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Background: It is not fully understood how different degrees of improvements in atopic dermatitis (AD) clinical outcome measures translate to improvements in patient‐reported outcome (PRO) measures, such as those assessing itch, symptoms, sleep, anxiety, depression, quality of life (QoL), and work productivity. Objectives: This post hoc analysis of three clinical studies assessed how more robust improvements in clinical responses are associated with improvements in PROs and QoL. Methods: Data from three randomized, double‐blind, placebo‐controlled, phase 3 trials in adults and adolescents with moderate to severe atopic dermatitis (Measure Up 1, Measure Up 2, and AD Up) were included. Patients were randomly assigned (1:1:1) to upadacitinib (15 or 30 mg) or placebo once daily (alone or in combination with topical corticosteroids). The mean percentage improvement from baseline to week 16 and percentage of patients achieving responses at week 16 were summarized by the Eczema Area and Severity Index (EASI) and validated Investigator Global Assessment of Atopic Dermatitis (vIGA‐AD) response level categories. Results: A total of 2392 patients from the three trials were included in the analysis. Increasingly greater mean percentage improvement and proportion of patients achieving response was observed at higher clinical response levels (i.e., stepwise pattern). Mean percentage improvement and proportion of patients achieving response exceeded 69% and 70% at EASI ≥ 90 and vIGA‐AD 0/1, respectively, for most PROs including Worst Pruritus Numeric Rating Scale, Patient Oriented Eczema Measure, and Dermatology Life Quality Index. Conclusions: Greater degrees of clinical responses are related to more robust improvements across multiple dimensions impacted by AD, including itch, skin pain, sleep, anxiety, depression, and QoL. [ABSTRACT FROM AUTHOR]

Background Although atopic dermatitis (AD) is a very common skin disease, data on the percentage of patients with really difficult-to-treat AD are scarce. From socio-economic perspective, it is important to have more insight into these numbers, as new very effective, but expensive, treatment options will be available in the near future for difficult-to-treat AD. Estimating the number of patients with AD using oral immunosuppressive drugs can give an impression of the percentage of difficult-to-treat patients in the total AD population. Objective To give an overview of the use of oral immunosuppressive drugs in patients with AD in the Netherlands. Methods Prescription data of oral immunosuppressive drugs in the Netherlands were extracted from a pharmaceutical database (NControl) containing data of 557 million prescriptions and 7.2 million patients. An algorithm, based on the WHO Anatomical Therapeutic Chemical (ATC) codes, was used to identify patients with AD. The prescription of oral immunosuppressive drugs in patients with AD between 1 January 2012 and 1 January 2017 was evaluated. Results Based on the algorithm, 65 943 patients with AD were selected. 943 patients with AD (1.4%) used cyclosporine A, methotrexate, azathioprine or mycophenolic acid. Methotrexate was most commonly used, followed by azathioprine and cyclosporine A. A switch in medication was rarely seen. In the evaluation period, a decrease in the prescription of cyclosporine A was seen, together with an increase in the prescription of methotrexate. In 31% of the patients who stopped treatment, the discontinuation took place within the first months of treatment. Conclusion In this study population, 1.4% of the patients with AD used oral immunosuppressive drugs for their eczema in a 5-year period. Methotrexate was the most commonly used systemic drug in the Netherlands for the treatment of AD. [ABSTRACT FROM AUTHOR]

Background: Azathioprine is frequently used in severe eczema. It is converted in the liver into active metabolites, including 6-thioguanine nucleotide (6-TGN) and methylated 6-methylmercaptopurine (6-MMP). In the past, the therapeutic potential of azathioprine may have not been fully utilized. Recent investigations on inflammatory bowel disease have led to a better understanding of azathioprine metabolism and optimizing treatment. Objective: To investigate whether measuring thiopurine metabolites in circulation can improve the effectiveness and safety of azathioprine treatment in patients with atopic dermatitis and/or chronic hand/foot eczema. Methods: Azathioprine metabolite levels were measured in eczema patients during maintenance treatment (Part I) and dose escalation (Part II). Clinical effectiveness, hepatotoxicity, and bone marrow suppression were analyzed and TPMT genotype was assessed. Results: A wide variation in metabolite levels in all dose groups was observed. In Part I (32 patients), there were no significant differences in 6-TGN levels between clinical responders and non-responders (p = .806). No hepatoxicity or myelotoxicity was observed. In Part II, all 6-TGN and 6-MMP levels increased during dose escalation. Hypermethylation was observed in 2/8 patients. Conclusion: For individual eczema patients treated with azathioprine, routinely measuring 6-TGN and 6-MMP can be helpful in optimizing azathioprine dose, improving clinical effectiveness, and preventing side effects. [ABSTRACT FROM AUTHOR]

