The Open Rheumatology Journal




ISSN: 1874-3129 ― Volume 13, 2019

Serum Adenosine Deaminase Level is High But Not Related with Disease Activity Parameters in Patients with Rheumatoid Arthritis



Gülseren Demir 1, Pınar Borman*, 2, Figen Ayhan 1, Tuba Özgün 3, Ferda Kaygısız 1, Gulsen Yilmez 3
1 Ankara Training and Research Hospital, Clinic of Physical Medicine and Rehabilitation
2 University of Hacettepe, Faculty of Medicine, Dept of Physical Medicine and Rehabilitation
3 Ankara Training and Research Hospital, Clinic of Biochemistry, Turkey

Abstract

Serum adenosine deaminase (ADA) has been previously proposed to predict disease activity in patients with rheumatoid arthritis (RA). The aim of this study was to investigate the level of serum ADA, and the relationship between ADA and disease activity markers, in a group of patients with RA.

A hundred and 10 patients with a diagnosis of RA were recruited from outpatient clinic of Rheumatology Unit. Demographic properties comprising age, gender, disease duration and drugs were recorded. Disease activity based on disease activity score (DAS)28-erythrocyte sedimentation rate (ESR) and DAS28- C reactive protein (CRP,) ESR, CRP levels, as well as pain by visual analog scale and rheumatoid factor (RF) were recorded. Serum ADA levels (IU/L) were determined in all RA patients and in 55 age and sex similar healthy control subjects.

Ninety-six female and 14 male RA patients with a mean age of 54.32±11.51, and with a mean disease duration of 11.5±9.13 years were included to the study. The control group comprised of 48 female and 7 male healthy subjects. 35.5% of the patients were on methotrexate (MTX) and 64.5% of patients were on combined DMARDs or combined MTX and anti-TNF therapies. The mean serum ADA level was statistically higher in RA patients than in control subjects (27.01±10.6 IU/L vs 21.8 ±9.9 IU/L). The mean values of ESR (23.2±14.8 mm/h), CRP (1.71±1.11mg/dL), pain by VAS (37.2±27.1), DAS28-ESR (2.72±0.77), DAS28 CRP (1.37±0.5) were not correlated with ADA levels (p>0.05).

Our results have shown that serum ADA levels are higher in RA patients than in controls but were not related with any of the disease activity markers. We conclude that ADA in the serum may not be a reliable biochemical marker to predict disease activity in patients with RA.

Keywords: Adenosine deaminase, disease activity, rheumatoid arthritis, serum..


Article Information


Identifiers and Pagination:

Year: 2014
Volume: 8
First Page: 24
Last Page: 28
Publisher Id: TORJ-8-24
DOI: 10.2174/1874312901408010024

Article History:

Received Date: 3/3/2014
Revision Received Date: 18/7/2014
Acceptance Date: 11/8/2014
Electronic publication date: 12/9/2014
Collection year: 2014

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open-access license: This is an open access article licensed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted, non-commercial use, distribution and reproduction in any medium, provided the work is properly cited.


* Address correspondence to this author at the University of Hacettepe, Faculty of Medicine, Department of Physical Medicine and Rehabilitation, Sihhiye, Ankara, Turkey; Tel: 90.532.4649897; Fax: 90.312.4186363; E-mail: pinarborman@gmail.com





