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The known risk factors for radiologic progression in rheumatoid arthritis (RA) are not optimally discriminative in patients with early disease who do not have evidence of radiologic damage. We sought to determine whether urinary C-terminal crosslinking telopeptide of type I (CTX-I) and type II (CTX-II) collagen (markers of bone and cartilage destruction, respectively) are associated with long-term radiologic progression in patients with early RA. This was a prospective study of 110 patients with early RA who were participating in the COBRA (Combinatietherapie Bij Reumatoïde Artritis) clinical trial and followup study, a randomized controlled trial comparing the efficacy of oral pulse prednisolone, methotrexate, plus sulfasalazine with sulfasalazine alone. We investigated the relationship between baseline levels of urinary CTX-I and CTX-II and the mean annual progression of joint destruction over a median of 4 years, as measured by changes in the modified Sharp score (average of 2 independent readers). In multivariate logistic regression analysis, baseline urinary CTX-I and CTX-II levels in the highest tertile were the strongest predictors of radiologic progression (Sharp score increase >2 units/year; odds ratio 7.9 and 11.2, respectively), independently of treatment group, erythrocyte sedimentation rate (ESR), Disease Activity Score in 28 joints, rheumatoid factor (RF), and baseline joint damage (Sharp score). The likelihood ratios for a positive test were 3.8 and 8.0 for CTX-I and CTX-II, respectively, which compared favorably with the likelihood ratios for the ESR (3.0), baseline joint damage (1.6), and RF (1.8). When patients were grouped according to the presence (Sharp score ≥4, n = 49) and absence (Sharp score <4, n = 61) of joint damage at baseline, CTX-I and CTX-II levels were predictive only in those without baseline joint damage (odds ratio 14.9 and 25.7, respectively). High baseline levels of urinary CTX-I and CTX-II independently predict an increased risk of radiologic progression over 4 years in patients with early RA, especially those without radiologic joint damage. Urinary CTX-I and CTX-II may be useful for identifying individual RA patients at high risk of progression very early in the disease, before erosions can be detected radiographically. Such patients may be in special need of treatments that inhibit bone and cartilage degradation.

The hallmark of osteoarthritis (OA) is the loss of articular cartilage. This loss arises from an imbalance between cartilage synthesis and cartilage degradation over a variable period of time. The aims of this study were to investigate the rates of these processes in patients with knee OA using two new molecular markers and to investigate whether the combined use of these markers could predict the progression of joint damage evaluated by both radiography and arthroscopy of the joints during a period of 1 year. Seventy-five patients with medial knee OA (51 women, 24 men; mean ± SD age 63 ± 8 years, mean ± SD disease duration 4.8 ± 5.2 years) were studied prospectively. At baseline, we measured serum levels of N-propeptide of type IIA procollagen (PIIANP) and urinary excretion of C-terminal crosslinking telopeptide of type II collagen (CTX-II) as markers of type II collagen synthesis and degradation, respectively. Joint space width (JSW) on radiography and medial chondropathy at arthroscopy (assessed using a 100-mm visual analog scale [VAS]) were measured in all patients at baseline and in 52 patients at 1 year. Progression of joint destruction was defined as a decrease of ≥0.5 mm in JSW on radiography and as increased chondropathy (an increase in the VAS score of >8.0 units) between the baseline and 1-year evaluations. At baseline, compared with 58 healthy age- and sex-matched controls, patients with knee OA had decreased serum levels of PIIANP (20 ng/ml versus 29 ng/ml; P < 0.001) and increased urinary excretion of CTX-II (618 ng/mmole creatinine [Cr] versus 367 ng/mmole Cr; P < 0.001). The highest discrimination between OA patients and controls was obtained by combining PIIANP and CTX-II in an uncoupling index (Z score CTX-II − Z score PIIANP), which yielded a mean Z score of 2.9 (P < 0.0001). Increased baseline values in the uncoupling index were associated with greater progression of joint damage evaluated either by changes in JSW (r = −0.46, P = 0.0016) or by VAS score (r = 0.36, P = 0.014). Patients with both low levels of PIIANP (less than or equal to the mean − 1 SD in controls) and high levels of CTX-II (greater than or equal to the mean + 1 SD in controls) had an 8-fold more rapid progression of joint damage than other patients (P = 0.012 and P < 0.0001 as assessed by radiography and arthroscopy, respectively) and had relative risks of progression of 2.9 (95% confidence interval [95% CI] 0.80–11.1) and 9.3 (95% CI 2.2–39) by radiography and arthroscopy, respectively. Patients with knee OA are characterized by an uncoupling of type II collagen synthesis and degradation which can be detected by assays for serum PIIANP and urinary CTX-II. The combination of these two new markers could be useful for identifying knee OA patients at high risk for rapid progression of joint damage.

