THE IMPACT OF HOMOCYSTEINE IN LUPUS ERYTHEMATOSUS: A LINK OF INFLAMMATION, SKIN AND CARDIOVASCULAR RISK

Authors

  • Nora Pollozhani University Clinic for Dermatology, Faculty of Medicine, Ss. Cyril and Methodius University in Skopje, Republic of North Macedonia
  • Nevenka Adjievska University Clinic for Dermatology, Faculty of Medicine, Ss. Cyril and Methodius University in Skopje, Republic of North Macedonia
  • Viktor Simeonovski University Clinic for Dermatology, Faculty of Medicine, Ss. Cyril and Methodius University in Skopje, Republic of North Macedonia
  • Rufije Ramuka Zyberi University Clinic for Dermatology, Faculty of Medicine, Ss. Cyril and Methodius University in Skopje, Republic of North Macedonia
  • Maja Dimova University Clinic for Dermatology, Faculty of Medicine, Ss. Cyril and Methodius University in Skopje, Republic of North Macedonia
  • Sevxhane Zhaku University Clinic for Dermatology, Faculty of Medicine, Ss. Cyril and Methodius University in Skopje, Republic of North Macedonia
  • Katerina Damevska University Clinic for Dermatology, Faculty of Medicine, Ss. Cyril and Methodius University in Skopje, Republic of North Macedonia

Keywords:

Homocystein, Lupus Erythematosus, Inflammation, Cardiovascular Risk

Abstract

Lupus erythematosus (LE) is a complex autoimmune disease with diverse clinical manifestations, ranging from systemic involvement to cutaneous lesions. Cutaneous lupus erythematosus (CLE) is the second most common manifestation of LE, resulting in disfiguring scaring, hair loss and significant burden for the patients’ quality of life.

Elevated homocysteine (Hcy) levels, or hyperhomocysteinemia (HHcy), are observed in both SLE and CLE. Hcy contributes to endothelial dysfunction, thrombosis risk, and immune activation through pro-inflammatory cytokine release, oxidative stress, and vascular damage. Additionally, it disrupts T-cell function and epigenetic regulation, further exacerbating autoimmune responses.

Several factors can cause HHcy, including genetics (such as MTHFR mutations), kidney problems, metabolic disorders, certain medications, and deficiencies in B vitamins (B6, B9, B12). Since B vitamins help regulate Hcy, a poor diet or an inability to properly absorb nutrients may contribute to higher Hcy levels in lupus patients. Additionally, HHcy is a recognized risk factor for cardiovascular disease (CVD), a major cause of morbidity in lupus patients. Increased Hcy levels contribute to arterial stiffness, endothelial injury, and thrombotic complications, elevating the risk of atherosclerosis, stroke, and myocardial infarction.

Hcy may act as a biomarker for disease severity and vascular risk in CLE. Interventions such as B-vitamin supplementation and lifestyle changes could offer therapeutic benefits. However, further research is needed to clarify its role in CLE pathogenesis and its potential for clinical management.

References

Werth VP. Clinical manifestations of cutaneous lupus erythematosus. Autoimmun Rev. 2005 Jun;4(5):296–302. doi: 10.1016/j.autrev.2005.01.003

Durosaro O, Davis MD, Reed KB, Rohlinger AL. Incidence of cutaneous lupus erythematosus, 1965–2005: a population based study. Arch Dermatol. 2009 Mar;145(3):249–53. doi: 10.1001/archdermatol.2009.21

Grönhagen CM, Fored CM, Granath F, Nyberg F. Cutaneous lupus erythematosus and the association with systemic lupus erythematosus: a population based cohort of 1 088 patients in Sweden. Br J Dermatol. 2011 Jun;164(6):1335–41. doi: 10.1111/j.1365-2133.2011.10272.x

Elmgren J, Nyberg F. Clinical aspects of cutaneous lupus erythematosus. Front Med (Lausanne). 2023 Jan 9;9:984229. doi: 10.3389/fmed.2022.984229

Gilliam JN, Sontheimer RD. Distinctive cutaneous subsets in the spectrum of lupus erythematosus. J Am Acad Dermatol. 1981 Apr;4(4):471–5. doi: 10.1016/S0190-9622(81)80261-7

