ABSTRACT
BACKGROUND: Hereditary angioedema is a disabling, potentially fatal condition caused by deficiency (type I) or dysfunction (type II) of the C1 inhibitor protein. In a phase 2 trial, the use of CSL830, a nanofiltered C1 inhibitor preparation that is suitable for subcutaneous injection, resulted in functional levels of C1 inhibitor activity that would be expected to provide effective prophylaxis of attacks. METHODS: We conducted an international, prospective, multicenter, randomized, double-blind, placebo-controlled, dose-ranging, phase 3 trial to evaluate the efficacy and safety of self-administered subcutaneous CSL830 in patients with type I or type II hereditary angioedema who had had four or more attacks in a consecutive 2-month period within 3 months before screening. We randomly assigned the patients to one of four treatment sequences in a crossover design, each involving two 16-week treatment periods: either 40 IU or 60 IU of CSL830 per kilogram of body weight twice weekly followed by placebo, or vice versa. The primary efficacy end point was the number of attacks of angioedema. Secondary efficacy end points were the proportion of patients who had a response (≥50% reduction in the number of attacks with CSL830 as compared with placebo) and the number of times that rescue medication was used. RESULTS: Of the 90 patients who underwent randomization, 79 completed the trial. Both doses of CSL830, as compared with placebo, reduced the rate of attacks of hereditary angioedema (mean difference with 40 IU, -2.42 attacks per month; 95% confidence interval [CI], -3.38 to -1.46; and mean difference with 60 IU, -3.51 attacks per month; 95% CI, -4.21 to -2.81; P<0.001 for both comparisons). Response rates were 76% (95% CI, 62 to 87) in the 40-IU group and 90% (95% CI, 77 to 96) in the 60-IU group. The need for rescue medication was reduced from 5.55 uses per month in the placebo group to 1.13 uses per month in the 40-IU group and from 3.89 uses in the placebo group to 0.32 uses per month in the 60-IU group. Adverse events (most commonly mild and transient local site reactions) occurred in similar proportions of patients who received CSL830 and those who received placebo. CONCLUSIONS: In patients with hereditary angioedema, the prophylactic use of a subcutaneous C1 inhibitor twice weekly significantly reduced the frequency of acute attacks. (Funded by CSL Behring; COMPACT EudraCT number, 2013-000916-10 , and ClinicalTrials.gov number, NCT01912456 .).
Subject(s)
Complement C1 Inhibitor Protein/administration & dosage , Hereditary Angioedema Types I and II/prevention & control , Adult , Complement C1 Inhibitor Protein/adverse effects , Complement C1 Inhibitor Protein/metabolism , Cross-Over Studies , Dose-Response Relationship, Drug , Double-Blind Method , Female , Hereditary Angioedema Types I and II/classification , Humans , Injections, Subcutaneous , Male , Risk , Self Administration , Severity of Illness IndexABSTRACT
BACKGROUND: Allergic sensitisation has been ascribed to a dysregulated relationship between allergen-specific Th1, Th2 and regulatory T cells. We hypothesised that the relationship between these T cell subsets could be better defined using a short-term allergen stimulation system followed by direct analysis of CD154-positive T cells. Using peripheral blood samples from birch pollinosis patients and healthy non-atopic controls, we sought to explore the frequencies and phenotype of birch-stimulated CD154-positive T helper cells following ex vivo birch allergen stimulation. RESULTS: Activated CD154-positive Th1, Th2 and Tr1-like cells, that co-expressed IFNγ, IL-4 and IL-10 respectively, were identified in both birch-allergic and non-allergic participants. We observed a close correlation between Th1, Th2 and Tr1-like cell frequency in non-allergic volunteers, such that the three parameters increased together to maintain a low Th2: Th1 ratio. The relationship between Th1, Th2 and Tr1-like responses was dysregulated in birch-allergic patients, with abrogation of the IL-10 response and a higher Th2: Th1 ratio. A close correlation was observed between Th2 cell frequency and the absolute concentration of birch-specific IgE within the birch-allergic group, and we confirmed previous reports of a more differentiated T cell phenotype in allergic subjects. CONCLUSIONS: The findings demonstrate an important balance between IFNγ, IL-4 and IL-10 T cell responses to birch allergen in health, where Th2 responses to allergens were frequently observed, but apparently balanced by Th1 and regulatory responses. The detection of CD154 positive T cells after short-term antigen stimulation may be a useful method for the detection of T cell responses to allergens when cost, speed and convenience are priorities.
