Introduction

Ustekinumab, an interleukin (IL) 12/23 inhibitor is a biologic used to treat inflammatory bowel disease (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC). Clinical and real-world evidence has demonstrated its ability to provide a clinically meaningful response and remission among patients; however, the economic impact of its use may not be favourable from the payer perspective. The objective of this targeted literature review was to understand the economic impact of ustekinumab reference product in the treatment of patients with IBD.

Aims & Methods

A literature search was conducted in MEDLINE for economic publications that evaluate the economic impact of ustekinumab or include ustekinumab within their analyses. Search terms included “budget impact model”, “budget impact analysis”, “cost-utility”, “cost-effect”, “ulcerative colitis”, “Crohn’s disease” and “ustekinumab” from database inception until Feb 8^th, 2024. Only studies published in English were eligible for inclusion.

Results

A total of 30 hits were screened for inclusion, yielding 12 relevant studies that discussed economic implications of ustekinumab. Five articles were conducted from the US payer perspective, two from the Japanese payer perspective, and one each from the Canadian, Swedish, Polish, French, and German perspectives. The economic models included budget impact models (n = 2), cost-effectiveness models (n = 8), and cost per responder/remitter analyses (n = 2). Five studies used a CD patient population, six studies focused on UC, and one study included a mixed population of CD and UC. In CD studies, two found ustekinumab was cost-effective: these studies were conducted from the perspective of Polish and Swedish payers in CD patients who failed anti-TNF therapy. Both studies used a Markov based model to assess cost-effectiveness of treatments. In the remaining CD studies, ustekinumab was associated with the highest cost per responder/remitter (Japanese payer perspective) and was dominated by other treatments in cost-effectiveness analyses (US payer perspective). The studies conducted in the UC patient population also found that, although clinically effective, ustekinumab was dominated (based on the incremental cost effectiveness ratio [ICER]) by other biologics included in the analyses (eg, vedolizumab and infliximab). Similar to the CD patient population, the cost per responder/remitter was highest for ustekinumab compared to five other therapies including tofacitinib and golimumab (US payer perspective). However, in two UC studies, ustekinumab was observed to be more effective than the most cost-effective treatment option (from the Japanese and US payer perspectives), highlighting that its price negatively affected its ICER. Moreover, cost-effectiveness analyses conducted by the German and Canadian perspectives, demonstrated that ustekinumab was not a cost-effective therapy at the current willingness to pay threshold (0% probability). Note, that no studies tested the possible cost-effectiveness of an ustekinumab biosimilar which would positively influence the cost associated with ustekinumab treatment.

Conclusion

This literature review demonstrated that, despite its high efficacy, ustekinumab is among the highest costing biologics available for the treatment of IBD with low probabilities of cost-effectiveness across several studies. As the economic burden for IBD is increasing globally, cost-saving therapeutic options such as biosimilars may help to provide savings that can be redistributed in a healthcare system or provide funds to expand patient access.

Disclosure

Kunal Shastri is an employee of Fresenius Kabi a manufacturer of biosimilars. Kerise Clarke, Margaret Ainslie-Garcia, Nicole Ferko are employees of EVERSANA a company who receives consulting fees from Fresenius Kabi.

Introduction

Capsule endoscopy is the first-line examination for digestive bleeding with likely origin in the small bowel, in hemodynamically stable patients. In the 2022 update, ESGE guidelines recommend that, in the context of overt bleeding, capsule enteroscopy should be performed as soon as possible, ideally within the first 48 hours. In the previous guidelines, published in 2015, the recommended window was 14 days.

Aims & Methods

This study aimed to evaluate the improvement in yield offered by the new recommendations regarding the timing of urgent capsule enteroscopy. Patients with suspected overt middle gastrointestinal bleeding between January 2005 and November 2022 were retrospectively analyzed. Diagnostic and therapeutic yield, rebleeding rate, and mortality were compared when capsule enteroscopy was performed within the first 48 hours, within the first 14 days, or between the 3rd and 14th day after admission.

