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  • 1.
    Almlöf, Jonas Carlsson
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Nystedt, Sara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Leonard, Dag
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Eloranta, Maija-Leena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Grosso, Giorgia
    Karolinska Univ Hosp, Karolinska Inst, Dept Med, Rheumatol Unit,Rheumatol, S-17177 Stockholm, Sweden.
    Sjowall, Christopher
    Linkoping Univ, Div Neuro & Inflammat Sci, Dept Clin & Expt Med, Rheumatol, S-58183 Linkoping, Sweden.
    Bengtsson, Anders A.
    Lund Univ, Skane Univ Hosp, Dept Clin Sci, Rheumatol, S-22242 Lund, Sweden.
    Jonsen, Andreas
    Lund Univ, Skane Univ Hosp, Dept Clin Sci, Rheumatol, S-22242 Lund, Sweden.
    Gunnarsson, Iva
    Karolinska Univ Hosp, Karolinska Inst, Dept Med, Rheumatol Unit,Rheumatol, S-17177 Stockholm, Sweden.
    Svenungsson, Elisabet
    Karolinska Univ Hosp, Karolinska Inst, Dept Med, Rheumatol Unit,Rheumatol, S-17177 Stockholm, Sweden.
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Sandling, Johanna K.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Whole-genome sequencing identifies complex contributions to genetic risk by variants in genes causing monogenic systemic lupus erythematosus2019In: Human Genetics, ISSN 0340-6717, E-ISSN 1432-1203, Vol. 138, no 2, p. 141-150Article in journal (Refereed)
    Abstract [en]

    Systemic lupus erythematosus (SLE, OMIM 152700) is a systemic autoimmune disease with a complex etiology. The mode of inheritance of the genetic risk beyond familial SLE cases is currently unknown. Additionally, the contribution of heterozygous variants in genes known to cause monogenic SLE is not fully understood. Whole-genome sequencing of DNA samples from 71 Swedish patients with SLE and their healthy biological parents was performed to investigate the general genetic risk of SLE using known SLE GWAS risk loci identified using the ImmunoChip, variants in genes associated to monogenic SLE, and the mode of inheritance of SLE risk alleles in these families. A random forest model for predicting genetic risk for SLE showed that the SLE risk variants were mainly inherited from one of the parents. In the 71 patients, we detected a significant enrichment of ultra-rare (0.1%) missense and nonsense mutations in 22 genes known to cause monogenic forms of SLE. We identified one previously reported homozygous nonsense mutation in the C1QC (Complement C1q C Chain) gene, which explains the immunodeficiency and severe SLE phenotype of that patient. We also identified seven ultra-rare, coding heterozygous variants in five genes (C1S, DNASE1L3, DNASE1, IFIH1, and RNASEH2A) involved in monogenic SLE. Our findings indicate a complex contribution to the overall genetic risk of SLE by rare variants in genes associated with monogenic forms of SLE. The rare variants were inherited from the other parent than the one who passed on the more common risk variants leading to an increased genetic burden for SLE in the child. Higher frequency SLE risk variants are mostly passed from one of the parents to the offspring affected with SLE. In contrast, the other parent, in seven cases, contributed heterozygous rare variants in genes associated with monogenic forms of SLE, suggesting a larger impact of rare variants in SLE than hitherto reported.

  • 2.
    Appelgren, Daniel
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Dahle, Charlotte
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
    Knopf, Jasmin
    Friedrich Alexander Univ Erlangen Nurnberg FAU, Germany.
    Bilyy, Rostyslav
    Friedrich Alexander Univ Erlangen Nurnberg FAU, Germany; Danylo Halytsky Lviv Natl Med Univ, Ukraine.
    Vovk, Volodymyr
    Danylo Halytsky Lviv Natl Med Univ, Ukraine.
    Sundgren, Pia C.
    Lund Univ, Sweden.
    Bengtsson, Anders A.
    Lund Univ, Sweden.
    Wetterö, Jonas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Munoz, Luis E.
    Friedrich Alexander Univ Erlangen Nurnberg FAU, Germany.
    Herrmann, Martin
    Friedrich Alexander Univ Erlangen Nurnberg FAU, Germany.
    Höög, Anders
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical pathology. Karolinska Inst, Sweden.
    Sjöwall, Christopher
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Rheumatology.
    Active NET formation in Libman-Sacks endocarditis without antiphospholipid antibodies: A dramatic onset of systemic lupus erythematosus2018In: Autoimmunity, ISSN 0891-6934, E-ISSN 1607-842X, Vol. 51, no 6, p. 310-318Article in journal (Refereed)
    Abstract [en]

    Although neutrophil extracellular traps (NETs) have been highlighted in several systemic inflammatory diseases, their clinical correlates and potential pathological role remain obscure. Herein, we describe a dramatic onset of systemic lupus erythematosus (SLE) with clear-cut pathogenic implications for neutrophils and NET formation in a young woman with cardiac (Libman-Sacks endocarditis) and central nervous system (psychosis and seizures) involvement. Despite extensive search, circulating antiphospholipid autoantibodies, a hallmark of Libman-Sacks endocarditis, could not be detected. Instead, we observed active NET formation in the tissue of the mitral valve, as well as in the circulation. Levels of NET remnants were significantly higher in serially obtained sera from the patient compared with sex-matched blood donors (p=.0011), and showed a non-significant but substantial correlation with blood neutrophil counts (r=0.65, p=.16). The specific neutrophil elastase activity measured in serum seemed to be modulated by the provided immunosuppressive treatment. In addition, we found anti-Ro60/SSA antibodies in the cerebrospinal fluid of the patient but not NET remnants or increased elastase activity. This case illustrates that different disease mechanisms mediated via autoantibodies can occur simultaneously in SLE. NET formation with release of cytotoxic NET remnants is a candidate player in the pathogenesis of this non-canonical form of Libman-Sacks endocarditis occurring in the absence of traditional antiphospholipid autoantibodies. The case description includes longitudinal results with clinical follow-up data and a discussion of the potential roles of NETs in SLE.

  • 3.
    Arkema, Elizabeth V
    et al.
    1Clinical Epidemiology Unit, Department of Medicine, Solna Karolinska Institute, Stockholm.
    Jönsen, Andreas
    Department of Clinical Sciences, Lund University, Lund.
    Rönnblom, Lars
    Department of Medical Sciences, Science for Life Laboratories, Uppsala University, Uppsala.
    Svenungsson, Elisabet
    Rheumatology Unit, Department of Medicine, Karolinska University Hospital, Karolinska Institute, Stockholm.
    Sjöwall, Christopher
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Rheumatology.
    Simard, Julia F
    Clinical Epidemiology Unit, Department of Medicine, Solna Karolinska Institute, Stockholm.
    Case definitions in Swedish register data to identify systemic lupus erythematosus2016In: BMJ Open, ISSN 2044-6055, E-ISSN 2044-6055, Vol. 6, no 1Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To develop and investigate the utility of several different case definitions for systemic lupus erythematosus (SLE) using national register data in Sweden.

    METHODS: The reference standard consisted of clinically confirmed SLE cases pooled from four major clinical centres in Sweden (n=929), and a sample of non-SLE comparators randomly selected from the National Population Register (n=24 267). Demographics, comorbidities, prescriptions and autoimmune disease family history were obtained from multiple registers and linked to the reference standard. We first used previously published SLE definitions to create algorithms for SLE. We also used modern data mining techniques (penalised least absolute shrinkage and selection operator logistic regression, elastic net regression and classification trees) to objectively create data-driven case definitions. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were calculated for the case definitions identified.

    RESULTS: Defining SLE by using only hospitalisation data resulted in the lowest sensitivity (0.79). When SLE codes from the outpatient register were included, sensitivity and PPV increased (PPV between 0.97 and 0.98, sensitivity between 0.97 and 0.99). Addition of medication information did not greatly improve the algorithm's performance. The application of data mining methods did not yield different case definitions.

    CONCLUSIONS: The use of SLE International Classification of Diseases (ICD) codes in outpatient clinics increased the accuracy for identifying individuals with SLE using Swedish registry data. This study implies that it is possible to use ICD codes from national registers to create a cohort of individuals with SLE.

  • 4.
    Arkema, Elizabeth V
    et al.
    Karolinska Institute, Stockholm, Sweden.
    Palmsten, Kristin
    University of California, San Diego, USA.
    Sjöwall, Christopher
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Rheumatology.
    Svenungsson, Elisabet
    Karolinska University Hospital, Karolinska Institute, Stockholm, Sweden.
    Salmon, Jane E
    Weill Cornell Medical College, New York, New York.
    Simard, Julia F
    Stanford School of Medicine, Stanford, California, USA ;Karolinska Institute, Stockholm, Sweden.
    What to Expect When Expecting With Systemic Lupus Erythematosus (SLE): A Population-Based Study of Maternal and Fetal Outcomes in SLE and Pre-SLE.2016In: Arthritis care & research, ISSN 2151-464X, E-ISSN 2151-4658, Vol. 68, no 7Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To assess maternal and fetal outcomes associated with subclinical (pre-systemic lupus erythematosus [SLE] and SLE presenting up to 5 years postpartum) and prevalent maternal SLE during pregnancy compared with the general population.

    METHODS: This prospective cohort study used population-based Swedish registers to identify 13,598 women with first singleton pregnancies registered in the Medical Birth Register (551 prevalent SLE, 65 pre-SLE within 0-2 years, 133 pre-SLE within 2-5 years, and 12,847 general population). SLE was defined as ≥2 SLE-coded discharge diagnoses in the patient register with ≥1 diagnosis from a specialist. Unadjusted risks of adverse pregnancy or birth outcomes were calculated by SLE status, and Cochran-Armitage tests evaluated trend across exposure groups.

    RESULTS: Maternal outcomes such as preeclampsia, hypothyroidism, stroke, and infection were more common among women with SLE. Sixteen percent of prevalent-SLE pregnancies were diagnosed with preeclampsia compared with 5% of those from the general population. Among the pre-SLE women, preeclampsia was found in 26% of those with SLE within 2 years postpartum and 13% in those with SLE within 2-5 years postpartum. Similarly, infant outcomes, such as preterm birth, infection, and mortality, were worse among those born to mothers with prevalent SLE and pre-SLE during pregnancy. The test for trend was significant for most outcomes.

    CONCLUSION: Our data demonstrate that adverse maternal and fetal outcomes are more common in SLE pregnancies. Furthermore, these unfavorable outcomes are observed in pregnancies occurring prior to the diagnosis of SLE. Thus, the underlying immunologic profile of SLE and alterations preceding clinical SLE may contribute to these pregnancy complications.

  • 5.
    Arkema, Elizabeth V
    et al.
    Clinical Epidemiology Unit, Karolinska Institutet, Stockholm.
    Rossides, Marios
    Clinical Epidemiology Unit, Karolinska Institutet, Stockholm.
    Von Euler, Mia
    Karolinska Institutet, Stockholm, Sweden.
    Svenungsson, Elisabet
    Rheumatology Unit, Karolinska Institutet, Stockholm.
    Sjöwall, Christopher
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Rheumatology.
    Simard, Julia F
    Karolinska Institutet, Stockholm, Sweden, Stanford School of Medicine, Stanford, California, USA.
    Response to 'Increased stroke incidence in systemic lupus erythematosus patients"2018In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 77, no 10, article id UNSP e72Article in journal (Refereed)
  • 6.
    Arkema, Elizabeth V.
    et al.
    Karolinska Institute, Sweden.
    Svenungsson, Elisabet
    Karolinska Institute, Sweden.
    Von Euler, Mia
    Karolinska Institute, Sweden.
    Sjöwall, Christopher
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Rheumatology.
    Simard, Julia F.
    Karolinska Institute, Sweden; Stanford School Med, CA USA; Stanford School Med, CA USA.
    Stroke in systemic lupus erythematosus: a Swedish population-based cohort study2017In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 76, no 9, p. 1544-1549Article in journal (Refereed)
    Abstract [en]

    Objective To study the occurrence of ischaemic and haemorrhagic stroke in systemic lupus erythematosus (SLE) compared with the general population by age, sex and time since SLE diagnosis Methods Adults with incident SLE were identified from the Swedish National Patient Register (NPR, n=3390) and general population comparators from the Total Population Register were matched on age, sex and county (n=16730). Individuals were followed prospectively until first of death, December 2013, emigration or incident stroke (identified from the NPR, Cause of Death Register and the Stroke Register). Incidence rates, rate differences and HR were estimated comparing SLE with non-SLE. Estimates were stratified by sex, age and time since diagnosis. Results We observed 126 strokes in SLE and 304 in the general population. Individuals with SLE had a twofold increased rate of ischaemic stroke compared with the general population (HR 2.2; 95% CI 1.7 to 2.8). The HR for intracerebral haemorrhage was 1.4 (95% CI 0.7 to 2.8). There was effect modification by sex and age, with the highest HRs for females and individuals amp;lt;50 years old. The HR for ischaemic stroke was highest in the first year of follow-up (3.7; 95% CI 2.1 to 6.5). Conclusions The relative risk of ischaemic stroke in SLE was more than doubled compared with the general population, and importantly, the highest relative risks were observed within the first year after SLE diagnosis. Thus, the first encounter with patients presents an opportunity for rheumatologists to screen for risk factors and intervene.

  • 7.
    Bentow, C.
    et al.
    Inova Diagnost, CA USA.
    Lakos, G.
    Inova Diagnost, CA USA.
    Martis, P.
    Inova Diagnost, CA USA.
    Wahl, E.
    Inova Diagnost, CA USA.
    Garcia, M.
    Hospital Clin Barcelona, Spain.
    Vinas, O.
    Hospital Clin Barcelona, Spain.
    Espinosa, G.
    Hospital Clin Barcelona, Spain.
    Cervera, R.
    Hospital Clin Barcelona, Spain.
    Sjöwall, Christopher
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Rheumatology.
    Carmona-Fernandes, D.
    University of Lisbon, Portugal.
    Santos, M. J.
    University of Lisbon, Portugal.
    Hanly, J. G.
    Dalhousie University, Canada.
    Mahler, M.
    Inova Diagnost, CA USA.
    International multi-center evaluation of a novel chemiluminescence assay for the detection of anti-dsDNA antibodies2016In: Lupus, ISSN 0961-2033, E-ISSN 1477-0962, Vol. 25, no 8, p. 864-872Article in journal (Refereed)
    Abstract [en]

    Objective: Anti-double stranded desoxyribonucleic acid (anti-dsDNA) antibodies are considered fairly specific for systemic lupus erythematosus (SLE) and their quantification is useful for the clinical management of SLE patients. We assessed the diagnostic performance of the QUANTA Flash dsDNA chemiluminescent immunoassay (CIA) in comparison to an ELISA, using patients from five participating countries. The main focus was to evaluate the correlation between anti-dsDNA antibody results from the CIA and global SLE disease activity, as measured by the SLE Disease Activity Index 2000 (SLEDAI-2K). Patients and methods: A total of 1431 samples (SLE, n=843; disease controls, n=588) from five countries (Canada, USA, Portugal, Sweden and Spain) were tested with QUANTA Flash dsDNA (Inova Diagnostics, San Diego, CA, USA). Data obtained with the QUANTA Lite dsDNA SC ELISA (Inova Diagnostics) were available for samples from three sites (Canada, USA and Sweden, n=566). The SLEDAI-2K scores were available for 805 SLE patients and a cut-off ofamp;gt;4 was used to define active disease. Results: QUANTA Flash dsDNA had a sensitivity of 54.3% for the diagnosis of SLE, combined with 89.8% specificity. Anti-dsDNA antibody levels were significantly higher (pamp;lt;0.0001) in active SLE (SLEDAI-2Kamp;gt;4; n=232; median value 83.0IU/mL) versus the inactive patients (n=573; median value 22.3IU/mL), and the SLEDAI-2K scoring correlated with their dsDNA antibody levels (Spearmans rho=0.44, pamp;lt;0.0001). Similar but less pronounced findings were also found for the ELISA, in relation to disease activity. Conclusions: The QUANTA Flash dsDNA assay showed good clinical performance in a large international multi-center study. Additionally, the strong correlation between anti-dsDNA antibody results and SLEDAI-2K scores supported the potential utility of QUANTA Flash dsDNA for monitoring disease activity.

