Haemophilia

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Leonard A Valentino - One of the best experts on this subject based on the ideXlab platform.

  • the biological efficacy profile of bax 855 a pegylated recombinant factor viii molecule
    Haemophilia, 2015
    Co-Authors: Leonard A Valentino, L Cong, C Enockson, X Song, F Scheiflinger, Evamaria Muchitsch, Peter Turecek, Narine Hakobyan
    Abstract:

    Summary Prophylaxis prevents joint and other bleeding episodes in patients with Haemophilia A. Development of new factor concentrates with longer circulating half-lives may encourage patients to start, continue or resume prophylaxis. The aim of this study was to compare the pharmacodynamic effect of a PEGylated full-length recombinant factor VIII (rFVIII) concentrate with that of an unmodified rFVIII concentrate with respect to the duration of prophylactic efficacy in a murine model of haemophilic joint bleeding. Mice were pretreated with BAX 855 or unmodified rFVIII at specified times before right knee puncture to induce haemarthrosis; left knee joints served as controls. Joint bleeding was evaluated using a combination of visual and histological assessments. Administration of a single dose of unmodified rFVIII before joint puncture prevented haemarthrosis in mice up to 24 h, whereas pretreatment with BAX 855 protected the joint from bleeding up to 48 h. This pharmacodynamic study showed prolonged efficacy of BAX 855 compared to ADVATE in a Haemophilia A mouse joint bleeding model. This finding supports the possibility of using BAX 855 to increase FVIII trough levels and/or extend the dosing interval in patients with Haemophilia A on prophylaxis, which may potentially improve prophylactic efficacy and long-term adherence.

  • rituximab for treatment of inhibitors in Haemophilia a a phase ii study
    Thrombosis and Haemostasis, 2014
    Co-Authors: Cindy A Leissinger, Cassandra D Josephson, Suzanne Granger, Rebecca Krusejarres, Leonard A Valentino, Janna M. Journeycake, Margaret V Ragni, Joan Cox Gill, Barbara A Konkle, Keith R Mccrae
    Abstract:

    The development of antibodies against infused factor VIII (FVIII) in patients with Haemophilia A is a serious complication leading to poorly controlled bleeding and increased morbidity. No treatment has been proven to reduce high titre antibodies in patients who fail immune tolerance induction or are not candidates for it. The Rituximab for the Treatment of Inhibitors in Congenital Hemophilia A (RICH) study was a phase II trial to assess whether rituximab can reduce anamnestic FVIII antibody (inhibitor) titres. Male subjects with severe congenital Haemophilia A and an inhibitor titre ≥5 Bethesda Units/ml (BU) following a FVIII challenge infusion received rituximab 375 mg/m² weekly for weeks 1 through 4. Post-rituximab inhibitor titres were measured monthly from week 6 through week 22 to assess treatment response. Of 16 subjects who received at least one dose of rituximab, three (18.8%) met the criteria for a major response, defined as a fall in inhibitor titre to

  • joint protection in Haemophilia
    Haemophilia, 2011
    Co-Authors: E C Rodriguezmerchan, Karin Knobe, Rolf Ljung, Victor Jimenezyuste, J A Aznar, Ulla Hedner, Christine A Lee, F Querol, Elena Santagostino, Leonard A Valentino
    Abstract:

    Haemarthroses (intra-articular haemorrhages) are a frequent finding typically observed in patients with Haemophilia. Diagnosis and treatment of these bleeding episodes must be delivered as early as possible. Additionally, treatment should ideally be administered intensively (enhanced on-demand treatment) until the resolution of symptoms. Joint aspiration plays an important role in acute and profuse haemarthroses as the presence of blood in the joint leads to chondrocyte apoptosis and chronic synovitis, which will eventually result in joint degeneration (haemophilic arthropathy). Ultrasonography (US) is an appropriate diagnostic technique to assess the evolution of acute haemarthrosis in Haemophilia, although magnetic resonance imaging remains the gold standard as far as imaging techniques are concerned. Some patients experience subclinical haemarthroses, which eventually tend to result in some degree of arthropathy, especially in the ankles. Nowadays, the most effective way of protecting these patients is primary prophylaxis, which in practice changes severe Haemophilia into moderate Haemophilia, preventing or at least minimizing the occurrence of haemarthrosis. If primary prophylaxis is, for whatever reason not an option, secondary prophylaxis and enhanced on demand treatment should be considered. Two alternatives are available for inhibitor patients: (i) control of haemostasis using by-passing agents (rFVIIa or aPCCs) either as enhanced on demand treatment or secondary prophylaxis, as appropriate, following the same basic principles used for non-inhibitor patients and (ii) immune tolerance induction (ITI) to eradicate the inhibitor.

