Haemophilia Early Arthropathy Detection Research Articles

Clinical analysis and quality of life survey of hemophilia B patients in the central and western regions of China.

To study the current status of hemophilia B (HB) patients in the central and western regions of China. This cross-sectional, multicenter study was conducted in seven provinces in the central and western regions of China from April 2019 to June 2023. Samples were collected for the factor IX activity, inhibitor screen, and gene mutation. Furthermore, the status of six index joints and quality of life (QoL) were assessed. A total of 185 HB patients (mild 15, moderate 75, and severe 95) with a median age of 12.17 years were enrolled. 30.3% (56/185) of patients had a family history of HB. 34.6% (64/185) of HB patients had diagnostic delay and 38.5% (69/179) experienced treatment delay. The incidence of inhibitors was 6.1% (11/179). We identified 123 genetic variants in this study, with missense mutations being the most common. 84.0% (89/106) of HB mothers were genetically identified as carriers, with 27.7% (13/47) of carriers having clotting factor levels less than 0.40 IU/ml. 71.4% (132/185) of HB patients had a history of joint hemorrhage, with a rate of target joint in these patients was 64.4% (85/132). Lower extremity joints were most often affected in patients. The Hemophilia Joint Health Score (HJHS) score was significantly positively correlated with the Hemophilia Early Arthropathy Detection with Ultrasound in China (HEAD-US-C) (r = 0.542, P < 0.001). Patients who received prevention treatment, inhibitor negative, without treatment delay, and without high-intensity replacement therapy showed a higher total score of the short form-36 health survey (SF-36). One-third of HB patients had delay in diagnosis and treatment, and the incidence of inhibitors was 6.1%. Target joints were present in nearly half of HB patients. Missense was the main mutation type. 84.0% of mothers of HB patients in this study were found to be carriers. HEAD-US-C and HJHS can complement each other in the evaluation of joint status and give a valid basis for early clinical management. Early detection and preventive treatment, as well as reducing high-intensity replacement therapy and inhibitor generation, can effectively improve the QoL of patients.

ASSESSMENT OF HAEMOPHILIC ARTHROPATHY IN PATIENTS WITH SEVERE HEMOPHILIA USING THE HEMOPHILIA EARLY ARTHROPATHY DETECTION WITH ULTRASOUND (HEAD-US) SCORE AND THE HEMOPHILIA JOINT HEALTH SCORE (HJHS) BY DIFFERENT CAREGIVERS

Objective: There are few studies on the assessment of hemophilic arthropathy using the hemophilia early arthropathy detection with ultrasound (HEAD-US) and hemophilia joint health score (HJHS) scores.This study aimed to examine how radiologists and rheumatologists could evaluate hemophilic arthropathy in individuals with severe hemophilia using HEAD- US and HJHS scores simultaneously. Material and Methods: Between 2021 and 2022, 168 joints from 28 individuals with severe hemophilia A and B were investigated at six-month intervals (TP1 and TP2). The HJHS scores of all patients were recorded. The HEAD-US in each hemophilic patient's six joints (elbow, knee, and ankle) were evaluated by radiologists and rheumatologists. Results: The ankle assessment by HEAD-US showed the highest rate (34%) of synovitis by radiologist evaluation at TP1 in patients with an HJHS score of 0. The knee assessment by HEAD-US showed the highest rate (56%) of synovitis and bone damage by rheumatologist evaluation at TP1 in patients with an HJHS score of 0. HEAD-US ankle and knee examinations revealed the highest rate of synovitis (34%) by radiologist evaluation at TP2 in patients with an HJHS score of 0. The HEAD-US knee assessment revealed the highest rate of synovitis (44%) by rheumatologist evaluation at TP2 in patients with an HJHS score of 0. In the assessment of elbow and knee joints, there was a moderate to good correlation between HJHS and HEAD-US scores by different caregivers at different time points (p&lt; 0.05). Conclusion: Our findings indicate that clinicians play a crucial role in the early diagnosis of subclinical hemophilic arthropathy, with HEAD-US scoring conducted by rheumatologists similar to radiologists in severe hemophilia patients without pathology in HJHS scoring.

Predictive parameters for spontaneous joint bleeding during emicizumab prophylaxis

AbstractEmicizumab is approved for prophylaxis of patients with hemophilia A (HA). Despite its efficacy in reducing bleeding, some patients on emicizumab still experience hemarthrosis, but no tool is yet available to identify those at a higher risk of spontaneous joint bleeding. This study aimed to evaluate whether laboratory measurements (global coagulation assays and emicizumab concentration) and/or arthropathy scores can distinguish patients at higher risk of spontaneous joint bleeding while on emicizumab prophylaxis. A thrombin generation assay was performed upon the addition of tissue factor and synthetic phospholipids. Nonactivated thromboelastography was performed on citrated whole blood. Emicizumab concentrations were measured using a modified 1-stage factor VIII assay. The degree of hemophilic arthropathy was assessed using the Hemophilia Joint Health Score and Hemophilia Early Arthropathy Detection with Ultrasound (HEAD-US) score. A Cox proportional hazards model was used to evaluate the association between variables and bleeding. The predictive power of these variables was investigated using receiver operating characteristic (ROC) analysis. Forty patients with severe HA, with or without inhibitors, on emicizumab prophylaxis were enrolled in an observational cohort study. Ten of 40 developed spontaneous joint bleeding. None of the laboratory parameters were able to distinguish patients with a higher risk of spontaneous joint bleeding. ROC analysis showed that during emicizumab prophylaxis, only the presence of synovitis and a higher HEAD-US score were associated with spontaneous joint bleeding (area under the curve, 0.84). A greater degree of arthropathy and the presence of synovitis could help predict the risk of spontaneous joint bleeding in patients with HA on emicizumab prophylaxis.

