Iraqi J Pharm Sci, Vol.23(1) 2014 Rosuvastatin in rheumatoid arthritis 7 Evaluation of Rosuvastatin Effect as Adjuvant Therapy to Methotrexate on Lipid Profile and the Possibility of its Cardioprotective Effect in Iraqi Patients with Active Rheumatoid Arthritis Ehab M. Mikhael *,1 , Ibrahim A. Majeed * , Faiq I. Gorial ** , Mohammad H. Al-Ossamy ** , Ali H. Falih ** and Dhikra Abdulhameed *** * Department of Clinical Pharmacy , College of Pharmacy, University of Baghdad, Baghdad, Iraq. ** Rheumatology Unit, College of Medicine, University of Baghdad, Baghdad, Iraq. *** Teaching Laboratories, Baghdad Teaching Hospital. Abstract Rheumatoid arthritis (RA) is a common inflammatory disease that associated with increased morbidity and mortality due to accelerated atherosclerosis. Rosuvastatin is a unique hydroxy methyl glutaryl Co A (HMGCoA) reductase inhibitor that has anti inflammatory effects. The aim of this study was to evaluate the effect of rosuvastatin as adjuvant therapy to methotrexate (MTX) on lipid profile and its possible cardioprotective effect in RA patients. A double blinded placebo controlled clinical trial with 8 weeks follow up periods at which 40 patients with active RA using MTX were randomized into 2 groups to receive either rosuvastatin 10mg or placebo as adjuvant therapy to MTX. In addition to twenty healthy subjects as control group. Lipid profile and erythrocyte sedimentation rate (ESR) was assessed at the start and at the end of the study. At the start of the study total cholesterol (TC), low density lipoprotein cholesterol (LDLc) and high density lipoprotein cholesterol (HDLc) values were not significantly different between RA patients and control group. At the end of the study rosuvastatin significantly reduced ESR, TC and LDLc after 8 weeks of treatment. It can be concluded that MTX has the ability to normalize lipid profile in RA patients. Rosuvastatin effectively reduce ESR, TC and LDLc; Moreover, Rosuvastatin might have a possible cardioprotective effect in RA patients. Keywords: Active rheumatoid arthritis, Methotrexate, Rosuvastatin. عهً انذهىن وجأثُره انقهبٍ انىقائٍ كعالج مضاف نهمُثىجركسُث جأثُر انروسىفاسحاجُهجقُُم انفعال صابُه بانحهاب انمفاصم انرثىٌانمححمم نهمرضً انعراقُُه انم اَهاب مضر مُخائُم *،1 فائق اَشى كىلاير ، ** ابراهُم ادهم مجُذ ، * انعصامٍ محمذ هادٌ ، ** ، عهٍ حسُه فانح ** ركري عبذ انحمُذ و *** * . انؼشاق ،تغذاد ،خايؼح تغذاد،كهٛح انصٛذنح ،فشع انصٛذنح انسشٚشٚح ** . انؼشاق ،تغذاد ،خايؼح تغذاد ،كهٛح انطة ،انشثٕٚح انًفاصم ٔحذج *** . يسرشفٗ تغذاد انرؼهًٛٙ ،انًخرثشاخ انرؼهًٛٛح الخالصة انرٓاب انًفاصم انشثٕ٘ ْٕ يشض انرٓاتٙ شائغ ٔٚرًٛض تضٚادج َسثح انًشاظح ٔانٕفٛاخ تسثة صٚادج سشػح ذصهة األٔػٛح كًا إٌ نّ خاصٛح يعادج (HMGCoA)انذيٕٚح . ٚؼرثش انشٔسٕفاسراذٍٛ يثثطا فشٚذا إلَضٚى ْاٚذسٔكسٙ يثٛم كهٕذاسٚم كٕ ا٘ نالنرٓاب. اٌ انٓذف يٍ ْزِ انذساسح ْٕ نرقٛٛى فائذج انشٔسٕفاسراذٍٛ كؼالج إظافٙ نهًٛثٕذشكسٛد ػهٗ انذٌْٕ ٔذأثٛشِ انًحرًم نٕقاٚح انقهة ػُذ صم انشثٕ٘ انفؼال ٔانزٍٚ يشظٗ انرٓاب انًفاصم انشثٕ٘ انفؼال.انثحث سشٚش٘ يضدٔج اإلػًاء شًم أستؼٌٕ يشٚعا تانرٓاب انًفا يهغشاو أٔ انؼالج 01ٚسرخذيٌٕ نهًٛثٕذشكسٛد ذًد يشاقثرٓى نًذج أساتٛغ تؼذ ذقسًٛٓى ػشٕائٛا نًدًٕػرٍٛ السرؼًال سٔسٕفاسراذٍٛ انٕاْى. تاإلظافح إنٗ ػششٍٚ شخصا كًدًٕػح يقاسَح. الَرٓاء يٍ ْزِ انذساسح. ػُذ تذء ْزِ انذساسح ذثٍٛ إٌ َسثح ذى قٛاط َسثح انذٌْٕ َٔسثح ذشسٛة كشٚاخ انذو انحًش ػُذ انثذء ٔػُذ ا انكٕنسرشٔل ٔانكٕنسرشٔل يُخفط ٔيشذفغ انكثافح الذخرهف تٍٛ انًشظٗ انًصاتٍٛ تانرٓاب انًفاصم انشٔياذٕٚذ٘ ػٍ َظشائٓى ة كشٚاخ انذو انحًش ٔانكٕنسرشٔل, تانًدًٕػح انًقاسَح ٔػُذ اَرٓاء انذساسح قهم انشٔسٕفاسراذٍٛ ٔتشكم يؼُٕ٘ يهحٕظ يٍ َسثح ذشس ٔانثشٔذٍٛ انًشذثط تانكٕنسرشٔل يُخفط انكثافح. َسرُرح يٍ رنك إٌ نهًٛثٕذشكسٛد قاتهٛح ذؼذٚم يسرٕٖ انذٌْٕ ػُذ يشظٗ انرٓاب انًفاصم انشثٕ٘ انفؼال ٔانشٔسٕفاسراذٍٛ نّ انقاتهٛح ذٍٛ انًشذثط تانكٕنسرشٔل يُخفط انكثافح إظافح