Background/Purpose: Rheumatoid arthritis (RA) is associated with neovascularization of the synovial membrane and increased risk of cardiovascular disease, consequent to vascular and endothelial dysfunction, which leads to remodeling, and degradation of the basement membrane proteins, such as type IV collagen. The purpose of the study was to investigate the association between basement membrane turnover and disease activity, as well as structural progression in RA.

Methods: Serum samples from patients giving informed consent of the LITHE (n=740) and RADIATE (n=217) studies (two phase III double-blinded placebo controlled studies testing 4- and 8-mg/kg tocilizumab (TCZ) in combination with methotrexate) were included. Basement membrane turnover was measured by the blood-based biomarker C4M reflecting MMP-degraded type IV collagen degradation at baseline, week 4, 16, 24 and 52, and at baseline and week 16 in the LITHE and the RADIATE study. Associations between basement membrane turnovers, treatment response and clinical parameters.

Results:  Basement membrane turnover was associated with clinical scores including visual analog scale for pain (p<0.0001) and DAS28 DAS28 (p=<0.0001) in both studies (table). It was dose-dependently reduced by TCZ (11-40%, figure) and baseline levels were significantly correlated with change in radiographic scores (joint space narrowing (p=0.001) and sharp score (p=0.0002)).    

Conclusion: Basement membrane remodeling was associated with disease activity and radiographic progression at baseline, and was dose-dependently inhibited by TCZ, suggesting a continuous clinical benefit extending past the joint tissue. These data suggest that active RA and disease progression is associated with increased remodeling of basement membrane collagen.

Figure 1. C4M levels were suppressed by IL-6R. A) Showing percentage change from baseline to week 4, 16, 24 and 54 for each of the 3 treatment groups in LITHE. B) Suppression of C4M in LITHE week 16. C) Suppression of C4M in RADIATE week 16. Error bars are shown as SEM. Significant levels are depicted *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001.