In arthritis, leukocyte ingress into the synovium occurs by leukocyte adhesion to ECs and then by transendothelial migration 12345678. The chemotaxis of these leukocytes is regulated mainly by various chemokines 1891011121314. Several CAMs have been implicated in leukocyte-EC interactions 123478. ECs play an active role in inflammation. Synovitis is associated with vasodilation and increased endothelial permeability (leakage) and vascular injury followed by endothelial regeneration 456. ECs secrete several vasodilatory mediators, including nitric oxide, prostacyclin (PGI₂), platelet-activating factor, histamine, and others 456. Increased vascular permeability associated with EC retraction and contraction may be a physiological process, while in inflammation, pro-inflammatory mediators trigger vascular damage 456. Increased vascular permeability is induced primarily by vasoactive agents such as histamine, serotonin, bradykinin, and others 45615. Vascular injury is caused primarily by activated neutrophils, inflammatory mediators released by these cells, including reactive oxygen intermediates and matrix metalloproteinases (MMPs). Anti-EC antibodies (AECAs), tumor necrosis factor-alpha (TNF-α), interleukin-1 (IL-1), or interferon-gamma (IFN-γ) stimulates EC injury 45615. The abundant production of AECAs, markers of vascular damage, has been reported in RA, SLE, systemic vasculitis, and other rheumatic diseases 15 (Table 1). Injury is followed by endothelial regeneration, which may be associated with angiogenesis or may occur without the formation of new blood vessels 5616.

The cascade of leukocyte transendothelial migration begins with the adhesion of leukocytes, including neutrophils, lymphocytes, and monocytes, to postcapillary venules. Leukocyte recruitment occurs through the wall of these venules. In some RA patients, specialized ECs resembling high endothelial venules (HEVs) are found in the synovium. These HEVs are surrounded by lymphoid aggregates composed of T cells 128. Inflammatory leukocyte recruitment into inflamed tissue is very similar to the 'homing' associated with physiological immune surveillance 123. Leukocyte adhesion to ECs or to extracellular matrix (ECM) constituents is mediated by endothelial CAMs and their counter-receptors on infiltrating white blood cells. Primarily selectins, integrins, and some members of the immunoglobulin superfamily of adhesion molecules (CAMs) have been implicated in leukocyte extravasation, but some other CAMs may also play a role in this process 237. These CAMs are summarized in Table 2. During leukocyte trans-endothelial migration, selectins mediate the initial 'tethering' and 'rolling' of leukocytes whereas integrins and other CAMs are involved in firm adhesion and migration of leukocytes 138. All selectins, most integrins, and members of the immunoglobulin superfamily are abundantly expressed in arthritic synovial tissues 23. Other CAMs involved in leukocyte-EC adhesion underlying inflammation include intra-cellular adhesion molecule-3 (ICAM-3), the lymphocyte function-associated antigen-3 (LFA-3)-CD2 counter-receptors, various alternative forms of CD44, vascular adhesion proteins (VAP-1 and VAP-2), endoglin (CD105), E-cadherin, N-cadherin, cadherin-11, platelet-endothelial cell adhesion molecule-1 (PECAM-1) (CD31), junctional adhesion molecules (JAMs), CD99, and others 1237. All of these CAMs have been detected in arthritic synovial tissues 123.

Chemokines are small proteins exerting chemotactic activity toward leukocytes 9101112141718. Chemokines have been classified into supergene families according to the location of cysteine (C) in their molecular structure. These families are designated as CXC, CC, C, and CX₃C chemokines; the particular chemokine ligand members are CXCL, CCL, CL, and CX₃CL, and the four chemokine receptor groups are CXCR, CCR, CR, and CX₃CR, respectively 91012. To date, more than 50 chemokines and 19 chemokine receptors have been identified 91012 (Table 3). Most CXC chemokines chemoattract neutrophils, but platelet factor-4 (PF4)/CXCL4 and IFN-γ-inducible 10-kDa protein (IP-10)/CXCL10 recruit lymphocytes and monocytes 9. Among CXC chemokines, IL-8/CXCL8, epithelial neutrophil-activating protein-78 (ENA-78)/CXCL5, growth-regulated oncogene-alpha (groα)/CXCL1, connective tissue-activating peptide-III (CTAP-III)/CXCL7, granulocyte chemotactic protein-2/CXCL6, IP-10/CXCL10, PF4/CXCL4, monokine induced by IFN-γ (Mig)/CXCL9, stromal cell-derived factor-1 (SDF-1)/CXCL12, B cell-activating chemokine-1/CXCL13, and CXCL16 have been implicated in the pathogenesis of synovial inflammation 141718. CC chemokines stimulate monocyte chemotaxis and some of them also chemoattract lymphocytes 10. Monocyte chemoattractant protein-1 (MCP-1)/CCL2, macrophage inflammatory protein-1-alpha (MIP-1α)/CCL3, MIP-3α/CCL20, RANTES (Regulated upon Activation, Normal T-cell Expressed and Secreted)/CCL5, Epstein-Barr virus-induced gene-1 ligand chemokine (ELC)/CCL19, secondary lymphoid tissue chemokine (SLC)/CCL21, and chemokine-like factor-1 (CKLF1) have been implicated in inflammatory mechanisms underlying synovitis 141718. The C chemokine family contains two members: lympho-tactin/XCL1 and single C motif-1-beta (SCM-1β)/XCL2 12. Lymphotactin/XCL1 has been detected on synovial T cells in RA 1418. The CX₃C chemokine subfamily contains frac- 1219. This chemokine chemoattracts talkine/CX₃CL1 mononuclear cells and also serves as a CAM 1719.