INTRODUCTION

Rheumatoid Arthritis (RA) is a chronic inflammatory multisystem disorder affecting primarily cartilage and joints, which aetiopathogenesis has not been clarified yet. The synovial inflammation and destruction of joints is often progressive and lead to joint destruction [1Hochberg MC, Silman AJ, Smolen JS, Brasington RD, Eds. Clinical features of rheumatoid arthritis. Rheumatology. 5th ed.. Philadelphia: Mosby-Elsevier. 2011; pp. 829-38., 2Mc Innes IB, Schett G. The pathogenesis of rheumatoid arthritis. N Engl J Med 2011; 365: 2205-9.]. As a result of cell-mediated immune response, the condition is characterized by secretion of different inflammatory products from activated lymphocytes, macrophages, fibroblasts and leukocytes in synovial joints. Endogenous adenosine suppress this process and actually adenosine pathway mediates the inflammatory cascade [2Mc Innes IB, Schett G. The pathogenesis of rheumatoid arthritis. N Engl J Med 2011; 365: 2205-9., 3Iwaki-Egawa S, Yamamoto T, Watanabe Y. Human plasma adenosine deaminase2 is secreted by activated monocytes. Biol Chem 2006; 387: 319-21.]. Adenosine indicates its modulator effects by interaction with G protein-coupled receptors, that exists in at least three molecular forms; A1, A2A, A2B and A3. In this regard, extracellular adenosine levels are important in determining its ability of regulating various biological processes [4Nakamachi Y, Koshiba M, Nakazawa T , et al. Specific increase in enzymatic activity of adenosine deaminase 1 in rheumatoid synovial fibroblasts. Arthritis Rheum 2003; 48: 668-74., 5Antonioli L, Colucci R, La Motta C , et al. Adenosine deaminase in the modulation of immune system and its potential as a novel target for treatment of inflammatory disorders. Curr Drug Targets 2012; 3(6): 842-62.]. Adenosine is metabolized by adenosine deaminase (ADA); one of the main enzymes of purine metabolic pathway. This catabolic enzyme ADA represents an exclusive checkpoint in the regulation of extracellular adenosine levels and, consequently, in the control of immune system activity through its modulation of adenosine pathways in several conditions like RA [4Nakamachi Y, Koshiba M, Nakazawa T , et al. Specific increase in enzymatic activity of adenosine deaminase 1 in rheumatoid synovial fibroblasts. Arthritis Rheum 2003; 48: 668-74.-14Nalesnik M, Nikolic JM, Jandric S. Adenosine deaminase and C-reactive protein in diagnosing and monitoring of rheumatoid arthritis. Med Glas (Zenica) 2011; 8(1): 163-8.]. Therefore determination of serum adenosine level can be an appropriate way to assess disease activity in RA.

There are conflicting reports about the relationship of ADA and disease activity parameters in the English literature [5Antonioli L, Colucci R, La Motta C , et al. Adenosine deaminase in the modulation of immune system and its potential as a novel target for treatment of inflammatory disorders. Curr Drug Targets 2012; 3(6): 842-62.-16Cordero OJ, Salgado FJ, Mera-Varela A, Nougueira M. Serum interleukin-12, interleukin-15, soluble CD26, and adenosine deaminase in patients with rheumatoid arthritis. Rheumatol Int 2001; 21(2): 69-74.]. Serum ADA was reported to be increased in serum and synovial fluid of RA patients compared with non-inflammatory arthritic conditions [7Sari RA, Taysi S, Yilmaz O, Bakan N. Correlation of serum levels of adenosine deaminase activity and its isoenzymes with disease activity in rheumatoid arthritis. Clin Exp Rheumatol 2003; 21: 87-90., 10Salesi M, Aghaye-Ghazvini R, Farajzadegan Z , et al. Serum adenosine deaminase in patients with rheumatoid arthritis treated with methotrexate. J Res Pharm Pract 2012; 1(2): 72-6., 11Yuksel H, Akoglu TF. Serum and synovial fluid adenosine deaminase activity in patients with rheumatoid arthritis, osteoarthritis and reactive arthritis. Ann Rheum Dis 1988; 47: 492-5.]. ADA has been suggested as a prediction marker or a useful biochemical marker of inflammatory process in patients with RA [13Zamani B, Jamali R, Jamali A. Serum adenosine deaminase may predict disease activity in rheumatoid arthritis. Rheumatol Int 2012; 32: 1967,-75., 14Nalesnik M, Nikolic JM, Jandric S. Adenosine deaminase and C-reactive protein in diagnosing and monitoring of rheumatoid arthritis. Med Glas (Zenica) 2011; 8(1): 163-8.], while some studies did not find a correlation between ADA levels and disease activity markers [15Erer B, Yilmaz G, Yilmaz FM, Koklu S. Assessment of adenosine deaminase levels in rheumatoid arthritis patients receiving anti-TNF –a therapy. Rheumatol Int 2009; 29: 651-4., 16Cordero OJ, Salgado FJ, Mera-Varela A, Nougueira M. Serum interleukin-12, interleukin-15, soluble CD26, and adenosine deaminase in patients with rheumatoid arthritis. Rheumatol Int 2001; 21(2): 69-74.]. In addition most of these studies have been performed with small sample size and have not explained patient characteristics and drugs in details [6Hitoglue S, Hatzstilianaou M, Gougoustamaou D, Athanassiadou F, Kotsis A, Catriu D. Adenosine deaminase activity and its isoenzyme pattern in patients with juvenile rheumatoid arthritis and systemic lupus erythematosus. Clin Rheumatol 2001; 20: 411-6.-16Cordero OJ, Salgado FJ, Mera-Varela A, Nougueira M. Serum interleukin-12, interleukin-15, soluble CD26, and adenosine deaminase in patients with rheumatoid arthritis. Rheumatol Int 2001; 21(2): 69-74.].

