THU0075 Impact of obesity on rheumatoid arthritis (RA) onset and progression. in vivo and in vitro effects of synthetic dmards on the ra-associated metabolic alterations
Authors: I. Arias De La Rosa, M. Ruiz-Ponce, A. Escudero, P. Ruiz-Limón, C. Pérez-Sánchez, M.D.C. Ábalos-Aguilera, Y. Jiménez-Gómez, E. Collantes, C. López-Pedrera, N. Barbarroja
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Objectives</h3> 1) To evaluate the impact of obesity in RA onset and progression, 2) To analyse the <i>in vivo</i> effects of synthetic disease-modifying antirheumatic drugs (sDMARDs) on the obesity and IR in an obese collagen-induced arthritis (CIA) mouse model. 3) To study the <i>in vitro</i> effects of sDMARDs on the lipid and glucose homeostasis in adipose tissue (AT). <h3>Methods</h3> CIA was developed in obese and lean mice. 55 C57Bl/6 mice (4–5 weeks) were used. Forty-one mice were fed with high fat diet (60%) until reaching 30 g (obese) (OB). OB-mice were treated with leflunomide (LFN)(10 mg/kg daily), methotrexate (MTX)(3 mg/kg three times/week) or hydroxychloroquine (HCQ)(60 mg/kg daily) for 15 days. After treatment, glucose tolerance test (GTT) was performed. Buffy coat, plasma and adipose tissue (AT) samples were collected. 3 T3-L1 adipocytes were treated with serum from RA patients (10%) alone or in combination with sDMARDs at day 9 of differentiation. Human subcutaneous AT samples were treated <i>ex vivo</i> with serum from RA patients (10%) alone or in combination with sDMARDs. Protein and gene expression of molecules involved in inflammation, insulin signalling and lipid accumulation was analysed through RT-PCR, western blot and ELISA in all the experiments. <h3>Results</h3> CIA-OB mice developed the arthritis earlier and more severe compared with CIA-lean mice. On the hand, arthritis increased the systemic levels of inflammation and HOMA-IR of OB-mice. The induction of arthritis in OB mice increased the inflammatory burden, accompanied by a reduction of genes involved in insulin signalling and lipid accumulation, inducing an aggravation of the insulin resistance (IR) state in AT. The therapies more effective inhibiting the generation of inflamed digits were HCQ and MTX. HCQ significantly reduced the body weight, accompanying by a reduction in insulin and glucose plasma levels leading to a decrease of HOMA-IR values. AT of CIA-OB mice treated with MTX and HCQ had restored levels of genes involved in lipid accumulation, adipogenesis and insulin signalling. Serum from RA patients elevated the levels of inflammatory markers, reduced the expression of genes related to lipid accumulation, adipogenesis and insulin signalling in 3 T3L1 adipocytes. Although LFN, MTX and HCQ <i>in vitro</i> treatment reduced inflammation, only MTX and HCQ regulated insulin sensitivity and lipid accumulation. These results were recapitulated in <i>ex vivo</i> treatments in human AT explants. <h3>Conclusions</h3> 1) Obesity accelerates the development and aggravates the outcome of the arthritis in mice. Arthritis exacerbates the inflammatory burden and the metabolic alterations in an obesity context. 2) <i>In vivo</i>, HCQ promotes a beneficial effect on the metabolism of CIA-OB mice, improving the insulin sensitivity at systemic and AT levels and reducing body weight. 3) <i>In vitro</i>, HCQ and MTX revert the metabolic alterations induced by RA serum in AT. Thus, HCQ and MTX might be considered as a valuable therapeutic strategy in RA patients to ameliorate the metabolic complications associated. <h3>Acknowledgements</h3> Supported by the Minister of Health (ISCIII, PI17/01316, CP15/0158, RIER RD16/0012/0015) cofinanced with FEDER funds and Roche Pharma, S.A. <h3>Disclosure of Interest</h3> None declared