Total and high-molecular weight plasma adiponectin associates with markers of inflammation and circulating chemokines in subjects with untreated newly diagnosed rheumatoid arthritis.

doi:10.21203/rs.3.rs-21871/v1

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Total and high-molecular weight plasma adiponectin associates with markers of inflammation and circulating chemokines in subjects with untreated newly diagnosed rheumatoid arthritis.

https://doi.org/10.21203/rs.3.rs-21871/v1

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Background Adiponectin is an adipokine circulating in blood in three forms, whereof the high molecular weight (HMW) is supposed to mediate the metabolic effects of adiponectin. Subjects with rheumatoid arthritis (RA) have elevated levels of adiponectin in serum and synovial fluid but it is unclear if circulating adiponectin associates with disease activity markers in subjects with RA. Here we aimed to determine whether total and/or HMW adiponectin levels associate with markers of disease activity and plasma chemokines in a cohort of subjects with untreated newly diagnosed RA.

Methods Inflammation and disease activity were assessed in a cohort of 70 subjects with untreated newly diagnosed RA using erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), number of tender or swollen joints, as well as disease activity scores (DAS28 and CDAI) Plasma levels of 15 chemokines were measured using flow cytometry bead-based immunoassay or ELISA. Total and HMW adiponectin plasma levels were determined with ELISA.

Results Both total and HMW adiponectin were positively associated with CRP (both P = 0.001) and ESR (P = 0.001 and P < 0.001 respectively). Furthermore, a positive association was found between total adiponectin and CXCL10 (P = 0.021), CCL2 (P = 0.012) and CXCL9 (P = 0.044), whereas HMW adiponectin associated with CXCL9 only (P = 0.033).

Conclusion Total and HMW adiponectin are associated with markers of inflammation as well as pro-inflammatory chemokines in a cohort of 70 subjects with untreated newly diagnosed RA. Our results support the hypothesis that adiponectin might be a pro-inflammatory factor involved in the pathogenesis of RA.

Rheumatology

Adiponectin

Chemokines

Inflammation

Rheumatoid Arthritis

Rheumatoid arthritis (RA) is a chronic, inflammatory, autoimmune disease mainly involving the joints (1). The disease is characterized by synovial inflammation after immune cell infiltration and stromal cell activation (2). Chemokines are small cell-signalling proteins that attract immune cells, which initiate the process of cartilage and bone destruction in the arthritic joint (3) (4). In subjects with RA, chemokines such as CCL2, CCL3, CCL4, and CXCL10, are elevated in plasma and synovial fluid (5). Moreover, the increase in circulating chemokines precedes the diagnosis of RA, indicating an early activation of the systemic immune system years before the onset of the first symptoms (6).

Adiponectin is a cytokine produced by the adipose tissue, a so called adipokine, and is involved in glucose and lipid metabolism as well as inflammation (7, 8). Adiponectin circulates in blood in three forms: low molecular weight (LMW) trimers, middle molecular weight (MMW) hexamers, and high molecular weight (HMW) multimers, consisting of 12 or more monomers (9). HMW adiponectin is supposedly the active form in the context of metabolism (10). It is however unclear which form mediates the inflammatory effects of adiponectin (11).

While adiponectin was traditionally thought of as an anti-inflammatory agent (12), recent studies have questioned this paradigm. In subjects with RA, adiponectin levels are elevated in both plasma and synovial fluid (13, 14). Nevertheless, it is debated if the increase in adiponectin levels is a mechanism to counterbalance the surrounding inflammation or whether adiponectin is pro-inflammatory in the context of RA. We have recently shown in a cohort of subjects with obesity that serum adiponectin levels increase several years before the development of RA (15). Moreover, adiponectin induces the production of pro-inflammatory cytokines, such as interleukin (IL)-6 in lymphocytes and fibroblast-like synoviocytes (FLS) from subjects with RA (16–18). Adiponectin is also able to induce the production of chemokines in both lymphocytes, where it stimulates CXCL1 and CXCL8 secretion, and in FLS from subjects with RA, where it stimulates CXCL8 (16, 17, 19). Besides, plasma adiponectin levels have been associated with circulating inflammatory cytokines in a cohort of subjects at high risk to develop RA (20). Taken all together, those results suggest that adiponectin might be a factor implicated in the initiation and progression of RA (21).

