The Immunology of Multisystem Inflammatory Syndrome in Children with COVID-19.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is typically very mild and often asymptomatic in children. A complication is the rare multisystem inflammatory syndrome in children (MIS-C) associated with COVID-19, presenting 4-6 weeks after infection as high fever, organ dysfunction, and strongly elevated markers of inflammation. The pathogenesis is unclear but has overlapping features with Kawasaki disease suggestive of vasculitis and a likely autoimmune etiology. We apply systems-level analyses of blood immune cells, cytokines, and autoantibodies in healthy children, children with Kawasaki disease enrolled prior to COVID-19, children infected with SARS-CoV-2, and children presenting with MIS-C. We find that the inflammatory response in MIS-C differs from the cytokine storm of severe acute COVID-19, shares several features with Kawasaki disease, but also differs from this condition with respect to T cell subsets, interleukin (IL)-17A, and biomarkers associated with arterial damage. Finally, autoantibody profiling suggests multiple autoantibodies that could be involved in the pathogenesis of MIS-C.

Autoantibodies against type I IFNs in humans with alternative NF-κB pathway deficiency.

Patients with autoimmune polyendocrinopathy syndrome type 1 (APS-1) caused by autosomal recessive AIRE deficiency produce autoantibodies that neutralize type I interferons (IFNs)1,2, conferring a predisposition to life-threatening COVID-19 pneumonia3. Here we report that patients with autosomal recessive NIK or RELB deficiency, or a specific type of autosomal-dominant NF-κB2 deficiency, also have neutralizing autoantibodies against type I IFNs and are at higher risk of getting life-threatening COVID-19 pneumonia. In patients with autosomal-dominant NF-κB2 deficiency, these autoantibodies are found only in individuals who are heterozygous for variants associated with both transcription (p52 activity) loss of function (LOF) due to impaired p100 processing to generate p52, and regulatory (IκBδ activity) gain of function (GOF) due to the accumulation of unprocessed p100, therefore increasing the inhibitory activity of IκBδ (hereafter, p52LOF/IκBδGOF). By contrast, neutralizing autoantibodies against type I IFNs are not found in individuals who are heterozygous for NFKB2 variants causing haploinsufficiency of p100 and p52 (hereafter, p52LOF/IκBδLOF) or gain-of-function of p52 (hereafter, p52GOF/IκBδLOF). In contrast to patients with APS-1, patients with disorders of NIK, RELB or NF-κB2 have very few tissue-specific autoantibodies. However, their thymuses have an abnormal structure, with few AIRE-expressing medullary thymic epithelial cells. Human inborn errors of the alternative NF-κB pathway impair the development of AIRE-expressing medullary thymic epithelial cells, thereby underlying the production of autoantibodies against type I IFNs and predisposition to viral diseases.

Integrating a Polygenic Risk Score into a clinical setting would impact risk predictions in familial breast cancer.

BACKGROUND: Low-impact genetic variants identified in population-based genetic studies are not routinely measured as part of clinical genetic testing in familial breast cancer (BC). We studied the consequences of integrating an established Polygenic Risk Score (PRS) (BCAC 313, PRS313) into clinical sequencing of women with familial BC in Sweden. METHODS: We developed an add-on sequencing panel to capture 313 risk variants in addition to the clinical screening of hereditary BC genes. Index patients with no pathogenic variant from 87 families, and 1000 population controls, were included in comparative PRS calculations. Including detailed family history, sequencing results and tumour pathology information, we used BOADICEA (Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm) V.6 to estimate contralateral and lifetime risks without and with PRS313. RESULTS: Women with BC but no pathogenic variants in hereditary BC genes have a higher PRS313 compared with population controls (mean+0.78 SD, p<3e-9). Implementing PRS313 in the clinical risk estimation before their BC diagnosis would have changed the recommended follow-up in 24%-45% of women. CONCLUSIONS: Our results show the potential impact of incorporating PRS313 directly in the clinical genomic investigation of women with familial BC.

A gene-centric approach to biomarker discovery identifies transglutaminase 1 as an epidermal autoantigen.

