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Serum Uric Acid Level in different phases of Multiple Sclerosis

 



Maryam Aghaei1, Gh.Reza Gassemi2*, Sayed Mohsen Hosseini3, Mansoor Shiri4, Nasim Dana5.



PhD Candidate of Skin Disease and Leishmaniasis Research Centre, Medical Science of Isfahan University, Isfahan,IRAN.


Associate Professor Research Consultant & Family Therapist Isfahan University of Medical Sciences, Isfahan, IRAN.


Asso. Prof. Skin Disease and Leishmaniasis Research Centre, Medical Science of Isfahan University, Isfahan, IRAN.


PhD Candidate of Health Psychology Behavioral Research Center, Isfahan University of Medical Sciences, IRAN.


PhD Candidate of Applied Physiology Research Center, Isfahan University of Medical Science, Isfahan, IRAN.





Corresponding author: Gh.Reza Gassemi
Tel.: +989392666300 
E-mail address: ghassemi@med.mui.ac.ir













Abstract

It has been assumed that low levels of serum UA (an antioxidant product of purine metabolism) is relative with multiple sclerosis (MS).
This study aimed to evaluate the level serum of uric acid
(UA), in various episodes of MS. Retrospectively the concentration Uric Acid  was measured in serum of 129 individuals, 69 inactive relapsing-remitting (RR) MS patients,25 active MS from 69 inactive MS, 20 CIS (Clinically Isolated Syndrom) and 40 age matched healthy controls by using the quantitative enzymatic assay method (ELISA). We considered UA levels in two different postures: during relapse and remission periods.

The mean concentration of UA in serum was 6.58(�3.34) mg/dL in patients with remitting MS, 4.72 (� 1.65) mg/dL in patients with relapsing MS, 4.82( � 1.7) mg/dL in CIS patients and 6.84 (�3.02)  mg/dL  in healthy controls.
There was a significant difference between mean UA concentration in patients with relapsing-MS and control (p <0.001), and between CIS patients and control (p < 0.002). Although no difference was found between remitting MS and control (p<0.62) or CIS and relapsing MS (p <0.85) or CIS cases before and after a medical diagnosis (p<0.81) and 25 MS patients in remission and relapse periods (p<0.114).

In despite of indifference between remitting MS and control, we did not find exact relation between UA level and MS pathogenesis.

 Key words: Relapsing-Remitting multiple sclerosis (RRMS), Uric Acid, ELISA.
                                        


















Introduction

Multiple sclerosis (MS) is an autoimmune disease, with irritation and neurodegeneration related to neuronal demyelination and axonal hurt. (1)

In 85% of multiple sclerosis (MS) patients, onset is a subacute clinically isolated syndrome (CIS) of the optic nerves, brainstem, or spinal cord; (2);but only a subset of CIS patients eventually develops towards  Relapsing/Remitting Multiple Sclerosis (RRMS) form within months or years while others remain clinically isolated. (3) Form of RRMS is characterized by intermittent episodes of relapses and prolonged remissions. (4)
Although the etiology of MS is unknown there is increasing evidence that oxidative stress is important  in pathogenesis of MS. The inflammatory surroundings in demyelinating lesions is concluded to the generation of reactive oxygen species such as peroxynitrite in MS and animal models of MS (EAE). (1)
Peroxynitrite, a reactive oxidant made from reaction of nitric oxide with superoxide at areas of inflammation in multiple sclerosis (MS), is able to damage tissues and cells. (5) This radical can change the structure and function of lipids, proteins, DNA, and mitochondria.
Researches showed  peroxynitrite-mediated injury in brain lesions of patients with MS.(6) As existence of nitrotyrosine, a biochemical marker for peroxynitrite-mediated damage, in cells surrounding plaques reflects likely role of peroxynitrite in brain lesions of  MS patients and animals with EAE. (7-10) Also presence of peroxynitrite during the chronic phase of MS can be impressive for disease progression. (11) These findings propose peroxynitrite role in the pathogenesis of MS.(12) Constantly, it turns out that neutralization of peroxynitrite-derived free radicals could participate to neuroprotection in MS.(6;13;14)


Uric Acid (UA), as  scavenger antioxidant of Peroxynitrite probably triggers the   EAE animals� recovery; (15;16); through inhibiting the invasion of inflammatory cells into the CNS and ceasing the nitration of peroxynitrite-mediated tyrosine and apoptosis in inflammatory areas of EAE. (5)
Some studies reported lower serum levels of uric acid in MS patients in the relapsing phase compared to the remitting phase and controls;(17-19); whilst other studies found no difference.(17;18) Hence there is not certain evident that decreased uric acid in MS is secondary to its peroxynitrite scavenging activity during inflammatory disease activity, or a primary deficiency.(5)
Therefore , with the hope of finding a new approach for the treatment of MS, we surveyed  the differences of serum UA concentrations in MS patients in comparison with  levels in healthy controls.








