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  • 1. Adoue, Veronique
    et al.
    Schiavi, Alicia
    Light, Nicholas
    Carlsson Almlöf, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lundmark, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ge, Bing
    Kwan, Tony
    Caron, Maxime
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Wang, Chuan
    Chen, Shu-Huang
    Goodall, Alison H
    Cambien, Francois
    Deloukas, Panos
    Ouwehand, Willem H
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Pastinen, Tomi
    Allelic expression mapping across cellular lineages to establish impact of non-coding SNPs2014In: Molecular Systems Biology, ISSN 1744-4292, E-ISSN 1744-4292, Vol. 10, no 10, p. 754-Article in journal (Refereed)
    Abstract [en]

    Most complex disease-associated genetic variants are located in non-coding regions and are therefore thought to be regulatory in nature. Association mapping of differential allelic expression (AE) is a powerful method to identify SNPs with direct cis-regulatory impact (cis-rSNPs). We used AE mapping to identify cis-rSNPs regulating gene expression in 55 and 63 HapMap lymphoblastoid cell lines from a Caucasian and an African population, respectively, 70 fibroblast cell lines, and 188 purified monocyte samples and found 40-60% of these cis-rSNPs to be shared across cell types. We uncover a new class of cis-rSNPs, which disrupt footprint-derived de novo motifs that are predominantly bound by repressive factors and are implicated in disease susceptibility through overlaps with GWAS SNPs. Finally, we provide the proof-of-principle for a new approach for genome-wide functional validation of transcription factor-SNP interactions. By perturbing NFκB action in lymphoblasts, we identified 489 cis-regulated transcripts with altered AE after NFκB perturbation. Altogether, we perform a comprehensive analysis of cis-variation in four cell populations and provide new tools for the identification of functional variants associated to complex diseases.

  • 2. af Klint, Erik
    et al.
    Catrina, Anca I
    Matt, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Neregråd, Petra
    Lampa, Jon
    Ulfgren, Ann-Kristin
    Klareskog, Lars
    Lindblad, Staffan
    Evaluation of arthroscopy and macroscopic scoring.2009In: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 11, no 3Article in journal (Refereed)
    Abstract [en]

    INTRODUCTION: Arthroscopy is a minimally invasive technique for retrieving synovial biopsies in rheumatology during the past 20 years. Vital for its use is continual evaluation of its safety and efficacy. Important for sampling is the fact of intraarticular variation for synovial markers. For microscopic measurements scoring systems have been developed and validated, but for macroscopic evaluations there is a need for further comprehensive description and validation of equivalent scoring systems.

    METHODS: We studied the complication rate and yield of arthroscopies performed at our clinic between 1998 and 2005. We also created and evaluated a macroscopic score set of instructions for synovitis.

    RESULTS: Of 408 procedures, we had two major and one minor complication; two haemarthrosis and one wound infection, respectively. Pain was most often not a problem, but 12 procedures had to be prematurely ended due to pain. Yield of biopsies adequate for histology were 83% over all, 94% for knee joints and 34% for smaller joints. Video printer photographs of synovium taken during arthroscopy were jointly and individually reviewed by seven raters in several settings, and intra and inter rater variation was calculated. A macroscopic synovial scoring system for arthroscopy was created (Macro-score), based upon hypertrophy, vascularity and global synovitis. These written instructions were evaluated by five control-raters, and when evaluated individual parameters were without greater intra or inter rater variability, indicating that the score is reliable and easy to use.

    CONCLUSIONS: In our hands rheumatologic arthroscopy is a safe method with very few complications. For knee joints it is a reliable method to retrieve representative tissue in clinical longitudinal studies. We also created an easy to use macroscopic score, that needs to be validated against other methodologies. We hope it will be of value in further developing international standards in this area.

  • 3. Alenius, Gerd-Marie
    et al.
    Husmark, Tomas
    Theander, Elke
    Larsson, Per
    Geijer, Mats
    Teleman, Annika
    Lindqvist, Ulla R. C.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Rheumatoid Arthritis, a More Severe Disease Than Psoriatic Arthritis?: A Comparison Of Disease Activity In Patients With Psoriatic Arthritis and Rheumatoid Arthritis From The Swedish Early Psoriatic Arthritis Registry (SwePsA) and The Swedish Rheumatology Registry For Early Rheumatoid Arthritis (SRR)2013In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 65, no Suppl. 10, p. S150-S150Article in journal (Other academic)
  • 4.
    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.

