Exploration of the pathogenesis of haemophilic ... - Wiley Online Library

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Exploration of the pathogenesis of haemophilic joint arthropathy: understanding implications for optimal clinical management Suchitra S. Acharya Hematology/Oncology/Stem Cell Transplantation, Cohen Children’s Medical Center, New Hyde Park, NY, USA

Summary Haemophilia is an inherited disorder of clotting factor deficiencies resulting in musculoskeletal bleeding, including haemarthroses, leading to orthopaedic complications. The pathogenesis of haemophilic joint arthropathy continues to be explored and there is evidence to suggest that iron, cytokines, and neo angiogenesis can initiate synovial and early cartilage damage resulting in molecular changes and the perpetuation of a chronic inflammatory state. This joint arthropathy has long term consequences for bone health resulting in chronic pain and quality of life issues in the individual with haemophilia. Haemarthroses can be prevented by the administration of clotting factor concentrates (prophylaxis). However, high costs and the need for venous access devices in younger children continue to complicate recommendations for universal prophylaxis. In patients who fail or refuse prophylaxis, procedures, such as synovectomy and arthroplasty, can provide relief from repeated haemarthroses. The optimal timing of these, however, is not well defined. Prevention of joint arthropathy needs to focus on prevention of haemarthroses through prophylaxis, identifying early joint disease through the optimal use of cost effective imaging modalities and the validation of serological markers of joint arthropathy. Screening for effects on bone health and optimal management of pain to improve quality of life are, likewise, important issues. Keywords: haemophilia, synovium, cartilage, haemarthroses, joint arthropathy.

Musculoskeletal bleeding, including haemarthroses, is the hallmark of haemophilia A/B (Factor [F]VIII/FIX deficiency). These are X-linked recessive disorders with an incidence of 1 in 10 000(FVIII) and 1 in 30 000(FIX) live male births

Correspondence: Suchitra S. Acharya, MD, Hematology/Oncology/ Stem Cell Transplantation, Suite # 255, Cohen Children’s Medical Center of New York, 269-01 76th Ave, New Hyde Park, NY 11040, USA. E-mail: [email protected]

respectively. These disorders affect all ethnicities and geographic areas without a significant predilection for any particular risk group (Heyworth et al, 2005). The bleeding phenotype may be variable, but is usually predictable and therefore, haemophilic joint arthropathy, secondary to recurrent haemarthroses, remains one of the most disabling and expensive complications of haemophilia (van Dijk et al, 2005). Clinical and sub clinical haemarthroses results in synovitis and destructive arthritis in both patients and animal models (Madhok et al, 1988; Rodriguez-Merchan, 1997; Hakobyan et al, 2005). The use of factor concentrate prophylaxis results in fewer joint bleeds, less joint arthropathy and fewer days lost from school or work (Liesner et al, 1996; Tagliaferri et al, 2008). However, access to clotting factor may be limited worldwide. Moreover, cost effectiveness at the current dose, frequency of prophylaxis and the need for venous access devices in younger children to conduct prophylaxis is still being investigated (Brown et al, 2002; Manco-Johnson et al, 2007). Furthermore, in the presence of joint arthropathy, prophylaxis may not stop further joint deterioration, necessitating the use of isotopic or arthroscopic synovectomy (Rodriguez-Merchan et al, 2007; Verma et al, 2007). The use of factor concentrates may also be complicated by the unpredictable development of an inhibitor (a high-affinity, function-neutralizing antibody directed against FVIII/FIX), with an estimated risk in the range of 25% and 6% respectively (Ehrenforth et al, 1992; Wight & Paisley, 2003; Astermark, 2006). These inhibitors can be successfully eradicated in about 75% of individuals with FVIII deficiency (Wight & Paisley, 2003), whereas FIX inhibitors are difficult to eradicate successfully (DiMichele et al, 2002). The kinetics of inhibitor eradication is unpredictable and during this time, these individuals may continue to bleed into their joints, increasing their risk for joint arthropathy (Morfini et al, 2007; DiMichele et al, 2010). Moreover, inhibitor management calls for the use of products that are less efficacious in treating the joint bleed, thus favouring the development of joint arthropathy (Morfini et al, 2007). Alternatively, the optimal implementation of strategies, such as prophylaxis and synovectomy, to prevent joint arthropathy would require a more sensitive tool for detecting joint

