1. Top of page
  2. Abstract
  9. Supporting Information


The purpose of this study was to explore whether nontraditional risk factors, such as apolipoprotein C-III (Apo C-III) and its corresponding Apo B lipoprotein (Lp) subclasses, contribute to the risk of cardiovascular disease in rheumatoid arthritis (RA) patients.


Apolipoprotein and lipoproteins were measured in 152 RA patients by immunoturbidimetric procedures, electroimmunoassay, and immunoprecipitation. Patients had a coronary artery calcium (CAC) score assessed at baseline and at year 3. Differences in the CAC scores between baseline and year 3 were calculated and dichotomized at 0, where patients with a difference score >0 were denoted as progressors and the rest were denoted as nonprogressors. Differences between means were tested with a 2-sided independent Student's t-test with Satterthwaite's adjustment. Proportion differences were tested with a chi-square test. Multiple logistic regression was performed to assess the relationship between apolipoprotein and lipoprotein levels and the dichotomized CAC score.


Progressors accounted for almost 60% of the cohort. Progressors had significantly higher levels of triglycerides, very low-density lipoprotein (VLDL) cholesterol, total cholesterol/high-density lipoprotein (HDL), triglycerides/HDL, Apo B, LpA-II:B:C:D:E, LpB:C, Apo B/Apo A-I, Apo C-III, and Apo C-III–heparin precipitate than the nonprogressors. After adjusting for age, sex, statin use (yes/no), and hypertension (yes/no), significant risk factors of progressors were total cholesterol, triglycerides, VLDL cholesterol, LDL cholesterol, Apo B, LpB:C, Apo C-III, and Apo B/Apo A-I.


Apo C-III–containing Apo B lipoprotein subclasses were found to be significantly elevated in progressors compared to nonprogressors. Many of these same lipoproteins were found to be associated with an increase in CAC scores among progressors. These lipoproteins may be considered new risk factors for progression of atherosclerosis in RA patients.


  1. Top of page
  2. Abstract
  9. Supporting Information

Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease characterized by progressive joint deformity and disability, affecting approximately 2.1 million adult Americans (1). Numerous recent studies have shown an increased risk for both subclinical atherosclerosis and for cardiovascular (CV) events in RA populations compared to control populations (2–4). Furthermore, it has been estimated that one-third to one-half of RA-related mortality is due to CV disease (3, 5). Traditional CV risk factors have not accounted for the increased prevalence or incidence of CV disease in RA patients (6). Growing evidence indicates that atherosclerosis is an inflammatory disorder, the pathogenic features of which overlap significantly with that of rheumatoid synovial inflammation (3, 7, 8). Therefore, it has been suggested that chronic inflammation is responsible for the increased risk of CV disease in patients with RA.

However, inflammatory pathways intersect significantly with metabolic pathways that convey CV risk. For example, in both clinical and preclinical studies, infusion of tumor necrosis factor α, a key inflammatory modulator in RA pathogenesis, induces both insulin resistance and a proatherogenic lipid profile (9). Disentangling the individual contributions of aberrant inflammatory versus aberrant metabolic pathways to CV risk can be difficult in clinical cohort studies, particularly since CV risk factors have been measured and defined relatively crudely in many studies (6, 9, 10). One example of this is in lipid biology, wherein most clinical studies of RA report serum levels of lipoproteins using the traditional classification by density gradient (e.g., high-density lipoprotein [HDL], low-density lipoprotein [LDL], and very low-density lipoprotein [VLDL]). However, this classification does not convey information on lipoprotein function, which is determined primarily by apolipoproteins, the protein components of plasma lipoproteins.

Apolipoprotein-defined lipoproteins consist of 2 major lipoprotein classes characterized by apolipoprotein A (Apo A-I + Apo A-II) and Apo B as their major protein components. Each of the major apolipoproteins can have several minor apolipoprotein peptides binding to it, such as a cluster of Apo C (Apo C-I, Apo C-II, and Apo C-III), Apo D, and Apo E. The Apo A–containing lipoprotein of high-density properties consists of 3 lipoprotein subclasses referred to as: lipoprotein A-I (LpA-I), LpA-II, and LpA-I:A-II. There are 5 major Apo B lipoprotein subclasses, including: LpB, LpB:E, LpB:C, LpB:E + LpB:C:E, and LpA-II:B:C:D:E. The Apo A-I and Apo B–containing lipoprotein subclasses differ not only in their apolipoprotein composition, but also in their metabolic and atherogenic properties (11, 12).

