Effects of Biologics on Vascular Function and Atherosclerosis Associated with Rheumatoid Arthritis

CONTEMPORARY CHALLENGES IN AUTOIMMUNITY Effects of Biologics on Vascular Function and Atherosclerosis Associated with Rheumatoid Arthritis György Kerekes, a Pál Soltész, a Henriett Dér, a Katalin Veres, a Zoltán Szabó, b Anikó Végvári, b Yehuda Shoenfeld, c and Zoltán Szekanecz b a Cardiovascular Unit, Third Department of Medicine, and b Department of Rheumatology, Institute of Medicine, University of Debrecen Medical and Health Science Center, Debrecen, Hungary c Department of Medicine B and Center for Autoimmune Diseases, Sheba Medical Center, Tel-Hashomer, Israel Endothelial dysfunction and accelerated atherosclerosis lead to increased cardiovascular morbidity and mortality in rheumatoid arthritis (RA). Sustained inflammation is a major risk factor. Apart from traditional vasculoprotective agents, biologics may also exert favorable effects on the vasculature. Indeed, tumor necrosis factor-α (TNF-α) inhibitors agents may transiently improve endothelial function. There are conflicting data regarding the effects of biologics on atherosclerosis and arterial stiffness. Infliximab stimulates the number and differentiation of endothelial progenitor cells that lead to vascular repair. There may be differences in the effects of TNF blockers on dyslipidemia, as long-term infliximab therapy may be proatherogenic, while some studies suggest that etanercept and adalimumab may exert beneficial effects on lipids. TNF blockers may decrease the incidence of cardiovascular events in RA. Preliminary data suggest that rituximab may also improve endothelial function and dyslipidemia. Further studies are needed to determine the net effects of biologics on the vasculature. Key words: rheumatoid arthritis; endothelial dysfunction; atherosclerosis; flowmediated vasodilatation; carotid intima-media thickness; arterial stiffness; lipid profile Introduction Accelerated atherosclerosis and increased cardiovascular risk have become major factors of mortality in rheumatoid arthritis (RA). 1 4 Both classical (Framingham) as well as inflammation-associated risk factors have been implicated in atherosclerosis associated with RA, as well as other rheumatic diseases. 2 5 Regarding traditional risk factors, cigarette smoking and dyslipidemia have been implicated in Address for correspondence: Zoltán Szekanecz, MD, PhD, Institute of Medicine, Department of Rheumatology, University of Debrecen Medical and Health Science Center, Hungary Móricz Zs krt. 22., H-4032 Debrecen, Hungary. szekanecz@iiibel.dote.hu the development of atherosclerosis in RA. 2,3 However, there is no clear evidence that obesity, hypertension, diabetes mellitus, or physical inactivity would be crucial in this respect. 2,3 Data on dyslipidemia in RA are also conflicting, and decreased high-density lipoprotein cholesterol (HDL-C) and increased low-density lipoprotein cholesterol (LDL-C) levels may be secondary to chronic inflammation. 2,3 Therefore, RA-associated atherosclerosis cannot be fully explained by Framingham risk factors (Table 1). Thus, inflammatory mechanisms underlying RA are crucial for early atherosclerosis and CVD development. 6,7 Homocysteine and C reactive protein (CRP) are independent risk Contemporary Challenges in Autoimmunity: Ann. N.Y. Acad. Sci. 1173: 814 821 (2009). doi: 10.1111/j.1749-6632.2009.04645.x c 2009 New York Academy of Sciences. 814

Kerekes et al.: Vascular Effects of Biologics in RA 815 TABLE 1. Common Pathogenic Factors in RA and Atherosclerosis 1. Traditional - age - smoking - dyslipidemia, oxldl - sedentary lifestyle immobilization 2. Inflammatory - acute phase proteins (CRP, fibrinogen) - autoantibodies (anti-ccp, RF, anti-oxldl, angti-hsp) - proatherogenic cytokines and chemokines - matrix-degrading metalloproteinases - increased cell adhesion molecule expression - hyperhomocysteinemia - defective apoptosis 3. Iatrogenic - methotrexate bimodal? - corticosteroids bimodal? factors for atherosclerosis. 1 3 Atherosclerotic plaques, as well as the RA joint, contain inflammatory leukocytes mainly T cells, proinflammatory cytokines, chemokines and matrix-degrading enzymes. 1 3,8,9 Endothelial activation, dysfunction, and atherogenesis have been associated with the increased expression of endothelial adhesion molecules. 