Clinical Case Summary

We present the case of a 52-year-old male patient with heavy alcohol consumption and a recent episode of mild acute pancreatitis. A magnetic resonance performed soon after showed a 5cm multiloculated peripancreatic collection in intimate correlation with the stomach, however he abandoned follow-up. He was readmitted to the hospital 5 months later for intense epigastric pain, nausea and vomiting for 3 days. He experienced upper abdomen discomfort and weight loss since the prior episode of pancreatitis. A computed tomography (CT) revealed a 7cm multiloculated heterogeneous peripancreatic collection arising from the pancreatic body and tail and extending to the upper gastric corpus and to the spleen. Antibiotic treatment led to clinical improvement until the appearance of hematemesis 1 week later. A CT angiography showed the peripancreatic collection now measuring 9cm with fistulization to the gastric wall and active bleeding presumably arising from left gastric or splenic artery branches. An upper GI endoscopy revealed a bulge in the posterior wall of the upper gastric corpus with active oozing bleeding from fistulous orifices. Cyanoacrylate with lipiodol was injected in one orifice and hemostatic powder was applied achieving bleeding control. An arteriography of the left gastric and splenic arteries confirmed obliteration of the bleeding vessels by dense material without any further need for endovascular treatment. The hemoglobin reached a minimum of 5.3 g/dL.The patient evolved favorably afterwards, and a CT scan one week later showed a residual collection filled with dense material.
Perforation of a peripancreatic collection into the stomach presenting with massive bleeding is a dreadful late complication of acute pancreatitis and usually mandates emergent endovascular embolization or surgical treatment. In this case, the endoscopic injection of cyanoacrylate inside the collection obliterated the bleeding vessels and was the definitive treatment for this patient.

References

1- Magnetic resonance showing the initial peripancreatic collection;
2- CT scan revealing a larger peripancreatic collection in hospital readmission;
3- CT angiography showing the peripancreatic collection now fistulized to the stomach and with active bleeding;
4- Upper GI endoscopy with active oozing bleeding from the fistulized collection to the upper body of the stomach - injection of cyanoacrylate through a fistulous orifice;
5- Arteriography confirming obliteration of the bleeding vessels by dense material;
6- CT scan showing the residual pancreatic collection.

Introduction

Recurrent abdominal pain is the predominant symptom of chronic pancreatitis (CP), contributing to significant morbidity and reduced quality of life. Medical management includes analgesics, antioxidants, neuromodulators, and pancreatic enzyme replacement therapy (PERT). While PERT is used for pancreatic exocrine insufficiency (PEI), it is also thought to reduce pain by suppressing pancreatic secretion via negative feedback. However, previous meta-analysis did not show pain reduction, though subgroup analysis suggested potential pain relief with non-enteric (NE) coated enzymes1. Unlike currently available enteric-coated formulations, high in lipase but low in proteas, non-enteric coated enzymes with high protease content dissolve rapidly and may more effectively suppress cholecystokinin-mediated pancreatic stimulation, potentially improving pain outcomes.

Aims & Methods

To primarily assess the effect of a high-protease, non-enteric-coated pancreatic enzyme preparation on pain in patients with painful chronic pancreatitis. The study was registered under ClinicalTrials.gov (NCT05042284).
We conducted a randomized, double-blind, placebo-controlled trial where we randomly assigned participants to a high protease (30,000 U)-containing, non-enteric-coated enzyme preparation (n=54) and a placebo (n=53) group. The study duration was 24 weeks. Patients with painful CP (per Mayo Clinic criteria) with chronic pain were enrolled. The primary outcome was to see a difference in mean Izbicki pain score at 12 and 24 weeks and a change in pain scores (VAS 0-10) using pain diaries. Secondary outcomes were changes in the number of painful days, analgesic requirements, patient’s global impression of change (PGIC), quality of life, and adverse effects. Weekly pain data were collated. Repeated measures, linear, and mixed-effects models were used to analyze the primary outcome. Analysis was intention-to-treat.

Results

107 out of 256 screened patients fulfilled enrollment criteria. The mean age was comparable between groups (35.1±10.6 vs. 33.6±12.3 years; p=0.51), and baseline characteristics were similar. The primary outcome using mixed model analysis showed no significant differences in the change in Izbicki pain scores between the two groups at 12 and 24 weeks (Table: Results). The mean difference in VAS pain score was -3.7(95%CI: -4.3to-3.1) in enzyme group vs. -3.5(95%CI: -4.2to-2.9) in placebo group (p=0.64) at 12 weeks. The changes were -4.2(95%CI: -4.7to-3.6) vs. -4.1(95%CI: -4.7to-3.5), respectively (p=0.79), at 24 weeks indicating no significant difference. The median number of painful days was also similar, at 12 weeks, 16 (IQR: 9–35) in the enzyme group vs. 16 (IQR: 4–36.5) in placebo (p=0.31); at 24 weeks, 3(IQR: 0–8.5) vs. 3(IQR: 0–7)(p=0.30) respectively. Analgesic use was higher in the enzyme group at 12 weeks (45(83.3%) vs. 37(69.8%); p=0.11) and 24 weeks (42(77.8%) vs. 35(66%); p=0.20). Differences in the change in global health status, quality of life, PGIC, and adverse effects at both time points were also non-significant.

