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  • 1. 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.

  • 2.
    Andrade, Luis E. C.
    et al.
    Univ Fed Sao Paulo, Escola Paulista Med, Dept Med, Rheumatol Div, Rua Botucatu 740, BR-04023062 Sao Paulo, SP, Brazil;Fleury Med & Hlth Labs, Immunol Div, Sao Paulo, Brazil.
    Klotz, Werner
    Med Univ Innsbruck, Dept Internal Med 2, Innsbruck, Austria.
    Herold, Manfred
    Med Univ Innsbruck, Dept Internal Med 2, Innsbruck, Austria.
    Conrad, Karsten
    Tech Univ Dresden, Inst Immunol, Dresden, Germany.
    Rönnelid, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Fritzler, Marvin J.
    Univ Calgary, Cumming Sch Med, Dept Med, Calgary, AB, Canada.
    von Mühlen, Carlos A.
    Brazilian Soc Autoimmun, Porto Alegre, RS, Brazil.
    Satoh, Minoru
    Univ Occupat & Environm Hlth, Dept Clin Nursing, Kitakyushu, Fukuoka, Japan.
    Damoiseaux, Jan
    Maastricht Univ, Med Ctr, Cent Diagnost Lab, Maastricht, Netherlands.
    Cruvinel, Wilson de Melo
    Univ Catolica Goias, Goiania, Go, Brazil.
    Chan, Edward K. L.
    Univ Florida, Dept Oral Biol, Gainesville, FL 32610 USA.
    International consensus on antinuclear antibody patterns: definition of the AC-29 pattern associated with antibodies to DNA topoisomerase I2018In: Clinical Chemistry and Laboratory Medicine, ISSN 1434-6621, E-ISSN 1437-4331, Vol. 56, no 10, p. 1783-1788Article in journal (Refereed)
    Abstract [en]

    The indirect immunofluorescence assay (IFA) on HEp-2 cells is the reference method for autoantibody screening. The HEp-2 IFA pattern provides useful information on the possible autoantibodies in the sample. The International Consensus on Antinuclear Antibody Patterns (ICAP) initiative seeks to define and harmonize the nomenclature of HEp-2 IFA patterns. The most relevant and usual patterns have been assigned an alphanumeric code from anti-cell (AC)-1 to AC-28 and were organized into a classification algorithm (www.ANApatterns.org). The systemic sclerosis-associated autoantibodies to DNA topoisomerase I (Topo I) produce a peculiar composite 5-element HEp-2 IFA pattern (Topo I-like pattern) comprising the staining of the nucleus, metaphase chromatin plate, nucleolar organizing region, cytoplasm and nucleolus. In a recent assessment of the European Consensus Finding Study Group on autoantibodies, a well-defined anti-Topo I sample was blindly analyzed and classified according to ICAP AC patterns by 43 participant laboratories across Europe. There were wide variations among these laboratories in reporting nuclear, nucleolar and cytoplasmic patterns, indicating the inadequacy of the existing AC patterns to report the Topo I-like pattern. Several ICAP member laboratories independently demonstrated the overall consistency of the HEp-2 IFA Topo I-like pattern using HEp-2 slides from different manufacturers. The ICAP committee reviewed 24 candidate images and selected the four most representative images to be available on the ICAP website. The proper recognition of the AC-29 pattern should trigger suspicion of the presence of anti-Topo I antibodies, which may engender appropriate analyte-specific reflex tests to confirm the autoantibody specificity.

  • 3. Arlestig, Lisbeth
    et al.
    Brink, Mikael
    Hansson, Monika
    Jakobsson, Per Johan
    Holmdahl, Rikard
    Mathsson, Linda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science.
    Rönnelid, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Klareskog, Lars
    Rantapaa-Dahlqvist, Solbritt M.
    Single Nucleotide Polymorphisms within the HLA-DRB1 Gene in Relation to Antibodies Against Citrullinated Peptides in Individuals Prior to the Development of Rheumatoid Arthritis2012In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 64, no S10, p. S180-S180Article in journal (Other academic)
  • 4.
    Baecklund, Eva
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Backlin, Carin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Rönnelid, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Toes, R
    Huizinga, Twj
    Åhlin, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Askling, J
    Hochberg, F H
    Klareskog, L
    Kay, J
    Smedby, K E
    Anti-cyclic citrullinated peptide antibodies, other common autoantibodies, and smoking as risk factors for lymphoma in patients with rheumatoid arthritis2018In: Scandinavian Journal of Rheumatology, ISSN 0300-9742, E-ISSN 1502-7732, Vol. 47, no 4, p. 270-275Article in journal (Refereed)
    Abstract [en]

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

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

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

    CONCLUSION: In this study, neither anti-CCP antibodies (IgG, IgG1–4, IgM, or IgA), nor other common autoantibodies, nor smoking predicted lymphoma risk in RA

  • 5. Berg, L
    et al.
    Rönnelid, Johan
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology. Klinisk immunologi.
    Klareskog, Lars
    Bucht, A
    T-cell receptor CD3z expression in rheumatoid arthritis and its influence on in vitro cellular hyporesponsiveness.2000In: Clin Exp Immunol, Vol. 120, p. 174-182Article in journal (Refereed)
  • 6. Berg, L
    et al.
    Rönnelid, Johan
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology. Klinisk immunologi.
    Sanjeevi, CB
    Lampa, J
    Klareskog, L
    Cellular reactivity to collagen type II in rheumatoid arthritis is associated with HLA DRB1*0401 and DQ82000In: Arthritis Research, Vol. 2, p. 75-78Article in journal (Refereed)
  • 7.
    Berntson, Lillemor
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Nordal, Ellen
    Fasth, Anders
    Aalto, Kristiina
    Herlin, Troels
    Nielsen, Susan
    Rygg, Marite
    Zak, Marek
    Rönnelid, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Anti-type II collagen antibodies, anti-CCP, IgA RF and IgM RF are associated with joint damage, assessed eight years after onset of juvenile idiopathic arthritis (JIA)2014In: Pediatric Rheumatology, ISSN 1546-0096, E-ISSN 1546-0096, Vol. 12, p. 22-Article in journal (Refereed)
    Abstract [en]

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

  • 8.
    Blom, Kristin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    ElShafie, Amir Ibrahim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Alribat Univ Hosp, Dept Clin Pathol & Microbiol, Khartoum, Sudan.
    Jönsson, Ulla-Britt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Rönnelid, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Håkansson, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Venge, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    The genetically determined production of the alarmin eosinophil-derived neurotoxin is reduced in visceral leishmaniasis2018In: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), ISSN 0903-4641, E-ISSN 1600-0463, Vol. 126, no 1, p. 85-91Article in journal (Refereed)
    Abstract [en]

    Visceral leishmaniasis (VL) is the most severe form of leishmaniasis. Recent findings indicate that dendritic cells have a key role in the defense against the Leishmania parasite and that the activity of this cell may be modified by the eosinophil secretory protein eosinophil-derived neurotoxin (EDN). We hypothesized that the interactions between dendritic cells and EDN might be of importance in the disease development. Cellular content of EDN was analyzed by ELISA. The single-nucleotide polymorphisms at positions 405, 416, and 1122 in the EDN gene were analyzed by real-time PCR with TaqMan((R)) reagents. The study cohorts comprised 239 Sudanese subjects (65 healthy controls and 174 with VL) and 300 healthy Swedish controls. The eosinophil content of EDN was lower in VL as compared with controls (p < 0.0001). The EDN405 (G>C) genotype distribution was similar among Swedish and Sudanese controls, whereas VL subjects had a higher prevalence of the EDN405-GG genotype (p < 0.0001). The content of EDN in the eosinophils was closely linked to the EDN405 polymorphism (p = 0.0002). Our findings suggest that the predisposition to acquire VL is related to the genetic polymorphism of the EDN gene and the reduced production by the eosinophil of this gene product.

