|Ahead of print publication
Serum adiponectin levels in patients with rheumatoid arthritis
Ganesh Veluri1, Kiranmayi S Vinapamula1, P VLN Srinivasa Rao1, Sirisha Kommireddy2, Suchitra Musturu Manohar1, Pullaiah Pasupuleti1
1 Department of Biochemistry, Sri Venkateswara Institute of Medical Sciences, Tirupati, Andhra Pradesh, India
2 Department of Rheumatology, Sri Venkateswara Institute of Medical Sciences, Tirupati, Andhra Pradesh, India
Kiranmayi S Vinapamula,
Department of Biochemistry, Sri Venkateswara Institute of Medical Sciences, Tirupati, Andhra Pradesh
Source of Support: None, Conflict of Interest: None
Background and Objective: Rheumatoid arthritis (RA) is a chronic inflammatory polyarthritis of common occurrence. Adiponectin is an adipocytokine shown to exert anti-inflammatory as well as pro-inflammatory effects. Our objective was to study the serum adiponectin levels in RA and explore its association with RA disease activity.
Materials and Methods: Forty RA patients (newly diagnosed n = 20, RA in clinical remission n = 20) and thirty age-, gender-, and body mass index (BMI)-matched apparently healthy controls were included. Serum adiponectin levels were measured by enzyme-linked immunosorbent assay. RA clinical remission was defined by a Disease Activity Score 28 of <2.6.
Results: Serum adiponectin levels were significantly lower in RA patients compared to controls. Both groups of RA patients had lower adiponectin levels than controls. There was no difference in adiponectin levels between the two groups of RA patients. There was no association of adiponectin with disease activity or BMI.
Conclusions: Serum adiponectin concentration is decreased in RA patients and was not associated with disease activity.
Keywords: Adiponectin, disease activity, Disease Activity Score 28, inflammation, rheumatoid arthritis
| Introduction|| |
Rheumatoid arthritis (RA) is the prototypical chronic inflammatory joint disease that primarily affects the joints and is marked by symmetric, peripheral polyarthritis. Various indices based on clinical, laboratory, and patient-reported variables are in use for the assessment of disease activity. Among them, the Disease Activity Score 28 (DAS28) is widely used for monitoring of disease activity. Management mainly aims at achieving clinical remission of the disease in order to improve the quality of life and also to prevent further complications. Adiponectin, a collagen-like protein mainly produced by adipocytes and present in different molecular isoforms in the blood, is found to exert several beneficial effects through its insulin-sensitizing, anti-inflammatory, vasoprotective, and atheroprotective effects. Circulating adiponectin levels are low in obesity, type 2 diabetes mellitus, atherosclerosis, vascular inflammation, and metabolic syndrome. There is accumulating evidence that adiponectin can control inflammation. On the other hand, there is also evidence that adiponectin acts as a pro-inflammatory mediator by promoting extracellular matrix degradation and joint disruption. It increases the expression of matrix metalloprotein-3 (MMP-3), involved in the synthesis and secretion of pro-inflammatory mediators, such as nitric oxide synthase Type II (NOS2)/inducible NOS, MMP-9, interleukin-6 (IL-6), monocyte chemoattractant protein-1, and IL-8.,
Some studies show that adiponectin may have a role in the pathophysiology of RA by increasing the gene expression and protein synthesis of pro-inflammatory molecules that participate in the pathophysiology of RA. However, the exact role of adiponectin in RA is still incompletely understood. In this background, the present study was taken up to evaluate serum adiponectin levels of patients with RA.
| Materials and Methods|| |
This was a cross-sectional study, conducted in the Department of Biochemistry, Sri Venkateswara Institute of Medical Sciences, Tirupati. Patients with RA attending the rheumatology outpatient clinic fulfilling the 2010 American College of Rheumatology/European League Against Rheumatism classification criteria were eligible to participate in the study. Patients with other forms of arthritis, thyroid disorders, cardiovascular disease, liver and kidney diseases, hypertension, diabetes mellitus, and smoking and/or alcoholism were excluded from the study. Disease activity was assessed by the DAS28 as described by Prevoo et al. Clinical remission was defined as DAS28 <2.6.
Forty patients with RA (newly diagnosed n = 20, those in clinical remission n = 20) were enrolled. We had enrolled 20 newly diagnosed and 20 who were in clinical remission for the purpose of exploring the relationship of adiponectin with disease activity. Thirty apparently healthy individuals who were matched for age, gender, and body mass index (BMI) were enrolled as controls. The sample size was calculated with a power of 80% and an alpha error of 0.05 based on the data obtained from the previous studies, and was found to be adequate.
Three milliliters of fasting venous blood sample was collected from all the participants and separated by centrifugation at 3000 rpm for 15 min. The separated serum samples were stored at −80°C until biochemical analysis. Lipid profile (total cholesterol, triglycerides, and high-density lipoprotein cholesterol) was analyzed by standard methods on Unicel DxC 600 autoanalyzer (Beckman Coulter, Galway, Ireland). Adiponectin was assayed by enzyme-linked immunosorbent assay on ChemWell analyzer (Awareness Technology, USA).
