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OA/RA Drug Development

Inflamation and Synovitis, YKL-40, PIINP, CRP

Inflammation and Synovitis 
In addition to bone and cartilage, the third important tissue compartment in the joint is the synovium. The importance of synovitis in the pathogenesis of rheumatoid arthritis (RA) is well recognized, and the destructive component of the disease is ascribed to a proliferative synovitis known as the pannus (1). Osteoarthritis (OA) has long been considered a degenerative disease, but recent evidence suggests that there is also a significant inflammatory component with synovitis (2, 3). Many of the markers of systemic inflammation likely also reflect local synovitis in the joint. Markers of systemic inflammation include CRP, fibrinogen, various cytokines, such as TNF-α and interleukins (IL-1, -2, -6, -10, etc.), and soluble adhesion molecules, such as E-selectin, ICAM-1 and VCAM-1. These markers are useful in measuring the state of the inflammatory activation, and the response to therapy, but changes in serum levels in these markers are not informative about specific events in the joints. A more specific marker of synovial involvement in both RA and OA is the N-propeptide of type III collagen (PIIINP), for which a serum assay is available. Another marker that has been found to correlate with joint inflammation is YKL-40, also known as human cartilage glycoprotein 39. YKL-40, PIIINP, and CRP are discussed further below.

YKL – 40 
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Several studies have shown that serum levels of YKL-40 are significantly increased (1.5-3-fold) in both RA and OA patients. Moreover, increased serum levels of YKL-40 in both RA and OA were significantly correlated with increased levels of YKL-40 in synovial fluid (10-15 higher than in serum), suggesting that the increased serum levels derived from arthritic joints (1, 2). In RA patients treated with disease-modifying therapy, there was a significant (21%) decrease in serum YKL-40 levels among responders (1). YKL-40 levels are increased in a broad spectrum of inflammatory arthritides, but the highest levels are found in RA (3, 4). Interestingly, YKL-40 levels correlate with markers of systemic inflammation, such as CRP, SAA, and ESR, but YKL- 40 is more specific for joint disease, and may reflect both cartilage damage and synovitis (3-5).

YKL-40 is clearly a promising marker for monitoring treatment response in both RA and OA, but it is important to note that YKL-40 is not specific for joints and that serum levels can change in cancer, cirrhosis, and possibly atherosclerosis (6). In OA, YKL-40 levels may enable stratification of patients into those with evidence of joint inflammation and/or polyarticular disease, especially if augmented with markers such as PIIINP and CRP (7).

Biochemical Markers of Synovitis – PIIINP 
A specific marker of synovial involvement in both OA and RA is the N-propeptide of type III collagen (PIIINP), for which a serum assay is available. In a recent cross-sectional study of knee OA, PIIINP was highly significantly correlated with radiographic joint damage as well as with WOMAC indices of pain and stiffness (1). PIIINP was also found to cluster with synovitis in the hip-OA ECHODIAH cohort (2). Type III collagen, however, is not specific for synovium and elevated PIIINP levels are also found in psoriatic patients with liver fibrosis after methotrexate therapy (3) and in scleroderma (4). Another marker that has been correlated with synovitis, and which appears to provide similar information to PIIINP, is urinary glucosyl-galactosyl pyridinoline (1).

Biochemical Markers of Inflammation – CRP 
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Measurement of CRP is informative about the level of systemic inflammation and polyarticular disease in OA, and may stratify patients into those with earlier and/or rapidly progressive disease. CRP levels also add to the information obtained from tests for serum YKL-40 and PIINP.

References

1. Smolen, J.S. & Steiner, G. Nature Rev. Drug Disc. 2: 473-488, 2003. 2. Sharif, M. et al. Ann. Rheum. Dis. 55: 47-51, 1996. 3. Wollheim, F.A. Ann. Rheum. Dis. 62: 1031-1032, 2003.

1. Harvey, S. et al. Clin. Chem. 44: 509-516, 1998. 2. Johansen, J.S. et al. Br. J. Rheumatol. 35: 553-559, 1996. 3. Vos, K. et al. Ann. Rheum. Dis. 59: 544-548, 2000. 4. Bernardi, D. et al. Clin. Chem. 49: 1685-1688, 2003. 5. Conrozier, T. et al. Ann. Rheum. Dis. 59: 828-831, 2000. 6. Register, T.C. et al. Clin. Chem. 47: 2159-2161, 2001. 7. Takahashi, M. et al. Arthr. Res. Ther. 6: R208-R212, 2004.

1. Garnero, P. et al. Ann. Rheum. Dis. 60: 619-626, 2001. 2. Garnero, P. et al. Arthr. Rheum. 48(9): S291, 2003. 3. Zacariae, H. et al. Br. J. Dermatol. 144: 100-103, 2001. 4. Sondergaard, K. et al. Br. J. Dermatol. 136: 47-53, 1997.

1. Smolen, J.S. & Steiner, G. Nature Rev. Drug Disc. 2: 473-488, 2003. 2. Wollheim, F.A. Ann. Rheum. Dis. 62: 1031- 1032, 2003. 3. Garnero, P. et al. Ann. Rheum. Dis. 60: 619-626, 2001. 4. Garnero, P. et al. Arthr. Rheum. 48(9): S291, 2003. 5. Conrozier, T. et al. Ann. Rheum. Dis.59: 828-831, 2000.

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