| 1. |
- Ajeganova, S, et al.
(author)
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Patients with SLE have higher risk of cardiovascular events and mortality in comparison with controls with the same levels of traditional risk factors and intima-media measures, which is related to accumulated disease damage and antiphospholipid syndrome: a case-control study over 10 years
- 2021
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In: Lupus science & medicine. - : BMJ. - 2053-8790. ; 8:1
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Journal article (peer-reviewed)abstract
- SLE is a strong risk factor for premature cardiovascular (CV) disease and mortality. We investigated which factors could explain poor prognosis in SLE compared with controls.MethodsPatients with SLE and population controls without history of clinical CV events who performed carotid ultrasound examination were recruited for this study. The outcome was incident CV event and death. Event-free survival rates were compared using Kaplan-Meier curves. Relative HR (95% CI) was used to estimate risk of outcome.ResultsPatients (n=99, 87% female), aged 47 (13) years and with a disease duration of 12 (9) years, had mild disease at inclusion, Systemic Lupus Erythematosus Diseases Activity Index score of 3 (1–6) and Systemic Lupus International Collaborating Clinics (SLICC) Damage Index score of 0 (0–1). The controls (n=109, 91% female) were 49 (12) years old. Baseline carotid intima-media thickness (cIMT) did not differ between the groups, but plaques were more prevalent in patients (p=0.068). During 10.1 (9.8-10.2) years, 12 patients and 4 controls reached the outcome (p=0.022). Compared with the controls, the risk of the adverse outcome in patients increased threefold to fourfold taking into account age, gender, history of smoking and diabetes, family history of CV, baseline body mass index, waist circumference, C reactive protein, total cholesterol, high-density lipoprotein, low-density lipoprotein, dyslipidaemia, cIMT and presence of carotid plaque. In patients, higher SLICC score and SLE-antiphospholipid syndrome (SLE-APS) were associated with increased risk of the adverse outcome, with respective HRs of 1.66 (95% CI 1.20 to 2.28) and 9.08 (95% CI 2.71 to 30.5), as was cIMT with an HR of 1.006 (95% CI 1.002 to 1.01). The combination of SLICC and SLE-APS with cIMT significantly improved prediction of the adverse outcome (p<0.001).ConclusionIn patients with mild SLE of more than 10 years duration, there is a threefold to fourfold increased risk of CV events and death compared with persons who do not have SLE with similar pattern of traditional CV risk factors, cIMT and presence of carotid plaque. SLICC, SLE-APS and subclinical atherosclerosis may indicate a group at risk of worse outcome in SLE.
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| 2. |
- Ajeganova, S, et al.
(author)
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Similar progression of carotid intima-media thickness in 7-year surveillance of patients with mild SLE and controls, but this progression is still promoted by dyslipidaemia, lower HDL levels, hypertension, history of lupus nephritis and a higher prednisolone usage in patients
- 2020
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In: Lupus science & medicine. - : BMJ. - 2053-8790. ; 7:1, s. e000362-
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Journal article (peer-reviewed)abstract
- To compare progression of subclinical atherosclerosis and factors promoting it in patients with SLE and controls.MethodsConsecutive patients with SLE and age-matched, sex-matched population controls from the SLEVIC cohort were assessed at inclusion and after 7 years with standardised data collection and carotid ultrasound. Effect of risk factors on carotid intima–media thickness (cIMT) progression was examined with adjusted linear mixed models.ResultsA total of 77 patients and 74 controls, 68% and 61% of the original cohort, completed follow-up. The patients were (mean) 47 years old, 90% were women, and controls were 51 years old, 92% women. Patients had disease duration of (mean) 11 years, mild disease activity and low severity at both assessments. Baseline cIMT did not differ between the groups. An average absolute cIMT progression was 0.009 mm/year in patients and 0.011 mm/year in controls, intergroup difference p=0.9.Of factors at inclusion, dyslipidaemia, lower levels of high-density lipoprotein (HDL) and carotid plaque in patients and controls, and higher systolic blood pressure, total cholesterol:HDL and LDL:HDL ratios and triglycerides in patients were associated with cIMT progression. Of factors at follow-up, hypertension and blood lipids in patients and HDL in controls were significantly associated with cIMT progression. History of lupus nephritis and a higher average dose of prednisolone used since diagnosis were associated with cIMT progression in patients. Associations of risk factors with cIMT progression were stronger in presence of plaques.ConclusionWe observed a statistically comparable progression of cIMT in patients with mild SLE and controls over 7 years, which implies that progression of subclinical atherosclerosis in some patients with SLE could follow that of the general population. Traditional cardiovascular (CV) risk factors, history of lupus nephritis and higher use of corticosteroids promote cIMT progression in SLE. Detection of carotid plaque may add to CV risk stratification.
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| 3. |
- Almeida-Brasil, Celline C., et al.
(author)
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Retinal toxicity in a multinational inception cohort of patients with systemic lupus on hydroxychloroquine
- 2022
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In: Lupus Science and Medicine. - : BMJ. - 2053-8790. ; 9:1
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Journal article (peer-reviewed)abstract
- Objective To evaluate hydroxychloroquine (HCQ)-related retinal toxicity in the Systemic Lupus International Collaborating Clinics (SLICC) inception cohort. Methods Data were collected at annual study visits between 1999 and 2019. We followed patients with incident SLE from first visit on HCQ (time zero) up to time of retinal toxicity (outcome), death, loss-to-follow-up or end of study. Potential retinal toxicity was identified from SLICC Damage Index scores; cases were confirmed with chart review. Using cumulative HCQ duration as the time axis, we constructed univariate Cox regression models to assess if covariates (ie, HCQ daily dose/kg, sex, race/ethnicity, age at SLE onset, education, body mass index, renal damage, chloroquine use) were associated with HCQ-related retinal toxicity. Results We studied 1460 patients (89% female, 52% white). Retinal toxicity was confirmed in 11 patients (incidence 1.0 per 1000 person-years, 0.8% overall). Average cumulative time on HCQ in those with retinal toxicity was 7.4 (SD 3.2) years; the first case was detected 4 years after HCQ initiation. Risk of retinal toxicity was numerically higher in older patients at SLE diagnosis (univariate HR 1.05, 95% CI 1.01 to 1.09). Conclusions This is the first assessment of HCQ and retinal disease in incident SLE. We did not see any cases of retinopathy within the first 4 years of HCQ. Cumulative HCQ may be associated with increased risk. Ophthalmology monitoring (and formal assessment of cases of potential toxicity, by a retinal specialist) remains important, especially in patients on HCQ for 10+ years, those needing higher doses and those of older age at SLE diagnosis.
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| 4. |
- Andraos, Rama, et al.
(author)
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Autoantibodies associated with systemic sclerosis in three autoimmune diseases imprinted by type I interferon gene dysregulation: a comparison across SLE, primary Sjogrens syndrome and systemic sclerosis
- 2022
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In: Lupus Science and Medicine. - : BMJ PUBLISHING GROUP. - 2053-8790. ; 9:1
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Journal article (peer-reviewed)abstract
- ObjectiveSLE, primary Sjogrens syndrome (pSS) and systemic sclerosis (SSc) are heterogeneous autoimmune diseases with a dysregulated type I interferon (IFN) system. The diseases often show overlapping clinical manifestations, which may result in diagnostic challenges. We asked to which extent SSc-associated autoantibodies are present in SLE and pSS, and whether these link to serum IFN-alpha, clinical phenotypes and sex. Samples with clinical data from patients with SSc and healthy blood donors (HBDs) served as controls. Finally, the diagnostic performance of SSc-associated autoantibodies was evaluated.MethodsSamples from well-characterised subjects with SLE (n=510), pSS (n=116), SSc (n=57) and HBDs (n=236) were analysed using a commercially available immunoassay (EuroLine Systemic Sclerosis Profile (IgG)). IFN-alpha was quantified by ELISA. Self-reported data on Raynauds phenomenon (RP) were available.ResultsWith exceptions for anti-Ro52/SSA and anti-Th/To, SSc-associated autoantibodies were more frequent in SSc than in SLE, pSS and HBDs regardless of sex. IFN-alpha levels correlated with the number of positive SSc-associated autoantibodies (r=0.29, p<0.0001) and associated with Ro52/SSA positivity (p<0.0001). By using data from SLE, SSc and HBDs, RP was significantly associated with topoisomerase I, centromere protein (CENP)-B, RNA polymerase III 11 kDa, RNA polymerase III 155 kDa and PM-Scl100 whereas Ro52/SSA associated inversely with RP. In SLE, CENP-A was associated with immunological disorder, CENP-B with serositis and Ku with lupus nephritis. By combining analysis of ANA (immunofluorescence) with SSc-associated autoantibodies, the diagnostic sensitivity reached 98% and the specificity 33%.ConclusionsThe 13 specificities included in the EuroLine immunoassay are commonly detected in SSc, but they are also frequent among individuals with other diseases imprinted by type I IFNs. These findings are valuable when interpreting serological data on patients with suspected SSc, especially as patients may present with disease manifestations overlapping different rheumatological diseases. In SLE, we observed associations between manifestations and SSc-associated autoantibodies which have not previously been reported.