Study area: This study was conducted in Isfahan, an industrialized part situated in  central Iran with crowd of about 4 million people of Caucasian race initially. In 2006, the prevalence of MS was reported 35.5 at per 100000 in this region, (20); that is much more than other Asian countries. (21)

Statistical analysis 
 UA density are indicated as mean � standard deviation [SD]. The Student� s t-test was used for comparison between groups.   
  A p-value < 0.05 was considered significant.

Study Description:
This study involved 69 MS patients and 20 CIS and 40 healthy control matched in age. Patients were randomly opted from registered patients of MS clinic affiliated to the Isfahan University of Medical Sciences. Tenets of the current version of the Declaration of Helsinki were followed, institutional ethical committee approval was granted, and the nature of the trial was explained to the patient. After a detailed discussion with the neurologist, each patient signed an informed consent form. All MS patients above were collected after exclusion of gout and any other diseases which could remarkably affect serum UA levels and were cured with immune system moderating drugs such as Rebif, Betaferon over the course of many years.
 Firstly, analyses were carried out using blood of 69 remitting definite MS patients, 40 healthy control  and 20 CIS patients, with initial sensory and optic neuritis symptoms of MS but before a medical diagnosis. A 7cc venous blood sample was taken from each person. Then Serum of samples was separated and stored at �70�C until assayed. 
During 6 months secondary analyses were conducted using blood of 25 patients( of 69 definite MS patients) during a relapse and 20 case of CIS individuals after the date of definite diagnosis of MS.
Serum UA concentrations were measured using the Uricase Quantitative Enzymatic Assay Method (manufacturer: BLOLABO SA, Maizy,France). Tests were conducted according to the manufacturer�s instructions.  Samples were tested in Roche  Hitachi 717 auto analyzer (Japan, Germany). 

Result
A whole of 69 patients with inactive MS (55females and 14 males, F:M = 3.9:1 ), 25 active MS (23 female, 2 male 11.5:1), 20 CIS patient (17 female, 3 male 5.7:1) and 40 controls (31 females and 9 males, 3.4:1)  were included in the study. Mean age was 30.82(�8.66)  years in inactive MS and 27.8(�7.32)   in CIS and   34.17 (� 10.57) years in the healthy control group. Patients were selected base on McDonald criteria.In the MS group, the mean time from diagnosis was 5.2( �3.8) years, the mean number of attacks per year was 1.47 (�0.8), and the mean Expanded Disability Status Scale (EDSS) score was 1.69 (�1.1). There were 9 patients (13.04%) with a positive family history for MS 
Baseline data and serum UA levels of all subjects (cases and controls) are shown in Table 1. Also correlation between UA levels and different phases of MS disease are displayed in Table 2.

The mean level of UA in the remitting MS patients was 6.58 (� 3.34) mg/dl, versus 6.84 (�3.02)   mg/dl in the control group (p < 0.62). The mean of UA in relapsing MS patients was 4.72( � 1.65) mg/dl, which was significantly lower than level in controls (P<0.001). Also Serum UA level in CIS 4.82 (� 1.7) was less than control (p<0.002) and remitting MS (P<0.002). 
When the analysis was performed in the female cohort separately, UA level was significantly lower in females than in males in all groups. 
 Also UA level was in CIS and active MS females lower than females in inactive MS and control groups. But there wasn�t any difference between females in CIS and active MS groups.
 It was also shown in our study that UA level in MS patients was not correlated with disease activity revealed by EDSS, Age, duration of disease and number of attacks in MS patients.  Relationship between UA levels and disease activity in MS patients are shown in Table 3 and 4.

