Introduction

Coeliac disease (CD) is an immune-mediated disorder of the small intestine triggered by dietary gluten. The diagnosis is based on serological testing and histological examination. Selective immunoglobulin (Ig) A deficiency is a more common condition amongst CD patients than in the general population, complicating the use of IgA antibodies to diagnose CD. Current guidelines suggest testing for the level of total immunoglobulin A (IgA) and the level of specific anti-transglutaminase 2 (TG2) IgA in the search for CD. Only when severe IgA deficiency is found, immunoglobulin G (IgG) based testing is recommended. In a pilot study for validating a dual TG2 IgA/IgG screening assay, we found CD patients primarily responding with TG2 IgG antibodies and not TG2 IgA, despite IgA sufficiency (1). Thus, these patients risk never being diagnosed.

Aims & Methods

The aim of this study was to assess the additional benefit of testing for TG2 IgG alongside TG2 IgA in screening for CD in adults. The study was based on the fourth Trøndelag Health Study (HUNT4), a population-based study of 56,000 adult (>20 years of age) Norwegians (2). Serum samples were analysed using a combined TG2 IgA and IgG assay and the seropositives were invited to endoscopy with duodenal biopsies for histological confirmation (Marsh grade 3). The prevalence of primary TG2 IgG responders and the positive predictive value (PPV) of TG2 IgG among TG2 IgA negative participants were calculated.

Results

Serum from 54,505 participants were analysed and 1107 were seropositive. The present study included 593 participants with histological examination and CD was confirmed in 403 participants. Primary TG2 IgG response was found in 75 participants, of whom four got CD confirmed. None of these four participants had total IgA deficiency. The PPV of TG2 IgG for CD among TG2 IgA negative participants was 5.3% (95% confidence interval 3.5-7.1). In comparison, the PPV of TG2 IgA was 77.0% (73.6-80.4).

Conclusion

This population-based screening for CD among adults found a small group of individuals with CD that risk not being diagnosed using the current diagnostic guidelines, due to primary TG2 IgG response in the absence of IgA deficiency. However, TG2 IgG is still too unspecific to be used in the screening of CD in the general population.

References

1. Klaasen RA, Warren DJ, Iversen R, Bolstad N, Andersen IL, Mjones P, et al. The development and validation of a high-capacity serological assay for celiac disease. Clin Biochem. 2022;107:13-8.
2. Lukina P, Andersen IL, Eggen PT, Mjones PG, Ronne E, Bolstad N, et al. Coeliac disease in the Trondelag Health Study (HUNT), Norway, a population-based cohort of coeliac disease patients. BMJ Open. 2024;14(1):e077131.

Introduction

Histological assessment in Inflammatory Bowel Disease (IBD) is often required with endoscopic diagnoses to establish disease activity. This is evident in patients where histological healing is a major therapeutic goal and when endoscopic healing can also exhibit microscopic disease. IBD can manifest in numerous landmark features which are structural and inflammatory related. Histological activity is determined through erosion/ulceration, architectural changes in tissue morphology, mucin depletion and presence of varied inflammatory cells the colonic crypts, Muscularis Mucosae (MM) and Lamina Propria (LP). Histological scoring systems vary in complexity and methodology and subject to discrepancies in inter-rater consensus. Our model aims to provide accurate measurements of key histological features in Ulcerative Colitis (UC) used in scoring systems as both a decision support tool for improving pathologist scoring alignment and sensitive quantitative metrics of inflammatory cells to evaluate disease activity.

Aims & Methods

We developed an ensemble of convolutional neural networks to identify cell types, tissue foreground, crypts, MM, and haemorrhage in H&E images of IBD biopsy data. Models were trained with expert-labelled annotations comprising 34,289 image-annotation pairs (80% training, 20% validation) from in-house and publicly available data. Model accuracy was assessed with 6,464 held-out image-annotation pairs from 26 Whole Slide Images (WSIs) from all sites of the large intestine commonly sampled during endoscopic investigation, while ground truth annotations were reviewed by GI-trained pathologists to certify accuracy. We used geospatial methods to derive boundaries of the LP from other predicted domains, associate cells to delineated regions, measure architectural changes and derive spatially differentiated metrics of inflammatory burden in 66 patients with confirmed UC.

