- Email: [email protected]
Is radiosynovectomy (RS) effective for joints damaged by haemophilia with articular degeneration in simple radiography (ADSR)?
Thrombosis Research 133 (2014) 875–879
Contents lists available at ScienceDirect
Thrombosis Research journal homepage: www.elsevier.com/locate/thromres
Regular Article
Is radiosynovectomy (RS) effective for joints damaged by haemophilia with articular degeneration in simple radiography (ADSR)? 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 Medicine, 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 18 December 2013 Received in revised form 18 December 2013 Accepted 26 January 2014 Available online 29 January 2014 Keywords: Haemophilia Synovitis Radiosynovectomy Joint degeneration Effectiveness
a b s t r a c t Background: Radiosynovectomy (RS) is known to be effective in the treatment of chronic haemophiliac synovitis. Its effectiveness may, however, be different when the joint treated shows articular degeneration in simple radiography (ADSR). Purpose: The purpose of this study was to investigate the effectiveness or otherwise of RS in the presence of ADSR. To this end, the objective improvement in five joint parameters (haemarthrosis, joint pain, range of motion, muscle strength and synovial size) has been analysed with respect to the pre-existence or otherwise of ADSR in the articulation treated. Materials and Methods: An observational retrospective cohort study was conducted. Between January 1993 and December 2006, RS was performed on 78 people with haemophilia. Their average age was 18 (range 7–51). RS procedures were performed on 104 different joints; some joints required more than one injection (a maximum of 3 were given, with a 6-month interval between them), which we refer to respectively as RS-1, RS-2, RS-3, resulting in a total of 156 procedures. The isotopes used were 90Y on 107 occasions and 186Re in 49 injections. Results: RS treatment reduced the frequency of haemarthroses, reduced joint pain and reduced synovial size, and resulted in improved muscle strength and range of motion both in joints with ADSR (N = 86) and in those without ADSR (N = 18). However, no articulation without ADSR required RS-3. Conclusion: The five parameters studied improved to an equal degree in joints with ADSR and without ADSR. No joint without ADSR required RS-3; this was the only difference our study found between joints without ADSR and those with ADSR at the time of the RS. © 2014 Elsevier Ltd. All rights reserved.
Introduction Unless minimized through primary prophylaxis with replacement clotting factor, the recurrent joint bleeds suffered by haemophilia patients from childhood eventually cause clinical symptoms of chronic synovitis. A vicious circle of haemarthrosis-synovitis-haemarthrosis then starts up, due to hyper-vascularisation of the hypertrophic synovial membrane, and this will result in joint degeneration within a few years. This joint degeneration is not initially visible in X-rays, although it will gradually become evident over time. Radiosynovectomy (RS) is known to be effective in the treatment of haemophilic synovitis [1,32]. Many aspects of its effectiveness have not, however, been fully clarified or quantified. The procedure requires 1 to 3 intra-articular injections of a radioactive isotope (RS-1, RS-2 and RS-3), with 6-month intervals between them. The purpose of this study was to evaluate quantitatively the effectiveness of RS in terms of objective improvements in five independent ⁎ 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). 0049-3848/$ – see front matter © 2014 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.thromres.2014.01.030
joint parameters (haemarthrosis, joint pain, range of motion-ROM-, muscle strength and synovial size) with respect to the pre-existence or otherwise of radiologically visible signs of joint degeneration (articular degeneration with simple radiography; ADSR) in the joint treated at the time of the RS. In other words, the aim was to discover whether RS is effective in the treatment of chronic haemophilic synovitis when ADSR is present.
Methods An observational retrospective cohort study was performed. Between January 1993 and December 2006, RS procedures were performed on 78 people with haemophilia. Their average age was 18 (range 7–51). These procedures were performed on 104 different joints. Some joints required more than one RS injection, resulting in a total of 156 procedures. The isotopes used were yttrium-90 (90Y) on 107 occasions and rhenium-186 (186Re) in 49 injections. For RS procedures on knees, only 90Y was used, while 186Re was used to inject elbows and ankles. The RS procedures did not require the patients to be admitted into hospital.
876
E.C. Rodriguez-Merchan et al. / Thrombosis Research 133 (2014) 875–879
Haemostatic Coverage
Specific Variables of the Joints Before Each RS
To reduce the risk of bleeding during the procedure, RS is always performed with haemostatic factor coverage using the replacement clotting factor. In our patients, haemostatic coverage was provided by an infusion of the replacement factor 30 minutes before injecting the radioisotope. In patients with haemophilia A, a dose of 50 IU/kg of clotting factor VIII was usually administered every 24 hours for 4 days. In patients with haemophilia B, a dose of 60 IU/kg of clotting factor IX was administered every 24 hours for 4 days. Patients with inhibitor could also be injected with the radioisotope with minimum risk of bleeding. These patients with circulating inhibitors received a dose of 75 IU/kg of aPCCs every 12 hours (4 days), or a dose of 90 μg/kg of rFVIIa every 2 hours (1 day).
The variables that were used in determining the joint's response to the RS treatment were the following: number of haemarthroses in the previous 6 months, joint pain, ROM (Table 1), muscle strength (Table 2) [33] and the size of the synovial membrane (degree of synovitis) in mm, measured by imaging tests (ultrasound and/or MRI). These variables were measured at the time of the RS, and 6 months later.
Isotope and Doses The isotopes used were yttrium-90 (90Y) and Rhenium-186 (186Re). 90Y is the isotope used in the knee joint, at a dose of 185 megabecquerels (MBq; 5 millicuries). The 186Re was used for elbows and ankles, in doses of 56–74 (1.5-2 millicuries) and 74 MBq (2 millicuries), respectively.
Injection Technique The intra-articular injection technique used for the radioactive isotope was very similar to that for joint fluid aspiration (arthrocentesis). As has already been discussed, before starting the procedure, the replacement clotting factor had already been administered. In addition, aseptic standards were observed. Size 0.8 × 40 mm intramuscular needles were used with 10 ml syringes. Once the needle reached the intra-articular space, aspiration was used to evacuate the synovial fluid (which was not always present). Once the fluid had been extracted, the syringe was removed, leaving the needle. The syringe loaded with the prepared radioisotope was then attached to the needle, and the radioisotope was injected slowly into the joint. Once all the radioisotope has been injected, the syringe is changed once more, attaching one loaded with a 2 ml vial of 6 mg/ml betamethasone acetate and 6 mg/ml betamethasone sodium phosphate (Celestone ® Chronodose ®), which was released as the needle was slowly withdrawn. The purpose of the corticosteroid is twofold: to reduce the risk of a post-injection inflammatory reaction, and to wash the path of the needle in order to prevent a possible isotope burn along its path or in the skin. Immediately after the needle was withdrawn, a compressive bandage was applied and left in place for 3 days.
