Hemophilia Joint Health Score Research Articles

Assessing joint health in haemophilia patients: The combined value of physical examination and ultrasound imaging.

Early diagnosis of joint damage is pivotal in haemophilia to prevent the occurrence and progression of haemophilic arthropathy thus providing optimal personalised management. The haemophilia joint health score version 2.1 (HJHS) is based on a physical examination of the mainly affected joints. Musculoskeletal ultrasound has demonstrated the capability to detect early changes in terms of synovitis and osteochondral damage. The haemophilia early detection with ultrasound (HEAD-US) score has been proposed as a simple and reliable evaluation tool. This study aims to investigate the correlation between the HJHS and the HEAD-US scores performed by two independent operators (physical therapist and musculoskeletal ultrasound expert) for the evaluation of the joint health status of patients with haemophilia. Consecutive adult patients independent of the severity degree were included. Elbows, knees and ankles were evaluated by a physical therapist by HJHS and by a musculoskeletal ultrasound expert following the HEAD-US protocol. We observed a good positive correlation between HJHS and HEAD-US (Spearman's rho 0.72). The main discrepancy in conceptually similar domains was found between the HJHS swelling and the HEAD-US synovitis (rho 0.17), as ultrasound was able to detect even mild synovitis when HJHS swelling was scored 0 in up to 40% of cases. The HJHS and HEAD-US correlate well even when performed by two independent operators. Musculoskeletal ultrasound is particularly useful for the early detection of synovitis. The routine assessment of both scores helps clinicians define the stage and extension of joint involvement and set up a personalised treatment.

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< 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.

Moderate- to vigorous-intensity physical activities for hemophilia A patients during low-dose pharmacokinetic-guided extended half-life factor VIII prophylaxis

BackgroundLow-dose pharmacokinetic (PK)-guided extended half-life (EHL) factor VIII (FVIII) prophylaxis can reduce the bleeding risk in hemophilia A (HA) patients. An increase in physical activities for promoting musculoskeletal health may enhance the benefits of prophylactic therapy.ObjectivesTo determine the clinical impact of moderate- to vigorous-intensity physical activities in HA patients during low-dose PK-guided EHL FVIII prophylaxis.Patients/MethodsThis prospective study enrolled patients with moderate/severe HA (baseline FVIII levels ≤ 5 IU/dL) who had received low-dose PK-guided EHL FVIII prophylaxis for ≥ 6 months. An individualized exercise protocol was introduced to each participant, targeting a 65% increase in the maximum predicted heart rate for ≥ 150 min/week, while continuing low-dose PK-guided EHL FVIII prophylaxis for 6 months. Before and after implementing the intervention, annualized bleeding rates (ABR), annualized joint bleeding rates (AJBR), Hemophilia Joint Health Scores (HJHS), skeletal muscle mass, hemophilia-specific quality-of-life (QoL) scores and annualized FVIII consumption were compared.ResultsOf 13 participants (mean age ± standard deviation [SD]: 20.1 ± 6.8 years), ABR, AJBR, and HJHS were significantly reduced (mean differences [MD] ± SD: −5.7 ± 2.6 bleeds/year, −4.2 ± 2.6 joint bleeds/year, and −4.3 ± 3.2 marks, respectively; P < 0.05) after applying the 6-month exercise protocol. Skeletal muscle mass and QoL scores had also improved (P = 0.001), while FVIII usage had decreased (MD ± SD: −129.1 ± 208.7 IU/kg/year; P < 0.05).ConclusionsThe combination of moderate- to vigorous-intensity physical activities with low-dose PK-guided EHL FVIII prophylaxis improves bleeding prevention, musculoskeletal status and QoL in patients with moderate/severe HA. By minimizing FVIII consumption, this strategy helps optimize hemophilia care in countries with budget constraints. ClinicalTrials.gov NCT05728528.

Force-sensing treadmill gait analysis system can detect gait abnormalities in haemophilia patients without arthropathy.

