Angioedema in chronic spontaneous urticaria is underdiagnosed and has a substantial impact: Analyses from ASSURE-CSU.

BACKGROUND: ASSURE-CSU revealed differences in physician and patient reporting of angioedema. This post hoc analysis was conducted to evaluate the actual rate of angioedema in the study population and explore differences between patients with and without angioedema. METHODS: This international observational study assessed 673 patients with inadequately controlled chronic spontaneous urticaria (CSU). Physicians abstracted angioedema data from medical records, which were compared with patient-reported data. Patients in the Yes-angioedema category had angioedema reported in the medical record and a patient-reported source. For those in the No-angioedema category, angioedema was reported in neither the medical record nor a patient-reported source. Those in the Misaligned category had angioedema reported in only one source. Statistical comparisons between Yes-angioedema and No-angioedema categories were conducted for measures of CSU activity, health-related quality of life (HRQoL), productivity and healthcare resource utilization (HCRU). Regression analyses explored the relationship between Dermatology Life Quality Index (DLQI) score and angioedema, adjusting for important covariates. RESULTS: Among evaluable patients, 259 (40.3%), 173 (26.9%) and 211 (32.8%) were in the Yes-angioedema, No-angioedema and Misaligned category, respectively. CSU activity and impact on HRQoL, productivity, and HCRU was greater for Yes-angioedema patients than No-angioedema patients. After covariate adjustment, mean DLQI score was significantly higher (indicating worse HRQoL) for patients with angioedema versus no angioedema (9.88 vs 7.27, P < .001). The Misaligned category had similar results with Yes-angioedema on all outcomes. CONCLUSIONS: Angioedema in CSU seems to be under-reported but has significant negative impacts on HRQoL, daily activities, HCRU and work compared with no angioedema.

The burden of chronic spontaneous urticaria is substantial: Real-world evidence from ASSURE-CSU.

BACKGROUND: Chronic spontaneous urticaria (CSU) can be debilitating, difficult to treat, and frustrating for patients and physicians. Real-world evidence for the burden of CSU is limited. The objective of this study was to document disease duration, treatment history, and disease activity, as well as impact on health-related quality of life (HRQoL) and work among patients with inadequately controlled CSU, and to describe its humanistic, societal, and economic burden. METHODS: This international observational study assessed a cohort of 673 adult patients with CSU whose symptoms persisted for ≥12 months despite treatment. Demographics, disease characteristics, and healthcare resource use in the previous 12 months were collected from medical records. Patient-reported data on urticaria and angioedema symptoms, HRQoL, and work productivity and activity impairment were collected from a survey and a diary. RESULTS: Almost 50% of patients had moderate-to-severe disease activity as reported by Urticaria Activity Score. Mean (SD) Dermatology Life Quality Index and Chronic Urticaria Quality of Life Questionnaire scores were 9.1 (6.62) and 33.6 (20.99), respectively. Chronic spontaneous urticaria markedly interfered with sleep and daily activities. Angioedema in the previous 12 months was reported by 66% of enrolled patients and significantly affected HRQoL. More than 20% of patients reported ≥1 hour per week of missed work; productivity impairment was 27%. These effects increased with increasing disease activity. Significant healthcare resources and costs were incurred to treat CSU. CONCLUSIONS: Chronic spontaneous urticaria has considerable humanistic and economic impacts. Patients with greater disease activity and with angioedema experience greater HRQoL impairments.

The United Kingdom Primary Immune Deficiency (UKPID) Registry: report of the first 4 years' activity 2008-2012.

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.

Immediate hypersensitivity to chlorhexidine is increasingly recognised in the United Kingdom.

BACKGROUND: Chlorhexidine is widely used as an antiseptic agent. It is a potentially allergenic substance that can cause severe hypersensitivity reactions. OBJECTIVE: We describe six patients who had anaphylactic reactions attributed to chlorhexidine during surgery. These patients were exposed to chlorhexidine in gels, swabs and catheters. MATERIALS AND METHODS: Six patients from three UK centres with clinical history suggestive of anaphylaxis during surgery are reported. Detailed history, review of case notes, determination of chlorhexidine specific IgE, mast cell tryptase and skin tests were performed. RESULTS: On detailed assessment five of six patients demonstrated a previous history of reactions on re-exposure to chlorhexidine. All six patients had elevated specific IgE to chlorhexidine. Skin prick test with chlorhexidine was performed in four of the six patients and was found to be positive. CONCLUSION: Immediate hypersensitivity to chlorhexidine appears to be common but underreported in the UK. We recommend that centres investigating patients with reactions during anaesthesia and surgery should routinely include testing for chlorhexidine allergy.

