Fischer, Kathelijn

Foppen, Wouter

Timmer, Merel A

van Leeuwen, Flora H P

Utrecht University Repository

Received: 27March 2024 Revised: 29 April 2024 Accepted: 20May 2024DOI: 10.1111/hae.15058COMMEN TAR YThe relevance ofMRI findings in joints of persons withhaemophilia: Insights from the last decadeWouter Foppen1 Flora H. P. van Leeuwen1 Merel A. Timmer2Kathelijn Fischer21Department of Radiology andNuclearMedicine, UniversityMedical Center Utrecht, Utrecht University, Utrecht, The Netherlands2Center for Benign Hematology, Thrombosis and Haemostasis, Van Creveldkliniek, UniversityMedical Center Utrecht, Utrecht University, Utrecht, The NetherlandsCorrespondenceWouter Foppen, Heidelberglaan 100, 3584 CXUtrecht, GAUtrecht, The Netherlands.Email: w.foppen@umcutrecht.nlKEYWORDShaemophilia, hemarthrosis, joint diseases, magnetic resonance imaging, osteochondral abnormalities, outcome assessment, subclinical bleedingMost bleeding episodes in persons with haemophilia (PwH) occurin the large synovial joints (elbows, knees, and ankles). Recurrentjoint bleeding eventually leads to irreversible haemophilic arthropa-thy, which causes pain, reduced functionality, and thus reducedquality of life. Prophylactic treatment prevents most bleedingepisodes.1 Even in the absence of clinically overt joint bleeding,long-term progression to arthropathy is observed. Subclinical bleed-ing and inflammation are therefore thought to contribute to thedevelopment of arthropathy.2–4 Detection of these subclinical pro-cesses is becoming increasingly important in the prevention ofarthropathy in PwH as overt spontaneous joint bleeding is almostcompletely avoided by prophylaxis with new (non-factor) replacementtherapies.5Magnetic resonance imaging (MRI) is considered the gold standardfor evaluation of early blood-induced joint changes in PwH. In 2005,the International Prophylaxis Study Group (IPSG) published compati-ble scales for progressive and additive MRI assessment based on theDenver MRI score and the European MRI score.6 These scores werecombined in a comprehensive scoring scheme in 2012.7 Based on anappraisal of the original IPSG MRI scale,8 the score is now updatedto the IPSG MRI Scale version 2.0 by Lundin and colleagues.9 To pro-vide more insight on the clinical relevance of MRI findings, we providean overview of research on the clinical relevance of MRI findingsevaluated by IPSGMRI Scale version 2.0.This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in anymedium, provided the original work is properly cited, the use is non-commercial and nomodifications or adaptations aremade.© 2024 The Author(s).Haemophilia published by JohnWiley & Sons Ltd.1 MRI DETECTS PREVIOUS (SUBCLINICAL)BLEEDINGSince the 1980s, there have been suspicions that chronic microbleed-ing or subclinical bleeding into the joints can cause arthropathy.10,11Manco-Johnson et al. found further evidence for this hypothesis afterobserving haemosiderin deposits and other joint changes on MRI injoints without any history of prior bleeding in a prospective clinicaltrial.2 Potentially, prophylaxismay reduce subclinical bleedingand jointdeterioration. Worth noting, haemosiderin deposits in joints withouta history of bleeds were observed in 26% of Canadian children withsevere haemophilia treated with tailored primary prophylaxis,12 in14% of Dutch adults with non-severe haemophilia (94% treated ondemand),13 and in 16% of Dutch adolescents and adults with severehaemophilia on prophylaxis.14 These observations implicate that sub-clinical bleeding occurs in non-severe haemophilia and is not fullyprevented by prophylaxis in severe haemophilia.The (longer-term) clinical consequences of the observed signs ofprevious subclinical bleeding are a topic of interest. Haemosiderinaccumulates in the synovial membrane and a previous study observedthat haemosiderin deposits were accompanied by synovial hypertro-phy in 88% of joints.15 In addition, synovial hypertrophy was a strongand independent predictor for 5-year joint bleeding (OR = 10.1).15Another study showed that the presence of synovial hypertrophy orHaemophilia. 