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  • 1.
    Coenen, Marieke J H
    et al.
    Radboud University Nijmegen.
    Enevold, Christian
    University of Copenhagen Hospital.
    Barrera, Pilar
    Radboud University Nijmegen.
    Schijvenaars, Mascha M V A P
    Radboud University Nijmegen.
    J M Toonen, Erik
    Radboud University Nijmegen.
    Scheffer, Hans
    Radboud University Nijmegen.
    Padyukov, Leonid
    Karolinska Institute.
    Kastbom, Alf
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Rheumatology in Östergötland.
    Klareskog, Lars
    Karolinska Institute.
    Barton, Anne
    University of Manchester.
    Kievit, Wietske
    Ziekenhuis Gelderse Vallei.
    Jansen, Tim L
    Medical Centre Leeuwarden.
    Swinkels, Dorine
    Radboud University Nijmegen.
    van Riel, Piet L C M
    Radboud University Nijmegen.
    Franke, Barbara
    Radboud University Nijmegen.
    Bendtzen, Klaus
    University of Copenhagen Hospital.
    Radstake, Timothy R D J
    Radboud University Nijmegen.
    Genetic Variants in Toll-Like Receptors Are Not Associated with Rheumatoid Arthritis Susceptibility or Anti-Tumour Necrosis Factor Treatment Outcome2010In: PLOS ONE, ISSN 1932-6203, Vol. 5, no 12Article in journal (Refereed)
    Abstract [en]

    Background: Several studies point to a role of Toll-like receptors (TLRs) in the development of rheumatoid arthritis (RA). We investigated if genetic variants in TLR genes are associated with RA and response to tumour necrosis factor blocking (anti-TNF) medication. Methodology and Principal Findings: 22 single nucleotide polymorphisms (SNPs) in seven TLR genes were genotyped in a Dutch cohort consisting of 378 RA patients and 294 controls. Significantly associated variants were investigated in replication cohorts from The Netherlands, United Kingdom and Sweden (2877 RA patients and 2025 controls). 182 of the Dutch patients were treated with anti-TNF medication. Using these patients and a replication cohort (269 Swedish patients) we analysed if genetic variants in TLR genes were associated with anti-TNF outcome. In the discovery phase of the study we found a significant association of SNPs rs2072493 in TLR5 and rs3853839 in TLR7 with RA disease susceptibility. Meta-analysis of discovery and replication cohorts did not confirm these findings. SNP rs2072493 in TLR5 was associated with anti-TNF outcome in the Dutch but not in the Swedish population. Conclusion: We conclude that genetic variants in TLRs do not play a major role in susceptibility for developing RA nor in anti-TNF treatment outcome in a Caucasian population.

  • 2.
    Enocsson, Helena
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Sjöwall, Christoffer
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Region Östergötland, Heart and Medicine Center, Department of Rheumatology. Linköping University, Faculty of Medicine and Health Sciences.
    Wirestam, Lina
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Dahle, Charlotte
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Region Östergötland, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Kastbom, Alf
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Region Östergötland, Heart and Medicine Center, Department of Rheumatology. Linköping University, Faculty of Medicine and Health Sciences.
    Ronnelid, Johan
    Uppsala University, Sweden.
    Wetterö, Jonas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Skogh, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Region Östergötland, Heart and Medicine Center, Department of Rheumatology. Linköping University, Faculty of Medicine and Health Sciences.
    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. Fishers 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.

  • 3.
    Enocsson, Helena
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences.
    Sjöwall, Christopher
    Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Rheumatology.
    Kastbom, Alf
    Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Rheumatology.
    Skogh, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Rheumatology.
    Eloranta, Maija-Leena
    Uppsala University, Sweden.
    Rönnblom, Lars
    Uppsala University, Sweden.
    Wetterö, Jonas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences.
    Association of Serum C-Reactive Protein Levels With Lupus Disease Activity in the Absence of Measurable Interferon-α and a C-Reactive Protein Gene Variant2014In: Arthritis & rheumatology (Hoboken, N.J.), ISSN 2326-5191, Vol. 66, no 6, p. 1568-1573Article in journal (Refereed)
    Abstract [en]

    Objectives: The type I interferon (IFN) system is important in the pathogenesis of systemic lupus erythematosus (SLE). We previously demonstrated an inhibitory effect of IFNα on interleukin 6 (IL-6) induced C-reactive protein (CRP) in vitro, hypothetically explaining the poor correlation between disease activity and CRP levels in SLE. Herein we investigated disease activity, IL-6 and CRP in relation to a CRP gene polymorphism and IFN.

    Methods: Sera from 155 SLE patients and 100 controls were analyzed for CRP. Patients were genotyped for a CRP single nucleotide polymorphism (rs1205) associated with low CRP levels. Serum IFNα and IL-6 was quantified by immunoassays. Clinical disease activity was assessed by SLE disease activity index 2000 (SLEDAI-2K).

    Results: CRP levels were increased in SLE patients compared to controls, but were not associated with SLEDAI-2K or IL-6 levels. However, exclusion of patients carrying at least one rs1205 minor allele revealed an association between disease activity and CRP levels (p=0.005). We found a strong association between disease activity and CRP levels (p<0.0005) when patients with measurable IFNα as well as the minor allele of rs1205 where excluded from the analysis. Similarly, when patients with raised IFNα and/or the rs1205 polymorphism were excluded, IL-6 associated with CRP levels.

    Conclusions: The present study demonstrates that serum IFNα as well as CRP genotype affects the CRP response in SLE patients. Lack of correlation between serum levels of CRP and disease activity could therefore be explained by activation of the type I IFN system and polymorphisms in the CRP gene. © 2014 American College of Rheumatology.

  • 4.
    Frodlund, Martina
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences.
    Dahlström, Örjan
    Linköping University, Department of Behavioural Sciences and Learning, Disability Research. Linköping University, Faculty of Arts and Sciences.
    Kastbom, Alf
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Rheumatology.
    Skogh, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Rheumatology.
    Sjöwall, Christopher
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Rheumatology.
    Associations between antinuclear antibody staining patterns and clinical features of systemic lupus erythematosus: analysis of a regional Swedish register2013In: BMJ Open, ISSN 2044-6055, E-ISSN 2044-6055, Vol. 3, p. 1-8Article in journal (Refereed)
    Abstract [en]

    Objective Antinuclear antibody (ANA) analysis by immunofluorescence (IF) microscopy remains a diagnostic hallmark of systemic lupus erythematosus (SLE). The clinical relevance of ANA fine-specificities in SLE has been addressed repeatedly, whereas studies on IF-ANA staining patterns in relation to disease manifestations are very scarce. This study was performed to elucidate whether different staining patterns associate with distinct SLE phenotypes.

    Design Observational cohort study.

    Setting One university hospital rheumatology unit in Sweden.

    Participants The study population consisted of 222 cases (89% women; 93% Caucasians), where of 178 met ≥4/11 of the 1982 American College of Rheumatology (ACR-82) criteria. The remaining 20% had an SLE diagnosis based on positive IF-ANA (HEp-2 cells) and ≥2 typical organ manifestations at the time of diagnosis (Fries’ criteria).

    Outcome measures The IF-ANA staining patterns homogenous (H-ANA), speckled (S-ANA), combined homogenous and speckled (HS-ANA), centromeric (C-ANA), nucleolar (N-ANA)±other patterns and other nuclear patterns (oANA) were related to disease manifestations and laboratory measures. Antigen-specificities were also considered regarding double-stranded DNA (Crithidia luciliae) and the following extractable nuclear antigens: Ro/SSA, La/SSB, Smith antigen (Sm), small nuclear RNP (snRNP), Scl-70 and Jo-1 (immunodiffusion and/or line-blot technique).

    Results 54% of the patients with SLE displayed H-ANA, 22% S-ANA, 11% HS-ANA, 9% N-ANA, 1% C-ANA, 2% oANA and 1% were never IF-ANA positive. Staining patterns among patients meeting Fries’ criteria alone did not differ from those fulfilling ACR-82. H-ANA was significantly associated with the 10th criterion according to ACR-82 (‘immunological disorder’). S-ANA was inversely associated with arthritis, ‘immunological disorder’ and signs of organ damage.

    Conclusions H-ANA is the dominant IF-ANA pattern among Swedish patients with SLE, and was found to associate with ‘immunological disorder’ according to ACR-82. The second most common pattern, S-ANA, associated negatively with arthritis and organ damage.

  • 5.
    Frodlund, Martina
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Rheumatology.
    Vikerfors, A.
    Karolinska Univ Hosp, Sweden; Swedish Med Prod Agcy, Sweden.
    Grosso, G.
    Karolinska Univ Hosp, Sweden.
    Skogh, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Rheumatology.
    Wetterö, Jonas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Elvin, K.
    Karolinska Inst, Sweden.
    Gunnarsson, I.
    Karolinska Univ Hosp, Sweden.
    Kastbom, Alf
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Rheumatology.
    Dahlström, Örjan
    Linköping University, Department of Behavioural Sciences and Learning, Disability Research. Linköping University, Faculty of Arts and Sciences. Linköping University, The Swedish Institute for Disability Research.
    Ronnelid, J.
    Uppsala Univ, Sweden.
    Svenungsson, E.
    Karolinska Univ Hosp, Sweden.
    Sjöwall, Christopher
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Rheumatology.
    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 Sjogrens 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.

  • 6.
    Ge, Changrong
    et al.
    Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
    Tong, Dongmei
    Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Southern Medical University, Guangzhou, China..
    Liang, Bibo
    Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm,Southern Medical University, Guangzhou, China.
    Lönnblom, Erik
    Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm.
    Schneider, Nadine
    University Hospital Frankfurt Goethe University, Frankfurt, Germany.
    Hagert, Cecilia
    University of Turku, Finland.
    Viljanen, Johan
    Biomedicinskt centrum, Uppsala University, Uppsala, Sweden.
    Ayoglu, Burcu
    KTH Royal Institute of Technology, Stockholm, Sweden.
    Stawikowska, Roma
    Florida Atlantic University, Jupiter, Florida, USA.
    Nilsson, Peter
    KTH Royal Institute of Technology, Stockholm, Sweden.
    Fields, Gregg B
    Florida Atlantic University, Jupiter, Florida, USA.
    Skogh, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Rheumatology.
    Kastbom, Alf
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Rheumatology.
    Kihlberg, Jan
    Uppsala University, Uppsala, Sweden.
    Burkhardt, Harald
    University Hospital Frankfurt Goethe University, Frankfurt, Germany.
    Dobritzsch, Doreen
    Uppsala University, Uppsala, Sweden.
    Holmdahl, Rikard
    Karolinska Institutet, Stockholm, Sweden; University of Turku, Turku, Finland, Southern Medical University, Guangzhou, China.
    Anti-citrullinated protein antibodies cause arthritis by cross-reactivity to joint cartilage2017In: JCI insight, ISSN 2379-3708, Vol. 2, no 13, article id 93688Article in journal (Refereed)
    Abstract [en]

    Today, it is known that autoimmune diseases start a long time before clinical symptoms appear. Anti-citrullinated protein antibodies (ACPAs) appear many years before the clinical onset of rheumatoid arthritis (RA). However, it is still unclear if and how ACPAs are arthritogenic. To better understand the molecular basis of pathogenicity of ACPAs, we investigated autoantibodies reactive against the C1 epitope of collagen type II (CII) and its citrullinated variants. We found that these antibodies are commonly occurring in RA. A mAb (ACC1) against citrullinated C1 was found to cross-react with several noncitrullinated epitopes on native CII, causing proteoglycan depletion of cartilage and severe arthritis in mice. Structural studies by X-ray crystallography showed that such recognition is governed by a shared structural motif "RG-TG" within all the epitopes, including electrostatic potential-controlled citrulline specificity. Overall, we have demonstrated a molecular mechanism that explains how ACPAs trigger arthritis.

