Utility of the Haemophilia Joint Health Score in study of episodically treated boys with severe haemophilia A and B in Lithuania

Summary. Musculoskeletal outcome remains the major hallmark of haemophilia. The purpose of the study was to assess joint status using a new musculoskeletal assessment tool in children with haemophilia and describe the development of haemophilic arthropathy during childhood and puberty focussing on the age of remarkable changes. The prospective study involved Lithuanian patients aged 4–17 years with severe haemophilia A and B, no signs of inhibitors and treatment on‐demand. Patients were subdivided into two groups according to actual age. Group I patients were 4–9 years and group II patients 10–17 years of age. The musculoskeletal status was measured using the Haemophilia Joint Health Score (HJHS). We report on 20 patients with a mean age of 11.5 years (SD 4.3, range 4–17.2 years). The mean HJHS score was 24.5 (SD 14.5, range 5–50). The most affected joints were ankles, followed by knees and elbows. Mean HJHS score in age group I (n = 7) was 11.6 (SD 6.5); in group II (n = 13) the score was significantly higher – mean 31.5 (SD 12.8) (P = 0.0002). Ankles, knees and elbows were significantly more impaired based on the HJHS scores in older patients as compared with younger ones. The HJHS appears to be a useful tool in evaluating musculoskeletal outcome of patients receiving treatment on‐demand. Children ≥10 years of age had significantly higher HJHS scores as a sign of progressing haemophilic arthropathy. We conclude that the most aggravating development of haemophilic joint damage seems to occur from the age of 10 and onwards.     

Controlled,cross‐sectional MRI evaluation of joint status in severe haemophilia A patients treated with prophylaxis vs. on demand

In patients with haemophilia A, factor VIII (FVIII) prophylaxis reduces bleeding frequency and joint damage compared with on‐demand therapy. To assess the effect of prophylaxis initiation age, magnetic resonance imaging (MRI) was used to evaluate bone and cartilage damage in patients with severe haemophilia A. In this cross‐sectional, multinational investigation, patients aged 12–35 years were assigned to 1 of 5 groups: primary prophylaxis started at age <2 years (group 1); secondary prophylaxis started at age 2 to <6 years (group 2), 6 to <12 years (group 3), or 12?18 years (group 4); or on‐demand treatment (group 5). Joint status at ankles and knees was assessed using Compatible Additive MRI scoring (maximum and mean ankle; maximum and mean of all 4 joints) and Gilbert scores in the per‐protocol population (n = 118). All prophylaxis groups had better MRI joint scores than the on‐demand group. MRI scores generally increased with current patient age and later start of prophylaxis. Ankles were the most affected joints. In group 1 patients currently aged 27?35 years, the median of maximum ankle scores was 0.0; corresponding values in groups 4 and 5 were 17.0 and 18.0, respectively [medians of mean index joint scores: 0.0 (group 1), 8.1 (group 2) and 13.8 (group 4)]. Gilbert scores revealed outcomes less pronounced than MRI scores. MRI scores identified pathologic joint status with high sensitivity. Prophylaxis groups had lower annualized joint bleeds and MRI scores vs. the on‐demand group. Primary prophylaxis demonstrated protective effects against joint deterioration compared with secondary prophylaxis.     

Joint health scores in a haemophilia A cohort from Pakistan with minimal or no access to factor VIII concentrate: correlation with thrombin generation and underlying mutation

