text: Optimal treatment strategies for hemophilia: achievements and limitations of current prophylactic regimens | Blood Journal
  ORCID record for Johannes Oldenburg
  Prophylaxis in children is most efficient when started at an early age. Prophylaxis initiated before the age of 2 years3 resulted in a better outcome than prophylaxis commenced at age 3 to 5 years or 6 to 9 years.4,5 National guidelines and recommendations in several European countries advise starting prophylaxis early.6,7 In the last decade, several studies suggest beginning with a once-weekly regimen.8⇓-10 The rationale behind this is either to avoid the placement of central venous access devices and to account for the different clinical presentations, thus tailoring therapy and optimizing cost-effectiveness,8,9 or to lower the risk of inhibitor formation.10 The Canadian primary prophylaxis experience begins with a once-weekly regimen (50 U/kg body weight [BW]), that, depending on number of bleeds, is intensified in a first step to twice-weekly treatment (2 times 30 U/kg BW) and, in a third step, to every-other-day therapy (25 IU/kg BW).11 Median ages at switching to steps 2 and 3 were 4.1 and 9.7 years, respectively. Twenty percent of the patients remained on the lowest regimen during the observation time of this study. For this regimen, switches depend on the number of bleeds. Long-term follow-up observation of this cohort is needed, in order to assess whether this regimen is still effective against late onset of arthropathy. Kurnik et al presented data that suggest that early initiation of prophylaxis may prevent inhibitor formation.10 Triggered by observations from the CANAL and RODIN studies12,13 where inhibitor formation was significantly less in the prophylaxis group, compared with the on-demand group, Kurnik et al proposed beginning prophylaxis with once-weekly 25 IU/kg BW at a median age of 10 months.10 The rational behind this regimen was that regularly administered, low factor VIII (FVIII) doses in the absence of bleeds, intensive treatment periods, and danger signals may induce tolerance to FVIII within the first 20 to 50 exposure days. By the time the first major joint bleeds are expected, tolerance would already have been achieved. Following this regimen, Baxter commenced the prospective Early Prophylaxis Immunologic Challenge (EPIC) study. However, the EPIC study was stopped after inclusion of only 19 patients because of the unexpectedly high incidence of inhibitors. The reasons given for stopping the study were difficulties in adherence to the complex protocol in a multinational, multicenter study setting and an increasingly unrealistic perspective for achieving a significantly lower inhibitor frequency within this study.14
  So far, only a few studies have addressed long-term outcomes of prophylaxis in hemophilia patients with observation times ranging from 5 years to 2 to 3 decades.1,5,15⇓⇓⇓-19 All studies support that, with the current treatment regimens, severe hemophilia patients will sooner or later develop joint arthropathy. Fischer et al compared The Netherlands' intermediate-dose prophylaxis (2100 IU/kg per year) with the Swedish higher-dose prophylaxis regimen (4000 IU/kg per year).19 After a median observation time of 20 years at an age of young adulthood between 19 and 30 years, the intermediate prophylaxis regimen showed a median Hemophilia Joint Health Score (HJHS) of 7 (range, 2-18) of 144, whereas the Swedish group presented a median HJHS of 4 (range, 2-6.8). The number of joint bleeds in the preceding 5 years in the groups were 2 per year vs 0.5 per year, respectively.19 The Swedish protocol had a slightly better outcome and the difference between the 2 cohorts is expected to become larger with time. However, even the high-dose Swedish protocol, with only 1 joint bleed every 2 years, did not entirely prevent joint arthropathy over a lifetime perspective. Furthermore, it has to be taken into account that the summarized results were mainly clinical scores which are indicating joint disease later than MRI.5 A 25-year follow-up of 30 Swedish patients confirmed that early initiation of primary prophylaxis continuing throughout life was successful in virtually eliminating joint bleeds and preserving an acceptable, however not normal, joint status.18 In a 1992 study, Brackmann et al followed 90 German patients with severe hemophilia A from 1978 to 1990, and found no worsening of the joint status over a 12-year period.16 A 26-year follow-up of 49 patients of the same cohort, however, demonstrated that 90% of these patients treated throughout life with an intensive prophylactic regimen exhibited joint disease at 30 to 40 years of age.20
