Introduction

Due to lack of published data on ustekinumab (UST) use in Greece, we aimed to generate local real-world evidence (RWE) on UST treatment persistence and clinical outcomes [including patient-reported outcomes (PROs)] in patients with Crohn’s Disease (CD).

Aims & Methods

REASSURE is an ongoing, non-interventional, 24-month prospective study of adult (18-80 years old) patients with CD, who commenced therapy with UST as 1^st, 2^nd or 3^rd biologic therapy as per approved label in Greece. Harvey-Bradshaw Index (HBI) and PROs are collected by routine assessments at baseline (start of UST) and every 6 months thereafter. PROs include the Inflammatory Bowel Disease Questionnaire (IBDQ), the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) Scale, and the Work Productivity and Activity Impairment Questionnaire in CD (WPAI:CD). Interim analysis was performed when all enrolled patients completed 1 year of follow-up.

Results

Between April 2019 and March 2022, 169 eligible patients [median (Interquartile range, IQR) age at baseline: 45 (35.0-54.0) years; bio-naïve: 35.5%; employed: 43.8%] were enrolled in 19 gastroenterology clinics and completed 1-year of follow-up. The median time from CD diagnosis to UST initiation was 7.0 (1.8-13.0) years.
The 12-month persistence rate was 84.0% (95% Confidence Interval: 78.5-89.5%). Over a median treatment duration of 12.3 months, a median of 7.0 (6.0 - 8.0) intravenous (IV) and subcutaneous (SC) injections were received. At 12 months, 14.2% (24/169) of patients discontinued UST (mean duration of 6.3 months) due to lack/loss of efficacy (10/24), safety issues (8/24), loss to follow-up (3/24), patient’s decision (2/24) and death (1/24; unrelated to UST).
The baseline median values for total ΗΒΙ (8.0), IBDQ (166.0), FACIT-F (33.0), WPAI:CD work productivity loss (30.0), and activity impairment scores (35.0) significantly improved (p<0.01) at 12 months, with median changes of -4.0, 17.1, 4.0, -10.0, and 10.0, respectively, among paired observations. Similar improvements were noted in the subgroups per treatment line. The UST-related adverse events (AE) and serious AE rates were 18.3% (31/169) and 4.7% (8/169) respectively. Baseline data and 12-month outcomes are shown in Table 1.

Table 1: Baseline characteristics and 12-month study outcomes

Conclusion

These data provide evidence for high persistence rate of UST in patients with CD in a real-world setting in Greece and demonstrate favorable effects on disease activity and PROs, accompanied by a predictable safety profile.

