Angiogenic cytokines can reflect the synovitis severity and treatment response to biologics in rheumatoid arthritis

Ji‐Won Kim,Saseong Lee,Wan-Uk Kim,Seung-Ah Yoo,Jingchun Jin,Jung Hee Koh,Jin-Sun Kong

doi:10.1038/s12276-020-0443-8

Abstract

Angiogenesis and synoviocyte hyperplasia, called ‘pannus,’ are pathologic hallmarks of rheumatoid arthritis (RA). To determine the clinical significance of angiogenic cytokines in RA, the levels of pro-angiogenic cytokines, including VEGF, placenta growth factor (PlGF), and IL-6, were measured in the synovial fluid (SF, n = 54) and sera of RA patients (n = 157) using ELISA. Patients (n = 103) with disease activity score 28 (DAS28) > 3.2, which indicates moderate to high RA activity, underwent follow-up blood sampling at 6 months after treatment with conventional disease-modifying anti-rheumatic drugs (c-DMARD) or biologic DMARD (b-DMARD) including an anti-TNFα antibody, an anti-IL-6 antibody, and abatacept. Ultrasonography (US) was performed on affected joints to define the synovitis severity at the time of sampling. Consequently, in the SF of RA patients, PlGF and IL-6 levels correlated well with synovitis severity determined by US. In RA sera, VEGF and IL-6 levels were elevated in proportion to synovitis severity, correlating with conventional markers for disease activity, including ESR, CRP, and DAS28. In c-DMARD users (n = 53), serially monitored levels of serum VEGF, IL-6, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) all decreased in good and moderate responders but not in nonresponders. In b-DMARD users (n = 49), only serum VEGF well represented the treatment response, while CRP nonspecifically decreased irrespective of the treatment outcome. By multivariable analysis, serum ΔVEGF, but not ΔESR or ΔCRP, was an independent factor associated with good and moderate responses to DMARD. In summary, the angiogenic cytokines PlGF and VEGF represent the synovitis severity of RA assessed by US. In patients receiving b-DMARD, serum VEGF may be more valuable than CRP in reflecting the treatment response.

Highlights

Rheumatoid arthritis (RA) is pathologically characterized by the abnormal proliferation of synoviocytes and extensive angiogenesis, called pannus formation[1]
We tested whether the levels of Vascular endothelial growth factor (VEGF), placenta growth factor (PlGF), and IL6, as pro-angiogenic cytokines mainly secreted from synoviocytes, could represent local and/or systemic inflammatory responses in RA patients
In this study, we postulate that angiogenic cytokines secreted from RA synoviocytes could represent a ‘pannus’ pathology and well reflect the pathologic and inflammatory status of RA when they overflow into the periphery

Summary

Introduction

Rheumatoid arthritis (RA) is pathologically characterized by the abnormal proliferation of synoviocytes and extensive angiogenesis, called pannus formation[1]. As a major component of the invasive pannus, angiogenesis is believed to be an essential step for the abnormal proliferation of synoviocytes and perpetuation. Vascular endothelial growth factor (VEGF), a representative angiogenic cytokine, can strongly induce endothelial cell activation and proliferation[9,10]. Kim et al Experimental & Molecular Medicine (2020) 52:843–853 receptors are highly expressed in RA synovial tissues. Their expression levels parallel the degree of synovial angiogenesis[11]. We have previously demonstrated that VEGF165 confers RA synoviocyte apoptotic resistance[19], providing important implications for the abnormal growth of synoviocytes, called pannus formation

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Conclusion