Background/Purpose

The 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). In this study we investigated the expression of NIK in ST of early arthritis patients and in autoantibody-positive individuals at risk for developing RA, and correlated this with both  systemic markers of disease activity (ESR and CRP) and with local disease activity in DMARD-naive early arthritis patients including magnetic resonance imaging (MRI) inflammation scores of the biopsied joint.

Methods

Arthroscopic ST biopsy samples were obtained from 154 early arthritis patients (arthritis duration less than 1 year, disease-modifying antirheumatic drug (DMARD) naïve; RA (n=64), unclassified arthritis (UA; n=61), crystal arthropathy (n=11), osteoarthritis (n=4) and spondyloarthritis (n=14)) and from 54 IgM-rheumatoid factor and/or anti-citrullinated peptide antibody positive individuals at risk for developing RA, who never had any evidence of arthritis upon physical examination. ST sections were stained for the expression of NIK and evaluated by digital image analysis. In addition, measures of disease activity such as ESR, CRP and swelling of the biopsied joint (score of 0 (no swelling) – 3 (severe swelling)) were collected. In a subset of these patients contrast enhanced MRI was performed in the same joint and scored for effusion, synovitis, edema, cartilage degeneration and erosions, each in 4-6 compartments. A score of 0-3 for each compartment was given and a total MRI score was calculated (0-81).

Results

In early arthritis patients, NIK was predominantly expressed in endothelial cells (EC) of small blood vessels. No significant difference in NIK expression was observed between baseline diagnosis groups. However, NIK⁺ EC were significantly increased in UA patients that remained undifferentiated after 2 years. Furthermore, we observed that NIK⁺ EC  may correlate better with disease activity than vWF⁺ EC, since NIK expression correlated with ESR (r=0.184; p=0.024), CRP (r=0.194; p=0.017), swelling of the biopsied joint (r=0.297; p<0.001), 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). NIK expression did not significantly correlate with edema, cartilage damage and erosion scores. In 18.5% of autoantibody-positive individuals NIK⁺ EC were present in the synovium before the clinical onset of arthritis, but this did was not predictive for the development of arthritis.

Conclusion

We demonstrate that NIK⁺ EC are already present in the earliest phase of synovial inflammation and may be indicative of high angiogenic activity in the inflamed synovial tissue. Therefore, NIK⁺ EC may play an important role in the persistence of synovial inflammation. Collectively, our data underscore the importance of angiogenesis in synovial inflammation and identify NIK as a potential therapeutic target in arthritis to prevent the switch from acute to chronic inflammation.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/nf-%ce%bab-inducing-kinase-nik-is-expressed-in-synovial-endothelial-cells-in-early-arthritis-patients-and-correlates-with-local-disease-activity-and-systemic-markers-of-inflammation/