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Treatment of itch in atopic dermatitis
Abstract
Atopic dermatitis (AD) is a disease that affects millions of patients worldwide and is characterized by debilitating itch. The pathophysiology of pruritus in AD consists of multiple players, including pruritogens, unique receptors, and ion channels found on unmyelinated C-nerve fibers. The sensation of the itch is also perpetuated by the disrupted epidermal skin barrier characterizing this disease, as well as sensitization phenomena in both the peripheral and central nervous systems. Thankfully, treatment options for atopic itch are abundant. These range from topical therapies, to systemic immunomodulators, to systemic therapies, which attenuate itch transmission in the nervous system. Topical treatment of itch includes a variety of medications including corticosteroids, calcineurin antagonists, and phosphodiesterase-4 inhibitors. Systemic treatment includes oral prednisone, methotrexate, cyclosporine, azathioprine, and mycophenolate mofetil. Moisturizing topical treatments remain one of the mainstays of treatment. Emerging therapies, such as novel monoclonal antibodies that are directed against itch mediators, such as interleukin-31, as well as drugs targeting the Janus kinase-STAT system, are promising treatments that will hopefully improve the lives of many patients.
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Background
Pruritus (itch) is a cardinal symptom in atopic dermatitis (AD).
Objective
Evaluate the timing and effect of dupilumab on itch.
Methods
Analysis of data from 1,505 patients with moderate-to-severe AD included in four randomized controlled studies, treated for up to 52 weeks. Adults received dupilumab 300 mg every 2 weeks (q2w) or placebo monotherapy (SOLO1-2; NCT02277743, NCT02277769), with concomitant topical corticosteroids (CHRONOS, NCT02260986); adolescents (≥12–<18 years) were treated with dupilumab monotherapy q2w (200 mg baseline weight <60 kg, 300 mg ≥60 kg) or placebo (AD ADOL NCT03054428).
Results
Dupilumab showed significant rapid improvements from baseline in daily Peak Pruritus Numerical Rating Scale (PP-NRS) scores vs placebo, by day 2 in adults and day 5 in adolescents. At treatment end, dupilumab vs placebo/control had greater least-squares mean percent change from baseline in the weekly average of PP-NRS scores: SOLO −47.5% vs −20.5%; AD-ADOL −47.9% vs −19.0%; CHRONOS −57.3% vs −30.9% (P < .0001 for all).
Limitations
Short duration of monotherapy trials (16 weeks).
Conclusion
Across four randomized trials, dupilumab treatment showed rapid and sustained improvements in the magnitude of itch, starting with first dose; responses progressively increased and were sustained through to the end of treatment, up to 1 year.
Importance
Interleukin 13 (IL-13) is a central pathogenic mediator driving multiple features of atopic dermatitis (AD) pathophysiology.
Objective
To evaluate the efficacy and safety of lebrikizumab, a novel, high-affinity, monoclonal antibody targeting IL-13 that selectively prevents formation of the IL-13Rα1/IL-4Rα heterodimer receptor signaling complex, in adults with moderate to severe AD.
Design, Setting, and Participants
A phase 2b, double-blind, placebo-controlled, dose-ranging randomized clinical trial of lebrikizumab injections every 4 weeks or every 2 weeks was conducted from January 23, 2018, to May 23, 2019, at 57 US centers. Participants were adults 18 years or older with moderate to severe AD.
Interventions
Patients were randomized 2:3:3:3 to placebo every 2 weeks or to subcutaneous injections of lebrikizumab at the following doses: 125 mg every 4 weeks (250-mg loading dose [LD]), 250 mg every 4 weeks (500-mg LD), or 250 mg every 2 weeks (500-mg LD at baseline and week 2).
Main Outcomes and Measures
The primary end point was percentage change in the Eczema Area and Severity Index (EASI) (baseline to week 16). Secondary end points for week 16 included proportion of patients achieving Investigator’s Global Assessment score of 0 or 1 (IGA 0/1); EASI improvement of at least 50%, 75%, or 90% from baseline; percentage change in the pruritus numeric rating scale (NRS) score; and pruritus NRS score improvement of at least 4 points. Safety assessments included treatment-emergent adverse events.
Results
A total of 280 patients (mean [SD] age, 39.3 [17.5] years; 166 [59.3%] female) were randomized to placebo (n = 52) or to lebrikizumab at doses of 125 mg every 4 weeks (n = 73), 250 mg every 4 weeks (n = 80), or 250 mg every 2 weeks (n = 75). Compared with placebo (EASI least squares mean [SD] percentage change, −41.1% [56.5%]), lebrikizumab groups showed dose-dependent, statistically significant improvement in the primary end point vs placebo at week 16: 125 mg every 4 weeks (−62.3% [37.3%], P = .02), 250 mg every 4 weeks (−69.2% [38.3%], P = .002), and 250 mg every 2 weeks (−72.1% [37.2%], P < .001). Differences vs placebo-treated patients (2 of 44 [4.5%]) in pruritus NRS improvement of at least 4 points were seen as early as day 2 in the high-dose lebrikizumab group (9 of 59 [15.3%]). Treatment-emergent adverse events were reported in 24 of 52 placebo patients (46.2%) and in lebrikizumab patients as follows: 42 of 73 (57.5%) for 125 mg every 4 weeks, 39 of 80 (48.8%) for 250 mg every 4 weeks, and 46 of 75 (61.3%) for 250 mg every 2 weeks; most were mild to moderate and did not lead to discontinuation. Low rates of injection-site reactions (1 of 52 [1.9%] in the placebo group vs 13 of 228 [5.7%] in all lebrikizumab groups), herpesvirus infections (2 [3.8%] vs 8 [3.5%]), and conjunctivitis (0% vs 6 [2.6%]) were reported.
Conclusions and Relevance
During 16 weeks of treatment, lebrikizumab provided rapid, dose-dependent efficacy across a broad range of clinical manifestations in adult patients with moderate to severe AD and demonstrated a favorable safety profile. These data support the central role of IL-13 in AD pathophysiology. If these findings replicate in phase 3 studies, lebrikizumab may meaningfully advance the standard of care for moderate to severe AD.
