Preference of treatment characteristics among people with haemophilia or their caregivers, and physicians in the Japanese healthcare environment.

INTRODUCTION: Studies of treatment preferences in haemophilia have been conducted in many countries. This study is the first to examine treatment characteristic preferences among people with haemophilia (PWH) and their caregivers, and physicians in Japan. AIM: To examine current treatment preferences of PWH and their caregivers, plus those of physicians at haemophilia treatment centres (HTCs) and non-HTCs for different treatment characteristics in Japan. METHODS: Physicians listed on a survey panel were invited to participate in the survey and to refer PWH and caregivers to participate in the survey. Web-based surveys were conducted to examine physician and PWH/caregiver background, prophylaxis background, prophylaxis goals, understanding of haemophilia treatment products, important information sources, preferences while choosing prophylaxis products, understanding of the patient's condition, and potential product switching. A discrete choice experiment exercise was included in the survey. RESULTS: A total of 107 physicians and 44 PWH/caregivers participated in the study. Key treatment goals of physicians included optimisation of haemophilia management. PWH/caregivers were focused on quality of life and reduced treatment burden. Consistent differences in haemophilia treatment strategies at HTCs and non-HTCs were observed for prescribed treatments, preferences in choosing prophylaxis products, understanding of patients' condition, and reasons for potential product switch. CONCLUSION: Our study utilises real-world survey data and presents preferences for haemophilia treatment characteristics among physicians, PWH and their caregivers in Japan, which could encourage improvements in individualised treatment and disease management. Alignment between treatment approaches at HTCs and non-HTCs could facilitate improvements in the quality of care for PWH across Japan.

Highly sensitive detection of Epstein-Barr virus-infected cells by EBER flow FISH.

When Epstein-Barr virus (EBV) infection is suspected, identification of infected cells is important to understand the pathogenesis, determinine the treatment strategy, and predict the prognosis. We used the PrimeFlow™ RNA Assay Kit with a probe to detect EBV-encoded small RNAs (EBERs) and multiple surface markers, to identify EBV-infected cells by flow cytometry. We analyzed a total of 24 patients [11 with chronic active EBV disease (CAEBV), 3 with hydroa vacciniforme lymphoproliferative disorder, 2 with X-linked lymphoproliferative disease type 1 (XLP1), 2 with EBV-associated hemophagocytic lymphohistiocytosis, and 6 with posttransplant lymphoproliferative disorder (PTLD)]. We compared infected cells using conventional quantitative PCR methods and confirmed that infected cell types were identical in most patients. Patients with CAEBV had widespread infection in T and NK cells, but a small amount of B cells were also infected, and infection in patients with XLP1 and PTLD was not limited to B cells. EBV-associated diseases are believed to be complex pathologies caused by EBV infecting a variety of cells other than B cells. We also demonstrated that infected cells were positive for HLA-DR in patients with CAEBV. EBER flow FISH can identify EBV-infected cells with high sensitivity and is useful for elucidating the pathogenesis.

Diagnostic delay of MYH9-related disorder in Japan.

MYH9-related disorder (MYH9-RD) is characterized by congenital macrothrombocytopenia and granulocyte inclusion bodies. MYH9-RD is often misdiagnosed as chronic immune thrombocytopenia. In this study, we investigated age at definitive diagnosis and indicative thrombocytopenia in 41 patients with MYH9-RD from the congenital thrombocytopenia registry in Japan. Our cohort comprises 54.8% adults over 18 years at confirmed diagnosis. We found a significant difference (p < 0.0001) between the median age at definitive diagnosis of 25.0 years and for indicative thrombocytopenia it was 9.0 years. Our findings strongly suggest diagnostic delay of MYH9-RD in Japan. Our registry system will continue to contribute to this issue.

Vitamin K prophylaxis in neonates: comparing two different oral regimens.

