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Radiosynovectomy in haemophilia: Long-term results of 500 procedures performed in a 38-year period
Thrombosis Research 134 (2014) 985–990
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Regular Article
Radiosynovectomy in haemophilia: Long-term results of 500 procedures performed in a 38-year period E.C. Rodriguez-Merchan a,⁎, H. De la Corte-Rodriguez b, V. Jimenez-Yuste c a b c
Department of Orthopaedic Surgery, La Paz University Hospital, Madrid, Spain Department of Rehabilitation and Physical Therapy, La Paz University Hospital, Madrid, Spain Department of Haematology, La Paz University Hospital, Madrid, Spain
a r t i c l e
i n f o
Article history: Received 21 June 2014 Received in revised form 19 August 2014 Accepted 23 August 2014 Available online 6 September 2014 Keywords: Haemophilia Synovitis Articular variables Radiosynovectomy Efficacy Results
a b s t r a c t Background: Radiosynovectomy (RS) can reduce the number of haemarthroses in chronic haemophilic synovitis. The purpose of this study was to assess the effectiveness of RS in terms of the objective improvement of five parameters (number haemarthroses, articular pain, degree of clinical synovitis, clinical score of the World Federation of Haemophilia (WFH), and radiological score of the WFH. Methods: In a 38-year period (1976-2013), five hundred radiosynovectomies were performed in 443 joints of 345 patients with haemophilia diagnosed with chronic synovitis. The mean patient age was 23.7 years (range, 6-53). The mean follow-up was 18.5 years (range: 6 months-38 years). The RS was carried out with either yttrium-90 or rhenium-186. We performed 1 to 3 injections (RS-1, RS-2, RS-3), with a 6-month interval between them. Results: RS resulted in significant improvement in all the parameters studied, except in the WFH radiologic score that showed no improvement. On average, the number of haemarthroses decreased by 64.1% and articular pain decreased by 69.4%. The degree of synovitis showed a reduction of 31.3%. The WFH clinical score revealed an improvement of 19%. The WFH radiological score showed no improvement. There were four complications (0.9%) of RS. Twenty-eight (6.3%) joints eventually had to be subjected to arthroscopic synovectomy or total knee replacement (TKR). No cancer was observed in this group of patients during the 38-year period. Conclusions: Radiosynovectomy (RS) is an effective, safe, minimally invasive, well tolerated procedure in the long-term for the treatment of chronic haemophilic synovitis. Moreover, it is very easy to perform. The knee required more injections than the elbow or the ankle and more severe synoviums required a higher number of RS procedures. © 2014 Elsevier Ltd. All rights reserved.
Introduction
Materials and methods
Radiosynovectomy (RS) is an effective type of non-surgical synovectomy that can diminish the number of bleeding episodes in patients with haemophilia suffering from chronic haemophilic synovitis [1–26]. The RS procedure requires 1-3 intra-articular injections of a radioactive isotope (RS-1, RS-2 or RS-3), with a 6-month interval between them. However, there are still many aspects concerning the beneficial effects of RS that have been as yet neither fully elucidated nor quantified. The purpose of this study has been to quantitatively assess the effectiveness of RS in terms of the objective improvement of five independent articular parameters.
This retrospective study reports results of 500 radiosyovectomies with an average follow-up of 18.5 years (6 months-38 years). Isotopes used were yttrium-90 (90Y) in 341 injections and rhenium-186 (186Re) in 159 injections. The variable used to identify subjects was the frequency of joint bleeding (2 or more epidoses of haemarthrosis in the previous 6 months). A new radiosynovectomy was performed in patients with two or more episodes of haemarthrosis in the following 6 months. The procedure in these cases was identical to that described for the first injection. The outcome measures were obtained 6 months after each RS and then every six months until the end of the follow-up. Regarding human protection, all patients signed an informed consent (except for patients under 18 years of age, in which the informed consent was signed by the parents of the patient). The study was performed with IRB/EB approval and patients had to provide informed consent.The study includes a total of 443 joints
⁎ Corresponding author at: Department of Orthopaedic Surgery, La Paz University Hospital, Paseo de la Castellana 261, 28046-Madrid, Spain. E-mail address: [email protected] (E.C. Rodriguez-Merchan).
http://dx.doi.org/10.1016/j.thromres.2014.08.023 0049-3848/© 2014 Elsevier Ltd. All rights reserved.
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treated with RS with the diagnosis of haemophilic synovitis during a 38-year period (1976-2013); 192 of these were knees, 135 ankles and 116 elbows. Prior to the procedure, 332 joints (75%) presented with signs of arthropathy on plain films. The procedures were performed on an outpatient basis, that is to say, patients were discharged from hospital the same day the isotope injection was performed. Given the limited availability of the isotope, injections were applied to groups of 4-8 patients each [27,28]. RS was systematically administered under haemostatic replacement with the deficient coagulation factor. In our patients, haemostatic cover was achieved by infusing the replacement factor 30 minutes prior to injection of the radioisotope. Patients with haemophilia A usually received a dose of 50 IU/Kg of coagulation factor VIII every 24 hours for 4 days. Patients with haemophilia B were administered a dose of 60 IU/Kg of coagulation factor IX every 24 hours for 4 days. Patients with an inhibitor were also amenable to being injected with the radioisotope with a minimal bleeding risk [28]. These patients with a circulating inhibitor received either a dose of 75 IU/Kg of aPCCs every 12 hours for 4 days or a dose of 90 mg/Kg of rFVIIa every 2 hours over one single day. Isotopes used were yttrium-90 (90Y) and rhenium-186 (186Re). 90Y is the isotope used for the knee joint, at a dose of 185 megabecquerels (MBq). 186Re was first used at the beginning of 2001 in elbows and ankles, at doses of 56-74 and 74 MBq, respectively. Prior to this date, 90 Y had also been used in elbows and ankles. The procedure was done the same way for 38 years (excepting the addition of Rhenium in the later years). The same person (the senior author EC R-M) performed himself all the procedures. The written protocol (was the following: Once the whole of the radioisotope was injected, the syringe was exchanged again, this time for another one loaded with a 2 ml vial of 3 mg/ml of betamethasone acetate and 3 mg/ml of betamethasone sodium phosphate (Celestone ® Cronodose ®, Merck, Whitehouse Station, NJ, USA.), which was gradually released as the needle was slowly removed (Fig. 1). After removal of the needle, a compression bandage was applied for 3 days. In the periprocedural period patients were encouraged to partially limit their activity for 3-4 days but moving the injected joint. In the lower limb weight-bearing was allowed. The variable used to determine the need for another injection of an isotope was the frequency of joint bleeding. A new infiltration was performed in patients with two or more episodes of haemarthrosis in the following 6 months. The procedure in these cases was identical to that described for the first injection. The five variables used to determine the joints’ response to RS treatment were measured 6 months after treatment (and then every 6 months until the end of follow-up) and were as follows: 1) the number of episodes of haemarthrosis in the previous 6 months; 2) articular pain (VAS, with scores between o and 10) [18,19]; 3) the degree of clinical synovitis (Table 1); 4) World Federation of Haemophilia (WFH) clinical score [29]; and 5) WFH radiological score [30]. The values of these variables were compared with the measurements obtained just before RS in order to determine the joints’ response to RS. In order to analyse the effectiveness of RS, the joint was considered to be the sampling unit for the study. Independent joint-related variables were used to determine the effectiveness of RS treatment in the joints studied. The statistical analysis to determine the effectiveness of RS was carried out independently for the first, second and third articular injections of the radioisotope (RS-1, RS-2 and RS-3). Statistical analysis As regards the comparative statistical study, the effectiveness of the different radioisotope injections was assessed by comparing the different quantitative variables measured before and 6 months after injection of the radioisotope, and then every 6 months until the end of the follow-up. Student t-test for paired samples or its nonparametric
Fig. 1. Radiosynovectomy (RS) technique: sites for needle insertion into the intra-articular space for the different joints. A) Knee: 2 cm proximal and 2 cm lateral (arrow) to the supero-lateral angle of the patella (cross). B) Ankle: at the depression (arrow) that lies between the anterior tibial tendon (line) and the medial malleolus (cross). C) Elbow: at the centre of the triangle (arrow) formed by the olecranon, the lateral epicondyle and the radial head (three crosses).
