High serum cholesterol predicts rheumatoid arthritis in women, but not in men: a prospective study

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.