Joint damage in patients with haemophilia (PwH) is commonly assessed by imaging, but few reports have described how structural changes in joints, for example, haemophilic arthropathy (HA)-affect gait ability. We evaluated gait function among PwH with HA, PwH without HA, and people without haemophilia (non-PwH) using a Zebris FDM-T treadmill (FDM-T), an easy-to-use gait assessment instrument with a force sensor matrix. The following gait parameters were collected: centre of pressure trajectory intersection (COPi) anterior/posterior variability, COPi lateral variability, COPi anterior/posterior symmetry, COPi lateral symmetry, single-limb support line (SLSL) length, and SLSL variability. Participants walked at their typical gait speed. The physical function of the PwH was assessed by the Hemophilia Joint Health Score (HJHS). Parameters were compared among the three groups. Twelve PwH with HA, 28 PwH without HA, and 12 non-PwH were enrolled. Gait speed significantly differed between groups (non-PwH, 3.1±0.7; PwH without HA, 2.0±0.7; PwH with HA; 1.5±0.4). The COPi anterior/posterior variability, COPi lateral variability, SLSL length, and SLSL variability were greater in the PwH groups than in the non-PwH group. The COPi lateral symmetry differed between PwH with HA and the other groups. The HJHS was not correlated with gait parameters among PwH with HA. Gait parameters and speed were abnormal in both PwH with HA and PwH without HA. The FDM-T can be used to identify early stages of physical dysfunction that cannot be detected by conventional functional assessments such as the HJHS.

Benefits of physical activity self-monitoring in patients with haemophilia: a prospective study with one-year follow-up.

Activity wristbands have been shown to be effective in relation to self-monitoring activity levels and increasing exercise adherence. However, previous reports have been based on short-term follow-ups in people with haemophilia (PWH). (1) To evaluate compliance with physical activity (PA) recommendations in PWH during a 1-year follow-up period using activity wristbands to record daily steps and intensity; (2) To determine the effect of PA self-monitoring on clinical outcomes. A prospective observational study was conducted in 27 adults with severe haemophilia undergoing prophylactic treatment. The Fitbit Charge HR was used to track daily PA for an entire year. The participants were encouraged to try to reach a goal of 10,000 steps/day and to track their progress. The pre- and post-evaluation included quality of life (A36 Hemophilia-QoL Questionnaire), joint health (Haemophilia Joint Health Score), functionality (Timed Up and Go test), and muscle strength. A total of 323.63 (95%CI: 194-364) valid days (i.e.,>2000 steps) were recorded. The annual average number of steps per day taken by participants was 10,379. Sixteen (59%) PWH reached 10,000 steps/day at baseline and 17 (63%) at 1 year follow-up, with no significant differences (x2=.33; p=.56). A statistically significant improvement was observed in daily moderate activity time (p=.012) and in the 'physical health' quality of life subscale (mean difference: 2.15 points; 95%CI:.64-3.65; p=.007). Our results suggest that patients with severe haemophilia who self-managed their PA can improve their long-term quality of life in the domain of physical health and also the daily time spent in moderate-intensity PA.

Using reference equations to standardise incremental shuttle walk test performance in children and young people with chronic conditions and facilitate the evaluation of exercise capacity and disease severity

AimsThe aim was to evaluate whether standardised exercise performance during the incremental shuttle walk test (ISWT) can be used to assess disease severity in children and young people (CYP) with...

The frequency of sarcopenia in haemophilia patients: Effects on musculoskeletal health and functional performance.

In patients with haemophilia A, chronic arthropathy develops over time as a result of recurrent joint bleeds, which leads to restricted mobility and disability in the affected joints. There are limited studies in the literature evaluating sarcopenia in patients with haemophilia. The present study aims to determine the prevalence of sarcopenia in severe haemophilia-A patients and to evaluate musculoskeletal health and functional performance. Thirty haemophilia-A patients and 26 adult male volunteers were enrolled in the study. For detection of sarcopenia, the appendicular skeletal muscle mass (ASM) obtained by bioelectrical impedance analysis (BIA) was divided by height squared (m2 ) to obtain the appendicular skeletal muscle mass index (ASMI) value. The thighs of both lower extremities were measured using the Modified Sonographic Tight Adjustment Ratio (STAR) method, which was obtained by adding the bilateral rectus femoris and vastus intermedius muscle thicknesses measured by ultrasound. Hand and quadriceps muscle strength (MS) were measured with a dynamometer. Physical performance was determined using the walking speed (WS), timed up-and-go test (TUGT), 5-repetition sit-to-stand test (5RSTS), and 6-min walk test (6MWT). Haemophilia Joint Health Score (HJHS) and Haemophilia Early Arthropathy Detection-Ultrasonography (HEAD-US) were also used to assess the musculoskeletal system. According to the modified STAR values calculated based on body mass index, sarcopenia was present in 15 (50%) of 30 patients. However, based on the ASMI-BIA values, sarcopenia was present in only two (6.6%) patients. A weak correlation was found between ASMI and HJHS, HEAD-US, WS, TUGT, and hand MS (left), while a moderate correlation was found with knee MS (right), knee MS (left), and 5RSTS. A strong correlation was found between the modified STAR score and HEAD-US, HJHS, knee MS (left), 5RSTS, TUGT, and WS, while a moderate correlation was found with hand MS (left), hand MS (right), and knee MS (right). This study showed muscle loss, joint mobility restrictions, and decreased functional capacity in haemophilia patients and demonstrated the presence of sarcopenia in these patients. The STAR measurement method showed stronger relationships with MS and functional performance values than ASMI measurements in terms of evaluating sarcopenia.

