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Melatonin serum levels in rheumatoid arthritis/Romatoid artritte serum melatonin duzeyleri.

Introduction

Rheumatoid arthritis (RA) is a chronic, inflammatory rheumatic disease with unknown etiology (1). The symptoms of the patients with RA demonstrate a circadian rhythm with joint stiffness and pain especially in the morning (2). Several studies have reported that increased concentration of oxidative stress have been found in RA patients. It has been suggested that oxidant status may be associated with increased disease activity (3-5).

Melatonin (MLT) was discovered as an antioxidant in 1993, thousand of investigations have confirmed the anti oxidative actions of MLT (6). It is also well established that MLT is one of the most powerful, endogenous free radical scavengers (3). The clinical studies support that MLT has antioxidant, immunomodulatory and anti-inflammatory functions (1,7). Evidence suggesting the involvement of MLT in RA has been published (1,2). However, the role of MLT in RA pathogenesis remains unclear (8).

In previously studies evaluating MLT concentrations in RA patients were found lower serum levels of MLT. It has been suggested that there was the link between the antioxidant activity loss of MLT hormone and disease activity (3,9). On the contrary, recent studies indicate that MLT production in patients with RA seems to be greater than in healthy controls (2,10). We, therefore, evaluated the serum MLT levels, and discussed the role of MLT in patients with RA.

Methods

Serum levels of MLT were evaluated in 29 patients with RA and in 25 healthy control subjects in the division of Rheumatology of Ataturk University. The diagnosis of RA fulfilled the American College Rheumatology (ACR) criteria. Each patient was diagnosed by a same physician. All patients had active disease. Each patient was receiving medications, either oral prednisolone or a disease-modifying anti-rheumatic drug. Control subjects consisted of healthy subjects. The age and sex of controls were matched for those of RA patients. There was no significant difference between the groups regarding mean age. Controls had no clinical evidence of rheumatic disease or any other disorders. All studies were carried out according to the standards set by the Declaration of Helsinki.

Blood samples were obtained at 8AM. The concentration of MLT in plasma collected in EDTA-containing tubes was measured by DRG melatonin enzyme-linked immunosorbent assay (ELISA) (EIA-1431).

10 ml blood sample was obtained through venipuncture from each patient. This sample was taken by a phlebotomist into heparin/EDTA tubes and was centrifuged at 3000 x g and stored at -80[degrees]C until biochemical analysis.

Statistical Analysis

Statistical analysis was carried out using the Mann-Whitney U-test. A probability (p) value of less than 0.05 was considered statistically significant.

Results

In the present study, the mean age [+ or -] standard deviation of mean in years in both RA patients and controls were 49.4 [+ or -] 0.8 and 47.8 [+ or -] 0.7, respectively. The numbers of female and male RA patients were 20 and 9, respectively, and those in controls were 17 and 8, respectively (Table 1). There was no statistically significant difference between RA patients and controls in age and sex.

Demographics and clinical features of patients are given in Table 1.

Serum levels of MLT in RA patients and controls are given in Table 2. RA patients had higher MLT concentrations at 8AM than in controls, at 15.40 [+ or -] 10.12, 10.03 [+ or -] 5.85 pg/ml (p<0.05).

Discussion

Since MLT is a part of many processes, it is considered to possibly be involved in the ethiopathogenesis of various conditions. In order to establish the role of MLT in disease prevention and or treatment, scientific evidence is being collected in experimental and clinical studies (11,12).

MLT is a neurohormone that in recent years has attracted great attention. Due to its wide-spectrum of properties, it has been suggested to be effective in the etiology and treatment of many diseases. It has actions on the immune diseases and on the immune system and also has antioxidant features. These draw interest to this hormone's role in chronic inflammatory diseases. In addition, detection of a correlation between the circadian release of MLT and rhythmic symptoms and signs of RA patients has lead to addressing its involvement in rheumatic diseases. RA shows rhythmic variation in clinical signs and symptoms depending on the biological clock (13). Preclinical and clinical evidences indicate an impulsive role of MLT in RA (14-16). MLT concentrations are increased in the serums of RA patients and it can be effective in inflamed joints either locally or systemically. The circadian release of MLT and its nocturnal peak are correlated with the daily rhythm of RA symptoms. MLT serum levels are significantly higher in RA patients when compared to controls between 8AM and 8PM. Maximal inflammation is observed between midnight and 8AM, and joint stiffness and pain complaints are more intense during morning hours (13-15).

