| 1. |
- Appelgren, Daniel, et al.
(författare)
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Active NET formation in Libman–Sacks endocarditis without antiphospholipid antibodies : A dramatic onset of systemic lupus erythematosus
- 2018
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Ingår i: Autoimmunity. - : Informa UK Limited. - 0891-6934 .- 1607-842X. ; 51:6, s. 310-318
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Tidskriftsartikel (refereegranskat)abstract
- Although neutrophil extracellular traps (NETs) have been highlighted in several systemic inflammatory diseases, their clinical correlates and potential pathological role remain obscure. Herein, we describe a dramatic onset of systemic lupus erythematosus (SLE) with clear-cut pathogenic implications for neutrophils and NET formation in a young woman with cardiac (Libman–Sacks endocarditis) and central nervous system (psychosis and seizures) involvement. Despite extensive search, circulating antiphospholipid autoantibodies, a hallmark of Libman–Sacks endocarditis, could not be detected. Instead, we observed active NET formation in the tissue of the mitral valve, as well as in the circulation. Levels of NET remnants were significantly higher in serially obtained sera from the patient compared with sex-matched blood donors (p =.0011), and showed a non-significant but substantial correlation with blood neutrophil counts (r = 0.65, p =.16). The specific neutrophil elastase activity measured in serum seemed to be modulated by the provided immunosuppressive treatment. In addition, we found anti-Ro60/SSA antibodies in the cerebrospinal fluid of the patient but not NET remnants or increased elastase activity. This case illustrates that different disease mechanisms mediated via autoantibodies can occur simultaneously in SLE. NET formation with release of cytotoxic NET remnants is a candidate player in the pathogenesis of this non-canonical form of Libman–Sacks endocarditis occurring in the absence of traditional antiphospholipid autoantibodies. The case description includes longitudinal results with clinical follow-up data and a discussion of the potential roles of NETs in SLE.
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| 2. |
- Enocsson, Helena, et al.
(författare)
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Association of Serum C-Reactive Protein Levels With Lupus Disease Activity in the Absence of Measurable Interferon-α and a C-Reactive Protein Gene Variant
- 2014
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Ingår i: Arthritis & rheumatology (Hoboken, N.J.). - Hoboken, NJ, United States : John Wiley & Sons. - 2326-5191 .- 2326-5205. ; 66:6, s. 1568-1573
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: The type I interferon (IFN) system is important in the pathogenesis of systemic lupus erythematosus (SLE). We previously demonstrated an inhibitory effect of IFNα on interleukin 6 (IL-6) induced C-reactive protein (CRP) in vitro, hypothetically explaining the poor correlation between disease activity and CRP levels in SLE. Herein we investigated disease activity, IL-6 and CRP in relation to a CRP gene polymorphism and IFN.Methods: Sera from 155 SLE patients and 100 controls were analyzed for CRP. Patients were genotyped for a CRP single nucleotide polymorphism (rs1205) associated with low CRP levels. Serum IFNα and IL-6 was quantified by immunoassays. Clinical disease activity was assessed by SLE disease activity index 2000 (SLEDAI-2K).Results: CRP levels were increased in SLE patients compared to controls, but were not associated with SLEDAI-2K or IL-6 levels. However, exclusion of patients carrying at least one rs1205 minor allele revealed an association between disease activity and CRP levels (p=0.005). We found a strong association between disease activity and CRP levels (p<0.0005) when patients with measurable IFNα as well as the minor allele of rs1205 where excluded from the analysis. Similarly, when patients with raised IFNα and/or the rs1205 polymorphism were excluded, IL-6 associated with CRP levels.Conclusions: The present study demonstrates that serum IFNα as well as CRP genotype affects the CRP response in SLE patients. Lack of correlation between serum levels of CRP and disease activity could therefore be explained by activation of the type I IFN system and polymorphisms in the CRP gene. © 2014 American College of Rheumatology.
