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  • 1.
    Agelii, M. Leu
    et al.
    Gothenburg Univ, Sweden.
    Andersson, M. L. E.
    Lund Univ, Sweden; Spenshult Res & Dev Ctr, Sweden.
    Jones, B. L.
    Univ Pittsburgh, PA USA.
    Sjöwall, Christopher
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Medicine Center, Department of Rheumatology.
    Kastbom, Alf
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Medicine Center, Department of Rheumatology.
    Hafstrom, I
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Forslind, K.
    Lund Univ, Sweden; Helsingborgs Hosp, Sweden.
    Gjertsson, I
    Gothenburg Univ, Sweden.
    Disease activity trajectories in rheumatoid arthritis: a tool for prediction of outcome2021In: Scandinavian Journal of Rheumatology, ISSN 0300-9742, E-ISSN 1502-7732, Vol. 50, no 1, p. 1-10Article in journal (Refereed)
    Abstract [en]

    Objective Predicting treatment response and disease progression in rheumatoid arthritis (RA) remains an elusive endeavour. Identifying subgroups of patients with similar progression is essential for understanding what hinders improvement. However, this cannot be achieved with response criteria based on current versus previous Disease Activity Scores, as they lack the time component. We propose a longitudinal approach that identifies subgroups of patients while capturing their evolution across several clinical outcomes simultaneously (multi-trajectories). Method For exploration, the RA cohort BARFOT (n = 2829) was used to identify 24 month post-diagnosis simultaneous trajectories of 28-joint Disease Activity Score and its components. Measurements were available at inclusion (0), 3, 6, 12, 24, and 60 months. Multi-trajectories were found with latent class growth modelling. For validation, the TIRA-2 cohort (n = 504) was used. Radiographic changes, assessed by the modified Sharp van der Heijde score, were correlated with trajectory membership. Results Three multi-trajectories were identified, with 39.6% of the patients in the lowest and 18.9% in the highest (worst) trajectory. Patients in the worst trajectory had on average eight tender and six swollen joints after 24 months. Radiographic changes at 24 and 60 months were significantly increased from the lowest to the highest trajectory. Conclusion Multi-trajectories constitute a powerful tool for identifying subgroups of RA patients and could be used in future studies searching for predictive biomarkers for disease progression. The evolution and shape of the trajectories in TIRA-2 were very similar to those in BARFOT, even though TIRA-2 is a newer cohort.

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  • 2.
    Ahmad, Awais
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
    Brylid, Andre
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
    Dahle, Charlotte
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
    Saleh, Muna Atallah
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Medicine Center, Department of Rheumatology.
    Dahlström, Örjan
    Linköping University, Department of Behavioural Sciences and Learning, Psychology. Linköping University, Faculty of Arts and Sciences. Linköping University, The Swedish Institute for Disability Research.
    Enocsson, Helena
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Medicine Center, Department of Rheumatology.
    Sjöwall, Christopher
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Medicine Center, Department of Rheumatology.
    Doubtful Clinical Value of Subtyping Anti-U1-RNP Antibodies Regarding the RNP-70 kDa Antigen in Sera of Patients with Systemic Lupus Erythematosus2023In: International Journal of Molecular Sciences, ISSN 1661-6596, E-ISSN 1422-0067, Vol. 24, no 12, article id 10398Article in journal (Refereed)
    Abstract [en]

    The detection of antinuclear antibodies is central to the diagnosis and prognosis of systemic lupus erythematosus (SLE), primary Sjogrens syndrome (pSS) and mixed connective tissue disease (MCTD). Anti-U1-RNP and anti-RNP70 antibodies were assayed in the sera of patients with SLE (n = 114), pSS (n = 54) and MCTD (n = 12). In the SLE group, 34/114 (30%) were anti-U1-RNP positive, and 21/114 (18%) were both anti-RNP70 positive and anti-U1-RNP positive. In the MCTD group, 10/12 (83%) were anti-U1-RNP positive, and 9/12 (75%) were anti-RNP70 positive. Only one individual with pSS was antibody positive (for both anti-U1-RNP and anti-RNP70). All anti-RNP70-positive samples were also anti-U1-RNP positive. Anti-U1-RNP-positive subjects with SLE were younger (p < 0.0001); showed lower concentrations of complement protein 3 (p = 0.03); had lower eosinophil (p = 0.0005), lymphocyte (p = 0.006) and monocyte (p = 0.03) counts; and had accrued less organ damage (p = 0.006) than the anti-U1-RNP-negative SLE patients. However, we observed no significant clinical or laboratory parameter differences between the anti-U1-RNP-positive individuals with/without anti-RNP70 in the SLE group. In conclusion, anti-RNP70 antibodies are not exclusive to MCTD but are rarely detected in pSS and healthy individuals. In SLE, anti-U1-RNP antibodies are associated with a clinical phenotype that resembles MCTD, with hematologic involvement and less damage accrual. Based on our results, the clinical value of subtyping anti-RNP70 in anti-U1-RNP-positive sera appears to be of limited value.

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  • 3.
    Ahmad, Awais
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
    Dahle, Charlotte
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
    Rönnelid, Johan
    Uppsala Univ, Sweden.
    Sjöwall, Christopher
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Medicine Center, Department of Rheumatology.
    Kechagias, Stergios
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Mag- tarmmedicinska kliniken.
    Autoantibodies Associated with Autoimmune Liver Diseases in a Healthy Population: Evaluation of a Commercial Immunoblot Test2022In: Diagnostics, ISSN 2075-4418, Vol. 12, no 7, article id 1572Article in journal (Refereed)
    Abstract [en]

    Autoantibodies constitute important tools for diagnosing the autoimmune liver diseases (AILD) autoimmune hepatitis and primary biliary cholangitis. The EUROLINE immunoblot assay, detecting multiple specificities, is widely used, but the clinical importance of weakly positive findings is unclear. The manufacturers recommended cut-off was evaluated by investigating AILD-associated autoantibodies in 825 blood donors and 60 confirmed AILD cases. Positive findings were followed up with immunofluorescence microscopy on rat tissue, anti-M2-ELISA, alternative immunoblot assay, and liver function tests. Thirty-six (4.4%) blood donors were positive with EUROLINE. The most common specificities were LC-1 (1.6%), gp210 (1.3%), and AMA-M2 (1.1%). In general, the positive results were higher in patients than in blood donors, whereas anti-LC-1 was higher in blood donors. The liver function tests were slightly elevated in 2 of the 36 immunoblot positive blood donors. The majority of the positive EUROLINE findings could not be confirmed with the follow-up tests. The EUROLINE-Autoimmune Liver Diseases-(IgG) immunoblot detected autoantibodies in 4.4% of blood donors without signs of AILD. Our findings indicate that the recommended cut-off can be raised for most specificities without loss of diagnostic sensitivity. The prevalence of anti-LC-1 among blood donors indicates a problem with the antigen source.

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  • 4.
    Ahmad, Awais
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
    Heijke, R.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Medicine Center, Department of Rheumatology.
    Eriksson, Per
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Medicine Center, Department of Rheumatology.
    Wirestam, Lina
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Medicine Center, Department of Rheumatology.
    Kechagias, Stergios
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Mag- tarmmedicinska kliniken.
    Dahle, Charlotte
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
    Sjöwall, Christopher
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Medicine Center, Department of Rheumatology.
    Autoantibodies associated with primary biliary cholangitis are common among patients with systemic lupus erythematosus even in the absence of elevated liver enzymes2021In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 203, no 1, p. 22-31Article in journal (Refereed)
    Abstract [en]

    Knowledge of concomitant autoimmune liver diseases (AILD) is more detailed in primary Sjogrens syndrome (pSS) compared to systemic lupus erythematosus (SLE). Herein, the prevalence of autoantibodies associated with autoimmune hepatitis (AIH) and primary biliary cholangitis (PBC) was investigated in stored sera from patients with SLE (n = 280) and pSS (n = 114). Antibodies against mitochondria (AMA), liver-kidney microsomal (LKM) antigen, smooth muscle (SMA) and anti-nuclear antibodies (ANA) were analysed with immunofluorescence microscopy. In addition, AILD-associated autoantibodies were tested with immunoblot. Prior to sampling, eight SLE (2 center dot 9%) and three pSS (2 center dot 6%) cases were diagnosed with AILD. Among SLE-cases without known AILD (n = 272), 26 (9 center dot 6%) had PBC-associated autoantibodies, 15 (5 center dot 5%) AIH-associated autoantibodies (excluding ANA) and one serological overlap. Most subjects with PBC-associated autoantibodies had liver enzymes within reference limits (22 of 27, 81%) or mild laboratory cholestasis (two of 27, 7 center dot 4%), while one fulfilled the diagnostic PBC-criteria. AMA-M2 detected by immunoblot was the most common PBC-associated autoantibody in SLE (20 of 272, 7 center dot 4%). The prevalence of SMA (4 center dot 4%) was comparable with a healthy reference population, but associated with elevated liver enzymes in four of 12 (25%), none meeting AIH-criteria. The patient with combined AIH/PBC-serology had liver enzymes within reference limits. Among pSS cases without known AILD (n = 111), nine (8 center dot 1%) had PBC-associated, 12 (10 center dot 8%) AIH-associated autoantibodies and two overlapped. PBC-associated autoantibodies were found as frequently in SLE as in pSS but were, with few exceptions, not associated with laboratory signs of liver disease. Overall, AILD-associated autoantibodies were predominantly detected by immunoblot and no significant difference in liver enzymes was found between AILD autoantibody-negative and -positive patients.

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  • 5.
    Andraos, Rama
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Medicine Center, Department of Rheumatology.
    Ahmad, Awais
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
    Eriksson, Per
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Medicine Center, Department of Rheumatology.
    Dahlström, Örjan
    Linköping University, Department of Behavioural Sciences and Learning, Psychology. Linköping University, Faculty of Arts and Sciences. Linköping University, The Swedish Institute for Disability Research.
    Wirestam, Lina
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Medicine Center, Department of Rheumatology.
    Dahle, Charlotte
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
    Hesselstrand, Roger
    Lund Univ, Sweden.
    Bengtsson, Anders A.
    Lund Univ, Sweden.
    Jonsen, Andreas
    Lund Univ, Sweden.
    Andreasson, Kristofer
    Lund Univ, Sweden.
    Sjöwall, Christopher
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Medicine Center, Department of Rheumatology.
    Autoantibodies associated with systemic sclerosis in three autoimmune diseases imprinted by type I interferon gene dysregulation: a comparison across SLE, primary Sjogrens syndrome and systemic sclerosis2022In: Lupus Science and Medicine, E-ISSN 2053-8790, Vol. 9, no 1, article id e000732Article in journal (Refereed)
    Abstract [en]

    ObjectiveSLE, primary Sjogrens syndrome (pSS) and systemic sclerosis (SSc) are heterogeneous autoimmune diseases with a dysregulated type I interferon (IFN) system. The diseases often show overlapping clinical manifestations, which may result in diagnostic challenges. We asked to which extent SSc-associated autoantibodies are present in SLE and pSS, and whether these link to serum IFN-alpha, clinical phenotypes and sex. Samples with clinical data from patients with SSc and healthy blood donors (HBDs) served as controls. Finally, the diagnostic performance of SSc-associated autoantibodies was evaluated.MethodsSamples from well-characterised subjects with SLE (n=510), pSS (n=116), SSc (n=57) and HBDs (n=236) were analysed using a commercially available immunoassay (EuroLine Systemic Sclerosis Profile (IgG)). IFN-alpha was quantified by ELISA. Self-reported data on Raynauds phenomenon (RP) were available.ResultsWith exceptions for anti-Ro52/SSA and anti-Th/To, SSc-associated autoantibodies were more frequent in SSc than in SLE, pSS and HBDs regardless of sex. IFN-alpha levels correlated with the number of positive SSc-associated autoantibodies (r=0.29, p<0.0001) and associated with Ro52/SSA positivity (p<0.0001). By using data from SLE, SSc and HBDs, RP was significantly associated with topoisomerase I, centromere protein (CENP)-B, RNA polymerase III 11 kDa, RNA polymerase III 155 kDa and PM-Scl100 whereas Ro52/SSA associated inversely with RP. In SLE, CENP-A was associated with immunological disorder, CENP-B with serositis and Ku with lupus nephritis. By combining analysis of ANA (immunofluorescence) with SSc-associated autoantibodies, the diagnostic sensitivity reached 98% and the specificity 33%.ConclusionsThe 13 specificities included in the EuroLine immunoassay are commonly detected in SSc, but they are also frequent among individuals with other diseases imprinted by type I IFNs. These findings are valuable when interpreting serological data on patients with suspected SSc, especially as patients may present with disease manifestations overlapping different rheumatological diseases. In SLE, we observed associations between manifestations and SSc-associated autoantibodies which have not previously been reported.

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  • 6.
    Aoun, Mike
    et al.
    Karolinska Inst, Sweden.
    Coelho, Ana
    Karolinska Inst, Sweden.
    Kraemer, Alexander
    Karolinska Inst, Sweden.
    Saxena, Amit
    Karolinska Inst, Sweden.
    Sabatier, Pierre
    Karolinska Inst, Sweden.
    Beusch, Christian Michel
    Karolinska Inst, Sweden.
    Loennblom, Erik
    Karolinska Inst, Sweden.
    Geng, Manman
    Xian JiaotongUniv, Peoples R China.
    Do, Nhu-Nguyen
    Karolinska Inst, Sweden; Fraunhofer Inst Translat Med & Pharmacol, Germany; Fraunhofer Cluster Excellence Immune Mediated Dis, Germany.
    Xu, Zhongwei
    Karolinska Inst, Sweden.
    Zhang, Jingdian
    Karolinska Inst, Sweden.
    He, Yibo
    Karolinska Inst, Sweden.
    Romero Castillo, Laura
    Karolinska Inst, Sweden.
    Abolhassani, Hassan
    Karolinska Univ Hosp, Sweden.
    Xu, Bingze
    Karolinska Inst, Sweden.
    Viljanen, Johan
    Uppsala Univ, Sweden.
    Rorbach, Joanna
    Karolinska Inst, Sweden.
    Fernandez Lahore, Gonzalo
    Karolinska Inst, Sweden.
    Gjertsson, Inger
    Univ Gothenburg, Sweden.
    Kastbom, Alf
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Medicine Center, Department of Rheumatology.
    Sjöwall, Christopher
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Medicine Center, Department of Rheumatology.
    Kihlberg, Jan
    Uppsala Univ, Sweden.
    Zubarev, Roman A.
    Karolinska Inst, Sweden; IM Sechenov First Moscow State Med Univ, Russia.
    Burkhardt, Harald
    Fraunhofer Inst Translat Med & Pharmacol, Germany; Fraunhofer Cluster Excellence Immune Mediated Dis, Germany; Goethe Univ, Germany.
    Holmdahl, Rikard
    Karolinska Inst, Sweden; Xian JiaotongUniv, Peoples R China.
    Antigen-presenting autoreactive B cells activate regulatory T cells and suppress autoimmune arthritis in mice2023In: Journal of Experimental Medicine, ISSN 0022-1007, E-ISSN 1540-9538, Vol. 220, no 11, article id e20230101Article in journal (Refereed)
    Abstract [en]

    B cells undergo several rounds of selection to eliminate potentially pathogenic autoreactive clones, but in contrast to T cells, evidence of positive selection of autoreactive B cells remains moot. Using unique tetramers, we traced natural autoreactive B cells (C1-B) specific for a defined triple-helical epitope on collagen type-II (COL2), constituting a sizeable fraction of the physiological B cell repertoire in mice, rats, and humans. Adoptive transfer of C1-B suppressed arthritis independently of IL10, separating them from IL10-secreting regulatory B cells. Single-cell sequencing revealed an antigen processing and presentation signature, including induced expression of CD72 and CCR7 as surface markers. C1-B presented COL2 to T cells and induced the expansion of regulatory T cells in a contact-dependent manner. CD72 blockade impeded this effect suggesting a new downstream suppressor mechanism that regulates antigen-specific T cell tolerization. Thus, our results indicate that autoreactive antigen-specific naive B cells tolerize infiltrating T cells against self-antigens to impede the development of tissue-specific autoimmune inflammation.

  • 7.
    Appelgren, Daniel
    et al.
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Enocsson, Helena
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences.
    Skogman, Barbro H
    Center for Clinical Research Dalarna-Uppsala University, Region Dalarna and Faculty of Medicine and Health Sciences, Örebro University.
    Nordberg, Marika
    Åland Central Hospital, Department of Infectious Diseases, AX-22 100 Mariehamn, Åland, Finland.
    Perander, Linda
    Åland Central Hospital, Department of Infectious Diseases, AX-22 100 Mariehamn, Åland, Finland.
    Nyman, Dag
    Bimelix AB, AX-22 100 Mariehamn, Åland, Finland.
    Nyberg, Clara
    Åland Central Hospital, Department of Infectious Diseases, AX-22 100 Mariehamn, Åland, Finland.
    Knopf, Jasmin
    Department of Internal Medicine 3-Rheumatology and Immunology, Universitätsklinikum Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), DE-91 054 Erlangen, Germany.
    Muñoz, Luis E
    Department of Internal Medicine 3-Rheumatology and Immunology, Universitätsklinikum Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), DE-91 054 Erlangen, Germany.
    Sjöwall, Christopher
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Medicine Center, Department of Rheumatology.
    Sjöwall, Johanna
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Medicine Center, Department of Infectious Diseases.
    Neutrophil Extracellular Traps (NETs) in the Cerebrospinal Fluid Samples from Children and Adults with Central Nervous System Infections.2020In: Cells, E-ISSN 2073-4409, Vol. 9, no 1, article id E43Article in journal (Refereed)
    Abstract [en]

    Neutrophils operate as part of the innate defence in the skin and may eliminate the Borrelia spirochaete via phagocytosis, oxidative bursts, and hydrolytic enzymes. However, their importance in Lyme neuroborreliosis (LNB) is unclear. Neutrophil extracellular trap (NET) formation, which is associated with the production of reactive oxygen species, involves the extrusion of the neutrophil DNA to form traps that incapacitate bacteria and immobilise viruses. Meanwhile, NET formation has recently been studied in pneumococcal meningitis, the role of NETs in other central nervous system (CNS) infections has previously not been studied. Here, cerebrospinal fluid (CSF) samples from clinically well-characterised children (N = 111) and adults (N = 64) with LNB and other CNS infections were analysed for NETs (DNA/myeloperoxidase complexes) and elastase activity. NETs were detected more frequently in the children than the adults (p = 0.01). NET presence was associated with higher CSF levels of CXCL1 (p < 0.001), CXCL6 (p = 0.007), CXCL8 (p = 0.003), CXCL10 (p < 0.001), MMP-9 (p = 0.002), TNF (p = 0.02), IL-6 (p < 0.001), and IL-17A (p = 0.03). NETs were associated with fever (p = 0.002) and correlated with polynuclear pleocytosis (rs = 0.53, p < 0.0001). We show that neutrophil activation and active NET formation occur in the CSF samples of children and adults with CNS infections, mainly caused by Borrelia and neurotropic viruses. The role of NETs in the early phase of viral/bacterial CNS infections warrants further investigation.

