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  • 1. Ahlin, Erik
    et al.
    Elshafei, Amir
    Nur, Musa
    El Safi, Sayda Hassan
    Ronnelid, Johan
    Elghazali, Gehad
    Retraction: Anti-citrullinated peptide antibodies and rheumatoid factor in Sudanese patients with Leishmania donovani infection (vol 51, pg 579, 2011)2014In: Revista Brasileira de Reumatologia, ISSN 0482-5004, E-ISSN 1809-4570, Vol. 54, no 3, p. 255-255Article in journal (Refereed)
  • 2.
    Ajeganova, Sofia
    et al.
    Karolinska Inst, Dept Med Huddinge, S-14186 Stockholm, Sweden..
    Tesfa, Daniel
    Karolinska Inst, Ctr Hematol & Regenerat Med, Dept Med Huddinge, S-14186 Stockholm, Sweden.;Roche AB, Med Affairs, S-10074 Stockholm, Sweden..
    Hägglund, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Fadeel, Bengt
    Karolinska Inst, Inst Environm Med, Unit Mol Toxicol, S-17177 Stockholm, Sweden..
    Vedin, Inger
    Karolinska Inst, Ctr Hematol & Regenerat Med, Dept Med Huddinge, S-14186 Stockholm, Sweden..
    Zignego, Anna Linda
    Univ Florence, Ctr Syst Manifestat Hepatitis Viruses, Dept Internal Med, I-50134 Florence, Italy..
    Palmblad, Jan
    Karolinska Inst, Ctr Hematol & Regenerat Med, Dept Med Huddinge, S-14186 Stockholm, Sweden..
    Effect of FCGR polymorphism on the occurrence of late-onset neutropenia and flare-free survival in rheumatic patients treated with rituximab2017In: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 19, article id 44Article in journal (Refereed)
    Abstract [en]

    Background: The causes and mechanisms of late-onset neutropenia (LON) following rituximab treatment in patients with rheumatic diseases are not known. In this study, we aimed to investigate the role of established Fc gamma receptor gene (FCGR) polymorphisms and B-cell-activating factor (BAFF) gene promoter polymorphisms for the development of LON and for the efficacy of rituximab in patients with rheumatic diseases. Methods: A single-center case-control retrospective study was nested in a cohort of 214 consecutive patients with rheumatic diseases treated with rituximab. Eleven patients presented with LON. Fifty non-LON control subjects were matched by diagnosis, age, sex, and treatments. Single-nucleotide polymorphisms of FCGR (FCGR2A 131H/R, FCGR2B 232I/T, FCGR3A 158V/F) and BAFF promoter polymorphism -871C/T were analyzed with polymerase chain reaction-based techniques, and serum immunoglobulin M (IgM) and BAFF levels were analyzed by enzyme-linked immunosorbent assay. Flare-free survival was related to LON occurrence and polymorphisms. Results: The FCGR3A V allele, but not other FCGR polymorphisms, correlated with the occurrence of LON; each V allele conferred a fourfold increased OR for LON (p = 0.017). FCGR3A 158V/V and presentation with LON were associated with a longer flare-free survival (p = 0.023 and p = 0.031, respectively). FCGR3A 158V/V was related to lower IgM levels (p = 0.016). Serum BAFF levels showed no relationship with LON and BAFF -871C/T promoter polymorphism. There was a tendency toward longer flare-free survival in patients with the BAFF -871T/T allotype compared with the C/T or C/C allotypes (p = 0.096). Conclusions: The results of the present study suggest that presentation with LON may be a result of the intrinsic efficacy of rituximab in patients with rheumatic diseases. LON could indicate a longer biological and therapeutic activity of rituximab modulated by a certain genotypic polymorphism: the high-affinity FCGR3A V allele. This genotype and the occurrence of LON are both related to longer flare-free survival, suggestive of common mechanisms for LON and duration of response to rituximab. The role of the BAFF -871C/T promoter polymorphism in LON occurrence is unclear.

  • 3. Alarcón-Riquelme, Marta E.
    et al.
    Marañón Lizana, Concepción
    Varela Hernández, Nieves
    Delgado-Vega, Angélica M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    La Etiopatogenia en el Lupus Eritematoso Sistémico2013In: Lupus eritematoso sistémico: Aspectos Clínicos y Terapéuticos, Rosario, Argentina: Carlos Antonio Battagliotti , 2013, 1, p. 65-85Chapter in book (Refereed)
  • 4.
    Alberdi-Saugstrup, M.
    et al.
    Copenhagen University Hospital, Rigshospitalet, Department of Paediatrics and Adolescent Medicine; Naestved Hospital, Department of Paediatrics; Copenhagen University Hospital, Rigshospitalet, Institute for Inflammation Research.
    Enevold, C.
    Copenhagen University Hospital, Rigshospitalet, Institute for Inflammation Research.
    Zak, M.
    Copenhagen University Hospital, Rigshospitalet, Department of Paediatrics and Adolescent Medicine.
    Nielsen, S.
    Copenhagen University Hospital, Rigshospitalet, Department of Paediatrics and Adolescent Medicine.
    Nordal, E.
    University Hospital of North Norway, Department of Paediatrics.
    Berntson, Lillemor
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Fasth, A.
    University of Gothenburg, Department of Paediatrics.
    Rygg, M.
    Norwegian University of Science and Technology, Department of Laboratory Medicine, Children’s and Women’s Health.
    Müller, K.
    Copenhagen University Hospital, Rigshospitalet, Department of Paediatrics and Adolescent Medicine; Copenhagen University Hospital, Rigshospitalet, Institute for Inflammation Research.
    Non-HLA gene polymorphisms in juvenile idiopathic arthritis: associations with disease outcome2017In: Scandinavian Journal of Rheumatology, ISSN 0300-9742, E-ISSN 1502-7732, Vol. 46, no 5, p. 369-376Article in journal (Refereed)
    Abstract [en]

    Objective: To test the hypothesis that non-HLA single-nucleotide polymorphisms (SNPs) associated with the risk of juvenile idiopathic arthritis (JIA) are risk factors for an unfavourable disease outcome at long-term follow-up.

    Methods: The Nordic JIA cohort is a prospective multicentre study cohort of patients from the Nordic countries. In all, 193 patients met the inclusion criteria of having an 8year follow-up assessment and available DNA sample. Seventeen SNPs met the inclusion criteria of having significant associations with JIA in at least two previous independent study cohorts. Clinical endpoints were disease remission, actively inflamed joints and joints with limitation of motion (LOM), articular or extra-articular damage, and history of uveitis.

    Results: Evidence of associations between genotypes and endpoints were found for STAT4, ADAD1-IL2-IL21, PTPN2, and VTCN1 (p=0.003-0.05). STAT4_rs7574865 TT was associated with the presence of actively inflamed joints [odds ratio (OR) 20.6, 95% confidence interval (CI) 2.2->100, p=0.003] and extra-articular damage (OR 7.9, 95% CI 1-56.6, p=0.057). ADAD1_rs17388568 AA was associated with a lower risk of having joints with LOM (OR 0.1, 95% CI 0-0.55, p=0.016). PTPN2_rs1893217 CC was associated with a lower risk of having joints with LOM (OR 0.2, 95% CI 0-0.99, p=0.026), while VTCN1_rs2358820 GA was associated with uveitis (OR 3.5, 95% CI 1-12.1, p=0.029).

    Conclusion: This exploratory study, using a prospectively followed JIA cohort, found significant associations between long-term outcome and SNPs, all previously associated with development of JIA and involved in immune regulation and signal transduction in immune cells.

  • 5.
    Alberdi-Saugstrup, Mikel
    et al.
    Rigshosp, Dept Pediat & Adolescent Med, Copenhagen Univ Hosp, Copenhagen, Denmark.;Naestved Hosp, Dept Pediat, Naestved, Region Zealand, Denmark.;Rigshosp, Inst Inflammat Res, Copenhagen Univ Hosp, Copenhagen, Denmark..
    Zak, Marek
    Rigshosp, Dept Pediat & Adolescent Med, Copenhagen Univ Hosp, Copenhagen, Denmark..
    Nielsen, Susan
    Rigshosp, Dept Pediat & Adolescent Med, Copenhagen Univ Hosp, Copenhagen, Denmark..
    Herlin, Troels
    Aarhus Univ Hosp, Dept Pediat, Aarhus, Denmark..
    Nordal, Ellen
    Univ Hosp North Norway, Dept Pediat, Tromso, Norway..
    Berntson, Lillemor
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Fasth, Anders
    Univ Gothenburg, Dept Pediat, Gothenburg, Sweden..
    Rygg, Marite
    Norwegian Univ Sci & Technol, Dept Lab Med Childrens & Womens Hlth, Trondheim, Norway.;St Olavs Hosp, Dept Pediat, Trondheim, Norway..
    Müller, Klaus
    Rigshosp, Dept Pediat & Adolescent Med, Copenhagen Univ Hosp, Copenhagen, Denmark.;Rigshosp, Inst Inflammat Res, Copenhagen Univ Hosp, Copenhagen, Denmark..
    High-sensitive CRP as a predictive marker of long-term outcome in juvenile idiopathic arthritis2017In: Rheumatology International, ISSN 0172-8172, E-ISSN 1437-160X, Vol. 37, no 5, p. 695-703Article in journal (Refereed)
    Abstract [en]

    To evaluate whether C-reactive protein (CRP), including variation within the normal range, is predictive of long-term disease outcome in Juvenile Idiopathic Arthritis (JIA). Consecutive patients with newly diagnosed JIA were included prospectively from defined geographic areas of the Nordic countries from 1997 to 2000. Inclusion criteria were availability of a baseline serum sample within 12 months after disease onset and 8-year clinical assessment data. Systemic onset JIA was not included. CRP was measured by high-sensitive ELISA (detection limit of 0.2 mg/l). One hundred and thirty participants with a median follow-up time of 97 months (range 95-100) were included. At follow-up, 38% of the patients were in remission off medication. Absence of remission was associated with elevated level of CRP at baseline (odds ratio (OR) 1.33, confidence interval (CI) 1.08-1.63, p = 0.007). By applying a cutoff at the normal upper limit (> 10 mg/l), the risk of not achieving remission was increased to an OR of 8.60 (CI 2.98-24.81, p < 0.001). Variations of CRP within the normal range had no predictive impact on disease activity at follow-up. Baseline levels of ESR were available in 80 patients (61%) and elevated ESR was associated with absence of remission in a multivariable logistic regression analysis (OR 2.32, CI 1.35-4.00, p = 0.002). This results of this study indicate that baseline CRP concentrations above 10 mg/l are predictive of a poor outcome at 8-year follow-up. We could not demonstrate any predictive value of CRP variations within the normal range.

