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The factor VIII treatment history of non‐severe hemophilia A: COMMENT. Joint damage in adult patients with mild or moderate hemophilia A evaluated with the HEAD‐US system

2021; Elsevier BV; Volume: 19; Issue: 10 Linguagem: Inglês

10.1111/jth.15475

1538-7933

María Román, Hortensia de la Corte Rodríguez, Santiago Bonanad, María Eva Mingot‐Castellano, Nuria Fernández Mosteirín, Mónica Martín Salces, Felipe Querol, Mariana Canaro, Amparo Santamaría, Ramiro Núñez, L.J. García Frade, Carlo Martinoli, Hae‐Kyung Kim, Víctor Jiménez‐Yuste,

Platelet Disorders and Treatments

Abdi and colleagues reported important insights regarding the treatment history of non‐severe hemophilia A (HA) patients,1.Abdi A. Kloosterman F.R. Eckhardt C.L. et al.The factor VIII treatment history of non‐severe hemophilia A.J Thromb Haemost. 2020; 18: 3203-3210https://doi.org/10.1111/jth.15076Crossref PubMed Scopus (8) Google Scholar including incidence of joint bleeds in a large, international, and multi‐center non‐severe HA cohort (the INSIGHT cohort). Repeated intra‐articular bleeding episodes in hemophilia patients may lead to degenerative arthropathy, which is the most frequent complication in HA regardless of the degree of severity. Despite the interesting findings described on annualized bleeding rate in mild‐to‐moderate HA patients, the study by Abdi and colleagues did not provide information on the joint status. The early identification of joint damage is indeed crucial to prevent the progression to hemophilic arthropathy, and thus periodic monitorization of the joint status is recommended for non‐severe HA patients.2.Plut D. Kotnik B.F. Zupan I.P. et al.Diagnostic accuracy of haemophilia early arthropathy detection with ultrasound (HEAD‐US): a comparative magnetic resonance imaging (MRI) study.Radiol Oncol. 2019; 53: 178-186https://doi.org/10.2478/raon‐2019‐0027Crossref PubMed Scopus (19) Google Scholar However, subclinical intra‐articular bleeds may be hardly noticeable by clinical examination, especially in milder forms of HA; hemarthrosis and abnormalities may not be present for many years after birth, joint health awareness is usually lower, and most clinical evidence is generally extrapolated from severe patients' data.3.Benson G. Auerswald G. Dolan G. et al.Diagnosis and care of patients with mild haemophilia: practical recommendations for clinical management.Blood Transfus. 2018; 16: 535-544https://doi.org/10.2450/2017.0150‐17PubMed Google Scholar Diagnostic imaging is necessary to identify subtle alterations, and MRI is the gold standard for joint evaluation. Nevertheless, access to this technique is limited and its low feasibility for regular or on‐demand (OD) check‐ups has led to the implementation of musculoskeletal ultrasound as a point‐of‐care technique, with several reports supporting its usefulness.4.Acharya S.S. Rule B. McMillan O. Humphries T.J. Point‐of‐care ultrasonography (POCUS) in hemophilia A: a commentary on current status and its potential role for improving prophylaxis management in severe hemophilia A.Ther Adv Hematol. 2017; 8: 153-156https://doi.org/10.1177/2040620717690316Crossref PubMed Google Scholar This has been associated with the development of Hemophilia Early Arthropathy Detection with Ultrasound (HEAD‐US),5.Foppen W. van der Schaaf I.C. Fischer K. Value of routine ultrasound in detecting early joint changes in children with haemophilia using the 'haemophilia early arthropathy detection with ultrasound' protocol.Haemophilia. 2016; 22: 121-125https://doi.org/10.1111/hae.12769Crossref PubMed Scopus (35) Google Scholar a scoring system which enables a low‐cost and quick evaluation of the six major joints, namely left and right sided elbows (LE, RE), knees (LK, RK), and ankles (LA, RA). Here we report unpublished findings of a 28‐adult male patient subset with moderate (n = 14) and mild (n = 14) HA, with median age of 42.5 [IQR 32–60.5] years (40.5 [IQR 30.0–49.0] and 51.0 [IQR 34.0–63.0] years for moderate and mild, respectively) from a previously performed cross‐sectional study to assess joint status in Spain.6.Jiménez‐Yuste V. de la Corte‐Rodríguez H. Álvarez‐Román M.T. et al.Ultrasound evaluation of joint damage and disease activity in adult patients with severe haemophilia A using the HEAD‐US system.Haemophilia. 