  Before the era of prophylaxis (eg, in the 1970s), knee joint bleeds were the most frequently noted joint bleeds and knees were the clinically leading joint in most patients.21 With the beginning of the era of prophylaxis, the knee joint, as a muscle-controlled joint, became more stable and the ankle joints became the first joints to be affected and, thus, represent the clinically most indicative joint. Recently, Oldenburg et al observed higher MRI scores for ankle joints, and the scarcity of pathologic findings in knees for patients with unaffected ankles indicated that, in most patients, the ankle was the primary target joint of hemophilic arthropathy.22 These results are consistent with previous reports showing more hemarthroses and worse joint scores for ankles, compared with knees or elbows.5,23⇓⇓-26 Krämer et al's 2013 study20 followed the development of joint arthropathy in the cohort on intensive lifelong prophylaxis, initially described by Brackmann et al16 in their article in 1992. During a 26-year follow-up, Pettersson scores based on plain x-rays were taken every 3 to 5 years and Gilbert scores were obtained once per year. Ankles were the first joints to be found affected by Pettersson score, with median pathologic findings after 10 years, followed by significant effects for knee and elbow joints after about another 10 years.20 On average, the clinical Gilbert scores became pathologic about 1 to 2 decades later than the Pettersson scores.20 An abstraction/simplification of the findings from Krämer in 2013 is illustrated in Figure 2. Our study as well as those by other authors indicate that imaging score-based diagnosis of arthropathy is possible long before being revealed by clinical scores.5 However, plain x-ray is too insensitive to diagnose early joint pathology, making it inappropriate to diagnose early joint damage. Ankles, as the first affected joints for the majority of patients, offer an interesting opportunity for diagnosing early joint disease and subsequently adapting clinical decisions.
  Outcome assessment comprises several tools including annual bleed rates, physical joint examination, and imaging measures such as plain x-rays, MRI, and ultrasound assessment. Quality-of-life questionnaires complement the instrumentarium for outcome assessment (as discussed by Blanchette et al27 in 2014). The HJHS is currently regarded as the state-of-the-art instrument for clinical assessment of joint status. It includes most of the elements of the previously used Gilbert score.28⇓⇓-31 Plain x-rays scored by the Pettersson scale had been a useful tool in the past, but are not able to recognize early joint disease.16,32 MRI is a very sensitive instrument for early detection of hemarthrosis, including synovial hypertrophy, hemosiderin deposition, and osteochondral changes. Scoring scales for reliable assessment of hemophilia arthropathy have been established.33⇓⇓-36 However, MRI application to young children is limited and also expensive. More recently, ultrasound has been used for diagnosis of joint disease in hemophiliacs. Advantages are its wide availability and its low cost. Soft-tissue changes such as synovial hypertrophy, which precede joint disease, especially can be effectively diagnosed. Standardized and simplified ultrasound scanning protocols for early arthropathy detection in ankles, knees, and elbows have been published.37⇓⇓-40 The joint measures for long-term outcome with respect to established scores, potency of detecting early joint disease and follow-up of severe arthropathy, suggested intervals for assessment, and costs are summarized in Table 1.
  The annual bleed rate (ABR) has become an important parameter in clinical studies as a surrogate for the efficiency of prophylaxis regimens. Some studies have also assessed the annual joint bleed rate. For intensive treatment protocols, the mean total ABRs range from 2 to 5, whereas the joint bleed ABR is in the order of 0.5.5,20,41⇓-43 Given the long-term dimension of developing joint arthropathy and the limitations of diagnosing early joint damage the ABR serves as an important clinical parameter to adjust treatment regimens.