10 It has been shown that sustained inflammatory activity may be the predominant risk factor for accelerated atherosclerosis and excess CVD mortality in RA. 1 4,8 Accelerated atherosclerosis indicated by increased common carotid intimal-medial thickness (ccimt) has been described in RA. 1 4 As previously reported by us and others, early endothelial dysfunction indicated by impaired flow-mediated vasodilatation (FMD) of the brachial artery precedes atherosclerosis in RA. 1 4,11 In addition, increased arterial stiffness indicated by increased pulse-wave velocity (PWV) and auigmentation index (AIx) has also been associated with RA. 11 13 The detection of early endothelial dysfunction, arterial stiffness and overt atherosclerosis is crucial for the early prevention and management of arthritisrelated vascular disease. Endothelial progenitor cells (EPCs) form a population of blood stem cells that are involved in tissue development, vascular repair, and atherosclerosis. 14 16 Under normal conditions, EPCs become mobilized from the bone marrow and differentiate into mature endothelial cells. 15,16 Attenuated vasculogenesis and vascular repair have been associated with vascular diseases, as well as with RA. 14 16 Defective vascular repair and low circulating EPC numbers were correlated with disease activity. 14 Furthermore, TNF-α inhibits the colony formation of EPCs. 14 After finding arthritis patients at high risk for vascular diseases, optimal prevention and management are needed in order to minimize vascular complications and decrease cardio- and cerebrovascular mortality. Until recently, there have been no official recommendations in this respect. Certainly, vasoprotective therapy, including aspirin, statins, folate, or vitamin B12, should be introduced to RA patients at a higher vascular risk. 2 4 Yet the effective control of systemic inflammation maybe even more important. Corticosteroids and methotrexate (MTX) may have bidirectional effects, as on one hand the use of these agents may be beneficial by controlling autoimmune inflammation, while on the other hand, corticosteroids and MTX themselves may be proatherogenic. 2 4 Recently, the European League Against Rheumatism (EULAR) has set up a task force that has prepared nine recommendations for cardiovascular risk management in arthritis. Apart from other recommendations, the EU- LAR task force suggests that adequate control of disease activity is necessary to lower the CVD risk (best evidence for anti-tnf treatment and MTX treatment). 17 Numerous recent publications have suggested that biologic agents, primarily tumor necrosis factor-α (TNF-α) inhibitors, may have significant effects on the vasculature. 10,18 40 For example, there have been several reports primarily on infliximab, but also on adalimumab and etanercept suggesting that these biologics may influence the lipid profile,

816 Annals of the New York Academy of Sciences endothelial dysfunction, carotid atherosclerosis, arterial stiffness, and probably CVD outcome in RA. 20 37 In addition, two recent studies indicated similar beneficial effects of rituximab. 18,19 In this review, we summarize recent, sometimes controversial data on the effects of various biologic agents on metabolic changes, atherosclerosis and CVD associated with RA. Endothelial Dysfunction Numerous recent reports have suggested that anti-tnf biologicals may have effects on the vasculature and lipid profile in RA patients. Some of these reports are controversial. Most data have been published with respect to infliximab. In the first study, published in 2002, FMD was assessed in 11 patients with active RA before and after 12 weeks of infliximab therapy. Infliximab improved endothelium-dependent vasodilation indicated by FMD, but it did not influence endothelium-independent vasodilation. The beneficial effect of infliximab on endothelial function was accompanied by decreased erythrocyte sedimentation rates and CRP levels. 20 In another study, FMD was assessed before and 36 weeks after infliximab therapy in comparison to patients on conventional immunosuppressive treatment. Anti- TNF therapy significantly improved endothelial function in comparison to traditionally treated patients. 21 Only a transient improvement of endothelial function upon infliximab therapy was reported in various studies. In a study of seven RA patients, infliximab treatment resulted in a rapid improvement of FMD in all subjects. However, after a short-term beneficial effect, FMD returned to baseline by 4 weeks after infusion. 22 In 10 patients with severe, long-standing RA, infliximab treatment resulted in a reversible, transient increase in FMD. 23 Infliximab treatment of 34 RA patients resulted in the suppression of soluble endothelial cell adhesion molecule production. 10 Low levels of circulating adiponectin have been associated with endothelial dysfunction. In a study of 15 RA patients, infliximab treatment resulted in a short-term increase of serum adiponectin levels, which was associated with significant improvement of endothelial function. 