Dysadipokinemia u chorych z wolem i jej związek z aktywnością choroby

Inna V. Orlova, Mykola A. Stanislavchuk, Iryna P. Gunko

National Pirogov Memorial Medical University, Vinnytsya, Ukraine

ABSTRACT

Introduction: In recent years, the role of adipokines in the development of rheumatic diseases has been a pressing issue. The available data suggest the dysadipokinemia in patients with rheumatoid arthritis, osteoarthritis and psoriatic arthritis. However, there is no data on changes in the levels of adipokines in patients with gout and their association with the activity of inflammatory process.

The aim was to study the levels of adipokines in gout patients and evaluate their association with the disease activity.

Materials and methods: We examined 151 male patients with gout. The control group consisted of 31 practically healthy men, represented by age. We used the Gout Activity Score (GAS) to assess gout severity. The levels of leptin and adiponectin were determined using the ELISA kit. For comprehensive evaluation of dysadipokinemia, we used a logarithmic ratio of leptin to adiponectin (lg A/L). Primary processing of results was carried out using MS Excel and Statistica SPSS22 statistical software packages.

Results: The patients with gout demonstrated higher leptin levels, lower levels of adiponectin, and lower lg A/L compared to practically healthy individuals. Among patients with gout, the disturbance of adipokin status was most pronounced in patients with tophi. Patients with high GAS activity had maximum disturbance of adipokin profile by lg A/L, while the manifestations of dysadipokinemia were minimal in the group with low activity of the disease. It was established that GAS disease activity, BMI, and the number of joints under attack may be considered the most significant independent predictors of dysadipokinemia.

Conclusions: The patients with gout presented an increase in leptin level, a decrease in adiponectin level, and a decrease in the ratio lg A/L. Dysadipokinemia was associated with high disease activity and could serve as a prognostic factor for assessing the severity of the disease.

Wiad Lek 2018, 71, 2 cz. II, -294

 

Introduction

Gout is a disease characterized by hyperuricemia and deposition of sodium urea crystals in tissues, clinically manifested by acute inflammatory arthritis, articular erosion, tophi, urine calculi and nephropathy in some cases, [1]. About 8.3 million (3.9%) of the US population [2] and 2.49% of the population of Great Britain [3] suffer from gout, whereas only 0.9% of Italian and French population have manifestations of gout [4, 5]. Gout gains the importance as a serious problem for the increasing prevalence. The disease has appeared to be a burden not only for patients, their families, but also for society as a whole through losing millions of unearned wages, spending higher health care costs, and facing significant disability of the population. That is why a search for new pathogenetic connections with the gouty arthritis, its chronicity and development of destructive articular changes might serve a proper ground for creation of prognostic models of the disease course and new approaches to treatment of the pathology.

In recent years, a question about the role of adipokines in development of autoimmune and inflammatory rheumatic diseases has been gaining momentum. It was found that patients with rheumatoid arthritis (RA) presented with increased leptin and reduced adiponectin levels, as well as with an association between adipokine levels and the disease activity [6-8]. Similar data for leptin and adiponectin levels were obtained in patients with psoriatic arthritis [9] and osteoarthritis [10]. We have also available the information that leptin acts as an inflammatory cytokine in the cases of systemic lupus erythematosus [11], RA [12] and psoriasis [13]. However, there is still no systemic data on changes in levels of adipokines in patients with gout, the effect of leptin and adiponectin on the course of the disease, as their association with the activity of the inflammatory process have not been studied yet. Therefore, this study may be considered topical.

The aim

The objective was to study the levels of adipokines in patients with gout and assess their association with the disease activity.

Materials and methods

We examined 151 male patients with gout. The diagnosis of gout was established on ACR/EULAR 2015 criteria [14]. Control
group subjects were compared with 31 practically healthy men, represented by age. Clinical examination consisted of collecting the anamnestic data (duration of the disease, number of attacks during the last year, the number of joints under attack, the presence of tophi) and physical examination (the detection of painful joints, counting the number of tophi). The intensity of pain was measured under the visual analog pain scale, where 0 – no pain, and 10 – the maximum pain.

The activity of gout was evaluated against the Gout Activity Score [15] by the formula:

GAS=0.09×number of attacks in the last 12 months+1.01×√UA+0.34×VAS+0.53×ln (1+number of tophi), where UA is the uric acid.

The serum leptin (ng/ml) and adiponectin (μg/ml) levels were determined by immune enzymatic method using Human Leptin ELISA Kit (DRG, Germany) and Human Adiponectin ELISA (Mediagnost, Germany) according to the manufacturer’s instructions. For a comprehensive assessment of dysadipokinemia, the logarithm of leptin/adiponectin ratio (lg A/L) was calculated.

