Rheumatology International

, Volume 27, Issue 6, pp 537–540

Measurement of the serum leptin level could assist disease activity monitoring in rheumatoid arthritis

Authors

  • Sang-Won Lee
    • Division of Rheumatology, Department of Internal Medicine, Institute for Immunology and Immunological disease, BK21 Project for Medical scienceYonsei University College of Medicine
  • Min-Chan Park
    • Division of Rheumatology, Department of Internal Medicine, Institute for Immunology and Immunological disease, BK21 Project for Medical scienceYonsei University College of Medicine
  • Yong-Beom Park
    • Division of Rheumatology, Department of Internal Medicine, Institute for Immunology and Immunological disease, BK21 Project for Medical scienceYonsei University College of Medicine
    • Division of Rheumatology, Department of Internal Medicine, Institute for Immunology and Immunological disease, BK21 Project for Medical scienceYonsei University College of Medicine
Original Article

DOI: 10.1007/s00296-006-0253-x

Cite this article as:
Lee, S., Park, M., Park, Y. et al. Rheumatol Int (2007) 27: 537. doi:10.1007/s00296-006-0253-x

Abstract

We investigated whether serum leptin levels are elevated in patients with active rheumatoid arthritis (RA) and whether these levels correlate with disease activity. Fifty RA patients were enrolled in this study, and their disease activity was assessed using the disease activity score 28 (DAS28). The patients were divided into two groups according to this score: a high activity group with DAS28 > 3.2 (n = 26) and a low activity group with DAS28 ≤ 3.2 (n = 24). Serum leptin levels were determined using a primate antibody radioimmunoassay. RA patients with high disease activity had significantly higher mean serum leptin levels, compared to those with low activity (14.2 ± 10.9 vs. 7.0 ± 3.4 ng/ml, < 0.05). Mean leptin levels adjusted according to BMI were 0.6 ± 0.5 ng m2/ml kg for the high activity group and 0.3 ± 0.2 ng m2/ml kg for the low activity group, respectively, which were also significantly different (< 0.05). Both serum leptin levels and leptin levels adjusted according to BMI correlated well with the DAS28 (r = 0.363 and 0.368, < 0.05) and CRP levels (r = 0.433 and 0.472, < 0.05), respectively. Sixteen of the 26 RA patients with high disease activity at the initial assessment were re-evaluated, at which point their DAS28 had decreased to less than 3.2. Mean follow-up leptin level was significantly lower than mean initial leptin level (7.8 ± 3.7 vs. 16.1 ± 12.7 ng/ml, < 0.05). In conclusion, serum leptin levels were higher in RA patients with high disease activity, correlated well with disease activity, and decreased significantly when disease was well controlled.

Keywords

Rheumatoid arthritisLeptinDisease activity

Introduction

Leptin is a 16-kDa non-glycosylated protein encoded by the obese (ob) gene, which is located on human chromosome 7. Leptin is mainly produced in white adipose tissue and regulates the balance between food intake and energy expenditure. Its plasma levels are correlated with total body fat mass [1, 2]. In addition, previous studies on leptin have provided compelling evidence that leptin has a significant role in the immune system. Leptin has a structural similarity to the type I cytokine family and its receptor is a member of the class I cytokine receptor family. Centrally, leptin affects thymic function, leading to the generation and proliferation of naïve T lymphocytes. In the periphery, leptin augments the differentiation of T lymphocytes into T helper-1 lymphocytes, which predominantly secrete pro-inflammatory cytokines, such as tumor necrosis factor (TNF)-α, interleukin (IL)-6, and interferon (IFN)-γ [36].

Rheumatoid arthritis (RA) is characterized by polyarticular synovitis and bony erosions, and the above-mentioned pro-inflammatory cytokines have been implicated in the development and progression of the disease [7, 8]. Thus, it is possible that leptin, another pro-inflammatory cytokine, might have an important role in the pathogenesis and aggravation of RA [911]. However, its role in the pathogenesis of RA remains controversial because the level of leptin is significantly affected by factors such as sex hormones, menopausal status, body mass index (BMI), and insulin resistance.

In this study, we investigated whether serum leptin levels are elevated in RA patients with high disease activity, and whether the level correlates with the disease activity in RA.

