Originalien Z Rheumatol DOI 10.1007/s00393-016-0050-1 © Springer-Verlag Berlin Heidelberg 2016 Redaktion U. Müller-Ladner, Bad Nauheim U. Lange, Bad Nauheim

Introduction Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease that predominantly affects the synovial joints, causing significant morbidity and shortened life expectancy [1]. RA is characterized by infiltration of the synovium with neutrophils, macrophages, T cells, B cells, and dendritic cells (DCs), and by tissue damage. Although its cause is not yet fully understood, it has been established that genetic and environmental factors contribute to the pathogenesis of RA [2]. Leptin is a peptide hormone synthesized mostly by white adipose tissue cells. Endothelial cells, T-lymphocytes, bone marrow cells and platelets also contribute to its production [3]. Leptin was initially described as a hormone that regulated food intake and energy balance. It is also a mediator of the inflammatory process, as it interacts with the immune system [4]. Leptin and its receptors share structural and functional similarities with cytokines of the IL-6 family [5]. Leptin activates monocytes/macrophages to release proinflammatory cytokines such as TNF-α and IL-6 and stimulates the differentiation of T lymphocytes into the Th1 phenotype [6]. Leptin plays a dual role in inflammation. It also exerts antiinflammatory activities, which induces IL-1 receptor antagonist and increases IL-4 production [7]. Previous studies have shown increased circulating levels of leptin during inflammation and the

Y. H. Lee1 · S.-C. Bae2 1

Division of Rheumatology, Department of Internal Medicine, Korea University Anam Hospital, Korea University College of Medicine, Seoul, Korea 2 Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul, Korea

Circulating leptin level in rheumatoid arthritis and its correlation with disease activity: a meta-analysis potential role it plays in modulating the immune response in autoimmune diseases such as experimental autoimmune encephalomyelitis, type 1 diabetes, systemic lupus erythematosus, and RA [8, 9]. Studies on circulating leptin status in RA patients compared with healthy

controls and on the relationship between leptin levels and RA activity have shown mixed results [10–22]. Reasons for this disparity may be the small sample size, the low statistical power, and/or clinical heterogeneity [23–25]. To overcome the limitations of individual studies, resolve inconsistencies, and reduce the likeli-

Fig. 1 8 Flow diagram of the study selection process Zeitschrift für Rheumatologie

Originalien 3. They provided enough data on the association between serum leptin levels and RA activity based on disease activity score 28 (DAS28) or C-reactive protein (CRP) level Studies were excluded if: 1. They contained overlapping or insufficient data 2. They were reviews or case reports The following information was extracted from each study: primary author, year of publication, country, ethnicity, number of participants, age, mean and standard deviation (SD) of the leptin level, and correlation coefficients between the leptin level and the DAS28 or CRP level. If the standard error of mean (SEM) was reported, we calculated the SD using a statistical formula. When the data consisted of median and range, we computed the data to gain the mean and SD values using formulas [26]. We scored the quality of each study included based on the Newcastle–Ottawa Scale [27]. The highest score was 9. Scores ranging from 6 to 9 were considered to indicate high methodological quality.

Evaluation of statistical associations

Fig. 2 8 Meta-analysis of the relationship between the leptin level and RA in a all study subjects and b each ethnic group

hood that random errors cause falsepositive or false-negative associations, we performed this meta-analysis. The present study was aimed at determining the serum/plasma leptin levels in RA patients compared with those in healthy controls, and at evaluating its correlation with disease activity using the metaanalysis.

Materials and Methods Identification of eligible studies and data extraction We performed a literature search for studies that examined leptin status in Zeitschrift für Rheumatologie

RA patients and controls, and the relationship between circulating (serum or plasma) leptin levels and RA activity. The PUBMED, EMBASE, and Cochrane databases were searched to identify all available past articles (up to October 2015; . Fig. 1). The following key words and subject terms were used in the search: “leptin level”, “rheumatoid arthritis,” and “RA”. All references cited were also reviewed to identify additional studies not covered by the above-mentioned electronic databases. Studies were considered eligible if: 1. They were case–control studies 2. They provided data on leptin levels in case and control groups

We performed a meta-analysis examining the relationship between the leptin level and RA, and the correlation coefficient between the leptin level and DAS28 or CRP level. For the continuity of data, results were presented as standardized mean differences (SMDs) and 95 % confidence intervals (CIs). Odd ratios (ORs) and 95 % CIs were calculated for dichotomous data. We assessed within-study and between-study variations and heterogeneities using Cochran’s Q test [28]. The heterogeneity test was used to assess the null hypothesis that all studies were evaluating the same effect. When the significant Q statistic (p < 0.10) indicated heterogeneity across studies, the random effects model was used for the meta-analysis [29]. If not, the fixed effects model was used. It assumed that all studies estimated the same underlying effect and it considered within-study variation only [28]. We quantified the effect of hetero-