Effectiveness of emicizumab in preventing bleeding events in severe and moderate hemophilia A: A single-center experience in Bangladesh.

Emicizumab is a monoclonal antibody that bridges activated factor IX (FIX) and factor X (FX) to replace the function of missing activated factor VIII (FVIII) in hemophilia A patients irrespective of FVIII inhibitor status. This study assessed the effectiveness of emicizumab in preventing bleeding episodes in patients with hemophilia A. This observational study included patients with moderate to severe hemophilia A who were undergoing episodic FVIII replacement therapy. The primary endpoint was the difference in annualized bleeding rates (ABR) and the secondary endpoint was the difference in Hemophilia Joint Health Score (HJHS) before and after emicizumab prophylaxis. A total of 30 male hemophilia patients were included, the mean age was 16.7 (SD: ±8.1) years, and most of them had moderate hemophilia A [63.3%]. Before prophylaxis, the median ABR was 48 (interquartile range [IQR]: 35-60), and 93.3% of patients had ABR greater than eight, whereas after prophylaxis the median ABR decreased significantly (median [IQR]: 0 [0.0-0.4], p<0.001), and 56.7% had zero bleeds. ABR was not significantly different in patient with and without FVIII inhibitors. The HJHS scores significantly improved after prophylaxis (10 vs. 2.5, p<0.001). The bleeding events were reduced significantly (23 vs. 0.0, p<0.001), and zero new target joints were reported after prophylaxis. Most of the patients [93.3%] did not face any serious adverse events after prophylaxis. Emicizumab prophylaxis was associated with a significantly lower rate of bleeding events among participants with hemophilia A, regardless of inhibitor status.

The effectiveness and safety of octocog alfa in patients with hemophilia A: up to 7-year follow-up of the real-world AHEAD international study.

Real-world data assessing treatment outcomes in patients with hemophilia A in routine clinical practice are limited. To evaluate the effectiveness and safety of octocog alfa in patients with moderate/severe hemophilia A receiving treatment in clinical practice. The international Antihemophilic Factor Hemophilia A Outcome Database study is an observational, noninterventional, prospective, multicenter study. This planned interim data read-out was conducted following 7 years of observation of patients receiving octocog alfa (cut-off, 30 June 2020). The primary endpoint was joint health status, assessed by the Gilbert Score. Secondary endpoints included annualized bleeding rates (ABRs), Hemophilia Joint Health Score (HJHS), health-related quality of life, consumption, and safety. This post hoc analysis stratified data by hemophilia severity at baseline [moderate, factor VIII (FVIII) 1-5%; severe, FVIII <1%]. Of the 711 patients in this analysis, 582 (82%) were receiving prophylaxis with octocog alfa at enrollment, and 498 (70%) had severe disease. Median Gilbert Scores were higher with on-demand therapy versus prophylaxis and scores were comparable in moderate and severe disease. In patients receiving prophylaxis, there was an improvement in HJHS Global Gait Score over 7 years of follow-up overall and in patients with severe disease. ABRs and annualized joint bleeding rates were low across all 7 years. An ABR of zero was reported in 34-56% of prophylaxis patients versus 20-40% in the on-demand group. ABRs were similar in severe and moderate disease. In total, 13/702 (1.9%) patients experienced 18 treatment-related adverse events. These data demonstrate the long-term effectiveness and safety of octocog alfa in patients with moderate and severe hemophilia A, especially in those receiving prophylaxis. The high number of patients receiving on-demand treatment experiencing zero bleeds could be due to selection bias within the study, with patients with less severe disease more likely to be receiving on-demand treatment. ClinicalTrials.gov: NCT02078427.