Association Between Leg Muscle Thickness and Walking Test with the Haemophilia-Specific Functional Parameters.

To evaluate the muscle thickness and walking test in people with haemophilia A (PWH) and their correlation to joint health and functional impairments. Cross-sectional study. 29 severe/moderate PWH were enrolled. Muscle thickness of quadriceps and medial gastrocnemius were measured using ultrasound. Joint health and functional capacity were assessed using Haemophilia Joint Health Score (HJHS), Haemophilia Early Arthropathy Detection with Ultrasound (HEAD-US), 6-Minute Walking test (6MWT), Haemophilia Quality of Life Questionnaire for Adults (Haem-A-QoL), and Haemophilia Activities List (HAL). Quadriceps muscle thickness significantly correlated with HJHS knee, HEAD-US knee, and HAL. Calf muscle thickness significantly correlated with the HJHS ankle. After adjusted age and BMI, calf muscle thickness was inversely associated with the HJHS ankle. 6MWT was found to significantly correlate with HJHS total, HEAD-US total, Haem-A-QoL, and HAL. Muscle thickness and the distance of 6MWT were linked to assessment of joint health, quality of life and activity participation in PWH. Ultrasound measurement of muscle thickness and walking test appear to be useful tools for the assessment of joint health and functional status in PWH.

A post hoc comparative real-world analysis of HEAD-US score for joint health assessment of patients with severe haemophilia A and B in Spain.

Joint damage due to haemarthrosis can be effectively monitored with point-of care ultrasound using the Haemophilia Early Arthropathy Detection with US (HEAD-US) scoring system. A post hoc comparative analysis of the joint status of patients with severe haemophilia A (HA) or B (HB) was performed. The databases of two observational, cross-sectional studies that recruited patients with HA or HB from 12 Spanish centres were analysed to compare the status of the elbows, knees and ankles in patients with severe disease according to treatment modality. The HEAD-US score was calculated in both studies by the same trained operators. Overall, 95 HA and 41 HB severe patients were included, with a mean age of 35.2±11.8 and 32.7±14.2 years, respectively. The percentage of patients who received prophylaxis, over on-demand (OD) treatment, was much higher in HA (91.6%) than in HB (65.8%) patients. With a similar number of target joints, the HEAD-US score was zero in 6.3% HA and 22.0% HB patients (p<.01), respectively. The HA population showed significantly worse HEAD-US scores. Whilst osteochondral damage occurred more frequently in patients OD or tertiary prophylaxis, our data suggest that articular damage is less prominent in primary/secondary prophylaxis, regardless of the type of haemophilia. These latter treatment modalities were also associated with a lower prevalence of synovial hypertrophy, particularly in HB patients. This post hoc analysis indicates that joint status seems to be significantly influenced by haemophilia type (HA or HB) and treatment modality in these severe Spanish populations with severe disease. Continuing HEAD-US monitoring for the early detection and management of intra-articular abnormalities, as well as more efficiently tailored therapies should be warranted.

The Correlation of Muscle Mass and Walking Distance with Joint Health and Functional Status in Hemophilic Arthropathy Among People with Hemophilia a (PwHA)