Trial Registration
ClinicalTrials.gov Identifier: NCT03443024
Atopic dermatitis (AD) in older adults (elderly AD) has recently emerged as a newly defined subgroup of AD. When selecting treatment options, clinical characteristics of elderly AD and age-specific factors of older patients must be considered. As in other age groups, regular application of moisturizers in combination with topical corticosteroids and calcineurin inhibitors, adjunctive administration of oral antihistamines/anti-allergic drugs, and avoidance of exacerbating factors comprise basic treatments for elderly AD. For moderate-to-severe cases and/or in those with a decreased ability to use topical treatments, powerful anti-inflammatory treatments may become necessary as additional treatment options. While low-dose oral corticosteroids may be useful for cases of elderly AD, careful attention should be paid to adverse effects. Oral cyclosporine (ciclosporin) is less commonly used due to the increased risk of malignancy and organ toxicity in older patients with AD. Narrow-band ultraviolet B phototherapy may also be useful for older patients, although the necessity of frequent hospital visits for irradiation therapy may become a burden of disease for such patients. As a biologic, dupilumab therapy markedly improves skin lesions and itch in older patients with AD, with a rapid response and non-serious adverse effects. Nevertheless, injection pain, expensive medical care, and regular follow-up every 2 weeks are disadvantages of dupilumab therapy. Therefore, clinicians must prioritize individualized treatment options that will reduce the burden of disease for cases of elderly AD.
Background:
Atopic dermatitis is a chronic inflammatory skin disease characterized by pruritic skin lesions.
Objective:
This study evaluated the safety and efficacy of multiple doses of the selective Janus kinase 1 inhibitor upadacitinib in patients with moderate-to-severe atopic dermatitis.
Methods:
In the 16-week, double-blind, placebo-controlled, parallel-group, dose-ranging portion of this 88-week trial in 8 countries (ClinicalTrials.gov, NCT02925117; ongoing, not recruiting), adults with moderate-to-severe disease and inadequate control by topical treatment were randomized 1:1:1:1, using an interactive response system and stratified geographically, to once-daily upadacitinib oral monotherapy 7.5, 15, or 30 mg or placebo. The primary endpoint was percentage improvement in Eczema Area and Severity Index from baseline at week 16. Efficacy was analyzed by intention-to-treat in all randomized patients. Safety was analyzed in all randomized patients who received study medication, based on actual treatment.
Results:
Patients (N=167) enrolled from November 21, 2016, to April 20, 2017. All were randomized and analyzed for efficacy (each upadacitinib group, n=42; placebo, n=41); 166 were analyzed for safety (each upadacitinib group, n=42; placebo, n=40). The mean (standard error) primary efficacy endpoint was 39% (6.2%), 62% (6.1%), and 74% (6.1%) for the upadacitinib 7.5-, 15-, and 30-mg groups, respectively, versus 23% (6.4%) for placebo (P=0.03, <0.001, and <0.001). Serious adverse events occurred in 4.8% [2/42], 2.4% [1/42], 0% [0/42] of upadacitinib groups (vs 2.5% [1/40] for placebo).
Conclusion:
A dose-response relationship was observed for upadacitinib efficacy; the 30-mg once-daily dose showed the greatest clinical benefit. Dose-limiting toxicity was not observed.
Itch is a defining symptom of atopic dermatitis. Crosstalk between keratinocytes, the immune system and non-histaminergic sensory nerves is responsible for the pathophysiology of chronic itch in atopic dermatitis. An expanding understanding of the contribution of the nervous system and its interaction with immune pathways in atopic itch are helping to identify new therapeutic strategies. © 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.
Barrier damage, dry skin and itch are intricately linked and form the basis of many common skin diseases. Damage from environmental insults, or genetic or inflammatory causes, can impair the skin barrier, resulting in an increase in transepidermal water loss and activation of itch-associated nerve fibres. The itch-scratch cycle can perpetuate skin barrier damage and itch. Topical therapeutic strategies are utilised to overcome dry skin and itch, primarily in the form of emollients. Recent advances in our understanding of the mechanisms underlying itch have enabled the development of new topical therapies, which may be incorporated into existing treatment regimes. Ultimately, treatment of dry skin and itch must be highly tailored to the individual according to their needs.
Background:
Nemolizumab targets the IL-31 receptor α subunit involved in atopic dermatitis (AD) pathogenesis.
Objective:
We sought to evaluate a new dosing strategy of nemolizumab in patients with AD.
Methods:
We performed a 24-week, randomized, double-blind, multicenter study of nemolizumab (10, 30, and 90 mg) subcutaneous injections every 4 weeks versus placebo, with topical corticosteroids in adults with moderate-to-severe AD, severe pruritus, and inadequate control with topical treatment (n = 226). The Eczema Area and Severity Index (EASI), the peak pruritus (PP) numeric rating scale (NRS), and the Investigator's Global Assessment (IGA) were assessed. Standard safety assessments were performed.
Results:
Nemolizumab improved EASI, IGA, and/or NRS-itch scores, with the 30-mg dose being most effective. Nemolizumab (30 mg) reduced EASI scores versus placebo at week 24 (-68.8% vs -52.1%, P = .016); significant differences were observed by week 8 (P ≤ .01). With significant improvement (P = .028) as early as week 4, IGA 0/1 rates were higher for 30 mg of nemolizumab versus placebo at week 16 (33.3% vs 12.3%, P = .008) but not week 24 because of an increased placebo/topical corticosteroid effect (36.8% vs 21.1%, P = .06). PP-NRS scores were improved for 30 mg of nemolizumab versus placebo at week 16 (-68.6% vs -34.3%, P < .0001) and week 24 (-67.3% vs -35.8%, P < .0001), with a difference by week 1 (P < .001). NRS response rates (≥4-point decrease) were greater for 30 mg of nemolizumab versus placebo at week 16 (P ≤ .001) and week 24 (P ≤ .01). Nemolizumab was safe and well tolerated. The most common adverse events were nasopharyngitis and upper respiratory tract infection.
Conclusions:
Nemolizumab resulted in rapid and sustained improvements in cutaneous signs of inflammation and pruritus in patients with AD, with maximal efficacy observed at 30 mg. Nemolizumab had an acceptable safety profile.
Introduction
The impact of crisaborole ointment, a nonsteroidal phosphodiesterase 4 inhibitor for the treatment of mild to moderate atopic dermatitis (AD), on quality of life (QoL) was assessed in two identically designed phase 3 studies (AD-301: NCT02118766; AD-302: NCT02118792, both at http://www.clinicaltrials.gov).
Methods
In both studies, patients aged ≥ 2 years with mild to moderate AD per the Investigator’s Static Global Assessment were randomly assigned 2:1 to receive crisaborole or vehicle twice daily for 28 days. QoL was assessed using the Children’s Dermatology Life Quality Index (CDLQI) (2–15 years), the Dermatology Life Quality Index (DLQI) (≥ 16 years), and the Dermatitis Family Impact Questionnaire (DFI) (parents/caregivers/family of patients aged 2–17 years). Established QoL score severity bands provided clinical context.
Results
Greater mean improvement in QoL was observed in crisaborole-treated patients than in vehicle-treated patients at day 29 [mean change from baseline (∆BL), CDLQI: − 4.6 vs. − 3.0; P < 0.001; DLQI: − 5.2 vs. − 3.5; P = 0.015]. At baseline, more than half the patients had a “moderate effect” or higher of AD on QoL. At day 29, there was a trend toward more crisaborole- than vehicle-treated patients having “small effect” to “no effect”, The QoL of parents/caregivers/family improved more for crisaborole-treated than for vehicle-treated patients (∆BL, DFI: − 3.7 vs. − 2.7; P = 0.003).
