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  • 1.
    Abelson, Anna-Karin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Delgado-Vega, Angélica Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Kozyrev, Sergey V.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Sánchez, Elena
    Velázquez-Cruz, Rafael
    Eriksson, Niclas
    Wojcik, Jerome
    Linga Reddy, Prasad
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Lima, Guadalupe
    D'Alfonso, Sandra
    Migliaresi, Sergio
    Baca, Vicente
    Orozco, Lorena
    Witte, Torsten
    Ortego-Centeno, Norberto
    Abderrahim, Hadi
    Pons-Estel, Bernardo A.
    Gutiérrez, Carmen
    Suárez, Ana
    González-Escribano, Maria Francisca
    Martin, Javier
    Alarcón-Riquelme, Marta E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    STAT4 Associates with SLE through two independent effects that correlate with gene expression and act additively with IRF5 to increase risk2009In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 68, no 11, p. 1746-1753Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: To confirm and define the genetic association of STAT4 and systemic lupus erythematosus, investigate the possibility of correlations with differential splicing and/or expression levels, and genetic interaction with IRF5. METHODS: 30 tag SNPs were genotyped in an independent set of Spanish cases and controls. SNPs surviving correction for multiple tests were genotyped in 5 new sets of cases and controls for replication. STAT4 cDNA was analyzed by 5'-RACE PCR and sequencing. Expression levels were measured by quantitative PCR. RESULTS: In the fine-mapping, four SNPs were significant after correction for multiple testing, with rs3821236 and rs3024866 as the strongest signals, followed by the previously associated rs7574865, and by rs1467199. Association was replicated in all cohorts. After conditional regression analyses, two major independent signals represented by SNPs rs3821236 and rs7574865, remained significant across the sets. These SNPs belong to separate haplotype blocks. High levels of STAT4 expression correlated with SNPs rs3821236, rs3024866 (both in the same haplotype block) and rs7574865 but not with other SNPs. We also detected transcription of alternative tissue-specific exons 1, indicating presence of tissue-specific promoters of potential importance in the expression of STAT4. No interaction with associated SNPs of IRF5 was observed using regression analysis. CONCLUSIONS: These data confirm STAT4 as a susceptibility gene for SLE and suggest the presence of at least two functional variants affecting levels of STAT4. Our results also indicate that both genes STAT4 and IRF5 act additively to increase risk for SLE.

  • 2. Agmon-Levin, Nancy
    et al.
    Damoiseaux, Jan
    Kallenberg, Cees
    Sack, Ulrich
    Witte, Torsten
    Herold, Manfred
    Bossuyt, Xavier
    Musset, Lucille
    Cervera, Ricard
    Plaza-Lopez, Aresio
    Dias, Carlos
    Sousa, Maria Jose
    Radice, Antonella
    Eriksson, Catharina
    Hultgren, Olof
    Viander, Markku
    Khamashta, Munther
    Regenass, Stephan
    Coelho Andrade, Luis Eduardo
    Wiik, Allan
    Tincani, Angela
    Rönnelid, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Bloch, Donald B.
    Fritzler, Marvin J.
    Chan, Edward K. L.
    Garcia-De la Torre, I.
    Konstantinov, Konstantin N.
    Lahita, Robert
    Wilson, Merlin
    Vainio, Olli
    Fabien, Nicole
    Sinico, Renato Alberto
    Meroni, Pierluigi
    Shoenfeld, Yehuda
    International recommendations for the assessment of autoantibodies to cellular antigens referred to as anti-nuclear antibodies2014In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 73, no 1, p. 17-23Article in journal (Refereed)
    Abstract [en]

    Anti-nuclear antibodies (ANA) are fundamental for the diagnosis of autoimmune diseases, and have been determined by indirect immunofluorescence assay (IIFA) for decades. As the demand for ANA testing increased, alternative techniques were developed challenging the classic IIFA. These alternative platforms differ in their antigen profiles, sensitivity and specificity, raising uncertainties regarding standardisation and interpretation of incongruent results. Therefore, an international group of experts has created recommendations for ANA testing by different methods. Two groups of experts participated in this initiative. The European autoimmunity standardization initiative representing 15 European countries and the International Union of Immunologic Societies/World Health Organization/Arthritis Foundation/Centers for Disease Control and Prevention autoantibody standardising committee. A three-step process followed by a Delphi exercise with closed voting was applied. Twenty-five recommendations for determining ANA (1-13), anti-double stranded DNA antibodies (14-18), specific antibodies (19-23) and validation of methods (24-25) were created. Significant differences between experts were observed regarding recommendations 24-25 (p<0.03). Here, we formulated recommendations for the assessment and interpretation of ANA and associated antibodies. Notably, the roles of IIFA as a reference method, and the importance of defining nuclear and cytoplasmic staining, were emphasised, while the need to incorporate alternative automated methods was acknowledged. Various approaches to overcome discrepancies between methods were suggested of which an improved bench-to-bedside communication is of the utmost importance. These recommendations are based on current knowledge and can enable harmonisation of local algorithms for testing and evaluation of ANA and related autoantibodies. Last but not least, new more appropriate terminologies have been suggested.

  • 3.
    Ambrosi, Aurelie
    et al.
    Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
    Salomonsson, Stina
    Eliasson, Hakan
    Zeffer, Elisabeth
    Skog, Amanda
    Dzikaite, Vijole
    Bergman, Gunnar
    Fernlund, Eva
    Tingstrom, Joanna
    Theander, Elke
    Rydberg, Annika
    Skogh, Thomas
    Öhman, Annika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Lundstrom, Ulla
    Mellander, Mats
    Winqvist, Ola
    Fored, Michael
    Ekbom, Anders
    Alfredsson, Lars
    Kallberg, Henrik
    Olsson, Tomas
    Gadler, Fredrik
    Jonzon, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Kockum, Ingrid
    Sonesson, Sven-Erik
    Wahren-Herlenius, Marie
    Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
    Development of heart block in children of SSA/SSB-autoantibody-positive women is associated with maternal age and displays a season-of-birth pattern2012In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 71, no 3, p. 334-340Article in journal (Refereed)
    Abstract [en]

    Objective Congenital heart block may develop in the fetuses of Ro/SSA-positive and La/SSB-positive mothers. Recurrence rates of only 10-20% despite persisting maternal antibodies indicate that additional factors are critical for the establishment of heart block. The authors investigated the influence of other maternal and fetal factors on heart block development in a Swedish population-based cohort.

    Methods The influence of fetal gender, maternal age, parity and time of birth on heart block development was analysed in 145 families, including Ro/La-positive (n=190) and Ro/La-negative (n=165) pregnancies.

    Results There was a recurrence rate of 12.1% in Ro/La-positive women, and no recurrence in Ro/La-negative women. Fetal gender and parity did not influence the development of heart block in either group. Maternal age in Ro/La-positive pregnancies with a child affected by heart block was, however, significantly higher than in pregnancies resulting in babies without heart block (p<0.05). Seasonal timing of pregnancy influenced the outcome. Gestational susceptibility weeks 18-24 occurring during January-March correlated with a higher proportion of children with heart block and lower vitamin D levels during the same period in a representative sample of Swedish women and a corresponding higher proportion of children with heart block born in the summer (p<0.02). Maternal age or seasonal timing of pregnancy did not affect the outcome in Ro/La-negative pregnancies.

    Conclusion This study identifies maternal age and seasonal timing of pregnancy as novel risk factors for heart block development in children of Ro/La-positive women. These observations may be useful for counselling when pregnancy is considered.

