P31 Elafibranor impacts inflammatory, fibrotic and symptom-associated markers in patients with primary biliary cholangitis (PBC): proteomic results from the ELATIVE trial
Notice bibliographique
Résumé
PBC is a rare, cholestatic liver disease characterized by inflammation, fibrosis, and destruction of intrahepatic bile ducts. Elafibranor, a peroxisome proliferator-activated receptor (PPAR) agonist exerting effects on PPAR alpha and delta, was efficacious and well-tolerated in patients with PBC in the phase III ELATIVE® trial (NCT04526665). Here, longitudinal protein expression profiles were evaluated in serum samples from patients in ELATIVE®, to provide insights into the immunoregulatory mechanism of elafibranor in PBC. For patients in ELATIVE® who consented, serum samples were collected at baseline, Week 26, and Week 52. Longitudinal protein expression profiles were analyzed using Olink® Proximity Extension Assay technology. Two Olink® panels, Target 96 Immune Response and Explore HT, were used, covering >5,500 proteins. Quality control and data normalization were conducted by Olink®. Linear mixed models were fitted to each protein from baseline to Week 52. Statistically significant changes in protein expression were identified using the Benjamini-Hochberg method with a 5% false discovery rate. Proteins with statistically significant changes in expression were assessed in elafibranor-treated patients with and without biochemical response, according to the primary endpoint of ELATIVE®. Pathway analyses were conducted using QIAGEN® Ingenuity Pathway Analysis (IPA®). Serum samples were analyzed from 121 patients, of whom 87 received elafibranor; 46 with and 41 without biochemical response at Week 52. Expression of control proteins, gamma-glutamyl transferase-1 (GGT1) and 5’-nucleotidase (NT5E), decreased with elafibranor treatment when measured by Olink® and standard methodologies, validating the use of Olink®. A network of >20 proteins involved in hepatic inflammation had statistically significant changes of expression in elafibranor-treated patients with biochemical response at Week 52. IPA® revealed a novel inflammatory signature, including downregulation of intercellular adhesion molecule 1 (ICAM-1), dipeptidyl peptidase 4 (DPP4) and SerpinA3. This network is known to be implicated in immune cell adhesion and inflammatory regulation, and maps to immunomodulation and fibrosis pathways. Similarly, biomarkers associated with itching and fibrosis, such as bone marrow stromal cell antigen 2 (BST2) or solute carrier family 39 member 14 (SLC39A14), were significantly downregulated. This is the first longitudinal proteomic analysis to characterize proteins with modulated expression in patients with PBC treated with elafibranor. These findings provide novel mechanistic insights into the anti-inflammatory effect of elafibranor in PBC, as well as the impact on proteins associated with PBC symptoms, through effects on PPAR alpha and delta.
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Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,002 | 0,001 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,001 | 0,001 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,001 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,001 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,002 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».