Conclusion
Crisaborole treatment results in clinically meaningful improvement in QoL for patients and their parents/caregivers/families.
Trial Registration
AD-301: http://www.clinicaltrials.gov, NCT02118766; AD-302: http://www.clinicaltrials.gov, NCT02118792.
Funding
Anacor Pharmaceuticals, Inc., a wholly owned subsidiary of Pfizer Inc., New York, NY.
The objective of this study was to explore characteristics of pruritus in atopic dermatitis (AD) in relation to the severity of AD. A web-questionnaire was used, which included the Patient-Oriented SCORing Atopic Dermatitis index, the 5-D itch scale and the Brest questionnaire. A total of 170 participants were included (86.5% women, mean age 30.9 years). Severity [AQ2] was mild for 8.2% of patients, moderate for 38.2% and severe for 53.5%. Mean 5-D itch scale was 13.2. The mean intensity of pruritus was 5.8, and mean sleep loss was 4.7 (from 0 to 10). The participants frequently described burning (61.8%) and stinging (58.8%); these symptoms suggest a neuropathic component. Pruritus was worse in severe AD compared with moderate AD, exhibiting a higher impact on sleep and more associated symptoms. The majority of participants reported sleep disturbance as a result of pruritus. The characteristics of pruritus varied depending on the severity of AD.
Background:
The patient-burden and quality of life (QOL) impact of atopic dermatitis (AD) in the United States population is not wellestablished.
Objective:
To elucidate the patient-burden of AD in the US population.
Methods:
A cross-sectional, population-based study of 602 adults was performed. AD was determined using modified UK Diagnostic Criteria for AD. AD severity was assessed using self-reported global AD severity, Patient-Oriented Eczema Measure (POEM), Patient-Oriented Scoring AD (POSCORAD), PO-SCORAD-itch and sleep. QOL was assessed using short-form (SF-)12 mental and physical health scores and Dermatology Life Quality Index (DLQI).
Results:
Adults with AD reported higher proportions of having only fair/poor overall health (25.8% vs. 15.8%), being somewhat/very dissatisfied with life (16.7% vs. 11.4%), lower weighted mean [SD] SF-12 mental (45.9 [9.9] vs. 50.9 [9.2]) and physical health subscores (53.0 [2.5] vs. 53.5 [2.3]) and higher DLQI (4.9 [6.5] vs. 1.1 [2.8]). In multivariable regression models adjusting for socio-demographics and multiple comorbid health disorders, there were significant stepwise decreases by AD severity (self-reported, POEM, PO-SCORAD) of overall health, life satisfaction, SF-12 mental health and increases of DLQI scores. SF-12 physical health scores were only associated with moderate AD. Concurrently severe PO-SCORAD, POEM and/or PO-SCORAD-itch was associated with very low mean SF-12 mental health (34.7) and high DLQI scores (24.7). AD commonly limited lifestyle (51.3%), led to avoidance of social interaction (39.1%) and impacted activities (43.3%).The most burdensome AD symptoms were itch (54.4%), excessive dryness/scaling (19.6%) and red/inflamed skin (7.2%).
Conclusion:
These data support the heavy burden that AD places on patients, particularly moderate and severe AD.
Background:
Interleukin (IL)-13 has an important role in atopic dermatitis (AD) pathogenesis. Tralokinumab is a fully human monoclonal antibody that potently and specifically neutralizes IL-13.
Objective:
To evaluate the efficacy and safety of tralokinumab in adults with moderate to severe AD.
Methods:
In this phase 2b study (NCT02347176), 204 adults were randomized 1:1:1:1 to receive subcutaneous tralokinumab 45 mg, 150 mg, or 300 mg, or placebo, every 2 weeks for 12 weeks, with concomitant topical glucocorticoids. Co-primary endpoints were change from baseline in Eczema Area Severity Index (EASI) and percentage of participants with an Investigator's Global Assessment (IGA) response (0/1 score and reduction of two grades or more from baseline) at week 12.
Results:
At week 12, tralokinumab 300 mg significantly improved change from baseline in EASI versus placebo (adjusted mean difference [95% confidence interval]: -4.9 [-8.76 to -1.13]; P = 0.01), and a greater percentage of participants achieved an IGA response: 26.7% versus 11.8%. Greater responses were found in participants with higher concentrations of biomarkers of increased IL-13 activity. Tralokinumab 300 mg-treated participants demonstrated improvements in Scoring of Atopic Dermatitis, Dermatology Life Quality Index, and pruritus numeric rating scale (7-day mean score) versus placebo. Upper respiratory tract infection was the most frequent treatment-emergent adverse event reported as related to study drug in the placebo (3.9%) and pooled tralokinumab groups (3.9%).
Conclusions:
Tralokinumab treatment was associated with early and sustained improvements in AD symptoms, and an acceptable safety and tolerability profile, thereby providing evidence for targeting IL-13 in AD.
Pruritus occurs in all patients with atopic dermatitis and requires quick relief to reduce disease exacerbation and improve quality of life. Crisaborole ointment is a non-steroidal phosphodiesterase 4 inhibitor for the treatment of mild-to-moderate atopic dermatitis. This post hoc analysis explores crisaborole ointment for early relief of pruritus in patients with mild to moderate atopic dermatitis from 2 phase III studies. Patients received crisaborole or vehicle twice daily for 28 days. Pruritus was graded on a 4-point scale of none (0) to severe (3). Early improvement in pruritus required a score of none (0) or mild (1), with a ≥ 1-grade improvement from baseline on day 6. Significantly more patients experienced early improvement in pruritus with crisaborole than with vehicle (56.6% vs 39.5%; p < 0.001), including at earliest assessment (day 2, 34.3% vs 27.3%; p = 0.013). Crisaborole is a topical treatment option that can rapidly relieve atopic dermatitis-associated pruritus.
Moisturizer is a major component of basic daily skin care, particularly in presence of epidermal barrier alteration and reduced epidermal water content. It is an important part of a dermatologist's strategy to maintain skin health as well as treating various dermatoses which co-exist with skin dryness, linked to impaired skin barrier function such as in atopic disorder as well as other types of dermatitis. Mastering the knowledge regarding action mechanism, application, dosage, adverse effects as well as specific clinical usage of moisturizers is must for a dermatologist, in order to support the capability to recommend their use, particularly for therapeutic purposes, in accordance with evidence-based medicine. This review is aimed to discuss the use of moisturizer both as skin health maintenance as well as a definitive or adjuvant therapy, particularly for many kinds of dermatitis.
Background:
Additional topical treatments for atopic dermatitis (AD) are needed that provide relief while minimizing risks.
