LDL-levels are increased by Proprotein convertase subtilisin kexin 9 (PCSK9) which targets the LDL-receptor (LDLR). We recently reported that PCSK9 ameliorates dendritic cell (DC) activation by oxidized LDL (OxLDL), which is abundant in atherosclerotic plaques and also raised and associated with cardiovascular disease (CVD) in SLE. We here investigate the role of PCSK9 in SLE.
PCSK9-levels were determined by ELISA among SLE patients (n=109) and age- and sex-matched population-based controls (n=91). Common carotid intima-media thickness (IMT) and plaque occurrence were determined by B-mode ultrasound. Plaques were graded by echogenicity. Human peripheral blood monocytes from SLE patients or controls were differentiated into DCs. Effects of PCSK9 and its inhibition by silencing were studied.
PCSK9-levels were non-significantly higher among SLE-patients as compared to controls but associated significantly with SLE disease activity, as determined by SLAM (0.020) or SLEDAI (0.0178). There was no association between PCSK9-levels and atherosclerosis as determined by IMT, prevalence of plaques or echolucent (potentially vulnerable) plaques. PCSK9 levels were significantly associated with CVD among SLE-patients but not after adjustment for age.
OxLDL induced PCSK9 in DCs and DC-maturation with increased expression of CD86 and HLA-DR. The effects were significantly stronger in DC from SLE patients than from controls. Silencing of PCSK9 abolished OxLDL-induced DC-maturation.
PCSK9 is associated with disease activity in SLE. One underlying cause could be OxLDL, promoting DC-activation which depends on PCSK9. OxLDL induces PCSK9, an effect which is higher among SLE-patients. PCSK9 could play an unexpected immunological role in SLE.
To compare atherogenicity of blood serum in women with untreated systemic lupus erythematosus (SLE) and healthy women.
37 patients (pts) (median age 30 years) with active SLE (SLADAI 17 [8;34]) were enrolled in the study. Lupus nephritis (LN) are defined in 41%, Antiphospholipid syndrome (APS) – in 22% of SLE pts. The control group consisted of 30 women. Atherogenicity of blood serum was determined in the culture of murine macrophages (MMs). Peritoneal MMs were isolated from the ascitic fluid of the line mice according to the generally accepted method J. Goldstein et al (1979y). Serum atherogenicity was determined by the accumulation of intracellular cholesterol (CS) induced by 10% of the blood serum of the pts, and expressed as a % of the content of CS in the control cells.
Elevated atherogenicity of blood serum was detected more frequently in SLE pts (65%) vs healthy controls (17%), p<0,01. The blood serum of SLE pts caused a 3-7-fold accumulation of intracellular CS, which significantly differed from healthy women (203±136% vs 127±42%, p<0,001). The ability to stimulate the accumulation of CS esters in MMs was not associated with age, duration of the disease, lipid spectrum and was the highest in pts with LN (305±141% vs 180±52%, p<0,05) and APS (253±130% vs 119±75%, p<0,05).
Serums of women with untreated SLE have had the capacity to stimulate the accumulation of CS in MMs in comparison with the serums of healthy women. The highest atherogenicity was found in blood serum of pts with LN and APS.
SLE is a multifaceted autoimmune disease characterized by immune-complex mediated organ damage caused by the breakdown in innate tolerance to self-nucleic acids. HMGB1 supports the inflammatory clearance of apoptotic cells by binding to molecules released from apoptotic cells and may act as a proinflammatory mediator through ligation to its receptors, in particular, RAGE, one of the main receptor system responsible for HMGB1 activity. This study aimed to address the presence of HMGB1 and the soluble receptor for advanced glycation end products (sRAGE) in SLE patients and to correlate it with clinical and laboratory features of disease activity and severity,
A total of 35 patients with SLE and 20 age and gender matched healthy controls were recruited. Demographic and clinical data were recorded. Disease activity was assessed using the SLE disease activity index (SLEDAI). Blood samples were collected and levels of HMGB1 and sRAGE were measured using ELISA. Correlations between HMGB1, sRAGE levels and clinical and laboratory characteristics were assessed.
SLE patients had significantly higher plasma levels of HMGB1 and significantly lower sRAGE levels compared to controls. HMGB1 and sRAGE levels correlated with SLE disease activity and severity and correlated with the levels of TNF-α and IL-6, hsCRP, C3, C4, white blood cell count and urine albumin creatinine ratio.
HMGB1/sRAGE is associated with the inflammation process in SLE and may be a risk factor for SLE. Furthermore, HMGB1 is a potential biomarker of disease severity and activity. Manipulation of HMGB1/sRAGE signalling is a potential therapeutic strategy for SLE.
Systemic lupus erythematosus (SLE) is a chronic disease that may be fatal. In the era of revolutionary emerging novel biologic agents, an attempt of targeted therapy for these patients is mandatory. Novel therapies under investigation in phase II-III clinical trials showed promising results and potential. Therapies target different pathways involved in SLE including cytokines, signal transduction inhibitors, B cell depletion, interference with co-stimulation and others. Of interest is the proof of concept of sequential therapy. To date, it is still difficult to crack the puzzle in SLE therapy; therefore a new strategy may encompass targeting more than one protein.
In this article, we performed an extensive literature search via PubMed, Medline, Elsevier Science and Springer Link databases between the years 2014-2020 using the following terms: SLE, novel treatments. We have reviewed 232 articles and chosen the articles which focused on phase II-III emerging therapies and new findings on existing therapies attempting to reveal new breakthrough concepts in SLE treatment.
It is time to change the approach from trials using lupus scores and proceed to blood tests that determine the subtype of lupus by the individual pathways which are activated. The key findings of our article are the substantial intensive ongoing research for new biologic therapy for SLE.
SLE therapy remains an enigma and a true challenge for drug development. Hopefully the future will enable ckinical bioengeneering technology which will lead to new SLE patints classifications. A breakthrough with interferon pathway related therapy is the most promising.
Patients with systemic lupus erythematosus (SLE) have a high burden of cardiovascular disease (CVD) of multifactorial origin. The aim of this systematic review is to analyze the role of the interferon I (IFN-I) signature and fibroblast growth factor-23 (FGF-23) in patients with SLE or cutaneous lupus erythematosus (CLE) herein.
We conducted a systematic literature search in PubMed and Scopus using keywords for major adverse cardiovascular events (MACE) and intermediate outcomes (endothelial dysfunction, subclinical atherosclerosis, platelet activation) associated with IFN-I or FGF-23 in patients with SLE and CLE.
4745 citations were screened, of which 12 studies were included. IFN-I was associated with MACE in two third of the studies and the association was strongest for cardiac events. An association of IFN-I was found in all studies investigating impaired vascular function, but only in 50% (respectively 40%) of reports examining the relation of IFN-I and platelet activation (respectively subclinical atherosclerosis). Altogether the reports were of variable bias and quality due to high variability of examined IFN-I biomarkers and inconsistent results for different outcome measures.
No studies investigating the cardiovascular risk of circulating IFN-I in CLE, nor FGF-23 in SLE or CLE were found.
Clinical studies measuring the association between IFN-I and direct / intermediate measures of CVD are rare and ambiguous in SLE and nonexistent in CLE, hampering a definite conclusion.