Post-injection Treatment After the injection of the radioactive isotope patients were advised to actively increase joint mobility (elbows, knees, ankles) and weight bearing (knees, ankles), depending on their tolerance. In addition, static stretching exercises and toning exercises were then prescribed, with the dual aim of preventing soft tissues retracting while improving muscle strength.
Evaluation of the Effectiveness of the RS Procedure In analysing the effectiveness of the RS, the joint was used as the sampling unit for the study including knees, elbows and ankles. Independent joint parameters were used to assess the effectiveness of the RS treatment in the joints studied. These variables were measured for each knee prior to the radioisotope injection and 6 months after it, and were statistically analysed to determine whether the improvements were significant or not. The statistical analysis to assess the effectiveness of the RS was performed independently for the first, second and third radioisotope injections into the joint (RS-1, RS-2, RS-3). An exploratory analysis was later run on the variables that could influence the effectiveness of RS on the joints studied. For this analysis, five of the specific joint variables were extracted and compared with the patient's variables, general variables of the joint and variables of the radioisotope injection technique itself. The five specific joint variables and the criteria for improvement that were taken into account were the following: Improvement in pain: The joint pain was considered to have improved when the visual analogue scale (VAS) dropped by at least 2 points 6 months after the radioisotope injection. Reduction in the number of haemarthroses: There was considered to have been an improvement in the number of haemarthroses when there were fewer joint bleeds in the 6 months following the injection than in the 6 months prior to it, even one fewer. Increase in joint ROM: There was considered to have been an improvement when the arc of joint motion in flexion or extension had increased by at least 7% when measured 6 months after the use of the radioisotope, compared to the ROM measured before the procedure. Increased muscle strength: There was considered to have been an improvement when the score on the Medical Research Council's scale for testing muscle strength had increased by at least 1 point in flexion or extension 6 months after the radioisotope injection. Reduction in synovial thickness: There was considered to have been an improvement in the degree of synovitis when a reduction in synovial thickness (in millimetres) was observed in imaging tests 6 months after the injection. The fundamental objective of our study was to investigate whether the absence of ADSR would influence response to the RS procedure. To do this, the improvement or otherwise of the variables studied was compared to the variable referred to as “presence of ADSR (yes-no)”.
Need to Repeat the RS Treatment The variable used to determine whether more than one injection (RS-1) was necessary, i.e. whether a second (RS-2) or third (RS-3) procedure should be performed, was the frequency of joint bleeds. An additional RS procedure was performed on those patients (despite compliance with prophylaxis) who suffered two or more haemarthroses in the 6 months after RS-1 or RS-2. In these cases, the procedure was identical to that described for the first injection (RS-1).
Table 1 Average (in degrees) of the normal values of the range of motion (ROM) in the sagittal plane for the elbow, knee and ankle. Joint
Degrees
Elbow Knee Ankle
Flexion: 140+/−5 Flexion: 140+/−5 Dorsal flexion: 15+/−5
Extension: 0+/−2 Extension: 0+/−3 Plantar flexion: 40+/−10
E.C. Rodriguez-Merchan et al. / Thrombosis Research 133 (2014) 875–879 Table 2 Scale for testing muscle strength (degree of muscle strength) of the Medical Research Council [33]. Degree
Description
0 1 2
Without contraction Sign or indication of contraction Actual movement, in a position in which gravity resistance is removed
Statistical Methods Used in the Analysis of Data Descriptive statistics: The categorical variables are represented by absolute frequencies and percentages, and the variables measured quantitatively by their means, standard deviations and median values. Analytical statistics: To assess the effectiveness of the RS procedures, the quantitative variables measured were compared before and after the radioisotope injection by using Student's t-test for paired measurements or its non-parametric equivalent (the Wilcoxon test) in the case of ordinal variables or if the sample size required it; McNemar's test was used to compare the categorical variables. To discover whether frequency of haemarthrosis is the variable that is the strongest determinant of effectiveness, it was compared to the other variables (pain, haemarthrosis, ROM, muscle strength and synovial size) with their improvement criteria established respectively, using Fisher's exact test. McNemar's test was used to compare the improvement of each of the joint variables used and to assess the effectiveness of RS-2 and RS-3 with respect to the previous procedure (RS-1 and RS-2, respectively). To examine the association between the five specific variables (improvement in pain, haemarthrosis, ROM, muscle strength and synovial size), the patient's age and the presence of ADSR at the time of RS, Pearson's chi-square test was used, or its non-parametric equivalent. Fisher's exact test was used when the variables explored were categorical, and Student's t-test for independent measurements or its nonparametric equivalent, the Mann Whitney U Test, were used for quantitative variables. When necessary, logistic regression models were used to determine whether the variables explored were independent factors or confounding factors. For this analysis, a univariate logistic regression model was applied to those variables that showed statistical significance in each of the effectiveness analyses performed, in order to determine the extent and accuracy of the significance by determining the odds ratio with 95% confidence intervals, in order to subsequently enter them into a multivariate logistic regression model for adjustment. Lastly, other comparisons were made using the appropriate statistical tests, depending on whether the measurements to be compared were quantitative or categorical. All the statistical tests were considered to be bilateral, and significant values were those with a p-value b0.05. The Microsoft Word 2000 program was used for word-processing and the realization of tables. The software used to complete the study was the SPSS for Windows statistical programme (version 15.0). Results Table 3 shows shows the relationship between the improvement in the number of haemarthroses after RS-1, RS2 and RS3 and the presence or absence of ADSR. Regarding the variable haemarthrosis, after RS-1, 93% (78/83) of joints improved. After RS-2, 83% (25/30) of joints improved. After RS-3, 66% (8/12) of joints improved. Table 4 shows shows the relationship between the improvement in pain (VAS, visual analogue scale) after RS-1, RS2 and RS3 and the presence or absence of ADSR. Concerning pain, after RS-1, 60% (55/93) of joints improved. After RS-2, 51% (16/31) of joints improved.