Conclusion

Despite the high protease content, Non-enteric coated enzyme preparations did not improve pain and quality of life in patients with painful chronic pancreatitis. Further RCTs are needed to evaluate benefits in distinct subgroups.

References

1. Yaghoobi, Mohammad, Julia McNabb-Baltar, Raheleh Bijarchi, and Peter B. Cotton. “Pancreatic Enzyme Supplements Are Not Effective for Relieving Abdominal Pain in Patients with Chronic Pancreatitis: Meta-Analysis and Systematic Review of Randomized Controlled Trials.” Canadian Journal of Gastroenterology and Hepatology. Doi: https://doi.org/10.1155/2016/8541839

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

As inflammatory bowel disease (IBD) is frequently diagnosed in young adults, the disease often coincides with pregnancy. About one in four female patients will have their first pregnancy after diagnosis. Current guidelines advise treatment through specialized clinics for IBD patients wishing to conceive, which are increasingly implemented. However, recent outcome data from these centers is scarce. In this study we therefore describe the pregnancy-course in three specialized Dutch IBD university clinics.

Aims & Methods

For this multicenter, retrospective cohort study, all adult female IBD-patients who had been pregnant during treatment in any of the three participating Dutch university medical centers between the inception of the respective electronic patient records and 2022 were included. Data on patient- and disease characteristics, lab values, medication usage and pregnancy outcomes was extracted from the electronic patient records. Topics relevant to pregnancy were logged, including intoxications, the use of folic acid and vitamin D, and gestational weight gain.

Results

Data was collected on 620 women who had been pregnant in the study period, including 376 (60.6%) with Crohn’s disease (CD), 230 (37.1%) with ulcerative colitis (UC), and 13 (2.1%) with inflammatory bowel disease unclassified (IBDU). Of the CD-patients, 68 (18.1%) had a history of perianal disease. The mean age at conception of the first pregnancy was 29.9 years. Altogether, 983 pregnancies were included, of which 10.3% was conceived using assisted reproductive technologies, including in vitro fertilization (IVF) in 3.6% of pregnancies. During 9.8% of pregnancies, the mother actively smoked tobacco at conception. Medication was used during 71.0% of pregnancies, most often consisting of thiopurines (27.1%) and amino salicylates (24.4%). Appropriate gestational weight gain was achieved in 31.1% of pregnancies. 152 (15.5%) pregnancies resulted in miscarriage, 12 (1.2%) pregnancies were ectopic. In the remaining pregnancies, 511 (62,4%) newborns were delivered vaginally. A caesarean section (CS) was performed in 234 cases (23.8%). Overall, 54 mothers (23.1%) who underwent a CS had perianal disease. An adverse pregnancy outcome was noted in 159 (21.3%) of pregnancies, including low birth weight in 78 (10.5%), prematurity in 85 (11.4%) and dysmaturity in 89 (11.9%). Adverse outcomes occurred more often in the group of women who experienced disease activity in any point during pregnancy, but this difference was not statistically significant (30.8% vs 21.7%, p=0.120). Two patients developed deep venous thromboembolism during or within six weeks after pregnancy.

Conclusion

In IBD the mean age at conception and the rate of pregnancies conceived using IVF were comparable with the general Dutch population. A CS was performed more frequently in this cohort when compared to healthy pregnancies in the Netherlands (23.8% vs 17.6%). In these specialized centers low birth weight (10.5% vs 5.7%), prematurity (11.4% vs 6.6%) and dysmaturity (11.9% vs 9.7%) occurred more often in comparison to the known rates in Dutch pregnancies, emphasizing that adequate counseling before and during pregnancy in IBD is essential.

Introduction

Lymphocytic colitis (LC) is a debilitating, non-destructive inflammatory bowel disease (IBD) that causes intense watery, non-bloody diarrhoea. LC is diagnosed by an increased lymphocyte infiltration in the mucosa that has been correlated with increased Th1/Th17 cytokine secretion and subsequent sodium malabsorption. Still, LC pathomechanisms have not been fully characterized and its relation to other forms of IBD is unclear.

Aims & Methods

Our aim was to define a LC-specific transcriptome to gain insight into LC pathology, identify genetic signatures uniquely linked to LC, and uncover potentially druggable disease pathways. For that, we performed whole mucosa bulk RNA-sequencing of LC and collagenous colitis (CC) samples from patients with active disease, and healthy controls (n=4-10 per cohort). Differential gene expression was analyzed by gene-set enrichment and deconvolution analyses to identify pathologically relevant pathways and cells, respectively, altered in LC. Key findings were validated using reverse transcription quantitative PCR and/or immunohistochemistry. Finally, we compared our sequencing data to a previous cohort of ulcerative colitis and Crohn’s disease patients (n=4 per group) to distinguish non-destructive from classic IBD.

