532 results on '"Leonard, Dag"'
Search Results
2. Low-density granulocytes are related to shorter pregnancy duration but not to interferon alpha protein blood levels in systemic lupus erythematosus
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Torell, Agnes, Stockfelt, Marit, Larsson, Gunilla, Blennow, Kaj, Zetterberg, Henrik, Leonard, Dag, Rönnblom, Lars, Saleh, Muna, Sjöwall, Christopher, Strevens, Helena, Jönsen, Andreas, Bengtsson, Anders A., Trysberg, Estelle, Sennström, Maria Majcuk, Zickert, Agneta, Svenungsson, Elisabet, Gunnarsson, Iva, Christenson, Karin, Bylund, Johan, Jacobsson, Bo, Rudin, Anna, and Lundell, Anna-Carin
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- 2023
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3. Patient global assessment and inflammatory markers in patients with idiopathic inflammatory myopathies – A longitudinal study
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Lodin, Karin, Espinosa-Ortega, Fabricio, Dastmalchi, Maryam, Vencovsky, Jiri, Andersson, Helena, Chinoy, Hector, Lilleker, James B., Shinjo, Samuel Katsuyuki, Maurer, Britta, Griger, Zoltan, Ceribelli, Angela, Torres-Ruiz, Jiram, Mercado M., Vazquez-Del, Leonard, Dag, Alexanderson, Helene, and Lundberg, Ingrid E.
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- 2024
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4. A survey of ficolin-3 activity in Systemic Lupus Erythematosus reveals a link to hematological disease manifestations and autoantibody profile
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Lindelöf, Linnea, Rantapää-Dahlqvist, Solbritt, Lundtoft, Christian, Sandling, Johanna K., Leonard, Dag, Sayadi, Ahmed, Rönnblom, Lars, Enocsson, Helena, Sjöwall, Christopher, Jönsen, Andreas, Bengtsson, Anders A., Hong, Mun-Gwan, Diaz-Gallo, Lina-Marcela, Bianchi, Matteo, Kozyrev, Sergey V., Lindblad-Toh, Kerstin, Nilsson Ekdahl, Kristina, Nilsson, Bo, Gunnarsson, Iva, Svenungsson, Elisabet, and Eriksson, Oskar
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- 2024
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5. Distinct HLA associations with autoantibody-defined subgroups in idiopathic inflammatory myopathies
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Bianchi, Matteo, Kozyrev, Sergey V., Sandling, Johanna K., Rönnblom, Lars, Eloranta, Maija-Leena, Syvänen, Ann-Christine, Leonard, Dag, Dahlqvist, Johanna, Lidén, Maria, Mathioudaki, Argyri, Meadows, Jennifer RS., Nordin, Jessika, Nordmark, Gunnel, Lundberg, Ingrid E., Notarnicola, Antonella, Padyukov, Leonid, Tjärnlund, Anna, Dastmalchi, Maryam, Eriksson, Daniel, Molberg, Øyvind, Andersson, Helena, Lindblad-Toh, Kerstin, Farias, Fabiana H.G., Wahren-Herlenius, Marie, Jalal, Awat, Hanna, Balsam, Hellström, Helena, Husmark, Tomas, Häggström, Åsa, Svärd, Anna, Skogh, Thomas, Diederichsen, Louise Pyndt, Lamb, Janine A., Rothwell, Simon, Chinoy, Hector, Cooper, Robert G., Pielberg, Gerli Rosengren, Lobell, Anna, Karlsson, Åsa, Murén, Eva, Ahlgren, Kerstin M., Andersson, Göran, Landegren, Nils, Kämpe, Olle, Söderkvis, Peter, Leclair, Valérie, Galindo-Feria, Angeles S., Kryštůfková, Olga, Zargar, Sepehr Sarrafzadeh, Mann, Herman, Klein, Martin, Tansley, Sarah, McHugh, Neil, Vencovský, Jiri, Holmqvist, Marie, and Diaz-Gallo, Lina-Marcela
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- 2023
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6. O4 Clinical characteristics of patients with high SLE-specific and high multitrait polygenic risk – An investigation of SLE risk loci
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Oparina, Nina, primary, Reid, Sarah, additional, Sayadi, Ahmed, additional, Eloranta, Maija-Leena, additional, Frodlund, Martina, additional, Lerang, Karoline, additional, Jönsen, Andreas, additional, Rantapää-Dahlqvist, Solbritt, additional, Bengtsson, Anders A, additional, Rudin, Anna, additional, Molberg, Øyvind, additional, Sjöwall, Christopher, additional, Rönnblom, Lars, additional, and Leonard, Dag, additional
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- 2024
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7. P145 Circulating interferon-α levels are elevated during pregnancy in women with SLE who deliver infants that are small for gestational age, preterm and/or have low birth weight
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Stockfelt, Marit, primary, Torell, Agnes, additional, Blennow, Kaj, additional, Zetterberg, Henrik, additional, Akhter, Tansim, additional, Leonard, Dag, additional, Rönnblom, Lars, additional, Pihl, Sofia, additional, Saleh, Muna, additional, Sjöwall, Christopher, additional, Strevens, Helena, additional, Jönsen, Andreas, additional, Bengtsson, Anders A, additional, Trysberg, Estelle, additional, Sennström, Maria Majcuk, additional, Zickert, Agneta, additional, Svenungsson, Elisabet, additional, Gunnarsson, Iva, additional, Jacobsson, Bo, additional, Lundell, Anna-Carin, additional, and Rudin, Anna, additional
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- 2024
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8. P146 Low CD4+ T cell count is related to specific anti-nuclear antibodies, IFNα protein positivity and disease activity in systemic lupus erythematosus pregnancy
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Torell, Agnes, primary, Stockfelt, Marit, additional, Blennow, Kaj, additional, Zetterberg, Henrik, additional, Akhter, Tansim, additional, Leonard, Dag, additional, Rönnblom, Lars, additional, Pihl, Sofia, additional, Saleh, Muna, additional, Sjöwall, Christopher, additional, Strevens, Helena, additional, Jönsen, Andreas, additional, Bengtsson, Anders A, additional, Trysberg, Estelle, additional, Sennström, Maria Majcuk, additional, Zickert, Agneta, additional, Svenungsson, Elisabet, additional, Gunnarsson, Iva, additional, Bylund, Johan, additional, Jacobsson, Bo, additional, Rudin, Anna, additional, and Lundell, Anna-Carin, additional
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- 2024
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9. O6 Epidemiology of moderate-to-severe SLE in Sweden
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Frodlund, Martina, primary, Leonard, Dag, additional, Haugli-Stephens, Thomas, additional, Remkus, Lauren, additional, Eek, Daniel, additional, Söderdahl, Fabian, additional, and Jönsen, Andreas, additional
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- 2024
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10. P77 Identification of a cluster of SLE risk loci associated with levels of multiple blood biomarkers in the general population – Implication for SLE sub-phenotypes
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Oparina, Nina, primary, Reid, Sarah, additional, Sayadi, Ahmed, additional, Eloranta, Maija-Leena, additional, Frodlund, Martina, additional, Lerang, Karoline, additional, Jönsen, Andreas, additional, Rantapää-Dahlqvist, Solbritt, additional, Bengtsson, Anders A, additional, Rudin, Anna, additional, Molberg, Øyvind, additional, Sjöwall, Christopher, additional, Rönnblom, Lars, additional, and Leonard, Dag, additional
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- 2024
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11. O10 Ischemic stroke subtypes in SLE-associations with a STAT4 risk genotype
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Hopia, Liisa, primary, Laveskog, Anna, additional, Jönsen, Andreas, additional, Leonard, Dag, additional, Gustafsson, Johanna T, additional, Gunnarsson, Iva, additional, Zickert, Agneta, additional, Nordmark, Gunnel, additional, Bengtsson, Anders A, additional, Elvin, Kerstin, additional, Sandling, Johanna K, additional, Syvänen, Ann-Christine, additional, Rönnblom, Lars, additional, Andersson, Magnus, additional, and Svenungsson, Elisabet, additional
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- 2024
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12. Variants in BANK1 are associated with lupus nephritis of European ancestry
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Bolin, Karin, Imgenberg-Kreuz, Juliana, Leonard, Dag, Sandling, Johanna K., Alexsson, Andrei, Pucholt, Pascal, Haarhaus, Malena Loberg, Almlöf, Jonas Carlsson, Nititham, Joanne, Jönsen, Andreas, Sjöwall, Christopher, Bengtsson, Anders A., Rantapää-Dahlqvist, Solbritt, Svenungsson, Elisabet, Gunnarsson, Iva, Syvänen, Ann-Christine, Lerang, Karoline, Troldborg, Anne, Voss, Anne, Molberg, Øyvind, Jacobsen, Søren, Criswell, Lindsey, Rönnblom, Lars, and Nordmark, Gunnel
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- 2021
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13. Glucocorticoid treatment in SLE is associated with infections, comorbidities and mortality-a national cohort study