Results

A total of 138 patients were included (58.7% men, median age 66 years), 87 of whom (63.0%) underwent capsule enteroscopy within the first 48 hours after hospital admission. The median follow-up was 55 months (5-180). The diagnostic yield (presence of blood or lesions with bleeding potential) was slightly higher when capsule enteroscopy was performed within the first 48 hours (81.6% versus 76.5%, p=0.349). On the other hand, capsule enteroscopy within the first 48 hours was significantly associated with higher therapeutic yield (endoscopic, radiologic, or surgical treatment) - 54.0% versus 39.2%, p=0.02. The rebleeding rate was significantly lower in patients undergoing enteroscopy within 48 hours after admission (19.5% versus 29.4%, p=0.04). On the other hand, overall mortality at 36 months did not differ between strategies (21.8% and 25.5%, p=0.401).

Conclusion

Performing capsule endoscopy within the first 48 hours, as recommended by recently published guidelines, is associated with favourable short- and long-term clinical outcomes.

Introduction

Endoscopic submucosal dissection (ESD) for esophageal squamous cell carcinoma (ESCC) with esophageal varices (EVs) is one of the most challenging endoscopic procedures due to the high risk of bleeding and fibrosis caused by prior treatment of varices. However, due to the small number of such cases, the clinical outcomes of ESD for ESCC with EVs have been reported in only a limited number of cases at single centers^​1-3.

Aims & Methods

We conducted a multicenter, retrospective, cohort study to clarify the safety and efficacy of ESD for ESCC with EVs.Eleven institutions in the Tohoku region of Japan participated in this multicenter, collaborative, retrospective study. We performed endoscopic resection for 3619 patients with esophageal carcinoma at the participating institutions during the period from January 2010 to April 2022. Among those, 30 patients who underwent ESD for ESCC with EVs were recruited for the present study.
Rates of en bloc resection and R0 resection, procedure time and adverse events were evaluated as indicators of the feasibility and safety of ESD. Additional treatment, recurrence and metastasis of the lesions were evaluated as indicators of the long-term efficacy of ESD.

Results

Portal hypertension was caused by cirrhosis, of which alcohol was the most common cause. En bloc resection was achieved in 93.3% and R0 resection in 80.0% of the patients. The median procedure time was 92 minutes. Adverse events included a case of uncontrolled intraoperative bleeding leading to discontinuation of ESD and a case of esophageal stricture due to extensive resection. During the follow-up period of a median for 42 months, a patient with local recurrence and another patient with liver metastasis were observed. One patient died of liver failure after receiving chemoradiotherapy as an additional treatment after ESD. No patient died of ESCC.

Conclusion

This multicenter, retrospective cohort study demonstrated the safety and efficacy of ESD for ESCC with EVs. Further studies are needed to establish appropriate treatment methods for EVs before ESD and additional treatments for patients with insufficient ESD.

References

1. Sawaguchi M, Jin M, Matsuhashi T, et al. The feasibility of endoscopic submucosal dissection for superficial esophageal cancer in patients with cirrhosis (with video). Gastrointest Endosc 2014;79:681-5.
2. Choi YK, Noh JH, Kim DH, et al. Outcomes of endoscopic submucosal dissection for superficial esophageal neoplasms in patients with liver cirrhosis. Clin Endosc 2022;55:381-9.
3. Zhang S, Liu YD, Chai NL, et al. Endoscopic submucosal dissection for early cancers or precancerous lesions of the upper gastrointestinal tract in cirrhotic patients with esophagogastric varices: Ten-year experience from a large tertiary center in China. Gastrointest Endosc 2023 Online ahead of print.

Disclosure

The authors declare that they have no conflicts of interest.

Introduction

Eosinophilic esophagitis (EoE) is a chronic, condition linked to a type 2 inflammatory response and frequently associated to other atopic conditions. EoE may presents either sporadically, or with aggregation of cases within a same family. Limited information has been provided on the differences in clinical characteristics and disease features between sporadic and familiar EoE, largely due to the lack of large patient cohorts.

