CIC Edizioni Internazionali. Cardio-metabolic comorbidities in rheumatoid arthritis and SLE. Review. 120 Clinical Dermatology 2013; 1 (2):

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Alfred David Woods
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1 Review Cardio-metabolic comorbidities in rheumatoid arthritis and SLE Andrea Doria Division of Rheumatology University of Padua, Italy Address for correspondence: Division of Rheumatology University of Padua Via Giustiniani, Padua, Italy adoria@unipd.it Summary The progressive improvement of diagnostic and therapeutic alternatives in rheumatic diseases has resulted into reduction in patient mortality and morbidity caused by disease activity. Therefore, new morbidity factors have emerged, i.e. atherosclerosis. It has an early onset and rapid evolution in patients who suffer from a number of rheumatic diseases, including systemic lupus erythematosus, rheumatoid arthritis, sclerodermia, Sjögren syndrome and vasculitis. The immune system and the endothelium are thought to play a crucial role in the atherosclerosis pathogenesis. The immune system is characterized by two different responses to infections: innate and adaptive responses. In the atherosclerotic process, inflammatory cells and molecules are involved which belong to both immune response types. Moreover, the opinion of most authors is that the endothelial damage is to be considered as a predictor for development of the atherosclerotic plaque. In the atherosclerosis pathogenesis, inflammatory and immune aspects play a crucial role. By studying the effect of chemokines, cytokines and autoantibodies, it was possible to better define the role of innate and specific immunity and, in the near future, it will be possible to better define the real biological impact of these mediators in cardiovascular events, setting them as targets for future therapeutic strategies. KEY WORDS: rheumatoid arthritis; systemic lupus erythematosus; atherosclerosis; innate immunity; adaptive immunity. Increased cardio-metabolic complications are usually observed in patients with rheumatoid arthritis and SLE compared to the general population (1). Atherosclerosis is undoubtedly the main cardio-metabolic complication. Historically, atherosclerosis was regarded as a condition characterized by lipid accumulation on vessel walls, resulting into a progressive vessel lumen reduction and the development of a cardiovascular event. Throughout the years, however, evidence has shown that a complex number of immuno-inflammatory processes develop in the vessel wall, which play a crucial role in the initiation and progression of the atherosclerotic process as well as in triggering the atherothrombotic event that in turn causes a cardiovascular event. While it has been established that endothelial dysfunction is the primary cause for the development of atherosclerosis, the mechanisms that originate endothelial dysfunction remain unclear. According to the classical hypothesis of atherosclerosis, traditional risk factors (hypertension, smoking, high cholesterol levels) may induce endothelial dysfunction; however, recent evidence has shown that infections or chronic inflammatory disease may play a role (2). All this factors may contribute to endothelial dysfunction through a common mechanism: immune system activation. Immunity can be distinguished into innate and adaptive, and these two components have different roles and features. It has been demonstrated that the effectors of both immunity components may play a key role in inducing the atherosclerotic process (Figure 1). If we observe the innate component of the immune system, it is clear that pattern recognition receptors, i.e. the receptors that identify common molecular pat- Figure 1 - Key features of innate and acquired immunity in atherogenesis. 120 Clinical Dermatology 2013; 1 (2):

