Introduction

Obefazimod (Obe) is an investigational, oral, once-daily (od), small molecule which enhances expression of microRNA-124 and is currently in phase 3 clinical trials for the treatment of patients (pts) with moderately to severely active ulcerative colitis (UC) [1]. Obe demonstrated efficacy and safety in pts with UC at week (wk)-8 in a placebo-controlled, Phase 2b induction trial and in the subsequent open-label maintenance (OLM) study [2]. This post hoc analysis reports corticosteroid (CS)-free efficacy and safety at wks 48 and 96 in pts receiving concomitant CS at induction baseline.

Aims & Methods

Pts received placebo or Obe 25mg, 50mg or 100mg od during the Phase 2b, induction trial and, irrespective of their clinical response, could enter the optional 96-wk OLM study with Obe 50mg od. Pts were followed monthly for safety and efficacy. At entry of the induction trial, pts could receive concomitant CS (prednisone or equivalent [≤20mg/day], budesonide [≤9mg/day], beclomethasone [≤5mg/day]) if on a stable dose ≥2wks immediately before screening; beginning at baseline of the OLM study, CS tapering was recommended but not required. CS-free was defined as withdrawal of CS ≥ 12wks prior to assessment timepoint. CS-free outcomes were assessed at wks 48 and 96 of the OLM and included CS-free clinical remission (CR), CS-free endoscopic improvement (EI), and CS-free endoscopic remission (ER). Safety among this subgroup was also assessed.

Results

At induction baseline, 115 pts (out of 252, 46%) received CS. Among pts with CS at induction baseline, CR rates were 56% (64/115) at wk 48 and 52% (60/115) at wk 96. CS-free CR was attained by 37% (43/115) at wk 48 and maintained at 35% (43/115) at wk 96 within the same cohort. Among the 21 pts that were in CR but did not meet the definition of CS-free at wk 48, the Principal Investigator (PI) did not attempt the optional CS tapering for 13 pts (13/21, 62%). An additional 4 pts (4/21, 19%) were CS free, but for less than 12wks before the wk 48 endpoint. Among the 20 pts that were in CR but did not meet the definition of CS-free at wk 96, the PI did not attempt the optional CS tapering for 8 pts (8/20, 62%). An additional 7 pts (7/20, 35%) were CS free, but for less than 12wks before the wk 96 endpoint. EI was achieved by 64% (73/115) at wk 48 and 58% (67/115) at wk 96, with CS-free EI achieved by 44% (50/115) of pts at wk 48 and 39% (45/115) at wk 96. ER was achieved by 33% (38/115) at wk 48 and 31% (36/115) at wk 96, with CS-free ER achieved by 24% (27/115) of pts at wk 48 and 21% (24/115) at wk 96 (Table 1). Overall, the safety profile within this cohort was consistent with the overall study population.

Table 1: Efficacy and CS-free efficacy at wks 48 and 96 of OLM study in patients with CS at induction baseline

Conclusion

Among pts receiving concomitant CS at induction baseline, meaningful proportions achieved CR, EI, and ER at both wks 48 and 96 in the OLM. Notably, a substantial proportion of pts met CS-free efficacy endpoints despite CS tapering not being required in this OLM study. Concomitant use of CS at induction baseline had no notable effect on the safety profile of Obe.

References

1. Vermeire S, et al. J Crohns Colitis. 2023; 17: 1689-1697
2. Vermeire S, et al. The Lancet Gastroenterology & Hepatology. 2022; 7: 1024-1035.

