Clin Rheumatol DOI 10.1007/s10067-014-2654-7
ORIGINAL ARTICLE
Atorvastatin effect on systemic lupus erythematosus disease activity: a double-blind randomized clinical trial Alimohammad Fatemi & Mahdi Moosavi & Zahra Sayedbonakdar & Ziba Farajzadegan & Mehdi Kazemi & Abbas Smiley
Received: 1 November 2013 / Revised: 24 March 2014 / Accepted: 26 April 2014 # Clinical Rheumatology 2014
Abstract We aimed to evaluate the therapeutic effects of atorvastatin on systemic lupus erythematosus disease activity index (SLEDAI). Ninety patients with SLE were consented and randomized to receive either atorvastatin, 20 mg/day, or placebo for 3 months. The primary outcome was change in SLEDAI. Lipids, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) were assessed as secondary end points. Analysis was done by “intention to treat” (ITT) as the primary analysis and “treatment completed analysis” (TCA) as the supplementary analysis. Demographic features, baseline characteristics, and distribution of medications were not significantly different between the two groups. Mean SLEDAI score at baseline in both groups was 3±0.5. By TCA and ITT, mean SLEDAI scores decreased to 1.7±0.4 and 2.7±0.5, respectively, in the atorvastatin group and 3±0.4 and 3±0.5, respectively, in the control group. The difference between the two groups after intervention was significant by TCA (P2 mg/dl, liver aminotransferase >2 times of normal, unexplained myalgia, current use of cyclosporine, prednisolone >0.5 mg/kg/day or equivalent dose of other corticosteroids, and finally, cyclophosphamide administration during the 3-month period before the start of study. Withdrawal criteria included drug intolerance, not regular use of administered medication (atorvastatin or placebo) during the intervention for 3 days in a month, and need to administer prednisolone >0.5 mg/kg/day or equivalent dose of other corticosteroids, cyclophosphamide, or cyclosporine during the study period.
were performed at baseline and after the end of the 3-month treatment period: complete blood count, urine analysis, fasting lipid profile, liver function tests, renal function tests, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), antidouble-stranded DNA (anti-dsDNA), C3, and C4. All laboratory exams were executed according to the standard routine techniques. Activity of SLE in each patient was measured using Systemic Lupus Erythematous Disease Activity Index2 K (SLEDAI-2 K), before and after the intervention [23]. The primary end point was change in SLEDAI-2 K score. The score was calculated twice. First, in order to show the practical value of intervention and to avoid the bias associated with the nonrandom loss of patients, intention to treat analysis (ITT) was carried out as primary analysis on all subjects enrolled in the study at the baseline. Second, in those who adhered to the intervention protocol and completed the course of treatment, treatment completed analysis (TCA) was done as a supplementary analysis. TCA is also known as per-protocol analysis. The secondary end points included changes of laboratory indices such as anti-ds DNA, C3, C4, CRP, ESR, and serum creatinine. Statistical analysis Using SPSS version 17 for Windows (Chicago, IL), data analyses were carried out. Descriptive analysis was done and normality of distribution of different variables was assessed using Kolmogorov–Smirnov test and plots. Normally
Table 1 Demographic and baseline features of patients enrolled in the study
Subjects, intervention, and follow-up Variables
90 patients were enrolled in the study. They were randomized to receive blindly either atorvastatin or placebo for 3 months. Simple randomization was applied to assign patients with even numbers to one group and those with odds numbers to the other group. Each group consisted of 45 patients. Patients in the intervention group received atorvastatin tablets, 20 mg/ day (Sobhan Darou Co.). Patients in the control group received placebo tablets, similar in shape, color, and size made by the same pharmaceutical company. The patients were given a 3-month supply of atrovastatin/placebo. In addition to patients, physician, pharmacy, and laboratory technicians were all blind to kind of administered treatment. To check adherence to the assigned protocol, phone calls and/or follow-up visits were performed at the end of the 1st and 2nd months. At the end of study period, the actual number of pills left was counted. All subjects were allowed to continue other medications as necessary for SLE treatment. Both groups were followed up during the study period. The following laboratory evaluations
Atorvastatin group
Control group
P
2 43
4 41
0.7
Age in years, mean (SD)
38.8 (11)
37 (11.5)
0.5
Duration, mean (SD), years
8 (0.65)
7 (0.7)
0.3
Sex, no. of patients
Males Females
Total cholesterol, median (IQR), mg/dl 160 (141–175) 157 (140–172) 0.8 HDL, median (IQR), mg/dl
39 (36–42)
LDL, median (IQR), mg/dl
125 (110–141) 128 (116–139) 0.5
39 (36–43)
0.9
TG, mean (SD), mg/dl
144 (5)
137.5 (4)
0.3
ALT, mean (SD)
17 (0.7)
17 (.07)
0.6
Creatinine, mean (SD)
0.92 (0.03)
1.07 (0.16)
0.4
CRP, mean (SD)
2.8 (0.2)
3.1 (0.2)
0.4
ESR, mean (SD)
18 (2)
14 (1)
0.07
Anti-dsDNA, mean (SD)
12.5 (2)
14 (2.5)
0.7
SLEDAI score, mean (SE)
3 (0.5)
3 (0.5)
0.9
SLEDAI SLE disease activity index, SD standard deviation, HDL highdensity lipoprotein, LDL low-density lipoprotein, IQR interquartile range, TG triglyceride, ALT alanine aminotranferase, CRP C-reactive protein, ESR erythrocyte sedimentation rate, Anti-ds DNA anti-doublestranded DNA
Clin Rheumatol
distributed variables were reported as mean (SD). Nonnormally distributed variables were reported as median (IQR). Characteristics between the two groups at baseline and after 3 months were compared using Mann–Whitney U test for nonparametric variables and Student t test for parametric variables. The changes from the baseline to the end of study period within each group were tested using Wilcoxon signedrank test for nonparametric variables and paired t test for parametric variables. P values less than 0.05 were considered significant.