Emicizumab Prophylaxis in Patients with Severe Hemophilia A: Insights from A Resource Limited Country.

In this prospective study, severe HA patients were recruited from January 2022 to June 2023. Inhibitor positive and inhibitor negative patients with annual bleeding rate (ABR) 8 or greater and past histories of bleeding like intra-cranial, intra-abdominal, and pseudo-tumors were included. Emicizumab loading dose was 3 mg/kg in the first 4 weeks, and the maintenance dose was started at week 5 at 6 mg/kg/month. Patients' detailed bleeding history and demographics were recorded. The five-level EuroQol five-dimensional questionnaire (EQ-5D-5L) was used to evaluate patients' HRQoL. Furthermore, Hemophilia Joint Health Score (HJHS) and Functional Independence score in Hemophilia (FISH) were applied for the assessment of joints at different time points. Results were analyzed by SPSS version 21. A total of 36 HA male patients with the mean age of 19.7 ± 14.42 years were recruited in the study; among them, 19 patients were inhibitor positive, while 17 were negative. Patients clinically presented with bleeding symptoms which included: hemarthrosis 95%, GI bleeding 13.8%, and bruises and gums bleeding 13.8%. Significant reduction was observed in the bleeding episodes after the therapeutic intervention, and joints assessment and Euro-Quality-of-life Visual Analog Scale showed a significant improvement in health after treatment. Similarly, there was a remarkable reduction in bleeding episodes and improved quality of life among HA patients. The ABR decreased from 53.6% episodes per year prior to treatment to 2.4% during Emicizumab therapy. Prior to initiating Emicizumab therapy, participants exhibited an average FISH score of 16 and HJHS score of 10, indicating moderate limitations due to joint-related issues. After treatment, the mean FISH score improved to 9 and HJHS score to 4 reflecting a substantial enhancement in participants' ability to perform daily activities (P < 0.057). Our results showed that HA patients on prophylactic treatment with Emicizumab were less restricted and had improved quality of life due to marked decrease in bleeding episodes which resulted in improved health and social lives. In addition, it was well tolerated, and no participant discontinued treatment because of adverse events.

Low-dose emicizumab prophylaxis in patients with severe hemophilia A: a retrospective study bringing new hope for our patients

BackgroundLow-dose emicizumab can potentially offer a cost-effective treatment option in persons with hemophilia A, especially in developing countries. ObjectivesTo compare the efficacy and safety of low-dose emicizumab with those on low-dose factor (F)VIII prophylaxis via chart review. MethodsAfter ethics approval, chart data of 2 groups of patients were reviewed: group 1 (low-dose emicizumab, n = 10; 3 mg/kg monthly without a loading dose) and group 2 (low-dose FVIII prophylaxis, n = 10; 10-20 IU/kg of FVIII concentrates twice a week). Outcomes were target joints, annual bleeding rate, annual joint bleeding rate, Hemophilia Joint Health Score, nonactivated thromboelastometry–rotational thromboelastometry clotting time, plasma emicizumab levels, and direct costs of treatment. ResultsAll outcome measures were significantly better in the low-dose emicizumab group than in the low-dose FVIII prophylaxis group. For nonactivated thromboelastometry–rotational thromboelastometry, median values after 6 months in the low-dose emicizumab group were comparable with values seen in patients with mild hemophilia, while the values in the low-dose FVIII prophylaxis group were similar to those of patients with moderate hemophilia. The direct cost of low-dose emicizumab was found to be approximately US $6000 and that for low-dose recombinant FVIII prophylaxis used in our study was US $6282 (the cost may range from US $3432 to $7920 depending on the type of factor) when compared to approximately US $15 000 for standard-dose emicizumab. ConclusionLow-dose emicizumab offers a cost-effective treatment option and can improve access in developing countries. These findings need to be confirmed in a larger and better-controlled study.

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.

