| 1. |
- 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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| 2. |
- Bengtsson, Christine, et al.
(författare)
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Systemic lupus erythematosus and cardiac risk factors : medical record documentation and patient adherence
- 2011
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Ingår i: Lupus. - Houndmills, Basingstoke, Hampshire : Stockton. - 0961-2033 .- 1477-0962. ; 20:10, s. 1057-1062
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Tidskriftsartikel (refereegranskat)abstract
- This study explores patients' knowledge of cardiac risk factors (CRFs), analyses how information and advice about CRFs are documented in clinical practice, and assesses patient adherence to received instructions to decrease CRFs. Systemic lupus erythematosus (SLE) patients with >= 4 ACR criteria participated through completing a validated cardiovascular health questionnaire (CHQ). Kappa statistics were used to compare medical records with the self-reported CHQ (agreement) and to evaluate adherence. Two hundred and eleven (72%) of the known patients with SLE participated. The mean age of the patients was 55 years. More than 70% of the SLE patients considered hypertension, obesity, smoking and hypercholesterolaemia to be very important CRFs. The agreement between medical record documentation and patients' reports was moderate for hypertension, overweight and hypercholesterolaemia (kappa 0.42-0.60) but substantial for diabetes (kappa 0.66). Patients' self-reported adherence to advice they had received regarding medication was substantial to perfect (kappa 0.65-1.0). For lifestyle changes in patients with hypertension and overweight, adherence was only fair to moderate (kappa 0.13-0.47). Swedish SLE patients' awareness of traditional CRFs was good in this study. However, the agreement between patients' self-reports and medical record documentation of CRF profiles, and patients' adherence to medical advice to CRF profiles, could be improved. Lupus (2011) 20, 1057-1062.
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| 3. |
- Bolin, Karin, et al.
(författare)
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Association of STAT4 Polymorphism with Severe Renal Insufficiency in Lupus Nephritis
- 2013
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Ingår i: PLOS ONE. - : Public Library of Science. - 1932-6203. ; 8:12, s. 84450-
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Tidskriftsartikel (refereegranskat)abstract
- Lupus nephritis is a cause of significant morbidity in systemic lupus erythematosus (SLE) and its genetic background has not been completely clarified. The aim of this investigation was to analyze single nucleotide polymorphisms (SNPs) for association with lupus nephritis, its severe form proliferative nephritis and renal outcome, in two Swedish cohorts. Cohort I (n = 567 SLE cases, n = 512 controls) was previously genotyped for 5676 SNPs and cohort II (n = 145 SLE cases, n = 619 controls) was genotyped for SNPs in STAT4, IRF5, TNIP1 and BLK. Case-control and case-only association analyses for patients with lupus nephritis, proliferative nephritis and severe renal insufficiency were performed. In the case-control analysis of cohort I, four highly linked SNPs in STAT4 were associated with lupus nephritis with genome wide significance with p = 3.7x10(-9), OR 2.20 for the best SNP rs11889341. Strong signals of association between IRF5 and an HLA-DR3 SNP marker were also detected in the lupus nephritis case versus healthy control analysis (pless than0.0001). An additional six genes showed an association with lupus nephritis with pless than0.001 (PMS2, TNIP1, CARD11, ITGAM, BLK and IRAK1). In the case-only meta-analysis of the two cohorts, the STAT4 SNP rs7582694 was associated with severe renal insufficiency with p = 1.6x10(-3) and OR 2.22. We conclude that genetic variations in STAT4 predispose to lupus nephritis and a worse outcome with severe renal insufficiency.
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| 4. |
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| 5. |
- Compagno, Michele, et al.
(författare)
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Low diagnostic and predictive value of anti-dsDNA antibodies in unselected patients with recent onset of rheumatic symptoms: results from a long-term follow-up Scandinavian multicentre study.
- 2013
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Ingår i: Scandinavian Journal of Rheumatology. - : Informa UK Limited. - 1502-7732 .- 0300-9742. ; 42:4, s. 311-316
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: To verify the diagnostic accuracy of anti-double-stranded DNA (anti-dsDNA) antibodies detected by the Crithidia luciliae immunofluorescence test (CLIFT) in a cohort of unselected patients, referred to a rheumatologist due to recent onset of rheumatic symptoms. Method: A total of 1073 consecutive patients were screened for anti-nuclear antibodies (ANAs). Serum samples from 292 ANA-positive and 292 matching ANA-negative patients were tested three times for anti-dsDNA antibodies, using two different CLIFT kits (ImmunoConcepts(®) and Euroimmun(®)). An initial clinical diagnosis was made by rheumatologists unaware of the results. The diagnoses were updated after a median follow-up of 4.8 years. Results: CLIFT was positive at least once in 60 patients but only 23 patients were CLIFT positive in all of the assays. Diagnosis of systemic lupus erythematosus (SLE) was made initially in 65 patients, of whom 24 (37%) were CLIFT positive. Many other diagnoses were observed among the CLIFT-positive patients. Overall, 16 (5.5%) ANA-negative patients were CLIFT positive. After approximately 5 years, the diagnosis of SLE remained unchanged in 63 patients (23 CLIFT positive) and altered in only two (one CLIFT positive). Among the 36 CLIFT-positive patients who were not diagnosed with SLE at study entry, only one developed SLE during the follow-up period. Conclusions: CLIFT was not reliable as a diagnostic tool in unselected patients with rheumatic symptoms. ANAs were of little value as a screening test before the CLIFT analysis. CLIFT had surprisingly low positive predictive value (PPV) for the diagnosis of SLE despite its high specificity. For non-SLE patients, being CLIFT positive poses little risk of developing SLE within 5 years.
