rheumatoid arthritis ( ra ) is a chronic , systemic inflammatory disorder that primarily targets the synovium and articular cartilage , leading to synovitis and progressive joint damage .
however the pathophysiology of ra is poorly understood , the pro - inflammatory adipocytokines such as leptin , resistin and visfatin have been suggested to have an important role in the pathogenesis of the disease ( 1 ) .  
leptin , which is mainly produced by white adipose tissue ( wat ) cells , is a hormone encoded by the obese gene ( ob ) , the murine homologue of the human lep ( 2 ) .
in addition to its well - known ability to regulate body weight by inhibiting food intake and increasing energy consumption , it also has inflammatory and immunomodulatory effects ( 3 ) .
serum leptin levels were increased in ra patients compared to healthy controls ( 4 - 7 ) ; it was significantly higher in women than in men ( 8) .
visfatin , a growth factor for b lymphocyte precursors , is another pro - inflammatory adipocytokine , seen in liver , skeletal muscles and bone marrow and produced by visceral wat , which mimics the effects of insulin ( 9 , 10 ) .
serum visfatin levels were increased in patients with ra ( 4 , 7 , 11 - 13 ) .
recently , reports have suggested the significant role of adipocytokines such as visfatin in mediating joint damage ( 4 , 14 , 15 ) .
nevertheless , it is still a matter of debate whether infliximab significantly changes the visfatin levels ( 16 ) .
the purpose of this study was to examine the association between serum levels of adipocytokines ( leptin and visfatin ) and radiographic joint damage in patients with ra .
this study was conducted on 29 patients with erosive rheumatoid arthritis ( ra ) and 25 patients with non - erosive ra .
all patients fulfilled the american college of rheumatology classification criteria for ra ( 17 ) .
eligible patients were those who met all of the following criteria : having ra for at least 1 year , but no more than 5 years ; aged between 20 and 50 at the disease onset ; and bmi  30 .
patients were excluded if they had any of the following concomitant diseases : erosive joint diseases such as gout , seronegative spondyloarthropathies ; osteoarthritis ; blood pressure  140/90 mmhg ; cardiovascular diseases such as congestive heart failure or coronary artery diseases .  
each subject signed a written informed consent after explaining the objective of the study and verification of the inclusion and exclusion criteria .
x - rays of the hands and feet were obtained from each of the subjects and 20 joints ( the wrists , 1 to 5 metacarpophalangeal joints , and 2 to 5 metatarsophalangeal joints ) were evaluated by a particular radiologist who was blinded to the study .
the amount of damage was quantified by using the larsen score , with ranging from 0 to 100 for all 20 joints ( 18 ) .  
after overnight fasting , blood samples were drawn from all patients and stored at -20c until the time of analysis by leptin kit , ( visfatin kit : rav bio human visfatin e1 america ; me diagnose company , code : ref - e07 germany ) through elisa .
descriptive statistics were calculated as mean standard deviation ( sd ) or median [ interquartile range ( iqr ) ] according to distributions of continuous variables .
statistical analysis was performed with spss for windows software version 11.5 ( spss inc . ,
the mann - whitney test was used to determine the mean differences . for evaluating relationships among normally distributed variables ,
the pearson correlation coefficient was calculated , whereas the spearman 's rho was calculated in case of nonparametric data .  
statistical analysis was performed with spss for windows software version 11.5 ( spss inc . ,
chicago , il , usa ) . mean values and standard deviations were used for continuous variables . for comparing means ,
the mann - whitney test was used to determine the mean differences . for evaluating relationships among normally distributed variables ,
the pearson correlation coefficient was calculated , whereas the spearman 's rho was calculated in case of nonparametric data .  
in our study , age , sex and bmi did not show any statistically significant differences between the two groups of patients ( erosive and non - erosive ra ) ( p - values > 0.05 ) .
the median disease durations were 5 years ( iqr ( 3 - 5 ) ) and 2 years ( iqr ( 1 - 4.5 ) ) in patients with erosive and non - erosive ra , respectively ; which showed statistically significant differences between the two groups of patients ( p=0.003 ) .