equivalent (Wilcoxon test) in the case of ordinal variables or where required according to sample size, while the McNemar test was used for comparing categorical variables.
E.C. Rodriguez-Merchan et al. / Thrombosis Research 134 (2014) 985–990 Table 1 Haemophilic synovitis assessment scale used in our centre. Grade Findings 1 2 3 4
Signs of synovial hyperthrophy on palpation Slight increase in joint diameter and identification of a slight synovial hyperthrophy on palpation Moderate increase in joint diameter and moderate synovial hyperthrophy on palpation Significant increase in joint diameter and marked synovial hypertrophy on palpation
Table 2 Median values of the five articular variables analysed in all the joints (N = 328) as measured before and after the first radiosynovectomy (RS-1), shown together with their percentage of improvement and statistical significance. Articular variables
BEFORE RS-1 Median (range)
AFTER RS-1 Median (range)
Improvement (%)
STATISTICAL SIGNIFICANCE p value
Haemarthrosis
6 (2-8) 3.5 (2-5) 1.9 (3-4) 5.21 (3-11) 4.4 (1-12)
1.9 (0-2) 0.98 (0-3) 1.2 (1-3) 4.3 (2-8) 4.8 (1-12)
64.1
b0.001⁎
69.4
b0.001⁎
38.6
b0.001⁎
18.8
b0.001⁎
Pain (VAS) Clinical synovitis
With the purpose of determining whether the explored variables were independent or confounding factors, use was made of logistic regression models, as required. To this effect, those variables exhibiting statistical significance in each of the effectiveness analyses made were included in a univariate logistic regression model to determine the magnitude and precision of the observed significance – determining the corresponding odds ratios (ORs) with their 95% confidence intervals (95%CI) – followed by joint introduction in a multivariate logistic regression model for adjustment. All statistical tests were two-sided, and a value of p b 0.05 was considered statistically significant. The statistical analysis was carried out using the SPSS version 15.0 statistical package for Microsoft Windows.
Results The study comprises a total of 345 individuals with haemophilia, aged between 6 and 53 years (mean: 23.7 years). The mean follow-up was 18.5 years (range: 6 months-38 years). Some data and results of 66 RS on 44 persons with haemophilia of this series [11], and the results of 156 RS performed in 104 joints of 78 persons with haemophilia of this series have been previously reported in other analyses/reviews by the authors [18–20,22,26]. The procedure was carried out in 443 individual joints; some of these required more than one RS injection (1.4 on average), which led to a total of 500 intra-articular injections of the radioactive isotope. Isotopes used were yttrium-90 (90Y) in 341 injections and rhenium-186 (186Re) in 159 injections. Prior to 2001, 90Y was used for RS in all three joints and since then we have used 186Re for elbows, 90Y for knee RS and 186Re for ankles. Of the 443 joints, 328 required a single injection of the radioisotope (RS-1), 109 required 2 injections (RS-2) and 63 required 3 injections (RS-3). Twenty-eight (6.3%) joints eventually had to be subjected to an arthroscopic synovectomy or a total knee replacement (TKR). Before administration of RS, 229 patients (66.3%) had been treated on demand (infusion of replacement factor when the patient had a bleed) whereas 116 (33.7%) patients had been treated by means of secondary prophylaxis (factor infused on a regular schedule after a person has had several bleeds into a single joint). Thirty-three patients (9.8%) had developed an inhibitor. In our series, 313 patients (90.7%) had haemophilia A and 32 (9%) had haemophilia B. As regards the severity of the condition, 281 patients (81.4%) had severe haemophilia, 57 (16.5%) had moderate haemophilia and 7 (2.1%) had mild haemophilia. Table 2 shows the values for the aforementioned variables before and 6 months after RS-1, as well as the degrees of improvement. The statistical analysis showed a statistically significant improvement after RS-1 in all variables (bleeding, pain, clinical synovitis, WFH clinical score), except for the WFH radiological score. A classification of the variables according to the degree of improvement achieved further to the radioisotope injection shows that haemarthrosis episodes and pain were the variables that experienced the greatest improvement, with a reduction in bleeding episodes of 64.1% on average and in the pain score of 69.4% on average. Synovial hypertrophy (as assessed clinically) also showed a mean reduction of
987
WFH clinical score^ WFH radiological score^^
–
0.102⁎⁎
VAS = visual analogue scale. ⁎ Paired Student’s t test. ⁎⁎ Wilcoxon Test. ^ World Federation of Haemophilia (WFH) Clinical Score. ^^ WFH Radiological Score.
31.3%. The WFH clinical score showed an improvement 19%. WFH radiological score showed no improvement. Table 3 shows the values for the aforementioned variables before and 6 months after RS-2, the degrees of improvement for each variable and their statistical significance. The statistical analysis determined that a significant improvement persists after the second RS injection in four of the variables in the study (bleeding, pain, clinical synovitis and the clinical score of the WFH). Nevertheless, RS-2 was not effective in improving the WFH radiological score. Table 4 shows the values for the aforementioned variables before and 6 months after RS-3, the degrees of improvement for each variable and their statistical significance. The data obtained in this study demonstrate that, after the third injection, RS is still effective as regards joint bleeding, pain, reduction in synovial thickness and improvement of the clinical score of the WFH. Nevertheless, the WFH radiological score showed no improvement. The different joints (knees, ankles, elbows) were studied separately. Tables 5-7 show the mean values of the five articular parameters studied in knees, ankles and elbows, before and after RS-1. The tables also show the degree of improvement and its statistical significance. Following RS, improvement was seen to be independent of patient age, haemophilia type and grade, previous haematological treatment, the presence or absence of circulating inhibitor, the degree of clinical synovitis, the type of joint (elbow, knee and ankle), the prior presence
Table 3 Median values of the five articular variables analysed in all the joints (N = 109) as measured before and after the second radiosynovectomy (RS-2), shown together with their percentage of improvement and statistical significance. Articular variables
BEFORE RS-2 Median (range)
AFTER RS-2 Median (range)
Improvement (%)
STATISTICAL SIGNIFICANCE P value
Haemarthrosis
4.2 (2-5) 3.1 (1-5) 2.1 (2-4) 5.8 (1-10) 6.8 (1-12)
1.6 (1-3) 1.3 (1-2) 1.4 (1-3) 4.5 (0-5) 7.1 (1-12)
62.3
b0.001⁎⁎
58.6
0.004⁎⁎
35.1
b0.001⁎⁎
24.9
0.001⁎⁎
–
1⁎⁎
Pain (VAS) Clinical synovitis WFH clinical score WFH radiological score
VAS = visual analogue scale. ^ World Federation of Haemophilia (WFH) Clinical Score. ^^ WFH Radiological Score. ⁎⁎ Wilcoxon test.
