| 111. |
- Saleh, Muna, et al.
(författare)
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Anti-phospholipid antibodies and renal involvement are the main features associated with adverse pregnancy outcomes in patients with Systemic Lupus Erythematosus. A long-term longitudinal study in Southern Sweden
- 2020
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Konferensbidrag (refereegranskat)abstract
- Background Systemic Lupus Erythematosus (SLE) affects mostly women in childbearing age. Modern management of SLE patients has improved the pregnancy outcomes over the last decades. However, there is still an increased risk of maternal, fetal and neonatal complications. In this longitudinal follow-up of pregnant women affected by SLE, we aimed to investigate which clinical and immunological features may predict for the occurrence of adverse pregnancy outcomes (APOs).Methods We investigated the outcome of 59 pregnancies in 28 SLE patients who have had one or more pregnancies, between 2002 and 2018. Longitudinal clinical and laboratory data from rheumatology, obstetrics and neonatal units were collected and analyzed. We assessed the association between the presence of SLE-related clinical and immunological features and the occurrence of adverse pregnancy outcomes.Results We recorded 52 APOs in 18 (64.3%) patients. The 59 investigated gestations resulted in 44 (31 vaginal and 13 C-sections) deliveries, 8 (18.2%) before the 37th gestational week, 13 (22%) early miscarriages and 2 (3.4%) induced abortions. HELLP syndrome and preeclampsia complicated 1 (2.3%) and 11 (25%) gestations, respectively. Moreover, 10 (22.7%) newborns had low birth weight, 5 (11.4%) fetuses had intra-uterine growth restriction, whereof 1 (2.3%) resulted in small for gestational age neonate. Neonatal lupus occurred in 1 (2.3%) baby. Previous lupus nephritis was associated with higher risk of APOs overall (OR=5.9-p = 0.01), in particular impaired fetal growth (OR=16.6-p = 0.01). The presence of anti-phospholipid antibodies was also associated with higher risk of APOs overall (OR=4.5-p = 0.01). In particular, the occurrence of preterm delivery and the incidence of miscarriage were associated with the presence during pregnancy of anti-cardiolipin antibodies (OR=6.8-p = 0.03) and with concomitant anti-phospholipid syndrome (APS) (OR=3.3-p = 0.04), respectively.Conclusions Several different APOs occur in the majority of SLE-patients, in particular in those with renal involvement, APS and presence of anti-phospholipid antibodies.
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| 112. |
- Saleh, Muna, et al.
(författare)
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Variation of Complement Protein Levels in Maternal Plasma and Umbilical Cord Blood during Normal Pregnancy : An Observational Study
- 2022
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Ingår i: Journal of Clinical Medicine. - : MDPI AG. - 2077-0383. ; 11:13
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Tidskriftsartikel (refereegranskat)abstract
- The complement system constitutes a crucial part of the innate immunity, mediating opsonization, lysis, inflammation, and elimination of potential pathogens. In general, there is an increased activity of the complement system during pregnancy, which is essential for maintaining the host's defense and fetal survival. Unbalanced or excessive activation of the complement system in the placenta is associated with pregnancy complications, such as miscarriage, preeclampsia, and premature birth. Nonetheless, the actual clinical value of monitoring the activation of the complement system during pregnancy remains to be investigated. Unfortunately, normal reference values specifically for pregnant women are missing, and for umbilical cord blood (UCB), data on complement protein levels are scarce. Herein, complement protein analyses (C1q, C3, C4, C3d levels, and C3d/C3 ratio) were performed in plasma samples from 100 healthy, non-medicated and non-smoking pregnant women, collected during different trimesters and at the time of delivery. In addition, UCB was collected at all deliveries. Maternal plasma C1q and C3d/C3 ratio showed the highest mean values during the first trimester, whereas C3, C4, and C3d had rising values until delivery. We observed low levels of C1q and C4 as well as increased C3d and C3d/C3 ratio, particularly during the first trimester, as a sign of complement activation in some women. However, the reference limits of complement analyses applied for the general population appeared appropriate for the majority of the samples. As expected, the mean complement concentrations in UCB were much lower than in maternal plasma, due to the immature complement system in neonates.
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| 113. |
- Sandling, Johanna K., et al.
