The Malmo International Brother Study (MIBS). Genetic defects and inhibitor development in siblings with severe hemophilia A

BACKGROUND AND OBJECTIVES: The strongest risk factor identified for inhibitor development in people with severe hemophilia A is the type of factor VIII gene mutation. The objective of this study was to evaluate the mutation type dependent concordance rate of inhibitor formation in siblings. DESIGN AND METHODS: The gene defect, treatment and inhibitor history were evaluated in 113 families in which two or more siblings had severe hemophilia A. RESULTS: Seventy-nine of the families (69.9%) were concordant in that either all or none of the siblings had a history of inhibitors. The concordance in 59 families with inhibitors was 42.4%. The corresponding figures for the 74 families with intron 22 inversion were 63.5% and 40.0%, respectively, and the overall concordance within 14 families with nonsense mutations was 78.6%. The siblings in two families with large gene deletions had no inhibitor history. A small proportion of the families with missense mutations, small deletions/insertions and splice site mutations developed inhibitors, but in four of the families two or more siblings developed high-responding inhibitors. In 18 of the 25 concordant families (72.0%) with inhibitors, the inhibitor was also of the same type (high-responding). INTERPRETATION AND CONCLUSIONS: This is the first study of the association between inhibitor formation and the causative factor VIII gene mutation in siblings. The data show that the type of mutation provides, to some extent, the basis for this relationship, but the mutation itself is not enough to predict the risk for therapy-induced inhibitor formation

Treatment outcomes in persons with severe haemophilia B in the Nordic region : The B-NORD study

Introduction Data on outcome in persons with haemophilia B (PwHB) are limited and mainly extrapolated from studies of haemophilia A (HA). Aim To characterize treatment outcomes in persons with severe HB in the Nordic region, with a focus on joint health, compared with matched controls with HA. Methods PwHB attending haemophilia centres in Denmark, Finland, Norway and Sweden were enrolled and matched with controls with HA. Joint assessment using Haemophilia Joint Health Score (HJHS) and ultrasound according to Haemophilia Early Arthropathy Detection protocol (HEAD-US) was conducted. Adherence was evaluated using the Validated Haemophilia Regimen Treatment Adherence Scale (VERITAS). Results Seventy-nine males with HB, with median age of 30 years (range 1-75), were enrolled. Eleven patients (14%) had a history of or current inhibitor. Twenty-nine PwHB (37%) reported joint bleeds during the prior year, and 35% had previously undergone joint surgery. Ninety-five per cent were on prophylaxis, and 70% used recombinant concentrates, with a median factor consumption of 3,900 IU/kg/year for standard half-life products. Only two patients had a VERITAS score corresponding to 'non-adherence'. Joint health, assessed with HJHS, showed a significant lower score among PwHB compared with HA controls, explained by a difference in the 18-49 age group, without observed differences in older or younger subgroups. The HEAD-US scores were overall low. Conclusion The Nordic cohort of PwHB is well treated by prophylaxis, but the goal of zero bleeds for all is not reached. Our findings suggest that patients with severe HB suffer from a milder arthropathy than patients with severe HA.Peer reviewe

Pain, depression and anxiety in people with haemophilia from three Nordic countries : Cross-sectional survey data from the MIND study

Introduction People with haemophilia (PwH) may experience symptoms of haemophilia-related pain, depression or anxiety, which can negatively impact health-related quality of life. Aim To obtain the perspective of PwH and treaters from Sweden, Finland and Denmark on the management of haemophilia-related pain, depression and anxiety using cross-sectional survey data from the MIND study (NCT03276130). Methods PwH or their caregivers completed a survey about experiences of pain, depression and anxiety related to haemophilia, and the standard EQ-5D-5L instrument. Five investigators at haemophilia treatment centres (HTC) were sent a complementary survey containing questions about the management of pain and depression/anxiety. Results There were 343 PwH (mild: 103; moderate: 53; severe: 180; seven lacking severity information) and 71 caregiver responses. Experience of pain in the last 6 months was reported by 50% of PwH respondents and 46% of caregiver respondents. Anxiety/depression was reported by 28% of PwH respondents. Reporting of pain and anxiety/depression was associated with disease severity. Whilst 62% of PwH who had experienced pain at any time point (n = 242) felt this was adequately addressed and treated at their HTC, only 24% of those who had experienced depression/anxiety (n = 127) felt this was adequately addressed. Disease severity was negatively associated with EQ-5D-5L utility value (p < .001). In the HTC survey, 4/5 and 2/5 agreed that pain and depression/anxiety, respectively, are adequately addressed. Conclusions Pain and depression/anxiety occur more frequently with increasing haemophilia severity, with negative impacts on health-related quality of life. PwH with depression/anxiety or unaddressed pain could benefit from improved management strategies.Peer reviewe

Matching-adjusted indirect comparison of bleeding outcomes in severe haemophilia A: Comparing valoctocogene roxaparvovec gene therapy, emicizumab prophylaxis, and FVIII replacement prophylaxis

