- Email: [email protected]
Effects of antirheumatic therapy on serum lipid levels in patients with rheumatoid arthritis: a prospective study
Effects of Antirheumatic Therapy on Serum Lipid Levels in Patients with Rheumatoid Arthritis: A Prospective Study Yong-Beom Park, MD, Hyon K. Choi, MD, MPH, Min-Young Kim, MD, Won-Ki Lee, MD, Jungsik Song, MD, Dong-Kee Kim, PhD, Soo-Kon Lee, MD, PhD BACKGROUND: Patients with newly diagnosed rheumatoid arthritis have adverse serum lipid profiles. We sought to determine the effects of treating rheumatoid arthritis with antirheumatic drugs on these abnormal lipid levels. SUBJECTS AND METHODS: We studied 42 patients with newly diagnosed rheumatoid arthritis who had not been treated with corticosteroids or disease-modifying antirheumatic drugs. We measured serum lipid profiles at baseline and 1 year later, and determined whether there were differences in the changes in lipid levels between patients who met the American College of Rheumatology criteria for a 20% improvement in rheumatoid arthritis and those who did not. RESULTS: Of the 42 patients, 27 (64%) met the criteria for a 20% improvement in rheumatoid arthritis during the 12month study. In these patients, mean high-density lipoprotein (HDL) cholesterol levels increased by 21% (P ⬍0.001), apoli-
poprotein A-I levels increased by 23% (P ⬍0.001), and the ratio of low-density lipoprotein (LDL) cholesterol to HDL cholesterol level decreased by 13% (P ⫽ 0.10). There were significant between-group differences (responders–nonresponders) in the mean 12-month changes in HDL cholesterol levels (8.0 mg/dL; 95% confidence interval [CI]: 3 to 13 mg/dL; P ⫽ 0.002), apolipoprotein A-I levels (21 mg/dL; 95% CI: 8 to 33 mg/dL; P ⫽ 0.003), and the LDL cholesterol to HDL cholesterol ratio (– 0.6; 95% CI: – 0.1 to –1.0; P ⫽ 0.03), but not in LDL cholesterol, apolipoprotein B-100, or lipoprotein(a) levels. CONCLUSION: Active rheumatoid arthritis is associated with an adverse lipid profile that improves substantially following effective treatment of rheumatoid arthritis. This improvement may reduce the risk of cardiovascular disease. Am J Med. 2002; 113:188 –193. ©2002 by Excerpta Medica, Inc.
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poprotein A-I level, and an increased ratio of low-density lipoprotein [LDL] cholesterol to HDL cholesterol levels) among patients with newly diagnosed rheumatoid arthritis who had not been treated with corticosteroids or disease-modifying antirheumatic drugs (13). These results suggest that inflammation from rheumatoid arthritis affects lipid levels, thereby increasing the risk of atherosclerosis. We hypothesized that effective treatment of rheumatoid arthritis would reverse these adverse lipid profiles.
nflammation may be involved in the development of atherosclerosis (1). For example, C-reactive protein, a marker of inflammation, is associated with the risk of cardiovascular disease (2– 4). However, there is a strong association between C-reactive protein levels and serum lipid levels in patients without apparent chronic inflammatory conditions (4 –7). Less is known about whether the association between inflammation and cardiovascular disease is causal (4), or whether inflammation per se is responsible for the increased cardiovascular mortality among patients with chronic inflammatory diseases such as rheumatoid arthritis (8 –11) and systemic lupus erythematosus (12). We recently observed adverse lipid profiles (decreased high-density lipoprotein [HDL] cholesterol and apoli-
From the Division of Rheumatology, Department of Internal Medicine, Institute for Immunology and Immunological Diseases, BK 21 Project for Medical Sciences (YBP, WKL, JS, SKL); Graduate School of Yonsei University (MYK); Department of Biostatistics (DKK), Yonsei University College of Medicine, Seoul, Korea; and Arthritis Unit (HKC), Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts. This study was supported by a research grant (1999) for research instructor at Yonsei University College of Medicine, Seoul, Korea. Requests for reprints should be addressed to Soo-Kon Lee, MD, PhD, Division of Rheumatology, Department of Internal Medicine, Yonsei University College of Medicine, Shinchon-dong 134, Seodaemun-ku, CPO Box 8044, Seoul, Korea 120-752, or [email protected] Manuscript submitted October 29, 2001, and accepted in revised form March 9, 2002. 188
©2002 by Excerpta Medica, Inc. All rights reserved.
METHODS Study Patients and Design Eligible patients were at least 18 years of age and had newly diagnosed rheumatoid arthritis that met the 1987 American Rheumatism Association criteria (14). We excluded patients if they had received corticosteroids or disease-modifying antirheumatic drugs before the study or if they had a clinical condition that affects lipid profiles, such as diabetes mellitus, dyslipidemia, hypothyroidism, nephrotic syndrome, alcoholism, chronic liver disease, Cushing syndrome, or obesity (body mass index ⬎30 kg/ m2). All patients were recruited at the Yonsei University Medical Center, Seoul, Korea. They were followed and provided with standard care for rheumatoid arthritis (15) throughout the 12-month study period. Use of prednisolone (10 mg/d or less) was allowed. Rheumatoid ar0002-9343/02/$–see front matter PII S0002-9343(02)01186-5
Lipid Profile in Rheumatoid Arthritis/Park et al
thritis disease activity was measured bimonthly using the core sets of rheumatoid arthritis outcome measurements for the American College of Rheumatology response criteria (16). After 1 year, we determined if each patient had fulfilled the American College of Rheumatology 20% response criteria, which require improvement by at least 20% in the tender and swollen joint count and by at least 20% in three of five other core set measures (patient global assessment, physician global assessment, physical disability score, acute-phase reactant, and patient pain assessment). No patients developed any exclusion criteria (disorders that affect lipid profiles) or used beta-blockers, oral contraceptives, vitamin E, or lipid-lowering drugs during the study. The Institutional Review Boards of Yonsei University Medical Center approved the study.