  • 9. Bos, Wouter H.
    et al.
    van de Stadt, Lotte A.
    Sohrabian, Azita
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Rönnelid, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    van Schaardenburg, Dirkjan
    Development of anti-citrullinated protein antibody and rheumatoid factor isotypes prior to the onset of rheumatoid arthritis2014In: ARTHRITIS RES THER, ISSN 1478-6354, Vol. 16, no 2, p. 405-Article in journal (Refereed)
  • 10.
    Bremer, Hanna D.
    et al.
    Swedish Univ Agr Sci SLU, Dept Clin Sci, Box 7054, SE-75007 Uppsala, Sweden..
    Lattwein, Erik
    Euroimmun AG, Lubeck, Germany..
    Renneker, Stefanie
    Euroimmun AG, Lubeck, Germany..
    Lilliehook, Inger
    Swedish Univ Agr Sci, Univ Anim Hosp, Clin Pathol Lab, Uppsala, Sweden..
    Rönnelid, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Hansson-Hamlin, Helene
    Swedish Univ Agr Sci SLU, Dept Clin Sci, Box 7054, SE-75007 Uppsala, Sweden..
    Identification of specific antinuclear antibodies in dogs using a line immunoassay and enzyme-linked immunosorbent assay2015In: Veterinary Immunology and Immunopathology, ISSN 0165-2427, E-ISSN 1873-2534, Vol. 168, no 3-4, p. 233-241Article in journal (Refereed)
    Abstract [en]

    Circulating antinuclear antibodies (ANA) are commonly present in the systemic autoimmune disease Systemic Lupus Erythematosus (SLE) and in other systemic rheumatic diseases, in humans as well as in dogs. The indirect immunofluorescence (IIF)-ANA test is the standard method for detecting ANA. Further testing for specific ANA with immunoblot techniques or ELISAs is routinely performed in humans to aid in the diagnosis and monitoring of disease. Several specific ANA identified in humans have been identified also in suspected canine SLE but, in contrast to humans, investigation of autoantibodies in canine SLE is mainly restricted to the IIF-ANA test. Our aim was to identify both known and novel specific ANA in dogs and to investigate if different IIF-ANA patterns are associated with different specific ANA in dogs. Sera from 240 dogs with suspicion of autoimmune disease (210 IIF-ANA positive (ANA(pos)) and 30 IIF-ANA negative (ANA(neg))) as well as sera from 27 healthy controls were included. The samples were analysed with a line immunoassay, LIA (Euroline ANA Profile 5, Euroimmun, Lubeck, Germany) and four different ELISAs (Euroimmun). The ANA(pos) dogs were divided in two groups depending on the type of IIF-ANA pattern. Of the 210 ANA(pos) samples 68 were classified as ANA homogenous (ANA(H)) and 141 as ANA speckled (ANA(S)), one sample was not possible to classify. Dogs in the ANA(H) group had, compared to the other groups, most frequently high levels of anti-double stranded deoxyribonucleic acid (dsDNA) and anti-nucleosome ANA. Anti-dsDNA antibodies were confirmed in some dogs with the Crithidia luciliae indirect immunofluorescence test (CLIFT).The frequency of ANA(H) dogs with values above those observed in the healthy group was significantly higher compared to ANA(S) dogs for anti-dsDNA, anti-nucleosome, and anti-histone reactivity. Dogs in the ANA(S) group had, compared to the other groups, most frequently high levels of anti-ribonucleoproteins (RNP) and/or anti-Smith (Sm) antibodies. Reactivity against Sjogren's syndrome related antigens (SS)-A (including the Ro-60 and Ro-52 subcomponents), SS-B, histidyl tRNA synthetase (Jo-1), topoisomerase I antigen (Scl-70), polymyositis-scleroderma antigen (PM-Scl) and proliferating cell nuclear antigen (PCNA) was also noted in individual dogs. In conclusion, by using a commercial LIA and different ELISAs originally developed for detection of human ANA, we identified several specific ANA in serum samples from dogs sampled for IIF-ANA testing. Further, we found that the types of IIF-ANA pattern were associated with reactivity against some particular nuclear antigens.

  • 11.
    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)
  • 12. Brink, M.
    et al.
    Verheul, M. K.
    Rönnelid, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Holmdahl, R.
    Toes, R. E. M.
    Klareskog, L.
    Trouw, L. A.
    Dahlqvist, S. R.
    The presence of anti-carbamylated protein antibodies prior to onset of symptoms of rheumatoid arthritis (RA) is associated with radiological progression in early RA2014In: Scandinavian Journal of Rheumatology, ISSN 0300-9742, E-ISSN 1502-7732, Vol. 43, no S127, p. 21-22Article in journal (Other academic)
  • 13. 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)
  • 14. Brink, Mikael
    et al.
    Hansson, Monika
    Mathsson, Linda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Jakobsson, Per-Johan
    Holmdahl, Rikard
    Hallmans, Goran
    Stenlund, Hans
    Rönnelid, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Klareskog, Lars
    Rantapaa-Dahlqvist, Solbritt
    Multiplex Analyses of Antibodies Against Citrullinated Peptides in Individuals Prior to Development of Rheumatoid Arthritis2013In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 65, no 4, p. 899-910Article in journal (Refereed)
    Abstract [en]

    Objective The presence of antibodies against cyclic citrullinated peptides has been demonstrated to precede the onset of symptoms of rheumatoid arthritis (RA) by several years. The aim of this study was to analyze antibodies against 10 citrullinated autoantigen-derived peptides for reactivity before the onset of RA symptoms. Methods A casecontrol study was conducted within the Medical Biobank of Northern Sweden. The study was performed in 409 individuals, 386 of whom donated 717 blood samples before the onset of symptoms of RA (pre-patients). The median period of time predating the onset of RA was 7.4 years. A total of 1,305 population-based control subjects were also studied. Antibodies to 10 citrullinated peptides, fibrinogen 573 (Fib573), Fib591, Fib3652, Fib72, Fib74, -enolase (citrullinated -enolase peptide 1 [CEP-1]), triple-helical type II collagen peptide C1 (citC1III), filaggrin, vimentin 217 (Vim217), and Vim6075, were analyzed using a microarray system. Results The fluorescence intensity of antibodies against Fib3652, Fib74, CEP-1, citC1III, and filaggrin was significantly increased in pre-patients compared with controls (P < 0.001). The levels of the earliest-detectable antibodies (Fib591 and Vim6075) fluctuated over time, with only a slight increase after the onset of disease. The frequency of antibodies against Fib3652, CEP-1, and filaggrin increased gradually, reaching the highest levels before symptom onset. The frequency of a cluster of antibodies, citC1III, Fib573, and Fib74, increased only slightly before the onset of symptoms but increased prominently after disease onset. The odds ratio for the development of RA in individuals expressing both CEP-1 and Fib3652 antibodies (using data from samples obtained <3.35 years predating symptom onset) was 40.4 (95% confidence interval 19.882.3) compared with having either antibody alone. Conclusion Development of an immune response toward citrullinated peptides is initially restricted but expands with time to induce a more specific response, with levels, particularly those of antibodies against CEP-1, Fib3652, and filaggrin, increasing during the predating time period closer to the onset of symptoms.

  • 15. Brink, Mikael
    et al.
    Hansson, Monika
    Mathsson-Alm, Linda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Rönnelid, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Klareskog, Lars
    Rantapaa-Dahlqvist, Solbritt
    Rheumatoid Factor Isotypes in Relation to Antibodies Against Citrullinated Peptides in Individuals before Onset of Rheumatoid Arthritis2014In: Arthritis & Rheumatology, ISSN 2326-5191, Vol. 66, no S10, p. S191-S191, article id 447Article in journal (Other academic)
  • 16.
    Brink, Mikael
    et al.
    Umea Univ, Dept Publ Hlth & Clin Med, Div Rheumatol, SE-90185 Umea, Sweden..
    Hansson, Monika
    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. Thermo Fisher Sci, Uppsala, Sweden..
    Wijayatunga, Priyantha
    Umea Univ, Dept Stat, S-90187 Umea, Sweden..
    Verheul, Marije K.
    Leiden Univ, Med Ctr, Dept Rheumatol, Leiden, Netherlands..
    Trouw, Leendert A.
    Leiden Univ, Med Ctr, Dept Rheumatol, Leiden, Netherlands..
    Holmdahl, Rikard
    Karolinska Inst, Med Inflammat Res Med Biophys & Biochem, Stockholm, Sweden..
    Rönnelid, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Klareskog, Lars
    Karolinska Inst, Dept Med, Rheumatol Unit, Stockholm, Sweden..
    Rantapaa-Dahlqvist, Solbritt
    Umea Univ, Dept Publ Hlth & Clin Med, Div Rheumatol, SE-90185 Umea, Sweden..
    Rheumatoid factor isotypes in relation to antibodies against citrullinated peptides and carbamylated proteins before the onset of rheumatoid arthritis2016In: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 18, article id 43Article in journal (Refereed)
    Abstract [en]

