Radiological and orthopedic score in pediatric hemophilic patients with early and late prophylaxis. Received: April 21, 1998 / Accepted: July 2, 1998. Abstract In ...
Ann Hematol (1998) 77 : 171–174
Q Springer-Verlag 1998
ORIGINAL ARTICLE M. Funk 7 H. Schmidt 7 C. Escuriola-Ettingshausen S. Pons 7 T. Dzinaj 7 C. Weimer 7 B. Kornhuber W. Kreuz
Radiological and orthopedic score in pediatric hemophilic patients with early and late prophylaxis
Received: April 21, 1998 / Accepted: July 2, 1998
Abstract In order to evaluate joint alteration, 17 patients with hemophilia A and B were investigated over a period of 4 years (1993–1997). Patients were subdivided into two groups, according to therapy regimens. In group 1 (np10) prophylactic treatment was initiated until the third year of life. In group 2 (np7) patients received prophylactic treatment at the age of 5 years and above. To assess alterations in knee, elbow, and ankle joints, the radiological score and the physical examination score of the Orthopedic Advisory Committee of the World Federation of Hemophilia were used. The sum of the scores of these six joints was defined as the patient-dependent score. Patients of group 1 (median age at the end of observation: 10 years) reached a median radiological score of 1.0 (range: 0–13) and an orthopedic score of 0 (range: 0–4), whereas patients of group 2 (median age: 14 years) had a radiological score of 20 (range: 2–47) and an orthopedic score of 8 (range: 0–12), which shows a significant difference (p~0.01). In both treatment groups a manifestation or progression of arthropathic alteration was seen in those children who had repeated joint bleeding ( 1 5) prior to the onset of prophylactic treatment (rp0.90, p 1 0.01). Altogether, two of 60 joints in group 1 and 12 of 42 joints in group 2 had a radiological score 64. Elbow joints were more often affected than knee and ankle joints. In conclusion, the number of joint bleedings before prophylactic treatment was started influenced the progression of arthropathy even in patients with early onset of prophylaxis. The aim of treatment in severe hemophilia should be early prophylaxis before repeated joint
M. Funk (Y) 7 C. Escuriola-Ettingshausen 7 S. Pons T. Dzinaj 7 C. Weimer 7 B. Kornhuber 7 W. Kreuz Department of Pediatrics III, J.W. Goethe University, Theodor Stern Kai 7, D-60596 Frankfurt am Main, Germany e-mail: mfunk6zki.uni-frankfurt.de, Tel.: 0049-69-6301-6090/6432, Fax: 0049-69-6301-4464 H. Schmidt Department of Radiology, J.W. Goethe University, Theodor Stern Kai 7, D-60596 Frankfurt am Main, Germany
bleeding occurs in order to prevent osteoarthropathic alteration. Key words Hemophilic arthropathy 7 Early vs. later onset of prophylaxis 7 Radiological and orthopedic score 7 Target joints 7 Joint bleeding
Introduction Osteoarthropathic alteration is a major cause of morbidity in patients with severe hemophilia. In order to prevent bleeding and joint alterations, prophylactic treatment is recommended for patients with severe hemophilia. Several studies have proven the benefit of prophylactic treatment based on radiological and orthopedic outcome. Summarizing 25 years of experience, Nilsson et al. [13] demonstrated that long-term prophylaxis from an early age prevents factor concentration from falling below 1% and can avoid hemophilic arthropathy. Aledort et al. [1] reported the best orthopedic outcome in patients undergoing full-time prophylaxis. Complications, cost, and efficacy of continuous prophylactic administration of clotting factor are discussed in various studies [3–5, 8, 9]. Although prophylaxis is undoubtedly preferable to on-demand therapy during infancy and adolescence, the age at which prophylaxis should be initiated remains controversial. Furthermore, few data exist concerning the influence of joint bleeding on later radiological outcome before prophylactic treatment is started. We therefore investigated the influence of joint bleeding before and after onset and of the age when prophylactic treatment was started on the radiological and orthopedic outcome in a group of 17 hemophilic patients.