Materials and methods

Patients

Fifty pre-menopausal female patients (mean age: 40.7 ± 10.2 years, range: 16–54 years) were enrolled in this study. All patients were diagnosed with RA at the Division of Rheumatology, Severance Hospital, Yonsei University Medical Center, Seoul, Korea, between August 2004 and January 2005, and all fulfilled the American College of Rheumatology classification criteria for RA [12]. Mean disease duration was 15.5 ± 9.6 months (range: 2–35 months). To remove confounding factors which could affect serum leptin levels, we excluded obese patients, defined as having a BMI > 25 kg/m², patients with diabetes mellitus or a fasting glucose > 100 mg/dl, hypertension, any systemic illness other than RA, and those who had been treated with corticosteroids (>5 mg/day) within 3 months prior to this study. Body mass index (BMI) was calculated as weight/height² (kg/m²), and disease activity was assessed using the disease activity score 28 (DAS28) [13]. The patients were divided into two subgroups according to their disease activity: the active disease group with DAS28 > 3.2 (n = 26) and the inactive disease group with DAS28 ≤ 3.2 (n = 24).

Laboratory assessment

Serum samples were collected from all 50 patients with RA, and collected samples were centrifuged at 1,000g for 15 min, aliquoted, and stored frozen at −20°C until use. The serum leptin levels were measured using radio-immunoassay (Linco Research Inc., St. Charles, MO, USA) according to the manufacturer’s protocol. The reference range for leptin levels in healthy pre-menopausal controls was under 7 ng/ml. Levels of fasting glucose, fasting insulin, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), triglyceride (TG), and high density lipoprotein (HDL)-cholesterol were also measured. The homeostasis model assessment (HOMA) index was calculated to determine insulin resistance. Presence of rheumatoid factor (RF) of any of the immunoglobulin isotypes was considered to be positive.

Follow-up assessment

Serum leptin levels in 16 of the 26 patients with active RA were measured again at follow-up, at which time their DAS28 had decreased to less than 3.2 (range: 8–13 months later).

Statistical analysis

All statistical analyses were conducted using the SPSS package for windows (version 11.5). Continuous variables were expressed as a mean ± SD. Differences between the high and low activity groups, and between mean initial and follow-up serum leptin levels in high-activity RA patients were calculated using the Mann–Whitney U test. Correlations between parameters studied were calculated with the Pearson’s correlation coefficient. For all statistical evaluation of the results, P values <0.05 were considered significant.

Results

The clinical characteristics of the patients with RA were summarized in Table 1. The mean age, mean disease duration, use of medications, and BMI did not differ between the high and low activity groups. Table 2 shows laboratory findings for the two groups. Mean ESR and CRP levels were significantly higher in RA patients with high activity than in those with low activity. However, the HOMA index for insulin resistance and TG/HDL-cholesterol ratio was not significantly different between the two groups.
Table 1

Demographic, clinical, and therapeutic characteristics of the patients with RA according to disease activity

 

High activity RA group (n = 26)

Low activity RA group (n = 24)

P value

Age (years)

42.34 ± 10.31

38.88 ± 9.93

NS

Disease duration (months)

14.89 ± 8.91

16.13 ± 10.42

NS

BMI (kg/m2)

21.48 ± 2.89

20.75 ± 2.78

NS

Tender joint count

5.31 ± 3.92

1.13 ± 3.27

<0.05

Swollen joint count

4.61 ± 5.14

0.21 ± 0.59

<0.05

Patient VAS (mm)

51.01 ± 24.31

21.03 ± 17.84

<0.05

DAS28

4.84 ± 0.86

2.44 ± 0.67

<0.05

MTX

23/26

19/24

NS

Other DMARDs

15/26

13/24

NS

Anti TNF alpha blockade

0

0

NS

BMI Body mass index, DAS28 disease activity score 28, MTX methotrexate, DMARDs disease modifying anti-rheumatic drugs, TNF tumor necrosis factor, NS no significance

Table 2

Laboratory findings in the patients with RA according to disease activity

 

High activity RA group (n = 26)

Low activity RA group (n = 24)

P value

ESR (mm/h)

45.96 ± 34.62

19.38 ± 14.29

<0.05

CRP (mg/dl)

1.43 ± 1.99

0.39 ± 0.81

<0.05

Leptin (ng/ml)

14.2 ± 10.9

7.0 ± 3.4

<0.05

Leptin/BMI (ng m2/ml kg)

0.6 ± 0.5

0.3 ± 0.2

<0.05

TG (mg/dl)

107.50 ± 52.89

84.46 ± 25.88

NS

HDL-cholesterol (mg/dl)