INTRODUCTION: Head-to-head evaluation of valoctocogene roxaparvovec, the first gene therapy approved for haemophilia A, with emicizumab is not available. Therefore, phase 3 trial data were indirectly compared. AIM: To compare bleeding rates in trials evaluating 6 × 1013  vg/kg valoctocogene roxaparvovec (GENEr8-1; NCT03370913), 1.5 mg/kg emicizumab dosed every week (HAVEN 3; NCT02847637), and FVIII prophylaxis (270-902) in participants with severe haemophilia A (FVIII ≤1 IU/dL). METHODS: Valoctocogene roxaparvovec versus emicizumab and FVIII prophylaxis as used in 270-902 versus emicizumab cross-trial comparisons were performed using matching-adjusted indirect comparison (MAIC). Individual participant data from GENEr8-1 and 270-902 were weighted to equalise aggregate participant baseline characteristics from HAVEN 3. After MAIC weighting, annualised bleeding rates (ABR) and proportions of participants without bleeds were compared for treated bleeds, all bleeds, treated joint bleeds, and treated spontaneous bleeds. RESULTS: After MAIC weighting, ABR for all bleeds was statistically significantly lower with valoctocogene roxaparvovec than emicizumab (rate ratio [95% CI], .55 [.33-.93]). Additionally, significantly higher proportions of participants had no treated joint bleeds (odds ratio [95% CI], 2.75 [1.20-6.31]) and no treated bleeds (3.25 [1.53-6.90]) with valoctocogene roxaparvovec versus emicizumab. When compared with the mainly standard half-life FVIII prophylaxis regimens in 270-902, mean ABRs (except for all bleeds) were significantly lower, and significantly higher proportions reported 0 bleeds for all outcomes with emicizumab. CONCLUSION: Valoctocogene roxaparvovec provided generally lower bleeding rates and higher probability of no bleeds, including treated joint bleeds, than emicizumab. Emicizumab was more effective than FVIII prophylaxis regimens used in 270-902

Factor IX antibodies and tolerance in hemophilia B in the Nordic countries - The impact of F9 variants and complications

Introduction: The development of inhibitory antibodies (inhibitors) in persons with hemophilia B (PwHB) causes significant morbidity. Data on the impact of the F9 variant and immune tolerance induction (ITI) outcome are limited.The aim of this study was to investigate the presence of neutralizing and non-neutralizing antibodies (NNA) in severe hemophilia B (HB) and to evaluate ITI outcome and complications in relation to the pathogenic F9 variant.Materials and methods: Persons with severe HB in the Nordic countries were enrolled and information on F9 variants, inhibitors, ITI and complications were collected. Analyses of anti-FIX antibodies with a fluorescence -immunoassay (xFLI) and an ELISA method were conducted.Results: Seventy-nine PwHB were enrolled. Null variants were seen in 33 (42 %) PwHB and 12 (15 %) had a current or former inhibitor. Eleven (92 %) of the inhibitor patients had experienced allergic manifestations and three (25 %) nephrotic syndrome. Of 10 PwHB with at least one ITI attempt, eight (80 %) were considered tolerant at enrolment. Immunosuppression was included in seven of eight successful or partially successful at-tempts. Five PwHB had at least one ITI failure before a successful or partially successful ITI. No NNA could be identified.Conclusion: A high proportion of severe F9 gene defects among persons with severe HB in the Nordic countries may explain the observed relatively high prevalence of inhibitors. ITI success was independent of the F9 variant and attained despite allergic manifestations and previous ITI failures. Inclusion of immunosuppression tenta-tively enhances the chances of ITI success. No NNA were observed.Peer reviewe

Inhibitor development: patient-determined risk factors.

Summary. The reasons that inhibitory factor VIII antibodies develop in only a fraction of patients with haemophilia A remain unclear, but studies of genetically related subjects have indicated that the immunological outcome of replacement therapy is to a large extent determined by patient-related risk factors. Non-genetic factors will also influence the inhibitor risk, since events challenging the immune system will elicit and stimulate immune regulatory processes with the potential of modifying the immune response. Further insight into the immunological pathways and risk factors involved will be important in order to better predict and prevent this complication. This review will briefly summarize the data obtained to date in unrelated and related subjects in the Malmö International Brother Study (MIBS) regarding genetic factors and discuss how these factors might interact with non-genetically determined factors and events

Why do inhibitors develop? Principles of and factors influencing the risk for inhibitor development in haemophilia.

The formation of inhibitory alloantibodies is, in the postinfectious era, the most severe and costly complication of replacement therapy in patients with haemophilia. The complexity of the immune response to the infused factor becomes more and more obvious as knowledge in the area increases. Antibodies develop as a result of a complex multi-factorial interaction between antigen-presenting cells, T- and B-lymphocytes. Genetic susceptibility of cell surface molecules, such as the major histocompatibility complex, the T-cell receptor and cytokine receptors, as well as various immunomodulatory molecules have a major impact on the outcome. In addition, environmental factors probably influence the risk of inhibitor development. The current concept of inhibitor development is reviewed. A better understanding of the pathophysiological mechanisms involved will facilitate improvement of therapy in the future, and hopefully provide an opportunity to prevent this complication of treatment