Race and ethnicity and the success of immune tolerance induction among people with severe haemophilia A in the United States.

INTRODUCTION: Immune tolerance induction (ITI) is the only treatment to eradicate inhibitors in people with severe haemophilia A with inhibitors. Since the risk of inhibitor development is greater among Black and Hispanic persons, it has been hypothesized that race and ethnicity may influence ITI success. Limited studies have evaluated this hypothesis. AIM: To examine the success of ITI according to race and ethnicity. METHODS: Participants who entered the Community Counts (CC) Registry between 2013 and 2017, were aged ≥3 years at study entry, and received ITI were included (n = 559). The proportion of participants with successful ITI was examined with adjusted prevalence ratios (aPRs) and corresponding 95% confidence intervals (95% CIs). RESULTS: Among 559 participants, 56.9%, 19.1%, 18.1% and 4.3% were Non-Hispanic (NH) White, NH Black, Hispanic and Asian, respectively, and 1.7% were coded as other or missing. Approximately 80% of Hispanic, NH Black and NH White participants had good/very good prognosis, defined as having a pre-ITI peak inhibitor of < 200 Bethesda Units per millilitre. Nearly 60% of participants (59.7%) achieved successful ITI, 20.7% and 19.5% experienced partially successful or failed ITI, respectively. Successful ITI was non-significantly lower in NH Black (54.2%; aPR = 0.95, 95% CI 0.62-1.44) and Hispanic (55.4%; aPR = 0.89, 95% CI 0.71-1.13) relative to NH White participants (62.6%). CONCLUSION: In this study, 60% of participants in the CC Registry had successful ITI, consistent with previous studies. The proportion with successful ITI was generally comparable across racial and ethnic groups with similar prognosis. These findings do not support the hypothesis that ITI response varies according to race or ethnicity.

Racial and ethnic differences in reported haemophilia death rates in the United States.

INTRODUCTION: People with haemophilia's life expectancies have improved over time. Whether progress has been experienced equitably is unknown. AIM: To examine recorded haemophilia death (rHD) rates according to race and ethnicity in the United States (US). METHODS: In this cohort study, rHDs were examined with US National Vital Statistics' 1999-2020 Multiple Cause-of-Death data. rHD was defined as having a haemophilia A (D66) or B (D67) ICD-10 code in the death certificate (underlying or multiple causes of death). Age-adjusted rHD rates were compared with age-adjusted rate ratios (aRR) and 95% Confidence Intervals (CI). RESULTS: There were 3115 rHDs in males with an rHD rate of 0.98 per 1 million males. Between 1999 and 2020, rHD rates declined by 46% in NH (Non-Hispanic) White, 44% in NH Black (aRR = 0.56, 95%CI 0.43, 0.74), and 42% in Hispanic (aRR = 0.58, 95%CI 0.39, 0.88) males. However, rHD rates remained higher and were on average 30% greater in NH Black versus NH White males (aRR = 1.30 95% CI 1.16, 1.46). Among males with rHD, the median age at death rose from 54.5 to 65.5 years between 1999 and 2020 and was 12 years lower in NH Black (56 years) versus NH White (68 years) males in 2010-2020. There were 930 females with rHD, with an age-adjusted rate of 0.22 per 1 million females, which was consistent between 1999 and 2020. CONCLUSION: Reported haemophilia-death rates improved in males across all race/ethnicities, but rates were higher Black versus White males. Given the inherent limitations of the current study's data source, further investigation of survival rates and disparities in haemophilia are needed.

Cross-sectional study evaluating the association of haemophilia-related distress and clinically relevant outcomes.