53.12 ± 13.15

55.96 ± 10.79

NS

TG/HDL-cholesterol

2.23 ± 1.79

1.57 ± 0.62

NS

Glucose (mM/l)

4.79 ± 0.47

4.69 ± 0.39

NS

Insulin (mU/l)

6.71 ± 5.56

6.03 ± 6.60

NS

HOMA-IR

1.42 ± 1.13

1.29 ± 1.53

NS

Rheumatoid factor

26/26

24/24

NS

ESR Erythrocyte sedimentation rate, CRP C-reactive protein, BMI body mass index, TG triglyceride, HDL high density lipoprotein, HOMA-IR homeostasis model assessment insulin resistance, NS not significant

RA patients with high activity had significantly higher mean leptin levels than those with low activity, and mean leptin level adjusted to BMI (leptin/BMI) was also significantly higher in high-activity RA patients (< 0.05) (Table 2). Leptin levels as well as those adjusted to BMI exhibited significant correlations with both the DAS28 (r = 0.363 and 0.368, < 0.05) and CRP levels (r = 0.433 and 0.472, < 0.05).

The mean follow-up leptin levels were significantly lower than those measured initially (16.1 ± 12.7 vs. 7.8 ± 3.7 ng/ml, < 0.05) in 16 of the RA patients with high disease activity at the initial assessment (Fig. 1).
https://static-content.springer.com/image/art%3A10.1007%2Fs00296-006-0253-x/MediaObjects/296_2006_253_Fig1_HTML.gif
Fig. 1

The comparison between mean initial and follow-up leptin levels. Mean follow-up leptin level was significantly lower than mean initial leptin level (16.1 ± 12.7 vs. 7.8 ± 3.7 ng/ml, < 0.05) in 16 RA patients whose disease activities were high at initial assessment

Discussion

In this study, we found a significant increase in serum leptin levels in RA patients with high disease activity, in comparison with those with low activity. Since the inclusion criteria were designed to reduce the impact of confounding factors affecting leptin levels, the contribution of disease activity to this difference in leptin levels was likely greater than expected. A previous report by Bokarewa showed increased plasma leptin levels in 76 patients with RA, as compared with healthy controls [10]. However, there was no comparison of serum leptin levels in RA patients with different levels of disease activity. Our study is distinguished by our investigation of serologic characteristics after dividing the subjects into two groups according to their disease activities, our adjustment according to confounding factors affecting levels of leptin, and our follow-up of the change in serum leptin levels after control of disease activity. We did not, however, study the effect of methotrexate on leptin levels because there was no difference in the duration or dose of methotrexate between the two groups.

Thus far, there have been several serologic markers, such as CRP and ESR, proposed to well represent the disease activity of RA. However, none of these markers have definitively allowed for accurate monitoring of RA disease activity. Accordingly, various markers have been used in combination to achieve more precision in such an evaluation. In this study, leptin levels and leptin levels adjusted to BMI were correlated significantly with both the DAS28 and CRP levels, both of which are known markers for the activity of RA.

Popa et al. [11] found a significant inverse correlation between inflammation and leptin concentration in patients with active RA 2 weeks after treatment with an anti-TNF-α agent; however, their study period was not long enough to demonstrate the relationship between disease activity and serum leptin level. In this study, we followed-up with 16 of the 26 patients with active RA and collected serum samples when their diseases were well-controlled (DAS28 < 3.2). We found that their leptin levels significantly decreased as their disease improved. These data compensate for the weaknesses of the cross-sectional design of the initial study and the challenges of generalizing from a population of pre-menopausal women only. Accordingly, measuring serum leptin level may help to monitor the disease activity of RA.

It has been well established that dyslipidemia is commonly encountered in patients with RA, and a recent study revealed a strong association between disease activity and insulin resistance in RA patients [14, 15]. In our study, the HOMA index for insulin resistance and the TG to HDL-cholesterol ratio for dyslipidemia were also higher in RA patients with high disease activity, although these differences were not statistically significant.

Our study was limited by a small number of subjects. In the future, another study including more RA patients might be needed.

In conclusion, significant elevations in serum leptin levels were found in RA patients with high disease activity. Furthermore, serum leptin levels correlated well with other markers for the disease activity of RA and decreased as the patients’ RA became well-controlled. Therefore, in addition to measuring other previously described serological markers reflecting the disease activity of RA, measuring serum leptin level could also help monitor disease activity in patients with RA.

Copyright information

© Springer-Verlag 2006