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Homocysteine levels are independently associated with damage accrual in systemic lupus erythematosus patients from a Latin-American cohort

  • Paola A. Zeña-Huancas
  • Haydee Iparraguirre-López
  • Rocío V. Gamboa-Cárdenas
  • Cristina Reátegui-Sokolova
  • Francisco Zevallos-Miranda
  • Mariela Medina-Chinchon
  • Victor R. Pimentel-Quiroz
  • Claudia Elera-Fitzcarrald
  • Omar Sarmiento-Velasquez
  • Jorge M. Cucho-Venegas
  • José L. Alfaro-Lozano
  • Zoila J. Rodríguez-Bellido
  • César A. Pastor-Asurza
  • Risto A. Perich-Campos
  • Graciela S. Alarcón
  • Manuel F. Ugarte-Gil
Original Article
  • 50 Downloads

Abstract

Objective

To determine the impact of homocysteine levels on damage accrual in systemic lupus erythematosus (SLE) patients.

Methods

This longitudinal study was conducted in consecutive patients seen every 6 months at our Rheumatology Department since 2012. Patients with available homocysteine levels and who had at least one subsequent visit were included. Univariable and multivariable Cox regression models were done to determine if homocysteine levels were predictive of damage accrual as per the SLICC Damage Index (SDI). The multivariable model was adjusted for pertinent variables (age at diagnosis, gender, socioeconomic status, disease duration, disease activity (SLEDAI), Framingham score, antimalarial and immunosuppressive drug use, average daily dose, and exposure time to prednisone (PDN)).

Results

One hundred forty-five patients were included; their mean (SD) age at diagnosis was 43.70 (12.09) years, 136 (93.8%) were female, and nearly all were Mestizo. At baseline, disease duration was 7.55 (6.73) years; patients were followed for 3.54 (1.27) years. The SLEDAI was 5.60 (4.34), and the SDI 0.97 (1.35). The average daily PDN dose was 7.30 (5.78) mg/day and the time of PDN exposure was 7.36 (6.73) years. Mean homocysteine levels were 10.07 (3.71) μmol/L. The highest tertile of homocysteine levels predicted new damage accrual in the univariable and multivariable models [HR 1.78 (95% CI, 1.042–3.039); p = 0.035 and HR 2.045 (95% CI, 1.077–3.883); p = 0.029, respectively]. Increased levels (> 15 μmol/L) were found in 12 (8.3%) patients; 75 (51.7%) patients increased ≥ 1 SDI point.

Conclusion

In SLE patients, homocysteine levels predicted damage accrual independently of other well-known risk factors for such occurrence.

Keywords

Damage accrual Homocysteine Systemic lupus erythematosus 

Notes

Author contributions

All authors were involved in drafting or critically revising this manuscript for important intellectual content, and all authors approved the final version to be published. Drs. Paola A. Zeña Huancas and Manuel F. Ugarte-Gil have full access to all the study’s data and take responsibility for their integrity and the accuracy of the analyses performed.

Funding information

The Almenara Lupus Cohort is partially supported by three institutional grants from EsSalud (1483-GCGP-ESSALUD-2013, 1733-GCGP-ESSALUD-2014 and the 2015 Kaelin Prize 2015) and one from the Panamerican League of Associations for Rheumatology (PANLAR) (2015 PANLAR Prize).

Compliance with ethical standards

Disclosures

None.

Supplementary material

10067_2018_4389_MOESM1_ESM.docx (15 kb)
Supplementary Table 1 (DOCX 15 kb)

