Haemophilia and joint disease: pathophysiology, evaluation, and management

Abstract

Introduction

Haemophilia is an X-linked heritable coagulopathy with an overall prevalence of approximately 1 in 10,000 individuals [1]. The most common form is factor VIII deficiency, or haemophilia A, which comprises approximately 80% of cases. Factor IX deficiency, or haemophilia B, comprises approximately 20% of cases [2]. Other heritable clotting disorders include von Willebrand disease and various other clotting factor deficiencies, but these are not commonly classified as ‘haemophilia’ [3]. Haemophilia is traditionally classified as ‘mild’, ‘moderate’, or ‘severe’, depending on the degree of clotting factor deficit compared with that found in the general population (Table 1) [4].

Phenotypically, patients with haemophilia are at risk of haemarthrosis (particularly of the knee, ankle, and elbow joints), soft-tissue haematomas, bruising, retroperitoneal bleeding, intracerebral haemorrhage, and post-surgical bleeding [5]. Generally speaking, individuals with ‘severe’ disease display clinical symptoms more frequently, and are considered at higher risk of haemorrhagic events and musculoskeletal problems, although this is not always the case [4]. Treatment for haemophilia is frequently prophylactic (particularly in moderate or severe disease) and aims to reduce the frequency and severity of bleeds. In addition, treatment needs to be given if the patient has, or suspects they have, a bleed. Replacement therapy uses intravenous infusions of the deficit clotting factor to reduce the risk of bleeding, and patients may receive this at regular intervals (‘prophylactic therapy’) or in response to an acute bleeding episode (‘on-demand therapy’) [6]. It should be mentioned that due to cost and lack of specialized care, access to replacement therapy is, to a large extent, limited to developed countries only. In these countries, children now grow up with a relatively good musculoskeletal status, but this is not yet the case for the majority of patients who live in developing countries and resource-limited settings. Other agents that may be used in the treatment of a bleed include antifibrinolytics (used in both haemophilia A and B) and the synthetic vasopressin analogue desmopressin (only in mild haemophilia A) [7]. Patients are advised to avoid drugs that affect platelet function (although they can be used in some cases), and to avoid trauma/contact sports (although low-impact exercise, such as cycling, is recommended to protect joints) [8].

The management of patients with haemophilia is complex as their condition is associated with a large number of comorbidities. Joint problems resulting from recurrent haemarthrosis, such as chronic synovitis and degenerative arthritis, are a major cause of morbidity [9, 10]. Repeated bleeding into joints can result in abnormalities in both bone growth and limb length [5]. Patients are also at increased risk of developing osteoporosis as a result of prolonged periods of immobility and reduced range of joint movement as a result of arthropathies [11]. Renal haemorrhage and haematuria are also cause for concern, and thromboses resulting from the use of antifibrinolytics may cause renal obstruction. Medications used for other comorbidities, such as blood-borne viral infections, are frequently nephrotoxic and hepatotoxic [5, 12]. Many patients with haemophilia, particularly those transfused before the introduction of virus-safe concentrates, were infected with hepatitis B, C, and HIV. These transfusion-acquired infections increase the risk of end-stage liver disease and cirrhosis, which in turn, increase the risk for hepatocellular carcinoma [13]. While a direct link between haemophilia and cancer is contentious, diagnosis and treatment of malignancy are problematic in these patients [14].

Replacement of missing clotting factors represents an effective method of treatment for patients with haemophilia; however, 20–30% of patients with haemophilia A and 5% of patients with haemophilia B develop inhibitory antibodies to factor VIII and factor IX, respectively, which drastically reduce the efficacy of replacement therapy [15]. This represents a serious complication of treatment, which results in poorer prognosis, reduced quality of life, and increased cost of treatment [16].

Over time, complications from recurrent haemarthrosis and soft-tissue haematomas can result in severe arthropathy, joint contractures, and pseudotumours, leading to chronic pain and disability and impairment of health-related quality of life. Arthropathy as a consequence of haemophilia represents the single largest cause of morbidity in patients with haemophilia, and as such, prevention of this is one of the main aims of treatment [5, 17].

