32P chromic phosphate radiosynovectomy for chronic haemophilic synovitis

The principal medical consequence of haemophilia is the development of arthropathy, initiated by a haemarthrosis giving rise to chronic synovitis. Traditional methods of synovectomy include open excision and arthroscopy each of which require substantial amounts of clotting factor concentrate for several weeks, and in the case of open synovectomy, is often associated with loss of range of motion and arthrofibrosis. Radiosynovectomy, the intra-articular injection of low penetration radiocolloids, has been utilized outside the United States for over 20 years. Since 1988, our centre has performed 170 radiosynovectomies utilizing ³²P chromic phosphate (³²P). This study reports results of 130 ³²P radiosyovectomies with an average follow-up of 36.5 months (6–140 months). 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. Regression analysis showed no correlation between results and age or degree of arthropathy. Radiation was well contained within the joint. There were no observed or identified complications. The procedure is highly cost effective in comparison to open surgical or arthroscopic synovectomy.     

Opinions on radiosynovectomy for chronic haemophilic synovitis: point/counterpoint

Joint bleeding is the hallmark of severe haemophilia and the major cause of disability in patients with this coagulopathy. Repeated bleeding into the same joint can lead to chronic synovitis and progressive arthropathy. Radiosynovectomy is one option for the treatment of chronic haemophilic synovitis, but concerns about the risks of exposure to ionizing radiation have divided clinicians as to the safety and appropriate use of the procedure. This article presents two differing viewpoints, one from a pair of orthopaedic surgeons who collectively have performed more than 300 radiosynovectomies in patients with haemophilia. They maintain that radiosynovectomy is a simple, effective, safe and low‐cost technique children and adults with chronic haemophilic synovitis. The other perspective is from an experienced haemophilia treater who directs a major US haemophilia treatment centre. She believes that unresolved questions about the safety of radiation exposure in children argue against the use of radiosynovectomy in paediatric patients with haemophilia.     

Yttrium-90 synoviorthesis for chronic haemophilic synovitis: Madrid experience

Between 1994 and 1999 we performed 66 Yttrium-90 (⁹⁰Y) synoviortheses on 44 persons with haemophilia (45 knees, 12 elbows, nine ankles). At the time of injection 23 patients were HIV+ and two had inhibitors. The average age was 21.1 years (range: 9–39). Five mCi of ⁹⁰Y were injected into the knees, and 3 mCi into the elbows and ankles. The average follow-up was 3.5 years (range: 1–6). Of the 45 knees, there were eight excellent, 10 good, 15 fair and 12 poor results. Of the 12 elbows there were three excellent results, five good, three fair and two poor. Of the nine ankles there were no excellent results, four good, three fair and two poor. The elbows had better results than the knees and ankles. The best results were obtained in the youngest patients, and in those with a moderate degree of synovitis, regardless of their HIV status and the presence of inhibitor. ⁹⁰Y synoviorthesis should be performed in very young patients, when the amount of synovium is still moderate. Once the degree of synovitis has become severe, the expected results of radioactive synoviorthesis are worse.     

Survival analysis of Y‐90 radiosynovectomy in the treatment of haemophilic synovitis of the knee: a 10‐year retrospective review

Despite recent advances including new therapeutic options and availability of primary prophylaxis in haemophiliacs, haemophilic synovitis is still the major clinical problem in significant patient population worldwide. We retrospectively reviewed our 10‐year experience with Y‐90 radiosynovectomy to determine the outcome in the knee joints of patients with haemophilic synovitis. Between 2002 and 2012, 82 knee joints of 67 patients with haemophilic synovitis were treated with Y‐90 radiosynovectomy. The mean age was 16.8 ± 7.8 years (range: 5–39 years). The mean follow‐up period was 39.6 ± 25.6 months (range: 12–95 months). Failure of therapy represented re‐bleeding after a radiosynovectomy was used as an end point in patient time to progression (TTP) analysis. The median TTP was calculated as 72.0 ± 3.6 months (95% CI 64.8–79.1 months) in Kaplan–Meier analysis. The 1, 3 and 5‐year survival rates were 89%, 73% and 63% respectively. Longer TTP (hazard ratio for progression, 2.5; P = 0.00) was evident in patients who have greater reduction in bleeding frequency within 6 months after radiosynovectomy. We did not find a relationship between the TTP and the following variables: age, type and severity of haemophilia, the presence or absence of inhibitor, the radiological score, range of motion status of joints and the pretreatment bleeding frequency. We concluded that Y‐90 radiosynovectomy in knee joint represents an important resource for the treatment of haemophilic synovitis, markedly reducing joint bleeding and long‐term durability, irrespective of the radiographic stage and inhibitor status.     

