Introduction

Celiac disease (CeD) is treated with gluten-free diet (GFD), which normalizes histological small intestinal inflammation and disease-specific antibodies [1]. Pathogenic T-cells can be studied with HLA-DQ2.5:gluten tetramers and express a phenotype resembling Tfollicula helper-cells [2]. Upon gluten re-introduction, persisting, HLA-restricted, gluten-specific T cells support pathogenic memory response [3]. To better understand the immunological memory in CeD, we monitored HLA-DQ2.5-restricted, gluten-specific CD4+ T cells along other biomarkers the first year of treatment.

Aims & Methods

We prospectively followed 17 CeD patients through five visits the first year on GFD and assessed activation and frequency of gluten-specific CD4+ blood and gut T cells with HLA-DQ2.5:gluten tetramers and flow cytometry in parallel with disease-specific serology, histology and symptom scores. In 16 of the 17 patients, mucosal healing at follow-up biopsies was seen. We followed proliferation, survival and 12 markers hallmarking gluten-specific blood T cells and serology the first three weeks on GFD (n =6).

Results

Gluten-specific CD4+ T-cells peaked at day 14 while upregulating Bcl-2 and downregulating Ki-67, then decreased significantly in frequency within 10 weeks of GFD. CD38, ICOS, HLA-DR and Ki-67 decreased significantly in gluten-specific cells within three days. Further markers changed significantly within 14 days. PD-1, CD39 and OX40 expression persisted even after 12 months. Disease-specific antibodies (IgA-TG2 and IgG-DGP) decreased significantly within four weeks on GFD and were, with one exception, below upper level of normal after 1 year.

Conclusion

GFD initiates instant changes in phenotype and number of gluten-specific CD4+ T cells, including a day-14 cell peak with accumulation of non-proliferating, non-apoptotic cells. The subsequent, prolonged alterations in T-cell phenotype associate with the chronic nature of CeD. The initial dynamics and chronic features of gluten-specific CD4+ T cells and the instant disease-specific antibody decrease may be used in diagnosis and to determine compliance to GFD and effect of novel treatment.

References

1. Al-Toma, A., et al., European Society for the Study of Coeliac Disease (ESsCD) guideline for coeliac disease and other gluten-related disorders. United European Gastroenterol J, 2019. 7(5): p. 583-613.
2. Christophersen, A., et al., Distinct phenotype of CD4(+) T cells driving celiac disease identified in multiple autoimmune conditions. Nat Med, 2019. 25(5): p. 734-737.
3. Christophers

Introduction

Tissue factor (TF) on cell membranes initiates blood clotting upon vessel trauma and exposure of subendothelial cells to blood flow. The risk of thromboembolic events is increased in patients with ulcerative colitis (UC). Tofacitinib, a JAK1 & 3 inhibitor, recently introduced in UC therapeutics, may further increase the risk¹.

Aims & Methods

To delineate thrombosis pathophysiology in this context, TF expression in primary human colonic mesenchymal cells (PHCMC) of patients with active UC was correlated with clinical, biochemical and endoscopic data. We then treated those PHCMC with tofacitinib, with or without cytokines to better mimic the in vivo milieu they are exposed to.
PHCMC were isolated and set to ex vivo culture from endoscopic biopsies of the inflamed mucosa of 10 UC patients with an endoscopic Mayo score ≥ 2 were treated with each one of all major T helper (Th)1 (TNF-α, IFN-γ), Th2 (IL-4, IL-13) or T regulatory (Treg; TGF-β, IL-10) cytokines with or without tofacitinib. Cells were lysed, RNA was isolated and reverse-transcribed to cDNA. TF and RPL4 (housekeeping) cDNAs were quantified as C_T cycles with real-time, reverse-transcription PCR. Wilcoxon and Mann-Whitney U tests were used to compare TF ΔΔC_T for paired or unpaired values, respectively, and Spearman’s rho to correlate TF ΔΔC_T with scale clinical variables and continuous laboratory values.

