Hemophilic Joint Disease Research Articles

AAV mediated repression of Neat1 lncRNA combined with F8 gene augmentation mitigates pathological mediators of joint disease in haemophilia.

Haemophilic arthropathy (HA), a common comorbidity in haemophilic patients leads to joint pain, deformity and reduced quality of life. We have recently demonstrated that a long non-coding RNA, Neat1 as a primary regulator of matrix metalloproteinase (MMP) 3 and MMP13 activity, and its induction in the target joint has a deteriorating effect on articular cartilage. In the present study, we administered an Adeno-associated virus (AAV) 5 vector carrying an short hairpin (sh)RNA to Neat1 via intra-articular injection alone or in conjunction with systemic administration of a capsid-modified AAV8 (K31Q) vector carrying F8 gene (F8-BDD-V3) to study its impact on HA. AAV8K31Q-F8 vector administration at low dose, led to an increase in FVIII activity (16%-28%) in treated mice. We further observed a significant knockdown of Neat1 (~40 fold vs. untreated injured joint, p = 0.005) in joint tissue of treated mice and a downregulation of chondrodegenerative enzymes, MMP3, MMP13 and the inflammatory mediator- cPLA2, in mice receiving combination therapy. These data demonstrate that AAV mediated Neat1 knockdown in combination with F8 gene augmentation can potentially impact mediators of haemophilic joint disease.

The value of radiosynoviorthesis for treatment of chronic synovitis in hemophilic joint disease.

Chronic synovitis is contributing to the development of arthropathy in hemophilia A and B. In most patients with severe and moderate hemophilia, during lifetime, joint damage progresses despite early prophylaxis and intense treatment with coagulation factor concentrates. Recurrent hemorrhages into the joints and subclinical bleeding lead to chronic inflammation of the synovium, neoangiogenesis and remodeling, sustaining a vicious circle of bleeding-remodeling-bleeding and progression of osteochondral damage. Imaging techniques including ultrasound and MRI are able to early visualize synovitis and osteochondral changes. Early detection and sustained therapy of synovitis are important preconditions to prevent further deterioration of joint status. Chronic synovitis requires intensified substitution of coagulation factors and concomitant analgetic, antiphlogistic and physical therapy. The value of early radiosynoviorthesis (RSO) as effective method to control ongoing synovitis is discussed here. RSO is recommended as first choice therapy in case of persistant chronic synovitis, recorded in both national and international guidelines.

The SLIM study-Shared medical appointments to change lifestyles of overweight people with haemophilia: A randomized multiple baseline (n-of-1) design.

IntroductionPeople with haemophilia suffer from haemophilic joint disease that may result in physical inactivity and overweight. Shared medical appointments (SMAs) might help limit the consequences of haemophilic arthropathy. SMAs are group meetings supervised by one or more healthcare professionals that can be utilized to improve lifestyle.AimTo evaluate the feasibility and efficacy of SMAs in people with haemophilia to improve physical activity and eating habits.MethodsA multiple baseline single‐case design was used. Overweight people with haemophilia were eligible to participate. Seven weekly SMAs were conducted using multiple behavioural change techniques to improve physical activity and eating habits. Feasibility of SMAs was evaluated using (a) dropout rate, (b) occurrence of adverse events (AEs), (c) adherence rate and (d) patient satisfaction. During 13 weeks, physical activity was measured daily and eating habits were measured three times per week. The efficacy of SMAs was determined using randomization tests and visual data inspection.ResultsOut of the six men participating in the study, one participant dropped out. No study‐related AEs occurred. The adherence rate of SMAs was 80%, and participants reported to be ‘very satisfied’ with the SMAs. Randomization tests and visual analyses demonstrated (statistical) improvements in physical activity (p = .03). No effect was found in self‐reported eating habits (p = .55).ConclusionShared medical appointments are feasible in people with haemophilia and appear to improve physical activity. The effect on improving eating habits could not be established. Scientific replication of our approach is warranted to confirm or refute the merit of SMAs in people with haemophilia.

