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.     

What patient,joint and isotope characteristics influence the response to radiosynovectomy in patients with haemophilia?

Summary. The literature describes radiosynovectomy (RS) as a good non‐surgical option for reducing synovial membrane size and thus the number of haemarthrosis episodes. However, there are still many aspects concerning the beneficial effects of RS that have not been quantified. A total of 156 radiosynovectomies (RS) were performed in 104 joints corresponding to 78 haemophiliacs (yttrium‐90, rhenium‐186). The mean patient age was 18 years. In another study involving the same group of patients, the parameters that improved most after RS were pain and haemarthrosis, followed by the World Federation of Hemophilia clinical score, muscle strength and range of movement (ROM). 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, synovial membrane size, the type of joint (elbow, knee and ankle), previous physical activity or lack of activity, the prior presence or absence of radiographic signs of joint degeneration (arthropathy) or the isotope used. RS is effective in treating haemophilic synovitis and may require 1–3 injections (RS‐1, RS‐2 and RS‐3) spaced 6 months apart. Following RS‐1, the knee had a 3.4‐ and 3.2‐fold greater risk of not improving in terms of pain, compared with the elbow and ankle, respectively. Regarding ROM, lesser improvement was recorded after RS‐1 in cases of severe haemophilia and the ankle. In other words, severe haemophilia implies a 2.1‐fold greater risk of no improvement in ROM compared with mild and moderate haemophilia. In addition, the ankle presented a 6‐fold greater risk of not improving in terms of ROM compared with the elbow and knee. RS affords effective treatment of chronic haemophilic synovitis. RS is effective in all patient groups, independently of the presence of circulating inhibitor antibody, the type of joint involved, the degree of synovial membrane hypertrophy and the presence of radiographic findings of joint degeneration (arthropathy).     

Haemophilic synovitis: basic concepts

Summary.  Chronic synovitis is a serious complication of haemophilia that should be understood to avoid or minimize its consequences (articular damage and joint degeneration). Haematological prophylaxis and treatment are paramount during the life of people with haemophilia. However, as about 80% of bleedings in haemophilia affect the musculo-skeletal system, the role of orthopaedic surgeons, rehabilitation physicians and physiotherapists is very important in the context of the multidisciplinary team. Synovitis can firstly be prevented and/or controlled with medical treatment and then be treated by synoviorthesis or surgical synovectomy. In this article, the author reviews some current basic principles on the prevention and treatment of haemophilic synovitis to avoid further development of joint destruction (haemophilic arthropathy).     

Ankle surgery in haemophilia with special emphasis on arthroscopic debridement

Summary. Various conservative options are available to treat ankle problems in haemophilia, which achieve a high rate of satisfactory results in the majority of cases. They are usually employed in combination and include the use of patellar tendon bearing (PTB) orthoses and radiosynoviorthesis. The effect of the PTB orthoses is that it allows the patient to walk without weight bearing of the ankle. Radiosynoviorthesis can be performed in cases of haemophilic arthropathy of the ankle, provided there is at least a minimal degree of synovitis within the joint, with a 75% of satisfactory results. If the conservative options fail, surgical intervention can be indicated. Alternatives to total ankle arthroplasty or arthrodesis include arthroscopic debridement, removal of osteophytes of the anterior aspect of the distal tibia and peri‐articular osteotomies to correct angular, rotational or translational malalignment. Ankle arthrodesis is the standard technique for end‐stage ankle arthropathy. Arthroscopic debridement of the ankle with haemophilic arthropathy can offer temporary relief; however, it is important to stress to patients that the degree of improvement is limited. The complication rate in ankle arthroscopy is high compared with other joints, which is especially true for neurological complications and postoperative infections. Orthopaedic procedures are not very frequent in the haemophilic ankle, because the majority of problems can be solved satisfactorily by conservative means (radiosynoviorthesis and PTB orthosis).     

Orthopaedic surgery of haemophilia in the 21st century: an overview

Close co-operation between haematologists, orthopaedic surgeons, rehabilitation physicians and physiotherapists is essential for obtaining satisfactory results after orthopaedic procedures that are performed on haemophilic patients. Although continuous prophylaxis could avoid the development of the orthopaedic complications of haemophilia that we still see in the 21st century, such a goal has not been achieved so far, not even in developed countries. Therefore, orthopaedic surgeons are still required to carry out many different surgical procedures, such as arthrocentesis, synoviorthesis, synovectomies, tendon lengthening, articular debridements, alignment osteotomies, joint arthroplasties, nerve releases, opening of compartment syndromes, removal of pseudotumours and osteosynthesis of fractures. Furthermore, the emergence of human immunodeficiency virus has meant that immunosuppressed patients in developed countries sometimes require an arthrotomy for the treatment of spontaneous septic arthritis, or the surgical drainage of a spontaneously infected haematoma (abscess). In addition, they have a high risk of postoperative infection after any surgical procedure, particularly a joint arthroplasty.     