  • 7.
    Ge, Changrong
    et al.
    Karolinska Inst, Sweden.
    Xu, Bingze
    Karolinska Inst, Sweden.
    Liang, Bibo
    Karolinska Inst, Sweden; Southern Med Univ, Peoples R China.
    Lonnblom, Erik
    Karolinska Inst, Sweden.
    Lundstrom, Susanna L.
    Karolinska Inst, Sweden.
    Zubarev, Roman A.
    Karolinska Inst, Sweden.
    Ayoglu, Burcu
    KTH Royal Inst Technol, Sweden.
    Nilsson, Peter
    KTH Royal Inst Technol, Sweden.
    Skogh, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Rheumatology.
    Kastbom, Alf
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Rheumatology.
    Malmstrom, Vivianne
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Klareskog, Lars
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Toes, Rene E. M.
    Leiden Univ, Netherlands.
    Rispens, Theo
    Univ Amsterdam, Netherlands.
    Dobritzsch, Doreen
    Uppsala Univ, Sweden.
    Holmdahl, Rikard
    Karolinska Inst, Sweden; Southern Med Univ, Peoples R China.
    Structural Basis of Cross-Reactivity of Anti-Citrullinated Protein Antibodies2019In: Arthritis & Rheumatology, ISSN 2326-5191, E-ISSN 2326-5205, Vol. 71, no 2, p. 210-221Article in journal (Refereed)
    Abstract [en]

    Objective Anti-citrullinated protein antibodies (ACPAs) develop many years before the clinical onset of rheumatoid arthritis (RA). This study was undertaken to address the molecular basis of the specificity and cross-reactivity of ACPAs from patients with RA. Methods Antibodies isolated from RA patients were expressed as monoclonal chimeric antibodies with mouse Fc. These antibodies were characterized for glycosylation using mass spectrometry, and their cross-reactivity was assessed using Biacore and Luminex immunoassays. The crystal structures of the antigen-binding fragment (Fab) of the monoclonal ACPA E4 in complex with 3 different citrullinated peptides were determined using x-ray crystallography. The prevalence of autoantibodies reactive against 3 of the citrullinated peptides that also interacted with E4 was investigated by Luminex immunoassay in 2 Swedish cohorts of RA patients. Results Analysis of the crystal structures of a monoclonal ACPA from human RA serum in complex with citrullinated peptides revealed key residues of several complementarity-determining regions that recognized the citrulline as well as the neighboring peptide backbone, but with limited contact with the side chains of the peptides. The same citrullinated peptides were recognized by high titers of serum autoantibodies in 2 large cohorts of RA patients. Conclusion These data show, for the first time, how ACPAs derived from human RA serum recognize citrulline. The specific citrulline recognition and backbone-mediated interactions provide a structural explanation for the promiscuous recognition of citrullinated peptides by RA-specific ACPAs.

  • 8.
    Hellberg, Sandra
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Eklund, Daniel
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Gawel, Danuta
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Köpsén, Mattias
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics. Linköping University, Faculty of Science & Engineering.
    Zhang, Huan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Nestor, Colm
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Kockum, Ingrid
    Karolinska Institute, Department Clin Neurosci, Neuroimmunol Unit, S-17177 Linkoping, Sweden.
    Olsson, Tomas
    Karolinska Institute, Department Clin Neurosci, Neuroimmunol Unit, S-17177 Linkoping, Sweden.
    Skogh, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Rheumatology.
    Kastbom, Alf
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Rheumatology.
    Sjöwall, Christopher
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Rheumatology.
    Vrethem, Magnus
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Neurology.
    Håkansson, Irene
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Benson, Mikael
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Allergy Center.
    Jenmalm, Maria
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Gustafsson, Mika
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics. Linköping University, Faculty of Science & Engineering.
    Ernerudh, Jan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
    Dynamic Response Genes in CD4+T Cells Reveal a Network of Interactive Proteins that Classifies Disease Activity in Multiple Sclerosis2016In: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 16, no 11, p. 2928-2939Article in journal (Refereed)
    Abstract [en]

    Multiple sclerosis (MS) is a chronic inflammatory disease of the CNS and has a varying disease course as well as variable response to treatment. Biomarkers may therefore aid personalized treatment. We tested whether in vitro activation of MS patient-derived CD4+ T cells could reveal potential biomarkers. The dynamic gene expression response to activation was dysregulated in patient-derived CD4+ T cells. By integrating our findings with genome-wide association studies, we constructed a highly connected MS gene module, disclosing cell activation and chemotaxis as central components. Changes in several module genes were associated with differences in protein levels, which were measurable in cerebrospinal fluid and were used to classify patients from control individuals. In addition, these measurements could predict disease activity after 2 years and distinguish low and high responders to treatment in two additional, independent cohorts. While further validation is needed in larger cohorts prior to clinical implementation, we have uncovered a set of potentially promising biomarkers.

  • 9.
    Kanmert, Daniel
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Physics. Linköping University, Faculty of Science & Engineering.
    Enocsson, Helena
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Science & Engineering.
    Wetterö, Jonas
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences.
    Kastbom, Alf
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Rheumatology in Östergötland.
    Skogh, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Rheumatology in Östergötland.
    Enander, Karin
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Physics. Linköping University, Faculty of Science & Engineering.
    Designed Surface with Tunable IgG Density as an in Vitro Model for Immune Complex Mediated Stimulation of Leukocytes2010In: Langmuir, ISSN 0743-7463, E-ISSN 1520-5827, Vol. 26, no 5, p. 3493-3497Article in journal (Refereed)
    Abstract [en]

    We present the design of an in vitro for immune-complex-mediated stimulation of leukocytes and its functional characteristics with respect to monocyte adhesion. The model was based on orientation-controlled immobilization of a humanized IgG1 monoclonal antibody (rituximab) via its interaction with a biotinylated peptide epitope derived from the CD20 marker. The peptide was linked to neutravidin covalently attached to it mixed self-assembled monolayer of carboxyl- and methoxy-terminated oligo(ethylene glycol) alkane thiolates on gold. The surface adhesion propensity of human monocytes (cell line U917) was highly dependent on the lateral IgG density and indicated that there exists a distance between IgG-Fc on the surface where interactions with Fc gamma receptors are optimal. This well-defined platform allows for a careful control of the size and orientation of artificial IgG immune complexes, it is easily made compatible with, for example, cellular imaging, and it will become useful for in vitro studies on the importance of Fc gamma receptor interactions in chronic immune-mediated diseases.

  • 10.
    Kanmert, Daniel
    et al.
    Linköping University, Department of Physics, Chemistry and Biology. Linköping University, The Institute of Technology.
    Kastbom, Alf
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Rheumatology in Östergötland.
    Almroth, Gunnel
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences.
    Skogh, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Rheumatology in Östergötland.
    Enander, Karin
    Linköping University, Department of Physics, Chemistry and Biology, Sensor Science and Molecular Physics . Linköping University, The Institute of Technology.
    Wetterö, Jonas
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences.
    IgG Rheumatoid Factor Against the Four Human Fc-gamma Subclasses in Early Rheumatoid Arthritis (the Swedish TIRA Project)Manuscript (preprint) (Other academic)
    Abstract [en]

    Rheumatoid factor (RF), i.e. a family of autoantibodies against the Fc part of IgG, is an important seromarker of rheumatoid arthritis (RA). Traditional particle agglutination without disclosing the antibody isotype remains the predominating diagnostic method in clinical routine. Although IgG-RF attracts pathogenic interest, its detection remains technically challenging. The present study aimed at developing a set of tests identifying IgG-RFs directed against the four IgG subclasses. IgG-RF against either subclass of human IgG-Fc were analyzed with four novel enzyme-linked immunosorbent assays (ELISAs) utilizing four recombinant human Fc-gamma fragments (hIgG1-4) as sources of antigen. Sera from 40 patients with recent-onset RA (20 seropositive and 20 seronegative by IgM-RF and IgA-RF-isotype specific ELISA) were analyzed. Sera from 20 healthy blood donors served as reference. Among the IgM-/IgA-RF positive RA-sera, IgG-RF was found directed against hIgG1, hIgG4, and most notably, with strikingly high reactivity against hIgG2, but not hIgG3. Significant correlations were seen between IgG-RF against hIgG2-Fc and IgA-RF (r = 0.513) and IgM-RF (r = 0.736) levels. Further prospective studies are warranted to elucidate any correlation to disease course and outcome.

  • 11.
    Kanmert, Daniel
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Physics. Linköping University, Faculty of Science & Engineering.
    Kastbom, Alf
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Rheumatology.
    Almroth, Gunnel
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences.
    Skogh, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Rheumatology.
    Enander, Karin
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Physics. Linköping University, Faculty of Science & Engineering.
    Wetterö, Jonas
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences.
    IgG Rheumatoid Factors Against the Four Human Fc-gamma Subclasses in Early Rheumatoid Arthritis (The Swedish TIRA Project)2012In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 75, no 1, p. 115-119Article in journal (Refereed)
    Abstract [en]

    Rheumatoid factor (RF), i.e. a family of autoantibodies against the Fc part of IgG, is an important seromarker of rheumatoid arthritis (RA). Traditional particle agglutination without disclosing the antibody isotype remains the predominating diagnostic method in clinical routine. Although IgG-RF attracts pathogenic interest, its detection remains technically challenging. The present study aimed at developing a set of tests identifying IgG-RFs directed against the four IgG subclasses. IgG-RF against either subclass of human IgG-Fc were analysed with four novel enzyme-linked immunosorbent assays (ELISAs) utilizing four recombinant human Fc-gamma fragments (hIgG14) as sources of antigen. Sera from 40 patients with recent onset RA (20 seropositive and 20 seronegative by IgM-RF and IgA-RF-isotype-specific ELISA) were analysed. Sera from 20 healthy blood donors served as reference. Among the IgM-/IgA-RF-positive RA-sera, IgG-RF was found directed against hIgG1 and hIgG2, but not against hIgG3 or hIgG4. Significant correlations were seen between IgG-RF against hIgG2-Fc and IgM-RF (r = 0.666) levels. Further prospective studies are warranted to elucidate any correlation to disease course and outcome.

  • 12.
    Kastbom, Alf
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Rheumatology in Östergötland.
    Autoantibodies and genetic variation in rheumatoid arthritis: aspects on susceptibility and disease course2007Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation and subsequent destruction of synovial joints. Although its causes remain largely unknown, a substantial genetic contribution is known to exist. During the last decades the benefits of early aggressive treatment have become evident, and more potent therapeutic options have become available. These advances have increased the demands for rapid accurate diagnosis and prognostic markers of disease course and therapy response.

    The ‘rheumatoid factor’ (RF) has long been used as a diagnostic and prognostic marker of RA. In this thesis, the utility of measuring antibodies to cyclic citrullinated peptides (CCP) was investigated. In a population-based arthritis incidence study, 69 very early arthritis patients (symptom duration < 3 months) were identified. The anti-CCP test, performed at baseline and related to diagnosis at the 2-year follow-up, had a diagnostic specificity for RA of 96% and a sensitivity of 44%, both of which were superior to RF. In a prospective cohort of 242 incident cases of RA (symptom duration < 1 year), 64% of the patients tested positive for anti-CCP at baseline (equal to RF). Despite receiving more active anti-rheumatic therapy, the anti-CCP-positive patients had a more aggressive disease course during 3 years as compared to those testing negative.

