Introduction

Capsule endoscopy (CE) is frequently employed as the first exam when mid-gastrointestinal bleeding is suspected, following normal upper and lower endoscopies. While its primary focus is on evaluating the small bowel, detection of vascular lesions both upstream and downstream could also hold clinical importance.

Aims & Methods

The aim of this study is to develop and test a Convolutional Neural Network (CNN)-based model for panendoscopic automatic detection of vascular lesions during CE. A retrospective study involving 2 centers was conducted, involving 1188 CE exams. A total of 152,312 frames were utilized, obtained from seven distinct types of CE devices, with 14,942 frames being classified as vascular lesions (angiectasias or varices) after triple validation. The data was divided in training/validation (90%) and test (10%) sets, using an exam-split design. A 5-fold cross-validation was conducted during training/validation set. The all process was iterated five times. The primary outcome measures were sensitivity, specificity, accuracy, area under the conventional receiver operating characteristic curve (AUC-ROC) and the precision-recall curve (AUC-PR), from the training/validation set.

Results

The model demonstrated a mean sensitivity and specificity of 87.5% (IC95% 81.5 – 93.6%) and 99.5% (IC95% 99.3 – 99.7%), respectively. Mean accuracy was 98.4% (IC95% 97.7 – 99.1%). Mean AUC-ROC value was 0.987 (IC95% 0.980 – 0.995), while AUC-PR value was 0.998 (IC95% 0.997 – 1.000).

Conclusion

This represents the first proof-of concept AI deep learning model developed for panendoscopic automatic detection of vascular lesions during CE. The CCN’s high diagnostic performance in multibrand devices addresses a critical issue of technological interoperability, allowing it to be replicated in multiple technological settings.

Introduction

Guselkumab (GUS), a dual-acting interleukin-23p19 subunit inhibitor, demonstrated efficacy in participants (pts) with ulcerative colitis (UC) treated with intravenous (IV) or subcutaneous (SC) induction. Here, we report the efficacy and safety of SC induction followed by SC maintenance through Week (W) 48 in ASTRO, a phase 3, randomized, double-blind, placebo (PBO)-controlled, treat-through study in pts with moderately to severely active UC.

Aims & Methods

Eligible pts had modified Mayo scores of 5 to 9, rectal bleeding subscore of ≥1, and Mayo endoscopic subscore (MES) ≥2. Pts also had documented inadequate response/intolerance to biologics, Janus kinase (JAK) inhibitors, and/or sphingosine-1-phosphate (S1P) inhibitors (BIO/JAKi/S1Pi-IR) or to corticosteroids, 6-mercaptopurine, or azathioprine. Randomization was stratified by baseline BIO/JAKi/S1Pi-IR status and MES with 418 pts allocated 1:1:1 to GUS 400 mg SC every 4 weeks (q4w) (×3)→GUS 200 mg SC q4w (N=140), GUS 400 mg SC q4w (×3)→GUS 100 mg SC every 8 weeks (q8w) (N=139), or PBO SC (N=139). PBO pts who met rescue criteria were switched to GUS at W16; GUS pts who met rescue criteria stayed on their assigned GUS dose regimen (sham rescue).

Results

At W48, greater proportions of pts in the GUS groups achieved clinical remission compared with PBO (36.7% for GUS 100 mg q8w [Δ 29.5%], 42.9% for GUS 200 mg q4w [Δ 35.6%], 7.2% for PBO) (Table). Endoscopic remission proportions were 25.9% for GUS 100 mg q8w (Δ 20.9%), 26.4% for GUS 200 mg q4w (Δ 21.4%), and 5.0% for PBO. Clinical response, symptomatic remission, endoscopic improvement, histologic improvement, and histologic remission proportions were also greater for GUS vs PBO. Consistent with the results of the overall population, efficacy was also observed for subpopulations of BIO/JAKi/S1Pi-naïve and BIO/JAKi/S1Pi-IR pts. Safety events per 100 pts-years were not greater in the GUS groups compared with the PBO group: adverse events (AE) (GUS 100 mg q8w and 200 mg q4w vs PBO: 308.3 and 310.7 vs 357.1), serious AEs (6.5 and 8.2 vs 38.4), serious infections (0.8 and 2.5 vs 3.7), and AEs leading to treatment discontinuation (4.9 and 4.1 vs 19.8).
Table. Efficacy endpoints at Week 48 in the overall population and by biologic, JAK inhibitor, and/or S1P inhibitor history

