the impact of statin use on lipid levels in statin-naive patients with rheumatoid arthritis (ra) vs....

The Impact of Statin Use on Lipid Levels in Statin-Naive Patients with Rheumatoid

Arthritis (RA) vs. non-RA Subjects: Results from a Population-Based Study

Elena Myasoedova, MD, PhD 1,2, Sherine E. Gabriel, MD, MSc1, 2, Abigail B. Green,

BA1, Eric L. Matteson, MD, MPH 1,2, Cynthia S. Crowson, MS1,2

Authors’ affiliations:

1 Department of Health Sciences Research, Mayo Clinic College of Medicine,

Rochester, MN, United States;

2 Division of Rheumatology, Mayo Clinic College of Medicine, Rochester, MN, United

States

Corresponding Author:

Cynthia S. Crowson, MS

Mayo Clinic 200 First Street SW Rochester, MN 55905

Phone: 507-284-5594 Fax: 507-284-9542

E-mail: [email protected]

Funding Source: This work was funded by a grant from Pfizer. This work was

supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases of

the National Institutes of Health under Award Number R01AR46849, and by the

National Institute on Aging of the National Institutes of Health under Award Number

R01AG034676. Its contents are solely the responsibility of the authors and do not

necessarily represent the official views of the National Institutes of Health

Financial Disclosures: None

Abstract Word Count: 248 Words.

Manuscript Word Count: 3,499 words

Keywords: rheumatoid arthritis, lipids, statins

Original Article Arthritis Care & ResearchDOI 10.1002/acr.22029

This article has been accepted for publication and undergone full peer review but has not beenthrough the copyediting, typesetting, pagination and proofreading process which may lead todifferences between this version and the Version of Record. Please cite this article as an‘Accepted Article’, doi: 10.1002/acr.22029© 2013 American College of RheumatologyReceived: Oct 26, 2012; Revised: Feb 19, 2013; Accepted: Mar 27, 2013

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Abstract

Objectives: To examine lipid profiles among statin-naive patients with rheumatoid

arthritis (RA) and those without RA before and after the initiation of statins.

Methods: Information regarding lipid measures and statin use was gathered in a

population-based incident cohort of patients with RA (1987 ACR criteria first met

between 1/1/1988 and 1/1/2008) and in a cohort of non-RA subjects from the same

underlying population. Only patients with no prior history of statin use were included.

Results: The study included 161 patients with RA (mean age 56.3 years, 57% female)

and 221 non-RA subjects (mean age 56.0 years, 66% female). Prior to the start of

statins, the levels of total cholesterol (TC) and low-density lipoprotein cholesterol (LDL)

were lower in RA vs non-RA cohort (p<0.001 and p=0.003, respectively). The absolute

and percent change in LDL after at least 90 days of statin use tended to be smaller in

RA vs non-RA cohort (p=0.03 and p=0.09). After at least 90 days of statin use patients

with RA were less likely to achieve therapeutic goals for LDL than the non-RA subjects

(p=0.046). Increased erythrocyte sedimentation rate (ESR) at baseline (OR 0.47; 95%

CI 0.26, 0.85) was associated with lower likelihood of achieving therapeutic LDL goals.

Conclusion: Patients with RA had lower TC and LDL levels before statin initiation and

lower likelihood of achieving therapeutic LDL goals following statin use than the non-RA

subjects. Some RA disease characteristics, in particular ESR at baseline, may have an

adverse impact on achieving therapeutic LDL goals.

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John Wiley & Sons, Inc.

Arthritis Care & Research

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Significance and Innovations.

• This retrospective population-based cohort study reports lower total

cholesterol and low-density cholesterol (LDL) levels before statin initiation

and lower likelihood of achieving therapeutic LDL goals following statin

use in statin-naïve patients with rheumatoid arthritis (RA) vs non-RA

subjects

• Some RA disease characteristics, in particular higher disease activity as

reflected for example in an elevated erythrocyte sedimentation rate at

baseline, may adversely affect the success of lipid lowering with statins in

RA

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Increased risk of cardiovascular (CV) disease in patients with rheumatoid arthritis

(RA) is well recognized (1-3). Unlike the general population, where increased serum

cholesterol levels are associated with increased CV risk, the relationship between RA

disease and lipid profile appears to be more complex and even paradoxical. Our

previous studies suggest that lower total cholesterol (TC) and low-density cholesterol

(LDL) are associated with increased CV risk in RA, and this association may be

confounded by inflammation (4).