877
Table 3 Relationship between the “improvement in the number of haemarthroses” following the first radiosynovectomy (RS-1), second radiosynovectomy (RS-2) and third radiosynovectomy (RS-3), and the presence or absence of articular degeneration in simple radiography (ADSR). SD = Standard deviation. RS-1 Variable explored
Improvement
No improvement
N = 78
N=5
Age (mean+/−SD) years Presence of ADSR -No -Yes
17.1 (6.1)
22.2 (10)
Variable explored
Improvement
No improvement
N = 25
N=5
18.5 (5.2)
18.6 (5.6)
16 (20.5%) 62 (79.5%)
0 (0%) 5 (100%)
Value of p
0.092 0.578
RS-2
Age (mean+/−SD) years Presence of ADSR -No -Yes
2 (8%) 23 (92%)
0 (0%) 5 (100%)
Value of p
0.976 1
RS-3 Variable explored
Age (mean+/−SD) years Presence of ADSR -No -Yes
Improvement
No improvement
N=8
N=4
21.6 (4)
20.2 (4.8)
0 (0%) 8 (100%)
0 (0%) 4 (100%)
Value of p
0.615 Not valid analysis
Table 5 shows shows the relationship between the improvement in joint range of motion (ROM) after RS-1, RS2 and RS3 and the presence or absence of ADSR. Regarding ROM, after RS-1, 52% (49/94) of joints improved: After RS-2, 61% (19/31) of joints improved. After RS-3, 46% (6/13) of joints improved. Table 6 shows the relationship between the improvement in the muscle strength after RS-1, RS2 and RS3 and the presence or absence of ADSR. Concerning muscle strength, after RS-1, 50% (42/84) of joints Table 4 Relationship between the “improvement in pain (VAS)” following the first radiosynovectomy (RS-1), second radiosynovectomy (RS-2) and third radiosynovectomy (RS-3), and the presence or absence of articular degeneration in simple radiography (ADSR). SD = Standard deviation. VSA = Visual Analog Scale. RS-1 Variable explored
Improvement
No improvement
N = 55
N = 38
Age (mean+/−SD) years Presence of ADSR -No -Yes
18.8 (8.5)
18.3 (8.6)
Variable explored
Improvement
No improvement
N = 16
N = 15
Age (mean+/−SD) years Presence of ADSR -No -Yes
18.8 (6.4)
19.1 (4.6)
Variable explored
Improvement
No improvement
N=7
N=6
20.5 (3.7)
20.6 (5.5)
10 (18.2%) 45 (81.8%)
8 (21.1%) 30 (78.9%)
Value of p
0.734 0.793
RS-2
0 (0%) 16 (100%)
2 (13.3%) 13 (86.7%)
Value of p
0.900 0.226
RS-3
Age (mean+/−SD) years Presence of ADSR -No -Yes
0 (0%) 7 (100%)
0 (0%) 6 (100%)
Value of p
0.971 Not valid analysis
878
E.C. Rodriguez-Merchan et al. / Thrombosis Research 133 (2014) 875–879
Table 5 Relationship between the “improvement in joint range of motion (ROM)” following the first radiosynovectomy (RS-1), second radiosynovectomy (RS-2) and third radiosynovectomy (RS-3), and the presence or absence of articular degeneration in simple radiography (ADSR). SD = Standard deviation.
Table 7 Relationship between the “improvement in synovial size” following the first radiosynovectomy (RS-1), second radiosynovectomy (RS-2) and third radiosynovectomy (RS-3), and the presence or absence of articular degeneration in simple radiography (ADSR). SD = Standard deviation.
RS-1 Variable explored
Age (mean+/−SD) years Presence of ADSR -No -Yes
RS-1
Improvement
No improvement
N = 49
N = 45
17.85 (7.8)
19.48 (9.2)
9 (18.4%) 40 (81.6%)
9 (20.0%) 36 (80,0%)
Value of p
0.356 1.000
Variable explored
Age (mean+/−SD) years Presence of ADSR -No -Yes
RS-2 Variable explored
Age (mean+/−SD) years Presence of ADSR -No -Yes
No improvement
N = 19
N = 12
1 (5.3%) 18 (94.7%)
19.5 (5.2) 1 (8.3%) 11 (91.7%)
Value of p
0.665 1
Variable explored
Age (mean+/−SD) years Presence of ADSR -No -Yes
RS-3 Variable explored
Age (mean+/−SD) years Presence of ADSR -No -Yes
Improvement
No improvement N=7
0 (0%) 6 (100%)
22.4 (4.8) 0 (0%) 7 (100%)
Value of p
0.117 Not valid analysis
improved. After RS-2, 43% (13/30) of joints improved. After RS-3, 30% (4/13) of joints improved. Table 7 shows the relationship between the improvement in the synovial membrane size after RS-1, RS-2 and RS-3 and the presence or absence of ADSR. Regarding synovial size, after RS-1, 65% (53/81) joints improved. After RS-2, 66% (18/27) of joints improved. After RS-3, 63% (7/11) of joints improved.
Table 6 Relationship between the “improvement in muscle strength” following the first radiosynovectomy (RS-1), second radiosynovectomy (RS-2) and third radiosynovectomy (RS-3), and the presence or absence of articular degeneration in simple radiography (ADSR). SD = Standard deviation. RS-1 Variable explored
Age (mean+/−SD) years Presence of ADSR -No -Yes
Improvement
No Improvement
N = 42
N = 42
19.4 (9.6) 11 (26.2%) 31 (73.8%)
Value of p
18 (7.2)
0.463
7 (16.7%) 35 (83.3%)
0.426
RS-2 Variable explored
Age (mean+/−TD) years Presence of ADSR -No -Yes
Improvement
No improvement
N = 13
N = 17
18 (7.2) 0 (0%) 13 (100%)
19.5 (4.3) 2 (1.8%) 15 (88.2%)
Value of p
0.501 0.492
RS-3 Variable explored
Age (mean+/−SD) years Presence of ADSR -No -Yes
Improvement
No improvement
N=4
N=9
21 (3.6) 0 (0%) 4 (100%)
17.7 (7.8)
18.8 (7.7)
12 (2.6%) 41 (77.4%)
4 (14.3%) 24 (85.7%)
Value of p
0.355 0.402
Improvement
No improvement
N = 18
N=9
18.6 (5.5)
18.9 (4.9)
1 (5.6%) 17 (94.4%)
1 (11.1%) 8 (88.9%)
Value of p
0.920 1
RS-3
N=6 18.5 (3)
No improvement N = 28
RS-2
Improvement
18.5 (5.9)
Improvement N = 53
24.4 (4.9) 0 (0%) 9 (100%)
Value of p
0.846 Not valid analysis
Variable explored
Age (mean+/−SD) years Presence of ADSR -No -Yes
Improvement
No Improvement
N=7
N=4
21.1 (3.8) 0 (0%) 7 (100%)
23 (3.6) 0 (0%) 4 (100%)
Value of p
0.450 Not valid analysis