RESULTS
Blood Sampling and Laboratory Methods
Among the entire cohort of patients, the 12-month change in C-reactive protein levels correlated significantly with the change in HDL cholesterol levels (r ⫽ – 0.38, P ⬍0.001) and apolipoprotein A-I levels (r ⫽ – 0.29, P ⫽ 0.01). Among the 27 responders (Table 2), mean HDL cholesterol levels increased by 21% (P ⬍0.001), mean apolipoprotein A-I levels increased by 23% (P ⬍0.001), and the mean ratio of LDL cholesterol to HDL cholesterol level decreased by 13% (P ⫽ 0.10). Among the 15 nonresponders, mean HDL cholesterol level and the mean LDL cholesterol to HDL cholesterol ratio did not change significantly (P ⫽ 0.93), and the mean apolipoprotein A-I level increased by 10% (P ⫽ 0.02). After adjusting for baseline values, there were significant between-group (responders vs. nonresponders) changes in HDL cholesterol level (P ⫽ 0.002), apolipoprotein A-I level (P ⫽ 0.003), and the LDL cholesterol to HDL cholesterol ratio (P ⫽ 0.03; Table 2). There were no other significant between-group differences in the 12month changes in lipid levels. Among responders, the number of patients with HDL cholesterol levels ⬍35 mg/dL decreased significantly (from 9 to 2 patients, P ⫽ 0.04) during the 12 months of rheumatoid arthritis treatment. In contrast, the number of patients with HDL cholesterol level ⬍35 mg/dL increased (from 3 to 4 patients) among nonresponders. The between-group comparison was significant (P ⫽ 0.04, Table 3). Prednisolone use (ⱕ10 mg/d) was not associated with significant differences in changes in any of the lipid levels in our study (all between-group P values ⬎0.1). Specifically, the between-group (prednisone [n ⫽ 24] – no prednisone [n ⫽ 18]) difference in mean change in HDL cholesterol level at 12 months was 2 mg/dL (95% confidence interval [CI]: – 4 to 7 mg/dL; P ⫽ 0.50); the difference in the mean change in apolipoprotein A-I level was –1 mg/dL (95% CI: ⫺15 to 13 mg/dL; P ⫽ 0.85). Similarly, there was no significant association between use of
Overnight fasting blood samples were obtained at baseline and after 1 year of follow-up. They were immediately centrifuged, and sera were frozen in aliquots and stored at ⫺70°C until analysis. Laboratory personnel were blinded to the clinical characteristics of the patients. At baseline and 12 months, we measured the same set of lipid markers that Ridker et al. had used in their studies of apparently healthy subjects (2,3). Total cholesterol, triglyceride, and HDL cholesterol levels were determined by the enzymatic method on a Hitachi 747 analyzer (Hitachi, Hitachi-Naka, Japan). Low-density lipoprotein cholesterol levels were estimated (17). Apolipoprotein A-I and apolipoprotein B-100 levels were determined by nephelometry (Bering, Marburg, Germany). C-reactive protein and rheumatoid factor levels were measured by nephelometry (Beckman, Brea, California). Lipoprotein(a) levels were measured using a commercial enzyme-linked immunosorbent assay kit (Immunozym, Immuno GMBH, Heidelberg, Germany).
Statistical Analysis Continuous variables were compared using the paired t test or Wilcoxon signed rank test, as appropriate. To determine the effects of control of rheumatoid arthritis disease activity on lipid profiles, we divided patients into two groups (responders and nonresponders) based on the American College of Rheumatology 20% improvement criteria. Comparisons of categorical variables between groups were analyzed using the chi-squared test or Fisher exact test, as appropriate. The Spearman rank test was used to test the correlation between levels of C-reactive protein and lipids. Analysis of covariance was used to compare lipid levels in responders and nonresponders, adjusting for baseline lipid levels. All tests used a twotailed significance level of 0.05. Analyses were performed using the STATA software package (STATA Corporation, College Station, Texas).
Thirty-seven women and 5 men were enrolled, with a mean (⫾ SD) age of 43 ⫾ 12 years (range, 22 to 69 years) and a mean duration of rheumatoid arthritis of 27 ⫾ 16 months. Twenty-seven patients (64%) were classified as responders (Table 1) according to the 20% improvement in rheumatoid arthritis activity criteria. Although all rheumatoid arthritis activity measures at baseline tended to be higher among responders, the only statistically significant difference was in C-reactive protein level (Table 1, P ⬍0.005). Treatment during the study period did not differ significantly between responders and nonresponders (Table 1).
Change in Lipid Levels
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Table 1. Baseline Demographic and Clinical Characteristics of the Patients with Newly Diagnosed Rheumatoid Arthritis, Stratified by Their Response to Antirheumatic Treatment Responders* (n ⫽ 27)
Nonresponders (n ⫽ 15)
P Value
Number (%) or Mean ⫾ SD Baseline characteristics Age (years) Female sex Rheumatoid factor positive Disease duration (months) Body mass index (kg/m2) Hypertension Smoking Current Past Menopausal status among women Disease activity measures Modified health assessment questionnaire (1 to 4 scale) Duration of morning stiffness (min) No. of tender joints (0 to 68 scale) No. of swollen joint count (0 to 66 scale) Pain (visual analog scale) Patient’s global assessment (0 to 10 scale) Physician’s global assessment (0 to 10 scale) C-reactive protein (mg/dL) Treatment during the study period Methotrexate Other disease-modifying antirheumatic drugs Prednisolone (ⱕ10 mg/d)
44 ⫾ 13 23 (85) 25 (93) 27 ⫾ 15 21.4 ⫾ 3.6 0 (0)
42 ⫾ 10 14 (93) 13 (87) 28 ⫾ 19 22.6 ⫾ 2.5 1 (7)
0.60 0.64 0.61 0.89 0.33 0.36
3 (11) 3 (11) 6/23 (26)
2 (13) 0 3/14 (21)
1.0 0.41 1.0
1.9 ⫾ 0.9
1.6 ⫾ 0.5
0.29
148 ⫾ 152 12 ⫾ 8.1 5 ⫾ 4.1
134 ⫾ 182 9 ⫾ 8.4 4 ⫾ 5.2
0.80 0.34 0.68
6.7 ⫾ 2.1 6.5 ⫾ 2.2
6.5 ⫾ 1.9 6.0 ⫾ 2.5
0.75 0.51
5.8 ⫾ 2.3
4.4 ⫾ 1.9
0.06
3.76 ⫾ 3.84
1.32 ⫾ 1.21
0.005
25 (93) 5 (19)
14 (93) 1 (7)
1.00 0.40
16 (59)
8 (53)
0.71
* Defined as at least a 20% improvement in rheumatoid arthritis disease activity, using the American College of Rheumatology criteria (16).
methotrexate or the other disease-modifying drugs and changes in any of the lipid levels (all between-group P values ⬎0.1).