Patients, material, and methods Fifteen patients with severe hemophilia A and B (factor activity ~2%) and two patients with moderate hemophilia A (factor ac-
172 Table 1 Radiological and orthopaedic outcome in 10 haemophilic patients of group 1 with early onset of prophylaxis patient number
age 1997 (years)
1 2 3 4 5 6 7 8 9 10
7 8 8 8 10 10 11 12 13 17
median range
10 7–17
haemophilia (A/B) A A A A A B A B A A
factor activity (%) 1 ~1 1 ~1 ~1 ~1 ~1 ~1 1 ~1
onset of prophylaxis (years of age)
(years)
bleeds bleeds before* under* prophylaxis (number/years)
3 3 3 1 1 2 1 3 2 3
4 5 5 7 9 8 10 9 11 14
5/3 6/3 5/3 1/1 0/1 2/2 1/1 1/3 1/2 2/3
0/4 0/5 4/5 0/7 3/9 1/8 4/10 2/9 4/11 2/14
0 0 0 0 0 0 0 0 2 0
1 0–2
0, 2 0–0.8
0 0–2
2, 5 1–3
duration of
9 4–14
joint score** radiological
target joints
joint score** orthopaedic
1993
1997
1997
1993
1997
8 8 13 1 0 0 0 1 4 0
1 0 1 0 0 0 0 0 0 0
0 0 0 0 0 0 0 0 0 0
4 4 4 0 0 0 0 0 0 2
0 0–1
0
0 0–4
1 0–13
* joint bleedings only ** patient scores were estimated by summarizing the radiological scores of elbow, knee and ankle joints for each patient
Table 2 Radiological and orthopaedic outcome in 7 haemophilic patients of group 2 with late onset of prophylaxis patient number
age 1997 (years)
1 2 3 4 5 6 7
9 10 10 14 15 17 17
median range
14 9–17
haemophilia (A/B) A A A A A B A
factor activity (%) ~1 ~1 3 ~1 3 ~1 ~1
onset of prophylaxis (years of age)
(years)
bleeds bleeds before* under* prophylaxis (number/years)
5 6 6 10 10 10 8
4 4 4 4 5 7 9
1/5 6/6 7/6 11/10 10/10 11/10 10/8
8 5–10
duration of
4 4–9
1, 1 0.2–1.2
1/4 0/4 0/4 2/4 2/5 10/7 10/9 0, 4 0–1.4
joint score** radiological
target joints
joint score** orthopaedic
1993
1997
1997
1993
1997
2 0 2 28 5 11 33
2 2 10 42 19 20 47
0 0 0 3 1 3 5
0 0 0 5 3 4 11
0 2 8 11 8 8 12
20 2–47
1 0–5
5 0–33
1, 5 0–11
8 0–12
* joint bleedings only ** patient scores were estimated by summarizing the radiological scores of elbow, knee and ankle joints for each patient
tivity 3%) were investigated retrospectively until 1993 and compared prospectively over a period of 4 years (1993–1997), as shown in Tables 1 and 2. Informed consent was obtained from their parents or legal guardian. Thirteen patients were treated with factor VIII (30–40 IU/kg body wt. three times a week). Eleven of 13 patients received plasma-derived clotting factor, the remaining two patients recombinant manufactured clotting factor. Three patients with hemophilia B were treated with plasma-derived factor IX (30–40 IU/kg body wt. twice a week). To assess joint alterations, the radiological score of the Orthopedic Advisory Committee of the World Federation of Hemophilia (WFH) was used [15]. Radiological score was estimated for each joint (maximum 13 points) and the sum for elbows, knees, and ankles were defined as the patient-dependent score, with a maximum of 78 points for each patient. ’Target’ joints were defined as those with a radiological score 64 points, because a rapid progression of arthropathy could be expected [2]. Clinical examination of all six joints was done using the physical examination score (maximum score for each joint 12 points) according to the Orthopedic Advisory Committee of the World Federation of Hemophilia [6]. Pharmacokinetic studies were performed in all patients every 12 months for adjustment of the dosages and the intervals between infusions. Factor VIII: C activity was assessed by a onestage assay, using FVIII-deficient plasma as substrate [7]. Factor
