Whether there is a higher risk of atherosclerosis and cardiovascular events as well as cancer in patients with RA and other autoimmune diseases is an issue of enormous importance as the diagnosis of a rheumatological condition is made at increasingly young ages [
14‐
16]. It is well established that autoimmune diseases are characterized by a chronic state of systemic inflammation [
17,
18], mediated also by microRNA [
19‐
22] and by the production of autoantibodies that can induce a higher risk of thromboembolism and atherosclerosis compared to the general population [
23,
24], as observed in the antiphospholipid syndrome [
14,
25]. Matsuura
et al. describes the main mechanisms that trigger inflammation in the atherosclerotic plaque, leading to its rupture and to the cardiovascular event [
26]. Among these factors, a key role is played by pro-inflammatory cytokines (that is, interleukin-1 beta (IL-1β)) and caspases that activate the NLRP3 inflammasome together with lysosomal damage and reactive oxygen species. Of note, this unsuspected connection strengthens the current view that autoimmunity and autoinflammatory diseases are indeed linked in their pathogenetic mechanisms [
27‐
29]. The prolonged inflammatory state further induces the production of C-reactive protein (CRP) that is capable of binding oxidized low density lipoprotein (oxLDL) and this complex induces an alteration of the arterial wall that accelerates atherosclerosis.
An antigenic component that plays a pathogenic role in autoimmune diseases is β2GPI, well known as the target of anti- β2GPI antibodies in the anti-phospholipid syndrome [
17,
30‐
33]. Also, this antigen can bind oxLDL and lead to the perpetuation of the inflammatory state in the vascular wall [
17]. The two diseases considered by Matsuura and colleagues as prototypes of chronic inflammation are RA and SLE which are associated with an increased cardiovascular risk and because they have high levels of anti-oxLDL and anti-oxLDL/β2GPI antibodies. Also, anti-nuclear antibodies (ANA) are often observed in autoimmune diseases [
34,
35] and a multivariate analysis showed that ANA are inversely correlated with carotid elasticity. From a cellular point of view, Th17 and Treg cells also play an important role in atherogenesis, which is protective and anti-atherogenic for Tregs and is still unknown for Th17. In conclusion, the authors describe all the inflammatory and autoimmune elements that induce higher risk of atherosclerosis in autoimmune diseases [
26]. Damjanov
et al. tackle the topic from a different point of view and address a key question which is complementary to the former, that is, the effect of anti-tumor necrosis factor alpha (TNFα) therapy on the cardiovascular risk in RA patients [
36]. The discussion of this topic shows that biologic therapies reduce the cardiovascular risk in RA, as supported also by previous reports. However, we remain unaware of the mechanisms by which anti-TNFα therapies can influence the inflammatory processes responsible for the altered vascular function and lipid profile that is transiently modified [
37]. An additional element that Damjanov and colleagues consider when describing the link of biologic therapy and cardiovascular disease in autoimmunity is that these new therapies also seem to increase the risk of cancer, mainly represented by melanoma and non-melanoma skin cancer, despite a possibly enhanced risk associated with autoimmunity
per se. In conclusion, biologic therapy reduces the cardiovascular risk in RA but may be responsible for increased risk of skin cancer. However, this risk should not be considered sufficient to induce changes in clinical practice or in treatment indication.