Tables 3 to 7 also show that none of the joints without ADSR required RS-3, and that the age of patients was not related to the response to RS. Discussion In our study, all the joints (those without ADSR and those that already showed ADSR) improved in terms of the five parameters studied (number of haemarthroses, pain, ROM, muscle strength and synovial size). Additionally, no joint without ADSR required RS-3. Papers have already been published stating that the RS procedure is more efficient in patients with little joint damage and that its effectiveness decreases as the haemophiliac arthropathy progresses. It has also been recommended that the RS procedure should preferably be performed before the radiologically-visible signs of haemophiliac arthropathy are detected [1,2,19,25]. This study has demonstrated the effectiveness of each of the RS procedures (RS-1, RS-2, RS-3). Many studies have been published that demonstrate the effectiveness of RS in terms of reducing joint bleeds [1,32]. In this respect our work confirms these results; it does, however, show that RS is also effective in improving other joint parameters (mainly the size of the synovium), regardless of whether or not ADSR is present when the RS is performed. Haemarthrosis showed the best response (93%, 83% and 66% improved after RS-1, RS-2 and RS-3, respectively) followed by synovial size (65%, 66% and 63% improved after RS-1, RS-2 and RS-3, respectively), whereas the other variables (pain, ROM and muscle strength) did not show as much of an effect. It is important to emphasise that the main goal of RS is to diminish the number of haemarthroses by decreasing the size of the synovial membrane of the joint. The other parameters (pain, ROM, muscle strength) are not direct objectives of RS, although we decided to analyse them in order to better understand the complexity of the problem. In conclusion, RS is a simple, safe and effective procedure for treating chronic haemophilic synovitis. The RS treatment with 90Y and 186Rh has been shown to reduce the number of haemarthroses, reduce joint pain and synovial size, and improve muscle strength and the range of motion,
E.C. Rodriguez-Merchan et al. / Thrombosis Research 133 (2014) 875–879
not only in joints with ADSR but also in those without ADSR. However, no articulation without ADSR needed an RS-3, and this is the fundamental difference found in our study between patients with chronic haemophilic synovitis without ADSR and those with ADSR. Conflict of Interest Statement No conflict of interest. References [1] Ahlberg A, Pettersson H. Synoviorthesis with radioactive gold in hemophiliacs. Clinical and radiological follow-up. Acta Orthop Scand 1979;50:513–7. [2] Heim M, Goshen E, Amit Y, Martinowitz U. Synoviorthesis with radioactive Yttrium in haemophilia: Israel experience. Haemophilia 2001;7(Suppl. 2):36–9. [3] 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. [4] Kavakli K, Aydogdu S, Omay SB, Duman Y, Taner M, Capaci K, et al. Longterm evaluation of radioisotope synovectomy with Yttrium 90 for chronic synovitis in Turkish haemophiliacs: Izmir experience. Haemophilia 2006;12:28–35. [5] 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. [6] Llinas A. The role of synovectomy in the management of a target joint. Haemophilia 2008;14(Suppl. 3):177–80. [7] Rivard GE, Girard M, Belanger R, Jutras M, Guay J-P, Marton D. Synoviorthesis with colloidal P32 chromic phosphate for the treatment of hemophilic arthropathy. J Bone Joint Surg Am 1994;76:482–8. [8] Rodriguez-Merchan EC, Jiménez-Yuste V, Villar A, Quintana M, López-Cabarcos C, Hernández-Navarro F. Yttrium-90 synoviorthesis for chronic haemophilic synovitis: Madrid experience. Haemophilia 2001;7(Suppl. 2):34–5. [9] Schneider P, Farahati J, Reiners C. Radiosynovectomy in rheumatology, orthopedics, and hemophilia. J Nucl Med 2005;46(Suppl. 1):48–54. [10] Silva M, Luck Jr JV, Siegel ME. 32P chromic phosphate radiosynovectomy for chronic haemophilic synovitis. Haemophilia 2001;7(Suppl. 2):40–9. [11] Thomas S, Gabriel MB, Assi PE, Barboza M, Perri MLP, Land MGP, et al. Radioactive synovectomy with Yttrium90 citrate in haemophilic synovitis: Brazilian experience. Haemophilia 2010;16:1–6. [12] 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. [13] Rodriguez-Merchan EC, Luck JV, Silva M, Quintana M. Synoviorthesis in haemophilia. In: Rodríguez-Merchán EC, editor. The Haemophilic Joints: New Perspectives. WileyBlackwell; 2003. p. 73–9. [14] 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].
879
[15] Rodriguez-Merchan EC, Wiedel JD. General principles and indications of synoviorthesis (medical synovectomy) in haemophilia. Haemophilia 2001;7(Suppl. 2):6–10. [16] 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]. [17] 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. [18] Barrenechea E, Navarra S, Chua M. Evaluation of the efficacy of radiosynovectomy with hemophilic arthropaty. Haemophilia 2006;12(Suppl. 2):80–90. [19] 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. [20] Li P, Chen G, Zhang H, Shen Z. Radiation synovectomy by 188Re-Sulfide in haemophilic synovitis. Haemophilia 2004;10:422–7. [21] Mahlangu J, Brittain D, Mbele S, Schwizer R, Gilham A. Management of recurrent haemarthrosis with 90Yttrium synoviorthesis: Johannesburg experience. Haemophilia 2006;12(Suppl. 2):80–90. [22] Heim M, Horoszowski H, Lieberman L, Varon D, Martinowitz U. Methods and results of radionucleotide synovectomies. Orthop Traumatol 1990;10:30–2. [23] Siegel HJ, Luck Jr JV, Siegel ME, Quines C, Anderson E. Hemarthrosis and synovitis associated with hemophilia: clinical use of P-32 chromic phosphate synoviorthesis for treatment. Radiology 1994;190:257–61. [24] 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. [25] Heim M, Tiktinsky R, Amit Y, Martinowitz U. Yttrium synoviorthesis of the elbow joints in persons with haemophilia. Haemophilia 2004;10:590–2. [26] 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. [27] Mortazavi JSM, Asadollahi S, Farzan M, Shahriaran S, Aghili M, Izadyar S, et al. 32)P colloid radiosynovectomy in treatment of chronic haemophilic synovitis: Iran experience. Haemophilia 2007;13:182–8. [28] 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. [29] 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. [30] De la Corte-Rodriguez H, Rodriguez-Merchan EC, Jimenez-Yuste V. Radiosynovectomy in patients with chronic haemophilic sinovitis: When is more than one injection necessary? Eur J Haematol 2011;86:430–5. [31] De la Corte-Rodriguez H, Rodriguez-Merchan EC, Jimenez-Yuste V. What patient, joint and isotope characteristics influence the response to radiosynovectomy in patients with haemophilia? Haemophilia 2011;17:e990–8. [32] De la Corte-Rodriguez H, Rodriguez-Merchan EC, Jimenez-Yuste V. Radiosynovectomy in haemophilia: Quantification of its effectiveness through the assessment of 10 articular parameters. J Thromb Haemost 2011;9:928–35. [33] Medical Research Council. Aids to the examination of the peripheral nervous system. Memorandum no. 45. London: Her Majesty's Stationery Office; 1981.