2024;30:877–879. wileyonlinelibrary.com/journal/hae 877878 FOPPEN ET AL.haemosiderin on interval MRIs was associated with new osteochon-dralMRI changes at follow-up (OR= 4.7 and 5.3 respectively).16 Theseresults emphasize the importance of monitoring joint status in PwHusing imaging whichmay be used to guide treatment.2 MRI EVALUATION OF JOINT EFFUSIONSThe IPSG MRI Scale version 2.0 includes the evaluation of jointeffusion/hemarthrosis.9 Evaluation of joint effusion may be relevantforPwHduring anacute episode toevaluate thepresenceof apotentialbleed and may be incorporated in MRI interpretation for clinical care.However, joint effusion is not haemophilia specific and is not associatedwith 5-year joint bleeding or progression of arthropathy on radio-graphs according to previous studies using the IPSG MRI criteria.15,17As a result, the incorporation of joint effusion dilutes the disease speci-ficity for long-term outcome assessment of haemophilic arthropathy.Future outcome studies using the IPSG MRI Scale version 2.0 may takethis into account by performing additional analyses without incorpora-tionof effusion in the soft tissue subscore, or the sumscore (summationof soft tissue and osteochondral subscores).The accuracy of conventional MRI protocols in differentiatingbetween physiological joint fluid andminor bleeding has not been con-clusively determined.18,19 Recently, it was shown that MRI T1 andT2 relaxometry could quantitatively distinguish synovial fluid fromhaemorrhagic joint effusion in vitro. The lowest detectable blood con-centrationswere5%usingT2mapping at 3TeslaMRI and10%usingT1mapping at 1.5 Tesla MRI.20 In vivo evaluation of the T2-relaxometrymethod at 3 Tesla MRI showed good feasibility and reproducibility.21The T2-relaxometry method needs to be validated in patients with(suspected) joint bleeding to evaluate the performance in a clinical set-ting. After validation, these methods could be incorporated into MRIprotocols to evaluate joint effusions non-invasively for evaluation ofdifficult clinical cases or research purposes.3 MRI EVALUATION OF OSTEOCHONDRALABNORMALITIESThe IPSG MRI Scale version 2.0 evaluates the following osteochondralchanges separately; bone erosions and/or subchondral endplate irreg-ularities, subchondral cysts, and cartilage degradation.9 The updateddefinitions aimed to overcome the methodological challenges in theevaluation of osteochondral changes. Whether the adjustments inthe IPSG MRI Scale version 2.0 would alter previous MRI scores usingthe original IPSG MRI scale remains to be evaluated. Nonetheless, itis important to specifically mention which version of the MRI scorewas used for the manuscript in preparation to allow for a reliablecomparison of studies.Osteochondral changes may also result from normal wear and tearand are may be unrelated to joint bleeding in PwH. In a system-atic review and meta-analysis, 5397 asymptomatic uninjured knees of4751 adults were evaluated. The pooled prevalence of asymptomaticcartilage defects was 11% for subjects< 40 years and 43% for subjects≥40 years.22 In PwH, self-reported joint bleeds were associated withnew osteochondral changes on MRI during follow-up.16 These maylater on progress into more severe arthropathy as observed in anotherstudy that showed that osteochondral MRI abnormalities werestrongly associated with the development of abnormalities on x-rays 5years later.15 These x-ray abnormalities are negatively associated withphysical functioning.23 Therefore, evaluation of early osteochondralchanges using MRI is important in the outcome assessment of currentfactor replacement therapies and new non-replacement therapies.4 MRI FOR RESEARCH AND CLINICAL CAREAs discussed above,MRI provides a complete overview of the joint sta-tus in PwH. Evaluated items of the new IPSG MRI Scale version 2.0maybe clinically relevant as well. In clinical practise, MRI is especially use-ful for problem solving in cases where x-rays and ultrasound could notprovide sufficient detail or understanding of the clinical complaints.Although formal scoring of MRIs may be unnecessary for clinical prac-tice, reporting on items of the IPSG MRI Scale is recommended. Asimplified version the new IPSGMRI Scale version 2.0 for clinical usage isunder development by the IPSG’s Imaging ExpertWorking Subgroup.9In summary, accumulating evidence from the past decade showsthe relevance and potential of MRI for the evaluation of haemophilicarthropathy. The new IPSG MRI Scale version 2.0 facilitates standard-izedMRI scoring of haemophilic arthropathy in future outcome studiesin PwH.CONFLICT OF INTEREST STATEMENTF.L. declares no conflicts of interest.W.F. received research grants fromNovoNordisk and Pfizer, all paid to the institution, and performed con-sultancy activities for Pfizer. M.T. received research grants from NovoNordisk and SOBI and performed consultancy activities for SOBI, allpaid to the institution. K.F. has received speaker’s fees fromBayer, Bax-ter/Shire, Sobi/Biogen, CSL Behring and Novo Nordisk; has performedconsultancy for Bayer, Biogen, CSL Behring, Freeline, Novo Nordisk,Roche and Sobi; and has received research support from Bayer, Bax-ter/Shire, Novo Nordisk, Pfizer and Biogen, all fees were paid to theinstitution.DATA AVAILABILITY STATEMENTData sharing is not applicable to this article as no new data werecreated or analysed in this study.ORCIDWouter Foppen https://orcid.org/0000-0003-4970-8555FloraH. P. van Leeuwen https://orcid.org/0000-0002-8384-4385Merel A. Timmer https://orcid.org/0000-0003-1910-999XKathelijn Fischer https://orcid.org/0000-0001-7126-6613REFERENCES1. Berntorp E, Fischer K, Hart DP, et al. Haemophilia.Nat Rev Dis Primers.2021;7(1):45. 