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COMPLEMENT REGULATOR CD55 DEFICIENT PROTEIN-LOSING ENTEROPATHY (CHAPLE DISEASE): SUCCESSFUL TREATMENT WITH POZELIMAB IN TWO SISTERS

Nikki van der Kruk 1,2, Esther C. W. de Boer 3,4,5, Richard B. Pouw 3,4,6, Taco W. Kuijpers 7,8, Johan E. van Limbergen 1,2

Affiliations

1 Department of Paediatric Gastroenterology and Nutrition, Emma Children's Hospital, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, Netherlands

2 Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology, Endoc

3 Sanquin Research, and Landsteiner Laboratory, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands

4 Amsterdam institute for Immunology and Infectious Diseases, Inflammatory diseases, Amsterdam, Netherlands

5 Department of Pediatric Immunology,

6 Sanquin Diagnostic Services, Amsterd

7 Department of Pediatric Immunology, Rheumatology and Infectious Diseases, Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands

8 Sanquin Research, and Landsteiner Laboratory, Amsterdam UMC, University of Amsterdam, Amst

Summary

AI Generated

Two sisters with CHAPLE disease, initially misdiagnosed as Crohn's Disease, achieved sustained remission with pozelimab, the first FDA-approved treatment for this rare complement-driven disorder.

CHAPLE disease is a rare hereditary immune disorder caused by CD55 deficiency leading to complement system overactivation, with fewer than 100 patients diagnosed worldwide.
Two Moroccan sisters initially diagnosed with Crohn's Disease presented with recurrent edemas, abdominal pain, bloody diarrhea, low serum albumin, and low IgG, refractory to multiple conventional treatments over several years.
Whole exome sequencing led to CHAPLE diagnosis, confirmed by flow cytometry showing total absence of CD55 antigen on both patients' blood cells.
Subcutaneous weekly pozelimab treatment resulted in symptom resolution within one month, normalization of inflammatory markers and IgG levels, discontinuation of all immunosuppressive medications within three months, and sustained remission with no related adverse events.
This case illustrates the diagnostic challenge of CHAPLE disease and the clinical utility of pozelimab, recently approved by the FDA as the first treatment for this condition.

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Abstract

Clinical Case Summary

CD55 deficiency with Complement Hyperactivation, Angiopathic thrombosis and Protein Losing Enteropathy (CHAPLE) is a rare hereditary immune disease, driven by an overactivation of the complement system, caused by loss-of-function variants of CD55.¹ With fewer than 100 patients diagnosed with CHAPLE worldwide, providing evidence-based care can be complex. Previous studies showed that eculizumab, a complement C5 inhibitor, was broadly effective in patients with CHAPLE disease.² Recently, the FDA approved pozelimab, an anti-C5 antibody, as the first treatment for CHAPLE. This clinical case describes two sisters affected by CHAPLE disease highlighting the diagnostic process as well as their recent treatment with pozelimab, considering both clinical and immunological aspects.

In a Moroccan pedigree, two sisters were diagnosed with Crohn’s Disease (CD) at the ages of 12, and 27. Both sisters’ symptoms included recurrent edemas, abdominal pain, (bloody) diarrhea, nausea and vomiting, and abnormally low serum albumin levels. Treatment with diets, antibiotics, corticosteroids, immunomodulators and biologicals over multiple years had little effect. When a low IgG level was found in the younger sister, we initiated whole exome sequencing. This led to the diagnosis of CHAPLE disease in both sisters. Flow cytometry showed total absence of CD55 antigen on both patients’ blood cells and reduced expression of CD55 on the mother’s blood cells compared to a healthy control. A brother diagnosed with irritable bowel syndrome was genetically affected without clinical CD, demonstrating a highly variable penetrance.

Subcutaneous weekly pozelimab was started and allowed discontinuation of all immunosuppressive medication within 3 months in both sisters. Within a month of treatment, their symptoms resolved and inflammatory markers including fecal calprotectin and plasma albumin, as well as IgG levels, normalized. They have sustained remission since and reported no related adverse events.

References

Ozen A, Comrie WA, Ardy RC, et al. CD55 Deficiency, Early-Onset Protein-Losing Enteropathy, and Thrombosis. N Engl J Med. 2017;377(1):52-61. doi:10.1056/NEJMoa1615887
Ozen A, Kasap N, Vujkovic-Cvijin I, et al. Broadly effective metabolic and immune recovery with C5 inhibition in CHAPLE disease. Nat Immunol. 2021;22(2):128-139. doi:10.1038/s41590-020-00830-z

Conference

UEG Week Vienna 2024

Topics

Colorectal

Submission format

Clinical Case

Session

Clinical Cases (Posters)

Published

2024

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UEG Presentation

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ABBV-466, A NOVEL DUAL-TARGETING THERAPY, LEADS TO ENDOSCOPIC REMISSION IN MODERATE-TO-SEVERE CROHN’S DISEASE: PRIMARY RESULTS AND MOLECULAR PROFILING FROM THE PHASE 2A TARGET-CD STUDY

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ABBV-466, A NOVEL DUAL-TARGETING THERAPY, LEADS TO ENDOSCOPIC REMISSION IN MODERATE-TO-SEVERE CROHN’S DISEASE: PRIMARY RESULTS AND MOLECULAR PROFILING FROM THE PHASE 2A TARGET-CD STUDY

Remo Panaccione 1, Silvio Danese 2, Laurent Peyrin-Biroulet 3, James O. Lindsay 4, Bram Verstockt 5, Jean-Frédéric Colombel 6, Marla C. Dubinsky 6, Jason Eccleston 7, Izabella Messina 7, Stephen Laroux 8, Alissa Zimmerman-Bennett 7, Meng Liu 7, Buvana Ravishankar 8, Tian Feng 7, Ronilda D'Cunha 7, David T. Rubin 9

Affiliations

1 University of Calgary, Calgary, Canada

2 IRCCS Ospedale San Raffaele and University Vita-Salute San Raffaele,, Milan, Italy

3 Northwestern Medicine Digestive Health Institute, Chicago, United States

4 Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom

5 University Hospitals Leuven, Department of Gastroenterology and Hepatology, Leuven, Belgium

6 Icahn School of Medicine at Mount Sinai, New York, United States

7 AbbVie Inc., North Chicago, United States

8 AbbVie Inc., Walthan, United States

9 University of Chicago Medicine, Chicago, United States

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Abstract

Introduction

Analysis of patients (pts) with Crohn’s disease (CD) treated with risankizumab (RZB) in the phase 3 studies who achieved clinical response, yet failed to achieve endoscopic remission, demonstrated a persistent signature of the α4β7 pathway in mucosal biopsies. ABBV-466 is a novel dual-targeting therapy comprising RZB against IL-23 p19 and trosunilimab (TROSU) against α4β7. Efficacy and safety of ABBV-466 are being investigated in TARGET-CD (NCT06548542), an ongoing open-label, treat-through, phase 2a platform study in pts with moderate-to-severe CD.

