Journal List > J Rheum Dis > v.26(4) > 1137069

Lee and Song: YKL-40 Levels in Rheumatoid Arthritis and Their Correlation with Disease Activity: A Meta-analysis

Abstract

Objective

To examine the relationship of serum/plasma YKL-40 levels with rheumatoid arthritis (RA) and their correlation with RA activity and rheumatoid factor (RF) level.

Methods

We performed a meta-analysis comparing the serum/plasma YKL-40 levels between patients with RA and controls and examined the correlation coefficients of the circulating YKL-40 level with the RF level and RA activity based on the 28-joint disease activity score (DAS28), erythrocyte sedimentation rate (ESR), and C-re-active protein (CRP) level.

Results

Nine studies (707 patients with RA and 1,041 controls) were included in the meta-analysis. The YKL-40 levels were significantly higher in the RA group than in the control group (standardized mean difference [SMD]=1.071, 95% confidence interval [CI]=0.726∼1.417, p<0.001). Stratification by ethnicity showed significantly elevated YKL-40 levels in the RA groups from European, Asian, North American, and Arab populations. The YKL-40 level was significantly higher in the RA group than in the control group in both age- and sex-matched and only age-matched populations (SMD=0.937, 95% CI=0.554∼1.320, p<0.001; SMD=2.951, 95% CI=1.389∼4.512, p<0.001, respectively). Subgroup analysis by sample size showed significantly increased YKL-40 levels in the RA group in both small (n<100) and large (n>100) populations. Meta-analysis of correlation coefficients showed a significant positive correlation between the YKL-40 levels and DAS28, ESR, CRP level, and RF level (DAS28: correlation coefficient=0.381, 95% CI=0.044∼0.640, p=0.028; RF level: correlation coefficient=0.341, 95% CI=0.176∼0.487, p<0.001).

Conclusion

The circulating YKL-40 levels are high in patients with RA and positively correlate with RA activity and RF level.