ª 2011 Blackwell Publishing Ltd, British Journal of Haematology, 156, 13–23

First published online 3 November 2011 doi:10.1111/j.1365-2141.2011.08919.x

Review arthropathy than is currently possible with clinical surveillance or plain radiographs. Magnetic resonance imaging (MRI) can detect both synovial and cartilage changes resulting from recurrent haemarthroses (Nuss et al, 2000; Manco-Johnson et al, 2007). However, MRI is expensive and requires sedation in most children under 6 years of age, limiting its utility for routine monitoring of arthropathy progression, especially as the median age for the first haemarthroses is about 17 months (Manco-Johnson et al, 2007). Ultrasonography with power Doppler is being investigated as a cost effective imaging tool to diagnose and monitor joint arthropathy (Zukotynski et al, 2007; Acharya et al, 2008). A better understanding of the factors involved in the pathogenesis of haemophilic joint arthropathy, along with the validation of user-friendly imaging modalities, might make it possible to define imaging and serological guidelines to identify individuals at higher risk for joint arthropathy. In order to elucidate these issues, this review will be divided into the following sections: 1 Clinical impact of joint arthropathy including general impact, bleeding phenotype, chronic pain, quality of life and bone health issues. 2 Pathogenesis of joint arthropathy including synovial and cartilage changes, factors modifying the impact of haemarthroses in the haemophilic joint. 3 Options for early diagnosis and treatment of haemophilic joint arthropathy.

Clinical impact of haemophilic joint arthropathy The development of joint arthropathy can be an enormous health burden and will be addressed in this section including general clinical impact, bleeding phenotype, chronic pain modifying quality of life and long term consequences on bone health.

General impact The median age at first joint haemorrhage has been reported to range from 17 months (Manco-Johnson et al, 2007) to 2Æ2 years, (Fischer et al, 2002a) in various studies. Around one-quarter of all patients with severe disease have at least one target joint, as defined by the United States Centres for Disease Control and Prevention as four episodes of haemarthrosis in a 6-month interval, or 20 joint haemorrhages over the lifetime of a joint (van Dijk et al, 2005). Compared with an on-demand treatment strategy, a primarily prophylactic treatment strategy led to a better joint arthropathy outcome at equal treatment costs in young adults with severe haemophilia (Fischer et al, 2002b). Furthermore, the use of high dose prophylaxis (mean clotting factor consumption of 4012 iu/kg/year) for joint arthropathy was twice as expensive as intermediate dose prophylaxis (1488 iu/kg/year) versus on demand therapy (1612 iu/kg/year), with slightly improved outcome in the high dose group (van den Berg et al, 2003). In Canada, Kern et al 14

(2004) reported that the total cost of treating a boy with ondemand factor concentrates increased by 119% after development of a target joint, from 20 091 Canadian dollars ($CDN) (in 2002) in the year before to $CDN 43 890 in the year after target joint development. Therefore, the unanswered question is determining when to start prophylaxis to prevent joint arthropathy. Starting at an early age could be cost-effective, because young patients would require small amounts of factor, which could result in fewer haemarthroses and less joint arthropathy in adulthood and consequently lower health care costs. Therefore, the physical and economic burden of joint arthropathy, if not optimally managed, can be considerable both to patients and care-givers.

Clinical bleeding phenotype and haemophilic joint arthropathy The scheduled administration of clotting factor concentrates (prophylaxis) is important in limiting bleeding in general and specifically joint bleeding and is widely considered to be the optimal therapy for people with haemophilia (Hoots & Nugent, 2006; Pipe & Valentino, 2007). The benefits of primary prophylaxis (starting before age 2 years and/or less than two bleeds into a joint) have been clearly established by the pioneering work of Nilsson and colleagues (Nilsson et al, 1992; Nilsson, 1993) and others (Plug et al, 2004; MancoJohnson et al, 2007). However, despite prophylaxis, joint bleeding and consequently, joint arthropathy is still observed. In a multi-centre US study, 7% of boys in the prophylaxis group versus 45% of those in the episodic-therapy group were considered to have an abnormal index-joint structure on MRI (Manco-Johnson et al, 2007). Factors involved in defining the bleeding phenotype impacting the development of joint arthropathy are not well established. Age at first joint bleed was inversely related to treatment requirement and arthropathy as measured by the Pettersson radiological joint score, suggesting an association with bleeding pattern (van Dijk et al, 2005). Although prophylaxis can modify the bleeding pattern, individual pharmacokinetic variability could hinder the maintenance of factor levels > 1% to avoid bleeding. This level cannot always be ensured in children who demonstrate a shorter factor half-life, necessitating more frequent factor administration for prophylaxis (Collins et al, 2009). Other factors, such as thrombophilic factors, might also have an impact on the bleeding phenotype and needs to be explored in larger studies (Arbini et al, 1995; Lee et al, 2000). Therefore, the impact of bleeding phenotype on joint arthropathy may be also be related to altered individual pharmacokinetics, noncompliance, insufficient dosing, and participation in activities with high risk of injury (van Dijk et al, 2005).