Contents lists available at ScienceDirect
Thrombosis Research journal homepage: www.elsevier.com/locate/thromres
Regular Article
Is radiosynovectomy (RS) effective for joints damaged by haemophilia with articular degeneration in simple radiography (ADSR)? 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 Medicine, 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 18 December 2013 Received in revised form 18 December 2013 Accepted 26 January 2014 Available online 29 January 2014 Keywords: Haemophilia Synovitis Radiosynovectomy Joint degeneration Effectiveness
a b s t r a c t Background: Radiosynovectomy (RS) is known to be effective in the treatment of chronic haemophiliac synovitis. Its effectiveness may, however, be different when the joint treated shows articular degeneration in simple radiography (ADSR). Purpose: The purpose of this study was to investigate the effectiveness or otherwise of RS in the presence of ADSR. To this end, the objective improvement in five joint parameters (haemarthrosis, joint pain, range of motion, muscle strength and synovial size) has been analysed with respect to the pre-existence or otherwise of ADSR in the articulation treated. Materials and Methods: An observational retrospective cohort study was conducted. Between January 1993 and December 2006, RS was performed on 78 people with haemophilia. Their average age was 18 (range 7–51). RS procedures were performed on 104 different joints; some joints required more than one injection (a maximum of 3 were given, with a 6-month interval between them), which we refer to respectively as RS-1, RS-2, RS-3, resulting in a total of 156 procedures. The isotopes used were 90Y on 107 occasions and 186Re in 49 injections. Results: RS treatment reduced the frequency of haemarthroses, reduced joint pain and reduced synovial size, and resulted in improved muscle strength and range of motion both in joints with ADSR (N = 86) and in those without ADSR (N = 18). However, no articulation without ADSR required RS-3. Conclusion: The five parameters studied improved to an equal degree in joints with ADSR and without ADSR. No joint without ADSR required RS-3; this was the only difference our study found between joints without ADSR and those with ADSR at the time of the RS. © 2014 Elsevier Ltd. All rights reserved.
Introduction Unless minimized through primary prophylaxis with replacement clotting factor, the recurrent joint bleeds suffered by haemophilia patients from childhood eventually cause clinical symptoms of chronic synovitis. A vicious circle of haemarthrosis-synovitis-haemarthrosis then starts up, due to hyper-vascularisation of the hypertrophic synovial membrane, and this will result in joint degeneration within a few years. This joint degeneration is not initially visible in X-rays, although it will gradually become evident over time. Radiosynovectomy (RS) is known to be effective in the treatment of haemophilic synovitis [1,32]. Many aspects of its effectiveness have not, however, been fully clarified or quantified. The procedure requires 1 to 3 intra-articular injections of a radioactive isotope (RS-1, RS-2 and RS-3), with 6-month intervals between them. The purpose of this study was to evaluate quantitatively the effectiveness of RS in terms of objective improvements in five independent ⁎ 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). 0049-3848/$ – see front matter © 2014 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.thromres.2014.01.030
joint parameters (haemarthrosis, joint pain, range of motion-ROM-, muscle strength and synovial size) with respect to the pre-existence or otherwise of radiologically visible signs of joint degeneration (articular degeneration with simple radiography; ADSR) in the joint treated at the time of the RS. In other words, the aim was to discover whether RS is effective in the treatment of chronic haemophilic synovitis when ADSR is present.
Methods An observational retrospective cohort study was performed. Between January 1993 and December 2006, RS procedures were performed on 78 people with haemophilia. Their average age was 18 (range 7–51). These procedures were performed on 104 different joints. Some joints required more than one RS injection, resulting in a total of 156 procedures. The isotopes used were yttrium-90 (90Y) on 107 occasions and rhenium-186 (186Re) in 49 injections. For RS procedures on knees, only 90Y was used, while 186Re was used to inject elbows and ankles. The RS procedures did not require the patients to be admitted into hospital.
876
E.C. Rodriguez-Merchan et al. / Thrombosis Research 133 (2014) 875–879
Haemostatic Coverage
Specific Variables of the Joints Before Each RS
To reduce the risk of bleeding during the procedure, RS is always performed with haemostatic factor coverage using the replacement clotting factor. In our patients, haemostatic coverage was provided by an infusion of the replacement factor 30 minutes before injecting the radioisotope. In patients with haemophilia A, a dose of 50 IU/kg of clotting factor VIII was usually administered every 24 hours for 4 days. In patients with haemophilia B, a dose of 60 IU/kg of clotting factor IX was administered every 24 hours for 4 days. Patients with inhibitor could also be injected with the radioisotope with minimum risk of bleeding. These patients with circulating inhibitors received a dose of 75 IU/kg of aPCCs every 12 hours (4 days), or a dose of 90 μg/kg of rFVIIa every 2 hours (1 day).
The variables that were used in determining the joint's response to the RS treatment were the following: number of haemarthroses in the previous 6 months, joint pain, ROM (Table 1), muscle strength (Table 2) [33] and the size of the synovial membrane (degree of synovitis) in mm, measured by imaging tests (ultrasound and/or MRI). These variables were measured at the time of the RS, and 6 months later.
Isotope and Doses The isotopes used were yttrium-90 (90Y) and Rhenium-186 (186Re). 90Y is the isotope used in the knee joint, at a dose of 185 megabecquerels (MBq; 5 millicuries). The 186Re was used for elbows and ankles, in doses of 56–74 (1.5-2 millicuries) and 74 MBq (2 millicuries), respectively.
Injection Technique The intra-articular injection technique used for the radioactive isotope was very similar to that for joint fluid aspiration (arthrocentesis). As has already been discussed, before starting the procedure, the replacement clotting factor had already been administered. In addition, aseptic standards were observed. Size 0.8 × 40 mm intramuscular needles were used with 10 ml syringes. Once the needle reached the intra-articular space, aspiration was used to evacuate the synovial fluid (which was not always present). Once the fluid had been extracted, the syringe was removed, leaving the needle. The syringe loaded with the prepared radioisotope was then attached to the needle, and the radioisotope was injected slowly into the joint. Once all the radioisotope has been injected, the syringe is changed once more, attaching one loaded with a 2 ml vial of 6 mg/ml betamethasone acetate and 6 mg/ml betamethasone sodium phosphate (Celestone ® Chronodose ®), which was released as the needle was slowly withdrawn. The purpose of the corticosteroid is twofold: to reduce the risk of a post-injection inflammatory reaction, and to wash the path of the needle in order to prevent a possible isotope burn along its path or in the skin. Immediately after the needle was withdrawn, a compressive bandage was applied and left in place for 3 days.