  • surgical experience with rfviia novoseven in congenital Haemophilia a and b patients with inhibitors to factors viii or ix
    Haemophilia, 2011
    Co-Authors: Leonard A Valentino, David L Cooper, B Goldstein
    Abstract:

    Summary.  Patients with congenital Haemophilia with inhibitors are at risk of peri-operative bleeding complications, since replacement of the missing coagulation factor is ineffective, presenting a therapeutic challenge in elective or emergency surgery. Therefore, the management of peri-operative bleeding requires the use of bypassing agents, such as recombinant activated FVII (rFVIIa, NovoSeven®). This article presents an updated evaluation of the safety and effectiveness of rFVIIa in the treatment of peri-operative bleeding in this patient population. Surgical and other medical procedures managed with rFVIIa from two randomized clinical trials, the Hemophilia Research Society/Hemophilia and Thrombosis Research Society (HRS/HTRS) registry databases and the medical literature were analysed. There were 395 rFVIIa-treated procedures (261 surgical, 89 dental and 45 other medical procedures) reported for 263 congenital Haemophilia patients with inhibitors. In trials, initial rFVIIa dosing was 35–90 mcg kg−1 bolus injection or 50 mcg kg−1 h−1 continuous infusion. Dosing in the registries and literature was more variable. Recombinant FVIIa effectiveness was comparable across data sources, with an overall rate of 84% (333/395). The incidence of thrombotic events was very low (0.4% of patients and 0.025% of procedures). Prior to the US approval of rFVIIa in 1999, surgical procedures in congenital Haemophilia patients with inhibitors were often considered too risky. Recombinant FVIIa has consistently demonstrated effectiveness in treatment of bleeding in these patients during such procedures. Thrombotic events were rare. This analysis confirms the value of corroborating clinical trial results with post-marketing surveillance registries to assess small patient populations with clinically challenging management decisions.

Catherine S Manno - One of the best experts on this subject based on the ideXlab platform.

  • modern management of haemophilic arthropathy
    British Journal of Haematology, 2007
    Co-Authors: Leslie Raffini, Catherine S Manno
    Abstract:

    Summary Currently available factor concentrates for treatment of patients with Haemophilia are virally inactivated or are made by recombinant technology and their broad use in developed nations has resulted in the dramatic elimination of the treatment-related viral illnesses that decimated the Haemophilia community in the late 20th century. The major morbidity experienced by patients with Haemophilia today is joint disease, a result of repeated bleeding episodes into joint spaces. Although administration of factor concentrates to prevent bleeding has been demonstrated to prevent haemophilic joint disease when applied assiduously, repeated bleeding episodes induce synovitis that is irreversible and may progress despite subsequent prophylaxis. Surgical and nuclear medicine interventions are available to reduce the pain of haemophilic arthropathy and to reduce further bleeding episodes. Patients with high titre inhibitors are at great risk for the development of joint disease and present the greatest therapeutic challenges when joint surgery is needed.

  • evidence for gene transfer and expression of factor ix in Haemophilia b patients treated with an aav vector
    Nature Genetics, 2000
    Co-Authors: Mark A Kay, Margaret V Ragni, Catherine S Manno, Peter J Larson, Linda B Couto, Alan Mcclelland, Bertil Glader, Amy J Chew
    Abstract:

    Pre-clinical studies in mice and haemophilic dogs have shown that introduction of an adeno-associated viral (AAV) vector encoding blood coagulation factor IX (FIX) into skeletal muscle results in sustained expression of F.IX at levels sufficient to correct the haemophilic phenotype. On the basis of these data and additional pre-clinical studies demonstrating an absence of vector-related toxicity, we initiated a clinical study of intramuscular injection of an AAV vector expressing human F.IX in adults with severe Haemophilia B. The study has a dose-escalation design, and all patients have now been enrolled in the initial dose cohort (2 x 10(11) vg/kg). Assessment in the first three patients of safety and gene transfer and expression show no evidence of germline transmission of vector sequences or formation of inhibitory antibodies against F.IX. We found that the vector sequences are present in muscle by PCR and Southern-blot analyses of muscle biopsies and we demonstrated expression of F.IX by immunohistochemistry. We observed modest changes in clinical endpoints including circulating levels of F.IX and frequency of FIX protein infusion. The evidence of gene expression at low doses of vector suggests that dose calculations based on animal data may have overestimated the amount of vector required to achieve therapeutic levels in humans, and that the approach offers the possibility of converting severe Haemophilia B to a milder form of the disease.

