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\begin{document}

\title{Body mass index and adipokines/cytokines dysregulation in Systemic
Sclerosis}



\author[1]{F Iannone}%
\author[1]{Emanuela Praino}%
\author[1]{Cinzia Rotondo}%
\author[2]{Dorotea Natuzzi}%
\author[2]{Rita Bizzoca}%
\author[2]{Nunzia Lacarpia}%
\author[1]{Marco Fornaro}%
\author[2]{Fabio Cacciapaglia}%
\affil[1]{Rheumatology Unit}%
\affil[2]{Rheumatolgy Unit}%


\vspace{-1em}



  
  \date{May 04, 2024}


\begingroup
\let\center\flushleft
\let\endcenter\endflushleft
\maketitle
\endgroup





\selectlanguage{english}
\begin{abstract}
Body fat has regulatory functions through producing cytokines and
adipokines whose role in the pathogenesis of Systemic Sclerosis (SSc) is
currently emerging. Changes in body mass, either overweight or
underweight status, entail a dysregulation of the cytokines/adipokines
network that may impact on SSc disease activity. We evaluated serum
levels of adipokines and cytokines in SSc patients and correlated them
to clinical features and body mass index (BMI) categories. The study
included 89 SSc patients and 26 healthy donors (HD). Serum levels of
adiponectin, leptin, resistin, visfatin, TNF\selectlanguage{greek}α, \selectlanguage{english}IFN\selectlanguage{greek}γ, \selectlanguage{english}IL-2, IL-10, and
IL-17A were measured by Multiplex Immunoassay, and correlated to BMI,
waist to hip ratio, and disease specific features. Mann-Whitney U-test
or t-Student for unpaired data, Kruskal-Wallis test or ANOVA, were used
for comparisons between groups. Spearman's or Pearson's test were used
for correlation analysis. Serum levels of TNF\selectlanguage{greek}α, \selectlanguage{english}IL-2, leptin, and
resistin, were significantly higher in SSc than in HD. The highest
levels of IL-17A, IL-2, IL-10, leptin and visfatin were detected in
obese SSc patients (p \textless{}0.01). Conversely, underweight SSc
patients showed the highest TNF\selectlanguage{greek}α \selectlanguage{english}levels (p\textless{}0.05), which were
negatively correlated with BMI (p=0.05). No correlation between
adipokines/cytokines and clinical characteristics was found. Adipokines,
IL-2, IL-10 and IL-17A were found to be increased in obese SSc patients,
but whether they play a role in the pathogenesis of the disease remains
to be investigated. Intriguingly, underweight patients had higher TNF\selectlanguage{greek}α
\selectlanguage{english}levels, suggesting a potential role of TNF\selectlanguage{greek}α \selectlanguage{english}in inducing the cachexia
observed in long-lasting disease.%
\end{abstract}%



\sloppy


\textbf{Title: Body mass index and adipokines/cytokines dysregulation in
Systemic Sclerosis}

\textbf{Running Title: Systemic sclerosis, adipokines and BMI}

Florenzo Iannone*, Emanuela Praino*, Cinzia Rotondo, Dorotea Natuzzi,
Rita Bizzoca, Nunzia Lacarpia, Fabio Cacciapaglia.

*These authors equally contributed to this work

\textsuperscript{1}Rheumatology Unit, Department of Emergency and
Transplantation, University of Bari, Bari Italy

\textsuperscript{2}Department of medical and surgical sciences -
Rheumatology Unit, University of Foggia, Italy

\textsuperscript{1}Florenzo Iannone

Full Professor of Rheumatology, MD, PhD florenzo.iannone@uniba.it

\textsuperscript{1}Emanuela Praino

Research Assistant, MD emanuelapraino@yahoo.it

\textsuperscript{2}Rotondo Cinzia

Research Assistant, MD cinzia.rotondo@gmail.com

\textsuperscript{1}Dorotea Natuzzi

Biologist, BD dorotea.natuzzi@uniba.it

\textsuperscript{1}Rita Bizzoca

Biologist, BD rita.bizzoca@uniba.it

\textsuperscript{1}Nunzia Lacarpia

Biologist, BD\emph{nunzia.lacarpia@uniba.it}

\textsuperscript{1}Marco Fornaro

Research Assistant, MD marco3987@hotmail.it

\textsuperscript{1}Fabio Cacciapaglia

Lecturer, MD, PhD fabio.cacciapaglia79@gmail.com

Corresponding author: Florenzo Iannone, MD, PhD, Full Professor of
Rheumatology

Rheumatology Unit, Department of Emergency and Transplantation,
Policlinico, Piazza G. Cesare 11, 70124 Bari, Italy.
E-mail:\emph{florenzo.iannone@uniba.it}

Key words: Visfatin, Leptin, Adiponectin, body weight

Competing interest: none

Funding: the study had no financial support.