24 Thus, short courses of infliximab only transiently improved endothelial function in most studies. Therefore, long-term use of anti-tnf biologics may be needed in order to reduce the cardiovascular complications in RA. Regarding other TNF blockers, eight RA patients refractory to infliximab were treated with adalimumab. There was a rapid increase of FMD at day 2 that was sustained for 12 weeks. This was accompanied by decreases of DAS28 and CRP levels. 25 In a recent pilot study on vascular effects of rituximab, we included five RA patients with a mean age of 42 years and a mean disease duration of 5.8 years. We administered two infusions of 1000 mg rituximab each at 2 weeks apart after corticosteroid premedication. We assessed brachial artery FMD at baseline, at week 2 (right before the second rituximab infusion), at week 6 and at week 16. All five patients exerted 22 112% of improvement in FMD by week 16, a time long enough to exclude corticosteroid effects. 19 In a very recent report, Gonzalez-Juanatey et al. 18 used the same protocol to treat five consecutive female patients with active RA refractory to TNF blockers with two infusions of 1000 mg rituximab each. FMD was assessed at baseline, at week 2 and at month 6. Rituximab treatment resulted in dramatic increases of FMD at week 2 and at month 6. Improvement of endothelial function was associated with decreases in CRP levels and DAS28 scores. Carotid Atherosclerosis Regarding carotid atherosclerosis, ccimt was assessed in 30 patients before infliximab or etanercept therapy and 12 months after therapy. A significant improvement in ccimt on both sides was observed, which was preceded

Kerekes et al.: Vascular Effects of Biologics in RA 817 by an early and lasting decrease in disease activity markers. 26 In contrast, 56-week infliximab treatment of 26 RA patients did not affect ccimt. 27 Thus, data are rather conflicting regarding the effects of TNF blockers on carotid atherosclerosis. In our rituximab study described above, despite of the short follow-up time of 16 weeks, carotid atherosclerosis significantly improved in three of five patients by the end of the observation period. 19 There have been no other reports on the effects of rituximab on overt atherosclerosis in RA. Arterial Stiffness Aortic stiffness was assessed in nine RA patients treated with etanercept at 0, 4, and 12 weeks. Anti-TNF therapy significantly reduced aortic PWV by weeks 4 and 12. 13 In a long-term cohort, 26 RA patients were treated with infliximab for one year. In this study, 56- week infliximab treatment resulted in a significant decrease of PWV. 27 In contrast, when 14 RA patients were treated with either infliximab, etanercept, or adalimumab, despite significant clinical response and reduction of inflammation, there was no change in arterial stiffness indicated by AIx. 28 Thus, results on arterial stiffness are rather controversial. However, different TNF blockers were used in the studies. In addition, some investigators assessed PWV, while others measured AIx. Therefore, data from different studies may not be comparable. Lipid Profile and Insulin Resistance Regarding lipid profiles, short-term infliximab treatment of 69 RA patients resulted in significant increases in both total cholesterol and HDL-cholesterol levels, which was not accompanied by a favorable effect on the atherogenic index. 29 Similar results were obtained from another study that included 34 consecutive RA patients treated with infliximab, etanercept, or adalimumab. Anti-TNF treatment resulted in significant increases in both total cholesterol and HDL-C levels, but no changes in the atherogenic index were observed. 30 In a study of 19 patients with active RA, infliximab treatment increased total cholesterol, HDL-C, LDL-C, and triglyceride levels, while the atherogenic index and the LDL-C/HDL- C ratio remained unchanged. 31 Thus, for most studies, even if infliximab altered the lipid profile, there was no change in the atherogenic index. Some other studies yielded negative results. In a study of 82 RA and ankylosing spondylitis patients, infliximab treatment exerted a neutral effect on the lipid profile since neither LDLcholesterol levels nor total cholesterol/hdl-c and triglyceride/hdl-c ratios changed during a 6-month course of treatment. 32 Others also did not observe any effects of infliximab, etanercept or adalimumab on the lipid profile including total cholesterol, triglyceride, HDL- C or LDL-C levels in 29 RA patients. 