Statistical processing of the results was carried out using MS Excel and Statistica SPSS22 statistical software packages. Student’s t-test criterion was used to assess the difference between the groups. Pearson correlation coefficient was used for evaluation of the relationship between indicators. The difference was considered statistically significant at p <0.05.

Results and discussion

The age of patients involved in the study (Table I) was 52.4±9.2 years old (M±σ). Individuals of the age ranging from 50 to 59 (about 70%) prevailed among the study subjects. The average duration/history of the disease was 8.9±6.6 years. The number of flares during the last year was 3.8±2.7 on the average. 7 subjects (4.6%) claimed no gout attacks in the last year, while a significant proportion of patients – 56 (37.2%) – had from 3 to 5 flares of the disease in the last year. The number of impaired joints was 8.0±5.4. Subcutaneous uric acid deposits were found in one third of the subjects – 51 (33.7%), among which 30 (58.8%) patients had more than 10 tophi. About 67.5% of the surveyed patients had BMI > 30 kg/m2, while the average index was 1.9±3.4. The serum UA was 8.1±2.0 mg/dl. The intensity of pain under VAS was 5.4 ± 2.4 cm.

The patients with gout presented with an increase in leptin level with a simultaneous drop of adiponectin level (Table II). It became apparent that leptin level in patients with gout was more than 2 times higher than that in practically healthy individuals. The average leptin level in patients was 6.6±4.3 ng/ml, whereas in the control group it was 3.0±1.4. The level of adiponectin appeared to be lower in patients with gout (3.3±1.9 μg/ml), whereas in the control group it was 8.6±3.4. The calculation of integral dysadipokinemia index (lg A/L) showed a significant decrease in this indicator in patients with gout – up to 2.7±0.5, whereas in practically healthy persons the value was at the level of 3.4±0.1

We analyzed the levels of leptin, adiponectin and their logarithmic ratio in gout patients, depending on the presence of tophi (Fig. 1-3).

The analysis of the leptin level (Figure 1) demonstrated significant differences between groups of tophi or tophi-free gout patients and the control group. The median and the interval (P25, P75) of leptin levels corresponded to a range of 9.7 (7.2; 13.2) in the gout patients with tophi, and to 4.1 (2.4, 5.9) and 2.7 (2.0, 3.6) – in tophi-free gout patients and practically healthy individuals, accordingly.

The results of percentile distribution of adiponectin level also showed a statistically significant difference between the groups of patients and the control group (Figure 2). Thus, in gout patients with tophi, the level of adiponectin was the lowest – 1.8 (1.4; 2.5). Somewhat higher the rates were found in tophi-free gout patients – 3.4 (2.5; 5.4) (statistically significant differences between groups of patients p<0.001). The highest level of adiponectin was registered in the control group – 6.5 (4.9; 8.4), which exceeded the indicator in patients with gout almost 2.5 times.

The analysis of the logarithmical ratio A/L (Figure 3) showed a significant difference between the groups of patients and the control group (p<0.001). It turned out that the median and interquartile interval (P25, P75) in practically healthy subjects corresponded to a range of 3.38 (3.35; 3.38), whereas in tophi-free gout patients it was 2.93 (2.63; 3.21), and in the patients with tophi – 2.2 (2.0; 2.5) (statistically significant differences between groups of patients p <0.001).

We first evaluated the activity of gout using the Gout Activity Score and found that most of the surveyed patients had the high-active disease. The average GAS activity in the group of patients was 5.9±2.1. In order to evaluate the association of the activity with the adipokine profile, we divided our group of patients by percentile and assigned them into three groups. The first group was patients with low activity of the disease <4.5 (<25), the second group – the patients with moderate activity of the disease ranging from 4.5 to 7.4 (P25-P75), and the third group – the patients with high-active gout > 7.4 (>P75).

The patients with high GAS activity of the disease > 7.4 (>Р75) presented the highest level of leptin (Figure 4) – 11.7±4.7 ng/ml, whereas the patients with moderate activity ranging from 4.5 to 7.4 (P25-P75) had 5.3±2.6 ng/ml, and the patients with a low activity of the disease <4.5 (<P25) – 3.9±1.4 ng/ml. The difference in leptin level between all groups was statistically significant (p<0.01).

In patients with a low activity of the disease <4.5 (<P25), the level of adiponectin (Figure 5) was the highest – 4.24±1.81 μg/ml, whereas in the group of patients with high GAS activity > 7.4 (>P75) the adiponectin level was the lowest – 2.19±1.71 μg/ml. The patients with moderate GAS activity of the disease ranging from 4.5 to 7.4 (P25-P75) had the adiponectin level 3.46±1.91 μg/ml (statistically significant differences between the groups of patients p<0.05).