Abstract · Zusammenfassung geneity using I2 = 100 % x (Q–df)/Q [30], where I2 measured the degree of inconsistency between studies and determined whether the percentage total variation across studies was due to heterogeneity or due to chance. I2 ranged between 0 % and 100 %; I2 values of 25 %, 50 %, and 75 % were referred to as low, moderate, and high estimates [30] respectively. Statistical manipulations were undertaken using the Comprehensive Meta-Analysis computer program (Biostat, Englewood, NJ, USA).

Evaluation of heterogeneity, sensitivity test, and publication bias To examine potential sources of heterogeneity observed in the meta-analysis, meta-regression analysis was performed using the following variables: ethnicity, publication year, sample size, and study quality. A sensitivity test was performed to assess the influence of each individual study on the pooled odds ratio by omitting each study individually. Although funnel plots are often used to detect publication bias, they require diverse study types of varying sample sizes, and interpretation involves subjective judgment. Considering these, we evaluated publication bias using Egger’s linear regression method [31], which measured funnel plot asymmetry using a natural logarithm scale of ORs.

Results Studies included in the metaanalysis We identified 89 studies using electronic and manual searchmethods. Twenty-one of these were selected for full-text review based on the title and abstract. Eight of these were excluded because they had no leptin data, English data, or data in review. Thus, 13 articles met the inclusion criteria [10–22]. One of the eligible studies contained data on two different groups [21], which were treated independently. Thus, 14 comparisons were considered in the meta-analysis, which consisted of 648 RA patients and 426 controls (. Tab. 1). All the studies examined

Z Rheumatol DOI 10.1007/s00393-016-0050-1 © Springer-Verlag Berlin Heidelberg 2016 Y. H. Lee · S.-C. Bae

Circulating leptin level in rheumatoid arthritis and its correlation with disease activity: a meta-analysis Abstract Objective. This study aimed to evaluate the relationship between the circulating serum leptin level and rheumatoid arthritis (RA) and to establish a correlation between serum leptin levels and RA activity. Methods. We searched the PUBMED, EMBASE, and Cochrane databases. A meta-analysis was performed, comparing the serum/plasma leptin levels in patients with RA and healthy controls. Correlation coefficients between serum leptin level and either disease activity score 28 (DAS28) or C-reactive protein (CRP) in RA patients were also examined. Results. Thirteen studies with a total of 648 RA patients and 426 controls were included in this meta-analysis. Circulating leptin level was significantly higher in the RA group than in the control group (SMD = 1.056, 95 % CI = 0.647–1.465, p = 4.2 × 10–7). In addition, stratification by ethnicity showed a significantly elevated leptin level in the RA group in Caucasian, Turkish, and

Arab populations (SMD = 0.813, 95 % CI = 0.137–1.490, p = 0.018, SMD = 0.981, 95 % CI = 0.307–1.655, p = 0.004, and SMD = 1.469, 95 % CI = 0.443–2.495, p = 0.005 respectively). A meta-analysis of correlation coefficients showed a small but significantly positive correlation between the circulating leptin level and either DAS28 (correlation coefficient = 0.275, 95 % CI = 0.076–0.452, p = 0.007) or CRP (correlation coefficient = 0.274, 95 % CI = 0.068–0.458, p = 0.010). Conclusions. Our meta-analysis demonstrated that the circulating leptin level is significantly higher in patients with RA and that a small but significantly positive correlation exists between leptin levels and RA activity. Keywords Leptin · Rheumatoid arthritis · Activity · Correlation · Meta-analysis

Zirkulierender Leptinwert bei rheumatischer Arthritis und seine Korrelation mit der Erkrankungsaktivität: eine Metaanalyse Zusammenfassung Ziel. Ziel der Studie war es, den Zusammenhang zwischen zirkulierendem Serumleptinspiegel und rheumatischer Arthritis (RA) zu untersuchen und eine Korrelation zwischen Serumleptinspiegeln und der RA-Aktivität festzustellen. Methoden. Wir durchsuchten die Datenbanken PUBMED, EMBASE und Cochrane. Eine Metaanalyse wurde durchgeführt, bei der die Serum-/Plasmaleptinspiegel bei RA-Patienten und bei gesunden Kontrollgruppen untersucht wurden. Der Korrelationskoeffizient zwischen Serumleptinspiegel und entweder der Krankheitsaktivität 28 (disease activity score; DAS28) oder C-reaktivem Protein (CRP) bei RA-Patienten wurden ebenfalls untersucht. Ergebnisse. Dreizehn Studien mit insgesamt 648 Patienten und 426 Kontrollpersonen wurde in die Metaanalyse einbezogen. Der zirkulierende Leptinspiegel war in der RA-Gruppe signifikant höher als in der Kontrollgruppe (SMD = 1,056, 95 % CI = 0,647–1,465, p = 4,2 × 10–7). Die Schichtung