Aims & Methods

Pts with a Simple Endoscopic Score for CD (SES-CD) ≥6 (or ≥4 for isolated ileal disease), CD Activity Index (CDAI) ≥220, and prior intolerance and/or inadequate response (IR) to conventional and/or unlimited number of targeted advanced therapies (TaTs) were eligible. Pts were randomized 1:1:1 to receive 24-weeks (wks) of ABBV-466 (N=106), RZB (N=94), or TROSU (N=100). Here we report the Wk12 results for all enrolled pts and Wk24 results for pts projected to reach Wk24 by the cutoff date (July 2026). The primary endpoint was endoscopic remission (SES-CD ≤4) at Wk12. Additional prespecified endpoints were assessed at Wk12 and Wk24, along with safety through Wk24. Bulk transcriptomic analyses of colonic biopsies were performed, including Wk12 complete responder/non-responder comparisons and Wk24 pathway enrichment analyses (false discovery rate <0.01, |log fold change| >0.5). Complete responders were defined as achieving both clinical and endoscopic response; partial responders as achieving either endpoint.

Results

Pts’ baseline characteristics reflect a highly active and treatment refractory population with a mean (SD) SES-CD of 14.0 (7.4); 75% were TaT-IR (of which, 24% were IR to 3+ prior TaTs), with majority having previously failed same/similar drug class (e.g., p19, p40, or α4β7 inhibitors) (Table). A greater proportion of pts receiving ABBV-466 achieved endoscopic remission at Wk12 (30.2%) vs those receiving RZB alone (21.3%, adjusted Δ=8.2%) and TROSU alone (18.0%, adjusted Δ=12.6%). By Wk24, 40.5% in the ABBV-466 group achieved endoscopic remission, numerically greater than RZB alone (22.4%, adjusted Δ=17.8%) and TROSU alone (20.0%, adjusted Δ=20.1%). Similar trends were observed in endoscopic response, mucosal healing, and SES-CD ulcerated subscore ≤1. Rates of serious adverse events (AEs) and AEs leading to discontinuation were comparable across treatment groups. Rates of serious infections were low and similar among all treatment groups.
Molecular analyses demonstrated ABBV-466 promoted colonic epithelial repair and barrier restoration mechanisms at Wk12 in complete as well as partial responders, of which 54% progressed to complete response by Wk24. Wk12 barrier repair in the ABBV-466 group was followed by tissue remodeling and metabolic changes at Wk24, not observed with either monotherapy.

Demographics and baseline characteristics	RZB (N=94)		TROSU (N=100)		ABBV-466 (N=106)
Age, mean (SD) CD duration, years, mean (SD) Corticosteroid use, n (%) Prior TaT failure, n (%): 0 1 2 3+ TNF inhibitor^a α4β7 inhibitor^a IL-12/23 inhibitor^a IL-23p19 inhibitor^a JAK inhibitor^a	41.1 (14.2) 10.5 (8.2) 29 (30.9) 25 (26.6) 29 (30.9) 23 (24.5) 17 (18.1) 63 (91.3) 15 (21.7) 28 (40.6) 2 (2.9) 5 (7.2)		40.3 (14.3) 10.3 (8.5) 33 (33.0) 25 (25.0) 34 (34.0) 23 (23.0) 18 (18.0) 64 (85.3) 12 (16.0) 33 (44.0) 11 (14.7) 11 (14.7)		41.4 (14.7) 11.1 (10.8) 32 (30.2) 25 (23.6) 30 (28.3) 31 (29.2) 20 (18.9) 73 (90.1) 22 (27.2) 33 (40.7) 8 (9.9) 11 (13.6)
Efficacy, n/N (%)	RZB		TROSU		ABBV-466
	Week 12	Week 24	Week 12	Week 24	Week 12	Week 24
Endoscopic remission^b Endoscopic response^c Mucosal healing^d SES-CD ulcerated subscore ≤1^e	20/94 (21.3) 31/94 (33.0) 15/94 (16.0) 33/84 (39.3)	17/76 (22.4) 31/76 (40.8) 18/76 (23.7) 27/68 (39.7)	18/100 (18.0) 28/100 (28.0) 11/99 (11.1) 26/93 (28.0)	16/80 (20.0) 23/80 (28.8) 12/79 (15.2) 21/74 (28.4)	32/106 (30.2) 46/106 (43.4) 24/106 (22.6) 41/94 (43.6)	34/84 (40.5) 44/84 (52.4) 28/84 (33.3) 42/75 (56.0)
TEAEs through Week 24, n (%)	RZB (N=94)		TROSU (N=100)		ABBV-466 (N=106)
AE AE related to study drug^f Serious AEs AE leading to discontinuation Death AESIs & other events: Serious infection Malignant tumors Non-melanoma skin cancer Serious hypersensitivity Adjudicated hepatic events	53 (56.4) 16 (17.0) 9 (9.6) 5 (5.3) 0 2 (2.1) 0 0 0 0		62 (62.0) 21 (21.0) 9 (9.0) 6 (6.0) 0 3 (3.0) 0 0 0 0		72 (67.9) 26 (24.5) 11 (10.4) 7 (6.6) 1 (0.9)^g 3 (2.8) 1 (0.9)^h 0 0 0
AE, adverse event; AESI, adverse event of special interest; CD, Crohn's disease; IL, interleukin; JAK, Janus kinase; RZB, risankizumab; SD, standard deviation; TaT, targeted advanced therapy; TEAE, treatment-emergent adverse event; TNF, tumor necrosis factor; TROSU, trosunilimab. ^aPercentage based on patients with at least 1 prior TaT failure. ^bEndoscopic remission: SES-CD ≤4 and no subscore greater than 1 in any individual variable (primary endpoint at week 12). ^cEndoscopic response: SES-CD ≥50% reduction from baseline ^dMucosal healing: SES-CD ulcerated surface subscore of 0 in patients with SES-CD ulcerated surface subscore ≥1 at baseline. ^eSES-CD ulcerated subscore ≤1: SES-CD ulcerated subscore ≤1 in each segment among patients with a SES-CD ulcerated surface subscore ≥2. ^fAs assessed by investigator. ^g25-year-old male, with persistent CD activity, cause of death as completed suicide; not related per investigator. ^h67-year-old male, multiple myeloma reported, not related per investigator; relevant history of thyroid cancer and family history of lymphoma.