Angiogenesis is increased in advanced haemophilic joint disease and characterised by normal pericyte coverage

Repeated intra-articular bleedings in patients with haemophilia results in a crippling arthropathy for which no specific treatment is currently available. Recent studies have shown that neoangiogenesis is involved in the pathologic process. The aim of this study was to determine whether angiogenesis is dysregulated in haemophilic joint disease (HJD). Synovial tissue and synovial fluid were collected from patients with severe haemophilia undergoing knee or hip replacement and from a control group consisting of non-haemophilic patients undergoing diagnostic procedures. In a second set of patients, blood samples were collected in patients with mild, moderate and severe haemophilia A when free from current bleeding. Analysis of microvascular density, vascular endothelial growth factor (VEGF) expression and pericyte coverage was performed by immunofluorescence. Analyses of VEGF concentrations in plasma, platelet lysates and synovial fluid were performed by ELISA. Microvascular density and VEGF expression were significantly increased in synovial tissue from haemophilic patients compared with controls (P=0.005 and P=0.02, respectively). There was no difference in pericyte coverage of synovial vessels or levels of VEGF in plasma, platelet lysates or synovial fluid. Angiogenesis observed as synovial microvascular density, and VEGF expression is increased in HJD. As pericyte coverage was similar in synovial vessels from haemophilic and non-haemophilic patients, we assume that the vessels were mature, suggesting that the rate of new vessel formation is low in the chronic phase of haemophilic joint disease.

Natural History Of Hemophilic Joint Disease Using Sensitive Imaging With Magnetic Resonance Imaging (MRI)

▪ IntroductionArthropathy, the most costly chronic complication of severe hemophilia A (HemA) can be prevented by routine replacement of factor VIII (FVIII) when initiated prior to joint bleeding (primary prophylaxis) [NEJM;357:535]. However, the efficacy of prophylaxis initiated after the onset of recurrent hemarthroses or with established arthropathy (secondary or tertiary prophylaxis) is unknown. This individual patient meta-analysis was performed to derive the natural history of arthropathy in HemA patients treated only in response to acute bleeding (on demand therapy) as a baseline for future work to estimate the amelioration of arthropathy attributable to secondary or tertiary prophylaxis. MethodsData from individual participants in 3 studies who received on demand therapy were aggregated into a single database. Eligibility for this analysis included FVIII ≤ 2%, negative history for inhibitor, bleeding history for 12 months prior to study data acquisition and assessment of both ankles, knees and elbows; joints were assessed using physical examination (PE) and T2* gradient echo MRI scored as previously described using the World Federation of Hemophilia Gilbert score and the 45 point extended MRI scales [Haemophilia;6:649; ISTH OP Mon 7/1/13, 9 am]. MRI data were divided into soft tissue and osteochondral changes. Bleeding and Gilbert data for all 6 joints and MRI data for knees and ankles were analyzed using standard descriptive statistics and regression methods to quantify the rate of change in scores of joint damage with age. ResultsThe 3 studies included the Joint Outcome Study [NEJM;357:535] and the JOS Continuation Study (JOSc), the Spinart Study baseline results [JTH;11:1119] and a Cross-Sectional MRI study [Haemophilia;189 Suppl3:117]. The 3 studies provide data on 275 individuals aged 1 to 50 years. Clinical, Gilbert and MRI data were extracted and analyzed from multiple joints in each of 157 individuals who were receiving on-demand treatment only. The median age was 21 (range 1 – 50), and across all studies the median number of bleeding episodes in the prior 12 months was 18 (range 0 to 82). The rate of change in outcomes as a function of age is shown in Table 1 and Figure 1. The number of bleeding episodes was approximately constant at 20 bleeding episodes per year regardless of age (Figure 1a; p = 0.72 for relationship with age). Gilbert scores showed a steeper rise in young patients but did not increase after the late teens (Figure 1b; change of 0.34 Gilbert points/year of life, p=0.07). [Display omitted] MRI scores, in contrast to bleeding rates and Gilbert scores, showed continued age-related deterioration (Figure 1c; change of 2 MRI points/year of life, p < 0.0001). Age-related total and osteochondral deterioration on MRI increased steadily with age (on average 2 MRI-points/year of age, p < 0.0001 for each), whereas soft tissue scores increased rapidly to approximately 9 by age 20, and then plateaued at a score of approximately 10 for ages 20-50 (0.08 MRI points/year, p =0.28). ConclusionsIndividual patient meta-analysis of bleeding frequency, joint PE and MRI joint structure was useful to determine the natural history of hemophilic arthropathy in patients treated with on-demand therapy, and showed a continuous increase in joint bone and cartilage abnormalities across the age span despite an early leveling in bleeding rate and joint physical function. These data will be critical to determine the quantitative effects of prophylaxis on mitigation of joint deterioration when initiated at various ages following the onset of joint bleeding. Disclosures:Manco-Johnson:Bayer HealthCare: Research Funding. Lundin:Bayer HealthCare: Research Funding. Hong:Bayer HealthCare: Employment. Oldenburg:Octapharma AG: Consultancy, Investigator Other. Manco-Johnson:Biogen Idec: Membership on an entity's Board of Directors or advisory committees; Baxter BioScience: Membership on an entity's Board of Directors or advisory committees; CSL Behring: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer HealthCare: Membership on an entity's Board of Directors or advisory committees, Research Funding; NovoNordisk: Membership on an entity's Board of Directors or advisory committees; Eisai: Research Funding.▪▪