Three-Year Interim Analysis Results of the AOZORA Study to Evaluate the Long-Term Safety and Joint Health in Children with Hemophilia A without Factor VIII Inhibitors Receiving Emicizumab

Background: Recurrent joint bleeding from a young age in people with hemophilia A (PwHA) may lead to hemophilic arthropathy, resulting in limited movement and chronic pain. Emicizumab is a bispecific monoclonal antibody that bridges activated factor (F) IX and FX to substitute for activated FVIII and provides stable plasma concentrations and maintenance of trough levels within the therapeutic range. Limitations in long-term joint health preservation have been reported with FVIII prophylaxis (Warren et al. Blood Adv 2020); it is expected that emicizumab may overcome these limitations, as joint health improvements have been demonstrated in PwHA aged 12-39 years (Kiialainen et al. Haemophilia 2022). Here, we report the 3-year interim analysis of the ongoing, open-label, Phase IV AOZORA study (JapicCTI-194701), analyzing long-term safety and joint health in pediatric PwHA without FVIII inhibitors receiving emicizumab (Shima et al. BMJ Open 2022). Methods: Eligible participants were aged &amp;lt;12 years with severe hemophilia A (HA) without FVIII inhibitors. Participants entered AOZORA as emicizumab-naïve or following the Phase III HOHOEMI study (Shima et al. Haemophilia 2019). Primary endpoints include adverse events (AEs), and joint health and function assessed by magnetic resonance imaging (MRI) and the Hemophilia Joint Health Score (HJHS) version 2.1. MRI evaluation uses the International Prophylaxis Study Group (IPSG) MRI scale; a positive IPSG score indicates pathological changes in the knee and/or ankle joints. Exploratory endpoints include annualized bleed rate (ABR) for treated bleeds and treated joint bleeds. All participants will receive emicizumab for 6 years from their first dose until study end. Results: Data cut-off was the last day of Week 145 for individual participants. Ten participants entered from HOHOEMI and 20 participants were newly enrolled. The median (range) age was 4.2 (0.7-11.1) years, all participants were male, and 27 (93.1%) participants had been treated with prior FVIII prophylaxis ( Table 1). One participant had 1 target joint (knee) at Week 1. In AOZORA, 5 (16.7%) participants experienced 7 emicizumab-related AEs: 6 injection site reactions in 5 participants and 1 case of anemia in 1 participant. Seven serious AEs, reported as unrelated to emicizumab, occurred in 5 (16.7%) participants. No thrombotic events or thrombotic microangiopathies occurred. Twenty-nine participants at Week 1 and 26 participants at Week 145 were assessed using the IPSG MRI scale. At Week 145, MRI scores remained at 0 for 11 (42.3%) of the 26 participants. Of 116 joints assessed at Week 1, 28 (24.1%) had soft tissue changes (effusion/hemarthrosis, synovial hypertrophy and/or hemosiderin deposition; Table 2). At Week 145, 104 joints were assessed and 33 (31.7%) of those had soft tissue changes. Of 10 (8.6%) joints with synovial hypertrophy and hemosiderin at Week 1, all had improved at Week 145 and synovial hypertrophy and hemosiderin were no longer present in 9 joints. One new joint developed synovial hypertrophy and hemosiderin at Week 145. The rest of the soft tissue changes were effusion/hemarthrosis, present in 21 (18.1%) joints at Week 1 and 31 (29.8%) at Week 145. Thirty participants at Week 1 and 27 participants at Week 145 were assessed using the HJHS v2.1. Eighteen (66.7%) participants' HJHS scores remained at 0 from Week 1 to Week 145 and 1 (3.7%) participant's remained at 4; 6 (22.2%) participants' scores improved; 2 (7.4%) participants' scores worsened. Mean (standard deviation) HJHS total score improved from 0.90 (1.79) at Week 1 to 0.44 (1.05) at Week 145. The mean (95% confidence interval [CI]) ABR for treated bleeds was 3.7 (0.94-9.80) prior to emicizumab and 0.7 (0.01-5.10) while receiving emicizumab. The mean (95% CI) ABR for treated joint bleeds was 0.4 (0.00-4.55) prior to emicizumab and 0.2 (0.00-4.04) while receiving emicizumab. Conclusions: This 3-year interim analysis of the AOZORA study confirmed the safety profile of emicizumab. The proportion of joints with effusion/hemarthrosis increased by Week 145. However, all joints with synovial hypertrophy and hemosiderin, which are strongly associated with the progression of arthropathy (Gualtierotti et al. J Thromb Haemost 2021), improved by Week 145. These results suggest that emicizumab is effective in maintaining and improving joint health in pediatric PwHA.