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Frodlund, Martina, Jonsen, Andreas, Remkus, Lauren, Telg, Gunilla, Soderdahl, Fabian, Leonard, Dag, Frodlund, Martina, Jonsen, Andreas, Remkus, Lauren, Telg, Gunilla, Soderdahl, Fabian, and Leonard, Dag
- Abstract
Objectives Patients with SLE have an increased risk of comorbidities and impaired survival. We aimed to assess whether various thresholds of oral CS (OCS) can predict development of infections, comorbidities, malignancies and survival in SLE using data from national health registries in Sweden. Methods All incident SLE cases, age >18 years, in Sweden (n = 5309) between 2005 and 2020 and matched population controls (n = 26 545) were included and followed until 2020, a total of 257 942 patient years. Data from national registers were retrieved including information from the National Prescribed Drug Register. Risk factors were analysed using time-dependent Cox regression models. Results Compared with no OCS, >0 to <5.0 mg/day, 5.0-7.5 mg/day as well as >7.5 mg/day OCS predicted development of infections (pneumonia, influenza, herpes zoster and urinary tract infection), osteoporosis, osteonecrosis, gastroduodenal ulcers, cataracts, hypertension and mortality (all P < 0.05). OCS >0 to <5.0 mg/day was associated with lower hazard ratios for these comorbidities than higher doses of OCS. Fifteen years after diagnosis, 48% of patients were taking OCS at a median dose of 5.7 mg/day. A small reduction of OCS treatment 5 years after diagnosis in patients diagnosed with SLE 2006-10 compared with 2011-15 was observed, 49% vs 46% respectively (P = 0.039). Conclusion Results highlight the potential harm associated with even low OCS dose treatment in SLE and the need to judiciously use OCS at the lowest possible dose to maximize efficacy and minimize harm., Funding Agencies|AstraZeneca
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- 2024
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14. Low CD4+T cell count is related to specific anti-nuclear antibodies, IFNa protein positivity and disease activity in systemic lupus erythematosus pregnancy
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Torell, Agnes, Stockfelt, Marit, Blennow, Kaj, Zetterberg, Henrik, Akhter, Tansim, Leonard, Dag, Roennblom, Lars, Pihl, Sofia, Saleh, Muna Atallah, Sjöwall, Christopher, Strevens, Helena, Joensen, Andreas, Bengtsson, Anders A., Trysberg, Estelle, Majczuk Sennstroem, Maria, Zickert, Agneta, Svenungsson, Elisabet, Gunnarsson, Iva, Bylund, Johan, Jacobsson, Bo, Rudin, Anna, Lundell, Anna-Carin, Torell, Agnes, Stockfelt, Marit, Blennow, Kaj, Zetterberg, Henrik, Akhter, Tansim, Leonard, Dag, Roennblom, Lars, Pihl, Sofia, Saleh, Muna Atallah, Sjöwall, Christopher, Strevens, Helena, Joensen, Andreas, Bengtsson, Anders A., Trysberg, Estelle, Majczuk Sennstroem, Maria, Zickert, Agneta, Svenungsson, Elisabet, Gunnarsson, Iva, Bylund, Johan, Jacobsson, Bo, Rudin, Anna, and Lundell, Anna-Carin
- Abstract
BackgroundLymphopenia, autoantibodies and activation of the type I interferon (IFN) system are common features in systemic lupus erythematosus (SLE). We speculate whether lymphocyte subset counts are affected by pregnancy and if they relate to autoantibody profiles and/or IFN alpha protein in SLE pregnancy.MethodsRepeated blood samples were collected during pregnancy from 80 women with SLE and 51 healthy controls (HC). Late postpartum samples were obtained from 19 of the women with SLE. Counts of CD4 + and CD8 + T cells, B cells and NK cells were measured by flow cytometry. Positivity for anti-nuclear antibodies (ANA) fine specificities (double-stranded DNA [dsDNA], Smith [Sm], ribonucleoprotein [RNP], chromatin, Sjogren's syndrome antigen A [SSA] and B [SSB]) and anti-phospholipid antibodies (cardiolipin [CL] and beta 2 glycoprotein I [beta 2GPI]) was assessed with multiplexed bead assay. IFN alpha protein concentration was quantified with Single molecule array (Simoa) immune assay. Clinical data were retrieved from medical records.ResultsWomen with SLE had lower counts of all lymphocyte subsets compared to HC throughout pregnancy, but counts did not differ during pregnancy compared to postpartum. Principal component analysis revealed that low lymphocyte subset counts differentially related to autoantibody profiles, cluster one (anti-dsDNA/anti-Sm/anti-RNP/anti-Sm/RNP/anti-chromatin), cluster two (anti-SSA/anti-SSB) and cluster three (anti-CL/anti-beta 2GPI), IFN alpha protein levels and disease activity. CD4 + T cell counts were lower in women positive to all ANA fine specificities in cluster one compared to those who were negative, and B cell numbers were lower in women positive for anti-dsDNA and anti-Sm compared to negative women. Moreover, CD4 + T cell and B cell counts were lower in women with moderate/high compared to no/low disease activity, and CD4 + T cell count was lower in IFN alpha protein positive relative to negative women. Finally, CD4 + T cell coun, Funding Agencies|University of Gothenburg; Swedish Research Council; Swedish state; ALF-agreement; foundations of The King Gustaf V's 80th Birthday found; Swedish Rheumatism Association; Gothenburg Society of Medicine; Foundation of Ulla; Foundation of Roland; Gustafsson; Nanna Svartz; Rune; Ulla Amloev; Hjalmar Svensson; IngaBritt; Arne Lundberg; Ingegerd Johansson; Emil and Wera Cornell; Swedish Society of Medicine
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- 2024
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15. Contributions of de novo variants to systemic lupus erythematosus
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Almlöf, Jonas Carlsson, Nystedt, Sara, Mechtidou, Aikaterini, Leonard, Dag, Eloranta, Maija-Leena, Grosso, Giorgia, Sjöwall, Christopher, Bengtsson, Anders A., Jönsen, Andreas, Gunnarsson, Iva, Svenungsson, Elisabet, Rönnblom, Lars, Sandling, Johanna K., and Syvänen, Ann-Christine
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- 2021
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16. B cell polygenic risk scores associate with anti-dsDNA antibodies and nephritis in systemic lupus erythematosus
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Hedenstedt, Anna, primary, Reid, Sarah, additional, Sayadi, Ahmed, additional, Eloranta, Maija-Leena, additional, Skoglund, Elisabeth, additional, Bolin, Karin, additional, Frodlund, Martina, additional, Lerang, Karoline, additional, Jönsen, Andreas, additional, Rantapää-Dahlqvist, Solbritt, additional, Bengtsson, Anders A, additional, Rudin, Anna, additional, Molberg, Øyvind, additional, Sjöwall, Christopher, additional, Sandling, Johanna K, additional, and Leonard, Dag, additional
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- 2023
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17. Distinct HLA associations with autoantibody-defined subgroups in idiopathic inflammatory myopathies
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Leclair, Valérie, primary, Galindo-Feria, Angeles S., additional, Rothwell, Simon, additional, Kryštůfková, Olga, additional, Zargar, Sepehr Sarrafzadeh, additional, Mann, Herman, additional, Diederichsen, Louise Pyndt, additional, Andersson, Helena, additional, Klein, Martin, additional, Tansley, Sarah, additional, Rönnblom, Lars, additional, Lindblad-Toh, Kerstin, additional, Syvänen, Ann-Christine, additional, Wahren-Herlenius, Marie, additional, Sandling, Johanna K., additional, McHugh, Neil, additional, Lamb, Janine A., additional, Vencovský, Jiri, additional, Chinoy, Hector, additional, Holmqvist, Marie, additional, Bianchi, Matteo, additional, Padyukov, Leonid, additional, Lundberg, Ingrid E., additional, Diaz-Gallo, Lina-Marcela, additional, Kozyrev, Sergey V., additional, Eloranta, Maija-Leena, additional, Leonard, Dag, additional, Dahlqvist, Johanna, additional, Lidén, Maria, additional, Mathioudaki, Argyri, additional, Meadows, Jennifer RS., additional, Nordin, Jessika, additional, Nordmark, Gunnel, additional, Notarnicola, Antonella, additional, Tjärnlund, Anna, additional, Dastmalchi, Maryam, additional, Eriksson, Daniel, additional, Molberg, Øyvind, additional, Farias, Fabiana H.G., additional, Jalal, Awat, additional, Hanna, Balsam, additional, Hellström, Helena, additional, Husmark, Tomas, additional, Häggström, Åsa, additional, Svärd, Anna, additional, Skogh, Thomas, additional, Cooper, Robert G., additional, Pielberg, Gerli Rosengren, additional, Lobell, Anna, additional, Karlsson, Åsa, additional, Murén, Eva, additional, Ahlgren, Kerstin M., additional, Andersson, Göran, additional, Landegren, Nils, additional, Kämpe, Olle, additional, and Söderkvis, Peter, additional