Conclusion

In pts with moderate-to-severe CD, ABBV-466 therapy demonstrated a higher endoscopic remission rate than either monotherapy at Wk12, which increased through Wk24. This was accompanied by coordinated mechanistic changes indicative of mucosal healing. ABBV-466 was well tolerated with no concerning safety signals.

Disclosure

RP has received consulting fees, speaker fees, and research support from Abbott, AbbVie, Abbivax, Alimentiv, Alentics Therapeutics, Amgen, AnaptysBio, Apogee Therapeutics, AstraZeneca, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, Caldera, Candid Therapeutics, Celgene, Celltrion, Cosmos Pharmaceuticals, Eisai, Elan, Eli Lilly, Enthera, Ferring, Galapagos, Inviva,Fresenius Kabi, Genentech, Gilead Sciences, Glaxo-Smith Kline, JAMP Bio, Janssen, Merck, Mirador, Net Biotix, Novartis, Oppilan Pharma, Odyssey Therapeutics, Organon, Oruka Therapeutics, Pandion Pharma, Pendopharm, Pfizer, Progenity, Prometheus Biosciences, Protagonist Therapeutics, Protillion, Repertoire Immune Medicines, Roche, Sandoz, Sanofi, Satisfai Health, Shattuck Labs, Shire, Soriso, Simcare Therapeutics, Sublimity Therapeutics, Spyre Therapeutics, Takeda Pharmaceuticals, Teva, Tillots, Trellus, Union Biopharma, Viatris, Ventyx, UCB, Xencor.
SD has received consultancy fees from AbbVie, Alimentiv, Allergan, Amgen, AstraZeneca, Athos Therapeutics, Biogen, Boehringer Ingelheim, Celgene, Celltrion, Eli Lilly, Enthera, Ferring Pharmaceuticals, Gilead, Hospira, Inotrem, Janssen, Johnson & Johnson, MSD, Mundipharma, Mylan, Pfizer, Roche, Sandoz, Sublimity Therapeutics, Takeda, TiGenix, UCB, and Vifor; lecture fees from AbbVie, Amgen, Dr Falk Pharma, Ferring Pharmaceuticals, Gilead, Janssen, Mylan, Pfizer, and Takeda.
LPB has received consulting fees from AbbVie, Abivax, Adacyte, Alimentiv, Alfasigma, Amgen, Apini, Banook, BMS, Celltrion, Enthera, Ferring, Fresenius Kabi, Galapagos, Genentech, Gilead, GSK, Hemay, Iterative Health, Janssen, Eli Lilly, LifeMine, Medac, Mirador, Morphic, MSD, Nordic Pharma, Novartis, Oddifact, Oncodesign Precision Medicine, Onco3R, ONO Pharma, OSE Immunotherapeuthics, Palisade Bio, Par' Immune, Pfizer, Prometheus, Roche, Roivant, Samsung, Sandoz, Sanofi, Sorriso, Spyre, Takeda, Teva, ThirtyfiveBio, Tillots, Vectivbio, Vedanta, Ventyx; stock options from Iterative Health, Oragen, Pharmanest, Thetis; lecture fees from AbbVie, Alfasigma, Amgen, Biogen, Celltrion, Ferring, Fresenius Kabi, Galapagos, Genentech, Gilead, Iterative Health, Janssen, Eli Lilly, Medac, MSD, Nordic Pharma, Novartis, Pfizer, Roche, Sandoz, Takeda, and Tillots.
JOL has received consultancy fees from AbbVie, Apini, Astra Zeneca, BMS, Celgene, Celltrion, Engytix, Ferring, Galapagos, Gilead, GSK, Janssen, Lilly, MSD, Orchard, Pfizer, Shattuck Labs and Takeda; speaker fees and travel support from AbbVie, Ferring, Galapagos, Gilead, High5MD, Janssen, Lilly, Materia Prima, MSD, Pfizer, Tillott’s, and Takeda; investigator-led research grants from AbbVie, Gilead, Pfizer, and Takeda.
BV has received research support from AbbVie, Celltrion, Pfizer, Sanofi, Nxera and Takeda; speaker’s fees from Abbvie, Agomab, Alfasigma, Biogen, Bristol Myers Squibb, Celltrion, Eli Lily, Falk, Galapagos, Materia Prima, Johnson and Johnson, Pfizer, Takeda and Truvion; consultancy fees from Abbvie, Agomab, Alfasigma, Alimentiv, Anaptys Bio, Astrazeneca, Atheneum, BenevolentAI, Biora Therapeutics, Boxer Capital, Bristol Myers Squibb, Domain Therapeutics, Eli Lily, Fides, Galapagos, Guidepont, Merck, Mirador Therapeutics, Nxera, IBD League, Inotrem, Johnson and Johnson, Onco3R/Coultreon, Pallisade Bio, Pfizer, Promakhos Therapeutics, Roche, Sandoz, Sanofi, Santa Ana Bio, Sapphire Therapeutics, Sosei Heptares, Takeda, Tillots Pharma and Viatris; and stock options from Vagustim and Thethis Pharma.
JFC has received research grants from AbbVie, Janssen Pharmaceuticals, and Takeda; payment for lectures from AbbVie, Allergan, Amgen, Ferring Pharmaceuticals, Shire, and Takeda; consulting fees from AbbVie, Amgen, Arena Pharmaceuticals, Boehringer Ingelheim, Bristol Myers Squibb, Celgene Corporation, Ferring Pharmaceuticals, Galmed Research, Genentech, GlaxoSmithKline, Imedex, Immunic, Iterative Scopes, Janssen Pharmaceuticals, Kaleido Biosciences, Lilly, Merck, Microbia, Novartis, PBM Capital, Pfizer, Protagonist Therapeutics, Sanofi, Takeda, TiGenix, and Vifor; and holds stock options in Intestinal Biotech Development.
MD has received consulting fees from AbbVie, Abivax, Astra Zeneca, , Boehringer Ingelheim, Bristol Myers Squibb, Celttrion, Eli Lilly, Genentech, , Janssen, Johnson and Johnson, Merck Pfizer, Prometheus Labs, Sanofi, Spyre, Takeda, Tentarix.
JE, IM, FSL, AZB, ML, BR, TF, and RD are employees of AbbVie and may own stock or stock options.
DR has served as a consultant for AbbVie, Altrubio, Apex, Avalo Therapeutics, Bristol-Myers Squibb, Buhlmann Diagnostics Corp, Celgene, Connect BioPharma, Intouch Group, Iterative Health, Janssen Pharmaceuticals, Lilly, Pfizer, Samsung Neurologica, and Takeda; served on the Board of Trustees of the Crohn’s & Colitis Foundation and on the Board of Directors of Cornerstones Health; received grants from Takeda.

