Dr. Solomon has research contracts (more than $10,000 each) with Amgen and Lilly, and has performed unpaid roles on trials for Lilly, BMS, Pfizer, and Novartis.
Lipid and Lipoprotein Levels and Trend in Rheumatoid Arthritis Compared to the General Population
Article first published online: 27 NOV 2013
Copyright © 2013 by the American College of Rheumatology
Arthritis Care & Research
Volume 65, Issue 12, pages 2046–2050, December 2013
How to Cite
Liao, K. P., Cai, T., Gainer, V. S., Cagan, A., Murphy, S. N., Liu, C., Churchill, S., Shaw, S. Y., Kohane, I., Solomon, D. H., Plenge, R. M. and Karlson, E. W. (2013), Lipid and Lipoprotein Levels and Trend in Rheumatoid Arthritis Compared to the General Population. Arthritis Care Res, 65: 2046–2050. doi: 10.1002/acr.22091
- Issue published online: 27 NOV 2013
- Article first published online: 27 NOV 2013
- Accepted manuscript online: 7 AUG 2013 12:43PM EST
- Manuscript Accepted: 15 JUL 2013
- Manuscript Received: 11 FEB 2013
- Informatics for Integrating Biology and the Bedside (i2b2) project/NIH. Grant Number: U54-LM-008748
- NIH. Grant Numbers: K08-AR-060257, K24-AR-055989, R01-AR-057108, R01-AR-056768, U01-GM-092691, R01-AR-059648, K24-AR-052501
- Harold and Duval Bowen Fund
- Career Award for Medical Scientists from the Burroughs Wellcome Fund
Differences in lipid levels associated with cardiovascular (CV) risk between rheumatoid arthritis (RA) patients and the general population remain unclear. Determining these differences is important in understanding the role of lipids in CV risk in RA.
We studied 2,005 RA subjects from 2 large academic medical centers. We extracted electronic medical record data on the first low-density lipoprotein (LDL) measurement, and total cholesterol and high-density lipoprotein (HDL) measurements within 1 year of the LDL measurement. Subjects with an electronic statin prescription prior to the first LDL measurement were excluded. We compared lipid levels in RA patients to recently published levels from the general US population using the t-test and stratifying by published parameters, i.e., 2007–2010, and women. We determined lipid trends using separate linear regression models for total cholesterol, LDL cholesterol, and HDL cholesterol, testing the association between year of measurement (1989–2010) and lipid level, adjusted by age and sex. Lipid trends in RA were qualitatively compared to the published general population trends.
Women with RA had a significantly lower total cholesterol (186 versus 200 mg/dl; P = 0.002) and LDL cholesterol (105 versus 118 mg/dl; P = 0.001) compared to the general population (2007–2010). HDL cholesterol was not significantly different in the 2 groups. In the RA cohort, total cholesterol and LDL cholesterol significantly decreased each year, while HDL cholesterol increased (all with P < 0.0001), consistent with overall trends observed in a previous study.
RA patients appear to have an overall lower total cholesterol and LDL cholesterol than the general population despite the general overall risk of CV disease in RA from observational studies.
Excess risk of cardiovascular disease (CVD) is a large contributor to a widening mortality gap observed between rheumatoid arthritis (RA) and the general population, whereby the survival rate of RA patients is not improving at the same rate as the general population (). Although lipids are a major risk factor for CVD and are routinely measured for CVD risk stratification, differences in the levels of total cholesterol, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol between RA patients and the general population remain unclear. Some studies observed that dyslipidemia has a higher prevalence in RA ([2, 3]) while others did not ([4, 5]). In most cases, relative lipid levels were reported as a covariate in the study of CVD risk but were not the primary variable of interest. Establishing the relative levels of lipids in RA compared to the general population is critical for understanding the role of lipids in CVD risk among RA patients.
Recently, Carroll et al reported lipid and lipoprotein levels in the general US population using data from the National Health and Nutrition Examination Surveys (NHANES) () from 1988–2010. They also observed significant declines in cross-sectional levels of total cholesterol and LDL cholesterol and increasing levels of HDL in the general population over this time interval. Whether these favorable secular trends in lipids are also occurring among RA patients is unknown.
The objectives of this study were to: 1) directly compare lipid levels in a large RA cohort to the general US population (using published data from NHANES) and 2) compare trends in lipid and lipoprotein levels in an RA cohort over time to trends in the general population.
Box 1. Significance & Innovations
- The relative differences in clinically measured lipids associated with cardiovascular (CV) risk have not been directly compared between a large rheumatoid arthritis (RA) cohort and a comprehensive sample of the general population. To address this gap in knowledge, this study takes advantage of 2 data sources that allow for this comparison: 1) a recent US population-based study on lipid levels and trends between 1988–2010, and 2) a large RA cohort with clinical and laboratory data on routinely measured lipids in the electronic medical record data from 1989–2010.
- We observed that total cholesterol and low-density lipoprotein (LDL) cholesterol were significantly lower in RA patients compared to the general population and were consistently lower over the past decade. These findings suggest that clinically measured lipid levels may not be as informative for CV risk in RA as in the general population.
