Role of resistin as a marker of inflammation in systemic lupus erythematosus

ar2366 ARJ Research article Role of resistin as a marker of inflammation in systemic lupus erythematosus Almehed Katarina katarina.almehed@vgregion.se d'Elia Forsblad Helena helena.forsblad@vgregion.se Bokarewa Maria maria.bokarewa@rheuma.gu.se Carlsten Hans hans.carlsten@rheuma.gu.se

Department of Rheumatology and Inflammation Research, Sahlgrenska Academy at Göteborg University Guldhedsgatan 10, S-413 46 Göteborg, Sweden

Arthritis Research & Therapy 1478-6354 2008 10 1 R15 http://arthritis-research.com/content/10/1/R15 18234104 10.1186/ar2366 26 9 2007 22 11 2007 23 12 2007 30 1 2008 30 1 2008 2008 Almehed et al.; licensee BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Introduction

Resistin is a cystein-rich secretory adipokine. It is proposed to have proinflammatory properties in humans. The aim of this study was to determine associations between serum levels of resistin and markers of inflammation and bone mineral density (BMD) in female patients with systemic lupus erythematosus (SLE).

Methods

One hundred sixty-three female patients with SLE (20 to 82 years old) were examined in a cross-sectional study. Venous blood samples were analyzed for resistin, erythrocyte sedimentation rate (ESR), C-reactive protein, creatinine, fasting lipids, complements, tumor necrosis factor-alpha, interleukin (IL)-1β, IL-6, sIL-6R (soluble IL-6 receptor), ICTP (C-terminal telopeptide of type I collagen), and PINP (N-terminal propeptide of type I procollagen). Simple and multiple regression analyses as well as logistic regression analyses were performed. Resistin in serum was compared with 42 healthy female controls with respect to age.

Results

Serum resistin levels in controls were similar to those of patients with SLE. Markers of inflammation and current dose of glucocorticosteroids correlated positively to resistin in serum. Markers of renal function, number of prevalent vertebral fractures, and BMD were also significantly associated with resistin. In a multiple regression model, ESR, creatinine, C3, current glucocorticosteroid dose, high-density lipoprotein, and BMD radius remained significantly associated with resistin. In logistic regression analyses with resistin as the independent variable, a significant association was found with ESR (normal or elevated) but not with S-creatinine or z score for hip and radius total.

Conclusion

Although resistin measurements did not differ between patients and controls, resistin was clearly associated with general inflammation, renal disease, treatment with glucocorticosteroids, and bone loss. We hypothesize that resistin has proinflammatory and disease-promoting properties in SLE. Further studies are needed to elucidate the mechanism behind these associations.

Introduction

Resistin is a recently described, low-molecular-weight, cystein-rich secretory peptide 123. It is also known as adipocyte-specific secretory factor. Animal studies show that resistin is produced mainly in white adipose tissue and may be the linkage between obesity and insulin resistance. In humans, the role of resistin is not yet fully established. There is evidence that resistin has proinflammatory properties and is abundant in inflammatory diseases (for instance, rheumatoid arthritis (RA) 4 and Crohn disease 5) and also is associated with inflammatory markers in several different populations 678. In humans, resistin is expressed in inflammatory cells, leukocytes, and macrophages 9 and has the potency of inducing production of interleukin (IL)-6 and tumor necrosis factor-alpha (TNF-α) 910. Resistin is accumulated in inflamed joints of patients with RA and has the capacity to induce arthritis in mice 11. There are also data indicating that resistin levels are inversely associated with renal function and possibly contribute to a low-grade inflammation in patients with chronic renal dysfunction 12. Resistin seems to be of importance in bone metabolism, stimulating osteoblast and osteoclast differentiation, possibly mediated directly or indirectly through the nuclear factor kappa B (NF-κB) pathway 13. Systemic lupus erythematosus (SLE) is a disease characterized by systemic inflammation with the property of affecting several organs throughout the body, including kidneys. Therefore, we wanted to examine the relationship and possible associations between resistin and different markers of disease activity, inflammation, renal function, lipids, and bone mineral density (BMD) in a female cohort of patients with SLE.