  • 5. 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.

  • 6.
    Antonodimitrakis, Pantelis
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Wassberg, Cecilia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Gerovasileiou, Spyridon
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Back, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Hallgren, Roger
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Olsen, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Fulminant hemophagocytic lymphohistiocytosis secondary to a reactivated EBV infection: A case report2013In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 118, no 1, p. 42-45Article in journal (Refereed)
    Abstract [en]

    Hemophagocytic lymphohistiocytosis (HLH) is an aggressive inflammatory syndrome that results from inappropriate activation of the immune system. HLH has a high mortality if not treated. We describe a case of a fulminant HLH, associated with a reactivation of an EBV infection. The patient responded well to steroid treatment.

  • 7. 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. Uppsala University, Science for Life Laboratory, SciLifeLab.
    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. Uppsala University, Science for Life Laboratory, SciLifeLab.
    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 homing2018In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 192, no 3, p. 259-270Article 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.

  • 8. 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)
  • 9. Arkema, Elizabeth V
    et al.
    Jonsson, Jerker
    Baecklund, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Bruchfeld, Judith
    Feltelius, Nils
    Askling, Johan
    Are patients with rheumatoid arthritis still at an increased risk of tuberculosis and what is the role of biological treatments?2015In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 74, no 6, p. 1212-1217Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To estimate the risk of tuberculosis (TB) in patients with rheumatoid arthritis (RA) both with and without exposure to biological therapy and to directly compare the risks between therapies.

    METHODS: Data from the Swedish National Population Registers, Tuberculosis Register and the Swedish Biologics Register were used to conduct a prospective population-based national cohort study (2002-2011). We estimated the rate of incident TB in the general population and in a cohort of biological-naïve and biological-exposed patients diagnosed with RA. Cox models were used to estimate HRs with particular attention to risks by calendar and follow-up time and individual biologics.

    RESULTS: Compared to the general population, RA patients not exposed to biologicals had a fourfold increased risk of TB (HR 4.2; 95% CI 2.7 to 6.7), which did not decline over calendar time. In contrast, the risk of TB in the biological-exposed RA population decreased since 2002 compared with biological-naïve; from HR=7.9 (95% CI 3.3 to 18.9) in 2002-2006 to HR=2.4 (95% CI 0.9 to 6.1) in 2007-2011. The HRs for most recent exposure to adalimumab and infliximab compared with etanercept were 3.1 (95% CI 0.8 to 12.5) and 2.7 (95% CI 0.7 to 10.9), respectively, and the HR for etanercept compared with biological-naïve RA was 1.7 (95% CI 0.6 to 4.6).

    CONCLUSIONS: In the past decade, the risk of TB has decreased among biological-exposed RA patients but remains higher than in biological-naïve RA patients. Most cases of TB in RA occur in biological-naïve RA patients, underscoring the elevated risk also in these patients.

  • 10. Arkema, Elizabeth V.
    et al.
    Jonsson, Jerker
    Baecklund, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Rutting, Maud
    Bruchfeld, Judith
    Feltelius, Nils
    Askling, Johan
    Are Patients With Rheumatoid Arthritis Still At An Increased Risk Of Tuberculosis and What Is The Role Of Biological Treatment?2013In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 65, no Suppl. 10, p. S719-S719Article in journal (Other academic)
  • 11. 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.

  • 12.
    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.

  • 13. Askling, J
    et al.
    Fored, C M
    Baecklund, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Brandt, L
    Backlin, Carin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Ekbom, A
    Sundström, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Molecular and Morphological Pathology.
    Bertilsson, L
    Cöster, L
    Geborek, P
    Jacobsson, L T
    Lindblad, S
    Lysholm, J
    Rantapää-Dahlqvist, S
    Saxne, T
    Klareskog, L
    Feltelius, N
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Haematopoietic malignancies in rheumatoid arthritis: lymphoma risk and characteristics after exposure to tumour necrosis factor antagonists2005In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 64, no 10, p. 1414-1420Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    Patients with rheumatoid arthritis (RA) are at increased risk of malignant lymphomas, and maybe also of leukaemia and multiple myeloma. The effect of tumour necrosis factor (TNF) antagonists on lymphoma risk and characteristics is unclear.