Post-injection Treatment After the injection of the radioactive isotope patients were advised to actively increase joint mobility (elbows, knees, ankles) and weight bearing (knees, ankles), depending on their tolerance. In addition, static stretching exercises and toning exercises were then prescribed, with the dual aim of preventing soft tissues retracting while improving muscle strength.
Evaluation of the Effectiveness of the RS Procedure In analysing the effectiveness of the RS, the joint was used as the sampling unit for the study including knees, elbows and ankles. Independent joint parameters were used to assess the effectiveness of the RS treatment in the joints studied. These variables were measured for each knee prior to the radioisotope injection and 6 months after it, and were statistically analysed to determine whether the improvements were significant or not. The statistical analysis to assess the effectiveness of the RS was performed independently for the first, second and third radioisotope injections into the joint (RS-1, RS-2, RS-3). An exploratory analysis was later run on the variables that could influence the effectiveness of RS on the joints studied. For this analysis, five of the specific joint variables were extracted and compared with the patient's variables, general variables of the joint and variables of the radioisotope injection technique itself. The five specific joint variables and the criteria for improvement that were taken into account were the following: Improvement in pain: The joint pain was considered to have improved when the visual analogue scale (VAS) dropped by at least 2 points 6 months after the radioisotope injection. Reduction in the number of haemarthroses: There was considered to have been an improvement in the number of haemarthroses when there were fewer joint bleeds in the 6 months following the injection than in the 6 months prior to it, even one fewer. Increase in joint ROM: There was considered to have been an improvement when the arc of joint motion in flexion or extension had increased by at least 7% when measured 6 months after the use of the radioisotope, compared to the ROM measured before the procedure. Increased muscle strength: There was considered to have been an improvement when the score on the Medical Research Council's scale for testing muscle strength had increased by at least 1 point in flexion or extension 6 months after the radioisotope injection. Reduction in synovial thickness: There was considered to have been an improvement in the degree of synovitis when a reduction in synovial thickness (in millimetres) was observed in imaging tests 6 months after the injection. The fundamental objective of our study was to investigate whether the absence of ADSR would influence response to the RS procedure. To do this, the improvement or otherwise of the variables studied was compared to the variable referred to as “presence of ADSR (yes-no)”.
Need to Repeat the RS Treatment The variable used to determine whether more than one injection (RS-1) was necessary, i.e. whether a second (RS-2) or third (RS-3) procedure should be performed, was the frequency of joint bleeds. An additional RS procedure was performed on those patients (despite compliance with prophylaxis) who suffered two or more haemarthroses in the 6 months after RS-1 or RS-2. In these cases, the procedure was identical to that described for the first injection (RS-1).
Table 1 Average (in degrees) of the normal values of the range of motion (ROM) in the sagittal plane for the elbow, knee and ankle. Joint
Degrees
Elbow Knee Ankle
Flexion: 140+/−5 Flexion: 140+/−5 Dorsal flexion: 15+/−5
Extension: 0+/−2 Extension: 0+/−3 Plantar flexion: 40+/−10
E.C. Rodriguez-Merchan et al. / Thrombosis Research 133 (2014) 875–879 Table 2 Scale for testing muscle strength (degree of muscle strength) of the Medical Research Council [33]. Degree
Description
0 1 2
Without contraction Sign or indication of contraction Actual movement, in a position in which gravity resistance is removed
Statistical Methods Used in the Analysis of Data Descriptive statistics: The categorical variables are represented by absolute frequencies and percentages, and the variables measured quantitatively by their means, standard deviations and median values. Analytical statistics: To assess the effectiveness of the RS procedures, the quantitative variables measured were compared before and after the radioisotope injection by using Student's t-test for paired measurements or its non-parametric equivalent (the Wilcoxon test) in the case of ordinal variables or if the sample size required it; McNemar's test was used to compare the categorical variables. To discover whether frequency of haemarthrosis is the variable that is the strongest determinant of effectiveness, it was compared to the other variables (pain, haemarthrosis, ROM, muscle strength and synovial size) with their improvement criteria established respectively, using Fisher's exact test. McNemar's test was used to compare the improvement of each of the joint variables used and to assess the effectiveness of RS-2 and RS-3 with respect to the previous procedure (RS-1 and RS-2, respectively). To examine the association between the five specific variables (improvement in pain, haemarthrosis, ROM, muscle strength and synovial size), the patient's age and the presence of ADSR at the time of RS, Pearson's chi-square test was used, or its non-parametric equivalent. Fisher's exact test was used when the variables explored were categorical, and Student's t-test for independent measurements or its nonparametric equivalent, the Mann Whitney U Test, were used for quantitative variables. When necessary, logistic regression models were used to determine whether the variables explored were independent factors or confounding factors. For this analysis, a univariate logistic regression model was applied to those variables that showed statistical significance in each of the effectiveness analyses performed, in order to determine the extent and accuracy of the significance by determining the odds ratio with 95% confidence intervals, in order to subsequently enter them into a multivariate logistic regression model for adjustment. Lastly, other comparisons were made using the appropriate statistical tests, depending on whether the measurements to be compared were quantitative or categorical. All the statistical tests were considered to be bilateral, and significant values were those with a p-value b0.05. The Microsoft Word 2000 program was used for word-processing and the realization of tables. The software used to complete the study was the SPSS for Windows statistical programme (version 15.0). Results Table 3 shows shows the relationship between the improvement in the number of haemarthroses after RS-1, RS2 and RS3 and the presence or absence of ADSR. Regarding the variable haemarthrosis, after RS-1, 93% (78/83) of joints improved. After RS-2, 83% (25/30) of joints improved. After RS-3, 66% (8/12) of joints improved. Table 4 shows shows the relationship between the improvement in pain (VAS, visual analogue scale) after RS-1, RS2 and RS3 and the presence or absence of ADSR. Concerning pain, after RS-1, 60% (55/93) of joints improved. After RS-2, 51% (16/31) of joints improved.
