Effect of Sarilumab on Atherosclerotic Disease Assessed by PET/CET in Patients With RA (SARIPET)

Overview

Rheumatoid arthritis (RA) is a condition associated with a high incidence of cardiovascular disease (CV), primarily as a result of accelerated atherosclerosis . Patients with RA also have a high prevalence of metabolic syndrome (MS) The state of chronic inflammation in RA patients contributes to increased CV risk. Deregulation of both genetic and serological adipocines, MS biomarkers, and biomarkers of endothelial activation and inflammation also contributes to the increased CV risk in these patients. An increased incidence of abnormal carotid intima-media thickness (cIMT) values and carotid plaques, considered surrogate markers of subclinical atherosclerotic disease, has also been described in patients with RA. Positron emission tomography/computed tomography (PET/CT) is a noninvasive imaging technique useful for the evaluation of inflammation (by 18F-FDG uptake) and mineralization (by 18F-NaF uptake) in carotid atheroma plaque. Atherosclerosis and RA share many common inflammatory pathways, and the mechanisms that lead to synovial inflammation are similar to those seen in atherosclerotic plaque. Interleukin (IL)-6 is a key pro-inflammatory cytokine involved in both the pathophysiology of RA and the development of atherosclerosis. Sarilumab is a human monoclonal antibody against the IL-6 receptor that has been shown to be effective in patients with RA, improving symptoms, as well as at the functional and radiographic levels. Treatment with IL-6 receptor inhibitors has been described to result in a modulation of lipid metabolism, mediated by a reduction in lipoprotein (a) (Lp(a)) and an improvement in the anti-oxidant function of high-density lipoprotein (HDL) . In this regard, Sarilumab may have beneficial effects in RA patients on MS, which is implicated in the development of atherosclerotic disease. Information regarding the beneficial effect of IL-6 receptor blockade on atheroma plaque formation and its effect at the vascular level in RA patients is scarce.

RA is a chronic inflammatory disease characterized by chronic and erosive arthritis that mainly involves peripheral joints. RA affects activities of daily living, significantly decreasing the quality of life of affected patients. Several studies have demonstrated that RA patients are at higher risk of developing CV disease that is the main cause of premature mortality and sudden death in these patients. In this sense, the increased risk of CV disease observed in patients with RA is the result of a process of accelerated atherosclerosis. In addition, a large meta-analysis also found an increased prevalence of obesity, dyslipidemia, and hypertension, alterations in glucose metabolism and insulin resistance, which are features of MS, in patients with RA. Such characteristics are associated with inflammation and endothelial dysfunction, an early step of atherosclerosis. Besides traditional CV risk factors, the chronic inflammatory state present in these patients also contributes to the increased CV risk in RA. Moreover, CV risk in RA patients is further enhanced by a dysregulation both at the genetic and serological level of adipokines, MS-related biomarkers, biomarkers of endothelial activation and inflammation, which appear to be crucial in the development of atherosclerotic disease. Accordingly, an adequate identification of patients at risk to develop CV events is needed. In this regard, carotid ultrasound and PET/CT are non-invasive techniques used to assess the extension and severity of atherosclerosis in RA. In this sense, molecular imaging techniques have the potential to study 'in vivo' the metabolic processes in the carotid atheroma. In fact, the incidence of abnormal cIMT values as well as the frequency of carotid plaques, which are surrogate markers of subclinical atherosclerotic disease, has been found increased in RA patients. In addition, it is well known that inflammation and mineralization are simultaneous phenomena in the atheroma plaque formation. In this regard, the uptake of 18F-FDG in relation with the inflammation of the carotid arteries has been demonstrated in patients with RA. Consequently, 18F-FDG may be considered as an established technique to evaluate the atheroma inflammation and to monitor the response to new anti-inflammatory therapies. Likewise, active calcification (which has a relevant role in the early phase of atherogenesis) measured by the uptake of 18F-NaF seems to be predominant over inflammation (18F-FDG) in symptomatic and asymptomatic carotid atheroma. This biological behavior opens new insights on the role of 18F-NaF in the study of calcification and in the identification of the vulnerable carotid atheroma. Atherosclerosis and RA share many common inflammatory pathways, and the mechanisms leading to synovial inflammation are similar to those found in atherosclerotic plaque. Indeed, pro-inflammatory cytokines produced within locally affected joints in RA, such as IL-6, which regulates both the innate and adaptive immune system with a pivotal role in the pathophysiology of RA, are also central to the development of atherosclerosis. Specifically, IL-6 is a pleiotropic cytokine produced by a variety of cells types, including T-lymphocytes, macrophages, monocytes, endothelial cells and fibroblasts. This cytokine leads to the production of acute phase proteins in the liver, including serum CRP, among others. The production of IL-6 and thus CRP are key mediators of the systemic and local inflammation observed in RA. Furthermore, it is important to highlight that IL-6 has been shown to be significantly associated with atherosclerosis in RA patients. On the one hand, this molecule plays a direct role in mediating IR by inhibiting insulin receptor signal transduction and insulin action. On the other hand, IL-6 is independently predictive of endothelial dysfunction and a reduction in its serum levels leads to decreased endothelial cell activation in patients with RA. In addition, it has been demonstrated that the levels of Lp(a), a lipoprotein with atherogenic and thrombogenic properties, are higher in individuals with elevated IL-6 serum concentrations. Both IL-6 functions and its circulating levels are partially controlled by its receptor (IL-6R). Several studies have demonstrated a favourable effect on lipid metabolism with an anti-IL-6R treatment, besides reducing inflammatory disease activity. Moreover, a modulation of lipid metabolism, mediated by reduction of Lp(a) and improvement of the anti-oxidant role of HDL-cholesterol, has been reported in patients with RA following anti-IL-6R treatment. In this sense, Sarilumab (the first fully human anti-IL-6Rα monoclonal antibody) binds membrane-bound and soluble human IL-6R with high affinity, thereby blocking IL-6 signaling, with no evidence of complement-dependent or antibody dependent cell-mediated cytotoxicity. In preclinical studies, Sarilumab has been shown to inhibit IL-6 signaling in a dose-dependent manner. In phase II studies, SC Sarilumab was reasonably well tolerated and led to a decrease in acute-phase reactant levels, mainly in CRP in patients with RA. In addition, in RA patients treated with Sarilumab in combination with methotrexate, both drugs provided sustained clinical efficacy, significant improvements in symptomatic, functional, and radiographic outcomes are shown. In this regard, although it is plausible to think that the blockage of IL-6R may lead to a beneficial effect on atherosclerosis and MetS in patients with RA, this potential effect has not been extensively evaluated yet. With respect to this, little is known about the beneficial effect that IL-6R blockade may cause in the formation of atheroma plaque as well as the net vascular effect of lipids and lipoproteins changes in RA patients, which makes it a potent target of major interest. Taking all these considerations into account, the aim of this study is to assess by PET/CT the effect of Sarilumab in the carotid atheroma plaque (effect on the inflammatory component as well as on mineralization) in patients diagnosed with RA over 6 months of Sarilumab treatment.