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[EFFICACY, PHARMACOKINETICS, PHARMACODYNAMICS, AND SAFETY OF INTRAVENOUS C1 INHIBITOR FOR LONG-TERM PROPHYLAXIS AND TREATMENT OF BREAKTHROUGH ATTACKS IN JAPANESE SUBJECTS WITH HEREDITARY ANGIOEDEMA: A PHASE 3 OPEN-LABEL STUDY].

August 14, 2020 By Manish Butte

[EFFICACY, PHARMACOKINETICS, PHARMACODYNAMICS, AND SAFETY OF INTRAVENOUS C1 INHIBITOR FOR LONG-TERM PROPHYLAXIS AND TREATMENT OF BREAKTHROUGH ATTACKS IN JAPANESE SUBJECTS WITH HEREDITARY ANGIOEDEMA: A PHASE 3 OPEN-LABEL STUDY].

Arerugi. 2020;69(3):192-203

Authors: Fukunaga A, Morita E, Miyagi T, Eto K, Shimizu A, Kagami S, Yamamoto H, Vardi M, Tang Y, Wang Y, Hide M

Abstract
BACKGROUND: Hereditary angioedema (HAE) is associated with recurrent, painful, and potentially lifethreatening attacks characterized by swelling of subcutaneous or submucosal tissues.
PURPOSE: To investigate the efficacy, safety, pharmacokinetics, and pharmacodynamics of repeat-use C1 inhibitor (C1-INH) replacement therapy for long-term prophylaxis and treatment of breakthrough attacks in the management of Japanese patients with HAE type I or II.
METHODS: An open-label, single-arm, Phase 3 study was conducted in Japanese patients with HAE (NCT02865720). For patients 6 years of age or older, 1000U were administered biweekly (by a healthcare professional or self-administered) via intravenous infusion.
RESULTS: In 8 enrolled patients, the mean number of attacks normalized per month was lower during C1-INH treatment than during the 3 months prior (1.826 vs. 3.375). Clinically meaningful mean change from baseline in the angioedema-quality of life (AE-QoL) total score was shown during treatment with C1-INH. Pharmacokinetic data showed markedly higher and enduring post-baseline plasma levels of C1-INH functional activity and C1-INH antigen concentration, starting from 0.5h after first dose of C1-INH and lasting up to 72 hours. C1-INH was well tolerated with no new safety signals identified in this population of Japanese patients with HAE.
CONCLUSION: C1-INH was effective for long-term prophylaxis and treatment of breakthrough attacks with favourable safety profile in Japanese patients with HAE.

PMID: 32435020 [PubMed – indexed for MEDLINE]

Eltrombopag Therapy in Children With Rare Disorders Associated With Thrombocytopenia.

August 14, 2020 By Manish Butte

Eltrombopag Therapy in Children With Rare Disorders Associated With Thrombocytopenia.

J Pediatr Hematol Oncol. 2020 03;42(2):113-117

Authors: Frączkiewicz J, Sęga-Pondel D, Kazanowska B, Ussowicz M

Abstract
Eltrombopag (ELT) is a thrombopoietin receptor activator that has shown efficacy in chronic immune thrombocytopenia. We report the outcome of ELT therapy in 4 children who were treated for rare hematologic disorders, including Pearson syndrome, DiGeorge syndrome, posttransplant allogeneic poor graft function (PGF), and Wiskott-Aldrich syndrome. The ELT tolerance in the analyzed group was good, with the exception of the child with Pearson syndrome, who experienced an exacerbation of cataracts and had to discontinue treatment. Thromboembolic events were observed in one child, who continued ELT therapy despite achieving normalized platelet counts. Independence from PLT transfusions was observed at the 4-week timepoint of therapy in patients with DiGeorge syndrome and PGF who responded to ELT. Discontinuation of therapy was successful in one child, who sustained the normal CBC values afterward. In 2 patients, an increase in neutrophil counts was observed during ELT therapy without additional intervention, and a positive correlation between neutrophil and platelet values during ELT therapy was observed in the child with PGF. ELT is effective in rare pediatric disorders, but response patterns are determined by the underlying disease. ELT shows promising results in patients, but constitutional hematopoiesis defects reduce the chances of a response.

PMID: 31205222 [PubMed – indexed for MEDLINE]

Development of a health-related quality of life instrument for patients with hereditary angioedema living in the United States.

