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The effect of pharmacological therapy on the cardiovascular system of patients with systemic rheumatic diseases
Autoimmunity Reviews 9 (2010) 835–839
Contents lists available at ScienceDirect
Autoimmunity Reviews j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / a u t r ev
Review
The effect of pharmacological therapy on the cardiovascular system of patients with systemic rheumatic diseases Fabiola Atzeni a, Maurizio Turiel b, Roberto Caporali c, Lorenzo Cavagna c, Livio Tomasoni b, Simona Sitia b, Piercarlo Sarzi-Puttini a,⁎ a b c
Rheumatology Unit, L. Sacco University Hospital, Milan, Italy Division of Rheumatology, University of Pavia, IRCCS San Matteo Foundation, Pavia, Italy Cardiology Unit, IRCCS Galeazzi Orthopedic Institute, University of Milan, Milan, Italy
a r t i c l e
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Article history: Accepted 24 July 2010 Available online 30 July 2010 Keywords: Disease-modifying antirheumatic drugs Biological agents Anti-TNF agents Autoimmune disease Tocilizumab Mortality
a b s t r a c t The higher mortality rate among rheumatoid arthritis (RA) patients in comparison with the general population is largely attributable to cardiovascular (CV) disease, particularly coronary atherosclerosis, but also non-fatal myocardial infarction and heart failure. It may be due to RA-specific risk factors such as hyperhomocysteinemia, disease-related dyslipidemia or vascular inflammation, or morbidity related to high levels of cytokines such as tumour necrosis factor (TNF) and RA medications. Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most important in rheumatology, but many are associated with CV disease. A number of randomised control trials have shown that, although exposure to low doses of corticosteroids for 1–3 years does not significantly increase CV risk, longer exposure can increase CV events. The use of disease-modifying antirheumatic drugs (DMARDs), particularly methotrexate, increases homocysteinemia, reduces inflammation and improves lipid profiles, thus reducing the development of atherosclerosis and clinically overt CVD. Although contraindicated in RA patients with severe heart failure, biological agents such as anti-TNF agents delay and even reverse the progression of endothelial dysfunction and atherosclerosis. Tocilizumab leads to changes in lipid profiles without increasing adverse vascular events. The effects on the CV system depend on the drug itself, the dose and the period of exposure, and so CV risk should be evaluated before starting treatment with any drug. © 2010 Elsevier B.V. All rights reserved.
Contents 1. 2. 3. 4. 5.
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Introduction . . . . . . . . . . . . . . . . Non-steroidal anti-inflammatory drugs . . . Corticosteroids . . . . . . . . . . . . . . . Statin treatment . . . . . . . . . . . . . . Disease-modifying antirheumatic drugs . . . 5.1. Methotrexate . . . . . . . . . . . . 5.2. Cyclosporin and leflunomide . . . . . 5.3. Sulfasalazine . . . . . . . . . . . . 5.4. Antimalarial agents . . . . . . . . . 5.5. Cyclophoshamide and mycophenolate 5.6. Conclusion . . . . . . . . . . . . . Biological agents . . . . . . . . . . . . . . 6.1. Anti-TNF agents infliximab, etanercept 6.2. Anakinra . . . . . . . . . . . . . . 6.3. Rituximab. . . . . . . . . . . . . . 6.4. Tocilizumab . . . . . . . . . . . . . 6.5. Abatacept . . . . . . . . . . . . . .
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⁎ Corresponding author. L. Sacco University Hospital of Milan, Via G.B. Grassi 74, 20175 Milano, Italy. Tel.: +39 0239042208. E-mail addresses: [email protected], [email protected] (P. Sarzi-Puttini). 1568-9972/$ – see front matter © 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.autrev.2010.07.018
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7. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Take-home messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction Inflammatory rheumatic diseases are associated with a substantial increase in accelerated atherosclerosis [1]. Studies have demonstrated that mortality is higher in patients with rheumatoid arthritis (RA) than in the general population, and most of the excess mortality is due to accelerated atherosclerosis. Although RA and atherosclerotic cardiovascular (CV) disease share risk factors such as smoking and poor diet, the increased risk of CV disease in RA patients cannot be explained by traditional risk factors alone. Various disease-related mechanisms may be involved in the development of premature vascular damage, including an increased synthesis of pro-inflammatory mediators (cytokines, chemokines and adhesion molecules), autoantibodies against endothelial cell components, perturbations in T cell subsets, genetic polymorphisms, hyperhomocysteinemia, oxidative stress, abnormal vascular repair, and iatrogenic factors [1,2]. 2. Non-steroidal anti-inflammatory drugs Non-steroidal anti-inflammatory drugs (NSAIDs) are a large number of compounds that act by non-selectively inhibiting the cyclo-oxygenase isoenzymes COX-1 and/or COX-2. Two main classes are currently on the market: classic NSAIDs, which consist of various sub-classes that block both COX-1 and COX-2 (e.g. enolic, acetic, propionic and fenamic acid derivates), and the COXIBs that act selectively on inducible COX-2 (e.g. celecoxib and etoricoxib). The CV toxicity of these drugs is a relatively recent issue that was raised in 2004 when rofecoxib was withdrawn from the market on the basis of the results of the Adenomatous Polyp Prevention on Vioxx (APPROVe) study [3] because its long-term use was related to a higher incidence of acute myocardial infarction (AMI) in comparison with placebo. This withdrawal markedly changed the prescribing pattern of pain-killing drugs, leading to a striking decrease in the use of COXIBs without any increase in the use of other NSAIDs, as shown in a recently published survey [4]. It was subsequently found that celecoxib was also associated with an increased risk of CV disease [5], with both dose and pharmacokinetics possibly affecting the onset of adverse events. The Alzheimer's Disease Anti-Inflammatory Prevention Trial (ADAPT) [6] found that naproxen (220 mg twice daily) increased the risk of CV events in comparison with celecoxib (200 mg twice daily), and a subsequent meta-analysis showed that the risk of AMI is increased in the users of COXIBs (OR 1.73, 95% CI:1.37–2.19) and classic NSAIDs (OR −1.41, 95% CI:1.23–1.61), with diclofenac (OR 1.51, 95% CI:1.22–1.87) and ibuprofen (OR 1.56, 95% CI:1.19–2.05) having the worst profile among the latter [7]. It has been found that NSAID-treated patients with a history of heart failure (HF) have an increased dose-dependent risk of death due to AMI and HF [8], and the fact that NSAIDs were used for a short time in the majority of case indicates their relatively acute cardiotoxic effects. Factors such as an age of N80 years, hypertension, prior CV events, RA and chronic obstructive pulmonary disease identify sub-groups at increased risk when using specific agents, with rofecoxib and ibuprofen leading to higher CV risk rates across the sub-groups [9]. Furthermore, many classic NSAIDs (particularly diclofenac and ibuprofen) are sold over the counter, which makes it more difficult to assess the CV toxicity of prescribed NSAIDs. In our study, we found that 44% of the RA/ osteoarthritis (OA) outpatients referring to our division and prescribed NSAIDs were also taking unprescribed diclofenac and ibuprofen for