Number of words:

\textbf{ABSTRACT}

Body fat has regulatory functions through producing cytokines and
adipokines whose role in the pathogenesis of Systemic Sclerosis (SSc) is
currently emerging. Changes in body mass, either overweight or
underweight status, entail a dysregulation of the cytokines/adipokines
network that may impact on SSc disease activity. We evaluated serum
levels of adipokines and cytokines in SSc patients and correlated them
to clinical features and body mass index (BMI) categories.

The study included 89 SSc patients and 26 healthy donors (HD). Serum
levels of adiponectin, leptin, resistin, visfatin, TNF\selectlanguage{greek}α, \selectlanguage{english}IFN\selectlanguage{greek}γ, \selectlanguage{english}IL-2,
IL-10, and IL-17A were measured by Multiplex Immunoassay, and correlated
to BMI, waist to hip ratio, and disease specific features. Mann-Whitney
U-test or t-Student for unpaired data, Kruskal-Wallis test or ANOVA,
were used for comparisons between groups. Spearman's or Pearson's test
were used for correlation analysis.

Serum levels of TNF\selectlanguage{greek}α, \selectlanguage{english}IL-2, leptin, and resistin, were significantly
higher in SSc than in HD. The highest levels of IL-17A, IL-2, IL-10,
leptin and visfatin were detected in obese SSc patients (\emph{p
\textless{}0.01} ). Conversely, underweight SSc patients showed the
highest TNF\selectlanguage{greek}α \selectlanguage{english}levels (\emph{p\textless{}0.05} ), which were negatively
correlated with BMI (\emph{p=0.05} ). No correlation between
adipokines/cytokines and clinical characteristics was found.

Adipokines, IL-2, IL-10 and IL-17A were found to be increased in obese
SSc patients, but whether they play a role in the pathogenesis of the
disease remains to be investigated. Intriguingly, underweight patients
had higher TNF\selectlanguage{greek}α \selectlanguage{english}levels, suggesting a potential role of TNF\selectlanguage{greek}α \selectlanguage{english}in inducing
the cachexia observed in long-lasting disease.

\textbf{Introduction}

Systemic sclerosis (SSc) is a connective tissue disease characterized by
small vessels vasculopathy associated with fibrosis of multiple organs.
The pathogenesis is unclear, but an autoimmune dysregulation and an
abnormal inflammatory response seem to be involved in the early stage of
the disease. Emerging evidence suggests that white adipose tissue (WAT),
besides having the role of energy storage, is now acknowledged as a
pleiotropic organ with endocrine functions and regulating immune and
inflammatory responses, being a source of cytokines and adipokines
(leptin, adiponectin, visfatin, resistin) (1). Indeed, obesity may have
an impact on disease activity as well as on clinical response of
patients with rheumatoid arthritis and psoriatic arthritis (2,3). In
obese subjects, leptin induces the expression of adhesion molecules on
endothelial cells and activates macrophages, while hindering adiponectin
production by adipocytes, contributing to the ``low-grade inflammatory
state'' associated with obesity (1).

Recently, the role of cytokines/adipokines in the pathophysiology of SSc
has become a matter of investigation but studies correlating them with
the clinical subsets or particular organ involvement were not always
consistent. Serum leptin levels were found to be positively correlated
with body mass index (BMI), negatively with disease activity in SSc
patients, but not increased in comparison with healthy controls (4,5).
Conversely, serum levels of leptin, resistin and TNF\selectlanguage{greek}α \selectlanguage{english}were higher in a
small cohort of 16 SSc patients than in control subjects but no
correlation with skin involvement, disease duration and disease activity
was seen (6). A newly discovered adipokine, adipsin, was significantly
higher in limited cutaneous SSc (lcSSc) than in diffuse cutaneous SSc
(dcSSc) and was strongly associated with pulmonary arterial hypertension
(7). Interestingly, adiponectin seems to play a protective role in SSc,
as the levels were found to be low in dcSSc patients and inversely
correlated with the extension of skin fibrosis, C-reactive protein (CRP)
and erythrocyte sedimentation rate (ESR) (5,8-10). However, the
interweave among body mass, cytokines/adipokines and SSc clinical
phenotypes has been poorly investigated.

