ABSTRACT
BACKGROUND: Children aged ≥ 6 to < 12 years with severe atopic dermatitis (AD) have limited treatment options. In a 16-week, randomized, placebo-controlled, phase III trial in children, dupilumab, a monoclonal antibody inhibiting interleukin (IL)-4/IL-13 signalling, significantly improved signs and symptoms with acceptable safety; longer-term safety and efficacy data are lacking. OBJECTIVES: To report the pharmacokinetic profile and long-term safety and efficacy of dupilumab in children (aged ≥ 6 to < 12 years) with severe AD. METHODS: Children (aged ≥ 6 to < 12 years) with severe AD were enrolled in a global, multicentre, phase IIa, open-label, ascending-dose, sequential cohort study and subsequent open-label extension (OLE) study. Patients received single-dose dupilumab 2 or 4 mg kg-1 followed by 8-week pharmacokinetic sampling, then 2 or 4 mg kg-1 weekly for 4 weeks (phase IIa), followed by the same weekly regimen (OLE). Primary endpoints were dupilumab concentration-time profile and treatment-emergent adverse events (TEAEs); secondary assessments included Eczema Area and Severity Index (EASI) and Peak Pruritus Numeric Rating Scale (PP-NRS) score. RESULTS: Of 38 children enrolled, 37 completed phase IIa and 33 continued to the OLE. Nonlinear, target-mediated pharmacokinetics characterized dupilumab concentrations (week 24-48 mean serum concentrations: 2 mg kg-1 , 61-77 mg L-1 ; 4 mg kg-1 , 143-181 mg L-1 ). TEAEs were mostly mild to moderate and transient; none led to treatment discontinuation. The most commonly reported TEAEs were nasopharyngitis (2 mg kg-1 , 47%; 4 mg kg-1 , 56%) and AD exacerbation (29% and 13%, respectively). Single-dose dupilumab rapidly improved AD with further improvements through week 52. Mean EASI and PP-NRS improved by -37%/-33% and -17%/-20% at week 2 (phase IIa) and -92%/-84% and -70%/-58% at week 52 (OLE), respectively. CONCLUSIONS: These safety and efficacy results support the use of dupilumab as a continuous long-term treatment for children aged ≥ 6 to < 12 years with severe AD.
Subject(s)
Dermatitis, Atopic , Antibodies, Monoclonal, Humanized , Child , Cohort Studies , Dermatitis, Atopic/drug therapy , Double-Blind Method , Humans , Severity of Illness Index , Treatment OutcomeABSTRACT
BACKGROUND: Dupilumab (monoclonal antibody inhibiting IL-4/IL-13 signalling) is approved for use in adolescents aged ≥ 12 years with inadequately controlled moderate-to-severe atopic dermatitis (AD). Dupilumab significantly improved AD signs/symptoms in a 16-week, randomised, placebo-controlled phase III trial in adolescents (NCT03054428). OBJECTIVES: To characterize the pharmacokinetics of dupilumab, and long-term safety and efficacy in adolescents. METHODS: This was a global, multicentre, phase IIa, open-label, ascending-dose, sequential cohort study with a phase III open-label extension (OLE) in adolescents with moderate-to-severe AD. In the phase IIa study, patients received one dupilumab dose (2 mg kg-1 or 4 mg kg-1 ) and 8 weeks of pharmacokinetic sampling. Thereafter, patients received the same dose weekly for 4 weeks, with 8-week safety follow-up. Patients then enrolled in the OLE, continuing 2 mg kg-1 or 4 mg kg-1 dupilumab weekly. Primary end points were dupilumab concentration-time profile and incidence of treatment-emergent adverse events (TEAEs). Secondary outcomes included Eczema Area and Severity Index (EASI). RESULTS: Forty adolescents received dupilumab in the phase IIa study; 36 enrolled in the OLE. Dupilumab showed nonlinear, target-mediated pharmacokinetics. Mean ± SD trough dupilumab concentrations in serum at week 48 (OLE) were 74 ± 19 mg L-1 and 161 ± 60 mg L-1 for 2 mg kg-1 and 4 mg kg-1 , respectively. Dupilumab was well tolerated over 52 weeks; the most common TEAEs were nasopharyngitis (week 52: 41% [2 mg kg-1 ], 47% [4 mg kg-1 ]) and AD exacerbation (29%, 42%). After one dupilumab dose in the phase IIa study, EASI improved from baseline to week 2 [mean ± SD reduction -34% ± 20% (2 mg kg-1 ) and -51% ± 29% (4 mg kg-1 )]. With continuing treatment, EASI scores improved further [week 52: -85% ± 12% (2 mg kg-1 ) and -84% ± 20% (4 mg kg-1 )]. CONCLUSIONS: In adolescents with moderate-to-severe AD, dupilumab's pharmacokinetic profile was similar to that in adults. These 52-week safety and efficacy data support long-term use of dupilumab in this patient population. What's already known about this topic? Adolescents with