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  • 8.
    Appelgren, Daniel
    et al.
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Puli, Srinivasulu
    Department of Clinical Sciences in Lund, Nephrology, Lund University and Skåne University Hospital, Lund, Sweden.
    Hellmark, Thomas
    Department of Clinical Sciences in Lund, Nephrology, Lund University and Skåne University Hospital, Lund, Sweden.
    Pochard, Pierre
    LBAI, UMR1227, Univ Brest, Inserm, CHU de Brest, Brest, France.
    Pers, Jacques-Olivier
    LBAI, UMR1227, Univ Brest, Inserm, Brest, France.
    Ernerudh, Jan
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
    Eriksson, Per
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Medicine Center, Department of Rheumatology.
    Segelmark, Mårten
    Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Region Östergötland, Medicine Center, Department of Nephrology. Department of Clinical Sciences in Lund, Nephrology, Lund University and Skåne University Hospital, Lund, Sweden.
    Regulatory B cells are reduced in the blood in patients with granulomatosis with polyangiitis, and fail to regulate T-cell IFN-γproduction2023In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 213, no 2, p. 190-201Article in journal (Refereed)
    Abstract [en]

    Regulatory B (Breg) cells can dampen inflammation, autoreactivity, and transplant rejection. We investigated the frequencies, phenotypes, and function of Breg cells in granulomatosis with polyangiitis (GPA) to gain further knowledge as to whether there are numerical alterations or limitations of their ability to regulate T-cell function. Frequencies and phenotypes of CD24hiCD27+ and CD24hiCD38hi B-cells in the blood were determined with flow cytometry in 37 GPA patients (22 in remission and 15 with active disease) and 31 healthy controls (HC). A co-culture model was used to study the capacity of Breg cells to regulate T-cell activation and proliferation in cells from 10 GPA patients in remission and 12 HC. T-cell cytokine production in vitro and levels in plasma were determined with enzyme-linked immunosorbent assay. Frequencies of CD24hiCD27+ B-cells were reduced both during active disease and remission compared with HC (P = 0.005 and P = 0.010, respectively), whereas CD24hiCD38hi B-cells did not differ. Patient CD24hiCD27+ B-cells exhibited decreased expression of CD25 but increased expression of PD-L1 and PD-L2 during remission. B-cells from GPA patients regulated T-cell proliferation but failed to regulate interferon (IFN)-γproduction (median T-cells alone 222 ng/ml vs. T-cells + B-cells 207 ng/ml, P = 0.426). IFN-γwas also elevated in patient plasma samples (P = 0.016). In conclusion, GPA patients exhibit altered numbers and phenotypes of CD24hiCD27+ B-cells. This is accompanied by a disability to control T-cell production of Th1-type cytokines during remission, which might be of fundamental importance for the granulomatous inflammation that characterizes the chronic phase of this disease. © 2023 The Author(s). Published by Oxford University Press on behalf of the British Society for Immunology.

  • 9.
    Areskoug-Josefsson, Kristina
    et al.
    Jönköping University, Sweden; Oslo Metropolitan University, Oslo, Norway; VID Specialized University, Sandnes, Norway.
    Hjalmarsson, Sara
    Swedish Rheumatism Association, Norrköping, Sweden.
    Björk, Mathilda
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Prevention, Rehabilitation and Community Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Medicine Center, Department of Rheumatology.
    Sverker, Annette M.
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Prevention, Rehabilitation and Community Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Activity and Health. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Rehabilitation Medicine.
    Co-Creation of a Working Model to Improve Sexual Health for Persons Living with Rheumatological Diseases2020In: Open Journal of Rheumatology and Autoimmune Diseases, ISSN 2163-9914, Vol. 10, no 3, p. 109-124Article in journal (Refereed)
    Abstract [en]

    Background: Sexual health needs are insufficiently met for persons living with rheumatological diseases and it is necessary to create better ways to meet these needs.Objective: To co-create a working model to improve sexual health for persons living with rheumatological diseases, that can be used by rheumatological teams in regular rheumatology practice.Design: This study applied a co-creation design with three key features: 1) it took a systems perspective with emergent multiple interactive entities; 2) the research process was viewed as a creative endeavour with strong links to design, while human imagination and the individual experience of patient and staff were at the core of the creative design effort; 3) the process of the co-creative efforts was as important as the generated product.Results: A model defining the role of the patient, the professionals, and the team in optimizing sexual health for persons living with rheumatological diseases was co-created. The model can be seen as a practice guideline, which includes the support needed from and to each participant in the process of promoting sexual health, while being within the professional scope of the professionals’ knowledge and capacity, and in line with the needs of the persons living with rheumatological diseases.Discussion and Conclusions: The co-creative work process identified crucial factors in promoting sexual health, resulting in a useful model for patients, professionals and teams. Co-creation was experienced to be a useful research design to improve rheumatological care, through valuing and using the competence of all research members equally.

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  • 10.
    Arkema, Elizabeth V. V.
    et al.
    Karolinska Inst, Sweden.
    Saleh, Muna Atallah
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences.
    Simard, Julia F. F.
    Karolinska Inst, Sweden; Stanford Univ, CA USA.
    Sjöwall, Christopher
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Medicine Center, Department of Rheumatology.
    Epidemiology and Damage Accrual of Systemic Lupus Erythematosus in Central Sweden: A Single-Center Population-Based Cohort Study Over 14 Years From ostergotland County2023In: ACR Open Rheumatology, E-ISSN 2578-5745, Vol. 5, no 8, p. 426-432Article in journal (Refereed)
    Abstract [en]

    ObjectiveVariations in prevalence and incidence of systemic lupus erythematosus (SLE) within a geographically defined area of central Sweden over a time period of 14 years were examined. Longitudinal differences in disease activity, laboratory test results, and damage accrual were investigated. MethodsAdults (aged & GE;18 years) residing in ostergotland County between 2008 and 2021 (mean adult population: 357,000 citizens) with confirmed SLE were identified and followed prospectively until death, December 31, 2021, or emigration. We estimated annual incidence per 100,000 inhabitants stratified by sex and age. Linear regression with year of diagnosis as the outcome assessed whether each clinical measurement at diagnosis varied over time. ResultsPrevalence on December 31, 2021, was 71.5 of 100,000 (87% female). One hundred twenty-six new cases were identified during the study period, yielding a mean annual incidence of 3.0 of 100,000 inhabitants; this was higher in females (4.8/100,000) than in males (1.2/100,000). Mean age at diagnosis was 43.7 years (SD 17.3). Age at diagnosis and disease activity measures increased over the calendar year of diagnosis (P &lt; 0.05) whereas disease manifestations, including lupus nephritis, did not vary significantly. Accrual of organ damage was demonstrated over time since diagnosis and stratified by sex, lupus nephritis, and corticosteroid-related damage. Approximately 40% developed damage within 5 years. ConclusionSLE prevalence and incidence estimates remained constant over 14 years, and disease phenotypes at SLE onset were similar. SLE was diagnosed also among older individuals with a smaller female-to-male ratio. Estimates of prevalence and incidence were comparable to previous Scandinavian reports but lower than observed in registry data from the US and the UK.

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  • 11.
    Barbulescu, Andrei
    et al.
    Karolinska Inst, Sweden.
    Askling, Johan
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Chatzidionysiou, Katerina
    Karolinska Univ Hosp, Sweden; Karolinska Inst, Sweden.
    Forsblad-dElia, Helena
    Univ Gothenburg, Sweden.
    Kastbom, Alf
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Medicine Center, Department of Rheumatology.
    Lindstrom, Ulf
    Univ Gothenburg, Sweden.
    Turesson, Carl
    Lund Univ, Sweden.
    Frisell, Thomas
    Karolinska Inst, Sweden.
    Effectiveness of baricitinib and tofacitinib compared with bDMARDs in RA: results from a cohort study using nationwide Swedish register data2022In: Rheumatology, ISSN 1462-0324, E-ISSN 1462-0332, Vol. 61, no 10, p. 3952-3962Article in journal (Refereed)
    Abstract [en]

    Objectives To describe the use of baricitinib and tofacitinib by Swedish RA patients and to compare their effectiveness with that of biologic DMARDs (bDMARDs). Methods RA patients who initiated baricitinib (n = 1420), tofacitinib (n = 316), abatacept (n = 1050), IL-6 inhibitors (IL-6is; n = 849), rituximab (n = 1101) or TNF inhibitors (TNFis; n = 6036) between January 2017 and November 2019 were followed for a minimum of 1 year using data from several linked Swedish national registers. Proportions reaching a good EULAR 28-joint DAS (DAS28) response, HAQ Disability Index (HAQ-DI) improvement &gt;0.2 units and Clinical Disease Activity Index (CDAI) remission were compared at 1 year, imputing discontinued treatments as non-response. Additionally, we compared drug retention and changes in DAS28, HAQ-DI and CDAI from baseline to 3 months after treatment initiation. Results On average, baricitinib, and particularly tofacitinib, were initiated as later lines of therapy and more frequently as monotherapy compared with rituximab and TNFi. Adjusted 1 year response proportions were consistently lower on TNFi compared with baricitinib, with differences of -4.3 percentage points (95% CI -8.7, 0.1) for good EULAR response, -9.9 (-14.4 to -5.4) for HAQ-DI improvement and -6.0 (-9.8 to -2.2) for CDAI remission. Comparisons with non-TNFi bDMARDs also favoured baricitinib, but not consistently. Treatment responses for tofacitinib were only marginally lower than those for baricitinib and generally similar to those of bDMARDs, with precision limited by low power. Comparisons of drug retention and changes in disease activity from baseline to 3 months supported the 1 year findings. Conclusions Baricitinib and tofacitinib showed at least equivalent effectiveness compared with bDMARDs after exploring several different effectiveness measures.

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  • 12.
    Bergström, Maria
    et al.
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Prevention, Rehabilitation and Community Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Dahlström, Örjan
    Linköping University, Department of Behavioural Sciences and Learning, Psychology. Linköping University, Faculty of Arts and Sciences.
    Thyberg, Ingrid
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Medicine Center, Department of Rheumatology.
    Björk, Mathilda
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Prevention, Rehabilitation and Community Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Pain and Rehabilitation Center.
    The role of support from significant others in the association between disease-related factors and sickness absence in early rheumatoid arthritis: a longitudinal study2021In: Scandinavian Journal of Rheumatology, ISSN 0300-9742, E-ISSN 1502-7732, Vol. 50, no 6, p. 427-434Article in journal (Refereed)
    Abstract [en]

    Objective: The aim of this study was to analyse how support from significant others affects the associations between disease-related variables and sickness absence during the first 2 years after rheumatoid arthritis (RA) diagnosis. Method: Data from 274 people with RA (73% women) of working age (18-63 years) were retrieved from the Swedish early RA cohort TIRA-2. These data concerned disease-related variables (disease activity, activity limitations, pain intensity, and grip force), sickness absence, and perceived support from significant others. Associations of disease-related variables with sickness absence and how these associations were moderated by support from significant others were analysed using zero-inflated negative binomial regression. Results: During the 2 years after diagnosis, higher disease activity was significantly associated with increased odds of sickness absence, a connection strengthened by perceived support from family during the first year. More perceived support was also directly and significantly associated with increased odds of sickness absence during the first year. Conclusions: Support from significant others is related to sickness absence in RA, specifically during the first year after diagnosis. Although patients report high levels of support from significant others, this does not necessarily lead to more positive work outcomes. Therefore, it is important to consider other aspects of support that might influence work outcomes, e.g. type and quality of support. Future research should investigate these forms of support, and when significant others should be encouraged to support in the rehabilitation process to increase the chances of people with RA having a well-functioning and sustainable work life.

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  • 13.
    Bergström, Maria
    et al.
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Prevention, Rehabilitation and Community Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Larsson Ranada, Åsa
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Prevention, Rehabilitation and Community Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Sverker, Annette M.
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Prevention, Rehabilitation and Community Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Activity and Health. Linköping University, Department of Culture and Society, Division of Social Work. Region Östergötland, Primary Care Center, Operations management PVC.
    Thyberg, Ingrid
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Medicine Center, Department of Rheumatology.
    Björk, Mathilda
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Prevention, Rehabilitation and Community Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Pain and Rehabilitation Center.
    A dyadic exploration of support in everyday life of persons with RA and their significant others2023In: Scandinavian Journal of Occupational Therapy, ISSN 1103-8128, E-ISSN 1651-2014, Vol. 30, no 5, p. 616-627Article in journal (Refereed)
    Abstract [en]

    Background Support from significant others is important for participation in everyday life for persons with rheumatoid arthritis (RA). Meanwhile, significant others also experience limitations. Aims To explore how support is expressed by persons with RA and significant others, and how support relates to participation in everyday life of persons with RA. Material and methods Sixteen persons with RA and their significant others participated in individual semi-structured interviews. The material was analyzed using dyadic analysis. Results Persons with RA and significant others reported that RA and support had become natural parts of everyday life, especially emotional support. The reciprocal dynamics of support were also expressed as imperative. Also, support from people outside of the dyads and well-functioning communication facilitated everyday life. Conclusions Significant others and the support they give are prominent factors and facilitators in everyday life of persons with RA. Concurrently, the support persons with RA provide is important, along with support from outside of the dyads. Significance The results indicate that the interaction between persons with RA and the social environment is central to gain insight into how support should be provided for optimal participation in everyday life. Significant others can preferably be more involved in the rehabilitation process.

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  • 14.
    Bergström, Maria
    et al.
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Prevention, Rehabilitation and Community Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Sverker, Annette
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Prevention, Rehabilitation and Community Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Activity and Health.
    Larsson, Åsa
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Prevention, Rehabilitation and Community Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Valtersson, Eva
    Linköping University, Department of Health, Medicine and Caring Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Activity and Health.
    Thyberg, Ingrid
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Medicine Center, Department of Rheumatology.
    Ostlund, Gunnel
    Malardalen Univ, Sweden.
    Björk, Mathilda
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Prevention, Rehabilitation and Community Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Medicine Center, Department of Rheumatology.
    Significant others influence on participation in everyday life: the perspectives of persons with early diagnosed rheumatoid arthritis2020In: Disability and Rehabilitation, ISSN 0963-8288, E-ISSN 1464-5165, Vol. 42, no 3, p. 385-393Article in journal (Refereed)
    Abstract [en]

    Purpose: To describe the meaning of significant others in relation to participation in everyday life of persons with early diagnosed rheumatoid arthritis (RA). Materials and methods: Fifty-nine persons participated in this interview study. Inclusion criteria were three years experience of diagnosis and being of working age. Semi-structured interviews were conducted using critical incident technique (CIT), and the material was analysed using content analysis. Results: Four categories were revealed: (1) My early RA causes activity adaptations for us all, referring to the person and significant others modifying activities. (2) Making the significant others balance between shortfalls and participation, where the participants distinguished between needing help and feeling involved in activities. (3) Physical interactions with significant others, referring to both the problematic and manageable impact RA could have on body contact. (4) Emotions in relation to activities with others, where participants described feelings of failing others, and anxiety about future activities. Conclusions: For persons with early diagnosed RA, significant others can be both hindering and facilitating for participation in everyday life. As a clinical implication, it is valuable to identify how significant others can be involved in the rehabilitation process, to enhance participation in everyday life early in the disease process.

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  • 15.
    Björk, Mathilda
    et al.
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Prevention, Rehabilitation and Community Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Medicine Center, Department of Rheumatology.
    Bergström, Maria
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Prevention, Rehabilitation and Community Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Sverker, Annette
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Prevention, Rehabilitation and Community Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Activity and Health.
    Brodin, N.
    Karolinska Inst, Sweden; Danderyd Hosp, Sweden.
    Measures of Participation in Persons With Musculoskeletal Conditions2020In: Arthritis care & research, ISSN 2151-464X, E-ISSN 2151-4658, Vol. 72, p. 486-498Article in journal (Refereed)
    Abstract [en]

    n/a

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  • 16.
    Bolin, Karin
    et al.
    Uppsala Univ, Sweden; Uppsala Univ, Sweden.
    Imgenberg-Kreuz, Juliana
    Uppsala Univ, Sweden; Uppsala Univ, Sweden.
    Leonard, Dag
    Uppsala Univ, Sweden; Uppsala Univ, Sweden.
    Sandling, Johanna K.
    Uppsala Univ, Sweden; Uppsala Univ, Sweden.
    Alexsson, Andrei
    Uppsala Univ, Sweden; Uppsala Univ, Sweden.
    Pucholt, Pascal
    Uppsala Univ, Sweden; Uppsala Univ, Sweden.
    Haarhaus, Malena Loberg
    Karolinska Univ Hosp Stockholm, Sweden.
    Almlöf, Jonas Carlsson
    Uppsala Univ, Sweden.
    Nititham, Joanne
    Univ Calif San Francisco, CA 94132 USA.
    Jönsen, Andreas
    Lund Univ, Sweden.
    Sjöwall, Christopher
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Medicine Center, Department of Rheumatology.
    Bengtsson, Anders A.
    Lund Univ, Sweden.
    Rantapää-Dahlqvist, Solbritt
    Umea Univ, Sweden.
    Svenungsson, Elisabet
    Karolinska Univ Hosp Stockholm, Sweden.
    Gunnarsson, Iva
    Karolinska Univ Hosp Stockholm, Sweden.
    Syvänen, Ann-Christine
    Uppsala Univ, Sweden.
    Lerang, Karoline
    Univ Oslo, Norway.
    Troldborg, Anne
    Aarhus Univ Hosp, Denmark; Aarhus Univ, Denmark.
    Voss, Anne
    Odense Univ Hosp, Denmark.
    Molberg, Öyvind
    Univ Oslo, Norway.
    Jacobsen, Sören
    Copenhagen Univ Hosp, Denmark.
    Criswell, Lindsey
    Univ Calif San Francisco, CA 94132 USA.
    Rönnblom, Lars
    Uppsala Univ, Sweden; Uppsala Univ, Sweden.
    Nordmark, Gunnel
    Uppsala Univ, Sweden; Uppsala Univ, Sweden.
    Variants in BANK1 are associated with lupus nephritis of European ancestry2021In: Genes and Immunity, ISSN 1466-4879, E-ISSN 1476-5470, Vol. 22, p. 194-202Article in journal (Refereed)
    Abstract [en]

    The genetic background of lupus nephritis (LN) has not been completely elucidated. We performed a case-only study of 2886 SLE patients, including 947 (33%) with LN. Renal biopsies were available from 396 patients. The discovery cohort (Sweden, n = 1091) and replication cohort 1 (US, n = 962) were genotyped on the Immunochip and replication cohort 2 (Denmark/Norway, n = 833) on a custom array. Patients with LN, proliferative nephritis, or LN with end-stage renal disease were compared with SLE without nephritis. Six loci were associated with LN (p &lt; 1 x 10(-4), NFKBIA, CACNA1S, ITGA1, BANK1, OR2Y, and ACER3) in the discovery cohort. Variants in BANK1 showed the strongest association with LN in replication cohort 1 (p = 9.5 x 10(-4)) and proliferative nephritis in a meta-analysis of discovery and replication cohort 1. There was a weak association between BANK1 and LN in replication cohort 2 (p = 0.052), and in the meta-analysis of all three cohorts the association was strengthened (p = 2.2 x 10(-7)). DNA methylation data in 180 LN patients demonstrated methylation quantitative trait loci (meQTL) effects between a CpG site and BANK1 variants. To conclude, we describe genetic variations in BANK1 associated with LN and evidence for genetic regulation of DNA methylation within the BANK1 locus. This indicates a role for BANK1 in LN pathogenesis.