13652516, 2024, 4, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/hae.15058 by Cochrane Netherlands, Wiley Online Library on [17/07/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons LicenseFOPPEN ET AL. 8792. Manco-Johnson MJ, Abshire TC, Shapiro AD, et al.. Prophylaxis ver-sus episodic treatment to prevent joint disease in boys with severehemophilia.N Engl J Med. 2007;357:535-544.3. Den Uijl IEM, De Schepper AM, Camerlinck M, et al. Magnetic reso-nance imaging in teenagers and young adults with limited haemophilicarthropathy: baseline results from a prospective study. Haemophilia.2011;17(6):926-930.4. NijdamA, FoppenW, de Kleijn P, et al. Discontinuing early prophylaxisin severe haemophilia leads to deterioration of joint status despite lowbleeding rates. 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Pettersson H, Nilsson IM, Hedner U, Noréhn K, Ahlberg A. Radiologicevaluation of prophylaxis in severe haemophilia. Acta Paediatr Scnd.1981;70:565-570.11. Soreff J, BlombackM. Arthropathy in children with severe hemophiliaA. Acta Paediatr Scand. 1980;69:667-673.12. Kraft J, Blanchette V, Babyn P, et al. Magnetic resonance imaging andjoint outcomes in boys with severe hemophilia A treated with tailoredprimaryprophylaxis inCanada. J ThrombHaemosts. 2012;10(12):2494-2502.13. Zwagemaker AF, Kloosterman FR, Hemke R, et al. Joint sta-tus of patients with nonsevere hemophilia A. J Thromb Haemost.2022;20(5):1126-1137.14. van Leeuwen FHP, van Bergen EDP, Timmer MA, et al. Magneticresonance imaging evidence for subclinical joint bleeding in a Dutchpopulation of people with severe hemophilia on prophylaxis. J ThrombHaemost. 2023;21(5):1156-1163.15. Foppen W, van der Schaaf IC, Beek FJA, Mali WPTM, Fischer K. MRIpredicts 5-year joint bleeding and development of arthropathy onradiographs in hemophilia. Blood Adv. 2020;4(1):113-121.16. Stimec J, Dover S, Pullenayegum E, et al. Magnetic resonance imaginginboyswith severehemophiliaA: serial andend-of-study findings fromtheCanadianHemophilia Primary Prophylaxis Study.Res Pract ThrombHaemost. 2021;5(7):e12565.17. FoppenW, van der Schaaf ICC, Witkamp TDD, Fischer K. Is joint effu-sion on MRI specific for haemophilia? Haemophilia. 2014;20(4):582-586.18. NguyenS, LuX,MaY,DuJ,ChangEY, vonDrygalskiA.Musculoskeletalultrasound for intra-articular bleed detection: a highly sensitive imag-ingmodality compared to conventional magnetic resonance imaging. JThromb Haemost. 2018;16(14):490-499.19. Regi SS, Livingstone RS, Kandagaddala M, et al. Ultrasound and mag-netic resonance imaging for the detection of blood: an ex-vivo study.Haemophilia. 2021;27(3):488-493.20. van LeeuwenFHP, LenaB, Zwanenburg JJM, et al. Detecting lowbloodconcentrations in joints using T1 and T2 mapping at 1.5, 3, and 7 T: anin vitro study. Eur Radiol Exp. 2021;5(1):51.21. van Leeuwen FHP, Lena B, van Bergen EDP, et al. Quantitative MRIassessment of joint effusion using T2-relaxometry at 3 Tesla: a fea-sibility and reproducibility study. Skeletal Radiol. 2024. doi:10.1007/s00256-024-04652-022. Culvenor AG, Øiestad BE, Hart HF, Stefanik JJ, Guermazi A, CrossleyKM.Prevalenceof kneeosteoarthritis features onmagnetic resonanceimaging in asymptomatic uninjured adults: a systematic review andmeta-analysis. Br J Sports Med. 2019;53(20):1268-1278.23. Fischer K, de Kleijn P, Negrier C, et al. The association of haemophilicarthropathy with Health-Related Quality of Life: a post hoc analysis.Haemophilia. 2016;22(6):833-840.How to cite this article: FoppenW, van Leeuwen FHP, TimmerMA, Fischer K. The relevance ofMRI findings in joints ofpersons with haemophilia: Insights from the last decade.Haemophilia. 2024;30:877–879.https://doi.org/10.1111/hae.15058 13652516, 2024, 4, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/hae.15058 by Cochrane Netherlands, Wiley Online Library on [17/07/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License

The relevance of MRI findings in joints of persons with haemophilia: Insights from the last decade

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The relevance of MRI findings in joints of persons with haemophilia: Insights from the last decade

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