moderate-to-severe atopic dermatitis (AD) have high unmet medical need, with significant disease burden and limited treatment options. Dupilumab (monoclonal antibody against interleukin-4 receptor α) is approved for the treatment of adolescents with moderate-to-severe AD who are inadequately responsive to standard of care (U.S.A.) or candidates for systemic therapy (European Union). A 16-week, randomized, placebo-controlled phase III trial in adolescents demonstrated significant improvements in AD signs/symptoms with an acceptable safety profile. What does this study add? These studies demonstrate the long-term safety and efficacy of dupilumab in adolescents with moderate-to-severe AD for up to 52 weeks of treatment, thus extending and reinforcing the findings from the 16-week dupilumab phase III trial. The data from these studies also support the use of dupilumab in combination with current standard of care (topical corticosteroids), which was not evaluated in the 16-week phase III monotherapy trial.
Subject(s)
Dermatitis, Atopic , Eczema , Adolescent , Antibodies, Monoclonal, Humanized , Cohort Studies , Dermatitis, Atopic/drug therapy , Double-Blind Method , Humans , Severity of Illness Index , Treatment OutcomeABSTRACT
Good's syndrome (thymoma and hypogammaglobulinaemia) is a rare secondary immunodeficiency disease, previously reported in the published literature as mainly individual cases or small case series. We use the national UK-Primary Immune Deficiency (UKPID) registry to identify a large cohort of patients in the UK with this PID to review its clinical course, natural history and prognosis. Clinical information, laboratory data, treatment and outcome were collated and analysed. Seventy-eight patients with a median age of 64 years, 59% of whom were female, were reviewed. Median age of presentation was 54 years. Absolute B cell numbers and serum immunoglobulins were very low in all patients and all received immunoglobulin replacement therapy. All patients had undergone thymectomy and nine (12%) had thymic carcinoma (four locally invasive and five had disseminated disease) requiring adjuvant radiotherapy and/or chemotherapy. CD4 T cells were significantly lower in these patients with malignant thymoma. Seventy-four (95%) presented with infections, 35 (45%) had bronchiectasis, seven (9%) chronic sinusitis, but only eight (10%) had serious invasive fungal or viral infections. Patients with AB-type thymomas were more likely to have bronchiectasis. Twenty (26%) suffered from autoimmune diseases (pure red cell aplasia, hypothyroidism, arthritis, myasthenia gravis, systemic lupus erythematosus, Sjögren's syndrome). There was no association between thymoma type and autoimmunity. Seven (9%) patients had died. Good's syndrome is associated with significant morbidity relating to infectious and autoimmune complications. Prospective studies are required to understand why some patients with thymoma develop persistent hypogammaglobulinaemia.
Subject(s)
Autoimmune Diseases/epidemiology , B-Lymphocytes/immunology , Immunologic Deficiency Syndromes/immunology , Infections/epidemiology , Thymoma/epidemiology , Agammaglobulinemia , Aged , Cohort Studies , Female , Humans , Immunologic Deficiency Syndromes/epidemiology , Immunologic Deficiency Syndromes/mortality , Male , Middle Aged , Prognosis , Prospective Studies , Registries , Severity of Illness Index , Survival Analysis , United Kingdom/epidemiologyABSTRACT
This is the second report of the United Kingdom Primary Immunodeficiency (UKPID) registry. The registry will be a decade old in 2018 and, as of August 2017, had recruited 4758 patients encompassing 97% of immunology centres within the United Kingdom. This represents a doubling of recruitment into the registry since we reported on 2229 patients included in our first report of 2013. Minimum PID prevalence in the United Kingdom is currently 5·90/100 000 and an average incidence of PID between 1980 and 2000 of 7·6 cases per 100 000 UK live births. Data are presented on the frequency of diseases recorded, disease prevalence, diagnostic delay and treatment modality, including haematopoietic stem cell transplantation (HSCT) and gene therapy. The registry provides valuable information to clinicians, researchers, service commissioners and industry alike on PID within the United Kingdom, which may not otherwise be available without the existence of a well-established registry.
