Introduction

Current data suggests that biosimilar is safe and effective for patients with inflammatory bowel disease (IBD).^1-2 However, the drug discontinuation and nocebo effect after switching from originator to biosimilar have increased over time. ³

Aims & Methods

We aimed to evaluate clinical efficacy, biomarkers activity, therapeutic drug monitoring (TDM) adverse events (AEs), and nocebo effect in IBD patients who underwent biosimilar switch. A prospective observational study of consecutive IBD patients who underwent non-medical biosimilar switch at McGill University Health Centre, Montreal, Canada, between April 1, 2022 – March 31, 2023. The patients were follow-up until 24 weeks following the switch. Disease activity, biomarkers, TDM and AEs including nocebo effect were captured at 8 weeks before switch, at time of the switch (baseline), 12 and 24 weeks after the switch.

Results

A total of 210 patients were included [81.4% were Crohn’s disease (CD), median age at inclusion: 42 years (IQR 29-61)]. There was no significant difference in the rates of clinical remission at week 8 before the switch, baseline, week 12, and 24 after the switch; 89.0%, 93.4%, 86.3% and 90.8%, p=0.129. The rates of sustained clinical remission at week 12 and week 24 after switching were 79.4% and 69.6% respectively. The proportion of patients remaining in biomarkers remission was not significantly different at week 8 before the switch, baseline, week 12, and 24 after the switch; CRP: 81.3%/ 74.7%/ 81.2%/ 73.0%, p=0.343; Fecal calprotectin: 78.3%/ 74.5%/ 71.7%/ 76.3%, p=0.829. The rates of maintaining in therapeutic level (84.7%/ 83.9%/ 83.0%/ 85.3%, p=0.597) and prevalence of positive anti-drug antibodies remained unchanged before and after the switch. Nocebo effect was observed in 13.3% and 4.3% of patients discontinued biosimilar therapy. Main results of the study outcomes in IBD patients following Biosimilar switch is shown in Table 1.

Outcomes monitoring, n (%)	8 weeks before the switch	At switch (baseline)	Week 12 after switch	Week 24 after switch	p-value
Clinical remission	187/210 (89.0%)	184/197 (93.4%)	164/190 (86.3%)	167/184 (90.8%)	0.129
Steroid-free clinical remission	185/210 (88.1%)	181/197 (91.8%)	163/190 (85.8%)	166/184 (90.2%)	0.113
IBD flare	NA	6/184 (3.3%)	14/167 (8.4%)	10/161 (6.2%)	0.121
CRP remission	113/139 (81.3%)	59/79 (74.7%)	69/85 (81.2%)	73/100 (73.0%)	0.343
Fecal calprotectin remission	65/83 (78.3%)	41/55 (74.5%)	43/60 (71.7%)	58/76 (76.3%)	0.829
Maintaining in therapeutic level	72/85 (84.7%)	47/56 (83.9%)	88/106 (83.0%)	99/116 (85.3%)	0.597
Adalimumab anti-drug Ab positive	0/44 (0%)	0/28 (0%)	2/49 (4.1%)	2/50 (4.0%)	0.345
Infliximab anti-drug Ab positive	1/41 (2.4%)	0/28 (0%)	1/57 (1.8%)	2/66 (3.0%)	0.616
Nocebo effect	NA	9 (4.3%)	13 (6.4%)	6 (3.0%)	NS

Conclusion

Despite a significant number of early nocebo complaints within the first 6 months after the biosimilar switch, no significant changes were found in clinical efficacy, biomarkers, therapeutic drug level, and anti-drug antibodies.

References

1. Danese, S. et al. ECCOJC 2017, 11, 26–34
2. Jørgensen, K.K. et al.The Lancet 2017, 389, 2304–2316
3. Queiroz et al. Arq. Gastroenterol. 2020, 57, 232–243

Introduction

The use of artificial intelligence (AI) systems for decision support has recently gained great popularity in the medicine.¹ However, recent studies have shown possible limitations emerging from the interaction between humans and AI. Among these, the term “automation bias (AB)” refers to human errors deriving from over-relying on AI’s false alarms such that the human changes a correct initial interpretation.² AB is poorly investigated in the medical field and was never tested in the gastroenterological setting.