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- 2023
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18. A rare regulatory variant in the MEF2D gene affects gene regulation and splicing and is associated with a SLE sub-phenotype in Swedish cohorts
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Farias, Fabiana H. G., Dahlqvist, Johanna, Kozyrev, Sergey V., Leonard, Dag, Wilbe, Maria, Abramov, Sergei N., Alexsson, Andrei, Pielberg, Gerli R., Hansson-Hamlin, Helene, Andersson, Göran, Tandre, Karolina, Bengtsson, Anders A., Sjöwall, Christopher, Svenungsson, Elisabet, Gunnarsson, Iva, Rantapää-Dahlqvist, Solbritt, Syvänen, Ann-Christine, Sandling, Johanna K., Eloranta, Maija-Leena, Rönnblom, Lars, and Lindblad-Toh, Kerstin
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- 2019
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19. Whole-genome sequencing identifies complex contributions to genetic risk by variants in genes causing monogenic systemic lupus erythematosus
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Almlöf, Jonas Carlsson, Nystedt, Sara, Leonard, Dag, Eloranta, Maija-Leena, Grosso, Giorgia, Sjöwall, Christopher, Bengtsson, Anders A., Jönsen, Andreas, Gunnarsson, Iva, Svenungsson, Elisabet, Rönnblom, Lars, Sandling, Johanna K., and Syvänen, Ann-Christine
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- 2019
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20. Glucocorticoid treatment in SLE is associated with infections, comorbidities and mortality—a national cohort study
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Frodlund, Martina, primary, Jönsen, Andreas, additional, Remkus, Lauren, additional, Telg, Gunilla, additional, Söderdahl, Fabian, additional, and Leonard, Dag, additional
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- 2023
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21. B cell polygenic risk scores associate with anti-dsDNA antibodies and nephritis in systemic lupus erythematosus
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Hedenstedt, Anna, Reid, Sarah, Sayadi, Ahmed, Eloranta, Maija-Leena, Skoglund, Elisabeth, Bolin, Karin, Frodlund, Martina, Lerang, Karoline, Joensen, Andreas, Rantapaeae-Dahlqvist, Solbritt, Bengtsson, Anders A., Rudin, Anna, Molberg, Oyvind, Sjoewall, Christopher, Sandling, Johanna K., Leonard, Dag, Hedenstedt, Anna, Reid, Sarah, Sayadi, Ahmed, Eloranta, Maija-Leena, Skoglund, Elisabeth, Bolin, Karin, Frodlund, Martina, Lerang, Karoline, Joensen, Andreas, Rantapaeae-Dahlqvist, Solbritt, Bengtsson, Anders A., Rudin, Anna, Molberg, Oyvind, Sjoewall, Christopher, Sandling, Johanna K., and Leonard, Dag
- Abstract
Objective: 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. Methods: 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. Results: 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). Conclusions: 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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- 2023
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22. Additional file 2 of Low-density granulocytes are related to shorter pregnancy duration but not to interferon alpha protein blood levels in systemic lupus erythematosus
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Torell, Agnes, Stockfelt, Marit, Larsson, Gunilla, Blennow, Kaj, Zetterberg, Henrik, Leonard, Dag, Rönnblom, Lars, Saleh, Muna, Sjöwall, Christopher, Strevens, Helena, Jönsen, Andreas, Bengtsson, Anders A., Trysberg, Estelle, Sennström, Maria Majcuk, Zickert, Agneta, Svenungsson, Elisabet, Gunnarsson, Iva, Christenson, Karin, Bylund, Johan, Jacobsson, Bo, Rudin, Anna, and Lundell, Anna-Carin
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Additional file 2: Supplementary Table 1. Numbers of collected blood samples. Supplementary Table 2. Antibodies used for flow cytometry.
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- 2023
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23. Additional file 1 of Low-density granulocytes are related to shorter pregnancy duration but not to interferon alpha protein blood levels in systemic lupus erythematosus
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Torell, Agnes, Stockfelt, Marit, Larsson, Gunilla, Blennow, Kaj, Zetterberg, Henrik, Leonard, Dag, Rönnblom, Lars, Saleh, Muna, Sjöwall, Christopher, Strevens, Helena, Jönsen, Andreas, Bengtsson, Anders A., Trysberg, Estelle, Sennström, Maria Majcuk, Zickert, Agneta, Svenungsson, Elisabet, Gunnarsson, Iva, Christenson, Karin, Bylund, Johan, Jacobsson, Bo, Rudin, Anna, and Lundell, Anna-Carin
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Additional file 1: Supplementary figure 1. (A) Expression of CD15 and CD14 on low-density granulocytes (LDG) from two pregnant women with SLE (two left panels, samples from trimester three) and two healthy pregnant controls (HC, two right panels, one sample from trimester three and one sample from trimester one). (B) Analysis of proportions of LDG and shedding of CD62L by NDG in blood from pregnant women with SLE and healthy pregnant controls between 17 and 24 h post venipuncture i.e., the time span when all samples in the study were analyzed. (C) Analysis of total number of granulocytes, proportions of LDG and shedding of CD62L by normal-density granulocytes (NDG) from one pregnant woman with SLE in trimester three and one healthy pregnant control in trimester one at 5 and 24 h post venipuncture. Supplementary figure 2. Comparison of (A) proportions of low-density granulocytes (LDG), (B) proportions of LDG that have shed CD62L, (C) proportions of normal-density granulocytes (NDG) that have shed CD62L and (D) total granulocyte counts during compared to after pregnancy among women with SLE from whom late postpartum samples were collected. *p < 0.05, **p < 0.01 and ***p < 0.001, Kruskal-Wallis followed by Dunn’s multiple comparison test. Supplementary figure 3. Comparison of LDG proportions in pregnant women with SLE with or without a moderate/high disease activity (SLEDAI-2K ≥ 4) in (A) trimester one, (B) trimester two and (C) trimester three. Mann-Whitney U test. Supplementary figure 4. Comparison of (A) LDG proportions, (B) LDG activation by CD62L shedding, (C) NDG activation by CD62L shedding and (D) IFNα protein levels in SLE and healthy pregnancy for each trimester. *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001 Mann-Whitney U test. Supplementary figure 5. Comparison of the proportions of low-density granulocytes (LDG) and normal-density granulocytes (NDG) that have shed CD62L in pregnant women with SLE and in healthy pregnant controls (HC). **** p < 0.0001, Mann-Whitney U test. Supplementary figure 6. Concentrations of G-CSF (A) and GM-CSF (B) in plasma during pregnancy (first, second and third trimester) compared to the late postpartum period among women with SLE from whom late postpartum samples were collected. Concentrations of G-CSF (C) and GM-CSF (D) in plasma in the first, second and third trimester in SLE compared to healthy pregnancies. Supplementary figure 7. (A) OPLS loading column plot depicting granulocyte-related immune variables positively or negatively associated with prednisone use in SLE pregnancy, and low-density proportions in pregnant women with SLE who were treated with prednisone compared to those who were not treated. (B) OPLS plot depicting granulocyte-related immune variables positively or negatively associated with azathioprine use in SLE pregnancy and CD62L shedding of normal-density granulocytes in pregnant women with SLE who were treated with azathioprine compared to those who were not treated. (C) OPLS plot depicting granulocyte-related immune variables positively or negatively associated with low molecular weight heparin use in SLE pregnancy. * p < 0.05, Mann-Whitney U test. Supplementary figure 8. IFNα plasma protein concentrations in trimester one, two and three from pregnant women with SLE who were treated or not with prednisone (A), azathioprine (B) or low molecular weight heparin (C). Supplementary figure 9. IFNα plasma protein concentrations in trimester one, two and three from pregnant women with SLE who were anti-SSA positive compared to those who were negative. ** p < 0.01, Mann-Whitney U test. Supplementary figure 10. (A) Gestational age at birth among women with SLE with induced compared to spontaneous delivery. (B) Gestational age at birth in women with SLE with induced or spontaneous delivery who were positive or negative for anti-CL, anti-β2GPI or LAC. (C) Correlations between gestational age at birth and proportions of LDG in trimester three, two and one among women with SLE with induced or spontaneous delivery. * p < 0.05, (B) Mann-Whitney U test and (C) Spearman rank correlation test.