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.     

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.     

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.     

Radiosynovectomy in patients with chronic haemophilic synovitis: when is more than one injection necessary?

One hundred and fifty‐six radiosynovectomies (RSs) were performed in 104 joints of 78 haemophilic patients diagnosed with chronic haemophilic synovitis. Mean patient age was 18 yr. Previous studies on the same group of patients indicated that RS is an effective procedure for treating chronic haemophilic synovitis, which may require the performance of 1–3 injections (RS‐1, RS‐2, RS‐3), with a 6‐month interval between them. Those studies also revealed that the parameters showing the greatest improvement after RS were pain and haemarthrosis, followed by the World Federation of Haemophilia (WFH) clinical score and muscle strength and range of motion. Such studies also demonstrated that the improvement achieved further to RS is independent of the patient’s age, the type and severity of haemophilia, the previous haematologic treatment regime administered (on demand or prophylactic), the presence or absence of a circulating inhibitor, the patients’ previous level or activity (or inactivity), the presence or absence of previous arthropathy (joint degeneration), of the isotope used (yttrium‐90 or rhenium‐186) and of the appearance or otherwise of RS‐derived complications. In this study, we looked into the potential relationship between the type of joint treated and the degree of synovitis present with the need of one or more further RSs, and we found that the knee requires more injections than the elbow or the ankle and that the more severe synovites require a higher number of RS procedures.     

Outcome of surgical concepts in haemophilic arthropathy of the hindfoot

The ankle is one of the most frequent joint affected by haemophilia, in the second decade of life it can be considered as the most common site for haemophilic arthropathy. The aim of this study is to evaluate the results of 15 surgical interventions of the hindfoot performed on 11 patients. Twenty-seven of 70 male patients suffering from haemophilia were treated for haemophilic arthropathy of the hindfoot. We performed 15 operations on 11 patients with a mean age of 33.5 (range: 10-53) years. The surgical treatment consisted of 15 operations, 12 of which concerned the talocrural joint (six synovectomies, three radiosynoviorthesis, four arthrodeses, one achilles tendon lengthening) and one the talocalcaneonavicular joint (one triplearthrodesis). The arthrodeses of the talocrural joint were undertaken by screw, the triplearthrodesis by clamp fixation. The synovectomies were all late synovectomies and performed by open means. The mean follow-up period was 32.0 (range: 12-84) months. The mean age at surgery was 29.6 (range: 8-51) years. No perioperative complications were registered when adequate replacement therapy was carried out. The consolidation of the arthrodeses was accomplished within 8-12 weeks. All synovectomies stopped or reduced significantly recurrent joint bleeding. With both procedures we achieved pain relief and walking ability improvement. The aim of synovectomy is to reduce bleeding episodes. If synovectomy can halt the progression of the haemophilic arthropathy is controversially discussed, especially when surgery was carried out in the presence of an established arthropathy. If synovectomy fails, the arthrodesis proves to be a good treatment option.     

Management of haemophilic arthropathy

Summary.  Despite the tremendous benefit offered by primary prophylaxis, recurrent joint bleeding with progression to chronic synovitis and haemophilic arthropathy is still a daily concern for the multidisciplinary health care teams managing patients with severe haemophilia or haemophilia complicated by inhibitor development. Advanced stages of arthropathy could be prevented by regular assessment of musculoskeletal status and thus early detection of symptoms, daily rehabilitation exercises at home, and implementation of appropriate physiotherapy and medical training. Patient's education and psychological counselling are crucial. New tools such as magnetic resonance imaging are promising for the monitoring of these patients and might promote early detection of arthropathy and thus appropriate preventive measures to avoid further joint deterioration can be implemented. Medical synovectomy such as radionucleide synoviorthesis is a simple and non-invasive procedure that often delays the need for surgery which despite considerable improvement in techniques and postoperative rehabilitation remains a high-risk strategy in patients with severe haemophilia, especially those with inhibitors. In these high risk patients, availability of specific clotting factors such as activated prothrombin complex concentrate (FEIBA^®, Baxter, Vienna, Austria) and more recently, recombinant factor VIIa (rFVIIa, NovoSeven^®, Bagsvaerd, Denmark) has allowed to perform effective and safe orthopaedic procedures. The on-going EUREKA study will undoubtedly provide additional information about the optimal use of rFVIIa in this context.     