In this study, we aimed at evaluating serum levels of adipokines
(leptin, resistin, visfatin, adiponectin) and cytokines (TNF\selectlanguage{greek}α,
\selectlanguage{english}Interferon-gamma (IFN\selectlanguage{greek}γ\selectlanguage{english}), IL-2, IL-10, IL-17A) in SSc patients according
to BMI categories and disease specific characteristics.

\textbf{Materials \& Methods}

\textbf{Ethical approval}

The study obtained the approval of the local ethics committee (Azienda
Policlinico Bari, n.5351 14/09/2017). The study was conducted in
compliance with the Helsinki's declaration, and all patients gave their
written informed consent to participate and for use of their data for
publication, with explicit protection of their identity

\textbf{Patient group}

We evaluated 89 Caucasian patients with Systemic Sclerosis (SSc)
fulfilling the 2013 ACR/ EULAR classification criteria (11) and 26
healthy blood donors (HD) as control group, including subjects not
suffering from any disease and not taking medications at enrolment.

\textbf{Cytokine assay}

Blood samples obtained from all participants were centrifuged and serum
was separated and stored in aliquots at \selectlanguage{ngerman}\emph{-80 °C} until use. Serum
levels of adipokines (adiponectin, leptin, resistin, visfatin) and
cytokines (TNF\selectlanguage{greek}α, \selectlanguage{english}IFN\selectlanguage{greek}γ, \selectlanguage{english}IL-2, IL-10, IL-17A) were measured, in duplicate,
using kits manufactured by Bio-Rad (Bioplex ProTM Cytokine / Chemokine
and Growth Factor Assay and Bioplex Pro Diabetes Assay) for Multiplex
Immunoassay (Bioplex 200 System by Bio-Rad Laboratories, Hercules (CA,
USA). The analyses were carried out according to the manufacturer's
instructions.

\textbf{Clinical data}

In all patients we collected clinical, anthropometric and laboratory
features, including disease duration, onset of Raynaud's phenomenon,
skin involvement according to the modified Rodnan Skin Score (mRSS) (12)
and cutaneous subset according to LeRoy criteria (13). Moreover, the
presence/absence of interstitial lung disease (ILD) defined by chest
HR-CT scan, pulmonary function test (PFT) with FVC, FEV1/FVC, DLCO and
RV estimation, the 6-minute walking distance test (6mWDT), the
presence/absence of pulmonary arterial hypertension (PAH) diagnosed by
right heart catheterization, the presence/absence of esophagopathy
evaluated at esophageal scintigraphy or esophageal manometry or chest
HR-CT scan, the presence of digital pitting-scars and/or digital ulcers
(past or active), the nailfold capillaroscopic pattern ''Early'',
''Active'' and ''Late'' (14), the disease activity according to the ESSG
(European Scleroderma Study Group) disease activity index (15), were
recorded. Drugs investigated were: peripheral vasodilators, iloprost,
immunosuppressive drugs, glucocorticoids, antihypertensive and
lipid-lowering agents, targeted therapy for the treatment of PAH
(bosentan, sildenafil, tadalafil, ambrisentan), oxygen therapy. The BMI,
waist circumference (Waist C) and Waist-to-Hip Ratio (WHR),
cardiovascular risk index, acute phase proteins, cholesterol and
triglycerides serum levels, previous smoking status, comorbidity (such
as arterial hypertension, diabetes mellitus and hyperlipidemia) were
also assessed. The BMI was calculated as weight in kilograms divided by
the height in square meters and in accordance with the WHO BMI category
classification, patients were considered underweight (BMI
\textless{}18.5), normal-weight (BMI= 18.5-24.99), overweight (BMI=
25-29.99) and obese ([?]30). The cardiovascular (CV) risk was estimated as
the ratio of total cholesterol/high-density-lipoprotein (HDL), or
applying the Framingham Risk Score (FRS).

\textbf{Statistical Analysis}

Data were analyzed using IBM-SPSS Statistics 20 software. The comparison
between two groups were done by Mann-Whitney U-test or t-Student, or
chi-square test where appropriate. Comparisons among several groups were
made using Kruskal-Wallis test or ANOVA, as appropriate. Spearman's or
Pearson's test were used for correlations between cytokine/adipokines
and clinical characteristics. Multiple linear regressions were performed
for the analysis of predictors. A \emph{p-value [?] 0.05} was considered
statistically significant.