Exploring the biological basis of haemophilic joint disease: experimental studies

Haemophilia has been recognized as the most severe among the inherited disorders of blood coagulation since the beginning of the first millennium. Joint damage is the hallmark of the disease. Despite its frequency and severity, the pathobiology of blood-induced joint disease remains obscure. Although bleeding into the joint is the ultimate provocation, the stimulus within the blood inciting the process and the mechanisms by which bleeding into a joint results in synovial inflammation (synovitis) and cartilage and bone destruction (arthropathy) is unknown. Clues from careful observation of patient material, supplemented with data from animal models of joint disease provide some clues as to the pathogenesis of the process. Among the questions that remain to be answered are the following: (i) What underlies the phenotypic variability in bleeding patterns of patients with severe disease and the development of arthropathy in some but not all patients with joint bleeding? (ii) What is the molecular basis underlying the variability? (iii) Are there strategies that can be developed to counter the deleterious effects of joint bleeding and prevent blood-induced joint disease? Understanding the key elements, genetic and/or environmental, that are necessary for the development of synovitis and arthropathy may lead to rational design of therapy for the targeted prevention and treatment of blood-induced joint disease.

Neoangiogenesis contributes to the development of hemophilic synovitis

AbstractJoint arthropathy secondary to recurrent hemarthroses remains a debilitating complication of hemophilia despite the use of prophylactic factor concentrates. Increased vascularity and neoangiogenesis have been implicated in the progression of musculoskeletal disorders and tumor growth. We hypothesized that de novo blood vessel formation could play a major role in the pathogenesis of hemophilic joint disease (HJD). We observed a 4-fold elevation in proangiogenic factors (vascular endothelial growth factor-A [VEGF-A], stromal cell–derived factor-1, and matrix metalloprotease-9) and proangiogenic macrophage/monocyte cells (VEGF+/CD68+ and VEGFR1+/CD11b+) in the synovium and peripheral blood of HJD subjects along with significantly increased numbers of VEGFR2+/AC133+ endothelial progenitor cells and CD34+/VEGFR1+ hematopoietic progenitor cells. Sera from HJD subjects induced an angiogenic response in endothelial cells that was abrogated by blocking VEGF, whereas peripheral blood mononuclear cells from HJD subjects stimulated synovial cell proliferation, which was blocked by a humanized anti-VEGF antibody (bevacizumab). Human synovial cells, when incubated with HJD sera, could elicit up-regulation of HIF-1α mRNA with HIF-1α expression in the synovium of HJD subjects, implicating hypoxia in the neoangiogenesis process. Our results provide evidence of local and systemic angiogenic response in hemophilic subjects with recurrent hemarthroses suggesting a potential to develop surrogate biologic markers to identify the onset and progression of hemophilic synovitis.