Objective:
We sought to assess the efficacy and safety of crisaborole ointment, a phosphodiesterase 4 inhibitor, in two phase III AD studies (AD-301: NCT02118766; AD-302: NCT02118792).
Methods:
Two identically designed, vehicle-controlled, double-blind studies enrolled and randomly assigned (2:1, crisaborole:vehicle) patients aged 2 years or older with an Investigator's Static Global Assessment (ISGA) score of mild or moderate for twice-daily application for 28 days. The primary end point was ISGA score at day 29 of clear (0)/almost clear (1) with 2-grade or greater improvement from baseline. Additional analyses included time to success in ISGA score, percentage of patients achieving clear/almost clear, reduction in severity of AD signs, and time to improvement in pruritus.
Results:
More crisaborole- than vehicle-treated patients achieved ISGA score success (clear/almost clear with ≥2-grade improvement; AD-301: 32.8% vs 25.4%, P = .038; AD-302: 31.4% vs 18.0%, P < .001), with a greater percentage with clear/almost clear (51.7% vs 40.6%, P = .005; 48.5% vs 29.7%, P < .001). Crisaborole-treated patients achieved success in ISGA score and improvement in pruritus earlier than those treated with vehicle (both P ≤ .001). Treatment-related adverse events were infrequent and mild to moderate in severity.
Limitations:
Short study duration was a limitation.
Conclusions:
Crisaborole demonstrated a favorable safety profile and improvement in all measures of efficacy, including overall disease severity, pruritus, and other signs of AD.
In this review, we discuss the importance of capsaicin to the current understanding of neuronal modulation of pain and explore the mechanisms of capsaicin-induced pain. We will focus on the analgesic effects of capsaicin and its clinical applicability in treating pain. Furthermore, we will draw attention to the rationale for other clinical therapeutic uses and implications of capsaicin in diseases such as obesity, diabetes, cardiovascular conditions, cancer, airway diseases, itch, gastric, and urological disorders.
Background:
Phosphodiesterase-4 (PDE4) is a promising target in atopic dermatitis (AD) treatment. The pharmacokinetics (PK), safety, and efficacy of crisaborole topical ointment, 2% (formerly AN2728) (Anacor Pharmaceuticals, Palo Alto, CA), a boron-based benzoxaborole PDE4 inhibitor, were evaluated in children with mild to moderate AD.
Methods:
This phase 1b, open-label, maximal-use study of crisaborole topical ointment, 2% applied twice daily (dose 3 mg/cm(2) ) for 28 days enrolled patients ages 2 to 17 years with extensive AD involving 25% or more or 35% or more treatable body surface area, depending on age. Primary PK and safety assessments included systemic exposure to crisaborole and its metabolites after 7 days of treatment and the incidence of treatment-emergent adverse events (TEAEs). Secondary efficacy assessments included change from baseline in Investigator Static Global Assessment (ISGA), treatment success (ISGA score ≤1 with a two-grade or greater improvement from baseline), and improvement in five AD signs and symptoms.
Results:
Of 34 patients enrolled, 31 completed the study. Crisaborole was rapidly absorbed, with limited systemic exposure between days 1 and 8. Twenty-three of 34 patients reported one or more TEAEs; 95% were mild or moderate and one patient discontinued because of a TEAE. Mean ISGA scores declined from 2.65 at baseline to 1.15 at day 29, 47.1% of patients achieved treatment success, and 64.7% of patients achieved ISGA scores of clear (0) or almost clear . Mean severity scores for AD signs and symptoms declined throughout the study.
Conclusions:
This open-label study provides evidence that crisaborole topical ointment, 2% was well tolerated, with limited systemic exposure under maximal-use conditions in patients ages 2 years and older.
Background:
The adult burden of atopic dermatitis (AD) is poorly characterized.
Objective:
We sought to characterize AD burden in adults with moderate to severe disease from the patient's perspective.
Methods:
Patient-reported outcomes collected at screening in a phase 2b clinical trial of dupilumab included pruritus numeric rating scale, 5-Dimension Pruritus Scale, subjective components of SCORing AD, Patient-Oriented Eczema Measure, Hospital Anxiety and Depression Scale, Dermatology Life Quality Index, and 5-Dimension EuroQol.
Results:
Most of the 380 patients had been living with AD for nearly all their lives, whereas approximately 40% were given a diagnosis as adults; 40.3% had asthma and 60.5% had other allergic conditions. Despite 48.2% of patients using systemic therapies in the past year, patients reported problems with itch frequency (85% of patients), duration (41.5% reported itching ≥18 h/d), and severity (6.5 of 10 on numeric rating scale); 55% reported AD-related sleep disturbances 5 d/wk or more. Hospital Anxiety and Depression Scale scores suggesting clinically relevant anxiety or depression were reported by 21.8% of patients. Quality of life was impaired on Dermatology Life Quality Index and 5-dimension EuroQol.
Limitations:
This study had limited generalizability; conclusions may not reflect those with mild AD or not participating in a clinical trial.
Conclusions:
Adults with moderate to severe AD report multidimensional burden including disease activity, patient-reported symptoms, comorbidities, and quality-of-life impact.
Background:
Since the treatment guidelines for atopic dermatitis (AD) were issued by the Korean Atopic Dermatitis Association (KADA) work group in 2006, there have been further advances in the systemic treatment of AD.
Objective:
We aimed to establish updated evidence- and experience-based systemic treatment guidelines for Korean AD.
Methods:
We compiled a database of references from relevant systematic reviews and guidelines regarding the systemic management of AD, including antihistamines, antimicrobials, systemic immunomodulators, allergen-specific immunotherapy, phototherapy, adjunctive treatment, and complementary and alternative medicines. Evidence for each statement was graded and classified based on the strength of the recommendation. Thirty-nine council members of KADA participated in the three rounds of votes and expert consensus recommendations were established.
Results:
The use of antihistamines is recommended to relieve pruritus and to prevent exacerbation due to scratching in AD patients. Infection should be controlled as needed and long-term medication should be avoided. For moderate to severe AD patients, concomitant active treatments with systemic immunomodulators are indicated. Cyclosporine is the first choice among systemic immunomodulators and others should be considered as second-line alternatives. Allergen-specific immunotherapy could be effective in AD patients with aeroallergen hypersensitivity. Phototherapy can be useful for moderate to severe AD patients and narrow-band ultraviolet B is the most effective option. Complementary and alternative medicines cannot be recommended for treating AD.
Conclusion:
We expect these recommendations to be a reference guide for physicians and AD patients in choosing the appropriate treatment to improve quality of life and decrease unnecessary social medical costs.