Tebbe B, Orfanos CE. Epidemiology and socioeconomic impact of skin disease in lupus erythematosus. Lupus. 1997;6(2):96–104. doi: 10.1177/096120339700600204

Petri M, Orbai AM, Alarcón GS, et al. Derivation and validation of the Systemic Lupus International Collaborating Clinics classification criteria for systemic lupus erythematosus. Arthritis Rheum. 2012 Aug;64(8):2677–86. doi: 10.1002/art.34473

Erazo Martínez V, Tobón GJ, Cañas CA. Circulating and skin biopsy-present cytokines related to the pathogenesis of cutaneous lupus erythematosus. Autoimmun Rev. 2023 Feb;22(2):103262. doi: 10.1016/j.autrev.2022.103262

Okon LG, Werth VP. Cutaneous lupus erythematosus: diagnosis and treatment. Best Pract Res Clin Rheumatol. 2013 Jun;27(3):391–404. doi: 10.1016/j.berh.2013.07.008

Chan LS, Vanderlugt CJ, Hashimoto T, Nishikawa T, Zone JJ, Black MM, Wojnarowska F, Stevens SR, Chen M, Fairley JA, Woodley DT, Miller SD, Gordon KB. Epitope spreading: lessons from autoimmune skin diseases. J Invest Dermatol. 1998 Feb;110(2):103–9. doi: 10.1046/j.1523-1747.1998.00107.x

Wenzel J. Cutaneous lupus erythematosus: new insights into pathogenesis and therapeutic strategies. Nat Rev Rheumatol. 2019 Sep;15(9):519–532. doi: 10.1038/s41584-019-0272-0

McCully KS. Homocysteine and vascular disease. Nat Med. 1996 Apr;2(4):386–9. doi: 10.1038/nm0496-386

Schalinske KL, Smazal AL. Homocysteine imbalance: a pathological metabolic marker. Adv Nutr. 2012 Nov 1;3(6):755–62. doi: 10.3945/an.112.002758

Wenzel J. Cutaneous lupus erythematosus: new insights into pathogenesis and therapeutic strategies. Nat Rev Rheumatol. 2019 Sep;15(9):519–532. doi: 10.1038/s41584-019-0272-0

Assefa Z, Van Laethem A, Garmyn M, Agostinis P. Ultraviolet radiation-induced apoptosis in keratinocytes: on the role of cytosolic factors. Biochim Biophys Acta. 2005 Jul 25;1755(2):90–106. doi: 10.1016/j.bbcan.2005.04.001

Grönhagen CM, Nyberg F. Cutaneous lupus erythematosus: An update. Indian Dermatol Online J. 2014 Jan;5(1):7–13. doi: 10.4103/2229-5178.126020

Sarkar MK, Hile GA, Tsoi LC, Xing X, Liu J, Liang Y, Berthier CC, Swindell WR, Patrick MT, Shao S, Tsou PS, Uppala R, Beamer MA, Srivastava A, Bielas SL, Harms PW, Getsios S, Elder JT, Voorhees JJ, Gudjonsson JE, Kahlenberg JM. Photosensitivity and type I IFN responses in cutaneous lupus are driven by epidermal-derived interferon kappa. Ann Rheum Dis. 2018 Nov;77(11):1653–1664. doi: 10.1136/annrheumdis-2018-213197

Psarras A, Emery P, Vital EM. Type I interferon-mediated autoimmune diseases: pathogenesis, diagnosis and targeted therapy. Rheumatology (Oxford). 2017 Oct;56(10):1662–1675. doi: 10.1093/rheumatology/kew431

Hile GA, Werth VP. Understanding the Role of Type I Interferons in Cutaneous Lupus and Dermatomyositis: Toward Better Therapeutics. Arthritis Rheumatol. 2025 Jan;77(1):1–11. doi: 10.1002/art.42983

Ivashkiv LB, Donlin LT. Regulation of type I interferon responses. Nat Rev Immunol. 2014 Jan;14(1):36–49. doi: 10.1038/nri3581

Damsky W, King BA. JAK inhibitors in dermatology: The promise of a new drug class. J Am Acad Dermatol. 2017 Apr;76(4):736–744. doi: 10.1016/j.jaad.2016.12.005

