Mechanistic, Epidemiologic Clues Suggest Possible Link Between Obesity, Inflammation in Rheumatoid Arthritis

Although no direct scientific evidence exists, both mechanistic and epidemiologic clues suggest a possible link between obesity and RA.
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Obesity has an established systemic inflammatory component. Could that be a trigger for the inflammation seen in rheumatoid arthritis (RA) and other rheumatic diseases? Although there is no direct scientific evidence, both mechanistic and epidemiologic clues do give some intriguing suggestions of a possible link.

“At first, we thought that fat was involved only in energy storage and helping insulate the body from cold,” says Michael B. Brenner, MD, chief of the Division of Rheumatology, Immunology and Allergy at Brigham and Women’s Hospital in Boston. “We now realize that there is an entire immune system within adipose tissue [AT] that switches from a Type 2 anti-inflammatory state to a pro-inflammatory state characterized by many of the same cytokines and cells that we see in RA.”

All Fat Not Created Equal

It has also been established that all fat is not created equal. Visceral fat has a larger number of leukocytes and a greater influence on systemic metabolism than subcutaneous fat.

The color is also important. White adipose tissue is a component of energy storage and insulation, and produces the adipocyte hormones, leptin and adiponectin. Brown fat produces heat and is a key regulator of basal metabolic rate and weight. Beige fat is induced by cold and exercise, and produces heat.

Good & Bad Cytokines & Immune Cells

In the lean state, Interleukin (IL) 4, IL-10 and IL-13 are the main cytokines produced. IL-4 and IL-13 drive M2 (alternatively activated) macrophages, and IL-10 does that in addition to blocking the effects of tumor necrosis factor (TNF) and Nuclear Factor kB (NF-kB), all of which inhibits inflammation. There are also higher levels of regulatory T cells (Tregs) in AT in the lean state.¹

In obesity, there is a completely different response, showing an increase in what Dr. Brenner calls “bad leukocytes.” At higher body mass index (BMI) levels, there is an up-regulation of M1 macrophages and various T cells that results in higher levels of TNFα, IL-1β, Interferon γ and lower levels of IL-10, IL-4 and IL-13. This mix tends to increase the level of inflammation and is responsible for insulin resistance.²

If you overeat, fat cells get very large, doubling in size when 10 lbs. are gained. Then they start to rupture, which releases material that is supposed to be intracellular into the fat tissue. This, in turn, triggers the macrophages to come in and clean up the debris.

“The macrophages begin to release the inflammatory cytokines and the T cells come in and make Interferon γ,” says Dr. Brenner. “Now, you have gone from the anti-inflammatory state with IL-4, IL-10 and IL-13 being predominant, to a more pro-inflammatory one with higher production of TNF and IL-1 and IL-6.”

Models for Possible Systemic Effects

For these factors to have any relevance in rheumatic disease, they must have a systemic effect outside of the fat cells themselves. It has been shown that elevated serum levels of these pro-inflammatory cytokines are seen in obese people. Although there is still little direct evidence for how obesity affects inflammatory illnesses, such as RA and others, mouse models strongly suggest that inflammation does have a role to play in type 2 diabetes and could be a general model for discussions in humans.

“Type 2 diabetes is not a disease in which there is too little insulin, but rather one of insulin resistance where there is interference with insulin-stimulated glucose entry into the cells,” says Dr. Brenner. “TNF, for example, interferes with insulin receptor signaling through inappropriate phosphorylation of one of its substrates.”

Similar Profiles

There are some interesting, if not yet proved, similarities between the cytokine profiles seen in insulin resistance and rheumatic diseases. In obesity, the M1 inflammatory macro­phage becomes the dominant cell of this type.³

“This is similar to what you see in the synovium in RA,” says Dr. Brenner. “You find these macrophages making TNF and IL-1, which leads to the activation of synovial fibroblasts. This results in the recruitment of leukocytes that drive a cycle of increased inflammation that activates fibroblasts and drives osteoclastogenesis. The same cytokines that drive insulin resistance in obesity are those that play a role in changes in the synovium, namely TNF, IL-β and IL-6.”

The lack of Tregs in obesity is another component of a possible link between RA and obesity. Tregs are important because they fulfill an anti-inflammatory role, stopping inflammation promoting cells from other T cells, B cells or macrophages.⁴

“In obesity, the Treg cells either decrease in number or functionality, which is also seen in RA,” says Dr. Brenner. “Down-regulation results in less suppression of inflammation. Your system not only steps on the gas, but also takes its foot off the brake.”