Aims & Methods

To find differences in sporadic and familiar cases of EoE which may support distinct clinical management, a cross-sectional analysis of the multicenter EoE CONNECT registry was performed. Demographic and clinical from patients recruited at 42 hospitals in 4 European countries were extracted on March 28th, 2025. Information extracted included 1) age at diagnosis and diagnostic delay; 2) symptoms leading to diagnosis; 3) disease endoscopic and histologic features at diagnosis; and 4) atopic concomitances.

Results

	S-EoE	F-EoE
Age at diagnosis (n= 3,179) <18 years old	18.5%	30.6%
Inflammatory Score (n= 2,723)	1.62 ± 1.3	1.93 ± 1.32
Fibrosis Score (n=2,723)	1.04 ± 1.04	0.97 ± 1.08
Fibrosis (n=1,701)	58.6 %	62.8 %
EoE-Phenotype (n=3,017)
Inflammatory	75.9 %	79.6 %
Mixed	12.6 %	8.6 %
Stricturing	11.5 %	11.8 %

Overall, 4,053 patients (75.4 % males, mean age 33.3 ±15.2 years) were analyzed, including 3028 (74.7 %) sporadic (S-EoE), 714 (17.6%) without familiar data and 311 (7.7 %) familiar (F-EoE) cases including 89 families. Among the family forms, n= 76 families showed 2 affected members, n= 11 presented 3 members, and n= 2 with 4 members. In 85/89 families we identified the index case consisting in sons (13), parents (23), siblings (38), or other distant kinships.
The F-EoE forms were diagnosed at younger mean ± SD ages than S-EoE (29.8±15.6 vs. 33.7±15.1; p<0.001) and included a higher proportion of pediatric patients (considered as those below 18 at diagnosis; 30.6% vs. 18.5%; p<0.001)
Symptoms leading to EoE diagnosis were similar across study groups, with slightly higher presences of abdominal pain (as they included more pediatric cases; 7.7% vs. 4.5%; p=0.01) and chocking episodes (7.7% vs. 4.5%; p=0.01) among F-EoE.
Endoscopy presented more severe features according to EREFS among F-EoE (mean ± SD being 2.86 ± 1.66 vs. 2.64 ± 1.68; p=0.054) at the expense of both fibrotic and inflammatory features, despite only the later reach statistical significance (1.93 ± 1.32 vs. 1.62 ± 1.3; p<0.001). Esophageal biopsies exhibited higher mean ± SD peak eosinophil counts in F-EoE cases (57.11 ± 40.7 vs. 52.87 ± 37.97; p=0.04).
F-EoE were more allergic patients, as they presented a higher mean ± SD number of concomitant atopies (1.44 ± 1.25 vs. 1.25 ± 1.22; p=0.009) and all were more common among them, with conjunctivitis and hives reaching statistical significance (p=0.01 and p=0.002 respectively). Overall, a higher proportion of F-EoE had at least one atopy compared to S-EoE (69.4 % vs. 63.8%).

Conclusion

F-EoE seems to present more severely, with earlier onset, more inflammatory load in endoscopy and biopsies and higher concomitant allergic manifestations.

Introduction

Inflammatory cells and cytokines play an instrumental role in the pathogenesis and disease course of ulcerative colitis (UC) and are thus accepted therapeutic targets. NX-13 is a first-in-class, orally active, once-daily, gut-selective NLRX1 agonist in development for UC. NLRX1 is a mitochondrial associated protein with a novel, bimodal, immunometabolic mechanism which upregulates mitochondrial metabolism, reduces oxidative stress, and decreases pro-inflammatory cell differentiation and cytokine release broadly in mouse models of IBD¹. NX-13 was well tolerated and showed gut selectivity with low systemic drug exposure in Phase 1 studies reported previously^2,3. We now present data from the phase 1b study describing changes in tissue cytokine levels and related to clinical response.

