Background/Purpose: Patients with active rheumatoid arthritis (RA) tend to have low cholesterol levels due to effects of inflammation on lipid metabolism. However, several prospective studies have indicated that a high serum cholesterol may be associated with increased risk of of RA. Metabolic pathways in the development of RA may be affected by hormonal factors, and have a different impact in men and women. The purpose of this study was to examine sex-specific effects of total serum cholesterol on the future risk of RA.

Methods:

Between 1974 and 1992, subjects (n=33346; 22444 men and 10902 women) from a defined catchment area were included in a Preventive Medicine Program (PMP). Information on life style factors was obtained using a self-administered questionnaire. Blood samples were taken in the morning, after an overnight fast. Serum cholesterol was immediately assessed by an enzymatic method routinely used by the local hospital laboratory. From this population, we identified individuals who developed RA after inclusion by linking the PMP register to the local community based RA register and to local and national patient administrative databases. In a structured review of the medical records, patients were classified according to the 1987 American College of Rheumatology criteria for RA. Four controls for each validated case, matched for sex, year of birth and year of screening, who were alive and free of  RA when the index person was diagnosed with RA, were selected from the PMP register. The impact of serum cholesterol on the risk of RA was examined in conditional logistic regression models, stratified by sex.

Results:

Two hundred and ninety patients [151 men and 139 women; median time from inclusion to RA diagnosis 12 years (interquartile range 8–18, range 1-28); mean age at diagnosis 60 years] were diagnosed with RA and fulfilled the ACR criteria after inclusion in the PMP. There was no difference in cholesterol levels between men who subsequently developed RA and controls (mean 5.66 vs. 5.64 mmol/l). By contrast, women with a diagnosis of RA during the follow-up had higher cholesterol levels at baseline compared to controls [mean 6.04; standard deviation (SD) 1.16 vs. 5.71 (SD 1.11) mmol/l; OR 1.54 per SD; 95 % confidence interval (CI) 1.22-1.94)]. A higher cholesterol was predictive of RF positive RA (OR 1.45 per SD; 95 % CI 1.08-1.94) as well as RF negative RA (1.85 per SD; 95 % CI 1.22-2.80) in women.  The association between higher cholesterol and subsequent development of RA in women remained significant in separate multivariate analyses adjusted for smoking (p=0.001) or early menopause (at age <46 vs. ≥ 46 years) (p=0.01). The association with future RA was statistically significant among those included 1-12 years before RA diagnosis (OR 1.36 per SD; 95 % CI 1.02-1.80) as well as among those included 13-28 years before RA diagnosis (OR 1.94 per SD; 95 % CI 1.30-2.87).

Conclusion: A higher serum cholesterol was associated with increased risk of RA in women, but not in men. This suggests that sex-specific exposures modify the impact of lipids on the risk of RA. The strong association with higher cholesterol among women surveyed long before RA diagnosis implicates early metabolic pathways in the etiology of RA.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/high-serum-cholesterol-predicts-rheumatoid-arthritis-in-women/