REFERENCES

1. Lee YH, Bae SC, Choi SJ, Ji JD, Song GG. Genomewide pathway analysis of genomewide association studies on systemic lupus erythematosus and rheumatoid arthritis. Mol Biol Rep. 2012; 39:10627–35.
crossref
2. Hakala BE, White C, Recklies AD. Human cartilage gp-39, a major secretory product of articular chondrocytes and synovial cells, is a mammalian member of a chitinase protein family. J Biol Chem. 1993; 268:25803–10.
crossref
3. Johansen JS. Studies on serum YKL-40 as a biomarker in diseases with inflammation, tissue remodelling, fibroses and cancer. Dan Med Bull. 2006; 53:172–209.
4. Zivanović S, Rackov LP, Vojvodić D, Vucetić D. Human cartilage glycoprotein 39–biomarker of joint damage in knee osteoarthritis. Int Orthop. 2009; 33:1165–70.
5. Furuhashi K, Suda T, Nakamura Y, Inui N, Hashimoto D, Miwa S, et al. Increased expression of YKL-40, a chiti-nase-like protein, in serum and lung of patients with idiopathic pulmonary fibrosis. Respir Med. 2010; 104:1204–10.
crossref
6. Turkyilmaz AK, Devrimsel G, Kirbas A, Cicek Y, Karkucak M, Capkin E, et al. Relationship between pulse wave velocity and serum YKL-40 level in patients with early rheumatoid arthritis. Rheumatol Int. 2013; 33:2751–6.
crossref
7. Kazakova M, Batalov A, Deneva T, Mateva N, Kolarov Z, Sarafian V. Relationship between sonographic parameters and YKL-40 levels in rheumatoid arthritis. Rheumatol Int. 2013; 33:341–6.
crossref
8. Nielsen KR, Steffensen R, Boegsted M, Baech J, Lundbye-Christensen S, Hetland ML, et al. Promoter polymorphisms in the chitinase 3-like 1 gene influence the serum concentration of YKL-40 in Danish patients with rheumatoid arthritis and in healthy subjects. Arthritis Res Ther. 2011; 13:R109.
crossref
9. Johansen JS, Kirwan JR, Price PA, Sharif M. Serum YKL-40 concentrations in patients with early rheumatoid arthritis: relation to joint destruction. Scand J Rheumatol. 2001; 30:297–304.
10. Janckila AJ, Neustadt DH, Yam LT. Significance of serum TRACP in rheumatoid arthritis. J Bone Miner Res. 2008; 23:1287–95.
crossref
11. Vos K, Steenbakkers P, Miltenburg AM, Bos E, van Den Heuvel MW, van Hogezand RA, et al. Raised human cartilage glycoprotein-39 plasma levels in patients with rheumatoid arthritis and other inflammatory conditions. Ann Rheum Dis. 2000; 59:544–8.
crossref
12. Jafari-Nakhjavani MR, Ghorbanihaghjo A, Bagherzadeh-Nobari B, Malek-Mahdavi A, Rashtchizadeh N. Serum YKL-40 levels and disease characteristics in patients with rheumatoid arthritis. Caspian J Intern Med. 2019; 10:92–7.
13. Basok BI, Kucur M, Kizilgul M, Yilmaz I, Ekmekci OB, Uzunlulu M, et al. Increased chitotriosidase activities in patients with rheumatoid arthritis: a possible novel marker? J Med Biochem. 2014; 33:245–51.
crossref
14. Matsumoto T, Tsurumoto T. Serum YKL-40 levels in rheumatoid arthritis: correlations between clinical and labo-rarory parameters. Clin Exp Rheumatol. 2001; 19:655–60.
15. Hozo SP, Djulbegovic B, Hozo I. Estimating the mean and variance from the median, range, and the size of a sample. BMC Med Res Methodol. 2005; 5:13.
crossref
16. Ridout KK, Ridout SJ, Price LH, Sen S, Tyrka AR. Depression and telomere length: a meta-analysis. J Affect Disord. 2016; 191:237–47.
crossref
17. Moher D, Liberati A, Tetzlaff J, Altman DG. PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med. 2009; 6:e1000097.
crossref
18. McGough JJ, Faraone SV. Estimating the size of treatment effects: moving beyond p values. Psychiatry (Edgmont). 2009; 6:21–9.
19. Egger M, Smith GD, Phillips AN. Meta-analysis: principles and procedures. BMJ. 1997; 315:1533–7.
crossref
20. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986; 7:177–88.
crossref
21. Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med. 2002; 21:1539–58.
crossref
22. Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997; 315:629–34.
crossref
23. Knudsen LS, Klarlund M, Skjødt H, Jensen T, Ostergaard M, Jensen KE, et al. Biomarkers of inflammation in patients with unclassified polyarthritis and early rheumatoid arthritis. Relationship to disease activity and radiographic outcome. J Rheumatol. 2008; 35:1277–87.
24. Peltomaa R, Paimela L, Harvey S, Helve T, Leirisalo-Repo M. Increased level of YKL-40 in sera from patients with early rheumatoid arthritis: a new marker for disease activity. Rheumatol Int. 2001; 20:192–6.
crossref
25. Ling H, Recklies AD. The chitinase 3-like protein human cartilage glycoprotein 39 inhibits cellular responses to the inflammatory cytokines interleukin-1 and tumour necrosis factor-alpha. Biochem J. 2004; 380:651–9.
crossref
26. Recklies AD, Ling H, White C, Bernier SM. Inflammatory cytokines induce production of CHI3L1 by articular chondrocytes. J Biol Chem. 2005; 280:41213–21.
crossref
27. Lee CG, Da Silva CA, Dela Cruz CS, Ahangari F, Ma B, Kang MJ, et al. Role of chitin and chitinase/chitinase-like proteins in inflammation, tissue remodeling, and injury. Annu Rev Physiol. 2011; 73:479–501.
crossref
28. Joosten LA, Coenen-de Roo CJ, Helsen MM, Lubberts E, Boots AM, van den Berg WB, et al. Induction of tolerance with intranasal administration of human cartilage gp-39 in DBA/1 mice: amelioration of clinical, histologic, and radiologic signs of type II collagen-induced arthritis. Arthritis Rheum. 2000; 43:645–55.
crossref