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| 6. |
- Ekman, Carl, et al.
(författare)
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Plasma concentrations of Gas6 and sAxl correlate with disease activity in systemic lupus erythematosus.
- 2011
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Ingår i: Rheumatology (Oxford, England). - : Oxford University Press (OUP). - 1462-0332 .- 1462-0324. ; 50, s. 1064-1069
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Tidskriftsartikel (refereegranskat)abstract
- Objectives. SLE is a systemic autoimmune disease with an annual incidence of 3.8 per 100 000. Several pathogenic mechanisms are believed to be operating in SLE, including an impaired clearance of apoptotic cells, activation of the type I IFN pathway and generation of autoimmune leucocytes. Growth arrest-specific protein 6 (Gas6) and its receptor Axl are known to regulate inflammation and may be implicated in lupus pathogenesis. We have recently developed immunological methods to quantify the vitamin-K-dependent protein Gas6 and its soluble receptor sAxl in human plasma, which we have used to investigate the role of Gas6 and soluble Axl in SLE. Methods. We have investigated the relation between the plasma concentrations of Gas6 and sAxl and disease activity and specific symptoms in 96 SLE patients. Results. Gas6 and sAxl concentrations correlated with SLEDAI (r = 0.48, P < 0.001 and r = 0.39, P < 0.001, respectively). Furthermore, concentrations of Gas6 and sAxl correlated with ESR and CRP and inversely with haemoglobin levels. Gas6 and sAxl concentrations were significantly higher in patients with anti-DNA antibodies, leucopenia and GN. Conclusion. The plasma concentrations of Gas6 and sAxl vary with disease activity in SLE, in particular GN, and may have a role in lupus pathogenesis. Furthermore, Gas6 and sAxl may be of use as biomarkers of disease activity.
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| 7. |
- Gullstrand, Birgitta, et al.
(författare)
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Combination of Autoantibodies Against Different Histone Proteins Influences Complement-dependent Phagocytosis of Necrotic Cell Material by Polymorphonuclear Leukocytes in Systemic Lupus Erythematosus.
- 2012
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Ingår i: Journal of Rheumatology. - : The Journal of Rheumatology. - 0315-162X .- 1499-2752. ; 39:8, s. 1619-1627
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Polymorphonuclear leukocytes (PMN) with autoantibody-coated engulfed necrotic cell material (NC) are frequently seen in systemic lupus erythematosus (SLE). We evaluated the roles of complement, different antihistone antibodies (anti-H ab), and oxidative burst in the phagocytosis of NC by PMN, as well as association to disease activity and clinical phenotype in SLE. METHODS: ELISA and immunoblot were used to measure antibodies to different histone proteins in sera from patients with SLE and complement-deficient individuals. Phagocytosis of NC by PMN and oxidative burst activity was assessed by flow cytometry. RESULTS: A clearly increased phagocytosis of NC was seen in patients with active SLE, which was associated with high levels of anti-H ab concentrations and oxidative burst activity. The complement system contributed to efficient phagocytosis of NC by PMN through activation of the classical pathway, and the phagocytosis was mediated by FcγRIIA, FcγRIIIB, and CR1 in combination. A pattern of high phagocytosis, consumption of classical pathway components, and a broad anti-H ab repertoire was seen particularly in patients with nephritis and serositis. The combination of antibodies to several different histone proteins, often with anti-DNA antibodies, promoted an efficient uptake of NC, whereas antibodies against only histone H1 or a few histones seemed to be of less importance. CONCLUSION: The distributions of specificities among anti-H ab are of great importance in the complement-dependent phagocytosis of debris from NC in SLE. Measurement of anti-H ab could be useful in monitoring of this disease and contribute to improved understanding of the autoimmune process.
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| 8. |
- Jönsen, Andreas, et al.