3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors are a class of

“statin” cholesterol-lowering medications with a spectrum of pleiotropic CV protective

effects including anti-inflammatory and immunomodulatory properties (5). In the general

population, statin use has been linked to substantial CV risk reduction which is

proportional to the degree of LDL lowering (6). Additional CV protective mechanisms of

statin use may be associated with reduction of inflammation as evidenced by the

findings from the Justification for the Use of Statins in Prevention: an Intervention Trial

Evaluating Rosuvastatin (JUPITER) (7).

Lipid lowering with statins appears to be associated with favorable effect on CV

disease in patients with RA as well (8-10). However, mechanisms underlying the effects

of statins in RA are poorly understood and the impact of RA characteristics on lipid-

lowering effect of statins has not been defined. The aim of this study was to examine

lipid profiles before and after the initiation of statins in a population-based inception

cohort of patients with RA and subjects without RA from the same underlying

population, and to determine RA disease related predictors for meeting therapeutic LDL

goals in patients with RA.

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Materials and Methods

Study setting and design

This population-based longitudinal study was performed using the resources of

the Rochester Epidemiology Project (REP) a centralized community-wide medical

record linkage system. The unique features of the REP and its capabilities for the

population-based research in rheumatic diseases have been described in details

elsewhere (11, 12).

The study included a population-based incidence cohort of patients with RA who

were Olmsted County, Minnesota residents >18 years of age and first fulfilled the 1987

American College of Rheumatology (ACR) criteria for RA (13) between 1/1/1988 and

1/1/2008. The date when the patient fulfilled >4 ACR criteria for RA was considered the

RA incidence date. For each subject with RA, a comparison subject without RA was

randomly selected from Olmsted County residents of the same age and sex in the same

calendar year that each patient developed RA. Each non-RA subject was assigned an

index date corresponding to the RA incidence date of the designated RA patient. Only

patients with no prior history of statin use who started a statin for dyslipidemia between

1 year prior to RA incidence/index date and last follow-up were included.

Information on the following CV risk factors was collected at baseline as

previously described (14): family history of premature coronary heart disease (CHD),

smoking (current/former); body mass index (BMI; kg/m2), hypertension/antihypertensive

treatment and diabetes mellitus. Data on personal history of CHD (i.e. angina pectoris;

coronary artery disease; myocardial infarction [MI], including silent events; and coronary

revascularization procedures [i.e. coronary artery bypass graft, percutaneous

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angioplasty, insertion of stents and atherectomy]) were also gathered from the medical

records.

The results of all clinically performed fasting serum lipid measures including TC,

LDL, high-density lipoproteins (HDL) and triglycerides (TG) were abstracted. Abnormal

lipid levels for both cohorts were defined according to the National Cholesterol

Education Program (NCEP) Adult Treatment Panel III (ATPIII) guidelines (15) as

TC>240 mg/dL, LDL>160 mg/dL, TG>200 mg/dL or HDL<40 mg/dL. Desirable lipid

levels were defined as follows: TC<200 mg/dL, TG<150 mg/dL, HDL>50 mg/dL for

women and >40 mg/dL for men, TC/HDL ratio <4. Therapeutic goals for LDL were

defined according to patient’s CV risk factor profile as recommended in the

NCEP/ATPIII guidelines (15). In patients with 0-1 risk factor the LDL goal was <160

mg/dL, in patients with > 2 risk factors the goal was <130 mg/dL, and in patients with

major comorbidities (i.e. CHD/diabetes mellitus) the goal was <100 mg/dL. Risk factors

for defining LDL goals included: age (>45 years in men, >55 years in women), family

history of premature CHD, current cigarette smoking, hypertension/antihypertensive

treatment, low HDL (<40 mg/dL) measured on >3 different occasions. High HDL (>60

mg/dL) at baseline was considered a protective CV risk factor and allowed subtraction

of one other risk factor from the total count. Information on statin use including start and

stop dates for each statin was gathered in both cohorts.

For patients with RA, information on RA characteristics (i.e. RA duration;

rheumatoid factor [RF] positivity; erythrocyte sedimentation rates [ESR] and C-reactive

protein [CRP] at the time of statin initiation (baseline); joint erosions/destructive changes

on radiographs, large joint swelling, the presence of rheumatoid nodules and severe

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extra-articular manifestations of RA was collected (16). The data regarding the use of

antirheumatic medications, i.e. methotrexate, hydroxychloroquine, other disease-

modifying antirheumatic drugs (DMARDs, including sulfasalazine, leflunomide,

azathioprine), biologic response modifiers (BRM), glucocorticosteroids and non-

steroidal antirheumatic drugs (NSAIDs), including coxibs, were also gathered. Data on

the use of acetylsalicylic acid (ASA) for arthritis (the use of >6 tablets/day of ASA

[>1950 mg/day] for >3 months) were recorded. The study protocol was approved by the

Institutional Review Boards from Mayo Clinic and Olmsted Medical Center.