    OBJECTIVE:

    To assess expected rates and relative risks of haematopoietic malignancies, especially those associated with TNF antagonists, in large population based cohorts of patients with RA.

    METHODS:

    A population based cohort study was performed of patients with RA (one prevalent cohort (n = 53,067), one incident cohort (n = 3703), and one TNF antagonist treated cohort 1999 through 2003 (n = 4160)), who were linked with the Swedish Cancer Register. Additionally, the lymphoma specimens for the 12 lymphomas occurring in patients with RA exposed to TNF antagonists in Sweden 1999 through 2004 were reviewed.

    RESULTS:

    Study of almost 500 observed haematopoietic malignancies showed that prevalent and incident patients with RA were at increased risk of lymphoma (SIR = 1.9 and 2.0, respectively) and leukaemia (SIR = 2.1 and 2.2, respectively) but not of myeloma. Patients with RA treated with TNF antagonists had a tripled lymphoma risk (SIR = 2.9) compared with the general population. After adjustment for sex, age, and disease duration, the lymphoma risk after exposure to TNF antagonists was no higher than in the other RA cohorts. Lymphomas associated with TNF antagonists had characteristics similar to those of other RA lymphomas.

    CONCLUSION:

    Overall, patients with RA are at equally increased risks for lymphomas and leukaemias. Patients with RA treated with TNF antagonists did not have higher lymphoma risks than other patients with RA. Prolonged observation is needed to determine the long term effects of TNF antagonists on lymphoma risk.

  • 14. 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.

  • 15. 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.

  • 16. Askling, Johan
    et al.
    Baecklund, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Granath, F.
    Geborek, P.
    Fored, M.
    Backlin, Carin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Bertilsson, L.
    Cöster, L.
    Jacobsson, L. T.
    Lindblad, S.
    Lysholm, J.
    Rantapää-Dahlqvist, S.
    Saxne, T.
    van Vollenhoven, R.
    Klareskog, L.
    Feltelius, N.
    Anti-tumour necrosis factor therapy in rheumatoid arthritis and risk of malignant lymphomas: relative risks and time trends in the Swedish Biologics Register2009In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 68, no 5, p. 648-653Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    Tumour necrosis factor (TNF) antagonists have proved effective as treatment against rheumatoid arthritis (RA), but the unresolved issue of whether the use of anti-TNF therapy increases the already elevated risk of lymphoma in RA remains a concern.

    METHODS:

    Using the Swedish Biologics Register (ARTIS), the Swedish Cancer Register, pre-existing RA cohorts and cross-linkage with other national health and census registers, a national RA cohort (n = 67,743) was assembled and patients who started anti-TNF therapy between 1998 and July 2006 (n = 6604) were identified. A general population comparator (n = 471,024) was also assembled and the incidence of lymphomas from 1999 to 31 December 2006 was assessed and compared in these individuals.

    RESULTS:

    Among the 6604 anti-TNF-treated RA patients, 26 malignant lymphomas were observed during 26,981 person-years of follow-up, which corresponded to a relative risk (RR) of 1.35 (95% CI 0.82 to 2.11) versus anti-TNF-naive RA patients (336 lymphomas during 365,026 person-years) and 2.72 (95% CI 1.82 to 4.08) versus the general population comparator (1568 lymphomas during 3,355,849 person-years). RA patients starting anti-TNF therapy in 1998-2001 accounted for the entire increase in lymphoma risk versus the two comparators. By contrast, RR did not vary significantly by time since start of first treatment or with the accumulated duration of treatment, nor with the type of anti-TNF agent.

    CONCLUSION:

    Overall and as used in routine care against RA, TNF antagonists are not associated with any major further increase in the already elevated lymphoma occurrence in RA. Changes in the selection of patients for treatment may influence the observed risk.

  • 17. Askling, Johan
    et al.
    Fored, C. Michael
    Brandt, Lena
    Baecklund, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Bertilsson, Lennart
    Cöster, Lars
    Geborek, Pierre
    Jacobsson, Lennart T.
    Lindblad, Staffan
    Lysholm, Jörgen
    Rantapää-Dahlqvist, Solbritt
    Saxne, Tore
    Romanus, Victoria
    Klareskog, Lars
    Feltelius, Nils
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Risk and case characteristics of tuberculosis in rheumatoid arthritis associated with tumor necrosis factor antagonists in Sweden2005In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 52, no 7, p. 1986-1992Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE:

    Because treatment with tumor necrosis factor (TNF) antagonists may increase the risk of tuberculosis (TB), and because knowledge of the risk of TB in rheumatoid arthritis (RA) not treated with biologics is scarce and of uncertain generalizability to low-risk populations, this study sought to determine the risk of TB among Swedish patients with RA.