nach Ethnie zeigte einen signifikant erhöhten Leptinspiegel in der RA-Gruppe bei der hellhäutigen, türkischen und arabischen Bevölkerung (SMD = 0,813, 95 % CI = 0,137–1,490, p = 0,018, SMD = 0,981, 95 % CI = 0,307–1,655, p = 0,004 bzw. SMD = 1,469, 95 % CI = 0,443–2,495, p = 0,005). Eine Metaanalyse der Korrelationskoeffizienten zeigte eine kleine, aber signifikant positive Korrelation zwischen dem zirkulierendem Leptinspiegel und entweder DAS28 (Korrelationskoeffizient = 0,275, 95 % CI = 0,076–0,452, p = 0,007) oder CRP (Korrelationskoeffizient = 0,274, 95 % CI = 0,068–0,458, p = 0,010). Zusammenfassung. Unsere Metaanalyse konnte darlegen, dass der zirkulierende Leptinspiegel bei Patienten mit RA signifikant höher ist und dass eine kleine aber signifikant positive Korrelation zwischen Leptinspiegeln und der RA-Aktivität besteht. Schlüsselwörter Leptin · Rheumatische Arthritis · Aktivität · Korrelation · Meta-Analyse

Zeitschrift für Rheumatologie

Originalien Tab. 1 Characteristics of individual studies included in the meta-analysis Authors Country Number of Age (SD) patients RA

Leptin level (ng/ml)

Control RA

Control

RA

Correlation coefficient

Control

DAS28

Quality

CRP

Abdalla et al. [10]

Egypt

60

30

40.81 (9.11)

Age matched

24.86

10.70

na

na

8

Olama et al. [11]

Egypt

40

30

46.8 (9.9)

43.1 (8.4)

32.40

21.20

0.494

0.41

9

Allam and Radwan [12]

Egypt

37

34

45.95 (12.20)

47.73 (12.84)

12.15

3.99

–0.02

–0.2

7

Ismail et al. [13]

Egypt

40

30

32.83 (7.39)

34.17 (7.81)

32.40

21.52

0.58

na

7

El-Batch et al. [14]

Turkey

30

15

49.4 (10.1)

48.1 (10.6)

20.50

12.20

0.235

0.3

8

Seven et al. [15]

Turkey

20

15

40.20 (13.80)

37.06 (9.73)

18.35

11.01

0.493

0.17

8

Rho et al. [16]

USAc

167 91

54.2 (11.8)

53.3 (11.6)

23.00

14.70

0.23

0.27

9

Turhanoğlu et al. [17]

Turkey

52

52

46 (12)

47 (12)

34.30

11.10

na

na

9

Hizmetli et al. [18]

Turkey

41

25

49.31 (11.76)

51.08 (13.39)

3.91

4.94

na

na

7

Gunaydin et al. [19]

Turkey

50

34

56.34 (12.43)

53.22 (9.19)

53.17

23.03

–0.111

–0.04

6

Otero et al. [20]

Spain

31

18

46.1 (14.1a)

48.3 (16.1a) 33.90

13.30

na

0.71

7

Popa et al. [21]

Netherlands

11

9

61

38.4

6.00

4.20

na

0.46

6

Popa et al. [21]

Netherlands

20

9

61

38.4

15.10

13.40

na

na

6

6.20

2.00

na

na

6

Bokarewa et al. [22]

Sweden

49

34

64 (12b)

b

42 (14 )

SD standard deviation, DAS disease activity score, na not available a 84.6 % Caucasians in controls, 88.6 % in RA patients b Standard error c United States of America Tab. 2 Meta-analysis of leptin level in RA patients compared with controls Population No. of No. of patients Test of association studies RA Control SMD 95 % CI

p value

Model

p value

I

Publication bias p value

Overall

0.647–1.465

4.2x10–7

R

0.000

88.3

0.672

14

648

426

1.056

Test of heterogeneity 2

Caucasian

5

278

161

0.813

0.137–1.490

0.018

R

0.000

87.2

na

Turkish

5

193

141

0.981

0.307–1.655

0.004

R

0.000

87.1

na

Egyptian

4

177

124

1.469

0.443–2.495

0.005

R

0.000

83.3

na

SMD standard mean difference, CI confidence interval, R random effects model, na Not available Tab. 3 Meta-analysis of the correlation coefficient between the leptin level and RA activity (DAS28, CRP) Comparison No. of No. of RA Test of association Test of heterogeneity studies patients Correlation 95 % CI p value Model p value I2