Haemophilia A is associated with recurrent joint bleeding which leads to synovitis and debilitating arthropathy. Coagulation factor VIII level is an important determinant of bleed number and development of arthropathy . The aim of this study was to compare the haemophilia joint health score (HJHS) and Gilbert score with severity, age, thrombin generation (TG) and underlying mutation in a haemophilia A cohort which had minimal access to haemostatic replacement therapy. Ninety‐two haemophilia A individuals were recruited from Pakistan. Age, age at first bleed, target joints, haemophilic arthropathy joints, HJHS and Gilbert score were recorded. A strong correlation was found between HJHS and Gilbert score (r = 0.98), both were significantly higher in severe (n = 59) compared with non‐severe (n = 29) individuals before the age of 12 years (P ≤ 0.01) but not thereafter. When individuals were divided according to developmental age (<12 years, 12–16 years and >16 years), both HJHS and Gilbert score were significantly lower in the youngest group (P ≤ 0.001), there was no difference between 12–16 years and >16 years. In severe individuals there was no correlation between in vitro TG and joint score, whereas in non‐severe individuals there was a weak negative correlation. In the severe group, no significant difference was observed for either joint score according to the underlying mutation type (inversion, missense, nonsense, frameshift). In this cohort of haemophilia A individuals with minimal access to haemostatic treatment, haemophilic arthropathy correlated with severity and age; among severe individuals, joint health scores did not relate to either the underlying mutation or in vitro TG.     

Haemophilia Joint Health Score in healthy adults playing sports

To evaluate outcome of prophylactic clotting factor replacement in children with haemophilia, the Haemophilia Joint Health Score (HJHS) was developed aiming at scoring early joint changes in children aged 4–18. The HJHS has been used for adults on long‐term prophylaxis but interpretation of small changes remains difficult. Some changes in these patients may be due to sports‐related injuries. Evaluation of HJHS score in healthy adults playing sports could improve the interpretation of this score in haemophilic patients. The aim of this study was to evaluate the HJHS scores in a cohort of young, healthy men participating in sports. Concomitant with a project collecting MRI images of ankles and knees in normal young adults, HJHS scores were assessed in 30 healthy men aged 18–26, participating in sports one to three times per week. One physiotherapist assessed their clinical function using the HJHS 2.1. History of joint injuries was documented. MRI images were scored by a single radiologist, using the International Prophylaxis Study Group additive MRI score. Median age of the study group was 24.3 years (range 19.0–26.4) and median frequency of sports activities was three times per week (range 1–4). Six joints (five knees, one ankle) had a history of sports‐related injury. The median overall HJHS score was 0 out of 124 (range 0–3), with 60% of subjects showing no abnormalities on HJHS. All joints were normal on MRI. These results suggest that frequent sports participation and related injuries are not related with abnormalities in HJHS scores.     

Joint health and functional ability in children with haemophilia who receive intensive replacement therapy

Summary. Joint physical examination is an important outcome in haemophilia; however its relationship with functional ability is not well established in children with intensive replacement therapy. Boys aged 4–16 years were recruited from two European and three North American treatment centres. Joint physical structure and function was measured with the Haemophilia Joint Health Score (HJHS) while functional ability was measured with the revised Childhood Health Assessment Questionnaire (CHAQ₃₈). Two haemophilia‐specific domains were created by selecting items of the CHAQ₃₈ that cover haemophilia‐specific problems. Associations between CHAQ, HJHS, cumulative number of haemarthroses and age were assessed. A total of 226 subjects – mean 10.8 years old (SD 3.8) – participated; the majority (68%) had severe haemophilia. Most severe patients (91%) were on prophylactic treatment. Lifetime number of haemarthroses [median = 5; interquartile range (IQR) = 1–12] and total HJHS (median = 5; IQR = 1–12) correlated strongly (ρ = 0.51). Total HJHS did not correlate with age and only weakly (ρ = ?0.19) with functional ability scores (median = 0; IQR = ?0.06–0). Overall, haemarthroses were reported most frequently in the ankles. Detailed analysis of ankle joint health scores revealed moderate associations (ρ = 0.3–0.5) of strength, gait and atrophy with lower extremity tasks (e.g. stair climbing). In this population, HJHS summating six joints did not perform as well as individual joint scores, however, certain elements of ankle impairment, specifically muscle strength, atrophy and gait associated significantly with functional loss in lower extremity activities. Mild abnormalities in ankle assessment by HJHS may lead to functional loss. Therefore, ankle joints may warrant special attention in the follow up of these children.     

