title: Nuclear Factor-κB-inducing Kinase Is Expressed in Synovial Endothelial Cells in Patients with Early Arthritis and Correlates with Markers of Inflammation: A Prospective Cohort Study.
abstract: OBJECTIVE
  The nuclear factor-κB (NF-κB) family of transcription factors is strongly involved in synovial inflammation. We have previously shown that NF-κB-inducing kinase (NIK) is a key regulator of inflammation-induced angiogenesis in rheumatoid arthritis (RA) synovial tissue (ST). Here, we investigated synovial NIK expression in patients with early arthritis and in autoantibody-positive individuals at risk of developing RA.
  
  
  METHODS
  ST biopsies were obtained by arthroscopy from 154 patients with early arthritis (duration < 1 yr) with various diagnoses and 54 IgM rheumatoid factor-positive and/or anticitrullinated protein antibodies-positive individuals without evidence of arthritis. ST was stained for NIK and endothelial cell (EC) markers. Additionally, measures of disease activity were collected and contrast-enhanced magnetic resonance imaging (MRI) was performed in a subset of these patients.
  
  
  RESULTS
  In patients with early arthritis, NIK was predominantly expressed in EC of small blood vessels. Further, NIK expression correlated with erythrocyte sedimentation rate (r 0.184, p = 0.024), C-reactive protein (r 0.194, p = 0.017), joint swelling (r 0.297, p < 0.001), synovial immune cell markers (lining r 0.585, p < 0.001; sublining macrophages r 0.728, p < 0.001; T cells r 0.733, p < 0.001; and B cells r 0.264, p = 0.040), MRI effusion (r 0.665, p < 0.001), MRI synovitis (r 0.632, p < 0.001), and MRI total score (r 0.569, p < 0.001). In 18.5% of autoantibody-positive individuals, ST NIK(+)EC were present, but this was not predictive of the development of arthritis.
  
  
  CONCLUSIONS
  NIK(+)EC are present in the earliest phase of synovial inflammation and may be indicative of high angiogenic activity in the inflamed ST. Therefore, NIK(+)EC may play an important role in the persistence of synovitis. Collectively, our data underscore the importance of angiogenesis in synovial inflammation and identify NIK as a potential therapeutic target in arthritis.
authors.affiliation: From the Division of Clinical Immunology and Rheumatology, the Department of Experimental Immunology, and the Department of Radiology, Academic Medical Center/University of Amsterdam, Amsterdam, the Netherlands; GlaxoSmithKline, Stevenage; University of Cambridge, Cambridge, UK.K.I. Maijer, MD, Division of Clinical Immunology and Rheumatology, Academic Medical Center/University of Amsterdam; A.R. Noort, MSc, Division of Clinical Immunology and Rheumatology, and Department of Experimental Immunology, Academic Medical Center/University of Amsterdam; M.J. de Hair, MD, PhD, Division of Clinical Immunology and Rheumatology, Academic Medical Center/University of Amsterdam; C. van der Leij, MD, Department of Radiology, Academic Medical Center/University of Amsterdam; K.P. van Zoest, BSc, Division of Clinical Immunology and Rheumatology, and Department of Experimental Immunology, Academic Medical Center/University of Amsterdam; I.Y. Choi, MD, Division of Clinical Immunology and Rheumatology, Academic Medical Center/University of Amsterdam; D.M. Gerlag, MD, PhD, Division of Clinical Immunology and Rheumatology, Academic Medical Center/University of Amsterdam, and GlaxoSmithKline; M. Maas, MD, PhD, Department of Radiology, Academic Medical Center/University of Amsterdam; P.P. Tak, MD, PhD, Division of Clinical Immunology and Rheumatology, Academic Medical Center/University of Amsterdam, and GlaxoSmithKline, Stevenage, and University of Cambridge; S.W. Tas, MD, PhD, Division of Clinical Immunology and Rheumatology, and Department of Experimental Immunology, Academic Medical Center/University of Amsterdam.
