title: The interleukin-20 receptor axis in early rheumatoid arthritis: novel links between disease-associated autoantibodies and radiographic progression.
abstract: BACKGROUND
  Rheumatoid arthritis (RA) is often characterized by the presence of rheumatoid factor, anti-citrullinated protein antibodies, and bone erosions. Current therapies can compromise immunity, leading to risk of infection. The interleukin-20 receptor (IL-20R) axis comprising IL-19, IL-20, and IL-24 and their shared receptors activates tissue homeostasis processes but not the immune system. Consequently, modulation of the IL-20R axis may not lead to immunosuppression, making it an interesting drug target. We evaluated the role of the IL-20R axis in RA and associations between plasma cytokine levels and clinical disease.
  
  
  METHODS
  Plasma IL-19, IL-20, and IL-24 levels were measured in early RA patients during a treat-to-target strategy by enzyme-linked immunosorbent assays. The IL-20R1 and IL-22R1 levels in paired peripheral blood mononuclear cells and synovial fluid mononuclear cells from a different cohort of RA patients were evaluated by flow cytometry and confocal microscopy. Monocytes/macrophages were stimulated with heat-aggregated human immunoglobulin immune complexes and immune complexes containing citrullinated fibrinogen, and osteoclasts were incubated with IL-19, IL-20, and IL-24.
  
  
  RESULTS
  The plasma concentrations of IL-20 and IL-24 (but not IL-19) were increased in early RA patients compared with healthy controls (both P < 0.002) and decreased after 6 months of treatment (both P < 0.0001). The expression of IL-22R1 (but not IL-20R1) was increased on monocytes from RA synovial fluid compared with monocytes from both RA and healthy control peripheral blood. The plasma concentrations of IL-20 and IL-24 were increased in rheumatoid factor and anti-citrullinated protein antibody positive compared with negative early RA patients (all P < 0.0001). Immune complexes stimulated the production of the IL-20R cytokines by monocytes/macrophages. Increased baseline plasma concentrations of IL-20 and IL-24 were associated with Sharp-van der Heijde score progression after 24 months (Spearman's rho = 0.19 and 0.26, both P < 0.05) in the early RA patients. The IL-22R1 was expressed by osteoclast precursors and in multinucleated osteoclasts. IL-20 and IL-24 increased the secretion of monocyte chemoattractant protein 1 by these cells.
  
  
  CONCLUSIONS
  This study suggests that IL-20 and IL-24 link RA-associated autoantibodies with radiographic progression via the IL-22R1. Modulation of this axis holds promise as feasible anti-erosive treatment modalities in seropositive RA.
authors.affiliation: Department of Biomedicine, Aarhus University, Aarhus, Denmark. kragstrup@biomed.au.dk.|Department of Immunology and Rheumatology, Stanford University, Stanford, CA, USA. kragstrup@biomed.au.dk.|Department of Rheumatology, Aarhus University Hospital, Aarhus, Denmark. kragstrup@biomed.au.dk.
authors.forename: Tue Wenzel
authors.initials: TW
authors.lastname: Kragstrup
authors.affiliation: Department of Biomedicine, Aarhus University, Aarhus, Denmark.
authors.forename: Stinne Ravn
authors.initials: SR
authors.lastname: Greisen
authors.affiliation: Department of Biomedicine, Aarhus University, Aarhus, Denmark.
authors.forename: Morten Aagaard
authors.initials: MA
authors.lastname: Nielsen
authors.affiliation: Department of Immunology and Rheumatology, Stanford University, Stanford, CA, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Rhodes
authors.affiliation: Department of Rheumatology, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Kristian
authors.initials: K
authors.lastname: Stengaard-Pedersen
authors.affiliation: Copenhagen Center for Arthritis Research, Center for Rheumatology and Spine Diseases, Rigshospitalet and Glostrup Hospital, Glostrup, Denmark.|Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Merete Lund
authors.initials: ML
authors.lastname: Hetland
authors.affiliation: University of Southern Denmark, Odense, Denmark.
authors.forename: Kim
authors.initials: K
authors.lastname: Hørslev-Petersen
authors.affiliation: Odense University Hospital, Odense, Denmark.
authors.forename: Peter
authors.initials: P
authors.lastname: Junker
authors.affiliation: Copenhagen Center for Arthritis Research, Center for Rheumatology and Spine Diseases, Rigshospitalet and Glostrup Hospital, Glostrup, Denmark.|Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Mikkel
authors.initials: M
authors.lastname: Østergaard
authors.affiliation: Department of Biomedicine, Aarhus University, Aarhus, Denmark.|Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
authors.forename: Malene
authors.initials: M
authors.lastname: Hvid
authors.affiliation: Department of Biomedicine, Aarhus University, Aarhus, Denmark.
authors.forename: Thomas
authors.initials: T
authors.lastname: Vorup-Jensen
authors.affiliation: Department of Immunology and Rheumatology, Stanford University, Stanford, CA, USA.
authors.forename: William H
authors.initials: WH
authors.lastname: Robinson
authors.affiliation: Department of Immunology and Rheumatology, Stanford University, Stanford, CA, USA.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Sokolove
authors.affiliation: Department of Biomedicine, Aarhus University, Aarhus, Denmark.|Department of Rheumatology, Aarhus University Hospital, Aarhus, Denmark.|Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
authors.forename: Bent
authors.initials: B
authors.lastname: Deleuran
mesh_terms: D000068879:Adalimumab / Q000627:therapeutic use; D000328:Adult; D018501:Antirheumatic Agents / Q000627:therapeutic use; D001172:Arthritis, Rheumatoid / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000276:immunology*; D001323:Autoantibodies / Q000276:immunology*; D015415:Biomarkers / Q000032:analysis; D018450:Disease Progression; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007378:Interleukins / Q000097:blood* / Q000276:immunology; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008297:Male; D008727:Methotrexate / Q000627:therapeutic use; D018613:Microscopy, Confocal; D008875:Middle Aged; D010010:Osteoclasts / Q000378:metabolism; D018123:Receptors, Interleukin / Q000032:analysis / Q000276:immunology / Q000378:metabolism*; D012217:Rheumatoid Factor / Q000276:immunology; D000099180:Interleukin-24
chemical_list: D000068879:Adalimumab; D018501:Antirheumatic Agents; D001323:Autoantibodies; D015415:Biomarkers; D007378:Interleukins; D008727:Methotrexate; D018123:Receptors, Interleukin; D012217:Rheumatoid Factor; D000099180:Interleukin-24; C421250:IL19 protein, human; C492510:interleukin-20 receptor; C415369:interleukin-22 receptor; C422042:interleukin 20
keywords: Autoantibody(ies); Bone resorption; Cytokines; Monocytes/macrophages; Rheumatoid arthritis