A recent meta-analysis found no association between circulating total adiponectin levels and disease activity in subjects with RA based on the composite index Disease Activity Score in 28 joints (DAS28) and C-reactive protein (CRP) levels (22). Conversely, adiponectin levels in blood predict radiographic progression as well as joint destruction in subjects with RA (23–26). Interestingly, circulating total, but not HMW, adiponectin levels positively associate with RA radiographic progression (27). However, most of the studies on this topic have been performed in subjects with established RA, who were treated with disease-modifying anti-rheumatic drugs (DMARDs) or corticosteroids. Anti-rheumatic drugs affect the levels of circulating adiponectin which complicates the study of the relation between adiponectin and disease activity in subjects with RA (28–30).

The aim of this study was to investigate whether circulating total and HMW adiponectin levels were associated with disease activity markers, markers of inflammation and 15 plasma chemokines. In a cohort of 70 subjects with newly diagnosed RA we showed an association between total and HMW adiponectin and markers of inflammation as well as pro-inflammatory chemokines

Patient Cohort

The patient group consisted of 70 treatment-naïve subjects with newly diagnosed RA. Diagnosis of RA was made in accordance with the American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) 2010 criteria. Inclusion criteria were ≥ 18 years of age, rheumatoid factor (RF)-positivity and/or anti-citrullinated protein antibodies (ACPA)-positivity and/or CRP ≥ 10 mg/L, disease activity based on DAS28-CRP > 3.2 and ≥ 2 swollen (SJC) and tender joints (TJC) based on a 66/68 joint count. Other inclusion criteria were a symptom duration of less than 24 months, the absence of previous treatment with DMARD or corticosteroids and a good general health. The latter was established by medical history, physical examinations, laboratory profile, electrocardiogram and chest X-ray. Collection of blood samples was performed within 2 weeks of the initial RA diagnosis. Subject recruitment was carried out at the Rheumatology Clinics of Sahlgrenska University Hospital in Gothenburg and Skåne University Hospital (Sweden). All subjects gave their written consent and study approval was given by the regional ethics committees of Gothenburg and Lund, Sweden.

Clinical and biochemical assessment

For every subject, swollen (66) and tender joint (68) count was performed and CRP and ESR were measured. DAS28 based on 28 joints and Clinical Disease Activity Index (CDAI) were calculated for each subject. Smoking was defined as current daily smoking. Multiplexed anti-CCP test (BioPlex, BioRad, Hercules, CA, USA) was used for the demonstration of ACPA positivity and nephelometry (Beckman Coulter, Brea, CA, USA) for RF positivity. The detection of ≥ 20 IU/ml anti-CCP or RF in serum was considered as ACPA- or RF-positive, respectively. Plasma was isolated from whole blood with the use of Lymphoprep (Axis-Shield, Oslo, Norway).

Assessment of total and HMW adiponectin

Total and HMW adiponectin were measured using enzyme-linked immunosorbent assays (ELISA), Human Total Adiponectin/Acrp30 Quantikine ELISA and Human HMW Adiponectin/Acrp30 Quantikine ELISA (R&D Systems, Bio-Techne, MN, USA) respectively. The experiments were performed according to the manufacturer’s instructions.