\textbf{Results}

\textbf{Patient characteristics}

Clinical characteristics of SSs patients are shown in Table 1. Most
patients had limited cutaneous SSc (83\%), and 27\% had active disease
([?] 3 ESSG score). Of note, only 5 (6\%) patients were obese (BMI [?] 30),
while 9 (10\%) were underweight (BMI [?] 18.5). At study entry, drugs
taken were: calcium channel blockers (CCB) (67.4\%), iloprost (48.3\%)
glucocorticoids (34.8\%), endothelin receptor antagonists (ERA)
(22.3\%), methotrexate (19.5\%), mycophenolate mofetil (13.5\%),
phosphodiesterase-5 inhibitors (PDE5i) (tadalafil, sildefanil) (8.9\%).
No patient was taking non-steroidal anti-inflammatory drugs. In Table 2,
the comparison of demographics, anthropometric characteristics, and
serum levels of cytokines and adipokines between SSc and HD are shown.
No significant differences in anthropometric characteristics were
detected, but a trend toward a lower BMI was seen in SSc patients.

\textbf{Adipokines and Cytokines}

Table 2 shows the comparison of cytokines and adipokines between HD and
the whole SSc cohort. Leptin and resistin were significantly higher in
SSc than in HD. Visfatin was also increased in SSc, but the difference
from HD did not reach the statistically significance. Adiponectin was
measured only in the SSc group (see below). Remarkably, SSc patients
showed significantly higher levels of TNF\selectlanguage{greek}α \selectlanguage{english}and IL-2 than HD. Because of
a possible bias by drugs, serum levels of cytokines and adipokines were
correlated to the different treatments by multiple linear regression
models. To this end, patients were grouped into SSc-glucocorticoids,
SSc-ERA, SSc-immunosuppressants, SSc-CCB, SSc-iloprost, SSc-PDE5i. Only
PDE5 inhibitors were independently associated with higher levels of
leptin (OR 3.27, 95\% CI 12892-52716, p=0.002) and visfatin (OR 2.66,
95\% CI 4340-29950, p=0.009). Therefore, SSc patients were stratified
into those taking PDE5i and those who did not, and compared by cytokines
and adipokines levels (Table 2). Although only 8 SSc patients were on
treatment with PDE5i, their levels of leptin and visfatin were
significantly higher than in SSc patients without PDE5i (Table 2), while
no difference was detected of the remaining cytokines.

No statistically significant difference in cytokines/adipokines levels
between early SSc (\textless{}2 years of disease duration) and late
disease (\textgreater{}2 years of disease duration) was observed. We
also stratified SSc patients as high and low CV risk according to the
Framingham score and other indices (cholesterol /HDL ratio
\textgreater{}4.5, waist circumference \textgreater{}88 cm, WHR
\textgreater{}0.8). As only 3 patients had high/medium CV FRS,
statistical comparison with those showing low risk CV FRS could not be
made (data not shown). Furthermore, no significant differences were
found when patients were stratified according to DLCO \textless{}75\%
or FVC \textless{}70\% values, or the disease activity index ESSG
\textless{} 3. Likewise, no peculiar pattern of cytokines/adipokines was
found in lcSSc or dcSSc subsets.

\textbf{BMI categories}

When SSc patients were subdivided by BMI categories, some meaningful
differences emerged (Table 3). As expected, leptin (Figure 1) and
visfatin levels were significantly higher in obese than in other BMI
classes (\emph{p=0.0001} and \emph{p=0.002} , respectively), while no
significant changes were observed for resistin. Obese SSc patients also
had the highest serum levels of IL-17A (\emph{p=0.01} ), IL-2
(\emph{p=0.001} ) and IL-10 (\emph{p=0.01} ). Adiponectin levels did not
significantly change among the BMI subgroups, but the leptin/adiponectin
ratio, a functional biomarker of adipose tissue inflammation, was
significantly higher in obese patients (\emph{p=0.0001} ). A striking
finding was the increased TNF\selectlanguage{greek}α \selectlanguage{english}levels observed in underweight SSc
patients. The latter had significantly higher TNF\selectlanguage{greek}α \selectlanguage{english}levels (\emph{p=0.01}
) than the other BMI classes (Table 3, Figure 2). IL-17A, leptin, and
visfatin levels were found to be positively correlated, and TNF\selectlanguage{greek}α
\selectlanguage{english}negatively, with increasing BMI values (table 4). BMI was also
correlated with ESR, CRP, triglycerides and cholesterol levels (Table
4).