Studies from this and other laboratories have characterized the metabolic and atherogenic role of Apo C-III, a minor component of the Apo C cluster of polypeptides occurring in triglyceride-rich Apo B–containing lipoproteins. Apo C-III, in both the lipoprotein form (Apo C-III–rich VLDL) and Apo C-III alone, increases adhesion of human monocytes to vascular endothelial cells via up-regulation of vascular cell adhesion molecule 1 and intercellular cell adhesion molecule 1 (13, 14). Furthermore, Apo C-III induces insulin resistance in endothelial cells and reduces production of the potent vasodilator nitric oxide.

Regarding its atherogenic properties, Apo C-III inhibits lipoprotein lipase activity (15) and interferes with the binding of Apo B–containing lipoproteins to hepatic B/E receptors (16). In clinical studies, higher levels of Apo C-III alone or bound to Apo-B–containing lipoproteins were associated with insulin resistance and dyslipidemic profiles, including hypertriglyceridemia (17, 18). Moreover, Apo C-III levels have been linked in multiple studies to increased risk for progression of atherosclerosis and for CV events (19–23).

The recognition of Apo C-III as a link between atherogenicity and inflammation suggests that this minor apolipoprotein could play a role in the accelerated atherosclerosis observed in RA patients. The objective of this study, therefore, was to explore whether Apo C-III and its corresponding Apo-B–containing lipoprotein subclasses contribute to the prevalence or progression of atherosclerosis in a well-characterized RA population.

Significance & Innovations

  • This is the first time apolipoproteins have been measured in a prospective cohort of rheumatoid arthritis (RA) patients.

  • Apolipoprotein-defined lipoproteins proved to be independent risk factors for cardiovascular disease in RA patients.


  1. Top of page
  2. Abstract
  9. Supporting Information

RA patients.

Participants consisted of 195 patients with RA enrolled in the Evaluation of Subclinical Cardiovascular Disease and Predictors of Events in Rheumatoid Arthritis (ESCAPE RA) study, a cohort study of the prevalence, progression, and risk factors for subclinical CV disease in men and women with RA (24). Enrollment in ESCAPE RA required a diagnosis of RA for 6 months, fulfillment of the American College of Rheumatology 1987 criteria for the classification of RA, and age 45–84 years (25). Prevalent CV disease at baseline (defined as self-reported physician-diagnosed myocardial infarction, heart failure, coronary artery revascularization, angioplasty, peripheral arterial disease or procedures, pacemaker or defibrillator devices, and current atrial fibrillation) was excluded. Additional exclusions included weight exceeding 300 pounds (due to imaging equipment restrictions) and a computed tomography (CT) scan of the chest within 6 months prior to enrollment (to limit radiation exposure). Participants were recruited from among patients followed at the Johns Hopkins Arthritis Center and by referral from local rheumatologists. The study was approved by the Johns Hopkins Hospital Institutional Review Board. All participants provided written consent prior to enrollment occurring from October 2004 through May 2006. During the study, 5 participants had a nonfatal cardiac event.

Measurement of coronary artery calcium (CAC) events.

All 195 participants underwent cardiac multidetector row CT scanning at the baseline visit (visit 1) using methodology described previously (26). CAC was quantified using the Agatston method (27). The results of the analysis of the baseline CAC scores have been published previously (24). Of these 195 participants, 152 returned for a repeat cardiac CT scan at visit 3, approximately 30 months after the baseline visit. The current analysis consists of these 152 participants who had 2 CAC measurements.

Baseline covariate assessment.

Information on demographics, smoking, and family history was collected at the baseline visit (visit 1) by questionnaire. Resting blood pressure (BP) was measured 3 times in the seated position, and the average of the last 2 measurements was used in the analysis. Hypertension was defined by systolic BP 140 mm Hg, diastolic BP 90 mm Hg, or antihypertensive medication use. Diabetes mellitus was defined as a fasting serum glucose 126 mg/dl or use of antidiabetic medications. Physical activity was assessed using a modified 7-Day Physical Activity Recall questionnaire. Prescription and over-the-counter medications used in the preceding 2 weeks were documented from containers supplied by the participant.

RA-specific covariates.