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other painful conditions (73%) or because their disease-related pain was unsatisfactorily controlled (21%). Another problem is that a number of rheumatic conditions such as RA and systemic lupus erythematosus (SLE) are themselves associated with an increased CV risk due to accelerated atherosclerosis [10], and diseases such as OA are typically observed in subjects at high CV risk (e.g. older people with multiple comorbidities) [11]. NSAIDs remain as some of the most important drugs in the rheumatological field, but it is clearly essential to assess the CV risk of patients before they are used [12]. 3. Corticosteroids Corticosteroids (CTs) are powerful anti-inflammatory agents used for the symptomatic treatment of RA. They may have cardioprotective effects mediated by their anti-inflammatory and anti-proliferative action on vessel walls, but their long-term use at high doses can affect blood pressure, insulin resistance, lipid profiles, body weight and fat distribution, all of which may significantly increase the risk of CV disease [2]. A recent systematic review of the literature has revealed a weak association between low-dose CTs and CV risk factors, and identified a dose-related trend of increasing major CV events [13]. Exposure to low CT doses may beneficially affect lipid profiles and increase insulin levels, and have no effect on blood pressure, atherosclerosis, ventricular function or heart rate variability, but there is disagreement concerning their effects on arterial stiffness. In particular, four out of six studies have found an association between low CT doses and major CV events [14,15], including AMI (hazard ratio 1.7 [1.2–2.3]), stroke (odds ratio 4.36 [1.60–11.90] at doses of 6–10 mg/day), mortality (hazard ratio 2.03 [1.25–3.32]), and a composite index of CV events (with a hazard ratio of 2.21 [1.22– 4.00] in a group of patients with rheumatoid factor-positive RA); the other two studies did not find any significant association between low CT doses and mortality (odds ratio 2.25 [0.29–102.5]) or a composite index of CV events (odds ratio 1.3 [0.8–2.0]) [16,17]. The EULAR recommendations suggest using CTs only in cases of early arthritis and at doses of 7–10 mg per day for b6 months. A number of randomised controlled trials have found that exposure to low CT doses for 1–3 years does not significantly increase CV risk, but longer exposure can increase the risk of major CV events, which is doubled or tripled if prednisone is given at a dose of N10 mg per day. As RA is itself a risk factor for major CV events, physicians should only prescribe CTs for a short time at the very beginning of arthritis, and stop their use as soon as possible. The dose of prednisone should be based on patient weight. 4. Statin treatment Statins (3-hydroxy-3-methylglutarylcoenzyme-A reductase inhibitors) reduce CVD morbidity and mortality [18]. Different mechanisms are responsible for this result: effects on lipid levels, antiinflammatory and immunomodulating effects include suppression of leukocyte cytokine release, reduction of MHC class II expression and reduction of production of reactive oxygen species [18]. Moreover, in RA patients apart from reducing lipid levels, treatment with statins, as it was demonstrated on clinical trial, may also have a modest but clinically useful effect on arthritis [19]. Take together, these data suggests using statins in clinical practice in rheumatic systemic disease patients.
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5. Disease-modifying antirheumatic drugs 5.1. Methotrexate There are some indications that disease-modifying antirheumatic drugs (DMARDs) can alter CV risk by influencing atherosclerotic processes directly through inflammation or indirectly by affecting CV risk factors. However, few studies have investigated their effects on the occurrence of CV disease in RA patients, with methotrexate (MTX, a DMARD that inhibits dihydrofolate reductase and reduces folate levels) being the most widely studied [20]. A first observational study of MTX found that it led to increased serum homocysteine levels and higher mortality in patients with RA [21] although, after adjusting for all confounders, Choi et al. [22] found that CV-related mortality was 70% less in RA patients treated with MTX than in those treated with other traditional DMARDs. They also found that mortality was less in patients treated with MTX and folic acid, thus suggesting that folic acid supplementation may be beneficial [22]. Furthermore, a large cohort study of 107,908 RA patients found that MTX was associated with a significant decrease in the rate of AMI [23], and similar results was reported by Van Halm et al. in relation to coronary, cerebral and peripheral arterial disease [24]. In addition to being associated with decreased CV morbidity (even after adjusting for traditional CV risk factors), the use of MTX is also associated with decrease in hospital admissions due to HF [24]; however, folate supplementation is recommended, particularly in patients receiving MTX with sulfasalazine. 5.2. Cyclosporin and leflunomide The findings of some studies suggest that, like cyclosporin, leflunomide may adversely affect CV risk by increasing blood pressure and lipid levels, although recent studies indicate the opposite [25]. It has been reported that leflunomide can improve vascular function by: 1) inhibiting the nuclear factor kappa B signal transduction pathway associated with the pro-inflammatory and pro-atherosclerotic phenotype in endothelial cells; 2) reducing the subendothelial migration of peripheral blood mononuclear cells; 3) and impairment of antigenpresenting dendritic cells [25]. Taken together, these data suggest that leflunomide may have important vasculoprotective effects and reduce the risk of developing AMI, but the results are controversial. Suissa et al. found that leflunomide significantly decreased the rate of AMI [26], whereas Solomon et al. [27] found that patients treated with cytotoxic immunosuppressive DMARDs (leflunomide, azathioprine and cyclosporine) alone or in combination were at greater risk of AMI and stroke than those treated with MTX. 5.3. Sulfasalazine The impact of traditional DMARDs on CV disease is not only related to improvements in inflammation, but also to DMARD-induced changes in lipid profiles. Park et al. [28] found that the levels of high density lipid cholesterol (HDL-C) decreased in responders to DMARDs, and another two studies of RA patients treated with MTX (0.2 mg/kg/week) and low dose of prednisolone (7.5 mg/day) or an intensive combination of MTX plus sulfasalazine and prednisolone or sulfasalazine alone found that HDL-C increased and the atherogenic ratio decreased, thus suggesting a beneficial effect [29,30]. 5.4. Antimalarial agents It has also been shown that hydroxychloroquine, which was initially used as an antimalarial agents but is also useful in autoimmune diseases such as RA and SLE, protects against thrombotic events and improves glucose and lipid profiles, thus apparently