All the individuals were included in the study after taking informed consent. The study was approved by the Institutional Ethics Committee (IEC No: 586, date 09.01.2017). The difference in the adiponectin levels between RA patients and controls was assessed using Student's t-test or Mann–Whitney U-test and ANOVA or Kruskal–Wallis test followed by pair-wise comparisons, as appropriate. The association between the variables was studied using Pearson or Spearman rank correlation analysis. Statistical analysis was performed using Microsoft Excel spreadsheets and SPSS for Windows version 16.0 (SPSS Inc, Chicago, IL, USA). P <0.05 was considered statistically significant.
| Results|| |
The demographic characteristics and biochemical parameters of the RA patients and controls are shown in [Table 1]. Patients with RA had significantly higher fasting blood glucose and triglycerides when compared to controls. Patients in remission had a mean DAS28 score of 2.31, whereas newly diagnosed RA patients had a mean DAS28 score of 6.03. Serum adiponectin concentrations were significantly lower in RA patients compared to healthy controls [Table 1] and [Figure 1].
|Table 1: Demographic characteristics and biochemical parameters studied in healthy controls and rheumatoid arthritis patients|
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|Figure 1: Serum adiponectin levels in controls and rheumatoid arthritis patients|
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A comparison of the demographic characteristics and biochemical parameters between controls (Group 1), RA patients in clinical remission (Group 2), and RA patients who were newly diagnosed (Group 3) is presented in [Table 2]. Analysis of variance showed significantly increased fasting blood glucose levels and decreased serum adiponectin concentration across the three study groups (P = 0.003 and P < 0.001 for fasting blood sugar and adiponectin, respectively). Further analysis using post hoc tests revealed that both groups of RA patients had significantly higher fasting blood glucose when compared to controls (P = 0.008 and P = 0.015 for RA patients in remission and patients newly diagnosed, respectively). On the other hand, serum adiponectin levels were observed to be significantly decreased in both groups of RA patients than in controls (P = 0.021 and P < 0.001 for RA patients in remission and patients newly diagnosed, respectively). However, both subgroups of RA patients had similar adiponectin levels (P = 0.625). Adiponectin did not show significant association with BMI or DAS28 in any of the groups.
|Table 2: Demographic characteristics and biochemical parameters studied in healthy controls, rheumatoid arthritis patients in remission, and newly diagnosed rheumatoid arthritis patients|
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| Discussion|| |
In this study, we found that RA patients had significantly lower serum adiponectin levels when compared to controls. Similar to our findings, El-Hini et al. and Li et al., have reported lower adiponectin levels in RA patients compared to healthy controls. In both the studies (El-Hini et al. and Li et al.), the patient population were treatment-naïve early RA with disease duration <1 year. Contrastingly, Chennareddy et al. from India reported higher serum adiponectin levels in treatment-naïve early RA patients. A recent meta-analysis by Lee and Bae et al. reported that circulating adiponectin levels were significantly higher in RA patients when compared to controls. In our study, we found adiponectin to be low in RA as compared to controls. We had included both newly diagnosed untreated cases and those who were in remission. The results of our study may just suggest that the actual relationship of adiponectin with inflammatory milieu of RA is quite complex. Physiologically, adiponectin inhibits the release of pro-inflammatory cytokines and increase the production of anti-inflammatory cytokines from activated inflammatory cells. Conversely, pro-inflammatory mediators such as tumor necrosis factor-alpha (TNF-α) and IL-6 are known to suppress adiponectin production. Some experimental studies have demonstrated that the association of adiponectin with TNF-α is bidirectional and inverse., Studies have shown that anti-TNF-α treatment results in increased adiponectin levels. Other reasons why adiponectin concentrations have shown variable results between studies include variable disease duration, disease activity, sample size, and ethnicity of the study population.,
We did not find a significant correlation of adiponectin either with BMI or DAS28. Similar to our results, Senolt et al. and Chennareddy et al. found no significant association of adiponectin with BMI or disease activity of RA patients. On the other hand, both positive and negative association between adiponectin and disease activity has also been reported earlier. The meta-analysis of Lee and Bae, reported that circulating adiponectin was not associated with RA disease activity. One plausible explanation of this variation of results is that circulating adiponectin exists in multimeric forms and the various forms of adiponectin differ with respect to their biological activity. Findings of Li et al. have shown that among all the multimeric forms of adiponectin, the low molecular weight form is more strongly associated with disease activity. Hence, total adiponectin levels may not adequately reflect the effects of adiponectin on disease activity in RA. Thus, measurement of the various forms of adiponectin and exploring their association with disease activity may help in a better understanding of the role of adiponectin in RA. RA being an inflammatory condition is associated with increased levels of inflammatory cytokines. The increased cytokines could have resulted in the lower adiponectin levels observed in RA patients. However, we have not measured inflammatory markers in these patients; this is one major limitation of the study. Besides this, the lack of availability of data on disease duration and serology are the other limitations of the study.
| Conclusions|| |
RA patients in the present study have significantly lower serum adiponectin levels when compared to controls. Adiponectin has a complex role in RA, and circulating levels may not accurately reflect the underlying inflammatory process in the synovium.