  • 4.
    Andersen, M.
    et al.
    Aalborg Univ, Hlth Sci & Technol, Aalborg, Denmark..
    Meyer, M. K.
    Aalborg Univ, Hlth Sci & Technol, Aalborg, Denmark..
    Nagaev, I.
    Nagaeva, O.
    Wikberg, Jarl E. S.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Mincheva-Nilsson, L.
    Andersen, G. N.
    Aalborg Univ, Clin Med, Aalborg, Denmark..
    Resistin Gene Transcription Is Regulated in Adaptive and Innate Immunity in Rheumatoid Arthritis2016In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 75, p. 904-904Article in journal (Other academic)
  • 5.
    Andersen, M.
    et al.
    Aalborg Univ, Hlth Sci & Technol, Aalborg, Denmark..
    Meyer, M. K.
    Aalborg Univ, Hlth Sci & Technol, Aalborg, Denmark..
    Nagaev, I.
    Nagaeva, O.
    Wikberg, Jarl E. S.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Mincheva-Nilsson, L.
    Andersen, G. N.
    Aalborg Univ, Clin Med, Aalborg, Denmark..
    The Melanocortin System Is Responsive in Disease Driving Immune Cells in Rheumatoid Arthritis and May Offer A Pathway To Curative Treatment2016In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 75, p. 903-904Article in journal (Other academic)
  • 6. Andersson, M. L. E.
    et al.
    Petersson, I. F.
    Karlsson, Kristin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Jonsson, E. Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Månsson, B.
    Heinegård, D.
    Saxne, T.
    Diurnal variation in serum levels of cartilage oligomeric matrix protein in patients with knee osteoarthritis or rheumatoid arthritis2006In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 65, no 11, p. 1490-1494Article in journal (Refereed)
    Abstract [en]

    Objective: To monitor changes in serum concentrations of cartilage oligomeric matrix protein (COMP) during a 24-h period to determine any diurnal variation, and to estimate the half life of COMP in the circulation in patients with symptomatic knee osteoarthritis and in those with rheumatoid arthritis.

    Methods: Serum samples were drawn every 4 h (7 samples/patient over 24 h) in 10 patients with knee osteoarthritis and 14 patients with rheumatoid arthritis. Osteoarthritis was defined radiographically and clinically (American College of Rheumatology (ACR) criteria) and rheumatoid arthritis according to the 1987 ACR criteria. Serum COMP was measured by sandwich ELISA. A statistical model for the diurnal variation in the COMP levels was developed using the computer program NONMEM.

    Results: No considerable changes in COMP levels were observed during the day between 08:00 and 21:00 in either group. A significant decrease in serum COMP was apparent during bed rest at night, reaching the lowest levels between 04:00 and 05:00 (p < 0.03 or better v all other time points) in patients with osteoarthritis and in those with rheumatoid arthritis. From the rate of decreasing serum COMP levels, a putative half life of COMP in the circulation was estimated to be 7.4 h.

    Conclusion: During normal daytime activities, serum COMP levels are constant. The decrease during the night indicates a rapid elimination of COMP once it has reached the circulation. The stable COMP levels during the day suggest that it is not necessary to further standardise the time of serum sampling in clinical practice.

  • 7. Appel, Silke
    et al.
    Le Hellard, Stephanie
    Bruland, Ove
    Brun, Johan G.
    Omdal, Roald
    Kristjansdottir, Gudlaug
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Theander, Elke
    Nordmark, Gunnel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Kvarnström, Marika
    Eriksson, Per
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Wahren-Herlenius, Marie
    Jonsson, Roland
    Potential association of muscarinic receptor 3 gene variants with primary Sjogren's syndrome2011In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 70, no 7, p. 1327-1329Article in journal (Refereed)
    Abstract [en]

    Background: Primary Sjögren's 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 Schirmer's 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.

  • 8. Arkema, E.
    et al.
    Jonsen, A.
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Sjowall, C.
    Svenungsson, E.
    Simard, J. F.
    Utility of Swedish Register Data in Classifying Systemic Lupus2014In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 73, p. 444-444Article in journal (Other academic)
  • 9. Arkema, Elizabeth V
    et al.
    Feltelius, Nils
    Olsson, Tomas
    Askling, Johan
    No association between rheumatoid arthritis, amyotrophic lateral sclerosis, and tumour necrosis factor inhibitor treatment.2014In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 73, no 11Article in journal (Refereed)
  • 10. Arkema, Elizabeth V
    et al.
    Jonsson, Jerker
    Baecklund, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Bruchfeld, Judith
    Feltelius, Nils
    Askling, Johan
    Are patients with rheumatoid arthritis still at an increased risk of tuberculosis and what is the role of biological treatments?2015In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 74, no 6, p. 1212-1217Article in journal (Refereed)
    Abstract [en]

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

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

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

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

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

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

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

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

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

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

  • 12.
    Arvidson, Nils Gunnar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Gudbjörnsson, Björn
    Elfman, Lena
    Rydén, Ann Christin
    Tötterman, Thomas H.
    Hällgren, Roger
    Circadian rhytm of serum interleukin-6 in rheumatoid arthritis1994In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 53, no 8, p. 521-4Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES--To test the hypothesis of a diurnal variation in circulating levels of interleukin-6 (IL-6) and/or tumour necrosis factor-alpha (TNF-alpha) in rheumatoid arthritis and other inflammatory connective tissue diseases. METHODS--Serum levels of IL-6 and TNF-alpha were measured at three hour intervals from 7:30 to 22:30 in 48 patients with different rheumatic diseases as well as ten healthy controls. In four of the patients with rheumatoid arthritis, serum IL-6 levels were measured before and after one week of treatment with prednisolone 15-20 mg daily. RESULTS--IL-6 and TNF-alpha could not be detected in serum from healthy controls. However, serum IL-6 levels were substantially increased in patients with rheumatoid arthritis. Furthermore, patients with rheumatoid arthritis showed a statistically significant circadian variation in levels of IL-6. Peak values appeared in the morning and low values in the afternoon and evening. In contrast, levels were low and stable in other connective tissue diseases. Levels of TNF-alpha were low in patients with rheumatoid arthritis and high in patients with other connective tissue diseases, but without circadian rhythm. After treatment with prednisolone, levels of serum IL-6 decreased significantly, but the circadian rhythm remained. CONCLUSIONS--The circadian rhythm of circulating IL-6 might correspond to the circadian rhythm of symptoms in rheumatoid arthritis. The diurnal variation of IL-6, and possibly other cytokines, might explain the conflicting results previously reported on the inter-relationship between circulating IL-6 levels and disease activity in rheumatoid arthritis.

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

    BACKGROUND:

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

    OBJECTIVE:

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

    METHODS:

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

    RESULTS:

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

    CONCLUSION:

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

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

    BACKGROUND:

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

    OBJECTIVE:

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

    METHODS:

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

    RESULTS:

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

    CONCLUSION:

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

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

    BACKGROUND:

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

    OBJECTIVE:

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

    METHODS:

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

    RESULTS:

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

    CONCLUSIONS:

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

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

    BACKGROUND:

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

    METHODS:

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

    RESULTS:

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

    CONCLUSION:

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

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

    OBJECTIVES:

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

    METHODS:

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

    RESULTS:

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

    CONCLUSION:

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

  • 18.
    Baecklund, Eva
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Hellgren, K.
    Sundström, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Askling, J.
    Does Biological Therapy Alter the Lymphoma Risk or Distribution of Lymphoma Subtypes in Patients with ra?2013In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 72, no Suppl. 3, p. 427-427Article in journal (Other academic)
  • 19.
    Berggren, Olof
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Eloranta, Maija-Leena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Activated Plasmacytoid Dendritic Cells (PDCS) Alter The Composition of The Blood B Cell Subsets2016In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 75, p. 179-179Article in journal (Other academic)
  • 20. Bolstad, Anne Isine
    et al.
    Le Hellard, Stephanie
    Kristjansdottir, Gudlaug
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Vasaitis, Lilian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Kvarnström, Marika
    Sjöwall, Christopher
    Johnsen, Svein Joar Auglænd
    Eriksson, Per
    Omdal, Roald
    Brun, Johan G
    Wahren-Herlenius, Marie
    Theander, Elke
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Nordmark, Gunnel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Jonsson, Roland
    Association between genetic variants in the tumour necrosis factor/lymphotoxin α/lymphotoxin β locus and primary Sjogren's syndrome in Scandinavian samples2012In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 71, no 6, p. 981-988Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES:

    Lymphotoxin β (LTB) has been found to be upregulated in salivary glands of patients with primary Sjögren's syndrome (pSS). An animal model of pSS also showed ablation of the lymphoid organisation and a marked improvement in salivary gland function on blocking the LTB receptor pathway. This study aimed to investigate whether single-nucleotide polymorphisms (SNP) in the lymphotoxin α (LTA)/LTB/tumour necrosis factor (TNF) gene clusters are associated with pSS.