Statistical Methods

The absolute and percent changes in lipid levels were calculated as the change

from baseline to >90 days of follow-up. The most recent lipid measure before the day of

statin initiation and the closest lipid measure to 90 days of follow-up were used for the

analyses. T-tests and linear regression models were used to compare changes in lipid

profiles between the RA and non-RA cohorts. Logistic regression models were used to

examine factors associated with meeting LDL goals in RA, adjusting for age, sex and

duration of RA at statin initiation; each risk factor was examined individually.

Results

A total of 161 patients with RA and 221 non-RA subjects without a history of

statin use earlier than 1 year prior to RA diagnosis/index date were included. Table 1

shows baseline characteristics for both cohorts. Patients with RA had less favorable CV

profile than non-RA subjects (p=0.02, Table 1).

The mean (standard deviation, SD) time from index date to the start of statins

was similar in RA vs non-RA cohort: 8.0 (6.6) years vs 8.8 (6.7) years, respectively

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(p=0.17). The mean time from the baseline lipid test to the start of statins was also

similar in both cohorts (p=0.56). The median (range) follow-up after the initiation of

statin treatment was 7.0 (0.1-20.2) years in patients with RA vs 8 (0.0-24.1) years in the

non-RA subjects.

Table 2 shows lipid levels at baseline and their change during the follow-up in

both cohorts. Prior to the start of statins, the levels of TC and LDL in RA were

significantly lower than in the non-RA cohort (p<0.001 and p=0.003, respectively); HDL

level was marginally lower in RA vs non-RA (p=0.05). Following >90 days of statin use,

the level of TC remained lower in RA vs non-RA subjects (p=0.006). The decrease in

absolute LDL values after >90 days of statin use was less pronounced in the RA vs non-

RA cohort (p=0.03); a similar trend was observed for percentage change in LDL, but this

did not reach statistical significance (p=0.09).

After adjusting for age, sex, smoking, diabetes mellitus, hypertension, and CHD,

the absolute change in TC and LDL from baseline to follow-up was significantly smaller

in RA vs non-RA cohort (p=0.003 and p=0.002, respectively). After adjusting for age,

sex, smoking, diabetes mellitus, hypertension, and CHD the percentage change in TC,

but not in other lipids, was significantly smaller (by 18%) in RA vs non-RA cohort

(p=0.007). There were no statistically significant differences in baseline and/or follow-up

levels of HDL and TG as well as TC/HDL ratio in RA vs non-RA cohort.

Table 3 shows proportions of subjects who had desirable lipid levels at baseline

and during the follow-up. TC <200 mg/dL at baseline was more common in RA vs non-

RA cohort (p<0.001). The likelihood of achieving desirable levels of TC, TG, HDL, and

TC/HDL during the follow-up was similar in RA and non-RA cohorts. However, patients

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with RA, in particular those with altered LDL levels at baseline, were less likely to reach

therapeutic LDL goals during the follow-up than the non-RA subjects (Table 3).

A subgroup analysis of patients with RA (n=100) and non-RA subjects (n=170)

without CHD revealed that baseline cholesterol levels were lower in RA (TC: 231.2±53.1

mg/dL and LDL: 146.9±51.4 mg/dL) vs non-RA subjects (TC: 249.6±39.4 mg/dL,

p=0.004 and LDL: 160.8±38.2 mg/dL, p=0.02). A similar trend was noted for TC and

LDL at 90 days of follow-up: TC levels were 189.4±47.7 mg/dL in RA vs 202.6±41.1

mg/dL in the non-RA subjects (p=0.004); LDL levels were 107.1±44.7 mg/dL in RA and

113.6±36.9 mg/dL in the non-RA cohort (p=0.08). There were no statistically significant

differences in absolute and percent change in TC and LDL in RA vs non-RA subjects

without CHD (all p>0.05).