Event

UEG Week Barcelona 2026

Topics

Standards & Guidelines Paediatrics Mechanisms & Personalised Medicine Immunology IBD Endoscopy

Submission format

Late-Breaking Abstract

Session

Late-Breaking: IBD Trials

Citation

2026: United European Gastroenterology Journal 2026; 14 (S1)

Published

2026

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MAST CELLS AS KEY PLAYERS OF VISCERAL HYPERSENSITIVITY TRIGGERED BY MICROBIAL HISTAMINE

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UEG Presentation

New

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PREVALENCE OF GERD IN PATIENTS WITH EOSINOPHILIC ESOPHAGITIS AND ITS IMPACT ON TREATMENT OUTCOMES: INSIGHTS FROM A SWEDISH TERTIARY CENTRE COHORT

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PREVALENCE OF GERD IN PATIENTS WITH EOSINOPHILIC ESOPHAGITIS AND ITS IMPACT ON TREATMENT OUTCOMES: INSIGHTS FROM A SWEDISH TERTIARY CENTRE COHORT

Kotryna Truskaite 1,2, Fredrik Kvelebro 2,1, Greger Lindberg 1,2, Aldona Dlugosz 1

Affiliations

1 Karolinska Institutet, Stockholm, Sweden

2 Karolinska University Hospital, Stockholm, Sweden

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Abstract

Introduction

Eosinophilic esophagitis (EoE) and gastroesophageal reflux disease (GERD) are common inflammatory esophageal disorders with overlapping clinical and histological features. Differentiation between them is challenging though important for appropriate patient management. EoE exhibit a rising incidence and prevalence while GERD is far more prevalent in the general population compared to EoE. GERD prevalence (symptom-based) is estimated at 10-25% among adults in Western population and up to 30% in the USA. Global age-standardised prevalence is 8% in Western Europe. The true burden of concomitant EoE and GERD remain uncertain. This study aimed to access GERD prevalence among EoE patients and to evaluate maintenance treatment at a single tertiary care centre in Sweden.

Aims & Methods

This retrospective study analysed medical records of adult EoE patients diagnosed and treated at Karolinska University Hospital between 2012 and 2025. GERD diagnoses were made using updated Lyon consensus criteria and pH-metry tests.

Results

Fifty-eight of 305 patients with EoE (19%) had concomitant GERD. These patients were older (median 45 vs 35 years; p<0.05) with high male predominance (86% vs 75%). Dysphagia and food bolus impaction dominated in both groups, while reflux symptoms and hiatal hernia were significantly more common in EoE +GERD group (p<0.05). Barretts esophagus was identified in 9 patients (3% overall; 16% of EoE +GERD). All EoE +GERD patients received PPI therapy compared with 92% of EoE non-GERD patients with higher clinical response in EoE +GERD (88% vs 66%) (p<0.05). Corticosteroid use and response to treatment were similar (EoE +GERD, 55% vs EoE non-GERD 61%). Among patients receiving topical corticosteroids, budesonide was used more often than fluticasone (44%, vs 30%) and was associated with higher histological remission (84% vs 58%; RR 1.47, 95% CI 1.19-1.81; p<0.05) and lower treatment failure (4% vs 16%; RR 0.23, 95% CI 0.08-0.66; p<0.05). EoE +GERD patients were more frequently maintained on PPI therapy alone (62% vs 34%, p<0.001) or in combination with corticosteroids (21% vs 7%; p=0.002). The proportion of patients remaining on PPI despite persistent histological activity was similar in EoE +GERD and non-GERD groups (31% vs 32%). Corticosteroid only maintenance (33% vs 7%; p<0.001) particularly budesonide (28% vs 5%; p<0.001) and food elimination diet therapy (13% vs 2%; p=0.03) were more common in EoE non-GERD patients. PPI maintenance therapy was associated with significantly higher odds of loss to follow up (OR 2.86, 95% CI 1.74-4.70; p<0.001) in EoE patients.

Conclusion

In total 19% of EoE patients had concomitant GERD. This prevalence is within the range reported in general Western population but higher than age-standardised estimates for Western Europe. Barrett’s esophagus was observed in 3% of all EoE patients and 16% of those with concomitant GERD, appearing higher than in the general population. EoE +GERD patients more frequently received PPI-based maintenance therapy. In contrast, EoE non-GERD patients more often required escalation to corticosteroid or dietary therapy. Treatment response and the proportion of patients remaining on PPI despite persistent histological activity were similar between the groups. Larger prospective studies are needed to confirm these findings.