Fractalkine/CX₃CL1 has also been detected in RA synovial tissues 19. Fractalkine/CX₃CL1 has also been implicated in the development of accelerated atherosclerosis 18, a topic discussed later. Chemokines bind to their seven-transmembrane domain receptors expressed on the target cells 1218. Some of these receptors have numerous chemokine ligands whereas others are specific receptors for single ligands 14. Chemokine receptors have also been associated with various histological subtypes of inflammation. For example, whereas CXCR3 and CCR5 may be involved primarily in Th1 type diseases (such as RA), CCR3, CCR4, and CCR8 may play a role in leukocyte migration underlying Th2 type inflammation (such as asthma) 11. Most CXC and CC chemokine receptors mentioned above as well as XCR1 and CX₃CR1 are expressed in the arthritic synovium 141718.

Leukocyte adhesion to ECs occurs following a cascade of events. White blood cells in the bloodstream weakly adhere to the endothelium lining the inner vessel wall (tethering) followed by rolling of leukocytes on the endothelial layer. Tethering and rolling are mediated primarily by selectins and their ligands. These events are followed by leukocyte activation, which is dependent upon interactions between chemokine receptors expressed on leukocytes and proteoglycans on ECs. Activation-dependent firm adhesion occurs next, involving α₄β₁ integrin/VCAM-1 (vascular cell adhesion molecule-1), β₂ integrin/ICAM-1, and JAM/integrin interactions. This is associated with the secretion of chemokines. These chemokines may also upregulate integrin expression on the adhering cells via PI3K (phosphatidylinositol 3-kinase)- mediated pathways. Leukocyte diapedesis through the endothelial layer involving integrins occurs when chemokines bind to endothelial heparan sulphate. Chemokines preferentially chemoattract EC-adherent leukocytes. These processes lead to the transmigration of leukocytes into the inflamed tissue 18.

Inhibition of cell adhesion, chemokines, and migration using specific antibodies or purified ligands has provided an important perspective on the molecular pathogenesis of RA. In addition, some of these strategies may be included in the future therapy of arthritis 20. Regarding anti-CAM trials, an anti-human ICAM-1 antibody (enlimomab) was tried in refractory RA with little success 220. Other antiadhesion strategies have been introduced into the treatment of other inflammatory diseases. For example, efalizumab (anti-LFA-1) and alefacept (LFA-3-Ig fusion protein) have been tried in psoriasis, natalizumab (anti-α₄ integrin) in multiple sclerosis and Crohn disease, and an anti-α₄β₇ integrin monoclonal antibody in ulcerative colitis 2320. These and other anti-CAM strategies may be tried in arthritis as well 2320. Chemokines and chemokine receptors can be targeted in a number of ways. Disease-modifying antirheumatic drugs (DMARDs) and anti-TNF biologics, currently used in the treatment of RA, may indirectly influence chemokine production 18. Antibodies to IL-8/CXCL8, ENA-78/CXCL5, CXCL16, MIP-1α/CCL3, MCP-1/CCL2, and fractalkine/CX₃CL1 have been used to control arthritis in various rodent models 181920. Several oral chemokine receptor antagonists, including CXCR2, CXCR4, CCR1, CCR2, and CCR5 inhibitors, have been tried in human RA as well as in animal models of arthritis 18202122.

