Rheumatoid arthritis and diabetes mellitus: evidence for an association?

There is now a large body of epidemiological evidence linking rheumatoid arthritis (RA) with the premature development of cardiovascular disease1-4. This relates, at least in part, to the systemic inflammatory burden in RA, which has been shown to predispose to the development of premature atherosclerosis in individuals with this condition. Raised levels of systemic inflammation have also been shown to predispose to developing both insulin resistance5,6 and type 2 diabetes mellitus (DM)7-9. In the case of the latter, Pradhan and colleagues reported that the development of type 2 DM in women was predicted by elevated levels of Creactive protein (CRP) and interleukin 6, both markers of systemic inflammation7. The authors of 2 further longitudinal cohort studies found that markers of inflammation such as CRP, raised white cell count, and low serum albumin were associated with development of diabetes over prolonged periods8,9. The potential role of insulin resistance as a cardiovascular risk factor in patients with inflammatory arthritis has been examined by Svenson, et al, who reported impaired glucose handling in a sample of RA patients compared to controls10. These investigators also found evidence of an inverse relationship between insulin sensitivity and acute phase markers in RA. More recently, Dessein, et al reported significantly higher levels of insulin resistance in patients with inflammatory arthritis compared with controls, and an association between high CRP concentrations and insulin resistance11,12. Glucocorticoids, which are commonly used in RA therapy, would also be expected to contribute to insulin resistance13. Given that chronic systemic inflammation has been associated with both insulin resistance and type 2 DM, the question arises whether the prevalence of DM is increased in patients with RA. Although no studies to date have directly addressed this question, it has been indirectly examined in some of the studies addressing cardiovascular risk in RA. The results of these studies have been conflicting. Han, et al, using a clinic-based population, found a significantly higher prevalence of type 2 DM in RA patients compared with matched controls14. However, contrasting findings were reported from 2 large cohort studies. Solomon and colleagues did not find evidence of an association between RA and DM in a prospective cohort of women15. Although del Rincon and colleagues noted a significantly higher frequency of diabetes in a cohort of patients with RA compared with that in a population-based cohort of persons without RA, this difference disappeared when the samples were stratified for age16. Simard and Mittleman’s population-based study, in this issue of The Journal, is the first to directly address the question of an association between prevalent RA and DM17. These investigators used population-based data collected as part of the National Health and Nutrition Examination Survey (NHANES) III, which included 5302 study subjects aged > 60 years. A total of 144 of these subjects fulfilled criteria for RA, of whom 24 had prevalent diabetes. After controlling for a number of potential confounding factors, including demographic factors, body mass index, physical inactivity, and glucocorticoid prescription, a significant association between RA and DM was not found. These findings must, however, be interpreted in light of the limitations of this study. In particular, the numbers of subjects with RA and DM are very small. This is reflected in the wide confidence intervals of the odds ratios, and suggests that the study may not have adequate power to pick up a moderate association between these 2 conditions. It is worth noting in this context that the adjusted odds ratios for DM in the subset of RA subjects not currently taking glucocorticoids and fasting for at least 8 hours prior to blood draw ranged from 1.29 to 1.57, although again, these findings were not statistically significant. As an additional concern, included subjects with RA had