    Background: The presence of rheumatoid factor (RF), anti-carbamylated protein antibodies (anti-CarP) and antibodies against citrullinated protein and peptides (ACPA) precedes the onset of symptoms of rheumatoid arthritis (RA) by several years. Relationships between the development of these antibodies are not obvious. Methods: Three isotypes [immunoglobulin A (IgA), IgG and IgM) of RF were analysed in 321 pre-symptomatic individuals who provided 598 samples collected a median of 6.2 (interquartile range 7.2) years before the onset of symptoms, and in 492 population control subjects. All samples were donated to the Biobank of Northern Sweden. RF isotypes were analysed using the EliA system (Phadia GmbH, Freiburg, Germany) with 96 % specificity according to receiver operating characteristic curves. Ten ACPA specificities were analysed using the ImmunoCAP ISAC system, and anti-CCP2 and anti-CarP antibodies were evaluated using enzyme-linked immunosorbent assays. Results: The frequencies of RF isotypes in pre-symptomatic individuals were significantly increased compared with control subjects (p < 0.0001). In samples collected >= 15 years before the onset of symptoms, the IgA-RF isotype was significantly more prevalent than the most frequent ACPAs. Combinations of IgM- and IgA-RF isotypes with ACPA specificities [a-enolase (CEP-1/Eno(5-21))], fibrinogen (Fib)beta(36-52), Fiba(580-600), filaggrin (CCP-1/Fil(307-324)) and anti-CCP2 antibodies were associated with a significantly shorter time to onset of symptoms (p < 0.001-0.05). Using conditional inference tree analysis, anti-CCP2 in combination with anti-filaggrin antibodies gave the highest probability, 97.5 %, for disease development. Conclusions: RF isotypes predicted the development of RA, particularly in combination with ACPA, anti-CCP2 or anti-CarP antibodies. The highest probability for disease development was the presence of anti-CCP2 and anti-filaggrin antibodies.

  • 17. 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)
  • 18. 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)
  • 19. Brink, Mikael
    et al.
    Verheul, Marije K.
    Rönnelid, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Berglin, Ewa
    Holmdahl, Rikard
    Toes, Rene E. M.
    Klareskog, Lars
    Trouw, Leendert A.
    Rantapaa-Dahlqvist, Solbritt
    Anti-carbamylated protein antibodies in the pre-symptomatic phase of rheumatoid arthritis, their relationship with multiple anti-citrulline peptide antibodies and association with radiological damage2015In: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 17, article id 25Article in journal (Refereed)
    Abstract [en]

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

  • 20.
    Båve, Ullvi
    et al.
    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.
    Lövgren, Tanja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Rönnelid, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Cajander, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Eloranta, Maija-Leena
    Alm, Gunnar V.
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Activation of the type I interferon system in primary Sjögren's syndrome: a possible etiopathogenic mechanism2005In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 52, no 4, p. 1185-1195Article in journal (Refereed)
    Abstract [en]

    Objective

    The etiopathogenesis of primary Sjögren's syndrome (SS) is largely unknown. In other autoimmune diseases, type I interferon (IFN) may play a pivotal role by triggering and sustaining the disease process. We therefore aimed to determine whether patients with primary SS had an activated type I IFN system.

    Methods

    Salivary gland biopsy specimens and sera from patients with primary SS were investigated for the occurrence of IFNα-producing cells and measurable IFNα levels, respectively. The ability of primary SS sera together with apoptotic or necrotic cells to induce IFNα production in normal peripheral blood mononuclear cells was examined. The IFNα inducer was characterized, and IFNα-producing cells were identified. Clinical data were correlated with the IFNα-inducing capacity of primary SS sera.

    Results

    Numerous IFNα-producing cells were detected in salivary gland biopsy specimens, despite low serum IFNα levels. Autoantibodies to RNA-binding proteins, combined with material released by necrotic or late apoptotic cells, were potent inducers of IFNα production in plasmacytoid dendritic cells (PDCs). This appeared to be attributable to RNA-containing immune complexes triggering PDCs by means of RNA and interaction with Fcγ receptor IIa. The IFNα-inducing capacity of sera was associated with positive results of a labial salivary gland biopsy (focus score ≥1) and with dermatologic, hematologic, and pulmonary manifestations.

    Conclusion

    Patients with primary SS have an activated type I IFN system. Although virus may initiate the production of IFN, the continued IFNα synthesis is caused by RNA-containing immune complexes that activate PDCs to prolong IFNα production at the tissue level. This IFNα promotes the autoimmune process by a vicious circle–like mechanism, with increased autoantibody production and formation of more endogenous IFNα inducers.

  • 21. 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)
  • 22.
    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)
  • 23. 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)
  • 24. Cerqueira, Catia
    et al.
    Ossipova, Elena
    Hansson, Monika
    Mathsson, Linda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Klareskog, Lars
    Rönnelid, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Jakobsson, Per Johan
    Neutralization Of Anti-Citrullinated Protein Antibodies - a Way To Go?2013In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 65, no Suppl. 10, p. S391-S392Article in journal (Other academic)
  • 25. 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)
  • 26. 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)
  • 27.
    Dalin, Frida
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology. Uppsala University, Science for Life Laboratory, SciLifeLab. Karolinska Inst, Ctr Mol Med, Dept Med Solna, SE-17176 Stockholm, Sweden.
    Nordling Eriksson, Gabriel
    Karolinska Inst, Dept Mol Med & Surg, SE-17176 Stockholm, Sweden.
    Dahlqvist, Per
    Umea Univ, Dept Publ Hlth & Clin Med, SE-90736 Umea, Sweden.
    Hallgren, Åsa
    Karolinska Inst, Ctr Mol Med, Dept Med Solna, SE-17176 Stockholm, Sweden.
    Wahlberg, Jeanette
    Linkoping Univ, Div Endocrinol, Dept Med & Hlth Sci, Fac Hlth Sci, SE-58183 Linkoping, Sweden.
    Ekwall, Olov
    Linkoping Univ, Div Pediat, Dept Clin & Expt Med, SE-58183 Linkoping, Sweden.
    Söderberg, Stefan
    Umea Univ, Dept Publ Hlth & Clin Med, SE-90736 Umea, Sweden.
    Rönnelid, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Olcén, Per
    Univ Orebro, Dept Lab Med, SE-70281 Orebro, Sweden.
    Winqvist, Ola
    Karolinska Inst, Karolinska Univ Hosp, Translat Immunol, Dept Med Solna, SE-17176 Stockholm, Sweden.
    Catrina, Sergiu-Bogdan
    Karolinska Inst, Karolinska Univ Hosp, Dept Endocrinol Metab & Diabet, SE-17176 Stockholm, Sweden.
    Kriström, Berit
    Umea Univ, Inst Clin Sci, Pediat, SE-90736 Umea, Sweden.
    Laudius, Maria
    Umea Univ, Dept Publ Hlth & Clin Med, SE-90736 Umea, Sweden.
    Isaksson, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity.
    Halldin Stenlid, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Paediatric Inflammation Research.
    Gustafsson, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Paediatric Inflammation Research.
    Gebre-Medhin, Gennet
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Paediatric Inflammation Research.
    Björnsdottir, Sigridur
    Karolinska Inst, Dept Mol Med & Surg, SE-17176 Stockholm, Sweden; Karolinska Inst, Karolinska Univ Hosp, Dept Endocrinol Metab & Diabet, SE-17176 Stockholm, Sweden.
    Janson, Annika
    Karolinska Inst, Dept Womens & Childrens Hlth, SE-17176 Stockholm, Sweden.
    Åkerman, Anna-Karin
    Univ Orebro, Dept Lab Med, SE-70281 Orebro, Sweden.
    Åman, Jan
    Univ Orebro, Dept Pediat, Fac Med & Hlth, SE-70281 Orebro, Sweden.
    Duchen, Karel
    Linkoping Univ, Div Pediat, Dept Clin & Expt Med, SE-58183 Linkoping, Sweden.
    Bergthorsdottir, Ragnhildur
    Univ Gothenburg, Inst Med, SE-40530 Gothenburg, Sweden; Univ Gothenburg, Dept Endocrinol, Sahlgrenska Univ Hosp, Sahlgrenska Acad, SE-40530 Gothenburg, Sweden.
    Johannsson, Gudmundur
    Univ Gothenburg, Inst Med, SE-40530 Gothenburg, Sweden; Univ Gothenburg, Dept Endocrinol, Sahlgrenska Univ Hosp, Sahlgrenska Acad, SE-40530 Gothenburg, Sweden.
    Lindskog, Emma
    Univ Gothenburg, Dept Pediat, Inst Clin Sci, SE-40530 Gothenburg, Sweden.
    Landin-Olsson, Mona
    Skane Univ Hosp, Dept Endocrinol, SE-22362 Lund, Sweden.
    Elfving, Maria
    Lund Univ, Dept Pediat, Pediat Endocrinol, Clin Sci, SE-22362 Lund, Sweden.
    Waldenström, Erik
    Skane Univ Hosp, Dept Endocrinol, SE-22362 Lund, Sweden.
    Hulting, Anna-Lena
    Karolinska Inst, Dept Mol Med & Surg, SE-17176 Stockholm, Sweden.
    Kämpe, Olle
    Karolinska Inst, Ctr Mol Med, Dept Med Solna, SE-17176 Stockholm, Sweden; Karolinska Inst, Karolinska Univ Hosp, Dept Endocrinol Metab & Diabet, SE-17176 Stockholm, Sweden.
    Bensing, Sophie
    Karolinska Inst, Dept Mol Med & Surg, SE-17176 Stockholm, Sweden; Karolinska Inst, Karolinska Univ Hosp, Dept Endocrinol Metab & Diabet, SE-17176 Stockholm, Sweden.
    Clinical and immunological characteristics of Autoimmune Addison's disease: a nationwide Swedish multicenter study2017In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 102, no 2, p. 379-389Article in journal (Refereed)
    Abstract [en]