Among subjects without CHD, patients with RA were more likely to have

desirable TC levels at baseline: TC<200 mg/dL was found in 29 (30%) patients with RA

vs 13 (8%) non-RA subjects (p<0.001), and during the follow-up: TC<200 mg/dL was

found in 64 (66%) patients with RA vs 82 (52%) non-RA subjects (p=0.03). There were

no statistically significant differences in the likelihood of achieving therapeutic LDL goals

at 90 days in RA vs non-RA patients without CHD: 32 (34%) vs 63 (40%), respectively

(p=0.29).

We examined the impact of each of the RA disease characteristics individually on

achieving LDL goals in RA, adjusting for age, sex and RA duration at statin initiation

(Table 4). Increased ESR at baseline was associated with significantly lower likelihood

of achieving LDL goals (odds ratio [OR] per 10 mm/hr increase in ESR: 0.47, 95%

confidence interval [CI]: 0.26, 0.85). There was a trend towards lower likelihood of

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achieving LDL goals in patients with longer RA duration and in those using other

DMARDs, but this did not reach statistical significance (p=0.12 and p=0.09,

respectively). There was no statistically significant association between the calendar

year of statin initiation and the likelihood of achieving LDL goals (p=0.39, Table 4).

Of traditional CV risk factors, older age (OR 0.43, 95%CI 0.29, 0.65), male sex

(OR 0.39, 95%CI 0.16, 0.97) and BMI>30 kg/m2 (OR 0.27, 95%CI 0.10, 0.71) but not

other CV risk factors, were significantly associated with a lower likelihood of meeting

LDL goals. LDL level at baseline was not associated with the likelihood of achieving

LDL goals (OR 1.03, 95%CI 0.95, 1.11, p=0.51).

When statin use was compared in the RA vs non-RA cohort, the rates of

prescription of each statin (i.e. atorvastatin, cerivastatin, fluvastatin, lovastatin,

pravastatin, rosuvastatin, and simvastatin with or without ezetimibe) and the frequency

of changes in statin use were similar in RA vs non-RA cohort (data not shown). There

were no apparent changes in the use of DMARDs, BRM and glucocorticosteroids in

patients with RA from time before the start of statin therapy to >90 days of follow-up: at

baseline 44 (27%) patients used methotrexate, 22 (14%) used hydroxychloroquine, 13

(8%) used other DMARDs, 10 (6%) received BRM, and 55 (34%) used

glucocorticosteroids; after >90 days of statin use the numbers were: 45 (28%), 25

(16%), 12 (7%), 10 (6%) and 58 (36%), respectively.

Discussion

This retrospective population-based study found that patients with RA have lower

TC and LDL levels before statin initiation than the non-RA subjects. Absolute and

relative decreases in TC and LDL values following statin initiation tended to be smaller

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in RA vs non-RA subjects. Consequently, patients with RA had lower likelihood of

achieving therapeutic LDL goals following statin use than the non-RA subjects.

The impact of statin treatment on lipid profile in RA and other inflammatory joint

diseases has been reported in a series of studies using post-hoc analysis data from two

large clinical trials: Incremental Decrease in Endpoints through Aggressive Lipid

lowering (IDEAL) and Treating to New Targets (TNT) (9, 17). Similar to our study,

baseline levels of TC and LDL in the IDEAL study were lower in RA vs non-RA subjects.

Except for the higher increase in HDL and ApoA1 levels in atorvastatin users, there

were no statistically significant differences in changes of absolute lipid levels in RA vs

non-RA subjects followed for 4.8 years in that study. This was different from our study

where decreases in TC and LDL during >90 days of statin treatment tended to be

smaller in RA vs non-RA subjects. Longer follow-up and lower proportion of patients

with CHD in our study may at least in part account for these differences. Alternatively,

these seemingly discrepant findings could be explained by differences in the lipid-

lowering effect of intensive vs conventional regimen of statin treatment.

Concordant with the findings from Reversal of Atherosclerosis with Aggressive

Lipid Lowering (REVERSAL) Trial (18), the post-hoc analyses data from the TNT and

IDEAL trials showed that intensive lipid lowering with atorvastatin 80 mg induced the

highest reduction of TC and LDL in patients with and without inflammatory joint

diseases compared to conventional lipid-lowering regimens(17). While complete

information regarding statin doses was not available in our study, it is unlikely that a

substantial proportion of patients in our observational study received the intensive lipid-

lowering treatment used in clinical trials, and thus smaller lipid-lowering effect of statins

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could be expected. Nevertheless, the degree of TC lowering following statin use in our

study (-14% in the entire RA cohort and -16% in RA patients without CHD) was similar

to that reported in a retrospective population-based study of RA subjects from Scotland

where a 15% decrease in TC level was reported for patients with CHD and a 16%

decrease was found in patients without CHD (10).