August 13, 2020 By Manish Butte

Development of a health-related quality of life instrument for patients with hereditary angioedema living in the United States.

J Allergy Clin Immunol Pract. 2019 May – Jun;7(5):1679-1683.e7

Authors: Busse PJ, Christiansen SC, Birmingham JM, Overbey JR, Banerji A, Otani IM, Lumry W, Goryachkovsky A, Zuraw BL

PMID: 30550806 [PubMed – indexed for MEDLINE]

Induced Pluripotent Stem Cell Meets Severe Combined Immunodeficiency.

August 12, 2020 By Manish Butte

Induced Pluripotent Stem Cell Meets Severe Combined Immunodeficiency.

Cell J. 2020 Jul;22(suppl 1):1-10

Authors: Kouchaki R, Abd-Nikfarjam B, Maali AH, Abroun S, Foroughi F, Ghaffari S, Azad M

Abstract
Severe combined immunodeficiency (SCID) is classified as a primary immunodeficiency, which is characterized by impaired T-lymphocytes differentiation. IL2RG, IL7Ralpha, JAK3, ADA, RAG1/RAG2, and DCLE1C (Artemis) are the most defective genes in SCID. The most recent SCID therapies are based on gene therapy (GT) of hematopoietic stem cells (HSC), which are faced with many challenges. The new studies in the field of stem cells have made great progress in overcoming the challenges ahead. In 2006, Yamanaka et al. achieved “reprogramming” technology by introducing four transcription factors known as Yamanaka factors, which generate induced pluripotent stem cells (iPSC) from somatic cells. It is possible to apply iPSC-derived HSC for transplantation in patients with abnormality or loss of function in specific cells or damaged tissue, such as T-cells and NK-cells in the context of SCID. The iPSC-based HSC transplantation in SCID and other hereditary disorders needs gene correction before transplantation. Furthermore, iPSC technology has been introduced as a promising tool in cellular-molecular disease modeling and drug discovery. In this article, we review iPSC-based GT and modeling for SCID disease and novel approaches of iPSC application in SCID.

PMID: 32779449 [PubMed]

Children with chronic-refractory autoimmune cytopenias: a single center experience.

August 12, 2020 By Manish Butte

Children with chronic-refractory autoimmune cytopenias: a single center experience.

Turk J Pediatr. 2020;62(4):525-532

Authors: Karapınar TH, Durgun E, Oymak Y, Gülez N, Ay Y, Genel F, Gözmen S, Serdaroğlu E, Köker SA, Töret E, Vergin C

Abstract
BACKGROUND AND OBJECTIVES: Autoimmune cytopenias are a group of heterogeneous disorders characterized by immune-mediated destruction of one or more hematopoietic lineage cells. The differential diagnosis of children with autoimmune cytopenias requires much time and laboratory investigations. The aim of the present study was to evaluate the clinical course and significance of autoimmune cytopenias due to immunodeficiency or autoimmune diseases in children at a single children`s hospital.
METHOD: Between February 1997 and September 2015, chronic/refractory autoimmune cytopenias patient data were evaluated retrospectively. Twenty-three patients were assessed in this study.
RESULTS: The median duration of following was 2.6 years (4 months-18.5 years). The median age of diagnosis was 3.1 years (6 months-16 years). A total of 13 patients (56.5%) had single-lineage and 10 (46.5%) had multilineage cytopenias. The most frequent single-lineage cytopenia was thrombocytopenia, followed by anemia. In 22 of the patients, cytopenias was detected before the primary diseases. All of the patients were treated with corticosteroids or intravenous immune globulin as first-line treatment. Ten patients (43.5%) needed second or further-line immunosuppressive therapies that patients diagnosed as systemic lupus erythematosus, hypogammaglobulinemia, or common variable immunodeficiency. A total of 8 patients (34.7%) recovered from autoimmune cytopenias after the treatment of primer disease. Cytopenias were continued in 14 patients.
CONCLUSION: Cytopenia may be the first finding of an immunodeficiency or autoimmune disease and primary disease may be diagnosed in the clinical course. Taking the new targeted treatment options into consideration; early diagnosis is likely to become more important in the near-future in order to begin the treatment for the underlying disease as early as possible.