Factors affecting the Haemophilia Joint Health Score in children with severe haemophilia

Joint damage from bleeding episodes leads to physical or functional limitations in people with haemophilia. Various factors may influence the frequency and severity of joint damage. This study examined whether age, prophylaxis, history of high‐titre inhibitors (HTI) and bleeding events influenced the Haemophilia Joint Health Score (HJHS) in children. Medical and physiotherapy notes of boys with severe haemophilia, aged 4–18 years, were reviewed to identify factors associated with increased HJHS. The HJHS of 83 boys (median age: 11) ranged from 0 to 25, with 44/83 (53%) having a score of zero. The median HJHS was 0 (mean 2.6). In the non‐HTI group, the HJHS for boys on late prophylaxis was 2.68 times higher than those who started early and the HJHS was on average 10% higher for every additional recent bleed. In this group the odds of having a zero score fell by 30% for every year increase in age. Boys with a history of HTI had higher HJHS scores than the non‐HTI group, and age, number of recent bleeds and tolerized status were positively associated with HJHS. The score rose on average by 28% for every year of age and by 76% for non‐tolerized boys. This study provides further evidence supporting early prophylaxis use and the importance of immune tolerance therapy. The HJHS is a useful tool for identifying and tracking changes in joint health with respect to therapy or disease progression. With improvements in haemophilia treatment, the disproportionate number of zero scores will continue to make interpretation of the HJHS challenging.     

Chinese Hemophilia Joint Health Score 2.1 reliability study

To meet the rapidly expanding need for musculoskeletal (MSK) specialists [physiotherapists (PTs), physiatrists] in haemophilia care in China, a 4‐day Train the Trainer workshop was conducted in July/August 2009 in Beijing. A key focus was to train the participants to administer the Hemophilia Joint Health Score (HJHS) version 2.1 for effectively evaluating the MSK health of boys <18 years of age with haemophilia. The aim of this study was to test the HJHS version 2.1 inter‐ and intra‐rater reliability in a group of Chinese PTs and physiatrists with limited experience in haemophilia care. Each of the trained Chinese physiatrists and PTs examined eight boys 4–17 years old with moderate and severe haemophilia on day 1 and repeated the examination on the same patients the next day using the HJHS version 2.1. The boys had a wide range of target joint involvement and arthropathy. The HJHS score sheet, work sheets and manual had been translated into simple Chinese prior to the study. The interrater (ICC 0.90) and intra‐rater (ICC 0.91) reliability was excellent. The internal consistency of the HJHS items was also excellent with Cronbach's alpha of 0.86. With basic training in the administration of the HJHS version 2.1, the tool was reliably administered by Chinese PTs and physiatrists with limited haemophilic experience.     

Patient characteristics that influence efficacy of prophylaxis with rFVIII‐FS three times per week: a subgroup analysis of the LIPLONG study

Prospective data on the efficacy of secondary prophylaxis in adults with haemophilia A are limited. To analyse bleeding outcomes in the sucrose‐formulated recombinant factor VIII [rFVIII‐FS (control)] arm of the LIPLONG study, a randomized, double‐blind, 52‐week trial was conducted in patients with severe haemophilia A receiving prophylaxis with the investigational product BAY 79‐4980 or rFVIII‐FS. The per‐protocol population of previously treated patients with severe haemophilia A without a history of inhibitors (n = 68 males; mean age, 34.4 years) received 25 IU kg^?1 rFVIII‐FS three times per week for a median of 50.7 weeks. Annualized bleeding rates were assessed and analysed according to predefined target joint status at study start, prestudy treatment type (prophylaxis vs. on demand), age (<30 or ≥30 years), geographical region, bleeding frequency during the previous 6 months and physical activity status during the study using the Student t‐test. The annualized median (range) number of bleeds was 2.2 (0.0–23) bleeds per year. The median (range) number of bleeds per year was significantly lower in patient subgroups without vs. with target joints [0.5 (0.0–17.1) vs. 4.2 (0.0–22.8); P = 0.02] and in those with ≤9 vs. >9 bleeds during the previous 6 months [1.1 (0.0–19.2) vs. 5.3 (0.0–22.8); P = 0.01]. Following randomization to prophylaxis with rFVIII‐FS, bleeding frequency was effectively reduced. Absence of target joints and prestudy bleeding frequency were predictors of a low bleeding frequency during prophylaxis treatment.     