Event

UEG Week Barcelona 2026

Topics

Oesophagus Small Intestine & Nutrition Neurogastroenterology & Motility

Submission format

Abstract

Session

Functional upper GI disorders: From epidemiology to therapies

Citation

2026: United European Gastroenterology Journal 2026; 14 (S1)

Published

2026

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OVERDIAGNOSIS OF SUPERIOR MESENTERIC ARTERY SYNDROME: LIMITED DIAGNOSTIC CONCORDANCE BETWEEN IMAGING MODALITIES AND LIMITED BENEFIT OF SURGERY

Tim Vanuytsel

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Carmen Alonso-Cotoner

MAST CELLS AS KEY PLAYERS OF VISCERAL HYPERSENSITIVITY TRIGGERED BY MICROBIAL HISTAMINE

Giada De Palma

UEG Presentation

New

Share via Email Share on Facebook Share on X Share on LinkedIn Share on Bluesky

OVERDIAGNOSIS OF SUPERIOR MESENTERIC ARTERY SYNDROME: LIMITED DIAGNOSTIC CONCORDANCE BETWEEN IMAGING MODALITIES AND LIMITED BENEFIT OF SURGERY

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OVERDIAGNOSIS OF SUPERIOR MESENTERIC ARTERY SYNDROME: LIMITED DIAGNOSTIC CONCORDANCE BETWEEN IMAGING MODALITIES AND LIMITED BENEFIT OF SURGERY

Christian von Muhlenbrock 1,2,3, Sandrien Abbeel 4, Thomas Debrouwere 1, Dirk Vanbeckevoort 1, Jan Tack 1, Tim Vanuytsel 1

Affiliations

1 KU Leuven, Leuven, Belgium

2 Universidad de Chile, Santiago, Chile

3 Universidad de los Andes, Santiago, Chile

4 KU Leuven, Eppegem, Belgium

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Abstract

Introduction

Superior mesenteric artery (SMA) syndrome is traditionally described as a rare vascular cause of duodenal obstruction. However, overlapping symptoms with functional gastrointestinal disorders and variable radiological criteria raise concerns regarding overdiagnosis.

Aims & Methods

We aimed to evaluate diagnostic concordance across modalities and clinical outcomes following medical and surgical treatment in patients referred for suspected SMA syndrome.We retrospectively analyzed 49 consecutive patients undergoing hypotonic barium duodenography (HBD) for suspected SMA syndrome based on symptoms and standard imaging (ultrasound or CT) in a tertiary neurogastroenterology center (2003–2023). SMA syndrome was defined by the combination of fixed abrupt narrowing of the third duodenum and proximal duodenal dilatation on HBD, the gold standard for the diagnosis in our center, in the absence of a more plausible diagnosis. CT-based aortomesenteric angle (AMA) and distance (AMD), intestinal manometry findings, gastric emptying, and treatment outcomes were also assessed.

Results

Only 11/49 patients (22%) met strict HBD criteria for SMA syndrome. Clinical presentation, BMI, and weight loss were indistinguishable between HBD-confirmed cases and controls (Table 1). CT criteria lacked specificity: 4 patients with positive CT findings had negative HBD and were ultimately diagnosed with alternative disorders of gut–brain interaction. AMA was lower in confirmed cases (18.8° vs 26.5°, p=0.05), whereas AMD did not significantly differ. Conservative medical management (n=6) led to symptom improvement in 50%. In contrast, despite >5% weight gain in 80% of patients undergoing a duodenojejunostomy (n=4) or gastroenterostomy (n=1) , meaningful symptom improvement occurred in only one patient, with procedure-related complications observed (dumping syndrome in 2 and worsening of gastroparesis-like symptoms in 1 patient).

Parameters	Patients with SMA syndrome on HBD (N=11)	Control group (N=38)	p-value
Age (years)	30.5 ± 3.2	34.0 ± 1.9	0.37
Body mass index (kg/m2)	17.5 (16.2, 19.3)	17.5 (16.4, 19.1)	1.00
Gender Male Female	1 (9%) 10 (91%)	7 (18%) 31 (82%)	0.66
Patients reporting weight loss	10 (91%)	32 (84%)	1.00
Weight loss (kg)	8.7 ± 1.6	9.8 ± 1.5	0.96
Weight loss of >10%	8 (73%)	22 (58%)	0.49
Aortamesenteric angle (°)	18.8 ± 2.52	26.5 ± 2.11	0.05
Aortamesenteric distance (mm)	5 (4.5, 7.5)	7.0 (6, 9)	0.13
Gastric emptying study: t1/2 (minutes)	70 (64.5, 85.5)	119 (74, 159)	0.02

Conclusion

In a tertiary referral setting, most patients suspected of SMA syndrome do not meet strict diagnostic criteria on HBD. Standard radiological findings alone may overestimate the condition, and surgical intervention frequently fails to improve symptoms. These findings question whether SMA syndrome represents a distinct clinical entity in most cases and support a highly restrictive, conservative management strategy.

Event

UEG Week Barcelona 2026

Topics

Small Intestine & Nutrition Endoscopy

Submission format

Abstract

Session

Small intestine diseases: Inside the black box

Citation

2026: United European Gastroenterology Journal 2026; 14 (S1)

Published

2026

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OVERDIAGNOSIS OF SUPERIOR MESENTERIC ARTERY SYNDROME: LIMITED DIAGNOSTIC CONCORDANCE BETWEEN IMAGING MODALITIES AND LIMITED BENEFIT OF SURGERY

Tim Vanuytsel

COLONIC MAST CELL ACTIVATION IS LINKED TO MENTAL AND SOMATIC SYMPTOM SEVERITY IN IRRITABLE BOWEL SYNDROME: RESULTS FROM THE DISCOVERIE PROJECT (EU-FUNDED PROJECT Nº: 848228)

Carmen Alonso-Cotoner

TRANSCRIPTOMIC AND PROTEOMIC PROFILING OF COLONIC MUCOSA IN PATIENTS WITH IRRITABLE BOWEL SYNDROME WITH OR WITHOUT MENTAL/SOMATIC COMORBIDITIES: RESULTS FROM THE EUROPEAN MULTICENTER DISCOVERIE STUDY

Carmen Alonso-Cotoner

MAST CELLS AS KEY PLAYERS OF VISCERAL HYPERSENSITIVITY TRIGGERED BY MICROBIAL HISTAMINE

Giada De Palma

UEG Presentation

New

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COLONIC MAST CELL ACTIVATION IS LINKED TO MENTAL AND SOMATIC SYMPTOM SEVERITY IN IRRITABLE BOWEL SYNDROME: RESULTS FROM THE DISCOVERIE PROJECT (EU-FUNDED PROJECT Nº: 848228)