patients are summarized in Table 1. Seven patients were lost to follow-up in each group (Fig. 1). The only symptom of drug intolerance was dyspepsia. There were no other recorded adverse effects. Important biochemical parameters were compared using TCA within each group and between the two groups; the results are demonstrated in Tables 2 and 3, respectively. As it shows, the atorvastatin and the control groups were not significantly different at baseline. But, after the 3month treatment with atorvastatin, HDL, LDL, and CRP levels were significantly different between the two groups. Medications
Results Patients Descriptive analysis showed normality of distribution of all variables but cholesterol, HDL, and LDL. Baseline features of Fig. 1 Consort flow chart of study
Frequency distribution of all medications used by patients of the atorvastatin and the patients of control groups were not significantly different during the course of study (Table 4). Mean (SD) dosage of prednisolone in atorvastatin and placebo groups were 6 (3) and 5.95 (3.2), respectively (P=0.9).
Clin Rheumatol Table 2 Comparison of different biochemical parameters and SLEDAI scores before and after intervention within the two groups using TCA analysis Variables, mean (SD)
Atorvastatin
Total cholesterol, median (IQR), mg/dl HDL, median (IQR), mg/dl LDL, median (IQR), mg/dl TG, mean (SD), mg/dl ALT, mean (SD) Creatinine, mean (SD) CRP, mean (SD) ESR, mean (SD) Anti-dsDNA, Mean (SD) SLEDAI score, Mean (SE)
Control
Baseline
After intervention
P
Baseline
After intervention
P
160 (141–175) 39 (36–42) 125 (110–141) 144 (5) 17 (0.7) 0.92 (0.03) 2.8 (0.2) 18 (2) 12.5 (2) 3 (0.5)
143 (124–160) 44 (39–47) 104 (92–120) 134 (5) 17 (0.7) 0.96 (0.04) 2.5 (0.3) 15 (2) 9 (2) 1.7 (0.4)
0.0001 0.0001 0.0001 0.001 0.1 0.02 0.4 0.001 0.002 0.02
157 (140–172) 39 (36–43) 128 (116–139) 137.5 (4) 17 (.07) 1.07 (0.16) 3.1 (0.2) 14 (1) 14 (2.5) 3 (0.5)
161 (142–172) 38 (35–45) 132 (121–144) 140 (4) 18 (0.7) 0.95 (0.04) 3.2 (0.2) 15 (1) 14 (3) 3 (0.4)
0.046 0.3 0.001 0.09 0.3 0.5 0.1 0.03 0.5 0.7
Values in ital are statistically significant SLEDAI SLE disease activity index, SD standard deviation, SE standard error, HDL high-density lipoprotein, LDL low-density lipoprotein, IQR interquartile range, TG triglyceride, ALT alanine aminotranferase, CRP C-reactive protein, ESR erythrocyte sedimentation rate, Anti-ds DNA anti-doublestranded DNA
Disease activity The range of SLEDAI scores in the atorvastatin group was 0 to 14 whereas in the control group was 0 to 8. The clinical manifestations comprising the SLEDAI were compared between the two groups (Table 5). The comparisons of SLEDAI mean scores within each group before and after intervention are demonstrated in Table 2. The baseline SLEDAI mean scores of the two groups are revealed in Table 3. Once TCA (per-protocol analysis) was applied, mean (SE) SLEDAI score Table 3 Comparison of different biochemical parameters and SLEDAI scores after intervention between the two groups using TCA analysis. The reported values are mean (SD) for all variables but for total cholesterol, HDL, and LDL in which median (IQR) are reported Variables
Total cholesterol (mg/dl) HDL (mg/dl) LDL (mg/dl) TG (mg/dl) ALT Creatinine CRP ESR Anti-ds DNA
After intervention Atorvastatin
Control
P
143 (124–160) 44 (39–47) 104 (92–120) 134 (5) 17 (0.7) 0.96 (0.04) 2.5 (0.3) 15 (2) 9 (2)
161 (142–172) 38 (35–45) 132 (121–144) 140 (4) 18 (0.7) 0.95 (0.04) 3.2 (0.2) 15 (1) 14 (3)
0.001 0.002 0.0001 0.3 0.3 0.7 0.03 0.9 0.1
Values in ital are statistically significant SD standard deviation, HDL high-density lipoprotein, LDL low-density lipoprotein, IQR interquartile range, TG triglyceride, ALT alanine aminotranferase, CRP C-reactive protein, ESR erythrocyte sedimentation rate, Anti-ds DNA anti-double-stranded DNA
after intervention in atorvastatin group [1.7 (0.4)] improved significantly (P=0.02) when compared with either the baseline score [3 (0.5)] or the corresponding score in the control group [3 (0.4)]. By application of the worst case scenario and inclusion of all 45 cases enrolled in each group at baseline (ITT analysis), the recorded mean SLEDAI scores in atorvastatin and control groups were 2.7±0.5 vs. 3±0.6, respectively. The difference was not significant (P=0.1). In atorvastatin group, SLEDAI score decreased in 10 patients and increased in 1 patient whereas in placebo group it decreased in only 1 patient and increased in 2 patients. Log-rank test showed significant difference between the two groups (P=0.005).