    METHODS:

    527 pSS patients and 532 controls participated in the study, all of Caucasian origin from Sweden and Norway. 14 SNP markers were genotyped and after quality control filtering, 12 SNP were analysed for their association with pSS using single marker and haplotype tests, and corrected by permutation testing.

    RESULTS:

    Nine markers showed significant association with pSS at the p=0.05 level. Markers rs1800629 and rs909253 showed the strongest genotype association (p=1.64E-11 and p=4.42E-08, respectively, after correcting for sex and country of origin). When the analysis was conditioned for the effect of rs1800629, only the association with rs909253 remained nominally significant (p=0.027). In haplotype analyses the strongest effect was observed for the haplotype rs909253G_rs1800629A (p=9.14E-17). The associations were mainly due to anti-Ro/SSA and anti-La/SSB antibody-positive pSS.

    CONCLUSIONS:

    A strong association was found between several SNP in the LTA/LTB/TNFα locus and pSS, some of which led to amino acid changes. These data suggest a role for this locus in the development of pSS. Further studies are needed to examine if the genetic effect described here is independent of the known genetic association between HLA and pSS.

  • 21. Bos, W.
    et al.
    van de Stadt, L.
    Sohrabian, Azita
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Ronnelid, J.
    van Schaardenburg, D.
    Development of Anti-Citrullinated Protein Antibody and Rheumatoid Factor Isotypes in Relation to Smoking Prior to the Onset of Rheumatoid Arthritis2013In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 72, no S3, p. 819-819Article in journal (Other academic)
  • 22.
    Brauner, Susanna
    et al.
    Karolinska Univ Hosptial, Karolinska Inst, Dept Med, Stockholm, Sweden..
    Folkersen, Lasse
    Karolinska Univ Hosptial, Karolinska Inst, Dept Med, Stockholm, Sweden..
    Kvarnstrom, Marika
    Karolinska Univ Hosptial, Karolinska Inst, Dept Med, Stockholm, Sweden..
    Meisgen, Sabrina
    Karolinska Univ Hosptial, Karolinska Inst, Dept Med, Stockholm, Sweden..
    Petersen, Sven
    Karolinska Univ Hosptial, Karolinska Inst, Dept Med, Stockholm, Sweden..
    Franzen-Malmros, Michaela
    Karolinska Univ Hosptial, Karolinska Inst, Dept Med, Stockholm, Sweden..
    Mofors, Johannes
    Karolinska Univ Hosptial, Karolinska Inst, Dept Med, Stockholm, Sweden..
    Brokstad, Karl A.
    Univ Bergen, Dept Clin Sci, Broegelmann Res Lab, Bergen, Norway..
    Klareskog, Lars
    Karolinska Univ Hosptial, Karolinska Inst, Dept Med, Stockholm, Sweden..
    Jonsson, Roland
    Univ Bergen, Dept Clin Sci, Broegelmann Res Lab, Bergen, Norway..
    Westerberg, Lisa S.
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Stockholm, Sweden..
    Trollmo, Christina
    Karolinska Univ Hosptial, Karolinska Inst, Dept Med, Stockholm, Sweden..
    Malmstrom, Vivianne
    Karolinska Univ Hosptial, Karolinska Inst, Dept Med, Stockholm, Sweden..
    Ambrosi, Aurelie
    Karolinska Univ Hosptial, Karolinska Inst, Dept Med, Stockholm, Sweden..
    Kuchroo, Vijay K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Nordmark, Gunnel
    Harvard Med Sch, Evergrande Ctr Immunol Dis, Boston, MA USA.;Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA..
    Wahren-Herlenius, Marie
    Karolinska Univ Hosptial, Karolinska Inst, Dept Med, Stockholm, Sweden..
    H1N1 vaccination in Sjogren's syndrome triggers polyclonal B cell activation and promotes autoantibody production2017In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 76, no 10, p. 1755-1763Article in journal (Refereed)
    Abstract [en]