إنٗ ذأثٛشِ انٕقائٙ ػهٗ ذقهٛم يسرٕٖ ذشسة كشٚاخ انذو انحًش, انكٕنسرشٔل, ٔانثشٔ انًحرًم نهقهة ػُذ يشظٗ انرٓاب انًفاصم انشثٕ٘ انفؼال. انكهمات انمفحاحُة: انحهاب انمفاصم انرثىٌ انفعال, مُثىجركسُث, روسىفاسحاجُه. 1 Corresponding author E-mail: ehab_pharma84@yahoo.com Received:3 /11/2012 Accepted:21 /9/2013 Iraqi J Pharm Sci, Vol.23(1) 2014 Rosuvastatin in rheumatoid arthritis 8 Introduction Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease of unknown etiology characterized by articular and extra articular features (1) . The atherogenic lipid profile and subclinical atherosclerosis are features of early RA (2). Rheumatoid arthritis is associated with increased mortality, which is predominantly due to accelerated coronary artery atherosclerosis (3) . Cardiovascular (CV) morbidity and mortality are increased twofold in RA patients compared to those of the general population (4, 5) . This increased CV risk may be due to systemic inflammation and its interplay with traditional CV risk factors like smoking, personal and family history of ischemic heart disease, hypertension, hyperlipidemia, higher body mass index and diabetes mellitus (DM) (6) . The association between lipids and CV risk in RA appears to be more complex than in the general population, with systemic inflammation being a notable contributor to the lipid profile changes (7) . Inflammation leads to pro-atherogenic changes of the lipoprotein metabolism and an increased disease activity is associated with lower total cholesterol (TC) levels and even more depressed high density lipoprotein – cholesterol (HDLc) levels and lowered apolipoprotein-A1 (apo-A1) levels (4). Beside that active inflammation increases oxidized fatty acids in circulating lipoproteins, promoting low density lipoprotein (LDL) oxidation and HDL dysfunction, thereby increasing atherosclerotic risk (8) . Rosuvastatin is a unique hydroxy methyl glutaryl CoA (HMGCoA) reductase inhibitor that used to treat dyslipidemia (9) . It also exerts important anti-inflammatory effects in addition to its lipid-lowering actions (10) . Aim of the study Evaluating the effect of rosuvastatin as adjuvant therapy to MTX on lipid profile and its possible cardioprotective effect in Iraqi patients with active RA. Methods Study design This was an 8-week randomized double blind placebo-controlled single center study conducted at Rheumatology Unit, Baghdad Teaching Hospital, Baghdad, Iraq from August 2011 till May 2012. Patients were randomly allocated to receive each day either rosuvastatin 10mg tablet or capsule prefilled with glucose as placebo (PBO). Rosuvastatin was bought from Unipharma Company/ Syria whereas glucose was bought from SDI/ Iraq. Methotrexate ampoules from Ebewe Company/ Austria. Patients were evaluated at baseline and at week 8. Sample selection Eligible patients had confirmed to have active RA according to the 1987 American College of Rheumatology (ACR) criteria and had ESR values greater than 20 mm/hr for men and greater than 30 for females(11). Additionally all patients included were selected to be users of Methotrexate (MTX) regularly for at least 3 previous consecutive months. The exclusion criteria included patients who were taking lipid-lowering therapy, had hypersensitivity to statin, pregnancy, breast feeding, renal and liver impairment, patients younger than 18 years old and those using steroids. Additionally 20 healthy individuals with age and sex matched were considered as a control group. Informed consent was obtained from all participants and this study was approved by the ethical committee of Baghdad University, College of Medicine - Medical Department. Blood sample collection and laboratory evaluation Blood specimen collection: 5 ml of venous blood was obtained from forearm for doing laboratory analysis (at baseline and after 8 weeks). 