Discussion The current study demonstrated that the effect of 3-month atorvastatin therapy on SLE activity was unconvincing. One study on 88 patients (64 in intervention and 24 in control groups) showed dissimilar effects on SLEDAI after 8 weeks Table 4 Frequency distribution of administered medications during the course of study compared between the two groups Medications
Atorvastatin (n=45)
Control (n=45)
P
Prednisolone Hydroxychloroquine Losartan Mycophenolate mofetil Azathioprine Methotrexate Captopril
30 30 14 8 5 0 8
37 34 10 11 4 1 7
0.2 0.3 0.3 0.4 0.7 0.5 0.8
Clin Rheumatol Table 5 Frequency distribution of different components of the SLEDAI in all patients in the two groups, before and after intervention SLEDAI components
Atorvastatin, no. of patients
Control, no. of patients
Baseline After intervention Baseline After intervention Arthritis
2
2
6
5
Lupus headache
3
2
0
0
Vasculitis
1
1
0
0
Rash
1
0
0
0
Alopecia
4
3
5
5
Mucosal ulcers
1
0
0
0
Psychosis
0
0
1
1
Increased anti-ds DNA Low C3 or C4
6
6
6
6
6
2
4
5
Leukopenia
1
2
3
1
Thrombocytopenia 1
1
2
2
Proteinuria
13
15
15
14
Hematuria
0
1
1
1
Urinary cast
0
1
0
0
Pyuria
0
1
1
1
Total score
135
122
133
131
SLEDAI SLE disease activity index, anti-ds DNA anti-double-stranded DNA
of treatment with 20 mg/day atorvastatin [24] whereas the findings of Kruif et al. and the Lupus Atherosclerosis Prevention Study (LAPS) were in agreement with our results [18, 20]. In Kruif et al. study, 19 patients were prescribed either 10 mg rouvastatin or no treatment for 3 months. After 3 months of wash-out period, the regimen was changed [18]. In the LAPS, 99 and 101 patients received atorvastatin and placebo, respectively, for 2 years [20]. Interestingly, many studies have shown that statins can reduce CRP levels [25–29]. This effect was recorded in our investigation whereas it was not observed in two other studies [18, 20]. In the LAPS, the concurrent effects of other immunosuppressive medications were not taken into account. In other words, it was not demonstrated whether the two groups of intervention and placebo were similar in relation to the dosages of received other immunosuppressive agents. Then, other immunosuppressive medications might have masked the effects of statins on CRP. Moreover, in Kruif et al. study, the sample size was not large enough to record a significant effect [18]. Also, atorvastatin demonstrated stronger immunomodulatory effects compared to other statins [30]. Although in the current study, the creatinine levels increased in the intervention group, the final recorded levels were in the normal range. Interestingly, Bianchi et al. revealed modifying effects of atorvastatin on creatinine in lupus patients with chronic glomerulonephritis [31]. Also, atorvastatin was safe on liver after the 3-month intervention in our study.
Since single-center studies mainly include homogenous study population, limited external validity was the main limitation of the current investigation. Other limitations were relatively small sample size, single-dose atorvastatin, and short follow-up period. This study did not also include patients with severe SLE status. Moreover, it was better to calculate the glomerular filtration rate (GFR) than serum creatinine because GFR is a better index of patient’s renal function. It is suggested that the future investigations include severe patients with longer periods of follow-up in multiple centers. Comparison of the effects of different statins could be more clarifying too. Acknowledgment This study was supported by the grant of Isfahan University of Medical Sciences with the reference number of 390369. Disclosures None.