IX activity was measured by a one-stage assay in the same way. The results were expressed as percentage (%) of activity. Prior to radiological and clinical examinations of the knee, elbow, and ankle joints, patients were subdivided into two groups according to therapy regimens. In group 1 prophylactic treatment was initiated between birth and the third year of life (median: 2.5; range: 1–3 years) and has continued until now (np10, age at the end of the study: 7–17 years, median: 10). In order to ease venous access, four of the younger patients were provided with a PortA-Cath implant. In group 2, patients received on-demand therapy during the first years of life. Prophylactic treatment was started at the age of 5 years and above (median: 8; 5–10 years) and has continued until now (np7, age at the end of the study: 9–17 years, median: 14). Comparison between the radiological joint alterations of both groups was done using the Wilcoxon rank sum test. Sixty joints in group 1 and 42 joints in group 2 were evaluated at the beginning and after 4 years of study. The correlation between the number of joint bleedings before treatment onset and radiological outcome was determined using the nonparametric Spearman rank test.
173
Results
diological scores 64 increased from 7 to 12 after a period of 4 years.
Number of joint bleedings Tables 1 and 2 summarize variables that affect the radiological outcome in patients of both treatment groups. In group 1, the median number of joint bleedings per year was 1.0 (range: 0–2) before onset of prophylaxis and 0.2 (range: 0–0.8) under prophylaxis. In group 2,the median number of joint bleedings per year was 1.1 (range: 0.2–1.2) before and 0.4 (range 0–1.4) under prophylactic treatment. The median sum of joint bleedings before onset of prophylaxis was 1 (range: 0–6) in group 1 and 10 (range: 1–11) in group 2. Three patients in group 1 and five patients in group 2 with joint bleedings 65 before treatment onset had a radiological score 68, whereas six patients of group 1 and one patient of group 2 with ^2 joint bleeds before treatment onset had a radiological score ^2 at the end of the study. The absolute number of joint bleedings before onset of prophylaxis correlated significantly with radiological outcome in patients of both groups (rp0.907, p~0.01), whereas the number of bleedings during prophylactic treatment did not give such a good correlation (rp0.485, pp0.05).
Radiological score and target joints In group 1, 20 elbow, 20 knee, and 20 ankle joints, for a total of 60, and in group 2, 14 elbow, 14 knee, and 14 ankle joints, for a total of 42 joints were examined. As shown in Table 1, one patient in group 1 had a radiological score of 2 at the beginning, whereas the other patients had scores of 0. Four years later, four patients remained with no radiological signs of arthropathy. Scores of the other patients ranged between 1 and 13. The median score of group 1 was 1.0 at the end of the study. In group 2 the median score of 5 (range: 0–33) at the beginning increased to 20 (range: 2–48) after 4 years (Table 2). One patient had a score of 0 in 1993, whereas every patient had signs of joint alteration after 4 years. For five patients a radiological score 610 was found. Calculating 60 joint scores of group 1 versus 42 joint scores of group 2, a significant difference was demonstrated between the two groups at the end of observation (p~0.01, Wilcoxon rank sum test). Joints with a radiological score 64 were defined as ’target’ joints, with a high risk of further alterations. At the end of the study, six of 17 patients (both groups) had target joints, two in group 1 and four in group 2 (Tables 1 and 2). In all, 14 of 102 examined joints met the definition, two joints in group 1 and 12 joints in group 2. Seven of 34 elbow joints, were affected, four of 34 ankle joints, and three of 34 knee joints. In group 1 the radiological scores of two joints rose from ~4 to 64, whereas in group 2 the number of joints with ra-
Orthopedic score Concerning the orthopedic score, no pathological abnormalities were detected in group 1 at the inital examination, while after 4 years two joints had mild alterations, such as crepitus on motion and loss of ~33% of total ”full range of motion“ [6]. In group 2 the number of joints with mild alterations increased from 2 to 4. Severe alterations such as flexion contracture and loss of 1 33% of total ”full range of motion“ were found in three joints at the inital examination and in eight joints after 4 years of observation.
