Skip Navigation


Rheumatology Advance Access originally published online on March 9, 2006
Rheumatology 2006 45(9):1148-1153; doi:10.1093/rheumatology/kel082
This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow All Versions of this Article:
45/9/1148    most recent
kel082v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (3)
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Tso, T. K.
Right arrow Articles by Chang, C.-K.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Tso, T. K.
Right arrow Articles by Chang, C.-K.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© The Author 2006. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Relationship of plasma interleukin-18 concentrations to traditional and non-traditional cardiovascular risk factors in patients with systemic lupus erythematosus

Tim K. Tso1,, Wen-Nan Huang2, Hui-Yu Huang1 and Chen-Kang Chang3

1Graduate Institute of Food Science, Nutrition, and Nutraceutical Biotechnology, Shih Chien University, Taipei, 2Department of Allergy, Immunology and Rheumatology, Taichung Veterans General Hospital, Taichung and 3Sport Science Research Center and Department of Sport Management, National Taiwan College of Physical Education, Taichung, Taiwan.

Correspondence to: Tim K. Tso, Graduate Institute of Food Science, Nutrition and Nutraceutical Biotechnology, Shih Chien University, 70 Ta-Chih Street, Taipei104, Taiwan. E-mail: timtso{at}mail.usc.edu.tw


   Abstract
Top
 Abstract
Introduction
 Materials and methods
 Results
 Discussion
 References
 
Objectives. Systemic lupus erythematosus (SLE) is associated with premature atherosclerosis. Recent studies indicated that the concentrations of circulating interleukin (IL)-18, a novel proinflammatory T helper-1 cytokine, in SLE patients were significantly higher than those in healthy control subjects. The objective of this study was to examine the relationship between IL-18 and cardiovascular risk factors in patients with SLE.

Methods. Both traditional and non-traditional cardiovascular risk factors including body mass index (BMI), systolic blood pressure, diastolic blood pressure (DBP), fasting insulin and glucose, plasma lipid profile, plasma homocysteine, thiobarbituric acid-reactive substances, titres of autoantibodies against oxidized low-density lipoprotein, and brachial–ankle pulse wave velocity (baPWV) were determined in a total of 72 female SLE patients. All patients were further classified into subgroups based on tertiles of plasma IL-18 concentrations.

Results. Plasma concentrations of IL-18 were significantly higher in SLE patients than age-matched healthy controls. SLE patients with IL-18 concentration in the top tertile compared with the bottom tertile had significantly higher plasma levels of insulin, triglyceride, homocysteine and values of homeostasis model assessment insulin resistance (HOMA IR) and HOMA ß-cell. In addition, plasma concentrations of IL-18 correlated positively and significantly with BMI, insulin, HOMA IR, HOMA ß-cell, triglyceride, homocysteine, DBP and baPWV in all SLE patients.

Conclusions. This is th first report showing the relationship between IL-18 and cardiovascular risk factors in SLE. In patients with SLE, the synergistic effects of hyperinsulinaemia, insulin resistance, hyperhomocysteinaemia, and vascular stiffness most likely contribute to the elevation of plasma IL-18 concentrations.

KEY WORDS: Brachial–ankle pulse wave velocity, Cardiovascular risk, Homocysteine, Insulin, Interleukin-18, Systemic lupus erythematosus.


   Introduction
Top
 Abstract
 Introduction
Materials and methods
 Results
 Discussion
 References
 
Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by ample autoantibody production [1]. It has been increasingly recognized that patients with SLE have high cardiovascular morbidity and mortality [2, 3]. However, cardiovascular disease cannot be entirely predicted by traditional risk factors [4, 5], and non-traditional risk factors including lipoprotein oxidation [6, 7], hyperhomocysteinaemia [8–12] and vascular stiffness [13–15] may also significantly contribute to the pathogenesis of cardiovascular disease. In addition, antiphospholipid antibody in SLE was one of the disease-associated risk factors for thrombosis but may not completely explain the cardiovascular risk, and the pathogenetic mechanisms for thrombosis in patients with familial SLE could be multifactorial [16].

Cytokines are important mediators of differentiation and activation for T and B cells, and they have been functionally divided into two subgroups, T helper-1 (Th-1) and T helper-2 (Th-2) [17]. IL-18 is a novel proinflammatory Th-1 cytokine produced by various cell types including Kupffer cells, activated macrophages, keratinocytes, intestinal epithelial cells, osteroblasts and adrenal cortex cells [18]. IL-18 is a member of the IL-1 family and has a synergistic effect with IL-12 on the activation of natural killer cells and cytotoxic T lymphocytes [19].