Aims & Methods

The aim of the study was to investigate the impact of AI on human diagnostic performance in gastrointestinal endoscopy, including AB.
Ninety high-quality endoscopic videoclips (16 seconds) extracted from small bowel (SB) capsule endoscopy (N=60) and proctosigmoidoscopy (N=30) were edited with the addition of a mock AI system designed with diagnostic accuracy, sensitivity and specificity of 80%, 86% and 75%. The ground truth was settled on the agreement of 9 established experts about the presence of SB lesions with significant hemorrhagic potential according to the Saurin classification (30 videoclips), inflammatory lesions relevant for the diagnosis of SB Crohn's disease according to the Lewis score (30 videoclips) and assessing the Ulcerative Colitis (UC) Endoscopic Index of Severity (30 videos). The videoclips were randomly divided into three sessions and submitted around Europe to fully trained endoscopist, trainees and endoscopic technicians. Participants were instructed to the accuracy measures of AI annotations and scored each videoclip first without, then with AI support. Participants’ performances with and without AI were calculated. Subgroup analyses were made after stratification by participants’ experience level in each endoscopic setting and test performances.

Results

A total of 12.660 videoclips (both with and without AI) were visualized in 422 sessions (182, 118 and 122 participants completed the first, second and third session, respectively). A strong and significant difference between the respondents' performance (N=281) when they were unaided by AI (average accuracy (M)=0.78, [0.77, 0.79] and when they were supported by the AI (M=0.81, [0.80, 0.82], paired t-test, t(276)=11.2, p<0.001) was found. Size effect and the evidence in favour of a significant positive effect of AI were large, 0.67 (Cohen's D) and very large (Bayes Factor>100), respectively. Interestingly, no significant difference between trainees and specialists both in regard to their performance, either unaided, M=0.77 [0.74, 0.79] vs M=0.78, [0.77, 0.79] or aided M=0.80 [0.78, 0.82] vs M=0.81 [0.80, 0.82] and their accuracy improvement (M=0.03, [0.02, 0.05] vs M=0.03, [0.02, 0.04] (unaided t-value=-0.89, p=0.37; aided t-value=-0.69, p=0.49, difference t-value=0.54, p=0.59) were found. A strong leveller effect emerged, with low-performers improving their accuracy much more than top-performers (average improvement 5%, [0.04, 0.06] vs 1%, [0.00, 0.02], paired T test, t=6.53, p<0.001). Nine percent of the final decisions involved disregarding correct AI advice in favour of incorrect human judgment, while AB occurred in 2% of cases.

Conclusion

In this study, the application of AI to assess SB bleeding, SB inflammatory lesions, and UC activity brings significant improvement in diagnostic accuracy, with the benefit appearing to be greater in the low-performers. However, in rare cases, AI may induce diagnostic errors due to AB. Future studies directly evaluating the impact of AI in real-life clinical settings are needed to confirm these data.

References

1. Cabitza F, Campagner A, Angius R, Natali C, Reverberi C. 2023. AI Shall Have No Dominion: on How to Measure Technology Dominance in AI-supported Human decision-making. In Proceedings of the 2023 CHI Conference on Human Factors in Computing Systems (CHI '23). Association for Computing Machinery, New York, NY, USA, Article 354, 1–20. https://doi.org/10.1145/3544548.3581095
2. Reverberi, C., Rigon, T., Solari, A. et al. Experimental evidence of effective human–AI collaboration in medical decision-making. Sci Rep 12, 14952 (2022). https://doi.org/10.1038/s41598-022-18751-2

Introduction

The incidental finding of terminal ileal inflammation during routine colonoscopy is not uncommon and is of unclear significance. It has been reported among asymptomatic persons undergoing non-diagnostic colonoscopy. There is limited data on long term follow-up and outcomes of such findings.(1)

Aims & Methods

This is a monocentric retrospective observational study spanning from 2018 to 2023, comparing two periods: the first period (P1) before the impact of the Covid-19 pandemic in 2020, and the second period (P2) starting 2020 reflecting the impact the pandemic left on colonoscopies. For each patient, variables were collected from medical records.

