Complement component 3 as biomarker of disease activity and cardiometabolic risk factor in rheumatoid arthritis and spondyloarthritis

Abstract

Objective: To analyze the relationship between complement component 3 (C3) and the prevalence of cardiometabolic risk factors and disease activity in the rheumatic diseases having the highest rates of cardiovascular morbidity and mortality: rheumatoid arthritis (RA), psoriatic arthritis (PsA) and axial spondyloarthritis (axSpA). Methods: This is a cross-sectional study including 200 RA, 80 PsA, 150 axSpA patients and 100 healthy donors. The prevalence of cardiometabolic risk factors [obesity, insulin resistance, type 2 diabetes mellitus, hyperlipidemia, apolipoprotein B/apolipoprotein A (apoB/apoA) and atherogenic risks and hypertension] was analyzed. Serum complement C3 levels, inflammatory markers and disease activity were evaluated. Cluster analysis was performed to identify different phenotypes. Receiver operating characteristic (ROC) curve analysis to assess the accuracy of complement C3 as biomarker of insulin resistance and disease activity was carried out. Results: Levels of complement C3, significantly elevated in RA, axSpA and PsA patients, were associated with the prevalence of cardiometabolic risk factors. Hard clustering analysis identified two distinctive phenotypes of patients depending on the complement C3 levels and insulin sensitivity state. Patients from cluster 1, characterized by high levels of complement C3 displayed increased prevalence of cardiometabolic risk factors and high disease activity. ROC curve analysis showed that non-obesity related complement C3 levels allowed to identify insulin resistant patients. Conclusions: Complement C3 is associated with the concomitant increased prevalence of cardiometabolic risk factors in rheumatoid arthritis and spondyloarthritis. Thus, complement C3 should be considered a useful marker of insulin resistance and disease activity in these rheumatic disorders.

Synapses, Microglia, and Lipids in Alzheimer’s Disease

“…A number of recent studies highlight the impact of lipid metabolism on complement signalling pathways. For instance, complement factor C3 and C4 levels have been associated with cardiometabolic risk factors such as obesity and insulin resistance ( Arias de la Rosa et al, 2020 ), fat distribution ( Fu et al, 2020 ), and metabolic syndrome and diabetes ( Copenhaver et al, 2020 ) in humans. In animal studies, findings have also demonstrated that peptide antagonists of complement receptors C3aR and C5aR inhibited diet-induced obesity, adipose inflammation, and metabolic dysfunction in rats and ameliorated inflammatory responses in murine macrophages ( Lim et al, 2013 )—a topic reviewed by Barbu et al (2015) .…”

Beyond Systemic Lupus Erythematosus and Anti-Phospholipid Syndrome: The Relevance of Complement From Pathogenesis to Pregnancy Outcome in Other Systemic Rheumatologic Diseases

“…C1q serum levels have been shown to correlate with clinical disease activity ( Holers and Banda, 2018 ), whereas MBL serum levels have been associated with a favourable outcome ( Garred et al, 2000 ). More recently, RA patients have been found to present higher plasma levels of C2, C3a and sC5b9 compared to control subjects, suggesting a potential activation of the classical pathway ( Bemis et al, 2019 ; Arias de la Rosa et al, 2020 ). Higher levels of C3b/iC3b, a split product of C3, and factor I were also reported in female compared to male patients, suggesting a counter regulatory mechanisms in women, who are more prone to develop RA ( Bemis et al, 2019 ).…”

“…Interestingly, among patients with RA, C3 has emerged as marker of metabolic disease: increased C3 was associated with insulin resistance in both obese and non-obese subjects ( Ursini et al, 2017a ), accurately identifying patients with type 2 diabetes ( Ursini and Abenavoli, 2018 ) and fatty liver disease ( Ursini et al, 2017b ). Very recently, in a cohort of 200 RA patients, de la Rosa and colleagues reported increased C3 to be associated with cardiometabolic risk and high disease activity at cluster analysis ( Arias de la Rosa et al, 2020 ).…”

“…There is a wide amount of data about the relevance of complement in psoriasis, while lesser evidence is available for PsA. Serum C3 and C4 levels have been shown to be higher in patients with PsA compared to healthy controls ( Chimenti et al, 2012 ; Ursini et al, 2014 ; Arias de la Rosa et al, 2020 ). C3 and C4 levels paralleled disease activity, thus such overexpression is potentially due to concomitant inflammation.…”

“…The close interplay between C3, insulin resistance and disease activity in PsA has been recently confirmed in the already cited study by de la Rosa and coworkers. Indeed, these authors recruited also 80 PsA patients, which emerged as the inflammatory arthropathy with the highest prevalence of cardiovascular risk factors ( Arias de la Rosa et al, 2020 ).…”