    The 158VV genotype of Fcγ Receptor type IIIA (FcγRIIIA), which binds IgG with higher affinity than 158FF, was associated with an increased susceptibility to RA in men, but not in women. Previous studies report conflicting results, and none stratified according to gender. The 158V/F polymorphism of FcγRIIIA was not found to influence outcome of anti-tumour necrosis factor therapy in 282 RA patients, contradicting hints from previous studies. Genetic variation in proteins of the inflammasome, an interleukin-1 (IL-1) regulating intracellular protein complex, is associated with rare autoinflammatory conditions and possibly with Crohn’s disease. In this first study on genetic variation of the inflammasome in RA, we describe a compound polymorphism of the genes CIAS1 and TUCAN that associates both with susceptibility to RA and to the severity of the disease. Hypothetically, these genes may identify a subgroup of RA patients that would benefit from anti-IL-1 therapy.

    This thesis work emphasizes the benefits of testing for anti-CCP in the diagnosis and outcome prediction in early arthritis. FcγRIIIA genotype is likely to affect RA susceptibility and further work should apply a gender perspective. Inflammasome genetics may influence the risk of developing RA. Additional studies are warranted to settle whether it also identifies a subgroup of RA patients benefiting from IL-1 targeted therapy.

    List of papers
    1. Antibodies against cyclic citrullinated peptide (CCP) and levels of cartilage oligomeric matrix protein (COMP) in very early arthritis: relation to diagnosis and disease activity
    Open this publication in new window or tab >>Antibodies against cyclic citrullinated peptide (CCP) and levels of cartilage oligomeric matrix protein (COMP) in very early arthritis: relation to diagnosis and disease activity
    Show others...
    2004 (English)In: Scandinavian Journal of Rheumatology, ISSN 0300-9742, Vol. 33, no 3, p. 185-188Article in journal (Refereed) Published
    Abstract [en]

    Objective: To measure serum levels of antibodies against cyclic citrullinated peptide (anti-CCP antibodies) and serum cartilage oligomeric matrix protein (COMP) in patients with early joint inflammation, and to study the correlation of these two tests with clinical measurements.

    Methods: Adult patients with recent-onset arthritis, of <3 months' duration, were referred from primary healthcare centres to rheumatologists. Serum levels of anti-CCP antibodies and COMP at baseline were analysed by enzyme immunoassay (EIA) and compared with clinical baseline data.

    Results: Sixty-nine patients were included. The specificity of the anti-CCP antibody test for RA was 96%, and the sensitivity was 44%. There was a significant difference between the four diagnosis groups in the anti-CCP antibody test, probability (p)<0.001, whereas no significant differences were found concerning COMP. The baseline serum COMP test correlated with age (p=0.0001), joint score for swollen joints (p=0.02), and C-reactive protein (CRP) (p=0.02).

    Conclusion: This study confirms the high diagnostic specificity of anti-CCP antibodies for rheumatoid arthritis (RA) in a prospective population-based study of very early arthritis. Raised serum COMP levels were common in all diagnosis groups in this series, indicating cartilage involvement in both self-limiting and non-erosive disease.

    Keywords
    anti-CCP antibodies, COMP, rheumatoid arthritis
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-14376 (URN)10.1080/03009740310004856 (DOI)
    Available from: 2007-04-20 Created: 2007-04-20 Last updated: 2015-08-31
    2. Anti-CCP antibody test predicts the disease course during 3 years in early rheumatoid arthritis (the Swedish TIRA project)
    Open this publication in new window or tab >>Anti-CCP antibody test predicts the disease course during 3 years in early rheumatoid arthritis (the Swedish TIRA project)
    2004 (English)In: Annals of the Rheumatic Diseases, ISSN 0003-4967, Vol. 63, no 9, p. 1085-1089Article in journal (Refereed) Published
    Abstract [en]

    Objectives: To evaluate the diagnostic sensitivity of antibodies to cyclic citrullinated peptide (CCP) in recent onset rheumatoid arthritis (RA) at diagnosis and 3 years later, and to evaluate anti-CCP antibody as a predictor of the disease course during 3 years.

    Methods: 242 patients with recent onset (≤ 1 year) RA were followed up regularly during 3 years after inclusion in the Swedish multicentre study "TIRA" 1996-98. Anti-CCP antibodies were analysed by an enzyme immunoassay (EIA). Rheumatoid factors (RFs) were analysed by latex agglutination and two isotype-specific (IgM and IgA) EIAs. Disease activity was assessed by plasma CRP, ESR, 28 joint disease activity score, and the physician's global assessment of disease activity. Functional ability was evaluated by the Health Assessment Questionnaire.

    Results: Overall, the diagnostic sensitivity of anti-CCP antibodies was 64% and the proportion of positive tests increased with the number of fulfilled classification criteria according to the American College of Rheumatology. The anti-CCP antibody results correlated with RF, but were better than RF as predictor of a more aggressive disease course. After 3 years 5/97 patients had changed anti-CCP status: 2 from negative to positive and 3 from positive to negative. The mean level of anti-CCP antibodies declined by 131 U/ml during the 3 year follow up (95% Cl 34 to 228 U/ml).

    Conclusion: The anti-CCP antibody assay has a similar diagnostic sensitivity to that of RF in early RA, but is better as a predictor of the disease course over 3 years. Although the mean serum level declines, anti-CCP antibody positivity remains essentially unaltered 3 years after diagnosis and start of antirheumatic treatment.

    Keywords
    anti-CCP antibody, rheumatoid factor, early rheumatoid arthritis, inflammation, disease course
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-14377 (URN)10.1136/ard.2003.016808 (DOI)
    Available from: 2007-04-20 Created: 2007-04-20 Last updated: 2015-08-31
    3. The 158V polymorphism of Fc gamma receptor type IIIA in early rheumatoid arthritis: increased susceptibility and severity in male patients (the Swedish TIRA project)
    Open this publication in new window or tab >>The 158V polymorphism of Fc gamma receptor type IIIA in early rheumatoid arthritis: increased susceptibility and severity in male patients (the Swedish TIRA project)
    2005 (English)In: Rheumatology, ISSN 1462-0324, Vol. 44, no 10, p. 1294-1298Article in journal (Refereed) Published
    Abstract [en]

    Objectives. To evaluate the influence of Fc receptor IIIA (FcRIIIA) 158V/F polymorphism on susceptibility and disease severity in early rheumatoid arthritis (RA).

    Methods. In 181 Swedish patients (128 women, 53 men) with RA of recent onset, disease and disability variables such as erythrocyte sedimentation rate, 28-joint disease activity score (DAS28) and health assessment questionnaire (HAQ) scores were monitored regularly during 3 yr. Three hundred and sixty-two controls were recruited from the same geographical area as the patients. FcRIIIA genotyping was performed using denaturing high-performance liquid chromatography.

    Results. In all RA patients, FcRIIIA-158VV was significantly over-represented compared with controls [odds ratio (OR) 1.9, 95% confidence interval (CI) 1.01–3.5, P<0.05]. After stratifying for sex, the difference remained in the male population (OR 3.2, 95%CI 1.03–11, P<0.05) but disappeared among women (OR 1.4, 95%CI 0.7–3.1, P=0.4). In addition, 158VV patients were more likely to exhibit early joint erosions (OR 6.1, 95%CI 1.4–28, P<0.01). At baseline, patients with different FcRIIIA genotypes did not differ with respect to measures of disease activity or functional ability. Thereafter, in male patients with at least one V allele the mean DAS28 and HAQ scores were higher compared with 158FF. In contrast, female patients with at least one 158V allele displayed lower mean DAS28 and HAQ scores compared with those with 158FF.

    Conclusions. In a male population, the FcRIIIA-158VV genotype is associated with an increased risk of developing RA, and the 158V allele with more severe disease in early RA.

    Keywords
    Disease course, Early rheumatoid arthritis, Fc receptor, Single-nucleotide polymorphism
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-14378 (URN)10.1093/rheumatology/kei010 (DOI)
    Available from: 2007-04-20 Created: 2007-04-20 Last updated: 2015-08-31
    4. Fcγ receptor type IIIA genotype and response to tumor necrosis factor alpha-blocking agents in patients with rheumatoid arthritis
    Open this publication in new window or tab >>Fcγ receptor type IIIA genotype and response to tumor necrosis factor alpha-blocking agents in patients with rheumatoid arthritis
    Show others...
    2007 (English)In: Arthritis and Rheumatism, ISSN 0004-3591, Vol. 56, no 2, p. 448-452Article in journal (Refereed) Published
    Abstract [en]

    Objective: To determine whether a functional single-nucleotide polymorphism in the gene encoding Fc receptor type IIIA (FcRIIIA) correlates with the response to treatment with tumor necrosis factor inhibitors in rheumatoid arthritis (RA).

    Methods: The study population comprised 282 Swedish patients with RA in whom the therapeutic efficacy of conventional disease-modifying antirheumatic drugs had been insufficient. Infliximab or etanercept treatment was initiated, and patients were evaluated after 3 months, using the American College of Rheumatology 20% improvement criteria (ACR20), the ACR50, and the ACR70 or the European League Against Rheumatism (EULAR) criteria. The chi-square test was used to compare response rates across FcRIIIA genotypes.

    Results: No differences in genotype distribution were observed among nonresponders compared with ACR20 responders (P = 0.80), ACR50 responders (P = 0.56), or ACR70 responders (P = 0.91). Similar results were observed when analyzing infliximab and etanercept separately or when using the EULAR response criteria.

    Conclusion: Unlike the findings of a previous study, the results of the current study suggest that the 158V/F polymorphism of FcRIIIA is very unlikely to influence the clinical efficacy of infliximab or etanercept in patients with RA.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-14379 (URN)10.1002/art.22390 (DOI)
    Available from: 2007-04-20 Created: 2007-04-20 Last updated: 2015-08-31
    5. Genetic variation in proteins of the cryopyrin inflammasome influences susceptibility and severity of rheumatoid arthritis (the Swedish TIRA project)
    Open this publication in new window or tab >>Genetic variation in proteins of the cryopyrin inflammasome influences susceptibility and severity of rheumatoid arthritis (the Swedish TIRA project)
    Show others...
    2008 (English)In: Rheumatology, ISSN 1462-0324, Vol. 47, no 4, p. 415-417Article in journal (Refereed) Published
    Abstract [en]

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

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

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

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

    Keywords
    Disease course, Genetics, Inflammasome, Rheumatoid arthritis
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-14380 (URN)10.1093/rheumatology/kem372 (DOI)
    Available from: 2007-04-20 Created: 2007-04-20 Last updated: 2015-08-31Bibliographically approved
  • 13.
    Kastbom, Alf
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology . Linköping University, Faculty of Health Sciences.
    Ahmadi, Ahmad
    Linköping University, Department of Clinical and Experimental Medicine, Cellbiology. Linköping University, Faculty of Health Sciences.
    Söderkvist, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Cellbiology. Linköping University, Faculty of Health Sciences.
    Skogh, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology . Linköping University, Faculty of Health Sciences.
    The 158V polymorphism of Fc gamma receptor type IIIA in early rheumatoid arthritis: increased susceptibility and severity in male patients (the Swedish TIRA project)2005In: Rheumatology, ISSN 1462-0324, Vol. 44, no 10, p. 1294-1298Article in journal (Refereed)
    Abstract [en]

    Objectives. To evaluate the influence of Fc receptor IIIA (FcRIIIA) 158V/F polymorphism on susceptibility and disease severity in early rheumatoid arthritis (RA).