Results

Increased TF mRNA abundance in PHCMC was associated with increased partial Mayo score (Spearman's rho 0.661, p < 0.044), reduced serum albumin (Spearman's rho -0.723, p < 0.05) and more severe endoscopic lesions (endoscopic Mayo score 3). No association with CRP was found (p > 0.999). Cells originating from UC patients of an endoscopic Mayo score 3 expressed 20 times more TF than those from an endoscopic Mayo score 2 (p < 0.017). Furthermore, PHCMC from difficult-to-treat patients, defined as requiring > 1 biologics, expressed 9 times more TF than those from patients requiring ≤ 1 biologics.
Interestingly, treatment of PHMC with tofacitinib did not upregulate TF. PHCMC expressed receptors and responded to treatment with all major Th1 (TNF-α, IFN-γ), Th2 (IL-4, IL-13) or Treg (TGF-β, IL-10) cytokines by further upregulating TF by 5.5-7.5 times (p 0.001 - 0.035). IL-13 had the maximal effect. Even when tofacitinib was added together with the aforementioned cytokines, it did not further upregulate TF. Instead, it tended to partially inhibit their effects; for example, it decreased upregulation of TF by IL-13 by 40%.

Conclusion

The expression of TF mRNA in active UC is significantly associated with clinically and endoscopically severe disease and resistance to treatment. Tofacitinib per se does not increase TF. Instead, it may limit the upregulating effect of pro-inflammatory cytokines.

References

1. Sandborn WJ, Panés J, Sands BE, Reinisch W, Su C, Lawendy N, Koram N, Fan H, Jones TV, Modesto I, Quirk D, Danese S. Venous thromboembolic events in the tofacitinib ulcerative colitis clinical development programme. Aliment Pharmacol Ther. 2019 Nov;50(10):1068-1076.

Disclosure

Procurement of reagents and consumables for this project was partially supported by Pfizer Inc. with competitive grant # 64132481.

Introduction

Not all patients with ulcerative colitis (UC) respond initially to treatment with biologic agents, and predicting their efficacy prior to treatment is difficult. Vedolizumab, a humanized monoclonal antibody against alpha 4 beta 7 (α4β7) integrin, suppresses immune cell migration by blocking the interaction between α4β7 integrin and mucosal addressin cell adhesion molecule 1, and is used to treat patients with UC with moderate-to-severe activity. Reports about histological features that predict vedolizumab efficacy are scarce.

Aims & Methods

We evaluated the infiltration of inflammatory cells in the colonic mucosa prior to the induction of vedolizumab and examined the association between histological features and vedolizumab efficacy.
This was a multicenter, retrospective study. Patients with UC who were treated with vedolizumab between November 2018 and April 2021 were enrolled in this study. All eligible patients had moderate-to-severe disease activity at the time of the initial treatment with vedolizumab. Biopsy specimens taken from the colonic mucosa prior to vedolizumab induction were used, and the areas positively stained for CD4, CD68, and CD45 per unit area of the lamina propria were calculated. Clinical and histological features were compared between those with and without remission at week 22, and the factors associated with clinical outcomes were identified.

Results

A total of 42 patients were included in this study. 17 (40.5%) patients achieved clinical remission at week 22. Significantly more CD4+ cells were found in the colonic mucosal tissues of patients with remission than in those without remission (odds ratio [OR]=1.44, P=0.014). In contrast, the CD68-positive area and the CD45-positive were not significantly different between the two groups. The concomitant use of corticosteroids and high Mayo scores had a negative association with the vedolizumab response (OR=0.11, P=0.008 and OR=0.50, P=0.009, respectively).

Conclusion

A high CD4+ infiltration in the colonic mucosa was associated with remission after vedolizumab treatment. Histological evaluation for CD4+ cell infiltration may be helpful in selecting patients who can benefit from vedolizumab.

Introduction

In contrast to ulcerative colitis (UC), the impact of bowel urgency (BU) in patients with moderate-to-severe Crohn’s disease (CD) is unclear. The Communicating Needs and Features of IBD Experiences (CONFIDE) survey aims to understand the experience and impact of symptoms on lives of patients with UC or CD worldwide (United States [US], Europe [EU], and Japan). This survey also explores the communication gaps between healthcare professionals (HCPs) and patients. Previously reported CONFIDE data suggested that BU was the second most reported symptom among US and EU5 (France, Germany, Italy, Spain, and UK) patients with moderate-to-severe UC.¹ Persistent BU was reported in 46% US and 28% EU5 patients receiving advanced therapies for UC and 45% US and 37% EU5 patients reported wearing diapers/pads/protection at least once every week.¹ Here, we present patient and HCP perspectives on the experiences and impact of CD-related symptoms.