To evaluate whether measurements of urinary glucosyl-galactosyl-pyridinoline (Glc-Gal-PYD) and urinary C-terminal crosslinking telopeptide of type II collagen (CTX-II), 2 new markers of destruction of the synovium and cartilage collagen breakdown, respectively, are associated with the progression of joint damage in patients with early rheumatoid arthritis (RA), and to compare this association with that with serum matrix metalloproteinase 3 (MMP-3), a proteinase expressed by synovial tissue and chondrocytes, and that with serum C-reactive protein (CRP), an index of systemic inflammation. The prospective study cohort comprised 116 patients with early RA who were part of a large, double-blind, randomized study comparing the efficacy of etanercept and methotrexate. The relationship between baseline levels of urinary Glc-Gal-PYD, urinary CTX-II, and serum MMP-3 and the progression of joint destruction, as measured by changes in the modified Sharp score (average findings of 2 independent readers) over 1 year, was investigated. Levels of urinary Glc-Gal-PYD (+70%), urinary CTX-II (+104%), and serum MMP-3 (+219%) were elevated compared with the levels in 76 healthy controls. The baseline levels of Glc-Gal-PYD (r = 0.30), CTX-II (r = 0.25), and MMP-3 (r = 0.29) correlated with the changes over 1 year in the total Sharp score (joint space narrowing and bone erosion). Patients with baseline levels of Glc-Gal-PYD, CTX-II, and MMP-3 that were higher than the mean + 2 SD in healthy controls had a significantly greater progression of joint damage, with an increase in the total Sharp score over 1 year that was from 3- to 8-fold higher than that in patients with low baseline levels of these markers. Moreover, patients with these higher levels of Glc-Gal-PYD, CTX-II, and MMP-3 had a higher risk of progression of the disease (increase in total Sharp score ≥0.5 units) than did the other patients (relative risks and 95% confidence intervals [95% CI] 3.3 [95% CI 1.5–7.4], 2.5 [95% CI 1.1–5.7], and 2.5 [95% CI 1.1–5.6], respectively). The baseline serum level of CRP was not significantly associated with the progression of joint damage. Adjustment of the levels of Glc-Gal-PYD, CTX-II, and MMP-3 according to radiologic damage at baseline did not alter their association with progression. After adjustment for serum CRP, the relative risk slightly decreased, but remained significant, for Glc-Gal-PYD (2.6 [95% CI 1.1–6.3]). Patients with both increased levels of the molecular markers and radiologic damage at baseline had a higher risk of progression of joint damage than did those with either high molecular marker levels or radiologic damage. High baseline levels of Glc-Gal-PYD, CTX-II, and MMP-3 are associated with increased risk of progression of joint destruction over 1 year in early RA. The association between baseline levels of urinary Glc-Gal-PYD and progression of joint erosion was independent of the severity of radiologic damage and inflammation at baseline. Combining the measurements of these molecular markers with radiologic assessment of joint damage may be useful for identifying patients with RA who are at high risk of rapid progression and for whom early aggressive treatment would be beneficial.

No abstract.