Introduction: Hemophilic arthropathy resulting from repeat joint bleeding is a common complication for people with hemophilia (PWH), despite the current prophylaxis therapy. Monitoring the status of musculoskeletal health for PWH is necessary. Muscle plays a critical role in maintaining and promoting the joint health. Muscle atrophy is one of the key features of haemophilic arthropathy. Up to date, there are more studies focusing on joint health of PWH but few having attention on the impact of limbs muscles on joint status of PWH. Clinical assessments such as muscle circumference and manual muscle strength tests fail to detect subtle muscle changes. The study aimed to evaluate the ultrasound measurement of muscle thickness in people with hemophilia A (PwHA) and its correlation to joint health and functional impairments. Methods and Materials: In the observational cross-sectional study, 29 PwHA (median age 35 years; range 13-63) were enrolled, including 27 severe-type diseases on prophylaxis therapy and 2 moderate-type diseases on episodic treatment. Muscle thickness of quadriceps and medial gastrocnemius were measured by ultrasound. Joint health and functional capacity were assessed using Haemophilia Joint Health Score (HJHS), Haemophilia Early Arthropathy Detection with Ultrasound (HEAD-US), Haemophilia Quality of Life Questionnaire for Adults (Haemo-A-QoL), and Haemophilia Activities List (HAL). 6-Minute Walking Test (6MWT) for global functional evaluation. Results: At the time when the 29 patients receiving this survey of joint health, there were 28 on rFVIIIFc treatment for an average of 31.2 months (mean: 33.5, range 19.5－43), among whom 26 severe-type patients had rFVIIIFc prophylaxis and 2 moderate-type patients had on-demand therapy with rFVIIIFc. Only one severe-type patient had received non-rFVIIFc product prophylaxis for &amp;gt; 3 years. Totally 174 joints were examined. By correlation analysis, a significant correlation was found between both quadriceps and calf muscle thickness and the HJHS knee and ankle scores, respectively, with a negative correlation ( r= -0.45, p=0.015*, right quadriceps; r= -0.60, p&amp;lt;0.001***, left quadriceps; r= -0.39, p=0.039*, right calf; r= -0.58, p&amp;lt;0.001***, left calf). A significant correlation between muscle thickness and HEAD-US was observed between quadriceps muscle and knee score, with a negative correlation ( r= -0.56, p=0.017*, right quadriceps; r= -0.36, p=0.0048**, left quadriceps). Therefore, Quadriceps muscle thickness significantly correlated with HJHS knee, HEAD-US knee, and HAL. Calf muscle thickness significantly correlated with the HJHS ankle. After adjusted age and BMI, calf muscle thickness was significantly associated with the HJHS ankle. Muscle thickness was also observed to correlate with Haem-A-QoL and HAL. 6MWT was found to significantly correlated with HJHS total, HEAD-US total, Haem-A-QoL, and HAL ( r= -0.42, p=0.0231*, HJHS; r= -0.52, p=0.0037**, HEAD-US; r= -0.60, p&amp;lt;0.0001***, Haem-A-QoL; r= 0.64, p&amp;lt;0.001***, HAL). Conclusion: For the first time, limbs muscle thickness and the distance of 6MWT were linked to assessment of joint health, quality of life and activity participation in PwHA. Ultrasound measurement of muscle thickness appears to be a reliable tool for the assessment of muscle mass in PwHA.The 6MWT also appears to be useful tool for assessment of physical capacity and endurance in PwHA. Disclosures: No relevant conflicts of interest to declare.

A Prospective, Observational, Multi-Center Study of Rurioctocog Alfa Pegol Pharmacokinetic-Guided Prophylaxis Using Mypkfit in Severe Hemophilia a Patients in Taiwan (ATTRACT-HA Study): An Interim Analysis

Background Rurioctocog alfa pegol is a polyethylene glycol (PEG)-ylated recombinant antihemophilic factor VIII (FVIII) with an extended half-life, which allows prolonged dosing intervals. Using myPKFiT, the first and only FDA-cleared PK dosing software, healthcare professionals can simulate dosing regimens using patients' pharmacokinetic profiles. According to 2020 WFH Guidelines for the Management of Hemophilia, the trough level is suggested to be increased from &amp;gt;1% to 3-5% or higher to improve patient care (Srivastava et al. Haemophilia 2020). The Phase 3b Continuationstudy demonstrated that maintaining trough levels ≥3% with PK-guided prophylaxis in patients with severe haemophilia A reduced spontaneous annual bleeding rate (sABR), and thus led to the resolution of target joints (Chowdary et al. Haemophilia 2020). The ATTRACT-HA study will provide the first multi-center real-world evidence in Taiwan whether maintaining a predicted trough level of ≥3% using rurioctocog alfa pegol PK-guided prophylaxis using myPKFiT in severe hemophilia A patients can result in improved clinical outcomes as well as a better quality of life.This interim analysis will focus on the hemophilia-related characterization of the enrolled patients. Methods We enrolled patients, ≥12 years old with body weights of ≥30 kg and ≤140 kg, diagnosed with severe hemophilia A (FVIII clotting activity &amp;lt;1%). The enrolled patients were required to be on prophylaxis with rurioctocog alfa pegol for more than a month before the baseline visit and their historical bleeding data, 6 months prior to the screening visit, was also collected. Patients with a stable dosing regimen at the baseline underwent a myPKFiT PK assessment to determine if a patient was in the trough level &amp;lt;3% or ≥3% group (Figure 1). The primary endpoint of this study was to evaluate the clinical outcomes based on ABR and AJBR. Secondary endpoints included the scores of clinical outcomes with haemophilia early arthropathy detection with ultrasound (HEAD-US), the Haemophilia Quality of Life Questionnaire, and the international physical activity questionnaire (IPAQ) assessing patients' daily activity level performed at the baseline visit and in month 12. The date of data cut-off for this interim analysis was 5 th of January 2023. Results A total of 16 patients with severe hemophilia A were enrolled and stratified by myPKFiT PK assessment into two groups, with a trough level either &amp;lt;3% or ≥3%. There were 7 patients (median age: 23.0 y/o; Q1-Q3 15-29) in the trough level &amp;lt;3% group and 9 patients (median age: 43.0 y/o; Q1-Q3 35-55) in the trough level ≥3% group. Within 6 months prior to enrollment, 71.43% of the patients in the trough level &amp;lt;3% group experienced episodic bleeding, while only 44.44% of the patients experienced episodic bleeding in the trough level ≥3% group (Table 1). The median baseline HEAD-US score was numerically lower in the trough level &amp;lt;3% compared to the trough level ≥3% group (4.29 vs 24.11). The median score of Haem-A-QoL was 25.93 (Q1-Q3; 16.67-47.28) in the trough level &amp;lt;3% group and 42.93 (Q1-Q3; 28.89-48.37) in the trough level ≥3% group. Prospective 1-year follow-up assessments will be performed thereafter. Conclusion The ATTRACT-HA study is the first prospective, multi-center, observational study currently ongoing in Taiwan to provide real-world evidence of the effectiveness of rurioctocog alfa pegol PK-guided prophylaxis using myPKFiT app in patients with severe hemophilia A. In this interim report, we described the clinical features and factors of the study participants at the beginning of this real-world study. Between the two trough levels, we observed a higher percentage of patients experiencing episodic bleeding prior to PK-guided prophylaxis and lower baseline HEAD-US scores in the &amp;lt;3% trough level group, which may be in part due to the younger median age in this group. Acknowledgments The authors thank Dr. Brenden Chen for his contribution of clinical insight and editorial support during the abstract development. This study was funded by Takeda Pharmaceuticals Taiwan, Ltd. Disclosures Yi-Rou Lei, Chieh-Min Chen, Melody Cheng, Brenden Chen are employees of Takeda Pharmaceuticals Taiwan, Ltd. All the other authors disclose no relevant conflicts of interest.

