Introduction

Ustekinumab (UST), an inhibitor of the p40 subunit of interleukins 12 and 23, is approved for the treatment of moderate and severe Crohn disease (CD) but a significant number of patients either partially respond or do not benefit at all. Therapeutic drug monitoring can be used to optimize the efficacy of biological drugs by ensuring adequate exposure to these drugs.

Aims & Methods

The aim of our research was to identify the relationship between serum concentrations of UST during the induction and biochemical remission at week 16 in patients with CD.

All CD patients treated with UST included in a local database were identified. Only patients with a fecal calprotectin (FCP) > 250 mg/g were selected. All patients were treated with an initial intravenous induction therapy of UST, followed by subcutaneous maintenance therapy. Disease activity was assessed retrospectively by clinical (Harvey–Bradshaw Index [HBI]) and biochemical parameters (FCP; C-reactive protein (CRP) and Albumin) at Week 0, Week 4, week 8 and week 16. UST trough levels were measured at 4, 8 and 16 weeks using a commercially available validated enzyme-linked immunosorbent assay (ELISA).
Main outcome was biochemical remission, defined by a decreased of calprotectin levels more than 80% or an absolute value less than 200 mg/g at week 16.

Results

Seventy-six patients were included. Patients’ Characteristics at baseline are listed in table 1. Median [IQR] HBI was 5,5 [3-8] at the beginning of treatment. Evolution of biochemical parameters throughout induction is showed in table 2. At the end of the induction phase (week 16), HBI, CRP and FCP decreased significantly from baseline. At this moment HBI was less than 2 in 51% of patients. FCP was available in 63 patients. Biochemical remission was observed in 26/63 (41,3%) patients. Median [IQR] UST serum concentrations were 20,9 μg/mL [13,7–26,3] at w4, 10,1 μg/mL [3,5–7,4] at w8 and 4,1 μg/mL [1,4–3,9] at w16. Quartile analysis demonstrated that 100% and 66% with an UST serum concentration in the highest quartile [Q4], at w4 and w8, achieved a biochemical remission by w16 [p = 0.05 and p <0,02 respectively]. The area under the receiving operating characteristic curve (AUROC) of UST levels to predict biochemical remission at week 4 and week 8 were 0,84 CI_95% (0,62-1) and 0,74 CI_95% (0,57-0,91) respectively.

Conclusion

Serum concentrations of UST at week 4 and 8 after intravenous infusion could be used to stratify patients according to the probability of achieving remission. This measurements during induction could be used to optimize treatment of CD.

Introduction

A successful colonoscopy requires ideal stool preparation, yet the percentage of insufficient bowel preparation is still very high. Frequently, the patients use website information on colonoscopy preparation. Conversely, the daily activity of the hospital staff consists of spending time with patients, communicating with them and giving answers to a high number of questions coming from patients regarding the preparation for the procedure or the exam itself. Hence, the idea to adopt a rapid and intuitive patient-oriented digital service to respond to their needs, the virtual assistant Eric.

Aims & Methods

Endo-Chat is an automated online communication platform, powered by AI (Artificial Intelligence) with the use of the Natural Language Processing and Deep Learning technologies, that answers procedure-related questions in real-time. The engine is named ERIC, stands for "Endoscopy Robot for Intelligent Chat" and is an intelligent chatbot, capable of answering autonomously to most of the doubts of a patient who is supposed to undergo an endoscopic examination.

Results

Since the introduction of the conversational artificial intelligence system at the Policlinico Gemelli starting from 24^th of January 2022 to the 16^th of March 2023, Eric has been able to autonomously manage 94% of the questions sent by patients, thus forwarding only the remaining 6% (of the requests) to specialized human operators.
We calculated that in the pre-pilot phase, a large part of the daily activity of nurses was dedicated to communicating with patients, around 40 hours per week, while in the post-pilot phase, the time spent for communication was significantly reduced to 15 hours per week. According to OECD Health Statistics 2022, the average annual salary of a European nurse is 35,300 euros, with an annual hypothetical saving of 22,062 euros, comparable to a part-time contract.
Also, the number of cancelled procedures for poor patient preparation has fallen from 22 to 7 per week, considering a volume of 200 procedures per week.
Regarding patient's experience, users can leave voluntary feedback on their virtual assistant experience directly on the ERIC website, evaluating the quality of the service. Patient service evaluations were enthusiastic till now, as 63% rated the service as excellent.