References 1. Avina-Zubieta JA, Choi HK, Sadatsafavi M, Etminan M, Esdaile JM, Lacaille D (2008) Risk of cardiovascular mortality in patients with rheumatoid arthritis: a meta-analysis of observational studies. Arthritis Rheum 59(12):1690–1697 2. Hak AE, Karlson EW, Feskanich D, Stampfer MJ, Costenbader KH (2009) Systemic lupus erythematosus and the risk of cardiovascular disease: results from the nurses’ health study. Arthritis Rheum 61(10):1396–1402 3. Solomon DH, Karlson EW, Rimm EB, Cannuscio CC, Mandl LA, Manson JE, Stampfer MJ, Curhan GC (2003) Cardiovascular morbidity and mortality in women diagnosed with rheumatoid arthritis. Circulation 107(9):1303–1307 4. Ward MM (1999) Premature morbidity from cardiovascular and cerebrovascular diseases in women with systemic lupus erythematosus. Arthritis Rheum 42(2):338–346 5. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebocontrolled trial (2002). Lancet 360 (9326):7-22. 6. Shepherd J, Cobbe SM, Ford I, Isles CG, Lorimer AR, MacFarlane PW, McKillop JH, Packard CJ (1995) Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group. N Engl J Med 333(20): 1301–1307 7. Libby P (2002) Inflammation in atherosclerosis. Nature 420(6917): 868–874 8. Schonbeck U, Libby P (2004) Inflammation, immunity, and HMGCoA reductase inhibitors: statins as antiinflammatory agents? Circulation 109(21 Suppl 1):II18–II26 9. Abeles AM, Pillinger MH (2006) Statins as antiinflammatory and immunomodulatory agents: a future in rheumatologic therapy? Arthritis Rheum 54(2):393–407 10. Meroni PL, Luzzana C, Ventura D (2002) Anti-inflammatory and immunomodulating properties of statins. An additional tool for the therapeutic approach of systemic autoimmune diseases? Clin Rev Allergy Immunol 23(3):263–277 11. Jury EC, Isenberg DA, Mauri C, Ehrenstein MR (2006) Atorvastatin restores Lck expression and lipid raft-associated signaling in T cells from patients with systemic lupus erythematosus. J Immunol 177(10):7416–7422
Clin Rheumatol 12. McCarey DW, McInnes IB, Madhok R, Hampson R, Scherbakov O, Ford I, Capell HA, Sattar N (2004) Trial of Atorvastatin in Rheumatoid Arthritis (TARA): double-blind, randomised placebocontrolled trial. Lancet 363(9426):2015–2021 13. Vollmer T, Key L, Durkalski V, Tyor W, Corboy J, Markovic-Plese S, Preiningerova J, Rizzo M, Singh I (2004) Oral simvastatin treatment in relapsing-remitting multiple sclerosis. Lancet 363(9421):1607– 1608 14. Jury EC, Ehrenstein MR (2005) Statins: immunomodulators for autoimmune rheumatic disease? Lupus 14(3):192–196 15. Lawman S, Mauri C, Jury EC, Cook HT, Ehrenstein MR (2004) Atorvastatin inhibits autoreactive B cell activation and delays lupus development in New Zealand black/white F1 mice. J Immunol 173(12):7641–7646 16. Graham KL, Lee LY, Higgins JP, Steinman L, Utz PJ, Ho PP (2008) Failure of oral atorvastatin to modulate a murine model of systemic lupus erythematosus. Arthritis Rheum 58(7):2098–2104 17. Abud-Mendoza C, de la Fuente H, Cuevas-Orta E, Baranda L, CruzRizo J, Gonzalez-Amaro R (2003) Therapy with statins in patients with refractory rheumatic diseases: a preliminary study. Lupus 12(8): 607–611 18. de Kruif MD, Limper M, Hansen HR, de Ruiter J, Spek CA, van Gorp EC, ten Berge IJ, Rowshani AT, ten Cate H, Meesters EW (2009) Effects of a 3-month course of rosuvastatin in patients with systemic lupus erythematosus. Ann Rheum Dis 68(10):1654 19. Costenbader KH, Liang MH, Chibnik LB, Aizer J, Kwon H, Gall V, Karlson EW (2007) A pravastatin dose-escalation study in systemic lupus erythematosus. Rheumatol Int 27(11):1071–1077 20. Petri MA, Kiani AN, Post W, Christopher-Stine L, Magder LS (2011) Lupus Atherosclerosis Prevention Study (LAPS). Ann Rheum Dis 70(5):760–765 21. Iranian Registry of Clinical Trials (2012) Comparison the efficacy of atorvastatin with placebo on disease activity in patients with systemic lupus erythematosus. http://www.irct.ir/.
22. Hochberg MC (1997) Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 40(9):1725 23. Gladman DD, Ibanez D, Urowitz MB (2002) Systemic lupus erythematosus disease activity index 2000. J Rheumatol 29(2):288–291 24. Ferreira GA, Navarro TP, Telles RW, Andrade LE, Sato EI (2007) Atorvastatin therapy improves endothelial-dependent vasodilation in patients with systemic lupus erythematosus: an 8 weeks controlled trial. Rheumatology (Oxford) 46(10):1560–1565 25. Ridker PM, Rifai N, Clearfield M, Downs JR, Weis SE, Miles JS, Gotto AM Jr (2001) Measurement of C-reactive protein for the targeting of statin therapy in the primary prevention of acute coronary events. N Engl J Med 344(26):1959–1965 26. Ridker PM, Rifai N, Pfeffer MA, Sacks F, Braunwald E (1999) Longterm effects of pravastatin on plasma concentration of C-reactive protein. The Cholesterol and Recurrent Events (CARE) Investigators. Circulation 100(3):230–235 27. Albert MA, Danielson E, Rifai N, Ridker PM (2001) Effect of statin therapy on C-reactive protein levels: the pravastatin inflammation/ CRP evaluation (PRINCE): a randomized trial and cohort study. JAMA 286(1):64–70 28. Ridker PM, Rifai N, Lowenthal SP (2001) Rapid reduction in Creactive protein with cerivastatin among 785 patients with primary hypercholesterolemia. Circulation 103(9):1191–1193 29. Ridker PM, Danielson E, Fonseca FA, Genest J, Gotto AM Jr, Kastelein JJ, Koenig W, Libby P, Lorenzatti AJ, MacFadyen JG, Nordestgaard BG, Shepherd J, Willerson JT, Glynn RJ (2008) Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med 359(21):2195–2207 30. Kwak B, Mulhaupt F, Myit S, Mach F (2000) Statins as a newly recognized type of immunomodulator. Nat Med 6(12):1399–1402 31. Bianchi S, Bigazzi R, Caiazza A, Campese VM (2003) A controlled, prospective study of the effects of atorvastatin on proteinuria and progression of kidney disease. Am J Kidney Dis 41(3):565–570
ORIGINAL ARTICLE
Atorvastatin effect on systemic lupus erythematosus disease activity: a double-blind randomized clinical trial Alimohammad Fatemi & Mahdi Moosavi & Zahra Sayedbonakdar & Ziba Farajzadegan & Mehdi Kazemi & Abbas Smiley