Aims & Methods

In this double-blind phase 1B trial (NCT04862741)³, 36 patients with active UC (Total Mayo Score 4-10; Mayo endoscopic subscore 2-3) were randomly assigned to NX-13 250mg Immediate Release (IR), 500mg IR, 500mg Delayed Release (DR) or Placebo QD for 4 weeks. Protein levels of IFNγ, IL-10, IL-12(p40), IL-17, IL-4, IL-6, IL-8, MCP1, and TNFα in colonic tissue from NX-13 treated patients collected at screening (baseline) and week 4 of treatment were determined by Human Cytokine/Chemokine Panel – Immunology Multiplex Assay (Millipore Sigma) normalized to total protein concentrations. Patients from all NX-13 dose groups with paired baseline and week 4 samples (n=18) were included in this analysis. Mann-Whitney U testing was used for comparisons between responders (Resp) and non-responders (NR).

Results

Baseline cytokines levels were not different between Resp (change from baseline of at least –3, or –30% in total Mayo Score) and NR. NX-13 treatment resulted in a decrease of multiple proinflammatory cytokines at week 4 compared to baseline in most patients, and especially in Resp. compared to NR at week 4 (Table 1). Primarily, the reduction (% change from baseline) of Th1 cytokines IL-12(p40) and IFNγ was greater in NX-13 treated patients with clinical response compared to NR, resulting in significantly lower values in Resp compared to NR at the end of the 4-week study. Similarly, IL-6 also tended to be lower among Resp. after 4 weeks of treatment with NX-13. Additionally, Th2 cytokine IL-4 values were significantly lower after 4 weeks of NX-13 in patients in clinical response compared to NR. Myeloid cell recruitment may also have been affected by cytokine changes induced by NX-13 as IL-8 and MCP levels were lower in clinical Resp. Reduced myeloid cell recruitment is consistent with higher levels of histologic remission in NX-13 treated patients³.

		Mean % CFB (95% CI)			Mean Value Week 4 / End of Study (95% CI)
Cytokine	Primary Function	NR (n=7)	Resp (n=11)	p=	NR (n=7)	Resp (n=11)	p=
IL-12 (p40)	Th1	199 (-5.83-404)	-2.42 (-45.0-40.1)	0.03*	12.3 (1.2-23.5)	2.0 (1.2-2.9)	0.005**
IFNg	Th1	1208 (-837-3253)	53.4 (-164-271)	0.004**	143.4 (-135.6-422.3)	6.3 (0.03-12.6)	0.01*
IL-6	Th1	3864 (-3044-10771)	63.7 (-126-253)	ns	120.4 (-17.5-258.4)	4.5 (1.4-7.6)	0.06#
IL-4	Th2	390 (-262-1041)	-13.7 (-61.9-34.4)	ns	31.0 (3.7-58.3)	3.7 (1.7-5.6)	0.01*
IL-8	Chemoattractant	1207 (-648-3063)	568 (-817-1954)	0.07#	204.3 (-0.1-408.6)	29.4 (7.4-51.4)	0.06#
MCP-1	Chemoattractant	968 (-769-2726)	7483 (-9258-24225)	ns	1684.2 (454.9-2913.4)	475.0 (145.6-804.4)	0.05#
CFB = Change from Baseline; NR= Clinical Non-Responder; Resp = Clinical Responder defined as CFB of at least –3, or –30% in total Mayo Score; **p≤0.005, *p≤0.05, #p≤0.10. ns p>0.10 by Mann-Whitney U testing.

Conclusion

Broad changes in tissue cytokine expression were specifically observed in patients that responded to NX-13- after 4 weeks of treatment, compared to non-responders. These changes mirror those seen in preclinical mouse colitis models where a broad array of cytokines is reduced¹. The early onset of cytokine shifts associated with clinical response to NX-13 at week 4 is notable and will be assessed in the ongoing phase 2 NEXUS study in patients with moderate to severe UC (NCT05785715).

