Background/Purpose:
Protease activity, especially MMP3, is known to be
increased with arthritis, such as rheumatoid arthritis. MMP3 is mainly
expressed by fibroblasts; a key cell in arthritis. In RA, Serum levels of MMP3 isassociated
with structural progression and elevated compared to OA. The present methods
for assessing MMP3 is ELISA of total MMP3 (tMMP3) or the activity by using a
substrate. However, neither of these approaches provide serological information
about the level of the active form of MMP3 (acMMP3). In this study we used a serological
biomarker detecting acMMP3, to investigate if this biomarker was a biomarker of
treatment efficacy (Tocilizumab; TCZ), aid in dose-finding and if it was
related to radiographic progression.

Methods: LITHE biomarker study (n=585) was a 1-year phase III, double-blind,
placebo (PBO)-controlled, parallel group study of  4 or 8 mg/kg every 4 weeks,
in RA patients on stable doses of methotrexate (MTX). acMMP3 was tested in
serum from baseline (BL) and week 4, 16, 24 and 52 and tMMP3 in serum from BL
and week 4 and 16. Patients not reaching ACR20 remission at week 16 or 24 received
rescue treatment (escape); 4mg/kg patients received 8mg/kg for the rest of the
study. Spearman’s correlation was analysed between BL level of acMMP3 (log
transformed) and clinical measures. Associations between BL acMMP3 and change
in JSN and mTSS were investigated in the PBO group was assessed by Spearman’s
correlations. Change in acMMP3 levels were studied as a function of time and
treatment. Relation to radiographic progression was assessed t-test when
segregating the treated population into 2 group; more or less than 35% change
in acMMP3 at week 16 .  

Results: At BL tMMP3, but not acMMP3, was correlated with radiographic change
(erosion rho 0.22 and modified total sharp score rho: 0.21) at 1 year and HAQ
(rho -0.19) at 24 weeks and acMMP3, and tMMP3 were correlated to each other
(rho 0.15). Percentage change in acMMP3 at week 16 in the TCZ groups was negatively
correlated to change in radiographic change at 1 year (erosion rho -0.20 and
modified total sharp score rho -0.20), but for joint space narrowing only in
the 4mg/kg group (rho -0.27). Percentage change in tMMP3 at week 16 in the
4mg/kg group was correlated to disease activity measures (DAS rho 0.21, HAQ rho
0.20, VAS pain rho 0.21). acMMP3 was dose-dependently decreased by TCZ (p=0.026)
already at week 4, whereas tMMP3 was decreased by treatment (p=0.0001) without
dose-differentiation. Furthermore, acMMP3 was decreased in escapers compared to
non-escapers at 1 year.

Conclusion:   Serum acMMP3 and tMMP3 were efficacy biomarkers of TCZ at
week 4 and acMMP3, but not tMMP3, differentiated doses. The change in acMMP3 at
week 16 was inversely associated with radiographic change at 1 year, whereas
the change in tMMP3 was associated with disease activity. This study
illustrates that the activity of a protease can assess early, who will benefit
from TCZ.