	Overall			BIO/JAKi/S1Pi-naïve			BIO/JAKi/S1Pi-IR
Outcomes at Week 48	Placebo SC (N=139)	GUS 400 mg SC→ GUS 100 mg SC q8w (N=139)	GUS 400 mg SC→ GUS 200 mg SC q4w (N=140)	Placebo SC (N=79)	GUS 400 mg SC→ GUS 100 mg SC q8w (N=81)	GUS 400mg SC→ GUS 200mg SC q4w (N=83)	Placebo SC (N=56)	GUS 400 mg SC→ GUS 100 mg SC q8w (N=57)	GUS 400 mg SC→ GUS 200 mg SC q4w (N=55)
Clinical remission	10 (7.2)	51 (36.7) Δ 29.5 P<0.001	60 (42.9) Δ 35.6 P<0.001	6 (7.6)	39 (48.1) Δ 40.3 P<0.001	42 (50.6) Δ 43.0 P<0.001	4 (7.1)	12 (21.1) Δ 13.7 P=0.034	18 (32.7) Δ 25.2 P<0.001
Clinical response	26 (18.7)	78 (56.1) Δ 37.4 P<0.001	83 (59.3) Δ 40.6 P<0.001	19 (24.1)	52 (64.2) Δ 39.5 P<0.001	54 (65.1) Δ 40.8 P<0.001	7 (12.5)	25 (43.9) Δ 30.9 P<0.001	29 (52.7) Δ 39.3 P<0.001
Endoscopic improvement	16 (11.5)	62 (44.6) Δ 33.1 P<0.001	66 (47.1) Δ 35.6 P<0.001	10 (12.7)	46 (56.8) Δ 44.0 P<0.001	45 (54.2) Δ 41.7 P<0.001	6 (10.7)	16 (28.1) Δ 16.0 P=0.024	21 (38.2) Δ 26.8 P<0.001
Endoscopic remission	7 (5.0)	36 (25.9) Δ 20.9 P<0.001	37 (26.4) Δ 21.4 P<0.001	5 (6.3)	27 (33.3) Δ 26.9 P<0.001	28 (33.7) Δ 27.5 P<0.001	2 (3.6)	9 (15.8) Δ 11.5 P=0.033	9 (16.4) Δ 12.6 P=0.025
Symptomatic remission	20 (14.4)	66 (47.5) Δ 33.1 P<0.001	75 (53.6) Δ 39.2 P<0.001	15 (19.0)	47 (58.0) Δ 38.6 P<0.001	51 (61.4) Δ 42.3 P<0.001	5 (8.9)	19 (33.3) Δ 24.3 P=0.001	24 (43.6) Δ 34.0 P<0.001
Histologic improvement	18 (12.9)	65 (46.8) Δ 33.8 P<0.001	73 (52.1) Δ 39.2 P<0.001	13 (16.5)	45 (55.6) Δ 38.6 P<0.001	50 (60.2) Δ 43.8 P<0.001	4 (7.1)	20 (35.1) Δ 26.8 P<0.001	23 (41.8) Δ 34.1 P<0.001
Histologic remission	15 (10.8)	52 (37.4) Δ 26.6 P<0.001	63 (45.0) Δ 34.2 P<0.001	11 (13.9)	35 (43.2) Δ 29.1 P<0.001	41 (49.4) Δ 35.5 P<0.001	4 (7.1)	17 (29.8) Δ 21.5 P=0.002	22 (40.0) Δ 32.4 P<0.001
Data are presented as n (%); ∆% (adjusted treatment difference) versus placebo; nominal p-value versus placebo. The adjusted treatment difference was based on the common risk difference by use of the Mantel-Haenszel stratum weights and the Sato variance estimator. In the overall population, the p-values were based on the Mantel-Haenszel test, stratified by BIO/JAKi/S1Pi-IR status (Yes/No) and Mayo endoscopic subscore at baseline (Moderate [2]/Severe [3]). For the BIO/JAKi/S1Pi-naive/-IR subgroups, the p-values were stratified only by the Mayo endoscopic subscore at baseline. Participants who, prior to Week 48, had an ostomy or colectomy, a prohibited change in UC medications, discontinued study agent due to lack of efficacy or an AE of worsening of UC, or met rescue criteria per IWRS were considered not to have achieved any of the key efficacy endpoints shown at Week 48. For participants who discontinued study agent due to COVID-19-related reasons (excluding COVID-19 infection) or regional crisis, their observed values were used, if available. Participants who discontinued study agent prior to Week 48 due to other reasons were considered not to have achieved any of the efficacy endpoints shown at Week 48. Participants who were missing one or more of the components pertaining to an endpoint at Week 48 were considered not to have achieved the endpoint. Endpoint definitions: clinical remission, Mayo SFS 0/1 and not increased from BL, Mayo RBS=0, and MES 0/1 with no friability; clinical response, ≥30% and ≥2-point decrease from BL in Modified Mayo score with ≥1-point decrease from BL in RBS or RBS 0/1; endoscopic improvement, MES 0/1 with no friability; endoscopic remission, MES of 0; symptomatic remission, SFS 0/1 and not increased from BL and RBS=0; histologic improvement, neutrophil infiltration in <5% of crypts; no crypt destruction; and no erosions, ulcerations, or granulation tissue per Geboes grading system; histologic remission, absence of neutrophils from the mucosa (both lamina propria and epithelium); no crypt destruction; and no erosions, ulcerations, or granulation tissue per Geboes grading system. AE=adverse event; BIO=biologic; BL=baseline; COVID-19=coronavirus disease 2019; GUS=guselkumab; IR=inadequate response; IWRS=Interactive Web Response System; JAK=Janus kinase; JAKi=JAK inhibitor; MES=Mayo endoscopic subscore; N=population size; n=sample size; [HZ1] q4w=every 4 weeks; q8w=every 8 weeks; RBS=rectal bleeding subscore; S1P=sphingosine-1-phosphate; S1Pi=S1P inhibitor; SC=subcutaneous; SFS=stool frequency subscore; UC=ulcerative colitis