2 Cardio-metabolic comorbidities in rheumatoid arthritis and SLE terns and pathogens, may play a role. These receptors include scavenger receptors, which may engulf modified LDL and turn macrophages into foamy cells. Toll-like receptors are expressed in both macro - phages and endothelial cells that can be activated; activation of endothelial cells may induce adhesion molecules, chemotactic factors and pro-inflammatory cytokines. Nod-like receptors have been recently identified and may be activated by cholesterol crystals, and following inflammasome activation they may determine interleukin 1 production. All these cytokines act within the plaque and play a specific role in the inflammatory process, by amplifying it within the plaque. Pentraxins are a family of proteins that regulate resistance to pathogens. There are two types of pentraxins: C-reactive protein (long pentraxin), and pentraxin 3 (short pentraxin). C-reactive protein activates the complement, may stimulate macrophages to engulf modified LDLs, and may stimulate smooth muscle cells, endothelial cells to produce adhesion molecules, cytokines and chemotactic factors, as well as tissue factor. Therefore, C-reactive protein may play an active role within the plaque, and it has proven to be expressed inside the plaque. C-reactive protein expression within the plaque correlates with its circulating levels. Evidence from several epidemiologic studies has clearly shown that C-reactive protein is an independent predictor for cardiovascular risk in the general population (3). This was confirmed by the Jupiter study (4), published in 2008: the study was conducted in patients without a history a cardiovascular event or ischemic heart disease, had normal cholesterol levels and showed increased C-reactive protein. Patients were randomized to receive rosuvastatin or placebo. Rosuvastatin reduced cardiovascular e - vents by 44%, thus showing that C-reactive protein is a reliable marker for cardiovascular risk. Acquired immunity is also involved in the development of atherosclerotic events: 25% of the cells that infiltrate the atherosclerotic plaque consist of lymphocytes, i.e. the typical cells of adaptive immunity (5). Th1-lymphocytes are known to be pre-atherogenic cells, in particular they seem to be a clonal expansion of CD4+ and CD28- populations. This clonal subpopulation has shown to be expanded in patients with unstable angina. These lymphocytes produce high amounts of interferon-gamma, are self-reactive cells and have a cytotoxic and cytolytic effect on the endothelium. The role of Th17- and Th2-lymphocytes is more controversial. Dendritic cells that penetrate the plaque from the circulation can internalize antigens, for example oxidized LDLs. Then they migrate to lymph nodes, where they present the antigen to naïve CD4-lymphocytes that become effector cells before returning to the circulation. They may re-enter at the plaque level, where they may encounter the autoantigen again, this time presented by the macrophage, by the dendritic cell. This originates a secondary response. B-cells, on the contrary, are not found inside the plaque but outside the vessel wall, where they can originate tertiary structures with a germinal center. This is the place where the auto-antibody response is generated against some autoantigens that are found inside the plaque. Several antigens are present inside the plaque, which may become the target of an antibody response (6). The main antibodies that have shown to be associated with atherosclerosis are those against oxidized LDLs, beta2- glycoprotein 1 and heat shock protein. Several groups have demonstrated that high levels of antioxidized LDL antibodies are associated with ischemic heart disease in humans (7); at the experimental level, it has also been demonstrated that the passive transfer of T cells specific for oxidized LDLs in hypercholesterolemic mice may accelerate the atherosclerotic process (8). Other studies have shown that immunization with oxidized LDLs in animals susceptible to atherosclerosis may cause either a suppression or a worsening of atherogenesis (9), and that infusion with anti-oxidized LDL monoclonal antibodies (in animals susceptible to atherosclerosis) may inhibit oxidized LDL uptake by macrophages (10). Therefore, it is likely that the group of anti-oxidized LDL antibodies include both protective and pathogenetic antibodies. Under normal conditions, anti-oxidized LDL antibodies may help in the removal of oxidized LDLs by macrophages, but in special circumstances e.g. an increased oxidation in smokers there could be a formation of anti-oxidized LDL antibodies directed against different epitopes, and these antibodies may favor oxidized LDL uptake by