Rheumatoid Arthritis Clinical Trial
Official title:
Effect of Sarilumab Therapy on Atherosclerotic Disease Assessed by Positron Emission Tomography/Computed Tomography (PET/CT) in Patients With Rheumatoid Arthritis
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.
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