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reducing the risk of CV disease and increasing survival in SLE patients [31]. However, they were also associated with lower blood pressure. These effects of antimalarials in the cohort of patients with RA are much more prominent than in patients with SLE [31]. 5.5. Cyclophoshamide and mycophenolate In SLE patients, disease duration and damage index scores are closely associated with vascular disease. The use of cyclophosphamide is independently associated with a reduced risk of ultrasonographically detected carotid plaque, which suggests that intensive control of disease activity may prevent atherosclerosis, and mycophenolate mofetil seems to have some anti-atherogenic properties. 5.6. Conclusion The use of DMARDs, particularly MTX, potently suppresses inflammation and improves lipid profiles, thus reducing the development of atherosclerosis and subsequent clinically overt CV disease. However, the real effect of individual immunosuppressants on atherosclerosis in patients with RA or SLE is still unclear. 6. Biological agents 6.1. Anti-TNF agents infliximab, etanercept and adalimumab The increased mortality of patients with RA may be due to RAspecific risk factors such as hyperhomocysteinemia, disease-related dyslipidemia, vascular inflammation, drug-related morbidity, or high levels of cytokines such as tumour necrosis factor (TNF). TNF, an inflammatory cytokine released by activated monocytes, macrophages and T lymphocytes, favours the inflammatory responses that are important in the pathogenesis of RA [2]. It also promotes dyslipidemia and insulin resistance, both of which are traditional risk factors for atherosclerosis, upregulates adhesion molecules leading to fatty streak formation and the initiation of atherosclerosis, and is involved in the inflammation leading to plaque rupture [2]. It may also promote thrombophilia by encouraging thrombotic events. It plays a protective role in the physiological adaptive response to injury and limits infarct size, but its overexpression can lead to maladaptive effects such as left ventricular dysfunction [32]. The introduction of the anti-TNF agents infliximab, etanercept and adalimumab has greatly improved the outcomes of severe RA and reduced the burden of CV disease. A number of studies have investigated their effects on the lipid profiles of patients with RA [2,32], most of which have found an increase in HDL and cholesterol levels, although with some disagreement about its duration [32]. A Spanish study of 27 RA patients found a significant reduction in insulin levels and the insulin/glucose index and improved insulin resistance 2 h after infliximab infusion [33]. The levels of circulating adhesion molecules, such as serum E-selectin and intercellular adhesion molecule-1, are also decreased by anti-TNF agents. Hurlimann et al. [34] showed that short-term anti-TNF treatment improved vascular function in 11 RA patients, and a Spanish group measured carotid intima-media thickness (IMT) in eight patients with RA before and after a median of 3 years of anti-TNF treatment and found no significant difference in progression in comparison with matched controls [35]. Sidiropoulos et al. [36] reported a sustained improvement in endothelial function and no change in common carotid artery IMT after 18 months of treatment with anti-TNF agents. We have demonstrated the efficacy of long-term DMARD treatment (MTX and anti-TNF agents) in reducing disease activity, and delaying or even reversing the progression of endothelial dysfunction and atherosclerosis as a result of an increase in coronary flow reserve, with no changes in IMT [37].
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Patients with severe chronic heart failure (CHF) have higher circulating levels of TNF than healthy subjects but studies have found that that etanercept has no effect on CHF and that high-dose infliximab has detrimental effects on patients with moderate to severe CHF. Consequently, severe heart failure contraindicates anti-TNF treatment in patients with RA [38].
6.2. Anakinra A randomised, controlled clinical trial assessing the safety of the IL1 receptor antagonist anakinra found no difference in the incidence of AMI or CHF between the anakinra and placebo group [2].
6.3. Rituximab Rituximab, a chimeric monoclonal antibody against CD20 that effectively depletes B cells in peripheral blood, efficacy and safety in the treatment of RA, increased flow-mediated endotheliumdependent vasodilatation and endothelium-independent vasodilatation (post-nitroglycerin) after 2 weeks (before the second infusion) in six consecutive patients with active RA refractory to TNF inhibition (5 women; age 55–79 years), and was associated with a significant decrease in C-reactive protein (CRP) levels and disease activity scores after 6 months [39].
6.4. Tocilizumab Interleukin-6 (IL-6) is a pro-inflammatory cytokine that stimulates hepatocytes to synthesise acute phase response proteins such as CRP and fibrinogen. It may also contribute to atherosclerosis and arterial thrombosis by enhancing endothelial cell adhesiveness, activating the production of tissue factor, fibrinogen and factor VIII, increasing platelet production and aggregation, and decreasing endogenous anticoagulant levels [40]. A number of phase III clinical trials have shown that tocilizumab, a humanised monoclonal antibody against IL6 receptor, has a favourable risk/benefit ratio in the treatment of adults with moderate–severe active RA who responded inadequately or were intolerant to previous therapy with one or more DMARDs or TNF inhibitors. Tocilizumab-treated patients have experienced moderate reversible increases in the mean serum levels of total cholesterol, LDL-C, HDL-C and triglycerides, but no differences in adverse vascular events were observed between patients treated for 24 weeks with tocilizumab plus MTX or MTX alone, and there were few changes in the atherogenic index in the patients receiving tocilizumab for up to 1 year [40].
6.5. Abatacept No information is available as to whether abatacept, a fully human soluble fusion protein consisting of the extracellular domain of human CTLA-4 and the modified Fc portion of human IgG1, also decrease the excess cardiovascular morbidity and mortality associated with RA.
7. Conclusions The role of antirheumatic drugs in the development of CV involvement in RA patients is controversial. As RA is itself a risk factor for CV events, physicians should stop corticosteroids as soon as possible and screen all patients for CV disease before administering NSAIDs. Biological drugs act not only on disease activity, but also on endothelial dysfunction and the progression of atherosclerosis, thus preventing CV complications and possibly reducing mortality.
Take-home messages • Users of COXIBs and classic NSAIDs (particularly diclofenac and ibuprofen) are at increased risk of acute myocardial infarction. • Short (1–3 year) exposures to low corticosteroid doses does not significantly increase CV risk, but longer exposure may increase the risk of major CV events. • The use of statins improves lipid profile and acts modestly on arthritis. • The use of DMARDs (particularly MTX) potently suppresses inflammation and improves the lipid profile, thus reducing the development of atherosclerosis and clinically overt CV disease. • Anti-TNF agents not only reduce disease activity, but also delay and may even reverse the progression of endothelial dysfunction and atherosclerosis. • Rituximab therapy greatly increases flow-mediated endotheliumdependent and endothelium-independent vasodilatation, and can positively influence CV outcomes.