    Methods. In 181 Swedish patients (128 women, 53 men) with RA of recent onset, disease and disability variables such as erythrocyte sedimentation rate, 28-joint disease activity score (DAS28) and health assessment questionnaire (HAQ) scores were monitored regularly during 3 yr. Three hundred and sixty-two controls were recruited from the same geographical area as the patients. FcRIIIA genotyping was performed using denaturing high-performance liquid chromatography.

    Results. In all RA patients, FcRIIIA-158VV was significantly over-represented compared with controls [odds ratio (OR) 1.9, 95% confidence interval (CI) 1.01–3.5, P<0.05]. After stratifying for sex, the difference remained in the male population (OR 3.2, 95%CI 1.03–11, P<0.05) but disappeared among women (OR 1.4, 95%CI 0.7–3.1, P=0.4). In addition, 158VV patients were more likely to exhibit early joint erosions (OR 6.1, 95%CI 1.4–28, P<0.01). At baseline, patients with different FcRIIIA genotypes did not differ with respect to measures of disease activity or functional ability. Thereafter, in male patients with at least one V allele the mean DAS28 and HAQ scores were higher compared with 158FF. In contrast, female patients with at least one 158V allele displayed lower mean DAS28 and HAQ scores compared with those with 158FF.

    Conclusions. In a male population, the FcRIIIA-158VV genotype is associated with an increased risk of developing RA, and the 158V allele with more severe disease in early RA.

  • 14.
    Kastbom, Alf
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Region Östergötland, Heart and Medicine Center, Department of Rheumatology. Linköping University, Faculty of Medicine and Health Sciences.
    Arlestig, Lisbeth
    Umeå University, Sweden.
    Rantapaa-Dahlqvist, Solbritt
    Umeå University, Sweden.
    Genetic Variants of the NLRP3 Inflammasome Are Associated with Stroke in Patients with Rheumatoid Arthritis2015In: Journal of Rheumatology, ISSN 0315-162X, E-ISSN 1499-2752, Vol. 42, no 10, p. 1740-1745Article in journal (Refereed)
    Abstract [en]

    Objective. Inflammasomes are intracellular protein complexes important for the production of proinflammatory cytokines. Studies have suggested that the NLRP3 inflammasome influences both the severity of rheumatoid arthritis (RA) and development of atherosclerosis. Therefore, we investigated whether functional genetic variants related to the NLRP3 inflammasome influence the risk of cardiovascular (CV) disease (CVD) in patients with RA. Methods. The incidence of CVD was assessed in 522 patients with established RA by a retrospective survey of medical records in combination with a 6-year prospective followup. NLRP3-Q705K and CARD8-C10X genotypes were analyzed in relation to CVD by logistic regression, adjusting for traditional risk factors, antirheumatic treatment, and age at the onset of RA. Results. Carriage of the NLRP3-Q705K minor allele was associated with an increased risk of stroke/transient ischemic attack (TIA; OR 2.01, 95% CI 1.0-4.1, p = 0.05), while CARD8-C10X was not associated with any type of CV event. Patients with greater than= 1 variant allele in both polymorphisms had an increased risk of CVD when compared with patients without variant alleles present in both polymorphisms (adjusted OR 3.05, 95% CI 1.42-6.54, p = 0.004). Stratification showed that this risk was confined to stroke/TIA (adjusted OR 5.09, 95% CI 2.27-11.44, p less than 0.0001) and not to myocardial infarction (MI)/angina pectoris (adjusted OR 1.58, 95% CI 0.67-3.73). Risk estimates were consistently higher among female patients. Conclusion. Genetic variants of the NLRP3 inflammasome influence the risk of stroke/TIA, but not of MI/angina pectoris in Swedish patients with established RA.

  • 15.
    Kastbom, Alf
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Rheumatology in Östergötland.
    Bratt, Johan
    Karolinska University Hospital Huddinge and Karolinska Institutet, Stockholm, Sweden.
    Ernestam, Sofia
    Karolinska University Hospital Huddinge and Karolinska Institutet, Stockholm, Sweden.
    Lampa, Jon
    Karolinska University Hospital Solna and Karolinska Institutet, Stockholm, Sweden.
    Padyukov, Leonid
    Karolinska University Hospital Solna and Karolinska Institutet, Stockholm, Sweden.
    Söderkvist, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Skogh, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Rheumatology in Östergötland.
    Fcγ receptor type IIIA genotype and response to tumor necrosis factor alpha-blocking agents in patients with rheumatoid arthritis2007In: Arthritis and Rheumatism, ISSN 0004-3591, Vol. 56, no 2, p. 448-452Article in journal (Refereed)
    Abstract [en]

    Objective: To determine whether a functional single-nucleotide polymorphism in the gene encoding Fc receptor type IIIA (FcRIIIA) correlates with the response to treatment with tumor necrosis factor inhibitors in rheumatoid arthritis (RA).

    Methods: The study population comprised 282 Swedish patients with RA in whom the therapeutic efficacy of conventional disease-modifying antirheumatic drugs had been insufficient. Infliximab or etanercept treatment was initiated, and patients were evaluated after 3 months, using the American College of Rheumatology 20% improvement criteria (ACR20), the ACR50, and the ACR70 or the European League Against Rheumatism (EULAR) criteria. The chi-square test was used to compare response rates across FcRIIIA genotypes.

    Results: No differences in genotype distribution were observed among nonresponders compared with ACR20 responders (P = 0.80), ACR50 responders (P = 0.56), or ACR70 responders (P = 0.91). Similar results were observed when analyzing infliximab and etanercept separately or when using the EULAR response criteria.

    Conclusion: Unlike the findings of a previous study, the results of the current study suggest that the 158V/F polymorphism of FcRIIIA is very unlikely to influence the clinical efficacy of infliximab or etanercept in patients with RA.

  • 16.
    Kastbom, Alf
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Rheumatology in Östergötland.
    Cöster, Lars
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Rheumatology in Östergötland.
    Ärlestig, Lisbeth
    Umeå University, Sweden .
    Chatzidionysiou, Aikaterini
    Karolinska University Hospital and Karolinska Institute, Stockholm, Sweden .
    van Vollenhoven, Ronald F.
    Karolinska University Hospital and Karolinska Institute, Stockholm, Sweden .
    Padyukov, Leonid
    Karolinska University Hospital and Karolinska Institute, Stockholm, Sweden .
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Sweden .
    Saevarsdottir, Saedis
    Karolinska University Hospital and Karolinska Institute, Stockholm, Sweden .
    Influence of FCGR3A genotype on the therapeutic response to rituximab in rheumatoid arthritis: an observational cohort study2012In: BMJ Open, ISSN 2044-6055, E-ISSN 2044-6055, Vol. 2, no 5Article in journal (Refereed)
    Abstract [en]

    Objectives To determine whether a polymorphism in the Fcγ receptor type IIIA (FCGR3A-F158V), influencing immunoglobulin G binding affinity, relates to the therapeutic efficacy of rituximab in rheumatoid arthritis (RA) patients.

    Design Observational cohort study.

    Setting Three university hospital rheumatology units in Sweden.

    Participants Patients with established RA (n=177; 145 females and 32 males) who started rituximab (Mabthera) as part of routine care.

    Primary outcome measures Response to rituximab therapy in relation to FCGR3A genotype, including stratification for sex.

    Results The frequency of responders differed significantly across FCGR3A genotypes (p=0.017 in a 3×2 contingency table). Heterozygous patients showed the highest response rate at 83%, as compared with patients carrying 158FF (68%) or 158VV (56%) (p=0.028 and 0.016, respectively). Among 158VV patients, response rates differed between male and female patients (p=0.036), but not among 158FF or 158VF patients (p=0.72 and 0.46, respectively).

    Conclusions Therapeutic efficacy of rituximab in RA patients is influenced by FCGR3A genotype, with the highest response rates found among heterozygous patients. This may suggest that different rituximab mechanisms of action in RA are optimally balanced in FCGR3A-158VF patients. Similar to the previously described associations with RA susceptibility and disease course, the impact of 158VV on rituximab response may be influenced by sex.

  • 17.
    Kastbom, Alf
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Region Östergötland, Heart and Medicine Center, Department of Rheumatology. Linköping University, Faculty of Medicine and Health Sciences. Karolinska Institute, Sweden.
    Forslind, Kristina
    Helsingborgs Lasarett, Sweden; Skåne University Hospital, Sweden.
    Ernestam, Sofia
    Karolinska Institute, Sweden.
    Geborek, Pierre
    Skåne University Hospital, Sweden.
    Karlsson, Johan A.
    Skåne University Hospital, Sweden.
    Petersson, Ingemar F.
    Lund University, Sweden.
    Saevarsdottir, Saedis
    Karolinska Institute, Sweden.
    Klareskog, Lars
    Karolinska Institute, Sweden.
    van Vollenhoven, Ronald F.
    Karolinska Institute, Sweden.
    Lundberg, Karin
    Karolinska Institute, Sweden.
    Changes in the anticitrullinated peptide antibody response in relation to therapeutic outcome in early rheumatoid arthritis: results from the SWEFOT trial2016In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 75, no 2, p. 356-361Article in journal (Refereed)
    Abstract [en]

    Objective To determine the relationship between changes in antibody levels towards citrullinated peptides derived from different candidate autoantigens and therapeutic outcome in early rheumatoid arthritis (RA). Methods Baseline and 3-month serum samples from 316 patients with early RA enrolled in the Swedish Farmacotherapy (SWEFOT) trial were analysed for antibodies against cyclic citrullinated peptides (CCP) and citrullinated peptides derived from vimentin (cVim), fibrinogen (cFib) and a-enolase (CEP-1). At 3-month follow-up, methotrexate monotherapy-inadequate responders were randomised to add-on therapy with sulfasalazine and hydroxychloroquine or infliximab. In these patients, anticitrullinated peptide antibodies (ACPA) were also assessed at 12 and 24 months. The proportion of antibody-positive patients and relative changes in antibody levels were compared across ACPA specificities and related to therapeutic response and radiographic progression. Results During the 2-year follow-up, the proportion of patients testing positive declined significantly regarding antibodies to cVim, cFib and CEP-1, while anti-CCP antibody occurrence remained stable over time. Turning anti-cVim antibody negative was most common, and anti-cVim antibody seroreversion during the first three months associated with significantly less 2-year radiographic progression compared with patients who remained positive. Median antibody levels of all tested ACPAs declined uniformly during initial methotrexate therapy and following response to add-on therapy, with no significant relation to treatment regimen or radiographic progression. Conclusions The influence of early antirheumatic therapy on ACPA seroreversions was markedly different across specificities, and early disappearance of anti-cVim antibodies associated with better radiological outcome. Thus, these data suggest that the disappearance of particular ACPA reactivities may be beneficial in early RA.

  • 18.
    Kastbom, Alf
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Rheumatology in Östergötland.
    Johansson, Martin
    Umeå University.
    Verma, Deepti
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Söderkvist, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Rantapaa-Dahlqvist, Solbritt
    Umeå University.
    CARD8 p.C10X polymorphism is associated with inflammatory activity in early rheumatoid arthritis2010In: ANNALS OF THE RHEUMATIC DISEASES, ISSN 0003-4967, Vol. 69, no 4, p. 723-726Article in journal (Refereed)
    Abstract [en]

    Objectives CARD8 and NLRP3 are constituents of the inflammasome which regulates interleukin 1 beta production. The influence of polymorphisms in CARD8 and NLRP3 on rheumatoid arthritis (RA) susceptibility and severity were evaluated. Methods CARD8 p.C10X and NLRP3 p.Q705K genotypes were assessed in andgt;500 controls and patients with early RA from northern Sweden. The patients were monitored regularly over a 2-year period. The 28-joint disease activity score (DAS28) and its separate components were compared across genotypes. Results Patients with one or more variant alleles in CARD8 (CARD8-X) had increased DAS28, tender joint count and erythrocyte sedimentation rate during the 2-year follow-up period despite receiving disease-modifying antirheumatic drugs to a greater extent. CARD8-X was significantly over-represented among patients who received anti-tumour necrosis factor therapy during the first 2 years. CARD8 and NLRP3 genotypes did not influence radiological joint damage and were not associated with an increased susceptibility. Conclusions Carriage of CARD8-X is associated with a worse disease course in early RA.

