Author summary So far, genetic studies of allergic disease have investigated the presence of the disease rather than the age at which the first allergic symptoms develop. We aimed to identify genetic risk variants associated with the age at which symptoms of allergic disease first develop, considering information from asthma, hay fever and eczema by examining 117,130 genotyped individuals of European ancestry from the UK Biobank study. We identified 50 variants with a significant independent association (P<3x10-8) with age-of-onset. Forty-five variants had comparable effects on the onset of the three individual diseases and 38 were also associated with allergic disease case-control status in an independent study (n = 222,484). We then performed a multivariate GWAS of age-of-onset and case-control status identified a further 26 associations that were missed by the univariate analyses of age-of-onset or case-control status only. 18 of 76 variants identified represent novel associations for allergic disease. We identified 81 likely target genes of the 76 genetic variants, including ADAM15, FOSL2, TRIM8, BMPR2, CD200R1, PRKCQ, NOD2, SMAD4, ABCA7 and UBE2L3. Our results support the notion that early and late onset allergic disease have partly distinct genetic architectures, potentially explaining known differences in pathophysiology between individuals.
Summary Background Subcutaneous immunotherapy for respiratory allergy has shown a long‐lasting efficacy after its discontinuation, whereas this evidence is still lacking for sublingual immunotherap...
This JAMA Insights Clinical Update reviews recent evidence favoring use of inhaled corticosteroids (ICS)in all patients with asthma, regardless of frequency, and summarizes the SMART (single maintenance and reliever therapy) treatment approach, which uses an inhaler combining ICS and formotero
PubMed comprises more than 30 million citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.
Abstract Background Most studies addressing the association between RSV and recurrent wheezing (RW) and asthma have been conducted in patients at risk for lung morbidity. Data in full‐term infant
Abstract Allergen Immunotherapy (AIT) was introduced in clinical practice on an empirical basis more than 100 years ago. Since the first attempts, AIT was administered subcutaneously. Indeed, other routes of administration were proposed and studied, in particular to improve the safety, but only the sublingual route (SLIT) achieved a credibility based on evidence, and was then accepted as a viable “alternative” option to the subcutaneous route. SLIT was largely used in clinical trials and clinical practice in this last 30 years. Thus, a large amount of data is available, coming from either controlled trials and post‐marketing surveillance studies. It is clear that SLIT is overall effective, but it is also clear that the efficacy is not “class‐related”, as derived from meta‐analyses, but restricted to each specific product. The 30‐year lasting use of SLIT allowed to clarify many clinical aspects, such as efficacy, safety, use in asthma, regimens of administration, optimal doses. In parallel, the mechanisms of action of AIT were elucidated, and new indications were proposed (e.g. food allergy, atopic dermatitis). In addition, the introduction of molecular‐based diagnosis, allowed to better refine the prescription of SLIT, based on specific sensitization profiles.
The present article will describe the origin and evolution of SLIT for respiratory allergy, taking into account the clinical context that suggested this form of treatment, the recently developed aspects, the future perspectives and unmet needs, This is not, therefore, a systematic review, rather a narrative historical description of the past history, and a look forward to the future opportunities.
Over the last decades, an increasing appearance of allergies and atopic disorders, such as asthma, dermatitis, and rhinitis, has been observed.The mechanisms of these disorders remain unclear, and th...
For each of the five biologics the authors shall summarize the known safety profiles and also the potential adverse effects as their usage is extended long term with suggestions for real world studies to help us develop our knowledge base.
Key words: asthma, biologics, safety, omalizumab, mepolizumab, reslizumab, benralizumab, dupilumab, real world evidence
Type 2-low asthma represents a critical unmet need and an opportunity for new drug discovery. Here, Maun et al. demonstrate that increased mast cell tryptase levels are associated with asthma severity independent of type 2 inflammation and that increased active tryptase alleles are associated with decreased clinical responses to anti-IgE treatment. They generated a noncompetitive inhibitory anti-tryptase antibody with in vivo activity in humanized mouse and cynomolgus monkey models as a clinical candidate for severe asthma treatment.
1,19 – dioctadecyl ‐ 3, 3, 39, 39 – tetramethylindocarbocyanine (DiD)‐respiratory syncytial virus and DiD‐influenza adhered to human eosinophils. Both viruses were internalized and inactivated b
Abstract It has become increasingly clear that interleukin‐33 (IL‐33) plays a crucial role in initiation of type 2 immunity. The last decade of intense research has uncovered multiple mechanism
Abstract Background Synergistic role of exposure to cats, dogs, and farm animals during infancy on the risk of childhood asthma and allergy remains unknown. Objectives To investigate independent an...
The European Academy of Allergy and Clinical Immunology has developed a clinical practice guideline providing evidence‐based recommendations for the use of house dust mites (HDM) AIT as an add‐on...
Type 2 (T2) inflammation plays a key role in the pathogenesis of asthma. IL-4, IL-5, and IL-13, along with other inflammatory mediators, lead to increased cellular eosinophilic inflammation. It is likely that around half of all patients with asthma have evidence of T2-high inflammation. Sputum and blood eosinophils, exhaled nitric oxide, blood IgE levels, and airway gene expression markers are frequently used biomarkers of T2-high asthma. Individuals with T2-high asthma tend to have several features of increased asthma severity, including reduced lung function and increased rates of asthma exacerbations, and T2-high patients demonstrate distinct pathologic features including increased airway remodeling and alterations in airway mucus production.