Disclosure

This study was sponsored by Janssen - Cilag, Greece.
Giorgos Bamias Advisor/lecturer fees: Janssen, Pfizer, Takeda, Abbvie, MSD, Mylan, Genesis Pharma, Adacyte Therapeutics, Amgen, Ferring, Cooper; Funding (Grants/Honoraria) from: Pfizer, Takeda, Abbvie, Aenorasis; Research/Clinical Trials for: Abbvie, Takeda.
Gerassimos J. Mantzaris has served as consultant/advisor board member and/or speaker for AbbVie, Aenorasis, Dr Falk, Ferring, Janssen, Merck Sharp & Dohme, Pfizer, Takeda, Vianex and has received research grants from: AbbVie, Genesis, Merck Sharp & Dohme, and Takeda.
Christos Gkamaloutsos, Ioannis Kanistras and Angeliki Kekki are employees of Janssen - Cilag, Greece.
Konstantinos Thomopoulos has not disclosed any conflicts
Maria Tzouvala has received clinical research funding from: AbbVie, Janssen, Takeda, consulting and/or speaking fees from: Janssen, AbbVie, Pfizer, MSD, Amgen and has served as advisory board member for: Janssen, AbbVie, Vianex, Amgen, Pfizer, Ferring
Ioannis Koutroubakis has received support by Abbvie, Genesis, Faran, Ferring, Janssen, MSD, Pfizer, Vianex, Viatris and Takeda
Vasileios Delis has no conflicts to disclose
Christos Liatsos has received clinical research funding from: Janssen, Excelya GR, EPSILON HEALTH, and speaking fees from: Boston SCI, Amgen, Galenica
Stergios Vradelis has no conflicts to disclose
Theodosios Sdonas has not disclosed any conflicts
Georgios Papatheodoridis Αdvisor/lecturer for Abbvie, Albireo, Amgen, Dicerna, Genesis, Gilead, GlaxoSmithKline, Ipsen, Janssen, Merck Sharp & Dohme, Novo Nordisk, Roche and Takeda; Research grants from Abbvie, Gilead and Takeda
Dimitrios Christodoulou has received speaking fees from Janssen, MSD, Galenica
Konstantina Paraskeva: has received clinical research funding from Janssen
Ioannis Goulis has received clinical research funding from: BMS, Janssen; consulting and/or speaking fees from: Janssen, Vianex and has served as advisory board member for: Vianex
Georgios Germanidis has received clinical research funding from Janssen
Vasileios Xourgias has not disclosed any conflicts.
Andreas Protopapas has no conflicts to disclose
Konstantinos Soufleris has received honoraria from: Abbvie, Janssen, Pfizer, MSD, Takeda, Amgen.
Ioannis Pachiadakis has received clinical research funding from Janssen
Evanthia Zambeli has received clinical research funding from BMS, Janssen, consulting and/or speaking fees from Janssen, Takeda, Abbvie, Pfizer, Amgen, and has served as advisory board member for Takeda, Janssen.
Spyridon Michopoulos has received clinical research funding from Janssen, Takeda, BMS, consulting and/or speaking fees from Takeda, and has served as advisory board member for Takeda

Clinical Case Summary

A 22-year-old female without comorbidities presented with epigastric and lower retroesternal chest pain, nausea and vomiting since 3 days that didn't response to oral medication. Patient denied dysphagia or odinophagia. Assessed in the emergency, treated with intravenous (IV) medications and discharged with prescription. Next day, the pain increased and vomited 15 times. Patient was admitted as a case of acute gastritis on intravenous proton pump inhibitors (PPIs) and metoclopramide. Routine laboratory and upper abdominal ultrasound done without significant findings only remarkable mild hyponatremia 134 (135-145).
Physical examination looked unwell. Vitally stable 105/75 mmHg. Afebrile (36.2). Malnourished. Weight 28.7 Height 145cms BMI 14.2. Mild epigastric tenderness.
Due to refractory symptoms despite IV medication. Endoscopy was done and showed round and serpiginous ulcers in the lower third of the esophagus with yellowish exudate suggestive of infectious esophagitis Cytomegalovirus vs Herpes. Normal aspect of stomach and duodenum. Histopathology confirmed herpes simplex esophagitis.
Under the suspicion of infectious esophagitis HIV serology came negative, CMV antibodies IgM negative IgG positive. Normal immunoelectrophoresis. No previous herpes viral infection. The only risk factor identified for the patient was the malnutrition, nevertheless vitamins and proteins were normal.
With histological confirmation after 48 hours of the endoscopy she was started on Acyclovir IV 5mg/kg every 8 hours with significant improvement in the next 48 hours. Patient discharged in stable condition after re-starting oral intake and completing the oral acyclovir 400 mg every 8 hours for 10 days. Patient responded well was assessed 7 days after discharge, free of symptoms and a weight gain of 1.3 kg.
Infectious esophagitis needs to be considered in immunocompetent host. Odynophagia/dysphagia can be absent. Endoscopy findings alone isn't sufficient to make a definitive diagnosis.

References

Endoscopy and histopathology.

Introduction

A significant proportion of patients with inflammatory bowel diseases (IBD) have extraintestinal manifestations (EIM), which may be very disabling. The presence of EIM and immunomediated diseases (IMIDs) may influence the selection of the biologic agent. On the other hand, biologic agents have been associated with the onset of IMIDs.