  • 8.
    Björk, Mathilda
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Community Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Rehabilitation Center. Jonköping University, Sweden.
    Dahlström, Örjan
    Linköping University, Department of Behavioural Sciences and Learning, Disability Research. Linköping University, Faculty of Arts and Sciences. Linköping University, The Swedish Institute for Disability Research.
    Wetterö, Jonas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Sjöwall, Christoffer
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Rheumatology.
    Quality of life and acquired organ damage are intimately related to activity limitations in patients with systemic lupus erythematosus2015In: BMC Musculoskeletal Disorders, ISSN 1471-2474, E-ISSN 1471-2474, Vol. 16, no 188Article in journal (Refereed)
    Abstract [en]

    Background: Systemic lupus erythematosus (SLE) is an autoimmune multi-organ disease, characterized by episodes of disease flares and remissions over time, which may restrain affected patients ability to perform daily activities. The purpose of the present study was to characterize variation in activity limitations among well-defined SLE patients, and to describe disease phenotypes, acquired organ damage and their relations to activity limitation and self-reported health, respectively. Methods: The disease phenotypes were organized into 4 different clinical groups and logistic regression analyses were used to identify how an elevated health assessment questionnaire (HAQ) score was related to disease variables such as phenotypes, disease activity and damage accrual. Correlation and multiple linear regression analyses were used to examine the association between each group of variables - background variables, disease variables and self-reported measurements - and the degree of elevated HAQ. Results: We found a higher proportion of activity limitation in patients with skin and joint involvement compared to others. The presence of activity limitation, as detected by the HAQ instrument, was significantly associated with quality of life (EuroQol-5D) and accrual of organ damage using the Systemic Lupus International Collaborative Clinics/ACR damage index. Conclusions: The findings highlight the differing requirements of the multi-professional rehabilitation interventions for the various SLE phenotypes in order to optimize the clinical care of the patients.

  • 9.
    Blomgran, Robert
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Brodin Patcha, Veronika
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Verma, Deepti
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Bergström, Ida
    Linköping University, Department of Medical and Health Sciences, Cardiology. Linköping University, Faculty of Health Sciences.
    Söderkvist, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Sjöwall, Christoffer
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Rheumatology in Östergötland.
    Eriksson, Per
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Nephrology UHL.
    Lerm, Maria
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Stendahl, Olle
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Sarndahl, Eva
    University of Örebro.
    Common Genetic Variations in the NALP3 Inflammasome Are Associated with Delayed Apoptosis of Human Neutrophils2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 3Article in journal (Refereed)
    Abstract [en]

    Background: Neutrophils are key-players in the innate host defense and their programmed cell death and removal are essential for efficient resolution of inflammation. These cells recognize a variety of pathogens, and the NOD-like receptors (NLRs) have been suggested as intracellular sensors of microbial components and cell injury/stress. Some NLR will upon activation form multi-protein complexes termed inflammasomes that result in IL-1 beta production. NLR mutations are associated with auto-inflammatory syndromes, and our previous data propose NLRP3 (Q705K)/CARD-8 (C10X) polymorphisms to contribute to increased risk and severity of inflammatory disease by acting as genetic susceptibility factors. These gene products are components of the NALP3 inflammasome, and approximately 6.5% of the Swedish population are heterozygote carriers of these combined gene variants. Since patients carrying the Q705K/C10X polymorphisms display leukocytosis, the aim of the present study was to find out whether the inflammatory phenotype was related to dysfunctional apoptosis and impaired clearance of neutrophils by macrophages. less thanbrgreater than less thanbrgreater thanMethods and Findings: Patients carrying the Q705K/C10X polymorphisms displayed significantly delayed spontaneous as well as microbe-induced apoptosis compared to matched controls. Western blotting revealed increased levels and phosphorylation of Akt and Mcl-1 in the patients neutrophils. In contrast to macrophages from healthy controls, macrophages from the patients produced lower amounts of TNF; suggesting impaired macrophage clearance response. less thanbrgreater than less thanbrgreater thanConclusions: The Q705K/C10X polymorphisms are associated with delayed apoptosis of neutrophils. These findings are explained by altered involvement of different regulators of apoptosis, resulting in an anti-apoptotic profile. Moreover, the macrophage response to ingestion of microbe-induced apoptotic neutrophils is altered in the patients. Taken together, the patients display impaired turnover and clearance of apoptotic neutrophils, pointing towards a dysregulated innate immune response that influences the resolution of inflammation. The future challenge is to understand how microbes affect the activation of inflammasomes, and why this interaction will develop into severe inflammatory disease in certain individuals.

  • 10.
    Bolin, Karin
    et al.
    Uppsala University, Sweden .
    Sandling, Johanna K.
    Uppsala University, Sweden Uppsala University, Sweden .
    Zickert, Agneta
    Karolinska University Hospital, Sweden Karolinska Institute, Sweden .
    Jonsen, Andreas
    Lund University, Sweden .
    Sjöwall, Christoffer
    Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Rheumatology.
    Svenungsson, Elisabet
    Karolinska University Hospital, Sweden Karolinska Institute, Sweden .
    Bengtsson, Anders A.
    Lund University, Sweden .
    Eloranta, Maija-Leena
    Uppsala University, Sweden .
    Ronnblom, Lars
    Uppsala University, Sweden Uppsala University, Sweden .
    Syvanen, Ann-Christine
    Uppsala University, Sweden Uppsala University, Sweden .
    Gunnarsson, Iva
    Karolinska University Hospital, Sweden Karolinska Institute, Sweden .
    Nordmark, Gunnel
    Uppsala University, Sweden .
    Association of STAT4 Polymorphism with Severe Renal Insufficiency in Lupus Nephritis2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 12, p. 84450-Article in journal (Refereed)
    Abstract [en]

    Lupus nephritis is a cause of significant morbidity in systemic lupus erythematosus (SLE) and its genetic background has not been completely clarified. The aim of this investigation was to analyze single nucleotide polymorphisms (SNPs) for association with lupus nephritis, its severe form proliferative nephritis and renal outcome, in two Swedish cohorts. Cohort I (n = 567 SLE cases, n = 512 controls) was previously genotyped for 5676 SNPs and cohort II (n = 145 SLE cases, n = 619 controls) was genotyped for SNPs in STAT4, IRF5, TNIP1 and BLK. Case-control and case-only association analyses for patients with lupus nephritis, proliferative nephritis and severe renal insufficiency were performed. In the case-control analysis of cohort I, four highly linked SNPs in STAT4 were associated with lupus nephritis with genome wide significance with p = 3.7x10(-9), OR 2.20 for the best SNP rs11889341. Strong signals of association between IRF5 and an HLA-DR3 SNP marker were also detected in the lupus nephritis case versus healthy control analysis (pless than0.0001). An additional six genes showed an association with lupus nephritis with pless than0.001 (PMS2, TNIP1, CARD11, ITGAM, BLK and IRAK1). In the case-only meta-analysis of the two cohorts, the STAT4 SNP rs7582694 was associated with severe renal insufficiency with p = 1.6x10(-3) and OR 2.22. We conclude that genetic variations in STAT4 predispose to lupus nephritis and a worse outcome with severe renal insufficiency.

  • 11.
    Boström, E A
    et al.
    University of Gothenburg.
    Ekstedt, Mattias
    Linköping University, Department of Clinical and Experimental Medicine, Gastroenterology and Hepatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Endocrinology and Gastroenterology UHL.
    Kechagias, Stergios
    Linköping University, Department of Medical and Health Sciences, Internal Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Endocrinology and Gastroenterology UHL.
    Sjöwall, Christoffer
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Rheumatology in Östergötland.
    Bokarewa, M I
    University of Gothenburg.
    Almer, Sven
    Linköping University, Department of Clinical and Experimental Medicine, Gastroenterology and Hepatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Endocrinology and Gastroenterology UHL.
    Resistin is Associated with Breach of Tolerance and Anti-nuclear Antibodies in Patients with Hepatobiliary Inflammation2011In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 74, no 5, p. 463-470Article in journal (Refereed)
    Abstract [en]

    Resistin is a cysteine-rich protein, which is abundantly expressed at the site of inflammation, and acts as a regulator of the NF-kB-dependent cytokine cascade. The aim of this study was to evaluate resistin levels in relation to inflammatory mediators, disease phenotype and autoantibody status in a spectrum of pathological conditions of the gastrointestinal tract. Resistin levels were measured with an ELISA in sera originated from 227 patients and 40 healthy controls (HC). Fifty patients diagnosed with non-alcoholic fatty liver disease (NAFLD), 53 ulcerative colitis (UC), 51 Crohns disease (CD), 46 autoimmune hepatitis (AIH) and 27 primary sclerosing cholangitis (PSC) were included. The sera were analysed with respect to biochemical parameters of systemic inflammation and liver function and to the presence of antibodies to nuclear antigens (ANA), mitochondria (AMA) and smooth muscle (SMA). Compared with HC, resistin levels were raised in AIH (P = 0.017) and PSC (P = 0.03); compared with NAFLD, levels were elevated in CD (P = 0.041), AIH (P andlt; 0.001) and PSC (P andlt; 0.001). Patients with elevated levels of resistin were more often treated with corticosteroids, but no difference was found between active disease and clinical remission. Resistin levels were significantly higher in ANA-positive individuals compared with ANA-negative (P = 0.025). Resistin levels were directly correlated with IL-6 (r = 0.30, P = 0.02) and IL-8 (r = 0.51, P andlt; 0.001). Elevated levels of resistin were prominent in patients with hepatobiliary inflammation and were associated with breach of self-tolerance, i.e. ANA positivity. Thus, we propose that resistin may be an important marker of disease severity in autoantibody-mediated gastrointestinal inflammatory diseases.

  • 12.
    Carlsson Almlöf, Jonas
    et al.
    Uppsala University, Sweden.
    Alexsson, Andrei
    Uppsala University, Sweden.
    Imgenberg-Kreuz, Juliana
    Uppsala University, Sweden.
    Sylwan, Lina
    Uppsala University, Sweden; Karolinska Institute, Sweden.
    Backlin, Christofer
    Uppsala University, Sweden.
    Leonard, Dag
    Uppsala University, Sweden.
    Nordmark, Gunnel
    Uppsala University, Sweden.
    Tandre, Karolina
    Uppsala University, Sweden.
    Eloranta, Maija-Leena
    Uppsala University, Sweden.
    Padyukov, Leonid
    Karolinska University Hospital, Sweden.
    Bengtsson, Christine
    Umeå University, Sweden.
    Jonsen, Andreas
    Lund University, Sweden.
    Rantapaa Dahlqvist, Solbritt
    Umeå University, Sweden.
    Sjöwall, Christopher
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Rheumatology.
    Bengtsson, Anders A.
    Lund University, Sweden.
    Gunnarsson, Iva
    Karolinska University Hospital, Sweden.
    Svenungsson, Elisabet
    Karolinska University Hospital, Sweden.
    Ronnblom, Lars
    Uppsala University, Sweden.
    Sandling, Johanna K.
    Uppsala University, Sweden; Uppsala University, Sweden.
    Syvanen, Ann-Christine
    Uppsala University, Sweden.
    Novel risk genes for systemic lupus erythematosus predicted by random forest classification2017In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 6236Article in journal (Refereed)
    Abstract [en]

    Genome-wide association studies have identified risk loci for SLE, but a large proportion of the genetic contribution to SLE still remains unexplained. To detect novel risk genes, and to predict an individuals SLE risk we designed a random forest classifier using SNP genotype data generated on the "Immunochip" from 1,160 patients with SLE and 2,711 controls. Using gene importance scores defined by the random forest classifier, we identified 15 potential novel risk genes for SLE. Of them 12 are associated with other autoimmune diseases than SLE, whereas three genes (ZNF804A, CDK1, and MANF) have not previously been associated with autoimmunity. Random forest classification also allowed prediction of patients at risk for lupus nephritis with an area under the curve of 0.94. By allele-specific gene expression analysis we detected cis-regulatory SNPs that affect the expression levels of six of the top 40 genes designed by the random forest analysis, indicating a regulatory role for the identified risk variants. The 40 top genes from the prediction were overrepresented for differential expression in B and T cells according to RNA-sequencing of samples from five healthy donors, with more frequent over-expression in B cells compared to T cells.

  • 13.
    Carlsson Almlöf, Jonas Carlsson
    et al.
    Uppsala Univ, Sweden.
    Nystedt, Sara
    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 Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and 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.
    Rönnblom, Lars
    Uppsala Univ, Sweden.
    Sandling, Johanna K.
    Uppsala Univ, Sweden.
    Syvanen, Ann-Christine
    Uppsala Univ, Sweden.
    Whole-genome sequencing identifies complex contributions to genetic risk by variants in genes causing monogenic systemic lupus erythematosus2019In: Human Genetics, ISSN 0340-6717, E-ISSN 1432-1203, Vol. 138, no 2, p. 141-150Article in journal (Refereed)
    Abstract [en]

    Systemic lupus erythematosus (SLE, OMIM 152700) is a systemic autoimmune disease with a complex etiology. The mode of inheritance of the genetic risk beyond familial SLE cases is currently unknown. Additionally, the contribution of heterozygous variants in genes known to cause monogenic SLE is not fully understood. Whole-genome sequencing of DNA samples from 71 Swedish patients with SLE and their healthy biological parents was performed to investigate the general genetic risk of SLE using known SLE GWAS risk loci identified using the ImmunoChip, variants in genes associated to monogenic SLE, and the mode of inheritance of SLE risk alleles in these families. A random forest model for predicting genetic risk for SLE showed that the SLE risk variants were mainly inherited from one of the parents. In the 71 patients, we detected a significant enrichment of ultra-rare (0.1%) missense and nonsense mutations in 22 genes known to cause monogenic forms of SLE. We identified one previously reported homozygous nonsense mutation in the C1QC (Complement C1q C Chain) gene, which explains the immunodeficiency and severe SLE phenotype of that patient. We also identified seven ultra-rare, coding heterozygous variants in five genes (C1S, DNASE1L3, DNASE1, IFIH1, and RNASEH2A) involved in monogenic SLE. Our findings indicate a complex contribution to the overall genetic risk of SLE by rare variants in genes associated with monogenic forms of SLE. The rare variants were inherited from the other parent than the one who passed on the more common risk variants leading to an increased genetic burden for SLE in the child. Higher frequency SLE risk variants are mostly passed from one of the parents to the offspring affected with SLE. In contrast, the other parent, in seven cases, contributed heterozygous rare variants in genes associated with monogenic forms of SLE, suggesting a larger impact of rare variants in SLE than hitherto reported.

  • 14.
    Crisci, Elisa
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Ellegård, Rada
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Nyström, Sofia
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
    Rondahl, Elin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Infectious Diseases.
    Serrander, Lena
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Infectious Diseases.
    Bergström, Tomas
    University of Gothenburg, Gothenburg, Sweden.
    Sjöwall, Christopher
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Rheumatology.
    Eriksson, Kristina
    University of Gothenburg, Gothenburg, Sweden.
    Larsson, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Complement opsonization promotes HSV-2 infection of human dendritic cells2016In: Journal of Virology, ISSN 0022-538X, E-ISSN 1098-5514, Vol. 90, no 10, p. 4939-4950Article in journal (Refereed)
    Abstract [en]

    Herpes virus type 2 (HSV2) is one of the most common sexually transmitted infections globally with a very high prevalence in many countries. During HSV2 infection viral particles become coated with complement proteins and antibodies, both existent in the genital fluids, which could influence the activation of the immune responses. In genital mucosa, the primary target cells for HSV2 infection are epithelial cells, but resident immune cells such as dendritic cells (DCs) are also infected. The DCs are the activators of the ensuing immune responses directed against HSV2, and the aim of this study was to examine the effects opsonization of HSV2, either with complement alone or with complement and antibodies, had on the infection of immature DCs and their ability to mount inflammatory and antiviral responses. Complement opsonization of HSV2 enhanced both the direct infection of immature DCs and their production of new infectious viral particles. The enhanced infection required activation of the complement cascade and functional complement receptor 3. Furthermore, HSV2 infection of DCs required endocytosis of viral particles and their delivery into an acid endosomal compartment. The presence of complement in combination with HSV1 or HSV2 specific antibodies more or less abolished the HSV2 infection of DCs.Our results clearly demonstrate the importance of studying HSV2 infection under conditions that ensue in vivo, i.e. when the virions are covered in complement fragments and complement fragments and antibodies, as this will shape the infection and the subsequent immune response and needs to be further elucidated.

