Zeitschrift für Rheumatologie

, Volume 77, Issue 3, pp 240–248 | Cite as

Correlation between circulating VEGF levels and disease activity in rheumatoid arthritis: a meta-analysis

Originalie

Abstract

Objective

To systematically review evidence regarding the relationship between circulating vascular endothelial growth factor (VEGF) levels and rheumatoid arthritis (RA), the correlation between serum VEGF levels and RA activity, and the association between VEGF polymorphisms and RA susceptibility.

Methods

We conducted a meta-analysis of the serum/plasma VEGF levels in patients with RA and controls, the correlation coefficients between the circulating VEGF levels and disease activity in patients with RA, and the association between VEGF −2578 A/C, −634 C/G, +936 T/C, and −1154 A/G polymorphisms and the risk for RA.

Results

In total, 13 studies including 2508 patients with RA and 2489 controls were included. Meta-analysis revealed that VEGF level was significantly higher in the RA than in the control group (standard mean difference [SMD] = 1.480, 95% confidence interval [CI] = 0.71–2.241, p = 1.4 × 10−4). Stratification by adjustment for age and gender revealed significantly higher VEGF levels for the adjustment and non-adjustment groups in the RA group (SMD = 1.360, 95% CI = 0.445–2.276, p = 0.004; SMD = 1.557, 95% CI = 0.252–2.861, p = 0.019, respectively). Meta-analysis of correlation coefficients showed a significantly positive correlation between circulating VEGF levels and disease activity in RA, and between circulating VEGF and C‑reactive protein levels. However, no association was found between RA and the VEGF −2578 A/C, −634 C/G, +936 T/C, and −1154 A/G polymorphisms.

Conclusion

Our meta-analysis revealed significantly higher circulating VEGF levels in patients with RA and a positive correlation between VEGF levels and disease activity in RA, but no association between the VEGF −2578 A/C, −634 C/G, +936 T/C, and −1154 A/G polymorphisms and the development of RA.

Keywords

VEGF Level Polymorphism Rheumatoid arthritis 

Korrelation zwischen dem Spiegel des zirkulierenden vaskulären endothelialen Wachstumsfaktors und Krankheitsaktivität bei rheumatoider Arthritis: eine Metaanalyse

Zusammenfassung

Ziel der Arbeit

Ziel war eine systematische Übersicht über die Evidenz für eine Beziehung zwischen den Werten für den zirkulierenden vaskulären endothelialen Wachstumsfaktor (VEGF) und rheumatoider Arthritis (RA), die Korrelation zwischen Serum-VEGF-Werten und RA-Aktivität sowie den Zusammenhang zwischen VEGF-Polymorphismen und der Suszeptibilität für RA.

Methoden

Die Autoren führten eine Metaanalyse durch zu den Serum-/Plasma-VEGF-Werten bei Patienten mit RA und Kontrollen, zu den Korrelationskoeffizienten zwischen den Spiegeln des zirkulierenden VEGF und der Krankheitsaktivität bei Patienten mit RA und zu dem Zusammenhang zwischen den VEGF-Polymorphismen −2578 A/C, −634 C/G, +936 T/C und −1154 A/G und dem Risiko für eine RA.

Ergebnisse

Insgesamt wurden 13 Studien mit 2508 RA-Patienten und 2489 Kontrollen in die Auswertung einbezogen. Die Metaanalyse ergab, dass der VEGF-Wert in der RA-Gruppe signifikant höher war als in der Kontrollgruppe (Standardmittelwertdifferenz, „standard mean difference“, SMD: 1,480; 95%-Konfidenzintervall, 95%-KI: 0,71–2,241; p = 1,4 × 10−4). Die Stratifizierung unter Berücksichtigung des Alters und Geschlechts erbrachte in der RA-Gruppe signifikant höhere VEGF-Werte für die Gruppen mit und ohne Adjustierung als bei den Kontrollen (SMD: 1,360; 95%-KI: 0,445–2,276; p = 0,004 bzw. SMD: 1,557; 95%-KI: 0,252–2,861; p = 0,019). Die Metaanalyse der Korrelationskoeffizienten zeigte eine signifikant positive Korrelation zwischen den Werten für den zirkulierenden VEGF und der Krankheitsaktivität bei RA sowie zwischen den Spiegeln des zirkulierenden VEGF und den Werten für C‑reaktives Protein. Es wurde jedoch kein Zusammenhang zwischen RA und den VEGF-Polymorphismen −2578 A/C, −634 C/G, +936 T/C und −1154 A/G festgestellt.