Sequential Use of Monthly Low Dose Emicizumab and Factor VIII Concentrate Prophylaxis Among Patients with Hemophilia a: A Case Series Report

Introduction: The effectiveness of monthly low dose emicizumab of 1.0 to 2.0 mg/kg has been reported among patients with and without inhibitor. However, their trough level of emicizumab was rather low ranging from 5.9 to 11.9 mg/mL and breakthrough bleeding episodes often occurred at the 4 th week after administering emicizumab. Moreover, non-exposure to factor VIII is one concern among patients receiving emicizumab prophylaxis. Therefore, the study aimed to evaluate the effectiveness of sequential use of monthly low dose emicizumab and factor VIII concentrate prophylaxis among patients with hemophilia A. Methods: Patients with hemophilia A without inhibitor were recruited. Sequential use of monthly low dose emicizumab in the first week and factor VIII concentrate in the 4 th week was provided. Patients were closely monitored concerning the number and sites of bleeding episode, cause of bleeding from spontaneous or trauma-related conditions and the amount of additional factor VIII concentrate to treat breakthrough bleeding episodes. Also, the comparison of quality of life, hemophilia joint health score (HJHS), hemophilia early arthropathy detection by ultrasound (HEAD-US) and ultrasonography of bilateral elbows, knees and ankles before and after prophylaxis was conducted. Results: Five male patients (4 adults, 1 boy) with hemophilia A (severe 2, moderate 3) without inhibitor were enrolled in the study with the mean (SD) age of 26.8 (15.5) years. They encompassed low bleeding risk circumstances including avoidance of contact sports and high velocity activities. Four adults initially received episodic treatment and subsequent low dose prophylaxis at 15-20 units/kg twice weekly but breakthrough bleeding episodes frequently occurred. The only boy also received low dose prophylaxis at 14 units/kg once weekly at the age of 5.9 years and increased to twice weekly one month later due to frequent spontaneous bleeding at the right knee. However, the difficulty in venous access created constraint in achieving adequate prophylaxis. Therefore, all patients were switched to receive the whole vial of emicizumab at the monthly low dose ranging from 1.14 to 1.25 mg/kg without 4-loading doses for 2 years and sequential use of median (IQR) monthly low dose emicizumab of 1.50 (1.31, 1.65) mg/kg in the first week and factor VIII concentrate 15 units/kg twice weekly in the 4 th week in the third year. The duration of follow-up in the third year was 6 months. The results revealed the median (interquartile range, IQR) trough level of plasma emicizumab concentration at the 4 th weeks before factor VIII administration determined by a modified one stage factor VIII assay using emicizumab calibrator was maintained at 8.5 (6.2,10.8) µg/mL. The median (IQR) APTT of all patients at 6-month prophylaxis of 25.7 sec (25.3, 26.0) was shortened compared with a baseline of 66.9 sec (54.3, 105.1) demonstrating the presence of emicizumab and the likely absence of anti-emicizumab antibodies. Also, no inhibitor to factor VIII clotting activity was detected among all patients before and after prophylaxis. Their median (IQR) annual bleeding rate significantly decreased from baseline of 30.0 (13, 36.5) to 5.0 (3, 12.5) in the first year, 1.0 (0.5, 8.5) in the second year and 1 (0, 3) in the third year of prophylaxis with p-values of 0.043. Impressively, zero annual bleeding rate in the third year of the current study was found among 2 patients while 2 patients exhibited one episode of trauma-related bleeding at the ankle and one patient had frequent epistaxis from high PM 2.5 in his hometown. Ultimately, all patients achieved annual spontaneous joint bleeding rate ≤1 episode during a 6-month period of sequential use of emicizumab and factor concentrate prophylaxis. In addition, quality of life, HJHS, HEAD-US and ultrasonography study were improved in all studied patients. Factor VIII concentrate was helpful in preventing bleeding especially at the 4 th week after administering emicizumab and providing other biological activities beyond hemostasis related to bone remodeling, dysregulated macrophage polarization and inflammatory processes among studied patients. Conclusion: The sequential use of monthly low dose emicizumab and factor VIII concentrate prophylaxis showed effectiveness with annual spontaneous joint bleeding rate ≤1 episode among all studied patients. The musculoskeletal system and quality of life were also improved.