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Table 4 Median values of the five articular variables analysed in all the joints (N = 63) as measured before and after the third radiosynovectomy (RS-3), shown together with their percentage of improvement and statistical significance. Articular variables
BEFORE RS3 Median (range)
AFTER RS3 Median (range)
Improvement STATISTICAL (%) SIGNIFICANCE P value
Haemarthrosis
3.1 (2-5) 2.8 (1-7) 2.1 (2-4) 6.2 (2-10) 5.6 (1-12)
1.3 (1-3) 0.7 (0-2) 1.7 (1-2) 5.4 (1-8) 6.1 (1-12)
61.8
0.020⁎⁎
77.8
0.008⁎⁎
20.4
0.059⁎⁎
13.3
0.039⁎⁎
–
–
Pain (VAS) Clinical synovitis WFH clinical score WFH radiological score
Table 6 Median values of the five articular variables analysed in the knees (N = 183) as measured before and after the first radiosynovectomy (RS-1), shown together with their percentage of improvement and statistical significance. Articular variables
BEFORE RS-1 Median (range)
AFTER RS-1 Median (range)
Improvement (%)
STATISTICAL SIGNIFICANCE p value
Haemarthrosis
5.8 (2-6) 2.2 (0-3) 2.4 (2-4) 4.9 (1-9) 4.4 (1-12)
1.9 (1-3) 0.5 (0-2) 1.6 (1-2) 4.1 (1-7) 4.3 (1-12)
69.1
b0.001⁎
81.2
b0.001⁎
37.8
0.001⁎
16.8
0.001⁎
–
1⁎⁎
Pain (VAS) Clinical synovitis WFH clinical score^ WFH radiological score^^
VAS = visual analogue scale. ⁎ Paired Student’s t test. ⁎⁎ Wilcoxon Test. ^ World Federation of Haemophilia (WFH) Clinical Score. ^^ WFH Radiological Score.
VAS = visual analogue scale. ^ World Federation of Haemophilia (WFH) Clinical Score. ^^ WFH Radiological Store. ⁎⁎ Wilcoxon Test.
or absence of radiographic signs of joint degeneration (arthropathy) or the isotope used. The knee required more injections than the elbow or the ankle and that the more severe synoviums require a higher number of RS procedures. In those subjects that had multiple RS, their results before RS-2 and RS-3 were significantly worse than the outcomes measures after RS-1 suggesting some decline in improvement. No difference in outcome was found between patients receiving prophylaxis and those being treated on demand. There were four complications (0.9%): one knee septic arthritis (resolved by arthrotomy and intravenous antibiotics), two ankles with severe swelling after the procedure resolved by a short course of oral COX-2 inhibitors (COX, cyclooxigenase), and one extra-articular spill in a knee that caused a small cutaneous burn with no clinical significance. No genotoxic effects of the procedure were found during the 38-year period of study. Twenty-eight (6.3%) joints eventually had to be subjected to arthroscopic synovectomy or TKR. Discussion The results of 78 patients (156 radiosynovectomies) have been published previously [18–20,26]. Publications report that the majority of patients requiring more than one RS (RS-2, RS-3) had a satisfactory
Table 5 Median values of the five articular variables analysed in the elbows (N = 92) as measured before and after the first radiosynovectomy (RS-1), shown together with their percentage of improvement and statistical significance.
final response, but without specifying the type of response obtained for each of the procedures [1–26]. This study has shown the effectiveness of RS for each of the individual radioisotope injections performed, from RS-1 to RS-3, in one same joint. In general, studies refer to the overall response to the use of RS and pay little attention to the number of articular injections required. Other authors have carried out an overall analysis of the articular variables. According to these analyses, a total of 17.7% of results were excellent, 22.2% were good, 33.3% were fair and 26.6% were poor [11]. Regarding the number of haemarthroses, satisfactory long-term results of 75-80% have been published following RS, suggesting the decrease for many years [31]. Several studies report decrease in the amount of bleeding episodes [14,15,32,33]. In a study by Thomas et al., the reduction in the number of articular bleeds at 6 months was 87% for elbows, 56% for knees and 83.6% for ankles [34]. In our group of patients the number of bleeding episodes was one of the variables showing greatest improvement after RS, with a significant reduction in articular bleeding. The percentage of reduction in articular bleeding episodes, measured before and after RS, was 63.7%. In our study there were no significant differences in the relative reduction in the number of bleeding episodes for the different types of joint (elbows, knees, ankles).
Table 7 Median values of the five articular variables analysed in the ankles (N = 53) as measured before and after the first radiosynovectomy (RS-1), shown together with their percentage of improvement and statistical significance.
Articular variables
BEFORE RS-1 Median (range)
AFTER RS-1 Median (range)
Improvement (%)
STATISTICAL SIGNIFICANCE p value
Articular variables
BEFORE RS-1 Median (range)
AFTER RS-1 Median (range)
Improvement (%)
STATISTICAL SIGNIFICANCE p value
Haemarthrosis
6 (2-6) 4.3 (1-6) 1.6 (1-4) 6.2 (1-10) 7.1 (1-12)
1.9 (1-3) 1.1 (0-2) 0.7 (1-2) 5.1 (1-6) 7.2 (1-12)
70.2
b0.001⁎
Haemarthrosis
0.001⁎
b0.001⁎
Pain (VAS)
74.1
0.001⁎
53.8
b0.001⁎
Clinical synovitis
40.3
0.019⁎
18.2
0.001⁎
WFH clinical score^
25.2
0.016⁎
–
1⁎⁎
WFH radiological score^^
2.7 (1-3) 2.1 (0-3) 0.9 (1-2) 3.2 (1-7) 3.8 (1-12)
61.2
76.4
6.7 (2-5) 5.2 (2-7) 1.6 (1-4) 4.2 (1-11) 3.1 (1-12)
–
1⁎⁎
Pain (VAS) Clinical synovitis WFH clinical score^ WFH radiological score^^
VAS = visual analogue scale. ⁎ Paired Student’s t test. ⁎⁎ Wilcoxon Test. ^ World Federation of Haemophilia (WFH) Clinical Score. ^^ WFH Radiological Score.
VAS = visual analogue scale. ⁎ Paired Student’s t test. ⁎⁎ Wilcoxon Test. ^ World Federation of Haemophilia /WFH) Clinical Score. ^^ WFH Radiological Score.