Recently, MLT is found to be involved in the mechanisms of an opposite response to the cortisol effects in RA patients (13). Generally, MLT shows an immune-strengthening effect. It activates T lymphocytes, monocytes, NK cells and even neutrophils activate antibody-dependent cytotoxicity and increased antibody response. Increasing the synthesis of pro- inflammatory cytokines and nitric acid is a feature that has also been demonstrated (14,17). Cytokines reach a peak during the night and early morning, when cortisol is at its lowest level and MLT is at its highest. IL-l, IL-2, IL-6, IL-12 and tumour necrosis factor (TNF) are considered to be functional, MLT seems to play a role in stimulating a more active inflammatory response during the night. Moreover, MLT has been detected at high levels in the synovial fluids of RA patients (16,18-20). Regarding these results, the inhibition of MLT synthesis or administration of its antagonists may hold a therapeutic effect for RA (13,21).

A number of studies have addressed the anti-inflammatory and immunoregulatory features of MLT. West and Oosthuizen (9) initially found that the daytime MLT concentration was significantly lower in untreated RA patients. In the second part of their study, healthy individuals received indomethacin at a dose 100 mg/day, leading to a reduction in MLT levels. In view of these findings, it could be considered that MLT and indomethacin, which are structurally similar within the body, retain a synergistic effect, and that MLT is able to simultaneously perform an anti-inflammatory activity. Owing to its antioxidant and anti-inflammatory properties (3,9), Forrest et al. (3) investigated the use of MLT in the treatment of 75 RA patients.

As a result, MLT shows a slowly developing anti-oxidant profile in patients with arthritis and increased the concentrations of some inflammatory indicators. By experimentally inducing arthritis, Cardinali et al. (22) compared the inflammatory and immune responses elicited by physiological and pharmacological doses of MLT; while a recovering inflammatory response to low doses was observed at a lower rate in pinealectomized rats, however, under high doses, both inflammatory and immune responses were increased.

The investigation of a genetic correlation between MLT and RA has been performed by Ha et al. in Korea (1). It was verified that MLT receptor type, 1B single-nucleotide polymorphism was related to the presence of rheumatoid factor in RA patients.

MLT, cortisol, and cytokine levels in RA patients were measured in Northern Europe (Estonia) and Southern Europe (Italy). MLT concentrations were higher and reached an earlier peak in RA patients from Estonia (10).

In previous research, the macrophages infiltrating the synovial fluid of RA patients were found specific MLT bindings sites. In addition, MLT were also determined at high concentrations in the synovial fluid. However, administration of MLT has been accused of flaring up experimentally induced arthritis in mice (3,23,24).

Experimental studies showed that there are MLT receptors on synovial macrophages (3,18,25). Consequently, it has been suggested that the higher MLT concentrations may help to explain the morning stiffness and joint swelling in arthritic patients (3,16,19).

In the present study, we evaluated the serum levels of MLT in RA patients. We found that MLT concentrations were significantly higher in RA patients than in controls. The increased levels of MLT may have been a compensatory response to the inflammation of RA. These findings suggest that MLT might play a promoting role in RA. In addition, we suggest that inhibition of MLT synthesis and action by specific antagonist might be of therapeutic value. The MLT-RA relationship might explain why clinical symptoms of rheumatoid synovitis are more evident in the early morning.

As a result, all potential effects, advantages, and risks of MLT have not been ascertained yet. Further studies are needed to determine the possible role of MLT in patients with RA.

Conflict of Interest

Authors reported no conflicts of interest.

DOI: 10.4274/tftr.26122

References

(1.) Ha C, Choe BK, Jung KH, Yoon SH, Park HJ, Park HK, et al. Positive relationship between melatonin receptor type 1B polymorfism and rheumatoid factor in rheumatoid arthritis patients in the Korean population. J Pineal Res 2005;39:201-5.

(2.) Maestroni GJ, Cardinali DP Esquitino Al, Pandi-Perumal SR. Does melatonin play a disease-promoting role in rheumatoid arthritis? Neuroimmunol 2005;158:106-11.