INTRODUCTION: In chronic diseases, disease-related distress can impact disease outcomes. Distress and haemophilia-related distress has been demonstrated in people with haemophilia (PwH). The association of haemophilia-related distress on disease outcomes among PwH is unknown. AIM: To study the association of haemophilia-related distress with haemophilia specific outcomes, including adherence to prophylactic therapy, the presence of a target joint, healthcare utilization and work-impairment. METHODS: In a cross-sectional study, adults with haemophilia A or B were enrolled in a study to validate the haemophilia-related distress questionnaire (HRDq). In this planned analysis, univariate and multivariate associations between the HRDq total score and disease outcomes were explored. RESULTS: The 114 participants in this analysis were male, mostly with haemophilia A (92%) and severe disease (52%) with a median age of 31.9 years. On univariate analysis, HRDq total score (5-point change) was associated with the presence of a target joint (P = .002), high healthcare utilization (P = .011), poor adherence (P = .033) and work-impairment (P ≤ .001). After adjustment for age, race, severity and other potential confounders, adherence (aß 0.33, 95% CI .17, .49) and work-impairment (aß 4.69, 95% CI 3.27-6.1) remained statistically significantly associated with HRDq total score. CONCLUSION: Haemophilia-related distress is associated with poor adherence to factor prophylaxis and work-impairment. The direction of the association (causation) is yet to be determined and requires future study.

Cost-effectiveness of prophylactic emicizumab versus prophylactic recombinant factor VIII in patients with moderate or mild hemophilia A without inhibitors in the United States.

Prophylactic emicizumab is cost-ineffective in adults with moderate or mild hemophilia A without inhibitors at current pricing. The price of prophylactic emicizumab would need to decrease by >35% to become cost-effective in this patient population.

Effect of emicizumab prophylaxis on bone and joint health markers in people with haemophilia A without factor VIII inhibitors in the HAVEN 3 study.

INTRODUCTION: Emicizumab prophylaxis significantly reduces bleeding events; however, the associated impact on bone/joint health is unknown. AIM: To explore the effect of emicizumab prophylaxis on bone/joint health in people with haemophilia A (PwHA) without FVIII inhibitors enrolled in HAVEN 3 (NCT02847637). METHODS: Haemophilia joint health scores (HJHS; v2.1) were evaluated at baseline and Weeks 49 and 97 in PwHA receiving emicizumab (n = 134), and at baseline and Weeks 49, 73 and 97 in PwHA who switched to emicizumab after 24 weeks of no prophylaxis (n = 17). Bone and joint biomarkers were measured in 117 PwHA at baseline and at Weeks 13, 25, 49 and 73. RESULTS: HJHS was lower for PwHA who were previously on FVIII prophylaxis, aged <40 years or had no target joints at baseline compared with PwHA who were receiving no prophylaxis, aged ≥40 years or with target joints. Clinically significant mean (95% confidence interval) improvements from baseline of -2.13 (-3.96, -.29) in HJHS joint-specific domains were observed at Week 49 in PwHA with at least one target joint at study entry (n = 71); these changes were maintained through Week 97. Improvements in HJHS from baseline were also observed for PwHA aged 12-39 years. Biomarkers of bone resorption/formation, cartilage degradation/synthesis, and inflammation did not change significantly during emicizumab prophylaxis. CONCLUSIONS: Clinically relevant improvements in HJHS were observed in younger PwHA and those with target joints after 48 weeks of emicizumab in HAVEN 3. Biomarkers of bone/joint health did not show significant changes during 72 weeks of emicizumab prophylaxis.

Quality of life in a large multinational haemophilia B cohort (The B-Natural study) - Unmet needs remain.

INTRODUCTION: The B-Natural study is a multicentre, multinational, observational study of haemophilia B (HB) designed to increase understanding of clinical manifestations, treatment and quality of life (QoL). AIM: To characterise and compare QoL in HB across disease severity groups and individuals with inhibitors to identify gaps in treatment. METHODS: A total of 224 individuals from 107 families were enrolled from a total of 24 centres in North America (n = 16), Europe (n = 7) and Asia (n = 1). Of these, 68 (30.4%) subjects had severe (<1 IU/dL), median age 15.6 years, 114 (50.9%) moderate (1-5 IU/dL), age 13.3 years, and 42 (18.8%) mild (>5-< 40 IU/dL), age 12.1 years, disease. Twenty-nine participants had inhibitors or a history of inhibitors. Three versions of the EQ-5D instrument were used as a measure of QoL: proxy (ages 4-7), youth (ages 8-15) and self (age 16+). Each instrument included a visual analogue scale ranging from 100 (best health) to 0 (worst health) to assess current day's health (EQ VAS). Range-of-motion (ROM) for elbows, knees and ankles was assessed using a four-point scale, from which a composite score was calculated. RESULTS: In all severity groups, a proportion of subjects showed less than optimal QoL. The majority of the mild and moderate severe participants reported a normal EQ-5D health profile (79% and 72%, respectively), whereas about half (47%) of the severe participants and only 13% of the inhibitor participants reported this profile. CONCLUSION: The B-Natural study reveals impacted QoL in all disease severities of HB including those with inhibitors. Unmet needs remain and include nonsevere HB.