SLE has been considered a Th-2 polarized disease [20], but recent reports indicated that circulating concentrations of the proinflammatory Th-1 cytokine IL-18 were elevated in SLE patients [21–28], and this elevation is correlated with disease activity [21–23, 25] or clinical manifestations [26–28]. In addition, there is some evidence that IL-18 concentrations may be linked with type 2 diabetes mellitus [29, 30], metabolic syndrome [31], hyperhomocysteinaemia [29, 32], obesity [33, 34] and insulin resistance [34].

However, to the best of our knowledge, the association of proinflammatory cytokines with cardiovascular risk in SLE patients has not been extensively established. Thus, the purpose of this study was to determine whether plasma IL-18 is associated with cardiovascular risk factors in patients with SLE.


   Materials and methods
Top
 Abstract
 Introduction
 Materials and methods
Results
 Discussion
 References
 
Patients
We studied 72 Chinese female SLE patients; the mean age and disease duration were 38 and 9 yrs, respectively. SLE patients were randomly selected from out-patient clinics at Taichung Veterans General Hospital (Taichung, Taiwan) and 40 age-matched healthy females from the local community served as controls. All qualified SLE patients fulfilled the 1982 revised American College of Rheumatology criteria [35]. Patients’ disease activity was evaluated according to the SLE Disease Activity Index (SLEDAI) [36], and the median value for SLEDAI for all patients was four, indicating that most patients had inactive or moderately active disease status [36–40]. The mean dosage for prednisolone was 8 mg/day. Patients were excluded if they had cardiovascular diseases, renal disease or type 2 diabetes mellitus. In order to examine the association of plasma IL-18 with cardiovascular risk factors in SLE, all patients were classified into subgroups based on the tertiles of plasma IL-18 concentrations. Written informed consent was obtained from all participants including SLE patients and healthy controls, and the Taichung Veterans General Hospital's ethical committee approved the study.

Experimental assays
Blood specimens were obtained after an overnight fast for measurements of tested variables. Quantitative measurement of patients’ fasting insulin concentrations was conducted using an Abbott IMx Insulin Kit based on a microparticle enzyme immunoassay (MEIA) (Abbott Laboratories, Dainabot, Tokyo, Japan). The fasting glucose concentration was determined using an enzymatic colorimetric method (Sigma Chemical Company, St Louis, MO, USA). Homeostasis model assessment insulin resistance (HOMA IR) and HOMA ß-cell were calculated according to the formulas in the HOMA model [41, 42]. Plasma cortisol concentrations were determined by solid-phase technique—chemiluminescence immunoassays (Immulite 2000, DPC, Los Angeles, CA, USA). Anti-double-stranded DNA (anti-dsDNA) was measured according to enzyme-linked immunosorbent assay (ELISA) using a Quanta LiteTM dsDNA Kit (INOVA Diagnostics, Inc., San Diego, CA, USA). Quantitative determinations of C3 and C4 in patients’ sera were conducted using N Antisera to Human Complement Factor reagents with Behring nephelometers (Dade Behring, Inc., Newark, DE, USA).

Enzymatic methods were used to determine plasma concentrations of total cholesterol (Beckman TC Reagent) and triglyceride (Beckman TG Reagent). Magnesium–dextran sulphate precipitation reagent was used to separate high-density lipoprotein-cholesterol (HDL-C), which was then assessed enzymatically. Low-density lipoprotein-cholesterol (LDL-C) was determined by the Friedewald equation [43]. Plasma homocysteine levels were measured using a high-performance liquid chromatographic procedure with fluorescence detection. Thiobarbituric acid-reactive substances (TBARS) were measured according to previous reports [44, 45]. Susceptibility of LDL to oxidation was determined according to titres of autoantibodies against oxidized LDL (ox-LDL) using an ImmuLisaTM Anti-oxLDL Antibody ELISA Kit (IMMCO Diagnostics, Buffalo, NY, USA). Brachial–ankle pulse wave velocity (baPWV) was measured using a non-invasive vascular screening device (Colin VP-1000; Colin Co., Ltd., Komaki, Japan). The VP-1000 records electrocardiogram, phonocardiogram and pulse volume simultaneously and calculates the time delay of the pulse to obtain the pulse wave transmit time (PTT). The VP-1000 can measure PWV in the right brachium (La) and right/left lower limbs (Lb, Lc). baPWV (from brachial artery to ankle) was calculated using the following formula: baPWV (right) = (Lb – La)/PTT; baPWV (left) = (Lc – La)/PTT. In this study, we used a mean right/left baPWV value during analysis.

