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  • 1.
    Almroth, Gabriel
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Nephrology. Östergötlands Läns Landsting, Centre for Medicine, Department of Nephrology UHL.
    Eriksson, Per
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Rheumatology. Östergötlands Läns Landsting, Centre for Medicine, Department of Rheumatology in Östergötland.
    Berlin, G
    Andersson, B
    Hahn-Zoric, M
    Långtidsresultat av cyklofosfamidbehandling vid ANCA-associerad systemisk vaskulit med njurengagemang2004In: Svenska Läkaresällskapets,2004, 2004Conference paper (Other academic)
  • 2.
    Almroth, Gabriel
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Nephrology. Östergötlands Läns Landsting, Centre for Medicine, Department of Nephrology UHL.
    Eriksson, Per
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Rheumatology. Östergötlands Läns Landsting, Centre for Medicine, Department of Rheumatology in Östergötland.
    Berlin, G
    Hahn-Zoric, M
    Andersson, B
    Cyklophosphamide pulse treatment and infections in systemic vasculitis with renal involvement2004In: JASN 15 2004,2004, 2004Conference paper (Other academic)
  • 3.
    Andersson, Malin
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Faculty of Medicine and Health Sciences.
    Jägervall, Karl
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Eriksson, Per
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Region Östergötland, Heart and Medicine Center, Department of Rheumatology. Linköping University, Faculty of Medicine and Health Sciences.
    Persson, Anders
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Radiology in Linköping. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Granerus, Göran
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Clinical Physiology in Linköping.
    Wang, Chunliang
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV). KTH Royal Institute Technology, Sweden.
    Smedby, Örjan
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Radiology in Linköping. Linköping University, Center for Medical Image Science and Visualization (CMIV). KTH Royal Institute Technology, Sweden.
    How to measure renal artery stenosis - a retrospective comparison of morphological measurement approaches in relation to hemodynamic significance2015In: BMC Medical Imaging, ISSN 1471-2342, E-ISSN 1471-2342, Vol. 15, no 42Article in journal (Refereed)
    Abstract [en]

    Background: Although it is well known that renal artery stenosis may cause renovascular hypertension, it is unclear how the degree of stenosis should best be measured in morphological images. The aim of this study was to determine which morphological measures from Computed Tomography Angiography (CTA) and Magnetic Resonance Angiography (MRA) are best in predicting whether a renal artery stenosis is hemodynamically significant or not. Methods: Forty-seven patients with hypertension and a clinical suspicion of renovascular hypertension were examined with CTA, MRA, captopril-enhanced renography (CER) and captopril test (Ctest). CTA and MRA images of the renal arteries were analyzed by two readers using interactive vessel segmentation software. The measures included minimum diameter, minimum area, diameter reduction and area reduction. In addition, two radiologists visually judged the diameter reduction without automated segmentation. The results were then compared using limits of agreement and intra-class correlation, and correlated with the results from CER combined with Ctest (which were used as standard of reference) using receiver operating characteristics (ROC) analysis. Results: A total of 68 kidneys had all three investigations (CTA, MRA and CER + Ctest), where 11 kidneys (16.2 %) got a positive result on the CER + Ctest. The greatest area under ROC curve (AUROC) was found for the area reduction on MRA, with a value of 0.91 (95 % confidence interval 0.82-0.99), excluding accessory renal arteries. As comparison, the AUROC for the radiologists visual assessments on CTA and MRA were 0.90 (0.82-0.98) and 0.91 (0.83-0.99) respectively. None of the differences were statistically significant. Conclusions: No significant differences were found between the morphological measures in their ability to predict hemodynamically significant stenosis, but a tendency of MRA having higher AUROC than CTA. There was no significant difference between measurements made by the radiologists and measurements made with fuzzy connectedness segmentation. Further studies are required to definitely identify the optimal measurement approach.

  • 4. Anfelter, P
    et al.
    Granerus, Göran
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Clinical Physiology. Östergötlands Läns Landsting, Heart Centre, Department of Clinical Physiology.
    Stenström, Hugo
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Medical Radiology. Östergötlands Läns Landsting, Centre for Medical Imaging, Department of Radiology UHL.
    Eriksson, Per
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Rheumatology. Östergötlands Läns Landsting, Centre for Medicine, Department of Rheumatology in Östergötland.
    Nyström, Fredrik
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Internal Medicine. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
    The effect of percutaneous dilatation of renal arterial stenosis on captopril renography in hypertension2005In: Blood Pressure, ISSN 0803-7051, E-ISSN 1651-1999, Vol. 14, no 6, p. 359-365Article in journal (Refereed)
    Abstract [en]

    Background. The clinical effects of percutaneous transluminal renal artery angioplasty (PTRA) in patients with renal vascular stenosis and hypertension is controversial. Methods. We consecutively recruited all 23 patients referred for evaluation of renovascular hypertension that eventually underwent unilateral PTRA, to be investigated with captopril MAG3 renography (CR), both before and after the endovascular procedure. Data were evaluated on an intention-to-treat basis. Results. We found that the relative MAG3 clearance of the stenotic kidney increased (from 29.9 ± 14% to 35.1 ± 14%, p=0.01) and that the creatinine levels fell following the intervention (from 110 ± 19 to 99 ± 17 μmol/l, p=0.0003). Blood pressure levels were also lowered (from 173 ± 32/93 ± 17 to 158 ± 31/86 ± 15 mmHg, p<0.006) while the mean number of anti-hypertensive drugs was unchanged following PTRA (2.9 ± 1.4 before and 2.8 ± 1.3 drugs after the intervention, respectively, p-0.6). Conclusion. This prospective trial showed statistically significant improvements of individual kidney function as measured by CR and blood pressure in subjects with suspected renovascular hypertension treated with PTRA. Although the endovascular procedure was found to be safe, the magniture of the absolute improvements was rather modest. © 2005 Taylor & Francis.

  • 5.
    Appel, Silke
    et al.
    Broegelmann Research Laboratory, The Gade Institute, University of Bergen, Bergen, Norway .
    Le Hellard, Stephanie
    Department of Clinical Medicine, University of Bergen, Bergen, Norway .
    Bruland, Ove
    Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway .
    Brun, Johan G
    Department of Rheumatology, Haukeland University Hospital, Bergen, Norway .
    Omdal, Roald
    Clinical Immunology Unit, Department of Internal Medicine, Stavanger University Hospital, Stavanger, Norway .
    Kristjansdottir, Gudlaug
    Molecular Medicine, Department of Medical Sciences, Uppsala University, Uppsala.
    Theander, Elke
    Department of Rheumatology, Malmö University Hospital, Malmö.
    Nordmark, Gunnel
    Section of Rheumatology, Department of Medical Sciences, Uppsala University, Uppsala.
    Kvarnstrom, Marika
    Rheumatology Unit, Department of Medicine, Karolinska Institutet, Stockholm.
    Eriksson, Per
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Nephrology UHL.
    Rönnblom, Lars
    Section of Rheumatology, Department of Medical Sciences, Uppsala University, Uppsala.
    Wahren-Herlenius, Marie
    Rheumatology Unit, Department of Medicine, Karolinska Institutet, Stockholm.
    Jonsson, Roland
    Broegelmann Research Laboratory, The Gade Institute, University of Bergen, Bergen, Norway.
    Potential association of muscarinic receptor 3 gene variants with primary Sjögrens syndrome2011In: ANNALS OF THE RHEUMATIC DISEASES, ISSN 0003-4967, Vol. 70, no 7, p. 1327-1329Article in journal (Refereed)
    Abstract [en]

    Background Primary Sjogrens syndrome (pSS) is characterised by a chronic inflammation of exocrine glands. Salivary gland infiltrates, however, do not correlate well with disease symptoms, and a primary role for the salivary gland parenchyma in disease development has been suggested. Specifically, dysfunction of exocrine pathways involving the muscarinic receptor 3 (CHRM3) has been indicated. Objective To investigate possible genetic divergence in the CHRM3 gene in patients with pSS. Methods 530 patients with pSS and 532 controls from a combined Swedish and Norwegian cohort were genotyped for 84 single nucleotide polymorphisms (SNPs) distributed throughout CHRM3. Results Genetic association was observed with five SNPs localised in intron 3 and 4 of CHRM3, the strongest being rs7548522 (minor allele frequency = 0.06, OR=1.93, 95% CI (1.24 to 3.01); p=0.0033). In addition, clinical parameters, including focus score, abnormal Schirmers test and presence of autoantibodies, were associated with different SNPs in CHRM3. Conclusion The study demonstrates a novel association of CHRM3 polymorphisms with pSS, suggesting a functional role for CHRM3 and the salivary gland parenchyma in the pathogenesis of pSS.

  • 6.
    Blomgran, Robert
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Brodin Patcha, Veronika
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Verma, Deepti
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Bergström, Ida
    Linköping University, Department of Medical and Health Sciences, Cardiology. Linköping University, Faculty of Health Sciences.
    Söderkvist, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Sjöwall, Christoffer
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Rheumatology in Östergötland.
    Eriksson, Per
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Nephrology UHL.
    Lerm, Maria
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Stendahl, Olle
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Sarndahl, Eva
    University of Örebro.
    Common Genetic Variations in the NALP3 Inflammasome Are Associated with Delayed Apoptosis of Human Neutrophils2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 3Article in journal (Refereed)
    Abstract [en]

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

  • 7.
    Eriksson, Per
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Rheumatology.
    Nine patients with anti-neutrophil cytoplasmic antibody-positive vasculitis successfully treated with rituximab2005In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 257, no 6, p. 540-548Article in journal (Refereed)
    Abstract [en]

    Objectives. Rituximab (RIT) is a monoclonal anti-CD20 antibody, which depletes B-lymphocytes but not plasma cells. RIT is used for treatment of B-cell lymphomas, but has also shown beneficial effects in autoimmune diseases. In this case series RIT was used in anti-neutrophil cytoplasmic antibody (ANCA)-positive vasculitis. Design. Case series with a structured follow-up of treated patients. Setting. Departments of Nephrology and Rheumatology of a university hospital. Subjects. Two women with myeloperoxidase-ANCA-positive microscopic polyangiitis and seven patients (five men and two women) with proteinase 3-ANCA-positive Wegener's granulomatosis. All patients were resistant to conventional therapy or had relapsed repeatedly after cessation of cyclophosphamide (Cyc). Interventions. The cases were treated with intravenous infusions of RIT once a week two times (three cases) or four times (six cases). To prevent formation of antibodies to RIT, mycophenolate mofetil (five patients), azathioprine (one patient), or a short course of Cyc (two patients) were added or allowed to continue. Mainoutcome measures. Remission at 6 months assessed with Birmingham vasculitis activity score. The cases were followed 6-24 months and relapse rate was also noted. Results. Eight of nine patients responded completely and one case responded partially. Pulmonary X-ray improved (four cases), progress of lower extremity gangrene stopped (one case), remission of neuropathy was stable (one patient), renal vasculitis went into remission (two cases), and severe musculoskeletal pain improved (one case). Minor relapse in the nose occurred in two cases. No adverse events or major infections were noted. Conclusion. RIT seems promising and safe in ANCA-positive vasculitis, and controlled studies should be conducted. © 2005 Blackwell Publishing Ltd.

  • 8.
    Eriksson, Per
    Linköping University, Department of Medicine and Care, Internal Medicine. Linköping University, Department of Molecular and Clinical Medicine, Rheumatology. Linköping University, Department of Medicine and Care, Nephrology. Linköping University, Department of Biomedicine and Surgery, Urology. Linköping University, Faculty of Health Sciences.
    Renal disease in primary Sjögren's syndrome1996Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Primary Sjögren's syndrome (SS) is characterised by inflammation in the lacrimal and salivary glands. The kidneys may be involved, e.g. tubulointerstitial nephritis (TIN) and distal renal tubular acidosis (dRTA). dRTA is often associated with hypocitraturia, and both represent risk factors for the development of urolithiasis. The present investigations were undertaken to evaluate renal tubular function (including -dRTA), glomerular filtration rate (GFR), renal histopathology and mechanisms of stone formation, as well as the serum IgG subclass pattern in patients with SS. Furthermore, patients presenting with urolithiasis and dRTA in absence of sicca symptoms, as well as patients with urolithiasis andhypocitraturia, were studied with respect to autoantibodies and clinical features of SS.

    Renal tubular dysfunction, such as dRTA; impaired urine concentrating ability; hypocitraturia; and decreased tubular reabsorption of phosphate (1RP%), was conunonly detected in the SS-patients. Tubular proteinuria (al-microglobulin) and tubular enzymuria (NAG) were primarily associated with decreased GFR.

    GFR, investigated with 5Icr-EDTA plasma clearance, was below the reference limit in 33% of SS-patients. An inverse correlation was found between GFR and the extent of tubulointerstitial nephritis (adjusted CTIN score). Decreased GFR was mostly due to TIN, although urolithiasis and upper urinary tract infections may have contributed in some patients.

    TIN was demonstrated in most biopsied patients with SS, and the histopathological picture was characterised by mainly focal interstitial inflanunation, tubular atrophy, interstitial fibrosis and a varying extent of glomerular sclerosis.

    Fourty-one percent of the SS-patients had formed at least one stone, and calcium phosphate was the main constituent in most stones. All stone formers had dRTA, and most of them had hypocitraturia. Urinary calcium and urate excretion was also significantly higher than in non-stone formers.

    The SS-patients often had low serum levels of IgG2, despite high levels of total IgG. Low levels of IgG2 were sometimes associated with infections. A high IgG lngG2 ratio indicated autoimmune disease.

    Of 10 patients presenting with urolithiasis and dRTA, anti-SS-A antibodies were detected in eight. Subjective sicca symptoms subsequently developed l-48 years after the presentation of urolithiasis, and objective signs of SS were found in 7 patients.

    In a large population of hypocitraturic stone formers, ANA and anti-SS-A antibodies were commonly detected in the women but not in the men. Four of 14 evaluated hypocitraturic women with anti-SS-A antibodies or ANA, fulfilled the criteria for SS.

    In conclusion, the present investigations show that 24-hour urinary excretion of citrate is a valuable tool for detection of renal disease in SS, slightly-moderately decreased GFR is not unusual in SS-patients with. renal disease, the "adjusted CTIN score" can be a useful tool for quantifying the extent of tu'bulointerstitial nephritis, and the urine composition in stone formers with SS is similar to that of other dRT A-patients.

    The possibility of a Sjögren-related renal disease charcterised by urolithiasis and/or dRTA and antibodies to SS-A, regardless of whether subjective sicca symptoms are present or not, is hypothesised.

