Hormones, Signaling Proteins in SSc Altered With BMI, Analysis Finds

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by Steve Bryson, PhD |

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Altered levels of immune signaling proteins (cytokines) and fat-based hormones in systemic sclerosis (SSc) are associated with changes in body mass, a blood analysis determined.

Researchers say their findings suggest that “an abnormal twist … takes place in SSc” between the immune signaling proteins, these hormones, and body mass index or BMI, a measure of body fat based on height and weight.

“Further investigation is warranted to establish whether these findings may represent the pathogenetic [disease-related] background of specific clinical manifestations of SSc,” the researchers wrote.

The analysis was published in the journal Clinical & Experimental Immunology, in a study titled “Body mass index and adipokines/cytokines dysregulation in systemic sclerosis.”

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SSc, also called scleroderma, is a chronic disease that impacts skin and connective tissue. Although the underlying cause is unclear, mistaken immune attacks on healthy tissue and abnormal inflammatory responses are thought to drive the early stages of the disease.

Adipose (fat) tissue is known to store energy, but emerging evidence suggests it also has hormonal functions, and roles regulating immune and inflammatory responses.

These functions are controlled by the production of immune signaling proteins called cytokines as well as adipokines, which are involved in appetite, sugar and fat metabolism, blood pressure regulation, and inflammation and immune functions.

Adipokines also have been associated with changes in BMI and may impact SSc disease activity. However, the interplay between cytokines and adipokines, body mass, and clinical characteristics of SSc has not been thoroughly investigated.

Now, researchers based at the University of Bari, in Italy, measured the levels of cytokines and adipokines in the bloodstream of people with SSc and correlated them with BMI and disease characteristics.

The study included 89 SSc patients, with a mean age of 52.1, of whom 84 (94%) were women. The mean disease duration was 8.1 years, and most (83%) had limited cutaneous SSc. Active disease was seen in 27%, as measured by an ESSG (European Scleroderma Study Group) score of 3 or greater.

Five participants (6%) were considered obese, with a BMI of 30 or greater, while nine (10%) were underweight, defined by a BMI of 18.5 or less. A group of 26 healthy blood donors without disease or medication use was selected as a control group.

The analysis of blood samples found significantly elevated levels of two adipokines — leptin and resistin — in SSc patients compared with controls. Another adipokine called visfatin also was found at higher levels in those with SSc, but the difference was not statistically significant. Additionally, SSc patients had significantly higher levels of immune signaling proteins called TNF-alpha and interleukin-2 than did controls.

“These findings are globally consistent with the literature reporting an increase in cytokines/adipokines in SSc to different extents,” the team wrote. “We may speculate that the leptin increase in SSc might be due to some adipocyte [fat cell] dysfunction rather than to an over-production by visceral [organ] fat, or arises from different cellular sources.”

The use of a class of blood vessel widening medications called PDE5 inhibitors — commonly used in pulmonary hypertension — was independently associated with more than threefold higher levels of leptin and more than twofold higher visfatin.

However, this association may have been influenced by those with pulmonary arterial hypertension (PAH), the scientists said. This disease often coexists with SSc and is characterized by high blood pressure in the arteries that supply the lungs. Here, leptin and resistin levels were significantly higher in those with both SSc and PAH than in no-PAH with SSc.

In addition, leptin levels were significantly higher in SSc patients with interstitial lung disease (ILD), a group of disorders marked by scarring in the lungs. Also, cytokine interleukin-17 was found to be significantly elevated among participants with limited cutaneous SSc as compared with those with diffuse cutaneous SSc, which increases the risk of damage to internal organs.

Disease duration did not affect cytokine and adipokine levels, nor did the presence of sores in the fingers or toes (digital ulcers), lung function tests, or ESSG disease activity.

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Patients with a normal BMI (less than 25) had higher levels of leptin, resistin and the cytokine IFN-gamma compared with controls. For overweight or obese patients — those with a BMI of 25 or greater — only resistin was significantly higher. Leptin levels also were elevated, but the difference was not significant.

SSc participants were then further subdivided into BMI categories. Expectedly, leptin and visfatin levels were significantly higher among obese patients than in those in other BMI categories, but not for resistin. Obese patients also had the highest levels of the cytokine interleukin-17A.

Although another adipokine called adiponectin was not significantly different among the BMI subgroups, the ratio of leptin to adiponectin, a biomarker of adipose tissue inflammation, was significantly higher in obese patients. In underweight SSc individuals, levels of TNF-alpha were significantly elevated compared with other BMI categories.

Finally, increasing BMI was associated with higher interleukin-17A, leptin, and visfatin levels, and with lower TNF-alpha. BMI also was associated with erythrocyte sedimentation rate and C-reactive protein, both measures of inflammation, and with triglyceride fats and cholesterol levels.

“This study suggests that an abnormal twist between cytokines, adipokines and BMI takes place in SSc,” the scientists concluded. “These changes in adipokines may be related to a disfunction of adipocytes or other, different, sources, as SSc patients with PAH or ILD showed high leptin levels.”