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Rheumatology Advance Access originally published online on May 29, 2008
Rheumatology 2008 47(7):1082-1087; doi:10.1093/rheumatology/ken187
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© The Author 2008. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Resistin in serum is associated with higher levels of IL-1Ra in post-menopausal women with rheumatoid arthritis

H. Forsblad d’Elia, R. Pullerits, H. Carlsten and M. Bokarewa

Department of Rheumatology and Inflammation Research, Sahlgrenska Academy at Göteborg University, Göteborg, Sweden.

Correspondence to: H. Forsblad d’Elia, Department of Rheumatology and Inflammation Research, Sahlgrenska Academy at Göteborg University, Guldhedsgatan 10, S-413 46 Göteborg, Sweden. E-mail: helena.forsblad{at}vgregion.se


   Abstract
Top
 Abstract
Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
Objectives. The aim of this study was to investigate associations between serum levels of resistin, an adipokine and markers of inflammation, bone metabolism, plasma lipids and kidney function in post-menopausal RA patients and to evaluate if HRT during 2 yrs affected resistin levels.

Methods. Eighty-eight women were randomly allocated to receive HRT, vitamin D3 and calcium or vitamin D3 and calcium alone. Serum levels of resistin, IL-1β, IL-1 receptor antagonist (IL-1Ra), IL-6, IL-6 soluble receptor, TNF-{alpha} were measured by ELISA, markers of bone metabolism, carboxyterminal cross-linked telopeptide of type I collagen (ICTP) and carboxyterminal propeptide of type I procollagen by RIA, ESR, CRP, Hb, creatinine and lipids by standard laboratory techniques, BMD and total lean mass (TLM) by DXA and joint destruction by Larsen score. Resistin was also measured in 42 healthy control women.

Results. There was no difference in resistin concentration between patients and healthy controls. Resistin was significantly correlated with IL-1Ra, CRP, TNF-{alpha}, ICTP, glucocorticosteroids and Larsen score and inversely with BMD, hip and with TLM. In multiple regression analysis, IL-1Ra, TLM and use of corticosteroids remained determinants of resistin. Patients treated with HRT displayed significant increase in resistin compared with controls in the first but not the second year.

Conclusions. Resistin was associated with increased inflammation, particularly by the acute-phase reactant IL-1Ra antagonizing IL-1β, joint destruction, glucocorticosteroids and with reduced BMD and TLM. These findings suggest resistin being a significant mediator in the inflammatory process in RA. Further studies examining the mechanisms behind the relation between resistin and IL-1Ra are encouraged. HRT does not seem to have important long-term effect on resistin.

KEY WORDS: Rheumatoid arthritis, Resistin, Hormone replacement therapy, Oestrogen, Oestradiol, Cytokines, Interleukin-1Ra, Glucocorticosteroids, Bone mineral density, Total lean mass


   Introduction
Top
 Abstract
 Introduction
Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
Resistin is an adipokine that was independently discovered by three different groups some years ago. It was identified as an adipose tissue-specific secreted factor [1] and as a protein ‘found in inflammatory zone 3’ (FIZZ3) [2] and as a hormone that potentially linked obesity to diabetes [3]. In mouse, resistin is almost exclusively expressed in white adipose tissue whereas the production of resistin by human adipose tissue is significantly lower and sometimes even undetectable. Instead, in humans, resistin is expressed, for instance, in bone marrow and lungs [4], in non-fat cells of adipose tissue [5], in placental tissue [6], in pancreatic islet cells [7] and in synovial tissue [8].

Mouse and human resistin genes are localized on different chromosomes and mouse and human resistin share 64.4% sequence homology at mRNA level and 59% identity at the amino acid level [9]. Thus, there seems to be differences in the functions of resistin between different species.

In humans, it has been found that plasma resistin levels correlate with determinants of the metabolic syndrome and with obesity [10, 11], with inflammation and impaired function in patients with chronic kidney disease [12, 13], with histological inflammatory score in patients with non-alcoholic fatty liver disease [14], with inflammation in IBD [15], with high risk for adverse cardiac events in patients with congestive heart failure [16] and inversely with BMD in lumbar spine in men [17]. In apparently healthy individuals, resistin was strongly influenced by genetic factors and only to a small extent associated with measures of inflammation [18]. Resistin polymorphisms have also been found to be associated with certain phenotypes [19, 20].