  • 9.
    Eriksson, Per
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Rheumatology.
    Andersson, Carina
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
    Cassel, Petra
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
    Nyström, Sofia
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
    Ernerudh, Jan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
    Letter: Increase in Th17-associated CCL20 and decrease in Th2-associated CCL22 plasma chemokines in active ANCA-associated vasculitis2015In: Scandinavian Journal of Rheumatology, ISSN 0300-9742, E-ISSN 1502-7732, Vol. 44, no 1, p. 80-83Article in journal (Other academic)
    Abstract [en]

    n/a

  • 10.
    Eriksson, Per
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Rheumatology.
    Andersson, Carina
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Rheumatology.
    Ekerfelt, Christina
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Clinical Immunology.
    Ernerudh, Jan
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Clinical Immunology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Immunology and Transfusion Medicine.
    Skogh, Thomas
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Rheumatology. Östergötlands Läns Landsting, Centre for Medicine, Department of Rheumatology in Östergötland.
    Relationship between serum levels of IL-18 and IgG1 in patients with primary Sjögren's syndrome, rheumatoid arthritis and healthy controls2004In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 137, no 3, p. 617-620Article in journal (Refereed)
    Abstract [en]

    Primary Sjögren's syndrome (SS) is characterized by inflammation in salivary and lachrymal glands, with a local predominance of Th1-like cytokines, as well as the pleiotropic cytokine interleukin (IL) 18. High serum levels of polyclonal IgG are common, with a subclass imbalance in which IgG1 is increased and IgG2 is normal or low. IL-18 is also of pathogenetic importance in rheumatoid arthritis. In the present study we looked for any relationship between serum IL-18 as well as transforming growth factor (TGF) β1 versus IgA, IgM, and IgG subclass levels in SS (n = 16), rheumatoid arthritis (RA) (n = 15), and healthy controls (n = 15). SS was defined by the revised American-European classification criteria. IL-18 and TGF-β1 were analyzed with enzyme immunoassays (EIA), and IgG1, IgG2 and IgG3 by single radial immunodiffusion. In the composite group of RA, SS and normal controls, IgG1 and IL-18 were related (R = 0.52, P = 0.0005). No relation was found neither between IL-18 versus IgG2, IgG3 or IgA, nor between serum TGF-β1 versus any of the immunoglobulins. Since serum levels of IL-18 are related to serum IgG1, IL-18 may be of importance for IgG1 switch and/or release.

  • 11.
    Eriksson, Per
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Rheumatology.
    Andersson, Carina
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Rheumatology.
    Ekerfelt, Christina
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Clinical Immunology.
    Ernerudh, Jan
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Clinical Immunology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Immunology and Transfusion Medicine.
    Skogh, Thomas
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Rheumatology. Östergötlands Läns Landsting, Centre for Medicine, Department of Rheumatology in Östergötland.
    Sjögren´s syndrome with myalgia is associated with subnormal secretion of cytokines by peripheral blood mononuclear cells.2004In: Journal of Rheumatology, ISSN 0315-162X, E-ISSN 1499-2752, Vol. 31, p. 729-735Article in journal (Refereed)
  • 12.
    Eriksson, Per
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Nephrology UHL.
    Ernerudh, Jan
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Immunology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Immunology and Transfusion Medicine.
    Nyström, Sofi A
    Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
    Backteman, Karin
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Immunology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Immunology and Transfusion Medicine.
    Sardell, Christina
    Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
    Increased plasma levels of CXCL1 and CCL20 reflecting Th17 activity in active WG and MPA in CLINICAL AND EXPERIMENTAL IMMUNOLOGY, vol 164, issue , pp 150-1502011In: CLINICAL AND EXPERIMENTAL IMMUNOLOGY, Blackwell Publishing Ltd , 2011, Vol. 164, p. 150-150Conference paper (Refereed)
    Abstract [en]

    n/a

  • 13.
    Eriksson, Per
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Rheumatology in Östergötland.
    Jacobs, Claudia
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Rheumatology in Östergötland.
    Johansson, Karl-Erik
    Linköping University, Department of Clinical and Experimental Medicine, Surgery. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery UHL.
    Remission of arthritis after esophagectomy in three patients with severe achalasia2013In: Diseases of the esophagus, ISSN 1120-8694, E-ISSN 1442-2050, Vol. 26, no 3, p. 226-230Article in journal (Refereed)
    Abstract [en]

    In the 1960s and 1970s, intestinal bypass surgery was performed to treat patients with extreme obesity. However, this is now done with great restriction due to the risk of complications, for instance, polyarthritis. An association between severe achalasia and arthritis has also been described, but very few articles on this topic are cited in PubMed, and most of the published case reports are old. In this article, we present a retrospective case series of three patients with severe achalasia and arthritis from the departments of rheumatology and surgery at a university hospital. The complaints from the esophagus as well as arthritis were resolved after esophagectomy and esophageal reconstruction. We conclude that severe achalasia can be associated with arthritis, and both can be cured by esophageal reconstruction. Thus, we want to remind of this rare, but probably largely unrecognized, association between achalasia and joint disease.

  • 14.
    Eriksson, Per
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Rheumatology.
    Jacobs, Claudia
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Rheumatology.
    Söderkvist, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    A patient with Phenotype of Adult-onset Still Disease, But a Genotype Typical of Cryopyrin-associated Periodic Fever Syndrome2013In: Journal of Rheumatology, ISSN 0315-162X, E-ISSN 1499-2752, Vol. 40, no 9, p. 1632-1633Article in journal (Other academic)
  • 15.
    Eriksson, Per
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Rheumatology in Östergötland.
    Jacobsson, L
    Malmö University Hospital.
    Lindell, A
    Skogsfrid Primary Care Centre.
    Nilsson, J-A
    Malmö University Hospital.
    Skogh, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Rheumatology in Östergötland.
    Improved outcome in Wegener's granulomatosis and microscopic polyangiitis? A retrospective analysis of 95 cases in two cohorts.2009In: Journal of internal medicine, ISSN 1365-2796, Vol. 265, no 4, p. 496-506Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: Mortality rates for Wegener's granulomatosis (WG) and microscopic polyangiitis (MPA) have decreased after the introduction of cyclophosphamide. Standardized mortality ratio (SMR) expresses the overall mortality of patients compared with the general population. The aims of this study were to compare survival in an old and a recent cohort of patients with WG and MPA using SMR and to determine predictors for death in both groups combined. DESIGN: Survival analyses were performed by Kaplan-Meier survival curves, SMR and proportional hazards regression models. SETTING: The nephrology and rheumatology clinics at Linköping University Hospital, Sweden. SUBJECTS: All patients diagnosed with WG or MPA in the catchment area during 1978-2005 were divided into two cohorts; patients diagnosed before (n=32, old cohort) and after (n=63, recent cohort) December 31, 1996. RESULTS: The two cohorts differed regarding the proportion of WG (75% vs. 56%, P=0.03) and a tendency for more pronounced kidney involvement in the old cohort: 266 micromol L(-1) (16% dialysis-dependent) vs. 192 micromol L(-1) (5% dialysis-dependent), but were comparable regarding disease severity. SMR at 1 and 5 years were 2.1 (95% CI: 0.43-6.09) and 1.6 (95% CI: 0.6-3.2) in the recent cohort and 5.2 (95% CI: 1.07-15.14) and 2.5 (95% CI: 0.93-5.52) in the old cohort. Five-year survival was 87% and 81%. Serum creatinine, age, end-stage renal disease, diagnosis before 1997 and first relapse were independent predictors for death. CONCLUSION: Patient survival in WG and MPA analysed with SMR may be better than previously believed. Severe renal disease and disease relapse were the major predictors of reduced survival.

  • 16.
    Eriksson, Per
    et al.
    Linköping University, Department of Medicine and Health Sciences, Internal Medicine . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Nephrology UHL.
    Mohammed, Ahmed Abdulilah
    Linköping University, Department of Medicine and Health Sciences, Radiology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medical Imaging, Department of Radiology in Linköping.
    De Geer, Jakob
    Linköping University, Department of Medicine and Health Sciences, Radiology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medical Imaging, Department of Radiology in Linköping. Linköping University, Center for Medical Image Science and Visualization, CMIV.
    Kihlberg, Johan
    Linköping University, Center for Medical Image Science and Visualization, CMIV. Linköping University, Department of Medicine and Health Sciences, Radiology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medical Imaging, Department of Radiology in Linköping.
    Persson, Anders
    Linköping University, Center for Medical Image Science and Visualization, CMIV. Linköping University, Department of Medicine and Health Sciences, Radiology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medical Imaging, Department of Radiology in Linköping.
    Granerus, Göran
    Linköping University, Center for Medical Image Science and Visualization, CMIV. Linköping University, Department of Medicine and Health Sciences, Clinical Physiology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart Centre, Department of Clinical Physiology.
    Nyström, Fredrik
    Linköping University, Department of Medicine and Health Sciences, Internal Medicine . Linköping University, Faculty of Health Sciences.
    Smedby, Örjan
    Linköping University, Center for Medical Image Science and Visualization, CMIV. Linköping University, Department of Medicine and Health Sciences, Radiology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medical Imaging, Department of Radiology in Linköping.
    Non-invasive investigations of potential renal artery stenosis in renal insufficiency2010In: Nephrology, Dialysis and Transplantation, ISSN 0931-0509, E-ISSN 1460-2385, Vol. 25, no 11, p. 3607-3614Article in journal (Refereed)
    Abstract [en]

    Background. The diagnostic value of non-invasive methods for diagnosing renal artery stenosis in patients with renal insufficiency is incompletely known.

    Methods. Forty-seven consecutive patients with moderately impaired renal function and a clinical suspicion of renal artery stenosis were investigated with computed tomography angiography (CTA), gadolinium-enhanced magnetic resonance angiography (MRA), contrast-enhanced Doppler ultrasound and captopril renography. The primary reference standard was stenosis reducing the vessel diameter by at least 50% on CTA, and an alternative reference standard (‘morphological and functional stenosis’) was defined as at least 50% diameter reduction on CTA or MRA, combined with a positive finding from ultrasound or captopril renography.

    Results. The frequency of positive findings, calculated on the basis of individual patients, was 70% for CTA, 60% for MRA, 53% for ultrasound and 30% for captopril renography. Counting kidneys rather than patients, corresponding frequencies were 53%, 41%, 29% and 15%, respectively. In relation to the CTA standard, the sensitivity (and specificity) at the patient level was 0.81 (0.79) for MRA, 0.70 (0.89) for ultrasound and 0.42 (1.00) for captopril renography, and at the kidney level 0.76 (0.82), 0.53 (0.81) and 0.30 (0.86), respectively. Relative to the alternative reference standard, corresponding values at the patient level were 1.00 (0.62) for CTA, 0.90 (0.69) for MRA, 0.91 (1.00) for ultrasound and 0.67 (1.00) for captopril renography, and at the kidney level 0.96 (0.76), 0.85 (0.79), 0.71 (0.97) and 0.50 (0.97), respectively.

    Conclusions. CTA and MRA are superior to ultrasound and captopril renography at diagnosing morphological stenosis, but ultrasound may be useful as a screening method and captopril renography for verifying renin-dependent hypertension.

  • 17.
    Eriksson, Per
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Rheumatology in Östergötland.
    Sandell, Christina
    Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
    Backteman, Karin
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Immunology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
    Ernerudh, Jan
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Immunology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
    B Cell Abnormalities in Wegeners Granulomatosis and Microscopic Polyangiitis: Role of CD25+-expressing B Cells2010In: JOURNAL OF RHEUMATOLOGY, ISSN 0315-162X, Vol. 37, no 10, p. 2086-2095Article in journal (Refereed)
    Abstract [en]

    Objective. The use of rituximab in vasculitis has increased interest in B cell biology. A subpopulalion of B cells expressing CD25 shows antigen-presenting properties and may have regulatory functions. We assessed subpopulations of B cell maturation (Bm) and markers related to activity and antigen presentation, and related the findings to disease activity. Methods. Multiparameter flow cytometry was used to assess numbers and proportions of circulating lymphocytes from 34 patients with vasculitis (16 remission, 18 active) and 20 controls. Results. Active vasculitis samples showed decreased proportions of Bm1 (7.8% vs 11%; p = 0.041), Bm2 (0.2% vs 0.7%; p = 0.002), and Bm3/Bm4 (0.1% vs 0.3%; p = 0.006), compared with controls; Bm2 cells were the most frequently occurring B cells but they were not significantly different in active vasculitis (74% vs 62%; p = 0.083). In patients with remission the proportion of CD25+ B cells was increased compared to controls (48% vs 29%, respectively; p = 0.006) and also compared to active vasculitis (23%; p = 0.006). The proportion of CD86+ B cells was also increased (31%) compared to active vasculitis (8%; p = 0.001), and to controls (6%; p = 0.0003). In multivariate analysis. Bm2 cells and CD25+27- B cells were independently influencing the patient group. Conclusion. In active vasculitis, a lower proportion of Bm I cells may indicate activated B cells. Patients in remission had higher proportions of CD25+ (a-chain of interleukin 2 receptor) and CD86+ (costimulatory molecule) B cells. We suggest that these B cells may have a regulatory role, or alternatively may result from previous treatment.

  • 18.
    Eriksson, Per
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Rheumatology in Östergötland.
    Sandell, Christina
    Backteman, Karin
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Immunology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Immunology and Transfusion Medicine.
    Ernerudh, Jan
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Immunology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Immunology and Transfusion Medicine.
    B lymphocyte subpopulations in Wegeners granulomatosis and microscopic polyangiitis with special reference to CD25+-expressing B cells2009In: in APMIS vol 117, 2009, Vol. 117, p. 116-116Conference paper (Refereed)
    Abstract [en]

    n/a

  • 19.
    Eriksson, Per
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Nephrology UHL.
    Sandell, Christina
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Ernerudh, Jan
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Immunology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
    Expansions of CD4+CD28-and CD8+CD28-T cells in Granulomatosis with Polyangiitis and Microscopic Polyangiitis Are Associated with Cytomegalovirus Infection But Not with Disease Activity2012In: Journal of Rheumatology, ISSN 0315-162X, E-ISSN 1499-2752, Vol. 39, no 9, p. 1840-1843Article in journal (Refereed)
    Abstract [en]

    Objective. T helper cells lacking CD28 (CD4+CD28-) have been implicated in the pathogenesis of granulomatosis with polyangiitis (Wegener; GPA) and microscopic polyangiitis (MPA). Expansions of CD4+CD28- and CD8+CD28- T cells have also been associated with latent cytomegalovirus (CMV) infection. We assessed these T cells with and without coexpression of CD56 and CD57 in relation to vasculitis as well as CMV status. less thanbrgreater than less thanbrgreater thanMethods. Blood from 16 patients in remission (12 GPA, 4 MPA), 18 patients with active vasculitis (12 GPA, 6 MPA), and 20 healthy controls was examined by flow cytometry for expression of CD4, CD8, CD56, CD57, and CD28 on T cells. The influence of age, CMV status, presence of disease, and disease activity on T cell subpopulations was tested with multiple regression analyses. less thanbrgreater than less thanbrgreater thanResults. In active vasculitis, the total numbers and proportion of lymphocytes were decreased. Total numbers of CD4+, CD8+, CD4+CD28-, CD8+CD28-, CD4+CD57+, and CD8+CD57+ T subpopulations were decreased to the same extent, implying unchanged proportions. Multivariate analyses showed no associations between vasculitis and CD28- or CD57+ T subpopulations, whereas immunoglobulin G antibodies to CMV were associated with expanded proportions of CD28 and CD57+ T cells, in both the CD4+ and the CD8+ compartments. less thanbrgreater than less thanbrgreater thanConclusion. CD28- and CD57+ T cells were associated with latent CMV infection and not with a diagnosis of GPA or MPA. Vasculitis assessment should include CMV status.