(författare)
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Molecular pathways in patients with systemic lupus erythematosus revealed by gene-centred DNA sequencing
- 2021
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Ingår i: Annals of the Rheumatic Diseases. - : BMJ. - 0003-4967 .- 1468-2060. ; 80:1, s. 109-117
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: Systemic lupus erythematosus (SLE) is an autoimmune disease with extensive heterogeneity in disease presentation between patients, which is likely due to an underlying molecular diversity. Here, we aimed at elucidating the genetic aetiology of SLE from the immunity pathway level to the single variant level, and stratify patients with SLE into distinguishable molecular subgroups, which could inform treatment choices in SLE. Methods: We undertook a pathway-centred approach, using sequencing of immunological pathway genes. Altogether 1832 candidate genes were analysed in 958 Swedish patients with SLE and 1026 healthy individuals. Aggregate and single variant association testing was performed, and we generated pathway polygenic risk scores (PRS). Results: We identified two main independent pathways involved in SLE susceptibility: T lymphocyte differentiation and innate immunity, characterised by HLA and interferon, respectively. Pathway PRS defined pathways in individual patients, who on average were positive for seven pathways. We found that SLE organ damage was more pronounced in patients positive for the T or B cell receptor signalling pathways. Further, pathway PRS-based clustering allowed stratification of patients into four groups with different risk score profiles. Studying sets of genes with priors for involvement in SLE, we observed an aggregate common variant contribution to SLE at genes previously reported for monogenic SLE as well as at interferonopathy genes. Conclusions: Our results show that pathway risk scores have the potential to stratify patients with SLE beyond clinical manifestations into molecular subsets, which may have implications for clinical follow-up and therapy selection.
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| 114. |
- Simard, Julia F, et al.
(författare)
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Systemic Lupus Prevalence in Sweden in 2010 : What do national registers say?
- 2014
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Ingår i: Arthritis care & research. - : John Wiley & Sons. - 2151-4658 .- 2151-464X .- 0893-7524 .- 1529-0123. ; 66:11, s. 1710-1717
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Worldwide prevalence estimates of systemic lupus erythematosus (SLE) range from 3-207 per 100,000 depending on region and population, SLE definition, case sources and other methodological considerations. We aimed to determine the prevalence of SLE in Sweden on January 1, 2010 using population-based registers.Methods: Linking multiple national registers we identified all possible inpatient and outpatient visits with SLE-specific discharge diagnoses and relevant prescription dispensations among living individuals registered in Sweden on January 1, 2010. SLE was defined from a lenient classification (requiring only a single visit) to stricter definitions, which required multiple visits with a history of relevant specialist care and a dispensation for common SLE medications. Prevalence was calculated overall, and by sex, age (0-14, 15-49, 50+yrs, as well as in 5-year age groups), and county of residence.Result: Overall prevalence ranged from 46 per 100,000 for the strictest definition to 85 per 100,000 for the least strict definition. As expected, SLE was more common among females (ranged from 79 to 144/100,000) than males (12-25/100,000) and varied by age. The up to four-fold variation by county was unexpected. Prevalence generally increased with age (2, 52, and 95 per 100,000 by increasing age group, 0-14/15-49/50+, using a moderately strict definition) and also varied by county.Conclusion: Variations of prevalence by age and sex were consistent with previous studies and overall ranged from 46 to 85 per 100,000. We observed a surprising geographical variation in the prevalence of SLE in Sweden on January 1, 2010 according to multiple definitions.
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| 115. |
- Sjöwall, Christopher, 1975-, et al.
(författare)
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Abnormal Antinuclear Antibody Titers Are Less Common Than Generally Assumed in Established Cases of Systemic Lupus Erythematosus
- 2008
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Ingår i: Journal of Rheumatology. - 0315-162X .- 1499-2752. ; 35, s. 1994-2000
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To evaluate antinuclear antibody (ANA) tests in established cases of systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) by indirect immunofluorescence microscopy (F-ANA) and enzyme-immunoassays detecting antinucleosomal antibodies (ANSA-EIA). METHODS: Sera from 50 patients with SLE and 65 patients with RA were analyzed regarding abnormal concentrations of F-ANA (serum dilution >/= 1:200 = 95th percentile among 300 healthy blood donors). The sera were also analyzed with 2 commercial ANSA-EIA kits. RESULTS: An abnormal F-ANA titer occurred in 76% of the SLE sera compared to 23% in RA, and was not related to present use of antirheumatic drugs. At dilution 1:50, 84% of the SLE sera were F-ANA-positive compared to 20% of healthy women. Forty percent and 56%, respectively, of the SLE sera tested positive in the 2 ANSA-EIA kits. By the most sensitive assay, 96% of the ANSA-positive SLE sera produced a homogenous (chromosomal) F-ANA staining pattern compared to 18% of the ANSA-negative SLE sera. Ten of the 15 F-ANA-positive RA sera (63%) generated homogenous F-ANA staining and 13 (20%) tested positive in the most sensitive ANSA-EIA, but with no correlation to the F-ANA staining pattern. CONCLUSION: The sensitivity of F-ANA at an abnormal titer was surprisingly low (76%) in established cases of SLE. ANSA occurred in 56% of the SLE sera, but also in a fair number (20%) of RA sera. Practically all ANSA-positive SLE sera were identified by chromosomal F-ANA staining. We conclude that the antigen-specific antinucleosomal EIA does not have high enough diagnostic specificity to justify use of this analysis for routine diagnostic purposes.