Angiogenesis is the formation of new capillaries from pre-existing vessels, whereas vasculogenesis involves circulating endothelial progenitor cells (EPCs) 14162324252627. Angiogenesis involves cell surface-bound and soluble angiogenic mediators, which activate vascular ECs (Table 4). In response, ECs release MMPs, which digest the underlying basal membrane and the ECM enabling the emigration of ECs. Single ECs will then gather to form capillary sprouts. Lumen formation within the sprouts leads to capillary loops. Finally, the synthesis of new basement membrane leads to the formation of new capillaries 23. Regarding vasculogenesis, a subpopulation of circulating CD34⁺ cells expressing the vascular endothelial growth factor-2 (VEGF-2) receptor has been identified and characterized as functional EPCs. Decreased numbers of EPCs as well as impaired vasculogenesis have been associated with arthritis 2728.

The major chemoattractant that drives EPCs is the SDF-1/CXCL12 chemokine and its receptor, CXCR4 29. In arthritis, proinflammatory cytokines stimulate the production of SDF-1/CXCL12 and thus tissue vasculogenesis by recruiting CXCR4⁺ EPCs 141729.

The hypoxia-VEGF-angiopoietin pathway is an essential angiogenic network in synovitis 1623242530. VEGF, a growth factor that binds to heparin in the synovial ECM, plays a central role in the regulation of neovascularization 2330. There is hypoxia present within the joint cavity, and hypoxia as well as TNF-α and IL-1 stimulate VEGF release 16. Hypoxia acts through the hypoxia-inducible factor heterodimer, HIF-1α/HIF-1β 16. Several other angiogenic mediators also act indirectly via VEGF 23. Angiopoietin-1 (Ang1) and Ang2 regulate EC functions upon stimulation by VEGF. Both Ang1 and Ang2 interact with the Tie2 endothelial tyrosine kinase receptor 1624. Ang1-Tie2 interactions result in vessel stabilization. On the other hand, Ang2, an antagonist of Ang1, inhibits vessel maturation 24. Another important player in this network is survivin, an apoptosis inhibitor, which is also involved in VEGF-induced angiogenesis and EC survival 16. VEGF, HIF-1, Ang1, Tie2, and survivin are all expressed in the arthritic synovium 1625. Growth factors other than VEGF but implicated in angiogenesis include fibroblast (FGF-1 and FGF-2), hepatocyte, platelet-derived, epidermal (EGF), insulin-like, and transforming (TGF-β) growth factors 162425. Among chemokines described above, CXC chemokines that contain the ELR (glutamic acid-leucine-arginine) amino acid motif promote angiogenesis 13. ELR⁺CXC chemokines that stimulate angiogenesis and also synovial inflammation include IL-8/CXCL8, ENA-78/CXCL5, groα/CXCL1, and CTAP-III/CXCL7. SDF-1/CXCL12 is a unique CXC chemokine as it exerts mainly a homeostatic function, yet it has been implicated in inflammation such as in RA 13141729. Moreover, this chemokine lacks the ELR motif but is still angiogenic 1429. The crucial role of SDF-1/CXCL12 in vasculogenesis is discussed above 29. In contrast to angiogenic CXC chemokines, the ELR^-PF4/CXCL4, IP-10/CXCL10, and Mig/CXCL9 suppress neovascularization 131417. Regarding CC chemokines, MCP-1/CCL2 promotes neovascularization induced by growth factors 1417. The sole CX₃C chemokine, fractalkine/CX₃CL1, also promotes synovial angiogenesis 141719. Regarding chemokine receptors, CXCR2, which binds most ELR⁺ CXC chemokines described above, is a crucial chemokine receptor in angiogenesis 131417. CXCR4 has been implicated in SDF-1/CXCL12-induced neovascularization in arthritis 141729. In contrast, CXCR3, a receptor for the angiostatic IP-10/CXCL10 and Mig/CXCL9, may be involved in chemokine-mediated angiostasis 1417. Numerous proinflammatory cytokines, such as TNF-α, IL-1, IL-6, IL-15, IL-17, IL-18, granulocyte and granulocyte-macrophage colony-stimulating factors, oncostatin M, and macrophage migration inhibitory factor, also induce synovial angiogenesis 1631. In contrast, other cytokines, such as IFN-α, IFN-γ, IL-4, IL-12, IL-13, and leukemia inhibitory factor, suppress the production of angiogenic mediators and thus inhibit neovascularization 163132. ECM components, matrix-degrading proteases, and cellular adhesion molecules described above may be involved in EC emigration, sprouting, and thus angiogenesis. Among ECM components, various types of collagen, fibronectin, laminin, vitronectin, tenascin, and proteoglycans promote neovascularization 16. Proteolytic enzymes, such as MMPs and plasminogen activators, play a role in matrix degradation underlying synovial angiogenesis 1625. On the other hand, tissue inhibitors of metallo-proteinases and plasminogen activator inhibitors antagonize the angiogenic effects of proteases described above 1632. Among CAMs, β₁ and β₃ integrins, E-selectin, glycoconjugates (including Lewis^y/H), melanoma cell adhesion molecule (MUC18), VCAM-1, PECAM-1, and endoglin have been implicated in neovascularization 216253334. The α_Vδ₃ integrin is of outstanding importance as this CAM mediates both synovial angiogenesis and osteoclast-mediated bone resorption and the development of erosions in RA 34. Other important angiogenic factors not mentioned above include endothelin-1, angiogenin, angiotropin, and many others 1625 (Table 4). Angiostatic mediators and compounds also include angiostatin (a fragment of plasminogen), endostatin (a fragment of type XIII collagen), thrombospondin-1, 2-methoxyestradiol, paclitaxel, osteonectin, chondromodulin-1, and others 16303235 (Table 4). These molecules suppress the action of angiogenic mediators, such as VEGF, HIFs, or the α_Vβ₃ integrin 16303235.

