colon, or elevated inflammatory biomarkers, are more likely to benefit from UST IV re-induction therapy.

Disclosure

I. Marín-Jiménez has served as a consultant, advisory member, speaker or has received research funding from Abbvie, Chiesi, Faes Farma, FalkPharma, Ferring, Gebro Pharma, Hospira, Janssen, MSD, Otsuka Pharmaceutical, Pfizer, Shire, Takeda, Tillots and UCB Pharma. S. Schreiber has received personal fees from AbbVie, Amgen, Arena, Biogen, Bristol Myers Squibb, Celgene, Celltrion Healthcare, Dr. Falk Pharma, Fresenius, Galapagos/Gilead, Hikma, I-Mab, Janssen, MSD, Mylan, Pfizer, Protagonist, ProventionBio, Takeda and Theravance Biopharma. S. Lee served as a consultant for Applied Molecular Transport, Arena, Boehringer Ingelheim, Bridge Biotherapeutics, Bristol-Myers Squibb, Celgene, Celltrion Healthcare, Cornerstones Health, Eli Lilly and Company, Janssen, KCRN Research, Samsung Bioepis and UCB; and received research grants from AbbVie, AbGenomics, Arena, Celgene, Janssen, Salix, Takeda and UCB. C.J. van der Woude received grant support from Falk Ben-elux, Ferring and Pfizer; received speaker fees from AbbVie, Takeda, Ferring, Dr Falk Pharma and Pfizer; and served as a consultant for Janssen. D. Wolf has received honoraria as a speaker, consultant and/or advisory board member from AbbVie, Arena, Celgene/Bristol Myers Squibb, Janssen, Pfizer and Takeda. E. Schnoy has received personal fees from AbbVie, Bristol Myers Squibb, Celltrion Healthcare, Dr. Falk Pharma, Galapagos/Gilead, I-Mab, Janssen, Lilly, Pfizer, Pharmacosmos, Takeda and Tillotts Pharma. B. Salzberg served as a consultant for Johnson and Johnson and has received honoraria as a speaker from AbbVie, Bristol-Myers Squibb and Johnson and Johnson. M. Nazar is an employee of Janssen-Cilag Polska Sp. z o.o., and has restricted stocks. C. Busse, W. Langholff, C. Gasink, T. Baker and B. Godwin report employment with/funding by Janssen Research & Development, LLC, a wholly owned subsidiary of Johnson & Johnson, and stock ownership in Johnson & Johnson. B. Feagan received grant/research support from AbbVie Inc., Amgen Inc., AstraZeneca/MedImmune Ltd., Atlantic Pharmaceuticals Ltd., Boehringer-Ingelheim, Celgene Corporation, Celltech, Genentech Inc/Hoffmann-La Roche Ltd., Gilead Sciences Inc., GlaxoSmithKline (GSK), Janssen Research & Development LLC., Pfizer Inc., Receptos Inc./Celgene International, Sanofi, Santarus Inc., Takeda Development Center Americas Inc., Tillotts Pharma AG and UCB; was a consultant for Abbott/AbbVie, AdMIRx Inc., Akebia Therapeutics, Allergan, Amgen, Applied Molecular Transport Inc., Aptevo Therapeutics, Asta Pharma, Astra Zeneca, Atlantic Pharma, Avir Pharma, Biogen Idec, BioMx Israel, Boehringer-Ingelheim, Boston Pharmaceuticals, Bristol-Myers Squibb, Calypso Biotech, Celgene, Elan/Biogen, EnGene, Ferring Pharma, Galapagos, Galen/Atlantica, GiCare Pharma, Gilead, Gossamer Pharma, GSK, Inception IBD Inc, Intact Therapeutics, JnJ/Janssen, Kyowa Kakko Kirin Co Ltd., Lexicon, Lilly, Lycera BioTech, Merck, Mesoblast Pharma, Millennium, Nestles, Nextbiotix, Novonordisk, ParImmune, Parvus Therapeutics Inc., Pfizer, Prometheus Therapeutics and Diagnostics, Progenity, Protagonist, Qu Biologics, Rebiotix, Receptos, Roche/Genentech, Salix Pharma, Shire, Sienna Biologics, Sigmoid Pharma, Sterna Biologicals, Synergy Pharma Inc., Takeda, Teva Pharma, TiGenix, Tillotts, UCB Pharma, Vertex Pharma, Vivelix Pharma, VHsquared Ltd. and Zyngenia; was a member of the speakers bureau for Abbott/AbbVie, JnJ/Janssen, Lilly, Takeda, Tillotts and UCB Pharma; a member of the scientific advisory board for Abbott/AbbVie, Allergan, Amgen, Astra Zeneca, Atlantic Pharma, Avaxia Biologics Inc., Boehringer-Ingelheim, Bristol-Myers Squibb, Celgene, Centocor Inc., Elan/Biogen, Galapagos, Genentech/Roche, JnJ/Janssen, Merck, Nestles, Novartis, Novonordisk, Pfizer, Prometheus Laboratories, Protagonist, Salix Pharma, Sterna Biologicals, Takeda, Teva, TiGenix, Tillotts Pharma AG and UCB Pharma; and was a Senior Scientific Officer for Robarts Clinical Trials Inc.

