The prevalence of obesity has risen dramatically in recent years. History of obesity is a significant risk factor for the development of RA even after adjustment for smoking status. Our findings indicate that obesity could explain 52% of the recent rise in incidence of RA. While smoking is a stronger risk factor for RA in our cohort (OR>1.4), smoking can not explain the increase in incidence of RA because the prevalence of smoking has not increased in recent years. While the relative effect of obesity on development of RA did not appear to differ in men vs. women and the prevalence of obesity was similar (and in some age groups higher) in men vs. women, the absolute impact of obesity on the trends in incidence of RA was smaller in men than in women due to the lower incidence of RA among men.
Several well-conducted studies have examined the potential effect of obesity on the development of RA with inconsistent results (). Symmons et al reported a large effect of obesity on development of RA in Norfolk, England (OR: 3.74) (18
). Significant effects with OR for obesity of approximately 1.5 were reported by Voigt et al and Pedersen et al (7
). In contrast, no effect of obesity was found in the Nurses’ Health Study, the Iowa Women’s Health Study, or in the United Kingdom General Practice Research Database (5
). The bulk of the evidence seems to point towards a modest increased risk of RA associated with obesity, likely OR<1.5, as reported in our study. Thus, the latter studies which were conducted using data from 1976–1997, at a time when the prevalence of obesity was around 10% may have been underpowered to detect a modest risk (e.g., OR< 1.5) associated with a risk factor with low prevalence. In fact, in order for a study to have 80% power to detect an association with an odds ratio of 1.5 for a risk factor with prevalence of 10%, a sample size of 957 cases and 957 controls would be needed. Given the rapidly increasing prevalence of obesity, a re-examination of obesity as a risk factor for RA is warranted.
Obesity and the risk of rheumatoid arthritis
The inconsistent results of the impact of obesity on development of RA stem from its modest effect, which has led to under-recognition of obesity as a risk factor for RA. In fact, obesity has been nearly forgotten in recent years, as several review articles listing environmental risk factors for RA have not mentioned it (21
). Articles speculating on potential causes for the recent increase in incidence of RA have made only passing mention of obesity, while addressing an extensive list of potential environmental influences on development of RA, including cigarette smoking, use of oral contraceptives, breast feeding, vitamin D insufficiency, infections, immunizations, socioeconomic status, occupational exposures, alcohol use and air pollution among others. Genetic factors are unlikely to explain the recent increase in RA incidence because they change in populations over centuries rather than decades. Thus environmental factors, or possibly epigenetic factors, are most likely responsible for the recent changes in incidence of RA. The strongest environmental factors influencing development of RA are arguably cigarette smoking and use of oral contraceptives. However, the prevalence of these factors has been stable in recent years, so they are unlikely to explain the recent rise in RA incidence.
The mechanism by which obesity may lead to RA is unknown, but several mechanisms have been postulated. One plausible mechanism is the association between obesity and chronic inflammation. The amount of adipose tissue increases during weight gain, and adipocytes produce adipocytokines and inflammatory cytokines, including adiponectin, leptin, tumor necrosis factor, interleukin-6, C-reactive protein and many others (1
). The major adipocytokines have immune-modulatory properties and impact inflammation (2
). This is an active area of research, and both adipocytokines and inflammatory cytokines are implicated in the pathophysiology of rheumatic diseases, such as RA. A second possibility involves the association between obesity and vitamin D deficiency. Obese patients often have vitamin D deficiency (24
). Merlino et al reported vitamin D intake was inversely associated with development of RA (26
). Others have found associations between vitamin D deficiency and the development of autoimmune diseases, such as multiple sclerosis and Type 1 diabetes mellitus, but these results have not been consistent across studies (27
). Third, the relationship between obesity and sex hormones could also influence the development of RA. Obese men and women have higher levels of estrogens and androgens (29
). Given the sex-bias in RA incidence and the protective effect of oral contraceptives, sex hormones are thought to play a role in the development of RA, which might be modified by obesity (32
). Furthermore, estrogen levels are positively correlated with adipocytokines (33
). Finally, obesity has been linked to development of psoriatic arthritis, and Soltani-Arabshahi et al postulate that the link between obesity and autoimmune diseases could be driven by a genetic variation that predisposes patients to both conditions (34
). Hence, while there are many plausible connections between obesity and RA, further research is needed to understand the complex mechanisms whereby obesity influences the development of RA.
One question of interest is whether obesity comes first or whether the mechanisms that cause RA are already in place when obesity develops. This question is difficult to answer. However, in our study obesity at incidence / index date was not significantly associated with development of RA, despite small differences in patients fulfilling the definition for history of obesity vs. obesity at incidence / index date (10% of RA and 8% of control subjects met the definition of history of obesity, but were not obese at incidence / index date). This finding, along with the potential associations between obesity and RA discussed in the previous paragraph, would suggest that obesity manifests prior to development of RA. However, the possibility of a common antecedent to both obesity and RA cannot be excluded. Thus, further research is needed to address this question.
Furthermore, several studies have reported a protective effect of increasing body mass for radiographic joint damage and mortality in RA (35
). These findings may seem to contradict our findings of an association between obesity and the development of RA. However, patients with RA may experience weight loss associated with their disease severity, which can lead to rheumatoid cachexia.
Our study has several strengths including its population-based design and standardized approach to case identification, as well as the availability of extensive medical history prior to RA incidence/index date. The population of Olmsted County, MN is 90% white suggesting that the results of our study may not be generalizable to other, more racially diverse populations. However, our trends in the prevalence of obesity over time were remarkably similar to those in the US population reported by the National Health and Nutrition Examination Survey (NHANES) (9
). In addition, as with any observational study, our study precludes determination of causality. However, randomizing patients to obesity or not is infeasible. Hence, we cannot exclude the possibility that our findings of an association between obesity and the development of RA may not be causal due to confounding by another related factor. For instance, altered energy expenditure resulting from loss of muscle mass and increase in fat mass, referred to as rheumatoid cachexia, may play a role. In addition, BMI may not accurately reflect abdominal adiposity, so a measure of abdominal fat mass, such as waist circumference, would have been useful to further elucidate the relationship between adiposity and development of RA. However, a measure of abdominal fat mass was not available in this retrospective study, as this information is not routinely collected during clinical care. Furthermore, data on the length of time that patients were obese was not collected. However, the vast majority of patients with a history of obesity who were no longer obese at incidence / index date remained overweight.
In conclusion, obesity is associated with a modest risk for developing RA. Given the recent rapid increase in the prevalence of obesity, this risk factor appears to have a significant impact on the incidence of RA and may account for a large proportion of the recent increase in incidence of RA among women. These findings suggest that unless the obesity epidemic is controlled, the incidence and prevalence of RA will continue to rise, leading to increasing demands for rheumatological care.