3 ml was transferred to plane test tube and left to be coagulated then centrifuged at 3000 rpm for 10 minutes and then serum obtained for biochemical measurements of total cholesterol, LDLc, HDLc, and triglyceride (TG) and measuring Rheumatoid factor. Lipid profile tests were done by specialized laboratory workers who did not participate in this study using specialized kits from Randox ® company. Total cholesterol was measured by cholesterol oxidase - peroxidase aminophenazone (CHOD-PAP) enzymatic colorimetric method (12) . TG estimation was done by Glycerol-3- phosphate oxidase – peroxidase (GPO-PAP) enzymatic colorimetric method under the principle of Bucolo and David 1973 (13) .HDLc was measured by Polyethylene Glycol (PEG) / CHOD – PAP method , according to the principle of Lopes (14) . Whereas LDLc level was estimated according to the Friedewald formula (15) . ESR was measured by Westergren method and also was done by blinded non interested laboratory worker (16) .Rheumatoid factor was measured qualitatively just at start of study by serological agglutination test through antigen antibody reaction using specialized kit from spectrum company/ Egypt (17) . Iraqi J Pharm Sci, Vol.23(1) 2014 Rosuvastatin in rheumatoid arthritis 9 Statistical analysis Statistical package for social sciences (SPSS) version 12, was used for data input and analysis. Continuous variables were presented as mean ± standard deviation (SD) and discrete variables were presented as numbers and frequencies. Chi square test for independence was used to test the significance of association between discrete variables. Continuous variables were tested by a web version of Shapiro Wilk test to determine if they were normally or abnormally distributed. Analysis of variance (ANOVA) test was used to test the significance of difference in the mean of 3 independent samples in normally distributed continuous variables. Paired T test was used to test the significance of difference in means of pre and post treatment in normally distributed continuous variables, whereas Wilcoxon test was used in case of abnormally distributed continuous variables. Unpaired T test was used to test the significance of difference in the mean of two independent samples in normally distributed continuous variables and Mann Whitney test for abnormally distributed data. All P values used were asymptotic and two sided. Findings with P value less than 0.05 were considered significant whereas P values less than 0.01 considered highly significant. Statistical power was not calculated since it is a pilot study. Results Of the 74 patients who were randomized in this double-blind study, only 40 patients completed the 8weeks of treatment (20 from the rosuvastatin group and 20 from the PBO). The two groups did not differ significantly in baseline characteristics. Another 20 healthy controls aged and sex matched were also participated (figure1, table 1). Baseline lipid profile (table 2) showed that there was a non significant difference at baseline level of TC, LDLc and HDLc between RA patients and control subjects and only TG level was significantly higher in RA patients of PBO group than that in the control group. But unfortunately there was a significant difference at a baseline level of TC, LDLc, and TG between rosuvastatin and PBO group (table 3). Additionally baseline ESR was higher in RA patients, but with no any significant difference between rosuvastatin and placebo group (Table 2, 3). After 8 weeks of starting adjuvant treatment with either rosuvastatin or placebo, TC, LDLc and ESR decreased significantly by rosuvastatin (p<0.05) while other parameters showed no any difference between