2021; 27: 479-487https://doi.org/10.1111/hae.14280Crossref PubMed Scopus (2) Google Scholar Not surprisingly we found 19 patients non‐subjected to any evaluation by imaging modalities over the last 12 months (85.7% mild; 53.8% moderate), and also a HEAD‐US score of 0 in all joints in 5 (35.7%) and 3 (21.4%) patients with mild and moderate HA, respectively. However, we observed 8 patients with target joint in at least one joint, being the ankles the most affected ones (4 patients), and total knee replacement was present in 1 mild patient (RK) and 1 moderate patient (LK). Noticeably, the ankle was the most affected joint, with a score of ≥3 in 25% of patients for the LA, and in 39.3% for the RA. Status of each joint by disease severity according to the HEAD‐US score shown in Table 1.TABLE 1Joint status according to the HEAD‐US scoreHEAD‐US scoreTotal non‐severe (n)By severityBy treatment modalityMild (n)Moderate (n)OD (n)SP (n)TP (n)Left elbowSynovium≥18 (28.6%)3 (21.4%)5 (35.7%)6 (27.3%)1 (25%)1 (50%)Cartilage≥18 (28.6%)4 (28.6%)4 (28.6%)5 (22.7%)2 (50%)1 (50%)Bone≥14 (14.3%)2 (14.3%)2 (14.3%)2 (9.1%)1 (25%)1 (50%)Overall019 (67.9%)10 (71.4%)9 (64.3%)16 (72.7%)2 (50%)1 (50%)1–24 (14.3%)1 (7.1%)3 (21.4%)3 (13.6%)1 (25%)0≥35 (17.9%)3 (21.4%)2 (14.3%)3 (13.6%)1 (25%)1 (50%)Right elbowSynovium≥15 (17.9%)1 (7.1%)4 (30.8%)3 (13.6%)02 (100%)Cartilage≥19 (32.1%)4 (28.6%)5 (35.7%)5 (22.7%)2 (50%)2 (100%)Bone≥12 (7.1%)02 (14.3%)002 (100%)Overall018 (64.3%)10 (71.4%)8 (57.1%)16 (72.7%)2 (50%)01–26 (21.4%)3 (21.4%)3 (21.4%)4 (18.2%)2 (50%)0≥34 (14.3%)1 (7.1%)3 (21.4)2 (9.1%)02 (100%)Left kneeaOne moderate patient treated OD with joint replacement.Synovium≥18 (29.6%)3 (21.4%)5 (38.5%)7 (33.4%)1 (25%)0Cartilage≥18 (29.6%)4 (28.6%)4 (30.8%)7 (33.4%)01 (50%)Bone≥14 (14.8%)2 (14.3%)2 (15.4%)4 (18.2%)00Overall016 (59.3%)10 (71.4%)6 (46.2%)12 (57.1%)3 (75%)1 (50%)1–26 (22.2%)1 (7.1%)5 (38.5%)4 (19.0%)1 (25%)1 (50%)≥35 (18.5%)3 (21.4%)2 (15.4%)5 (23.8%)00Right kneebOne mild patient treated OD with joint replacement.Synovium≥18 (29.6%)3 (23.1%)5 (35.7%)6 (28.6%)1 (25%)1 (50%)Cartilage≥14 (14,8%)2 (15.4%)2 (14,3%)3 (14.4%)01 (50%)Bone≥13 (11,1%)1 (7.7%)2 (14,3%)2 (9.5%)01 (50%)Overall018 (66.7%)9 (69.2%)9 (64.3%)14 (66.7%)3 (75%)1 (50%)1–26 (22.2&)3 (23.1%)3 (21.4%)5 (23.8%)1 (25%)0≥33 (11.1%)1 (7.7%)2 (14.3%)2 (9.5%)01 (50%)Left ankleSynovium≥15 (17.9%)2 (14.3%)3 (21.4%)4 (18.2%)01 (50%)Cartilage≥19 (32.1%)4 (28.6%)5 (35.7%)7 (31.8%)1 (25%)1 (50%)Bone≥17 (25%)2 (14.3%)5 (35.7%)5 (22.7%)1 (25%)1 (50%)Overall018 (64.3%)9 (64.3%)9 (64.3%)14 (63.6%)3 (75%)1 (50%)1–23 (10.7%)3 (21.4%)03 (13.6%)00≥37 (25%)2 (14.3%)5 (35.7%)5 (22.7%)1 (25%)1 (50%)Right ankleSynovium≥111 (39.3%)5 (35.7%)6 (42.9%)8 (36.4%)1 (25%)2 (100%)Cartilage≥111 (39.3%)5 (35.7%)6 (42.9%)7 (31.8%)2 (50%)2 (100%)Bone≥110 (35.7%)4 (28.6%)6 (42.9%)6 (27.3%)2 (50%)2 (100%)Overall015 (53.6%)8 (57.1%)7 (50%)13 (59.1%)2 (50%)01–22 (7.1%)1 (7.1%)1 (7.1%)2 (9.1%)00≥311 (39.3%)5 (35.7%)6 (42.9)7 (31.8%)2 (50%)2 (100%)Abbreviations: OD, on demand; SP, secondary prophylaxis; TP, tertiary prophylaxis.a One moderate patient treated OD with joint replacement.b One mild patient treated OD with joint replacement. Open table in a new tab Abbreviations: OD, on demand; SP, secondary prophylaxis; TP, tertiary prophylaxis. Signs of cartilage and bone degeneration at different degrees were detected in all the six joints studied. The poorest score was observed in the ankles: 14.3% and 21.4% of mild patients had complete cartilage destruction in the LA and RA, respectively, which is in line with previous research showing that arthropathy of the ankle in mild HA patients is also observed and is highly disabling.7.Ling M. Heysen J.P. Duncan E.M. Rodgers S.E. Lloyd J.V. High incidence of ankle arthropathy in mild and moderate haemophilia A.Thromb Haemost. 