Materials and methods

Patients

All patients with SLE treated in the rheumatology clinics in Göteborg and Borås, in western Sweden, were identified from administrative registers and invited to participate in this cross-sectional study. The procedure of enrollment has been described in detail 14. In short, 339 patients (298 women and 41 men) were identified. There was a 70% reply frequency among the female patients. One hundred sixty-three female patients fulfilling at least four of the 1982 American College of Rheumatology (ACR) classification criteria for SLE 15 were included in and completed the study. Only data regarding female patents have been analyzed. For each patient, data on age, duration of disease, weight, and height were recorded. Medication, smoking habits, physical activity, and clinical fractures were assessed by self-administered questionnaires. The Systemic Lupus Erythematosus Disease Activity Index (SLEDAI-2K) 16 was used to score disease activity. Disease damage was recorded according to the Systemic Lupus International Collaborative Clinics/ACR Damage Index 17. Glomerular filtration rate (GFR) was predicted using the Cockcroft and Gault equation 18. GFR (mL/minute) = (140 - age) × weight (kg) × 1.04/S-creatinine (μmol/L). Cumulative corticosteroid intake was calculated by reading the medical records of all patients. The same rheumatologist assessed all patients (KA).

Laboratory tests

Venous blood samples were taken after a one-night fast. Serum from the venous blood samples was stored at -70°C until the time of analyses. However, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), blood cell count, creatinine, C3, C4, and the plasma lipoproteins, total cholesterol, high-density lipoprotein (HDL), low-density lipoprotein, and triglycerides (Tg) were analyzed consecutively using standard laboratory techniques in the Department of Clinical Chemistry of Sahlgrenska University Hospital.

Bone markers

The bone resorption marker, C-terminal telopeptide of type I collagen (ICTP), and the bone formation marker, N-terminal propeptide of type I procollagen (PINP), were analyzed quantitatively in serum by radioimmunoassay (Orion Diagnostica, Espoo, Finland). Detection limits were ICTP 0.7 μg/L and PINP 2 μg/L.

Resistin

Resistin levels were detected with a sandwich enzyme-linked immunosorbent assay (ELISA) (R&D Systems, Inc., Minneapolis, MN, USA). Briefly, samples diluted 1:10 with 1% bovine serum albumin phosphate-buffered saline were introduced into the parallel strips coated with capture polyclonal anti-resistin antibodies. Biotin-labelled anti-resistin antibodies, streptavidin-horseradish peroxidase conjugate, and corresponding substrate were used for color development. The obtained absorbance values were compared with the serial dilution of recombinant human resistin. The lowest detectable level was 31 pg/mL.

Cytokines

Quantitative sandwich ELISA kits were used for measurement of proinflammatory cytokines TNF-α, IL-1β, IL-6, and soluble IL-6 receptor (sIL-6R) (Quantikine; R&D Systems, Inc.) with detection limits of 0.12, 0.1, 0.7, and 6.5 pg/mL, respectively.

Bone mineral density measurements

Lumbar spine (L2–L4), non-dominant hip (femoral neck and total hip), and non-dominant distal forearm were measured by DXA (dual-energy x-ray absorptiometry) with a Lunar Prodigy densitometer 12165 (GE Healthcare, Little Chalfont, Buckinghamshire, UK). The precisions for duplicate measurements were 0.9% for lumbar spine, 0.5% for left total hip and femoral neck, and 2.8% for radius. All BMD results were expressed in absolute values (g/cm²) and as the number of standard deviations (SDs) above or below the mean results of age-matched women (z score).

Fractures

Lateral x-rays of thoracic and lumbar spine (Th4-L4) were evaluated for prevalent vertebral compression fractures by a visual semiquantitative method (the method of Genant and colleagues 19). All vertebral deformities of at least 20% to 25% reduction of height, anterior, middle and/or dorsal were regarded as compression fractures. One radiologist performed all analyses.

Healthy controls

A control group of 12 female healthy blood donors and 30 healthy female staff members and PhD students in the Department of Rheumatology were analyzed for serum levels of resistin.

Ethical considerations

All patients gave informed written consent prior to participation, and the study was approved by the ethics committee at Sahlgrenska Academy at Göteborg University.

Statistical analysis

Analyses were performed using SPSS version 12.0.1 (SPSS Inc., Chicago, IL, USA). Descriptive statistics are presented as median and range or as mean and SD. All variables were tested with the Kolmogorov-Smirnov normality test. Pearson correlation was used when the variables were normally distributed; otherwise, Spearman correlation was used. Significant variables were then entered in the multiple linear regression analyses as independent variables and resistin as a dependent variable. A forward stepwise method was used.