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| 5. |
- Antovic, A, et al.
(author)
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Obstetric antiphospholipid syndrome
- 2018
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In: Lupus science & medicine. - : BMJ. - 2053-8790. ; 5:1, s. e000197-
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Journal article (peer-reviewed)abstract
- The present clinical and laboratory classification criteria for antiphospholipid syndrome (APS) were established in Sydney, Australia, in 2006. In this review, we focus on the obstetric subset of APS (OAPS), defined by persistent positivity for antiphospholipid antibodies together with either early recurrent pregnancy loss, early fetal death, stillbirth or premature birth <34 gestational weeks due to pre-eclampsia, eclampsia and placental insufficiency. It is important to diagnose these cases since most women suffering from OAPS can, when given appropriate treatment, have successful pregnancies. Furthermore, patients with OAPS may, depending on the antibody profile, be at enhanced risk of thrombotic events later in life. We present an update on the present knowledge of possible underlying pathogenesis, risk factors and risk estimations for adverse pregnancy outcomes before and during pregnancy, current treatment concepts, and long-term outcomes for women with OAPS and their children.
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| 6. |
- Arat, Seher, et al.
(author)
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Illness representations of systemic lupus erythematosus and systemic sclerosis: a comparison of patients, their rheumatologists and their general practitioners.
- 2017
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In: Lupus science & medicine. - : BMJ. - 2053-8790. ; 4:1
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Journal article (peer-reviewed)abstract
- Discrepancies in illness representations between patients and physicians result in treatment difficulties, decreased well-being of patients and misunderstandings and disrupted communication. Hence, the objective of this study was to compare illness perceptions of individual patients with systemic lupus erythematosus (SLE) and systemic sclerosis (SSc), their rheumatologists and their general practitioners (GPs) and explore potential differences.This study has a cross-sectional design. Patients with SLE and SSc, who were followed at the rheumatology department of the University Hospitals Leuven (Belgium), completed the revised Illness Perception Questionnaire which measures patients' perceptions of their condition and captures nine dimensions. Physicians completed the Revised Illness Perception Questionnaire for Healthcare Professionals which consists of seven dimensions and measures perceptions of the healthcare professional regarding the disease of their patients. Intraclass correlation was performed to examine relationships between pairs of respondents; Cohen's d was used for estimating the magnitude of the difference.Questionnaires were sent to 284 patients of whom 241 (113 SSc and 128 SLE patients) were included. Five rheumatologists and 160 GPs participated. For both diseases, positive correlations were found for 'consequences', 'illness coherence' and 'emotional representations' among patients, rheumatologists and GPs. GPs scored higher on the 'consequences' of these diseases for the patient (d=0.71 for SLE; d=0.80 for SSc). Differences between rheumatologists and GPs were small for SSc and moderate to large for 'consequences' (d=0.56) and 'timeline acute/chronic' (d=0.95) in SLE with higher scores for GPs.For both diseases and among the three groups, significant correlations are detected for the dimensions 'consequences', 'illness coherence' and 'emotional representations'. Differences between rheumatologists and GPs were mainly detected in the case of SLE patients. This can have implications for the collaboration between these two groups of physicians in daily clinical practice.NCT02655640; Pre-results.
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| 7. |
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| 8. |
- Bernatsky, Sasha, et al.
(author)
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Lupus-related single nucleotide polymorphisms and risk of diffuse large B-cell lymphoma
- 2017
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In: Lupus Science and Medicine. - : BMJ. - 2053-8790. ; 4:1
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Journal article (peer-reviewed)abstract
- Objective: Determinants of the increased risk of diffuse large B-cell lymphoma (DLBCL) in SLE are unclear. Using data from a recent lymphoma genome-wide association study (GWAS), we assessed whether certain lupus-related single nucleotide polymorphisms (SNPs) were also associated with DLBCL. Methods: GWAS data on European Caucasians from the International Lymphoma Epidemiology Consortium (InterLymph) provided a total of 3857 DLBCL cases and 7666 general-population controls. Data were pooled in a random-effects meta-analysis. Results: Among the 28 SLE-related SNPs investigated, the two most convincingly associated with risk of DLBCL included the CD40 SLE risk allele rs4810485 on chromosome 20q13 (OR per risk allele=1.09, 95% CI 1.02 to 1.16, p=0.0134), and the HLA SLE risk allele rs1270942 on chromosome 6p21.33 (OR per risk allele=1.17, 95% CI 1.01 to 1.36, p=0.0362). Of additional possible interest were rs2205960 and rs12537284. The rs2205960 SNP, related to a cytokine of the tumour necrosis factor superfamily TNFSF4, was associated with an OR per risk allele of 1.07, 95% CI 1.00 to 1.16, p=0.0549. The OR for the rs12537284 (chromosome 7q32, IRF5 gene) risk allele was 1.08, 95% CI 0.99 to 1.18, p=0.0765. Conclusions: These data suggest several plausible genetic links between DLBCL and SLE.
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| 9. |
- Buyon, J, et al.
(author)
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Editorial
- 2014
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In: Lupus science & medicine. - : BMJ. - 2053-8790. ; 1:1, s. e000028-
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Journal article (peer-reviewed)
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| 10. |
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| 11. |
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| 12. |
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| 13. |
- Compagno, Michele, et al.
(author)
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Plasma levels of osteopontin in SLE
- 2022
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In: Lupus Science and Medicine. - : Lupus Foundation of America. - 2053-8790. ; 9:Suppl 2, s. 85-86
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Conference paper (peer-reviewed)
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| 14. |
- Crow, Mary K., et al.
(author)
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Report of the inaugural Interferon Research Summit : interferon in inflammatory diseases
- 2018
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In: Lupus Science and Medicine. - : BMJ. - 2053-8790. ; 5:1
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Research review (peer-reviewed)abstract
- An international summit on interferon (IFN) in inflammatory diseases, held in Gaithersburg, Maryland, USA (4-5 May 2017), united 22 internationally renowned clinicians and scientists with backgrounds in basic science, translational science and clinical medicine. The objectives of the summit were to assess the current knowledge of the role of type I IFN in inflammatory diseases and other conditions, discuss the available clinical trial data of anti-IFN therapeutic agents and identify key clinical and therapeutic knowledge gaps and future directions to advance the treatment landscape of diseases involving the type I IFN pathway. A discussion-based consensus process was used to assess three main clinical areas: the role of type I IFN in innate immunity, the role of type I IFN in autoimmune diseases and rational therapeutic targets in the IFN pathway. These are described here, along with current knowledge gaps and resulting recommendations. The advisors unanimously agreed that, despite significant obstacles, the field should transition from an organ-based model to a pathophysiology-based model. A better understanding of the molecular pathways could help inform potential therapeutic targets, thus progressing towards personalised medicine by tailoring the therapy to each patient.