Immunological indicators of coeliac disease activity are not altered by long-term oats challenge.

Coeliac disease is a gluten-sensitive enteropathy that develops in genetically susceptible individuals. The disease exhibits many features of an autoimmune disorder. These include the production of highly specific anti-endomysial autoantibodies directed against the enzyme tissue transglutaminase. It is well accepted that wheat-, barley- and rye-based foods should be excluded in the gluten-free diet. Although several studies report that oats ingestion is safe in this diet, the potential toxicity of oats remains controversial. In the current study, 46 coeliac patients ingested oats for 1 year and were investigated for a potential immunogenic or toxic effect. Stringent clinical monitoring of these patients was performed and none experienced adverse effects, despite ingestion of a mean of 286 g of oats each week. Routine histological analysis of intestinal biopsies showed improvement or no change in 95% of the samples examined. Furthermore, tissue transglutaminase expression in biopsy samples, determined quantitatively using the IN Cell Analyzer, was unchanged. Employing immunohistochemistry, oats ingestion was not associated with changes in intraepithelial lymphocyte numbers or with enterocyte proliferation as assessed by Ki-67 staining. Finally, despite the potential for tissue transglutaminase to interact with oats, neither endomysial nor tissue transglutaminase antibodies were generated in any of the patients throughout the study. To conclude, this study reaffirms the lack of oats immunogenicity and toxicity to coeliac patients. It also suggests that the antigenic stimulus caused by wheat exposure differs fundamentally from that caused by oats.

Collagenase and Dispase enzymes disrupt lymphocyte surface molecules.

Collagenase and Dispase enzymes are often used to disaggregate tissue. In this study, we examined by flow cytometry the effects of these enzyme preparations on peripheral blood lymphocyte surface marker expression. Peripheral blood mononuclear cells (PBMC) were obtained from seven healthy volunteers. Cells were incubated with collagenase (128 U/ml, type 1 A) for 3 h and overnight and with Dispase (1.6 mg/ml, grade II) for 15 min, 30 min, 1 h, 3 h and overnight. The intensity of expression of CD3, CD4, CD8, alpha beta and gamma delta T cell receptors was decreased by 25-40% in all cases, while CD4+ and CD8+ lymphocyte populations were undetectable after treatment with Dispase. Moreover, reappearance of these surface molecules did not occur following the incubation of cells in culture medium for 3 h. The results of this study emphasise the importance of considering the influence of isolation procedures on cell characteristics.

Coeliac disease and epilepsy.

Whether there is an association between coeliac disease and epilepsy is uncertain. Recently, a syndrome of coeliac disease, occipital lobe epilepsy and cerebral calcification has been described, mostly in Italy. We measured the prevalence of coeliac disease in patients attending a seizure clinic, and investigated whether cerebral calcification occurred in patients with both coeliac disease and epilepsy. Screening for coeliac disease was by IgA endomysial antibody, measured by indirect immunofluorescence using sections of human umbilical cord. Of 177 patients screened, four patients were positive. All had small-bowel histology typical of coeliac disease. The overall frequency of coeliac disease in this mixed patient sample was 1 in 44. In a control group of 488 pregnant patients, two serum samples were positive (1 in 244). Sixteen patients with both coeliac disease and epilepsy, who had previously attended this hospital, were identified. No patient had cerebral calcification on CT scanning. Coeliac disease appears to occur with increased frequency in patients with epilepsy, and a high index of suspicion should be maintained. Cerebral calcification is not a feature of our patients with epilepsy and coeliac disease, and may be an ethnically-or geographically-restricted finding.

CD4+ CD8+ and CD8alpha+ beta- T lymphocytes in human small intestinal lamina propria.

OBJECTIVE: To examine CD8 expression by T-lymphocyte subpopulations from disease-free human lamina propria. METHODS: Single-cell suspensions were prepared from the epithelial layer and the lamina propria of small intestinal biopsies obtained endoscopically from disease-free patients. Monoclonal antibodies against CD3, CD4, CD8, CD56, CD8alphabeta, CD8alpha, TCR alphabeta and TCR gammadelta were used for dual and three-colour flow cytometric analysis. RESULTS: In addition to classical CD4+ and CD8+ T lymphocytes a substantial proportion of lamina propria T lymphocytes were CD4+ CD8+ or 'double positive' (mean 14%, range 4-26%). This population was significantly lower in the epithelial layer of the same patients (mean 7%, range 3-21%, P < 0.007). Three-colour flow cytometric analysis revealed that expression of the CD8 molecule on double positive T cells in the lamina propria was limited to the CD8alpha chain. Furthermore, of the CD8+ population, CD8+ T cells which only expressed the alpha chain were present in greater numbers in the lamina propria (mean 35%, range 14-54%) than in the epithelial layer (mean 18%, range 5-37%, P < 0.02). NK (CD56+) cells were not detected and few gammadeltaTCR+ T lymphocytes were detected in the lamina propria (mean 2%, range 0.5-6.6%) when compared with the epithelial layer (mean 8%, range 0.2-14%, P < 0.008). CONCLUSION: A significant population of CD4+ CD8alpha+ T lymphocytes which are CD8beta chain negative have been detected in the intestinal lamina propria. These cells form a more significant component of the lamina propria than the epithelial layer T-cell repertoire and may have a unique function in intestinal immunoregulation.

