| 1. |
- Vikerfors, Anna, et al.
(author)
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Clinical manifestations and anti-phospholipid antibodies in 712 patients with systemic lupus erythematosus : evaluation of two diagnostic assays
- 2013
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In: Rheumatology. - : Oxford University Press (OUP). - 1462-0324 .- 1462-0332. ; 34:5, s. 345-353
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Journal article (peer-reviewed)abstract
- ObjectivesTo evaluate the agreement and performance of two tests for aPLs with regard to association with manifestations of the APS in patients with SLE.MethodsWe investigated 712 SLE patients and 280 population controls. Cardiolipin and β2 glycoprotein-I antibodies were measured with routine ELISA and a new automated method. Three positivity cut-offs (99%, 90% of controls and recommended cut-off by manufacturers) were used. Associations with previous thrombotic events, thrombocytopenia and, in a subgroup of patients, obstetric morbidity (n = 296) were evaluated. Results were compared with the LA test, performed in 380 patients.ResultsInter-test agreement was moderate (demonstrated by κ-values 0.16–0.71). Performance of the two tests was similar: at the 99th percentile cut-off, sensitivity for any thrombotic event ranged from 3.7% to 24.8%, while specificity was 84.7–97.7%. Regardless of assay, IgG isotypes were associated with venous thrombosis and ischaemic cerebrovascular disease, whereas aPLs of IgM isotype were weakly associated with ischaemic heart disease. Associations were greatly affected by aPL level. LA performed better than the specific aPL tests. LA was associated with any thrombotic event, odds ratio 5.4 (95% CI 3.1, 9.4), while the specific aPL tests ranged from non-significant to an odds ratio of 1.9 (95% CI 1.03, 3.4) using criteria cut-off. LA was also convincingly associated with other APS manifestations.ConclusionIn relation to thrombotic manifestations, there was moderate agreement but no clear advantages when comparing a routine aPL ELISA with an automated method. APL isotype and titre as well as LA positivity are important for risk assessment in SLE patients.
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| 2. |
- Vikerfors, Anna, et al.
(author)
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Severe group A streptococcal infections in Uppsala County, Sweden : clinical and molecular characterization of a case cluster from 2006 to 2007
- 2009
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In: Scandinavian Journal of Infectious Diseases. - : Informa UK Limited. - 0036-5548 .- 1651-1980. ; 41:11-12, s. 823-830
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Journal article (peer-reviewed)abstract
- This study describes a recent cluster of 30 patients (median age 52 years) with serious group A streptococcal (GAS) infections in Uppsala County, Sweden, from December 2006 to May 2007. Patients hospitalized with a severe GAS infection, i.e. cases with either invasive GAS (iGAS) disease or patients with a positive non-sterile site culture/rapid antigen test for GAS and clinically considered as having a critical disease, were included in the study. Common clinical presentations were skin and soft tissue infections (53%) and pneumonia (17%). Eight patients (27%) were diagnosed with streptococcal toxic shock syndrome. In 40% of the cases no relevant underlying disease was reported. Among the 16 patients with soft tissue infections, the upper chest, neck or upper arm area was frequently affected and the infection was associated with severe pain. Among the 20 collected isolates, the T1/emm1 type dominated (80%). The majority (86%) of 7 analysed acute sera lacked neutralizing activity against superantigens produced by the patients' own infecting isolate. The study underscores the association between T1/emm1 and outbreaks of serious GAS infections. This highlights the importance of surveillance for prompt identification of more aggressive isolates in the community, thereby increasing awareness among healthcare professionals of these life-threatening infections.
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| 3. |
- Böös, Malin, et al.
(author)
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Who should record surgical complications? : Results from a third-party assessment of complications after radical cystectomy
- 2019
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In: Scandinavian journal of urology. - : Informa Healthcare. - 2168-1805 .- 2168-1813. ; 53:5, s. 339-343
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Journal article (peer-reviewed)abstract
- Objective: In Sweden complications after radical cystectomy have been reported to the nationwide population-based Swedish Cystectomy Registry since 2011. Here, validation of the reporting was assessed in two healthcare regions.Materials and methods: Complications were ascertained from patient records by a third party not involved in the care delivered to 429 randomly selected patients from 949 who had undergone radical cystectomy since 2011 in four hospitals. Without knowledge of the outcome in the primary registration, post-operative complications within 90 days post-operatively were assessed by an independent review of patient charts, and the results were compared with the primary reports in the Swedish Cystectomy Registry.Results: The third-party assessment identified post-operative complications in 310 patients (72%). Low-grade complications (Clavien-Dindo I-II) were noted in 110 (26%) of the patients in the primary registration, but increased to 182 (42%) in the validation (p < 0.00001). High-grade complications (Clavien-Dindo III-V) were reported in 113 (26%) patients in the primary registration, but in 128 (30%) of the patients in the validation (p = 0.02). According to the third-party assessment, 18 patients (4%) had Clavien-Dindo grade IV complications and 12 (3%) died within 90 days of surgery (Clavien-Dindo grade V); corresponding values in the primary registration were 15 (3%) and 9 (2%), respectively. The readmission rate within 90 days increased from 27 to 32% in the validation (p < 0.00001).Conclusions: Compared with registry data, third-party assessment revealed more complications and readmissions after radical cystectomy. Hence such evaluation may improve the validity of reported complication data.