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| 3. |
- Enocsson, Helena, 1982-
(författare)
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Biomarkers and mediators in systemic lupus erythematosus : IFNα versus the CRP response, and evaluation of suPAR and anti-dsDNA antibody assays
- 2014
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease which may affect multiple organ systems. Interferon alpha (IFNα) and autoantibodies that form immune complexes with nuclear antigens (ANA) are hallmarks believed to drive the disease into a vicious circle of inflammation, tissue damage, autoantigen exposure and autoantibody production.In SLE, the disease course is characterized by episodes of exacerbations alternating with remissions. In order to best treat the patient it is important to closely monitor symptoms and signs of disease activity. Because of the disease heterogeneity, no single biomarker has yet been found to reflect SLE disease activity in general, although antidouble stranded DNA (anti-dsDNA) antibodies sometimes indicate activity, primarily with renal involvement, and constitutes an item of the SLE disease activity score SLEDAI-2K. However, the method of anti-dsDNA measurement is not standardized and therefore varies between different laboratories. In many other inflammatory conditions, such as rheumatoid arthritis and during bacterial infections, the C-reactive protein (CRP) level is a good indicator of ongoing inflammation, but in SLE and during viral infections, CRP commonly fails to reflect the degree of inflammation. Both viral infections and SLE are characterized by IFNα, and we thus aimed to elucidate whether IFNα can inhibit CRP production. Further, four assays for anti-dsDNA antibody measurements were evaluated with regard to SLE disease specificity and activity, and a new potential biomarker of inflammation, the soluble urokinase plasminogen activator receptor (suPAR), was assessed in relation to disease activity and organ damage.An in vitro inhibitory effect of IFNα on CRP transcription and production was found in hepatocytes, and this was consolidated by in vivo studies of CRP and IFNα in sera from well-characterized SLE patients (KLURING; Kliniskt lupusregister i nordöstra Götaland). Here, CRP and disease activity were associated among patients without IFNα and without a CRP lowering gene variant (SNP rs1205). The poor disease activity compliance of CRP could therefore be explained, at least in part, by polymorphisms in the CRP gene and increased levels of IFNα. Critical differences between the methods measuring anti-dsDNA were found regarding disease specificity and ability to reflect disease activity and the results suggests the Crithidia luciliae immunofluorescence test (CLIFT) for diagnostic purposes and a bead-based multiplex assay (FIDIS) for monitoring of disease activity. Evaluation of suPAR in SLE revealed no association of suPAR with disease activity, but interestingly instead with accumulated organ damage. suPAR could therefore possibly be used to advert patients at high risk of organ damage.A detailed biological and clinical characterization of established and emerging SLE biomarkers is of importance since it may improve the clinical management as well as increase the knowledge about disease mechanisms.
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| 4. |
- Enocsson, Helena, et al.
(författare)
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C-Reactive Protein Levels in Systemic Lupus Erythematosus Are Modulated by the Interferon Gene Signature and CRP Gene Polymorphism rs1205
- 2021
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Ingår i: Frontiers in Immunology. - : Frontiers Media SA. - 1664-3224. ; 11
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: Patients with systemic lupus erythematosus (SLE) often display modest elevations of C-reactive protein (CRP) despite raised disease activity and increased interleukin (IL-) 6. We asked to what extent IL-6 levels, the CRP polymorphism rs1205, and the type I interferon (IFN) gene signature affects the basal CRP levels in patients with SLE during a quiescent phase of the disease. Methods: CRP and IL-6 were analyzed in plasma from 57 patients meeting established classification criteria for SLE. The CRP polymorphism rs1205 was assessed and gene expression analyzed including four type I IFN-regulated genes (IGS). Results: CRP was increased in patients with detectable IL-6 levels (p=0.001) and decreased among IGS-positive subjects (p=0.033). A multiple linear regression model revealed IL-6 to have a positive association with CRP levels, whereas both IGS-positivity and CRP genotype (rs1205) AA/GA were negatively associated with CRP-levels. Conclusion: Our data offer an explanation to the modest CRP levels seen in viral infections and IFN-α driven autoimmunity and corroborate prior observations showing an IFN-α dependent downregulation of CRP. The latter observation, together with the fact that the CRP-lowering polymorphism rs1205 is overrepresented in human SLE, could explain low basal CRP and inadequate CRP-responses among patients with active SLE.
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| 5. |
- Enocsson, Helena, et al.