Results

Our initial database included 11200 colonoscopies, from which we randomly selected 2394 patients proportionally to the annual activity (mean of 1686/year before 2020 and 1189/year after 2020). Among indications of colonoscopy were screening and follow-up, change in bowel habits, anemia and bleeding. We excluded 287 patients (known history of inflammatory bowel disease and no ileum intubation). Then the sample was divided into P1 (681 patients) and P2 (1483 patients). Characteristics and findings are shown in Table 1. We noted better bowel preparation (77.1 vs 91.7%) and a higher ileum intubation in P2 (79.7 in P1 vs 93.8% in P2).
​

N=2164			P1 (N1=681)	P2 (N2= 1483)	p
Age (years)			57.5	56.9	NS
Overall endoscopic findings n(%)	Endoscopic aspect of ileitis		0 (0)	71 (5.8)	<0.001
	Abnormal ileal findings on histology		23 (3.4)	169 (11.4)	<0.001
	Diagnosis of Crohn's disease		0 (0)	19 (0.9)	<0.001
Overall histological findings n(%)	Active ileitis		19 (2.8)	147 (9.9)	<0.001
	Focal ileitis		10 (1.5)	89 (6)	<0.001
	Ulcerative ileitis		11 (1.6)	48 (3.2)	0.031
	Erosive ileitis		3 (0.4)	31 (2.1)	0.004
	Architectural distortion		1 (0.1)	16 (1.1)	0.023

Overall ileoscopy findings showed an increased aspect of ileitis on endoscopy (0% in P1 and 5.8% in P2, with p<0.001), correlating with a significant increase in the incidence of histological findings on ileal biopsies (3.4% in P1 vs 11.4% in P2; p<0.001). These histological findings included active, focal and ulcerative ileitis, with more architectural distortion. However, these results corresponded to a less severe ileitis (0.3 vs 2.3%; p=0.001). Nineteen of these patients with positive results of ileitis were diagnosed with Crohn’s disease.

Conclusion

This study showed an increase in endoscopic and histologic ileitis on colonoscopy following the Covid-19 era. This could be the result of the direct virologic effect that the virus has on intestinal inflammation, its indirect effect on immunity triggering the onset of enteritis, or the consequence of the mass vaccination campaign held to protect from the virus. Furthermore, histology showed granulomatous inflammation similar to Crohn’s disease, which may lead to misdiagnosis and probably overtreatment.

References

1. Agrawal M, Miranda MB, Walsh S, Narula N, Colombel JF, Ungaro RC. Prevalence and Progression of Incidental Terminal Ileitis on Non-diagnostic Colonoscopy: A Systematic Review and Meta-analysis. J Crohns Colitis. 2021 Feb 14;15(9):1455–63.