Recently, it was shown that resistin in SF from patients with RA displayed significantly higher levels as compared with control samples and with patients with OA [8, 21, 22] and that resistin was associated with laboratory measures of inflammation and disease activity in RA [8, 21, 23].

It has been discussed that gender- and sex-hormones may be one factor influencing resistin expression and function since female plasma resistin has been found to be higher as compared with the level in men [18, 24, 25].

The aim of this study was to investigate relationships between resistin and markers of inflammation in post-menopausal women with RA and also to relate resistin with factors that have not previously been studied in RA in the context of resistin. Thus, associations between resistin and laboratory markers of inflammation, kidney function, plasma lipids, bone metabolism and measures of body composition including BMD, total lean mass (TLM) and body fat were assessed. In addition, we wanted, for the first time, to evaluate the long-term effect of HRT on resistin levels in serum in a 2-yr-controlled trial of post-menopausal women with RA.


   Materials and methods
Top
 Abstract
 Introduction
 Materials and methods
Results
 Discussion
 Acknowledgements
 References
 
Patients
Women with RA aged between 45 and 65 yrs were invited by mail to enter an observational and at the same time 2-yr randomized controlled trial (RCT) evaluating effects of HRT. The included patients had an active disease that met at least two of the following criteria: more than six painful joints, more than three swollen joints, ESR >20 mm/h, CRP >10 mg/l and they also fulfilled the ARA 1987 revised criteria for adult RA [26]. A maximum daily dose of 7.5 mg of prednisolone was accepted and IA and intramuscular glucocorticosteroid injections were allowed during the study period. The women should be post-menopausal and should have no contraindications for HRT. For additional information, please see previous report also [27].

All patients gave informed consent and the study was approved by the Ethics Committee at Sahlgrenska Academy at Göteborg University.

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

Assessment of outcome variables
Disease activity score 28
Disease activity score (DAS 28) was assessed [28].

Glucocorticosteroids
The cumulative dose of oral prednisolone was calculated and any present use was registered for each participant.

Venous blood samples
Venous blood samples were obtained in the morning after an overnight fast. The samples were stored at –70°C until the time of analysis. Serum samples were analysed simultaneously except ESR, CRP, Hb and creatinine, which were measured consecutively at the Department of Clinical Chemistry, Sahlgrenska University Hospital. RF had been measured in the past.

Plasma lipoproteins
High-density lipoprotein (HDL), low-density lipoprotein (LDL) and triglycerides were analysed using standard laboratory techniques in the Department of Clinical Chemistry, Sahlgrenska University Hospital.

Oestradiol
Oestradiol (E2) levels in serum were measured (around 12 h after tablet intake) at baseline and yearly thereafter using RIA (Clinical AssaysTM, DiaSorin, Vercelli, Italy). The detection limit of the test was 18 pmol/l.

Resistin
Resistin levels were detected with a quantitative sandwich ELISA (R & D Systems, Minneapolis, MN, USA). Lowest detectable level was 31 pg/ml.

Cytokines
Quantitative sandwich ELISA kits were used for measurements of TNF-{alpha}, IL-1β, IL-1 receptor antagonist (IL-1Ra), IL-6 and IL-6 soluble receptor (sIL-6R) (Quantikine® HS, R & D Systems). The sensitivity of the assays were; TNF-{alpha} 0.18 pg/ml, IL-1β 0.1 pg/ml, IL-1Ra 14 pg/ml, IL-6 0.7 pg/ml and sIL-6R 6.5 pg/ml.

The IL-6 levels were undetectable in 17% of the patients and the IL-1β concentration was low and under the detectable level in 49% of the RA patients. The other cytokines were detected in all women.

Markers of bone turnover
RIA was used for the quantitative determination in serum of the bone resorption marker, carboxyterminal cross-linked telopeptide of type I collagen (ICTP) and for the bone formation marker, carboxyterminal propeptide of type I procollagen (PICP) (Orion Diagnostica, Espoo, Finland). The detection limit of the tests were; ICTP 0.5 µg/l and PICP 1.2 µg/l.

Radiographs
Radiographs of the hands, wrists and forefeet were evaluated according to Larsen [29]. The scores for each patient were summarized and then divided by the number of examined joints to give the mean Larsen score for each patient ranging from 0 to 5.

BMD and body composition
BMD at left hip and lumbar spine and body composition with TLM and percentage of fat were measured by DXA with Hologic QDR-4500A (Hologic®, Bedford, MA, USA).