Results

The AI model spatially differentiates and segments cell types and tissue compartments. This produces metrics for inflammatory cell counts in regions of interest such as crypts, LP, and MM. Goblet cell segmentation within crypts allows for measurement of mucin depletion. This can be visualized for pathologists where each inflammatory cell type across the WSI is represented as density metrics. Automated quantification of inflammatory cells across AI-identified tissue domains throughout the bowels of UC patients revealed large intra- and inter-patient variability.

Conclusion

Our AI model can measure histological healing by detecting architectural change, inflammatory cell number, goblet cell reduction and erosions and ulceration. This allows for metrics and visual overlays to assist with pathologist reading and quantifying changes in mucosal biopsies in a clinical trial setting which requires extremely sensitive tools only AI can provide.

Disclosure

DW/AM/RL/PA/PW and CL are employees at Perspectum Ltd. EF and RG are consultants for Perspectum Ltd. All other co-authors have no conflicts of interest to declare relevant to this work.

Introduction

Targeted therapies have revolutionized the management of immune-mediated inflammatory diseases (IMIDs), however, there is a substantial number of patients who respond poorly to a given drug. There is a big need to understand the factors that are associated with this heterogeneity.

Aims & Methods

The DoCTIS project (1) aims to characterize molecular variation both at the disease and drug response levels across six different IMIDs. We applied single cell RNA sequencing to 360 peripheral blood mononuclear cell (PBMC) samples from 176 patients from six prevalent IMIDs –psoriasis (PS), psoriatic arthritis (PsA), Crohn’s Disease (CD), ulcerative colitis (UC), rheumatoid arthritis (RA), and systemic lupus erythematosus (SLE)- treated with five different drugs targeting TNF, IL12p40, IL6R, BLySS, IL17 and JAK pathways. All patients were analyzed at two time points including baseline and at the week of clinical response creating an immune landscape of more than two million peripheral immune cells.

Results

We found large inter-disease differences both at the compositional and genetic regulatory programs. ScRNA-Seq analysis revealed large differences at the systemic level between the six IMIDs. Compositional analyses demonstrated that the circulating immune cell profiles of UC and CD were more similar to each other than to the rest of IMIDs, and also identified differences in pDC, MAIT, NK CD16- and T CD4+ Memory subsets between both diseases. At the transcriptional level, we found the expected upregulated interferon response signature affecting multiple cell types in SLE, but also novel findings like strong regulatory differences in B and CD14+ monocyte compartments between UC and CD, two diseases with a highly shared genetic risk. The impact of each drug was found to be largely disease-specific. Furthermore, we found multiple regulatory features associated with the effect of each drug as well the association to response.

Conclusion

The scRNA-Seq atlas developed in DoCTIS provides a unique resource for the understanding of drug response and disease heterogeneity across immune-mediated inflammatory diseases.

References

1. Decision on Optimal Combinatorial Therapies in IMIDS using Systems Approaches (DoCTIS). https://doctis.eu/

Disclosure

Antonio Julià: None declared, Yolanda Guillén: None declared, Paloma Vela Casasempere: None declared, Antonio Fernández Nebro: None declared, Carlos Marras: None declared, Santos Castañeda Bristol-Myers Squibb, Eli Lilly, Bristol-Myers Squibb, Jaime Calvo Alén: None declared, Jesús Tornero Molina: None declared, Juan de Dios Cañete Crespillo: None declared, Eugeni Domènech: None declared, Javier Gisbert: None declared, Jose M Carrascosa: None declared, Eduardo Fonseca: None declared, Luis Bujanda Fernández de Pierola: None declared, Valle García Sánchez: None declared, Britta Siegmund: AbbVie, AlfaSigma, BMS, CED Service GmbH, Dr. Falk Pharma, Eli Lilly, MSD, Ferring, Galapagos, Janssen, Pfizer, and Takeda, Abivax, Boehringer Ingelheim, Endpoint Health, Gilead, Janssen, Landos, Materia Prima, PredictImmune, Giampiero Girolomoni: AbbVie, Almirall, Amgen, Boehringer-Ingelheim, Bristol-Myers Squibb, Eli-Lilly, Leo Pharma, Merck Serono, Novartis, Pfizer, Pierre Fabre, Samsung bioepis and Sanofi, Almirall, Amgen, Bristol-Myers Squibb, Eli-Lilly, Leo Pharma, Merck Serono, Novartis, Pfizer, Samsung bioepis and Sanofi, Pfizer, Holger Heyn: Mirxes, Moderna, Nanostring, Omniscope, Singularity, Laura Jimenez: None declared, Pere Santamaría: None declared, Edgar Angelats: None declared, Rick Myers: None declared, Sergio H. Martínez-Mateu: None declared, Juan Angel Patiño Galindo: None declared, Ernest Choy: AbbVie, Amgen, Biocon, Biogen, Chugai, Eli Lilly, Fresenus Kabi, Gilead, Janssen, Novartis, Pfizer, Regeneron, Roche, RPharm, and Sanofi, Bio-Cancer, Biogen, Novartis, PFizer, and Sanofi, AbbVie, Amgen, Bristol-Myers Squibb, Chugai, Eli Lilly, Fresenus Kabi, Galapagos, Gilead, Novartis, Pfizer, Regeneron, Roche, RPharm, Sanofi, and UCB Pharma, Sara Marsal: None declared