leptin concentrations did not show any statistically significant differences between the two groups of patients ( p=0.903 ) .
visfatin concentrations were significantly higher in patients with erosive ra ( 34.6 [ 29.1 - 100 ] ng / ml ) compared with non - erosive ra ( 28.4 [ 22.1 - 34.5 ] ng / ml ) ( p=0.013 ) ( table 1 ) .   leptin and visfatin correlations with bmi , disease duration and larsen score are shown in table 2 .
bmi correlated positively with leptin ( r=0.494 , p<0.001 ) , figure 1 while disease duration correlated positively with visfatin ( r=0.488 , p<0.001 ) figure 2 .
no correlations were seen between larsen score and leptin and visfatin ( r= -0.318 , p=0.093 and r=0.254 , p=0.184 respectively ) . by using the linear regression coefficient model ,
leptin showed correlation with bmi ( t=4.096 , p<0.001 ) and visfatin showed positive correlations with c - reactive protein ( crp ) and disease duration ( t=2.165 , p=0.035 and t=2.719 , p=0.009 respectively ) .
nevertheless , using univariate variance analysis , there was no correlation between leptin and bmi in the two groups of ra ( p=0.508 ) , and leptin serum levels in the two study groups were not significantly different , not considering the bmi ( p=0.522 ) . while there was a positive correlation between visfatin and crp ( p=0.008 ) , no correlation was seen between visfatin and disease duration in the two erosive and non - erosive ra groups ( p=0.247 ) .
there are a few studies about the effect of adipokines like leptin and visfatin on radiographic changes of involved joints in rheumatoid arthritis . in giles
et al study , in 2009 , there was no association between the level of leptin and radiographic joint damage ( 14 ) .
however , in rho et al studies , there was a positive correlation between these adipokines with radiographic changes , and higher levels of leptin were associated with less radiographic damage ( 13 ) . in this case - control study , we evaluated the association between the serum levels of leptin and visfatin with radiographic damage in two groups of patients with rheumatoid arthritis : with and without radiographic damage , to better understand the physiology of radiologic joint damage in rheumatoid arthritis patients which is the most important cause of morbidity in rheumatoid arthritis .
we found that serum levels of visfatin in our rheumatoid arthritis patients with joint erosion were much higher than those in patients without joint erosion .
there was no correlation between serum levels of visfatin with either sedimentation rate or crp .
there was a statistically significant positive correlation between visfatin serum levels with disease duration ( p<0.001 , r=0.538 ) .
c - reactive protein level and disease duration were correlated to serum visfatin by linear regression method .  
univariate analysis showed that serum visfatin in our two study groups had a statistically significant positive correlation ( p=0.008 ) with radiographic damage disregarding crp as co - founder ( p=0.008 ) .
however , dispensing with the disease duration , visfatin serum levels in the two groups had no statistical significance ( p=0.695 ) .
these findings represent that serum visfatin level , independently , with serum crp as an inflammatory marker , is associated with joint damage in radiographic studies , but this correlation ( visfatin level and radiographic damage ) depends on the disease duration .
our study was similar to the rho et al study in 2009 , which revealed that visfatin serum levels were positively correlated with radiographic joint damage considering age , gender , disease duration , bmi , and inflammation , with statistical significance ( 13 ) .  
although visfatin is an adipokine , based on previous studies , there is no correlation between visfatin and obesity ( 17 ) .
however , some studies have shown that there is an association between visfatin and inflammatory markers ( 18 , 19 ) . in the rho
et al study there was a positive relationship between visfatin serum levels and inflammatory mediators like crp , tnf and il6 with statistical significance , but no correlation between visfatin and bmi . in our study , we could not find a correlation between bmi and visfatin levels .
this finding is probably due to the difference between inflammatory markers and also qualitative use of data in our study .
brentano and colleagues reported that visfatin was accumulated in the invasive synovial tissue in rheumatoid arthritis patients and its levels were increased in synovial fibroblasts as well ( 20 ) .