Experience with Emicizumab Among People with Hemophilia A in the Canadian Hemophilia Bleeding Disorders Registry

Background: The use of emicizumab as prophylaxis to prevent bleeding or reduce the frequency of bleeding episodes in congenital hemophilia A (HA) was approved by Health Canada for the treatment of people living with HA (PwHA) with FVIII inhibitors in 2018, and without inhibitors in 2019. Here we present the results of a non-interventional, cohort study, using data routinely collected by the Canadian Bleeding Disorders Registry (CBDR) to evaluate treatment patterns of emicizumab in Canada and the associated safety and effectiveness outcomes, including quality of life. Methods: De-identified data were extracted from the CBDR database for all registered PwHA who had received emicizumab at least once prior to December 31, 2022. Baseline demographic characteristics were stratified by disease severity (defined by the level of endogenous FVIII activity) and age. Effectiveness outcomes were measured by the proportion of patients with zero, traumatic, spontaneous, or joint bleeds as well as annualized bleeding rates (ABR) for any treated bleed. Intra-patient comparisons of bleeding were performed for all patients and for those with at least six months follow-up in both pre- and post-emicizumab periods as a sensitivity analysis. Effectiveness outcomes also included patients' Hemophilia Joint Health Score (HJHS), Patient Reported Outcomes, Burdens and Experiences (PROBE), and EQ-5D index and visual analog scale (VAS) scores. We performed a complete data analysis, without imputation. This study was approved by the research ethics board of McMaster University and other participating centers, and abides by the guiding principles of the Declaration of Helsinki. Results: In total, 533 PwHA received at least one dose of emicizumab (PwHA E) in the CBDR database. Overall, 498 (93.4%) PwHA E had severe disease, 28 (5.3%) had moderate disease, and 7 (1.3%) had mild disease. At start of emicizumab exposure, 220 (41.3%) PwHA E were &amp;lt;18 years old; 78 (14.6%) PwHA E had current FVIII inhibitors, 82 (15.4%) had a history of FVIII inhibitors, and 373 (70%) had no history of inhibitors ( Table 1). A total of 13 adverse events were reported in the entire observation period, including one event of thrombosis (occurring in one person with COVID-19), seven allergic reactions, two FVIII Inhibitor development, two neurological events (headache; and headache, nausea, and vomiting) and one case of large hematoma developed at operative site following removal of port-a-cath. Moreover, nine COVID-19 cases were reported as adverse events. Over a median (first quartile, third quartile) follow-up time of 249 (136, 395) days, 388 (72.8%) PwHA E had no recorded bleeds. Out of 145 PwHA E with recorded bleeds, 106 had joint bleeds, 87 had traumatic bleeds, 69 had spontaneous bleeds and 46 had other bleeds (Table 2). An intra-patient comparison in all PwHA E (n=533) showed a decrease in mean (95% confidence interval [CI]) annualized bleeding rate (ABR) from 1.22 (1.06, 1.42), pre-emicizumab (2018, prior to first dose) to 0.50 (0.41, 0.60) post-emicizumab (rate ratio (95% CI) 0.41 (0.33, 0.50), p-value &amp;lt;0.001). The Intra-patient comparison in PwHA E without current inhibitor (n=455) showed a decrease in mean ABR (95% CI) from 1.02 (0.87, 1.19) to 0.54 (0.44, 0.66) (rate ratio (95% CI) 0.53 (0.43, 0.65), p-value &amp;lt;0.001). The Intra-patient comparison in PwHA E with current inhibitor (n=78) showed a decrease in mean ABR (95% CI) from 5.03 (3.30, 7.66) to 0.41 (0.26, 0.65) (rate ratio (95% CI) 0.08 (0.04, 0.15), p-value &amp;lt;0.001). Conclusions: This analysis describes the baseline characteristics, safety and effectiveness outcomes of Canadian PwHA treated with emicizumab before December 31, 2022. A total of 387 new patients were included in this analysis compared to the previous one (data cut: December 31, 2021, n=146). The data shows that 72.8% PwHA E had no recorded bleeds since they started emicizumab and that there was a substantial decrease in bleeds post-emicizumab in both PwHA with and without current FVIII inhibitor. The safety profile of emicizumab was consistent with previous reports. The CBDR allows for a longitudinal follow-up of the Canadian hemophilia A population, which can inform healthcare practitioners and regulatory authorities of the safety and efficacy outcomes of treatments in routine clinical practice.