    METHODS:

    Using data from Swedish nationwide and population-based registers and data from an ongoing monitoring program of TNF antagonists, the relative risks of TB in patients with RA (versus the general population) and of TB associated with TNF antagonists (versus RA patients not treated with biologics) were determined by comparing the incidence of hospitalization for TB in 3 RA cohorts and 2 general population cohorts from 1999 to 2001. We also reviewed the characteristics of all reported cases of TB in RA patients treated with TNF antagonists in Sweden and calculated the incidence of TB per type of TNF antagonist between 1999 and 2004.

    RESULTS:

    During 1999-2001, RA patients who were not treated with TNF antagonists were at increased risk of TB versus the general population (relative risk 2.0, 95% confidence interval [95% CI] 1.2-3.4). RA patients treated with TNF antagonists had a 4-fold increased risk of TB (relative risk 4.0, 95% CI 1.3-12) versus RA patients not treated with TNF antagonists. The reported TB cases during 1999-2004 in RA patients exposed to TNF antagonists (9 infliximab, 4 etanercept, 2 both) were predominantly pulmonary. TB occurred up to 3 years following the start of treatment.

    CONCLUSION:

    Irrespective of whether TNF antagonists are administered, Swedish patients with RA are at increased risk of TB. During 1999-2001, TNF antagonists were associated with an increased risk of TB, up to 4-fold in magnitude. This increased risk may persist over time during treatment and is related to both infliximab and etanercept.

  • 18. Askling, Johan
    et al.
    Fored, C. Michael
    Brandt, Lena
    Baecklund, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Bertilsson, Lennart
    Feltelius, Nils
    Cöster, Lars
    Geborek, Pierre
    Jacobsson, Lennart T.
    Lindblad, Staffan
    Lysholm, Jörgen
    Rantapää-Dahlqvist, Solbritt
    Saxne, Tore
    van Vollenhoven, Ronald F.
    Klareskog, Lars
    Time-dependent increase in risk of hospitalisation with infection among Swedish RA patients treated with TNF antagonists2007In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 66, no 10, p. 1339-1344Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES:

    The degree to which treatment with tumour necrosis factor (TNF) antagonists may be associated with increased risks for serious infections is unclear. An observational cohort study was performed using prospectively collected data from the Swedish Biologics Register (ARTIS) and other national Swedish registers.

    METHODS:

    First, in the ARTIS, all 4167 rheumatoid arthritis (RA) patients starting TNF antagonist treatment between 1999 and 2003 were identified. Secondly, in the Swedish Inpatient Register, all individuals hospitalised for any reason and who also carried a diagnosis of RA, between 1964 and 2003 (n = 44 946 of whom 2692 also occurred in ARTIS), were identified. Thirdly, in the Swedish Inpatient Register, all hospitalisations listing an infection between 1999 and 2003 were identified. By cross-referencing these three data sets, RRs for hospitalisation with infection associated with TNF antagonist treatment were calculated within the cohort of 44 946 RA patients, using Cox regression taking sex, age, geography, co-morbidity and use of inpatient care into account.

    RESULTS:

    Among the 4167 patients treated with TNF antagonists, 367 hospitalisations with infections occurred during 7776 person-years. Within the cohort of 44 496 RA patients, the RR for infection associated with TNF antagonists was 1.43 (95% CI 1.18 to 1.73) during the first year of treatment, 1.15 (95% CI 0.88 to 1.51) during the second year of treatment, and 0.82 (95% CI 0.62 to 1.08) for subjects remaining on their first TNF antagonist treatment after 2 years.

    CONCLUSION:

    Treatment with TNF antagonists may be associated with a small to moderate increase in risk of hospitalisation with infection, which disappears with increasing treatment duration.