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| 4. |
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| 5. |
- Grosso, Giorgia, et al.
(author)
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The Complex Relationship between C4b-Binding Protein, Warfarin, and Antiphospholipid Antibodies
- 2021
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In: Thrombosis and Haemostasis. - : Georg Thieme Verlag KG. - 0340-6245 .- 2567-689X. ; 121:10, s. 1299-1309
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Journal article (peer-reviewed)abstract
- Background Low levels of total C4b-binding protein (C4BPt), a circulating inhibitor of the classical/lectin complement pathways, were observed in patients with antiphospholipid antibodies (aPLs) and during warfarin treatment. Objectives To investigate the associations between aPL and C4BPt in patients with persistently positive (++) aPL, with/without clinical manifestations and systemic lupus erythematosus (SLE), and in controls. Furthermore, we explored the impact of anticoagulation on C4BPt and in relation to complement activation. Methods In a cross-sectional design we investigated defined subgroups: primary (p) antiphospholipid syndrome (APS, N =67), aPL++ individuals without clinical manifestations (aPL carriers, N =15), SLE-aPL++ ( N =118, among them, secondary [s] APS, N =56), aPL negative (-) SLE (SLE-aPL-, N =291), and 322 controls. Clinical characteristics, including treatment, were tabulated. C4BPt was determined with a magnetic bead method. Complement proteins (C1q, C2, C3, C4, C3a, C3dg, sC5b-9, factor I [FI]) were measured. A mediation analysis was performed to decompose the total effect of aPL++ on C4BPt into the direct and indirect effects of aPL++ through warfarin. Results Overall, C4BPt is 20% decreased in aPL++ patients, regardless of SLE, APS, clinical manifestations, and aPL profile. C4BPt levels associate positively with complement proteins C1q, C2, C3, and C4, and negatively with complement activation product C3dg. In the SLE group, warfarin treatment contributes to approximately half of the C4BPt reduction (9%) Conclusion Both aPLs and warfarin are associated with C4BPt reduction. Complement activation in aPL++ patients may partly be explained by impaired inhibition through depressed C4BPt levels. Further studies are needed to understand the clinical implications.
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| 6. |
- Gustafsson, Johanna T, et al.
(author)
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Cigarette smoking, antiphospholipid antibodies and vascular events in Systemic Lupus Erythematosus
- 2015
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In: Annals of the Rheumatic Diseases. - : BMJ. - 0003-4967 .- 1468-2060. ; 74:8, s. 1537-1543
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Journal article (peer-reviewed)abstract
- OBJECTIVE: Smoking can induce autoantibodies in persons who are genetically predisposed to rheumatoid arthritis. We investigated the association between smoking and antiphospholipid antibodies (aPL) in systemic lupus erythematosus (SLE), a question not previously addressed. Further, we explored the relationship between smoking, aPL and vascular events (arterial and venous, VE).METHODS: In this cross-sectional study, clinical evaluation and questionnaire data were collected from 367 prevalent SLE patients. At the same time, we measured aPL (anticardiolipin (aCL), anti-β2 glycoprotein-1 (aβ2GP1) antibodies IgG/IgM/IgA, and lupus anticoagulant (LA)), and a large set of other SLE-associated autoantibodies for comparison. Association analyses using logistic regression models with smoking, (ever, former and current with never as reference) and antibody status as outcome variable were performed. As a secondary outcome, we investigated the associations between aPL, smoking and VE.RESULTS: In multivariable-adjusted models ever, and in particular former, cigarette smoking was associated with the most pathogenic aPL; LA, aCL IgG and aβ2GP1 IgG. Other SLE-associated autoantibodies were not associated with smoking. The combination of smoking and aPL was strongly associated with VE. We noted a positive interaction between smoking-LA and smoking-'triple aPL' positivity for previous VE.CONCLUSIONS: We investigated a large set of commonly occurring autoantibodies in SLE, but only aPL were positively associated with a history of smoking. This association was especially apparent in former smokers. Among ever regular smokers who were aPL positive, we observed a strikingly high frequency of former VE. The underlying mechanisms and temporality between smoking, aPL and VE need further investigations.