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| 15. |
- Crow, Mary K., et al.
(author)
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Type I interferons in host defence and inflammatory diseases
- 2019
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In: Lupus Science and Medicine. - : BMJ Publishing Group Ltd. - 2053-8790. ; 6:1
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Research review (peer-reviewed)abstract
- Type I interferons (IFN) can have dual and opposing roles in immunity, with effects that are beneficial or detrimental to the individual depending on whether IFN pathway activation is transient or sustained. Determinants of IFN production and its functional consequences include the nature of the microbial or nucleic acid stimulus, the type of nucleic acid sensor involved in inducing IFN, the predominant subtype of type I IFN produced and the immune ecology of the tissue at the time of IFN expression. When dysregulated, the type I IFN system drives many autoimmune and non-autoimmune inflammatory diseases, including SLE and the tissue inflammation associated with chronic infection. The type I IFN system may also contribute to outcomes for patients affected by solid cancers or myocardial infarction. Significantly more research is needed to discern the mechanisms of induction and response to type I IFNs across these diseases, and patient endophenotyping may help determine whether the cytokine is acting as 'friend' or 'foe', within a particular patient, and at the time of treatment. This review summarises key concepts and discussions from the second International Summit on Interferons in Inflammatory Diseases, during which expert clinicians and scientists evaluated the evidence for the role of type I IFNs in autoimmune and other inflammatory diseases.
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| 16. |
- Giannakou, Ioanna, et al.
(author)
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Predictors of persistent disease activity and long quiescence in systemic lupus erythematosus: results from the Hopkins Lupus Cohort
- 2018
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In: Lupus science & medicine. - : BMJ. - 2053-8790. ; 5:1, s. e000287-
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Journal article (peer-reviewed)abstract
- The aim of this study is to identify prognostic factors of persistent disease activity and long quiescence in systemic lupus erythematosus (SLE).MethodsPatients enrolled in the Hopkins Lupus Cohort from 1987 to 2012, who attended at least three visits per year during 3 consecutive years following baseline and had available information on disease activity were included. Patterns of SLE disease activity over the 3-year period were defined as: persistent long quiescent (pLQ), persistent relapsing-remitting (pRR), persistent chronic active (pCA) and mixed based on Modified SLE Disease Activity Index (M-SLEDAI). Possible predictors of pCA (vs pLQ, pRR and mixed) and pLQ (vs pCA, pRR and mixed) were identified by univariate and multivariate logistic regression analyses.Results916 patients were included. In the multivariate analysis, use of hydroxychloroquine (OR: 0.45, 95% CI 0.22 to 0.92, p=0.03), African American ethnicity (OR: 2.36, 95% CI 1.15 to 4.85, p=0.02) and baseline SLEDAI (OR: 1.10, 95% CI 1.03 to 1.17, p=0.005) remained significant predictors of pCA. Higher education (>12 years; OR. 2.07, 95% CI 1.07 to 4.03, p=0.03) and lower baseline SLEDAI (OR: 0.67, 95% CI 0.56 to 0.82, p<0.001) were significant predictors of pLQ, while African American (OR: 0.38, 95% CI 0.17 to 0.83, p=0.02) and female patients (OR: 0.26, 95% CI 0.12 to 0.57, p<0.001) were less likely to achieve pLQ.ConclusionAfrican American ethnicity and high disease activity at baseline predict chronic activity in SLE, regardless of treatment, years of education and income. Higher education, low disease activity at baseline and male sex predict long quiescence. The use of hydroxychloroquine is independently associated with a lower risk of chronically active disease.
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| 17. |
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| 18. |
- Han, Bobby Kwanghoon, et al.
(author)
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Neutrophil and lymphocyte counts are associated with different immunopathological mechanisms in systemic lupus erythematosus
- 2020
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In: Lupus Science and Medicine. - : BMJ. - 2053-8790. ; 7:1
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Journal article (peer-reviewed)abstract
- Objective: Neutrophils contribute to the SLE pathogenesis. Neutrophil to lymphocyte ratio (NLR) is reported to correlate with disease activity in SLE. The aim of the study was to evaluate whether NLR reflects underlying immunopathogenic activity in SLE, as well as to determine the contribution of each component of NLR, neutrophil and lymphocyte count. Methods: Data were obtained from a cohort of patients with SLE (n=141) recruited at Lund University, Sweden. NLR levels were compared between patients with SLE and healthy controls (n=79). The relationship between NLR and clinical and immunological markers was examined using Mann-Whitney U test and logistic regression analysis. High NLR was defined as above the 90th percentile of healthy individuals. Results: Patients with SLE had elevated neutrophil count (p=0.04) and reduced lymphocyte count (p<0.0001), resulting in elevated NLR as compared with healthy controls (p<0.0001). Patients with high NLR had more active disease, and were more frequently on prednisone use and immunosuppressive medicines. High NLR was associated with immune complex (IC)-driven disease with presence of antidouble-stranded DNA antibodies (p=0.006), circulating ICs (p=0.02) and type I interferon (IFN) activity (p=0.009). Further, high NLR was associated with neutrophil abnormalities, including enrichment for low-density granulocytes (LDGs) (p=0.001), and increased levels of the serum neutrophil activation marker, calprotectin (p=0.02). Assessing the individual components within NLR, that is, neutrophil and lymphocyte count, high neutrophil count was associated with neutrophil activation markers (p<0.0001), whereas low lymphocyte count was associated with type I IFN activity and elevated numbers of LDGs (p=0.006 and p=0.001, respectively). Conclusions: NLR is elevated in patients with SLE as compared with healthy individuals, and is associated with key immunopathological events, including type I IFN activity and neutrophil activation. Neutrophil and lymphocyte count reflected different aspects of the pathogenesis of SLE. Further studies are needed to determine the causality of the associations.
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| 19. |
- Hedenstedt, Anna, et al.
(author)
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B cell polygenic risk scores associate with anti-dsDNA antibodies and nephritis in systemic lupus erythematosus.
- 2023
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In: Lupus science & medicine. - : BMJ Publishing Group Ltd. - 2053-8790. ; 10:2
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Journal article (peer-reviewed)abstract
- B cell function and autoantibodies are important in SLE pathogenesis. In this work, we aimed to investigate the impact of cumulative SLE B cell genetics on SLE subphenotype and autoantibody profile.Female patients with SLE (n=1248) and healthy controls (n=400) were genotyped using Illumina's Global Screening Array. Two polygenic risk scores (PRSs), one representing B cell genes and the other B cell activation genes, were calculated for each individual using risk loci for SLE in genes assigned to B cell-related pathways according to the Kyoto Encyclopedia of Genes and Genomes, Gene Ontology and Reactome Databases.Double-stranded DNA (dsDNA) antibodies were more prevalent among patients with a high compared with a low SLE B cell PRS (OR 1.47 (1.07 to 2.01), p=0.018), and effect sizes were augmented in patients with human leucocyte antigen (HLA) risk haplotypes HLA-DRB1*03:01 and HLA-DRB1*15:01 (DRB1*03/15 -/- (OR 0.99 (0.56 to 1.77), p=0.98; DRB1*03/15 +/- or -/+ (OR 1.64 (1.06 to 2.54), p=0.028; and DRB1*03/15 +/+ (OR 4.47 (1.21 to 16.47), p=0.024). Further, a high compared with a low B cell PRS was associated with low complement levels in DRB1*03/15 +/+ patients (OR 3.92 (1.22 to 12.64), p=0.022). The prevalence of lupus nephritis (LN) was higher in patients with a B cell activation PRS above the third quartile compared with patients below (OR 1.32 (1.00 to 1.74), p=0.048).High genetic burden related to B cell function is associated with dsDNA antibody development and LN. Assessing B cell PRSs may be important in order to determine immunological pathways influencing SLE and to predict clinical phenotype.
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| 20. |
- Häyry, Aliisa, et al.