  • 19. Askling, Johan
    et al.
    van Vollenhoven, Ronald F.
    Granath, Fredrik
    Raaschou, Pauline
    Fored, C. Michael
    Baecklund, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Dackhammar, Christina
    Feltelius, Nils
    Cöster, Lars
    Geborek, Pierre
    Jacobsson, Lennart T.
    Lindblad, Staffan
    Rantapää-Dahlqvist, Solbritt
    Saxne, Tore
    Klareskog, Lars
    Cancer risk in patients with rheumatoid arthritis treated with anti-tumor necrosis factor alpha therapies: does the risk change with the time since start of treatment?2009In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 60, no 11, p. 3180-3189Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE:

    To determine the short-term and medium-term risks of cancer in patients receiving anti-tumor necrosis factor alpha (anti-TNFalpha) therapies that have proven effective in the treatment of chronic inflammatory conditions.

    METHODS:

    By linking together data from the Swedish Biologics Register, Swedish registers of RA, and the Swedish Cancer Register, we identified and analyzed for cancer occurrence a national cohort of 6,366 patients with RA who first started anti-TNF therapy between January 1999 and July 2006. As comparators, we used a national biologics-naive RA cohort (n = 61,160), a cohort of RA patients newly starting methotrexate (n = 5,989), a cohort of RA patients newly starting disease-modifying antirheumatic drug combination therapy (n = 1,838), and the general population of Sweden. Relative risks (RRs) were estimated using Cox regression analyses, examining overall RR as well as RR by time since the first start of anti-TNF therapy, by the duration of active anti-TNF therapy, and by the anti-TNF agent received.

    RESULTS:

    During 25,693 person-years of followup in 6,366 patients newly starting anti-TNF, 240 first cancers occurred, yielding an RR of 1.00 (95% confidence interval 0.86-1.15) versus the biologics-naive RA cohort, and similar RRs versus the other 2 RA comparators. RRs did not increase with increasing time since the start of anti-TNF therapy, nor with the cumulative duration of active anti-TNF therapy. During the first year following the first treatment start, but not thereafter, dissimilar cancer risks for adalimumab, etanercept, and infliximab were observed.

    CONCLUSION:

    During the first 6 years after the start of anti-TNF therapy in routine care, no overall elevation of cancer risk and no increase with followup time were observed.

  • 20.
    Baecklund, Eva
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Askling, Johan
    Rosenquist, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Ekbom, Anders
    Klareskog, Lars
    Rheumatoid arthritis and malignant lymphomas2004In: Current Opinion in Rheumatology, ISSN 1040-8711, E-ISSN 1531-6963, Vol. 16, no 3, p. 254-261Article in journal (Refereed)
    Abstract [en]

    PURPOSE OF REVIEW:

    The reason for the increased lymphoma risk in patients with rheumatoid arthritis (RA) has remained unclear. Reports of lymphomas in patients treated with TNF-blockers have brought renewed interest in this issue. This review summarizes data on possible associations between RA and lymphomas, including different treatments and RA disease related risk factors.

    RECENT FINDINGS:

    Some recent studies reported increased lymphoma risks linked to RA disease activity. The hypothesis that disease-modifying drugs, and in particular methotrexate, would increase the lymphoma risk receives little support. Observation times for the TNF-blocking therapies are still short, but so far no clear increased risk for lymphoma has been observed. Presence of Epstein-Barr virus, as analyzed with EBER in situ hybridization, appears to be uncommon in RA related lymphomas. Hypothetically, an increased proliferative drive caused by self or non-self antigens may play a role in lymphoma development in RA patients, but this has to be further studied.

    SUMMARY:

    Rheumatologists need to be aware of the increased lymphoma risk in their RA patients. The reason for the increased lymphoma risk in RA patients is still unclear, but available studies rather support the hypothesis of a link between RA disease severity and the risk of lymphoma than increased risks associated with specific treatment regimens. To facilitate the future evaluation of lymphoma risks in connection with treatment, we suggest that patients treated with new drugs should be subject to structured surveillance. Collected information should include data about RA disease activity and severity.

  • 21.
    Baecklund, Eva
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Backlin, Carin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Iliadou, Anastasia
    Granath, Fredrik
    Ekbom, Anders
    Amini, Rose-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Feltelius, Nils
    Enblad, Gunilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Sundström, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Klareskog, Lars
    Askling, Johan
    Rosenquist, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Characteristics of diffuse large B cell lymphomas in rheumatoid arthritis2006In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 54, no 12, p. 3774-3781Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE:

    Patients with rheumatoid arthritis (RA) are at increased risk of malignant lymphomas, with a correlation between RA disease severity and lymphoma risk, most pronounced for diffuse large B cell lymphomas (DLBCLs), which also constitute the majority of RA-associated lymphomas. DLBCLs can be further subdivided into germinal center (GC)-like and non-GC-like subtypes, with different cellular origins and prognoses. This study was undertaken to investigate whether RA displays a specific association with any of the DLBCL subtypes.