PMID: 32779404 [PubMed – in process]

APDS2 and SHORT Syndrome in a Teenager with PIK3R1 Pathogenic Variant.

August 12, 2020 By Manish Butte

APDS2 and SHORT Syndrome in a Teenager with PIK3R1 Pathogenic Variant.

J Clin Immunol. 2020 Aug 10;:

Authors: Ramirez L, Tamayo W, Ale H

Abstract
Activated PI3K δ syndrome (APDS) is a primary immunodeficiency caused by heterogeneous germline gain-of-function mutations which ultimately lead to the hyperactivation of the phosphoinositide-3-kinase δ (PI3K δ). PI3K δ exists as a heterodimer composed of a catalytic and a regulatory subunit. APDS type 2 is caused by mutations in the PIK3R1 gene affecting the p85α regulatory subunit. SHORT syndrome is a rare multisystem disorder characterized by short stature, hyperextensible joints, ocular depression, Rieger anomaly, and tooth eruption delay. The primary causes of SHORT syndrome are heterozygous loss-of-function mutations in the PIK3R1 gene. The combination of APDS2 and SHORT syndrome is rare, with few cases reported to date. Here we describe a 17-year-old female with phenotypic features consistent with SHORT syndrome and history of sinopulmonary infections and hypogammaglobulinemia. Invitae immunodeficiency panel genetic testing revealed a pathogenic loss-of-function variant in an intronic splice site in the gene PIK3R1 (c.1425 + 1G > C). This pathogenic variant had been previously associated with APDS2; however, it had not been associated with SHORT syndrome. The exact mechanisms linking both conditions are yet to be identified. This case report emphasizes the importance of screening for comorbidities associated with SHORT syndrome in APDS2 patients and vice versa.

PMID: 32778990 [PubMed – as supplied by publisher]

Subcutaneous immunoglobulin in primary immunodeficiency – impact of training and infusion characteristics on patient-reported outcomes.

August 12, 2020 By Manish Butte

Subcutaneous immunoglobulin in primary immunodeficiency – impact of training and infusion characteristics on patient-reported outcomes.

BMC Immunol. 2020 Aug 10;21(1):47

Authors: Mallick R, Henderson T, Lahue BJ, Kafal A, Bassett P, Scalchunes C

Abstract
BACKGROUND: Subcutaneous immunoglobulin (SCIG) is increasingly utilized in primary immunodeficiency (PI). Understanding factors associated with treatment experience and satisfaction can optimize patient outcomes. We analyzed Immune Deficiency Foundation (IDF) survey data to evaluate patient-reported outcomes (PROs) in relation to SCIG training and infusion characteristics. Respondents’ PRO scores were rank ordered into ‘best’, ‘intermediate’, and ‘worst’ tertiles. Predicted probabilities of being in the best tertile with any combination of characteristics were generated for each PRO.
RESULTS: In 366 SCIG respondents, higher odds of being in the best PRO tertile were driven by favorable training characteristics (particularly, higher confidence post-training and no training barriers) and efficient infusions (infusion preparation ≤20 min and actual infusion < 2 h). Age (≤17 years old) and treatment experience (> 2 years) increased the odds of being in the best tertiles. Compared with the least favorable training/infusion characteristics, those with the most favorable training/infusion characteristics had higher predicted probabilities of being in the best tertiles: TSQM side effects, 59% vs 4%; convenience, 52% vs 4%; effectiveness, 27% vs 13%; global, 26% vs 3%; PROMIS Fatigue, 44% vs 18%.
CONCLUSIONS: Increased experience with SCIG consistently improved PROs, but our findings predicted that enhanced training and infusion characteristics improve patient treatment satisfaction beyond that achieved by experience alone.

PMID: 32778048 [PubMed – in process]

Evaluation of awareness about primary immunodeficiencies among physicians before and after implementation of the educational program: A longitudinal study.

August 12, 2020 By Manish Butte

Evaluation of awareness about primary immunodeficiencies among physicians before and after implementation of the educational program: A longitudinal study.