  • 20.
    Geetha, Duvuru
    et al.
    Johns Hopkins University, Baltimore, MD, USA.
    Hruskova, Zdenka
    Charles University, Prague, Czech Republic .
    Segelmark, Mårten
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Nephrology.
    Hogan, Jonathan
    Hospital of the University of Pennsylvania, Philadelphia, USA.
    Morgan, Matthew D
    University of Birmingham, UK .
    Cavero, Teresa
    Hospital 12 de Octubre, Madrid, Spain .
    Eriksson, Per
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Rheumatology.
    Seo, Philip
    John Hopkins University, Baltimore, USA.
    Manno, Rebecca L
    John Hopkins University, Baltimore, USA.
    Dale, Jessica
    University of Birmingham, Birmingham, UK.
    Harper, Lorraine
    University of Birmingham, UK.
    Tesar, Vladimir
    Charles University, Prague, Czech Republic .
    Jayne, David Rw
    Addenbrooke's Hospital, Cambridge, UK .
    Rituximab for treatment of severe renal disease in ANCA associated vasculitis2016In: JN. Journal of Nephrology (Milano. 1992), ISSN 1121-8428, E-ISSN 1724-6059, Vol. 29, no 2, p. 195-201Article in journal (Refereed)
    Abstract [en]

    Background

    Rituximab (RTX) is approved for remission induction in ANCA associated vasculitis (AAV). However, data on use of RTX in patients with severe renal disease is lacking.

    Methods

    We conducted a retrospective multi-center study to evaluate the efficacy and safety of RTX with glucocorticoids (GC) with and without use of concomitant cyclophosphamide (CYC) for remission induction in patients presenting with e GFR less than 20 ml/min/1.73 m2. We evaluated outcomes of remission at 6 months (6 M), renal recovery after acute dialysis at diagnosis, e-GFR rise at 6 M, patient and renal survival and adverse events.

    Results

    A total 37 patients met the inclusion criteria. The median age was 61 years. (55–73), 62 % were males, 78 % had new diagnosis and 59 % were MPO ANCA positive. The median (IQR) e-GFR at diagnosis was 13 ml/min/1.73 m2 (7–16) and 15 required acute dialysis. Eleven (30 %) had alveolar hemorrhage. Twelve (32 %) received RTX with GC, 25 (68 %) received RTX with GC and CYC and seventeen (46 %) received plasma exchange. The median (IQR) follow up was 973 (200–1656) days. Thirty two of 33 patients (97 %) achieved remission at 6 M and 10 of 15 patients (67 %) requiring dialysis recovered renal function. The median prednisone dose at 6 M was 6 mg/day. The mean (SD) increase in e-GFR at 6 months was 14.5 (22) ml/min/m2. Twelve patients developed ESRD during follow up. There were 3 deaths in the first 6 months. When stratified by use of concomitant CYC, there were no differences in baseline e GFR, use of plasmapheresis, RTX dosing regimen or median follow up days between the groups. No differences in remission, renal recovery ESRD or death were observed.

    Conclusions

    This study of AAV patients with severe renal disease demonstrates that the outcomes appear equivalent when treated with RTX and GC with or without concomitant CYC.

  • 21.
    Haldorsen, K
    et al.
    University of Bergen.
    Appel, S
    University of Bergen.
    Bruland, O
    Haukeland Hospital.
    Le Hellard, S
    University of Bergen.
    Brun, J G
    University of Bergen.
    Omdal, R
    Stavanger University Hospital.
    Kristjansdottir, G
    Uppsala University.
    Theander, E
    Malmö University Hospital.
    Nordmark, G
    Uppsala University.
    Kvamstrom, M
    Karolinska Institute.
    Eriksson, Per
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Rheumatology in Östergötland.
    Ronnblom, L
    Uppsala University.
    Wahren-Herlenius, M
    Karolinska Institute.
    Jonsson, R
    University of Bergen.
    I Bolstad, A
    University of Bergen.
    Fc gamma receptor IIA, IIIA and IIIB single nucleotide polymorphisms and Fc gamma receptor IIIB copy number variation: No association with primary Sjogrens syndrome in SCANDINAVIAN JOURNAL OF RHEUMATOLOGY, vol 39, issue , pp 36-362010In: SCANDINAVIAN JOURNAL OF RHEUMATOLOGY, Informa Healthcare , 2010, Vol. 39, p. 36-36Conference paper (Refereed)
    Abstract [en]

    n/a

  • 22.
    Haldorsen, K.
    et al.
    University of Bergen, Norway University of Bergen, Norway .
    Appel, S.
    University of Bergen, Norway .
    Le Hellard, S.
    University of Bergen, Norway .
    Bruland, O.
    Haukeland Hospital, Norway .
    Brun, J. G.
    Haukeland Hospital, Norway .
    Omdal, R.
    Stavanger University Hospital, Norway .
    Kristjansdottir, G.
    Uppsala University, Sweden .
    Theander, E.
    Lund University, Sweden .
    Fernandes, C. P. D.
    University of Bergen, Norway .
    Kvarnstrom, M.
    Karolinska Institute, Sweden .
    Eriksson, Per
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Rheumatology.
    Ronnblom, L.
    Uppsala University, Sweden .
    Herlenius, M. W.
    Karolinska Institute, Sweden .
    Nordmark, G.
    Uppsala University, Sweden .
    Jonsson, R.
    University of Bergen, Norway Haukeland Hospital, Norway .
    Bolstad, A. I.
    University of Bergen, Norway .
    No association of primary Sjogrens syndrome with Fc gamma receptor gene variants2013In: Genes and Immunity, ISSN 1466-4879, E-ISSN 1476-5470, Vol. 14, no 4, p. 234-237Article in journal (Refereed)
    Abstract [en]

    The genetic background of primary Sjogrens syndrome (pSS) is partly shared with systemic lupus erythematosus (SLE). Immunoglobulin G Fc receptors are important for clearance of immune complexes. Fcg receptor variants and gene deletion have been found to confer SLE risk. In this study, four Fc gamma receptor single-nucleotide polymorphisms (SNPs) and one copy number variation (CNV) were studied. Swedish and Norwegian pSS patients (N = 527) and controls (N = 528) were genotyped for the Fc gamma receptor gene variant FCGR2A H131R (rs1801274) by the Illumina GoldenGate assay. FCGR3A F158V (rs396991) was analysed in 488 patients and 485 controls, FCGR3B rs447536 was analysed in 471 patients and 467 controls, and FCGR3B rs448740 was analysed in 478 cases and 455 controls, using TaqMan SNP genotyping assays. FCGR3B CNV was analysed in 124 patients and 139 controls using a TaqMan copy number assay. None of the SNPs showed any association with pSS. Also, no FCGR3B CNV association was detected. The lack of association of pSS with Fc gamma receptor gene variants indicates that defective immune complex clearance may not be as important in pSS pathogenesis as in SLE, and may point to important differences between SLE and pSS.

  • 23.
    Haldorsen, Karstein
    et al.
    University of Bergen, Norway .
    Appel, Silke
    University of Bergen, Norway .
    Le Hellard, Stephanie
    University of Bergen, Norway .
    Bruland, Ove
    Haukeland Hospital, Norway .
    Brun, Johan G.
    Haukeland Hospital, Norway University of Bergen, Norway .
    Omdal, Roald
    Stavanger University Hospital, Norway .
    Kristjansdottir, Gudlaug
    Uppsala University, Sweden .
    Theander, Elke
    Malmö University Hospital, Sweden .
    Fernandes, Carla P. D.
    University of Bergen, Norway .
    Nordmark, Gunnel
    Uppsala University, Sweden .
    Kvarnstrom, Marika
    Karolinska Institute, Sweden .
    Eriksson, Per
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Nephrology.
    Ronnblom, Lars
    Uppsala University, Sweden .
    Wahren Herlenius, Marie
    Karolinska Institute, Sweden .
    Jonsson, Roland
    University of Bergen, Norway Haukeland Hospital, Norway .
    Isine Bolstad, Anne
    University of Bergen, Norway .
    No Association of Primary Sjogrens Syndrome with Fc gamma?Receptor Gene Variants2012In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 76, no 2, p. 198-198Article in journal (Refereed)
  • 24.
    Isine Bolstad, Anne
    et al.
    University of Bergen.
    Le Hellard, Stephanie
    University of Bergen.
    Kristjansdottir, Gudlaug
    Uppsala University.
    Vasaitis, Lilian
    Uppsala University.
    Kvarnstrom, Marika
    Karolinska Institute.
    Sjöwall, Christoffer
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Rheumatology in Östergötland.
    Joar Auglaend Johnsen, Svein
    Stavanger University Hospital.
    Eriksson, Per
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Nephrology UHL.
    Omdal, Roald
    Stavanger University Hospital.
    Brun, Johan G
    University of Bergen.
    Wahren-Herlenius, Marie
    Karolinska Institute.
    Theander, Elke
    Lund University.
    Syvanen, Ann-Christine
    Uppsala University.
    Ronnblom, Lars
    Uppsala University.
    Nordmark, Gunnel
    Uppsala University.
    Jonsson, Roland
    University of Bergen.
    Association between genetic variants in the tumour necrosis factor/lymphotoxin alpha/lymphotoxin beta locus and primary Sjogrens syndrome in Scandinavian samples2012In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 71, no 6, p. 981-988Article in journal (Refereed)
    Abstract [en]

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

  • 25.
    Kastbom, Alf
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Rheumatology.
    Klingberg, E
    University of Gothenburg, Sweden .
    Verma, Deepti
    Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences.
    Carlsten, H
    University of Gothenburg, Sweden .
    Forsblad-dElia, H
    University of Gothenburg, Sweden .
    Wesamaa, J
    Örebro University Hospital, Sweden .
    Cedergren, Jan
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Rheumatology.
    Eriksson, Per
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Rheumatology.
    Söderkvist, P
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Genetic variants in CARD8 but not in NLRP3 are associated with ankylosing spondylitis2013In: Scandinavian Journal of Rheumatology, ISSN 0300-9742, E-ISSN 1502-7732, Vol. 42, no 6, p. 465-468Article in journal (Refereed)
    Abstract [en]

    Objectives: The NOD-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome is important for interleukin-1beta (IL-1 beta) processing as part of an innate immune response. Caspase recruitment domain family, member 8 (CARD8) is an inhibitor of nuclear factor kappa B (NF-kappa B) and possibly also a part of the NLRP3 inflammasome. The objective of this study was to evaluate one single nucleotide polymorphism (SNP) in CARD8 and three SNPs in NLRP3 in ankylosing spondylitis (AS) susceptibility and disease phenotype. less thanbrgreater than less thanbrgreater thanMethod: We recruited 492 AS patients from Southern Sweden fulfilling the modified New York criteria for AS, and assessed phenotypic characteristics from medical records and questionnaires. Patients with psoriasis or clinically overt inflammatory bowel disease (IBD) were excluded, as were patients without human leucocyte antigen B27 (HLA-B27). Three NLRP3 SNPs (rs35829419, rs4353135, and rs10733113) and one SNP in CARD8 (rs2043211) were genotyped by commercially available TaqMan assays, and the results compared at genotype and allele levels to those of 793 population-based controls. In a subgroup of the patients (n = 169), faecal calprotectin was assessed as a marker of subclinical intestinal inflammation. less thanbrgreater than less thanbrgreater thanResults: The minor allele (A) of CARD8-C10X (rs2043211) was associated with a decreased risk of AS in a dominant model [odds ratio (OR) 0.74, 95% confidence interval (CI) 0.54-0.94, p = 0.012] and at the allelic level (OR 0.81, 95% CI 0.68-0.97, p = 0.02), but was not associated with levels of faecal calprotectin. There was no association regarding NLRP3 SNPs and AS susceptibility, and none of the investigated SNPs were associated with iritis, anti-tumour necrosis factor (anti-TNF) therapy, or peripheral joint involvement. less thanbrgreater than less thanbrgreater thanConclusion: In a Swedish population, the minor allele of CARD8-C10X is associated with a decreased risk of AS, but not with levels of faecal calprotectin or disease phenotype.

  • 26.
    Kastbom, Alf
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences.
    Verma, Deepti
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Eriksson, Per
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences.
    Skogh, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences.
    Wingren, Gun
    Linköping University, Department of Clinical and Experimental Medicine, Occupational and Environmental Medicine. Linköping University, Faculty of Health Sciences.
    Söderkvist, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Genetic variation in proteins of the cryopyrin inflammasome influences susceptibility and severity of rheumatoid arthritis (the Swedish TIRA project)2008In: Rheumatology, ISSN 1462-0324, Vol. 47, no 4, p. 415-417Article in journal (Refereed)
    Abstract [en]

    Objectives: The genetic background to RA is incompletely understood.As new cytokine-targeted therapies emerge, early predictorsof disease severity are becoming increasingly important. Theinflammasomes are essential regulators of cytokine production.We investigated whether two polymorphisms in the genes encodingcryopyrin (CIAS1) and TUCAN (CARD8) influence susceptibilityand disease course in RA.

    Methods: Genotype frequencies were assessed in 174 Swedish patientswith early RA and 360 population-based controls without rheumaticdisease. Genotypes were categorized according to the presence(+) or absence (–) of two wild-type alleles and comparedbetween patients and controls. In the RA patients, antibodiestowards cyclic citrullinated peptides (anti-CCP) and the ‘sharedepitope’ (SE) were assessed, and medication and measuresof disease activity were monitored regularly during 3 yrs.

    Results: The combination of CIAS1/TUCAN/–, ascompared with CIAS1/TUCAN +/+, was significantly more commonamong patients than in controls [odds ratio (OR) 2.2, 95% CI1.03–4.6]. This association was strengthened when patientswere divided into anti-CCP+ [OR 2.8 (1.1–6.7)] or presenceof 1 SE copy [OR 2.8 (1.3–6.2)]. At most time-points duringthe 3-yr follow-up, patients with CIAS1/TUCAN/–showed significantly higher disease activity. Furthermore, CIAS1/TUCAN/– patients proved to be much more likely to receiveTNF-blocking therapy [relative risk 20 (2.6–149)].

    Conclusions: Compound polymorphisms in CIAS1 and TUCAN associatewith RA susceptibility and severity. The cryopyrin inflammasomeneeds further attention regarding a possible aetiopathogeneticconnection with RA.