macrophages, and therefore accelerate atherosclerosis. Protective antibodies might belong to the IgM class, while pathogenetic antibodies to the IgG class (11). The second group of antibodies includes antiphospholipid antibodies, i.e. those associated with arterial or venous thrombosis, both in vivo and in obstetric complications. The main antigen targeted by antiphospholipid antibodies is β2 glycoprotein I, a polypeptide chain consisting of five domains: the fifth domain presents positively charged amino acids and is thought to be responsible for β2 glycoprotein I binding with negatively-charged phospholipid wall. In the majority of cases, anti-β2 glycoprotein I antibodies are directed against the first domain. β2 glycoprotein I not only binds to phospholipids, but also to other negatively-charged molecules, including lipoproteins. β2 glycoprotein I is expressed on endothelial cell membranes and intimal medial borders of human atherosclerotic plaques obtained after carotid endarterectomies. It co-localizes with CD4-positive lymphocytes (12). The role of β2 glycoprotein I in atherosclerosis has been also demonstrated by experiments conducted in animals: immunization of LDL-receptor deficient mice induces anti- β2 antibody production and a worsening of atherosclerosis. If we take lymphocytes from immunized mice and transfer them to mice with a similar genetic background, an acceleration of atherosclerosis will be seen in these mice as well. This will not be seen after lymphocyte depletion. Therefore, β2 gly- Clinical Dermatology 2013; 1 (2):

3 A. Doria coprotein I-specific lymphocyte may increase atherosclerosis and this involves that β2 is a relevant antigen in this process (13). Antiphospholipid antibodies have shown to be associated with several cardiovascular events in humans (14) while the association between antiphospholipid antibodies and subclinical atherosclerosis is more controversial (15). A similar phenomenon is observed with heat shock proteins (HSP 60) that are produced by damaged cells and protect other proteins from denaturation (Figure 2). Heat shock proteins may be produced by endothelial cells in response to stressors (hypertension, smoking, etc.) and represent a target for autoimmunity under certain circumstances. Clinical subclinical and experimental data show that these antibodies are associated with atherosclerosis (16). Results from animal studies are similar to those obtained for β2 glycoprotein I: immunization of LDLreceptor deficient mice with heat shock protein 65 induces antibody production and more atherosclerosis. If we take the antibodies produced by mice or the lymphocytes specific for heat shock proteins and transfer them to animals with a comparable genetic background, these animals will develop more atherosclerosis. Therefore, autoantigens have been identified and isolated within the atherosclerotic plaque, along with Figure 2 - Features of heat shock proteins (HSP 60). autoreactive lymphocytes and antibodies that are found in the circulation but infiltrate the plaque as well. It has been observed that the disease can be induced in experimental animals after immunization with antigens and/or passive transfer of antibodies and lymphocytes (17). This means that atherosclerosis meets five of the criteria used to define autoimmune diseases (Figure 3). Therefore, can we consider atherosclerosis as an autoimmune disease? Perhaps it is, but autoimmunity plays a relevant role in the development of atherosclerosis. As a logical consequence, atherosclerosis appears to be accelerated in autoimmune rheumatic conditions, especially rheumatoid arthritis and SLE (18). The relative risk of cardiovascular events in rheumatoid arthritis is 3.9-fold higher than in the general population, while in SLE the risk is 17-fold higher, and it increases in age groups of young patients: in SLE female patients of the age range an age group that usually is not affected by atherosclerosis the risk of developing a myocardial infarction is 50-fold higher than in the general population (19, 20). Why is atherosclerosis accelerated in autoimmune diseases? Findings from the studies reported in Table 1 show a very high variability of plaque prevalence between studies, ranging from 17 to 40%. Such difference could be explained by the