Plasma levels of IL-18 were assessed by ELISA using a Human IL-18 ELISA kit (Medical & Biological Laboratories Co., Ltd., Nagoya, Japan) in accordance with the manufacturer's instructions and analysed with a Dynex MRX II microplate reader (DYNEX Technologies, Inc., Chantilly, VA, USA) at a wavelength of 450 nm. This commercial kit for detecting only bioactive IL-18, not the immature pro-IL-18, has been widely used [21–27].

Statistical analysis
Statistical analysis in this study was performed using the Statistical Package of Social Sciences (SPSS) 10.0 for Windows (SPSS, Inc., Chicago, IL, USA). Tested variables for comparison of means were expressed as mean±standard error of mean (SEM). The distribution of tested variables was examined graphically for normality. One-way analysis of variance (ANOVA) was used to examine the mean differences of cardiovascular risk factors between patients in the respective plasma IL-18 tertiles. The Bonferroni test was used for post hoc analysis. Mean levels of plasma IL-18 according to categorical risk factors were compared by Mann–Whitney test or Kruskal–Wallis test. Pearson's correlation analysis was used to examine the relationships between plasma IL-18 and tested cardiovascular risk factors. P values <0.05 were considered significant for all statistical analyses in this study.


   Results
Top
 Abstract
 Introduction
 Materials and methods
 Results
Discussion
 References
 
Plasma concentrations of IL-18 were significantly higher in SLE patients than age-matched healthy controls by the Mann–Whitney test (254.34±15.16 pg/ml, n = 72 vs 177.16±11.01 pg/ml, n = 40, P = 0.002). The characteristics of SLE patients stratified into tertiles based on plasma IL-18 concentrations are shown in Table 1. There were no statistical differences in cortisol, anti-dsDNA, C3, C4, dosage for prednisone, and SLEDAI between the tertiles. Mean differences for cardiovascular risk factors of all patients in the respective plasma IL-18 tertiles are shown in Table 2. SLE patients with plasma IL-18 concentration in the top tertile compared with the bottom tertile had significantly higher plasma levels of insulin, triglyceride, homocysteine and values of HOMA IR and HOMA ß-cell.


View this table:
[in this window]
[in a new window]

  		TABLE 1. Characteristics of all patients in the respective tertiles of plasma IL-18 concentrationa

 

View this table:
[in this window]
[in a new window]

  		TABLE 2. Cardiovascular risk factors of all patients in the respective tertiles of plasma IL-18 concentrationa

 
Table 3 shows the mean concentrations of plasma IL-18 according to categorical risk factors including body mass index (BMI), dyslipidaemia, hypertension, hyperhomocysteinaemia, vascular stiffness, hyperinsulinaemia and insulin resistance. Only 27% of studied patients were overweight or obese, 25% of studied patients were considered dyslipidaemic (total cholesterol >5.18 mmol/l, triglyceride >1.695 mmol/l, LDL-C >3.367 mmol/l or HDL-C <1.3 mmol/l) [46, 47], and 30% of studied patients were considered hypertensive [systolic blood pressure (SBP) >140 mm Hg or diastolic blood pressure (DBP) >90 mm Hg] [46, 47]. About 57% of SLE patients in this study were considered to have mild (plasma total homocysteine 10–30 µmol/l) or moderate hyperhomocysteinaemia (plasma total homocysteine 30–100 µmol/l) [48]. A cutoff value of 1400 cm/s for baPWV was used to evaluate vascular stiffness [45, 49]. In this study, hyperhomocysteinaemia and vascular stiffness were associated with elevated plasma IL-18, and patients with fasting insulin and HOMA IR in the top tertile compared with the bottom tertile had significantly higher plasma IL-18 concentrations.


View this table:
[in this window]
[in a new window]

  		TABLE 3. Mean concentrations of plasma IL-18 according to categorical risk factors in SLE patients

 
The correlation of plasma IL-18 with cardiovascular risk factors in all SLE patients is shown in Table 4. Plasma concentrations of IL-18 correlated positively and significantly with BMI, insulin, HOMA IR, HOMA ß-cell, triglyceride, homocysteine, DBP and baPWV in all SLE patients.