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F. Atzeni et al. / Autoimmunity Reviews 9 (2010) 835–839 [20] Westlake SL, Colebatch AN, Baird J, Kiely P, Quinn M, Choy E, et al. The effect of methotrexate on cardiovascular disease in patients with rheumatoid arthritis: a systematic literature review. Rheumatology (Oxford) 2010;49:295–307. [21] Landewe RB, van den Borne BE, Breedveld FC, Dijkmans BA. Methotrexate effects in patients with rheumatoid arthritis with cardiovascular comorbidity. Lancet 2000;355:1616–7. [22] Choi HK, Hernan MA, Seeger JD, Robins JM, Wolfe F. Methotrexate and mortality in patients with rheumatoid arthritis: a prospective study. Lancet 2002;359:1173–7. [23] Bernatsky S, Hudson M, Suissa S. Anti-rheumatic drug use and risk of hospitalization for congestive heart failure in rheumatoid arthritis. Rheumatology (Oxford) 2005;44:677–80. [24] van Halm VP, Nurmohamed MT, Twisk JW, Dijkmans BA, Voskuyl AE. Diseasemodifying antirheumatic drugs are associated with a reduced risk for cardiovascular disease in patients with rheumatoid arthritis: a case control study. Arthritis Res Ther 2006;8:R151. [25] Rozman B, Praprotnik S, Logar D, Tomsic M, Hojnik M, Kos- Golja M, et al. Leflunomide and hypertension. Ann Rheum Dis 2002;61:567–9. [26] Suissa S, Bernatsky S, Hudson M. Antirheumatic drug use and the risk of acute myocardial infarction. Arthritis Rheum 2006;55:531–6. [27] Solomon DH, Avorn J, Katz JN, Weinblatt ME, Setoguchi S, Levin R, et al. Immunosuppressive medications and hospitalization for cardiovascular events in patients with rheumatoid arthritis. Arthritis Rheum 2006;54:3790–8. [28] Park YB, Choi HK, Kim MY, Lee WK, Song J, Kim DK, et al. Effects of antirheumatic therapy on serum lipid levels in patients with rheumatoid arthritis: a prospective study. Am J Med 2002;113:188–93. [29] Georgiadis AN, Papavasiliou EC, Lourida ES, Alamanos Y, Kostara C, Tselepis AD, et al. Atherogenic lipid profile is a feature characteristic of patients with early rheumatoid arthritis: effect of early treatment — a prospective, controlled study. Arthritis Res Ther 2006;8:R82. [30] Boers M, Nurmohamed MT, Doelman CJ, Lard LR, Verhoeven AC, Voskuyl AE, et al. Influence of glucocorticoids and disease activity on total and high density lipoprotein cholesterol in patients with rheumatoid arthritis. Ann Rheum Dis 2003;62:842–5.
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[31] Ruiz-Irastorza G, Ramos-Casals M, Brito-Zeron P, Khamashta MA. Clinical efficacy and side effects of antimalarials in systemic lupus erythematosus: a systematic review. Ann Rheum Dis 2010;69:20–8. [32] Dixon WG, Symmons DP. What effects might anti-TNFalpha treatment be expected to have on cardiovascular morbidity and mortality in rheumatoid arthritis? A review of the role of TNFalpha in cardiovascular pathophysiology. Ann Rheum Dis 2007;66:1132–6. [33] Gonzalez-Gay MA, De Matias JM, Gonzalez-Juanatey C, Garcia-Porrua C, SanchezAndrade A, Martin J, et al. Anti-tumor necrosis factor-alpha blockade improves insulin resistance in patients with rheumatoid arthritis. Clin Exp Rheumatol 2006;24:83–6. [34] Hürlimann D, Forster A, Noll G, Enseleit F, Chenevard R, Distler O, et al. Anti-tumor necrosis factor-alpha treatment improves endothelial function in patients with rheumatoid arthritis. Circulation 2002;22(106):2184–7. [35] Gonzalez-Juanatey C, Testa A, Garcia-Castelo A, Garcia-Porrua C, Llorca J, Gonzalez-Gay MA. Active but transient improvement of endothelial function in rheumatoid arthritis patients undergoing long-term treatment with anti-tumor necrosis factor alpha antibody. Arthritis Rheum 2004;51:447–50. [36] Sidiropoulos PI, Siakka P, Pagonidis K, Raptopoulou A, Kritikos H, Tsetis D, et al. Sustained improvement of vascular endothelial function during anti-TNFalpha treatment in rheumatoid arthritis patients. Scand J Rheumatol 2009;38:6–10. [37] Turiel M, Tomasoni L, Sitia S, Cicala S, Gianturco L, Ricci C, et al. Effects of long-term disease-modifying antirheumatic drugs on endothelial function in patients with early rheumatoid arthritis. Cardiovasc Ther 2010 Mar 10 [Epub ahead of print]. [38] Sarzi-Puttini P, Atzeni F, Shoenfeld Y, Ferraccioli G. TNF-alpha, rheumatoid arthritis, and heart failure: a rheumatological dilemma. Autoimmun Rev 2005;4: 153–61. [39] Gonzalez-Juanatey C, Llorca J, Vazquez-Rodriguez TR, Diaz-Varela N, GarciaQuiroga H, Gonzalez-Gay MA. Short-term improvement of endothelial function in rituximab-treated rheumatoid arthritis patients refractory to tumor necrosis factor alpha blocker therapy. Arthritis Rheum 2008;59:1821–4. [40] Senolt L, Vencovský J, Pavelka K, Ospelt C, Gay S. Prospective new biological therapies for rheumatoid arthritis. Autoimmun Rev 2009;9:102–7.