33 In one report, infliximab treatment of 32 patients with refractory RA resulted in the induction of very high VLDL-triglyceride levels. 34 Although this result has not been confirmed by larger studies, RA patients treated with infliximab may need careful serum triglyceride level monitoring. After these short-term studies, 55 RA patients were treated with infliximab and followed for 6 months, while 31 of these patients were treated and followed for one year. The shortterm effects of anti-tnf therapy on the lipid profile seemed beneficial; however, plasma concentrations of total cholesterol, LDL-C and the atherogenic index increased after 6 months and up to one year of infliximab therapy. Thus, long-term infliximab treatment may rather be proatherogenic. 35 Regarding other TNF blockers, in a study on 33 RA patients, adalimumab treatment resulted in significantly increased HDL-C levels, while LDL-C and triglyceride levels did not change, 36 suggesting a favorable effect of

818 Annals of the New York Academy of Sciences adalimumab on the HDL-C/LDL-C ratio. Adalimumab also reduced the atherogenic index after 12 weeks of treatment in eight RA patients. 25 When 65 consecutive patients with RA and ankylosing spondylitis were treated with infliximab or etanercept, infliximab treatment increased total cholesterol and LDL-C levels but had no effects on HDL-C and triglyceride production, whereas etanercept significantly increased HDL-Cbut had no effects on total cholesterol or LDL-C levels. 37 Although the majority of studies have been performed administering infliximab, data summarized above suggest that various TNF-α blockers may have different effects on the lipid profile and atherogenicity. While longterm infliximab treatment may be proatherogenic, etanercept and adalimumab treatment may be associated with a less atherogenic profile. As one possible explanation of these differences, while etanercept inhibits both TNFα and lymphotoxin-α, infliximab only blocks TNF-α. Indeed, lymphotoxin-α was found to be far more atherogenic than TNF-α.Thus,the blockade of lymphotoxin-α in addition to that of TNF-α by etanercept may account for the anti-atherogenic profile of etanercept in comparison to infliximab. 37 In our study described above, rituximab treatment decreased total cholesterol and increased HDL-C levels in four of five patients, yielding a mean 8.5% decrease in total cholesterol and a mean 35.4% increase in HDL-C by week 16. In contrast, effects on LDL-C and triglyceride levels were rather controversial, as both increases and decreases in LDL- C and triglyceride production were observed even in the same patient during the follow-up period. 19 To date, no other reports are available on the effects of rituximab on lipid profiles in RA. Endothelial Progenitor Cells As described above, there is a deficiency of EPCs in RA, which has been associated with abnormal vascular repair in atherosclerosis. 14 16 As TNF-α suppresses the colony-forming activity of EPCs, 14 anti-tnf treatment may have beneficial effects on EPC number and function. Indeed, infliximab treatment of 14 active RA patients resulted in a 33% increase in circulating EPC numbers. Anti- TNF treatment also improved EPC adhesion and differentiation. The stimulation of EPC number and function by infliximab was correlated with clinical response indicated by DAS28 changes. 38 Clinical Vascular Effects After describing the mechanisms of action of biologics on atherosclerosis, endothelial function, arterial stiffness, lipid profile, and vasculogenesis, it is even more important to know whether these effects will influence the morbidity and mortality of CVD. In a Swedish national register, 531 RA patients received infliximab or etanercept therapy between 1999 and 2005 and the primary end point was the first CVD event. In the anti-tnf treated patients, the age- and sex-adjusted incidence rate of first CVD events was less than half of that observed in the anti-tnf nontreated patients. 39 Recently, data from the British Society for Rheumatology Biologics Register were analyzed and rates of myocardial infarction (MI) were compared in 8,670 RA patients treated with TNF blockers and 2,170 patients treated with traditional DMARDs. There was no difference in the incidence of MI between the two patient groups. However, when anti-tnf responders and nonresponders were compared, the risk of MI was markedly reduced in patients exerting a good clinical response after 6 months of anti-tnf therapy in comparison to nonresponders. 40 Certainly, more epidemiological data from large cohorts are needed to determine how molecular and morphological effects of biologics translate to clinical changes of vascular morbidity and mortality.