The aim of this study was to determine the level of ADA in a large group of RA patients and evaluate its association with disease activity parameters.

MATERIALS AND METHODS

A hundred and ten patients with RA, who met the American College of Rheumatology revised criteria [17Arnett FC, Edworthy SM, Block DA , et al. American College of Rheumatology 1987, revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 1988; 31: 315-24.] for RA, were enrolled from the outpatient clinics of Ankara Training and Research Hospital, Rheumatology unit of Physical Medicine and Rehabilitation Clinic, between 2012 January and December. Patients with a mean BMI>35, aged<18, and >80 years patients with these comorbid diseases (chronic renal failure, hepatic insufficiency, thyroid disease, heart failure, tuberculosis, septic conditions and uncontrolled diabetes mellitus) were not included to the study. 144 patients with rheumatoid arthritis were assessed for eligibility. 5 patients refused to participate in the study and 29 patients were excluded due to age or comorbid diseases. Therefore 110 RA patients were included to the study. Fifty- five age and sex similar (within ± 2 years) healthy control subjects who were the members of the hospital staff and volunteered to participate in the study, were comprised. We obtained informed consent from all the patients and controls, and the study was approved by the ethics committee of the hospital.

Demographic characteristics including age, sex, body mass index (BMI) in all subjects, and drug intake and disease duration of RA patients were recorded. All patients underwent a clinical interview and physical examination. In order to determine disease activity in patients with RA, disease activity score (DAS)28 was performed [18Wells G, Becker JC, Teng J , et al. Validation of the 28-joint disease activity scoe (DAS28):and EULAR response criteria based on CRP against disease progression in patients with rheumatoid arthritis, and comparison with the DAS28 based on erythrocyte sedimentation rate. Ann Rheum Dis 2009; 68: 954-60.].

Blood samples of the patients were taken to determine hemoglobin (Hb), erythrocyte sedimentation rate (ESR) using the Westergren method, rheumatoid factor (RF) using nephelometric method and C reactive protein (CRP) by turbidimetric method in RA group. The numbers of tender and swollen joints as well as joint pain assessed by visual analog scale (VAS) were collected from patient files. DAS 28-ESR and DAS28-CRP were calculated for each patient using well-known calculations which included the number of tender and swollen joints, ESR and CRP, and patients’ global assessment of general health expressed on visual analog scale [18Wells G, Becker JC, Teng J , et al. Validation of the 28-joint disease activity scoe (DAS28):and EULAR response criteria based on CRP against disease progression in patients with rheumatoid arthritis, and comparison with the DAS28 based on erythrocyte sedimentation rate. Ann Rheum Dis 2009; 68: 954-60.]. The ESR, CRP, DAS28 and pain by VAS were considered as disease activity parameters.

Serum ADA levels in patient and control groups were determined and the relation between ADA level and disease activity parameters were evaluated. Although the exact effect of MTX on the ADA enzymatic activity is not clearly understood, it is assumed that in purine enzyme metabolic pathway, MTX increases adenosine and inhibits ADA both directly and indirectly [10Salesi M, Aghaye-Ghazvini R, Farajzadegan Z , et al. Serum adenosine deaminase in patients with rheumatoid arthritis treated with methotrexate. J Res Pharm Pract 2012; 1(2): 72-6.]. Therefore the RA group was divided into two groups as patients receiving MTX and patients on drugs other than MTX. Subgroup analysis was performed in regard to ADA and related activity parameters.

The serum level of ADA was determined in all subjects. Serum samples were obtained from venous blood, routine laboratory investigations were performed on samples of RA patients and after this all serum samples were frozen immediately. The samples were stored at -80°C until measuring time. ADA activity was determined by an enzymatic spectrophotometric method with Schimadzu CL-770 clinical spectrophotometer [19Ungerer JP, Oosthuizen HM, Bissbort SH, Vermaak JH. Serum adenosine deaminase Isoenzymes and diagnostic application. Clin Chem 1992; 38(7): 1322-6.].

Statistical Analysis

Data analysis was performed using the SPSS statistical package program version 15.0 for Windows. Data for variables were described using mean ± SD. The comparisons for continuous variables between the two groups (patients and controls) were performed by independent sample t test and Mann–Whitney U test as appropriate.

Correlation analysis for continuous variables was performed using the Spearman’s correlation test. Scatter plot was performed to indicate the correlation between two continuous variables (ADA and DAS28). The value of p<0.05 was considered significant.