Autoantigen discovery is a critical challenge for the understanding and diagnosis of autoimmune diseases. While autoantibody markers in current clinical use have been identified through studies focused on individual disorders, we postulated that a reverse approach starting with a putative autoantigen to explore multiple disorders might hold promise. We here targeted the epidermal protein transglutaminase 1 (TGM1) as a member of a protein family prone to autoimmune attack. By screening sera from patients with various acquired skin disorders, we identified seropositive subjects with the blistering mucocutaneous disease paraneoplastic pemphigus. Validation in further subjects confirmed TGM1 autoantibodies as a 55% sensitive and 100% specific marker for paraneoplastic pemphigus. This gene-centric approach leverages the wealth of data available for human genes and may prove generally applicable for biomarker discovery in autoimmune diseases.

A polygenic risk score to help discriminate primary adrenal insufficiency of different etiologies.

BACKGROUND: Autoimmune Addison's disease (AAD) is the most common cause of primary adrenal insufficiency (PAI). Despite its exceptionally high heritability, tools to estimate disease susceptibility in individual patients are lacking. We hypothesized that polygenic risk score (PRS) for AAD could help investigate PAI pathogenesis in pediatric patients. METHODS: We here constructed and evaluated a PRS for AAD in 1223 seropositive cases and 4097 controls. To test its clinical utility, we reevaluated 18 pediatric patients, whose whole genome we also sequenced. We next explored the individual PRS in more than 120 seronegative patients with idiopathic PAI. RESULTS: The genetic susceptibility to AAD-quantified using PRS-was on average 1.5 standard deviations (SD) higher in patients compared with healthy controls (p < 2e - 16), and 1.2 SD higher in the young patients compared with the old (p = 3e - 4). Using the novel PRS, we searched for pediatric patients with strikingly low AAD susceptibility and identified cases of monogenic PAI, previously misdiagnosed as AAD. By stratifying seronegative adult patients by autoimmune comorbidities and disease duration we could delineate subgroups of PRS suggesting various disease etiologies. CONCLUSIONS: The PRS performed well for case-control differentiation and susceptibility estimation in individual patients. Remarkably, a PRS for AAD holds promise as a means to detect disease etiologies other than autoimmunity.

Patients diagnosed with COVID-19 and treated with anakinra: a real-world study in the USA.

Anakinra, a recombinant, non-glycosylated human interleukin (IL)-1 receptor antagonist, has been used in real-world clinical practice to manage hyperinflammation in coronavirus disease 2019 (COVID-19). This retrospective, observational study analyses US hospital inpatient data of patients diagnosed with moderate/severe COVID-19 and treated with anakinra between 1 April and 31 August 2020. Of the 119 patients included in the analysis, 63.9% were male, 48.6% were of black ethnicity, and the mean (standard deviation [SD]) age was 64.7 (12.5) years. Mean (SD) time from hospital admission to anakinra initiation was 7.3 (6.1) days. Following anakinra initiation, 73.1% of patients received antibiotics, 55.5% received antithrombotics, and 91.0% received corticosteroids. Overall, 64.7% of patients required intensive care unit (ICU) admittance, and 28.6% received mechanical ventilation following admission. Patients who did not require ICU admittance or who were discharged alive experienced a significantly shorter time between hospital admission and receiving anakinra treatment compared with those admitted to the ICU (5 vs. 8 days; P = 0.002) or those who died in hospital (6 vs. 9 days; P = 0.01). Patients with myocardial infarction or renal conditions were six times (P < 0.01) and three times (P = 0.01), respectively, more likely to die in hospital than be discharged alive. A longer time from hospital admission until anakinra treatment was associated with significantly higher mortality (P = 0.01). Findings from this real-world study suggest that a shorter time from hospital admission to anakinra treatment is associated with significantly lower ICU admissions and mortality among patients with moderate/severe COVID-19.

Screening for autoantibody targets in post-vaccination narcolepsy using proteome arrays.

