Discussion
In this study, we investigated the serum levels of different adipokines (adiponectin, leptin, resistin, visfatin) and cytokines (TNFα, INF, IL-12, IL-10, IL-17A) in SSc patients and searched for possible correlations with BMI and specific clinical manifestations of the disease. TNFα, IL-2, leptin and resistin were higher in SSc patients than in HD. These findings are globally consistent with the literature reporting an increase in cytokines/adipokines in SSc to different extents (4,8,9,16-24). However, attempts to correlate each cytokine/adipokine to the disease activity of SSc and to BMI have yielded conflicting results. All the studies but one (25) showed increased serum levels of leptin in SSc, sometimes correlating with BMI. We found significantly higher leptin levels in SSc than HD and a positive correlation of leptin with BMI, but no correlations with PHA or other clinical manifestations were detected. Instead, a previous study had demonstrated that leptin serum levels were higher in idiopathic PHA and SSc-PAH patients than controls and that dysfunctional endothelial cells from SSC-PAH lung produced leptin “in vitro ”, although a link with BMI was not investigated (26). Furthermore, we detected significantly higher resistin in SSc patients than in HD, but it was not regulated by BMI, as already reported (6). On the contrary, we found that visfatin levels rose with BMI increases in SSc patients but they were still statistically comparable to HD. Masui et al (22) had detected similar levels of visfatin in SSc patients and controls, but noticed higher visfatin levels in dsSSc patients with late disease, without exploring BMI status. This general inconsistency may be also influenced by treatments, as we found that SSc patients taking PDE5i (tadalafil or sildefanil) but not bosentan, had significantly higher leptin and visfatin levels than patients without PDE5i. Furthermore, SSc-PDE5i patients had 2-3 folds the odds to have high leptin and visfatin levels. It is conceivable that this might be a specific PDE5i effect, rather than related to PAH, as adipokines secretion by white adipocytes is regulated by cAMP and increases upon PDE inhibition “in vitro” (27).
Adiponectin can generally be accounted as leptin antagonist with anti-inflammatory properties and decreases in obesity (28). Adiponectin has also been suggested to have also anti-fibrotic activities and seems to be regulated in SSc, depending on the skin fibrosis extension and disease duration. Some studies demonstrated that adiponectin is low in dcSSc patients both in serum and in lesional skin, but increases in dcSSc patients with a disease duration longer than 5 years, when skin thickness reduces (9,20,21,29). We found low, although not statistically significantly low levels of adiponectin in obese SSc, but we could not confirm previous data as we studied only 15 patients with dcSSc. Interestingly, the ratio leptin/adiponectin was 10-fold higher in obese SSc patients suggesting that the reciprocal leptin/adiponectin regulation is functionally unbalanced in SSc. At this point, a critical question to be addressed is “why is leptin increased in SSc patients as their BMI was lower than in HD”? Indeed, no study has ever demonstrated an increased frequency of obesity among SSc patients. In our cohort, only 6% had a BMI >30 compared to 12.3% of the general population in Apulia (ISTAT, report Osservasalute 2016 ) implying that leptin overexpression in SSc might be due to some adipocyte dysfunction rather than to an increase production by visceral fat.
Among the investigated cytokines, we found significantly higher levels of TNFα and IL-2 in SSc as compared to HD, presumably linked to the biologic activity of the disease, despite no correlation with the clinical manifestations nor with the global disease activity was found. Within the SSc cohort, obese patients had significantly higher levels of IL-17A and IL-10. A correlation between IL-17A and obesity was expected as high IL-17 mRNA expression has been found in visceral fat of morbidly obese women (30). On the other hand, the significantly higher IL-10 levels in SSc obese patients were unexpected, as in obese subjects IL-10 tends to be low and increases with exercise and weight loss (31). Maybe the most intriguing finding in our analysis was the strikingly high levels of TNFα in underweight SSc patients, roughly 10-folds higher than in normal-weight patients. Increased levels of TNFα in SSc had already been reported (6,18,19,32) although a link with a particular phenotype was not shown. Only one study had demonstrated a correlation of TNFα levels with lung fibrosis and impairment of pulmonary vital capacity (32). Of note, TNFα blocking agents have been successfully used in SSc patients with arthritis (33) and further investigations should focus on this possible pathogenic association. In our study, 10% of SSc patients were underweight, and loss of body mass has been associated mainly with malabsorption (34). Besides, an overexpression of TNF may also be considered as a further mechanism involved in the chachexia-like status of SSc. During the 1980s, that TNFα and cachectin were demonstrated to be the two faces of the same coin (35). In an experimental model, TNFα induced weight loss directly proportional to the decreased food and water intake (36). Moreover, it is known that anti-TNFα drugs may increase body weight and it has been reported that etanercept treatment promoted weight gain and reduced chachexia in patients with rheumatoid arthritis (37).
In conclusion, despite some limitations, such as the cross-sectional design, drug interference, mainly PDE5i, the relatively small sample size of our SSc cohort, this study suggests that an abnormal twist between cytokines, adipokines and BMI takes place in SSc, and these changes in adipokines maybe related to a disfunction of adipocytes (or of other different sources) rather than to the BMI. Further investigation is warranted to establish whether these findings may represent the pathogenetic background of specific clinical manifestations of SSc.
Authors’ contributions
FI and EP conceived the study, were the major participants in its design, coordination, interpretation of results and statistical analysis, they also prepared draft manuscript. DN, RB and NL carried out biological assays, RC, MF and FC collected clinical data and participated in study design coordination. All authors were involved in draft manuscript modifications and approved the final version of the manuscript.
Conflicts of interest: The authors declare no conflict of interest
Data availability statement: Data available on request due to privacy/ethical restrictions.
Funding statement: None