authors.forename: Karen I
authors.initials: KI
authors.lastname: Maijer
authors.affiliation: From the Division of Clinical Immunology and Rheumatology, the Department of Experimental Immunology, and the Department of Radiology, Academic Medical Center/University of Amsterdam, Amsterdam, the Netherlands; GlaxoSmithKline, Stevenage; University of Cambridge, Cambridge, UK.K.I. Maijer, MD, Division of Clinical Immunology and Rheumatology, Academic Medical Center/University of Amsterdam; A.R. Noort, MSc, Division of Clinical Immunology and Rheumatology, and Department of Experimental Immunology, Academic Medical Center/University of Amsterdam; M.J. de Hair, MD, PhD, Division of Clinical Immunology and Rheumatology, Academic Medical Center/University of Amsterdam; C. van der Leij, MD, Department of Radiology, Academic Medical Center/University of Amsterdam; K.P. van Zoest, BSc, Division of Clinical Immunology and Rheumatology, and Department of Experimental Immunology, Academic Medical Center/University of Amsterdam; I.Y. Choi, MD, Division of Clinical Immunology and Rheumatology, Academic Medical Center/University of Amsterdam; D.M. Gerlag, MD, PhD, Division of Clinical Immunology and Rheumatology, Academic Medical Center/University of Amsterdam, and GlaxoSmithKline; M. Maas, MD, PhD, Department of Radiology, Academic Medical Center/University of Amsterdam; P.P. Tak, MD, PhD, Division of Clinical Immunology and Rheumatology, Academic Medical Center/University of Amsterdam, and GlaxoSmithKline, Stevenage, and University of Cambridge; S.W. Tas, MD, PhD, Division of Clinical Immunology and Rheumatology, and Department of Experimental Immunology, Academic Medical Center/University of Amsterdam.
authors.forename: Ae Ri
authors.initials: AR
authors.lastname: Noort
authors.affiliation: From the Division of Clinical Immunology and Rheumatology, the Department of Experimental Immunology, and the Department of Radiology, Academic Medical Center/University of Amsterdam, Amsterdam, the Netherlands; GlaxoSmithKline, Stevenage; University of Cambridge, Cambridge, UK.K.I. Maijer, MD, Division of Clinical Immunology and Rheumatology, Academic Medical Center/University of Amsterdam; A.R. Noort, MSc, Division of Clinical Immunology and Rheumatology, and Department of Experimental Immunology, Academic Medical Center/University of Amsterdam; M.J. de Hair, MD, PhD, Division of Clinical Immunology and Rheumatology, Academic Medical Center/University of Amsterdam; C. van der Leij, MD, Department of Radiology, Academic Medical Center/University of Amsterdam; K.P. van Zoest, BSc, Division of Clinical Immunology and Rheumatology, and Department of Experimental Immunology, Academic Medical Center/University of Amsterdam; I.Y. Choi, MD, Division of Clinical Immunology and Rheumatology, Academic Medical Center/University of Amsterdam; D.M. Gerlag, MD, PhD, Division of Clinical Immunology and Rheumatology, Academic Medical Center/University of Amsterdam, and GlaxoSmithKline; M. Maas, MD, PhD, Department of Radiology, Academic Medical Center/University of Amsterdam; P.P. Tak, MD, PhD, Division of Clinical Immunology and Rheumatology, Academic Medical Center/University of Amsterdam, and GlaxoSmithKline, Stevenage, and University of Cambridge; S.W. Tas, MD, PhD, Division of Clinical Immunology and Rheumatology, and Department of Experimental Immunology, Academic Medical Center/University of Amsterdam.