OBJECTIVE: This prospective study compared PIVKA-II and PT-INR levels in infants who received two vitamin K (VK) prophylactic regimens. METHODS: A single institution administered 119 healthy newborns 2 mg of VK syrup. Infants were assigned to a 3-time regimen (n = 56) with VK at birth, five days (5D), and 1-month-old (1 M), or a 13-time regimen (n = 63) with VK at birth, 5D, and then weekly for 11 weeks. RESULTS: The 13-time regimen significantly lowered PIVKA-II and reduced PT-INR at 1 M in both breastfed (PIVKA-II: 18-16 mAU/mL, p = 0.02; PT-INR: 1.37-1.13, p < 0.01) and formula-fed infants (PIVKA-II: 18-15 mAU/mL, p = 0.01; PT-INR: 1.54-1.24, p < 0.01), compared to baseline measurements taken at 5D. The 3-time regimen did not significantly alter PIVKA-II levels and only improved PT-INR (2.00-1.50, p < 0.01) in formula-fed infants. CONCLUSION: The 13-time VK regimen significantly enhanced coagulation profiles more effectively than the 3-time regimen.

Rapid and long-lasting efficacy of high-dose ambroxol therapy for neuronopathic Gaucher disease: A case report and literature review.

Gaucher disease (GD) is a lysosomal storage disorder caused by a deficiency in the GBA1-encoded enzyme, ß-glucocerebrosidase. Enzyme replacement therapy is ineffective for neuronopathic Gaucher disease (nGD). High-dose ambroxol has been administered as an alternative treatment for a group of patients with nGD. However, little is known about the clinical indication and the long-term outcome of patients after ambroxol therapy. We herein report a case of a female patient who presented with a progressive disease of GD type 2 from 11 months of age and had the pathogenic variants of p.L483P (formerly defined as p.L444P) and p.R502H (p.R463H) in GBA1. A combined treatment of imiglucerase with ambroxol started improving the patient's motor activity in 1 week, while it kept the long-lasting effect of preventing the deteriorating phenotype for 30 months. A literature review identified 40 patients with nGD, who had received high-dose ambroxol therapy. More than 65% of these patients favorably responded to the molecular chaperone therapy, irrespective of p.L483P homozygous, heterozygous or the other genotypes. These results highlight the long-lasting effect of ambroxol-based chaperone therapy for patients with an expanding spectrum of mutations in GBA1.

Early hematopoietic cell transplantation for familial hemophagocytic lymphohistiocytosis in a regional treatment network in Japan.

Familial hemophagocytic lymphohistiocytosis (FHLH) is a fatal hyperinflammation syndrome arising from the genetic defect of perforin-mediated cytolysis. Curative hematopoietic cell transplantation (HCT) is needed before development of central nervous system (CNS) disease. We studied treatment outcomes of 13 patients (FHLH2 n = 11, FHLH3 n = 2) consecutively diagnosed from 2011 to 2022 by flow cytometric screening for non-myeloablative HCT in a regional treatment network in Kyushu, Japan. One patient with a novel PRF1 variant escaped screening, but all patients with FHLH2 reached diagnosis and 8 of them received HCT until 3 and 9 months of age, respectively. The earliest HCT was conducted 65 days after birth. Three pretransplant deaths occurred in newborns with liver failure at diagnosis. Ten posttransplant patients have remained disease-free, 7 of whom had no neurological involvement. Time from first etoposide infusion to HCT was shorter in patients without CNS disease or bleeding than in patients with those factors (median [range] days: 62 [50-81] vs. 122 [89-209], p = 0.016). Six of 9 unrelated patients had a PRF1 c.1090_1091delCT variant. These results suggest that the critical times to start etoposide and HCT are within 3 months after birth and during etoposide control, respectively. Newborn screening may increase the percentage of disease-free survivors without complications.

Pharmacokinetics, safety, and efficacy of 20% subcutaneous immunoglobulin (Ig20Gly) administered weekly or every 2 weeks in Japanese patients with primary immunodeficiency diseases: a phase 3, open-label study.