    CONTEXT: Studies on clinical and immunological features of Autoimmune Addison's disease (AAD) are needed to understand the disease burden and increased mortality.

    OBJECTIVE: To provide upgraded data on autoimmune comorbidities, replacement therapy, autoantibody profiles and cardiovascular risk factors.

    DESIGN, SETTING AND PARTICIPANTS: Cross sectional, population-based study. 660 AAD patients were included utilizing the Swedish Addison Registry (SAR) 2008-2014. When analyzing cardiovascular risk factors, 3,594 individuals from the population-based survey in Northern Sweden, MONICA (MONItoring of Trends and Determinants of CArdiovascular Disease), served as controls.

    MAIN OUTCOME MEASURE: Prevalence of autoimmune comorbidities and cardiovascular risk factors. Autoantibodies against 13 autoantigens were determined.

    RESULTS: Sixty percent of the SAR cohort consisted of females. Mean age at diagnosis was significantly higher for females than for males (36.8 vs. 31.1 years). The proportion of 21-hydroxylase autoantibody positive patients was 83% and 62% of patients had one or more associated autoimmune diseases, more frequently coexisting in females (p<0.0001). AAD patients had lower BMI (p<0.0001) and prevalence of hypertension (p=0.027) compared with controls. Conventional hydrocortisone tablets were used by 89% of patients; with the mean dose 28.1±8.5 mg/day. The mean hydrocortisone equivalent dose normalized to body surface was 14.8±4.4 mg/m(2)/day. Higher hydrocortisone equivalent dose was associated with higher incidence of hypertension (p=0.046).

    CONCLUSIONS: Careful monitoring of AAD patients is warranted to detect associated autoimmune diseases. Contemporary Swedish AAD patients do not have increased prevalence of overweight, hypertension, T2DM or hyperlipidemia. However, high glucocorticoid replacement doses may be a risk factor for hypertension.

  • 28.
    Eloranta, Maija-Leena
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Lövgren, Tanja
    Uppsala University.
    Finke, Doreen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Mathsson, Linda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Rönnelid, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Kastner, Berthold
    Alm, Gunnar V.
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Regulation of the interferon-alpha production induced by RNA-containing immune complexes in plasmacytoid dendritic cells2009In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 60, no 8, p. 2418-2427Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Interferon-alpha (IFNalpha) is produced in several autoimmune diseases, including systemic lupus erythematosus (SLE), and may be important in their pathogenesis. We undertook this study to investigate how IFNalpha production induced by RNA-containing immune complexes (ICs) in plasmacytoid dendritic cells (PDCs) is regulated. METHODS: Normal PDCs purified from peripheral blood mononuclear cells (PBMCs) were cocultivated with other cell populations isolated from healthy individuals or SLE patients. IFNalpha production was induced by RNA-containing ICs, which consisted of anti-RNP autoantibodies and U1 small nuclear RNP particles, and the effects of prostaglandin E2 (PGE2), reactive oxygen species (ROS), or the cytokines IFNalpha2b, granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-10 (IL-10), or tumor necrosis factor alpha (TNFalpha) were explored. RESULTS: Monocytes inhibited IFNalpha production by PDCs in PBMC cultures, while natural killer (NK) cells were stimulatory. The monocytes had little effect on IFNalpha production by pure PDCs but inhibited its stimulation by NK cells. Monocytes from SLE patients were less inhibitory. Exposure of PBMCs or PDCs to IFNalpha2b/GM-CSF increased their IFNalpha production. RNA-containing ICs caused production of ROS, PGE2, and TNFalpha, especially in monocytes. These mediators and IL-10 suppressed IFNalpha production in PBMC cultures, with ROS and PGE2 also inhibiting IFNalpha production by purified PDCs. Inhibition by all of these agents, except for ROS, was abolished by IFNalpha2b/GM-CSF. The inhibitory effect of monocytes was significantly counteracted by the ROS scavengers serotonin and catalase. CONCLUSION: IFNalpha production induced by RNA-containing ICs in PDCs is regulated by a network of interactions between monocytes, NK cells, and PDCs, involving several pro- and antiinflammatory molecules. This should be considered when designing and applying new therapies.

  • 29.
    Elshafie, Amir
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Elkhalifa, Abdalla D.
    Weitoft, Thomas
    Nur, Musa
    Elagib, Elnour
    Aledrissy, Mawahib
    Elbagir, Sahwa
    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.
    Disease Severity and Treatment of Rheumatoid Arthritis: A Comparative Study Between Sudan and Sweden2014In: ARTHRITIS & RHEUMATOLOGY, ISSN 2326-5191, Vol. 66, no S10, p. S676-S676, article id 1534Article in journal (Other academic)
  • 30.
    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)
  • 31.
    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)
  • 32. ElShafie, Amir Ibrahim
    et al.
    Elghazali, Gehad
    Rönnelid, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Venge, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Cystatin C as a marker of immune complex-associated renal impairment in a sudanese population with visceral leishmaniasis2006In: American Journal of Tropical Medicine and Hygiene, ISSN 0002-9637, E-ISSN 1476-1645, Vol. 75, no 5, p. 864-868Article in journal (Refereed)
    Abstract [en]

    Renal function was studied in visceral leishmaniasis (VL) and post-kala-azar dermal leishmaniasis (PKDL) by means of the specific marker cystatin C and related to circulating immune complexes and cytokine production. Forty patients with VL (23 with sub-acute disease and 17 with acute disease), 17 patients with PKDL, and 22 healthy controls were included. Cystatin C, but not creatinine, was significantly raised in VL (P = 0.004). The highest levels of cystatin C were found in those with acute disease (P < 0.0001). In VL, cystatin C levels were positively correlated to circulating immune complexes and production of granulocyte-macrophage colony stimulating factor (GM-CSF), but negatively correlated to aspartate aminotransferase and lactate dehydrogenase. We conclude that cystatin C is a superior marker of glomerular function in leishmaniasis and that immune complex deposition and GM-CSF are two functions that most likely are causally involved in the mechanisms leading to glomerular dysfunction in leishmaniasis.

  • 33.
    ElShafie, Amir Ibrahim
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Elkhalifa, Abdalla D.
    Gavle Cent Hosp, Rheumatol Unit, Gavle, Sweden..
    Elbagir, Sahwa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Khartoum Fertil Ctr, Khartoum, Sudan..
    Aledrissy, Mawahib I. E.
    Alribat Univ Hosp, Rheumatol Unit, Khartoum, Sudan..
    Elagib, Elnour M.
    Mil Hosp, Rheumatol Unit, Omdurman, Sudan..
    Nur, Musa A. M.
    Alribat Univ Hosp, Rheumatol Unit, Khartoum, Sudan..
    Weitoft, Tomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Research and Development, Gävleborg. Gavle Cent Hosp, Rheumatol Unit, Gavle, Sweden.
    Rönnelid, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Active Rheumatoid Arthritis in Central Africa: A Comparative Study Between Sudan and Sweden2016In: Journal of Rheumatology, ISSN 0315-162X, E-ISSN 1499-2752, Vol. 43, no 10, p. 1777-1786Article in journal (Refereed)
    Abstract [en]

    Objective. To compare clinical characteristics and treatment between simultaneously investigated Sudanese and Swedish outpatients with rheumatoid arthritis (RA).