View this table:
[in this window]
[in a new window]

  		TABLE 4. Correlation coefficient of plasma IL-18 with cardiovascular risk factors in SLE patients

 

   Discussion
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
References
 
This is the first study to demonstrate a possible relationship between plasma IL-18 and cardiovascular risk factors in patients with SLE. The major finding was that the elevation of plasma IL-18 in patients with SLE is significantly associated with increases in fasting insulin levels, homocysteine and baPWV.

In this study, we confirmed that plasma concentrations of mature and bioactive IL-18 were elevated in SLE patients compared with healthy controls [21–27]. Recently, Hung et al. [31] showed that IL-18 concentrations in a general population were positively and significantly associated with a range of metabolic risk traits including BMI, waist circumference, triglyceride, blood pressure, fasting glucose and insulin levels. Prospective studies have shown that circulating IL-18 concentration was an independent predictor of death from cardiovascular causes in patients with coronary artery disease [50] and of coronary events in healthy men [51]. Esposito et al. [33] reported that plasma IL-18 levels were higher in obese women than in normal-weight control women and were positively associated with body weight, BMI, waist-to-hip ratio and fasting insulin levels.

Circulating IL-18 concentrations were also increased in type 1 and type 2 diabetes mellitus individuals [52] and in polycystic ovary syndrome patients compared with those in controls [34]. In the present study, we also identified positive correlations of plasma IL-18 with insulin levels and insulin resistance in patients with SLE. This finding suggests that elevation of plasma IL-18 may at least in part link inflammation with hyperinsulinaemia and/or insulin resistance in SLE patients.

Lipid and lipoprotein profiles in SLE patients are often abnormal compared with those of the general population [53, 54]. In the present study, although mean levels of lipids and lipoproteins in our patients were within a normal range, based on the National Cholesterol Education Program (NCEP) criteria [46, 47], we still found that SLE patients with IL-18 concentration in the top tertile compared with the bottom tertile had significantly higher plasma triglyceride levels, and plasma IL-18 concentration positively correlated with triglyceride in patients overall. However, there was no statistical difference for lipid and lipoprotein oxidations between SLE IL-18 tertile subgroups. This suggests that elevation of plasma IL-18 levels may not enhance lipid and lipoprotein oxidations in patients with SLE.

Hyperhomocysteinaemia has been shown to be an independent risk factor for atherosclerosis and thrombosis [8–12]. In addition, plasma homocysteine has also been identified as a risk factor for atherothrombotic events in patients with SLE [55–57]. Refai et al. [55] showed that SLE patients with elevated homocysteine concentration had a 3-fold increase in the incidence of thrombotic events after adjusting for other risk factors. We also reported that plasma homocysteine levels were elevated in SLE patients when compared with those in the healthy controls, and SLE patients with anticardiolipin antibody (aCL) had significantly higher plasma homocysteine levels than SLE patients without aCL [58].

In the present study, the mean value for homocysteine concentration was 11.35±4.66 µmol/l, and 57% of studied SLE patients were considered to have a mild or moderate hyperhomocysteinaemia [48]. Although both homocysteine and IL-18 seem to be involved in vascular inflammation and coronary artery disease, few studies have investigated the relationship between plasma homocysteine level and plasma IL-18 concentration. Recently, McLachlan et al. [32] reported that homocysteine is positively associated with plasma IL-18 concentrations in coronary artery bypass surgery patients. Aso et al. [29] found that plasma total homocysteine levels were significantly higher in type 2 diabetic patients with high plasma IL-18 concentration than in those with normal plasma IL-18 concentration. However, an association between homocysteine and IL-18 has not been previously investigated in SLE patients. We demonstrated a positive correlation between plasma concentrations of IL-18 and homocysteine in patients with SLE. SLE patients with IL-18 concentration in the top tertile compared with the bottom tertile had significantly higher plasma levels of homocysteine. SLE patients in the present study with mild or moderate hyperhomocysteinaemia had significantly higher IL-18 concentrations compared with SLE patients with normal homocysteine levels. It is likely that an elevation of homocysteine by IL-18 or vice versa in SLE promotes inflammation and enhances the development and progression of homocysteine- and/or IL-18-related atherosclerosis. However, this hypothetical mechanism remains to be elucidated.