This phase 3, open-label, multidose study (NCT04346108) evaluated the pharmacokinetics, safety, tolerability, and efficacy of immunoglobulin subcutaneous (human) 20% solution (Ig20Gly) administered weekly and every 2 weeks in Japanese patients with primary immunodeficiency diseases (PIDs). The study was conducted at eight study sites in Japan and enrolled patients aged ≥2 years with PIDs treated using a stable intravenous immunoglobulin dose for ≥3 months prior to the study. Patients received intravenous immunoglobulin every 3 or 4 weeks at pre-study dose (200-600 mg/kg) for 13 weeks (Epoch 1), subcutaneous Ig20Gly (50-200 mg/kg) once weekly for 24 weeks (Epoch 2), and Ig20Gly (100-400 mg/kg) every 2 weeks for 12 weeks (Epoch 3). The primary endpoint was serum total immunoglobulin G (IgG) trough levels during Epochs 2 and 3. Overall, 17 patients were enrolled (median [range] age: 24 [5-69] years; 59% male) and participated in Epochs 1 and 2; seven patients entered Epoch 3. Serum total IgG trough levels were maintained at >8 g/l: geometric means (95% confidence intervals) at the end of Epochs 2 and 3 were 8.56 (8.03-9.12) g/l and 8.39 (7.89-8.91) g/l, respectively. Related treatment-emergent adverse events were all mild in severity; the most common treatment-emergent adverse events (excluding infections) in Epochs 2 and 3 were injection site swelling (24%) and injection site erythema (18%). This is the first trial to demonstrate the efficacy and favourable safety profile of 20% subcutaneous immunoglobulin administered every 2 weeks in adult and paediatric Japanese patients with PIDs.

Clinical Characteristics of Cryopyrin-Associated Periodic Syndrome and Long-Term Real-World Efficacy and Tolerability of Canakinumab in Japan: Results of a Nationwide Survey.

OBJECTIVE: We assess the clinical characteristics of patients with cryopyrin-associated periodic syndrome (CAPS) in Japan and evaluate the real-world efficacy and safety of interleukin-1 (IL-1) inhibitors, primarily canakinumab. METHODS: Clinical information was collected retrospectively, and serum concentrations of canakinumab and cytokines were analyzed. RESULTS: A total of 101 patients were included, with 86 and 15 carrying heterozygous germline and somatic mosaic mutations, respectively. We identified 39 mutation types, and the common CAPS-associated symptoms corresponded with those in previous reports. Six patients (5.9% of all patients) died, with four of the deaths caused by CAPS-associated symptoms. Notably, 73.7% of patients (100%, 79.6%, and 44.4% of familial cold autoinflammatory syndrome, Muckle-Wells syndrome, and chronic infantile neurological cutaneous articular syndrome/neonatal onset multisystem inflammatory disease, respectively) achieved complete remission with canakinumab, and early therapeutic intervention was associated with better auditory outcomes. In some patients, canakinumab treatment stabilized the progression of epiphysial overgrowth and improved height gain, visual acuity, and renal function. However, 23.7% of patients did not achieve inflammatory remission with crucial deterioration of organ damage, with two dying while receiving high-dose canakinumab treatment. Serological analysis of canakinumab and cytokine concentrations revealed that the poor response was not related to canakinumab shortage. Four inflammatory nonremitters developed inflammatory bowel disease (IBD)-unclassified during canakinumab treatment. Dual biologic therapy with canakinumab and anti-tumor necrosis factor-α agents was effective for IBD- and CAPS-associated symptoms not resolved by canakinumab monotherapy. CONCLUSION: This study provides one of the largest epidemiologic data sets for CAPS. Although early initiation of anti-IL-1 treatment with canakinumab is beneficial for improving disease prognosis, some patients do not achieve remission despite a high serum concentration of canakinumab. Moreover, IBD may develop in CAPS after canakinumab treatment.

