J.-P. Raynauld

Value of biomarkers in osteoarthritis: current status and perspectives.

Osteoarthritis affects the whole joint structure with progressive changes in cartilage, menisci, ligaments and subchondral bone, and synovial inflammation. Biomarkers are being developed to quantify joint remodelling and disease progression. This article was prepared following a working meeting of the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis convened to discuss the value of biochemical markers of matrix metabolism in drug development in osteoarthritis. The best candidates are generally molecules or molecular fragments present in cartilage, bone or synovium and may be specific to one type of joint tissue or common to them all. Many currently investigated biomarkers are associated with collagen metabolism in cartilage or bone, or aggrecan metabolism in cartilage. Other biomarkers are related to non-collagenous proteins, inflammation and/or fibrosis. Biomarkers in osteoarthritis can be categorised using the burden of disease, investigative, prognostic, efficacy of intervention, diagnostic and safety classification. There are a number of promising candidates, notably urinary C-terminal telopeptide of collagen type II and serum cartilage oligomeric protein, although none is sufficiently discriminating to differentiate between individual patients and controls (diagnostic) or between patients with different disease severities (burden of disease), predict prognosis in individuals with or without osteoarthritis (prognostic) or perform so consistently that it could function as a surrogate outcome in clinical trials (efficacy of intervention). Future avenues for research include exploration of underlying mechanisms of disease and development of new biomarkers; technological development; the ‘omics’ (genomics, metabolomics, proteomics and lipidomics); design of aggregate scores combining a panel of biomarkers and/or imaging markers into single diagnostic algorithms; and investigation into the relationship between biomarkers and prognosis.

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.

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.

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.

What is the predictive value of MRI for the occurrence of knee replacement surgery in knee osteoarthritis

Knee osteoarthritis is associated with structural changes in the joint. Despite its many drawbacks, radiography is the current standard for evaluating joint structure in trials of potential disease-modifying osteoarthritis drugs. MRI is a non-invasive alternative that provides comprehensive imaging of the whole joint. Frequently used MRI measurements in knee osteoarthritis are cartilage volume and thickness; others include synovitis, synovial fluid effusions, bone marrow lesions (BML) and meniscal damage. Joint replacement is considered a clinically relevant outcome in knee osteoarthritis; however, its utility in clinical trials is limited. An alternative is virtual knee replacement on the basis of symptoms and structural damage. MRI may prove to be a good alternative to radiography in definitions of knee replacement. One of the MRI parameters that predicts knee replacement is medial compartment cartilage volume/thickness, which correlates with radiographic joint space width, is sensitive to change, and predicts outcomes in a continuous manner. Other MRI parameters include BML and meniscal lesions. MRI appears to be a viable alternative to radiography for the evaluation of structural changes in knee osteoarthritis and prediction of joint replacement.

OARSI Clinical Trials Recommendations: Knee imaging in clinical trials inosteoarthritis

Significant advances have occurred in our understanding of the pathogenesis of knee osteoarthritis (OA) and some recent trials have demonstrated the potential for modification of the disease course. The purpose of this expert opinion, consensus driven exercise is to provide detail on how one might use and apply knee imaging in knee OA trials. It includes information on acquisition methods/techniques (including guidance on positioning for radiography, sequence/protocol recommendations/hardware for magnetic resonance imaging (MRI)); commonly encountered problems (including positioning, hardware and coil failures, sequences artifacts); quality assurance (QA)/control procedures; measurement methods; measurement performance (reliability, responsiveness, validity); recommendations for trials; and research recommendations.

Temporal assessment of bone marrow lesions on magnetic resonance imaging in a canine model of knee osteoarthritis: impact of sequence selection