Introduction

MORF-057 is an oral α₄β₇ integrin inhibitor that prevents immune cell entry into the gut to alleviate inflammation.

Aims & Methods

EMERALD-2 is a phase 2b, randomized, double-blind, placebo-controlled study evaluating MORF-057 efficacy and safety in adults with moderately to severely active ulcerative colitis (UC). Participants with Modified Mayo Score (MMS) 5–9, inadequate/loss of response or intolerance to conventional or advanced therapy (AT), and who were integrin inhibitor-naïve received 1 of 3 MORF-057 doses or placebo (1:1:1:1). The primary efficacy endpoint was clinical remission at Week 12; secondary and exploratory efficacy endpoints were rates of clinical response and endoscopic improvement, respectively. Pharmacokinetic and pharmacodynamic endpoints and safety were evaluated. The study is registered with ClinicalTrials.gov (NCT05611671).

Results

The study enrolled 280 participants (mean [SD] age, 40.2 [14.6] years; 55.4% male; mean [SD] time since UC diagnosis, 6.7 [7.2] years). At baseline, mean (SD) MMS was 6.7 (1.0); 39.3% of participants were on a stable corticosteroid dose, 20.4% were on an immunomodulator, and 31.1% were AT-experienced.
Clinical remission rate with MORF-057 at Week 12 was dose dependent, ranging from 17.1% (100 mg QD) to 31.9% (200 mg BID) vs. 24.3% with placebo (Table 1), with the same trend in the AT-experienced subgroup (N=87; 100 mg QD, 4.3%; 100 mg BID, 13.6%; 200 mg BID, 21.1%; placebo, 13.0%). Compared with placebo, 200 mg BID MORF-057 had numerically higher clinical response and endoscopic and histo-endoscopic mucosal improvement (HEMI) rates, with the latter 2 endpoints showing an increasing trend with higher doses.

Table 1. Efficacy endpoints in EMERALD-2 at Week 12

Rate (proportion of patients, %)	MORF-057			Placebo (n=70)
	100 mg QD (n=70)	100 mg BID (n=71)	200 mg BID (n=69)
Clinical Remissiona	17.1	23.9	31.9	24.3
Clinical Responseb	57.1	53.5	62.3	54.3
Endoscopic Improvementc	31.4	32.4	43.5	31.4
Histo-Endoscopic Mucosal Improvementd	27.1	31.0	42.0	25.7

^aBased on MMS (stool frequency=0/1, RB=0, MES=0/1 [excluding friability]). Non-significant vs. placebo.
^b≥2-point reduction in MMS and ≥30% change from baseline, and ≥1-point reduction in RB score from baseline or RB=0/1.
^cMES≤1.
^dMES=0/1 (excluding friability) and neutrophil infiltration in <5% of crypts; no crypt destruction; and no erosions, ulcerations, or granulation tissue (Geboes scoring).
MES, Mayo Endoscopic Subscore; MMS, Modified Mayo Score; RB, rectal bleeding.