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  • 17.
    Bower, Hannah
    et al.
    Karolinska Inst, Sweden.
    Frisell, Thomas
    Karolinska Inst, Sweden.
    di Giuseppe, Daniela
    Karolinska Inst, Sweden.
    Delcoigne, Benedicte
    Karolinska Inst, Sweden.
    Ahlenius, Gerd-Marfie
    Umea Univ, Sweden.
    Baecklund, Eva
    Uppsala Univ, Sweden.
    Chatzidionysiou, Katerina
    Karolinska Inst, Sweden.
    Feltelius, Nils
    Swedish Med Prod Agcy, Sweden; Uppsala Univ, Sweden.
    Forsblad-dElia, Helena
    Univ Gothenburg, Sweden.
    Kastbom, Alf
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Medicine Center, Department of Rheumatology.
    Klareskog, Lars
    Karolinska Inst, Sweden.
    Lindqvist, Elisabet
    Lund Univ, Sweden.
    Lindstrom, Ulf
    Univ Gothenburg, Sweden.
    Turesson, Carl
    Lund Univ, Sweden.
    Sjöwall, Christopher
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Medicine Center, Department of Rheumatology.
    Askling, Johan
    Karolinska Inst, Sweden.
    Effects of the COVID-19 pandemic on patients with inflammatory joint diseases in Sweden: from infection severity to impact on care provision2021In: RMD Open, E-ISSN 2056-5933, Vol. 7, no 3, article id e001987Article in journal (Refereed)
    Abstract [en]

    Objectives To compare risks for COVID-19-related outcomes in inflammatory joint diseases (IJDs) and across disease-modifying antirheumatic drugs (DMARDs) during the first two waves of the pandemic and to assess effects of the pandemic on rheumatology care provision. Methods Through nationwide multiregister linkages and cohort study design, we defined IJD and DMARD use annually in 2015-2020. We assessed absolute and relative risks of hospitalisation or death listing COVID-19. We also assessed the incidence of IJD and among individuals with IJD, rheumatologist visits, DMARD use and incidence of selected comorbidities. Results Based on 115 317 patients with IJD in 2020, crude risks of hospitalisation and death listing COVID-19 (0.94% and 0.33% across both waves, respectively) were similar during both waves (adjusted HR versus the general population 1.33, 95% CI 1.23 to 1.43, for hospitalisation listing COVID-19; 1.23, 95% CI 1.08 to 1.40 for death listing COVID-19). Overall, biological disease-modifying antirheumatic drugs (bDMARDs)/targeted synthetic disease-modifying antirheumatic drugs (tsDMARDs) did not increase risks of COVID-19 related hospitalisation (with the exception of a potential signal for JAK inhibitors) or death. During the pandemic, decreases were observed for IJD incidence (-7%), visits to rheumatology units (-16%), DMARD dispensations (+6.5% for bDMARD/tsDMARDs and -8.5% for conventional synthetic DMARDs compared with previous years) and for new comorbid conditions, but several of these changes were part of underlying secular trends. Conclusions Patients with IJD are at increased risk of serious COVID-19 outcomes, which may partially be explained by medical conditions other than IJD per se. The SARS-CoV-2 pandemic has exerted measurable effects on aspects of rheumatology care provision demonstrated, the future impact of which will need to be assessed.

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  • 18.
    Bower, Hannah
    et al.
    Karolinska Inst, Sweden.
    Frisell, Thomas
    Karolinska Inst, Sweden.
    Di Giuseppe, Daniela
    Karolinska Inst, Sweden.
    Delcoigne, Benedicte
    Karolinska Inst, Sweden.
    Ahlenius, Gerd-Marie
    Umea Univ, Sweden.
    Baecklund, Eva
    Uppsala Univ, Sweden.
    Chatzidionysiou, Katerina
    Karolinska Inst, Sweden.
    Feltelius, Nils
    Swedish Med Prod Agcy, Sweden.
    Forsblad-dElia, Helena
    Univ Gothenburg, Sweden.
    Kastbom, Alf
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Medicine Center, Department of Rheumatology.
    Klareskog, Lars
    Karolinska Inst, Sweden.
    Lindqvist, Elisabet
    Lund Univ, Sweden.
    Lindström, Ulf
    Univ Gothenburg, Sweden.
    Turesson, Carl
    Lund Univ, Sweden.
    Sjöwall, Christopher
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Medicine Center, Department of Rheumatology.
    Askling, Johan
    Karolinska Inst, Sweden.
    Impact of the COVID-19 pandemic on morbidity and mortality in patients with inflammatory joint diseases and in the general population: a nationwide Swedish cohort study2021In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 80, no 8, p. 1086-1093Article in journal (Refereed)
    Abstract [en]

    Objectives To estimate absolute and relative risks for all-cause mortality and for severe COVID-19 in inflammatory joint diseases (IJDs) and with antirheumatic therapies. Methods Through Swedish nationwide multiregister linkages, we selected all adult patients with rheumatoid arthritis (RA, n=53 455 in March 2020), other IJDs (here: spondyloarthropathies, psoriatic arthritis and juvenile idiopathic arthritis, n=57 112), their antirheumatic drug use, and individually matched population referents. We compared annual all-cause mortality March-September 2015 through 2020 within and across cohorts, and assessed absolute and relative risks for hospitalisation, admission to intensive care and death due to COVID-19 March-September 2020, using Cox regression. Results During March-September 2020, the absolute all-cause mortality in RA and in other IJDs was higher than 2015-2019, but relative risks versus the general population (around 2 and 1.5) remained similar during 2020 compared with 2015-2019. Among patients with IJD, the risks of hospitalisation (0.5% vs 0.3% in their population referents), admission to intensive care (0.04% vs 0.03%) and death (0.10% vs 0.07%) due to COVID-19 were low. Antirheumatic drugs were not associated with increased risk of serious COVID-19 outcomes, although for certain drugs, precision was limited. Conclusions Risks of severe COVID-19-related outcomes were increased among patients with IJDs, but risk increases were also seen for non-COVID-19 morbidity. Overall absolute and excess risks are low and the level of risk increases are largely proportionate to those in the general population, and explained by comorbidities. With possible exceptions, antirheumatic drugs do not have a major impact on these risks.

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  • 19.
    Cao, Shan
    et al.
    Friedrich Alexander Univ FAU Erlangen Nurnberg, Germany; Univ Klinikum Erlangen, Germany; Friedrich Alexander Univ FAU Erlangen Nurnberg, Germany; Shanghai Jiao Tong Univ, Peoples R China.
    Li, Yixuan
    Friedrich Alexander Univ FAU Erlangen Nurnberg, Germany; Univ Klinikum Erlangen, Germany; Friedrich Alexander Univ FAU Erlangen Nurnberg, Germany; Shanghai Jiao Tong Univ, Peoples R China.
    Song, Rui
    Friedrich Alexander Univ FAU Erlangen Nurnberg, Germany; Univ Klinikum Erlangen, Germany; Friedrich Alexander Univ FAU Erlangen Nurnberg, Germany; Shanghai Jiao Tong Univ, Peoples R China.
    Meng, Xianyi
    Friedrich Alexander Univ FAU Erlangen Nurnberg, Germany; Univ Klinikum Erlangen, Germany; Friedrich Alexander Univ FAU Erlangen Nurnberg, Germany.
    Fuchs, Maximilian
    Friedrich Alexander Univ FAU Erlangen Nurnberg, Germany; Fraunhofer Inst Toxicol & Expt Med, Germany.
    Liang, Chunguang
    Friedrich Alexander Univ FAU Erlangen Nurnberg, Germany; Univ Wurzburg Hubland, Germany.
    Kachler, Katerina
    Friedrich Alexander Univ FAU Erlangen Nurnberg, Germany; Univ Klinikum Erlangen, Germany; Friedrich Alexander Univ FAU Erlangen Nurnberg, Germany.
    Meng, Xinyu
    Shanghai Jiao Tong Univ, Peoples R China.
    Wen, Jinming
    Friedrich Alexander Univ FAU Erlangen Nurnberg, Germany; Univ Klinikum Erlangen, Germany; Friedrich Alexander Univ FAU Erlangen Nurnberg, Germany; Sun Yat sen Univ, Peoples R China.
    Schloetzer-Schrehardt, Ursula
    Friedrich Alexander Univ FAU Erlangen Nurnberg, Germany.
    Taudte, Verena
    Friedrich Alexander Univ FAU Erlangen Nurnberg, Germany; Philipps Univ Marburg, Germany.
    Gessner, Arne
    Friedrich Alexander Univ FAU Erlangen Nurnberg, Germany.
    Kunz, Meik
    Friedrich Alexander Univ FAU Erlangen Nurnberg, Germany; Fraunhofer Inst Toxicol & Expt Med, Germany.
    Schleicher, Ulrike
    Univ Klinikum Erlangen, Germany; Friedrich Alexander Univ FAU Erlangen Nurnberg, Germany.
    Zaiss, Mario M.
    Friedrich Alexander Univ FAU Erlangen Nurnberg, Germany; Univ Klinikum Erlangen, Germany; Friedrich Alexander Univ FAU Erlangen Nurnberg, Germany.
    Kastbom, Alf
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Medicine Center, Department of Rheumatology.
    Chen, Xiaoxiang
    Shanghai Jiao Tong Univ, Peoples R China.
    Schett, Georg
    Friedrich Alexander Univ FAU Erlangen Nurnberg, Germany; Univ Klinikum Erlangen, Germany; Friedrich Alexander Univ FAU Erlangen Nurnberg, Germany.
    Bozec, Aline
    Friedrich Alexander Univ FAU Erlangen Nurnberg, Germany; Univ Klinikum Erlangen, Germany; Friedrich Alexander Univ FAU Erlangen Nurnberg, Germany.
    L-arginine metabolism inhibits arthritis and inflammatory bone loss2023In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060Article in journal (Refereed)
    Abstract [en]

    ObjectivesTo investigate the effect of the L-arginine metabolism on arthritis and inflammation-mediated bone loss.MethodsL-arginine was applied to three arthritis models (collagen-induced arthritis, serum-induced arthritis and human TNF transgenic mice). Inflammation was assessed clinically and histologically, while bone changes were quantified by mu CT and histomorphometry. In vitro, effects of L-arginine on osteoclast differentiation were analysed by RNA-seq and mass spectrometry (MS). Seahorse, Single Cell ENergetIc metabolism by profilIng Translation inHibition and transmission electron microscopy were used for detecting metabolic changes in osteoclasts. Moreover, arginine-associated metabolites were measured in the serum of rheumatoid arthritis (RA) and pre-RA patients.ResultsL-arginine inhibited arthritis and bone loss in all three models and directly blocked TNF alpha-induced murine and human osteoclastogenesis. RNA-seq and MS analyses indicated that L-arginine switched glycolysis to oxidative phosphorylation in inflammatory osteoclasts leading to increased ATP production, purine metabolism and elevated inosine and hypoxanthine levels. Adenosine deaminase inhibitors blocking inosine and hypoxanthine production abolished the inhibition of L-arginine on osteoclastogenesis in vitro and in vivo. Altered arginine levels were also found in RA and pre-RA patients.ConclusionOur study demonstrated that L-arginine ameliorates arthritis and bone erosion through metabolic reprogramming and perturbation of purine metabolism in osteoclasts.

  • 20.
    Carlsson Almlof, Jonas
    et al.
    Uppsala Univ, Sweden.
    Nystedt, Sara
    Uppsala Univ, Sweden.
    Mechtidou, Aikaterini
    Uppsala Univ, Sweden.
    Leonard, Dag
    Uppsala Univ, Sweden.
    Eloranta, Maija-Leena
    Uppsala Univ, Sweden.
    Grosso, Giorgia
    Karolinska Univ Hosp, Sweden.
    Sjöwall, Christopher
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Medicine Center, Department of Rheumatology.
    Bengtsson, Anders A.
    Lund Univ, Sweden.
    Jonsen, Andreas
    Lund Univ, Sweden.
    Gunnarsson, Iva
    Karolinska Univ Hosp, Sweden.
    Svenungsson, Elisabet
    Karolinska Univ Hosp, Sweden.
    Ronnblom, Lars
    Uppsala Univ, Sweden.
    Sandling, Johanna K.
    Uppsala Univ, Sweden.
    Syvanen, Ann-Christine
    Uppsala Univ, Sweden.
    Contributions of de novo variants to systemic lupus erythematosus2021In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 29, p. 184-193Article in journal (Refereed)
    Abstract [en]

    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.

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  • 21.
    Dahlqvist, Johanna
    et al.
    Uppsala Univ, Sweden; Broad Inst MIT & Harvard Univ, MA USA.
    Ekman, Diana
    Stockholm Univ, Sweden.
    Sennblad, Bengt
    Uppsala Univ, Sweden.
    Kozyrev, Sergey V
    Uppsala Univ, Sweden.
    Nordin, Jessika
    Uppsala Univ, Sweden.
    Karlsson, Åsa
    Uppsala Univ, Sweden.
    Meadows, Jennifer R. S.
    Uppsala Univ, Sweden.
    Hellbacher, Erik
    Uppsala Univ, Sweden.
    Rantapää-Dahlqvist, Solbritt
    Umeå Univ, Sweden.
    Berglin, Ewa
    Umeå Univ, Sweden.
    Stegmayr, Bernd
    Umeå Univ, Sweden.
    Baslund, Bo
    Copenhagen Univ Hosp, Denmark.
    Palm, Oyvind
    Oslo Univ Hosp, Norway.
    Haukeland, Hilde
    Martina Hansens Hosp, Norway.
    Gunnarsson, Iva
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Bruchfeld, Annette
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Medicine Center, Department of Nephrology. Karolinska Univ Hosp, Sweden; CLINTEC Karolinska Inst, Sweden.
    Segelmark, Mårten
    Lund Univ, Sweden; Skåne Univ Hosp, Sweden.
    Ohlsson, Sophie
    Lund Univ, Sweden; Skåne Univ Hosp, Sweden.
    Mohammad, Aladdin J.
    Lund Univ, Sweden; Univ Cambridge, England.
    Svärd, Anna
    Uppsala Univ, Sweden.
    Pullerits, Rille
    Univ Gothenburg, Sweden; Sahlgrens Univ Hosp, Sweden.
    Herlitz, Hans
    Univ Gothenburg, Sweden.
    Söderbergh, Annika
    örebro Univ Hosp, Sweden.
    Pielberg, Gerli Rosengren
    Uppsala Univ, Sweden.
    Rosenberg, Lina Hultin
    Uppsala Univ, Sweden.
    Bianchi, Matteo
    Uppsala Univ, Sweden.
    Murén, Eva
    Uppsala Univ, Sweden.
    Omdal, Roald
    Stavanger Univ Hosp, Norway; Univ Bergen, Norway.
    Jonsson, Roland
    Univ Bergen, Norway.
    Eloranta, Maija-Leena
    Uppsala Univ, Sweden.
    Rönnblom, Lars
    Uppsala Univ, Sweden.
    Söderkvist, Peter
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Knight, Ann
    Uppsala Univ, Sweden.
    Eriksson, Per
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Medicine Center, Department of Rheumatology.
    Lindblad-Toh, Kerstin
    Uppsala Univ, Sweden; Broad Inst MIT & Harvard Univ, MA USA.
    Identification and functional characterization of a novel susceptibility locus for small vessel vasculitis with MPO-ANCA2022In: Rheumatology, ISSN 1462-0324, E-ISSN 1462-0332, Vol. 61, no 8, p. 3461-3470Article in journal (Refereed)
    Abstract [en]

    Objective To identify and characterize genetic loci associated with the risk of developing ANCA-associated vasculitides (AAV).

    Methods Genetic association analyses were performed after Illumina sequencing of 1853 genes and subsequent replication with genotyping of selected single nucleotide polymorphisms in a total cohort of 1110 Scandinavian cases with granulomatosis with polyangiitis or microscopic polyangiitis, and 1589 controls. A novel AAV-associated single nucleotide polymorphism was analysed for allele-specific effects on gene expression using luciferase reporter assay.

    Results PR3-ANCA+ AAV was significantly associated with two independent loci in the HLA-DPB1/HLA-DPA1 region [rs1042335, P = 6.3 x 10-61, odds ratio (OR) 0.10; rs9277341, P = 1.5 x 10-44, OR 0.22] and with rs28929474 in the SERPINA1 gene (P = 2.7 x 10-10, OR 2.9). MPO-ANCA+ AAV was significantly associated with the HLA-DQB1/HLA-DQA2 locus (rs9274619, P = 5.4 x 10-25, OR 3.7) and with a rare variant in the BACH2 gene (rs78275221, P = 7.9 x 10-7, OR 3.0), the latter a novel susceptibility locus for MPO-ANCA+ granulomatosis with polyangiitis/microscopic polyangiitis. The rs78275221-A risk allele reduced luciferase gene expression in endothelial cells, specifically, as compared with the non-risk allele.

    Conclusion We identified a novel susceptibility locus for MPO-ANCA+ AAV and propose that the associated variant is of mechanistic importance, exerting a regulatory function on gene expression in specific cell types.

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  • 22.
    Di Giuseppe, Daniela
    et al.
    Karolinska Inst, Sweden.
    Lindström, Ulf
    Univ Gothenburg, Sweden.
    Bower, Hannah
    Karolinska Inst, Sweden.
    Delcoigne, Benedicte
    Karolinska Inst, Sweden.
    Frisell, Thomas
    Karolinska Inst, Sweden.
    Chatzidionysiou, Katerina
    Karolinska Inst, Sweden.
    Sjöwall, Christopher
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Medicine Center, Department of Rheumatology.
    Lindqvist, Elisabet
    Lund Univ, Sweden.
    Askling, Johan
    Karolinska Inst, Sweden.
    Comparison of treatment retention of originator vs biosimilar products in clinical rheumatology practice in Sweden2022In: Rheumatology, ISSN 1462-0324, E-ISSN 1462-0332, Vol. 61, no 9, p. 3596-3605Article in journal (Refereed)
    Abstract [en]

    Objectives To compare treatment retention between biosimilars and their originator products among first starters (etanercept, infliximab, adalimumab and rituximab), as well as after non-medical switch. Methods Patients with rheumatic diseases starting, for the first time, an originator or biosimilar etanercept, infliximab, adalimumab or rituximab were identified in the national Swedish Rheumatology Quality Register. Moreover, patients switching from an originator to its biosimilar were identified and individually matched to patients continuing on the originator. One-year treatment retention was calculated and hazard ratios (HR) for discontinuation with 95% CIs were estimated, adjusting for comorbidities and socio-economic factors. Results In total, 21 443 first treatment courses were identified. The proportion of patients still on the drug at 1 year and the HR for discontinuation revealed no differences across adalimumab (Humira, Imraldi, Amgevita and Hyrimoz) nor across rituximab products (Mabthera, Ritemvia/Truxima and Rixathon). The proportions on the drug at 1 year were similar for Benepali (77%) and Enbrel (75%) and the adjusted HR for Benepali compared with Enbrel was 0.91 (95% CI 0.83, 0.99). For infliximab, the proportion still on the drug at 1 year was 67% for Remicade and 66% for Remsima/Inflectra and the HR compared with Remicade was 1.16 (95% CI 1.02, 1.33). Among 2925 patients switching from an originator drug to one of its biosimilars, we noted no statistically significant or clinically relevant differences in drug survival compared with those who remained on originator therapy. Conclusion This large observational study supports the equivalence of biologic DMARD biosimilar products and originators when used in routine rheumatology care.