Conclusion

In our observational pilot study, the first in Europe to our knowledge, we assessed the benefits measurement for patients and Hospital staff. Starting from these preliminary interesting results, we can speculate that the introduction of Endo-Chat in high-volume endoscopy service is feasible and useful not only for patients but also for hospital staff.

Disclosure

The authors declare no conflict of interest

Introduction

Eosinophilic esophagitis (EoE) is a chronic inflammatory and progressive fibrotic condition of the esophagus characterized by the infiltration of eosinophils into the esophageal mucosa and esophageal dysfunction. There remain limited treatment options for EoE and accordingly, a substantial unmet need for effective and safe medical therapies. Drug development in EoE has been hampered by heterogeneous placebo response rates, especially for clinical outcomes, and uncertainty regarding appropriate endpoint configurations. Accurate characterization of placebo response in EoE randomized controlled trials (RCTs) will help inform more future efficient trial designs.

Aims & Methods

To conduct a systematic review and meta-analysis to characterize symptomatic, endoscopic, and histologic placebo response rates in placebo controlled EoE RCTs.
Electronic database (CENTRAL, MEDLINE, EMBASE) searching (inception to 1 JAN 2024) identified placebo controlled RCTs evaluating medical therapies for adults with EoE. Studies were screened independently by 2 reviewers (AR and SA), and full texts were then reviewed for eligibility. The proportion of clinical, endoscopic, and histologic responders (improvement and remission) assigned to placebo were pooled using a random-effect model. The Stuart-Ord inverse double arcsine square root transformation method was used to compute 95% confidence intervals (CI) for point estimates of placebo response. Heterogeneity was evaluated using the I² method. Analyses were conducted in StatsDirect 3.3.6.

Results

A total of 25 placebo-controlled RCTs (placebo sample size range: N = 4–105) were included. The pooled proportion of patients receiving placebo who achieved clinical response was 41.0% (n = 11; 95% CI 29.7%, 52.8%) with substantial heterogeneity (I² = 74.9%%). Definitions of clinical response varied between studies. The pooled proportion for histologic remission (peak eosinophil count [PEC] ≤6 eos per high power field [hpf]) was 4.3% (n = 20; 95% CI 2.6%, 6.2%) with low heterogeneity (I² = 23.6%), while a more stringent definition of histologic remission (PEC ≤1 eos/hpf) yielded a pooled placebo remission rate of 1.3% (n = 18; 95% CI 0.5%, 2.5%) with low heterogeneity (I² = 0%). The pooled histologic improvement rate was 6.2% (n = 15; 95% CI 3.3%, 10.0%) with substantial heterogeneity (I² = 50.6%). Limited studies reported on endoscopic improvement and remission (Table 1).

Conclusion

More than 1 in 3 patients assigned to placebo in EoE RCTs will achieve clinical response (substantial heterogeneity detected), while less than 1 in 10 of these patients will achieve histologic remission (low heterogeneity detected). These findings highlight 1) the need to develop validated and responsive patient-reported outcome measures, which may be difficult due to the episodic nature of symptoms in EoE; and 2) the challenge of using a coprimary clinical and histologic outcome in EoE RCTs, given the discordance between symptoms and objective disease activity measures.

Table 1. Pooled proportion of placebo patients achieving measured outcomes in EoE studies