Banchereau R, Hong S, Cantarel B, Baldwin N, Baisch J, Edens M, Cepika AM, Acs P, Turner J, Anguiano E, Vinod P, Kahn S, Obermoser G, Blankenship D, Wakeland E, Nassi L, Gotte A, Punaro M, Liu YJ, Banchereau J, Rossello Urgell J, Wright T, Pascual V. Personalized Immunomonitoring Uncovers Molecular Networks that Stratify Lupus Patients. Cell. 2016 Apr 21;165(3):551–65. doi: 10.1016/j.cell.2016.03.008

Niewold TB. Type I interferon in human autoimmunity. Front Immunol. 2014 Jun 30;5:306. doi: 10.3389/fimmu.2014.00306

Furie R, Khamashta M, Merrill JT, Werth VP, Kalunian K, Brohawn P, Illei GG, Drappa J, Wang L, Yoo S; CD1013 Study Investigators. Anifrolumab, an Anti Interferon α Receptor Monoclonal Antibody, in Moderate to Severe Systemic Lupus Erythematosus. Arthritis Rheumatol. 2017 Feb;69(2):376–386. doi: 10.1002/art.39962

Hu FQ, Zhang YP, Yin J, Tang ZQ, Han YF, Shi ZR, Tan GZ, Wang L. Characterization of autoantibodies and cytokines related to cutaneous lupus erythematosus. Lupus. 2021 Feb;30(2):315–319. doi: 10.1177/0961203320967759

Somers EC, Zhao W, Lewis EE, Wang L, Wing JJ, Sundaram B, Kazerooni EA, McCune WJ, Kaplan MJ. Type I interferons are associated with subclinical markers of cardiovascular disease in a cohort of systemic lupus erythematosus patients. PLoS One. 2012;7(5):e37000. doi: 10.1371/journal.pone.0037000

Banchereau J, Pascual V. Type I interferon in systemic lupus erythematosus and other autoimmune diseases. Immunity. 2006 Sep;25(3):383–92. doi: 10.1016/j.immuni.2006.08.010

Li T, Chen Y, Li J, Yang X, Zhang H, Qin X, Hu Y, Mo Z. Serum Homocysteine Concentration Is Significantly Associated with Inflammatory/Immune Factors. PLoS One. 2015 Sep 14;10(9):e0138099. doi: 10.1371/journal.pone.0138099

Tanasescu C, Balanescu E, Balanescu P, Olteanu R, Badea C, Grancea C, Vagu C, Bleotu C, Ardeleanu C, Georgescu A. IL 17 in cutaneous lupus erythematosus. Eur J Intern Med. 2010 Jun;21(3):202–7. doi: 10.1016/j.ejim.2010.03.004

Li H, Dang Y, Yan Y. Serum interleukin 17 A and homocysteine levels in children with autism. BMC Neurosci. 2024 Mar 12;25(1):17. doi: 10.1186/s12868-024-00860-5

Lovato BH, Fogagnolo L, Souza EM, Silva LJBD, Velho PENF, Cintra ML, Teixeira F. IL 1β and IL 17 in cutaneous lupus erythematous skin biopsies: could immunohistochemicals indicate a tendency towards systemic involvement? An Bras Dermatol. 2024 Jan–Feb;99(1):66–71. doi: 10.1016/j.abd.2023.02.007

Wang N, Tang H, Wang X, Wang W, Feng J. Homocysteine upregulates interleukin 17A expression via NSun2 mediated RNA methylation in T lymphocytes. Biochem Biophys Res Commun. 2017 Nov 4;493(1):94–99. doi: 10.1016/j.bbrc.2017.09.069

Kumar A, Palfrey HA, Pathak R, Kadowitz PJ, Gettys TW, Murthy SN. The metabolism and significance of homocysteine in nutrition and health. Nutr Metab (Lond). 2017 Dec 22;14:78. doi: 10.1186/s12986-017-0233-z

Austin RC, Lentz SR, Werstuck GH. Role of hyperhomocysteinemia in endothelial dysfunction and atherothrombotic disease. Cell Death Differ. 2004 Jul;11 Suppl 1:S56–64. doi: 10.1038/sj.cdd.4401451

Tyagi N, Sedoris KC, Steed M, Ovechkin AV, Moshal KS, Tyagi SC. Mechanisms of homocysteine induced oxidative stress. Am J Physiol Heart Circ Physiol. 2005 Dec;289(6):H2649–56. doi: 10.1152/ajpheart.00548.2005

