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 Table of Contents  
ORIGINAL ARTICLE
Year : 2020  |  Volume : 4  |  Issue : 3  |  Page : 358-364

Effect of high serum uric acid level on systemic lupus erythematosus manifestations


Department of Internal Medicine, Faculty of Medicine for Girls, Al-Azhar University, Cairo, Egypt

Date of Submission19-Mar-2020
Date of Decision08-Apr-2020
Date of Acceptance14-Apr-2020
Date of Web Publication2-Oct-2020

Correspondence Address:
MBBC Amany F Ali
Department of Internal Medicine, Faculty of Medicine for Girls, Al-Azhar University, Kafr El Shiekh, 33713
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/sjamf.sjamf_36_20

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  Abstract 


Background Systemic lupus erythematosus (SLE) is a chronic, progressive, autoimmune disorder that affects multiple organ systems, with a broad range of clinical and laboratory manifestations. Considering the role of uric acid (UA) as a pro-inflammatory compound in SLE, serum levels of UA and its relation to severity and activity of the disease were assessed in patients with SLE.
Objectives To evaluate the relation between high serum UA and SLE manifestations and correlate it with the disease activity.
Patients and methods This study was conducted on 40 patients with SLE fulfilling the 2012 SLICC criteria for SLE classification and 20 sex-matched and age-matched apparently healthy participants as control group. All patients and controls were assessed by full clinical examination and laboratory investigations including serum urea and creatinine, serum lipids, 24-h urinary protein, antinuclear antibody, anti-double-stranded DNA, C3, C4, and serum UA. All patients were assessed for SLE disease activity by the systemic lupus erythematosus disease activity index.
Results Serum UA was significantly higher in patients with SLE compared with the control group (P<0.001), and there was a significant increase of mean UA level in patients with active SLE (group Ia) compared with patients with inactive SLE (group Ib) (P<0.01). There were significant positive correlations between UA and protein in urine, pulmonary artery pressure, and disease activity in patients with SLE (group I) (r=0.362, 0.372, and 0.650, respectively; P<0.05).
Conclusion Serum UA was higher in patients with SLE than control and correlated with disease activity, suggesting that it might play a role in SLE pathogenesis and can be used as a marker for SLE activity.

Keywords: systemic lupus erythematosus disease activity index, systemic lupus erythematosus, uric acid


How to cite this article:
Ali AF, El Refaei KE, Maghraby HM. Effect of high serum uric acid level on systemic lupus erythematosus manifestations. Sci J Al-Azhar Med Fac Girls 2020;4:358-64

How to cite this URL:
Ali AF, El Refaei KE, Maghraby HM. Effect of high serum uric acid level on systemic lupus erythematosus manifestations. Sci J Al-Azhar Med Fac Girls [serial online] 2020 [cited 2020 Oct 26];4:358-64. Available from: http://www.sjamf.eg.net/text.asp?2020/4/3/358/296939




  Introduction Top


Systemic lupus erythematosus (SLE) is a complex autoimmune disease of unknown etiology that is characterized by multiple end-organ damage and predominantly affects premenopausal women aged 15–45 years [1]. Uric acid (UA), the final product of purine degradation, is formed in the liver from precursor proteins and is excreted by the kidneys and intestines. At physiologic concentrations, UA exhibits excellent antioxidant activity; however, when UA exceeds its physiologic levels, it can propagate oxidative damage. Furthermore, chronic elevation of UA constitutes a risk factor for many diseases, as it can promote inflammation and endothelial dysfunction [2]. Hyperuricemia occurs in conditions of serum UA overproduction, such as increased intake of purine rich diets, malignancies, rhabdomyolysis, and cellular proliferation, or in conditions of reduced serum UA excretion, such as chronic kidney disease, diabetic ketoacidosis, and starvation [3]. Other conditions associated with hyperuricemia include diabetic nephropathy, IgA nephropathy, metabolic syndrome, and cardiovascular disease [4].