2011; 105: 261-268https://doi.org/10.1160/th10‐07‐0492Crossref PubMed Scopus (34) Google Scholar As also observed for the frequency of joint bleeding in the study by Abdi and colleagues,1.Abdi A. Kloosterman F.R. Eckhardt C.L. et al.The factor VIII treatment history of non‐severe hemophilia A.J Thromb Haemost. 2020; 18: 3203-3210https://doi.org/10.1111/jth.15076Crossref PubMed Scopus (8) Google Scholar these numbers were worse for moderate patients (35.7% for LA and 28.6% for RA). In addition, signs of deranged subchondral bone were detected, and especially in the ankles of moderate patients (2 LA, 4 RA). Regarding disease activity, none of the mild patients showed severe synovitis in any joint, but mild‐to‐moderate synovitis was sometimes observed in the six joints (ranging from 7.1% to 35.7%). Severe synovitis was found only in joints of some moderate patients (2 LE, 1 RE, 1 LK, 1 LA and 1 RA). Overall, none of the mild patients reached the highest score of 8, but moderate patients presented several joints with the maximum score (2 LE, 1 RE, 1 LA). Data on the treatment history of patients with non‐severe HA was pointed out by Abdi and colleagues to be relevant when estimating bleeding phenotypes.1.Abdi A. Kloosterman F.R. Eckhardt C.L. et al.The factor VIII treatment history of non‐severe hemophilia A.J Thromb Haemost. 2020; 18: 3203-3210https://doi.org/10.1111/jth.15076Crossref PubMed Scopus (8) Google Scholar In our study, when analyzing the joint status depending on the treatment modality, overall score of 0 for all joints was found for 7 (31.8%) patients (4 mild and 3 moderate) under OD and only 1 (16.7%) mild patient under prophylactic regimen (secondary prophylaxis [SP]). A substantial number of OD patients scored 0 for each evaluated joint (57.1% to 72.7%), which, as observed in severe HA patients, may implicate a significant association between arthropathy and treatment modality, with worse results in patients with OD treatments.6.Jiménez‐Yuste V. de la Corte‐Rodríguez H. Álvarez‐Román M.T. et al.Ultrasound evaluation of joint damage and disease activity in adult patients with severe haemophilia A using the HEAD‐US system.Haemophilia. 2021; 27: 479-487https://doi.org/10.1111/hae.14280Crossref PubMed Scopus (2) Google Scholar, 8.Jimenez‐Yuste V. Alvarez‐Roman M.T. Martin‐Salces M. et al.Joint status in Spanish haemophilia B patients assessed using the haemophilia early arthropathy detection with ultrasound (HEAD‐US) score.Haemophilia. 2019; 25: 144-153https://doi.org/10.1111/hae.13628Crossref PubMed Scopus (8) Google Scholar Severe synovitis was only observed for 1 LK and 1 LA in the OD population, although mild‐to‐moderate damage was detected for all six joints. Also, ankles of several patients had advanced cartilage damage (5 LA and 5 RA) and deranged subchondral bone (3 LA, 3 RA). Noteworthily, there were 4 OD patients with target joints (3 knees, 1 ankle). Prophylaxis with coagulation factor concentrate is not the standard treatment for non‐severe patients, and, according to Abdi and colleagues, there is a lack on the detailed knowledge of the timing of treatment.1.Abdi A. Kloosterman F.R. Eckhardt C.L. et al.The factor VIII treatment history of non‐severe hemophilia A.J Thromb Haemost. 2020; 18: 3203-3210https://doi.org/10.1111/jth.15076Crossref PubMed Scopus (8) Google Scholar It is thus important to consider that, among mild and moderate HA patients, only those with worse joint status receive prophylactic treatment. Among patients on prophylaxis regimen, those on SP (n = 4) had better scores than those on tertiary prophylaxis (TP) (n = 2). For those on SP, only 1 LE (score 8) and the ankles had scores >2 (1 LA, 2 RA). Some joints appeared severely affected in certain patients under TP with scores of 6–8 (1 LE, 2 RE, 1 RK, 1 LA, 2 RA) while left knees scored ≤2. Interestingly, patients on TP (2 moderate patients with target joints, i.e., 1 in the elbow and the other in elbow and ankle) had imaging studies performed in the