Schlussfolgerung

Die vorliegende Metaanalyse ergab bei RA-Patienten signifikant höhere Werte für den zirkulierenden VEGF und eine positive Korrelation zwischen VEGF-Werten und RA-Krankheitsaktivität, aber keinen Zusammenhang zwischen den VEGF-Polymorphismen −2578 A/C, −634 C/G, +936 T/C und −1154 A/G und dem Auftreten einer RA.

Schlüsselwörter

VEGF Wert Polymorphismus Rheumatoide Arthritis 

Notes

Acknowledgements

This study was supported in part by a grant of the Korea Healthcare technology R&D Project, Ministry for Health and Welfare, Republic of Korea (HI15C2958).

Compliance with ethical guidelines

Conflict of interest

Y.H. Lee and S.-C. Bae declare that they have no financial or non-financial conflict of interest.

This article does not contain any studies with human participants or animals performed by any of the authors.

References

  1. 1.
    Harris ED Jr. (1990) Rheumatoid arthritis. Pathophysiology and implications for therapy. N Engl J Med 322(18):1277–1289CrossRefPubMedGoogle Scholar
  2. 2.
    Mellado M, Martínez-Muñoz L, Cascio G, Lucas P, Pablos JL, Rodríguez-Frade JM (2015) T cell migration in rheumatoid arthritis. Front Immunol 6. doi: 10.3389/fimmu.2015.00384 PubMedPubMedCentralGoogle Scholar
  3. 3.
    Paleolog EM (2009) The vasculature in rheumatoid arthritis: cause or consequence? Int J Exp Pathol 90(3):249–261CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Ferrara N (2004) Vascular endothelial growth factor: basic science and clinical progress. Endocr Rev 25(4):581–611CrossRefPubMedGoogle Scholar
  5. 5.
    Hamamichi Y, Ichida F, Yu X, Hirono KI, Uese KI, Hashimoto I et al (2001) Neutrophils and mononuclear cells express vascular endothelial growth factor in acute Kawasaki disease: its possible role in progression of coronary artery lesions. Pediatr Res 49(1):74–80CrossRefPubMedGoogle Scholar
  6. 6.
    Neufeld G, Cohen T, Gengrinovitch S, Poltorak Z (1999) Vascular endothelial growth factor (VEGF) and its receptors. FASEB J 13(1):9–22CrossRefPubMedGoogle Scholar
  7. 7.
    Carmeliet P (2005) Angiogenesis in life, disease and medicine. Nature 438(7070):932–936CrossRefPubMedGoogle Scholar
  8. 8.
    Kasama T, Kobayashi K, Yajima N, Shiozawa F, Yoda Y, Takeuchi H et al (2000) Expression of vascular endothelial growth factor by synovial fluid neutrophils in rheumatoid arthritis (RA). Clin Exp Immunol 121(3):533–538CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Ballara S, Taylor PC, Reusch P, Marmé D, Feldmann M, Maini RN et al (2001) Raised serum vascular endothelial growth factor levels are associated with destructive change in inflammatory arthritis. Arthritis Rheum 44(9):2055–2064CrossRefPubMedGoogle Scholar
  10. 10.
    Paradowska-Gorycka A, Pawlik A, Romanowska-Prochnicka K, Haladyj E, Malinowski D, Stypinska B et al (2016) Relationship between VEGF gene polymorphisms and serum VEGF protein levels in patients with rheumatoid arthritis. PLOS ONE 11(8):e0160769CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Yi JP, Wu YZ, Yu N, Yu ZW, Xie FY, Yuan Q (2016) VEGF gene polymorphisms affect serum protein levels and alter disease activity and synovial lesions in rheumatoid arthritis. Med Sci Monit 22:316–324CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Schroeder M, Viezens L, Fuhrhop I, Ruther W, Schaefer C, Schwarzloh B et al (2013) Angiogenic growth factors in rheumatoid arthritis. Rheumatol Int 33(2):523–527CrossRefPubMedGoogle Scholar