Point‐of‐care musculoskeletal ultrasound is critical for the diagnosis of hemarthroses,inflammation and soft tissue abnormalities in adult patients with painful haemophilic arthropathy

We previously demonstrated in adult patients with haemophilia (PWH) that hemarthrosis is present in only ~1/3rd of acutely painful joints by using point‐of‐care‐musculoskeletal ultrasound (MSKUS). Therefore, other unrecognized tissue abnormalities must contribute to pain. Using high resolution MSKUS, employing grey scale and power Doppler, we sought to retrospectively (i) investigate soft tissue abnormalities in painful haemophilic joints and (ii) to determine to what extent MSKUS findings, functional or radiographic joint scores correlate with biomarkers of inflammation in PWH. Findings were correlated with Hemophilia Joint Health Scores (HJHS), Pettersson scores, high sensitivity C‐reactive protein and von Willebrand factor activity and antigen levels. A total of 65 MSKUS examinations for acute and chronic joint pains were performed for 34 adult haemophilia patients, mostly for chronic joint pains (72.3%). The most prominent findings (66.5%) pertained to inflammatory soft tissue changes including synovitis, tendinitis, enthesitis, bursitis and fat pad inflammation. Effusions were present in 55.5% and 46.8% of MSKUS performed for acute and chronic pain, respectively. Of those, 90.0% were bloody during acute and 47.6% during persistent pains. While inflammatory biomarkers correlated well with overall HJHS and total Pettersson scores (P < 0.05), they did not differ between those patients with synovitis and those without. MSKUS is emerging as an important modality to diagnose treatable musculoskeletal abnormalities contributing to pain in haemophilic arthropathy, and therefore seems critical for a personalized approach to haemophilia care. The role of biomarkers in this setting remains less clear and requires further investigation.     

Habitual physical activity in Dutch children and adolescents with haemophilia

Summary. For patients with haemophilia, a physically active lifestyle is important to maintain musculoskeletal health and to prevent chronic diseases, such as cardiovascular disease. Therefore, we studied physical activity levels, in Dutch children and adolescents with haemophilia as well as its association with aerobic fitness and joint health. Forty‐seven boys with haemophilia (aged 8–18) participated. Physical activity was measured using the Modifiable Activity Questionnaire (MAQ) and was compared with the general population. Aerobic fitness was determined using peak oxygen uptake (VO_2peak). Joint health was measured using the Haemophilia Joint Health Score (HJHS). Associations between physical activity, joint health and aerobic fitness were evaluated by correlation analysis. Subjects were 12.5 (SD 2.9) years old, had a Body Mass Index (BMI) of 19.5 (SD 3.1; z‐score 0.5) and a median HJHS score of 0 (range 0–6). Cycling, physical education and swimming were most frequently reported (86%, 69% and 50% respectively). Children with severe haemophilia participated significantly less in competitive soccer and more in swimming than children with non‐severe haemophilia. Physical activity levels were similar across haemophilia severities and comparable to the general population. VO_2peak kg^?1 was slightly lower than healthy boys (42.9 ± 8.6 vs. 46.9 ± 1.9 mL kg^?1 min^?1; P = 0.03). Joint health, aerobic fitness and physical activity showed no correlation. Dutch children with haemophilia engaged in a wide range of activities of different intensities and showed comparable levels of physical activity to the general population. Aerobic fitness was well preserved and showed no associations with physical activity levels or joint health.     