Flow-cytometric detection of lactase expression in normal and coeliac intestinal epithelium.

OBJECTIVE: Enterocyte lactase expression is a useful marker of gluten toxicity. In this study, the technique of flow cytometry was evaluated to quantify lactase expression in coeliac disease (CD). METHODS: Duodenal enterocyte suspensions were obtained from 23 patients with CD, four patients with dermatitis herpetiformis (DH), and 33 control subjects. The percentage of enterocytes that reacted with anti-lactase monoclonal antibody was determined by flow cytometry. In some subjects, organ culture of duodenal biopsies in the presence of various stimuli (including gluten fractions) was performed before enterocyte analysis. RESULTS: This study demonstrated that lactase expression can be readily investigated semi-quantitatively using flow cytometry. Moreover, the level of expression correlated with the extent of mucosal damage in gluten-sensitive individuals. However, in organ culture experiments, lactase expression did not change in the presence of gluten or after marked T-cell activation for 48 h. CONCLUSIONS: Measurement of enterocyte lactase expression by flow cytometry is a useful adjunctive test in the diagnosis and monitoring of gluten-sensitive enteropathy. However, lactase expression is not a suitable marker of gluten-induced toxicity in organ culture.

Tumour necrosis factor blocking agents: a new therapeutic modality for inflammatory disorders.

Development of anti-tumour necrosis factor-alpha (anti-TNF alpha) treatment offers the potential to alter radically the course of inflammatory diseases such as rheumatoid arthritis and Crohn's disease using modalities directed against a specific inflammatory mediator. Controlled randomised trials in these diseases demonstrate clinical benefit associated with significant improvement in patients with severe active joint and intestinal disease, often when conventional therapies are unsuccessful. To date, anti-TNF alpha therapy has been well tolerated and shows a favourable safety profile. This review considers the nature of this therapy and current evidence of its clinical benefit and adverse effects.

Endomysial antibody detection using human umbilical cord tissue as substrate: reactivity of cells in Wharton's jelly.

The measurement of immunoglobulin A (IgA) endomysial antibodies is now established as an important diagnostic test in gluten-sensitive disease. Monkey oesophagus is the commonly used tissue substrate, but it has been proposed that human umbilical cord tissue may be a suitable alternative for antibody detection. In this study, we report a modified method of examining endomysial antibody reactivity with cord tissue. This involves examination of antibody reactivity with cells in Wharton's jelly, and with umbilical cord blood vessel. A total of 370 patients being investigated for coeliac disease were studied and this diagnosis was established in 42. Endomysial antibodies were found in all 42 using umbilical cord tissue, and the test results were confirmed with monkey oesophagus substrate. In three of the remaining 328 non-coeliacs, a false-positive endomysial antibody test was noted and small intestine histology was normal in these patients. All positive sera were found to react with cells in Wharton's jelly, and reticular staining of blood vessels was also present. Examination for immunofluorescence in both Wharton's jelly and blood vessel components of cord tissue greatly simplified test interpretation.

Haemophilus influenzae pneumonia and immunodeficiency in association with thymoma--a presentation of Good's syndrome.

INTRODUCTION: Good's Syndrome is a rare cause of immunodeficiency associated with thymoma. Patients with this syndrome are prone to infections with encapsulated microorganisms. The diagnosis may be delayed for a considerable time period even after the thymectomy. CASE PRESENTATION: We describe the case of a 70-year-old woman with a background of thymectomy who presented with pneumonia and gram negative sepsis. Haemophilus influenzae was found in blood cultures. Moreover, there was evidence of impaired B and T cell immunity consistent with Good's Syndrome. She was commenced on immunoglobulin replacement following treatment of sepsis and remains well 18 months after the initial presentation. CONCLUSION: This case illustrates the importance of considering Good's Syndrome in the context of pneumonia and immunodeficiency associated with encapsulated organisms such as Haemophilus influenzae. This clinical entity is associated with a significant mortality and should be considered as a cause of immunodeficiency even years after thymectomy.