  • 27.
    Kottyan, Leah C.
    et al.
    Division of Rheumatology, Center for Autoimmune Genomics and Etiology and US Department of Veterans Affairs Medical Center, Cincinnati, OH, USA .
    Zoller, Erin E.
    Division of Rheumatology, Center for Autoimmune Genomics and Etiology.
    Bene, Jessica
    Division of Rheumatology, Center for Autoimmune Genomics and Etiology.
    Lu, Xiaoming
    Division of Rheumatology, Center for Autoimmune Genomics and Etiology .
    Kelly, Jennifer A.
    Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA..
    Rupert, Andrew M.
    Division of Biomedical Informatics, Cincinnati Childrens Hospital Medical Center, Cincinnati, OH, USA..
    Lessard, Christopher J.
    Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA Department of Pathology .
    Vaughn, Samuel E.
    Division of Rheumatology, Center for Autoimmune Genomics and Etiology.
    Marion, Miranda
    Department of Biostatistical Sciences and Center for Public Health Genomics .
    Weirauch, Matthew T.
    Division of Rheumatology, Center for Autoimmune Genomics and Etiology and US Department of Veterans Affairs Medical Center, Cincinnati, OH, USA Division of Biomedical Informatics, Cincinnati Childrens Hospital Medical Center, Cincinnati, OH, USA..
    Namjou, Bahram
    Division of Rheumatology, Center for Autoimmune Genomics and Etiology .
    Adler, Adam
    Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA..
    Rasmussen, Astrid
    Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA..
    Glenn, Stuart
    Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA..
    Montgomery, Courtney G.
    Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA..
    Hirschfield, Gideon M.
    NIHR Biomedical Research Unit, University of Birmingham, Birmingham, UK..
    Xie, Gang
    Mount Sinai Hospital Samuel Lunenfeld Research Institute, Toronto, ON, Canada..
    Coltescu, Catalina
    Liver Centre, Toronto Western Hospital, Toronto, ON, Canada..
    Amos, Chris
    Department of Community and Family Medicine, Geisel School of Medicine, Dartmouth College, Hanover, NH, USA..
    Li, He
    Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA Department of Pathology and..
    Ice, John A.
    Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA..
    Nath, Swapan K.
    Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA..
    Mariette, Xavier
    Department of Rheumatology, Hôpitaux Universitaires Paris-Sud, INSERM U1012, Le Kremlin Bicêtre, France..
    Bowman, Simon
    Rheumatology Department, University Hospital Birmingham, Birmingham, UK..
    Rischmueller, Maureen
    The Queen Elizabeth Hospital, Adelaide, Australia..
    Lester, Sue
    The Queen Elizabeth Hospital, Adelaide, Australia The University of Adelaide, Adelaide, Australia..
    Brun, Johan G.
    Institute of Internal Medicine, University of Bergen, Bergen, Norway Department of Rheumatology, Haukeland University Hospital, Bergen, Norway..
    Gøransson, Lasse G.
    Clinical Immunology Unit, Department of Internal Medicine, Stavanger University Hospital, Stavanger, Norway..
    Harboe, Erna
    Clinical Immunology Unit, Department of Internal Medicine, Stavanger University Hospital, Stavanger, Norway..
    Omdal, Roald
    Clinical Immunology Unit, Department of Internal Medicine, Stavanger University Hospital, Stavanger, Norway..
    Cunninghame-Graham, Deborah S.
    Department of Medical and Molecular Genetics, Kings College London, London, UK..
    Vyse, Tim
    Department of Medical and Molecular Genetics, Kings College London, London, UK..
    Miceli-Richard, Corinne
    Department of Rheumatology, Hôpitaux Universitaires Paris-Sud, INSERM U1012, Le Kremlin Bicêtre, France..
    Brennan, Michael T.
    Department of Oral Medicine, Carolinas Medical Center, Charlotte, NC, USA..
    Lessard, James A.
    Valley Bone and Joint Clinic, Grand Forks, ND, USA..
    Wahren-Herlenius, Marie
    Department of Medicine, Karolinska Institute, Stockholm, Sweden..
    Kvarnström, Marika
    Department of Medicine, Karolinska Institute, Stockholm, Sweden..
    Illei, Gabor G.
    National Institute of Dental and Craniofacial Research, NIH, Bethesda, MD, USA..
    Witte, Torsten
    Hannover Medical School, Hanover, Germany..
    Jonsson, Roland
    Department of Rheumatology, Haukeland University Hospital, Bergen, Norway Broegelmann Research Laboratory, The Gade Institute, University of Bergen, Bergen, Norway..
    Eriksson, Per
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Rheumatology.
    Nordmark, Gunnel
    Department of Medical Sciences, Rheumatology, Uppsala University, Uppsala, Sweden..
    Ng, Wan-Fai
    Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK..
    Anaya, Juan-Manuel
    Center for Autoimmune Diseases Research (CREA), Universidad del Rosario, Bogotá, Colombia..
    Rhodus, Nelson N.
    Department of Oral Surgery, University of Minnesota School of Dentistry, Minneapolis, MN, USA..
    Segal, Barbara M.
    Division of Rheumatology, University of Minnesota Medical School, Minneapolis, MN, USA..
    Merrill, Joan T.
    Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA..
    James, Judith A.
    Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA..
    Guthridge, Joel M.
    Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA..
    Hal Scofield, R
    Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA Division of Veterans Affairs Medical Center, Oklahoma City, OK, USA Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA..
    Alarcon-Riquelme, Marta
    Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA de Genómica e Investigación Oncológica (GENYO), Pfizer-Universidad de Granada-Junta de Andalucia, Granada, Spain..
    Bae, Sang-Cheol
    Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul, South Korea..
    Boackle, Susan A.
    Division of Rheumatology, University of Colorado School of Medicine, Aurora, CO, USA..
    Criswell, Lindsey A.
    Division of Rheumatology, Rosalind Russell Medical Research Center for Arthritis, University of California San Francisco, San Francisco, CA, USA..
    Gilkeson, Gary
    Division of Rheumatology and Immunology, Medical University of South Carolina, Charleston, SC, USA..
    Kamen, Diane L
    Division of Rheumatology and Immunology, Medical University of South Carolina, Charleston, SC, USA..
    Jacob, Chaim O.
    Divison of Gastrointestinal and Liver Diseases, Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA..
    Kimberly, Robert
    Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA..
    Brown, Elizabeth
    Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA..
    Edberg, Jeffrey
    Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA..
    Alarcón, Graciela S.
    Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA..
    Reveille, John D.
    Division of Rheumatology and Clinical Immunogenetics, The Univeristy of Texas Health Science Center at Houston, Houston, TX, USA..
    Vilá, Luis M.
    University of Puerto Rico Medical Sciences Campus, San Juan, Puerto Rico, USA..
    Petri, Michelle
    Division of Rheumatology, Johns Hopkins, Baltimore, MD, USA..
    Ramsey-Goldman, Rosalind
    Division of Rheumatology, Northwestern University, Chicago, IL, USA..
    Freedman, Barry I.
    Wake Forest School of Medicine, Winston-Salem, NC, USA..
    Niewold, Timothy
    Division of Rheumatology and Immunology, Mayo Clinic, Rochester, MN, USA..
    Stevens, Anne M.
    University of Washington and Seattle Childrens Hospital, Seattle, WA, USA..
    Tsao, Betty P.
    David Geffen School of Medicine, University of California, Los Angeles, CA, USA..
    Ying, Jun
    MD Anderson Cancer Center, University of Texas, Houston, TX, USA..
    Mayes, Maureen D.
    MD Anderson Cancer Center, University of Texas, Houston, TX, USA..
    Gorlova, Olga Y.
    MD Anderson Cancer Center, University of Texas, Houston, TX, USA..
    Wakeland, Ward
    University of Texas Southwestern Medical School, Dallas, TX, USA..
    Radstake, Timothy
    Department of Rheumatology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands..
    Martin, Ezequiel
    Instituto de Parasitología y Biomedicina López Neyra Avda, Granada, Spain and..
    Martin, Javier
    Instituto de Parasitología y Biomedicina López Neyra Avda, Granada, Spain and..
    Siminovitch, Katherine
    Mount Sinai Hospital Samuel Lunenfeld Research Institute, Toronto, ON, Canada Department of Medicine, University of Toronto, Toronto, ON, Canada..
    Moser Sivils, Kathy L.
    Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA..
    Gaffney, Patrick M.
    Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA..
    Langefeld, Carl D.
    Department of Biostatistical Sciences and Center for Public Health Genomics and..
    Harley, John B.
    Division of Rheumatology, Center for Autoimmune Genomics and Etiology and US Department of Veterans Affairs Medical Center, Cincinnati, OH, USA..
    Kaufman, Kenneth M.
    Division of Rheumatology, Center for Autoimmune Genomics and Etiology and US Department of Veterans Affairs Medical Center, Cincinnati, OH, USA..
    The IRF5-TNPO3 association with systemic lupus erythematosus has two components that other autoimmune disorders variably share.2015In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 24, no 2, p. 582-596Article in journal (Refereed)
    Abstract [en]

    Exploiting genotyping, DNA sequencing, imputation and trans-ancestral mapping, we used Bayesian and frequentist approaches to model the IRF5-TNPO3 locus association, now implicated in two immunotherapies and seven autoimmune diseases. Specifically, in systemic lupus erythematosus (SLE), we resolved separate associations in the IRF5 promoter (all ancestries) and with an extended European haplotype. We captured 3230 IRF5-TNPO3 high-quality, common variants across 5 ethnicities in 8395 SLE cases and 7367 controls. The genetic effect from the IRF5 promoter can be explained by any one of four variants in 5.7 kb (P-valuemeta = 6 × 10(-49); OR = 1.38-1.97). The second genetic effect spanned an 85.5-kb, 24-variant haplotype that included the genes IRF5 and TNPO3 (P-valuesEU = 10(-27)-10(-32), OR = 1.7-1.81). Many variants at the IRF5 locus with previously assigned biological function are not members of either final credible set of potential causal variants identified herein. In addition to the known biologically functional variants, we demonstrated that the risk allele of rs4728142, a variant in the promoter among the lowest frequentist probability and highest Bayesian posterior probability, was correlated with IRF5 expression and differentially binds the transcription factor ZBTB3. Our analytical strategy provides a novel framework for future studies aimed at dissecting etiological genetic effects. Finally, both SLE elements of the statistical model appear to operate in Sjögrens syndrome and systemic sclerosis whereas only the IRF5-TNPO3 gene-spanning haplotype is associated with primary biliary cirrhosis, demonstrating the nuance of similarity and difference in autoimmune disease risk mechanisms at IRF5-TNPO3.

  • 28.
    Kurz, Tino
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences.
    Weiner, Maria
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Nephrology.
    Skoglund, Camilla
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences.
    Basnet, Sandeep
    Linköping University, Department of Medical and Health Sciences. Linköping University, Faculty of Health Sciences.
    Eriksson, Per
    Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Rheumatology.
    Segelmark, Mårten
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Nephrology.
    A myelopoiesis gene signature during remission in ANCA associated vasculitis does not predict relapses but seems to reflect ongoing prednisolone therapy2014In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 175, no 2, p. 215-226Article in journal (Refereed)
    Abstract [en]

    A myelopoiesis gene signature in circulating leucocytes, exemplified by increased myeloperoxidase (MPO) and proteinase 3 (PR3) mRNA levels, has been reported in patients with active anti-neutrophil cytoplasm antibody associated vasculitis (AAV) and to a lesser extent during remission. We hypothesized that this signature could predict disease relapse. mRNA levels of PR3, MPO, selected myelopoiesis transcription factors (CEBPA, CEBPB, SPIB, SPI1) and microRNAs (miRNAs) from patient and control peripheral blood mononuclear cells (PBMCs) and polymorphonuclear cells (PMNs) were analyzed and associated with clinical data. Patients in stable remission had higher mRNA levels for PR3 (PBMCs, PMNs) and MPO (PBMCs). PR3 and SPIB mRNA correlated positively in control but negatively in patient PBMCs. Statistically significant correlations existed between PR3 mRNA and several miRNAs in controls, but not in patients. PR3/MPO mRNA levels were not associated with previous or future relapses but correlated to steroid treatment. Prednisolone doses were negatively linked to SPIB and miR-155-5p, miR-339-5p (PBMCs) and to miR-221, miR-361, miR-505 (PMNs). PR3 mRNA in PBMCs correlated with time since last flare, blood leucocyte count and estimated glomerular filtration rate. Our results show that elevated leucocyte PR3 mRNA levels in AAV patients in remission do not predict relapse. The origin seems multifactorial, but to an important part explainable by prednisolone action. Gene signatures in patients with AAV undergoing steroid treatment should therefore be interpreted accordingly.

  • 29.
    Larsson, Martin
    et al.
    Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Faculty of Health Sciences.
    Persson, Anders
    Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Department of Medical and Health Sciences, Radiology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medical Imaging, Department of Radiology in Linköping.
    Eriksson, Per
    Linköping University, Department of Medical and Health Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Nephrology.
    Kihlberg, Johan
    Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Department of Medical and Health Sciences, Radiology. Linköping University, Faculty of Health Sciences.
    Smedby, Örjan
    Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Department of Medical and Health Sciences, Radiology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medical Imaging, Department of Radiology in Linköping.
    Renal artery stenosis: extracting quantitative parameters with a mathematical model fitted to magnetic resonance blood flow data2008In: Journal of Magnetic Resonance Imaging, ISSN 1053-1807, E-ISSN 1522-2586, Vol. 27, no 1, p. 140-147Article in journal (Refereed)
    Abstract [en]

    Purpose: To investigate the feasibility of quantitative parameter extraction from a mathematical model fitted to renal artery magnetic resonance flow data.

    Material and methods: Sixteen subjects, 8 patients and 8 normal controls, were examined with cine phase-contrast velocity measurements, and blood flow data from the aorta and both renal arteries were extracted by means of contour detection. A mathematical model with eight parameters describing the time, duration and amplitude of the systolic acceleration and the diastolic deceleration was fitted to the aorta and renal artery blood flow data from each subject. The curve fitting was evaluated with R2 values. Statistical analysis was performed with unpaired Wilcoxon tests and stepwise logistic regression.

    Results: Three data sets out of 48 yielded R2 values below 0.80 and were considered unreliable for parameter estimation. Basal flow was significantly, and systolic peak amplitude almost significantly, lower in stenotic arteries. Logistic regression indicated that two parameters describing basal flow and the duration of acceleration can accurately predict stenosis.

    Conclusion: The results suggest that it is technically feasible to fit a mathematical model to renal blood flow data, extracting quantitative parameters that may prove useful for quantification and diagnosis of renal artery stenosis.