Unraveling hemophilic arthropathy

In this issue of Blood, Acharya and colleagues provide evidence for the role of angiogenesis in the pathophysiology of hemophilic joint disease. Is this the linchpin that unravels this important clinical condition or merely a cog in a not so stepwise process?

Vitamin D deficiency in children with haemophilia

Background: Recent studies have shown that children with severe haemophilia could have moderately reduced bone density compared with gender‐ and age‐matched control subjects. Patients with more established changes resulting from haemophilic joint disease exhibited the lowest bone mineral density. The reason for this includes factors such as lack of weight‐bearing physical activity, lower height and weight reached by these patients, muscle atrophy and hepatitis C seropositivity. A lower peak bone density reached during late adolescence and young adulthood predisposes to the development of osteoporosis in the later years.Objective: While Vitamin D and calcium supplementation has been recommended by many authors for haemophiliacs, there are no studies looking at Vitamin D levels in these patients. The aim of this study was to evaluate for the prevalence of Vitamin D deficiency and the need for supplementation in the haemophiliac patients in our centre.Methods: The 25‐hydroxy Vitamin D3 (25‐OH D3), calcium, phosphorus and PTH levels were measured in patients between the ages of 1–18 years during their regular visits to the haemophilia centre. A 25‐OH D3 level of &gt;30ng mL−1 is considered as adequate, levels of 21–29 ng mL−1 indicates a relative insufficiency and a level &lt;20ng mL−1 is defined by most experts as being absolutely Vitamin D deficient.Results: Of the 33 patients, 21 of them were Vitamin D deficient (63.6%). Calcium, phosphorus and PTH levels did not correlate with Vitamin D levels.Conclusions: Vitamin D deficiency is highly prevalent in patients with haemophilia in our centre, and given their propensity to develop osteopenia, Vitamin D supplementation is essential in this group of patients. As the calcium, phosphorus and PTH level do not correlate with Vitamin D levels, evaluation of Vitamin D deficiency needs the measurement of serum 25‐hydroxy D3 level. The reasons for a deficiency of Vitamin D in these patients, the amount of supplementation needed and the effect of supplementation of Vitamin D on attaining the peak bone mass density of these patients need to be explored further. Vitamin D status in patients with haemophilia (25‐OH D3 level) &gt;30 ng mL−1 (normal) 21–29 ng mL−1 (relative insufficiency) &lt;20 ng mL−1 (severe insufficiency) &lt;30 ng mL−1 (vitamin D deficiency) Haemophilia A&amp;B (# of patients) 12 9 12 21/33 = 63.6%