Andrea S Doria - One of the best experts on this subject based on the ideXlab platform.

  • state of the art imaging techniques for the evaluation of haemophilic arthropathy present and future
    Haemophilia, 2010
    Co-Authors: Andrea S Doria
    Abstract:

    Summary.  In spite of the fact that the diagnosis of Haemophilia is essentially clinical and laboratory-based, imaging has become an important tool for the evaluation of complications, diagnostic confirmation and/or complementation and therapeutic follow-up in haemophilic arthropathy. Radiography remains the workforce horse in the diagnosis and follow-up of haemophilic arthropathy. The radiographical findings in arthropathy follow an expected sequence of events and are overall similar in different joints. Magnetic resonance imaging (MRI) has advantages over radiography based on its capability of visualizing soft tissue and cartilage changes in haemophilic joints. The recent development and standardization of MRI scoring systems for measuring soft tissue and cartilage abnormalities may enable the comparison of pathological joint findings in clinical trials conducted at different institutions across the world. The implementation of high-frequency transducers and colour/power Doppler capabilities has provided new insights for clinical applications of ultrasonography (US) in haemophilic arthropathy. In spite of the imaging modality's technical challenges such as operator-dependency, US has advantages over MRI. One of these advantages is its ability of differentiating synovium hypertrophy and hemosiderin deposition, which is not possible with MRI given the presence of susceptibility artefacts from extracellular hemosiderin on gradient-echo MR images. In addition to the aforementioned conventional imaging modalities, novel imaging techniques (blood oxygen level dependent, ultrasmall superparamagnetic iron-oxide contrast-enhanced, and T1 and T2 mapping MRI, ultrasound biomicroscopy, microbubble contrast-enhanced US and positron emission tomography, among others) hold promise for early assessment of haemophilic arthropathy in the future upon completion of their clinical validation.

  • sonography for assessment of haemophilic arthropathy in children a systematic protocol
    Haemophilia, 2007
    Co-Authors: Katherine Zukotynski, J Jarrin, P S Babyn, Manuel Carcao, J Pazminocanizares, A M Stain, Andrea S Doria
    Abstract:

    Summary.  Radiological imaging of joints in children with Haemophilia is important to detect abnormalities, grade their severity and monitor the effects of treatment. Scoring systems for staging haemophilic arthropathy have been developed based on plain film or magnetic resonance imaging (MRI) findings. Radiographs alone may be inadequate for evaluating joint disease in children with Haemophilia on prophylaxis while MRI may be difficult to access and require the child to be sedated. Sonography can be a useful complementary modality in the evaluation of haemophilic arthropathy that is readily available and does not require the child to be sedated. In this paper, we briefly review the current imaging scales available for the assessment of haemophilic arthropathy and present a systematic protocol for sonographic assessment of the knee and ankle in haemophilic children along with examples of findings in joint effusion/hemarthrosis, synovial hypertrophy and cartilage loss. Also, we correlate the ultrasound findings with the corresponding MRI images demonstrating the anatomic planes used for imaging acquisition. Sonography is a promising technique for the assessment of soft tissue changes which are the earliest findings in haemophilic arthropathy. Further investigation is required for evaluation of osteochondral changes given limitations of sonography in this regard and in minimizing operator dependency, especially if applied in multicentric clinical trials.

H M Berg - One of the best experts on this subject based on the ideXlab platform.