At the baseline visit, 44 joints were examined by a single trained assessor for swelling, tenderness, deformity, and surgical replacement or fusion. RA disease duration was calculated based on self-report from time of physician diagnosis. RA activity was calculated using the Disease Activity Score for 28 joints (DAS28) with high-sensitivity C-reactive protein (CRP) (28). Functional limitation was assessed with the Stanford Health Assessment Questionnaire (29). Current and past use of glucocorticoids and biologic and nonbiologic disease-modifying antirheumatic drugs (DMARDs) were ascertained by interviews. Single-view, anteroposterior radiographs of the hands and feet were obtained and scored for radiographic damage of RA by using the modified Sharp/van der Heijde score (30) by a single trained radiologist blinded to patient characteristics. For 5 subjects with incomplete radiographic assessments, the missing score (hand or foot) was imputed from the available data based on a regression equation using data from the remaining subjects in the cohort.

Laboratory assessments.

Fasting sera and plasma were collected at the baseline visit, separated by centrifugation, and stored at −70°C. CRP level and interleukin-6 (IL-6) were measured as previously described (31). The RA autoantibodies, rheumatoid factor (RF) and anti–cyclic citrullinated peptide (anti-CCP) antibodies, were defined as positive at concentrations of 60 and ≥40 units, respectively.

Lipids, apolipoproteins, and lipoprotein subclasses.

Density-defined lipoprotein classes, including total cholesterol, triglycerides, and HDL cholesterol, were measured as previously described (32, 33). VLDL cholesterol and LDL cholesterol were calculated according to the Friedewald formula (34). Apo A-I, Apo B, and Apo C-III were quantified by the immunoturbidimetric procedure of Riepponen et al (35) using corresponding monospecific polyclonal antisera generated in this laboratory. Apo C-III bound to Apo A-I–containing lipoproteins (Apo C-III–heparin soluble [HS]) and to Apo B–containing lipoproteins (Apo C-III–heparin precipitate [HP]) were measured by electroimmunoassay in HS and HP fractions, respectively (11). The ratio of Apo C-III–HS/Apo C-III–HP is denoted as Apo C-III-Ratio, or just Apo C-III-R.

Apolipoprotein-defined lipoprotein subclasses were measured as follows: 1) LpA-I and LpA-I:A-II according to the procedure by März et al (36) and 2) LpB, LpB:C, LpB:E, LpB:C:E, and LpA-II:B:C:D:E by sequential immunoprecipitation as previously described. The antisera to Apo A-II, Apo E, and Apo C-III were prepared according to a previously described procedure (37). The concentrations of the LpB, LpB:C, LpB:E + LpB:C:E, and LpA-II:B:C:D:E subclasses were expressed in terms of their Apo B content (Table 1).

Table 1. Baseline levels of lipids, apolipoproteins, and apolipoprotein-containing subclasses in 152 patients with RA who had CAC progression or nonprogression*
 Progressors (ΔCAC >0)Nonprogressors (ΔCAC ≤0)
  • *

    Values are the mean ± SD. Two-sampled independent Satterthwaite's t-tests were performed on continuous data, and 2-sampled proportion tests were performed on categorical data. Chi-square test was performed on categorical data with more than 2 levels. RA = rheumatoid arthritis; CAC = coronary artery calcification; VLDL = very low-density lipoprotein; HDL = high-density lipoprotein; Apo = apolipoprotein; Lp = lipoprotein; HS = heparin soluble; HP = heparin precipitate.

  • P < 0.001.

  • P < 0.01.

  • §

    P < 0.05.

Total cholesterol200 ± 39.89191.159 ± 40.22
Log2 (triglycerides)6.98 ± 0.746.58 ± 0.63
Log2 (VLDL cholesterol)4.63 ± 0.694.25 ± 0.63
LDL cholesterol122.21 ± 33.27112.41 ± 33.82
HDL cholesterol51.54 ± 18.7555.88 ± 18.50
Apo B100.65 ± 15.8793.22 ± 15.33
LpA-II:B:C:D:E17.37 ± 7.9214.65 ± 6.43§
LpBE + LpB:C:E11.61 ± 4.7110.85 ± 4.08
LpB61.39 ± 7.2359.42 ± 8.00
LpB:C10.28 ± 4.098.31 ± 4.41
Apo A-I140.88 ± 22.73145.34 ± 20.27
LpA-I34.11 ± 4.4734.29 ± 4.29
LpA-I:A-II106.77 ± 19.27111.05 ± 17.35
Apo C-III10.38 ± 4.178.97 ± 2.99§
Apo C-III–HS7.23 ± 2.646.60 ± 2.11
Apo C-III–HP3.11 ± 1.602.57 ± 1.02§
Apo C-III–Ratio2.56 ± 0.872.70 ± 0.73
Apo B/Apo A-I0.73 ± 0.170.63 ± 0.13
Total cholesterol/HDL4.37 ± 1.803.70 ± 1.25
Triglycerides/HDL3.65 ± 4.762.29 ± 1.81§

Statistical analysis.

