This retrospective cohort study illustrates the longitudinal trends in lipids in a population-based cohort of RA patients and non-RA subjects from the same underlying community during the period from 5 years before to 5 years after RA incidence/index date. There was a significant decrease in TCh and LDL levels, and a significant decrease in TCh:HDL ratio during the 5-year period before RA incidence. Lipid trends were otherwise similar in the RA and non-RA cohorts during the period from 5 years before to 5 years after RA. During the 5 years before RA incidence/index date, the proportion of RA patients with elevated TCh or LDL measures was significantly less compared to non-RA subjects.
To the best of our knowledge, this is the first longitudinal population-based study reporting long-term lipid trends in RA and non-RA populations both before and after RA incidence/index date. The major finding of our study is the significant decline in TCh and LDL levels occurring during the 5 years before RA incidence/index date in RA patients as compared to non-RA subjects. Consistent with the dynamics of TCh and HDL changes (i.e. decrease in TCh levels and unchanged HDL levels), RA patients also experienced a larger decline in TCh:HDL ratio than non-RA subjects during the 5 years before RA. The declines in TCh and LDL levels were similar when using the date of the first joint swelling as an index date. We also found a significant reduction of the proportion of patients with lipid abnormalities (elevated TCh or LDL measures) during 5 years before incidence/index date in the RA cohort, but not in non-RA subjects. The only previous longitudinal study describing lipid levels in the pre-RA period was performed using the samples of blood donors in Netherlands during 1984-1999 period who later developed RA.[19
] These authors showed a more atherogenic lipid profile in the preclinical phase of rheumatoid arthritis. However, due to the differences in study population and design, as well as different time periods under study, these findings can not be directly compared to ours. The declining trend in TCh and LDL levels is concordant with studies showing lower TCh and LDL levels in active RA.[8
] This observation is also consistent with the concept of lowering of the plasma cholesterol concentrations in acute (particularly, inflammatory) conditions.[20
] In fact, this decrease in TCh and LDL levels might result from their increased catabolism or increased retention (i.e., subendothelial deposition) rather than decreased lipid production.[24
] Subendothelial lipid deposition might explain the paradox of lower cholesterol levels and increased CV risk in RA. Indeed, low cholesterol concentrations have been previously associated with high mortality risk [26
] and a poor response to tissue stress. [28
Given that the major declines in TCh and LDL occurred during the pre-RA period, even before the first joint swelling, these changes were unlikely to be affected by antirheumatic treatment. The decreases in TCh and LDL levels in RA in our study are unlikely to be solely due to the use of lipid-lowering therapy either, since use of lipid lowering medications was lower in RA than in non-RA subjects and the lipid trends in RA patients were similar when statin users were excluded from the analysis. Hence, the lipid changes in the RA cohort occurring during the 5 years prior to RA are likely to be associated with the ongoing preclinical inflammation rather than the effect of antirheumatic and lipid-lowering medications. Lipid changes in non-RA subjects are consistent with the major lipid trends in the US population (studies NHANES and ARIC) suggesting that non-RA cohort reflects the general population.[30
] These lipid changes can be explained by increasing usage of lipid-lowering drugs in the general population during the recent decades.[31
] Similar explanation might be suggested for the changes in HDL and TG levels in non-RA subjects over time. Although trends in HDL and TG levels in the RA cohort were not significantly different from non-RA subjects, RA-specific mechanisms for these changes in RA patients can't be excluded. However, from this observational study, it is impossible to make inferences regarding the pathophysiological and clinical implications of lipid profile changes in RA. Thus, the reasons for these lipid changes in the RA population and the association of these trends with excess CV risk in RA are uncertain.
Strengths of the study include the population-based study design and the comprehensive data collection. The unique record linkage system allowed ascertainment of all RA cases from Olmsted County within the study period and provided comprehensive data on RA and non-RA subjects for the study. Our study takes advantage of the longitudinal design and parallel analysis of the lipid trends in RA patients and the non-RA comparison cohort within the same calendar period.
This study has a number of potential limitations. First, RA patients may have more physician visits and consequently may be more likely to have more lipid measurements than non-RA subjects. Similarly, patients with abnormal lipid values are more likely to have repeat measurements. However, the number of lipid measurements was similar in the RA and non-RA cohorts. Further, this weakness was minimized during the statistical analysis by accounting for multiple lipid measurements per subject. In this observational study, we did not analyze the role of traditional CV risk factors, inflammatory characteristics and antirheumatic medications in lipid profile changes in RA. The impact of these three potential contributors on lipid profile in RA was shown previously [7
] and was beyond the scope of the present study. While data on lipid-lowering medications were not available prior to 1997, this was unlikely to bias the results as the limitation applied equally to both the RA and non-RA cohorts. While quantitative change in body weight in RA patients during the study period was not significant, there may have been changes in body composition which were not measured and thus may have been missed. A decrease in the muscle mass and an increase in the fat mass are common in RA patients and were shown to be associated with dyslipidemia.[34
] However, increased, not decreased TCh and LDL levels would be expected in RA patients with rheumatoid cachectic obesity [36
], so these metabolic changes are unlikely to explain the observed lipid changes in RA patients. Finally, during the calendar period of investigation the population of Olmsted County, MN was predominantly white. Thus, the results may not be generalizable to non-white individuals. Except for the higher proportion of the population with higher educational levels, other sociodemographic characteristics of Olmsted County, MN residents are similar to US whites.
In conclusion, RA patients experienced a significant decrease in TCh and LDL levels during the 5 years before RA incidence as compared to non-RA subjects. Lipid trends were otherwise similar in RA and non-RA cohorts during the 5 years before and 5 years after RA. The prevalence of abnormal TCh or LDL measures significantly decreased in the RA, but not in the non-RA cohort, during 5 years before RA incidence/index date. These lipid changes in RA are unlikely to be solely due to lipid-lowering therapy or changes in BMI. The reasons and the clinical significance for the apparent changes in lipid profile before RA are uncertain. Further studies regarding the association of RA characteristics and antirheumatic medications with lipid profile and CV outcomes in RA over time are underway.