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COLONIC MAST CELL ACTIVATION IS LINKED TO MENTAL AND SOMATIC SYMPTOM SEVERITY IN IRRITABLE BOWEL SYNDROME: RESULTS FROM THE DISCOVERIE PROJECT (EU-FUNDED PROJECT Nº: 848228)

Ana Maria González 1,2, Núria Vilaplana 1, Beatriz Lobo Alvarez 1,2,3, Elba Expósito 1, Marc Pigrau Pastor 3, Irina Midenfjord 4, Magnus Simrén 4, Andrei Pop 5, Ricard Farré 6, Giovanni Barbara 7, Amanda Rodriguez 8,9, Javier Santos 3,2,1, Carmen Alonso-Cotoner 3,2,1

Affiliations

1 Vall d’Hebron Institut de Recerca, Barcelona, Spain

2 Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBER-EHD), Madrid, Spain

3 Hospital Universitari Vall d'Hebron, Barcelona, Spain

4 Institute of Medicine, University of Gothenburg, Gothenburg, Sweden

5 University of Medicine and Pharmacy Cluj-Napoca, Cluj-Napoca, Romania

6 KU Leuven, Leuven, Belgium

7 University of Bologna and IRCCS Azienda Ospedaliero Universitaria di Bologna, Bologna, Italy

8 University Hospital Vall d’Hebron, Barcelona, Spain

9 CIBERSAM, Madrid, Spain

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Abstract

Introduction

Irritable bowel syndrome (IBS) is a disorder of brain-gut interaction in which low‑grade mucosal inflammation, particularly involving mast cells (MCs), has emerged as a key mechanism linking epithelial barrier dysfunction, immune activation, visceral hypersensitivity and symptom generation. Mental comorbidities such as anxiety and depression, as well as somatic comorbidities including fibromyalgia and chronic fatigue syndrome, are highly prevalent in IBS. However, the specific role of MC in IBS patients with and without comorbidities remains unknown.

Aims & Methods

To characterize MC activation in the colonic mucosa of patients with IBS with or without mental comorbidities (depression, anxiety) and/or somatic comorbidities (fibromyalgia and/or chronic fatigue), and to evaluate its role in clinical severity. We included healthy volunteers (HV, n=10) and IBS patients fulfilling Rome IV criteria were prospectively recruited across five European hospitals: IBS without comorbidity (IBS-A, n=9); IBS with mental comorbidity (IBS-Co, n=10) and IBS with both mental and somatic comorbidities (IBS-Mco, n=10). Colonic mucosal biopsies and clinical information were obtained from all participants. Validated questionnaires were used to assess IBS severity (IBS-SSS), depression (PHQ‑9), anxiety (GAD‑7), fibromyalgia (FIQ), chronic fatigue (MFI), and other physical symptoms (PHQ‑15). Mast cell activation was characterized by anti‑tryptase immunohistochemistry and transmission electron microscopy (TEM). Tryptase+ cells were quantified per high‑power field, and the percentage of tryptase‑stained area in the lamina propria was analyzed using QuPath software. MC ultrastructure, including granule morphology, degranulation profile, and proximity to nerve fibres, was evaluated by TEM.

Results

All groups showed similar MC infiltration in the lamina propria and epithelium. However, IBS-Co and IBS-Mco groups exhibited higher % of tryptase-stained area compared to IBS-A (p=0.038, p=0.021, respectively). Ultrastructurally, HV-MCs showed more electrodense core pattern granules, while IBS groups showed a predominant scroll pattern. IBS-Mco showed higher % of MCs with a very high activation profile (vesicles fusion and piecemeal) compared to HV (p=0.009) and IBS-A (p=0.031). Furthermore, IBS-Co and IBS-Mco groups had higher % of MCs in close proximity (<5 μm) to nerve fibres compared to HV (p=0.013). Notably, the % of tryptase-stained area correlated with PHQ15 (r=0.352; p=0.04), MFI Mental (r=0.438; p=0.01) and MFI physical fatigue (r=0.376; p=0.03); and the % of MC <5 μm to nerve fibres with IBS-SSS (r=0.56; p=0.03).

Conclusion

Mast cell activation, regardless of mast cell count, is a clinical marker of abdominal pain and of greater severity of both mental and somatic symptoms in IBS, indicating the involvement of MCs in the pathophysiology of IBS with comorbidities. Further studies are needed to characterize the interaction between MCs and the symptoms associated with disorders of the brain–gut axis.

Event

UEG Week Barcelona 2026

Topics

Small Intestine & Nutrition Primary Care Colorectal

Submission format

Abstract

Session

Insights into IBS

Citation

2026: United European Gastroenterology Journal 2026; 14 (S1)

Published

2026

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David T. Rubin

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Aldona Dlugosz

OVERDIAGNOSIS OF SUPERIOR MESENTERIC ARTERY SYNDROME: LIMITED DIAGNOSTIC CONCORDANCE BETWEEN IMAGING MODALITIES AND LIMITED BENEFIT OF SURGERY

Tim Vanuytsel

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Carmen Alonso-Cotoner

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Carmen Alonso-Cotoner

MAST CELLS AS KEY PLAYERS OF VISCERAL HYPERSENSITIVITY TRIGGERED BY MICROBIAL HISTAMINE

Giada De Palma

UEG Presentation

New

Share via Email Share on Facebook Share on X Share on LinkedIn Share on Bluesky

TRANSCRIPTOMIC AND PROTEOMIC PROFILING OF COLONIC MUCOSA IN PATIENTS WITH IRRITABLE BOWEL SYNDROME WITH OR WITHOUT MENTAL/SOMATIC COMORBIDITIES: RESULTS FROM THE EUROPEAN MULTICENTER DISCOVERIE STUDY

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TRANSCRIPTOMIC AND PROTEOMIC PROFILING OF COLONIC MUCOSA IN PATIENTS WITH IRRITABLE BOWEL SYNDROME WITH OR WITHOUT MENTAL/SOMATIC COMORBIDITIES: RESULTS FROM THE EUROPEAN MULTICENTER DISCOVERIE STUDY