Narcolepsy type 1 (NT1) is a chronic sleep disorder caused by a specific loss of hypocretin-producing neurons. The incidence of NT1 increased in Sweden, Finland and Norway following Pandemrix®-vaccination, initiated to prevent the 2009 influenza pandemic. The pathogenesis of NT1 is poorly understood, and causal links to vaccination are yet to be clarified. The strong association with Human leukocyte antigen (HLA) DQB1*06:02 suggests an autoimmune pathogenesis, but proposed autoantigens remain controversial. We used a two-step approach to identify autoantigens in patients that acquired NT1 after Pandemrix®-vaccination. Using arrays of more than 9000 full-length human proteins, we screened the sera of 10 patients and 24 healthy subjects for autoantibodies. Identified candidate antigens were expressed in vitro to enable validation studies with radiobinding assays (RBA). The validation cohort included NT1 patients (n = 39), their first-degree relatives (FDR) (n = 66), population controls (n = 188), and disease controls representing multiple sclerosis (n = 100) and FDR to type 1 diabetes patients (n = 41). Reactivity towards previously suggested NT1 autoantigen candidates including Tribbles homolog 2, Prostaglandin D2 receptor, Hypocretin receptor 2 and α-MSH/proopiomelanocortin was not replicated in the protein array screen. By comparing case to control signals, three novel candidate autoantigens were identified in the protein array screen; LOC401464, PARP3 and FAM63B. However, the RBA did not confirm elevated reactivity towards either of these proteins. In summary, three putative autoantigens in NT1 were identified by protein array screening. Autoantibodies against these candidates could not be verified with independent methods. Further studies are warranted to identify hypothetical autoantigens related to the pathogenesis of Pandemrix®-induced NT1.

Effectiveness and safety of rivaroxaban and warfarin for prevention of major adverse cardiovascular or limb events in patients with non-valvular atrial fibrillation and type 2 diabetes.

AIMS: To assess the effectiveness and safety of rivaroxaban versus warfarin for the prevention of major adverse cardiovascular events (MACE) and major adverse limb events (MALE) in patients with type 2 diabetes (T2D) and non-valvular atrial fibrillation (NVAF). MATERIALS AND METHODS: Using MarketScan data from January 2012 to December 2017, we identified oral anticoagulant-naïve patients with NVAF and comorbid T2D and ≥12 months of insurance coverage prior to rivaroxaban or warfarin initiation. Differences in baseline covariates between cohorts were adjusted for using inverse probability of treatment weights based on propensity scores (absolute standardized differences <0.1 achieved for all covariates after adjustment). Patients were followed until a MACE, MALE or major bleeding event, oral anticoagulant discontinuation/switch, insurance disenrolment or end of data availability. Hazard ratios (HRs) and 95% confidence intervals (CIs) comparing the cohorts were calculated using Cox regression. RESULTS: We identified 10 700 rivaroxaban users (24.1% received a reduced dose) and 13 946 warfarin users. The median (25%, 75% range) age was 70 (62, 79) years, CHA2DS2-VASc score was 4 (3, 5) and duration of available follow-up was 1.4 (0.6, 2.7) years. Eleven percent of patients had peripheral artery disease, 5.1% had coronary artery disease, and 5.1% had a prior MALE, at baseline. Rivaroxaban was associated with a 25% (95% CI 4-41) reduced risk of MACE and a 63% (95% CI 35-79) reduced risk of MALE compared to warfarin. Major bleeding risk did not significantly differ between cohorts (HR 0.95). CONCLUSIONS: Among patients with NVAF and T2D treated in routine practice, rivaroxaban was associated with lower risks of both MACE and MALE versus warfarin, with no significant difference in major bleeding.

Effectiveness and Safety of Rivaroxaban in Patients With Cancer-Associated Venous Thrombosis.

Background: Although not designated as guideline-recommended first-line anticoagulation therapy, patients are receiving rivaroxaban for the treatment and secondary prevention of cancer-associated venous thrombosis (CAT). We sought to estimate the cumulative incidence of recurrent venous thromboembolism (VTE), major bleeding, and mortality/hospice care in patients with CAT treated with outpatient rivaroxaban in routine practice. Methods: Using US MarketScan claims data from January 2012 through June 2015, we identified adults with active cancer (using SEER program coding) who had ≥1 primary hospitalization or emergency department discharge diagnosis code for VTE (index event) and received rivaroxaban as their first outpatient anticoagulant within 30 days of the index VTE. Patients were required to have ≥180 days of continuous medical/prescription benefits prior to the index VTE. Patients with a previous claim for VTE, atrial fibrillation, or valvular disease or receiving anticoagulation during the baseline period were excluded. We estimated the cumulative incidence with 95% CIs of recurrent VTE, major bleeding, and mortality or need for hospice care at 180 days, assuming competing risks. Results: A total of 949 patients with active cancer were initiated on rivaroxaban following their index VTE. Time from active cancer diagnosis to index CAT was ≤90 days for 27% of patients, 91 to 180 days for 19%, and >180 days for 54%. The mean [SD] age of patients was 62.5 [12.8] years, 43.6% had pulmonary embolism, and metastatic disease was present in 42.6%. During follow-up, there were 37 cases of recurrent VTE, 22 cases of major bleeding (17 gastrointestinal, 3 intracranial, 1 genitourinary, and 1 other bleed), and 105 deaths/hospice claims. The cumulative incidence estimate was 4.0% (95% CI, 2.8%-5.4%) for recurrent VTE, 2.7% (95% CI, 1.7%-4.0%) for major bleeding, and 11.3% (95% CI, 9.2%-13.6%) for mortality/hospice care. Conclusions: Event rates observed in this rivaroxaban-treated cohort were overall consistent with previous studies of patients with rivaroxaban- and warfarin-managed CAT.