The numerical difference in CAC scores between visits 1 and 3 was calculated, thus creating a new variable, denoted as ΔCAC, which was dichotomized at 0. Individuals with ΔCAC >0 were denoted as “progressors,” while those with ΔCAC ≤0 were denoted as “nonprogressors.” Distributions of the continuous variables were examined and, if needed, log2 transformed in order to meet the normality assumption. Given the broad range of apolipoprotein variability, we standardized all their values with a Z transformation.

Means were compared between progressors and nonprogressors through a 2-sampled t-test with the Satterthwaite adjustment. Proportion differences between categorical groups were tested with a chi-square test. To assess the association between apolipoprotein and lipoprotein levels and the dichotomized dependent variable, ΔCAC, multiple logistical regression was performed to obtain both a crude odds ratio (OR) and an adjusted OR. The adjusted OR contained adjustments for sex, age, statin use, hypertension, smoking status, body mass index (BMI), DMARD use, biologic agent use, and steroid use. In all tests a nominal alpha level of 0.05 was considered statistically significant. Due to the hierarchical nature of the apolipoproteins, we chose not to adjust for multiple comparisons.


  1. Top of page
  2. Abstract
  9. Supporting Information

Demographic and RA characteristics in progressors and nonprogressors.

Progression of CAC (▵CAC >0) occurred in 89 (59%) of the 152 study participants between visits 1 and 3. The cutoff of 0 for CAC progression was arbitrary; however, sensitivity analysis revealed that changing the cutoff to 20 did not have an effect on any of the following results. Baseline demographic and RA characteristics, as well as conventional CV risk factors, in the progressors and nonprogressors are shown in Table 2. Progressors were older on average and more likely to be women. Hypertension, statin use, systolic BP, and homocysteine levels were higher in the progressors, as was the Framingham risk score. None of the measures of RA disease activity (DAS28, swollen joint count or tender joint count, CRP level, or IL-6 level) or of disease severity (RF, CCP, and Sharp/van der Heijde score) differed between the 2 groups. Likewise, use of disease-modifying treatments for RA (hydroxychloroquine, methotrexate, or biologic agents) did not differ significantly between the 2 groups. There were not enough diabetic patients to allow for adequate statistical adjustment in this cohort.

Table 2. Baseline characteristics of 152 patients with RA who had CAC progression or nonprogression*
 Progressors, ΔCAC >0 (n = 89)Nonprogressors, ΔCAC ≤0 (n = 63)
  • *

    Values are the mean ± SD unless otherwise indicated. Two-sampled independent Satterthwaite's t-tests were performed on continuous data. Two-sampled proportion tests were performed on categorical data. Chi-square test was performed on categorical data with more than 2 levels. RA = rheumatoid arthritis; CAC = coronary artery calcification; BMI = body mass index; DAS28 = Disease Activity Score in 28 joints; CRP = C-reactive protein; TJC = tender joint count; SJC = swollen joint count; HAQ = Health Assessment Questionnaire; IL-6 = interleukin-6; RF = rheumatoid factor; CCP = cyclic citrullinated peptide; BP = blood pressure.

  • P < 0.05.

  • P < 0.01.

  • §

    P < 0.001.