Characterization of Joint Disease in Women with Hemophilia: The Carriers Ultrasound Project (CUP) Study

Introduction: Women with hemophilia (WWH) are at risk for bleeding despite normal or mildly reduced plasma factor VIII (FVIII) or IX (FIX) activity levels. Subclinical joint bleeds can contribute to longstanding and irreversible joint damage. Although joint health has been well-studied among men with hemophilia, there is currently a gap in knowledge on the prevalence, clinical characteristics, and natural history of joint health in women with hemophilia. No prior studies have utilized point-of-care musculoskeletal ultrasound (POC-MSKUS) to assess the presence and characteristics of joint changes in carrier women. Aim: This multi-institutional, cross-sectional study primarily aimed to evaluate and compare the prevalence and extent of joint-related symptoms and joint changes in WWH compared to age-matched controls utilizing validated clinical tools including the Hemophilia Early Arthropathy Detection with Ultrasound (HEAD-US) protocol. We also aimed to examine the relationship between innate FVIII and FIX levels and presence of joint disease changes in this population. Methods: Between 2017-2023, women aged 18 to 40 years were enrolled and divided in 2 cohorts. The “carrier cohort” included women with a confirmed hemophilia A or B diagnosis, regardless of factor activity level. The “control cohort” included women without personal or family history of a bleeding disorder. Individuals were excluded if they had history of joint trauma or surgery within 12 months prior to enrollment or any history of joint replacement. Collected clinical information included presence of bleeding symptoms, joint-related symptoms, and historical use of hemostatic medications. Participants underwent clinical and radiological assessment of bilateral elbows, knees, and ankles using the Hemophilia Joint Health Score (HJHS) and HEAD-US protocol. Factor activity levels were measured in the carrier cohort. Descriptive and interferential statistics were performed using SPSS software with p&amp;lt;0.05 considered statistically significant. Results: Fifty-eight women, including 30 controls (51.7%) and 28 carriers (48.3%) were enrolled. The mean age at enrollment was 30.7 years (range: 19-39 years). Most women were White (79.3%) and Hispanic (51.7%). Of the 28 carriers, 85.6% (n=24) were hemophilia A carriers and 14.3% (n=4) hemophilia B carriers, respectively ( TABLE 1). Among carriers, the mean and median factor activity levels were 56% and 54% (range 20-120%) respectively. Carriers reported significantly higher prevalence of bleeding symptoms when compared to controls, including heavy menstrual bleeding (64.3% vs. 10%, p&amp;lt;0.001), epistaxis (25% vs. 3.3%, p=0.017), gingival bleeding (25% vs. 3.3%, p=0.017), and easy bruising (50% vs. 3.3%, p&amp;lt;0.001). The majority (53.5%, n=15) of carriers reported presence of joint-related symptoms when compared to controls, including joint pain (50% vs. 3.3%, p&amp;lt;0.001) and joint swelling (28.6% vs. 0%, p=0.02). Three (10.7%) carriers reported history of overt joint bleeds. Carriers had significantly higher mean HJHS scores (4.7 vs. 1.5, p&amp;lt;0.001) than did controls, however no significant changes in HEAD-US scores were found. A high body mass index (BMI) (&amp;gt;25kg/m2) was significantly associated with an increased prevalence of joint bleeding (25% vs. 0%, p=0.03) among carriers. When dividing carriers in 2 groups based on their baseline factor activity level (&amp;gt;40% versus &amp;lt;40%), the prevalence of bleeding manifestations and joint-related symptoms were similar ( TABLE 2). Carriers with factor levels &amp;lt;40% were more likely to require factor replacement on-demand (60% vs. 17.4%, p=0.046) and anti-fibrinolytics (60% vs. 17.4%, p=0.046) than carriers with factor levels &amp;gt;40%. There were no changes in mean HJHS or mean HEAD-US scores among the two groups. Conclusions: Women with hemophilia are at increased risk of bleeding manifestations and joint-related symptoms, regardless of factor activity levels. This population also seems to have poorer joint health than do non-carrier women as assessed by HJHS. Dedicated follow-up to help prevent and treat joint-related complications among WWH seems imperative. Our study did not detect significant ultrasonographic joint changes in the carrier cohort. However, joint findings may become more evident later in life or when assessed with magnetic resonance imaging. Further long-term studies are needed to support our hypothesis.