  • 6.
    Alimohammadi, Mohammad
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology.
    Knight, Ann
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Scalp necrosis as a late sign of giant-cell arteritis2013In: Case reports in immunology, ISSN 2090-6609, Vol. 2013, article id 231565Article in journal (Refereed)
    Abstract [en]

    Retinal infarction and scalp necrosis are described as unusual but devastating complications of giant-cell arteritis. We report a patient with this rare complication and emphasize the importance of timely diagnosis and treatment of giant-cell arteritis.

  • 7. Allum, Fiona
    et al.
    Shao, Xiaojian
    Guénard, Frédéric
    Simon, Marie-Michelle
    Busche, Stephan
    Caron, Maxime
    Lambourne, John
    Lessard, Julie
    Tandre, Karolina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Hedman, Åsa K
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Kwan, Tony
    Ge, Bing
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    McCarthy, Mark I
    Deloukas, Panos
    Richmond, Todd
    Burgess, Daniel
    Spector, Timothy D
    Tchernof, André
    Marceau, Simon
    Lathrop, Mark
    Vohl, Marie-Claude
    Pastinen, Tomi
    Grundberg, Elin
    Characterization of functional methylomes by next-generation capture sequencing identifies novel disease-associated variants2015In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 6, article id 7211Article in journal (Refereed)
    Abstract [en]

    Most genome-wide methylation studies (EWAS) of multifactorial disease traits use targeted arrays or enrichment methodologies preferentially covering CpG-dense regions, to characterize sufficiently large samples. To overcome this limitation, we present here a new customizable, cost-effective approach, methylC-capture sequencing (MCC-Seq), for sequencing functional methylomes, while simultaneously providing genetic variation information. To illustrate MCC-Seq, we use whole-genome bisulfite sequencing on adipose tissue (AT) samples and public databases to design AT-specific panels. We establish its efficiency for high-density interrogation of methylome variability by systematic comparisons with other approaches and demonstrate its applicability by identifying novel methylation variation within enhancers strongly correlated to plasma triglyceride and HDL-cholesterol, including at CD36. Our more comprehensive AT panel assesses tissue methylation and genotypes in parallel at ∼4 and ∼3 M sites, respectively. Our study demonstrates that MCC-Seq provides comparable accuracy to alternative approaches but enables more efficient cataloguing of functional and disease-relevant epigenetic and genetic variants for large-scale EWAS.

  • 8.
    Andersen, M.
    et al.
    Aalborg Univ, Hlth Sci & Technol, Aalborg, Denmark..
    Meyer, M. K.
    Aalborg Univ, Hlth Sci & Technol, Aalborg, Denmark..
    Nagaev, I.
    Nagaeva, O.
    Wikberg, Jarl E. S.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Mincheva-Nilsson, L.
    Andersen, G. N.
    Aalborg Univ, Clin Med, Aalborg, Denmark..
    Resistin Gene Transcription Is Regulated in Adaptive and Innate Immunity in Rheumatoid Arthritis2016In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 75, p. 904-904Article in journal (Other academic)
  • 9.
    Andersen, M.
    et al.
    Aalborg Univ, Hlth Sci & Technol, Aalborg, Denmark..
    Meyer, M. K.
    Aalborg Univ, Hlth Sci & Technol, Aalborg, Denmark..
    Nagaev, I.
    Nagaeva, O.
    Wikberg, Jarl E. S.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Mincheva-Nilsson, L.
    Andersen, G. N.
    Aalborg Univ, Clin Med, Aalborg, Denmark..
    The Melanocortin System Is Responsive in Disease Driving Immune Cells in Rheumatoid Arthritis and May Offer A Pathway To Curative Treatment2016In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 75, p. 903-904Article in journal (Other academic)
  • 10. Andersen, M.
    et al.
    Olesen, M. K.
    Nagaev, I.
    Nagaeva, O.
    Wikberg, Jarl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Mincheva-Nilsson, L.
    Andersen, G. N.
    Adalimumab (Humira (R)) normalizes melanocortin receptor subtype 2, 3, and 4 expression in CD8+, CD14+, and CD19+leucocyte subsets in rheumatoid arthritis2014In: Scandinavian Journal of Rheumatology, ISSN 0300-9742, E-ISSN 1502-7732, Vol. 43, p. 25-26Article in journal (Other academic)
  • 11.
    Andersson, Sofia E. M.
    et al.
    Univ Gothenburg, Sahlgrenska Acad, Inst Med, Dept Rheumatol & Inflammat Res, Box 480, SE-40530 Gothenburg, Sweden..
    Eneljung, Tove
    Univ Gothenburg, Sahlgrenska Acad, Inst Med, Dept Rheumatol & Inflammat Res, Box 480, SE-40530 Gothenburg, Sweden.;Sahlgrens Univ Hosp, Gothenburg, Sweden..
    Tengvall, Sara
    Univ Gothenburg, Sahlgrenska Acad, Inst Med, Dept Rheumatol & Inflammat Res, Box 480, SE-40530 Gothenburg, Sweden.;Sahlgrens Univ Hosp, Gothenburg, Sweden..
    Jirholt, Pernilla
    Univ Gothenburg, Sahlgrenska Acad, Inst Med, Dept Rheumatol & Inflammat Res, Box 480, SE-40530 Gothenburg, Sweden..
    Stern, Anna
    Univ Gothenburg, Sahlgrenska Acad, Inst Med, Dept Rheumatol & Inflammat Res, Box 480, SE-40530 Gothenburg, Sweden..
    Henningsson, Louise
    Univ Gothenburg, Sahlgrenska Acad, Inst Med, Dept Rheumatol & Inflammat Res, Box 480, SE-40530 Gothenburg, Sweden..
    Liang, Bibo
    Karolinska Inst, Dept Med Biochem & Biophys, Med Inflammat Res, Solna, Sweden.;Southern Med Univ, Guangzhou, Guangdong, Peoples R China..
    Thorarinsdottir, Katrin
    Univ Gothenburg, Sahlgrenska Acad, Inst Med, Dept Rheumatol & Inflammat Res, Box 480, SE-40530 Gothenburg, Sweden.;Sahlgrens Univ Hosp, Gothenburg, Sweden..
    Kihlberg, Jan
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Holmdahl, Rikard
    Karolinska Inst, Dept Med Biochem & Biophys, Med Inflammat Res, Solna, Sweden.;Southern Med Univ, Guangzhou, Guangdong, Peoples R China..
    Martensson, Inga-Lill
    Univ Gothenburg, Sahlgrenska Acad, Inst Med, Dept Rheumatol & Inflammat Res, Box 480, SE-40530 Gothenburg, Sweden..
    Gustafsson, Kenth
    UCL, Inst Child Hlth, Mol Immunol Unit, London, England..
    Gjertsson, Inger
    Univ Gothenburg, Sahlgrenska Acad, Inst Med, Dept Rheumatol & Inflammat Res, Box 480, SE-40530 Gothenburg, Sweden.;Sahlgrens Univ Hosp, Gothenburg, Sweden..
    Collagen epitope expression on B cells is sufficient to confer tolerance to collagen-induced arthritis2016In: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 18, article id 140Article in journal (Refereed)
    Abstract [en]

    Background: The mechanisms underlying tolerance induction and maintenance in autoimmune arthritis remain elusive. In a mouse model of rheumatoid arthritis, collagen type II (CII)-induced arthritis, we explore the contribution of B cells to antigen-specific tolerance. Methods: To generate expression of the CII-peptide specifically on B-cell major histocompatibility complex type II, lentiviral-based gene therapy including a B-cell-specific Igk promoter was used. Results: Presentation of the CII-peptide on B cells significantly reduced the frequency and severity of arthritis as well as the serum levels of CII -specific IgG antibodies. Further, both frequency and suppressive function of regulatory T cells were increased in tolerized mice. Adoptive transfer of regulatory T cells from tolerized mice to naive mice ameliorated the development of CII-induced arthritis. Conclusion: Our data suggest that endogenous presentation of the CII-peptide on B cells is one of the key contributors to arthritis tolerance induction and maintenance.

  • 12. Aqrawi, Lara A
    et al.
    Ivanchenko, Margarita
    Björk, Albin
    Ramírez Sepúlveda, Jorge I
    Imgenberg-Kreuz, Juliana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Kvarnström, Marika
    Haselmayer, Philipp
    Jensen, Janicke Liaaen
    Nordmark, Gunnel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Chemin, Karine
    Skarstein, Kathrine
    Wahren-Herlenius, Marie
    Diminished CXCR5 expression in peripheral blood of patients with Sjögren's syndrome may relate to both genotype and salivary gland homing.2018In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249Article in journal (Refereed)
    Abstract [en]

    cells in circulation was also related to homing of B and T cells to the autoimmune target organ. Therapeutic drugs targeting the CXCR5/CXCL13 axis may be useful in SS. This article is protected by copyright. All rights reserved.

  • 13. Arkema, E.
    et al.
    Jonsen, A.
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Sjowall, C.
    Svenungsson, E.
    Simard, J. F.
    Utility of Swedish Register Data in Classifying Systemic Lupus2014In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 73, p. 444-444Article in journal (Other academic)
  • 14. Arkema, Elizabeth V
    et al.
    Feltelius, Nils
    Olsson, Tomas
    Askling, Johan
    No association between rheumatoid arthritis, amyotrophic lateral sclerosis, and tumour necrosis factor inhibitor treatment.2014In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 73, no 11Article in journal (Refereed)
  • 15. Arkema, Elizabeth V
    et al.
    Jönsen, Andreas
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Svenungsson, Elisabet
    Sjöwall, Christopher
    Simard, Julia F
    Case definitions in Swedish register data to identify systemic lupus erythematosus2016In: BMJ Open, ISSN 2044-6055, E-ISSN 2044-6055, Vol. 6, no 1, article id e007769Article 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.