different composition of study populations (mean age, male:female ratio, race, history of cardiovascular events). However, if we observe IMT values, they are quite similar between the studies, ranging from 0.55 mm to 0.71 mm. Since IMT is considered to be normal up to 0.9 mm, the values shown in the Table are all normal, and they are identical regardless of plaque prevalence. In a 2003 study by Roman et al., it was reported that mean IMT was significantly lower in SLE patients compared to healthy subjects (21). In a study published in 2007 (a post mortem study on an appropriate number of patients who died for myocardial infarction, and stratified according to the presence or absence of rheumatoid arthritis), the extent of atherosclerotic plaques was higher in patients who had died for myocardial infarction but without rheumatoid arthritis compared to those who were affected by rheumatoid arthritis. Likewise, the degree of stenosis was higher in patients without rheumatoid arthritis than in the others. Patients with rheumatoid arthritis had more vulnerable plaques (22). Therefore, in patients with rheumatoid arthritis, plaque vulnerability is caused by the inflammation inside the plaque: vulnerability is directly proportional to the degree of inflammation. Therefore, the atherosclerotic plaque hosts several immuno-inflammatory processes that may be very similar to those involved in rheumatoid arthritis. In SLE, in lupus glomerulonephritis, some of the genes that control immuno-inflammatory processes are likely to be the same as those involved in atherosclerosis (23). For these genes, too, there are polymorphisms of both the TNFα gene and of the group of Figure 3 - Diagnostic criteria for autoimmune diseases. 122 Clinical Dermatology 2013; 1 (2):

4 Cardio-metabolic comorbidities in rheumatoid arthritis and SLE Table 1 - Results from the main carotid ultrasound studies in SLE. Carotid ultrasound studies in SLE Manzi Svenungsson Roman Doria Selzer Thompson (1999) (2001) (2003) (2003) (2004) (2008) Patients n Mean age (years) Female % White % 87 NR ~ Previous CVD % Plaque definition >50% than IMT>1 mm >50% than IMT>1.3 mm >50% than >50% than surrounding surrounding surrounding surrounding area area area area Plaque % Mean IMT (mm) 0.71± ± ± ± ± ±0.1 Risk factor evaluation Cross Cross Cross Longitudinal Cross Longitudinal sectional sectional sectional sectional genes involved in interferon signature, i.e. the genetic signature that predisposes and is the first step in the development of autoimmune diseases. Therefore, it is possible that some mediators produced in the synovium or in lupus glomerulonephritis are released into the circulation and induce endothelial dysfunction, regarded as the primum movens, either directly or indirectly through C-reactive protein production. Once the inflammation has developed inside the plaque, this becomes vulnerable and fragile, the fibrous cap breaks down and this leads to the development of the atherothrombotic mechanism and the resulting acute cardiovascular event. However, cardiovascular events especially in thrombophilic patients may also develop as a consequence of thrombus formation on a superficial erosion. It is possible that, in patients with rheumatoid arthritis or SLE, the cardiovascular event develops following rupture of an unstable plaque, but it may also happen that in SLE patients or in those with antiphospholipid antibody syndrome the cardiovascular event is caused by the other mechanism. i.e. thrombus formation on an endothelial erosion. In this respect, it should be noted that endothelial erosions are a frequent occurrence and they are generally repaired by endothelial progenitor cells or by angiogenic myelomonocytic cells. Interestingly, inteferon-alpha the cytokine involved in autoimmune diseases induces apoptosis in myelomonocytic endothelial progenitor cells, and therefore can reduce the repair of endothelial erosions (24). The association between autoimmune inflammatory rheumatic diseases and cardiovascular risk is certainly very strong; we have mainly discussed disease-related factors, namely immuno-inflammatory factors, which are certainly a new field of research; however, we should not neglect traditional risk factors and the pharmacological treatments currently used, that may play a role in the development of atherosclerosis (25). References 1. Symmons DPM, Gabriel SE. Epidemiology of CVD in rheumatic disease, with a focus on RA and SLE. Nat Rev Rheumatol 7, (2011). 