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. [3] www.lhprime.com Background

• Haemophilia is an inherited disorder with low or absent levels of clotting factors [1]. ; which occurs due to a deficiency in clotting factor VIII (an essential blood-clotting protein that participates in blood )

Haemophilia B; which occurs due to a deficiency in clotting factor IX. 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 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 , 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

[9][8]

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 , 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 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 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 • Authorisation ARSAC holder

• Fit splint Pre-treatment Haemophilia Clinic • Baseline physio assessment • Risk Assessment by physics

• Consent obtained by IR RS Procedure inRS IR Procedure in IR • Radiologist, Radiographer and Physicist in IR • Performed under GA

Post-procedural imaging NM • Whole-body and SPECT-CT imaging

Inpatient stay on ward • Side room treated as supervised area

Post-procedural physio • 6 weeks, 3 months, 6 months and 12 months Imaging

Various imaging modalities are involved. The SPECT CT component is used to evaluate the bio-distribution of the radio-colloid following intra-articular administration.

IPSG scoring included in report T1 SE

In this example, the post therapy SPECT CT demonstrates that the radioisotope accumulates within the synovial joint space of the left ankle, correspondent to the pre-therapy MR.

As there is no migration from the joint capsule, the desired effect can be anticipated. Case Studies Case Studies 15 year old male. Severe Haemophilia A with late prophylaxis with bone joint synovitis.

T1 TSE_Sagittal T1 DIXON Fat-Suppression Both the T1 and T2 sequences return abnormal signal in keeping with hypertrophy and haemosiderin deposition. There is significant synovial enhancement indicating synovitis, however no destruction to the bony structures. T1SE T2TSEFS IPSG scoring Soft Tissue Changes: 6 Osteochondral Changes: 2 T2-STAR_Sagittal Total Score: 8

Injection of Re186 into the joint capsule under fluoroscopic guidance within interventional .

Needle position confirmed with contrast (omnipaque). Then, injection of Re186 into the joint capsule

Final flush with steroid to prevent needle track burns Case Studies

ANT POST

The whole body image demonstrates exclusive localisation of Re186 sulphate within the left elbow.

T1SE T2TSEFS The SPECT CT shows localisation of therapeutic activity at the site of synovial inflammation demonstrated on MRI. Case Studies 13 year old male. Haemophilia A. Severe involvement of left knee.

Supra-patellar pouch

T1SE T2TSEFS

The pre-therapy MR demonstrates focal osteo-cartilaginous destruction and haemosiderin deposit with synovial thickening and joint effusion.. Case Studies US guided left knee intra- articular needle placement

Needle Placement Skin surface

Fascia Plane

Joint Space Femoral Condyle

Tibial Condyle

n n o o i i t

Orientation B-Mode t c c e e r r i i D D

t d e a e e F H Longitudinal Plane Linear Probe 10-15MHz Case Studies

Injection of Re186 into the joint capsule under sonographic and fluoroscopic guidance within .

Prior to injection, needle position within the joint capsule. Case Studies

The SPECT CT shows localisation of the therapeutic radionuclide within the synovial joint space, mainly in the supra-patellar and left tibial condyle region(s).

This corresponds to the foci of haemosiderin deposit demonstrated on MR. Case Studies

However there is prominent distribution of the therapeutic radionuclide within the liver, with minimal splenic and bone marrow distribution, indicating moderate migration of Re186 from the joint.

Possible complication, despite significant planning. Dosimetry Assessment

VOI analysis

Radiopharmaceutical migration is a known risk for which patients/guardians consent [25]. The likelihood of radiopharmaceutical migration is reduced by immobilising the treated joint.

In this case, 218MBq was administered, the estimated activity in the liver and spleen was 98MBq and 6MBq.