E.C. Rodriguez-Merchan et al. / Thrombosis Research 134 (2014) 985–990
In regards to the effectiveness of RS in terms of the percentage of joints where the number of bleeds after injection was lower, our results are comparable to the others [2,3,6,8,11,12,14,15,17,27,29,35–38,39–46]. This study proves that apart from reducing the number of articular bleeds by 64.1% on average, RS results in pain relief by 69.4% on average, and a reduction in the degree of clinical synovitis by 31.3% on average. When comparing the results with the Yttrium and Rhenium with those studies that report on RS with P32, Silva et al. reported 170 radiosynovectomies utilizing 32P with an average follow-up of 36.5 months (6-140 months) [14]. For primary procedures, excellent and good results (haemarthrosis reduction from 75 to 100%) were obtained in 79.2% of cases at 6 months to 8 years. For repeat procedures a combination of excellent and good results were obtained in 62.4% of cases at 6 months to 3 years [14]. Siegel et al. performed one hundred twenty-five radiosynovectomies with 32 P in 81 patients, with a twoto 10-year followup [16]. Of 125 procedures, 54% resulted in complete cessation of bleeding into the treated joint after the procedure, and 73% of patients reported improved mobility of the treated joint. Of patients 18 years old and younger, 79% had a greater than 75% reduction in bleeding incidence, and of patients older than 40 years, only 56% had a similar reduction. In Mortazavi´s report, 46 patients were followed for an average of 31 months [44]. The mean age of patients at the time of injection was 15.9 years (range: 6-28). There were three repeat injections in latest follow-up, 77% of patients reported at least a 50% decrease in bleeding frequency after treatment. Regarding a potential genotoxic effect of RS, no increase in the risk of cancer has been reported by Infante-Rivard et al. [47]. Moreover, they found no dose-response relationship with the amount of radioisotope administered or number of RSs. The study of Infante-Rivard et al. provided some indication for the safety of RS but homogenous diagnostic groups of younger haemophilic patients receiving RS require more evaluation. In conclusion, radiosynovectomy (RS) is an effective, safe, minimally invasive, well tolerated procedure in the long-term for the treatment of chronic haemophilic synovitis. Moreover, it is very easy to perform. RS with yttium-90 and rhenium-186 decreased the number of bleeding episodes by 64.1%, joint pain by 69.4% and the degree of clinical synovitis by 31.3%. RS also improved the WFH clinical score by 19%. RS, however, did not succeed in improving the WFH radiological score. Conflict of interest No conflict of interest References [1] Fernandez-Palazzi F, Cedeño M, Maldonado JC, Boadas A, De Saez AR, Chacal BF, et al. Chemical synoviorthesis with oxytetracycline clorhydrate (Emicine) in recurrent haemarthrosis. Haemophilia 2008;14:21–4. [2] Ahlberg A, Pettersson H. Synoviorthesis with radioactive gold in haemophiliacs. Clinical and radiológical follow-up. Acta Orthop Scand 1979;50:513–7. [3] Dawson TM, Ryan PF, Stree AM, Robertson PL, Kalff V, Kelly MJ, et al. Yttrium synovectomy in haemophilic arthropathy. Br J Rheumatol 1994;33:351–6. [4] Fernandez-Palazzi F, Caviglia HA, Salazar JR, López J, Aoun R. Intraarticular dexamethasone in advanced chronic synovitis in hemophilia. Clin Orthop Relat Res 1997;343:25–9. [5] Gilbert MS, Cornwall R. The history of synoviorthesis in haemophilia. Haemophilia 2001;7(Suppl. 2):3–5. [6] Heim M, Goshen E, Amit Y, Martinowitz U. Synoviorthesis with radioactive Yttrium in haemophilia: Israel experience. Haemophilia 2001;7(Suppl. 2):36–9. [7] Kampen WU, Brenner S, Kroeger S, Sawula JA, Bohuslaviski KH, Henze E. Long term results of radiation synovectomy: a clinical follow up study. Nucl Med Commun 2001;22:239–46. [8] Kavakli K, Aydog S, Omay SB, Duman Y, Taner M, Capaci K, et al. Long-term evaluation of radioisotope synovectomy with Yttrium 90 for chronic synovitis in Turkish haemophiliacs: Izmir experience. Haemophilia 2006;12:28–35. [9] Kresnik E, Mikosch P, Gallowitsch HJ, Jesenko R, Just H, Kogler D, et al. Clinical outcome of radiosynoviorthesis: a meta-analysis including 2190 treated joints. Nucl Med Commun 2002;23:683–8.
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[25] Turkmen C, Kilicoglu O, Dikici F, Bezgal F, Kuyumcu S, Gorgun O, et al. Survival analysis of Y-90 radiosynovectomy in the treatment of haemophilic synovitis of the knee: a 10-year retrospective review. Haemophilia 2014;20:e45–50. [26] Rodriguez-Merchan EC, De La Corte-Rodriguez H, Jimenez-Yuste V. Is radiosynovectomy (RS) effective for joints damaged by haemophilia with articular degeneration in simple radiography (ADSR)? Thromb Res 2014;133:875–9. [27] Türkmen C, Zülflkar B, Taser O, Tokmak H, Kílíçoglu O, Mudun A, et al. Radiosynovectomy in hemophilic synovitis: correlation of therapeutic response and blood-pool changes. Cancer Biother Radiopharm 2005;20:363–70. [28] Rodriguez-Merchan EC, Luck JV, Silva M, Quintana M. Synoviorthesis in haemophilia. In: Rodriguez-Merchan EC, editor. The Haemophilic Joints: New Perspectives. WileyBlackwell; 2003. p. 73–9. [29] Gilbert MS. Prophylaxis: musculoskeletal evaluation. Semin Hematol 1993; 30(Suppl. 2):3–6. [30] Pettersson H, Ahlberg A, Nilsson IM. A radiologic classification of hemophilic arthropathy. Clin Orthop Relat Res 1980;149:153–9. [31] Stephensen D, Tait RC, Brodie N, Collins P, Cheal R, Keeling D, et al. Changing patterns of bleeding in patients with severe haemophilia A. Haemophilia 2009;15: 1210–4. [32] Alioglu B, Ozsoy H, Koca G, Dallar Y. The effectiveness of radioisotope synovectomy for chronic synovitis in Turkish pediatric haemophiliacs. Haemophilia 2008; 14(Suppl. 2):80 [abstract 12 PO 57]. [33] Rodriguez-Merchan EC, Wiedel JD. General principles and indications of synoviorthesis (medical synovectomy) in haemophilia. Haemophilia 2001; 7(Suppl. 2):6–10. [34] Thomas S, Assi P, Marycel B, Correa M, Liberato W, Brito V. Yttrium 90-hydroxyapatite, a new radioisotope for chronic synovitis in hemophilia. Haemophilia 2008;14(Suppl. 2): 77 [Abstract 12 FP 38]. [35] Fernandez-Palazzi F, Ribas S, Cibeira JL, Dib O, Viso R. Radioactive synoviorthesis in hemophilic hemarthrosis: material, techniques and dangers. Clin Orthop Relat Res 1996;328:14–8. [36] Barrenechea E, Navarra S, Chua M. Evaluation of the efficacy of radiosynovectomy withhemophilic arthropaty. Haemophilia 2006;12(Suppl. 2):80–90. [37] Kavakli K, Aydogdu S, Taner M, Balkan C. Radioisotope synovectomy with yttrium 90 and rhenium1 86 for hemophilic synovitis: 7 years, 181 patients, 209 joints, 221 applications: Izmir experience. Haemophilia 2008;14(Suppl. 2):1–120. [38] Li P, Chen G, Zhang H, Shen Z. Radiation synovectomy by 188Re-Sulfide in haemophilic synovitis. Haemophilia 2004;10:422–7. [39] Van Genderen F, van Meeteren N, van Den Berg M, Helders P. Functional limitations and disability in patients with severe haemophilia. Haemophilia 2006;12(Suppl. 2): 80–90. [40] Dauty M, Bresson C, Trossaert M. Application of the isokinetic test to quantify knee muscle strength in haemophiliac patients. Haemophilia 2009;15:973–5.