Hemophilic joint disease – current perspective and potential future strategies

Recurrent hemarthroses can lead to hemophilic joint disease (HJD), which is one of the most disabling complications of these X-linked recessive disorders characterized by a deficiency of clotting factors VIII/IX. The pathogenesis of HJD is not well understood and there is evidence to suggest that iron may play a central role in the pathogenetic process causing changes at the molecular level and through the release of cytokines and perpetuation of a chronic inflammatory state. Also, there may be a role for angiogenesis in accelerating the joint damage begun by recurrent hemarthroses. Hemophilic joint disease can be diagnosed by MRI which provides information about the pathology of the synovium, articular cartilage and bone. However, it is expensive, and maybe cumbersome in young children who require sedation. Newer, cost-effective imaging tools such as ultrasonography need to be explored to facilitate diagnosis and monitoring of joint disease. Repeated bleeds into the joint could be prevented by reducing the number of bleeds by the prophylactic infusion of factor concentrates on a bi-weekly to alternate day schedule depending on the activity level and bleeding phenotype. However, the dose, schedule and timing of prophylaxis still remain unresolved despite some multi-center clinical studies proving its benefit in preserving joint function. Prohibitive costs and the need for venous access devices in delivering factor concentrates in younger children continue to complicate universal recommendations of prophylaxis. In those patients who fail or refuse prophylaxis, procedures such as isotopic synovectomy can provide relief from repeated joint bleeds, again the timing of which is not well-defined. Newer strategies to identify early joint disease through the use of serological markers are needed. Also, cost-effective imaging modalities are needed so that treatment strategies such as prophylaxis and isotopic synovectomy can be appropriately timed to reap maximum benefits. A combination of serological and imaging evidence of early joint disease might ultimately impact on the optimal management of hemophilic joint disease.

Pathogenesis of haemophilic synovitis: experimental studies on blood‐induced joint damage

Hemarthrosis is a common manifestation of haemophilia, and joint arthropathy remains a frequent complication. Even though the exact mechanisms related to blood-induced joint disease have not yet been fully elucidated, it is likely that iron deposition in the synovium induces an inflammatory response that causes not only immune system activation but also stimulates angiogenesis. This process ultimately results in cartilage and bone destruction. Investigating the processes that occur in the early stages of blood-induced joint disease in humans has been very limited. Therefore, the use of haemophilic animal models is critical to augment the understanding of this phenomenon. This article discusses three cellular regulators (p53, p21 and TRAIL) induced in synovial tissue that are important for iron metabolism. A cartilage remodelling programme induced by the release of cytokines and growth factors that result in articular damage is also discussed. Full elucidation of the pathogenesis of haemophilic joint disease is required to identify new avenues for prevention and therapy.

Radiation Exposure of Hemophiliacs After Radiosynoviorthesis with 186Re Colloid

Very limited data are available in the literature on the doses of unwanted radiation that patients receive following treatment with radiosynoviorthesis (RSO). The aim of this study was to assess the radiation exposure after RSO with (186)Re colloid in hemophiliacs. This study involved 12 hemophiliacs who were treated for hemophilic joint disease with 14 RSOs by using (186)Re colloid. Whole-body scintigrams were performed 1, 6, and 24 hours and 3 and 7 days after RSO. Measurements, using a whole-body counter, were done immediately after scintigraphy, with the treated joint protected with a lead shield. The cumulative activity of (186)Re in the body and in the lymph nodes was calculated. The distribution of (186)Re in the body was determined by using the values for small colloids as proposed by the International Commission on Radiological Protection (ICRP) Publication 53. The computer code, OLINDA/EXM (Vanderbilt University, Nashville, TN), was used for the calculation of the internal dose. A constant distance of 1 m between the ankle joint and body organs, and of 0.33 m between the elbow or shoulder joint and body organs, was used to calculate the contribution of gamma radiation to the effective radiation dose. The mean effective dose received by hemophiliacs after RSO with (186)Re colloid was 28 +/- 9 microSv/MBq of the activity injected into the joint. The patients received 0.8-3.7 mSv (1.9 +/- 0.8 mSv) owing to the leakage of (186)Re from the treated joint and its retention in the body. The highest doses were established in the spleen (26.0 +/- 10.7 mGy), the liver (17.6 +/- 7.2 mGy), and red marrow (3.0 +/- 0.8 mGy). The contribution of gamma radiation to the effective dose was less than 0.1 mSv in RSO of the ankle, 0.4 mSv in the elbow, and 0.6 mSv in the shoulder-joint treatment. The activity of (186)Re in the regional lymph nodes was noted in 4 of the 14 treatments. In these cases, the estimated average dose received by individual lymph nodes was 14.7 +/- 1.9 Gy. RSO with (186)Re colloid is a safe treatment method. The effective dose received by patients after RSO by using (186)Re colloid is low, as are the radiation doses to the most exposed organs. If (186)Re is retained in the regional lymph nodes, the lymph node radiation dose would be high.