Some of the patients had incomplete data due to shortage of the samples. The numbers of patients with available data are presented in all tables.

HRT
Patients were assigned by the gynaecologists to one of two treatment groups, the HRT group or the control group by simple randomization. Forty-one patients were randomized to the HRT group and 47 to the control group. Women in the HRT group who were more than 2 yrs post-menopausal were given continuous treatment with 2 mg E2 plus 1 mg noretisterone acetate daily (23 women), those with a previous hysterectomy just 2 mg E2 (4 women) and the remaining women obtained 2 mg E2 during 12 days followed by 10 days of 2 mg E2 plus 1 mg noretisterone acetate followed by 6 days of 1 mg E2 (14 women). The investigators at the rheumatology departments were blinded to the identity of the therapy but not the gynaecologist. All patients were treated with a daily dose of 500 mg calcium and 400 IU vitamin D3. Regular medication for RA could be altered by the clinician but not by the investigator.

There were no significant differences in baseline characteristics between the HRT group and the control group regarding age, disease duration, treatment and disease activity measurements [27].

Six patients in the HRT group and two in the control group withdrew from the study before completing the 2 yrs. No serious side-effects were observed [27].

Statistical analysis
Descriptive statistics are presented as mean and S.D. The majority of data were not normally distributed, tested by Kolmogorov–Smirnov's test. However, resistin in serum was normally distributed in the RA patients as well as in the healthy controls. In the aim of finding out if there were any difference between serum levels of resistin in the RA patients and healthy controls, the constant and the regression coefficient of RA patients were compared with healthy controls with respect to resistin and age with a special t-test [30].

Associations between different variables and resistin were assessed by Spearman's rank correlation test. Significant variables were then entered in the multiple linear regression analyses as independent variables and resistin as dependent variable. A forward stepwise method was used.

Comparisons between the HRT groups and the control group at study start and changes between the groups were made using Mann–Whitney U-test and changes within the HRT and control groups by Wilcoxon rank sum test. Chi-square test was also used to compare any differences between the HRT and control group.

Patients who dropped out were included in calculations until withdrawal. Analyses were performed using SPSS version 11.0.1. All tests were two-tailed and P ≤ 0.05 was considered statistically significant.


   Results
Top
 Abstract
 Introduction
 Materials and methods
 Results
Discussion
 Acknowledgements
 References
 
Patient population
Eighty-eight women entered the trial. Characteristics of the patients, disease activity measurements, cytokines, plasma lipids, BMD, TLM, percentage of fat, radiological Larsen score and markers of bone turnover are shown in Table 1.


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  		TABLE 1. Demographic and disease-related variables in 88 post-menopausal women with RA

 
Resistin in post-menopausal women with RA compared with healthy controls
The mean serum level of resistin in the RA women was 5.1 ± 1.7 ng/ml (n = 80) and the mean serum resistin level in 42 healthy control women with a mean age of 49.2 ± 12.5 yrs was 6.4 ± 3.2 ng/ml. The constant and the regression coefficients of the RA patients, with respect to resistin values and age, were compared vs the corresponding parameters of the controls by use of a special t-test. No significant difference was found between the serum levels of resistin in RA patients compared with the healthy controls (Fig. 1).


Figure 1
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  		FIG. 1. Correlation between serum resistin levels and age in RA patients and controls. The constant and the regression coefficient, 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.

 
Associations with resistin
The baseline concentrations of resistin in serum were correlated with the variables in Table 1 and significant correlations are shown in Table 2.


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  		TABLE 2. Significant correlations between resistin in serum and disease- and bone-related variables in post-menopausal women with RA

 
Resistin was strongly correlated with IL-1Ra at baseline (rs = 0.47, P < 0.001, Fig. 2a). Also, the change in resistin was associated with the change in IL-1Ra at 2 yrs (rs = 0.37, P = 0.001, Fig. 2b).


Figure 2
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  		FIG. 2. The associations between (a) baseline serum values of resistin and IL-1Ra and (b) changes in resistin and IL-1Ra after 2 yrs follow-up are shown in scattergram plots. Spearman rank correlation coefficients (rs) and P-values are given. One extreme value of IL-1Ra, 3640 pg/ml at baseline and two values of IL-1Ra changes, 2289 and 2653 pg/ml are excluded from the figures.