RESULTS

The study group comprised 110 RA patients and 55 healthy control subjects. The demographic characteristics of the subjects are shown in Table 1. No statistical difference was observed between the groups according to age, sex and BMI (p>0.05). The clinical features including the disease activity parameters of RA patients are shown in Table 2. Thirty-two (35.5%) of the patients were on methotrexate (MTX) and 64.5% of patients were on combined disease modifying antirheumatic drug (DMARD)s or combined MTX and anti- tumor necrosis factor (TNF) therapies, 14 patients (12%) were on leflunomide (LEF) therapy, 44 patients (40%) were using corticosteroids and/or NSAIDs in addition to DMARDs. All patients using MTX were also receiving folic acid supplementation 5mg/week. The mean MTX and folic acid dosages were 15.4 mg/week and 5 mg/week respectively. The mean ADA level was determined as 27.01±10.6 IU/L in the RA group and was found to be statistically higher than in the control group (21.8±9.9 IU/L), (independent sample t test, p<0.05). No relationship was observed between the mean ADA level and disease activity parameters (Spearman correlation test, p>0.05) (Figs. 1, 2).

Fig. (1)

The correlation between of ADA levels and DAS28-ESR values, indicated as scatter plot.



Fig. (2)

The correlation between ADA levels and DAS28-CRP values indicated as scatter plot.



Table 1

The demographic characteristics of the patients and control subjects (descriptives).




Table 2

The mean±SD values of the clinical activity parameters and RF levels in the patient group (descriptives).




Table 3

The relationship between ADA and disease activity parameters in both patient groups using MTX and using other DMARDs (Spearman correlation test, p>0.05).




Depending on the assumption that MTX decreases the inflammation by stimulating the adenosine receptors and by inhibiting ADA, we assessed the serum ADA of RA patients receiving MTX and taking DMARDs other than MTX. Patients with RA were divided into two groups according to the use of MTX. According to this classification, 71 patients were on MTX while 39 were on DMARDs other than MTX. There was no statistically significant difference between patients with MTX and patients with other DMARDs, in regard to serum ADA level (independent sample t test, p>0.05, 27.53±11.4 vs 24.16±7.8 respectively). we evaluated the relationship between disease activity markers and ADA levels in groups with regard to MTX usage, and we could not find any relationship between disease activity markers and ADA levels in none of these groups (Table 3, Spearman correlation analysis, p>0.05).