Radioisotope synovectomy with rhenium186 in haemophilic synovitis for elbows, ankles and shoulders

Summary. We have performed 221 radioisotope synovectomy (RS) in more than 150 children and young adults with haemophilia, age ranging 3–30 years (mean 15) in Ege Hemophilia Center, Izmir, Turkey for last 7 years. We always preferred to use Yttrium 90 (Y⁹⁰) for knees; however, since 2005, we started using rhenium 186 (Re¹⁸⁶) for medium‐sized joints with respect to safety. In this article, we have evaluated long‐term experience ranging from 6 months to 3 years (mean 18 months) with Re¹⁸⁶ for elbows (n = 35), ankles (n = 26) and shoulders (n = 2) in total of 63 RS procedures for 49 patients. Their age range was 3–30 years and mean age was 15.5. Two mCi of Re¹⁸⁶ intra‐articularly injected for treating target joints and chronical synovitis. After RS, joint bleedings were decreased for all patients. The best results were obtained for all joints in patients with grade‐II synovitis as like earlier experience with Y⁹⁰. Excellent rates (no bleeding) were observed in grade‐II synovitis in 81% and 46% for elbows vs. 86% and 57% for ankles after 6 months and after 1 year follow‐up of patients, respectively. In grade‐III synovitis, excellent rates were 53% and 25% for elbows and 44% and 29% for ankles, respectively. In five joints for five patients, repeated injections were needed for better outcome. No adverse events such as radioisotope leakage, local inflamatory reactions or malignancy development were observed during and after RS. For medium‐sized joints, RS with Re¹⁸⁶ seems to be either effective or safe treatment method. Our results confirm those previously published by others on the value of Re¹⁸⁶ synoviorthesis in medium‐sized joints in haemophilia patients. After this experience, we changed our protocol and we use Re¹⁸⁶ for all medium‐sized joints for treating chronical synovitis.     

Treatment of chronic haemophilic synovitis in humans with D-penicillamine

Chronic proliferative synovitis secondary to haemathroses is a major complication in patients with severe haemophilia. Current management strategies include prophylactic infusions of the missing coagulation factor, corticosteroids, synoviorthesis and/or synovectomy with variable degrees of benefit. In addition, patients with coagulation factor inhibitors are not amenable to the invasive therapeutic modalities. The gross and microscopic findings of the synovitis in haemophilic arthritis are remarkably similar to those seen in patients with rheumatoid arthritis, although the pathophysiology of these two conditions are quite different. Haemophilic arthropathy, in the later stages, resembles degenerative rather than inflammatory joint disease. Oral D-penicillamine, a drug effective in the proliferative synovitis of rheumatoid arthritis, was evaluated in 16 patients. Ten patients had an unequivocal response, while three had a reduction in palpable synovium and three had no response. Thus 81% of the patients had a beneficial response. Minor reversible drug side-effects occurred in two patients (proteinuria in one and a rash in the second). The results of this study suggest that D-penicillamine is an effective and safe drug for the treatment of haemophilic chronic synovitis.     