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  • 23.
    Ekman, Diana
    et al.
    Stockholm Univ, Sweden.
    Sennblad, Bengt
    Stockholm Univ, Sweden.
    Knight, Ann
    Uppsala Univ, Sweden.
    Karlsson, Asa
    Uppsala Univ, Sweden.
    Rantapaa-Dahlqvist, Solbritt
    Umea Univ, Sweden.
    Berglin, Ewa
    Umea Univ, Sweden.
    Stegmayr, Bernd
    Umea Univ, Sweden.
    Baslund, Bo
    Rigshosp, Denmark.
    Palm, Oyvind
    Oslo Univ Hosp, Norway.
    Haukeland, Hilde
    Martina Hansens Hosp, Norway.
    Gunnarsson, Iva
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Bruchfeld, Annette
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Karolinska Univ Hosp, Sweden; Karolinska Inst, Sweden.
    Segelmark, Marten
    Lund Univ, Sweden; Skane Univ Hosp, Sweden.
    Ohlsson, Sophie
    Lund Univ, Sweden; Skane Univ Hosp, Sweden.
    Mohammad, Aladdin J.
    Lund Univ, Sweden; Univ Cambridge, England.
    Svard, Anna
    Uppsala Univ, Sweden.
    Pullerits, Rille
    Univ Gothenburg, Sweden; Sahlgrens Univ Hosp, Sweden.
    Herlitz, Hans
    Univ Gothenburg, Sweden.
    Soderbergh, Annika
    Orebro Univ Hosp, Sweden.
    Omdal, Roald
    Stavanger Univ Hosp, Norway; Univ Bergen, Norway.
    Jonsson, Roland
    Univ Bergen, Norway.
    Ronnblom, Lars
    Uppsala Univ, Sweden.
    Eriksson, Per
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Medicine Center, Department of Rheumatology.
    Lindblad-Toh, Kerstin
    Uppsala Univ, Sweden; Broad Inst MIT & Harvard Univ, MA USA.
    Dahlqvist, Johanna
    Uppsala Univ, Sweden; Uppsala Univ, Sweden; Broad Inst MIT & Harvard Univ, MA USA.
    Stratified genetic analysis reveals sex differences in MPO-ANCA-associated vasculitis2023In: Rheumatology, ISSN 1462-0324, E-ISSN 1462-0332, Vol. 62, no 9, p. 3213-3218Article in journal (Refereed)
    Abstract [en]

    Objective To identify and genetically characterize subgroups of patients with ANCA-associated vasculitides (AAV) based on sex and ANCA subtype. Methods A previously established SNP dataset derived from DNA sequencing of 1853 genes and genotyping of 1088 Scandinavian cases with AAV and 1589 controls was stratified for sex and ANCA subtype and analysed for association with five top AAV SNPs. rs9274619, a lead variant at the HLA-DQB1/HLA-DQA2 locus previously associated with AAV positive for myeloperoxidase (MPO)-ANCA, was analysed for association with the cumulative disease involvement of ten different organ systems. Results rs9274619 showed a significantly stronger association to MPO-ANCA-positive females than males [P = 2.0 x 10(-4), OR = 2.3 (95% CI 1.5, 3.5)], whereas proteinase 3 (PR3)-ANCA-associated variants rs1042335, rs9277341 (HLA-DPB1/A1) and rs28929474 (SERPINA1) were equally associated with females and males with PR3-ANCA. In MPO-ANCA-positive cases, carriers of the rs9274619 risk allele were more prone to disease engagement of eyes [P = 0.021, OR = 11 (95% CI 2.2, 205)] but less prone to pulmonary involvement [P = 0.026, OR = 0.52 (95% CI 0.30, 0.92)]. Moreover, AAV with both MPO-ANCA and PR3-ANCA was associated with the PR3-ANCA lead SNP rs1042335 [P = 0.0015, OR = 0.091 (95% CI 0.0022, 0.55)] but not with rs9274619. Conclusions Females and males with MPO-ANCA-positive AAV differ in genetic predisposition to disease, suggesting at least partially distinct disease mechanisms between the sexes. Double ANCA-positive AAV cases are genetically similar to PR3-ANCA-positive cases, providing clues to the clinical follow-up and treatment of these patients.

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  • 24.
    Eloff, Emma
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Clinical Chemistry and Pharmacology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Medicine Center, Department of Rheumatology.
    Martinsson, Klara
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences.
    Ziegelasch, Michael
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Medicine Center, Department of Rheumatology.
    Cedergren, Jan
    Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Medicine Center, Department of Rheumatology. Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection.
    Reckner, Åsa
    Linköping University, Department of Biomedical and Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Medicine Center, Department of Rheumatology.
    Skogh, Thomas
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Medicine Center, Department of Rheumatology.
    Karlsson, Louise
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pharmacology.
    Ärlemalm, Andreas
    Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pharmacology. Linköping University, Department of Biomedical and Clinical Sciences, Division of Clinical Chemistry and Pharmacology.
    Borggreven, N. V
    Leiden Univ, Netherlands.
    Trouw, L. A.
    Leiden Univ, Netherlands.
    Kastbom, Alf
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Medicine Center, Department of Rheumatology.
    Autoantibodies are major predictors of arthritis development in patients with anti-citrullinated protein antibodies and musculoskeletal pain2021In: Scandinavian Journal of Rheumatology, ISSN 0300-9742, E-ISSN 1502-7732, Vol. 50, no 3, p. 189-197Article in journal (Refereed)
    Abstract [en]

    Objectives: Predictors of arthritis development are highly warranted among patients with anti-citrullinated protein antibodies (ACPAs) and musculoskeletal symptoms to optimize clinical management. We aimed to identify clinical and laboratory predictors of arthritis development, including biochemically assessed alcohol consumption, among ACPA-positive patients with musculoskeletal pain.

    Method: 82 ACPA-positive individuals with musculoskeletal pain but no clinical arthritis were followed for a median of 72 months (interquartile range 57–81 months). We evaluated the prognostic value of baseline clinical and laboratory factors including smoking, symptom duration, age, gender, shared epitope, rheumatoid factor (RF), anti-carbamylated protein antibodies, ACPA levels, erythrocyte sedimentation rate, C-reactive protein levels, tender joint count, patient-reported general well-being, 28-joint Disease Activity Score, and alcohol consumption as measured by phosphatidyl ethanol (PEth) levels in whole blood.

    Results: During follow-up, 48% developed at least one arthritis. Multivariable analysis revealed an increased risk of arthritis development with RF positivity [hazard ratio (HR) = 2.3, 95% confidence interval (CI) 1.1–4.8, p = 0.028] and higher ACPA levels (HR = 1.0, 95% CI 1.000–1.001, p = 0.002). High levels of RF (HR = 4.4, 95% CI 1.7–11) entailed the highest HR in this ACPA-positive population. Neither clinical characteristics nor alcohol consumption measured by PEth conferred significant prognostic value.

    Conclusions: ACPA levels and concurrent presence of RF are independent predictors of arthritis development among ACPA-positive patients with musculoskeletal pain. The results are compatible with a dose–response relationship between RA-related autoantibodies and risk of arthritis development. 

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  • 25.
    Enocsson, Helena
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences.
    Gullstrand, Birgitta
    Lund Univ, Sweden.
    Eloranta, Maija-Leena
    Uppsala Univ, Sweden.
    Wetterö, Jonas
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences.
    Leonard, Dag
    Uppsala Univ, Sweden.
    Ronnblom, Lars
    Uppsala Univ, Sweden.
    Bengtsson, Anders A.
    Lund Univ, Sweden.
    Sjöwall, Christopher
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Medicine Center, Department of Rheumatology.
    C-Reactive Protein Levels in Systemic Lupus Erythematosus Are Modulated by the Interferon Gene Signature and CRP Gene Polymorphism rs12052021In: Frontiers in Immunology, E-ISSN 1664-3224, Vol. 11, article id 622326Article in journal (Refereed)
    Abstract [en]

    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.

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  • 26.
    Enocsson, Helena
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences.
    Karlsson, Jesper
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences.
    Li, Hai-Yun
    Xi An Jiao Tong Univ, Peoples R China.
    Wu, Yi
    Xi An Jiao Tong Univ, Peoples R China; Xi An Jiao Tong Univ, Peoples R China.
    Kushner, Irving
    Case Western Reserve Univ, OH 44109 USA.
    Wetterö, Jonas
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences.
    Sjöwall, Christopher
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Medicine Center, Department of Rheumatology.
    The Complex Role of C-Reactive Protein in Systemic Lupus Erythematosus2021In: Journal of Clinical Medicine, E-ISSN 2077-0383, Vol. 10, no 24, article id 5837Article, review/survey (Refereed)
    Abstract [en]

    C-reactive protein (CRP) is well-known as a sensitive albeit unspecific biomarker of inflammation. In most rheumatic conditions, the level of this evolutionarily highly conserved pattern recognition molecule conveys reliable information regarding the degree of ongoing inflammation, driven mainly by interleukin-6. However, the underlying causes of increased CRP levels are numerous, including both infections and malignancies. In addition, low to moderate increases in CRP predict subsequent cardiovascular events, often occurring years later, in patients with angina and in healthy individuals. However, autoimmune diseases characterized by the Type I interferon gene signature (e.g., systemic lupus erythematosus, primary Sjogrens syndrome and inflammatory myopathies) represent exceptions to the general rule that the concentrations of CRP correlate with the extent and severity of inflammation. In fact, adequate levels of CRP can be beneficial in autoimmune conditions, in that they contribute to efficient clearance of cell remnants and immune complexes through complement activation/modulation, opsonization and phagocytosis. Furthermore, emerging data indicate that CRP constitutes an autoantigen in systemic lupus erythematosus. At the same time, the increased risks of cardiovascular and cerebrovascular diseases in patients diagnosed with systemic lupus erythematosus and rheumatoid arthritis are well-established, with significant impacts on quality of life, accrual of organ damage, and premature mortality. This review describes CRP-mediated biological effects and the regulation of CRP release in relation to aspects of cardiovascular disease and mechanisms of autoimmunity, with particular focus on systemic lupus erythematosus.

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  • 27.
    Enocsson, Helena
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Medicine Center, Department of Rheumatology.
    Lukic, Tanja
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences.
    Ziegelasch, Michael
    Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Region Östergötland, Medicine Center, Department of Rheumatology.
    Kastbom, Alf
    Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Region Östergötland, Medicine Center, Department of Rheumatology.
    Serum levels of the soluble urokinase plasminogen activator receptor (suPAR) correlates with disease activity in early rheumatoid arthritis and reflects joint damage over time2021In: Translational Research: The Journal of Laboratory and Clinical Medicine, ISSN 1931-5244, E-ISSN 1878-1810, Vol. 232, p. 142-149Article in journal (Refereed)
    Abstract [en]

    Soluble urokinase plasminogen activator receptor (suPAR) is intensively studied as a biomarker of inflammation and disease outcome in various diseases. In rheumatoid arthritis (RA), suPAR have shown an association with inflammation and swollen joints, but data on suPAR in relation to early disease course and disease progression are lacking. This study investigates the potential of suPAR to predict or reflect disease outcome in early RA. Serum suPAR was measured by enzyme-linked immunosorbent assay at disease onset and after 3 and 36 months in 252 patients from a Swedish prospective observational early RA cohort. Levels and changes of suPAR were analyzed in relation to the 28-joint disease activity score (DAS28) and joint damage according to the Larsen score at inclusion and during follow-up. 100 healthy blood donors served as controls. Circulating levels of suPAR were higher in RA patients at all time points as compared to healthy controls. Baseline suPAR was significantly associated with baseline disease activity whereas suPAR levels at 36 months were associated with joint damage at 36 months. No predictive value of suPAR levels or changes in suPAR levels over time were found. In conclusion, suPAR levels associate with disease activity in early untreated RA and reflects joint damage at later stages. Increased suPAR in established RA could indicate patients in need of frequent monitoring of joint status, irrespective of disease activity. In the view of suPAR as a rapidly emerging biomarker, it is important to be aware of its ability to reflect both inflammation and subsequent damage. (Translational Research 2021; 232:142-149)

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  • 28.
    Enocsson, Helena
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences.
    Wetterö, Jonas
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences.
    Eloranta, Maija-Leena
    Uppsala Univ, Sweden.
    Gullstrand, Birgitta
    Lund Univ, Sweden.
    Svanberg, Cecilia
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Molecular Medicine and Virology. Linköping University, Faculty of Medicine and Health Sciences.
    Larsson, Marie
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Molecular Medicine and Virology. Linköping University, Faculty of Medicine and Health Sciences.
    Bengtsson, Anders A.
    Lund Univ, Sweden.
    Rönnblom, Lars
    Uppsala Univ, Sweden.
    Sjöwall, Christopher
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Medicine Center, Department of Rheumatology.
    Comparison of Surrogate Markers of the Type I Interferon Response and Their Ability to Mirror Disease Activity in Systemic Lupus Erythematosus2021In: Frontiers in Immunology, E-ISSN 1664-3224, Vol. 12, article id 688753Article in journal (Refereed)
    Abstract [en]

    Objectives Type I interferons (IFNs) are central and reflective of disease activity in systemic lupus erythematosus (SLE). However, IFN-alpha levels are notoriously difficult to measure and the type I IFN gene signature (IGS) is not yet available in clinical routine. This study evaluates galectin-9 and an array of chemokines/cytokines in their potential as surrogate markers of type I IFN and/or SLE disease activity. Methods Healthy controls and well-characterized Swedish SLE patients from two cross-sectional cohorts (n=181; n=59) were included, and a subgroup (n=21) was longitudinally followed. Chemokine/cytokine responses in immune complex triggered IFN-alpha activity was studied in healthy donor peripheral blood mononuclear cells (PBMC). Levels of chemokines/cytokines and galectin-9 were measured by immunoassays. Gene expression was quantified by qPCR. Results The IGS was significantly (p&lt;0.01) correlated with galectin-9 (rho=0.54) and CXCL10 (rho=0.37) levels whereas serum IFN-alpha correlated with galectin-9 (rho=0.36), CXCL10 (rho=0.39), CCL19 (rho=0.26) and CCL2 (rho=0.19). The strongest correlation was observed between galectin-9 and TNF (rho=0.56). IFN-alpha and disease activity (SLEDAI-2K) were correlated (rho=0.20) at cross-sectional analysis, but no significant associations were found between SLEDAI-2K and galectin-9 or chemokines. Several inflammatory mediators increased at disease exacerbation although CCL19, CXCL11, CXCL10, IL-10 and IL-1 receptor antagonist were most pronounced. Immune complex-stimulation of PBMC increased the production of CCL2, CXCL8 and TNF. Conclusion Galectin-9 and CXCL10 were associated with type I IFN in SLE but correlated stronger with TNF. None of the investigated biomarkers showed a convincing association with disease activity, although CXCL10 and CCL19 performed best in this regard.

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  • 29.
    Enocsson, Helena
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences.
    Wirestam, Lina
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences.
    Dahle, Charlotte
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
    Padyukov, Leonid
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Jonsen, Andreas
    Lund Univ, Sweden.
    Urowitz, Murray B.
    Toronto Western Hosp, Canada; Univ Toronto, Canada.
    Gladmane, Dafna D.
    Toronto Western Hosp, Canada; Univ Toronto, Canada.
    Romero-Diaz, Juanita
    Inst Nacl Ciencias Med and Nutr Salvador Zubiran, Mexico.
    Bae, Sang-Cheol
    Hanyang Univ, South Korea.
    Fortin, Paul R.
    Univ Laval, Canada.
    Sanchez-Guerrero, Jorge
    Toronto Western Hosp, Canada; Univ Toronto, Canada.
    Clarke, Ann E.
    Univ Calgary, Canada.
    Bernatsky, Sasha
    McGill Univ, Canada.
    Gordon, Caroline
    Univ Birmingham, England.
    Hanly, John G.
    Queen Elizabeth 2 Hlth Sci Ctr, Canada; Queen Elizabeth 2 Hlth Sci Ctr, Canada; Dalhousie Univ, Canada.
    Wallace, Daniel J.
    Univ Calif Los Angeles, CA USA.
    Isenberg, David A.
    UCL, England.
    Rahman, Anisur
    UCL, England.
    Merrill, Joan T.
    Oklahoma Med Res Fdn, OK 73104 USA.
    Ginzler, Ellen
    Suny Downstate Med Ctr, NY 11203 USA.
    Alarcon, Graciela S.
    Univ Alabama Birmingham, AL 35294 USA.
    Chatham, W. Winn
    Univ Alabama Birmingham, AL 35294 USA.
    Petri, Michelle
    Johns Hopkins Univ, MD USA.
    Khamashta, Munther
    Kings Coll London, England.
    Aranow, Cynthia
    Feinstein Inst Med Res, NY USA.
    Mackay, Meggan
    Feinstein Inst Med Res, NY USA.
    Dooley, Mary Anne
    Univ N Carolina, NC 27515 USA.
    Manzi, Susan
    Allegheny Hlth Network, PA USA.
    Ramsey-Goldman, Rosalind
    Northwestern Univ, IL 60611 USA; Feinberg Sch Med, IL USA.
    Nived, Ola
    Lund Univ, Sweden.
    Steinsson, Kristjan
    Landspitali Univ Hosp, Iceland.
    Zoma, Asad A.
    Hairmyres Hosp, Scotland.
    Ruiz-Irastorza, Guillermo
    Univ Basque Country, Spain.
    Lim, S. Sam
    Emory Univ, GA USA.
    Kalunian, Kenneth C.
    UCSD Sch Med, CA USA.
    Inanc, Murat
    Istanbul Univ, Turkey.
    van Vollenhoven, Ronald F.
    Univ Amsterdam, Netherlands; Free Univ VU Amsterdam, Netherlands; Amsterdam Rheumatol and Immunol Ctr, Netherlands.
    Ramos-Casals, Manuel
    Hosp Clin Barcelona, Spain.
    Kamen, Diane L.
    Med Univ South Carolina, SC 29425 USA.
    Jacobsen, Soren
    Copenhagen Univ Hosp, Denmark.
    Peschken, Christine A.
    Univ Manitoba, Canada.
    Askanase, Anca
    Columbia Univ, NY USA.
    Stoll, Thomas
    Kantousspital, Switzerland.
    Bruce, Ian N.
    Univ Manchester, England; Manchester Univ Hosp NHS Fdn Trust, England.
    Wetterö, Jonas
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences.
    Sjöwall, Christopher
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Medicine Center, Department of Rheumatology.
    Soluble urokinase plasminogen activator receptor (suPAR) levels predict damage accrual in patients with recent-onset systemic lupus erythematosus2020In: Journal of Autoimmunity, ISSN 0896-8411, E-ISSN 1095-9157, Vol. 106, article id 102340Article in journal (Refereed)
    Abstract [en]

    Objective

    The soluble urokinase plasminogen activator receptor (suPAR) has potential as a prognosis and severity biomarker in several inflammatory and infectious diseases. In a previous cross-sectional study, suPAR levels were shown to reflect damage accrual in cases of systemic lupus erythematosus (SLE). Herein, we evaluated suPAR as a predictor of future organ damage in recent-onset SLE.

