Introduction

Bowel urgency is a common and disruptive symptom in patients with ulcerative colitis (UC).¹ Fatigue is also common and has been associated with greater disease activity and lower quality of life in these patients.² However, little is known regarding the relationship between bowel urgency remission, bowel urgency clinically meaningful improvement, rectal bleeding remission, or stool frequency remission and improvement in fatigue. We examined the association between bowel urgency remission or bowel urgency clinically meaningful improvement and Fatigue Numeric Rating Scale (NRS) scores in the presence of rectal bleeding remission or stool frequency remission using pooled data from LUCENT-1 (NCT03518086) and LUCENT-2 (NCT03524092) phase 3 trials.

Aims & Methods

Bowel urgency was assessed by the Urgency NRS (UNRS), ranging from 0 (no urgency) to 10 (worst possible urgency). Bowel urgency remission was defined as a UNRS score of 0 or 1; bowel urgency clinically meaningful improvement was defined as a ≥3-point decrease in UNRS score from baseline.³ Rectal bleeding remission was defined as a modified Mayo subscore of 0; stool frequency remission was defined as a subscore of 0 or 1 with ≥1-point decrease from baseline.⁴ Fatigue was assessed by the Fatigue NRS, ranging from 0 (no fatigue) to 10 (worst possible fatigue), using change from baseline in Fatigue NRS score. Mediation analyses were performed to separately examine the relative association between the direct effects of bowel urgency remission and bowel urgency clinically meaningful improvement (predictor variables) and Fatigue NRS scores while adjusting for rectal bleeding remission and stool frequency remission (mediation variables). Analyses were treatment agnostic and combined mirikizumab and placebo treatment groups from LUCENT-1 (N=1162) and LUCENT-2 (N=544).

Results

The direct effect of bowel urgency remission at Week 12 and Week 40 (52 weeks continuous treatment) accounted for 68.3% and 62.1%, respectively, of the improvement in change from baseline in Fatigue NRS score. Substantially greater proportions of the Fatigue NRS score improvements were related to bowel urgency remission versus rectal bleeding remission (Week 12: 13.4% and Week 40: 16.4%) or stool frequency remission (Week 12: 18.3% and Week 40: 21.5%). Results were similar for bowel urgency clinically meaningful improvement at Week 12 (91.8%) and Week 40 (87.4%).

Conclusion

These findings provide strong evidence for a direct association between improvement or remission in bowel urgency and improvement in fatigue in patients with moderately-to-severely active UC.

References

1. Hibi T, et al. Inflamm Intest Dis. 2020;5(1):27.
2. Regueiro MD, et al. Adv Ther. Online Nov 12, 2022. doi: 10.1007/s12325-022-02364-2.
3. Dubinsky MC, et al., J Patient Rep Outcomes. 2022;6(1):114.
4. ClinicalTrials.gov. Updated October 27, 2022. Access December 1, 2022. clinicaltrials.gov/ct2/show/NCT03518086.

Disclosure

D. T. Rubin has been a consultant for and/or received research grants from: AbbVie, AbGenomics, Allergan, Biomica, Boehringer Ingelheim, Bristol Myers Squibb, Celgene/Syneos Health, Check-Cap, Dizal Pharma, Eli Lilly and Company, Galen/Atlantica, Genentech/Roche, Gilead Sciences, GlaxoSmithKline, Ichnos Sciences, InDex Pharmaceuticals, Janssen, Narrow River Management, Pfizer, Prometheus Therapeutics and Diagnostics, Reistone Biopharma, Shire, Takeda, and TechLab; is a shareholder at: AbGenomics and Biomica; is on the Board of Trustees at: American College of Gastroenterology; is cofounder and CFO of: Cornerstones Health (non-profit); and is cofounder of: GoDuRn; P. Hindryckx has received consulting fees from: AbbVie, Boston Scientific, Eli Lilly and Company, Janssen, Taewoong Medical, and Takeda; has received speaker fees from: AbbVie, Chiesi, Dr. Falk Pharma, Ferring Pharmaceuticals, Takeda, Tillotts Pharma AG, and Vifor Pharma; and has received research support from: Eli Lilly and Company; T. Hibi has received lecture fees from: AbbVie, EA Pharma, Janssen, JIMRO, Mitsubishi Tanabe Pharma, Mochida Pharmaceutical, Pfizer, Sand K.K., Takeda, and Zeria Pharmaceutical; has received advisory and/or consultancy fees from: AbbVie, Celltrion, EA Pharma, Eli Lilly and Company, Gilead Sciences, Janssen, Mitsubishi Tanabe Pharma, Nichi-Iko Pharmaceutical, Nippon Kayaku, Takeda, and Zeria Pharmaceutical; has received research grants from: AbbVie, Activaid, Alfresa Pharma, Bristol Myers Squibb, Eli Lilly Japan K.K., Ferring Pharmaceuticals, Gilead Sciences, Janssen Pharmaceutical K.K., JMDC, Mochida Pharmaceutical, Nippon Kayaku, Pfizer Japan Inc., and Takeda; has received scholarship•contributions from: Mitsubishi Tanabe Pharma, Nippon Kayaku, Pfizer Japan Inc., and Zeria Pharmaceutical; has belonged to study group sponsorship by: Alfresa Pharma, JIMRO, Kyorin, and Mochida Pharmaceutical; and has received grants and/or funds from: MIYARISAN Pharmaceutical Co., Ltd. and Zeria Pharmaceutical; K. McGinnis, T. Hunter Gibble, and A. Keohane are employees and shareholders of:
Eli Lilly and Company; M. Regueiro has received consulting fees from: AbbVie, Allergan, Amgen, Celgene, Eli Lilly and Company, Genentech, Gilead Sciences, Janssen, Miraca Life Sciences, Pfizer, Prometheus Therapeutics and Diagnostics, Salix Pharmaceuticals, Seres Therapeutics, Takeda, Target RWE, and UCB Pharma; and has received research support from: AbbVie, Janssen, Pfizer, and Takeda

