Background/Purpose: Previously, we demonstrated the direct pro-inflammatory role of the vascular endothelial growth factor (VEGF) and the placenta growth factor (PlGF), and angiogenic factors in rheumatoid arthritis (RA) pathogenesis (Arthritis Rheum 2009, Nat Immunol 2019). Here, we investigated whether these factors can reflect ultrasound (US)-defined synovitis, disease activity, and treatment response in RA patients.

Methods: US was performed to determine synovial hypertrophy (GSUS) and vascularity (PDUS) scores in RA patients (n=54) who underwent arthrocentesis; GSUS ≥2 or PDUS ≥1 was defined as severe synovitis. Serum samples were obtained from 157 RA patients, and among them, RA patients with disease activity score 28 (DAS28) > 3.2 underwent serial serum sampling 6 months after treatment with conventional DMARD (cDMARD, n=53) or biologic DMARD (bDMARD, n=49). Angiogenic proteins primarily produced by synoviocytes, including VEGF, PlGF, soluble flt-1 (sflt-1), and IL6, were measured in the synovial fluid (SF) and sera using an enzyme-linked immunosorbent assay.

Results: SF and serum VEGF, PlGF, sflt-1, and IL6 concentrations were significantly elevated in RA patients compared with osteoarthritis controls. For SF, RA patients with severe synovitis on US examination showed higher concentrations of PlGF, but not VEGF, than those without. In contrast, serum VEGF, but not PlGF, reflected well synovitis severity in the joints, correlating with acute phase reactants and DAS28. In cDMARD users, the serial follow-up of serum VEGF, IL6, ESR, and CRP could all predict the treatment response. However, in biologic drug users (n=49), serial monitoring of VEGF only, but neither IL6 nor CRP, significantly predicted treatment response. Using a multiple logistic regression model, older age, low baseline sharp score, and high VEGF difference were associated with good and moderate treatment response; area under the ROC curve from this model was 0.872.

Conclusion: Angiogenic factors PlGF and VEGF represent well the joint pathology of RA assessed by US. Serum VEGF shows a better value to predict a therapeutic response to anti-rheumatic drugs than CRP and IL6, particularly in patients treated with biologic agents.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/angiogenic-factors-for-assessing-rheumatoid-arthritis-in-the-era-of-sonographic-diagnosis-and-biologic-therapy/