Received: 1 November 2013 / Revised: 24 March 2014 / Accepted: 26 April 2014 # Clinical Rheumatology 2014
Abstract We aimed to evaluate the therapeutic effects of atorvastatin on systemic lupus erythematosus disease activity index (SLEDAI). Ninety patients with SLE were consented and randomized to receive either atorvastatin, 20 mg/day, or placebo for 3 months. The primary outcome was change in SLEDAI. Lipids, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) were assessed as secondary end points. Analysis was done by “intention to treat” (ITT) as the primary analysis and “treatment completed analysis” (TCA) as the supplementary analysis. Demographic features, baseline characteristics, and distribution of medications were not significantly different between the two groups. Mean SLEDAI score at baseline in both groups was 3±0.5. By TCA and ITT, mean SLEDAI scores decreased to 1.7±0.4 and 2.7±0.5, respectively, in the atorvastatin group and 3±0.4 and 3±0.5, respectively, in the control group. The difference between the two groups after intervention was significant by TCA (P2 mg/dl, liver aminotransferase >2 times of normal, unexplained myalgia, current use of cyclosporine, prednisolone >0.5 mg/kg/day or equivalent dose of other corticosteroids, and finally, cyclophosphamide administration during the 3-month period before the start of study. Withdrawal criteria included drug intolerance, not regular use of administered medication (atorvastatin or placebo) during the intervention for 3 days in a month, and need to administer prednisolone >0.5 mg/kg/day or equivalent dose of other corticosteroids, cyclophosphamide, or cyclosporine during the study period.
were performed at baseline and after the end of the 3-month treatment period: complete blood count, urine analysis, fasting lipid profile, liver function tests, renal function tests, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), antidouble-stranded DNA (anti-dsDNA), C3, and C4. All laboratory exams were executed according to the standard routine techniques. Activity of SLE in each patient was measured using Systemic Lupus Erythematous Disease Activity Index2 K (SLEDAI-2 K), before and after the intervention [23]. The primary end point was change in SLEDAI-2 K score. The score was calculated twice. First, in order to show the practical value of intervention and to avoid the bias associated with the nonrandom loss of patients, intention to treat analysis (ITT) was carried out as primary analysis on all subjects enrolled in the study at the baseline. Second, in those who adhered to the intervention protocol and completed the course of treatment, treatment completed analysis (TCA) was done as a supplementary analysis. TCA is also known as per-protocol analysis. The secondary end points included changes of laboratory indices such as anti-ds DNA, C3, C4, CRP, ESR, and serum creatinine. Statistical analysis Using SPSS version 17 for Windows (Chicago, IL), data analyses were carried out. Descriptive analysis was done and normality of distribution of different variables was assessed using Kolmogorov–Smirnov test and plots. Normally
Table 1 Demographic and baseline features of patients enrolled in the study
Subjects, intervention, and follow-up Variables
90 patients were enrolled in the study. They were randomized to receive blindly either atorvastatin or placebo for 3 months. Simple randomization was applied to assign patients with even numbers to one group and those with odds numbers to the other group. Each group consisted of 45 patients. Patients in the intervention group received atorvastatin tablets, 20 mg/ day (Sobhan Darou Co.). Patients in the control group received placebo tablets, similar in shape, color, and size made by the same pharmaceutical company. The patients were given a 3-month supply of atrovastatin/placebo. In addition to patients, physician, pharmacy, and laboratory technicians were all blind to kind of administered treatment. To check adherence to the assigned protocol, phone calls and/or follow-up visits were performed at the end of the 1st and 2nd months. At the end of study period, the actual number of pills left was counted. All subjects were allowed to continue other medications as necessary for SLE treatment. Both groups were followed up during the study period. The following laboratory evaluations
Atorvastatin group
Control group
P
2 43
4 41
0.7
Age in years, mean (SD)
38.8 (11)
37 (11.5)
0.5
Duration, mean (SD), years
8 (0.65)
7 (0.7)
0.3
Sex, no. of patients
Males Females
Total cholesterol, median (IQR), mg/dl 160 (141–175) 157 (140–172) 0.8 HDL, median (IQR), mg/dl
39 (36–42)
LDL, median (IQR), mg/dl
125 (110–141) 128 (116–139) 0.5
39 (36–43)
0.9
TG, mean (SD), mg/dl
144 (5)
137.5 (4)
0.3
ALT, mean (SD)
17 (0.7)
17 (.07)
0.6
Creatinine, mean (SD)
0.92 (0.03)
1.07 (0.16)
0.4
CRP, mean (SD)
2.8 (0.2)
3.1 (0.2)
0.4
ESR, mean (SD)
18 (2)
14 (1)
0.07
Anti-dsDNA, mean (SD)
12.5 (2)
14 (2.5)
0.7
SLEDAI score, mean (SE)
3 (0.5)
3 (0.5)
0.9
SLEDAI SLE disease activity index, SD standard deviation, HDL highdensity lipoprotein, LDL low-density lipoprotein, IQR interquartile range, TG triglyceride, ALT alanine aminotranferase, CRP C-reactive protein, ESR erythrocyte sedimentation rate, Anti-ds DNA anti-doublestranded DNA
Clin Rheumatol
distributed variables were reported as mean (SD). Nonnormally distributed variables were reported as median (IQR). Characteristics between the two groups at baseline and after 3 months were compared using Mann–Whitney U test for nonparametric variables and Student t test for parametric variables. The changes from the baseline to the end of study period within each group were tested using Wilcoxon signedrank test for nonparametric variables and paired t test for parametric variables. P values less than 0.05 were considered significant.