Health-related quality of life across all stages of autosomal dominant polycystic kidney disease.

BACKGROUND: A limited number of studies have assessed health-related quality of life (HRQoL) in autosomal dominant polycystic kidney disease (ADPKD). Results to date have been conflicting and studies have generally focused on patients with later stages of the disease. This study aimed to assess HRQoL in ADPKD across all stages of the disease, from patients with early chronic kidney disease (CKD) to patients with end-stage renal disease. METHODS: A study involving cross-sectional patient-reported outcomes and retrospective clinical data was undertaken April-December 2014 in Denmark, Finland, Norway and Sweden. Patients were enrolled into four mutually exclusive stages of the disease: CKD stages 1-3; CKD stages 4-5; transplant recipients; and dialysis patients. RESULTS: Overall HRQoL was generally highest in patients with CKD stages 1-3, followed by transplant recipients, patients with CKD stages 4-5 and patients on dialysis. Progressive disease predominately had an impact on physical health, whereas mental health showed less variation between stages of the disease. A substantial loss in quality of life was observed as patients progressed to CKD stages 4-5. CONCLUSIONS: Later stages of ADPKD are associated with reduced physical health. The value of early treatment interventions that can delay progression of the disease should be considered.

Real-world costs of autosomal dominant polycystic kidney disease in the Nordics.

BACKGROUND: There is limited real-world data on the economic burden of patients with autosomal dominant polycystic kidney disease (ADPKD). The objective of this study was to estimate the annual direct and indirect costs of patients with ADPKD by severity of the disease: chronic kidney disease (CKD) stages 1-3; CKD stages 4-5; transplant recipients; and maintenance dialysis patients. METHODS: A retrospective study of ADPKD patients was undertaken April-December 2014 in Denmark, Finland, Norway and Sweden. Data on medical resource utilisation were extracted from medical charts and patients were asked to complete a self-administered questionnaire. RESULTS: A total of 266 patients were contacted, 243 (91%) of whom provided consent to participate in the study. Results showed that the economic burden of ADPKD was substantial at all levels of the disease. Lost wages due to reduced productivity were large in absolute terms across all disease strata. Mean total annual costs were highest in dialysis patients, driven by maintenance dialysis care, while the use of immunosuppressants was the main cost component for transplant care. Costs were twice as high in patients with CKD stages 4-5 compared to CKD stages 1-3. CONCLUSIONS: Costs associated with ADPKD are significant and the progression of the disease is associated with an increased frequency and intensity of medical resource utilisation. Interventions that can slow the progression of the disease have the potential to lead to substantial reductions in costs for the treatment of ADPKD.

Autoantibodies Targeting a Collecting Duct-Specific Water Channel in Tubulointerstitial Nephritis.

Tubulointerstitial nephritis is a common cause of kidney failure and may have diverse etiologies. This form of nephritis is sometimes associated with autoimmune disease, but the role of autoimmune mechanisms in disease development is not well understood. Here, we present the cases of three patients with autoimmune polyendocrine syndrome type 1 who developed tubulointerstitial nephritis and ESRD in association with autoantibodies against kidney collecting duct cells. One of the patients developed autoantibodies targeting the collecting duct-specific water channel aquaporin 2, whereas autoantibodies of the two other patients reacted against the HOXB7 or NFAT5 transcription factors, which regulate the aquaporin 2 promoter. Our findings suggest that tubulointerstitial nephritis developed in these patients as a result of an autoimmune insult on the kidney collecting duct cells.

Identification of autoimmune polyendocrine syndrome type 1 in patients with isolated hypoparathyroidism.