Female sex, no. (%)47 (53)47 (63)
Age, years61 ± 8.357.13 ± 8.2
BMI, kg/m227.81 ± 4.8827.96 ± 5.18
Prednisone, no. (%)31 (35)24 (38)
Plaquenil, no. (%)20 (22)18 (29)
Methotrexate, no. (%)52 (58)46 (73)
Biologic agents, no. (%)40 (45)27 (43)
Hypertension, no. (%)54 (61)24 (39)
Statin, no. (%)20 (22)5 (8)
DAS283.57 ± 1.053.68 ± 1.01
Log2(CRP + 1)1.99 ± 1.302.06 ± 1.35
Log2(TJC + 1), range 0–442.60 ± 1.482.79 ± 1.42
Log2(SJC + 1), range 0–422.68 ± 1.042.71 ± 1.09
Log2(HAQ + 1)0.66 ± 0.570.77 ± 0.52
Log2(IL-6 + 1)2.32 ± 1.012.14 ± 1.13
RF positive, no. (%)56 (63)33 (52)
CCP positive, no. (%)60 (68)40 (63)
Diabetes mellitus, no. (%)  
 Normal glucose (0)63 (71)54 (86)
 Impaired fasting glucose (1)17 (19)9 (14)
 Untreated diabetes mellitus (2)1 (1)0 (0)
 Treated diabetes mellitus (3)8 (9)0 (0)
Smoking, no. (%)  
 Never37 (42)30 (48)
 Former42 (47)28 (44)
 Current10 (11)5 (8)
Homocysteine9.96 ± 2.968.60 ± 2.21§
Systolic BP, mm Hg128.34 ± 16.91121.90 ± 17.49
Diastolic BP, mm Hg76.12 ± 9.1273.55 ± 8.68
Metabolic syndrome, no. (%)14 (16)4 (6)
Framingham risk score0.09 ± 0.070.05 ± 0.07

Levels of lipids, apolipoproteins, and lipoproteins in CAC progressors and nonprogressors.

Baseline plasma concentrations of lipids, apolipoproteins, and lipoproteins for the progressors and nonprogressors are shown in Table 1. Among the density-defined lipoprotein classes, levels of triglycerides and VLDL cholesterol, as well as the ratios of total cholesterol/HDL and triglycerides/HDL, were significantly higher in progressors than nonprogressors. Among the Apo B and Apo B–containing lipoprotein subclasses, progressors exhibited significantly higher levels of Apo B, LpA-II:B:C:D:E, LpB:C, and Apo B/Apo A-I than nonprogressors. There were no significant differences in levels of Apo A or Apo A–containing lipoprotein subclasses between progressors and nonprogressors. However, among Apo C-III and Apo C-III–containing lipoprotein subclasses, progressors exhibited significantly higher levels of Apo C-III and of Apo C-III bound to Apo B–containing lipoproteins (Apo C-III–HP) than nonprogressors.

Variables associated with progression of CAC.

The crude and adjusted ORs are presented in Table 3. The crude OR included: triglycerides, VLDL cholesterol, Apo B, LpA-II:B:C:D:E, LpB:C, Apo C-III, Apo C-III–HP, and triglycerides/HDL as being statistically significant. After adjusting the crude OR for age, sex, hypertension status, BMI, smoking, the use of statins, DMARDs, biologic agents, and steroids (Table 3), the following remained significantly associated with progression of CAC: triglycerides, VLDL cholesterol, Apo B, LpA-II:B:C:D:E, and LpB:C. Total cholesterol and LDL cholesterol became significantly associated after adjustment; however, triglycerides/HDL ratio and Apo C-III–HP lost significance from the adjustment. Supplementary Table 1 (available in the online version of this article at displays the upper triangle of the Spearman's covariance matrix across the lipids, apolipoproteins, and lipoproteins. Due to the hierarchical biochemical nature of these peptides, they exhibit strong covariance. For example, Apo A-I has a correlation of 0.78 with LpA-I and of 0.99 with LpA-I:A-II. This is due to the fact that both LpA-I and LpA-I:A-II are members of the Apo A class.

Table 3. Crude and adjusted ORs for progressors vs. nonprogressors per SD increase in lipids, apolipoproteins, and lipoproteins*
 OR (95% CI)Adjusted OR (95% CI)
  • *

    Adjusting for age, sex, statin, hypertension, smoking, disease-modifying antirheumatic drugs, steroids, biologic agents, and body mass index. OR = odds ratio; 95% CI = 95% confidence interval; VLDL = very low-density lipoprotein; HDL = high-density lipoprotein; Apo = apolipoprotein; Lp = lipoprotein; HS = heparin soluble; HP = heparin precipitate.

  • P < 0.05.

  • P < 0.001.

  • §

    P < 0.01.