Meeting Summary Asthma is one of the most common chronic diseases, with ≤25% of patients experiencing uncontrolled disease.1Patients with uncontrolled, moderate-to-severe asthma are at increased risk of recurrent exacerbations, accelerated decline in lung function, fixed airway obstruction, and have increased utilisation of health care resources.2,3Furthermore, reduced lung function, as assessed by measures such as forced expiratory volume in 1 second (FEV1), is a strong independent predictor of exacerbations, progressive decline in lung function, and all-cause pulmonary and cardiovascular mortality in patients with asthma.2 Achieving asthma control in these patients is therefore critical. The recognition of distinct inflammatory phenotypes within this population has been instrumental in addressing this need. In these patients, there is robust evidence of the pathogenic role of Th2 cytokines, such as IL-4 and IL-13, in the eosinophilic and allergic inflammatory processes.4This in turn has driven the development of targeted biological therapies, particularly selective targeted monoclonal antibodies such as dupilumab which inhibit the biological effects of both IL-4 and IL-13.5 This article reviews four posters displayed at the European Respiratory Society (ERS) International Congress 2019 that presented results demonstrating the efficacy and safety of dupilumab, an anti-IL-4 receptor human monoclonal antibody, compared to placebo for the treatment of uncontrolled, moderate-to-severe asthma, as measured by a range of outcomes. Background Atypical production of several Th2 cytokines, including IL-4, IL-5, and IL-13, play a central pathogenic role in multiple atopic conditions.6-9Specifically, IL-4 and IL-13 are associated with the pathogenesis of certain types of asthma, including allergic and nonallergic forms.5,6,9-12 IL-4 and IL-13 were historically thought to mediate identical signalling pathways because they share receptor complexes; however, IL-4 and IL-13 elicit distinct allergic hallmarks.IL‑4 is the central mediator of Th2 cell differentiation, isotype class switching (especially to IgE), B cell growth, and eosinophil (EoS) recruitment.12-14IL‑13 has roles in goblet cell hyperplasia induction and smooth muscle contractility.9,15Therefore, IL-4 and IL-13 activate multiple cell types and induce various mediators involved in inflammation, contributing to airflow limitation and increasing the risk of severe exacerbations.11-15Little is currently known regarding the roles of IL-4/IL-13 in IgE and non-IgE-mediated inflammatory pathways, or the effect of inhibiting IL-4/IL-13 in these pathways in asthma. Dupilumab, a fully human anti-IL-4Rαmonoclonal antibody, inhibits signalling of both IL-4 and IL-13 by specifically binding to the IL-4Rαsubunit shared by both receptor complexes.5,10-12This effect is associated with the marked suppression of biomarkers of Type 2 inflammation including total serum IgE, thymus and activation regulated chemokine, eotaxin-3, and fractional exhaled nitric oxide (FeNO).13 Liberty Asthma QUEST Trial The Liberty Asthma QUEST16was a Phase III, randomised, placebo-controlled, parallel-group trial in 1,902 patients with persistent asthma, receiving continuous inhaled corticosteroids (ICS), plus up to two additional controller medications.17Patients with uncontrolled, moderate-to-severe asthma (based on the Global Initiative for Asthma [GINA] 2015 guidelines),18with a history of one or more exacerbations in the previous year and without a minimum requirement for baseline blood EoS count or any other Type 2 biomarkers (FeNO or serum total lgE),19were randomised in a 2:2:1:1 ratio to receive 52 weeks of add-on therapy with subcutaneously administered dupilumab 200 mg or 300 mg every 2 weeks, or matched placebo.5 The co-primary efficacy endpoints included an annualised rate of severe exacerbation events during the 52-week treatmentperiod and absolute change from baseline in pre-bronchodilator (BD) FEV1at Week 12. A secondary endpoint was the percentage change from baseline to Week 12 in pre-BD FEV1.19 This study showed that add-on dupilumab significantly reduced severe asthma exacerbations; improved lung function, asthma control, and quality-of-life measures; and was generally well-tolerated.13 Moreover, treatment effects were greater in patients with elevated Type 2 biomarkers at baseline (blood EoS and FeNO).17,19 Dupilumab Effect on Lung Function in Patients with Uncontrolled, Moderate-to-Severe Asthma with an Allergic Phenotype Professor Mario Castro This post hoc subset analysis of the Liberty Asthma QUEST trial assessed the effect of dupilumab on lung function parameters in patients with uncontrolled, moderate-to-severe asthma with and without evidence of allergic asthma. In this study, allergic asthma was defined as total serum IgE ≥30.00 IU/mL and ≥1.00 perennial aeroallergen-specific IgE ≥0.35 kU/L. The study assessments included the change from baseline in pre-BD FEV1(L), post-BD FEV1(L), pre-BD forced expiratory flow at 25–75% of pulmonary volume (FEF25–75%, L/s), and pre-BD FEV1/forced vital capacity (FVC) ratio (%) during the 52-week treatment period in patients receiving dupilumab 200 mg every 2 weeks, 300 mg every 2 weeks, or matched placebos stratified by evidence of allergic asthma.20 Of the patients, 57% had allergic asthma (n=1,083) with a mean age of 44.40 years, 58.40% were female, and the mean number of severe exacerbations was 1.96. In the nonallergic asthma group, the mean age was 52.70 years, 70.40% were female, and the mean number of severe exacerbations was 2.32.20 This post hoc analysis showed that dupilumab improved pre and post-BD FEV1, pre-BD FEF25-75% (L/s), and FEV1/FVC ratio (%) at Weeks 12 and 52 in patients with uncontrolled, moderate-to-severe asthma with and without evidence of allergic asthma. Dupilumab 200 mg and 300 mg every 2 weeks versus