Disclosure

Bruce E Sands has served as a consultant or received speaker’s fees from AbbVie, Abivax, Adiso Therapeutics, AgomAb, Alimentiv, Amgen, Arena Pharmaceuticals, Artizan Biosciences, Artugen Therapeutics, AstraZeneca, Bacainn Therapeutics, Biora Therapeutics, Boehringer Ingelheim, Boston Pharmaceuticals, Bristol Myers Squibb, Calibr, Celltrion, ClostraBio, Connect Biopharm, Cytoki Pharma, Eli Lilly and Company, Enthera, Evommune, Ferring, Fresenius Kabi, Galapagos, Gilead Sciences, Genentech, Glaxo SmithKline, Gossamer Bio, HMP Acquisition, Imhotex, Immunic, InDex Pharmaceuticals, Innovation Pharmaceuticals, Inotrem, Ironwood Pharmaceuticals, Janssen, Johnson & Johnson, Kaleido, Kalyope, Merck, MiroBio, Morphic Therapeutic, MRM Health, OSE Immunotherapeutics, Pfizer, Progenity, Prometheus Biosciences, Prometheus Laboratories, Protagonist Therapeutics, Q32 Bio, RedHill Biopharma, Sun Pharma Global, Surrozen, Synlogic Operating Company, Takeda, Target RWE, Theravance Biopharma R&D, TLL Pharmaceutical, USWM Enterprises, Ventyx Biosciences, Viela Bio, and stock options from Ventyx Biosciences.
Séverine Vermeire has received grants from AbbVie, J&J, Pfizer, Takeda and Galapagos; SV has received 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, Zealand Pharma.
Laurent Peyrin-Biroulet has received grants from Celltrion, Fresenius Kabi, Takeda; LPB has served as a consultant or received speaker’s fees from Abbvie, Abivax, Alimentiv, Alma Bio Therapeutics, Amgen, Applied Molecular Transport, Arena, Biogen, BMS, Celltrion, Connect Biopharm , Cytoki Pharma, Enthera, Ferring, Fresenius Kabi, Galapagos, Genentech, Gilea, Gossamer Bio, GSK, Hac Pharm, IAC Image Analysis, Index Pharmaceuticals, Inotrem, Janssen, Lilly, Medac, Mopa, Morphic, MSD, Norgine, Novartis, OM Pharma, ONO Pharma, OSE Immunotherapeuthics, Pandion Therapeuthics, Par' Immune, Pfizer, Prometheus, Protagonist, Roche, Roivant, Samsung, Sandoz, Sanofi, Takeda, Theravance, Thermo Fischer, Tigenix, Tillots, Viatris, Vifor, Vectivbio, Ventyx, Ysopia.
Silvio Danese has served as consultant or received speaker’s fees from AbbVie, Ferring, Hospira, Johnson & Johnson, Merck, MSD, Takeda, Mundipharma, Pfizer Inc, Tigenix, UCB Pharma, Vifor, Biogen, Celgene, Allergan, Celltrion, Sandoz, Boehringer Ingelheim.
Parambir Dulai received speaker’s fees from Abbvie, Abivax, Adiso, Bristol Meyer Squibb, Geneoscopy, GSK, Janssen, Lilly, Pfizer, Takeda.
Herbert Tilg has served as a consultant or received speaker’s fees from Abbvie, Abivax, Dr Falk Pharma, ferring, Galapagos, Microbiotica, MSD, Pfizer, Takeda.
Britta Siegmund has served as consultant for Abbvie, Abivax, Arena, BMS, Boehringer, CED Service GmbH, Celgene, CT Scout, Endpoint Health, Falk, Forga Software, Galapagos, Janssen, Lilly, Materia Prima, Pfizer, Takeda, Pharma Insight, Predictimmune, PsiCro; Speaker fees: AbbVie, BMS, CED Service GmbH, Chiesi, Falk, Ferring, Gilead, Janssen, Lilly, Materia Prima, Takeda, Pfizer and grant support by Arena/Pfizer (served as representative of the Charité).

Introduction

Paraduodenal pancreatitis (PP) is a particular form of chronic pancreatitis that affects an area, defined by some authors as "groove", between the head of the pancreas, the duodenum and the main biliary tract. [1] The two forms of PP, the cystic and the “solid” form, [2] may extend to the adjacent pancreatic tissue and the entire main pancreatic duct, causing chronic obstructive pancreatitis ("diffuse" form), leading to heterogeneous clinical presentations.[3,4] Pathogenesis and natural history is still unclear, even if it has been linked to exogenous factors, especially alcohol and smoking, and the treatment include both medical therapy and surgery [5].

Aims & Methods

We performed a multicentre retrospective observational study to explore the burden of the disease, and its evolution towards exocrine pancreatic insufficiency(EPI) considering also the risk of neoplastic evolution. We collected data from both academic and non-academic Italian centers. All patients with diagnosis of PP were included in the registry. Data were extracted at the time of diagnosis and during follow-up. Univariate and multivariate analysis were performed to explore the relations between variables and outcomes of interest.