Haemophilic magnetic resonance imaging score in healthy controls playing sports

Magnetic resonance imaging (MRI) is the most sensitive imaging modality to assess joint lesions, but the clinical relevance of subtle joint changes in haemophilic patients playing sports is unknown. A haemophilia specific MRI score is available, but was never evaluated in physically active healthy controls. It is not known if unexpected MRI changes in young active haemophilic patients are due to sports participation. The aim of this study was to evaluate knees and ankles in a cohort of young active healthy men using a haemophilia specific MRI score to provide context for joint evaluation by MRI in young haemophilic patients. Three Tesla MRI of knees and ankles were performed in 30 healthy men aged 18–26 years, regularly active in sports. MR images were scored by a single independent radiologist, using the International Prophylaxis Study Group additive MRI score. One physiotherapist assessed clinical function using the Haemophilia joint health scores (HJHS). History of complaints or injuries affecting knees and/or ankles, very intensive sports and current sports activities were documented. Median age was 24.3 years (range 19.0–26.4) and median number of sports activities per week was 3 (range 1–4). Six joints (five knees, one ankle) had a history of a sports‐related injury. The median HJHS per joint was 0 out of 20 (range 0–1). All joints had a MRI score of 0. These results suggest that regular sports participation or very low HJHS scores are not associated with haemophilia specific MRI changes in knees and ankles.     

Lifelong prophylaxis in a large cohort of adult patients with severe haemophilia: a beneficial effect on orthopaedic outcome and quality of life

Background: In the 1950s, Sweden initiated prophylaxis as a lifelong treatment for haemophilia. It was the first country to do so. Objectives: To describe and evaluate dosing and outcome of prophylactic treatment in a large cohort of adult people with severe haemophilia who have been using prophylaxis most of their lives. Methods: Eighty‐one patients born between 1932 and1992 were divided into two groups (Group A started prophylaxis at the age of ≤ 3 yr; Group B at three or more years of age) and evaluated retrospectively. Outcome was evaluated using the Hemophilia Joint Health Score (HJHS) and SF‐36, a measure of quality of life. Results: The median number of joint bleeds per year was 0 in both study groups; however, the annual number of joint bleeds during the final 3 yr of observation was higher in group B than in group A (P < 0.006). Twenty‐five of 30 patients in group A and 27/51 patients in group B had no joint bleeds in that period. Group A had significantly better joint outcomes than group B. Patients in group A experienced better physical and social health than those in group B. Conclusions: This follow‐up has provided for the first time more extensive and detailed information regarding the practice of prophylactic treatment in a large cohort of adults with severe haemophilia. The present study confirms that early start of prophylaxis continuing throughout the lifespan has been successful in virtually eliminating joint bleeds, preserving a close to normal joint status, and keeping patients healthy and able to live normal lives.     

Prophylaxis with FEIBA in paediatric patients with haemophilia A and inhibitors

The benefits shown with factor VIII (FVIII) prophylaxis relating to joint health and quality of life (QoL) provide the rationale for FEIBA prophylaxis in haemophilia A patients with persistent FVIII inhibitors. FEIBA has previously shown efficacy in preventing bleeds in inhibitor patients who failed to respond to, or were ineligible for immune tolerance induction (ITI). The study examined the outcome of paediatric patients undergoing long‐term FEIBA prophylaxis. A retrospective chart review included severe haemophilia A patients with persistent inhibitors aged ≤13 years at the start of FEIBA prophylaxis. Baseline characteristics captured dose, frequency of prophylaxis, history of inhibitor development, including baseline titre, historical peak titre and history of ITI. Outcome measurements included annual bleed rate before and during FEIBA prophylaxis, joint status and school days missed. Sixteen cases of FEIBA prophylaxis from two centres are presented. The mean age of subjects at prophylaxis initiation was 7.5 ± 3.6 years and median baseline inhibitor titre was 23 (range 3.1–170) BU. Prior to prophylaxis initiation, median annual joint bleeds among all patients was 4 (0–48), which dropped significantly after the first year of prophylaxis, to a median annual joint bleed rate of 1 (0–7; P = 0.0179). Subsequent years (median = 9) of prophylaxis therapy demonstrated similarly low annual joint bleed rates. There were no life‐threatening bleeds, no viral seroconversions or thrombotic events during FEIBA prophylaxis treatment. FEIBA prophylaxis was effective for preventing joint bleeds and subsequent joint damage, delaying arthropathy and improving outcomes in children with haemophilia A and inhibitors to FVIII, who failed or were ineligible for ITI.     

