Effects of shared medical appointments compared to individual appointments in children with atopic dermatitis: A pragmatic randomized controlled trial.

BACKGROUND: Atopic dermatitis (AD) needs intensive treatment and has a negative impact on quality of life. Shared medical appointments (SMAs) showed to be effective in clinical outcomes of chronic diseases, but little is known about the effects on children and families. OBJECTIVE: To evaluate the effects of SMAs compared to individual appointments (IA) for children with AD and their parents on coping and clinical outcomes. METHODS: In a pragmatic randomized controlled trial, new patients in UMC Utrecht with AD, younger than 18 years, and their parents were assigned to the SMA group or the IA group using a covariate adaptive randomization method, controlled for age. Before the intervention, 2 months (primary time-point) and 6 months thereafter, we assessed parental emotional coping (primary outcome), quality of life, anxiety about corticosteroids and patient disease activity. Patients, parents and healthcare professionals could not be blinded to group assignment. RESULTS: Of 140 patients, enrolled in the trial, 69 patients were assigned to the SMA and 71 to the IA intervention of whom 114 completed the intervention (SMA: 49; IA: 65). After 2 months, there were no differences between SMAs and IAs in effects on emotional coping: b 0.66, 95% CI -0.7 to 2.03; P = 0.33 (mean difference: 0.30; 95% CI -1.56 to 2.16; N SMA: 11; IA: 24), quality of life, anxiety about corticosteroids and disease activity. From the initial appointment to long-term follow-up, both groups showed substantial improvements, but not significant in disease activity and significant reduction in anxiety about corticosteroids. This study is limited by a low response rate; therefore, linear mixed models and dropout analyses were performed. No serious adverse events were reported. CONCLUSION AND CLINICAL RELEVANCE: For children with AD and their parents, there were no additional benefits of GMAs in parental emotional coping, anxiety about corticosteroids, quality of life and disease activity. TRIAL REGISTRATION: www.ISRCTN.org, ISRCTN08506572.

Patterns of topical corticosteroids prescriptions in children with asthma.

OBJECTIVES: To study topical corticosteroid use in Dutch asthmatic children using pharmacy dispensing data and to assess whether Dutch physicians prescribe topical corticosteroids in this population according to clinical guidelines. METHODS: Medication histories of children using asthma medication were extracted from the pharmacy dispensing system in 100 Dutch community pharmacies. The incidence rate and the potency of topical corticosteroid prescriptions per age were assessed. The topical corticosteroid incidence rates of the different age groups were compared using the Pearson chi-square test. Generalized linear models were used to study the prescription behavior of general practitioners and atopic dermatitis-related specialists regarding different classes of topical corticosteroids. RESULTS: Thirty percent of the infants received a topical corticosteroid prescription, compared with 15%-18% of the children aged 4 and older. Similarly, the mean number of topical corticosteroid prescriptions in infants was 2.2 per year, compared with 1.6-1.9 in children aged 4 and older. In concordance with the clinical guidelines, we observed that atopic dermatitis-related specialists more often prescribed first prescriptions of potent and very potent topical corticosteroids than general practitioners (relative risk = 2.55, 95% confidence interval = 1.79-3.63). Statistically significant differences (P < .01) were found between potencies of prescribed topical corticosteroids. CONCLUSION: Younger children receive more topical corticosteroid prescriptions than children aged 4 and older, and there is a statistically significantly higher prescription rate of topical corticosteroid for infants. Sometimes general practitioners do not follow guidelines and prescribe more-potent topical corticosteroids without a prior prescription of the same potency by a specialist.

Moving toward endotypes in atopic dermatitis: Identification of patient clusters based on serum biomarker analysis.