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- 2023
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24. Complement C4 Copy Number Variation is Linked to SSA/Ro and SSB/La Autoantibodies in Systemic Inflammatory Autoimmune Diseases
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Lundtoft, Christian, Pucholt, Pascal, Martin, Myriam, Bianchi, Matteo, Lundstrom, Emeli, Eloranta, Maija-Leena, Sandling, Johanna K., Sjöwall, Christopher, Jonsen, Andreas, Gunnarsson, Iva, Rantapaa-Dahlqvist, Solbritt, Bengtsson, Anders A., Leonard, Dag, Baecklund, Eva, Jonsson, Roland, Hammenfors, Daniel, Forsblad-dElia, Helena, Eriksson, Per, Mandl, Thomas, Bucher, Sara Magnusson, Norheim, Katrine B., Johnsen, Svein Joar Auglaend, Omdal, Roald, Kvarnstrom, Marika, Wahren-Herlenius, Marie, Notarnicola, Antonella, Andersson, Helena, Molberg, Oyvind, Diederichsen, Louise Pyndt, Almlof, Jonas, Syvanen, Ann-Christine, Kozyrev, Sergey V, Lindblad-Toh, Kerstin, Nilsson, Bo, Blom, Anna M., Lundberg, Ingrid E., Nordmark, Gunnel, Diaz-Gallo, Lina Marcela, Svenungsson, Elisabet, Ronnblom, Lars, Lundtoft, Christian, Pucholt, Pascal, Martin, Myriam, Bianchi, Matteo, Lundstrom, Emeli, Eloranta, Maija-Leena, Sandling, Johanna K., Sjöwall, Christopher, Jonsen, Andreas, Gunnarsson, Iva, Rantapaa-Dahlqvist, Solbritt, Bengtsson, Anders A., Leonard, Dag, Baecklund, Eva, Jonsson, Roland, Hammenfors, Daniel, Forsblad-dElia, Helena, Eriksson, Per, Mandl, Thomas, Bucher, Sara Magnusson, Norheim, Katrine B., Johnsen, Svein Joar Auglaend, Omdal, Roald, Kvarnstrom, Marika, Wahren-Herlenius, Marie, Notarnicola, Antonella, Andersson, Helena, Molberg, Oyvind, Diederichsen, Louise Pyndt, Almlof, Jonas, Syvanen, Ann-Christine, Kozyrev, Sergey V, Lindblad-Toh, Kerstin, Nilsson, Bo, Blom, Anna M., Lundberg, Ingrid E., Nordmark, Gunnel, Diaz-Gallo, Lina Marcela, Svenungsson, Elisabet, and Ronnblom, Lars
- Abstract
Objective Copy number variation of the C4 complement components, C4A and C4B, has been associated with systemic inflammatory autoimmune diseases. This study was undertaken to investigate whether C4 copy number variation is connected to the autoimmune repertoire in systemic lupus erythematosus (SLE), primary Sjogrens syndrome (SS), or myositis. Methods Using targeted DNA sequencing, we determined the copy number and genetic variants of C4 in 2,290 well-characterized Scandinavian patients with SLE, primary SS, or myositis and 1,251 healthy controls. Results A prominent relationship was observed between C4A copy number and the presence of SSA/SSB autoantibodies, which was shared between the 3 diseases. The strongest association was detected in patients with autoantibodies against both SSA and SSB and 0 C4A copies when compared to healthy controls (odds ratio [OR] 18.0 [95% confidence interval (95% CI) 10.2-33.3]), whereas a weaker association was seen in patients without SSA/SSB autoantibodies (OR 3.1 [95% CI 1.7-5.5]). The copy number of C4 correlated positively with C4 plasma levels. Further, a common loss-of-function variant in C4A leading to reduced plasma C4 was more prevalent in SLE patients with a low copy number of C4A. Functionally, we showed that absence of C4A reduced the individuals capacity to deposit C4b on immune complexes. Conclusion We show that a low C4A copy number is more strongly associated with the autoantibody repertoire than with the clinically defined disease entities. These findings may have implications for understanding the etiopathogenetic mechanisms of systemic inflammatory autoimmune diseases and for patient stratification when taking the genetic profile into account., Funding Agencies|Swedish Research Council for Medicine and Health; Swedish Rheumatism Association; Swedish Society of Medicine; Swedish Heart Lung Foundation; Stockholm County; Karolinska Institutet; Wallenberg Scholarship; King Gustav Vs 80-Year Foundation
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- 2022
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25. Strong Association of Combined Genetic Deficiencies in the Classical Complement Pathway With Risk of Systemic Lupus Erythematosus and Primary Sjögren's Syndrome
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Lundtoft, Christian, Sjöwall, Christopher, Rantapää‐Dahlqvist, Solbritt, Bengtsson, Anders A., Jönsen, Andreas, Pucholt, Pascal, Wu, Yee Ling, Lundström, Emeli, Eloranta, Maija-Leena, Gunnarsson, Iva, Baecklund, Eva, Jonsson, Roland, Hammenfors, Daniel, Forsblad‐d'Elia, Helena, Eriksson, Per, Mandl, Thomas, Bucher, Sara, Norheim, Katrine B., Auglaend Johnsen, Svein Joar, Omdal, Roald, Kvarnström, Marika, Wahren‐Herlenius, Marie, Truedsson, Lennart, Nilsson, Bo, Kozyrev, Sergey V., Bianchi, Matteo, Lindblad‐Toh, Kerstin, Yu, Chack‐Yung, Nordmark, Gunnel, Sandling, Johanna K., Svenungsson, Elisabet, Leonard, Dag, Rönnblom, Lars, Lundtoft, Christian, Sjöwall, Christopher, Rantapää‐Dahlqvist, Solbritt, Bengtsson, Anders A., Jönsen, Andreas, Pucholt, Pascal, Wu, Yee Ling, Lundström, Emeli, Eloranta, Maija-Leena, Gunnarsson, Iva, Baecklund, Eva, Jonsson, Roland, Hammenfors, Daniel, Forsblad‐d'Elia, Helena, Eriksson, Per, Mandl, Thomas, Bucher, Sara, Norheim, Katrine B., Auglaend Johnsen, Svein Joar, Omdal, Roald, Kvarnström, Marika, Wahren‐Herlenius, Marie, Truedsson, Lennart, Nilsson, Bo, Kozyrev, Sergey V., Bianchi, Matteo, Lindblad‐Toh, Kerstin, Yu, Chack‐Yung, Nordmark, Gunnel, Sandling, Johanna K., Svenungsson, Elisabet, Leonard, Dag, and Rönnblom, Lars
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Objective: Complete genetic deficiency of the complement component C2 is a strong risk factor for monogenic systemic lupus erythematosus (SLE), but whether heterozygous C2 deficiency adds to the risk of SLE or primary Sjögren's syndrome (SS) has not been studied systematically. This study was undertaken to investigate potential associations of heterozygous C2 deficiency and C4 copy number variation with clinical manifestations in patients with SLE and patients with primary SS. Methods: The presence of the common 28-bp C2 deletion rs9332736 and C4 copy number variation was examined in Scandinavian patients who had received a diagnosis of SLE (n = 958) or primary SS (n = 911) and in 2,262 healthy controls through the use of DNA sequencing. The concentration of complement proteins in plasma and classical complement function were analyzed in a subgroup of SLE patients. Results: Heterozygous C2 deficiency—when present in combination with a low C4A copy number—substantially increased the risk of SLE (odds ratio [OR] 10.2 [95% confidence interval (95% CI) 3.5–37.0]) and the risk of primary SS (OR 13.0 [95% CI 4.5–48.4]) when compared to individuals with 2 C4A copies and normal C2. For patients heterozygous for rs9332736 with 1 C4A copy, the median age at diagnosis was 7 years earlier in patients with SLE and 12 years earlier in patients with primary SS when compared to patients with normal C2. Reduced C2 levels in plasma (P = 2 × 10−9) and impaired function of the classical complement pathway (P = 0.03) were detected in SLE patients with heterozygous C2 deficiency. Finally, in a primary SS patient homozygous for C2 deficiency, we observed low levels of anti–Scl-70, which suggests a risk of developing systemic sclerosis or potential overlap between primary SS and other systemic autoimmune diseases. Coclusions: We demonstrate that a genetic pattern involving partial deficiencies of C2 and C4A in the classical complement pathway is a strong risk factor for SLE and for primary
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- 2022
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26. Mer-tyrosine kinase : a novel susceptibility gene for SLE related end-stage renal disease
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Yavuz, Sule, Pucholt, Pascal, Sandling, Johanna K., Bianchi, Matteo, Leonard, Dag, Bolin, Karin, Imgenberg-Kreuz, Juliana, Eloranta, Maija-Leena, Kozyrev, Sergey V., Lanata, Cristina M., Jonsen, Andreas, Bengtsson, Anders A., Sjowall, Christopher, Svenungsson, Elisabet, Gunnarsson, Iva, Rantapaa-Dahlqvist, Solbritt, Nititham, Joanne, Criswell, Lindsey A., Lindblad-Toh, Kerstin, Rönnblom, Lars, Yavuz, Sule, Pucholt, Pascal, Sandling, Johanna K., Bianchi, Matteo, Leonard, Dag, Bolin, Karin, Imgenberg-Kreuz, Juliana, Eloranta, Maija-Leena, Kozyrev, Sergey V., Lanata, Cristina M., Jonsen, Andreas, Bengtsson, Anders A., Sjowall, Christopher, Svenungsson, Elisabet, Gunnarsson, Iva, Rantapaa-Dahlqvist, Solbritt, Nititham, Joanne, Criswell, Lindsey A., Lindblad-Toh, Kerstin, and Rönnblom, Lars