Changes in vitamin D levels in patients with systemic lupus erythematosus: effects on fatigue, disease activity, and damage To analyze whether changes in serum 25-hydroxyvitamin D (25[OH]D) levels affect activity, irreversible organ damage, and fatigue in systemic lupus erythematosus (SLE). Thus, Ruiz-Irastorza G. et al (Arthritis care & Research 2010; 62: 1160–65) performed an observational study of 80 patients with SLE included in a previous cross-sectional study of 25[OH]D, reassessed 2 years later. Oral vitamin D, was recommended in those with low baseline 25[OH]D levels. The relationship between changes in 25[OH]D levels from baseline and changes in fatigue (measured by a 0-10 visual analog scale [VAS]). SLE activity (measured by the systemic lupus erythematosus activity index [SLEDAI]), irreversible organ damage (measured by the systemic lupus international collaborating clinics/American College of rheumatology damage index [SDI]) were analyzed. Sixty patients took vitamin D3. Mean 25[OH]D) levels increased among all treated patients (p = 0.044), in those with baseline vitamin D levels b 30 ng/ml (p b 0.001), and in those with baseline vitamin D levels b 10 ng/ml (p = 0.005). Fifty-seven patients (71%) still had 25 [OH]D levels b 30 ng/ml and 5 (6%) had 25[OH]D) levels b 10 ng/ml. Inverse significant correlations between 25[OH]D levels and the VAS (p=0.001) and between changes in 25[OH]D levels and changes in the VAS in patients with baseline 25[OH]D levels b 30 ng/ml (p = 0.017) were found. No significant correlations were seen between the variation of the SLEDAI or SDI values and the variation in 25[OH]D levels (p = 0.87) and P = 0.63, respectively). Thus, increasing 25[OH]D levels may have a beneficial effect on fatigue. These results do not support any effects of increasing 25[OH]D levels on SLE severity, although they are limited by the insufficient 25[OH]D response to the recommended regimen of oral vitamin D3 replacement.
2010 rheumatoid arthritis classification criteria: An American College of Rheumatology/European League Against Rheumatism Collaborative Initiative The 1987 American College of Rheumatology (ACR) classification criteria for rheumatoid arthritis (RA) have been criticized for their lack of sensitivity in early disease. This work was undertaken to develop new classification criteria for RA. Aletaha D. et al. (Arthritis & Rheum 201; 62: 2569–81). A joint working group from the ACR and the European League Against Rheumatism developed, in 3 phases, a new approach to classifying RA. The work focused on identifying, among patients newly presenting with undifferentiated inflammatory synovitis, factors that best discriminated between those who were and those who were not at high risk for persistent and/or erosive disease – this being the appropriate current paradigm underlying the disease construct "rheumatoid arthritis". In this new criteria set, classification as "definite RA" is based on the confirmed presence of synovitis in at least 1 joint, absence of an alternative diagnosis that better explains the synovitis, and achievement of a total score of 6 or greater (of a possible 10) from the individual scores in 4 domains: number and site of involved joints (score 0–5), serologic abnormality (score range 0–3), elevated acute-phase response (score range 0–1), and symptom duration (2 levels; range 0–1). This new classification redefines the current paradigm of RA by focusing on features at earlier stages of disease that are associated with persistent and/or erosive disease, rather than defining the disease by its late-stage features. This will refocus attention on the important need for earlier diagnosis and institution of effective disease-suppressing therapy to prevent or minimize the occurrence of the undesirable sequelae that currently comprise the paradigm underlying the disease construct "rheumatoid arthritis".
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Autoimmunity Reviews j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / a u t r ev
Review
The effect of pharmacological therapy on the cardiovascular system of patients with systemic rheumatic diseases Fabiola Atzeni a, Maurizio Turiel b, Roberto Caporali c, Lorenzo Cavagna c, Livio Tomasoni b, Simona Sitia b, Piercarlo Sarzi-Puttini a,⁎ a b c
Rheumatology Unit, L. Sacco University Hospital, Milan, Italy Division of Rheumatology, University of Pavia, IRCCS San Matteo Foundation, Pavia, Italy Cardiology Unit, IRCCS Galeazzi Orthopedic Institute, University of Milan, Milan, Italy
a r t i c l e
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Article history: Accepted 24 July 2010 Available online 30 July 2010 Keywords: Disease-modifying antirheumatic drugs Biological agents Anti-TNF agents Autoimmune disease Tocilizumab Mortality
a b s t r a c t The higher mortality rate among rheumatoid arthritis (RA) patients in comparison with the general population is largely attributable to cardiovascular (CV) disease, particularly coronary atherosclerosis, but also non-fatal myocardial infarction and heart failure. It may be due to RA-specific risk factors such as hyperhomocysteinemia, disease-related dyslipidemia or vascular inflammation, or morbidity related to high levels of cytokines such as tumour necrosis factor (TNF) and RA medications. Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most important in rheumatology, but many are associated with CV disease. A number of randomised control trials have shown that, although exposure to low doses of corticosteroids for 1–3 years does not significantly increase CV risk, longer exposure can increase CV events. The use of disease-modifying antirheumatic drugs (DMARDs), particularly methotrexate, increases homocysteinemia, reduces inflammation and improves lipid profiles, thus reducing the development of atherosclerosis and clinically overt CVD. Although contraindicated in RA patients with severe heart failure, biological agents such as anti-TNF agents delay and even reverse the progression of endothelial dysfunction and atherosclerosis. Tocilizumab leads to changes in lipid profiles without increasing adverse vascular events. The effects on the CV system depend on the drug itself, the dose and the period of exposure, and so CV risk should be evaluated before starting treatment with any drug. © 2010 Elsevier B.V. All rights reserved.
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Introduction . . . . . . . . . . . . . . . . Non-steroidal anti-inflammatory drugs . . . Corticosteroids . . . . . . . . . . . . . . . Statin treatment . . . . . . . . . . . . . . Disease-modifying antirheumatic drugs . . . 5.1. Methotrexate . . . . . . . . . . . . 5.2. Cyclosporin and leflunomide . . . . . 5.3. Sulfasalazine . . . . . . . . . . . . 5.4. Antimalarial agents . . . . . . . . . 5.5. Cyclophoshamide and mycophenolate 5.6. Conclusion . . . . . . . . . . . . . Biological agents . . . . . . . . . . . . . . 6.1. Anti-TNF agents infliximab, etanercept 6.2. Anakinra . . . . . . . . . . . . . . 6.3. Rituximab. . . . . . . . . . . . . . 6.4. Tocilizumab . . . . . . . . . . . . . 6.5. Abatacept . . . . . . . . . . . . . .