    Objectives

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

    Methods

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

    Results

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

    Conclusions

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

  • 23. Brauner, Susanna
    et al.
    Zhou, Wei
    Backlin, Carin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Green, Tina M.
    Young, Ken He
    Lofstrom, Bjorn
    Lundberg, Ingrid
    Pedersen, Lars Moller
    Moller, Michael Boe
    Sundström, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Enblad, Gunilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Baecklund, Eva
    Wahren-Herlenius, Marie
    Ro52 Expression is a Prognostic Factor for Survival in B Cell Lymphoma2013In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 72, no S1, p. A40-A40Article in journal (Other academic)
  • 24.
    Brink, M.
    et al.
    Umea Univ, Rheumatol, Publ Hlth & Clin Med, Umea, Sweden..
    Hansson, M.
    Karolinska Inst, Dept Med, Rheumatol Unit, Stockholm, Sweden..
    Mathsson Alm, Linda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Cornillet, M.
    Univ Toulouse, INSERM, U 1056, Toulouse, France..
    Rönnelid, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Skriner, K.
    Charite, Med, Berlin, Germany..
    Serre, G.
    Univ Toulouse, INSERM, U 1056, Toulouse, France..
    Holmdahl, R.
    Karolinska Inst, Med Inflammat Res, Stockholm, Sweden..
    Klareskog, L.
    Karolinska Inst, Dept Med, Rheumatol Unit, Stockholm, Sweden..
    Rantapaa-Dahlqvist, S.
    Umea Univ, Rheumatol, Publ Hlth & Clin Med, Umea, Sweden..
    Acpa Against Different Citrullinated Peptides Identify Specific Phenotypes Of Rheumatoid Arthritis2017In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 76, p. 792-792Article in journal (Other academic)
  • 25. Brink, M.
    et al.
    Verheul, M. K.
    Rönnelid, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Toes, R. E.
    Klareskog, L.
    Trouw, L. L.
    Dahlqvist, S. Rantapaa
    Anti-Carbamylated Protein Antibodies Precede the Onset of Symptoms of Rheumatoid Arthritis in A Swedish Biobank Cohort2014In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 73, no S2, p. 397-398Article in journal (Other academic)
  • 26. Brink, Mikael
    et al.
    Hansson, Monika
    Rönnelid, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Klareskog, Lars
    Dahlqvist, Solbritt Rantapaa
    The autoantibody repertoire in periodontitis: a role in the induction of autoimmunity to citrullinated proteins in rheumatoid arthritis? Antibodies against uncitrullinated peptides seem to occur prior to the antibodies to the corresponding citrullinated peptides2014In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 73, no 7Article in journal (Refereed)
  • 27. Brink, Mikael
    et al.
    Rönnelid, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Hansson, Monika
    Mathsson, Linda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Serre, Guy
    Jakobsson, Per-Johan
    Holmdahl, Rikard
    Klareskog, Lars
    Dahlqvist, Solbritt Rantapaa
    Antibodies against native collagen and citrullinated proteins precede the development of rheumatoid arthritis with a consecutive pattern2012In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 71, p. A22-A22Article in journal (Other academic)
  • 28.
    Brito-Zeron, P.
    et al.
    Hosp CIMA Sanitas, Barcelona, Spain.;Hosp Clin Barcelona, Barcelona, Spain..
    Acar-Denizli, N.
    Msgsu, Istanbul, Turkey..
    Zeher, M.
    Univ Debrecen, Debrecen, Hungary..
    Rasmussen, A.
    OMRF, Oklahoma City, OK USA..
    Li, X.
    Anhui Hosp, Hefei, Anhui, Peoples R China..
    Baldini, C.
    Univ Pisa, Pisa, Italy..
    Gottenberg, J-E
    Danda, D.
    CMC, Vellore, Tamil Nadu, India..
    Quartuccio, L.
    Santa Maria, Udine, Italy..
    Hernandez-Molina, G.
    INCMNSZ, Mexico City, DF, Mexico..
    Kruize, A. A.
    UMC, Utrecht, Netherlands..
    Park, S-H
    Kvarnstrom, M.
    Karolinska Inst, Stockholm, Sweden..
    Praprotnik, S.
    UMCL, Ljubljana, Slovenia..
    Sene, D.
    Lariboisiere Hosp, Paris, France..
    Alunno, A.
    Univ Perugia, Perugia, Italy..
    Solans, R.
    Hosp Valle De Hebron, Barcelona, Spain..
    Mandl, T.
    Lund Univ, Malmo, Sweden..
    Suzuki, Y.
    Univ Kanazawa, Kanazawa, Ishikawa, Japan..
    Rischmueller, M.
    TQEH, Adelaide, SA, Australia..
    Nordmark, Gunnel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Fraile, G.
    Hosp Ramon & Cajal, Madrid, Spain..
    Wiland, P.
    Med Hosp, Wroclaw, Poland..
    Bootsma, H.
    Univ Groningen, Groningen, Netherlands..
    Nakamura, T.
    Univ Nagasaki, Nagasaki, Japan..
    Valim, V.
    UFES, Vitoria, Spain..
    Giacomelli, R.
    Univ Aquila, Laquila, Italy..
    Seror, R.
    Univ Sud, Paris, France..
    Devauchelle-Pensec, V.
    Univ Brest, Brest, France..
    Hofauer, B.
    TUM, Munich, Germany..
    Bombardieri, M.
    QMUL, London, England..
    Trevisani, V.
    Univ Fed Sao Paulo, Sao Paulo, Brazil..
    Hammenfors, D.
    Haukeland Hosp, Bergen, Norway..
    Minniti, A.
    Sapienza Univ, Rome, Italy..
    Pasoto, S. G.
    Univ Sao Paulo, Sao Paulo, Brazil..
    Morel, J.
    Univ Montpellier, Montpellier, France..
    Retamozo, S.
    INICSA, Cordoba, Argentina..
    Gheita, T. A.
    Cairo Univ, Cairo, Egypt..
    Atzeni, F.
    L Sacco Univ, Milan, Italy..
    Vollenveider, C.
    German Hosp, Buenos Aires, DF, Argentina..
    Mariette, X.
    Univ Sud, Paris, France..
    Ramos-Casals, M.
    Hosp Clin Barcelona, Barcelona, Spain..
    Baseline Essdai/ Das Scores In 8061 Patients With Primary Sjögren Syndrome: Characterization Of Systemic Disease2017In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 76, p. 464-465Article in journal (Other academic)
  • 29.
    Brito-Zeron, P.
    et al.
    Hosp CIMA Sanitas, Barcelona, Spain.;Hosp Clin Barcelona, Barcelona, Spain..
    Acar-Denizli, N.
    Msgsu, Istanbul, Turkey..
    Zeher, M.
    Univ Debrecen, Debrecen, Hungary..
    Rasmussen, A.
    OMRF, Oklahoma City, OK USA..
    Li, X.
    Anhui Hosp, Hefei, Anhui, Peoples R China..
    Baldini, C.
    Univ Pisa, Pisa, Italy..
    Gottenberg, J-E
    Danda, D.
    CMC, Vellore, Tamil Nadu, India..
    Quartuccio, L.
    Santa Maria, Udine, Italy..
    Hernandez-Molina, G.
    INCMNSZ, Mexico City, DF, Mexico..
    Kruize, A. A.
    UMC, Utrecht, Netherlands..
    Park, S-H
    Kvarnstrom, M.
    Karolinska Instit, Stockholm, Sweden..
    Praprotnik, S.
    UMCL, Ljubljana, Slovenia..
    Sene, D.
    Lariboisiere Hosp, Paris, France..
    Bartoloni, E.
    Univ Perugia, Perugia, Italy..
    Solans, R.
    Hasp Vall Hebron, Barcelona, Spain..
    Mandl, T.
    Lund Univ, Malmo, Sweden..
    Suzuki, Y.
    Univ Kanazawa, Kanazawa, Ishikawa, Japan..
    Rischmueller, M.
    TQEH, Adelaide, SA, Australia..
    Nordmark, Gunnel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Fraile, G.
    Hosp Ramon & Cajal, Madrid, Spain..
    Sebastian, A.
    Med Hosp, Wroclaw, Poland..
    Bootsma, H.
    Univ Groningen, Groningen, Netherlands..
    Nakamura, T.
    Univ Nagasaki, Nagasaki, Japan..
    Valim, V.
    Univ Fed Espirito Santo, Vitoria, Brazil..
    Giacomelli, R.
    Univ Nagasaki, Nagasaki, Japan.;Univ Aquila, Laquila, Italy..
    Seror, R.
    Univ Paris Sud, Paris, France..
    Devauchelle-Pensec, V.
    Univ Brest, Brest, France..
    Hofauer, B.
    TUM, Munich, Germany..
    Bombaidieri, M.
    QMUL, London, England..
    Trevisani, V.
    Univ Fed Sao Paulo, Sao Paulo, Brazil..
    Hammenfors, D.
    Haukeland Hosp, Bergen, Norway..
    Priori, R.
    Sapienza Univ, Rome, Italy..
    Pasoto, S. G.
    Univ Sao Paulo, Sao Paulo, Brazil..
    Morel, J.
    Univ Montpellier, Montpellier, France..
    Retamozo, S.
    INICSA, Cordoba, Argentina..
    Gheita, T. A.
    Cairo Univ, Cairo, Egypt..
    Atzeni, F.
    L Sacco Univ Hasp, Milan, Italy..
    Vollenveider, C.
    German Hosp, Buenos Aires, DF, Argentina..
    Mariette, X.
    Univ Paris Sud, Paris, France..
    Ramos-Casals, M.
    Hosp Clin Barcelona, Barcelona, Spain..
    Predicting Survival In 6240 Patients With Primary Sjögren' Syndrome (Big Data Sjögren Project)2017In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 76, p. 311-311Article in journal (Other academic)
  • 30.
    Brito-Zeron, P.
    et al.
    Hosp Clínic, Barcelona, Spain.
    Acar-Denizli, N.
    Msgsu, Istanbul, Turkey.
    Zeher, M.
    Univ Debrecen, Debrecen, Hungary..
    Rasmussen, A.
    OMRF, Oklahoma City, OK USA..
    Seror, R.
    Univ Paris Sud, Paris, France..
    Mandl, T.
    Lund Univ, Malmo, Sweden..
    Li, X.
    Anhui Hosp, Hefei, Anhui, Peoples R China..
    Baldini, C.
    Univ Pisa, Pisa, Italy..
    Gottenberg, J. -E
    Danda, D.
    CMC, Vellore, Tamil Nadu, India..
    Priori, R.
    Sapienza Univ, Rome, Italy..
    Quartuccio, L.
    Santa Maria, Udine, Italy..
    Hernandez-Molina, G.
    INCMNSZ, Mexico City, DF, Mexico..
    Kruize, A.
    UMC, Utrecht, Netherlands..
    Park, S. -H
    Catholic Univ Korea, Seoul, South Korea..
    Kvarnstrom, M.
    Karolinska Inst, Stockholm, Sweden..
    Praprotnik, S.
    UMCL, Ljubljana, Slovenia..
    Sene, D.
    Lariboisiere Hosp, Paris, France..
    Bartoloni, E.
