Can haemophilic arthropathy be prevented?

The simple answer is that, nowadays, it can. An abundance of published evidence unequivocally attests that haemophilic arthropathy can be prevented in boys with severe haemophilia A or B by the early initiation of regular prophylactic treatment with the respective factor concentrate (FVIII or FIX) ( Nilsson et al, 1970 , 1976, 1992; Petrini et al, 1991 ; Aledort et al, 1994 ; Liesner et al, 1996 ). As outlined in joint recommendations by the WHO (World Health Organization) and the WFH (World Federation of Hemophilia), agreed on at Geneva in 1994. ‘Since the main goal is to prevent joint bleeding and its sequelae, prophylaxis should be considered optimal management for persons with severe haemophilia A or B (i.e. with basal factor VIII/IX levels <1% of normal). Treatment should be started at the age of 1–2 years and be continued indefinitely. Where prophylaxis is not feasible or appropriate, on-demand therapy should be given’ ( Berntorp et al, 1995 ). This type of prophylaxis is sometimes referred to as primary (long-term or permanent) prophylaxis, as distinct from secondary prophylaxis, i.e. short-term prophylactic treatment given after the onset of recurrent bleeds when arthropathy is usually already manifest. In too many parts of the world, however, fulfilment of these recommendations must be viewed as a long-range goal in haemophilia care, as national economic resources are insufficient for regular prophylactic treatment to be achievable. In many countries the health authorities do not consider the provision of prophylactic treatment to be a necessary criterion of a medically acceptable standard of haemophilia care. Moreover, medical opinion differs not only regarding the relative merits of on-demand treatment, and primary and secondary prophylaxis, but also, even among adherents of primary prophylaxis, regarding the optimal regimen. The most extensive accumulation of long-term experience in prophylactic treatment to have been published is that of the Swedish series reviewed by Nilsson et al (1992 ). Prophylactic treatment of haemophilia A was started on a small scale in 1958 and of haemophilia B in the late 1960s, and has been successively and cautiously developed and improved. The rationale for the prophylactic treatment model was the observation that chronic arthropathy was less frequent and less severe in moderate haemophilia (i.e. factor VIII or IX concentrations 1–4% of normal) than in severe (i.e. factor VIII/IX concentrations <1% of normal) haemophilia ( Ahlberg, 1965). Table I summarizes the data elicited in a 25-year survey of prophylactic treatment by Nilsson et al (1992 ) and Nilsson (1994). The series comprised 65 patients with severe haemophilia A, divided into three groups. In the group of oldest patients (n = 25, born 1958–72, age 21–35 at follow-up), prophylactic treatment was started at various times between 3 and 13 years of age, and several patients already had arthropathy prior to the start of treatment. Initially they were given considerably lower annual dosages (400–1000 IU/kg) than those used today, and the infusions were sometimes given only once a week. The treatment was successively optimized, the mean annual incidence of joint bleeds being 5 (range 0.5–16), the mean orthopaedic joint score 5.1 (range 0–15) and the mean radiological score 18.0 (range 0–41). In the next group, which was composed of 19 boys born 1973–81 (aged 13–20 at follow-up), prophylaxis started at 1–4 years of age, usually being given twice weekly at dosages (800–2500 IU/kg/year) somewhat higher than those used in the previous group, and successively increased to an average of 5400 IU/kg/year. The mean annual incidence of joint bleeds was reduced to 2.6 (range 0.2–17), the mean orthopaedic joint score was 1.2 (range 0–7) and the mean radiological score 4.8 (0–22). Of the 19 boys, 14 had orthopaedic scores of zero, and 11 had radiological scores of zero, i.e. this group had only minor, non-disabling arthropathy. The youngest group, 21 boys born 1981–90, aged 3–12 at follow-up, started prophylactic treatment at the age of 1–2 and annual dosages ranged from 4000 to 9000 IU FVIII per kg body weight. There were almost no bleeding episodes in these cases. The orthopaedic and radiological scores were zero in all 21 patients. In this youngest age group it was usually possible to maintain FVIII/IX concentrations above 1% between infusions. Although a weakness of this study is the lack of a control group, nonetheless the findings clearly show that the more intensive prophylactic treatment received by the youngest children, with an early start and designed to maintain plasma FVIII or FIX levels above 1% of normal, yielded better results than earlier regimens with lower dosages. This derives further support from the results of a retrospective comparison which showed the orthopaedic and radiological scores for the subgroup who were 15 years of age at the time of the study to be significantly better than those recorded for the older subgroup when they were 15 years of age ( Nilsson et al, 1992 ). A longitudinal orthopaedic outcome study of severe haemophilia A patients was performed by Aledort et al (1994 ) in an attempt to establish optimal therapeutic regimens for haemophiliacs. 