patients are summarized in Table 1. Seven patients were lost to follow-up in each group (Fig. 1). The only symptom of drug intolerance was dyspepsia. There were no other recorded adverse effects. Important biochemical parameters were compared using TCA within each group and between the two groups; the results are demonstrated in Tables 2 and 3, respectively. As it shows, the atorvastatin and the control groups were not significantly different at baseline. But, after the 3month treatment with atorvastatin, HDL, LDL, and CRP levels were significantly different between the two groups. Medications
Results Patients Descriptive analysis showed normality of distribution of all variables but cholesterol, HDL, and LDL. Baseline features of Fig. 1 Consort flow chart of study
Frequency distribution of all medications used by patients of the atorvastatin and the patients of control groups were not significantly different during the course of study (Table 4). Mean (SD) dosage of prednisolone in atorvastatin and placebo groups were 6 (3) and 5.95 (3.2), respectively (P=0.9).
Clin Rheumatol Table 2 Comparison of different biochemical parameters and SLEDAI scores before and after intervention within the two groups using TCA analysis Variables, mean (SD)
Atorvastatin
Total cholesterol, median (IQR), mg/dl HDL, median (IQR), mg/dl LDL, median (IQR), mg/dl TG, mean (SD), mg/dl ALT, mean (SD) Creatinine, mean (SD) CRP, mean (SD) ESR, mean (SD) Anti-dsDNA, Mean (SD) SLEDAI score, Mean (SE)
Control
Baseline
After intervention
P
Baseline
After intervention
P
160 (141–175) 39 (36–42) 125 (110–141) 144 (5) 17 (0.7) 0.92 (0.03) 2.8 (0.2) 18 (2) 12.5 (2) 3 (0.5)
143 (124–160) 44 (39–47) 104 (92–120) 134 (5) 17 (0.7) 0.96 (0.04) 2.5 (0.3) 15 (2) 9 (2) 1.7 (0.4)
0.0001 0.0001 0.0001 0.001 0.1 0.02 0.4 0.001 0.002 0.02
157 (140–172) 39 (36–43) 128 (116–139) 137.5 (4) 17 (.07) 1.07 (0.16) 3.1 (0.2) 14 (1) 14 (2.5) 3 (0.5)
161 (142–172) 38 (35–45) 132 (121–144) 140 (4) 18 (0.7) 0.95 (0.04) 3.2 (0.2) 15 (1) 14 (3) 3 (0.4)
0.046 0.3 0.001 0.09 0.3 0.5 0.1 0.03 0.5 0.7
Values in ital are statistically significant SLEDAI SLE disease activity index, SD standard deviation, SE standard error, HDL high-density lipoprotein, LDL low-density lipoprotein, IQR interquartile range, TG triglyceride, ALT alanine aminotranferase, CRP C-reactive protein, ESR erythrocyte sedimentation rate, Anti-ds DNA anti-doublestranded DNA
Disease activity The range of SLEDAI scores in the atorvastatin group was 0 to 14 whereas in the control group was 0 to 8. The clinical manifestations comprising the SLEDAI were compared between the two groups (Table 5). The comparisons of SLEDAI mean scores within each group before and after intervention are demonstrated in Table 2. The baseline SLEDAI mean scores of the two groups are revealed in Table 3. Once TCA (per-protocol analysis) was applied, mean (SE) SLEDAI score Table 3 Comparison of different biochemical parameters and SLEDAI scores after intervention between the two groups using TCA analysis. The reported values are mean (SD) for all variables but for total cholesterol, HDL, and LDL in which median (IQR) are reported Variables
Total cholesterol (mg/dl) HDL (mg/dl) LDL (mg/dl) TG (mg/dl) ALT Creatinine CRP ESR Anti-ds DNA
After intervention Atorvastatin
Control
P
143 (124–160) 44 (39–47) 104 (92–120) 134 (5) 17 (0.7) 0.96 (0.04) 2.5 (0.3) 15 (2) 9 (2)
161 (142–172) 38 (35–45) 132 (121–144) 140 (4) 18 (0.7) 0.95 (0.04) 3.2 (0.2) 15 (1) 14 (3)
0.001 0.002 0.0001 0.3 0.3 0.7 0.03 0.9 0.1
Values in ital are statistically significant SD standard deviation, HDL high-density lipoprotein, LDL low-density lipoprotein, IQR interquartile range, TG triglyceride, ALT alanine aminotranferase, CRP C-reactive protein, ESR erythrocyte sedimentation rate, Anti-ds DNA anti-double-stranded DNA
after intervention in atorvastatin group [1.7 (0.4)] improved significantly (P=0.02) when compared with either the baseline score [3 (0.5)] or the corresponding score in the control group [3 (0.4)]. By application of the worst case scenario and inclusion of all 45 cases enrolled in each group at baseline (ITT analysis), the recorded mean SLEDAI scores in atorvastatin and control groups were 2.7±0.5 vs. 3±0.6, respectively. The difference was not significant (P=0.1). In atorvastatin group, SLEDAI score decreased in 10 patients and increased in 1 patient whereas in placebo group it decreased in only 1 patient and increased in 2 patients. Log-rank test showed significant difference between the two groups (P=0.005).