References

  1. 1.
    Manzi S, Meilahn EN, Rairie JE, Conte CG, Medsger TA Jr, Jansen-McWilliams L, D'Agostino RB, Kuller LH (1997) Age-specific incidence rates of myocardial infarction and angina in women with systemic lupus erythematosus: comparison with the Framingham Study. Am J Epidemiol 145:408–415CrossRefGoogle Scholar
  2. 2.
    Bruce IN, Urowitz MB, Gladman DD, Ibañez D, Steiner G et al (2003) Risk factors for coronary heart disease in women with systemic lupus erythematosus: the Toronto Risk Factor Study. Arthritis Rheum 48(11):3159–3167.  https://doi.org/10.1002/art.11296 CrossRefPubMedGoogle Scholar
  3. 3.
    Petri M, Roubenoff R, Dallal GE, Nadeau MR, Selhub J, Rosenberget IH (1996) Plasma homocysteine as a risk factor for atherothrombotic events in systemic lupus erythematosus. Lancet 348:1120–1124.  https://doi.org/10.1016/S0140-6736(96)03032-2 CrossRefPubMedGoogle Scholar
  4. 4.
    Svenungsson E, Jensen-Urstad K, Heimburger M, Silveira A, Hamsten A, de Faire U et al (2001) Risk factor for cardiovascular disease in systemic lupus erythematosus. Circulation 104:1887–1893CrossRefGoogle Scholar
  5. 5.
    Refai TMK, Al-Salem H, Nkansa-Dwamena D, Al-Salem MH (2002) Hyperhomocysteinaemia and risk of thrombosis in systemic lupus erythematosus patients. Clin Rheumatol 21:457–461.  https://doi.org/10.1007/s100670200115 CrossRefPubMedGoogle Scholar
  6. 6.
    Asanuma Y, Oeser A, Shintani AK, Turner E, Olsen N, Fazio S (2003) Premature coronary artery atherosclerosis in systemic lupus erythematosus. N Engl J Med 349:2407–2415.  https://doi.org/10.1056/NEJMoa035611 CrossRefPubMedGoogle Scholar
  7. 7.
    Petri M, Fu W (2016) Hyperhomocysteinemia in SLE [abstract 2792]. Arthritis Rheumatol 68(suppl 10):3744–3347Google Scholar
  8. 8.
    Moroni G, Novembrino C, Quaglini S, , De Giuseppe R, Gallelli B, Uva V, et al (2010) Oxidative stress and homocysteine metabolism in patients with lupus nephritis. Lupus 19(1):65–72. doi:  https://doi.org/10.1177/0961203309346906 CrossRefPubMedGoogle Scholar
  9. 9.
    Bonciani D, Antiga E, Bonciolini V, Verdelli A, Del Bianco E, Volpi W et al (2016) Homocysteine serum levels are increased and correlate with disease severity in patients with lupus erythematosus. Clin Exp Rheumatol 34(1):76–81PubMedGoogle Scholar
  10. 10.
    Škovierová H, Vidomanová E, Mahmood S, Sopková J, Drgová A, Červeňová T, Halašová E, Lehotský J (2016) The molecular and cellular effect of homocysteine metabolism imbalance on human health. Int J Mol Sci 17(10):1733.  https://doi.org/10.3390/ijms17101733 CrossRefPubMedCentralGoogle Scholar
  11. 11.
    Durand P, Prost M, Loreau N, Alberts MJ, Benavente O, Furie K et al (2011) Impaired homocysteine metabolism and atherothrombotic disease. Lab Investig 81(5):645–672CrossRefGoogle Scholar
  12. 12.
    Faraci FM, Lentz SR (2004) Hyperhomocysteinemia, oxidative stress, and cerebral vascular dysfunction. Stroke 35:345–347.  https://doi.org/10.1161/01.STR.0000115161.10646.67 CrossRefPubMedGoogle Scholar
  13. 13.
    Tam LS, Fan B, Li EK, Thomas GN, Yim SF, Haines CJ et al (2003) Patients with systemic lupus erythematosus show increased platelet activation and endothelial dysfunction induced by acute hyperhomocysteinemia. J Rheumatol 30(7):1479–1484PubMedGoogle Scholar
  14. 14.
    Skaggs BJ, Hahn BH, McMahon M (2012) Accelerated atherosclerosis in patients with SLE—mechanisms and management. Nat Rev Rheumatol 8(4):214–223.  https://doi.org/10.1038/nrrheum.2012.14 CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Lazzerini PE, Capecchi PL, Selvi E, Lorenzini S, Bisogno S, Galeazzi M, Laghi Pasini F (2007) Hyperhomocysteinemia, inflammation and autoimmunity. Autoimmun Rev 6:503–509.  https://doi.org/10.1016/j.autrev.2007.03.008 CrossRefPubMedGoogle Scholar
  16. 16.
    Schroecksnadel K, Frick B, Wirleitner B, Winkler C, Schennach H, Fuchs D et al (2004) Moderate hyperhomocysteinemia and immune activation. Curr Pharm Biotechnol 5:107–118.  https://doi.org/10.1515/CCLM.2003.221 CrossRefPubMedGoogle Scholar
  17. 17.
    Gualtierotti R, Biggioggero M, Penatti AE, Meroni PL (2010) Updating on the pathogenesis of systemic lupus erythematosus. Autoimmun Rev 10:3–7.  https://doi.org/10.1016/j.autrev.2010.09.007 CrossRefPubMedGoogle Scholar
  18. 18.
    Mak A, Cheung MW, Chiew HJ, Liu Y, Ho RC (2012) Global trend of survival and damage of systemic lupus erythematosus: meta-analysis and meta-regression of observational studies from the 1950s to 2000s. Semin Arthritis Rheum 41:830–839.  https://doi.org/10.1016/j.semarthrit.2011.11.002 CrossRefPubMedGoogle Scholar
  19. 19.
    Ugarte-Gil MF, Gamboa-Cárdenas RV, Zevallos F, Medina M, Cucho-Venegas JM, Perich-Campos RA, Alfaro-Lozano JL, Rodriguez-Bellido Z, Alarcón GS, Pastor-Asurza CA (2014) High prolactin levels are independently associated with damage accrual in systemic lupus erythematosus patients. Lupus 23:969–974.  https://doi.org/10.1177/0961203314531083 CrossRefPubMedGoogle Scholar
  20. 20.
    Hochberg MC (1997) Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 40(9):1725.  https://doi.org/10.1002/1529-0131(199709)40:9<1725::AID-ART29>3.0.CO;2-Y CrossRefGoogle Scholar
  21. 21.
    Méndez-Csstellano HM, Méndez MC (1994) Sociedad y Estratificación. Método Graffar-Méndez Castellano FUNDACREDESA, Caracas, pp 7–35Google Scholar
  22. 22.
    Gladman DD, Ibañez D, Urowitz MB (2002) Systemic lupus erythematosus disease activity index 2000. J Rheumatol 29(2):288–291PubMedGoogle Scholar
  23. 23.