Results

208 patients(87.5% male) from 16 centres were collected into our national registry. Mean age at diagnosis was 51(± 11) years and mean time from clinical presentation to diagnosis was 18(±29) months. 88.4% had history of alcohol abuse and 89% of smoking. 36 patients(17.9%) had diabetes at diagnosis, while 80 patients (41.5%) had chronic pancreatitis. Clinical presentation included abdominal pain(89.1%), jaundice(18.5%), nausea(47.1%) and vomiting(32.6%). Initial laboratory tests showed a mean increase of bilirubin of 1.62(±1.7) times upper limit of normal(ULN), Amylase 2.9(±2.5) times ULN, Lipase 3.2(±3.1) times ULN. 6(3%) patients developed pancreatic cancer after a mean time of 10.3(±10.8) months from PP diagnosis. 49 patients(23.6%) had EPI at diagnosis , while further 49 patients developed it during follow up. Among patients with EPI at diagnosis, 19(38.8%) recovered with no more signs of EPI at the last follow up. Preliminary analyses showed that EPI at diagnosis was associated to EPI at the last follow up(OR 2.6, p=0.012). Mean time to develop EPI was 17.1(±23.5) months. Conservative treatment was the treatment of choice in 54.3% cases, surgery in 17.3% and endoscopic therapy in 16.35% cases. Over a median follow-up of 36 (range, 1-168) months, mortality was 4.8%.

Conclusion

Paraduodenal pancreatitis is an uncommon disease, mainly diagnosed in male patients with history of alcohol and smoking. Moreover, conservative strategy was the treatment of choice in our cohort of patients.

References

1. Adsay NV and G. Zamboni, Paraduodenal pancreatitis: a clinico-pathologically distinct entity unifying "cystic dystrophy of heterotopic pancreas", "para-duodenal wall cyst", and "groove pancreatitis". Semin Diagn Pathol 2004;21(4):247-54.
2. de Pretis N, Capuano F, Amodio A, Pellicciari M, Casetti L, Manfredi R, Zamboni G, Capelli P, Negrelli R, Campagnola P, Fuini A, Gabbrielli A, Bassi C, Frulloni L. Clinical and Morphological Features of Paraduodenal Pancreatitis: An Italian Experience With 120 Patients. Pancreas 2017;46(4):489-495.
3. Pezzilli R, Santini D, Calculli L, Casadei R, Morselli-Labate AM, Imbrogno A, Fabbri D, Taffurelli G, Ricci C, Corinaldesi R. Cystic dystrophy of the duodenal wall is not always associated with chronic pancreatitis. World J Gastroenterol 2011;17(39):4349-64.
4. López-Muñoz P, Lorenzo-Zúñiga V, Alonso-Lázaro N, et al. Endoscopic findings of paraduodenal or groove pancreatitis. Endoscopy. 2022;54(12):E735-E736. doi:10.1055/a-1773-0499
5. Balduzzi A, Marchegiani G, Andrianello S, Romeo F, Amodio A, De Pretis N, Zamboni G, Malleo G, Frulloni L, Salvia R, Bassi C. Pancreaticoduodenectomy for paraduodenal pancreatitis is associated with a higher incidence of diabetes but a similar quality of life and pain control when compared to medical treatment. Pancreatology 2020;20(2):193-198.

Introduction

Avoidant/restrictive eating is common in people with neurogastroenterology disorders including functional dyspepsia (FD). There is debate on whether avoidant/restrictive food intake disorder (ARFID) is an expected response to severe symptoms or simply a common comorbid disorder. To address this, among adults with FD, we aimed to contrast those with and without ARFID on FD symptoms, quality of life, psychosocial factors, nutrient tolerance, and gut transit.

Aims & Methods

Adults with Rome-IV confirmed FD and healthy controls (HC) from an ongoing study participated. ARFID diagnosis was assigned based on a semi-structured DSM-5 diagnostic interview. Surveys: Patient Assessment of GI Disorders Symptom Severity Index (PAGI-SYM), Short Form Nepean Dyspepsia Inventory (SF-NDI), Nine-Item ARFID Screen (NIAS), Fear of Food Questionnaire (FFQ), Visceral Sensitivity Index (VSI), and Hospital Anxiety/Depression Scale (HADS). Nutrient Drink Test (NDT) measured gastric tolerance—liquid nutrient ingestion at 30mL/minute until subject reported unbearable fullness. Wireless Motility Capsule (WMC) measured gut transit. Height/weight was measured for body mass index (BMI).