  • 19.
    Kastbom, Alf
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Rheumatology.
    Klingberg, E
    University of Gothenburg, Sweden .
    Verma, Deepti
    Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences.
    Carlsten, H
    University of Gothenburg, Sweden .
    Forsblad-dElia, H
    University of Gothenburg, Sweden .
    Wesamaa, J
    Örebro University Hospital, Sweden .
    Cedergren, Jan
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Rheumatology.
    Eriksson, Per
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Rheumatology.
    Söderkvist, P
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Genetic variants in CARD8 but not in NLRP3 are associated with ankylosing spondylitis2013In: Scandinavian Journal of Rheumatology, ISSN 0300-9742, E-ISSN 1502-7732, Vol. 42, no 6, p. 465-468Article in journal (Refereed)
    Abstract [en]

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

  • 20.
    Kastbom, Alf
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Rheumatology.
    Roos Ljungberg, Karin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Ziegelasch, Michael
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Rheumatology.
    Wetterö, Jonas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Skogh, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Rheumatology.
    Martinsson, Klara
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Changes in anti-citrullinated protein antibody isotype levels in relation to disease activity and response to treatment in early rheumatoid arthritis2018In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 194, no 3, p. 391-399Article in journal (Refereed)
    Abstract [en]

    Rheumatoid arthritis (RA) is a chronic inflammatory disease where serum analysis of anti-citrullinated peptide/protein antibodies (ACPA) is an important diagnostic/prognostic tool. Levels and changes of ACPA in RA patients have been studied previously in relation to disease course and therapy response, but less is known regarding ACPA isotype changes in early RA. Hence, recent-onset RA patients (n = 231) were subjected to a 3-year clinical and radiological follow-up. Serum samples were serially collected and ACPA isotypes were analysed using the second-generation cyclic citrullinated peptide (CCP) as capture antigen. Changes in ACPA isotype levels and status were related to disease course and pharmacotherapy. At inclusion, 74% of the patients tested positive for ACPA IgG; 55% for immunoglobulin (Ig)A, 37% for secretory IgA (SIgA) and 35% for IgM. The proportion of positive patients decreased significantly at follow-up regarding ACPA SIgA, IgM and IgA. During the initial 3 months, reduction of the 28-joint disease activity score (DAS28) correlated with reduced levels of ACPA IgG (Rho = 0 center dot 242, P = 0 center dot 003), IgA (Rho = 0 center dot 260, P = 0 center dot 008), IgM (Rho = 0 center dot 457, P amp;lt; 0 center dot 001) and SIgA (Rho = 0 center dot 402, P amp;lt; 0 center dot 001). Levels of ACPA SIgA (P = 0 center dot 008) and IgM (P = 0 center dot 021) decreased significantly among patients with good response to treatment, which was not seen regarding ACPA IgA or IgG. Changes in ACPA isotype levels were not associated with radiographic damage. In conclusion, ACPA SIgA and IgM declined rapidly upon anti-rheumatic therapy and correlated with decreased disease activity in recent-onset RA. This may indicate that down-regulation of mucosal immunity to citrullinated proteins/peptides and recruitment of new B cells are key features of therapy responses in early RA.

  • 21.
    Kastbom, Alf
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Rheumatology in Östergötland.
    Strandberg, Gunnar
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Rheumatology in Östergötland.
    Lindroos, Annette
    Skogh, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Rheumatology in Östergötland.
    Anti-CCP antibody test predicts the disease course during 3 years in early rheumatoid arthritis (the Swedish TIRA project)2004In: Annals of the Rheumatic Diseases, ISSN 0003-4967, Vol. 63, no 9, p. 1085-1089Article in journal (Refereed)
    Abstract [en]

    Objectives: To evaluate the diagnostic sensitivity of antibodies to cyclic citrullinated peptide (CCP) in recent onset rheumatoid arthritis (RA) at diagnosis and 3 years later, and to evaluate anti-CCP antibody as a predictor of the disease course during 3 years.

    Methods: 242 patients with recent onset (≤ 1 year) RA were followed up regularly during 3 years after inclusion in the Swedish multicentre study "TIRA" 1996-98. Anti-CCP antibodies were analysed by an enzyme immunoassay (EIA). Rheumatoid factors (RFs) were analysed by latex agglutination and two isotype-specific (IgM and IgA) EIAs. Disease activity was assessed by plasma CRP, ESR, 28 joint disease activity score, and the physician's global assessment of disease activity. Functional ability was evaluated by the Health Assessment Questionnaire.

    Results: Overall, the diagnostic sensitivity of anti-CCP antibodies was 64% and the proportion of positive tests increased with the number of fulfilled classification criteria according to the American College of Rheumatology. The anti-CCP antibody results correlated with RF, but were better than RF as predictor of a more aggressive disease course. After 3 years 5/97 patients had changed anti-CCP status: 2 from negative to positive and 3 from positive to negative. The mean level of anti-CCP antibodies declined by 131 U/ml during the 3 year follow up (95% Cl 34 to 228 U/ml).

    Conclusion: The anti-CCP antibody assay has a similar diagnostic sensitivity to that of RF in early RA, but is better as a predictor of the disease course over 3 years. Although the mean serum level declines, anti-CCP antibody positivity remains essentially unaltered 3 years after diagnosis and start of antirheumatic treatment.

  • 22.
    Kastbom, Alf
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences.
    Verma, Deepti
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Eriksson, Per
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences.
    Skogh, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences.
    Wingren, Gun
    Linköping University, Department of Clinical and Experimental Medicine, Occupational and Environmental Medicine. Linköping University, Faculty of Health Sciences.
    Söderkvist, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Genetic variation in proteins of the cryopyrin inflammasome influences susceptibility and severity of rheumatoid arthritis (the Swedish TIRA project)2008In: Rheumatology, ISSN 1462-0324, Vol. 47, no 4, p. 415-417Article in journal (Refereed)
    Abstract [en]

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

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

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

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

  • 23.
    Martinsson, Klara
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Johansson, Anders
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Kastbom, Alf
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Rheumatology.
    Skogh, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Rheumatology.
    Immunoglobulin (Ig)G1 and IgG4 anti-cyclic citrullinated peptide (CCP) associate with shared epitope, whereas IgG2 anti-CCP associates with smoking in patients with recent-onset rheumatoid arthritis (the Swedish TIRA project).2017In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 188, no 1, p. 53-62Article in journal (Refereed)
    Abstract [en]

    Given the possible importance of anti-citrullinated peptide/protein antibodies (ACPA) for initiation and progression of rheumatoid arthritis (RA), extended knowledge about the different isotypes and subclasses is important. In the present study, we analysed the immunoglobulin (Ig)G subclasses regarding reactivity against cyclic citrullinated peptides (anti-CCP) among 504 clinically well-characterized patients with recent-onset RA in relation to smoking habits, shared epitope (SE) status and IgA and pan-IgG anti-CCP antibodies. All patients, regardless of pan-IgG anti-CCP status, were analysed for IgG1-4 CCP reactivity. Sixty-nine per cent were positive in any IgG anti-CCP subclass, and of these 67% tested positive regarding IgG1, 35% IgG2, 32% IgG3, and 59% IgG4 anti-CCP. Among ever-smokers the percentages of IgG2 anti-CCP (P = 0·01) and IgA anti-CCP (P = 0·002)-positive cases were significantly higher compared to never-smokers. A positive IgG anti-CCP subclass -negative cases. Combining SE and smoking data revealed that IgG1 and IgG4 anti-CCP were the IgG anti-CCP isotypes associated with expression of SE, although the lower number of patients positive for IgG2 or IgG3 anti-CCP could, however, have influenced the results. High levels of IgG2 anti-CCP were shown to correlate with expression of the 'non-SE' allele human leucocyte antigen (HLA)-DRB1*15. In conclusion, in this study we describe different risk factor characteristics across the IgG anti-CCP subclasses, where IgG2 appears similar to IgA anti-CCP regarding the predominant association with smoking, while IgG1 and IgG4 related more distinctly to the carriage of SE genes.

  • 24.
    Odqvist, Lina
    et al.
    AstraZeneca RandD Gothenburg, Sweden.
    Jevnikar, Zala
    AstraZeneca RandD Gothenburg, Sweden.
    Riise, Rebecca
    AstraZeneca RandD Gothenburg, Sweden.
    Oberg, Lisa
    AstraZeneca RandD Gothenburg, Sweden.
    Rhedin, Magdalena
    AstraZeneca RandD Gothenburg, Sweden.
    Leonard, Dag
    Uppsala Univ, Sweden.
    Yrlid, Linda
    AstraZeneca RandD Gothenburg, Sweden.
    Jackson, Sonya
    AstraZeneca RandD Gothenburg, Sweden.
    Mattsson, Johan
    AstraZeneca RandD Gothenburg, Sweden.
    Nanda, Sambit
    Univ Dundee, Scotland.
    Cohen, Philip
    Univ Dundee, Scotland.
    Knebel, Axel
    Univ Dundee, Scotland.
    Arthur, Simon
    Univ Dundee, Scotland.
    Thorn, Kristofer
    AstraZeneca RandD Gothenburg, Sweden.
    Svenungsson, Elisabet
    Karolinska Inst, Sweden.
    Jonsen, Andreas
    Lund Univ, Sweden.
    Gunnarsson, Iva
    Karolinska Inst, Sweden.
    Tandre, Karolina
    Uppsala Univ, Sweden.
    Alexsson, Andrei
    Uppsala Univ, Sweden.
    Kastbom, Alf
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Rheumatology.
    Rantapaa-Dahlqvist, Solbritt
    Umea Univ, Sweden.
    Eloranta, Maija-Leena
    Uppsala Univ, Sweden.
    Syvanen, Ann-Christine
    Uppsala Univ, Sweden.
    Bengtsson, Anders
    Lund Univ, Sweden.
    Johansson, Patrik
    AstraZeneca RandD Gothenburg, Sweden.
    Sandling, Johanna K.
    Uppsala Univ, Sweden.
    Sjöwall, Christopher
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Rheumatology.
    Ronnblom, Lars
    Uppsala Univ, Sweden.
    Collins, Barry
    AstraZeneca RandD Gothenburg, Sweden.
    Vaarala, Outi
    AstraZeneca RandD Gothenburg, Sweden; MedImmune LLC, MD 20878 USA.
    Genetic variations in A20 DUB domain provide a genetic link to citrullination and neutrophil extracellular traps in systemic lupus erythematosus2019In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 78, no 10, p. 1363-1370Article in journal (Refereed)
    Abstract [en]

    Objectives Genetic variations in TNFAIP3 (A20) deubiquitinase (DUB) domain increase the risk of systemic lupus erythematosus (SLE) and rheumatoid arthritis. A20 is a negative regulator of NF-kappa B but the role of its DUB domain and related genetic variants remain unclear. We aimed to study the functional effects of A20 DUB-domain alterations in immune cells and understand its link to SLE pathogenesis. Methods CRISPR/Cas9 was used to generate human U937 monocytes with A20 DUB-inactivating C103A knock-in (KI) mutation. Whole genome RNA-sequencing was used to identify differentially expressed genes between WT and C103A KI cells. Functional studies were performed in A20 C103A U937 cells and in immune cells from A20 C103A mice and genotyped healthy individuals with A20 DUB polymorphism rs2230926. Neutrophil extracellular trap (NET) formation was addressed ex vivo in neutrophils from A20 C103A mice and SLE-patients with rs2230926. Results Genetic disruption of A20 DUB domain in human and murine myeloid cells did not give rise to enhanced NF-kappa B signalling. Instead, cells with C103A mutation or rs2230926 polymorphism presented an upregulated expression of PADI4, an enzyme regulating protein citrullination and NET formation, two key mechanisms in autoimmune pathology. A20 C103A cells exhibited enhanced protein citrullination and extracellular trap formation, which could be suppressed by selective PAD4 inhibition. Moreover, SLE-patients with rs2230926 showed increased NETs and increased frequency of autoantibodies to citrullinated epitopes. Conclusions We propose that genetic alterations disrupting the A20 DUB domain mediate increased susceptibility to SLE through the upregulation of PADI4 with resultant protein citrullination and extracellular trap formation.

