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.
Footnotes
K.I. Maijer and A.R. Noort are shared first authors of this manuscript.
Supported by the Dutch Arthritis Foundation (grant number 06-1-303, 11-1-407, 12-2-050), the Netherlands Organization for Health Research and Development (ZonMw; grant number 200310003), a Veni grant of the Netherlands Organization for Scientific Research (NHW; grant number 91696015), a Clinical Fellowship (ZonMw; grant number 90700359) to SWT, the Innovative Medicines Initiative European Union funded project BeTheCure (grant number 115142), and the European Union Seventh Framework Programme (project EuroTEAM; FP7-HEALTHF2-2012; grant number 305549).
- Accepted for publication May 27, 2015.