systemic lupus erythematosus ( sle ) is a chronic systemic inflammatory disease affecting mainly women during childbearing age .
although life expectancy has improved significantly , no changes in morbidity and mortality related to cardiovascular disease ( cvd ) have been observed in sle patients in the past decades [ 2 , 3 ] .
in addition to traditional risk factors , many lupus - specific factors are linked to the increased risk of cvd observed in sle [ 46 ] .
obesity - associated systemic inflammation is characterized by increased circulating proinflammatory cytokines and activation of several kinases that regulate inflammation [ 79 ] .
recent evidence supports that obesity - induced inflammation is mediated primarily by immune cells such as the macrophages and t lymphocytes present in metabolic tissues . adipose
tissue derived cells can produce inflammatory cytokines , such as tumor necrosis factor alpha ( tnf- ) , interleukin ( il ) 6 , and il-10 [ 10 , 11 ] .
tnf- and il-6 are proinflammatory cytokines associated with an increased insulin resistance , inhibition of insulin receptor autophosphorylation , and signal transduction .
upregulation of il-10 locally or systemically reduces atherosclerosis development in mouse models [ 1315 ] .
the aim of this study was to evaluate the association between obesity , measures of body fat content , and serum tnf- , il-6 , and il-10 in csle .
fifty - two consecutive csle patients , recruited from the pediatric rheumatology outpatient clinic of the state university of campinas were included in this study .
patients were included in the present study if they ( i ) fulfilled at least four criteria of the american college of rheumatology ( acr ) ; ( ii ) were below 18 years of age at disease onset ; and ( iii ) had a follow - up duration of at least 6 months ( time necessary to evaluate damage index ) .
fifty - two healthy volunteers ( caregivers or students ) matched by age , gender , and sociodemographic characteristics were included as a control group .
this study was approved by the ethics committee at our institution , and the informed written consent was obtained from each participant and/or legal guardian .
all patients had their medical histories and clinical , and serological characteristics entered at the time of csle diagnosis into special computer database programs .
features included in this protocol were age at the onset of disease ( defined as the age at which the first symptoms clearly attributable to sle occurred ) , age at diagnosis ( defined as the age when patients fulfilled four or more of the 1987 revised criteria for the classification of sle ) , and follow - up time ( defined as the time from disease onset until december 2012 ) .
total doses and length of use the of corticosteroids since the onset of disease were calculated by careful review of the medical charts .
the cumulative dose of corticosteroids used was calculated by the sum of the daily dosages versus the time ( days ) of treatment .
we also calculated the cumulative corticosteroid dose adjusted by weight by summing up the daily corticosteroid dose per weight at each routine visit .
disease activity was measured by the systemic lupus erythematosus disease activity index ( sledai ) .
sledai scores range between 0 and 105 , and the scores of 3 were considered as active disease .
adjusted sledai scores over time were calculated by careful review of the medical charts and preview exams .
cumulative sle - related damage in all patients was determined by using the systemic lupus international collaborating clinics ( slicc)/acr damage index ( sdi ) .
body mass index ( bmi ) was calculated as weight ( kg ) divided by height ( m ) squared ( kg / m ) .
criteria used to define nutritional status were based on the world health organization ( who ) criteria .
bmi cutoff points for brazilian children and adolescents were used for individuals between 2 and 18 years .
percentual body fat ( pbf ) , fat mass , and lean mass were obtained by dxa scan ( hologic discovery wii ) , through whole body auto fan beam .
this scan determines total fat mass and total lean mass in kilograms in addition to total fat mass and total lean mass as a percentage of total body mass .
blood samples were collected from peripheral veins of all individuals in dry tubes and left to clot at room temperature for 30 minutes .
blood samples were then centrifuged for 15 minutes at 3000  rpm , and the serum was then stored in aliquots at 80c for future use .
we did not collect blood samples from individuals during an episode of acute or chronic infection .
commercially available kits from r&d systems ( london , uk ) were used for the measurement of serum tnf- , il-6 , and il-10 levels by enzyme - linked immunosorbent assay ( elisa ) , carried out in accordance with the manufacturer 's instructions .