visfatin is able to induce il6 , matrix metalloproteinase ( mmp1 and mmp3 ) in synovial fibroblasts in ra patients and induce tnf  and il6 in monocytes too ( 20 ) . in our study
, we found that visfatin level is associated with radiographic damage and has a catabolic effect on joints ; therefore it has an important role in pathophysiology in rheumatoid arthritis .  
busso et al , revealed that in arthritic rats , visfatin inhibitors induce remission exactly like tnf  inhibitors ( 21 ) .
interestingly , pharmacologic inhibition in visfatin , decreases intracellular nad levels ( intracellular nucleotide adenine deaminase ) in inflammatory cells and reduces production of il6 and tnf  in the involved joints of ra patients ( 21 ) . with respect to above findings
, we can come to the conclusion that visfatin is an independent mediator in the pathogenesis of rheumatoid arthritis and is related to radiographic joint damage .
visfatin level was not related to esr , crp , larsen score or disease duration , but had a meaningful , positive statistical relation with bmi ( p=0.004 , r=0.385 ) .
our study showed that leptin levels in ra patients with or without joint erosion were not any different .
rho et al ( 13 ) showed that serum leptin level associated with less joint space narrowing after suppression of inflammatory process .
also there is a positive relation among leptin , das28 , crp , il6 , and bmi which is statistically significant in ra patients . in our study
, we found a correlation between leptin and bmi and no association between leptin with disease activity , crp and il6 .
this discrepancy might be due to the design difference between our study and that of rho et al .
we did not evaluate disease activity score in our patients ; all patients had had rheumatoid arthritis for less than 5 years . according to the studies of westhoff et al ( 22 ) , kaufmann et al ( 23 ) and van der helmm et al ( 24 ) obesity has a protective effect in joint damage in ra patients ( 22 - 24 ) .
therefore , the important roles of adipocytokines like leptin and adiponectin in obesity should be considered in ra patients .
we found that visfatin level as an inflammatory marker , independently of crp level , is associated with joint radiographic damage and is related to disease duration .
the mechanism of visfatin as a proinflammatory and its catabolic role is not known and visfatin biology seems to be complex ; the key roles of visfatin as a treatment are still obscure . additionally , our study is one of the earliest in the field of association of adipocytokine levels and radiographic joint damage .
therefore , we suggest evaluating levels of adipocytokines before and after treatment in longitudinal studies to make clear the relationship between adipocytokines and joint damage in human models in the future .   in future research , it would be reasonable to measure leptin and visfatin simultaneously , in addition to the other adipocytokines like adipocytokines of resistin .
 objective ( s):rheumatoid arthritis ( ra ) is a chronic systemic inflammatory disorder , primarily targeting the synovium and articular cartilage that leads to joint damage . 
 recent reports have suggested the role of adipocytokines in mediating joint damage ; however it still is a matter of debate . 
 the purpose of this study was to evaluate the association between serum values of adiopocytokines ( leptin , visfatin ) and radiographic joint damage in patients with ra.materials and methods : fifty - four patients diagnosed with ra , based on revised acr criteria 2010 , with 1 - 5 year disease duration since diagnosis , were enrolled . 
 twenty - nine of patients had erosion in radiographic studies and 25patients had no erosion . 
 radiographic joint damages were defined according to larsen score . additionally , serum levels of adipocytokines were measured and cross - sectional associations with radiographic damage were explored , adjusting for pertinent confounders.results:the serum level of visfatin were significantly higher in patients with radiographic joint damage compared with patients with no joint damage ( p=0.013 ) . 
 this difference remained significant after adjustment for c - reactive protein levels ( p=0.008 ) , but not after adjustment for disease duration ( p=0.247 ) . the mean leptin serum levels were not different between these two groups ( p=0.903 ) . 
 there was a positive correlation between leptin levels and bmi ( r=0.494 , p<0.001 ) . 
 however , after adjustment for bmi , leptin levels had no difference between two groups ( p=0.508).conclusion : this study revealed that visfatin levels were significantly higher in patients with radiographic joint damage dependently to disease duration . 
 therefore , it seems that adipocytokine may be a valuable factor in therapeutic targets in the future . 