Clinical Case Summary

EUS-BD is an alternative therapeutic approach in case of unsuccessful biliary drainage by ERCP (1,2). Our aim is to report another possible indication of EUS-BD as a salvage treatment in a case of post-ERCP perforation around the papilla.
This is a case-report of a 79-years-old woman admitted for obstructive jaundice with bilirubin levels of 18 mg/dL. A MRI displayed marked dilation of intrahepatic bile ducts, gallbladder and choledochus (18-mm) until its distal part where and abrupt stop and a regular stricture was observed. An ERCP failed to cannulate the common bile duct. After a precut procedure, retroperitoneal extravasation of the contrast was observed. After consultation with the surgical team and fully information to the family of the patient about therapeutic alternatives, an EUS-BD was performed immediately after the ERCP as a therapeutic approach aiming to treat simultaneously the perforation and the obstructive jaundice without delay.
EUS-BD was performed according to the standardized technique with a transgastric approach. The intrahepatic bile duct was puncture with a 19-gauge needle. A 0.025” guide-wire was inserted and the fistula was created using a 6French cystostome with pure current. After exchanging the guide-wire for another of 0.035” and passing it to the duodenum, a 6-cm long, fully-covered metal stent was deployed at the stricture as antegrade fashion.
A further CT-scan displayed no collections with decreasing of the bile duct dilation. The clinical outcome of the patient was uneventful, being discharged one-week after the EUS-BD.
One month later, a scheduled pancreaticoduodenectomy was performed. The surgical specimen showed a 4-mm wide distal cholangiocarcinoma.
EUS-BD with fully-covered metal stenting was effective to both drainage and covering perforation site. EUS-BD could be deemed as another potential indication in selected cases as an immediate rescue therapy after ERCP adverse events such as perforation.

References

Nakai Y, Isayama H, Wang HP, Rerknimitr R, Khor C, Yasuda I, et al. International consensus statements for endoscopic management of distal biliary stricture. J Gastroenterol Hepatol. 2020;35(6):967-79.
Huh G, Park DH. EUS-guided transhepatic biliary drainage for next-generation ERCPists. Gastrointest Endosc. 2022;95(3):452-4.

Disclosure

Rafael Romero-Castro is consultant to Cook Medical since February 28th, 2023.

Clinical Case Summary

Secondary aortoenteric fistula (AEF) is an abnormal connection between the aorta and gastrointestinal tract (GT) resulting from reconstructive surgery for an abdominal aortic aneurysm (AAA), including open repair surgery and endovascular treatment. Despite the low incidence (1.6 to 4%) [1–4], it is life-threatening and has a high mortality rate (24 to 45.8%) [5–6].
A 79- year-old man reported to the emergency department of our hospital with overt bleeding from the stoma. The patient had a history of open Dacron graft repair for a ruptured AAA eight months previosly, which became complicated on the 5th postoperative day by sigmoid ishemia that required an emergency Hartmann procedure.
His blood pressure was 90/60 mmHg, heart rate 93/minute and hemoglobin level 7.5 g/dL.
The patient was admitted to our department. He underwent upper and lower endoscopy and no bleeding lesions were found. After endoscopy the patient presented another episode of overt bleeding from the stoma and we decided to perform Small-bowel capsule endoscopy (SBCE) which showed activ bleeding within the proximal ileum. The contrast-enhanced CT demostrated an aneurysm sac enlargement, a close proximity of the small bowel loops with the aneurysm sac in the pelvic cavity and a suspected leakage at the distal part of the aneurysm sac.
The patient was therefore admitted to the Surgical Derpatment and underwent an emergency endovascular repair of the leakage caused by distal detachment of the aorto-aortic prosthesis using a bifurcated stant graft. No more bleeding from the stoma occurred and the patient was discharged three days later with a diagnosis of distal aortic anastomosis leakage with aorto-ileal fistula.
The duplex ultrasound of the graft after one, three and six months showed no sign of endoleak.
This case shows that the SBCE may be useful in patients with history of recostructive surgery for AAA who manifest overt bleeding from the GT and no lesions are found in upper and lower endoscopy.