    Methods. Outpatients with RA from Sudan (n = 281) and Sweden (n = 542) diagnosed according to the 1987 American College of Rheumatology criteria were recruited between December 2008 and September 2010 and compared concerning clinical presentation, treatment, and laboratory findings, including immunoglobulin M with rheumatoid factor (IgM-RF).

    Results. Sudanese patients had lower inclusion age (median 49 vs 68 yrs), disease duration (48 vs 107 mos), and disease onset age (43 vs 56 yrs) as compared with Swedish patients (p < 0.0001 for all). When stratified concerning the age of inclusion, Swedish patients between 41-50 years had, however, a significantly lower age of onset, with a similar trend for all age groups above 30 years. The female preponderance was higher among Sudanese patients (89.3% vs 72.5%, p < 0.0001), and smoking was nonexistent among Sudanese female patients (p < 0.0001). Erythrocyte sedimentation rate levels and number of tender joints were significantly higher among Sudanese patients. The proportion of IgM-RF positivity was lower among Sudanese patients with RA (52.4% vs 75.5%, p < 0.0001). Higher proportions of Sudanese patients with RA were treated with methotrexate (MTX) and disease-modifying antirheumatic drug combinations, but none of them used biologics. Sudanese patients used lower doses of MTX and sulfasalazine (p < 0.0001) and higher doses of prednisolone (p < 0.0001) than Swedish patients.

    Conclusion. Sudanese patients with RA have significantly higher disease activity and are often IgM-RF-seronegative. Together with reports from Uganda and Cameroon, our data indicate a cluster of highly active and often seronegative RA in central Africa.

  • 34.
    Elshafie, Amir Ibrahim
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Åhlin, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Mathsson, Linda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    ElGhazali, Gehad
    Rönnelid, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Circulating immune complexes (IC) and IC-induced levels of GM-CSF are increased in sudanese patients with acute visceral Leishmania donovani infection undergoing sodium stibogluconate treatment: implications for disease pathogenesis2007In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 178, no 8, p. 5383-5389Article in journal (Refereed)
    Abstract [en]

    Infection with Leishmania donovani is associated with IL-10 as well as with GM-CSF. Immune complexes (IC) exert important functions by stimulation of monocytes/macrophage-mediated production of pro- and anti-inflammatory cytokines in rheumatic diseases. In this investigation, we have explored IC-induced cytokine production during Leishmania infection. Sera from 43 patients with visceral leishmaniasis (VL), 17 patients with post-kala-azar dermal leishmaniasis, and 20 healthy Sudanese controls were precipitated with polyethylene glycol (PEG). The PEG precipitates were added to serum-free PBMC for 20 h,whereupon supernatant levels of IL-1β, IL-6, IL-10, IL-1 receptor antagonist protein, TNF-α, TNF receptor p75, and GM-CSF were investigated using ELISA. Circulating levels of C1q-binding IC were also measured in the serum samples. PEG precipitates from Leishmania-infected patients induced significantly higher levels of GM-CSF (p = 0.0037) and IL-10 (p < 0.0001), as well as of IL-6 (p < 0.0001) and IL-1 receptor antagonist (p = 0.0238) as compared with PEG precipitates from controls. Patients with acute VL as well as VL patients receiving sodium stibogluconate treatment displayed significantly increased levels of PEG precipitate-induced GM-CSF. The induction of GM-CSF by circulating IC was especially prominent in acute VL patients receiving sodium stibogluconate treatment; ANOVA revealed significant interaction between disease activity and treatment for PEG precipitate-induced levels of GM-CSF (disease activity, p = 0.0006; treatment, p = 0.0005; interaction, p = 0.0046). Parallel associations were determined for C1q-binding immune complexes, but not for any cytokine other than GM-CSF. The importance of IC-induced GM-CSF in leishmaniasis warrants further study.

  • 35.
    Elshafie, Amir
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Mullazehi, Mohammed
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Rönnelid, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    General false positive ELISA reactions in visceral leishmaniasis. Implications for the use of enzyme immunoassay analyses in tropical Africa.2016In: JIM - Journal of Immunological Methods, ISSN 0022-1759, E-ISSN 1872-7905, Vol. 431, p. 66-71Article in journal (Refereed)
    Abstract [en]

    Leishmaniasis is a neglected disease in tropical countries. Clinical and laboratory features may mimic auto immune diseases and this can complicate the Leishmania diagnosis. Due to our previous investigation for false anti-CCP2 reactivity in Leishmania-infected subjects and our interest in immunity against the joint-specific collagen type II (CII) in rheumatoid arthritis (RA) we investigated the same cohort for anti-CII antibodies. We found elevated anti-CII reactivity in Leishmania-infected patients as compared to controls. When anti-CII OD values were compared with BSA-blocked control plates we found higher reactivity against BSA than in CII-coated plates in many Leishmania-infected patients. The percentage of such false positive anti-CII reactions increased with inflammatory activity, and was found in almost all Leishmania patients with highly active inflammatory disease, but was as low in Sudanese healthy controls as well as among Swedish RA patients. The correlation coefficients between false positive anti-CII and anti-CCP2 measured with a commercial ELISA were highest for patients with the most inflammatory disease but non-significant for Sudanese controls and Swedish RA patients, arguing that our findings may have general implications for ELISA measurements in leishmaniasis. ELISA investigations in areas endemic for leishmaniasis might benefit from individual-specific control wells for each serum sample. This approach might also be applicable to other geographical areas or patient groups with high incidence of inflammatory and infectious diseases.

  • 36.
    Elshafie, Amir
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Åhlin, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Mathsson, Linda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    EIGhazali, Gehad
    Rönnelid, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Circulating immune complexes (IC) and IC-induced levels of GM-CSF are increased in sudanese patients with acute visceral Leishmania donovani infection undergoing sodium stibogluconate treatment: implications for disease pathogenesis2007In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 178, no 8, p. 5383-5389Article in journal (Refereed)
    Abstract [en]

    Infection with Leishmania donovani is associated with IL-10 as well as with GM-CSF. Immune complexes (IC) exert important functions by stimulation of monocytes/macrophage-mediated production of pro- and anti-inflammatory cytokines in rheumatic diseases. In this investigation, we have explored IC-induced cytokine production during Leishmania infection. Sera from 43 patients with visceral leishmaniasis (VL), 17 patients with post-kala-azar dermal leishmaniasis, and 20 healthy Sudanese controls were precipitated with polyethylene glycol (PEG). The PEG precipitates were added to serum-free PBMC for 20 h,whereupon supernatant levels of IL-1beta, IL-6, IL-10, IL-1 receptor antagonist protein, TNF-alpha, TNF receptor p75, and GM-CSF were investigated using ELISA. Circulating levels of C1q-binding IC were also measured in the serum samples. PEG precipitates from Leishmania-infected patients induced significantly higher levels of GM-CSF (p = 0.0037) and IL-10 (p < 0.0001), as well as of IL-6 (p < 0.0001) and IL-1 receptor antagonist (p = 0.0238) as compared with PEG precipitates from controls. Patients with acute VL as well as VL patients receiving sodium stibogluconate treatment displayed significantly increased levels of PEG precipitate-induced GM-CSF. The induction of GM-CSF by circulating IC was especially prominent in acute VL patients receiving sodium stibogluconate treatment; ANOVA revealed significant interaction between disease activity and treatment for PEG precipitate-induced levels of GM-CSF (disease activity, p = 0.0006; treatment, p = 0.0005; interaction, p = 0.0046). Parallel associations were determined for C1q-binding immune complexes, but not for any cytokine other than GM-CSF. The importance of IC-induced GM-CSF in leishmaniasis warrants further study.