(författare)
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Comparison of Surrogate Markers of the Type I Interferon Response and Their Ability to Mirror Disease Activity in Systemic Lupus Erythematosus
- 2021
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Ingår i: Frontiers in Immunology. - : Frontiers Media S.A.. - 1664-3224. ; 12
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: Type I interferons (IFNs) are central and reflective of disease activity in systemic lupus erythematosus (SLE). However, IFN-alpha levels are notoriously difficult to measure and the type I IFN gene signature (IGS) is not yet available in clinical routine. This study evaluates galectin-9 and an array of chemokines/cytokines in their potential as surrogate markers of type I IFN and/or SLE disease activity.Methods: Healthy controls and well-characterized Swedish SLE patients from two cross-sectional cohorts (n=181; n=59) were included, and a subgroup (n=21) was longitudinally followed. Chemokine/cytokine responses in immune complex triggered IFN-alpha activity was studied in healthy donor peripheral blood mononuclear cells (PBMC). Levels of chemokines/cytokines and galectin-9 were measured by immunoassays. Gene expression was quantified by qPCR.Results: The IGS was significantly (p<0.01) correlated with galectin-9 (rho=0.54) and CXCL10 (rho=0.37) levels whereas serum IFN-alpha correlated with galectin-9 (rho=0.36), CXCL10 (rho=0.39), CCL19 (rho=0.26) and CCL2 (rho=0.19). The strongest correlation was observed between galectin-9 and TNF (rho=0.56). IFN-alpha and disease activity (SLEDAI-2K) were correlated (rho=0.20) at cross-sectional analysis, but no significant associations were found between SLEDAI-2K and galectin-9 or chemokines. Several inflammatory mediators increased at disease exacerbation although CCL19, CXCL11, CXCL10, IL-10 and IL-1 receptor antagonist were most pronounced. Immune complex-stimulation of PBMC increased the production of CCL2, CXCL8 and TNF.Conclusion: Galectin-9 and CXCL10 were associated with type I IFN in SLE but correlated stronger with TNF. None of the investigated biomarkers showed a convincing association with disease activity, although CXCL10 and CCL19 performed best in this regard.
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| 6. |
- Enocsson, Helena, et al.
(författare)
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Serum C-reactive protein (CRP) associates with lupus disease activity in the absence of measurable interferon alpha and a CRP gene variant
- 2014
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Ingår i: Arthritis & rheumatology. - : Wiley. - 2326-5205 .- 2326-5191. ; 66:6, s. 1568-1573
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: The type I interferon (IFN) system is important in the pathogenesis of systemic lupus erythematosus (SLE). We previously demonstrated an inhibitory effect of IFNα on interleukin 6 (IL-6) induced C-reactive protein (CRP) in vitro, hypothetically explaining the poor correlation between disease activity and CRP levels in SLE. Herein we investigated disease activity, IL-6 and CRP in relation to a CRP gene polymorphism and IFNαMethods: Sera from 155 SLE patients and 100 controls were analyzed for CRP. Patients were genotyped for a CRP single nucleotide polymorphism (rs1205) associated with low CRP levels. Serum IFNα and IL-6 was quantified by immunoassays. Clinical disease activity was assessed by SLE disease activity index 2000 (SLEDAI-2K).Results: CRP levels were increased in SLE patients compared to controls, but were not associated with SLEDAI-2K or IL-6 levels. However, exclusion of patients carrying at least one rs1205 minor allele revealed an association between disease activity and CRP levels (p=0.005). We found a strong association between disease activity and CRP levels (p<0.0005) when patients with measurable IFNα as well as the minor allele of rs1205 where excluded from the analysis. Similarly, when patients with raised IFNα and/or the rs1205 polymorphism were excluded, IL-6 associated with CRP levels.Conclusions: The present study demonstrates that serum IFNα as well as CRP genotype affects the CRP response in SLE patients. Lack of correlation between serum levels of CRP and disease activity could therefore be explained by activation of the type I IFN system and polymorphisms in the CRP gene.
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| 7. |
- Enocsson, Helena, et al.
(författare)
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Soluble urokinase plasminogen activator receptor (suPAR) levels predict damage accrual in patients with recent-onset systemic lupus erythematosus
- 2020
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Ingår i: Journal of Autoimmunity. - : Elsevier BV. - 0896-8411 .- 1095-9157. ; 106
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Tidskriftsartikel (refereegranskat)abstract
- Objective: The soluble urokinase plasminogen activator receptor (suPAR) has potential as a prognosis and severity biomarker in several inflammatory and infectious diseases. In a previous cross-sectional study, suPAR levels were shown to reflect damage accrual in cases of systemic lupus erythematosus (SLE). Herein, we evaluated suPAR as a predictor of future organ damage in recent-onset SLE. Methods: Included were 344 patients from the Systemic Lupus International Collaborating Clinics (SLICC) Inception Cohort who met the 1997 American College of Rheumatology classification criteria with 5-years of follow-up data available. Baseline sera from patients and age- and sex-matched controls were assayed for suPAR. Organ damage was assessed annually using the SLICC/ACR damage index (SDI). Results: The levels of suPAR were higher in patients who accrued damage, particularly those with SDI≥2 at 5 years (N = 32, 46.8% increase, p = 0.004), as compared to patients without damage. Logistic regression analysis revealed a significant impact of suPAR on SDI outcome (SDI≥2; OR = 1.14; 95% CI 1.03–1.26), also after adjustment for confounding factors. In an optimized logistic regression to predict damage, suPAR persisted as a predictor, together with baseline disease activity (SLEDAI-2K), age, and non-Caucasian ethnicity (model AUC = 0.77). Dissecting SDI into organ systems revealed higher suPAR levels in patients who developed musculoskeletal damage (SDI≥1; p = 0.007). Conclusion: Prognostic biomarkers identify patients who are at risk of acquiring early damage and therefore need careful observation and targeted treatment strategies. Overall, suPAR constitutes an interesting biomarker for patient stratification and for identifying SLE patients who are at risk of acquiring organ damage during the first 5 years of disease.