DISCUSSION

Serum ADA was previously reported to be increased in serum and synovial fluid of RA patients compared with non-inflammatory arthritic conditions [7Sari RA, Taysi S, Yilmaz O, Bakan N. Correlation of serum levels of adenosine deaminase activity and its isoenzymes with disease activity in rheumatoid arthritis. Clin Exp Rheumatol 2003; 21: 87-90., 10Salesi M, Aghaye-Ghazvini R, Farajzadegan Z , et al. Serum adenosine deaminase in patients with rheumatoid arthritis treated with methotrexate. J Res Pharm Pract 2012; 1(2): 72-6.-12Zekeri Z, Izadi S, Niazi A , et al. Comparison of adenosine deaminase levels in serum and synovial fluid between patients with rheumatoid arthritis and osteoarthritis. Int J Clin Exp Med 2012; 5(2): 195-200., 20Pallinti V, Ganesan N, Anbazhagan M, Rajasekhar G. Serum biochemical markers in rheumatoid arthritis. Indian J Biochem Biophys 2009; 46: 342-4.]. Yuksel et al. found an increased level of ADA activity in synovial fluid of patients with RA, than in their control group [11Yuksel H, Akoglu TF. Serum and synovial fluid adenosine deaminase activity in patients with rheumatoid arthritis, osteoarthritis and reactive arthritis. Ann Rheum Dis 1988; 47: 492-5.]. Zekeri et al. indicated higher serum ADA activity in RA patients when compared with osteoarthritic patients [12Zekeri Z, Izadi S, Niazi A , et al. Comparison of adenosine deaminase levels in serum and synovial fluid between patients with rheumatoid arthritis and osteoarthritis. Int J Clin Exp Med 2012; 5(2): 195-200.]. Most of the previous studies had shown a significant relation between the mean serum ADA level and disease activity markers [7Sari RA, Taysi S, Yilmaz O, Bakan N. Correlation of serum levels of adenosine deaminase activity and its isoenzymes with disease activity in rheumatoid arthritis. Clin Exp Rheumatol 2003; 21: 87-90., 11Yuksel H, Akoglu TF. Serum and synovial fluid adenosine deaminase activity in patients with rheumatoid arthritis, osteoarthritis and reactive arthritis. Ann Rheum Dis 1988; 47: 492-5., 13Zamani B, Jamali R, Jamali A. Serum adenosine deaminase may predict disease activity in rheumatoid arthritis. Rheumatol Int 2012; 32: 1967,-75., 14Nalesnik M, Nikolic JM, Jandric S. Adenosine deaminase and C-reactive protein in diagnosing and monitoring of rheumatoid arthritis. Med Glas (Zenica) 2011; 8(1): 163-8.] Sari et al. investigated the relation betweeen serum ADA level and its isoenzymes with disease activity of RA and showed that total ADA and ADA2 had correlation with RA activity [7Sari RA, Taysi S, Yilmaz O, Bakan N. Correlation of serum levels of adenosine deaminase activity and its isoenzymes with disease activity in rheumatoid arthritis. Clin Exp Rheumatol 2003; 21: 87-90.]. Nalesnik et al. have shown that ADA activity is related with inflammation and serum ADA could be a useful biochemical marker of inflammatory process in RA [14Nalesnik M, Nikolic JM, Jandric S. Adenosine deaminase and C-reactive protein in diagnosing and monitoring of rheumatoid arthritis. Med Glas (Zenica) 2011; 8(1): 163-8.]. Zamani et al. determined a relationship between ADA and disease activity and reported that ‘serum ADA may help to predict disease activity in patients with RA’ [13Zamani B, Jamali R, Jamali A. Serum adenosine deaminase may predict disease activity in rheumatoid arthritis. Rheumatol Int 2012; 32: 1967,-75.]. On the other hand Erer et al. could not find a relation between ADA levels and disease activity parameters in their RA group receiving DMARD and/or anti TNF therapy [15Erer B, Yilmaz G, Yilmaz FM, Koklu S. Assessment of adenosine deaminase levels in rheumatoid arthritis patients receiving anti-TNF –a therapy. Rheumatol Int 2009; 29: 651-4.]. Also Cordero did not define a relation between serum ADA and disease activity in their study group [16Cordero OJ, Salgado FJ, Mera-Varela A, Nougueira M. Serum interleukin-12, interleukin-15, soluble CD26, and adenosine deaminase in patients with rheumatoid arthritis. Rheumatol Int 2001; 21(2): 69-74.]. In this study we determined higher levels of ADA in RA patients than in healthy control subjects similar to previous data, but could not find a significant relationship between ADA activity and disease activity parameters. In our group, disease activity was relatively not so high compared to previous papers, which might be related with the maintenance of variable treatments during the study. We speculate that the ADA levels might be related with disease activity parameters if the study group included patients with high disease activity and without treatment. As this is not ethical, further studies with recently diagnosed RA patients may clarify these points and would be of importance.

Serum ADA reflects monocyte/macrophage activity in several inflammatory disease like RA, viral conditions or tuberculosis [8Calis M, Ates F, Yazici C , et al. Adenosine deaminase enzyme levels, their relation with disease activity, and the effect of colchicine on adenosine deaminase levels in patients with Behcet’s disease. Rheumatol Int 2005; 25: 452-6., 9Meunier P, Filipe P, Emerit I , Freitas J, Guerra Rodrigo F, Manso C. Adenosine deaminase in progressive systemic sclerosis. Acta Derm Venerol 1995; 75: 297-9., 21Tuon FF, Litvoc MN, Lopes MI. Adenosine deaminase and tuberculosis pericarditis- a systematic review with meta-analysis. Acta Trop 2006; 99: 67-74.]. Etiology of RA is considered mostly to be a T helper- mediated disease. Endogenous adenosine has anti-inflammatory function but due to some local factors, its concentration may decrease in the emission area. Inflammation triggers adenosine release suppression and elevation of ADA activity, which causes adenosine disturbance and lead to decreased enzyme activity which disintegrates ATP to adenosine. Therefore reduction of local concentration of adenosine by ADA may contribute to joint inflammation of RA [5Antonioli L, Colucci R, La Motta C , et al. Adenosine deaminase in the modulation of immune system and its potential as a novel target for treatment of inflammatory disorders. Curr Drug Targets 2012; 3(6): 842-62., 10Salesi M, Aghaye-Ghazvini R, Farajzadegan Z , et al. Serum adenosine deaminase in patients with rheumatoid arthritis treated with methotrexate. J Res Pharm Pract 2012; 1(2): 72-6., 22Nakamachi Y, Koshiba M, Nakazawa T , et al. Specific increase in enzymatic activity of adenosine deaminase 1 in rheumatoid synovial fibroblasts. Arthritis Rheum 2003; 48: 668-74., 23Cronstein BN, Naime D, Firestein G. The anti-inflammatory effects of an adenosine kinase inhibitor are mediated by adenosine. Arthritis Rheum 1995; 38(8): 1040-5.]. Regarding these points; the higher levels of ADA found in our and previous RA patients are not surprising.