Emicizumab Prophylaxis in Patients Who Have Hemophilia A without Inhibitors.

BACKGROUND: Emicizumab is a bispecific monoclonal antibody that bridges activated factor IX and factor X to replace the function of missing activated factor VIII, thereby restoring hemostasis. In a phase 3, multicenter trial, we investigated its use as prophylaxis in persons who have hemophilia A without factor VIII inhibitors. METHODS: We randomly assigned, in a 2:2:1 ratio, participants 12 years of age or older who had been receiving episodic treatment with factor VIII to receive a subcutaneous maintenance dose of emicizumab of 1.5 mg per kilogram of body weight per week (group A) or 3.0 mg per kilogram every 2 weeks (group B) or no prophylaxis (group C). The primary end point was the difference in rates of treated bleeding (group A vs. group C and group B vs. group C). Participants who had been receiving factor VIII prophylaxis received emicizumab at a maintenance dose of 1.5 mg per kilogram per week (group D); intraindividual comparisons were performed in those who had participated in a noninterventional study. RESULTS: A total of 152 participants were enrolled. The annualized bleeding rate was 1.5 events (95% confidence interval [CI], 0.9 to 2.5) in group A and 1.3 events (95% CI, 0.8 to 2.3) in group B, as compared with 38.2 events (95% CI, 22.9 to 63.8) in group C; thus, the rate was 96% lower in group A and 97% lower in group B (P<0.001 for both comparisons). A total of 56% of the participants in group A and 60% of those in group B had no treated bleeding events, as compared with those in group C, who all had treated bleeding events. In the intraindividual comparison involving 48 participants, emicizumab prophylaxis resulted in an annualized bleeding rate that was 68% lower than the rate with previous factor VIII prophylaxis (P<0.001). The most frequent adverse event was low-grade injection-site reaction. There were no thrombotic or thrombotic microangiopathy events, development of antidrug antibodies, or new development of factor VIII inhibitors. CONCLUSIONS: Emicizumab prophylaxis administered subcutaneously once weekly or every 2 weeks led to a significantly lower bleeding rate than no prophylaxis among persons with hemophilia A without inhibitors; more than half the participants who received prophylaxis had no treated bleeding events. In an intraindividual comparison, emicizumab therapy led to a significantly lower bleeding rate than previous factor VIII prophylaxis. (Funded by F. Hoffmann-La Roche and Chugai Pharmaceutical; HAVEN 3 ClinicalTrials.gov number, NCT02847637 .).

Therapeutic plasma exchange for COVID-19-associated hyperviscosity.