Chronic pain issues and quality of life Joint bleeding results in pain (Choiniere & Melzack, 1987; Rattray et al, 2005), limitations in joint function, (Soucie et al,


Review 2004) and long-term orthopaedic complications (RodriguezMerchan, 1996). Treatment of pain seems to be inadequate in the haemophilia population with non-availability of welldefined scales to assess chronic pain related to joint arthropathy. In one study, 76% of patients (age: 21–63 years) used analgesic medications for acute and chronic pain (Wallny et al, 2001). Non-steroidal anti-inflammatory drugs, such as rofecoxib, have been used in a small study with proven benefit (Rattray et al, 2005). However, recent evidence of an association of this and similar drugs with serious cardiovascular side effects has limited their use. Other treatment modalities including pool therapy, massage, acupuncture, acupressure, heat, relaxation, hypnosis and biofeedback, were used in 12 bleeding episodes in the prophylaxis group experienced 25% of their bleeds in their target joints. These data support the assertion that therapeutic care programmes in this population must be evaluated not only in terms of financial cost to achieve adequate musculoskeletal

outcomes, but also the individual and societal benefits of increased academic accomplishments through adequate suppression of haemorrhagic events. (Shapiro et al, 2001).

Bone health Haemarthroses – induced joint arthropathy can affect bone health and compromise quality of life (Remor et al, 2005; von Mackensen, 2007). Several paediatric and adult studies specifically addressing low bone mineral density in haemophilia patients have been published recently. One study has reported the prevalence of low bone mineral density as high as 70% in their adult haemophilia population (Gerstner et al, 2009). Correlation with low vitamin D levels, low body mass index (BMI), lower activity scores, decreased joint range of motion, human immunodeficiency virus (HIV) and hepatitis C virus (HCV), history of inhibitor and age were observed. However, no fractures were reported. Interestingly, in another study, a 12% incidence of fractures was reported in adult life (Nair et al, 2007). A meta analysis of bone mineral density studies in paediatric and adult patients with haemophilia reported a significantly lower lumbar bone mineral density that was not significantly correlated with reduction in BMI or HCV infection (Iorio et al, 2010). Low osteocalcin levels in children with haemophilia predominated in those with low bone mineral density, indicating a diminished osteoblastic bone formation (Tlacuilo–Parra et al, 2011). Early prophylaxis (started before age 3 years) correlated with normal bone mineral density scores in a Swedish population (Khawaji et al, 2011). Therefore, screening for low bone mineral density to reduce the risk of osteoporosis and fractures in adulthood might be warranted in haemophilia populations who have not been on adequate prophylaxis. Further studies are needed to assess the impact of low bone mineral density on long-term bone health.

Pathogenesis of haemophilic joint disease Components of the synovial joint Haemarthroses predominantly occurs in large synovial joints, which comprise two connected bones enclosed by a capsule composed of ligaments with synovial tissue on the inside. This synovium is responsible for the production of synovial fluid, which nourishes and lubricates the articular cartilage that covers bone ends (Fig 1). Synovial tissue has a lining and a sublining layer. The sublining layer has fatty and fibrous tissue and an abundance of blood vessels and capillaries, which tend to be the source of joint bleeds (Garnero, 2008). Articular cartilage covers bone ends and is not lined by synovial tissue and hence is avascular. The chondrocyte is the only cartilage cell type that cannot self-renew (Muir, 1995; Archer & Francis– West, 2003). Collagen, a main component of cartilage matrix entraps proteoglycans, which are responsible for its integrity. Any perturbation from blood or trauma can cause excessive


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Fig 1. Diagram of a normal synovial joint: The articular cartilage provides a cushion to resist the load of weight bearing. The fibrous capsule encases the articulating surfaces. The synovial membrane, which is responsible for production of synovial fluid, nourishes and lubricates the articular cartilage that covers bone ends and is composed of a lining and a sublining layer. The synovial lining layer contains type A synovial cells, which are macrophages, and type B synovial cells, which are specialized fibroblasts. These fibroblasts have a synthetic function whereas macrophages provide a scavenger function; removing blood and other deleterious substances from the joint space. Beneath the sublining layer there is a rich network of delicate blood vessels to provide nutrients, oxygen and growth factors to the synovium and articular cartilage.

proteoglycan release contributing to long lasting cartilage damage (Sandell et al, 2008). Synovium, cartilage and bone changes seem to influence each other and are involved in the pathogenesis of haemophilic joint arthropathy.

