Attempting to remedy sub-optimal medication adherence in haemophilia: The rationale for repeated ultrasound visualisations of the patient's joint status

Abstract

Haemophilia is marked by joint bleeding (haemarthrosis) leading to cartilage damage (arthropathy). Lifelong prophylaxis—initiated after the first bleeding episode—leads to a dramatic decrease in arthropathy in haemophilia patients. However, adherence to continuous intravenous administrations of factor VIII (FVIII) or FIX products is challenging, and patients potentially suffer from breakthrough bleedings while on prophylaxis. Newer FVIII/FIX products with enhanced convenience attributes and/or easier infusion procedures are intended to improve adherence. However, pharmacokinetic data should be harmonised with information from individual attitudes and treatment needs, to tailor intravenous dosing and scheduling in patients who receive extended half-life products. Nor is there sound evidence as to how subcutaneous non-FVIII/FIX replacement approaches (concizumab; emicizumab; fitusiran) or single intravenous injections of adeno-associated viral vectors (when employing gene therapy) will revolutionize adherence in haemophilia. In rheumatoid arthritis, repeated ultrasound examination of a patient's major joints is a valuable tool to educate patients and parents to understand the disease and provide an objective framework for clinicians to acknowledge patient's adherence. Joint ultrasound examination in haemophilia significantly correlates with cartilage damage, effusion, and synovial hypertrophy evaluated by magnetic resonance imaging. Furthermore, in patients with haemophilia undergoing prophylaxis with an extended half-life product for a ≈ 2.8 year period, a significant continued improvement in joint health is detected at the physical examination. This provides the rationale for studies on repeated ultrasound examinations of joint status to attempt to remedy sub-optimal medication adherence and help identify which approach is most suited on which occasion and for which patient.

Introduction

In the clinical management of diseases, medications are only effective if taken on a regular basis under limited supervision. Medication adherence (or compliance with treatment) defines the extent to which a patient implements a prescribed remedy [1]. To what extent the patient's behaviour coincides with the action(s) agreed with the clinician is what medication adherence measures [2]. Despite the fact that a careful delivery of established drug treatments would save more lives than would discovery of innovations [3], medication adherence is higher during treatment of acute conditions, while it decreases after the first 3 months of treatment in chronic diseases [1]. In medical patients with chronic diseases, non-adherence is found across all types of treatments and can limit its effectiveness [4]. In those aged 65 years or older, the problems caused by non-adherence include hospital admissions, disease progression and increased costs for the health care system [5]. Variables associated with poor adherence (Fig. 1) are common to the most chronic conditions and can be categorized into patient factors, clinician factors, and health system factors—often with interactions between the categories [6].

Haemophilia is an X-linked chronic bleeding disorder, characterized by the quantitative abnormality of the clotting factor VIII (FVIII) (Haemophilia A, HA) or FIX, (Haemophilia B, HB). The severity of haemophilia is defined according to the level of circulating clotting factor present in the individual patient, <1% being defined as severe, 1–5% as moderate, and 6–40% as mild haemophilia [7]. As a rule, the bleeding rate of a severe haemophilia patient dramatically differs from that of a mild or moderate one. However, the tendency to bleed is individual, and should be measured based on information from a sufficiently long period of observation. Although haemophilia patients are at risk of spontaneous bleeding in all soft tissues, joint bleeding is the major cause of morbidity, especially in severe haemophilia [8,9]. Even a single episode of joint bleeding can lead to an irreversible damage and foster the occurrence of new local bleedings, in a vicious circle which, if not stopped, will end up in severe arthropathy. Since its first occurrence, bleeding inside joints triggers the release of inflammation mediators from synovial tissue (Il-1, TNF-α, MMP); from red blood cells (Fe⁺⁺), and from macrophages (Il-1β). Cartilage damage starts within few days of a single joint bleed, as proteoglycan synthesis decreases significantly as early as four days after cartilage exposure to blood [10,11]. On the other hand, the release of Vessel Endothelial Grow Factor—an event that almost invariably takes place after recurrent joint bleedings (haemarthroses)-leads to synovial hypertrophy, vessel proliferation and progressive cartilage damage with the development of ‘target’ joints [12,13]. From a clinical standpoint, these changes are marked by joint pain, swelling and functional impairment, and lead to progressive loss of joint function (ankyloses), decreasing patient mobility [14]. Consequently, daily activities taken for granted by most people without haemophilia require considerable planning, particularly in children and adolescents with haemophilia. In addition to a negative impact on the quality of life, costs for replacement treatment dramatically increase in haemophilia patients with arthropathy [15]. Intensive treatment does not revert the damage once joint destruction has occurred [16].

