Hereditary angioedema (HAE) in Belgium: results from a national survey.

Background: Hereditary angioedema (HAE) is a rare heritable disorder that is characterized by recurrent, circumscribed, nonpitting, nonpruritic, often painful subepithelial swellings of sudden unpredictable onset that generally fade during 48-72 h. Epidemiological data of hereditary angioedema patients in Belgium is lacking. Methods: We set up a nation-wide, multicentric study involving the 8 Belgian hospitals known to follow-up patients with Type I and II HAE. All Belgium HAE patients were asked to fill out questionnaires that mainly covered demographic data, family history, and detailed information about diagnosis, treatment and burden of their Type I and II HAE. Results: 112 patients with type I or type II HAE could be included. Median delay between first symptoms and diagnosis was 7 years. 51% of patients had experienced pharyngeal or tongue swelling and 78% had experienced abdominal symptoms, both known to cause an important reduction in quality of life. 60% of symptomatic patients reported to receive long term prophylactic treatment. Human plasma-derived C1-esterase inhibitor concentrate was used by 56.3% of patients. 16.7% and 27.1% of patients used a 17-α-alkylated androgen and tranexamic acid as long term prophylactic therapy. Conclusions: We present the first nation-wide epidemiological study regarding HAE in Belgium. Our data show that the morbidity of HAE is not to be underestimated. Knowledge and dissemination of this data is critical in raising awareness, encouraging development of therapies and optimising nationwide management.

Clinical practice of hereditary angioedema in Belgium: opportunities for optimized care.

INTRODUCTION: Hereditary angioedema (HAE) is a rare disorder characterized by unpredictable painful and potentially life-threatening swelling episodes. The international WAO/EAACI guideline on the diagnosis and management of HAE was recently updated and provides up-to-date guidance for the management of. In this paper, we assessed to what extent the Belgian clinical practice was aligned with the revised guideline, and whether there were opportunities to optimise Belgian clinical practice in HAE. METHODS: We compared the updated international guideline for HAE with information we acquired on Belgian clinical practice, a Belgian patient registry and expert opinion analysis. The Belgian patient registry was developed with the involvement of eight Belgian reference centers for HAE patients. Eight Belgian experts, physicians in the participating centers, included patients in the patient registry and participated in the expert opinion analysis. RESULTS: The main action points to further optimise the Belgian clinical practice of HAE are Work towards total disease control and normalize patients' life by considering the use of new and innovative long-term prophylactic treatment options; (2) inform C1-INH-HAE patients about new long-term prophylactic therapies; (3) assure the availability of on-demand therapy for all C1-INH-HAE patients; (4) implement a more universally used assessment including multiple aspects of the disease (e.g. quality of life assessment) in daily clinical practice; and (5) continue and expand an existing patient registry to assure continued data availability on C1-INH-HAE in Belgium. CONCLUSIONS: In light of the updated WAO/EAACI guideline, five action points were identified and several other suggestions were made to optimise the Belgian clinical practice in C1-INH-HAE.

[Rare manifestations of monoclonal gammopathies: About two clinical cases and literature review]. / Manifestations rares des gammapathies monoclonales : à propos de 2 cas et revue de la littérature.

INTRODUCTION: Monoclonal gammopathies are common over the age of 50. Patients are usually asymptomatic. However, some patients present with secondary clinical manifestations, which are now grouped under the entity « Monoclonal Gammopathy of Clinical Significance ¼ (MGCS). CASE REPORT: Here, we report two rare cases of MGCS: an acquired von Willebrand syndrome (AvWS) and an acquired angioedema (AAE). CONCLUSION: The discovery of a decrease in von Willebrand activity (vWF:RCo) or angioedema in a patient over 50 years of age, in the absence of a family history, should prompt a search for a hemopathy and in particular, a monoclonal gammopathy.

Incidental finding of unreported large duplication in F8 gene during prenatal analysis: Which management for genetic counselling?

Detection of incidental finding and variant of unknown significance (VUS) during prenatal diagnosis has particularly increased with the emergence of genetic tests such chromosomal microarray analysis (CMA). Many factors and clear guidelines need to be applied in the interpretation of the potential clinical consequences of unreported complex copy number variations (deletions/duplications). From a clinical case where an unreported and not completely intragenic duplication in F8 gene has been identified in a 12-week-old fetus without haemophilia A history documented in the family, we will examine and study the difficulties of interpretation and the challenges that the detection of such variant has on genetic counselling.

