21 News and views: Exciting new approaches in therapy, double-hit therapies, JAK inhibitors
Notice bibliographique
Résumé
What have we learned from all randomized controlled trials with new agents added on to standard of care for the treatment of patients with systemic lupus erythematosus (SLE)? While positive studies have revealed clinical response rates of 40–60% a substantial proportion (40–60%) of patients still do not achieve an adequate response when these agents are introduced as a late addition to their treatment regimen. This persistent unmet need has spurred a critical shift towards the concept of combined, multitarget therapy at induction. This strategy aims to address the inherent heterogeneity of SLE pathogenesis by simultaneously modulating multiple dysregulated pathways from the outset.While multitarget approaches are sometimes achieved with a single therapeutic agent, they more commonly involve the strategic combination of two or more agents. Emerging ‘double-hit’ single therapies include telitacicept (an anti-BAFF and anti-APRIL agent), ianalumab (which both enhances antibody-dependent cellular cytotoxicity-mediated B-cell depletion and blocks BAFF:BAFF-R signaling), and a novel BCMA-CD19 CAR-T cell therapy that targets both BCMA and CD19.1–3 Newer single hit therapies, which could be used in conjunction with standard of care, are the JAK inhibitors. These agents include upadacitinib a classic JAK 1 inhibitor, deucravacitinib a TYK2 inhibitor and baricitinib a JAK1/2 inhibitor.4–6 These small molecule drugs have the advantage of being oral agents. Both these approaches offer multitarget approaches more appropriate for the heterogenous pathogenic mechanisms’ characteristic of SLE.Learning Objectives At the end of this presentation participants will be able to:Explain the limitations of traditional add-on therapeutic strategies in SLE, specifically recognizing the suboptimal response rates (40–60%) observed in randomized controlled trials, when newer agents are added to failed standard of careExplain the evolving paradigm in SLE treatment, emphasizing the rationale for earlier, multitargeted therapeutic approaches, whether through single ‘double-hit’ agents or combination regimensIdentify and describe specific examples of emerging ‘double-hit’ single therapies for SLE, including telitacicept, ianalumab, and BCMA-CD19 CAR-T cell therapyDiscuss the role of newer oral small molecule kinase inhibitors, such as upadacitinib and deucravacitinib, as potential additions to standard of care in SLE, considering their mechanisms and current developmental statusReferences Agmon-Levin N, Ignatenko S, Gordienko A, et al. OP0089 phase 2 safety and efficacy of subcutaneous (s.C.) dose ianalumab (vay736; anti-baffr mab) administered every 4 weeks up to 48 weeks in patients with systemic lupus erythematosus (sle). Ann Rheum Dis. 2024;83(Suppl 1):140. doi: 10.1136/annrheumdis-2024-eular.634Jin HZ, Li YJ, Wang X, et al. Efficacy and safety of telitacicept in patients with systemic lupus erythematosus: A multicentre, retrospective, real-world study. Lupus Sci Med. 2023;10(2). doi: 10.1136/lupus-2023-001074Wang W, He S, Zhang W, et al. BCMA-CD19 compound CAR T cells for systemic lupus erythematosus: a phase 1 open-label clinical trial. Ann Rheum Dis. 2024. doi: 10.1136/ard-2024-225785Merrill JT, Tanaka Y, D’Cruz D, et al. Efficacy and safety of upadacitinib or elsubrutinib alone or in combination for patients with systemic lupus erythematosus: a phase 2 randomized controlled trial. Arthritis Rheumatol. 2024;76(10):1518–29. doi: 10.1002/art.42926Morand E, Pike M, Merrill JT, et al. Deucravacitinib, a tyrosine kinase 2 inhibitor, in systemic lupus erythematosus: a phase II, randomized, double-blind, placebo-controlled trial. Arthritis Rheumatol. 2023;75(2):242–52. doi: 10.1002/art.42391Shah HH, Ashfaque F, Hadi Z, et al. Baricitinib in the treatment of systemic lupus erythematosus: a systematic review of randomized controlled trials. Ann Med Surg (Lond). 2024;86(8):4738–44. doi: 10.1097/ms9.0000000000002298
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 | 0,005 | 0,014 |
| Méta-épidémiologie (sens strict) | 0,001 | 0,001 |
| Méta-épidémiologie (sens large) | 0,001 | 0,002 |
| Bibliométrie | 0,001 | 0,001 |
| Études des sciences et des technologies | 0,001 | 0,003 |
| Communication savante | 0,008 | 0,006 |
| Science ouverte | 0,002 | 0,002 |
| Intégrité de la recherche | 0,011 | 0,015 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,040 | 0,019 |
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 ».