OBJECTIVE: The prevalence of autoimmune polyendocrine syndrome type 1 (APS1) among isolated hypoparathyroidism (HP) or primary adrenal insufficiency (PAI) is not well established. We studied the frequency of APS1 in patients with HP or PAI by measuring interferon-α (IFN-α) antibody levels, a highly sensitive and specific marker for APS1. DESIGN, PATIENTS AND MEASUREMENTS: In a single-centre cross-sectional study, 37 Indian patients with isolated HP and 40 patients with PAI were tested for IFN-α antibody using an indirect ELISA. In patients with elevated IFN-α antibody, the autoimmune regulator (AIRE) gene was bidirectionally sequenced. RESULTS: Three (8·1%) patients with isolated HP had elevated IFN-α antibody levels (range: 367-17382 units; positive titre >56 units). Homozygous or compound heterozygous AIRE mutations were detected in all three patients, including a novel mutation (p.T68P). All three APS1 patients had atypical features. The first patient, diagnosed at 7 years of age, died suddenly 5 months later. The second patient had late-onset HP (at the age of 34 years) and a solitary episode of transient mucocutaneous candidiasis 5 years later. The final patient developed HP at the age of 14 years and premature ovarian insufficiency 14 years later. Interleukin-22 antibodies, as well as most other organ-specific antibodies, were absent in the 3 APS1 patients. All patients with PAI were negative for IFN-α antibody. CONCLUSION: Eight percentage of patients with isolated HP had elevated IFN-α antibody levels and AIRE mutation-positive APS1. All APS1 patients had atypical clinical features. Testing for IFN-α antibody should be considered in patients with idiopathic HP.

Cross-sectional survey in CKD patients across Europe describing the association between quality of life and anaemia.

BACKGROUND: Deteriorating renal function in chronic kidney disease (CKD) patients is commonly associated with reduced haemoglobin levels, adding to the already considerable humanistic burden of CKD. This analysis evaluated the impact of anaemia on disease burden in patients with CKD stages 3-4, and in those on dialysis. METHODS: This was a descriptive, cross-sectional analysis of European data from an Adelphi CKD Disease-Specific Programme. This programme collected data from patients and their treating nephrologists/endocrinologists; patient- and physician-reported data were matched for each patient. Health-related quality of life (HRQoL) data were obtained through patient completion of the EQ-5D, SF-12 and KDQOL-36. Additional information was obtained via physician reporting of patient symptoms, and patients' reports of impaired activity. Anaemia was defined by haemoglobin level and/or current use of erythropoiesis stimulating agents. RESULTS: Significant, but modest Spearman's rank correlations were observed between haemoglobin levels and extent of HRQoL impairment, regardless of instrument used (range 0.19-0.23; all P-values < 0.0001). When stratified by anaemia status, impairment was consistently lower for anaemic than non-anaemic CKD patients across measurement scales (e.g. EQ-5D index value [standard deviation {SD}] 0.72 [0.31] vs 0.83 [0.23], respectively; P < 0.0001). Physician-reported patient tiredness was associated with increased disease burden at all levels of CKD studied (total EQ-5D index value [SD] in patients reporting no tiredness vs tiredness 0.81 [0.26] vs 0.70 [0.30] respectively; P < 0.0001) with P < 0.0001 for no tiredness vs tiredness at all stages of CKD. The presence of anaemia was associated with impaired activity levels at CKD stages 3 (37.5 % vs 28.4 %, respectively; P = 0.0044) and 4 (48.1 % vs 39.9 %, respectively; P = 0.0292), and in patients on dialysis (52.0 % vs 45.0 %, respectively; P = 0.0732). CONCLUSIONS: The analysis found that CKD patients with anaemia typically had a lower HRQoL than those without anaemia. The impairment correlated with anaemia was more apparent in non-dialysis patients with CKD stages 3 or 4 than in those receiving dialysis. Coexisting CKD and anaemia may have an impact on patient HRQoL similar to other chronic conditions such as diabetes, epilepsy or certain forms of cancer.

Clinical burden of pneumonia, meningitis and septicemia in Norway 2 years after 7-valent pneumococcal conjugate vaccine introduction.