 
At baseline, resistin was also positively associated with treatment with corticosteroids and with the cumulative oral dose of corticosterosids, CRP and TNF-{alpha}, ICTP and Larsen score and inversely with BMD in the total hip and femoral neck as well as with the TLM (Table 2).

A multiple regression model with resistin as dependent variable was performed. High serum level of IL-1Ra, treatment with glucocorticosteroids and low TLM remained significant baseline markers of high resistin (R2 = 0.36, Table 3).


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  		TABLE 3. Multiple stepwise regression analyses of resistin (dependent variables) and demographic and disease-related variables (independent variables)

 
Resistin was not significantly correlated with Il-1β, which might be explained by the fact that only 51% of the patients showed IL-1β above the detectable level. Therefore, we investigated the mean serum level of resistin in patients with IL-1β above the 75th percentile (n = 17) and found it significantly higher as compared with the resistin level in patients with IL-1β below the 75th percentile (n = 63) (Fig. 3a). In the same way, the value of resistin was significantly higher in patients with IL-1Ra above the 75th percentile as compared with patients displaying IL-1Ra below the 75th percentile (Fig. 3b).


Figure 3
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  		FIG. 3. Comparisons between the levels of resistin in serum in patients with values of (a) IL-1β and (b) IL-1Ra above the 75th percentile, high (n = 17) and patients with values below the 75th percentile, low (n = 63).

 
Impact of HRT on serum levels of resistin
In Table 4, the mean serum levels of resistin are demonstrated in the HRT and in the control group. There was a significant increase in resistin at 1 yr compared with the change in the control group. At 2 yrs there was no difference in changes between the study groups. Resistin increased significantly at 1 and 2 yrs in the HRT group compared with baseline values and in the controls there was a significant increase at 1 yr but not at 2 yrs.


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  		TABLE 4. The impact of HRT on resistin in serum in post-menopausal women with RA

 
The serum concentration of E2 increased significantly in the HRT group but did not change in the controls. In the HRT group, the mean value at baseline was 48 ± 48 pmol/l and at 2 yrs 176 ± 124 pmol/l, and in the control group 37 ± 26 pmol/l and 38 ± 39 pmol/l, respectively.

At baseline, E2 levels were not significantly correlated with resistin in serum.


   Discussion
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
Acknowledgements
 References
 
The purpose of this study was to investigate connections with resistin in the aim of finding out the most important markers of resistin in post-menopausal RA women. Also, we have for the first time studied the long-term effect of HRT on resistin levels in a 2-yr RCT. We found that resistin was associated with laboratory markers of inflammation, particularly IL-1Ra, with glucocorticosteroids, joint destruction, with reduced BMD and TLM. In the prospective study, HRT resulted in a transient increase in resistin which did not sustain after 2 yrs compared with controls.

Serum values of resistin in the post-menopausal RA patients were also compared with levels in healthy control women. No difference was found between the groups in serum resistin concentration. This result is in line with some previous findings displaying no dissimilarity to controls [22, 31] whereas others have shown higher resistin levels in serum in RA [8, 23]. The discrepancy might be due to differences in disease activity in the diverse RA groups. For instance, our patients had a mean DAS 28 score at 5.3, ESR 29 mm/h and CRP at 17 mg/l at baseline as compared with the study of Senolt et al. [8], showing higher resistin values compared with their controls, demonstrating median DAS 28 score at 6.0, ESR 35 mm/h and CRP at 66 mg/l.

In the trial by Senolt et al. [8] serum resistin was associated with DAS 28 and CRP and Migita et al. [23] reported correlations between serum resistin and CRP, ESR and TNF-{alpha}. We also found significant connections between serum resistin and measures of inflammation; CRP, TNF-{alpha} and IL-1Ra, which underlines its role as an adipokine associated with inflammation. IL-1Ra, a member of the IL-1 family, binds to IL-1 receptors but does not induce any intracellular response. IL-1Ra is produced by hepatic cells, and also expressed in spleen and white adipose tissue, with the characteristics of an acute-phase protein and is at the same time believed to have an important anti-inflammatory role [32–34]. Interestingly, IL-1Ra has been found to be associated with leptin, another adipokine and strongly with lean body mass, in obese subjects [35]. However, we did not find an association between IL-1Ra and weight, BMI or TLM in post-menopausal RA women. IL-1Ra is elevated in blood in many rheumatic diseases including RA [36]. In RA, it seems to be a dysregulation of the endogenous IL-1Ra production with a relative deficiency as compared with the pro-inflammatory cytokine IL-1β [36]. In accordance, treatment with IL-1Ra in RA have exhibited improvement in clinical parameters and decreased radiological progression [37]. In this study, we found a significant and strong correlation between resistin and IL-1Ra and in the multiple regression analysis IL-1Ra remained an important determinant of resistin. Furthermore, the change in resistin in all patients during 2 yrs was significantly correlated with the change in IL-1Ra. In addition, the serum levels of resistin in patients with IL-1β above the 75th percentile, was significantly higher as compared with resistin in patients with IL-1β below the 75th percentile, although the mean serum level of IL-1β was low and below the detectable level in half of the patients.

