Introduction
Rheumatoid arthritis (RA) is a chronic inflammatory disease of multifactorial etiology. Genetics [
1] as well as environmental factors [
2] have been implicated. Smoking is an established predictor of RA [
3], and smoking and low socioeconomic status, as reflected by current occupation [
4] or level of formal education [
5], have been shown to have independent effects on disease development. Overall, women have a two- to three-fold higher incidence of RA than men [
6]. We have previously demonstrated that women with early menopause (at age 45 or earlier) had an increased risk of RA compared with those with normal/late menopause in models adjusted for smoking, level of education, and length of breast-feeding, suggesting that hormone-related factors play a part in the pathogenesis [
7].
Metabolic factors may also be important in this context. Recently, it has been suggested that obesity may influence both RA onset and disease severity [
8]. Interestingly, the effect of obesity may be different in men and women, and findings indicate a reduced risk of RA in obese men [
9,
10] and a positive association in women, in particular with obesity at a young age [
11].
In a previous study of blood donors who subsequently developed RA and matched controls, average serum levels of total cholesterol (TC) and triglycerides (TGs) were higher in pre-RA cases than in controls [
12]. This contrasts with studies of patients with established RA, in which lipid levels tend to be lower than in the general population, in particular in those with active, uncontrolled inflammation [
13]. Furthermore, treatment with potent biologic anti-rheumatic drugs for severe, refractory RA has been associated with an increase in lipid levels, although the atherogenic index—ratio of low-density lipoprotein (LDL) cholesterol to high-density lipoprotein (HDL) cholesterol—appears to be unchanged in most cases [
14,
15]. These patterns are of particular interest because of the increased risk of cardiovascular disease (CVD) in patients with RA compared with the general population [
16], and data from some studies suggesting a “lipid paradox” in established RA, in which low TC and TG levels, probably related to active inflammation, are associated with CVD events [
17].
The purpose of this study was to examine the effect of serum TC and TG levels on the risk of RA in a prospective study of men and women who were included in a large population-based health survey. To the best of our knowledge, this is the first prospective study to investigate this issue in women and men separately.
Discussion
In this nested case-control study, women with a high serum TC were at an increased risk of developing RA in the future. By contrast, TC did not have any significant impact on the risk of RA in men. Serum TG levels were not predictive of RA.
Since there was no major change in these patterns in analyses adjusted for smoking and other potential confounders, it is unlikely that they are explained by such exposures. Rates of self-reported key co-morbidities were low and similar in cases and controls. Still, residual confounding by other factors remains a possibility.
Data on treatment with statins and other lipid-lowering therapy were not available in the present study. In the 1970s and 1980s, when most of the study participants were screened, such treatment was not commonly prescribed for primary prevention of CVD in Sweden. For example, the overall utilization of lipid-lowering drugs in 1987 was estimated to be 0.6 defined daily doses per 1000 inhabitants per day in a Swedish population-based survey [
29]. Furthermore, baseline rates of self-reported CVD and diabetes in the present sample were low, further supporting that statin treatment at the time of inclusion was limited. However, subsequent prescription of lipid-lowering agents in individuals with high TC at inclusion in the MPMP could influence the present results.
It has previously been suggested that treatment with statins may be associated with an increased risk of developing RA [
30]. This was based on a study using the Netherlands Information Network of General Practice, in which patients with RA were demonstrated to be more likely to have been prescribed statin treatment before diagnosis compared with matched controls, although there was no consistent impact of treatment duration or number of defined daily doses [
30]. Another study found that, among individuals prescribed statins, those on persistent therapy had a reduced risk of RA compared with those with a lower proportion of days covered by statin prescriptions [
31]. Taken together, this suggests that the relation between statin exposure and RA development is likely to be complex.
The observation that high TC was significantly associated with increased risk of RA in women only may reflect underlying mechanisms that are sex-specific (e.g., effects related to female sex hormones). It is well established that TC levels increase during menopause [
32] and that women with premature menopause have increased TC levels compared with age-matched controls [
33]. As expected, we found that TC levels were higher in women with a history of early menopause, and there was a trend toward an increased risk of RA in this subset, similar to previous reports [
7,
34,
35]. However, the association between higher TC and RA development remained significant in models adjusted for history of early menopause. Still, we cannot rule out that hormone-related factors leading to increased TC levels explain the present results. For example, a history of short-term breastfeeding (≤6 months) has been associated with higher lipid levels, reduced insulin resistance, and abdominal obesity at follow-up 16–20 years after the last pregnancy [
36], and we [
37] and others [
38] have previously shown that women who breast-feed their children for an extended time have a reduced risk of RA. Unfortunately, data on previous breastfeeding were not available in the studied cohort. The fact that significant associations were seen between TC and subsequent RA development in younger women (younger than 46 years old at inclusion), and in women included more than 13 years before diagnosis, suggests that long-term effects of metabolic pathways influence susceptibility to RA in women.