  13. 13.
    Westra J, de Groot L, Plaxton SL, Brouwer E, Posthumus MD, Kallenberg CG et al (2011) Angiopoietin-2 is highly correlated with inflammation and disease activity in recent-onset rheumatoid arthritis and could be predictive for cardiovascular disease. Rheumatology (Oxford) 50(4):665–673CrossRefGoogle Scholar
  14. 14.
    Kuryliszyn-Moskal A, Klimiuk PA, Sierakowski S, Ciolkiewicz M (2006) A study on vascular endothelial growth factor and endothelin-1 in patients with extra-articular involvement of rheumatoid arthritis. Clin Rheumatol 25(3):314–319CrossRefPubMedGoogle Scholar
  15. 15.
    Klimiuk PA, Sierakowski S, Latosiewicz R, Cylwik JP, Cylwik B, Skowronski J et al (2002) Soluble adhesion molecules (ICAM-1, VCAM-1, and E‑selectin) and vascular endothelial growth factor (VEGF) in patients with distinct variants of rheumatoid synovitis. Ann Rheum Dis 61(9):804–809CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Sone H, Sakauchi M, Takahashi A, Suzuki H, Inoue N, Iida K et al (2001) Elevated levels of vascular endothelial growth factor in the sera of patients with rheumatoid arthritis correlation with disease activity. Life Sci 69(16):1861–1869CrossRefPubMedGoogle Scholar
  17. 17.
    Kikuchi K, Kubo M, Kadono T, Yazawa N, Ihn H, Tamaki K (1998) Serum concentrations of vascular endothelial growth factor in collagen diseases. Br J Dermatol 139(6):1049–1051CrossRefPubMedGoogle Scholar
  18. 18.
    Zhang Y, Qiu H, Zhang H, Wang L, Zhuang C, Liu R (2013) Vascular endothelial growth factor A (VEGFA) polymorphisms in Chinese patients with rheumatoid arthritis. Scand J Rheumatol 42(5):344–348CrossRefPubMedGoogle Scholar
  19. 19.
    Konenkov VI, Korolev MA, Shevchenko AV, Prokofyev VF, Ubshaeva YB, Sokolova OS et al (2013) Genetic factors of angiogenic dysregulation in women with rheumatoid arthritis. Ter Arkh 85(5):16–23PubMedGoogle Scholar
  20. 20.
    Lv HZ, Lin T, Xia LP, Shen H, Zhu XY, Zhang JT et al (2011) Vascular endothelial growth factor gene polymorphisms and rheumatoid arthritis. J Investig Med 59(3):593–598CrossRefPubMedGoogle Scholar
  21. 21.
    Rueda B, Gonzalez-Gay MA, Lopez-Nevot MA, Garcia A, Fernandez-Arquero M, Balsa A et al (2005) Analysis of vascular endothelial growth factor (VEGF) functional variants in rheumatoid arthritis. Hum Immunol 66(8):864–868CrossRefPubMedGoogle Scholar
  22. 22.
    Han SW, Kim GW, Seo JS, Kim SJ, Sa KH, Park JY et al (2004) VEGF gene polymorphisms and susceptibility to rheumatoid arthritis. Rheumatology (Oxford) 43(9):1173–1177CrossRefGoogle Scholar
  23. 23.
    Lee YH, Woo JH, Choi SJ, Ji JD, Song GG (2010) Induction and maintenance therapy for lupus nephritis: a systematic review and meta-analysis. Lupus 19(6):703–710CrossRefPubMedGoogle Scholar
  24. 24.
    Lee YH, Woo JH, Choi SJ, Ji JD, Song GG (2009) Association of programmed cell death 1 polymorphisms and systemic lupus erythematosus: a meta-analysis. Lupus 18(1):9–15CrossRefPubMedGoogle Scholar