  • 30.
    Lessard, Christopher J.
    et al.
    Oklahoma Medical Research Fdn, OK USA .
    Li, He
    Oklahoma Medical Research Fdn, OK USA .
    Adrianto, Indra
    Oklahoma Medical Research Fdn, OK USA .
    Ice, John A.
    Oklahoma Medical Research Fdn, OK USA .
    Rasmussen, Astrid
    Oklahoma Medical Research Fdn, OK USA .
    Grundahl, Kiely M.
    Oklahoma Medical Research Fdn, OK USA .
    Kelly, Jennifer A.
    Oklahoma Medical Research Fdn, OK USA .
    Dozmorov, Mikhail G.
    Oklahoma Medical Research Fdn, OK USA .
    Miceli-Richard, Corinne
    University of Paris 11, France .
    Bowman, Simon
    University Hospital Birmingham, England .
    Lester, Sue
    Queen Elizabeth Hospital, Australia .
    Eriksson, Per
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Rheumatology.
    Eloranta, Maija-Leena
    Uppsala University, Sweden .
    Brun, Johan G.
    University of Bergen, Norway .
    Goransson, Lasse G.
    Stavanger University Hospital, Norway .
    Harboe, Erna
    Stavanger University Hospital, Norway .
    Guthridge, Joel M.
    Oklahoma Medical Research Fdn, OK USA .
    Kaufman, Kenneth M.
    Cincinnati Childrens Hospital Medical Centre, OH USA .
    Kvarnstrom, Marika
    Karolinska Institute, Sweden .
    Jazebi, Helmi
    Karolinska Institute, Sweden .
    Cunninghame Graham, Deborah S.
    Kings Coll London, England .
    Grandits, Martha E.
    United Medical Specialties, MN USA .
    Nazmul-Hossain, Abu N M.
    University of Colorado, CO USA .
    Patel, Ketan
    University of Minnesota, MN USA .
    Adler, Adam J.
    Oklahoma Medical Research Fdn, OK USA .
    Maier-Moore, Jacen S.
    Oklahoma Medical Research Fdn, OK USA .
    Darise Farris, A
    Oklahoma Medical Research Fdn, OK USA .
    Brennan, Michael T.
    Carolinas Medical Centre, NC USA .
    Lessard, James A.
    Valley Bone and Joint Clin, ND USA .
    Chodosh, James
    Harvard University, MA USA .
    Gopalakrishnan, Rajaram
    University of Minnesota, MN USA .
    Hefner, Kimberly S.
    Hefner Eye Care and Opt Centre, OK USA .
    Houston, Glen D.
    University of Oklahoma, OK USA .
    Huang, Andrew J W.
    Washington University, MO USA .
    Hughes, Pamela J.
    University of Oklahoma, OK USA .
    Lewis, David M.
    University of Oklahoma, OK USA .
    Radfar, Lida
    University of Oklahoma, OK USA .
    Rohrer, Michael D.
    University of Minnesota, MN USA .
    Stone, Donald U.
    University of Oklahoma, OK USA .
    Wren, Jonathan D.
    Oklahoma Medical Research Fdn, OK USA .
    Vyse, Timothy J.
    Kings Coll London, England .
    Gaffney, Patrick M.
    Oklahoma Medical Research Fdn, OK USA .
    James, Judith A.
    Oklahoma Medical Research Fdn, OK USA .
    Omdal, Roald
    Stavanger University Hospital, Norway .
    Wahren-Herlenius, Marie
    Karolinska Institute, Sweden .
    Illei, Gabor G.
    National Institute Dent and Craniofacial Research, MD USA .
    Witte, Torsten
    Hannover Medical Sch, Germany .
    Jonsson, Roland
    Haukeland Hospital, Norway .
    Rischmueller, Maureen
    Queen Elizabeth Hospital, Australia .
    Ronnblom, Lars
    Uppsala University, Sweden .
    Nordmark, Gunnel
    Uppsala University, Sweden .
    Ng, Wan-Fai
    Newcastle University, England .
    Mariette, Xavier
    University of Paris 11, France .
    Anaya, Juan-Manuel
    University of Rosario, Colombia .
    Rhodus, Nelson L.
    University of Minnesota, MN USA .
    Segal, Barbara M.
    University of Minnesota, MN USA .
    Hal Scofield, R
    Oklahoma Medical Research Fdn, OK USA .
    Montgomery, Courtney G.
    Oklahoma Medical Research Fdn, OK USA .
    Harley, John B.
    Cincinnati Childrens Hospital Medical Centre, OH USA .
    Sivils, Kathy L.
    Oklahoma Medical Research Fdn, OK USA .
    Variants at multiple loci implicated in both innate and adaptive immune responses are associated with Sjogren's syndrome2013In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 45, no 11, p. 1284-+Article in journal (Refereed)
    Abstract [en]

    Sjogrens syndrome is a common autoimmune disease (affecting similar to 0.7% of European Americans) that typically presents as keratoconjunctivitis sicca and xerostomia. Here we report results of a large-scale association study of Sjogrens syndrome. In addition to strong association within the human leukocyte antigen (HLA) region at 6p21 (P-meta = 7.65 x 10(-114)), we establish associations with IRF5-TNPO3 (P-meta = 2.73 x 10(-19)), STAT4 (Pmeta = 6.80 x 10-15), IL12A (P-meta = 1.17 x 10(-10)), FAM167ABLK (P-meta = 4.97 x 10(-10)), DDX6-CXCR5 (P-meta = 1.10 x 10(-8)) and TNIP1 (P-meta = 3.30 x 10(-8)). We also observed suggestive associations (P-meta andlt; 5 x 10(-5)) with variants in 29 other regions, including TNFAIP3, PTTG1, PRDM1, DGKQ, FCGR2A, IRAK1BP1, ITSN2 and PHIP, among others. These results highlight the importance of genes that are involved in both innate and adaptive immunity in Sjogrens syndrome.

  • 31.
    Li, He
    et al.
    Oklahoma Medical Research Fdn, OK 73104 USA; University of Oklahoma, OK USA; University of Calif San Diego, CA 92093 USA.
    Ragna Reksten, Tove
    Oklahoma Medical Research Fdn, OK 73104 USA; University of Bergen, Norway.
    Ice, John A.
    Oklahoma Medical Research Fdn, OK 73104 USA.
    Kelly, Jennifer A.
    Oklahoma Medical Research Fdn, OK 73104 USA.
    Adrianto, Indra
    Oklahoma Medical Research Fdn, OK 73104 USA.
    Rasmussen, Astrid
    Oklahoma Medical Research Fdn, OK 73104 USA.
    Wang, Shaofeng
    Oklahoma Medical Research Fdn, OK 73104 USA.
    He, Bo
    Oklahoma Medical Research Fdn, OK 73104 USA; University of Oklahoma, OK USA.
    Grundahl, Kiely M.
    Oklahoma Medical Research Fdn, OK 73104 USA.
    Glenn, Stuart B.
    Oklahoma Medical Research Fdn, OK 73104 USA.
    Miceli-Richard, Corinne
    University of Paris Sud, France.
    Bowman, Simon
    University Hospital Birmingham, England.
    Lester, Sue
    Queen Elizabeth Hospital, Australia.
    Eriksson, Per
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Region Östergötland, Heart and Medicine Center, Department of Rheumatology. Linköping University, Faculty of Medicine and Health Sciences.
    Eloranta, Maija-Leena
    Uppsala University, Sweden.
    Brun, Johan G.
    University of Bergen, Norway; Haukeland Hospital, Norway.
    Goransson, Lasse G.
    Stavanger University Hospital, Norway.
    Harboe, Erna
    Stavanger University Hospital, Norway.
    Guthridge, Joel M.
    Oklahoma Medical Research Fdn, OK 73104 USA.
    Kaufman, Kenneth M.
    Cincinnati Childrens Hospital Medical Centre, OH 45229 USA; US Department Vet Affairs, OH USA.
    Kvarnstrom, Marika
    Karolinska Institute, Sweden.
    Cunninghame Graham, Deborah S.
    Kings Coll London, England.
    Patel, Ketan
    University of Minnesota, MN 55455 USA; North Mem Medical Centre, MN USA.
    Adler, Adam J.
    Oklahoma Medical Research Fdn, OK 73104 USA.
    Darise Farris, A.
    Oklahoma Medical Research Fdn, OK 73104 USA; University of Oklahoma, OK USA.
    Brennan, Michael T.
    Carolinas Medical Centre, NC 28203 USA.
    Chodosh, James
    Harvard Medical Sch, MA USA.
    Gopalakrishnan, Rajaram
    University of Minnesota, MN 55455 USA.
    Weisman, Michael H.
    Cedars Sinai Medical Centre, CA 90048 USA.
    Venuturupalli, Swamy
    Cedars Sinai Medical Centre, CA 90048 USA.
    Wallace, Daniel J.
    Cedars Sinai Medical Centre, CA 90048 USA.
    Hefner, Kimberly S.
    Cedars Sinai Medical Centre, CA 90048 USA; Hefner Eye Care and Opt Centre, OK USA.
    Houston, Glen D.
    University of Oklahoma, OK USA; Heartland Pathol Consultants, OK USA.
    Huang, Andrew J. W.
    Washington University, MO 63130 USA.
    Hughes, Pamela J.
    University of Minnesota, MN 55455 USA.
    Lewis, David M.
    University of Oklahoma, OK USA.
    Radfar, Lida
    University of Oklahoma, OK USA.
    Vista, Evan S.
    Oklahoma Medical Research Fdn, OK 73104 USA; University of Santo Tomas Hospital, Philippines.
    Edgar, Contessa E.
    Oklahoma Baptist University, OK USA.
    Rohrer, Michael D.
    University of Minnesota, MN 55455 USA.
    Stone, Donald U.
    Johns Hopkins University, MD USA.
    Vyse, Timothy J.
    Kings Coll London, England.
    Harley, John B.
    Cincinnati Childrens Hospital Medical Centre, OH 45229 USA; US Department Vet Affairs, OH USA.
    Gaffney, Patrick M.
    Oklahoma Medical Research Fdn, OK 73104 USA.
    James, Judith A.
    Oklahoma Medical Research Fdn, OK 73104 USA; University of Oklahoma, OK USA; University of Oklahoma, OK USA.
    Turner, Sean
    Oklahoma Medical Research Fdn, OK 73104 USA.
    Alevizos, Ilias
    National Institute Dent and Craniofacial Research, MD USA.
    Anaya, Juan-Manuel
    University of Rosario, Colombia.
    Rhodus, Nelson L.
    University of Minnesota, MN 55455 USA.
    Segal, Barbara M.
    University of Minnesota, MN 55455 USA.
    Montgomery, Courtney G.
    Oklahoma Medical Research Fdn, OK 73104 USA.
    Hal Scofield, R.
    Oklahoma Medical Research Fdn, OK 73104 USA; University of Oklahoma, OK USA; US Department Vet Affairs, OK USA.
    Kovats, Susan
    Oklahoma Medical Research Fdn, OK 73104 USA.
    Mariette, Xavier
    University of Paris Sud, France.
    Ronnblom, Lars
    Uppsala University, Sweden.
    Witte, Torsten
    Hannover Medical Sch, Germany.
    Rischmueller, Maureen
    Queen Elizabeth Hospital, Australia; University of Adelaide, Australia.
    Wahren-Herlenius, Marie
    Karolinska Institute, Sweden.
    Omdal, Roald
    Stavanger University Hospital, Norway.
    Jonsson, Roland
    University of Bergen, Norway; Haukeland Hospital, Norway.
    Ng, Wan-Fai
    Newcastle University, England; Newcastle University, England.
    Nordmark, Gunnel
    Uppsala University, Sweden.
    Lessard, Christopher J.
    Oklahoma Medical Research Fdn, OK 73104 USA; University of Oklahoma, OK USA.
    Sivils, Kathy L.
    Oklahoma Medical Research Fdn, OK 73104 USA; University of Oklahoma, OK USA.
    Identification of a Sjögrens syndrome susceptibility locus at OAS1 that influences isoform switching, protein expression, and responsiveness to type I interferons2017In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 13, no 6, article id e1006820Article in journal (Refereed)
    Abstract [en]

    Sjogrens syndrome (SS) is a common, autoimmune exocrinopathy distinguished by keratoconjunctivitis sicca and xerostomia. Patients frequently develop serious complications including lymphoma, pulmonary dysfunction, neuropathy, vasculitis, and debilitating fatigue. Dysregulation of type I interferon (IFN) pathway is a prominent feature of SS and is correlated with increased autoantibody titers and disease severity. To identify genetic determinants of IFN pathway dysregulation in SS, we performed cis-expression quantitative trait locus (eQTL) analyses focusing on differentially expressed type I IFN-inducible transcripts identified through a transcriptome profiling study. Multiple cis-eQTLs were associated with transcript levels of 2-5-oligoadenylate synthetase 1 (OAS1) peaking at rs10774671 (PeQTL = 6.05 x 10(-14)). Association of rs10774671 with SS susceptibility was identified and confirmed through meta-analysis of two independent cohorts (P-meta = 2.59 x 10(-9); odds ratio = 0.75; 95% confidence interval = 0.66-0.86). The risk allele of rs10774671 shifts splicing of OAS1 from production of the p46 isoform to multiple alternative transcripts, including p42, p48, and p44. We found that the isoforms were differentially expressed within each genotype in controls and patients with and without autoantibodies. Furthermore, our results showed that the three alternatively spliced isoforms lacked translational response to type I IFN stimulation. The p48 and p44 isoforms also had impaired protein expression governed by the 3 end of the transcripts. The SS risk allele of rs10774671 has been shown by others to be associated with reduced OAS1 enzymatic activity and ability to clear viral infections, as well as reduced responsiveness to IFN treatment. Our results establish OAS1 as a risk locus for SS and support a potential role for defective viral clearance due to altered IFN response as a genetic pathophysiological basis of this complex autoimmune disease.

  • 32.
    Lindvall, Björn
    et al.
    Linköping University, Department of Neuroscience and Locomotion, Neurology. Linköping University, Faculty of Health Sciences.
    Bengtsson, Ann
    Linköping University, Department of Molecular and Clinical Medicine, Rheumatology. Linköping University, Faculty of Health Sciences.
    Ernerudh, Jan
    Linköping University, Department of Molecular and Clinical Medicine, Clinical Immunology. Linköping University, Faculty of Health Sciences.
    Eriksson, Per
    Linköping University, Department of Molecular and Clinical Medicine, Rheumatology. Linköping University, Faculty of Health Sciences.
    Subclinical myositis is common in primary Sjögren's syndrome and is not related to muscle pain2002In: Journal of Rheumatology, ISSN 0315-162X, E-ISSN 1499-2752, Vol. 29, no 4, p. 717-725Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Although muscle pain is common in primary Sjögren's syndrome (SS), the underlying mechanisms are mainly unknown. We studied all patients with SS at our rheumatology unit with respect to muscle pain in general and to fibromyalgia (FM), and correlated clinical data to muscle biopsy findings.

    METHODS: We investigated 48 patients with SS according to the modified European diagnostic criteria. The ACR criteria for FM were used to subgroup the patients. Muscle biopsy was performed in 36 patients. Light microscope morphology and immunohistochemical expression of MHC class I, MHC class II, and membrane attack complex (MAC) were studied.