DISCUSSION Our objective was to determine whether treating rheumatoid arthritis can reverse adverse lipid profiles in these patients. We followed patients with newly diagnosed rheumatoid arthritis who had not been treated with corticosteroids or disease-modifying antirheumatic drugs at baseline for 12 months. Patients received usual antirheumatic care; 64% of them achieved the American College of Rheumatology criteria for a 20% improvement by the end of the study. The improvement in several components of the lipid profile (HDL cholesterol and apolipoprotein A-I levels, and the ratio of LDL cholesterol to 190
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HDL cholesterol level) was substantially greater among those whose rheumatoid arthritis responded to treatment than among those who did not respond to treatment. These benefits were achieved without using lipid-lowering drugs. These results suggest that these lipid levels correlate with rheumatoid arthritis disease activity and that effective control of rheumatoid arthritis can reverse, at least partially, the adverse lipid profiles in patients with rheumatoid arthritis. The magnitude of improvement in lipid profile among responders was clinically meaningful. For example, the 21% improvement in HDL cholesterol level was substantially better than the 8% to 10% benefit of statins (18), and similar to that of nicotinic acid (20%) (19). Moreover, there was a significant reduction in the proportion of patients with an HDL cholesterol level ⬍35 mg/dL, a well-established risk factor for coronary heart disease, among the responders during the study.
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Table 2. Change in Lipid Profile and Rheumatoid Arthritis Disease Activity Measures during the 12-Month Study Baseline Responders (n ⫽ 27)
Change at 12 Months
Nonresponders (n ⫽ 15)
Responders (n ⫽ 27)
Within-Group P Values*
Difference Nonresponders Responders Nonresponders (Responders ⫺ Nonresponders) Between-Group in 12-Month Change P Value† (n ⫽ 15) (n ⫽ 27) (n ⫽ 15)
Mean ⫾ SD
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169 ⫾ 40 41 ⫾ 12 103 ⫾ 37 124 ⫾ 79 2.7 ⫾ 1.1
173 ⫾ 31 42 ⫾ 8 110 ⫾ 28 103 ⫾ 65 2.9 ⫾ 1.1
15 ⫾ 33 8⫾9 6 ⫾ 34 ⫺5 ⫾ 57 ⫺0.4 ⫾ 1.1
7 ⫾ 28 0⫾9 8 ⫾ 28 ⫺9 ⫾ 28 0.02 ⫾ 0.81
0.03 ⬍0.01 0.38 0.69 0.10
0.34 0.93 0.25 0.29 0.69
6.0 (⫺12, 24) 8 (3, 13) ⫺7 (⫺24, 11) 10 (⫺19, 38) ⫺0.6 (⫺1.1, ⫺0.1)
0.50 0.002 0.46 0.49 0.03
133 ⫾ 29 101 ⫾ 28 25 ⫾ 17
130 ⫾ 16 104 ⫾ 27 35 ⫾ 23
32 ⫾ 22 8 ⫾ 25 ⫺1 ⫾ 18
13 ⫾ 18 3 ⫾ 12 1 ⫾ 13
⬍0.01 0.13 0.80
0.02 0.37 0.49
21 (8, 33) 3 (⫺9, 16) ⫺4 (⫺18, 10)
0.003 0.62 0.55
1.9 ⫾ 0.9
1.6 ⫾ 0.5
1.2 ⫾ 0.6
1.8 ⫾ 0.8
⬍0.01
0.42
⫺0.6 (⫺1.0, ⫺0.2)
0.003
148 ⫾ 152
134 ⫾ 182
41 ⫾ 49
95 ⫾ 92
0.47
⫺58 (⫺104, ⫺11)
0.02
12 ⫾ 8
9⫾8
3⫾4
11 ⫾ 8
⬍0.01
0.41
⫺8 (⫺12, ⫺5)
⬍0.001
5⫾4
4⫾5
2⫾2
5⫾1
⬍0.01
0.61
⫺4 (⫺6, ⫺2)
0.001
7⫾2 7⫾2
7⫾2 6⫾3
4⫾2 4⫾2
5⫾3 6⫾3
⬍0.01 ⬍0.01
⬍0.01 0.43
⫺1 (⫺3, 0) ⫺2 (⫺4, 0)
0.09 0.01
6⫾2
4⫾2
2⫾1
5⫾1
⬍0.01
0.92
⫺3 (⫺4, ⫺2)
⬍0.001
3.76 ⫾ 3.84
1.32 ⫾ 1.21
1.13 ⫾ 1.29
1.25 ⫾ 1.58
⬍0.01
0.82
⫺0.52 (⫺1.44, 0.41)
0.26
0.7 ⫾ 0.1 56 ⫾ 2 21.4 ⫾ 3.6
0.8 ⫾ 0.1 57 ⫾ 7 22.6 ⫾ 2.5
0.0 ⫾ 0.1 0⫾1 0.1 ⫾ 0.5
0.1 ⫾ 0.1 0⫾1 0.1 ⫾ 0.4
⬍0.01 0.43 0.38
0.04 0.37 0.34
0.0 (0.0, 0.10) 0 (⫺1, 1) ⫺0.1 (⫺0.0, 0.1)
0.50 0.78 0.50
* P value comparing lipid levels between baseline and 12 months. † Comparing changes in lipid levels between responders and nonresponders. HDL ⫽ high-density lipoprotein; LDL ⫽ low-density lipoprotein.
0.002
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Lipid profile Total cholesterol (mg/dL) HDL cholesterol (mg/dL) LDL cholesterol (mg/dL) Triglyceride (mg/dL) LDL cholesterol to HDL cholesterol ratio Apolipoprotein A-I (mg/dL) Apolipoprotein B-100 (mg/dL) Lipoprotein(a) (mg/dL) Disease activity measures Modified health assessment questionnaire (1 to 4 scale) Duration of morning stiffness (min) No. of tender joints (0 to 68 scale) No. of swollen joint count (0 to 66 scale) Pain (visual analog scale) Patient’s global assessment (0 to 10 scale) Physician’s global assessment (0 to 10 scale) C-reactive protein (mg/dL) Other characteristics Serum creatinine (mg/dL) Body weight (kg) Body mass index (kg/m2)
Mean (95% Confidence Interval)
Lipid Profile in Rheumatoid Arthritis/Park et al
Table 3. Change in HDL Cholesterol Levels during the Study, Stratified by Response to Antirheumatic Therapy HDL Cholesterol Level (mg/dL)
Responders (n ⫽ 27) Baseline
Nonresponders (n ⫽ 15)
12 Months
Baseline
12 Months
Between-Group P Value*
4 (27) 7 (47) 4 (27)
0.04 0.66 0.07
Number (%) ⬍35 35–49 ⱖ50
9 (33) 13 (48) 5 (19)
2 (7) 10 (37) 15 (55)
3 (20) 10 (67) 2 (13)
* Comparison of proportions of responders versus nonresponders in each HDL cholesterol category at 12 months, after adjusting for baseline HDL cholesterol level. HDL ⫽ high-density lipoprotein.
