ABSTRACT
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.
Subject(s)
Antirheumatic Agents/therapeutic use , Arthritis, Psoriatic/drug therapy , Biological Products/therapeutic use , Interleukin-17/antagonists & inhibitors , Abatacept/therapeutic use , Adult , Antibodies, Monoclonal, Humanized/therapeutic use , Antirheumatic Agents/adverse effects , Biological Products/adverse effects , Clinical Decision-Making , Humans , Immune Checkpoint Inhibitors/therapeutic use , Network Meta-Analysis , Placebos/administration & dosage , Safety , Severity of Illness Index , Treatment OutcomeABSTRACT
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.
Subject(s)
Chemistry, Pharmaceutical/methods , Proto-Oncogene Proteins c-bcl-2/chemistry , Tetrahydroisoquinolines/chemistry , Apoptosis , Binding Sites , Crystallography, X-Ray/methods , Drug Design , Humans , Ligands , Magnetic Resonance Spectroscopy , Molecular Conformation , Molecular Structure , Protein Binding , Protein Interaction Mapping , Structure-Activity RelationshipABSTRACT
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.