  • effects of haemophilic arthropathy on health related quality of life and socio economic parameters
    Haemophilia, 2005
    Co-Authors: K Fischer, Evelien P Mauserbunschoten, Goris Roosendaal, H M Berg
    Abstract:

    Summary.  Although prophylactic treatment is advised for all children with severe Haemophilia, the optimal regimen is still under discussion. Should all joint bleeds be prevented, or can a limited amount of arthropathy be tolerated in adulthood without loss of quality of life? To answer this question, the effect of haemophilic arthropathy on health-related quality of life (HRQoL) needs to be quantified. In a retrospective study, the effect of arthropathy on HRQoL and socio-economic parameters was assessed in a single-centre cohort of 96 patients with severe and moderate Haemophilia with a minimum age of 13 years. Arthropathy was measured by the radiological Pettersson score of the elbows, knees and ankles (maximum: 78 points). HRQoL was assessed by the Short Form 36 (SF36), measuring eight domains of health. Labourforce participation and medical consumption were assessed using a separate questionnaire. Patients were studied at a mean age of 28.6 years (range: 13–54), the mean time between evaluation and the last Pettersson score was 0.4 years (SD: 1.1). The overall median Pettersson score was 13 (range: 0–78). There was a trend towards lower quality of life with increasing Pettersson scores and age, especially in the physical domains of the SF36. An age-adjusted analysis showed that arthropathy had a small but significant effect on HRQoL in the domain of ‘physical function’ of the SF36, but not on its other domains, or on labourforce participation and medical consumption. Thus suggesting that the SF36 can be used to assess the effects of haemophilic arthropathy, especially in the domain of ‘physical function’.

  • changes in treatment strategies for severe Haemophilia over the last 3 decades effects on clotting factor consumption and arthropathy
    Haemophilia, 2001
    Co-Authors: K Fischer, Evelien P Mauserbunschoten, Goris Roosendaal, R Prejs, Diederick E Grobbee, H M Berg
    Abstract:

    Abstract A cohort study was performed among 214 patients with severe Haemophilia, born 1944-1994, to describe changes in treatment over the last 3 decades and its effects on clotting factor consumption and haemophilic arthropathy. Data on treatment strategy, clotting factor consumption, and outcome were collected for 3567 patient years (from 1972 to 1998), and 493 Pettersson scores were analysed. Median follow up was 17 years (range 6-27 years), and median age in 1998 was 27.6 years. Since 1965, replacement therapy, prophylaxis, and home treatment have been used and treatment intensified. Over the last 3 decades, annual clotting factor consumption increased by 260%, for both prophylactic and on-demand treatment. Annual clotting factor consumption kg-1 increased during childhood and appeared to stabilize in early adulthood for patients born 1965-79, who were treated with early replacement therapy or early prophylaxis. In contrast, clotting factor consumption increased continuously for patients born before 1965, who had had no access to replacement therapy during the early years of their life. The annual number of joint bleeds decreased over the years. Arthropathy as measured by the Pettersson score generally became apparent around the age of 15 years and was lowest in patients treated with primary prophylaxis. In conclusion, clotting factor consumption has increased and haemophilic arthropathy has decreased due to the intensification of treatment for severe Haemophilia over the last 3 decades. Annual clotting factor consumption stabilizes in adulthood for patients who receive early intensive treatment.

  • iron deposits and catabolic properties of synovial tissue from patients with Haemophilia
    Journal of Bone and Joint Surgery-british Volume, 1998
    Co-Authors: Goris Roosendaal, M J G Wenting, A C Van Rinsum, H M Berg, M. E. Vianen, Floris P J G Lafeber, Johannes W. J. Bijlsma
    Abstract:

    Haemophilic arthropathy is characterised by iron deposits in synovial tissues. We investigated the suggestion that iron plays an important role in synovial changes. We obtained synovial tissue from six patients with Haemophilia during arthroplasty, finding that brown haemosideritic tissue was often adjacent to tissue with a macroscopically normal appearance in the same joint. Samples from both types of synovial tissue were analysed histologically and biochemically to determine catabolic activity. Macroscopically haemosideritic synovium showed a significantly higher inflammatory activity than that with a normal appearance. Cultures of abnormal synovial tissue gave a significantly enhanced production of IL-1, IL-6 and TNFα compared with cultures of synovial tissue with a normal appearance. In addition, the supernatant fluids from the cultures showed greater catabolic activity from haemosideritic tissue, as determined by the inhibition of the synthesis of articular cartilage matrix. We conclude that in patients with haemophilic arthropathy, local synovial iron deposits are associated with increased catabolic activity.