Assessment of pro-inflammatory chemokines

The evaluation of pro-inflammatory chemokines in plasma was performed with the use of bead-based immunoassay, LEGENDplex™ Human Proinflammatory Chemokine Panel (BioLegend, CA, USA) or with DuoSet ELISA (R&D Systems, Bio-Techne, MN, USA), according to manufacturers’ instructions. The bead-based panel was used for the measurement of CCL2 (MCP-1), CCL5 (RANTES), CXCL10 (IP-10), CCL17 (TARC), CCL3 (MIP-1α), CCL4 (MIP-1β), CXCL9 (MIG), CCL20 (MIP-3α), CXCL5 (ENA-78), CXCL1 (GROα), CXCL11 (I-TAC) and CXCL8 (IL-8). A FACSVerse equipped with FACSuite software (BD Biosciences, San Jose, CA, USA) was used for sample acquisition and the FCAP Array software (Soft Flow, Pecs, Hungary) for data analysis. ELISA (DuoSet) was used for the measurement of CCL22 (MDC) and CXCL13 (BCL) since those two chemokines were not included in the above Multiplex set. CCL11 (Eotaxin) was also measured by ELISA since values given by the bead-based immunoassay were higher compared to previously published levels (31).

To assess possible false positive results in the analysis of chemokine and adiponectin levels caused by heterophilic antibody interference, HeteroBlock (Omega Biologicals, MT, USA) was used. The detected levels of chemokines and adiponectin with or without HeteroBlock treatment in RF-positive subjects did not differ significantly (data not shown).

Statistical analysis

Kolmogorov–Smirnov test was used to check for normality of the distribution for each variable. Since most of the variables did not follow a normal distribution, all variables were log-transformed in all analyses. Multivariate factor analysis orthogonal projection to latent structures (OPLS) was performed to identify associations between total or HMW adiponectin (y variables) and clinical disease activity measures or concentrations of various chemokines in plasma (x variables) in linear multivariate models (SIMCA software; Sartorius Stedim Biotech, Umeå, Sweden). The data were scaled to unit variance in SIMCA by dividing each variable by 1/standard deviation, resulting in all variables being given equal weight regardless of their absolute value. The scale of the axes in OPLS is dimensionless and there is normalization of the loading vector to a length of one. For the quality appraisal of the OPLS models, parameters R2 (how well the variation of the variables is explained by the model) and Q2 (how well a variable can be predicted by the model) are presented for each OPLS model. Multiple linear regression analysis was performed using SPSS Statistics 25 (IBM, NY, USA) to examine the relationship of total and HMW adiponectin with clinical markers of disease activity and chemokines in the subjects with untreated newly diagnosed RA. Any chemokine value below the detection range, was included in the analysis with a value equal to half the detection limit. Graphs were made with GraphPad Prism version 8.2.0 (GraphPad Software, San Diego, CA, USA).

Clinical characteristics and chemokine measurement

Clinical characteristics of the cohort of 70 treatment-naïve subjects with newly diagnosed RA are described in Table 1. The cohort included mostly women (69%), with median age of 55 years, median BMI of 25 and median subject-reported symptom duration of 5 months. ACPA positivity was 81% and RF positivity was 69%.

Table 1

Clinical characteristics of the cohort of subjects with untreated newly diagnosed RA
Characteristic	no = 70
Women, no (%)	47 (69)
Age, yr	55 (42–64)
BMI	25 (23–28)
CRP, mg/L	9 (4–31)
ESR, mm/hour	24 (12–38)
SJC28	9 (5–12)
TJC28	9 (4–13)
DAS28-CRP	5 (4–6)
DAS28-ESR	5 (5–6)
ACPA+, no (%)	57 (81%)
RF+, no (%)	48 (69%)
CDAI	28 (22–38)
Symptom Duration (months)	5 (3–8)
Smoking, no (%)*	15 (22%)
Data shown as median (interquartile range), unless noted as no (%) in which case they are shown as number (percentage).
* Defined as current daily smoking.
Abbreviations: ACPA, Anti–citrullinated protein antibody; BMI, Body-mass index; CDAI, Clinical Disease Activity Index; CRP, C-reactive protein; DAS28, disease activity score in 28 joints; ESR, erythrocyte sedimentation rate; RA, Rheumatoid arthritis; RF, Rheumatoid factor; SJC28, swollen joint counts of 28; TJC28 tender joint counts of 28.