Mittal M, Siddiqui MR, Tran K, Reddy SP, Malik AB. Reactive oxygen species in inflammation and tissue injury. Antioxid Redox Signal. 2014 Mar 1;20(7):1126–67. doi: 10.1089/ars.2012.5149

Esse R, Barroso M, Tavares de Almeida I, Castro R. The Contribution of Homocysteine Metabolism Disruption to Endothelial Dysfunction: State of the Art. Int J Mol Sci. 2019 Feb 17;20(4):867. doi: 10.3390/ijms20040867

Wang X, Khalil RA. Matrix Metalloproteinases, Vascular Remodeling, and Vascular Disease. Adv Pharmacol. 2018;81:241–330. doi: 10.1016/bs.apha.2017.08.002

Pushpakumar S, Kundu S, Sen U. Endothelial dysfunction: the link between homocysteine and hydrogen sulfide. Curr Med Chem. 2014;21(32):3662–72. doi: 10.2174/0929867321666140706142335

Calvani N, Richards HB, Tucci M, Pannarale G, Silvestris F. Up regulation of IL 18 and predominance of a Th1 immune response is a hallmark of lupus nephritis. Clin Exp Immunol. 2004 Oct;138(1):171–8. doi: 10.1111/j.1365-2249.2004.02588.x

Moro García MA, Mayo JC, Sainz RM, Alonso Arias R. Influence of Inflammation in the Process of T Lymphocyte Differentiation: Proliferative, Metabolic, and Oxidative Changes. Front Immunol. 2018 Mar 1;9:339. doi: 10.3389/fimmu.2018.00339

Zhang L, Jin Y, Wang R, et al. Homocysteine activates T lymphocytes through the p38 MAPK pathway. Arch Med Res. 2010;41(7):558–65. doi: 10.1016/j.arcmed.2010.08.006

Mansoor MA, Seljeflot I, Arnesen H, Knudsen A, Bates CJ, Mishra G, Larsen TW. Endothelial cell adhesion molecules in healthy adults during acute hyperhomocysteinemia and mild hypertriglyceridemia. Clin Biochem. 2004 May;37(5):408–14. doi: 10.1016/j.clinbiochem.2004.01.003

Yuan D, Chu J, Lin H, Zhu G, Qian J, Yu Y, Yao T, Ping F, Chen F, Liu X. Mechanism of homocysteine mediated endothelial injury and its consequences for atherosclerosis. Front Cardiovasc Med. 2023 Jan 16;9:1109445. doi: 10.3389/fcvm.2022.1109445

Düsing P, Zietzer A, Goody PR, Hosen MR, Kurts C, Nickenig G, Jansen F. Vascular pathologies in chronic kidney disease: pathophysiological mechanisms and novel therapeutic approaches. J Mol Med. 2021 Mar;99(3):335–348. doi: 10.1007/s00109-021-02037-7

Yang Q, Lu Y, Deng Y, Xu J, Zhang X. Homocysteine level is positively and independently associated with serum creatinine and urea nitrogen levels in old male patients with hypertension. Sci Rep. 2020 Oct 22;10(1):18050. doi: 10.1038/s41598-020-75073-x

Tawfik A, Elsherbiny NM, Zaidi Y, Rajpurohit P. Homocysteine and Age Related Central Nervous System Diseases: Role of Inflammation. Int J Mol Sci. 2021 Jun 10;22(12):6259. doi: 10.3390/ijms2212625.

Fang P, Zhang D, Cheng Z, Yan C, Jiang X, Kruger WD, Meng S, Arning E, Bottiglieri T, Choi ET, Han Y, Yang XF, Wang H. Hyperhomocysteinemia potentiates hyperglycemia induced inflammatory monocyte differentiation and atherosclerosis. Diabetes. 2014 Dec;63(12):4275–90. doi: 10.2337/db14-0809

Kamat PK, Vacek JC, Kalani A, Tyagi N. Homocysteine Induced Cerebrovascular Dysfunction: A Link to Alzheimer’s Disease Etiology. Open Neurol J. 2015 Jun 24;9:9–14. doi: 10.2174/1874205X01509010009