21 international haemophilia centres enrolled a total of 477 evaluable patients under 25 years of age. The purpose was to determine whether increasing factor utilization would produce a decrease in arthropathy, as evaluated in terms of orthopaedic and radiological scores for ankles, knees and elbows over a 6-year period. This was the largest study made to date of orthopaedic outcome in haemophilia patients. Most patients in this study were treated on-demand but the series also included patients on primary prophylaxis (>45 weeks/year; n = 66) or short-term secondary prophylaxis. One of the conclusions was that higher consumption of factor per se does not necessarily result in a better orthopaedic outcome. However, as compared to the rest of the group (without primary prophylaxis), patients on prophylactic treatment had significantly fewer joint bleeds (mean 5.6 v 16.5) and total bleeding episodes (mean 9.4 v 25.5) and better initial and final orthopaedic scores ( Table II). Patients on prophylaxis also manifested better radiological outcome during the study period. Patients treated with on-demand therapy were characterized by significantly greater progression both physically and radiologically than those on prophylaxis. Annual factor concentrate consumption was almost 3000 IU per kg body weight in the prophylactic group, as compared to 1000 IU per kg body weight in the rest of the study group. A noteworthy finding was that 16% of the patients who received on-demand treatment consumed similar levels of factor per year as the average patient on prophylactic treatment. Bohn et al (1994 ) published a cost–benefit analysis of prophylactic versus on-demand therapy, based on data from the Orthopaedic Outcome Study by Aledort et al (1994 ). Although the methodology is complex, the results suggest that patients on primary prophylaxis consumed no more factor concentrate than the subgroup whose frequent bleeding episodes necessitated a combination of on-demand treatment and secondary prophylaxis. In a retrospective study, Smith et al (1996 ) reported that the cohort who received prophylactic treatment (n= 27) had fewer bleeding events per year (median 3 v 31), but used more concentrate (3323 v 1015 IU/kg/year) than the cohort who received episodic infusions for bleeding events. When making a medical assessment of published reports of the outcome of on-demand treatment, it is important to bear in mind that it is a somewhat heterogenous concept. In all probability, on-demand treatment given in the patient's home with broad indications in the event of a bleed yields better results than treatment which, for various reasons, is given only after the onset of symptoms. Multicentre studies of intensive on-demand treatment are in progress in the U.S.A. (Manco-Johnson, personal communication). Liesner et al (1996 ) studied 27 children with severe haemophilia A receiving prophylactic treatment. The median age at start of prophylaxis was rather high (6.2 years; range 1.3–15.9) and the mean cumulative duration of follow-up was 30 months (range 7–76). Prior to prophylaxis, mean annual incidence of bleeding episodes was 14.7 (range 3.7–35.4), figures comparable to those reported by Aledort et al (1994 ). On prophylactic treatment at a mean annual dosage of 4900 IU per kg body weight (range 1900–8200), the mean incidence of bleeds fell to 1.5 (range 0–12.5). This is a significant finding, since two of the major determinants of good orthopaedic outcome identified in the study by Aledort et al (1994 ) were the annual incidence of bleeding episodes, and that of joint bleeds. In the three studies mentioned above ( Nilsson et al, 1992 ; Aledort et al, 1994 ; Liesner et al. 1996 ) the advantages of prophylactic treatment were expressed in terms of the clinical assessment of joint status on the basis of orthopaedic scores and radiological changes. All three reports also contained socio-medical data showing those on prophylaxis to have been characterized by a clear reduction of house calls or hospitalization, and less disease-related absence from school or work. Bleedings into joints and muscles account for the greater part of morbidity figures for haemophiliacs, and are therefore a high-priority aim for improvement by prophylaxis. However, it should be borne in mind that prophylactic treatment also provides protection from all other forms of haemorrhage that may occur spontaneously or as a result of trivial trauma in the untreated haemophilic child. Trauma to the head may cause life-threatening cerebral haemorrhage. Although no large population studies have been published which shed light on the actual magnitude of this risk in on-demand versus prophylactic treatment subgroups, some light was shed on this problem by the findings of the Kogenate PUP (previously untreated patients) study ( Lusher et al, 1993 ). The children in this study were enrolled at an early age (4–5 months) and had free access to Kogenate (recombinant FVIII) in accordance with routine protocols at the treatment centre. Meticulous records were kept of all bleeding episodes and treatment events. During the first 2 years of follow-up the on-demand treatment group (n = 38) was characterized by the occurrence of bleeding episodes requiring treatment at a rate of one every 30 d, four of the episodes being classifiable