Using the Haemophilia Joint Health Score for assessment of teenagers and young adults: exploring reliability and validity

Outcome assessment in haemophilia is important to assess results of prophylactic treatment. Recently, the Haemophilia Joint Health Score (HJHS) was developed to assess early joint damage in children with haemophilia. Thus, the aim of this study was to assess reliability and explore validity of the HJHS in teenagers and young adults with haemophilia. Twenty‐two patients with haemophilia (mean age 20.4, range 14–30, including 15 severe) were assessed by the HJHS1.0, Haemophilia Activities List (HAL), SF36 and self‐evaluation was performed using a Visual Analogue Scale (VAS) scale. A subset of 12 patients were assessed by three physiotherapists to establish interobserver reliability (intraclass correlation coefficient: ICC). Total HJHS1.0 scores were calculated without overall global gait. Validity was explored by the assessment of Pearson's correlation with all outcome parameters and recent Pettersson scores. Overall outcome was good, with median HJHS score of 5.5 of a maximum 144 (range 0–34), median patients' VAS of 96.5 and maximum scores for HAL and SF36 physical functioning for the majority of patients. Pettersson scores were low (median 3.5 of 78, N = 18). Interobserver reliability was good (ICC 0.84), with limits of agreement of ±7.2 points. ICC was unaffected by different score calculation methods. Exploration of validity in 22 patients showed weak correlations of HJHS scores with patients' VAS (0.33) and HAL (?0.40) and strong correlations with SF36‐PF (?0.66) and Pettersson scores (0.86). These results suggest that interobserver reliability of the HJHS1.0 in teenagers and young adults with limited joint damage is excellent. Preliminary data on validity were similar or better than those in children.     

No difference in quality of life between persons with severe haemophilia A and B

Introduction

Good health-related quality of life (HRQoL) is an important goal in the treatment of persons with haemophilia B (PwHB). Studies focusing on this population are limited, however, and data are insufficient.

Aim

To assess the HRQoL in PwHB and to compare this to data on persons with haemophilia A (PwHA), as well as to evaluate the impact of joint health on HRQoL and to identify areas of insufficient care.

Methods

The B-NORD study enrolled persons with severe haemophilia B and matched controls with haemophilia A. HRQoL was assessed using the EQ-5D-3L questionnaire and joint health using Haemophilia Joint Health Score 2.1 (HJHS).

Results

The EQ-5D-3L was completed by 63 PwHB and 63 PwHA. Mobility problems were reported by 46% of PwHB and 44% of PwHA, pain/discomfort by 62% and 56%, and anxiety/depression by 33% and 17%, respectively. No significant difference was observed between PwHA and PwHB in EQ-5D profiles, level sum score, EQ-5D index (PwHB mean .80, PwHA mean .83, p = .24), or EQ VAS score (PwHB: mean 70, PwHA: mean 77, p = .061). Linear regression adjusted for age demonstrated that an increase in HJHS score was associated with a significant decrease in both EQ-5D index (B -.003, R₂ .22) and EQ VAS score (B -.37, R₂ .17).

Conclusion

Despite the majority of patients being treated with prophylaxis, impaired HRQoL was reported in both PwHB and PwHA. No differences in HRQoL were found between the two groups. Impaired joint health had a significant negative impact on HRQoL.     