    Gladman D, Ginzler E, Goldsmith C, Fortin P, Liang M, Urowitz M et al (1996) The development and initial validation of the Systemic Lupus International Collaborating Clinics/American College of Rheumatology damage index for systemic lupus erythematosus. Arthritis Rheum 39:363–369.  https://doi.org/10.1002/art.1780390303 CrossRefPubMedGoogle Scholar
  24. 24.
    Sabio JM, Vargas-Hitos JA, Martinez-Bordonado J, Navarrete-Navarrete N, Díaz-Chamorro A, Olvera-Porcel C, Zamora-Pasadas M, Jiménez-Alonso J (2014) Relationship between homocysteine levels and hypertension in systemic lupus erythematosus. Arthritis Care Res (Hoboken) 66(10):1528–1535.  https://doi.org/10.1002/acr.22340 CrossRefGoogle Scholar
  25. 25.
    Afeltra A, Vadacca M, Conti L, Mitterhofer AP, Ferri GM, Del Porto F et al (2005) Thrombosis in systemic lupus erythematosus: congenital and acquired risk factors. Arthritis Rheum 53(3):452–459.  https://doi.org/10.1002/art.21172 CrossRefPubMedGoogle Scholar
  26. 26.
    Guthikonda S, Haynes WG (2006) Homocysteine: role and implications in atherosclerosis. Curr Atheroscler Rep 8(2):100–106CrossRefGoogle Scholar
  27. 27.
    Malinow MR, Nieto FJ, Szklo M, Chambless LE, Bond G (1993) Carotid artery intimal-medial wall thickening and plasma homocyst(e)ine in asymptomatic adults. The atherosclerosis risk in communities study. Circulation 87(4):1107–1113CrossRefGoogle Scholar
  28. 28.
    Perna M, Roman M, Alpert D, Crow MK, Lockshin MD, Sammaritano L et al (2010) Relationship of asymmetric dimethylarginine and homocysteine to vascular aging in systemic lupus erythematosus patients. Arthritis Rheum 62(6):1718–1722.  https://doi.org/10.1002/art.27392 CrossRefPubMedGoogle Scholar
  29. 29.
    Roman MJ, Crow MK, Lockshin MD, Devereux RB, Paget SA, Sammaritano L, Levine DM, Davis A, Salmon JE (2007) Rate and determinants of progression of atherosclerosis in systemic lupus erythematosus. Arthritis Rheum 56:3412–3419.  https://doi.org/10.1002/art.22924 CrossRefPubMedGoogle Scholar
  30. 30.
    McMahon M, Skaggs BJ, Grossman JM, Sahakian L, FitzGerald J, Wong WK, Lourenco EV, Ragavendra N, Charles-Schoeman C, Gorn A, Karpouzas GA, Taylor MB, Watson KE, Weisman MH, Wallace DJ, Hahn BH (2014) A panel of biomarkers is associated with increased risk of the presence and progression of atherosclerosis in women with systemic lupus erythematosus. Arthritis Rheumatol 66(1):130–139.  https://doi.org/10.1002/art.38204 CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Castejon R, Jimenez-Ortiz C, Rosado S, Tutor-Ureta P, Mellor-Pita S, Yebra-Bango M et al (2016) Metabolic syndrome is associated with decreased circulating endothelial progenitor cells and increased arterial stiffness in systemic lupus erythematosus. Lupus 25(2):129–136.  https://doi.org/10.1177/0961203315603138 CrossRefPubMedGoogle Scholar
  32. 32.
    Desai A, Lankford HA, Warren JS (2001) Homocysteine augments cytokine-induced chemokine expression in human vascular smooth muscle cells: implications for atherogenesis. Inflammation 25:179–186CrossRefGoogle Scholar
  33. 33.
    Wang G, O K (2001) Homocysteine stimulates the expression of monocyte chemoattractant protein-1 receptor (CCR2) in human monocytes: possible involvement of oxygen free radical. Biochem J 357:233–240.  https://doi.org/10.1042/bj3570233 CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Tso TK, Huang WN, Hy H, Chang CK (2006) Relationship of plasma interleukin-18 concentrations to traditional and nontraditional cardiovascular factors in patients with systemic lupus erythematosus. Rheumatology 45:1148–1153.  https://doi.org/10.1093/rheumatology/kel082 CrossRefPubMedGoogle Scholar
  35. 35.
    Deng J, Lu S, Liu H, Liu B, Jiang C, Xu Q et al (2017) Homocysteine activates B cells via regulating PKM2-dependent metabolic reprogramming. J Immunol 98(1):170–183.  https://doi.org/10.4049/jimmunol.1600613 CrossRefGoogle Scholar
  36. 36.
    Padjas A, Undas A, Swadźba J, Musial J (2007) Antibodies to N-homocysteinylated albumin in patients with systemic lupus erythematosus. Pol Arch Med Wewn 117(3):80–85Google Scholar
  37. 37.
    Sabio J, Vargas J, Martínez J, Navarrete N, Díaz A, Olvera C et al (2016) Cumulated organ damage is associated with arterial stiffness in women with systemic lupus erythematosus irrespective of renal function. Clin Exp Rheumatol 34(1):53–57PubMedGoogle Scholar
  38. 38.
    Urowitz M, Ibañez D, Su J, Gladman D (2016) Modified Framingham risk factor score for systemic lupus erythematosus. J Rheumatol May 43(5):875–879.  https://doi.org/10.3899/jrheum.150983 CrossRefGoogle Scholar
  39. 39.
    Bruce IN, O'Keeffe AG, Farewell V, Hanly JG, Manzi S, Su L, Gladman DD, Bae SC, Sanchez-Guerrero J, Romero-Diaz J, Gordon C, Wallace DJ, Clarke AE, Bernatsky S, Ginzler EM, Isenberg DA, Rahman A, Merrill JT, Alarcón GS, Fessler BJ, Fortin PR, Petri M, Steinsson K, Dooley MA, Khamashta MA, Ramsey-Goldman R, Zoma AA, Sturfelt GK, Nived O, Aranow C, Mackay M, Ramos-Casals M, van Vollenhoven RF, Kalunian KC, Ruiz-Irastorza G, Lim S, Kamen DL, Peschken CA, Inanc M, Urowitz MB (2015) Factors associated with damage accrual in patients with systemic lupus erythematosus: results from the Systemic Lupus International Collaborating Clinics (SLICC) Inception Cohort. Ann Rheum Dis 74(9):1706–1713.  https://doi.org/10.1136/annrheumdis-2013-205171 CrossRefPubMedGoogle Scholar
  40. 40.
    Fu W, Petri M (2016) Treatment of homocysteine improves urine protein/Cr ratio in SLE [abstract 963]. Arthritis Rheumatol 68(suppl 10):1276–1277Google Scholar