Non-conditioned cord blood transplantation for infection control in athymic CHARGE syndrome.

OBJECTIVE: CHARGE syndrome is a congenital malformation syndrome caused by heterozygous mutations in the CHD7 gene. Severe combined immunodeficiency (SCID) arises from congenital athymia called CHARGE/complete DiGeorge syndrome. While cultured thymus tissue implantation (CTTI) provides an immunological cure, hematopoietic cell transplantation (HCT) is an alternative option for immuno-reconstitution of affected infants. We aimed to clarify the clinical outcomes of patients with athymic CHARGE syndrome after HCT. METHODS: We studied the immunological reconstitution and outcomes of four patients who received non-conditioned unrelated donor cord blood transplantation (CBT) at Kyushu University Hospital from 2007 to 2022. The posttransplant outcomes were compared with the outcomes of eight reported patients. RESULTS: Four index cases received CBT 70-144 days after birth and had no higher than grade II acute graft-versus-host disease. One infant was the first newborn-screened athymic case in Japan. They achieved more than 500/µL naïve T cells with balanced repertoire 1 month post transplant, and survived more than 12 months with home care. Twelve patients including the index cases received HCT at a median 106 days after birth (range: 70-195 days). One-year overall survival rate was significantly higher in patients who underwent non-conditioned HCT than in those who received conditioned HCT (100% vs. 37.5%, p = .02). Nine patients died, and the major cause of death was cardiopulmonary failure. CONCLUSIONS: Athymic infants achieved a prompt reconstitution of non-skewing naïve T cells after non-conditioned CBT that led to home care in infancy without significant infections. Non-conditioned CBT is a useful bridging therapy for newborn-screened cases toward an immunological cure by CTTI.

Pretransplant ribavirin and interferon-α therapy for rhinovirus interstitial pneumonia in a RAG1-deficient infant.

Severe combined immunodeficiency (SCID) is one of the most serious inborn errors of immunity leading to a fatal infection in early infancy. Allogeneic hematopoietic cell transplantation (HCT) or elective gene therapy prior to infection or live-attenuated vaccination is the current standard of curative treatment. Even in the era of newborn screening for SCID, pretransplant control of severe infection is challenging for SCID. Multiple pathogens are often isolated from immunocompromised patients, and limited information is available regarding antiviral strategies to facilitate curative HCT. We herein present a case of successfully controlled pretransplant pneumonia after ribavirin and interferon-α therapy in an infant with RAG1-deficiency. A four-month-old infant presented with severe interstitial pneumonia due to a co-infection of rhinovirus and Pneumocystis jirovecii. The tentative diagnosis of SCID prompted to start antibiotics and trimethoprim-sulfamethoxazole on ventilatory support. Because of the progressive respiratory failure four days after treatment, ribavirin and then pegylated interferon-α were started. He showed a drastic response to the treatment that led to a curative HCT 32 days after admission. This patient received the genetic diagnosis of RAG1-deficiency. Currently, he is an active 3-year-old boy with normal growth and development. The review of literature indicated that rhinovirus had a comparable or rather greater impact on the mortality of pediatric patients than respiratory syncytial virus. Considered the turn-around time to the genetic diagnosis of SCID, prompt ribavirin plus interferon-α therapy may help to control severe rhinovirus pneumonia and led to the early curative HCT for the affected infants.

The clinical and genetic landscape of early-onset thrombophilia in Japan.

