Abstract
Disease severity, progression and response to therapy might be worse in obese rheumatoid arthritis (RA) patients, but paradoxically, obesity also might protect from radiographic joint damage. Thus, the intricate relationship between obesity and RA needs urgent clarification. The aim of this study was to assess the influence of obesity on the onset and development of RA and to determine whether arthritis could modify the adipose tissue biology and whether conventional Disease Modifying Anti-Rheumatic Drugs (cDMARDs) can modulate these alterations. Two strategies were followed: (1) clinical profiling of two cohorts of RA: non-obese and obese patients; and (2) mechanistic studies carried out in both a collagen-induced arthritis (CIA) in an obese mouse model and 3T3-L1 adipocytes treated with cDMARDs (leflunomide, methotrexate, and hydroxychloroquine). In our cohort of RA patients with low-moderate disease activity, the presence of obesity was not related to a higher activity of the disease; actually, disease activity score 28-erythrocyte sedimentation rate (DAS28-ESR) was reduced in the obese RA patients. However, the induction of arthritis promoted transcriptomic changes in the adipose tissue under obesity condition in the obese CIA model. Treatment with hydroxychloroquine reduced weight and insulin resistance, accompanied by beneficial metabolic effects in the adipose tissue. These molecular changes in adipose tissue were also observed after methotrexate administration. In sum, arthritis might affect directly the inflammatory burden and metabolic alterations associated with obesity in adipose tissue. Clinicians should be cautious measuring the activity of the disease in obesity and managing the best therapeutic options for the metabolic comorbidities of these patients, where the combination of hydroxychloroquine and methotrexate should be considered to improve adipose tissue dysfunction in obese RA.
Highlights
Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease that comprises joint inflammation and bone destruction which might cause disability
No changes were noticed in erythrocyte sedimentation rate (ESR) between the two RA groups, which was translated into a reduction in the disease activity index (DAS28-ESR) in obese RA patients
This study shows for the first time the molecular changes that arthritis could promote in adipose tissue, and adds clarification about the association between RA and obesity, using human cohorts of obese and lean RA patients and a model of obese arthritic mouse
Summary
Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease that comprises joint inflammation and bone destruction which might cause disability. RA is closely associated with diverse comorbidities, including cardiovascular disease, which is reported to be the primary cause of death in RA [1] In this sense, environmental risk factors include infections, smoking, periodontitis, hormonal and dietary factors, physical inactivity, type 2 diabetes mellitus, and obesity. Adipokines are crucial players in energy metabolism and in inflammation and immunity, most of them being increased in obesity and contributing to the associated “lowgrade inflammatory state” [8]. This demonstrates that in addition of the role of adipose tissue as an energy storage under conditions of caloric surplus, it is an active participant in regulating physiologic and pathologic processes such as immunity and inflammation. The aim of this study was to assess the influence of obesity on the onset and development of RA, and to determine whether arthritis could modify the adipose tissue biology in an obesity context and how cDMARDs could modulate these metabolic alterations
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