Folate‐targeted nanoparticles show efficacy in the treatment of inflammatory arthritis

Objective To investigate the uptake of a poly(amidoamine) dendrimer (generation 5 [G5]) nanoparticle covalently conjugated to polyvalent folic acid (FA) as the targeting ligand into macrophages, and to investigate the activity of an FA‐ and methotrexate (MTX)–conjugated dendrimer (G5‐FA‐MTX) as a therapeutic for the inflammatory disease of arthritis. Methods In vitro studies were performed in macrophage cell lines and in isolated mouse macrophages to check the cellular uptake of fluorescence‐tagged G5‐FA nanoparticles, using flow cytometry and confocal microscopy. In vivo studies were conducted in a rat model of collagen‐induced arthritis to evaluate the therapeutic potential of G5‐FA‐MTX. Results Folate‐targeted dendrimer bound and internalized in a receptor‐specific manner into both folate receptor β–expressing macrophage cell lines and primary mouse macrophages. The conjugate G5‐FA‐MTX acted as a potent antiinflammatory agent and reduced arthritis‐induced parameters of inflammation such as ankle swelling, paw volume, cartilage damage, bone resorption, and body weight decrease. Conclusion The use of folate‐targeted nanoparticles to specifically target MTX into macrophages may provide an effective clinical approach for antiinflammatory therapy in rheumatoid arthritis.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/86938/1/30459_ftp.pd

Genetic data: The new challenge of personalized medicine, insights for rheumatoid arthritis patients

Rapid advances in genotyping technology, analytical methods, and the establishment of large cohorts for population genetic studies have resulted in a large new body of information about the genetic basis of human rheumatoid arthritis (RA). Improved understanding of the root pathogenesis of the disease holds the promise of improved diagnostic and prognostic tools based upon this information. In this review, we summarize the nature of new genetic findings in human RA, including susceptibility loci and gene-gene and gene-environment interactions, as well as genetic loci associated with sub-groups of patients and those associated with response to therapy. Possible uses of these data are discussed, such as prediction of disease risk as well as personalized therapy and prediction of therapeutic response and risk of adverse events. While these applications are largely not refined to the point of clinical utility in RA, it seems likely that multi-parameter datasets including genetic, clinical, and biomarker data will be employed in the future care of RA patients

Genetic Polymorphisms Modifying Oxidative Stress Are Associated with Disease Activity in Rheumatoid Arthritis Patients

Reactive oxygen and nitrogen species are involved in the pathology of rheumatoid arthritis (RA). Polymorphisms in genes coding for superoxide dismutases (SOD2 and SOD3), catalase (CAT), tumor necrosis factor-alpha (TNFA) and inducible NO synthase (NOS2A) may influence RA activity. We determined SOD2 Ala-9Val, SOD3 Arg213Gly, CAT C-262T, TNFA G-308A, TNFA C-857T and NOS2A (CCTTT)n polymorphisms in 327 RA patients. Carriers of CAT -262T and TNFA -308A allele had lower mean disease activity score of 28 joint count (DAS28) values than patients with CAT -262CC and TNFA -308GG genotypes (p = 0.014 and p = 0.046, respectively). Patients with the combination of CAT -262T and TNFA -308A allele had lower mean DAS28 values and a higher probability for low disease activity than non-carriers (p = 0.003, OR = 3.585, 95% CI = 1.538–8.357). Our results suggest that CAT and TNFA polymorphisms alone and in combination influence the activity of RA

Association between SLC19A1 gene polymorphism and high dose methotrexate toxicity in childhood acute lymphoblastic leukaemia and non Hodgkin malignant lymphoma: introducing a haplotype based approach

We investigated the clinical relevance of SLC 19A1 genetic variability for high dose methotrexate (HD-MTX) related toxicities in children and adolescents with acute lymphoblastic leukaemia (ALL) and non Hodgkin malignant lymphoma (NHML)