OBJECTIVES: To determine the optimal management for early-onset thrombophilia (EOT), the genetic and clinical features of protein C (PC)-, protein S (PS)-, or antithrombin (AT)-deficient patients of ≤20 years of age were studied in Japan. METHODS/RESULTS: Clinical and genetic information of all genetically diagnosed cases was collected through the prospective, retrospective study, and literature review. One-hundred-one patients had PC (n = 55), PS (n = 29), or AT deficiency (n = 18). One overlapping case had PC- and PS-monoallelic variant. Fifty-five PC-deficient patients (54%) had 26 monoallelic or 29 biallelic variant(s), and 29 (29%) PS-deficient patients had 20 monoallelic or nine biallelic variant(s). None of the patients had AT-biallelic variants. The frequent low-risk allele p.K193del (PC-Tottori) was found in five patients with monoallelic (19%) but not 29 with biallelic variant(s). The most common low-risk allele p.K196E (PS-Tokushima) was found in five with monoallelic (25%) and six with biallelic variant(s) (67%). One exceptional de novo PC variant was found in 32 families with EOT. Only five parents had a history of thromboembolism. Thrombosis concurrently developed in three mother-newborn pairs (two PC deficiency and one AT deficiency). The prospective cohort revealed the outcomes of 35 patients: three deaths with PC deficiency and 20 complication-free survivors. Neurological complications were more frequently found in patients with PC-biallelic variants than those with PC-, PS-, or AT-monoallelic variants (73% vs. 24%, p = .019). CONCLUSIONS: We demonstrate the need for elective screening for EOT targeting PC deficiency in Japan. Early prenatal diagnosis of PC deficiency in mother-infant pairs may prevent perinatal thrombosis in them.

Clinical Features of Pediatric Uveitis at a Tertiary Referral Center in the Western Region of Japan.

PURPOSE: This study aimed to assess the clinical features of pediatric uveitis at a tertiary referral center in Western Japan. METHODS: One hundred forty eyes of 80 patients aged <20 years at the time of uveitis onset, who visited Kyushu University Hospital between January 2010 and December 2019 were included in this study. Clinical records were retrospectively reviewed. Demographics, clinical findings, treatments, and visual prognoses were compared between the disease groups. RESULTS: Of 80 patients, 32 were males and 48 were females. The average age of onset was 12.5 ± 4.8 (0-19) years. Tubulointerstitial nephritis and uveitis (TINU) and juvenile idiopathic arthritis (JIA) were the most frequent causes, accounting for 11.3% and 10% of cases, respectively, followed by sarcoidosis (5%), Behçet's disease, acute anterior uveitis, Vogt-Koyanagi-Harada disease, and juvenile chronic iridocyclitis (3.8% each). Infectious uveitis accounted for 7.6% of the cases: cytomegalovirus was the most frequent agent. Of these cases, 43.8% were unclassified. Systemic therapies were administered to 87.5% of the patients with JIA, 33.3% of those with TINU, and 28.6% of the other diagnostic groups. In the unclassified group, 80% of the patients were followed up with only topical corticosteroids. LogMAR visual acuity of 0 or less accounted for more than 80% in the final examination. CONCLUSION: TINU and JIA were the most common causes of pediatric uveitis. Although each required systemic therapy, most unclassified cases of pediatric uveitis were managed by topical corticosteroids alone with good visual prognosis. Accurate diagnosis is important for pediatric uveitis management.

Patient-reported outcomes in patients with primary immunodeficiency diseases in Japan: baseline results from a prospective observational study.

