| 1. |
- Belfrage, Emma, et al.
(författare)
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Role of Mannose-binding Lectin and Association with Microbial Sensitization in a Cohort of Patients with Atopic Dermatitis
- 2023
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Ingår i: Acta Dermato-Venereologica. - : Medical Journals Sweden AB. - 1651-2057 .- 0001-5555. ; 103, s. 1-5
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Tidskriftsartikel (refereegranskat)abstract
- Atopic dermatitis is a relapsing inflammatory skin condition, in which bacteria, fungi and viruses may colonize the skin and aggravate the condition. Mannose-binding lectin is part of the innate immune system. Polymorphism in the mannose-binding lectin gene can result in deficiency of mannose-binding lectin, which may affect defence against microbes. The aim of this study was to investigate whether polymorphisms in the mannose-binding lectin gene affect the extent of sensitization to common skin microbes, the skin barrier function, or the severity of the disease in a cohort of patients with atopic dermatitis. Genetic testing of mannose-binding lectin polymorphism was performed in 60 patients with atopic dermatitis. The disease severity, skin barrier function, and serum levels of specific immunoglobulin E against skin microbes were measured. In patients with low mannose-binding lectin genotype (group 1) 6 of 8 (75%) were sensitized to Candida albicans, compared to 14 of 22 (63.6%) patients with intermediate mannose-binding genotype (group 2) and 10 of 30 (33.3%) patients with high mannose-binding genotype (group 3). Group 1 (low mannose-binding lectin) was more likely to be sensitized to Candida albicans compared with group 3 (high mannose-binding lectin) (odds ratio 6.34, p-value 0.045). In this cohort of patients with atopic dermatitis, mannose-binding lectin deficiency was associated with increased sensitization to Candida albicans.
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| 2. |
- Foltyn Zadura, Anna, et al.
(författare)
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Factor H autoantibodies and deletion of Complement Factor H-Related protein-1 in rheumatic diseases in comparison to atypical hemolytic uremic syndrome.
- 2012
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Ingår i: Arthritis research & therapy. - : Springer Science and Business Media LLC. - 1478-6362 .- 1478-6354. ; 14:4
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Tidskriftsartikel (refereegranskat)abstract
- ABSTRACT: INTRODUCTION: Complement activation is involved in rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and atypical hemolytic uremic syndrome (aHUS). Autoantibodies to complement inhibitor factor H (FH), particularly in association with deletions of the gene coding for FH-related protein 1 (CFHR1), are associated with aHUS. METHODS: Autoantibodies against FH, factor I (FI) and C4b-binding protein (C4BP) were measured by ELISA, while CFHR1 homozygous deletion was determined with Western blotting of sera. Epitopes for FH autoantibodies were mapped using recombinant fragments of FH. RESULTS: FH autoantibodies were detected in SLE (6.7%, n = 60, RA patients (16.5%, n = 97 in the Swedish cohort and 9.2%, n = 217 in the Dutch cohort) and thrombosis patients positive for the lupus anticoagulants (LA+) test (9.4%, n = 64) compared with aHUS patients (11.7%, n = 103). In the control groups (n = 354), an average of 4% of individuals were positive for FH autoantibodies. The frequencies observed in both RA cohorts and LA+ patients were statistically significantly higher than in controls. We also found that an average of 15.2% of the FH-autoantibody positive individuals in all studied disease groups had homozygous deficiency of CFHR1 compared with 3.8% of the FH autoantibody negative patients. The levels of FH autoantibodies varied in individual patients over time. FH autoantibodies found in LA+, SLE and RA were directed against several epitopes across FH in contrast to those found in aHUS, which bound mainly to the C-terminus. Autoantibodies against FI and C4BP were detected in some patients and controls but they were not associated with any of the diseases analyzed in this study. CONCLUSIONS: Autoantibodies against FH are not specific for aHUS but are present at a significant frequency in rheumatic diseases where they could be involved in pathophysiological mechanisms.
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| 3. |
- Linge, Carl Petrus, et al.