The pathogenesis of vascular disease in SLE patients may involve interactions between chronic vascular inflammation, corticosteroid use, augmented traditional risk factors, kidney dysfunction and hypertension [59]. These multifactorial influences contribute to alterations of the vasculature, and the development of vascular stiffness and atherosclerosis [59]. Increased vascular stiffness may increase cardiovascular mortality [13, 14]. Choi et al. [60] reported that baPWV was closely associated with the cardiovascular risk factors of metabolic syndrome in women.

Recently, PWV has been used as a non-invasive method in the analysis of vascular stiffness for the assessment of atherosclerosis in patients with SLE [45, 59]. Selzer et al. [59] showed that traditional cardiovascular risk factors including age, SBP, fasting blood glucose, and obesity were associated with aortic stiffness measured by aortic PWV in post-menopausal SLE women. In the present study, we demonstrated a positive correlation between IL-18 and baPWV. Although there was no statistical difference for baPWV in IL-18 tertile subgroups, SLE patients with IL-18 concentration in the top tertile compared with the bottom tertile tended to have higher baPWV. We recently reported that a previously identified cutoff value of 1400 cm/s for baPWV was also applicable for patients with SLE [45, 49]. SLE patients in this study with baPWV value >1400 cm/s had significantly higher plasma IL-18 compared with SLE patients with baPWV value <1400 cm/s (309.70±29.97 pg/ml vs 215.75±22.15 pg/ml, P = 0.022). These results indicate that IL-18 may be involved in the development of vascular stiffness in patients with SLE.

In conclusion, this is the first report showing the relationship between IL-18 and cardiovascular risk factors in SLE patients. In patients with SLE, the synergistic effects of hyperinsulinaemia, insulin resistance, hyperhomocysteinaemia, and vascular stiffness most likely contribute to the elevation of plasma IL-18 concentrations.

Formula


   Acknowledgments
 
This study was partly supported by a research grant from Taichung Veterans General Hospital (TCVGH-943802B). The authors thank Ms Ying-Ju Liao and Ms Shin-Yi Chang for their technical assistance in biochemical analyses.