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[41] Dunn AL, Busch MT, Wyly B, Abshire TC. Radionuclide synovectomy for hemophilic arthropathy: a comprehensive review of safety and efficacy and recommendation for a standardized treatment protocol. Thromb Haemost 2002;87: 383–93. [42] Heim M, Tiktinsky R, Amit Y, Martinowitz U. Yttrium synoviorthesis of the elbow joints in persons with haemophilia. Haemophilia 2004;10:590–2. [43] Nuss R, Kilcoyne RF, Geraghty S, Shroyer AL, Rosky JW, Mawhinney S, et al. MRI findings in haemophilic joints treated with radiosynoviorthesis with development of an MRI scale of joint damage. Haemophilia 2000;6:162–9. [44] Mortazavi SM, Asadollahi S, Farzan M, Shahriaran S, Aghili M, Izadyar, et al. (32)P colloid radiosynovectomy in treatment of chronic haemophilic synovitis: Iran experience. Haemophilia 2007;13:182–8.
[45] Calegaro JU, Machado J, De Paula JC, De Almeida JSC, Casularis LA. Clinical evaluation after 1 year of 153-samarium hydroxyapatite synovectomy in patients with haemophilic arthropathy. Haemophilia 2009;15:240–6. [46] Cho YJ, Kim KI, Chun YS, Rhyu KH, Kwon BK, Kim DY, et al. Radioisotope synoviorthesis with Holmium-166-chitosan complex in haemophilic arthropathy. Haemophilia 2010; 16:640–6. [47] Infante-Rivard C, Rivard GE, Derome F, Cusson A, Winikoff R, Chartrand R, et al. A retrospective cohort study of cancer incidence among patients treated with radiosynoviorthesis. Haemophilia 2012;18:805–9.
Contents lists available at ScienceDirect
Thrombosis Research journal homepage: www.elsevier.com/locate/thromres
Regular Article
Radiosynovectomy in haemophilia: Long-term results of 500 procedures performed in a 38-year period E.C. Rodriguez-Merchan a,⁎, H. De la Corte-Rodriguez b, V. Jimenez-Yuste c a b c
Department of Orthopaedic Surgery, La Paz University Hospital, Madrid, Spain Department of Rehabilitation and Physical Therapy, La Paz University Hospital, Madrid, Spain Department of Haematology, La Paz University Hospital, Madrid, Spain
a r t i c l e
i n f o
Article history: Received 21 June 2014 Received in revised form 19 August 2014 Accepted 23 August 2014 Available online 6 September 2014 Keywords: Haemophilia Synovitis Articular variables Radiosynovectomy Efficacy Results
a b s t r a c t Background: Radiosynovectomy (RS) can reduce the number of haemarthroses in chronic haemophilic synovitis. The purpose of this study was to assess the effectiveness of RS in terms of the objective improvement of five parameters (number haemarthroses, articular pain, degree of clinical synovitis, clinical score of the World Federation of Haemophilia (WFH), and radiological score of the WFH. Methods: In a 38-year period (1976-2013), five hundred radiosynovectomies were performed in 443 joints of 345 patients with haemophilia diagnosed with chronic synovitis. The mean patient age was 23.7 years (range, 6-53). The mean follow-up was 18.5 years (range: 6 months-38 years). The RS was carried out with either yttrium-90 or rhenium-186. We performed 1 to 3 injections (RS-1, RS-2, RS-3), with a 6-month interval between them. Results: RS resulted in significant improvement in all the parameters studied, except in the WFH radiologic score that showed no improvement. On average, the number of haemarthroses decreased by 64.1% and articular pain decreased by 69.4%. The degree of synovitis showed a reduction of 31.3%. The WFH clinical score revealed an improvement of 19%. The WFH radiological score showed no improvement. There were four complications (0.9%) of RS. Twenty-eight (6.3%) joints eventually had to be subjected to arthroscopic synovectomy or total knee replacement (TKR). No cancer was observed in this group of patients during the 38-year period. Conclusions: Radiosynovectomy (RS) is an effective, safe, minimally invasive, well tolerated procedure in the long-term for the treatment of chronic haemophilic synovitis. Moreover, it is very easy to perform. The knee required more injections than the elbow or the ankle and more severe synoviums required a higher number of RS procedures. © 2014 Elsevier Ltd. All rights reserved.
Introduction
Materials and methods
Radiosynovectomy (RS) is an effective type of non-surgical synovectomy that can diminish the number of bleeding episodes in patients with haemophilia suffering from chronic haemophilic synovitis [1–26]. The RS procedure requires 1-3 intra-articular injections of a radioactive isotope (RS-1, RS-2 or RS-3), with a 6-month interval between them. However, there are still many aspects concerning the beneficial effects of RS that have been as yet neither fully elucidated nor quantified. The purpose of this study has been to quantitatively assess the effectiveness of RS in terms of the objective improvement of five independent articular parameters.
This retrospective study reports results of 500 radiosyovectomies with an average follow-up of 18.5 years (6 months-38 years). Isotopes used were yttrium-90 (90Y) in 341 injections and rhenium-186 (186Re) in 159 injections. The variable used to identify subjects was the frequency of joint bleeding (2 or more epidoses of haemarthrosis in the previous 6 months). A new radiosynovectomy was performed in patients with two or more episodes of haemarthrosis in the following 6 months. The procedure in these cases was identical to that described for the first injection. The outcome measures were obtained 6 months after each RS and then every six months until the end of the follow-up. Regarding human protection, all patients signed an informed consent (except for patients under 18 years of age, in which the informed consent was signed by the parents of the patient). The study was performed with IRB/EB approval and patients had to provide informed consent.The study includes a total of 443 joints
⁎ Corresponding author at: Department of Orthopaedic Surgery, La Paz University Hospital, Paseo de la Castellana 261, 28046-Madrid, Spain. E-mail address: [email protected] (E.C. Rodriguez-Merchan).
http://dx.doi.org/10.1016/j.thromres.2014.08.023 0049-3848/© 2014 Elsevier Ltd. All rights reserved.
