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

Karen I Maijer; Ae Ri Noort; Maria J H de Hair; Christiaan van der Leij; Katinka P M van Zoest; Ivy Y Choi; Daniëlle M Gerlag; Mario Maas; Paul P Tak; Sander W Tas

doi:10.3899/jrheum.150245

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

J Rheumatol. 2015 Sep;42(9):1573-81. doi: 10.3899/jrheum.150245. Epub 2015 Jul 15.

Affiliations

¹ 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.
² 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.

PMID: 26178280
DOI: 10.3899/jrheum.150245

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.

Conclusion: 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.

Keywords: EARLY ARTHRITIS; NF-κB–INDUCING KINASE; NUCLEAR FACTOR-κB; RHEUMATOID ARTHRITIS; SYNOVIUM.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adult
Arthritis, Rheumatoid / metabolism*
Arthritis, Rheumatoid / pathology
Endothelial Cells / metabolism*
Endothelial Cells / pathology
Female
Humans
Inflammation / metabolism*
Inflammation / pathology
Male
Middle Aged
NF-kappaB-Inducing Kinase
Prospective Studies
Protein Serine-Threonine Kinases / metabolism*
Synovial Membrane / metabolism*
Synovial Membrane / pathology
Synovitis / metabolism*
Synovitis / pathology

Substances

Protein Serine-Threonine Kinases