(author)
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Interleukin (IL) 16 : a candidate urinary biomarker for proliferative lupus nephritis
- 2022
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In: Lupus Science and Medicine. - : BMJ Publishing Group Ltd. - 2053-8790. ; 9:1
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Journal article (peer-reviewed)abstract
- OBJECTIVE: Lupus nephritis (LN) is a severe manifestation of systemic lupus erythematosus (SLE). The pathogenesis is incompletely understood and diagnostic biomarkers are scarce. We investigated interleukin (IL) 16 as a potential biomarker for LN in a well-characterised cohort of patients with SLE.METHODS: We measured urinary (u-) and plasma (p-) levels of IL-16 in predefined patient groups using ELISA: LN (n=84), active non-renal SLE (n=63), inactive non-renal SLE (n=73) and matched population controls (n=48). The LN group included patients with recent biopsy-confirmed proliferative (PLN, n=47), mesangioproliferative (MES, n=11) and membranous (MLN, n=26) LN. Renal expression of IL-16 was investigated by immunohistochemistry. Associations between IL-16 measurements and clinical parameters and the diagnostic value for LN were explored.RESULTS: p-IL-16 was detected in all investigated cases and high p-IL-16 levels were observed in patients with active SLE. u-IL-16 was detected (dt-u-IL-16) in 47.6% of patients with LN, while only up to 17.8% had dt-u-IL-16 in other groups. In the LN group, 68% of patients with PLN had dt-u-IL-16, while the proportions in the MLN and MES groups were lower (11.5% and 45.5%, respectively). The highest u-IL-16 levels were detected in the PLN group. In the regression model, u-IL-16 levels differentiated PLN from other LN patient subgroups (area under the curve 0.775-0.896, p<0.0001). dt-u-IL-16 had superior specificity but slightly lower sensitivity than elevated anti-double-stranded DNA and low complement C3 or C4 in diagnosing PLN. A high proportion of LN kidney infiltrating cells expressed IL-16.CONCLUSIONS: We demonstrate that detectable u-IL-16 can differentiate patients with PLN from those with less severe LN subtypes and active non-renal SLE. Our findings suggest that u-IL-16 could be used as a screening tool at suspicion of severe LN. Furthermore, the high IL-16 levels in plasma, urine and kidney tissue imply that IL-16 could be explored as a therapeutic target in SLE.
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| 21. |
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| 22. |
- Kraaij, Tineke, et al.
(author)
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Measuring plasma C4D to monitor immune complexes in lupus nephritis
- 2019
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In: Lupus Science and Medicine. - : BMJ. - 2053-8790. ; 6:1
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Journal article (peer-reviewed)abstract
- Objective Because currently available assays that measure circulating immune complexes (ICx) are suboptimal, a novel assay was recently developed measuring C4d, a stable product of activation of the classical complement pathway. The present study aimed to establish the value of measuring plasma C4d levels in a longitudinal cohort of patients with severe refractory SLE who were treated with a combination therapy of rituximab with belimumab (RTX+BLM). Methods Fifteen patients with SLE who were treated with RTX+BLM in a phase 2A, open label study were included to sequentially measure plasma C4d levels and correlated to well-established markers of ICx-formation, that is, autoantibodies against double-stranded (ds) DNA, autoantibodies against C1q and proteinuria. The performance of plasma C4d measurements, C4 measurements and the ratio of C4d over C4 (C4d:C4) was evaluated. Results After establishing that on RTX+BLM treatment kinetics of C4d levels was distinct from traditional C3 and C4 levels, we found strong correlation of C4d:C4 with anti-dsDNA (R=0.76, p<0.001) and anti-C1q (R=0.65, p<0.001) autoantibody levels, which outperformed both stand-alone C4 and C4d levels. Additionally, changes in C4d:C4 over time correlated strongly with changes in proteinuria (R=0.59, p<0.001) as well as anti-dsDNA (R=0.46, p=0.003) and anti-C1q (R=0.47, p=0.002). Conclusion In patients with severe SLE, plasma C4d levels in relation to C4 levels is useful for longitudinal monitoring after RTX+BLM treatment to reflect amelioration of classical complement activation by ICx as well as proteinuria.
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| 23. |
- Krustev, Eugene, et al.
(author)
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Anti-KIF20B autoantibodies are associated with cranial neuropathy in systemic lupus erythematosus
- 2024
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In: Lupus Science and Medicine. - 2053-8790. ; 11:1
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Journal article (peer-reviewed)abstract
- Background Cranial neuropathies (CN) are a rare neuropsychiatric SLE (NPSLE) manifestation. Previous studies reported that antibodies to the kinesin family member 20B (KIF20B) (anti-KIF20B) protein were associated with idiopathic ataxia and CN. We assessed anti-KIF20B as a potential biomarker for NPSLE in an international SLE inception cohort. Methods Individuals fulfilling the revised 1997 American College of Rheumatology (ACR) SLE classification criteria were enrolled from 31 centres from 1999 to 2011 and followed annually in the Systemic Lupus Erythematosus International Collaborating Clinics inception cohort. Anti-KIF20B testing was performed on baseline (within 15 months of diagnosis or first annual visit) samples using an addressable laser bead immunoassay. Logistic regression (penalised maximum likelihood and adjusting for confounding variables) examined the association between anti-KIF20B and NPSLE manifestations (1999 ACR case definitions), including CN, occurring over the first 5 years of follow-up. Results Of the 1827 enrolled cohort members, baseline serum and 5 years of follow-up data were available on 795 patients who were included in this study: 29.8% were anti-KIF20B-positive, 88.7% female, and 52.1% White. The frequency of anti-KIF20B positivity differed only for those with CN (n=10) versus without CN (n=785) (70.0% vs 29.3%; OR 5.2, 95% CI 1.4, 18.5). Compared with patients without CN, patients with CN were more likely to fulfil the ACR haematological (90.0% vs 66.1%; difference 23.9%, 95% CI 5.0%, 42.8%) and ANA (100% vs 95.7%; difference 4.3%, 95% CI 2.9%, 5.8%) criteria. In the multivariate analysis adjusting for age at baseline, female, White race and ethnicity, and ACR haematological and ANA criteria, anti-KIF20B positivity remained associated with CN (OR 5.2, 95% CI 1.4, 19.1). Conclusion Anti-KIF20B is a potential biomarker for SLE-related CN. Further studies are needed to examine how autoantibodies against KIF20B, which is variably expressed in a variety of neurological cells, contribute to disease pathogenesis.
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| 25. |
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| 26. |
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| 27. |
- Nived, Ola, et al.
(author)
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Disease duration, age at diagnosis and organ damage are important factors for cardiovascular disease in SLE
- 2020
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In: Lupus science & medicine. - : BMJ. - 2053-8790. ; 7
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Journal article (peer-reviewed)abstract
- OBJECTIVE: To report the incidence rate ratios (IRR) of acute myocardial infarctions (AMI) and cerebrovascular events (CVE) in incident SLE cases from a defined population. To study the risk factors for cardiovascular events in all patients with SLE at our unit.METHODS: Patients with SLE diagnosed from 1981 to 2006 were followed through to 2016. IRRs of AMI and CVE were calculated. The AMI and CVE incidence patterns for patients with SLE were studied in relation to hypertension, smoking, renal dysfunction, anticardiolipin (aCL) antibodies at diagnosis, disease duration and organ damage before an event.RESULTS: 262 patients with SLE were included in the study; of these 175 were from the defined population. Overall, 37 AMI and 44 CVE were recorded. An increased IRR of 3 for AMI was found (p<0.001). Smoking, hypertension and reduced renal function were risk factors for AMI. An increased IRR of 3.3 for ischaemic CVE was found for women (p<0.001). Hypertension and aCL were risk factors for CVE. Organ damage before events was increased.CONCLUSIONS: Cardiovascular events are increased in SLE and are associated with hypertension, smoking and increased damage rate.
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| 28. |
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| 29. |
- Parodis, I., et al.