BACKGROUND: Recent data suggests an association between blood hyperviscosity and both propensity for thrombosis and disease severity in patients with COVID-19. This raises the possibility that increased viscosity may contribute to endothelial damage and multiorgan failure in COVID-19, and that therapeutic plasma exchange (TPE) to decrease viscosity may improve patient outcomes. Here we sought to share our experience using TPE in the first 6 patients treated for COVID-19-associated hyperviscosity. STUDY DESIGN AND METHODS: Six critically ill COVID-19 patients with plasma viscosity levels ranging from 2.6 to 4.2 centipoise (cP; normal range, 1.4-1.8 cP) underwent daily TPE for 2-3 treatments. RESULTS: TPE decreased plasma viscosity in all six patients (Pre-TPE median 3.75 cP, range 2.6-4.2 cP; Post-TPE median 1.6 cP, range 1.5-1.9 cP). TPE also decreased fibrinogen levels in all five patients for whom results were available (Pre-TPE median 739 mg/dL, range 601-1188 mg/dL; Post-TPE median 359 mg/dL, range 235-461 mg/dL); D-dimer levels in all six patients (Pre-TPE median 5921 ng/mL, range 1134-60 000 ng/mL; Post-TPE median 4893 ng/mL, range 620-7518 ng/mL); and CRP levels in five of six patients (Pre-TPE median 292 mg/L, range 136-329 mg/L; Post-TPE median 84 mg/L, range 31-211 mg/L). While the two sickest patients died, significant improvement in clinical status was observed in four of six patients shortly after TPE. CONCLUSIONS: This series demonstrates the utility of TPE to rapidly correct increased blood viscosity in patients with COVID-19-associated hyperviscosity. Large randomized trials are needed to determine whether TPE may improve clinical outcomes for patients with COVID-19.

Management of comorbidities in haemophilia.

With the introduction of clotting factor concentrates in the early 1970s, significant improvements in quality of life and life expectancy of persons with haemophilia (PWH) were realized. Unfortunately, as a result of transmission of HIV and hepatitis C virus (HCV) by contaminated concentrates in the 1980s, many of these gains were lost. Now with four decades of PWH unexposed to contaminated factor products and current treatments capable of suppressing and eliminating HIV and HCV, respectively, the survival rate is once again increasing. In addition to the usual comorbidities associated with advanced age in the general population, several specific issues occur in patients with bleeding disorders. This manuscript explores the incidence and management of the comorbidities of the ageing PWH with a focus on cardiovascular disease and osteoporosis.

An evaluation of PROMIS health domains in adults with haemophilia: A cross-sectional study.

INTRODUCTION: The Patient-Reported Outcomes Measurement Information System (PROMIS) provides measures of health status that assess physical, mental and social well-being from the patient perspective. PROMIS measures are used in clinical practice and research across various patient populations but are not yet validated among patients with haemophilia. AIM: Evaluate the sensitivity of PROMIS to indicators of haemophilia clinical severity and compare PROMIS measures to those from other PRO instruments. METHODS: Male adults with haemophilia (n = 115) completed the PROMIS-29 short form which includes 4 questions for each of 7 domains: depression, anxiety, ability to participate in social roles and activities, physical function, pain interference, fatigue and sleep disturbance. Participant responses for each domain were scored on a T-score metric with a mean of 50 and a standard deviation of 10 based on the original PROMIS reference sample of US adults. Participants also completed other generic and haemophilia-specific health-related quality of life questionnaires. RESULTS: Participants who experienced higher pain and depression levels reported significantly worse health in every PROMIS domain compared with their peers. Those who had recently needed to use crutches, visit an emergency department or were currently unemployed or disabled also reported poor PROMIS scores on most domains. Construct validity was supported by correlations between PROMIS domain scores and domain scores reported using the EQ-5D-5L and Haem-A-QoL. CONCLUSION: The PROMIS instrument provides a potentially valuable tool to evaluate the impact of haemophilia and suggests usefulness in research and clinical practice.

Shortening the Haemophilia Activities List (HAL) from 42 items to 18 items.