References

1.Wilson WR, Bower TC, Creager MA, Amin-Hanjani S, O’Gara PT, Lockhart PB, Darouiche RO, Ramlawi B, Derdeyn CP, Bolger AF, et al. Vascular Graft Infections, Mycotic Aneurysms, and Endovascular Infections: A Scientific Statement From the American Heart Association. Circulation. 2016;134(20): e412–60
2.Champion MC, Sullivan S, Coles J, Goldbach M, Watson WC. Aortoenteric fistula. Incidence, presentation recognition, and management. Ann Surg. 1982;195(3):314–7
3.Hallett JW Jr, Marshall DM, Petterson TM, Gray DT, Bower TC, Cherry KJ Jr, Gloviczki P, Pairolero PC. Graft-related complications after abdominal aortic aneurysm repair: reassurance from a 36-year population-based experience. J Vasc Surg. 1997;25(2):277–84. discussion 285-276
4.Chenu C, Marcheix B, Barcelo C, Rousseau H. Aorto-enteric fistula after endovascular abdominal aortic aneurysm repair: case report and review. Eur J Vasc Endovasc Surg. 2009;37(4):401–6
5.Malik MU, Ucbilek E, Sherwal AS. Critical gastrointestinal bleed due to secondary aortoenteric fistula. J Community Hosp Intern Med Perspect. 2015;5(6):29677
6.Gnus J, Ferenc S, Koscielna M, Paprocka-Borowicz M, Dawidczyk P, Dziewiszek M, Witkiewicz W. Secondary Aortoenteric Fistula After Abdominal Aortic Graft Implementation in Our Own Material. Adv Clin Exp Med. 2016;25(6):1265–71

Introduction

Tyrosine kinase 2 (TYK2) mediates cytokine signalling in immune-mediated inflammatory diseases, including Crohn’s disease (CD). Zasocitinib (TAK-279) is a highly selective, oral, allosteric TYK2 inhibitor with efficacy and acceptable safety shown in patients with psoriasis and psoriatic arthritis.^1,2 This phase 2b study (NCT06233461) aims to assess the efficacy and safety of zasocitinib in patients with moderately to severely active CD.

Aims & Methods

This is a multicentre, randomized, double-blind induction, placebo-controlled, dose-ranging, treat-through study in patients (18–75 years) with moderately to severely active ileal, ileocolonic or colonic CD (CD Activity Index [CDAI] score 220–450 and ulcerations characteristic of CD defined by ileocolonoscopy at screening and Simple Endoscopic Score for CD [SES-CD] ≥6 or ≥4 for isolated ileitis). Eligible patients must have inadequate/loss of response or intolerance to ≥1 of oral aminosalicylates, corticosteroids, immunosuppressants, biologics, JAK inhibitors (JAKi) or sphingosine-1-phosphate (S1P) receptor modulators. Patients who have also failed <3 classes of advanced therapies will be included. After screening (30 days), approximately 268 patients will be randomized 1:1:1:1 to receive low-, medium- or high-dose zasocitinib or placebo orally once daily for 12 weeks (induction phase), followed by a 40-week maintenance period and a 4-week safety follow-up. At or after Week 12, patients receiving placebo with disease worsening based on PRO2 score will receive active zasocitinib treatment. Study doses are expected to provide ≥90% TYK2 inhibition over the 24-hour dosing interval, and were associated with efficacy in preclinical models.³ Randomization will be stratified based on previous biologic, JAKi or S1P receptor modulator therapies, and steroid use at baseline. The number of patients who received previous biologic, JAKi, S1P receptor modulator, anti-interleukin (IL)-23p19 or anti-IL-12/23p40 therapy will be capped.
Primary endpoint analysis will be conducted using a Cochran–Mantel–Haenszel (CMH) test. Binary secondary endpoints will be analysed similarly to primary endpoints. Longitudinal continuous secondary endpoints up to Week 12 will be analysed using a mixed-effects model with repeated measures. Safety data will be presented by treatment group and assessment period.