    RESULTS: We found 44% of patients complained of muscle pain; 27% fulfilled the ACR criteria for FM, whereas 17% had other forms of myalgia. Muscle pain could not be related to histopathological findings. Signs of inflammation were found in 26 of 36 biopsies (72%), and inflammation combined with degeneration/regeneration (i.e., histological signs of polymyositis) in 17 biopsies (47%). However, only 5 patients (14%) had clinical as well as histological signs of polymyositis. Eight muscle biopsies (22%) showed histological features of inclusion body myositis (IBM). However, no patient had clinical symptoms suggestive of this disease. Abnormal expression of MHC class I, MHC class II, and MAC was found in 18 (50%), 16 (44%), and 27 (75%) patients, respectively.

    CONCLUSION: Muscle pain, especially FM, is common in SS. Histopathological signs of myositis are very common in SS. However, muscle symptoms are not related to histological signs of muscle inflammation. IBM-like findings may represent vacuolar myopathic degeneration due to previous subclinical muscle inflammation rather than a specific clinical entity.

  • 33.
    Lindvall, Björn
    et al.
    Linköping University, Department of Neuroscience and Locomotion, Neurology. Linköping University, Faculty of Health Sciences.
    Eriksson, Per
    Linköping University, Department of Molecular and Clinical Medicine, Rheumatology. Linköping University, Faculty of Health Sciences.
    Ernerudh, Jan
    Linköping University, Department of Molecular and Clinical Medicine, Clinical Immunology. Linköping University, Faculty of Health Sciences.
    Inclusion body myopathy in Primary Sjögren's syndrome: clinical and histopathological features in relation to sporadic inclusion body myositisManuscript (preprint) (Other academic)
    Abstract [en]

    Inclusion body myositis (IBM) is a chronic, acquired inflammatory myopathy with typical clinical symptoms and characteristic histopathological features in muscle biopsy. However, there are still uncertainties in diagnostic criteria, implying that disorders of potentially different origin may be classified as IBM. In particular, muscle biopsy findings of vacuolar myopathy in Sjögren's syndrome have indicated an association with IBM, and so far vacuolar Sjögren myopathy is included in the IBM entity.

    We therefore compared clinical and histopathological features in a group of patients with sporadic-IBM (s-IBM, n=11) with a group of patients with primary Sjögren's syndrome (pSS) with IBM-like findings in their muscle biopsies (n=10). Biopsies from s-IBM but not from Sjögren patients stained for Congo-red, whereas no other obvious differences were fonnd concerning morphological or biochemical fmdings of vacuolar content (hyperphosphorylated tau-protein: SMI 31 and SMI 310, ubiquitin, tau-protein, ß-amyloid, ß-amyloid precursor protein). Striking differences were fonnd in the clinical picture, age of onset and gender preponderance (females in pSS and males in s-IBM).

    Based on the different clinical features and the difference in Congo-red staining, we suggest that vacuolar myopathy in pSS should be regarded as a separate entity, not to be included in the classical s-IBM group. IBM-like fmdings in muscle biopsy are observed in different types of systemic inflammatory diseases, and could preferably be designated as autoimmune associated IBM (a-IBM).

  • 34.
    Liu, Ke
    et al.
    University of Cincinnati, OH USA; Cincinnati Childrens Hospital Medical Centre, OH 45229 USA.
    Kurien, Biji T.
    University of Oklahoma, OK 73190 USA; Oklahoma City VA Medical Centre, OK USA.
    Zimmerman, Sarah L.
    Cincinnati Childrens Hospital Medical Centre, OH 45229 USA.
    Kaufman, Kenneth M.
    Cincinnati Childrens Hospital Medical Centre, OH 45229 USA; Cincinnati VA Medical Centre, OH USA.
    Taft, Diana H.
    Cincinnati Childrens Hospital Medical Centre, OH 45229 USA.
    Kottyan, Leah C.
    Cincinnati Childrens Hospital Medical Centre, OH 45229 USA.
    Lazaro, Sara
    Cincinnati Childrens Hospital Medical Centre, OH 45229 USA.
    Weaver, Carrie A.
    Cincinnati Childrens Hospital Medical Centre, OH 45229 USA.
    Ice, John A.
    Oklahoma Medical Research Fdn, OK 73104 USA.
    Adler, Adam J.
    Oklahoma City VA Medical Centre, OK USA; Oklahoma Medical Research Fdn, OK 73104 USA.
    Chodosh, James
    Massachusetts Eye and Ear Infirm, MA 02114 USA; Harvard University, MA USA.
    Radfar, Lida
    University of Oklahoma, OK USA; University of Oklahoma, OK USA.
    Rasmussen, Astrid
    Oklahoma Medical Research Fdn, OK 73104 USA.
    Stone, Donald U.
    University of Oklahoma, OK USA; University of Oklahoma, OK 73190 USA.
    Lewis, David M.
    University of Oklahoma, OK USA; University of Oklahoma, OK USA.
    Li, Shibo
    University of Oklahoma, OK USA; University of Oklahoma, OK 73190 USA.
    Koelsch, Kristi A.
    Oklahoma Medical Research Fdn, OK 73104 USA.
    Igoe, Ann
    Oklahoma Medical Research Fdn, OK 73104 USA.
    Talsania, Mitali
    University of Oklahoma, OK USA; University of Oklahoma, OK 73190 USA.
    Kumar, Jay
    Oklahoma Medical Research Fdn, OK 73104 USA.
    Maier-Moore, Jacen S.
    University of Oklahoma, OK 73190 USA; Oklahoma City VA Medical Centre, OK USA; University of Texas El Paso, TX 79968 USA.
    Harris, Valerie M.
    Oklahoma Medical Research Fdn, OK 73104 USA.
    Gopalakrishnan, Rajaram
    University of Minnesota, MN USA.
    Jonsson, Roland
    University of Bergen, Norway; Haukeland Hospital, Norway.
    Lessard, James A.
    Valley Bone and Joint Clin, ND USA.
    Lu, Xianglan
    University of Oklahoma, OK USA; University of Oklahoma, OK 73190 USA.
    -Eric Gottenberg, Jacques
    Strasbourg University, France.
    -Manuel Anaya, Juan
    University of Rosario, Colombia.
    Cunninghame-Graham, Deborah S.
    Kings Coll London, England.
    Huang, Andrew J. W.
    University of Minnesota, MN USA.
    Brennan, Michael T.
    Carolinas Medical Centre, NC 28203 USA.
    Hughes, Pamela
    University of Minnesota, MN USA.
    Mei, Gabor G.
    MedImmune, MD USA; National Institute Dent and Craniofacial Research, MD USA.
    Miceli-Richard, Corinne
    University of Paris 11, France; INSERM, France.
    Keystone, Edward C.
    Mt Sinai Hospital, Canada; University of Toronto, Canada.
    Bykerk, Vivian P.
    Mt Sinai Hospital, Canada; University of Toronto, Canada; Hospital Special Surg, NY 10021 USA; Weill Cornell Med, NY USA.
    Hirschfield, Gideon
    University of Birmingham, England.
    Xie, Gang
    Mt Sinai Hospital, Canada; University of Toronto, Canada; Toronto Gen Hospital, Canada.
    Ng, Wan-Fai
    NIHR Newcastle Biomed Research Centre, England.
    Nordmark, Gunnel
    Uppsala University, Sweden.
    Eriksson, Per
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Region Östergötland, Heart and Medicine Center, Department of Rheumatology. Linköping University, Faculty of Medicine and Health Sciences. Newcastle University, England.
    Omda, Roald
    Stavanger University Hospital, Norway.
    Rhodus, Nelson L.
    University of Minnesota, MN 55455 USA.
    Rischmueller, Maureen
    Queen Elizabeth Hospital, Australia; University of Adelaide, Australia.
    Rohrer, Michael
    University of Minnesota, MN USA.
    Sega, Barbara M.
    University of Minnesota, MN 55455 USA; Hennepin County Medical Centre, MN 55415 USA.
    Vvse, Timothy J.
    Kings Coll London, England.
    Wahren-Herlenius, Marie
    Karolinska Institute, Sweden.
    Witte, Torsten
    Hannover Medical Sch, Germany.
    Pons-Este, Bernardo
    Sanatorio Parque, Argentina.
    Alarcon-Riquelme, Marta E.
    Oklahoma Medical Research Fdn, OK 73104 USA; Centre Pfizer University of Granada Junta de Andalucia Genom, Spain.
    Guthridge, Joel M.
    Oklahoma Medical Research Fdn, OK 73104 USA.
    James, Judith A.
    Oklahoma Medical Research Fdn, OK 73104 USA.
    Lessard, Christopher J.
    Oklahoma Medical Research Fdn, OK 73104 USA.
    Kelly, Jennifer A.
    Oklahoma Medical Research Fdn, OK 73104 USA.
    Thompson, Susan D.
    University of Cincinnati, OH USA; Cincinnati Childrens Hospital Medical Centre, OH 45229 USA.
    Gaffney, Patrick M.
    Oklahoma Medical Research Fdn, OK 73104 USA.
    Montgomery, Courtney G.
    Oklahoma Medical Research Fdn, OK 73104 USA.
    Edberg, Jeffrey C.
    University of Alabama Birmingham, AL USA.
    Kimberly, Robert P.
    University of Alabama Birmingham, AL USA.
    Alarcon, Gracicla S.
    University of Alabama Birmingham, AL USA.
    Langefeld, Carl L.
    Wake Forest University, NC 27109 USA.
    Gilkeson, Gary S.
    Medical University of S Carolina, SC USA.
    Kamen, Diane L.
    Medical University of S Carolina, SC USA.
    Tsao, Betty P.
    University of Calif Los Angeles, CA 90095 USA.
    Joseph McCune, W.
    University of Michigan, MI 48109 USA.
    Salmon, Jane E.
    Hospital Special Surg, NY 10021 USA; Weill Cornell Med, NY USA.
    Merrill, Joan T.
    University of Oklahoma, OK USA; University of Oklahoma, OK 73190 USA.
    Weisman, Michael H.
    Cedars Sinai Medical Centre, CA 90048 USA.
    Wallace, Daniel J.
    Cedars Sinai Medical Centre, CA 90048 USA; University of Calif Los Angeles, CA 90095 USA.
    Utset, Tammy
    University of Chicago, IL 60637 USA.
    Bottinger, Erwin P.
    Mt Sinai Hospital, NY 10029 USA.
    Amos, Christopher I.
    Dartmouth Coll, NH 03755 USA.
    Siminovitch, Katherine A.
    Mt Sinai Hospital, Canada; University of Toronto, Canada; Toronto Gen Hospital, Canada.
    Mariette, Xavier
    University of Paris 11, France; INSERM, France.
    Sivils, Kathy L.
    Oklahoma Medical Research Fdn, OK 73104 USA.
    Harley, John B.
    University of Cincinnati, OH USA; Cincinnati Childrens Hospital Medical Centre, OH 45229 USA; Cincinnati VA Medical Centre, OH USA.
    Hal Scofield, R.
    University of Oklahoma, OK 73190 USA; Oklahoma City VA Medical Centre, OK USA.
    X Chromosome Dose and Sex Bias in Autoimmune Diseases2016In: Arthritis & Rheumatology, ISSN 2326-5191, E-ISSN 2326-5205, Vol. 68, no 5, p. 1290-1300Article in journal (Refereed)
    Abstract [en]

    Objective. More than 80% of autoimmune disease predominantly affects females, but the mechanism for this female bias is poorly understood. We suspected that an X chromosome dose effect accounts for this, and we undertook this study to test our hypothesis that trisomy X (47, XXX; occurring in similar to 1 in 1,000 live female births) would be increased in patients with female-predominant diseases (systemic lupus erythematosus [SLE], primary Sjogrens syndrome [SS], primary biliary cirrhosis, and rheumatoid arthritis [RA]) compared to patients with diseases without female predominance (sarcoidosis) and compared to controls. Methods. All subjects in this study were female. We identified subjects with 47, XXX using aggregate data from single-nucleotide polymorphism arrays, and, when possible, we confirmed the presence of 47, XXX using fluorescence in situ hybridization or quantitative polymerase chain reaction. Results. We found 47, XXX in 7 of 2,826 SLE patients and in 3 of 1,033 SS patients, but in only 2 of 7,074 controls (odds ratio in the SLE and primary SS groups 8.78 [95% confidence interval 1.67-86.79], P = 0.003 and odds ratio 10.29 [95% confidence interval 1.18-123.47], P = 0.02, respectively). One in 404 women with SLE and 1 in 344 women with SS had 47, XXX. There was an excess of 47, XXX among SLE and SS patients. Conclusion. The estimated prevalence of SLE and SS in women with 47, XXX was similar to 2.5 and similar to 2.9 times higher, respectively, than that in women with 46, XX and similar to 25 and similar to 41 times higher, respectively, than that in men with 46, XY. No statistically significant increase of 47, XXX was observed in other female-biased diseases (primary biliary cirrhosis or RA), supporting the idea of multiple pathways to sex bias in autoimmunity.