placebo also improved lung function parameters at Week 12 (change from baseline least squares [LS] mean difference pre-BD FEV1:0.13/0.16 L; post-BD FEV1:0.13/0.11 L; FEF25–75%: 0.14/0.22 L/s; FVC: 0.15/0.11 L; FEV1/FVC ratio: 0.56/2.78%; all p<0.05 except dupilumab 200mg, FEV1/FVC ratio [p=0.35]). Sustained or better improvements were observed at Week 52 (all p<0.05).20 The incidence of treatment-emergent adverse events (TEAE) was similar across treatment groups and the most common TEAE reported were viral upper respiratory tract infections (18.2% versus 19.6%), injection-site erythema (13.8% versus 5.5%), upper respiratory tract infection (11.6% versus 13.6%), and bronchitis (11.4% versus 14.0%) in dupilumab versus placebo, respectively.20 Prof Castro concluded that in addition to reducing severe asthma exacerbations and biomarkers of Type 2 inflammation, including total serum IgE,21dupilumab therapy demonstrated rapid and sustained improvement in lung function in uncontrolled, moderate-to-severe asthma patients, with or without evidence of allergic asthma, during the 52-week treatment period. Dupilumab improved both large (pre and post-BD FEV1) and small (pre-BD FEF25-75%)airway function, as well as airway obstruction (pre-BD FEV1 /FVC). The magnitude of improvement was consistent between patients with and without evidence of allergic inflammation and the maximum effect was achieved by Week 12 and sustained to Week 52.20These results are supported by a previous post hoc analysis, in which similar results were observed in QUEST patients with and without evidence of allergic asthma.21 Dupilumab Efficacy in Patients with Uncontrolled, Moderate-to-Severe Asthma by Immunoglobulin E Levels at Baseline Doctor Warner W. Carr This post hoc analysis assessed the effect of dupilumab on severe exacerbations and FEV1, as well as the impact on overall asthma control in patients with uncontrolled, moderate-to-severe asthma as defined by baseline IgE levels. The aim was to investigate whether there was a differential effect on these efficacy measures defined by baseline IgE levels. The study assessments included the annualised rate of severe exacerbations, LS mean change from baseline in pre-BD FEV1(L), and LS mean change from baseline in the 5-item Asthma Control Questionnaire (ACQ-5) score during the 52-week treatment period.22 Patients with uncontrolled, moderate-to-severe asthma were characterised at baseline by IgE level (381 patients had an IgE level <100; 782 patients had ≥100 to <500; 419 patients had ≥500; 313 patients had ≥700; and 212 patients had ≥1,000 IU/mL Figure 1. Baseline demographics and disease characteristics were generally similar across IgE groups.22 Dupilumab 200 mg and 300 mg every 2 weeks versus placebo significantly reduced severe exacerbations in all baseline IgE groups (-38.9 to -67.9%; all p<0.05) and significantly improved pre-BD FEV1at Weeks 24 and 52 in all baseline IgE groups (LS mean difference: 0.11–0.31 L; all p<0.05), except for 300 mg in IgE <100 IU/mL and ≥1,000 IU/mL groups (Figure 2).22 In the overall safety population, the incidence of TEAE was similar across treatment groups. Conjunctivitis was observed in 2.3% versus 3.3% of patients receiving dupilumab versus placebo, respectively.22 Dr Carr concluded that in general, baseline demographics and disease characteristics were balanced between treatment groups across the patient subgroups by total serum IgE levels at baseline. Dupilumab reduced severe asthma exacerbation rates and improved FEV1and asthma control in patients with moderate-to-severe asthma in all IgE subgroups. For exacerbations, these effects reached statistical significance for both dupilumab 200 mg and 300 mg every 2 weeks groups in all IgE subgroups. For FEV1and asthma control, these effects reached statistical significance for patients receiving dupilumab 200 mg every 2 weeks in all IgE subgroups; but for where dupilumab was prescribed 300 mg every 2 weeks dose, not all IgE subgroups reached statistical significance. In conclusion, regardless of atopic status as categorised by baseline IgE levels, dupilumab can reduce severe exacerbations and improve FEV1.22 Dupilumab Efficacy in Type 2 Inflammatory Asthma: Liberty Asthma QUEST Study (Poster OA3807) Professor Ian D. Pavord The new GINA report for difficult-to-treat and severe asthma proposes baseline blood Eos ≥150 cells/µL and/or baseline FeNO ≥20 parts per billion (ppb) as cut-offs to define Type 2 inflammatory asthma.23 This post hoc analysis assessed dupilumab efficacy in patient subgroups defined by the GINA proposed markers for Type 2 asthma, namely in patients with baseline Eos ≥150 cells/µL, FeNO ≥20 ppb, and in other quadrant subgroups. The endpoints assessed included annualised rate of severe exacerbations during the 52-week treatment period and change from baseline in pre-BD FEV1(L) at Week 12.24 Baseline disease characteristics were generally comparable across the subgroups. The mean age was 47.20 years, 59.00% were female, the mean percent predicted pre-BD FEV1was 58.55, the mean exacerbations in the past year was 2.22, and the mean ACQ-5 score was 2.76.24 In patients with baseline Eos ≥150 cells/µL and FeNO ≥20 ppb (n=922), dupilumab 200 mg and 300 mg every 2 weeks versus placebo significantly reduced severe exacerbations by 66% and 63% respectively, and improved FEV1 by 0.26 L and 0.22 L, respectively (all p<0.0001). Similar results were observed at Week 52 and dupilumab efficacy was not significant in the other patient subgroups.24 Overall, the most frequently reported AE in the dupilumab versus placebo group was injection-site reactions.24 Prof Pavord concluded that dupilumab significantly reduced severe exacerbations and improved FEV1in patients with Type 2 inflammatory asthma. Moreover, the effect of dupilumab treatment in reducing exacerbations and improving FEV1was greatest in