previous year, but only 1 out of the 4 SP patient underwent US evaluation, despite 2 of them having target joints identified in the ankles and elbow. It is therefore conceivable that patients on TP were poorly controlled prior to the establishment of the prophylactic regimen and had a joint status already compromised. Considering the obtained HEAD‐US results, the investigator considered the opportunity to switch the treatment modality for the 25.0% (n = 3) and 33.3% (n = 4) of mild and moderate patients, respectively. Given the importance of the treatment history of non‐severe HA patients,1.Abdi A. Kloosterman F.R. Eckhardt C.L. et al.The factor VIII treatment history of non‐severe hemophilia A.J Thromb Haemost. 2020; 18: 3203-3210https://doi.org/10.1111/jth.15076Crossref PubMed Scopus (8) Google Scholar the identification of joint damage and its impact on treatment modality could thus translate into relevant clinical implications. In agreement, it has been reported that articular damage and disease activity in HB and severe HA patients varied depending on treatment modality, with increased prevalence in patients treated OD.6.Jiménez‐Yuste V. de la Corte‐Rodríguez H. Álvarez‐Román M.T. et al.Ultrasound evaluation of joint damage and disease activity in adult patients with severe haemophilia A using the HEAD‐US system.Haemophilia. 2021; 27: 479-487https://doi.org/10.1111/hae.14280Crossref PubMed Scopus (2) Google Scholar, 8.Jimenez‐Yuste V. Alvarez‐Roman M.T. Martin‐Salces M. et al.Joint status in Spanish haemophilia B patients assessed using the haemophilia early arthropathy detection with ultrasound (HEAD‐US) score.Haemophilia. 2019; 25: 144-153https://doi.org/10.1111/hae.13628Crossref PubMed Scopus (8) Google Scholar The establishment of a clinical follow‐up plan immediately after the diagnosis is strongly recommended by the recently published guidelines of the World Federation of Hemophilia9.Srivastava A. Santagostino E. Dougall A. et al.Guidelines for the Management of Hemophilia.Haemophilia. 2020; 26: 1-158https://doi.org/10.1111/hae.14046Crossref PubMed Scopus (467) Google Scholar also for non‐severe forms of HA, as it is for severe patients. Interestingly, out of the 28 non‐severe patients, 8 already had target joints, an observation that suggests a delayed detection and suboptimal prevention of articular damage. We believe this damage is result of the hemophilic arthropathy, as a huge proportion of patients showed joint damage together with signs of synovitis. However, as arthritic changes associated with age was not considered, this may constitute a limitation. Here we report patients with mild or moderate HA that presented signs such as synovitis, deranged subchondral bone or complete cartilage destruction. Taken all together and considering that most HA patients experience hemarthroses at some point in their lifetime, this study points out that arthropathy and signs of disease (synovitis) can also be detected in mild and moderate patients, a finding that is in line with former studies. Furthermore, the results are consistent with Abdi and colleagues' data warning on the substantial percentage of mild and moderate HA patients who present an intense bleeding phenotype.1.Abdi A. Kloosterman F.R. Eckhardt C.L. et al.The factor VIII treatment history of non‐severe hemophilia A.J Thromb Haemost. 2020; 18: 3203-3210https://doi.org/10.1111/jth.15076Crossref PubMed Scopus (8) Google Scholar In this subset of patients, the degree of articular damage, even though it might be subjected to the severity of the condition, may be comparable with that of severe HA. Although non‐severe patients still represent most of the hemophilic population, they are still underdiagnosed and undertreated as compared with patients with severe hemophilia. Close monitoring of these patients is, therefore, of utmost importance. Given that the HEAD‐US system allows a rapid and low‐cost monitorization of six joints at a time even by non‐imaging specialists, its point‐of‐care application is feasible and should not be limited