Tumor Necrosis Factor Blocking Therapy Alters Joint Inflammation and Hypoxia

Objective: To examine the effect of tumor necrosis factor (TNF) blocking therapy on hypoxia in vivo, macroscopic and microscopic inflammation, and magnetic resonance imaging (MRI) results in patients with inflammatory arthritis.

Methods: Patients with inflammatory arthritis (n = 20) underwent full clinical assessment, arthroscopy, synovial biopsy, and MRI before and after initiation of biologic therapy. Macroscopic synovitis/vascularity was assessed with a visual analog scale, and tissue PO(2) (tPO(2) ) was measured at arthroscopy using a Licox probe. Cell-specific markers (CD4, CD8, CD68, CD20, and CD19) and blood vessel maturity were quantified by immunohistologic analysis and dual-immunofluorescence factor VIII/α-smooth muscle actin staining, respectively. Contiguous gadoteric acid-enhanced MRI of the target knee was used to assess synovial enhancement.

Results: Biologic therapy responders showed a significant increase of tPO(2) in vivo (P < 0.05). This response was associated with significant reductions in 28-joint Disease Activity Score using the C-reactive protein level (DAS28-CRP) (P = 0.012), macroscopic synovitis (P = 0.017), macroscopic vascularity (P = 0.05), CD4+ T cells (P < 0.041), and CD68+ macrophages (P < 0.011). Blood vessel numbers were also reduced in responders; however, this did not reach statistical significance. Strong inverse correlations were demonstrated between changes in tPo(2) levels and changes in DAS28-CRP (r = -0.53, P < 0.001), CD4 (r = -0.44, P < 0.026), CD68 (r = -0.46, P < 0.003), and macroscopic vascularity (r = -0.314, P = 0.049) after therapy. Furthermore, changes in inflammation as measured by MRI showed a strong inverse correlation with tPO(2) levels (r = -0.688, P < 0.002) and positive correlations with CRP levels (r = 0.707, P = 0.001), macroscopic synovitis (r = 0.457, P = 0.056), macroscopic vascularity (r = 0.528, P= 0.017), CD4 (r = 0.553, P < 0.032), and CD68 (r = 0.670, P < 0.002) after therapy.

Conclusion: This is the first study to show that successful biologic therapy significantly improves in vivo synovial hypoxia. Changes are strongly associated with changes in macroscopic and microscopic measures of joint inflammation and MRI improvement. These data further strengthen the concept that hypoxia is an important event driving synovial inflammation.