Differential vascular morphology may exist in the synovia of RA versus psoriatic arthritis (PsA) patients 1625. Furthermore, VEGF production may be associated with increased disease activity and accelerated angiogenesis in PsA and ankylosing spondylitis 16. In SLE, angiogenic EGF, FGF, and IL-18 as well as angiostatic endostatin have been detected in the sera of patients. Serum VEGF levels were correlated with the SLAM (systemic lupus activity measure) activity score 1625. Angiogenesis in SSc is somewhat controversial. On one hand, there is significant loss of vessels in scleroderma despite severe tissue hypoxia associated with increased concentrations of the angiostatic endostatin 1628. On the other hand, SSc skin biopsy explants stimulated neovascularization and there is increased production of VEGF in the sera and skin of scleroderma patients 1628. Thus, hypoxia may induce angiogenesis in SSc but this is transient and the newly formed vessels are rather unstable in this disease 28. Furthermore, sustained production of VEGF results in the formation of giant capillaries seen using capillaroscopy in SSc 1628. Similarly to SSc, in inflammatory myopathies, expression of hypoxia-associated increased HIF-1, α_Vβ₃ integrin, and VEGF receptor in muscle biopsies was not sufficient to compensate the loss of blood vessels 1625. Regarding systemic vasculitides, abundant production of angiogenic VEGF and TGF-β has been associated with Kawasaki syndrome 16. Increased serum levels of TGF-β were found in ANCA (antineutrophil cytoplasmic antibody)-associated vaculitides, including Wegener granulomatosis, Churg-Strauss syndrome, and microscopic polyangiitis 1625.