Disclosure

AR: No conflicts of interest
SA: No conflicts of interest
YY: No conflicts of interest
AQ: Is an employee of Alimentiv Inc.
DBO: Is an employee of Alimentiv Inc.
BGF: consulting fees from AbbVie, Abivax, Adiso, AgomAB Therapeutics, Allianthera, Amgen, AnaptysBio, Arena Pharma, Avoro Capital Advisors, Atomwise,, BioJamp, Biora Therapeutics, Blackbird Laboratories,Boehringer-Ingelheim, Boxer Capital, Celsius Therapeutics, Celgene/BMS, Celltrion, Connect BioPharma, Cytoki, Disc Medicine, Duality, EcoR1, Eli Lilly, Equillium, Ermium, First Wave, Forbion, Galapagos, Galen Atlantica, Genentech/Roche, Gilead, Gossamer Pharma, GSK, Hinge Bio, Index Pharma, Imhotex, Immunic Therapeutics, Intercept, JAKAcademy, Janssen, Japan Tobacco Inc., Kaleido Biosciences, Klick Health, Landos Biopharma, Lenczner Slaght, LifeSci Capital, Lument AB, Mage Biologics, Mestag, Millennium, MiroBio, Monte Rose Tx, Morgan Lewis, Morphic Therapeutics, Mylan, Nexys Therapeutics, Nimbus Therapeutics, OM Pharma, OrbiMed Origo BioPharma, Orphagen, Pandion Therapeutics, Pendopharm, Pfizer, Prometheus Therapeutics and Diagnostics (Merck), Progenity, Protagonist, PTM Therapeutics, Q32 Bio, Rebiotix, REDX, Roche, Roivant/Televant, Sandoz, Sanofi, Seres Therapeutics, Silverback Therapeutics, Sobi, Spyre Therapeutics, Surrozen Inc., Sun Pharma, Synedgen, Takeda, Teva, Thelium, Tigenix, Tillotts, Triastek, TR1X Inc. Ventyx Biosciences, Zagbio, Zealand Pharma. Speaker fees from AbbVie, Janssen, Takeda.
VJ: consulting/advisory board fees from AbbVie, Alimentiv, Arena pharmaceuticals, Asahi Kasei Pharma, Asieris, Anaptyis Bio, Astra Zeneca, Avoro Capital, Bristol Myers Squibb, Celltrion, Eli Lilly, Endpoint Health, Enthera, Ferring, Flagship Pioneering, Fresenius Kabi, Galapagos, Gilde Healthcare, GlaxoSmithKline, Genentech, Gilead, Innomar, JAMP, Janssen, Merck, Metacrine, Mylan, Pandion, Pendopharm, Pfizer, Protagonist, Prometheus Biosciences, Reistone Biopharma, Roche, Roivant, Sandoz, Second Genome, Sorriso, Synedgen, Takeda, TD Securities, Teva, Topivert, Ventyx, Vividion; and speaker’s fees from, Abbvie, Ferring, Bristol Myers Squibb, Galapagos, Janssen Pfizer Shire, Takeda, Fresenius Kabi.
AJB: AJB received research funding from Nutricia, Thelial, Sanofi/Regeneron, SST, and Dr. Falk Pharma and received speaker and/or consulting fees from Laborie, Medtronic, BMS, Dr. Falk Pharma, Calypso Biotech, Eupraxia, Aqilion, Alimentiv, Sanofi/Regeneron, Reckitt and AstraZeneca
ESD: Research funding: Adare/Ellodi, Allakos, Arena/Pfizer, AstraZeneca, Eupraxia, Ferring, GSK, Meritage, Miraca, Nutricia, Celgene/Receptos/BMS, Regeneron, Revolo, Shire/Takeda
Consultant: Abbott, Abbvie, Adare/Ellodi, Aimmune, Akesobio, Alfasigma, ALK, Allakos, Amgen, Apollo, Aqilion, Arena/Pfizer, Aslan, AstraZeneca, Avir, Biorasi, Calypso, Celgene/Receptos/BMS, Celldex, Eli Lilly, EsoCap, Eupraxia, Dr. Falk Pharma, Ferring, GSK, Gossamer Bio, Holoclara, Invea, Knightpoint, Landos, LucidDx, Morphic, Nexstone Immunology/Uniquity, Nutricia, Parexel/Calyx, Phathom, Regeneron, Revolo, Robarts/Alimentiv, Salix, Sanofi, Shire/Takeda, Target RWE, Upstream Bio
Educational grant: Allakos, Aqilion, Holoclara, Invea
CM: consulting fees from AbbVie, Alimentiv, Amgen, AVIR Pharma Inc, Bristol Myers Squibb, Celltrion, Eli Lilly, Ferring, Fresenius Kabi, Janssen, McKesson, Mylan, Pendopharm, Pfizer, Prometheus Biosciences Inc., Roche, Sanofi, Takeda, Tillotts Pharma; speaker's fees from AbbVie, Amgen, AVIR Pharma Inc, Alimentiv, Bristol Myers Squibb, Eli Lilly, Ferring, Fresenius Kabi, Janssen, Organon, Pendopharm, Pfizer, Sanofi, Takeda, Tillotts Pharma; royalties from Springer Publishing; research support from AbbVie, Ferring, Pfizer.

