Comparative analysis of Hemophilia Early Arthropathy Detection with Ultrasound (HEAD-US) scores in persons with nonsevere hemophilia A and B reveals a high degree of joint damage in both disease types

Hemophilia A (HA) and B (HB) are rare blood genetic diseases caused by coagulation factor VIII (FVIII) and factor IX (FIX) deficiency, respectively [[1]Escobar M. Sallah S. Hemophilia A and hemophilia B: focus on arthropathy and variables affecting bleeding severity and prophylaxis.J Thromb Haemost. 2013; 11: 1449-1453Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar]. The identification of early articular changes is crucial for decision-making in hemophilia management, yet subtle changes in joint status can be easily missed during routine physical examination, especially in mild and moderate patients. Although magnetic resonance imaging is the gold standard for joint evaluation [[2]St-Louis J. Abad A. Funk S. Tilak M. Classey S. Zourikian N. et al.The Hemophilia Joint Health Score version 2.1 Validation in Adult Patients study: a multicenter international study.Res Pract Thromb Haemost. 2022; 6e12690https://doi.org/10.1002/rth2.12690Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar], it is not feasible as a regular check-up technique, and musculoskeletal ultrasound (MSK-US) evaluation is now the gold standard point-of-care technique [[3]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: 153-156Crossref PubMed Google Scholar,[4]Plut D. Kotnik B.F. Zupan I.P. Kljucevsek D. Vidmar G. Snoj Z. et al.Diagnostic accuracy of haemophilia early arthropathy detection with ultrasound (HEAD-US): a comparative magnetic resonance imaging (MRI) study.Rad Oncol. 2019; 53: 178-186Crossref Scopus (27) Google Scholar]. The Hemophilia Early Arthropathy Detection with Ultrasound (HEAD-US) scoring system provides a fast, inexpensive evaluation of the 6 most affected target joints in hemophilia: left and right elbows (LE and RE, respectively), left and right knees (LK and RK, respectively), and left and right ankles (LA and RA, respectively). Target joints are those with 3 or more spontaneous bleeding episodes over a period of 6 consecutive months [[5]Blanchette V.S. Key N.S. Ljung L.R. Manco-Johnson M.J. van den Berg H.M. Srivastava A. et al.Subcommittee on Factor VIII, Factor IX and Rare Coagulation Disorders of the Scientific and Standardization Committee of the International Society on Thrombosis and Hemostasis. Definitions in hemophilia: communication from the SSC of the ISTH.J Thromb Haemost. 2014; 12: 1935-1939Abstract Full Text Full Text PDF PubMed Scopus (471) Google Scholar]. We previously used the HEAD-US system to assess the joint status of persons with HA [[6]Jiménez-Yuste V. de la Corte-Rodríguez H. Álvarez-Román M.T. Martín-Salces M. Querol F. Bonanad S. 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: 479-487Crossref PubMed Scopus (5) Google Scholar,[7]Álvarez Román M.T. de la Corte Rodríguez H. Bonanad Boix S. Mingot-Castellano M.E. Fernández Mosteirín N. ARTIHA Spanish Study GroupThe 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.J Thromb Haemost. 2021; 19: 2638-2641Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar] and HB [[8]Jimenez-Yuste V. Alvarez-Roman M.T. Martin-Salces M. De la Corte-Rodriguez H. Altisent C. Parra R. et al.Joint status in Spanish haemophilia B patients assessed using the Haemophilia Early Arthropathy Detection with Ultrasound (HEAD-US) score.Haemophilia. 2019; 25: 144-153Crossref PubMed Scopus (11) Google Scholar]. A total of 123 persons with HA (aged ≥18 years) and 82 with HB (aged ≥14 years) were included in this analysis, regardless of disease severity and treatment modality. The procedures used have been described previously [[6]Jiménez-Yuste V. de la Corte-Rodríguez H. Álvarez-Román M.T. Martín-Salces M. Querol F. Bonanad S. 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: 479-487Crossref PubMed Scopus (5) Google Scholar,[8]Jimenez-Yuste V. Alvarez-Roman M.T. Martin-Salces M. De la Corte-Rodriguez H. Altisent C. Parra R. et al.Joint status in Spanish haemophilia B patients assessed using the Haemophilia Early Arthropathy Detection with Ultrasound (HEAD-US) score.Haemophilia. 