Recent studies have shown associations between C-reactive protein levels, lipid levels, and coronary heart disease in patients without apparent inflammatory conditions. These studies used high-sensitivity C-reactive protein assay methods to detect small differences in C-reactive protein level within the normal range (2,3). In contrast, our study used regular C-reactive protein measurements as a marker of rheumatoid arthritis activity; levels of C-reactive protein were approximately 10 times higher than those reported among patients without apparent inflammatory conditions. Nonetheless, we observed a similar correlation between C-reactive protein levels and lipid levels (HDL cholesterol and apolipoprotein A-I) in patients with rheumatoid arthritis (13). Furthermore, the change in levels of these protective lipids showed a strong, negative correlation with the changes in C-reactive protein level. High-density lipoprotein cholesterol and apolipoprotein A-I levels are negatively correlated with disease activity in several rheumatologic disorders, including Kawasaki’s disease, systemic lupus erythematosus, Behc¸ et’s disease, and gout (20 –23), as well as in other conditions associated with inflammation, such as acute infection and lymphoma (24,25). In animal models, inflammation decreases the levels of HDL cholesterol and apolipoprotein A-I during the acute-phase response (26,27). These reports, together with our current results, provide evidence that inflammation adversely affects these lipid levels. It is unlikely that the better improvement in lipid profile among responders is due to the effects of increased exercise. The effects of strenuous regular exercise programs on HDL cholesterol levels have been disappointing (28 –30), and we do not believe that even responders could have achieved this sort of increase in physical exercise during the study. Similarly, it is unlikely that response to antirheumatic treatment is a marker for other factors—such as differential general health habits or alcohol intake between the groups during the study period—that may be associated with improvements in lipid levels. 192
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It is not known why there is a correlation between inflammation and lipid levels in patients with rheumatoid arthritis. Among patients without apparent inflammatory disorders, subcutaneous adipose tissue produces interleukin 6, which regulates C-reactive protein production in the liver (4). Although this mechanism may explain part of our results, other factors may link inflammation and lipid profiles in patients with rheumatoid arthritis (31–35). Several studies have reported an increased risk of cardiovascular disease among patients with rheumatoid arthritis (8 –11), perhaps as a result of side effects of medication, decreased mobility, or inflammation itself. Our results suggest that a chronic inflammatory condition may be a risk factor for atherosclerosis, at least partly via adverse changes in lipid levels. This hypothesis is supported by a preliminary report of a significant association between an increased erythrocyte sedimentation rate and long-term cardiovascular mortality among patients with rheumatoid arthritis (36). In summary, we found that active rheumatoid arthritis is associated with an adverse lipid profile before treatment with disease-modifying antirheumatic drugs or low-dose corticosteroids, suggesting that the effect is not from these drugs. This lipid profile can be improved by treating rheumatoid arthritis without the use of lipidlowering agents. Better control of rheumatoid arthritis is associated with a better lipid profile, which in turn may reduce the risk of cardiovascular disease.
ACKNOWLEDGMENT The authors thank Drs. Fred Wolfe and John D. Seeger for their valuable review of the manuscript and Ms. Chan-Sook Shin for her research assistance.
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20. Cabana VG, Gidding SS, Getz GS, et al. Serum amyloid A and high density lipoprotein participate in the acute phase response of Kawasaki disease. Pediatr Res. 1997;42:651–655. 21. Borba EF, Bonfa E. Dyslipoproteinemias in systemic lupus erythematosus: influence of disease, activity, and anticardiolipin antibodies. Lupus. 1997;6:533–539. 22. Orem A, Deger O, Memis O, et al. Lp(a) lipoprotein levels as a predictor of risk for thrombogenic events in patients with Behcet’s disease. Ann Rheum Dis. 1995;54:726 –729. 23. Chou CT, Chao PM. Lipid abnormalities in Taiwan Aborigines with gout. Metabolism. 1999;48:131–133. 24. Gidding SS, Stone NJ, Bookstein LC, et al. Month-to-month variability of lipids, lipoproteins, and apolipoproteins and the impact of acute infection in adolescents. J Pediatr. 1998;133:242–246. 25. Blackman JD, Cabana VG, Mazzone T. The acute-phase response and associated lipoprotein abnormalities accompanying lymphoma. J Intern Med. 1993;233:201–204. 26. Cabana VG, Lukens JR, Rice KS, et al. HDL content and composition in acute phase response in three species: triglyceride enrichment of HDL a factor in its decrease. J Lipid Res. 1996;37:2662– 2674. 27. Hosoai H, Webb NR, Glick JM, et al. Expression of serum amyloid A protein in the absence of the acute phase response does not reduce HDL cholesterol or apoA-I levels in human apoA-I transgenic mice. J Lipid Res. 1999;40:648 –653. 28. Stefanick ML, Mackey S, Sheehan M, et al. Effects of diet and exercise in men and postmenopausal women with low levels of HDL cholesterol and high levels of LDL cholesterol. N Engl J Med. 1998; 339:12–20. 29. Cauley JA, Kriska AM, LaPorte RE, et al. A two year randomized exercise trial in older women: effects on HDL-cholesterol. Atherosclerosis. 1987;66:247–258. 30. Thompson CE, Thomas TR, Araujo J, et al. Response of HDL cholesterol, apolipoprotein A-I, and LCAT to exercise withdrawal. Atherosclerosis. 1985;54:65–73. 31. Badolato R, Oppenheim JJ. Role of cytokines, acute-phase proteins, and chemokines in the progression of rheumatoid arthritis. Semin Arthritis Rheum. 1996;26:526 –538. 32. Feldmann M, Maini RN. The role of cytokines in the pathogenesis of rheumatoid arthritis. Rheumatology (Oxford). 1999;38:3–7. 33. Cutolo M, Sulli A, Villaggio B, et al. Relations between steroid hormones and cytokines in rheumatoid arthritis and systemic lupus erythematosus. Ann Rheum Dis. 1998;57:573–577. 34. Carroll G, Bell M, Wang H, et al. Antagonism of the IL-6 cytokine subfamily—a potential strategy for more effective therapy in rheumatoid arthritis. Inflamm Res. 1998;47:1–7. 35. Pasceri V, Yeh ET. A tale of two diseases: atherosclerosis and rheumatoid arthritis. Circulation. 1999;100:2124 –2126. 36. Wolfe F, Hawley DJ, Anderson J. Inflammation as measured by the ESR predicts cardiovascular mortality across all rheumatic disorders: a 25-year prospective study of 5,822 patients. Arthritis Rheum. 1999;42(suppl):S299.