    METHODS:

    We identified 139 patients with DLBCLs within a population-based case-control study of 378 RA patients with lymphoma. The DLBCLs were examined for CD10, Bcl-6, and interferon regulatory factor 4 expression patterns, subclassified into GC and non-GC subtypes, and then correlated with clinical parameters.

    RESULTS:

    We found a statistically significant predominance of the non-GC subtype (97 patients; 70% of all DLBCLs). These patients more often had an advanced stage of lymphoma at diagnosis and had a worse 5-year overall survival rate (16% versus 33%) compared with patients with the GC subtype. There was a strong association with RA disease activity in both subtypes, with >70% of the GC and non-GC cases occurring in RA patients with the highest overall disease activity scores.

    CONCLUSION: These findings suggest that severe RA is particularly associated with the non-GC subtype of DLBCL, and indicate a critical role of activated peripheral B cells as the cells of origin in these lymphomas.

  • 22.
    Baecklund, Eva
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Backlin, Carin
    Iliadou, Anastasia
    Granath, Fredrik
    Ekbom, Anders
    Amini, Rose-Marie
    Feltelius, Nils
    Enblad, Gunilla
    Sundström, Christer
    Klareskog, Lars
    Askling, Johan
    Rosenquist, Richard
    Diffuse large B-cell lymphomas in rheumatoid arthritis display a predominance of non-germinal center typeManuscript (Other academic)
    Abstract
  • 23.
    Baecklund, Eva
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Backlin, Carin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Mansouri, Mahmoud
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Klareskog, Lars
    Askling, Johan
    Iliadou, Anastasia Nyman
    Enblad, Gunilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Lossos, Izidore S.
    Natkunam, Yasodha
    Rosenquist, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Hematology and Immunology.
    LMO2 protein expression predicts survival in patients with rheumatoid arthritis and diffuse large B-cell lymphoma2011In: Leukemia and Lymphoma, ISSN 1042-8194, E-ISSN 1029-2403, Vol. 52, no 6, p. 1146-1149Article in journal (Refereed)
  • 24.
    Baecklund, Eva
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Backlin, Carin
    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, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    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 1502-7732, Vol. 47, no 4, p. 270-275Article 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: In this study, neither anti-CCP antibodies (IgG, IgG1–4, IgM, or IgA), nor other common autoantibodies, nor smoking predicted lymphoma risk in RA

  • 25.
    Baecklund, Eva
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Ekbom, Anders
    Sparén, Pär
    Feltelius, Nils
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Klareskog, Lars
    Disease activity and risk of lymphoma in patients with rheumatoid arthritis: nested case-control study1998In: British Medical Journal, Vol. 317, p. 180-181Article in journal (Refereed)
  • 26.
    Baecklund, Eva
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Hellgren, K.
    Sundström, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Askling, J.
    Does Biological Therapy Alter the Lymphoma Risk or Distribution of Lymphoma Subtypes in Patients with ra?2013In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 72, no Suppl. 3, p. 427-427Article in journal (Other academic)
  • 27.
    Baecklund, Eva
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Iliadou, Anastasia
    Askling, Johan
    Ekbom, Anders
    Backlin, Carin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Granath, Fredrik
    Catrina, Anca Irinel
    Rosenquist, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Feltelius, Nils
    Sundström, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Klareskog, Lars
    Association of chronic inflammation, not its treatment, with increased lymphoma risk in rheumatoid arthritis2006In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 54, no 3, p. 692-701Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE:

    Chronic inflammatory conditions such as rheumatoid arthritis (RA) have been associated with malignant lymphomas. This study was undertaken to investigate which patients are at highest risk, and whether antirheumatic treatment is hazardous or protective.