Conclusion

GUS SC induction followed by SC maintenance was efficacious through 1 year in pts with moderately to severely active UC, and the safety profile is consistent with GUS in its approved indications including UC.

Disclosure

ML reports research support from Lilly, Pfizer, and Takeda; consulting for AbbVie, Bristol Myers Squibb, Intercept, Janssen (Johnson & Johnson), Lilly, Pfizer, Prometheus, Roivant, Takeda, and Target RWE.
JRA reports grant support from Janssen, Merck, and Pfizer; consultancy fees from AbbVie, Adiso, Bristol Myers Squibb, Ferring, Genentech, GlaxoSmithKline, Janssen, Merck, Pfizer, Roivant, Celltrion, TrexBio, Shattuck Labs and Seres Therapeutics; payments for speaking from AbbVie, Bristol Myers Squibb, and Janssen; and is a steering committee member and investigator for Janssen.
SD reports consultancy fees from AbbVie, Alimentiv, Allergan, Amgen, AstraZeneca, Athos, Biogen, Boehringer Ingelheim, Celgene, Celltrion, Eli Lilly, Enthera, Ferring, Gilead, Hospira, Inotrem, Janssen, Johnson & Johnson, MSD, Mundipharma, Mylan, Pfizer, Roche, Sandoz, Sublimity, Takeda, TiGenix, UCB, and Vifor; and reports lecture fees from AbbVie, Amgen, Ferring, Gilead, Janssen, Mylan, Pfizer, and Takeda.
MG, TB, YA, KH, SJ, LJ, and HZ are employees of and may own stock in Johnson & Johnson.
TH reports research grants from AbbVie GK, Boston Scientific Corporation, EA Pharma Co. Ltd., JIMRO Co. Ltd., Kissei Pharmaceutical Co. Ltd., Kyorin Pharmaceutical Co. Ltd., Mitsubishi Tanabe Pharma Corporation, Mochida Pharmaceutical Co. Ltd., Nippon Kayaku Co. Ltd., Pfizer Inc., Takeda Pharmaceutical Co. Ltd., and Zeria Pharmaceutical Co. Ltd.; consulting fees from AbbVie GK, Abivax, Bristol Myers Squibb, EA Pharma Co. Ltd., Gilead Sciences, Janssen Pharmaceutical K.K., Lilly, Mitsubishi Tanabe Pharma Corporation, and Pfizer Inc.; and lecture fees from AbbVie GK, EA Pharma Co. Ltd., Janssen Pharmaceutical K.K., JIMRO Co., Kissei Pharmaceutical Co. Ltd., Kyorin Pharmaceutical Co. Ltd., Mitsubishi Tanabe Pharma Corporation, Mochida Pharmaceutical Co., Ltd., Pfizer Inc., and Takeda Pharmaceutical Co. Ltd.
DTR reports consulting and/or speaker fees and/or advisory board participation for AbbVie, Altrubio, Apex, Avalo, Bristol Myers Squibb, Buhlmann Diagnostics, Celgene, Connect BioPharma, Intouch Group, Iterative Health, Janssen (Johnson & Johnson), Lilly, Pfizer, Samsung Neurologica, and Takeda; Altrubio, Datos Health, and Iterative Health stock options; grants from Takeda; and membership on the Board of Directors of Cornerstones Health, Inc. and on the Crohn’s & Colitis Foundation’s Board of Trustees.
LPB reports grants or contracts from Celltrion, Fresenius Kabi, Medac, MSD, and Takeda; consulting and/or payment or honoraria and/or data safety monitoring board or advisory board participation for AbbVie, Abivax, Adacyte, Alfasigma, Alimentiv, Amgen, Applied Molecular Transport, Arena, Banook, Biogen, Bristol Myers Squibb, Celltrion, Connect Biopharm, Cytoki Pharma, Enthera, Ferring, Fresenius Kabi, Galapagos, Genentech, Gilead, Gossamer Bio, GlaxoSmithKline, IAC Image Analysis, Index Pharmaceuticals, Inotrem, Janssen, Kern Pharma, Lilly, Medac, Mopac, Morphic, MSD, Nordic Pharma, Novartis, Oncodesign Precision Medicine, ONO Pharma, OSE Immunotherapeutics, Pandion Therapeutics, Par' Immune, Pfizer, Prometheus, Protagonist, Roche, Samsung, Sandoz, Sanofi, Satisfay, Takeda, Telavant, Theravance, Thermo Fischer, Tigenix, Tillots, Viatris, Vectivbio, Ventyx, and Ysopia; and meeting attendance/travel support from AbbVie, Alfasigma, Amgen, Celltrion, Connect Biopharm, Ferring, Galapagos, Genentech, Gilead, Gossamer Bio, Janssen, Lilly, Medac, Morphic, MSD, Pfizer, Sandoz, Takeda, Thermo Fischer, and Tillots.