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| 8. |
- Enocsson, Helena, et al.
(författare)
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The Complex Role of C-Reactive Protein in Systemic Lupus Erythematosus
- 2021
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Ingår i: Journal of Clinical Medicine. - : MDPI. - 2077-0383. ; 10:24
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Forskningsöversikt (refereegranskat)abstract
- C-reactive protein (CRP) is well-known as a sensitive albeit unspecific biomarker of inflammation. In most rheumatic conditions, the level of this evolutionarily highly conserved pattern recognition molecule conveys reliable information regarding the degree of ongoing inflammation, driven mainly by interleukin-6. However, the underlying causes of increased CRP levels are numerous, including both infections and malignancies. In addition, low to moderate increases in CRP predict subsequent cardiovascular events, often occurring years later, in patients with angina and in healthy individuals. However, autoimmune diseases characterized by the Type I interferon gene signature (e.g., systemic lupus erythematosus, primary Sjogrens syndrome and inflammatory myopathies) represent exceptions to the general rule that the concentrations of CRP correlate with the extent and severity of inflammation. In fact, adequate levels of CRP can be beneficial in autoimmune conditions, in that they contribute to efficient clearance of cell remnants and immune complexes through complement activation/modulation, opsonization and phagocytosis. Furthermore, emerging data indicate that CRP constitutes an autoantigen in systemic lupus erythematosus. At the same time, the increased risks of cardiovascular and cerebrovascular diseases in patients diagnosed with systemic lupus erythematosus and rheumatoid arthritis are well-established, with significant impacts on quality of life, accrual of organ damage, and premature mortality. This review describes CRP-mediated biological effects and the regulation of CRP release in relation to aspects of cardiovascular disease and mechanisms of autoimmunity, with particular focus on systemic lupus erythematosus.
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| 9. |
- Frodlund, Martina, 1978-
(författare)
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Antinuclear and antiphospholipid antibodies versus disease manifestations and clinical outcomes in systemic lupus erythematosus
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Systemic lupus erythematosus (SLE) has an exceptionally heterogeneous clinical spectrum, ranging from mild disease limited to skin and joints to severe manifestations with renal disorder, central nervous system disease, severe cytopenias and thromboembolic events. Important clinical challenges include the prediction of disease flares and the identification of individuals that are likely to evolve severe disease with accrual of organ damage and worse prognosis. Autoantibodies, i.e. antinuclear antibodies (ANA) and antiphospholipid antibodies (aPL), and interferon alpha (IFN-α) that contribute to formation of immune complexes with nuclear antigens, are hallmarks considered to drive the disease in a vicious circle of antigen exposure, autoantibody production, inflammation and organ damage. There are few good biomarkers to predict severe SLE and organ damage. The aim of this PhD project was thus to increase the knowledge regarding ANA as well as aPL, and other potential biomarkers in relation to clinical features and disease outcomes in SLE.As expected, we found that the homogeneous ANA staining pattern was most common, and that it was associated with the occurrence of the ‘immunological disorder’ criterion. Speckled ANA was the second most common staining pattern, and it was inversely associated with arthritis, the ‘immunological disorder’ criterion and organ damage (Paper I). We also demonstrated that a considerable proportion of the patients lost ANA-positivity over time, whereas consistent staining patterns were most frequent (Paper V).Survival of patients with SLE has improved. Yet, in comparison to the general population, irreversible organ damage and increased mortality remains a critical concern. In Paper II, our cross-sectional analysis showed that more than a quarter of the patients had any aPL isotype (IgG, IgM or IgA class), and 14% were classified with antiphospholipid antibody syndrome (APS). A positive lupus anticoagulant (LA) test