Ann E. Clarke

Loss-of-function variants in the filaggrin gene are a significant risk factor for peanut allergy

Background IgE-mediated peanut allergy is a complex trait with strong heritability, but its genetic basis is currently unknown. Loss-of-function mutations within the filaggrin gene are associated with atopic dermatitis and other atopic diseases; therefore, filaggrin is a candidate gene in the etiology of peanut allergy. Objective To investigate the association between filaggrin loss-of-function mutations and peanut allergy. Methods Case-control study of 71 English, Dutch, and Irish oral food challenge–positive patients with peanut allergy and 1000 non peanut-sensitized English population controls. Replication was tested in 390 white Canadian patients with peanut allergy (defined by food challenge, or clinical history and skin prick test wheal to peanut ≥8 mm and/or peanut-specific IgE ≥15 kUL−1) and 891 white Canadian population controls. The most prevalent filaggrin loss-of-function mutations were assayed in each population: R501X and 2282del4 in the Europeans, and R501X, 2282del4, R2447X, and S3247X in the Canadians. The Fisher exact test and logistic regression were used to test for association; covariate analysis controlled for coexistent atopic dermatitis. Results Filaggrin loss-of-function mutations showed a strong and significant association with peanut allergy in the food challenge–positive patients (P = 3.0 × 10−6; odds ratio, 5.3; 95% CI, 2.8-10.2), and this association was replicated in the Canadian study (P = 5.4 × 10−5; odds ratio, 1.9; 95% CI, 1.4-2.6). The association of filaggrin mutations with peanut allergy remains significant (P = .0008) after controlling for coexistent atopic dermatitis. Conclusion Filaggrin mutations represent a significant risk factor for IgE-mediated peanut allergy, indicating a role for epithelial barrier dysfunction in the pathogenesis of this disease.

Belimumab reduces autoantibodies, normalizes low complement levels, and reduces select B cell populations in patients with systemic lupus erythematosus

OBJECTIVEnTo assess the effects of the B lymphocyte stimulator (BLyS)-specific inhibitor belimumab on immunologic biomarkers, including B cell and T cell populations, and maintenance of antibody titers to prior vaccines in autoantibody-positive systemic lupus erythematosus (SLE) patients.nnnMETHODSnPooled data from 2 phase III trials, the Study of Belimumab in Subjects with SLE 52-week (BLISS-52) and 76-week (BLISS-76) trials, comparing belimumab 1 mg/kg or 10 mg/kg versus placebo (plus standard SLE therapy for each group) were analyzed for changes in autoantibody, immunoglobulin, and complement levels. BLISS-76 patients were also analyzed for changes in B cell and T cell populations and effects on prior vaccine-induced antibody levels.nnnRESULTSnBelimumab-treated patients experienced significant sustained reductions in IgG and autoantibodies and improvement in C3/C4 levels, resulting in greater positive-to-negative conversion rates for IgG anti-double-stranded DNA (anti-dsDNA), anti-Sm, anticardiolipin, and anti-ribosomal P autoantibodies and normalization of hypergammaglobulinemia and low C3/C4 levels. Belimumab-treated patients experienced significant decreases in the numbers of naive and activated B cells, as well as plasma cells, whereas memory B cells and T cell populations did not decrease. Belimumab did not substantially affect preexisting antipneumococcal or anti-tetanus toxoid antibody levels. Post hoc analysis showed greater reductions in SLE disease activity and the risk of severe flares in patients treated with belimumab 10 mg/kg (P≤0.01) who were anti-dsDNA positive and had low C3/C4 levels at baseline. Normalization of the C3 or anti-dsDNA level by 8 weeks, irrespective of therapy, was predictive of a reduced risk of severe flare over 52 weeks.nnnCONCLUSIONnBelimumab appears to promote normalization of serologic activity and reduce BLyS-dependent B cell subsets in serologically and clinically active SLE. Greater serologic activity may predict a better treatment response to belimumab.