INTRODUCTION: The Haemophilia Activities List (HAL) was developed to measure activities and participation in persons with haemophilia (PWH). Shortening the questionnaire may facilitate use of the HAL. AIM: The aim of this study was to determine which items of the HAL are redundant, to construct a shorter version of the HAL, and to determine the construct validity of the HALshort . METHODS: A secondary analysis was performed on pooled data of two published studies using the HAL (seven domains, 42 items, optimum score: 100) in adults with haemophilia A/B. Data were divided into a derivation (62%) and a validation set (38%). Redundant items were identified by evaluation of: floor and ceiling effects, proportions of missing and 'not applicable' responses, inter-item correlations, component loadings in an exploratory factor analysis, internal consistency, and item-total correlations. Correlations with the SF-36 and EQ-5D-5L were used to determine construct validity of the HALshort . RESULTS: Data on 680 PWH were evaluated. In the derivation dataset (n = 420), median age was 30 years (range 18-80), 43% had severe haemophilia and 61% received prophylaxis. Median (IQR) HAL sum score was 65.0 (55.7-88.8). The stepwise procedure resulted in a HALshort of 18 items with a median sum score of 63.3 (54.4-86.7). Construct validity was similar for the HAL and HALshort in the validation dataset (n = 260). CONCLUSION: This clinimetric study resulted in a >50% shortening of the HAL. The 18-item HALshort reduces patient burden and is expected to capture the information on activities and participation. The HALshort needs further validation.

Development and testing of the Satisfaction Questionnaire with Intravenous or Subcutaneous Hemophilia Injection and results from the Phase 3 HAVEN 3 study of emicizumab prophylaxis in persons with haemophilia A without FVIII inhibitors.

INTRODUCTION: Emicizumab is a subcutaneously (SC) administered prophylactic agent for persons with haemophilia A (PwHA). As part of its clinical development, a new instrument was required to measure treatment satisfaction. AIM: Describe development of the Satisfaction Questionnaire with Intravenous or Subcutaneous Hemophilia Injection (SQ-ISHI) and its subsequent testing with HAVEN 3 study participants to measure patient satisfaction with emicizumab. METHODS: To develop the SQ-ISHI, we conducted four rounds of in-person interviews at five qualitative research facilities. Participants aged ≥12 years with moderate or severe haemophilia A, receiving intravenous factor VIII (FVIII) prophylaxis, provided feedback to optimize content understanding, ease of completion and item relevance. The final SQ-ISHI was completed by HAVEN 3 participants who previously received FVIII prophylaxis; baseline scores were compared with those at Week 21 or 25 of emicizumab prophylaxis. RESULTS: Sixty-three HAVEN 3 participants were eligible to complete the questionnaire and rate their satisfaction on a scale of 0 ('not at all satisfied') to 10 ('extremely satisfied'). Mean 'overall satisfaction' with previous FVIII prophylaxis at baseline was 6.9 (95% confidence interval [CI]: 6.2 to 7.7) increasing to 8.8 (95% CI: 8.4 to 9.3) at follow-up (Week 21/25 of treatment with emicizumab). The greatest improvement was observed in satisfaction with treatment half-life (mean score at baseline: 5.8 [95% CI: 4.9 to 6.6] vs 8.6 [95% CI: 8.0 to 9.2] at follow-up). CONCLUSION: These results demonstrate that emicizumab prophylaxis leads to greater treatment satisfaction compared with FVIII prophylaxis, reflecting in part the low treatment burden of emicizumab associated with its infrequent, SC administration.

The B-Natural study-The outcome of immune tolerance induction therapy in patients with severe haemophilia B.

INTRODUCTION: Inhibitors develop less frequently in haemophilia B (HB) than haemophilia A (HA). However, when present, the success of tolerization by immune tolerance induction (ITI) therapy is lower and the risk of complications higher. AIM: To evaluate the use and outcome of ITI in patients with HB and inhibitors. METHODS: Subjects include singletons or siblings with a current/history of inhibitors enrolled in B-Natural-an observational study designed to increase understanding of clinical management of patients with HB. Patients were followed for 6 months and information on demographics, medical and social history, and treatment were recorded. RESULTS: Twenty-nine patients with severe HB and inhibitors were enrolled in 24 centres. Twenty-two underwent one or more courses of ITI with or without immune suppression. Eight patients (36.4%) were successfully tolerized after the first course of ITI. One of these successes (12.5%) experienced allergic manifestations, whereas the corresponding number for the 10 treatment failures was five (50%). One of seven (14.2%) patients with large deletions and three of eight (37.5%) with nonsense mutations were tolerized at the first attempt, and all patients experiencing nephrosis either failed or were on-going. At study end, 11 (50%) were considered successfully tolerized after one or more ITI courses, three were unsuccessful, and eight were still undergoing treatment. CONCLUSION: Our data underscore the possibilities and difficulties of achieving tolerization in patients with HB with inhibitors. The type of mutation and complications appear to correlate with ITI outcome, but more accurate definitions of successful ITI are warranted.