Diagnostic Value of the HEAD-US-C Scale for the Knees of Severe Hemophilia A Patients.

This study aimed to assess the reliability of the Hemophilia Early Arthropathy Detection with Ultrasound in China (HEAD-US-C) scale for the knees of severe hemophilia A (SHA) patients and to determine its diagnostic accuracy for assessments of knee-joint lesions in comparison with magnetic resonance imaging (MRI). We collected data from 32 knee joints of 21 patients diagnosed with SHA. The knees were evaluated based on the HEAD-US-C scale and the results were compared with the International Prevention Study Group (IPSG) scale. The HEAD-US-C scale was applied independently by two trained ultrasonographers blinded to the MRI results. The IPSG scale was applied independently by two radiologists blinded to the clinical data and ultrasound (US) results. The IPSG and HEAD-US-C scales exhibited good to excellent inter-rater reliability. Additionally, there was good to excellent agreement between the US and MRI results for the detection of knee lesions in SHA patients. The sensitivities of US for joint effusion, synovial hyperplasia, cartilage loss, and bone-surface irregularities in the knees of patients were 92.59, 100, 95.45, and 87.50%, respectively. The HEAD-US-C scale was positively correlated with the IPSG scale. US is important for evaluating knee lesions in patients with SHA and may potentially replace MRI.

PB0207 Joint Bleeding and Joint Evaluation in Von Willebrand Disease Assessed Using the Haemophilia Early Arthropathy Detection with Ultrasound (HEAD-US) Score

PB0207 Joint Bleeding and Joint Evaluation in Von Willebrand Disease Assessed Using the Haemophilia Early Arthropathy Detection with Ultrasound (HEAD-US) Score

How does joint impairment affect the functional capacity of the lower limb in early haemophilia-related arthropathy?

The impact of joint damage on functional capacity in patients with mild haemophilia (PwMH) has yet to be well studied. The primary aim of this study was to investigate the effect of joint impairment on the functional capacity of the lower limb in PwMH. The secondary aim was to identify physical predictors of lower limb functional capacity. Forty-nine PwMH were evaluated. Dynamic balance was assessed using Time Up and Go (TUG). Thirty-second sit-to-stand (30-STS) and 60-second-STS (60-STS) were used to assess muscle power and endurance, respectively. Haemophilia Early Arthropathy Detection with Ultrasound (HEAD-US) was used to assess joint damage. PwMH were divided based on HEAD-US: with joint damage (≥3 points) and without or with very low joint damage (0-2 points). Univariate ANOVA and multiple regression analyses were performed to identify differences in functional capacity and potential physical predictors. Only 30-STS showed significant differences between groups (p=.002). TUG and 60-STS were primarily explained by age (r2 =.21 and r2 =.44, respectively), while for 30-STS, age combined with joint damage and pain level explains 54% of the variance. Our findings indicate that the 30-STS is useful for assessing functional deterioration in people with early-stage haemophilia-related arthropathy. Our results also indicate that joint damage, combined with ageing and pain, may impact 30-STS outcomes in PwMH. Furthermore, our findings show that the loss in TUG and 60-STS performance in PwMH is related to ageing.

Factors associated with physical activity in young people with haemophilia A on prophylaxis.

Physical activity (PA) is influenced by numerous factors, and the literature describing why people with haemophilia (PWH) are physically active or not is inconclusive. To investigate factors associated with PA (mean min/day in light (LPA), moderate (MPA), vigorous (VPA) and total PA, and proportion meeting World Health Organization (WHO) weekly moderate-to-vigorous (MVPA) recommendations) among young PWH A. Forty PWH A on prophylaxis from the HemFitbit study were included. PA was measured using Fitbit devices and participant characteristics were collected. Potential factors associated with PA were investigated by univariable linear regression models for continuous PA outcomes, and descriptively for teenagers meeting/not meeting WHO MVPA recommendations only, because all except one adult met PA recommendations. Mean age (n=40) was 19.5 years (SD 5.7). Annual bleeding rate was nearly zero and joint scores were low. We found an increase of four min/day in LPA (95% confidence interval (CI) 1-7) per year increase in age. Participants with 'Haemophilia Early Arthropathy Detection with Ultrasound' (HEAD-US) score ≥1 engaged in mean 14 min/day less MPA (95% CI -23.2 to -3.8), and 8 min less VPA (95% CI -15.0 to -0.4) compared to participants with HEAD-US score 0. Teenagers who met PA recommendations had slightly better joint status compared to those who did not meet recommendations. These findings indicate that presence of mild arthropathy does not affect LPA but may have a negative impact on PA of higher intensities. Early start of prophylaxis may be an important determinant of PA.