    Methods

    Included were 344 patients from the Systemic Lupus International Collaborating Clinics (SLICC) Inception Cohort who met the 1997 American College of Rheumatology classification criteria with 5-years of follow-up data available. Baseline sera from patients and age- and sex-matched controls were assayed for suPAR. Organ damage was assessed annually using the SLICC/ACR damage index (SDI).

    Results

    The levels of suPAR were higher in patients who accrued damage, particularly those with SDI≥2 at 5 years (N = 32, 46.8% increase, p = 0.004), as compared to patients without damage. Logistic regression analysis revealed a significant impact of suPAR on SDI outcome (SDI≥2; OR = 1.14; 95% CI 1.03–1.26), also after adjustment for confounding factors. In an optimized logistic regression to predict damage, suPAR persisted as a predictor, together with baseline disease activity (SLEDAI-2K), age, and non-Caucasian ethnicity (model AUC = 0.77). Dissecting SDI into organ systems revealed higher suPAR levels in patients who developed musculoskeletal damage (SDI≥1; p = 0.007).

    Conclusion

    Prognostic biomarkers identify patients who are at risk of acquiring early damage and therefore need careful observation and targeted treatment strategies. Overall, suPAR constitutes an interesting biomarker for patient stratification and for identifying SLE patients who are at risk of acquiring organ damage during the first 5 years of disease.

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  • 30.
    Eriksson, Per
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Medicine Center, Department of Rheumatology.
    Mölne, Johan
    Univ Gothenburg, Sweden.
    Wirestam, Lina
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences.
    Sjöwall, Christopher
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Medicine Center, Department of Rheumatology.
    Successful Treatment of AA Amyloidosis in Ankylosing Spondylitis Using Tocilizumab: Report of Two Cases and Review of the Literature2021In: Frontiers in Medicine, E-ISSN 2296-858X, Vol. 8, article id 661101Article, review/survey (Refereed)
    Abstract [en]

    Historically, secondary amyloidosis has been a feared complication of chronic inflammatory conditions. The fibril protein AA derives from the acute phase reactant serum amyloid A (SAA). Long-term elevation of SAA levels remains a major risk factor for the development of AA amyloidosis in rheumatic diseases, and the prognosis may be unpredictable. Nowadays, with increased availability of effective biological agents, the incidence of AA amyloidosis seems to be declining. Still, genetically predisposed subjects with slowly progressive disease and mild symptoms combined with ongoing systemic inflammation may be at risk. Interleukin-6 (IL-6) is one of the drivers of SAA release and effectiveness of the humanized anti-IL-6 receptor antibody tocilizumab (TCZ) for the treatment of AA amyloidosis has been observed in some rheumatic conditions. Herein, we report two male subjects with longstanding ankylosing spondylitis (AS) complicated by renal amyloidosis who received TCZ with rapid and beneficial effects regarding inflammation and proteinuria. To the best of our knowledge, the use of TCZ in AS patients with this extra-articular manifestation has not previously been described. The paper includes histopathology, clinical follow-up, and longitudinal data of the two cases along with a comprehensive review of relevant literature. Mechanisms behind amyloid-mediated tissue damage and organ dysfunction are discussed. Altogether, our data highlight that blocking IL-6 signaling may represent a promising therapeutic option in patients with renal AA amyloidosis.

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  • 31.
    Eriksson, Per
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Medicine Center, Department of Rheumatology.
    Skoglund, Oliver
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Medicine Center, Department of Rheumatology.
    Hemgren, Cecilia
    Cty Hosp Ryhov, Sweden.
    Sjöwall, Christopher
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Medicine Center, Department of Rheumatology.
    Clinical experience and safety of Janus kinase inhibitors in giant cell arteritis: a retrospective case series from Sweden2023In: Frontiers in Immunology, E-ISSN 1664-3224, Vol. 14, article id 1187584Article in journal (Refereed)
    Abstract [en]

    The Janus kinase (JAK)-STAT signaling pathway is relevant in both Takayasu and giant cell arteritis (GCA), and the use of JAK inhibitors (JAKi) in arthritis, psoriasis, and inflammatory bowel disease is nowadays common. Some evidence of the clinical efficacy of JAKi in GCA exists and a phase III randomized controlled trial (RCT) of upadacitinib is currently recruiting. In 2017, we started using barcitinib in a GCA patient with inadequate response to corticosteroids, and later on, we treated other 14 GCA patients with baricitinib/tofacitinib during intense follow-up. The retrospective data of these 15 individuals are here summarized. GCA was diagnosed based on the ACR criteria and/or imaging techniques combined with increased C-reactive protein (CRP) and/or erythrocyte sedimentation rate (ESR) followed by a good initial response to corticosteroids. JAKi was initiated based on inflammatory activity, with increased CRP, presumably dependent on GCA with clinical symptoms, despite unsatisfying high doses of prednisolone. The mean age at JAKi initiation was 70.1 years and the mean exposure to JAKi was 19 months. From initiation, significant reductions in CRP were seen already at 3 (p = 0.02) and 6 (p = 0.02) months. A slower decrease was observed regarding ESR at 3 (p = 0.12) and 6 (p = 0.02) months. Furthermore, the daily prednisolone doses were reduced at 3 (p = 0.02) and 6 (p = 0.004) months. No GCA relapses were observed. Two patients were affected by serious infections, but JAKi therapy was retained or reintroduced after recovery. We present encouraging observational data on JAKi in GCA in one of the hitherto largest case series with long-term follow-up. Our clinical experiences will complement the results from the awaited RCT.

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  • 32. Order onlineBuy this publication >>
    Frodlund, Martina
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Medicine Center, Department of Rheumatology.
    Antinuclear and antiphospholipid antibodies versus disease manifestations and clinical outcomes in systemic lupus erythematosus2020Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Systemic lupus erythematosus (SLE) has an exceptionally heterogeneous clinical spectrum, ranging from mild disease limited to skin and joints to severe manifestations with renal disorder, central nervous system disease, severe cytopenias and thromboembolic events. Important clinical challenges include the prediction of disease flares and the identification of individuals that are likely to evolve severe disease with accrual of organ damage and worse prognosis. Autoantibodies, i.e. antinuclear antibodies (ANA) and antiphospholipid antibodies (aPL), and interferon alpha (IFN-α) that contribute to formation of immune complexes with nuclear antigens, are hallmarks considered to drive the disease in a vicious circle of antigen exposure, autoantibody production, inflammation and organ damage. There are few good biomarkers to predict severe SLE and organ damage. The aim of this PhD project was thus to increase the knowledge regarding ANA as well as aPL, and other potential biomarkers in relation to clinical features and disease outcomes in SLE.

    As expected, we found that the homogeneous ANA staining pattern was most common, and that it was associated with the occurrence of the ‘immunological disorder’ criterion. Speckled ANA was the second most common staining pattern, and it was inversely associated with arthritis, the ‘immunological disorder’ criterion and organ damage (Paper I). We also demonstrated that a considerable proportion of the patients lost ANA-positivity over time, whereas consistent staining patterns were most frequent (Paper V).

    Survival of patients with SLE has improved. Yet, in comparison to the general population, irreversible organ damage and increased mortality remains a critical concern. In Paper II, our cross-sectional analysis showed that more than a quarter of the patients had any aPL isotype (IgG, IgM or IgA class), and 14% were classified with antiphospholipid antibody syndrome (APS). A positive lupus anticoagulant (LA) test and/or IgG aPL tests were associated with most APS-related events and organ damage. Lupus nephritis, tobacco smoking, LA-positivity and the use of statins and/or corticosteroids were strongly associated with damage accrual, while hydroxychloroquine seemed to be protective. IgA aPL was not uncommon (16%) in Swedish cases of SLE, and analysis of IgA aPL may add information among clinically suspected APS-patients testing negative for LA and other aPL isotypes.

    Despite modern management and tax-funded health care with universal access, almost two thirds of the patients accrued organ damage over time, and the main causes of death were identified as malignancy, infection, and cardiovascular disease. We could confirm well established risk factors for organ damage such as APS, hypertension, and/or the use of corticosteroids, but we also observed that other factors such as pericarditis, haemolytic anaemia, lymphopenia and myositis seems to be of importance in this view (Paper IV).

    We also demonstrated that levels of the extracellular matrix protein osteopontin (OPN) was correlated with disease activity in patients with recent-onset SLE. In addition, OPN levels reflected global organ damage and were associated with APS and could have potential as a valuable biomarker in SLE (Paper III).

    Additional studies are warranted to further establish the clinical and mechanistic relevance of ANA seroconversion, OPN, as well as the importance of IgA aPL. Vigilance for malignancies, a restricted use of corticosteroids and prevention of cardiovascular disease and APS events are among modifiable factors to prevent organ damage and premature mortality.

    This thesis emphasizes the importance of autoantibodies in the pathogenesis, and diagnosis, of SLE. The autoantibody profile can be of great importance for tailored therapy in order to minimize the risk of organ damage accrual, morbidity as well as mortality.

    List of papers
    1. Associations between antinuclear antibody staining patterns and clinical features of systemic lupus erythematosus: analysis of a regional Swedish register
    Open this publication in new window or tab >>Associations between antinuclear antibody staining patterns and clinical features of systemic lupus erythematosus: analysis of a regional Swedish register
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    2013 (English)In: BMJ Open, E-ISSN 2044-6055, Vol. 3, p. 1-8Article in journal (Refereed) Published
    Abstract [en]

    Objective Antinuclear antibody (ANA) analysis by immunofluorescence (IF) microscopy remains a diagnostic hallmark of systemic lupus erythematosus (SLE). The clinical relevance of ANA fine-specificities in SLE has been addressed repeatedly, whereas studies on IF-ANA staining patterns in relation to disease manifestations are very scarce. This study was performed to elucidate whether different staining patterns associate with distinct SLE phenotypes.

    Design Observational cohort study.

    Setting One university hospital rheumatology unit in Sweden.

    Participants The study population consisted of 222 cases (89% women; 93% Caucasians), where of 178 met ≥4/11 of the 1982 American College of Rheumatology (ACR-82) criteria. The remaining 20% had an SLE diagnosis based on positive IF-ANA (HEp-2 cells) and ≥2 typical organ manifestations at the time of diagnosis (Fries’ criteria).

    Outcome measures The IF-ANA staining patterns homogenous (H-ANA), speckled (S-ANA), combined homogenous and speckled (HS-ANA), centromeric (C-ANA), nucleolar (N-ANA)±other patterns and other nuclear patterns (oANA) were related to disease manifestations and laboratory measures. Antigen-specificities were also considered regarding double-stranded DNA (Crithidia luciliae) and the following extractable nuclear antigens: Ro/SSA, La/SSB, Smith antigen (Sm), small nuclear RNP (snRNP), Scl-70 and Jo-1 (immunodiffusion and/or line-blot technique).

    Results 54% of the patients with SLE displayed H-ANA, 22% S-ANA, 11% HS-ANA, 9% N-ANA, 1% C-ANA, 2% oANA and 1% were never IF-ANA positive. Staining patterns among patients meeting Fries’ criteria alone did not differ from those fulfilling ACR-82. H-ANA was significantly associated with the 10th criterion according to ACR-82 (‘immunological disorder’). S-ANA was inversely associated with arthritis, ‘immunological disorder’ and signs of organ damage.

    Conclusions H-ANA is the dominant IF-ANA pattern among Swedish patients with SLE, and was found to associate with ‘immunological disorder’ according to ACR-82. The second most common pattern, S-ANA, associated negatively with arthritis and organ damage.

    National Category
    Rheumatology and Autoimmunity
    Identifiers
    urn:nbn:se:liu:diva-91381 (URN)10.1136/bmjopen-2013-003608 (DOI)000326882800019 ()
    Conference
    10th International Congress on SLE- Lupus 2013, 18-21 April 2013, Buenos Aires, Argentina
    Available from: 2013-04-23 Created: 2013-04-23 Last updated: 2023-08-28
    2. Immunoglobulin A anti-phospholipid antibodies in Swedish cases of systemic lupus erythematosus: associations with disease phenotypes, vascular events and damage accrual
    Open this publication in new window or tab >>Immunoglobulin A anti-phospholipid antibodies in Swedish cases of systemic lupus erythematosus: associations with disease phenotypes, vascular events and damage accrual
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    2018 (English)In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 194, no 1, p. 27-38Article in journal (Refereed) Published
    Abstract [en]

    Immunoglobulin (Ig) G- and IgM-class anti-cardiolipin antibodies (aCL) and lupus anti-coagulant (LA) are included in the 1997 update of the American College of Rheumatology (ACR-97) systemic lupus erythematosus (SLE) criteria. Despite limited evidence, IgA-aCL and IgA anti-(2)-glycoprotein-I (anti-(2)GPI) were included in the 2012 Systemic Lupus International Collaborating Clinics criteria. The present study aimed to evaluate IgG-/IgA-/IgM-aCL and anti-(2)GPI occurrence in relation to disease phenotype, smoking habits, pharmacotherapy, anti-phospholipid syndrome (APS) and organ damage among 526 Swedish SLE patients meeting ACR-97. Patients with rheumatoid arthritis (n=100), primary Sjogrens syndrome (n=50) and blood donors (n=507) served as controls. Anti-phospholipid antibodies (aPL) were analysed by fluoroenzyme-immunoassays detecting aCL/anti-(2)GPI. Seventy-six (14%) SLE cases fulfilled the Sydney APS-criteria, and 1 aCL/anti-(2)GPI isotype (IgG/IgA/IgM) occurred in 138 SLE patients (26%). Forty-five (9%) of the SLE cases had IgA-aCL, 20 of whom (4%) lacked IgG-/IgM-aCL. Seventy-four (14%) tested positive for IgA anti-(2)GPI, 34 (6%) being seronegative regarding IgG/IgM anti-(2)GPI. Six (1%) had APS manifestations but were seropositive regarding IgA-aCL and/or IgA anti-(2)GPI in the absence of IgG/IgM-aPL and LA. Positive LA and IgG-aPL tests were associated with most APS-related events and organ damage. Exclusive IgA anti-(2)GPI occurrence associated inversely with Caucasian ethnicity [odds ratio (OR)=021, 95% confidence interval (CI)=006-072) and photosensitivity (OR=019, 95% CI=005-072). Nephritis, smoking, LA-positivity and statin/corticosteroid-medication associated strongly with organ damage, whereas hydroxychloroquine-medication was protective. In conclusion, IgA-aPL is not rare in SLE (16%) and IgA-aPL analysis may have additional value among SLE cases with suspected APS testing negative for other isotypes of aPL and LA.

    Place, publisher, year, edition, pages
    WILEY, 2018
    Keywords
    anti-phospholipid antibodies; anti-phospholipid syndrome; autoantibodies; immunoglobulin A; systemic lupus erythematosus
    National Category
    Gastroenterology and Hepatology
    Identifiers
    urn:nbn:se:liu:diva-151933 (URN)10.1111/cei.13180 (DOI)000445601500004 ()30208508 (PubMedID)
    Note

    Funding Agencies|Swedish Society for Medical Research; Swedish Rheumatism Association; Swedish Society of Medicine; King Gustaf Vs 80-year foundation; King Gustaf V and Queen Victorias Freemasons foundation; Swedish Heart-Lung Foundation; Swedish Research Council; County Council of Stockholm; County Council of Uppsala; County Council of Ostergotland

    Available from: 2018-10-16 Created: 2018-10-16 Last updated: 2021-12-28
    3. Osteopontin is associated with disease severity and antiphospholipid syndrome in well characterised Swedish cases of SLE
    Open this publication in new window or tab >>Osteopontin is associated with disease severity and antiphospholipid syndrome in well characterised Swedish cases of SLE
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    2017 (English)In: Lupus Science and Medicine, E-ISSN 2053-8790, Vol. 4, no 1, p. 7article id 000225Article in journal (Refereed) Published
    Abstract [en]

    Objective The variety of disease phenotypes among patients with SLE challenges the identification of new biomarkers reflecting disease activity and/or organ damage. Osteopontin (OPN) is an extracellular matrix protein with immunomodulating properties. Although raised levels have been reported, the pathogenic implications and clinical utility of OPN as a biomarker in SLE are far from clear. Thus, the aim of this study was to characterise OPN in SLE.

    Methods Sera from 240 well-characterised adult SLE cases classified according to the American College of Rheumatology (ACR) and/or the Systemic Lupus International Collaborating Clinics (SLICC) criteria, and 240 population-based controls were immunoassayed for OPN. The SLE Disease Activity Index 2000 (SLEDAI-2K) was used to evaluate disease activity and the SLICC/ACR Damage Index (SDI) to detect damage accrual.

    Results Serum OPN levels were in average raised fourfold in SLE cases compared with the controls (p<0.0001). OPN correlated with SLEDAI-2K, especially in patients with a disease duration of <12 months (r=0.666, p=0.028). OPN was highly associated with SDI (p<0.0001), especially in the renal (p<0.0001), cardiovascular (p<0.0001) and malignancy (p=0.012) domains. Finally, OPN associated with coherent antiphospholipid syndrome (APS; p=0.009), and both clinical and laboratory criteria of APS had significant positive impact on OPN levels.

    Conclusions In this cross-sectional study, circulating OPN correlates with disease activity in recent-onset SLE, reflects global organ damage and associates with APS. Longitudinal studies to dissect whether serum OPN also precedes and predicts future organ damage are most warranted.