  • 16. Arkema, Elizabeth V
    et al.
    van Vollenhoven, Ronald F
    Askling, Johan
    Incidence of progressive multifocal leukoencephalopathy in patients with rheumatoid arthritis: a national population-based study2012In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 71, no 11, p. 1865-1867Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Cases of progressive multifocal leukoencephalopathy (PML), a rare but serious disease, have been reported in patients with rheumatoid arthritis (RA) in association with biological therapy, but little is known about the incidence of PML in patients with RA in the absence of treatment exposure.

    OBJECTIVE: To estimate the incidence rate of PML in patients with RA compared with the general population, with and without exposure to biological agents.

    METHODS: Patients with adult onset RA, exposure to biological agents and a diagnosis of PML from 1999 through 2009 were identified from national registries and linked using each Swedish resident's unique personal identification number. General population comparators matched on age, sex and county were also identified. Crude and age- and sex-standardised incidence rates (cases per 100 000 person-years) were calculated with 95% CI.

    RESULTS: 66 278 patients with RA and 286 949 general population comparators were included in the study. The incidence rate of PML in the overall RA population was 1.0 (95% CI 0.3 to 2.5) compared with 0.3 (95% CI 0.1 to 0.6) in the general population. The difference in incidence rate was 0.7 (95% CI -0.3 to 17). Among all patients exposed to biological agents, only one patient was diagnosed with PML.

    CONCLUSION: Data from this national population-based cohort study suggest that patients with RA may have an increased rate of PML compared with the general population.

  • 17.
    Arnaud, Laurent
    et al.
    Univ Strasbourg, Ctr Natl Reference Malad Syst & Autoimmunes Rares, INSERM, UMR S 1109, Strasbourg, Sweden.;Karolinska Inst, Karolinska Univ Hosp, Stockholm, Sweden..
    Nordin, Annica
    Karolinska Inst, Karolinska Univ Hosp, Stockholm, Sweden..
    Lundholm, Hannes
    Karolinska Inst, Karolinska Univ Hosp, Stockholm, Sweden..
    Svenungsson, Elisabet
    Karolinska Inst, Karolinska Univ Hosp, Stockholm, Sweden..
    Hellbacher, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Wikner, Johan
    Karolinska Inst, Stockholm, Sweden.;Soder Sjukhuset, Stockholm, Sweden..
    Zickert, Agneta
    Karolinska Inst, Karolinska Univ Hosp, Stockholm, Sweden..
    Gunnarsson, Iva
    Karolinska Inst, Karolinska Univ Hosp, Stockholm, Sweden..
    Effect of Corticosteroids and Cyclophosphamide on Sex Hormone Profiles in Male Patients With Systemic Lupus Erythematosus or Systemic Sclerosis2017In: Arthritis & Rheumatology, ISSN 2326-5191, E-ISSN 2326-5205, Vol. 69, no 6, p. 1272-1279Article in journal (Refereed)
    Abstract [en]

    Objective: Systemic lupus erythematosus (SLE) and systemic sclerosis (SSc) are autoimmune diseases that predominantly affect female patients, and therefore fewer investigations have been conducted in men. The aim of this study was to analyze sex hormone levels in male patients with SLE and those with SSc, compared to matched controls, in relation to the use of corticosteroids and cyclophosphamide (CYC).

    Methods: Sex hormone levels were measured in fasting blood samples from male patients with SLE (n=71) and those with SSc (n=29) and compared to population-based, age-matched male controls. Relevant hormone profiles were identified using cluster analysis.

    Results: Male SLE patients had higher levels of luteinizing hormone (LH) (P<0.0001) and more frequent bioactive testosterone deficiency (P=0.02) than their matched controls. The current dosage of prednisolone correlated inversely with the levels of bioactive testosterone (r=-0.36, P=0.03). Cluster analysis identified a subset of SLE patients with increased levels of follicle-stimulating hormone, LH, and prolactin as well as lower levels of bioactive testosterone (P<0.0001) in relation to higher daily doses of prednisolone. In male SSc patients, levels of testosterone (P=0.03) and bioactive testosterone (P=0.02) were significantly lower than those in matched controls. Use of CYC during the previous year was associated with lower bioactive testosterone levels in both SLE patients (P=0.02) and SSc patients (P=0.01), after adjustment for age.

    Conclusion: The results of this study highlight the negative impact of corticosteroids on gonadal function in men with SLE. Furthermore, use of CYC during the year prior to study inclusion impaired bioactive testosterone levels in male patients with either SLE or SSc. Physicians should be more aware of the possibility of hypogonadism in male patients with autoimmune diseases. The need for hormonal supplementation remains to be formally evaluated in these patients.

  • 18.
    Arvonen, Miika
    et al.
    Kuopio Univ Hosp, Dept Pediat, Kuopio, Finland.;Oulu Univ Hosp, Med Res Ctr, Oulu, Finland.;Univ Oulu, Oulu, Finland.;Univ Oulu, PEDEGO Res Unit, Oulu, Finland..
    Berntson, Lillemor
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Pokka, Tytti
    Oulu Univ Hosp, Med Res Ctr, Oulu, Finland.;Univ Oulu, Oulu, Finland.;Univ Oulu, PEDEGO Res Unit, Oulu, Finland.;Oulu Univ Hosp, Dept Children & Adolescents, Oulu, Finland..
    Karttunen, Tuomo J.
    Oulu Univ Hosp, Med Res Ctr, Oulu, Finland.;Univ Oulu, Oulu, Finland.;Univ Oulu, Canc & Translat Med Res Unit, Oulu, Finland.;Oulu Univ Hosp, Dept Pathol, Oulu, Finland..
    Vahasalo, Paula
    Oulu Univ Hosp, Med Res Ctr, Oulu, Finland.;Univ Oulu, Oulu, Finland.;Univ Oulu, PEDEGO Res Unit, Oulu, Finland.;Oulu Univ Hosp, Dept Children & Adolescents, Oulu, Finland..
    Stoll, Matthew L.
    Univ Alabama Birmingham, Dept Pediat, CPP N 210 M,1600 7th Ave South, Birmingham, AL 35233 USA..
    Gut microbiota-host interactions and juvenile idiopathic arthritis2016In: Pediatric Rheumatology, ISSN 1546-0096, E-ISSN 1546-0096, Vol. 14, article id 44Article, review/survey (Refereed)
    Abstract [en]

    Background: Juvenile idiopathic arthritis is the most common form of chronic arthritis in children. There is mounting evidence that the microbiota may influence the disease. Main body: Recent observations in several systemic inflammatory diseases including JIA have indicated that abnormalities in the contents of the microbiota may be factors in disease pathogenesis, while other studies in turn have shown that environmental factors impacting the composition of the microbiota, such as delivery mode and early exposure to antibiotics, affect the risk of chronic inflammatory diseases including JIA. Microbial alterations may predispose to JIA through a variety of mechanisms, including impaired immunologic development, alterations in the balances of pro- versus anti-inflammatory bacteria, and low-grade mucosal inflammation. Additional confirmatory studies of microbiota aberrations and their risk factors are needed, as well as additional mechanistic studies linking these alterations to the disease itself. Conclusions: The microbiota may influence the risk of JIA and other systemic inflammatory conditions through a variety of mechanisms. Additional research is required to improve our understanding of the links between the microbiota and arthritis, and the treatment implications thereof.

  • 19. Askling, J
    et al.
    Fored, C M
    Brandt, L
    Baecklund, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Bertilsson, L
    Feltelius, N
    Medical Products Agency, Uppsala, Sweden .
    Cöster, L
    Geborek, P
    Jacobsson, L T
    Lindblad, S
    Lysholm, J
    Rantapää-Dahlqvist, S
    Saxne, T
    Klareskog, L
    Risks of solid cancers in patients with rheumatoid arthritis and after treatment with tumour necrosis factor antagonists2005In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 64, no 10, p. 1421-1426Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    Existing studies of solid cancers in rheumatoid arthritis (RA) reflect cancer morbidity up until the early 1990s in prevalent cohorts admitted to hospital during the 1980s.

    OBJECTIVE:

    To depict the cancer pattern of contemporary patients with RA, from updated risk data from prevalent and incident RA populations. To understand the risk of solid cancer after tumour necrosis factor (TNF) treatment by obtaining cancer data from cohorts treated in routine care rather than trials.

    METHODS:

    A population based study of three RA cohorts (one prevalent, admitted to hospital 1990-2003 (n = 53,067), one incident, diagnosed 1995-2003 (n = 3703), and one treated with TNF antagonists 1999-2003 (n = 4160)), which were linked with Swedish nationwide cancer and census registers and followed up for cancer occurrence through 2003.

    RESULTS:

    With 3379 observed cancers, the prevalent RA cohort was at marginally increased overall risk of solid cancer, with 20-50% increased risks for smoke related cancers and +70% increased risk for non-melanoma skin cancer, but decreased risk for breast (-20%) and colorectal cancer (-25%). With 138 cancers, the incident RA cohort displayed a similar cancer pattern apart from non-decreased risks for colorectal cancer. TNF antagonist treated patients displayed solid cancer (n = 67) risks largely similar to those of other patients with RA.

    CONCLUSION:

    The cancer pattern in patients treated with TNF antagonists mirrors those of other contemporary as well as historic RA cohorts. The consistent increase in smoking associated cancers in patients with RA emphasises the potential for smoking cessation as a cancer preventive measure in RA.

  • 20. Askling, J
    et al.
    Klareskog, L
    Hjalgrim, H
    Baecklund, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Björkholm, M
    Ekbom, A
    Do steroids increase lymphoma risk? A case-control study of lymphoma risk in polymyalgia rheumatica/giant cell arteritis2005In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 64, no 12, p. 1765-1768Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    Recent studies indicate increased risks of malignant lymphomas among individuals treated with corticosteroids, but have not taken into account the underlying reasons for steroid use, so the increased risks might be attributable to the underlying disease or concomitant treatments other than steroids. Polymyalgia rheumatica (PMR) and temporal arteritis (giant cell arteritis, GCA) are common inflammatory conditions treated with steroids as single immunosuppressive therapy, but data on lymphoma risk in GCA/PMR are limited.