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.

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.

Changes in Health-Related Quality of Life, Pain and Functional Parameters in People with Hemophilia and People with Osteoarthritis - a Comparative Follow-up of Physiotherapeutic Training (Physio-FUN Study)

Background: Spontaneous joint bleeding is common in people with hemophilia (PWH). These bleeds lead to reduced physical activity and thus to a weakening of the musculature. Common sequelae of this are synovitis and cartilage damage. In the long term, secondary osteoarthritis, so-called hemophilic arthropathy, occurs with changes and progressive destruction of joint structures (Lafeber et al., 2008). Hemophilic arthropathy is age-independent and can lead to severe movement restrictions and significant limitations in health-related quality of life (HRQoL) of affected PWH (Varaklioti et al., 2018). To prevent advanced stages of arthropathy not only regular assessment of musculoskeletal status and early detection of symptoms, but also daily rehabilitation exercises at home, and implementation of appropriate physiotherapy and medical training are important (Bossard et al., 2008). Home exercises and manual therapy can be used without causing bleeding or pain to improve pain, HRQoL and functionality (Tat et al., 2021). The primary aim of the Physio-FUN study was to assess the subjective (Hemophilia Exercise Project Test-Questionnaire [HEP-Test-Q]) and objective physical functioning (Hemophilia Joint Health Score [HJHS]) during the course of 1-year applied physiotherapy comparing PWH with arthropathy and patients with osteoarthritis (PWO). Methods: In this prospevtive, controlled monocentric cohort study it was planned to enroll 20 adult PWH A or B compared to 20 gender-matched adult PWO without a bleeding disorder. Patients with a blood pressure ≥ 180/110 mmHg were excluded. A positive ethical approval for the study was obtained by the Ethics Committee North Rhine, Germany. After informed consent had been obtained, the study participants underwent examinations based on clinician-reported outcomes (ClinRO) and performance outcomes (PerfO) and completed different patient-reported outcomes (PROs). ClinROs included ultrasound, functional movement screen (FMS) and the collection of anthropometric and clinical data; PerfOs included cardiopulmonary performance, 6-minute walk test (6MWT), blood pressure measurement before and after 6MWT, joint mobility (neutral-zero method) and Functional Movement Screen (FMS) to evaluate movement pattern quality; PROs included the assessment of sociodemographic data, HRQoL (SF-12), Physical Activity Questions (EPIC - Simple Index), pain sensation scale (SES) and Borg Rating of Perceived Exertion (RPE) measuring physical activity intensity level. All patients took part in regular physiotherapy (once a week) at the ARZD as prescribed by a physician. During the study, PWH continued to receive their usual hemophilia treatment regimen without study-related changes. Over a period of 12 months, ClinROs, PerfOs and PROs were collected repeatedly on a quarterly basis. Each patient was supposed to participate in 5 measure points (baseline, every 12 weeks over a one-year period). Ultrasound examinations were performed at baseline and at the conclusion at MZP5 in all patients. Results: At baseline 17 PWH (mean age 43.29±13.1 years) and 12 PWO (mean age 61.42±8.5 years) were enrolled; most PWH had HA (88.2%) were severely affected (58.8%) and 6/17 had a knee endoprosthesis. 88.2% of PWH had a disabled card (most with a disability degree of ≥ 80) compared to 45.5% of PWO (most with a disability degree of 50). PWH had a significant worse orthopaedic joint status ( p&amp;lt;.002) and subjective physical functioning ( p&amp;lt;.001) compared to PWO; PWH had a mean HJHS of 26.76±18.0 vs. 11.0±5.7 and a mean HEP-Test-Q of 48.12±16.4 vs. 67.08±9.1. PWO reported highest impairments in the domain ‘mobility’, while PWH suffered mainly under reduced ‘endurance’. With respect to their age, height and weight most of the PWH were below the predicted lower limit of the 6MWD compared to the PWO who all were above the lower limit of the 6MWD. No difference was found between the groups regarding FMS (11.34±3.8) and RPE before (11.5±3.3) after 6MWT (11.5±3.3). Conclusions: Our study took place during the Corona pandemic and was quite time consuming for the participants, resulting in a failure to reach the desired number of cases and lead to a high drop-out rate over the duration of the project. Although PWH were significantly younger than PWO, they had a significantly worse subjective (HEP-Test-Q) and objective physical functioning (HJHS).