ESR and S-creatinine were defined as normal or pathological according to standard laboratory normal values. These variables were dependent in a logistic forward regression analyses with resistin as the independent variable. The same method was used for z score hip total and radius total with the cutoff value of -1 SD. A receiver operating characteristic (ROC) curve was then calculated with ESR (elevated or not), S-creatinine (elevated or not), z score hip total, and z score radius total (cutoff value of -1 SD) as the state variable and resistin as the test variable. The constant and the regression coefficients of patients with SLE were compared with controls with respect to resistin and age by means of a special t test. All tests were two-tailed, and a p value of less than 0.05 was considered statistically significant.

Results

Demographic and disease-related variables

The SLE patients participating in this study did not differ significantly in age from those who were invited but did not participate. The general characteristics of the study population are presented in Table 1. The participants' ages ranged from 20 to 82 years. Seventy-two (44%) women were premenopausal. Ninety-one (56%) were on disease-modifying antirheumatic drugs, and 85 (52%) were treated with glucocorticosteroids. Only one person had end-stage renal disease, but 4 (2.5%) had impaired renal function with a GFR of less than 30 mL/minute, and 23 (14%) had a GFR of less than 50 mL/minute by use of the predicted GFR value.

Table 1

Demographic and disease-related variables in 163 female patients with systemic lupus erythematosus

Demographic variables

Value

Patient age, years

47 (20 to 82)

Weight, kg

66 (42 to 99)

Height, cm

166 (145 to 182)

Body mass index, kg/m²

24.2 (17.2 to 37.2)

Menopausal status

Premenopausal, n (%)

72 (44)

Disease variables

Disease duration, years

11 (1 to 41)

SLEDAI-2K

5 (0 to 31)

SLICC/ACR Damage Index

2 (0 to 11)

Kidney affection ever by SLE, n (%)

40 (25)

S-creatinine, μmol/L

87 (49 to 291)

Glomerular filtration rate, mL/minute

74 (22 to 172)

Proteinuria, >3.5 g/24 hours, n (%)

9 (6)

End-stage kidney disease, n (%)

1 (0.6)

Hemoglobin, g/L

131 (75 to 158)

Erythrocyte sedimentation rate, mm/hour

25 (2 to 125)

C-reactive protein, mg/L

5 (3 to 100)

Cholesterol, mmol/L

5.4 (2.4 to 9.3)

High-density lipoprotein, mmol/L

1.6 (0.5 to 2.8)

Low-density lipoprotein, mmol/L

3.1 (<0.1 to 6.3)

Triglycerides, mmol/L

1.2 (0.3 to 6.0)

Albumin, g/L

40 (11 to 53)

IgG, g/L

13.5 (5 to 28)

IgA, g/L

2.5 (0.07 to 11)

IgM, g/L

1.0 (0.05 to 4.6)

C3, g/L

0.93 (0.28 to 1.68)

C4, g/L

0.14 (0.02 to 0.28)

Tumor necrosis factor-alpha, pg/mL

2.16 (0.40 to 36.96)

Interleukin-1β, pg/mL

0.47 (0.0 to 9.65)

Interleukin-6, pg/mL

9.67 (2.81 to 119.0)

sIL-6R, ng/mL

48.87 (11.56 to 107.15)

Glucocortocosteroid user, n (%)

85 (52)

Glucocorticosteroid dose, mg

5 (2.5 to 35)

BMD lumbal spine, g/cm², mean (SD)

1.12 (0.18)

BMD total hip, g/cm², mean (SD)

0.92 (0.15)

BMD femur neck, g/cm², mean (SD)

0.89 (0.15)

BMD radius total, g/cm², mean (SD)

0.50 (0.08)

Number of vertebral fractures per patient

0 (0 to 11)

ICTP, μg/L

3.59 (0.9 to 16.38)

PINP, μg/L

43.0 (9.1 to 177.94)

Values are presented as median (and range) unless indicated otherwise. BMD, bone mineral density; ICTP, C-terminal telopeptide of type I collagen; Ig, immunoglobulin; PINP, N-terminal propeptide of type I procollagen; SD, standard deviation; sIL-6R, soluble interleukin-6 receptor; SLE, systemic lupus erythematosus; SLEDAI, Systemic Lupus Erythematosus Disease Activity Index; SLICC/ACR, Systemic Lupus International Collaborative Clinics/American College of Rheumatology.