    IMPORTANCE: During HSV2 infection viral particles should become coated with complement proteins and antibodies, both existent in the genital fluids, which could influence the activation of the immune responses. The dendritic cells are the activators of the immune responses directed against HSV2, and the aim of this study was to examine the effects of complement alone or complement and antibodies, on the HSV2 infection of dendritic cells and their ability to mount inflammatory and antiviral responses.Our results demonstrate that the presence of antibodies and complement in the genital environment can influence HSV2 infection under in vitro conditions that reflect the in vivo situation. We believe that our findings are highly relevant for the understanding of HSV2 pathogenesis.

  • 15.
    Dahlström, Örjan
    et al.
    Linköping University, Department of Behavioural Sciences and Learning, Psychology. Linköping University, Faculty of Arts and Sciences. Linköping University, The Swedish Institute for Disability Research.
    Sjöwall, Christopher
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Rheumatology.
    The diagnostic accuracies of the 2012 SLICC criteria and the proposed EULAR/ACR criteria for systemic lupus erythematosus classification are comparable2019In: Lupus, ISSN 0961-2033, E-ISSN 1477-0962, Vol. 28, no 6, p. 778-782Article in journal (Refereed)
    Abstract [en]

    In a joint effort, the European League Against Rheumatism (EULAR) and the American College of Rheumatology (ACR) recently proposed new criteria for the classification of systemic lupus erythematosus (SLE) with the overarching goal to identify potential participants for clinical studies. Herein, we present the first independent evaluation of these criteria in comparison with older classification grounds using an adult Scandinavian study population of confirmed SLE cases and individuals with SLE-mimicking conditions. We included 56 confirmed SLE cases meeting the 1982 ACR criteria (ACR-82) and/or the Fries diagnostic principle (antinuclear antibodies on at least one occasion plus involvement of at least two defined organ systems) and 55 controls with possible systemic autoimmune disease, including the presence of any SLE-related autoantibody. The proposed EULAR/ACR criteria showed a diagnostic sensitivity of 93% (95% confidence interval (CI), 0.83-0.98) compared with 83% (95% CI, 0.72-0.91) for the updated ACR criteria from 1997. The diagnostic accuracy of all tested classification grounds was fairly similar, achieving approximately 85%. However, the disease specificity of the EULAR/ACR criteria reached only 73% (95% CI, 0.59-0.83), which was comparable with the 2012 Systemic Lupus International Collaborating Clinics (SLICC) criteria, 75% (95% CI, 0.61-0.85), but clearly lower than for ACR-82, 94% (95% CI, 0.83-0.99). In this first independent evaluation of a limited number of cases, we found comparable results with respect to diagnostic sensitivity, specificity and accuracy regarding the SLICC-12 and the proposed EULAR/ACR classification criteria. However, their specificity for SLE appeared to be lower compared with ACR-82.

  • 16.
    Di Giuseppe, Daniela
    et al.
    Karolinska Inst, Sweden.
    Frisell, Thomas
    Karolinska Inst, Sweden.
    Ernestam, Sofia
    Karolinska Univ Hosp, Sweden.
    Forsblad-DElia, Helena
    Umea Univ, Sweden.
    Lindqvist, Elisabet
    Lund Univ, Sweden; Skane Univ Hosp, Sweden.
    Lindstrom, Ulf
    Gothenburg Univ, Sweden.
    Sjöwall, Christopher
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Rheumatology.
    Askling, Johan
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Uptake of rheumatology biosimilars in the absence of forced switching2018In: Expert Opinion on Biological Therapy, ISSN 1471-2598, E-ISSN 1744-7682, Vol. 18, no 5, p. 499-504Article in journal (Refereed)
    Abstract [en]

    Background: To describe the uptake and system-level effects of the introduction of biosimilars in a setting without forced switching.Research design and methods: We used data from the Swedish Rheumatology Quality register from start of marketing of infliximab (Remsima (R) and Inflectra (R)) and etanercept (Benepali (R)) biosimilars until 31 December 2016. We compared users of each originator-product and its biosimilar(s) by line of treatment: bDMARD-naive patients, non-medical switchers (vs. matched patients remaining on originator), and patients switching from a previous bDMARD of another type.Results: From the start of marketing 1343 patients started an infliximab biosimilar (22 months) and 2691 started etanercept (9months). Overall, the introduction of these biosimilars resulted in an increase of the total number of ongoing infliximab and etanercept treatments (originator + biosimilar) . At the end of the study period, biosimilars accounted for 31% of all infliximab treatments and 31% of all etanercept-treated patients. For each line of therapy, we noted only small differences in patient characteristics between those starting the originator product vs. its biosimilar(s).Conclusions: Introduction of biosimilars have effects beyond replacement of the originator product, in terms of an increased rate of bDMARD initiation. Selection to non-medical switching displayed no particular disease- or patient-characteristics.

  • 17. Di Giuseppe, Daniela
    et al.
    Frisell, Thomas
    Ernestam, Sofia
    Forsblad-d'Elia, Helena
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Lindqvist, Elisabet
    Lindström, Ulf
    Sjöwall, Christopher
    Askling, Johan
    Uptake of rheumatology biosimilars in the absence of forced switching2018In: Expert Opinion on Biological Therapy, ISSN 1471-2598, E-ISSN 1744-7682, Vol. 18, no 5, p. 499-504Article in journal (Refereed)
    Abstract [en]

    Background: To describe the uptake and system-level effects of the introduction of biosimilars in a setting without forced switching.Research design and methods: We used data from the Swedish Rheumatology Quality register from start of marketing of infliximab (Remsima (R) and Inflectra (R)) and etanercept (Benepali (R)) biosimilars until 31 December 2016. We compared users of each originator-product and its biosimilar(s) by line of treatment: bDMARD-naive patients, non-medical switchers (vs. matched patients remaining on originator), and patients switching from a previous bDMARD of another type.Results: From the start of marketing 1343 patients started an infliximab biosimilar (22 months) and 2691 started etanercept (9months). Overall, the introduction of these biosimilars resulted in an increase of the total number of ongoing infliximab and etanercept treatments (originator + biosimilar) . At the end of the study period, biosimilars accounted for 31% of all infliximab treatments and 31% of all etanercept-treated patients. For each line of therapy, we noted only small differences in patient characteristics between those starting the originator product vs. its biosimilar(s).Conclusions: Introduction of biosimilars have effects beyond replacement of the originator product, in terms of an increased rate of bDMARD initiation. Selection to non-medical switching displayed no particular disease- or patient-characteristics.

  • 18.
    Dieker, Jurgen
    et al.
    Radboud University of Nijmegen, Netherlands.
    Berden, Jo H.
    Radboud University of Nijmegen, Netherlands.
    Bakker, Marinka
    Radboud University of Nijmegen, Netherlands.
    Briand, Jean-Paul
    CNRS, France.
    Muller, Sylviane
    CNRS, France.
    Voll, Reinhard
    University of Medical Centre Freiburg, Germany; University of Medical Centre Freiburg, Germany.
    Sjöwall, Christopher
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Rheumatology.
    Herrmann, Martin
    Friedrich Alexander University of Erlangen Nuremberg, Germany.
    Hilbrands, Luuk B.
    Radboud University of Nijmegen, Netherlands.
    van der Vlag, Johan
    Radboud University of Nijmegen, Netherlands.
    Autoantibodies against Modified Histone Peptides in SLE Patients Are Associated with Disease Activity and Lupus Nephritis2016In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 10, article id e0165373Article in journal (Refereed)
    Abstract [en]

    Persistent exposure of the immune system to death cell debris leads to autoantibodies against chromatin in patients with systemic lupus erythematosus (SLE). Deposition of antichromatin/ chromatin complexes can instigate inflammation in multiple organs including the kidney. Previously we identified specific cell death-associated histone modifications as targets of autoantibodies in SLE. In this study we addressed, in a large cohort of SLE patients and controls, the question whether plasma reactivities with specific histone peptides associated with serology and clinical features. Plasma from SLE patients with and without lupus nephritis, disease controls, and healthy controls, were tested in ELISA with histone H4 peptide acetylated at lysines 8, 12 and 16 (H4p(ac)), H2B peptide acetylated at lysine 12 (H2Bp(ac)), H3 peptide trimethylated at lysine 27 (H3p(me)), and their unmodified equivalents. SLE patients displayed a higher reactivity with the modified equivalent of each peptide. Reactivity with H4p(ac) showed both a high sensitivity (89%) and specificity (91%) for SLE, while H2Bp(ac) exhibited a high specificity (96%) but lower sensitivity (69%). Reactivity with H3p(me) appeared not specific for SLE. Anti-H4p(ac) and anti-H2Bp(ac) reactivity demonstrated a high correlation with disease activity. Moreover, patients reacting with multiple modified histone peptides exhibited higher SLEDAI and lower C3 levels. SLE patients with renal involvement showed higher reactivity with H2B/H2Bp(ac) and a more pronounced reactivity with the modified equivalent of H3p(me) and H2Bp(ac). In conclusion, reactivity with H4p(ac) and H2Bp(ac) is specific for SLE patients and correlates with disease activity, whereas reactivity with H2Bp(ac) is in particular associated with lupus nephritis.

  • 19.
    Ellegård, Rada
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Crisci, Elisa
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Burgener, Adam
    University of Manitoba, Winnipeg, Canada; Public Health Agency of Canada, Winnipeg, Canada.
    Sjöwall, Christoffer
    Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Rheumatology.
    Birse, Kenzie
    University of Manitoba, Winnipeg, Canada; Public Health Agency of Canada, Winnipeg, Canada.
    Westmacott, Garrett
    Public Health Agency of Canada, Winnipeg, Canada.
    Hinkula, Jorma
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Lifson, Jeffrey D.
    Leidos Biomedical Research, Inc., Frederick, MD, USA.
    Larsson, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Complement Opsonization of HIV-1 Results in Decreased Antiviral and Inflammatory Responses in Immature Dendritic Cells via CR32014In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 193, no 9, p. 4590-4601Article in journal (Refereed)
    Abstract [en]

    Immature dendritic cells (iDCs) in genital and rectal mucosa may be one of the first cells to come into contact with HIV-1 during sexual transmission of virus. HIV-1 activates the host complement system, which results in opsonization of virus by inactivated complement fragments, for example, iC3b. We investigated antiviral and inflammatory responses induced in human iDCs after exposure to free HIV-1 (F-HIV), complement-opsonized HIV-1 (C-HIV), and complement and Ab-opsonized HIV-1 (CI-HIV). F-HIV gave rise to a significantly higher expression of antiviral factors such as IFN-beta, myxovirus resistance protein A, and IFN-stimulated genes, compared with C-HIV and CI-HIV. Additionally, F-HIV induced inflammatory factors such as IL-1 beta, IL-6, and TNF-alpha, whereas these responses were weakened or absent after C-HIV or CI-HIV exposure. The responses induced by F-HIV were TLR8-dependent with subsequent activation of IFN regulatory factor 1, p38, ERK, PI3K, and NF-kappa B pathways, whereas these responses were not induced by C-HIV, which instead induced activation of IFN regulatory factor 3 and Lyn. This modulation of TLR8 signaling was mediated by complement receptor 3 and led to enhanced infection. The impact that viral hijacking of the complement system has on iDC function could be an important immune evasion mechanism used by HIV-1 to establish infection in the host.

  • 20.
    Enocsson, Helena
    et al.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Sjöwall, Christoffer
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Rheumatology in Östergötland.
    Skogh, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Rheumatology in Östergötland.
    Eloranta, Maija-Leena
    Uppsala Univ, Uppsala, Sweden.
    Ronnblom, Lars
    Uppsala Univ, Uppsala, Sweden.
    Wetterö, Jonas
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences.
    Interferon-alpha Mediates Suppression of C-Reactive Protein Explanation for Muted C-Reactive Protein Response in Lupus Flares?2009In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 60, no 12, p. 3755-3760Article in journal (Refereed)
    Abstract [en]

    Objective. C-reactive protein (CRP) is synthesized by hepatocytes in response to interleukin-6 (IL-6) during inflammation. Despite raised IL-6 levels and extensive systemic inflammation, serum CRP levels remain low during most viral infections and disease flares of systemic lupus erythematosus (SLE). Because both viral infections and SLE are characterized by high levels of interferon-alpha (IFN alpha), the aim of this study was to determine whether this cytokine can inhibit the induction of CRP. Methods. The interference of all 12 IFN alpha subtypes with CRP promoter activity induced by IL-6 and IL-1 beta was studied in a CRP promoter- and luciferase reporter-transfected human hepatoma cell line, Hep-G2. CRIP secretion by primary human hepatocytes was analyzed by enzyme-linked immunosorbent assay. Results. CRP promoter activity was inhibited by all single IFN alpha subtypes, as well as by 2 different mixtures of biologically relevant IFN alpha subtypes. The most prominent effect was seen using a leukocyte-produced mixture of IFN alpha (56% inhibition at 1,000 IU/ml). The inhibitory effect of IFN alpha was confirmed in primary human hepatocytes. CRP promoter inhibition was dose dependent and mediated via the type I IFN receptor. Transferrin production and Hep-G2 proliferation/viability were not affected by IFN alpha. Conclusion. The current study demonstrates that IFN alpha is an inhibitor of CRP promoter activity and CRP secretion. This finding concords with previous observations of up-regulated IFN alpha and a muted CRP response during SLE disease flares. Given the fundamental role of both IFN alpha and CRP in the immune response, our results are of importance for understanding the pathogenesis of SLE and may also contribute to understanding the differences in the CRP response between viral and bacterial infections.

  • 21.
    Enocsson, Helena
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Sjöwall, Christoffer
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Rheumatology.
    Wetterö, Jonas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Soluble urokinase plasminogen activator receptor: A valuable biomarker in systemic lupus erythematosus?2015In: Clinica Chimica Acta, ISSN 0009-8981, E-ISSN 1873-3492, Vol. 444, p. 234-241Article, review/survey (Refereed)
    Abstract [en]

    Systemic lupus erythematosus (SLE) is a potentially severe autoimmune condition with an unpredictable disease course, often with fluctuations in disease activity over time. Long term inflammation and drug-related side-effects may subsequently lead to permanent organ damage, a consequence which is intimately connected to decreased quality of life and mortality. New lupus biomarkers that convey information regarding inflammation and/or organ damage are thus warranted. Today, there is no clinical biomarker that indicates the risk of damage accrual. Herein we highlight the urokinase plasminogen activator receptor (uPAR) and especially its soluble form (suPAR) that besides having biological functions in e.g. proteolysis, cell migration and tissue homeostasis, recently has emerged as a promising biomarker of inflammation and prognosis of several disorders. A strong association between suPAR and organ damage in SLE was recently demonstrated, and preliminary data (presented in this review) suggests the possibility of a predictive value of suPAR blood levels. The involvement of suPAR in the pathogenesis of SLE remains obscure, but its effects in leukocyte recruitment, phagocytic uptake of dying cells (efferocytosis) and complement regulation suggests that the central parts of the SLE pathogenesis could be regulated by suPAR, and vice versa.

