Background/Purpose: Numerous studies have demonstrated the closely association between rheumatoid arthritis (RA) and metabolic complications such as obesity and insulin resistance (IR). Thus, there is an urgent need for the use of therapies targeting both the activity of the disease and such metabolic disorders. Yet, the beneficial/negative effect of conventional synthetic DMARDs (disease-modifying antirheumatic drugs) on the metabolic complications associated with cardiovascular disease prominent in RA patients is unknown yet. Objective: To analyze and compare the effects of methotrexate (MTX), leflunomide (LFN) and hydroxychloroquine (HDQ) on the obesity and IR in an obese collagen-induced arthritis (CIA) mouse model.

Methods: CIA was developed in obese-induced by high fat diet (HFD) and lean mice. 55 C57Bl/6 mice (4-5 weeks) were used. Groups of study: 5 non-diseased lean mice, 9 CIA lean mice, 5 non-diseased OB mice, 9 OB-CIA mice, 9 OB-CIA mice treated with LFN, 9 OB-CIA mice treated with MTx and 9 OB-CIA mice treated with HDQ for 15 days. Mice were weighted and the number of total swollen digits was recorded daily. After treatment, glucose tolerance test (GTT) was performed. HOMA-IR was calculated in all groups. Serum, plasma and adipose tissue were collected. Gene and protein expression of molecules involved in inflammation, insulin signaling and lipid metabolism.

Results: HFD promoted an early development of arthritis onset, however fat overloading did not affect the CIA effector phase. In contrast, the development of arthritis had not effect on body weight. Although the disease overcome was unaffected, obese CIA mice were more insulin resistant and display an elevated inflammatory state and an alteration of adipokines (at serum/plasma and adipose tissue levels) compared to lean CIA mice and non-arthritic obese mice. After 15 days of treatment, the therapies more effective on the disease progression were HDQ and MTX. Only the treatment with HDQ significantly reduced the body weight and improved insulin sensitivity at systemic level (HOMA-IR and area under the curve-GTT). Although systemic and adipose tissue high inflammatory status was reverted by the three DMARDs, MTX and HDQ, these were able to restore the metabolic alterations observed on adipose tissue. Thus, these DMARDs increased the expression of genes involved in insulin signaling (IRS-1 and 2, GLUT4 and AKT), lipid accumulation (DGAT, PLIN), and adipogenesis (PPARg, SREBP1 and INSIG1) and modulate the expression of leptin and adiponectin.

Conclusion: 1) Lipid overloading accelerates the disease onset in CIA mice. Although disease overcome was unaffected, the induction of arthritis in an obese state aggravates the metabolic alterations, suggesting that inflammation associated with RA strongly contributes to the development of metabolic complications. 2) MTX and HDQ can reduce the metabolic abnormalities induced by arthritis, modulating glucose and lipid metabolism and favoring the improvement of insulin sensitivity. Thus, they can be used as an excellent therapeutic strategy in patients with metabolic complications related to RA. Funded by ISCIII-FIS (CP15/00158) and Roche Pharma S.A

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/effects-of-synthetic-dmards-on-the-insulin-resistance-and-obesity-associated-with-rheumatoid-arthritis-an-obese-mouse-model-of-arthritis/