Goris Roosendaal - One of the best experts on this subject based on the ideXlab platform.

  • haemarthrosis stimulates the synovial fibrinolytic system in haemophilic mice
    Thrombosis and Haemostasis, 2013
    Co-Authors: Laurens Nieuwenhuizen, Goris Roosendaal, Floris P J G Lafeber, K Coeleveld, Erik Lubberts, Douwe H Biesma, Roger E G Schutgens
    Abstract:

    Recurrent joint bleeding is the most common manifestation of Haemophilia resulting in haemophilic arthropathy (HA). The exact pathophysiology is unknown, but it is suggested that arthropathy is stimulated by liberation of fibrinolytic activators from the synovium during haemarthrosis. The aim of this study was to test the hypothesis that haemarthrosis activates the local synovial fibrinolytic system in a murine Haemophilia model. The right knees of haemophilic and control mice were punctured to induce haemarthrosis. The left knees served as internal control joints. Synovial levels of urokinase-type plasminogen activator (uPA), plasminogen activator inhibitor 1 (PAI-1), plasmin, and alpha-2-antiplasmin (A2AP) were compared between the punctured and control knees. In haemophilic mice, an increase in synovial cells expressing urokinase-type plasminogen activator (uPA) in the right punctured knee versus the left unaffected knee was observed: (47% vs 43%) (p=0.03). Additionally, in haemophilic mice, haemarthrosis induced an increase in uPA (0.016 ng/ml vs 0.01 ng/ml) (p=0.03) and plasmin (0.53 μg/ml vs 0.46 μg/ml) (p=0.01) as promoters of fibrinolysis. Synovial levels of PAI-1 (0.32 ng/ml vs 0.17 ng/ml) (p

  • understanding haemophilic arthropathy an exploration of current open issues
    British Journal of Haematology, 2008
    Co-Authors: N W Jansen, Goris Roosendaal, Floris P J G Lafeber
    Abstract:

    Summary Haemophilic arthropathy is joint damage evolving from recurrent joint bleeds that occur in patients suffering from the clotting disorder Haemophilia. Insight into the patho- genetic mechanism of this blood-induced arthropathy yields possible treatment targets and modalities useful to reduce this invalidating co-morbidity of Haemophilia. Joint bleeding leads to initially independent adverse changes in both the synovial tissue and the articular cartilage. These subsequently influence each other: the synovial inflammatory changes enhancing cartilage damage and vice versa. Consequently, effective treatment strategies will have to affect both pathways. Haemophilic arthropathy is joint damage that evolves from joint bleeds in patients with the clotting disorder Haemophilia. Predominantly patients with the severe form of the disease suffer from spontaneous joint bleeds. The administration of the deficient clotting factor is important in limiting bleeding in general and therefore in limiting joint bleeding. However, despite the fact that the administration of clotting factor is possible, the overall occurrence of joint bleeding and hence blood-induced joint damage is still observed. This has several reasons. Not all patients in the whole world have access to (sufficient amounts of) clotting factor, either due to limited availability or due to the high costs of clotting factor concentrates. Even if patients do receive clotting factor, joint bleeds are limited in number and possibly in severity, but still occur; complete substitution is not realistic because of the high costs (Roosendaal & Lafeber, 2007). Moreover, joint bleeding does not only occur in patients with Haemophilia, but can also occur in non-Haemophiliacs due to joint trauma, for instance intra-articular fractures or ligament rupture. Due to all these reasons, blood-induced arthropathy in general and haemo- philic arthropathy in specific cannot be prevented completely. Therefore, there is a need for interventions to prevent blood- induced arthropathy. To enable this, insight in the patho- genetic mechanism of blood-induced joint damage is crucial, because it will reveal targets for interventions leading to potential treatment strategies. This review provides an over- view of the knowledge of haemophilic arthropathy gained thus far and highlights 'open issues' that need to be addressed. An introduction on Haemophilia and the synovial joint forms the basis for understanding of the mechanisms of blood-induced

  • effects of haemophilic arthropathy on health related quality of life and socio economic parameters
    Haemophilia, 2005
    Co-Authors: K Fischer, Evelien P Mauserbunschoten, Goris Roosendaal, H M Berg
    Abstract:

