Ultrasonography in Hemophilic Joint Disease and Serum Markers
Condition: Hemophilia A; Hemophilia B; Hemarthroses
MeSH terms: Joint Diseases; Hemarthrosis; Hemophilia A; Hemophilia B
Study type: Observational

Summary: 
      Hemophilia is a bleeding disorder (deficiency of a blood clotting factor/ protein) resulting
      in bleeding in joints and muscles. As patients continue to bleed into their joints they
      develop progressive joint damage leading to joint contractures, disability and days missed
      from work and school resulting in chronic debilitating pain and compromised quality of life.
      Current therapy is the administration of the missing protein or factor concentrate on a
      scheduled basis to prevent bleeding into the joints referred to as prophylaxis. This factor
      concentrate is expensive ~ $ 3,000 - 6,000 per infusion/ week in a child weighing 20 kg
      translating into $ 77,000 /yr for life. This regimen has been shown to be effective to
      prevent joint bleeds but the timing is unclear and not based on adequate evidence. Currently
      joint damage is diagnosed using MRI which is expensive and requires sedation in children < 6
      yrs of age. Therefore there is a need for a user friendly tool such as a ultrasound to
      monitor for the development of joint disease and tailor treatment based on an individual
      child's needs. This would also enable differentiating a joint bleed from a soft tissue bleed
      which present similarly and duration of treatment tends to be longer for a joint bleed.
      Acharya et al have previously shown that ultrasound is comparable to MRI for the diagnosis of
      hemophilic joint disease in hemophilia patients over the age of 6 years. However, the
      diagnostic findings in children < 18 years with hemophilia on ultrasound is not well
      defined(1).

      The hemophilic synovium after repeated joint bleeds reveals the development of new vessels
      which are fragile and contribute to recurrent joint bleeds. Acharya et al have previously
      shown that angiogenesis, a process of new vessel formation is active in hemophilic synovium
      and angiogenic markers were significantly elevated in hemophilic patients with joint disease
      when compared to those without (2). Since ultrasound can detect these new vessel changes in
      the hemophilic synovium in hemophilia patients with joint disease and hemophilia patients
      with joint disease demonstrate elevated markers of new vessel formation these investigators
      would now like to determine whether radiological findings of hemophilic joint disease
      correlate with serological angiogenic markers. This may enable the development of biomarkers
      for hemophilic joint disease.

      Findings from this study will enable the development of ultrasound as a user friendly tool in
      the hemophilia clinic in order to understand whether every pain and swelling in a joint is
      actually a joint bleed or soft tissue bleed and to monitor for joint changes to institute or
      augment scheduled factor infusions ( prophylaxis). This will also result in significant
      improvement in quality of life with tailored prophylaxis .
    

Detailed description: 
      Background: Hemophilic joint disease secondary to recurrent hemarthroses is one of the most
      disabling and costly complications of hemophilia. Prior to widespread use of prophylactic
      factor concentrates, children in the United States with severe hemophilia A and B (X-linked
      recessive disorders with <1% factor VIII/IX (FVIII/FIX) activity) experienced an average of
      30-35 hemarthroses per year reported for FVIII deficiency (3,4 ). Clinical and sub clinical
      hemarthroses during childhood results in synovitis (hypertrophied synovium characterized by
      villous formation, markedly increased vascularity and chronic inflammatory cells (5)
      eventually leading to pannus formation and destructive arthritis (6, 7). At this time,
      synovial bleeding may be related not only to clotting factor deficiency but also to
      pre-existing vascular damage and inflammation, which is difficult to control clinically. Use
      of factor concentrate prophylaxis results in hemophilia patients experiencing fewer joint
      bleeds, less rapid deterioration of joint function and fewer days lost from school or work.
      However, it may be complicated by the unpredictable development of an inhibitor (a
      high-affinity, polyclonal, function-neutralizing antibody directed against FVIII/FIX), with
      an incidence of about 25% and 6% respectively (8) . These individuals have limited treatment
      options or are treated with products that are less efficacious in treating the joint bleed
      along with potential deleterious side effects such as thrombogenecity( 9) thus favoring joint
      disease development.