  • 22.
    Enocsson, Helena
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Sjöwall, Christoffer
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Region Östergötland, Heart and Medicine Center, Department of Rheumatology. Linköping University, Faculty of Medicine and Health Sciences.
    Wirestam, Lina
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Dahle, Charlotte
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Region Östergötland, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Kastbom, Alf
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Region Östergötland, Heart and Medicine Center, Department of Rheumatology. Linköping University, Faculty of Medicine and Health Sciences.
    Ronnelid, Johan
    Uppsala University, Sweden.
    Wetterö, Jonas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Skogh, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Region Östergötland, Heart and Medicine Center, Department of Rheumatology. Linköping University, Faculty of Medicine and Health Sciences.
    Four Anti-dsDNA Antibody Assays in Relation to Systemic Lupus Erythematosus Disease Specificity and Activity2015In: Journal of Rheumatology, ISSN 0315-162X, E-ISSN 1499-2752, Vol. 42, no 5, p. 817-825Article in journal (Refereed)
    Abstract [en]

    Objective. Analysis of antibodies against dsDNA is an important diagnostic tool for systemic lupus erythematosus (SLE), and changes in anti-dsDNA antibody levels are also used to assess disease activity. Herein, 4 assays were compared with regard to SLE specificity, sensitivity, and association with disease activity variables. Methods. Cross-sectional sera from 178 patients with SLE, of which 11 were followed consecutively, from a regional Swedish SLE register were analyzed for immunoglobulin G (IgG) anti-dsDNA by bead-based multiplex assay (FIDIS; Theradig), fluoroenzyme-immunoassay (EliA; Phadia/Thermo Fisher Scientific), Crithidia luciliae immunofluorescence test (CLIFT; ImmunoConcepts), and line blot (EUROLINE; Euroimmun). All patients with SLE fulfilled the 1982 American College of Rheumatology and/or the 2012 Systemic Lupus International Collaborating Clinics (SLICC-12) classification criteria. Healthy individuals (n = 100), patients with rheumatoid arthritis (n = 95), and patients with primary Sjogren syndrome (n = 54) served as controls. Results. CLIFT had the highest SLE specificity (98%) whereas EliA had the highest sensitivity (35%). When cutoff levels for FIDIS, EliA, and EUROLINE were adjusted according to SLICC-12 (i.e., double the reference limit when using ELISA), the specificity and sensitivity of FIDIS was comparable to CLIFT. FIDIS and CLIFT also showed the highest concordance (84%). FIDIS performed best regarding association with disease activity in cross-sectional and consecutive samples. Fishers exact test revealed striking differences between methods regarding associations with certain disease phenotypes. Conclusion. CLIFT remains a good choice for diagnostic purposes, but FIDIS performs equally well when the cutoff is adjusted according to SLICC-12. Based on results from cross-sectional and consecutive analyses, FIDIS can also be recommended to monitor disease activity.

  • 23.
    Enocsson, Helena
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences.
    Sjöwall, Christopher
    Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Rheumatology.
    Kastbom, Alf
    Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Rheumatology.
    Skogh, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Rheumatology.
    Eloranta, Maija-Leena
    Uppsala University, Sweden.
    Rönnblom, Lars
    Uppsala University, Sweden.
    Wetterö, Jonas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences.
    Association of Serum C-Reactive Protein Levels With Lupus Disease Activity in the Absence of Measurable Interferon-α and a C-Reactive Protein Gene Variant2014In: Arthritis & rheumatology (Hoboken, N.J.), ISSN 2326-5191, Vol. 66, no 6, p. 1568-1573Article in journal (Refereed)
    Abstract [en]

    Objectives: The type I interferon (IFN) system is important in the pathogenesis of systemic lupus erythematosus (SLE). We previously demonstrated an inhibitory effect of IFNα on interleukin 6 (IL-6) induced C-reactive protein (CRP) in vitro, hypothetically explaining the poor correlation between disease activity and CRP levels in SLE. Herein we investigated disease activity, IL-6 and CRP in relation to a CRP gene polymorphism and IFN.

    Methods: Sera from 155 SLE patients and 100 controls were analyzed for CRP. Patients were genotyped for a CRP single nucleotide polymorphism (rs1205) associated with low CRP levels. Serum IFNα and IL-6 was quantified by immunoassays. Clinical disease activity was assessed by SLE disease activity index 2000 (SLEDAI-2K).

    Results: CRP levels were increased in SLE patients compared to controls, but were not associated with SLEDAI-2K or IL-6 levels. However, exclusion of patients carrying at least one rs1205 minor allele revealed an association between disease activity and CRP levels (p=0.005). We found a strong association between disease activity and CRP levels (p<0.0005) when patients with measurable IFNα as well as the minor allele of rs1205 where excluded from the analysis. Similarly, when patients with raised IFNα and/or the rs1205 polymorphism were excluded, IL-6 associated with CRP levels.

    Conclusions: The present study demonstrates that serum IFNα as well as CRP genotype affects the CRP response in SLE patients. Lack of correlation between serum levels of CRP and disease activity could therefore be explained by activation of the type I IFN system and polymorphisms in the CRP gene. © 2014 American College of Rheumatology.

  • 24.
    Enocsson, Helena
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences.
    Wetterö, Jonas
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences.
    Skogh, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Rheumatology in Östergötland.
    Sjöwall, Christoffer
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Rheumatology in Östergötland.
    Limited Value of Soluble Urokinase Plasminogen Activator Receptor As a Disease Activity Marker in Patients with Systemic Lupus Erythematosus in ARTHRITIS AND RHEUMATISM, vol 63, issue 10, pp S556-S5572011In: ARTHRITIS AND RHEUMATISM, Wiley-Blackwell , 2011, Vol. 63, no 10, p. S556-S557Conference paper (Refereed)
    Abstract [en]

    n/a

  • 25.
    Enocsson, Helena
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences.
    Wetterö, Jonas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences.
    Skogh, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Rheumatology.
    Sjöwall, Christoffer
    Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Rheumatology.
    Soluble urokinase plasminogen activator receptor levels reflect organ damage in systemic lupus erythematosus2013In: Translational Research: The Journal of Laboratory and Clinical Medicine, ISSN 1931-5244, E-ISSN 1878-1810, Vol. 162, no 5, p. 287-296Article in journal (Refereed)
    Abstract [en]

    Assessments of disease activity and organ damage in systemic lupus erythematosus (SLE) remain challenging because of the lack of reliable biomarkers and disease heterogeneity. Ongoing inflammation can be difficult to distinguish from permanent organ damage caused by previous flare-ups or medication side effects. Circulating soluble urokinase plasminogen activator receptor (suPAR) has emerged as a potential marker of inflammation and disease severity, and an outcome predictor in several disparate conditions. This study was done to evaluate suPAR as a marker of disease activity and organ damage in SLE. Sera from 100 healthy donors- and 198 patients with SLE fulfilling the 1982 American College of Rheumatology classification criteria and/or the Fries criteria were analyzed for suPAR by enzyme immunoassay. Eighteen patients with varying degree of disease activity were monitored longitudinally. Disease activity was assessed by the SLE disease activity index 2000 and the physicians global assessment. Organ damage was evaluated by the Systemic Lupus International Collaborating Clinics/American College of Rheumatology damage index (SDI). Compared with healthy control subjects, serum suPAR levels were elevated significantly in patients with SLE. No association was recorded regarding suPAR levels and SLE disease activity in cross-sectional or consecutive samples. However, a strong association was observed between suPAR and SDI (P andlt; 0.0005). Considering distinct SDI domains, renal, neuropsychiatric, ocular, skin, and peripheral vascular damage had.a significant effect on suPAR levels. This study is the first to demonstrate an association between serum suPAR and irreversible organ damage in SLE. Further studies are warranted to evaluate suPAR and other biomarkers as predictors of evolving organ damage.

  • 26.
    Eriksson, Per
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Rheumatology.
    Wallin, Philip
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Rheumatology.
    Sjöwall, Christopher
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Rheumatology.
    Clinical Experience of Sirolimus Regarding Efficacy and Safety in Systemic Lupus Erythematosus2019In: Frontiers in Pharmacology, ISSN 1663-9812, E-ISSN 1663-9812, Vol. 10, article id 82Article in journal (Refereed)
    Abstract [en]

    New treatment options constitute unmet needs for patients diagnosed with systemic lupus erythematosus (SLE). Inhibition of the mammalian target of rapamycin (mTOR) pathway by sirolimus, a drug approved and in clinical use to prevent transplant rejection, has shown promising effects in lupus animal models as well as in patients with both antiphospholipid syndrome and SLE. Sirolimus inhibits antigen-induced T cell proliferation and increases the number of circulating regulatory T cells. Recently, sirolimus was tested in an open label phase 1/2 trial, including 43 patients with active SLE, resistant or intolerant to conventional medications. The results were encouraging showing a progressive improvement, including mucocutaneous and musculoskeletal manifestations. At our university unit, we have more than 16 years experience of sirolimus as treatment for non-renal manifestations of SLE. Herein, we retrospectively evaluated data on tolerance, dosage, affected organ systems, disease activity measures, corticosteroid reduction, concomitant immunosuppressive therapies, and patient-reported outcome measures (PROMs) such as pain intensity, fatigue, well-being and quality-of-life (QoL) in 27 Caucasian patients with mildly active SLE. Musculoskeletal manifestation was the main reason for sirolimus treatment followed by skin involvement and leukocytopenia. Mean time on sirolimus was 47.1 (range 2-140) months. Decreasing global disease activity was observed, as measured by the clinical SLE disease activity index-2000, with a mean reduction of 2.5 points (range -10 to 0) and a corresponding mean reduction of the physicians global assessment (0-4) of 0.64 (range -2 to 0). The mean daily dose of corticosteroids (prednisolone) was reduced by 3.3 mg (-12.5 to 0). Non-significant trends toward improvements of QoL and pain intensity were found. Serious side-effects were not seen during sirolimus treatment, but early withdrawal due to nausea (n = 4) and non-serious infections (n = 2) appeared. This observational study, including longtime real-life use of sirolimus in SLE, is the largest to date and it essentially confirms the results of the recent phase 1/2 trial. Our data indicate that sirolimus is efficient in patients with musculoskeletal SLE manifestations, particularly arthritis and tendinitis. Further randomized controlled trials evaluating the potential benefits of sirolimus in SLE are warranted, but should aim to enroll patients with shorter disease duration, less accrued damage, and more diverse ethnicities.

  • 27. Farias, Fabiana H. G.
    et al.
    Dahlqvist, Johanna
    Kozyrev, Sergey V.
    Leonard, Dag
    Wilbe, Maria
    Abramov, Sergei N.
    Alexsson, Andrei
    Pielberg, Gerli R.
    Hansson-Hamlin, Helene
    Andersson, Goran
    Tandre, Karolina
    Bengtsson, Anders A.
    Sjöwall, Christopher
    Svenungsson, Elisabet
    Gunnarsson, Iva
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Syvanen, Ann-Christine
    Sandling, Johanna K.
    Eloranta, Maija-Leena
    Rönnblom, Lars
    Lindblad-Toh, Kerstin
    A rare regulatory variant in the MEF2D gene affects gene regulation and splicing and is associated with a SLE sub-phenotype in Swedish cohorts2019In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 27, no 3, p. 432-441Article in journal (Refereed)
    Abstract [en]

    Systemic lupus erythematosus (SLE) is an autoimmune disorder with heterogeneous clinical presentation and complex etiology involving the interplay between genetic, epigenetic, environmental and hormonal factors. Many common SNPs identified by genome wide-association studies (GWAS) explain only a small part of the disease heritability suggesting the contribution from rare genetic variants, undetectable in GWAS, and complex epistatic interactions. Using targeted resequencing of coding and conserved regulatory regions within and around 215 candidate genes selected on the basis of their known role in autoimmunity and genes associated with canine immune-mediated diseases, we identified a rare regulatory variant rs200395694:G > T located in intron 4 of the MEF2D gene encoding the myocyte-specific enhancer factor 2D transcription factor and associated with SLE in Swedish cohorts (504 SLE patients and 839 healthy controls, p = 0 .014 , CI = 1.1-10). Fisher's exact test revealed an association between the genetic variant and a triad of disease manifestations including Raynaud, anti-Ul-ribonucleoprotein (anti-RNP), and anti-Smith (anti-Sm) antibodies (p = 0.00037) among the patients. The DNA-binding activity of the allele was further studied by EMSA, reporter assays, and minigenes. The region has properties of an active cell-specific enhancer, differentially affected by the alleles of rs200395694:G > T. In addition, the risk allele exerts an inhibitory effect on the splicing of the alternative tissue-specific isoform, and thus may modify the target gene set regulated by this isoform. These findings emphasize the potential of dissecting traits of complex diseases and correlating them with rare risk alleles with strong biological effects.

  • 28.
    Farias, Fabiana H. G.
    et al.
    Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Box 582, SE-751 24, Uppsala, Sweden // Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, 63110, USA.
    Dahlqvist, Johanna
    Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Box 582, SE-751 24, Uppsala, Sweden.
    Kozyrev, Sergey V.
    Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Box 582, SE-751 24, Uppsala, Sweden.
    Leonard, Dag
    Science for Life Laboratory, Department of Medical Sciences, Section of Rheumatology, Uppsala University, SE-751 85, Uppsala, Sweden.
    Wilbe, Maria
    Department of Animal Breeding and Genetics, Swedish University of Agricultural Sciences (SLU), Box 7023, SE-750 07, Uppsala, Sweden.
    Abramov, Sergei N.
    Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Box 582, SE-751 24, Uppsala, Sweden // Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, 420008, Russia.
    Alexsson, Andrei
    Science for Life Laboratory, Department of Medical Sciences, Section of Rheumatology, Uppsala University, SE-751 85, Uppsala, Sweden.
    Pielberg, Gerli R.
    Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Box 582, SE-751 24, Uppsala, Sweden.
    Hansson-Hamlin, Helene
    Department of Clinical Sciences, Swedish University of Agricultural Sciences (SLU), Box 7054, SE-750 07, Uppsala, Sweden.
    Andersson, Göran
    Department of Animal Breeding and Genetics, Swedish University of Agricultural Sciences (SLU), Box 7023, SE-750 07, Uppsala, Sweden.
    Tandre, Karolina
    Science for Life Laboratory, Department of Medical Sciences, Section of Rheumatology, Uppsala University, SE-751 85, Uppsala, Sweden.
    Bengtsson, Anders A.
    Department of Clinical Sciences Lund, Lund University, Skane University Hospital, SE-221 00, Lund, Sweden.
    Sjöwall, Christopher
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Svenungsson, Elisabet
    Rheumatology Unit, Department of Medicine, Solna, Karolinska Institutet, Karolinska University Hospital, SE-171 76, Stockholm, Sweden.
    Gunnarsson, Iva
    Rheumatology Unit, Department of Medicine, Solna, Karolinska Institutet, Karolinska University Hospital, SE-171 76, Stockholm, Sweden.
    Rantapää-Dahlqvist, Solbritt
    Department of Public Health and Clinical Medicine/Rheumatology, Umeå University, SE-901 85, Umeå, Sweden.
    Syvänen, Ann-Christine
    Science for Life Laboratory, Department of Medical Sciences, Section of Rheumatology, Uppsala University, SE-751 85, Uppsala, Sweden // Department of Medical Sciences, Molecular Medicine and Science for Life Laboratory, Uppsala University, SE-754 11, Uppsala, Sweden.
    Sandling, Johanna K.
    Science for Life Laboratory, Department of Medical Sciences, Section of Rheumatology, Uppsala University, SE-751 85, Uppsala, Sweden.
    Eloranta, Maija-Leena
    Science for Life Laboratory, Department of Medical Sciences, Section of Rheumatology, Uppsala University, SE-751 85, Uppsala, Sweden.
    Rönnblom, Lars
    Science for Life Laboratory, Department of Medical Sciences, Section of Rheumatology, Uppsala University, SE-751 85, Uppsala, Sweden.
    Lindblad-Toh, Kerstin
    Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Box 582, SE-751 24, Uppsala, Sweden // Broad Institute, Cambridge, 7 Cambridge Center, Cambridge, MA, 02142, USA.
    A rare regulatory variant in the MEF2D gene affects gene regulation and splicing and is associated with a SLE sub-phenotype in Swedish cohorts2019In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 27, no 3, p. 432-441Article in journal (Refereed)
    Abstract [en]

    Systemic lupus erythematosus (SLE) is an autoimmune disorder with heterogeneous clinical presentation and complex etiology involving the interplay between genetic, epigenetic, environmental and hormonal factors. Many common SNPs identified by genome wide-association studies (GWAS) explain only a small part of the disease heritability suggesting the contribution from rare genetic variants, undetectable in GWAS, and complex epistatic interactions. Using targeted re-sequencing of coding and conserved regulatory regions within and around 215 candidate genes selected on the basis of their known role in autoimmunity and genes associated with canine immune-mediated diseases, we identified a rare regulatory variant rs200395694:G > T located in intron 4 of the MEF2D gene encoding the myocyte-specific enhancer factor 2D transcription factor and associated with SLE in Swedish cohorts (504 SLE patients and 839 healthy controls, p = 0.014, CI = 1.1–10). Fisher’s exact test revealed an association between the genetic variant and a triad of disease manifestations including Raynaud, anti-U1-ribonucleoprotein (anti-RNP), and anti-Smith (anti-Sm) antibodies (p = 0.00037) among the patients. The DNA-binding activity of the allele was further studied by EMSA, reporter assays, and minigenes. The region has properties of an active cell-specific enhancer, differentially affected by the alleles of rs200395694:G > T. In addition, the risk allele exerts an inhibitory effect on the splicing of the alternative tissue-specific isoform, and thus may modify the target gene set regulated by this isoform. These findings emphasize the potential of dissecting traits of complex diseases and correlating them with rare risk alleles with strong biological effects.