\textbf{Discussion}

In this study, we investigated the serum levels of different adipokines
(adiponectin, leptin, resistin, visfatin) and cytokines (TNF\selectlanguage{greek}α, \selectlanguage{english}INF,
IL-12, IL-10, IL-17A) in SSc patients and searched for possible
correlations with BMI and specific clinical manifestations of the
disease. TNF\selectlanguage{greek}α, \selectlanguage{english}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 ``\emph{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 \textgreater{}30 compared to 12.3\% of the general
population in Apulia (\emph{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 TNF\selectlanguage{greek}α \selectlanguage{english}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 TNF\selectlanguage{greek}α \selectlanguage{english}in underweight SSc patients, roughly 10-folds higher than
in normal-weight patients. Increased levels of TNF\selectlanguage{greek}α \selectlanguage{english}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 TNF\selectlanguage{greek}α
\selectlanguage{english}levels with lung fibrosis and impairment of pulmonary vital capacity
(32). Of note, TNF\selectlanguage{greek}α \selectlanguage{english}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 TNF\selectlanguage{greek}α \selectlanguage{english}and cachectin were demonstrated to
be the two faces of the same coin (35). In an experimental model, TNF\selectlanguage{greek}α
\selectlanguage{english}induced weight loss directly proportional to the decreased food and
water intake (36). Moreover, it is known that anti-TNF\selectlanguage{greek}α \selectlanguage{english}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.

\textbf{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.

\textbf{Conflicts of interest:} The authors declare no conflict of
interest

\textbf{Data availability statement:} Data available on request due to
privacy/ethical restrictions.

\textbf{Funding statement:} None

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10. \selectlanguage{polish}Ż\selectlanguage{ngerman}ó\selectlanguage{polish}ł\selectlanguage{english}kiewicz J, Stochmal A, Rudnicka L. Arch Dermatol Res The role of
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13. LeRoy EC, Medsger TA. J Rheumatol Criteria for the classification of
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14. Cutolo M, Matucci Cerinic M. Clin Exp Rheumatol Nailfold
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15. Valentini G, Della Rossa A, Bombardieri S, Bencivelli W, Silman AJ,
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19. Hasegawa M, Fujimoto M, Matsushita T, Hamaguchi Y, Takehara K, Sato
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21. Lakota K, Wei J, Carns M, Hinchcliff M, Lee J, Whitfield ML,\emph{et
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Table 1. Clinical findings of Systemic Sclerosis (SSc) cohort (n. 89
patients).\selectlanguage{english}
\begin{longtable}[]{@{}ll@{}}
\toprule
Disease duration (years), mean\selectlanguage{ngerman}±SD & 8.1 \selectlanguage{ngerman}±6.6\tabularnewline
\midrule
\endhead
Underweight (BMI \selectlanguage{english}[?]18.5), n. (\%) & 9 (10 \%)\tabularnewline
Normal weight (BMI \textgreater{}8.5 \textless{}25), n. (\%) & 49 (55
\%)\tabularnewline
Overweight (BMI [?]25 [?]30), n. (\%) & 26 (29 \%)\tabularnewline
Obese (BMI \textgreater{}30), n. (\%) & 5 (6 \%)\tabularnewline
Diabetes Mellitus, n. (\%) & 1 (9 \%)\tabularnewline
Dyslipidemia, n. (\%) & 11 (12 \%)\tabularnewline
Tot-Cholesterol/HDL, mean \selectlanguage{ngerman}±SD & 3.3 \selectlanguage{ngerman}±1.0\tabularnewline
Framingham risk score, mean ±SD & 3.7 \selectlanguage{ngerman}±2.9\tabularnewline
Previous smokers, n (\%) & 5 (6 \%)\tabularnewline
Arterial Hypertension, n (\%) & 8 (7 \%)\tabularnewline
Active patients with disease activity index [?]3 ESSG, n. (\%) & 24 (27
\%)\tabularnewline
Erythrocyte Sedimentation Rate (mm/h), mean\selectlanguage{ngerman}±SD & 19 \selectlanguage{ngerman}± 14\tabularnewline
C-Reactive Protein (mg/l), mean±SD & 4.3 \selectlanguage{ngerman}± 5\tabularnewline
Limited cutaneous SSc, n. (\%) & 74 (83 \%)\tabularnewline
Interstitial lung disease, n. (\%) & 51 (57 \%)\tabularnewline
Esophageal Involvement, n. (\%) & 79 (89 \%)\tabularnewline
Bowel incontinence, n. (\%) & 2 (3 \%)\tabularnewline
Active digital ulcers, n. (\%) & 18 (20 \%)\tabularnewline
Digital pitting scars, n. (\%) & 55 (62 \%)\tabularnewline
Calcinosis, n. (\%) & 79 (89 \%)\tabularnewline
Renal Involvement, n. (\%) & 5 (6 \%)\tabularnewline
Pulmonary Arterial Hypertension, n. (\%) & 7 (8 \%)\tabularnewline
Capillaroscopy scleroderma pattern, n. (\%) & Early 6 (7
\%)\tabularnewline
& Active 49 (55 \%)\tabularnewline
& Late 34 (38 \%)\tabularnewline
\bottomrule
\end{longtable}