OBJECTIVE To assess the evolution of bone marrow lesions (BMLs) in a canine model of knee osteoarthritis (OA) using three different magnetic resonance imaging (MRI) sequences. DESIGN Three MRI sequences [coronal, T1-weighted three-dimensional fast gradient recalled echo (T1-GRE), sagittal fat-suppressed 3D spoiled gradient echo at a steady state (SPGR), and sagittal T2-weighted fast spin echo with fat saturation (T2-FS)] were performed at baseline, and at week 4, 8 and 26 in five dogs following transection of the anterior cruciate ligament. The same reader scored (0-3) subchondral BMLs twice, in blinded conditions, according to their extent in nine joint subregions, for all imaging sessions, and independently on the three MRI sequences. Correlation coefficients and Bland-Altman plots evaluated intra-reader repeatability. Readings scores were averaged and the nine subregions were summed to generate global BML scores. RESULTS BMLs were most prevalent in the central and medial portions of the tibial plateau. Intra-reader repeatability was good to excellent for each sequence (r(s)=0.87-0.97; P<0.001). Maximal intra-reader variability (24%) was reached on T2-FS and was associated to higher scores (P<0.05). Global BML scores increased similarly on all three sequences until week 8 (P<0.05). At week 26, score on T2-FS was decreased, being lower when compared to T1-GRE and SPGR (P<0.05). CONCLUSION In this canine OA model, the extent of BMLs varies in time on different MRI sequences. Until the complex nature of these lesions is fully resolved, it is suggested that to accurately assess the size and extent of BMLs, a combination of different sequences should be used.

Association of polymorphisms in the peroxisome proliferator-activated receptor γ gene and osteoarthritis of the knee

Objectives: To study the association between two common polymorphisms in the peroxisome proliferator-activated receptor γ (PPARγ) gene and susceptibility to, and severity of, osteoarthritis in a French-Canadian population. Methods: Genomic DNA was obtained from 172 patients with osteoarthritis and 210 ethnically matched healthy controls. Genotyping for the polymorphisms in the PPARγ gene (Pro12Ala and C1431T) was carried out using polymerase chain reaction–restriction fragment length polymorphism. The standard Kellgren–Lawrence grading score and the French version of the Western Ontario and McMaster Universities Osteoarthritis Index were used to assess the radiological and functional severity of the disease. Estimated haplotypes were generated using the expectation maximisation algorithm. Genotype and allele frequencies were analysed using the χ2 test. Results: Genotype and allele frequencies for either polymorphism in the PPARγ gene did not differ significantly between patients with osteoarthritis and controls. Moreover, no significant differences were observed after stratification of patients according to age at disease onset, radiological or functional severity. Similarly, haplotype analysis of both polymorphisms in the PPARγ gene showed no association of any haplotype with susceptibility to, or severity of, osteoarthritis. Conclusion: These findings suggest that the examined polymorphisms in the PPARγ gene do not contribute to susceptibility to, or severity of, osteoarthritis in the French-Canadian population.

SAT0336 The Long-Term Effects of Sysadoa Treatment on Knee Osteoarthritis Symptoms and Progression of Structural Changes: Participants from the Osteoarthritis Initiative Progression Cohort

Objectives To explore the effects of commonly used medications for treatment of knee osteoarthritis (OA) on structural progression. Methods Participants (n=600) were selected from the Osteoarthritis Initiative (OAI) progression cohort (http://www.oai.ucsf.edu/) (n=1,390) who met the following criteria: 24 consecutive months of follow-up with clinical and imaging data including radiographs and magnetic resonance imaging (MRI) of the index (highest WOMAC pain) knee. Data for joint space width (JSW) were obtained from the OAI database and cartilage volume was measured using fully-automated MRI. Results Participants reported taking (+) (n=300) or not taking (-) (n=300) OA treatment (analgesic/NSAID) over 24 months, with or without glucosamine and chondroitin sulfate (Glu/CS). The +analgesic/NSAID subjects had higher WOMAC scores (p<0.0001) and smaller JSW (p=0.013) reflecting more severe disease at baseline. In the -analgesic/NSAID group, subjects taking Glu/CS had a smaller loss of JSW at 12 months (p=0.057) and cartilage volume at 24 months in the medial central tibial plateau (p=0.022 univariate and p=0.025 multivariate analysis). In the +analgesic/NSAID group, the subjects taking Glu/CS had significantly lower WOMAC scores (pain, p<0.0001; stiffness, p=0.0373; disability, p=0.0004) and higher KOOS scores at baseline as well as a smaller cartilage volume loss in the tibial plateau at both 12 (p=0.029) and 24 months (p=0.033). In the -analgesic/NSAID groups, those who took Glu/CS and had JSW at baseline higher than the median showed less cartilage volume loss at 24 months in the medial compartment (p=0.025) and condyle (p=0.01). Conclusions In both the +analgesic/NSAID and -analgesic/NSAID groups, participants who took Glu/CS had reduced loss of JSW and cartilage volume over 24 months. These effects of Glu/CS on structural changes support results from previous studies. Disclosure of Interest None Declared