Low dose secondary prophylaxis reduces joint bleeding in severe and moderate haemophilic children: a pilot study in China

Summary. The most common bleeding in haemophilic patients is in joints, and joint disability is the most common complications in these patients receiving inadequate treatment. Limited by economy and inadequate treatment, developing countries face huge challenge to reduce disability and improve quality of life (QoL) of haemophilic children. The aim of this study was to investigate the effect of low dose secondary prophylaxis in China. Children with moderate and severe haemophilia from the Beijing Children Hospital, Beijing, China, and with established joint disease, were followed for a 12‐week observation period followed by a 12‐week low dose secondary prophylaxis‐study period (for haemophilia A, factor VIII concentrate 10 IU kg^?1 twice weekly; for haemophilia B, factor IX concentrate 20 IU kg^?1 weekly). The reduction of joint bleeding, improvement of joint function and QoL during prophylaxis were analysed. In total 34 children (median age 7.8 years) were analyzable. The number of joint bleeds decreased from a total of 337 (individual range 3–24, mean 9.9) during the observation period to 57 (range 0–6, mean 1.7) during the study period with an overall of reduction 83%. Joint function improved in 66.7% of disease joints, with 23.2% of which were considered good to moderate. School attendance improved in all subjects, sports participation and daily activity improved moderately. Low dose secondary prophylaxis significantly reduces frequency of joint bleeding; with moderate improvement in joint function, school attendance, sport participation and daily activities. Low dose secondary prophylaxis is therefore, cost‐effective as applied to developing countries such as China, although there are still unresolved issues.     

Long‐standing prophylactic therapy vs. episodic treatment in young people with severe haemophilia: a comparison of age‐matched Danish and Russian patients

Two distinctly different substitution principles are commonly used in haemophilia: treatment at bleeding episodes only referred to as on‐demand treatment, and prophylactic factor administration. The aim of the cross‐sectional study which was undertaken in young patients suffering severe haemophilia A was to challenge our hypothesis that on‐demand treatment is inferior to prophylactic substitution in prevention of chronic joint disease at young age. The method involved an investigation of 40 patients from Russia (n = 27) and Denmark (n = 13) born between 1975 and 1990 with no history of inhibitors; Russian patients had exclusively received factor VIII on demand, while Danish patients were managed with prophylactic treatment during a mean period of 16 years since median age of 5 years. The study endpoints were clinical joint scores, Quality of Life scores and functional independence scores. Matched by identical age (±1 year) 13 Danish and 13 Russian patients were compared, while 14 age similar Russian patients served as controls. Demographic data among all groups were quite comparable. The results are that Russian patients presented with clinical joint scores at 27 ± 8.5 (mean ± SD) while matched Danish counterparts scored 3.8 ± 5.3 (mean ± SD), differences being highly significant. The number of joint bleeds in recent 5 years were 199.5 ± 135 (mean ± SD) vs. 8.1 ± 8.7 (mean ± SD). Likewise, Quality of Life and functional independence scores were significantly higher in patients on prophylaxis as compared to on‐demand treatment. In conclusion, the study outcomes confirmed our hypothesis. Longer term prophylactic factor administration during childhood and adolescence prevents joint destruction.     

Impact of timing of prophylaxis commencement,F8 genotype and age on factor consumption and health-related quality of life in patients with severe haemophilia A

Introduction

The timing of prophylaxis and F8 genotype can impact treatment outcomes in adults with severe haemophilia A (HA).

Aim

To investigate how F8 genotype, timing, and type of prophylaxis influence arthropathy, bleeding rates, factor consumption and health-related quality of life (HRQoL).

Methods

Thirty-eight patients with severe HA were enrolled. Bleeding events were recorded retrospectively during median 12.5 months. F8 gene variants were classified as null or non-null. Joint health and HRQoL were assessed with HJHS and EQ-5D-5L, respectively.