  • 25.
    Roos, Karin
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Martinsson, Klara
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Ziegelasch, Michael
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Rheumatology.
    Sommarin, Yngve
    Euro Diagnost AB, Sweden.
    Svärd, Anna
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Falun Central Hospital, Sweden.
    Skogh, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Rheumatology.
    Kastbom, Alf
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Region Östergötland, Heart and Medicine Center, Department of Rheumatology. Linköping University, Faculty of Medicine and Health Sciences.
    Circulating secretory IgA antibodies against cyclic citrullinated peptides in early rheumatoid arthritis associate with inflammatory activity and smoking2016In: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 18, no 119Article in journal (Refereed)
    Abstract [en]

    Background: A possible association between mucosal immunization and inflammation, as well as the initiation and propagation of rheumatoid arthritis (RA), is attracting renewed interest. The aim of this study was to evaluate the possible occurrence and clinical correlations of circulating secretory immunoglobulin A (SIgA) antibodies against the second-generation cyclic citrullinated peptides (CCP) among patients with recent-onset RA followed prospectively over 3 years. Methods: Baseline serum samples from 636 patients with recent-onset RA were analyzed for SIgA anti-CCP antibodies by using an enzyme-linked immunosorbent assay with a secondary antibody directed against secretory component. SIgA anti-CCP status at baseline was analyzed in relation to smoking, HLA-DRB1/shared epitope (SE), and the disease course over 3 years. Significant findings were evaluated in regression analysis that included age, sex, smoking, and SE. Results: Seventeen percent of the patients tested positive for circulating SIgA anti-CCP, and the occurrence was confirmed by detection of secretory component in an affinity-purified IgA anti-CCP fraction. SIgA anti-CCP positivity at baseline was associated with slightly higher baseline erythrocyte sedimentation rate (ESR) (mean 38 vs. 31 mm/first hour, p = 0.004) and C-reactive protein (CRP) (mean 30 vs. 23 mg/L, p = 0.047). During follow-up, SIgA anti-CCP-positive patients had a higher mean AUC regarding ESR (adjusted p = 0.003), although there were no significant differences regarding CRP, tender and swollen joint counts, or radiological joint damage (median Larsen progression 1.0 vs. 1.0, p = 0.22). SIgA anti-CCP was associated significantly with smoking (79 % ever smokers among SIgA anti-CCP-positive patients vs. 59 % in SIgA anti-CCP-negative patients, adjusted OR 2.19, 95 % CI 1.01-4.37, p = 0.027) but not with carriage of the SE (80 % vs. 73 %, p = 0.62). Conclusions: Circulating SIgA anti-CCP, which is present in a subgroup of patients with early RA, is not related to SE, but it is environmentally linked to cigarette smoking. This finding strengthens the hypothesis that immunization against citrullinated peptides and/or proteins may occur at mucosal surfaces of the airways. Analysis of SIgA antibodies in serum may be a convenient and more versatile means to investigate the "mucosal connection" in RA compared with analyses in mucosal fluid samples.

  • 26.
    Sandin, Charlotta
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Rheumatology. Linköping University, Faculty of Medicine and Health Sciences.
    Eriksson, Per
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Rheumatology. Linköping University, Faculty of Medicine and Health Sciences.
    Segelmark, Mårten
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Region Östergötland, Heart and Medicine Center, Department of Nephrology. Linköping University, Faculty of Medicine and Health Sciences.
    Skogh, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Rheumatology. Linköping University, Faculty of Medicine and Health Sciences.
    Kastbom, Alf
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Rheumatology. Linköping University, Faculty of Medicine and Health Sciences.
    IgA- and SIgA anti-PR3 antibodies in serum versus organ involvement and disease activity in PR3-ANCA associated vasculitis.2016In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 184, no 2, p. 208-215Article in journal (Refereed)
    Abstract [en]

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

  • 27.
    Sjöwall, Christoffer
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Rheumatology.
    Kastbom, Alf
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Rheumatology.
    Almroth, Gunnel
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences.
    Wetterö, Jonas
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences.
    Skogh, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Rheumatology.
    Beware of Antibodies to Dietary Proteins in "Antigen-specific" Immunoassays! Falsely Positive Anticytokine Antibody Tests Due to Reactivity with Bovine Serum Albumin in Rheumatoid Arthritis (The Swedish TIRA Project)2011In: JOURNAL OF RHEUMATOLOGY, ISSN 0315-162X, Vol. 38, no 2, p. 215-220Article in journal (Refereed)
    Abstract [en]

    Objective. To evaluate (1) to what extent sera from healthy subjects and patients with rheumatoid arthritis (RA) contain antibodies to bovine serum albumin (BSA); and (2) if anti-BSA antibodies interfere with results of enzyme-linked immunoassays (ELISA) containing BSA. Methods. The ELISA used was a previously developed in-house assay of autoantibodies to tumor necrosis factor (TNF). Anti-TNF and anti-BSA antibodies were analyzed by ELISA in 189 patients with early RA and 186 healthy blood donors. TNF preparations containing either BSA or human serum albumin (HSA) as carrier proteins were used as antigens in the anti-TNF assay. The presence and levels of antibodies were analyzed in relation to disease course and to the presence/absence of rheumatoid factor (RF). Results. In patients with RA, anti-TNF/BSA levels strongly correlated with anti-BSA levels (r = 0.81, p andlt; 0.001), whereas anti-TNF/HSA did not (r = -0.09). Neither the presence nor the levels of anti-BSA in RA patients were associated with disease progression, and antibody levels were not significantly altered compared to controls (p = 0.11). IgG reactivity with TNF/HSA was neglible. In paired sera, preincubation with BSA abolished the anti-TNF/BSA reactivity. There were no indications of RF interference with anti-BSA or anti-TNF reactivity. Conclusion. Antibodies to BSA are common in patients with RA as well as in healthy individuals. Their presence does not seem to be associated with RA disease activity or disease course, but may severely interfere with ELISA containing BSA. The use of BSA as a "blocking agent" or carrier protein in immunoassays should therefore be avoided.

  • 28.
    Skogh, Thomas
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Rheumatology . Östergötlands Läns Landsting, Centre for Medicine, Department of Rheumatology in Östergötland.
    Kastbom, Alf
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Rheumatology . Östergötlands Läns Landsting, Centre for Medicine, Department of Rheumatology in Östergötland.
    Sjöwall, Christoffer
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Rheumatology . Östergötlands Läns Landsting, Centre for Medicine, Department of Rheumatology in Östergötland.
    The B cells are back!2005In: Drug Discovery Today: Disease Mechanisms, ISSN 1740-6765, Vol. 2, no 3, p. 351-357Article, review/survey (Refereed)
    Abstract [en]

    New interest has emerged regarding the central roles of B cells in physiological immunoregulation and immunopathogenesis of rheumatoid arthritis (RA), a condition traditionally viewed as T-cell mediated. Thus, B cells, autoantibodies, immune complexes, complement and their cellular receptors are experiencing renewed interest concerning their roles in the initiation and propagation of arthritis. The discovery of citrullinated proteins as targets of autoimmune response in RA has implications regarding aetiopathogenesis, prediction of future disease, diagnosis of recent onset and established arthritis and prediction of disease course and disease outcome. Antibody-based therapies against cytokines, cytokine receptors and B cells contribute to the important advances in antirheumatic therapy. © 2005 Elsevier Ltd. All rights reserved.

  • 29.
    Stuemer, J.
    et al.
    Friedrich Alexander University of Erlangen Nurnberg FAU, Germany.
    Biermann, M. H. C.
    Friedrich Alexander University of Erlangen Nurnberg FAU, Germany.
    Knopf, J.
    Friedrich Alexander University of Erlangen Nurnberg FAU, Germany.
    Magorivska, I.
    Friedrich Alexander University of Erlangen Nurnberg FAU, Germany; Danylo Halytsky Lviv National Medical University, Ukraine.
    Kastbom, Alf
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Rheumatology.
    Svärd, A.
    Falun Central Hospital, Sweden.
    Janko, C.
    Friedrich Alexander University of Erlangen Nurnberg FAU, Germany; University Hospital Erlangen, Germany.
    Bilyy, R.
    Friedrich Alexander University of Erlangen Nurnberg FAU, Germany; Danylo Halytsky Lviv National Medical University, Ukraine.
    Schett, G.
    Friedrich Alexander University of Erlangen Nurnberg FAU, Germany.
    Sjöwall, Christopher
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Rheumatology.
    Herrmann, M.
    Friedrich Alexander University of Erlangen Nurnberg FAU, Germany.
    Munoz, L. E.
    Friedrich Alexander University of Erlangen Nurnberg FAU, Germany.
    Altered glycan accessibility on native immunoglobulin G complexes in early rheumatoid arthritis and its changes during therapy2017In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 189, no 3, p. 372-382Article in journal (Refereed)
    Abstract [en]

    The goal of this study was to investigate the glycosylation profile of native immunoglobulin (Ig)G present in serum immune complexes in patients with rheumatoid arthritis (RA). To accomplish this, lectin binding assays, detecting the accessibility of glycans present on IgG-containing immune complexes by biotinylated lectins, were employed. Lectins capturing fucosyl residues (AAL), fucosylated tri-mannose N-glycan core sites (LCA), terminal sialic acid residues (SNA) and O-glycosidically linked galactose/N-acetylgalactosamine (GalNac-L) were used. Patients with recent-onset RA at baseline and after 3-year follow-up were investigated. We found that native IgG was complexed significantly more often with IgM, C1q, C3c and C-reactive protein (CRP) in RA patients, suggesting alterations of the native structure of IgG. The total accessibility of fucose residues on captured immune complexes to the respective lectin was significantly higher in patients with RA. Moreover, fucose accessibility on IgG-containing immune complexes correlated positively with the levels of antibodies to cyclic citrullinated peptides (anti-CCP). We also observed a significantly higher accessibility to sialic acid residues and galactose/GalNAc glyco-epitopes in native complexed IgG of patients with RA at baseline. While sialic acid accessibility increased during treatment, the accessibility of galactose/GalNAc decreased. Hence, successful treatment of RA was associated with an increase in the SNA/GalNAc-L ratio. Interestingly, the SNA/GalNAc-L ratio in particular rises after glucocorticoid treatment. In summary, this study shows the exposure of glycans in native complexed IgG of patients with early RA, revealing particular glycosylation patterns and its changes following pharmaceutical treatment.