patients with elevation of both baseline blood EoS count (≥150 cells/µL) and FeNO (≥20 ppb).24 Dupilumab Efficacy in Asthma Patients with FEV160–80% Predicted on Medium-Dose Inhaled Corticosteroids : LIBERTY ASTHMA QUEST Study Professor Alberto Papi This post hoc analysis aimed to assess dupilumab efficacy in patients with moderate asthma defined as asthma with baseline pre-BD FEV160–80% predicted (60–90% in adolescents <18 years), on medium-dose ICS (implying milder asthma than other QUEST patients), and one or more additional controller therapy, without a minimum requirement for baseline blood Eos count or FeNO. The co-primary endpoints were the annualised severe asthma exacerbation rates during the 52-week treatment period and the change from baseline in pre-BD FEV1at Week 12, analysed using negative binomial models and mixed-effects models with repeated measures, respectively. Study assessments included the annualised severe exacerbation rates, LS mean change from baseline in pre-BD FEV1(L), and LS mean change from baseline in the ACQ-5 score during the 52-week treatment period. The medium ICS dose was fluticasone propionate at a total daily dose of 250–500 μg or an equipotent equivalent.25 Twenty-seven percent (517/1,902) of patients had pre-BD FEV160–80% predicted and were on medium-dose ICS at baseline. The mean age was 43.50 years, 61.90% were female, the mean percent predicted pre-BD FEV1was 69.49, the mean exacerbations in the past year was 1.82, and the mean ACQ-5 score was 2.56.25 In these patients, dupilumab 200 mg and 300 mg every 2 weeks versus placebo reduced annualised severe exacerbation rates by 44% and 51%, respectively (p=0.06; p=0.01; Figure 3. Dupilumab 200 mg and 300 mg every 2 weeks versus placebo also improved FEV1at Week 12 with a LS mean difference of 0.11 L/ 0.09 L, respectively (p=0.01/p=0.05).25 Overall, the most frequent adverse event reported in the dupilumab 200 mg and 300 mg groups versus placebo groups were injection-site reactions (15%/18% versus 5%/10%).25 Conclusion Prof Papi concluded that dupilumab demonstrated meaningful reductions in severe exacerbations and significantly improved pre-BD FEV1in the studied patient population. The magnitude of these effects was comparable to those previously seen in the LIBERTY ASTHMA QUEST patients with severe asthma. Numerical improvements in ACQ-5 were observed at all time points, with the trend comparable to results observed in the overall QUEST population and, furthermore, dupilumab was generally well-tolerated.25 Dupilumab is approved in the European Union (EU) for patients >12 years as an add-on maintenance treatment for severe asthma with Type 2 inflammation. This is characterised by raised blood EoS and/or raised FeNO; inadequately controlled with high dose ICS and another medicinal product for maintenance treatment; and in certain patients with asthma, chronic rhinosinusitis with nasal polyps, or atopic dermatitis in a number of countries.17,26-33These four posters presented at the ERS International Congress 2019 demonstrate that dupilumab treatment is relatively well-tolerated and could significantly improve FEV1, symptoms, asthma control, quality of life, and reduce severe exacerbation risk in patients with uncontrolled asthma. This therapy offers an important new option for respiratory clinicians to manage their patients with uncontrolled asthma.
Abstract Objective Asthma is a syndrome that incorporates many immune phenotypes. The immunologic effects of subcutaneous immunotherapy (SCIT) exerts on allergic asthma remain still largely unknown. Here, we investigated the effects of SCIT on cytokine production and peripheral blood levels of lymphocyte subtypes in children with mite-induced moderate and severe allergic asthma.
Methods The study included 60 kids with mite-induced allergic asthma from 5 to 10 years old. All subjects had received antiasthmatic pharmacologic for 3 months at baseline. Half of the children were treated with SCIT combined with pharmacologic treatment named the SCIT group and the other half only with pharmacologic therapy named the no-SCIT group. Total asthma symptom score (TASS) and total medication score (TMS) were recorded. Flow cytometry was used to identify lymphocyte subtypes: type 2 innate lymphocytes (ILC2s), type 1 (Th1) and type 2 (Th2) helper T cells, T helper 17 (Th17) cells, and regulatory T (Treg) cells. ELISA, flow cytometry, and cytometric bead array were used to assess cytokines IL-13, IFN-γ, IL-4, IL-17, and TGF-β, at baseline and 3 and 6 months after study treatment in both groups of patients.
Results Both groups can significantly improve clinical symptoms in children with asthma. SCIT can significantly reduce asthma medication after 6 months of treatment. SCIT induced a significantly higher and progressive reduction in ILC2 percentage and IL-13 levels after 3 and 6 months of treatment compared with baseline and compared with no-SCIT patients. Significant differences were detected in the Th1/Th2 cell ratio and IFN-γ/IL-4 cytokine ratio between groups after 6 months of treatment. Similarly, the Th17/Treg ratio and IL-17/TGF-β ratio in the SCIT group were much lower than those in the no-SCIT group after 3-6 months of treatment.
Conclusion SCIT is a promising option to reduce the percentage of ILC2 and regulate Th1/Th2 and Th17/Treg immune balance in the peripheral blood of children with asthma.
PubMed comprises more than 30 million citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.
PubMed comprises more than 30 million citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.
Tolle Totum Lisa Ghent, ND Atopic diseases are a collection of problems that arise when the immune system has an exaggerated IgE-mediated response to what are normally harmless antigens.1 Atopic diseases include atopic dermatitis, allergic rhinitis, asthma, and food allergies, and are one of the...