Aims & Methods

Aim: To evaluate the impact of ustekinumab on EIMs and IMIDs in a cohort of ulcerative colitis (UC) patients in real life.
Methods: Retrospective, multicenter study including UC patients who had received the first ustekinumab dose at least 16 weeks before the inclusion. Patients were followed-up from the first ustekinumab dose to treatment discontinuation or last visit, whichever came first. The evolution of previous EIMs and IMIDs was evaluated based on clinicians’ judgment. The onset of new EIMs and IMIDs under ustekinumab treatment was recorded.

Results

376 patients have been included so far (91% had PMS >2 at ustekinumab initiation, 96% had been previously exposed to biologics, and 25% had failed to anti-TNF, vedolizumab and tofacitinib). Median follow-up was 12 months (m). A total of 122 patients (32%) had previous EIM and/or IMIDs at ustekinumab start. A total of 80 patients (21%) had at least one EIM and/or IMIDs inactive at ustekinumab start, being the most frequent ones peripheral arthropathy (5%), axial spondyloarthropathy (3%) and psoriasis (3%). Some patients worsened from these conditions: a patient (6%) with peripheral arthropathy (partial response of UC), 2 (15%) patients with axial spondyloarthropathy (one in remission and one non-responder), a patient (33%) with rheumatoid arthritis (non-responder) and a patient (20%) with uveitis (non-responder). A total of 65 patients (17%) had active EIM and/or IMIDs at ustekinumab start; the outcomes of these patients are summarized in table 1. A total of 15 patients (4%) developed EIM and/or IMIDs after ustekinumab start: 6 (1.6%) patients developed peripheral arthropathy, 2 (0.5%) patients erythema nodosum, a patient (0.3%) was diagnosed with primary sclerosing cholangitis, a patient (0.3%) was diagnosed with vasculitis, and 6 (1.6%) patients developed other conditions.

Conclusion

In patients with active EIM at the start of ustekinumab treatment, improvement of those related to disease (UC) activity was observed. Other EIM and IMIDs not related to disease activity (axial spondyloarthropathy, uveitis, or rheumatoid arthritis) worsened. Treatment with ustekinumab does not appear to be associated with an increased risk of developing EIM or IMIDs.

Disclosure

This is an investigator-initiated study with financial support from Janssen (CNTO1275UCO4008).

Introduction

Crohn’s disease (CD) clinical trials have evolved from evaluating symptoms to including endoscopic outcomes as coprimary endpoints, as was done in clinical trials of upadacitinib (UPA), an oral, reversible Janus kinase inhibitor, and ustekinumab (UST), an anti-interleukin 12/23. Endoscopic healing has been recommended as a long-term treatment target by the Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE) initiative.

Aims & Methods

The objective of this study is to conduct a placebo (PBO)-anchored matching-adjusted indirect comparison (MAIC) of endoscopic outcomes between UPA and UST among patients with moderately to severely active CD. Data from phase 3 UPA trials (NCT: 03105128, 03104413, 03105102) and an UST endoscopy substudy (NCT: 01369329, 01369342, 01369355) from the phase 3 UNITI/IM-UNITI program were used. For induction, patients (pts) received UPA 45mg once daily (QD) for 12 weeks (wks), UST 6mg/kg intravenously, or PBO. For maintenance, pts received UPA 15mg or 30mg QD, subcutaneous UST 90mg every 8 (Q8W) or 12 wks (Q12W), or PBO. Individual pt level data from the UPA trials included pts with baseline (BL) CD Activity Index between 220-450 and excluded pts with prior UST or vedolizumab exposure or missing data due to COVID. Induction BL characteristics identified as treatment-effect modifiers, including disease duration, location, and phenotype, median c-reactive protein, prior biologic failure, and mean Simple Endoscopic Score for CD (SES-CD), were weighted to match those reported in the UST endoscopy substudy for both induction and maintenance. Endoscopic outcomes were evaluated after induction (Wk 12 UPA, Wk 8 UST) and maintenance (Wk 52 UPA, Wk 44 UST). Endoscopic outcomes included endoscopic response (reduction of ≥50% from induction BL in SES-CD) and remission (total SES-CD ≤2), mucosal healing (present with ulceration in at least 1 ileocolonic segment at induction BL) and change in SES-CD score from induction BL.