    Summary.  Although prophylactic treatment is advised for all children with severe Haemophilia, the optimal regimen is still under discussion. Should all joint bleeds be prevented, or can a limited amount of arthropathy be tolerated in adulthood without loss of quality of life? To answer this question, the effect of haemophilic arthropathy on health-related quality of life (HRQoL) needs to be quantified. In a retrospective study, the effect of arthropathy on HRQoL and socio-economic parameters was assessed in a single-centre cohort of 96 patients with severe and moderate Haemophilia with a minimum age of 13 years. Arthropathy was measured by the radiological Pettersson score of the elbows, knees and ankles (maximum: 78 points). HRQoL was assessed by the Short Form 36 (SF36), measuring eight domains of health. Labourforce participation and medical consumption were assessed using a separate questionnaire. Patients were studied at a mean age of 28.6 years (range: 13–54), the mean time between evaluation and the last Pettersson score was 0.4 years (SD: 1.1). The overall median Pettersson score was 13 (range: 0–78). There was a trend towards lower quality of life with increasing Pettersson scores and age, especially in the physical domains of the SF36. An age-adjusted analysis showed that arthropathy had a small but significant effect on HRQoL in the domain of ‘physical function’ of the SF36, but not on its other domains, or on labourforce participation and medical consumption. Thus suggesting that the SF36 can be used to assess the effects of haemophilic arthropathy, especially in the domain of ‘physical function’.

  • changes in treatment strategies for severe Haemophilia over the last 3 decades effects on clotting factor consumption and arthropathy
    Haemophilia, 2001
    Co-Authors: K Fischer, Evelien P Mauserbunschoten, Goris Roosendaal, R Prejs, Diederick E Grobbee, H M Berg
    Abstract:

    Abstract A cohort study was performed among 214 patients with severe Haemophilia, born 1944-1994, to describe changes in treatment over the last 3 decades and its effects on clotting factor consumption and haemophilic arthropathy. Data on treatment strategy, clotting factor consumption, and outcome were collected for 3567 patient years (from 1972 to 1998), and 493 Pettersson scores were analysed. Median follow up was 17 years (range 6-27 years), and median age in 1998 was 27.6 years. Since 1965, replacement therapy, prophylaxis, and home treatment have been used and treatment intensified. Over the last 3 decades, annual clotting factor consumption increased by 260%, for both prophylactic and on-demand treatment. Annual clotting factor consumption kg-1 increased during childhood and appeared to stabilize in early adulthood for patients born 1965-79, who were treated with early replacement therapy or early prophylaxis. In contrast, clotting factor consumption increased continuously for patients born before 1965, who had had no access to replacement therapy during the early years of their life. The annual number of joint bleeds decreased over the years. Arthropathy as measured by the Pettersson score generally became apparent around the age of 15 years and was lowest in patients treated with primary prophylaxis. In conclusion, clotting factor consumption has increased and haemophilic arthropathy has decreased due to the intensification of treatment for severe Haemophilia over the last 3 decades. Annual clotting factor consumption stabilizes in adulthood for patients who receive early intensive treatment.

  • iron deposits and catabolic properties of synovial tissue from patients with Haemophilia
    Journal of Bone and Joint Surgery-british Volume, 1998
    Co-Authors: Goris Roosendaal, M J G Wenting, A C Van Rinsum, H M Berg, M. E. Vianen, Floris P J G Lafeber, Johannes W. J. Bijlsma
    Abstract:

    Haemophilic arthropathy is characterised by iron deposits in synovial tissues. We investigated the suggestion that iron plays an important role in synovial changes. We obtained synovial tissue from six patients with Haemophilia during arthroplasty, finding that brown haemosideritic tissue was often adjacent to tissue with a macroscopically normal appearance in the same joint. Samples from both types of synovial tissue were analysed histologically and biochemically to determine catabolic activity. Macroscopically haemosideritic synovium showed a significantly higher inflammatory activity than that with a normal appearance. Cultures of abnormal synovial tissue gave a significantly enhanced production of IL-1, IL-6 and TNFα compared with cultures of synovial tissue with a normal appearance. In addition, the supernatant fluids from the cultures showed greater catabolic activity from haemosideritic tissue, as determined by the inhibition of the synthesis of articular cartilage matrix. We conclude that in patients with haemophilic arthropathy, local synovial iron deposits are associated with increased catabolic activity.