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