Resistin and associated factors

The median serum resistin level was 6.53 (2.23 to 19.14) ng/mL. Several clinical and laboratory disease-related variables were significantly associated with resistin levels in serum using a simple regression model (Table 2). Markers of inflammation in SLE such as raised ESR, CRP, immunoglobulin G (IgG), proinflammatory cytokines, and low S-albumin levels correlated to resistin in serum. There was also an association between resistin and impaired renal function and current dose of corticosteroids. Bone variables such as number of vertebral fractures, low BMD in three of four measured sites, and the bone resorption marker ICTP also correlated to high resistin. Tg values were positively associated with resistin, whereas HDL was inversely associated with resistin. A multiple regression model, with resistin as the dependent variable and with the variables significantly correlated to resistin (Table 2) as independent variables, was performed. High inflammation, impaired renal function, medication with glucocorticosteroids, high HDL, and low BMD in radius remained significant markers of high resistin levels (Table 3).

Table 2

Correlation coefficients (r) of resistin (dependent variable) and disease-related variables (independent variables).

Resistin (ng/mL)

r_s

Erythrocyte sedimentation rate, mm/hour

0.316^a

C-reactive protein, mg/L

0.193^c

S-albumin, g/L

-0.302^a

IgG, g/L

0.178^c

S-C3, g/L

-0.216^b

Interleukin-6, pg/mL

0.315^a

sIL-6R, pg/mL

0.183^c

Tumor necrosis factor-alpha, pg/mL

0.312^a

S-high-density lipoprotein, mmol/L

-0.177^c

S-triglycerides, mmol/L

0.252^b

S-creatinine, μmol/L

0.180^c

Glomerular filtration rate, mL/minute

-0.228^b

Nephritis ever (yes = 1 and no = 0)

0.178^c

Corticosteroid current dose, mg/day

0.157^c

BMD lumbar spine, g/cm²

-0.165^c

BMD total hip, g/cm²

-0.170^c

BMD radius total, g/cm²

-0.261^b

Number of vertebral fractures per patient

-0.171^c

S-ICTP, μg/L

0.193^c

All variables were tested with the Kolmogorov-Smirnov normality test. Pearson correlation was used when the variables were normally distributed; otherwise, Spearman correlation was used. Only significant variables are shown. ^ap < 0.001; ^bp < 0.01; ^cp < 0.05. BMD, bone mineral density; ICTP, C-terminal telopeptide of type I collagen; IgG, immunoglobulin G; r, Pearson correlation coefficient; r_s, Spearman correlation coefficient; sIL-6R, soluble interleukin-6 receptor; SLE, systemic lupus erythematosus.

Table 3

Multiple stepwise regression analysis of resistin (dependent variable) and demographic and disease-related variables (independent variables)

Resistin (ng/mL)

11.155

P value

Erythrocyte sedimentation rate, mm/hour

0.044

0.012

0.001

S-creatinine, μmol/L

0.035

0.008

<0.001

Complement factor C3, g/L

-2.915

1.023

0.005

Glucocorticosteroid current dose, mg/day

0.127

0.051

0.014

High-density lipoprotein, mmol/L

-1.438

0.580

0.014

Bone mineral density radius, g/cm²

-7.133

3.156

0.026

R²

0.42

The regression equation of resistin (ng/mL) = 11.155 + 0.044 × erythrocyte sedimentation rate (mm/hour) + 0.035 × S-creatinine (μmol/L) - 2.915 × C3 (g/L) + 0.127 × current steroid dose (mg/day) - 1.438 × high-density lipoprotein (mmol/L) - 7.133 × bone mineral density radius (g/cm²). Beta values are unstandardized regression coefficients. R²is equal to the variance explained in the model. SE, standard error.

Logistic forward regression analyses were performed with resistin as the independent variable and normal or pathological ESR or S-creatinine as dependent variables. Analyses were also performed with z score total hip and radius as dependent variables using a cutoff value as -1 SD for normal or reduced bone mass. Resistin was significantly associated with ESR but not with S-creatinine, z score hip total, or z score radius total (Table 4).

Table 4

Resistin as independent variable in logistic regressions and test variable in area under ROC curves

Logistic regression with resistin as independent variable^a

ROC curve with resistin as test variable^b

P value

Area under ROC curve (95% CI)

Erythrocyte sedimentation rate

0.001

0.66 (0.58 to 0.75)

S-creatinine

0.19

0.55 (0.46 to 0.65)

Z score hip total

0.2

0.57 (0.46 to 0.67)

Z score radius total

0.13

0.56 (0.46 to 0.66)

^aErythrocyte sedimentation rate (ESR) and S-creatinine were defined as normal or pathological according to standard laboratory normal values. These variables were dependent in logistic conditional forward regression analyses with resistin as independent variable. The same method was used for z score hip total and radius total with the cutoff value of -1 standard deviation (SD). ^bArea under the receiver operating characteristic (ROC) curve was calculated with ESR (normal or not), S-creatinine (normal or not), z score hip total, and z score radius total (above or below -1 SD) as the state variable and resistin as test variable. Null hypothesis: true area under ROC curve = 0.5. CI, confidence interval.