Discussion The current study demonstrated that the effect of 3-month atorvastatin therapy on SLE activity was unconvincing. One study on 88 patients (64 in intervention and 24 in control groups) showed dissimilar effects on SLEDAI after 8 weeks Table 4 Frequency distribution of administered medications during the course of study compared between the two groups Medications
Atorvastatin (n=45)
Control (n=45)
P
Prednisolone Hydroxychloroquine Losartan Mycophenolate mofetil Azathioprine Methotrexate Captopril
30 30 14 8 5 0 8
37 34 10 11 4 1 7
0.2 0.3 0.3 0.4 0.7 0.5 0.8
Clin Rheumatol Table 5 Frequency distribution of different components of the SLEDAI in all patients in the two groups, before and after intervention SLEDAI components
Atorvastatin, no. of patients
Control, no. of patients
Baseline After intervention Baseline After intervention Arthritis
2
2
6
5
Lupus headache
3
2
0
0
Vasculitis
1
1
0
0
Rash
1
0
0
0
Alopecia
4
3
5
5
Mucosal ulcers
1
0
0
0
Psychosis
0
0
1
1
Increased anti-ds DNA Low C3 or C4
6
6
6
6
6
2
4
5
Leukopenia
1
2
3
1
Thrombocytopenia 1
1
2
2
Proteinuria
13
15
15
14
Hematuria
0
1
1
1
Urinary cast
0
1
0
0
Pyuria
0
1
1
1
Total score
135
122
133
131
SLEDAI SLE disease activity index, anti-ds DNA anti-double-stranded DNA
of treatment with 20 mg/day atorvastatin [24] whereas the findings of Kruif et al. and the Lupus Atherosclerosis Prevention Study (LAPS) were in agreement with our results [18, 20]. In Kruif et al. study, 19 patients were prescribed either 10 mg rouvastatin or no treatment for 3 months. After 3 months of wash-out period, the regimen was changed [18]. In the LAPS, 99 and 101 patients received atorvastatin and placebo, respectively, for 2 years [20]. Interestingly, many studies have shown that statins can reduce CRP levels [25–29]. This effect was recorded in our investigation whereas it was not observed in two other studies [18, 20]. In the LAPS, the concurrent effects of other immunosuppressive medications were not taken into account. In other words, it was not demonstrated whether the two groups of intervention and placebo were similar in relation to the dosages of received other immunosuppressive agents. Then, other immunosuppressive medications might have masked the effects of statins on CRP. Moreover, in Kruif et al. study, the sample size was not large enough to record a significant effect [18]. Also, atorvastatin demonstrated stronger immunomodulatory effects compared to other statins [30]. Although in the current study, the creatinine levels increased in the intervention group, the final recorded levels were in the normal range. Interestingly, Bianchi et al. revealed modifying effects of atorvastatin on creatinine in lupus patients with chronic glomerulonephritis [31]. Also, atorvastatin was safe on liver after the 3-month intervention in our study.
Since single-center studies mainly include homogenous study population, limited external validity was the main limitation of the current investigation. Other limitations were relatively small sample size, single-dose atorvastatin, and short follow-up period. This study did not also include patients with severe SLE status. Moreover, it was better to calculate the glomerular filtration rate (GFR) than serum creatinine because GFR is a better index of patient’s renal function. It is suggested that the future investigations include severe patients with longer periods of follow-up in multiple centers. Comparison of the effects of different statins could be more clarifying too. Acknowledgment This study was supported by the grant of Isfahan University of Medical Sciences with the reference number of 390369. Disclosures None.