Fifteen chemokines as well as total and HMW adiponectin were measured in the plasma of the untreated newly diagnosed RA cohort. Plasma concentration of chemokines and total and HMW adiponectin are reported in Table 2. Median total adiponectin was 6.0 mg/L, while median HMW adiponectin was 3.0 mg/L (Table 2). As a positive control we tested whether adiponectin was associated with BMI, sex and age as previously reported (8, 32). Total adiponectin was significantly associated with BMI (P value = 0.002, β = -0.416), male sex (P = 0.007, β = -0.371) and age (P = 0.030, β = 0.304) while HMW showed a significant association only with BMI (P = 0.002, β = -0.401).

Table 2

Adiponectin and Plasma Chemokines
Characteristic	no = 70
Total Adiponectin (mg/L)	6.0 (4.0-10.3)
HMW Adiponectin (mg/L)	3.0 (1.5–5.2)
CXCL8/IL-8	489 (162–1001)
CXCL10/IP-10	1024 (748–1859)
CCL17/TARC	301 (215–516)
CCL2/MCP-1	960 (746–1195)
CCL5/RANTES	17538 (13354–22134)
CCL3/MIP-1α*	29 (14–56)
CXCL9/MIG*	245 (89–813)
CXCL5/ENA-78	547 (311–762)
CCL20/MIP-3α*	25 (2–74)
CXCL1/GROα*	214 (147–341)
CXCL11/I-TAC	985 (736–1446)
CCL4/MIP-1β*	44 (28–72)
CCL22/MDC	466 (356–620)
CXCL13/BCL	490 (205–990)
CCL11/Eotaxin	732 (628–1056)
Data shown as median (interquartile range). All units are in pg/ml, unless otherwise noted.
* CCL3/MIP-1α was undetectable in 15% of samples, CXCL9/MIG in 14%, CCL20/MIP-3a in 35%, CXCL1/GROα in 17% and CCL4/MIP-1β in 11%.
Abbreviations: ACPA, anti–citrullinated protein antibody; CDAI, clinical disease activity index; CRP, C-reactive protein; DAS28, disease activity score in 28 joints; ESR, erythrocyte sedimentation rate; HMW, high molecular weight; OPLS, orthogonal projection to latent structures; RF, Rheumatoid factor; SJC28, swollen joint counts of 28; TJC28, tender joint counts of 28.
Abbreviations: BMI, body-mass index; CDAI, clinical disease activity index; CRP, C-reactive protein; DAS28, disease activity score in 28 joints; ESR, erythrocyte sedimentation rate; HMW, high molecular weight.
Abbreviations: HMW, high molecular weight; OPLS, orthogonal projection to latent structures.
Abbreviations: BMI, body-mass index; HMW, high molecular weight.

Association of total adiponectin and HMW adiponectin with disease activity markers of RA

We first investigated whether total and/or HMW adiponectin were associated with disease activity markers in subjects with newly diagnosed RA. Multivariate OPLS analysis demonstrated that both total and HWM adiponectin were positively associated with markers of disease activity, such as DAS28, CDAI, CRP and ESR as shown in Figs. 1A and B. We next aimed to confirm those associations by multiple linear regression analysis after adjustment for sex, age and BMI. Total adiponectin was positively associated with DAS28-ESR (P = 0.024, β = 0.331), DAS28-CRP (P = 0.026, β = 0.335), ESR (P = 0.001, β = 0.442) and CRP (P = 0.001, β = 0.485), as shown in Fig. 2. Similarly, HMW adiponectin was positively associated with DAS28-ESR (P = 0.017, β = 0.335), ESR (P < 0.001, β = 0.507) and CRP (P = 0.001, β = 0.463) but not DAS28-CRP (P = 0.053, β = 0.282) as shown in Fig. 2. Neither total nor HMW adiponectin were associated with CDAI (P = 0.275, β = 0.165 and P = 0.293, β = 0.153, respectively, Fig. 2C and H).

Association of total adiponectin and HMW adiponectin with chemokines

Subsequently, OPLS models depicting the association of total and HMW adiponectin with chemokines were created. Both total and HMW adiponectin associated with CXCL10, CCL2, CXCL11 and CXCL9 based on the OPLS models shown in Fig. 3. Those associations were also tested by multiple linear regression analysis after adjustment for age, sex and BMI. Total adiponectin was found associated with CXCL10 (P = 0.021, β = 0.344), CCL2 (P = 0.012, β = 0.342) and CXCL9 (P = 0.044, β = 0.308) (Fig. 4). HMW adiponectin was only associated with CXCL9 (P = 0.033, β = 0.315, Fig. 4). Neither total nor HMW adiponectin were found associated with CXCL11 (Fig. 4C and G).