  • 37. Enocsson, Helena
    et al.
    Sjowall, Christopher
    Wirestam, Lina
    Dahle, Charlotte
    Kastbom, Alf
    Rönnelid, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Wettero, Jonas
    Skogh, Thomas
    Four Anti-dsDNA Antibody Assays in Relation to Systemic Lupus Erythematosus Disease Specificity and Activity2015In: Journal of Rheumatology, ISSN 0315-162X, E-ISSN 1499-2752, Vol. 42, no 5, p. 817-825Article in journal (Refereed)
    Abstract [en]

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

  • 38.
    Eriksson, Daniel
    et al.
    Karolinska Inst, Dept Med Solna, Ctr Mol Med, Stockholm, Sweden; Karolinska Univ Hosp, Dept Endocrinol Metab & Diabet, Stockholm, Sweden.
    Dalin, Frida
    Uppsala University, Science for Life Laboratory, SciLifeLab. Karolinska Inst, Dept Med Solna, Ctr Mol Med, Stockholm, Sweden.
    Eriksson, Gabriel Nordling
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.
    Landegren, Nils
    Uppsala University, Science for Life Laboratory, SciLifeLab. Karolinska Inst, Dept Med Solna, Ctr Mol Med, Stockholm, Sweden.
    Bianchi, Matteo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Hallgren, Åsa
    Uppsala University, Science for Life Laboratory, SciLifeLab. Karolinska Inst, Dept Med Solna, Ctr Mol Med, Stockholm, Sweden.
    Dahlqvist, Per
    Umeå Univ, Dept Publ Hlth & Clin Med, Umeå, Sweden.
    Wahlberg, Jeanette
    Linköping Univ, Dept Endocrinol, Linköping, Sweden; Linköping Univ, Dept Med & Hlth Sci, Linköping, Sweden; Linköping Univ, Dept Clin & Expt Med, Linköping, Sweden.
    Ekwall, Olov
    Univ Gothenburg, Dept Pediat, Inst Clin Sci, Sahlgrenska Acad, Gothenburg, Sweden; Univ Gothenburg, Dept Rheumatol & Inflammat Res, Inst Med, Sahlgrenska Acad, Gothenburg, Sweden.
    Winqvist, Ola
    Karolinska Inst, Dept Med Solna, Stockholm, Sweden.
    Catrina, Sergiu-Bogdan
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.
    Rönnelid, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Hulting, Anna-Lena
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.
    Lindblad-Toh, Kerstin
    Uppsala University, Science for Life Laboratory, SciLifeLab.
    Alimohammad, Mohammad
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology.
    Husebye, Eystein S
    Karolinska Inst, Dept Med Solna, Ctr Mol Med, Stockholm, Sweden; Univ Bergen, Dept Clin Sci, Bergen, Norway; Univ Bergen, Dept Med, Bergen, Norway; KG Jebsen Ctr Autoimmune Disorders, Bergen, Norway.
    Knappskog, Per Morten
    Univ Bergen, Dept Clin Sci, Bergen, Norway; Haukeland Hosp, Ctr Med Genet & Mol Med, Bergen, Norway.
    Pielberg, Gerli Rosengren
    Uppsala University, Science for Life Laboratory, SciLifeLab.
    Bensing, Sophie
    Karolinska Univ Hosp, Dept Endocrinol Metab & Diabet, Stockholm, Sweden; Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden .
    Kämpe, Olle
    Uppsala University, Science for Life Laboratory, SciLifeLab. Karolinska Inst, Dept Med Solna, Ctr Mol Med, Stockholm, Sweden; Karolinska Univ Hosp, Dept Endocrinol Metab & Diabet, Stockholm, Sweden; KG Jebsen Ctr Autoimmune Disorders, Bergen, Norway.
    Cytokine Autoantibody Screening in the Swedish Addison Registry Identifies Patients With Undiagnosed APS12018In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 103, no 1, p. 179-186Article in journal (Refereed)
    Abstract [en]

    Context: Autoimmune polyendocrine syndrome type 1 (APS1) is a monogenic disorder that features autoimmune Addison disease as a major component. Although APS1 accounts for only a small fraction of all patients with Addison disease, early identification of these individuals is vital to prevent the potentially lethal complications of APS1.

    Objective: To determine whether available serological and genetic markers are valuable screening tools for the identification of APS1 among patients diagnosed with Addison disease.

    Design: We systematically screened 677 patients with Addison disease enrolled in the Swedish Addison Registry for autoantibodies against interleukin-22 and interferon-α4. Autoantibody-positive patients were investigated for clinical manifestations of APS1, additional APS1-specific autoantibodies, and DNA sequence and copy number variations of AIRE.

    Results: In total, 17 patients (2.5%) displayed autoantibodies against interleukin-22 and/or interferon-α4, of which nine were known APS1 cases. Four patients previously undiagnosed with APS1 fulfilled clinical, genetic, and serological criteria. Hence, we identified four patients with undiagnosed APS1 with this screening procedure.

    Conclusion: We propose that patients with Addison disease should be routinely screened for cytokine autoantibodies. Clinical or serological support for APS1 should warrant DNA sequencing and copy number analysis of AIRE to enable early diagnosis and prevention of lethal complications.

  • 39. Ernestam, Sofia
    et al.
    Lampa, Jon
    Rogberg, Siv
    Rönnelid, Johan
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology. Klinisk immunologi.
    Klareskog, Lars
    Hafström, Ingiäld
    Evidence for immunostimulatory effects of intramuscular gold in patients with: correlation with skin reactions.2003In: J Rheumatol, ISSN 0315-162X, Vol. 30, no 8, p. 1748-55Article in journal (Other scientific)
  • 40. 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)
  • 41.
    Falorni, Alberto
    et al.
    Univ Perugia, Dept Med, I-06126 Perugia, Italy..
    Bini, Vittorio
    Univ Perugia, Dept Med, I-06126 Perugia, Italy..
    Betterle, Corrado
    Univ Padua, Dept Med, Endocrine Unit, Padua, Italy..
    Brozzetti, Annalisa
    Univ Perugia, Dept Med, I-06126 Perugia, Italy..
    Castano, Luis
    Univ Basque Country, Cruces Univ Hosp, Ciberdem, BioCruces, Bilbao, Spain..
    Fichna, Marta
    Poznan Univ Med Sci, Dept Endocrinol & Metab, Poznan, Poland.;Polish Acad Sci, Inst Human Genet, PL-60479 Poznan, Poland..
    Kämpe, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Mellgren, Gunnar
    Haukeland Hosp, Hormone Lab, N-5021 Bergen, Norway.;Univ Bergen, Dept Clin Sci, Bergen, Norway..
    Peterson, Pärt
    Univ Tartu, Inst Biomed & Translat Med, Mol Pathol, EE-50090 Tartu, Estonia..
    Chen, Shu
    RSR Ltd, FIRS Labs, Cardiff, S Glam, Wales..
    Rönnelid, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Seissler, Jochen
    Klinikum Univ Munchen, Med Klin & Poliklin 4, Diabet Zentrum, Munich, Germany..
    Tiberti, Claudio
    Univ Roma La Sapienza, Dept Expt Med, I-00185 Rome, Italy..
    Uibo, Raivo
    Univ Tartu, Inst Biomed & Translat Med, Dept Immunol, EE-50090 Tartu, Estonia..
    Yu, Liping
    Univ Colorado Denver, Barbara Davis Ctr Diabet, Aurora, CO USA..
    Lernmark, Åke
    Lund Univ, Skane Univ Hosp, Dept Clin Sci, Malmo, Sweden..
    Husebye, Eystein
    Univ Bergen, Dept Clin Sci, Bergen, Norway.;Haukeland Hosp, Dept Med, N-5021 Bergen, Norway..
    Determination of 21-hydroxylase autoantibodies: inter-laboratory concordance in the Euradrenal International Serum Exchange Program2015In: Clinical Chemistry and Laboratory Medicine, ISSN 1434-6621, E-ISSN 1437-4331, Vol. 53, no 11, p. 1761-1770Article in journal (Refereed)
    Abstract [en]

    Background: 21-Hydroxylase autoantibodies (21OHAb) are markers of an adrenal autoimmune process that identifies individuals with autoimmune Addison's disease (AAD). Quality and inter-laboratory agreement of various 21OHAb tests are incompletely known. The objective of the study was to determine inter-laboratory concordance for 21OHAb determinations. Methods: Sixty-nine sera from 51 patients with AAD and 51 sera from 51 healthy subjects were blindly coded by a randomization center and distributed to 14 laboratories that determined 21OHAb, either by an "in-house" assay (n=9) using in vitro-translated S-35-21OH or luciferase-labeled 21OH or a commercial kit with I-125-21OH (n=5). Main outcome measures were diagnostic accuracy of each participating laboratory and inter-laboratory agreement of 21OHAb assays. Results: Intra-assay coefficient of variation ranged from 2.6% to 5.3% for laboratories using the commercial kit and from 5.1% to 23% for laboratories using "in-house" assays. Diagnostic accuracy, expressed as area under ROC curve (AUC), varied from 0.625 to 0.947 with the commercial kit and from 0.562 to 0.978 with "in-house" methods. Cohen's. of inter-rater agreement was 0.603 among all 14 laboratories, 0.691 among "in-house" laboratories, and 0.502 among commercial kit users. Optimized cutoff levels, calculated on the basis of AUCs, increased the diagnostic accuracy of every laboratory (AUC >0.9 for 11/14 laboratories) and increased the Cohen's. of inter-rater agreement. Discrepancies in quantitation of 21OHAb levels among different laboratories increased with increasing autoantibody levels. Conclusions: The quality of 21OHAb analytical procedures is mainly influenced by selection of cutoff value and correct handling of assay materials. A standardization program is needed to identify common standard sera and common measuring units.