   References
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 

  1. Steinberg AD and Klinman DM. (1988) Pathogenesis of systemic lupus erythematosus. Rheum Dis Clin N Am 14:25–41.[Web of Science][Medline]
  2. Abu-Shakra M, Urowitz MB, Gladman DD, Gough J. (1995) Mortality studies in systemic lupus erythematosus: results from a single center. I. Causes of death. J Rheumatol 22:1259–64.[Web of Science][Medline]
  3. Ward MM. (1999) Premature morbidity from cardiovascular and cerebrovascular diseases in women with systemic lupus erythematosus. Arthritis Rheum 42:338–46.[CrossRef][Web of Science][Medline]
  4. Laurent S, Boutouyrie P, Asmar R, et al. (2001) Aortic stiffness is an independent predictor of all-cause and cardiovascular mortality in hypertensive patients. Hypertension 37:1236–41.[Abstract/Free Full Text]
  5. Esdaile JM, Abrahamowicz M, Grodzicky T, et al. (2001) Traditional Framingham risk factors fail to fully account for accelerated atherosclerosis in systemic lupus erythematosus. Arthritis Rheum 44:2331–7.[CrossRef][Web of Science][Medline]
  6. Svenungsson E, Jensen-Urstad K, Heimburger M, et al. (2001) Risk factors for cardiovascular disease in systemic lupus erythematosus. Circulation 104:1887–93.[Abstract/Free Full Text]
  7. Frostegard J, Svenungsson E, Wu R, et al. (2005) Lipid peroxidation is enhanced in patients with systemic lupus erythematosus and is associated with arterial and renal disease manifestations. Arthritis Rheum 52:192–200.[CrossRef][Web of Science][Medline]
  8. Clarke R, Daly L, Robinson K, et al. (1991) Hyperhomocysteinemia: an independent risk factor for vascular disease. N Engl J Med 324:1149–55.[Abstract]
  9. Ueland PM, Refsum H, Beresford SAA, Vollset SE. (2000) The controversy over homocysteine and cardiovascular risk. Am J Clin Nutr 72:324–32.[Abstract/Free Full Text]
  10. Welch GN and Loscalzo JN. (1998) Homocysteine and atherothrombosis. N Engl J Med 338:1042–50.[Free Full Text]
  11. Hsu TS, Hsu LA, Chang CJ, et al. (2001) Importance of hyperhomocysteinemia as a risk factor for venous thromboembolism in a Taiwanese population. A case-control study. Thromb Res 102:387–95.[CrossRef][Web of Science][Medline]
  12. den Heijer M, Koster T, Blom HJ, et al. (1996) Hyperhomocysteinemia as a risk factor for deep-vein thrombosis. N Engl J Med 334:759–62.[Abstract/Free Full Text]
  13. Meaume S, Benetos A, Henry OF, Rudnichi A, Safar ME. (2001) Aortic pulse wave velocity predicts cardiovascular mortality in subjects >70 years of age. Arterioscler Thromb Vasc Biol 21:2046–50.[Abstract/Free Full Text]
  14. Shoji T, Emoto M, Shinohara K, et al. (2001) Diabetes mellitus, aortic stiffness, and cardiovascular mortality in end-stage renal disease. J Am Soc Nephrol 12:2117–24.[Abstract/Free Full Text]
  15. Brodszki J, Bengtsson C, Lanne T, Nived O, Sturfelt G, Marsal K. (2004) Abnormal mechanical properties of larger arteries in postmenopausal women with systemic lupus erythematosus. Lupus 13:917–23.[Abstract/Free Full Text]
  16. Koskenmies S, Vaarala O, Widen E, Kere J, Palosuo T, Julkunen H. (2004) The association of antibodies to cardiolipin, ß2-glycoprotein I, prothrombin, and oxidized low-density lipoprotein with thrombosis in 292 patients with familial and sporadic systemic lupus erythematosus. Scand J Rheumatol 33:246–52.[CrossRef][Web of Science][Medline]
  17. Romagnani S. (1997) The Th-1/Th-2 paradigm. Immunol Today 18:263–6.[Web of Science][Medline]
  18. Dinarello CA. (1999) IL-18: a Th-1-inducing, pro-inflammatory cytokine and new member of the IL-1 family. J Allergy Clin Immunol 103:11–24.[CrossRef][Web of Science][Medline]
  19. Fehniger TA, Shah MH, Turner MJ, et al. (1999) Differential cytokine and chemokine gene expression by human NK cells following activation with IL-18 or IL-15 in combination with IL-12: implications for the innate immune response. J Immunol 162:4511–20.[Abstract/Free Full Text]
  20. Ogawa N, Itoh M, Goto Y. (1992) Abnormal production of B cell growth factor in patients with systemic lupus erythematosus. Clin Exp Immunol 89:26–31.[Web of Science][Medline]
  21. Wong CK, Li EK, Ho CY, Lam CWK. (2000) Elevation of plasma interleukin-18 concentration is correlated with disease activity in systemic lupus erythematosus. Rheumatology 39:1078–81.[Abstract/Free Full Text]
  22. Wong CK, Ho CY, Li EK, Lam CWK. (2000) Elevation of pro-inflammatory cytokine (IL-18, IL-17, IL-12) and Th-2 cytokine (IL-4) concentrations in patients with systemic lupus erythematosus. Lupus 9:589–93.[Abstract/Free Full Text]