Factors contributing to synovial changes Another function of synovial tissue is removal of blood and its components after haemarthroses. However, removal of blood in large amounts also triggers the synovial cells to proliferate and hypertrophy with the release of hydrolytic enzymes (Arnold & Hilgartner, 1977). These enzymes, along with elevated levels of prostaglandins, help maintain the inflammatory response in the synovium. Iron, a breakdown product of haemoglobin, seems to be a potential trigger in synovial proliferation. The histological observation of a highly vascular synovium in active synovitis has implicated a role for neoangiogenesis in the joint arthropathy process. Inflammation is part and parcel of a joint bleed, strongly suggesting a role for inflammatory mediators in the joint disease process. Therefore, haemophilic joint arthropathy is thought to be degenerative and inflammatory in nature with hypertrophied synovium characterized by villous formation, markedly increased vascularity and chronic inflammatory cells eventually leading to pannus formation and destructive arthritis (Rodriguez-Merchan, 1997). Role of iron, MYC, and MDM2. Bleeding into the joint space exposes synovial cells to blood and its components including iron. Morris et al (1986) proposed a central role for iron in the development of haemophilic synovitis. Iron deposits were observed in the cytoplasm of the lining synovial cells as discrete granules along with lymphocytic infiltration and neo16

vascularization in the haemosiderotic tissues (Roosendaal et al, 1998). It was further observed that when iron loaded tissues were cultured in vitro, they synthesized more proinflammatory cytokines, such as interleukin (IL) 6, IL1b, and tumour necrosis factor a (TNFa), compared to normalappearing synovial tissue (Roosendaal et al, 1998). Moreover, Wen et al (2002) showed that iron increased human synovial cell proliferation and induced MYC, the cell growth promoting transcription factor. They further showed that iron might be linked to multiple molecular changes leading to pathologic proliferation of synovial cells (Wen et al, 2002). Iron was also shown to induce MDM2 gene expression in synovial cells by these authors in a subsequent study (Hakobyan et al, 2004). An increase in MDM2 expression decreased p53 activity resulting in abrogation of synovial apoptosis and/or increase in proliferation (Hakobyan et al, 2004). Thus, it seems that the presence of blood in the joint can lead to pro-proliferative and anti-apoptotic cellular changes that may contribute to synovial cell transformation leading to pannus formation. Role of angiogenic mediators. Angiogenesis and the concomitant recruitment of bone marrow-derived progenitors has been implicated in disease progression in other fibroproliferative disorders, such as rheumatoid arthritis, osteoarthritis, and tumour growth (Folkman & Shing, 1992). Acharya et al (2011) observed direct evidence for the involvement of angiogenesis in the development and sustenance of haemophilic synovitis. A four-fold elevation in pro-angiogenic factors [vascular endothelial growth factor (VEGF), stromal cell-derived factor-1 (SDF-1) and matrix metalloproteinase 9 (MMP-9)] and pro-angiogenic macrophage/monocyte cells (VEGF+/CD68+ and VEGFR1+/CD11b+ and VEGF/CD68+) in the synovium and peripheral blood of


Review haemophilic joint arthropathy subjects, along with significantly increased numbers of VEGFR2/AC133+ endothelial progenitor cells (EPCs) and CD34/VEGFR1+ haematopoietic progenitor cells (HPCs) was observed. Sera from haemophilic subjects with joint arthropathy induced an angiogenic response in endothelial cells that was abrogated by blocking VEGF while peripheral blood mononuclear cells from these subjects stimulated synovial cell proliferation, which was blocked by a humanized anti-VEGF antibody (bevacizumab). Human synovial cells when incubated with haemophilic sera could elicit upregulation of hypoxia-inducible factor 1 a (HIF1A) mRNA, implicating hypoxia in the neo-angiogenesis process. Therefore, synovial changes could be initiated by blood and its breakdown products leading to synovial proliferation creating hypoxia and release of HIF1A. This in turn could initiate angiogenesis within the synovium, leading to the development of active synovitis and joint arthropathy.