authors.forename: Maria J H
authors.initials: MJ
authors.lastname: de Hair
authors.affiliation: From the Division of Clinical Immunology and Rheumatology, the Department of Experimental Immunology, and the Department of Radiology, Academic Medical Center/University of Amsterdam, Amsterdam, the Netherlands; GlaxoSmithKline, Stevenage; University of Cambridge, Cambridge, UK.K.I. Maijer, MD, Division of Clinical Immunology and Rheumatology, Academic Medical Center/University of Amsterdam; A.R. Noort, MSc, Division of Clinical Immunology and Rheumatology, and Department of Experimental Immunology, Academic Medical Center/University of Amsterdam; M.J. de Hair, MD, PhD, Division of Clinical Immunology and Rheumatology, Academic Medical Center/University of Amsterdam; C. van der Leij, MD, Department of Radiology, Academic Medical Center/University of Amsterdam; K.P. van Zoest, BSc, Division of Clinical Immunology and Rheumatology, and Department of Experimental Immunology, Academic Medical Center/University of Amsterdam; I.Y. Choi, MD, Division of Clinical Immunology and Rheumatology, Academic Medical Center/University of Amsterdam; D.M. Gerlag, MD, PhD, Division of Clinical Immunology and Rheumatology, Academic Medical Center/University of Amsterdam, and GlaxoSmithKline; M. Maas, MD, PhD, Department of Radiology, Academic Medical Center/University of Amsterdam; P.P. Tak, MD, PhD, Division of Clinical Immunology and Rheumatology, Academic Medical Center/University of Amsterdam, and GlaxoSmithKline, Stevenage, and University of Cambridge; S.W. Tas, MD, PhD, Division of Clinical Immunology and Rheumatology, and Department of Experimental Immunology, Academic Medical Center/University of Amsterdam.
authors.forename: Christiaan
authors.initials: C
authors.lastname: van der Leij
authors.affiliation: From the Division of Clinical Immunology and Rheumatology, the Department of Experimental Immunology, and the Department of Radiology, Academic Medical Center/University of Amsterdam, Amsterdam, the Netherlands; GlaxoSmithKline, Stevenage; University of Cambridge, Cambridge, UK.K.I. Maijer, MD, Division of Clinical Immunology and Rheumatology, Academic Medical Center/University of Amsterdam; A.R. Noort, MSc, Division of Clinical Immunology and Rheumatology, and Department of Experimental Immunology, Academic Medical Center/University of Amsterdam; M.J. de Hair, MD, PhD, Division of Clinical Immunology and Rheumatology, Academic Medical Center/University of Amsterdam; C. van der Leij, MD, Department of Radiology, Academic Medical Center/University of Amsterdam; K.P. van Zoest, BSc, Division of Clinical Immunology and Rheumatology, and Department of Experimental Immunology, Academic Medical Center/University of Amsterdam; I.Y. Choi, MD, Division of Clinical Immunology and Rheumatology, Academic Medical Center/University of Amsterdam; D.M. Gerlag, MD, PhD, Division of Clinical Immunology and Rheumatology, Academic Medical Center/University of Amsterdam, and GlaxoSmithKline; M. Maas, MD, PhD, Department of Radiology, Academic Medical Center/University of Amsterdam; P.P. Tak, MD, PhD, Division of Clinical Immunology and Rheumatology, Academic Medical Center/University of Amsterdam, and GlaxoSmithKline, Stevenage, and University of Cambridge; S.W. Tas, MD, PhD, Division of Clinical Immunology and Rheumatology, and Department of Experimental Immunology, Academic Medical Center/University of Amsterdam.
authors.forename: Katinka P M
authors.initials: KP
authors.lastname: van Zoest
authors.affiliation: From the Division of Clinical Immunology and Rheumatology, the Department of Experimental Immunology, and the Department of Radiology, Academic Medical Center/University of Amsterdam, Amsterdam, the Netherlands; GlaxoSmithKline, Stevenage; University of Cambridge, Cambridge, UK.K.I. Maijer, MD, Division of Clinical Immunology and Rheumatology, Academic Medical Center/University of Amsterdam; A.R. Noort, MSc, Division of Clinical Immunology and Rheumatology, and Department of Experimental Immunology, Academic Medical Center/University of Amsterdam; M.J. de Hair, MD, PhD, Division of Clinical Immunology and Rheumatology, Academic Medical Center/University of Amsterdam; C. van der Leij, MD, Department of Radiology, Academic Medical Center/University of Amsterdam; K.P. van Zoest, BSc, Division of Clinical Immunology and Rheumatology, and Department of Experimental Immunology, Academic Medical Center/University of Amsterdam; I.Y. Choi, MD, Division of Clinical Immunology and Rheumatology, Academic Medical Center/University of Amsterdam; D.M. Gerlag, MD, PhD, Division of Clinical Immunology and Rheumatology, Academic Medical Center/University of Amsterdam, and GlaxoSmithKline; M. Maas, MD, PhD, Department of Radiology, Academic Medical Center/University of Amsterdam; P.P. Tak, MD, PhD, Division of Clinical Immunology and Rheumatology, Academic Medical Center/University of Amsterdam, and GlaxoSmithKline, Stevenage, and University of Cambridge; S.W. Tas, MD, PhD, Division of Clinical Immunology and Rheumatology, and Department of Experimental Immunology, Academic Medical Center/University of Amsterdam.