AIMS: This population-based, retrospective study quantified the rates of all-cause and pneumococcal pneumonia, meningitis and septicemia in Norway from 2008 to 2009 and determined the proportions of cases caused by pneumococcal vaccine serotypes. METHODS: Data on patients with all-cause and pneumococcal pneumonia, meningitis and septicemia were obtained from the Norwegian Patient Registry, which collects hospitalization data from all Norwegian public hospitals based on International Classification of Diseases codes. Norwegian Patient Registry case records linked to the Norwegian Surveillance System for Communicable Diseases provided serotype data for invasive pneumococcal disease in patients with microbiological cultures. RESULTS: In 2008 and 2009, hospitalization rates were relatively stable for all-cause pneumonia (5.28 and 5.35, respectively, per 1000), meningitis (10.70 and 9.67, respectively, per 100,000), and septicemia (from 171.81 to 161.46 per 100,000). In contrast, rates decreased for International Classification of Diseases-10 diagnosed pneumococcal pneumonia (from 13.66 to 10.52 per 100,000), although these cases may be under-reported because of inclusion in all-cause pneumonia. Rates also decreased in diagnosed pneumococcal meningitis (from 1.60 to 1.19 per 100,000) and diagnosed pneumococcal septicemia (from 9.08 to 7.94 per 100,000). Diagnosed pneumococcal disease rates were highest in younger children and older adults, peaking at ⩾ 60 years old. Pneumococcal pneumonia, meningitis and septicemia caused by serotypes included in the 7-valent pneumococcal conjugate vaccine decreased substantially during the study period, with corresponding serotype replacement by non-7-valent pneumococcal conjugate vaccine serotypes. CONCLUSIONS: From 2008 to 2009, International Classification of Diseases-10 diagnosed pneumococcal pneumonia, meningitis and septicemia decreased in most age groups but remained greatest among subjects aged 0-1 and ⩾ 60 years.

A need for greater awareness: a mixed methods study of patient and healthcare professional perspectives on the diagnosis journey for haemophagocytic lymphohistiocytosis (HLH).

OBJECTIVES: Our aim was to better understand and raise awareness of the diagnosis journey and quantify any barriers for timely diagnosis of haemophagocytic lymphohistiocytosis (HLH), to support patients' struggle with diagnosis and reduce time to diagnosis. METHODS: Patients diagnosed with, or caregivers for those diagnosed with primary or secondary HLH and physicians involved in the treatment of HLH were recruited. Quantitative interviews were undertaken with patients/caregivers to quantify key elements of the diagnosis journey, followed by qualitative interviews with participants. Interviews took place between March-May 2021. RESULTS: Thirty-three patients/caregivers and nine physicians took part in this mixed methods study. Lack of physician awareness of HLH was a common frustration for patients/caregivers, causing delayed diagnosis. All physicians indicated bone-marrow testing is a key step in the diagnosis process, and some patients/caregivers had frustrations around testing. Emergency care doctors, although not usually involved in the diagnosis process, were among the most-seen specialists by patients/caregivers. Patients/caregivers suggested potential improvements in available information, such as providing information on treatment options and condition management. DISCUSSION: Patients/caregivers and physicians agreed on the need to raise overall awareness of HLH signs/symptoms among priority groups of physicians to recognise how signs/symptoms can progress and develop. Improvements in the testing process and communication would directly impact the speed of diagnosis and support patients/caregivers during the diagnostic journey, respectively. CONCLUSION: Raising awareness of key issues, such as signs/symptoms, tests and diagnostic procedures, and improved communication and support for patients/caregivers, are key to speeding up HLH diagnosis and improving outcomes.

Long-term efmoroctocog alfa prophylaxis improves perceived pain, mental, and physical health in patients with hemophilia A: post hoc analysis of phase III trials using patient-reported outcomes.