Subject(s)
Allergens/immunology , Betula/immunology , CD40 Ligand/metabolism , Health , T-Lymphocyte Subsets/immunology , T-Lymphocytes/immunology , Adult , Cell Differentiation/immunology , Cytokines/metabolism , Epitopes , Female , Humans , Immune Tolerance/immunology , Leukocyte Common Antigens/metabolism , Lymphocyte Activation/immunology , Male , Phenotype , Pollen/immunology , Rhinitis, Allergic, Seasonal/immunology , Seasons , T-Lymphocytes, Regulatory/immunology , Th1 Cells/immunology , Th2 Cells/immunology , Tumor Necrosis Factor Receptor Superfamily, Member 7/metabolismABSTRACT
BACKGROUND: Allergic sensitisation has been ascribed to a dysregulated relationship between allergen-specific Th1, Th2 and regulatory T cells. We sought to utilise our short-term CD154 detection method to further analyse the relationship between these T cell subsets and investigate differences between seasonal and perennial allergens. Using peripheral blood samples from grass-allergic, cat-allergic and healthy non-atopic subjects, we compared the frequencies and phenotype of CD154-positive T helper cells following stimulation with seasonal (grass) and perennial (cat dander) allergens. RESULTS: We identified a higher frequency of CD154+ T cells in grass-allergic individuals compared to healthy controls; this difference was not evident following stimulation with cat allergen. Activated Th1, Th2 and Tr1-like cells, that co-express IFNγ, IL4 and IL10, respectively, were identified in varying proportions in grass-allergic, cat-allergic and non-allergic individuals. We confirmed a close correlation between Th1, Th2 and Tr1-like cell frequency in non-allergic volunteers, such that the three parameters increased together to maintain a low Th2: Th1 ratio. This relationship was dysregulated in grass-allergic individuals with no correlation between the T cell subsets and a higher Th2: Th1 ratio. We confirmed previous reports of a late-differentiated T cell phenotype in response to seasonal allergens compared to early-differentiated T cell responses to perennial allergens. CONCLUSIONS: The findings confirm our existing work illustrating an important balance between Th1, Th2 and Tr1-like responses to allergens in health, where Th2 responses are frequently observed, but balanced by Th1 and regulatory responses. We confirm previous tetramer-based reports of phenotypic differences in T cells responding to seasonal and perennial allergens.
