No association of complement mannose-binding lectin deficiency with cardiovascular disease in patients with Systemic Lupus Erythematosus

Abstract

Cardiovascular (CV) morbidity is the major cause of death in patients with Systemic LupusErythematosus (SLE). Previous studies on mannose-binding lectin (MBL) gene polymorphisms in SLE patients suggest that low levels of complement MBL are associated with cardiovascular disease (CVD). However, as large studies on MBL deficiency based on resulting MBL plasma concentrations are lacking, the aim of our study was to analyze the association of MBL concentrations with CVD in SLE patients. Plasma MBL levels SLE patients included in the Swiss SLE Cohort Study were quantified by ELISA. Five different CV organ manifestations were documented. Of 373 included patients (85.5% female) 62 patients had at least one CV manifestation. Patients with MBL deficiency (levels below 500 ng/ml or 1000 ng/ml) had no significantly increased frequency of CVD (19.4% vs. 15.2%, P = 0.3 or 17.7% vs. 15.7%, P = 0.7). After adjustment for traditional CV risk factors, MBL levels and positive antiphospholipid serology (APL+) a significant association of CVD with age, hypertension, disease duration and APL+ was demonstrated. In our study of a large cohort of patients with SLE, we could not confirm previous studies suggesting MBL deficiency to be associated with an increased risk for CVD.Systemic lupus erythematosus (SLE) is an idiopathic, chronic and highly heterogeneous inflammatory disorder, driven by an immune response against self-antigens. The prevalence generally ranges from 20 to 70 per 100.000 1 and affects both sexes of any age but predominates in women of childbearing age 2 with a male-to-female ratio of about 9:1 3 .The etiology of SLE is multifactorial and the complexity of different factors (genetic, hormonal, immunological and environmental) matches the diversity of clinical manifestations in SLE patients 4 . Associated with the presence of immune complexes, ongoing complement system activation leads to inflammation and consumption of complement proteins 5 . This chronic inflammatory state predisposes SLE patients to premature cardiovascular disease (CVD) and infections.Premature CVD, mostly related to accelerated atherosclerosis 6 , is acknowledged as the major cause of death in SLE patients, regardless of the time after diagnosis 7,8 , resulting in a bimodal mortality curve, first described by Urowitz et al. in the 1970s 9 . The 5-year survival after diagnosis nowadays exceeds 90% 10-12 , but this survival rate has not improved since the 1980s.The prevalence of ischemic heart disease in SLE patients is estimated to be between 3.8 and 16% 13-18 , a 10-fold higher prevalence compared to the general population 19 . Moreover, the risk of myocardial infarction in young

Mannose-Binding Lectin in Human Health and Disease

“…Study in Indian females Panda et al ( 2013 ) Autoimmune diseases Systemic lupus erythematosus A tendency of higher frequency of the B allele was observed in Spanish patients with SLE Losada López et al ( 2016 ) Autoimmune diseases CVD and SLE MBL variant alleles are associated with an increased risk of arterial thrombosis. Study in Danish patients with SLE Øhlenschlæger et al ( 2004 ) Autoimmune diseases CVD and SLE MBL deficiency is not determinant of CVD in SLE patients, independent of other risk factors Kieninger-Gräfitsch et al ( 2020 ) Virus infection Influenza MBL doesn’t increase susceptibility to severe influenza infection in pediatric patients Levy et al ( 2019 ) Bacterial infection Pulmonary tuberculosis MBL-2 gene polymorphisms may be involved in the pathogenesis of PTB (pulmonary tuberculosis) and serum may be a biomarker for the diagnosis of PTB Tong et al ( 2019 ) Autoimmune diseases RA MBL2 polymorphisms at codon 52, 54 and 57, as well as at promoter position −220, were not associated with increased risk to RA. (Meta-analysis) Epp Boschmann et al ( 2016 ) Neonatal sepsis MBL is protective toward the development of neonatal sepsis and low MBL levels at birth are associated with an increased risk of hospital-acquired sepsis in infants De Benedetti et al ( 2007 ) Neonatal sepsis Low MBL levels were not associated neither with gestational age or sepsis in infants Hartz et al ( 2018 ) Sepsis MBL2 exon polymorphisms with low serum levels of MBL increase the risk of sepsis infection and septic shock in pediatric patients Fidler et al ( 2004 ) Neonatal sepsis MBL levels below 400 ng/mL increase the chances of developing sepsis Dzwonek et al ( 2008 ) Neonatal sepsis No major impact on sepsis risk unless in infants between 32–36 gestational age Hartz et al ( ...…”

“…On the other hand, several reports are showing that there is no such link (Larsen et al 2018 ) (Table 1 ). Also, a recent publication that studied whether MBL deficiency, based on the blood concentrations (<1000 ng/mL), is associated with an increased incidence of CVD in SLE patients, showed that this is not the case (Kieninger-Gräfitsch et al 2020 ) (Table 1 ). Large prospective studies with long follow-ups would be required to exclude definitely a role of MBL in SLE-associated CVD, as also for SLE.…”