Monoclonal Antibody Therapies for Atopic Dermatitis: Where Are We Now in the Spectrum of Disease Management? JCAD Online Editor | February 1, 2019 This ongoing column explores emerging treatment options, drug development trends, and pathophysiologic concepts in the field of dermatology. J Clin Aesthet Dermatol. 2019;12(2):39–43 by James Q. Del Rosso, DO Dr. Del Rosso is Research Director of JDR Dermatology Research in Las Vegas, Nevada; is with Thomas Dermatology in Las Vegas, Nevada; and is Adjunct Clinical Professor (Dermatology) with Touro University Nevada in Henderson, Nevada. FUNDING: There was no funding related to the development, writing, or publication of this article. DISCLOSURES: Dr. Del Rosso is a consultant, speaker, and/or researcher for several companies who market products used in the management of atopic dermatitis or have compounds under development. These include Almirall, Dermira, Galderma, Genentech, LaRoche Posay, Leo Pharma, Loreal, Ortho Dermatologics, Pfizer, Promius, Regeneron, Sanofi-Genzyme, Skinfix, Sonoma, Sun Pharma, and Taro. Abstract: Atopic dermatitis (AD) is a chronic disorder that requires thorough patient education and a therapeutic management strategy designed to control flares, decrease recurrences, and reduce pruritus. In cases that cannot be controlled by proper skin care and barrier repair, topical therapy, and avoidance of triggers, systemic therapy is often required to control flares and maintain remission. It is important for clinicians to avoid becoming overly dependent on the intermittent use of systemic corticosteroid therapy to control flares, without incorporating other treatment options that might more optimally control AD over time. This article provides an overview of systemic therapies, including conventional oral therapy options and injectable biologic agents, that modulate the immune dysregulation in AD. Major emphasis is placed on the monoclonal antibodies currently available (e.g., dupilumab) for the treatment of AD, as well as those in latter stages of development, with a focus on agents targeting IL-4 and/or IL-13. KEYWORDS: Atopic dermatitis, calcineurin inhibitors, phosphodiesterase-4 inhibitors, immunosuppressants, interleukin-4, interleukin-13 Many patients with atopic dermatitis (AD) are able to control their disease primarily with topical agents, including corticosteroids, calcineurin inhibitors, phosphodiesterase-4 (PDE4) inhibitors, moisturizers/barrier repair agents, wet wraps, and the avoidance of triggers.1,2 However, it is important to better define the word “control,” as AD is a chronic disorder characterized by marked flares of eczema and pruritus, variable periods of persistent eczema of lesser severity with itching, and complete remission, all of which vary in intensity, frequency, and duration among each individual affected by AD. Marked flares can often be mitigated with topical agents of adequate potency and duration, and, in selected cases, in conjunction with short courses of systemic corticosteroid (CS) therapy. The most difficult therapeutic challenges in AD are effective control of eczematous dermatitis (eczema) and pruritus, both of which are persistent but of a lesser overall severity, and the maintenance of remission after control of disease flares.1–5 Many patients with AD, including the parents/guardians of children with AD, deserve a discussion of what options exist beyond topical management alone and intermittent systemic CS therapy. This discussion often needs to be initiated by the clinician, as patients with AD or other chronic disorders depend on their clinician to direct them toward what is likely to be the most effective treatment for them at any given point in time. There are only so many oral CS courses or intramuscular CS injections a clinician can prescribe to help control AD flares without tipping the benefit versus risk balance toward too much risk. This same principle also applies to repeated use of topical CS therapy, which can progress to use so frequent that the risk for adverse effects is increased significantly. Skin barrier repair agents and steroid-sparing topical agents (e.g., pimecrolimus, tacrolimus, crisaborole) provide marked benefit in some cases of AD, especially on certain anatomic sites or when the affected body surface area (BSA) is not too extensive.1–3 However, most patients with AD would benefit from systemic therapies that are designed to achieve optimal suppression of AD, including eczematous dermatitis and/or pruritus. Daily diffuse application of a well-formulated moisturizer for skin barrier maintenance and the application of prescription topical therapies to persistent AD lesions remain part of the standard therapeutic regimen, especially for localized refractory and lichenified sites.1–6 Finding the optimal balance of therapeutic choices varies among individual patients and requires careful consideration of the overall clinical situation and specific patient-related factors, such as age, severity of AD signs and symptoms, and patient and clinician comfort levels with the treatments selected. Ultimately, the clinician should identify what is most likely to achieve an optimal level of control and express their treatment recommendations to the patient with realistic confidence and a proper benefit versus risk discussion. The time has come for clinicians treating AD to consider moving from a rescue approach for flares to treating AD as a chronic, inflammatory, cutaneous and systemic disorder by using therapies that more selectively suppress the underlying disease pathophysiology, effectively treat eczema and pruritus, mitigate flares, and sustain long-term control of the disease. While topical therapies to manage epidermal barrier dysfunction and inflammation of AD should remain an important component of the total management approach for patients with AD, clinicians would be prudent to also consider therapies with better short-term and long-term safety profiles than the conventional oral agents that are currently available. In this article, an overview of the current conventional oral systemic therapeutic options for atopic dermatitis are presented, followed by an overview of the new systemic therapeutic options for AD, namely monoclonal antibody agents, including the currently available agent, duplimab, and other agents in latter stages of development, with a focus on compounds targeting IL-4 and/or IL-13. Other monoclonal antibodies that have been studied and/or are currently under evaluation for treatment of AD, such mepolizumab (anti-IL-5), nemolizumab (anti-IL-31), and omalizumab (anti-IgE), as well as other drug classes, will be discussed in future installments of “What’s New in the Medicine Chest.” Conventional Systemic Therapeutic Options for Atopic Dermatitis—Oral Agents When patients with moderate-to-severe AD and their clinicians are considering