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treated with RS with the diagnosis of haemophilic synovitis during a 38-year period (1976-2013); 192 of these were knees, 135 ankles and 116 elbows. Prior to the procedure, 332 joints (75%) presented with signs of arthropathy on plain films. The procedures were performed on an outpatient basis, that is to say, patients were discharged from hospital the same day the isotope injection was performed. Given the limited availability of the isotope, injections were applied to groups of 4-8 patients each [27,28]. RS was systematically administered under haemostatic replacement with the deficient coagulation factor. In our patients, haemostatic cover was achieved by infusing the replacement factor 30 minutes prior to injection of the radioisotope. Patients with haemophilia A usually received a dose of 50 IU/Kg of coagulation factor VIII every 24 hours for 4 days. Patients with haemophilia B were administered a dose of 60 IU/Kg of coagulation factor IX every 24 hours for 4 days. Patients with an inhibitor were also amenable to being injected with the radioisotope with a minimal bleeding risk [28]. These patients with a circulating inhibitor received either a dose of 75 IU/Kg of aPCCs every 12 hours for 4 days or a dose of 90 mg/Kg of rFVIIa every 2 hours over one single day. Isotopes used were yttrium-90 (90Y) and rhenium-186 (186Re). 90Y is the isotope used for the knee joint, at a dose of 185 megabecquerels (MBq). 186Re was first used at the beginning of 2001 in elbows and ankles, at doses of 56-74 and 74 MBq, respectively. Prior to this date, 90 Y had also been used in elbows and ankles. The procedure was done the same way for 38 years (excepting the addition of Rhenium in the later years). The same person (the senior author EC R-M) performed himself all the procedures. The written protocol (was the following: Once the whole of the radioisotope was injected, the syringe was exchanged again, this time for another one loaded with a 2 ml vial of 3 mg/ml of betamethasone acetate and 3 mg/ml of betamethasone sodium phosphate (Celestone ® Cronodose ®, Merck, Whitehouse Station, NJ, USA.), which was gradually released as the needle was slowly removed (Fig. 1). After removal of the needle, a compression bandage was applied for 3 days. In the periprocedural period patients were encouraged to partially limit their activity for 3-4 days but moving the injected joint. In the lower limb weight-bearing was allowed. The variable used to determine the need for another injection of an isotope was the frequency of joint bleeding. A new infiltration was performed in patients with two or more episodes of haemarthrosis in the following 6 months. The procedure in these cases was identical to that described for the first injection. The five variables used to determine the joints’ response to RS treatment were measured 6 months after treatment (and then every 6 months until the end of follow-up) and were as follows: 1) the number of episodes of haemarthrosis in the previous 6 months; 2) articular pain (VAS, with scores between o and 10) [18,19]; 3) the degree of clinical synovitis (Table 1); 4) World Federation of Haemophilia (WFH) clinical score [29]; and 5) WFH radiological score [30]. The values of these variables were compared with the measurements obtained just before RS in order to determine the joints’ response to RS. In order to analyse the effectiveness of RS, the joint was considered to be the sampling unit for the study. Independent joint-related variables were used to determine the effectiveness of RS treatment in the joints studied. The statistical analysis to determine the effectiveness of RS was carried out independently for the first, second and third articular injections of the radioisotope (RS-1, RS-2 and RS-3). Statistical analysis As regards the comparative statistical study, the effectiveness of the different radioisotope injections was assessed by comparing the different quantitative variables measured before and 6 months after injection of the radioisotope, and then every 6 months until the end of the follow-up. Student t-test for paired samples or its nonparametric
Fig. 1. Radiosynovectomy (RS) technique: sites for needle insertion into the intra-articular space for the different joints. A) Knee: 2 cm proximal and 2 cm lateral (arrow) to the supero-lateral angle of the patella (cross). B) Ankle: at the depression (arrow) that lies between the anterior tibial tendon (line) and the medial malleolus (cross). C) Elbow: at the centre of the triangle (arrow) formed by the olecranon, the lateral epicondyle and the radial head (three crosses).
equivalent (Wilcoxon test) in the case of ordinal variables or where required according to sample size, while the McNemar test was used for comparing categorical variables.
E.C. Rodriguez-Merchan et al. / Thrombosis Research 134 (2014) 985–990 Table 1 Haemophilic synovitis assessment scale used in our centre. Grade Findings 1 2 3 4
Signs of synovial hyperthrophy on palpation Slight increase in joint diameter and identification of a slight synovial hyperthrophy on palpation Moderate increase in joint diameter and moderate synovial hyperthrophy on palpation Significant increase in joint diameter and marked synovial hypertrophy on palpation
Table 2 Median values of the five articular variables analysed in all the joints (N = 328) as measured before and after the first radiosynovectomy (RS-1), shown together with their percentage of improvement and statistical significance. Articular variables
BEFORE RS-1 Median (range)
AFTER RS-1 Median (range)
Improvement (%)
STATISTICAL SIGNIFICANCE p value
Haemarthrosis
6 (2-8) 3.5 (2-5) 1.9 (3-4) 5.21 (3-11) 4.4 (1-12)
1.9 (0-2) 0.98 (0-3) 1.2 (1-3) 4.3 (2-8) 4.8 (1-12)
64.1
b0.001⁎
69.4
b0.001⁎
38.6
b0.001⁎
18.8
b0.001⁎
Pain (VAS) Clinical synovitis
With the purpose of determining whether the explored variables were independent or confounding factors, use was made of logistic regression models, as required. To this effect, those variables exhibiting statistical significance in each of the effectiveness analyses made were included in a univariate logistic regression model to determine the magnitude and precision of the observed significance – determining the corresponding odds ratios (ORs) with their 95% confidence intervals (95%CI) – followed by joint introduction in a multivariate logistic regression model for adjustment. All statistical tests were two-sided, and a value of p b 0.05 was considered statistically significant. The statistical analysis was carried out using the SPSS version 15.0 statistical package for Microsoft Windows.
Results The study comprises a total of 345 individuals with haemophilia, aged between 6 and 53 years (mean: 23.7 years). The mean follow-up was 18.5 years (range: 6 months-38 years). Some data and results of 66 RS on 44 persons with haemophilia of this series [11], and the results of 156 RS performed in 104 joints of 78 persons with haemophilia of this series have been previously reported in other analyses/reviews by the authors [18–20,22,26]. The procedure was carried out in 443 individual joints; some of these required more than one RS injection (1.4 on average), which led to a total of 500 intra-articular injections of the radioactive isotope. Isotopes used were yttrium-90 (90Y) in 341 injections and rhenium-186 (186Re) in 159 injections. Prior to 2001, 90Y was used for RS in all three joints and since then we have used 186Re for elbows, 90Y for knee RS and 186Re for ankles. Of the 443 joints, 328 required a single injection of the radioisotope (RS-1), 109 required 2 injections (RS-2) and 63 required 3 injections (RS-3). Twenty-eight (6.3%) joints eventually had to be subjected to an arthroscopic synovectomy or a total knee replacement (TKR). Before administration of RS, 229 patients (66.3%) had been treated on demand (infusion of replacement factor when the patient had a bleed) whereas 116 (33.7%) patients had been treated by means of secondary prophylaxis (factor infused on a regular schedule after a person has had several bleeds into a single joint). Thirty-three patients (9.8%) had developed an inhibitor. In our series, 313 patients (90.7%) had haemophilia A and 32 (9%) had haemophilia B. As regards the severity of the condition, 281 patients (81.4%) had severe haemophilia, 57 (16.5%) had moderate haemophilia and 7 (2.1%) had mild haemophilia. Table 2 shows the values for the aforementioned variables before and 6 months after RS-1, as well as the degrees of improvement. The statistical analysis showed a statistically significant improvement after RS-1 in all variables (bleeding, pain, clinical synovitis, WFH clinical score), except for the WFH radiological score. A classification of the variables according to the degree of improvement achieved further to the radioisotope injection shows that haemarthrosis episodes and pain were the variables that experienced the greatest improvement, with a reduction in bleeding episodes of 64.1% on average and in the pain score of 69.4% on average. Synovial hypertrophy (as assessed clinically) also showed a mean reduction of
987
WFH clinical score^ WFH radiological score^^
–
0.102⁎⁎
VAS = visual analogue scale. ⁎ Paired Student’s t test. ⁎⁎ Wilcoxon Test. ^ World Federation of Haemophilia (WFH) Clinical Score. ^^ WFH Radiological Score.