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| 116. |
- Sjöwall, Christopher, et al.
(författare)
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Abnormal Antinuclear Antibody Titers Are Less Common Than Generally Assumed in Established Cases of Systemic Lupus Erythematosus.
- 2008
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Ingår i: Journal of Rheumatology. - 0315-162X. ; 35, s. 1994-2000
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To evaluate antinuclear antibody (ANA) tests in established cases of systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) by indirect immunofluorescence microscopy (F-ANA) and enzyme-immunoassays detecting antinucleosomal antibodies (ANSA-EIA). METHODS: Sera from 50 patients with SLE and 65 patients with RA were analyzed regarding abnormal concentrations of F-ANA (serum dilution >/= 1:200 = 95th percentile among 300 healthy blood donors). The sera were also analyzed with 2 commercial ANSA-EIA kits. RESULTS: An abnormal F-ANA titer occurred in 76% of the SLE sera compared to 23% in RA, and was not related to present use of antirheumatic drugs. At dilution 1:50, 84% of the SLE sera were F-ANA-positive compared to 20% of healthy women. Forty percent and 56%, respectively, of the SLE sera tested positive in the 2 ANSA-EIA kits. By the most sensitive assay, 96% of the ANSA-positive SLE sera produced a homogenous (chromosomal) F-ANA staining pattern compared to 18% of the ANSA-negative SLE sera. Ten of the 15 F-ANA-positive RA sera (63%) generated homogenous F-ANA staining and 13 (20%) tested positive in the most sensitive ANSA-EIA, but with no correlation to the F-ANA staining pattern. CONCLUSION: The sensitivity of F-ANA at an abnormal titer was surprisingly low (76%) in established cases of SLE. ANSA occurred in 56% of the SLE sera, but also in a fair number (20%) of RA sera. Practically all ANSA-positive SLE sera were identified by chromosomal F-ANA staining. We conclude that the antigen-specific antinucleosomal EIA does not have high enough diagnostic specificity to justify use of this analysis for routine diagnostic purposes.
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| 117. |
- Sjöwall, Christopher, et al.
(författare)
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Altered glycosylation of complexed native IgG molecules is associated with disease activity of systemic lupus erythematosus
- 2015
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Ingår i: Lupus. - : Sage Publications. - 0961-2033 .- 1477-0962. ; 24:6, s. 569-581
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Tidskriftsartikel (refereegranskat)abstract
- In addition to the redundancy of the receptors for the Fc portion of immunoglobulins, glycans result in potential ligands for a plethora of lectin receptors found in immune effector cells. Here we analysed the exposure of glycans containing fucosyl residues and the fucosylated tri-mannose N-type core by complexed native IgG in longitudinal serum samples of well-characterized patients with systemic lupus erythematosus. Consecutive serum samples of a cohort of 15 patients with systemic lupus erythematosus during periods of increased disease activity and remission were analysed. All patients fulfilled the 1982 American College of Rheumatology classification criteria. Sera of 15 sex- and age-matched normal healthy blood donors served as controls. The levels and type of glycosylation of complexed random IgG was measured with lectin enzyme-immunosorbent assays. After specifically gathering IgG complexes from sera, biotinylated lectins Aleuria aurantia lectin and Lens culinaris agglutinin were employed to detect IgG-associated fucosyl residues and the fucosylated tri-mannose N-glycan core, respectively. In sandwich-ELISAs, IgG-associated IgM, IgA, C1q, C3c and C-reactive protein (CRP) were detected as candidates for IgG immune complex constituents. We studied associations of the glycan of complexed IgG and disease activity according to the physician's global assessment of disease activity and the systemic lupus erythematosus disease activity index 2000 documented at the moment of blood taking. Our results showed significantly higher levels of Aleuria aurantia lectin and Lens culinaris agglutinin binding sites exposed on IgG complexes of patients with systemic lupus erythematosus than on those of normal healthy blood donors. Disease activity in systemic lupus erythematosus correlated with higher exposure of Aleuria aurantia lectin-reactive fucosyl residues by immobilized IgG complexes. Top levels of Aleuria aurantia lectin-reactivity were found in samples taken during the highest activity of systemic lupus erythematosus. Our results show that native circulating IgG complexes from active systemic lupus erythematosus patients expose fucosyl residues and their glycan core is accessible to soluble lectins. Two putative mechanisms may contribute to the increased exposure of these glycans: (1) the canonical N-glycosylation site of the IgG-CH2 domain; (2) an IgG binding non-IgG molecule, like complement or C-reactive protein. In both cases the complexed IgG may be alternatively targeted to lectin receptors of effector cells, e.g. dendritic cells.