2019; 25: 144-153Crossref PubMed Scopus (11) Google Scholar]. In short, patients were invited to participate in the study during routine visits at recruiting centers. HEAD-US bilateral evaluation of elbows, knees, and ankles was performed by the same study coordinating team in a single visit to each of the participating centers, using a portable US scanner [[9]Martinoli C. Della Casa Alberighi O. Di Minno G. Graziano E. Molinari A.C. Pasta G. et al.Development and definition of a simplified scanning procedure and scoring method for Haemophilia Early Arthropathy Detection with Ultrasound (HEAD-US).Thromb Haemost. 2013; 109: 1170-1179Crossref PubMed Scopus (168) Google Scholar]. We showed that current prophylaxis treatments for severe patients largely fail to prevent articular damage, especially in HA. Here, we report findings of a comparative analysis between the subset of persons with nonsevere HA (mild n = 14 and moderate n = 14) and nonsevere HB (mild n = 22 and moderate n =19) from our previous studies [[6]Jiménez-Yuste V. de la Corte-Rodríguez H. Álvarez-Román M.T. Martín-Salces M. Querol F. Bonanad S. 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: 479-487Crossref PubMed Scopus (5) Google Scholar,[8]Jimenez-Yuste V. Alvarez-Roman M.T. Martin-Salces M. De la Corte-Rodriguez H. Altisent C. Parra R. et al.Joint status in Spanish haemophilia B patients assessed using the Haemophilia Early Arthropathy Detection with Ultrasound (HEAD-US) score.Haemophilia. 2019; 25: 144-153Crossref PubMed Scopus (11) Google Scholar]. The mean age at evaluation, in years, was slightly lower in persons with moderate HA (moHA) but comparable between cohorts (Table). Regarding the treatment modality, on-demand (OD) treatment was the main therapeutic regimen of choice for most persons with moderate and mild hemophilia, and none were treated with primary prophylaxis. Two persons with moHA, 2 with mild hemophilia A (miHA), 1 with moderate HB (moHB), and 3 with mild hemophilia B (miHB) were on secondary prophylaxis. Two persons with miHB and 2 with moHA were on tertiary prophylaxis. We observed a rather infrequent follow-up of potential articular damage events by imaging techniques, regardless of disease severity (Table).TablePatient demographics, clinical characteristics, and joint status of persons with nonsevere hemophilia A and B.Disease severityMildModerate Hemophilia typeHAHBHAHB No. of patients (n)14221419Demographics, mean ± SD Age at evaluation (y)47.9 ± 18.145.9 ± 15.640.9 ± 13.344.3 ± 17.3 Age at diagnosis (y)19.0 ± 15.511.7 ± 14.05.9 ± 7.810.6 ± 17.1 Weight (kg)75.3 ± 12.975.9 ± 11.378.6 ± 11.982.4 ± 17.0Treatment modality, n (%) On-demand12 (85.7)17 (77.3)10 (71.4)18 (94.7) Primary prophylaxis0 (0)0 (0)0 (0)0 (0) Secondary prophylaxis2 (14.3)3 (13.6)2 (14.3)1 (5.3) Tertiary prophylaxis0 (0)2 (9.1)2 (14.3)0 (0)No. of patients with target jointsaDefined as joints with 3 or more spontaneous bleeding episodes within a 6-month period [5]., n (%) None12 (85.7)18 (81.8)8 (57.1)6 (31.6) Elbow0 (0)3 (13.6)3 (21.4)3 (15.8) Knee1 (7.1)1 (4.5)2 (14.3)9 (47.4)aDefined as joints with 3 or more spontaneous bleeding episodes within a 6-month period [5]. Ankle1 (7.1)2 (9.1)3 (21.4)3 (15.8) Other1 (7.1)1 (4.5)0 (0)1 (5.3)Imaging technique used in the previous 12 months, n (%) None12 (85.7)19 (95.0)7 (53.8)12 (63.2) Magnetic resonance imaging1 (7.1)0 (0)2 (15.4)1 (5.3) Ultrasonography0 (0)1 (5)3 (23.1)2 (10.6) Other1 (7.1)0 (0)1 (7.7)4 (21.1)HA, hemophilia A, HB, hemophilia B.a Defined as joints with 3 or more spontaneous bleeding episodes within a 6-month period [[5]Blanchette V.S. Key N.S. Ljung L.R. Manco-Johnson M.J. van den Berg H.M. Srivastava A. et al.Subcommittee on Factor VIII, Factor IX and Rare Coagulation Disorders of the Scientific and Standardization Committee of the International Society on Thrombosis and Hemostasis. Definitions in hemophilia: communication from the SSC of the ISTH.J Thromb Haemost. 