    Place, publisher, year, edition, pages
    BMJ Publishing Group Ltd, 2017. p. 7
    National Category
    Rheumatology and Autoimmunity Neurology Clinical Laboratory Medicine Cardiac and Cardiovascular Systems Gastroenterology and Hepatology
    Identifiers
    urn:nbn:se:liu:diva-140711 (URN)10.1136/lupus-2017-000225 (DOI)
    Available from: 2017-09-08 Created: 2017-09-08 Last updated: 2023-02-21Bibliographically approved
    4. The majority of Swedish systemic lupus erythematosus patients are still affected by irreversible organ impairment: factors related to damage accrual in two regional cohorts
    Open this publication in new window or tab >>The majority of Swedish systemic lupus erythematosus patients are still affected by irreversible organ impairment: factors related to damage accrual in two regional cohorts
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    2019 (English)In: Lupus, ISSN 0961-2033, E-ISSN 1477-0962, Vol. 28, no 10, p. 1261-1272Article in journal (Refereed) Published
    Abstract [en]

    Background Although the survival of patients with systemic lupus erythematosus (SLE) has improved, irreversible organ damage remains a critical concern. We aimed to characterize damage accrual and its clinical associations and causes of death in Swedish patients. Methods Accumulation of damage was evaluated in 543 consecutively recruited and well-characterized cases during 1998-2017. The Systemic Lupus International Collaborating Clinics (SLICC)/American College of Rheumatology damage index (SDI) was used to estimate damage. Results Organ damage (SDI amp;gt;= 1) was observed in 59%, and extensive damage (SDI amp;gt;= 3) in 25% of cases. SDI amp;gt;= 1 was significantly associated with higher age at onset, SLE duration, the number of fulfilled SLICC criteria, neurologic disorder, antiphospholipid antibody syndrome (APS), hypertension, hyperlipidemia, depression and secondary Sjogrens syndrome (SS). In addition, SDI amp;gt;= 3 was associated with serositis, renal and haematological disorders and interstitial lung disease. A multiple regression model identified not only well-known risk factors like APS, antihypertensives and corticosteroids, but pericarditis, haemolytic anaemia, lymphopenia and myositis as being linked to SDI. Malignancy, infection and cardiovascular disease were the leading causes of death. Conclusions After a mean SLE duration of 17 years, the majority of todays Swedish SLE patients have accrued damage. We confirm previous observations and report some novel findings regarding disease phenotypes and damage accrual.

    Place, publisher, year, edition, pages
    SAGE PUBLICATIONS LTD, 2019
    Keywords
    Damage accrual; immunosuppressants; mortality; SLE phenotypes; Sweden; systemic lupus erythematosus
    National Category
    Rheumatology and Autoimmunity
    Identifiers
    urn:nbn:se:liu:diva-159259 (URN)10.1177/0961203319860198 (DOI)000477186800001 ()31296137 (PubMedID)
    Note

    Funding Agencies|Swedish Rheumatism Association; County Council of Ostergotland; Swedish Society of Medicine; King Gustaf Vs 80-year Anniversary foundation; King Gustaf V and Queen Victorias Freemasons foundation; Ingegerd Johansson donation; Selander foundation; County Council of Uppsala

    Available from: 2019-08-06 Created: 2019-08-06 Last updated: 2020-04-22
    5. Longitudinal anti-nuclear antibody (ANA) seroconversion in systemic lupus erythematosus: a prospective study of Swedish cases with recent-onset disease
    Open this publication in new window or tab >>Longitudinal anti-nuclear antibody (ANA) seroconversion in systemic lupus erythematosus: a prospective study of Swedish cases with recent-onset disease
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    2020 (English)In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 199, no 3, p. 245-254Article in journal (Refereed) Published
    Abstract [en]

    Serum immunoglobulin (Ig)G anti-nuclear antibodies (ANA) detected by indirect immunofluorescence (IF) microscopy remains a hallmark of systemic lupus erythematosus (SLE). Whether or not IF-ANA status varies over time is controversial. We therefore designed a prospective study with longitudinal follow-up of patients with recent-onset SLE. The study population consisted of 54 recently diagnosed SLE cases, all meeting the 1982 American College of Rheumatology (ACR) and/or the 2012 Systemic Lupus International Collaborating Clinics (SLICC) criteria. Clinical follow-up data, including disease activity, organ damage and sera, were collected from clinical onset of SLE and onwards, in most cases yearly (0-96 months). IF-ANA was analysed on human epithelial cells-2 (HEp-2) cells and categorized regarding staining patterns. Using an addressable laser bead assay (FIDIS (TM) Connective profile), we measured IgG-ANA fine specificities against Ro52/SSA, Ro60/SSA, Sjogrens syndrome type B antigen (La/SSB), Smith antigen (Sm), Smith antigen/ribonucleoprotein (Sm/RNP), U1 RNP (U1RNP), dsDNA, ribosomal-P protein and histone. At baseline, all patients were judged ANA-positive at an abnormal titre corresponding to the 95th percentile of healthy blood donors, but seven of 54 patients (13%) lost ANA-positivity over time. Homogeneous (AC-1; 46%) and speckled (AC-4 or 5; 31%) were the most frequently observed patterns at inclusion, whereas 7% switched pattern at least once during follow-up. Established associations between ANA fine specificities and clinical data were confirmed. Levels of anti-Sm/RNP, but not of anti-dsDNA, correlated with clinical disease activity [modified SLE disease activity 2000 (mSLEDAI-2K)]. Our data indicate that a considerable proportion of Swedish patients with SLE lose ANA-positivity over time, whereas consistent staining patterns were frequent. The clinical and mechanistic relevance of ANA seroconversion remains uncertain. Further prospective evaluations in larger SLE populations with more diverse ethnicities are warranted.

    Place, publisher, year, edition, pages
    Wiley-Blackwell Publishing Inc., 2020
    Keywords
    autoantibodies; autoimmunity; complement; human; systemic lupus erythematosus
    National Category
    Gastroenterology and Hepatology
    Identifiers
    urn:nbn:se:liu:diva-164196 (URN)10.1111/cei.13402 (DOI)000513952100007 ()31778219 (PubMedID)2-s2.0-85076720021 (Scopus ID)
    Note

    Funding Agencies|the Swedish Society of Medicine; Swedish Society of Medicine; the County Council of Ostergotland; Swedish Rheumatism Association; the Swedish Rheumatism Association; the King Gustaf V and Queen Victorias Freemasons foundation; the King Gustaf Vs 80-year Anniversary foundation

    Available from: 2020-03-11 Created: 2020-03-11 Last updated: 2021-05-05Bibliographically approved
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  • 33.
    Frodlund, Martina
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Medicine Center, Department of Rheumatology.
    Jonsen, Andreas
    Lund Univ, Sweden.
    Remkus, Lauren
    AstraZeneca AS, Denmark.
    Telg, Gunilla
    AstraZeneca Nord, Sweden.
    Soderdahl, Fabian
    Statisticon AB, Sweden.
    Leonard, Dag
    Uppsala Univ, Sweden.
    Glucocorticoid treatment in SLE is associated with infections, comorbidities and mortality-a national cohort study2023In: Rheumatology, ISSN 1462-0324, E-ISSN 1462-0332Article in journal (Refereed)
    Abstract [en]

    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 &gt;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, &gt;0 to &lt;5.0 mg/day, 5.0-7.5 mg/day as well as &gt;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 &lt; 0.05). OCS &gt;0 to &lt;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.

  • 34.
    Frodlund, Martina
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Medicine Center, Department of Rheumatology.
    Nived, Per
    Lund Univ, Sweden; Skane Univ Hosp, Sweden.
    Chatzidionysiou, Aikaterini
    Karolinska Univ Hosp, Sweden.
    Sodergren, Anna
    Umed Univ, Sweden.
    Klingberg, Eva
    Univ Gothenburg, Sweden.
    Bengtsson, Anders
    Lund Univ, Sweden; Skane Univ Hosp, Sweden.
    Hansson, Monika
    Karolinska Univ Hosp, Sweden.
    Olsson, Sophie
    Skane Univ Hosp, Sweden; Lund Univ, Sweden.
    Pin, Elisa
    KTH Royal Inst Technol, Sweden.
    Klareskog, Lars
    Karolinska Univ Hosp, Sweden.
    Kapetanovic, Meliha C.
    Lund Univ, Sweden; Skane Univ Hosp, Sweden.
    The impact of immunomodulating treatment on the immunogenicity of COVID-19 vaccines in patients with immune-mediated inflammatory rheumatic diseases compared to healthy controls. A Swedish nationwide study (COVID19-REUMA)2023In: Vaccine, ISSN 0264-410X, E-ISSN 1873-2518, Vol. 41, no 20, p. 3247-3257Article in journal (Refereed)
    Abstract [en]

    Objectives: To elucidate antibody responses after the second and third dose of COVID-19 vaccine in patients with inflammatory rheumatic diseases (IRD) treated with biologic/targeted disease modifying anti-rheumatic drugs (b/ts DMARDs).Methods: Antibody levels to antigens representing spike full length protein and spike S1 were measured before vaccination, 2-12 weeks after the second dose, before and after the third dose using multiplex bead-based serology assay. Positive antibody response was defined as antibody levels over cut off (seropositivity) in seronegative individuals or &gt;= 4-fold increase in antibodies in individuals seropositive for both spike proteins.Results: Patients (n = 414) receiving b/ts DMARDs (283 had arthritis, 75 systemic vasculitis and 56 other autoimmune diseases) and controls (n = 61) from five Swedish regions participated. Treatments groups were: rituximab (n = 145); abatacept (n = 22); Interleukin 6 receptor inhibitors [IL6i (n = 79)]; JAnus Kinase Inhibitors [JAKi (n = 58)], Tumour Necrosis Factor inhibitor [TNFi (n = 68)] and Interleukin12/23/17 inhibitors [IL12/23/17i (n = 42)]. Percentage of patients with positive antibody response after two doses was significantly lower in rituximab (33,8%) and abatacept (40,9%) (p &lt; 0,001) but not in IL12/23/17i, TNFi or JAKi groups compared to controls (80,3%). Higher age, ritux-imab treatment and shorter time between last rituximab course and vaccination predicted impaired anti-body response. Antibody levels collected 21-40 weeks after second dose decreased significantly (IL6i: p = 0,02; other groups: p &lt; 0,001) compared to levels at 2-12 week but most participants remained seropositive. Proportion of patients with positive antibody response increased after third dose but was still significantly lower in rituximab (p &lt; 0,001).Conclusions: Older individuals and patients on maintenance rituximab have an impaired response after two doses of COVID-19 vaccine which improves if the time between last rituximab course and vaccina-tion extends and also after an additional vaccine dose. Rituximab patients should be prioritized for (2023) booster vaccine doses. TNFi, JAKi and IL12/23/17i does not diminished humoral response to primary and an additional vaccination.(c) 2023 The Authors. Published by Elsevier Ltd.

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  • 35.
    Frodlund, Martina
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Medicine Center, Department of Rheumatology.
    Walhelm, Tomas
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Medicine Center, Department of Rheumatology.
    Dahle, Charlotte
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
    Sjöwall, Christopher
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Medicine Center, Department of Rheumatology.
    Longitudinal Analysis of Anti-cardiolipin and Anti-beta 2-glycoprotein-I Antibodies in Recent-Onset Systemic Lupus Erythematosus: A Prospective Study in Swedish Patients2021In: Frontiers in Medicine, E-ISSN 2296-858X, Vol. 8, article id 646846Article in journal (Refereed)
    Abstract [en]

    Background: Anti-phospholipid syndrome (APS) and systemic lupus erythematous (SLE) are autoimmune disorders that often co-occur. Anti-phospholipid antibodies (aPL) are typical of both conditions and may be associated with vascular events and pregnancy-related morbidities. Whereas, aPL-screening is mandatory for individuals with suspected SLE, the clinical value of longitudinal aPL analyses in established SLE is unclear. Methods: We investigated the occurrence and variation of IgG/IgA/IgM anti-cardiolipin (aCL) and anti-beta 2-glycoprotein-I (anti-beta 2GPI) antibodies, using both the manufacturers cut-off and a cut-off based on the 99th percentile of 400 apparently healthy donors, in recent-onset SLE. Furthermore, we evaluated the relationships between aPL levels and SLE/APS manifestations, as well as the pharmacotherapy. Patients with SLE who met validated classification criteria were included in this prospective study (N = 54). Samples were obtained at 0, 6, 12, 24, 36, 48, 60, 72, 84, and 96 months after SLE diagnosis. Results: Depending on the cut-off applied, 61.1 or 44.4% showed a positive result for at least one aPL isotype or the lupus anticoagulant test over time. Median values for all six aPL isotypes numerically decreased from inclusion to last follow-up, but none of the isotypes met statistical significance. Seroconversion (from positive to negative, or the opposite direction) was occasionally seen for both aCL and anti-beta 2GPI. IgA and IgM anti-beta 2GPI were the most common isotypes, followed by IgM aCL. Presence of IgG aCL associated significantly with myocardial infarction and miscarriage, and IgG/IgA anti-beta 2GPI with miscarriage. Conclusion: aPL were common during the first years of SLE. Even though the levels fluctuated over time, the patients tended to remain aPL positive or negative. Repeated aPL testing in the absence of new symptoms seems to be of uncertain value in patients with recent-onset SLE.

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  • 36.
    Frodlund, Martina
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Medicine Center, Department of Rheumatology.
    Wetterö, Jonas
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences.
    Dahle, Charlotte
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
    Dahlström, Örjan
    Linköping University, Department of Behavioural Sciences and Learning, Psychology. Linköping University, Faculty of Arts and Sciences. Linköping University, The Swedish Institute for Disability Research.
    Skogh, Thomas
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Medicine Center, Department of Rheumatology.
    Ronnelid, J.
    Uppsala Univ, Sweden.
    Sjöwall, Christopher
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Medicine Center, Department of Rheumatology.
    Longitudinal anti-nuclear antibody (ANA) seroconversion in systemic lupus erythematosus: a prospective study of Swedish cases with recent-onset disease2020In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 199, no 3, p. 245-254Article in journal (Refereed)
    Abstract [en]

    Serum immunoglobulin (Ig)G anti-nuclear antibodies (ANA) detected by indirect immunofluorescence (IF) microscopy remains a hallmark of systemic lupus erythematosus (SLE). Whether or not IF-ANA status varies over time is controversial. We therefore designed a prospective study with longitudinal follow-up of patients with recent-onset SLE. The study population consisted of 54 recently diagnosed SLE cases, all meeting the 1982 American College of Rheumatology (ACR) and/or the 2012 Systemic Lupus International Collaborating Clinics (SLICC) criteria. Clinical follow-up data, including disease activity, organ damage and sera, were collected from clinical onset of SLE and onwards, in most cases yearly (0-96 months). IF-ANA was analysed on human epithelial cells-2 (HEp-2) cells and categorized regarding staining patterns. Using an addressable laser bead assay (FIDIS (TM) Connective profile), we measured IgG-ANA fine specificities against Ro52/SSA, Ro60/SSA, Sjogrens syndrome type B antigen (La/SSB), Smith antigen (Sm), Smith antigen/ribonucleoprotein (Sm/RNP), U1 RNP (U1RNP), dsDNA, ribosomal-P protein and histone. At baseline, all patients were judged ANA-positive at an abnormal titre corresponding to the 95th percentile of healthy blood donors, but seven of 54 patients (13%) lost ANA-positivity over time. Homogeneous (AC-1; 46%) and speckled (AC-4 or 5; 31%) were the most frequently observed patterns at inclusion, whereas 7% switched pattern at least once during follow-up. Established associations between ANA fine specificities and clinical data were confirmed. Levels of anti-Sm/RNP, but not of anti-dsDNA, correlated with clinical disease activity [modified SLE disease activity 2000 (mSLEDAI-2K)]. Our data indicate that a considerable proportion of Swedish patients with SLE lose ANA-positivity over time, whereas consistent staining patterns were frequent. The clinical and mechanistic relevance of ANA seroconversion remains uncertain. Further prospective evaluations in larger SLE populations with more diverse ethnicities are warranted.

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  • 37.
    Ge, Changrong
    et al.
    Karolinska Inst, Sweden.
    Tong, Dongmei
    Karolinska Inst, Sweden.
    Lönnblom, Erik
    Karolinska Inst, Sweden.
    Liang, Bibo
    Karolinska Inst, Sweden; Southern Med Univ, Peoples R China.
    Cai, Weiwei
    Karolinska Inst, Sweden.
    Fahlquist-Hagert, Cecilia
    Karolinska Inst, Sweden; Univ Turku, Finland.
    Li, Taotao
    Karolinska Inst, Sweden.
    Kastbom, Alf
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Medicine Center, Department of Rheumatology.
    Gjertsson, Inger
    Univ Gothenburg, Sweden.
    Dobritzsch, Doreen
    Uppsala Univ, Sweden.
    Holmdahl, Rikard
    Karolinska Inst, Sweden; Southern Med Univ, Peoples R China.
    Antibodies to Cartilage Oligomeric Matrix Protein Are Pathogenic in Mice and May Be Clinically Relevant in Rheumatoid Arthritis2022In: Arthritis & Rheumatology, ISSN 2326-5191, E-ISSN 2326-5205, Vol. 74, no 6, p. 961-971Article in journal (Refereed)
    Abstract [en]

    Objective Cartilage oligomeric matrix protein (COMP) is an autoantigen in rheumatoid arthritis (RA) and experimental models of arthritis. This study was undertaken to investigate the structure, function, and relevance of anti-COMP antibodies. Methods We investigated the pathogenicity of monoclonal anti-COMP antibodies in mice using passive transfer experiments, and we explored the interaction of anti-COMP antibodies with cartilage using immunohistochemical staining. The interaction of the monoclonal antibody 15A11 in complex with its specific COMP epitope P6 was determined by x-ray crystallography. An enzyme-linked immunosorbent assay and a surface plasma resonance technique were used to study the modulation of calcium ion binding to 15A11. The clinical relevance and value of serum IgG specific to the COMP P6 epitope and its citrullinated variants were evaluated in a large Swedish cohort of RA patients. Results The murine monoclonal anti-COMP antibody 15A11 induced arthritis in naive mice. The crystal structure of the 15A11-P6 complex explained how the antibody could bind to COMP, which can be modulated by calcium ions. Moreover, serum IgG specific to the COMP P6 peptide and its citrullinated variants was detectable at significantly higher levels in RA patients compared to healthy controls and correlated with a higher disease activity score. Conclusion Our findings provide the structural basis for binding a pathogenic anti-COMP antibody to cartilage. The recognized epitope can be citrullinated, and levels of antibodies to this epitope are elevated in RA patients and correlate with higher disease activity, implicating a pathogenic role of anti-COMP antibodies in a subset of RA patients.