      Primary prophylaxis (infusion of FVIII concentrates (25 - 40 u/kg thrice weekly or FIX
      concentrates - 80-100u/kg twice a week starting at age 1-2 yrs) before the onset of joint
      bleeds is used in Sweden since the 1960s to keep the trough level of factor VIII/FIX > 1%,
      converting a severe hemophilia patient (FVIII/FIX activity <1%) into a milder form (FVIII/FIX
      >5%) (10 ) . This strategy is expensive (~ $77,760/year for a 20 kg child based on the use of
      3000 to 6,000 u/kg/yr with recombinant factor VIII), and may require the use of venous access
      devices in young children, which is complicated by severe infections, bleeding and thrombosis
      (11) . Secondary prophylaxis on the other hand, which involves the use of FVIII/FIX
      concentrates after "target joints" (at least four bleeds occurring into a single joint in the
      previous six months) have been identified may limit bleeding and subsequent joint damage.
      However, progression of existing joint disease continues and it is unclear whether secondary
      prophylaxis can actually prevent joint deterioration (12) . Furthermore, studies comparing
      primary and secondary prophylaxis in relation to cost-effectiveness and long-term joint
      morbidity suggest that primary prophylaxis improved long-term joint outcome but was twice as
      expensive (13 ) . For these reasons, the optimum age, subject population, and timing of
      prophylaxis is highly debated. Finally, therapeutic options for individuals who fail or
      cannot use prophylaxis (inhibitor patients) or refuse prophylaxis include isotopic (IS) and
      surgical synovectomy. Isotopic synovectomy involves intraarticular injection of 32P- colloid
      with the intent of scarring off the synovium leading to a subsequent reduction in
      hemarthroses (14) , both procedures being recommended for patients with chronic synovitis and
      ongoing hemarthroses. Again, the timing of these strategies in relation to the onset of
      synovitis remain unclear. Hence, if prophylaxis is not started early (before the occurrence
      of joint bleeds) and subject population is not optimized, a strategy to detect and monitor
      synovitis and joint arthropathy is urgently needed so that prophylaxis and synovectomy can be
      timed based on evidence to reap optimum benefits. Furthermore, in hemophilic children who
      complain of joint pains, clinical examination sometimes, may not clearly define whether the
      symptoms are related to a joint bleed, synovitis or surrounding soft tissue bleeds. Studies
      in animals suggest that cartilage damage can occur concurrently with synovial damage (15)
      contributing to joint arthropathy. Therefore, it seems that determination of both synovial
      and cartilage changes would be imperative and may help to guide prophylaxis.

      Traditionally, hemophilic arthropathy has been diagnosed by clinical examination and plain
      radiographs of joints, which together tend to underestimate the extent of joint destruction
      (16) . Magnetic Resonance Imaging (MRI) can estimate the degree of bony damage associated
      with hemophilic joint disease (14 , 17 -19). The investigators have previously shown the
      utility of ultrasound-power Doppler sonography( USG-PDS) in detecting synovitis associated
      with hemophilic joint disease when compared to MRI ( 1) . The need for sedation in children
      and high costs ($ 2500 for MRI with sedation versus $ 600 for USG- PDS - no sedation at this
      institution) override the utility of this tool when repeated studies may be required for
      closer surveillance of joint disease progression. Visualization of cartilage is clinically
      relevant because benefits of both prophylaxis and synovectomy are realized only if there is
      minimal damage to cartilage. Furthermore, there is scattered evidence to suggest that
      isotopic synovectomy in a joint affected by bony arthropathy can lead to progression of the
      arthropathy leading to crippling arthritis.

      The pathogenesis of HJD is not well defined. Neoangiogenesis is a critical factor in
      processes, such as tumor growth and inflammatory arthritis (20). Increased vascularity and
      neoangiogenesis have been implicated in the progression of musculoskeletal disorders and
      tumor growth. Vascular endothelial growth factor (VEGF), the principal signaling molecule in
      angiogenesis, can be induced by hypoxia and certain cytokines through interaction with its
      receptors, VEGFR1 and VEGFR2 (21 -23). The synovitic pannus in other joint diseases that
      share histologic similarities with hemophilic joint disease (HJD) have enhanced oxygen demand
      and show evidence of de novo blood vessel formation, including endothelialization of the
      synovium( 24) . Further, VEGF expression in the serum has been correlated with disease
      activity in rheumatoid arthritis ( 25) . Endothelialization may occur as a result of mature
      endothelial cell migration or through the recruitment of bone marrow (BM)-derived endothelial
      progenitor cells (EPCs) and hematopoietic progenitor cells (HPCs) from the peripheral
      circulation (26) . Importantly, proliferating synovium can secrete chemocytokines, such as
      VEGF, that might promote recruitment of endothelial cells (ECs) to sites of active
      angiogenesis ( 25) . Co-localization of hypoxia-inducible factor- 1 (HIF-1 α) which is a
      transcription factor involved in the induction of VEGF and produced in response to hypoxia
      within the joint and VEGF emphasizes the role of hypoxia in the up-regulation of angiogenesis
      in rheumatoid joint diseases ( 27).

      The investigators have previously 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 hemophilic joint disease (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. The investigators results
      provided 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( 2). Therefore, evidence of
      increased synovial vascularity on USG-PDS and elevated angiogenic markers suggestive of
      increased vascularity in hemophilic joint disease subjects provides a compelling opportunity
      to develop surrogate biological markers for hemophilic joint disease. This would also further
      aid in tailoring strategies such as prophylaxis and synovectomy in an individual patient.
    

Intervention name(s): ultrasound
Intervention type(s): Other
Intervention description(s): ultrasound will be performed in hemophilia boys with a history of 20 joint bleeds- Group I, less than 2 joint bleeds into a joint -Group II and no joint bleeds- Group III
Observational model: Cohort
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        Boys with hemophilia and inherited bleeding disorders with and without a history of
        hemarthroses
      
Biospecimen description: 
      plasma samples for angiogenic and cartilage degradation markers
    
Keywords: ultrasound,; ultrasonography; hemophilic joint; Doppler