    METHODS:

    We performed a matched case-control study of 378 consecutive Swedish RA patients in whom malignant lymphoma occurred between 1964 and 1995 (from a population-based RA cohort of 74,651 RA patients), and 378 controls. Information on disease characteristics and treatment from onset of RA until lymphoma diagnosis was abstracted from medical records. Lymphoma specimens were reclassified and tested for Epstein-Barr virus (EBV). Relative risks (odds ratios [ORs]) for lymphomas (by subtype) associated with deciles of cumulative disease activity were assessed, as were ORs associated with drug treatments.

    RESULTS:

    The relative risks of lymphoma were only modestly elevated up to the seventh decile of cumulative disease activity. Thereafter, the relative risk increased dramatically (OR ninth decile 9.4 [95% confidence interval 3.1-28.0], OR tenth decile 61.6 [95% confidence interval 21.0-181.0]). Most lymphomas (48%) were of the diffuse large B cell type, but other lymphoma subtypes also displayed an association with cumulative disease activity. Standard nonbiologic treatments did not increase lymphoma risk. EBV was present in 12% of lymphomas.

    CONCLUSION:

    Risk of lymphoma is substantially increased in a subset of patients with RA, those with very severe disease. High inflammatory activity, rather than its treatment, is a major risk determinant.

  • 28.
    Baecklund, Eva
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Natkunam, Yasodha
    Backlin, Carin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Iliadou, Anastasia
    Askling, Johan
    Ekbom, Anders
    Feltelius, Nils
    Klareskog, Lars
    Enblad, Gunilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Lossos, Izidore S.
    Levy, Ronald
    Sundström, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Rosenquist, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Expression of the human germinal-centre-associated lymphoma protein in diffuse large B-cell lymphomas in patients with rheumatoid arthritis2008In: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 141, no 1, p. 69-72Article in journal (Refereed)
    Abstract [en]

    Diffuse large B-cell lymphomas (DLBCL) can be subdivided into germinal centre (GC)-like and non-GC-like subtypes by CD10, BCL6 and MUM1/IRF4 status. We previously reported that patients with severe rheumatoid arthritis (RA) are at increased risk of non-GC DLBCL. This study examined a new GC-marker, human germinal-centre-associated lymphoma (HGAL) protein, in RA-DLBCL. Of 111, 38 (34%) DLBCL were HGAL-positive and showed less disseminated disease and a tendency toward improved overall survival compared to HGAL-negative cases. This supports that a majority of RA-DLBCL are of non-GC origin, indicating a specific role for activated peripheral B cells in the pathogenesis of RA-DLBCL.

  • 29.
    Baecklund, Eva
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Smedby, Karin E.
    Sutton, Lesley-Ann
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Askling, Johan
    Rosenquist, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Hematology and Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lymphoma development in patients with autoimmune and inflammatory disorders: What are the driving forces?2014In: Seminars in Cancer Biology, ISSN 1044-579X, E-ISSN 1096-3650, Vol. 24, p. 61-70Article, review/survey (Refereed)
    Abstract [en]

    For decades, it has been known that patients with certain autoimmune and inflammatory disorders, such as rheumatoid arthritis (RA) and primary Sjogren's syndrome (pSS), have an increased risk of developing malignant lymphoma. Although the clinico-biological reasons for this association remain largely unknown, our knowledge has improved and new insights have been obtained. First, the direct link between autoimmunity and lymphomagenesis has been strengthened by large epidemiological studies showing a consistent risk increase of lymphoma associated with certain autoimmune/inflammatory conditions in independent cohorts from different countries. Second, a number of local and systemic disease-related risk factors in these diseases have been repeatedly linked to lymphoma development, with the prime examples being disease severity and the degree of inflammatory activity. Considering the key role of B- and T-cell activation in the pathogenesis of both autoimmunity and lymphoma, it is perhaps not surprising that longstanding chronic inflammation and/or antigen stimulation have emerged as major predisposing factors of lymphoma in patients with active autoimmune disease. Finally, increasing evidence suggests that lymphomas associated with autoimmunity constitute a different spectrum of entities compared to lymphomas arising in patients without any known autoimmune or inflammatory conditions, pointing to a different pathobiology. In this review, we summarize the recent literature that supports a direct or indirect link between immune-mediated disease and lymphoma and describe the characteristics of lymphomas developing in the different diseases. We also discuss molecular, genetic and microenvironmental factors that may come into play in the pathobiology of these disorders.