    OBJECTIVE:

    To assess the risk of lymphoma associated with steroid treatment of GCA/PMR.

    METHODS:

    The association between GCA/PMR and malignant lymphomas (overall, and separately for non-Hodgkin lymphoma, Hodgkin lymphoma, and chronic lymphatic leukaemia) was examined in a nationwide, population based, case-control study of 42,676 lymphoma cases and 78,487 matched population controls, using prospectively recorded data on lymphomas from the Swedish cancer register 1964-2000 and data on pre-lymphoma hospital admissions for GCA/PMR from the Swedish inpatient register 1964-2000. Odds ratios (OR) associated with a pre-lymphoma hospital admission for GCA/PMR were calculated using conditional logistic regression.

    RESULTS:

    153 lymphoma cases and 345 population controls had a history of GCA/PMR, resulting in an overall OR for malignant lymphomas of 0.81 (95% confidence interval, 0.67 to 0.98). The OR varied little with lymphoma type, sex, age, and calendar period. The OR for GCA was 0.67 (0.48 to 0.98) and for PMR, 0.83 (0.67 to 1.04).

    CONCLUSIONS:

    Treated GCA is not associated with increased lymphoma risks, which suggests that even at considerable cumulative doses, steroids may not appreciably increase lymphoma risk.

  • 21.
    Baecklund, Eva
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Backlin, C
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Rönnelid, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Toes, R
    Huizinga, Twj
    Åhlin, E
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Askling, J
    Hochberg, F H
    Klareskog, L
    Kay, J
    Smedby, K E
    Anti-cyclic citrullinated peptide antibodies, other common autoantibodies, and smoking as risk factors for lymphoma in patients with rheumatoid arthritis2018In: Scandinavian Journal of Rheumatology, ISSN 0300-9742, E-ISSN 1502-7732Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: Patients with rheumatoid arthritis (RA) are at increased risk of lymphoma. There is no biomarker to indicate future lymphoma risk in RA and it is not known whether factors associated with an increased risk of RA also confer an increased risk of lymphoma. We investigated whether anti-cyclic citrullinated peptide (CCP) antibodies, other autoantibodies, and smoking, are associated with lymphoma development in RA.

    METHOD: subclasses of anti-CCP antibodies and for 15 antinuclear antibody (ANA)-associated specific autoantibodies. Relative risks were estimated as crude and adjusted odds ratios (adjOR) with 95% confidence intervals (CIs) using logistic regression.

    RESULTS: We found no association between anti-CCP IgG ≥ 25 units/mL (adjOR 1.4, 95% CI 0.7-2.7), anti-CCP IgG ≥ 500 units/mL (adjOR 1.4, 95% CI 0.7-3.0), anti-CCP Ig of other isotypes, other autoantibodies (adjOR any vs none 0.6, 95% CI 0.3-1.2), or cigarette smoking (adjOR ever vs never 1.1, 95% CI 0.5-2.2) and lymphoma risk among patients with RA.

    CONCLUSION: , IgM, or IgA), nor other common autoantibodies, nor smoking predicted lymphoma risk in RA.

  • 22. Balboni, Imelda
    et al.
    Niewold, Timothy B
    Morgan, Gabrielle
    Limb, Cindy
    Eloranta, Maija-Leena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Utz, Paul J
    Pachman, Lauren M
    Brief Report: Interferon-α Induction and Detection of Anti-Ro, Anti-La, Anti-Sm, and Anti-RNP Autoantibodies by Autoantigen Microarray Analysis in Juvenile Dermatomyositis2013In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 65, no 9, p. 2424-2429Article in journal (Refereed)
    Abstract [en]

    Objective:

    To evaluate serum interferon- (IFN) activity in the context of autoantibody profiles in patients with juvenile dermatomyositis (JDM). 

    Methods:

    Sera from 36 patients with JDM were analyzed. Autoantibody profiles were determined by probing microarrays, which were fabricated with approximate to 80 distinct autoantigens, with serum and a Cy3-conjugated secondary antibody. Arrays were scanned and analyzed to determine antigen reactivity. Serum IFN activity was measured using a functional reporter cell assay. Sera were assayed alone or in combination with cellular material released from necrotic U937 cells to stimulate peripheral blood mononuclear cells from healthy donors in vitro, and IFN production in culture was measured by a dissociation-enhanced lanthanide fluoroimmunoassay (DELFIA). 

    Results:

    Reactivity against at least 1 of 41 autoantigens on the microarray, including Ro 52, Ro 60, La, Sm, and RNP, was observed in 75% of the serum samples from patients with JDM. IFN activity was detected in 7 samples by reporter cell assay. The reporter cell assay showed a significant association of reactivity against Ro, La, Sm, and proliferating cell nuclear antigen with serum IFN activity (P = 0.005). Significance Analysis of Microarrays (SAM) identified increased reactivity against Sm, RNP, Ro 52, U1-C, and Mi-2 in these sera. Sixteen samples induced IFN production as measured by DELFIA, and there was a significant association of reactivity against Ro, La, Sm, and RNP with the induction of IFN by serum and necrotic cell material (P = 0.034). SAM identified increased reactivity against Ro 60 in these sera. 

    Conclusion:

    These data support the hypothesis that nucleic acid-associated autoantibodies, including the Ro/La and Sm/RNP complexes, may stimulate the production of active IFN in children with JDM.

  • 23.
    Bengtsson, A. A.
    et al.
    Lund Univ, Skane Univ Hosp, Dept Clin Sci Lund, Rheumatol, Lund, Sweden..
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Systemic lupus erythematosus: still a challenge for physicians2017In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 281, no 1, p. 52-64Article, review/survey (Refereed)
    Abstract [en]

    Systemic lupus erythematosus (SLE) has a complex clinical picture, and a number of defects in the immune system have been described in patients with the disease. Most organs can be involved in SLE, and in addition to the typical major organ manifestations (e.g. from kidneys and the central nervous system), early cardiovascular disease is a major determinant of prognosis. Several important findings during the last decade have increased the understanding of the mechanisms behind the disease characteristics and the underlying autoimmune process. Amongst, these are defects in the handling of apoptotic cells, increased expression of type I interferon-regulated genes and activation of autoreactive B cells, with both the type I interferon system and the B lymphocyte stimulator (BLyS) having key roles. In addition, a large number of genes have been identified that contribute to these abnormalities. It has also become clear that certain SLE risk genes are associated with some organ manifestations, such as STAT4 with nephritis and IRF8 with myocardial infarction. Furthermore, environmental factors that can induce SLE or trigger a disease flare have been identified. As a consequence of this increased knowledge, new treatments for SLE have been developed. The most recently approved drug for SLE is belimumab, which blocks BLyS, and several new therapies and therapeutic strategies are in the pipeline for clinical application.

  • 24.
    Bengtsson, Anders A.
    et al.
    Lund Univ, Skdne Univ Hosp, Dept Clin Sci Lund, Rheumatol, S-22185 Lund, 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.
    Role of interferons in SLE2017In: Baillière's Best Practice & Research: Clinical Rheumatology, ISSN 1521-6942, E-ISSN 1532-1770, Vol. 31, no 3, p. 415-428Article in journal (Refereed)
    Abstract [en]

    Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disease that affects many different organ systems, with excessive production of type I interferons (IFNs) and auto antibodies against nucleic acids as hallmarks. Activation of the type I IFN system in SLE is due to continuous stimulation of plasmacytoid dendritic cells by endogenous nucleic acids, leading to sustained type I IFN production. This is reflected by an over expression of type I IFN-regulated genes or an IFN signature. Type I IFNs have effects on both the innate and adaptive immune systems, which contribute to both loss of tolerance and the autoimmune disease process. In this review, we discuss the current understanding of IFNs in SLE, focusing on their regulation, the influence of genetic background, and environmental factors and therapies that are under development aiming to inhibit the type I IFN system in SLE.

  • 25. Bengtsson, Anders A
    et al.
    Sturfelt, Gunnar
    Lood, Christian
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    van Vollenhoven, Ronald F
    Axelsson, Bengt
    Sparre, Birgitta
    Tuvesson, Helén
    Wallén Öhman, Marie
    Leanderson, Tomas
    Pharmacokinetics, tolerability, and preliminary efficacy of ABR-215757, a new quinoline-3-carboxamide derivative, in murine and human SLE2012In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 64, no 5, p. 1579-1588Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To assess the efficacy of ABR-215757, a new immunomodulatory small molecule in a murine SLE model, to evaluate the pharmacokinetics and tolerability in SLE patients at doses predicted to be efficacious and safe, and to determine the maximum tolerated dose (MTD).

    METHODS: The efficacy of ABR-215757 was studied in lupus prone MRLlpr/lpr mice and compared with established SLE treatments. Dose response data of ABR-215757 were together with pharmacokinetic data used to calculate effective and safe clinical doses. The pharmacokinetics and tolerance of ABR-215757 were evaluated in a Phase Ib double-blind, placebo controlled, dose-escalation study where cohorts of SLE patients received daily oral treatment for 12 weeks.

    RESULTS: Disease inhibition in MRLlpr/lpr mice, comparable to that of prednisolone and mycophenolate mofetil, was obtained with ABR-215757. Prominent effects on disease manifestations, serological markers and a steroid sparing effect were seen for ABR-215757. The pharmacokinetic properties in SLE patients were linear and well suitable for once daily oral treatment. The majority of the adverse events (AEs) were mild or moderate and transient. The most frequent AEs were arthralgia and myalgia, reported at the highest (4.5 and 6 mg/day) dose levels. At 4.5 mg and higher some AEs of severe intensity and serious adverse events (SAEs) were reported.

    CONCLUSION: ABR-215757 effectively inhibited disease and had a steroid sparing effect in experimental lupus. Clinical doses up to 3 mg/day, dose levels predicted from pre-clinical studies to be efficacious and safe, were well tolerated in the SLE patients. The MTD was concluded to be 4.5 mg/day.