Despite these extensive comorbidities, with appropriate treatment, patients with haemophilia can expect a near-normal life expectancy and an excellent health-related quality of life [18–21]. The effectiveness of treatments means that increasingly, patients with haemophilia are experiencing more of the health concerns associated with advancing age in the general population, such as cardiovascular disease, cancer, and declining renal function [19, 20, 22, 23]. Owing to the increasing age and number of older people living with haemophilia, the incidence of comorbidity and consequently high-risk patients is also increasing, and as survival of patients with haemophilia continues to improve, the impact of comorbidity and how best to manage it will become more important [19, 20, 24]. The presence of haemophilia and comorbidity raises important issues with regard to clinical decision-making and treatment decisions, and currently there is very little guidance for physicians to manage chronic comorbidity. This article reviews comorbid joint disease in haemophilia and how to manage it.

Haemophilia and joint disease: background

Joint disease is a disabling and common complication of severe (and, to a lesser extent, moderate) haemophilia, in which a characteristic chronic arthropathy develops as a result of recurrent bleeding into joints. Individuals with severe haemophilia are more likely to develop joint problems and reduced range of movement (ROM) of joints [25]. Other risk factors for developing ROM limitations include age and increased body mass index [25]. In those with severe disease, higher frequency of bleeds, presence of inhibitors, and recent orthopaedic procedures are also associated with increased likelihood of ROM limitation [25]. Data from the Universal Data Collection (UDC; US national public health surveillance project) showed that patients with severe haemophilia were more at risk of developing a target joint (a joint in which recurrent bleeding has occurred four or more times in the past 6 months) than those with moderate or mild haemophilia (33.1% versus 18.8% and 5%, respectively) [26].

The most commonly affected joints in patients not treated with prophylaxis are the knees (45%), followed by the elbows (30%), ankles (15%), shoulders (3%), and wrists (2%) [8]. Today, at least in patients on prophylaxis, this pattern appears to have changed, and the ankle joint now accounts for the most common site of bleeding [27]. This may be due to the fact that current prophylactic regimens and treatment in the home allow patients to be more active and able to participate in higher impact sports and activities, which could render the ankle the most vulnerable joint [27]. In individuals with severe haemophilia, the first occurrence of haemarthrosis ordinarily occurs by around the age of 2 years [8]. If not treated adequately, these individuals will develop haemophilic arthropathy by the age of 20 years [28]. An acute bleed into a joint results in severe pain as the pressure in the synovial cavity and bone marrow rises, and may lead to avascular osteonecrosis (particularly in the femoral head following a bleed into the hip joint) [5]. Recurrent bleeding leads to chronic synovitis and damage to both cartilage and bone, in addition to the synovial damage [8]. If patients with severe disease do not receive appropriate treatment, they will develop clinical symptoms: pain, swelling, and reduced ROM by early adolescence that will severely affect their health and quality of life [21, 28].

Haemophilia and joint disease: pathophysiology

The development of haemophilic arthritis occurs in three stages [29]:

1. Acute haemarthrosis
2. Chronic synovitis
3. Degenerative arthritis.

While the synovium lining a joint has a limited capacity for absorbing blood following an isolated incident of haemarthrosis, recurrent bleeding into the joint results in a level of blood breakdown products that the synovial membrane cannot remove. Iron, a key constituent of haemoglobin found in erythrocytes, is thought to play a major part in inflaming the synovium [29]. The presence of the iron-rich breakdown product haemosiderin is thought to promote the production of pro-inflammatory cytokines such as interleukin (IL)-1, IL-6, and tumour necrosis factor-alpha [30, 31], and the induction of genes that causes cellular proliferation such as mdm2 [32] that result in the changes seen in synovial tissue in haemophilic synovitis. The synovium becomes increasingly vascular and hypertrophic, and inflammatory cells are recruited to the area in greater numbers. This vascular and hypertrophied tissue is more likely to become impinged between the articular surfaces of the joint, resulting in increased likelihood of further haemarthrosis that creates a vicious cycle of bleeding and inflammation (Figure 1) [29, 33]. Furthermore, the inflammatory mediators released interfere with the normal maintenance of articular cartilage. Damage to the articular cartilage is thought to occur both through direct exposure of the cartilage to blood and through synovium-associated inflammation [34, 35], and it has been shown that the exposure of cartilage to blood, even in the short term, leads to prolonged cartilage damage [33, 34]. The marked inflammation and synovial hypertrophy noted in haemophilic arthropathy bear resemblance to the pathological mechanisms seen in rheumatoid arthritis, while the progressive degeneration of the hyaline cartilage mimics that observed in osteoarthritis. These processes occurring in parallel result in a degenerative arthritis that progresses until the joint is completely destroyed [33, 36].