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| 118. |
- Sjöwall, Christopher, et al.
(författare)
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Autoantibodies to C-reactive protein is a common finding in SLE, but not in primary Sjögren’s syndrome, rheumatoid arthritis or inflammatory bowel disease
- 2002
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Ingår i: Journal of Autoimmunity. - : Elsevier BV. - 0896-8411. ; 19:3, s. 155-160
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Tidskriftsartikel (refereegranskat)abstract
- The occurrence of antibodies to human C-reactive protein (CRP) was analysed by enzyme-linked immunosorbent assay (ELISA) in 56 patient sera known to contain antibodies to double-stranded DNA (dsDNA) and in 16 sera from patients with primary Sjögren's syndrome (SS), 15 rheumatoid arthritis, 31 Crohn's disease, and 37 ulcerative colitis. Eighty-seven per cent of the patients with anti-dsDNA antibodies had systemic lupus erythematosus (SLE) and the remaining had autoimmune hepatitis. The cut-off for positive anti-CRP test was set at the 95th percentile of 100 healthy blood donors. Twenty of 56 anti-dsDNA sera (36%) and two of 16 SS sera (13%) had antibodies reactive with human CRP, whereas all other samples were negative. Thirteen of 27 SLE patients (48%) were positive on at least one occasion. The sera containing anti-CRP antibodies only reacted with surface-bound antigen, but not with native CRP in solution. In conclusion, we found that autoantibodies to CRP are common in sera from patients with anti-dsDNA antibodies. It is not likely that this explains the relative failure of CRP response in patients with active SLE. However, it cannot be excluded that anti-CRP autoantibodies have other biological potentials of pathophysiological interest in SLE, for instance by binding to CRP deposited on cell and tissue surfaces.
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| 119. |
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| 120. |
- Sjöwall, Christopher, 1975-
(författare)
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C-reactive protein (CRP) and anti-CRP autoantibodies in systemic lupus erythematosus : a study on the occurrence and clinical implications of anti-CRP antibodies and CRP-mediated complement activation
- 2006
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by production of a wide range of autoantibodies, multiple organ involvement and by local formation or tissue deposition of immune complexes (ICs) in the inflamed organs. In contrast to most systemic inflammatory conditions, and despite raised levels of pro-inflammatory cytokines, SLE flares are rarely reflected by elevated C-reactive protein (CRP), an important acute-phase reactant in man with homologs in vertebrates and several invertebrates. As a part of the innate immune system, CRP binds certain molecules exposed on the surface of dying cells/apoptotic bodies and on the surface of pathogens and mediates their elimination by uptake in the reticuloendothelial system. CRP also interacts with IgG-containing immune complexes, binds Fc receptors and activates the complement system via C1q.The aims of this thesis were to investigate the complement activation properties of CRP; to elucidate if anti-CRP antibodies occur in SLE and, if so, whether anti-CRP antibody levels correlate with disease activity in SLE; to test the hypothesis that autoantibodies to pro-inflammatory cytokines prevent rise of CRP; and to survey if autoantibodies to certain nuclear antigens or to CRP correlate with cytokine-inducing properties of ICs from SLE sera.We have demonstrated that CRP bound to phosphorylcholine is a powerful activator of the classical complement pathway already in the CRP concentration range 4 to 10 mg/L, but with a marked inhibition at CRP levels above 150 mg/L. Autoantibodies to the monomeric form of CRP were found in approximately 40 percent of SLE patients and in a few sera from patients with primary Sjögren’s syndrome, but not in rheumatoid arthritis or in inflammatory bowel disease. The anti-CRP antibody levels showed significant correlations to several laboratory and clinical measurements, and anti-CRP positivity was associated with renal involvement in SLE. Native CRP levels were not correlated with anti-CRP or anti-cytokine antibody levels. Hence, the presence of antibodies to monomeric CRP or to CRP-inducing cytokines is an unlikely explanation to the relative failure of CRP response in patients with active lupus. However, antibodies to TNFα were found in subnormal levels at disease flares, whereas antibodies to TGFβ were found in supranormal levels as compared to healthy subjects. In contrast to antibodies against CRP and DNA, anti-SSA and anti-SSB antibodies may regulate the inflammatory process in SLE by enhancing IC formation and subsequent production of cytokines such as IL-6, IL-10 and IL-12p40. Hypothetically, anti-CRP autoantibodies may be of pathogenic importance, for instance by binding to monomeric CRP on cell and tissue surfaces and thereby increasing the risk of extrahepatic deposition of apoptotic material and in situ formation of ICs.
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