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⁎ Corresponding author. L. Sacco University Hospital of Milan, Via G.B. Grassi 74, 20175 Milano, Italy. Tel.: +39 0239042208. E-mail addresses: [email protected], [email protected] (P. Sarzi-Puttini). 1568-9972/$ – see front matter © 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.autrev.2010.07.018
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7. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Take-home messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction Inflammatory rheumatic diseases are associated with a substantial increase in accelerated atherosclerosis [1]. Studies have demonstrated that mortality is higher in patients with rheumatoid arthritis (RA) than in the general population, and most of the excess mortality is due to accelerated atherosclerosis. Although RA and atherosclerotic cardiovascular (CV) disease share risk factors such as smoking and poor diet, the increased risk of CV disease in RA patients cannot be explained by traditional risk factors alone. Various disease-related mechanisms may be involved in the development of premature vascular damage, including an increased synthesis of pro-inflammatory mediators (cytokines, chemokines and adhesion molecules), autoantibodies against endothelial cell components, perturbations in T cell subsets, genetic polymorphisms, hyperhomocysteinemia, oxidative stress, abnormal vascular repair, and iatrogenic factors [1,2]. 2. Non-steroidal anti-inflammatory drugs Non-steroidal anti-inflammatory drugs (NSAIDs) are a large number of compounds that act by non-selectively inhibiting the cyclo-oxygenase isoenzymes COX-1 and/or COX-2. Two main classes are currently on the market: classic NSAIDs, which consist of various sub-classes that block both COX-1 and COX-2 (e.g. enolic, acetic, propionic and fenamic acid derivates), and the COXIBs that act selectively on inducible COX-2 (e.g. celecoxib and etoricoxib). The CV toxicity of these drugs is a relatively recent issue that was raised in 2004 when rofecoxib was withdrawn from the market on the basis of the results of the Adenomatous Polyp Prevention on Vioxx (APPROVe) study [3] because its long-term use was related to a higher incidence of acute myocardial infarction (AMI) in comparison with placebo. This withdrawal markedly changed the prescribing pattern of pain-killing drugs, leading to a striking decrease in the use of COXIBs without any increase in the use of other NSAIDs, as shown in a recently published survey [4]. It was subsequently found that celecoxib was also associated with an increased risk of CV disease [5], with both dose and pharmacokinetics possibly affecting the onset of adverse events. The Alzheimer's Disease Anti-Inflammatory Prevention Trial (ADAPT) [6] found that naproxen (220 mg twice daily) increased the risk of CV events in comparison with celecoxib (200 mg twice daily), and a subsequent meta-analysis showed that the risk of AMI is increased in the users of COXIBs (OR 1.73, 95% CI:1.37–2.19) and classic NSAIDs (OR −1.41, 95% CI:1.23–1.61), with diclofenac (OR 1.51, 95% CI:1.22–1.87) and ibuprofen (OR 1.56, 95% CI:1.19–2.05) having the worst profile among the latter [7]. It has been found that NSAID-treated patients with a history of heart failure (HF) have an increased dose-dependent risk of death due to AMI and HF [8], and the fact that NSAIDs were used for a short time in the majority of case indicates their relatively acute cardiotoxic effects. Factors such as an age of N80 years, hypertension, prior CV events, RA and chronic obstructive pulmonary disease identify sub-groups at increased risk when using specific agents, with rofecoxib and ibuprofen leading to higher CV risk rates across the sub-groups [9]. Furthermore, many classic NSAIDs (particularly diclofenac and ibuprofen) are sold over the counter, which makes it more difficult to assess the CV toxicity of prescribed NSAIDs. In our study, we found that 44% of the RA/ osteoarthritis (OA) outpatients referring to our division and prescribed NSAIDs were also taking unprescribed diclofenac and ibuprofen for
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other painful conditions (73%) or because their disease-related pain was unsatisfactorily controlled (21%). Another problem is that a number of rheumatic conditions such as RA and systemic lupus erythematosus (SLE) are themselves associated with an increased CV risk due to accelerated atherosclerosis [10], and diseases such as OA are typically observed in subjects at high CV risk (e.g. older people with multiple comorbidities) [11]. NSAIDs remain as some of the most important drugs in the rheumatological field, but it is clearly essential to assess the CV risk of patients before they are used [12]. 3. Corticosteroids Corticosteroids (CTs) are powerful anti-inflammatory agents used for the symptomatic treatment of RA. They may have cardioprotective effects mediated by their anti-inflammatory and anti-proliferative action on vessel walls, but their long-term use at high doses can affect blood pressure, insulin resistance, lipid profiles, body weight and fat distribution, all of which may significantly increase the risk of CV disease [2]. A recent systematic review of the literature has revealed a weak association between low-dose CTs and CV risk factors, and identified a dose-related trend of increasing major CV events [13]. Exposure to low CT doses may beneficially affect lipid profiles and increase insulin levels, and have no effect on blood pressure, atherosclerosis, ventricular function or heart rate variability, but there is disagreement concerning their effects on arterial stiffness. In particular, four out of six studies have found an association between low CT doses and major CV events [14,15], including AMI (hazard ratio 1.7 [1.2–2.3]), stroke (odds ratio 4.36 [1.60–11.90] at doses of 6–10 mg/day), mortality (hazard ratio 2.03 [1.25–3.32]), and a composite index of CV events (with a hazard ratio of 2.21 [1.22– 4.00] in a group of patients with rheumatoid factor-positive RA); the other two studies did not find any significant association between low CT doses and mortality (odds ratio 2.25 [0.29–102.5]) or a composite index of CV events (odds ratio 1.3 [0.8–2.0]) [16,17]. The EULAR recommendations suggest using CTs only in cases of early arthritis and at doses of 7–10 mg per day for b6 months. A number of randomised controlled trials have found that exposure to low CT doses for 1–3 years does not significantly increase CV risk, but longer exposure can increase the risk of major CV events, which is doubled or tripled if prednisone is given at a dose of N10 mg per day. As RA is itself a risk factor for major CV events, physicians should only prescribe CTs for a short time at the very beginning of arthritis, and stop their use as soon as possible. The dose of prednisone should be based on patient weight. 4. Statin treatment Statins (3-hydroxy-3-methylglutarylcoenzyme-A reductase inhibitors) reduce CVD morbidity and mortality [18]. Different mechanisms are responsible for this result: effects on lipid levels, antiinflammatory and immunomodulating effects include suppression of leukocyte cytokine release, reduction of MHC class II expression and reduction of production of reactive oxygen species [18]. Moreover, in RA patients apart from reducing lipid levels, treatment with statins, as it was demonstrated on clinical trial, may also have a modest but clinically useful effect on arthritis [19]. Take together, these data suggests using statins in clinical practice in rheumatic systemic disease patients.