A population-based study on peanut, tree nut, fish, shellfish, and sesame allergy prevalence in Canada

BACKGROUNDnRecent studies suggest an increased prevalence of food-induced allergy and an increased incidence of food-related anaphylaxis. However, prevalence estimates of food allergies vary considerably between studies.nnnOBJECTIVESnTo determine the prevalence of peanut, tree nut, fish, shellfish, and sesame allergy in Canada.nnnMETHODSnUsing comparable methodology to Sicherer et al in the United States in 2002, we performed a cross-Canada, random telephone survey. Food allergy was defined as perceived (based on self-report), probable (based on convincing history or self-report of physician diagnosis), or confirmed (based on history and evidence of confirmatory tests).nnnRESULTSnOf 10,596 households surveyed in 2008 and 2009, 3666 responded (34.6% participation rate), of which 3613 completed the entire interview, representing 9667 individuals. The prevalence of perceived peanut allergy was 1.00% (95% CI, 0.80%-1.20%); tree nut, 1.22% (95% CI, 1.00%-1.44%); fish, 0.51% (95% CI, 0.37%-0.65%); shellfish, 1.60% (95% CI, 1.35%-1.86%); and sesame, 0.10% (95% CI, 0.04%-0.17%). The prevalence of probable allergy was 0.93% (95% CI, 0.74%-1.12%); 1.14% (95% CI, 0.92%-1.35%); 0.48% (95% CI, 0.34%-0.61%); 1.42% (95% CI, 1.18%-1.66%); and 0.09% (95% CI, 0.03%-0.15%), respectively. Because of the infrequency of confirmatory tests and the difficulty in obtaining results if performed, the prevalence of confirmed allergy was much lower.nnnCONCLUSIONnThis is the first nationwide Canadian study to determine the prevalence of severe food allergies. Our results indicate disparities between perceived and confirmed food allergy that might contribute to the wide range of published prevalence estimates.

Anaphylaxis: past, present and future

To cite this article: Ben‐Shoshan M, Clarke AE. Anaphylaxis: past, present and future. Allergy 2011; 66: 1–14.

Overall prevalence of self-reported food allergy in Canada

Estimate 1: Including all adults Peanut 1.77 (1.21-2.33) 0.78 (0.58-0.97) 1.00 (0.80-1.20) Tree nut 1.73 (1.16-2.30) 1.07 (0.84-1.30) 1.22 (1.00-1.44) Fish 0.18 (0.00-0.36) 0.60 (0.43-0.78) 0.51 (0.37-0.65) Shellfish 0.55 (0.21-0.88) 1.91 (1.60-2.23) 1.60 (1.35-1.86) Sesame 0.23 (0.03-0.43) 0.07 (0.01-0.13) 0.10 (0.04-0.17) Milk 2.23 (1.51-2.95) 1.89 (1.56-2.21) 1.97 (1.64-2.29) Egg 1.23 (0.69-1.77) 0.67 (0.48-0.86) 0.80 (0.61-0.99) Wheat 0.45 (0.08-0.83) 0.86 (0.63-1.08) 0.77 (0.57-0.96) Soy 0.32 (0.08-0.55) 0.16 (0.07-0.25) 0.20 (0.10-0.30) Fruits 1.14 (0.68-1.60) 1.61 (1.32-1.89) 1.50 (1.25-1.75) Vegetables 0.45 (0.17-0.74) 1.29 (1.02-1.55) 1.10 (0.88-1.31) Other 1.32 (0.80-1.84) 1.67 (1.37-1.97) 1.59 (1.32-1.86) All foods 7.14 (5.92-8.36) 8.34 (7.69-8.99) 8.07 (7.47-8.67) Estimate 2: Excluding some adults All foods 7.14 (5.92-8.36) 6.56 (5.99-7.13) 6.69 (6.15-7.24) Estimate 3: Estimate 2 adjusted for nonresponse All foods 7.12 (6.07-8.28) 6.58 (6.22-6.96) 6.67 (6.19-7.17)