Publication bias p value

coefficient DAS28

7

384

0.275

0.076–0.452

0.007

R

0.003

69.2

0.641

CRP

8

479

0.274

0.068–0.458

0.010

R

0.000

73.2

0.826

CI confidence interval, R random effects model, DAS disease activity score

Zeitschrift für Rheumatologie

Heterogeneity, sensitivity test, and publication bias Between-study heterogeneity was identified during the meta-analyses of leptin status in RA patients (. Tab. 2). Meta-regression analysis showed that study quality (1.0 × 10–5), publication year (p = 0.009) and sample size had a significant impact on heterogeneity in the metaanalysis of the leptin level in RA patients; however, ethnicity was not implicated (. Tab. 3). Sensitivity analysis showed that no individual study significantly affected the meta-analysis results, indicating the robust results of this metaanalysis. Funnel plots to detect publication bias showed symmetry. Egger’s regression analysis showed no evidence of publication bias for the meta-analysis of leptin (. Tab. 2 and 3).

Discussion

Fig. 3 8 Meta-analysis of the correlation coefficient between a the leptin level and DAS28, and b the leptin level and CRP

the leptin level in the RA and control groups. Seven studies provided correlation coefficients between the leptin level and DAS28, while eight studies provided correlation coefficients between the leptin and CRP levels. The quality assessment score of each study ranged from 6 to 9. . Tab. 1 shows the characteristic features of the study participants and their reported quality assessments.

Meta-analysis of the circulating leptin level in RA patients compared with controls The leptin level was significantly higher in the RA group than in the control group (SMD = 1.056, 95 % CI = 0.647–1.465, p = 4.2 × 10–7; . Fig. 2; . Tab. 2). In addition, stratification by ethnicity showed a significantly elevated leptin level in the RA group in Caucasian, Turkish, and Arab populations (SMD = 0.813, 95 % CI =

0.137–1.490, p = 0.018, SMD = 0.981, 95 % CI = 0.307–1.655, p = 0.004, SMD = 1.469, 95 % CI = 0.443–2.495, p = 0.005, respectively; . Fig. 2; . Tab. 2).

Meta-analysis of the relationship between circulating leptin levels and RA activity The meta-analysis revealed that the circulating leptin level was positively associated with RA activity based on DAS28 and CRP level (. Tab. 3). A meta-analysis of the correlation coefficients showed a small but significantly positive correlation between the circulating leptin level and DAS28 (correlation coefficient = 0.275, 95 % CI = 0.076–0.452, p = 0.007; . Fig. 3; . Tab. 3). It yielded similar results in the comparison of the leptin and CRP levels (correlation coefficient = 0.274, 95 % CI = 0.068–0.458, p = 0.010; . Fig. 3; . Tab. 3).

Leptin plays an important role in regulating neuroendocrine and immune responses [5]. Leptin activates monocyte/ macrophage cells, increases the production of inflammatory cytokines, and directs T cell differentiation to the Th1 phenotype [6]. Proinflammatory cytokines increase circulating leptin concentrations [32]. Leptin plays an important role in the inflammatory processes involving T cells by modulating T-helper cell activity in the cellular immune response [7]. It has been known that leptin has an effect on myelopoiesis and lymphopoiesis, increasing the number of macrophages and granulocytes. This leads to increased phagocytosis and synthesis of proinflammatory cytokines [6]. Interactions between the neuroendocrine and immune systems may contribute to the pathogenesis of RA [4]. However, the exact role of leptin in chronic inflammatory diseases such as RA is still unclear. Clinical studies on circulating leptin level in RA patients and on the relationship between leptin levels and RA activity have yielded inconsistent results [10–22]. In this meta-analysis, we combined the evidence of circulating leptin status in RA and the correlation between serum leptin levels and RA activity. This metaanalysis of 13 studies involving 648 RA Zeitschrift für Rheumatologie