For centuries, itch was categorized as a submodality of pain. Recent research over the last decade has led to the realization that itch is in fact a separate and distinct, albeit closely related, sensation. Chronic itch is a common complaint and has numerous etiologies. Various receptors (TRPA1, TRPV1, PAR2, gastrin-releasing peptide receptor (GRPR), Mas-related G proteins), secreted molecules (histamine, nerve growth factor (NGF), substance P (SP), proteases), and cytokines/chemokines (thymic stromal lymphopoietin (TSLP), IL-2, IL-4, IL-13, and IL-31) are implicated as mediators of chronic pruritus. While much remains unknown regarding the mechanisms of chronic itch, this much is certain: there is no singular cause of itch. Rather, itch is caused by a complex interface between skin, keratinocytes, cutaneous nerve fibers, pruritogenic molecules, and the peripheral and central nervous systems. Atopic dermatitis is one of the most itchy skin dermatoses and affects millions worldwide. The sensation of atopic itch is mediated by the interplay between epidermal barrier dysfunction, upregulated immune cascades, and the activation of structures in the central nervous system. Clinicians are in possession of an arsenal of different treatment options ranging from moisturizers, topical immunomodulators, topical anesthetic ion channel inhibitors, systemic immunomodulators, as well as oral drugs capable of reducing neural hypersensitization. Emerging targeted therapies on the horizon, such as dupilumab, promise to usher in a new era of highly specific and efficacious treatments. Alternative medicine, stress reduction techniques, and patient education are also important treatment modalities. This review will focus on the mediators of chronic pruritus mainly associated with atopic dermatitis (atopic itch), as well as numerous different therapeutic options.
Background
Asteatotic eczema (AE) is characterized by itchy, dry, rough, and scaling skin. The treatments for AE are mainly emollients, usually containing urea, lactic acid, or a lactate salt. N-palmitoylethanolamine (PEA) and N-acetylethanolamine (AEA) are both endogenous lipids used as novel therapeutic tools in the treatment of many skin diseases. The purpose of this study was to compare a PEA/AEA emollient with a traditional emollient in the treatment of AE.
Methods
A monocentric, randomized, double-blind, comparative trial was conducted in 60 AE patients to evaluate and compare the efficacy of the two emollients. The level of skin dryness among the subjects ranged from mild to moderate. The subjects’ skin barrier function and the current perception threshold were tested for 28 days by clinical scoring and bioengineering technology.
Results
The results showed that, although some aspects were improved in both groups, the group using the emollient containing PEA/AEA presented a better skin surface change in capacitance. However, the most impressive finding was the ability of the PEA/AEA emollient to increase the 5 Hz current perception threshold to a normal level after 7 days, with a significant difference between values at baseline and after 14 days. A current perception threshold of 5 Hz was positively and significantly correlated with skin surface hydration and negatively correlated with transepidermal water loss in the PEA/AEA emollient group.
Conclusion
Compared with traditional emollients, regular application of a topical PEA/AEA emollient could improve both passive and active skin functions simultaneously.
Background:
Dupilumab, a fully human monoclonal antibody that blocks interleukin-4 and interleukin-13, has shown efficacy in patients with asthma and elevated eosinophil levels. The blockade by dupilumab of these key drivers of type 2 helper T-cell (Th2)-mediated inflammation could help in the treatment of related diseases, including atopic dermatitis.
Methods:
We performed randomized, double-blind, placebo-controlled trials involving adults who had moderate-to-severe atopic dermatitis despite treatment with topical glucocorticoids and calcineurin inhibitors. Dupilumab was evaluated as monotherapy in two 4-week trials and in one 12-week trial and in combination with topical glucocorticoids in another 4-week study. End points included the Eczema Area and Severity Index (EASI) score, the investigator's global assessment score, pruritus, safety assessments, serum biomarker levels, and disease transcriptome.
Results:
In the 4-week monotherapy studies, dupilumab resulted in rapid and dose-dependent improvements in clinical indexes, biomarker levels, and the transcriptome. The results of the 12-week study of dupilumab monotherapy reproduced and extended the 4-week findings: 85% of patients in the dupilumab group, as compared with 35% of those in the placebo group, had a 50% reduction in the EASI score (EASI-50, with higher scores in the EASI indicating greater severity of eczema) (P<0.001); 40% of patients in the dupilumab group, as compared with 7% in the placebo group, had a score of 0 to 1 (indicating clearing or near-clearing of skin lesions) on the investigator's global assessment (P<0.001); and pruritus scores decreased (indicating a reduction in itch) by 55.7% in the dupilumab group versus 15.1% in the placebo group (P<0.001). In the combination study, 100% of the patients in the dupilumab group, as compared with 50% of those who received topical glucocorticoids with placebo injection, met the criterion for EASI-50 (P=0.002), despite the fact that patients who received dupilumab plus glucocorticoids used less than half the amount of topical glucocorticoids used by those who received placebo plus the topical medication (P=0.16). Adverse events, such as skin infection, occurred more frequently with placebo; nasopharyngitis and headache were the most frequent adverse events with dupilumab.
Conclusions:
Patients treated with dupilumab had marked and rapid improvement in all the evaluated measures of atopic dermatitis disease activity. Side-effect profiles were not dose-limiting. (Funded by Regeneron Pharmaceuticals and Sanofi; ClinicalTrials.gov numbers, NCT01259323, NCT01385657, NCT01639040, and NCT01548404.).
Atopic dermatitis (AD), a common chronic inflammatory skin disease, is characterized by inflammatory cell skin infiltration. The JAK-STAT pathway has been shown to play an essential role in the dysregulation of immune responses in AD, including the exaggeration of Th2 cell response, the activation of eosinophils, the maturation of B cells, and the suppression of regulatory T cells (Tregs). In addition, the JAK-STAT pathway, activated by IL-4, also plays a critical role in the pathogenesis of AD by upregulating epidermal chemokines, pro-inflammatroy cytokines, and pro-angiogenic factors as well as by downregulating antimicrobial peptides (AMPs) and factors responsible for skin barrier function. In this review, we will highlight the recent advances in our understanding of the JAK-STAT pathway in the pathogenesis of AD.
The intermittent use of dilute sodium hypochlorite "bleach baths" has shown efficacy as adjunctive therapy for atopic dermatitis (AD). This feasibility study evaluated the clinical response and patient acceptability of treatment with a cleansing body wash containing sodium hypochlorite in children with AD. This was a 12-week open-label feasibility study of 18 children with AD conducted in a pediatric dermatology outpatient clinic between May 2011 and July 2012. Children with moderate to severe AD, defined as an Investigator Global Assessment (IGA) score of at least 3 on a 5-point scale, who were age 6 months and older and had lesional cultures positive for Staphylococcus aureus at baseline were included. Patients were instructed to wash 3 days/week for 12 weeks with the sodium hypochlorite-containing cleansing body wash. During the study period, patient's individualized topical and systemic treatment regimens were continued. Clinical response to treatment was measured using an IGA score and the percentage of body surface area (BSA) affected. Parents were also administered a retrospective questionnaire evaluating acceptability of the product. There was a statistically significant reduction in IGA score at all time points, with an overall mean reduction from baseline to final measurement using the last observation carried forward in all patients of 1.0 (p = 0.001, n = 18). Similarly the mean reduction of BSA affected was 14.8% (p = 0.005, n = 18). Parents reported that the body wash was significantly easier to use than traditional bleach baths (p < 0.001). The significant reductions in clinical disease severity scores with use of this formulation are encouraging.