Factors contributing to cartilage changes Human and animal studies have suggested that cartilage changes may occur independently of synovial changes (Roosendaal et al, 1997; Hakobyan et al, 2005). These cartilage changes seem to be occurring even after the first haemarthroses. The direct effects of cartilage exposure to blood have been shown in a canine model after injection of blood in canine knees. A direct decrease in proteoglycan – glycosaminoglycan (GAG) synthesis and an increase in its release were observed (Roosendaal et al, 1999). The underlying mechanism for this blood-induced joint damage is unclear but seems to be a consequence of erythrocytes, and mononuclear cells in the joint space (Roosendaal et al, 1997). Prolonged exposure of cartilage to blood can lead to apoptosis of the chondrocyte (Hooiveld et al, 2003). As chondrocytes hardly proliferate, apoptosis leads to long lasting and irreversible damage to cartilage matrix (Burkhardt et al, 1986).It is probable that the IL-1 b produced by activated monocyte/macrophages in the joint cavity during haemarthrosis increases the production of H2O2 by chondrocytes, which causes irreversible oxidant damage (Hooiveld et al, 2003).

Factors and genes modifying synovial and cartilage response to haemarthroses Variability in the bleeding phenotype of severe haemophilia is well known in clinical practise, which may be reflected by variability in onset and frequency of bleeding, treatment requirements and the development of joint arthropathy. In a multicentre study, seven of 14 patients treated with 0–500 iu/ kg/year had no joint arthropathy after 6 years (Aledort et al, 1994). Furthermore, Fischer et al (2001) reported that about 20% of patients with severe haemophilia permanently switched to an on-demand regimen while maintaining a low joint bleed frequency. Therefore, the ability to remain on on-demand treatment may also suggest a milder bleeding pattern in a

cohort intended for treatment with individually tailored prophylaxis. This variable impact of haemarthroses raises questions about modifying factors on the response of the haemophilic joint to haemarthroses. HFE mutations. In a study by Cruz et al (2005), the severity of haemophilic joint arthropathy, as measured by the number of haemarthroses per year and number of affected joints, was associated with the presence of HFE mutations, particularly C28Y and H63D. A cohort of 34 haemophilia patients (ages: 20–71 years) with these HFE mutations suffered worse joint arthropathy as compared to controls, which was attributed to the systemic effect of iron associated with deregulated iron absorption. Mechanisms may involve abnormal circulating iron levels in C28Y carriers and/or an increased efflux of iron from macrophages in affected joints (Cruz et al, 2005). These HFE mutations have been described in patients with hereditary haemochromatosis who develop a characteristic arthropathy (Carroll et al, 2011). Protective role of IL10. On the other hand, cartilage and synovial tissue obtained from end stage haemophilic arthropathy joints when cultured in the presence of IL10 were protected from the damaging effects of blood exposure as measured by proteoglycan turnover (Jansen et al, 2008). IL10 beneficially influenced cartilage from haemophilic arthropathy patients and reduced production of the inflammatory cytokines IL1b and TNF a by haemophilic synovial tissue. Whether mutations in IL10 modify the response of an individual patient with haemophilia needs to be further explored (Jansen et al, 2008). Therefore, the pathogenesis of haemophilic joint arthropathy seems to be multifactorial, with changes occurring in the synovium, bone, cartilage and blood vessels associated with affected joints (Fig 2). Iron may be central to this process, along with MYC, MDM2, angiogenic mediators and endothelial and haematopoietic progenitors, HIF1A, and inflammatory cytokines IL1b and TNF-a contributing to the initiation and maintenance of synovial proliferation, which could be further modified by HFE mutations and IL10. However, all these processes may be occurring concomitantly rather than sequentially in the joint. Therefore, prevention of haemarthroses still seems to be crucial in mitigating the development and progression of joint arthropathy.

Options for early diagnosis and treatment of haemophilic joint arthropathy Though prophylaxis has been demonstrated to be the standard of care to prevent haemophilic joint arthropathy, patients can bleed despite prophylaxis. Furthermore, when prophylaxis cannot be effectively implemented due to cost, venous access and access to care issues, strategies to detect and monitor joint arthropathy after the onset of bleeding and before the onset of joint damage needs to be explored.


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Fig 2. Synovial and cartilage pathobiological changes in haemophilic joint arthropathy. Recurrent haemarthroses can cause synovial changes mediated by iron, which can upregulate MYC, causing synovial proliferation and MDM2 upregulation leading to decreased synovial apoptosis. As synovial cells proliferate, hypoxia caused within the joint can upregulate HIF1A, which can induce the angiogenic mediators VEGF, SDF1 and MMP9. These in turn can mobilize EPCs and HPCs into the synovium causing neo-angiogenesis in the synovium and active synovitis. This cycle could be selfperpetuating and could aid in maintaining a highly vascularized joint. Concomitantly, cartilage changes from haemarthroses reflected by increased GAG release, IL1b and TNFa also occurs. These can cause irreversible oxidant damage to cartilage, which cannot self-renew, leading to cartilage loss. All these changes can culminate in decreased bone osteocalcin, leading to decreased bone mineral density. VEGF: vascular endothelial growth factor; MMP-9: matrix metalloproteinase 9; SDF-1: stromal-derived factor 1; HIF1A: hypoxia-inducible factor 1 a; VEGFR1: vascular endothelial growth factor receptor 1; VEGFR2: vascular endothelial growth factor receptor 2; CXCR4: chemokine receptor type 4; HPCs: haematopoietic progenitor cells; EPCS: endothelial progenitor cells; GAG: glycosaminoglycan; IL-1b: interleukin1b; TNF-a: tumour necrosis factor a.

