RESUMEN
BACKGROUND: Biologic disease-modifying antirheumatic drugs (bDMARDs) and targeted synthetic DMARDs are used in patients with psoriatic arthritis (PsA), but few studies directly compare their clinical efficacy. In such situations, network meta-analysis (NMA) can inform evidence-based decision-making. OBJECTIVE: To evaluate the comparative efficacy and safety of approved bDMARDs in patients with PsA. METHODS: Bayesian NMA was conducted to compare the clinical efficacy of bDMARDs at weeks 12â16 in bDMARD-naïve patients with PsA in terms of American College of Rheumatology (ACR) criteria, Psoriatic Arthritis Response Criteria (PsARC) and Psoriasis Area and Severity Index (PASI). Safety end points were evaluated in the overall mixed population of bDMARD-naive and bDMARD-experienced patients. RESULTS: For ACR, all treatments except abatacept were statistically superior to placebo. Infliximab was most effective, followed by golimumab and etanercept, which were statistically superior to most other treatments. Ixekizumab 80 mg every 2 weeks (Q2W) was statistically superior to abatacept subcutaneous, apremilast and both regimens of ustekinumab; similar findings were observed for ixekizumab 80 mg Q4W. For PsARC response, ixekizumab did not significantly differ from other therapies, except for golimumab, infliximab and etanercept, which were superior to most other agents including ixekizumab. For PASI response, infliximab was numerically most effective, but was not statistically superior to ixekizumab, which was the next best performing agent. Analysis of safety end points identified few differences between treatments. CONCLUSION: Our NMA confirms the efficacy and acceptable safety profile of bDMARDs in patients with active PsA. There were generally few statistically significant differences between most treatments.
Asunto(s)
Antirreumáticos/uso terapéutico , Artritis Psoriásica/tratamiento farmacológico , Productos Biológicos/uso terapéutico , Interleucina-17/antagonistas & inhibidores , Abatacept/uso terapéutico , Adulto , Anticuerpos Monoclonales Humanizados/uso terapéutico , Antirreumáticos/efectos adversos , Productos Biológicos/efectos adversos , Toma de Decisiones Clínicas , Humanos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Metaanálisis en Red , Placebos/administración & dosificación , Seguridad , Índice de Severidad de la Enfermedad , Resultado del TratamientoRESUMEN
The separation of atropisomeric conformers of 1,2,3,4-tetrahydroisoquinoline amide Bcl-2 ligands allowed the identification of the bioactive conformer which was subsequently confirmed by X-ray crystallography.
Asunto(s)
Química Farmacéutica/métodos , Proteínas Proto-Oncogénicas c-bcl-2/química , Tetrahidroisoquinolinas/química , Apoptosis , Sitios de Unión , Cristalografía por Rayos X/métodos , Diseño de Fármacos , Humanos , Ligandos , Espectroscopía de Resonancia Magnética , Conformación Molecular , Estructura Molecular , Unión Proteica , Mapeo de Interacción de Proteínas , Relación Estructura-ActividadRESUMEN
Anti-apoptotic Bcl-2 protects cells from apoptosis by binding to pro-apoptotic members of the Bcl-2 family thereby playing a role in tumour survival in response to chemo- or radiation therapy. We describe a series of phenyl pyrazoles that have high affinity for Bcl-2 and rationalise the observed SAR by means of an X-ray crystal structure.