Subject(s)
Allergens/immunology , CD40 Ligand/immunology , Rhinitis, Allergic, Perennial/immunology , Rhinitis, Allergic, Seasonal/immunology , T-Lymphocyte Subsets/immunology , Adult , Animals , CD40 Ligand/metabolism , Cats , Female , Flow Cytometry , Humans , Interferon-gamma/immunology , Interferon-gamma/metabolism , Interleukin-10/immunology , Interleukin-10/metabolism , Interleukin-4/immunology , Interleukin-4/metabolism , Lymphocyte Count , Male , Middle Aged , Poaceae/immunology , Pollen/immunology , Rhinitis, Allergic, Perennial/blood , Rhinitis, Allergic, Perennial/metabolism , Rhinitis, Allergic, Seasonal/blood , Rhinitis, Allergic, Seasonal/metabolism , T-Lymphocyte Subsets/metabolism , T-Lymphocyte Subsets/pathology , T-Lymphocytes, Helper-Inducer/immunology , T-Lymphocytes, Helper-Inducer/metabolism , T-Lymphocytes, Helper-Inducer/pathology , T-Lymphocytes, Regulatory/immunology , T-Lymphocytes, Regulatory/metabolism , T-Lymphocytes, Regulatory/pathology , Th1 Cells/immunology , Th1 Cells/metabolism , Th1 Cells/pathology , Th2 Cells/immunology , Th2 Cells/metabolism , Th2 Cells/pathology , Young AdultABSTRACT
BACKGROUND: Detailed demographic data on people with hereditary angioedema (HAE) and acquired C1 inhibitor deficiency in the United Kingdom are relatively limited. Better demographic data would be beneficial in planning service provision, identifying areas of improvement, and improving care. OBJECTIVE: To obtain more accurate data on the demographics of HAE and acquired C1 inhibitor deficiency in the United Kingdom, including treatment modalities and services available to patients. METHODS: A survey was distributed to all centers in the United Kingdom that look after patients with HAE and acquired C1 inhibitor deficiency to collect these data. RESULTS: The survey identified 1152 patients with HAE-1/2 (58% female and 92% type 1), 22 patients with HAE with normal C1 inhibitor, and 91 patients with acquired C1 inhibitor deficiency. Data were provided by 37 centers across the United Kingdom. This gives a minimum prevalence of 1:59,000 for HAE-1/2 and 1:734,000 for acquired C1 inhibitor deficiency in the United Kingdom. A total of 45% of patients with HAE were on long-term prophylaxis (LTP) with the most used medication being danazol (55% of all patients on LTP). Eighty-two percent of patients with HAE had a home supply of acute treatment with C1 inhibitor or icatibant. A total of 45% of patients had a supply of icatibant and 56% had a supply of C1 inhibitor at home. CONCLUSIONS: Data obtained from the survey provide useful information about the demographics and treatment modalities used in HAE and acquired C1 inhibitor deficiency in the United Kingdom. These data are useful for planning service provision and improving services for these patients.
Subject(s)
Angioedemas, Hereditary , Humans , Female , Male , Angioedemas, Hereditary/epidemiology , Angioedemas, Hereditary/drug therapy , Complement C1 Inhibitor Protein/therapeutic use , Danazol/therapeutic use , United Kingdom/epidemiology , Surveys and QuestionnairesABSTRACT
OBJECTIVE: The roll-out of the Pfizer-BioNTech BNT162b2 COVID-19 vaccine has brought many logistical challenges, such as the absence of comprehensive stability data leading to strict handling instructions during dilution and administration. Accidental mishandling therefore presents challenging clinical dilemmas, which often led vaccine providers to err on the side of caution and discard mishandled vials rather than risk administering ineffective vaccine. This study aims to answer key questions about the vaccine's stability to allow for a more informed decision-making process should a non-conformity occur. METHODS: Residual vaccine in freshly used, but appropriately stored vials collected from vaccination centres in Brighton, UK, were tested after exposure to various handling conditions and analysed by dynamic light scattering to determine the size of the lipid-mRNA nanoparticles, and gel electrophoresis to visualise the mRNA integrity and separation from the lipid formulation. RESULTS: Knocking or dropping vaccine samples from small heights resulted in lowest levels of instability, indicating low risk of compromising clinical efficacy. However, repeated drawing and injecting through 23 G needles at high speed and, more significantly, shaking and vortexing led to progressive increase in the size and polydispersity index of the lipid-mRNA nanoparticles, coupled with or caused by up to ~50% release of mRNA from the lipid formulation. This is thought to impact the vaccine's efficacy due to lack of free mRNA protection and cellular internalisation. CONCLUSIONS: These results reiterate the importance of adhering to the manufacturer's instructions on handling, especially with regard to shaking and exposing the vaccine to excessive vibration.