systemic therapy for AD, a variety of treatment options are available.3,5–12 Prior to 2018, available systemic therapies for AD were primarily oral agents, such as cyclosporin, methotrexate, azathioprine, and mycophenolate mofetil, all of which appear to modulate the underlying pathophysiologic pathways that contribute to AD.3,6–8 Each of these agents has variable amounts of data available regarding its use in children and adults for treatment of AD.3,6–12 However, none of these oral agents are approved by the United States Food and Drug Administration (FDA) for the treatment of AD, and all exhibit immunosuppressant properties.3,8 Oral antihistamines have also been used as part of the treatment regimen for AD, primarily as an adjunctive therapy to help reduce pruritus and/or decrease interference with sleep (i.e., sedating antihistamines).12 It is important to note that chronic or frequent use of systemic CS is best avoided in children and adults due to the risk of several significant AEs.6,10–12 Cyclosporin. Among the conventional systemic oral agents used in the management of AD, cyclosporin appears to exhibit the fastest onset of efficacy, but its use is limited by its safety profile, which includes risks of nausea, cephalgia, hypertension, nephrotoxicity, sequelae of chronic immunosuppression, gingival hyperplasia, and drug interactions.6,8,10 Cyclosporin is primarily recommended for treatment-resistant and/or uncontrolled AD, after which patients are usually transitioned to a safer, long-term approach; continuous use of cyclosporin beyond 12 to 24 months generally is not advisable.6,8,10 Methotrexate. Methotrexate therapy, another conventional systemic oral treatment for AD, can exhibit efficacy in as little as 4 to 8 weeks, but, like cyclosporin, warrants careful monitoring due to potential adverse events (AEs); these include nausea, bone marrow suppression (including pancytopenia), hepatotoxicity, pulmonary fibrosis, potential sequelae of immunosuppression, drug interactions, and the need to avoid alcohol intake.6,8,10 As with cyclosporin, long-term use of methotrexate should likely be avoided. Azathioprine. Azathioprine is another conventional systemic oral treatment option for AD, but it is not usually considered an initial systemic option due to its slower onset of efficacy and potential toxicities. Potential AEs include bone marrow suppression, increased malignancy risk, other sequelae of immunosuppression, severe nausea/vomiting, abdominal pain, hepatotoxicity, drug hypersensitivity syndrome, and risk for drug-drug interactions (e.g., allopurinol).6,8,10 Mycophenolate mofetil. Finally, although data for use of mycophenolate mofetil as a treatment option for AD are more limited than cyclosporin data, mycophenolate mofetil appears to be the safest oral agent, when compared with cyclosporin, methotrexate, and azathioprine; it has an efficacy onset range of 4 to 12 weeks, making it a logical choice when transitioning patients to longer-term oral maintenance therapy after initial use of cyclosporin for treatment-refractory or severe AD. Potential AEs include gastrointestinal side effects, fatigue, hematologic changes, and potential sequelae of immunosuppression.6,8,10 Biologics for Treatment of Atopic Dermatitis Research is in progress evaluating a variety of injectable and/or oral agents, including PDE4 inhibitors, Janus kinase (JAK) inhibitors, cannabinoid receptor agonists, kappa-opioid receptor agonists, and agents that target thymic stromal lymphopoietin (TSLP).14–17 A systematic review and meta-analysis of published studies evaluating the efficacy of biologics in AD treatment (published in April 2018) reported good evidence, to date, regarding agents that inhibit IL-4 and/or IL-13; a relative lack of evidence supporting efficacy in AD was noted thus far in studies with biologics modulating other targets, such as omalizumab (anti-IgE), infliximab ((anti-tumor necrosis factor), ustekinumab (anti-IL-12/23), and rituximab (anti-B-cell).19 IL-4 and IL-13 are reported to play prominent roles in AD with inflammation in skin and/or blood, epidermal barrier impairment, pruritis, and susceptibility to infection (Figure 1).18 Monoclonal antibodies that inhibit the effects of various ILs (i.e., IL-4, IL 13, IL-5, IL-17, IL-22, IL-31, IL-33) are showing therapeutic promise for the treatment of AD. Monoclonal Antibody Interleukin-4 and Interleukin-13 Inhibitor Dupilumab. Dupilumab is an injectable human IgG4 monoclonal antibody that inhibits IL-4 and IL-13 cytokine responses, including the expression and/or release of proinflammatory cytokines, chemokines, and IgE; binding of dupilumab occurs with both Types I and II IL-4 alpha receptors, found on hematopoietic cells and keratinocytes, respectively.13,20,21 In March 2017, duplimab was FDA-approved for the treatment of moderate-to-severe AD in adult patients (aged ?18 years) in whom the disease has not been adequately controlled with prescription topical therapies or in cases where such therapies are not advisable. In October 2018, duplimab was also approved as an add-on maintenance treatment in adolescent and adult patients (aged ?12 years of age) for moderate-to-severe asthma with an eosinophilic phenotype or oral–corticosteroid-dependent asthma.13 13 The dosing regimens for AD and asthma might differ between patients; however, the common regimen includes a 600mg loading dose (2×300mg2/mL injections), followed by a single 300mg injection every two weeks; with regard to asthma, dupilumab is not indicated or recommended for relief of acute bronchospasm or status asthmaticus.13 Clinical response. In the pivotal randomized, controlled trials (RCTs) evaluating dupilumab for AD, which included a Phase II, dose-ranging study, two 16-week monotherapy RCTs versus placebo, and a 52-week RCT that allowed for combination use with a topical CS, 1,472 subjects received dupilumab, with 739 treated for more than 52 weeks.13,20–22 Efficacy was substantiated by improvements in several assessment parameters versus placebo, both clinically and statistically, including positive changes in Investigator Global Assessment (IGA), marked reductions in Eczema Area Severity Index (EASI) scores, and significant decreases in pruritus, with clinical improvements sustained in the 52-week study without any loss of efficacy.13,20,21 Many patients reported a definite improvement in eczema and pruritus within the first few injections of dupilumab; however, onset of efficacy occurred later in some individuals (within 2 to 3 months after starting therapy). In patients currently undergoing other systemic therapies for severe AD (e.g., cyclosporin, methotrexate) who are starting dupilumab, researchers recommended that therapy be bridged without abrupt discontinuation of the patients’ previous therapy in order to avoid rebound exacerbation of AD while waiting for the clinical effects of dupilumab to manifest. Clinicians should then determine, on a case-by-case basis, the optimal approach to take when tapering patients off previous systemic therapy. 