    Univ Perugia, Perugia, Italy..
    Solans, R.
    Hosp Valle De Hebron, Barcelona, Spain..
    Suzuki, Y.
    Univ Hosp, Kanazawa, Ishikawa, Japan..
    Isenberg, D.
    UCL, London, England..
    Rischmueller, M.
    TQEH, Adelaide, SA, Australia..
    Nordmark, Gunnel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Fraile, G.
    Hosp Ramon & Cajal, Madrid, Spain..
    Sebastian, A.
    Med Hosp, Wroclaw, Poland..
    Vissink, A.
    Univ Groningen, Groningen, Netherlands..
    Nakamura, T.
    Univ Nagasaki, Nagasaki, Japan..
    Valim, V.
    Univ Fed Espirito Santo, Vitoria, Brazil..
    Giacomelli, R.
    Univ Aquila, Laquila, Italy..
    Devauchelle-Pensec, V.
    Univ Brest, Brest, France..
    Hofauer, B.
    TUM, Munich, Germany..
    Bombardieri, M.
    QMUL, London, England..
    Trevisani, V.
    Univ Fed Sao Paulo, Sao Paulo, Brazil..
    Hammenfors, D.
    Haukeland Hosp, Bergen, Norway..
    Carsons, S. E.
    Sch Med SBU, Mineola, NY USA..
    Pasoto, S. G.
    Univ Sao Paulo, Sao Paulo, Brazil..
    Morel, J.
    Univ Montpellier, Montpellier, France..
    Retamozo, S.
    INICSA, Cordoba, Argentina..
    Gheita, T. A.
    Cairo Univ, Cairo, Egypt..
    Atzeni, F.
    L Sacco Univ, Milan, Italy..
    Vollenveider, C.
    German Hosp, Buenos Aires, DF, Argentina..
    Mariette, X.
    Univ Paris Sud, Paris, France..
    Ramos-Casals, M.
    Hosp Clin Barcelona, Barcelona, Spain..
    Analysis Of 9302 Patients From The Big Data International Primary Sjogren Syndrome Cohort: Clinical Presentation At Diagnosis Of European Vs Non-European Patients2017In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 76, p. 886-887Article in journal (Other academic)
  • 31.
    Brito-Zeron, P.
    et al.
    Hosp Clin Barcelona, Barcelona, Spain..
    Acar-Denizli, N.
    Mimar Sinan Univ, Istanbul, Turkey..
    Zeher, M.
    Debrecen Univ, Debrecen, Hungary..
    Rasmussen, A.
    OMRF, Oklahoma City, OK USA..
    Seror, R.
    Paris Sud Univ, Paris, France..
    Mandl, T.
    Lund Univ, Malmo, Sweden..
    Li, X.
    Anhui Hosp, Hefei, Peoples R China..
    Baldini, C.
    Rheumatol Clin, Pisa, Italy..
    Gottenberg, J. -E
    Danda, D.
    Christian Med Coll & Hosp, Vellore, Tamil Nadu, India..
    Quartuccio, L.
    Santa Maria Misericordia Hosp, Udine, Italy..
    Priori, R.
    Sapienza Univ, Rome, Italy..
    Hernandez-Molina, G.
    INNSZ, Mexico City, DF, Mexico..
    Kruize, A.
    UMCU, Utrecht, Netherlands..
    Valim, V.
    Espirito Santo Univ, Vitoria, Spain..
    Kvarnstrom, M.
    Karolinska Univ Hosp, Stockholm, Sweden..
    Sene, D.
    Lariboisiere Hosp, Paris, France..
    Bartoloni, E.
    Perugia Univ, Perugia, Italy..
    Praprotnik, S.
    Clin Ctr Univ, Ljubljana, Slovenia..
    Isenberg, D.
    UCL, London, England..
    Solans, R.
    Vall Hebron Hosp, Barcelona, Spain..
    Rischmueller, M.
    Queen Elizabeth Hosp, Woodville, SA, Australia..
    Kwok, S. -K
    Nordmark, Gunnel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Suzuki, Y.
    Kanazawa Univ, Kanazawa, Ishikawa, Japan..
    Giacomelli, R.
    Laquila Univ, Laquila, Italy..
    Devauchelle-Pensec, V.
    Brest Univ Hosp, Brest, France..
    Bombardieri, M.
    QMUL, London, England..
    Hofauer, B.
    Rechts Isar Hosp, Munich, Germany..
    Bootsma, H.
    Univ Groningen, Groningen, Netherlands.;Haukeland Hosp, Bergen, Norway..
    Hammenfors, D.
    Fraile, G.
    Ramon Cajal Hosp, Madrid, Spain..
    Carsons, S.
    SUNY Stony Brook, Mineola, NY USA..
    Gheita, T.
    Cairo Univ, Cairo, Egypt..
    Morel, J.
    Montpellier Hosp, Montpellier, France..
    Vollenveider, C.
    German Hosp, Buenos Aires, DF, Argentina..
    Atzeni, F.
    L Sacco Univ, Milan, Italy..
    Retamozo, S.
    Privado Hosp, Cordoba, Argentina..
    Horvath, I. -F
    Sivils, K.
    OMRF, Oklahoma City, OK USA..
    Theander, E.
    Lund Univ, Malmo, Sweden..
    Sandhya, P.
    Christian Med Coll & Hosp, Vellore, Tamil Nadu, India..
    De Vita, S.
    Santa Maria Misericordia Hosp, Udine, Italy..
    Sanchez-Guerrero, J.
    INNSZ, Mexico City, DF, Mexico..
    van der Heijden, E.
    UMCU, Utrecht, Netherlands..
    Moca-Trevisano, V.
    Sao Paulo Fed Univ, Sao Paulo, Brazil..
    Wahren-Herlenius, M.
    Karolinska Univ Hosp, Stockholm, Sweden..
    Mariette, X.
    Paris Sud Univ, Paris, France..
    Ramos-Casals, M.
    Hosp Clin Barcelona, Barcelona, Spain..
    Worldwide Heterogeneous Diagnostic Approach To Primary Sjögren Syndrome in 8315 Patients (EULAR-SS Task Force Big Data Sjögren Project)2016In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 75, p. 314-315Article in journal (Other academic)
  • 32.
    Brito-Zeron, P.
    et al.
    Hosp Clin Barcelona, Barcelona, Spain..
    Acar-Denizli, N.
    Mimar Sinan Univ, Istanbul, Turkey..
    Zeher, M.
    Debrecen Univ, Debrecen, Hungary..
    Rasmussen, A.
    OMRF, Oklahoma City, OK USA..
    Seror, R.
    Paris Sud Univ, Paris, France..
    Mandl, T.
    Lund Univ, Malmo, Sweden..
    Li, X.
    Anhui Hosp, Hefei, Peoples R China..
    Baldini, C.
    Rheumatol Clin, Pisa, Italy..
    Gottenberg, J. -E
    Danda, D.
    Christian Med Coll & Hosp, Vellore, Tamil Nadu, India..
    Quartuccio, L.
    Santa Maria Misericordia Hosp, Udine, Italy..
    Priori, R.
    Sapienza Univ, Rome, Italy..
    Hernandez-Molina, G.
    INNSZ, Mexico City, DF, Mexico..
    Kruize, A.
    UMCU, Utrecht, Netherlands..
    Valim, V.
    Espirito Santo Univ, Vitoria, Brazil..
    Kvarnstrom, M.
    Karolinska Univ Hosp, Stockholm, Sweden..
    Sene, D.
    Lariboisiere Hosp, Paris, France..
    Gerli, R.
    Perugia Univ, Perugia, Italy..
    Praprotnik, S.
    Clin Ctr Univ, Ljubljana, Slovenia..
    Isenberg, D.
    UCL, London, England..
    Solans, R.
    Vall Hebron Hosp, Barcelona, Spain..
    Rischmueller, M.
    Queen Elizabeth Hosp, Woodville, SA, Australia..
    Park, S. -H
    Nordmark, Gunnel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Suzuki, Y.
    Kanazawa Univ, Kanazawa, Ishikawa, Japan..
    Giacomelli, R.
    LAquila Univ, Laquila, Italy..
    Saraux, A.
    Brest Univ Hosp, Brest, France..
    Bombardieri, M.
    QMUL, London, England..
    Hofauer, B.
    Rechts Isar Hosp, Munich, Germany..
    Bootsma, H.
    Univ Groningen, Groningen, Netherlands..
    Hammenfors, D.
    Haukeland Hosp, Bergen, Norway..
    Fraile, G.
    Ramon Cajal Hosp, Madrid, Spain..
    Carsons, S.
    SUNY Stony Brook, Mineola, NY USA..
    Gheita, T.
    Cairo Univ, Cairo, Egypt..
    Morel, J.
    Montpellier Hosp, Montpellier, France..
    Vollenveider, C.
    German Hosp, Buenos Aires, DF, Argentina..
    Atzeni, F.
    L Sacco Univ, Milan, Italy..
    Retamozo, S.
    Privado Hosp, Cordoba, Argentina..
    Horvath, I. -F
    Sivils, K.
    OMRF, Oklahoma City, OK USA..
    Theander, E.
    Lund Univ, Malmo, Sweden..
    Sandhya, P.
    Christian Med Coll & Hosp, Vellore, Tamil Nadu, India..
    De Vita, S.
    Santa Maria Misericordia Hosp, Udine, Italy..
    Sanchez-Guerrero, J.
    INNSZ, Mexico City, DF, Mexico..
    van der Heijden, E.
    UMCU, Utrecht, Netherlands..
    Moca-Trevisano, V.
    Sao Paulo Fed Univ, Sao Paulo, Brazil..
    Wahren-Herlenius, M.
    Karolinska Univ Hosp, Stockholm, Sweden..
    Mariette, X.
    Paris Sud Univ, Paris, France..
    Ramos-Casals, M.
    Hosp Clin Barcelona, Barcelona, Spain..
    Ethnic Differences Strongly Influence The Phenotypic Expression of Primary Sjögren: Study of 7887 Patients from 20 Countries on 5 Continents (EULAR-SS Task Force Big Data Sjögren Project)2016In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 75, p. 772-772Article in journal (Other academic)
  • 33. Brito-Zerón, Pilar
    et al.
    Acar-Denizli, Nihan
    Zeher, Margit
    Rasmussen, Astrid
    Seror, Raphaele
    Theander, Elke
    Li, Xiaomei
    Baldini, Chiara
    Gottenberg, Jacques-Eric
    Danda, Debashish
    Quartuccio, Luca
    Priori, Roberta
    Hernandez-Molina, Gabriela
    Kruize, Aike A
    Valim, Valeria
    Kvarnstrom, Marika
    Sene, Damien
    Gerli, Roberto
    Praprotnik, Sonja
    Isenberg, David
    Solans, Roser
    Rischmueller, Maureen
    Kwok, Seung-Ki
    Nordmark, Gunnel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Suzuki, Yasunori
    Giacomelli, Roberto
    Devauchelle-Pensec, Valerie
    Bombardieri, Michele
    Hofauer, Benedikt
    Bootsma, Hendrika
    Brun, Johan G
    Fraile, Guadalupe
    Carsons, Steven E
    Gheita, Tamer A
    Morel, Jacques
    Vollenveider, Cristina
    Atzeni, Fabiola
    Retamozo, Soledad
    Horvath, Ildiko Fanny
    Sivils, Kathy
    Mandl, Thomas
    Sandhya, Pulukool
    De Vita, Salvatore
    Sanchez-Guerrero, Jorge
    van der Heijden, Eefje
    Trevisani, Virginia Fernandes Moça
    Wahren-Herlenius, Marie
    Mariette, Xavier
    Ramos-Casals, Manuel
    Influence of geolocation and ethnicity on the phenotypic expression of primary Sjögren's syndrome at diagnosis in 8310 patients: a cross-sectional study from the Big Data Sjögren Project Consortium2017In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 76, no 6, p. 1042-1050Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: To analyse the influence of geolocation and ethnicity on the clinical presentation of primary Sjögren's syndrome (SjS) at diagnosis.