(author)
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Evaluation of B lymphocyte stimulator and a proliferation inducing ligand as candidate biomarkers in lupus nephritis based on clinical and histopathological outcome following induction therapy
- 2015
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In: Lupus Science and Medicine. - : BMJ. - 2053-8790. ; 2:1, s. e000061-e000061
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Journal article (peer-reviewed)abstract
- Objectives: Lupus nephritis (LN) is a major cause of morbidity in patients with systemic lupus erythematosus (SLE). B cells have a central role in the pathogenesis of SLE. B lymphocyte stimulator (BLyS) and a proliferation inducing ligand (APRIL) are pivotal in B cell homeostasis. We aimed to investigate a potential role of serum BLyS and APRIL as biomarkers in LN, especially as predictors of treatment response. Methods: Sixty-four patients with active LN (52 proliferative lupus nephritis (PLN); 12 membranous LN) were included. Renal biopsies were performed at baseline and after immunosuppressive treatment. Serum levels of BLyS, APRIL and autoantibodies were measured on both biopsy occasions and in 64 individually matched controls. Renal biopsies were evaluated using the International Society of Nephrology/Renal Pathology Society classification, and scored for Activity Index and Chronicity Index. Clinical responders (CR) were required to have ≥50% reduction in proteinuria, normal or improved renal function, and inactive urinary sediment. Histopathological responders (HR) were required to have ≥50% improvement in Activity Index. Results: Baseline BLyS levels were significantly higher in LN patients compared with controls (p<0.001) and remained unchanged following induction treatment. APRIL levels were significantly higher in patients compared with controls at baseline (p=0.005) and decreased following treatment ( p<0.001). Among PLN patients, APRIL levels decreased significantly only in responders (CR: p=0.009; HR: p=0.01). Baseline BLyS levels <1.5 ng/mL predicted treatment response, attaining a positive predictive value of 92% for CR with PLN at baseline. Conclusions: BLyS and APRIL were affected differently by immunosuppression; BLyS levels remained unchanged following therapy while APRIL levels decreased. Despite unchanged BLyS levels following therapy, low baseline levels predicted both clinical and histopathological improvement. Our data support APRIL as a candidate biomarker of renal disease activity in lupus patients with proliferative glomerulonephritis and point to low baseline BLyS levels predicting treatment response in LN, especially in PLN.
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| 30. |
- Parodis, I, et al.
(author)
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Prediction of prognosis and renal outcome in lupus nephritis
- 2020
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In: Lupus science & medicine. - : BMJ. - 2053-8790. ; 7:1, s. e000389-
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Journal article (peer-reviewed)abstract
- Lupus nephritis (LN) is a severe manifestation of SLE, characterised by subendothelial and/or subepithelial immune complex depositions in the afflicted kidney, resulting in extensive injury and nephron loss during the acute phase and eventually chronic irreversible damage and renal function impairment if not treated effectively. The therapeutic management of LN has improved during the last decades, but the imperative need for consensual outcome measures remains. In order to design trials with success potentiality, it is important to define clinically important short-term and long-term targets of therapeutic and non-therapeutic intervention. While it is known that early response to treatment is coupled with favourable renal outcomes, early predictors of renal function impairment are lacking. The information gleaned from kidney biopsies may provide important insights in this direction. Alas, baseline clinical and histopathological information has not been shown to be informative. By contrast, accumulating evidence of pronounced discrepancies between clinical and histopathological outcomes after the initial phase of immunosuppression has prompted investigations of the potential usefulness of per-protocol repeat kidney biopsies as an integral part of treatment evaluation, including patients showing adequate clinical response. This approach appears to have merit. Hopefully, clinical, molecular or genetic markers that reliably reflect kidney histopathology and portend the long-term prognosis will be identified. Novel non-invasive imaging methods and employment of the evolving artificial intelligence in pattern recognition may also be helpful towards these goals. The molecular and cellular characterisation of SLE and LN will hopefully result in novel therapeutic modalities, maybe new taxonomy perspectives, and ultimately personalised management.
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| 31. |
- Ruacho, Guillermo, et al.
(author)
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Inflammatory markers in saliva and urine reflect disease activity in patients with systemic lupus erythematosus
- 2022
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In: Lupus Science and Medicine. - : BMJ Publishing Group Ltd. - 2053-8790. ; 9:1
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Journal article (peer-reviewed)abstract
- Background Laboratory tests of blood and sometimes urine are used to diagnose and to monitor disease activity (DA) in SLE. Clinical practice would be simplified if non-invasive urine and salivary tests could be introduced as alternatives to blood samples. We therefore explored the levels of innate immunity-related biomarkers in matched serum, urine and saliva samples from patients with SLE. Methods A total of 84 patients with SLE selected to represent high and low general DA, and 21 controls were included. All participants underwent a thorough clinical examination. General DA and renal DA were measured. The levels of colony-stimulating factor (CSF)-1, interleukin (IL)-34, tumour necrosis factor (TNF)-alpha, interferon-gamma-induced protein (IP)-10, monocyte chemoattractant protein (MCP)-1, calprotectin, macrophage inflammatory protein (MIP)-1 alpha and MIP-1 beta were analysed by immunoassays and related to DA. Results CSF-1, TNF-alpha, IP-10 and MCP-1 in saliva, serum and urine, as well as calprotectin in saliva and urine were increased in patients with SLE as compared with controls (p<0.05). TNF-alpha, IP-10 and MCP-1 in saliva, serum and urine, and CSF-1 in saliva and serum distinguished patients with SLE from controls (area under the curve >0.659; p<0.05 for all). CSF-1 in serum and urine, and calprotectin in saliva and urine, as well as TNF- alpha, IP-10 and MCP-1 in urine correlated positively with measures of general DA (p<0.05). Patients with SLE with active renal disease presented elevated levels of TNF-alpha, IP-10 and MCP-1 in urine and CSF-1 and IP-10 in serum as compared with patients with SLE with non-active renal disease. Conclusions Our investigation demonstrates that saliva is a novel alternative body fluid, with potential for surveillance of general DA in patients with SLE, but urine is more informative in patients with SLE with predominantly renal DA.
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| 32. |
- Ryden-Aulin, Monica, et al.
(author)
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Off-label use of rituximab for systemic lupus erythematosus in Europe
- 2016
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In: Lupus Science and Medicine. - : BMJ. - 2053-8790. ; 3:1
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Research review (peer-reviewed)abstract
- Objectives: Rituximab (RTX) is a biological treatment used off-label in patients with systemic lupus erythematosus (SLE). This survey aimed to investigate the off-label use of RTX in Europe and compare the characteristics of patients receiving RTX with those receiving conventional therapy. Methods: Data on patients with SLE receiving RTX were taken from the International Registry for Biologics in SLE retrospective registry and complemented with data on patients with SLE treated with conventional therapy. For nationwide estimates of RTX use in patients with SLE, investigators were asked to provide data through case report forms (CRFs). Countries for which no data were submitted through CRFs, published literature and/or personal communication were used, and for European countries where no data were available, estimates were made on the assumption of similarities with neighbouring countries. Results: The estimated off-label use of RTX in Europe was 0.5%-1.5% of all patients with SLE. In comparison with patients with SLE on conventional therapy, patients treated with RTX had longer disease duration, higher disease activity and were more often treated with immunosuppressives. The most frequent organ manifestations for which either RTX or conventional therapy was initiated were lupus nephritis followed by musculoskeletal and haematological. The reason for treatment was, besides disease control, corticosteroid-sparing for patients treated with conventional therapy. Conclusions: RTX use for SLE in Europe is restrictive and appears to be used as a last resort in patients for whom other reasonable options have been exhausted.
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| 33. |
- Rönnblom, Lars, et al.