Is on‐demand treatment effective in patients with severe haemophilia?

Summary. On‐demand therapy enables stopping haemorrhages rapidly, reducing joint pain and restoring joint mobility, but does not prevent the beginning and subsequent development of haemophilic arthropathy. The main objective of this study was to identify the clinical and orthopaedic status of severe haemophilic patients with bleeding phenotype receiving on‐demand treatment in Spain. We conducted an epidemiological, observational, retrospective study, recruiting 167 patients from 36 centres (92% of them with haemophilia A), median age at enrolment of 35 years. Forty per cent of the patients received a combination of on‐demand and short‐term prophylaxis regimen; the rest was under on‐demand treatment. One hundred and forty‐five patients (87%) reported at least one bleeding episode and 22 (13%) of the biologically severe patients had no bleeding phenotype. Seventy‐one per cent of the studied population presented established haemophilic arthropathy, reaching 80% if we exclude patients without bleeding phenotype. Forty‐three per cent of these patients had one or two joints affected, 28% of them had three or four affected joints, 20% reported five or six affected joints and 9% more than six injured joints. An increase in established haemophilic arthropathy with age was observed. Forty‐six patients underwent orthopaedic surgery at least once. These data show that on‐demand therapy is not effective in preventing the development of haemophilic arthropathy in severe haemophilic population with bleeding phenotype. Therefore, we suggest that the optimal treatment in these patients should be based on prophylaxis. We recommend analysing the reasons for ending prophylaxis, in case its reinstatement should be necessary.     

The role of physiotherapy after total knee arthroplasty in patients with haemophilia

Summary. With the availability of clotting factor concentrates, advances in surgical techniques, better implant design, and improvements in postoperative management, total knee arthroplasty has become the treatment of choice for haemophilia patients suffering from end‐stage haemophilic knee arthropathy. The success of this surgery is also dependent on close collaborations among the orthopaedic surgeon, the haematologist and the physiotherapist. Although haemophilic patients undergoing this surgery would likely benefit from a targeted rehabilitation programme, its specificities, modalities and limitations have thus far not been extensively studied. Employing the published data of rehabilitation after knee prosthesis in patients with osteoarthritis and haemophilic arthropathy along with clinical experience, the authors present a comprehensive and original review of the role of physiotherapy for patients with haemophilia undergoing knee arthroplasty.     

Cartilage damage in the haemophilic joints: pathophysiology, diagnosis and management

Intra-articular bleeding affects the metabolism and repair of articular cartilage. Biomechanical data have shown that blood causes harmful effects on overall cartilage function under loading conditions. Therefore, haemophilic patients suffering a haemarthrosis should be subjected to blood aspiration (arthrocentesis) to prevent cartilage damage. MRI and ultrasonography have shown themselves to be excellent noninvasive tools for the evaluation of early cartilage damage that remains undetectable by conventional radiography in haemophilic patients. Prophylaxis with the deficient factor can prevent cartilage deterioration and reduce the incidence of joint haemorrhage in children with haemophilia. Radiosynovectomy has proved to be a highly effective procedure to decrease both the frequency and the severity of recurrent intra-articular bleeding episodes. Nowadays, the most usual surgical procedures for treating articular cartilage defects (cartilage repair) include abrasion chondroplasty, microfracture, mosaicplasty, autologous chondrocyte implantation (ACI), and matrix-induced ACI. In small defects (<2-4 cm(2)), ostechondral autograft or microfracture are the recommended options. In large defects (>2-4 cm(2)), ACI or osteochondral allograft are indicated. However, these techniques have not been applied in haemophilic patients because inflammatory conditions and advanced degenerative change (>50% joint space narrowing) are contraindications for cartilage repair. Thus, prevention of cartilage damage is paramount in haemophilia. The definitive remedy for advanced cartilage damage is either (knee or hip) replacement or (ankle) arthrodesis. Primary prophylaxis and radiosynovectomy are the best alternatives at our disposal to protect our patients against cartilage damage and arthropathy in haemophilic joints.     