  • 29.
    Frodlund, Martina
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences.
    Dahlström, Örjan
    Linköping University, Department of Behavioural Sciences and Learning, Disability Research. Linköping University, Faculty of Arts and Sciences.
    Kastbom, Alf
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Rheumatology.
    Skogh, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Rheumatology.
    Sjöwall, Christopher
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Rheumatology.
    Associations between antinuclear antibody staining patterns and clinical features of systemic lupus erythematosus: analysis of a regional Swedish register2013In: BMJ Open, ISSN 2044-6055, E-ISSN 2044-6055, Vol. 3, p. 1-8Article in journal (Refereed)
    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.

  • 30.
    Frodlund, Martina
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Rheumatology.
    Reid, S.
    Uppsala Univ, Sweden.
    Wetterö, Jonas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. 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. Linköping University, The Swedish Institute for Disability Research.
    Sjöwall, Christopher
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Rheumatology.
    Leonard, D.
    Uppsala Univ, Sweden.
    The majority of Swedish systemic lupus erythematosus patients are still affected by irreversible organ impairment: factors related to damage accrual in two regional cohorts2019In: Lupus, ISSN 0961-2033, E-ISSN 1477-0962, article id UNSP 0961203319860198Article in journal (Refereed)
    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.

  • 31.
    Frodlund, Martina
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Rheumatology.
    Vikerfors, A.
    Karolinska Univ Hosp, Sweden; Swedish Med Prod Agcy, Sweden.
    Grosso, G.
    Karolinska Univ Hosp, Sweden.
    Skogh, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Rheumatology.
    Wetterö, Jonas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Elvin, K.
    Karolinska Inst, Sweden.
    Gunnarsson, I.
    Karolinska Univ Hosp, Sweden.
    Kastbom, Alf
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Rheumatology.
    Dahlström, Örjan
    Linköping University, Department of Behavioural Sciences and Learning, Disability Research. Linköping University, Faculty of Arts and Sciences. Linköping University, The Swedish Institute for Disability Research.
    Ronnelid, J.
    Uppsala Univ, Sweden.
    Svenungsson, E.
    Karolinska Univ Hosp, Sweden.
    Sjöwall, Christopher
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Rheumatology.
    Immunoglobulin A anti-phospholipid antibodies in Swedish cases of systemic lupus erythematosus: associations with disease phenotypes, vascular events and damage accrual2018In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 194, no 1, p. 27-38Article in journal (Refereed)
    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.

  • 32.
    Gron, Kathrine Lederballe
    et al.
    Rigshosp, Denmark; Rigshosp, Denmark; Univ Copenhagen, Denmark.
    Arkema, Elizabeth V.
    Karolinska Inst, Sweden.
    Glintborg, Bente
    Rigshosp, Denmark; Rigshosp, Denmark; Copenhagen Univ Hosp, Denmark.
    Mehnert, Frank
    Aarhus Univ Hosp, Denmark.
    Ostergaard, Mikkel
    Rigshosp, Denmark; Rigshosp, Denmark; Univ Copenhagen, Denmark.
    Dreyer, Lene
    Aalborg Univ Hosp, Denmark.
    Norgaard, Mette
    Aarhus Univ Hosp, Denmark.
    Krogh, Niels Steen
    ZiteLab ApS, Denmark.
    Askling, Johan
    Karolinska Inst, Sweden.
    Hetland, Merete Lund
    Rigshosp, Denmark; Univ Copenhagen, Denmark.
    Askling, Johan
    Karolinska Inst, Sweden.
    Klareskog, Lars
    Karolinska Inst, Sweden.
    Feltelius, Nils
    Karolinska Inst, Sweden.
    Baecklund, Eva
    Uppsala Univ, Sweden.
    Sjöwall, Christopher
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Rheumatology.
    Rantapaa-Dahlqvist, Solbritt
    Umea Univ, Sweden.
    Forsblad-dElia, Helena
    Umea Univ, Sweden.
    Jacobsson, Lennart
    Sahlgrens Acad, Sweden.
    Turesson, Carl
    Lund Univ, Sweden.
    Lindqvist, Elisabet
    Lund Univ, Sweden.
    Nisell, Ralph
    Swedish Rheumatol Qual Register, Sweden.
    Risk of serious infections in patients with rheumatoid arthritis treated in routine care with abatacept, rituximab and tocilizumab in Denmark and Sweden2019In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 78, no 3, p. 320-327Article in journal (Refereed)
    Abstract [en]

    Objective To estimate (1) crude and age-and gender-adjusted incidence rates (IRs) of serious infections (SI) and (2) relative risks (RR) of SI in patients with rheumatoid arthritis (RA) initiating treatment with abatacept, rituximab or tocilizumab in routine care. Methods This is an observational cohort study conducted in parallel in Denmark and Sweden including patients with RA in Denmark (DANBIO) and Sweden (Anti-Rheumatic Treatment in Sweden Register/Swedish Rheumatology Quality Register) who started abatacept/rituximab/tocilizumab in 2010-2015. Patients could contribute to more than one treatment course. Incident SI (hospitalisations listing infection) and potential confounders were identified through linkage to national registries. Age-and gender-adjusted IRs of SI per 100 person years and additionally adjusted RRs of SI during 0-12 and 0-24 months since start of treatment were assessed (Poisson regression). Country-specific RRs were pooled using inverse variance weighting. Results We identified 8987 treatment courses (abatacept: 2725; rituximab: 3363; tocilizumab: 2899). At treatment start, rituximab-treated patients were older, had longer disease duration and more previous malignancies; tocilizumab-treated patients had higher C reactive protein. During 0-12 and 0-24 months of follow-up, 456 and 639 SI events were identified, respectively. The following were the age-and gender-adjusted 12-month IRs for abatacept/rituximab/tocilizumab: 7.1/8.1/6.1 for Denmark and 6.0/6.4/4.7 for Sweden. The 24-month IRs were 6.1/7.5/5.2 for Denmark and 5.6/5.8/4.3 for Sweden. Adjusted 12-month RRs for tocilizumab versus rituximab were 0.82 (0.50 to 1.36) for Denmark and 0.76 (0.57 to 1.02) for Sweden, pooled 0.78 (0.61 to 1.01); for abatacept versus rituximab 0.94 (0.55 to 1.60) for Denmark and 0.86 (0.66 to 1.13) for Sweden, pooled 0.88 (0.69 to 1.12); and for abatacept versus tocilizumab 1.15 (0.69 to 1.90) for Denmark and 1.14 (0.83 to 1.55) for Sweden, pooled 1.13 (0.91 to 1.42). The adjusted RRs for 0-24 months were similar. Conclusion For patients starting abatacept, rituximab or tocilizumab, differences in baseline characteristics were seen. Numerical differences in IR of SI between drugs were observed. RRs seemed to vary with drug (tocilizumab amp;lt; abatacept amp;lt; rituximab) but should be interpreted with caution due to few events and risk of residual confounding.

  • 33.
    Hellberg, Sandra
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Eklund, Daniel
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Gawel, Danuta
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Köpsén, Mattias
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics. Linköping University, Faculty of Science & Engineering.
    Zhang, Huan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Nestor, Colm
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Kockum, Ingrid
    Karolinska Institute, Department Clin Neurosci, Neuroimmunol Unit, S-17177 Linkoping, Sweden.
    Olsson, Tomas
    Karolinska Institute, Department Clin Neurosci, Neuroimmunol Unit, S-17177 Linkoping, Sweden.
    Skogh, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Rheumatology.
    Kastbom, Alf
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Rheumatology.
    Sjöwall, Christopher
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Rheumatology.
    Vrethem, Magnus
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Neurology.
    Håkansson, Irene
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Benson, Mikael
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Allergy Center.
    Jenmalm, Maria
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Gustafsson, Mika
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics. Linköping University, Faculty of Science & Engineering.
    Ernerudh, Jan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
    Dynamic Response Genes in CD4+T Cells Reveal a Network of Interactive Proteins that Classifies Disease Activity in Multiple Sclerosis2016In: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 16, no 11, p. 2928-2939Article in journal (Refereed)
    Abstract [en]

    Multiple sclerosis (MS) is a chronic inflammatory disease of the CNS and has a varying disease course as well as variable response to treatment. Biomarkers may therefore aid personalized treatment. We tested whether in vitro activation of MS patient-derived CD4+ T cells could reveal potential biomarkers. The dynamic gene expression response to activation was dysregulated in patient-derived CD4+ T cells. By integrating our findings with genome-wide association studies, we constructed a highly connected MS gene module, disclosing cell activation and chemotaxis as central components. Changes in several module genes were associated with differences in protein levels, which were measurable in cerebrospinal fluid and were used to classify patients from control individuals. In addition, these measurements could predict disease activity after 2 years and distinguish low and high responders to treatment in two additional, independent cohorts. While further validation is needed in larger cohorts prior to clinical implementation, we have uncovered a set of potentially promising biomarkers.

  • 34.
    Ighe, Anna
    et al.
    Region Östergötland, Heart and Medicine Center, Department of Rheumatology. Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Dahlström, Örjan
    Linköping University, Department of Behavioural Sciences and Learning, Disability Research. Linköping University, The Swedish Institute for Disability Research. Linköping University, Faculty of Arts and Sciences.
    Skogh, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Rheumatology.
    Sjöwall, Christopher
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Rheumatology.
    Application of the 2012 systemic lupus international collaborating clinics classification criteria to patients on a Regional Swedish systemic lupus erythematosus register2015In: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 17, article id 3Article in journal (Refereed)
    Abstract [en]

    Introduction

    In 2012, the Systemic Lupus International Collaborating Clinics (SLICC) network presented a new set of criteria (SLICC-12) to classify systemic lupus erythematosus (SLE). The present study is the first to evaluate the performance of SLICC-12 in an adult European study population. Thus, SLICC-12 criteria were applied to confirmed SLE cases in our regional SLE register as well as to individuals with a fair suspicion of systemic autoimmune disease who were referred to rheumatology specialists at our unit.     

    Methods

    We included 243 confirmed SLE patients who met the 1982 American College of Rheumatology (ACR-82) classification criteria and/or the Fries ‘diagnostic principle’ (presence  of antinuclear antibodies on at least one occasion plus involvement of at least two defined organ systems) and 55 controls with possible systemic autoimmune disease, including the presence of any SLE-related autoantibody.     

    Results

    SLICC-12 showed a diagnostic sensitivity of 94% (95% confidence interval (CI), 0.90 to 0.96) compared with 90% (95% CI, 0.85 to 0.93) for the updated set of ACR criteria from 1997 (ACR-97), whereas ACR-82 failed to identify every fifth true SLE case. However, the disease specificity of SLICC-12 reached only 74% (95% CI, 0.60 to 0.84) and did not change much when involvement of at least two different organs was required as an indicator of systemic disease. In addition, SLICC-12 misclassified more of the controls compared to ACR-82, ACR-97 and Fries.     

    Conclusions

    Establishing a standard definition of SLE continues to challenge lupus researchers and clinicians. We confirm that SLICC-12 has advantages with regard to diagnostic sensitivity, whereas we found the diagnostic specificity to be surprisingly low. To accomplish increased sensitivity and specificity figures, a combination of criteria sets for clinical SLE studies should be considered.

  • 35. Imgenberg-Kreuz, Juliana
    et al.
    Almlof, Jonas Carlsson
    Leonard, Dag
    Alexsson, Andrei
    Nordmark, Gunnel
    Eloranta, Maija-Leena
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Bengtsson, Anders A.
    Jonsen, Andreas
    Padyukov, Leonid
    Gunnarsson, Iva
    Svenungsson, Elisabet
    Sjowall, Christopher
    Ronnblom, Lars
    Syvanen, Ann-Christine
    Sandling, Johanna K.
    DNA methylation mapping identifies gene regulatory effects in patients with systemic lupus erythematosus2018In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 77, no 5, p. 736-743Article in journal (Refereed)
    Abstract [en]

    Objectives Systemic lupus erythematosus (SLE) is a chronic autoimmune condition with heterogeneous presentation and complex aetiology where DNA methylation changes are emerging as a contributing factor. In order to discover novel epigenetic associations and investigate their relationship to genetic risk for SLE, we analysed DNA methylation profiles in a large collection of patients with SLE and healthy individuals. Methods DNA extracted from blood from 548 patients with SLE and 587 healthy controls were analysed on the Illumina HumanMethylation 450 k BeadChip, which targets 485 000 CpG sites across the genome. Single nucleotide polymorphism (SNP) genotype data for 196 524 SNPs on the Illumina ImmunoChip from the same individuals were utilised for methylation quantitative trait loci (cis-meQTLs) analyses. Results We identified and replicated differentially methylated CpGs (DMCs) in SLE at 7245 CpG sites in the genome. The largest methylation differences were observed at type I interferon-regulated genes which exhibited decreased methylation in SLE. We mapped cis-meQTLs and identified genetic regulation of methylation levels at 466 of the DMCs in SLE. The meQTLs for DMCs in SLE were enriched for genetic association to SLE, and included seven SLE genome-wide association study (GWAS) loci: PTPRC (CD45), MHC-class III, UHRF1BP1, IRF5, IRF7, IKZF3 and UBE2L3. In addition, we observed association between genotype and variance of methylation at 20 DMCs in SLE, including at the HLADQB2 locus. Conclusions Our results suggest that several of the genetic risk variants for SLE may exert their influence on the phenotype through alteration of DNA methylation levels at regulatory regions of target genes.