Subject(s)
Epidemiological Monitoring , Immunologic Deficiency Syndromes/epidemiology , Registries/statistics & numerical data , Female , Humans , Immunologic Deficiency Syndromes/immunology , Immunologic Deficiency Syndromes/therapy , Male , United Kingdom/epidemiologyABSTRACT
Immunoglobulin replacement therapy enhances survival and reduces infection risk in patients with agammaglobulinaemia. We hypothesized that despite regular immunoglobulin therapy, some patients will experience ongoing respiratory infections and develop progressive bronchiectasis with deteriorating lung function. One hundred and thirty-nine (70%) of 199 patients aged 1-80 years from nine cities in the United Kingdom with agammaglobulinaemia currently listed on the UK Primary Immune Deficiency (UKPID) registry were recruited into this retrospective case study and their clinical and laboratory features analysed; 94% were male, 78% of whom had Bruton tyrosine kinase (BTK) gene mutations. All patients were on immunoglobulin replacement therapy and 52% had commenced therapy by the time they were 2 years old. Sixty per cent were also taking prophylactic oral antibiotics; 56% of patients had radiological evidence of bronchiectasis, which developed between the ages of 7 and 45 years. Multivariate analysis showed that three factors were associated significantly with bronchiectasis: reaching 18 years old [relative risk (RR) = 14·2, 95% confidence interval (CI) = 2·7-74·6], history of pneumonia (RR = 3·9, 95% CI = 1·1-13·8) and intravenous immunoglobulin (IVIG) rather than subcutaneous immunoglobulin (SCIG) = (RR = 3·5, 95% CI = 1·2-10·1), while starting immunoglobulin replacement after reaching 2 years of age, gender and recent serum IgG concentration were not associated significantly. Independent of age, patients with bronchiectasis had significantly poorer lung function [predicted forced expiratory volume in 1 s 74% (50-91)] than those without this complication [92% (84-101)] (P < 0·001). We conclude that despite immunoglobulin replacement therapy, many patients with agammaglobulinaemia can develop chronic lung disease and progressive impairment of lung function.
Subject(s)
Agammaglobulinemia/epidemiology , Bronchiectasis/epidemiology , Immunoglobulins, Intravenous/therapeutic use , Lung/metabolism , Respiratory Tract Infections/epidemiology , Adolescent , Adult , Agammaglobulinemia/therapy , Aged , Aged, 80 and over , Bronchiectasis/therapy , Child , Child, Preschool , Female , Humans , Infant , Lung/pathology , Male , Middle Aged , Respiratory Tract Infections/therapy , United Kingdom , Young AdultABSTRACT
Idiopathic hypogammaglobulinaemia, including common variable immune deficiency (CVID), has a heterogeneous clinical phenotype. This study used data from the national UK Primary Immune Deficiency (UKPID) registry to examine factors associated with adverse outcomes, particularly lung damage and malignancy. A total of 801 adults labelled with idiopathic hypogammaglobulinaemia and CVID aged 18-96 years from 10 UK cities were recruited using the UKPID registry database. Clinical and laboratory data (leucocyte numbers and serum immunoglobulin concentrations) were collated and analysed using uni- and multivariate statistics. Low serum immunoglobulin (Ig)G pre-immunoglobulin replacement therapy was the key factor associated with lower respiratory tract infections (LRTI) and history of LRTI was the main factor associated with bronchiectasis. History of overt LRTI was also associated with a significantly shorter delay in diagnosis and commencing immunoglobulin replacement therapy [5 (range 1-13 years) versus 9 (range 2-24) years]. Patients with bronchiectasis started immunoglobulin replacement therapy significantly later than those without this complication [7 (range 2-22) years versus 5 (range 1-13) years]. Patients with a history of LRTI had higher serum IgG concentrations on therapy and were twice as likely to be on prophylactic antibiotics. Ensuring prompt commencement of immunoglobulin therapy in patients with idiopathic hypogammaglobulinaemia is likely to help prevent LRTI and subsequent bronchiectasis. Cancer was the only factor associated with mortality. Overt cancer, both haematological and non-haematological, was associated with significantly lower absolute CD8(+) T cell but not natural killer (NK) cell numbers, raising the question as to what extent immune senescence, particularly of CD8(+) T cells, might contribute to the increased risk of cancers as individuals age.
