Advanced magnetic resonance imaging of cartilage components in haemophilic joints reveals that cartilage hemosiderin correlates with joint deterioration

Abstract

Introduction: Evidence suggests that toxic iron is involved in haemophilic joint destruction. Aim:To determine whether joint iron deposition is linked to clinical and imaging outcomes in order to optimize management of haemophilic joint disease. Methods: Adults with haemophiliaA or haemophilia B (n = 23, ≥ age 21) of all severities were recruited prospectively to undergo assessment with Hemophilia Joint Health Scores (HJHS), pain scores (visual analogue scale [VAS]) and magnetic resonance imaging (MRI) at 3T using conventional MRI protocols and 4-echo 3D-UTE-Cones sequences for one affected arthropathic joint. MRI was scored blinded by two musculoskeletal radiologists using the International Prophylaxis Study Group (IPSG) MRI scale. Additionally, UTE-T2* values of cartilage were quantified. Correlations between parameters were performed using Spearman rank correlation. Two patients subsequently underwent knee arthroplasty, which permitted linking of histological findings (including Perl's reaction) with MRI results.Results: MRI scores did not correlate with pain scores or HJHS. Sixteen joints had sufficient cartilage for UTE-T2* analysis. T2* values for cartilage correlated inversely with HJHS (r s = −0.81, P < 0.001) and MRI scores (r s = −0.52, P = 0.037). This was unexpected since UTE-T2* values decrease with better joint status in patients with osteoarthritis, suggesting that iron was present and responsible for the effects.Histological analysis of cartilage confirmed iron deposition within chondrocytes, associated with low UTE-T2* values. Conclusions: Iron accumulation can occur in cartilage (not only in synovium) andshows a clear association with joint health. Cartilage iron is a novel biomarker which, if quantifiable with innovative joint-specific MRI T2* sequences, may guide treatment optimization.

Inhibition of Fenton reaction is a novel mechanism to explain the therapeutic effect of intra‐articular injection of PRP in patients with chronic haemophilic synovitis

“…In addition, the clearance of haemosiderin‐laden macrophages and the normalization of synovial fluid cellular composition were also evidenced. These findings are in agreement with previous reports that indicate that the presence of intracellular haemosiderin deposits in cartilage and synovium is associated with joint deterioration in patients with haemophilia 28,29 . Moreover, the macrophages haemosiderin‐intracellular vesicles could remain stables during weeks even after reduction of free iron overload 23 .…”

Ultrashort echo time quantitative susceptibility mapping (UTE‐QSM) for detection of hemosiderin deposition in hemophilic arthropathy: A feasibility study

“…Surgery yielded multiple pieces of bone tissue from the femur, patella, and tibia, including some attached hypertrophic synovium. The tissues were fixed in 10% formalin (3.7% formaldehyde) for 48 h and decalcified in 10% formic acid including 0.2% K 4 Fe(CN) 6 to allow the Perl’s reaction during decalcification 32 . Resulting tissue was stained blue in iron‐rich locations and was dehydrated and embedded in paraffin.…”

“…The tissues were fixed in 10% formalin (3.7% formaldehyde) for 48 h and decalcified in 10% formic acid including 0.2% K 4 Fe(CN) 6 to allow the Perl's reaction during decalcification. 32 Resulting tissue was stained blue in iron-rich locations and was dehydrated and embedded in paraffin. A total of 6-to 8-μm sections were counterstained with hematoxylin under acidic conditions for a red nuclear counterstain, and imaged on an Olympus AH-2 microscope with a 2.5× objective.…”

Asymptomatic Joint Bleeding and Joint Health in Hemophilia: A Review of Variables, Methods, and Biomarkers

“…85 Iron accumulation in cartilage is another biomarker that has been shown to correlate with joint damage and progression of hemophilic arthropathy, further it has the advantage of being easily detected with MRI T2* sequences. 86 The development and validation of iron quantification MRI methods could assist in detecting asymptomatic joint bleeding, and provide a tool to evaluate and adjust treatment in patients with hemophilia. 86 Vascularization and angiogenesis have been found to be increased in patients with joint damage.…”

“…86 The development and validation of iron quantification MRI methods could assist in detecting asymptomatic joint bleeding, and provide a tool to evaluate and adjust treatment in patients with hemophilia. 86 Vascularization and angiogenesis have been found to be increased in patients with joint damage. One study found that proangiogenic factors and proangiogenic macrophage/monocyte cells were up-regulated in patients with joint disease and expression of VEGFR2/AC133 endothelial progenitor cells and CD34/VEGFR1 hematopoietic progenitor cells were increased.…”