Results

The LC-specific transcriptome was defined by a limited mucosal immune response against microbiota compared to CC and classic IBD samples. In contrast, we noted a distinct induction of regulatory non-coding RNA species in LC samples. Moreover, compared to CC, we observed decreased water channel and cell adhesion molecule gene expression, which was associated with reduced intestinal epithelial cell proliferation.

Conclusion

We conclude that LC is a pathomechanistically distinct disease that is characterized by a dampened immune response despite massive mucosal immune cell infiltration. Our results point to regulatory micro-RNAs as a potential disease-specific feature that may be amenable to therapeutic intervention.

References

1. Carrasco A. et al. Immunological Differences between Lymphocytic and Collagenous Colitis. J Crohns Colitis. 2016 Sep;10(9):1055-66.
2. Kumawat AK. et al. Microscopic colitis patients demonstrate a mixed Th17/Tc17 and Th1/Tc1 mucosal cytokine profile. Mol Immunol. 2013 Oct;55(3-4):355-64.
3. Barmeyer C. et al. ENaC Dysregulation Through Activation of MEK1/2 Contributes to Impaired Na+ Absorption in Lymphocytic Colitis. Inflamm Bowel Dis. 2016 Mar;22(3):539-47.

Disclosure

CEH, SK and AM received financial support from Ferring Pharmaceuticals (Switzerland). AM has received salary for consultancies from Tillots Pharma AG, Ferring, Vifor, and Dr Falk Pharma, speaker's honoraria from Tillots Pharma AG and Vifor. The remaining authors declare no conflicts of interest.

Introduction

Xanthine oxidase (XO) catalyzes the oxidation of hypoxanthine to xanthine and xanthine to uric acid (UA) with the production of superoxide anion. The accumulation of UA has been shown to initiate the inflammatory process through NLRP3 inflammasome and the production of reactive oxygen species (ROS), which contributes to inflammation-related tissue damage observed in inflammatory bowel disease (IBD). In murine models of colitis, XO inhibitors, allopurinol or febuxostat, reduced the expression of proinflammatory cytokines supporting the involvement of XO in the intestinal inflammatory process.

Aims & Methods

The aim of this study was to evaluate the expression level and enzymatic activity of XO in the intestinal mucosa of IBD patients (pts), both ulcerative colitis (UC) and Crohn’s disease (CD), compared to healthy controls (HC).
Sigmoid-colon biopsies from consecutive UC and CD pts, with a confirmed diagnosis (by ECCO guidelines) in regular follow-up at University Hospital of Cagliari with an indication to endoscopy according to standard clinical practice, were collected. Site-matched biopsies from individuals undergoing screening colonoscopy for colorectal cancer were used as controls.
Demographic data and endoscopic grade for disease activity scored by endoscopic Mayo and SES-CD score were collected. Real-Time PCR was used to evaluate XO relative expression levels (RQ) and data was confirmed by analyzing GEO database (study code GSE11223). XO activity was measured in whole protein extracts from biopsies by spectrophotometric quantification of UA production and expressed as nmol of UA/min/mg of total protein. The relative abundance of XO was further investigated by Western Blot. Finally, XO expression was assessed in sections of paraffin-embedded intestinal biopsies by immunohistochemistry.

Results

Biopsies of 15 HC, 20 UC, and 15 CD pts were collected. Mean age was 50 for UC, 49 for CD and 54 for HC. Mayo endoscopic subscore was 0 in 25% of UC pts, 1 in 18,75%, 2 in 21,2% and 3 in 25%. SES-CD was between 0-2 in 28,6% of CD pts, 3-6 in 21,4%, 7-14 in 42,8% and >14 in 7,1%. Real-time PCR showed that XO expression values were increased in the sigmoid mucosa of pts with UC compared with HC individuals (RQ 1,93 vs 0,99. p=0,004). This data was confirmed by analysis of XO expression in the GEO database study code GSE11223. The difference in XO expression between HC and CD was not statistically significant (p=0,13). Western blot analysis of XO protein expression in CD and UC pts compared with HC showed a significant increase in IBD pts (p<0,001).
XO activity was significantly higher in UC and CD pts as compared to HC. XO activity mean was 3,75 in UC pts and 5,10 in CD pts vs 1,11 nmol of UA/min/mg of protein in HC individuals (p<0.001). Moreover, in UC pts XO activity was correlated with Mayo endoscopic sub-score (r= 0.346; p=0.05). Immunohistochemistry confirmed higher expression of XO in IBD pts than HC with a prevalent expression observed in epithelial cells.

Conclusion

XO expression was higher in UC pts than in HC individuals. XO activity was higher in both CD and UC pts than HC and in UC pts XO activity correlated with endoscopic disease suggesting its potential role as therapeutic target.