Emollients can perform an important role in the treatment of a number of dermatological conditions. Currently, the use of emollient therapy in the UK is supported only by limited guidelines and a best-practice statement, although guidelines do exist for specific conditions such as childhood eczema. To address this need, a group of clinical professionals covering acute community-care settings and medicines management met to review current data and practice. Their aim was to support other professionals in their approach to the use of emollient therapies in dry-skin conditions.
Glucocorticoids are anti-inflammatory drugs that are widely used for the treatment of numerous (autoimmune) inflammatory diseases. They exert their actions by binding to the glucocorticoid receptor (GR), a member of the nuclear receptor family of transcription factors. Upon ligand binding, the GR translocates to the nucleus, where it acts either as a homodimeric transcription factor that binds glucocorticoid response elements (GREs) in promoter regions of glucocorticoid (GC)-inducible genes, or as a monomeric protein that cooperates with other transcription factors to affect transcription. For decades, it has generally been believed that the undesirable side effects of GC therapy are induced by dimer-mediated transactivation, whereas its beneficial anti-inflammatory effects are mainly due to the monomer-mediated transrepressive actions of GR. Therefore, current research is focused on the development of dissociated compounds that exert only the GR monomer-dependent actions. However, many recent reports undermine this dogma by clearly showing that GR dimer-dependent transactivation is essential in the anti-inflammatory activities of GR. Many of these studies used GR(dim/dim) mutant mice, which show reduced GR dimerization and hence cannot control inflammation in several disease models. Here, we review the importance of GR dimers in the anti-inflammatory actions of GCs/GR, and hence we question the central dogma. We summarize the contribution of various GR dimer-inducible anti-inflammatory genes and question the use of selective GR agonists as therapeutic agents.
Background
Abrocitinib, an oral selective Janus kinase 1 inhibitor, was effective and well tolerated in adults with moderate-to-severe atopic dermatitis in a phase 2b trial. We aimed to assess the efficacy and safety of abrocitinib monotherapy in adolescents and adults with moderate-to-severe atopic dermatitis.
Methods
In this multicentre, double-blind, randomised phase 3 trial (JADE MONO-1), patients (aged ≥12 years) with moderate-to-severe atopic dermatitis (Investigator Global Assessment score ≥3, Eczema Area and Severity Index [EASI] score ≥16, percentage of body surface area affected ≥10%, and Peak Pruritus Numerical Rating Scale score ≥4) with a bodyweight of 40 kg or more, were enrolled at 69 sites in Australia, Canada, Europe, and the USA. Patients were randomly assigned (2:2:1) to oral abrocitinib 100 mg, abrocitinib 200 mg, or placebo once daily for 12 weeks. Randomisation was done using an interactive response technology system, stratified by baseline disease severity and age. Patients, investigators, and the funder of the study were masked to study treatment. The coprimary endpoints were the proportion of patients who had achieved an Investigator Global Assessment response (score of 0 [clear] or 1 [almost clear] with a ≥2-grade improvement from baseline), and the proportion of patients who achieved at least a 75% improvement in EASI score from baseline (EASI-75) score, both assessed at week 12. Efficacy was assessed in the full analysis set, which included all randomised patients who received at least one dose of study medication. Safety was assessed in all randomised patients. This study is registered with ClinicalTrials.gov, NCT03349060.
Findings
Between Dec 7, 2017, and March 26, 2019, 387 patients were enrolled: 156 were assigned to abrocitinib 100 mg, 154 to abrocitinib 200 mg, and 77 to placebo. All enrolled patients received at least one dose of study treatment and thus were evaluable for 12-week efficacy. Of the patients with available data for the coprimary endpoints at week 12, the proportion of patients who had achieved an Investigator Global Assessment response was significantly higher in the abrocitinib 100 mg group than in the placebo group (37 [24%] of 156 patients vs six [8%] of 76 patients; p=0·0037) and in the abrocitinib 200 mg group compared with the placebo group (67 [44%] of 153 patients vs six [8%] of 76 patients; p<0·0001). Of the patients with available data for the coprimary endpoints at week 12, compared with the placebo group, the proportion of patients who had achieved an EASI-75 response was significantly higher in the abrocitinib 100 mg group (62 [40%] of 156 patients vs nine [12%] of 76 patients; p<0·0001) and abrocitinib 200 mg group (96 [63%] of 153 patients vs nine [12%] of 76 patients; p<0·0001). Adverse events were reported in 108 (69%) of 156 patients in the abrocitinib 100 mg group, 120 (78%) of 154 patients in the abrocitinib 200 mg group, and 44 (57%) of 77 patients in the placebo group. Serious adverse events were reported in five (3%) of 156 patients in the abrocitinib 100 mg group, five (3%) of 154 patients in the abrocitinib 200 mg group, and three (4%) of 77 patients in the placebo group. No treatment-related deaths were reported.
Interpretation
Monotherapy with oral abrocitinib once daily was effective and well tolerated in adolescents and adults with moderate-to-severe atopic dermatitis.
Funding
Pfizer.
Background:
Baricitinib, an oral selective Janus kinase 1 and 2 inhibitor, effectively reduced atopic dermatitis (AD) severity in a Phase 2 study with concomitant topical corticosteroids.
Objectives:
To evaluate the efficacy and safety of baricitinib in patients with moderate-to-severe AD and an inadequate response to topical therapies.
Methods:
In two independent, multicentre, double-blind, Phase 3 monotherapy trials, BREEZE-AD1 and BREEZE-AD2, adults with moderate-to-severe AD were randomised 2:1:1:1 to once-daily placebo, baricitinib 1-mg, 2-mg or 4-mg for 16 weeks.
Results:
At Week 16, more patients achieved the primary endpoint of Validated Investigator's Global Assessment of AD (0, 1) on baricitinib 4-mg and 2-mg compared with placebo in BREEZE-AD1 (N=624; 4-mg 16.8%, 2-mg 11.4%, 1-mg 11.8%, placebo 4.8%; P<0.001, P<0.05, P<0.05), and BREEZE-AD2 (N=615; 4-mg 13.8%, 2-mg 10.6%, 1-mg 8.8%, placebo 4.5%; P=0.001, P<0.05, P=0.085). Improvement in itch was achieved as early as Week 1 for 4-mg and Week 2 for 2-mg. Improvements in night-time awakenings, skin pain, and quality-of-life measures were observed by Week 1 for both 4-mg and 2-mg (P≤0.05, all comparisons). The most common adverse events in baricitinib-treated patients were nasopharyngitis and headache. No cardiovascular events, venous thromboembolism, gastrointestinal perforation, significant haematological changes, or death were observed with any baricitinib dose.