  23. Park MC, Park YB, Lee SK. (2004) Elevated interleukin-18 levels correlated with disease activity in systemic lupus erythematosus. Clin Rheumatol 23:225–9.[CrossRef][Web of Science][Medline]
  24. Robak E, Robak T, Wozniacka A, Zak-Prelich M, Sysa-Jedrzejowska A, Stepien H. (2002) Pro-inflammatory interferon-gamma-inducing monokines (interleukin-12, interleukin-18, interleukin-15) – serum profile in patients with systemic lupus erythematosus. Eur Cytokine Netw 13:364–8.[Web of Science][Medline]
  25. Amerio P, Frezzolini A, Abeni D, et al. (2002) Increased IL-18 in patients with systemic lupus erythematosus: relations with Th-1, Th-2, pro-inflammatory cytokines and disease activity. IL-18 is a marker of disease activity but does not correlate with pro-inflammatory cytokines. Clin Exp Rheumatol 20:535–8.[Web of Science][Medline]
  26. Calvani N, Richards HB, Tucci M, Pannarale G, Silvestris F. (2004) Up-regulation of IL-18 and predominance of a Th-1 immune response is a hallmark of lupus nephritis. Clin Exp Immunol 138:171–8.[CrossRef][Web of Science][Medline]
  27. Wong CK, Ho CY, Li EK, Tam LS, Lam CWK. (2002) Elevated production of interleukin-18 is associated with renal disease in patients with systemic lupus erythematosus. Clin Exp Immunol 130:345–51.[CrossRef][Web of Science][Medline]
  28. Wong CK, Lit LCW, Tam LS, Li EK, Lam CWK. (2005) Elevation of plasma osteopontin concentration is correlated with disease activity in patients with systemic lupus erythematosus. Rheumatology 44:602–6.[Abstract/Free Full Text]
  29. Aso Y, Okumura K, Takebayashi K, Wakabayashi S, Inukai T. (2003) Relationships of plasma interleukin-18 concentrations to hyperhomocysteinemia and carotid intimal-media wall thickness in patients with type 2 diabetes. Diabetes Care 26:2622–7.[Abstract/Free Full Text]
  30. Esposito K, Nappo F, Giugliano F, et al. (2003) Cytokine milieu tends toward inflammation in type 2 diabetes. Diabetes Care 26:1647.[Free Full Text]
  31. Hung J, McQuillan BM, Chapman CML, Thompson PL, Beilby JP. (2005) Elevated interleukin-18 levels are associated with the metabolic syndrome independent of obesity and insulin resistance. Arterioscler Thromb Vasc Biol 25:1268–73.[Abstract/Free Full Text]
  32. McLachlan CS, Chua WC, Wong PT, Kah TL, Chen C, El Oakley RM. (2005) Homocysteine is positively associated with cytokine IL-18 plasma levels in coronary artery bypass surgery patients. Biofactors 23:69–73.[Web of Science][Medline]
  33. Esposito K, Pontillo A, Ciotola M, et al. (2002) Weight loss reduces IL-18 levels in obese women. J Clin Endocrinol Metab 87:3864–6.[Abstract/Free Full Text]
  34. Escobar-Morreale HF, Botella-Carretero JI, Villuendas G, Sancho J, San Millan JL. (2004) Serum interleukin-18 concentrations are increased in the polycystic ovary syndrome: relationship to insulin resistance and to obesity. J Clin Endocrinol Metab 89:806–11.[Abstract/Free Full Text]
  35. Tan EM, Cohen AS, Fries JF, et al. (1982) The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 25:1271–7.[Web of Science][Medline]
  36. Bombardier C, Gladman DD, Urowitz MB, et al. (1992) Derivation of the SLEDAI: a disease activity index for lupus patients. Arthritis Rheum 35:630–40.[Web of Science][Medline]
  37. Tso TK, Huang HY, Chang CK, Liao YJ, Huang WN. (2004) Clinical evaluation of insulin resistance and ß-cell function by the homeostasis model assessment in patients with systemic lupus erythematosus. Clin Rheumatol 23:416–20.[CrossRef][Web of Science][Medline]
  38. Chang DM, Lan JL, Lin HY, Luo SF. (2002) Dehydroepiandrosterone treatment of women with mild-to-moderate systemic lupus erythematosus. Arthritis Rheum 46:2924–7.[CrossRef][Web of Science][Medline]
  39. Gomez D, Correa PA, Gomez LM, Cadena J, Molina JF, Anaya JM. (2004) Th-1/Th-2 cytokines in patients with systemic lupus erythematosus: is tumor necrosis factor-{alpha} protective? Semin Arthritis Rheum 33:404–13.[CrossRef][Web of Science][Medline]
  40. Grossman JM and Kalunian KC. Wallace DJ and Hahn BH. (2002) Definition, classification, activity, and damage indices: Dubois’ lupus erythematosus. (Lippincott, Williams and Wilkins, Philadelphia)19–31.
  41. Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RL. (1985) Homeostasis model assessment: insulin resistance and ß-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 28:412–9.[CrossRef][Web of Science][Medline]
  42. Haffner SM, Miettinen H, Stern MP. (1997) The homeostasis model in the San Antonio Heart Study. Diabetes Care 20:1087–92.[Abstract]