(3.) Forrest CM, Mackay GM, Stay N, Stone TW, Darlington LG. Inflammatory status and kynurenine metabolism in rheumatoid arthritis treated with melatonin. Br J Clin Pharmacol 2007;64:517-26.

(4.) Akyol O, Isci N, Temel I, Ozgocmen S, Uz E, Murat M, Buyukberber S. The relationships between plasma and erythrocyte antioxidant enzymes and lipid peroxidation in patients with rheumatoid arthritis. Joint Bone Spine 2001;68:311-7.

(5.) Kamanli A, Naziroglu M, Aydilek N, Hacievliyagil C. Plasma lipid peroxidation and antioxidant levels in patients with rheumatoid arthritis. Cell Biochem Function 2003;22:53-7.

(6.) Korkmaz A. Melatonin as an adjuvant therapy in patients with rheumatoid arthritis. Br J Clin Pharmacol 2008;66:316-7.

(7.) Reiter RJ. Melatonin; Clinical relevance. Best Pract Res Clin Endocrinol Mel 2003;17:273-85.

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(9.) West SK, Oosthuizen JM. Melatonin levels are decreased in rheumatoid arthritis. J Basic Clin Physiol Pharmacol 1992;3:33-40.

(10.) Cutolo M, Maestroni GJ, Otsa K, Aakre O, Villaggio B, Capellino S, et al. Circadian melatonin and cortisol levels in rheumatoid arthritis patients in winter time: a North and South Europa comparison. Ann Rheum Dis 2005;64:212-6.

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(15.) Cutolo M, Villaggio B, Otsa K, Aakre O, Sulli A, Seriolo B. Altered circadian rhythyms in rheumatoid arthritis patients play a role in the disease's symptoms. Autoimmune Rev 2005;4:497-502.

(16.) Cutolo M, Maestroni GJ. The melatonin-cytokine connection in rheumatoid arthritis. Ann Rheum Dis 2005;64:1109-11.

(17.) Jimenez-Caliani AJ, Jimenez-Jorge S, Molinero P, Guerrers JM, Fernandez-Santos JM, Martin-Lacavel I, Osuna C. Dual affect of melatonin as pro-inflammatory and antioxidant in collagen-induced arthritis in rats. J Pineal Res 2005;38:93-9.

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(22.) Cardinali DP Garcia AP Cano P Esquifino AI. Melatonin role in experimental arthritis. Curr Drug Targets Immune Endor Metabol Disord 2004;4:1-10.

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(24.) Hansson I, Holindahl R, Mattsson R. Pinealectomy ameliorates collagen-II-induced arthritis in mice. Clin Exp Immunol 1993;92:432-6.

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Tuba BAYKAL, Kazim SENEL, Meltem ALKAN MELIKOGLU, Akin ERDAL, Hamit Hakan ALP *, Mahir UGUR

Ataturk University School of Medicine, Department of Physical Medicine and Rehabilitation, Erzurum, Turkey

* Ataturk University School of Medicine, Department of Biochemistry, Erzurum, Turkey

Address for Correspondence:/Yazima Adresi: Kazim Senel MD, Ataturk University School of Medicine, Department of Physical Medicine and Rehabilitation, Erzurum, Turkey Phone: +90 442 233 11 22 E-mail: kazimsenel@gmail.com Received/Gelis Tari hi: March/Mart 2011 Accepted/Kabul Tari hi: September/Ekim 2011
Table 1. Demographics and clinical features in RA patients and
controls.

Controls (n=25)
Patients (n=29)

Age (mean [+ or -] SD)    47.8 [+ or -] 0.7   49.4 [+ or -] 0.8
Female/male               17/8                20/9
Disease duration                              6.4 [+ or -] 0.6
  (mean [+ or -] SD.yr)
RF (+) (%)                                    20

Table 2: Serum Levels of MLT in controls and RA patients.

Group     MLT concentrations (pg/ml)

Control   10.03 [+ or -] 5.85
RA        15.40 [+ or -] 10.12 *

* p<0.05
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Title Annotation:Original Article/Orijinal Makale
Author:Baykal, Tuba; Senel, Kazim; Melikoglu, Meltem Alkan; Erdal, Akin; Alp, Hamit Hakan; Ugur, Mahir
Publication:Turkish Journal of Physical Medicine and Rehabilitation
Article Type:Report
Geographic Code:7TURK
Date:Mar 1, 2013
Words:2253
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