  25. 25.
    Lee YH, Woo JH, Choi SJ, Ji JD, Song GG (2010) Associations between osteoprotegerin polymorphisms and bone mineral density: a meta-analysis. Mol Biol Rep 37(1):227–234CrossRefPubMedGoogle Scholar
  26. 26.
    Hozo SP, Djulbegovic B, Hozo I (2005) Estimating the mean and variance from the median, range, and the size of a sample. Bmc Med Res Methodol 5:13CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Ridout KK, Ridout SJ, Price LH, Sen S, Tyrka AR (2016) Depression and telomere length: A meta-analysis. J Affect Disord 191:237–247CrossRefPubMedGoogle Scholar
  28. 28.
    Egger M, Smith GD, Phillips AN (1997) Meta-analysis: principles and procedures. BMJ 315(7121):1533–1537CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    DerSimonian R, Laird N (1986) Meta-analysis in clinical trials. Control Clin Trials 7(3):177–188CrossRefPubMedGoogle Scholar
  30. 30.
    Higgins JP, Thompson SG (2002) Quantifying heterogeneity in a meta-analysis. Stat Med 21(11):1539–1558CrossRefPubMedGoogle Scholar
  31. 31.
    Egger M, Davey Smith G, Schneider M, Minder C (1997) Bias in meta-analysis detected by a simple, graphical test. BMJ 315(7109):629–634CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Jackson J, Minton J, Ho M, Wei N, Winkler J (1997) Expression of vascular endothelial growth factor in synovial fibroblasts is induced by hypoxia and interleukin 1beta. J Rheumatol 24(7):1253–1259PubMedGoogle Scholar
  33. 33.
    Yi J‑P, Wu Y‑Z, Yu N, Yu Z‑W, Xie F‑Y, Yuan Q (2016) VEGF gene polymorphisms affect serum protein levels and alter disease activity and synovial lesions in rheumatoid arthritis. Med Sci Monit Int Med J Exp Clin Res 22:316Google Scholar
  34. 34.
    Ramonda R, Modesti V, Ortolan A, Scanu A, Bassi N, Oliviero F et al (2013) Serological markers in psoriatic arthritis: promising tools. Exp Biol Med 238(12):1431–1436CrossRefGoogle Scholar
  35. 35.
    Koukourakis MI, Papazoglou D, Giatromanolaki A, Bougioukas G, Maltezos E, Sivridis E (2004) VEGF gene sequence variation defines VEGF gene expression status and angiogenic activity in non-small cell lung cancer. Lung Cancer 46(3):293–298CrossRefPubMedGoogle Scholar
  36. 36.
    Shahbazi M, Fryer AA, Pravica V, Brogan IJ, Ramsay HM, Hutchinson IV et al (2002) Vascular endothelial growth factor gene polymorphisms are associated with acute renal allograft rejection. J Am Soc Nephrol 13(1):260–264PubMedGoogle Scholar
  37. 37.
    Watson CJ, Webb NJ, Bottomley MJ, Brenchley PE (2000) Identification of polymorphisms within the vascular endothelial growth factor (VEGF) gene: correlation with variation in VEGF protein production. Cytokine 12(8):1232–1235CrossRefPubMedGoogle Scholar
  38. 38.
    Walker E, Hernandez AV, Kattan MW (2008) Meta-analysis: Its strengths and limitations. Cleve Clin J Med 75(6):431–439CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  1. 1.Division of Rheumatology, Department of Internal MedicineKorea University College of MedicineSeoulKorea (Republic of)
  2. 2.Department of RheumatologyHanyang University Hospital for Rheumatic DiseasesSeoulKorea (Republic of)

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