the dose escalation approach is ‘worth it’ in different cohorts of haemophiliacs across the world. The use of novel

imaging techniques may allow for earlier and more accurate quantification of arthropathic changes both cross-sectionally and over time. Conventional MRI techniques in clinical use do not provide mTOR inhibitor a comprehensive assessment of cartilage and are lacking spatial resolution or specific information about cartilage physiology. The following techniques have been tested experimentally in animal models of arthritis or small cohorts of patients, but hold promise for future translation into clinical trials. Blood oxygen level dependent  This method relies on MRI contrast

resulting from changes in the microvascular ratio of oxyhemoglobin (oxyHb) to deoxyhaemoglobin (deoxyHb). OxyHb is diamagnetic, whereas deoxyHb is paramagnetic, which produces a local bulk magnetic susceptibility effect and subsequent MRI signal change [43]. The changes are typically observed Barasertib datasheet in T2*-weighted functional MRI scans. However, there has recently been interest in BOLD as a way to evaluate microcirculation of any normal or diseased tissue. This technique detects temporal changes in the synovial response of the joint to a stimulus [44] and holds the potential to predict future cartilage changes in an early stage of haemophilic arthropathy. Ultrasmall superparamagnetic iron-oxide contrast-enhanced MRI  It is well known that synovial iron deposition that is easily detectable by conventional gradient-echo MRI techniques is suggested to be indicative of the severity of haemophilic arthropathy [45]. Previous studies showed that iron deposits at localized sites in the synovium are associated with the production of pro-inflammatory cytokines and an ability to inhibit the formation Nutlin-3 molecular weight of human cartilage matrix [46]. Proposed mechanisms include the effects of lysosomal enzymes and catabolic cytokines produced by monocytes/macrophages [47–49]. This supports

the hypothesis that iron plays a leading role in the induction of synovial changes and the consequent production of catabolic mediators harmful to cartilage. Newly developed nanoparticle contrast media, known as ‘ultrasmall superparamagnetic iron-oxide (USPIO)’ particles, have been shown [50] to localize to the synovial macrophages in experimental haemophilic arthropathy. Within the joints, the nanoparticles provide significant MRI ‘negative’ contrast, with signal loss on T2-weighted imaging due to T2 shortening caused by their magnetic susceptibility. This negative contrast effect is highly located to the specific areas of macrophage accumulation within affected joints and appears to be quantitatively measurable.