Introduction

Upper endoscopy (EGD) with esophageal biopsies is required to rule out eosinophilic esophagitis (EoE) in patients reporting dysphagia. Moreover, EoE monitoring currently requires esophageal biopsies to assess treatment response based on eosinophil counts on histology. Non-invasive screening and monitoring strategies are needed to reduce the diagnostic delay and streamline the follow-up of patients with EoE.

Aims & Methods

In this prospective cross-sectional multicenter study conducted at three EoE-referral centers in Italy, we investigated whether absolute eosinophil count (AEC) and eosinophil percentage (EosPercent) could a) predict a diagnosis of EoE among patients referred for dysphagia, b) serve as a marker of histological remission in treated EoE patients. We enrolled consecutive patients undergoing EGD with six esophageal biopsies for suspected or known EoE. For all patients, a full blood count was obtained prior to the EGD. A diagnosis of active EoE or histological remission was performed based on current guidelines. Non-EoE dysphagia (NED) patients were identified based on the presence of <15 eosinophils/high-power field in all six esophageal biopsies while off eosinophil-depleting treatments. Demographic, clinical, AEC, and EosPercent data were collected. Kruskal-Wallis Rank Sum Test and Pearson’s Chi-squared were used for comparisons as appropriate. ROC curve analysis was used to assess the diagnostic accuracy (AUC) of AEC and EosPercent. Significance threshold was p<0.05.

Results

Of the 92 included patients, 33 had active EoE, 18 had EoE in histological remission while on budesonide orodispersible tablets (BOT) or proton pump inhibitors (PPI), and 41 had NED. Patients with EoE were younger and more frequently male and atopic compared to NED (p<0.01 for all). Overall, 98% (50/51) of EoE had AEC, and 84.3% (43/51) had EosPercent within the normal range. Similarly, 100% (41/41) of NED had AEC, and 90.2% (37/41) had EosPercent within the normal range. There were no differences between EoE and NED in terms of proportion of patients with AEC or EosPercent above the upper limit of normal (p>0.4 for all) (Table 1). Median AEC [380 (210, 460)/mm3 vs 120 (70, 220)/mm3; p<0.001) and EosPercent [5.40 (3.60, 7.05)% vs 1.80 (0.8, 3.0)%; p<0.01] were significantly higher in active EoE compared to NED. Based on ROC curve analysis, a cut-off of 155 eosinophils/mm3 segregated active EoE from NED with AUC of 0.82, specificity of 91.0%, and sensitivity of 65.8%, while a cut off value of 2.5% of EosPercent had AUC of 0.83 with 68.2% specificity and 93.5% sensitivity for the identification of EoE among patients with dysphagia. In terms of prediction of BOT or PPI response, median AEC [380 (210, 460)/mm3 vs 150 (98, 268)/mm3; p<0.01) and EosPercent [5.40 (3.60, 7.05)% vs 1.85 (1.55, 4.47)%; p<0.01] were significantly higher in active EoE compared to EoE in histological remission. Based on ROC curve analysis, a cut-off of 375 eosinophils/mm3 had AUC of 0.75 with 94.1% specificity and 54.5% sensitivity, while a cut off value of 2.25% of EosPercent had AUC of 0.79 with 93.5% specificity and 60.0% sensitivity for the identification of histological remission among EoE patients (Table 2).