Methotrexate is the anchor drug for therapy of RA and more often its combination with other DMARDs is used commonly. Since the anti-inflammatory effect of MTX is via the stimulation of adenosine receptors, it was considered that the therapeutic effects of MTX could be as a result of catalytic activity of ADA in the serum [5Antonioli L, Colucci R, La Motta C , et al. Adenosine deaminase in the modulation of immune system and its potential as a novel target for treatment of inflammatory disorders. Curr Drug Targets 2012; 3(6): 842-62., 10Salesi M, Aghaye-Ghazvini R, Farajzadegan Z , et al. Serum adenosine deaminase in patients with rheumatoid arthritis treated with methotrexate. J Res Pharm Pract 2012; 1(2): 72-6.]. The pathophysiology of adenosine secretion is also related with MTX pathways [10Salesi M, Aghaye-Ghazvini R, Farajzadegan Z , et al. Serum adenosine deaminase in patients with rheumatoid arthritis treated with methotrexate. J Res Pharm Pract 2012; 1(2): 72-6., 24Riksen NP, Barrera P, Van den Broek PHH, van Riel PLCM, Smits P. Methotrexate modulates the kinetics of adenosine in humans in vivo. Ann Rheum Dis 2006; 65: 465-70.-26Van Ede AE, Laan RFJM, De Abreu RA, Stegeman ABJ, van de Putte LBA. Purine enzymes in patients with rheumatoid arthritis treated with methotrexate. Ann Rheum Dis 2002; 61: 1060-4.]. Previous studies indicated that ‘adenosine is an effector molecule mediating the therapeutic effects of MTX via adenosine receptor signalling’ [5Antonioli L, Colucci R, La Motta C , et al. Adenosine deaminase in the modulation of immune system and its potential as a novel target for treatment of inflammatory disorders. Curr Drug Targets 2012; 3(6): 842-62., 14Nalesnik M, Nikolic JM, Jandric S. Adenosine deaminase and C-reactive protein in diagnosing and monitoring of rheumatoid arthritis. Med Glas (Zenica) 2011; 8(1): 163-8.]. It is suggested that MTX inhibits ADA and increases vasodilatation induced by adenosine. Therefore it is an assumption that ADA activity in serum may be a possible biochemical marker for monitoring the therapeutic effects of MTX in RA patients [5Antonioli L, Colucci R, La Motta C , et al. Adenosine deaminase in the modulation of immune system and its potential as a novel target for treatment of inflammatory disorders. Curr Drug Targets 2012; 3(6): 842-62., 14Nalesnik M, Nikolic JM, Jandric S. Adenosine deaminase and C-reactive protein in diagnosing and monitoring of rheumatoid arthritis. Med Glas (Zenica) 2011; 8(1): 163-8.]. Nalenisk et al. determined a significant correlation between ADA and CRP concentrations in serum of RA patients who were not on MTX therapy [14Nalesnik M, Nikolic JM, Jandric S. Adenosine deaminase and C-reactive protein in diagnosing and monitoring of rheumatoid arthritis. Med Glas (Zenica) 2011; 8(1): 163-8.]. Van Ede et al. concluded a relationship between ADA and MTX treatment in patients receiving MTX and folic acid [26Van Ede AE, Laan RFJM, De Abreu RA, Stegeman ABJ, van de Putte LBA. Purine enzymes in patients with rheumatoid arthritis treated with methotrexate. Ann Rheum Dis 2002; 61: 1060-4., 27Baggott JE, Morgan ST, Ha TS, Alarcon GS, Koopman WJ, Krumdieck CL. Antifolates in rheumatoid arthritis a hypothetical mechanism of action. Clin Exp Rheumatol 1993; 11(Suppl 8): S101-5.]. Salesi et al. determined ADA levels before and after the MTX treatment in their RA group and indicated an association with ADA levels with the efficacy of MTX treatment [10Salesi M, Aghaye-Ghazvini R, Farajzadegan Z , et al. Serum adenosine deaminase in patients with rheumatoid arthritis treated with methotrexate. J Res Pharm Pract 2012; 1(2): 72-6.]. But these studies did not defined disease activity status nor the MTX and/or folic acid dosages of their patients. In our study we have determined ADA levels with regard to MTX usage but could not find a difference between the groups. In addition we could not detect a relationship between ADA level and disease activity in patients with and without MTX treatment. The mean dosage of MTX was 15.6 mg and disease activity was relatively not so high, in our study group. The different results of our data from the previous literature may be due to MTX and/or folic acid dosages or disease activity status.