Introduction

The risk of post-resection colorectal stricture significantly increases when more than 90% of the circumference is affected.

Aims & Methods

In this study, we aimed to evaluate post-resectional stricture incidence and predictive factors in patients undergoing colorectal ESD for whole circumferential lesions. We retrospectively analysed a prospectively maintained dataset of patients undergoing ESD for colorectal lesions involving≥90% of the luminal circumference at 27 tertiary referral centres across Europe, North Africa, Asia, and North America between June 2018 and September 2024. Baseline clinical data and procedural outcomes, including effectiveness, safety and stricture development were collected. The primary endpoint was to evaluate the incidence and predictive factors of post-resectional strictures after circumferential ESD.

Results

Overall, 301 patients were included in the analysis [median age: 71 (IQR: 62-79); female sex: 175 (58.1%)] 254 (84.4%) lesions were from the rectum, 47 (15.6%) were colonic, showing a median long-axis of 95 (70.5-130) mm. 100% circumferential involvement was present in 97 (63.8%) cases. Among those, one case was aborted due to technical issues (99.7% technical success). The median procedure time was 184 (IQR:133.5-270) minutes. R0 and oncological curative resection rates were 81.7% and 80.3%, respectively. Histopathological diagnosis showed the presence of adenocarcinoma in 107 (35.7%) cases. In 29 (9.7%) cases, patients underwent surgery either due to delayed perforation (2/29, 6.9%) or invasive adenocarcinoma (27/29, 93.1%). Consistently, 271 lesions were available for stricture assessment. 92/271 (33.9%) patients developed stricture, with 84/92 (91.3%) reporting symptoms after a median time of 31 (IQR:21-72) days. Most cases (87/92, 94.6%) were in the rectum, while a few belonged to the colon (5/43, 5.4%) (p<0.001). Strictures needed treatment in 87/92 (94.5%), either with endoscopic balloon dilation (65/92, 62.1%), bougie dilation (23/92, 26.4%) or other methods, such as home self-dilation (6/92, 6.5%), self-expandable metals stents (SEMs) placement (1/92, 1.1%), lumen apposing metal stents (LAMs) (2/92, 2.3%) or incisional therapy (4/92, 4.6%). All cases were successfully managed. Risk factors for rectal stricture development were a higher median long-axis of the specimen (p<0.001), 100% circumferential involvement (p<0.001), the whole rectum (p=0.02) and the oral side rectal (p=0.02) location. At multivariate analysis, the 100% circumferential involvement and higher long-axis confirmed to be risk factors, showing an odd ratio of 3.38 (CIs 1.77-6.08) and 1.01 (CIs 1.01-1.20), respectively.