    METHODS: The Big Data Sjögren Project Consortium is an international, multicentre registry designed in 2014. By January 2016, 20 centres from five continents were participating. Multivariable logistic regression analyses were performed.

    RESULTS: We included 7748 women (93%) and 562 men (7%), with a mean age at diagnosis of primary SjS of 53 years. Ethnicity data were available for 7884 patients (95%): 6174 patients (78%) were white, 1066 patients (14%) were Asian, 393 patients (5%) were Hispanic, 104 patients (1%) were black/African-American and 147 patients (2%) were of other ethnicities. SjS was diagnosed a mean of 7 years earlier in black/African-American compared with white patients; the female-to-male ratio was highest in Asian patients (27:1) and lowest in black/African-American patients (7:1); the prevalence of sicca symptoms was lowest in Asian patients; a higher frequency of positive salivary biopsy was found in Hispanic and white patients. A north-south gradient was found with respect to a lower frequency of ocular involvement in northern countries for dry eyes and abnormal ocular tests in Europe (OR 0.46 and 0.44, respectively) and Asia (OR 0.18 and 0.49, respectively) compared with southern countries. Higher frequencies of antinuclear antibodies (ANAs) were reported in northern countries in America (OR=1.48) and Asia (OR=3.80) while, in Europe, northern countries had lowest frequencies of ANAs (OR=0.67) and Ro/La (OR=0.69).

    CONCLUSIONS: This study provides the first evidence of a strong influence of geolocation and ethnicity on the phenotype of primary SjS at diagnosis.

  • 34. Castillejo-Lopez, Casimiro
    et al.
    Delgado-Vega, Angélica M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics.
    Wojcik, Jerome
    Kozyrev, Sergey V.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Thavathiru, Elangovan
    Wu, Ying-Yu
    Sanchez, Elena
    Pöllmann, David
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Lopez-Egido, Juan R.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Fineschi, Serena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Dominguez, Nicolas
    Lu, Rufei
    James, Judith A.
    Merrill, Joan T.
    Kelly, Jennifer A.
    Kaufman, Kenneth M.
    Moser, Kathy L.
    Gilkeson, Gary
    Frostegård, Johan
    Pons-Estel, Bernardo A.
    D'Alfonso, Sandra
    Witte, Torsten
    Luis Callejas, Jose
    Harley, John B.
    Gaffney, Patrick M.
    Martin, Javier
    Guthridge, Joel M.
    Alarcon-Riquelme, Marta E.
    Genetic and physical interaction of the B-cell systemic lupus erythematosus-associated genes BANK1 and BLK2012In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 71, no 1, p. 136-142Article in journal (Refereed)
    Abstract [en]

    Objectives

    Altered signalling in B cells is a predominant feature of systemic lupus erythematosus (SLE). The genes BANK1 and BLK were recently described as associated with SLE. BANK1 codes for a B-cell-specific cytoplasmic protein involved in B-cell receptor signalling and BLK codes for an Src tyrosine kinase with important roles in B-cell development. To characterise the role of BANK1 and BLK in SLE, a genetic interaction analysis was performed hypothesising that genetic interactions could reveal functional pathways relevant to disease pathogenesis.

    Methods

    The GPAT16 method was used to analyse the gene-gene interactions of BANK1 and BLK. Confocal microscopy was used to investigate co-localisation, and immunoprecipitation was used to verify the physical interaction of BANK1 and BLK.

    Results

    Epistatic interactions between BANK1 and BLK polymorphisms associated with SLE were observed in a discovery set of 279 patients and 515 controls from northern Europe. A meta-analysis with 4399 European individuals confirmed the genetic interactions between BANK1 and BLK. As BANK1 was identified as a binding partner of the Src tyrosine kinase LYN, the possibility that BANK1 and BLK could also show a protein-protein interaction was tested. The co-immunoprecipitation and co-localisation of BLK and BANK1 were demonstrated. In a Daudi cell line and primary naive B cells endogenous binding was enhanced upon B-cell receptor stimulation using anti-IgM antibodies.

    Conclusions

    This study shows a genetic interaction between BANK1 and BLK, and demonstrates that these molecules interact physically. The results have important consequences for the understanding of SLE and other autoimmune diseases and identify a potential new signalling pathway.

