Background Recent studies have reported the influence of osteoprotegerin (OPG) 1), a decoy receptor that binds directly to the receptor activator of NF-κB ligand (RANKL), and the Wnt antagonist Dickkopf-1 (DKK-1) on bone destruction in patients with rheumatoid arthritis (RA), and these substances are thus thought to regulate bone metabolism in RA.
Objectives To prospectively evaluate the utility of markers of bone and cartilage metabolism as predictive factors for joint destruction, by examining changes in these markers before and after treatment with tocilizumab (TCZ), a humanized anti-interleukin-6 (IL-6) receptor antibody.
Methods Twenty RA patients (four male and 16 female with a mean age of 57.0 years and a mean disease duration of 8.8 years; 11 had previously been treated with biological products) were enrolled in this study and administered TCZ 8 mg/kg every four weeks. Before treatment and at Weeks 12, 24 and 52 of treatment or at discontinuation, disease activity, serum IL-6 levels, and markers of bone and cartilage metabolism (OPG, DKK-1, osteocalcin [OC], matrix metalloprotease 3 [MMP-3], urinary type I collagen cross-linked N-telopeptide [uNTX], and urinary type II collagen C-terminal telopeptide [uCTX-II]) were measured to examine changes in, and correlations among, these markers. A Δscore was calculated with scores at an initial treatment and a final observation (Last Observation Carried Forward: LOCF).
Results Changes in parameters are shown in the table below.
DAS28-ESR was decreased from 5.1±1.4 at baseline to 1.9±0.9 (LOCF) (p<0.0001), with a remission rate (DAS28-ESR<2.6) of 85% (17/20). The percentages of patients who achieved normalisation of individual parameters were 46.2% (6/13) for MMP-3, 42.1% (8/19) for uNTX, 64.7% (11/17) for OC and 41.2% (8/19) for uCTX-II. DKK-1 was significantly decreased from 3210.7±838.6 at baseline to 2626.7±660.8 (LOCF) (p=0.0235). Correlations were noted between ΔuCTX-II and ΔMMP-3 (r=0.5594) and between ΔuCTX-II and ΔuNTX (r=0.4912).
Additional analysis of patients with a disease duration of less than 5 years revealed strong correlations between ΔDAS28-ESR and ΔIL-6 (r=0.700), between ΔDAS28-ESR and ΔMMP-3 (r=0.900), between ΔIL-6 and ΔMMP-3 (r=1.000) and between ΔuCTX-II and ΔMMP-3 (r=0.600), and correlations between ΔDKK-1 and ΔOC (r=0.500), between ΔOPG and ΔDAS28-ESR (r=0.5429) and between ΔOPG and ΔIL-6 (r=0.500).
Conclusions Although more than half of the patients had been treated with TNF inhibitors, TCZ treatment markedly improved disease activity and resulted in normalisation of markers of bone and cartilage metabolism in 40% or more of the patients. The correlations we noted between uCTX-II and MMP-3 and between DKK-1 and OC, before and after treatment of patients with rapidly progressing bone destruction and a disease duration of less than five years, suggest that uCTX-II and DKK-1 are useful as markers of bone and cartilage metabolism. Since OPG was found to be correlated with DAS28-ESR and with serum IL-6 levels, further investigation using a larger sample size may show its usefulness as a marker of metabolism of bone and cartilage.
Geusens P, Landewé R, Garnero P, Chen D, Dunstan C, Lems W. The ratio of Circulating steoprotegerin to RANKL in Early Rheumatoid Arthritis Predicts Later Joint Destruction. Arthritis Rheum 2006; 54: 1772.
Disclosure of Interest None Declared