Diagnostic tools to identify early joint arthropathy As the bleeding phenotype in severe haemophilia can be variable, the effects of blood on synovium and cartilage unpredictable, and cost of prophylaxis considerable, universal prophylaxis may be beyond the reach of many patients. Thus, it might be worthwhile to consider monitoring for early onset changes in the synovium and cartilage by imaging studies to implement prophylaxis before the onset of joint arthropathy. MRI can detect both synovial and cartilage changes resulting from recurrent haemarthroses (Nuss et al, 2000). Higher costs and sedation requirements in children less than 6 years of age could limit its utility for routine monitoring of arthropathy. Ultrasonography (USG) with power Doppler (USG-PDS) is emerging as a tool to diagnose synovial and cartilage changes in haemophilia. USG-PDS measurements of synovial thickness and synovial vascularity correlated strongly with those obtained with contrast enhanced-MRI in 33 joints with haemophilic arthropathy with a history of >20 bleeds into the imaged joint (Acharya et al, 2008). Whether this tool is sensitive enough to detect changes after only a few joint bleeds needs to be further explored.

Serological markers to identify joint damage Angiogenic mediators –VEGF, MMP-9, SDF-1, HPCs and EPCs in the serum have been reported to signify synovial damage (Acharya et al, 2011), as previously mentioned. In this 18

study, a 10-fold increase in plasma VEGFA levels was observed in a retrospective cohort of haemophilic subjects with active synovitis (synovial changes) diagnosed by MRI, compared to subjects with advanced joint arthropathy (including synovial and cartilage changes). Interestingly, subjects with advanced joint arthropathy demonstrated VEGFA levels similar to control subjects. This finding suggests that VEGFA levels could rise during the phase of active synovitis, playing a role in synovitis initiation and progression, and fall after progression to chronic synovitis and arthropathy, which is characterized by a predominance of fibrous tissue and decreased vascularity. Therefore, VEGFA levels, along with the presence of circulating HPCs and EPCs, may serve as surrogate biological markers for active synovitis and needs to be confirmed in a larger study (Acharya et al, 2011). Whether these markers are sensitive enough for the detection of synovial damage after a single episode of haemarthoses also needs to be further investigated. Furthermore, Jansen et al (2009) showed that a combination of biomarkers, urinary C-terminal telopeptide (a marker of cartilage degradation and bone turnover) along with serum cartilage oligomeric matrix protein and serum chondroitin sulphate correlated with radiographic joint damage in haemophilic arthropathy. The potential of these markers to monitor joint bleeding and the development of joint arthropathy also need to be explored (Jansen et al, 2009). Future studies should focus on correlating and validating these markers of synovial and cartilage damage along with imaging studies in order to tailor treatment strategies to prevent joint arthropathy.


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Mechanical aspects of joint disease: reduce loading on a joint Animal studies raise questions about early exercise vs. nonweight-bearing following blood-induced injury. An animal study (Hakobyan et al, 2005) showed that forced loading of a joint with intra-articular blood compared with a similar joint without forced loading resulted in more cartilage matrix damage. There are no human studies available; however, it might be attractive to hypothesize that avoidance of weight bearing of a joint with intra-articular blood, and the use of crutches in the first few days after an intra-articular bleed may reduce joint damage.