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Conflicts of interest
There are no conflicts of interest.
| References|| |
Kadowaki T, Yamauchi T. Adiponectin and adiponectin receptors. Endocr Rev 2005;26:439-51.
Robinson K, Prins J, Venkatesh B. Clinical review: Adiponectin biology and its role in inflammation and critical illness. Crit Care 2011;15:221.
Lago R, Gomez R, Otero M, Lago F, Gallego R, Dieguez C, et al.
Anew player in cartilage homeostasis: Adiponectin induces nitric oxide synthase type II and pro-inflammatory cytokines in chondrocytes. Osteoarthritis Cartilage 2008;16:1101-9.
Gómez R, Scotece M, Conde J, Gómez-Reino JJ, Lago F, Gualillo O, et al.
Adiponectin and leptin increase IL-8 production in human chondrocytes. Ann Rheum Dis 2011;70:2052-4.
Choi HM, Lee YA, Lee SH, Hong SJ, Hahm DH, Choi SY, et al.
Adiponectin may contribute to synovitis and joint destruction in rheumatoid arthritis by stimulating vascular endothelial growth factor, matrix metalloproteinase-1, and matrix metalloproteinase-13 expression in fibroblast-like synoviocytes more than proinflammatory mediators. Arthritis Res Ther 2009;11:R161.
Aletaha D, Neogi T, Silman AJ, Funovits J, Felson DT, Bingham CO 3rd
, et al.
2010 rheumatoid arthritis classification criteria: An American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheum 2010;62:2569-81.
Prevoo ML, van 't Hof MA, Kuper HH, van Leeuwen MA, van de Putte LB, van Riel PL, et al.
Modified disease activity scores that include twenty-eight-joint counts. Development and validation in a prospective longitudinal study of patients with rheumatoid arthritis. Arthritis Rheum 1995;38:44-8.
Fransen J, Creemers MC, Van Riel PL. Remission in rheumatoid arthritis: Agreement of the disease activity score (DAS28) with the ARA preliminary remission criteria. Rheumatology (Oxford) 2004;43:1252-5.
Alkady EA, Ahmed HM, Tag L, Adel M. Adipocytokines: Adiponectin, resistin and visfatin in serum and synovial fluid of rheumatoid arthritis patients and their relation to disease activity. Med J Cairo Univ 2010;78:723-9.
El-Hini SH, Mohamed FI, Hassan AA, Ali F, Mahmoud A, Ibraheem HM, et al.
Visfatin and adiponectin as novel markers for evaluation of metabolic disturbance in recently diagnosed rheumatoid arthritis patients. Rheumatol Int 2013;33:2283-9.
Li P, Yang L, Ma CL, Liu B, Zhang X, Ding R, et al.
Low-molecular-weight adiponectin is more closely associated with disease activity of rheumatoid arthritis than other adiponectin multimeric forms. Clin Rheumatol 2015;34:1025-30.
Chennareddy S, Kishore Babu KV, Kommireddy S, Varaprasad R, Rajasekhar L. Serum adiponectin and its impact on disease activity and radiographic joint damage in early rheumatoid arthritis – A cross-sectional study. Indian J Rheumatol 2016;11:82-5. [Full text]
Lee YH, Bae SC. Circulating adiponectin and visfatin levels in rheumatoid arthritis and their correlation with disease activity: A meta-analysis. Int J Rheum Dis 2018;21:664-72.
Bruun JM, Lihn AS, Verdich C, Pedersen SB, Toubro S, Astrup A, et al.
Regulation of adiponectin by adipose tissue-derived cytokines:In vivo
investigations in humans. Am J Physiol Endocrinol Metab 2003;285:E527-33.
Nagashima T, Okubo-Fornbacher H, Aoki Y, Kamata Y, Kimura H, Kamimura T, et al.
Increase in plasma levels of adiponectin after administration of anti-tumor necrosis factor agents in patients with rheumatoid arthritis. J Rheumatol 2008;35:936-8.
Senolt L, Pavelka K, Housa D, Haluzík M. Increased adiponectin is negatively linked to the local inflammatory process in patients with rheumatoid arthritis. Cytokine 2006;35:247-52.
Ozgen M, Koca SS, Dagli N, Balin M, Ustundag B, Isik A, et al.
Serum adiponectin and vaspin levels in rheumatoid arthritis. Arch Med Res 2010;41:457-63.
Komai N, Morita Y, Sakuta T, Kuwabara A, Kashihara N. Anti-tumor necrosis factor therapy increases serum adiponectin levels with the improvement of endothelial dysfunction in patients with rheumatoid arthritis. Mod Rheumatol 2007;17:385-90.
[Table 1], [Table 2]