Despite the smaller decrease in TC levels, patients with RA and non-RA subjects

in our study had a similar likelihood of achieving desirable TC levels, which is a

secondary target for lipid lowering therapy. In contrast to what we observed regarding

TC reduction, the rate of decrease of LDL in patients with RA was not sufficient to

achieve the primary target for statin intervention, i.e. therapeutic LDL goals, with similar

likelihood as in non-RA subjects. Indeed, the majority (79%) of patients with RA did not

meet LDL goals after >90 days of follow-up.

This lack of success in achieving the LDL targets after statin treatment has been

reported in the general population, particularly in patients with high CV risk(19, 20).

Extending these observations, our study shows that the risk of not achieving LDL goals

may be even higher in RA vs non-RA subjects, highlighting the gap in success of lipid-

lowering treatment in RA vs general population. It could be suggested that intensive

lipid-lowering treatment in RA may be beneficial in some patients with RA, especially in

those who failed to achieve LDL goals with conventional lipid-lowering regimen.

Concordant with this suggestion, a treatment-to-target strategy for statin use, where

lipid-lowering treatment was adjusted until lipid goals were achieved, was found to be

successful in 92% of patients with RA referred to preventive cardio-rheumatology clinic

(21).

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The lack of success in meeting LDL goals in our study was not apparent in

patients without CHD where both patients with RA and non-RA subjects had a similar

chance of achieving the LDL goals. This finding suggests important benefits of statin

treatment in primary prevention in RA and may at least in part explain significant

reduction of CV disease and mortality following statin use in RA in primary, but not

secondary prevention (10).

Some studies from the general population suggest that the degree of lipid

lowering may be less pronounced in patients with decreased baseline lipid levels.

Indeed, clinical trial data from statin-naïve patients with recent coronary syndrome

suggest that the degree of LDL-lowering during the 4 months of statin use decrease

significantly from highest to lowest baseline LDL quartile(22). In our study LDL level at

baseline was not a predictor of meeting LDL goals, suggesting that factors associated

with success of lipid-lowering in RA may be different from the general population.

To better understand the mechanisms underlying lipid lowering in statin users

with RA we investigated the impact of RA characteristics on achieving therapeutic LDL

goals. Increased ESR level at baseline was associated with decreased likelihood of

meeting the LDL goals after >90 days of statin use in our study. Statin treatment has

been previously associated with decrease in RA disease activity in the Trial of

Atorvastatin in Rheumatoid Arthritis (TARA) (8). The results of our study to some extent

explicate these findings and suggest that there may be also an association between

inflammation and degree of lipid lowering where inflammation may adversely affect the

success of statin treatment in patients with RA. These findings support the need for

more stringent control of inflammation and scrupulous lipid monitoring in RA, and raise

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the possibility that tailoring of the statin treatment regimen to the degree of inflammatory

activity may be advantageous in patients with RA.

While the underlying mechanisms for the association of ESR with achieving LDL

goals are unclear, impaired cholesterol transport in patients with increased ESR may be

a contributory factor. This hypothesis is in line with the observations of increased

cholesterol ester transfer protein activity in patients with active RA vs controls (23), as

well as with the recent reports on associations between measures of RA disease

activity, including ESR, and impaired cholesterol efflux(24). Certainly some

antirheumatic treatments may also affect the degree of lipid lowering in statin users as

suggested by somewhat lower likelihood of achieving the LDL goals in patients with RA

patients who used DMARDs other than methotrexate and hydroxychloroquine. A better

understanding of the association between inflammation and lipid lowering in RA and the

clinical implications of these findings awaits further investigation.

Our study has several potential limitations. Full information on statin dosages

used in the study populations, as well as information on the type of health care provider

(i.e. rheumatologist/internist), and information regarding patients’ compliance with statin

treatment was not available in this retrospective study. Therefore we were not able to

compare in detail statin treatment regimens in RA and non-RA subjects. However, there

was no statistically significant difference in the rates of prescription of each statin and

the frequency of changes in statin use in RA vs non-RA cohorts, which we believe

minimizes this limitation. Since the study aimed to explore lipid lowering with statins,

other approaches for lipid lowering including lifestyle modifications were not assessed.

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Optimal lipid values were defined according to the NCEP/ATP III guidelines

which do not account for CV risk associated with RA. Some authors have previously

attempted to include RA as an additional risk factor while defining therapeutic LDL goals

with NCEP/ATP III guidelines which resulted in the more stringent treatment goals(25).