  • 30.
    Svärd, Anna
    et al.
    Linköping University, Department of Molecular and Clinical Medicine, Rheumatology. Linköping University, Faculty of Health Sciences.
    Kastbom, Alf
    Linköping University, Department of Molecular and Clinical Medicine, Rheumatology. Linköping University, Faculty of Health Sciences.
    Reckner Olsson, Åsa
    Linköping University, Department of Molecular and Clinical Medicine, Rheumatology. Linköping University, Faculty of Health Sciences.
    Skogh, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences.
    Presence and utility of IgA-class antibodies to cyclic citrullinated peptides in early rheumatoid arthritis: the Swedish TIRA project2008In: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 10, no 4Article in journal (Refereed)
    Abstract [en]

    Introduction

    The present study was carried out to assess whether IgA-class antibodies against cyclic citrullinated peptides (IgA anti-CCP) in recent-onset rheumatoid arthritis add diagnostic and/or prognostic information to IgG anti-CCP analysis.

    Methods

    Serum samples were obtained from 228 patients with recent-onset (<12 months) rheumatoid arthritis at the time of inclusion in the Swedish TIRA cohort (Swedish Early Intervention in Rheumatoid Arthritis). Sera from 72 of these patients were also available at the 3-year follow-up. Disease activity and functional ability measures (erythrocyte sedimentation rate, serum C-reactive protein, 28-joint count Disease Activity Score, physician's assessment of disease activity, and the Swedish version of the Health Assessment Questionnaire) were registered at inclusion and at regular follow-ups during 3 years. An IgA anti-CCP assay was developed based on the commercially available IgG-specific enzyme immunoassay from EuroDiagnostica (Arnhem, the Netherlands), replacing the detection antibody by an anti-human-IgA antibody. A positive IgA anti-CCP test was defined by the 99th percentile among healthy blood donors.

    Results

    At baseline, a positive IgA anti-CCP test was observed in 29% of the patient sera, all of which also tested positive for IgG anti-CCP at a higher average level than sera containing IgG anti-CCP alone. The IgA anti-CCP-positive patients had significantly higher disease activity over time compared with the IgA anti-CCP-negative patients. After considering the IgG anti-CCP level, the disease activity also tended to be higher in the IgA anti-CCP-positive cases – although this difference did not reach statistical significance. The proportion of IgA anti-CCP-positive patients was significantly larger among smokers than among nonsmokers.

    Conclusion

    Anti-CCP antibodies of the IgA class were found in about one-third of patients with recent-onset rheumatoid arthritis, all of whom also had IgG anti-CCP. The occurrence of IgA-class antibodies was associated with smoking, and IgA anti-CCP-positive patients had a more severe disease course over 3 years compared with IgA anti-CCP-negative cases. Although IgA anti-CCP analysis does not seem to offer any diagnostic information in addition to IgG anti-CCP analysis, further efforts are justified to investigate the prognostic implications.

  • 31.
    Svärd, Anna
    et al.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Kastbom, Alf
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Rheumatology in Östergötland.
    Sommarin, Yngve
    EuroDiagnostica AB, Malmö.
    Skogh, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Rheumatology in Östergötland.
    A disease-modifying role for mucosal IgA antibodies to citrullinated antigens?2012In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 71, no Issue suppl. 1, p. A38-A39Article in journal (Refereed)
    Abstract [en]

    Objective

    The aim of this study was to investigate whether immunoglobulin A (IgA) antibodies to cyclic citrullinated peptides CCP) can be detected in saliva of patients with established heumatoid arthritis (RA) and if it relates to clinical manifestations.

    Methods

    Salivary samples were collected (by ‘passive drooling’) from 63 consecutive patients with established RA at a visit to the rheumatology outpatient clinic (Falun, Sweden), and from 20 healthy persons (hospital staff). The samples were centrifuged and kept frozen at −70°C until analysis. IgA-class anti-CCP antibodies in saliva were analysed by adaptation of commercial ELISA (Immunoscan RA, Euro-Diagnostica AB, Malmo, Sweden) using polyclonal rabbit antihuman α-chain specific antibodies conjugated with horseradish peroxidase(DakoCytomation, Glostrup, Denmark) as secondary antibody. To ensure specificity of the reaction, a corresponding ELISA was set up to analyse IgA antibodies to control antigen(cyclic arginine peptide, CAP), and anti-CCP/anti-CAP ratios were calculated. Also, inhibition studies were performed by preincubation of sera with soluble CCP or CAP. Clinical and laboratory data on disease activity, that is, C reactive protein (CRP), erythrocyte sedimentation rate (ESR), and 28-joint count disease activity score (DAS28) as well as radiological outcome (occurrence or absence of erosions as judged by a radiologist in diagnostic routine) were achieved retrospectively via the patients’ medical records.

    Results

    Background reactivity against CCP was found in virtually all patients and healthy subjects, whereas a positive anti-CCP/anti-CAP ratio (≥1.5) was found in 14 out of 63 RA patients (22%) and in one healthy subject (5%). Salivary IgA-reactivity with CCP was dose-dependently inhibited by soluble CCP (but not with CAP) in sera with anti-CCP/anti- CAP ratios ≥1.5. No IgG-reactivity to CCP was found in saliva, although all patients with salivary IgA anti-CCP tested IgG anti-CCP-positive in serum. Furthermore, less than half of those testing IgA-positive in saliva were IgA anti-CCP positive in serum, strongly arguing against passive leakage of anti-CCP antibodies from blood to saliva. The patients testing positive for salivary IgA antibodies had lower average disease activity measures (CRP, ESR, DAS28) at presentation and fewer developed bony erosions within 6 years after presentation (p=0.043, Fisher’s exact test).

    Conclusion

    Salivary IgA antibodies to citrullinated proteins were found in a subset of IgG anti-CCP positive RA patients. In contrast to their serum counterparts, salivary IgA antibodies may associate with a milder/less destructive disease course. This accords with the notion that secretory IgA antibodies exert anti-inflammatory actions, and that they may be associated with induction of systemic tolerance (oral tolerance). The possible disease-modifying role of mucosal immunity to citrullinated proteins needs further investigation!

                    

                                                                    

  • 32.
    Svärd, Anna
    et al.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Kastbom, Alf
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Rheumatology in Östergötland.
    Sommarin, Yngve
    Eurodiagnostica AB.
    Skogh, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Rheumatology in Östergötland.
    A Disease-Modifying Role for Mucosal IgA Antibodies to Citrullinated Antigens? in ARTHRITIS AND RHEUMATISM, vol 63, issue 10, pp S849-S8492011In: ARTHRITIS AND RHEUMATISM, Wiley-Blackwell , 2011, Vol. 63, no 10, p. S849-S849Conference paper (Refereed)
    Abstract [en]

    n/a

  • 33.
    Svärd, Anna
    et al.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Kastbom, Alf
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Rheumatology in Östergötland.
    Sommarin, Yngve
    Euro-Diagnostica AB, Malmö, Sweden.
    Skogh, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Rheumatology in Östergötland.
    Salivary IgA antibodies to cyclic citrullinated peptides (CCP) in rheumatoid arthritis2013In: Immunobiology, ISSN 0171-2985, E-ISSN 1878-3279, Vol. 218, no 2, p. 232-237Article in journal (Refereed)
    Abstract [en]

    Circulating IgG anti-cyclic citrullinated peptide antibodies (CCP) are highly specific for rheumatoid arthritis (RA) and prognostic of poor outcome. Serum IgA anti-CCP occurs in a subset of IgG-positive cases and relates to still more aggressive disease. Mucosal IgA-class antibodies, however, are generally associated with anti-inflammatory actions and systemic tolerance induction. In the present study, unstimulated salivary samples from 63 patients with established RA and 20 healthy persons were analysed by enzyme-linked immunoassay for the presence of IgA anti-CCP antibodies. To ensure antigen specificity, IgA-reactivity with the corresponding uncitrullinated antigen, cyclic arginine peptide (CAP), was analysed and anti-CCP/anti-CAP ratios calculated. Retrospective data regarding disease activity and radiological outcome were achieved via medical records. Salivary IgA anti-CCP was found in 14/63 (22%) patients and one (5%) control (positive test = anti-CCP/anti-CAP ratio andgt; 1.5). Salivary IgA reactivity was dose-dependently inhibited by pre-incubation with soluble CCP to a degree strongly correlating with anti-CCP/anti-CAP ratio. In salivary IgA anti-CCP positive patients, joint erosions within 6 years of diagnosis was significantly lower (p = 0.043), and at the time for diagnosis there was a trend towards lower erythrocyte sedimentation rate (p = 0.071) and C-reactive protein (p = 0.085). Contrasting to circulating IgG and IgA anti-CCP, our results imply that salivary IgA antibodies may be associated with a less severe outcome of RA. Hypothetically, this relates to an anti-inflammatory and protective immunomodulating role of secretory IgA-class autoantibodies against citrullinated antigens presented at mucosal surfaces.

  • 34.
    Svärd, Anna
    et al.
    Rheumatology Clinic, Falun Hospital, Falun.
    Kastbom, Alf
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences.
    Söderlin, Maria K.
    Spenshult Rheumatology Centre, Oskarström, Sweden.
    Reckner-Olsson, Åsa
    Linköping University, Department of Clinical and Experimental Medicine, Occupational and Environmental Medicine. Linköping University, Faculty of Health Sciences.
    Skogh, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Rheumatology.
    A Comparison Between IgG- and IgA-class Antibodies to Cyclic Citrullinated Peptides and to Modified Citrullinated Vimentin in Early Rheumatoid Arthritis and Very Early Arthritis2011In: Journal of Rheumatology, ISSN 0315-162X, E-ISSN 1499-2752, Vol. 38, no 7, p. 1265-1272Article in journal (Refereed)
    Abstract [en]

    Objective. Because of their slightly higher sensitivity, it has been argued that antibodies to modified citrullinated vimentin (anti-MCV) are superior to antibodies to cyclic citrullinated peptides (anti-CCP), while others claim that anti-CCP is preferable because of higher diagnostic specificity for rheumatoid arthritis (RA). We evaluated IgG- and IgA-class anti-MCV and anti-CCP as diagnostic and prognostic markers in early arthritis. less thanbrgreater than less thanbrgreater thanMethods. Two Swedish arthritis populations were examined: 215 patients with early RA (andlt;= 12 months duration) from the Swedish TIRA-1 cohort, and 69 patients with very early arthritis (andlt;= 3 months duration) from the Kronoberg Arthritis Incidence cohort, in which 22% were diagnosed with RA. IgG anti-CCP and anti-MCV antibodies were analyzed with commercial kits. These tests were modified for IgA-class antibody detection. less thanbrgreater than less thanbrgreater thanResults were related to disease course, smoking habits, and shared epitope status. Results. In the TIRA-1 cohort, occurrence of IgG anti-MCV and IgG anti-CCP showed a 93% overlap, although IgG anti-MCV had higher diagnostic sensitivity. Twenty-four percent tested positive for IgA anti-MCV compared to 29% for IgA anti-CCP. In the Kronoberg Arthritis Incidence cohort, 15% tested positive for IgG anti-MCV and 6% for IgA anti-MCV, compared to 10% positive for IgG anti-CCP and 3% positive for IgA anti-CCP, revealing that anti-CCP had higher diagnostic specificity for RA. As previously reported for IgA anti-CCP, IgA anti-MCV antibodies occurred in a small proportion of high-level IgG antibody-positive sera and were associated with a more aggressive disease course. Smokers were more often positive for antibodies to citrullinated proteins, most strikingly among the patients who were IgA anti-MCV-positive. less thanbrgreater than less thanbrgreater thanConclusion. The occurrences of IgG-class anti-MCV and anti-CCP in early RA largely overlap. The sensitivity of anti-MCV is slightly higher, while the diagnostic specificity is higher for anti-CCP. In both instances a positive test predicts an unfavorable disease course, possibly slightly more so for anti-MCV. Although associated with a more active disease over time, IgA-class anti-CCP or anti-MCV do not add any diagnostic advantage.