31.3%. The WFH clinical score showed an improvement 19%. WFH radiological score showed no improvement. Table 3 shows the values for the aforementioned variables before and 6 months after RS-2, the degrees of improvement for each variable and their statistical significance. The statistical analysis determined that a significant improvement persists after the second RS injection in four of the variables in the study (bleeding, pain, clinical synovitis and the clinical score of the WFH). Nevertheless, RS-2 was not effective in improving the WFH radiological score. Table 4 shows the values for the aforementioned variables before and 6 months after RS-3, the degrees of improvement for each variable and their statistical significance. The data obtained in this study demonstrate that, after the third injection, RS is still effective as regards joint bleeding, pain, reduction in synovial thickness and improvement of the clinical score of the WFH. Nevertheless, the WFH radiological score showed no improvement. The different joints (knees, ankles, elbows) were studied separately. Tables 5-7 show the mean values of the five articular parameters studied in knees, ankles and elbows, before and after RS-1. The tables also show the degree of improvement and its statistical significance. Following RS, improvement was seen to be independent of patient age, haemophilia type and grade, previous haematological treatment, the presence or absence of circulating inhibitor, the degree of clinical synovitis, the type of joint (elbow, knee and ankle), the prior presence
Table 3 Median values of the five articular variables analysed in all the joints (N = 109) as measured before and after the second radiosynovectomy (RS-2), shown together with their percentage of improvement and statistical significance. Articular variables
BEFORE RS-2 Median (range)
AFTER RS-2 Median (range)
Improvement (%)
STATISTICAL SIGNIFICANCE P value
Haemarthrosis
4.2 (2-5) 3.1 (1-5) 2.1 (2-4) 5.8 (1-10) 6.8 (1-12)
1.6 (1-3) 1.3 (1-2) 1.4 (1-3) 4.5 (0-5) 7.1 (1-12)
62.3
b0.001⁎⁎
58.6
0.004⁎⁎
35.1
b0.001⁎⁎
24.9
0.001⁎⁎
–
1⁎⁎
Pain (VAS) Clinical synovitis WFH clinical score WFH radiological score
VAS = visual analogue scale. ^ World Federation of Haemophilia (WFH) Clinical Score. ^^ WFH Radiological Score. ⁎⁎ Wilcoxon test.
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Table 4 Median values of the five articular variables analysed in all the joints (N = 63) as measured before and after the third radiosynovectomy (RS-3), shown together with their percentage of improvement and statistical significance. Articular variables
BEFORE RS3 Median (range)
AFTER RS3 Median (range)
Improvement STATISTICAL (%) SIGNIFICANCE P value
Haemarthrosis
3.1 (2-5) 2.8 (1-7) 2.1 (2-4) 6.2 (2-10) 5.6 (1-12)
1.3 (1-3) 0.7 (0-2) 1.7 (1-2) 5.4 (1-8) 6.1 (1-12)
61.8
0.020⁎⁎
77.8
0.008⁎⁎
20.4
0.059⁎⁎
13.3
0.039⁎⁎
–
–
Pain (VAS) Clinical synovitis WFH clinical score WFH radiological score
Table 6 Median values of the five articular variables analysed in the knees (N = 183) as measured before and after the first radiosynovectomy (RS-1), shown together with their percentage of improvement and statistical significance. Articular variables
BEFORE RS-1 Median (range)
AFTER RS-1 Median (range)
Improvement (%)
STATISTICAL SIGNIFICANCE p value
Haemarthrosis
5.8 (2-6) 2.2 (0-3) 2.4 (2-4) 4.9 (1-9) 4.4 (1-12)
1.9 (1-3) 0.5 (0-2) 1.6 (1-2) 4.1 (1-7) 4.3 (1-12)
69.1
b0.001⁎
81.2
b0.001⁎
37.8
0.001⁎
16.8
0.001⁎
–
1⁎⁎
Pain (VAS) Clinical synovitis WFH clinical score^ WFH radiological score^^
VAS = visual analogue scale. ⁎ Paired Student’s t test. ⁎⁎ Wilcoxon Test. ^ World Federation of Haemophilia (WFH) Clinical Score. ^^ WFH Radiological Score.
VAS = visual analogue scale. ^ World Federation of Haemophilia (WFH) Clinical Score. ^^ WFH Radiological Store. ⁎⁎ Wilcoxon Test.
or absence of radiographic signs of joint degeneration (arthropathy) or the isotope used. The knee required more injections than the elbow or the ankle and that the more severe synoviums require a higher number of RS procedures. In those subjects that had multiple RS, their results before RS-2 and RS-3 were significantly worse than the outcomes measures after RS-1 suggesting some decline in improvement. No difference in outcome was found between patients receiving prophylaxis and those being treated on demand. There were four complications (0.9%): one knee septic arthritis (resolved by arthrotomy and intravenous antibiotics), two ankles with severe swelling after the procedure resolved by a short course of oral COX-2 inhibitors (COX, cyclooxigenase), and one extra-articular spill in a knee that caused a small cutaneous burn with no clinical significance. No genotoxic effects of the procedure were found during the 38-year period of study. Twenty-eight (6.3%) joints eventually had to be subjected to arthroscopic synovectomy or TKR. Discussion The results of 78 patients (156 radiosynovectomies) have been published previously [18–20,26]. Publications report that the majority of patients requiring more than one RS (RS-2, RS-3) had a satisfactory
Table 5 Median values of the five articular variables analysed in the elbows (N = 92) as measured before and after the first radiosynovectomy (RS-1), shown together with their percentage of improvement and statistical significance.
final response, but without specifying the type of response obtained for each of the procedures [1–26]. This study has shown the effectiveness of RS for each of the individual radioisotope injections performed, from RS-1 to RS-3, in one same joint. In general, studies refer to the overall response to the use of RS and pay little attention to the number of articular injections required. Other authors have carried out an overall analysis of the articular variables. According to these analyses, a total of 17.7% of results were excellent, 22.2% were good, 33.3% were fair and 26.6% were poor [11]. Regarding the number of haemarthroses, satisfactory long-term results of 75-80% have been published following RS, suggesting the decrease for many years [31]. Several studies report decrease in the amount of bleeding episodes [14,15,32,33]. In a study by Thomas et al., the reduction in the number of articular bleeds at 6 months was 87% for elbows, 56% for knees and 83.6% for ankles [34]. In our group of patients the number of bleeding episodes was one of the variables showing greatest improvement after RS, with a significant reduction in articular bleeding. The percentage of reduction in articular bleeding episodes, measured before and after RS, was 63.7%. In our study there were no significant differences in the relative reduction in the number of bleeding episodes for the different types of joint (elbows, knees, ankles).