(author)
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Interferon pathway in SLE : one key to unlocking the mystery of the disease
- 2019
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In: Lupus Science and Medicine. - : BMJ Publishing Group Ltd. - 2053-8790. ; 6:1
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Research review (peer-reviewed)abstract
- SLE is characterised by an activation of the interferon (IFN) system, which leads to an increased expression of IFN-regulated genes. The reasons behind the IFN signature in SLE are (1) the existence of endogenous IFN inducers, (2) activation of several IFN-producing cell types, (3) production of many different IFNs, (4) a genetic setup promoting IFN production and (5) deficient negative feedback mechanisms. The consequences for the immune system is a continuous stimulation to an immune response, and for the patient a number of different organ manifestations leading to typical symptoms for SLE. In the current review, we will present the existing knowledge of the IFN system and pathway activation in SLE. We will also discuss how this information can contribute to our understanding of both the aetiopathogenesis and some organ manifestations of the disease. We will put forward some issues that are unresolved and should be clarified in order to make a proper stratification of patients with SLE, which seems important when selecting a therapy aiming to downregulate the IFN system.
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| 34. |
- Samuelsson, I, et al.
(author)
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Myocardial infarctions, subtypes and coronary atherosclerosis in SLE: a case-control study
- 2021
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In: Lupus science & medicine. - : BMJ. - 2053-8790. ; 8:1
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Journal article (peer-reviewed)abstract
- Patients with SLE have increased risk of myocardial infarction (MI). Few studies have investigated the characteristics of SLE-related MIs. We compared characteristics of and risk factors for MI between SLE patients with MI (MI-SLE), MI patients without SLE (MI-non-SLE) and SLE patients without MI (non-MI-SLE) to understand underlying mechanisms.MethodsWe identified patients with a first-time MI in the Karolinska SLE cohort. These patients were individually matched for age and gender with MI-non-SLE and non-MI-SLE controls in a ratio of 1:1:1. Retrospective medical file review was performed. Paired statistics were used as appropriate.ResultsThirty-four MI-SLE patients (88% females) with a median age of 61 years were included. These patients had increased number of coronary arteries involved (p=0.04), and ≥50% coronary atherosclerosis/occlusion was numerically more common compared with MI-non-SLE controls (88% vs 66%; p=0.07). The left anterior descending artery was most commonly involved (73% vs 59%; p=0.11) and decreased (<50%) left ventricular ejection fraction occurred with similar frequency in MI-SLE and MI-non-SLE patients (45% vs 36%; p=0.79). Cardiovascular disease (44%, 5.9%, 12%; p<0.001) and coronary artery disease (32%, 2.9%, 0%; p<0.001), excluding MI, preceded MI/inclusion more commonly in MI-SLE than in MI-non-SLE and non-MI-SLE patients, respectively. MI-SLE patients had lower plasma albumin levels than non-MI-SLE patients (35 (29–37) vs 40 (37–42) g/L; p=0.002).ConclusionIn the great majority of cases, MIs in SLE are associated with coronary atherosclerosis. Furthermore, MIs in SLE are commonly preceded by symptomatic vascular disease, calling for attentive surveillance of cardiovascular disease and its risk factors and early atheroprotective treatment.
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| 35. |
- Selvaraja, M, et al.
(author)
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Human leucocyte antigens profiling in Malay female patients with systemic lupus erythematosus: are we the same or different?
- 2022
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In: Lupus science & medicine. - : BMJ. - 2053-8790. ; 9:1
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Journal article (peer-reviewed)abstract
- SLE is a heterogeneous autoimmune disease, in terms of clinical presentation, incidence and severity across diverse ethnic populations. We investigated the human leucocyte antigens (HLA) profile (ie, HLA-A, HLA-B and HLA-C, HLA-DRB1, HLA-DQA1, HLA-DQB1, HLA-DPA1 and HLA-DPB1) in Malaysian Malay female patients with SLE and determined the generalisability of the published HLA risk factors across different ethnic populations globally including Malaysia.MethodsOne hundred Malay female patients with SLE were recruited between January 2016 and October 2017 from a nephrology clinic. All patients were genotyped for HLA-A, HLA-B, HLA-C, HLA-DRB1, HLA-DQA1, HLA-DQB1, HLA-DPA1 and HLA-DPB1 alleles using PCR sequence-specific oligonucleotides method on Luminex platform. A total of 951 HLA genotyped population-based Malay control subjects was used for association testing by means of OR with 95% CIs.ResultsOur findings convincingly validated common associations between HLA−A*11 (OR=1.65, p=3.36×10−3, corrected P (Pc)=4.03×10−2) and DQB1*05:01 (OR=1.56, p=2.02×10−2, Pc=non−significant) and SLE susceptibility in the Malay population. In contrast, DQB1*03:01 (OR=0.51, p=4.06×10−4, Pc=6.50×10−3) were associated with decreased risk of SLE in Malay population. Additionally, we also detected novel associations of susceptibility HLA genes (ie, HLA-B*38:02, DPA1*02:02, DPB1*14:01) and protective HLA genes (ie, DPA1*01:03). When comparing the current data with data from previously published studies from Caucasian, African and Asian populations, DRB1*15 alleles, DQB1*03:01 and DQA1*01:02 were corroborated as universal susceptibility and protective genes.ConclusionsThis study reveals multiple HLA alleles associated with susceptibility and protection against risk of developing SLE in Malay female population with renal disorders. In addition, the published data from different ethnic populations together with our study further support the notion that the genetic effects from association with DRB1*15:01/02, DQB1*03:01 and DQA1*01:02 alleles are generalised to multiple ethnic populations of Caucasian, African and Asian descents.
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| 36. |
- Simard, JF, et al.
(author)
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Infection hospitalisation in systemic lupus in Sweden
- 2021
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In: Lupus science & medicine. - : BMJ. - 2053-8790. ; 8:1
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Journal article (peer-reviewed)abstract
- Immune dysregulation in SLE and the corresponding immune-modulating and immunosuppressive nature of the treatments may play key roles in infection risk. We compared serious infection rates among individuals with incident SLE with the general population, and examined the role of treatment initiation in SLE.MethodsNewly diagnosed patients with SLE (2006–2013) and general population comparators from the Swedish Lupus Linkage cohort were followed for serious infection through 2016. Adjusted Cox and frailty models estimated the relative risk of first and recurrent infections, respectively. Using a new-user design, rates of serious infections were compared between disease-modifying antirheumatic drugs (DMARDs) and hydroxychloroquine (HCQ) initiators. We then evaluated three DMARDs (azathioprine, mycophenolate mofetil and methotrexate) in multivariable-adjusted models.ResultsIndividuals with SLE experienced more infections (22% vs 6%), especially during the first year of follow-up, and recurrent serious infections were also more common (HR=2.22, 95% CI 1.93 to 2.56). DMARDs were associated with a higher rate of serious infection versus HCQ (HR=1.82, 95% CI 1.27 to 2.60), which attenuated after multivariable-adjustment (HR=1.30, 95% CI 0.86 to 1.95). Among DMARDs, azathioprine was associated with infection (HR=2.19, 95% CI 1.14 to 4.21) and mycophenolate mofetil yielded an HR=1.39 (95% CI 0.65 to 2.96) in multivariable-adjusted models compared with methotrexate. Results were comparable across numerous sensitivity analyses.ConclusionIndividuals with incident SLE were 2–4 times more likely to be hospitalised for infection and experienced more recurrent infections than the general population. Among DMARD initiators, azathioprine was associated with the highest rate.
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| 37. |
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| 38. |
- Stockfelt, Marit, et al.