There may be some limitations of our study. One of them is the absence of detection of ADA isoenzymes. Also not covering the synovial ADA levels to compare and determine the relationship with activity markers may be accepted as another limitation. The major strengths of the present study include a large sample of RA patients, defining the therapies in details and inclusion of the control group.

In conclusion this study showed that level of ADA was higher in Turkish RA patients than in healthy control subjects but not related with any of the disease activity parameters. We suggest that ADA activity does not seem to help to predict disease activity. According to our results traditional disease activity parameters still remain the best strategy for determining the activity and monitoring the treatment in patients suffering from RA.

CONFLICT OF INTEREST

The authors confirm that this article content has no conflict of interest.

ACKNOWLEDGEMENTS

Declared none.

REFERENCES

[1] Hochberg MC, Silman AJ, Smolen JS, Brasington RD, Eds. Clinical features of rheumatoid arthritis. Rheumatology. 5th ed.. Philadelphia: Mosby-Elsevier. 2011; pp. 829-38.
[2] Mc Innes IB, Schett G. The pathogenesis of rheumatoid arthritis. N Engl J Med 2011; 365: 2205-9.
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[4] Nakamachi Y, Koshiba M, Nakazawa T , et al. Specific increase in enzymatic activity of adenosine deaminase 1 in rheumatoid synovial fibroblasts. Arthritis Rheum 2003; 48: 668-74.
[5] Antonioli L, Colucci R, La Motta C , et al. Adenosine deaminase in the modulation of immune system and its potential as a novel target for treatment of inflammatory disorders. Curr Drug Targets 2012; 3(6): 842-62.
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[8] Calis M, Ates F, Yazici C , et al. Adenosine deaminase enzyme levels, their relation with disease activity, and the effect of colchicine on adenosine deaminase levels in patients with Behcet’s disease. Rheumatol Int 2005; 25: 452-6.
[9] Meunier P, Filipe P, Emerit I , Freitas J, Guerra Rodrigo F, Manso C. Adenosine deaminase in progressive systemic sclerosis. Acta Derm Venerol 1995; 75: 297-9.
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[11] Yuksel H, Akoglu TF. Serum and synovial fluid adenosine deaminase activity in patients with rheumatoid arthritis, osteoarthritis and reactive arthritis. Ann Rheum Dis 1988; 47: 492-5.
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[13] Zamani B, Jamali R, Jamali A. Serum adenosine deaminase may predict disease activity in rheumatoid arthritis. Rheumatol Int 2012; 32: 1967,-75.
[14] Nalesnik M, Nikolic JM, Jandric S. Adenosine deaminase and C-reactive protein in diagnosing and monitoring of rheumatoid arthritis. Med Glas (Zenica) 2011; 8(1): 163-8.
[15] Erer B, Yilmaz G, Yilmaz FM, Koklu S. Assessment of adenosine deaminase levels in rheumatoid arthritis patients receiving anti-TNF –a therapy. Rheumatol Int 2009; 29: 651-4.
[16] Cordero OJ, Salgado FJ, Mera-Varela A, Nougueira M. Serum interleukin-12, interleukin-15, soluble CD26, and adenosine deaminase in patients with rheumatoid arthritis. Rheumatol Int 2001; 21(2): 69-74.
[17] Arnett FC, Edworthy SM, Block DA , et al. American College of Rheumatology 1987, revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 1988; 31: 315-24.
[18] Wells G, Becker JC, Teng J , et al. Validation of the 28-joint disease activity scoe (DAS28):and EULAR response criteria based on CRP against disease progression in patients with rheumatoid arthritis, and comparison with the DAS28 based on erythrocyte sedimentation rate. Ann Rheum Dis 2009; 68: 954-60.
[19] Ungerer JP, Oosthuizen HM, Bissbort SH, Vermaak JH. Serum adenosine deaminase Isoenzymes and diagnostic application. Clin Chem 1992; 38(7): 1322-6.
[20] Pallinti V, Ganesan N, Anbazhagan M, Rajasekhar G. Serum biochemical markers in rheumatoid arthritis. Indian J Biochem Biophys 2009; 46: 342-4.
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[22] Nakamachi Y, Koshiba M, Nakazawa T , et al. Specific increase in enzymatic activity of adenosine deaminase 1 in rheumatoid synovial fibroblasts. Arthritis Rheum 2003; 48: 668-74.
[23] Cronstein BN, Naime D, Firestein G. The anti-inflammatory effects of an adenosine kinase inhibitor are mediated by adenosine. Arthritis Rheum 1995; 38(8): 1040-5.
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Daniel Pesut
(Indiana University School of Nursing, USA)