Results

The effective sample sizes for induction MAICs were 207 UPA and 155 UST pts and ranged from 16–53 (UPA) and 17–46 (UST) for maintenance MAICs. A significantly (P<0.05) greater proportion of UPA vs UST pts achieved endoscopic response and remission, mucosal healing, and had a larger reduction from BL in mean SES-CD score at the end of induction; PBO-adjusted treatment differences were 26.3%, 9.9%, 13.0%, and –3.7 points, respectively. Endoscopic remission rates at the end of maintenance were numerically higher for UPA 30mg vs UST 90mg (Q8W+Q12W). PBO-adjusted rate differences in endoscopic response and mucosal healing between UPA 30mg and UST Q12W were significant (35.5% and 39.0%, respectively; p<0.05); other outcomes (UPA 15mg vs UST) were comparable.

Conclusion

Greater proportions of pts on UPA vs UST achieved endoscopic outcomes at the end of induction for pts with moderately to severely active CD. Although sample sizes during maintenance were limited, these MAICs show endoscopic outcomes are achieved in a numerically higher proportion of pts treated with UPA 30mg vs. UST, while outcomes are comparable with UPA 15mg vs UST.

Disclosure

C Ma has received consulting fees from AbbVie, Alimentiv, Amgen, AVIR Pharma Inc, BioJAMP, Bristol Myers Squibb, Celltrion, Ferring, Fresenius Kabi, Janssen, McKesson, Mylan, Takeda, Pendopharm, Pfizer, Prometheus Biosciences Inc., Roche, Sanofi, Tillotts; speaker's fees from AbbVie, Amgen, AVIR Pharma Inc, Alimentiv, Bristol Myers Squibb, Ferring, Fresenius Kabi, Janssen, Takeda, Pendopharm, and Pfizer; royalties from Springer Publishing; research support from Ferring, Pfizer.
MC Dubinsky has received consulting fees from AbbVie, Abivax, Astra Zeneca, Bristol Myers Squibb, Eli Lilly, Janssen, Merck, Pfizer, Prometheus Biosciences, Prometheus Labs, Takeda
JE Axelrad reports receiving research grants from BioFire Diagnostics; consultancy fees or honorarium from BioFire Diagnostics, Janssen, Pfizer, Abbvie, and BMS; and holds US Patent 2012/0052124A1 and no other conflicts of interest.
J Griffith, S Anyanwu, and N Joshi are employees of AbbVie and may own stock.
J Tran is a funded PhD student at the University of Washington and a contractor for AbbVie.

Introduction

The Phase 3 QUASAR Induction Study (NCT04033445) was a randomized, double-blind, placebo-controlled, parallel-group, multicenter study of guselkumab (GUS), an interleukin-23 p19 subunit antagonist, as induction therapy in patients (pts) with moderately to severely active ulcerative colitis (UC). Here the early onset of symptom improvement was evaluated.

Aims & Methods

Pts were randomized in a 3:2 ratio to receive IV GUS 200mg or placebo (PBO) at Weeks (Wks) 0, 4, and 8. The primary analysis population included treated pts with a baseline modified Mayo score of 5 to 9, , and an endoscopy subscore ≥ 2 (centrally read). Through Wk12, pts recorded stool production and episodes of rectal bleeding in a diary. Symptomatic remission at Wks 2, 4, and 12 were major secondary endpoints. All other analyses were prespecified but not multiplicity controlled (nominal p-values).