Subject(s)
Agammaglobulinemia/diagnosis , Bronchiectasis/diagnosis , Common Variable Immunodeficiency/diagnosis , Lung Neoplasms/diagnosis , Registries , Respiratory Tract Infections/diagnosis , Adolescent , Adult , Agammaglobulinemia/drug therapy , Agammaglobulinemia/immunology , Agammaglobulinemia/mortality , Aged , Aged, 80 and over , Bronchiectasis/drug therapy , Bronchiectasis/immunology , Bronchiectasis/mortality , Common Variable Immunodeficiency/drug therapy , Common Variable Immunodeficiency/immunology , Common Variable Immunodeficiency/mortality , Female , Humans , Immunoglobulins/blood , Immunoglobulins, Intravenous/therapeutic use , Leukocyte Count , Lung/drug effects , Lung/immunology , Lung/pathology , Lung Neoplasms/drug therapy , Lung Neoplasms/immunology , Lung Neoplasms/mortality , Male , Middle Aged , Phenotype , Respiratory Tract Infections/drug therapy , Respiratory Tract Infections/immunology , Respiratory Tract Infections/mortality , Risk Factors , Survival Analysis , Time Factors , United KingdomABSTRACT
INTRODUCTION: Complement immunodeficiencies (excluding hereditary angioedema and mannose binding lectin deficiency) are rare. Published literature consists largely of case reports and small series. We collated data from 18 cities across Europe to provide an overview of primarily homozygous, rather than partial genotypes and their impact and management. METHODS: Patients were recruited through the ESID registry. Clinical and laboratory information was collected onto standardized forms and analyzed using SPSS software. RESULTS: Seventy-seven patients aged 1 to 68 years were identified. 44 % presented in their first decade of life. 29 % had C2 deficiency, defects in 11 other complement factors were found. 50 (65 %) had serious invasive infections. 61 % of Neisseria meningitidis infections occurred in patients with terminal pathway defects, while 74 % of Streptococcus pneumoniae infections occurred in patients with classical pathway defects (p < 0.001). Physicians in the UK were more likely to prescribe antibiotic prophylaxis than colleagues on the Continent for patients with classical pathway defects. After diagnosis, 16 % of patients suffered serious bacterial infections. Age of the patient and use of prophylactic antibiotics were not associated with subsequent infection risk. Inflammatory/autoimmune diseases were not seen in patients with terminal pathway, but in one third of patients classical and alternative pathway defects. CONCLUSION: The clinical phenotypes of specific complement immunodeficiencies vary considerably both in terms of the predominant bacterial pathogen, and the risk and type of auto-inflammatory disease. Appreciation of these phenotypic differences should help both immunologists and other specialists in their diagnosis and management of these rare and complex patients.
Subject(s)
Complement System Proteins/deficiency , Complement System Proteins/genetics , Immunologic Deficiency Syndromes/epidemiology , Immunologic Deficiency Syndromes/genetics , Adolescent , Adult , Aged , Child , Child, Preschool , Complement Activation/genetics , Complement Activation/immunology , Complement System Proteins/immunology , Consanguinity , Databases, Factual , Disease Management , Europe/epidemiology , Female , Genotype , Humans , Immunologic Deficiency Syndromes/diagnosis , Immunologic Deficiency Syndromes/therapy , Infant , Male , Middle Aged , Young AdultABSTRACT
Hereditary angioedema (HAE) and acquired angioedema (AAE) are rare life-threatening conditions caused by deficiency of C1 inhibitor (C1INH). Both are characterized by recurrent unpredictable episodes of mucosal swelling involving three main areas: the skin, gastrointestinal tract and larynx. Swelling in the gastrointestinal tract results in abdominal pain and vomiting, while swelling in the larynx may be fatal. There are limited UK data on these patients to help improve practice and understand more clearly the burden of disease. An audit tool was designed, informed by the published UK consensus document and clinical practice, and sent to clinicians involved in the care of HAE patients through a number of national organizations. Data sets on 376 patients were received from 14 centres in England, Scotland and Wales. There were 55 deaths from HAE in 33 families, emphasizing the potentially lethal nature of this disease. These data also show that there is a significant diagnostic delay of on average 10 years for type I HAE, 18 years for type II HAE and 5 years for AAE. For HAE the average annual frequency of swellings per patient affecting the periphery was eight, abdomen 5 and airway 0·5, with wide individual variation. The impact on quality of life was rated as moderate or severe by 37% of adult patients. The audit has helped to define the burden of disease in the UK and has aided planning new treatments for UK patients.