Conclusions:
Baricitinib improved clinical signs and symptoms in patients with moderate-to-severe AD within 16 weeks of treatment and induced rapid reduction of itch. The safety profile remained consistent with prior findings from baricitinib clinical development in AD, with no new safety concerns.
Background:
Pruritus is a leading cause of reduced health-related quality of life (QoL) in atopic dermatitis (AD). Crisaborole ointment is a non-steroidal phosphodiesterase 4 inhibitor for the treatment of mild-to-moderate AD. In identical Phase 3 studies (NCT02118766, NCT02118792), crisaborole reduced disease and pruritus severity versus vehicle.
Objective:
Quantify the relationship between pruritus and QoL using data from these studies.
Methods:
Patients aged ≥2 years were randomly assigned 2 : 1 to receive crisaborole:vehicle twice daily for 28 days. QoL was measured at baseline and day 29 using the Dermatology Life Quality Index (DLQI; patients aged ≥16 years), the Children's Dermatology Life Quality Index (CDLQI; patients aged 2-15 years) and the Dermatitis Family Impact (DFI; caregivers of patients aged 2-17 years). Pruritus was measured using the Severity of Pruritus Scale (SPS), a 4-point scale from 0 ('no itching') to 3 ('bothersome itching/scratching that disturbs sleep'), and captured morning and evening via electronic diary. Data from crisaborole and vehicle arms were pooled for this analysis. A repeated-measures longitudinal model was used to estimate relationships between pruritus (SPS) and QoL (DLQI, CDLQI and DFI in separate analyses).
Results:
One thousand five hundred and twenty two patients received crisaborole or vehicle. A linearity assumption for the relationship between SPS and DLQI (n = 294), CDLQI (n = 1200), and DFI (n = 1293) was appropriate. For DLQI, SPS score of 0 was associated with 'no negative effect on patient QoL'; SPS score of 1 was associated with 'small effect on patient QoL'; SPS score of 2 was associated with 'moderate effect on patient QoL'; and SPS score of 3 was associated with 'very large effect on patient QoL'. The pattern of relationships between SPS and CDLQI and DFI was similar.
Conclusions:
The relationships between SPS and DLQI, CDLQI and DFI substantiate the significant link between pruritus and patient/caregiver QoL in AD.
Itch is a common sensory experience that is prevalent in patients with inflammatory skin diseases, as well as in those with systemic and neuropathic conditions. In patients with these conditions, itch is often severe and significantly affects quality of life. Itch is encoded by 2 major neuronal pathways: histaminergic (in acute itch) and nonhistaminergic (in chronic itch). In the majority of cases, crosstalk existing between keratinocytes, the immune system, and nonhistaminergic sensory nerves is responsible for the pathophysiology of chronic itch. This review provides an overview of the current understanding of the molecular, neural, and immune mechanisms of itch: beginning in the skin, proceeding to the spinal cord, and eventually ascending to the brain, where itch is processed. A growing understanding of the mechanisms of chronic itch is expanding, as is our pipeline of more targeted topical and systemic therapies. Our therapeutic armamentarium for treating chronic itch has expanded in the last 5 years, with developments of topical and systemic treatments targeting the neural and immune systems.
Tapinarof cream is a novel topical nonsteroidal agent that represents a unique class of anti-inflammatory molecules targeting the aryl hydrocarbon receptor. Study 201851 was an open-label, 2-cohort sequential study that assessed the systemic pharmacokinetics, safety, and efficacy of tapinarof in adults with moderate to severe atopic dermatitis. A total of 11 participants were enrolled: 5 received 2% cream, and 6 received 1% cream. Tapinarof was systemically absorbed, and measurable amounts were detected in both cohorts. Generally, plasma exposure was greater with the 2% cream and decreased from day 1 to day 21. Median Tmax ranged from 1 to 4 hours. Preliminary efficacy results were similar between the 1% and 2% concentrations, with the 1% cream showing better tolerability based on 3 subjects in the 2% cohort who discontinued treatment because of systemic AEs. The efficacy and safety of 1% tapinarof support results of previous positive studies that used a different formulation. However, conclusions in the present study are limited because of the open-label design and small number of participants. The 1% cream was selected as the concentration for use in future studies because of its lower AE incidence and efficacy comparable to the 2% cream.
Atopic dermatitis (AD) is the most common itchy dermatosis that affects millions of children and adults worldwide. Chronic itch in this condition has significant impact on measures of quality of life, such as sleep. Treating itch in AD has been challenging for decades, but new drugs have emerged in the last year with significant anti-pruritic effect. The optimal treatment regimen for atopic itch addresses barrier dysfunction, inflammation, neural hypersensitivity, and the itch–scratch cycle. Topical moisturizers remain the foundation of treatment and should be used by all patients with AD-associated pruritus. Step-wise therapy, from topical anti-inflammatory creams to systemic monoclonal antibodies and immunosuppressants, is recommended. There are multiple adjuvant therapies that can be used, especially to target itch in the setting of minimal skin inflammation. Finally, patient education, sleep management, and stress relief are important components to optimize outcomes. This review assesses the latest advances and treatment recommendations for pruritus in AD. Finally, suggested therapeutic ladders and emerging treatments are discussed.
Methods:
Two double-blind, split-body, randomized studies in 66 male and female subjects, ages 11+ years, with history of atopic dermatitis (AD). Itch severity was assessed on a 10-point scale (where 0=none and 7-9=severe). Study one: single applications of ceramide-containing lotion or cream incorporating 1% pramoxine hydrochloride applied to opposite sides of the body. Study two (part 1): single application of ceramide-containing cream or hydrocortisone 1% cream. Study two (part 2): ceramide-containing pramoxine cream applied up to 4 times in a 24-hour period, over the course of 6 days. Itch relief assessed at baseline, 2, and 5 minutes, 1 (2 in study two), 4, and 8 hours post-application. Efficacy and aesthetic attributes were assessed at the same timepoints. Clinical evaluation of performance and mildness of the ceramide-containing 1% pramoxine hydrochloride cream at day 6 (study two, part 2).