	Rectal stenosis development (n=87)		No stenosis occurrence (n=140)		p-value
Female sex, n (%) Age (years), median (IQR) CCI, median (IQR) Median long-axis, mm (IQR) 100% circumferential involvement, n (%) Whole rectal surface involvement, n (%) Anal verge involvement, n (%) Mid rectum involvement. n (%) Proximal rectum involvement, n (%) Rectosigmoid junction, n (%) Moderate-to-severe fibrosis, n (%) Triamcinolone local prophylaxis, n (%)	44 (50.6%) 73 (59-79) 3 (2-4) 120 (85-150) 42 (48.3%) 27 (30.0%) 55 (63.2%) 52 (59.8%) 45 (51.7%) 14 (16.1%) 13 (14.9%) 8 (9.2%)		86 (61.4%) 70 (63.3-79.0) 3 (2-4) 95 (70-120) 28 (32.2%) 25 (28.7%) 77 (88.5%) 72 (82.8%) 52 (37.1%) 14 (10%) 13 (9,3%) 17 (12.1%)		0.07 0.88 0.43 < 0.001 < 0.001 0.02 0.14 0.14 0.02 0.13 0.14 0.32
		Colonic stenosis development (n=5)		No stenosis occurrence (n=39)			p-value
Female sex, n (%) Age (years), median (IQR) CCI, median (IQR) Median long-axis, mm (IQR) 100% circumferential involvement, n (%) Sigmoid colon, n (%) Descending colon, n (%) Transverse colon, n (%) Ascending colon, n (%) Caecum, n (%) Moderate-to-severe fibrosis, n (%)	5 (100%) 77 (63-81) 4 (2-5.5) 60 (35-110) 2 (40%) 3 (60%) 2 (40%) 0 0 0 2 (40%)		0 69 (63-76) 3 (2-4) 75 (50-94) 13 (33.3%) 10 (25.6%) 4 (12.3%) 7 (17.9%) 8 (20.5%) 9 (23.1%) 4 (10.3%)		0.17 0.54 0.31 0.50 0.60 0.14 0.13 0.4 0.35 0.30 0.13

Conclusion

Circumferential ESD for colorectal lesions involving≥90% of the circumference is a feasible technique, showing a high rate of stricture development, which can be effectively treated through endoscopy. Leaving a small island of normal mucosa within the resection (especially when there is a long axis) could be an effective strategy to prevent stricture development.

Introduction

Eosinophilic Esophagitis (EoE) is a chronic, inflammatory, immune-mediated disease, characterised by eosinophilic infiltration. EoE requires a lifelong pharmacological treatment, aimed at achieving clinical (ie. symptoms of esophageal dysfunction), endoscopic and histological remission, and slowing down the possible process of esophageal fibrosis. Recently, a novel formulation of budesonide orodispersible tablet (BOT) has become available, showing a high efficacy in randomised placebo-controlled trials. Nowadays, only few real-life data are available in literature.

Aims & Methods

This is a multicentre, prospective, observational study, aimed to evaluate in real-life setting the long-term safety profile and the clinical, endoscopic and histological effectiveness of BOT in EoE patients. Patients diagnosed with EoE, aged ≥ 18 years, treated with BOT 1 mg bid, as induction treatment for 12 weeks (T1), and with 1 mg qd as maintenance for 52 weeks (T2), were enrolled. Clinical, demographic and medication data were collected at baseline. BOT treatment outcomes were evaluated after T1 and after T2, considering EoE Endoscopic Reference Score (EREFS) for endoscopic appearance, and 3-segments eosinophilic peak infiltration for histological assessment. Moreover, the Dysphagia Symptom Questionnaire (DSQ) and Health-Related Quality of Life (HRQoL) were also collected in order to evaluate clinical response.

Results

Two-hundreds ninety-two patients (232 males, 79%; mean age 37±14) treated with BOT were enrolled, in 8 Italian Centres and 1 Israelian Centre. The most frequent symptoms at diagnosis were dysphagia (82%) and food bolus impaction (68%). At least 1 allergic comorbidity was present in 67% of patients. 259 patients were evaluated at T1: endoscopic remission was achieved in 53% of patients, with a reduction of the mean EREFS score from 3±2 to 2±1 (p<0.0001). Histological remission was obtained in 93% of patients, with 19/259 treatment non-responders. The DSQ showed a significant reduction from 30±23 vs 6±12 (p<0.001). HRQoL questionnaire score passed from 112±37 to 153±30 (p<0.0001). 136 patients completed 1 year of treatment, and 76% of them resulted in endoscopic remission. In particular, the presence of stenosis passed from 31/292 at baseline (T0) to 1/136 at T2 (p<0.0001). Histological remission was maintained in 92%, while 11/136 lost histological response after BOT tapering. As well as for T1, both DSQ (4±10) and HRQoL score (153±28) resulted improved (p<0.0001). Side effects occurred in 36 out of 292 patients (12%), and the main one was candidiasis (25/36, 70%). Only 15 of patients needed to stop the treatment. All data are resumed in Table 1.