  • 35. Cerqueira, C. F.
    et al.
    Ossipova, E.
    Hansson, M.
    Mathsson, L.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Klareskog, L.
    Rönnelid, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Jakobsson, P-J
    Neutralization of Acpa in Rheumatoid Arthritis -a Novel Principle of Treatment2013In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 72, no S3, p. 174-174Article in journal (Other academic)
  • 36.
    Cerqueira, C. Fernandes
    et al.
    Karolinska Inst, Karolinska Univ Hosp, Rheumatol Unit, Dept Med, Stockholm, Sweden..
    Sohrabian, Azita
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Albrecht, I.
    Karolinska Inst, Karolinska Univ Hosp, Rheumatol Unit, Dept Med, Stockholm, Sweden..
    Notarnicola, A.
    Karolinska Inst, Karolinska Univ Hosp, Rheumatol Unit, Dept Med, Stockholm, Sweden..
    Ossipova, E.
    Karolinska Inst, Karolinska Univ Hosp, Rheumatol Unit, Dept Med, Stockholm, Sweden..
    Lengqvist, J.
    Karolinska Inst, Karolinska Univ Hosp, Rheumatol Unit, Dept Med, Stockholm, Sweden..
    Fati, M.
    Karolinska Inst, Resp Med Unit, Dept Med, Karolinska Univ Hosp, Stockholm, Sweden..
    Pruijn, G. J.
    Radboud Univ Nijmegen, Dept Biomol Chem, Radboud Inst Mol Life Sci, Nijmegen, Netherlands.;Radboud Univ Nijmegen, Inst Mol & Mat, Nijmegen, Netherlands..
    Grunewald, J.
    Karolinska Inst, Resp Med Unit, Dept Med, Karolinska Univ Hosp, Stockholm, Sweden..
    Rönnelid, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Lundberg, I. E.
    Karolinska Inst, Karolinska Univ Hosp, Rheumatol Unit, Dept Med, Stockholm, Sweden..
    Jakobsson, P. -J
    Characterization of Extracellular Histidyl-TRNA Synthetase in Myositis2016In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 75, p. 736-737Article in journal (Other academic)
  • 37. Cerqueira, C.
    et al.
    Ossipova, E.
    Hansson, M.
    Mathsson, L.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Klareskog, L.
    Rönnelid, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Jakobsson, P-J
    Neutralisation of ACPA – A Way to Go?2013In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 72, no S1, p. A68-A68Article in journal (Other academic)
  • 38. Checa, C. Magro
    et al.
    Zirkzee, E. J. M.
    Beaart, H. J. L.
    Sohrabian, Azita
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Rönnelid, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Trouw, L. A.
    Huizinga, T. W. J.
    Steup-Beekman, G. M.
    Cluster Analysis of an ARRAY of Autoantibodies in Neuropsychiatric Systemic Lupus Erythematosus (NPSLE)2014In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 73, p. 532-533Article in journal (Other academic)
  • 39. Dahlqvist, S. Rantapaa
    et al.
    Arlestig, L.
    Brink, M.
    Rönnelid, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Klareskog, L.
    Clusters of Single Nucleotide Polymorphisms Within the Hla-Drb1 Gene in Relation to Antibodies Against Citrullinated Peptides in Individuals Prior to the Development of Rheumatoid Arthritis2013In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 72, no S3, p. 112-113Article in journal (Other academic)
  • 40. de Jong, T. D.
    et al.
    Vosslamber, S.
    Eloranta, Maija-Leena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Mantel, E.
    Gelderman, K. A.
    von Blomberg, M. E.
    Bultink, I. E.
    Voskuyl, A. E.
    Verweij, C. L.
    On the Origin of the Type I Interferon Activity in Rheumatoid Arthritis2013In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 72, no S1, p. A79-A79Article in journal (Other academic)
  • 41.
    Delgado-Vega, Angélica M.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics.
    Dozmorov, Mikhail G.
    Bernal Quiros, Manuel
    Wu, Ying-Yu
    Martinez-Garcia, Belen
    Kozyrev, Sergey V.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Frostegård, Johan
    Truedsson, Lennart
    de Ramon, Enrique
    Gonzalez-Escribano, Maria F.
    Ortego-Centeno, Norberto
    Pons-Estel, Bernardo A.
    D'Alfonso, Sandra
    Sebastiani, Gian Domenico
    Witte, Torsten
    Lauwerys, Bernard R.
    Endreffy, Emoke
    Kovacs, Laszlo
    Vasconcelos, Carlos
    da Silva, Berta Martins
    Wren, Jonathan D.
    Martin, Javier
    Castillejo-Lopez, Casimiro
    Alarcon-Riquelme, Marta E.
    Fine mapping and conditional analysis identify a new mutation in the autoimmunity susceptibility gene BLK that leads to reduced half-life of the BLK protein2012In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 71, no 7, p. 1219-1226Article in journal (Refereed)
    Abstract [en]

    Objectives

    To perform fine mapping of the autoimmunity susceptibility gene BLK and identify functional variants involved in systemic lupus erythematosus (SLE).

    Methods

    Genotyping of 1163 European SLE patients and 1482 controls and imputation were performed covering the BLK gene with 158 single-nucleotide polymorphisms. Logistic regression analysis was done using PLINK and conditional analyses using GENABEL's test score. Transfections of BLK constructs on HEK293 cells containing the novel mutation or the wild type form were analysed for their effect on protein half-life using a protein stability assay, cycloheximide and western blot. CHiP-qPCR for detection of nuclear factor. B (NFkB) binding.

    Results

    Fine mapping of BLK identified two independent genetic effects with functional consequences: one represented by two tightly linked associated haplotype blocks significantly enriched for NF kappa B-binding sites and numerous putative regulatory variants whose risk alleles correlated with low BLK mRNA levels. Binding of NFkBp50 and p65 to an associated 1.2 Kb haplotype segment was confirmed. A second independent genetic effect was represented by an Ala71Thr, low-frequency missense substitution with an OR = 2.31 (95% CI 1.38 to 3.86). The 71Thr decreased BLK protein half-life.

    Conclusions

    These results show that rare and common regulatory variants in BLK are involved in disease susceptibility and both, albeit independently, lead to reduced levels of BLK protein.

  • 42.
    Eloranta, Maija-Leena
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Franck-Larsson, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Lövgren, Tanja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Kalamajski, Sebastian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Rönnblom, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Rubin, Kristofer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Alm, Gunnar V.
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Type I interferon system activation and association with disease manifestations in systemic sclerosis2010In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 69, no 7, p. 1396-1402Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: To study the presence of interferogenic autoantibodies in systemic sclerosis (SSc) and their correlation with clinical manifestations, serum levels of interferon alpha (IFNalpha) and chemokines of importance in the disease process. METHODS: Peripheral blood mononuclear cells (PBMCs) or purified plasmacytoid dendritic cells (pDCs) from healthy donors were stimulated with sera from patients with SSc (n=70) or healthy individuals (n=30), together with necrotic or apoptotic cell material. The IFNalpha produced and serum levels of IFNalpha, IFN-inducible protein-10 (IP-10)/chemokine (C-X-C motif) ligand 10, monocyte chemoattractant protein-1 (MCP-1)/(C-C motif) ligand-2 (CCL-2), macrophage inflammatory protein-1alpha (MIP-1alpha)/CCL-3 and RANTES/CCL-5 were measured and correlated with the presence of autoantibodies and clinical manifestations in the patients with SSc. RESULTS: Sera from both diffuse SSc and limited SSc contained interferogenic antibodies, which correlated with the presence of anti-ribonucleoprotein and anti-Sjögren syndrome antigen autoantibodies. The pDCs were responsible for the IFNalpha production which required interaction with FcgammaRII and endocytosis. Increased serum levels of IP-10 were associated with vascular manifestations such as cardiac involvement (p=0.027) and pulmonary arterial hypertension (p=0.036). Increased MCP-1 or IFNalpha serum levels were associated with lung fibrosis (p=0.019 and 0.048, respectively). Digital ulcers including digital loss were associated with increased serum levels of IFNalpha (p=0.029). CONCLUSION: An activated type I IFN system previously seen in several other systemic autoimmune diseases is also present in SSc and may contribute to the vascular pathology and affect the profibrotic process.