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poprotein A-I levels increased by 23% (P ⬍0.001), and the ratio of low-density lipoprotein (LDL) cholesterol to HDL cholesterol level decreased by 13% (P ⫽ 0.10). There were significant between-group differences (responders–nonresponders) in the mean 12-month changes in HDL cholesterol levels (8.0 mg/dL; 95% confidence interval [CI]: 3 to 13 mg/dL; P ⫽ 0.002), apolipoprotein A-I levels (21 mg/dL; 95% CI: 8 to 33 mg/dL; P ⫽ 0.003), and the LDL cholesterol to HDL cholesterol ratio (– 0.6; 95% CI: – 0.1 to –1.0; P ⫽ 0.03), but not in LDL cholesterol, apolipoprotein B-100, or lipoprotein(a) levels. CONCLUSION: Active rheumatoid arthritis is associated with an adverse lipid profile that improves substantially following effective treatment of rheumatoid arthritis. This improvement may reduce the risk of cardiovascular disease. Am J Med. 2002; 113:188 –193. ©2002 by Excerpta Medica, Inc.
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poprotein A-I level, and an increased ratio of low-density lipoprotein [LDL] cholesterol to HDL cholesterol levels) among patients with newly diagnosed rheumatoid arthritis who had not been treated with corticosteroids or disease-modifying antirheumatic drugs (13). These results suggest that inflammation from rheumatoid arthritis affects lipid levels, thereby increasing the risk of atherosclerosis. We hypothesized that effective treatment of rheumatoid arthritis would reverse these adverse lipid profiles.
nflammation may be involved in the development of atherosclerosis (1). For example, C-reactive protein, a marker of inflammation, is associated with the risk of cardiovascular disease (2– 4). However, there is a strong association between C-reactive protein levels and serum lipid levels in patients without apparent chronic inflammatory conditions (4 –7). Less is known about whether the association between inflammation and cardiovascular disease is causal (4), or whether inflammation per se is responsible for the increased cardiovascular mortality among patients with chronic inflammatory diseases such as rheumatoid arthritis (8 –11) and systemic lupus erythematosus (12). We recently observed adverse lipid profiles (decreased high-density lipoprotein [HDL] cholesterol and apoli-
From the Division of Rheumatology, Department of Internal Medicine, Institute for Immunology and Immunological Diseases, BK 21 Project for Medical Sciences (YBP, WKL, JS, SKL); Graduate School of Yonsei University (MYK); Department of Biostatistics (DKK), Yonsei University College of Medicine, Seoul, Korea; and Arthritis Unit (HKC), Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts. This study was supported by a research grant (1999) for research instructor at Yonsei University College of Medicine, Seoul, Korea. Requests for reprints should be addressed to Soo-Kon Lee, MD, PhD, Division of Rheumatology, Department of Internal Medicine, Yonsei University College of Medicine, Shinchon-dong 134, Seodaemun-ku, CPO Box 8044, Seoul, Korea 120-752, or [email protected] Manuscript submitted October 29, 2001, and accepted in revised form March 9, 2002. 188
©2002 by Excerpta Medica, Inc. All rights reserved.
METHODS Study Patients and Design Eligible patients were at least 18 years of age and had newly diagnosed rheumatoid arthritis that met the 1987 American Rheumatism Association criteria (14). We excluded patients if they had received corticosteroids or disease-modifying antirheumatic drugs before the study or if they had a clinical condition that affects lipid profiles, such as diabetes mellitus, dyslipidemia, hypothyroidism, nephrotic syndrome, alcoholism, chronic liver disease, Cushing syndrome, or obesity (body mass index ⬎30 kg/ m2). All patients were recruited at the Yonsei University Medical Center, Seoul, Korea. They were followed and provided with standard care for rheumatoid arthritis (15) throughout the 12-month study period. Use of prednisolone (10 mg/d or less) was allowed. Rheumatoid ar0002-9343/02/$–see front matter PII S0002-9343(02)01186-5
Lipid Profile in Rheumatoid Arthritis/Park et al
thritis disease activity was measured bimonthly using the core sets of rheumatoid arthritis outcome measurements for the American College of Rheumatology response criteria (16). After 1 year, we determined if each patient had fulfilled the American College of Rheumatology 20% response criteria, which require improvement by at least 20% in the tender and swollen joint count and by at least 20% in three of five other core set measures (patient global assessment, physician global assessment, physical disability score, acute-phase reactant, and patient pain assessment). No patients developed any exclusion criteria (disorders that affect lipid profiles) or used beta-blockers, oral contraceptives, vitamin E, or lipid-lowering drugs during the study. The Institutional Review Boards of Yonsei University Medical Center approved the study.