2. Steinberg D, Parthasarathy S, Carew TE, Khoo JC, Witztum JL. Beyond cholesterol: modifications of low-density lipoprotein that increase its atherogenicity. N Engl J Med 1989;320: Danesh J, et al. C-Reactive Protein and Other Circulating Markers of Inflammation in the Prediction of Coronary Heart Disease. N Engl J Med 2004;350: Ridker PM, et al. Rosuvastatin to Prevent Vascular Events in Men and Women with Elevated C-Reactive Protein. N Eng J Med 2008; 359: Taleb S, et al. Adaptive T cell immune responses and atherogenesis. Cur Opin Pharmacol 2010; 10: Doria A, Sherer Y, Meroni PL, Shoenfeld Y. Inflammation and accelerated atherosclerosis Basic mechanisms. Rheum Dis Clin N Am 2005; 31: Fredrikson GN, et al. Identification of immune responses against aldehyde-modified peptide sequences in apob associated with cardiovascular Clinical Dermatology 2013; 1 (2):

5 A. Doria disease. Arterioscl Thromb Vasc Biol 23, 872-8, Zhou X, et al. Adoptive transfer of CD4+ T cells reactive to modified low-density lipoprotein aggravates atherosclerosis. Atheroscler Thromb Vasc Biol 26, , Nilsson J, et al. Immunomodulation of atherosclerosis: implications for vaccine development. Atheroscler Tromb Vasc Biol 25, 18-28, Shaw PX, et al. Human-derived anti-oxidized LDL autoantibody blocks uptake of oxidized LDL by macrophages and localizes to atherosclerotic lesions in vivo. Arterioscler Thromb Vasc Biol 2001 Aug;21(8): Narshi CB, et al. The endothelium: an interface between autoimmunity and atherosclerosis in systemic lupus erythematosus? Lupus 2011 Jan;20(1): George J, et al. Immunolocalization of beta2-glycoprotein I (apolipoprotein H) to human atherosclerotic plaques: potential implications for lesion progression. Circulation 1999 May 4;99(17): George J, et al. Adoptive transfer of beta(2)-glycoprotein I-reactive lymphocytes enhances early atherosclerosis in LDL receptor-deficient mice. Circulation Oct 10;102(15): Kobayashi K, et al. Circulating oxidized LDL forms complexes with beta2-glycoprotein I: implication as an atherogenic autoantigen. J Lipid Res 2003 Apr;44(4): Gresele P, et al. Patients with primary antiphospholipid antibody syndrome and without associated vascular risk factors present a normal endothelial function. Thromb Res 2009;123(3): SoRelle R. Blood containing high levels of antibodies to heat shock protein 65 (hsp65) were found to be at increased risk of subsequent cardiovascular events. Circulation 2002 Nov 26;106(22). 17. George J, et al. Cellular and humoral immune responses to theat shock proteim both involved in promoting fatty-streak formation in LDL-deficient mice. J Am Coll Cardiol 38: , Shoenfeld Y, et al. Accelerated atherosclerosis in autoimmune rheumatic diseases. Circulation 2005 Nov 22;112(21): Maradit-Kremers H, et al. Increased unrecognized coronary heart disease and sudden deaths in rheumatoid arthritis: a population-based cohort study. Arthritis Rheum 2005 Feb;52(2): Fisher LM, et al. Effect of rheumatoid arthritis or systemic lupus erythematosus on the risk of firsttime acute myocardial infarction. Am J Cardiol 2004 Jan 15;93(2): Roman MJ, et al. Prevalence and correlates of accelerated atherosclerosis in systemic lupus erythematosus. N Engl J Med 2003 Dec 18; 349(25): Aubry MC, et al. Differences in atherosclerotic coronary heart disease between subjects with and without rheumatoid arthritis. J Rheumatol 2007 May;34(5): Full LE, et al. The inextricable link between atherosclerosis and prototypical inflammatory diseases rheumatoid arthritis and systemic lupus erythematosus. Arthritis Res Ther 2009, 11: Libby P. Role of inflammation in atherosclerosis associated with rheumatoid arthritis. Am J Med 2008; 121: S21-S Symmons DPM. Gabriel SE. Epidemiology of CVD in rheumatic disease, with a focus on RA and SLE. Nat Rev Rheumatol 7, (2011). 124 Clinical Dermatology 2013; 1 (2):

THE CARDIOVASCULAR INFLAMMATORY CONTINUUM DR AB MAHARAJ

THE CARDIOVASCULAR INFLAMMATORY CONTINUUM DR AB MAHARAJ Disclosures: On National Advisory Boards of: (1) Pfizer Pharmaceuticals (2) MSD (3) Roche Pharmaceuticals (4) Abbott International: AfME Rheumatology