Resistin in patients with systemic lupus erythematosus compared with controls

Forty-two healthy controls with a median age of 52 (18 to 67) years had a median serum resistin value of 6.24 (0.47 to 17.12) ng/mL. The constant and the regression coefficients of the patients with SLE, with respect to resistin values and age, were compared versus the corresponding parameters of the controls by use of a special t test. No significant difference was found between the patients with SLE and the controls (Figure 1).

Figure 1

Correlation between serum resistin levels and age in systemic lupus erythematosus (SLE) patients and controls

Correlation between serum resistin levels and age in systemic lupus erythematosus (SLE) patients and controls. The constant and the regression coefficients, with respect to resistin values and age, were compared with the corresponding parameters of the controls by use of a special t test. The regression coefficient is the slope. No significant difference was found between these parameters.

Discussion

Resistin is an adipokine and a novel cytokine with proinflammatory properties in humans. To our knowledge, this is the first time resistin has been analyzed in the serum of a large cohort of patients with SLE. Our results indicate a clear association between resistin and inflammation, complement levels, BMD, and renal function in SLE. It is too early to assess resistin as a pathogenic factor in SLE disease, although the associations of resistin with low complement levels and the apparent central position in the proinflammatory cytokine cascade make it an interesting subject for further investigation.

In this cross-sectional study of female patients with SLE, resistin was positively associated with inflammation even though resistin levels were not significantly increased compared with controls. Resistin exerts its main action locally in different tissue departments, and the measured serum levels may reflect only a small spillover into the blood compartment 11.

Inflammation in SLE is in contrast to inflammation in other rheumatic diseases characterized by elevated ESR while CRP often remains low. In spite of this, there were associations between resistin and CRP (r = 0.193) as well as between resistin and ESR (r = 0.316). Severe SLE flares (for example, in kidneys and skin) are known to be immune-complex-mediated and accompanied by complement activation and consumption. In our material, resistin correlated to low C3 and high IgG as well as to elevated proinflammatory cytokines such as IL-1β, IL-6, sIL-6R, and TNF-α. The low serum albumin reflects inflammation, but in the case of nephrotic syndrome in 9 (6%) patients, large renal loss of proteins could affect the simple regression outcome. In multiple regression analyses, with resistin as the dependent variable, ESR and low C3 remained significant markers of high resistin levels. Our interpretation is that resistin acts as a marker both of general inflammation exemplified by ESR and of SLE-specific immune-complex-mediated disease activity exemplified by low C3. When ESR was used as the dependent variable in logistic regression analyses (elevated ESR or not), resistin was also significantly associated with ESR (area under the ROC curve = 0.66). In comparison with this result, one may refer to an investigation showing a similar connection, in which the risk of peripheral arterial disease in type 2 diabetes mellitus when HbA1c increased 1 SD generated an area under the ROC curve of 0.64 20.

An association between resistin and inflammation has been reported in several different diseases, including RA 21 and inflammatory bowel disease 5, but is very weak or nonexistent in studies of apparently healthy individuals 22. We found that current glucocorticosteroid dose correlated positively to resistin levels and remained a significant variable of resistin in multiple regression analyses. Resistin production in mouse adipocytes has been shown to increase after exposure to dexamethasone 23. In a patient population, however, it is difficult, if not impossible, to separate the effect of steroid medication by itself from the disease activity it is meant to influence.

The relationship between obesity and expression of resistin is not clear in humans, although the transcription of resistin mRNA is high in preadipocytes during differentiation. Resistin has been shown to correlate to low HDL in a cross-sectional Japanese population 24 and to low HDL and high Tg in a European general population 25. In rheumatic diseases, dyslipoproteinemia is seen and is also known to be linked to inflammation in SLE 262728 and possibly also to the use of glucocorticosteroids 29. We found that resistin was associated with high Tg and low HDL but not with total cholesterol, weight, or body mass index. HDL was significantly associated with resistin in the multiple regression model. If resistin acts as a proinflammatory molecule, it could be one important link in the intricate interactions between inflammation and dyslipoproteinemia and subsequently atherosclerosis seen in SLE and other inflammatory conditions 3031.