Introduction

Clostridioides difficile infection (CDI) includes severe clinical pictures of disease that are associated with considerable risk of complications, including bloodstream infection, toxic megacolon, death, and others, and represent a relevant burden for healthcare system.1,2 Fecal microbiota transplantation (FMT) is an established treatment for recurrent CDI,3 but its role in severe clinical pictures of CDI is still not well defined.

Aims & Methods

Our aim is to report efficacy and safety of FMT in a large cohort of patients with severe and severe-complicated CDI.
We included consecutive patients with severe CDI treated with FMT at our center from June 2013 to January 2023. Severe and severe-complicated CDI were defined according to international guidelines.1,2 We collected demographical and baseline clinical data of patients, including age, sex, risk factors for CDI, comorbidities assessed with the Charlson Comorbidity Index (CCI), number of previous CDI recurrences. Enrolled patients were followed up with visits or telephone calls up to 12 weeks after the last FMT.
The primary outcome was the clinical resolution of CDI (defined as resolution of diarrhea) at 8 weeks after FMT, while the secondary outcomes were the overall survival at 90 days, and the safety of FMT. Candidate stool donors were screened, following international guidelines (3-5), through a preliminary interview, blood tests, stool tests, and, more recently, with nasopharyngeal swab for SARS-CoV-2.
FMT procedures were carried out by colonoscopy, after a 3-day pre-treatment with oral vancomycin and bowel cleansing, using a single-donor solution of at least 50 grams of fresh feces (before 2017) or frozen feces (after 2017). All patients received at least one fecal infusion. Moreover, after 2015 we planned a sequential FMT approach in this subset of patients, by repeating FMT until the disappearance of diarrhea.

Results

In the study period, 85 patients were enrolled. Of them, 71 had severe CDI and 14 had severe-complicated CDI. Of them, 54 (63,5%) were female, and the mean age was 73 years while the median number of CDI recurrences was 2.
Overall, 39 patients had history of chronic therapy with PPIs, 68 patients had history of antibiotic therapy in the 30 days prior to FMT, 72 patients were hospitalized, and 24 patients were bedridden. The mean CCI was 5.5.
Forty-four patients received sequential FMT, for a total of 158 FMT procedures. Most procedures were performed using frozen feces (n= 102, 64.6%) from unrelated donors (n= 137, 86.7%).
Overall, 76 patients (89.4%) experienced resolution of CDI (65 with severe CDI and 11 with severe-complicated CDI). Thirty-six patients (47.4%) achieved CDI cure with a single FMT procedure.
Fifteen patients (17.6%) died within the 12-week follow-up period. Seven of the 15 patients died for overwhelming CDI. No deaths were attributable to FMT.
At multiple linear regression, enticement was significantly associated with lower CDI cure (p= 0.0026) and higher risk of death (p= 0.0013).
We observed also severe adverse events in 4 patients (4.7%). Three patients developed a bloodstream infection and one patient with chronic heart failure experienced an episode of acute heart failure after FMT. All these events were transient and resolved in few days.

Conclusion

In a large cohort of patients from a high-volume FMT center, FMT was a highly effective and safe treatment for severe and severe-complicated CDI, being also associated with high rates of overall survival in the mid-term. Enticement was identified as a risk factor for FMT failure and death.

References

1) PMID: 34678515
2) PMID: 24118601
3) PMID: 28087657
4) PMID: 32620549
5) PMID: 31563878

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.