Results

The study is actively enrolling with the first patient randomized in March 2024. An open-label extension is planned for zasocitinib responders. The primary efficacy endpoint is the achievement of endoscopic response at Week 12 (>50% decrease in SES-CD from baseline [for patients with isolated ileal disease: SES-CD ≤4 or ≥2-point reduction]). Secondary efficacy endpoints at Week 12 include: clinical remission (CDAI <150), clinical response (CDAI reduction from baseline of ≥100), endoscopic remission (SES-CD ≤4 or ≤2 for patients with ileal disease, no subscore >1), patient-reported symptoms and disease-specific health-related quality of life (HRQoL). Safety and tolerability will be assessed by treatment-emergent adverse events (AEs), serious AEs and AEs of special interest throughout the study. Intestinal ultrasound measurements, using the International Bowel Ultrasound Segmental Activity Score (IBUS-SAS), will be assessed at Weeks 4, 12 and 52 in a subset of patients.

Conclusion

Alongside evaluating the efficacy and safety of zasocitinib in patients with moderately to severely active CD, this unique 52-week treat-through study design will assess the impact of treatment on HRQoL, an area of significant unmet need in this population.

References

1. Armstrong A et al. AAD 2023.
2. Kivitz A et al. Arthritis Rheumatol 2023;75(Suppl 9).
3. Kong KF et al. J Crohns Colitis 2024;18(Suppl 18).

Disclosure

VJ has received: consulting/advisory board fees from AbbVie, Alimentiv, Arena Pharmaceuticals, Asahi Kasei Pharma, Asieris, AstraZeneca, Avoro Capital, Bristol Myers Squibb, Celltrion, Eli Lilly, Endpoint Health, Enthera, Ferring, Flagship Pioneering, Fresenius Kabi, Galapagos, Genentech, Gilde Healthcare, Gilead, GlaxoSmithKline, Innomar, JAMP, Janssen, Merck, Metacrine, Mylan, Pandion, Pendopharm, Pfizer, Prometheus Biosciences, Protagonist, Reistone Biopharma, Roche, Roivant, Sandoz, Second Genome, Sorriso, Synedgen, Takeda, TD Securities, Teva, Topivert, Ventyx and Vividion; and speaker fees from AbbVie, Bristol Myers Squibb, Ferring, Fresenius Kabi, Galapagos, Janssen, Pfizer, Shire and Takeda. VG, LZ, VN, OA, AND, FN, TF, LS and NS are employees and equity holders of Takeda.

Clinical Case Summary

Familial intrahepatic cholestasis is a heterogeneous group of genetic diseases with autosomal recessive transmission. BSEP (Bile-Salt Export Pump) is the main bile acid export pump in hepatocytes. Mutations in the gene encoding BSEP, ABCB11, are associated with heterogeneous clinical phenotypes ranging from diseases with a benign course to severe forms requiring liver transplantation. Here we report the case of a 17-year-old girl admitted to our Clinic because of severe jaundice and itching. She reported a similar episode 2 years earlier with spontaneous recovery. Family history is positive for cholelithiasis. On admission, laboratory tests showed: total and direct bilirubin values of 24.5 mg/dl and 18.9 mg/dl, AST 307 IU/L and ALT 238 IU/L, respectively. GammaGT was normal. Viral, autoimmune, metabolic causes, and biliary obstruction were excluded. Liver biopsy showed a picture of hepatocellular and intracanalicular cholestasis with cholestatic rosettes, inflammatory activity, and mild portal and pericellular fibrosis. Immunohistochemical staining for BSEP showed only weak diffuse expression. Genetic testing documented compound heterozygosity of the ABCB11 gene with the variants c.1460G>A - p(Arg487His) of paternal origin and c2599C>T -(Gln867*) of maternal origin. Genetic testing of relatives is also ongoing. The patient was treated with ursodesoxycholic acid, cholestyramine and cetirizine for 4 months with disappearance of jaundice and pruritus and normalization of bilirubin levels. Follow-up at 1 year was free of events without therapy. This is the first time that the c2599C>T -(Gln867*) variant has been described in a patient with familial intrahepatic cholestasis. Application of the "temporal test" will allow this new variant to be attributed to the BRIC2 form rather than PFIC2.