877
Table 3 Relationship between the “improvement in the number of haemarthroses” following the first radiosynovectomy (RS-1), second radiosynovectomy (RS-2) and third radiosynovectomy (RS-3), and the presence or absence of articular degeneration in simple radiography (ADSR). SD = Standard deviation. RS-1 Variable explored
Improvement
No improvement
N = 78
N=5
Age (mean+/−SD) years Presence of ADSR -No -Yes
17.1 (6.1)
22.2 (10)
Variable explored
Improvement
No improvement
N = 25
N=5
18.5 (5.2)
18.6 (5.6)
16 (20.5%) 62 (79.5%)
0 (0%) 5 (100%)
Value of p
0.092 0.578
RS-2
Age (mean+/−SD) years Presence of ADSR -No -Yes
2 (8%) 23 (92%)
0 (0%) 5 (100%)
Value of p
0.976 1
RS-3 Variable explored
Age (mean+/−SD) years Presence of ADSR -No -Yes
Improvement
No improvement
N=8
N=4
21.6 (4)
20.2 (4.8)
0 (0%) 8 (100%)
0 (0%) 4 (100%)
Value of p
0.615 Not valid analysis
Table 5 shows shows the relationship between the improvement in joint range of motion (ROM) after RS-1, RS2 and RS3 and the presence or absence of ADSR. Regarding ROM, after RS-1, 52% (49/94) of joints improved: After RS-2, 61% (19/31) of joints improved. After RS-3, 46% (6/13) of joints improved. Table 6 shows the relationship between the improvement in the muscle strength after RS-1, RS2 and RS3 and the presence or absence of ADSR. Concerning muscle strength, after RS-1, 50% (42/84) of joints Table 4 Relationship between the “improvement in pain (VAS)” following the first radiosynovectomy (RS-1), second radiosynovectomy (RS-2) and third radiosynovectomy (RS-3), and the presence or absence of articular degeneration in simple radiography (ADSR). SD = Standard deviation. VSA = Visual Analog Scale. RS-1 Variable explored
Improvement
No improvement
N = 55
N = 38
Age (mean+/−SD) years Presence of ADSR -No -Yes
18.8 (8.5)
18.3 (8.6)
Variable explored
Improvement
No improvement
N = 16
N = 15
Age (mean+/−SD) years Presence of ADSR -No -Yes
18.8 (6.4)
19.1 (4.6)
Variable explored
Improvement
No improvement
N=7
N=6
20.5 (3.7)
20.6 (5.5)
10 (18.2%) 45 (81.8%)
8 (21.1%) 30 (78.9%)
Value of p
0.734 0.793
RS-2
0 (0%) 16 (100%)
2 (13.3%) 13 (86.7%)
Value of p
0.900 0.226
RS-3
Age (mean+/−SD) years Presence of ADSR -No -Yes
0 (0%) 7 (100%)
0 (0%) 6 (100%)
Value of p
0.971 Not valid analysis
878
E.C. Rodriguez-Merchan et al. / Thrombosis Research 133 (2014) 875–879
Table 5 Relationship between the “improvement in joint range of motion (ROM)” following the first radiosynovectomy (RS-1), second radiosynovectomy (RS-2) and third radiosynovectomy (RS-3), and the presence or absence of articular degeneration in simple radiography (ADSR). SD = Standard deviation.
Table 7 Relationship between the “improvement in synovial size” following the first radiosynovectomy (RS-1), second radiosynovectomy (RS-2) and third radiosynovectomy (RS-3), and the presence or absence of articular degeneration in simple radiography (ADSR). SD = Standard deviation.
RS-1 Variable explored
Age (mean+/−SD) years Presence of ADSR -No -Yes
RS-1
Improvement
No improvement
N = 49
N = 45
17.85 (7.8)
19.48 (9.2)
9 (18.4%) 40 (81.6%)
9 (20.0%) 36 (80,0%)
Value of p
0.356 1.000
Variable explored
Age (mean+/−SD) years Presence of ADSR -No -Yes
RS-2 Variable explored
Age (mean+/−SD) years Presence of ADSR -No -Yes
No improvement
N = 19
N = 12
1 (5.3%) 18 (94.7%)
19.5 (5.2) 1 (8.3%) 11 (91.7%)
Value of p
0.665 1
Variable explored
Age (mean+/−SD) years Presence of ADSR -No -Yes
RS-3 Variable explored
Age (mean+/−SD) years Presence of ADSR -No -Yes
Improvement
No improvement N=7
0 (0%) 6 (100%)
22.4 (4.8) 0 (0%) 7 (100%)
Value of p
0.117 Not valid analysis
improved. After RS-2, 43% (13/30) of joints improved. After RS-3, 30% (4/13) of joints improved. Table 7 shows the relationship between the improvement in the synovial membrane size after RS-1, RS-2 and RS-3 and the presence or absence of ADSR. Regarding synovial size, after RS-1, 65% (53/81) joints improved. After RS-2, 66% (18/27) of joints improved. After RS-3, 63% (7/11) of joints improved.
Table 6 Relationship between the “improvement in muscle strength” following the first radiosynovectomy (RS-1), second radiosynovectomy (RS-2) and third radiosynovectomy (RS-3), and the presence or absence of articular degeneration in simple radiography (ADSR). SD = Standard deviation. RS-1 Variable explored
Age (mean+/−SD) years Presence of ADSR -No -Yes
Improvement
No Improvement
N = 42
N = 42
19.4 (9.6) 11 (26.2%) 31 (73.8%)
Value of p
18 (7.2)
0.463
7 (16.7%) 35 (83.3%)
0.426
RS-2 Variable explored
Age (mean+/−TD) years Presence of ADSR -No -Yes
Improvement
No improvement
N = 13
N = 17
18 (7.2) 0 (0%) 13 (100%)
19.5 (4.3) 2 (1.8%) 15 (88.2%)
Value of p
0.501 0.492
RS-3 Variable explored
Age (mean+/−SD) years Presence of ADSR -No -Yes
Improvement
No improvement
N=4
N=9
21 (3.6) 0 (0%) 4 (100%)
17.7 (7.8)
18.8 (7.7)
12 (2.6%) 41 (77.4%)
4 (14.3%) 24 (85.7%)
Value of p
0.355 0.402
Improvement
No improvement
N = 18
N=9
18.6 (5.5)
18.9 (4.9)
1 (5.6%) 17 (94.4%)
1 (11.1%) 8 (88.9%)
Value of p
0.920 1
RS-3
N=6 18.5 (3)
No improvement N = 28
RS-2
Improvement
18.5 (5.9)
Improvement N = 53
24.4 (4.9) 0 (0%) 9 (100%)
Value of p
0.846 Not valid analysis
Variable explored
Age (mean+/−SD) years Presence of ADSR -No -Yes
Improvement
No Improvement
N=7
N=4
21.1 (3.8) 0 (0%) 7 (100%)
23 (3.6) 0 (0%) 4 (100%)
Value of p
0.450 Not valid analysis