ABSTRACT
Common variable immunodeficiency (CVID) represents a heterogeneous group of primary antibody deficiency disorders characterized by recurrent infection and by inflammatory, granulomatous, and autoimmune complications. Recently, there have been significant advances in understanding the pathogenesis of the disease, with five genetic mutations identified in patients who have a CVID phenotype. Clinical care also has progressed with refinements in treatment and the development of classification schemes for prognostic and research purposes. Significant delays in diagnosis remain, however. It is likely that more genetic defects will be identified in the future, further shrinking the pool of patients who have CVID of unknown cause.
Subject(s)
Common Variable Immunodeficiency/etiology , Common Variable Immunodeficiency/therapy , Transmembrane Activator and CAML Interactor Protein/deficiency , Animals , Antigens, CD19/metabolism , Antigens, Differentiation, T-Lymphocyte/metabolism , Cell Cycle Proteins/genetics , Cell Cycle Proteins/metabolism , Common Variable Immunodeficiency/genetics , Common Variable Immunodeficiency/immunology , Cytokines/immunology , Cytokines/metabolism , Humans , Immune System Diseases/immunology , Immune System Diseases/metabolism , Inducible T-Cell Co-Stimulator Protein , Infections/etiology , Mutation , Quality of Life , Recurrence , Transmembrane Activator and CAML Interactor Protein/immunologySubject(s)
Common Variable Immunodeficiency/surgery , Hematopoietic Stem Cell Transplantation , Adult , Common Variable Immunodeficiency/etiology , Female , Humans , Lymphoproliferative Disorders/complications , Lymphoproliferative Disorders/surgery , Male , Transplantation, Homologous , Treatment OutcomeABSTRACT
The only disease-modifying treatment available for IgE-mediated disease is specific immunotherapy, but the retention of B cell epitopes in whole allergen preparations confers a risk of IgE-mediated systemic reactions to their administration. Compelling evidence for the central role of T cells in allergic disease suggests that IgE-binding epitopes could be removed from such therapy, improving safety without affecting efficacy. Short, allergen-derived peptides lack the conformational determinants required for IgE crosslinking and are, therefore, an attractive therapeutic possibility. However, human leukocyte antigen (HLA) polymorphism means that T cell peptide epitopes present a huge diversity, which makes the design of peptide-based vaccines problematic. Over the past 10 years, advances in our understanding of epitope selection and major histocompatibility complex (MHC)-peptide-T cell receptor interactions have taken this therapy forward to early clinical trials with human volunteers.
Subject(s)
Hypersensitivity/therapy , Immunotherapy , Peptides/therapeutic use , Animals , Clinical Trials as Topic , Humans , Hypersensitivity/pathologyABSTRACT
The association of systemic lupus erythematosus and hereditary angioedema (HAE) has formed the basis of numerous case reports and is hypothesised to result from consumption of complement C4 with consequent impaired clearance of apoptotic cells. We describe the development of frank lupus or lupus-like syndrome in four HAE patients with uncontrolled angioedema and low levels of serum C4. Measures that limit hypocomplementaemia in HAE may reduce the incidence of secondary SLE.
Subject(s)
Angioedema/complications , Angioedema/immunology , Complement C4/deficiency , Lupus Erythematosus, Systemic/complications , Lupus Erythematosus, Systemic/immunology , Adolescent , Adult , Angioedema/physiopathology , Female , Humans , Lupus Erythematosus, Systemic/physiopathology , Male , Middle AgedABSTRACT
The term WHIM syndrome (WHIMS) is an acronym describing a rare primary immunodeficiency disorder characterized by warts, hypogammaglobulinemia, immunodeficiency, and myelokathexis, the unusual association of neutropenia with bone marrow myeloid hypercellularity. WHIMS was recently associated with mutations in the gene encoding the chemokine receptor CXCR4 and as such is the first disease ascribed to abnormalities of chemokine signaling. We report a sporadic case of WHIMS in a woman presenting with recurrent infections and human papilloma virus-related genital dysplasia.