(författare)
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Enrichment of Complement, Immunoglobulins, and Autoantibody Targets in the Proteome of Platelets from Patients with Systemic Lupus Erythematosus
- 2022
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Ingår i: Thrombosis and Haemostasis. - : Georg Thieme Verlag KG. - 0340-6245 .- 2567-689X. ; 122:9, s. 1486-1501
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Tidskriftsartikel (refereegranskat)abstract
- Background Systemic lupus erythematosus (SLE) is a complex disease characterized by autoimmunity toward apoptotic cells, excessive amounts of circulating immune complexes, and complement activation. A decreased platelet size has been observed in SLE and their nonhemostatic functions may play an active role in the disease. The main objective of this study was to find clues that could explain their decreased size and functional role, analyzing the entire platelet proteome. Methods Platelets were isolated from 23 patients with SLE. The five individuals with the highest and lowest average platelet forward scatter were selected for further analysis. Platelet protein content was analyzed using liquid chromatography with tandem mass spectrometry (LC-MS/MS) and compared with platelets from five healthy controls. Data are available via ProteomeXchange with identifier PXD031202. Results Out of 2,572 proteins identified, 396 had significantly different levels (ANOVA q-value ≤ 0.01). Forty proteins, including immunoglobulin-, complement- and phosphatidylserinebinding proteins had higher abundance in platelets from SLE patients, largely independent of size (fold difference of ≥1.5 and a t-test p-value of ≤0.05 as cut-off). Functional characterization revealed increased degranulation and skewed hemostatic balance in platelets from SLE patients. In the SLE proteome, immunoglobulin proteins were negatively correlated to serum complement C3 and C4 and the highest relative levels were detected in platelets of normal size. Conclusion Platelets from SLE patients shared a specific protein profile, including immunoglobulins, complement proteins, and autoantigens, largely independent of the platelet size and in agreement with an integrated role for platelets in SLE.
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| 4. |
- Wirestam, Lina, et al.
(författare)
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Low Intra-Individual Variation in Mean Platelet Volume Over Time in Systemic Lupus Erythematosus
- 2021
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Ingår i: Frontiers in Medicine. - : Frontiers Media SA. - 2296-858X. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- Platelets have recently emerged as important immune modulators in systemic lupus erythematosus (SLE), in addition to their role in thrombosis and cardiovascular disease. However, studies investigating mean platelet volume (MPV) in SLE are often scarce, conflicting and cross-sectional. In this study, MPV was measured in clinical routine throughout a defined time-period to quantify both individual MPV fluctuations and investigate if such variations are associated with disease activity and clinical phenotypes of SLE. Of our 212 patients, 34 patients had only one MPV value reported with the remaining 178 patients having between 2 and 19 visits with recorded MPV values. The intra-individual MPV variation was low, with a median variation of 0.7 fL. This was further supported by the finding that 84% of patients stayed within their reference interval category (i.e., small, normal or large) over time. In our cohort, no correlation between disease activity and MPV neither cross-sectionally nor longitudinally was found. Mean platelet volume values were significantly smaller in SLE patients (mean 10.5 fL) compared to controls (mean 10.8 fL), p < 0.0001. Based on the reference interval, 2.4% (n = 5) of patients had large-sized platelets, 84.4% (n = 179) had normal-sized and 13.2% (n = 28) had small-sized. A larger proportion (85.7%) of patients with small-sized platelets met the anti-dsDNA criterion (ACR10b; p = 0.003) compared to patients with normal and large (57.6%) sized platelets. In conclusion, the intra-individual MPV variation was of low magnitude and fluctuations in disease activity did not have any significant impact on MPV longitudinally. This lack of variability in MPV over time indicates that measuring MPV at any time-point is sufficient. Further studies are warranted to evaluate MPV as a possible biomarker in SLE, as well as to determine the underlying mechanisms influencing platelet size in SLE.
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| 5. |
- Zervides, Kristoffer A, et al.