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  • 38.
    Geijer, Mats
    et al.
    Univ Gothenburg, Sweden; Sahlgrens Univ Hosp, Sweden; Lund Univ, Sweden.
    Alenius, Gerd-Marie
    Umea Univ, Sweden; Helsinborgs Lasarett, Sweden.
    Andre, Lars
    Helsinborgs Lasarett, Sweden.
    Husmark, Tomas
    Falun Cent Hosp, Sweden.
    Larsson, Per T.
    Karolinska Univ Hosp Huddinge, Sweden.
    Lindqvist, Ulla
    Uppsala Univ, Sweden.
    Thyberg, Ingrid
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Medicine Center, Department of Rheumatology.
    Theander, Elke
    Skane Univ Hosp, Sweden; Lund Univ, Sweden.
    Health-related quality of life in early psoriatic arthritis compared with early rheumatoid arthritis and a general population2021In: Seminars in Arthritis & Rheumatism, ISSN 0049-0172, E-ISSN 1532-866X, Vol. 51, no 1, p. 246-252Article in journal (Refereed)
    Abstract [en]

    Objective: Both psoriatic arthritis (PsA) and rheumatoid arthritis (RA) have a significant impact on quality of life, but few reports have compared the two diseases. The current study assessed health-related quality of life (HRQoL) in PsA at diagnosis and after five years compared with early rheumatoid arthritis (RA) and a matched general population. Methods: Patients with early PsA and early RA included in two Swedish registries with HRQoL data measured by the Medical Outcomes Study Short Form 36 (SF-36) at baseline and at five years follow-up were included. Differences in SF-36 scores compared with the general population were calculated for each patient. Physical function, disease activity, the delay before diagnosis, pain, and general wellbeing were used as explanatory variables. Statistical tests included t-tests and univariate and multivariate linear regression. Results: PsA (n = 166) and RA (n = 133) patients of both sexes had significantly reduced HRQoL at disease onset. After five years, PsA patients still had impairments in several domains of SF-36, whereas RA patients had an almost normalized HRQoL. The time from symptom onset to diagnosis, disease activity, and disability independently contributed to the reduced improvement in PsA. Conclusion: Both early PsA and RA are characterized by severely reduced HRQoL. Despite more severe disease at inclusion, normalization of HRQoL is seen in patients with RA but not PsA. This may be due to delay in the diagnosis of PsA or more powerful interventions in RA. Earlier detection, lifestyle intervention, and more aggressive management strategies may be needed for PsA. (C) 2020 Elsevier Inc. All rights reserved.

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  • 39.
    Gomez, Alvaro
    et al.
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Jagerback, Sandra
    Karolinska Inst, Sweden; Danderyd Hosp, Sweden.
    Sjöwall, Christopher
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Medicine Center, Department of Rheumatology.
    Parodis, Ioannis
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden; Orebro Univ, Sweden.
    Belimumab and antimalarials combined against renal flares in patients treated for extra-renal systemic lupus erythematosus: results from 4 phase III clinical trials2023In: Rheumatology, ISSN 1462-0324, E-ISSN 1462-0332Article in journal (Refereed)
    Abstract [en]

    Objectives To determine the effect of antimalarial agents (AMA) and different doses and pharmaceutical forms of belimumab on preventing renal flares in patients with SLE treated for extra-renal disease. Methods We pooled data from the BLISS-52, BLISS-76, BLISS-SC and BLISS-Northeast Asia trials of belimumab (n = 3225), that included patients with active SLE yet no severe ongoing nephritis. Participants were allocated to receive intravenous belimumab 1 mg/kg, intravenous belimumab 10 mg/kg, subcutaneous belimumab 200 mg, or placebo in addition to standard therapy. We estimated hazards of renal flare development throughout the study follow-up (52-76 weeks) using Cox regression analysis. Results In total, 192 patients developed a renal flare after a median of 197 days. Compared with placebo, the risk of renal flares was lower among patients receiving intravenous belimumab 10 mg/kg (HR: 0.62; 95% CI: 0.41, 0.92; P = 0.018) and intravenous belimumab 1 mg/kg (HR: 0.42; 95% CI: 0.22, 0.79; P = 0.007), while no significant association was found for subcutaneous belimumab 200 mg. AMA use yielded a lower hazard of renal flares (HR: 0.66; 95% CI: 0.55, 0.78; P &lt; 0.001). The protection conferred was enhanced when belimumab and AMA were co-administered; the lowest flare rate was observed for the combination intravenous belimumab 1 mg/kg and AMA (18.5 cases per 1000 person-years). Conclusions The protection conferred from belimumab against renal flare development in patients treated for extra-renal SLE appears enhanced when belimumab was administered along with AMA. The prominent effect of low-dose belimumab warrants investigation of the efficacy of intermediate belimumab doses.

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  • 40.
    Gronwall, Caroline
    et al.
    Karolinska Inst, Sweden.
    Liljefors, Lisa
    Karolinska Inst, Sweden.
    Bang, Holger
    ORGENTEC Diagnost GmbH, Germany.
    Hensvold, Aase H.
    Karolinska Inst, Sweden; Stockholm Hlth Reg, Sweden; Karolinska Univ Hosp, Sweden.
    Hansson, Monika
    Karolinska Inst, Sweden.
    Mathsson-Alm, Linda
    Thermo Fisher Sci, Sweden; Uppsala Univ, Sweden.
    Israelsson, Lena
    Karolinska Inst, Sweden.
    Joshua, Vijay
    Karolinska Inst, Sweden.
    Svärd, Anna
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Uppsala Univ, Sweden.
    Stalesen, Ragnhild
    Karolinska Inst, Sweden.
    Titcombe, Philip J.
    Karolinska Inst, Sweden; Univ Minnesota, MN 55455 USA; Univ Minnesota, MN 55455 USA.
    Steen, Johanna
    Karolinska Inst, Sweden.
    Piccoli, Luca
    Univ Svizzera Italiana, Switzerland.
    Sherina, Natalia
    Karolinska Inst, Sweden.
    Clavel, Cyril
    Univ Toulouse, France.
    Svenungsson, Elisabet
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Gunnarsson, Iva
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Saevarsdottir, Saedis
    Karolinska Inst, Sweden; Univ Iceland, Iceland.
    Kastbom, Alf
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Medicine Center, Department of Rheumatology.
    Serre, Guy
    Univ Toulouse, France.
    Alfredsson, Lars
    Karolinska Inst, Sweden; Stockholm Hlth Reg, Sweden.
    Malmstrom, Vivianne
    Karolinska Inst, Sweden.
    Ronnelid, Johan
    Uppsala Univ, Sweden.
    Catrina, Anca I.
    Karolinska Inst, Sweden; Stockholm Hlth Reg, Sweden; Karolinska Univ Hosp, Sweden.
    Lundberg, Karin
    Karolinska Inst, Sweden.
    Klareskog, Lars
    Karolinska Inst, Sweden; Stockholm Hlth Reg, Sweden; Karolinska Univ Hosp, Sweden.
    A Comprehensive Evaluation of the Relationship Between Different IgG and IgA Anti-Modified Protein Autoantibodies in Rheumatoid Arthritis2021In: Frontiers in Immunology, E-ISSN 1664-3224, Vol. 12, article id 627986Article in journal (Refereed)
    Abstract [en]

    Seropositive rheumatoid arthritis (RA) is characterized by the presence of rheumatoid factor (RF) and anti-citrullinated protein autoantibodies (ACPA) with different fine-specificities. Yet, other serum anti-modified protein autoantibodies (AMPA), e.g. anti-carbamylated (Carb), -acetylated (KAc), and malondialdehyde acetaldehyde (MAA) modified protein antibodies, have been described. In this comprehensive study, we analyze 30 different IgG and IgA AMPA reactivities to Cit, Carb, KAc, and MAA antigens detected by ELISA and autoantigen arrays in N=1985 newly diagnosed RA patients. Association with patient characteristics such as smoking and disease activity were explored. Carb and KAc reactivities by different assays were primarily seen in patients also positive for anti-citrulline reactivity. Modified vimentin (mod-Vim) peptides were used for direct comparison of different AMPA reactivities, revealing that IgA AMPA recognizing mod-Vim was mainly detected in subsets of patients with high IgG anti-Cit-Vim levels and a history of smoking. IgG reactivity to acetylation was mainly detected in a subset of patients with Cit and Carb reactivity. Anti-acetylated histone reactivity was RA-specific and associated with high anti-CCP2 IgG levels, multiple ACPA fine-specificities, and smoking status. This reactivity was also found to be present in CCP2+ RA-risk individuals without arthritis. Our data further demonstrate that IgG autoreactivity to MAA was increased in RA compared to controls with highest levels in CCP2+ RA, but was not RA-specific, and showed low correlation with other AMPA. Anti-MAA was instead associated with disease activity and was not significantly increased in CCP2+ individuals at risk of RA. Notably, RA patients could be subdivided into four different subsets based on their AMPA IgG and IgA reactivity profiles. Our serology results were complemented by screening of monoclonal antibodies derived from single B cells from RA patients for the same antigens as the RA cohort. Certain CCP2+ clones had Carb or Carb+KAc+ multireactivity, while such reactivities were not found in CCP2- clones. We conclude that autoantibodies exhibiting different patterns of ACPA fine-specificities as well as Carb and KAc reactivity are present in RA and may be derived from multireactive B-cell clones. Carb and KAc could be considered reactivities within the "Cit-umbrella" similar to ACPA fine-specificities, while MAA reactivity is distinctly different.

  • 41.
    Gutefeldt, Kerstin
    et al.
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Medicine Center, Department of Endocrinology.
    Hedman, Christina
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Medicine Center, Department of Endocrinology.
    Thyberg, Ingrid
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Medicine Center, Department of Rheumatology.
    Bachrack Lindström, Margareta
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Nursing Sciences and Reproductive Health. Linköping University, Faculty of Medicine and Health Sciences.
    Arnqvist, Hans
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Medicine Center, Department of Endocrinology.
    Spångeus, Anna
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Acute Internal Medicine and Geriatrics.
    Low health-related quality of life is strongly linked to upper extremity impairments in type 1 diabetes with a long duration2021In: Disability and Rehabilitation, ISSN 0963-8288, E-ISSN 1464-5165, Vol. 43, no 18, p. 2578-2584Article in journal (Refereed)
    Abstract [en]

    Purpose: To compare health-related quality of life (HRQOL) in type 1 diabetes and non-diabetic controls and possible links to upper extremity impairments (UEIs). Prevalence of sick-leave and causes were investigated.

    Materials and methods: This Swedish population-based case-control study included type 1 diabetes patients <67 years old and with a diabetes duration ≥20 years. Participants completed a postal questionnaire including Short Form 36, and questions regarding UEIs, and sick-leave.

    Results: In total, 773 patients, aged 50 ± 10 years (diabetes duration 35 ± 10 years), and 708 non-diabetic controls, aged 54 ± 9 years, completed the study. Patients reported significantly lower HRQOL compared with controls. The difference was greatest for general health, vitality, and bodily pain. Patients with shoulder or hand but not finger impairments scored significantly lower than asymptomatic patients. The prevalence of sick leave was higher in patients vs. controls (23% vs. 9%, p < 0.001), and nearly half cited impairments from back, muscles, or joints as the main reason.

    Conclusions: Health-related quality of life is lower in type 1 diabetes than controls and in patients with shoulder and hand impairments than in asymptomatic. Musculoskeletal impairments (back/muscle/joints) have impact on work ability. Identification of UEIs is important for initiating preventative-, therapeutic-, and rehabilitative interventions.

    Implications for rehabilitation

    • Upper extremity impairments (UEIs) that are common in type 1 diabetes, and associated with reduced health-related quality of life, should preferably be screened for on a regular basis along with other known diabetes complications.

    • Early identification of UEIs is important to improve health by initiating preventive as well as therapeutic multi-professional rehabilitative interventions.

    • Sick leave is higher in type 1 diabetes than in controls. Musculoskeletal impairments, including the back, muscles, and joints, are a common cause for sick leave warranting further studies.

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  • 42.
    Gutefeldt, Kerstin
    et al.
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Medicine Center, Department of Endocrinology.
    Lundstedt, Simon
    Linköping University, Department of Health, Medicine and Caring Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Thyberg, Ingrid
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Medicine Center, Department of Rheumatology.
    Bachrach-Lindström, Margareta
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Nursing Sciences and Reproductive Health. Linköping University, Faculty of Medicine and Health Sciences.
    Arnqvist, Hans
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Medicine Center, Department of Endocrinology.
    Spångeus, Anna
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Acute Internal Medicine and Geriatrics.
    Clinical Examination and Self-Reported Upper Extremity Impairments in Patients with Long-Standing Type 1 Diabetes Mellitus2020In: Journal of Diabetes Research, ISSN 2314-6745, E-ISSN 2314-6753, Journal of Diabetes Research, Vol. 2020, article id 4172635Article in journal (Refereed)
    Abstract [en]

    Aim. The aims of the current study were (1) to determine the prevalence of upper extremity impairments (UEIs) in patients with type 1 diabetes by clinical investigation; (2) to investigate if self-reported impairments were concordant with clinical findings and if key questions could be identified; and (3) to investigate if answers to our self-reported questionnaire regarding UEIs are reliable. Methods. Patients with type 1 diabetes were invited to participate in a cross-sectional study of clinical and self-reported (12 items) UEIs in adjunction to ordinary scheduled clinical visit. Before the visit, a questionnaire on UEIs was filled in twice (test-retest) followed by clinical testing at the planned visit. Results. In total, 69 patients aged and with diabetes duration were included in the study. In the clinical examination, two-thirds (65%) of the patients showed one or more UEI, with failure to perform hand against back as the most common clinical finding (40%) followed by positive Phalen’s test (27%), Tinel’s test (26%), and Prayer’s sign (24%). UEIs observed by clinical examination were often bilateral, and multiple impairments often coexisted. Self-reported shoulder stiffness was associated with impaired shoulder mobility and with Prayer’s sign. Self-reported reduced hand strength was associated to lower grip force, Prayer’s sign, trigger finger, fibrosis string structures, and reduced thenar strength as well as reduced shoulder mobility. In addition, self-reporting previous surgery of carpal tunnel and trigger finger was associated with several clinical UEIs including shoulder, hand, and finger. The test-retest of the questionnaire showed a high agreement of 80-98% for reported shoulder, hand, and finger impairments. Conclusion. UEIs are common in type 1 diabetes. Self-reported shoulder stiffness and reduced hand strength might be used to capture patients with UEIs in need of clinical investigation and enhanced preventive and therapeutic strategies, as well as rehabilitative interventions.

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  • 43.
    Hammer, Hilde Berner
    et al.
    Diakonhjemmet Hosp, Norway; Univ Oslo, Norway.
    Hansen, Inger Marie Jensen
    Svendborg Sygehus, Denmark.
    Järvinen, Pentti
    Kiljava Med Res, Finland.
    Leirisalo-Repo, Marjatta
    Univ Helsinki, Finland.
    Ziegelasch, Michael
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Medicine Center, Department of Rheumatology.
    Agular, Birte
    Roche, Denmark.
    Terslev, Lene
    Rigshosp Glostrup, Denmark.
    Rheumatoid arthritis patients with predominantly tender joints rarely achieve clinical remission despite being in ultrasound remission2021In: Rheumatology: Advances in Practice, E-ISSN 2514-1775, Vol. 5, no 2, article id rkab030Article in journal (Refereed)
    Abstract [en]

    Objectives. Given that subjective variables might reduce remission by composite DAS (CDAS), the main objectives were to explore whether RA patients with mainly tender vs mainly swollen joints had differences in patient-reported outcome measures (PROMs), clinical or US assessments or in achieving remission defined by CDAS or US. Methods. In a Nordic multicentre study, RA patients initiating tocilizumab were assessed by PROMs, clinical, laboratory and US assessments (36 joints and 4 tendons) at baseline, 4, 12 and 24 weeks. Remission was defined according to clinical disease activity index (CDAI)/Boolean or no Doppler activity present. Tender-swollen joint differences (TSJDs) were calculated. Statistics exploring changes over time/differences between groups included Wilcoxon, Mann-Whitney, Kruskal-Wallis and Spearman tests. Results. One hundred and ten patients were included [mean (S.D.) age 55.6 (12.1) years, RA duration 8.7 (9.5) years]. All PROMs, clinical, laboratory and US scores decreased during follow-up (P &lt; 0.001). During follow-up, tender joint counts were correlated primarily with PROMs [r = 0.24-0.56 (P &lt; 0.05-0.001)] and swollen joint counts with US synovitis scores [r = 0.33-0.72 (P &lt; 0.05-0.001)]. At 24 weeks, patients with TSJD &gt; 0 had higher PROMs and CDAI (P &lt; 0.05-0.001) but lower US synovitis scores (P &lt; 0.05). Remission by CDAI/Boolean was seen in 26-34% and by Doppler 53%, but only 2-3% of patients with TSJD &gt; 0 achieved CDAI/Boolean remission. Conclusion. Patients with more tender than swollen joints scored higher on subjective assessments but had less US synovitis. They seldom achieved CDAS remission despite many being in Doppler remission. If patients with predominantly tender joints do not reach CDAS remission, objective assessments of inflammation should be performed.

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  • 44.
    Hedenstedt, Anna
    et al.
    Uppsala Univ, Sweden.
    Reid, Sarah
    Uppsala Univ, Sweden.
    Sayadi, Ahmed
    Uppsala Univ, Sweden.
    Eloranta, Maija-Leena
    Uppsala Univ, Sweden.
    Skoglund, Elisabeth
    Uppsala Univ, Sweden.
    Bolin, Karin
    Uppsala Univ, Sweden.
    Frodlund, Martina
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Medicine Center, Department of Rheumatology.
    Lerang, Karoline
    Oslo Univ Hosp, Norway.
    Joensen, Andreas
    Lund Univ, Sweden.
    Rantapaeae-Dahlqvist, Solbritt
    Umea Univ, Sweden.
    Bengtsson, Anders A.
    Lund Univ, Sweden.
    Rudin, Anna
    Univ Gothenburg, Sweden.
    Molberg, Oyvind
    Oslo Univ Hosp, Norway.
    Sjöwall, Christopher
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Medicine Center, Department of Rheumatology.
    Sandling, Johanna K.
    Uppsala Univ, Sweden.
    Leonard, Dag
    Uppsala Univ, Sweden.
    B cell polygenic risk scores associate with anti-dsDNA antibodies and nephritis in systemic lupus erythematosus2023In: Lupus Science and Medicine, E-ISSN 2053-8790, Vol. 10, no 2, article id e000926Article in journal (Refereed)
    Abstract [en]

    ObjectiveB 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.MethodsFemale patients with SLE (n=1248) and healthy controls (n=400) were genotyped using Illuminas 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.ResultsDouble-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).ConclusionsHigh 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.