the effect of rosuvastatin and placebo (p>0.05, table 4). Figure 1: Schematic presentation for patient participating in the study Iraqi J Pharm Sci, Vol.23(1) 2014 Rosuvastatin in rheumatoid arthritis 10 Table ( 1) Demographic data and baseline characteristics of both rheumatoid patients and control subjects Parameter Rosuvastatin PBO Control P Value Age ( years) 43.35 ± 9.96 44.4 ±13.53 42.95±10.39 0.917 Female: Male Ratio 14:6 (70%) 16:4 (80%) 15:5(75%) 0.766 Dose of MTX 13.88± 4.40 13.25 ± 3.54 - 0.624 Smoking 3 2 5 0.431 Family Hx of CVD n (%) 3 (15%) 2 (10%) 3 (15%) 0.865 Hypertension n (%) 5 (25%) 5 (25%) - 1 DM n (%) 5 (25%) 3 (15%) - 0.429 Positive RF n (%) 13 (65%) 12 (60%) - 0.743 Table (2) Comparison in baseline laboratory data of rheumatoid arthritis patients with control subjects Parm Rosuva Control P PBO Control P TC (Mg/dl) 168.9±38.22 180.05±54.29 0.457 202.85±28.68 180.05±54.29 0.105 LDLc (Mg/dl) 99.71±33.24 114.78±52.46 0.285 123.21±19.57 114.78±52.46 0.505 HDLc (Mg/dl) 42.25±9.42 43.45±6.06 0.635 43.6±10.34 43.45±6.06 0.956 TG (Mg/dl) 134.7±63.91 109.1±43.80 0.148 180.2±51.16 109.1±43.80 0.000 ESR (mm/hr) 48.95± 31.1 11.7±3.85 0.000 38.25±19.00 11.7±3.85 0.000 TC = Total cholesterol, normal range < 200mg/dl; LDLc = Low density lipoprotein cholesterol, normal range < 100mg/dl; HDLc = High density lipoprotein cholesterol, normal range 40 – 60mg/dl; TG = triglyceride , normal range < 150mg/dl; ESR = erythrocyte sedimentation rate, normal range < 20 for men and < 30 for females. Table (3) Difference in baseline laboratory parameters between RA patients in rosuvastatin and placebo group Parameter Rosuva PBO P TC 168.9±38.22 202.85±28.68 0.003 LDLc 99.71±33.24 123.21±19.57 0.01 HDLc 42.25±9.42 43.6±10.34 0.669 TG 134.7±63.91 180.2±51.16 0.017 ESR 48.95± 31.1 38.25±19.00 0.197 Table (4) Change produced in lipid profile and ESR after 8 weeks of treatment with either rosuvastatin or placebo Parameter Rosuvastatin (%) PBO (%) P value TC -39.3 ± 29.21 (-23.27%) -6.25 ± 17.99 (-3.08%) 0.000 LDLc -36.28 ± 27.10 (-36.39%) -8.49 ± 21.61 (-6.89%) 0.001 HDLc 0.7 ± 8.71 (1.66%) 0.4 ± 4.28 (0.92%) 0.956 TG -18.6 ± 33.11 (-13.81%) 9.2 ± 53.97 (5.11%) 0.096 ESR -16.85 ± 28.66 (- 34.42%) -0.55 ± 17.72 (-1.44) 0.012 Iraqi J Pharm Sci, Vol.23(1) 2014 Rosuvastatin in rheumatoid arthritis 11 Discussion The results of this study showed a non significant difference in TC, LDL-C and HDL- C level between RA patients using MTX and control subjects; the results of other studies were controversial: in one study it was found that both TC and LDL-C level were elevated in RA patients whereas HDL-C level was decreased in patients with early RA, and this atherogenic lipid profile can be improved by initiation of therapy (18) . Whereas other studies found that systemic inflammation was a notable contributor to the lipid profile changes. Growing evidences suggested that patients with active untreated RA have reduced TC, LDL-C and HDL-C levels (7,19) ; and these abnormal lipid profiles were improved through suppression of inflammation by many disease modifying anti rheumatic drugs (DMARDs) (20) . Any how what ever the baseline level of lipid profile in Iraqi patients with RA, it seemed that the use of MTX could improve it. The results of this study showed that there was a significant difference in the baseline level of both TC and LDLc between rosuvastatin and placebo group, which may be resulted by chance in such a randomized controlled trial of small sample size. Results of this study showed that rosuvastatin produced a significant reduction in both TC and LDLc level; similar finding was reported in many other studies, comparing the effect of different statins, rosuvastatin (21) , atorvastatin (22) and simvastatin (23) to placebo in patients with RA. Rosuvastatin reduced TC by more than 23% and LDL-C by more than 36% which was close to that found in UK survey for use of rosuvastatin in general practice (–28% for cholesterol and – 40% for LDL-C ) (24) . Such result can be explained according to the fact that rosuvastatin is one of the HMG CoA reductase inhibitors which lower plasma cholesterol due to the inhibition of endogenous cholesterol synthesis in the liver, and subsequently increased expression of LDL receptors, resulting in an up-regulated catabolic rate for plasma LDL (25). Moreover, the results showed that rosuvastatin was unable to significantly increase HDL-C despite its greater effect when compared to placebo; similar finding was observed in TARA study, at which 40mg atorvastatin failed to improve HDL-C (22) ; however, rosuvastatin 10mg was sufficient to increase HDL-C significantly in RA patients after 1 year of therapy (21) , this mean that short duration of follow up period in this study may be a limiting factor in achieving a real result regarding the effect on HDL-C. The results of the current study showed that TG level was higher in active RA patients than those in the control group, and only those in placebo group were significantly higher than control group; similar finding was observed in patients with early active RA by Georgiadis et al (18) . Limitation in the current study may be related to the significant difference in baseline level of TG between patients in placebo and rosuvastatin group which may be caused by the small sample size; Any how only rosuvastatin significantly reduced TG from baseline level, this effect was not statistically significant when compared to that of placebo; similarly the use of low dose rosuvastatin in patients with mildly active RA failed to achieve significant reduction in TG level (21) . The absence of clinically significant effect on TG level may be attributed to the low dose of rosuvastatin that used in the current study, since Ooi et al. found that rosuvastatin effect to reduce TG level was dose dependent (26) . Regarding ESR which is sensitive for most types of inflammation, but cannot distinguish if the underlying cause is infectious, inflammatory, or paraneoplastic (27) , however it provides a reliable means for discrimination between drugs that provide symptomatic relief only and those with a more profound effect in RA (28). The results of this study showed that ESR level in RA patients who participated in this study was significantly higher than that in healthy control subjects, which was similar to the finding in the study of Yildirim K et al. (29) Since we included only patients with high ESR level. More importantly, rosuvastatin (but not placebo) significantly reduced ESR level; similarly, in two other studies 40mg atorvastatin have the ability to reduce ESR significantly (22,30) . However, a study regarding the effect of 10mg rosuvastatin showed no any benefit, which may be explained in that patients who participated in that study had low initial ESR level since they have just mildly active RA disease (21) , whereas this study excluded any patient with mild or inactive RA disease who had low ESR values ( less than 20 mm/hr ). Myasoedova et al found that Inflammatory measures (particularly ESR) were significantly associated with the risk of CVD in RA (31) . In addition, it was found that controlling both RA disease activity and dyslipidemia is mandatory for minimizing the cardiac risk in RA patients (32). Iraqi J Pharm Sci, Vol.23(1) 2014 Rosuvastatin in rheumatoid arthritis 12 This study showed that rosuvastatin significantly reduced both traditional (TC and LDLc) and non traditional (ESR) risk factors for CVD in RA patients which