Clinical Significance of Cartilage Biomarkers for Monitoring Structural Joint Damage in Rheumatoid Arthritis Patients Treated with Anti-TNF Therapy

PURPOSE: With the current use of biologics in rheumatoid arthritis (RA), there is a need to monitor ongoing structural joint damage due to the dissociation of articular cartilage damage from disease activity of RA. This study longitudinally analyzed levels of serum cartilage biomarkers during 54 weeks of infliximab therapy, to evaluate the feasibility of biomarkers for monitoring structural joint damage. METHODS: Subjects comprised 33 patients with early RA and 33 patients with established RA. All patients received 3 mg/kg of infliximab and methotrexate for 54 weeks. Levels of the following serum cartilage markers were measured at baseline and at weeks 14, 22, and 54: hyaluronan (HA); cartilage oligometric matrix protein (COMP); type II collagen (CII)-related neoepitope (C2C); type II procollagen carboxy-propeptide (CPII); and keratin sulfate (KS). Time courses for each biomarker were assessed, and relationships between these biomarkers and clinical or radiographic parameters generally used for RA were investigated. RESULTS: Levels of CRP, MMP-3, DAS28-CRP, and annual progression of TSS were improved to similar degrees in both groups at week 54. HA and C2C/CPII were significantly decreased compared to baseline in the early RA group (p<0.001), whereas HA and COMP, but not C2C/CPII, were decreased in the established RA group. Strikingly, serum C2C/CPII levels were universally improved in early RA, regardless of EULAR response grade. Both ΔHA and ΔC2C/CPII from baseline to week 54 correlated significantly with not only ΔCRP, but also ΔDAS28 in early RA. Interestingly, when partial correlation coefficients were calculated by standardizing CRP levels, the significant correlation of ΔHA to ΔDAS28 disappeared, whereas correlations of ΔC2C/CPII to ΔDAS28, ΔJNS, and ΔHAQ remained significant. These results suggest a role of ΔC2C/CPII as a marker of ongoing structural joint damage with the least association with CRP, and that irreversible cartilage damage in established RA limits restoration of the C2C/CPII level, even with tight control of joint inflammation. CONCLUSION: The temporal course of C2C/CPII level during anti-TNF therapy indicates that CII turnover shifts toward CII synthesis in early RA, but not in established RA, potentially due to irreversible cartilage damage. ΔC2C/CPII appears to offer a useful marker reflecting ongoing structural joint damage, dissociated from inflammatory indices such as CRP and MMP-3

Improvement of C2C/CPII from baseline to week 54 was assessed in early RA (A), established RA (B), and all patients (C).

<p>Data are expressed as mean (± SD) percentage of baseline. Patients were divided into three subgroups according to the degree of clinical response at week 54 using EULAR response criteria. Positive values signify that the balance of CII synthesis/degradation is biased toward synthesis, while negative values indicate that the balance is biased toward degradation. Statistical analysis was performed using the Kruskal-Wallis test. *p<0.05.</p

Baseline characteristics of the patients with early and established RA enrolled in this study^*.

*<p>Except where indicated otherwise, values are expressed as the mean (range).</p

Spearman's correlation coefficients and partial correlation coefficients of cartilage markers vesus RA disease markers.

*<p>Values are correlation coefficients calculated using Spearman's rank correlation. P values are expressed in parentheses. p<0.05 is considered as statistically significant.</p>**<p>Partial correlation coefficients were obtained after controlling CRP level for each marker pair.</p>¶<p>n.a., not applicable.</p>†<p>n.s., not significant.</p>‡<p>n.d., not determined.</p

Time-course changes in the levels of cartilage biomarkers during 1-year infliximab therapy.

†<p>Values are expressed as mean (SD).</p>*<p>p<0.05 versus baseline levels.</p>**<p>p<0.001 versus baseline levels.</p

Temporal course of cartilage biomarker levels during 54-week infliximab therapy.

<p>Data for each time point represent mean levels of serum CRP, HA, COMP, KS, and C2C/CPII in early RA (A) and established RA (B). Standard deviation (SD) error bars are not plotted in these graphs for clarity and are shown in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0037447#pone-0037447-t003" target="_blank">Table 3</a>. Statistical analyses were performed using Wilcoxon's matched-pairs signed-ranks test, two-tailed. *p<0.05 versus level at baseline. **p<0.001 versus level at baseline.</p

Effectiveness and safety of adalimumab in Japanese patients with rheumatoid arthritis: retrospective analyses of data collected during the first year of adalimumab treatment in routine clinical practice (HARMONY study)

We retrospectively investigated the ability of adalimumab (ADA) to reduce disease activity, improve physical function, and retard the progression of structural damage in 167 patients with rheumatoid arthritis. Clinical and functional outcomes were compared between patients with or without prior biologic treatment and those with or without concomitant methotrexate (MTX) treatment. At week 52, 38.3% achieved clinical remission: 42.4 and 28.6% of patients achieved remission in those without and with previous biologics, respectively, while 42.7 and 12.5% of patients achieved remission in those with and without concomitant MTX, respectively. ADA treatment significantly reduced the rate of radiographic progression from 27.1 ± 46.0 (median 13.6; 25th–75th percentiles 8.3 to 28.9) at baseline to 0.8 ± 5.0 (median 0.0; 25th–75th percentiles −0.9 to 2.0) at week 52 (P < 0.0001). Radiographic progression was absent in 59.8% of patients. Sixty adverse events (34.21/100 patient-years) were reported, 16 of which were serious (9.12/100 patient-years). ADA therapy is highly effective for reducing disease activity, improving physical function, and limiting radiographic progression. It is generally safe and well tolerated by Japanese RA patients in routine clinical practice