  • 35.
    Mohammad, Aladdin J
    et al.
    Lunds University, Addenbrooke's Hospital Cambridge UK.
    Weiner, Maria
    Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Region Östergötland, Heart and Medicine Center, Department of Nephrology.
    Sjöwall, Christopher
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Rheumatology.
    Johansson, Martin E
    Lund University, Malmö .
    Bengtsson, Anders A
    Lund University, Lund .
    Ståhl-Hallengren, Christina
    Helsingborg Hospital .
    Nived, Ola
    Lund University.
    Eriksson, Per
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Rheumatology.
    Sturfelt, Gunnar
    Lund University.
    Segelmark, Mårten
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Nephrology. Linköping University, Faculty of Health Sciences.
    Incidence and disease severity of anti-neutrophil cytoplasmic antibody-associated nephritis are higher than in lupus nephritis in Sweden.2015In: Nephrology, Dialysis and Transplantation, ISSN 0931-0509, E-ISSN 1460-2385, Vol. 30, p. i23-i30Article in journal (Refereed)
    Abstract [en]

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

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

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

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

  • 36.
    Nordmark, G
    et al.
    Uppsala University.
    Kristjansdottir, G
    Uppsala University.
    Theander, E
    Malmö University Hospital.
    Appel, S
    University of Bergen, Norway.
    Eriksson, Per
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Nephrology UHL.
    Vasaitis, L
    Uppsala University.
    Kvarnström, M
    Karolinska Institutet, Stockholm.
    Delaleu, N
    University of Bergen, Norway.
    Lundmark, P
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences.
    Lundmark, A
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences.
    Sjöwall, Christopher
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Rheumatology in Östergötland.
    Brun, J G
    Haukeland Hospital, Bergen, Norway.
    Jonsson, M V
    University of Bergen, Norway.
    Harboe, E
    Stavanger University Hospital, Norway.
    Gøransson, L G
    Stavanger University Hospital, Norway.
    Johnsen, S J
    Stavanger University Hospital, Norway.
    Söderkvist, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Eloranta, M-L
    Uppsala University.
    Alm, G
    Swedish University of Agricultural Sciences, Uppsala.
    Baecklund, E
    Uppsala University.
    Wahren-Herlenius, M
    Karolinska Institutet, Stockholm.
    Omdal, R
    Stavanger University Hospital, Norway.
    Rönnblom, L
    Uppsala University.
    Jonsson, R
    University of Bergen, Norway.
    Syvänen, A-C
    Uppsala University.
    Association of EBF1, FAM167A(C8orf13)-BLK andTNFSF4 gene variants with primary Sjo¨gren’s syndrome2011In: Genes and Immunity, ISSN 1466-4879, E-ISSN 1476-5470, Vol. 12, no 2, p. 100-109Article in journal (Refereed)
    Abstract [en]

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

  • 37.
    Nordmark, G
    et al.
    Uppsala University.
    Kristjansdottir, G
    Uppsala University.
    Theander, E
    Malmö University Hospital.
    Eriksson, Per
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Rheumatology in Östergötland.
    Brun, J G
    Haukeland Hospital.
    Wang, C
    Uppsala University.
    Padyukov, L
    Karolinska University Hospital.
    Truedsson, L
    Lund University.
    Alm, G
    Swedish University of Agriculture Science.
    Eloranta, M-L
    Uppsala University.
    Jonsson, R
    Haukeland Hospital.
    Ronnblom, L
    Uppsala University.
    Syvanen, A-C
    Uppsala University.
    Additive effects of the major risk alleles of IRF5 and STAT4 in primary Sjogrens syndrome2009In: GENES AND IMMUNITY, ISSN 1466-4879, Vol. 10, no 1, p. 68-76Article in journal (Refereed)
    Abstract [en]

    Primary Sjogrens syndrome (SS) shares many features with systemic lupus erythematosus (SLE). Here we investigated the association of the three major polymorphisms in IRF5 and STAT4 found to be associated with SLE, in patients from Sweden and Norway with primary SS. These polymorphisms are a 5-bp CGGGG indel in the promoter of IRF5, the single nucleotide polymorphism (SNP) rs10488631 downstream of IRF5 and the STAT4 SNP rs7582694, which tags the major risk haplotype of STAT4. We observed strong signals for association between all three polymorphisms and primary SS, with odds ratios (ORs) > 1.4 and P-values < 0.01. We also found a strong additive effect of the three risk alleles of IRF5 and STAT4 with an overall significance between the number of risk alleles and primary SS of P = 2.5 x 10(-9). The OR for primary SS increased in an additive manner, with an average increase in OR of 1.78. For carriers of two risk alleles, the OR for primary SS is 1.43, whereas carriers of five risk alleles have an OR of 6.78. IRF5 and STAT4 are components of the type I IFN system, and our findings emphasize the importance of this system in the etiopathogenesis of primary SS.

  • 38.
    Nordmark, Gunnel
    et al.
    University Uppsala Hospital.
    Kristjansdotti, Gudlaug
    Uppsala University.
    Theander, Elke
    Lund University.
    Appel, Silke
    University of Bergen.
    Eriksson, Per
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Rheumatology in Östergötland.
    Vasaitis, Lilian
    University Uppsala Hospital.
    Wahren-Herlenius, Marie
    Karolinska Institute.
    Omdal, Roald
    University of Bergen.
    Ronnblom, Lars
    University Uppsala Hospital.
    Jonsson, Roland
    Uppsala University.
    GENE VARIANTS IN FAM167A-BLK AND TNFSF4 ARE ASSOCIATED WITH PRIMARY SJOGRENS SYNDROME in SCANDINAVIAN JOURNAL OF RHEUMATOLOGY, vol 39, issue , pp 32-322010In: SCANDINAVIAN JOURNAL OF RHEUMATOLOGY, Informa Healthcare , 2010, Vol. 39, p. 32-32Conference paper (Refereed)
    Abstract [en]

    n/a

  • 39.
    Nordmark, Gunnel
    et al.
    Uppsala University, Sweden .
    Wang, Chuan
    Uppsala University, Sweden .
    Vasaitis, Lilian
    Uppsala University, Sweden .
    Eriksson, Per
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Rheumatology.
    Theander, Elke
    Lund University, Sweden .
    Kvarnström, Marika
    Karolinska Institutet, Stockholm, Sweden.
    Forsblad-d'Elia, Helena
    University of Gothenburg, Sweden .
    Jazebi, Helmi
    Karolinska Institutet, Stockholm, Sweden.
    Sjöwall, Christoffer
    Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Rheumatology.
    Reksten, Tove Ragna
    University of Bergen, Norway .
    Brun, Johan G.
    Haukeland University Hospital, Bergen, Norway.
    Jonsson, Malin V.
    University of Bergen, Norway .
    Johnsen, Svein J.
    Stavanger University Hospital, Norway .
    Wahren-Herlenius, Marie
    Karolinska Institutet, Stockholm, Sweden.
    Omdal, Roald
    Stavanger University Hospital, Norway .
    Jonsson, Roland
    University of Bergen, Norway.
    Bowman, Simon
    University Hospital Birmingham, UK.
    Ng, Wan-Fai
    Newcastle University, UK.
    Eloranta, Maija-Leena
    Uppsala University, Sweden .
    Syvänen, Ann-Christine
    Uppsala University, Sweden .
    Association of Genes in the NF-κB Pathway with Antibody-Positive Primary Sjögren's Syndrome2013In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 78, no 5, p. 447-454Article in journal (Refereed)
    Abstract [en]

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

  • 40.
    Reksten, Tove Ragna
    et al.
    University of Bergen, Norway / Uppsala University, Sweden .
    Johnsen, Svein Joar Auglænd
    Stavanger University Hospital, Norway.
    Jonsson, Malin Viktoria
    University of Bergen, Norway .
    Omdal, Roald
    Stavanger University Hospital, Norway.
    Brun, Johan G
    University of Bergen, Norway .
    Theander, Elke
    Skåne University Hospital, Lund University, Malmö, Sweden .
    Eriksson, Per
    Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Rheumatology.
    Wahren-Herlenius, Marie
    Karolinska Institutet, Stockholm, Sweden .
    Jonsson, Roland
    University of Bergen, Norway / Haukeland University Hospital, Bergen, Norway .
    Nordmark, Gunnel
    Uppsala University, Sweden.
    Genetic associations to germinal centre formation in primary Sjogren's syndrome2014In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 73, no 6, p. 1253-1258Article in journal (Refereed)
    Abstract [en]

    Background Primary Sjögren's syndrome (pSS) is an autoimmune rheumatic disease mainly characterised by focal mononuclear cell infiltration in the salivary and lacrimal glands, and by the symptoms xerostomia and keratoconjunctivitis sicca. Germinal centre-like structures (GC) are found in the minor salivary glands of approximately 25% of patients. In this study, we aimed to assess genetic variations in pSS patients with GC-like formations (GC+) compared with patients without such formations (GC−).                                

    Methods Minor salivary gland biopsies from Swedish and Norwegian pSS patients (n=320) were evaluated for GC-like formations, identifying 76 GC+ and 244 GC− patients. A panel of 1536 single-nucleotide polymorphisms (SNPs) in 107 genes was genotyped. Minor allele frequencies in GC+ and GC− patients were compared using Fisher's exact test, and associations were considered significant when p<4.7×10−4 and suggestive when p<0.01.                                

    Results In this case-only analysis, we identified two SNPs in CCL11 (eotaxin) associated with GC-like structures (p<4.7×10−4, OR 0.45 and 0.41, respectively). A haplotype of the two minor alleles was associated with GC status with p=2.6×10−4, OR 0.40. Suggestive associations (p<0.01) were found in SNPs in the B cell activation and/or GC-formation related genes AICDA, BANK1 and BCL2. Furthermore, SNPs in IL17A, ICA1, PKN1 and SNPs in the NF-κB pathway genes CARD8, IKBKE and TANK were found suggestively associated with GC-like structures.                                

    Conclusions Our findings suggest that genetic variations may explain why ectopic GC-like structures are present in some pSS patients, and support the hypothesis that GC+ and GC− patients represent distinct disease phenotypes.

  • 41.
    Rusakiewicz, Sylvie
    et al.
    Institut Gustave Roussy (IGR), Villejuif, France .
    Nocturne, Gaetane
    Université Paris-Sud, Le Kremlin Bicêtre, France.
    Lazure, Thierry
    Hôpitaux Universitaires Paris-Sud, Le Kremlin Bicêtre, France. .
    Semeraro, Michaela
    Institut Gustave Roussy (IGR), Villejuif, France .
    Flament, Caroline
    Institut Gustave Roussy (IGR), Villejuif, France .
    Caillat-Zucman, Sophie
    Hôpital St-Vincent de Paul, Paris, France.
    Sene, Damien
    Hôpital St-Vincent de Paul, Paris, France.
    Delahaye, Nicolas
    Institut Gustave Roussy (IGR), Villejuif, France .
    Vivier, Eric
    Centre d'Immunologie Marseille Luminy, INSERM, U1104, France.
    Chaba, Kariman
    Institut Gustave Roussy (IGR), Villejuif, France .
    Poirier-Colame, Vichnou
    Institut Gustave Roussy (IGR), Villejuif, France .
    Nordmark, Gunnel
    Uppsala University, Sweden .
    Eloranta, Maija-Leena
    Uppsala University, Sweden .
    Eriksson, Per
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Rheumatology.
    Theander, Elke
    Skåne University Hospital, Lund University, Malmö, Sweden.
    Forsblad-dElia, Helena
    Sahlgrenska Academy at University of Gothenburg, Sweden.
    Omdal, Roald
    Stavanger University Hospital, Norway .
    Wahren-Herlenius, Marie
    Karolinska Institutet, Stockholm, Sweden.
    Jonsson, Roland
    University of Bergen, Norway .
    Rönnblom, Lars
    Uppsala University, Sweden .
    Nititham, Joanne
    University of California, San Francisco, USA .
    Taylor, Kimberly E.
    University of California, San Francisco, USA .
    Lessard, Christopher J.
    University of Oklahoma Health Sciences Center, Oklahoma City, USA .
    Moser Sivils, Kathy L.
    University of Oklahoma Health Sciences Center, Oklahoma City, USA .
    Gottenberg, Jacques-Eric
    Strasbourg University Hospital, France .
    Criswell, Lindsey A.
    University of California, San Francisco, USA .
    Miceli-Richard, Corinne
    Institut Gustave Roussy (IGR), Villejuif, France .
    Zitvogel, Laurence
    Institut Gustave Roussy (IGR), Villejuif, France .
    Mariette, Xavier
    Université Paris-Sud, Le Kremlin Bicêtre, France.
    NCR3/NKp30 Contributes to Pathogenesis in Primary Sjögren’s Syndrome2013In: Science Translational Medicine, ISSN 1946-6234, E-ISSN 1946-6242, Vol. 5, no 195Article in journal (Refereed)
    Abstract [en]

    Primary Sjögrens syndrome (pSS) is a chronic autoimmune disease characterized by a lymphocytic exocrinopathy. However, patients often have evidence of systemic autoimmunity, and they are at markedly increased risk for the development of non-Hodgkins lymphoma. Similar to other autoimmune disorders, a strong interferon (IFN) signature is present among subsets of pSS patients, although the precise etiology remains uncertain. NCR3/NKp30 is a natural killer (NK)-specific activating receptor regulating the cross talk between NK and dendritic cells and type II IFN secretion. We performed a case-control study of genetic polymorphisms of the NCR3/NKp30 gene and found that rs11575837 (Gandgt;A) residing in the promoter was associated with reduced gene transcription and function as well as protection to pSS. We also demonstrated that circulating levels of NCR3/NKp30 were significantly increased among pSS patients compared with controls and correlated with higher NCR3/NKp30 but not CD16-dependent IFN-gamma secretion by NK cells. Excess accumulation of NK cells in minor salivary glands correlated with the severity of the exocrinopathy. B7H6, the ligand of NKp30, was expressed by salivary epithelial cells. These findings suggest that NK cells may promote an NKp30-dependent inflammatory state in salivary glands and that blockade of the B7H6/NKp30 axis could be clinically relevant in pSS.

  • 42.
    Sahdo, Berolla
    et al.
    Örebro University, Sweden.
    Fransén, Karin
    Örebro University, Sweden.
    Asfaw Idosa, Berhane
    Örebro University, Sweden.
    Eriksson, Per
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Rheumatology.
    Söderquist, Bo
    Örebro University Hospital, Sweden.
    Kelly, Anne
    Örebro University Hospital and Örebro University, Sweden.
    Särndahl, Eva
    Örebro University, Sweden.
    Cytokine Profile in a Cohort of Healthy Blood Donors Carrying Polymorphisms in Genes Encoding the NLRP3 Inflammasome2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 10Article in journal (Refereed)
    Abstract [en]

    Background: The NLRP3 inflammasome has been recognized as one of the key components of the innate immunity by sensing a diversity of insults. Inflammasome activation results in the maturation of the pro-inflammatory cytokines interleukin (IL)-1 beta and IL-18. Increased production of IL-1 beta is found in patients with gain-of-function polymorphisms in genes encoding the NLRP3 inflammasome. Since approximately 5% of the Swedish population are heterozygote carriers of these combined gene variants, their impact on inflammasome status and a relationship on disease development is therefore highly relevant to study. The present study investigates levels of inflammasome-produced cytokines as a measure of inflammasome activation in healthy individuals carrying Q705K polymorphism in the NLRP3 gene combined with C10X in the CARD8 gene. Materials and Methods: Genotyping of 1006 healthy blood donors was performed for the polymorphisms Q705K in the NLRP3 and C10X in the CARD8 genes. IL-1 beta, IL-18, IL-33, as well as a number of other pro-inflammatory cytokines, were analyzed by Luminex or ELISA in plasma from individuals carrying the polymorphisms and in age and gender matched non-carrier controls. Results & Discussion: The prevalence of the polymorphisms was in line with previous studies. Plasma levels of IL-1 beta and IL-33 were elevated among carriers of combined Q705K+C10X polymorphisms compared to controls, whereas no difference was found for IL-18 and the other cytokines measured. Moreover, carriers of C10X or Q705K per se had similar plasma levels of IL-1 beta as non-carriers. These data suggest that the combined polymorphisms create inflammasomes with increased basal activation state, which might provide a more favourable innate immune response. In spite of this, it could also represent the mechanisms by which the inflammatory loop is triggered into a long-term inflammatory phenotype.