PLoS One. 2020;15(5):e0233342

Authors: Hariyan T, Kinash M, Kovalenko R, Boyarchuk O

Abstract
Increasing physicians’ awareness is one of the main ways to improve early diagnosis of rare diseases. A survey among physicians of different specialties to evaluate the knowledge about primary immunodeficiencies (PID) was conducted in 2016 and in 2019 -before and after the implementation of an educational program. We compare responses from 82 doctors who participated in the 2016 survey, and 67 doctors who have taken part in the survey in 2019: pediatricians, general practitioners / family physicians and physicians of pediatric sub specialties. The percentage of correct answers to all survey questions after the implementation of the educational program has significantly increased (79.0% in 2019 versus 58.3% in 2016, P<0.0001). This increase in the percentage of correct answers was noted among the surveyed doctors of all specialties. Particular progress was found among pediatricians, who have achieved more than 80% of correct answers. In 2019 the doctors demonstrated better knowledge on the warning signs of PID and specific features of Nijmegen breakage syndrome, DiGeorge syndrome and ataxia-telangiectasia syndrome. Thus, the implementation of an educational program improved physicians' awareness of PIDs, and will contribute to early detection of PIDs and their medical care.

PMID: 32470021 [PubMed – indexed for MEDLINE]

Perioperative Management of Patients With Hereditary Angioedema With Special Considerations for Cardiopulmonary Bypass.

August 12, 2020 By Manish Butte

Perioperative Management of Patients With Hereditary Angioedema With Special Considerations for Cardiopulmonary Bypass.

Anesth Analg. 2020 07;131(1):155-169

Authors: Tanaka KA, Mondal S, Morita Y, Williams B, Strauss ER, Cicardi M

Abstract
Hereditary angioedema (HAE) is a rare autosomal dominant disorder mostly due to the deficiency of C1-esterase inhibitor (C1-INH). Reduced C1-INH activity below ~38% disrupts homeostasis of bradykinin (BK) formation by increasing kallikrein activation and causes recurrent angioedema attacks affecting the face, extremities, genitals, bowels, oropharynx, and larynx. HAE symptoms can be debilitating and potentially life-threatening. The recent clinical developments of biological and pharmacological agents have immensely improved acute and long-term care of patients with moderate-to-severe HAE. The therapies are given as on-demand and/or prophylaxis, and self-administration is highly recommended and performed with some agents via intravenous or subcutaneous route. Perioperative clinicians need to be familiar with the symptoms and diagnosis of HAE as well as available therapies because of the potential need for airway management, sedation, or anesthesia for various medical and surgical procedures and postoperative care. Cardiovascular surgery using cardiopulmonary bypass is a unique condition in which heparinized blood comes into direct contact with an artificial surface while pulmonary circulation, a major reserve of angiotensin-converting enzyme (ACE), becomes excluded. These changes result in systemic kallikrein activation and BK formation even in non-HAE patients. The objectives of this review are (1) to review pathophysiology of HAE and laboratory testing, (2) to summarize pertinent pharmacological data on the prophylactic and on-demand treatment strategies, and (3) to discuss available clinical data for perioperative management in cardiovascular surgery.

PMID: 32102012 [PubMed – indexed for MEDLINE]

Myeloid malignancies with somatic GATA2 mutations can be associated with an immunodeficiency phenotype.

August 12, 2020 By Manish Butte

Myeloid malignancies with somatic GATA2 mutations can be associated with an immunodeficiency phenotype.

Leuk Lymphoma. 2019 08;60(8):2025-2033

Authors: Alfayez M, Wang SA, Bannon SA, Kontoyiannis DP, Kornblau SM, Orange JS, Mace EM, DiNardo CD

Abstract
Germline mutations in GATA2 are associated with a complex immunodeficiency and cancer predisposition syndrome. Somatic GATA2mut in myeloid malignancies may impart a similar phenotype. We reviewed adult patients with a diagnosis of GATA2mut hematological malignancy who were referred to our HHMC for genetic testing, and identified to have somatic GATA2mut. Nine patients with a median age of 63 years were included. Six patients (66.7%) were males. Atypical CML and acute myeloid leukemia were the most common initial presentation. The median overall VAF was 47.14%. Monocytopenia was pronounced when the GATA2mut involved the C-terminal ZFD. GATA2 N-terminal ZFD mutations tend to be co-mutated with biCEBPAmut. Unlike germline GATA2 mutations, monocytopenia associated with somatic GATA2 mutations often resolved at remission. We concluded that similar to germline GATA2 mutations, a subset of somatic GATA2 mutations can impart a germline phenotype.

PMID: 30648453 [PubMed – indexed for MEDLINE]