In this study we show that both circulating total and HMW adiponectin are associated with markers of inflammation in a cohort of 70 untreated subjects with newly diagnosed RA. Moreover, plasma adiponectin levels were also associated with several CXCR3- and CCR2-binding chemokines.

Adiponectin is an adipokine whose levels are elevated in both plasma and synovial fluid of subjects with RA (13, 14). Despite being traditionally considered as anti-inflammatory (33), adiponectin has been demonstrated to induce pro-inflammatory responses in different cells known to play a role in RA pathophysiology (16, 18, 19). Nevertheless, it remains a matter of debate whether adiponectin levels are associated with markers of disease activity in subjects with RA (22-28). Recently, a meta-analysis of eleven studies showed that circulating total adiponectin levels were not associated with disease activity in subjects with RA, assessed as DAS28 and CRP levels (22). However, most of the studies included in the meta-analysis were performed in cohorts of subjects with established RA, where both the treatment and the long-term disease could have affected the results. In fact, DMARDs and glucocorticoids have an impact on both circulating adiponectin (28-30) and chemokine levels (34-37) which precludes the use of treated subjects in studies of association between levels of adiponectin and clinical markers or chemokines. To overcome this hurdle, we selected a cohort of 70 treatment-naïve subjects with newly diagnosed RA.

A previous study has investigated whether adiponectin associated with markers of disease activity in an untreated, newly diagnosed RA cohort and found no association (28). However, the study was performed in a small cohort of 40 subjects and, based on the effect size found in our analyses, was underpowered to detect an association between adiponectin levels and markers of RA activity. Our cohort of 70 subjects with untreated, newly-diagnosed RA showed that circulating levels of total adiponectin were associated with CRP and ESR. Adiponectin levels were also associated with both DAS28-CRP and DAS28-ESR, but not with SJC, TJC nor CDAI. As DAS28 index includes CRP or ESR in its formula, there is reason to believe that the association between DAS28 and adiponectin was mainly driven by CRP and ESR.

We have also screened 15 chemokines in the plasma of 70 subjects with untreated RA and found that CXCL10, CXCL9 and CCL2 were positively associated with total adiponectin levels. CXCL10 and CXCL9 share the same receptor, CXCR3, which is predominantly expressed by activated T cells and regulates cell activation and trafficking (38). Notably, in a subgroup of our cohort, it has been previously shown that plasma CXCL10 levels are positively associated with multiple disease activity markers of RA, such as DAS28-CRP, DAS28-ESR, CRP and ESR (31). The same study also showed that circulating CXCL9 was associated with ESR. CCL2 has been reported as strongly related to the future incidence of RA in healthy women from the Nurses’ Health Studies, particularly within the following 5 years (39). Moreover, circulating CCL2 levels are elevated in subjects with RA compared to healthy controls and this increase precedes the onset of RA (6). Histological examination of RA synovia has also revealed extensive CCL2 expression (40). Hence, our results show that adiponectin levels associated with chemokines which are closely linked to the pathophysiology and activity of RA.

Adiponectin circulates in blood in three different forms, whereof the HMW seems to be the form mediating the metabolic effects (9, 10). To determine whether HMW adiponectin was also the form exerting inflammatory functions involved in RA pathophysiology, we measured total and HMW adiponectin in our cohort of subjects with untreated newly diagnoses RA. Both total and HMW adiponectin associated positively with DAS28, CRP and ESR. This result might suggest that the HMW form drives the association between adiponectin and markers of inflammation in treatment-naïve subjects suffering from RA. HMW was also associated with CXCL9 but not with CXCL10 or CCL2, as total adiponectin did. Based on the effect size of the analyses, our cohort is probably underpowered to detect a significant association between those chemokines and HMW adiponectin. Another possible explanation is that the association of total adiponectin with CXCL10 and CCL2 is mediated by another adiponectin form. However, one naturally arising limitation of the current study is that no measurement of LMW or MMW adiponectin was performed due to lack of commercial products available to measure them. Without the assessment of all circulating forms of adiponectin it is hard to draw a clear conclusion on the associations of the predominant form with markers of inflammation and plasma chemokines.