Total cholesterol1.25 (0.90–1.77)1.62 (2.62–1.05)
Triglycerides2.17 (1.33–3.86)2.05 (3.99–1.17)
VLDL cholesterol1.83 (1.24–2.87)§1.71 (2.84–1.11)
LDL cholesterol1.36 (0.96–1.95)1.44 (2.08–1.02)
HDL cholesterol0.79 (0.56–1.10)0.85 (1.24–0.57)
Apo B1.69 (1.18–2.50)§1.91 (3.19–1.22)
LpA-II:B:C:D:E1.50 (1.06–2.21)1.6 (2.61–1.03)
LpB:E+LpB:C:E1.19 (0.86–1.66)1.19 (1.75–0.82)
LpB1.31 (0.94–1.87)1.45 (2.23–0.98)
LpB:C1.68 (1.17–2.48)§1.69 (2.71–1.11)
Apo A-I0.81 (0.58–1.13)0.82 (1.31–0.5)
LpA-I0.96 (0.69–1.33)1.06 (1.69–0.67)
LpAI:A-II0.79 (0.56–1.10)0.79 (1.25–0.49)
Apo C-III1.59 (1.07–2.53)1.29 (1.96–0.89)
Apo C-III–HS1.32 (0.93–1.95)1.14 (1.63–0.82)
Apo C-III–HP1.64 (1.09–2.68)1.29 (2–0.87)
Apo C-III–Ratio0.84 (0.60–1.18)0.93 (1.26–0.68)
Apo B/Apo A-I0.94 (1.30–0.68)1.02 (1.5–0.7)
Total cholesterol/HDL0.85 (1.14–0.63)0.94 (1.33–0.66)
Triglycerides/HDL0.95 (1.36–0.66)§1.01 (1.65–0.7)


  1. Top of page
  2. Abstract
  9. Supporting Information

The recent recognition of Apo C-III as a link between atherogenesis and inflammation has offered opportunity to explore whether this minor apolipoprotein plays a role in the accelerated atherosclerosis in RA patients. Since various classes of lipoproteins have different metabolic and atherogenic properties, based in large part on their apolipoprotein content, the corresponding subclasses of these lipoproteins were measured. To our knowledge, this is the first time subclasses of these lipoproteins were measured in patients with RA (11, 12). Using change in CAC over 3 years as a measure of progression of coronary atherosclerosis, we observed no statistically significant differences in baseline levels of Apo A-I, or of levels of LpA-I and LpA-I:A-II subclasses, between progressors and nonprogressors. Among Apo B–containing lipoprotein subclasses, there were also no baseline differences in the levels of cholesterol-rich LpB and LpB:E+LpB:C:E between progressors and nonprogressors. However, the levels of triglyceride-rich and Apo C-III–containing LpB:C and LpA-II:B:C:D:E subclasses were found to be significantly higher in progressors compared to nonprogressors. The levels of lipid and apolipoprotein constituents of these 2 subclasses, including triglycerides, VLDL cholesterol, Apo B, and Apo C-III–HP, were also significantly associated with CAC progression.

This recognition of Apo C-III–rich LpB:C and LpA-II:B:C:D:E subclasses as potential novel risk factors for progression of atherosclerosis in RA patients could be explained by the dual characteristics of Apo C-III as a major contributor to the atherogenicity of Apo B–containing lipoproteins on one hand and as an independent contributor to inflammatory processes on the other. We and others have shown in several clinical studies that Apo C-III–containing Apo B lipoproteins are independent risk factors for CV disease (19–23). The marked atherogenicity of LpB:C subclass reflects the metabolic properties of this lipoprotein subclass. Under normal metabolic conditions, the efficient lipolytic degradation of LpB:C particles results in low plasma concentrations of this lipoprotein. However, even a slight impairment in the formation and/or degradation of LpB:C, further exacerbated by the lack of binding activity to B/E receptors (16), results not only in increased plasma levels and residence time, but also in an enhanced uptake of these lipoprotein particles by macrophages (12, 38, 39). Due to a low affinity for lipoprotein lipase, LpA-II:B:C:D:E has a prolonged residence time in the circulation (40); although this subclass may be taken up by B/E receptors, its uptake by macrophages seems to be higher than that of LpB or LpB:E subclasses.

Kawakami and Yoshida have shown that Apo C-III itself rather than other apolipoproteins and lipids present in Apo C-III–rich VLDL caused the pro-adhesive effect (14, 41). Furthermore, lipids extracted from Apo C-III–containing VLDL did not increase monocytic adhesion. Since a number of previous studies have emphasized the role of lipid moieties as carriers of lipoprotein atherogenicity, Kawakami and Yoshida have clearly established that an apolipoprotein, such as Apo C-III, is a distinct contributor to inflammation and atherosclerosis.

