Introduction

Etrasimod is an investigational, oral, once-daily, selective sphingosine 1‑phosphate (S1P)_1,4,5 receptor modulator in development for the treatment of moderately to severely active ulcerative colitis (UC). Prior analyses demonstrated etrasimod efficacy in UC¹ and greater improvement from baseline in Inflammatory Bowel Disease Questionnaire (IBDQ) total score and domains vs placebo (PBO).²

Aims & Methods

This post hoc subgroup analysis examined the effect of prior and concomitant therapies on IBDQ scores in the phase 3 ELEVATE UC clinical programme. In ELEVATE UC 52 (NCT03945188) and ELEVATE UC 12 (NCT03996369), eligible patients (pts) with modified Mayo scores of 4–9 completed the 32‑item IBDQ at Weeks (Wks)12 (both trials) and 52 (ELEVATE UC 52). In this analysis, pts were stratified by prior biologic/Janus kinase inhibitor (bio/JAKi) and baseline corticosteroid (CS) use. Least squares (LS) mean change from baseline in IBDQ total and domain scores were compared for etrasimod vs PBO (data as observed). Proportions of pts with IBDQ remission (total score ≥ 170) were analysed (nonresponder imputation).

Results

Among all randomised patients, there were 304/433 and 236/354 pts without prior bio/JAKi use and 298/433 and 255/354 pts without baseline CS use in ELEVATE UC 52 and ELEVATE UC 12, respectively. Overall, mean baseline IBDQ total scores were similar in pts with and without prior bio/JAKi or baseline CS use. At Wks12 (both trials) and 52 (ELEVATE UC 52), LS mean change from baseline in IBDQ total and domain scores was higher (p<0.05) for etrasimod vs PBO in pts without prior bio/JAKi and pts without baseline CS use (Table). IBDQ remission was generally achieved by significantly higher proportions of pts receiving etrasimod vs PBO regardless of prior bio/JAKi or baseline CS use at Wk52 (prior bio/JAKi use: No, 46.8% vs 21.2% [p<0.001] and Yes, 25.0% vs 11.1% [p=0.043]; baseline CS use: No, 41.3% vs 15.7% [p<0.001] and Yes, 38.7% vs 23.8% [p=0.087]).

Conclusion

Pts receiving etrasimod had improvements in IBDQ total score and in all 4 domains at Wk12, maintained at Wk52. Significant differences were shown in these outcomes with etrasimod vs PBO in pts without prior bio/JAKi and without baseline CS use. IBDQ remission was generally achieved by higher proportions of pts without vs with prior bio/JAKi or without vs with baseline CS use.

References

1. Sandborn W et al. Lancet 2023: Epub ahead of print
2. Armuzzi A et al. J Crohns Colitis 2023: 17; i593–i594

Disclosure

AA: research support: Biogen, MSD, Takeda, Pfizer Inc; lecture fees: AbbVie, Amgen, Biogen, Bristol-Myers Squibb, Ferring Pharmaceuticals, Galapagos, Gilead Sciences, Janssen, MSD, Novartis, Pfizer Inc, Roche, Samsung Bioepis, Sandoz, Takeda, TiGenix; consultancy fees: AbbVie, Allergan, Amgen, Arena Pharmaceuticals, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Celltrion, Eli Lilly, Ferring Pharmaceuticals, Galapagos, Gilead Sciences, Janssen, MSD, Mylan, Pfizer Inc, Roche, Samsung, Bioepis, Sandoz, Takeda.
DTR: grant support: Takeda, Helmsley Charitable Trust and GastroIntestinal Research Foundation; consultancy fees/advisory boards: AbbVie, AltruBio, ASLAN Pharmaceuticals, Athos Therapeutics, Bellatrix Pharmaceuticals, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Chronicles, Syneos, ClostraBio, Connect Biopharma, EcoR1, Genentech/Roche, Gilead Sciences, Iterative Health, Janssen Pharmaceuticals, Kaleido Biosciences, Eli Lilly, Pfizer, Prometheus, Reistone, Seres Therapeutics, Takeda, Target RWE, Trellus Health; Board of Trustees: Crohn’s & Colitis Foundation and Cornerstones Health, Inc; stock options: Alike Health, AltruBio, Datos Health, Iterative Health.
SS: lecture/speaker fees: AbbVie, Arena Pharmaceuticals, Biogen, Bristol-Myers Squibb, Celgene, Celltrion, Dr. Falk Pharma, Fresenius, Janssen, MSD, Pfizer Inc, Takeda; consultancy/advisory fees: AbbVie, Arena, Biogen, Bristol-Myers Squibb, Celgene, Celltrion, Dr. Falk Pharma, Fresenius, Gilead Sciences, IMAB, Janssen, MSD, Mylan, Pfizer Inc, Protagonist, Provention Bio, Takeda, Theravance.
JP: personal fees: AbbVie, Arena Pharmaceuticals, Athos, Atomwise, Boehringer Ingelheim, Celgene, Celltrion, Ferring Pharmaceuticals, Galapagos, Genentech/Roche, GSK, Immunic, Janssen, Mirum, Morphic, Nestlé, Origo, Pandion, Pfizer Inc, Progenity, Revolo, Takeda, Theravance Biopharma, Wassermann; grant support: AbbVie and Pfizer Inc.
MF, LB, JW: employees and shareholders of Pfizer Inc.
MG: employee & shareholder of Pfizer AG.
AB: employee of Pfizer Healthcare India & shareholder of Pfizer.
MC: grant support: Pfizer, Galapagos, Janssen; consultancy fees: Takeda, Janssen, Gilead Sciences, Pfizer Inc, Lily, Tillotts; investigator: Takeda, Janssen Cilag International NV, AbbVie, Shire, Janssen Cilag International LV, Genentech, Celgene, F Hoffmann La Roche, Shield, Boehringer Ingelheim, Hospira, Millenium Pharmaceuticals; principal investigator: Janssen, AbbVie, Takeda, MSD, Ferring Pharmaceuticals.
MCD: consultancy fees: AbbVie, Arena Pharmaceuticals, Bristol-Myers Squibb, Celgene, Eli Lilly, Galapagos, Genentech, Gilead Sciences, Janssen Pharmaceuticals, Pfizer Inc, Prometheus Laboratories, Takeda, Trellus Health, UCB; grant/research support: Janssen; shares/royalties in Trellus Health; directorship/ownership interests: Trellus Health.