2014; 12: 1935-1939Abstract Full Text Full Text PDF PubMed Scopus (471) Google Scholar]. Open table in a new tab HA, hemophilia A, HB, hemophilia B. Our HEAD-US comparative analysis revealed a trend toward a higher percentage of joints with a score of 1 or higher in the total population of persons with miHA than in miHB (Figure A ), except for LE, in which a similar percentage was observed. We noted similar trends in the population treated OD, with higher HEAD-US ≥1 percentages in miHA vs miHB, which were statistically significant (P < .05) for LK and LA. In the moderate patient population, a trend toward higher moHA vs moHB percentages was only observed in elbows and LK (Figure B) in both the total patient population and those treated OD. In all the other joints, we observed similar percentages in moHA and moHB. Of note, >40% of the evaluated ankles in moHB showed a HEAD-US score ≥1, and for HA, this was true of the RAs in the mild population. These observations are in sharp contrast to those reported in a recent study of a Nordic population of people with moHA and moHB [[10]Måseide R.J. Berntorp E. Astermark J. Hansen J. Olsson A. Bruzelius M. et al.Haemophilia early arthropathy detection with ultrasound and haemophilia joint health score in the moderate haemophilia (MoHem) study.Haemophilia. 2021; 27: e253-e259https://doi.org/10.1111/hae.14245Crossref PubMed Scopus (9) Google Scholar]. In this article, Måseide et al. [[10]Måseide R.J. Berntorp E. Astermark J. Hansen J. Olsson A. Bruzelius M. et al.Haemophilia early arthropathy detection with ultrasound and haemophilia joint health score in the moderate haemophilia (MoHem) study.Haemophilia. 2021; 27: e253-e259https://doi.org/10.1111/hae.14245Crossref PubMed Scopus (9) Google Scholar] detected HEAD-US ≥1 in 15% of elbows, 20% of knees, and 23% of ankles (for both hemophilia types together), which is generally much lower than the percentages we found in the Spanish cohort (compare with Figure B). In fact, 52% of their patients obtained a HEAD-US score of 0 in all joints, which is roughly double the percentage we observed (21.4% moHA and 26.3% moHB). In mild patients, the percentage of joints with synovium hypertrophy was more frequent in miHA than in miHB, with statistically significant differences in knees (21.4%/23.1% vs 0%/0% for LK/RK, respectively; P < .05). In the moderate severity population, the occurrence of synovium hypertrophy (score >0) was much less frequently encountered by Måseide et al. [[10]Måseide R.J. Berntorp E. Astermark J. Hansen J. Olsson A. Bruzelius M. et al.Haemophilia early arthropathy detection with ultrasound and haemophilia joint health score in the moderate haemophilia (MoHem) study.Haemophilia. 2021; 27: e253-e259https://doi.org/10.1111/hae.14245Crossref PubMed Scopus (9) Google Scholar] vs our study for all evaluated joints: 5% (moHA + moHB, any elbow) vs 36%/28% to 26%/16% (moHA-moHB, LE/RE), 7% (moHA + moHB, any knee) vs 39%/36% to 16%/33% (moHA-moHB, LK/RK), and 7% (moHA + moHB, any ankle) vs 21%/43% to 16%/16% (moHA-moHB, LA/RA). As Abdi et al. [[11]Kloosterman F.R. Abdi A. Gouw S.C. Hart D.P. Fijnvandraat K. The factor VIII treatment history of non-severe hemophilia A-Response from original authors Abdi et al.J Thromb Haemost. 2021; 19: 2642-2644Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar] suggested that the disparities between both studies may be explained by the marked difference in patient age at evaluation, with a median of 23 years in Måseide et al. [[10]Måseide R.J. Berntorp E. Astermark J. Hansen J. Olsson A. Bruzelius M. et al.Haemophilia early arthropathy detection with ultrasound and haemophilia joint health score in the moderate haemophilia (MoHem) study.Haemophilia. 2021; 27: e253-e259https://doi.org/10.1111/hae.14245Crossref PubMed Scopus (9) Google Scholar] vs 41-44 years (moHA-moHB) in our study. It has been extensively shown that age correlates with the development of osteoarthritis in the general population [12Culvenor A.G. Oiestad B.E. Hart H.F. Stefanik J.J. Guermazi A. Crossley K.M. Prevalence of knee osteoarthritis features on magnetic resonance imaging in asymptomatic uninjured adults: a systematic review and meta-analysis.Br J Sports Med. 2019; 53: 1268-1278Crossref PubMed Scopus (123) Google Scholar, 13Kloppenburg M. Berenbaum F. Osteoarthritis year in review 2019: epidemiology and therapy.Osteoarthr Cartil. 