This is an exploratory study with its limitations. First of all, the above-mentioned lack of measurement of plasma LMW and MMW adiponectin. Moreover, a bigger cohort of subjects with untreated RA is needed to confirm the association between adiponectin and markers of inflammation and chemokines. Data on the follow-up of subjects with RA would also give information on how treatment affects adiponectin levels, whether higher baseline adiponectin associates with a worse prognosis and whether its levels are an indicator of treatment outcomes.

In conclusion, by studying a clinically well characterized cohort of subjects with newly diagnosed untreated RA, we have shown an association between circulating adiponectin and markers of inflammation and pro-inflammatory chemokines involved in the pathogenesis of RA. Our results support the hypothesis that adiponectin might be a pro-inflammatory factor involved in the development of RA.

ACPA, anti-citrullinated protein antibodies; ACR; American College of Rheumatology, BMI, body-mass index; CDAI, Clinical Disease Activity Index; CRP, C-reactive protein; DAS28, Disease Activity Score in 28 joints; DMARD, disease-modifying anti-rheumatic drug; ELISA, enzyme-linked immunosorbent assays; ESR, erythrocyte sedimentation rate; EULAR, European League Against Rheumatism; FLS, fibroblast-like synoviocytes; HMW, high molecular weight; IL, interleukin; LMW, low-molecular weight; MMW, middle molecular weight; OPLS, orthogonal projection to latent structures; RA, rheumatoid arthritis; RF, rheumatoid factor; SJC, swollen joint count; TJC, tender joint count.

Ethics approval and consent to participate

The study was approved by the regional ethics committees of Gothenburg, Sweden (ethical approval number: 691–12, amendment number: T270–13), and all the participants signed an informed consent form.

Consent for publication

Not applicable

Availability of data and material

The authors declare that data supporting the findings of this study are available within the article and its supplementary information files.

Competing Interests

The authors declare that they have no competing interests

Funding

This work was supported by the Knut and Alice Wallenberg Foundation and the Wallenberg Centre for Molecular and Translational Medicine at the University of Gothenburg, Sweden to Cristina Maglio. This study was also supported by grants from Swedish Research Council (grant

2016–01574); Region Västra Götaland (agreement concerning research and education of doctors; ALF; grant ALFGBG-143331) to Anna Rudin.

Authors' contributions

GV contributed to the design of the study, performed experiments, analysed and interpreted the data and wrote the first draft of the manuscript. ACL contributed to the analysis of the data and interpreted the results. YZ contributed to the design of the study, performed experiments and interpreted the results. KA performed experiments, was involved in collecting samples and analysis of the data. IG was involved in collecting samples and clinical data. AR was involved in collecting samples and clinical data and contributed to the interpretation of the results. CM designed the study, interpreted the data and continuously supervised all aspects of the work. All authors were involved in drafting the manuscript or revising it critically for important intellectual content, and all authors approved the final version to be published.

Acknowledgments

We thank Piero Pingitore and Jonathan Aldridge, University of Gothenburg, for useful discussion.

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Total and high-molecular weight plasma adiponectin associates with markers of inflammation and circulating chemokines in subjects with untreated newly diagnosed rheumatoid arthritis.

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Abstract

Figures

Introduction

Patients And Methods

Patient Cohort

Clinical and biochemical assessment

Assessment of total and HMW adiponectin

Assessment of pro-inflammatory chemokines

Statistical analysis

Results

Clinical characteristics and chemokine measurement

Association of total adiponectin and HMW adiponectin with disease activity markers of RA

Association of total adiponectin and HMW adiponectin with chemokines

Discussion

Abbreviations

Declarations

References

Status:

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