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.

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.

• Authors: 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
• Journal: The Journal of rheumatology (J Rheumatol) Vol. 42 Issue 9 Pg. 1573-81 (Sep 2015) ISSN: 0315-162X [Print] Canada
• PMID: 26178280 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Protein Serine-Threonine Kinases
• NF-kappa B kinase

Topics

• Adult
• Arthritis, Rheumatoid (metabolism, pathology)
• Endothelial Cells (metabolism, pathology)
• Female
• Humans
• Inflammation (metabolism, pathology)
• Male
• Middle Aged
• Prospective Studies
• Protein Serine-Threonine Kinases (metabolism)
• Synovial Membrane (metabolism, pathology)
• Synovitis (metabolism, pathology)