	n T0	n T1	n T2	T0 vs T1	p	T0 vs T2	p	T1 vs T2	p
EREFS ± SD	292	259	136	3±2 vs 2±1	<0.0001	3±2 vs 1±1	<0.0001	2±1 vs 1±1	0.1
Stenosis, n	31	6	1	31/292 vs 6/259	<0.0001	31/292 vs 1/136	<0.0001	6/259 vs 1/136	0.5
Distal Esophagus Eosinophilic peak ± SD	292	259	136	40±38 vs 5±12	<0.0001	40±38 vs 5±13	<0.0001	5±12 vs 5±13	1
Mid Esophagus Eosinophilic peak ± SD	292	259	136	31±38 vs 3±12	<0.0001	31±38 vs 3±13	<0.0001	3±12 vs 3±13	1
Proximal Esophagus Eosinophilic peak ± SD	292	259	136	28±30 vs 3±11	<0.0001	28±30 vs 1±5	<0.0001	3±11 vs 1±5	0.04
DSQ ± SD	195	172	137	30±23 vs 6±12	<0.0001	30±23 vs 4±10	<0.0001	6±12 vs 4±10	0.1
HRQoL ± SD	191	162	135	112±37 vs 153±30	<0.0001	112±37 vs 153±28	<0.0001	153±30 vs 153±28	1

Table 1: Clinical, endoscopic and histologic data at baseline, after induction period and after maintenance period.

Conclusion

This study confirms the effectiveness of the treatment with BOT in both inducting and maintaining remission of EoE in a real-life setting, either considering clinical, endoscopic and histologic outcomes. Our data also showed a good safety profile, with a few patients requiring drug interruption.

References

Geow R, Arena G, Siah C, Picardo S. A retrospective real-world study on the safety and efficacy of budesonide orodispersible tablets for the induction therapy of eosinophilic oesophagitis. Therap Adv Gastroenterol. 2024 Oct 16;17:17562848241290346. doi: 10.1177/17562848241290346. PMID: 39421000; PMCID: PMC11483688.
Lucendo AJ, Miehlke S, Schlag C, Vieth M, von Arnim U, Molina-Infante J, Hartmann D, Bredenoord AJ, Ciriza de Los Rios C, Schubert S, Brückner S, Madisch A, Hayat J, Tack J, Attwood S, Mueller R, Greinwald R, Schoepfer A, Straumann A; International EOS-1 Study Group. Efficacy of Budesonide Orodispersible Tablets as Induction Therapy for Eosinophilic Esophagitis in a Randomized Placebo-Controlled Trial. Gastroenterology. 2019 Jul;157(1):74-86.e15. doi: 10.1053/j.gastro.2019.03.025. Epub 2019 Mar 26. PMID: 30922997.
Straumann A, Lucendo AJ, Miehlke S, Vieth M, Schlag C, Biedermann L, Vaquero CS, Ciriza de Los Rios C, Schmoecker C, Madisch A, Hruz P, Hayat J, von Arnim U, Bredenoord AJ, Schubert S, Mueller R, Greinwald R, Schoepfer A, Attwood S; International EOS-2 Study Group. Budesonide Orodispersible Tablets Maintain Remission in a Randomized, Placebo-Controlled Trial of Patients With Eosinophilic Esophagitis. Gastroenterology. 2020 Nov;159(5):1672-1685.e5. doi: 10.1053/j.gastro.2020.07.039. Epub 2020 Jul 25. PMID: 32721437.

Introduction

JAK inhibitors have become an efficacious oral treatment option to antibody-based therapies for ulcerative colitis (UC). However, they have received a black box warning by the FDA for causing serious systemic adverse events.
To increase safety, OST-122 is being developed as an orally administered, GI-targeted and non-systemic JAK3/TYK2 inhibitor for the local treatment of UC. In preclinical models and in healthy volunteers, OST-122 has demonstrated excellent safety and tolerability with minimal systemic exposure reducing the risk of causing serious systemic toxicities associated with current JAK inhibitors.
Here, we report the results of a phase 2a study in patients with UC on the safety, tolerability, pharmacokinetics and preliminary efficacy of OST-122.

Aims & Methods

In this randomized, double-blind trial, 37 adult patients with active UC were treated with oral OST-122 400 mg (n=28) or placebo (n=9) for 28 days. Eligibility criteria required a total Mayo Score TMS 5-10, endoscopic Mayo Score EMS ≥2, inadequate/loss of response to conventional therapy (5-ASA, steroids, immunomodulators) or biologics (anti-TNFα, anti-integrin, anti-interleukin 12/23). Stable cotreatment with oral 5’ASAs and corticosteroids was permitted.
To evaluate the safety and tolerability of OST-122, the number and severity of AEs, including changes in vital signs, safety laboratory values and ECGs, were analyzed. Plasma, tissue and stool samples were collected at various time points to examine the gut-restricted pharmacokinetic profile of the compound in UC patients. Preliminary efficacy was assessed through Mayo Clinical Scores including rectal bleeding (RB) and stool frequency (SF) along with clinical response and remission.