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

The healthcare sector generates millions of tonnes of waste worldwide each year and GI endoscopy is one of the largest contributors (1).
Despite the proven negative health and environmental impacts of incineration, many European public health agencies and national governments still require incineration as the only safe waste management solution for hospitals’ waste (2).
In November 2022, we started a project around waste management in our endoscopy unit. Until then we did not segregate any of our waste except dangerous medical material such as needles, medication and potentially infectious and toxic products. Moreover, even this segregation, seemed to have different interpretation rules in different hospital departments. This lack of segregation and separate waste streams causes that the quantity of waste categorised as hazardous is unnecessarily much higher than it needs to be, increasing not only the environmental impact of disposal methods, but also the financial costs of disposal and treatment. The large majority of waste produced by the healthcare sector (approximately 85%), however, is actually non-hazardous and similar to domestic waste i.e. much of it can be easily recycled. Over 50% of non-hazardous waste from hospitals is paper, cardboard, and plastics, while the rest comprises discarded food, metal, glass, textiles, and wood (3).

Aims & Methods

We want to raise awareness about the amount of waste produced in a GI endoscopy room and its environmental impact. Moreover, we want to investigate whether most non-hazardous waste from our department is potentially recyclable or compostable. Finally, we would like to promote practices that reduce the volume of waste generated and ensure we can do a proper waste segregation in our endoscopy rooms.
We planned on measuring the amount of residual waste during 3 months in 3 different endoscopy rooms and kept track of the procedures that were done during that period. After these 3 months, we would start to segregate waste and measure again our different bins. To make this segregation possible we placed in every endoscopy room 3 different bins: 1 for residual waste, 1 for plastics and 1 for non-confidential paper and cardboard.
By measuring and calculating the difference, we would like to motivate our medical and nursing staff to continue doing this small effort with enormous results.

Results

In December 2022, January 2023 and February 2023 we collected 205,98 kg, 197,3 kg and 205,22 kg for 606, 583 and 545 endoscopies, respectively. We have now closed our first segregation month, March 2023 and we measured 190,8 kg for 565 endoscopies from which 144,78 kg was residual waste, 38,7 kg were plastics and 7,32 kg was non-confidential paper and cardboard.
The biggest problem we encountered was the training of our staff how to choose the right bin since there is a big difference between munipicial and hospital waste. We will continue to measure for another 3 months and provide training and workshops to our staff.

Conclusion

After one month of segregation, we found that we were able to lower residual waste by 24%. Problems we encountered during our process were the training of our staff and the different segregation policies we have, in combination with the fact that certain categories of waste require specific approaches. The current sustainability metrics and guidelines, though confusing sometimes, offer a unique opportunity to take the first step to the so needed sustainability transformation. Sustainability reporting allows a company to first observe its environmental footprint and then improve its business model and operations.

References

1. Enrique Rodríguez de Santiago*, Mario Dinis-Ribeiro*, Heiko Pohl, Deepak Agrawal, Marianna Arvanitakis, Robin Baddeley, Elzbieta Bak, Pradeep Bhandari, Michael Bretthauer, Patricia Burga, Leigh Donnelly, Axel Eickhoff, Bu'Hussain Hayee, Michal F. Kaminski, Katarina Karlović, Vicente Lorenzo-Zúñiga, Maria Pellisé, Mathieu Pioche, Keith Siau, Peter D. Siersema, William Stableforth, Tony C. Tham, Konstantinos Triantafyllou, Alberto Tringali, Andrew Veitch, Andrei M. Voiosu, George J. Webster, Ariane Vienne, Ulrike Beilenhoff, Raf Bisschops, Cesare Hassan, Ian M. Gralnek, Helmut Messmann. Reducing the environmental footprint of gastrointestinal endoscopy: European Society of Gastrointestinal endoscopy (ESGE) and European Society of Gastroenterology and Endoscopy Nurses and Associates (ESGENA) Position Statement. Endoscopy 2022; 54: 797-826
2. Sustainable healthcare waste management in the EU Circular Economy model. November 2020. www.noharm-europe.org
3. WHO (2014). Safe management of wastes from health-care activities, 2nd ed. www.who.int/water_sanitation_health/publications/safe-management-of-wastes-fromhealthcare-activities/en/ HCWH Europe Page 2 of 7

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.