Campylobacter jejuni cellulitis in a patient with pan-hypogammaglobulinaemia.

The case of a 17-year-old male with recurrent episodes of cellulitis affecting his left shin is presented. The cellulitis had been present on an intermittent basis over an 18-month period despite several courses of both intravenous and oral antibiotics. Each course of antibiotics resulted in a temporary remission, but on four occasions the cellulitis then relapsed. The patient was known to have pan-hypogammaglobulinaemia and was receiving intravenous IgG replacement therapy every 3 weeks. Other than cellulitis, he remained generally well. The organism responsible for the cellulitis was unknown until Campylobacter jejuni was grown in blood cultures during one of the relapse episodes. Based on microbial sensitivity, the patient was treated with ciprofloxacin. This resulted in full resolution of the cellulitis and he remains well. This case illustrates the value of blood cultures in helping microbial identification, particularly in immunocompromised patients with atypical infections.

Administering intravenous immunoglobulin during infection is associated with infusion reactions in selected patients.

BACKGROUND: Guidelines vary regarding the safety of administering intravenous immunoglobulin (IVIG) during infections, although evidence for this advice is lacking and is based on expert opinion. AIMS: We retrospectively studied patients with common variable immunodeficiency who reacted during IVIG therapy as to whether routinely obtained markers of infection such as C-reactive protein (CRP) were elevated. METHODS: 19 patients on replacement IVIG therapy in a hospital-based infusion unit were studied. CRP levels obtained were normalized to baseline levels without reactions (defined as 100). RESULTS: 8 of 19 patients had 16 reactions over a total of 107 infusions. Normalized CRP levels during reactions were higher [mean (±SD) of 258 (±215)] than during infusions with no reaction [mean 100 (±54.9), p = 0.017], and higher than in patients who did not react [mean 100 (±79.7), p = 0.017]. CONCLUSIONS: Some patients with IVIG reactions had elevated CRP levels suggesting that concurrent infection may have caused the reaction. Pre-emptive antibiotic therapy and delaying infusion could prevent unnecessary morbidity.

Investigation of molecular markers in the diagnosis of refractory coeliac disease in a large patient cohort.

AIMS: Some patients with coeliac disease, despite strict adherence to a gluten-free diet, continue to have significant symptoms and/or a severe small intestinal histological lesion. The term "refractory coeliac disease" (rCD) is used to describe this condition. The purpose of this study was to investigate the value of tissue molecular markers reported to help in the diagnosis of rCD. METHODS: Details on 61 patients with suspected rCD were collected. The clinical and laboratory findings in these patients were carefully evaluated, in part to determine whether patients were adhering to a strict gluten-free diet. The co-expression of CD3 and CD8 on intraepithelial lymphocytes was investigated by monoclonal antibody staining of small intestinal biopsy tissue; a finding of less than 50% CD3+ cells co-expressing CD8 was defined as an aberrant phenotype. T cell receptor gene rearrangement was assessed when a sufficient tissue sample was available. RESULTS: A diagnosis of rCD was made in 38 patients based on clinical, laboratory and histological data. An aberrant intraepithelial lymphocyte population was found in 20 of these patients and in this group a clonal T cell population was found in five of seven patients tested. In the remaining 18 patients, the CD3/CD8 ratio was normal and two of seven tested had a clonal T cell population. After detailed monitoring, a diagnosis of rCD was excluded in the remaining 23 patients. CONCLUSIONS: This study supports the use of phenotypic and T cell clonality investigations in identifying patients with true rCD.

Dermatitis herpetiformis: no evidence of bone disease despite evidence of enteropathy.

The majority of patients with dermatitis herpetiformis (DH) have small intestinal enteropathy that may result in bone loss. The objective of this study was to evaluate bone mineral density (BMD) in DH and to examine whether dietary treatment or degree of the small intestinal lesion correlate with BMD. Twenty-five patients with DH (18 men) were investigated. Detailed dietary assessment and duodenal biopsies were performed on all patients before entry into the study. BMD at lumbar spine and femur was determined by DXA scan. Bone biomarkers, vitamin D, and parathyroid status were assessed. Twenty patients had enteropathy. None of the patients had hypovitaminosis D or secondary hyperparathyroidism. Resorption and formation markers were within normal limits. BMD Z-scores were not significantly different from expected (-0.38; CI, -0.84 to 0.07) and femur (0.46; CI, -0.06 to 0.97). There was no relationship between BMD Z-scores and the severity of the degree of enteropathy. We conclude that enteropathy of differing severity is present in 80% of patients with DH, but this is not associated with bone disease.