Introduction

Cystic fibrosis (CF) is a chronic, progressive, autosomal recessive disease caused by mutations of a single gene on the long arm of chromosome 7 that codes for the CF transmembrane regulator (CFTR)¹. Gastrointestinal symptoms and pancreatic insufficiency occur in more than 70% of people with CF (pwCF) and 96% of them showed at least one abnormal sign at intestinal ultrasound (IUS)².
Several studies^3,4,6 also documented a significant reduction of pancreatic stiffness in pwCF with pancreatic insufficiency as compared to those without. Elexacaftor-Tezacaftor-Ivacaftor (ETI), a triple combination of CFTR modulators, increases CFTR protein activity and significantly reduces morbidity and improves quality of life in pwCF⁸.

Aims & Methods

The aim of this prospective study, which is still ongoing, was to assess intestinal symptoms, IUS signs and pancreas elastography findings at baseline (T0) and their modification after different predefined lengths (T6 and T 12) of treatment with ETI.
Between October 2021 and March 2023 all consecutive pwCF candidate for starting ETI were enrolled. Clinical, biochemical, IUS signs and pancreas elastography (2D-shear-wave elastography, Philips) were collected at T0, T6 and T12.
The results of pancreatic elastography in CF were compared to those of a group of healthy controls.
Statistical analysis was performed using statistical package (SPSS) trial version 27.0.

Results

At T0, 141 patients (mean age 20±5.8; females 40.4%) were enrolled, 84 (60%) of them were re-assessed at T6 and 34 (24%) at T12. The healthy control group included 22 participants (mean age of 22.5 ±6.6 years, female 50%).
Main gastrointestinal symptoms and IUS signs are summarized in Table 1.
As previously reported, median pancreatic stiffness in pwCF was significantly lower than in controls (4.774 kPa ±0.864 vs 6.178 kPa ± 0.649, p<0.05). In addition, pancreatic stiffness values were similar at T0 and T6 (4.67 kPa ± 0.4 vs 4.774 KPa ±0.864, p=0.7) and significantly increased after one year of ETI treatment (5.442 kPa ±1.275 vs 4.774 kPa ± 0.864, p < 0.05).

Table

Conclusion

In pwCF, ETI significantly reduced gastrointestinal symptoms and pathological IUS signs. Pancreatic stiffness values, significantly lower than in healthy controls at T0, increased to normal values in PwCF treated for one year.

References

1. Shteinberg M, et al. Cystic Fibrosis. Lancet 2021; 397 (10290): 2195-2211.
2. Fraquelli M, et al. Bowel ultrasound imaging in patients with cystic fibrosis: Relationship with clinical symptoms and CFTR genotype. Dig Liver Dis. 2016 Mar;48(3):271-6.
3. Friedrich-Rust M, et al. Non-invasive measurement of liver and pancreas fibrosis in patients with cystic fibrosis. J Cyst Fibros. 2013 Sep;12(5):431-9.
4. Piskin FC, et al. A comparative study of the pancreas in pediatric patients with cystic fibrosis and healthy children using two-dimensional shear wave elastography. J Ultrasound. 2020 Dec;23(4):535-542.
5. Sigrist RMS, et al. Ultrasound Elastography: Review of Techniques and Clinical Applications. Theranostics. 2017 Mar 7;7(5):1303-1329
6. Yılmaz K, et al. Evaluation of children and adolescent with cystic fibrosis by pancreatic elastography. Pediatr Int. 2022 Jan;64(1): e14951.
7. Middleton PG, et al. Elexacaftor-Tezacaftor-Ivacaftor for Cystic Fibrosis with a Single Phe508del Allele. N Engl J Med. 2019 Nov 7;381(19):1809-1819.
8. Bacalhau M, et al. Elexacaftor-Tezacaftor-Ivacaftor: A Life-Changing Triple Combination of CFTR Modulator Drugs for Cystic Fibrosis. Pharmaceuticals (Basel). 2023 Mar 8;16(3):410.