Long‐term outcomes in haemophilic synovitis after radiosynovectomy using rhenium‐186: a single‐centre experience

Radiosynovectomy has been performed successfully for more than 10 years in our hospital. This study investigated the long‐term outcome in the context of time to progression (TTP) analysis and the factors influencing TTP following radiosynovectomy with Re‐186 in patients with haemophilic synovitis. Radiosynovectomy performed in 165 joints (81 elbows, 74 ankles, 8 shoulder and 2 hip joints) of 106 patients (median age was 18.0 ± 7.5 years; 91 haemophilia A, 13 haemophilia B and 2 von Willebrand's disease between June 2001 and July 2011. The mean follow‐up was 48 months (range: 9–120 months). This study revealed that patients' mean TTP after primary radiosynovectomy was satisfactory for both the ankle and elbow joints. There was no TTP differences between the ankle and elbow joint groups (67 vs. 72 months respectively; P = 0.22). We did not find a relationship between the TTP and the following variables: age, type and severity of haemophilia, the presence or absence of inhibitor, the radiological score, range of motion (ROM) status of joints and the pretreatment bleeding frequency. In this study, 18–20% of the treated joints had improved ROM and 82–79% of the treated joints had unchanged ROM after treatment both the ankle and elbow joints respectively. In this report including TTP analysis in the largest series with long‐term follow‐up, we demonstrated long‐term effectiveness of Re‐186 radiosynovectomy in haemophilic synovitis. In our experience, the main predictor of outcome following radiosynovectomy is the number of joint bleeding within 6 months after therapy.     

Monitoring the genotoxic effects of radiosynovectomy with Re-186 in paediatric age group undergoing therapy for haemophilic synovitis

PURPOSE: The aim of this study was to investigate the genotoxic effect on the peripheral blood lymphocytes potentially induced by Re-186 in paediatric age group undergoing radiosynovectomy for haemophilic synovitis, by using chromosomal aberration analysis (CA) and the micronuclei (MN) assay for detecting chromosomal aberrations, as well as the sister chromatid exchanges (SCE) technique for assessing DNA damage. METHODS: Cytogenetic analyses were evaluated in 20 boys (mean age: 13.8 +/- 2.7 years) before, and 2 and 90 days after radiosynovectomy from the peripheral lymphocytes of the patients. Joint retention and extra-articular spread of the radionuclides were evaluated by using quantitative gamma camera imaging. RESULTS: Imaging after radiosynovectomy revealed local lymph node visualization in 8 (40%) patients and hepatosplenic visualization in 3 (15%) patients due to extra-articular leakage of radioactive material. The mean frequency of chromosome aberrations (0.2 +/- 0.4/1000 cells) determined prior to the onset of therapy was not significantly increased in comparison with control values obtained 2 days (0.4 +/- 0.5/1000 cells) and 90 days (0.2 +/- 0.4/1000 cells) after therapy (P = 0.754 and P = 1.0). In the analysis of MN and SCE, when we compare the baseline levels, the mean MN and SCE frequencies were slightly higher in the control analyses performed 2 and 90 days after radiosynovectomy but there were no significant differences between baseline and control levels (chi(2) = 2.621, P = 0.270 and F = 0.573, P = 0.569, respectively). CONCLUSION: The major finding of this study with relatively small sample is that, radiosynovectomy with Re-186 does not seem to induce early genotoxic effects on the peripheral blood lymphocytes in paediatric age group.     

90Yttrium‐hydroxyapatite: a new therapeutic option for radioactive synovectomy in haemophilic synovitis

Summary. Recurrent haemarthroses often lead to chronic synovitis in patients with haemophilia and von Willebrand disease. Radioactive synovectomy with yttrium‐90 (⁹⁰Y) citrate is frequently used to treat this complication, usually with good results. Since 2006, the Nuclear Energy Research Institute (IPEN, Sao Paulo, Brazil) has produced hydroxyapatite particles labelled with ⁹⁰Y for radioactive synovectomy. The aim of this study was to compare the results achieved by both forms of ⁹⁰Y in the treatment of haemophilic synovitis. We included 221 joints from 136 patients (age range: 6–20 years), treated by one of the two radiopharmaceuticals, at the Hemocenter of Mato Grosso, Brazil. The outcomes analysed were the annual frequency of haemarthrosis, articular pain and joint range of motion before and 1 year after RS. Similar results were achieved regardless of whether ⁹⁰Y hydroxyapatite or ⁹⁰Y citrate was used, and results were independent of the joint type, age, gender, radiologic stage and presence of inhibitors. ⁹⁰Y hydroxyapatite appears to be equivalent to the reference product ⁹⁰Y citrate in the treatment of chronic synovitis associated with bleeding disorders.     