Obesity in the global haemophilia population: prevalence, implications and expert opinions for weight management.

Overweight and obesity may carry a significant disease burden for patients with haemophilia (PWH), who experience reduced mobility due to joint inflammation, muscle dysfunction and haemophilic arthropathy. This review aimed to define the prevalence and clinical impact of overweight/obesity in the global population of PWH. A detailed literature search pertaining to overweight/obesity in haemophilia in the last 15 years (2003-2018) was conducted, followed by a meta-analysis of epidemiological data. The estimated pooled prevalence of overweight/obesity in European and North American PWH was 31%. Excess weight in PWH is associated with a decreased range in motion of joints, accelerated loss of joint mobility and increase in chronic pain. Additionally, the cumulative disease burden of obesity and haemophilia may impact the requirement for joint surgery, occurrence of perioperative complications and the prevalence of anxiety and depression that associates with chronic illness. Best practice guidelines for obesity prevention and weight management, based on multidisciplinary expert perspectives, are considered for adult and paediatric PWH. Recommendations in the haemophilia context emphasize the importance of patient education and tailoring engagement in physical activity to avoid the risk of traumatic bleeding.

Review of molecular mechanisms at distal Xq28 leading to balanced or unbalanced genomic rearrangements and their phenotypic impacts on hemophilia.

The distal Xq28 region is very gene-rich, comprising a relatively large number of low-copy repeats (LCRs) predisposing to genomic rearrangements. The best-known rearrangement at this locus is the F8 intron 22 inversion, responsible for up to 45% of severe hemophilia A (HA) cases. An additional inversion of intron 1 of F8 has more recently been described, affecting 2%-5% of patients with severe HA. These "balanced" rearrangements are mediated by intrachromosomal homologous recombination between inversely oriented LCRs located in intron 1 or 22 and other extragenic copies positioned more telomerically outside the F8 gene. The successive innovations of semi-quantitative technologies like multiplex ligation-dependent probe amplification (MLPA) and array comparative genomic hybridization (array CGH) have rendered it possible to highlight a significant number of "unbalanced" rearrangements associated or not with these inversions. Some rearrangements are generated by the non-allelic homologous recombination (NAHR) pathway between directly oriented LCRs. Others are probably the result of unequal crossing-over or U-loop exchanges during female meiosis. This review sought to provide an overview of the mechanisms underlying rearrangements at the distal Xq28 locus and discuss their clinical impacts other than HA, such as risks of developing high inhibitor levels and spontaneous abortion, as well as other pathologies like cardiovascular disease or potentially X-linked intellectual disease.

Women with bleeding disorders.

Diagnosis of the genetic status and assessment of potential clotting factor deficiency in haemophilia carriers are performed more easily nowadays. However, delays in providing those diagnosis and appropriate management are often reported despite increased availability of genetic techniques and improved awareness that carriers may have bleeding experiences. Women with von Willebrand disease (VWD) and rare factor deficiencies (RFD) may bleed during pregnancy and following childbirth and in some cases may experience adverse foetal/neonatal outcomes. This review describes the evolution of practice, unmet needs and options for both girls and women in families with haemophilia as well as the clinical and laboratory characteristics during pregnancy and recommendation for the delivery and the postpartum follow-up in women with VWD and RFD.

Recombinant factor VIII: past, present and future of treatment of hemophilia A.