to the severe forms of the disease. M. T. Álvarez‐Román have participated as speaker, in advisory boards and sponsored symposia with Novo Nordisk, Bayer, Takeda, Roche, Pfizer, Octapharma, Amgen, Novartis, CSL Behring and Sobi. H. de la Corte‐Rodríguez has received honoraria for attending symposia/congresses and/or for speaking and/or consulting, and/or funds for research from Pfizer, Roche, Sobi, Novo Nordisk, Takeda and Bayer. M. Martín‐Salces has received honoraria for attending symposia/congresses and/or speaking and/or consulting from CSL Behring, Novo Nordisk, Pfizer, Roche, Amgen, Novartis and Takeda. F. Querol has received honoraria for authoring/speaking at educational textbooks and training courses financed by Bayer, Takeda, Novo Nordisk, Sobi and speaking/consulting at advisory boards, seminars from Bayer, CSL Behring, Novo Nordisk, Pfizer, Sanofi, Takeda, and funds/awards for research projects from Grifols, Novo Nordisk, Pfizer, Sobi, Takeda. S. Bonanad has received personal honoraria from Pfizer, Novo Nordisk, grants and personal honoraria from Takeda, SOBI and Bayer. M. E. Mingot‐Castellano has received fees for consulting services and training activities from Novo Nordisk, Takeda, Bayer, Sobi, Roche, Amgen, Novartis, CSL Behring and Alexion. N. Fernández‐Mosteirín has received personal honoraria from Pfizer, Grifols, Octapharma, Takeda, Novo Nordisk, Roche and CSL Behring, for collaboration as a speaker. M. Canaro has received research grants, and lecture and consultancy honoraria from Takeda, Bayer and Pfizer. A. Santamaría has acted as a paid consultant and has receiving honoraria as a speaker from Shire, Takeda, Sobi, Octopharma, Novo Nordisk, Bayer, Pfizer and Roche. R. Núñez has received personal honoraria for consulting services from Novo Nordisk, Takeda, Pfizer, Bayer, Sobi, Roche, CSL Behring and Alexion. L. J. García‐Frade has received honoraria for speaking and/or consulting and/or funds for research from Amgen, Pfizer, Takeda, and Sobi, unrelated with this manuscript. C. Martinoli has acted as paid consultant for Pfizer, and received speaker fees from Pfizer, Sobi, Takeda, Novartis, Novo Nordisk, outside of the submitted work. H. K. Kim is employee of Pfizer SLU. V. Jiménez‐Yuste has received honoraria for attending symposia/congresses and/or for speaking and/or consulting, and/or funds for research from Takeda, Bayer, Biomarin, Sanofi, CSL‐Behring, Grifols, Novo Nordisk, Sobi, Roche, Octapharma and Pfizer. V. Jiménez‐Yuste contributed to the design of the study, performed research, interpreted data, and contributed to discussion of results. H. de la Corte‐Rodríguez acquired data, performed ultrasound studies, and participated in assessment and discussion of the results. M. T. Álvarez‐Román, M. Martín‐Salces, F. Querol, S. Bonanad Boix, M. E. Mingot‐Castellano, M. Canaro, N. Fernández‐Mosteirín, A. Santamaría, R. Núñez, and L. J. García‐Frade acquired data and participated in assessment and discussion of the results. C. Martinoli was consulted for the design of the study, interpreted data, and contributed to discussion of results. H. K. Kim contributed with the conception and design of the study, interpreted data, and contributed to the discussion of results. All authors had full access to all data, take responsibility for the interpretation of data and participated in the critical revision of the manuscript for important intellectual content. All authors approved the final version of the manuscript. The authors thank Dr. Laura Hidalgo, Dr. Blanca Piedrafita, and Dr. Javier Arranz‐Nicolás (Medical Statistics Consulting S. L., Valencia, Spain) for medical writing support and editing, which was funded by Pfizer SLU, Spain.Pfizer SLU ARTIHA Spanish Study Group Mónica Martín Salces (Madrid, Spain). Felipe Querol (Valencia, Spain). Mariana Canaro (Mallorca, Spain). Amparo Santamaría (Barcelona, Spain). Ramiro Núñez (Sevilla, Spain). Luis Javier García Frade (Valladolid, Spain). Carlo Martinoli (Genova, Italy). Hae Kyung Kim (Madrid, Spain). Víctor Jiménez‐Yuste (Madrid, Spain).