2020; 28: 242-248Abstract Full Text Full Text PDF PubMed Scopus (283) Google Scholar, 14Murray C. Marshall M. Rathod T. Bowen C.J. Menz H.B. Roddy E. Population prevalence and distribution of ankle pain and symptomatic radiographic ankle osteoarthritis in community dwelling older adults: a systematic review and cross-sectional study.PLoS One. 2018; 13e0193662https://doi.org/10.1371/journal.pone.0193662Crossref Scopus (66) Google Scholar, 15Pereira D. Peleteiro B. Araujo J. Branco J. Santos R.A. Ramos E. The effect of osteoarthritis definition on prevalence and incidence estimates: a systematic review.Osteoarthritis Cartilage. 2011; 19: 1270-1285Abstract Full Text Full Text PDF PubMed Scopus (563) Google Scholar]. A Spanish cohort study [[16]Prieto-Alhambra D. Judge A. Javaid M.K. Cooper C. Diez-Perez A. Arden N.K. Incidence and risk factors for clinically diagnosed knee, hip and hand osteoarthritis: influences of age, gender and osteoarthritis affecting other joints.Ann Rheum Dis. 2014; 73: 1659-1664Crossref PubMed Scopus (489) Google Scholar] revealed that osteoarthritis risk increased slowly with age, with the steepest slope from the age of 50, especially in women, affecting predominantly the hands, knees, hips, and spine. However, we are confident that the changes detected by ultrasound in our study are mainly due to hemophilia-related damages rather than part of natural age-related changes since aging as a confounding factor in persons with hemophilia in their 40s does not significantly impact arthrosis as disease-related damage has been already aggressive and developed earlier in life [[17]De la Corte-Rodriguez H. Rodriguez-Merchan E.C. Alvarez-Roman M.T. Martin-Salces M. Rivas-Pollmar I. Jimenez-Yuste V. Arthropathy in people with mild haemophilia: exploring risk factors.Thromb Res. 2022; 211: 19-26Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar,[18]Daffunchio C. Landro M.E. Galatro G. Neme D. Cambiaggi G. Moretti N. et al.How mild is mild haemophilia?.Haemophilia. 2023; 29: 530-537Crossref PubMed Scopus (2) Google Scholar]. In fact, recent work by Zwagemaker et al. [[19]Zwagemaker A.F. Kloosterman F.R. Hemke R. Gouw S.C. Coppens M. Romano L.G.R. et al.Joint status of patients with nonsevere hemophilia A.J Thromb Haemost. 2022; 20: 1126-1137Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar] analyzed persons with nonsevere HA of the same age range as our study by magnetic resonance imaging and, similar to our findings, they detected osteochondral changes in 16% of knees and 47% of ankles of moderate patients; also, their subanalysis of younger patients revealed that even this population presented joint damage. Complete cartilage destruction and deranged subchondral bone were seldom detected in persons with HB, regardless of disease severity, with only a few individuals showing these problems in the ankles. In fact, the presence of total cartilage destruction was significantly more elevated in persons with HA than in HB, especially in ankles (LA/RA) in mild (14.3%/21.4% vs 0%/4.5%; P = .285/P < .05) and moderate (35.7%/28.6% vs 0%/0%; P < .01/P < .05) patients. Deranged subchondral bone was also rare in persons with miHA but significantly higher in LA/RA in moHA vs moHB (14.3%/28.6% vs 5.3%/0%; P = .598/P < .05). Our comparative analysis of persons with nonsevere HA and HB has revealed that a substantial percentage of individuals (>45%) show early joint changes that could develop into arthropathy (HEAD-US ≥1) in at least 1 target joint, regardless of hemophilia type. Since most of these patients are treated OD, improved schemes to monitor joint status could contribute to better-informed decisions about treatment course, as we have suggested in previous studies on HA [[6]Jiménez-Yuste V. de la Corte-Rodríguez H. Álvarez-Román M.T. Martín-Salces M. Querol F. Bonanad S. 