Is the prevalence of peanut allergy increasing? A 5-year follow-up study in children in Montreal

BACKGROUNDnStudies suggest that peanut allergy prevalence might be increasing, but these results have not yet been substantiated.nnnOBJECTIVEnWe conducted a follow-up study to determine whether peanut allergy prevalence in Montreal is increasing.nnnMETHODSnQuestionnaires regarding peanut ingestion were administered to parents of children in randomly selected kindergarten through grade 3 classrooms between December 2000 and September 2002 and between October 2005 and December 2007. Respondents were stratified as (1) peanut tolerant, (2) never/rarely ingest peanut, (3) convincing history of peanut allergy, or (4) uncertain history of peanut allergy. Children in group 3 with positive skin prick test responses were considered to have peanut allergy. Children in groups 2 and 4 with positive skin prick test responses had peanut-specific IgE levels measured, and if the value was less than 15 kU/L, an oral peanut challenge was performed. Multiple imputation was used to generate prevalence estimates that incorporated respondents providing incomplete data and nonrespondents.nnnRESULTSnOf 8,039 children surveyed in 2005-2007, 64.2% of parents responded. Among those providing complete data, the prevalence was 1.63% (95% CI, 1.30% to 2.02%) in 2005-2007 versus 1.50% (95% CI, 1.16% to 1.92%) in 2000-2002. After adjustment for missing data, the prevalence was 1.62% (95% credible interval, 1.31% to 1.98%) versus 1.34% (95% credible interval, 1.08% to 1.64%), respectively. The differences between the prevalences in 2005-2007 and 2000-2002 were 0.13% (95% credible interval, -0.38% to 0.63%) among those providing complete data and 0.28% (95% credible interval, -0.15% to 0.70%) after adjustment for missing data.nnnCONCLUSIONSnThis is the first North American study to document temporal trends in peanut allergy prevalence by corroborating history with confirmatory tests. The results suggest a stable prevalence, but wide CIs preclude definitive conclusions.

Lupus and cancer

Individuals with systemic lupus erythematosus (SLE) have an increased susceptibility to certain types of cancer. Of particular concern are haematologic malignancies, specifically non-Hodgkin lymphoma, where a three- to four-fold increased risk is seen in SLE, compared with the general population. There is some evidence that immunosuppressive exposures play a role, although there appear to be other factors driving the risk. Lupus disease activity, with resultant dysregulated lymphocyte proliferation, may itself be a mediator of the association between SLE and lymphoma. Aside from haematologic malignancy risk, lung cancer also is increased in SLE compared with the general population, and smoking likely drives this risk in large part. Last but not least, cervical dysplasia is a concern in women with SLE, particularly with exposure to immunosuppressants; routine screening for this complication should not be neglected.

Biologic therapy and pregnancy outcomes in women with rheumatic diseases

Most of the autoimmune rheumatic diseases are more common in women than in men. Because many of these conditions (e.g., rheumatoid arthritis [RA]) affect women of childbearing potential, reproductive issues related to disease management often emerge. Although some autoimmune rheumatic diseases tend to improve during pregnancy, treatment is sometimes required throughout the pregnancy and/or during the postpartum period. Unfortunately, some important therapeutic agents (e.g., methotrexate [MTX] in RA and cyclophosphamide in vasculitis) are teratogenic; therefore, treatment options during pregnancy are limited, and newer treatment options would be welcome. However, none of the newer biologic therapies (anti–tumor necrosis factor [anti-TNF] agents, anakinra, rituximab, or abatacept) are classified by the US Food and Drug Administration (FDA) as safe to use during pregnancy (1). This lack of safety classification is mainly attributable to the lack of adequate and well-controlled studies. Still, in the last decade, numerous case series and case reports of pregnant patients exposed to biologic therapy have accumulated in the literature. Because biologic agents may constitute an important therapeutic alternative in pregnant women experiencing persistent or increased disease activity, we present a comprehensive review of the relevant data. Search strategy. We performed a systematic literature review to identify all studies with original human data on fetal and/or child outcomes following exposure to biologic agents during pregnancy and/or lactation. We searched the following electronic databases for primary studies: PubMed (1950 to October 2008), EMBase (1996 to October 2008), and Web of Science (1991 to October 2008). Our search strategy was restricted to articles published in English, French, or Spanish and included the following medical subject headings (MeSH)