Table 2. Demographics and cytokines/adipokines serum levels in Systemic
Sclerosis (SSc) patients as whole cohort and

subdivided according to phosphodiesterase-5 (PDE5) inhibitors
(tadalafil/sildefanil) intake, and healthy donors (HD).

Data are shown as mean \selectlanguage{ngerman}± standard deviation.\selectlanguage{english}
\begin{longtable}[]{@{}lllllll@{}}
\toprule
\begin{minipage}[b]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[b]{0.12\columnwidth}\raggedright\strut
Comparison SSc-all vs healthy donors (HD)\strut
\end{minipage} & \begin{minipage}[b]{0.12\columnwidth}\raggedright\strut
Comparison SSc-all vs healthy donors (HD)\strut
\end{minipage} & \begin{minipage}[b]{0.12\columnwidth}\raggedright\strut
Comparison SSc-all vs healthy donors (HD)\strut
\end{minipage} & \begin{minipage}[b]{0.12\columnwidth}\raggedright\strut
Comparison SSc tadalafil/sildefanil vs SSc other drugs (OD)\strut
\end{minipage} & \begin{minipage}[b]{0.12\columnwidth}\raggedright\strut
Comparison SSc tadalafil/sildefanil vs SSc other drugs (OD)\strut
\end{minipage} & \begin{minipage}[b]{0.12\columnwidth}\raggedright\strut
Comparison SSc tadalafil/sildefanil vs SSc other drugs (OD)\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
SSc all (n. 89)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
HD (n. 26)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
p\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
SSc PDE5 inhibitors (n. 8)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
SSc OD (81)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
p\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Age (years)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
52.1 \selectlanguage{ngerman}± 14\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
49.4 \selectlanguage{ngerman}± 11\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\emph{0.07}\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
64.5 \selectlanguage{ngerman}± 14\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
50.3 \selectlanguage{ngerman}± 13\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\emph{0.0001}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Female n (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
84 (94 \%)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
23 (88\%)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\emph{0.37}\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
7 (87\%)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
76 (93\%)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\emph{0.37}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Waist circumference (cm)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
80.7 \selectlanguage{ngerman}± 9.5\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
88.4 \selectlanguage{ngerman}± 12\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\emph{0.49}\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
90 \selectlanguage{ngerman}± 5.6\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
79.6 \selectlanguage{ngerman}± 9.4\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\emph{0.06}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Hip circumference (cm)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
97.5 \selectlanguage{ngerman}± 10\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
102.5 \selectlanguage{ngerman}± 9.9\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\emph{0.15}\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
110 \selectlanguage{ngerman}± 4.2\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
95.9 \selectlanguage{ngerman}±10\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\emph{0.06}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
WHR (Waist/Hip ratio)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
0.83 \selectlanguage{ngerman}± 0.7\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
0.86 \selectlanguage{ngerman}± 0.08\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\emph{0.26}\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
0.81 \selectlanguage{ngerman}± 0.01\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
0.83 \selectlanguage{ngerman}± 0.07\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\emph{0,53}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Body Mass Index (Kg/m\textsuperscript{2})\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
23.6 \selectlanguage{ngerman}± 4.2\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
25.13 \selectlanguage{ngerman}± 4.4\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\emph{0.12}\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
27.1 \selectlanguage{ngerman}± 5.5\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
23.2 \selectlanguage{ngerman}± 3.9\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\emph{0.01}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
IL-17A\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
2.4 \selectlanguage{ngerman}± 6\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
1.7 \selectlanguage{ngerman}± 3.1\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\emph{0.96}\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
1.3 \selectlanguage{ngerman}± 2\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
1.8 \selectlanguage{ngerman}± 7\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\emph{0.94}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
TNF-\selectlanguage{greek}α\selectlanguage{english}\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
57.2 \selectlanguage{ngerman}± 62\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
1.0 \selectlanguage{ngerman}± 1.1\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\emph{0.02}\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
31.4 \selectlanguage{ngerman}± 60\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
60.4 \selectlanguage{ngerman}± 280\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\emph{0.50}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
INF-\selectlanguage{greek}γ\selectlanguage{english}\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
88.9 \selectlanguage{ngerman}± 172\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
29.6 \selectlanguage{ngerman}± 23\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\emph{0.09}\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
110 \selectlanguage{ngerman}± 175\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
166.1 \selectlanguage{ngerman}± 492\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\emph{0.25}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
IL-2\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
42 \selectlanguage{ngerman}± 162\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
3.57 \selectlanguage{ngerman}± 1.3\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\emph{0.01}\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
104.5 \selectlanguage{ngerman}± 285\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
38 \selectlanguage{ngerman}± 149.6\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\emph{0.17}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
IL-10\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
40 \selectlanguage{ngerman}± 175\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
4.3 \selectlanguage{ngerman}± 9.8\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\emph{0.29}\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
127.6 \selectlanguage{ngerman}± 342\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
33.4 \selectlanguage{ngerman}± 153.2\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\emph{0.12}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Leptin\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
15266 \selectlanguage{ngerman}± 26679\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
2822 \selectlanguage{ngerman}± 2045\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\emph{0.00003}\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
28353 \selectlanguage{ngerman}± 33778\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
11768 \selectlanguage{ngerman}± 11488\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\emph{0.0001}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Resistin\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
6146 \selectlanguage{ngerman}± 2344\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
1705 \selectlanguage{ngerman}± 279\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\emph{0.00001}\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
6019 \selectlanguage{ngerman}± 3211\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
6322 \selectlanguage{ngerman}± 2147\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\emph{0.85}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Visfatin\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
4459 \selectlanguage{ngerman}± 15177\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
2555 \selectlanguage{ngerman}± 12083\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\emph{0.55}\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
17732 \selectlanguage{ngerman}± 46746\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
3245 \selectlanguage{ngerman}± 6650\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\emph{0.01}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Adiponectin\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
/\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
5848562 \selectlanguage{ngerman}± 6204076\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
6833220\selectlanguage{ngerman}±5694341\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\emph{0.64}\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