Outcomes for studies assessing the efficacy of hemostatic therapies in persons with congenital bleeding disorders.

INTRODUCTION: Management strategies and hemostatic treatments to achieve control of bleeding are relevant across many disease areas. Identification of primary outcomes for studies assessing hemostatic intervention was the objective of a National Heart, Lung and Blood Institute (NHLBI) sponsored multidisciplinary initiative. The aim of this report is to summarize the evidence reviewed, and the outcomes identified by the subgroup tasked to assess outcomes for inherited bleeding disorders. METHODS: The subgroup decided to focus on haemophilia, the prototypal congenital bleeding disorder and the one with the largest available body of evidence. MEDLINE, EMBASE and PsycINFO, The Cochrane Review, CINAHL, and Web of Science were searched for systematic and narrative reviews on outcomes used in haemophilia clinical trials. Three different clinical goals were identified as typical objectives of future research. RESULTS: Out of 1322 unique citations, 24 reviews published in the period 2002-2019 were included. We identified 113 outcome measures, categorized in 6 domains: health-related quality of life (HRQoL), comorbidities and mortality, overall physical functioning and participation, bleeding and hemostasis, joint health, and costs and resource use. Three different clinical goals were identified as typical objectives of future research: Episodic 'on demand' replacement therapy, prevention of bleeding (Prophylaxis), and long-term and overall impact of bleeding. For each of these scenarios, specific outcomes were recommended. CONCLUSIONS: Primary outcomes for clinical trials assessing the efficacy of hemostatic treatment in achieving control, prevention and limiting long-term consequences of bleeding in inherited bleeding disorders are suggested, and their strength and limitations discussed.

Validation of a new instrument to measure disease-related distress among patients with haemophilia.

INTRODUCTION: In patients with haemophilia, general psychological distress as measured by the National Comprehensive Cancer Network (NCCN) distress thermometer has been associated with pain, disability and increased healthcare utilization. AIMS: To develop and validate a measure of haemophilia-related distress. METHODS: After qualitative interviews, the Hemophilia-Related Distress Questionnaire (HRDq) was developed. To validate the HRDq, adults (≥18 years) with haemophilia were enrolled, reported demographic and clinical information, and completed the HRDq and other questionnaires that measured similar constructs. Analysis included factor analysis and assessment of internal consistency using Cronbach's α, convergent validity using Pearson's correlation coefficient, and discriminant validity by comparing subgroups of patients. Test-retest reliability was assessed using an intraclass correlation coefficient (ICC). RESULTS: Among 130 enrolled participants, 126 (median age=32.7 years) completed the 24 item HRDq in a median time of 5.4 minutes with overall HRDq scores ranging from 2 to 83 (median score=31.5; higher scores indicating higher distress). Assessment of convergent validity demonstrated a strong correlation (ρ>.60) of the HRDq total score with the NCCN Distress Thermometer, Haem-A-QoL total Score, and PROMIS-29 Profile social role domain and a mild to moderate correlation with all other questionnaire domains (.3-.59, p < .05). Distress was higher among those who had less education, were not employed, and were disabled and was not significantly different among those with severe compared with non-severe disease. Assessment of test-retest reliability demonstrated an ICC value of .84 (95% CI .71-.91) for the total score. CONCLUSIONS: The HRDq demonstrates good internal consistency, construct and discriminant validity, and retest reliability with a low responder burden.

Natural history study of factor IX deficiency with focus on treatment and complications (B-Natural).