Higher prevalence of hyperuricemia in patients with SLE might be owing to several endogenous and exogenous mechanisms such as inflammation, hypertension, and renal involvement, which are prevalent in patients with SLE and have been identified as provoking hyperuricemia through different mechanisms. On the contrary, increased levels of UA can aggravate inflammation, hypertension, and renal disease, thus creating a vicious cycle [2]. Hyperactivity of the xanthine oxidase enzyme in patients with SLE and some of the drugs used in the treatment of SLE are among the other possible reasons for the higher prevalence of hyperuricemia in patients with SLE [2]. High UA levels have been reported in patients with SLE to be associated with the occurrence of stroke, peripheral neuropathy, pulmonary hypertension (PH), and lupus nephritis (LN) [5]. Hyperuricemia contributes with other factors in LN development and could be considered as a prognostic factor for the worse progression of LN (i.e. higher levels of serum creatinine and BUN, low serum C3, higher LN activity index, and more proteinuria). Elevated serum UA levels can be used as a provisional prognostic marker of LN in patients with SLE [5]. A significantly increased level of serum UA was observed in patients with pulmonary arterial pressure suggesting that serum UA level could be a prognostic marker of pulmonary arterial pressure in patients with SLE, which correlates with disease severity. Hence, it may help to reduce clinical demands for echocardiography in patients with normal UA levels [6].


  Patients and methods Top


This was a cross-sectional case–control study conducted on 40 patients with SLE (group I) fulfilling the SLICC 2012 criteria for SLE classification in addition to 20 sex-matched and age-matched apparently healthy volunteers as a control group (group II). Patients were selected from the rheumatology outpatient clinic of AL-Zahraa Hospital, Cairo, Egypt, during the period from December 2018 to December 2019. All patients gave their informed consents before their inclusion in the study, and the study was approved by the Ethics committee of Al-Azhar University. Patients with SLE were divided into two groups according to disease activity index [systemic lupus erythematosus disease activity index (SLEDAI)]: group Ia included 14 patients with active SLE who had SLEDAI more than 6 points, and group Ib included 26 patients with inactive SLE who had SLEDAI less than 6 points. We have excluded patients with previous history of diabetes, hypertension, coronary artery disease, or using drugs that interfere with UA. All patients were subjected to the following: full medical history, as well as general and rheumatologic examination, including age, disease duration, and drug treatment in use. SLEDAI was used for assessment of disease activity of patients.

Laboratory studies

Complete blood count, erythrocyte sedimentation rate, kidney functions, liver function, and serum lipids (cholesterol and triglyceride) were sampled. Moreover, complete urine analysis and 24-h urine collection for measurement of urinary protein and creatinine clearance were done.

Immunological tests

Antinuclear antibody was measured by enzyme-linked immunosorbent assay. Anti-double-stranded DNA was detected by an immunoenzyme dot assay method. Complement (C3 and C4) levels were detected by complement fixation test using immunodiffusion plates.

Serum uric acid level measurement

UA level in the serum was quantified using the uricase method via AU680 (Beckman Coulter, Brea, CA, USA). Serum UA levels more than or equal to 6.0 mg/dl in female patients and more than or equal to 7.0 mg/dl in male patients were considered indicative of hyperuricemia.

Imaging

All patients were investigated by pelvi-abdominal ultrasound. Transthoracic echocardiography was performed in all patients as a screening test for pH, by experienced cardiologists.

Statistical analysis

Results were collected and analyzed by a personal computer and statistical package for social science software (SPSS Inc., Chicago, Illinois, USA), version 20. Parametric data were expressed as mean and SD. Comparing the mean±SD between two groups was done using Student t test. Moreover, Pearson correlation coefficient (r) was used to measure the association between two quantitative variables. The level of significance was set as P value less than 0.05.


  Results Top


The current study enrolled 40 patients with SLE (group I) diagnosed according to the 2012 SLICC criteria and 20 apparently healthy persons who served as a control group (group II). Patients with SLE comprised 37 (92.5%) females and three (7.5%) males, and their ages ranged from 18 to 47 years, with a mean of 32.85±9.31 years, and duration of disease ranged from 2 to 202 months, with mean±SD of 60.40±58.68 months ([Table 1]). Group II included 20 sex-matched and age-matched apparently healthy volunteers as a control group.
Table 1 Demographic characteristic of the studied 40 patients with systemic lupus erythematosus

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The most frequent clinical manifestations were renal manifestations (65%) followed by musculoskeletal manifestations (60%) ([Table 2]).
Table 2 Frequency of clinical manifestations among 40 patients with systemic lupus erythematosus

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There was a highly significant increase in mean serum level of UA in 40 patients with SLE (group I) when compared with the control group (group II) (P<0.001) ([Table 3]) ([Figure 1]).
Table 3 Comparison of some parameters in patients with systemic lupus erythematosus and control

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Figure 1 Comparison between serum uric acid level in patients with SLE (group I) and control group (group II). SLE, systemic lupus erythematosus.

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There were significant increases in mean serum levels of urea, cholesterol, triglyceride, and proteinuria in patients with SLE compared with the control group (P<0.01), whereas there were significant decreases in mean serum calcium and albumin levels in patients with SLE compared with the control group (P<0.001) but no significant change in creatinine and phosphate ([Table 3]).