The development of recombinant factor VIII (rFVIII) was initially driven by the necessity to treat hemophilia A (HA) patients with FVIII concentrates without the risk of transmitting infectious agents. Over the last three decades the safety of rFVIII has been further improved by completely removing animal or human proteins from the manufacturing process, so that patients would not be exposed to known or emerging pathogens. Recent efforts have concentrated on improving the expression of rFVIII, reducing its immunogenicity and enhancing its pharmacokinetic (PK) behavior. These new goals have been possible thanks to the develop-ment of biotechnology and a better knowledge of the function and structure of FVIII. Several approaches such as deletion of the B-domain, expression of FVIII by human cell lines, sequence modification, structural modification, co-expression with other proteins, fusion with the Fc fragment of immunoglobulins and PEGylation have been utilized. As a result of these efforts, different rFVIII products have been validated in terms of efficacy, immunogenicity and PK profile. Other technologies are currently being explored to improve the PK of FVIII and allow its subcutaneous administration. Although nonreplacement therapies and HA gene therapy appear to be promising alternatives for HA, rFVIII will very likely remain as a critical component for the treatment of HA because of its physiological activity and mode of action, as well as its unique ability to induce or restore tolerance to exogenous FVIII. This review summarizes the principal features of past, current and emerging rFVIII products for HA.

Pharmacokinetic modelling and validation of the half-life extension needed to reduce the burden of infusions compared with standard factor VIII.

INTRODUCTION: Currently, no universally accepted definition of extended half-life (EHL) recombinant FVIII (rFVIII) exists. Identifying the minimum half-life extension ratio required for a reduction in dosing frequency compared with standard rFVIII could enable a more practical approach to decisions around prophylaxis with EHL rFVIII. AIM: To identify the half-life extension ratio required to decrease rFVIII dosing frequency by at least 1 day while maintaining the proportion of patients with plasma rFVIII levels above 1 IU/dL and without increasing the total weekly dose. METHODS: A previously published population pharmacokinetic model for standard rFVIII was used to estimate the percentage of patients with factor VIII (FVIII) levels always >1 IU/dL using various benchmark regimens. Using modelling, dosing frequency was reduced while rFVIII half-life was extended until the percentage of patients with FVIII >1 IU/dL equalled that of the benchmark regimen. RESULTS: Benchmark 3×/wk dosing totalling 100 IU/kg/wk of rFVIII resulted in 56.6% of patients with FVIII levels always >1 IU/dL. With 2×/wk dosing, totalling 80 or 90 IU/kg/wk, half-life extensions required to maintain 56.6% of patients at FVIII levels >1 IU/dL were 1.30 and 1.26, respectively. A half-life extension ratio of 1.33 was required to change dosing from every 48 hours to every 72 hours (both at 105 IU/kg/wk) while maintaining 92.8% of patients with FVIII >1 IU/dL. CONCLUSION: Based on this investigation, EHL rFVIII products should have a minimum half-life extension ratio of 1.3 to provide a reduction in dosing frequency from 3× to 2×/wk compared with standard rFVIII products while maintaining the same minimum FVIII trough level.

European principles of inhibitor management in patients with haemophilia.

BACKGROUND: In spite of recent major advances in the understanding and treatment of inhibitor development in patients with haemophilia, multidisciplinary management of many of these patients remains suboptimal and highly heterogenous across Europe. METHODS: Following a series of multidisciplinary meetings and a review of the literature, the European haemophilia community of health professionals and patients jointly defined practical optimum standards for ensuring and harmonizing treatment and care for patients with an inhibitor. RESULTS: Ten complementary principles for the management of inhibitors in haemophilia have been developed, emphasizing the importance and benefits of a centralized, multidisciplinary, expert and holistic approach. CONCLUSIONS: This document will serve as a benchmark to improve the multidisciplinary and practical management of patients with inhibitor. Implementation and adherence to each of these principles should have a major positive impact on the management and outcomes of patients developing an inhibitor.

Defining extended half-life rFVIII-A critical review of the evidence.

INTRODUCTION: Recent haemophilia treatment advances include new recombinant FVIII (rFVIII) products with improved pharmacokinetic (PK) properties that aim to reduce the burden of prophylaxis. These treatments are commonly referred to as extended half-life rFVIII products (EHL rFVIII). There is no uniform definition of what constitutes an EHL rFVIII. Such a definition would help physicians, patients and funders understand the properties of standard and EHL rFVIIIs and thus provide clarity when selecting an EHL in clinical settings. AIM: To critically assess the published evidence on new and emerging rFVIII products in order to propose a definition to classify EHL rFVIIIs. METHODS: We systematically searched PubMed, EMBASE and regulatory authorities (FDA/EMA/Health Canada) websites for publications and regulatory submissions describing prospective crossover PK studies evaluating rFVIIIs that demonstrate improved PK parameters in adults and adolescents with severe haemophilia A. RESULTS: Following critical analyses of the published data, we developed a holistic approach to defining rFVIIIs as EHLs, which requires all of the following: (i) using technology designed to extend rFVIII half-life; (ii) lacking bioequivalence with a standard rFVIII comparator-above the FDA/EMA cut-off of 125% for the 90% confidence intervals for area under the curve ratio; and (iii) having an extended half-life ratio measured in a PK comparator crossover study. CONCLUSION: In this systematic review, a pragmatic definition of EHL rFVIII has been proposed that should provide better clarity in clinical discussions surrounding the appropriate use of rFVIII products. At present, only products using PEGylation or Fc fusion half-life extension technology meet the proposed criteria for definition of EHL rFVIII.

