Faculty Bibliography

BACKGROUND: The purpose of this study was to use MRI to determine if a loss of meniscal intra-substance integrity, as determined by T2* relaxation time, is associated with an increase of Kellgren-Lawrence (KL) grade, and if this was correlated with risk factors for cartilage degeneration, namely meniscal extrusion, contact area and anterior-posterior (AP) displacement. METHODS: Eleven symptomatic knees with a KL 2 to 4 and 11 control knees with a KL 0 to 1 were studied. A 3 Tesla MRI scanner was used to scan all knees at 15 degrees of flexion. With a 222N compression applied, a 3D SPACE sequence was obtained, followed by a spin echo 3D T2* mapping sequence. Next, an internal tibial torque of 5Nm was added and a second 3D SPACE sequence obtained. The MRI scans were post-processed to evaluate meniscal extrusion, contact area, AP displacement and T2* relaxation time. RESULTS: KL grade was correlated with T2* relaxation time for both the anterior medial meniscus (r=0.79, p<0.001) and the posterior lateral meniscus (r=0.55, p=0.009). In addition, T2* relaxation time was found to be correlated with risk factors for cartilage degeneration. The largest increases in meniscal extrusion and decreases in contact area were noted for those with meniscal tears (KL 3 to 4). All patients with KL 3 to 4 indicated evidence of meniscal tears. CONCLUSIONS: This suggests that a loss of meniscal integrity, in the form of intra-substance degeneration, is correlated with risk factors for cartilage degeneration.

OBJECTIVE: Tanezumab, a monoclonal antibody against nerve growth factor, has demonstrated efficacy in clinical trials of chronic pain in osteoarthritis (OA) and chronic low back pain (CLBP). Unexpected adverse events (AEs) described as osteonecrosis (ON) occurred during tanezumab development leading the US Food and Drug Administration to impose a partial clinical hold for all indications but cancer pain. A blinded Adjudication Committee (AC) including orthopedic surgeons, rheumatologists, and an orthopedic pathologist reviewed and adjudicated joint related AEs in the tanezumab clinical program. METHODS: The AC reviewed all reported ON events and cases of total joint replacement (TJR) with available radiology images taken within 9 months of the surgery. The AC pre-specified categories for joint safety events including Primary ON, Worsening OA (rapid progression [RPOA]; normal progression, insufficient information to distinguish between the two), Other, or Insufficient information to distinguish between primary ON and worsening OA or another diagnosis. RESULTS: Events from 249 of 386 subjects with either a report of ON and/or TJR were reviewed. Two events were adjudicated as primary ON, 200 as worsening OA, 68 of which were classified as RPOA, 29 events had another diagnosis, 11 insufficient information to distinguish ON from worsening OA, and 7 didn't have committee member consensus. CONCLUSIONS: Despite initial reports, tanezumab treatment was not associated with an increase in ON, but was associated with an increase in RPOA. Higher doses of tanezumab, tanezumab administered with NSAIDs, and preexisting subchondral insufficiency fractures were risk factors for RPOA in this cohort

The disabling and painful disease osteoarthritis (OA) is the most common form of arthritis. Strong evidence suggests that a subpopulation of OA patients has a form of OA driven by inflammation. Consequently, understanding when inflammation is the driver of disease progression and which OA patients might benefit from anti-inflammatory treatment is a topic of intense research in the OA field. We have reviewed the current literature on OA, with an emphasis on inflammation in OA, biochemical markers of structural damage, and anti-inflammatory treatments for OA. The literature suggests that the OA patient population is diverse, consisting of several subpopulations, including one associated with inflammation. This inflammatory subpopulation may be identified by a combination of novel serological inflammatory biomarkers. Preliminary evidence from small clinical studies suggests that this subpopulation may benefit from anti-inflammatory treatment currently reserved for other inflammatory arthritides.

BACKGROUND: During osteoarthritis and following surgical procedures, the environment of the knee is rich in proinflammatory cytokines such as IL-1. Introduction of tissue-engineered cartilage constructs to a chemically harsh milieu may limit the functionality of the implanted tissue over long periods. A chemical preconditioning scheme (application of low doses of IL-1) was tested as a method to prepare developing engineered tissue to withstand exposure to a higher concentration of the cytokine, known to elicit proteolysis as well as rapid degeneration of cartilage. METHODS: Using an established juvenile bovine model system, engineered cartilage was preconditioned with low doses of IL-1alpha (0.1 ng/mL, 0.5 ng/mL, and 1.0 ng/mL) for 7 days before exposure to an insult dose (10 ng/mL). The time frame over which this protection is afforded was investigated by altering the amount of time between preconditioning and insult as well as the time following insult. To explore a potential mechanism for this protection, one set of constructs was preconditioned with CoCl2, a chemical inducer of hypoxia, before exposure to the IL-1alpha insult. Finally, we examined the translation of this preconditioning method to extend to clinically relevant adult, passaged chondrocytes from a preclinical canine model. RESULTS: Low doses of IL-1alpha (0.1 ng/mL and 0.5 ng/mL) protected against subsequent catabolic degradation by cytokine insult, preserving mechanical stiffness and biochemical composition. Regardless of amount of time between preconditioning scheme and insult, protection was afforded. In a similar manner, preconditioning with CoCl2 similarly allowed for mediation of catabolic damage by IL-1alpha. The effects of preconditioning on clinically relevant adult, passaged chondrocytes from a preclinical canine model followed the same trends with low-dose IL-1beta offering variable protection against insult. CONCLUSIONS: Chemical preconditioning schemes have the ability to protect engineered cartilage constructs from IL-1-induced catabolic degradation, offering potential modalities for therapeutic treatments.