Results

Sample (80% female, M_age=37.1±14.4y) included 37 FD+ARFID, 14 FD only, and 18 HC. Groups did not significantly differ in sex or age. Adjusted pairwise comparisons showed small (r=.1-.2) non-significant differences between FD and FD+ARFID on FD symptoms by PAGI-SYM and SF-NDI (Table 1). However, FD+ARFID had significantly worse scores compared to FD with medium effects (r=.3-.4) on: FD-related quality of life by SF-NDI, Fear of Food by NIAS-Fear and FFQ, GI-anxiety by VSI, and anxiety by HADS. FD+ARFID vs FD also had small differences (rs=.2) on: feeling more bothered by FD symptoms on SF-NDI, worse depression by HADS, lower BMI, and less NDT consumption. Compared to HC, FD and FD+ARFID had significantly worse survey scores with large effects for FD+ARFID (r=.6-.8) and medium effects for FD vs HC (r=.3-4). For the NDT, FD+ARFID consumed significantly less than HC with large effect (r=.6) but with a trend medium effect for FD consuming less than HC (r=.3). Groups did not significantly differ in WMC transit times.

Conclusion

Our findings suggest ARFID, when present in FD, does not reflect a response to more severe FD symptoms. Thus, ARFID is a legitimate secondary condition in FD. ARFID may reflect more profoundly altered distress around symptoms (e.g., fear of symptoms, anxiety sensitivity) and greater negative impacts (e.g., FD-related quality of life, lower liquid nutrient tolerance).

Introduction

The appropriateness of lower gastrointestinal (GI) endoscopy in patients with inflammatory bowel disease (IBD) is a key issue in endoscopic practice, especially given limited healthcare resources, the growing demand for endoscopic procedures, and the increasing prevalence of IBD. While numerous studies have examined the appropriateness of endoscopy, particularly upper GI endoscopic procedures, in general gastrointestinal disorders,^{[1, 2]} there is a relative lack of literature specifically addressing the appropriateness of lower GI endoscopy in patients with IBD.^{[3, 4]}

Aims & Methods

This study aimed to evaluate the appropriateness of lower GI endoscopic examinations in patients with IBD at a tertiary referral center. Secondary objectives were identifying reasons for inappropriateness and assessing the presence of clinically significant pathological findings in inappropriate procedures. This was a prospective, observational, monocentric study including all adult patients affected by IBD who underwent lower GI endoscopy at a tertiary referral center between September 2024 and April 2025, with a confirmed IBD diagnosis for at least six months. Data collected included IBD subtype, endoscopic procedure appropriateness based on the 2023 ECCO Guidelines,^[5] and endoscopic/histological findings.

Results

Among 406 endoscopic procedures, 26 were excluded from the analysis due to inappropriate timing resulting from patients lost to follow-up. Therefore, a total of 380 IBD patients were included (mean age 52.9 ± 15.1 years; 57% male). Among them, 135 (35.5%) had Crohn’s disease (CD), 176 (46.3%) ulcerative colitis (UC), 60 (15.8%) ileal pouch, and 9 (2.4%) unclassified IBD (IBD-U). Lower endoscopic procedures included colonoscopy (256, 67.4%), rectosigmoidoscopy (61, 16.1%), pouchoscopy (60, 15.8%), and trans-stomal ileoscopy (3, 0.8%). Overall, 308 procedures (81.1%) were deemed appropriate. Appropriateness was higher in CD (115/135, 85.2%), in UC (147/176, 83.5%) and IBD-U (8/9, 88.9%), and lower in ileal pouch (38/60, 63.3%). Between the different endoscopic procedures, rectosigmoidoscopy showed the highest appropriateness (56/61, 91.8%), followed by colonoscopy (213/256, 83.2%), pouchoscopy (38/60, 63.3%), and trans-stomal ileoscopy (1/3, 33.3%). Among the 72 inappropriate procedures (18.9%), 23 (31.9%) were performed too early, 20 (27.8%) too late, 27 (37.5%) were unwarranted, and 2 (2.8%) were improper endoscopic procedures. Most early procedures were prescribed by physicians (78.3%), while the remaining (21.7%) were requested by patients. Despite being considered inappropriate, 27 of the 72 examinations (37.5%) revealed endoscopic pathological findings, and 17 (23.6%) led to clinically relevant conclusions (based on both endoscopic and histological findings), including 4 cases of dysplasia. It is noteworthy that, among the inappropriate examinations that led to clinically relevant conclusions, almost 60% were performed either too early or were considered unwarranted, while only the remaining 40% were performed too late.

