J.-P. Pelletier

Therapeutic role of dual inhibitors of 5-LOX and COX, selective and non-selective non-steroidal anti-inflammatory drugs

Dual 5-LOX/COX inhibitors are potential new drugs to treat inflammation. They act by blocking the formation of both prostaglandins and leucotrienes but do not affect lipoxin formation. Such combined inhibition avoids some of the disadvantages of selective COX-2 inhibitors and spares the gatrointestinal mucosa.

Correlation between bone lesion changes and cartilage volume loss in patients with osteoarthritis of the knee as assessed by quantitative magnetic resonance imaging over a 24-month period

Objective: To evaluate in patients with knee osteoarthritis (OA) the size changes in bone oedema and cysts over 24 months, and to contrast these changes with cartilage volume loss using quantitative magnetic resonance imaging. Methods: 107 patients with knee OA, selected from a large trial evaluating the effect of a bisphosphonate, were analysed by magnetic resonance imaging at baseline and 24 months. Assessments of subchondral bone oedema and cysts, and cartilage volume were done. Results: At baseline, 86 patients showed the presence of at least one type of bone lesion: 71 oedema, 61 cysts and 51 both. At 24 months, although not statistically significant, the oedema total size change increased by 2.09 (SD 15.03) mm, and the cyst by 1.09 (8.13) mm; mean size change for the oedema was +0.38 (2.18) mm and −0.10 (4.36) mm for the cyst. When analysed according to subregions, an increase was found for the cyst size in the trochlea (+0.67 (2.74) mm, p = 0.02) and in the lateral tibial plateau (+0.15 (0.83) mm, p = 0.09), and for the oedema size in the medial tibial plateau (+1.73 (8.11) mm, p = 0.05). At 24 months, significant correlations were seen between the loss of cartilage volume and oedema size change in the medial condyle (−0.40, p = 0.0001) and the medial tibial plateau (−0.23, p = 0.03), and the changes in cyst size in the medial condyle (−0.29, p = 0.01). A multivariate analysis showed that the oedema size change was strongly and independently associated with medial cartilage volume loss (−0.31, p = 0.0004). Conclusion: These data demonstrate that bone lesions are prevalent in knee OA. The correlation of the oedema and cyst size increase in the medial compartment over time with a greater loss of cartilage volume in this area underlines the importance of subchondral bone lesions in OA pathophysiology.

IGF/IGFBP axis in cartilage and bone in osteoarthritis pathogenesis

Abstract. In the context of joint biology, insulin-like growth factor-1 (IGF-1) is the most likely candidate to affect the anabolism of cartilage matrix molecules. Mechanisms for controlling the effects of IGF-1 include alterations in the level of this growth factor, its receptor and/or the IGF-1 affinity or availability to its receptor. Disturbance of any one of the above elements may induce a disregulation of the mechanisms involved in the local control of joint tissue integrity. This review focuses on recent studies of the IGF system, and the potential relevance of these results to in vivo effects in osteoarthritic (OA) tissues. It has been shown that, although the IGF-1s expression and synthesis are increased in OA cartilage, chondrocytes are hyporesponsive to IGF-1 stimulation. This phenomenon appears to be related, at least in part, to an increased level of IGF-binding proteins (IGFBP). The IGFBP have a high affinity for IGF-1, and appear to be important biomodulators for IGF action. Though to date seven IGFBP have been cloned and sequenced, disregulation in IGFBP-3 and -4 appears instrumental to arthritic disorders. Proteolytic activity directed against IGFBP has been found in both cartilage and bone; this activity appears to belong to serine- and/or metallo-proteases families. It has been suggested that a thickening of the subchondral bone participates in OA pathophysiology, and that IGF-1 production by bone and/or subchondral bone cells may contribute to these changes. An abnormal regulation of subchondral bone formation via an increase in the local activation of IGF-1 in bone cells, possibly via abnormal IGFBP synthesis due to aberrant PA/plasmin regulation of the IGF-1/IGFBP system, is believed to be a plausible hypothesis.