13,20–22 Safety. During the RCTs, no significant changes occurred in laboratory test results of the study subjects; thus, laboratory monitoring was not required by the FDA to be included in the approved product labeling for dupilumab.13 The most common AEs observed in the RCTs were injection site reactions and conjunctivitis (10–16% in active arms vs. 2–9% in placebo arms); separately, hypersensitivity reactions (e.g., urticaria, serum sickness-type reactions) were observed in less than one percent of the active-treatment study subjects.13,20–22 Most cases of conjunctivitis did not require stopping dupilumab, and were treated with topical ophthalmic lubricants and anti-inflammatory agents, and appeared to resolve or markedly improve despite continued use of the drug; however, some cases were severe enough to require discontinuation of dupilumab therapy.13,20–23 New onset or worsening ocular symptoms warrant referral to an ophthalmologist for evaluation.13,23 Ocular abnormalities inherent to AD that are unrelated to dupilumab use, including conjunctivitis and blepharitis, are not uncommon; the cause of the conjunctivitis that occurs related to use of dupilumab is not fully understood.24 Dupilumab and concomitant systemic therapy. A complete review of publications on dupilumab are beyond the scope of this article; however, a few articles provide information on the effective and safe use of dupilumab in a subpopulation of patients previously treated with cyclosporin. In a 16-week RCT study of adults with AD (N=390), responses to dupilumab therapy in conjunction with a medium-potency topical CS were assessed in subjects with inadequate response to or intolerance of oral cyclosporin or those in whom it was clinically inadvisable to use cyclosporin.25 Researchers reported that, following individual clinical assessment, topical CS therapy was safely tapered and/or stopped in many patients. Results of the study indicate that dupilumab with concomitant topical CS therapy (when needed) might signi?cantly improve signs and symptoms of AD and patient quality of life, with no new safety signals noted by the investigators.25 Infection risk. Eight RCTs that assessed outcomes with dupilumab versus placebo in patients with AD were analyzed by meta-analysis, with an emphasis on the incidence of AEs.26 Regarding infection rate risks, dupilumab had a lower risk of skin infection (risk ratio: 0.54), compared with placebo, with similar to negligible risks noted for nasopharyngitis, urinary tract infection, upper respiratory tract infection, and herpes virus infection. These observations further support the concept that dupilumab is immunomodulatory through the mitigation of IL-4 and IL-13 signaling, without a significant increased risk of infection, which can occur with immunosuppressive agents. It is important to note that by counteracting certain immune dysfunctions that lead to epidermal barrier impairment and cascades of Th2-driven humoral and cutaneous inflammation, dupilumab might help to normalize certain immunologic processes that are dysregulated in AD. Continued research and pharmacovigilance will help elucidate the efficacy and safety factors associated with dupilumab in greater detail. Monoclonal Antibody Interleukin-13 Inhibitors Lebrikizumab. Lebrikizumab is an injectable monoclonal antibody that exhibits high-affinity binding to soluble IL-13, thus preventing pro-inflammatory signaling by inhibiting heterodimerization of the IL-13 alpha/IL-4 alpha complex.27 In a preliminary Phase II, dose/frequency-ranging 12-week RCT, 209 adults with moderate-to-severe AD were treated with one of three dosing regimens of active drug versus placebo. Following a two-week “run in” with medium-potency topical CS therapy (triamcinolone acetonide 0.1% applied twice daily with lower potency hydrocortisone 2.5% allowed for facial AD), patients were randomized to receive lebrikizumab 125mg every four weeks, a single dose of lebrikizumab (125mg or 250mg), or placebo. Primary efficacy endpoint was the percent of subjects achieving a 50-percent reduction in EASI at Week 12.27 Investigators reported that patients in the lebrikizumab 125mg every four weeks achieved markedly superior results compared with those in the single-dose lebrikizumab group and those in the control group. Superiority to placebo was also observed in other parameters (e.g., SCORAD-50, reduction in BSA). An increasing trajectory of favorable response based on the EASI-50 results was noted at the end of the study (12 weeks) in the group receiving lebrikizumab 125mg every four weeks. Overall, the safety profile was favorable in all study arms.27 Data from this early study in AD suggest that lebrikizumab for AD shows promise as a treatment for AD. Additional research is needed on whether further increases in the dose per injection or treatment frequency (i.e., interval between doses) and use of a loading dose improve lebrikisumab’s efficacy, without affecting safety, for initial and maintenance therapy for AD. Tralokinumab. Tralokinumab, an IgG4 human monoclonal antibody that specifically neutralizes IL-13, was evaluated in a Phase IIb, dose-ranging, 12-week RCT of adult subjects (N=202) with moderate-to-severe AD.28,29 Patients were randomized to receive a 45mg (n=50), 150mg (n=51), or 300mg (n=51) subcutaneous injection of tralokinumab or placebo (n=50) every two weeks after a two-week “run in” with a mid-strength topical CS.29 Several efficacy parameters were assessed, with the coprimary endpoints being the change from baseline in total EASI score at Week 12 and the percent of IGA responders at Week 12 versus baseline (IGA score of clear/almost clear + at least a 2-grade reduction). Overall, AEs were generally similar among all study arms. Interestingly, six of the 204 subjects (2.9%) exhibited treatment-emergent conjunctivitis during the study (placebo, n= 2 [3.9%], tralokinumab 45mg, n =1 [2.0%], and tralokinumab 150mg, n=3 [5.9%]). Another important observation was that the serum level of dipeptidyl peptidase 4 might serve as a predictive biomarker for patients who could benefit from tralokinumab therapy.29 As with lebrikizumab, initial results with this agent for AD are encouraging and hopefully will be further supported by additional RCTs. Summary Points AD is a chronic disorder that, from the outset, requires a management strategy designed to control flares, decrease recurrences, and reduce pruritus. Cases of AD that are not adequately controlled with conventional measures and topical therapy can usually be effectively treated with incorporation of systemic therapy. It is important to assess the benefits versus the risks of various options in each case. It is also