Summary: Background: Guidelines discourage the use of systemic corticosteroids for atopic dermatitis (AD), but their use remains widespread. Objectives: To reach consensus among an international group of AD experts on the use of systemic corticosteroids for AD. Methods: A survey consisting of statements accompanied by visual analogue scales ranging from ‘strongly disagree’ to ‘neutral’ to ‘strongly agree’ was distributed to the International Eczema Council (IEC). Consensus was reached in agreement on a statement if < 30% of respondents marked to the left of ‘neutral’ towards ‘strongly disagree’. Results: Sixty of 77 (78%) IEC members participated. Consensus was reached on 12 statements, including that systemic corticosteroids should generally be avoided but can be used rarely for severe AD under certain circumstances, including a lack of other treatment options, as a bridge to other systemic therapies or phototherapy, during acute flares in need of immediate relief, in anticipation of a major life event or in the most severe cases. If used, treatment should be limited to the short term. Most respondents agreed that systemic corticosteroids should never be used in children, but consensus was not reached on that statement. The conclusions of our expert group are limited by a dearth of high‐quality published evidence. If more stringent consensus criteria were applied (e.g. requiring < 20% of respondents marking towards ‘strongly disagree’), consensus would have been reached on fewer statements. Conclusions: Based on expert opinion from the IEC, routine use of systemic corticosteroids for AD is generally discouraged and should be reserved for special circumstances. [ABSTRACT FROM AUTHOR]

Atopic dermatitis (AD) is a very common chronic inflammatory skin disease requiring long-term treatment. Mycophenolic acid (MPA) is used off-label in treatment of patients with severe AD failing Cyclosporin A (CsA) treatment, however clinical efficacy is observed in only half of the AD patients. In blood, MPA levels are known to have a large interindividual variability. Low MPA exposure and increased enzyme activity correlates with the presence of UGT1A9 polymorphisms. In this retrospective study, 65 adult AD patients treated with MPA were classified as responder or non-responder to MPA treatment. UGT1A9 polymorphisms were determined using PCR. A significantly higher number of UGT1A9 polymorphisms was found in the group that did not respond to MPA treatment. Of the patients that carried a UGT1A9 polymorphism, 85.7% were non-responsive to MPA treatment. This implies that non-responsiveness in AD patients is more likely to occur in carriers of a UGT1A9 polymorphism. In a binary logistic regression analysis the odds ratio (OR) was 8.65 (95% confidence interval: 0.93–80.17). Our results show that UGT1A9 polymorphisms can be used to identify patients with non-responsiveness to MPA. Patients with UGT1A9 polymorphisms might benefit from higher MPA dosage. [ABSTRACT FROM AUTHOR]

Background: Although total IgE levels have been proposed as a biomarker for disease severity in atopic dermatitis (AD) and are increased in the majority of AD patients, they do not correlate with disease severity during short-term follow-up. During the synthesis of immunoglobulins, free light chains (Ig-FLCs) are produced in excess over heavy chains. In comparison with IgE molecules, Ig-FLCs have a very short serum half-life. Therefore, Ig-FLCs might be more suitable as a biomarker for disease severity during follow-up. Recent studies showed increased serum levels of kappa Ig-FLCs in infants with AD, correlating with disease severity. The aim of this study was to investigate serum kappa Ig- FLC levels in adults with AD, and their correlation to disease severity. Methods: Serum kappa If-FLC and total IgE levels were measured in 82 moderate to severe AD patients and 49 nonatopic controls. Blood was collected from patients before start of treatment with potent topical steroids (European classification: III-IV). 32 patients were treated during a clinical admission, and in this subpopulation a second blood sample was taken after 2 weeks of treatment. Clinical severity was determined by the Six Area Six Sign Atopic Dermatitis (SASSAD) severity score and a panel of serum biomarkers, including thymus and activation-regulated chemokine (TARC). Results: Serum kappa Ig-FLCs levels in adult AD patients were not increased compared to non-atopic controls. Moreover, we observed no correlation between kappa Ig-FLC serum levels and disease severity determined by SASSAD and a panel of serum biomarkers, including TARC. Serum kappa Ig-FLC levels did also not decrease during treatment. Conclusion: There are no differences in serum kappa Ig-FLC levels between adult patients suffering from moderate to severe AD compared to non-atopic controls. Moreover, serum levels of kappa Ig-FLCs cannot be used as a biomarker for disease severity in adult AD. [ABSTRACT FROM AUTHOR]

