The relationship between target joints and direct resource use in severe haemophilia

Haemophilia is an inherited, lifelong bleeding disorder characterised by prolonged traumatic or spontaneous bleeding due to a lack of clotting factor in the body. Haemophilia is a recessive X-linked disorder and primarily affects males; symptoms are present from infancy [1]. The two most common forms of the condition are Haemophilia A (Factor VIII deficiency) and Haemophilia B (Factor IX deficiency). Global incidence of haemophilia A is approximately 1 in every 5000 male births; haemophilia B is approximately six times rarer than haemophilia A [2].

Bleed events may be musculoskeletal or mucosal in nature but are most commonly observed in the joints of the body. In the absence of preventative ‘prophylaxis’ factor replacement therapy, most persons with severe haemophilia (<1% of normal factor level) will develop a first haemarthrosis between the ages of 1 and 5 years. Approximately four-fifths of bleed events occur in the knees, elbows, and ankles; arthroses in the hip, shoulder, carpus, or small hand or foot joints are less frequently observed [3].

Repeat intra-articular bleed events within a short timeframe (3–6 months) are associated with chronic synovial inflammation and in the longer term induce haemophilic arthropathy [4]. Such joints, known as target joints, exhibit continuous swelling and reduced range of motion; repeat acute and subacute haemarthoses lead to irreversible degradation of the joint, resulting in chronic pain and poor physical function and requiring orthopaedic intervention, ranging from removal of the synovium to replacement or fusion of the joint [5]. Bleed frequency, as well as age, body mass index, and inhibitor formation are known drivers of joint disease and functional limitation in persons with severe haemophilia [6‐8]. The economic burden of frequent hospitalisations and palliative joint surgeries is reinforced by the psychosocial impact of chronic pain and disability, including limited employment opportunities, decreased social participation, and poor mental health [9, 10].

Prophylaxis regimens initiated at a young age (≤4 years of age) are shown to reduce bleed frequency and joint deterioration later into adulthood [5], and are therefore considered the benchmark in care for severe haemophilia [2]. However, introduction of universal prophylaxis has been protracted in many developed countries, due to a lack of evidence regarding clinical benefits of prophylaxis initiation later into adolescence and adulthood, as well as the substantial per-capita costs associated with replacement therapy [11‐13]. Prophylaxis replacement therapy has recently undergone tentative economic evaluation by several European organisations. There is a need for greater clarity regarding the economic impact of care for persons with severe haemophilia in Europe, specifically regarding the cost of management of individuals with musculoskeletal complications, and in particular those patients receiving suboptimal therapy protocols.

The objective of this paper is to explore the relationship between target joints and direct medical costs for persons with severe haemophilia, and the extent to which health resource utilisation and direct medical costs (excluding replacement therapy) in severe haemophilia are driven by long-term clinical complications of the disease. While this topic has been explored to some detail within single-country studies [12, 14], this is the first to take a universal methodology across several European countries in assessing resource use and cost burden among persons with severe haemophilia.

This study has sought to quantify the economic burden associated with management and alleviation of joint-related complications in severe haemophilia. NDDCs represent a small proportion of total costs for persons with severe haemophilia (between 2% and 5% in most European studies) [14], and as a result their prioritisation for research has until now been limited. Nevertheless, it is critical to understand both physiological, psychosocial, and economic impacts of inadequate bleed control within haemophilia, and the longer-term repercussions of joint deterioration associated with suboptimal therapy and patient management. The results of this analysis suggest that cost drivers are not limited to surgical interventions, but in fact encompass more intensive ambulatory and outpatient care, including a higher volume of specialist visits, tests, and examinations among persons with severe haemophilia exhibiting chronic joint inflammation.

The CHESS study was a cross-sectional survey of clinicians and persons with severe haemophilia across five European countries, which captured a large volume of clinical and demographic information about consulting patients. However, we are limited in our ability to explore the causal relationship between management of haemophilia in early life and subsequent outcomes. Further work is required to understand the long-term impact of switching from on-demand to prophylaxis in late childhood and adulthood, when joint deterioration may already be present. Presence of target joints in the CHESS patient group is significantly higher among those receiving prophylaxis; whilst initially counterintuitive, it points to a large number of patients moving away from on-demand regimens due to poor bleed control and joint damage. As shown in previous work, this is particularly pertinent for those patients over the age of 30 years for whom prophylaxis in early childhood was not widely available. While the outcomes observed in this study population are not necessarily translatable to children born with haemophilia in the current era, suggestions of reducing access to prophylaxis give rise to a need to highlight the economic burden arising from conservative therapy among persons with severe haemophilia.

A target joint in this analysis is defined by the presence of chronic synovitis, the physiological manifestation of frequent intra-articular bleed events. In the more oft-observed scenario, sufficient time between bleed events (~3–4 weeks) allows for gradual alleviation of swelling and restoration of joint motion, via intensive infusions of replacement therapy and regular physiotherapy. Frequent recurrence of bleeding, however, precludes the reinstatement of a baseline level of motion, strength, and physical appearance; inadequate resolution of trauma arising from such events can in turn exacerbate bleed frequency. This cyclical process results in the longer term in a state of chronic synovitis and progressive arthropathy, due to excessive volumes of synovium and blood retained within the joint space and gradual deterioration of the joint tissue [4].

Other definitions in literature focus instead on the frequency of bleed events over a short-term (≤6 months) period in order to propose a diagnosis of a target joint. The most recent International Society of Thrombosis and Hemostasis (ISTH) definition, for example, is one in which three or more spontaneous bleeds into a single joint occur within a consecutive 6-month period [23]. In the case of the ISTH guidelines, however, the joint ceases to be a target joint when there have been less than two bleeds into the joint within 12 consecutive months. While alternative definitions allow for more or less frequent bleeds and shorter or longer observation periods [24, 25], their commonality is the use of short-term bleed rates as a measure, and an observable follow-up period within which a target joint may no longer be defined as such.

In combination, these rules present a definition that is well-suited to clinical trials with finite follow-up periods and observable improvements in outcomes, but which lacks the consideration of the long-term complications associated with persistent bleed events. A recent paper published on behalf of the United Kingdom Haemophilia Centres Doctors Organisation (UKHCDO) highlights the long term changes effected to the soft tissue of the joint as a result of frequent bleed events, and thus a need for continuous, targeted monitoring of the afflicted joint beyond the period in which synovitis is observed [26]. Our choice of definition, therefore, encompasses an assumption of high bleed frequency via the identification of synovitis, as well as considering the long-term, irreversible changes to the joint tissue and structure that arise from repeat haemorrhage. We acknowledge, however, that there is substantial overlap between definitions.

Regardless of nuances in the definition of a target joint, the results presented in this study suggest that chronic synovitis in severe haemophilia is associated with greater intensity of patient management, resulting in higher levels of health resource use and direct medical costs. Approaches to minimising the long-term risk of joint damage and deterioration among these patients – beginning at a young age with proactive therapy protocols to minimise bleed frequency and severity – will serve to reduce future burdens on hospital systems and are a justification for continued access to preventative therapy protocols. Further studies should seek to incorporate the health-related quality of life impact of bleed events and joint disease, and hence to quantify the cost effectiveness of current therapy protocols among severe persons with haemophilia.

While non drug-related direct medical costs in severe haemophilia are small in relation to the costs of replacement therapy, our analysis demonstrates that the majority of individuals with this disease experience medical complications requiring substantial follow-up in the hospital setting. Further, the presence of one or more target joint can have a major impact on medical resource utilisation and subsequent costs for patients with severe haemophilia.