  • 42. Fernandes-Cerqueira, Catia
    et al.
    Ossipova, Elena
    Gunasekera, Sunithi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Hansson, Monika
    Mathsson, Linda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Catrina, Anca I.
    Sommarin, Yngve
    Klareskog, Lars
    Lundberg, Karin
    Rönnelid, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Göransson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Jakobsson, Per-Johan
    Targeting of anti-citrullinated protein/peptide antibodies in rheumatoid arthritis using peptides mimicking endogenously citrullinated fibrinogen antigens2015In: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 17, article id 155Article in journal (Refereed)
    Abstract [en]

    Introduction: We have previously identified endogenously citrullinated peptides derived from fibrinogen in rheumatoid arthritis (RA) synovial tissues. In this study, we have investigated the auto-antigenicity of four of those citrullinated peptides, and explored their feasibility to target anti-citrullinated protein/peptide antibodies (ACPA). Methods: The autoantigenic potential of the fibrinogen peptides was investigated by screening 927 serum samples from the Epidemiological Investigation of RA (EIRA) cohort on a peptide microarray based on the ImmunoCAP ISAC (R) system. In order to assay for ACPA blocking, two independent pools of purified ACPA were incubated with the respective targeting peptide prior to binding to cyclic citrullinated peptide (CCP) 2 using the CCPlus (R) ELISA kit. Results: Two peptides derived from the fibrinogen a chain, Arg573Cit (563-583) and Arg591Cit (580-600), referred to as Cit573 and Cit591, and two peptides from the fibrinogen beta chain, Arg72Cit (62-81) and Arg74Cit (62-81) (Cit72 and Cit74), displayed 65 %, 15 %, 35 %, and 53 % of immune reactivity among CCP2-positive RA sera, respectively. In CCP2-negative RA sera, a positive reactivity was detected in 5 % (Cit573), 6 % (Cit591), 8 % (Cit72), and 4 % (Cit74). In the competition assay, Cit573 and Cit591 peptides reduced ACPA binding to CCP2 by a maximum of 84 % and 63 % respectively. An additive effect was observed when these peptides were combined. In contrast, Cit74 and Cit72 were less effective. Cyclization of the peptide structure containing Cit573 significantly increased the blocking efficiency. Conclusions: Here we demonstrate extensive autoantibody reactivity against in vivo citrullinated fibrinogen epitopes, and further show the potential use of these peptides for antagonizing ACPA.

  • 43. 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.

     

  • 44.
    Frodlund, M.
    et al.
    Linkoping Univ, Dept Clin & Expt Med, Div Neuro & Inflammat Sci, Linkoping, Sweden.
    Vikerfors, A.
    Karolinska Univ Hosp, Karolinska Inst, Dept Med, Unit Rheumatol, Stockholm, Sweden.
    Elvin, K.
    Karolinska Inst, Dept Clin Immunol & Transfus Med, Div Clin Immunol, Stockholm, Sweden.
    Rönnelid, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Svenungsson, E.
    Karolinska Univ Hosp, Karolinska Inst, Dept Med, Unit Rheumatol, Stockholm, Sweden.
    Sjowall, C.
    Linkoping Univ, Dept Clin & Expt Med, Div Neuro & Inflammat Sci, Linkoping, Sweden.
    Immunoglobulin A anti-phospholipid antibodies in Swedish cases with systemic lupus erythematosus: associations with disease phenotypes, vascular events, and damage accrual2018In: Scandinavian Journal of Rheumatology, ISSN 0300-9742, E-ISSN 1502-7732, Vol. 47, p. 48-48Article in journal (Other academic)
  • 45.
    Frodlund, M.
    et al.
    Linkoping Univ, Div Neuro & Inflammat Sci, Dept Clin & Expt Med, Linkoping, Sweden.
    Vikerfors, A.
    Swedish Med Prod Agcy, SE-75103 Uppsala, Sweden;Karolinska Univ Hosp, Karolinska Inst, Dept Med Solna, Unit Rheumatol, Stockholm, Sweden.
    Grosso, G.
    Karolinska Univ Hosp, Karolinska Inst, Dept Med Solna, Unit Rheumatol, Stockholm, Sweden.
    Skogh, T.
    Linkoping Univ, Div Neuro & Inflammat Sci, Dept Clin & Expt Med, Linkoping, Sweden.
    Wetterö, J.
    Linkoping Univ, Div Neuro & Inflammat Sci, Dept Clin & Expt Med, Linkoping, Sweden.
    Elvin, K.
    Karolinska Inst, Dept Clin Immunol & Transfus Med, Unit Clin Immunol, Stockholm, Sweden.
    Gunnarsson, I.
    Karolinska Univ Hosp, Karolinska Inst, Dept Med Solna, Unit Rheumatol, Stockholm, Sweden.
    Kastbom, A.
    Linkoping Univ, Div Neuro & Inflammat Sci, Dept Clin & Expt Med, Linkoping, Sweden.
    Dahlström, Ö.
    Linkoping Univ, Swedish Inst Disabil Res, Dept Behav Sci & Learning, Linkoping, Sweden.
    Rönnelid, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Svenungsson, E.
    Karolinska Univ Hosp, Karolinska Inst, Dept Med Solna, Unit Rheumatol, Stockholm, Sweden.
    Sjöwall, C.
    Linkoping Univ, Div Neuro & Inflammat Sci, Dept Clin & Expt Med, Linkoping, Sweden.
    Immunoglobulin A anti-phospholipid antibodies in Swedish cases of systemic lupus erythematosus: associations with disease phenotypes, vascular events and damage accrual2018In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 194, no 1, p. 27-38Article in journal (Refereed)
    Abstract [en]

    Immunoglobulin (Ig) G- and IgM-class anti-cardiolipin antibodies (aCL) and lupus anti-coagulant (LA) are included in the 1997 update of the American College of Rheumatology (ACR-97) systemic lupus erythematosus (SLE) criteria. Despite limited evidence, IgA-aCL and IgA anti-(2)-glycoprotein-I (anti-(2)GPI) were included in the 2012 Systemic Lupus International Collaborating Clinics criteria. The present study aimed to evaluate IgG-/IgA-/IgM-aCL and anti-(2)GPI occurrence in relation to disease phenotype, smoking habits, pharmacotherapy, anti-phospholipid syndrome (APS) and organ damage among 526 Swedish SLE patients meeting ACR-97. Patients with rheumatoid arthritis (n=100), primary Sjogren's syndrome (n=50) and blood donors (n=507) served as controls. Anti-phospholipid antibodies (aPL) were analysed by fluoroenzyme-immunoassays detecting aCL/anti-(2)GPI. Seventy-six (14%) SLE cases fulfilled the Sydney APS-criteria, and 1 aCL/anti-(2)GPI isotype (IgG/IgA/IgM) occurred in 138 SLE patients (26%). Forty-five (9%) of the SLE cases had IgA-aCL, 20 of whom (4%) lacked IgG-/IgM-aCL. Seventy-four (14%) tested positive for IgA anti-(2)GPI, 34 (6%) being seronegative regarding IgG/IgM anti-(2)GPI. Six (1%) had APS manifestations but were seropositive regarding IgA-aCL and/or IgA anti-(2)GPI in the absence of IgG/IgM-aPL and LA. Positive LA and IgG-aPL tests were associated with most APS-related events and organ damage. Exclusive IgA anti-(2)GPI occurrence associated inversely with Caucasian ethnicity [odds ratio (OR)=021, 95% confidence interval (CI)=006-072) and photosensitivity (OR=019, 95% CI=005-072). Nephritis, smoking, LA-positivity and statin/corticosteroid-medication associated strongly with organ damage, whereas hydroxychloroquine-medication was protective. In conclusion, IgA-aPL is not rare in SLE (16%) and IgA-aPL analysis may have additional value among SLE cases with suspected APS testing negative for other isotypes of aPL and LA.