Results

The median age at prophylaxis start was 1.25 years in the primary prophylaxis group (N = 15, median age 26 years) and 31.5 years in the secondary group (N = 22, 45 years), respectively. There were significant differences in the medians of HJHS (4 vs. 20, p < .001), EQ-5D-5L index (0.9647 vs. 0.904, p = .022), EQ VAS (87 vs. 75, p = .01) and FVIII consumption (3883 vs. 2737 IU/kg/year, p = .02), between the primary and secondary groups, respectively. Median annualized bleeding rate (ABR) was 0 for both groups. Twenty-five null and thirteen non-null F8 gene variants were identified. In the secondary prophylaxis group, lower median FVIII consumption (1926 vs. 3370 IU/kg/year) was shown for non-null compared to null variants, respectively, with similar ABR and HJHS.

Conclusion

Delayed prophylaxis start with intermediate dose intensity prevents bleeds but at a cost of more arthropathy and reduced HRQoL, compared to higher intensity primary prophylaxis. Non-null F8 genotype may allow lower factor consumption with similar HJHS and bleeding rates, compared to null genotype.     

The biological efficacy profile of BAX 855, a PEGylated recombinant factor VIII molecule

Prophylaxis prevents joint and other bleeding episodes in patients with haemophilia A. Development of new factor concentrates with longer circulating half‐lives may encourage patients to start, continue or resume prophylaxis. The aim of this study was to compare the pharmacodynamic effect of a PEGylated full‐length recombinant factor VIII (rFVIII) concentrate with that of an unmodified rFVIII concentrate with respect to the duration of prophylactic efficacy in a murine model of haemophilic joint bleeding. Mice were pretreated with BAX 855 or unmodified rFVIII at specified times before right knee puncture to induce haemarthrosis; left knee joints served as controls. Joint bleeding was evaluated using a combination of visual and histological assessments. Administration of a single dose of unmodified rFVIII before joint puncture prevented haemarthrosis in mice up to 24 h, whereas pretreatment with BAX 855 protected the joint from bleeding up to 48 h. This pharmacodynamic study showed prolonged efficacy of BAX 855 compared to ADVATE in a haemophilia A mouse joint bleeding model. This finding supports the possibility of using BAX 855 to increase FVIII trough levels and/or extend the dosing interval in patients with haemophilia A on prophylaxis, which may potentially improve prophylactic efficacy and long‐term adherence.     

Improved joint health in subjects with severe haemophilia A treated prophylactically with recombinant factor VIII Fc fusion protein

Introduction

Joint arthropathy is the long‐term consequence of joint bleeding in people with severe haemophilia.

Aim

This study assessed change in joint health over time in subjects receiving recombinant factor VIII Fc fusion protein (rFVIIIFc) prophylaxis.

Methods

ALONG is the phase 3 pivotal study in which the benefit of rFVIIIFc as a prophylactic treatment for bleeding control was shown in previously treated severe haemophilia patients ≥12 years of age (arm 1: 25‐65 IU/kg every 3‐5 days, arm 2: 65 IU/kg weekly and arm 3: episodic). After completing ALONG, subjects had the option to enrol into the extension study (ASPIRE). This interim, post hoc analysis assessed changes in joint health over ~2.8 years in these patients.

Results

Forty‐seven subjects had modified Haemophilia Joint Health Score (mHJHS) data at A‐LONG baseline, ASPIRE baseline and ASPIRE Year 1 and Year 2. Compared with A‐LONG baseline (23.4), mean improvement at ASPIRE Year 2 was ?4.1 (95% confidence interval [CI], ?6.5, ?1.8; P = .001). Regardless of prestudy treatment regimen, subjects showed continuous improvement in mHJHS from A‐LONG baseline through ASPIRE Year 2 (prestudy prophylaxis: ?2.4, P = .09; prestudy episodic treatment: ?7.2, P = .003). Benefits were seen in subjects with target joints (?5.6, P = .005) as well as those with severe arthropathy (?8.8, P = .02). The mHJHS components with the greatest improvement at ASPIRE Year 2 were swelling (?1.4, P = .008), range of motion (?1.1, P = .03) and strength (?0.8, P = .04).

Conclusions

Prophylaxis with rFVIIIFc may improve joint health over time regardless of prestudy prophylaxis or episodic treatment regimens.