Table 3. Cytokines and adipokines in Systemic Sclerosis patients by BMI
categories (mean \selectlanguage{ngerman}± SD).\selectlanguage{english}
\begin{longtable}[]{@{}llllll@{}}
\toprule
\begin{minipage}[b]{0.14\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[b]{0.14\columnwidth}\raggedright\strut
Underweight\strut
\end{minipage} & \begin{minipage}[b]{0.14\columnwidth}\raggedright\strut
Normal-weight\strut
\end{minipage} & \begin{minipage}[b]{0.14\columnwidth}\raggedright\strut
Overweight\strut
\end{minipage} & \begin{minipage}[b]{0.14\columnwidth}\raggedright\strut
Obese\strut
\end{minipage} & \begin{minipage}[b]{0.14\columnwidth}\raggedright\strut
\emph{p}\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
IL-17A\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
0.05 \selectlanguage{ngerman}± 0.1\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
2.24 \selectlanguage{ngerman}± 9.1\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
0.8 \selectlanguage{ngerman}± 1.5\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
6.9 \selectlanguage{ngerman}± 6.7 \emph{vs: UW, NW OW}\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
\emph{0.01}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
TNF\selectlanguage{greek}α\selectlanguage{english}\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
144.2 \selectlanguage{ngerman}± 271 \emph{vs: NW OW, Ob}\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
12.1 \selectlanguage{ngerman}± 43\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
31.1 \selectlanguage{ngerman}± 121\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
42 \selectlanguage{ngerman}± 71\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
\emph{0.03}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
INF\selectlanguage{greek}γ\selectlanguage{english}\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
76.4 \selectlanguage{ngerman}± 125\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
83.7 \selectlanguage{ngerman}± 251\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
105.0 \selectlanguage{ngerman}± 303\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
91.5 \selectlanguage{ngerman}± 249\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\emph{0.97}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
IL-2\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
23.4 \selectlanguage{ngerman}± 85\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
11.4 \selectlanguage{ngerman}± 45\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
35.9 \selectlanguage{ngerman}± 129\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
233 \selectlanguage{ngerman}± 350 \emph{vs: UW, NW OW}\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
\emph{0.001}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
IL-10\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
12.0 \selectlanguage{ngerman}± 31\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
12.8 \selectlanguage{ngerman}± 35\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
30.1 \selectlanguage{ngerman}± 112\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
204 \selectlanguage{ngerman}± 431 vs: UW, NW OW\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
\emph{0.01}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Leptin\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
9033 \selectlanguage{ngerman}± 7181\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
9623\selectlanguage{ngerman}± 14097\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
17465 \selectlanguage{ngerman}± 10335\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
64970 \selectlanguage{ngerman}± 89346 \emph{vs: UW, NW OW}\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
\emph{0.0001}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Visfatin\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
127 \selectlanguage{ngerman}± 234\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
2154 \selectlanguage{ngerman}± 4199\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
4340 \selectlanguage{ngerman}± 7900\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
28551 \selectlanguage{ngerman}± 58672 \emph{vs: UW, NW OW}\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
\emph{0.002}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Resistin\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
6997 \selectlanguage{ngerman}± 956\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
6109 \selectlanguage{ngerman}± 2519\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
6637 \selectlanguage{ngerman}± 1727\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
6964 \selectlanguage{ngerman}± 1800\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\emph{0.57}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Adiponectin\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
9829075 \selectlanguage{ngerman}± 66275\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
6582923 \selectlanguage{ngerman}± 53445\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
7459125 \selectlanguage{ngerman}± 65585\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
3248520 \selectlanguage{ngerman}± 10425\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\emph{0.22}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Leptin/Adiponec\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
0.002 \selectlanguage{ngerman}± 0.002\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
0.002 \selectlanguage{ngerman}± 0.004\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
0.003 \selectlanguage{ngerman}± 0.0006\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
0.02 \selectlanguage{ngerman}± 0.04 \emph{vs: UW, NW OW}\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
\emph{0.0001}\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