Joint aspiration after a bleed to reduce load of intraarticular blood and total iron load After a massive episode of haemarthroses, there may be prolonged exposure of synovium and cartilage to iron and other cytokines. In vitro studies have shown that a 4-d duration of blood exposure produces a blood concentrationand time-dependent inhibition of cartilage matrix, resulting in matrix loss (Jansen et al, 2007). If intra-articular blood is not evacuated early, it can affect the synthesis of proteoglycans by chondrocytes, which eventually leads to the apoptosis of chondrocytes. Therefore, after a massive bleed it appears worthwhile to consider joint aspiration after initial factor replacement. There is very limited literature addressing this area of management in patients with haemophilia, and, except for selected cases, it is not generally recommended in consensus guidelines. A single randomized control trial included 22 adults with intermediate swelling of the knee joint, half of whom underwent aspiration under local anaesthesia, reported a statistically significant improved range of movement on day 1, but no difference by day 5 (Ingram et al, 1972a). Another retrospective study of 27 cases of children and adults with haemophilia and a knee haemarthrosis, concluded that aspiration was safe and effective in restoring early joint function in established severe haemarthrosis (Banta et al, 1975). A gain of extension and an overall increase in range of motion by day 4, with return to normal school and employment within 48 h of the procedure compared to 3–7 d in-patient hospitalization in historical controls was reported in this study (Banta et al, 1975). A more recent case report found symptomatic improvement in all five patients who underwent ultrasound aspiration of hip haemarthrosis that failed to resolve on factor replacement (Robertson et al, 2009). Based on these limited clinical data, and experimental observations of synovial and cartilage damage after short term exposure to blood in animal models, aspiration of the haemarthrotic joint needs to be strongly considered to reduce synovial and cartilage damage and possible quicker return to school or work. Again, collaborative clinical trials to address this modality of therapy are urgently needed.

Synovectomy: isotopic or arthroscopic Synovitis characterized by neo-vascularization and villous formation sets up a vicious cycle of synovitis – haemarthroses – synovitis, leading to the development of a target joint. Once a target joint develops, bleeding into the joint occurs not only due to clotting factor deficiency but also to the fragility of these new vessels, which can rupture spontaneously (Stein & Duthie, 1981). Therefore, procedures aimed at reduction of synovial tissue, such as synovectomy, may provide benefits by improving pain control and quality of life. Arthroscopic synovectomy was utilized to control proliferative synovitis by removal of friable villous synovium. Sustained reduction in haemarthroses of 89–97% was observed at a mean of 3Æ3 and 6 years respectively from the procedure (Journeycake et al, 2003; Dunn et al, 2004). Despite significant advantages of this procedure, prolonged factor replacement, requirement for physiotherapy post-procedure to restore range of motion, as well as progression of radiographic changes despite reduction in haemarthroses warrants a closer look at this procedure. Radionuclide or isotopic synovectomy involves instillation of a radioisotope intra-articularly to sclerose the neo-vessels in the synovium (Manco-Johnson et al, 2002; Rodriguez-Merchan et al, 2007). The greatest advantage of this procedure includes outpatient setting, non-requirement for aggressive physical therapy or factor replacement and relatively lower costs (Rodriguez-Merchan et al, 2007). As the presence of active synovitis with newly formed fragile vessels can trigger recurrent haemarthroses leading to progression of joint arthropathy, the optimal timing of these procedures needs to be explored in future studies. These procedures, when applied early in the course of development of joint arthropathy, may also delay the requirement for expensive joint replacement surgeries, which could be more complicated in the inhibitor patient.

Role of other ancillary measures Steroids have been used to reduce inflammation associated with chronic synovitis and arthropathy (Gilbert & Radomisli, 1997). Also, muscle strength training with low resistance and focus on proprioceptive function has proven to be useful in advanced arthropathy to preserve joint function (Hilberg et al, 2003). In a study of adults with haemophilic joint arthropathy, regular exercise was shown to prevent progression of arthropathy (Harris & Boggio, 2006). Anti-fibrinolytic agents, such as epsilon amino caproic acid and tranexamic acid, are widely used for the treatment of mucus membrane bleeding in bleeding disorder patients (Mannucci, 1998). These agents act by potentiating the fibrinolytic inhibitor, thrombin activated fibrinolysis inhibitor (TAFI). Several studies have reported reduction in perioperative blood loss and requirement for allogeneic blood transfusion with the use of tranexamic acid during joint arthroplasty and other major non-emergency surgeries (Henry et al, 2011; Sukeik et al, 2011). A double blind study using tranexamic acid in 15 patients with severe


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Fig 3. Suggested schema for approach to prevention and management of haemophilic joint arthropathy after the first haemarthroses. After the first joint bleed, measuring serum and whole blood markers for synovial and cartilage damage and carrying out ultrasonography studies is suggested. If serological mediators are normal and there is no evidence of synovial or cartilage damage on imaging studies, observation versus low dose prophylaxis (once weekly) is suggested and repeat studies after every 3–5 joint bleeds. If there is evidence of elevated serological mediators and/or evidence of synovial or cartilage changes on imaging, either initiation of full dose prophylaxis (three times/week) or augmentation of previous low dose prophylaxis is suggested. After a joint has sustained over 20 joint bleeds (target joint), assessment of quality of life (QoL), and screening bone density scans and assessment for the need for synovectomy versus arthroplasty is suggested.