Reliability of a quantification imaging system using magnetic resonance images to measure cartilage thickness and volume in human normal and osteoarthritic knees

OBJECTIVE The aim of this study was to evaluate the reliability of a software tool that assesses knee cartilage volumes using magnetic resonance (MR) images. The objectives were to assess measurement reliability by: (1) determining the differences between readings of the same image made by the same reader 2 weeks apart (test-retest reliability), (2) determining the differences between the readings of the same image made by different readers (between-reader agreement), and (3) determining the differences between the cartilage volume readings obtained from two MR images of the same knee image acquired a few hours apart (patient positioning reliability). METHODS Forty-eight MR examinations of the knee from normal subjects, patients with different stages of symptomatic knee osteoarthritis (OA), and a subset of duplicate images were independently and blindly quantified by three readers using the imaging system. The following cartilage areas were analyzed to compute volumes: global cartilage, medial and lateral compartments, and medial and lateral femoral condyles. RESULTS Between-reader agreement of measurements was excellent, as shown by intra-class correlation (ICC) coefficients ranging from 0.958 to 0.997 for global cartilage (P<0.0001), 0.974 to 0.998 for the compartments (P<0.0001), and 0.943 to 0.999 for the condyles(P<0.0001). Test-retest reliability of within-reader data was also excellent, with Pearson correlation coefficients ranging from 0.978 to 0.999 (P<0.0001). Patient positioning reliability was also excellent, with Pearson correlation coefficients ranging from 0.978 to 0.999 (P<0.0001). CONCLUSIONS The results of this study establish the reliability of this MR imaging system. Test-retest reliability, between-reader agreement, and patient positioning reliability were all extremely high. This study represents a first step in the overall validation of an imaging system designed to follow progression of human knee OA.

Protective effects of licofelone, a 5-lipoxygenase and cyclo-oxygenase inhibitor, versus naproxen on cartilage loss in knee osteoarthritis: a first multicentre clinical trial using quantitative MRI

Objective: In a multicentre study to explore the effects of licofelone as a disease-modifying osteoarthritis drug in comparison with naproxen in patients with knee osteoarthritis (OA), using MRI and x-ray examination. Methods: Patients with knee OA (n = 355) were randomised to receive either licofelone (200 mg twice a day) or naproxen (500 mg twice a day). MRI and x-ray examinations were performed at baseline, 6 months (MRI only), 12 and 24 months. MRI was used to assess quantitatively changes in cartilage volume, and x-ray examinations (Lyon–Schuss) to measure changes in the mean and minimum joint space width (JSW) in the medial compartment. Questionnaires probing symptoms were completed. Data were presented as intention to treat (ITT) and according to protocol (ATP). Results: Cartilage volume loss in the global joint and medial and lateral compartments was significantly less in the licofelone than in the naproxen group for ITT at 12 and 24 months and for ATP at all times except in the medial compartment. Patients with medial meniscal extrusion had a greater loss of cartilage volume. In these patients, licofelone markedly reduced the cartilage loss for both ITT and ATP at 12 and 24 months. Although licofelone showed less reduction in the JSW than naproxen, this did not reach significance. All clinical variables were improved at 24 months (p<0.001) for both groups, with a good safety profile. Conclusion: Licofelone and naproxen were equally effective in reducing OA symptoms; however, licofelone significantly reduced cartilage volume loss over time, thus having a protective effect in patients with knee OA. This study proves the superiority of quantitative MRI over x-ray examinations in a multicentre clinical trial.

Computer-aided method for quantification of cartilage thickness and volume changes using MRI: validation study using a synthetic model

The primary objective of this study was to develop a computer-aided method for the quantification of three-dimensional (3-D) cartilage changes over time in knees with osteoarthritis (OA). We introduced a local coordinate system (LCS) for the femoral and tibial cartilage boundaries that provides a standardized representation of cartilage geometry, thickness, and volume. The LCS can be registered in different data sets from the same patient so that results can be directly compared. Cartilage boundaries are segmented from 3-D magnetic resonance (MR) slices with a semi-automated method and transformed into offset-maps , defined by the LCS. Volumes and thickness are computed from these offset-maps. Further anatomical labeling allows focal volumes to be evaluated in predefined subregions. The accuracy of the automated behavior of the method was assessed, without any human intervention, using realistic, synthetic 3-D MR images of a human knee. The error in thickness evaluation is lower than 0.12 mm for the tibia and femur. Cartilage volumes in anatomical subregions show a coefficient of variation ranging from 0.11% to 0.32%. This method improves noninvasive 3-D analysis of cartilage thickness and volume and is well suited for in vivo follow-up clinical studies of OA knees.

The OARSI histopathology initiative - recommendations for histological assessments of osteoarthritis in the dog.

The dog is a common model for study of osteoarthritis (OA). Subjective histologic scoring systems have often served as the reference standard for presence and severity of OA. However, these scoring systems have perceived shortcomings. The system developed for this report attempts to address these shortcomings by providing a standardized methodology for global assessment of the joint, versatility and the potential for relative weighting of pathology, allowing for comparison among time points, studies, and centers, and critical analysis of the systems reliability. The proposed system for assessment of canine tissues appears to provide an effective method for global assessment of articular pathology in OA. The system is versatile, comprehensive, and reliable and appears to have advantages over conventional scoring systems.