However, we chose to use standard NCEP/ATP III guidelines to allow fair comparison of

the cohorts based on the traditional CV risk factor profile.

Unfavorable changes in composition and impaired functional properties of lipids,

in particular HDL, in patients with RA are the subject of active research (24, 26).

Decrease in the atheroprotective effect of HDL has been suggested in patients with RA.

Therefore, when defining LDL goals it is possible that the impact of HDL>60 mg/dL as a

protective CV factor is different in RA vs non-RA subjects. However, the predictive value

of changes in HDL properties on CV risk in RA is not fully understood, and specific

guidelines on defining LDL goals in RA are lacking. Thus, a similar definition of

therapeutic LDL goals based on the NCEP/ATP III guidelines was applied to both

patients with RA and non-RA subjects.

Statistical power may be limited in some analyses of associations between RA

characteristics and LDL goals suggesting that these analyses should be interpreted with

caution. Finally, during the period of investigation the population of Olmsted County,

Minnesota was predominantly white. Thus, the results may not be generalizable to non-

white individuals.

To our knowledge, this is the first population-based study to report the impact of

RA characteristics on lipid-lowering effect of statins. Other important strengths of this

study include its longitudinal population-based design, inclusion of two large NIH-funded

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cohorts of patients with RA and non-RA subjects from the same underlying population,

and the use of extensive data on RA characteristics and lipid measures available

through the REP.

In conclusion, before statin initiation, patients with RA had significantly lower TC

and LDL levels than non-RA subjects. Absolute and relative decreases in LDL values

following statin initiation were smaller in RA than in non-RA subjects. Patients with RA

were less likely to achieve therapeutic goals for LDL compared to the non-RA subjects.

Some RA disease characteristics, in particular higher disease activity as reflected in

elevated erythrocyte sedimentation rate at baseline, may adversely affect the success

of lipid lowering with statins in RA. More studies are needed to assess the mechanisms

underlying the association of inflammation and lipid lowering in RA, and to determine

the impact of improvement in lipid profile with statin use on CV risk reduction in RA.

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22. Giraldez RR, Giugliano RP, Mohanavelu S, Murphy SA, McCabe CH, Cannon CP, et al.

Baseline low-density lipoprotein cholesterol is an important predictor of the benefit of intensive

lipid-lowering therapy: a PROVE IT-TIMI 22 (Pravastatin or Atorvastatin Evaluation and

Infection Therapy-Thrombolysis In Myocardial Infarction 22) analysis. J Am Coll Cardiol.

2008;52:914-20.

23. Georgiadis AN, Papavasiliou EC, Lourida ES, Alamanos Y, Kostara C, Tselepis AD, et

al. Atherogenic lipid profile is a feature characteristic of patients with early rheumatoid arthritis:

effect of early treatment--a prospective, controlled study. Arthritis Res Ther. 2006;8:R82.

24. Charles-Schoeman C, Lee YY, Grijalva V, Amjadi S, FitzGerald J, Ranganath VK, et al.

Cholesterol efflux by high density lipoproteins is impaired in patients with active rheumatoid

arthritis. Ann Rheum Dis. 2012;71:1157-62.

25. Soubrier M, Zerkak D, Dougados M. Indications for lowering LDL cholesterol in

rheumatoid arthritis: an unrecognized problem. J Rheumatol. 2006;33:1766-9.

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lipoprotein cholesterol subfractions HDL2 and HDL3 are reduced in women with rheumatoid

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Arthritis Res Ther. 2012;14:R116.

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19

Table 1: Baseline characteristics of statin-naïve patients with RA and those without RA

who started a statin between 1 year prior to RA incidence/ index date and last follow-up

Characteristic# RA (N=161) Non-RA (N=221) p valueX

Age (years), mean ± SD 56.3 ± 13.2 56.0 ± 12.1 0.86

Female 91 (57%) 146 (66%) 0.058

Smoking

Never

Former

Current

57 (35%)

61 (38%)

43 (27%)

119 (54%)

62 (28%)

40 (18%)

0.002

Family history of CHD 41 (25%) 67 (30%) 0.30

BMI > 30 kg/m2, ever 74 (46%) 108 (49%) 0.57

Diabetes Mellitus 43 (27%) 56 (25%) 0.76

Hypertension 149 (93%) 173 (78%) <0.001

Dyslipidemia*

HDL < 40 mg/dL

HDL > 60 mg/dL

159 (99%)