Subject(s)
Angioedemas, Hereditary , Cost of Illness , Medical Audit , Quality of Life , Adult , Angioedemas, Hereditary/diagnosis , Angioedemas, Hereditary/economics , Angioedemas, Hereditary/mortality , Angioedemas, Hereditary/therapy , Female , Humans , Male , Middle Aged , Time Factors , United Kingdom/epidemiologyABSTRACT
This report summarizes the establishment of the first national online registry of primary immune deficency in the United Kingdom, the United Kingdom Primary Immunodeficiency (UKPID Registry). This UKPID Registry is based on the European Society for Immune Deficiency (ESID) registry platform, hosted on servers at the Royal Free site of University College, London. It is accessible to users through the website of the United Kingdom Primary Immunodeficiency Network (www.ukpin.org.uk). Twenty-seven centres in the United Kingdom are actively contributing data, with an additional nine centres completing their ethical and governance approvals to participate. This indicates that 36 of 38 (95%) of recognized centres in the United Kingdom have engaged with this project. To date, 2229 patients have been enrolled, with a notable increasing rate of recruitment in the past 12 months. Data are presented on the range of diagnoses recorded, estimated minimum disease prevalence, geographical distribution of patients across the United Kingdom, age at presentation, diagnostic delay, treatment modalities used and evidence of their monitoring and effectiveness.
Subject(s)
Immunologic Deficiency Syndromes , Internet , Registries , Female , Humans , Immunologic Deficiency Syndromes/diagnosis , Immunologic Deficiency Syndromes/epidemiology , Immunologic Deficiency Syndromes/therapy , Male , United Kingdom/epidemiologyABSTRACT
BACKGROUND: Although adrenaline is recommended as first line treatment for anaphylaxis, it is often not utilized. There has been a debate about when adrenaline autoinjectors should be prescribed and how many should be dispensed. OBJECTIVES: To see how many adrenaline autoinjectors were used during anaphylactic reactions and to determine why they were not used in situations where they were clinically indicated. METHODS: Patients were recruited prospectively at 14 paediatric allergy clinics throughout UK. Participants completed a questionnaire covering demographic data, atopic status and details of allergic reactions in the previous year and reasons for using more than one device. RESULTS: A total of 969 patients were recruited of whom 466 (48.1%, 95% CI: 37.9-58.2) had had at least one reaction in the previous year; 245 (25.3%, 95% CI: 16.2-34.4) of these reactions were anaphylaxis. An adrenaline autoinjector was used by 41 (16.7%, 95% CI: 11.7-21.3) participants experiencing anaphylaxis. Thirteen participants received more than one dose of adrenaline, for nine of these a health professional gave at least one. The commonest reasons for using more than one were severe breathing difficulties (40%), lack of improvement with first dose (20%) and miss-firing (13.3%). The commonest reasons for not using adrenaline in anaphylaxis were 'thought adrenaline unnecessary' (54.4%) and 'unsure adrenaline necessary' (19.1%). Many with wheeze did not use their autoinjector. CONCLUSIONS AND CLINICAL RELEVANCE: Adrenaline is used by only a minority of patients experiencing anaphylaxis in the community. Thirteen of the 41 patients with anaphylaxis who used their autoinjector needed another dose of adrenaline. Further research is needed to consider how to best encourage the usage of adrenaline when clinically indicated in anaphylaxis.