There may be two major strategies to control angiogenesis in arthritis as well as in malignancies 163235. Endogenous inhibitors of neovascularization described above, including cytokines, chemokines, protease inhibitors, and others, are naturally produced in the arthritic synovium. However, angiogenic mediators are abundant within the inflamed tissue; therefore, these endogenous angiostatic molecules need to be administered in excess in order to attenuate neovascularization. In addition, numerous synthetic compounds currently used to control inflammation and to treat arthritis may, among other effects, inhibit capillary formation as well. These exogenous angiostatic compounds include corticosteroids, traditional disease-modifying agents (DMARDs) and biologics, antibiotic derivatives, thalidomide, and others 163235 (Table 5). Among endogenous angiogenesis inhibitors, angiostatin and endostatin block α_Vβ₃ integrin-dependent angiogenesis and both molecules inhibited the development of arthritis in various animal models 1635. Thrombospondin-1 and -2 are angiostatic ECM components produced by RA synovial macrophages and fibroblasts 1632. IL-4 and IL-13 gene transfer attenuated synovial inflammation and angiogenesis in rats 16. The PF4/CXCL4 chemokine has also been tried in rodent models 16. Fumagillin analogs, such as TNP-470 and PPI2458, also exert angiostatic and antiarthritic properties 163235. Traditional DMARDs and biologics exert various anti-inflammatory effects. In addition, these compounds may inhibit synovial vessel formation by nonspecifically blocking the action of angiogenic mediators 1617. Thalidomide, recently introduced into the treatment of RA and lupus, is a potent TNF-α antagonist and angiogenesis inhibitor 1635. CC1069, a thalidomide analog, even more potently inhibited arthritis in rats 35. The hypoxia-HIF pathway may also be targeted using nonspecific inhibitor compounds, including YC-1 1635. 2-Methoxyestradiol, mentioned above, and paclitaxel (taxol), a drug already used in human cancer, destabilize the intracellular cytoskeleton and also block HIF-1α 35. Soluble Fas ligand (CD178) inhibited synovial VEGF production and angiogenesis 16. Pioglitazone, an anti-diabetic PPAR-γ (peroxisome proliferator-activated receptor-gamma) agonist, is also angiostatic. Pioglitazone effectively controlled psoriatic arthritis in 10 patients 1635. Regarding specific exogenous strategies, VEGF is the key target 3035. Numerous synthetic VEGF and VEGF receptor inhibitors (including vatalanib, sunitinib, sorafenib, and vandetanib), anti-VEGF antibodies (including bevacizumab), and inhibitors of VEGF and VEGF receptor signaling inhibit neovascularization and are under development for cancer therapy 3035. To date, vatalanib has been tried and attenuated knee arthritis in rabbits 35. The Ang-Tie system may also be targeted. A soluble Tie2 receptor transcript was delivered via an adenoviral vector to mice. The inhibition of Tie2 delayed the onset and attenuated the severity of arthritis 1635. Vitaxin, a humanized antibody to the α_Vβ₃ integrin, inhibited synovial angiogenesis 1634 but, in a phase II human RA trial, showed only limited efficacy 35. Numerous specific MMP inhibitors have been tried in angiogenesis models 1635. Endothelin-1 antagonists currently used in the therapy of primary and SSc-associated secondary pulmonary hypertension may also exert angiostatic effects 1628.

Accelerated atherosclerosis and increased cardiovascular morbidity and mortality have been associated with RA, SLE, APS, and SSc 363738394041. Cardiovascular disease (CVD) causes reduced life expectancy and became a major mortality factor in these diseases 363738394041. Atherosclerosis is also considered an inflammatory disease; thus, it may share common pathogenic mechanisms with rheumatic diseases 364243 (Table 6). Numerous studies have demonstrated the role of traditional, Framingham, and inflammation-associated risk factors in atherosclerosis associated with arthritis 36373844. Among traditional risk factors, cigarette smoking not only is a major risk factor for CVD but has recently been implicated in tissue citrullination, the production of anti-cyclic citrullinated peptide (anti-CCP) antibodies, and thus susceptibility to RA 3638. In addition to smoking, physical inactivity, obesity, hypertension, dyslipidemia, and diabetes mellitus may be implicated in accelerated atherosclerosis 36373844. Yet excess CVD mortality occurs predominantly in RA patients with a higher degree of systemic inflammation 36; therefore, accelerated atherosclerosis cannot be fully explained on the basis of traditional risk factors 4243.

Indeed, several inflammatory and atherogenic mediators, including homocysteine, lipoprotein (a), C-reactive protein (CRP), hyperhomocysteinemia, and folate, and vitamin B₁₂ deficiency and decreased paraoxonase-1 activity are strongly associated with atherosclerosis and CVD 364243. Athero-sclerotic plaques, similarly to the RA joint, are characterized by enhanced accumulation of inflammatory monocytes/macrophages and T cells. These inflammatory leukocytes abundantly produce proinflammatory cytokines, chemokines, and MMPs 4243. CD4⁺ T cells, especially the CD4⁺/CD28^- T-cell subset, have been associated with both arthritis and inflammation-related vascular damage 373843. Regarding proinflammatory cytokines, TNF-α and IL-6 play an important role in atherosclerosis as well as in RA 313643. Increased production of TNF-α and IL-6 has been associated with heart failure as well as with insulin resistance, dys-lipidemia, and obesity 3643. In contrast, IL-4 and IL-10 may exert an anti-inflammatory role during the development of atherosclerosis by driving Th2 responses 3143 (Table 6).