  • 30.
    Baecklund, Eva
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Sundström, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Ekbom, Anders
    Catrina, Anca
    Biberfeld, Peter
    Feltelius, Nils
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Klareskog, Lars
    Lymphoma subtypes in patients with rheumatoid arthritis: Increased proportion of diffuse large B cell lymphoma2003In: Arthritis & Rheumatism, Vol. 48, no 6, p. 1543-1550Article in journal (Refereed)
  • 31. 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.

  • 32.
    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.

  • 33.
    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.

  • 34. Bentham, James
    et al.
    Morris, David L
    Cunninghame Graham, Deborah S
    Pinder, Christopher L
    Tombleson, Philip
    Behrens, Timothy W
    Martín, Javier
    Fairfax, Benjamin P
    Knight, Julian C
    Chen, Lingyan
    Replogle, Joseph
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    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.
    Graham, Robert R
    Wither, Joan E
    Rioux, John D
    Alarcón-Riquelme, Marta E
    Vyse, Timothy J
    Genetic association analyses implicate aberrant regulation of innate and adaptive immunity genes in the pathogenesis of systemic lupus erythematosus2015In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 47, no 12, p. 1457-1464Article in journal (Refereed)
    Abstract [en]

    Systemic lupus erythematosus (SLE) is a genetically complex autoimmune disease characterized by loss of immune tolerance to nuclear and cell surface antigens. Previous genome-wide association studies (GWAS) had modest sample sizes, reducing their scope and reliability. Our study comprised 7,219 cases and 15,991 controls of European ancestry, constituting a new GWAS, a meta-analysis with a published GWAS and a replication study. We have mapped 43 susceptibility loci, including ten new associations. Assisted by dense genome coverage, imputation provided evidence for missense variants underpinning associations in eight genes. Other likely causal genes were established by examining associated alleles for cis-acting eQTL effects in a range of ex vivo immune cells. We found an over-representation (n = 16) of transcription factors among SLE susceptibility genes. This finding supports the view that aberrantly regulated gene expression networks in multiple cell types in both the innate and adaptive immune response contribute to the risk of developing SLE.

  • 35.
    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.

    Keywords
    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
  • 36.
    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.
    Alm, Gunnar V.
    Syvanen, Ann-Christine
    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.
    Variation of Interferon-Alpha Production in Healthy Individuals and Association with Autoimmune Susceptibility Genes2012In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 64, no S10, p. S961-S961Article in journal (Other academic)
  • 37.
    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.

  • 38.
    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)
  • 39.
    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.
    Hagberg, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Alexsson, Andrei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Weber, Gert
    Ernst Moritz Arndt Univ Greifswald, Inst Biochem, Dept Mol Struct Biol, Greifswald, Germany..
    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.
    Plasmacytoid dendritic cells and RNA-containing immune complexes drive expansion of peripheral B cell subsets with an SLE-like phenotype2017In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 8, article id e0183946Article in journal (Refereed)
    Abstract [en]

    Background Hyperactive B cells and a continuous interferon (IFN)-alpha production by plasmacytoid dendritic cells (pDCs) play a key role in systemic lupus erythematosus (SLE). We asked whether the interaction between B cells and pDCs stimulated with RNA-containing immune complexes affects peripheral B cell subsets. Methods B cells and pDCs were isolated from blood of healthy individuals and stimulated with immune complexes consisting of SLE-IgG and U1snRNP (RNA-IC). Expression of cell surface molecules as well as IL-6 and IL-10 production were determined by flow cytometry and immunoassays. Gene expression profiles were determined by a NanoString nCounter expression array. Results We found a remarkable increase of double negative CD27-IgD-B cells, from 7% within fresh CD19+B cells to 37% in the RNA-IC-stimulated co-cultures of B cells and pDCs, comparable to the frequency of double negative B cells in SLE patients. Gene expression analysis of the double negative CD27-IgD -and the CD27 + IgD-memory B cells revealed that twenty-one genes were differentially expressed between the two B cell subsets (>= 2-fold, p< 0.001). The, IL21R, IL4R, CCL4, CCL3, CD83 and the IKAROS Family Zinc Finger 2 (IKZ2) showed higher expression in the double negative CD27-IgD-B cells. Conclusion The interactions between B cells and pDCs together with RNA-containing IC led to an expansion of B cells with similar phenotype as seen in SLE, suggesting that the pDC-B cell crosstalk contributes to the autoimmune feed-forward loop in SLE.

  • 40.
    Berggren, Olof
    et al.