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Figure 1

A chronic, self-perpetuating cycle of haemarthrosis–synovitis–haemarthrosis [29]. Reproduced with permission. © World Federation of Hemophilia, 2004.

Haemophilia and joint disease: evaluation

Clinical evaluation of the joints, gait, motion, muscle tone, functional level of disability, pain and swelling must be performed to assist in the diagnosis of chronic synovitis and to guide treatment decisions. Traditionally, clinical examination and plain film radiography have been used to diagnose haemophilic arthropathy. Radiographs adequately demonstrate advanced bone changes such as epiphyseal overgrowth, joint space narrowing, and osteoporosis, but have poor sensitivity in demonstrating early soft-tissue changes that occur before irreversible cartilage damage [17, 37, 38].

Other imaging methods may be more useful in detecting early soft-tissue changes. Magnetic resonance imaging (MRI) is currently the gold standard for diagnosing haemophilic arthropathy and is particularly useful for identifying soft-tissue changes [39]. MRI can accurately detect synovial hypertrophy and joint effusions, which are common findings at all stages of joint disease. A recent prospective study showed that MRI was more sensitive than radiography in detecting joint abnormalities in boys with severe haemophilia A [17]. However, MRI is often limited owing to high costs, cumbersome use, requirement for sedation in children, and inability to differentiate active versus inactive synovium [38, 40]. Modalities such as contrast ultrasonography may be useful for visualizing synovial changes. The advantages of ultrasonography are that it is simple, inexpensive, convenient, and radiation-free [41–43].

Several scoring systems, including clinical and imaging, have been developed to assess haemophilic joints. The World Federation of Hemophilia (WFH) scoring system, described by Gilbert [44], is based on the clinical evaluation of the six index joints to assess several key parameters of severe haemophilic arthropathy. However, various shortcomings, including lack of established reliability, validity, and sensitivity to smaller changes in patients with less severe joint disease, means that various modifications have been introduced. The current modified clinical system is the Haemophilia Joint Health Score (HJHS) (Table 2) [45]. The Pettersson score [46] and the European MRI scale [47] are imaging techniques that derive the final score from the sum of scores for individually rated features. The Arnold–Hilgartner score [48] and the Denver MRI scale [49] produce radiological scores based on the most severe changes present. The international MRI subgroup has developed a consensus scoring system aimed at facilitating international comparisons between MRI data on haemophilic arthropathy [50].

Haemophilia and joint disease: management

Conclusions

Prophylaxis by replacement of the missing factor in patients with haemophilia is the optimal way to prevent the occurrence of haemarthrosis and thereby the onset of arthropathy, provided that it is started early in life. Dosing should be individualized and increased in the case of bleeding. Prevention of bleeding episodes through early treatment will prevent accumulation of blood in the joint and the subsequent inflammation and potential haemophilic arthropathy. Treatment must be maintained until bleeding remission and patients have recovered as much of their ROM and muscular strength as possible. Clinical evaluation of the joints, gait, motion, muscle tone, functional level of disability, pain, and swelling, as well as imaging techniques, must be performed to assist in the diagnosis of chronic synovitis and to guide treatment decisions. The first step to treating synovitis, refractory to medical treatment, is the use of synovectomies, non-surgical or surgical interventions. In many cases, joint deformities have to be treated by open orthopaedic surgery. State-of-the-art treatment of patients with haemophilia requires a multidisciplinary team.

Acknowledgments

References