Aims & Methods

Online, quantitative, cross-sectional surveys were conducted separately among HCPs and patients with CD from US and EU5 between May and October 2021. Moderate-to-severe CD was defined using criteria based on previous treatment, steroid use, and/or hospitalization. Data are presented as descriptive statistics.

Results

Surveys were completed by 215 US (male [M]=55%, mean age 41 years) and 547 EU5 (M=55%, mean age 38 years) patients. Of these, 58% US and 63% EU5 patients were receiving advanced therapies (biologic/novel oral) and 66% and 63% were receiving steroids at the time of survey completion, respectively. Most patients in the US (61%) and EU5 (62%) reported moderate CD, followed by severe (25% and 10%), and mild CD (14% and 28%).
In both US and EU5 populations, top three symptoms currently (past month) experienced by patients were diarrhoea (US: 55%, EU5: 55%), BU (US: 42%, EU5: 38%), and increased stool frequency (US: 40%, EU5: 37%). Among the patients receiving advanced therapies (US: 58%, EU5: 63%), 46% US and 39% EU5 patients experienced BU and 27% US and 19% EU5 patients reported fistula-related symptoms around the anus/rectum. Of the patients who had experienced BU, only 40% US and 27% EU5 patients were completely comfortable discussing BU with their HCPs and only 27% US and 23% EU5 patients felt comfortable discussing BU-related accidents. Embarrassment was the most common reason for discomfort associated with discussing BU (US: 73%, EU5: 64%) and BU-related accidents (US: 72%, EU5: 66%) with HCPs.
A total of 200 US (M=78%) and 503 EU5 (M=71%) HCPs completed the surveys, of which 92% were gastroenterologists or specialists in internal medicine and 7% were non-physicians. According to HCPs, the top three patient-reported symptoms were diarrhoea (US: 67%, EU5: 66%), blood in stool (US: 44%, EU5: 24%), and increased stool frequency (US: 32%, EU5: 28%). BU was reported among the top three symptoms only by 19% US and 16% EU5 HCPs. Many HCPs (US: 34%, EU5: 40%) reported not proactively discussing BU, with the most common reason being that they “expect the patient to bring this up if this is an issue” (US: 34%, EU5: 42.0%).

Conclusion

Similar to the findings in UC patients¹, bowel urgency was the second most reported symptom among patients with CD, but not among the HCP-perceived top three symptoms. A large proportion of patients with moderate-to-severe CD receiving advanced therapies continued to experience bowel urgency. These results indicate a communication gap between HCPs and patients with CD, highlighting the underappreciation of the impacts of bowel urgency on patients’ daily lives.

References

1. Rubin, D. T. et al. (2021) P028 Communicating Needs and Features of IBD Experiences (CONFIDE) Survey: Patient and Healthcare Professional Perspectives on Experience of Ulcerative Colitis Symptoms. The American Journal of Gastroenterology, 116:p S7. https://doi.org/10.14309/01.ajg.0000798712.28363.8b