(author)
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Activated low-density granulocytes in peripheral and intervillous blood and neutrophil inflammation in placentas from SLE pregnancies
- 2021
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In: Lupus Science and Medicine. - : BMJ. - 2053-8790. ; 8:1
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Journal article (peer-reviewed)abstract
- Objective Women with SLE face an increased risk of adverse pregnancy outcomes compared with healthy women, but the underlying immunological mechanisms are unknown. Given the recognised association of neutrophil activation with SLE pathogenesis, we examined whether there is increased neutrophil activation and inflammation in blood and placenta in SLE relative to healthy pregnancy. Methods At delivery, peripheral blood, maternal-derived intervillous blood and placentas were collected from 12 SLE and 10 healthy control pregnancies. The proportion of low-density granulocytes (LDGs) and the activation status of LDG and normal-density granulocytes were examined with flow cytometry. The chemokines CXCL8 and CXCL1 were quantified with a cytometric bead-based assay and interferon alpha (IFNα) protein levels with a Simoa method. IFNα-stimulated maternal-derived decidual stromal cells were examined for CXCL8 gene expression with qPCR. A pathologist, blinded to the patient background, examined all placentas. Results Women with SLE had significantly higher proportions of LDG in peripheral blood compared with controls (p=0.02), and LDG in both peripheral and intervillous blood were more activated in SLE relative to healthy pregnancies (peripheral blood: p=0.002 and intervillous blood: p=0.05). There were higher levels of CXCL8 and CXCL1 in intervillous compared with peripheral blood in women with SLE (p=0.004 and p=<0.0001, respectively) but not in controls. In SLE pregnancy, IFNα was detectable in 6 out of 10 intervillous blood samples but only in one control. Stimulation with IFNα upregulated CXCL8 gene expression in decidual stromal cells from both SLE and healthy pregnancy. Histological chorioamnionitis was present in 6 out of 12 placentas from women with SLE and in 1 out of 10 controls. Conclusions In women with SLE, locally produced chemokines in the placenta are increased and may attract and activate neutrophils. This in turn could contribute to placental inflammation and dysfunction and increased risk of placenta-related pregnancy complications.
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| 39. |
- Svenungsson, E., et al.
(author)
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Quick Systemic Lupus Activity Questionnaire (Q-SLAQ): a simplified version of SLAQ for patient-reported disease activity
- 2021
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In: Lupus Science & Medicine. - : BMJ. - 2053-8790. ; 8
-
Journal article (peer-reviewed)abstract
- Objectives Most indices of disease activity in SLE combine physicians' assessments and laboratory tests. However, there is also a need to capture patients' perspectives of disease activity. Consequently, we need new, preferably quick and easy instruments to collect this information, which can be very useful for online consultations and registry purposes. We compared patients' assessments of SLE disease impact/activity, as reported by a shorter version of the Quick Systemic Lupus Activity Questionnaire (Q-SLAQ), with physicians' assessments using SLE Activity Measure (SLAM) and SLE Disease Activity Index (SLEDAI-2K) and with the original Systemic Lupus Activity Questionnaire (SLAQ). Methods Patients with SLE (n=115), with a disease duration of 15 years (IQR 17), completed the Q-SLAQ prior to physicians' assessments by SLAM and SLEDAI-2K. A second set of patients (n=85) with similar characteristics filled out Q-SLAQ and SLAQ. Spearman's rho correlations were explored between patients' total Q-SLAQ and subscales (Symptom Score, Patient's Global Disease Activity) and physicians' SLAM and SLEDAI-2K, with and without laboratory items (SLAM-nolab and SLEDAI-2K-nolab) and SLAQ. Corresponding items in Q-SLAQ and SLAM were compared. Results Correlations between patients' and physicians' assessments were higher for SLAM-nolab (total Q-SLAQ, rho=0.71; Symptom Score, rho=0.67; and Patient's Global Disease Activity, rho=0.68) than for the original SLAM (total Q-SLAQ, rho=0.53; Symptom Score, rho=0.50; and Patient's Global Disease Activity, rho=0.53). Regarding specific symptoms, fatigue (rho=0.72) and alopecia (rho=0.71) correlated best, while pulmonary/respiratory symptoms correlated least (rho=0.19, p=0.039). Physicians assessment with SLEDAI-2K-nolab correlated weakly with patients' assessments (total Q-SLAQ, rho=0.30; Symptom Score, rho=0.30; and Patient's Global Disease Activity, rho=0.36). Bivariate correlations between Q-SLAQ and SLAQ were good (rho=0.82-0.96). Conclusions Q-SLAQ and the original SLAQ performed equally well, demonstrating that the shorter Q-SLAQ can safely be used to monitor patients' perception of disease impact/activity. We also noted an intriguing discrepancy between physicians' and patients' evaluations of pulmonary/respiratory symptoms, which requires further investigations.
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| 40. |
- Tessier-Cloutier, Basile, et al.
(author)
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Cell of origin in diffuse large B-cell lymphoma in systemic lupus erythematosus : molecular and clinical factors associated with survival
- 2019
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In: Lupus Science and Medicine. - : BMJ PUBLISHING GROUP. - 2053-8790. ; 6:1
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Journal article (peer-reviewed)abstract
- Background SLE is associated with increased risk of diffuse large B-cell lymphoma (DLBCL). DLBCL is routinely classified by cell of origin (COO), with germinal centre B-cell (GCB) being more common and indicating better prognosis in the general population. We studied COO subtyping in patients with SLE diagnosed with DLBCL and their survival. Patients and methods We evaluated 20 cases of SLE with DLBCL. Immunohistochemistry analysis was performed (BCL2, MYC, BCL6, CD10, CD20, FOXP1, GCET1, MUM1) in tissue microarrays. We examined associations between molecular and clinical features, including overall survival. Results Of the 20 DLBCL SLE cases, 12/20 cases (60%) were classified as non-GCB using Hans or Choi algorithms. MYC and BCL2 protein expression was positive in 6/20 (30%) and 8/20 (40%) SLE cases, respectively, with 2/20 (10%) co-expressing both markers. Seven (7/20) had only extranodal involvement at DLBCL diagnosis. As expected, non-GCB cases had worse survival. Cases presenting exclusively with extranodal disease were associated with shorter SLE duration and better survival despite higher BCL2 protein expression. Conclusions We present novel data characterising DLBCL in SLE. Sixty per cent of the DLBCL in patients with SLE were non-GCB. The nodal and extranodal distribution in SLE was similar to what is known in the general population, but extranodal disease occurred more often with short SLE duration and was associated with longer overall survival. More research on cancer in SLE is the key to further understanding the complex interplay between cancer and the immune system.
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| 41. |
- Ugarte-Gil, Manuel Francisco, et al.
(author)
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Impact of glucocorticoids on the incidence of lupus-related major organ damage : A systematic literature review and meta-regression analysis of longitudinal observational studies
- 2021
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In: Lupus Science and Medicine. - : BMJ. - 2053-8790. ; 8:1
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Research review (peer-reviewed)abstract
- Objective In systemic lupus erythematosus (SLE), disease activity and glucocorticoid (GC) exposure are known to contribute to irreversible organ damage. We aimed to examine the association between GC exposure and organ damage occurrence. Methods We conducted a literature search (PubMed (Medline), Embase and Cochrane January 1966-October 2021). We identified original longitudinal observational studies reporting GC exposure as the proportion of users and/or GC use with dose information as well as the occurrence of new major organ damage as defined in the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index. Meta-regression analyses were performed. Reviews, case-reports and studies with <5 years of follow-up, <50 patients, different outcomes and special populations were excluded. Results We selected 49 articles including 16 224 patients, 14 755 (90.9%) female with a mean age and disease duration of 35.1 years and of 37.1 months. The mean follow-up time was 104.9 months. For individual damage items, the average daily GC dose was associated with the occurrence of overall cardiovascular events and with osteoporosis with fractures. A higher average cumulative dose adjusted (or not)/number of follow-up years and a higher proportion of patients on GC were associated with the occurrence of osteonecrosis. Conclusions We confirm associations of GC use with three specific damage items. In treating patients with SLE, our aim should be to maximise the efficacy of GC and to minimise their harms.
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| 42. |
- Urowitz, M. B., et al.