The cell types seen in insulin resistance from obesity in mice are basically the same in both insulin resistance and RA in humans and how they work in this context is well established. What is open to conjecture is whether this increase in pro-inflammatory cytokines in fat is the reason that we see higher levels of RA in those who are obese and why they have a harder time treating it.

How Does This Fit with RA?

The question then becomes how this might fit in with RA and other rheumatic diseases. Dr. Brenner thinks the higher levels of cytokines may serve to prime the synovium for inflammation or push the body over a minimum threshold that triggers the disease process. This might be an explanation for both the increasing incidence of RA being seen in younger patients and some less responsiveness to medications seen in some obese patients.

“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

There may also be an ACPA/BMI interaction at work in some cases. A recent study found a 20-fold increased RA risk for those with two or more ACPA antibodies on research assays and overweight/obese women compared with women with fewer than two ACPA antibodies and normal BMI in the Nurse’s Health Studies.⁸

“To me this indicates that perhaps men and women have different paths to RA in this framework,” he says. “ACPA status can define a phenotype that is more homogenous so it may be that the ACPA-negative aspect makes this a more malleable phenotype. Perhaps the obesity is driving RA risk for this subset instead of just being a bystander.”

Qin and colleagues completed a meta-analysis of 11 studies on the subject. Their results showed that the higher the BMI, the higher the relative risk of RA. Overall, there was a 31% increase in RA for those with obesity when compared to normal body mass index.⁹

“Something to consider when looking at these results is that these studies typically compare one BMI category to another,” Dr. Sparks says. “This implies that if someone lost weight and changed from the obese to normal category, their risk for RA would be reduced. However, few studies have actually evaluated whether weight change also affects RA risk.”

Food & Drink Intake

Food and drink intake are also linked to RA risk, according to the results of multiple studies. Increased sugar-sweetened soda intake was associated with RA, especially the older-onset, seropositive phenotype.¹⁰ On the other side, consuming one to three servings of fish per week showed a protective effect (relative risk ratio of 0.76) compared with less frequent intake.¹¹ Moderate alcohol intake also had a modest protective effect compared with infrequent drinking.¹²

Dr. Sparks and colleagues assessed the effect of healthful eating on RA risk using the Healthy Eating Index scale. Those who ate the healthiest had a significantly decreased risk for rheumatoid arthritis. The result was especially strong among those diagnosed with RA before 55 years of age.¹³

Studies of the Etiology of Rheumatoid Arthritis (SERA) findings from first-degree relatives of RA patients who were showing no signs of the disease did see an association of smoking and joint inflammation, but no association with BMI.¹⁴ This gives less clarity on the issue of when the obesity/RA hazard period begins.

Consistent Picture

“There is a very consistent picture developing whether you look at the animal studies, the molecular studies or the human studies for RA risk,” says Dr. Sparks. “We see the same cytokines and inflammatory cells in obesity studies that are also important in RA pathogenesis. In the epidemiologic results in the preclinical period, we are finding the observations we would expect from those molecular underpinnings.”

The discussion of RA pathogenesis is just the first part. Outcomes are also an important piece of the RA/obesity/inflammation puzzle.

Impact on RA Outcomes

“Investigating the effect of obesity on RA outcomes may not be as clean as preclinical pathogenesis because there are more confounding factors, such as medications, diet changes and changes in physical activity,” says Dr. Sparks. “But overall, most of the findings indicate that obesity is also important in patients with established RA.”

One of the more compelling indicators of the possible link between outcomes in RA and BMI is Dr. Sparks’ recent research into what happens to RA following extensive weight loss from bariatric surgery. They hypothesized that adiposity was driving RA activity and that it would improve following recovery.¹⁵

They found major positive outcomes among patients. C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) markers for inflammation were dramatically reduced from baseline (28.1 to 4.1 mg/L and 45.7 to 18.0 mm/hr, respectively) at the most recent follow-up. Following bariatric surgery, patients had significant improvements in RA disease activity and reductions in use of RA-related medications.

“What really hit home clinically from my perspective was the sheer number of RA patients in remission,” says Dr. Sparks. “Almost one in every four patients had no symptoms and were off all RA-related medications one year after bariatric surgery. That is almost unheard of among RA patients in any other setting.”