BACKGROUND: Atopic dermatitis (AD) is a complex, chronic, inflammatory skin disease with a diverse clinical presentation. However, it is unclear whether this diversity exists at a biological level. OBJECTIVE: We sought to test the hypothesis that AD is heterogeneous at the biological level of individual inflammatory mediators. METHODS: Sera from 193 adult patients with moderate-to-severe AD (six area, six sign atopic dermatitis [SASSAD] score: geometric mean, 22.3 [95% CI, 21.3-23.3] and 39.1 [95% CI, 37.5-40.9], respectively) and 30 healthy control subjects without AD were analyzed for 147 serum mediators, total IgE levels, and 130 allergen-specific IgE levels. Population heterogeneity was assessed by using principal component analysis, followed by unsupervised k-means cluster analysis of the principal components. RESULTS: Patients with AD showed pronounced evidence of inflammation compared with healthy control subjects. Principal component analysis of data on sera from patients with AD revealed the presence of 4 potential clusters. Fifty-seven principal components described approximately 90% of the variance. Unsupervised k-means cluster analysis of the 57 largest principal components delivered 4 distinct clusters of patients with AD. Cluster 1 had high SASSAD scores and body surface areas with the highest levels of pulmonary and activation-regulated chemokine, tissue inhibitor of metalloproteinases 1, and soluble CD14. Cluster 2 had low SASSAD scores with the lowest levels of IFN-α, tissue inhibitor of metalloproteinases 1, and vascular endothelial growth factor. Cluster 3 had high SASSAD scores with the lowest levels of IFN-ß, IL-1, and epithelial cytokines. Cluster 4 had low SASSAD scores but the highest levels of the inflammatory markers IL-1, IL-4, IL-13, and thymic stromal lymphopoietin. CONCLUSION: AD is a heterogeneous disease both clinically and biologically. Four distinct clusters of patients with AD have been identified that could represent endotypes with unique biological mechanisms. Elucidation of these endotypes warrants further investigation and will require future intervention trials with specific agents, such as biologics.

Risk of Non-melanoma Skin Cancer in Patients with Atopic Dermatitis Treated with Oral Immunosuppressive Drugs.

There is uncertainty about the risk of developing non-melanoma skin cancer (NMSC), including basal cell carcinoma and squamous cell carcinoma (SCC), in patients with atopic dermatitis (AD) treated with oral immunosuppressive drugs. A total of 557 patients with AD treated with these drugs in the University Medical Center Utrecht and Groningen, the Netherlands, were analysed. NMSC after oral immunosuppressive treatment was reported in 18 patients (3.2%). The standardized incidence ratio for developing SCC was 13.1 (95% confidence interval (95% CI) 6.5-19.7). Patients developing NMSC were older at the start of therapy (p<0.001) and data lock (p<0.001) compared with patients without NMSC. No significant differences were found in sex, cumulative days of oral immunosuppressive drugs and follow-up between these groups (p=0.42, p=0.88, and p=0.34, respectively). In interpreting these results it is important to include other factors, such as lack of association between treatment duration and tumour development and the long interval between treatment discontinuation and tumour development in some patients.

Allergenicity and safety of recombinant human C1 esterase inhibitor in patients with allergy to rabbit or cow's milk.

BACKGROUND: Recombinant human C1 inhibitor (rhC1INH) for on-demand treatment of hereditary angioedema is purified from milk of transgenic rabbits. It contains low amounts (<0.002%) of host-related impurities, which could trigger hypersensitivity reactions in patients with rabbit allergy (RA) and/or cow's milk allergy (CMA). OBJECTIVE: This study is an assessment of allergenicity and safety of rhC1INH in patients with RA and/or CMA. METHODS: Patients with CMA and/or RA underwent skin prick test (SPT), intracutaneous test (ICT), and, when results for both were negative, subcutaneous (SC) challenge with up to 2100U (14 mL) rhC1INH. The negative predictive value of the skin test protocol was calculated, defined as the ratio of patients without systemic symptoms of hypersensitivity following SC challenge, over the number of patients having tested negative for both the SPT and the ICT. Adverse events after exposure to rhC1INH were recorded. RESULTS: Twenty-six patients with RA and/or CMA were enrolled. Twenty-four had negative SPT and ICT results for rhC1INH, whereas 2 had negative SPT result but positive ICT result to rhC1INH (only the highest concentration). Twenty-two patients with negative SPT and ICT results underwent SC challenge. None developed allergic symptoms. Local treatment-emergent adverse events occurred in 7 patients (32%) after SC challenge. In 5 these were considered drug related. All were mild. CONCLUSIONS: None of the patients with negative SPT and ICT results for rhC1INH had allergic symptoms during rhC1INH challenge. The negative predictive value of the combination of SPT and ICT for the outcome of the SC challenge was 100% (95% CI, 84.6%-100%). SC administration of rhC1INH was well tolerated.

