Correlations Between Serum Uric Acid Level and Disease Activity,Intrathecal Inflammation Reactivity in Patients with Multiple Sclerosis

Cai-yan Liu ,Yan Xu ,Li-ying Cui ＊,Bin Peng ,Li-zhen Zhong ,Xing-wang Chen ,and Jian-ming Wang

1Department of Neurology,Peking Union Medical College Hospital,Chinese Academy of Medical Sciences &Peking Union Medical College,Beijing 100730,China

2Department of Neurology,Dalian Central Hospital,Dalian 116033,China

3Department of Neurology,Shandong Traffic Hospital,Jinan 250031,China

MULTIPLE sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system.Uric acid (UA) is believed to be the final product of the purine nucleoside metabolism pathway and a strong peroxynitrite scavenger that antagonizes the toxic effects of peroxynitrite on neurons,axons,and glial cells.1Peroxynitrite is the product of the free radicals such as nitric oxide and superoxide,and it increases the permeability of blood-central nervous system barrier,contributing to demyelination,oligodendrocyte destruction,and axonal damage.1Hooper and his colleagues firstly reported lower serum UA levels in MS patients compared to controls,who were mainly patients with spinal cord injury or Parkinson’s disease.2Reduced serum UA levels have been reported in patients with MS and optic neuritis.3-6Furthermore,UA is considered as a surrogate marker of MS activity.

It is still unknown whether the reduced UA level in patients with MS is a cause or a consequence of disease activity.Mostertet al7observed that nitric oxide generated by peripheral blood leukocytes was increased in MS patients,but these patients had no primary deficit in serum UA.It will be helpful to investigate the relationship between the serum UA level and intrathecal inflammation reactivity.

In our study,we compared the serum UA levels of groups of MS patients with different genders,disease durations,and disease disabilities assessed by the Expanded Disability Status Scale (EDSS) score8.We also investigated the correlations between the serum UA levels and cerebrospinal fluid (CSF) parameters,including CSF protein,white blood cell (WBC) counts,oligoclonal band (OB),24-hour IgG index values,and myelin basic protein (MBP).

PATIENTS AND METHODS

Patients

We reviewed serum UA levels previously determined in 47 relapsing onset MS inpatients (41:6,females:males) hospitalized in our neurological clinic from 2008 to 2010.The mean age was 37.38 ±13.33 years (range:15-62 years).All of the patients were diagnosed according to Mcdonald’s criteria.9The exclusion criteria included treatment with steroids,acetylsalicylic acid,thiazide diuretics,and ibuprofen and other drugs that could increase or affect UA levels.Subjects with diabetes or renal failure were also excluded.

Data concerning demographic variables,such as age and sex,and clinical variables,such as age of onset,disease course,disease duration,EDSS score,total number of relapses,and relapse rate (number of relapses/time from onset in years) were collected.

The control group included 49 cerebral infarction (CI)patients hospitalized in our neurology unit from 2008 to 2009.The exclusion criteria were the same as MS patients’.In the control group,there were 36 women and 13 men.The mean age was 46.31 ± 13.82 years (range:21-67 years).The MS patients and control patients were matched for age and gender.

Methods

All the venous blood samples were drawn after overnight fasting.In the MS patients,blood was collected during a relapse before treatment with steroids.In the CI patients,the blood was collected soon after they were admitted.Totally,59 serum UA measurements from MS patients and 49 measurements from CI patients were analyzed.The serum UA measurements included those taken during the re-admissions of 6 patients in the MS group.

UA concentration was measured by the direct enzymatic method,in which UA was oxidized by uricase coupled with peroxidase.Serum UA was measured using a Clinical Analyzer Olympus AU5400 (Olympus,Japan).In our hospital,the normal range of serum UA values is 140-390 μmol/L in women and 200-500 μmol/L in men.

Prior to steroid treatment,41 patients underwent 46 lumbar punctures and had cerebrospinal fluid examinations.The CSF protein,WBC count,MBP,OB,and the 24-hour IgG index were measured.

CSF protein was measured using a Clinical Analyzer Dimension RXL MX HM (SIEMENS,German),and the normal range is 0.35-0.45 g/L.The WBC count was measured by manual counting under the microscope,and the normal range is 0-5/μL.MBP was tested using the enzyme-linked immunosorbent assay,and the normal range is below 0.55 nmol/L.OB was observed to be positive or negative by polyacrylamide gel electrophoresis.The 24-hour IgG index was measured by immunoprecipitation,and the normal range is from -9.900 to 3.300.

Statistical analysis

Quantitative data were expressed as mean ± standard deviation (SD).The student’st-test was used to compare serum UA levels between the MS patients and controls.Correlations of different variables in MS patients were analyzed with thePearsonlinear regression model.Multivariate linear regression analysis was performed for the MS patients to detect any independent effects of the variables on the serum UA levels.Linear correlation analyses were performed to investigate associations between serum UA levels and CSF protein level,WBC count,MBP level,or OB.AP-value less than 0.05 was used to indicate statistical significance.All statistical analyses were performed with the Statistical Package for Social Sciences(SPSS) software version 11.5.

