“Several in vitro studies have suggested a pathogenic role of ACPAs in RA,” according to Prof. Kira Astakhova (Technical University of Denmark, Denmark) who presented the late-breaking abstract. The authors hypothesised that reducing ACPA levels would have a therapeutic effect by blocking cytokine production. Thus, a series of therapeutic nanoparticles for specific targeting of ACPA in synovial fluid was prepared and tested.
Nanoparticles were prepared by the microdroplet method and then decorated with synthetic cyclic citrullinated peptide aptamer PEP2, PEG/hexanoic acid, and fluorophore (Cy5.5). Nanoparticles were used in a series of in vitro assays and in vivo studies including disease activity scores, cytokine measurements, and near-infrared imaging. A fibrinogen-derived 21-amino-acid-long citrullinated peptide with high selectivity toward autoantibodies in RA samples was then identified. Subsequently, this aptamer was incorporated in the chitosan-hyaluronic acid nanoparticle formulation. A fluorescence-activated cell sorting study showed selective uptake of Cy5.5 labelled aptamer-nanoparticle conjugates by neutrophils in the concentration range 0.5-4 nM. No apparent immunogenicity for this nanoparticle formulation was demonstrated, which was in line with results from other trials. A reduction of disease activity of over 50% was achieved in vivo in 3 weeks treatment using as little as 1 nM drug candidate (dosed every 48 hours) in the collagen-induced mouse model of RA (n=30). The same was seen in the serum transfer model (n=10). The aptamer-nanoparticle conjugate significantly reduced interleukin(IL)-6 and tumour necrosis factor (TNF)α levels in the mouse sera. The effects were non-inferior to controls treated with tocilizumab (n=30). The mode of action was then confirmed by applying Cy5.5-labelled aptamer-nanoparticles in the collagen-induced mouse model (n=10). An over 6-fold higher signal accumulation in inflamed versus healthy joints was confirmed; this strongly supports the highly specific nature of the aptamer to the inflammatory process [2]. Given that human RA is characterised by ACPA antibodies preceding disease with distinct kinetics to the animal models reported, it will be interesting to see if these novel strategies will translate in the clinical arena.
- Khatri S, et al. Abstract LB0002. EULAR E-Congress, 3-6 June 2020.
- Khatri S, et al. Bioconjug Chem. 2019 Oct 16;30(10):2584-2593.
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Table of Contents: EULAR 2020
Featured articles
COVID-19 and inflammatory rheumatic disease: some key issues
Secukinumab monotherapy as efficient as adalimumab
AxSpA real-life remission rates higher on biologics
Olokizumab significantly improves RA features and patient-reported outcomes
Rheumatoid Arthritis
New nanoparticle promising future agent in RA
Olokizumab significantly improves RA features and patient-reported outcomes
Low DAS at 4 months predicts sustained DMARD-free remission
Ankylosing Spondylitis
Reduced maintenance dose of certolizumab pegol can be used in axSpA
Worse response axSpA patients to second TNFi versus first TNFi
AxSpA real-life remission rates higher on biologics
Certolizumab pegol reduces acute anterior uveitis in axial spondyloarthritis
TNF-α inhibitors improve bone mineral density in AS patients
Psoriatic Arthritis
Ixekizumab shows sustained improvements in pain and fatigue at 3 years
Adalimumab added to methotrexate yields better results in PsA than methotrexate escalatio
Upadacitinib provides fast onset of improvement in psoriatic arthritis
Secukinumab monotherapy as efficient as adalimumab
Osteoporosis and Osteoarthritis
Higher mortality risk with tramadol versus NSAIDs for osteoarthritis patients
Hydroxychloroquine not effective in patients with hand osteoarthritis
Positive effect denosumab on fall risk
Systemic Sclerosis and Systemic Lupus Erythematosus
Anifrolumab achieves rapid and durable BICLA-response
Subclinical myocardial involvement progresses in SSc patients
Composite endpoint CRESS for primary Sjögren’s syndrome
COVID-19
COVID-19 and inflammatory rheumatic disease: some key issues
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