Disclosure

• Simon Travis, Grants: AbbVie, ECCO, Eli Lilly and Company, Helmsley Trust International, Organization for the Study of Inflammatory Bowel Disease, Norman Collision Foundation, Pfizer, Takeda, UCB Pharma, UKIERI, Vifor Pharma; Consultancy fees: AbbVie, Allergan, Amgen, Apexian, Asahi Kasei Pharma, Bioclinica, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, ChemoCentryx, Cosmo Pharmaceuticals, Eli Lilly and Company, Enterome, Equillium, Ferring Pharmaceuticals, Genentech/Roche, GlaxoSmithKline, Giuliani SpA, Immunocore, Immunometabolism, Janssen, Merck, Merck Sharp & Dohme, Mestag Therapeutics, Neovacs, Novartis, Novo Nordisk, NPS Pharmaceuticals/Nycomed, Pfizer, Protagonist Therapeutics, Proximagen, Receptos, Roche, Satisfai Health, Sensyne Health, Shire, Sigmoid Pharma, Sorriso Pharmaceuticals, Takeda, UCB Pharma, VHsquared, Vifor Pharma, and Zeria Pharmaceutical.
• Marla C. Dubinsky, Consultancy fees: AbbVie, Arena Pharmaceuticals, Boehringer Ingelheim International GmbH, Bristol Myers Squibb, Celgene Corporation, Eli Lilly and Company, F. Hoffman-La Roche Ltd, Genentech Inc., Gilead Sciences, Janssen, LLC, Pfizer, Prometheus Biosciences, Takeda Pharmaceuticals USA, Inc., and UCB; Stockholder: Trellus Health Inc.; Research support: AbbVie, Janssen, LLC, Pfizer, and Prometheus Biosciences; Licensing fees: Takeda.
• Toshifumi Hibi, Consultancy fees/grant/research support/speaker: AbbVie GK and Mitsubishi-Tanabe Pharma; Grant/Lecture/speaker fees: JIMRO, Mochida Pharmaceutical, Takeda Pharmaceutical, and Zeria Pharmaceutical; Consultancy/ Lecture/speaker fees: Pfizer, EA Pharma; Grants: Kyorin, Otuska Holdings; Consultancy fees: Bristol-Myers Squibb, Eli Lilly and company, Gilead Sciences, Janssen, Nichi-Iko Pharmaceutical; Lecture/speaker fees: Sondoz K.K.
• David T. Rubin, Consultancy fees: Abbvie, Alimentiv Inc., Altrubio, Arena Pharmaceuticals, Aslan Pharmaceuticals, Athos Therapeutics, Bellatrix Pharmaceuticals, Boehringer Ingelheim Ltd., Bristol-Myers Squibb, Celgene Corp/Syneos, ClostraBio, Connect BioPharma, EcoR1, Genentech/Roche, Gilead Sciences, Ironwood Pharmaceuticals, Iterative Scopes, Janssen Pharmaceuticals, Kaleido Biosciences, Eli Lilly and company, Materia Prima, Pfizer, Prometheus Biosciences, Reistone, Seres Therapeutics, Takeda, Target RWE, Techlab Inc., and Trellus Health; Stockholder: Altrubio, Alike, and Iterative Scopes.
• Remo Panaccione, Consultancy/speaker fees and/or advisory board member: AbbVie, Amgen, Arena Pharmaceuticals, Bristol-Myers Squibb, Celgene, Eli Lilly and Company, Ferring, Fresenius Kabi, Gilead Sciences, Janssen, Merck, Organon, Pfizer, Roche, Sandoz, Shire, and Takeda; Consultancy fees and/or advisory board member: Alimentiv, AstraZeneca, Biogen, Boehringer Ingelheim, Genentech, Glaxo-Smith Kline, JAMP Bio, Mylan, Novartis, Oppilan Pharma, Pandion Pharma, Progenity, Protagonist Therapeutics, Sublimity Therapeutics, Ventyx; Consultancy fees: Abbivax, Abbott, Celltrion, Cosmos Pharmaceuticals, Eisai, Elan, Galapagos, JAMP Bio, Pendopharm, Satisfai Health, Theravance Biopharma, Trellus, Viatris, and UCB.
• Stefan Schreiber, Consultancy fees: AbbVie, Arena, Biogen, Bristol-Myers Squibb, Celgene, Celltrion, Falk, Fresenius, Gilead Sciences, IMAB, Janssen, Eli Lilly and Company, MSD, Mylan, Pfizer Inc, Protagonist, Provention Bio, Takeda, and Theravance
• Christian Atkinson, Employee: Adelphi Real World
• Theresa H. Gibble, Cem Kayhan, Alison P. Bleakman, Tommaso Panni, and Angelo Favia are employees and stockholders of Eli Lilly and Company.

Introduction

Although CADe/x systems increase colorectal polyp detection, their ability to predict histological diagnosis is limited.