Results

During the 6-week observation period, no serious AEs nor treatment-related AEs leading to discontinuation were reported. Most AEs were tabulated as mild, followed by moderate, and the number of subjects reporting AEs were distributed equally in the placebo and OST-122 group (78% vs. 71%). There were no clinically relevant changes in vital signs, laboratory values or ECG parameters which raise any safety concerns.
Pharmacokinetic analysis indicated minimal plasma concentrations (C_max 0.92 ng/mL) and therapeutically relevant levels in colon tissue (15.5 ug/g tissue) confirming a gut-restricted PK profile of OST-122.
Preliminary efficacy data after 28 days of treatment are summarized in the table below:

Outcome	400 mg OST-122 (n=28)	Placebo (n=9)	∆
Rectal Bleeding Improvement of RB score by ≥1	63% (17/27)	33% (3/9)	33%
Stool Frequency Improvement of SF score by ≥1	52% (14/27)	33% (3/9)	19%
PRO-2 score (RB + SF) Improvement of PRO-2 by ≥2	48% (13/27)	11% (1/9)	37%
Clinical Response Decrease of TMS by ≥3 or ≥30 %, plus improvement in RB by ≥1 and an absolute RB of 0 or 1	44% (12/27)	11% (1/9)	33%
Clinical Remission TMS ≤2 and no individual subscore >1, plus RB of 0	22% (6/27)	0% (0/9)	22%

63% of patients taking OST-122 showed an improvement in rectal bleeding and 52% in stool frequency (vs 33% in the placebo group), and 48% had an improvement of ≥2 in PRO-2 (RB+SF, vs 11% Pbo). Clinical response was achieved by 44% (vs 11% Pbo) and 22% reached clinical remission (vs 0% Pbo). In addition, 16% of patients in the OST-122 group achieved both histological response and remission (vs 0% Pbo). A subgroup analysis showed that OST-122 was able to induce clinical response both in bionaïve and bioexperienced patients. Confirmatory studies will be designed to determine dose and statistical significance.

Conclusion

GI-restricted OST-122 was well tolerated during the 4-week treatment. Its excellent safety profile, minimal systemic exposure and promising trends of clinical activity may provide a safer therapeutic option for a broad range of ulcerative colitis patients.

Disclosure

M. Barreiro de Acosta has served as a speaker, consultant and advisory member for or has received research funding from MSD, AbbVie, Janssen, Kern Pharma, Celltrion, Takeda, Gillead, Celgene, Pfizer, Sandoz, Biogen, Fresenius, Ferring, Faes Farma, Dr. Falk Pharma, Chiesi, Gebro Pharma, Adacyte, Vifor Pharma and Oncostellae.
C. Rodríguez has received consultancy and/or speaking honoraria fees from AbbVie, Ferring, Galapagos, Janssen, Pfizer, Lilly and Takeda.
M.D. Martin-Arranz has received fees as a speaker, consultant and advisory member for or has received funding from MSD, AbbVie, Hospira, Pfizer, Takeda, Janssen, Shire Pharmaceuticals, Tillots Pharma, and Faes Pharma.
L. Torrealba has served as a speaker for Janssen.
E. Iglesias Flores has served as a speaker, consultant and advisory member for or has received research funding from AbbVie, Janssen, Takeda, Gillead, Celgene, Pfizer, Lilly, Ferring, Faes Farma, Dr. Falk Pharma, Chiesi, and Adacyte.
F. Argüelles-Arias has served as a speaker, consultant and advisory member or has received research funding from MSD, AbbVie, Janssen, Kern Pharma, Celltrion, Takeda, Gillead, Celgene, Pfizer, Sandoz, Biogen, Fresenius, Ferring, Faes Farma, Dr. Falk Pharma, Chiesi, Gebro Pharma, Adacyte and Vifor Pharma.
Y. Ber-Nieto has served as a speaker from Abbvie and has received education funding from Abbvie and Pfizer.

Introduction

While trans-perineal ultrasound (TPUS) is promising, its accuracy compared to trans-abdominal ultrasound (TAS) and endoscopic ultrasound (EUS) in predicting rectal histoendoscopic activity in ulcerative colitis (UC) is unclear.