Postural control during a transition task in haemophilic children, adolescents and young adults with haemophilic ankle arthropathy.

BACKGROUND: The aim of this study was to determine whether young haemophilic boys with and without MRI-based signs of ankle arthropathy demonstrate reduced balance ability during a transition task with eyes open and eyes closed. METHODS: Thirty-four haemophilic bodies and 28 typically developing boys aged 6-20 years participated to this study. Structural integrity of the tarsal foot joints of all haemophilic boys was assessed with MRI. All participants performed a standard transition task from double-leg stance to single-leg stance with eyes open and eyes closed. Comparison of balance features derived from the centre of pressure displacement captured by a single force platform was performed between the different haemophilia subgroups and sex-age-height matched peers. FINDINGS: The haemophilic boys without signs of arthropathy presented only a higher intermediate phase velocity during the eyes closed condition (P = .05). The haemophilic boys with signs of arthropathy had significantly higher displacement after the time to new stability point, and 95% Ellipse Sway Area and Balance Area compared to their matched peers during eyes open test (P < .05). Similar findings were observed during the eyes closed test for the displacement after the time to new stability point and 95% Ellipse Sway Area (P < .05). No significant differences were observed between affected and non-affected side of the unilateral affected patients. INTERPRETATION: We suggest that the pathophysiological cascade associated with chronic bleeding episodes should not be considered as a "simple" musculoskeletal injury, hence more as a complex neurophysiological dysfunction which may originate both from unilateral and bilateral deterioration of the musculoskeletal system.

Assessment of passive musculoarticular ankle stiffness in children, adolescents and young adults with haemophilic ankle arthropathy.

OBJECTIVES: To measure passive musculoarticular ankle stiffness (PMAAS) and its intra- and interday reliability in adult control subjects without ankle disorders. We also sought to quantify PMAAS in children, adolescents and young adults with haemophilia (CAAwH) taking into account the accurate tibiotalar and subtalar joints structural status obtained by magnetic resonance imaging (MRI). METHODS: We included 23 CAAwH and 23 typically developing boys (TDB) matched by age, weight and height, along with 25 healthy volunteers for reliability assessment. All CAAwH underwent bilateral ankle MRI, with anatomical status assessed using the International Prophylaxis Study Group MRI scale. All CAAwH underwent PMAAS testing for both sides randomly vs the dominant side (DS) in TDBs. For assessing viscous stiffness (VS) and elastic stiffness (ES), eight different oscillation frequencies were randomly repeated three times for each subject. RESULTS: Good-to-excellent intra- and interday reliability was observed for ES and VS variables. No relevant differences were observed between the ankle viscoelastic properties in CAAwH without joint damage and matched TDBs, whereas the study revealed significantly increased ES in the affected ankles of CAAwH with severe unilateral joint involvement compared to the non-affected joint. CONCLUSION: This study confirmed increased ES in the severely affected ankles of CAAwH compared to non-affected sides. No differences in the ankle viscoelastic properties of CAAwH with or without joint damage were observed, however, compared to matched TDB.

Reliability and clinical features associated with the IPSG MRI tibiotalar and subtalar joint scores in children, adolescents and young adults with haemophilia.