haemophilia for 1 year did not reduce soft tissue, muscle or joint bleeds or the requirement for factor concentrates (Ingram et al, 1972b). However, a more recent study reported increased levels of TAFI in the synovial fluid in both inflammatory (rheumatoid arthritis) and degenerative (osteoarthritis) joint diseases as compared to healthy controls (So et al, 2003). Since haemophilic joint arthropathy demonstrates both inflammatory and degenerative characteristics, it remains to be explored whether antifibrinolytic agents might aid in quicker resolution of joint bleeds when used concomitantly with factor concentrates in future clinical studies, to reduce the impact of blood on synovium and cartilage and consequent joint arthropathy.

Joint arthroplasty When all strategies for the treatment of joint disease fail, joint arthroplasty may need to be performed. Reports on arthroplasties of hips and knees are more commonplace while shoulders, elbows and ankles are limited to case reports or small series. Arthroplasty needs to be performed by a multidisciplinary team, which involves the haematologist, orthopaedist and rehabilitation medicine specialist (Beeton et al, 2000). While there is general consensus that advanced surgery, particularly joint replacement, has no role in children during their growing years, an aggressive approach needs to be adopted for the young adult who deserves optimal physical health while musculature is still in good condition. Further-

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more, younger patients can be rehabilitated better after these procedures than older patients, leading to better outcomes of these procedures and long term improvement in quality of life, reduction in pain and correction of functional disability (Ingerslev & Hvid, 2006).

The haemophilia care model of the future Our understanding of the pathogenesis and treatment strategies used in haemophilia to prevent joint arthropathy has progressed over the last five decades since the introduction of prophylaxis by Nilsson and colleagues in the early 1960s. We understand that prophylaxis after the first joint bleed can postpone the onset of joint arthropathy (Fischer et al, 2002a). Recent clinical and animal studies have provided evidence for the role of iron, cytokines, angiogenic and inflammatory mediators in causing synovial and cartilage damage. In individuals who have developed joint arthropathy, low bone mineral density affecting bone health and quality of life has been observed. Based on available clinical and animal data implicating these causative factors in joint arthropathy, urgent clinical studies are needed to address their role to optimize clinical management. There is an urgent need for studies to validate imaging (USG-PDS) and serological (synovial and cartilage) markers to prevent and optimize treatment for joint arthropathy in a cost-effective manner. Also, screening for low bone mineral density, a regular exercise programme to improve HRQOL, and evaluation of the optimal timing for synovectomy


Review and joint arthroplasty need to be explored. A schema to use these strategies is proposed that could have a positive impact on the long-term health of individuals with haemophilia (Fig 3). Previous reports have shown that patients who start prophylaxis after the first joint bleed show little arthropathy in adulthood (Fischer et al, 2002a). Therefore, this model proposes evaluation by imaging and serological markers after the first haemarthroses. Abnormalities in imaging and serological markers may serve as a guide to either initiation or augmentation of the prophylaxis regimen. After target joint development [>20 haemarthroses into a joint (van Dijk et al, 2005)], screening for bone health effects may be warranted. This paradigm should be tested in a multi institutional cohort of haemophilia patients in order to provide evidence-based guidelines to optimally diagnose early joint changes. Findings could be translated into tailored optimal therapy for better long-term joint outcomes after the onset of haemarthroses and before the onset of joint arthropathy. The current infrastructure for the care of children and adults with haemophilia should facilitate this research along with correlation with laboratory science.

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Conclusion In summary, understanding the immediate and long-term effects of haemophilic joint arthropathy warrants a multifaceted approach in terms of diagnostics and therapeutics. Prophylaxis should be instituted before the onset of joint arthropathy after the start of haemarthroses, and should be continued even into adulthood to avoid undue expense, suffering and effects on bone health and HRQOL. After the first joint bleed it would be prudent to validate tools, such as USG-PDS, to diagnose early joint damage along with the use of serological markers of synovial and cartilage damage to monitor for joint arthropathy progression. These tools should also be evaluated to determine the optimal timing of procedures, such as synovectomy and arthroplasty. During an acute haemarthroses, consideration should be given to institute joint aspiration to reduce blood-related damage to the synovium and cartilage. During ongoing prophylaxis, monitoring of bone health status, HRQOL and academic achievement should be considered and regular exercise to preserve joint and bone health should be encouraged.

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