In our study, there were ∼14 (35%) patients with SLE who had PH and 10 (71%) of them had hyperuricemia, whereas four (29%) had normal serum UA ([Table 4]).
Table 4 Hyperuricemia in studied 40 patients with systemic lupus erythematosus according to the presence or absence of pulmonary hypertension

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There was a significant increase of mean UA level in patients with active SLE (group Ia) compared with patients with inactive SLE (group Ib) (P<0.001) ([Table 5]).
Table 5 Comparison between group Ia and group Ib regarding serum uric acid level

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There were significant positive correlations between UA and protein in urine, pulmonary artery pressure, and disease activity in 40 patients with SLE (group I) (r=0.362, 0.372, and 0.650, respectively; P<0.05) ([Figure 2],[Figure 3],[Figure 4]), whereas there was a significant negative correlation between UA and C3 (r=−0.343, P<0.05) ([Figure 5]).
Figure 2 Correlation between serum uric acid and 24-h protein in urine in 40 patients with SLE. SLE, systemic lupus erythematosus.

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Figure 3 Correlation between serum uric acid and pulmonary artery pressure by echocardiography.

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Figure 4 Correlation between uric acid and disease activity (SLEDAI) in 40 patients with SLE. SLE, systemic lupus erythematosus; SLEDAI, systemic lupus erythematosus disease activity index.

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Figure 5 Correlation between serum uric acid and C3 in 40 patients with SLE. SLE, systemic lupus erythematosus.

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There was a significant negative correlation between UA and white blood cell (r=−0.375, P<0.01). Moreover, there were significant positive correlations between UA and urea, creatinine, and phosphate (r=0.446, 0.481, and 0.350, respectively; P<0.001) ([Figure 5]), whereas there were significant negative correlations between UA, calcium, and albumin (r=0.350, 0.440, and 0.350, respectively; P<0.05).

There were no statistical significant correlations between UA and age, disease duration, cholesterol, and triglyceride ([Table 6]).
Table 6 Correlation of serum uric acid and various parameters in 40 patients with systemic lupus erythematosus

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  Discussion Top


SLE is a complex multisystem autoimmune disease characterized by a wide spectrum of clinical, laboratory, and immunological abnormalities and a variable course and outcome. The pathogenesis of SLE is complex and not fully elucidated but has been recognized to result from the complex interplay of immunological, genetic, and environmental factors [7].

UA is the poorly soluble circulating end product of the purine nucleotide metabolism in human beings and is determined by the net balance between its production and either reabsorption by the kidney and secretion by the intestine. It plays an important role in SLE pathogenesis, and persistently high UA levels may be predictive of damage in patients with SLE [4]. A close association between SLE and hyperuricemia has been identified, and UA was considered a risk factor for renal involvement in SLE. It is an important predictor of poor prognosis in patients with LN and may be a promising risk factor for renal damage in patients with LN [3].

This study was done to assess the relation between serum UA level and SLE disease activity. There was a statistically significant increase in mean serum level of UA in patients with SLE compared with control group, and the elevation correlated positively with disease activity, and there were significant increases in UA level in patients with active SLE when compared with patients with inactive SLE. Moreover, a significantly higher circulating UA level in patients with SLE, with a positive correlation between UA levels and SLE activity, was detected by Aghdashi et al. [6].

Similarly, another study found that serum UA concentrations were significantly higher in patients with SLE with renal impairment and in patients with SLE than controls and high UA correlated significantly with SLEDAI in all patients. UA production could be associated with the inflammatory process of SLE development and may serve as a potential disease marker of SLE [5]. Calich et al. [8] reported that serum UA levels were significantly higher in 28% of patients with LN with normal renal function. In contrast to our study, Yang et al. [9] as well as Xie et al. [3] found that there was no association between serum UA level and disease activity score, which indicated that increased serum UA had no association with SLE activity. However, our results can be explained by the positive correlation between hyperuricemia and proteinuria, thrombocytopenia, and leucopenia, which are SLEDAI score descriptors.

In this study, we found that hyperuricemia contributes with other factors in LN development and could be considered as a prognostic factor for the worse progression of LN (i.e. higher levels of serum creatinine and urea, low serum C3 and more proteinuria). In our study, hyperuricemia was found in 50% of patients with SLE with proteinuria (LN +ve), whereas it was present in ∼50% of patients with SLE without proteinuria (LN −ve). This agreed with Xie et al. [3] who found in a study of 177 patients with LN that ∼43% of patients had hyperuricemia and 57% of patients had no hyperuricemia. Development of LN in 62.5% of group I (SLE with hyperuricemia) in comparison with 20% in group II (SLE without hyperuricemia) was reported by Okba et al. [5].