authors.forename: Ivy Y
authors.initials: IY
authors.lastname: Choi
authors.affiliation: From the Division of Clinical Immunology and Rheumatology, the Department of Experimental Immunology, and the Department of Radiology, Academic Medical Center/University of Amsterdam, Amsterdam, the Netherlands; GlaxoSmithKline, Stevenage; University of Cambridge, Cambridge, UK.K.I. Maijer, MD, Division of Clinical Immunology and Rheumatology, Academic Medical Center/University of Amsterdam; A.R. Noort, MSc, Division of Clinical Immunology and Rheumatology, and Department of Experimental Immunology, Academic Medical Center/University of Amsterdam; M.J. de Hair, MD, PhD, Division of Clinical Immunology and Rheumatology, Academic Medical Center/University of Amsterdam; C. van der Leij, MD, Department of Radiology, Academic Medical Center/University of Amsterdam; K.P. van Zoest, BSc, Division of Clinical Immunology and Rheumatology, and Department of Experimental Immunology, Academic Medical Center/University of Amsterdam; I.Y. Choi, MD, Division of Clinical Immunology and Rheumatology, Academic Medical Center/University of Amsterdam; D.M. Gerlag, MD, PhD, Division of Clinical Immunology and Rheumatology, Academic Medical Center/University of Amsterdam, and GlaxoSmithKline; M. Maas, MD, PhD, Department of Radiology, Academic Medical Center/University of Amsterdam; P.P. Tak, MD, PhD, Division of Clinical Immunology and Rheumatology, Academic Medical Center/University of Amsterdam, and GlaxoSmithKline, Stevenage, and University of Cambridge; S.W. Tas, MD, PhD, Division of Clinical Immunology and Rheumatology, and Department of Experimental Immunology, Academic Medical Center/University of Amsterdam.
authors.forename: Daniëlle M
authors.initials: DM
authors.lastname: Gerlag
authors.affiliation: From the Division of Clinical Immunology and Rheumatology, the Department of Experimental Immunology, and the Department of Radiology, Academic Medical Center/University of Amsterdam, Amsterdam, the Netherlands; GlaxoSmithKline, Stevenage; University of Cambridge, Cambridge, UK.K.I. Maijer, MD, Division of Clinical Immunology and Rheumatology, Academic Medical Center/University of Amsterdam; A.R. Noort, MSc, Division of Clinical Immunology and Rheumatology, and Department of Experimental Immunology, Academic Medical Center/University of Amsterdam; M.J. de Hair, MD, PhD, Division of Clinical Immunology and Rheumatology, Academic Medical Center/University of Amsterdam; C. van der Leij, MD, Department of Radiology, Academic Medical Center/University of Amsterdam; K.P. van Zoest, BSc, Division of Clinical Immunology and Rheumatology, and Department of Experimental Immunology, Academic Medical Center/University of Amsterdam; I.Y. Choi, MD, Division of Clinical Immunology and Rheumatology, Academic Medical Center/University of Amsterdam; D.M. Gerlag, MD, PhD, Division of Clinical Immunology and Rheumatology, Academic Medical Center/University of Amsterdam, and GlaxoSmithKline; M. Maas, MD, PhD, Department of Radiology, Academic Medical Center/University of Amsterdam; P.P. Tak, MD, PhD, Division of Clinical Immunology and Rheumatology, Academic Medical Center/University of Amsterdam, and GlaxoSmithKline, Stevenage, and University of Cambridge; S.W. Tas, MD, PhD, Division of Clinical Immunology and Rheumatology, and Department of Experimental Immunology, Academic Medical Center/University of Amsterdam.