as serious: one intracranial haemorrhage, one haematoma in the thigh, one case of melaena, and one intra-abdominal haemorrhage. This suggests that, during childhood, haemophiliacs are at no small risk of serious bleedings other than joint or muscle bleeds. In the prophylactic treatment group (n = 9), bleedings were infrequent, and none were serious (unpublished observations). Published reports by proponents of prophylaxis are characterized by diversity of opinion as to when such treatment should be started. Some consider the ideal time to start treatment to be before occurrence of the first joint bleed, which in practice means around the age of 1 year when the child begins to walk ( Nilsson et al, 1992 ). The rationale for this view is twofold: to avoid the risk of a target joint developing, and to prevent other serious bleeds. At other centres the occurrence of isolated joint bleeds before the start of prophylaxis is considered acceptable ( Petrini et al, 1991 ; Scheibel, 1994). Petrini et al (1991 ) clearly demonstrated the importance of an early start to prophylaxis. Two groups of seven boys on prophylaxis each received treatment two or three times a week at an annual dosage exceeding 3000 IU/kg, the main difference between the groups being the mean age at start of treatment, 3 years in one group and 5 years in the other. Follow-up at 5–12 years of age showed the earlier treatment start group had fewer bleeding episodes and virtually no arthropathy, whereas in the later start group radiological changes were manifest in the ankles in 71% (5/7) of cases and in the knees in 57% (4/7). Evidence in support of an early start to treatment also derives from a recent study by Löfqvist et al (1997 ) who, in 1990 and again in 1995, investigated joint status in the 34 youngest children on prophylaxis at the Malmö centre. Children who have developed target joints generally require higher dosages of factor concentrate in order to remain free from bleeding episodes, and continue to be at risk of joint deterioration despite adequate prophylactic treatment. One argument for accepting a few joint bleeds before starting prophylaxis is that it enables the child's proneness to bleeding episodes to be assessed and treatment to be adjusted accordingly, which at some centres may mean that on-demand treatment is given instead of prophylaxis. Long clinical experience has shown bleeding diatheses to be characterized by marked individual differences, as exemplified by findings in the Orthopaedic Outcome Study which showed that, of the subgroup with normal joints at the start of the study (i.e. 10% of the series as a whole), 50% still had normal joints 6 years later ( Aledort et al, 1994 ). Even in the long-term follow-up series studied at Malmö in Sweden ( Nilsson et al, 1992 ) there were patients in the oldest treatment group, born 1958–72, who, despite a late start of treatment, and irregular prophylaxis at low dosages in early childhood, nonetheless manifested fairly normal joint status as adults. In my opinion, however, to treat patients differently, solely on the basis of the sparsity of their joint bleeds, is ethically indefensible in view of the risk of other types of bleedings and the effect on the child's overall quality of life. No comparative studies have shown unequivocally that tolerating a few isolated joint bleeds before the start of treatment is a poorer alternative than starting treatment before the first joint bleed, provided that treatment is started during the second year of life. However, in the series studied by Petterson et al (1980 ) some patients already manifested joint changes at the start of prophylaxis, though they had had no clinically recognized joint bleeds. This suggests that subclinical bleeds may trigger the development of arthropathy in children with only isolated clinical bleedings, if the start of their regular prophylactic treatment is delayed too long. An extreme variant of delayed prophylactic treatment is starting secondary prophylaxis when frequent bleedings have occurred during on-demand treatment. This approach was the focus of a study by Manco-Johnson et al (1994 ), in which 13 children were started on secondary prophylaxis at a mean age of 6.9 years (range 2.0–12.5) after having suffered recurrent bleeding episodes (mean 43; range 8–127, approx. 50% of them joint bleeds) during the previous 12-month period while being given on-demand treatment. After a mean duration of secondary prophylaxis of 21 months (range 6–51) the situation had improved for 62% (8/13) of the children, and target joints could be controlled by increasing the dosages of factor concentrate. However, a crucial finding was that the radiological changes in several children progressed despite secondary prophylaxis, a finding also previously reported by others ( Petrini et al, 1991 ; Schramm et al, 1993). Over the years, prophylactic treatment has been successively intensified at most centres where this principle has been adopted. A common regimen today is 20–40 IU of factor VIII per kg body weight three times weekly in cases of haemophilia A, whereas the same dosage of FIX twice weekly is sufficient in cases of haemophilia B, owing to the longer half-life of the factor. In early studies it had been noted that scheduling short intervals between