If, indeed, LpB:C and LpA-II:B:C:D:E subclasses are to be considered as novel risk factors for progression of atherosclerosis in RA patients, their abnormal concentrations become targets for normalization. One may briefly speculate about the potential of available pharmacologic agents for affecting, if not normalizing, the levels of Apo C-III–containing LpB:C and LpA-II:B:C:D:E. At the present time, the main goal of therapeutic interventions has been to positively affect not only inflammatory mediators but especially lipid profiles as the most characteristic risk factors of CV disease in RA (9, 42, 43). Due to their well-established lipid-lowering effects and antiinflammatory properties, statins have been recommended and used almost exclusively in the therapeutic studies.

It should be emphasized that none of these studies dealt with the effects of statins on CV disease mortality of RA patients. In one of these studies, referred to as Trial of Atorvastatin in Rheumatoid Arthritis, 116 RA patients were randomized in a double-blind placebo-controlled study to atorvastatin (40 mg/day) or placebo as an adjunct to DMARD therapy (44). After 6 months of treatment, the levels of total cholesterol, triglycerides, and LDL cholesterol were significantly decreased, but there was no change in the levels of HDL cholesterol. More importantly, the DAS28 European League Against Rheumatism response was achieved in 18 (31%) of 58 patients on atorvastatin and 6 (10%) of 58 allocated to placebo. As concluded by the authors, atorvastatin can only mediate a modest outcome by clinically apparent antiinflammatory effects. In another study, based on 29 RA patients, atorvastatin (20 mg/day) significantly reduced arterial stiffness and the levels of total cholesterol and LDL cholesterol, but serum inflammatory markers remained unchanged (45). In a pilot study, treatment of 20 RA patients with atorvastatin (80 mg/day) for 12 weeks significantly reduced the levels of total cholesterol and LDL cholesterol, but had no significant effect on triglyceride levels (46). In a separate study of 20 RA patients, simvastatin (20 mg/day) and, separately, ezetimibe (10 mg/day) significantly reduced the levels of total cholesterol and LDL cholesterol, but not the triglycerides levels after 6 weeks of treatment. In addition, both simvastatin and ezetimibe reduced DAS28 scores, inflammatory markers, and aortic pulse valve velocity to a similar extent in RA patients (47). As stated by the authors, it still remains unanswered whether a reduction of arterial stiffness and improvement in endothelial dysfunction results in improved CV outcome in RA patients.

In the present study, only 25 or 16% of the total 152 RA patients were treated with statins; among this relatively small group of patients, 20 were progressors and only 5 were nonprogressors. There were no differences in the level of total cholesterol and total cholesterol–rich LpB subclass between progressors and nonprogressors receiving statins. However, the CAC progressors were characterized by higher levels of triglycerides, Apo B, Apo C-III–HP, LpB:C, LpB:E+LpB:C:E, and LpA-II:B:C:D:E than nonprogressors, indicating the prevalence of triglycerides and Apo C-III–containing Apo B lipoproteins as the major contributors to the acceleration of atherosclerosis in RA patients. While statins are very effective drugs in reducing the levels of total cholesterol–rich LpB and LpB:E subclasses, they seem to be less effective in lowering triglyceride-rich and Apo C-III–containing LpB:C, LpB:E+ LpB:C:E, and LpA-II:B:C:D:E subclasses (39, 48–50). In that respect, it has been shown in a recent study that fenofibrates displayed more antiinflammatory and antidyslipidemic activity than statins in RA patients (51).

The main weaknesses of this study are the relatively small number of progressors and nonprogressors, a short time interval (3 years) for following the number of progressors and nonprogressors, and a lack of a non-RA control group.

The strength of this study is that it has shown for the first time that Apo C-III–containing Apo B lipoproteins are risk factors for the progression of atherosclerosis in patients with RA. The next step would include confirmation of these results in another RA population, as well as a comparison to non-RA controls, and evaluation of the effects of a statin-fibrate combination on CV morbidity and mortality in RA patients.


  1. Top of page
  2. Abstract
  9. Supporting Information

All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be submitted for publication. Mr. Knowlton had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study conception and design. Knowlton, Centola, Giles, Bathon, Alaupovic.

Acquisition of data. Knowlton, Giles, Bathon, Alaupovic.

Analysis and interpretation of data. Knowlton, Wages, Giles, Bathon, Quiroga, Alaupovic.


  1. Top of page
  2. Abstract
  9. Supporting Information
  • 1
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  • 2
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