authors.forename: Mario
authors.initials: M
authors.lastname: Maas
authors.affiliation: From the Division of Clinical Immunology and Rheumatology, the Department of Experimental Immunology, and the Department of Radiology, Academic Medical Center/University of Amsterdam, Amsterdam, the Netherlands; GlaxoSmithKline, Stevenage; University of Cambridge, Cambridge, UK.K.I. Maijer, MD, Division of Clinical Immunology and Rheumatology, Academic Medical Center/University of Amsterdam; A.R. Noort, MSc, Division of Clinical Immunology and Rheumatology, and Department of Experimental Immunology, Academic Medical Center/University of Amsterdam; M.J. de Hair, MD, PhD, Division of Clinical Immunology and Rheumatology, Academic Medical Center/University of Amsterdam; C. van der Leij, MD, Department of Radiology, Academic Medical Center/University of Amsterdam; K.P. van Zoest, BSc, Division of Clinical Immunology and Rheumatology, and Department of Experimental Immunology, Academic Medical Center/University of Amsterdam; I.Y. Choi, MD, Division of Clinical Immunology and Rheumatology, Academic Medical Center/University of Amsterdam; D.M. Gerlag, MD, PhD, Division of Clinical Immunology and Rheumatology, Academic Medical Center/University of Amsterdam, and GlaxoSmithKline; M. Maas, MD, PhD, Department of Radiology, Academic Medical Center/University of Amsterdam; P.P. Tak, MD, PhD, Division of Clinical Immunology and Rheumatology, Academic Medical Center/University of Amsterdam, and GlaxoSmithKline, Stevenage, and University of Cambridge; S.W. Tas, MD, PhD, Division of Clinical Immunology and Rheumatology, and Department of Experimental Immunology, Academic Medical Center/University of Amsterdam.
authors.forename: Paul P
authors.initials: PP
authors.lastname: Tak
authors.affiliation: From the Division of Clinical Immunology and Rheumatology, the Department of Experimental Immunology, and the Department of Radiology, Academic Medical Center/University of Amsterdam, Amsterdam, the Netherlands; GlaxoSmithKline, Stevenage; University of Cambridge, Cambridge, UK.K.I. Maijer, MD, Division of Clinical Immunology and Rheumatology, Academic Medical Center/University of Amsterdam; A.R. Noort, MSc, Division of Clinical Immunology and Rheumatology, and Department of Experimental Immunology, Academic Medical Center/University of Amsterdam; M.J. de Hair, MD, PhD, Division of Clinical Immunology and Rheumatology, Academic Medical Center/University of Amsterdam; C. van der Leij, MD, Department of Radiology, Academic Medical Center/University of Amsterdam; K.P. van Zoest, BSc, Division of Clinical Immunology and Rheumatology, and Department of Experimental Immunology, Academic Medical Center/University of Amsterdam; I.Y. Choi, MD, Division of Clinical Immunology and Rheumatology, Academic Medical Center/University of Amsterdam; D.M. Gerlag, MD, PhD, Division of Clinical Immunology and Rheumatology, Academic Medical Center/University of Amsterdam, and GlaxoSmithKline; M. Maas, MD, PhD, Department of Radiology, Academic Medical Center/University of Amsterdam; P.P. Tak, MD, PhD, Division of Clinical Immunology and Rheumatology, Academic Medical Center/University of Amsterdam, and GlaxoSmithKline, Stevenage, and University of Cambridge; S.W. Tas, MD, PhD, Division of Clinical Immunology and Rheumatology, and Department of Experimental Immunology, Academic Medical Center/University of Amsterdam. s.w.tas@amc.uva.nl.
authors.forename: Sander W
authors.initials: SW
authors.lastname: Tas
mesh_terms: D000328:Adult; D001172:Arthritis, Rheumatoid / Q000378:metabolism* / Q000473:pathology; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006801:Humans; D007249:Inflammation / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D013583:Synovial Membrane / Q000378:metabolism* / Q000473:pathology; D013585:Synovitis / Q000378:metabolism* / Q000473:pathology; D000097782:NF-kappaB-Inducing Kinase
chemical_list: D017346:Protein Serine-Threonine Kinases; D000097782:NF-kappaB-Inducing Kinase
keywords: EARLY ARTHRITIS; NF-κB–INDUCING KINASE; NUCLEAR FACTOR-κB; RHEUMATOID ARTHRITIS; SYNOVIUM