References

¹Leber, et al. J Immunol 203(12); ²Leber, et al. UEGW J 9(Supp); ³Verstockt, et al. JCC epub 11NOV2023

Disclosure

BS has received grant support from Pfizer (to institution); served as a consultant (served as a representative of Charité) for AbbVie, Arena, BMS, Boehringer, Celgene, Endpoint Health, Falk, Galapagos, Janssen, Landos, Lilly, Pfizer, PredictImmune, and Takeda; and has received speaker’s fees (served as a representative of Charité) from AbbVie, CED Service GmbH, Falk, Ferring, Galapagos, Janssen, Lilly, Pfizer, and Takeda; support for attending meetings/travel from Falk; and served as president of ECCO. | SV has received grants from AbbVie, J&J, Pfizer, Takeda, and Galapagos; consulting and/or speaking fees from AbbVie, Abivax, AbolerIS Pharma, AgomAb, Alimentiv, Arena Pharmaceuticals, AstraZeneca, Avaxia, BMS, Boehringer Ingelheim, Celgene, CVasThera, Cytoki Pharma, Dr Falk Pharma, Ferring, Galapagos, Genentech-Roche, Gilead, GSK, Hospira, Imidomics, Janssen, J&J, Lilly, Materia Prima, MiroBio, Morphic, MrMHealth, Mundipharma, MSD, Pfizer, Prodigest, Progenity, Prometheus, Robarts Clinical Trials, Second Genome, Shire, Surrozen, Takeda, Theravance, Tillots Pharma AG, and Zealand Pharma. | AY reports consulting fees from Takeda, Prometheus Labs, Arena Pharmaceuticals, and Bristol Myers Squibb; and speaker bureau fees from Bristol Myers Squibb. | SS has received personal fees from AbbVie, Amgen, Arena Pharmaceuticals, Bristol Myers Squibb, Boehringer Ingelheim, Celltrion, Dr Falk Pharma, Ferring, Fresenius, Galapagos, Genentech, GSK, Gilead, I-MAB Biopharma, Janssen, Lilly, Merck, Novartis-Sandoz, Pfizer, Protagonist, Takeda, and Theravance. | SD reports consultancy fees from AbbVie, Alimentiv, Allergan, Amgen, AstraZeneca, Athos Therapeutics, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Celltrion, Dr Falk Pharma, Eli Lilly, Enthera, Ferring Pharmaceuticals Inc., Gilead, Hospira, Inotrem, Janssen, Johnson & Johnson, MSD, Mundipharma, Mylan, Pfizer, Roche, Sandoz, Sublimity Therapeutics, Takeda, TiGenix, UCB Inc., and Vifor; he reports lecture fees from Abbvie, Amgen, Ferring Pharmaceuticals Inc., Gilead, Janssen, Mylan, Pfizer, and Takeda. | RM is an employee of Landos. | FC is an employee of Landos. | BV has received grants from Abbvie, Biora Therapeutics, Landos, Pfizer, Sossei Heptares, and Takeda; Speaker’s fees from Abbvie, Biogen, Bristol Myers Squibb, Celltrion, Chiesi, Falk, Ferring, Galapagos, Janssen, MSD, Pfizer, R-Biopharm, Takeda, Truvion and Viatris. Consultancy fees from Abbvie, Alimentiv, Applied Strategic, Atheneum, Biora Therapeutics, Bristol Myers Squibb, Galapagos, Guidepoint, Landos, Mylan, Inotrem, Ipsos, Janssen, Progenity, Sandoz, Sosei Heptares, Takeda, Tillots Pharma and Viatris. | MCD reports consulting fees from AbbVie, Arena, Bristol Myers Squibb, Celgene, Eli Lilly, Genentech, Gilead, Janssen, Pfizer, Prometheus Labs, and Takeda; and is founder and a shareholder of Trellus Health.