agreed with the recent EULAR recommendation for using statins for cardiovascular risk management in RA patients (33). Conclusions Methotrexate has the ability to normalize lipid profile in RA patients. Rosuvastatin effectively reduce ESR, TC and LDLc with little effect on TG and HDLc in RA patients; Moreover, Rosuvastatin might have a possible cardioprotective effect in RA patients. Reference 1. Manole Cojocaru, Inimioara Mihaela Cojocaru, Isabela Silosi, Camelia Doina Vrabie, and R Tanasescu . Extra-articular Manifestations in Rheumatoid Arthritis: Maedica (Buchar) 2010; 5(4): 286–91. 2. Georgiadis AN, Voulgari PV, Argyropoulou MI, et al. Early treatment reduces the cardiovascular risk factors in newly diagnosed rheumatoid arthritis patients. Semin Arthritis Rheum 2008; 38(1):13-9. 3. Kaplan MJ. Cardiovascular disease in rheumatoid arthritis. Curr Opin Rheumatol 2006; 18:289-97. 4. Nurmohamed MT. Atherogenic lipid profiles and its management in patients with rheumatoid arthritis. Vasc Health Risk Manag 2007; 3:845-52. 5. Nicola PJ, Maradit-Kremers H, Roger VL, et al. The risk of congestive heart failure in rheumatoid arthritis: a population-based study over 46 years. Arthritis Rheum 2005; 52:412-20. 6. Kitas GD, Gabriel SE. Cardiovascular disease in rheumatoid arthritis: state of the art and future perspectives: Ann Rheum Dis. 2011 Jan;70(1):8-14. 7. Choy E, Sattar N. Interpreting lipid levels in the context of high-grade inflammatory states with a focus on rheumatoid arthritis: a challenge to conventional: cardiovascular risk actions. Ann Rheum Dis 2009; 68:460- 9. 8. Christina CS, David M, Yuen YL. et al. Oxidation products of arachidonic acid and linoleic acid are increased in high density lipoprotein and low density lipoprotein from patients with active rheumatoid arthritis. Arthritis Rheum 2011; 63(Suppl. 10):763. 9. White CM. A review of the pharmacologic and pharmacokinetic aspects of rosuvastatin. J Clin Pharmacol 2002; 42:963-70. 10. Timothy J Stalker, Allan M Lefer, and Rosario Scalia. A new HMG-CoA reductase inhibitor, rosuvastatin, exerts anti-inflammatory effects on the microvascular endothelium: the role of mevalonic acid: Br J Pharmacol. 2001 June; 133(3): 406–12. 11. Joseph T D, Chisholm-Burns MA, et al. Pharmacotherapy: principle and practice, 1 st edn., McGraw-Hill; 2008:867-79. 12. Allain CC, Poon IS, Chan C H G, et al. Enzymatic determination of serum total cholesterol. ClinChem. 1974; 20: 470-1. 13. Bucolo, G. and H. David. Quantitative determination of serum triglycerides by the use of enzymes. ClinChem. 1973;19: 476- 82. 14. Lopes VMF, Stone P, Ellis S, Colwell JA. Cholesterol determination in high density lipoprotein separated by three different methods. ClinChem 1977; 23:882-4. 15. Friedwall VT, Levy RI, Fredrickson DS. Estimation of low density lipoprotein cholesterol in plasma, without use of preprative Centrifuge. Clin Chem. 1972; 18: 499. 16. J. M. JOU, S. M. LEWIS, et al. Review of the measurement of the erythrocyte sedimentation rate: International Journal of Laboratory Hematology 2011; 33(2): 125– 32. 17. Singer, J.M. C.M., Plotz, E. Parker & S.K. Elster. Amer. J. Clin. Path 1957;28: 611. 18. Georgiadis AN, Papavasiliou EC, Lourida ES, 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(3):R82. Epub 2006 Apr 28. 19. Lazarevic MB, Vitic J, Mladenovic V, et al. Dyslipoproteinemia in the course of active rheumatoid arthritis. Semin Arthritis Rheum. 1992;22(3):172-8. 20. Steiner G, Urowitz MB. Lipid profiles in patients with rheumatoid arthritis: mechanisms and the impact of treatment. Semin Arthritis Rheum. 2009 Apr;38(5):372-81. 21. Tam LS, Li EK, Shang Q, et al. Effects of rosuvastatin on subclinical atherosclerosis and arterial stiffness in rheumatoid arthritis: a randomized controlled pilot trial. Scand J Rheumatol 2011; 40(6):411-21. 