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| 7. |
- Idborg, Helena, et al.
(author)
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STRATIFICATION OF SLE PATIENTS FOR IMPROVED DIAGNOSIS AND TREATMENT
- 2013
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In: Annals of the Rheumatic Diseases. - : BMJ. - 0003-4967 .- 1468-2060. ; 72, s. A80-A80
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Journal article (other academic/artistic)abstract
- Background. Systemic autoimmune diseases (SAIDs) affect about 2% of the population in Western countries. Sufficient diagnostic criteria are lacking due to the heterogeneity within diagnostic categories and apparent overlap regarding symptoms and patterns of autoantibodies between different diagnoses. Systemic lupus erythematosus (SLE) is regarded as a prototype for SAIDs and we hypothesise that subgroups of patients with SLE may have different pathogenesis and should consequently be subject to different treatment strategies.Objectives. Our goal is to find new biomarkers to be used for the identification of more homogenous patient populations for clinical trials and to identify sub-groups of patients with high risk of for example cardiovascular events.Methods. In this study we have utilised 320 SLE patients from the Karolinska lupus cohort and 320 age and gender matched controls. The SLE cohort was characterised based on clinical, genetic and serological data and combined by multivariate data analysis in a systems biology approach to study possible subgroups. A pilot study was designed to verify and investigate suggested subgroups of SLE. Two main subgroups were defined: One group was defined as having SSA and SSB antibodies and a negative lupus anticoagulant test (LAC), i.e., a “Sjögren-like” group. The other group was defined as being negative for SSA and SSB antibodies but positive in the LAC test.i.e. an “APS-like” group. EDTA-plasma from selected patients in these two groups and controls were analysed using a mass spectrometry (MS) based proteomic and metabolomic approach. Pathway analysis was then performed on the obtained data.Results. Our pilot study showed that differences in levels of proteins and metabolites could separate disease groups from population controls. The profile/pattern of involved factors in the complement system supported a division of SLE in two major subgroups, although each individual factor was not significantly different between subgroups. Complement factor 2 (C2) and membrane attack complex (MAC) were analysed in the entire cohort with complementary methods and C2 verifies our results while the levels of MAC did not differ between SLE subgroups. The generated metabolomics data clearly separated SLE patients from controls in both gas chromatography (GC)-MS and liquid chromatography (LC)-MS data. We found for example that tryptophan was lower in the SLE patients compared to controls.Conclusions. Our systems biology approach may lead to a better understanding of the disease and its pathogenesis, and assigning patients into subgroups will result in improved diagnosis and better outcome measures of SLE.
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| 8. |
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| 9. |
- Mobarrez, Fariborz, et al.
(author)
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Microparticles in the blood of patients with systemic lupus erythematosus (SLE) : phenotypic characterization and clinical associations
- 2016
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In: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 6
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Journal article (peer-reviewed)abstract
- Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease characterized by circulating autoantibodies and the formation of immune complexes. In these responses, the selecting self-antigens likely derive from the remains of dead and dying cells, as well as from disturbances in clearance. During cell death/activation, microparticles (MPs) can be released to the circulation. Previous MP studies in SLE have been limited in size and differ regarding numbers and phenotypes. Therefore, to characterize MPs more completely, we investigated 280 SLE patients and 280 individually matched controls. MPs were measured with flow cytometry and phenotyped according to phosphatidylserine expression (PS(+)/PS(-)), cellular origin and inflammatory markers. MPs, regardless of phenotype, are 2-10 times more abundant in SLE blood compared to controls. PS(-) MPs predominated in SLE, but not in controls (66% vs. 42%). Selectively in SLE, PS(-) MPs were more numerous in females and smokers. MP numbers decreased with declining renal function, but no clear association with disease activity was observed. The striking abundance of MPs, especially PS(-) MPs, suggests a generalized disturbance in SLE. MPs may be regarded as "liquid biopsies" to assess the production and clearance of dead, dying and activated cells, i.e. pivotal events for SLE pathogenesis.