the minimum detectable dose ( mdd ) was 0.106  pg / ml for tnf- , 0.039  pg / ml for il-6 , and 3.9  pg / ml for il-10 .
all the data were tested for their normal distribution ( kolmogorov - smirnov test ) .
mann - whitney u test was used to compare anthropometric measure and laboratory studies between patients and controls .
spearman 's correlation was used to correlate continuous variables ( e.g. , tnf- levels , sledai , and sdi scores ) . for all analyses ,
statistical analysis was carried out using ibm spss statistics 16.0 software ( spss / ibm , chicago , il , usa ) .
forty - seven ( 90.3% ) were women with mean age of 17.6 years ( standard deviation ( sd )  3.7 years ) .
the control group consisted of 52 controls ( 47 women ) with mean age of 18.2 years ( sd  6.4 ) .
patients and healthy controls were statistically comparable in terms of age and sex ( table 1 ) .
bmi was similar between patients ( median 21.74  kg / m ; range : 16.131.12  kg / m ) and controls ( median 21.43  kg / m ; range : 14.3628.54  kg / m ) ( p = 0.101 ) .
sixteen ( 31% ) csle patients were overweight compared to 6 ( 11.5% ) controls ( p = 0.018 ) .
we did not observe an association between bmi and sledai , sdi , and cumulative corticosteroid dose . on whole body analysis
, we observed a median fat mass of 22.38  kg ( range : 7.67  kg36.62  kg ) , a median lean mass of 35.49  kg ( range : 25.31  kg52.14  kg ) , and a median pbf of 34.1% ( range : 12.154.4% ) in csle . in the trunk region
we observed a median fat mass of 8.62  kg ( range 2.98  kg17.59  kg ) , median lean mass of 16.80  kg ( range : 11.24  kg26.19  kg ) and a pbf of 42.3% ( range : 12.154.4% ) .
serum tnf- ( p = 0.004 ) , il-6 ( p = 0.002 ) , and il-10 ( p < 0.001 ) levels were significantly increased in csle patients when compared to healthy controls ( table 2 ) .
we observed higher serum tnf- levels in obese csle patients when compared with nonobese csle patients ( p = 0.036 ) , obese controls ( p = 0.039 ) and non - obese controls ( p < 0.0001 ) ( table 3 ) .
no difference in serum tnf- levels was observed between obese and non - obese healthy controls ( p > 0.05 ) .
we observed an association between tnf- and pbf ( p = 0.046 ) and total fat mass on trunk region ( p = 0.035 ) analyzed by dxa scans .
no association between serum il-6 and il-10 levels and sledai or sdi scores was observed .
in addition , no difference in these cytokine levels in csle patients and controls with and without obesity was observed .
adipose tissue is known to be capable of secreting cytokines such as tnf- , il-6 , and il-10 . therefore , the purpose of this study was to assess whether the levels of these cytokines were increased in obese csle when compared to nonobese csle and healthy controls .
the observation that obese csle patients had higher serum tnf- levels when compared to nonobese csle and healthy controls is the major finding of our study .
in addition , we observed that serum tnf- levels correlated with pbf and total fat mass in trunk region in csle .
recent studies have demonstrated that increased adipose tissue mass contributes towards an increase in chronic inflammation [ 26 , 27 ] .
chronic inflammation is further enhanced by inflammatory markers produced in the liver and in other organs .
recently , it has been demonstrated that obesity is associated with a low - grade inflammatory process , characterized by increased circulating levels of proinflammatory cytokines such as tnf- , il-6 , and acute - phase proteins ( crp ) [ 2932 ] .
the mechanism underlying increased inflammation in the setting of obesity remains unclear , but it is known that mononuclear cells are activated and proinflammatory cytokines are upregulated in obese individuals [ 33 , 34 ] .
we observed an association between serum tnf- levels and pbf and total fat mass in trunk region .
studies analyzing the association between serum tnf- and dxa scans have not been reported in csle so far , but studies on healthy women and type-2 diabetes patients showed an association between plasma levels of tnf- and visceral adipose tissue volume measured by ct - scan [ 3538 ] .