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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=1.0x10(-6). We observed decreased methylation levels in peripheral blood cells from SLE patients with ESRD, compared with patients without renal SLE (p=2.7x10(-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)=1.6x10(-5), OR=0.58) and APOA1BP (NAXE) (rs942960, p(meta)=1.2x10(-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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- 2022
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27. A single nucleotide polymorphism in the NCF1 gene leading to reduced oxidative burst is associated with systemic lupus erythematosus
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Olsson, Lina M, Johansson, Åsa C, Gullstrand, Birgitta, Jönsen, Andreas, Saevarsdottir, Saedis, Rönnblom, Lars, Leonard, Dag, Wetterö, Jonas, Sjöwall, Christopher, Svenungsson, Elisabet, Gunnarsson, Iva, Bengtsson, Anders A, and Holmdahl, Rikard
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- 2017
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28. Four Systemic Lupus Erythematosus Subgroups, Defined by Autoantibodies Status, Differ Regarding HLA‐DRB1 Genotype Associations and Immunological and Clinical Manifestations
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Diaz‐Gallo, Lina‐Marcela, primary, Oke, Vilija, additional, Lundström, Emeli, additional, Elvin, Kerstin, additional, Ling Wu, Yee, additional, Eketjäll, Susanna, additional, Zickert, Agneta, additional, Gustafsson, Johanna T., additional, Jönsen, Andreas, additional, Leonard, Dag, additional, Birmingham, Daniel J., additional, Nordmark, Gunnel, additional, Bengtsson, Anders A., additional, Rönnblom, Lars, additional, Gunnarsson, Iva, additional, Yu, Chack‐Yung, additional, Padyukov, Leonid, additional, and Svenungsson, Elisabet, additional
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- 2021
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29. Clinical Experience of Proteasome Inhibitor Bortezomib Regarding Efficacy and Safety in Severe Systemic Lupus Erythematosus: A Nationwide Study
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Walhelm, Tomas, primary, Gunnarsson, Iva, additional, Heijke, Rebecca, additional, Leonard, Dag, additional, Trysberg, Estelle, additional, Eriksson, Per, additional, and Sjöwall, Christopher, additional
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- 2021
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30. Quick Systemic Lupus Activity Questionnaire (Q-SLAQ): a simplified version of SLAQ for patient-reported disease activity
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Svenungsson, Elisabet, primary, Gunnarsson, Iva, additional, Illescas-Bäckelin, Vera, additional, Trysberg, Estelle, additional, Jönsen, Andreas, additional, Leonard, Dag, additional, Sjöwall, Christopher, additional, and Pettersson, Susanne, additional
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- 2021
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31. Molecular pathways in patients with systemic lupus erythematosus revealed by gene-centred DNA sequencing
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Sandling, Johanna K., Pucholt, Pascal, Hultin-Rosenberg, Lina, Farias, Fabiana H. G., Kozyrev, Sergey V., Eloranta, Maija-Leena, Alexsson, Andrei, Bianchi, Matteo, Padyukov, Leonid, Bengtsson, Christine, Jonsson, Roland, Omdal, Roald, Lie, Benedicte A., Massarenti, Laura, Steffensen, Rudi, Jakobsen, Marianne A., Lillevang, Soren T., Lerang, Karoline, Molberg, Oyvind, Voss, Anne, Troldborg, Anne, Jacobsen, Soren, Syvänen, Ann-Christine, Jonsen, Andreas, Gunnarsson, Iva, Svenungsson, Elisabet, Rantapaa-Dahlqvist, Solbritt, Bengtsson, Anders A., Sjowall, Christopher, Leonard, Dag, Lindblad-Toh, Kerstin, and Rönnblom, Lars
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Adult ,Male ,Multifactorial Inheritance ,Adolescent ,T-Lymphocytes ,Polymorphism, Single Nucleotide ,Systemic Lupus Erythematosus ,White People ,CLASSIFICATION ,polymorphism ,Young Adult ,DOUBLE-BLIND ,immune system diseases ,Cluster Analysis ,Humans ,Lupus Erythematosus, Systemic ,skin and connective tissue diseases ,Blood Coagulation ,Complement Activation ,Aged ,Janus Kinases ,Rheumatology and Autoimmunity ,Aged, 80 and over ,Sweden ,Antigen Presentation ,Reumatologi och inflammation ,REVISED CRITERIA ,Lymphopoiesis ,autoimmunity ,Sequence Analysis, DNA ,Middle Aged ,systemic ,Immunity, Innate ,STAT Transcription Factors ,Case-Control Studies ,Interferon Type I ,PATTERNS ,Female ,genetic ,lupus erythematosus ,Signal Transduction - 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. Funding Agencies|AstraZeneca-Science for Life Laboratory Research Collaboration grant (DISSECT); Swedish Research Council for Medicine and Health [2018-02399, 2018-02535]; Swedish Rheumatism Association; King Gustav Vs 80-year Foundation; Swedish-Heart-Lung foundationSwedish Heart-Lung Foundation; Wallenberg Scholar Award; Swedish Society of Medicine; Science for Life Laboratory; Swedish Research Council (VR-RFI)Swedish Research Council; Uppsala University; Knut and Alice Wallenberg FoundationKnut & Alice Wallenberg Foundation
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- 2021
32. Toll-like receptors revisited : a possible role for TLR1 in lupus nephritis
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Yavuz, Sule, Bianchi, Matteo, Kozyrev, Sergey, Bolin, Karin, Leonard, Dag, Pucholt, Pascal, Sandling, Johanna K, Bengtsson, Anders, Jönsen, Andreas, Rantapää-Dahlqvist, Solbritt, Sjöwall, Christopher, Svenungsson, Elisabet, Gunnarsson, Iva, Lindblad-Toh, Kerstin, and Rönnblom, Lars
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lupus nephritis ,Reumatologi och inflammation ,Letter ,Respiratory Medicine and Allergy ,Toll-Like Receptors ,Immunology in the medical area ,systemic ,Toll-Like Receptor 1 ,polymorphism ,Immunologi inom det medicinska området ,Genetics ,Humans ,Lupus Erythematosus, Systemic ,Genetic Predisposition to Disease ,Genetik ,genetic ,lupus erythematosus ,Lungmedicin och allergi ,Rheumatology and Autoimmunity - Published
- 2021
33. Contributions of de novo variants to systemic lupus erythematosus
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Carlsson Almlöf, Jonas, Nystedt, Sara, Mechtidou, Aikaterini, Leonard, Dag, Eloranta, Maija-Leena, Grosso, Giorgia, Sjöwall, Christopher, Bengtsson, Anders A, Jönsen, Andreas, Gunnarsson, Iva, Svenungsson, Elisabet, Rönnblom, Lars, Sandling, Johanna K., and Syvänen, Ann-Christine
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Reumatologi och inflammation ,immune system diseases ,skin and connective tissue diseases ,Medical Genetics ,Rheumatology and Autoimmunity ,Medicinsk genetik - Abstract
By performing whole-genome sequencing in a Swedish cohort of 71 parent-offspring trios, in which the child in each family is affected by systemic lupus erythematosus (SLE, OMIM 152700), we investigated the contribution of de novo variants to risk of SLE. We found de novo single nucleotide variants (SNVs) to be significantly enriched in gene promoters in SLE patients compared with healthy controls at a level corresponding to 26 de novo promoter SNVs more in each patient than expected. We identified 12 de novo SNVs in promoter regions of genes that have been previously implicated in SLE, or that have functions that could be of relevance to SLE. Furthermore, we detected three missense de novo SNVs, five de novo insertion-deletions, and three de novo structural variants with potential to affect the expression of genes that are relevant for SLE. Based on enrichment analysis, disease-affecting de novo SNVs are expected to occur in one-third of SLE patients. This study shows that de novo variants in promoters commonly contribute to the genetic risk of SLE. The fact that de novo SNVs in SLE were enriched to promoter regions highlights the importance of using whole-genome sequencing for identification of de novo variants. Funding Agencies|Knut and Alice Wallenberg FoundationKnut & Alice Wallenberg Foundation; Swedish Research Council for Medicine and Health [2018-02399, 2017-02000]; Swedish Rheumatism Association; King Gustaf Vs 80-year Foundation; Swedish Society of Medicine; Ingegerd Johansson donation