Histone deacetylase inhibitors suppress interleukin-1β-induced nitric oxide and prostaglandin E2 production in human chondrocytes

OBJECTIVE Overproduction of nitric oxide (NO) and prostaglandin E(2) (PGE(2)) plays an important role in the pathogenesis of osteoarthritis (OA). In the present study, we determined the effect of trichostatin A (TSA) and butyric acid (BA), two histone deacetylase (HDAC) inhibitors, on NO and PGE(2) synthesis, inducible NO synthase (iNOS) and cyclooxygenase (COX)-2 expression, and nuclear factor (NF)-kappaB DNA-binding activity, in interleukin-1beta (IL-1)-stimulated human OA chondrocytes, and on IL-1-induced proteoglycan degradation in cartilage explants. METHODS Chondrocytes were stimulated with IL-1 in the absence or presence of increasing concentrations of TSA or BA. The production of NO and PGE(2) was evaluated using Griess reagent and an enzyme immunoassay, respectively. The expression of iNOS and COX-2 proteins and mRNAs was evaluated using Western blotting and real-time reverse transcriptase-polymerase chain reaction (RT-PCR), respectively. Proteoglycan degradation was measured with dimethymethylene blue assay. Electrophoretic mobility shift assay (EMSA) was utilized to analyze the DNA-binding activity of NF-kappaB. RESULTS HDAC inhibition with TSA or BA resulted in a dose-dependent inhibition of IL-1-induced NO and PGE(2) production. IL-17- and tumor necrosis factor-alpha (TNF-alpha)-induced NO and PGE(2) production was also inhibited by TSA and BA. This inhibition correlated with the suppression of iNOS and COX-2 protein and mRNA expression. TSA and BA also prevented IL-1-induced proteoglycan release from cartilage explants. Finally, we demonstrate that the DNA-binding activity of NF-kappaB, was induced by IL-1, but was not affected by treatment with HDAC inhibitors. CONCLUSIONS These data indicate that HDAC inhibitors suppressed IL-1-induced NO and PGE(2) synthesis, iNOS and COX-2 expression, as well as proteoglycan degradation. The suppressive effect of HDAC inhibitors is not due to impaired DNA-binding activity of NF-kappaB. These findings also suggest that HDAC inhibitors may be of potential therapeutic value in the treatment of OA.

A new non-invasive method to assess synovitis severity in relation to symptoms and cartilage volume loss in knee osteoarthritis patients using MRI.

OBJECTIVES Synovitis in knee osteoarthritis (OA) patients is a significant risk factor for disease progression. This study aimed at developing a magnetic resonance imaging (MRI) scoring system allowing reliable and sensitive assessment of synovitis severity in knee OA patients without the use of a contrast agent. METHODS Imaging was performed without contrast agent, using a 1.5T and a knee coil. For the synovial membrane, the MRI exam included two axial sequences: a T2-weighted (synovial fluid) and a gradient echo (GRE) (synovial membrane). Synovial membrane thickness was measured on four regions of interest (ROI): medial and lateral recesses, and medial and lateral suprapatellar bursa, with each graded/scored from 0 to 3, for a maximum of 12. A validation study was performed on a cohort of 27 knee OA patients having MRI at baseline. A subset of 14 patients had an additional MRI acquisition and symptom assessment at Day 60. Evaluation of disease symptoms was done with Western Ontario and McMaster Universities OA Index and visual analog scale, and of cartilage volume, menisci and subchondral bone, with MR images from a 3D spoiled gradient recalled (SPGR) sequence. RESULTS The synovial membrane thickness grade was 1.9+/-0.5 (mean+/-SD) with a score of 7.1+/-2.3. The intra-reader (r=0.91) and inter-reader (r=0.82) correlation coefficients were excellent (P<0.0001). The medial compartment grade was 1.9+/-0.6 and score was 3.4+/-1.4, and of the lateral compartment were 2.0+/-0.7 and 3.7+/-1.5, respectively. The grade and score for the suprapatellar bursa and recess were 1.8+/-0.7 and 3.5+/-1.5, and 2.1+/-0.5 and 3.9+/-0.9, respectively. No statistically significant differences in the ROI score and grade were observed between medial and lateral compartments or between recess and suprapatellar bursa. A positive correlation was found between the global severity of synovitis at baseline and the presence of a medial meniscal extrusion (P<0.04), and the loss of cartilage volume at 60 days (P<0.03). CONCLUSION This newly developed MRI technology for the assessment of synovial membrane thickness in knee OA patients was shown to be accurate and reproducible.

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

Objectives 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). Conclusion 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.