OBJECTIVES: To assess the reliability of the IPSG MRI scale for tibiotalar (TTJ) and subtalar joint (STJ) changes in young haemophilic patients, correlating MRI findings with functional scores and 3D-rearfoot kinematics. METHODS: A total of 37 haemophilic patients underwent bilateral MRI of the footankle, clinical evaluation and quantitative assessment of their 3D-rearfoot kinematics during walking. TTJ and STJ soft tissues were assessed twice along with osteochondral changes by two radiologists using the IPSG MRI scale. Inter- and intra-observer reproducibility of MRI scoring were tested by means of kappa statistics. Correlational analyses were performed between MRI findings and the Haemophilia Joint Health Score 2.1 (HJHS) and 3D-rearfoot kinematic data. RESULTS: The intra-reader reliability of MRI scoring was good to excellent (Kappa: 0.62-1), whereas the inter-reader reliability was moderate to good (Kappa: 0.54-0.79). Weak yet significant correlations were found between the frontal plane rearfoot range of motion (ROM) during loading response of gait and STJ score, as well as between frontal plane rearfoot ROM during the terminal stance phase and the rearfoot osteochondral lesions. CONCLUSION: The IPSG score appears applicable to not only the TTJ but also the STJ. Contrary to TTJ lesions, those of the STJ do not correlate with the HJHS but do with 3D-rearfoot kinematic data.

Pattern of bleeding in a large prospective cohort of haemophilia A patients: A three-year follow-up of the AHEAD (Advate in HaEmophilia A outcome Database) study.

INTRODUCTION: Outcome data on treatment of patients with haemophilia A spanning several years of real-world evidence collection are currently very limited. AIM AND METHODS: The global prospective long-term Advate® Haemophilia A Outcome Database (AHEAD) cohort study collects real-world data from patients with severe and moderate haemophilia. We report an interim data read-out after three years of observation. RESULTS: A total of 522 patients were enrolled from 21 countries: 334 completed year 1 follow-up, 238 completed year 2 and 136 completed year 3, with an overall follow-up of 811 patient-years. Median annual bleeding rates (ABR) were 1.7 in the prophylaxis group and 8.9 in the on-demand group at year 1 visit, 1.6 and 13.0, respectively, at year 2 visit and 2.2 and 10.3, respectively, at year 3 visit. Moreover, about 42% of patients on prophylaxis vs 12% of patients on on-demand had zero annual joint bleeding rates (AJBR). Effectiveness of prophylaxis and on-demand treatment was deemed excellent/good in the majority of cases. Octocog alfa (Advate® ) was well tolerated. The inhibitors that developed in nine patients all disappeared spontaneously. Three patients had been previously exposed to FVIII for ≤50 exposure days (EDs), 3 for >50 EDs and 3 showed a borderline positive inhibitory activity (≤0.6 BU/mL). CONCLUSIONS: These data confirm that the goal of zero bleeds is achievable, although not yet achieved in all patients. Understanding reasons behind the lower response to standard prophylaxis regimens in some patients and personalizing prophylactic treatment may further improve outcome in patients with haemophilia A.

Deficits of ankle muscle strength not found in children, adolescents and young adults with haemophilic ankle arthropathy.

OBJECTIVES: Adequate management of haemophilia patients requires early detection of joint impairment in relatively asymptomatic patients. This study sought to quantify the impact of the ankle's structural impairment on muscle strength in children, adolescent and young adults with haemophilia (CAAwH). METHODS: Twenty-three CAAwH underwent bilateral magnetic resonance imaging (MRI) assessing the anatomical status of tibiotalar joint (TTJ) and subtalar joint (STJ) using the International Prophylaxis Study Group MRI scale. An isokinetic dynamometer enabled a detailed evaluation of muscle strength at slow and fast speed. In parallel, 10 typically developing healthy boys (TDB) participated in a 1-week interval test-retest assessment to assess the test's reliability. RESULTS: Forty-six MRI ankle scores were obtained, with 11 patients unilaterally affected and one bilaterally. Of the 13 affected feet, nine showed abnormalities at TTJ, three at the posterior STJ and the remaining one at both joints. Muscle strength was not reduced in CAAwH exhibiting TTJ and/or STJ arthropathy, as compared to healthy TDB, nor was there any difference between the CAAwH's affected or unaffected sides. CONCLUSION: Contrarily to adult patients, CAAwH with repeated ankle bleeding may be less impaired than current structural evaluations imply, with possibly a latency between the occurrence of structural and functional damage.