Discussion A comparison of the two groups of hemophilic patients in a longitudinal study shows that early factor prophylaxis provides a better radiological outcome in children and adolescents. After 4 years a significant difference was demonstrated; patients of group 1 with a median age of 10 years reached a median patient-dependent radiological score of 1 (range: 0–13), whereas patients of group 2 (median age: 14 years) had a radiological score of 20 (2–47). Our results confirm the data of Nilsson et al. [13], who followed up patients who had received prophylactic treatment beginning at the age of 1–2 years. At the age of 7–12 years they had a radiological score of 0, at the age of 13–17 years a median score of 4.8 within a range of 0–22. As previously described by Lofqvist [10], 20% of these patients had an abnormal radiological and orthopedic joint score at the age of 7–22 years. Comparable to these data, we found radiological alteration in three of ten patients with an early prophylaxis who had had five and more joint bleedings before the onset of prophylaxis. Nilsson et al. also reported a group of older patients with a late onset of prophylaxis (at the age of 3–13 years). These patients, comparable to our patients in group 2, had a median radiological score of 12 (20 points in our patients) by the age of 15 years (14 years in our patients). Several of these patients already had osteoarthropathic alterations [12]. Regarding progression of radiological alteration, three patients of group 1 showed a radiological score of 0 (1993) and changed to 8 or 13 within 4 years. In group 2 all patients showed radiological alteration by the end of the study. In five of seven patients the radiological score differed by 8 points and more within 4 years. Concerning target joints and orthopedic score, manifest differences were seen between patients of the two groups. Two joints of group 1 patients and 12 joints of group 2 patients had a radiological score 64. Elbow joints were affected more often than ankle and knee joints, confirming results previously described by Aron-
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stam et al. and Nilsson et al. [2, 13]. The clinical examination revealed mild orthopedic alteration in both of the two affected joints in group 1 and in four of the 12 joints in group 2. Severe orthopedic alterations were found only in patients of group 2. The number increased from 3 to 8 joints, despite a clear decrease in the number of joint bleedings during the 4 years of prophylactic treatment. A good correlation was seen between the number of joint bleedings before treatment onset and radiological outcome in patients of both treatment groups. Aledort et al. [1] emphasized the reduction in the number of joint bleedings as the most critical factor for a good orthopedic outcome. In addition, we demonstrated that a good radiological score was achieved in patients with a limited number of joint bleedings during and also before the onset of prophylaxis. In patients with more than five joint bleedings during the first years of life high radiological scores were estimated and a progression of arthropathy was seen even when prophylaxis was started early. In our opinion, the radiological and finally the orthopedic outcome in hemophilic patients is a result of the number of clinical and subclinical joint bleedings during childhood. Although radiological alterations are not detectable in joints of younger patients, first signs of synovial hypertrophy and cartilage damage can be demonstrated by magnetic resonance imaging [14]. With repeated bleeding episodes, the synovium proliferates and a continued leaking of red blood cells adds to the synovial iron load, with continued macrophage accumulation, pannus formation, and synoviocyte hyperplasia finally resulting in destructive arthritis [11, 12, 16]. At this time synovial bleeding may be related not only to clotting factor deficiency but also to pre-existing vascular damage. The aim of hemophilic treatment should be early prophylaxis before repeated joint bleeding occurs, and it should be continued during childhood and adolescence to enable hemophiliacs to have a normal physical development.
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