Changes in MR relaxation times of the meniscus with acute loading: an in vivo pilot study in knee osteoarthritis.

PURPOSE: To prospectively evaluate changes in T1ρ and T2 relaxation times in the meniscal body with acute loading using MRI in osteoarthritic knees and to compare these findings with those of age-matched healthy controls. MATERIALS AND METHODS: Female subjects above 40 years of age with (N1 = 20) and without osteoarthritis (OA) (N2 = 10) were imaged on a 3 Tesla MR scanner using a custom made loading device. MR images were acquired, with the knee flexed at 20°, with and without a compressive load of 50% of the subject's bodyweight. The subjects were categorized based on the radiographic evidence of OA. Three different zones (outer, middle, and inner) of meniscus body were defined (each occupying 1/3rd the width). After adjusting for age and body mass index in the general linear regression model, repeated measures analysis of variance was used to detect significant differences in T1ρ and T2 with and without loading. RESULTS: In the unloaded condition, the average T1ρ and T2 times were elevated in the outer and middle zones of the medial meniscus in OA subjects compared with the controls. In the loaded condition, T1ρ and T2 times of the outer zone of the medial meniscus was significantly elevated in OA subjects compared with controls. Finally the change (from unloaded to loaded) was significantly higher in controls than OA subjects (15.1% versus 8.3%; P = 0.039 for ΔT1ρ , and 11.5% versus 6.9%, P = 0.049 for ΔT2 ). CONCLUSION: These findings suggest that while the OA process appears to affect the relaxation times of all regions within the meniscus, it may affect some regions sooner or to a greater degree. Furthermore, the differences in the change in relaxation times between unloaded and loaded conditions may reveal evidence about load transmission failure of the outer zone of the medial meniscus in subjects with knee OA. It is possible that these metrics (ΔT1ρ and ΔT2 ) may be valuable as an early biomechanical biomarker, which could be used to predict load transmission to the underlying articular cartilage.

A role for PACE4 in osteoarthritis pain: evidence from human genetic association and null mutant phenotype.

OBJECTIVES: The aim of this study was to assess if genetic variation in the PACE4 (paired amino acid converting enzyme 4) gene Pcsk6 influences the risk for symptomatic knee osteoarthritis (OA). METHODS: Ten PCSK6 single nucleotide polymorphisms were tested for association in a discovery cohort of radiographic knee OA (n=156 asymptomatic and 600 symptomatic cases). Meta-analysis of the minor allele at rs900414 was performed in three additional independent cohorts (total n=674 asymptomatic and 2068 symptomatic). Pcsk6 knockout mice and wild-type C57BL/6 mice were compared in a battery of algesiometric assays, including hypersensitivity in response to intraplantar substance P, pain behaviours in response to intrathecal substance P and pain behaviour in the abdominal constriction test. RESULTS: In the discovery cohort of radiographic knee OA, an intronic single nucleotide polymorphism at rs900414 was significantly associated with symptomatic OA. Replication in three additional cohorts confirmed that the minor allele at rs900414 was consistently increased among asymptomatic compared to symptomatic radiographic knee OA cases in all four cohorts. A fixed-effects meta-analysis yielded an OR=1.35 (95% CI 1.17 to 1.56; p=4.3×10(-5) and no significant between-study heterogeneity). Studies in mice revealed that Pcsk6 knockout mice were significantly protected against pain in a battery of algesiometric assays. CONCLUSIONS: These results suggest that a variant in PCSK6 is strongly associated with protection against pain in knee OA, offering some insight as to why, in the presence of the same structural damage, some individuals develop chronic pain and others are protected. Studies in Pcsk6 null mutant mice further implicate PACE4 in pain.

Osteoarthritis of the knee at 3.0 T: comparison of a quantitative and a semi-quantitative score for the assessment of the extent of cartilage lesion and bone marrow edema pattern in a 24-month longitudinal study.

OBJECTIVE: To compare a semi-quantitative and a quantitative morphological score for assessment of early osteoarthritis (OA) evolution. MATERIALS AND METHODS: 3.0 T MRI of the knee was performed in 60 women, 30 with early OA (each 15 with Kellgren-Lawrence grade 2 and 3) and 30 age-matched controls at baseline and at 12 and 24 months. Pathological condition was assessed with the whole-organ magnetic resonance imaging score (WORMS). Cartilage abnormalities and bone marrow edema pattern (BMEP) were also quantified using a previously introduced morphological quantitative score. These data were correlated with changes in clinical parameters and joint space width using generalized estimation equations (GEE). RESULTS: At baseline, OA patients had significantly (p < 0.05) more and larger cartilage lesions and BMEP. During follow-up, cartilage lesions increased significantly (p < 0.05) in the patients compared with controls: WORMS showed progression only at the lateral patella, whereas the quantitative score revealed progression additionally at the trochlea and at the medial compartment. Both scores showed a significant (p < 0.05) increase in BMEP at the lateral femur in OA patients. In addition, quantitative scores of BMEP of the whole knee decreased significantly (p < 0.05) after 12 months and increased after 24 months in the patients, but showed an increase in controls at all follow-up examinations. Only weak correlations between structural imaging findings and clinical parameters were observed. CONCLUSION: Quantitative assessment of cartilage lesions and BMEP is more sensitive to changes during the course of the disease than semi-quantitative scoring. However, structural imaging findings do not correlate well with the clinical progression of OA.

