Obesity Causes Rheumatoid Arthritis to Develop Earlier, Delays Treatment Effect in Mice

Obesity Causes Rheumatoid Arthritis to Develop Earlier, Delays Treatment Effect in Mice

New research in mice shows that obesity causes rheumatoid arthritis (RA) to develop earlier, and may play a role in slowing the effect of anti-TNF-alpha antibody drugs, the current standard medication for treating the disease.

The study reporting the findings, “Differential impact of obesity on the pathogenesis of RA or preclinical models is contingent on the disease status,” was published in the journal Annals of the Rheumatic Diseases.

RA is a chronic, progressive autoimmune disease causing inflammation in the joints and resulting in painful deformity and immobility, especially in the fingers, wrists, feet and ankles. Epidemiological studies have demonstrated an increased incidence of RA among obese individuals. In addition, obesity has been associated with elevated disease severity and inferior response to treatment in some clinical studies.

In this new study, researchers at the University of Illinois at Chicago College of Medicine conducted experiments in mice to analyze the significance of obesity in RA. The team found that obese mice displayed signs of RA sooner than mice with normal weight.

“Onset was about two days earlier in obese mice compared to normal-weight mice after induction of arthritis,” said Shiva Shahrara, senior author of the study, in a press release.

When researchers examined the fat from mice’s ankle joints, they found that early arthritis triggered by obesity was caused by an elevated amount of a pro-inflammatory factor known as MIP2. Obese mice had about two times more MIP2 than mice with normal weight. However, after about seven days, the severity of RA was the same for obese and normal-weight mice.

MIP2 attracts neutrophils (white blood cells) to the joints. During the onset of RA, neutrophils are the first cells of the immune system to migrate into the joints. Shahrara and colleagues found that the fat tissue from the joints of humans with RA had the same elevated levels of IL-8, the human version of MIP2.

“Once the neutrophil phase passed and the disease set in, it looked the same in terms of joints swelling in the obese and normal-weight mice,” Shahrara said.

The team then looked to an acute mouse model, in which the time between onset and resolution of RA is about 72 hours. Compared to obese mice, the researchers found that joint swelling went down more quickly in mice with normal weight. Looking at the joints’ tissues, the researchers noticed that, compared to normal-weight mice, obese mice had higher levels of macrophages, an immune cell linked with RA. As the disease progressed, the levels of macrophages lowered more slowly in obese mice.

As Shahrara noted, the higher level of macrophages in the joints of obese mice offer a clue as to why RA anti-TNF-alpha antibody drugs (e.g., Remicade (infliximab) and Humira (adalimumab)) work much more slowly in people with obesity than normal-weight people.

“I see this all the time in the clinic — my heavier patients take a lot longer to get relief from the medications we prescribe,” Shahrara said. “If obese patients have more macrophages in their joints to begin with, like we saw in our mice in this study, it would make sense that anti-TNF-alpha antibody takes longer to work, since it works by reducing the numbers of macrophages in the joints,” she said.

The researchers believe that obesity sustains RA by up-regulating the production of a molecule that binds to TLR4, a toll-like receptor protein responsible for activating the innate immune system. When this molecule binds to TLR4 in the joint, it induces the transformation of immune cells into pro-inflammatory macrophages — the cells that sustain RA.

“Since we saw that the TLR4-binding molecule is found in higher levels in the adipose tissue of obese mice, then if fat is a kind of reservoir for this molecule, then that could be the mechanism by which fat causes rheumatoid arthritis to be more resistant to drug treatment in heavier people,” Shahrara concluded.

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