Originalien patients and 426 controls showed that the serum leptin level was significantly higher in the RA group compared with the control group. Leptin had a positive correlation with RA activity measured by DAS28 and CRP level. The leptin level reflected a small but significant increase in disease activity. The meta-analysis data suggested that circulating leptin might play a role in the pathogenesis of RA. It also supported the notion that adipocytokines might play a role in the proinflammatory state in RA. Fasting patients with RA exhibited an improvement of disease activity that was associated with a decrease in serum leptin level and a shift toward Th2 cytokine production [19]. These changes suggested that leptin might affect the inflammatory mechanisms of RA through the induction of Th1 response. A plausible mechanism for our results is that leptin may influence the inflammatory mechanism of RA through the induction of Th1 responses. Leptin affects innate immunity and adaptive immunity [33]. In innate immunity, leptin promotes the phagocytosis and chemotaxis of monocytes and macrophages, and the production of inflammatory cytokines such as IL-1, IL-6, and TNFα [34]. In adaptive immunity, it increases Th1 cell activation, and has negative effects on regulatory T cells (Treg) [35]. Leptin plays a proinflammatory role during joint inflammation [33]. Leptin binding to its receptor affects the physiological function via the JAK2/STAT signaling pathway [36]. Leptin increases IL6 production in RA by activating JAK2/ STAT3 [37]. Cytokines of the IL-6 family are GP130-signaling cytokines and leptin-induced STAT3 phosphorylation can occur through IL-6/gp130 transactivation [38]. As leptin is a proinflammatory mediator, blocking the signal pathways of leptin may constitute a treatment for RA [39]. A monoclonal antibody to the leptin receptor suppressed proinflammatory activity in a leptin signaling bioassay [40]. Leptin downregulation with small interference RNA is associated with the inhibition of MMP-13 expression in chondrocyte culture [41]. Activated JAK2 phosphorylates tyrosine residues in the intraZeitschrift für Rheumatologie

cellular domain of leptin receptor ObRb, providing binding motifs for SHP2 and STAT proteins [36]. The SH2-containing cytoplasmic tyrosine phosphatase SHP2 has been shown to play a critical role in leptin signaling by downregulating the STAT3 pathway [42]. Targeting the JAK/STAT and SOCS3 pathways may be a possible effective treatment [42]. Obesity may influence the therapeutic responses to disease-modifying antirheumatic drugs (DMARDs) in RA. Patients with a high body mass index who underwent treatment with infliximab failed to achieve a low DAS [36], and obesity or being overweight was associated with a lower chance of achieving remission under DMARDs [43]. An excess of fat mass is a source of cytokines, and adipokines, including leptin, may induce the expression of proinflammatory cytokines [44]. Adipose tissue provides an inflammatory milieu that may be related to the resistance to drugs in RA [44]. Thus, future studies are needed to see whether obese or overweight patients with high leptin levels might be susceptible to leptin-targeting therapy. This meta-analysis has some shortcomings that need to be considered. First, most of the studies had a small sample size and only a small number of studies evaluated the correlation coefficient between the leptin level and RA activity. Thus, the meta-analysis may be underpowered. Second, the studies included in the meta-analysis were heterogeneous with regard to demographic characteristics and clinical features. The heterogeneity and confounding factors such as body mass index, sex, and limited clinical information provided by the study population may have affected the results. These limited data did not allow further analysis, even though we performed a sensitivity test and a meta-regression analysis. Nevertheless, this meta-analysis also has its strengths. To the best of our knowledge, our meta-analysis is the first study that provides combined evidence for leptin status in RA patients. Individual studies only included population sizes ranging from 11 to 167, but our pooled analysis involved 471 patients. Compared with individual studies, our study was able to provide more accurate

data on the relationship between leptin level and RA by increasing the statistical power and resolution through pooling the results of independent analyses. In conclusion, there was a significant difference in serum leptin level between RA and control groups, with a significantly positive correlation between leptin level and RA activity. Our meta-analysis demonstrated that the circulating leptin level was significantly higher in RA patients compared with controls and that a small but significantly positive correlation existed between the leptin level and RA activity. Our meta-analysis proposed that leptin likely plays an important role in the pathogenesis of RA. Further studies are necessary to elucidate the direct contribution of leptin level to the pathogenesis of RA.

Corresponding address PD Dr. Y. H. Lee Division of Rheumatology, Department of Internal Medicine, Korea University Anam Hospital, Korea University College of Medicine 73, Inchon-ro, Seongbuk-gu, 136-705 Seoul, Korea [email protected] Acknowledegment. This study was supported in part by a grant from the Korea Healthcare technology R&D Project, Ministry for Health and Welfare, Republic of Korea (HI13C2124).

Compliance with ethical guidelines Conflicts of interest. Y. H. Lee and S.-C. Bae states that there are no conflicts of interest. The accompanying manuscript does not include studies on humans or animals.

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