Modern management of haemophilic arthropathy

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.

Power Doppler Sonography Is a Promising Imaging Tool in the Diagnosis of Hemophilic Synovitis - Preliminary Analyses.

Hemarthrosis, a common manifestation of hemophilia, results in synovial proliferation leading to the development of synovitis, followed by arthropathy. Selective strategies like prophylaxis or isotopic synovectomy (IS) could be applied to prevent imminent joint deterioration but these are expensive, and their timing is unclear. Conventionally, synovitis was diagnosed based on clinical examination and radiography, which together tend to underestimate the extent of joint damage. Currently, magnetic resonance imaging (MRI) is utilized for the evaluation of cartilage and synovium in hemophilic joint disease (HJD). However, the need for sedation in younger children and high costs preclude its utility especially when frequent monitoring may be needed for management decisions. More recently, Power Doppler sonography (PDS) has been utilized to both detect and quantitate alterations in vascular flow in other arthritides. In the current study we compared findings obtained on PDS(using a Elegra scanner with a 7.5 MHz linear phased array transducer in tissue harmonic mode) in 12 subjects with HJD to MRI (using 3.0T GE scanner with dynamic gadolinium contrast enhanced perfusion studies and gradient echo sequence) as a reference standard. Clinical Joint scores were determined as per the Petrini Scoring system. Radiological Joint scores were as follows: No synovitis (0), mild (1), moderate (2) and intense (3). Our preliminary analyses showed that MRI and PDS could detect increased vascularity of the synovium in all subjects with clinically active synovitis (6/12) and that Clinical Joint scores correlated with Synovitis scores on MRI and PDS. Further, synovial thickness, vascularity of synovium defined as enhancement on post-contrast MRI (MRI flow) and pixel count on PDS (PDS flow) correlated significantly between the two methods - Table 1. We previously observed that HJD subjects have significantly elevated levels of angiogenic markers such as vascular endothelial growth factor (VEGF) as compared to controls thus implicating VEGF as a serological marker for synovitis. Acknowledging the fact that PDS detects flow at the microvascular level we further observed that subjects with increased synovial vascularity showed significant positive correlations with VEGF levels - Table 1. Hence, our data suggest that PDS in children may be a promising and inexpensive imaging tool in diagnosing synovitis associated with HJD. It could be potentially used as a screening tool after one or two joint bleeds to monitor for the development of early synovitis and aid in tailoring prophylaxis. Based upon these preliminary analyses, correlation of data obtained from PDS with serological markers of angiogenesis may further aid in predicting joint disease activity.ComparisonMRIPDSp-valueClinical Joint Score (Petrini)1.54 (synovitis score)0.01*Clinical Joint Score (Petrini)1.46 (synovitis)0.04*Mean Synovial Thickness (cm)4.777.970.03*Flow (Vascularity)138.10 (pce**)9.22 (pixel count)0.009*Mean Synovial Thickness vs. Flow***0.12Mean Synovial Thickness vs. Flow***0.02*VEGF Levels vs. Flow***0.03*VEGF Levels vs. Flow***0.049** p-values < 0.05 are significant as assessed by Spearman rank correlation coefficient; ** pce = post contrast enhancement; *** Synovial Thickness or VEGF Levels compared to indicated imaging technique

A Role for Angiogenesis in Hemophilic Synovitis.