UW= Underweight, NW= Normal-weight, OW= Overweight, Ob= Obese.

Table 4. Correlation of cytokines/adipokines with anthropometric and
clinical findings. Data are shown as mean \selectlanguage{ngerman}± SD. Only the significant
correlations are reported.\selectlanguage{english}
\begin{longtable}[]{@{}lllllllll@{}}
\toprule
\begin{minipage}[b]{0.08\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[b]{0.08\columnwidth}\raggedright\strut
IL-17A\strut
\end{minipage} & \begin{minipage}[b]{0.08\columnwidth}\raggedright\strut
Leptin\strut
\end{minipage} & \begin{minipage}[b]{0.08\columnwidth}\raggedright\strut
Visfatin\strut
\end{minipage} & \begin{minipage}[b]{0.08\columnwidth}\raggedright\strut
TNF\selectlanguage{greek}α\selectlanguage{english}\strut
\end{minipage} & \begin{minipage}[b]{0.08\columnwidth}\raggedright\strut
Trigl\strut
\end{minipage} & \begin{minipage}[b]{0.08\columnwidth}\raggedright\strut
Chol LDL\strut
\end{minipage} & \begin{minipage}[b]{0.08\columnwidth}\raggedright\strut
ESR\strut
\end{minipage} & \begin{minipage}[b]{0.08\columnwidth}\raggedright\strut
CRP\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
BMI\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
\emph{r 0.25} \emph{p 0.02}\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
\emph{r 0.41} \emph{p 0.0001}\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
\emph{r 0.25} \emph{p 0.02}\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
\emph{r -0.27} \emph{p 0.05}\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
\emph{r 0.28} \emph{p 0.02}\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
\emph{r 0.46} \emph{p 0.002}\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
\emph{r 0.30} \emph{p 0.007}\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
\emph{r 0.32} \emph{p 0.004}\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

BMI= Body, Mass, Index, Trigl= Triglycerides, Chol= Cholesterol, ESR=
Erythrocyte Sedimentation Rate, CRP= C-reactive protein, r= coefficient
correlation, p= significance level

\textbf{Legends}

\textbf{Figure 1} . Serum leptin levels in healthy donors (HD) and
Systemic Sclerosis (SSc) patients with different categories of body mass
index. (U-W: under-weight, N-W normal-weight, O-W over-weight). Mean
(95\% CI)

\textbf{Figure 2} . Serum TNF\selectlanguage{greek}α \selectlanguage{english}levels in healthy donors (HD) and
Systemic Sclerosis (SSc) patients with different categories of body mass
index. (U-W: under-weight, N-W normal-weight, O-W over-weight). Mean
(95\% CI)\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-1/Figure-1}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-2/Figure-2}

\end{center}
\end{figure}

\selectlanguage{english}
\FloatBarrier
\end{document}