There is clear evidence that on-demand treatment (i.e. the usual treatment strategy, still largely employed in haemophilia individuals) only partly reduces the risk of bleeding. By the age of 25 years, 90% of haemophilia subjects exhibit degenerative changes in 1–6 joints [17], and 25% of severe haemophilia subjects have at least one target joint and are restricted in their physical activities [18]. On the other hand, that patients with endogenous FVIII levels ≥ 3 IU dL⁻¹ had, on the average, less arthropathy than those with lower FIII levels was established already in the mid-'60s [19]. Prophylaxis in HA with regular dosing of FVIII was started in Sweden in the late 1950s, with the intention to convert severe haemophilia into the moderate form of the disease by keeping FVIII levels above 1 IU dL⁻¹, thereby avoiding joint involvement and disability and decreasing the risk of other serious bleedings [20]. Life-long prophylaxis with clotting products –initiated after the first joint bleed, i.e. at 1–2 years of age- [21] to maintain circulating plasma FVIII/IX levels ≥1% of normal, has resulted in a dramatic reduction in haemophilic arthropathy and bleeding frequency in patients with severe (and some with moderate) haemophilia living in the Western World [22]. A multicentre, open-label randomized trial to define optimal treatment in severe HA in the US strongly supported this treatment strategy [23]. In that trial, the outcomes of patients given prophylactic FVIII infusions every other day were compared with the outcomes of patients treated with an intensive replacement regimen initiated at the time of a haemarthrosis (enhanced episodic treatment). The primary outcome was the proportion of children (6 years of age) with normal structure in the six index joints (bilateral ankles, knees and elbows). Joint assessments by magnetic resonance imaging (MRI) indicated that all six joints were normal in 93% of the children in the prophylaxis group, compared to 55% of children in the episodic-treatment group (P = .002). Joint damage was similar in the prophylaxis and episodic-treatment groups in very young children, but sharply diverged by the age of 5 years. Since other outcomes—e.g. number of joint bleedings per year and total bleedings per year—were significantly better in the prophylaxis group, the difference between the groups argued for clinically undetectable micro-haemorrhages as occurring only in the joints of very young children receiving on-demand treatment. At variance with secondary prophylaxis–whose effects are only limited to reducing annual bleeding rate, thus improving the quality of life of these patients — [24,25] primary prophylaxis was felt as the effective manner to prevent irreversible arthropathy in haemophilia, due to its ability to reduce the incidence of joint bleeding (including clinically undetectable episodes) at an early age. By paying a higher cost for factor concentrates (Table 1) than for on-demand treatments, the quality of life of patients with severe haemophilia on long-term primary prophylaxis has significantly improved, and these patients are increasingly more involved in working activities [26]. In addition, the life expectancy of European and American patients with severe haemophilia on prophylaxis has normalized to that of age-matched healthy individuals in their community [27]. However, although non-adherence or stopping prophylaxis is associated with a worse physical status, more chronic pain and orthopaedic surgery [28,29], adherence to prophylaxis is a lifelong challenge [30,31], and this is also true in the era of comprehensive care, with different disciplines supporting the haemophilia patient throughout life [32,33].