Zhang CE, Wei W, Liu YH, Peng JH, Tian Q, Liu GP, Zhang Y, Wang JZ. Hyperhomocysteinemia increases beta amyloid by enhancing expression of gamma-secretase and phosphorylation of amyloid precursor protein in rat brain. Am J Pathol. 2009 Apr;174(4):1481–91. doi: 10.2353/ajpath.2009.081036

Drenkard C, Barbour KE, Greenlund KJ, Lim SS. The Burden of Living With Cutaneous Lupus Erythematosus. Front Med. 2022;9:897987. doi: 10.3389/fmed.2022.897987

Tabbarah S, Sulaiman H, Ansah Owusu F, Rajeev Joshi M, Marepalli NR, Pino N, Saleem Azam S, Ali Ahmed A, Abraham Suárez Álvarez J. Shared Pathophysiology of Inflammatory Bowel Disease and Psoriasis: Unraveling the Connection. Cureus. 2024 Sep 25;16(9):e70148. doi: 10.7759/cureus.70148

Aviña Zubieta JA, Choi HK, Sadatsafavi M, Etminan M, Esdaile JM, Lacaille D. Risk of cardiovascular mortality in patients with rheumatoid arthritis: a meta analysis of observational studies. Arthritis Rheum. 2008;59(12):1690–7. doi: 10.1002/art.24092

Castellon X, Bogdanova V. Chronic Inflammatory Diseases and Endothelial Dysfunction. Aging Dis. 2016 Jan 2;7(1):81–9. doi: 10.14336/AD.2015.0803

Corona Meraz FI, Vázquez Del Mercado M, Sandoval García F, Robles De Anda JA, Tovar Cuevas AJ, Rosales Gómez RC, Guzmán Ornelas MO, González Inostroz D, Peña Nava M, Martín Márquez BT. Biomarkers in Systemic Lupus Erythematosus along with Metabolic Syndrome. J Clin Med. 2024 Mar 29;13(7):1988. doi: 10.3390/jcm13071988

Sabio JM, Zamora Pasadas M, Jiménez Jáimez J, Albadalejo F, Vargas Hitos J, Rodríguez del Aguila MD, Hidalgo Tenorio C, Gonzalez Gay MA, Jimenez Alonso J. Metabolic syndrome in patients with systemic lupus erythematosus from Southern Spain. Lupus. 2008 Sep;17(9):849–59. doi: 10.1177/0961203308093554

Anyfanti P, Dara A, Angeloudi E, Bekiari E, Dimitroulas T, Kitas GD. Monitoring and Managing Cardiovascular Risk in Immune Mediated Inflammatory Diseases. J Inflamm Res. 2021 Dec 14;14:6893–6906. doi: 10.2147/JIR.S276986

Di Cesare M, Perel P, Taylor S, Kabudula C, Bixby H, Gaziano TA, McGhie DV, Mwangi J, Pervan B, Narula J, Pineiro D, Pinto FJ. The Heart of the World. Glob Heart. 2024 Jan 25;19(1):11. doi: 10.5334/gh.1288

Guo LN, Nambudiri VE. Cutaneous lupus erythematosus and cardiovascular disease: current knowledge and insights into pathogenesis. Clin Rheumatol. 2021 Feb;40(2):491–499. doi: 10.1007/s10067-020-05257-3

Zhao M, Feng R, Werth VP, Williams KJ. State of current management of the heightened risk for atherosclerotic cardiovascular events in an established cohort of patients with lupus erythematosus. Lupus Sci Med. 2023 Aug;10(2):e000908. doi: 10.1136/lupus-2023-000908

Olbrich H, Kridin K, Zirpel H, Sadik CD, Terheyden P, Thaçi D, Ludwig RJ, Boch K. Cutaneous lupus erythematosus is associated with an increased risk of cardiac and vascular diseases: a large-scale, propensity matched global retrospective cohort study. EBioMedicine. 2023 Jul;93:104639. doi: 10.1016/j.ebiom.2023.104639

Ahlehoff O, Wu JJ, Raunsø J, Kristensen SL, Khalid U, Kofoed K, Gislason G. Cutaneous lupus erythematosus and the risk of deep venous thrombosis and pulmonary embolism: A Danish nationwide cohort study. Lupus. 2017 Nov;26(13):1435–1439. doi: 10.1177/0961203317716306

Downloads

Published

2025-06-12

Issue

Section

Review Article