  • 45.
    Heijke, Rebecca
    et al.
    Reg Jönköping Cty, Sweden.
    Ahmad, Awais
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
    Frodlund, Martina
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Medicine Center, Department of Rheumatology.
    Wirestam, Lina
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences.
    Dahlström, Örjan
    Linköping University, Department of Behavioural Sciences and Learning, Psychology. Linköping University, Faculty of Arts and Sciences.
    Dahle, Charlotte
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
    Kechagias, Stergios
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Mag- tarmmedicinska kliniken.
    Sjöwall, Christopher
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Medicine Center, Department of Rheumatology.
    Usefulness of Clinical and Laboratory Criteria for Diagnosing Autoimmune Liver Disease among Patients with Systemic Lupus Erythematosus: An Observational Study2021In: Journal of Clinical Medicine, E-ISSN 2077-0383, Vol. 10, no 17, article id 3820Article in journal (Refereed)
    Abstract [en]

    Abnormal liver function tests are frequently observed during follow-up of patients with systemic lupus erythematosus (SLE) but data on co-existence with autoimmune liver diseases (AILD) are scarce. This retrospective study aimed to describe the prevalence of autoimmune hepatitis (AIH) and primary biliary cholangitis (PBC) among well-characterized subjects with SLE. We also evaluated whether the presence of autoantibodies to complement protein 1q (C1q) and/or ribosomal P protein (anti-ribP) are, directly or inversely, associated with AIH, as proposed in some reports. The number of screened patients was 287 (86% females), and all cases were included in a regional Swedish cohort. Each subject of the study population met the 1982 American College of Rheumatology classification criteria and/or the Fries diagnostic principle. By applying the simplified diagnostic AIH criteria combined with persistent transaminasemia, 40 (13.9%) cases reached at least "probable AIH". However, merely 8 of these had been diagnosed with AIH (overall AIH prevalence 2.8%). Neither anti-C1q nor anti-ribP associated significantly with AIH. By applying the recent PBC guidelines, 6 (2.1%) cases were found, but only 3 of them had actually been diagnosed with PBC and one additional subject was not identified by the guidelines (overall PBC prevalence 1.4%). Compared to prevalence data from the general Swedish population, both AIH and PBC were highly overrepresented in our study population. The sensitivity of the diagnostic AIH criteria was impeccable but the specificity was less impressive, mainly due to positive ANA and hypergammaglobulinemia. Based on our findings, among subjects with SLE, the AIH criteria are less useful and liver biopsy combined with detection of other AILD-associated autoantibodies should be performed.

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  • 46.
    Heijke, Rebecca
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Björk, Mathilda
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Prevention, Rehabilitation and Community Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Medicine Center, Department of Rheumatology.
    Frodlund, Martina
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Medicine Center, Department of Rheumatology.
    McDonald, Laura
    Bristol Myers Squibb, England.
    Alemao, Evo
    Bristol Myers Squibb, NJ USA.
    Sjöwall, Christopher
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Medicine Center, Department of Rheumatology.
    Relationship between remission, disease activity and patient-reported outcome measures in patients with recent-onset systemic lupus erythematosus2020In: Lupus, ISSN 0961-2033, E-ISSN 1477-0962, Vol. 29, no 6, p. 625-630Article in journal (Refereed)
    Abstract [en]

    Objective Definitions of remission in systemic lupus erythematosus (SLE; DORIS (1A/1B/2A/2B)), disease activity assessments and patient-reported outcome measures (PROMs) are useful in shared decision making between patients with SLE and physicians. We used longitudinal registry data from well-characterized Swedish patients with recent-onset SLE to explore potential correlations between DORIS status or disease activity, and PROMs. Methods Patients from the Clinical Lupus Register in North-Eastern Gothia, Sweden, who fulfilled the 1982 American College of Rheumatology and/or the 2012 Systemic Lupus International Collaborating Clinics classification criteria without prior organ damage, were enrolled at diagnosis. Data on treatments, serology, remission status (DORIS), disease activity (SLE Disease Activity Index-2000 (SLEDAI-2K)) and PROMs (quality of life: EuroQoL-5 Dimensions (EQ-5D); pain intensity, fatigue and well-being: visual analog scale (VAS) 0-100 mm) were collected during rheumatology clinic visits at months 0 (diagnosis), 6, 12, 24, 36, 48 and 60. Correlations were assessed using Pearson correlation and/or beta regression coefficients. Results A total of 41 patients were enrolled (median age = 39 years, 80% female, 85% white). Achievement of DORIS 1A and 2A (neither of which includes serology) significantly correlated with all PROMs (EQ-5D: p &lt;= 0.02; pain: p = 0.0001; fatigue: p = 0.0051; well-being: p &lt; 0.0001). Disease activity measures were correlated with VAS pain intensity (p &lt; 0.03) and VAS well-being (p &lt; 0.04). Conclusions Our findings illustrate the importance of the interplay between remission, disease activity assessments and PROMs. PROMs may be a useful tool in clinical practice, being administered prior to patient visits to streamline clinical care.

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  • 47.
    Heijke, Rebecca
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences.
    Björk, Mathilda
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Prevention, Rehabilitation and Community Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Pain and Rehabilitation Center.
    Thyberg, Ingrid
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Medicine Center, Department of Rheumatology.
    Kastbom, Alf
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Medicine Center, Department of Rheumatology.
    McDonald, Laura
    Bristol Myers Squibb, England.
    Sjöwall, Christopher
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Medicine Center, Department of Rheumatology.
    Comparing longitudinal patient-reported outcome measures between Swedish patients with recent-onset systemic lupus erythematosus and early rheumatoid arthritis2022In: Clinical Rheumatology, ISSN 0770-3198, E-ISSN 1434-9949, Vol. 41, no 5, p. 1561-1568Article in journal (Refereed)
    Abstract [en]

    The onset of rheumatic disease affects each patient differently and may impact quality of life with progression. We investigated the relationship between patient-reported outcome measure (PROM) scores and organ damage in patients with recent-onset systemic lupus erythematosus (SLE) and those with early rheumatoid arthritis (RA). Patients with recent-onset SLE without prior organ damage from the Clinical Lupus Register in Northeastern Gothia and patients with early RA from the observational 2nd Timely Interventions in Early RA study, Sweden, were included. Systemic Lupus International Collaborating Clinics/American College of Rheumatology damage index (SDI) was used to assess organ damage. PROM (visual analog scale [VAS]: pain, fatigue, well-being, Health Assessment Questionnaire, and EQ-5D-3L) scores were captured at months 0, 6, 12, 24, 36, 48, and 60 after diagnosis. Statistical tests included Pearson correlation coefficients and t-tests. Forty-one patients with recent-onset SLE and 522 with early RA were included. Numerical differences were seen in age and sex. PROMs were worse for patients with RA versus SLE but improved by month 6 following diagnosis, while SLE PROMs remained stable. The incidence of organ damage in SLE was 13.6 per 100 patient-years. SDI significantly correlated with EQ-5D-3L (- 0.48, P = 0.003), VAS fatigue (0.44, P = 0.009), and well-being (0.41, P = 0.01) at month 24. As illustrated, the complexity of disease burden in patients with SLE is clear and may result from disease-related multiorgan system effects and slower symptom resolution compared with RA. This underscores the need for improved multiprofessional interventions to manage all aspects of SLE.

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  • 48.
    Hetland, Merete Lund
    et al.
    Rigshosp, Denmark; Univ Copenhagen, Denmark.
    Haavardsholm, Espen A.
    Diakonhjemmet Hosp, Norway.
    Rudin, Anna
    Sahlgrens Univ Hosp, Sweden; Univ Gothenburg, Sweden.
    Nordstrom, Dan
    Helsinki Univ Hosp, Finland; Univ Helsinki, Finland; Univ Southern Denmark, Denmark.
    Nurmohamed, Michael
    Amsterdam Rheumatol & Immunol Ctr, Netherlands; Univ Amsterdam, Netherlands; Univ Amsterdam, Netherlands.
    Gudbjornsson, Bjorn
    Landspitali Univ Hosp, Iceland; Univ Iceland, Iceland.
    Lampa, Jon
    Karolinska Univ Hosp, Sweden.
    Horslev-Petersen, Kim
    Univ Hosp Southern Denmark, Denmark; Univ Southern Denmark, Denmark.
    Uhlig, Till
    Univ Oslo, Norway.
    Grondal, Gerdur
    Landspitali Univ Hosp, Iceland; Univ Iceland, Iceland.
    Ostergaard, Mikkel
    Rigshosp, Denmark; Univ Copenhagen, Denmark.
    Heiberg, Marte S.
    Diakonhjemmet Hospital, Oslo, Norway.
    Twisk, Jos
    Univ Amsterdam, Netherlands.
    Lend, Kristina
    Karolinska Univ Hosp, Sweden.
    Krabbe, Simon
    Karolinska Univ Hosp, Sweden.
    Hyldstrup, Lise Hejl
    Rigshosp, Denmark.
    Lindqvist, Joakim
    Karolinska Univ Hosp, Sweden.
    Ekwall, Anna-Karin Hultgard
    Karolinska Univ Hosp, Sweden.
    Gron, Kathrine Lederballe
    Rigshospitalet, Glostrup, Denmark.
    Kapetanovic, Meliha
    Skane Univ Hosp, Sweden; Lund Univ, Sweden.
    Faustini, Francesca
    Svendborg Hospital OUH, Denmark.
    Tuompo, Riitta
    Univ Helsinki, Finland.
    Lorenzen, Tove
    Silkeborg Univ Clin, Denmark.
    Cagnotto, Giovanni
    Skane Univ Hosp, Sweden; Lund Univ, Sweden; Jyvaskyla Cent Hosp, Finland; Univ Eastern Finland, Finland.
    Baecklund, Eva
    Uppsala Univ, Sweden.
    Hendricks, Oliver
    University Hospital of Southern Denmark, Sønderborg, Denmark.
    Vedder, Daisy
    Amsterdam Rheumatology and Immunology Center, Reade, Netherlands.
    Sokka-Isler, Tuulikki
    Jyvaskyla Cent Hosp, Finland.
    Husmark, Tomas
    Univ Eastern Finland, Finland.
    Ljosa, Maud-Kristine Aga
    Falun Cent Hosp, Sweden.
    Brodin, Eli
    Iesund Hosp, Norway.
    Ellingsen, Torkell
    Haukeland Hosp, Norway; Univ Southern Denmark, Denmark.
    Soderbergh, Annika
    Orebro Univ Hosp, Sweden.
    Rizk, Milad
    Vastmanlands Hosp Vasteras, Sweden.
    Reckner-Olsson, Åsa
    Region Östergötland, Medicine Center, Department of Rheumatology.
    Larsson, Per
    Acad Specialist Ctr, Sweden.
    Uhrenholt, Line
    Aalborg Univ Hosp, Denmark.
    Just, Soren Andreas
    Amsterdam Rheumatol & Immunol Ctr, Netherlands; Univ Iceland, Iceland; Svendborg Hosp OUH, Denmark.
    Stevens, David John
    Univ Trondheim Hosp, Norway.
    Laurberg, Trine Bay
    Aarhus Univ Hosp, Denmark.
    Bakland, Gunnstein
    Univ Hosp North Norway, Norway.
    Olsen, Inge C.
    Oslo Univ Hosp, Norway.
    van Vollenhoven, Ronald
    Univ Amsterdam, Netherlands; Univ Iceland, Iceland.
    Active conventional treatment and three different biological treatments in early rheumatoid arthritis: phase IV investigator initiated, randomised, observer blinded clinical trial2020In: The BMJ, E-ISSN 1756-1833, Vol. 371, article id m4328Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE To evaluate and compare benefits and harms of three biological treatments with different modes of action versus active conventional treatment in patients with early rheumatoid arthritis. DESIGN Investigator initiated, randomised, open label, blinded assessor, multiarm, phase IV study. SETTING Twenty nine rheumatology departments in Sweden, Denmark, Norway, Finland, the Netherlands, and Iceland between 2012 and 2018. PARTICIPANTS Patients aged 18 years and older with treatment naive rheumatoid arthritis, symptom duration less than 24 months, moderate to severe disease activity, and rheumatoid factor or anti-citrullinated protein antibody positivity, or increased C reactive protein. INTERVENTIONS Randomised 1:1:1:1, stratified by country, sex, and anti-citrullinated protein antibody status. All participants started methotrexate combined with (a) active conventional treatment (either prednisolone tapered to 5 mg/day, or sulfasalazine combined with hydroxychloroquine and intraarticular corticosteroids), (b) certolizumab pegol, (c) abatacept, or (d) tocilizumab. MAIN OUTCOME MEASURES The primary outcome was adjusted clinical disease activity index remission (CDAI &lt;= 2.8) at 24 weeks with active conventional treatment as the reference. Key secondary outcomes and analyses included CDAI remission at 12 weeks and over time, other remission criteria, a non-inferiority analysis, and harms. RESULTS 812 patients underwent randomisation. The mean age was 54.3 years (standard deviation 14.7) and 68.8% were women. Baseline disease activity score of 28 joints was 5.0 (standard deviation 1.1). Adjusted 24 week CDAI remission rates were 42.7% (95% confidence interval 36.1% to 49.3%) for active conventional treatment, 46.5% (39.9% to 53.1%) for certolizumab pegol, 52.0% (45.5% to 58.6%) for abatacept, and 42.1% (35.3% to 48.8%) for tocilizumab. Corresponding absolute differences were 3.9% (95% confidence interval -5.5% to 13.2%) for certolizumab pegol, 9.4% (0.1% to 18.7%) for abatacept, and -0.6% (-10.1% to 8.9%) for tocilizumab. Key secondary outcomes showed no major differences among the four treatments. Differences in CDAI remission rates for active conventional treatment versus certolizumab pegol and tocilizumab, but not abatacept, remained within the prespecified non-inferiority margin of 15% (per protocol population). The total number of serious adverse events was 13 (percentage of patients who experienced at least one event 5.6%) for active conventional treatment, 20 (8.4%) for certolizumab pegol, 10 (4.9%) for abatacept, and 10 (4.9%) for tocilizumab. Eleven patients treated with abatacept stopped treatment early compared with 20-23 patients in the other arms. CONCLUSIONS All four treatments achieved high remission rates. Higher CDAI remission rate was observed for abatacept versus active conventional treatment, but not for certolizumab pegol or tocilizumab versus active conventional treatment. Other remission rates were similar across treatments. Non-inferiority analysis indicated that active conventional treatment was non-inferior to certolizumab pegol and tocilizumab, but not to abatacept. The results highlight the efficacy and safety of active conventional treatment based on methotrexate combined with corticosteroids, with nominally better results for abatacept, in treatment naive early rheumatoid arthritis.

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  • 49.
    Hopkins, Francis
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Molecular Medicine and Virology. Linköping University, Faculty of Medicine and Health Sciences.
    Nordgren, Johan
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Molecular Medicine and Virology. Linköping University, Faculty of Medicine and Health Sciences.
    Fernandez-Botran, Rafael
    Univ Louisville, KY USA.
    Enocsson, Helena
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences.
    Govender, Melissa
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Molecular Medicine and Virology. Linköping University, Faculty of Medicine and Health Sciences.
    Svanberg, Cecilia
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Molecular Medicine and Virology. Linköping University, Faculty of Medicine and Health Sciences.
    Svensson, Lennart
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Molecular Medicine and Virology. Linköping University, Faculty of Medicine and Health Sciences. Karolinska Inst, Sweden.
    Hagbom, Marie
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Molecular Medicine and Virology. Linköping University, Faculty of Medicine and Health Sciences.
    Nilsdotter-Augustinsson, Åsa
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Medicine Center, Department of Infectious Diseases.
    Nyström, Sofia
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
    Sjöwall, Christopher
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Medicine Center, Department of Rheumatology.
    Sjöwall, Johanna
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Medicine Center, Department of Infectious Diseases.
    Larsson, Marie
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Molecular Medicine and Virology. Linköping University, Faculty of Medicine and Health Sciences.
    Pentameric C-reactive protein is a better prognostic biomarker and remains elevated for longer than monomeric CRP in hospitalized patients with COVID-192023In: Frontiers in Immunology, E-ISSN 1664-3224, Vol. 14, article id 1259005Article in journal (Refereed)
    Abstract [en]

    The differing roles of the pentameric (p) and monomeric (m) C-reactive protein (CRP) isoforms in viral diseases are not fully understood, which was apparent during the COVID-19 pandemic regarding the clinical course of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Herein, we investigated the predictive value of the pCRP and mCRP isoforms for COVID-19 severity in hospitalized patients and evaluated how the levels of the protein isoforms changed over time during and after acute illness. This study utilized samples from a well-characterized cohort of Swedish patients with SARS-CoV-2 infection, the majority of whom had known risk factors for severe COVID-19 and required hospitalization. The levels of pCRP were significantly raised in patients with severe COVID-19 and in contrast to mCRP the levels were significantly associated with disease severity. Additionally, the pCRP levels remained elevated for at least six weeks post inclusion, which was longer compared to the two weeks for mCRP. Our data indicates a low level of inflammation lasting for at least six weeks following COVID-19, which might indicate that the disease has an adverse effect on the immune system even after the viral infection is resolved. It is also clear that the current standard method of testing pCRP levels upon hospitalization is a useful marker for predicting disease severity and mCRP testing would not add any clinical relevance for patients with COVID-19.

  • 50.
    Juneblad, K.
    et al.
    Umea Univ, Sweden.
    Kastbom, Alf
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Medicine Center, Department of Rheumatology.
    Johansson, L.
    Umea Univ, Sweden.
    Rantapaa-Dahlqvist, S.
    Umea Univ, Sweden.
    Söderkvist, Peter
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Alenius, G-M
    Umea Univ, Sweden.
    Association between inflammasome-related polymorphisms and psoriatic arthritis2021In: Scandinavian Journal of Rheumatology, ISSN 0300-9742, E-ISSN 1502-7732, Vol. 50, no 3, p. 206-212Article in journal (Refereed)
    Abstract [en]

    Objective: Psoriatic arthritis (PsA) is a heterogeneous inflammatory disease associated with psoriasis. Underlying genetic factors are considered important for disease expression and prognosis of PsA. Interleukin-1β-regulating protein complexes called inflammasomes are associated with several inflammatory diseases, e.g. rheumatoid arthritis and psoriasis. The aim was to determine whether inflammasome-related genetic variation is associated with PsA susceptibility or different disease phenotypes.

    Method: DNA from 724 patients with PsA and 587 population-based controls from northern Sweden was analysed for single-nucleotide polymorphisms in NLRP3-Q750K (rs35829419), NLRP3 (rs10733113), CARD8-C10X (rs2043211), NLRP1 (rs8079034), and NLRP1 (rs878329).

    Results: Significant associations were found with the genotype AA (vs AT+TT) of rs2043211 for PsA patients compared with controls [odds ratio (OR), 95% confidence interval (CI) 1.32 (1.05–1.65), p = 0.016]; and between the C-allele of rs878329 and axial involvement of PsA [OR (95% CI) 1.37 (1.02–1.84), p = 0.035], the T-allele of rs8079034 with prescription of conventional synthetic disease-modifying anti-rheumatic drugs [OR (95% CI) 1.76 (1.23–2.53), p = 0.0020], the G-allele of rs10733113 and patients with a skin disease with early onset [OR (95% CI) 1.58 (1.13–2.21), p = 0.007], and the C-allele of rs35829419 and a destructive/deforming disease [OR (95% CI) 1.63 (1.04–2.55), p = 0.030].

    Conclusions: This study is the first to show an association with a genetic polymorphism in an inflammasome-related gene, CARD8-C10X (rs2043211), in patients with PsA. Associations between different phenotypes of PsA and different polymorphisms of the inflammasome genes were also found. Our results indicate the involvement of inflammasome genes in the pathogenesis and disease expression of PsA. 

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