Point‐of‐care musculoskeletal ultrasound is critical for the diagnosis of hemarthroses,inflammation and soft tissue abnormalities in adult patients with painful haemophilic arthropathy

We previously demonstrated in adult patients with haemophilia (PWH) that hemarthrosis is present in only ~1/3rd of acutely painful joints by using point‐of‐care‐musculoskeletal ultrasound (MSKUS). Therefore, other unrecognized tissue abnormalities must contribute to pain. Using high resolution MSKUS, employing grey scale and power Doppler, we sought to retrospectively (i) investigate soft tissue abnormalities in painful haemophilic joints and (ii) to determine to what extent MSKUS findings, functional or radiographic joint scores correlate with biomarkers of inflammation in PWH. Findings were correlated with Hemophilia Joint Health Scores (HJHS), Pettersson scores, high sensitivity C‐reactive protein and von Willebrand factor activity and antigen levels. A total of 65 MSKUS examinations for acute and chronic joint pains were performed for 34 adult haemophilia patients, mostly for chronic joint pains (72.3%). The most prominent findings (66.5%) pertained to inflammatory soft tissue changes including synovitis, tendinitis, enthesitis, bursitis and fat pad inflammation. Effusions were present in 55.5% and 46.8% of MSKUS performed for acute and chronic pain, respectively. Of those, 90.0% were bloody during acute and 47.6% during persistent pains. While inflammatory biomarkers correlated well with overall HJHS and total Pettersson scores (P < 0.05), they did not differ between those patients with synovitis and those without. MSKUS is emerging as an important modality to diagnose treatable musculoskeletal abnormalities contributing to pain in haemophilic arthropathy, and therefore seems critical for a personalized approach to haemophilia care. The role of biomarkers in this setting remains less clear and requires further investigation.     

Celecoxib in the treatment of haemophilic synovitis, target joints, and pain in adults and children with haemophilia

Joint haemorrhage and subsequent haemophilic arthropathy are significant complications of haemophilia. The pathophysiology involves inflammation and angiogenesis. Cyclo-oxygenase 2 (COX-2) inhibitors have anti-inflammatory, anti-angiogenic and analgesic properties yet do not affect platelet function in the manner of traditional non-steroidal anti-inflammatory drugs. We have previously reported the successful use of rofecoxib in the management of haemophilic arthropathy and currently report our use of celecoxib. A retrospective chart review was conducted of all patients with haemophilia A or B seen at the Children's Hospital of Orange County and treated with celecoxib for chronic synovitis, target joint or pain. Efficacy in chronic synovitis and pain reduction was judged subjectively as effective, partially effective or ineffective. Efficacy in resolution of target joints was judged as effective if the target joint resolved or ineffective if it did not resolve. Twelve patients between 9 and 54 years old were treated for a total of 14 courses of celecoxib treatment. All courses were evaluated for safety and efficacy. Celecoxib was used in eight patients with chronic synovitis, three patients with pain, and in one patient with a target joint on three occasions. A response was noted in seven of eight for synovitis, three of three with pain, but no response in the target joint patient. No serious adverse events including hypertension were observed. This is the first study evaluating celecoxib as adjunctive therapy in haemophilia and suggests that celecoxib is safe and effective in treating chronic synovitis and joint pain similar to the previous study of rofecoxib.     

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.     

The history of synoviorthesis in haemophilia

The history of synoviorthesis and recent studies have shown that it is a safe procedure and that the results are similar to those seen following open surgical and arthroscopic synovectomy. If the safety of this procedure is definitively proven in long‐term studies it will become the procedure of choice for treatment of recurrent haemarthroses and synovitis. That is, until the time when the haematologists and geneticists eliminate the need for orthopaedic intervention in the care of persons with haemophilia.     

Is joint effusion on MRI specific for haemophilia?

Magnetic resonance imaging (MRI) scores for haemophilic arthropathy are useful for evaluation of early and moderate arthropathy. The most recent additive International Prophylaxis Study Group (IPSG) MRI scale for haemophilic arthropathy includes joint effusion. However, it is unknown whether joint effusion is haemophilia specific. Correct interpretation of joint effusion is needed for outcome assessment of prophylactic therapies in haemophilia care. The aim of this study was to compare joint effusion on MRI between young adults with haemophilia and healthy controls. MRI's of both knees and ankles of 26 haemophilic patients (104 joints) and 30 healthy active men (120 joints) were assessed. Scans in both groups were performed in 2009/2010 and 2012 respectively. Joint effusion was measured and scored according to the MRI atlas referred by the IPSG MRI scale for haemophilic arthropathy. Median age of haemophilic patients and healthy controls was 21 and 24 years respectively. In haemophilic patients 23% of knees and 22% of ankles showed joint effusion. Healthy controls had significantly more positive scores for knee effusion (67%, P < 0.01) and a comparable scores for effusion in the ankle (17%). Joint effusion according to criteria of the IPSG MRI scale was observed significantly more often in knees of healthy controls, while findings in ankles were similar. These data suggest that joint effusion in knees and ankles is not haemophilia specific. Inclusion of joint effusion in the MRI scale is expected to reduce its specificity for haemophilic arthropathy.