Conclusion

AEC and EosPercent are within the normal range in most EoE patients regardless of histological disease activity. Nevertheless, AEC and EosPercent values accurately predict a diagnosis of EoE among patients reporting dysphagia, as well as histological remission among BOT- or PPI-treated EoE patients. If these findings are replicated on a larger scale, AEC and EosPercent could be used as biomarkers in clinical practice.

Introduction

Etrasimod is an oral, once-daily, selective sphingosine 1‑phosphate (S1P)_1,4,5 receptor modulator for the treatment of moderately to severely active ulcerative colitis (UC). In patients with moderately to severely active UC, treatment guidelines recommend early use of advanced therapies rather than gradual step up after failure of 5-aminosalicylate (5-ASA).¹

Aims & Methods

This prespecified subgroup analysis assessed the efficacy of etrasimod vs placebo in patients in ELEVATE UC 52 (NCT03945188) with, and without, prior oral 5-ASA failure only (defined as inadequate response, loss of response or intolerance to previous treatment with oral 5-ASA but not to any other previous UC medication). Efficacy endpoints assessed at Weeks 12 and 52 included clinical remission, endoscopic improvement, symptomatic remission and composite histological endpoints.

Results

In total, 45 and 29 patients receiving etrasimod and placebo, respectively, had prior 5-ASA failure only and 244 and 115 patients did not. At Weeks 12 and 52, among those who had failed prior 5-ASA only, significantly more patients receiving etrasimod vs placebo achieved clinical remission (Week 12, % difference [Δ]: 38.3%, p < 0.001; Week 52, Δ: 45.0%, p < 0.001), endoscopic improvement (Week 12, Δ: 54.7%, p < 0.001; Week 52, Δ: 47.8%, p < 0.001), symptomatic remission (Week 12, Δ: 38.6%, p < 0.001; Week 52, Δ: 45.0%, p < 0.001) and endoscopic improvement-histologic remission (Week 12, Δ: 35.6%, p < 0.001; Week 52, Δ: 31.1%, p < 0.001; Table). Significantly more patients receiving etrasimod vs placebo in this subgroup achieved endoscopic normalisation-histologic remission (Week 12, Δ: 19.9%, p = 0.002; Week 52, Δ: 24.3%, p < 0.001) and disease clearance (Week 12, Δ: 15.6%, p = 0.008; Week 52, Δ: 27.8%, p < 0.001). Among those who had failed other therapies, significantly more patients receiving etrasimod vs placebo also achieved all endpoints at Weeks 12 and 52 (p < 0.01).

Conclusion

Etrasimod demonstrated robust efficacy as first-line advanced therapy in patients who had failed oral 5-ASA only, across all evaluated endpoints including stringent composite histological endpoints, consistent with the overall ELEVATE UC population. Etrasimod shows efficacy when used early in the UC treatment algorithm.

References

1. Singh S et al. Gastroenterology 2024; 167: 1307–1343.
Pfizer’s generative artificial intelligence tool MAIA was used to assist production of the abstract first draft. Authors reviewed/edited and take responsibility for the content.