In the group of patients with low activity of the disease (n=36) (Fig. 6), the A/L ratio was the highest – 3.0±0.3, whereas in patients with moderate activity (n=77) this indicator was equal to 2.8±0.4. The patients with high-active gout (n=38) appeared to have the smallest ratio of lg A/L – 2.3±0.3 (statistically significant differences between groups of patients p<0.05).

To find independent predictors of lg A/L drop in patients with gout, we chose age, duration/history of the disease, a number of affected joints, BMI, and GAS among possible regressors. As a dependent variable, the lg A/L indicator was used. The most important factor influencing dysadipokinemia appeared to be a disease activity under GAS scale (coefficient β=-0.39), somewhat less influence had lg A/L, BMI and the number of affected joints with regression coefficients β=-0.25 and -0.22, respectively (Table III). Non-standardized regression coefficients were statistically significant and reliable (t>3.0). This model of influence on lg A/L indicator was sufficiently informative and statistically reliable, taking into account Fischer criterion (29.9; p <0.00) and df, the multiplicative determination coefficient.

Thus, we have established certain patterns of changes in the levels of adipokines in gout patients, namely: the higher level of leptin, the lower level of adiponectin, and a lower lg A/L ratio compared to practically healthy subjects, indicating a significant imbalance of adipocytokines in gout patients. The data we received are quite in the line with those obtained by other researchers [16, 17].

Disorder of adipokine status was most pronounced in gout patients with tophi.

The GAS activity in our group of patients appeared to be 5.9±2.1, whereas, according to the British scientists Jonathan La-Crette et al., this figure was 2.9±0.7 in their group of patients [18]. Such differences were preconditioned with clinical specifics of the group of patients we studied.

The patients with high GAS activity had the maximum disturbance of the adipokin profile by lg A/L factor, whereas the subjects from the group with low activity of the disease presented with minimal manifestations of dysadipokinemia. The dysadipokinemia indicator (lg A/L) statistically significantly correlated with age, duration/history of the disease, the annual number of gout attacks, the number of impaired joints, the number of tophi, BMI, serum UA and VAS pain. It was found that the most significant independent predictors for dysadipokinemia were GAS disease activity, BMI, and the number of impaired joints (coefficient β -0.39, -0.25 and -0.22, respectively).

Conclusions

The gout patients had a disorder of adipokin status, namely, an increased leptin level, a decreased adiponectin level and lg A/L, the logarithmic ratio thereof. Dysadipokinemia was associated with high GAS activity, the number of impaired joints, and the body mass index. The association of dysadipokinemia with clinical and laboratory parameters may indicate a certain pathogenetic role of adipokines in gout. Further studies are required to justify using these data in daily clinical practice.

References

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3. Kuo CF, Grainge, MJ, Mallen, C et al. Rising burden of gout in the UK but continuing suboptimal management: a nationwide population study. Annals of the rheumatic diseases. 2014;74(4):661-7.

4. Trifirò G, Morabito P, Cavagna L et al. Epidemiology of gout and hyperuricaemia in Italy during the years 2005–2009: a nationwide population-based study. Annals of the rheumatic diseases.2012; 72(5):694-700.

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6. Sun X, Wei J, Tang Y et al. Leptin-induced migration and angiogenesis in rheumatoid arthritis is mediated by reactive oxygen species. FEBS open bio. 2017;7(12):1899-1908.

7. Stygar MV, Stanislavchuk MA, Urovni adipokinov u bolnykh revmatoidnym artritom: sviaz s aktivnostiu zabolevaniia. Viestnik Rossiiskoi voienno-medycynskoi akademii.2013;1(45):95-98.

8. Kontny E, Zielińska A, Księżopolska-Orłowska K, & Głuszko, P. Secretory activity of subcutaneous abdominal adipose tissue in male patients with rheumatoid arthritis and osteoarthritis–association with clinical and laboratory data. Reumatologia. 2016;54(5): 227.

9. Xue Y, Jiang L, Cheng Q et al. Adipokines in psoriatic arthritis patients: the correlations with osteoclast precursors and bone erosions. PLoS One. 2012;7(10): e46740.

10. Wu J, Xu J, Wang K et al. Associations between circulating adipokines and bone mineral density in patients with knee osteoarthritis: a cross-sectional study. BMC musculoskeletal disorders. 2018;19(1):16.