References 1. Avina-Zubieta JA, Choi HK, Sadatsafavi M, Etminan M, Esdaile JM, Lacaille D (2008) Risk of cardiovascular mortality in patients with rheumatoid arthritis: a meta-analysis of observational studies. Arthritis Rheum 59(12):1690–1697 2. Hak AE, Karlson EW, Feskanich D, Stampfer MJ, Costenbader KH (2009) Systemic lupus erythematosus and the risk of cardiovascular disease: results from the nurses’ health study. Arthritis Rheum 61(10):1396–1402 3. Solomon DH, Karlson EW, Rimm EB, Cannuscio CC, Mandl LA, Manson JE, Stampfer MJ, Curhan GC (2003) Cardiovascular morbidity and mortality in women diagnosed with rheumatoid arthritis. Circulation 107(9):1303–1307 4. Ward MM (1999) Premature morbidity from cardiovascular and cerebrovascular diseases in women with systemic lupus erythematosus. Arthritis Rheum 42(2):338–346 5. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebocontrolled trial (2002). Lancet 360 (9326):7-22. 6. Shepherd J, Cobbe SM, Ford I, Isles CG, Lorimer AR, MacFarlane PW, McKillop JH, Packard CJ (1995) Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group. N Engl J Med 333(20): 1301–1307 7. Libby P (2002) Inflammation in atherosclerosis. Nature 420(6917): 868–874 8. Schonbeck U, Libby P (2004) Inflammation, immunity, and HMGCoA reductase inhibitors: statins as antiinflammatory agents? Circulation 109(21 Suppl 1):II18–II26 9. Abeles AM, Pillinger MH (2006) Statins as antiinflammatory and immunomodulatory agents: a future in rheumatologic therapy? Arthritis Rheum 54(2):393–407 10. Meroni PL, Luzzana C, Ventura D (2002) Anti-inflammatory and immunomodulating properties of statins. An additional tool for the therapeutic approach of systemic autoimmune diseases? Clin Rev Allergy Immunol 23(3):263–277 11. Jury EC, Isenberg DA, Mauri C, Ehrenstein MR (2006) Atorvastatin restores Lck expression and lipid raft-associated signaling in T cells from patients with systemic lupus erythematosus. J Immunol 177(10):7416–7422
Clin Rheumatol 12. McCarey DW, McInnes IB, Madhok R, Hampson R, Scherbakov O, Ford I, Capell HA, Sattar N (2004) Trial of Atorvastatin in Rheumatoid Arthritis (TARA): double-blind, randomised placebocontrolled trial. Lancet 363(9426):2015–2021 13. Vollmer T, Key L, Durkalski V, Tyor W, Corboy J, Markovic-Plese S, Preiningerova J, Rizzo M, Singh I (2004) Oral simvastatin treatment in relapsing-remitting multiple sclerosis. Lancet 363(9421):1607– 1608 14. Jury EC, Ehrenstein MR (2005) Statins: immunomodulators for autoimmune rheumatic disease? Lupus 14(3):192–196 15. Lawman S, Mauri C, Jury EC, Cook HT, Ehrenstein MR (2004) Atorvastatin inhibits autoreactive B cell activation and delays lupus development in New Zealand black/white F1 mice. J Immunol 173(12):7641–7646 16. Graham KL, Lee LY, Higgins JP, Steinman L, Utz PJ, Ho PP (2008) Failure of oral atorvastatin to modulate a murine model of systemic lupus erythematosus. Arthritis Rheum 58(7):2098–2104 17. Abud-Mendoza C, de la Fuente H, Cuevas-Orta E, Baranda L, CruzRizo J, Gonzalez-Amaro R (2003) Therapy with statins in patients with refractory rheumatic diseases: a preliminary study. Lupus 12(8): 607–611 18. de Kruif MD, Limper M, Hansen HR, de Ruiter J, Spek CA, van Gorp EC, ten Berge IJ, Rowshani AT, ten Cate H, Meesters EW (2009) Effects of a 3-month course of rosuvastatin in patients with systemic lupus erythematosus. Ann Rheum Dis 68(10):1654 19. Costenbader KH, Liang MH, Chibnik LB, Aizer J, Kwon H, Gall V, Karlson EW (2007) A pravastatin dose-escalation study in systemic lupus erythematosus. Rheumatol Int 27(11):1071–1077 20. Petri MA, Kiani AN, Post W, Christopher-Stine L, Magder LS (2011) Lupus Atherosclerosis Prevention Study (LAPS). Ann Rheum Dis 70(5):760–765 21. Iranian Registry of Clinical Trials (2012) Comparison the efficacy of atorvastatin with placebo on disease activity in patients with systemic lupus erythematosus. http://www.irct.ir/.
22. Hochberg MC (1997) Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 40(9):1725 23. Gladman DD, Ibanez D, Urowitz MB (2002) Systemic lupus erythematosus disease activity index 2000. J Rheumatol 29(2):288–291 24. Ferreira GA, Navarro TP, Telles RW, Andrade LE, Sato EI (2007) Atorvastatin therapy improves endothelial-dependent vasodilation in patients with systemic lupus erythematosus: an 8 weeks controlled trial. Rheumatology (Oxford) 46(10):1560–1565 25. Ridker PM, Rifai N, Clearfield M, Downs JR, Weis SE, Miles JS, Gotto AM Jr (2001) Measurement of C-reactive protein for the targeting of statin therapy in the primary prevention of acute coronary events. N Engl J Med 344(26):1959–1965 26. Ridker PM, Rifai N, Pfeffer MA, Sacks F, Braunwald E (1999) Longterm effects of pravastatin on plasma concentration of C-reactive protein. The Cholesterol and Recurrent Events (CARE) Investigators. Circulation 100(3):230–235 27. Albert MA, Danielson E, Rifai N, Ridker PM (2001) Effect of statin therapy on C-reactive protein levels: the pravastatin inflammation/ CRP evaluation (PRINCE): a randomized trial and cohort study. JAMA 286(1):64–70 28. Ridker PM, Rifai N, Lowenthal SP (2001) Rapid reduction in Creactive protein with cerivastatin among 785 patients with primary hypercholesterolemia. Circulation 103(9):1191–1193 29. Ridker PM, Danielson E, Fonseca FA, Genest J, Gotto AM Jr, Kastelein JJ, Koenig W, Libby P, Lorenzatti AJ, MacFadyen JG, Nordestgaard BG, Shepherd J, Willerson JT, Glynn RJ (2008) Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med 359(21):2195–2207 30. Kwak B, Mulhaupt F, Myit S, Mach F (2000) Statins as a newly recognized type of immunomodulator. Nat Med 6(12):1399–1402 31. Bianchi S, Bigazzi R, Caiazza A, Campese VM (2003) A controlled, prospective study of the effects of atorvastatin on proteinuria and progression of kidney disease. Am J Kidney Dis 41(3):565–570