The effectiveness of radioisotope synovectomy for chronic synovitis in Turkish paediatric haemophiliacs: Ankara experience

Summary. Between January 2006 and December 2009, 37 radioisotope synovectomy (RS) in 18 severe haemophilic patients (factor 8 < 1%) have been performed at our centre. The distribution of joint injected was as follows: rhenium‐186 [Re186], 19 joints (ankles, 8 and elbows, 11) and yttrium‐90 [Y90] 18 joints (knees, 18). Their mean age was 12 years (range: 8–20 years). Mean follow‐up period after procedure was 22.6 months. We preferred to use Y90 for all large joints and Re186 for small joints. Haemophilic patients with grade‐II or III synovitis were selected for RS in our study. Radioisotope synovectomy was performed in eight ankles for seven patients, 11 elbows for seven patients and 18 knees for 13 patients. Mean bleeding counts before the procedure and after the procedure were as follows: Ankles, 3.43 vs. 0.62 (P = 0.002); elbows, 3.12 vs. 0.55 (P = 0.000); and 3.83 vs. 0.62 (P = 0.011). No major complications requiring secondary treatments were observed. In summary, an early RS is the best way to halt the evolution of chronic haemophilia synovitis to devastating haemophilic arthropathy. Radioisotope synovectomy is very effective and safe in the treatment of chronic synovitis of children with haemophilia. Our data confirm the efficacy of RS for the treatment of chronic haemophilic synovitis, which has been previously published by many authors around the world. We highly recommend this procedure for developing countries to prevent joint disabilities. For a better and a healthier generation, RS has to be introduced in all the developing countries.     

Radioactive synovectomy with Yttrium90 citrate in haemophilic synovitis: Brazilian experience

Summary. Recurrent haemarthroses leading to chronic synovitis and arthropathy remain a major cause of morbidity in patients with haemophilia. Radioactive synovectomy (RS) is considered the first choice of treatment for chronic haemophilic synovitis. The aim of this study was to evaluate the effect of RS with Yttrium⁹⁰ citrate (C‐Y⁹⁰) in the joints of patients with chronic haemophilic synovitis. From 2003 to 2007, 245 joints (118 knees, 76 elbows, 49 ankles and two shoulders) of 190 patients with haemophilia or von Willebrand disease were submitted to RS with C‐Y⁹⁰ at Hemocentro de Mato Grosso, Brazil. Forty joints had radiographic Pettersson scores above 8. There were 36 joints of 22 patients with inhibitors to factor VIII. The procedure was safe with low occurrence of adverse events. The main effect was the overall reduction in joint bleeding frequency, from 19.8 to 2.6 per year post‐RS. Similar results were obtained in cases with high radiographic scores and in inhibitor patients. Pain reduction was observed in most cases. Average range of motion was maintained or increased 1 year post‐RS in most joints. Extension was stable or increased in 88.2% of the knees and 86.5% of the elbows. Ankle plantarflexion was stable or increased in 90.9%, whereas dorsiflexion was maintained or increased in 87.9%. Worsening of the range of motion, when present, ranged from 14 to 17 degrees. We concluded that RS with C‐Y⁹⁰ represents an important resource for the treatment of chronic haemophilic synovitis, markedly reducing joint bleeding frequency and pain, irrespective of the radiographic stage and inhibitor status.     

