The identification of common genetic, molecular, and cellular pathogenic mechanisms in diabetes and rheumatoid arthritis may shed new light in the development of a metabolic disease during a chronic inflammatory process and may identify new specific targets to derive a precision medicine driven therapeutic strategy

Obiettivi del progetto

Rheumatoid arthritis (RA) is a systemic, autoimmune disorder involving synovial tissue of multiple joints. In the last years, it has been suggested that chronic activation of the immune system is associated with changes in metabolism leading to insulin resistance (IR) and type II diabetes (T2D). T2D may be observed in about 10% of RA patients, the latter showing some traditional risk factors for developing metabolic diseases such as glucocorticoid therapy, obesity, lifestyle factors. In the last years, proinflammatory cytokines have been recognized to play a crucial role in the pathogenesis of both the diseases. In this context, the results of a multicentre, open-label, randomized controlled trial in patients with rheumatoid arthritis and type 2 diabetes (TRACK) showed that IL-1 inhibition with anakinra, a human IL-1-receptor antagonist, improved both glycemic and inflammatory parameters in participants with RA and T2D. In addition to proinflammatory cytokines, several other proteins including adipokines and incretins that are secreted by peripheral immune cells, synoviocytes and macrophages are associated with perpetuation of chronic inflammation. On the other hand, it has been shown that some new anti-diabetic drugs, such as glucagon like peptide-1 (GLP-1) receptor agonists (i.e., liraglutide), may have immunoregulative effects, for example IL-1β downregulation and modulation of innate immune response, directly acting on macrophages and monocytes functions.

In this study we aim to investigate the genetic, molecular, cellular, and clinical factors that may be observed in RA with comorbid T2D. We will evaluate the inflammatory cytokines signatures and genomic patterns that characterize patients with RA and comorbid T2D in comparison with patients with RA without comorbid T2D and patients with T2D only. Furthermore, we will explore immune modulating features of GLP1 agonists on key cells involved in RA-T2D axis. Moreover, we plan compare synovial features among T2D and RA patients based on genomic, histologic, and ultrasound evaluations.

RA and T2D share the treat-to-target approach, in which an intensive pharmacological strategy is devoted to achieving the predetermined therapeutic goal, which has been shown to be associated with better long-term outcome and decreased mortality. On this basis, the study of mechanisms involved in both the diseases is mandatory to identify new molecular targets allowing clinicians to use a single treatment controlling both these diseases.

On these bases, the identification of common genetic, molecular, and cellular pathogenic mechanisms in diabetes and rheumatoid arthritis may shed new light in the development of a metabolic disease during a chronic inflammatory process and may identify new specific targets to derive a precision medicine driven therapeutic strategy.

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Altre Istituzioni coinvolte

• Università degli Studi dell’Aquila
• Università degli Studi di Torino

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