We demonstrated a positive correlation between resistin, creatinine, and ever having had nephritis and a negative correlation between resistin and GFR. Similar associations have been shown in different patient groups (for example, in patients with coronary heart disease 32, in kidney allograft recipients 7, and in a small number of children with end-stage renal disease 33). Yaturu and colleagues 12 found significantly higher resistin levels in patients with chronic kidney disease compared with controls but no correlation to GFR. Several of the mentioned reports also revealed a correlation between resistin and inflammation. In our study, serum levels of creatinine remained a significant variable to resistin in the multiple regression analyses. Whether this is due to high systemic inflammation in the patients having ongoing lupus nephritis or to resistin merely being accumulated in the serum of patients with low GFR cannot be decided. Resistin has been shown to be a regulator and to increase the release of IL-1β, IL-6, and TNF-α in human peripheral blood mononuclear cells via the NF-κB pathway. Several endogenous substances like proinflammatory cytokines have also been shown to upregulate resistin gene expression 1134. The NF-κB pathway is involved in osteoclastogenesis, and resistin has been found to stimulate osteoclast differentiation from human peripheral monocytes and, to a lesser extent, osteoblast proliferation in humans 13. Several studies indicate a more pronounced development of osteopenia and osteoporosis in patients with SLE than in controls, and not only due to the use of glucocorticosteroids 14. Therefore, it was interesting that BMD in three of four measured locations and the number of radiological vertebral compression fractures correlated inversely to resistin. The bone resorption marker ICTP correlated positively to resistin. In multiple regression analyses, only BMD in radius remained associated with resistin. Oh and colleagues 35 have shown an inverse correlation of resistin to BMD in lumbar spine in an adult male Korean patient cohort also indicating the connection between resistin and bone metabolism.

Conclusion

In patients with SLE, we now show a clear association between resistin and inflammation, impaired kidney function, low complement levels, use of glucocorticosteroids, BMD, and low HDL. Whether resistin has pathophysiological significance in SLE or whether it should be regarded solely as a marker of inflammation is, for the moment, impossible to say. We encourage and look forward to both clinical and mechanistical studies in this field.

Abbreviations

ACR = American College of Rheumatology; BMD = bone mineral density; CRP = C-reactive protein; ELISA = enzyme-linked immunosorbent assay; ESR = erythrocyte sedimentation rate; GFR = glomerular filtration rate; HDL = high-density lipoprotein; ICTP = C-terminal telopeptide of type I collagen; IgG = immunoglobulin G; IL = interleukin; NF-κB = nuclear factor kappa B; PINP = N-terminal propeptide of type I procollagen; RA = rheumatoid arthritis; ROC = receiver operating characteristic; SD = standard deviation; sIL-6R = soluble interleukin-6 receptor; SLE = systemic lupus erythematosus; Tg = triglycerides; TNF-α = tumor necrosis factor-alpha.

Competing interests

The authors declare that they have no competing interests.

Authors' contributions

KA conceived the study, participated in its design and coordination, performed most of the statistical analyses, and drafted the manuscript. HFd'E participated in study design and coordination, interpretation of statistical analyses, and revision of the manuscript. MB contributed with samples from controls, contributed important knowledge about resistin, and participated in revision of the manuscript. HC participated in study design, interpretation of data, and revision of the manuscript. All authors read and approved the final manuscript.

Acknowledgements

This study was supported by grants from the regional research sources from Västra Götaland, the Medical Society of Göteborg, Rune and Ulla Amlövs Foundation for Rheumatology Research, and the Swedish and Göteborg Association Against Rheumatism. We are grateful to all of the patients in the study. We thank Andrej Shestakov for technical assistance and Anders Odén for statistical advice and support. We thank Anna Jacobsson, Gunilla Håwi, and Ingela Carlberg for their assistance with the patients and Gunnar Sturfelt for critical evaluation of the manuscript.