Hemarthrosis, or bleeding into a joint, is the most common manifestation of hemophilia. Recurrent hemarthroses and synovial proliferation leads to the formation of a thickened synovial pannus, or synovitis, followed by destructive infiltration into the adjacent cartilage and bone, a condition known as hemophilic arthropathy. While the clinical sequence of events in hemophilic joint disease is understood, the pathogenesis of synovitis has not yet been elucidated. As such, there is scant objective evidence for the selective application of strategies like prophylaxis or isotopic synovectomy (IS) to prevent imminent joint deterioration. In other fibroproliferative disorders such as rheumatoid arthritis, osteoarthritis, psoriatic arthritis, and tumor growth, angiogenesis and the concomitant recruitment of bone marrow-derived (BMD) progenitors has been implicated in disease progression. Here, for the first time, we report direct evidence for the involvement of angiogenesis in the development and sustenance of hemophilic synovitis. Histological sections of synovial tissue from patients with hemophilic synovitis and arthropathy were highly vascularized and contained a high number of inflammatory cells, predominantly CD68+ macrophages, which co-localized with secreted pro-angiogenic factors including vascular endothelial growth factor (VEGF), basic fibroblastic growth factor (bFGF), matrix metalloproteinase-9 (MMP-9), tumor necrosis factor-alpha (TNF-a) and cyclooxygenase-2 (COX-2). Hemophiliacs with joint disease exhibited a five-fold increase in 12 circulating angiogenesis-related cytokines compared to individuals with a bleeding disorder without joint disease and to healthy controls, as profiled by a protein array. Likewise, plasma VEGF and MMP-9, critical mediators of BMD progenitor mobilization and important pro-angiogenic factors, were significantly elevated in hemophiliacs with joint disease compared to the non-joint disease groups (Table 1). Accordingly, hemophiliacs with joint disease (n=9) exhibited an increased percentage of circulating CD34+ progenitor cells as compared to control groups (n=6). Finally, in a functional in vitro assay, plasma from hemophiliacs with joint disease showed a markedly enhanced capacity to elicit an angiogenic response from human umbilical vein endothelial cells (HUVECs) as evidenced by the induction of morphogenetic changes resembling capillary-like structure tube formation and cord-like processes connecting cellular nodes. These data collectively suggest that angiogenesis may play an important role in the development of synovial proliferation and synovitis in hemophilia. Indexing circulating angiogenic growth factors and CD34+ precursors may provide effective means of detecting early synovial proliferation and identifying candidates for early intervention with prophylaxis or IS. Ultimately, anti-angiogenic agents may provide a novel preventative treatment strategy for hemophilic arthropathy.Table 1. Plasma concentrations of pro-angiogenic factors.FactorHemophiliacs w/ joint diseaseBleeding disorders w/o joint diseaseHealthy controlsP1P2VEGF, pg/ml93.2±16 (n=60)24.7±3 (n=42)24.7±3 (n=42)0.0010.026MMP-9, ng/ml157.8±53 (n=27)36.0±6 (n=27)34.8±8 (n=20)0.0290.050P1 indicates joint diseased hemophiliacs versus bleeding disorders w/o joint disease; P2 versus healthy controls.

Arthroscopic Synovectomy for Hemophilic Joint Disease in a Pediatric Population

Summary: Children with hemophilia can develop progressive arthropathy. Arthroscopic synovectomy has been used to reduce hemarthroses, but few long-term results have been published. In this article the authors review their first 12 years of experience. Data are reported on 44 pediatric patients (69 joints: 39 ankles, 21 elbows, 7 knees, 2 shoulders). The median age at surgery was 10 years Median follow-up was 79 months. Joints with sufficient follow-up data showed a median bleeding frequency decline of 84% (P < 0.001). Median arc of motion was stable or improved in the year after surgery in ankles, elbows, and shoulders. Complications were rare. Radiographic scores worsened slightly. In this largest analysis of arthroscopic synovectomy for children with hemophilia, rehabilitation was not problematic.

Arthroscopic synovectomy for hemophilic joint disease in a pediatric population.