22. McCarey DW, McInnes IB, Madhok R, et al. Trial of Atorvastatin in Rheumatoid Arthritis (TARA): double-blind, randomized placebo-controlled trial. Lancet 2004; 363(9426):2015-21. http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=search&db=PubMed&term=%20Cojocaru%2BM%5bauth%5d http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=search&db=PubMed&term=%20Cojocaru%2BIM%5bauth%5d http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=search&db=PubMed&term=%20Cojocaru%2BIM%5bauth%5d http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=search&db=PubMed&term=%20Silosi%2BI%5bauth%5d http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=search&db=PubMed&term=%20Vrabie%2BCD%5bauth%5d http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=search&db=PubMed&term=%20Vrabie%2BCD%5bauth%5d http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=search&db=PubMed&term=%20Tanasescu%2BR%5bauth%5d http://www.ncbi.nlm.nih.gov/pubmed?term=Georgiadis%20AN%5BAuthor%5D&cauthor=true&cauthor_uid=18191989 http://www.ncbi.nlm.nih.gov/pubmed?term=Voulgari%20PV%5BAuthor%5D&cauthor=true&cauthor_uid=18191989 http://www.ncbi.nlm.nih.gov/pubmed?term=Argyropoulou%20MI%5BAuthor%5D&cauthor=true&cauthor_uid=18191989 http://www.ncbi.nlm.nih.gov/pubmed?term=Athanasios%20N%20G%2C%20Paraskevi%20V%20V.%20Early%20Treatment%20Reduces%20the%20Cardiovascular%20Risk%20Factors%20in%20Newly%20Diagnosed%20Rheumatoid%20Arthritis%20Patients http://www.ncbi.nlm.nih.gov/pubmed?term=Kitas%20GD%5BAuthor%5D&cauthor=true&cauthor_uid=21109513 http://www.ncbi.nlm.nih.gov/pubmed?term=Gabriel%20SE%5BAuthor%5D&cauthor=true&cauthor_uid=21109513 http://www.ncbi.nlm.nih.gov/pubmed/21109513## http://www.ncbi.nlm.nih.gov/pubmed/21109513## http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=search&db=PubMed&term=%20Stalker%2BTJ%5bauth%5d http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=search&db=PubMed&term=%20Lefer%2BAM%5bauth%5d http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=search&db=PubMed&term=%20Scalia%2BR%5bauth%5d http://onlinelibrary.wiley.com/doi/10.1111/ijlh.2011.33.issue-2/issuetoc http://www.ncbi.nlm.nih.gov/pubmed?term=Georgiadis%20AN%5BAuthor%5D&cauthor=true&cauthor_uid=16646989 http://www.ncbi.nlm.nih.gov/pubmed?term=Papavasiliou%20EC%5BAuthor%5D&cauthor=true&cauthor_uid=16646989 http://www.ncbi.nlm.nih.gov/pubmed?term=Lourida%20ES%5BAuthor%5D&cauthor=true&cauthor_uid=16646989 http://www.ncbi.nlm.nih.gov/pubmed?term=Lourida%20ES%5BAuthor%5D&cauthor=true&cauthor_uid=16646989 http://www.ncbi.nlm.nih.gov/pubmed/16646989## http://www.ncbi.nlm.nih.gov/pubmed/1295090## http://www.ncbi.nlm.nih.gov/pubmed/1295090## http://www.ncbi.nlm.nih.gov/pubmed/18395771## http://www.ncbi.nlm.nih.gov/pubmed?term=%22Tam%20LS%22%5BAuthor%5D http://www.ncbi.nlm.nih.gov/pubmed?term=%22Li%20EK%22%5BAuthor%5D http://www.ncbi.nlm.nih.gov/pubmed?term=%22Shang%20Q%22%5BAuthor%5D http://www.ncbi.nlm.nih.gov/pubmed?term=Effects%20of%20rosuvastatin%20on%20subclinical%20atherosclerosis%20and%20arterial%20stiffness%20in%20rheumatoid%20arthritis%3A%20a%20randomized%20controlled%20pilot%20trial%20%3A%20Scand%20J%20Rheumatol%202011 http://www.ncbi.nlm.nih.gov/pubmed?term=Effects%20of%20rosuvastatin%20on%20subclinical%20atherosclerosis%20and%20arterial%20stiffness%20in%20rheumatoid%20arthritis%3A%20a%20randomized%20controlled%20pilot%20trial%20%3A%20Scand%20J%20Rheumatol%202011 Iraqi J Pharm Sci, Vol.23(1) 2014 Rosuvastatin in rheumatoid arthritis 13 23. Kanda H, Yokota K, Kohno C, et al. Effects of low-dosage simvastatin on rheumatoid arthritis through reduction of Th1/Th2 and CD4/CD8 ratios. Mod Rheumatol 2007; 17(5):364-8. 