  • 26.
    Berg, L.
    et al.
    Karolinska Inst, S-10401 Stockholm, Sweden..
    Sundström, Y.
    Karolinska Inst, S-10401 Stockholm, Sweden..
    Aftab, Obaid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Bergqvist, F.
    Karolinska Inst, S-10401 Stockholm, Sweden..
    Kultima, Kim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Gustafsson, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Larsson, Rolf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Sundström, M.
    Karolinska Inst, S-10401 Stockholm, Sweden..
    Ossipova, E.
    Karolinska Inst, S-10401 Stockholm, Sweden..
    Lengqvist, J.
    Karolinska Inst, S-10401 Stockholm, Sweden..
    Jakobsson, P-J
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Rubin, Jenny
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Characterizing the effects of epigenetic regulation in assays using peripheral blood mononuclear cells from patients with inflammatory diseases2016In: Scandinavian Journal of Rheumatology, ISSN 0300-9742, E-ISSN 1502-7732, Vol. 45, p. 44-45Article in journal (Other academic)
  • 27.
    Berggren, Olof
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Regulation of Type I Interferon Production in Plasmacytoid Dendritic Cells: Effect of Genetic Factors and Interactions with NK Cells and B Cells2015Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The type I interferon (IFN) system plays a central role in the etiopathogenesis of many autoimmune diseases, e.g. systemic lupus erythematosus (SLE). Activation of the type I IFN system in SLE is promoted by endogenous nucleic acid-containing immune complexes (ICs) which stimulate plasmacytoid dendritic cells (pDCs). This thesis focuses on the regulation of IFN-α production in pDCs, by interactions with B cells and natural killer (NK) cells, and by genetic factors.

    In Study I, RNA-IC-stimulated CD56dim NK cells were found to be activated via FcγRIIIa and enhanced the IFN-α production by pDCs. The enhancing effect of the NK cells was mediated via both soluble factors, such as the cytokine MIP-1β, and in a cell-cell contact mediated manner via the adhesion molecule LFA-1. In Study II, B cells enhanced the IFN-α production by pDCs via cell-cell contact or soluble factors, depending on the stimuli. The cell-cell contact-mediated enhancement, when the cells were stimulated with RNA-IC, was abolished by blocking the cell adhesion molecule CD31. B cells stimulated with the oligonucleotide ODN2216 enhanced the IFN-α production via soluble factors. In Study III, gene variants related to autoimmune or inflammatory diseases were analyzed for the association to the IFN-α production by pDCs, alone or in coculture with NK or B cells. Depending on cell combination, 18-86 SNPs (p < 0.001) were associated with the IFN-α production. Several of the SNPs showed novel associations to the type I IFN system, while some loci have been described earlier for their association with SLE, e.g. IL10 and PXK. In Study IV, several B cell populations were affected by cocultivation with pDCs and stimulation with RNA-IC. The frequency of CD24hiCD38hi B cells of regulatory character was increased in the pDC-B cell cocultures. However, RNA-IC-stimulation only induced modest levels of IL-10. A remarkably increased frequency of double negative CD27-IgD- B cells was found in the RNA-IC-stimulated cocultures of pDCs and B cells.

    In conclusion, the findings in the present thesis reveal novel mechanisms behind the regulation of the type I IFN system which could be important targets in autoimmune diseases with constantly activated pDCs.

    List of papers
    1. IFN-α Production by Plasmacytoid Dendritic Cells Stimulated with RNA-Containing Immune Complexes Is Promoted by NK Cells via MIP-1β and LFA-1
    Open this publication in new window or tab >>IFN-α Production by Plasmacytoid Dendritic Cells Stimulated with RNA-Containing Immune Complexes Is Promoted by NK Cells via MIP-1β and LFA-1
    Show others...
    2011 (English)In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 186, no 9, p. 5085-5094Article in journal (Refereed) Published
    Abstract [en]

    Several systemic autoimmune diseases display a prominent IFN signature. This is caused by a continuous IFN-α production by plasmacytoid dendritic cells (pDCs), which are activated by immune complexes (ICs) containing nucleic acid. The IFN-α production by pDCs stimulated with RNA-containing IC (RNA-IC) consisting of anti-RNP autoantibodies and U1 small nuclear ribonucleoprotein particles was recently shown to be inhibited by monocytes, but enhanced by NK cells. The inhibitory effect of monocytes was mediated by TNF-α, PGE2, and reactive oxygen species, but the mechanisms for the NK cell-mediated increase in IFN-α production remained unclear. In this study, we investigated the mechanisms whereby NK cells increase the RNA-IC–induced IFN-α production by pDCs. Furthermore, NK cells from patients with systemic lupus erythematosus (SLE) were evaluated for their capacity to promote IFN-α production. We found that CD56dim NK cells could increase IFN-α production >1000-fold after RNA-IC activation, whereas CD56bright NK cells required costimulation by IL-12 and IL-18 to promote IFN-α production. NK cells produced MIP-1α, MIP-1β, RANTES, IFN-γ, and TNF-α via RNA-IC–mediated FcγRIIIA activation. The IFN-α production in pDCs was promoted by NK cells via MIP-1β secretion and LFA-mediated cell–cell contact. Moreover, NK cells from SLE patients displayed a reduced capacity to promote the RNA-IC–induced IFN-α production, which could be restored by exogenous IL-12 and IL-18. Thus, different molecular mechanisms can mediate the NK cell-dependent increase in IFN-α production by RNA-IC–stimulated pDCs, and our study suggests that the possibility to therapeutically target the NK–pDC axis in IFN-α–driven autoimmune diseases such as SLE should be investigated.

    Keyword
    interferon, plasmacytoid dendritic cells, MIP-1beta, NK cells
    National Category
    Rheumatology and Autoimmunity
    Research subject
    Medicine
    Identifiers
    urn:nbn:se:uu:diva-150274 (URN)10.4049/jimmunol.1003349 (DOI)000289679600011 ()21430220 (PubMedID)
    Available from: 2011-03-29 Created: 2011-03-29 Last updated: 2017-12-11Bibliographically approved
    2. B lymphocytes enhance the interferon-α production by plasmacytoid dendritic cells
    Open this publication in new window or tab >>B lymphocytes enhance the interferon-α production by plasmacytoid dendritic cells
    Show others...
    2012 (English)In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 64, no 10, p. 3409-3419Article in journal (Refereed) Published
    Abstract [en]

    OBJECTIVE:

    Type I interferon (IFN) system and B cells are activated in many autoimmune diseases, e.g. systemic lupus erythematosus (SLE). IFNα produced by plasmacytoid dendritic cells (pDC) stimulate several B cell functions, including autoantibody production. However, not much is known how B cells influence the pDC function. We therefore investigated the regulatory effect of B cells on IFNα production by pDC.

    METHODS:

    PDC and B cells from healthy blood donor PBMC were stimulated with RNA-containing immune complexes (RNA-IC) consisting of U1 snRNP and IgG from SLE patients, herpes simplex virus (HSV) or oligonucleotide ODN2216, alone or in co-cultures. IFNα, several other cytokines and pDC or B cell-associated surface molecules were analyzed by immunoassays or flow cytometry.

    RESULTS:

    B cells enhanced the IFNα production by pDC up to 47-fold, and the effect was most pronounced for pDC stimulated with RNA-IC. Anti-CD31 antibody reduced the RNA-IC-induced IFNα production by 80%, but not when ODN2216 was used as IFN-inducer. Supernatants from ODN2216-stimulated B cells promoted IFNα production by pDC, while supernatants from RNA-IC-stimulated B cells did not.

    CONCLUSION:

    Our results reveal a novel B cell function, enhancing the type I IFN production by pDC. Since B cells are activated by type I IFN, this pDC-B cell cross-talk might be of fundamental importance in the etiopathogenesis of SLE, and contribute to a chronic immune activation in SLE and other systemic rheumatic diseases.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-177989 (URN)10.1002/art.34599 (DOI)000309403000039 ()22736048 (PubMedID)
    Available from: 2012-07-23 Created: 2012-07-23 Last updated: 2017-12-07Bibliographically approved
    3. IFN-α production by plasmacytoid dendritic cell associations with polymorphisms in gene loci related to autoimmune and inflammatory diseases
    Open this publication in new window or tab >>IFN-α production by plasmacytoid dendritic cell associations with polymorphisms in gene loci related to autoimmune and inflammatory diseases
    Show others...
    2015 (English)In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 24, no 12, p. 3571-3581Article in journal (Refereed) Published
    Abstract [en]

    The type I interferon (IFN) system is persistently activated in systemic lupus erythematosus (SLE) and many other systemic autoimmune diseases. Studies have shown an association between SLE and several gene variants within the type I IFN system. We investigated whether single nucleotide polymorphisms (SNPs) associated with SLE and other autoimmune diseases affect the IFN-α production in healthy individuals. Plasmacytoid dendritic cells (pDCs), B and NK cells were isolated from peripheral blood of healthy individuals and stimulated with RNA-containing immune complexes (IC), herpes simplex virus (HSV) or the oligonucleotide ODN2216. IFN-α production by pDCs alone or in cocultures with B or NK cells was measured by an immunoassay. All donors were genotyped with the 200K ImmunoChip and a 5bp CGGGG length polymorphism in the IFN regulatory factor 5 gene (IRF5) was genotyped by PCR. We found associations between IFN-α production and 18-86 SNPs (p ≤ 0.001), depending on the combination of the stimulated cell types. However, only three of these associated SNPs were shared between the cell type combinations. Several SNPs showed novel associations to the type I IFN system among all the associated SNPs, while some loci have been described earlier for their association with SLE. Furthermore, we found that the SLE-risk variant of the IRF5 CGGGG-indel was associated with lower IFN-α production. We conclude that the genetic variants affecting the IFN-α production highlight the intricate regulation of the type I IFN system and the importance of understanding the mechanisms behind the dysregulated type I IFN system in SLE.