  43. Friedewald WT, Levy RI, Fredrickson DS. (1972) Estimation of the concentration of low-density lipoprotein cholesterol in plasma without use of the preparative ultracentrifuge. Clin Chem 18:499–502.[Abstract]
  44. Oteiza PI, Olin KL, Fraga CG, Keen CL. (1995) Zinc deficiency causes oxidative damage to proteins, lipids and DNA in rat testes. J Nutr 125:823–9.[Abstract/Free Full Text]
  45. Tso TK, Huang WN, Huang HY, Chang CK. (2005) Association of brachial-ankle pulse wave velocity with cardiovascular risk factors in systemic lupus erythematosus. Lupus 14:878–83.[Abstract/Free Full Text]
  46. Executive summary of the third report of the National Cholesterol Education Program (NCEP) Expert Panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III). JAMA (2001) 285:2486–97.[Free Full Text]
  47. National Cholesterol Education Program (NCEP) Expert Panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III). (2002) Third report of the National Cholesterol Education Program (NCEP) Expert Panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III final report). Circulation 106:3143–421.[Free Full Text]
  48. Lentz SR and Haynes WG. (2004) Homocysteine: is it a clinically important cardiovascular risk factor? Cleve Clin J Med 71:729–34.[Abstract/Free Full Text]
  49. Yamashina A, Tomiyama H, Arai T, et al. (2003) Brachial-ankle pulse wave velocity as a marker of atherosclerotic vascular damage and cardiovascular risk. Hypertens Res 26:615–22.[CrossRef][Web of Science][Medline]
  50. Blankenberg S, Tiret L, Bickel C, et al. AtheroGene Investigators. (2002) Interleukin-18 is a strong predictor of cardiovascular death in stable and unstable angina. Circulation 106:24–30.[Abstract/Free Full Text]
  51. Blankenberg S, Luc G, Ducimetiere P, et al. PRIME Study Group. (2003) IL-18 and the risk of coronary heart disease in European men: the Prospective Epidemiological Study of Myocardial Infarction (PRIME). Circulation 108:2453–9.[Abstract/Free Full Text]
  52. Mahmoud RA, el-Ezz SA, Hegazy AS. (2004) Increased serum levels of interleukin-18 in patients with diabetic nephropathy. Ital J Biochem 53:73–81.[Medline]
  53. Wierzbicki AS. (2000) Lipids, cardiovascular disease and atherosclerosis in systemic lupus erythematosus. Lupus 9:194–201.[Abstract/Free Full Text]
  54. Formiga F, Meco JF, Pinto X, Jacob J, Moga I, Pujol R. (2001) Lipid and lipoprotein levels in premenopausal systemic lupus erythematosus patients. Lupus 10:359–63.[Abstract/Free Full Text]
  55. Refai TMK, Al-Salem IH, Nkansa-Dwamena D, Al-Salem MH. (2002) Hyperhomocysteinaemia and risk of thrombosis in systemic lupus erythematosus patients. Clin Rheumatol 21:457–61.[CrossRef][Web of Science][Medline]
  56. Petri M, Roubenoff R, Dallal GE, et al. (1996) Plasma homocysteine as a risk factor for atherothrombotic events in systemic lupus erythematosus. Lancet 348:1120–4.[CrossRef][Web of Science][Medline]
  57. Fijnheer R, Roest M, Haas FJ, et al. (1998) Homocysteine, methylenetetrahydrofolate reductase polymorphism, antiphospholipid antibodies, and thromboembolic events in systemic lupus erythematosus: a retrospective cohort study. J Rheumatol 25:1737–42.[Web of Science][Medline]
  58. Tso TK, Huang HY, Chang CK, Huang WN. A positive correlation between homocysteine and brachial-ankle pulse wave velocity in patients with systemic lupus erythematosus. Clin Rheumatol 21: Epub ahead of print.
  59. Selzer F, Sutton-Tyrrell K, Fitzgerald S, Tracy R, Kuller L, Manzi S. (2001) Vascular stiffness in women with systemic lupus erythematosus. Hypertension 37:1075–82.[Abstract/Free Full Text]
  60. Choi KM, Lee KW, Seo JA, et al. (2004) Relationship between brachial-ankle pulse wave velocity and cardiovascular risk factors of the metabolic syndrome. Diabetes Res Clin Pract 66:57–61.[CrossRef][Web of Science][Medline]
Submitted 9 December 2005; revised version accepted 10 February 2006.
Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 Nephrol Dial TransplantHome page
T. Porazko, J. Kuzniar, M. Kusztal, T. J. Kuzniar, W. Weyde, M. Kuriata-Kordek, and M. Klinger
IL-18 is involved in vascular injury in end-stage renal disease patients
Nephrol. Dial. Transplant., February 1, 2009; 24(2): 589 - 596.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow All Versions of this Article:
45/9/1148    most recent
kel082v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (3)
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Tso, T. K.
Right arrow Articles by Chang, C.-K.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Tso, T. K.
Right arrow Articles by Chang, C.-K.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?