The estimated additional lifetime risk of cancer as a result of the absorbed dose to the liver and spleen is 1.5% [26] Potential Factors in Migration • Joint retention stable after first scan? • Hypertrophied tissues / inflamed synovium the cause? Potential Factors for Patient’s pathological Particle Size Tracer state? Migration

Y-90 vs. Re-186 • Y-90 larger particles 50% >3µm • Cases of 40% migration without • Migration not evident in other immobilisation (pre-guidance) in literature patients (Re-186 used) • Joint flexion observed within splint after • Deepest limit of target volume recovering from GA. within therapeutic range for Y- • 90 and Re-186, but Re-186 Rigid immobilisation required, but splint spares bone dose. also needs to allow for swelling and preferable to avoid metal parts for imaging. • Could some patients have Local Anaesthesia? Outcome Measures Outcome Measures

Current policy drivers emphasise the need to provide value for publicly funded healthcare and ensure best use of finite resources [27]

The effectiveness of the radiosynovectomy as an intervention for haemophilic synovitis is evaluated against the following outcome measures;

Joint Bleed frequency Functional Measures Joint Pain Scores MR image scoring

A widely used scoring tool used of the 17‐point IPSG MRI scale, developed by the International Prophylaxis Study Group (IPSG) [28]. It is used to evaluate soft‐tissue changes and the osteochondral changes occurring in the most severely damaged bone end of a joint.

Most haemophilia centres in the UK monitor with joint assessment score performed by physiotherapists using the Haemophilia Joint Health Score (HJHS) as an objective measure of joint function [29].

SO-FIT multicentre randomised cross-over study, which assesses self-reported outcome measures of subjective/ perceived physical function and health-related quality of life (HRQoL) [30]. Future Research Aims Future Research Aims

Treatment planning

EC Directive 2013/59/Euratom [31] stipulates that all radiotherapeutic exposures of target volumes should be individually planned and their delivery appropriately verified.

The published evidence from centres performing radiosynovectomy in paediatrics for haemophilic synovitis, indicate little deviation or optimisation from the suggested EANM procedural guidelines.

At GOSH, a research project is currently being undertaken to investigate the absorbed radiation dose to target and non-target tissues.

A future aim is to prescribe a target absorbed dose to achieve a desired clinical outcome, and scale the administered radioactivity accordingly. Thankyou for listening References

[1] Mödder G., Radiosynoviorthesis (Radiation Synovectomy), Clinical Nuclear ; Chapter 29 Schneider P, Radiosynovectomy –Science and practise in Radionuclide and hybrid bone imaging ( Fogelman I et al Springer’s 2013 [2] Fijnvandraat K., Cnossen M., Leebeek F., Peters M., (2012) Diagnosis and management of haemophilia, British Medical Journal, Vol. 344, No. 7855, p36-40. [3] http://www.lhprime.com/news/is-hemophilia-contagious/ [4] https://www.nuh.com.sg/ktp-nucmi/health/diseases-and-conditions/cancer-and-blood-problems/haemophilia.html [5] https://i.pinimg.com/originals.jpg [6] https://fineartamerica.com/featured/red-blood-cells-and-antibodies-artwork-science-photo-library.html [7] Hoffman M., Dargaud Y., (2012) Mechanisms and monitoring of bypassing agent therapy, J Thromb Haemost. Vol10(8), p1478-85 [8] https://www.news-medical.net/health/What-is-Cartilage.aspx [9] Vulpen L., Roosendaal G., Sweder van Asbeck B., Mastbergen S., Lafeber F., Schutgens R., (2015), The detrimental effects of iron on the joint: a comparison between haemochromatosis and haemophilia, Journal of , vol. 68, p592 [10] Vigorita VJ: The synovium. In Vigorita VJ [ed]: Orthopaedic pathology, Philadelphia, 2008, Lippincott Williams & Wilkins.) [11] Lichman M., Kipps T., Seligsohn U., Kaushansky K., Prchal J., Williams Haematology, 8th edition, http:accessmedicine.com [12] https://radiopaedia.org/articles/haemophilic-arthropathy?lang=gb [access: Feb 2019] [13] http://www.radiologyassistant.nl/en/p50cf8392cbd97/us-guided-injection-of-joints.html#in50d5d2f9808cd [14] https://focusedcollection.com/176885094/stock-photo-computer-illustration-macrophage-white-blood.html [15] Clunie GPR, Ell PJ. (1995) A survey of radiation synovectomy in Europe, 1991–1993. Eur J Nucl Med; 22:970–976. [16] Tjønnfjord Pål Andre Holme, G. E. (2007). Factor eight inhibitor bypass activity (FEIBA) in the management of bleeds in hemophilia patients with high-titer inhibitors. Vascular Health and Risk Management (Vol. 3). References