  • 46. Frostegard, J
    et al.
    Huang, Y H
    Rönnelid, Johan
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Schafer-Elinder, L
    Oxidized LDL and PAF induce immune activation by a common mechanism1997In: Athorosclerosis, Thrombosis and Vascular Biology, Vol. 17, p. 963-Article in journal (Refereed)
  • 47. 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.

  • 48.
    Gerstner, Christina
    et al.
    Karolinska Univ Hosp, Karolinska Inst, Ctr Mol Med, Rheumatol Unit,Dept Med Solna, Stockholm, Sweden..
    Dubnovitsky, Anatoly
    Karolinska Inst, Ctr Mol Med, Dept Clin Neurosci, Neuroimmunol Unit, Stockholm, Sweden.;Karolinska Inst, Dept Med Solna, Sci Life Lab, Stockholm, Sweden..
    Sandin, Charlotta
    Karolinska Univ Hosp, Karolinska Inst, Ctr Mol Med, Rheumatol Unit,Dept Med Solna, Stockholm, Sweden..
    Kozhukh, Genadiy
    Karolinska Univ Hosp, Karolinska Inst, Ctr Mol Med, Rheumatol Unit,Dept Med Solna, Stockholm, Sweden.;Karolinska Inst, Dept Med Solna, Sci Life Lab, Stockholm, Sweden..
    Uchtenhagen, Hannes
    Karolinska Univ Hosp, Karolinska Inst, Ctr Mol Med, Rheumatol Unit,Dept Med Solna, Stockholm, Sweden.;Virginia Mason, BRI, Translat Res Program, Seattle, WA USA..
    James, Eddie A.
    Virginia Mason, BRI, Tetramer Core, Seattle, WA USA..
    Rönnelid, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Ytterberg, Anders Jimmy
    Karolinska Univ Hosp, Karolinska Inst, Ctr Mol Med, Rheumatol Unit,Dept Med Solna, Stockholm, Sweden.;Karolinska Inst, Dept Med Biochem & Biophys, Stockholm, Sweden..
    Pieper, Jennifer
    Karolinska Univ Hosp, Karolinska Inst, Ctr Mol Med, Rheumatol Unit,Dept Med Solna, Stockholm, Sweden..
    Reed, Evan
    Karolinska Univ Hosp, Karolinska Inst, Ctr Mol Med, Rheumatol Unit,Dept Med Solna, Stockholm, Sweden..
    Tandre, Carolina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Rieck, Mary
    Virginia Mason, BRI, Translat Res Program, Seattle, WA USA..
    Zubarev, Roman A.
    Karolinska Inst, Dept Med Biochem & Biophys, Stockholm, Sweden..
    Ronnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala Univ, Dept Med Sci, Sci Life Lab, Rheumatol, Uppsala, Sweden..
    Sandalova, Tatyana
    Karolinska Inst, Dept Med Solna, Sci Life Lab, Stockholm, Sweden.;Karolinska Univ Hosp Solna, Dept Infect Dis, Stockholm, Sweden..
    Buckner, Jane H.
    Virginia Mason, BRI, Translat Res Program, Seattle, WA USA..
    Achour, Adnane
    Karolinska Inst, Dept Med Solna, Sci Life Lab, Stockholm, Sweden.;Karolinska Univ Hosp Solna, Dept Infect Dis, Stockholm, Sweden..
    Malmstrom, Vivianne
    Karolinska Univ Hosp, Karolinska Inst, Ctr Mol Med, Rheumatol Unit,Dept Med Solna, Stockholm, Sweden..
    Functional and Structural Characterization of a Novel HLA-DRB1*04:01-Restricted alpha-Enolase T Cell Epitope in Rheumatoid Arthritis2016In: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 7, article id 494Article in journal (Refereed)
    Abstract [en]

    Antibodies to citrullinated proteins, common in rheumatoid arthritis (RA) patients, are strongly associated to a specific set of HLA-DR alleles including HLA-DRB1*04:01, *04:04, and *01:01. Here, we first demonstrate that autoantibody levels toward the dominant citrullinated B cell epitope from alpha-enolase are significantly elevated in HLA-DRB1*04:01-positive RA patients. Furthermore, we identified alpha-enolase-derived T cell epitopes and demonstrated that native and citrullinated versions of several peptides bind with different affinities to HLA-DRB1*04:01, *04:04, and *01:01. The citrulline residues in the eight identified peptides are distributed throughout the entire length of the presented epitopes and more specifically, localized at peptide positions p-2, p2, p4, p6, p7, p10, and p11. Importantly, in contrast to its native version peptide 26 (TSKGLFRAAVPSGAS), the HLA-DRB1*04:01-restricted citrullinated peptide Cit26 (TSKGLFCitAAVPSGAS) elicited significant functional T cell responses in primary cells from RA patients. Comparative analysis of the crystal structures of HLA-DRB1*04:01 in complex with peptide 26 or Cit26 demonstrated that the posttranslational modification did not alter the conformation of the peptide. And since citrullination is the only structural difference between the two complexes, this indicates that the neo-antigen Cit26 is recognized by T cells with high specificity to the citrulline residue.

  • 49. Gröndal, G
    et al.
    Gunnarsson, I
    Rönnelid, Johan
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology. Klinisk immunologi.
    Rogberg, S
    Klareskog, L
    Lundberg, I
    Cytokine production, serum levels and clinical profile in systemic lupus erythematosus.2000In: Clin Exp Rheumatol, Vol. 18, p. 565-Article in journal (Refereed)
  • 50.
    Grönwall, Caroline
    et al.
    Karolinska Univ Hosp, Karolinska Inst, Dept Med, Rheumatol Unit, Stockholm, Sweden..
    Hardt, Uta
    Karolinska Univ Hosp, Karolinska Inst, Dept Med, Rheumatol Unit, Stockholm, Sweden..
    Gustafsson, Johanna T.
    Karolinska Univ Hosp, Karolinska Inst, Dept Med, Rheumatol Unit, Stockholm, Sweden..
    Elvin, Kerstin
    Karolinska Univ Hosp, Karolinska Inst, Dept Clin Immunol & Transfus Med, Unit Clin Immunol, Stockholm, Sweden..
    Jensen-Urstad, Kerstin
    Karolinska Inst, Dept Clin Physiol, Sodersjukhuset, Stockholm, Sweden..
    Kvarnstrom, Marika
    Karolinska Univ Hosp, Karolinska Inst, Dept Med, Rheumatol Unit, Stockholm, Sweden..
    Grosso, Giorgia
    Karolinska Univ Hosp, Karolinska Inst, Dept Med, Rheumatol Unit, Stockholm, Sweden..
    Rönnelid, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Padykov, Leonid
    Karolinska Univ Hosp, Karolinska Inst, Dept Med, Rheumatol Unit, Stockholm, Sweden..
    Gunnarsson, Iva
    Karolinska Univ Hosp, Karolinska Inst, Dept Med, Rheumatol Unit, Stockholm, Sweden..
    Silverman, Gregg J.
    NYU, Sch Med, Dept Med, Div Rheumatol, New York, NY USA..
    Svenungsson, Elisabet
    Karolinska Univ Hosp, Karolinska Inst, Dept Med, Rheumatol Unit, Stockholm, Sweden..
    Depressed serum IgM levels in SLE are restricted to defined subgroups2017In: Clinical Immunology, ISSN 1521-6616, E-ISSN 1521-7035, Vol. 183, p. 304-315Article in journal (Refereed)
    Abstract [en]

    Natural IgM autoantibodies have been proposed to convey protection from autoimmune pathogenesis. Herein, we investigated the IgM responses in 396 systemic lupus erythematosus (SLE) patients, divided into subgroups based on distinct autoantibody profiles. Depressed IgM levels were more common in SLE than in matched population controls. Strikingly, an autoreactivity profile defined by IgG anti-Ro/La was associated with reduced levels of specific natural IgM targeting phosphoiylcholine (PC) antigens and malondialdehyde (MDA) modified-protein, as well as total IgM, while no differences were detected in SLE patients with an autoreactivity profile defined by anti-cardiolipin/beta(2)glycoprotein-I. We also observed an association of reduced IgM levels with the HEA-DRB1*03 allelic variant among SLE patients and controls. Associations of low IgM anti-PC with cardiovascular disease were primarily found in patients without antiphospholipid antibodies. These studies further highlight the clinical relevance of depressed IgM. Our results suggest that low IgM levels in SLE patients reflect immunological and genetic differences between SLE subgroups.

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