Kerekes et al.: Vascular Effects of Biologics in RA 819 Conclusions Accelerated atherosclerosis and increased cardio- and cerebrovascular morbidity and mortality have been associated with RA, as well as other inflammatory rheumatic diseases. It is likely that sustained systemic inflammation and clinical activity of arthritis are major contributors to atherogenesis. Aspirin, statins, folic acid, and vitamin B12 have been introduced to the prevention and therapy of vascular diseases in RA; however, they primarily treat traditional Framingham risk factors. Corticosteroids and methotrexate may exert both beneficial and detrimental effects on the vasculature. Biological agents, primarily TNF-α inhibitors, effectively suppress arthritis and have various effects on the vascular system. Short-term administration of infliximab and possibly also etanercept and adalimumab may improve endothelial function, but in most cases this is a transient effect. There is much less data available on the effects of TNF blockers on carotid atherosclerosis and arterial stiffness. Results of the small number of studies are rather conflicting, and therefore, this issue needs further confirmation in larger cohorts. Infliximab may have a favorable short-term effect on the lipid profile, but an increasing amount of data has become available suggesting that the long-term use of infliximab may rather be proatherogenic. There are only few studies regarding influences of etanercept and adalimumab on lipids. In these studies, both anti-tnf agents had beneficial effects on dyslipidemia. Thus, different TNF blockers may have variable effects on the lipid profile, but, again, larger studies are needed to confirm this variability. Preliminary data on rituximab suggestthatitmayalsohavefavorableeffectson the lipid profile, endothelial dysfunction, and atherosclerosis. Some studies suggest that TNF blockers, primarily infliximab, may increase the number and stimulate the functions of EPCs. Thus, anti-tnf treatment may induce vasculogenesis and enhance vascular repair underlying inflammatory atherosclerosis. Finally, it is important to see how these metabolic and vascular effects translate to the clinical setting. Preliminary data from large registries indicate that anti-tnf agents may delay the first cardiovascular events and in anti-tnf responders, TNF blockade may decrease the incidence of myocardial infarction. The net effects of anti-tnf agents and other biologics on the vasculature and on vascular diseases, variability between individual agents, and differences between shortand long-term effects should be determined by more detailed analysis of patient cohorts and large registries. Due to the length of this chapter we are unable to summarize all of the cutting-edge issues that surround this research. For this reason, we recommend reading recent literature on this subject. 1,11,25,27,33,37 Acknowledgments This work was supported by research grants T 048541 (Z. S.) and a Bolyai Research Grant (P.S.). Conflicts of Interest The authors declare no conflicts of interest. References 1. Kerekes, G., Z. Szekanecz, H. Dér, et al. 2008. Endothelial dysfunction and atherosclerosis in rheumatoid arthritis: a multiparametric analysis using imaging techniques and laboratory markers of inflammation and autoimmunity. J. Rheumatol. 35: 398 406. 2. Giles, J.T., W. Post, R.S. Blumenthal & J.M. Bathon. 2006. Therapy insight: managing cardiovascular risk in patients with rheumatoid arthritis. Nat. Clin. Pract. Rheumatol. 2: 320 329. 3. Shoenfeld, Y., R. Gerli, A. Doria, et al. 2005. Accelerated atherosclerosis in autoimmune rheumatic diseases. Circulation 112: 3337 3347. 4. Szekanecz, Z., G. Kerekes, H. Dér, et al. 2007. Accelerated atherosclerosis in rheumatoid arthritis. Ann. N. Y. Acad. Sci. 1108: 349 358. 5. Ross, R. 1999. Atherosclerosis an inflammatory disease. N.Engl.J.Med.340: 115 126. 6. Solomon, D.H., E.W. Karlson, E.B. Rimm, et al. 2003. Cardiovascular morbidity and mortality in

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