"It is important that students and researchers from all over the world can have easy access to relevant, high-standard and timely scientific information. This is exactly what Open Access Journals provide and this is the reason why I support this endeavor."


Jacques Descotes
(Centre Antipoison-Centre de Pharmacovigilance, France)

"Publishing research articles is the key for future scientific progress. Open Access publishing is therefore of utmost importance for wider dissemination of information, and will help serving the best interest of the scientific community."


Patrice Talaga
(UCB S.A., Belgium)

"Open access journals are a novel concept in the medical literature. They offer accessible information to a wide variety of individuals, including physicians, medical students, clinical investigators, and the general public. They are an outstanding source of medical and scientific information."


Jeffrey M. Weinberg
(St. Luke's-Roosevelt Hospital Center, USA)

"Open access journals are extremely useful for graduate students, investigators and all other interested persons to read important scientific articles and subscribe scientific journals. Indeed, the research articles span a wide range of area and of high quality. This is specially a must for researchers belonging to institutions with limited library facility and funding to subscribe scientific journals."


Debomoy K. Lahiri
(Indiana University School of Medicine, USA)

"Open access journals represent a major break-through in publishing. They provide easy access to the latest research on a wide variety of issues. Relevant and timely articles are made available in a fraction of the time taken by more conventional publishers. Articles are of uniformly high quality and written by the world's leading authorities."


Robert Looney
(Naval Postgraduate School, USA)

"Open access journals have transformed the way scientific data is published and disseminated: particularly, whilst ensuring a high quality standard and transparency in the editorial process, they have increased the access to the scientific literature by those researchers that have limited library support or that are working on small budgets."


Richard Reithinger
(Westat, USA)

"Not only do open access journals greatly improve the access to high quality information for scientists in the developing world, it also provides extra exposure for our papers."


J. Ferwerda
(University of Oxford, UK)

"Open Access 'Chemistry' Journals allow the dissemination of knowledge at your finger tips without paying for the scientific content."


Sean L. Kitson
(Almac Sciences, Northern Ireland)

"In principle, all scientific journals should have open access, as should be science itself. Open access journals are very helpful for students, researchers and the general public including people from institutions which do not have library or cannot afford to subscribe scientific journals. The articles are high standard and cover a wide area."


Hubert Wolterbeek
(Delft University of Technology, The Netherlands)

"The widest possible diffusion of information is critical for the advancement of science. In this perspective, open access journals are instrumental in fostering researches and achievements."


Alessandro Laviano
(Sapienza - University of Rome, Italy)

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Philippe Hernigou
(Paris University, France)

"There are many scientists who can not afford the rather expensive subscriptions to scientific journals. Open access journals offer a good alternative for free access to good quality scientific information."


Fidel Toldrá
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Peter Chiba
(University of Vienna, Austria)

"Open access journals are probably one of the most important contributions to promote and diffuse science worldwide."


Jaime Sampaio
(University of Trás-os-Montes e Alto Douro, Portugal)

"Open access journals make up a new and rather revolutionary way to scientific publication. This option opens several quite interesting possibilities to disseminate openly and freely new knowledge and even to facilitate interpersonal communication among scientists."


Eduardo A. Castro
(INIFTA, Argentina)

"Open access journals are freely available online throughout the world, for you to read, download, copy, distribute, and use. The articles published in the open access journals are high quality and cover a wide range of fields."


Kenji Hashimoto
(Chiba University, Japan)

"Open Access journals offer an innovative and efficient way of publication for academics and professionals in a wide range of disciplines. The papers published are of high quality after rigorous peer review and they are Indexed in: major international databases. I read Open Access journals to keep abreast of the recent development in my field of study."


Daniel Shek
(Chinese University of Hong Kong, Hong Kong)

"It is a modern trend for publishers to establish open access journals. Researchers, faculty members, and students will be greatly benefited by the new journals of Bentham Science Publishers Ltd. in this category."


Jih Ru Hwu
(National Central University, Taiwan)


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