infusions was more important than achieving high peak plasma factor concentrations ( Kasper et al, 1970 ; Schimpf et al, 1977 ; Soreff & Blombäck, 1980; Petrini et al, 1991 ). The most important aim of all is to ensure that the plasma factor concentration does not fall below a certain minimum level before the next infusion. By maintaining a minimum level >1% of normal, severe haemophilia can be converted to moderate haemophilia, which should be the goal of prophylactic treatment ( Nilsson et al, 1992 ). However, the lowest effective level of FVIII or FIX must be determined individually for each patient, and the goal of maintaining a level >1% of normal should be seen as a guideline since experience has shown satisfactory control of the bleeding diathesis in most cases. Prophylactic treatment can and should be optimized by means of pharmacokinetic studies to determine the individual patient's FVIII or FIX metabolism ( Carlsson et al, 1993 ). In a cross-over study of 21 patients with severe haemophilia A, Carlsson et al (1997 ) studied plasma FVIII concentrations, bleeding frequency and FVIII consumption during two 6-month periods at different dosages. During one 6-month period the patients were given the standard dosage of 25–40 IU/ kg body weight three times weekly. Using individual single-dose pharmacokinetic data, FVIII:C curves deriving from various dosages and dose intervals were computer-simulated for each patient. From these pharmacokinetic data, an appropriate dose was chosen for the second 6-month period, enabling a trough level >1% of normal to be maintained at all times. The patients were all over 8 years of age and had a wide variation in the half-life of FVIII in plasma (7.8–18.3 h), with a tendency for the half-life to increase with age. It was found that, during the period on pharmacokinetic doses (generally lower doses but given at shorter intervals), consumption of FVIII was reduced by 31%, though the clinical effect was comparable with that of standard dosages, and the trough levels were higher. The study thus showed that the cost-effectiveness of prophylactic treatment can be enhanced by using this pharmacokinetic dosage titration approach. Computer-simulated curves of FVIII levels at different dosages and dose intervals are also invaluable visual aids to show the patient when discussing the most appropriate regimen, and scheduling treatment with regard to his daily activities. The same pharmacokinetic approach can be used in scheduling treatment for patients with haemophilia B, and in most cases shows that a lower dosage administered every other day yields higher trough levels and lower overall consumption. Owing to the longer plasma half-life of FIX, there is less advantage in daily doses than there is with FVIII ( Björkman et al, 1994 ). To obtain an effective prophylactic treatment it is desirable to begin regular injections three or four times a week at 1–2 years of age. Many children and their parents find this early frequent need of venous access to a vein stressful and impossible to perform in an optimal manner. One option in this situation is to begin with one or two injections per week and slowly increase the frequency. Another option is a central venous line, preferably using an implanted venous access device such as the Port-a-Cath ( Ljung et al, 1992b ; Liesner et al, 1995 ; Blanchette et al, 1996 ; Warrier et al, 1997 ). The largest series where an implantable venous access system (Port-a-Cath) was used was composed of 53 children with severe or moderate haemophilia A or B (unpublished observations). The cumulative duration of follow-up was 1578 months (median 30 months; range 1–114). Of the devices implanted, 70% (37/53) were used without complication (median follow-up 32 months; range 1–114), and the remaining 30% (16/53) were associated with various types of complications: infection, bacteraemia or septicaemia in 56% (9/16) of cases, i.e. a rate of 0.07 per follow-up year or 0.19 per 1000 patient days, or various technical complications occurring after a median of 32 months (range 4–75) of uncomplicated in the remaining Of the patients with manifested Of the patients without had various and parents consider that the Port-a-Cath device could be used with an acceptable frequency and of which enables regular prophylactic or on-demand home treatment of children with haemophilia to be at an early age. When central venous it is important to consider the of time the child has from the device before complications There are no data that support the that regular prophylactic treatment is associated with an increased risk of development ( Nilsson et al, 1992 ; Ljung et al, 1992; et al, 1993 ). usually during the first infusions of a child treated usually the at a earlier age than the child treated This does not the of of To haemophilic arthropathy can be prevented by early initiation of regular prophylactic treatment. As in most countries the is the to the of this of haemophilia care, it is important to cost-effectiveness in such as individual dosage or the development of with longer in and of improved means of Although cost–benefit of prophylactic treatment are under both in the U.S.A. and in its both and to haemophilic children and their is to in economic This study was by from the Swedish and of the