Background: Hemophilia-associated bleeding and resultant joint pain and mobility restrictions can predispose patients to poor health-related quality of life (HRQoL). Therefore, efficacy of a treatment needs to address more than just annualized bleed rates. Objectives: Describe the evolution of HRQoL, pain, and activity in patients with hemophilia A, treated with efmoroctocog alfa prophylaxis. Design: A post hoc analysis from Kids A-LONG (NCT01458106), A-LONG (NCT01181128), and long-term extension study ASPIRE (NCT01454739) assessed change in pain and activity-related patient-reported outcomes (PROs). Methods: Physical health, pain, and HRQoL were assessed by PROs for a cumulative treatment duration of up to ~6 years. The primary endpoint was change from baseline in EuroQoL (EQ)-5D and Haemophilia Quality of Life Questionnaire (Haem-A-QoL). Results: 118 adult/adolescents and 71 pediatric patients were included. The proportion of adults and adolescents reporting no problem in the EQ-5D analysis of 'pain/discomfort' significantly increased from A-LONG baseline (35.04%; 41/117) to ASPIRE month 30 (44.68%; 21/47; p = 0.024). Mean (standard deviation) Haem-A-QoL subdomain scores for 'feeling' and 'physical health' at A-LONG baseline improved by -3.24 (15.13; p = 0.018) and -3.85 (23.07; p = 0.047), respectively, at study end. Proportion of pediatric patients reporting no problem on the EQ-5D analysis of 'pain/discomfort', significantly increased from A-LONG baseline (75.0%; 42/56) to ASPIRE baseline (95.56%; 43/45; p = 0.046). Satisfaction levels for pediatric patients were high at A-LONG baseline and maintained until study end. Conclusion: Long-term efmoroctocog alfa prophylaxis reduces pain and improves HRQoL in adult and adolescent patients with hemophilia A. In pediatric patients, it reduces perceived pain and maintains satisfaction levels. Trial registration: NCT01458106, NCT01181128, NCT01454739.

Cost-Effectiveness of Recombinant Factor IX Fc Prophylaxis and Recombinant Factor IX On-Demand Treatment in Patients with Haemophilia B Without Inhibitors.

INTRODUCTION: Recombinant factor IX (rFIX) and recombinant FIX Fc fusion protein (rFIXFc) are standard half-life and extended half-life FIX replacement therapies, respectively, and represent established treatment options indicated for adults and children with haemophilia B. These FIX replacement therapies can be administered as prophylaxis (to prevent bleeding) or 'on-demand' (to stop bleeding). This analysis aimed to estimate the cost-effectiveness of once-weekly prophylaxis with rFIXFc versus on-demand treatment with rFIX in patients with haemophilia B without inhibitors in the Italian healthcare setting. METHODS: A Markov model was developed to assess a hypothetical cohort of adolescent or adult male patients (≥ 12 years) with haemophilia B (FIX level of ≤ 2 IU/dL) without inhibitors. Model inputs were derived from the pivotal phase 3 clinical studies for rFIXFc and rFIX, published literature and assumptions when published data were unavailable. The model employed a lifelong time horizon with 6-monthly transitions between health states, and it estimated total costs, total quality-adjusted life years (QALYs), number of bleeds, number of surgeries and incremental cost-effectiveness ratio. RESULTS: rFIXFc prophylaxis was associated with lower total costs per patient (€5,308,625 versus €6,564,510) and greater total QALYs per patient (15.936 versus 11.943) compared with rFIX on-demand; rFIXFc prophylaxis was therefore the dominant treatment strategy. The model also demonstrated that rFIXFc prophylaxis was associated with fewer incremental bleeds (- 682.29) and surgeries (- 0.39) compared with rFIX on-demand. CONCLUSIONS: rFIXFc prophylaxis provides improved health outcomes and lower costs, and represents a cost-effective treatment option compared with rFIX on-demand for adolescent and adult male patients with haemophilia B. This comparative assessment of cost-effectiveness should help to inform both clinicians and healthcare policy makers when making treatment decisions for patients with haemophilia B.

Rare copy number variation in autoimmune Addison's disease.

Autoimmune Addison's disease (AAD) is a rare but life-threatening endocrine disorder caused by an autoimmune destruction of the adrenal cortex. A previous genome-wide association study (GWAS) has shown that common variants near immune-related genes, which mostly encode proteins participating in the immune response, affect the risk of developing this condition. However, little is known about the contribution of copy number variations (CNVs) to AAD susceptibility. We used the genome-wide genotyping data from Norwegian and Swedish individuals (1,182 cases and 3,810 controls) to investigate the putative role of CNVs in the AAD aetiology. Although the frequency of rare CNVs was similar between cases and controls, we observed that larger deletions (>1,000 kb) were more common among patients (OR = 4.23, 95% CI 1.85-9.66, p = 0.0002). Despite this, none of the large case-deletions were conclusively pathogenic, and the clinical presentation and an AAD-polygenic risk score were similar between cases with and without the large CNVs. Among deletions exclusive to individuals with AAD, we highlight two ultra-rare deletions in the genes LRBA and BCL2L11, which we speculate might have contributed to the polygenic risk in these carriers. In conclusion, rare CNVs do not appear to be a major cause of AAD but further studies are needed to ascertain the potential contribution of rare deletions to the polygenic load of AAD susceptibility.