There was a dose-dependent increasing trend in α4β7 receptor occupancy. Treatment-emergent adverse events (TEAEs) in the MORF-057 groups were mostly of mild (42/76, 55.3%) or moderate (25/76, 32.9%) severity; TEAE frequency was similar to the placebo group (36.0% [pooled rate for 3 dose regimens] vs. 34.8%). Among all participants, there were 5 serious AEs not considered treatment-related (UC exacerbation [n=2], AST increase, pneumothorax, vertebral disc herniation). There were no cases of progressive multifocal leukoencephalopathy or meaningfully increased absolute lymphocyte count and no deaths.

Conclusion

Dose-dependent responses to MORF-057 were observed for clinical remission and hard-to-achieve endpoints such as HEMI at Week 12. The clinical remission rate with MORF-057 was numerically higher but did not achieve statistical significance vs. placebo, which showed higher-than-expected responses. MORF-057 had a favorable safety profile with no meaningful safety findings. The study is ongoing to evaluate maintenance safety and efficacy, with further clinical development of MORF-057 planned.

Disclosure

BES: Honoraria for consulting--AbbVie, Adiso Therapeutics, Agomab, Alimentiv, Amgen, AnaptysBio, Arena Pharmaceuticals, Artugen Therapeutics, Astra Zeneca, Biolojic Design, Biora Therapeutics, Boehringer Ingelheim, Boston Pharmaceuticals, Calibr, Celgene, Celltrion, ClostraBio, Equillium, Enthera, Enveda Biosciences, Evommune, Ferring, Fresenius Kabi, Fzata, Galapagos, Genentech (Roche), Gilead Sciences, GlaxoSmithKline, Gossamer Bio, Imhotex, Index Pharmaceuticals, Innovation Pharmaceuticals, Inotrem, Kaleido, Kallyope, Merck & Co., Microbiotica, Mitsubishi Tanabe, Mobius Care, Morphic Therapeutics, MRM Health, Nexus Therapeutics, Nimbus Discovery, Odyssey Therapeutics, OSE Immunotherapeutics, Palisade Bio, Progenity, Prometheus Biosciences, Prometheus Laboratories, Protagonist Therapeutics, Q32 Bio, Rasayana Therapeutics, Recludix Therapeutics, Reistone Biopharma, Sanofi, Sorriso Therapeutics, Spyre Therapeutics, Surrozen, Target RWE, Teva, TLL Pharmaceutical, Tr1X, Union Therapeutics, Ventyx Biosciences. Consulting and speaking fees--Abivax. Consulting and speaking fees and other support--Eli Lilly and Company. Research grants, consulting and speaking fees, and other support--Bristol Myers Squibb, Eli Lilly and Company, Janssen, Pfizer, Takeda. Research grants and consulting fees--Janssen. Stock/stock options--Ventyx Biopharma.
BGF: Senior Scientific Director at Alimentiv Inc. Consulting--AbbVie, Abivax, Adiso, AgomAB Therapeutics, Akros, Alira Health, Ally Bridge Group, AnaptysBio, Apini Therapeutics, Argenx, Attovia Tx, Avoro Capital Advisors, Belmore Law, BioFactura, BioJamp, Biora Therapeutics, Blackbird Laboratories, Boehringer-Ingelheim, Boxer Capital, Celsius Therapeutics, Celgene/Bristol Myers Squibb, Celltrion, Clarivate, Connect BioPharma, Disc Medicine, Duality, EcoR1, Eli Lilly and Company, Ensho Therapeutics, Equillium, Evida, Enveda, Faes Farma, First Wave, Forbion, Galapagos, Galen Atlantica, Genentech/Roche, General Atlantic, Genesis Therapeutics, Gilead, Gossamer Pharma, GSK, Imhotex, ImmiDomics, Immunic Therapeutics, Intercept, Janssen, Japan Tobacco Inc., Klick Health, LifeMine Therapeutics, Mage Biologics, Merck, Mestag, Mirador Therapeutics, Mobius Care, Monte Rosa Tx, Morphic Therapeutics, Nexys Therapeutics, Nighthawk Therapeutics, Nimbus Therapeutics, Novartis, OncoC4, OrbiMed, Orphagen, Palisade Bio, Pendopharm, Pfizer, Protagonist,32 Bio, REDX, Roche, Roivant/Televant, Sanofi, Sobi, Sorriso, Spyre Therapeutics, SRT