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: 479-487Crossref PubMed Scopus (5) Google Scholar] and HB [[8]Jimenez-Yuste V. Alvarez-Roman M.T. Martin-Salces M. De la Corte-Rodriguez H. Altisent C. Parra R. et al.Joint status in Spanish haemophilia B patients assessed using the Haemophilia Early Arthropathy Detection with Ultrasound (HEAD-US) score.Haemophilia. 2019; 25: 144-153Crossref PubMed Scopus (11) Google Scholar]. Despite few significant differences in specific alterations of some joints (as discussed above), our current data comparing nonsevere HA vs HB showed no overt differences in the overall degree of articular damage between groups, hinting at a more similar course of clinical alterations than previously anticipated in other studies dealing with either population of people with HA or HB separately. Therefore, although HA is traditionally approached with more concern than HB in clinical practice, we suggest that management and follow-up evaluation routines should be standardized according to disease severity regardless of hemophilia type. Nevertheless, several limitations of our study should be considered: First, we analyzed a relatively low number of patients. Second, some of the arthropathy signs that we observed could be attributed to the older age of our patient population compared with other studies. Therefore, the absence of an unaffected control group of matched older individuals to compare our results poses another limitation of our study. Third, patients were invited to receive the HEAD-US evaluation at a specific date, which could have introduced a recruitment bias because some of them may not have been able to attend. Finally, the different dates of the HA [[6]Jiménez-Yuste V. de la Corte-Rodríguez H. Álvarez-Román M.T. Martín-Salces M. Querol F. Bonanad S. 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: 479-487Crossref PubMed Scopus (5) Google Scholar] and HB [[8]Jimenez-Yuste V. Alvarez-Roman M.T. Martin-Salces M. De la Corte-Rodriguez H. Altisent C. Parra R. et al.Joint status in Spanish haemophilia B patients assessed using the Haemophilia Early Arthropathy Detection with Ultrasound (HEAD-US) score.Haemophilia. 2019; 25: 144-153Crossref PubMed Scopus (11) Google Scholar] studies may have also introduced certain biases since patient care in hemophilia could have slightly evolved between them. With the development of nonreplacement treatments [[20]Kizilocak H. Marquez-Casas E. Malvar J. Carmona R. Young G. Determining the approximate factor VIII level of patients with severe haemophilia A on emicizumab using in vivo global haemostasis assays.Haemophilia. 2021; 27: 730-735Crossref PubMed Scopus (13) Google Scholar] and gene therapy strategies [[21]Batty P. Lillicrap D. Gene therapy for hemophilia: current status and laboratory consequences.Int J Lab Hematol. 2021; 43: 117-123Crossref PubMed Scopus (13) Google Scholar], the phenotype of persons with severe hemophilia treated by these methods might gradually shift to a mild/moderate profile. Our current clinical knowledge of nonsevere hemophilia is relatively limited, and yet they account for most people with this disease. Given the availability of a greater variety of monitoring resources, there is a justified need to intensify follow-up of nonsevere patients to adjust treatment accordingly and provide the best possible clinical care. The capacity of imaging studies to identify subclinical hemorrhages and subtle tissue changes is crucial for proper clinical management. We believe MSK-US is an inexpensive technique that can be used in routine assessment of joint status. This approach may reduce the incidence of joint damage in these patients since most of them had developed arthropathy by the time they were evaluated by our team. However, more research is needed to confirm the validity of the technique in studies comparing MSK-US evaluation of patients with nonsevere hemophilia with age-matched controls. The authors thank Drs Blanca Piedrafita and Anchel González-Barriga (Medical Statistics Consulting S. L., Valencia, Spain) for medical writing support and editing, which was funded by Pfizer SLU, Spain. This study was sponsored by Pfizer SLU, Spain.