Is There an Additional Value of Inpatient Treatment for Patients with Atopic Dermatitis?

An inpatient treatment and education programme has been developed for patients with difficult to control atopic dermatitis (AD), with the aim of achieving adequate self-management and long-term disease control. This observational study included adult patients diagnosed with difficult to control AD, admitted for a structured inpatient treatment and education programme. The primary outcome was the Six Area, Six Sign Atopic Dermatitis (SASSAD) score. In total, 79 patients (mean ± SD age 38.8 ± 17.1 years) were included. The median duration of hospitalization was 11 days (interquartile range 8-14). The mean percentage decrease in SASSAD score between admission and discharge was 60.7%, of which 64 (81.0%) patients achieved SASSAD50. The mean percentage decrease in SASSAD score was 69.0% during follow-up, of which 63 (79.7%) patients still had a SASSAD50. In the majority of these patients with difficult to control AD the admission resulted in sustained disease control. This could be achieved by optimization of treatment with topical corticosteroids.

IgG antibodies in food allergy influence allergen-antibody complex formation and binding to B cells: a role for complement receptors.

Allergen-IgE complexes are more efficiently internalized and presented by B cells than allergens alone. It has been suggested that IgG Abs induced by immunotherapy inhibit these processes. Food-allergic patients have high allergen-specific IgG levels. However, the role of these Abs in complex formation and binding to B cells is unknown. To investigate this, we incubated sera of peanut- or cow's milk-allergic patients with their major allergens to form complexes and added them to EBV-transformed or peripheral blood B cells (PBBCs). Samples of birch pollen-allergic patients were used as control. Complex binding to B cells in presence or absence of blocking Abs to CD23, CD32, complement receptor 1 (CR1, CD35), and/or CR2 (CD21) was determined by flow cytometry. Furthermore, intact and IgG-depleted sera were compared. These experiments showed that allergen-Ab complexes formed in birch pollen, as well as food allergy, contained IgE, IgG1, and IgG4 Abs and bound to B cells. Binding of these complexes to EBV-transformed B cells was completely mediated by CD23, whereas binding to PBBCs was dependent on both CD23 and CR2. This reflected differential receptor expression. Upon IgG depletion, allergen-Ab complexes bound to PBBCs exclusively via CD23. These data indicated that IgG Abs are involved in complex formation. The presence of IgG in allergen-IgE complexes results in binding to B cells via CR2 in addition to CD23. The binding to both CR2 and CD23 may affect Ag processing and presentation, and (may) thereby influence the allergic response.

Serum creatinine levels during and after long-term treatment with cyclosporine A in patients with severe atopic dermatitis.

Safety data with respect to kidney function during long-term treatment with cyclosporine A (CsA) in patients with atopic dermatitis is limited. Data on serum creatinine levels before, during and after CsA treatment were collected in a retrospective cohort of adult patients with atopic dermatitis. The median duration of treatment of 150 patients was 280 days (interquartile range 203-528 days). There was a significant, but not clinically relevant, increase in serum creatinine compared with the baseline level after 3 weeks of treatment with CsA and stabilization during the maintenance phase at the group level. Twenty-two (14.7%) patients had a greater than 30% increase in serum creatinine (cut-off point for clinically relevant change) compared with baseline. These patients were significantly older than the patients without a 30% increase (mean ± standard deviation age 41.4 ± 15.6 vs. 33.8 ± 11.7 years (p = 0.01)). During follow-up, all patients had a less than 30% increase in serum creatinine levels compared with baseline levels. At the group level serum creatinine levels during follow-up were not significantly different from baseline.

