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Editorial
Rheumatoid Arthritis and Diabetes Mellitus: Evidence for an Association? MICHELE DORAN, MD, FRCPI,
Dublin 8, Ireland Address reprint requests to Dr. Doran. E-mail: micheledoran@ireland.com 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 C-reactive 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 very mild disease. Only 10% of RA cases were taking disease-modifying drugs, and mean CRP level was only 1.04 mg/dl. Further, the proportion of patients with positive rheumatoid factor was smaller than that seen in other population-based studies of RA18,19. Even given the community-based setting of this study, these results are surprising and suggest the possibility that patients in the community with more severe RA did not participate in NHANES due to disease-related disability. This would mean the sample of subjects with RA in this study is not representative of all patients with RA. Because DM might be expected to occur more often in patients with more severe RA, who have higher levels of inflammation, the noted prevalence of DM in these patients may be an underestimation. Other factors that may have led to dilution of a true association between RA and DM include the cross-sectional design of the data used in this study. If patients with both RA and DM in the community had increased mortality, the number of survivors in this group would be lower, thus leading to underestimation of the concurrence of these 2 conditions. Further, due to missing data on fasting glucose in a large number of study participants, the prevalence of diabetes could have been underestimated due to asymptomatic patients with type 2 DM not having been included. Finally, the criteria used for definition of RA could have allowed inclusion of patients with other forms of inflammatory arthritis, thus diluting an association between RA and DM. Given the limitations outlined above, an association between RA and DM has not yet been ruled out, despite the lack of a significant association noted in this study. Rather, these findings point to the need for further investigation of this interesting question. Future studies would ideally be prospective, use predefined criteria for diagnosis of both RA and DM, and include larger numbers than in the current study. The study reported by Simard and Mittleman in this issue, along with most recent studies examining the association between RA and DM, have concentrated on type 2 DM. This is of particular interest at present due to the association of this condition with systemic inflammation. There are also, however, reasons for speculation about a possible association between type 1 DM and RA. These include evidence of familial clustering of autoimmune diseases, including RA and type 1 DM, and the common association of the HLA-DR4 allele with both DM and RA20. One study found that 13% of 295 RA patients had a first-degree relative with type 1 diabetes21. However, another study that examined a cohort of hospitalized RA patients found a prevalence of type 1 DM in the RA cohort similar to that in the general population20. Simard and Mittleman do not specify whether they included both type 1 and 2 DM, but given that all patients included in the study were over 60 years of age, it is likely that the majority of patients included in this study had type 2 DM. Chronic systemic inflammation has been clearly shown to predispose to premature atherosclerosis and cardiovascular risk in patients with RA. Chronic inflammation also appears to predispose to development of both insulin resistance and DM. The important question remains whether there is an increased prevalence of DM in patients with RA. Ideally, large-scale, prospective studies are needed to gain a clearer picture of the true prevalence of DM in RA patients in the community. 2. Myllykangas-Luosujarvi R, Aho K, Kautiainen H, Isomaki H. Cardiovascular mortality in women with rheumatoid arthritis. J Rheumatol 1995;22:1065-7. [MEDLINE] 3. Prior P, Symmons DP, Scott DL, Brown R, Hawkins CF. Cause of death in rheumatoid arthritis. Br J Rheumatol 1984;23:92-9. [MEDLINE] 4. Allebeck P. Increased mortality in rheumatoid arthritis. Scand J Rheumatol 1982;11:81-6. [MEDLINE] 5. Xu H, Barnes GT, Yang Q, et al. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Invest 2003;112:1821-30. [MEDLINE] 6. Festa A, D'Agostino R Jr, Howard G, Mykkanen L, Tracy RP, Haffner SM. Chronic subclinical inflammation as part of the insulin resistance syndrome: the Insulin Resistance Atherosclerosis Study (IRAS). Circulation 2000:102:42-7. [MEDLINE] 7. Pradhan AD, Manson JE, Rifai N, Buring JE, Ridker PM. C-reactive protein, interleukin-6, and risk of developing Type 2 diabetes mellitus. JAMA 2001;286:327-34. [MEDLINE] 8. Schmidt MI, Duncan BB, Sharrett AR, et al. Markers of inflammation and prediction of diabetes mellitus in adults (Atherosclerosis Risk in Communities Study): a cohort study. Lancet 1999;353:1649-52. [MEDLINE] 9. Barzilay JI, Abraham L, Heckbert SR, et al. The relation of markers of inflammation to the development of glucose disorders in the elderly. Diabetes 2001;50:2384-9. [MEDLINE] 10. Svenson KL, Pollare T, Lithell H, Hallgren R. Impaired glucose handling in active rheumatoid arthritis: relationship to peripheral insulin resistance. Metabolism 1988;37:125-30. [MEDLINE] 11. Dessein PH, Stanwix AE, Joffe BI. Cardiovascular risk in rheumatoid arthritis versus osteoarthritis: acute phase response related decreased insulin sensitivity and high-density lipoprotein cholesterol as well as clustering of metabolic syndrome features in rheumatoid arthritis. Arthritis Res 2002;4:R5. [MEDLINE] 12. Dessein PH, Joffe BI, Stanwix AE, Christian BF, Veller M. The acute phase response does not fully predict the presence of insulin resistance and dyslipidemia in inflammatory arthritis. J Rheumatol 2002;29:462-6. [MEDLINE] 13. Dessein PH, Joffe BI, Stanwix A, Botha AS, Moomal Z. Glucocorticoids and insulin sensitivity in rheumatoid arthritis. J Rheumatol 2004;31:867-74. [MEDLINE] 14. Han C, Robinson DW Jr, Hackett MV, Paramore LC, Fraeman KH, Bala MV. Cardiovascular disease and risk factors in patients with rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis. J Rheumatol 2006;33:2167-72. [MEDLINE] 15. Solomon DH, Karlson EW, Rimm EB, et al. Cardiovascular morbidity and mortality in women diagnosed with rheumatoid arthritis. Circulation 2003;107:1303-7. [MEDLINE] 16. del Rincon I, Williams K, Stern MP, Freeman GL, Escalante A. High incidence of cardiovascular events in a rheumatoid arthritis cohort not explained by traditional risk factors. Arthritis Rheum 2001;44:2737-45. [MEDLINE] 17. Simard JF, Mittleman MA. Prevalent rheumatoid arthritis and diabetes among NHANES III participants aged 60 and older. J Rheumatol 2007;34:469-73. 18. Kaipiainen-Seppanen O, Aho K, Isomaki H, Laakso M. Incidence of rheumatoid arthritis in Finland during 1980-1990. Ann Rheum Dis 1996;55:608-11. [MEDLINE] 19. Doran MF, Pond GR, Crowson CS, O'Fallon WM, Gabriel SE. Trends in incidence and mortality in rheumatoid arthritis in Rochester, Minnesota over a 40-year period. Arthritis Rheum 2002;46:625-31. [MEDLINE] 20. Hakala M, Vahlberg T, Niemi PM, et al. No association between rheumatoid arthritis and insulin dependent diabetes mellitus: an epidemiologic and immunogenetic study. J Rheumatol 1992;19:856-8. [MEDLINE] 21. Thomas DJ, Young A, Gorsuch AN, Bottazzo GF, Cudworth AG. Evidence for an association between rheumatoid arthritis and autoimmune endocrine disease. Ann Rheum Dis 1983;42:297-300. [MEDLINE]
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