Magnetic resonance imaging evidence for subclinical joint bleeding in a Dutch population of people with severe hemophilia on prophylaxis

BackgroundPrevious studies suggest that subclinical bleeding occurs in persons with hemophilia. ObjectivesThe aim of this study was to investigate whether patients with lifelong access to prophylaxis showed signs of previous subclinical bleeding on magnetic resonance imaging (MRI) in joints without a history of joint bleeding. MethodsThis single-center cross-sectional study included persons with severe hemophilia A on prophylaxis, aged 16 to 33 years, with lifetime bleeding records available. Per participant, 1 index joint without a history of joint bleeding was evaluated with 3-Tesla MRI, including hemosiderin sensitive sequences. MRI scans were reviewed according to the International Prophylaxis Study Group (IPSG) additive MRI scale (range, 0-17/joint). Hemosiderin deposits with/without synovial hypertrophy were considered signs of previous subclinical bleeding. Additionally, physical examination was performed, followed by ultrasound examination according to the Hemophilia Early Arthropathy Detection with Ultrasound protocol. ResultsIn 43 patients with a median age of 23.5 years, 43 joints (16 elbows, 13 knees, 14 ankles) without reported bleeds were evaluated with MRI. The median IPSG MRI score was 1 (range, 0-9). Signs of previous subclinical bleeding were observed in 7 of 43 joints (16%; 95% CI, 7-30): 7 of 7 joints showed hemosiderin deposits, with concomitant synovial hypertrophy in 2 of 7 joints. MRI changes were accompanied by swelling and ultrasound-detected synovial hypertrophy in 1 ankle only. None of the other joints showed abnormalities at physical examination and ultrasound. ConclusionIn this study, 16% of the joints without reported bleeds showed signs of previous subclinical bleeding, providing evidence for subclinical bleeding in people with severe hemophilia with lifelong access to prophylaxis.

How mild is mild haemophilia?

People with mild haemophilia (PWMH) experience sporadic bleeds and are less likely to receive an early diagnosis, appropriate treatment and medical care. Arthropathy is a key determinant of health-related quality of life (QoL), producing pain, limitations in mobility and daily activities. The aim of this study is to evaluate the incidence, risk factors and QoL associated with arthropathy in PWMH. Observational, cross-sectional cohort study. Data were collected in a single interview and evaluated by a physiotherapist and an orthopaedist and analysed on demographics; baseline factor levels; as well as clinical (Haemophilia Joint Health Score [HJHS]), ultrasound (Haemophilia Early Arthropathy Detection with Ultrasound [HEAD-US]), radiological (Pettersson score [PS]), pain (visual analogue scale [VAS]) and QoL evaluations. We defined arthropathy when at least one of the joints shown with a HEAD-US score≥1. Eighty-five patients and 510 joints were included. Patients' mean age was 35.9years-old. Median age was 44.2 in patients with arthropathy versus 14.9 in patients without; the difference was statistically significant (p<.001). In patients over 20years old, 90.5% shown arthropathy. Only 24 (28%) patients had no joint damage (HEAD-US=0), and 61 (72%) had at least one joint with a HEAD-US≥1. The ankle was the most affected joint. Patient age was found to be the most important risk factor associated with the development of arthropathy. Joint damage as a result of prior hemarthrosis was the most relevant factor associated with lower QoL, and emphasised the importance of early diagnosis and appropriate management in this particular population.

Long-term impact of primary prophylaxis on joint status in patients with severe hemophilia A

BackgroundPrimary prophylaxis with factor VIII concentrates is the therapeutic gold standard for severe hemophilia A. Although this approach will change substantially with the use of nonsubstitutive therapies, the long-term effects of primary prophylaxis remain unclear. We present information on joint health with tailored primary prophylaxis in a consecutive series at a single center. MethodsWe retrospectively analyzed 60 patients who did not develop early inhibitors. The annual bleeding rate and annual joint bleeding rate, prophylaxis characteristics, physical activity, adherence, and development of inhibitors were compared between those with and without joint involvement at the end of follow-up. Joint involvement was defined as a Hemophilia Joint Health Score or Hemophilia Early Arthropathy Detection with an ultrasound score ≥1. ResultsAmong 60 patients with median follow-up of 113 ± 6 months after starting prophylaxis, 76.7% had no joint involvement at the end of the follow-up. Those without joint involvement started prophylaxis at a younger median age (1 [IQR 1-1] year vs 3 [IQR 2-4.3] years). They also had lower annual joint bleeding rate (0.0 [IQR 0-0.2] vs 0.2 [IQR 0.1-0.5]), were more often physically active (70% vs 50%), and had lower trough factor VIII levels. Adherence to treatment was not significantly different between groups. ConclusionInitiation of primary prophylaxis at a younger age was the main factor associated with long-term preservation of joint status in patients with severe hemophilia A.

Reliability of haemophilia early arthropathy detection with ultrasound (HEAD-US) in children: a comparative magnetic resonance imaging (MRI) study.