INTRODUCTION: Haemophilia B (HB) is less well studied than haemophilia A (HA); despite similarities between the two inherited bleeding disorders, important differences remain that require further research. AIM: B-Natural is a multi-centre, prospective, observational study of HB, designed to increase understanding of clinical manifestations, treatment, quality-of-life (QoL), inhibitor development, immune tolerance induction (ITI) outcome, renal function and create a biorepository for future investigations. METHODS: Participants include sibling pairs/groups without a current/history of inhibitors and singletons or siblings with a current/history of inhibitors followed for six months. Demographics, medical, social history and treatment were recorded. A physical examination including joint range of motion (ROM) was performed; QoL was assessed. Samples were collected for F9 gene mutation, HLA typing, non-inhibitory antibodies and renal function testing. RESULTS: Twenty-four centres enrolled 224 individuals from 107 families including 29 with current/history of inhibitors. Of these, 68, 30.4%, had severe (<1% FIX level of normal); 114, 50.9%, moderate (1%-5%); and 42, 18.8%, mild (>5-<40%) disease. At enrolment, 53.1% had 50 + exposure days to exogenous FIX. Comparison of joint scores showed significant (P < .05) differences between those with severe (with/without inhibitors), and those with moderate/mild disease. The majority with severe disease, 80.0% with current/history of inhibitors and 64.3% of those without, were treated with prophylaxis. CONCLUSION: B-Natural provides data supporting an increased understanding of HB and its impact throughout life. The need for optimal disease control to normalize physical and psychosocial outcomes is underscored, and further analyses will contribute to an increased understanding of critical issues in HB.

Evaluating international Haemophilia Joint Health Score (HJHS) results combined with expert opinion: Options for a shorter HJHS.

INTRODUCTION: The Hemophilia Joint Health Score (HJHS) was developed to detect early changes in joint health in children and adolescents with haemophilia. The HJHS is considered by some to be too time consuming for clinical use and this may limit broad adoption. AIM: This study was a first step to develop a shorter and/or more convenient version of the HJHS for the measurement of joint function in children and young adults with haemophilia, by combining real-life data and expert opinion. METHODS: A cross-sectional multicenter secondary analysis on pooled data of published studies using the HJHS (0-124, optimum score 0) in persons with haemophilia A/B aged 4-30 was performed. Least informative items, scoring options and/or joints were identified. An expert group of 19 international multidisciplinary experts evaluated the results and voted on suggestions for adaptations in a structured meeting (consensus set at ≥ 80%). RESULTS: Original data on 499 persons with haemophilia from 7 studies were evaluated. Median age was 15.0 years [range 4.0-29.9], 83.2% had severe haemophilia and 61.5% received prophylaxis. Median (IQR) HJHS total was 6.0 (1.0-17.0). The items 'duration swelling' and 'crepitus' were identified as clinically less informative and appointed as candidates for reduction. CONCLUSION: Analysis of 499 children and young adults with haemophilia showed that the HJHS is able to discriminate between children and adults and different treatment regimens. Reduction of the items 'duration swelling' and 'crepitus' resulted in the HJHSshort , which had the same discriminative ability. Additional steps are needed to achieve a substantially shorter HJHS assessment.

Disease-related distress among adults with haemophilia: A qualitative study.

INTRODUCTION: Distress related to disease burden has been defined and described among people with chronic diseases including diabetes and cancer. In these populations, disease-specific distress is associated with health outcomes. Haemophilia-related distress is less understood. AIM: To identify qualitative features of haemophilia-related distress among affected adults to ultimately inform the creation of a measurement tool. METHODS: Adults with haemophilia A or B associated with a large haemophilia treatment centre in the south-eastern U.S. were recruited to participate in this qualitative study. Fifteen participants completed semi-structured telephone interviews. Interviews lasted 1-2 hours and explored experiences of distress related to various aspects of haemophilia. Interviews were audio taped, transcribed and coded using NVIVO, software for organizing, managing and analysing qualitative data. Coding was deductive and inductive, and the analysis was thematic. RESULTS: Haemophilia-related distress was broadly related to feelings of isolation and vulnerability which incorporated health system factors, physical functioning, caretaker roles and psychological considerations. Specific features associated with haemophilia-related distress included lack of trust in the knowledge of haemophilia and care provided by staff in community healthcare settings, concerns about the future such as health insurance access and ageing/disability, long-standing feelings of being different from others and feeling like an outsider, treatment burdens and fear of acute bleeds. Protective factors included supportive relationships with family, friends and haemophilia care teams through which participants received practical and emotional support. CONCLUSION: Features of haemophilia-related distress were identified. Results will facilitate distress measurement and intervention efforts to reduce distress in adults with haemophilia.