[17] Young G., Callaghan M., Dunn A., Kruse-Jarres R., Pipe S., (2018) Emicizumab for hemophilia A with factor VIII inhibitors, Expert Rev Hematol. Nov;11(11), p835-846. [18] Rodriguez-Merchan, E. C., H. De la Corte-Rodriguez, and V. Jimenez-Yuste, 2014, Radiosynovectomy in haemophilia: long-term results of 500 procedures performed in a 38-year period: Thromb Res, v. 134, p. 985-90. [19] Turkmen, C., O. Kilicoglu, F. Dikici, F. Bezgal, S. Kuyumcu, O. Gorgun, O. Taser, and B. Zulfikar, 2014, Survival analysis of Y-90 radiosynovectomy in the treatment of haemophilic synovitis of the knee: a 10-year retrospective review: Haemophilia, v. 20, p. e45-50. [20] Zulfikar, B., C. Turkmen, O. Kilicoglu, F. Dikici, F. Bezgal, O. Gorgun, and O. Taser, 2013, Long-term outcomes in haemophilic synovitis after radiosynovectomy using rhenium-186: a single-centre experience: Haemophilia, v. 19, p. 275-80 [21] Turkmen, C., S. Ozturk, S. N. et al (2007_, Monitoring the genotoxic effects of radiosynovectomy with Re-186 in paediatric age group undergoing therapy for haemophilic synovitis: Haemophilia, v13 57-64. [22] Clunie, G., M. Fischer, and EANM, 2003, EANM procedure guidelines for radiosynovectomy: Eur J Nucl Med Mol Imaging, v. 30, p. 12-16 (https://eanm.org/publications/guidelines/gl_radio_synovectomy_1.pdf) [23] CIS Bio international. (2018). Rhenium (186Re)-Sulfid, Cis Bio international - compendium.ch. Retrieved February 21, 2019, from https://compendium.ch/mpro/mnr/25071/html/de?Platform=Desktop [24] Schneider, P. F., J. Biko, L. Varazashvili, and S. Neumann, 2014, β‐Radiation exposure to fingertips after using a trained routine application method during radiosynovectomy: Nucl Med Commun, v. 35, p. 1175-8. [25] van der Zant, F. M., Z. N. Jahangier, J. D. Moolenburgh, W. van der Zee, R. O. Boer, and J. W. Jacobs, 2004, Radiation synovectomy of the ankle with 75 MBq colloidal 186rhenium-sulfide: effect, leakage, and radiation considerations: J Rheumatol, v. 31, p. 896-901. [26] https://www.nap.edu/catalog/11340/health-risks-from-exposure-to-low-levels-of-ionizing-radiation [27] The NHS Constitution (2015), the NHS belongs to us all https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/480482/NHS_Constitution_WEB.pdf [28] Lundin B., Manco-Johnson M., Ignas D., et al (2012) An MRI scale for assessment of haemophilic arthropathy from the International Prophylaxis Study Group, Haemophilia, Volume 18, Issue 6, p962-970 [29] McLaughlin P., Bladen M., Holland M., Khair K., (2014) Joint assessment in haemophilia – current physiotherapist practice in the UK, The Journal of Haemophilia Practice, 1(3), p9-13. References

[30] Khair K., Bladen M., Holland M., (2014) Physical function and quality of life in adolescents with haemophilia (SO-FIT study), The journal of Haemophilia Practice, 1(2), p11-14. [31] EC Directive 2013/59/Euratom (https://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L:2014:013:0001:0073:EN:PDF)