Background Severe atopic dermatitis (AD) is often treated successfully with oral immunosuppressive drugs such as ciclosporin (CsA) or oral corticosteroids. However, some patients develop adverse effects or are unresponsive to these first-choice oral immunosuppressive drugs. Objectives To evaluate whether enteric-coated mycophenolate sodium (EC-MPS) is an effective treatment in patients with severe, recalcitrant AD. Methods Ten patients with severe, recalcitrant AD were treated with EC-MPS 720 mg twice daily for 6 months. All patients had to discontinue other oral immunosuppressive drugs due to adverse effects ( n = 8) or nonresponsiveness ( n = 2). Disease activity was monitored using the Severity Scoring of Atopic Dermatitis (modified SCORAD) index and the Leicester Sign Score (LSS). Additionally, the level of serum thymus and activation-regulated cytokine (TARC) was measured. During treatment, safety laboratory examination was performed. Total serum immunoglobulin E (IgE) was followed during treatment. Use of topical corticosteroids was recorded before and during treatment. Results Compared with baseline, the mean scores for disease activity significantly decreased during treatment with EC-MPS [modified SCORAD ( P = 0·04), LSS severity ( P = 0·01), LSS extent ( P = 0·01)]. In addition, serum TARC levels and total serum IgE levels significantly decreased after treatment compared with before ( P = 0·03; P = 0·05). Disease activity decreased after approximately 2 months of treatment and stabilized during the 6-month treatment period. No differences in the amount of topical corticosteroids used in the 6 months prior to treatment compared with the 6-month treatment period were found ( P = 0·4). None of the patients discontinued use of EC-MPS and only mild adverse effects were seen. Conclusions In this study EC-MPS at a dose of 720 mg twice daily for 6 months has proven to be an effective and well-tolerated treatment for patients with severe, recalcitrant AD. [ABSTRACT FROM AUTHOR]

Background: The atopy patch test (APT) is an in vivo model to study the induction of eczema by inhalant allergens in atopic dermatitis (AD) patients. Mepolizumab is a monoclonal antibody to interleukin-5, which reduces peripheral blood eosinophils. Previously, we reported that mepolizumab treatment did not result in clinical improvement in AD. The current study investigates the effect of mepolizumab therapy on the APT in the same patients. Methods: Mepolizumab treatment was given at days 0 and 7 in a double-blind placebo-controlled design. The APT was applied at days –2, 0, 14 and 28. Clinical evaluation of each APT was conducted 48 h after application at days 0, 2, 16 and 30. Skin biopsies were taken at days 0, 2 and 16 for eosinophil counts. Results: The mepolizumab-treated group showed no significant reduction in macroscopic outcome of the APT. Tissue eosinophils were reduced in the mepolizumab-treated group at day 16 compared with placebo; however, this was not significant. Conclusion: Mepolizumab therapy cannot prevent the eczematous reaction induced by the APT. Furthermore, the influx of tissue eosinophil numbers in the APT is not significantly inhibited after mepolizumab treatment compared with placebo, despite a significant reduction in peripheral blood eosinophils. Copyright © 2006 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

The atopy patch test (APT) is an in vivo model to study the induction of eczema by inhalant allergens. This study was designed to compare two commonly used APT methods. In the first method, the allergen is dissolved in aqueous solution, which is applied on tape-stripped skin. In the second method, the allergen is dissolved in petrolatum and applied without tape stripping. Thirteen patients with atopic dermatitis sensitized to inhalant allergens were patch tested using both methods. Reactions were evaluated macroscopically and microscopically after 48 h. Nine out of 13 patients displayed a positive reaction for both methods. One patient had a positive APT for the aqueous method alone and three for the petrolatum method alone. Reactions were significantly stronger when using the petrolatum method. Histological evaluation of the nine patients positive for both methods showed no significant differences in number of eosinophils, T-cells and neutrophils. The APT using the petrolatum vehicle induces a higher number of positive reactions and is significantly stronger relative to the APT using allergen in aqueous vehicle. The cellular influx in both test methods is comparable. Both methods can be used to study the mechanisms in the induction of eczema by inhalant allergens. [ABSTRACT FROM AUTHOR]