    National Category
    Rheumatology and Autoimmunity
    Identifiers
    urn:nbn:se:uu:diva-246523 (URN)10.1093/hmg/ddv095 (DOI)000355674400023 ()
    Available from: 2015-03-09 Created: 2015-03-09 Last updated: 2017-12-04Bibliographically approved
    4. Activated plasmacytoid dendritic cells alter the composition of peripheral blood B cell subsets
    Open this publication in new window or tab >>Activated plasmacytoid dendritic cells alter the composition of peripheral blood B cell subsets
    (English)Manuscript (preprint) (Other academic)
    National Category
    Rheumatology and Autoimmunity
    Identifiers
    urn:nbn:se:uu:diva-246525 (URN)
    Available from: 2015-03-09 Created: 2015-03-09 Last updated: 2015-04-17
  • 28.
    Berggren, Olof
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Alexsson, Andrei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Morris, David
    King’s College London School of Medicine, Guy’s Hospital, London.
    Tandre, Karolina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Weber, Gert
    Free University of Berlin.
    Vyse, Timothy
    King’s College London School of Medicine, Guy’s Hospital, London.
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Eloranta, Maija-Leena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    IFN-α production by plasmacytoid dendritic cell associations with polymorphisms in gene loci related to autoimmune and inflammatory diseases2015In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 24, no 12, p. 3571-3581Article in journal (Refereed)
    Abstract [en]

    The type I interferon (IFN) system is persistently activated in systemic lupus erythematosus (SLE) and many other systemic autoimmune diseases. Studies have shown an association between SLE and several gene variants within the type I IFN system. We investigated whether single nucleotide polymorphisms (SNPs) associated with SLE and other autoimmune diseases affect the IFN-α production in healthy individuals. Plasmacytoid dendritic cells (pDCs), B and NK cells were isolated from peripheral blood of healthy individuals and stimulated with RNA-containing immune complexes (IC), herpes simplex virus (HSV) or the oligonucleotide ODN2216. IFN-α production by pDCs alone or in cocultures with B or NK cells was measured by an immunoassay. All donors were genotyped with the 200K ImmunoChip and a 5bp CGGGG length polymorphism in the IFN regulatory factor 5 gene (IRF5) was genotyped by PCR. We found associations between IFN-α production and 18-86 SNPs (p ≤ 0.001), depending on the combination of the stimulated cell types. However, only three of these associated SNPs were shared between the cell type combinations. Several SNPs showed novel associations to the type I IFN system among all the associated SNPs, while some loci have been described earlier for their association with SLE. Furthermore, we found that the SLE-risk variant of the IRF5 CGGGG-indel was associated with lower IFN-α production. We conclude that the genetic variants affecting the IFN-α production highlight the intricate regulation of the type I IFN system and the importance of understanding the mechanisms behind the dysregulated type I IFN system in SLE.

  • 29.
    Berggren, Olof
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Alexsson, Andrei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Tandre, Karolina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Syvanen, A-C
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Eloranta, Maija-Leena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Effect of single-nucleotide polymorphisms on type I interferon production by plasmacytoid dendritic cells stimulated with SLE-associated immune complexes2014In: Scandinavian Journal of Rheumatology, ISSN 0300-9742, E-ISSN 1502-7732, Vol. 43, no S127, p. 92-92Article in journal (Other academic)
  • 30.
    Berggren, Olof
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Eloranta, Maija-Leena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Activated plasmacytoid dendritic cells alter the composition of peripheral blood B cell subsetsManuscript (preprint) (Other academic)
  • 31.
    Berggren, Olof
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    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.
    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.
    Activated Plasmacytoid Dendritic Cells (PDCS) Alter The Composition of The Blood B Cell Subsets2016In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 75, p. 179-179Article in journal (Other academic)
  • 32.
    Berggren, Olof
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Eloranta, Maija-Leena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    The effect of PTPN22 Gene Variant R620W on the Type I Interferon Production Stimulated by Different TLR7 Agonists: Comment on Article by Wang et al (pages 2403-2414)2016In: Arthritis & Rheumatology, ISSN 2326-5191, E-ISSN 2326-5205, Vol. 68, no 4, p. 1045-1045Article in journal (Refereed)
  • 33.
    Berglund, Britta
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Family Medicine and Preventive Medicine.
    Pettersson, Carina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Family Medicine and Preventive Medicine.
    Pigg, Maritta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Kristiansson, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Family Medicine and Preventive Medicine.
    Self-reported quality of life, anxiety and depression in individuals with Ehlers-Danlos syndrome (EDS): a questionnaire study2015In: BMC Musculoskeletal Disorders, ISSN 1471-2474, E-ISSN 1471-2474, Vol. 16, article id 89Article in journal (Refereed)
    Abstract [en]

    Background: Many individuals with Ehlers-Danlos Syndrome (EDS) are hypermobile, suffer from long term pain, and have complex health problems. Since these sometimes have no objective physical signs, individuals with EDS sometimes are referred for psychiatric evaluation. The aim was therefore to identify the level of anxiety and quality of life in a Swedish group of individuals with EDS. Methods: A postal survey in 2008 was distributed to 365 members over 18 years of the Swedish National EDS Association and 250 with EDS diagnosis responded. Two questionnaires, the Hospital Anxiety and Depression Scale (HADS) and SF-36, were used. A Swedish population study was used to compare results from SF-36. Independent Student's t-test was used to compare differences between groups, possible relationships were tested using Spearman's correlation coefficient and the General Linear Model was used for regression analyses. Higher scores on HADS represent higher levels of anxiety and depression and higher scores on SF-36 represent higher quality of health. Results: Of the respondents 74.8% scored high on anxiety and 22.4% scored high on depression on the HADS. Age, tiredness and back pain was independently associated with the HAD anxiety score in a multiple regression analysis, When comparing the SF-36 scores from the EDS group and a Swedish population group, the EDS group scored significantly lower, indicating lower health-related quality of health than the general population (p < 0.001). Conclusions: In comparison with a Swedish population group, a lower health-related quality of life was found in the EDS group. Also, higher levels of anxiety and depression were detected in individuals with EDS. The importance to explore the factors behind these results and what initiatives can be taken to alleviate the situation for this group is emphasized.

  • 34.
    Berntson, Lillemor
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Anti-inflammatory effect by exclusive enteral nutrition (EEN) in a patient with juvenile idiopathic arthritis (JIA): brief report2014In: Clinical Rheumatology, ISSN 0770-3198, E-ISSN 1434-9949, Vol. 33, no 8, p. 1173-1175Article in journal (Refereed)
    Abstract [en]

    There is extensive evidence for influence of gut microbiota on health. Exclusive enteral nutrition (EEN) possibly changes gut microbiota, but the exact pathophysiological role is unknown. EEN has been shown to have an anti-inflammatory effect in children with Mb Crohn, an inflammatory bowel disease. The intestinal tract is very scarcely studied in children with juvenile idiopathic arthritis (JIA), but data points to an immunologically important role. The aim of this study was to explore if EEN had any anti-inflammatory effect in children with JIA. The first patient enrolled in the study was followed for 1 year. She had onset of severe polyarticular disease at 3.2 years of age, negative in RF, anti-CCP, ANA, and HLA-B27. She was included in the study at 7.4 years of age. Exclusive enteral nutrition was given in two periods of almost 7 weeks each, several months apart, during the year of the study. Clinical and laboratory status were assessed before, during, and after treatment periods. In this patient, EEN had remarkable anti-inflammatory effect that was sustained for months after each of two separate treatment periods. Exclusive enteral nutrition is a possible anti-inflammatory treatment in patients with JIA, but to what extent EEN is effective in other children with JIA needs to be explored, as well as the possible pathophysiological role of EEN in those children.

  • 35.
    Berntson, Lillemor
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Hedlund-Treutiger, I.
    Karolinska Inst Sodersjukhuset, Sachs Childrens Hosp, Stockholm, Sweden..
    Alving, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Anti-inflammatory effect of exclusive enteral nutrition in patients with juvenile idiopathic arthritis2016In: Clinical and Experimental Rheumatology, ISSN 0392-856X, E-ISSN 1593-098X, Vol. 34, no 5, p. 941-945Article in journal (Refereed)
    Abstract [en]

    Objective There is extensive evidence for an influence of gut microbiota on the immune system, which has consequences for inflammatory diseases. Exclusive enteral nutrition (EEN), which may change the gut microbiota, is an effective anti-inflammatory treatment for Crohn's disease in children. We wanted to explore the immediate anti-inflammatory effect of EEN in children with juvenile idiopathic arthritis (JIA). Methods Thirteen patients with JIA (7-17 years of age), in a disease flare-up, were included in the study. Six children dropped out within 1.5-2.0 weeks of treatment, and seven patients continued, constituting the study cohort. EEN was given for three to eight weeks, with clinical and laboratory status assessed before and after treatment periods. In addition to conventional laboratory tests, 92 inflammatory proteins were analysed with a multiplex system (Proseek Multiplex Inflammation I, Olink Bioscience). Results EEN had a significant anti-inflammatory effect on active joints (p=0.031), JADAS27 (p=0.016) and morning stiffness (p=0.031). In the multiplex analysis of inflammatory proteins, MMP-1 (matrix metalloproteinase), involved in the degradation of collagens in chondrocytes, decreased significantly (p=0.047), as did MCP-4 (p=0.031) and 4E-BP1 (p=0.031). Conclusion Exclusive enteral nutrition for three to eight weeks had anti-inflammatory effect in all children with JIA that continued with EEN for more than two weeks. The study is only exploratory but the result supports an immunologically important role for the intestinal canal in these patients.