Juan Manuel Garcia 1, Ana Maria Gonzalez-Castro 1,2, Beatriz Lobo Alvarez 1,2,3, Elba Exposito 1, Marc Pigrau Pastor 4,3, Amanda Rodriguez 1,3,5, Ricard Farré 6, Magnus Simrén 7, Giovanni Barbara 8,9, Maria Raffaella Barbaro 9,8, Maaike Van Den Houte 10, Andrei Pop 11, Daisy Mae Jonkers 12, Javier Santos 1,2,3, Carmen Alonso-Cotoner 1,2,3

Affiliations

1 Vall d’Hebron Research Institute, Barcelona, Spain

2 CIBEREHD, Madrid, Spain

3 Vall d’Hebron Hospital Universitari, Vall d’Hebron Barcelona Hospital Campus, Barcelona, Spain

4 Universitat Autonoma de Barcelona, Barcelona, Spain

5 CIBERSAM, Madrid, Spain

6 University of Leuven, Translational Research Center for Gastrointestinal Disorders (TARGID), Leuven, Belgium

7 Sahlgrenska University Hospital - Dept of Internal Medicine, Sahlgrenska University Hospital ; Gothe, Gothenburg, Sweden

8 University of Bologna, Bologna, Italy

9 Università di Bologna, Bologna, Italy

10 Laboratory for Brain-Gut Axis Studies, Translational Research in Gastrointestinal Disorders (TARGID), Leuven, Belgium

11 Iuliu Hatieganu University of Medicine and Pharmacy Cluj-Napoca, Cluj-Napoca, Romania

12 Maastricht University Medical Center, Maastricht, Netherlands

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Abstract

Introduction

Irritable bowel syndrome (IBS) is a chronic, relapsing disorder frequently associated with psychiatric and/or somatic comorbidities, including depression, anxiety, fibromyalgia, and chronic fatigue. Although its pathogenesis is multifactorial, dysfunction of the gut-brain axis is considered a key underlying mechanism. However, the specific molecular alterations and pathways involved remain poorly characterized.

Aims & Methods

We aimed to characterize the transcriptomic and proteomic profiles of colonic mucosa in irritable bowel syndrome (IBS) patients with or without mental and/or somatic comorbidities compared with healthy subjects. Methods: Within the European DISCOvERIE project, IBS patients and healthy volunteers (HV) were recruited across five European centers. Colonic biopsies and demographic and clinical variables, including symptom severity scores for IBS (IBS-SSS), depression (PHQ-9), anxiety (GAD-7), somatic symptoms (PHQ-15), fibromyalgia (FIQ), and fatigue (MFI) were collected. RNA was extracted and analyzed by RNA sequencing (RNA-seq). Libraries were prepared using TruSeq Stranded mRNA (Illumina) and sequenced on a NovaSeq 6000 platform. Differential gene expression (DE) analysis was performed using the DESeq2 package in R, with gene-level validation by qPCR. Proteomic analysis was performed through LC-MS/MS and quantified using Proteome Discoverer 2.5. Protein DE was assessed using the limma package in R.

Results

A total of 174 subjects (131 IBS patients and 43 HV) were included. For transcriptomic analysis, a subset was randomly selected comprising 20 HV (10 male/10 female) and 60 IBS patients (17 M/43 F), stratified into IBS without comorbidities (IBS-A: n=20), IBS with anxiety and/or depression (IBS-Co:N=20), and IBS with both mental and somatic comorbidities (IBS-MCo; N=20). Symptom severity scores for IBS, depression, anxiety, somatic symptoms, fibromyalgia, and fatigue increased progressively along with the number of comorbidities (p<0.001). In colonic mucosa, seven DE genes were identified between HV and IBS-MCo (FDR<0.1), two of which were related to barrier function and immune response. qPCR confirmed increased expression of both genes in IBS (p=0.023 and p=0.083). Proteomic analysis identified 271 DE proteins in IBS-MCo compared with HV. These proteins were enriched in pathways related to DNA/RNA processing and extracellular matrix-receptor interaction, oxidative phosphorylation, and thermogenesis. Additionally, 18, 12, and 3 DE proteins were identified in IBS-A, IBS-Co, and IBS-MCo, respectively. Interestingly, 46 DE proteins were identified in HV compared with IBS, of which 4 were consistently DE across all three IBS subgroups.

Conclusion

Integrated transcriptomic and proteomic analysis of colonic mucosa reveals distinct molecular alterations in IBS patients, depending on comorbidity burden. Several potential diagnostic biomarkers emerged from this analysis. Further validation studies are required to confirm these findings.

References

EU-FUNDED PROJECT Nº: 848228

Event

UEG Week Barcelona 2026

Topics

Mechanisms & Personalised Medicine Immunology Digestive Oncology Colorectal

Submission format

Abstract

Session

The gut talks back

Citation

2026: United European Gastroenterology Journal 2026; 14 (S1)

Published

2026

More Like This:

ABBV-466, A NOVEL DUAL-TARGETING THERAPY, LEADS TO ENDOSCOPIC REMISSION IN MODERATE-TO-SEVERE CROHN’S DISEASE: PRIMARY RESULTS AND MOLECULAR PROFILING FROM THE PHASE 2A TARGET-CD STUDY

David T. Rubin

PREVALENCE OF GERD IN PATIENTS WITH EOSINOPHILIC ESOPHAGITIS AND ITS IMPACT ON TREATMENT OUTCOMES: INSIGHTS FROM A SWEDISH TERTIARY CENTRE COHORT

Aldona Dlugosz

OVERDIAGNOSIS OF SUPERIOR MESENTERIC ARTERY SYNDROME: LIMITED DIAGNOSTIC CONCORDANCE BETWEEN IMAGING MODALITIES AND LIMITED BENEFIT OF SURGERY

Tim Vanuytsel

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Carmen Alonso-Cotoner

TRANSCRIPTOMIC AND PROTEOMIC PROFILING OF COLONIC MUCOSA IN PATIENTS WITH IRRITABLE BOWEL SYNDROME WITH OR WITHOUT MENTAL/SOMATIC COMORBIDITIES: RESULTS FROM THE EUROPEAN MULTICENTER DISCOVERIE STUDY