In RA, age, gender, ethnicity, traditional risk factors described above as well as (among RA-related risk factors) disease duration, activity, and severity, functional impairment, rheumatoid factor and anti-CCP status, CRP, radiographic indicators, presence of the shared epitope, and treatment modalities have been implicated in the development of accelerated atherosclerosis 36373844. We have recently assessed common carotid intima-media thickness (ccIMT) indicating atherosclerosis and flow-mediated vasodilation (FMD), a marker of endothelial dysfunction in RA. Increased ccIMT and impaired FMD have been associated with age, disease duration, and anti-CCP, CRP, and IL-6 production 44. In SLE, primary APS (PAPS) and secondary APS associated with SLE, traditional, and autoimmune-inflammatory factors are involved 40. Among these factors, longer disease duration and cumulative corticosteroid dose seem to

be the major predictors of clinical atherosclerosis 37384041. Additional inflammatory risk factors include CRP, fibrinogen, IL-6, costimulatory molecules (CD40/CD40L), CAMs, anti-phospholipid antibodies (APAs), including anti-cardiolipin and anti-β2 glycoprotein I (anti-β2GPI), anti-oxidized low-density lipoprotein (anti-oxLDL), anti-oxidized palmitoyl arachidonoyl phosphocholine (anti-oxPAPC), anti-HDL and anti-hsp antibodies, homocysteine, and lipoprotein (a) 374041. APAs are of importance in both SLE and APS. APAs may bind to neoepitopes of oxLDL as well as to oxLDL-

β2GPI complexes, and both APA and anti-oxLDL antibodies have been implicated in the pathogenesis of atherosclerosis associated with SLE and APS 37384041. Autoantibodies against oxLDL-β2GPI complexes have been detected in SLE and PAPS patients 4041. Both APA and anti-oxLDL may account for increased mortality in CVD 41. The β2GPI phospholipid cofactor has been detected in the wall of large arteries in the vicinity of CD4⁺ T-cell infiltrates. Macrophages and ECs bind to β2GPI during the atherosclerotic process 373841. Atherosclerosis is the most pronounced in lupus-associated secondary APS, in which traditional and nontraditional risk factors are multiplied and atherosclerosis occurs more prematurely 4041. SSc is associated with both macrovascular disease (including CVD, pulmonary hypertension, and peripheral arterial occlusion) and micro-vascular disease (including Raynaud phenomenon) 3738394546. Pathogenic factors involved in SSc-associated vascular damage include increased LDL, homocysteine, and CRP production 373946. We recently described the association of 5,10-methylene-tetrahydrofolate reductase (MTHFR) C677T polymorphism with homocysteine, vitamin B₁₂ production, and macrovascular abnormalities in SSc 46. Increased arterial stiffness and ccIMT as well as impaired FMD have been detected by us 3945 and others 37 in scleroderma.

Anti-inflammatory treatment used in inflammatory rheumatic diseases may be either proatherogenic or antiatherogenic 3747. Corticosteroids are atherogenic by augmenting dys-lipidemia, hypertension, and diabetes mellitus 3647. In autopsy studies, long exposure to corticosteroid therapy was associated with the development of atherosclerosis. However, other clinical studies could not confirm this association 3647. Glucocorticoids may exert a bimodal action as they are atherogenic but, on the other hand, also anti-inflammatory. There is evidence that the above-described inflammatory factors associated with more active disease may exert higher risk for atherosclerosis than anti-inflammatory treatment 3747. In contrast to corticosteroids, antimalarial drugs such as chloroquine and hydroxychloroquine may exert evident antiatherogenic properties. Antimalarials may reduce LDL cholesterol, very LDL cholesterol, and (in corticosteroid-treated patients) triglyceride production 363747. Methotrexate (MTX) exerts bipolar effects on atherosclerosis in RA: on one hand, MTX treatment increases plasma levels of homocysteine, but, on the other hand, MTX controls several other mediators of inflammation and thus may beneficially influence the net outcome of CVD in RA 3647. Concomitant folate supplementation prevented the increase of homocysteine production and reduced CVD mortality in MTX-treated patients 36. Among biologic agents, TNF-α blockers may have significant effects on the vasculature 48. In RA, infliximab treatment reduced endothelial dysfunction and ccIMT 48. We recently proposed that rituximab may also exert favorable effects on FMD, ccIMT, and dyslipidemia 49. Atherosclerosis treatment strategies in rheumatic diseases should include an aggressive control of all traditional risk factors, including hyperlipidemia, hypertension, smoking, obesity, and diabetes mellitus. Both pharmacological treatment and changes in lifestyle should be introduced in these patients 47. There is very little solid evidence from randomized controlled trials indicating the preventative action of any drugs in arthritis-associated CVD 47. Drug therapy may include the use of antiplatelet agents, statins, folic acid, B vitamins, and (as described above) possibly antimalarials 3647. A recommendation from the European League Against Rheumatism for the prevention and management of CVD in arthritis is about to be published 50.