Long-term evaluation of radioisotope synovectomy with Yttrium 90 for chronic synovitis in Turkish haemophiliacs: Izmir experience

Since 2001 we have performed 105 radioisotope synovectomy (RS) in 65 children and young adults, age ranging from 3 to 25 years with a average of 15 years in Ege University Hospital, Izmir, Turkey. One fourth of cases were below 10 years of age. All patients had severe haemophilia A and B. Ten patients (17 joints) had high responder inhibitor. We prefer to use Yttrium 90 for all joints (5 mCi for knees; 2 mCi for others). The knees were injected in 56 cases, elbows in 24 cases, ankles in 23 cases and shoulders in two cases. Steroid injections were not preferred as the principle drug of choice. Mean follow-up period after procedure was 2 years (range: 6 months to 3.5 years). All inhibitor patients had satisfactory results. The best results were obtained in elbows than knees and ankles. Excellent rates (no bleeding) were observed in grade-II synovitis 84% for knees, 93% for elbows and 50% for ankles. Because of the excellent and good response (bleeding reduction to 75%), rates were 100% for knees and elbows and 92% for ankles. In six cases, repeated injections were given at 6-month interval and all of them had good results. The grading of synovitis seems to be an important parameter than the age of the patient. Even in patients below 10 years of age, outcomes are not satisfactory in all joints with grade-III vs. grade-II synovitis (12% vs. 73%). No serious complications were observed during and after procedure except two cases. A mild and transient inflammatory reaction was observed in the ankle. There was a minimal radioisotope leakage to superficial skin in the elbow. RS seems to be a safe and effective treatment for chronic synovitis causing recurrent joint bleedings.     

Radionuclide synovectomy and chronic haemophilic synovitis in Asians: a retrospective study

Radionuclide synovectomy has been identified as the procedure of choice in treating chronic haemophilic synovitis among Caucasian populations. Its effectiveness among East Asians has not been studied. A retrospective study was carried out on 12 Asian haemophiliacs who underwent 12 radionuclide synovectomies. The average follow-up was 30.7 months (range 6-55) for primary procedures. 32P chromic phosphate and 188Re-tin colloid were injected into target joints according to protocol. There was a significant 80% decrease in the median frequency of haemarthrosis from 1.4 per month (range 0.2-7.0) to 0.25 per month (range 0.0-1.8) (P<0.05). Half of the patients had excellent results by 1 year of synovectomy. The median factor usage for target joint haemarthrosis postsynovectomy was 792 units per month (range 0-3209) reduced significantly from a presynovectomy level of 1452 units per month (range 306-7125) (P<0.05). Patients also reported a reduction in joint pain scores, and an improvement in joint mobility and quality of life. The majority of patients were satisfied with the overall outcome of radionuclide synovectomy. Radionuclide synovectomy appears to be effective in reducing the incidence of target joint haemarthrosis and quantity of factor usage for such bleeds among Asians with haemophilic synovitis.     

Prophylaxis and treatment of chronic synovitis in haemophilia patients with inhibitors

Summary.  Prophylaxis is paramount to try to avoid the development of haemophilic synovitis. The best treatment for synovitis in patients with inhibitors is radioactive synoviorthesis (rhenium for ankle and elbows, yttrium for knees). With both methods (prohylaxis and radioactive synoviorthesis), we can delay the development of severe haemophilic arthropathy, that eventually will require major orthopaedic surgery.     

Intra-articular hyaluronic acid in the treatment of haemophilic chronic arthropathy

We report our preliminary experience with the use of hyaluronic acid (Synvisc) in 29 joints from 25 different haemophilic patients (17 knees, six shoulders, four ankles, one elbow and one hip). All the joints were grade III of our classification, characterized by synovial thickening, axial deformities and muscle atrophy (chronic arthropathy). In view of the very satisfactory results obtained with this procedure, we have substituted Synvisc for the previous use of intra-articular long-standing corticosteroids that we had been used for some years. This method is theoretically more physiological and does not destroy the joint cartilage further, as corticosteroids can.