Table 7 Median values of the five articular variables analysed in the ankles (N = 53) as measured before and after the first radiosynovectomy (RS-1), shown together with their percentage of improvement and statistical significance.
Articular variables
BEFORE RS-1 Median (range)
AFTER RS-1 Median (range)
Improvement (%)
STATISTICAL SIGNIFICANCE p value
Articular variables
BEFORE RS-1 Median (range)
AFTER RS-1 Median (range)
Improvement (%)
STATISTICAL SIGNIFICANCE p value
Haemarthrosis
6 (2-6) 4.3 (1-6) 1.6 (1-4) 6.2 (1-10) 7.1 (1-12)
1.9 (1-3) 1.1 (0-2) 0.7 (1-2) 5.1 (1-6) 7.2 (1-12)
70.2
b0.001⁎
Haemarthrosis
0.001⁎
b0.001⁎
Pain (VAS)
74.1
0.001⁎
53.8
b0.001⁎
Clinical synovitis
40.3
0.019⁎
18.2
0.001⁎
WFH clinical score^
25.2
0.016⁎
–
1⁎⁎
WFH radiological score^^
2.7 (1-3) 2.1 (0-3) 0.9 (1-2) 3.2 (1-7) 3.8 (1-12)
61.2
76.4
6.7 (2-5) 5.2 (2-7) 1.6 (1-4) 4.2 (1-11) 3.1 (1-12)
–
1⁎⁎
Pain (VAS) Clinical synovitis WFH clinical score^ WFH radiological score^^
VAS = visual analogue scale. ⁎ Paired Student’s t test. ⁎⁎ Wilcoxon Test. ^ World Federation of Haemophilia (WFH) Clinical Score. ^^ WFH Radiological Score.
VAS = visual analogue scale. ⁎ Paired Student’s t test. ⁎⁎ Wilcoxon Test. ^ World Federation of Haemophilia /WFH) Clinical Score. ^^ WFH Radiological Score.
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In regards to the effectiveness of RS in terms of the percentage of joints where the number of bleeds after injection was lower, our results are comparable to the others [2,3,6,8,11,12,14,15,17,27,29,35–38,39–46]. This study proves that apart from reducing the number of articular bleeds by 64.1% on average, RS results in pain relief by 69.4% on average, and a reduction in the degree of clinical synovitis by 31.3% on average. When comparing the results with the Yttrium and Rhenium with those studies that report on RS with P32, Silva et al. reported 170 radiosynovectomies utilizing 32P with an average follow-up of 36.5 months (6-140 months) [14]. For primary procedures, excellent and good results (haemarthrosis reduction from 75 to 100%) were obtained in 79.2% of cases at 6 months to 8 years. For repeat procedures a combination of excellent and good results were obtained in 62.4% of cases at 6 months to 3 years [14]. Siegel et al. performed one hundred twenty-five radiosynovectomies with 32 P in 81 patients, with a twoto 10-year followup [16]. Of 125 procedures, 54% resulted in complete cessation of bleeding into the treated joint after the procedure, and 73% of patients reported improved mobility of the treated joint. Of patients 18 years old and younger, 79% had a greater than 75% reduction in bleeding incidence, and of patients older than 40 years, only 56% had a similar reduction. In Mortazavi´s report, 46 patients were followed for an average of 31 months [44]. The mean age of patients at the time of injection was 15.9 years (range: 6-28). There were three repeat injections in latest follow-up, 77% of patients reported at least a 50% decrease in bleeding frequency after treatment. Regarding a potential genotoxic effect of RS, no increase in the risk of cancer has been reported by Infante-Rivard et al. [47]. Moreover, they found no dose-response relationship with the amount of radioisotope administered or number of RSs. The study of Infante-Rivard et al. provided some indication for the safety of RS but homogenous diagnostic groups of younger haemophilic patients receiving RS require more evaluation. In conclusion, radiosynovectomy (RS) is an effective, safe, minimally invasive, well tolerated procedure in the long-term for the treatment of chronic haemophilic synovitis. Moreover, it is very easy to perform. RS with yttium-90 and rhenium-186 decreased the number of bleeding episodes by 64.1%, joint pain by 69.4% and the degree of clinical synovitis by 31.3%. RS also improved the WFH clinical score by 19%. RS, however, did not succeed in improving the WFH radiological score. Conflict of interest No conflict of interest References [1] Fernandez-Palazzi F, Cedeño M, Maldonado JC, Boadas A, De Saez AR, Chacal BF, et al. Chemical synoviorthesis with oxytetracycline clorhydrate (Emicine) in recurrent haemarthrosis. Haemophilia 2008;14:21–4. [2] Ahlberg A, Pettersson H. Synoviorthesis with radioactive gold in haemophiliacs. Clinical and radiológical follow-up. Acta Orthop Scand 1979;50:513–7. [3] Dawson TM, Ryan PF, Stree AM, Robertson PL, Kalff V, Kelly MJ, et al. Yttrium synovectomy in haemophilic arthropathy. Br J Rheumatol 1994;33:351–6. [4] Fernandez-Palazzi F, Caviglia HA, Salazar JR, López J, Aoun R. Intraarticular dexamethasone in advanced chronic synovitis in hemophilia. Clin Orthop Relat Res 1997;343:25–9. [5] Gilbert MS, Cornwall R. The history of synoviorthesis in haemophilia. Haemophilia 2001;7(Suppl. 2):3–5. [6] Heim M, Goshen E, Amit Y, Martinowitz U. Synoviorthesis with radioactive Yttrium in haemophilia: Israel experience. Haemophilia 2001;7(Suppl. 2):36–9. [7] Kampen WU, Brenner S, Kroeger S, Sawula JA, Bohuslaviski KH, Henze E. Long term results of radiation synovectomy: a clinical follow up study. Nucl Med Commun 2001;22:239–46. [8] Kavakli K, Aydog S, Omay SB, Duman Y, Taner M, Capaci K, et al. Long-term evaluation of radioisotope synovectomy with Yttrium 90 for chronic synovitis in Turkish haemophiliacs: Izmir experience. Haemophilia 2006;12:28–35. [9] Kresnik E, Mikosch P, Gallowitsch HJ, Jesenko R, Just H, Kogler D, et al. Clinical outcome of radiosynoviorthesis: a meta-analysis including 2190 treated joints. Nucl Med Commun 2002;23:683–8.
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