Therapeutics, Sun Pharma, Surrozen Inc., Synedgen, Takeda, Teva, Triastek, Trex Bio, TR1X Inc. TVM Lifesciences, Ventyx Biosciences, Versant Ventures, Vida Ventures, Zagbio. Speaker's Bureau--AbbVie, Janssen, Takeda. Scientific Advisory Board (DSMB)--AbbVie, AnaptysBio, Boehringer-Ingelheim, Celgene/Bristol Myers Squibb, Eli Lilly and Company, Genentech/Roche, Janssen, Merck, MiroBio, Origo BioPharma, Pfizer, REDX Pharma, Sanofi, Takeda, Teva, Ecor1Capital, Morphic, GSK. Stock shareholder--Connect BioPharma, EnGene. Provided expert testimony--Belmore Law.
SS: Received fees--AbbVie, Amgen, Arena, Biogen, Bristol Meyers Squibb, Celgene, Celltrion, Falk, Ferring, Fresenius Kabi, Galapagos, Gilead, IMAB, Janssen, Eli Lilly and Company, MSD, Mylan, Novartis, Pfizer, Protagonist, Provention Bio, Roche, Sandoz/Hexal, Shire, Takeda, Ventyx.
LP-B: Consulting--AbbVie, Abivax, Adacyte, 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, GSK, IAC Image Analysis, Index Pharmaceuticals, Inotrem, Janssen, Lilly, Medac, Mopac, Morphic, MSD, Nordic Pharma, Novartis, Oncodesign Precision Medicine, ONO Pharma, OSE Immunotherapeuthics, Pandion Therapeuthics, Par' Immune, Pfizer, Prometheus, Protagonist, Roche, Samsung, Sandoz, Sanofi, Satisfay, Takeda, Telavant, Theravance, Thermo Fischer, Tigenix, Tillots, Viatris, Vectivbio, Ventyx, Ysopia. Grants--Celltrion, Fresenius Kabi, Medac, MSD, Takeda. Lectures--AbbVie, Alfasigma, Amgen, Arena, Biogen, Celltrion, Ferring, Galapagos, Genentech, Gilead, Janssen, Kern Pharma, Eli Lilly and Company, Medac, MSD, Nordic Pharma, Pfizer, Sandoz, Takeda, Tillots, Viatris. Travel support--AbbVie, Alfasigma, Amgen, Celltrion, Connect Biopharm, Ferring, Galapagos, Genentech, Gilead, Gossamer Bio, Janssen, Eli Lilly and Company, Medac, Morphic, MSD, Pfizer, Sandoz, Takeda, Thermo Fischer, Tillots.
SD: Consultancy fees--AbbVie, Alimentiv, Allergan, Amgen, Applied Molecular Transport, AstraZeneca, Athos Therapeutics, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Celltrion, Dr Falk Pharma, Eli Lilly and Company, Enthera, Ferring Pharmaceuticals Inc., Gilead, Hospira, Inotrem, Janssen, Johnson & Johnson, Morphic, MSD, Mundipharma, Mylan, Pfizer, Roche, Sandoz, Sublimity Therapeutics, Takeda, Teladoc Health, TiGenix, UCB Inc., Vial, Vifor. Lecture fees--AbbVie, Amgen, Ferring Pharmaceuticals Inc., Gilead, Janssen, Mylan, Pfizer, Takeda.
BA, MC, YW, SKL, MM, AW, XZ, NME: Employees and stockholders of Eli Lilly and Company.

Introduction

We conducted a retrospective cohort study to evaluate the risk of serious infections in patients with Ulcerative Colitis (UC) initiating advanced biological or small molecule therapies

Aims & Methods

Using a large U.S. administrative, Optum Labs® database, we identified adult UC patients who initiated treatment with either tumor necrosis factor-α (TNF) antagonists (infliximab, adalimumab, and certolizumab pegol), IL-12/23 antagonists (ustekinumab), IL-23 antagonists (risankizumab), anti-integrin agents (vedolizumab), S1PR modulators (ozanimod), or Janus kinase (JAK) inhibitors (tofacitinib, upadacitinib) between 2016-2023. Eligible patients had at least one year of continuous insurance enrollment before and after treatment initiation. The primary outcome was the incidence and risk of serious infections requiring hospitalization. We used stabilized inverse probability of treatment weighting (IPW) based on multinomial propensity scores to balance baseline patient and disease characteristics. Comparative risk of serious infections was assessed through Cox proportional hazards models incorporating stabilized weights.