Factor VIII prophylaxis effects outweigh other hemostasis contributors in predicting severe haemophilia A joint outcomes.

INTRODUCTION: The Joint Outcome Study (JOS) demonstrated that previously untreated children with severe haemophilia A treated with prophylactic factor VIII (FVIII) concentrate had superior joint outcomes at age 6 years compared to those children treated episodically for bleeding. However, variation in joint outcome within each treatment arm was not well explained. AIM: In this study, we sought to better understand variation in joint outcomes at age 6 years in participants of the JOS. METHODS: We evaluated the influence of FVIII half-life, treatment adherence, constitutional coagulant and anticoagulant proteins, and global assays on joint outcomes (number of joint bleeds, total number of bleeds, total MRI score and joint physical exam score). Logistic regression was used to evaluate the association of variables with joint failure status on MRI, defined as presence of subchondral cyst, surface erosion or joint-space narrowing. Each parameter was also correlated with each joint outcome using Spearman correlations. RESULTS: Prophylaxis treatment arm and FVIII trough were each found to reduce risk of joint failure on univariate logistic regression analysis. When controlling for treatment arm, FVIII trough was no longer significant, likely because of the high level of covariation between these variables. We found no consistent correlation between any laboratory assay performed and any joint outcome parameter measured. CONCLUSION: In the JOS, the effect of prescribed prophylactic FVIII infusions on joint outcome overshadowed the contribution of treatment adherence, FVIII half-life, global assays of coagulation and constitutional coagulation proteins. (ClinicalTrials.gov number, NCT00207597).

Bleeding and safety outcomes in persons with haemophilia A without inhibitors: Results from a prospective non-interventional study in a real-world setting.

INTRODUCTION: Prospectively collected real-world data on bleeds, haemophilia treatment and safety in persons with haemophilia A (PwHA) without factor VIII (FVIII) inhibitors are limited. A global, non-interventional study (NIS; NCT02476942) prospectively collected real-world data in PwHA who were treated per local routine clinical practice. AIM: Assess annualized bleeding rate (ABR), haemophilia treatment practices and adverse events (AEs) in adult/adolescent PwHA without inhibitors. METHODS: Eligible participants aged ≥12 years with severe HA without history of inhibitors prospectively collected bleeding and treatment information. RESULTS: Ninety-four participants were enrolled (median [range] age, 34 [12-76] years) and monitored for a median (range) of 29.8 (12.4-47.7) weeks. In the episodic (n = 45) and prophylactic (n = 49) treatment groups, respectively, 872/1066 (81.8%) and 151/189 (79.9%), bleeds were treated; ABRs (95% confidence interval) were 36.1 (30.8-42.3) and 5.0 (3.3-7.5), respectively, for treated bleeds and 43.1 (36.5-50.9) and 6.2 (4.2-9.2), respectively, for all bleeds, and median (interquartile range) ABRs were 31.1 (19.8-51.6) and 1.9 (0.0-8.2), respectively, for treated bleeds and 35.3 (21.7-62.9) and 2.7 (0.0-9.4), respectively, for all bleeds. Half of the participants on FVIII prophylaxis had relatively high adherence to treatment, using 2.9 and 2.1 median doses/wk of standard and extended half-life FVIII, respectively. Serious AEs included gastrointestinal polyp haemorrhage and haemarthrosis; the most common AE was viral upper respiratory tract infection. CONCLUSION: PwHA without inhibitors continue to bleed on prophylaxis, consistent with the literature, and require treatment for breakthrough bleeds. This prospective NIS demonstrates the need for more efficacious haemostatic approaches.