previous studies have shown that visceral fat accumulation is associated with increased risk of cv risk .
in addition , with an increase in tnf- , a reduction in lipoprotein lipase activity in adipose tissue is observed .
there is also evidence that tnf- has a local effect , regulating adipocyte size in the face of increasing energy consumption [ 40 , 41 ] .
cytokines , such as tnf- and il-6 , are primarily involved in the early stages of the inflammatory response culminating in atherosclerosis [ 39 , 42 ] . increased tnf- levels in the endothelium promote initial atheroma plaque [ 39 , 42 ] .
however , so far , studies were not able to conclude whether tnf- is a causative factor of atherosclerosis .
both il-6 and tnf- are expressed and secreted by human adipose tissue . in obesity , increased secretion of il-6 may contribute to metabolic dysfunction [ 44 , 45 ] .
in addition , one previous study has shown that il-6 correlated positively with bmi and with measures of insulin resistance in abdominal obese male subjects . as previously described in adults sle patients , we observed higher il-6 and il-10 levels in csle patients when compared to healthy controls [ 4649 ] .
il-10 downregulates inflammatory activation of monocytes and macrophages by transcriptional and posttranscriptional inhibition of the entire range of proinflammatory cytokines .
il-10 has been shown to reduce atherosclerosis and it can be found in atheromatous plaque due to local macrophages production .
however , il-10 is involved in sle pathogenesis and it is increased in sle patients with cvd compared to sle patients without cvd [ 51 , 52 ] . in our study , we did not observe an association between sera il-10 levels and obesity .
we also did not observe an association between sera il-6 levels and obesity . in the literature
, it has been described that plasma il-6 levels are associated with increased cv risk and observed in sle patients with metabolic syndrome   and in patients with type 2 diabetes [ 44 , 54 ] . in a large healthy family population
study where children were included , il-6 levels were closely associated with traditional and nontraditional risk factors for atherosclerosis .
although csle is rare , it is important to consider that one limitation of our study is the small number of patients and controls included .
corticosteroids also cause a redistribution of fat deposition , occurring predominantly in the trunk and face [ 5659 ] .
however , we did not observe an association between serum tnf- , il-6 , and il-10 levels and corticosteroid dose . to the best of our knowledge ,
this is the first study to evaluate the association of bmi , body composition and serum tnf- , il-6 , and il-10 levels in csle patients .
although these cytokines have been shown to be associated with cvd in other populations , we only observed an association between serum tnf- levels and obesity , and pbf and total fat mass in trunk region .
our findings suggest that total fat mass may contribute to increased levels of serum tnf- levels in csle .
 
 background . in systemic lupus erythematosus ( sle ) 
 , atherosclerosis is attributed to traditional and lupus related risk factors , including metabolic syndrome ( mets ) , obesity , and inflammation . objective . to evaluate the association between obesity , measures of body fat content , serum tumor necrosis factor alpha ( tnf- ) , and interleukin ( il)-6 and -10 levels in childhood - onset sle ( csle ) . 
 methods . 
 we screened consecutive csle patients followed up in the pediatric rheumatology outpatient clinic of the state university of campinas . 
 csle patients were assessed for disease and damage . 
 obesity was definite as body mass index ( bmi ) 30  kg / m2 . 
 serum tnf- , il-6 , and il-10 levels were measured by elisa . 
 dual - energy x - ray absorptiometry was used to determine total fat mass , lean mass , and percent of body fat . 
 results . 
 we included 52 csle patients and 52 controls . 
 csle patients had higher serum tnf-  ( p = 0.004 ) , il-6 ( p = 0.002 ) , and il-10 ( p < 0.001 ) levels compared to controls . 
 we observed higher serum tnf-  ( p = 0.036 ) levels in csle patients with obesity . 
 an association between serum tnf- levels and body fat percent ( p = 0.046 ) and total fat mass on trunk region ( p = 0.035 ) was observed . conclusion . 
 serum tnf- levels were associated with obesity and body fat content in csle . 
 our finding suggests that obesity may contribute to the increase of serum tnf- levels in csle . 