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- 2021
34. C-Reactive Protein Levels in Systemic Lupus Erythematosus Are Modulated by the Interferon Gene Signature and CRP Gene Polymorphism rs1205
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Enocsson, Helena, Gullstrand, Birgitta, Eloranta, Maija-Leena, Wetterö, Jonas, Leonard, Dag, Ronnblom, Lars, Bengtsson, Anders A., Sjöwall, Christopher, Enocsson, Helena, Gullstrand, Birgitta, Eloranta, Maija-Leena, Wetterö, Jonas, Leonard, Dag, Ronnblom, Lars, Bengtsson, Anders A., and Sjöwall, Christopher
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Objectives Patients with systemic lupus erythematosus (SLE) often display modest elevations of C-reactive protein (CRP) despite raised disease activity and increased interleukin (IL-) 6. We asked to what extent IL-6 levels, the CRP polymorphism rs1205, and the type I interferon (IFN) gene signature affects the basal CRP levels in patients with SLE during a quiescent phase of the disease. Methods CRP and IL-6 were analyzed in plasma from 57 patients meeting established classification criteria for SLE. The CRP polymorphism rs1205 was assessed and gene expression analyzed including four type I IFN-regulated genes (IGS). Results CRP was increased in patients with detectable IL-6 levels (p=0.001) and decreased among IGS-positive subjects (p=0.033). A multiple linear regression model revealed IL-6 to have a positive association with CRP levels, whereas both IGS-positivity and CRP genotype (rs1205) AA/GA were negatively associated with CRP-levels. Conclusion Our data offer an explanation to the modest CRP levels seen in viral infections and IFN-alpha driven autoimmunity and corroborate prior observations showing an IFN-alpha dependent downregulation of CRP. The latter observation, together with the fact that the CRP-lowering polymorphism rs1205 is overrepresented in human SLE, could explain low basal CRP and inadequate CRP-responses among patients with active SLE., Funding Agencies|Swedish Research Council for Medicine and Health; Swedish Society of Medicine; Swedish Rheumatism Association; Region Ostergotland (ALF grants); King Gustaf Vs 80-year Anniversary Foundation; King Gustaf V and Queen Victorias Freemasons Foundation; Gustafsson Foundation; Selander Foundation; Alfred Osterlund Foundation; Anna-Greta Crafoord Foundation; Greta and Johan Kocks Foundation
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- 2021
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35. Interaction between the STAT4 rs11889341(T) risk allele and smoking confers increased risk of myocardial infarction and nephritis in patients with systemic lupus erythematosus
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Reid, Sarah, Hagberg, Niklas, Sandling, Johanna K., Alexsson, Andrei, Pucholt, Pascal, Sjöwall, Christopher, Lerang, Karoline, Jönsen, Andreas, Gunnarsson, Iva, Syvänen, Ann-Christine, Troldborg, Anne Margrethe, Voss, Anne, Bengtsson, Anders A., Molberg, Öyvind, Jacobsen, Sören, Svenungsson, Elisabet, Rönnblom, Lars, Leonard, Dag, Reid, Sarah, Hagberg, Niklas, Sandling, Johanna K., Alexsson, Andrei, Pucholt, Pascal, Sjöwall, Christopher, Lerang, Karoline, Jönsen, Andreas, Gunnarsson, Iva, Syvänen, Ann-Christine, Troldborg, Anne Margrethe, Voss, Anne, Bengtsson, Anders A., Molberg, Öyvind, Jacobsen, Sören, Svenungsson, Elisabet, Rönnblom, Lars, and Leonard, Dag
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Objective To investigate how genetics influence the risk of smoking-related systemic lupus erythematosus (SLE) manifestations. Methods Patients with SLE (n(discovery cohort)=776, n(replication cohort)=836) were genotyped using the 200K Immunochip single nucleotide polymorphisms (SNP) Array (Illumina) and a custom array. Sixty SNPs with SLE association (p<5.0x10(-8)) were analysed. Signal transducer and activator of transcription 4 (STAT4) activation was assessed in in vitro stimulated peripheral blood mononuclear cells from healthy controls (n= 45). Results In the discovery cohort, smoking was associated with myocardial infarction (MI) (OR 1.96 (95% CI 1.09 to 3.55)), with a greater effect in patients carrying any rs11889341 STAT4 risk allele (OR 2.72 (95% CI 1.24 to 6.00)) or two risk alleles (OR 8.27 (95% CI 1.48 to 46.27)). Smokers carrying the risk allele also displayed an increased risk of nephritis (OR 1.47 (95% CI 1.06 to 2.03)). In the replication cohort, the high risk of MI in smokers carrying the risk allele and the association between the STAT4 risk allele and nephritis in smokers were confirmed (OR 6.19 (95% CI 1.29 to 29.79) and 1.84 (95% CI 1.05 to 3.29), respectively). The interaction between smoking and the STAT4 risk allele resulted in further increase in the risk of MI (OR 2.14 (95% CI 1.01 to 4.62)) and nephritis (OR 1.53 (95% CI 1.08 to 2.17)), with 54% (MI) and 34% (nephritis) of the risk attributable to the interaction. Levels of interleukin-12-induced phosphorylation of STAT4 in CD8+ T cells were higher in smokers than in non-smokers (mean geometric fluorescence intensity 1063 vs 565, p=0.0063). Lastly, the IL12A rs564799 risk allele displayed association with MI in both cohorts (OR 1.53 (95% CI 1.01 to 2.31) and 2.15 (95% CI 1.08 to 4.26), respectively). Conclusions Smoking in the presence of the STAT4 risk gene variant appears to increase the risk of MI and nephritis in SLE. Our results also highlight the role of the IL12-STAT4 pathwa, Funding Agencies|Swedish Research Council for Medicine and Health [D0283001]; Swedish Rheumatism Association; King Gustav Vs 80-year Foundation; Swedish Society of Medicine; Ake Wibergs foundation; Gustafssons foundation; Selanders foundation; Norsk Revmatikerforbunds Forskningsfond; Pahles legat og Stortuens legat; Swedish Society for Medical Research [S20-0127]
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- 2021
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36. Clinical Experience of Proteasome Inhibitor Bortezomib Regarding Efficacy and Safety in Severe Systemic Lupus Erythematosus : A Nationwide Study
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Walhelm, Tomas, Gunnarsson, Iva, Heijke, Rebecca, Leonard, Dag, Trysberg, Estelle, Eriksson, Per, Sjöwall, Christopher, Walhelm, Tomas, Gunnarsson, Iva, Heijke, Rebecca, Leonard, Dag, Trysberg, Estelle, Eriksson, Per, and Sjöwall, Christopher
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As treatment options in advanced systematic lupus erythematosus (SLE) are limited, there is an urgent need for new and effective therapeutic alternatives for selected cases with severe disease. Bortezomib (BTZ) is a specific, reversible, inhibitor of the 20S subunit of the proteasome. Herein, we report clinical experience regarding efficacy and safety from all patients receiving BTZ as therapy for SLE in Sweden during the years 2014-2020. 8 females and 4 males were included with a mean disease duration at BTZ initiation of 8.8 years (range 0.7-20 years). Renal involvement was the main target for BTZ. Reduction of global disease activity was recorded by decreasing SLEDAI-2K scores over time and remained significantly reduced at the 6-month (p=0.007) and the 12-month (p=0.008) follow-up visits. From BTZ initiation, complement protein 3 (C3) levels increased significantly after the 2(nd) treatment cycle (p=0.05), the 6-month (p=0.03) and the 12-month (p=0.04) follow-up visits. The urine albumin/creatinine ratio declined over time and reached significance at the 6-month (p=0.008) and the 12-month follow-up visits (p=0.004). Seroconversion of anti-dsDNA (27%), anti-C1q (50%) and anti-Sm (67%) was observed. 6 of 12 patients experienced at least one side-effect during follow-up, whereof the most common adverse events were infections. Safety parameters (C-reactive protein, blood cell counts) mainly remained stable over time. To conclude, we report favorable therapeutic effects of BTZ used in combination with corticosteroids in a majority of patients with severe SLE manifestations irresponsive to conventional immunosuppressive agents. Reduction of proteinuria was observed over time as well as seroconversion of some autoantibody specificities. In most patients, tolerance was acceptable but mild adverse events was not uncommon. Special attention should be paid to infections and hypogammaglobinemia., Funding Agencies|Swedish Rheumatism Association; Region Ostergotland; Gustafsson Foundation; King Gustaf Vs 80-year Anniversary foundation; King Gustaf V and Queen Victorias Freemasons foundation