Another large study out of Sweden used the Disease Activity Scale 28 (DAS28) responses at two different time points. Increased BMI was associated with an increase in DAS28. In addition, obesity decreased the odds of being in remission. These were seen after adjusting for confounders such as steroid use, age, and gender.¹⁶

Dr. Sparks’ group performed a cross-sectional study of another cohort of RA patients using the Clinical Disease Activity Index (CDAI). Among those with normal BMI, only 30% were classified as having moderate or high disease activity. That flipped among obese patients with nearly 75% deemed to fit those two categories.¹⁷

However, increased BMI might paradoxically be protective for some long-term outcomes, particularly in joint damage and erosions in several studies according to Dr. Sparks. Even when stratified by ACPA status, the protective effect of obesity on radiographic damage remains.

“Currently, there are a lot of indicators both on the mechanistic and epidemiological side that give credence to the thought that obesity may have an impact on RA,” said Sparks. “However, at this time the best we can say is that it is an interesting, but fairly well supported, hypothesis. Further studies are needed to investigate the interesting and important interaction between obesity and RA.”

Kurt Ullman is a freelance writer based in Indiana.

References

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2. Ibid.
3. Schipper HS, Prakken B, Kalkhoven E, Boes M. Adipose tissue-resident immune cells: Key players in immunometabolism. Trends Endocrinol Metab. 2012 Aug;23(8):407–415.
4. Ibid.
5. Voigt LF, Koepsell TD, Nelson JL, et al. Smoking, obesity, alcohol consumption, and the risk of rheumatoid arthritis. Epidemiology. 1994 Sep;5(5):525–532.
6. Symmons DP, Bankhead CR, Harrison BJ, et al. Blood transfusion, smoking, and obesity as risk factors for the development of rheumatoid arthritis: Results from a primary care-based incident case-control study in Norfolk, England. Arthritis Rheum. 1997 Nov;40(11):1955–1961.
7. Wesley A, Bengtsson C, Elkan AC, et al. Association between body mass index and anti-citrullinated protein antibody-positive and anti-citrullinated protein antibody-negative rheumatoid arthritis: Results from a population-based case-control study. Arthritis Care Res (Hoboken). 2013 Jan;65(1):107–112.
8. Tedeschi SK, Cui J, Arkema EV, et al. Elevated BMI and ACPA interact to increase rheumatoid arthritis risk and shorten time to diagnosis: A nested case-control study of women in the Nurses’ Health Study. Semin Arthritis Rheum. 2016 (In Press).
9. Qin B, Yang M, Fu H, et al. Body mass index and the risk of rheumatoid arthritis: A systematic review and dose-response meta-analysis. Arthritis Res Ther. 2015 Mar 29;17:86.
10. Hu Y, Costenbader KH, Gao X, et al. Sugar-sweetened soda consumption and risk of developing rheumatoid arthritis in women. Am J Clin Nutr. 2014 Sep;100(3):959–967.
11. Di Giuseppe D, Crippa A, Orsini N, Wolk A. Fish consumption and risk of rheumatoid arthritis: a dose-response meta-analysis. Arthritis Res Ther. 2014 Sep 30;16(5):446.
12. Lu B, Solomon DH, Costenbader KH, Karlson EW. Alcohol consumption and risk of incident rheumatoid arthritis in women: A prospective study. Arthritis Rheumatol. 2014 Aug;66(8):1998–2005.
13. Sparks JA, Iversen MD, Miller Kroouze R, et. al. Personalized risk estimator for rheumatoid arthritis (PRE-RA) family study: Rationale and design for a randomized controlled trial evaluating rheumatoid arthritis risk education to first-degree relatives. Contemp Clin Trials. 2014 Sep;39(1):145–157.
14. Hu Y, Sparks JA, Costenbader KH, et al. Adherence to the dietary guidelines for Americans and risk of developing rheumatoid arthritis in young and middle-aged women [abstract]. Arthritis Rheumatol. 2015;67(suppl 10).
15. Sparks JA, Halperin F, Karlson JC, et al. Impact of bariatric surgery on patients with rheumatoid arthritis. Arthritis Care Res (Hoboken). 2015 Dec;67(12):1619–1626.
16. Ajeganova S, Andersson ML, Hafström I, et al. Association of obesity with worse disease severity in rheumatoid arthritis as well as with comorbidities: A long-term followup from disease onset. Arthritis Care Res (Hoboken). 2013 Jan;65(1):78–87.
17. Sparks JA, Olson AT, Halperin F, et al. Association of obesity with increased rheumatoid arthritis disease activity. Cardiovascular, Diabetes & Metabolic Disorders Research Center, Brigham Research Institute. Obesity Incubator Session, Boston, March 2016.