  • 36.
    Berntson, Lillemor
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Nordal, Ellen
    Fasth, Anders
    Aalto, Kristiina
    Herlin, Troels
    Nielsen, Susan
    Rygg, Marite
    Zak, Marek
    Rönnelid, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Anti-type II collagen antibodies, anti-CCP, IgA RF and IgM RF are associated with joint damage, assessed eight years after onset of juvenile idiopathic arthritis (JIA)2014In: Pediatric Rheumatology, ISSN 1546-0096, E-ISSN 1546-0096, Vol. 12, p. 22-Article in journal (Refereed)
    Abstract [en]

    Background: Early appearance of antibodies specific for native human type II collagen (anti-CII) characterizes an early inflammatory and destructive phenotype in adults with rheumatoid arthritis (RA). The objective of this study was to investigate the occurrence of anti-CII, IgM RF, IgA RF and anti-CCP in serum samples obtained early after diagnosis, and to relate the occurrence of autoantibodies to outcome after eight years of disease in children with juvenile idiopathic arthritis (JIA). Methods: The Nordic JIA database prospectively included JIA patients followed for eight years with data on remission and joint damage. From this database, serum samples collected from 192 patients, at a median of four months after disease onset, were analysed for IgG anti-CII, IgM RF, IgA RF and IgG anti-CCP. Joint damage was assessed based on Juvenile Arthritis Damage Index for Articular damage (JADI-A), a validated clinical instrument for joint damage. Results: Elevated serum levels of anti-CII occurred in 3.1%, IgM RF in 3.6%, IgA RF in 3.1% and anti-CCP in 2.6% of the patients. Occurrence of RF and anti-CCP did to some extent overlap, but rarely with anti-CII. The polyarticular and oligoarticular extended categories were overrepresented in patients with two or more autoantibodies. Anti-CII occurred in younger children, usually without overlap with the other autoantibodies and was associated with high levels of C-reactive protein (CRP) early in the disease course. All four autoantibodies were significantly associated with joint damage, but not with active disease at the eight-year follow up. Conclusions: Anti-CII, anti-CCP, IgA RF and IgM RF detected early in the disease course predicted joint damage when assessed after eight years of disease. The role of anti-CII in JIA should be further studied.

  • 37.
    Billing, Ewa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    McKenna, S. P.
    Staun, Margareta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine.
    Lindqvist, Ulla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Adaptation of the Psoriatic Arthritis Quality of Life (PsAQoL) instrument for Sweden2010In: Scandinavian Journal of Rheumatology, ISSN 0300-9742, E-ISSN 1502-7732, Vol. 39, no 3, p. 223-228Article in journal (Refereed)
    Abstract [en]

    Objective: The Psoriatic Arthritis Quality of Life (PsAQoL) questionnaire is the first disease-specific patient-derived instrument for assessing QoL in patients with PsA and has been extensively validated in this population. The aim of the adaptation process reported here was to develop a Swedish version of the PsAQoL that was equivalent to, and met the same psychometric and acceptability standards as, the original instrument, which was developed in the UK. Method:Translation of the original questionnaire into Swedish was performed by a professional and a lay panel. Field testing for face and content validity was performed by interviewing 13 patients. Finally, 123 patients with PsA were included in a test-retest postal survey designed to test reproducibility and construct validity. The PsAQoL was administered on two occasions approximately 2 weeks apart. The Nottingham Health Profile (NHP) was used as a comparator instrument. Results: The Swedish version of the PsAQoL questionnaire showed good reliability at both time points and, as expected, correlated with the NHP. The scale was able to distinguish between groups based on self-reported general health and flare-up. Patients with active symptoms of both arthritis and psoriasis had worse QoL. The results also indicated that duration of disease has a progressive impact on PsAQoL scores. Conclusions: This study provides evidence that the adapted PsAQoL can be used for clinical studies in Swedish patients. The instrument provides valuable information on the long-term effects of PsA on QoL.

  • 38.
    Bolin, Karin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. 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.
    Gunnarsson, I.
    Sjowall, C.
    Eriksson, P.
    Forsblad-d'Elia, H.
    Jonsen, A.
    Theander, E.
    Omdal, R.
    Jonsson, R.
    Sivils, K.
    Wahren-Herlenius, M.
    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.
    Nordmark, Gunnel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Early B Cell Factor 1 is Associated to Clinical Manifestations in Primary Sjogren's Syndrome and SLE2015In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 81, no 5, p. 416-416Article in journal (Other academic)
  • 39. Bolstad, Anne Isine
    et al.
    Le Hellard, Stephanie
    Kristjansdottir, Gudlaug
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Vasaitis, Lilian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Kvarnström, Marika
    Sjöwall, Christopher
    Johnsen, Svein Joar Auglænd
    Eriksson, Per
    Omdal, Roald
    Brun, Johan G
    Wahren-Herlenius, Marie
    Theander, Elke
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Nordmark, Gunnel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Jonsson, Roland
    Association between genetic variants in the tumour necrosis factor/lymphotoxin α/lymphotoxin β locus and primary Sjogren's 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 β (LTB) has been found to be upregulated in salivary glands of patients with primary Sjögren's 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 α (LTA)/LTB/tumour necrosis factor (TNF) gene clusters are associated with pSS.

    METHODS:

    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.

    RESULTS:

    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.

    CONCLUSIONS:

    A strong association was found between several SNP in the LTA/LTB/TNFα 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.

  • 40. Bos, Wouter H.
    et al.
    van de Stadt, Lotte A.
    Sohrabian, Azita
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Rönnelid, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    van Schaardenburg, Dirkjan
    Development of anti-citrullinated protein antibody and rheumatoid factor isotypes prior to the onset of rheumatoid arthritis2014In: ARTHRITIS RES THER, ISSN 1478-6354, Vol. 16, no 2, p. 405-Article in journal (Refereed)
  • 41. Brauner, S.
    et al.
    Zhou, W.
    Backlin, Carin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Green, T. M.
    Folkersen, L.
    Ivanchenko, M.
    Lofstrom, B.
    Xu-Monette, Z. Y.
    Young, K. H.
    Pedersen, L. Moller
    Moller, M. Boe
    Sundström, C.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Enblad, G.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Baecklund, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Wahren-Herlenius, M.
    Reduced expression of TRIM21/Ro52 predicts poor prognosis in diffuse large B-cell lymphoma patients with and without rheumatic disease2015In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 278, no 3, p. 323-332Article in journal (Refereed)
    Abstract [en]

    ObjectiveTRIM21 (also known as Ro52) is an autoantigen in rheumatic disease and is predominantly expressed in leucocytes. Overexpression is associated with decreased proliferation, and the TRIM21 gene maps to a tumour suppressor locus. We therefore investigated the expression of TRIM21 in patients with diffuse large B-cell lymphoma (DLBCL) and its potential usefulness as a prognostic biomarker. Materials and methodsTRIM21 expression levels were assessed by immunohistochemistry in lymphoma biopsies from three cohorts of patients with DLBCL: 42 patients with rheumatic disease treated with a cyclophosphamide, vincristine, doxorubicin and prednisone (CHOP)-like regimen, 76 CHOP-treated and 196 rituximab-CHOP-treated nonrheumatic patients. Expression was correlated with clinical and biomedical parameters. TRIM21 expression was assessed in relation to lymphocyte proliferation by quantitative PCR and correlated with H-3-thymidine incorporation and propidium iodine staining. ResultsTRIM21 expression levels differed in the lymphomas compared to normal lymphoid tissue, with reduced expression correlating with shorter overall survival in all three cohorts. In the two larger cohorts, progression-free survival was assessed and was also found to correlate with TRIM21 expression. The association was independent of commonly used clinical prognostic scores, lymphoma subtype and several previously reported prognostic biomarkers. In agreement with this clinical observation, we noted an inverse correlation between TRIM21 expression and proliferation of leucocytes invitro. ConclusionsWe show that loss of TRIM21 expression is associated with more aggressive lymphoma and increased proliferation, whereas maintenance of TRIM21 expression is associated with better prognosis in patients with DLBCL. Based on our findings, we suggest that TRIM21 should be considered as a novel biomarker for lymphoma characterization and for predicting patient survival.

  • 42.
    Brauner, Susanna
    et al.
    Karolinska Univ Hosptial, Karolinska Inst, Dept Med, Stockholm, Sweden..
    Folkersen, Lasse
    Karolinska Univ Hosptial, Karolinska Inst, Dept Med, Stockholm, Sweden..
    Kvarnstrom, Marika
    Karolinska Univ Hosptial, Karolinska Inst, Dept Med, Stockholm, Sweden..
    Meisgen, Sabrina
    Karolinska Univ Hosptial, Karolinska Inst, Dept Med, Stockholm, Sweden..
    Petersen, Sven
    Karolinska Univ Hosptial, Karolinska Inst, Dept Med, Stockholm, Sweden..
    Franzen-Malmros, Michaela
    Karolinska Univ Hosptial, Karolinska Inst, Dept Med, Stockholm, Sweden..
    Mofors, Johannes
    Karolinska Univ Hosptial, Karolinska Inst, Dept Med, Stockholm, Sweden..
    Brokstad, Karl A.
    Univ Bergen, Dept Clin Sci, Broegelmann Res Lab, Bergen, Norway..
    Klareskog, Lars
    Karolinska Univ Hosptial, Karolinska Inst, Dept Med, Stockholm, Sweden..
    Jonsson, Roland
    Univ Bergen, Dept Clin Sci, Broegelmann Res Lab, Bergen, Norway..
    Westerberg, Lisa S.
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Stockholm, Sweden..
    Trollmo, Christina
    Karolinska Univ Hosptial, Karolinska Inst, Dept Med, Stockholm, Sweden..
    Malmstrom, Vivianne
    Karolinska Univ Hosptial, Karolinska Inst, Dept Med, Stockholm, Sweden..
    Ambrosi, Aurelie
    Karolinska Univ Hosptial, Karolinska Inst, Dept Med, Stockholm, Sweden..
    Kuchroo, Vijay K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Nordmark, Gunnel
    Harvard Med Sch, Evergrande Ctr Immunol Dis, Boston, MA USA.;Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA..
    Wahren-Herlenius, Marie
    Karolinska Univ Hosptial, Karolinska Inst, Dept Med, Stockholm, Sweden..
    H1N1 vaccination in Sjogren's syndrome triggers polyclonal B cell activation and promotes autoantibody production2017In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 76, no 10, p. 1755-1763Article in journal (Refereed)
    Abstract [en]

    Objectives

    Vaccination of patients with rheumatic disease has been reported to result in lower antibody titres than in healthy individuals. However, studies primarily include patients on immunosuppressive therapy. Here, we investigated the immune response of treatment-naive patients diagnosed with primary Sjogren's syndrome (pSS) to an H1N1 influenza vaccine.

    Methods

    Patients with Sjogren's syndrome without immunomodulatory treatment and age-matched and gender-matched healthy controls were immunised with an H1N1 influenza vaccine and monitored for serological and cellular immune responses. Clinical symptoms were monitored with a standardised form. IgG class switch and plasma cell differentiation were induced in vitro in purified naive B cells of untreated and hydroxychloroquine-treated patients and healthy controls. Gene expression was assessed by NanoString technology.