Introduction: Primary immunodeficiency diseases (PIDs) are rare inherited diseases resulting in impaired immunity. People with PID experience lower health-related quality of life (HR-QOL) and disease-related burdens in daily activities. This ongoing, prospective observational study aims to evaluate disease activity, treatment status, treatment-related burden, daily activities, and HR-QOL in patients with PID in Japan over a 1-year period. In this interim report (database lock: July 29, 2022), we present baseline results. Methods: Participants were enrolled between November 2021 and May 2022; data were collected four times/year per participant until May 2023 using an online electronic patient-reported outcomes system. Patients with PID and healthy volunteers aged ≥12 years, residing in Japan, and with access to a smartphone were eligible. HR-QOL (primary endpoint) was assessed by the EuroQol-5 Dimensions-5 Levels (EQ-5D-5L) and the Medical Outcomes Study 36-Item Short Form Health Survey (SF-36). Work productivity was assessed by the Work Productivity and Activity Impairment (WPAI) Questionnaire. Other aspects of PID and burden were assessed with a new questionnaire developed in-house. The study is registered at the University hospital Medical Information Network clinical trials registry (UMIN000045622). Results: The full interim analysis set comprised 71 patients with PID and 47 healthy volunteers. The most common International Union of Immunological Societies PID category was primary antibody deficiency (56.3% of patients). Complications were common, especially recurrent respiratory tract infections (63.4%). Most patients with PID were treated with immunoglobulin replacement therapy (73.2%); 22.4% of these patients had serum immunoglobulin levels <700 mg/dL. Among patients who did not undergo hematopoietic cell transplantation, EQ-5D-5L (n=67) and SF-36 (n=59) Physical and Mental Component Summary scores were significantly lower than in healthy volunteers (p < 0.001). WPAI absenteeism, work productivity loss, and activity impairment scores were significantly lower in 42 working patients with PID than in 37 working healthy volunteers (p < 0.05). Other results indicated that patients with PID experience substantial burdens related to medical visits, expenses, work, and daily activities. Discussion: This interim analysis confirms that patients with PID in Japan have lower HR-QOL and work productivity compared with healthy individuals and experience substantial limitations and burdens in their daily lives.

[Genetic predisposition to early-onset thrombophilia: a study on challenges in personalized medicine for mothers, infants, and children].

The number of reports on genetic predisposition to pediatric thrombosis is increasing. The risk of thrombosis in childhood varies according to patient age, and the contribution of genetic predisposition also differs. The term early-onset thrombophilia, which occurs until the age of 20 years in patients with genetic diagnosis, was defined. Then, the registry in Japan was established. Further, publications were reviewed comprehensively, and results revealed the genetic and clinical characteristics of patients. Less than 60% of patients presented with protein C (PC) deficiency, and over half of them had PC-gene monoallelic variants. The number of patients with protein S or antithrombin deficiency increased with age. None of them were aged between 6 and 8 years. PC-Tottori and protein S-Tokushima, which are high-frequency and low-risk variants in Japanese, contributed to the development of thrombosis. However, PC-Tottori did not affect the development of severe PC deficiency. One exceptional de novo PC-deficient variant was identified in 32 EOT families, and thrombosis developed concurrently in three pairs of mothers-newborns. Appropriate EOT screening tests targeting PC deficiency are required to prevent maternal and neonatal thromboses.

Critical diseases in neonates after discharge home from birth hospital: A retrospective study from a tertiary hospital in Japan.

INTRODUCTION: To establish actionable neonatal screening during the first month of life, we investigated critical diseases in seemingly healthy newborns discharged from birth hospitals. METHODS: This retrospective study enrolled previously healthy full-term infants who visited our hospital, a tertiary hospital in Japan, from home between 5 and 28 days after birth from 2009 to 2018. Infants with known perinatal or congenital diseases, positive newborn screening results, or accidental injuries were excluded. Data were collected from electronic medical records, including principal diagnosis, clinical details, and prognosis at 18 months of age. RESULTS: Ninety-seven (58 %) of 168 eligible neonates were admitted to the hospital, and 71 (42 %) were not. The median admission rate in patients with disease onset at ≤14 days after birth (80 %) was significantly higher than that in patients with disease onset at ≥15 days (42 %). Among 45 patients who received intensive medical care, 5 died and 10 developed neurodevelopmental sequelae. Four of 5 patients died by 100 days. Among 25 diseases treated in intensive care unit, 17 (68 %) diseases had a prevalence of <1 per 2000 live births. The commonly used diagnostic methods were imaging (n = 58, 35 %) and physical examination (n = 34, 20 %). CONCLUSION: Critical diseases due to rare and heterogeneous causes in ostensibly healthy newborns occurred predominantly in the first two weeks of life. Optimal newborn screening and health check-up protocols may benefit from the wide spectrum of life-threatening diseases occurring in home after birth.

