“At this time, this link is just a hypothesis and pure speculation,” stresses Dr. Brenner. “But it does raise the possibility that the systemic increase in TNF and other pro-inflammatory cytokines being produced by the adipose tissue may have systemic effects that reach the synovium. That exposure may jump-start the RA pathological process in the synovium or combine with the incipient RA synovial process to overcome the threshold needed for disease activation.”
Although there are clues to a possible relationship between obesity, inflammation and rheumatic diseases based on basic studies in mice and epidemiologic studies in humans, there is no direct evidence showing that blocking inflammation in obesity will reverse the risk or responsiveness of RA.
Cross Talk Between Epidemiology & Basic Science
“There is a lot of cross talking between epidemiology and basic science,” says Jeffrey A. Sparks, MD, MMSc, associate physician and instructor in medicine at Brigham and Women’s Hospital. “If you see an unexpected observation in the epidemiologic studies, it might change your mechanistic framework. From the other side, the mechanistic findings can inform a hypothesis in order to initiate population-based investigations you might not have thought about otherwise.”
When viewing these studies, he notes that it’s important to take into account that most large epidemiologic studies have used body mass index (BMI), which may not always be an accurate measure of adiposity. However, most other research measures of adiposity that could be utilized are difficult to widely implement in the context of population studies requiring large sample sizes.
Preclinical Indicators
From a preclinical standpoint, Dr. Sparks says the epidemiologic evidence gives a consistent story for the effect of increased BMI and the risk of developing RA. Many case/control studies, a few cohort studies and a recent meta-analysis show that being overweight or obese, as measured by BMI, all indicate an increased risk for developing RA. In addition, there appears to be a robust dose/response relationship.
He points to two important studies in the mid-1990s that looked at several factors, with obesity being a common theme. Although these were both case/control studies that asked the patients what they remembered their BMI to be at diagnosis, there was still an increased risk of RA. The higher the body mass index within one year of reference date, the higher the odds ratio for RA development.5,6
ACPA Status & Obesity
A more recent study showed a somewhat different outcome when stratified by risk and anti-citrullinated protein antibody (ACPA) status. Obesity was associated with an increased risk of ACPA-negative RA in women, but decreases were seen in the risk of ACPA-positive RA in men.7