(författare)
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Serum S100A8/A9 concentrations are associated with neuropsychiatric involvement in systemic lupus erythematosus: a cross-sectional study
- 2022
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Ingår i: BMC Rheumatology. - : Springer Science and Business Media LLC. - 2520-1026. ; 6:1
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Neuropsychiatric (NP) involvement and fatigue are major problems in systemic lupus erythematosus (SLE). S100A8/A9 is a marker of inflammation and responds to therapy in SLE patients. S100A8/A9 has an immunopathogenic role in various neurological diseases. We investigated S100A8/A9 in relation to NP-involvement and fatigue in SLE.METHODS: 72 consecutive SLE outpatients at a tertiary centre and 26 healthy controls were included in this cross-sectional study. NPSLE was determined by specialists in rheumatology and neurology and defined according to three attribution models: "ACR", "SLICC A" and "SLICC B". Cerebral MRI was assessed by a neuroradiologist and neurocognitive testing by a neuropsychologist. The individuals were assessed by scores of pain (VAS), fatigue (VAS and FSS), and depression (MADRS-S). Concentrations of S100A8/A9 in serum and cerebrospinal fluid were measured with ELISA. Statistical calculations were performed using non-parametric methods.RESULTS: Serum concentrations of S100A8/A9 were higher in SLE patients compared with controls (medians 1230 ng/ml; 790 ng/ml, p = 0.023). The concentrations were higher in NPSLE patients compared with non-NPSLE patients when applying the SLICC A and ACR models, but not significant when applying the SLICC B model (medians 1400 ng/ml; 920 ng/ml, p = 0.011; 1560 ng/ml; 1090 ng/ml, p = 0.050; 1460 ng/ml; 1090 ng/ml, p = 0.083, respectively). No differences of CSF S100A8/A9 concentrations were observed between NPSLE and non-NPSLE patients. SLE patients with depression or cognitive dysfunction as an ACR NPSLE manifestation had higher serum S100A8/A9 concentrations than non-NPSLE patients (median 1460 ng/ml, p = 0.007 and 1380 ng/ml, p = 0.013, respectively). Higher serum S100A8/A9 correlated with higher VAS fatigue (r = 0.31; p = 0.008) and VAS pain (r = 0.27, p = 0.021) in SLE patients. Serum S100A8/A9 was not independently associated with NPSLE when adjusting for scores of fatigue (FSS) and pain (VAS) (OR 1.86, 95% CI 0.93-3.73, p = 0.08).CONCLUSIONS: Serum S100A8/A9 concentrations may be associated with NPSLE and fatigue. S100A8/A9 may be of interest in evaluating NPSLE, although further investigations are needed.
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| 6. |
- Abelson, Anna-Karin, et al.
(författare)
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No evidence of association between genetic variants of the PDCD1 ligands and SLE
- 2007
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Ingår i: Genes and Immunity. - : Springer Science and Business Media LLC. - 1466-4879 .- 1476-5470. ; 8:1, s. 69-74
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Tidskriftsartikel (refereegranskat)abstract
- PDCD1, an immunoreceptor involved in peripheral tolerance has previously been shown to be genetically associated with systemic lupus erythematosus (SLE). PDCD1 has two ligands whose genes are located in close proximity on chromosome 9p24. Our attention was drawn to these ligands after finding suggestive linkage to a marker (gata62f03, Z=2.27) located close to their genes in a genome scan of Icelandic families multiplex for SLE. Here, we analyse Swedish trios (N=149) for 23 single nucleotide polymorphisms (SNPs) within the genes of the PDCD1 ligands. Initially, indication of association to eight SNPs was observed, and these SNPs were therefore also analysed in Mexican trios (N=90), as well as independent sets of patients and controls from Sweden (152 patients, 448 controls) and Argentina (288 patients, 288 controls). We do not find support for genetic association to SLE. This is the first genetic study of SLE and the PDCD1 ligands and the lack of association in several cohorts implies that these genes are not major risk factors for SLE.
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| 7. |
- Almeida-Brasil, Celline C., et al.
(författare)
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Flares after hydroxychloroquine reduction or discontinuation : results from the Systemic Lupus International Collaborating Clinics (SLICC) inception cohort
- 2022
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Ingår i: Annals of the Rheumatic Diseases. - : BMJ. - 1468-2060 .- 0003-4967. ; 81:3, s. 370-378
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: To evaluate systemic lupus erythematosus (SLE) flares following hydroxychloroquine (HCQ) reduction or discontinuation versus HCQ maintenance. METHODS: We analysed prospective data from the Systemic Lupus International Collaborating Clinics (SLICC) cohort, enrolled from 33 sites within 15 months of SLE diagnosis and followed annually (1999-2019). We evaluated person-time contributed while on the initial HCQ dose ('maintenance'), comparing this with person-time contributed after a first dose reduction, and after a first HCQ discontinuation. We estimated time to first flare, defined as either subsequent need for therapy augmentation, increase of ≥4 points in the SLE Disease Activity Index-2000, or hospitalisation for SLE. We estimated adjusted HRs (aHRs) with 95% CIs associated with reducing/discontinuing HCQ (vs maintenance). We also conducted separate multivariable hazard regressions in each HCQ subcohort to identify factors associated with flare. RESULTS: We studied 1460 (90% female) patients initiating HCQ. aHRs for first SLE flare were 1.20 (95% CI 1.04 to 1.38) and 1.56 (95% CI 1.31 to 1.86) for the HCQ reduction and discontinuation groups, respectively, versus HCQ maintenance. Patients with low educational level were at particular risk of flaring after HCQ discontinuation (aHR 1.43, 95% CI 1.09 to 1.87). Prednisone use at time-zero was associated with over 1.5-fold increase in flare risk in all HCQ subcohorts. CONCLUSIONS: SLE flare risk was higher after HCQ taper/discontinuation versus HCQ maintenance. Decisions to maintain, reduce or stop HCQ may affect specific subgroups differently, including those on prednisone and/or with low education. Further study of special groups (eg, seniors) may be helpful.