Disclosure

DTR received grant support from Takeda; consultancy fees from AbbVie, Abivax SA, Altrubio, Avalo Therapeutics, Bausch Health, Bristol Myers Squibb, Buhlmann Diagnostics Corp, Celltrion, ClostraBio, Connect BioPharma, Douglas Pharmaceuticals, Eli Lilly & Co., Foresee, Genentech (Roche) Inc., Image Analysis Group, InDex Pharmaceuticals, Iterative Health, Janssen Pharmaceuticals, Odyssey Therapeutics, Pfizer Inc, Sanofi, Takeda Pharmaceuticals, Throne and Vedanta.
CWL received speaker fees from AbbVie, Dr Falk, Ferring, Hospira, Janssen, MSD, Pfizer Inc, Shire, Takeda and Warner-Chilcott; consultancy fees from AbbVie, Dr Falk, Gilead, GSK, Hospira, Iterative Scopes, Janssen, MSD, Oshi Health, Pfizer Inc, Pharmacosmos, Takeda, Topivert, Trellus Health and Vifor Pharma; research funding from AbbVie and Gilead.
FB received research/grant support from AbbVie, Amgen, Eurogenerics, Janssen and Takeda; lecture fees/speaker’s bureau from AbbVie, Arena Pharmaceuticals, Celltrion, Ferring, Galapagos, Janssen, Merck Sharp & Dohme, Pfizer Inc and Takeda; consultancy fees from AbbVie, Abivax, Amgen, Arena Pharmaceuticals, Celgene, Celltrion, Ferring, Fresenius Kabi, Janssen, Merck Sharp & Dohme, Pfizer Inc and Sandoz.
MK is an employee and shareholder of Pfizer Inc.
AB is an employee of Pfizer Healthcare India Private Ltd and shareholder of Pfizer Inc.
KL is an employee of Pfizer AG and shareholder of Pfizer Inc.
MG is an employee of Pfizer AG and shareholder of Pfizer Inc.
AMM is an employee and shareholder of Pfizer Inc.
KW is an employee of Pfizer Canada Inc and shareholder of Pfizer Inc.
JKM is an advisory committee/board member on AbbVie, Alimentiv, Amgen, AstraZeneca, Bausch Health, Bristol Myers Squibb, Celltrion, Ferring, Fresenius Kabi, Janssen, Lilly, Lupin, Organon, Paladin, Pfizer Inc, Pharmascience, Qu Biologics, Roche, Sandoz, SCOPE, Takeda, Teva and Viatris; receives lecture/speaker fees from AbbVie, Amgen, Bausch Health, Ferring, Fresenius Kabi, Janssen, Organon, Pfizer Inc, Pharmascience, Roche, Takeda and Viatris.

Introduction

Incidence of sporadic ductal pancreatic adenocarcinoma (PDAC) in the Czech Republic is the third highest in Europe (23.1/100,000 population). New-onset diabetes mellitus with weight loss (> 5% within < 6 months) in patients over sixty can be an early sign of PDAC. New-onset diabetes mellitus was recorded in 12.2% subjects three years prior to the diagnosis of PDAC (in the 60-74+ age group:13.8%) in the Czech Republic in the period 2017-2021 [ref. 1].

Aims & Methods

The aim of this study was to evaluate the standardized incidence ratio (SIR) of PDAC in patients with diabetes mellitus with and without previous history of any other malignancy within a 12-year period.
Methods: The analysis was based on individual population data from the Czech National Registry of Reimbursed Health Services, the National Cancer Registry, and the Death Certificate Information System in the period 2010 - 2021. Patients were divided into two groups: the first one included subjects with diabetes mellitus who had a history of any malignancy prior to the diagnosis of diabetes (follow-up 865,956 person-years); the second cohort consisted of people with diabetes mellitus who had no history of malignancy prior to the diagnosis of diabetes (7,971,090 person-years). The calculated person-years at risk were stratified by sex, age and time periods (2010-2013; 2014-2017; 2018-2021). Subgroup analyses were performed considering follow-up and age at diagnosis of diabetes. The first report of any antidiabetic drug (ATC group A10) was the determinant for the diagnosis of diabetes mellitus in a particular individual. SIR was calculated as the ratio of observed to expected (estimated from incidence in the general population) cases of PDAC.

Results

Selected SIRs stratified according to age and follow-up are displayed in Table 1.
A significantly higher risk of PDAC in diabetes mellitus with a history of previous malignant diseases (compared to the general population) was found for the following: head and neck cancer (SIR 2.54), gastric cancer (2.12), colorectal cancer (1.38), laryngeal cancer (2,51), malignant melanoma (1.65), breast cancer (1.61), cervical cancer (2.22), uterine cancer (1.72), prostate cancer (1.59), testicular cancer (3.1), kidney cancer (1.75), urinary bladder cancer (1.74), thyroid cancer (2.13), Hodgkin lymphoma (2.74), non-Hodgkin lymphoma (2.15) and leukaemias (1.93).

Table 1
Risk of PDAC in diabetes mellitus

Conclusion

Risk of PDAC in patients with diabetes mellitus was higher in subjects with a history of various malignant diseases compared to those with no previous history of any malignancy. Particular attention should be paid to new-onset diabetes (diagnosis made within one last year). History of a malignancy, as an important risk factor for PDAC, should be taken into account when surveilling patients with diabetes mellitus.

Funding: Research projects MO1012 (DZVRO) and MH CZ-DRO (UHHK, 00179906).

References

Ref. 1: UEG Journal 2024; 12 (Suppl S8): 565.

Disclosure

There is conflict of interest.