  • 43.
    Elshafie, Amir I.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Nourein, Sahwa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Manivel, Vivek Anand
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Sohrabian, Azita
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Elidrisi, Mawahib I. E.
    Elagib, Elnour M.
    Nur, Musa A. M.
    Rönnelid, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    High Disease Activity and Erosion Rate in Sudanese Rheumatoid Arthritis Patients2013In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 72, no S1, p. A45-A46Article in journal (Other academic)
  • 44.
    Elshafie, Amir I.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Nourein, Sahwa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Manivel, Vivek Anand
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Sohrabian, Azita
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Elidrisi, Mawahib I. E.
    Elagib, Elnour M.
    Nur, Musa A. M.
    Rönnelid, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    IgA Rheumatoid Factor is more Predominant than anti-CCP in Sudanese Rheumatoid Arthritis Patients, whereas IgG RF is a Strong Prognostic Marker and Associated with Early Onse2013In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 72, no S1, p. A77-A77Article in journal (Other academic)
  • 45.
    Eriksson, Karin G.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Zickert, Agneta
    Sandling, Johanna K.
    Jonsen, Andreas
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Behrens, Timothy W.
    Graham, Robert R.
    Ortmann, Ward
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Gunnarsson, Iva
    Nordmark, Gunnel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Association of STAT4, IRF5 and BLK polymorphisms with severity and outcome in lupus nephritis2012In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 71, p. A55-A55Article in journal (Other academic)
  • 46. Falkenburg, W.
    et al.
    Bos, W. H.
    Sohrabian, Azita
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Rönnelid, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Wolbink, G.
    van Schaardenburg, D.
    Igg ACPA Level Increase Drives Rheumatoid Factor Response Maturation in Patients before Onset of Clinically Apparent Rheumatoid Arthritis2014In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 73, no S2, p. 359-360Article in journal (Other academic)
  • 47. Fisher, Benjamin A.
    et al.
    Plant, Darren
    Brode, Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    van Vollenhoven, Ronald F.
    Mathsson, Linda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Symmons, Deborah
    Lundberg, Karin
    Rönnelid, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Venables, Patrick J.
    Antibodies to citrullinated α-enolase peptide 1 and clinical and radiological outcomes in rheumatoid arthritis2011In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 70, no 6, p. 1095-1098Article in journal (Refereed)
    Abstract [en]

    INTRODUCTION:

    The anticyclic citrullinated peptide 2 (anti-CCP2) assay is a generic test for antibodies to citrullinated proteins, among which there is a subset of about 50% with antibodies to citrullinated enolase peptide 1 (CEP-1). The anti-CEP-1 positive subset is strongly associated with the HLA-DRB1 shared epitope and its interaction with smoking.

    OBJECTIVE:

    To investigate whether anti-CEP-1 antibodies may be helpful in predicting outcome.

    METHODS:

     Anti-CEP-1 and anti-CCP2 antibodies were measured in two prospective cohorts of patients (Karolinska n=272, Norfolk Arthritis Register (NOAR) n=408) with early rheumatoid arthritis (RA). Outcomes measured were C-reactive protein, erythrocyte sedimentation rate, visual analogue scales for pain and global assessment of disease activity, Health Assessment Questionnaire, physician's assessment, swollen and tender joint counts and radiological progression.

    RESULTS:

     Anti-CCP2 antibodies were present in 57% and 50%, and anti-CEP-1 in 27% and 24% of the Karolinska and NOAR cohorts, respectively. Importantly, no statistically significant differences in clinical outcomes were demonstrated between the anti-CEP-1-/CCP2+ and the anti-CEP-1+/CCP2+ subsets in either cohort, or in radiological outcomes in the Karolinska cohort.

    CONCLUSION:

     Although antibodies to specific citrullinated proteins may have distinct genetic and environmental risk factors, the similarity in clinical phenotype suggests that they share common pathways in the pathogenesis of joint disease in RA.

     

  • 48.
    Frisell, T.
    et al.
    Karolinska Inst, Stockholm, Sweden..
    Baecklund, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Bengtsson, K.
    Sahlgrens Acad, Gothenburg, Sweden..
    Di Giuseppe, D.
    Karolinska Inst, Stockholm, Sweden..
    Forsblad-d'Elia, H.
    Umea Univ, Umea, Sweden..
    Askling, J.
    Karolinska Inst, Stockholm, Sweden..
    Confounding By Indication Will Make Non-Tnfi Bdmards Appear More Harmful Than Tnfi Bdmards A Nationwide Study Of Channeling In Sweden 2010-20142017In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 76, p. 134-135Article in journal (Other academic)
  • 49. Frisell, Thomas
    et al.
    Baecklund, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Bengtsson, Karin
    Di Giuseppe, Daniela
    Forsblad-d'Elia, Helena
    Askling, Johan
    Patient characteristics influence the choice of biological drug in RA, and will make non-TNFi biologics appear more harmful than TNFi biologics2018In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 77, no 5, p. 650-657Article in journal (Refereed)
    Abstract [en]

    Objectives: With the wide range of biological disease-modifying anti-rheumatic drugs (bDMARDs) available for treating rheumatoid arthritis (RA), and limited evidence to guide the choice for individual patients, we wished to evaluate whether patient characteristics influence the choice of bDMARD in clinical practice, and to quantify the extent to which this would bias direct comparisons of treatment outcome.

    Methods: Register-based study of all Swedish patients with RA initiating necrosis factor inhibitor (TNFi), rituximab, abatacept or tocilizumab in 2011–2015 as their first bDMARD (n=6481), or after switch from TNFi as first bDMARD (n=2829). Group differences in demographics, clinical characteristics and medical history were assessed in multivariable regression models. Predicted differences in safety and treatment outcomes were calculated as a function of patient characteristics, through regression modelling based on observed outcomes among patients with RA starting bDMARDs 2006–2010.

    Results: Patients starting non-TNFi were older than those starting TNFi, had lower socioeconomic status, higher disease activity and higher burden of diseases including malignancy, serious infections and diabetes. Differences were most pronounced at first bDMARD initiation. These factors were linked to treatment outcome independent of therapy, yielding worse apparent safety and effectiveness for non-TNFi biologics, most extreme for rituximab. Standardising to the age/sex distribution of the TNFi group reduced differences considerably.

    Conclusions: There was significant channelling of older and less healthy patients with RA to non-TNFi bDMARDs, in particular as first bDMARD. Whether this channelling represents a maximised benefit/risk ratio is unclear. Unless differences in age, medical history and disease activity are accounted for, they will substantially confound non-randomised comparative studies of available bDMARDs’ safety and effectiveness.

  • 50. Gerlag, Danielle M.
    et al.
    Raza, Karim
    van Baarsen, Lisa G. M.
    Brouwer, Elisabeth
    Buckley, Christopher D.
    Burmester, Gerd R.
    Gabay, Cem
    Catrina, Anca I.
    Cope, Andrew P.
    Cornelis, Francois
    Dahlqvist, Solbritt Rantapaa
    Emery, Paul
    Eyre, Stephen
    Finckh, Axel
    Gay, Steffen
    Hazes, Johanna M.
    van der Helm-van Mil, Annette
    Huizinga, Tom W. J.
    Klareskog, Lars
    Kvien, Tore K.
    Lewis, Cathryn
    Machold, Klaus P.
    Rönnelid, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    van Schaardenburg, Dirkjan
    Schett, Georg
    Smolen, Josef S.
    Thomas, Sue
    Worthington, Jane
    Tak, Paul P.
    EULAR recommendations for terminology and research in individuals at risk of rheumatoid arthritis: report from the Study Group for Risk Factors for Rheumatoid Arthritis2012In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 71, no 5, p. 638-641Article in journal (Refereed)
    Abstract [en]

    The Study Group for Risk Factors for Rheumatoid Arthritis was established by the EULAR Standing Committee on Investigative Rheumatology to facilitate research into the preclinical and earliest clinically apparent phases of rheumatoid arthritis (RA). This report describes the recommendation for terminology to be used to define specific subgroups during different phases of disease, and defines the priorities for research in this area. Terminology was discussed by way of a three-stage structured process: A provisional list of descriptors for each of the possible phases preceding the diagnosis of RA were circulated to members of the study group for review and feedback. Anonymised comments from the members on this list were fed back to participants before a 2-day meeting. 18 participants met to discuss these data, agree terminologies and prioritise important research questions. The study group recommended that, in prospective studies, individuals without RA are described as having: genetic risk factors for RA; environmental risk factors for RA; systemic autoimmunity associated with RA; symptoms without clinical arthritis; unclassified arthritis; which may be used in a combinatorial manner. It was recommended that the prefix 'pre-RA with:' could be used before any/any combination of the five points above but only to describe retrospectively a phase that an individual had progressed through once it was known that they have developed RA. An approach to dating disease onset was recommended. In addition, important areas for research were proposed, including research of other tissues in which an adaptive immune response may be initiated, and the identification of additional risk factors and biomarkers for the development of RA, its progression and the development of extra-articular features. These recommendations provide guidance on approaches to describe phases before the development of RA that will facilitate communication between researchers and comparisons between studies. A number of research questions have been defined, requiring new cohorts to be established and new techniques to be developed to image and collect material from different sites.

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