IMPROVEMENT OF THROMBOSIS-RELEVANT BIOMARKERS WITH DEUCRAVACITINIB TREATMENT IN PATIENTS WITH SYSTEMIC LUPUS ERYTHEMATOSUS: RESULTS FROM THE PHASE 2 PAISLEY TRIAL
Notice bibliographique
Résumé
O051 / #519 Topic: AS04 - Biomarkers ABSTRACT CONCURRENT SESSION 08: RECENT ADVANCES IN LUPUS BIOMARKERS 23-05-2025 1:40 PM - 2:40 PM Background/Purpose Patients with systemic lupus erythematosus (SLE) have a significantly higher risk of venous thromboembolism compared with the general population.[1] Elevated D-dimer levels have been used to predict risk for recurrent deep vein thrombosis and pulmonary embolism,[2] and D-dimer levels are associated with higher thrombosis risk irrespective of antiphospholipid antibodies in patients with SLE.[3] Deucravacitinib, an oral, selective, allosteric tyrosine kinase 2 (TYK2) inhibitor, has a unique mechanism of action and has shown efficacy in the phase 2 PAISLEY study in patients with SLE ( NCT03252587 ). We used baseline D-dimer levels as a surrogate marker of thrombotic risk to investigate the impact of deucravacitinib or placebo on thrombosis-relevant biomarkers in patients with SLE with abnormal D-dimer levels from the PAISLEY study. Methods Samples from 319 patients with SLE were tested for D-dimer and Olink® Explore HT, covering > 5000 proteins. D-dimer levels were quantified by MLM Medical Labs with IMUCLONE D-dimer ELISA kits (BioMedica Diagnostics). Patients were categorized by baseline D-dimer value: normal (< 500 ng/mL, n = 174) or abnormal (≥ 500 ng/mL, n = 145). Fifty-four background-matched samples from normal healthy volunteers (NHVs) were also analyzed. Protein expression was compared in normal vs abnormal D-dimer groups. Changes in D-dimer levels were evaluated using linear mixed-effects modeling; pre- and posttreatment thrombosis-relevant biomarkers were studied in patients with SLE with abnormal baseline D-dimer levels. Results Significantly higher D-dimer levels were observed in patients with SLE compared with NHVs (P < 0.0001; Figure 1A). All 3 doses of deucravacitinib significantly reduced D-dimer levels in patients with SLE with abnormal baseline D-dimer levels (Figure 1B). Meaningful reductions in D-dimer levels were not observed with deucravacitinib in patients with normal baseline D-dimer levels (Figure 1C). In patients with abnormal baseline D-dimer levels, 1590 serum proteins associated with 20 biological pathways were significantly upregulated compared with patients with normal baseline D-dimer levels (adj. P < 0.05; fold change > 1). The top 2 identified pathways enriched in upregulated proteins were cytokine/chemokine signaling and lipid/atherosclerosis pathways. Deucravacitinib led to the normalization of proteins mediating these pathways (eg, TNF, VCAM1, ICAM1; Figure 2A) in the overall population and patients with abnormal baseline D-dimer levels. Further investigation of specific thrombosis-relevant pathways suggested elevation of the corresponding biomarkers (eg, AXL, VWF, MERTK, PDGFRA, PLAUR, GAS6) in patients with SLE with abnormal baseline D-dimer levels, followed by an improvement induced by deucravacitinib in a dose-dependent manner (Figure 2B). Figure 1. D-dimer levels at baseline and change from baseline after treatment with deucravacitinib or placebo in patients with SLE with normal or abnormal D-dimer levels at baseline Figure 2. Baseline biomarker expression relevant to lipid/atherosclerosis and coagulation pathways in patients with SLE with abnormal baseline D-dimer levels and change from baseline after deucravacitinib treatment at week 48 Conclusions Patients with SLE with elevated baseline D-dimer levels had increased serum levels of proteins involved in the mediation of inflammation, atherosclerosis, and thrombosis. Deucravacitinib reduced D-dimer levels and normalized biomarkers relevant to development of thrombosis. Further investigations will be conducted in large populations of patients with SLE from the ongoing phase 3 studies ( NCT05617677 , NCT05620407 ). References: [1.] Menichelli D. Autoimmun Rev 2023;22:103447. [2.] Eichinger S. JAMA 2003;290:1071-4. [3.] Wu H. Clin J Am Soc Nephrol 2008;3:1628-36. Acknowledgments: We thank the patients and families who made this study possible, as well as the clinical teams that participated. We also thank Zhaoqing Wang for data analysis. The study was supported by Bristol Myers Squibb. All authors contributed to and approved the abstract; professional medical writing and editorial assistance was provided by Stephanie V. Koebele, PhD, of Nucleus Global, funded by Bristol Myers Squibb.
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
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 | 0,002 |
| Méta-épidémiologie (sens strict) | 0,001 | 0,000 |
| Méta-épidémiologie (sens large) | 0,002 | 0,002 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,001 | 0,001 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,001 | 0,002 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,003 | 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 ».