Copyright information

© International League of Associations for Rheumatology (ILAR) 2018

Authors and Affiliations

  • Paola A. Zeña-Huancas
    • 1
  • Haydee Iparraguirre-López
    • 2
  • Rocío V. Gamboa-Cárdenas
    • 1
    • 3
  • Cristina Reátegui-Sokolova
    • 1
    • 4
  • Francisco Zevallos-Miranda
    • 1
  • Mariela Medina-Chinchon
    • 1
  • Victor R. Pimentel-Quiroz
    • 1
  • Claudia Elera-Fitzcarrald
    • 1
    • 5
  • Omar Sarmiento-Velasquez
    • 1
  • Jorge M. Cucho-Venegas
    • 1
  • José L. Alfaro-Lozano
    • 1
  • Zoila J. Rodríguez-Bellido
    • 1
    • 3
  • César A. Pastor-Asurza
    • 1
    • 3
  • Risto A. Perich-Campos
    • 1
    • 3
  • Graciela S. Alarcón
    • 6
  • Manuel F. Ugarte-Gil
    • 1
    • 5
  1. 1.Rheumatology DepartmentHospital Nacional Guillermo Almenara Irigoyen - EsSaludLimaPeru
  2. 2.Hematology Service, Clinical Pathology DepartmentHospital Guillermo Almenara Irigoyen - EsSaludLimaPeru
  3. 3.School of MedicineUniversidad Nacional Mayor de San MarcosLimaPeru
  4. 4.Unidad de Investigación para la Generación y Síntesis de Evidencias en SaludUniversidad San Ignacio de LoyolaLimaPeru
  5. 5.School of MedicineUniversidad Científica del SurLimaPeru
  6. 6.School of MedicineThe University of AlabamaBirminghamUSA

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