  • 36.
    Imgenberg-Kreuz, Juliana
    et al.
    Uppsala Univ, Sweden.
    Carlsson Almlöf, Jonas Carlsson
    Uppsala Univ, Sweden.
    Leonard, Dag
    Uppsala Univ, Sweden.
    Sjöwall, Christopher
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Rheumatology.
    Syvanen, Ann-Christine
    Uppsala Univ, Sweden.
    Ronnblom, Lars
    Uppsala Univ, Sweden.
    Sandling, Johanna K.
    Uppsala Univ, Sweden.
    Nordmark, Gunnel
    Uppsala Univ, Sweden.
    Shared and Unique Patterns of DNA Methylation in Systemic Lupus Erythematosus and Primary Sjogrens Syndrome2019In: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 10, article id 1686Article in journal (Refereed)
    Abstract [en]

    Objectives: To performa cross-comparative analysis of DNA methylation in patients with systemic lupus erythematosus (SLE), patients with primary Sjogrens syndrome (pSS), and healthy controls addressing the question of epigenetic sharing and aiming to detect disease-specific alterations. Methods: DNA extracted from peripheral blood from 347 cases with SLE, 100 cases with pSS, and 400 healthy controls were analyzed on the Human Methylation 450k array, targeting 485,000 CpG sites across the genome. A linear regression model including age, sex, and blood cell type distribution as covariates was fitted, and association p-values were Bonferroni corrected. A random forest machine learning classifier was designed for prediction of disease status based on DNA methylation data. Results: We established a combined set of 4,945 shared differentially methylated CpG sites (DMCs) in SLE and pSS compared to controls. In pSS, hypomethylation at type I interferon induced genes was mainly driven by patients who were positive for Ro/SSA and/or La/SSB autoantibodies. Analysis of differential methylation between SLE and pSS identified 2,244 DMCs with a majority of sites showing decreased methylation in SLE compared to pSS. The random forest classifier demonstrated good performance in discerning between disease status with an area under the curve (AUC) between 0.83 and 0.96. Conclusions: The majority of differential DNA methylation is shared between SLE and pSS, however, important quantitative differences exist. Our data highlight neutrophil dysregulation as a shared mechanism, emphasizing the role of neutrophils in the pathogenesis of systemic autoimmune diseases. The current study provides evidence for genes and molecular pathways driving common and disease-specific pathogenic mechanisms.

  • 37.
    Imgenberg-Kreuz, Juliana
    et al.
    Uppsala Univ, Sweden.
    Carlsson Almlöf, Jonas
    Uppsala Univ, Sweden.
    Leonard, Dag
    Uppsala Univ, Sweden.
    Alexsson, Andrei
    Uppsala Univ, Sweden.
    Nordmark, Gunnel
    Uppsala Univ, Sweden.
    Eloranta, Maija-Leena
    Uppsala Univ, Sweden.
    Rantapaa-Dahlqvist, Solbritt
    Umea Univ, Sweden.
    Bengtsson, Anders A.
    Lund Univ, Sweden.
    Jonsen, Andreas
    Lund Univ, Sweden.
    Padyukov, Leonid
    Karolinska Inst, Sweden.
    Gunnarsson, Iva
    Karolinska Inst, Sweden.
    Svenungsson, Elisabet
    Karolinska Inst, Sweden.
    Sjöwall, Christopher
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Rheumatology.
    Ronnblom, Lars
    Uppsala Univ, Sweden.
    Syvanen, Ann-Christine
    Uppsala Univ, Sweden.
    Sandling, Johanna K.
    Uppsala Univ, Sweden; Uppsala Univ, Sweden.
    DNA methylation mapping identifies gene regulatory effects in patients with systemic lupus erythematosus2018In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 77, no 5, p. 736-743Article in journal (Refereed)
    Abstract [en]

    Objectives Systemic lupus erythematosus (SLE) is a chronic autoimmune condition with heterogeneous presentation and complex aetiology where DNA methylation changes are emerging as a contributing factor. In order to discover novel epigenetic associations and investigate their relationship to genetic risk for SLE, we analysed DNA methylation profiles in a large collection of patients with SLE and healthy individuals. Methods DNA extracted from blood from 548 patients with SLE and 587 healthy controls were analysed on the Illumina HumanMethylation 450 k BeadChip, which targets 485 000 CpG sites across the genome. Single nucleotide polymorphism (SNP) genotype data for 196 524 SNPs on the Illumina ImmunoChip from the same individuals were utilised for methylation quantitative trait loci (cis-meQTLs) analyses. Results We identified and replicated differentially methylated CpGs (DMCs) in SLE at 7245 CpG sites in the genome. The largest methylation differences were observed at type I interferon-regulated genes which exhibited decreased methylation in SLE. We mapped cis-meQTLs and identified genetic regulation of methylation levels at 466 of the DMCs in SLE. The meQTLs for DMCs in SLE were enriched for genetic association to SLE, and included seven SLE genome-wide association study (GWAS) loci: PTPRC (CD45), MHC-class III, UHRF1BP1, IRF5, IRF7, IKZF3 and UBE2L3. In addition, we observed association between genotype and variance of methylation at 20 DMCs in SLE, including at the HLADQB2 locus. Conclusions Our results suggest that several of the genetic risk variants for SLE may exert their influence on the phenotype through alteration of DNA methylation levels at regulatory regions of target genes.

  • 38.
    Isine Bolstad, Anne
    et al.
    University of Bergen.
    Le Hellard, Stephanie
    University of Bergen.
    Kristjansdottir, Gudlaug
    Uppsala University.
    Vasaitis, Lilian
    Uppsala University.
    Kvarnstrom, Marika
    Karolinska Institute.
    Sjöwall, Christoffer
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Rheumatology in Östergötland.
    Joar Auglaend Johnsen, Svein
    Stavanger University Hospital.
    Eriksson, Per
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Nephrology UHL.
    Omdal, Roald
    Stavanger University Hospital.
    Brun, Johan G
    University of Bergen.
    Wahren-Herlenius, Marie
    Karolinska Institute.
    Theander, Elke
    Lund University.
    Syvanen, Ann-Christine
    Uppsala University.
    Ronnblom, Lars
    Uppsala University.
    Nordmark, Gunnel
    Uppsala University.
    Jonsson, Roland
    University of Bergen.
    Association between genetic variants in the tumour necrosis factor/lymphotoxin alpha/lymphotoxin beta locus and primary Sjogrens syndrome in Scandinavian samples2012In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 71, no 6, p. 981-988Article in journal (Refereed)
    Abstract [en]

    Objectives Lymphotoxin beta (LTB) has been found to be upregulated in salivary glands of patients with primary Sjogrens syndrome (pSS). An animal model of pSS also showed ablation of the lymphoid organisation and a marked improvement in salivary gland function on blocking the LTB receptor pathway. This study aimed to investigate whether single-nucleotide polymorphisms (SNP) in the lymphotoxin alpha (LTA)/LTB/tumour necrosis factor (TNF) gene clusters are associated with pSS. less thanbrgreater than less thanbrgreater thanMethods 527 pSS patients and 532 controls participated in the study, all of Caucasian origin from Sweden and Norway. 14 SNP markers were genotyped and after quality control filtering, 12 SNP were analysed for their association with pSS using single marker and haplotype tests, and corrected by permutation testing. less thanbrgreater than less thanbrgreater thanResults Nine markers showed significant association with pSS at the p=0.05 level. Markers rs1800629 and rs909253 showed the strongest genotype association (p=1.64E-11 and p=4.42E-08, respectively, after correcting for sex and country of origin). When the analysis was conditioned for the effect of rs1800629, only the association with rs909253 remained nominally significant (p=0.027). In haplotype analyses the strongest effect was observed for the haplotype rs909253G_rs1800629A (p=9.14E-17). The associations were mainly due to anti-Ro/SSA and anti-La/SSB antibody-positive pSS. less thanbrgreater than less thanbrgreater thanConclusions A strong association was found between several SNP in the LTA/LTB/TNF alpha locus and pSS, some of which led to amino acid changes. These data suggest a role for this locus in the development of pSS. Further studies are needed to examine if the genetic effect described here is independent of the known genetic association between HLA and pSS.

  • 39.
    Jönsen, Andreas
    et al.
    Department of Rheumatology, Lund University, Lund,.
    Hjalte, Frida
    The Swedish Institute for Health Economics, Lund.
    Willim, Minna
    Lunds University, Lund .
    Carlsson, Katarina Steen
    The Swedish Institute for Health Economics, Lund.
    Sjöwall, Christopher
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Rheumatology.
    Svenungsson, Elisabet
    Karolinska University Hospital, K, Karolinska Institutet, Stockholm .
    Leonard, Dag
    Department of Medical Sciences, Section of Rheumatology, Uppsala University, Uppsala, Sweden.
    Bengtsson, Christine
    Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden.
    Rantapää-Dahlqvist, Solbritt
    Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden.
    Pettersson, Susanne
    Karolinska University Hospital, Karolinska Institutet, Stockholm.
    Gunnarsson, Iva
    University Hospital, Karolinska Institutet, Stockholm.
    Zickert, Agneta
    University Hospital, Karolinska Institutet, Stockholm.
    Gustafsson, Johanna T
    University Hospital, Karolinska Institutet, Stockholm.
    Rönnblom, Lars
    Department of Medical Sciences, Section of Rheumatology, Uppsala University, Uppsala, Sweden.
    Petersson, Ingemar F
    Department of Orthopedics, Lund University, Lund.
    Bengtsson, Anders A
    Department of Rheumatology, Lund University, Lund,.
    Nived, Ola
    Department of Rheumatology, Lund University, Lund,.
    Direct and indirect costs for systemic lupus erythematosus in Sweden. A nationwide health economic study based on five defined cohorts.2016In: Seminars in Arthritis & Rheumatism, ISSN 0049-0172, E-ISSN 1532-866X, Vol. 45, no 6, p. 684-690Article, review/survey (Refereed)
    Abstract [en]

    OBJECTIVES: The main objectives of this study were to calculate total costs of illness and cost-driving disease features among patients with systemic lupus erythematosus (SLE) in Sweden.

    METHODS: Five cohorts of well-defined SLE patients, located in different parts of the country were merged. Incident and prevalent cases from 2003 through 2010 were included. The American College of Rheumatology (ACR) classification criteria was used. From the local cohorts, data on demographics, disease activity (SLEDAI 2K), and organ damage (SDI) were collected. Costs for inpatient care, specialist outpatient care and drugs were retrieved from national registries at the National Board of Health and Welfare. Indirect costs were calculated based on sickness leave and disability pensions from the Swedish Social Insurance Agency.

    RESULTS: In total, 1029 SLE patients, 88% females, were included, and approximately 75% were below 65 years at the end of follow-up, and thus in working age. The mean number of annual specialist physician visits varied from six to seven; mean annual inpatient days were 3.1-3.6, and mean annual sick leave was 123-148 days, all per patient. The total annual cost was 208,555 SEK ($33,369 = 22,941€), of which direct cost was 63,672kr ($10,188 = 7004€) and the indirect cost was 144,883 SEK ($23,181 = 15,937€), all per patient. The costs for patients with short disease duration were higher. Higher disease activity as measured by a SLEDAI 2K score > 3 was associated with approximately 50% increase in both indirect and direct costs. Damage in the neuropsychiatric and musculoskeletal domains were also linked to higher direct and indirect costs, while organ damage in the renal and ocular systems increased direct costs.

    CONCLUSION: Based on this study and an estimate of slightly more than 6000 SLE patients in Sweden, the total annual cost for SLE in the country is estimated at $188 million (=129.5 million €). Both direct (30%) and indirect costs (70%) are substantial. Medication accounts for less than 10% of the total cost. The tax paid national systems for health care and social security in Sweden ensure equal access to health care, sick leave reimbursements, and disability pensions nationwide. Our extrapolated annual costs for SLE in Sweden are therefore the best supported estimations thus far, and they clearly underline the importance of improved management, especially to reduce the indirect costs.

  • 40.
    Kalkan, Almina
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Health Care Analysis. Linköping University, Faculty of Health Sciences.
    Hallert, Eva
    Linköping University, Department of Medical and Health Sciences, Division of Health Care Analysis. Linköping University, Faculty of Health Sciences.
    Carlsson, Per
    Linköping University, Department of Medical and Health Sciences, Division of Health Care Analysis. Linköping University, Faculty of Health Sciences.
    Roback, Kerstin
    Linköping University, Department of Medical and Health Sciences, Division of Health Care Analysis. Linköping University, Faculty of Health Sciences.
    Sjöwall, Christopher
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Rheumatology.
    Individual variations in treatment decisions by Swedish rheumatologists regarding biological drugs for rheumatoid arthritis2015In: Scandinavian Journal of Rheumatology, ISSN 0300-9742, E-ISSN 1502-7732, Vol. 44, no 4, p. 265-270Article in journal (Refereed)
    Abstract [en]

    Objective: In Sweden, reports indicate surprisingly large regional variation in prescription of biological drugs, despite a growing number of clinical studies describing their beneficial effects and guidelines by professional organizations and agencies. Our objective was to ascertain whether there is also variation between individual rheumatologists in prescribing biologics to patients with rheumatoid arthritis (RA) and to evaluate reasons for treatment choices.

    Methods: Ten hypothetical patient cases were constructed and presented to 26 rheumatologists in five regions in Sweden. The cases were based on actual cases and were thoroughly elaborated by a senior rheumatologist and pre-tested in a pilot study. The respondents were asked whether they would treat the patients with a biological agent (YES/NO) and to explain their decisions.

    Results: The response rate was 26/105; 25%. Treatment choices varied considerably between the rheumatologists, some prescribing biologics to 9/10 patients and others to 2/10. In five of the ten hypothetical cases, approximately half of the respondents would prescribe biologics. No regions with particularly high or low prescription were identified. Both the decision to prescribe biologics, as well as not to prescribe, were mainly motivated by medical reasons. Some rheumatologists also referred to lifestyle-related factors or social function of the patient.

    Conclusion: The choice of initiation of biologics varied substantially among rheumatologists presented with hypothetical patient cases, and there were also disparities between rheumatologists practising at the same clinic. Treatment choices were primarily motivated by medical reasons. This situation raises concerns about a lack of consensus in RA treatment strategies.

  • 41.
    Kienhöfer, D
    et al.
    Universitätsklinikum Erlangen, Erlangen, Germany.
    Hahn, J
    Universitätsklinikum Erlangen, Erlangen, Germany.
    Schubert, I
    Universitätsklinikum Erlangen, Erlangen, Germany.
    Reinwald, C
    Universitätsklinikum Erlangen, Erlangen, Germany.
    Ipseiz, N
    Universitätsklinikum Erlangen, Erlangen, Germany.
    Lang, S C
    Universitätsklinikum Erlangen, Erlangen, Germany.
    Borràs, È Bosch
    Universitat Autònoma de Barcelona, Barcelona, Spain.
    Amann, K
    Universitätsklinikum Erlangen, Erlangen, Germany.
    Sjöwall, Christopher
    Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Rheumatology.
    Barron, A E
    Stanford University, Stanford, USA .
    Hueber, A J
    Universitätsklinikum Erlangen, Erlangen, Germany.
    Agerberth, B
    Karolinska University, Stockholm, Sweden.
    Schett, G
    Universitätsklinikum Erlangen, Erlangen, Germany.
    Hoffmann, M H
    Universitätsklinikum Erlangen, Erlangen, Germany.
    No evidence of pathogenic involvement of cathelicidins in patient cohorts and mouse models of lupus and arthritis2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 12, p. 1-19Article in journal (Refereed)
    Abstract [en]

    Apart from their role in the immune defence against pathogens evidence of a role of antimicrobial peptides (AMPs) in autoimmune diseases has accumulated in the past years. The aim of this project was to examine the functional impact of the human cathelicidin LL-37 and the mouse cathelicidin-related AMP (CRAMP) on the pathogenesis of lupus and arthritis. Serum LL-37 and anti-LL-37 levels were measured by ELISA in healthy donors and patients with Systemic Lupus Erythematosus (SLE) and Rheumatoid arthritis (RA). Pristane-induced lupus was induced in female wild type (WT) and cathelicidin-deficient (CRAMP-/-) mice. Serum levels of anti-Sm/RNP, anti-dsDNA, and anti-histone were determined via ELISA, cytokines in sera and peritoneal lavages were measured via Multiplex. Expression of Interferon I stimulated genes (ISG) was determined by real-time PCR. Collagen-induced arthritis (CIA) was induced in male WT and CRAMP-/- mice and arthritis severity was visually scored and analysed histomorphometrically by OsteoMeasure software. Serum levels of anti-LL-37 were higher in SLE-patients compared to healthy donors or patients with RA. However, no correlation to markers of disease activity or organ involvement was observed. No significant differences of autoantibody or cytokine/chemokine levels, or of expression of ISGs were observed between WT and CRAMP-/- mice after pristane-injection. Furthermore, lung and kidney pathology did not differ in the absence of CRAMP. Incidence and severity of CIA and histological parameters (inflammation, cartilage degradation, and bone erosion) were not different in WT and CRAMP-/- mice. Although cathelicidins are upregulated in mouse models of lupus and arthritis, cathelicidin-deficiency did not persistently affect the diseases. Also in patients with SLE, autoantibodies against cathelicidins did not correlate with disease manifestation. Reactivity against cathelicidins in lupus and arthritis could thus be an epiphenomenon caused by extensive overexpression in blood and affected tissues. In addition, other cationic AMPs could functionally compensate for the deficiency of cathelicidins.

