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Biochemical Markers for Rheumatoid Arthritis

Biochemical markers of tissue turnover have been used for decades in clinical trials of osteoporosis, but only recently in rheumatoid arthritis. In contrast to serum C-reactive protein (CRP), which is only a nonspecific indicator of systemic inflammation and not directly reflective of structural damage to joints, more recently developed biochemical markers of synovial, cartilage and bone turnover provide a better indication of destructive activity of the disease. Molecular markers are particularly useful for patient selection and treatment, but can be used in a variety of ways to accelerate clinical trials and reduce the uncertainty and cost of drug development.

SYNARC’s founding scientists pioneered the development of a number of biochemical markers of bone, cartilage and synovium to evaluate osteoporosis and rheumatoid arthritis in clinical trials. Dr. Garnero, Vice President of the Molecular Marker Division of SYNARC participated in the development of assays for osteocalcin and type I collagen crosslinks, as markers of bone formation and degradation, respectively. More recently, SYNARC has developed a unique molecular marker specific for the degradation of type II collagen, a major constituent of articular cartilage matrix. Dr. Garnero was one of the first to evaluate the technical performance of these new biochemical markers, to establish their reference ranges in large populations of healthy individuals, and to quantify bone, cartilage and synovium turnover in patients with rheumatoid arthritis.

Increased levels of biochemical markers of bone degradation are associated with bone erosion. The graph shows the rate of bone formation assessed with serum osteocalcin and of bone degradation assessed with serum C-terminal cross-linking type I collagen (CTX-I) in a large group of healthy controls and patients with rheumatoid arthritis, with and without evidence of joint damage. Note the increased levels of bone resorption in patients with destructive disease (Garnero, et al. Bone 1999).

 

Molecular markers of Synovium and cartilage destruction at baseline predict progression in RA. In the study, 116 patients with early RA were followed for one year. The graphs show that patients with increased levels of a new specific marker of synovium turnover) or C-terminal cross-linking telopeptide of type II collagen (CTX-II, a new specific marker of cartilage degradation) had a 3- to 8-fold greater rate of progression of joint damage (radiographic Sharp score) over 1 year than did patients with normal levels (Garnero et al., Arthritis Rheum, 2002).

 

Combination of molecular and radiographic markers improve prediction of progression in early RA. In the study, 116 patients with early RA were prospectively followed for one year. Progression was defined as an increase of radiolographic Sharp score >0.5 units. Patients with high joint damage at baseline (Sharp score in the highest tertile) had a 2.4-fold greater risk of progression than did the other patients. Those with high baseline urinary levels of a specific marker of synovium turnover had a 3-fold greater risk of progression. Combining the molecular marker of synovium turnover with the radiolographic marker of joint damage improved prediction of progression to 4.9-fold.

 

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