RESULTS

Clinical characteristics of 47 MS patients

There were 47 MS patients included.Their mean age of onset was 31.05±11.55 (range 10-62) years,mean duration of disease 3.72±4.15 (range 0.1-19) years,mean number of relapses 3.97±3.03 (range 1-18) times,mean relapse rate 2.75±3.05 (range 0.22-12.00) times/year,and the EDSS score 3.06±2.22 (range 1-8).

Comparison of serum UA levels between MS patients and control patients

The mean serum UA level in the MS patients was significantly lower than that in the control patients with CI,(247.75±52.59vs.277.94±74.33 μmol/L,P=0.025).The serum UA levels were lower than the normal lower limit in 3 of 47 (6%) MS patients,but the levels were not lower than the lower limit for any individuals in the control group.

Comparison of serum UA levels in MS patients by gender,age,relapse rate,course of illness,and EDSS score

The mean serum UA level was higher in men than that in women (263.00 ± 31.02vs.242.16 ± 56.12 μmol/L),but this difference was not statistically significant (P=0.312).Among the MS patients,we observed an inverse correlation between serum UA level and relapse rate (r=-0.259,P=0.025).There was no correlation between age (r=-0.119,P=0.186),duration of illness (r=0.049,P=0.358),or EDSS score (r=-0.012,P=0.464) and the serum UA level,respectively.Multivariate linear regression analyses showed that the serum UA level independently correlated with the relapse rate (β=-0.259,standard error=2.290,t=-2.008,P=0.049) in MS patients.

Correlations between serum UA level and CSF protein,WBC count,OB,24-hour IgG index,and MBP

In the subgroup of 41 MS patients who underwent 46 lumber punctures,the mean CSF protein level,WBC count,and MBP levels were much higher than those in normal persons (Table 1).In MS patients,those with lower serum UA levels tended to have higher WBC counts and MBP values.But there was no correlation between CSF protein levels (r=0.165,P=0.273),WBC counts (r=-0.051,P=0.732),IgG index (r=0.045,P=0.802),or MBP (r=-0.248,P=0.145) and the serum UA level,respectively.

OB detection was performed for 42 MS patients.The serum UA levels of the 11 OB-positive patients were lower than the levels of the 31 OB-negative patients,although this difference was not statistically significant (244.36±44.49vs.249.30±46.09 μmol/L,P=0.760).

Table 1.Correlations between serum UA levels and CSF protein,WBC counts,24-hour IgG index,MBP in CSF collected from multiple sclerosis patients

DISCUSSION

Serum UA,a natural scavenger of peroxynitrite,has been found to be of lower levels in patients with MS in some studies.4,6,10-12A meta-analysis was also performed by Liuet alto demonstrate the serum UA levels in MS patients.12They got the similar conclusion serum UA might serve as a marker of disease activity in MS.Some studies have evaluated correlation between UA levels and activity,disability,disease course,or disease duration with conflicting results.4,6,10-12

In our study,the mean serum UA level in MS patients was significantly lower than that in the control group,which was similar to previous reports.4,6,10-13We also observed the novel finding that serum UA levels in MS patients were inversely correlated with relapse rate.Our findings suggest that lower serum UA levels in MS patients might represent a primary and constitutive loss of protection against nitric oxide.We observed no statistical difference in the serum UA levels between male and female MS patients,which may be related to the limited sample number and the higher EDSS scores of male MS patients.

It is uncertain whether the reduction in UA levels in patients with active MS is a cause or a consequence of disease activity.Researchers proposed that soluble products like nitric oxide generated from infiltrating immune cells and glial cells contribute to the damage to myelin and oligodendroglia in MS.14Therefore,exploring the correlation between serum UA levels and CSF parameters will help work out the pathogenesis.

In our study,the correlations between serum UA levels and the CSF protein levels,WBC counts,MBP,OB,24-hour IgG index values were investigated.WBC counts,24-hour IgG index,and OB reflect the central nervous system inflammation and immunity reaction.CSF protein and MBP levels reflect the tissue damage.The patients who had lower serum UA levels tended to have higher WBC counts values,MBP levels,and positive OB,but no significant correlations were found.It is possible that as the central nervous system inflammation and tissue damage becomes more severe,the UA level is lower.However,further investigations are necessary to tell whether lower serum UA levels are the cause or consequence of MS disease activity.

In conclusion,serum UA levels were analyzed in 47 MS patients to identify correlations between serum UA levels and clinical as well as CSF parameters.The mean serum UA level in MS patients was significantly lower than that measured in the control group and had inversely correlations with the relapse rate.Serum UA level might be related with inflammation reactivity.Further experiments in animal models should been performed to examine the relationship between UA and MS.Perhaps this research will lead to a new therapeutic direction for MS.

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