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Radiosynovectomy for the Treatment of Haemophilic Synovitis in Paediatric Patients

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Radiosynovectomy for the Treatment of Haemophilic Synovitis in Paediatric Patients Radiosynovectomy for the Treatment of Haemophilic Synovitis in Paediatric Patients B. Thurlow1, L. Price1, N. Hubert2, M. Mathias2, L. Biassoni1 1Radiology Department, 2Haemophilia Centre, GOSH Why perform Radiosynovectomy in children? Background • In adults, radiosynovectomy is often used as a treatment option for inflammatory arthritis of the knee (such as rheumatoid arthritis), where the disease process involves an actively inflamed synovium [1]. • At GOSH radiosynovectomy is used to treat paediatric patients with haemophilic synovitis who have developed antibodies to the first line of treatment – prophylactic clotting factor replacement. • Due to the cost of prophylactic clotting factor replacement [2], a number of centres outside the UK have experience performing radiosynovectomy in paediatric patients with haemophilic synovitis. Haemophilia [3] www.lhprime.com Background • Haemophilia is an inherited bleeding disorder with low or absent levels of clotting factors [1]. Haemophilia A; which occurs due to a deficiency in clotting factor VIII (an essential blood-clotting protein that participates in blood coagulation) Haemophilia B; which occurs due to a deficiency in clotting factor IX. Haemophilia B is five times less common than haemophilia A Haemophilia C; which occurs due to a deficiency in clotting factor XI plasma thromboplastin antecedent Background Share the same symptoms X-Recessive Inheritance and inheritance patterns (ranging from mild to severe) Two chromosomes determine the sex of an individual X and Y. Genetic defect causing haemophilia is located on the X chromosome and not the Y chromosome. Daughter’s of a haemophiliac will inherit father’s X and be a carrier Son’s of a haemophiliac will not be affected at they inherit the father’s Y chromosome which does not carry the gene mutation. [4] Background Activation of clotting cascade Platelet Generation of Vasoconstriction Fibrinolysis Formation Fibrin Mesh Coagulation always follows a strict pattern – with each clotting protein (known as a coagulation factor) turned on in order. If one of the factors is missing then clotting cascade cannot happen. Injury to Vessels Normal s blood vessel constricts and r u results in Clotting factors c c bleeding activated Natural clotting helps Stable fibrin mesh O form platelet plug forms over sealed y r clot over platelet plug u j n I Haemophilia Lack of clotting Incomplete fibrin mesh This can lead to significant blood loss, factors means only allows bleeding to which can be severe and life-threatening a weak platelet continue. plug can form [5] Background • Clotting Factor Treatment Primary aim is to restore haemostasis. • On demand treatment is given following an injury or as part of planning surgery, for instance. This injection aims to boost the required clotting factors. It is used on a temporary basis to reduce the side effects of bleeding following an injury or during surgery. • Preventative treatment (maintain factor > 1%) aims to replace the missing or reduced Factor VIII with a man-made substitute. This is given regularly as an injection, often into a central venous access device such as an implantable port. [6] science photo library Background • Inhibitors often develop in young patients • Some patients with haemophilia develop antibodies to the clotting factor that they are receiving for treatment [3]. These are known as inhibitors. These patients are treated with bypassing products [7], Novo-Seven and FEIBA, however these drugs are extremely costly. Haemophilic Synovitis Background [8] [9] Blamb / Shutterstock Normal Joint Haemophilic Synovitis Background A chronic, self-perpetuating cycle of haemarthrosis Intra-articular haemorrhage Haemosiderin deposition Inhibition of proteoglycan synthesis and altered cartilage Synovial inflammation and metabolism hypertrophy Cartilage destruction and bone erosion Direct synovial invasion and Enzymatic degradation End stage Arthopathy Background Hyperplastic hemosiderin-laden, rust- brown synovium from hemophilic arthropathy. A, Gross. B and C, Microscopic (C shows Prussian blue stain for iron). [10] Vigorita VJ: The synovium. In Vigorita VJ [ed]: Orthopaedic pathology, Philadelphia, 2008, Lippincott Williams & Wilkins.) Background [11] [11] Moderate effusion in right knee and decrease in joint space, subchondral erosions and narrowed physis in comparison to other knee. The intercondylar notch in irregular and narrow. Arthrogram demonstrating inflamed synovium radiopaedia.org [12] Radiosynovectomy Treament Summary Radiosynovectomy (RS) is a well-established radionuclide therapy involving the intra-articular injection of a beta emitting colloidal