  • 43.
    Sandin, Charlotta
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Rheumatology. Linköping University, Faculty of Medicine and Health Sciences.
    Eriksson, Per
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Rheumatology. Linköping University, Faculty of Medicine and Health Sciences.
    Segelmark, Mårten
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Region Östergötland, Heart and Medicine Center, Department of Nephrology. Linköping University, Faculty of Medicine and Health Sciences.
    Skogh, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Rheumatology. Linköping University, Faculty of Medicine and Health Sciences.
    Kastbom, Alf
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Rheumatology. Linköping University, Faculty of Medicine and Health Sciences.
    IgA- and SIgA anti-PR3 antibodies in serum versus organ involvement and disease activity in PR3-ANCA associated vasculitis.2016In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 184, no 2, p. 208-215Article in journal (Refereed)
    Abstract [en]

    Circulating IgA class anti-neutrophil cytoplasm antibodies (ANCA) directed against proteinase 3 (PR3) have been reported in ANCA-associated vasculitis (AAV) with mucosal involvement. However, secretory IgA (SIgA) PR3-ANCA has not been reported previously. In this study we compared serum levels of SIgA PR3-ANCA and IgA PR3-ANCA with IgG PR3-ANCA in relation to disease characteristics. Among 73 patients with AAV and PR3-ANCA at diagnosis, 84% tested positive for IgG PR3-ANCA, 47% for IgA-ANCA and 36% for SIgA PR3-ANCA at the time of sampling for the present study. IgA and IgG PR3-ANCA were similarly represented among patients with different organ manifestations, i.e. upper airway, lung or kidney at time of sampling. However, SIgA PR3-ANCA was significantly less represented among patients with upper airway involvement. During active disease, the proportions of IgA PR3-ANCA and SIgA PR3-ANCA positive patients were significantly higher as compared to inactive disease. Eight patients were prospectively sampled during 24 months from onset of active disease. In these patients, IgA PR3-ANCA and SIgA PR3-ANCA more often turned negative after remission induction as compared to IgG PR3-ANCA. Our findings suggest that serum IgA PR3-ANCA and SIgA PR3-ANCA are more closely related to disease activity in AAV as compared to IgG PR3-ANCA. Further studies are required to reveal if this has implications for disease activity monitoring. The mean number of PR3-ANCA isotypes increased along with disease activity, suggesting a global B-cell activation during active disease. This article is protected by copyright. All rights reserved.

  • 44.
    Sjöwall, Christopher
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Rheumatology in Östergötland.
    Eriksson, Per
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Rheumatology in Östergötland.
    Almer, Sven
    Linköping University, Department of Clinical and Experimental Medicine, Gastroenterology and Hepatology . Linköping University, Faculty of Health Sciences.
    Skogh, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Rheumatology in Östergötland.
    Autoantibodies to C-reactive protein is a common finding in SLE, but not in primary Sjögren’s syndrome, rheumatoid arthritis or inflammatory bowel disease2002In: Journal of Autoimmunity, ISSN 0896-8411, Vol. 19, no 3, p. 155-160Article in journal (Refereed)
    Abstract [en]

    The occurrence of antibodies to human C-reactive protein (CRP) was analysed by enzyme-linked immunosorbent assay (ELISA) in 56 patient sera known to contain antibodies to double-stranded DNA (dsDNA) and in 16 sera from patients with primary Sjögren's syndrome (SS), 15 rheumatoid arthritis, 31 Crohn's disease, and 37 ulcerative colitis. Eighty-seven per cent of the patients with anti-dsDNA antibodies had systemic lupus erythematosus (SLE) and the remaining had autoimmune hepatitis. The cut-off for positive anti-CRP test was set at the 95th percentile of 100 healthy blood donors. Twenty of 56 anti-dsDNA sera (36%) and two of 16 SS sera (13%) had antibodies reactive with human CRP, whereas all other samples were negative. Thirteen of 27 SLE patients (48%) were positive on at least one occasion. The sera containing anti-CRP antibodies only reacted with surface-bound antigen, but not with native CRP in solution. In conclusion, we found that autoantibodies to CRP are common in sera from patients with anti-dsDNA antibodies. It is not likely that this explains the relative failure of CRP response in patients with active SLE. However, it cannot be excluded that anti-CRP autoantibodies have other biological potentials of pathophysiological interest in SLE, for instance by binding to CRP deposited on cell and tissue surfaces.

  • 45.
    Skoglund, Camilla
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Carlsen, A L
    Department of Clinical Biochemistry, Immunology and Genetics, Statens Serum Institut, Copenhagen, Denmark.
    Weiner, Maria
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Nephrology.
    Kurz, Tino
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Hellmark, Thomas
    Department of Clinical Sciences, Lund University, Sweden.
    Eriksson, Per
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Rheumatology.
    Heegaard, N H H
    Department of Clinical Biochemistry, Immunology and Genetics, Statens Serum Institut, Copenhagen; Department of Clinical Biochemistry and Pharmacology, University of Southern Denmark, Odense, Denmark.
    Segelmark, Mårten
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Nephrology.
    Circulating microRNA expression pattern separates patients with anti-neutrophil cytoplasmic antibody associated vasculitis from healthy controls.2015In: Clinical and Experimental Rheumatology, ISSN 0392-856X, E-ISSN 1593-098X, Vol. 33, no 2 Suppl 89, p. S64-S71Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: Antineutrophil cytoplasmic antibody associated vasculitis (AAV) has an unpredictable course and better biomarkers are needed. Micro-RNAs in body fluids are protected from degradation and might be used as biomarkers for diagnosis and prognosis, here we explore the potential in AAV.

    METHODS: Plasma samples from two AAV cohorts (n=67 and 38) were compared with samples from healthy controls (n=27 and 45) and disease controls (n=20). A panel of 32 miRNAs was measured using a microfluidic quantitative real-time PCR system, and results were compared with clinical data.

    RESULTS: Seven individual miRNAs were differently expressed compared to controls in both cohorts; miR-29a, -34a, -142-3p and -383 were up-regulated and miR-20a, -92a and -221 were down-regulated. Cluster analysis as well as principal component analysis (PCA) indicated that patterns of miRNA expression differentiate AAV patients from healthy subjects as well as from renal transplant recipients. Loadings plots indicated similar contribution of the same miRNAs in both cohorts to the PCA. Renal engagement was important for miRNA expression but consistent correlations between estimated glomerular filtration rate and miRNA levels were not found. We found no significant correlation between treatment regimens and circulating miRNA levels.

    CONCLUSIONS: In this first study ever on circulating miRNA profiles in AAV, we find clear indication of their potential as biomarkers for diagnosis and classification, but more studies are needed to identify the best markers as well as the mechanisms responsible for variations.

  • 46.
    Smedby, Örjan
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Medical Radiology. Östergötlands Läns Landsting, Centre for Medical Imaging, Department of Radiology UHL. Linköping University, Center for Medical Image Science and Visualization, CMIV.
    Öberg, R
    Åsberg, B
    Stenström, Hugo
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Medical Radiology. Östergötlands Läns Landsting, Centre for Medical Imaging, Department of Radiology UHL.
    Eriksson, Per
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Nephrology. Östergötlands Läns Landsting, Centre for Medicine, Department of Rheumatology in Östergötland.
    Standardized volume-rendering of contrast-enhanced renal magnetic resonance angiography2005In: Acta Radiologica, ISSN 0284-1851, E-ISSN 1600-0455, Vol. 46, no 5, p. 497-504Article in journal (Refereed)
    Abstract [en]

    Purpose: To propose a technique for standardizing volume-rendering technique (VRT) protocols and to compare this with maximum intensity projection (MIP) in regard to image quality and diagnostic confidence in stenosis diagnosis with magnetic resonance angiography (MRA). Material and Methods: Twenty patients were examined with MRA under suspicion of renal artery stenosis. Using the histogram function in the volume-rendering software, the 95th and 99th percentiles of the 3D data set were identified and used to define the VRT transfer function. Two radiologists assessed the stenosis pathology and image quality from rotational sequences of MIP and VRT images. Results: Good overall agreement (mean κ=0.72) was found between MIP and VRT diagnoses. The agreement between MIP and VRT was considerably better than that between observers (mean κ=0.43). One of the observers judged VRT images as having higher image quality than MIP images. Conclusion: Presenting renal MRA images with VRT gave results in good agreement with MIP. With VRT protocols defined from the histogram of the image, the lack of an absolute gray scale in MRI need not be a major problem. © 2005 Taylor & Francis.

  • 47.
    Svensson, Christina
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Clinical Physiology in Linköping.
    Dremetsika, Asimina
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Rheumatology.
    Eriksson, Per
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Rheumatology.
    Zachrisson, Helene
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV). Östergötlands Läns Landsting, Heart and Medicine Center, Department of Clinical Physiology in Linköping.
    High frequency ultrasound för early diagnosis of arteritis2014Conference paper (Other academic)
  • 48.
    Söderberg, Daniel
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Kurz, Tino
    Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Medical and Health Sciences, Division of Drug Research.
    Motamedi, Atbin
    Linköping University, Department of Medical and Health Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Hellmark, Thomas
    Lund University, Sweden.
    Eriksson, Per
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Region Östergötland, Heart and Medicine Center, Department of Rheumatology. Linköping University, Faculty of Medicine and Health Sciences.
    Segelmark, Mårten
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Nephrology.
    Increased levels of neutrophil extracellular trap remnants in the circulation of patients with small vessel vasculitis, but an inverse correlation to anti-neutrophil cytoplasmic antibodies during remission2015In: Rheumatology, ISSN 1462-0324, E-ISSN 1462-0332, Vol. 54, no 11, p. 2085-2094Article in journal (Refereed)
    Abstract [en]

    Objectives. Neutrophil extracellular traps (NETs) have been visualized at the site of ANCA-associated vasculitis (AAV) lesions. Increased levels of NET remnants in the circulation have been reported in some AAV patients with active disease. The aim of the present study was to analyse NET remnants in a larger cohort of AAV patients with varying degrees of disease activity and to elucidate possible factors responsible for remnant variation. Methods. Levels of NET remnants in the circulation of healthy controls (HCs; n =31) and AAV patients (n =93) were determined with ELISA. NET remnants were then correlated with ANCA levels, spontaneous and induced cell death (NETosis/necrosis) in vitro, neutrophil count and corticosteroid therapy. Results. Patients with active disease showed higher levels of circulating NET remnants compared with patients in remission (P=0.026) and HCs (P=0.006). From patients sampled during both remission and active disease, we found increased levels during active disease (P=0.0010). In remission, ANCA-negative patients had higher levels of NET remnants than ANCA-positive patients and a negative correlation was observed between NET remnants and PR3-ANCA (rs = 0.287, P=0.048). NET remnants correlated with neutrophil count in HCs (rs =0.503, P=0.014) but not in patients during remission. Neutrophils from patients showed enhanced spontaneous cell death (P=0.043). Conclusion. We found increased levels of circulating NET remnants in patients with active AAV. Furthermore, AAV patients exhibited an increased propensity for spontaneous cell death. NET remnant levels seem to be positively related to disease activity and neutrophil count, but inversely related to ANCA at least during remission.

  • 49.
    Verma, Deepti
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Eriksson, Per
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences.
    Sahdo, Berolla
    Örebro universitet, Sweden.
    Persson, Alexander
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Ejdebäck, Mikael
    Skövde universitet, Sweden.
    Särndahl, Eva
    Örebro universitet.
    Söderkvist, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Two adult siblings with atypical cryopyrin-associated periodic syndrome due to a novel M299V mutation in NLRP32010In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 62, no 7, p. 2138-2143Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: The NALP3 inflammasome is a multiprotein complex that triggers caspase 1-mediated interleukin-1beta (IL-1beta) release. Mutations in the gene encoding NALP3 (NLRP3) underlie the cryopyrin-associated periodic syndrome (CAPS). The aim of this study was to report a novel NLRP3 mutation in 2 siblings of Swedish descent in whom symptoms first presented in adulthood.

    METHODS: Mutation analysis of NLRP3 was performed on DNA from patients with CAPS and 100 control subjects. For assessment of caspase 1 and IL-1beta, blood was collected from patients and age- and sex-matched healthy control subjects. Genetic constructs containing mutant or wild-type NLRP3 were transduced into THP-1 cells, followed by assessment of IL-1beta levels in cell supernatant.

    RESULTS: Both siblings carried a novel M299V mutation in NLRP3, which was not present in the control population. The samples obtained from the patients displayed increased caspase 1 activity and elevated IL-1beta levels at basal conditions as compared with healthy control subjects. THP-1 cells expressing mutated M299V revealed almost 10-fold higher IL-1beta production compared with the wild-type construct.

    CONCLUSION: M299V is an activating mutation in NLRP3 resulting in elevated spontaneous caspase 1 activity and IL-1beta levels. The classic CAPS phenotype was lacking in these adult siblings. Whereas one sibling displayed a milder phenotype that has so far responded satisfactorily to oral nonsteroidal antiinflammatory drugs in combination with low-dose corticosteroids, the inflammatory symptoms in the sibling with the more severe case responded well to IL-1beta blockade. Understanding the pathogenic mechanism underlying such disorders can be helpful for the physician. Our study reinforces the importance of genetic testing and laboratory investigations in combination with careful phenotypic evaluation for the diagnosis of such patients.

  • 50.
    Verma, Deepti
    et al.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Lerm, Maria
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Blomgran Julinder, Robert
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Eriksson, Per
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Rheumatology in Östergötland.
    Söderkvist, Peter
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Cell Biology.
    Särndahl, Eva
    Örebro Universitet, Örebro.
    Gene polymorphisms in the NALP3 inflammasome are associated with interleukin-1 production and severe inflammation: Relation to Common Inflammatory Diseases?2008In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 58, no 3, p. 888-894Article in journal (Refereed)
    Abstract [en]

    Objective: NALP3, ASC, and TUCAN are components of the NALP3 inflammasome, which triggers caspase 1-mediated interleukin-1β (IL-1β) release. Activating mutations in the gene encoding NALP3 (NLRP3) have recently been linked to familial periodic fever syndromes. We undertook this study to determine whether a patient with arthritis and antibiotic-resistant fever carried mutations in the genes encoding the NALP3 inflammasome.

    Methods: Genetic analysis of NLRP3 and the gene encoding TUCAN (CARD-8) was performed on genomic DNA from the patient and from a population-based collection of DNA (806 subjects). For in vitro studies of IL-1β production and caspase 1 activity, blood was obtained from the patient at different time points after administration of anakinra, an IL-1 receptor antagonist, as well as from 5 healthy age- and sex-matched control subjects.

    Results: Mutation analysis of the patient's genes encoding NALP3, ASC, and TUCAN revealed variations in the NLRP3 (Q705K) and CARD-8 (C10X) genes. The allele frequencies of these single-nucleotide polymorphisms (SNPs) in the population were 6.5% and 34%, respectively. The elevated activity of caspase 1 and the high levels of IL-1β measured in samples from the patient returned to normal levels after treatment with anakinra.

    Conclusion: Our results indicate that the patient's symptoms were due to elevated levels of IL-1β, since treatment with anakinra effectively abolished the symptoms. The compound SNPs may explain the increased IL-1β levels and inflammatory symptoms observed, but further studies are needed to reveal a functional relationship. The prevalence of the polymorphisms (4% of the population carry both SNPs) in the general population may suggest a genetic predisposition for common inflammatory disorders.

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