The hormone resistin links obesity to diabetes Steppan CM Bailey ST Bhat S Brown EJ Banerjee RR Wright CM Patel HR Ahima RS Lazar MA Nature 2001 409 307 312 10.1038/35053000 11201732 A cysteine-rich adipose tissue-specific secretory factor inhibits adipocyte differentiation Kim KH Lee K Moon YS Sul HS J Biol Chem 2001 276 11252 11256 10.1074/jbc.C100028200 11278254 FIZZ1, a novel cysteine-rich secreted protein associated with pulmonary inflammation, defines a new gene family Holcomb IN Kabakoff RC Chan B Baker TW Gurney A Henzel W Nelson C Lowman HB Wright BD Skelton NJ Frantz GD Tumas DB Peale FV Jr Shelton DL Hébert CC EMBO J 2000 19 4046 4055 306596 10921885 10.1093/emboj/19.15.4046 The serum levels ofresistin in rheumatoid arthritis patients Migita K Maeda Y Miyashita T Kimura H Nakamura M Ishibashi H Eguchi K Clin Exp Rheumatol 2006 24 698 701 17207388 Circulating levels of leptin, adiponectin, resistin, and ghrelin in inflammatory bowel disease Karmiris K Koutroubakis IE Xidakis C Polychronaki M Voudouri T Kouroumalis EA Inflamm Bowel Dis 2006 12 100 105 10.1097/01.MIB.0000200345.38837.46 16432373 Resistin McTernan PG Kusminski CM Kumar S Curr Opin Lipidol 2006 17 170 175 10.1097/01.mol.0000217899.59820.9a 16531754 Resistin, a new adipokine, is related to inflammation and renal function in kidney allograft recipients Malyszko J Malyszko JS Pawlak K Mysliwiec M Transplant Proc 2006 38 3434 3436 10.1016/j.transproceed.2006.10.140 17175295 Relationship between serum resistin concentrations and inflammatory markers in patients with type 2 diabetes mellitus Hui-Bing H Migita K Miyashita T Maeda Y Nakamura M Yatsuhashi H Ishibashi H Eguchi K Kimura H Metabolism 2006 55 1670 1673 10.1016/j.metabol.2006.08.008 17142142 Resistin is expressed in human macrophages and directly regulated by PPAR gamma activators Patel L Buckels AC Kinghorn IJ Murdock PR Holbrook JD Plumpton C Macphee CH Smith SA Biochem Biophys Res Commun 2003 300 472 476 10.1016/S0006-291X(02)02841-3 12504108 Human resistin is a systemic immune-derived proinflammatory cytokine targeting both leukocytes and adipocytes Nagaev I Bokarewa M Tarkowski A Smith U PLoS ONE 2006 1 e31 1762367 17183659 10.1371/journal.pone.0000031 Resistin, an adipokine with potent proinflammatory properties Bokarewa M Nagaev I Dahlberg L Smith U Tarkowski A J Immunol 2005 174 5789 5795 15843582 Plasma and urine levels of resistin and adiponectin in chronic kidney disease Yaturu S Reddy RD Rains J Jain SK Cytokine 2007 37 1 5 10.1016/j.cyto.2007.02.003 17383891 Expression and regulation of resistin in osteoblasts and osteoclasts indicate a role in bone metabolism Thommesen L Stunes AK Monjo M Grøsvik K Tamburstuen MV Kjøbli E Lyngstadaas SP Reseland JE Syversen U J Cell Biochem 2006 99 824 834 10.1002/jcb.20915 16721825 Prevalence and risk factors of osteoporosis in female SLE patients-extended report Almehed K Forsblad d'Elia H Kvist G Ohlsson C Carlsten H Rheumatology (Oxford) 2007 46 1185 1190 10.1093/rheumatology/kem105 17500075 The 1982 revised criteria for the classification of systemic lupus erythematosus Tan EM Cohen AS Fries JF Masi AT McShane DJ Rothfield NF Schaller JG Talal N Winchester RJ Arthritis Rheum 1982 25 1271 1277 10.1002/art.1780251101 7138600 Derivation of the SLEDAI. A disease activity index for lupus patients. The Committee on Prognosis Studies in SLE Bombardier C Gladman DD Urowitz MB Caron D Chang CH Arthritis Rheum 1992 35 630 640 10.1002/art.1780350606 1599520 The reliability of the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index in patients with systemic lupus erythematosus Gladman DD Urowitz MB Goldsmith CH Fortin P Ginzler E Gordon C Hanly JG Isenberg DA Kalunian K Nived O Petri M Sanchez-Guerrero J Snaith M Sturfelt G Arthritis Rheum 1997 40 809 813 10.1002/art.1780400506 9153540 Prediction of creatinine clearance from serum creatinine Cockcroft DW Gault MH Nephron 1976 16 31 41 1244564 Vertebral fracture assessment using a semiquantitative technique Genant HK Wu CY van