Subject(s)
Adrenergic alpha-Agonists/administration & dosage , Anaphylaxis/prevention & control , Epinephrine/administration & dosage , Adolescent , Child , Child, Preschool , Female , Humans , Injections, Subcutaneous/instrumentation , Injections, Subcutaneous/methods , Male , Prospective Studies , United KingdomABSTRACT
AIMS: Although poor thymic function leading to viral and fungal infections can be a feature of chromosome 22q11.2 deletion syndrome, most patients have relatively normal immunity. The aim of this study was to investigate which clinical and laboratory parameters best predict the likelihood of serious or recurrent infections in patients with this syndrome. METHODS: Clinical and laboratory parameters from 64 patients with 22q11.2 deletion syndrome referred to two immunology centres in the north of England were studied retrospectively. RESULTS: 31 (48%) patients had no problems with infection, 21 (33%) had bacterial infections, and 12 (19%) had recurrent or persistent thrush and/or viral enteritis and bronchiolitis, the latter suggestive of a significant T cell immunodeficiency. Patients with a history of thrush/viral infections, but not those with bacterial infections, had significantly lower CD4+ and CD8+ T lymphocyte numbers (relative risk (95% CI) 0.3 (0.1 to 0.8)) and phytohaemagglutinin mitogen responses (0.4 (0.2 to 0.8)) adjusted for age at testing. Hypoparathyroidism was associated with low T lymphocyte numbers and function (p<0.05) as well as an increased risk of thrush/viral infections (p<0.0001) after adjusting for age at testing. CONCLUSIONS: 22q11.2 syndrome patients with hypoparathyroidism are more likely to have a clinically significant T cell immunodeficiency and lower laboratory parameters of T cell function, with a higher risk of thrush and viral bronchiolitis and enteritis. Measurement of absolute CD3 count is a simple and accurate predictor of fungal/viral infection risk, with phytohaemagglutinin mitogen responses providing little or no further value in most patients.
Subject(s)
DiGeorge Syndrome/immunology , Candidiasis, Oral/complications , Candidiasis, Oral/immunology , Child , Child, Preschool , DiGeorge Syndrome/complications , Female , Humans , Hypoparathyroidism/complications , Hypoparathyroidism/immunology , Immunity, Cellular , Lymphocyte Count , Male , Opportunistic Infections/complications , Opportunistic Infections/immunology , Phenotype , Recurrence , Retrospective Studies , T-Lymphocyte Subsets/immunology , Virus Diseases/complications , Virus Diseases/immunologyABSTRACT
Patients with chronic mucocutaneous candidiasis (CMC) have an unknown primary immune defect and are unable to clear infections with the yeast Candida. CMC includes patients with AIRE gene mutations who have autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED), and patients without known mutations. CMC patients have dysregulated cytokine production, suggesting that defective expression of pattern recognition receptors (PRRs) may underlie disease pathogenesis. In 29 patients with CMC (13 with APECED) and controls, we assessed dendritic cell (DC) subsets and monocyte Toll-like receptor (TLR) expression in blood. We generated and stimulated monocyte-derived (mo)DCs with Candida albicans, TLR-2/6 ligand and lipopolysaccharide and assessed PRR mRNA expression by polymerase chain reaction [TLR-1-10, Dectin-1 and -2, spleen tyrosine kinase (Syk) and caspase recruitment domain (CARD) 9] in immature and mature moDCs. We demonstrate for the first time that CMC patients, with or without APECED, have normal blood levels of plasmocytoid and myeloid DCs and monocyte TLR-2/TLR-6 expression. We showed that in immature moDCs, expression levels of all PRRs involved in anti-Candida responses (TLR-1, -2, -4, -6, Dectin-1, Syk, CARD9) were comparable to controls, implying that defects in PRR expression are not responsible for the increased susceptibility to Candida infections seen in CMC patients. However, as opposed to healthy controls, both groups of CMC patients failed to down-regulate PRR mRNA expression in response to Candida, consistent with defective DC maturation, as we reported recently. Thus, impaired DC maturation and consequent altered regulation of PRR signalling pathways rather than defects in PRR expression may be responsible for inadequate Candida handling in CMC patients.
Subject(s)
Candidiasis, Chronic Mucocutaneous/immunology , Polyendocrinopathies, Autoimmune/immunology , Receptors, Pattern Recognition/blood , Candida albicans/immunology , Candidiasis, Chronic Mucocutaneous/genetics , Cell Differentiation/immunology , Cells, Cultured , Dendritic Cells/immunology , Female , Gene Expression Regulation/immunology , Humans , Lipopolysaccharides/immunology , Male , Monocytes/immunology , Mutation , Polyendocrinopathies, Autoimmune/genetics , Polymerase Chain Reaction/methods , RNA, Messenger/genetics , Receptors, Pattern Recognition/biosynthesis , Receptors, Pattern Recognition/genetics , Signal Transduction/immunology , Transcription Factors/genetics , AIRE ProteinABSTRACT
Patients with chronic mucocutaneous candidiasis (CMC) suffer persistent infections with the yeast Candida. CMC includes patients with autoimmune regulator (AIRE) gene mutations who have autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED), and patients without known mutations. CMC patients have dysregulated cytokine production, and dendritic cells (DCs), as central orchestrators, may underlie pathogenic disease mechanisms. In 29 patients with CMC (13 with APECED) and controls, we generated monocyte-derived DCs, stimulated them with Candida albicans, Toll-like receptor-2/6 ligand and lipopolysaccharide to assess cytokine production [interleukin (IL)-12p70, IL-23, interferon (IFN)-gamma, IL-2, tumour necrosis factor (TNF)-alpha, IL-6, transforming growth factor-beta, IL-10, IL-5, IL-13] and cell-surface maturation marker expression (CD83, CD86, human leucocyte antigen D-related). In both APECED and non-APECED CMC patients, we demonstrate impairment of DC function as evidenced by altered cytokine expression profiles and DC maturation/activation: (1) both groups over-produce IL-2, IFN-gamma, TNF-alpha and IL-13 and demonstrate impaired DC maturation. (2) Only non-APECED patients showed markedly decreased Candida-stimulated production of IL-23 and markedly increased production of IL-6, suggesting impairment of the IL-6/IL-23/T helper type 17 axis. (3) In contrast, only APECED patients showed DC hyperactivation, which may underlie altered T cell responsiveness, autoimmunity and impaired response to Candida. We demonstrate different pathogenic mechanisms on the same immune response pathway underlying increased susceptibility to Candida infection in these patients.