Aims & Methods

We aimed to evaluate the reliability of TPUS in predicting rectal histoendoscopic activity in UC using EUS as the reference standard. This prospective study included adult UC patients who underwent TAS and TPUS, followed by EUS. Rectal total wall thickness (TWT) and vascularity (Modified Limberg Score, MLS) were measured on all modalities. Additionally, mucosal thickness (MT) and submucosal thickness (SMT) were assessed on EUS. Receiver operating characteristic (ROC) analysis was performed to determine the area under the curve (AUC) for predicting endoscopic activity (Ulcerative Colitis Endoscopic Index of Severity, UCEIS >1) and histologic activity (Nancy Index >1).

Results

A total of 142 UC patients (33.8% female, median age 40 years, BMI 22.5 kg/m²) were included. Disease extent was proctitis (12%), proctosigmoiditis (58%), and extensive colitis (30%). The median SCCAI score was 3 (range: 0-8). Most patients were on 5-ASA (90.8%), azathioprine (31%), and tofacitinib (10.6%).
The median rectal length visualized on TPUS was 3.9 cm (2.4-6.3 cm). Endoscopic remission (UCEIS ≤1) was observed in 49.3% of patients, and histologic remission (NHI ≤1) in 38.7%.
For endoscopic activity, EUS had the highest accuracy, with MT >0.95 mm (AUC: 0.96, sensitivity: 98.6%, specificity: 87%) and MLS >1 (AUC: 0.95, sensitivity: 81.7%, specificity: 94%). TPUS had moderate accuracy(TWT >5.4 mm, AUC: 0.73), while TAS performed poorly (TWT >5.8 mm, AUC: 0.63).
For histologic remission, EUS vascularity (MLS >1) was most predictive (AUC: 0.91, sensitivity: 66.3%, specificity: 98.1%), followed by rectal TWT ≥4 mm (AUC: 0.83) and MT ≥0.95 mm (AUC: 0.86). Among non-EUS techniques, TPUS (TWT ≥6.1 mm, AUC: 0.66) showed moderate accuracy, while TAS was the least predictive (AUC: 0.62).
The Milan Ultrasound Criteria (MUC) demonstrated highest accuracy for endoscopic remission with EUS MUC ≥8 (AUC: 0.94), followed by TPUS (AUC: 0.78) and TAS (AUC: 0.67). For histologic remission, EUS MUC >7 had the highest accuracy (AUC: 0.87), followed by TPUS (MUC ≥9.7, AUC: 0.70) and TAS (AUC: 0.64) (Table 1). BMI-based comparisons showed no significant differences in MUC scores.

Measure	Sensitivity	Specificity	AUC	p-value	95% CI
	Endoscopic Activity
TAS (MUC) (≥8.5)	67.6%	60.9%	0.67	<0.001	0.59-0.76
TPUS (MUC) (≥8)	86%	62.3%	0.78	<0.001	0.70-0.86
EUS (MUC) (≥8)	81.7%	81.2%	0.94	<0.001	0.85-0.95
	Histologic activity
TAS (MUC) (>8.6)	62.8%	66%	0.64	0.005	0.54-0.74
TPUS (MUC) (≥9.7)	59.3%	79.6%	0.70	<0.001	0.61-0.79
EUS (MUC) (>7)	83.7%	81.5%	0.87	<0.001	0.81-0.93

Correlation analysis showed a strong correlation between TPUS and EUS TWT (r=0.371, p<0.001). TPUS and TAS had moderate correlation (r=0.309, p<0.001), while TAS and EUS showed weaker correlation (r=0.264, p=0.002 for average TWT, r=0.234, p=0.005 for lower rectal TWT). MUC scores correlated best between EUS and TPUS (r=0.425, p<0.001).

Conclusion

While EUS remains the most accurate, TPUS shows moderate accuracy for assessing rectal inflammation in UC. However, TPUS is limited to the lower rectum and needs further validation for better reproducibility. Standardized cutoffs and integration into routine UC monitoring could enhance non-invasive assessment, reducing endoscopy reliance and improving patient management.(NCT06717906).

References

1. Sagami S, Kobayashi T, Aihara K, Umeda M, Morikubo H, Matsubayashi M, Kiyohara H, Nakano M, Ohbu M, Hibi T. Transperineal ultrasound predicts endoscopic and histological healing in ulcerative colitis. Aliment Pharmacol Ther. 2020;51(12):1373-1383. [10.1111/apt.15767]
2. Sagami S, Kobayashi T, Aihara K, Umeda M, Odajima K, Morikubo H, Asonuma K, Miyatani Y, Fukuda T, Matsubayashi M, Kiyohara H, Nakano M, Hibi T. Early improvement in bowel wall thickness on transperineal ultrasonography predicts treatment success in active ulcerative colitis. Aliment Pharmacol Ther. 2022;55(10):1320-1329. [10.1111/apt.16817]