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5. Disease-modifying antirheumatic drugs 5.1. Methotrexate There are some indications that disease-modifying antirheumatic drugs (DMARDs) can alter CV risk by influencing atherosclerotic processes directly through inflammation or indirectly by affecting CV risk factors. However, few studies have investigated their effects on the occurrence of CV disease in RA patients, with methotrexate (MTX, a DMARD that inhibits dihydrofolate reductase and reduces folate levels) being the most widely studied [20]. A first observational study of MTX found that it led to increased serum homocysteine levels and higher mortality in patients with RA [21] although, after adjusting for all confounders, Choi et al. [22] found that CV-related mortality was 70% less in RA patients treated with MTX than in those treated with other traditional DMARDs. They also found that mortality was less in patients treated with MTX and folic acid, thus suggesting that folic acid supplementation may be beneficial [22]. Furthermore, a large cohort study of 107,908 RA patients found that MTX was associated with a significant decrease in the rate of AMI [23], and similar results was reported by Van Halm et al. in relation to coronary, cerebral and peripheral arterial disease [24]. In addition to being associated with decreased CV morbidity (even after adjusting for traditional CV risk factors), the use of MTX is also associated with decrease in hospital admissions due to HF [24]; however, folate supplementation is recommended, particularly in patients receiving MTX with sulfasalazine. 5.2. Cyclosporin and leflunomide The findings of some studies suggest that, like cyclosporin, leflunomide may adversely affect CV risk by increasing blood pressure and lipid levels, although recent studies indicate the opposite [25]. It has been reported that leflunomide can improve vascular function by: 1) inhibiting the nuclear factor kappa B signal transduction pathway associated with the pro-inflammatory and pro-atherosclerotic phenotype in endothelial cells; 2) reducing the subendothelial migration of peripheral blood mononuclear cells; 3) and impairment of antigenpresenting dendritic cells [25]. Taken together, these data suggest that leflunomide may have important vasculoprotective effects and reduce the risk of developing AMI, but the results are controversial. Suissa et al. found that leflunomide significantly decreased the rate of AMI [26], whereas Solomon et al. [27] found that patients treated with cytotoxic immunosuppressive DMARDs (leflunomide, azathioprine and cyclosporine) alone or in combination were at greater risk of AMI and stroke than those treated with MTX. 5.3. Sulfasalazine The impact of traditional DMARDs on CV disease is not only related to improvements in inflammation, but also to DMARD-induced changes in lipid profiles. Park et al. [28] found that the levels of high density lipid cholesterol (HDL-C) decreased in responders to DMARDs, and another two studies of RA patients treated with MTX (0.2 mg/kg/week) and low dose of prednisolone (7.5 mg/day) or an intensive combination of MTX plus sulfasalazine and prednisolone or sulfasalazine alone found that HDL-C increased and the atherogenic ratio decreased, thus suggesting a beneficial effect [29,30]. 5.4. Antimalarial agents It has also been shown that hydroxychloroquine, which was initially used as an antimalarial agents but is also useful in autoimmune diseases such as RA and SLE, protects against thrombotic events and improves glucose and lipid profiles, thus apparently
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reducing the risk of CV disease and increasing survival in SLE patients [31]. However, they were also associated with lower blood pressure. These effects of antimalarials in the cohort of patients with RA are much more prominent than in patients with SLE [31]. 5.5. Cyclophoshamide and mycophenolate In SLE patients, disease duration and damage index scores are closely associated with vascular disease. The use of cyclophosphamide is independently associated with a reduced risk of ultrasonographically detected carotid plaque, which suggests that intensive control of disease activity may prevent atherosclerosis, and mycophenolate mofetil seems to have some anti-atherogenic properties. 5.6. Conclusion The use of DMARDs, particularly MTX, potently suppresses inflammation and improves lipid profiles, thus reducing the development of atherosclerosis and subsequent clinically overt CV disease. However, the real effect of individual immunosuppressants on atherosclerosis in patients with RA or SLE is still unclear. 6. Biological agents 6.1. Anti-TNF agents infliximab, etanercept and adalimumab The increased mortality of patients with RA may be due to RAspecific risk factors such as hyperhomocysteinemia, disease-related dyslipidemia, vascular inflammation, drug-related morbidity, or high levels of cytokines such as tumour necrosis factor (TNF). TNF, an inflammatory cytokine released by activated monocytes, macrophages and T lymphocytes, favours the inflammatory responses that are important in the pathogenesis of RA [2]. It also promotes dyslipidemia and insulin resistance, both of which are traditional risk factors for atherosclerosis, upregulates adhesion molecules leading to fatty streak formation and the initiation of atherosclerosis, and is involved in the inflammation leading to plaque rupture [2]. It may also promote thrombophilia by encouraging thrombotic events. It plays a protective role in the physiological adaptive response to injury and limits infarct size, but its overexpression can lead to maladaptive effects such as left ventricular dysfunction [32]. The introduction of the anti-TNF agents infliximab, etanercept and adalimumab has greatly improved the outcomes of severe RA and reduced the burden of CV disease. A number of studies have investigated their effects on the lipid profiles of patients with RA [2,32], most of which have found an increase in HDL and cholesterol levels, although with some disagreement about its duration [32]. A Spanish study of 27 RA patients found a significant reduction in insulin levels and the insulin/glucose index and improved insulin resistance 2 h after infliximab infusion [33]. The levels of circulating adhesion molecules, such as serum E-selectin and intercellular adhesion molecule-1, are also decreased by anti-TNF agents. Hurlimann et al. [34] showed that short-term anti-TNF treatment improved vascular function in 11 RA patients, and a Spanish group measured carotid intima-media thickness (IMT) in eight patients with RA before and after a median of 3 years of anti-TNF treatment and found no significant difference in progression in comparison with matched controls [35]. Sidiropoulos et al. [36] reported a sustained improvement in endothelial function and no change in common carotid artery IMT after 18 months of treatment with anti-TNF agents. We have demonstrated the efficacy of long-term DMARD treatment (MTX and anti-TNF agents) in reducing disease activity, and delaying or even reversing the progression of endothelial dysfunction and atherosclerosis as a result of an increase in coronary flow reserve, with no changes in IMT [37].
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Patients with severe chronic heart failure (CHF) have higher circulating levels of TNF than healthy subjects but studies have found that that etanercept has no effect on CHF and that high-dose infliximab has detrimental effects on patients with moderate to severe CHF. Consequently, severe heart failure contraindicates anti-TNF treatment in patients with RA [38].
6.2. Anakinra A randomised, controlled clinical trial assessing the safety of the IL1 receptor antagonist anakinra found no difference in the incidence of AMI or CHF between the anakinra and placebo group [2].