Children with hemophilia can develop progressive arthropathy. Arthroscopic synovectomy has been used to reduce hemarthroses, but few long-term results have been published. In this article the authors review their first 12 years of experience. Data are reported on 44 pediatric patients (69 joints: 39 ankles, 21 elbows, 7 knees, 2 shoulders). The median age at surgery was 10 years Median follow-up was 79 months. Joints with sufficient follow-up data showed a median bleeding frequency decline of 84% (P < 0.001). Median arc of motion was stable or improved in the year after surgery in ankles, elbows, and shoulders. Complications were rare. Radiographic scores worsened slightly. In this largest analysis of arthroscopic synovectomy for children with hemophilia, rehabilitation was not problematic.

Radiological assessment of haemophilic arthropathy with emphasis on MRI findings.

Medical imaging of haemophilic joints is important for detecting abnormalities, grading their severity and selecting the appropriate therapy. The plain-film scoring systems for staging joint disease that were developed prior to the availability of magnetic resonance imaging (MRI) are inadequate for planning modern prevention and treatment. MRI is capable of delineating all of the soft tissue findings long before they are evident on plain radiographs. In this paper, an MRI scoring system is presented along with examples of joint effusion, haemarthrosis, synovial hypertrophy, haemosiderin deposition, erosions, cysts and cartilage loss. MRI is a powerful tool in the diagnosis, staging and treatment of patients with haemophilic joint disease.

Radiological evaluation of hemophilic arthropathy.

Hemophilia leads to recurrent bleeding episodes in joints resulting in a severe destructive arthropathy in many cases. Staging of hemophilic joint disease is important for identifying the site of bleeding and planning appropriate therapy. However, classification systems based on plain X-ray findings have been insensitive at detecting the earlier, possibly reversible, changes of synovial hyperplasia. They may also underestimate the severity of cartilage damage. Magnetic resonance imaging (MRI) has been shown to more accurately assess a hemophilic joint. Tentative hemophilic arthropathy scales based on MRI findings are being developed. Hopefully, use of these scales will result in more consistent assessment of hemophilic joints and facilitate development of more targeted treatment and thus prevent or delay the later, destructive changes in the articular cartilage and bone.

C-myc proto-oncogene expression in hemophilic synovitis: in vitro studies of the effects of iron and ceramide

AbstractHemophilia is a rare congenital bleeding disorder that is due to the deficiency of blood coagulation factor VIII or IX. Recurrent musculoskeletal bleeding is common and bleeding into joints results in a chronic inflammatory condition termed hemophilic synovitis. This destructive process is characterized by hemosiderin deposition in the superficial and deeper layers of the synovial membrane as well as a proliferation of synovial fibroblasts and vascular cells. The hyperplastic synovium and neovascular changes are reminiscent of the histopathologic appearance observed in malignant tissues. Indeed, the benign hyperplastic synovium in patients with hemophilia displays similar invasive and destructive behaviors suggesting the possibility of analogous disturbances in growth control and locally invasive mechanisms. Iron plays a role in malignant cell growth, local invasion, and tumor progression, possibly due to changes in the expression of the proto-oncogene, c-myc. We hypothesized that iron plays a similar role in hemophilic synovitis. To explore this hypothesis, we investigated the in vitro effects of iron on the proliferation of a primary, human synovial fibroblast cell (HSFC) line and the involvement of c-myc in this process. We also examined the role of ceramide, a sphingolipid capable of inducing apoptosis in this model system. HSFC proliferation was increased in a dose-dependent fashion and c-myc expression was enhanced by ferric citrate compared to sodium citrate control. Ceramide prevented both the iron-induced increases in HSFC proliferation andc-myc expression. These results indicate that iron probably plays a role in the proliferative changes observed in hemophilic joint disease and that aberrant expression of c-myc may underlie the iron effects. Furthermore, these results suggest that there may be a therapeutic role for ceramide in reversing these changes.