Thus, there are several findings underscoring this connection between resistin and IL-1β/IL-1Ra, which needs to be further investigated. Is IL-1β/IL-1Ra influencing resistin or vice versa, or both?

We also found significant associations between resistin and glucocorticosteroids, which may be influenced by the fact that glucocorticosteroids may themselves be a marker of increased disease activity [38].

BMD and body composition was measured by DXA and interestingly resistin was inversely correlated with BMD in the hip and also with TLM. In accordance to these findings, inverse associations between resistin and BMD in several locations in women with SLE was recently reported [39]. It has been indicated that resistin has a role in osteoclastogenesis [40], in line with our findings, showing moderate correlations between resistin and the marker of increased osteoclast activity, ICTP. Notably, TLM was one of the most important factors of serum resistin found in the multiple regression model. TLM also showed strong positive connection to BMD (hip total rs = 0.63, P > 0.001; femoral neck rs = 0.60, P < 0.001; and lumbar spine rs = 0.48, P < 0.001), possibly due to the action of muscles, exerting mechanical stress on bone, improving bone mass [41].

Gender seems to influence serum resistin concentration; studies have shown higher resistin in pre-menopausal women [24] and in a group of both pre- and post-menopausal women [25] as compared with men. Exogenous oestrogen therapy has shown disparate results; in a trial of post-menopausal women with metabolic syndrome, short-term oral oestrogen treatment increased resistin levels [42] and in another study resistin levels were not affected by short-term oestrogen or by ovariectomy [43], whereas resistin remained unchanged by use of combined oral contraceptives in healthy young women [44].

We have for the first time assessed, in post-menopausal women with RA, the long-term effect of HRT on resistin in an RCT. At 1 yr in our trial, resistin had increased significantly in both the HRT and control group but significantly more in the HRT group compared with the controls. At 2 yrs, resistin was reduced compared with 1 yr but still significantly increased compared with baseline in the HRT. Thus, there is a group difference at 1 yr but this difference does not sustain at 2 yrs. We do not know the reason for this transitory increase but possibly some adaptive mechanisms related to HRT may be involved. We have no clear evidence that the transitory increase should be related to other medications since the percentage of patients treated with different DMARDs, MTX and corticosteroids were equal in the HRT and control group at all check points. In the present study, it is not possible to tell to which degree the different hormones, E2 and progesterone contributed to the results since only four women were treated with E2 alone.

In conclusion, the present study demonstrates associations between resistin and signs of increased laboratory inflammation, particularly with the acute-phase reactant IL-1Ra antagonizing the pro-inflammatory IL-1β, joint destruction, uses of glucocorticosteroids and with reduced BMD and TLM in post-menopausal women with RA. These findings suggest that resistin is a significant mediator in the inflammatory process in RA. We also believe that the mechanisms behind the strong connection between resistin and IL-1Ra needs to be further investigated. HRT (E2 and noretisterone acetate) does not seem to have important long-term effect on serum resistin concentration in this study population.

Formula


   Acknowledgements
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
References
 
We thank Anders Odén for statistical support.

Funding: This study has been supported by grants from The Health and Medical Care Executive Board of the Västra Götaland, Rune och Ulla Amlövs Foundation for Rheumatology Research, Göteborg's Association against Rheumatism, The Medical Society of Göteborg, the Medical Faculty of Göteborg (LUA) and the Margareta Research Foundation.

Disclosure statement: The authors have declared no conflicts of interest.


   References
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 

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Submitted 30 January 2008; revised version accepted 10 April 2008.
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F. Montecucco and F. Mach
Common inflammatory mediators orchestrate pathophysiological processes in rheumatoid arthritis and atherosclerosis
Rheumatology, January 1, 2009; 48(1): 11 - 22.
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