RESULTS
Blood Sampling and Laboratory Methods
Among the entire cohort of patients, the 12-month change in C-reactive protein levels correlated significantly with the change in HDL cholesterol levels (r ⫽ – 0.38, P ⬍0.001) and apolipoprotein A-I levels (r ⫽ – 0.29, P ⫽ 0.01). Among the 27 responders (Table 2), mean HDL cholesterol levels increased by 21% (P ⬍0.001), mean apolipoprotein A-I levels increased by 23% (P ⬍0.001), and the mean ratio of LDL cholesterol to HDL cholesterol level decreased by 13% (P ⫽ 0.10). Among the 15 nonresponders, mean HDL cholesterol level and the mean LDL cholesterol to HDL cholesterol ratio did not change significantly (P ⫽ 0.93), and the mean apolipoprotein A-I level increased by 10% (P ⫽ 0.02). After adjusting for baseline values, there were significant between-group (responders vs. nonresponders) changes in HDL cholesterol level (P ⫽ 0.002), apolipoprotein A-I level (P ⫽ 0.003), and the LDL cholesterol to HDL cholesterol ratio (P ⫽ 0.03; Table 2). There were no other significant between-group differences in the 12month changes in lipid levels. Among responders, the number of patients with HDL cholesterol levels ⬍35 mg/dL decreased significantly (from 9 to 2 patients, P ⫽ 0.04) during the 12 months of rheumatoid arthritis treatment. In contrast, the number of patients with HDL cholesterol level ⬍35 mg/dL increased (from 3 to 4 patients) among nonresponders. The between-group comparison was significant (P ⫽ 0.04, Table 3). Prednisolone use (ⱕ10 mg/d) was not associated with significant differences in changes in any of the lipid levels in our study (all between-group P values ⬎0.1). Specifically, the between-group (prednisone [n ⫽ 24] – no prednisone [n ⫽ 18]) difference in mean change in HDL cholesterol level at 12 months was 2 mg/dL (95% confidence interval [CI]: – 4 to 7 mg/dL; P ⫽ 0.50); the difference in the mean change in apolipoprotein A-I level was –1 mg/dL (95% CI: ⫺15 to 13 mg/dL; P ⫽ 0.85). Similarly, there was no significant association between use of
Overnight fasting blood samples were obtained at baseline and after 1 year of follow-up. They were immediately centrifuged, and sera were frozen in aliquots and stored at ⫺70°C until analysis. Laboratory personnel were blinded to the clinical characteristics of the patients. At baseline and 12 months, we measured the same set of lipid markers that Ridker et al. had used in their studies of apparently healthy subjects (2,3). Total cholesterol, triglyceride, and HDL cholesterol levels were determined by the enzymatic method on a Hitachi 747 analyzer (Hitachi, Hitachi-Naka, Japan). Low-density lipoprotein cholesterol levels were estimated (17). Apolipoprotein A-I and apolipoprotein B-100 levels were determined by nephelometry (Bering, Marburg, Germany). C-reactive protein and rheumatoid factor levels were measured by nephelometry (Beckman, Brea, California). Lipoprotein(a) levels were measured using a commercial enzyme-linked immunosorbent assay kit (Immunozym, Immuno GMBH, Heidelberg, Germany).
Statistical Analysis Continuous variables were compared using the paired t test or Wilcoxon signed rank test, as appropriate. To determine the effects of control of rheumatoid arthritis disease activity on lipid profiles, we divided patients into two groups (responders and nonresponders) based on the American College of Rheumatology 20% improvement criteria. Comparisons of categorical variables between groups were analyzed using the chi-squared test or Fisher exact test, as appropriate. The Spearman rank test was used to test the correlation between levels of C-reactive protein and lipids. Analysis of covariance was used to compare lipid levels in responders and nonresponders, adjusting for baseline lipid levels. All tests used a twotailed significance level of 0.05. Analyses were performed using the STATA software package (STATA Corporation, College Station, Texas).
Thirty-seven women and 5 men were enrolled, with a mean (⫾ SD) age of 43 ⫾ 12 years (range, 22 to 69 years) and a mean duration of rheumatoid arthritis of 27 ⫾ 16 months. Twenty-seven patients (64%) were classified as responders (Table 1) according to the 20% improvement in rheumatoid arthritis activity criteria. Although all rheumatoid arthritis activity measures at baseline tended to be higher among responders, the only statistically significant difference was in C-reactive protein level (Table 1, P ⬍0.005). Treatment during the study period did not differ significantly between responders and nonresponders (Table 1).
Change in Lipid Levels
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Table 1. Baseline Demographic and Clinical Characteristics of the Patients with Newly Diagnosed Rheumatoid Arthritis, Stratified by Their Response to Antirheumatic Treatment Responders* (n ⫽ 27)
Nonresponders (n ⫽ 15)
P Value
Number (%) or Mean ⫾ SD Baseline characteristics Age (years) Female sex Rheumatoid factor positive Disease duration (months) Body mass index (kg/m2) Hypertension Smoking Current Past Menopausal status among women Disease activity measures Modified health assessment questionnaire (1 to 4 scale) Duration of morning stiffness (min) No. of tender joints (0 to 68 scale) No. of swollen joint count (0 to 66 scale) Pain (visual analog scale) Patient’s global assessment (0 to 10 scale) Physician’s global assessment (0 to 10 scale) C-reactive protein (mg/dL) Treatment during the study period Methotrexate Other disease-modifying antirheumatic drugs Prednisolone (ⱕ10 mg/d)
44 ⫾ 13 23 (85) 25 (93) 27 ⫾ 15 21.4 ⫾ 3.6 0 (0)
42 ⫾ 10 14 (93) 13 (87) 28 ⫾ 19 22.6 ⫾ 2.5 1 (7)
0.60 0.64 0.61 0.89 0.33 0.36
3 (11) 3 (11) 6/23 (26)
2 (13) 0 3/14 (21)
1.0 0.41 1.0
1.9 ⫾ 0.9
1.6 ⫾ 0.5
0.29
148 ⫾ 152 12 ⫾ 8.1 5 ⫾ 4.1
134 ⫾ 182 9 ⫾ 8.4 4 ⫾ 5.2
0.80 0.34 0.68
6.7 ⫾ 2.1 6.5 ⫾ 2.2
6.5 ⫾ 1.9 6.0 ⫾ 2.5
0.75 0.51
5.8 ⫾ 2.3
4.4 ⫾ 1.9
0.06
3.76 ⫾ 3.84
1.32 ⫾ 1.21
0.005
25 (93) 5 (19)
14 (93) 1 (7)
1.00 0.40
16 (59)
8 (53)
0.71
* Defined as at least a 20% improvement in rheumatoid arthritis disease activity, using the American College of Rheumatology criteria (16).
methotrexate or the other disease-modifying drugs and changes in any of the lipid levels (all between-group P values ⬎0.1).
DISCUSSION Our objective was to determine whether treating rheumatoid arthritis can reverse adverse lipid profiles in these patients. We followed patients with newly diagnosed rheumatoid arthritis who had not been treated with corticosteroids or disease-modifying antirheumatic drugs at baseline for 12 months. Patients received usual antirheumatic care; 64% of them achieved the American College of Rheumatology criteria for a 20% improvement by the end of the study. The improvement in several components of the lipid profile (HDL cholesterol and apolipoprotein A-I levels, and the ratio of LDL cholesterol to 190
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HDL cholesterol level) was substantially greater among those whose rheumatoid arthritis responded to treatment than among those who did not respond to treatment. These benefits were achieved without using lipid-lowering drugs. These results suggest that these lipid levels correlate with rheumatoid arthritis disease activity and that effective control of rheumatoid arthritis can reverse, at least partially, the adverse lipid profiles in patients with rheumatoid arthritis. The magnitude of improvement in lipid profile among responders was clinically meaningful. For example, the 21% improvement in HDL cholesterol level was substantially better than the 8% to 10% benefit of statins (18), and similar to that of nicotinic acid (20%) (19). Moreover, there was a significant reduction in the proportion of patients with an HDL cholesterol level ⬍35 mg/dL, a well-established risk factor for coronary heart disease, among the responders during the study.