11. Vadacca M, Zardi EM, Margiotta D et al. Leptin, adiponectin and vascular stiffness parameters in women with systemic lupus erythematosus. Internal and emergency medicine. 2013;8(8):705-712.

12. Chen CY, Tsai CY, Lee PC et al. Long-term etanercept therapy favors weight gain and ameliorates cachexia in rheumatoid arthritis patients: roles of gut hormones and leptin. Current pharmaceutical design. 2013;19(10):1956-1964.

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17. Jung CH, Rhee EJ, Choi JH et al. The relationship of adiponectin/leptin ratio with homeostasis model assessment insulin resistance index and metabolic syndrome in apparently healthy Korean male adults. Korean diabetes journal. 2010;34(4):237-243.

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The work was carried out within the framework of the research work “Genetic and environmental factors in the emergence and progression of major rheumatologic diseases”.

State registration number – 0115U001282.

ADDRESS FOR CORRESPONDENCE

Inna V. Orlova

tel: +380969739928

e-mail: orlovainna17@gmail.com

Received: 05.11.2017

Accepted: 02.04.2018

Table I. Gout patients` baseline data

Indicator

Value

Gender: male

n (%)

151 (100)

Age, years

M±σ

52.4±9.2

Disease history, years

M±σ

8.9±6.6

Number of flares/last year

M±σ

3.8±2.7

Number of joints under attack

M±σ

8.0±5.4

Presence of tophi

n (%)

51 (33.7)

BMI, kg/m2

M±σ

31.9±3.4

sUA (mg/dl)

M±σ

8.1±2.0

VAS, cm

M±σ

5.4±2.4

Table II. Adipokine profile for patients with gout and practically healthy individuals

Groups

Leptin, ng/ml

Adiponectin, μg/ml

lg A/L

Gout (n=151)

6.6±4.3

3.3±1.9

2.7±0.5

Controls (n=31)

3.0±1.4*

8.6±3.4*

3.4±0.1*

* – statistically reliable differences compared to the control group (p<0.001)

Note. The top and bottom box margins correspond to P25 and P75, the lines outside the P5 and P95 boxes, the line in the middle of the boxes – median

* – p <0.001 relative to the group of patients with tophi

# – p <0.001 relative to the group of patients without tophi

Fig.1. Levels of leptin in control subjects and in patients with gout, depending on the presence of tophi.

Note. The top and bottom box margins correspond to P25 and P75, the lines outside the P5 and P95 boxes, the line in the middle of the boxes – median

* – p<0.001 relative to the group of patients with tophi

# – p<0.001 relative to the group of patients without tophi

Fig.2. Percentile distribution of adiponectin levels in controls and in patients with gout, depending on the presence of tophi.

Note. The top and bottom box margins correspond to P25 and P75, the lines outside the P5 and P95 boxes, the line in the middle of the boxes – median

* – p<0.001 relative to the group of patients with tophi

# – p<0.001 relative to the group of patients without tophi

Fig.3. Percentile distribution of lg A/L in controls and in patients with gout, depending on the presence of tophi.

Note:

* – statistically reliable differences compared to the group with low-active disease <4.5 (<Р25)

# – statistically reliable differences compared to the group with moderately active disease 4.5 to 7.4 (Р25 – Р75) (p<0.01).

Fig. 4. Distribution of leptin levels depending on the GAS score in patients with gout.

Note:

* – statistically reliable differences compared to the group with low-active disease <4.5 (<Р25)

# – statistically reliable differences compared to the group with moderately active disease 4.5 to 7.4 (Р25 – Р75) (p<0.01)

Fig. 5. Distribution of Adiponectin level depending on the GAS score in patients with gout.

Note:

* – statistically reliable differences compared to the group with low-active disease <4.5 (<Р25)

# – statistically reliable differences compared to the group with moderately active disease 4.5 to 7.4 (Р25 – Р75) (p<0.01)

Fig.6. Logarithmic A/L ratio in patients with gout depending on the GAS score.

Table III. Independent predictors of lg A/L reduction in patients with gout

Independent variable

beta

B

Standard error

t

P value

Constant

 

4.48

0.32

13.87

0.0000

Age, years

0.019

0.00

0.064

0.29

0.766

Disease duration, years

-0.035

-0.00

0.073

-0.48

0.626

Number of impaired d joints

-0.216

-0.01

0.074

-2.90

0.004

BMI, kg/m2

-0.252

-0.03

0.066

-3.79

0.000

GAS

-0.393

-0.08

0.080

-4.85

0.000

Regressive statistics

Multiple R

0.712

Indicator

df

F

P

Multiple R2

0.508

Corrected R2

0.491

Regression

5.145

29.9

0.000

Standard error

0.322