Characterization of T cell epitopes in bovine α-lactalbumin.

BACKGROUND: Recent studies have indicated that peptides containing T cell epitopes may be used for immunotherapy. While for several cow's milk allergens the T cell epitopes have been described, the T cell epitopes in the major allergen α-lactalbumin (α-LAC) are unknown. Therefore, the aim of this study was to determine the T cell epitopes in α-LAC. METHODS: Nineteen synthetic peptides spanning α-LAC were obtained. Cow's milk-specific T cell lines (TCLs) of 46 subjects were generated and tested for their specificity for α-LAC. The lines responding to α-LAC were subsequently tested to determine their activation in response to the peptides. RESULTS: More than half of the TCLs generated did not respond to α-LAC or lost their responsiveness during subsequent experiments, which indicates that α-LAC has low immunogenicity. Only 8 TCLs recognized 1 or more peptides. The recognition of the peptides was diverse and no major epitopes could be defined. CONCLUSION: The immunogenicity of α-LAC is very low compared to other major allergens in cow's milk. Moreover, there seems to be no dominant epitope present in the protein. Therefore, it seems unlikely that peptides of this protein can be used for immunotherapy.

The diagnostic value of specific IgE to Ara h 2 to predict peanut allergy in children is comparable to a validated and updated diagnostic prediction model.

BACKGROUND: A diagnostic prediction model for peanut allergy in children was recently published, using 6 predictors: sex, age, history, skin prick test, peanut specific immunoglobulin E (sIgE), and total IgE minus peanut sIgE. OBJECTIVES: To validate this model and update it by adding allergic rhinitis, atopic dermatitis, and sIgE to peanut components Ara h 1, 2, 3, and 8 as candidate predictors. To develop a new model based only on sIgE to peanut components. METHODS: Validation was performed by testing discrimination (diagnostic value) with an area under the receiver operating characteristic curve and calibration (agreement between predicted and observed frequencies of peanut allergy) with the Hosmer-Lemeshow test and a calibration plot. The performance of the (updated) models was similarly analyzed. RESULTS: Validation of the model in 100 patients showed good discrimination (88%) but poor calibration (P < .001). In the updating process, age, history, and additional candidate predictors did not significantly increase discrimination, being 94%, and leaving only 4 predictors of the original model: sex, skin prick test, peanut sIgE, and total IgE minus sIgE. When building a model with sIgE to peanut components, Ara h 2 was the only predictor, with a discriminative ability of 90%. Cutoff values with 100% positive and negative predictive values could be calculated for both the updated model and sIgE to Ara h 2. In this way, the outcome of the food challenge could be predicted with 100% accuracy in 59% (updated model) and 50% (Ara h 2) of the patients. CONCLUSIONS: Discrimination of the validated model was good; however, calibration was poor. The discriminative ability of Ara h 2 was almost comparable to that of the updated model, containing 4 predictors. With both models, the need for peanut challenges could be reduced by at least 50%.

Sensitization to Cor a 9 and Cor a 14 is highly specific for a hazelnut allergy with objective symptoms in Dutch children and adults.

BACKGROUND: Component-resolved diagnosis has been shown to improve the diagnosis of food allergy. OBJECTIVE: We sought to evaluate whether component-resolved diagnosis might help to identify patients at risk of objective allergic reactions to hazelnut. METHOD: A total of 161 hazelnut-sensitized patients were included: 40 children and 15 adults with objective symptoms on double-blind, placebo-controlled food challenges (DBPCFCs) and 24 adults with a convincing objective history were compared with 41 children and 41 adults with no or subjective symptoms on DBPCFCs (grouped together). IgE levels to hazelnut extract and single components were analyzed with ImmunoCAP. RESULTS: IgE levels to hazelnut extract were significantly higher in children with objective than with no or subjective symptoms. In 13% of children and 49% of adults with hazelnut allergy with objective symptoms, only sensitization to rCor a 1.04 was observed and not to other water-soluble allergens. Sensitization to rCor a 8 was rare, which is in contrast to rCor a 1. Sensitization to nCor a 9, rCor a 14, or both was strongly associated with hazelnut allergy with objective symptoms. By using adapted cutoff levels, a diagnostic discrimination between severity groups was obtained. IgE levels to either nCor a 9 of 1 kUA/L or greater or rCor a 14 of 5 kUA/L or greater (children) and IgE levels to either nCor a 9 of 1 kUA/L or greater or rCor a 14 of 1 kUA/L or greater (adults) had a specificity of greater than 90% and accounted for 83% of children and 44% of adults with hazelnut allergy with objective symptoms. CONCLUSION: Sensitization to Cor a 9 and Cor a 14 is highly specific for patients with objective symptoms in DBPCFCs as a marker for a more severe hazelnut allergic phenotype.