47 (31%)

41 (27%)

221 (100%)

38 (19%)

61 (30%)

0.10

0.007

0.56

CHD 61 (38%) 51 (23%) 0.002

Categories of patients according to the number of CV risk factors and comorbidities**

0.02

History of CHD or diabetes mellitus

> 2 risk factors

0-1 risk factors

90 (56%)

32 (20%)

39 (24%)

94 (43%)

48 (22%)

79 (36%)

#All values are given as n (%) unless indicated otherwise; X statistically significant differences (p<0.05) are shown in bold. * Dyslipidemia defined as TC >240 mg/dL, LDL >160 mg/dL, TG >200 mg/dL or HDL <40 mg/dL; ** Risk factors included: age (> 45 years in men, > 55 years in women), family history of premature CHD, current cigarette smoking, hypertension or antihypertensive treatment, low HDL cholesterol (< 40 mg/dL) measured on > 3 different occasions. High HDL cholesterol (> 60 mg/dL) at baseline was considered a protective CV risk factor and allowed subtraction of one other risk factor from the total count. Comorbidities included CHD and/or diabetes mellitus. Abbreviations: RA = rheumatoid arthritis; SD = standard deviation; BMI = body mass index; CHD = coronary heart disease; TC = total cholesterol; LDL = low density lipoprotein cholesterol; HDL = high density lipoprotein cholesterol, TG = triglycerides

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Table 2. Lipid levels at baseline and their change during the follow-up in patients with rheumatoid arthritis (RA) and non-RA subjects

Variable# n RA n Non-RA p-value

X

Baseline

TC, mg/dL 153 224.2 ± 54.0 208 241.1 ± 45.5 <0.001

LDL, mg/dL 151 139.9 ± 52.5 204 154.1 ± 40.3 0.003

HDL, mg/dL 153 50.3 ± 16.1 206 53.0 ± 15.2 0.05

TG, mg/dL 154 179.1 ± 131.1 207 173.2 ± 99.6 0.7

TC/HDL 153 4.8 ± 1.6 206 4.9 ± 1.6 0.53

Follow-up

TC, mg/dL 153 186.8 ± 48.5 207 197.5 ± 44.4 0.006

LDL, mg/dL 149 104.7 ± 43.7 203 109.1 ± 36.7 0.14

HDL, mg/dL 152 51.4 ± 16.2 205 53.1 ± 15.1 0.18

TG, mg/dL 153 155.4 ± 91.7 204 171.5 ± 119.1 0.27

TC/HDL 152 3.9 ± 1.4 205 4.0 ± 1.7 0.92

Absolute change

TC, mg/dL 152 -37.1 ± 46.4 207 -43.2 ± 41.6 0.15

LDL, mg/dL 148 -34.8 ± 42.7 201 -44.5 ± 38.3 0.03

HDL, mg/dL 151 1.2 ± 10.1 203 0.6 ± 7.6 0.41

TG, mg/dL 153 -24.1 ± 105.3 203 -2.2 ± 83.9 0.2

% change

TC 152 -14.3 ± 21.1 207 -16.8 ± 16.9 0.37

LDL 148 -16.7 ± 48.6 201 -26.8 ± 23.6 0.09

HDL 151 4.3 ± 20.7 203 2.0 ± 14.2 0.29

TG* 153 -9.8 (-72.2, -192.2) 203 -5.4 (-60.1, -347.1) 0.31

#All values are given as mean ± standard deviation, unless specified otherwise; * median (range) is reported for TG due to the extremely skewed distribution of values; X statistically significant differences (p<0.05) are shown in bold. Abbreviations: RA = rheumatoid arthritis; TC = total cholesterol; LDL = low density lipoprotein cholesterol; HDL = high density lipoprotein cholesterol, TG = triglycerides

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Table 3. Number (%) of subjects with desirable lipid levels in RA vs non-RA cohort