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Table 2. Change in Lipid Profile and Rheumatoid Arthritis Disease Activity Measures during the 12-Month Study Baseline Responders (n ⫽ 27)
Change at 12 Months
Nonresponders (n ⫽ 15)
Responders (n ⫽ 27)
Within-Group P Values*
Difference Nonresponders Responders Nonresponders (Responders ⫺ Nonresponders) Between-Group in 12-Month Change P Value† (n ⫽ 15) (n ⫽ 27) (n ⫽ 15)
Mean ⫾ SD
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169 ⫾ 40 41 ⫾ 12 103 ⫾ 37 124 ⫾ 79 2.7 ⫾ 1.1
173 ⫾ 31 42 ⫾ 8 110 ⫾ 28 103 ⫾ 65 2.9 ⫾ 1.1
15 ⫾ 33 8⫾9 6 ⫾ 34 ⫺5 ⫾ 57 ⫺0.4 ⫾ 1.1
7 ⫾ 28 0⫾9 8 ⫾ 28 ⫺9 ⫾ 28 0.02 ⫾ 0.81
0.03 ⬍0.01 0.38 0.69 0.10
0.34 0.93 0.25 0.29 0.69
6.0 (⫺12, 24) 8 (3, 13) ⫺7 (⫺24, 11) 10 (⫺19, 38) ⫺0.6 (⫺1.1, ⫺0.1)
0.50 0.002 0.46 0.49 0.03
133 ⫾ 29 101 ⫾ 28 25 ⫾ 17
130 ⫾ 16 104 ⫾ 27 35 ⫾ 23
32 ⫾ 22 8 ⫾ 25 ⫺1 ⫾ 18
13 ⫾ 18 3 ⫾ 12 1 ⫾ 13
⬍0.01 0.13 0.80
0.02 0.37 0.49
21 (8, 33) 3 (⫺9, 16) ⫺4 (⫺18, 10)
0.003 0.62 0.55
1.9 ⫾ 0.9
1.6 ⫾ 0.5
1.2 ⫾ 0.6
1.8 ⫾ 0.8
⬍0.01
0.42
⫺0.6 (⫺1.0, ⫺0.2)
0.003
148 ⫾ 152
134 ⫾ 182
41 ⫾ 49
95 ⫾ 92
0.47
⫺58 (⫺104, ⫺11)
0.02
12 ⫾ 8
9⫾8
3⫾4
11 ⫾ 8
⬍0.01
0.41
⫺8 (⫺12, ⫺5)
⬍0.001
5⫾4
4⫾5
2⫾2
5⫾1
⬍0.01
0.61
⫺4 (⫺6, ⫺2)
0.001
7⫾2 7⫾2
7⫾2 6⫾3
4⫾2 4⫾2
5⫾3 6⫾3
⬍0.01 ⬍0.01
⬍0.01 0.43
⫺1 (⫺3, 0) ⫺2 (⫺4, 0)
0.09 0.01
6⫾2
4⫾2
2⫾1
5⫾1
⬍0.01
0.92
⫺3 (⫺4, ⫺2)
⬍0.001
3.76 ⫾ 3.84
1.32 ⫾ 1.21
1.13 ⫾ 1.29
1.25 ⫾ 1.58
⬍0.01
0.82
⫺0.52 (⫺1.44, 0.41)
0.26
0.7 ⫾ 0.1 56 ⫾ 2 21.4 ⫾ 3.6
0.8 ⫾ 0.1 57 ⫾ 7 22.6 ⫾ 2.5
0.0 ⫾ 0.1 0⫾1 0.1 ⫾ 0.5
0.1 ⫾ 0.1 0⫾1 0.1 ⫾ 0.4
⬍0.01 0.43 0.38
0.04 0.37 0.34
0.0 (0.0, 0.10) 0 (⫺1, 1) ⫺0.1 (⫺0.0, 0.1)
0.50 0.78 0.50
* P value comparing lipid levels between baseline and 12 months. † Comparing changes in lipid levels between responders and nonresponders. HDL ⫽ high-density lipoprotein; LDL ⫽ low-density lipoprotein.
0.002
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Lipid profile Total cholesterol (mg/dL) HDL cholesterol (mg/dL) LDL cholesterol (mg/dL) Triglyceride (mg/dL) LDL cholesterol to HDL cholesterol ratio Apolipoprotein A-I (mg/dL) Apolipoprotein B-100 (mg/dL) Lipoprotein(a) (mg/dL) Disease activity measures Modified health assessment questionnaire (1 to 4 scale) Duration of morning stiffness (min) No. of tender joints (0 to 68 scale) No. of swollen joint count (0 to 66 scale) Pain (visual analog scale) Patient’s global assessment (0 to 10 scale) Physician’s global assessment (0 to 10 scale) C-reactive protein (mg/dL) Other characteristics Serum creatinine (mg/dL) Body weight (kg) Body mass index (kg/m2)
Mean (95% Confidence Interval)
Lipid Profile in Rheumatoid Arthritis/Park et al
Table 3. Change in HDL Cholesterol Levels during the Study, Stratified by Response to Antirheumatic Therapy HDL Cholesterol Level (mg/dL)
Responders (n ⫽ 27) Baseline
Nonresponders (n ⫽ 15)
12 Months
Baseline
12 Months
Between-Group P Value*
4 (27) 7 (47) 4 (27)
0.04 0.66 0.07
Number (%) ⬍35 35–49 ⱖ50
9 (33) 13 (48) 5 (19)
2 (7) 10 (37) 15 (55)
3 (20) 10 (67) 2 (13)
* Comparison of proportions of responders versus nonresponders in each HDL cholesterol category at 12 months, after adjusting for baseline HDL cholesterol level. HDL ⫽ high-density lipoprotein.