24. George K, John R, Cathy E, et al. A UK survey of rosuvastatin in general practice: reaching cholesterol targets: Br J Cardiol 2008;15(2):95-100. 25. Igel M, Sudhop T, Von Bergmann K .Pharmacology of 3-hydroxy-3- methylglutaryl-coenzyme A reductase inhibitors (statins), including rosuvastatin and pitavastatin. J Clin Pharmacol 2002; 42(8): 835-45. 26. Ooi EM, Watt GF, Nestel PJ, et al. Dose- Dependent Regulation of High-Density Lipoprotein Metabolism with Rosuvastatin in the Metabolic Syndrome . J Clin Endocrinol Metab. 2008;93(2):430-7. 27. Bridgen M. The erythrocyte sedimentation rate. Still a helpful test when used judiciously. Postgrad Med. 1998;103(5):257-62. 28. Amos RS, Constable TJ, Crockson RA, et al. Rheumatoid arthritis: relation of serum C-reactive protein and erythrocyte sedimentation rates to radiographic changes. Br Med J. 1977; 1(6055): 195–7. 29. Yildirim K, Karatay S, Melikoglu MA, et al. Associations between Acute Phase Reactant Levels and Disease Activity Score (DAS28) in Patients with Rheumatoid Arthritis. Ann Clin Lab Sci. 2004; 34(4):423-6. 30. Ljung, Lotta, Leirisalo-Repo, et al. Improvement of Cardiovascular Risk Markers with Atorvastatin Treatment in Rheumatoid Arthritis. Arthritis Rheum 2009; 60 Suppl 10: 430. 31. Myasoedova E, Crowson CS, Kremers HM, et al. Lipid paradox in rheumatoid arthritis: the impact of serum lipid measures and systemic inflammation on the risk of cardiovascular disease: Ann Rheum Dis 2011; 70(3):482–7. 32. Khaled Amer, Ahmed M. Ibrahim, Hosni A. Younis and Mohamed M. Ahmed. Evaluation of Cardiac Changes in Hyperlipidaemic Rheumatoid Arthritis Patients. Journal of American Science 2012; 8(3):517-22. 33. Peters MJ, Symmons DP, McCarey D, et al. EULAR evidence-based recommendations for cardiovascular risk management in patients with rheumatoid arthritis and other forms of inflammatory arthritis. Ann Rheum Dis. 2010;69(2):325- 31. http://www.ncbi.nlm.nih.gov/pubmed?term=%22Kanda%20H%22%5BAuthor%5D http://www.ncbi.nlm.nih.gov/pubmed?term=%22Yokota%20K%22%5BAuthor%5D http://www.ncbi.nlm.nih.gov/pubmed?term=%22Kohno%20C%22%5BAuthor%5D http://jcp.sagepub.com/search?author1=M+Igel&sortspec=date&submit=Submit http://jcp.sagepub.com/search?author1=T+Sudhop&sortspec=date&submit=Submit http://jcp.sagepub.com/search?author1=K+von+Bergmann&sortspec=date&submit=Submit http://www.ncbi.nlm.nih.gov/pubmed/18029469## http://www.ncbi.nlm.nih.gov/pubmed/18029469## http://www.ncbi.nlm.nih.gov/pubmed/9590999## http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=search&db=PubMed&term=%20Amos%2BRS%5bauth%5d http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=search&db=PubMed&term=%20Constable%2BTJ%5bauth%5d http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=search&db=PubMed&term=%20Crockson%2BRA%5bauth%5d http://www.ncbi.nlm.nih.gov/pubmed?term=Yildirim%20K%5BAuthor%5D&cauthor=true&cauthor_uid=15648784 http://www.ncbi.nlm.nih.gov/pubmed?term=Karatay%20S%5BAuthor%5D&cauthor=true&cauthor_uid=15648784 http://www.ncbi.nlm.nih.gov/pubmed?term=Melikoglu%20MA%5BAuthor%5D&cauthor=true&cauthor_uid=15648784 http://www.ncbi.nlm.nih.gov/pubmed/15648784## http://www.ncbi.nlm.nih.gov/pubmed?term=Myasoedova%20E%5BAuthor%5D&cauthor=true&cauthor_uid=21216812 http://www.ncbi.nlm.nih.gov/pubmed?term=Crowson%20CS%5BAuthor%5D&cauthor=true&cauthor_uid=21216812 http://www.ncbi.nlm.nih.gov/pubmed?term=Kremers%20HM%5BAuthor%5D&cauthor=true&cauthor_uid=21216812 http://www.ncbi.nlm.nih.gov/pubmed?term=Peters%20MJ%5BAuthor%5D&cauthor=true&cauthor_uid=19773290 http://www.ncbi.nlm.nih.gov/pubmed?term=Symmons%20DP%5BAuthor%5D&cauthor=true&cauthor_uid=19773290 http://www.ncbi.nlm.nih.gov/pubmed?term=McCarey%20D%5BAuthor%5D&cauthor=true&cauthor_uid=19773290 http://www.ncbi.nlm.nih.gov/pubmed/19773290##