preparation. www.radiologyassistant.nl [13] After intra-articular administration, the radiocolloids are phagocytized by macrophages of the inflamed synovium. This results in coagulation necrosis of the synovium and subsequently alleviation of symptoms. [14] focusedcollection.com / stock photo Service Development Service Development – Key findings from the literature • Due to the cost of prophylactic clotting factor replacement, a number of centres outside the UK have experience performing radiosynovectomy in paediatric patients with haemophilic synovitis. • Unlike clotting factor replacement, bypassing agents do not restore the normal pathways of haemostasis. Bypassing agents act by heightening thrombin generation despite the lack of platelet surface area. • Many physicians hold the view that bypassing agents do not have the same haemostatic efficacy as coagulation factors used for patients without inhibitors [16]. • A new drug Emicizumab (ACE910) has now become available which is unaffected by factor XIII inhibitors. However, depending on the access to the drug and the severity of the target joint, RSO remains an important treatment option [17]. • The available evidence demonstrates that radiosynovectomy is usually safe and effective at reducing the frequency of haemarthrosis and preventing progression to haemophiliac arthropathy [2, 15, 18, 19, 20]. • A serious complication of the therapy is migration of the radiopharmaceutical to organs such as the liver, spleen, lymph nodes and bone marrow [21]. • To reduce the likelihood of radiopharmaceutical migration the EANM guidance recommends joint immobilisation post procedure to reduce transport of particles via the lymphatic system, and joint puncture should be performed under imaging guidance (or by aspiration of the joint fluid for the knee) [22]. Service Development – Radionuclide Selection Radionuclide Application e- Half-life Range in soft tissue (days) (mm) maximum Y-90 (citrate) Large Kneeβ 2.67 11 mm Re-186(sulphide) MediumElbowβ / γ 3.72 3.7 mm Er-169 (citrate) Fingers and Toesβ 9.40 1 mm [22] https://eanm.org/publications/guidelines/gl_radio_synovectomy_1.pdf Conventional premise: select a radionuclide that has an electron range in tissue that is commensurate with the size of the synovium. Service Development – Radionuclide Selection Administered Activity Radionuclide Paediatric Administered Activity selection Ptients Paediatric Patients 90Y vs. 186Re [22] • Evidence in literature of paediatric • 90 EANM guidelines: Y for knee patients3.7 being mm treated for and 186Re for medium sized •Growth plate haemophilic synovitis. joints like the elbow and ankle. •Smaller joint volume • But wide age ranges and mean age • Max. beta energy 2.28 MeV •Potentially thinner reported, often unclear whether 90 186 Y vs. 1.02 MeV for Re. synovium activity scaling is used for children. • Total absorption plastic: • Some evidence in literature and 9.2 mm 90Y vs. 3.4 mm 186Re. How should EANM from other centres that activity is • 90Y larger particle size 50% procedural guidelines scaled to 50-100% of adult EANM >3µm vs. 186Re 95% >50nm. be adapted (if at all)? recommended levels [22] Clunie et al. 2003). Service Development • A multi-disciplinary approach was used to develop this service and was presented as a QIPP to the CCG. • As treatment options for this condition in children are limited, approval was based on making an effective treatment available with the combined benefit of a significant cost reduction through less prescribed clotting factor. Radiation Safety Radiation Safety [23] • Use Rhenium-186 (186Re): emits beta particles (β) and gamma rays (γ). • Physical half-life 3.8 days • Maximum range in soft tissue ~3.4mm Dose Limits non-classified worker Legislation Effective Equivalent Equivalent Equivalent Finger dose Dose Lens Eye Skin Extremities IRR99 6 mSv 50 mSv 150 mSv 150 mSv 370 MBq/procedure IRR17 6 mSv 15 mSV 150 mSv 150 mSv o 12 procedures/year o Handle unshielded syringe o Handle syringe for 5minutes Whole Body Dose (from patient) Extremity dose 140 mSv/year o 370 MBq max /procedure o 12 procedures/year Skin contamination o 30 cm from patient for 1 hour/procedure o 5 MBq drop Whole body gamma dose 0.2 mSv/year o On skin for 5 minutes (assuming all betas are contained with joint/patient) Skin dose 400 mSv Radiation Safety • 186Re drawn-up from vial in injection room. • Drawn-up with full PPE – gloves, gauntlets, apron, body badge and finger rings. • Drawn up behind acrylic shield with acrylic syringe shield on using long handled tongs. Syringe put in acrylic transport box to take to IR. • Never touch an unshielded vial or syringe even with gloves on. • If contamination is suspected the operator must be decontaminated immediately. [24] Patient Pathway Patient Pathway • Evidence of target joint (e.g. MRI/physio) Referral for RS from Haemophilia Centre • Poor response prophylaxis
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