(författare)
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Association of the Charlson Comorbidity Index With Mortality in Systemic Lupus Erythematosus
- 2011
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Ingår i: Arthritis Care and Research. - : Wiley. - 2151-4658 .- 2151-464X. ; 63:9, s. 1233-1237
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Tidskriftsartikel (refereegranskat)abstract
- Objective. To investigate whether comorbidity as assessed by the Charlson Comorbidity Index (CCI) is associated with mortality in a long-term followup of systemic lupus erythematosus (SLE) patients. Methods. Data were collected from 499 SLE patients attending the Lupus Clinic at the McGill University Health Center, Montreal, Quebec, Canada, and 170 SLE patients from the Department of Rheumatology at Lund University Hospital, Lund, Sweden. This included data on comorbidity, demographics, disease activity, the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI), and antiphospholipid antibody syndrome (APS). Variables were entered into a Cox proportional hazards survival model. Results. Mortality risk in the Montreal cohort was associated with the CCI (hazard ratio [HR] 1.57 per unit increase in the CCI, 95% confidence interval [95% CI] 1.18-2.09) and age (HR 1.04 per year increase in age, 95% CI 1.00-1.09). The CCI and age at diagnosis were also associated with mortality in the Lund cohort (CCI: HR 1.35, 95% CI 1.13-1.60; age: HR 1.09, 95% CI 1.05-1.12). Furthermore, the SDI was associated with mortality in the Lund cohort (HR 1.40, 95% CI 1.19-1.64), while a wide CI for the estimate in the Montreal cohort prevented a definitive conclusion (HR 1.20, 95% CI 0.97-1.48). We did not find a strong association between mortality and sex, race/ethnicity, disease activity, or APS in either cohort. Conclusion. In this study, comorbidity as measured by the CCI was associated with decreased survival independent of age, lupus disease activity, and damage. This suggests that the CCI may be useful in capturing comorbidity for clinical research in SLE.
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| 9. |
- Jönsen, Andreas, et al.
(författare)
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Mutations in genes encoding complement inhibitors CD46 and CFH affect the age at nephritis onset in patients with systemic lupus erythematosus
- 2011
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Ingår i: Arthritis Research & Therapy. - : Springer Science and Business Media LLC. - 1478-6354 .- 1478-6362. ; 13, s. R206-
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: Inherited deficiencies of several complement components strongly predispose to systemic lupus erythematosus (SLE) while deficiencies of complement inhibitors are found in kidney diseases such as atypical hemolytic uremic syndrome (aHUS). METHODS: The exons of complement inhibitor genes: CD46 and CFH (factor H) were fully sequenced using Sanger method in SLE patients with nephritis originating from two cohorts from southern and mid Sweden (n = 196). All identified mutations and polymorphisms were then analyzed in SLE patients without nephritis (n = 326) and healthy controls (n = 523). RESULTS: We found non-synonymous, heterozygous mutations in CFH in 6.1% patients with nephritis in comparison to 4.0% and 5.4% in patients without nephritis and controls, respectively. No associations of SLE or nephritis with common variants in CFH (V62I/Y402H/E936D) were found. Furthermore, we found two non-synonymous heterozygous mutations in CD46 in SLE patients but not in controls. The A353V polymorphism, known to affect function of CD46, was found in 6.6% of nephritis patients vs 4.9% and 6.1% of the non-nephritis SLE patients and controls. The presence of mutations in CD46 and CFH did not predispose to SLE or nephritis but was associated with earlier onset of nephritis. Furthermore, we found weak indications that there is one protective and one risk haplotype predisposing to nephritis composed of several polymorphisms in non-coding regions of CD46, which were previously implicated in aHUS. CONCLUSION: SLE nephritis is not associated with frequent mutations in CFH and CD46 as found in aHUS but these may be modifying factors causing earlier onset of nephritis.
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| 10. |
- Leffler, Jonatan, et al.
(författare)
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Degradation of neutrophil extracellular traps co-varies with disease activity in patients with systemic lupus erythematosus
- 2013
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Ingår i: Arthritis Research and Therapy. - : Springer Science and Business Media LLC. - 1478-6354. ; 15:4
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: The ability to degrade neutrophil extracellular traps (NETs) is reduced in a subset of patients with systemic lupus erythematosus (SLE). NETs consist of chromatin covered with antimicrobial enzymes and are normally degraded by DNase-I, an enzyme which is known to have reduced activity in SLE. Decreased ability to degrade NETs is associated with disease activity. In the current study we investigated how the ability of serum from SLE patients to degrade NETs varies during the course of SLE as well as what impact this may have for the clinical phenotype of SLE.Methods: Serum from 69 patients with SLE, included in a prospective study, was taken every 60 days for a median of 784 days. The ability of serum to degrade NETs was determined and associated with clinical parameters occurring before and at the time of sampling, as well as after sampling by using conditional logistic regression.Results: As many as 41% of all patients in the study showed decreased ability to degrade NETs at least once, but with a median of 20% of all time points. Decreased degradation was associated with manifestations of glomerulonephritis as well as low complement levels and elevated levels of antibodies directed against histones and DNA. Furthermore, the odds ratio for the patient to develop alopecia and fever after an episode of decreased NETs degradation was increased by four to five times compared to normal.Conclusions: Decreased degradation of NETs is associated with clinical manifestations in SLE and may contribute to disease pathogenesis. Potential therapeutics restoring the ability to degrade NETs could be beneficial for certain patients with SLE.
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