Results

A total of 9,430 UC patients were included (mean age: 47.5 ± 17.7 years; 49.2% female; 50% on concomitant corticosteroids), followed for a mean duration of 2.3 ± 0.8 years. The incidence rates (IR) per 100 person-years of serious infections were: TNF antagonists (n = 4,111; IR: 6.08 [5.47; 6.70]), vedolizumab (n = 3,165; IR: 5.03 [0.44; 5.65]), IL-12/23 or IL-23 antagonists (n = 1,342; IR: 4.25 [3.34; 5.21]), S1PR modulators (n = 111; IR: 5.17 [1.03; 10.34]) and JAK inhibitors (n = 701; IR: 4.09 [2.79; 5.49]). Risk of serious infections was lower with JAK inhibitors and IL-12/23, or IL-23 antagonists compared to TNF antagonists, and lower with IL-12/23 or IL-23 antagonists compared to vedolizumab. Hazard ratios are represented in the table 1.

Table 1: Risk of serious infections in patients with ulcerative colitis taking advanced biological therapies

Comparator	Therapeutic agent	Hazard ratio (95% CI)
TNF antagonists (reference)	Vedolizumab	0.88 [0.74; 1.04]
TNF antagonists (reference)	JAK inhibitors	0.61 [0.43; 0.88]
TNF antagonists (reference)	IL-12/23 or IL23 antagonists	0.58 [0.41; 0.82]
TNF antagonists (reference)	S1PR modulators	0.60 [0.25; 1.45]
Vedolizumab (reference)	JAK inhibitors	0.70 [0.49; 1.01]
Vedolizumab (reference)	IL-12/23 or IL23 antagonists	0.66 [0.46; 0.94]
Vedolizumab (reference)	S1PR modulators	0.69 [0.28; 1.66]
JAK inhibitors (reference)	IL-12/23 or IL23 antagonists	0.94 [0.58; 1.51]
IL-12/23 or IL23 antagonists (reference)	S1PR modulators	1.05 [0.41; 2.66]

Conclusion

In this large real-world cohort of UC patients, initiation with newly developed efficaeous agents like JAK inhibitors and drugs inhibiting the IL-23 pathway was associated with a lower risk of serious infection compared to TNF antagonists.

Disclosure

CM: Consulting fees from AbbVie, Alimentiv, Amgen, AVIR Pharma Inc, Bristol Myers Squibb, Celltrion, Eli Lilly, Ferring, Forte Biosciences, Fresenius Kabi, Gilead, Janssen, McKesson, Mirador Therapeutics, Mylan, Pendopharm, Pfizer, Prometheus Biosciences Inc., Roche, Sanofi, Takeda, Tillotts Pharma; speaker's fees from AbbVie, Amgen, AVIR Pharma Inc, Alimentiv, Bristol Myers Squibb, Eli Lilly, Ferring, Fresenius Kabi, Janssen, Merck, Organon, Pendopharm, Pfizer, Sanofi, Takeda, Tillotts Pharma; royalties from Springer Publishing; research support from AbbVie, Eli Lilly, Ferring, Pfizer.
VJ: Consulting/advisory board fees from AbbVie, Alimentiv Inc, Arena pharmaceuticals, Asahi Kasei Pharma, Asieris, Astra Zeneca, Bristol Myers Squibb, Celltrion, Eli Lilly, Ferring, Flagship Pioneering, Fresenius Kabi, Galapagos, GlaxoSmithKline, Genentech, Gilead, Janssen, Merck, Mylan, Pandion, Pendopharm, Pfizer, Protagonist, Prometheus, Reistone Biopharma, Roche, Sandoz, Second Genome,Takeda, Teva, Topivert, Ventyx, Vividion; speaker’s fees from, Abbvie, Ferring, Galapagos, Janssen Pfizer Shire, Takeda, Fresenius Kabi
SS: Research grants from Pfizer