(author)
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Cardiovascular events prior to or early after diagnosis of systemic lupus erythematosus in the systemic lupus international collaborating clinics cohort
- 2016
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In: Lupus Science and Medicine. - : BMJ. - 2053-8790. ; 3:1
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Journal article (peer-reviewed)abstract
- Objective To describe the frequency of myocardial infarction (MI) prior to the diagnosis of systemic lupus erythematosus (SLE) and within the first 2 years of follow-up. Methods The systemic lupus international collaborating clinics (SLICC) atherosclerosis inception cohort enters patients within 15 months of SLE diagnosis. MIs were reported and attributed on a specialised vascular event form. MIs were confirmed by one or more of the following: abnormal ECG, typical or atypical symptoms with ECG abnormalities and elevated enzymes (≥2 times upper limit of normal), or abnormal stress test, echocardiogram, nuclear scan or angiogram. Descriptive statistics were used. Results 31 of 1848 patients who entered the cohort had an MI. Of those, 23 patients had an MI prior to SLE diagnosis or within the first 2 years of disease. Of the 23 patients studied, 60.9% were female, 78.3% were Caucasian, 8.7% black, 8.7% Hispanic and 4.3% other. The mean age at SLE diagnosis was 52.5±15.0 years. Of the 23 MIs that occurred, 16 MIs occurred at a mean of 6.1±7.0 years prior to diagnosis and 7 occurred within the first 2 years of follow-up. Risk factors associated with early MI in univariate analysis are male sex, Caucasian, older age at diagnosis, hypertension, hypercholesterolaemia, family history of MI and smoking. In multivariate analysis only age (OR=1.06 95% CI 1.03 to 1.09), hypertension (OR=5.01, 95% CI 1.38 to 18.23), hypercholesterolaemia (OR=4.43, 95% CI 1.51 to 12.99) and smoking (OR=7.50, 95% CI 2.38 to 23.57) remained significant risk factors. Conclusions In some patients with lupus, MI may develop even before the diagnosis of SLE or shortly thereafter, suggesting that there may be a link between autoimmune inflammation and atherosclerosis.
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| 43. |
- Wirestam, Lina, 1986-, et al.
(author)
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Osteopontin is associated with disease severity and antiphospholipid syndrome in well characterised Swedish cases of SLE
- 2017
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In: Lupus Science and Medicine. - : BMJ Publishing Group Ltd. - 2053-8790. ; 4:1
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Journal article (peer-reviewed)abstract
- Objective The variety of disease phenotypes among patients with SLE challenges the identification of new biomarkers reflecting disease activity and/or organ damage. Osteopontin (OPN) is an extracellular matrix protein with immunomodulating properties. Although raised levels have been reported, the pathogenic implications and clinical utility of OPN as a biomarker in SLE are far from clear. Thus, the aim of this study was to characterise OPN in SLE.Methods Sera from 240 well-characterised adult SLE cases classified according to the American College of Rheumatology (ACR) and/or the Systemic Lupus International Collaborating Clinics (SLICC) criteria, and 240 population-based controls were immunoassayed for OPN. The SLE Disease Activity Index 2000 (SLEDAI-2K) was used to evaluate disease activity and the SLICC/ACR Damage Index (SDI) to detect damage accrual.Results Serum OPN levels were in average raised fourfold in SLE cases compared with the controls (p<0.0001). OPN correlated with SLEDAI-2K, especially in patients with a disease duration of <12 months (r=0.666, p=0.028). OPN was highly associated with SDI (p<0.0001), especially in the renal (p<0.0001), cardiovascular (p<0.0001) and malignancy (p=0.012) domains. Finally, OPN associated with coherent antiphospholipid syndrome (APS; p=0.009), and both clinical and laboratory criteria of APS had significant positive impact on OPN levels.Conclusions In this cross-sectional study, circulating OPN correlates with disease activity in recent-onset SLE, reflects global organ damage and associates with APS. Longitudinal studies to dissect whether serum OPN also precedes and predicts future organ damage are most warranted.
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| 44. |
- Yavuz, Sule, et al.
(author)
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Mer-tyrosine kinase : a novel susceptibility gene for SLE related end-stage renal disease
- 2022
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In: Lupus Science and Medicine. - : BMJ Publishing Group Ltd. - 2053-8790. ; 9:1
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Journal article (peer-reviewed)abstract
- Objective Lupus nephritis (LN) is a common and severe manifestation of SLE. The genetic risk for nephritis and progression to end-stage renal disease (ESRD) in patients with LN remains unclear. Herein, we aimed to identify novel genetic associations with LN, focusing on subphenotypes and ESRD. Methods We analysed genomic data on 958 patients with SLE (discovery cohort: LN=338) with targeted sequencing data from 1832 immunological pathway genes. We used an independent multiethnic cohort comprising 1226 patients with SLE (LN=603) as a replication dataset. Detailed functional annotation and functional epigenomic enrichment analyses were applied to predict functional effects of the candidate variants. Results A genetic variant (rs56097910) within the MERTK gene was associated with ESRD in both cohorts, meta-analysis OR=5.4 (2.8 to 10.6); p=1.0×10-6. We observed decreased methylation levels in peripheral blood cells from SLE patients with ESRD, compared with patients without renal SLE (p=2.7×10-4), at one CpG site (cg16333401) in close vicinity to the transcription start site of MERTK and located in a DNAse hypersensitivity region in T and B cells. Rs56097910 is linked to altered MERTK expression in kidney tissue in public eQTL databases. Two loci were replicated for association with proliferative LN: PRDM1 (rs6924535, p meta =1.6×10-5, OR=0.58) and APOA1BP (NAXE) (rs942960, p meta =1.2×10-5, OR=2.64). Conclusion We identified a novel genetic risk locus, MERTK, associated with SLE-ESRD using the data from two large SLE cohorts. Through DNA methylation analysis and functional annotation, we showed that the risk could be mediated through regulation of gene expression. Our results suggest that variants in the MERTK gene are important for the risk of developing SLE-ESRD and suggest a role for PRDM1 and APOA1BP in proliferative LN.
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| 45. |
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| 46. |
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| 47. |
- Åkesson, Karolina, et al.
(author)
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Kynurenine pathway is altered in patients with SLE and associated with severe fatigue
- 2018
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In: Lupus Science and Medicine. - : BMJ Publishing Group Ltd. - 2053-8790. ; 5:1
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Journal article (peer-reviewed)abstract
- Objective: Fatigue has been reported as the most disturbing symptom in a majority of patients with SLE. Depression is common and often severe. Together these symptoms cause significant morbidity and affect patients with otherwise relatively mild disease. Tryptophan and its metabolites in the kynurenine pathway are known to be important in several psychiatric conditions, for example, depression, which are often also associated with fatigue. We therefore investigated the kynurenine pathway in patients with SLE and controls.Methods: In a cross-sectional design plasma samples from 132 well-characterised patients with SLE and 30 age-matched and gender-matched population-based controls were analysed by liquid chromatography tandem mass spectrometry to measure the levels of tryptophan and its metabolites kynurenine and quinolinic acid. Fatigue was measured with Fatigue Severity Scale and depression with Hospital Anxiety and Depression Scale. SLE disease activity was assessed with Systemic Lupus Erythematosus Disease Activity Index (SLEDAI).Results: The kynurenine/tryptophan ratio, as a measure of indoleamine 2,3-dioxygenase (IDO) activity, was increased in patients with SLE. Patients with active disease (SLEDAI >= 6) showed lower tryptophan levels compared with controls (54 mu M, SD=19 vs 62 mu M, SD=14, p=0.03), although patients with SLE overall did not differ compared with controls. Patients with SLE had higher levels of tryptophan metabolites kynurenine (966 nM, SD=530) and quinolinic acid (546 nM, SD=480) compared with controls (kynurenine: 712 nM, SD=230, p=0.0001; quinolinic acid: 380 nM, SD=150, p=0.001). Kynurenine, quinolinic acid and the kynurenine/tryptophan ratio correlated weakly with severe fatigue (r(s)=0.34, r(s)=0.28 and r(s)=0.24, respectively) but not with depression.Conclusions: Metabolites in the kynurenine pathway are altered in patients with SLE compared with controls. Interestingly, fatigue correlated weakly with measures of enhanced tryptophan metabolism, while depression did not. Drugs targeting enzymes in the kynurenine pathway, for example, IDO inhibitors or niacin (B12) supplementation, which suppresses IDO activity, merit further investigation as treatments in SLE.
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