Conclusion
In the present study, the mean level of UA in sera from CIS and active MS patients clinically was lower than remitting MS and controls. However, the difference in the level of serum uric acid between remitting MS patients and the control group was not significant.
As it has been considered, cell-mediated responses and some autoimmune diseases such as MS are higher in women compared to men. (22) In this study, the female to male ratio was 4.23:1, a remarkable female predominance in contrast with other researches.
It has been demonstrated  that enhancing  levels of oxidative stress indexes such as peroxynitrite  and reducing levels of antioxidant components such as uric acid have been implicated in demyelination and axonal damage in MS patients. (23) So peroxynitrite may damage to the myelin sheath through inducing lipid peroxidation and oligodendrocyte  death.(24)
It has been proposed that UA , as a natural scavenger peroxynitrite, has a role in ImmunoSuppressive or ImmunoModulatory treatment. (16) 
UA prevents the onset of EAE in acute phase of the disease and triggers  long-term survival. It is evident that UA acts at two ways  in EAE: 1) by conserving the integrity of the blood-CNS barrier from ONOO(-)-induced permeability changes such that cell invasion and the resulting pathology is minimized; and 2) through a endangered blood-CNS barrier, by scavenging the ONOO(-) directly responsible for CNS tissue injury and death.(18)









Some of studies found that MS and neuromyelitis optica patients  have low serum levels of UA, although it has not been postulated if  this is a primary deficit or a secondary effect.(16)
In our study, Median serum UA levels did not differ between MS patients in remission phase and control group, which is in accordance with the results of Altinkaynak et al and Droluvic et al and contrary to Liu et al study. (17;18;25)
Although Massa et al and Iranmanesh et al and Sayad et al offered that serum UA was not a far risk agent for MS, other studies, comprising ours, found that UA levels in 25 relapsing patients was significantly lower than 69 remitting patients. Decreased serum UA concentrations might be due to both intrinsically reduced antioxidant capacity and increased UA consumption. (26;27;28;29) 

In concordance with our findings, Mattle et al found that, during relapse, the serum level of UA in patients with relapsing/remitting MS was significantly lower than in a control group. Similar to results of Rentzos et al we did not obtain significant difference between   patients with Clinically Isolated Syndromes (CIS) and control. (14;19)

In despite of findings of Guerrero et al we did not find UA value obtained in relapse and remission time span in 25 cases.(16) Also CIS patients were not found to have significantly lower UA concentrations in comparison to time of definite diagnosis of MS.   

The limitation of our study should be acknowledged. First, we performed both  descriptive case-control and cross-sectional studies. Second, this study was limited only to one center. The small number of cases and limitation to one center make generalization to other centers in Iran difficult. 

In despite of our previous study that UA had important role in prevention of  MS activity (30), with regard to be not difference between level of UA in  relapse and remission periods of CIS and relapsing �MS patients , this results suggest that serum UA levels in MS patients is not related to pathogenesis of MS. Although further researches are needed to verify this finding. 












References 

1) Carlson N. G, Rose J. W (2006).  Antioxidants in multiple sclerosis: do they have a role in therapy? CNS Drugs ; 20(6): 433-41.

2) Miller D, Barkhof F. (2005) Clinically isolated syndromes suggestive of multiple sclerosis, part I: natural history, pathogenesis, diagnosis, and prognosis. Lancet Neurol  ; 4(5): 281-8.

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Table1: Baseline data (Demographic and clinical characteristics of multiple sclerosis (MS) patients and healthy controls) and serum UA levels of patients with RRMS and Control group.


Remitting MS (n=69)Relapsing MS (n=25)CIS
  (n=20)Control             (n=40)
Sex                                   
Female
Male
            
           55
           14                                         

23
2
  17
   3
              31
                9
Age (years)30.82(�8.66)30 (�8.51)27.8(�7.32)34.17 (� 10.57)
Mean duration of disease (years)5.2(�3.8)5.4(�3.2) ----------------------Mean number of attacks (�SD)1.47(�0.8)
1.24(�0.77) -----------
-----------      EDSS    1.69 (�1.1)2.78(�1.9)
UA (mg/dl)	6.58(�3.34)	4.72 (� 1.65) 	4.82 (� 1.7)	6.84 (�3.02)  














Table2: Relationship between UA levels and MS patients

Remitting MS
(n=69)Relapsing MS(before)(n=25)CIS
(before)(n=20)Control
(n=50)Remitting MS(n=69)----------------------------------p < 0.62Relapsing MS(before)(n=25)-----------
------------- p <0.85P<0.001CIS(before)(n=20)p<0.002-------------------------p<0.002Relapsing MS(after)(n=25)

----------
p<0.114

------------
------------CIS
(after)(n=20)
---------
------------
p<0.81

------------


Table3: Relationship between UA levels and disease activity in Relapsing MS patients (N=25) 

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Table4: Relationship between UA levels and disease activity in Remitting MS patients (N=69)

AgeEDSSMean number of attacksMean duration of diseaseP<0.331P<0.613P<0.998P<0.068UA (mg/dl)



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