- We demonstrate for the first time secular trends in favorable lipid profiles (decreasing total cholesterol, LDL cholesterol, and increasing high-density lipoprotein cholesterol) among RA patients (from 1989–2010) similar to those observed in the general population (from 1988–2010).
We studied a validated RA ([7, 8]) cohort identified through the electronic medical record (EMR) data of Brigham and Women's Hospital and Massachusetts General Hospital (Boston). RA subjects were identified using a published RA EMR phenotype algorithm with a positive predictive value of 94% trained on a gold standard set of subjects classified either as RA or not RA cases by 3 board-certified rheumatologists (KPL, RMP, and EWK) using the 1987 American College of Rheumatology classification criteria for RA () as the benchmark. Details on development, training, and validation of this RA phenotype algorithm have been described previously ().
We extracted EMR data on the first LDL measurement, and total cholesterol and HDL cholesterol (within 1 year of the first LDL measurement) measured from 1989–2010, as well as age at lipid measurement, self-reported race, and anti–citrullinated protein antibody (ACPA) status for each subject. All subjects had prevalent RA, defined as subjects in the RA cohort with ≥1 RA International Classification of Diseases, Ninth Revision, code (714.x) or mention of “rheumatoid arthritis” in the text note prior to the first LDL measurement. Mentions of “rheumatoid arthritis” were extracted using natural language programming as described previously (). All RA cases with an electronic statin prescription prior to the first LDL measurement were excluded.
We calculated mean total cholesterol, LDL cholesterol, and HDL cholesterol levels in the RA cohort annually, stratifying by published parameters corresponding to an earlier study by Carroll et al (), replicable in our data set: age ≥20 years, not on statins prior to first lipid measurement (NHANES patient self-report), women (majority of RA subjects), and time periods 1999–2002 and 2007–2010. We further limited the analysis to non-Hispanic whites (majority of RA subjects) as a sensitivity analysis to control for racial heterogeneity between the 2 groups. We calculated the age-adjusted mean measurements for total cholesterol, LDL cholesterol, and HDL cholesterol using projected 2000 Census population estimates for each stratum as described previously (). We conducted unpaired t-tests to determine differences in mean lipid levels between the RA cohort and NHANES, stratifying by the parameters and time intervals, 1999–2002 and 2007–2010, published by Carroll et al ().
To determine cross-sectional changes in lipid levels in the RA cohort with each passing year, we constructed separate linear regression models for mean total cholesterol, LDL cholesterol, and HDL cholesterol. We tested the cross-sectional association between year of lipid measurement (1989–2010) and lipid level, adjusted by age and sex among all RA cases with available lipid levels. For this analysis, we comment only on whether the trend was qualitatively similar to NHANES, as we could not exactly replicate the time interval for their study which started in 1988, one year before the EMR data were widely available.
To estimate the potential statin misclassification in our analyses, we compared statin prescriptions from the EMRs in a subset of subjects for whom we had administrative medication data (Medicare data from 2006–2010). We conducted the comparison in subjects who had their first LDL measurement in the EMR between 2006 and 2010, had Medicare data available, and per the EMR data were not on statins before or at the time of the first LDL measurement. The extent of misclassification was calculated as the number of subjects with ≥1 statin prescription in Medicare divided by the total number of subjects in the subset.
This study was approved by the Partners' Institutional Review Board. Statistical analyses were conducted using the SAS and R 2.10 software packages.
Our cohort included 2,005 RA subjects not on statins prior to their first LDL measurement. Characteristics of RA subjects included a mean age of 52.9 years, 80.2% women, 76% non-Hispanic white, and 62.4% were ACPA positive (among 914 RA subjects with available ACPA data). Female RA patients had significantly lower mean total cholesterol and LDL cholesterol levels compared to women in the general population, both in the period from 1999–2002 and 2007–2010 (Table 1). HDL cholesterol levels were not statistically different between the 2 groups. We observed the same differences when the analysis was stratified by non-Hispanic white women.
|No.||Mean ± SD, mg/dl||No.||Mean ± SD, mg/dl|
|All race/ethnicity groups|
|1999–2002||363||196.75 ± 20.90||4,645||204 ± 69.54||0.048|
|2007–2010||290||185.76 ± 20.1||4,486||200 ± 64.17||0.0002|
|1999–2002||264||197.62 ± 20.95||1,918||206 ± 44.67||0.0027|
|2007–2010||222||186.38 ± 20.34||2,073||202 ± 46.46||< 0.0001|
|All race/ethnicity groups|
|1999–2002||369||111.12 ± 17.05||1,797||122 ± 64.88||0.0014|
|2007–2010||297||104.75 ± 17.50||2,027||118 ± 68.91||0.0010|
|1999–2002||267||111.41 ± 16.94||871||123 ± 45.17||< 0.0001|
|2007–2010||228||104.38 ± 17.72||923||118 ± 46.50||< 0.0001|
|All race/ethnicity groups|
|1999–2002||366||59.56 ± 9.60||4,645||56.6 ± 38.25||0.14|
|2007–2010||295||58.41 ± 9.70||4,486||58.3 ± 30.76||0.11|
|1999–2002||266||59.61 ± 8.89||1,918||57.1 ± 33.52||0.22|
|2007–2010||226||60.38 ± 9.67||2,073||58.9 ± 30.20||0.40|
Favorable trends in lipid levels were observed in the RA cohort from 1989–2010, qualitatively similar to the trends observed in NHANES from 1988–2010. In the RA cohort (men and women, all races), a significant linear decrease was observed in total cholesterol levels (2.3 mg/dl per year) and LDL cholesterol (2.0 mg/dl per year) (P < 0.0001 for both). A significant increase was observed in HDL cholesterol over time (0.27 mg/dl per year, P < 0.0001) (Table 2). All models were adjusted by age and sex.