Estimating the prevalence of polymyositis and dermatomyositis from administrative data: age, sex and regional differences

OBJECTIVEnTo estimate the prevalence of polymyositis and dermatomyositis using population-based administrative data, the sensitivity of case ascertainment approaches and patient demographics and these parameters.nnnMETHODSnCases were ascertained from Quebec physician billing and hospitalisation databases (approximately 7.5 million beneficiaries). Three different case definition algorithms were compared, and statistical methods were also used that account for imperfect case ascertainment, to generate estimates of disease prevalence and case ascertainment sensitivity. A hierarchical Bayesian latent class regression model was developed to assess patient characteristics with respect to these parameter estimates.nnnRESULTSnUsing methods that account for the imperfect nature of both billing and hospitalisation databases, the 2003 prevalence of polymyositis and dermatomyositis was estimated to be 21.5/100,000 (95% credible interval (CrI) 19.4 to 23.9). Prevalence was higher for women and for older individuals, with a tendency for higher prevalence in urban areas. Prevalence estimates were lowest in young rural men (2.7/100,000, 95% CrI 1.6 to 4.1) and highest in older urban women (70/100,000, 95% CrI 61.3 to 79.3). Sensitivity of case ascertainment tended to be lower for older versus younger individuals, particularly for rheumatology billing data. Billing data appeared more sensitive in ascertaining cases in urban (vs rural) regions, whereas hospitalisation data seemed most useful in rural areas.nnnCONCLUSIONSnMarked variations were found in the prevalence of polymyositis and dermatomyositis according to age, sex and region. These methods allow adjustment for the imperfect nature of multiple data sources and estimation of the sensitivity of different case ascertainment approaches.

Role of food labels in accidental exposures in food-allergic individuals in Canada

BACKGROUNDnLittle is known about the impact of food labeling on the allergic consumer.nnnOBJECTIVEnTo determine the proportion of food-allergic individuals attributing an accidental exposure to inappropriate labeling, failure to read a food label, or ignoring a precautionary statement and to identify factors associated with accidental exposures.nnnMETHODSnFood-allergic individuals or their caregivers were recruited from a Canadian registry of individuals with a physician-confirmed diagnosis of peanut allergy and from allergy awareness organizations. Participants completed questionnaires regarding accidental exposures due to specific food labeling issues. The association between accidental exposures and characteristics of food-allergic individuals or their caregivers was estimated using multivariate logistic regression models.nnnRESULTSnOf 1,862 potential participants, 1,454 (78.1%) responded. Of the 47.8% (95% confidence interval [CI], 45.1%-50.5%) of respondents who experienced an accidental exposure, 47.0% (95% CI, 43.1%-50.9%) attributed the event to inappropriate labeling, 28.6% (95% CI, 25.1%-32.2%) to failure to read a food label, and 8.3% (95% CI, 6.3%-10.7%) to ignoring a precautionary statement. Food-allergic individuals who were allergic to peanut, tree nut, fish, or shellfish were less likely to experience an accidental exposure due to the allergen not being identified in plain language.nnnCONCLUSIONSnA considerable proportion of accidental exposures are attributed to inappropriate labeling, failure to read labels, and ignoring precautionary statements. Clear and consistent labeling of food allergens combined with increased consumer education is necessary to improve consumer confidence and compliance and to reduce accidental exposures.