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- 2021
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37. De novo lupus nephritis during treatment with belimumab
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Parodis, Ioannis, Vital, Edward M., Hassan, Sabih-Ul, Jönsen, Andreas, Bengtsson, Anders A., Eriksson, Per, Leonard, Dag, Gunnarsson, Iva, Rönnblom, Lars, Sjöwall, Christopher, Parodis, Ioannis, Vital, Edward M., Hassan, Sabih-Ul, Jönsen, Andreas, Bengtsson, Anders A., Eriksson, Per, Leonard, Dag, Gunnarsson, Iva, Rönnblom, Lars, and Sjöwall, Christopher
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Objective In light of reports of de novo LN during belimumab (BLM) treatment, we sought to determine its frequency and contributing or protective factors in a real-life setting. Methods Patients with SLE who received BLM between 2011 and 2017 at five European academic practices were enrolled (n=95) and followed longitudinally for a median time of 13.1months [interquartile range (IQR): 6.0-34.7]; 52.6% were anti-dsDNA positive, 60.0% had low complement levels, and 69.5% had no renal involvement prior to/at BLM initiation [mean disease duration at baseline: 11.4(9.3)years]. Age- and sex-matched patients with non-renal SLE who had similar serological profiles, but were not exposed to BLM, served as controls (median follow-up: 132.0months; IQR: 98.3-151.2). Results We observed 6/66 cases (9.1%) of biopsy-proven de novo LN (4/6 proliferative) among the non-renal BLM-treated SLE cases after a follow-up of 7.4months (IQR: 2.7-22.2). Among controls, 2/66 cases (3.0%) of de novo LN (both proliferative) were observed after 21 and 50months. BLM treatment was associated with an increased frequency and/or shorter time to de novo LN [hazard ratio (HR): 10.7; 95% CI: 1.7, 67.9; P=0.012], while concomitant use of antimalarial agents along with BLM showed an opposing association (HR: 0.2; 95% CI: 0.03, 0.97; P=0.046). Conclusion Addition of BLM to standard-of-care did not prevent LN in patients with active non-renal SLE, but a favourable effect of concomitant use of antimalarials was implicated. Studies of whether effects of B-cell activating factor inhibition on lymphocyte subsets contribute to LN susceptibility are warranted., Funding Agencies|Alfred Osterlunds Foundation; Anna-Greta Crafoord Foundation; Greta and Johan Kocks Foundation; Gustafsson Foundation; King Gustaf V and Queen Victorias Freemasons Foundation; King Gustaf Vs 80-year Anniversary Foundation; Professor Nanna Svartz Foundation; Region Ostergotland (ALF grants); Selander Foundation; Skane University Hospital; Medical Faculty of Lund University; Swedish Research CouncilSwedish Research CouncilEuropean Commission; Swedish Rheumatism Association; Swedish Society of Medicine
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- 2021
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38. Quick Systemic Lupus Activity Questionnaire (Q-SLAQ) : a simplified version of SLAQ for patient-reported disease activity
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Svenungsson, Elisabet, Gunnarsson, Iva, Illescas-Backelin, Vera, Trysberg, Estelle, Jonsen, Andreas, Leonard, Dag, Sjowall, Christopher, Pettersson, Susanne, Svenungsson, Elisabet, Gunnarsson, Iva, Illescas-Backelin, Vera, Trysberg, Estelle, Jonsen, Andreas, Leonard, Dag, Sjowall, Christopher, and Pettersson, Susanne
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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
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- 2021
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39. Interaction between the STAT4 rs11889341(T) risk allele and smoking confers increased risk of myocardial infarction and nephritis in patients with systemic lupus erythematosus
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Reid, Sarah, primary, Hagberg, Niklas, additional, Sandling, Johanna K, additional, Alexsson, Andrei, additional, Pucholt, Pascal, additional, Sjöwall, Christopher, additional, Lerang, Karoline, additional, Jönsen, Andreas, additional, Gunnarsson, Iva, additional, Syvänen, Ann-Christine, additional, Troldborg, Anne Margrethe, additional, Voss, Anne, additional, Bengtsson, Anders A, additional, Molberg, Øyvind, additional, Jacobsen, Søren, additional, Svenungsson, Elisabet, additional, Rönnblom, Lars, additional, and Leonard, Dag, additional
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- 2021
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40. The development and validation of a polygenic risk score for myocardial infarction in SLE
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Reid, Sarah, Sandling, Johanna K, Alexsson, Andrei, Pucholt, Pascal, Sjöwall, Christopher, Lerang, Karoline, Jönsen, Andreas, Gunnarsson, Iva, Syvänen, Ann-Christine, Troldborg, Anne, Voss, Anne, Bengtsson, Anders, Molberg, Øyvind, Jacobsen, Søren, Svenungsson, Elisabet, Rönnblom, Lars, and Leonard, Dag
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- 2020
41. High genetic risk score is associated with early disease onset, damage accrual and decreased survival in systemic lupus erythematosus
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Reid, Sarah, Alexsson, Andrei, Frodlund, Martina, Morris, David, Sandling, Johanna K, Bolin, Karin, Svenungsson, Elisabet, Jönsen, Andreas, Bengtsson, Christine, Gunnarsson, Iva, Illescas Rodriguez, Vera, Bengtsson, Anders, Arve, Sabine, Rantapää-Dahlqvist, Solbritt, Eloranta, Maija-Leena, Syvänen, Ann-Christine, Sjöwall, Christopher, Vyse, Timothy James, Rönnblom, Lars, and Leonard, Dag
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Adult ,Male ,Risk ,Genotype ,gene polymorphism ,Systemic Lupus Erythematosus ,Risk Assessment ,Severity of Illness Index ,systemic lupus erythematosus ,Risk Factors ,cardiovascular disease ,Prevalence ,Humans ,Lupus Erythematosus, Systemic ,Genetic Predisposition to Disease ,Rheumatology and Autoimmunity ,lupus nephritis ,Reumatologi och inflammation ,Middle Aged ,Survival Rate ,beta 2-Glycoprotein I ,Antibodies, Anticardiolipin ,Case-Control Studies ,Lupus Coagulation Inhibitor ,Kidney Failure, Chronic ,Female ,antiphospholipid syndrome - Abstract
Objectives To investigate associations between a high genetic disease risk and disease severity in patients with systemic lupus erythematosus (SLE). Methods Patients with SLE (n=1001, discovery cohort and n=5524, replication cohort) and healthy controls (n=2802 and n=9859) were genotyped using a 200K Immunochip single nucleotide polymorphism array. A genetic risk score (GRS) was assigned to each individual based on 57 SLE risk loci. Results SLE was more prevalent in the high, compared with the low, GRS-quartile (OR 12.32 (9.53 to 15.71), p=7.9x10(-86) and OR 7.48 (6.73 to 8.32), p=2.2x10(-304) for the discovery and the replication cohorts, respectively). In the discovery cohort, patients in the high GRS-quartile had a 6-year earlier mean disease onset (HR 1.47 (1.22 to 1.75), p=4.3x10(-5)), displayed higher prevalence of damage accrual (OR 1.47 (1.06 to 2.04), p=2.0x10(-2)), renal disorder (OR 2.22 (1.50 to 3.27), p=5.9x10(-5)), anti-dsDNA (OR 1.83 (1.19 to 2.81), p=6.1x10(-3)), end-stage renal disease (ESRD) (OR 5.58 (1.50 to 20.79), p=1.0x10(-2)), proliferative nephritis (OR 2.42 (1.30 to 4.49), p=5.1x10(-3)), anti-cardiolipin-IgG (OR 1.89 (1.13 to 3.18), p=1.6x10(-2)), anti-beta 2-glycoprotein-I-IgG (OR 2.29 (1.29 to 4.06), p=4.8x10(-3)) and positive lupus anticoagulant test (OR 2.12 (1.16 to 3.89), p=1.5x10(-2)) compared with patients in the low GRS-quartile. Survival analysis showed earlier onset of the first organ damage (HR 1.51 (1.04 to 2.25), p=3.7x10(-2)), first cardiovascular event (HR 1.65 (1.03 to 2.64), p=2.6x10(-2)), nephritis (HR 2.53 (1.72 to 3.71), p=9.6x10(-7)), ESRD (HR 6.78 (1.78 to 26.86), p=6.5x10(-3)) and decreased overall survival (HR 1.83 (1.02 to 3.30), p=4.3x10(-2)) in high to low quartile comparison. Conclusions A high GRS is associated with increased risk of organ damage, renal dysfunction and all-cause mortality. Our results indicate that genetic profiling may be useful for predicting outcomes in patients with SLE.