Recent studies have shown associations between C-reactive protein levels, lipid levels, and coronary heart disease in patients without apparent inflammatory conditions. These studies used high-sensitivity C-reactive protein assay methods to detect small differences in C-reactive protein level within the normal range (2,3). In contrast, our study used regular C-reactive protein measurements as a marker of rheumatoid arthritis activity; levels of C-reactive protein were approximately 10 times higher than those reported among patients without apparent inflammatory conditions. Nonetheless, we observed a similar correlation between C-reactive protein levels and lipid levels (HDL cholesterol and apolipoprotein A-I) in patients with rheumatoid arthritis (13). Furthermore, the change in levels of these protective lipids showed a strong, negative correlation with the changes in C-reactive protein level. High-density lipoprotein cholesterol and apolipoprotein A-I levels are negatively correlated with disease activity in several rheumatologic disorders, including Kawasaki’s disease, systemic lupus erythematosus, Behc¸ et’s disease, and gout (20 –23), as well as in other conditions associated with inflammation, such as acute infection and lymphoma (24,25). In animal models, inflammation decreases the levels of HDL cholesterol and apolipoprotein A-I during the acute-phase response (26,27). These reports, together with our current results, provide evidence that inflammation adversely affects these lipid levels. It is unlikely that the better improvement in lipid profile among responders is due to the effects of increased exercise. The effects of strenuous regular exercise programs on HDL cholesterol levels have been disappointing (28 –30), and we do not believe that even responders could have achieved this sort of increase in physical exercise during the study. Similarly, it is unlikely that response to antirheumatic treatment is a marker for other factors—such as differential general health habits or alcohol intake between the groups during the study period—that may be associated with improvements in lipid levels. 192
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It is not known why there is a correlation between inflammation and lipid levels in patients with rheumatoid arthritis. Among patients without apparent inflammatory disorders, subcutaneous adipose tissue produces interleukin 6, which regulates C-reactive protein production in the liver (4). Although this mechanism may explain part of our results, other factors may link inflammation and lipid profiles in patients with rheumatoid arthritis (31–35). Several studies have reported an increased risk of cardiovascular disease among patients with rheumatoid arthritis (8 –11), perhaps as a result of side effects of medication, decreased mobility, or inflammation itself. Our results suggest that a chronic inflammatory condition may be a risk factor for atherosclerosis, at least partly via adverse changes in lipid levels. This hypothesis is supported by a preliminary report of a significant association between an increased erythrocyte sedimentation rate and long-term cardiovascular mortality among patients with rheumatoid arthritis (36). In summary, we found that active rheumatoid arthritis is associated with an adverse lipid profile before treatment with disease-modifying antirheumatic drugs or low-dose corticosteroids, suggesting that the effect is not from these drugs. This lipid profile can be improved by treating rheumatoid arthritis without the use of lipidlowering agents. Better control of rheumatoid arthritis is associated with a better lipid profile, which in turn may reduce the risk of cardiovascular disease.
ACKNOWLEDGMENT The authors thank Drs. Fred Wolfe and John D. Seeger for their valuable review of the manuscript and Ms. Chan-Sook Shin for her research assistance.
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20. Cabana VG, Gidding SS, Getz GS, et al. Serum amyloid A and high density lipoprotein participate in the acute phase response of Kawasaki disease. Pediatr Res. 1997;42:651–655. 21. Borba EF, Bonfa E. Dyslipoproteinemias in systemic lupus erythematosus: influence of disease, activity, and anticardiolipin antibodies. Lupus. 1997;6:533–539. 22. Orem A, Deger O, Memis O, et al. Lp(a) lipoprotein levels as a predictor of risk for thrombogenic events in patients with Behcet’s disease. Ann Rheum Dis. 1995;54:726 –729. 23. Chou CT, Chao PM. Lipid abnormalities in Taiwan Aborigines with gout. Metabolism. 1999;48:131–133. 24. Gidding SS, Stone NJ, Bookstein LC, et al. Month-to-month variability of lipids, lipoproteins, and apolipoproteins and the impact of acute infection in adolescents. J Pediatr. 1998;133:242–246. 25. Blackman JD, Cabana VG, Mazzone T. The acute-phase response and associated lipoprotein abnormalities accompanying lymphoma. J Intern Med. 1993;233:201–204. 26. Cabana VG, Lukens JR, Rice KS, et al. HDL content and composition in acute phase response in three species: triglyceride enrichment of HDL a factor in its decrease. J Lipid Res. 1996;37:2662– 2674. 27. Hosoai H, Webb NR, Glick JM, et al. Expression of serum amyloid A protein in the absence of the acute phase response does not reduce HDL cholesterol or apoA-I levels in human apoA-I transgenic mice. J Lipid Res. 1999;40:648 –653. 28. Stefanick ML, Mackey S, Sheehan M, et al. Effects of diet and exercise in men and postmenopausal women with low levels of HDL cholesterol and high levels of LDL cholesterol. N Engl J Med. 1998; 339:12–20. 29. Cauley JA, Kriska AM, LaPorte RE, et al. A two year randomized exercise trial in older women: effects on HDL-cholesterol. Atherosclerosis. 1987;66:247–258. 30. Thompson CE, Thomas TR, Araujo J, et al. Response of HDL cholesterol, apolipoprotein A-I, and LCAT to exercise withdrawal. Atherosclerosis. 1985;54:65–73. 31. Badolato R, Oppenheim JJ. Role of cytokines, acute-phase proteins, and chemokines in the progression of rheumatoid arthritis. Semin Arthritis Rheum. 1996;26:526 –538. 32. Feldmann M, Maini RN. The role of cytokines in the pathogenesis of rheumatoid arthritis. Rheumatology (Oxford). 1999;38:3–7. 33. Cutolo M, Sulli A, Villaggio B, et al. Relations between steroid hormones and cytokines in rheumatoid arthritis and systemic lupus erythematosus. Ann Rheum Dis. 1998;57:573–577. 34. Carroll G, Bell M, Wang H, et al. Antagonism of the IL-6 cytokine subfamily—a potential strategy for more effective therapy in rheumatoid arthritis. Inflamm Res. 1998;47:1–7. 35. Pasceri V, Yeh ET. A tale of two diseases: atherosclerosis and rheumatoid arthritis. Circulation. 1999;100:2124 –2126. 36. Wolfe F, Hawley DJ, Anderson J. Inflammation as measured by the ESR predicts cardiovascular mortality across all rheumatic disorders: a 25-year prospective study of 5,822 patients. Arthritis Rheum. 1999;42(suppl):S299.
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