Heterogeneity and mitochondrial vulnerability configurate the divergent immunoreactivity of human induced microglia-like cells.

Microglia play versatile roles in progression of and protection against neuroinflammatory diseases. Little is known, however, about the mechanisms underlying the diverse reactivity of microglia to inflammatory conditions. We investigated how human induced microglia-like (iMG) cells respond to innate immune ligands. Quantitative PCR showed that poly-I:C and lipopolysaccharide (LPS) activated the expression of IL1B and TNF. Immunoreactivity of iMG did not differ between controls (n = 11) and patients with neuroinflammatory diseases (n = 24). Flow cytometry revealed that CD14high cells expressed interleukin (IL) -1ß after LPS treatment. Immunoblotting showed that poly-I:C and LPS differentially activated inflammatory pathways but commonly induced mitochondrial instability and the expression of pyruvate kinase isoform M2 (PKM2). Furthermore, a potent stimulator of PKM2 (DASA-58) alleviated IL-1ß production after LPS treatment. These data indicate that heterogeneous cell populations and mitochondrial stability underlie the divergent immunoreactivity of human iMG in environments.

Ductus Arteriosus Aneurysm and Pulmonary Artery Thromboses in a Protein S-Deficient Newborn.

Ductus arteriosus aneurysm (DAA) asymptomatically occurs in newborn infants and resolves spontaneously. High-risk DAA with compression, rupture, and thrombosis requires early surgical intervention. Newborn infants have the highest risk of thrombosis among pediatric patients, but the genetic predisposition is difficult to determine in infancy. We herein report a neonatal case of massive thromboses in DAA and pulmonary artery. Desaturation occurred in an active full-term infant 2 days after birth. Echocardiography and contrast-enhanced computed tomography indicated thrombotic occlusion of the DAA and pulmonary artery thrombus. Urgent thrombectomy and ductus resection were successfully performed. After 6 months of anticoagulant therapy, the dissociated low plasma activity levels of protein S from protein C suggested protein S deficiency. A genetic study of PROS1 identified a heterozygous variant of protein S K196E, a low-risk variant of thrombophilia in Japanese populations. There have been seven reported cases with neonatal-onset symptomatic thromboses of DAA involving the pulmonary artery. All survived without recurrence after surgical intervention in five and anticoagulant therapy alone in two. Two newborns had a heterozygous methylenetetrahydrofolate reductase ( MTHFR ) variant, but information on thrombophilia was not available for any other cases. A genetic predisposition may raise the risk of DAA thrombosis, leading to rapid progression.

Human RELA dominant-negative mutations underlie type I interferonopathy with autoinflammation and autoimmunity.

Inborn errors of the NF-κB pathways underlie various clinical phenotypes in humans. Heterozygous germline loss-of-expression and loss-of-function mutations in RELA underlie RELA haploinsufficiency, which results in TNF-dependent chronic mucocutaneous ulceration and autoimmune hematological disorders. We here report six patients from five families with additional autoinflammatory and autoimmune manifestations. These patients are heterozygous for RELA mutations, all of which are in the 3' segment of the gene and create a premature stop codon. Truncated and loss-of-function RelA proteins are expressed in the patients' cells and exert a dominant-negative effect. Enhanced expression of TLR7 and MYD88 mRNA in plasmacytoid dendritic cells (pDCs) and non-pDC myeloid cells results in enhanced TLR7-driven secretion of type I/III interferons (IFNs) and interferon-stimulated gene expression in patient-derived leukocytes. Dominant-negative mutations in RELA thus underlie a novel form of type I interferonopathy with systemic autoinflammatory and autoimmune manifestations due to excessive IFN production, probably triggered by otherwise non-pathogenic TLR ligands.