Intestinal T cell responses to cereal proteins in celiac disease.

Celiac disease is caused by sensitivity to wheat gluten in genetically susceptible individuals. The etiological role of the other wheat-related cereals, barley, rye, and oats, is still debated. In order to investigate this issue further, in this study we examined the immune response of celiac mucosal T cell lines to fractions from all four cereals. Cell stimulation was assessed by measuring proliferation (employing (3)H-thymidine incorporation) or cytokine (IL-2, IFN-gamma) production. All five T cell lines demonstrated immunoreactivity to protein fractions from the four related cereals. In some cell lines, reactivity to wheat, barley, and rye was only evident when these cereal fractions had been pretreated with tissue transglutaminase. This study confirms the similar T cell antigenic reactivity of these four related cereals and has implications for their exclusion in the gluten-free diet. However, despite oats stimulation of T cell lines, this cereal does not activate a mucosal lesion in most celiac patients.

Haplotypes in the CTLA4 region are associated with coeliac disease in the Irish population.

Chromosomal region 2q33 encodes the immune regulatory genes, CTLA4, ICOS and CD28, which are involved in regulation of T-cell activity and has been studied as a candidate gene locus in autoimmune diseases, including coeliac disease (CD). We have investigated whether an association exists between this region and CD in the Irish population using a comprehensive analysis for genetic variation. Using a haplotype-tagging approach, this gene cluster was investigated for disease association in a case-control study comprising 394 CD patients and 421 ethnically matched healthy controls. Several SNPs, including CTLA4_CT60, showed association with disease; however, after correction for multiple-testing, CTLA4-658C/T was the only polymorphism found to show significant association with disease when allele, genotype, or carrier status frequency were analysed (carrier status (Allele C), P = 0.0016). Haplotype analysis revealed a haplotype incorporating the CD28/CTLA4 and two 5' ICOS polymorphisms to be significantly associated with disease (patients 24.1%; controls 31.5%; P = 0.035), as was a shorter haplotype composed of the CTLA4 markers only (30.9 vs 34.9%; P = 0.042). The extended haplotype incorporating CD28/CTLA4 and 5' ICOS is more strongly associated with disease than haplotypes of individual genes. This suggests a causal variant associated with this haplotype may be associated with disease in this population.

Primary immunodeficiency disorders in the Republic of Ireland: first report of the national registry in children and adults.

Data collection for the national registry for patients with primary immunodeficiency disorders in the Republic of Ireland commenced in 1996. One hundred and fifteen cases of primary immunodeficiency diseases were registered between December 1996 and February 2003. The most frequent primary immunodeficiency disorders were antibody deficiency (n = 53) and complement deficiency (n = 32). In addition, patients with T cell deficiency (n = 11) and chronic granulomatous disease (n = 11) were identified. A small number of patients with Wiskott-Aldrich syndrome, natural killer cell deficiency, DiGeorge syndrome and chronic mucocutaneous candidiasis were also registered. Comparison of our data with that recently reported in the European registry revealed that complement deficiency was more prevalent in the Republic of Ireland compared to other European countries. Results of our registry point to a significant prevalence of primary immunodeficiency disorders in the Republic of Ireland (2.9 cases per 100,000 population). However, it is likely that these figures underestimate the true prevalence of such cases in the country. We hope, with increased awareness of the national registry among primary care physicians, that more patients will be included and we will be able to identify accurately the frequency and the distribution of these disorders.

Chromosome 5q candidate genes in coeliac disease: genetic variation at IL4, IL5, IL9, IL13, IL17B and NR3C1.

Genetic predisposition to coeliac disease (CD) is determined primarily by alleles at the HLA-DQB locus, and evidence exists implicating other major histocompatibility complex-linked genes (6p21) and the CTLA4 locus on chromosome 2q33. In addition, extensive family studies have provided strong, reproducible evidence for a susceptibility locus on chromosome 5q (CELIAC2). However, the gene responsible has not been identified. We have assayed genetic variation at the IL4, IL5, IL9, IL13, IL17B and NR3C1 (GR) loci, all of which are present on chromosome 5q and have potential or demonstrated involvement in autoimmune and/or inflammatory disease, in a sample of 409 CD cases and 355 controls. Thirteen single nucleotide polymorphisms were chosen on the basis of functional relevance, prior disease association and, where possible, prior knowledge of the haplotype variation present in European populations. There were no statistically significant allele or haplotype frequency differences between cases and controls. Therefore, these results provide no evidence that these loci are associated with CD in this sample population.