Ultrasound (US) has been proven to be reliable in the assessment of early haemophilic arthropathy in the adult haemophilic population, however few studies so far focused on the reliability of US specifically in the paediatric haemophilic population. We were interested if the changing appearance of the growing bone hinders the ultrasonographic evaluation of the pathologic processes caused by haemophilic arthropathy. The aim of the study was to assess the reliability of US for evaluation of haemophilic arthropathy in children in comparison to magnetic resonance imaging (MRI). The study included all children aged 6 years or more with severe haemophilia in the country (n = 10). We assessed their elbows, knees, and ankles bilaterally by US and compared the results to the MRI as the reference standard. Pearson correlation coefficient (r) was used to analyse correlation. The correlation with MRI for the US for the total score was excellent for all joints (r = 0.849 for the elbows, r = 1 for knees, r = 0.842 for ankles). The correlation of scores for specific joint components showed fair, moderate, or excellent correlation for all joint components in all joints. The correlation was the lowest for the evaluation of cartilage and bone in the ankles (r = 0.546 and r = 0.478) and bone in the elbows (r = 0.499). Our study proved that US using the HEAD-US method performed by paediatric radiologists is a reliable tool for detection and quantification of haemophilic arthropathy in children in comparison to MRI.

Precisión diagnóstica de la Ecografía frente a la Resonancia Magnética en la afectación articular hemofílica

Background and objectives: In hemophiliac patients, recurrent intra-articular bleeding leads to progressive arthropathy. Magnetic resonance imaging (MRI) is the gold-standard technique for joint assessment. The development of ultrasound protocols and standardized scales such as “Hemophilia Early Arthropathy Detection with Ultrasound” (HEAD-US) and “Point-of-care Ultrasonography” (POC-US) allow patient monitoring. Our main objective is to establish the diagnostic accuracy of ultrasound in the early detection of hemophilic arthropathy, with MRI as the gold standard. The interobserver variability in the ultrasound and MRI scales, the association between the POC-US and HEAD-US protocol, and the ability of ultrasound to detect haemosiderotic remnants will also be established. Patients and Methods: 45 hemophiliac patients were included. 180 joints (knees and ankles) were evaluated with MRI (Denver scale) and Ultrasound (HEAD-US and POC-US scale). Results: There is a high and statistically significant association between the ultrasound and MRI scales. Only for the ankle effusion variable the association was medium. The specificity of HEAD-US was ≥90% in both joints. Sensitivity in the knee did not exceed 82% in any assessed aspect, being high in the ankle for the cartilage and bone alterations (97%) but low for effusions (55%). In general, the predictive values ​​were high, with the exception of the negative predictive value of joint leak in knee and ankle (close to 70%). Ultrasound did not detect haemosiderotic remnants in any case. Statistically significant interobserver agreement was obtained for HEAD-US and Denver-MRI assessment. The level of association between the HEAD-US scale and the POC-US protocol was medium. Conclusions: Ultrasound is a technique with high diagnostic accuracy and reproducibility to detect and quantify the early signs of hemophilic arthropathy. Ultrasound is insensitive to detect haemosiderin in synovial hypertrophy.

The value of ultrasonography in detecting early arthropathic changes and contribution to the clinical approach in patients of hemophilia.

The present study included 50 hemophilia patients who were admitted to Departments of Pediatric and Adult Hematology for routine follow-up. During routine follow-up controls, patients were scored by physical examination and HJHS 2.1 and by ultrasonography and HEAD US. Statistical tests were used to analyze joint health status and the results of US examination in the patient group. A total of 294 joints (elbow n=100, knee n=94, ankle n=100) were evaluated by ultrasonography. The mean HJHS and HEAD-US scores of the patients were 14.94 ± 15.18 and 15.6 ± 12.6, respectively. HEAD-US is accepted to be more sensitive than HJHS in detecting early signs of arthropathy. Detection of early abnormalities by ultrasonography will enable the development of individualized treatment protocols and to the prevention of arthropathy development.

The Application of Focused Medium-Energy Extracorporeal Shockwave Therapy in Hemophilic A Arthropathy.

Hemophilic arthropathy causes the damage of synovium, cartilage, and subchondral bone. The present study evaluated the safety and the effect of extracorporeal shockwave therapy (ESWT), a safe treatment widely used in musculoskeletal conditions in patients with hemophilic arthropathy. Between 1 August 2019 and 31 July 2020, seven hemophilia A patients were enrolled and treated with medium-energy ESWT on the knee joint in the first two months after prophylactic coagulation factor administration. At the beginning of the study and at 1-, 2-, 3-, and 6-month follow-ups, the Hemophilia Joint Health Score (HJHS), visual analog scale score (VAS), and Hemophilia Early Arthropathy Detection with Ultrasound score (HEAD-US) were evaluated for therapeutic effectiveness and safety, while serum bone morphogenetic protein 2 (BMP-2) and von Willebrand factor (vWF) levels were analyzed for assessing chondroprotection and bone healing. Magnetic resonance imaging (MRI) of the knee was performed at the beginning of the study and the 6-month follow-ups. As a result, a non-significant decrease in VAS scores (p = 0.151) but not HJHS after treatment was noticed. At the 3-month follow-up, there was a non-significant increase in BMP2 levels (p = 0.171) but not vWF. Ultrasonography showed no disease activity score elevation in five patients and no further disease damage in all patients. Repeated MRI examinations in three patients showed no structural progression during the 6-month follow-up. As to adverse events, redness, local heat, and mild swelling were noted in five patients without breakthrough bleeding. We concluded that medium-energy ESWT might be safe for hemophilic arthropathy once prophylactic coagulation factors are administered.