Rapid and sustained improvement in bone and cartilage turnover markers with the
anti-interleukin-6 receptor inhibitor tocilizumab plus methotrexate in rheumatoid
arthritis patients with an inadequate response to methotrexate: results from a
substudy of the multicenter double-blind, placebo-controlled trial of tocilizumab
in inadequate responders to methotrexate alone.
Author(s): Garnero P, Thompson E, Woodworth T, Smolen JS.
Affiliation(s): INSERM Unit 664, Lyon, France. patrickgarnero@free.fr
Publication date & source: 2010, Arthritis Rheum. , 62(1):33-43
OBJECTIVE: To investigate the effects of tocilizumab (TCZ) added to a stable
dosage of methotrexate (MTX) on biochemical markers of bone and cartilage
metabolism in patients in the multicenter double-blind, placebo-controlled OPTION
(Tocilizumab Pivotal Trial in Methotrexate Inadequate Responders) study who have
moderate-to-severe rheumatoid arthritis (RA) and an inadequate response to MTX.
METHODS: Included in this study were 416 of the 623 patients with active RA
enrolled in the OPTION study. Patients were randomized to receive TCZ (4 mg/kg or
8 mg/kg) or placebo intravenously every 4 weeks, with MTX continued at the stable
prestudy doses (10-25 mg for 20 weeks, with a final followup at week 24). Serum
biochemical markers of bone formation (osteocalcin, N-terminal propeptide of type
I collagen [PINP]), bone resorption (C-terminal crosslinking telopeptide of type
I collagen [CTX-I] and C-terminal crosslinking telopeptide of type I collagen
generated by matrix metalloproteinases [ICTP]), cartilage metabolism (N-terminal
propeptide of type IIA collagen [PIIANP]), collagen helical peptide [HELIX-II]),
and matrix metalloproteinase 3 (MMP-3) were measured at baseline and at weeks 4,
16, and 24.
RESULTS: TCZ induced marked dose-dependent reductions in PIIANP, HELIX-II, and
MMP-3 levels at week 4 that were maintained until week 24, an effect associated
with increased levels of bone formation markers that were significant as compared
with placebo only for PINP and only at 4 weeks (P < 0.01 for both TCZ doses). TCZ
induced significant decreases in the bone degradation markers CTX-I and ICTP,
providing initial evidence of a beneficial effect on bone turnover. TCZ-treated
patients who met the American College of Rheumatology 50% improvement criteria
(achieved an ACR50 response) or achieved clinical remission (as determined by a
Disease Activity Score in 28 joints <2.6) at week 24 had greater reductions in
ICTP, HELIX-II, and MMP-3 levels as compared with ACR50 nonresponders.
CONCLUSION: TCZ combined with MTX reduces systemic bone resorption, cartilage
turnover, and proteolytic enzyme MMP-3 levels, which provides evidence of a
limitation of joint damage and possible beneficial effects on skeletal structure
in patients with established moderate-to-severe RA.
|