and/or IgG aPL tests were associated with most APS-related events and organ damage. Lupus nephritis, tobacco smoking, LA-positivity and the use of statins and/or corticosteroids were strongly associated with damage accrual, while hydroxychloroquine seemed to be protective. IgA aPL was not uncommon (16%) in Swedish cases of SLE, and analysis of IgA aPL may add information among clinically suspected APS-patients testing negative for LA and other aPL isotypes.Despite modern management and tax-funded health care with universal access, almost two thirds of the patients accrued organ damage over time, and the main causes of death were identified as malignancy, infection, and cardiovascular disease. We could confirm well established risk factors for organ damage such as APS, hypertension, and/or the use of corticosteroids, but we also observed that other factors such as pericarditis, haemolytic anaemia, lymphopenia and myositis seems to be of importance in this view (Paper IV).We also demonstrated that levels of the extracellular matrix protein osteopontin (OPN) was correlated with disease activity in patients with recent-onset SLE. In addition, OPN levels reflected global organ damage and were associated with APS and could have potential as a valuable biomarker in SLE (Paper III).Additional studies are warranted to further establish the clinical and mechanistic relevance of ANA seroconversion, OPN, as well as the importance of IgA aPL. Vigilance for malignancies, a restricted use of corticosteroids and prevention of cardiovascular disease and APS events are among modifiable factors to prevent organ damage and premature mortality.This thesis emphasizes the importance of autoantibodies in the pathogenesis, and diagnosis, of SLE. The autoantibody profile can be of great importance for tailored therapy in order to minimize the risk of organ damage accrual, morbidity as well as mortality.
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| 10. |
- Frodlund, Martina, et al.
(författare)
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Immunoglobulin A anti-phospholipid antibodies in Swedish cases of systemic lupus erythematosus : associations with disease phenotypes, vascular events and damage accrual
- 2018
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Ingår i: Clinical and Experimental Immunology. - : WILEY. - 0009-9104 .- 1365-2249. ; 194:1, s. 27-38
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Tidskriftsartikel (refereegranskat)abstract
- Immunoglobulin (Ig) G- and IgM-class anti-cardiolipin antibodies (aCL) and lupus anti-coagulant (LA) are included in the 1997 update of the American College of Rheumatology (ACR-97) systemic lupus erythematosus (SLE) criteria. Despite limited evidence, IgA-aCL and IgA anti-(2)-glycoprotein-I (anti-(2)GPI) were included in the 2012 Systemic Lupus International Collaborating Clinics criteria. The present study aimed to evaluate IgG-/IgA-/IgM-aCL and anti-(2)GPI occurrence in relation to disease phenotype, smoking habits, pharmacotherapy, anti-phospholipid syndrome (APS) and organ damage among 526 Swedish SLE patients meeting ACR-97. Patients with rheumatoid arthritis (n=100), primary Sjogren's syndrome (n=50) and blood donors (n=507) served as controls. Anti-phospholipid antibodies (aPL) were analysed by fluoroenzyme-immunoassays detecting aCL/anti-(2)GPI. Seventy-six (14%) SLE cases fulfilled the Sydney APS-criteria, and 1 aCL/anti-(2)GPI isotype (IgG/IgA/IgM) occurred in 138 SLE patients (26%). Forty-five (9%) of the SLE cases had IgA-aCL, 20 of whom (4%) lacked IgG-/IgM-aCL. Seventy-four (14%) tested positive for IgA anti-(2)GPI, 34 (6%) being seronegative regarding IgG/IgM anti-(2)GPI. Six (1%) had APS manifestations but were seropositive regarding IgA-aCL and/or IgA anti-(2)GPI in the absence of IgG/IgM-aPL and LA. Positive LA and IgG-aPL tests were associated with most APS-related events and organ damage. Exclusive IgA anti-(2)GPI occurrence associated inversely with Caucasian ethnicity [odds ratio (OR)=021, 95% confidence interval (CI)=006-072) and photosensitivity (OR=019, 95% CI=005-072). Nephritis, smoking, LA-positivity and statin/corticosteroid-medication associated strongly with organ damage, whereas hydroxychloroquine-medication was protective. In conclusion, IgA-aPL is not rare in SLE (16%) and IgA-aPL analysis may have additional value among SLE cases with suspected APS testing negative for other isotypes of aPL and LA.
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