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| 8. |
- Almeida-Brasil, Celline C., et al.
(författare)
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Retinal toxicity in a multinational inception cohort of patients with systemic lupus on hydroxychloroquine
- 2022
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Ingår i: Lupus Science and Medicine. - : BMJ. - 2053-8790. ; 9:1
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Tidskriftsartikel (refereegranskat)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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| 9. |
- Almlöf, Jonas Carlsson, et al.
(författare)
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Whole-genome sequencing identifies complex contributions to genetic risk by variants in genes causing monogenic systemic lupus erythematosus
- 2019
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Ingår i: Human Genetics. - : SPRINGER. - 0340-6717 .- 1432-1203. ; 138:2, s. 141-150
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Tidskriftsartikel (refereegranskat)abstract
- Systemic lupus erythematosus (SLE, OMIM 152700) is a systemic autoimmune disease with a complex etiology. The mode of inheritance of the genetic risk beyond familial SLE cases is currently unknown. Additionally, the contribution of heterozygous variants in genes known to cause monogenic SLE is not fully understood. Whole-genome sequencing of DNA samples from 71 Swedish patients with SLE and their healthy biological parents was performed to investigate the general genetic risk of SLE using known SLE GWAS risk loci identified using the ImmunoChip, variants in genes associated to monogenic SLE, and the mode of inheritance of SLE risk alleles in these families. A random forest model for predicting genetic risk for SLE showed that the SLE risk variants were mainly inherited from one of the parents. In the 71 patients, we detected a significant enrichment of ultra-rare (0.1%) missense and nonsense mutations in 22 genes known to cause monogenic forms of SLE. We identified one previously reported homozygous nonsense mutation in the C1QC (Complement C1q C Chain) gene, which explains the immunodeficiency and severe SLE phenotype of that patient. We also identified seven ultra-rare, coding heterozygous variants in five genes (C1S, DNASE1L3, DNASE1, IFIH1, and RNASEH2A) involved in monogenic SLE. Our findings indicate a complex contribution to the overall genetic risk of SLE by rare variants in genes associated with monogenic forms of SLE. The rare variants were inherited from the other parent than the one who passed on the more common risk variants leading to an increased genetic burden for SLE in the child. Higher frequency SLE risk variants are mostly passed from one of the parents to the offspring affected with SLE. In contrast, the other parent, in seven cases, contributed heterozygous rare variants in genes associated with monogenic forms of SLE, suggesting a larger impact of rare variants in SLE than hitherto reported.
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| 10. |
- Arkema, Elizabeth V, et al.
(författare)
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Case definitions in Swedish register data to identify systemic lupus erythematosus
- 2016
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Ingår i: BMJ Open. - : B M J Group. - 2044-6055. ; 6:1
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To develop and investigate the utility of several different case definitions for systemic lupus erythematosus (SLE) using national register data in Sweden.METHODS: The reference standard consisted of clinically confirmed SLE cases pooled from four major clinical centres in Sweden (n=929), and a sample of non-SLE comparators randomly selected from the National Population Register (n=24 267). Demographics, comorbidities, prescriptions and autoimmune disease family history were obtained from multiple registers and linked to the reference standard. We first used previously published SLE definitions to create algorithms for SLE. We also used modern data mining techniques (penalised least absolute shrinkage and selection operator logistic regression, elastic net regression and classification trees) to objectively create data-driven case definitions. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were calculated for the case definitions identified.RESULTS: Defining SLE by using only hospitalisation data resulted in the lowest sensitivity (0.79). When SLE codes from the outpatient register were included, sensitivity and PPV increased (PPV between 0.97 and 0.98, sensitivity between 0.97 and 0.99). Addition of medication information did not greatly improve the algorithm's performance. The application of data mining methods did not yield different case definitions.CONCLUSIONS: The use of SLE International Classification of Diseases (ICD) codes in outpatient clinics increased the accuracy for identifying individuals with SLE using Swedish registry data. This study implies that it is possible to use ICD codes from national registers to create a cohort of individuals with SLE.
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