Variable n RA n Non-RA p-value X

At baseline

TC < 200 mg/dL 153 54 (35%) 208 28 (13%) <0.001

Therapeutic goals for LDL# 154 16 (11%) 208 25 (12%) 0.63

HDL* 153 88 (58%) 206 134 (65%) 0.15

TG <150 mg/dL 154 83 (54%) 207 103 (50%) 0.44

TC/HDL < 4.0 153 59 (29%) 206 54 (35%) 0.18

At follow-up

TC <200 mg/dL 153 103 (67%) 207 119 (57%) 0.06


HDL* 152 96 (63%) 205 136 (66%) 0.53

TG <150 mg/dL 153 87 (57%) 204 109 (53%) 0.52

TC/HDL < 4.0 152 121 (59%) 205 87 (57%) 0.73

At follow-up, among those with poor lipid levels at baseline**

TC <200 mg/dL 98 54 (55%) 179 95 (53%) 0.78


HDL* 64 18 (28%) 71 20 (28%) 0.99

TG <150 mg/dL 72 23 (32%) 104 29 (28%) 0.52

TC/HDL < 4.0 145 64 (44%) 100 37 (37%) 0.34 #Therapeutic goals for LDL were defined according to the NCEP/ATPIII guidelines based on the number of CV risk factors other than LDL. In patients with 0-1 risk factor the LDL goal was <160 mg/dL, in patients with multiple (> 2) risk factors <130 mg/dL, and in patients with major comorbidities (i.e. CHD or diabetes mellitus) <100 mg/dL; X statistically significant differences (p<0.05) are shown in bold; * HDL >50 mg/dL for women and >40 mg/dL for men; ** defined for each category of lipids separately, e.g. n (%) of patients who met LDL goals at follow-up among those who did not meet LDL goals at baseline; Abbreviations: RA = rheumatoid arthritis; TC = total cholesterol; LDL = low density lipoprotein cholesterol; HDL = high density lipoprotein cholesterol

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Table 4. Association between individual rheumatoid arthritis disease characteristics and meeting therapeutic LDL goals by 90 days of statin use among patients with rheumatoid arthritis (n=161)

Rheumatoid arthritis characteristics Value#

Odds ratio [OR]** (95%

confidence interval [CI])

adjusted for age, sex

and duration of RA at

statin initiation

p value X

Duration of RA (years), mean ± SD 7.8 ± 6.8 0.95 (0.88, 1.02) 0.12

Calendar year of statin initiation

(years), mean ± SD 2002 ± 4.4 1.05 (0.94, 1.17) 0.39

ESR at baseline (mm/hr), mean ±

SD 18.3 ± 18.6 0.47* (0.26, 0.85) 0.012

CRP at baseline^ (mg/L), mean ±

SD 6.4 ± 24.5 0.02 (0.0, 55.04) 0.34

Rheumatoid factor positive 106 (66%) 0.64 (0.26) 0.33

Joint erosions/destructive changes 71 (44%) 0.58 (0.24, 1.41) 0.23

Large joint swelling 112 (70%) 1.33 (0.46, 3.87) 0.60

Severe extra-articular

manifestations of RA^

15 (9%)

--

0.97

Rheumatoid nodules 42 (26%) 1.21 (0.47, 3.07) 0.69

Antirheumatic treatments^^:

Methotrexate

Hydroxychloroquine

Other DMARDs

Biological agents

Glucocorticosteroids

Coxibs

ASA***

NSAIDs

Cumulative dose of gluco-

corticosteroids (g), mean ± SD

74 (46%)

78 (48%)

52 (32%)

18 (11%)

90 (56%)

71 (44%)

70 (44%)

137 (85%)

8,224.0 ± 9,813.8

0.85 (0.36, 2.01)

0.71 (0.29, 1.73)

0.42 (0.15, 1.16)

0.98 (0.29, 3.32)

0.76 (0.31, 1.82)

1.10 (0.45, 2.67)

0.97 (0.35, 2.68)

1.79 (0.40, 7.91)

0.99 (0.92, 1.06)**

0.71

0.45

0.09

0.97

0.53

0.84

0.95

0.44

0.75

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#All values are given as n (%) unless indicated otherwise; X statistically significant association (p<0.05) is shown in bold; * Odds ratio per 10 mm/hr increase; ** Odds ratio per 1,000 g increase; *** use of acetylsalicylic acid (ASA) for arthritis, i.e. the use of > 6 tablets of ASA per day (> 1950 mg/day) for >3 months; ^ - none of patients with RA who had severe extra-articular manifestations achieved the LDL goals, thus OR was not estimated for this variable; ^^ - medication use at any time prior to initiation of statin therapy. Abbreviations: RA = rheumatoid arthritis; SD = standard deviation; ESR = erythrocyte sedimentation rate; CRP = C-reactive protein; DMARDs = disease modifying antirheumatic drugs; ASA = acetylsalicylic acid; NSAIDs = non-steroidal anti-inflammatory drugs

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the impact of statin use on lipid levels in statin-naive patients with rheumatoid arthritis (ra) vs....

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