Subject(s)
Candidiasis, Chronic Mucocutaneous/immunology , Cytokines/biosynthesis , Dendritic Cells/immunology , Polyendocrinopathies, Autoimmune/immunology , Adolescent , Adult , Cell Differentiation/immunology , Cells, Cultured , Child , Child, Preschool , Disease Susceptibility , Female , Humans , Inflammation Mediators/metabolism , Interleukin-23/biosynthesis , Male , Middle Aged , Th1 Cells/immunology , Th2 Cells/immunology , Young AdultABSTRACT
BACKGROUND: In view of the increasing complexity of research ethics committee (REC) applications and thus the time and expense involved in completing the forms, continual monitoring of outcome of clinical research studies for which ethics applications have been submitted is essential in determining whether resources are being effectively used, or alternatively whether significant numbers of research proposals are abandoned because of lack of funding or manpower. Previously published surveys for which data are available examined outcome of studies receiving REC approval 10 or more years ago. METHODS: A prospective questionnaire-based survey sent out in July 2006 to all 506 principal investigators who submitted research ethics applications to nine Greater Manchester RECs between April 2004 and March 2005. Data on the outcome of REC applications, and the status of the research study were collected and analysed. RESULTS: 288 of the 506 (57%) questionnaires were returned. 97% of REC applications were approved, and 87% of studies were in progress or had been completed 1-2 years after approval had been granted. Researchers employed by universities (51%), healthcare (43%) and the pharmaceutical industry (6%) had similar rates of success in initiating research studies. CONCLUSIONS: This survey suggests that most research studies submitted to RECs in Manchester, UK are approved and initiated.
Subject(s)
Biomedical Research/statistics & numerical data , Ethics Committees, Research/organization & administration , Biomedical Research/ethics , Biomedical Research/standards , Ethics Committees, Research/economics , Humans , Research Support as Topic , Surveys and Questionnaires , United KingdomABSTRACT
OBJECTIVES: C1q deficiency is a rare inherited defect in the early part of the complement cascade. In this report, we describe the varied clinical features of patients with this condition as well as the characteristic autoantibody profile. METHODS: A large Pakistani family with a high degree of consanguinity is described in which the father and five sons have C1q deficiency, all with different clinical manifestations. RESULTS: Clinical features of C1q deficiency can vary from almost no disease to fulminant bacterial infection and localized lupus-like skin, renal or CNS disease. Autoantibodies to ribonucleoproteins such as anti-Sm and Ro, but not dsDNA, were present. CONCLUSIONS: Awareness of the spectrum of clinical disease, autoantibody profiles and tests required to confirm the diagnosis of C1q deficiency are important if this life-threatening immunodeficiency disease is to be managed correctly.
