Background/Purpose:  It has recently been established that >75% of patients on methotrexate and a biologic do not achieve complete remission based on the new definition set by ACR/EULAR in 2011. These findings are supported by recent studies utilizing imaging technology such as PDUS or MRI that have detected “subclinical inflammation” in low disease activity patients that correlates with subsequent radiographic progression. Importantly, while anti-TNF-α therapies reduce neovascularization to some extent, the effect is incomplete. Our hypothesis is that inhibiting angiogenesis beyond that provided by anti-TNF-α therapy will provide tighter control of inflammation leading to greater impact on inhibiting disease progression. The key mediators of angiogenesis are members of the vascular endothelium growth factor (VEGF) and angiopoietin (Ang) families.  Several investigators have reported increased expression of these mediators in the RA and PsA joint when compared to normal or osteoarthritis biopsies. Based on previous work demonstrating efficacy of anti-Ang2 therapy in models of RA, we chose to utilize a combination of anti-Ang2 along with anti-TNF-α to explore this hypothesis.

Methods:  Arthritis was induced by immunization of DBA/1 mice with glucose-6-phosphate isomerase.  Animals were treated with either 10 mg/kg anti-Ang2 antibody, 10 mg/kg anti-TNF-α antibody or a combination of the two beginning 7 days following immunization.  Clinical scores were assessed daily.  Animals were terminated 15 days following immunization and joints were evaluated for histological changes (H&E), CD31 staining for endothelial cells, F4/80 staining for macrophages and Cathepsin K for osteoclasts. In addition, selected joints were evaluated for bone cortical roughness around the joints using magnetic resonance imaging.

Results:  Treatment with an anti-Ang2 antibody in addition to an anti-TNF-α antibody resulted in improved activity on clinical scores as well as protection from pathological changes in the joints compared to anti-TNF-α or anti-Ang2 treatment alone.  Combination treatment provided a greater effect on inflammation/pannus formation and inflammatory cell infiltrates as well as on osteolysis and periosteal proliferation.  CD31 staining revealed decreased vascularity in the synovium of combination treated mice with a concomitant decrease in macrophage and ostoeclast infiltration.  MRI analysis of the bone surface of the joints revealed augmented protection from damage (cortical bone roughness) that is observed in this model as a result of the ongoing tenosynovitis.

Conclusion:  These data suggest that the enhanced activity of combined anti-Ang2 and anti-TNF-α treatment is due to a greater effect in decreasing vascularity in the synovium which results in decreased infiltrating inflammatory cells, as well as osteoclasts, leading to decreased bone damage in the joint.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/neutralization-of-angiopoietin-2-enhances-the-efficacy-of-anti-tumor-necrosis-factor-alpha-treatment-in-a-mouse-model-of-rheumatoid-arthritis-by-decreasing-cellular-infiltration-into-the-joint-and-pro/