In our study, there was a significant decrease of complement C3 and C4 levels in serum of patients with LN with hyperuricemia. Similar results were obtained by others, who found a significant decrease of complement C3 and C4 levels in serum of patients with LN with hyperuricemia and referred this to the activation of C3 by hyperuricemia, through both classical and alternative pathways. The deposition of complement activation products, in turn, aggravates the renal tissue injury and development of LN [5],[10].

PH is one of the unusual cardiopulmonary manifestations in SLE but is a serious complication that carries a high mortality risk. Thus, early disease detection in the preclinical asymptomatic or mildly symptomatic phase is a critical step in the therapeutic strategy to improve the outcome [11]. It was considered that PH in active SLE might set up a favorable environment for generating UA, and serum UA levels closely correlated with functional severity and have independent prognostic implications in idiopathic pulmonary artery hypertension [12].

Our study revealed that ∼65% of patients with SLE had normal pulmonary pressure, whereas 35% of the patients with SLE had PH.

Moreover, Kim et al. [12] results showed that 7.9% of 114 patients with SLE had high pulmonary arterial pressure.

In our study, there was a significant increase in the level of serum UA in patients with SLE with PH than in those without PH. This result agreed with Aghdashi et al. [6] who found that there was a significant association between serum UA level and high pulmonary arterial pressure in patients with SLE. Mean pulmonary pressure in group with hyperuricemia was higher than in group with normal UA and serum UA level was associated with severity of pulmonary artery hypertension and ventricular dysfunction, as reported by Zhang et al. [11]. The measurement of UA instead of echocardiography can be used to screen patients with high pulmonary arterial pressure [11],[12].Moreover, Sheikh et al. [2] reported that the measurement of UA may be as an alternative to echocardiography for screening patients with lupus with high pulmonary arterial pressure. In contrast to our study, Castillo-Martínez et al. [13] conducted a study on 156 patients with SLE and reported that there was no association between PH and serum UA.

In our study, the increase of pulmonary arterial pressure was significantly associated with the severity of SLE, which was consistent with other studies which found an association between pulmonary arterial hypertension and rapid deterioration as well as poor prognosis of SLE. Serum UA level could be a prognostic marker of pulmonary arterial pressure in patients with SLE and correlates with disease severity [6],[14]. It also would help to reduce clinical demands for echocardiography in patients with normal UA levels.


  Conclusion Top


Serum level of UA was higher in patients with SLE and correlated with disease activity, suggesting that it might play a role in SLE pathogenesis and can be used as a marker of SLE activity.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Liu H, Cai X, Dai L, Ma J, Mo Y. Elevated uric acid levels in premenopausal female systemic lupus erythematosus patients: association with potential or existing renal damage. Eur J Inflamm 2018; 16:1–6.  Back to cited text no. 1
    
2.
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3.
Xie T, Chen M, Tang X, Yin H, Wang X, Li G et al. Hyperuricemia is an independent risk factor for renal pathological damage and poor prognosis in lupus nephritis patients. J Cent South Univ 2016; 41:1052–1057.  Back to cited text no. 3
    
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Li C, Hsieh MC, Chang SJ. Metabolic syndrome, diabetes and hyperuricemia. Curr Opin Rheumatol 2013; 25:210–216.  Back to cited text no. 10
    
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Zhang Ch-Y, Ma L, Wang L. Relationship between serum uric acid levels and ventricular function in patients with idiopathic pulmonary hypertension. Exp Clin Cardiol 2013; 18:e37–e39.  Back to cited text no. 11
    
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Kim KJ, Baek IW, Park YJ, Yoon CH, Kim WU, Cho CS. High levels of uric acid in systemic lupus erythematosus is associated with pulmonary hypertension. Int J Rheum Dis 2015; 18:524–532.  Back to cited text no. 12
    
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Castillo-Martínez D, Marroquín-Fabián E, Lozada-Navarro AC, Mora-Ramírez M, Juárez M, Sánchez-Muñoz F et al. Levels of uric acid may predict the future development of pulmonary hypertension in systemic lupus erythematosus: a seven-year follow-up study. Rheumatol Int 2011; 31:263–267.  Back to cited text no. 13
    
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Luo RQ, Lei YX, Zhang X, LIng F. Clinical analysis of patients with systemic lupus erythematosus and concomitant pulmonary hypertension. Nan Fang Yi Ke Da Xue Xue Bao 2008; 28:1860–1863.  Back to cited text no. 14
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]



 

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