  • 35.
    Svärd, Anna
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Skogh, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Rheumatology.
    Alfredsson, Lars
    Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
    Ilar, Anna
    Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
    Klareskog, Lars
    Rheumatology Unit, Department of Medicine, Karolinska Institutet/Karolinska University Hospital, Solna, Stockholm, Sweden.
    Bengtsson, Camilla
    Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
    Kastbom, Alf
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Rheumatology.
    Associations to smoking and shared epitope differ between IgA and IgG class antibodies to cyclic citrullinated peptides in early rheumatoid arthritis2015In: Arthritis & Rheumatology, ISSN 2326-5191, E-ISSN 2326-5205, Vol. 67, no 8, p. 2032-2037Article in journal (Refereed)
    Abstract [en]

    Background Smoking and HLA-DRB1/shared epitope (SE) are well-known interacting risk factors for developing rheumatoid arthritis (RA) with IgG anticitrullinated protein/peptide antibodies (ACPA). It remains unknown to what extent SE-genes and smoking associate with mucosal immune responses.

    Objectives This study was done to explore relations between cigarette smoking habits and SE versus circulating IgA and IgG anti-cyclic citrullinated peptide antibodies (anti-CCP) among early RA patients.

    Methods Patients from two early-RA cohorts were analysed, EIRA-1 (n=1663) and TIRA-2 (n=199). The patients were grouped into four subsets based on anti-CCP: IgG-/IgA-, IgG-/IgA+, IgG+/IgA- and IgG+/IgA+. Interaction between smoking and SE was calculated by the attributable proportion due to deviation from additivity. Analyzed controls (n=1100) were randomly selected from the EIRA-1 study base.

    Results Anti-CCP occurrence was similar in the two cohorts. Only in EIRA was IgA anti-CCP detected alone in a minority of cases (3%). Smoking was significantly overrepresented among IgA anti-CCP+ patients with or without IgG-class anti-CCP, but not with IgG anti-CCP alone. Presence of SE genes was overrepresented among IgG anti-CCP+ patients with or without IgA-class anti-CCP, but not with IgA anti-CCP alone. Smoking and SE interacted regarding the risk of IgG+/IgA+ RA (AP=0.5, 95 % CI=0.4-0.6), whereas no significant interaction was observed regarding IgG-/IgA+ or IgG+/IgA- RA.

    Conclusions Association between cigarette smoking and anti-CCP is limited to cases with IgA-class antibodies in addition to IgG anti-CCP. This suggests a causal relation between chronic mucosal irritation/inflammation, induction of a systemic IgA anti-CCP response and subsequent development of RA.

  • 36.
    Söderlin, Maria
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Rheumatology .
    Kastbom, Alf
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Rheumatology . Östergötlands Läns Landsting, Centre for Medicine, Department of Rheumatology in Östergötland.
    Kautiainen, H
    Leirisalo-Repo, M
    Strandberg, Gunnar
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Rheumatology . Östergötlands Läns Landsting, Centre for Medicine, Department of Rheumatology in Östergötland.
    Skogh, Thomas
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Rheumatology . Östergötlands Läns Landsting, Centre for Medicine, Department of Rheumatology in Östergötland.
    Antibodies against cyclic citrullinated peptide (CCP) and cartilage oligomeric matrix protein (COMP) in relation to disease activity and erosions in a prospective population-based study of very early arthritis.2003In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 48, no 9, p. 194-Conference paper (Other academic)
  • 37.
    Söderlin, Maria
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology . Linköping University, Faculty of Health Sciences.
    Kastbom, Alf
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Rheumatology in Östergötland.
    Kautiainen, Hannu
    Rheumatism Foundation Hospital, Heinola, Finland.
    Leirisalo-Repo, Marjatta
    Department of Medicine, Division of Rheumatology, Helsinki University Central Hospital, Huch, Finland.
    Strandberg, Gunnar
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Rheumatology in Östergötland.
    Skogh, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Rheumatology in Östergötland.
    Antibodies against cyclic citrullinated peptide (CCP) and levels of cartilage oligomeric matrix protein (COMP) in very early arthritis: relation to diagnosis and disease activity2004In: Scandinavian Journal of Rheumatology, ISSN 0300-9742, Vol. 33, no 3, p. 185-188Article in journal (Refereed)
    Abstract [en]

    Objective: To measure serum levels of antibodies against cyclic citrullinated peptide (anti-CCP antibodies) and serum cartilage oligomeric matrix protein (COMP) in patients with early joint inflammation, and to study the correlation of these two tests with clinical measurements.

    Methods: Adult patients with recent-onset arthritis, of <3 months' duration, were referred from primary healthcare centres to rheumatologists. Serum levels of anti-CCP antibodies and COMP at baseline were analysed by enzyme immunoassay (EIA) and compared with clinical baseline data.

    Results: Sixty-nine patients were included. The specificity of the anti-CCP antibody test for RA was 96%, and the sensitivity was 44%. There was a significant difference between the four diagnosis groups in the anti-CCP antibody test, probability (p)<0.001, whereas no significant differences were found concerning COMP. The baseline serum COMP test correlated with age (p=0.0001), joint score for swollen joints (p=0.02), and C-reactive protein (CRP) (p=0.02).

    Conclusion: This study confirms the high diagnostic specificity of anti-CCP antibodies for rheumatoid arthritis (RA) in a prospective population-based study of very early arthritis. Raised serum COMP levels were common in all diagnosis groups in this series, indicating cartilage involvement in both self-limiting and non-erosive disease.

  • 38.
    Ziegelasch, Michael
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Forslind, Kristina
    Helsingborg Hospital, Sweden; Lund University, Sweden.
    Skogh, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Rheumatology.
    Riklund, Katrine
    Umeå University Hospital, Sweden.
    Kastbom, Alf
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Rheumatology.
    Berglin, Ewa
    Umeå University Hospital, Sweden.
    Decrease in bone mineral density during three months after diagnosis of early rheumatoid arthritis measured by digital X-ray radiogrammetry predicts radiographic joint damage after one year2017In: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 19, article id 195Article in journal (Refereed)
    Abstract [en]

    Background: Periarticular osteopenia is an early sign of incipient joint injury in rheumatoid arthritis (RA), but cannot be accurately quantified using conventional radiography. Digital X-ray radiogrammetry (DXR) is a computerized technique to estimate bone mineral density (BMD) from hand radiographs. The aim of this study was to evaluate whether decrease in BMD of the hands (BMD loss), as determined by DXR 3 months after diagnosis, predicts radiographic joint damage after 1 and 2 years in patients with early RA. Methods: Patients (n = 176) with early RA (amp;lt; 12 months after onset of symptoms) from three different Swedish rheumatology centers were consecutively included in the study, and 167 of these patients were included in the analysis. Medication was given in accordance with Swedish guidelines, and the patients were followed for 2 years. Rheumatoid factor and antibodies to cyclic citrullinated peptides (anti-CCP) were measured at baseline, and 28-joint Disease Activity Score (DAS28) was assessed at each visit. Radiographs of the hands and feet were obtained at baseline, 3 months (hands only) and 1 and 2 years. Baseline and 1-year and 2-year radiographs were evaluated by the Larsen score. Radiographic progression was defined as a difference in Larsen score above the smallest detectable change. DXR-BMD was measured at baseline and after 3 months. BMD loss was defined as moderate when the decrease in BMD was between 0.25 and 2.5 mg/cm(2)/month and as severe when the decrease was greater than 2.5 mg/cm(2)/month. Multivariate regression was applied to test the association between DXR-BMD loss and radiographic damage, including adjustments for possible confounders. Results: DXR-BMD loss during the initial 3 months occurred in 59% of the patients (44% moderate, 15% severe): 32 patients (19%) had radiographic progression at 1 year and 45 (35%) at 2 years. In multiple regression analyses, the magnitude of DXR-BMD loss was significantly associated with increase in Larsen score between baseline and 1 year (p = 0.033, adjusted R-squared = 0.069). Conclusion: DXR-BMD loss during the initial 3 months independently predicted radiographic joint damage at 1 year in patients with early RA. Thus, DXR-BMD may be a useful tool to detect ongoing joint damage and thereby to improve individualization of therapy in early RA.

  • 39.
    Ziegelasch, Michael
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Region Östergötland, Heart and Medicine Center, Department of Rheumatology. Linköping University, Faculty of Medicine and Health Sciences.
    van Delft, Myrthe A M
    Leiden University Medical Center, Leiden, The Netherlands.
    Wallin, Philip
    Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science.
    Skogh, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Region Östergötland, Heart and Medicine Center, Department of Rheumatology. Linköping University, Faculty of Medicine and Health Sciences.
    Magro-Checa, César
    Leiden University Medical Center, Leiden, The Netherlands.
    Steup-Beekman, Gerda M
    Leiden University Medical Center, Leiden, The Netherlands.
    Trouw, Leendert A
    Leiden University Medical Center, Leiden, The Netherlands.
    Kastbom, Alf
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Region Östergötland, Heart and Medicine Center, Department of Rheumatology. Linköping University, Faculty of Medicine and Health Sciences.
    Sjöwall, Christopher
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Region Östergötland, Heart and Medicine Center, Department of Rheumatology. Linköping University, Faculty of Medicine and Health Sciences.
    Antibodies against carbamylated proteins and cyclic citrullinated peptides in systemic lupus erythematosus: results from two well-defined European cohorts.2016In: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 18, no 1Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Articular manifestations are common in systemic lupus erythematosus (SLE) whereas erosive disease is not. Antibodies to cyclic citrullinated peptide (anti-CCP) are citrulline-dependent in rheumatoid arthritis (RA), whereas the opposite is suggested in SLE, as reactivity with cyclic arginine peptide (CAP) is typically present. Antibodies targeting carbamylated proteins (anti-CarP) may occur in anti-CCP/rheumatoid factor (RF)-negative cases long before clinical onset of RA. We analysed these antibody specificities in sera from European patients with SLE in relation to phenotypes, smoking habits and imaging data.

    METHODS: Cases of SLE (n = 441) from Linköping, Sweden, and Leiden, the Netherlands, were classified according to American College of Rheumatology (ACR) and/or Systemic Lupus Erythematosus International Collaborating Clinics (SLICC) criteria. IgG anti-CCP, anti-CAP and anti-CarP were analysed by immunoassays. Radiographic data from 102 Swedish patients were available.

    RESULTS: There were 16 Linköping (6.8%) and 11 Leiden patients (5.4%) who were anti-CCP-positive, of whom approximately one third were citrulline-dependent: 40/441 (9.1%) were anti-CarP-positive, and 33% of the anti-CarP-positive patients were identified as anti-CCP-positive. No associations were found comparing anti-CCP or anti-CarP with ACR-defined phenotypes, immunologic abnormalities or smoking habits. Radiographically confirmed erosions were found in 10 patients, and were significantly associated with anti-CCP, anti-CarP and RF. Musculoskeletal ultrasonography scores were higher in anti-CCP-positive compared to anti-CCP-negative patients.

    CONCLUSIONS: In the hitherto largest anti-CarP study in SLE, we demonstrate that anti-CarP is more prevalent than anti-CCP and that the overlap is limited. We obtained some evidence that both autoantibodies seem to be associated with erosivity. Similar pathogenetic mechanisms to those seen in RA may be relevant in a subgroup of SLE cases with a phenotype dominated by arthritis.

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