Decrease in serum level of matrix metalloproteinases is predictive of the disease-modifying effect of osteoarthritis drugs assessed by quantitative MRI in patients with knee osteoarthritis.
OBJECTIVE
To explore the impact of disease-modifying osteoarthritis drug (DMOAD) treatment on biomarker levels and their correlation with cartilage volume loss and disease symptoms in a 2-year phase III clinical trial in patients with knee OA.


METHODS
161 patients with knee OA (according-to-protocol population) were selected from a 2-year DMOAD trial studying the effect of licofelone (200 mg twice daily) versus naproxen (500 mg twice daily). Clinical evaluation of patients was carried out using the Western Ontario and McMaster Universities (WOMAC) questionnaire. Biomarker measurements of matrix metalloproteinase (MMP)-1, MMP-3, interleukin (IL)-6, C reactive protein (CRP), cartilage oligomeric matrix protein (COMP) and type I collagen C-terminal telopeptide (CTX-I) in serum, type II collagen C-terminal telopeptide (CTX-II) in urine, and knee MRI were performed at baseline and 2 years.


RESULTS
Over time an increase occurred in all biomarker levels with the exception of IL-6, CRP and CTX-II which decreased. The increase in MMP-1 and MMP-3 was significantly less (p = 0.05; p < 0.01, respectively) in the licofelone group. The baseline MMP-1 level was significantly but inversely predictive of cartilage volume loss for the medial compartment in both univariate (p = 0.04) and multivariate (p ≤ 0.04) regression analyses, and COMP, a predictor for the lateral compartment, in both univariate and multivariate models (p < 0.01). Baseline levels of IL-6 and CRP also showed a significant relationship with volume loss for the medial compartment (univariate analysis, p = 0.04 and p = 0.01, respectively; multivariate analysis, p = 0.03, p = 0.01). A significant association (univariate) was observed between the change in the levels of MMP-1 (p = 0.03) and MMP-3 (p = 0.02) and cartilage volume loss (lateral compartment) over 2 years. Baseline levels of CTX-I correlated (p = 0.02) with an increase in the size of the bone marrow lesion in the medial compartment. The baseline CRP levels correlated with worsening of symptoms: WOMAC total index (p < 0.01), pain (p < 0.01) and function (p < 0.01).


CONCLUSIONS
Higher baseline values of IL-6, CRP and COMP are predictive of greater risk of cartilage loss in OA. However, over time a reduction in MMP-1 and MMP-3 levels correlated best with reduction in cartilage volume loss and the effect of drug treatment. Baseline CRP was found to be a good predictor of the symptomatic response to treatment.
Pelletier
J-P
JP
Osteoarthritis Research Unit, University of Montreal Hospital Research Centre (CRCHUM), Notre-Dame Hospital, Montreal, Quebec H2L 4M1, Canada. dr@jppelletier.ca
Raynauld
J-P
JP
Caron
J
J
Mineau
F
F
Abram
F
F
Dorais
M
M
Haraoui
B
B
Choquette
D
D
Martel-Pelletier
J
J
D000368:Aged; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D015415:Biomarkers / Q000097:blood; D002097:C-Reactive Protein / Q000378:metabolism; D002358:Cartilage, Articular / Q000473:pathology; D016903:Drug Monitoring / Q000379:methods; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D020782:Matrix Metalloproteinases / Q000097:blood*; D008875:Middle Aged; D009288:Naproxen / Q000627:therapeutic use; D020370:Osteoarthritis, Knee / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D011758:Pyrroles / Q000627:therapeutic use; D012720:Severity of Illness Index; D016896:Treatment Outcome
D000894:Anti-Inflammatory Agents, Non-Steroidal; D015415:Biomarkers; D011758:Pyrroles; D009288:Naproxen; D002097:C-Reactive Protein; D020782:Matrix Metalloproteinases; C088092:licofelone