Carmen Alonso-Cotoner

MAST CELLS AS KEY PLAYERS OF VISCERAL HYPERSENSITIVITY TRIGGERED BY MICROBIAL HISTAMINE

Giada De Palma

UEG Presentation

New

Share via Email Share on Facebook Share on X Share on LinkedIn Share on Bluesky

MAST CELLS AS KEY PLAYERS OF VISCERAL HYPERSENSITIVITY TRIGGERED BY MICROBIAL HISTAMINE

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MAST CELLS AS KEY PLAYERS OF VISCERAL HYPERSENSITIVITY TRIGGERED BY MICROBIAL HISTAMINE

Anushka Patel 1, Cynthia Lopez-Lopez 2, Josue Jaramillo Polanco 2, Yun Shi 2, Julien Pujo 1, Camila E. Perete de Freitas 1, Andy Jiang 1, Jun Lu 1, Graham Dinniwell 1, Stephen Collins 1, Stephen Vanner 2, Premysl Bercik 1, David E. Reed 2, Giada De Palma 1

Affiliations

1 McMaster University/Farncombe Institute, Hamilton, Canada

2 Queen's University/GIDRU, Kingston, Canada

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Abstract

Introduction

Irritable bowel syndrome (IBS) is a disorder of gut-brain interaction characterized by abdominal pain and altered motility. Although visceral hypersensitivity is a core feature of IBS, its pathophysiology is not fully understood but both mast cells and altered gut microbiota have been implicated. Clinical studies in IBS patients showed that colonic mast cells co-localize with nerve endings, and that histamine and tryptase are involved in pain regulation. We demonstrated in a mouse model of IBS that bacterial histamine drives visceral hypersensitivity through mast cell hyperplasia via histamine receptor 4 pathways. However, it is unclear whether microbial histamine acts only through the mast cells or can also act directly on sensory afferents.

Aims & Methods

The aim of this study is to investigate whether mast cells are required in induction of visceral hypersensitivity in mice colonized with high histamine (HH) producing microbiota from IBS patients.
Methods:We used 1) germ free (GF) NIH Swiss mice colonized with stool samples of IBS patients with high (IBS-HH) or low histamine (IBS-LH) producing microbiota treated or not (vehicle) with the mast cell stabilizer cromolyn (100mg/kg ip once daily for one week, starting 3 weeks after colonization), and 2) mast cell deficient (Cpa3-Cre;Mcl-1fl/fl; C57BL6 background) or WT (C57BL6) mice treated with antibiotics and colonized with stool samples of IBS-HH patients. Visceral motor responses (VMRs) to colorectal distension (CRD) were evaluated in all mice 4 weeks after colonization. Mice were euthanized thereafter, and serum, cecum content, and intestinal tissues were collected for further analyses. Absence of mast cells in Cpa3-Cre;Mcl-1fl/fl homozygous mice was verified through tryptase staining. Neuronal excitability of dorsal root ganglia (DRG) neurons from naïve mice exposed to colonic supernatants were measured.

Results

The mast cell stabilizer cromolyn decreased visceral hypersensitivity in mice colonized with IBS-HH microbiota but not in mice with IBS-LH microbiota (P=0.037; IBS-HH vehicle vs IBS-HH cromolyn). These results were mirrored by decrease of serum mast cell protease 1 in IBS-HH mice after cromolyn treatment (P=0.001; IBS-HH vehicle vs IBS-HH cromolyn). Neuronal excitability was decreased after incubating DRG neurons with colonic supernatants of IBS-HH mice treated with cromolyn (P=0.02 vs IBS-HH vehicle). Mast cell deficient mice, particularly females, colonized with IBS-HH microbiota displayed a reduction in visceral hypersensitivity compared to WT IBS-HH mice (P=0.05).

Conclusion

Our data suggest mast cells are key players in visceral hypersensitivity but only in mice colonized with IBS microbiota with high histamine production. Thus, mast cells directed treatment might be effective mainly in a subset of patients with evidence of high bacterial histamine production.

Disclosure

Nothing to disclose.

Event

UEG Week Barcelona 2026

Topics

Mechanisms & Personalised Medicine Immunology Digestive Oncology Colorectal

Submission format

Abstract

Session

The gut talks back

Citation

2026: United European Gastroenterology Journal 2026; 14 (S1)

Published

2026

More Like This:

ABBV-466, A NOVEL DUAL-TARGETING THERAPY, LEADS TO ENDOSCOPIC REMISSION IN MODERATE-TO-SEVERE CROHN’S DISEASE: PRIMARY RESULTS AND MOLECULAR PROFILING FROM THE PHASE 2A TARGET-CD STUDY

David T. Rubin

PREVALENCE OF GERD IN PATIENTS WITH EOSINOPHILIC ESOPHAGITIS AND ITS IMPACT ON TREATMENT OUTCOMES: INSIGHTS FROM A SWEDISH TERTIARY CENTRE COHORT

Aldona Dlugosz

OVERDIAGNOSIS OF SUPERIOR MESENTERIC ARTERY SYNDROME: LIMITED DIAGNOSTIC CONCORDANCE BETWEEN IMAGING MODALITIES AND LIMITED BENEFIT OF SURGERY

Tim Vanuytsel

COLONIC MAST CELL ACTIVATION IS LINKED TO MENTAL AND SOMATIC SYMPTOM SEVERITY IN IRRITABLE BOWEL SYNDROME: RESULTS FROM THE DISCOVERIE PROJECT (EU-FUNDED PROJECT Nº: 848228)

Carmen Alonso-Cotoner

TRANSCRIPTOMIC AND PROTEOMIC PROFILING OF COLONIC MUCOSA IN PATIENTS WITH IRRITABLE BOWEL SYNDROME WITH OR WITHOUT MENTAL/SOMATIC COMORBIDITIES: RESULTS FROM THE EUROPEAN MULTICENTER DISCOVERIE STUDY

Carmen Alonso-Cotoner

MAST CELLS AS KEY PLAYERS OF VISCERAL HYPERSENSITIVITY TRIGGERED BY MICROBIAL HISTAMINE

Giada De Palma