Tables 3 to 7 also show that none of the joints without ADSR required RS-3, and that the age of patients was not related to the response to RS. Discussion In our study, all the joints (those without ADSR and those that already showed ADSR) improved in terms of the five parameters studied (number of haemarthroses, pain, ROM, muscle strength and synovial size). Additionally, no joint without ADSR required RS-3. Papers have already been published stating that the RS procedure is more efficient in patients with little joint damage and that its effectiveness decreases as the haemophiliac arthropathy progresses. It has also been recommended that the RS procedure should preferably be performed before the radiologically-visible signs of haemophiliac arthropathy are detected [1,2,19,25]. This study has demonstrated the effectiveness of each of the RS procedures (RS-1, RS-2, RS-3). Many studies have been published that demonstrate the effectiveness of RS in terms of reducing joint bleeds [1,32]. In this respect our work confirms these results; it does, however, show that RS is also effective in improving other joint parameters (mainly the size of the synovium), regardless of whether or not ADSR is present when the RS is performed. Haemarthrosis showed the best response (93%, 83% and 66% improved after RS-1, RS-2 and RS-3, respectively) followed by synovial size (65%, 66% and 63% improved after RS-1, RS-2 and RS-3, respectively), whereas the other variables (pain, ROM and muscle strength) did not show as much of an effect. It is important to emphasise that the main goal of RS is to diminish the number of haemarthroses by decreasing the size of the synovial membrane of the joint. The other parameters (pain, ROM, muscle strength) are not direct objectives of RS, although we decided to analyse them in order to better understand the complexity of the problem. In conclusion, RS is a simple, safe and effective procedure for treating chronic haemophilic synovitis. The RS treatment with 90Y and 186Rh has been shown to reduce the number of haemarthroses, reduce joint pain and synovial size, and improve muscle strength and the range of motion,
E.C. Rodriguez-Merchan et al. / Thrombosis Research 133 (2014) 875–879
not only in joints with ADSR but also in those without ADSR. However, no articulation without ADSR needed an RS-3, and this is the fundamental difference found in our study between patients with chronic haemophilic synovitis without ADSR and those with ADSR. Conflict of Interest Statement No conflict of interest. References [1] Ahlberg A, Pettersson H. Synoviorthesis with radioactive gold in hemophiliacs. Clinical and radiological follow-up. Acta Orthop Scand 1979;50:513–7. [2] Heim M, Goshen E, Amit Y, Martinowitz U. Synoviorthesis with radioactive Yttrium in haemophilia: Israel experience. Haemophilia 2001;7(Suppl. 2):36–9. [3] 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. [4] Kavakli K, Aydogdu S, Omay SB, Duman Y, Taner M, Capaci K, et al. Longterm evaluation of radioisotope synovectomy with Yttrium 90 for chronic synovitis in Turkish haemophiliacs: Izmir experience. Haemophilia 2006;12:28–35. [5] 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. [6] Llinas A. The role of synovectomy in the management of a target joint. Haemophilia 2008;14(Suppl. 3):177–80. [7] Rivard GE, Girard M, Belanger R, Jutras M, Guay J-P, Marton D. Synoviorthesis with colloidal P32 chromic phosphate for the treatment of hemophilic arthropathy. J Bone Joint Surg Am 1994;76:482–8. [8] Rodriguez-Merchan EC, Jiménez-Yuste V, Villar A, Quintana M, López-Cabarcos C, Hernández-Navarro F. Yttrium-90 synoviorthesis for chronic haemophilic synovitis: Madrid experience. Haemophilia 2001;7(Suppl. 2):34–5. [9] Schneider P, Farahati J, Reiners C. Radiosynovectomy in rheumatology, orthopedics, and hemophilia. J Nucl Med 2005;46(Suppl. 1):48–54. [10] Silva M, Luck Jr JV, Siegel ME. 32P chromic phosphate radiosynovectomy for chronic haemophilic synovitis. Haemophilia 2001;7(Suppl. 2):40–9. [11] Thomas S, Gabriel MB, Assi PE, Barboza M, Perri MLP, Land MGP, et al. Radioactive synovectomy with Yttrium90 citrate in haemophilic synovitis: Brazilian experience. Haemophilia 2010;16:1–6. [12] 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. [13] Rodriguez-Merchan EC, Luck JV, Silva M, Quintana M. Synoviorthesis in haemophilia. In: Rodríguez-Merchán EC, editor. The Haemophilic Joints: New Perspectives. WileyBlackwell; 2003. p. 73–9. [14] 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].
879
[15] Rodriguez-Merchan EC, Wiedel JD. General principles and indications of synoviorthesis (medical synovectomy) in haemophilia. Haemophilia 2001;7(Suppl. 2):6–10. [16] 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]. [17] 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. [18] Barrenechea E, Navarra S, Chua M. Evaluation of the efficacy of radiosynovectomy with hemophilic arthropaty. Haemophilia 2006;12(Suppl. 2):80–90. [19] 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. [20] Li P, Chen G, Zhang H, Shen Z. Radiation synovectomy by 188Re-Sulfide in haemophilic synovitis. Haemophilia 2004;10:422–7. [21] Mahlangu J, Brittain D, Mbele S, Schwizer R, Gilham A. Management of recurrent haemarthrosis with 90Yttrium synoviorthesis: Johannesburg experience. Haemophilia 2006;12(Suppl. 2):80–90. [22] Heim M, Horoszowski H, Lieberman L, Varon D, Martinowitz U. Methods and results of radionucleotide synovectomies. Orthop Traumatol 1990;10:30–2. [23] Siegel HJ, Luck Jr JV, Siegel ME, Quines C, Anderson E. Hemarthrosis and synovitis associated with hemophilia: clinical use of P-32 chromic phosphate synoviorthesis for treatment. Radiology 1994;190:257–61. [24] 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. [25] Heim M, Tiktinsky R, Amit Y, Martinowitz U. Yttrium synoviorthesis of the elbow joints in persons with haemophilia. Haemophilia 2004;10:590–2. [26] 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. [27] Mortazavi JSM, Asadollahi S, Farzan M, Shahriaran S, Aghili M, Izadyar S, et al. 32)P colloid radiosynovectomy in treatment of chronic haemophilic synovitis: Iran experience. Haemophilia 2007;13:182–8. [28] 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. [29] 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. [30] De la Corte-Rodriguez H, Rodriguez-Merchan EC, Jimenez-Yuste V. Radiosynovectomy in patients with chronic haemophilic sinovitis: When is more than one injection necessary? Eur J Haematol 2011;86:430–5. [31] De la Corte-Rodriguez H, Rodriguez-Merchan EC, Jimenez-Yuste V. What patient, joint and isotope characteristics influence the response to radiosynovectomy in patients with haemophilia? Haemophilia 2011;17:e990–8. [32] De la Corte-Rodriguez H, Rodriguez-Merchan EC, Jimenez-Yuste V. Radiosynovectomy in haemophilia: Quantification of its effectiveness through the assessment of 10 articular parameters. J Thromb Haemost 2011;9:928–35. [33] Medical Research Council. Aids to the examination of the peripheral nervous system. Memorandum no. 45. London: Her Majesty's Stationery Office; 1981.