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| 10. |
- Vikerfors, Anna
(author)
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Studies of clinical and haemostatic features associated with antiphospholipid antibodies
- 2015
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Doctoral thesis (other academic/artistic)abstract
- Background: Antiphospholipid antibodies (aPL) are associated with a heterogeneous range of clinical conditions with predisposition for thrombosis, pregnancy morbidity and other autoimmune disorders, most frequently systemic lupus erythematosus (SLE). Both the clinical manifestations themselves and their treatment may be harmful to the affected individuals and aPL testing is still controversial. There is thus an urgent need for improved aPL diagnostics and individual risk assessments. Exploring the largely unknown disease aetiology may provide clues to new biomarkers. From previous studies of other pro-thrombotic conditions, we hypothesized that fibrin clot properties, fibrinolytic function, microparticle (MP) profile and smoking could be important in aPL-related disease. Aims: To study clinical, serological and haemostatic features of the antiphospholipid syndrome (APS) and aPL-related disorders, including SLE, in order to improve diagnostic methods and enhance understanding of disease pathogenesis. Materials and methods: Two patient groups were cross-sectionally studied. In paper I, IV, and V, the Karolinska SLE cohort was studied; in paper I together with patients from the Swedish SLE network (n=712 patients) and in paper IV in comparison with matched population controls (n=290 patients). In paper II and III, APS patients (n=49 and 52 patients, respectively) from Karolinska University Hospital were compared both to healthy controls (paper II and III) and to non- APS thrombotic controls (paper II). Laboratory assays included: different ELISAs for aPL detection, liquid permeation technique and scanning electron microscopy (SEM) for examination of fibrin network permeability and structure, turbidimetric clotting and lysis assays, and finally MP measurement by flow cytometry. Results: In paper I, we report only moderate agreement (Kappa-values 0.16-0.71) but similar, modest association with previous thrombotic events when comparing a new automated aPL method with standard assays in SLE patients. Antibody isotype and titer influenced the association with clinical events. Odds ratios for lupus anticoagulant (LA) for the associations with vascular events were generally higher than for the specific aPL immunoassays. In paper II, we report that fibrin clots formed in vitro in samples from APS patients have a decreased permeability compared to the clots formed in samples from healthy controls and non-APS thrombosis controls (p<0.0001 for both). SEM images visually confirmed denser fibrin structure in APS. No clear difference in fibrinolysis function between the APS patients and controls were observed (p>0.05 for two of the three investigated parameters) but APS patients with previous arterial thrombosis had prolonged clot lysis times compared to the controls (p<0.05). In paper III, we report that the number of lactadherin positive MPs, endothelial MPs, Tissue factor (TF)-positive endothelial MPs and monocyte MPs in APS samples were increased compared to healthy controls (p<0.001 for all analyses). There was no significant difference in the number of platelet MPs (p=0.13). APS patients had a high proportion of MPs negative to lactadherin. In paper IV, we report that the number of lactadherin positive MPs, endothelial MPs, platelet MPs and leukocyte MPs in SLE samples were increased compared to matched population controls (p<0.0001 for all analyses). Moreover, MPs exposing inflammation and/or activation markers such as CD40L, TF, vascular cell adhesion molecule 1(VCAM-1), high-mobility group protein B1 (HMGB1) and C4d also were also clearly increased in the SLE patients (p<0.0001 for all analyses). However, MP number could neither be used to distinctively discriminate between SLE patients with or without APS nor between SLE patients with or without previous vascular events in multivariable models (p-values for all analyses >0.05 except for VCAM-1- positive endothelial MPs which had p-values of 0.044 and 0.047 for positive associations in the vascular event models). In paper V we report a positive association between cigarette smoking (ever smoking and, most strikingly, former smoking) and the presence of aPL among patients with SLE (OR ≈3 for aPL of the IgG isotype and for LA and former smoking vs. never smoking in a multivariable model). A positive interaction between ever smoking and aPL was noted for the association with previous vascular events. The additive interaction analysis demonstrated a significant interaction between ever smoking and LA (attributable proportion due to interaction, AP=0.80, 95% CI 0.5 - 1.0) and ever smoking and triple aPL positivity (AP=0.85, 95% CI 0.6 - 1.0) for the association with presence of previous vascular events. Conclusions: Automated aPL assays are promising for facilitating aPL testing. However, it is crucial to also evaluate LA positivity, antibody titers and isotypes together with smoking status when aPL results are used for risk assessment in individual patients. Smoking, abnormal fibrin clot properties, fibrinolytic function, and MP profile may contribute to the pathogenesis of aPL-associated disease. MP formation is likely to play a role in SLE as well, which is a disorder closely related to APS. However, the exact relationship between aPL, vascular events and MPs in SLE patients needs to be further studied. Further mechanistic studies are needed to address how the different variables studied in this thesis are related to the pathogenesis of aPL-associated disease. The findings and conclusions in this thesis also need to be prospectively studied to clarify their prognostic value. With such additional studies, our observations could guide the search for new biomarkers and risk scores in aPL-related disease.
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