6.3. Rituximab Rituximab, a chimeric monoclonal antibody against CD20 that effectively depletes B cells in peripheral blood, efficacy and safety in the treatment of RA, increased flow-mediated endotheliumdependent vasodilatation and endothelium-independent vasodilatation (post-nitroglycerin) after 2 weeks (before the second infusion) in six consecutive patients with active RA refractory to TNF inhibition (5 women; age 55–79 years), and was associated with a significant decrease in C-reactive protein (CRP) levels and disease activity scores after 6 months [39].
6.4. Tocilizumab Interleukin-6 (IL-6) is a pro-inflammatory cytokine that stimulates hepatocytes to synthesise acute phase response proteins such as CRP and fibrinogen. It may also contribute to atherosclerosis and arterial thrombosis by enhancing endothelial cell adhesiveness, activating the production of tissue factor, fibrinogen and factor VIII, increasing platelet production and aggregation, and decreasing endogenous anticoagulant levels [40]. A number of phase III clinical trials have shown that tocilizumab, a humanised monoclonal antibody against IL6 receptor, has a favourable risk/benefit ratio in the treatment of adults with moderate–severe active RA who responded inadequately or were intolerant to previous therapy with one or more DMARDs or TNF inhibitors. Tocilizumab-treated patients have experienced moderate reversible increases in the mean serum levels of total cholesterol, LDL-C, HDL-C and triglycerides, but no differences in adverse vascular events were observed between patients treated for 24 weeks with tocilizumab plus MTX or MTX alone, and there were few changes in the atherogenic index in the patients receiving tocilizumab for up to 1 year [40].
6.5. Abatacept No information is available as to whether abatacept, a fully human soluble fusion protein consisting of the extracellular domain of human CTLA-4 and the modified Fc portion of human IgG1, also decrease the excess cardiovascular morbidity and mortality associated with RA.
7. Conclusions The role of antirheumatic drugs in the development of CV involvement in RA patients is controversial. As RA is itself a risk factor for CV events, physicians should stop corticosteroids as soon as possible and screen all patients for CV disease before administering NSAIDs. Biological drugs act not only on disease activity, but also on endothelial dysfunction and the progression of atherosclerosis, thus preventing CV complications and possibly reducing mortality.
Take-home messages • Users of COXIBs and classic NSAIDs (particularly diclofenac and ibuprofen) are at increased risk of acute myocardial infarction. • Short (1–3 year) exposures to low corticosteroid doses does not significantly increase CV risk, but longer exposure may increase the risk of major CV events. • The use of statins improves lipid profile and acts modestly on arthritis. • The use of DMARDs (particularly MTX) potently suppresses inflammation and improves the lipid profile, thus reducing the development of atherosclerosis and clinically overt CV disease. • Anti-TNF agents not only reduce disease activity, but also delay and may even reverse the progression of endothelial dysfunction and atherosclerosis. • Rituximab therapy greatly increases flow-mediated endotheliumdependent and endothelium-independent vasodilatation, and can positively influence CV outcomes.
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Changes in vitamin D levels in patients with systemic lupus erythematosus: effects on fatigue, disease activity, and damage To analyze whether changes in serum 25-hydroxyvitamin D (25[OH]D) levels affect activity, irreversible organ damage, and fatigue in systemic lupus erythematosus (SLE). Thus, Ruiz-Irastorza G. et al (Arthritis care & Research 2010; 62: 1160–65) performed an observational study of 80 patients with SLE included in a previous cross-sectional study of 25[OH]D, reassessed 2 years later. Oral vitamin D, was recommended in those with low baseline 25[OH]D levels. The relationship between changes in 25[OH]D levels from baseline and changes in fatigue (measured by a 0-10 visual analog scale [VAS]). SLE activity (measured by the systemic lupus erythematosus activity index [SLEDAI]), irreversible organ damage (measured by the systemic lupus international collaborating clinics/American College of rheumatology damage index [SDI]) were analyzed. Sixty patients took vitamin D3. Mean 25[OH]D) levels increased among all treated patients (p = 0.044), in those with baseline vitamin D levels b 30 ng/ml (p b 0.001), and in those with baseline vitamin D levels b 10 ng/ml (p = 0.005). Fifty-seven patients (71%) still had 25 [OH]D levels b 30 ng/ml and 5 (6%) had 25[OH]D) levels b 10 ng/ml. Inverse significant correlations between 25[OH]D levels and the VAS (p=0.001) and between changes in 25[OH]D levels and changes in the VAS in patients with baseline 25[OH]D levels b 30 ng/ml (p = 0.017) were found. No significant correlations were seen between the variation of the SLEDAI or SDI values and the variation in 25[OH]D levels (p = 0.87) and P = 0.63, respectively). Thus, increasing 25[OH]D levels may have a beneficial effect on fatigue. These results do not support any effects of increasing 25[OH]D levels on SLE severity, although they are limited by the insufficient 25[OH]D response to the recommended regimen of oral vitamin D3 replacement.
2010 rheumatoid arthritis classification criteria: An American College of Rheumatology/European League Against Rheumatism Collaborative Initiative The 1987 American College of Rheumatology (ACR) classification criteria for rheumatoid arthritis (RA) have been criticized for their lack of sensitivity in early disease. This work was undertaken to develop new classification criteria for RA. Aletaha D. et al. (Arthritis & Rheum 201; 62: 2569–81). A joint working group from the ACR and the European League Against Rheumatism developed, in 3 phases, a new approach to classifying RA. The work focused on identifying, among patients newly presenting with undifferentiated inflammatory synovitis, factors that best discriminated between those who were and those who were not at high risk for persistent and/or erosive disease – this being the appropriate current paradigm underlying the disease construct "rheumatoid arthritis". In this new criteria set, classification as "definite RA" is based on the confirmed presence of synovitis in at least 1 joint, absence of an alternative diagnosis that better explains the synovitis, and achievement of a total score of 6 or greater (of a possible 10) from the individual scores in 4 domains: number and site of involved joints (score 0–5), serologic abnormality (score range 0–3), elevated acute-phase response (score range 0–1), and symptom duration (2 levels; range 0–1). This new classification redefines the current paradigm of RA by focusing on features at earlier stages of disease that are associated with persistent and/or erosive disease, rather than defining the disease by its late-stage features. This will refocus attention on the important need for earlier diagnosis and institution of effective disease-suppressing therapy to prevent or minimize the occurrence of the undesirable sequelae that currently comprise the paradigm underlying the disease construct "rheumatoid arthritis".