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- 2020
42. Lymphopenia as a risk factor for neurologic involvement and organ damage accrual in patients with systemic lupus erythematosus : A multi-center observational study
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Yavuz, Sule, Cansu, Dondu U., Nikolopoulos, Dionysis, Crisafulli, Francesca, Antunes, Ana M., Adamichou, Christina, Reid, Sarah, Stagnaro, Chiara, Andreoli, Laura, Tincani, Angela, Moraes-Fontes, Maria Francisca, Mosca, Marta, Leonard, Dag, Jönsen, Andreas, Bengtsson, Anders, Svenungsson, Elisabet, Gunnarsson, Iva, Rantapää Dahlqvist, Solbritt, Sjöwall, Christopher, Bertsias, George, Fanouriakis, Antonis, Rönnblom, Lars, Yavuz, Sule, Cansu, Dondu U., Nikolopoulos, Dionysis, Crisafulli, Francesca, Antunes, Ana M., Adamichou, Christina, Reid, Sarah, Stagnaro, Chiara, Andreoli, Laura, Tincani, Angela, Moraes-Fontes, Maria Francisca, Mosca, Marta, Leonard, Dag, Jönsen, Andreas, Bengtsson, Anders, Svenungsson, Elisabet, Gunnarsson, Iva, Rantapää Dahlqvist, Solbritt, Sjöwall, Christopher, Bertsias, George, Fanouriakis, Antonis, and Rönnblom, Lars
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OBJECTIVE: Detailed analysis of hematological manifestations (HM) in systemic lupus erythematosus (SLE) are limited and their clinical impact on disease remain obscure. Here, we aimed to decipher factors associated with different hematological abnormalities in SLE patients and to assess their impact on disease related outcomes. METHODS: A dataset (GIPT) originating from SLE patients of six European tertiary centers was assessed. Six-monthly visits of each patient for at least 2 years were registered. The association between hematologic manifestations (HM; per ACR-1997criteria) and clinical/serologic variables, as well as the impact of HM on disease related outcomes (damage, infection and hemorrhage) were explored. Scores on the Systemic Lupus Erythematosus Disease Activity Index 2000(SLEDAI2K), the Systemic Lupus International Collaborating Clinics (SLICC)/American College of Rheumatology (ACR) Damage Index (SDI) and events for any infection and hemorrhage were recorded. Results were compared with a cross-sectional, well-characterized SLE dataset from Sweden. Descriptive statistics, the generalized estimating equations (GEE), general linear models (GLM), Cox regression models were applied. RESULTS: We monitored 1425 longitudinal visits in 286 SLE patients with HM (GIPT dataset: 88% female, 95% Caucasian, 68% dsDNA positive). Thrombocytopenia (regression coefficient [95% confidence interval] 1.86[1.1-3.13]) and neurologic involvement (ACR-8) (2.1[1.10-3.89]) were associated with lymphopenia (<1000/mm3); the latter was an independent predictor of organ damage accrual (1.68[1.2-2.62]). These associations were confirmed in an independent dataset of 1348 SLE patients (86% female, 93% Caucasian, 61% dsDNA positive) in Sweden.Severe lymphopenia (<500/mm3) and severe thrombocytopenia (<20 K/mm3) were associated with increased risk for infection (hazard ratio [95% confidence interval] 2.56[1.23-5.31]) and hemorrhage (4.38[2.10-11.1]), respectively, independent of th
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- 2020
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43. NCF1-339 polymorphism is associated with altered formation of neutrophil extracellular traps, high serum interferon activity and antiphospholipid syndrome in systemic lupus erythematosus
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Linge, Petrus, Arve, Sabine, Olsson, Lina M., Leonard, Dag, Sjöwall, Christopher, Frodlund, Martina, Gunnarsson, Iva, Svenungsson, Elisabet, Tyden, Helena, Jönsen, Andreas, Kahn, Robin, Johansson, Åsa, Rönnblom, Lars, Holmdahl, Rikard, Bengtsson, Anders, Linge, Petrus, Arve, Sabine, Olsson, Lina M., Leonard, Dag, Sjöwall, Christopher, Frodlund, Martina, Gunnarsson, Iva, Svenungsson, Elisabet, Tyden, Helena, Jönsen, Andreas, Kahn, Robin, Johansson, Åsa, Rönnblom, Lars, Holmdahl, Rikard, and Bengtsson, Anders
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Objectives: A single nucleotide polymorphism in the NCF1 gene (NCF1-339, rs201802880), encoding NADPH oxidase type II subunit NCF1/p47(phox), reducing production of reactive oxygen species (ROS) is strongly associated with the development of systemic lupus erythematosus (SLE). This study aimed at characterising NCF1-339 effects on neutrophil extracellular trap (NET) formation, type I interferon activity and antibody profile in patients with SLE. Methods: Neutrophil NET-release pathways (n=31), serum interferon (n=141) and finally antibody profiles (n=305) were investigated in SLE subjects from Lund, genotyped for NCF1-339. Then, 1087 SLE subjects from the rheumatology departments of four Swedish SLE centres, genotyped for NCF1-339, were clinically characterised to validate these findings. Results: Compared with patients with normal-ROS NCF1-339 genotypes, neutrophils from patients with SLE with low-ROS NCF1-339 genotypes displayed impaired NET formation (p<0.01) and increased dependence on mitochondrial ROS (p<0.05). Low-ROS patients also had increased frequency of high serum interferon activity (80% vs 21.4%, p<0.05) and positivity for anti-beta 2 glycoprotein I (p<0.01) and anticardiolipin antibodies (p<0.05) but were not associated with other antibodies. We confirmed an over-representation of having any antiphospholipid antibody, OR 1.40 (95% CI 1.01 to 1.95), anti-beta 2 glycoprotein I, OR 1.82 (95% CI 1.02 to 3.24) and the antiphospholipid syndrome (APS), OR 1.74 (95% CI 1.19 to 2.55) in all four cohorts (n=1087). Conclusions: The NCF1-339 SNP mediated decreased NADPH oxidase function, is associated with high interferon activity and impaired formation of NETs in SLE, allowing dependence on mitochondrial ROS. Unexpectedly, we revealed a striking connection between the ROS deficient NCF1-339 genotypes and the presence of phospholipid antibodies and APS.
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- 2020
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44. Molecular pathways in patients with systemic lupus erythematosus revealed by gene-centred DNA sequencing
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Sandling, Johanna K., Pucholt, Pascal, Hultin Rosenberg, Lina, Farias, Fabiana H.G., Kozyrev, Sergey V., Eloranta, Maija Leena, Alexsson, Andrei, Bianchi, Matteo, Padyukov, Leonid, Bengtsson, Christine, Jonsson, Roland, Omdal, Roald, Lie, Benedicte A., Massarenti, Laura, Steffensen, Rudi, Jakobsen, Marianne A., Lillevang, Søren T., Lerang, Karoline, Molberg, Øyvind, Voss, Anne, Troldborg, Anne, Jacobsen, Søren, Syvänen, Ann Christine, Jönsen, Andreas, Gunnarsson, Iva, Svenungsson, Elisabet, Rantapää-Dahlqvist, Solbritt, Bengtsson, Anders A., Sjöwall, Christopher, Leonard, Dag, Lindblad-Toh, Kerstin, Rönnblom, Lars, Sandling, Johanna K., Pucholt, Pascal, Hultin Rosenberg, Lina, Farias, Fabiana H.G., Kozyrev, Sergey V., Eloranta, Maija Leena, Alexsson, Andrei, Bianchi, Matteo, Padyukov, Leonid, Bengtsson, Christine, Jonsson, Roland, Omdal, Roald, Lie, Benedicte A., Massarenti, Laura, Steffensen, Rudi, Jakobsen, Marianne A., Lillevang, Søren T., Lerang, Karoline, Molberg, Øyvind, Voss, Anne, Troldborg, Anne, Jacobsen, Søren, Syvänen, Ann Christine, Jönsen, Andreas, Gunnarsson, Iva, Svenungsson, Elisabet, Rantapää-Dahlqvist, Solbritt, Bengtsson, Anders A., Sjöwall, Christopher, Leonard, Dag, Lindblad-Toh, Kerstin, and Rönnblom, Lars
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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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- 2020
45. C-Reactive Protein Levels in Systemic Lupus Erythematosus Are Modulated by the Interferon Gene Signature and CRP Gene Polymorphism rs1205
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Enocsson, Helena, primary, Gullstrand, Birgitta, additional, Eloranta, Maija-Leena, additional, Wetterö, Jonas, additional, Leonard, Dag, additional, Rönnblom, Lars, additional, Bengtsson, Anders A., additional, and Sjöwall, Christopher, additional
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- 2021
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46. De novo lupus nephritis during treatment with belimumab
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Parodis, Ioannis, primary, Vital, Edward M, additional, Hassan, Sabih-Ul, additional, Jönsen, Andreas, additional, Bengtsson, Anders A, additional, Eriksson, Per, additional, Leonard, Dag, additional, Gunnarsson, Iva, additional, Rönnblom, Lars, additional, and Sjöwall, Christopher, additional
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- 2020
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47. Lymphopenia as a risk factor for neurologic involvement and organ damage accrual in patients with systemic lupus erythematosus: A multi-center observational study
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Yavuz, Sule, primary, Cansu, Dondu U, additional, Nikolopoulos, Dionysis, additional, Crisafulli, Francesca, additional, Antunes, Ana M, additional, Adamichou, Christina, additional, Reid, Sarah, additional, Stagnaro, Chiara, additional, Andreoli, Laura, additional, Tincani, Angela, additional, Moraes-Fontes, Maria Francisca, additional, Mosca, Marta, additional, Leonard, Dag, additional, Jönsen, Andreas, additional, Bengtsson, Anders, additional, Svenungsson, Elisabet, additional, Gunnarsson, Iva, additional, Dahlqvist, Solbritt Rantapää, additional, Sjöwall, Christopher, additional, Bertsias, George, additional, Fanouriakis, Antonis, additional, and Rönnblom, Lars, additional
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- 2020
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48. HLA-DRB1*04/*13 alleles are associated with vascular disease and antiphospholipid antibodies in systemic lupus erythematosus
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Lundström, Emeli, Gustafsson, Johanna T, Jönsen, Andreas, Leonard, Dag, Zickert, Agneta, Elvin, Kerstin, Sturfelt, Gunnar, Nordmark, Gunnel, Bengtsson, Anders A, Sundin, Ulf, Källberg, Henrik, Sandling, Johanna K, Syvänen, Ann-Christine, Klareskog, Lars, Gunnarsson, Iva, Rönnblom, Lars, Padyukov, Leonid, and Svenungsson, Elisabet
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- 2013
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49. Clinical manifestations and anti-phospholipid antibodies in 712 patients with systemic lupus erythematosus: evaluation of two diagnostic assays
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Vikerfors, Anna, Johansson, Anna-Britta, Gustafsson, Johanna T., Jönsen, Andreas, Leonard, Dag, Zickert, Agneta, Nordmark, Gunnel, Sturfelt, Gunnar, Bengtsson, Anders, Rönnblom, Lars, Gunnarsson, Iva, Elvin, Kerstin, and Svenungsson, Elisabet
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- 2013
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50. Ischemic vascular disease and antiphospholipid antibodies are associated with HLA-DRB1 *04/*13 alleles in systemic lupus erythematosus
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Svenungsson, Elisabet, Lundström, Emeli, Gustafsson, Johanna, Jönsen, Andreas, Leonard, Dag, Zickert, Agneta, Elvin, Kerstin, Sturfelt, Gunnar, Nordmark, Gunnel, Bengtsson, Anders, Klareskog, Lars, Gunnarsson, Iva, Rönnblom, Lars, and Padyukov, Leonid
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- 2012
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