  • 42.
    Langefeld, Carl D.
    et al.
    Wake Forest School Med, NC 27101 USA; Wake Forest School Med, NC 27101 USA.
    Ainsworth, Hannah C.
    Wake Forest School Med, NC 27101 USA; Wake Forest School Med, NC 27101 USA.
    Cunninghame Graham, Deborah S.
    Kings Coll London, England.
    Kelly, Jennifer A.
    Oklahoma Medical Research Fdn, OK 73104 USA.
    Comeau, Mary E.
    Wake Forest School Med, NC 27101 USA.
    Marion, Miranda C.
    Wake Forest School Med, NC 27101 USA.
    Howard, Timothy D.
    Wake Forest School Med, NC 27101 USA.
    Ramos, Paula S.
    Medical University of South Carolina, SC 29425 USA.
    Croker, Jennifer A.
    UAB School Med, AL 35294 USA.
    Morris, David L.
    Kings Coll London, England.
    Sandling, Johanna K.
    Uppsala University, Sweden; University of Nacl Mayor San Marcos, Peru.
    Carlsson Almlof, Jonas
    Uppsala University, Sweden; University of Nacl Mayor San Marcos, Peru.
    Acevedo-Vasquez, Eduardo M.
    University of Nacl Mayor San Marcos, Peru.
    Alarcon, Graciela S.
    UAB School of Medicine, Birmingham, Alabama, USA.
    Babini, Alejandra M.
    Hospital Italiano Cordoba, Argentina.
    Baca, Vicente
    Hospital Pediat Mexico City, Mexico.
    Bengtsson, Anders A.
    Lund University, Sweden.
    Berbotto, Guillermo A.
    Hospital Eva Peron, Argentina.
    Bijl, Marc
    Martini Hospital, Netherlands.
    Brown, Elizabeth E.
    UAB School of Medicine, Birmingham, Alabama, USA..
    Brunner, Hermine I.
    Cincinnati Childrens Hospital Medical Centre, OH 45229 USA; University of Cincinnati, OH 45229 USA.
    Cardiel, Mario H.
    Centre Invest Clin Morelia, Mexico.
    Catoggio, Luis
    Hospital Italiano Buenos Aires, Argentina.
    Cervera, Ricard
    University of Barcelona, Spain.
    Cucho-Venegas, Jorge M.
    University of Nacl Mayor San Marcos, Peru.
    Rantapaa Dahlqvist, Solbritt
    Umeå University, Sweden.
    DAlfonso, Sandra
    University of Piemonte Orientale, Italy.
    Martins Da Silva, Berta
    University of Porto, Portugal.
    de la Rua Figueroa, Inigo
    Hospital University of Gran Canaria Dr Negrin, Spain.
    Doria, Andrea
    University of Padua, Italy.
    Edberg, Jeffrey C.
    UAB School Med, AL 35294 USA.
    Endreffy, Emoke
    University of Szeged, Hungary; University of Szeged, Hungary.
    Esquivel-Valerio, Jorge A.
    Hospital University of Dr Jose Eleuterio Gonzalez University of Autonom, Mexico.
    Fortin, Paul R.
    University of Laval, Canada.
    Freedman, Barry I.
    Wake Forest School Med, NC 27101 USA; Wake Forest School Med, NC 27101 USA; Wake Forest School Med, NC 27101 USA.
    Frostegard, Johan
    Karolinska Institute, Sweden.
    Garcia, Mercedes A.
    Hospital Interzonal Gen Agudos Gen San Martin, Argentina.
    Garcia de la Torre, Ignacio
    University of Guadalajara, Mexico.
    Gilkeson, Gary S.
    Medical University of South Carolina, SC 29425 USA.
    Gladman, Dafna D.
    Toronto Western Hospital, Canada.
    Gunnarsson, Iva
    Karolinska University Hospital, Sweden.
    Guthridge, Joel M.
    Oklahoma Medical Research Fdn, OK 73104 USA.
    Huggins, Jennifer L.
    Cincinnati Childrens Hospital Medical Centre, OH 45229 USA; University of Cincinnati, OH 45229 USA.
    James, Judith A.
    Hospital Eva Peron, Argentina; University of Oklahoma, OK 73104 USA; University of Oklahoma, OK 73104 USA.
    Kallenberg, Cees G. M.
    University of Medical Centre Groningen, Netherlands.
    Kamen, Diane L.
    Medical University of South Carolina, Charleston, USA.
    Karp, David R.
    University of Texas Southwestern Medical Centre Dallas, TX 75235 USA.
    Kaufman, Kenneth M.
    Cincinnati Childrens Hospital Medical Centre, OH 45229 USA.
    Kottyan, Leah C.
    Cincinnati Childrens Hospital Medical Centre, OH 45229 USA.
    Kovacs, Laszlo
    University of Szeged, Hungary.
    Laustrup, Helle
    Odense University Hospital, Denmark.
    Lauwerys, Bernard R.
    Catholic University of Louvain, Belgium; Catholic University of Louvain, Belgium.
    Li, Quan-Zhen
    University of Texas Southwestern Medical Centre Dallas, TX 75235 USA.
    Maradiaga-Cecena, Marco A.
    Hospital Gen Culiacan, Mexico.
    Martin, Javier
    CSIC, Spain.
    McCune, Joseph M.
    University of Michigan, MI 48103 USA.
    McWilliams, David R.
    Wake Forest School Med, NC 27101 USA; Wake Forest School Med, NC 27101 USA.
    Merrill, Joan T.
    Oklahoma Medical Research Fdn, OK 73104 USA.
    Miranda, Pedro
    Centre Estudios Reumatol, Chile.
    Moctezuma, Jose F.
    Hospital Gen Mexico City, Mexico.
    Nath, Swapan K.
    Oklahoma Medical Research Fdn, OK 73104 USA.
    Niewold, Timothy B.
    Mayo Clin, MN 94158 USA.
    Orozco, Lorena
    Institute Nacl Medical Genom INMEGEN, Mexico.
    Ortego-Centeno, Norberto
    Hospital University of San Cecilio, Spain.
    Petri, Michelle
    Johns Hopkins University, MD 21218 USA.
    Pineau, Christian A.
    McGill University, Canada.
    Pons-Estel, Bernardo A.
    Sanatorio Parque, Argentina.
    Pope, Janet
    University of Western Ontario, Canada.
    Raj, Prithvi
    University of Texas Southwestern Medical Centre Dallas, TX 75235 USA.
    Ramsey-Goldman, Rosalind
    Northwestern University, IL 60611 USA.
    Reveille, John D.
    University of Texas Health Science Centre Houston UTHealth, TX 77030 USA.
    Russell, Laurie P.
    Wake Forest School Med, NC 27101 USA.
    Sabio, Jose M.
    Hospital University of Virgen de las Nieves, Spain.
    Aguilar-Salinas, Carlos A.
    Institute Nacl Ciencias Medical and Nutr Salvador Zubiran, Mexico.
    Scherbarth, Hugo R.
    Autoinmunes HIGA Dr Alende Mar Plata, Argentina.
    Scorza, Raffaella
    Fdn IRCCS CaGranda Osped Ma Repiore Policlin, Italy; University of Milan, Italy.
    Seldin, Michael F.
    UC Davis School Med, CA 95616 USA.
    Sjöwall, Christopher
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Rheumatology.
    Svenungsson, Elisabet
    Karolinska University Hospital, Sweden.
    Thompson, Susan D.
    Cincinnati Childrens Hospital Medical Centre, OH 45229 USA.
    Toloza, Sergio M. A.
    Minist Heatlh, Argentina.
    Truedsson, Lennart
    Lund University, Sweden.
    Tusie-Luna, Teresa
    UNAM Institute Nacl Ciencias Medical and Nutr Salvador Zubir, Mexico.
    Vasconcelos, Carlos
    University of Porto, Portugal.
    Vila, Luis M.
    University of Puerto Rico, PR 00936 USA.
    Wallace, Daniel J.
    Cedars Sinai Medical Centre, CA 90048 USA.
    Weisman, Michael H.
    Cedars Sinai Medical Centre, CA 90048 USA.
    Wither, Joan E.
    Toronto Western Hospital, Canada.
    Bhangale, Tushar
    Genentech Inc, CA 94080 USA.
    Oksenberg, Jorge R.
    University of Calif San Francisco, CA 94158 USA; University of Calif San Francisco, CA 94158 USA.
    Rioux, John D.
    University of Montreal, Canada; Montreal Heart Institute, Canada.
    Gregersen, Peter K.
    Feinstein Institute Medical Research, NY 11030 USA.
    Syvanen, Ann-Christine
    Uppsala University, Sweden; University of Nacl Mayor San Marcos, Peru.
    Ronnblom, Lars
    Uppsala University, Sweden.
    Criswell, Lindsey A.
    UCSF School Med, CA 94158 USA.
    Jacob, Chaim O.
    Keck School Medical USC, CA 90033 USA.
    Sivils, Kathy L.
    Oklahoma Medical Research Fdn, OK 73104 USA.
    Tsao, Betty P.
    Medical University of South Carolina, SC 29425 USA.
    Schanberg, Laura E.
    Duke University, NC 27708 USA.
    Behrens, Timothy W.
    Genentech Inc, CA 94080 USA.
    Silverman, Earl D.
    Hospital Sick Children, Canada; Hospital Sick Children, Canada; University of Toronto, Canada.
    Alarcon-Riquelme, Marta E.
    Oklahoma Medical Research Fdn, OK 73104 USA; University of Granada, Spain; Karolinska Institute, Sweden.
    Kimberly, Robert P.
    UAB School Med, AL 35294 USA.
    Harley, John B.
    Cincinnati Childrens Hospital Medical Centre, OH 45229 USA.
    Wakeland, Edward K.
    University of Texas Southwestern Medical Centre Dallas, TX 75235 USA.
    Graham, Robert R.
    Genentech Inc, CA 94080 USA.
    Gaffney, Patrick M.
    Oklahoma Medical Research Fdn, OK 73104 USA.
    Vyse, Timothy J.
    Kings Coll London, England.
    Transancestral mapping and genetic load in systemic lupus erythematosus2017In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 8, article id 16021Article in journal (Refereed)
    Abstract [en]

    Systemic lupus erythematosus (SLE) is an autoimmune disease with marked gender and ethnic disparities. We report a large transancestral association study of SLE using Immunochip genotype data from 27,574 individuals of European (EA), African (AA) and Hispanic Amerindian (HA) ancestry. We identify 58 distinct non-HLA regions in EA, 9 in AA and 16 in HA (similar to 50% of these regions have multiple independent associations); these include 24 novel SLE regions (P amp;lt; 5 x 10(-8)), refined association signals in established regions, extended associations to additional ancestries, and a disentangled complex HLA multigenic effect. The risk allele count (genetic load) exhibits an accelerating pattern of SLE risk, leading us to posit a cumulative hit hypothesis for autoimmune disease. Comparing results across the three ancestries identifies both ancestry-dependent and ancestry-independent contributions to SLE risk. Our results are consistent with the unique and complex histories of the populations sampled, and collectively help clarify the genetic architecture and ethnic disparities in SLE.

  • 43. Leonard, Dag
    et al.
    Svenungsson, Elisabet
    Dahlqvist, Johanna
    Alexsson, Andrei
    Ärlestig, Lisbeth
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Taylor, Kimberly E.
    Sandling, Johanna K.
    Bengtsson, Christine
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Frodlund, Martina
    Jonsen, Andreas
    Eketjäll, Susanna
    Jensen-Urstad, Kerstin
    Gunnarsson, Iva
    Sjöwall, Christopher
    Bengtsson, Anders A.
    Eloranta, Maija-Leena
    Syvänen, Ann-Christine
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Criswell, Lindsey A.
    Rönnblom, Lars
    Novel gene variants associated with cardiovascular disease in systemic lupus erythematosus and rheumatoid arthritis2018In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 77, no 7, p. 1063-1069Article in journal (Refereed)
    Abstract [en]

    Objectives Patients with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) have increased risk of cardiovascular disease (CVD). We investigated whether single nucleotide polymorphisms (SNPs) at autoimmunity risk loci were associated with CVD in SLE and RA.

    Methods Patients with SLE (n=1045) were genotyped using the 200K Immunochip SNP array (Illumina). The allele frequency was compared between patients with and without different manifestations of CVD. Results were replicated in a second SLE cohort (n=1043) and in an RA cohort (n=824). We analysed publicly available genetic data from general population, performed electrophoretic mobility shift assays and measured cytokine levels and occurrence of antiphospholipid antibodies (aPLs).

    Results We identified two new putative risk loci associated with increased risk for CVD in two SLE populations, which remained after adjustment for traditional CVD risk factors. An IL19 risk allele, rs17581834(T) was associated with stroke/myocardial infarction (MI) in SLE (OR 2.3 (1.5 to 3.4), P=8.5x10(-5)) and RA (OR 2.8 (1.4 to 5.6), P=3.8x10(-3)), meta-analysis (OR 2.5 (2.0 to 2.9), P=3.5x10(-7)), but not in population controls. The IL19 risk allele affected protein binding, and SLE patients with the risk allele had increased levels of plasma-IL10 (P=0.004) and aPL (P=0.01). An SRP54-AS1 risk allele, rs799454(G) was associated with stroke/transient ischaemic attack in SLE (OR 1.7 (1.3 to 2.2), P=2.5x10(-5)) but not in RA. The SRP54-AS1 risk allele is an expression quantitative trait locus for four genes.

    Conclusions The IL19 risk allele was associated with stroke/MI in SLE and RA, but not in the general population, indicating that shared immune pathways may be involved in the CVD pathogenesis in inflammatory rheumatic diseases.

  • 44.
    Leonard, Dag
    et al.
    Uppsala University, Uppsala, Sweden.
    Svenungsson, Elisabet
    Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
    Dahlqvist, Johanna
    Uppsala University, Uppsala, Sweden.
    Alexsson, Andrei
    Rheumatology, Uppsala University, Uppsala, Sweden.
    Ärlestig, Lisbeth
    Umeå University, Umeå, Sweden.
    Taylor, Kimberly E
    Engleman Rheumatology Research Center, San Francisco, California, USA.
    Sandling, Johanna K
    Uppsala University, Uppsala, Sweden.
    Bengtsson, Christine
    Umeå University, Umeå, Sweden.
    Frodlund, Martina
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Rheumatology.
    Jönsen, Andreas
    Skåne University Hospital, Lund, Sweden.
    Eketjäll, Susanna
    Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Karolinska Institutet, Stockholm, Sweden.
    Jensen-Urstad, Kerstin
    Södersjukhuset, Karolinska Institutet, Stockholm, Sweden.
    Gunnarsson, Iva
    Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
    Sjöwall, Christopher
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Rheumatology.
    Bengtsson, Anders A
    Skåne University Hospital, Lund, Sweden.
    Eloranta, Maija-Leena
    Uppsala University, Uppsala, Sweden.
    Syvänen, Ann-Christine
    Uppsala University, Uppsala, Sweden.
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Umeå, Sweden.
    Criswell, Lindsey A
    Engleman Rheumatology Research Center, San Francisco, California, USA..
    Rönnblom, Lars
    Uppsala University, Uppsala, Sweden.
    Novel gene variants associated with cardiovascular disease in systemic lupus erythematosus and rheumatoid arthritis.2018In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 77, no 7, p. 1063-1069Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: Patients with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) have increased risk of cardiovascular disease (CVD). We investigated whether single nucleotide polymorphisms (SNPs) at autoimmunity risk loci were associated with CVD in SLE and RA.