Emicizumab Efficacy in Severe Hemophilia (A): Experience in Ecuador

Introduction: In Ecuador, there are 1708 cases of hemophilia in a population of 17,643,060 habitants; according to the World Federation of Hemophilia (WFH) Annual Global Survey Report 2020 released in October 2021. Eleven patients use emicizumab in Ecuador (ten patients under ministerial authorization, and one patient through private insurance); being the first administered in June 2021. Objectives: To describe the demographic characteristics of patients receiving emicizumab in Ecuador. To determine efficacy and response with emicizumab: based on annual bleeding rate (ABR), performance status assessment, activity, and participation. Methods: Population: Pediatric Severe Hemophilia A (PwHA) patients (&amp;lt;12 years) and adults/adolescents (&amp;gt;12 years), both from the public and private health sector. Study design: Retrospective, multicentric study, with a case-report research design. The sources of information were the medical records of the patients. Efficacy variables: ABR was calculated by: (number of bleeds/number of days times 365.25). Body structure and function was assessed with the Hemophilia Joint Health Score 2.1 (HJHS). Activity and participation were assessed with the Functional Independence Score in Hemophilia (FISH). Statistic analysis: Shapiro-Wilk test to know the distribution of the sample, t-Test paired tests (parametric), Wilcoxon statistic (non-parametric); Descriptive statistics: relative frequencies, measures of central tendency and dispersion, column graphs. Analysis and results: Ten patients with an average (Q1,Q3) age of 11.5 years (7.15) were registered. The youngest patient was one year old and the oldest, fifty years old. 90% (n:9) had hemophilia A with high-response inhibitors. Prior to starting emicizumab: 20% (n:2) presented Central Nervous System bleeding, 30% (n:3) had muscle bleeding, and 10% (n:1) developed catheter-associated infection. The mean ABR was 10 pre-emicizumab events, and 0.3 post-emicizumab events (p=0.002), with follow-ups at 22 months (n: 2), 17 months (n:2), 3 months (n:2 ), 4 months (n: 3), 5 months (n: 1). The mean HJHS (±SD, n) was 20.9 (± 20,096, 10) pre-emicizumab, and 9.7 (± 16.52, 10) (p=0.003) The mean by FISH (±SD, n) was 16.2 (± 8.59, 10) pre-emicizumab, and from 22.6 (± 11.62, 10) with the use of emicizumab. The use of the t-Test for paired samples determined that there are statistically significant differences between the pre-emicizumab and post-emicizumab groups for the variables ABR, HJHS and FISH (95% confidence level). Conclusion: The use of Emicizumab allowed better control of joint bleeding; and it contributed favorably in the evolutionary course of both the functional state and the activity. It is essential to corroborate these results with a longer follow-up and a larger sample size. Bibliography: 1. Alvarez Roman M: Spanish guidelines for the management of hemophilia. 2022, 1-190. 2. Callaghan M, Negrier C, Paz-Priel I, Chang T, Chebon S y col: Long-term outcomes with emicizumab prophylaxis for hemophilia A with or without FVIII inhibitors from the HAVEN 1-4 studies. Blood. 2021;137(16):2231-2242 3. Carcao M, Escurriola C, Santagostina E, Oldenburg J, Liesner R y col: The changing face of immune tolerance induction in haemophilia A with the advent of emicizumab. Haemophilia. 2019;25:676-684. 4. Ellsworth P, Ma A: Factor-mimetic and rebalancing therapies in hemophilia A and B: the end of factor concentrates?. Hematology Am Soc Hematol Educ Program. 2021, Dec 10;2021(1):219-225. 5. Young G: Management of children with hemophilia A: How emicizumab has changed the landscape. Journal of Thrombosis and Haemostasis. 2021 Jul;19(7):1629-1637