|No.||Δ mg/dl per year (SE)b||P for linear trend (1989–2010)||P for linear trend (1988–2010)|
|Total cholesterol||802||−2.4 (0.29)||< 0.0001||Decrease; < 0.001|
|LDL||804||−2.3 (0.24)||< 0.0001||Decrease; < 0.001|
|HDL||801||0.54 (0.12)||< 0.0001||Increase; < 0.001|
Due to concern for potential incomplete statin information in the EMR, we compared statin prescriptions in a subset of individuals for whom we had both EMR and administrative data (Medicare data from 2006–2010). We identified 40 subjects who had their first LDL measurement in the EMR checked between 2006 and 2010 with available Medicare data, and according to the EMR data were not on statins. Out of these 40 subjects, 2 (5%) had billing codes for statins in Medicare dated prior to the first LDL, not captured in the EMR.
Female RA patients in our study had significantly lower mean total cholesterol and LDL cholesterol levels than women in the general population. Specifically, the levels of total cholesterol and LDL cholesterol were consistently lower in RA patients in the 2 time intervals studied, 1999–2002 and 2007–2010. Establishing significant differences in lipid levels between RA and the general population addresses a gap in knowledge regarding relative lipid levels between the 2 groups and provides a foundation for continued studies investigating why these differences exist.
Our observation of lower total cholesterol and LDL cholesterol in prevalent RA extends findings from a previous study demonstrating significant decreases in total cholesterol and LDL cholesterol in the years prior to the development of RA (). Our study demonstrates that the decreases in total cholesterol and LDL cholesterol result in sustained lower levels after diagnosis of RA compared to the general population. These lower levels, in conjunction with known elevated CVD risk in RA compared to the general population from observational studies ([11, 12]), also support the concept of a lipid paradox in RA (). In the lipid paradox, lower total cholesterol was more associated with an elevated risk of CVD in RA than higher levels. Potential causes for this paradox include inflammation, which may lower total cholesterol and LDL levels while simultaneously elevating CVD risk.
The favorable trends in lipid profiles observed in the RA cohort, decreasing total cholesterol and LDL cholesterol and increasing HDL cholesterol, are qualitatively similar to trends observed in the general population (). The forces influencing these trends are unclear for both RA and the general population. However, these findings suggest that clinically measured lipid profiles are not likely to explain the mortality gap () between RA and the general population.
In this study, we did not account for other important RA clinical factors that may influence lipid levels, such as RA treatments and disease activity ([10, 14]) by design. The goal of this study was to determine the overall relative levels in a large RA cohort and the general population to provide a baseline for future studies of lipids. Notably, despite secular trends in management of RA, i.e., new biologic agents, total cholesterol and LDL cholesterol remained consistently lower in RA than the general population over the past decade.
A unique aspect of our study is the use of EMR data, which afforded the opportunity to perform a direct comparison on lipid levels in a large cohort of RA patients with clinical data, to a decade of data from NHANES. Few alternative clinical data sets have sufficient available data for this type of analysis.
Limitations of this study include potential incomplete capture of statin use in the EMR, which can bias towards lower total cholesterol and LDL cholesterol levels. We estimated that we missed 5% of statin prescriptions among our RA cohort. Statin use in the NHANES study was obtained using data from self-report, which can also lead to potential misclassification. We also had incomplete information on fasting status, which can have the opposite effect of incomplete statin capture, biasing towards higher total cholesterol and LDL cholesterol levels. However, a recent study demonstrated that in general there was no significant variation between fasting and nonfasting levels for total cholesterol and LDL cholesterol ().
In summary, RA subjects were observed to have significantly lower total cholesterol and LDL cholesterol levels than the general population and nonsignificant differences in HDL cholesterol levels. Thus, current routinely measured lipid profiles in RA may be unreliable predictors of CVD risk. Fortunately, the overall trends of lipid levels appear to be favorable for both RA patients and for the general population. Further studies are needed to integrate how inflammation and RA treatments may contribute to differences in lipid levels in RA compared to the general population, and the role of these combined factors for CVD risk in RA.
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. Dr. Liao 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. Liao, Cai, Murphy, Churchill, Kohane, Karlson.
Acquisition of data. Liao, Gainer, Cagan, Liu, Churchill.
Analysis and interpretation of data. Liao, Cai, Shaw, Solomon, Plenge, Karlson.