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.

Lymphopenia in atopic dermatitis patients treated with oral immunosuppressive drugs.

INTRODUCTION: Oral immunosuppressive drugs are commonly used in the treatment of atopic dermatitis (AD). In patients with autoimmune- and rheumatic diseases, these drugs have been associated with lymphopenia. Lymphopenia is related to an increased risk of opportunistic infections. The incidence of lymphopenia in patients with AD treated with oral immunosuppressive drugs is yet unknown. OBJECTIVE: To evaluate the occurrence of recurrent lymphopenia in patients with AD treated with oral immunosuppressive drugs and to make recommendations for screening in daily practice. METHODS: Patients with recurrent lymphopenia (i.e. >5 times lymphocyte counts below 0.8 × 109/L) during treatment with oral immunosuppressive drugs were included from our immunosuppressive drugs database and further analyzed. RESULTS: A total of 360 AD patients, treated with oral immunosuppressive drugs, were screened. A recurrent lymphopenia during treatment was found in 11 patients. In 8/11 patients, recurrent lymphopenia was observed during concomitant treatment with prednisone. No serious infections were observed. CONCLUSION: Lymphopenia is occasionally seen in AD patients treat with oral immunosuppressive drugs. Concomitant treatment with prednisone seems to be a risk factor. We suggest to include monitoring of lymphocyte counts in the standard follow-up for all AD patients treated with oral immunosuppressive drugs.

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.

Effectiveness and safety of antihistamines up to fourfold or higher in treatment of chronic spontaneous urticaria.

BACKGROUND: Treatment with second-generation antihistamines is recommended in patients with chronic spontaneous urticaria (CSU). Some patients remain unresponsive even after up-dosing up to fourfold. Many third line treatment options have limited availability and/or give rise to significant side effects. We investigated effectiveness and safety of antihistamine treatment with dosages up to fourfold and higher. METHODS: This retrospective analysis of patients' records was performed in adult CSU patients suffering wheals and/or angioedema (AE). Demographic, clinical, and therapeutic data was extracted from their medical records. We recorded the type, maximum prescribed dosage, effectiveness, and reported side effects of antihistamine treatment. RESULTS: Of 200 screened patients, 178 were included. Treatment was commenced with a once daily dose of antihistamines. Persisting symptoms meant that up-dosing up to fourfold occurred in 138 (78%) of patients, yielding sufficient response in 41 (23%). Up-dosing antihistamines was necessary in 110 (80%) patient with weals alone or weals with angioedema and 28 (64%) with AE only (p = 0.039). Of the remaining 97 patients with insufficient response, 59 were treated with dosages higher than fourfold (median dosage 8, range 5-12). This was sufficient in 29 patients (49%). Side effects were reported in 36 patients (20%), whereof 30 (17%) experienced somnolence. Side effects after up-dosing higher than fourfold were reported in six out of 59 patients (10%). CONCLUSION: Up-dosing antihistamines higher than fourfold dosage seems a feasible therapeutic option with regards to effectiveness and safety. The need for third line therapies could be decreased by 49%, with a very limited increase of reported side effects.

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.

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.

Clinical similarities among bradykinin-mediated and mast cell-mediated subtypes of non-hereditary angioedema: a retrospective study.

BACKGROUND: Non-hereditary angioedema (non-HAE) is characterized by local swelling due to self-limiting, subcutaneous or submucosal extravasation of fluid, and can be divided into three subtypes. These subtypes are believed to have different pathophysiological backgrounds and are referred to in recent guidelines as bradykinin-mediated (e.g. caused by angiotensin-converting-enzyme-inhibitors), mast cell-mediated (e.g. angioedema with wheals) or idiopathic (cause unknown). Bradykinin-mediated subtypes are more closely related to hereditary angioedema than the other forms. Because clinical features of these non-HAE subtypes have not been studied in detail, we have looked at the clinical characteristics of symptoms and potential differences in clinical presentation of bradykinin-mediated and mast cell-mediated angioedema (AE) subtypes. METHODS: A questionnaire was sent to patients presenting with AE at our tertiary outpatient clinic to document clinical characteristics, potential triggers and location of AE. The severity of AE attacks was analysed using visual analogue scales (VAS). RESULTS: The questionnaire was returned by 106 patients, of which 104 were included in the analysis. AE with wheals, idiopathic AE, and drug-associated AE occurred in 64 (62%), 25 (24%) and 15 patients (14%) respectively. Most patients (62%) reported prodromal symptoms while 63% reported multiple locations for an attack. Face and oropharynx were the main locations of AE attacks of any subtype while swelling was the symptom most frequently reported as severe. Overall severity of the last attack was indicated as severe by 68% of the patients. There were no differences between the subgroups. CONCLUSION: This similarity in clinical presentation raises the possibility that ACEi-induced, mast cell-mediated and idiopathic AE share common pathways.

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.

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.