From a number of cross-sectional and longitudinal studies, it can be concluded that there is a very close association between house dust mite (HDM) exposure and HDM sensitization. In addition, HDM exposure in already sensitized individuals can trigger an exacerbation of asthma, and prolonged exposure can lead to the persistence of symptoms. Asthma is usually more severe in sensitized patients who are exposed to higher allergen levels. There is clear biological plausibility for the role of HDM allergens, in that the proteolytic activity of their enzymes can actively damage the airway epithelium. In effectively mite allergen-free environments, as in hospitals or in high-altitude Alpine clinics, the condition of asthmatic patients improves both symptomatically and in terms of non-specific bronchial responsiveness. Even 1 month at high altitude can result in a reduction in airways inflammation, measured as adenosine monophosphate, bronchial hyper-responsiveness, blood eosinophils and eosinophilic cationic protein.

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BACKGROUND Prurigo nodularis is a chronic, debilitating, and severely pruritic neuroimmuno-logic skin disease. Nemolizumab, an interleukin-31 receptor alpha antagonist, down-regulates key pathways in the pathogenesis of prurigo nodularis. METHODS In this phase 3, double-blind, multicenter, randomized trial, we assigned adults with moderate-to-severe prurigo nodularis to receive an initial 60-mg dose of nemolizumab followed by subcutaneous injections of 30 mg or 60 mg (depending on baseline weight) every 4 weeks for 16 weeks or matching placebo. The primary end points were an itch response (a reduction of ≥4 points on the Peak Pruritus Numerical Rating Scale [PP-NRS; scores range from 0 to 10, with higher scores indicating more severe itch]) and an Investigator's Global Assessment (IGA) response (a score of 0 [clear] or 1 [almost clear] on the IGA [scores range from 0 to 4] and a reduction from baseline to week 16 of ≥2 points). There were five key secondary end points. RESULTS A total of 274 patients underwent randomization; 183 were assigned to the nemolizumab group, and 91 to the placebo group. Treatment efficacy was shown with respect to both primary end points at week 16; a greater percentage of patients in the nemolizumab group than in the placebo group had an itch response (56.3% vs. 20.9%; strata-adjusted difference, 37.4 percentage points; 95% confidence interval [CI], 26.3 to 48.5), and a greater percentage in the nemolizumab group had an IGA response (37.7% vs. 11.0%; strata-adjusted difference, 28.5 percentage points; 95% CI, 18.8 to 38.2) (P<0.001 for both comparisons). Benefits were observed for the five key secondary end points: itch response at week 4 (41.0% vs. 7.7%), PP-NRS score of less than 2 at week 4 (19.7% vs. 2.2%) and week 16 (35.0% vs. 7.7%), and an improvement of 4 or more points on the sleep disturbance numerical rating scale (range, 0 [no sleep loss] to 10 [unable to sleep at all]) at week 4 (37.2% vs. 9.9%) and week 16 (51.9% vs. 20.9%) (P<0.001 for all comparisons). The most common individual adverse events were headache (6.6% vs. 4.4%) and atopic dermatitis (5.5% vs. 0%). CONCLUSIONS Nemolizumab monotherapy significantly reduced the signs and symptoms of prurigo nodularis. [ABSTRACT FROM AUTHOR]

Background: Conjunctivitis is common in patients with atopic dermatitis (AD) in general and a commonly reported adverse event in AD clinical trials with dupilumab., Objective: To survey opinions and experience about conjunctivitis occurring in AD, including those during dupilumab treatment in a group of AD experts from the International Eczema Council (IEC)., Methods: Electronic survey and in-person discussion of management strategies., Results: Forty-six (53.5%) IEC members from 19 countries responded to the survey. Consensus was reached for several statements regarding diagnostic workup, referral and treatment. IEC members suggest that patients with AD should (i) routinely be asked about ocular complaints or symptoms, (ii) obtain information about the potential for conjunctivitis before starting dupilumab therapy and (iii) if indicated, be treated with dupilumab despite previous or current conjunctivitis. In cases of new-onset conjunctivitis, there was consensus that dupilumab treatment should be continued when possible, with appropriate referral to an ophthalmologist., Limitations: The study relies on expert opinion from dermatologists. Responses from few dermatologists without dupilumab access were not excluded from the survey., Conclusion: The IEC recommends that dermatologists address conjunctivitis in patients with AD, especially during treatment with dupilumab., (© 2019 The Authors. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venereology.)