  Although primary prophylaxis represents the gold standard for preserving joint function in children with severe hemophilia, prophylaxis in adult patients is still debated. There are 2 groups of adult patients who have to be addressed separately. The first group of patients includes those who started primary or secondary prophylaxis early in their life and maintained good joint health into adulthood. A small number of published studies suggest that these patients benefit from lifelong prophylaxis.16,18⇓-20 These studies reported a follow-up of 12 to 30 years and demonstrated that hemophilia patients with an ongoing prophylaxis regimen present with well-preserved joint function and only mild joint arthropathy at the age of 30 to 40 years.18⇓-20 The patients from The Netherlands with an intermediate dosage regimen had a slightly worse outcome at the age of 30 years than Swedish patients with a high-dose prophylaxis regimen.19 In the German cohort, 90% of patients showed some, mostly mild, arthropathy, mainly in their ankle joints after a 26-year follow-up.20 There are several reports that a proportion of young adults are switched to on-demand regimens and that some of these patients experience only slight bleeding and little joint arthropathy.44,45 However, no follow-up data are available that report joint condition of these patients at the age of 40 to 50 years or older. As initial joint damage always progresses, even in the absence of joint bleeds, a worsening of joint disease can be anticipated. The joint annual bleed rate might serve as a surrogate for switching those patients back to a prophylactic regimen. The joint ABR should not be higher than during an intensive prophylaxis regimen, which is about 1 to 2 joint bleeds within 2 years.
  A subset of 10% to 15% of patients with severe hemophilia A exhibits a mitigated disease phenotype, with significantly reduced frequencies of spontaneous bleeding and lower consumption of factor concentrates.48 This clinical heterogeneity is also reflected by the late onset of the first joint bleed and furthermore in development of only minimal arthropathy. This mitigated clinical phenotype is chiefly determined by the underlying mutations in the F8/F9 genes.49,50 Missense mutations, splice site mutations outside conserved regions, and small deletions within A series were especially associated with less bleeding.51 Furthermore, the inflammatory response to the presence of blood in a joint varies, which is believed to be in part dependent on genetic variations in the genes involved in the inflammatory and immune-regulatory pathways.52⇓-54 This variation may influence the subsequent development of chronic synovitis and also, ultimately, joint arthropathy. Indeed, the Joint Outcome Study reported several boys with multiple episodes of hemarthrosis who remained free of joint damage. Other patients showed joint damage in the absence of clinical bleeds.5 In patients with greater numbers of bleeds or with a stronger inflammatory response to a bleed, larger factor doses and more frequent application are required to prevent the onset of joint disease.
  Collins et al demonstrated a great variation of pharmacokinetics not only dependent on age (shorter half-life in young children than in adults) but also within patient groups of the same age, where he found an almost 100% difference in time-to-trough levels of >1% after application of a standardized FVIII dose.55 Several studies have shown that the level of the VWF has a major influence on the FVIII half-life.56⇓-58 Higher VWF levels correlate with increasing intervals of FVIII substitutions.57,58 Therefore, assessment of the patient's individual pharmacokinetic profile is regarded as important for individualization of therapy. Because a classical pharmacokinetic profile is based on numerous blood draws over 2 or more days, population pharmacokinetics presents an elegant approach to assess the pharmacokinetic profile by routine factor level measurements at regular visits in the treatment center.59,60 Population pharmacokinetics will become an important measure for individualized treatment regimens.60
  Correspondence: Johannes Oldenburg, Institute of Experimental Haematology and Transfusion Medicine, University Clinic Bonn, Bonn, Germany; e-mail: johannes.oldenburg{at}ukb.uni-bonn.de.
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  DOI: https://doi.org/10.1182/blood-2015-01-528414
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  Blood Mar 2015, 125 (13) 2038-2044; DOI: 10.1182/blood-2015-01-528414
  Oldenburg, J. (2015). Optimal treatment strategies for hemophilia: achievements and limitations of current prophylactic regimens. Blood, 125(13), 2038-2044. Accessed April 25, 2019. https://doi.org/10.1182/blood-2015-01-528414.