    METHODS: Patients with SLE (n=1045) were genotyped using the 200K Immunochip SNP array (Illumina). The allele frequency was compared between patients with and without different manifestations of CVD. Results were replicated in a second SLE cohort (n=1043) and in an RA cohort (n=824). We analysed publicly available genetic data from general population, performed electrophoretic mobility shift assays and measured cytokine levels and occurrence of antiphospholipid antibodies (aPLs).

    RESULTS: We identified two new putative risk loci associated with increased risk for CVD in two SLE populations, which remained after adjustment for traditional CVD risk factors. An IL19 risk allele, rs17581834(T) was associated with stroke/myocardial infarction (MI) in SLE (OR 2.3 (1.5 to 3.4), P=8.5×10-5) and RA (OR 2.8 (1.4 to 5.6), P=3.8×10-3), meta-analysis (OR 2.5 (2.0 to 2.9), P=3.5×10-7), but not in population controls. The IL19 risk allele affected protein binding, and SLE patients with the risk allele had increased levels of plasma-IL10 (P=0.004) and aPL (P=0.01). An SRP54-AS1 risk allele, rs799454(G) was associated with stroke/transient ischaemic attack in SLE (OR 1.7 (1.3 to 2.2), P=2.5×10-5) but not in RA. The SRP54-AS1 risk allele is an expression quantitative trait locus for four genes.

    CONCLUSIONS: The IL19 risk allele was associated with stroke/MI in SLE and RA, but not in the general population, indicating that shared immune pathways may be involved in the CVD pathogenesis in inflammatory rheumatic diseases.

  • 45.
    Mathsson, L.
    et al.
    Uppsala University.
    Åhlin, E.
    Uppsala University.
    Sjöwall, Christoffer
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Rheumatology in Östergötland.
    Skogh, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Rheumatology in Östergötland.
    Rönnelid, J.
    Uppsala University.
    Cytokine induction by circulating immune complexes and signs of in-vivo complement activation in systemic lupus erythematosus are associated with the occurrence of anti-Sjögren's syndrome A antibodies2007In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 147, no 3, p. 513-520Article in journal (Refereed)
    Abstract [en]

    Circulating immune complexes (IC) and levels of IC-induced cytokines have been correlated with complement activation and autoantibody profiles in systemic lupus erythematosus (SLE). SLE sera were analysed concerning levels of immune complexes (IC), classical complement function and different antinuclear and anti-C-reactive protein (CRP) autoantibodies. Blood mononuclear cells from healthy donors were stimulated with isolated IC and production of interleukin (IL)-10, IL-6 and IL-12p40 was measured. Functional experiments revealed that increased levels of IC-induced cytokines were associated with both increased classical complement activation and the occurrence of anti-Sjögren's syndrome A (SSA) and anti-SSB but not other autoantibodies. Biochemical measurement of circulating IC showed that the degree of complement activation and the occurrence of anti-SSA were synergistically associated with levels of circulating IC in SLE sera, as complement activation was a prerequisite for the enhancing effect of anti-SSA. Anti-CRP was associated with complement activation, but not with other autoantibodies. Our results indicate that anti-SSA and possibly anti-SSB antibodies influence IC formation and subsequent IC-induced cytokine induction, and that they thereby participate in the inflammatory process in active SLE.

  • 46.
    Mohammad, Aladdin J
    et al.
    Lunds University, Addenbrooke's Hospital Cambridge UK.
    Weiner, Maria
    Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Region Östergötland, Heart and Medicine Center, Department of Nephrology.
    Sjöwall, Christopher
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Rheumatology.
    Johansson, Martin E
    Lund University, Malmö .
    Bengtsson, Anders A
    Lund University, Lund .
    Ståhl-Hallengren, Christina
    Helsingborg Hospital .
    Nived, Ola
    Lund University.
    Eriksson, Per
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Rheumatology.
    Sturfelt, Gunnar
    Lund University.
    Segelmark, Mårten
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Nephrology. Linköping University, Faculty of Health Sciences.
    Incidence and disease severity of anti-neutrophil cytoplasmic antibody-associated nephritis are higher than in lupus nephritis in Sweden.2015In: Nephrology, Dialysis and Transplantation, ISSN 0931-0509, E-ISSN 1460-2385, Vol. 30, p. i23-i30Article in journal (Refereed)
    Abstract [en]

    Objectives :The objectives of this study were to compare incidence rates, renal and patient survival between lupus nephritis (LN) and anti-neutrophil cytoplasmic antibody-associated nephritis (AAN) during a 12-year period in two geographically defined populations in Sweden.

    METHODS: In the health care districts surrounding the Skåne University Hospital in Lund [mean population ≥18 years (1997-2008), 188 400] and the University Hospital in Linköping [mean population ≥18 years (1997-2008), 328 900] all patients with biopsy-proven LN and AAN during the period 1997-2008 were included in the study if they (i) were residing within the study areas at the time of onset of nephritis, (ii) had a clinical diagnosis of either SLE or ANCA-associated vasculitis (AAV) and (iii) experienced a first flare of biopsy-proven nephritis during the study period.

    RESULTS: Eighty-two patients (Lund 44 + Linköping 38) with biopsy-proven AAN were identified and 27 patients with LN (Lund 13 + Linköping 14). The annual incidence rate per million inhabitants aged ≥18 years in both study areas was estimated to be 13.2 (95% CI 10.4-16.1) for AAN and 4.3 (95% CI 2.7-6.0) for LN, P < 0.001. The patients were followed until January 2013. During the follow-up time 38 patients died (AAN 36, LN 2; P = 0.001), and 20 patients went into end-stage renal disease (AAN 19 and LN 1), P = 0.020.

    CONCLUSIONS: In Sweden, AAN was three times more common than LN, and the outcome was considerably worse. SLE is often diagnosed before the onset of nephritis leading to earlier treatment, while AAN is still often diagnosed at a later stage.

  • 47.
    Mummert, Eckart
    et al.
    Inova Diagnostics, Inc., San Diego, CA, USA.
    Fritzler, Marvin J
    University of Calgary, Calgary, Canada.
    Sjöwall, Christopher
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Rheumatology.
    Bentow, Chelsea
    Inova Diagnostics, Inc., San Diego, CA, USA.
    Mahler, Michael
    Inova Diagnostics, Inc., San Diego, CA, USA.
    The clinical utility of anti-double-stranded DNA antibodies and the challenges of their determination.2018In: JIM - Journal of Immunological Methods, ISSN 0022-1759, E-ISSN 1872-7905, Vol. 459, p. 11-19Article, review/survey (Refereed)
    Abstract [en]

    Autoantibodies against double-stranded DNA (dsDNA) were first described >60 years ago and although they are still one of the most clinically relevant autoantibodies, test results may be more challenging to interpret compared to other autoantibody tests. They are a serological hallmark of systemic lupus erythematosus (SLE) and are included in both the American College of Rheumatology (ACR) and the Systemic Lupus International Collaborating Clinics (SLICC) classification criteria for SLE. Furthermore, anti-dsDNA antibodies (a-dsDNA) have been shown to associate with SLE disease activity and coincide with renal involvement. Given their importance and long history, one might assume that immunological tests for a-dsDNA are standardized and give comparable results. However, even though there has been an international reference standard serum (the WHO Wo/80), different methods for the detection of a-dsDNA and tests from different manufacturers give different results for the same samples. This disparity is due to the diversity of possible antibodies generated to this biochemically complex antigen, which may have different clinical associations. The goal of this review is to summarize the current knowledge regarding the clinical associations with a-dsDNA, highlight challenges in a-dsDNA testing, and elucidate the reasons for discrepant results between methods or manufacturers.

  • 48.
    Nikiphorou, Elena
    et al.
    Jyvaskyla Central Hospital, Finland.
    Sjöwall, Christopher
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Rheumatology.
    Hannonen, Pekka
    Jyvaskyla Central Hospital, Finland.
    Rannio, Tuomas
    Jyvaskyla Central Hospital, Finland.
    Sokka, Tuulikki
    Jyvaskyla Central Hospital, Finland; University of Eastern Finland, Finland.
    Long-term outcomes of destructive seronegative (rheumatoid) arthritis - description of four clinical cases2016In: BMC Musculoskeletal Disorders, ISSN 1471-2474, E-ISSN 1471-2474, Vol. 17, article id 246Article in journal (Refereed)
    Abstract [en]

    Background: Seronegative rheumatoid arthritis is associated with a milder course of progression compared to seropositive disease. However, long-term follow-up data of the clinical course of seronegative rheumatoid arthritis are sparse. Here we describe four cases with a rare disease entity of aggressive destructive seronegative (rheumatoid) arthritis with 20-35 years of follow-up. Case presentation: The four cases are women with an initial presentation of seronegative rheumatoid arthritis in 1980-1996 and have received disease-modifying anti-rheumatic drugs since the diagnosis. In all cases, the condition has been refractory to treatments and evolved into a severe disease with destructions of the wrists, sub-talar and ankle joints, as well as large joints but not small joints of fingers and toes. All cases are negative with regard to rheumatoid factor, anti-cyclic citrullinated peptide antibodies and antibodies against carbamylated proteins. Conclusions: This report adds to the existing literature, making the reader aware of this sub-type of inflammatory arthritis which despite being seronegative, can have devastating disease consequences. The report highlights the need for further research into this field in order to better understand this disease sub-type, the pathogenesis, disease course and outcomes.

  • 49.
    Nordmark, G
    et al.
    Uppsala University.
    Kristjansdottir, G
    Uppsala University.
    Theander, E
    Malmö University Hospital.
    Appel, S
    University of Bergen, Norway.
    Eriksson, Per
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Nephrology UHL.
    Vasaitis, L
    Uppsala University.
    Kvarnström, M
    Karolinska Institutet, Stockholm.
    Delaleu, N
    University of Bergen, Norway.
    Lundmark, P
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences.
    Lundmark, A
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences.
    Sjöwall, Christopher
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Rheumatology in Östergötland.
    Brun, J G
    Haukeland Hospital, Bergen, Norway.
    Jonsson, M V
    University of Bergen, Norway.
    Harboe, E
    Stavanger University Hospital, Norway.
    Gøransson, L G
    Stavanger University Hospital, Norway.
    Johnsen, S J
    Stavanger University Hospital, Norway.
    Söderkvist, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Eloranta, M-L
    Uppsala University.
    Alm, G
    Swedish University of Agricultural Sciences, Uppsala.
    Baecklund, E
    Uppsala University.
    Wahren-Herlenius, M
    Karolinska Institutet, Stockholm.
    Omdal, R
    Stavanger University Hospital, Norway.
    Rönnblom, L
    Uppsala University.
    Jonsson, R
    University of Bergen, Norway.
    Syvänen, A-C
    Uppsala University.
    Association of EBF1, FAM167A(C8orf13)-BLK andTNFSF4 gene variants with primary Sjo¨gren’s syndrome2011In: Genes and Immunity, ISSN 1466-4879, E-ISSN 1476-5470, Vol. 12, no 2, p. 100-109Article in journal (Refereed)
    Abstract [en]

    We performed a candidate gene association study in 540 patients with primary Sjögren's Syndrome (SS) from Sweden (n=344) and Norway (n=196) and 532 controls (n=319 Swedish, n=213 Norwegian). A total of 1139 single-nucleotide polymorphisms (SNPs) in 84 genes were analyzed. In the meta-analysis of the Swedish and Norwegian cohorts, we found high signals for association between primary SS and SNPs in three gene loci, not previously associated with primary SS. These are the early B-cell factor 1 (EBF1) gene, P=9.9 × 10(-5), OR 1.68, the family with sequence similarity 167 member A-B-lymphoid tyrosine kinase (FAM167A-BLK) locus, P=4.7 × 10(-4), OR 1.37 and the tumor necrosis factor superfamily (TNFSF4=Ox40L) gene, P=7.4 × 10(-4), OR 1.34. We also confirmed the association between primary SS and the IRF5/TNPO3 locus and the STAT4 gene. We found no association between the SNPs in these five genes and the presence of anti-SSA/anti-SSB antibodies. EBF1, BLK and TNFSF4 are all involved in B-cell differentiation and activation, and we conclude that polymorphisms in several susceptibility genes in the immune system contribute to the pathogenesis of primary SS

  • 50.
    Nordmark, Gunnel
    et al.
    Uppsala University, Sweden .
    Wang, Chuan
    Uppsala University, Sweden .
    Vasaitis, Lilian
    Uppsala University, Sweden .
    Eriksson, Per
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Rheumatology.
    Theander, Elke
    Lund University, Sweden .
    Kvarnström, Marika
    Karolinska Institutet, Stockholm, Sweden.
    Forsblad-d'Elia, Helena
    University of Gothenburg, Sweden .
    Jazebi, Helmi
    Karolinska Institutet, Stockholm, Sweden.
    Sjöwall, Christoffer
    Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Rheumatology.
    Reksten, Tove Ragna
    University of Bergen, Norway .
    Brun, Johan G.
    Haukeland University Hospital, Bergen, Norway.
    Jonsson, Malin V.
    University of Bergen, Norway .
    Johnsen, Svein J.
    Stavanger University Hospital, Norway .
    Wahren-Herlenius, Marie
    Karolinska Institutet, Stockholm, Sweden.
    Omdal, Roald
    Stavanger University Hospital, Norway .
    Jonsson, Roland
    University of Bergen, Norway.
    Bowman, Simon
    University Hospital Birmingham, UK.
    Ng, Wan-Fai
    Newcastle University, UK.
    Eloranta, Maija-Leena
    Uppsala University, Sweden .
    Syvänen, Ann-Christine
    Uppsala University, Sweden .
    Association of Genes in the NF-κB Pathway with Antibody-Positive Primary Sjögren's Syndrome2013In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 78, no 5, p. 447-454Article in journal (Refereed)
    Abstract [en]

    Primary Sjogrens syndrome (SS) is a systemic autoimmune inflammatory disease characterized by focal lymphocytic infiltrates in the lachrymal and salivary glands and autoantibodies against the SSA/Ro and SSB/La antigens. Experimental studies have shown an activation of NF-B in primary SS. NF-B activation results in inflammation and autoimmunity and is regulated by inhibitory and activating proteins. Genetic studies have shown an association between multiple autoimmune diseases and TNFAIP3 (A20) and TNIP1 (ABIN1), both repressors of NF-B and of IKBKE (IKK epsilon), which is an NF-B activator. The aim of this study was to analyse single nucleotide polymorphisms (SNPs) in the IKBKE, NFKB1, TNIP1 and TNFAIP3 genes for association with primary SS. A total of 12 SNPs were genotyped in 1105 patients from Scandinavia (Sweden and Norway, n=684) and the UK (n=421) and 4460 controls (Scandinavia, n=1662, UK, n=2798). When patients were stratified for the presence of anti-SSA and/or anti-SSB antibodies (n=868), case-control meta-analysis found an association between antibody-positive primary SS and two SNPs in TNIP1 (P=3.4x10(-5), OR=1.33, 95%CI: 1.16-1.52 for rs3792783 and P=1.3x10(-3), OR=1.21, 95%CI: 1.08-1.36 for rs7708392). A TNIP1 risk haplotype was associated with antibody-positive primary SS (P=5.7x10(-3), OR=1.47, 95%CI: 1.12-1.92). There were no significant associations with IKBKE, NFKB1 or TNFAIP3 in the meta-analysis of the Scandinavian and UK cohorts. We conclude that polymorphisms in TNIP1 are associated with antibody-positive primary SS.

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