Results

Seven hundred one pts were randomized and treated in the primary analysis population (mean UC duration, 7.5yrs, Mayo endoscopy subscore=3 [severe disease], 67.9%, and mean modified Mayo score, 6.9, at baseline). At baseline, 49.1% had prior inadequate response/intolerance to advanced therapies (ADT-IR) for UC; nearly half of these (47.4%) had ≥2 ADT-IR classes. At baseline, for the GUS and PBO groups, respectively, the mean absolute number of stools per day were 7.10 and 6.96; stool frequency subscores of 0 or 1 were observed in 10.0% and 9.6%; and mean rectal bleeding subscores were 1.7 and 1.8.
As early as Wk2 and increasing through Wk12, greater symptomatic improvements were seen in pts treated with GUS compared with PBO. At Wks 2, 4, 8, and 12, symptomatic response was achieved by GUS- vs PBO-treated pts in 34.0% vs 23.6%, 53.2% vs 30.0%, 66.0% vs 39.6%, and 71.7% vs 35.0% (all p<0.001, except Wk2, p<0.01), respectively. Percentages of pts who achieved symptomatic remission with GUS vs PBO at Wks 2, 4, 8, and 12 were 12.1% vs 9.3%, 22.6% vs 12.9%, 39.7% vs 20.7%, and 49.9% vs 20.7% (all p<0.001, except Wk2, p=0.210), respectively. Mean changes from baseline in absolute number of stools per day at Wks 2, 4, 8 and 12 were -1.19 vs -0.61, -2.05 vs -0.75, -2.75 vs -1.31, and -3.15 vs -1.36 (all p<0.001, except Wk2, p<0.01), respectively. Percentages of pts with stool frequency subscore of 0 or 1 at Wks 2, 4, 8, and 12 were 26.1% vs 18.2%, 41.3% vs 25.4%, 53.4% vs 29.6%, and 60.1% vs 31.8% (all p<0.001, except Wk2, p<0.05), respectively. Mean changes from baseline in rectal bleeding subscores at Wks 2, 4, 8, and 12 were -0.6 vs -0.5, -0.8 vs -0.5, -1.1 vs -0.6, and -1.2 vs -0.6 (all p<0.001, except Wk2, p<0.01), respectively. Percentages of pts with rectal bleeding subscores of 0 at Wks 2, 4, 8, and 12 were 24.2% vs 19.3%, 36.8% vs 22.9%, 55.8% vs 33.2%, and 64.6% vs 28.6% (all p<0.001, except Wk2, p=0.110), respectively. Treatment differences for GUS vs PBO were evident across Wk 12 symptomatic outcomes (Table).

Table 1. Symptomatic outcomes at Wk12

Conclusion

GUS 200mg IV induction was effective in improving symptoms as early as 2 weeks after the first dose in pts with moderately to severely active UC. Symptomatic improvements increased through Wk12.

Disclosure

Gary R. Lichtenstein discloses relationships with Janssen/ Janssen Orthobiotech (Consultant, Research, Funding to University of PA [IBD Fellow Education]). Steering Committee member for Janssen.
Axel Dignass reports fees for participation in clinical trials, review activities such as data monitoring boards, statistical analysis and end point committees from Janssen; consultancy fees from Janssen; payment from lectures including service on speakers bureaus from Janssen. Steering Committee member for Janssen.
David T. Rubin has served as a consultant and Steering Committee member to Janssen Pharmaceuticals.
Shadi Yarandi is an employee of Johnson & Johnson and owns company stock/stock options.
Kuan-Hsiang G. Huang is an employee of Johnson & Johnson and owns company stock/stock options.
Matthew Germinaro is an employee of Johnson & Johnson and owns company stock/stock options.
Ye Miao is an employee of Johnson & Johnson and owns company stock/stock options.
Hongyan Zhang is an employee of Johnson & Johnson and owns company stock/stock options.
Jaroslaw Kierkus is a clinical investigator and consultant for Janssen.
Ursula Seidler reports research grants from and is advisor/speaker for Janssen.
Atsuo Maemoto is a clinical investigator and consultant for Janssen.
Jessica R. Allegretti is a consultant and Steering Committee member for Janssen.
Brian Bressler is an advisor/speaker and Steering Committee Member for and has received research support from Janssen.
Laurent Peyrin-Biroulet reports personal fees from Janssen and is a Steering Committee member for Janssen.