Aims & Methods

The aim of this study is to determine which factors related to morphology, histology and the image characteristics are associated with histology prediction by PolyDeep, a CADe/x system.
For this analysis, 5546 still images of colorectal polyps collected in PIBAdb database (https://www.iisgaliciasur.es/home/biobanco/colorectal-polyp-image-cohort-pibadb/?lang=en) were used. The images were obtained from videos recorded by endoscopist. Each image was associated with the endoscopy description (morphology, size), the final histology diagnosis and the characteristics (size, area) related with the Red, Green and Blue model (RGB model) and the Hue, Saturation and Value model (HSV model). Finally, the Convolutional Neural Network (CNN) determined the probability a polyp was classified as neoplastic lession (adenomatous, Traditional Serrated Adenoma,TSA, Sessile Serrated Lession, SSL). We determined Polydeep classified lesions as neoplastic if the probability was ≥0.5. We performed three analysis: (1) linear multiple regression in order to determine which variables are associated with the probability of classification as neoplastic lesions. (2). A multivariate logistic regresion analysis to define the variables associated with the classification as a neoplastic lesions. (3) A multivariate logistic regression to establish which variables are associated with missclassification of polyps. We use the R software for statistical computing.

Results

PolyDeep classified 84,51% of the lesions as neoplastic lession and managed to correctly classify 85.02% of the evaluated polyps (92.8% adenomas, 82.5% TSA, 84.2% SSL and 51.6% hyperplastic). The R² in the multiple linear regression is the 0.3655. The model associated to the neoplastic diagnosis has an Akaike Information Criterion (AIC) of 3363.3 and the model associated with missclassification, has an AIC of 3547.5. The variables associated to each regression model showed in the attached table.

Conclusion

The results obtained in this study allow us to establish strategies to improve Polydeep predicted histological diagnosis.

Introduction

Vedolizumab is a humanised monoclonal antibody whose mechanism of action is inhibition of the α4β7 integrin of T leukocytes. It is indicated for moderate or severe flare of inflammatory bowel disease. Subcutaneous (SC) vedolizumab, a new formulation recently approved, is a major advantage for patients for home administration.

Aims & Methods

Analyse the percentage of clinical and biochemical remission in patients on treatment with intravenous (IV) vedolizumab after switching to SC vedolizumab. In addition, the relationship between a treatment with intensified IV vedolizumab and subsequent drug levels versus patients without intensification.
Single-center, descriptive, observational, and retrospective study of a cohort of all of 19 patients diagnosed with ulcerative colitis (UC) and crohn disease (CD) teatred with IV vedolizumab in January 2022, who underwent a switch to SC vedolizumab. Analyse of clinical and analytical parameters (faecal calprotectin (FC), concomitant treatment, vedolizumab levels during follow-up, need for intensified intravenous treatment, ocurrence of adverse effects or loss of response) in patients on IV vedolizumab treatment and subsequent switch to SC vedolizumab with follow-up during weeks 4, 12, and 24.

Results

Ten patients (22.6%) were diagnosed with UC and 9 patients (47.3%) with CD. The baseline characteristics of the patients are described in table 1. 68% of patients were exposed to anti-TNF when initiating IV Vedolizumab due to loss of response, and 15,7% had been exposed to >1 anti-TNF. 31% (6 patients) were naive to Anti-TNF, 4 patients (21%) IV vedolizumab was started as the first line of treatment due to the increased risk of infections and a previous history of neoplasia and in 2 patients with CD (10.5%) vedolizumab was started as prevention of recurrence. Up to 8 patients (42.1%) were on an intensified IV vedolizumab prior to switching to SC vedolizumab. Biochemical remission (FC < 150 µg/g) was achieved in 14 patients (77.7%) at week 24 of follow-up. All 19 patients (100%) achieved clinical remission. It was noted that biochemical remission was not achieved in up to 50% of patients on the intensified regimen with IV vedolizumab. Mean baseline intravenous vedolizumab levels were 12.1 μg/ml. After switching to SC vedolizumab, the mean levels were 13.1 μg/ml at week 4, 19.9 μg/ml at week 12 and 22.9 μg/ml at week 24 (p= 0.001). There was no statistically significant difference in biochemical remission between patients who received an intensive IV vedolizumab regimen and those who did not. One adverse event (paraesthesia) was described in one patient (5.2%) in relation to IV vedolizumab.