Obesity, which may play a differential role in men and women with RA [
9,
28], may be important in this context. However, the estimated effects of TC in men and women were similar to the main results in models adjusted for BMI. Differences in body fat distribution and differences in the relation between biomarkers of inflammation and lipid metabolism in women and men may also contribute to this pattern and should be further studied. Our results are to some extent in agreement with those of van Halm et al., who reported higher TC in serial samples from pre-RA cases recruited from a population of blood donors investigated between 0.7 and 14.5 years before diagnosis [
12]. However, the present study extends these findings to a population-based health survey of individuals from a more heterogeneous background than most cohorts of blood donors and to women included long before RA diagnosis. In contrast to the study by van Halm et al. [
12], we found no association between TG levels and RA development. Potential explanations include methodological differences, such as the time of sampling (fasting in the present study).
In a retrospective study of a population-based cohort of patients with RA, serum TC and TGs decreased significantly compared with matched reference subjects during the last 5 years before RA diagnosis [
39]. Data on prescribed lipid-lowering agents did not appear to explain these changes, which may be due to early effects of inflammation in the pre-clinical phase of RA. These observations, together with the considerable lag time from inclusion to RA diagnosis and the low ESR levels in most participants in the present study, suggest that our observations of higher TC in women who later developed RA were not due to such inflammatory mechanisms. Further studies of biomarker patterns in pre-RA cases with high TC may give insights into the underlying mechanisms and eventually be the basis for disease preventive strategies.
Current guidelines suggest monitoring of TC [
40] or the TC/HDL cholesterol ratio [
41] in patients with RA and the use of these parameters in risk score models, similar to those recommended for the general population [
42]. However, there has been a lack of consistent associations between lipid levels and CVD co-morbidity in patients with established RA in several studies [
43‐
45] and a paradoxical reverse association with TC and LDL cholesterol in a population-based sample of patients whose RA was diagnosed between 1988 and 2007 [
17]. The present findings, suggesting an extended period of hypercholesterolemia before disease onset in some cases, are of interest for our understanding of atherosclerosis in the setting of RA. Further studies should examine the relation between pre-disease TC levels and CVD events after diagnosis.
Limitations of this study include the lack of data on HDL and LDL cholesterol as well as on apolipoproteins. Such data would be of particular interest, as women tend to have higher HDL cholesterol levels than men, although there is a decrease in HDL cholesterol and an increase in TC and LDL cholesterol after menopause [
46]. Sex-specific effects of cholesterol fractions, as well as of lipid-lowering treatment, should therefore be further studied.
Owing to the study design, longitudinal data on lipids were not available. Therefore, we cannot assess the impact of changes in TC and TGs over time on the risk of RA. In addition, since the analyses were based on samples obtained between 1974 and 1992, effects of recent secular trends in lipid levels and related exposures in the population would not be identified. Further studies should include data on serum lipid levels from more recent health surveys and cases with RA onset in the last few years.
Another limitation is the lack of data on anti-citrullinated antibody (ACPA) status after diagnosis, which is due to the fact that for the majority of patients the diagnosis was before routine ACPA analysis was available. However, we did have data on RF, and RF positivity and ACPA positivity are known to have a major overlap in patients with RA [
47]. Previous studies have indicated that predictors differ for RF/ACPA-positive versus RF/ACPA-negative RA [
48]. For example, smoking has consistently been found to be a significant predictor of seropositive RA but not seronegative RA [
5,
48,
49]. The positive association between higher TC and subsequent RA development in women was at least as strong for RF-negative RA as for RF-positive RA, suggesting distinct underlying disease mechanisms from those related to smoking.
The strengths of this study include the prospective study design, with exposures measured before RA diagnosis in a standardized manner. The low number of controls whose RA was diagnosed after the index date suggests that the potential impact of surveillance bias in patients with high TC and related diseases is limited. Furthermore, the inclusion of a relatively large sample of men who subsequently developed RA is a unique asset of this study. The population-based approach, with a high participation rate in the health survey, indicates that our cases were representative of patients with RA in the area. On the other hand, the cases were mainly Caucasians of Scandinavian heritage, and the results may not apply to other ethnic groups or other geographic settings.
Competing interests
The authors declare that they have no competing interests.
Authors’ contributions
CT conceived of the study, participated in the study design and the data collection, performed the statistical analyses, and drafted the manuscript. UB participated in the study design and the data collection and helped draft the manuscript. MP participated in the data collection and in the analysis and interpretation of the results and helped to revise the manuscript. J-ÅN participated in the study design, gave advice on the statistical analysis, and helped to revise the manuscript. LJ participated in the study design and in the analysis and interpretation of the results and revised the manuscript. All authors read and approved the final version of the manuscript.