important to avoid becoming dependent on the intermittent use of intramuscular and/or oral corticosteroid therapy to control flares. Incorporation of other treatment options that can more optimally control AD over time are recommended. With the use of oral immunosuppressive agents such as cyclosporin, methotrexate, mycophenolate mofetil, and azathioprine, baseline and periodic laboratory and clinical monitoring are very important. Each of these agents carries its own significant “side effects baggage” to keep track of with relevant testing. Dupilumab is a newer option shown to be effective in markedly decreasing signs and symptoms of AD. In the opinion of the author, based on the available data and experiences thus far, dupilumab therapy offers a more favorable overall safety profile in comparison with the available oral systemic agents. Lebrikizumab and tralokinumab, both inhibitors of IL-13, are currently under development and show promise based on preliminary studies in adult patients with moderate-to-severe AD. References Eichenfield LF, Tom WL, Berger TG, et al. Guidelines of care for the management of atopic dermatitis: section 2—management and treatment of atopic dermatitis with topical therapies. J Am Acad Dermatol. 2014;71(1):116–132. Sidbury R, Tom WL, Bergman JN, et al. Guidelines of care for the management of atopic dermatitis: section 4—prevention of disease flares and use of adjunctive therapies and approaches. J Am Acad Dermatol. 2014;71(6):1218–1233. Del Rosso JQ, Harper J, Kircik L, et al. Consensus recommendations on adjunctive topical management of atopic dermatitis. J Drugs Dermatol. 2018;17(10):1070–1076. Czarnowicki T, Krueger JG, Guttman-Yassky E. Novel concepts of prevention and treatment of atopic dermatitis through barrier and immune manipulations with implications for the atopic march. J Allergy Clin Immunol. 2017;139(6):1723–1734. Thomson J, Wernham AGH, Williams HC. Long-term management of moderate-to-severe atopic dermatitis with dupilumab and concomitant topical corticosteroids (LIBERTY AD CHRONOS): a critical appraisal. Br J Dermatol. 2018;178(4):897–902. Prezzano JC, Beck LA. Long-term treatment of atopic dermatitis. Dermatol Clin. 2017;35(3):335–349. Admani S, Eichenfield LF. Atopic dermatitis. In: Lebwohl MG, Berth-Jones J, Heymann WR, Coulson I, Eds. Treatment of Skin Disease: Comprehensive Therapeutic Strategies. 4th edition. Philadelphia, PA: Elsevier-Saunders; 2014: 52–60. Akhavan A, Rudikoff D. Systemic agents for the treatment of atopic dermatitis. In: Rudikoff D, Cohen SR, Scheinfeld N (eds). Atopic Dermatitis and Eczematous Disorders. Boca Raton, FL: CRC Press/Taylor & Francis Group; 2014:187–199. Dhadwal G, Albrecht L, Gniadecki R, et al. Approach to the assessment and management of adult patients with atopic dermatitis: a consensus document. section IV: treatment options for the management of atopic dermatitis. J Cutan Med Surg. 2018;22(1 Suppl):21S–29S. Mayba J, Gooderham M. Oral agents for atopic dermatitis: current and in development. In: Yamauchi PS (ed). Biologic and Systemic Agents in Dermatology. Cham, Switzerland: Springer International Publishing; 2018:319–330. Wolverton SE. Systemic corticosteroids. In: Wolverton SE (ed). Comprehensive Dermatologic Drug Therapy, 3rd edition. Philadelphia, PA: Elsevier-Saunders; 2013:143–168. Thomas K, Bath-Hextall F, Ravenscroft J, et al. Atopic eczema. In: Williams H. Bigby M, Diepgen T, et al (eds). Evidence-Based Dermatology, 2nd edition. Malden, MA: Blackwell Publishing; 2008: 128–163. Regeneron Pharmaceuticals and Sanofi-Genzyme. Dupixent (dupilumab) Injection, Full Prescribing Information. October 2018. Kusari A, Han AM, Schairer D, et al. Atopic dermatitis: new developments. Dermatol Clin. 2019;37(1):11–20. Patel N, Strowd LC. The future of atopic dermatitis treatment. Adv Exp Med Biol. 2017;1027:185–210. Edwards T, Patel NU, Blake A, et al. Insights into future therapeutics for atopic dermatitis. Expert Opin Pharmacother. 2018;19(3):265–278. Napolitano M, Marasca C, Fabbrocini G, et al. Adult atopic dermatitis: new and emerging therapies. Expert Rev Clin Pharmacol. 2018;11(9):867–878. Silverberg JI, Kantor R. The role of interleukins 4 and/or 13 in the pathophysiology and treatment of atopic dermatitis. Dermatol Clinic. 2017;35(3):327–334. Snast I, Reiter O, Hodak E, et al. Are biologics efficacious in atopic dermatitis: a systematic review and meta-analysis. Am J Clin Dermatol. 2018;19(2):145–165. Simpson EL, Bieber T, Guttman-Yassky E, et al. Two Phase 3 trials of dupilumab versus placebo in atopic dermatitis. N Engl J Med. 2016;375(24):2335–2348. Gooderham MJ, Hong HC, Eshtiaghi P, et al. Dupilumab: a review of its use in the treatment of atopic dermatitis. J Am Acad Dermatol. 2018;78(3S1):S28–S36. Hajar T, Hill E, Simpson E. Biologics for treatment of atopic dermatitis. In: Yamauchi PS (ed). Biologic and Systemic Agents in Dermatology. Cham, Switzerland: Springer International Publishing; 2018: 309–317. Treister AD, Kraff-Cooper C, Lio PA. Risk factors for dupilumab-associated conjunctivitis in patients with atopic dermatitis. JAMA Dermatol. 2018;154(10):1208–1211. Thyssen JP, Toft PB, Halling-Overgaard AS, et al. Incidence, prevalence, and risk of selected ocular disease in adults with atopic dermatitis. J Am Acad Dermatol. 2017;77(2):280–286. de Bruin-Weller M, Thaci D, Smith CH, et al. Dupilumab with concomitant topical corticosteroid treatment in adults with atopic dermatitis with an inadequate response or intolerance to ciclosporin A or when this treatment is medically inadvisable: a placebo-controlled, randomized phase III clinical trial (LIBERTY AD CAFE). Br J Dermatol. 2018;178(5): 1083–1101. Ou Z, Chen C, Chen A, et al. Adverse events of Dupilumab in adults with moderate-to-severe atopic dermatitis: a meta-analysis. Int Immunopharmacol. 2018;54:303–310. Simpson E, Flohr C, Eichenfield LE, et al. Efficacy and safety of lebrikizumab (an anti-IL-13 monoclonal antibody) in adults with severe moderate-to-severe atopic dermatitis inadequately controlled by topical corticosteroids: a randomized, placebo-controlled phase II trial (TREBLE). J Am Acad Dermatol. 2018;78(5):863–871. May RD, Monk PD, Cohen ES, et al. Preclinical development of CAT-354, an IL-13 neutralizing antibody, for the treatment of severe uncontrolled asthma. Br J Pharmacol. 2012;166(1):177–193. Wollenberg A, Howell MD, Guttman-Yassky E, et al. A Phase 2b dose-ranging efficacy and safety study of tralokinumab in adult patients with moderate to severe atopic dermatitis (AD). Poster presentation. Orlando, FL: American Academy of Dermatology Meeting. 3–7 Mar 2017. Tags: Atopic Dermatitis, calcineurin inhibitors, immunosuppressants, interleukin-13, interleukin-4, phosphodiesterase-4 inhibitors Category: Atopic Dermatitis, Past Articles, What's New in the Medicine Chest
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