Figure 1.
Meta-analysis of the relationship between the plasma/serum YKL-40 levels and rheumatoid arthritis (RA) in all study subjects. Std diff: standardized difference, CI: confidence interval.
jrd-26-257f1.tif
Figure 2.
Meta-analysis of the relationship between the plasma/serum YKL-40 levels and rheumatoid arthritis (RA) in each ethnic group. Std diff: standardized difference, CI: confidence interval.
jrd-26-257f2.tif
Figure 3.
Meta-analysis of the correlation coefficient between the YKL-40 levels and DAS28 (A) and ESR (B). DAS28: 28-joint disease activity score, ESR: erythrocyte sedimentation rate, CI: confidence interval.
jrd-26-257f3.tif
Table 1.
Characteristics of individual studies included in the meta-analysis
Authors Country Ethnicity Number of patients YKL-40 level (mean) YKL-40, unit Matched for age and/or sex Data type
RA Control RA Control
Jafari-Nakhjavani et al., 2019 [12] Iran Arab 60 30 951.63 444.92 pg/mL Age, sex Original
Basok et al., 2014 [13] Turkey European 27 27 66.95 48.70 ng/mL Age, sex Original
Turkyilmaz et al., 2013 [6] Turkey European 42 35 124.30 67.20 ng/mL Age, sex Original
Kozakova et al., 2013 [7] Bulgaria European 25 40 246.17 84.19 ng/mL Age, sex Original
Nielsen et al., 2011 [8] Denmark European 308 605 86.00 46.00 ng/mL Age Original
Janckila et al., 2008 [10] USA North American 50 26 710.00 67.15 μ g/L Sex Original
Matsumoto et al.-1, 2001 [14] Japan Asian 56 26 197.00 68.75 pg/mL Age, sex Calculated*
Matsumoto et al.-2, 2001 [14] Japan Asian 16 14 220.00 77.25 pg/mL Age, sex Calculated*
Johansen et al., 2001 [9] USA North American 76 191 156.25 72.00 ug/L Age Calculated*
Vos et al., 2000 [11] Netherlands European 47 47 38.30 15.50 ng/mL Age, sex Original

RA: rheumatoid arthritis, USA: United States of America.

* The means±standard deviations were calculated from the medians and ranges.

Table 2.
Meta-analysis of the YKL-40 levels between the patients with RA and controls
Groups Population Number of studies Test of association Test of heterogeneity
SMD* 95% CI p-value Model p-value I2
All Overall 10 1.071 0.726∼1.417 <0.001 R <0.001 86.6
Ethnicity European 5 0.762 0.418∼1.127 <0.001 R <0.001 74.8
  Asian 2 1.353 0.921∼1.785 <0.001 F 0.173 55.8
  North American 2 1.552 0.565∼2.539 0.002 R 0.001 90.9
  Arab 1 0.954 0.494∼1.414 <0.001 NA NA NA
Matched for age and/or sex Both 7 0.937 0.554∼1.320 <0.001 R 0.001 73.8
Age or sex 3 2.951 1.389∼4.512 <0.001 R <0.001 98.4
Sample size n<100 8 0.943 0.610∼1.276 <0.001 R <0.001 70.2
  n>100 2 1.463 0.358∼2.568 0.029 R <0.001 97.5
Data type Original 7 0.824 0.572∼1.075 <0.001 R 0.011 63.7
  Calculated 3 1.703 1.081∼2.325 <0.001 R <0.001 76.5

RA: rheumatoid arthritis, SMD: standardized mean difference, CI: confidence interval, F: fixed effects model, R: random effects model, NA: not applicable.

* Magnitude of Cohen's d effect size (SMD): 0.2∼0.5, small effect; 0.5∼0.8, medium effect; ≥0.8, large effect.

Table 3.
Meta-analysis of the correlation coefficient between the YKL-40 level and RA activity (DAS28, ESR, and CRP level) and RF level
Comparison Number of studies Test of association Test of heterogeneity
Correlation coefficient 95% CI p-value Model l p-value I2
DAS28 4 0.381 0.044∼0.640 0.028 R 0.001 80.6
ESR 3 0.402 0.216∼0.560 <0.001 F 0.981 0
CRP level 2 0.531 0.269∼0.693 <0.001 F 0.513 0
RF level 3 0.341 0.176∼0.487 <0.001 F 0.113 54.1

RA: rheumatoid arthritis, DAS28: 28-joint disease activity score, ESR: erythrocyte sedimentation rate, CRP: C-reactive protein, RF: rheumatoid factor, CI: confidence interval, R: random effects model, F: fixed effects model.

TOOLS
Similar articles