Table 1. Baseline characteristics.

Conclusion

78% of patients after switching from IV vedolizumab to SC vedolizumab, reached clinical and biochemical remission at 6 months of follow-up. In addition, vedolizumab levels increased progressiively after switching IV vedolizumab to SC treatment. These findings confirm that SC vedolizumab is a good therapeutic option for long-term maintenance.

References

• Ventress E, Young D, Rahmany S, Harris C, Bettey M, Smith T, Moyses H, Lech M, Gwiggner M, Felwick R, Cummings JRF. Transitioning from Intravenous to Subcutaneous Vedolizumab in Patients with Inflammatory Bowel Disease [TRAVELESS]. J Crohns Colitis. 2022 Jul 14;16(6):911-921. doi: 10.1093/ecco-jcc/jjab224.
• Vermeire S, D'Haens G, Baert F, Danese S, Kobayashi T, Loftus EV, Bhatia S, Agboton C, Rosario M, Chen C, Zhang W, Kisfalvi K, Sandborn WJ. Efficacy and Safety of Subcutaneous Vedolizumab in Patients With Moderately to Severely Active Crohn's Disease: Results From the VISIBLE 2 Randomised Trial. J Crohns Colitis. 2022 Jan 28;16(1):27-38. doi: 10.1093/ecco-jcc/jjab133.
• Bergqvist V, Holmgren J, Klintman D, Marsal J. Real-world data on switching from intravenous to subcutaneous vedolizumab treatment in patients with inflammatory bowel disease. Aliment Pharmacol Ther. 2022 Jun;55(11):1389-1401. doi: 10.1111/apt.16927.

Introduction

Limited evidence is available about predictors of response to specific medications for ulcerative colitis (UC). OCTN1, an organic cation transporter, with its variants, could modulate the inflammatory response and potentially modify drug response to immune-modulatory therapy (anti-TNFα and Vedolizumab), perhaps predicting individual response.

Aims & Methods

We first confirmed the ability of OCTN1 to differentially modulate IL1β secretion under different stimuli in a human leukemia monocytic cell line (THP-1) and in human peripheral blood mononuclear cells. We therefore prospectively enrolled a cohort of UC patients starting either anti-TNFα or Vedolizumab, determined their OCTN1 genotype and evaluated their clinical features at baseline and clinical response to therapy or disease remission (according to clinical Mayo score) after six weeks (T1) and six months (T2). We finally enrolled a cohort of UC patients in clinical and endoscopic remission (according to full Mayo score) under immune-modulatory therapy (anti-TNFα or Vedolizumab) for at least two years.

Results

OCTN1-deficient THP1 cells showed reduced IL-1β secretion in response to peptidoglycan (PGN) and Fusobacterium nucleatum (Fn), whilst primary monocytes bearing OCTN1 503F variant displayed an increased production of IL-1β in response to PGN and live bacteria. We therefore enrolled 90 patients, 50 starting anti-TNFα and 40 Vedolizumab. Patients with 503F genotype showed higher rates of pancolitis as compared to 503L genotype. Among patients with 503L phenotype, Vedolizumab results highly associated with long-term response (OR 8.92, 95%CI 0.50-11.0; p=0.019), whilst conversely co-presence of 503F genotype and Vedolizumab therapy disclosed an opposite role on the long-term response rate (OR 0.02, 95%CI 0.00-0.81; p=0.038).
The population of UC patients in clinical and endoscopic remission was composed by 92 patients, 63 under anti-TNFα and 29 under Vedolizumab. Of note, similar trends of disease extension were observed across genotypes: higher rates of pancolitis were observed in the 503F population as compared to 503L (62.5% vs 44%). Furthermore, among patients in remission with 503F genotype, the percentage of subjects receiving Vedolizumab was sensibly lower than among patients with 503L genotype (87.5% anti-TNFα vs 12.5% Vedolizumab among 503F genotype; 56% anti-TNFα vs 44% Vedolizumab among 503L genotype).

Conclusion

Mutated OCTN1 genotype (503F) favors an increased IL1β secretion from human stimulated leukocytes, thus suggesting a worse disease course with higher rate of pancolitis and lower response to Vedolizumab as compared to 503L.