Subject(s)
Autoantibodies/blood , Complement C1q/deficiency , Adolescent , Adult , Angioedemas, Hereditary/immunology , Child , Humans , Lupus Erythematosus, Discoid/immunology , Lupus Nephritis/immunology , Lupus Vasculitis, Central Nervous System/immunology , Magnetic Resonance Imaging , Male , Meningitis, Pneumococcal/immunology , Opportunistic Infections/immunology , Pedigree , Vasculitis/immunology , Vasculitis/pathologyABSTRACT
There is little information on the relative efficacy of topical tacrolimus and corticosteroids in the treatment of atopic dermatitis (AD) in children. In a single-centre, prospective, observer-blinded, side-to-side comparative study (ISRCTN65507338), 96 children with moderately severe AD were enrolled. The study aimed to compare the relative effectiveness of the child's usual topical corticosteroid with 0.03% tacrolimus ointment applied for 1 week, and if there was no difference, 0.1% tacrolimus ointment applied for a further week. Topical tacrolimus was found to be more effective than topical corticosteroid in 72 of the 93 children (77%) who completed the study. Using multiple-regression analysis with age, gender, pretreatment surface area affected and pretreatment corticosteroid potency as covariants, the only factor that reduced the chance of observing a beneficial effect with tacrolimus was moderate or potent topical corticosteroid use (OR = 0.13; 95% CI 0.02-0.74).
Subject(s)
Adrenal Cortex Hormones/therapeutic use , Dermatitis, Atopic/drug therapy , Immunosuppressive Agents/therapeutic use , Tacrolimus/therapeutic use , Administration, Topical , Adolescent , Child , Child, Preschool , Female , Humans , Infant , Male , Prospective StudiesABSTRACT
BACKGROUND: The hygiene hypothesis is often proposed to explain the high prevalence of atopy in the western world. Dysregulation of the immune system may result from inadequate exposure to micro-organisms such as mycobacteria. A small trial suggested that a killed extract of Mycobacterium vaccae ameliorates atopic dermatitis (AD). OBJECTIVES: To confirm in a large clinical trial whether killed M. vaccae ameliorates AD in 5-16-year-old children. METHODS: This was a randomized, placebo-controlled, double-blind, multi-centre study of the effect of intradermal injection of killed M. vaccae (0.1 or 1 mg) on patients, aged 5-16, with moderate-to-severe AD. Patients were followed up for 24 weeks. The primary end point was the change in severity of AD at 12 weeks, assessed using the six area, six-sign, atopic dermatitis (SASSAD) score. Secondary end points included changes in disease extent, patient's global assessment and children's dermatology life quality index. RESULTS: There were 166 patients randomized. The mean SASSAD score fell to a similar degree at week 12 in all treatment arms: from 33 to 24, (26%) in the high-dose group, from 30 to 23 (25%) in the low-dose group and from 36 to 27 (24%) in the placebo group (P>0.05). Secondary end points followed the same trend. Adverse events were generally those expected to occur in this population. Injection site reactions occurred in 32 patients at week 4. CONCLUSIONS: M. vaccae was no more effective than the placebo in ameliorating the severity of AD.
Subject(s)
Bacterial Vaccines/immunology , Dermatitis, Atopic/immunology , Mycobacterium/immunology , Adolescent , Bacterial Vaccines/administration & dosage , Bacterial Vaccines/adverse effects , Child , Child, Preschool , Dermatitis, Atopic/therapy , Double-Blind Method , Drug Administration Schedule , Eczema/drug therapy , Eczema/immunology , Female , Humans , Injections, Intradermal/adverse effects , Male , Severity of Illness Index , Treatment OutcomeABSTRACT
BACKGROUND: The psychological impact of childhood atopic eczema on parents and carers is poorly quantified. Objectives To compare the impact of caring for a child with atopic eczema vs. asthma on parents' sleep and well-being. METHODS: Ninety-two parents of 55 children who had moderate to severe atopic eczema or asthma took part in this prospective, questionnaire-based study. It was conducted at regional eczema and asthma outpatient clinics within a U.K. tertiary paediatric hospital. The main outcome measures were the number and duration of parents' sleep disturbances, as well as their anxiety and depression scores. RESULTS: Mothers caring for children with atopic eczema lost a median of 39 min of sleep per night and fathers lost 45 min sleep per night. This compared with a median of 0 min sleep lost by parents who had children with asthma (P < 0.001). These differences were independent of the age of the children, and whether the child came from a single-parent or two-parent family. There was a direct correlation between the severity of sleep disturbance and the level of maternal anxiety (rho = 0.58; P = 0.002) and depression (rho = 0.73; P < 0.001), as well as the level of paternal anxiety (rho = 0.59; P = 0.01). CONCLUSIONS: Compared with looking after a child with chronic asthma, caring for a child with chronic atopic eczema was associated with greater parental sleep disturbances. Disruption to parental sleep correlated with anxiety levels and, in the case of mothers, depression scores.