Conclusion

The appropriateness of lower gastrointestinal endoscopy in patients affected by IBD was found to be nearly 80% in a tertiary referral center. Notably, among the examinations classified as inappropriate, roughly 24% revealed clinically relevant findings based on both endoscopic and histological report. A greater spread and awareness among physicians of the latest international guidelines on IBD management could improve the appropriateness of endoscopic procedure prescriptions, while reducing waiting lists and related healthcare costs.

References

1. Tursi A, Palieri AP, Lattarulo V, Elefante A, Gigliobianco A, Spinazzola D, Elisei W, Papa A. How we can improve the appropriateness of ambulatory gastrointestinal endoscopy: the lesson of the COVID-19 outbreak. Eur J Gastroenterol Hepatol. 2023 Oct 1;35(10):1149-1153. doi: 10.1097/MEG.0000000000002626. Epub 2023 Jul 28. PMID: 37665614.
2. Bohara TP, Laudari U, Thapa A, Rupakheti S, Joshi MR. Appropriateness of Indications of Upper Gastrointestinal Endoscopy and its Association With Positive Finding. JNMA J Nepal Med Assoc. 2018 Jan-Feb;56(209):504-509. PMID: 30058633; PMCID: PMC8997324.
3. Manes G, Imbesi V, Ardizzone S, Cassinotti A, Bosani M, Massari A, Porro GB. Appropriateness and diagnostic yield of colonoscopy in the management of patients with ulcerative colitis: a prospective study in an open access endoscopy service. Inflamm Bowel Dis. 2008 Aug;14(8):1133-8. doi: 10.1002/ibd.20434. PMID: 18314901.
4. Manes G, Imbesi V, Ardizzone S, Cassinotti A, Bosani M, Massari A, Bianchi Porro G. Use of colonoscopy in the management of patients with Crohn's disease: appropriateness and diagnostic yield. Dig Liver Dis. 2009 Sep;41(9):653-8. doi: 10.1016/j.dld.2008.10.006. Epub 2008 Nov 25. PMID: 19036651.
5. Gordon H, Biancone L, Fiorino G, et al. ECCO Guidelines on Inflammatory Bowel Disease and Malignancies. J Crohns Colitis. 2023;17(6):827-854. doi:10.1093/ecco-jcc/jjac187

Introduction

Heavy alcohol consuption is one of the most common etiological factor in the development of acute pancreatitis (AP). We have previously shown that ethanol (EtOH) decreases the expression and activity of the cystic fibrosis transmembrane conductance regulator (CFTR) which plays a key role in alcohol-induced AP development. Orkambi (Ivacaftor and Lumacaftor) is available to correct the impaired CFTR function and expression in cystic fibrosis patients.

Aims & Methods

Our aim in this study was to investigate whether Orkambi is able to decrease the severity of experimental AP. Intact guinea pig pancreatic ducts (PDs) were treated with different concentrations of EtOH (30; 50; 100 mM) alone and in combination with Ivacaftor and/or Lumacaftor (1; 3; 5 and 10 µM) for 3, 7, 9 and 12 hours and CFTR expression and activity were evaluated by immunostaining and patch clamp, respectively. Alcoholic AP was induced in Orkambi-treated guinea pigs and standard laboratory and histological parameters were measured.

Results

Ivacaftor (10 µM) and Lumacaftor (10 µM) alone or in combination dose-dependently restored the localization and activity of the EtOH-damaged CFTR channel, during 12 hours of treatment. Oral administration of Orkambi decreased the severity of EtOH-induced pancreatitis.

Conclusion

We showed for the first time that Ivacaftor and Lumacaftor are able to restore the CFTR defect caused by alcohol and decreases the severity of pancreatitis. These results indicate that Orkambi may represent a novel therapeutic option in the treatment of AP.
The research was funded by the National Research, Development and Innovation Office (SNN134497 to VV, K135874 to ZR and K131996 to PH) and the Translational Medicine Foundation.