Quality of life is more impaired in patients seeking medical care for food allergy.

BACKGROUND: Food allergy (FA) affects 2-4% of adults, but only a small percentage visit an outpatient clinic for a thorough evaluation. METHODS: A matched case-control study was used to compare health-related quality of life (HRQL) of the Dutch general population that did not seek medical care for their FA with outpatients who did seek medical care. All participants were diagnosed as food allergic (i.e. with a suggestive history and corresponding positive IgE). HRQL was measured using the Food Allergy Quality of Life Questionnaire--Adult Form (FAQLQ-AF). A food allergy independent measure (FAIM) was used to evaluate the adult's perception of the severity of his/her disease. RESULTS: Total FAQLQ-AF score in individuals who never visited a doctor for their FA was significantly lower than that of patients who sought medical care (2.4 vs. 3.9, p = 0.03), indicating that the former had a better quality of life than patients who did seek medical care. Regarding the different domains of FAQLQ, the score for allergen avoidance and dietary restrictions and the score for emotional impact (EI) was significantly higher in the group that sought medical care (p = 0.02 and 0.03, respectively), indicating the importance of these domains. The FAIM score was significantly higher in the group that sought medical care, indicating that they perceived their FA as more severe. CONCLUSION AND CLINICAL RELEVANCE: Patients who seek medical care for their FA have a more impaired HRQL and perceive their FA as more severe. Food avoidance and issues related to the EI of FA are key areas of intervention aimed at improving HRQL in patients with FA.

Oral treatment with ß-lactoglobulin peptides prevents clinical symptoms in a mouse model for cow's milk allergy.

BACKGROUND: Prior exposure to partial whey hydrolysates has been shown to reduce the allergic response to whey in mice. This effect was more pronounced in combination with a diet containing non-digestible oligosaccharides (scGOS/lcFOS/pAOS). It is unknown which fractions/epitopes are responsible for this effect. Therefore, the prophylactic ability of synthetic peptides of ß-lactoglobulin with/without a scGOS/lcFOS/pAOS-containing diet to reduce the allergic response in a mouse model for cow's milk allergy was investigated. METHODS: Of 31 peptides, nine peptides were selected based on human T cell data. Mice were pre-treated orally with three peptide mixtures or single peptides for six consecutive days. During this period, they received a control or scGOS/lcFOS/pAOS-containing diet. Subsequently, mice were orally sensitized to whey and received an intradermal and oral challenge. After sacrifice, serum and mesenteric lymph nodes (MLN) were collected for further analysis. RESULTS: Prior exposure to peptide mixtures 1 and 3 significantly reduced the acute allergic skin response to whey. Mixture 2 showed no effect. An additive effect of the scGOS/lcFOS/pAOS-containing diet was only observed for mixture 1. Of the peptides in mixture 1, one peptide (LLDAQSAPLRVYVEELKP) showed the strongest effect on the acute allergic skin response. This peptide also tended to decrease whey-specific antibody levels and to increase the percentages of CD11b+CD103+ dendritic cells and CD25+Foxp3+ T cells in the MLN. CONCLUSIONS: Prior exposure to specific peptides of ß-lactoglobulin reduces the allergic response to whey, which may involve regulatory dendritic and T cells. Combining peptides with a sGOS/lcFOS/pAOS-containing diet enhances this effect.