Kuijk C Nevitt MC J Bone Miner Res 1993 8 1137 1148 8237484 UKPDS 59: hyperglycemia and other potentially modifiable risk factors for peripheral vascular disease in type 2 diabetes Adler AI Stevens RJ Neil A Stratton IM Boulton AJ Holman RR Diabetes Care 2002 25 894 899 10.2337/diacare.25.5.894 11978687 Resistin in rheumatoid arthritis synovial tissue, synovial fluid and serum Senolt L Housa D Vernerová Z Jirásek T Svobodová R Veigl D Anderlová K Müller-Ladner U Pavelka K Haluzík M Ann Rheum Dis 2007 66 458 463 10.1136/ard.2006.054734 17040961 Genetic and environmental determinants of circulating resistin level in a community-based sample Pantsulaia I Livshits G Trofimov S Kobyliansky E Eur J Endocrinol 2007 156 129 135 10.1530/eje.1.02311 17218736 Inhibition by insulin of resistin gene expression in 3T3-L1 adipocytes Haugen F Jorgensen A Drevon CA Trayhurn P FEBS Lett 2001 507 105 108 10.1016/S0014-5793(01)02968-4 11682067 Plasma resistin, associated with single nucleotide polymorphism -420, is correlated with insulin resistance, lower HDL cholesterol, and high-sensitivity C-reactive protein in the Japanese general population Osawa H Tabara Y Kawamoto R Ohashi J Ochi M Onuma H Nishida W Yamada K Nakura J Kohara K Miki T Makino H Diabetes Care 2007 30 1501 1506 10.2337/dc06-1936 17384338 Plasma resistin levels correlate with determinants of the metabolic syndrome Norata GD Ongari M Garlaschelli K Raselli S Grigore L Catapano AL Eur J Endocrinol 2007 156 279 284 10.1530/eje.1.02338 17287419 Elevated triglycerides and low levels of high-density lipoprotein as markers of disease activity in association with up-regulation of the tumor necrosis factor alpha/tumor necrosis factor receptor system in systemic lupus erythematosus Svenungsson E Gunnarsson I Fei GZ Lundberg IE Klareskog L Frostegard J Arthritis Rheum 2003 48 2533 2540 10.1002/art.11264 13130473 Dyslipoproteinemias in systemic lupus erythematosus: influence of disease, activity, and anticardiolipin antibodies Borba EF Bonfa E Lupus 1997 6 533 539 10.1177/096120339700600610 9256312 Dyslipoproteinemia during the active course of systemic lupus erythematosus in association with anti-double-stranded DNA (anti-dsDNA) antibodies Kashef S Ghaedian MM Rajaee A Ghaderi A Rheumatol Int 2007 27 235 241 10.1007/s00296-006-0195-3 16944155 Dyslipoproteinemia in systemic lupus erythematosus. Effect of corticosteroids Ettinger WH Goldberg AP Applebaum-Bowden D Hazzard WR Am J Med 1987 83 503 508 10.1016/0002-9343(87)90762-5 3661587 Effects of infection and inflammation on lipid and lipoprotein metabolism: mechanisms and consequences to the host Khovidhunkit W Kim MS Memon RA Shigenaga JK Moser AH Feingold KR Grunfeld C J Lipid Res 2004 45 1169 1196 10.1194/jlr.R300019-JLR200 15102878 The pathogenesis of atherosclerosis in autoimmune rheumatic diseases: Roles of inflammation and dyslipidemia Hahn BH Grossman J Chen W McMahon M J Autoimmun 2007 28 69 75 10.1016/j.jaut.2007.02.004 17433865 Relationship between glomerular filtration rate and the adipokines adiponectin, resistin and leptin in coronary patients with predominantly normal or mildly impaired renal function Risch L Saely C Hoefle G Rein P Langer P Gouya G Marte T Aczel S Drexel H Clin Chim Acta 2007 376 108 113 10.1016/j.cca.2006.07.026 16956602 Circulating resistin concentrations in children depend on renal function Nusken KD Kratzsch J Wienholz V Stohr W Rascher W Dotsch J Nephrol Dial Transplant 2006 21 107 112 10.1093/ndt/gfi084 16144855 Resistin messenger-RNA expression is increased by proinflammatory cytokines <it>in vitro</it> Kaser S Kaser A Sandhofer A Ebenbichler CF Tilg H Patsch JR Biochem Biophys Res Commun 2003 309 286 290 10.1016/j.bbrc.2003.07.003 12951047 The relationship between serum resistin, leptin, adiponectin, ghrelin levels and bone mineral density in middle-aged men Oh KW Lee WY Rhee EJ Baek KH Yoon KH Kang MI Yun EJ Park CY Ihm SH Choi MG Yoo HJ Park SW Clin Endocrinol (Oxf) 2005 63 131 138 10.1111/j.1365-2265.2005.02312.x 16060905