Determining clinically important changes in range of motion in patients with Dupuytren's Contracture: secondary analysis of the randomized, double-blind, placebo-controlled CORD I study.

BACKGROUND AND OBJECTIVE: Injectable collagenase Clostridium histolyticum is efficacious in correcting Dupuytren's contracture as assessed by changes in the angle of contracture and range of motion (ROM). However, clinically important changes in ROM have not been evaluated in depth. The objective of this secondary analysis of the CORD I trial was to identify severity levels using baseline ROM, estimate a clinically important difference (CID) for ROM, and link the results to collagenase treatment and patient satisfaction. METHODS: In the CORD I trial, patients with Dupuytren's disease and joint contractures ≥20° were randomized to receive a maximum of three collagenase 0.58 mg or placebo injections into the cord of the affected hand at 30-day intervals. The primary endpoint was reduction in contracture to ≤5° 30 days after the last injection (day 30). The secondary endpoints, which are reported in this analysis, were ROM, physician- and patient-rated severity ('normal', 'mild', 'moderate', 'severe') and improvement, and treatment satisfaction. Linear regression was used to model data for severity classification and CID estimation for ROM based on physician and patient ratings. RESULTS: At baseline, mean ROM was 43.9° in the collagenase-treated joints (n = 197) and 45.3° in the placebo-treated joints (n = 102). On day 30, mean ROM was 80.7° in the collagenase-treated joints and 49.5° in the placebo-treated joints. The mean increase in ROM was 36.7° in the collagenase-treated joints (p < 0.001) and 4.0° in the placebo-treated joints (not significant). The estimated CID for ROM was 13.5° (95% CI 11.9, 15.1), reflecting a one-category change in severity. The mean increase in ROM exceeded the CID in the collagenase-treated joints but not in the placebo-treated joints; the difference between collagenase treatment and placebo in the mean increase in ROM also exceeded the CID, implying that the improvement with collagenase was clinically relevant. The severity classification for ROM was: ≥67.0° ('normal'), ≥54.3 and <67.0° ('mild'), ≥41.6 and <54.3° ('moderate'), and <41.6° ('severe'). More collagenase- than placebo-treated patients achieved 'normal' (81% vs 25%; p < 0.0001) status, and more collagenase- than placebo-treated patients reported being 'very/quite satisfied' (87% vs 32%; p < 0.001). CONCLUSION: Injectable collagenase significantly improves ROM and treatment satisfaction versus placebo. ROM improvements are clinically relevant as well as statistically significant. These data support the potential need to include ROM and physician- and patient-rated severity and satisfaction as standard assessments for Dupuytren's contracture treatment outcomes. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00528606; other study identification number: AUX-CC-857 (Auxilium Pharmaceuticals, Inc.).

Disease modifying osteoarthritis drugs: facing development challenges and choosing molecular targets.

Osteoarthritis (OA) is a slowly, progressive, ultimately degenerative disorder of movable joints, mainly characterized by joint pain and functional limitation and affecting all joint structures not just articular cartilage, but also the subchondral bone, ligaments, capsule, synovial membrane, and menisci. OA occurs when the equilibrium between breakdown and repair of the joint tissues becomes unbalanced. There are currently no pharmacological interventions available to patients for modifying the underlying disease (DMOADs) in relation to major drug development challenges. The current regulatory draft guidances for clinical development programs for DMOAD agents suggest radiographic joint space narrowing (JSN) as a primary endpoint. However, research efforts must continue to characterize imaging alternatives with greater sensitivity to change to enable development of new DMOADs. Past experience with DMOAD clinical trials indicate that pharmacologic agents must demonstrate pristine safety, and that consideration for special populations is important to avoid failed studies. More research is needed to determine what constitutes clinically meaningfulness for DMOAD activity in particular as it relates to OA progression. Current research pursues a variety of molecular targets including anti-catabolic agents to slow or halt OA progression and anabolic drugs to induce cartilage re-growth.