    Results

    Surprisingly, treatment-naive patients with Sjogren's syndrome developed higher H1N1 IgG titres of greater avidity than healthy controls on vaccination. Notably, off-target B cells were also triggered resulting in increased anti-EBV and autoantibody titres. Endosomal toll-like receptor activation of naive B cells in vitro revealed a greater propensity of patient-derived cells to differentiate into plasmablasts and higher production of class switched IgG. The amplified plasma cell differentiation and class switch could be induced in cells from healthy donors by preincubation with type 1 interferon, but was abolished in hydroxychloroquine-treated patients and after in vitro exposure of naive B cells to chloroquine.

    Conclusions

    This comprehensive analysis of the immune response in autoimmune patients to exogenous stimulation identifies a mechanistic basis for the B cell hyperactivity in Sjogren's syndrome, and suggests that caution is warranted when considering vaccination in non-treated autoimmune patients.

  • 43.
    Brink, M.
    et al.
    Umea Univ, Rheumatol, Publ Hlth & Clin Med, Umea, Sweden..
    Hansson, M.
    Karolinska Inst, Dept Med, Rheumatol Unit, Stockholm, Sweden..
    Mathsson Alm, Linda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Cornillet, M.
    Univ Toulouse, INSERM, U 1056, Toulouse, France..
    Rönnelid, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Skriner, K.
    Charite, Med, Berlin, Germany..
    Serre, G.
    Univ Toulouse, INSERM, U 1056, Toulouse, France..
    Holmdahl, R.
    Karolinska Inst, Med Inflammat Res, Stockholm, Sweden..
    Klareskog, L.
    Karolinska Inst, Dept Med, Rheumatol Unit, Stockholm, Sweden..
    Rantapaa-Dahlqvist, S.
    Umea Univ, Rheumatol, Publ Hlth & Clin Med, Umea, Sweden..
    Acpa Against Different Citrullinated Peptides Identify Specific Phenotypes Of Rheumatoid Arthritis2017In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 76, p. 792-792Article in journal (Other academic)
  • 44. Brink, M.
    et al.
    Verheul, M. K.
    Rönnelid, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Holmdahl, R.
    Toes, R. E. M.
    Klareskog, L.
    Trouw, L. A.
    Dahlqvist, S. R.
    The presence of anti-carbamylated protein antibodies prior to onset of symptoms of rheumatoid arthritis (RA) is associated with radiological progression in early RA2014In: Scandinavian Journal of Rheumatology, ISSN 0300-9742, E-ISSN 1502-7732, Vol. 43, no S127, p. 21-22Article in journal (Other academic)
  • 45. Brink, M.
    et al.
    Verheul, M. K.
    Rönnelid, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Toes, R. E.
    Klareskog, L.
    Trouw, L. L.
    Dahlqvist, S. Rantapaa
    Anti-Carbamylated Protein Antibodies Precede the Onset of Symptoms of Rheumatoid Arthritis in A Swedish Biobank Cohort2014In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 73, no S2, p. 397-398Article in journal (Other academic)
  • 46. Brink, Mikael
    et al.
    Hansson, Monika
    Mathsson-Alm, Linda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Rönnelid, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Klareskog, Lars
    Rantapaa-Dahlqvist, Solbritt
    Rheumatoid Factor Isotypes in Relation to Antibodies Against Citrullinated Peptides in Individuals before Onset of Rheumatoid Arthritis2014In: Arthritis & Rheumatology, ISSN 2326-5191, Vol. 66, no S10, p. S191-S191, article id 447Article in journal (Other academic)
  • 47. Brink, Mikael
    et al.
    Hansson, Monika
    Rönnelid, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Klareskog, Lars
    Dahlqvist, Solbritt Rantapaa
    The autoantibody repertoire in periodontitis: a role in the induction of autoimmunity to citrullinated proteins in rheumatoid arthritis? Antibodies against uncitrullinated peptides seem to occur prior to the antibodies to the corresponding citrullinated peptides2014In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 73, no 7Article in journal (Refereed)
  • 48. Brink, Mikael
    et al.
    Rönnelid, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Hansson, Monika
    Mathsson, Linda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Serre, Guy
    Jakobsson, Per-Johan
    Holmdahl, Rikard
    Klareskog, Lars
    Dahlqvist, Solbritt Rantapaa
    Antibodies against native collagen and citrullinated proteins precede the development of rheumatoid arthritis with a consecutive pattern2012In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 71, p. A22-A22Article in journal (Other academic)
  • 49. Brink, Mikael
    et al.
    Verheul, Marije K.
    Rönnelid, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Berglin, Ewa
    Holmdahl, Rikard
    Toes, Rene E. M.
    Klareskog, Lars
    Trouw, Leendert A.
    Rantapaa-Dahlqvist, Solbritt
    Anti-carbamylated protein antibodies in the pre-symptomatic phase of rheumatoid arthritis, their relationship with multiple anti-citrulline peptide antibodies and association with radiological damage2015In: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 17, article id 25Article in journal (Refereed)
    Abstract [en]

    Introduction: The presence of a new autoantibody system, anti-carbamylated protein (anti-CarP) antibodies, has been identified in rheumatoid arthritis (RA). The presence of anti-CarP antibodies was evaluated in samples taken from individuals who subsequently developed RA before and after onset of symptoms and related to previously analysed antibodies against citrullinated peptides (ACPA specificities) and anti-CCP2. Methods: A total of 252 individuals, with 423 samples from before onset of symptoms of RA, and 197 population controls were identified as donors to the Medical Biobank of Northern Sweden; 192 of them were also sampled at the time of diagnosis. All samples were analysed for anti-CarP IgG and anti-CCP2 antibodies using ELISAs. Ten different antibody reactivities against citrullinated antigens (ACPA specificities) were analysed using a custom-made microarray based on the ImmunoCAP ISAC system (Phadia). Results: The concentration of anti-CarP antibodies was significantly increased in the pre-symptomatic individuals compared with controls (P < 0.001) and also increased significantly after disease onset (P < 0.001). The sensitivity for anti-CarP antibodies in the pre-symptomatic individuals was 13.9% (95% CI: 11 to 17.6) and 42.2% (95% CI: 35.4 to 49.3) following development of RA. Anti-CarP antibody positivity was found in 5.1% to 13.3% of individuals negative for anti-CCP2 or ACPA specificities. Presence of anti-CarP antibodies was significantly related to radiological destruction at baseline, at 24 months and also to radiological change (P < 0.05, all). Conclusions: The results indicate that anti-CarP antibodies are associated with disease development, even after adjusting for the presence of different ACPA fine specificities, and in anti-CCP2 negative individuals and contribute to the identification of a subset of patients with worse radiological progression of the disease independent of ACPA.

  • 50.
    Brito-Zeron, P.
    et al.
    Hosp CIMA Sanitas, Barcelona, Spain.;Hosp Clin Barcelona, Barcelona, Spain..
    Acar-Denizli, N.
    Msgsu, Istanbul, Turkey..
    Zeher, M.
    Univ Debrecen, Debrecen, Hungary..
    Rasmussen, A.
    OMRF, Oklahoma City, OK USA..
    Li, X.
    Anhui Hosp, Hefei, Anhui, Peoples R China..
    Baldini, C.
    Univ Pisa, Pisa, Italy..
    Gottenberg, J-E
    Danda, D.
    CMC, Vellore, Tamil Nadu, India..
    Quartuccio, L.
    Santa Maria, Udine, Italy..
    Hernandez-Molina, G.
    INCMNSZ, Mexico City, DF, Mexico..
    Kruize, A. A.
    UMC, Utrecht, Netherlands..
    Park, S-H
    Kvarnstrom, M.
    Karolinska Inst, Stockholm, Sweden..
    Praprotnik, S.
    UMCL, Ljubljana, Slovenia..
    Sene, D.
    Lariboisiere Hosp, Paris, France..
    Alunno, A.
    Univ Perugia, Perugia, Italy..
    Solans, R.
    Hosp Valle De Hebron, Barcelona, Spain..
    Mandl, T.
    Lund Univ, Malmo, Sweden..
    Suzuki, Y.
    Univ Kanazawa, Kanazawa, Ishikawa, Japan..
    Rischmueller, M.
    TQEH, Adelaide, SA, Australia..
    Nordmark, Gunnel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Fraile, G.
    Hosp Ramon & Cajal, Madrid, Spain..
    Wiland, P.
    Med Hosp, Wroclaw, Poland..
    Bootsma, H.
    Univ Groningen, Groningen, Netherlands..
    Nakamura, T.
    Univ Nagasaki, Nagasaki, Japan..
    Valim, V.
    UFES, Vitoria, Spain..
    Giacomelli, R.
    Univ Aquila, Laquila, Italy..
    Seror, R.
    Univ Sud, Paris, France..
    Devauchelle-Pensec, V.
    Univ Brest, Brest, France..
    Hofauer, B.
    TUM, Munich, Germany..
    Bombardieri, M.
    QMUL, London, England..
    Trevisani, V.
    Univ Fed Sao Paulo, Sao Paulo, Brazil..
    Hammenfors, D.
    Haukeland Hosp, Bergen, Norway..
    Minniti, A.
    Sapienza Univ, Rome, Italy..
    Pasoto, S. G.
    Univ Sao Paulo, Sao Paulo, Brazil..
    Morel, J.
    Univ Montpellier, Montpellier, France..
    Retamozo, S.
    INICSA, Cordoba, Argentina..
    Gheita, T. A.
    Cairo Univ, Cairo, Egypt..
    Atzeni, F.
    L Sacco Univ, Milan, Italy..
    Vollenveider, C.
    German Hosp, Buenos Aires, DF, Argentina..
    Mariette, X.
    Univ Sud, Paris, France..
    Ramos-Casals, M.
    Hosp Clin Barcelona, Barcelona, Spain..
    Baseline Essdai/ Das Scores In 8061 Patients With Primary Sjögren Syndrome: Characterization Of Systemic Disease2017In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 76, p. 464-465Article in journal (Other academic)
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