Results:
Study one: Relief of itching was rapid and long-lasting with significant reductions in severity after 2 minutes, and continued improvement over the 8 hour test period (P less than .001 versus baseline at all timepoints). Mean itch severity scores reduced progressively from 6 (moderate) at baseline to 1-2 (mild) after 8 hours, with all patients experiencing relief from itching. Rapid and long-lasting relief to dry, itchy, irritated skin was confirmed through patient self-assessment. Both lotion and cream formulations were non-greasy, absorbed quickly and easily, and were non-irritating. Study two: Ceramide-containing cream incorporating 1% pramoxine hydrochloride provided comparable improvement in itch relief (24.6% reduction in mean itch severity 2 minutes post-application, and 58.0% reduction 8 hours post-application) compared to hydrocortisone cream 1% (18.5% reduction and 59.7% reduction, respectively). Daily use of the ceramide-containing 1% pramoxine cream over 6-days provided all-night relief (87.5% agreement), and perception of skin looking and feeling healthier with each use (71.9% and 81.3% agreement, respectively).
Limitations:
Results of study one and subsequent comparative study with hydrocortisone 1% cream are based on a single application. There were no placebo controls.
Conclusions:
Ceramide-containing lotion or cream containing 1% pramoxine provides both rapid and long-lasting relief of itching following a single application in atopic patients with or without active flare. Both formulations were well tolerated with aesthetic appeal. Comparable itch relief to hydrocortisone 1% cream was seen with the ceramide-containing cream over an 8-hour period following a single application. Further ceramide-containing 1% pramoxine hydrochloride cream was well tolerated with continued use over 6 days, delivering comfort and all-night relief for patients with atopic history suffering from reoccurrant itching.
J Drugs Dermatol. 2017;16(3):243-247.
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BACKGROUND: The epidermal barrier in patients with atopic dermatitis (AD) is deficient in ceramides and cathelicidins. Such epidermal defects may be a trigger for AD, thereby encouraging research toward development of skin-barrier-targeted preventive strategies.
METHODS: Two single-center, single-arm clinical trials were conducted (study 1, age greater than equal to 8 years and study 2, greater than equal to 10 years) in patients with mild to moderate AD to evaluate the effects of an over-the-counter 1% colloidal oatmeal cream administered for 14 days. Study 1 assessed the Eczema Area and Severity Index (EASI) and Investigator’s Global Atopic Dermatitis Assessment (IGADA) on day 3, and itch severity using a Visual Analogue Scale (VAS) immediately after application as primary efficacy endpoints. In study 2, the primary efficacy endpoint was change from baseline in patients’ assessment of itch. Both studies assessed safety through adverse event (AE) recording.
RESULTS: Study 1: 29 patients were enrolled (mean age [range], 27.07 [8 –67]). Comparing to baseline, EASI, IGADA, and itch were improved after the application, and improvements were maintained until day 14. Improvements of greater than/equal to 20% over baseline were noted in 53.6% and 25.0% patients at day 3 for EASI and IGADA scores, respectively, and in 37.9% patients for itch score immediately after the product application. On day 14, these percentages were 82.8%, 62.1%, and 85.7%, respectively.
STUDY 2: 30 patients were enrolled (mean age [range], 32.9 [10-80]). Itch severity and EASI score were significantly improved after product application and improvements were maintained until day 14. Transepidermal water loss values were significantly reduced and skin hydration was significantly increased at all assessment time points. No adverse events (AEs) were reported in study 2 and 2 AEs were reported by 1 patient in study 1.
CONCLUSIONS: The colloidal oatmeal cream was well tolerated and clinically effective in patients with mild to moderate AD.
J Drugs Dermatol. 2017;16(7):671-676.
Chronic or episodic severe itch is recurrent in atopic dermatitis (AD). Non-histaminergic neuronal itch pathways are suggested to dominate in AD itch, contributing to an "itch-scratch-itch cycle" that prolongs and worsens itch, pain, and skin lesions. We hypothesized that non-histaminergic neuronal sensitization contributes to itch in AD. Hence, we compared sensitivity to thermal, mechanical, and chemical pruritic stimuli in AD patients and controls. The study comprised 25 AD patients with chronic itch and 25 healthy controls. Questionnaires on itch characteristics were administered, and sensory tests were conducted intra-lesionally, extra-lesionally, and in homologous areas of controls. Thermal and mechanical quantitative sensory testing (QST) as well as histamine and cowhage provocations were performed. Subsequently, hyperknesis and vasomotor reactivity were assessed. Average itch and associated pain among AD patients were 60.7±4.3 and 39.7±5.2 (VAS0-100), respectively. Patients experienced significantly higher itch from cowhage both intra- and extra-lesionally compared to controls, whereas histamine-evoked itch intensity was not significantly different between groups. No group differences were found for thermal QSTs or pain evoked by itch provocations. Patients had decreased mechanical detection thresholds intra-lesionally and increased mechanical pain sensitivity intra- and extra-lesionally. Lastly, patients exhibited intra- and extra-lesional hyperknesis prior to chemical itch provocations and augmented hyperknesis following itch provocations. Increased itch to a non-histaminergic pruritogen (but not histamine) suggests pathway-specific itch sensitization in AD while increased susceptibility to mechanically-evoked itch and pain, particularly intra-lesionally, suggests sensitization of normally non-pruritic mechano-sensitive circuitry. Drugs targeting the non-histaminergic (PAR2/TRPA1) itch-pathway and itch sensitization are promising for treating AD itch.
Tapinarof (GSK2894512) is a naturally derived topical treatment with demonstrated efficacy for psoriasis and atopic dermatitis (AD) patients, although the biologic target and mechanism of action had been unknown. We demonstrate that the anti-inflammatory properties of tapinarof are mediated through activation of the Aryl hydrocarbon Receptor (AhR). We show that tapinarof binds and activates AhR in multiple cell types, including cells of the target tissue –human skin. In addition, tapinarof moderates proinflammatory cytokine expression in stimulated peripheral blood CD4+ T cells and ex vivo human skin, and impacts barrier gene expression in primary human keratinocytes; both of these processes are likely to be downstream of AhR activation based on current evidence. That the anti-inflammatory properties of tapinarof derive from AhR agonism is conclusively demonstrated using the mouse model of imiquimod-induced psoriasiform skin lesions. Topical treatment of AhR-sufficient mice with tapinarof leads to compound-driven reductions in erythema, epidermal thickening and tissue cytokine levels. In contrast, tapinarof has no impact on imiquimod-induced skin inflammation in AhR-deficient mice. In summary, these studies identify tapinarof as an AhR agonist, and confirm that its efficacy is dependent on AhR.
Background:
Dupilumab (an anti-interleukin-4-receptor-α monoclonal antibody) blocks signalling of interleukin 4 and interleukin 13, type 2/Th2 cytokines implicated in numerous allergic diseases ranging from asthma to atopic dermatitis. Previous 16-week monotherapy studies showed that dupilumab substantially improved signs and symptoms of moderate-to-severe atopic dermatitis with acceptable safety, validating the crucial role of interleukin 4 and interleukin 13 in atopic dermatitis pathogenesis. We aimed to evaluate the long-term efficacy and safety of dupilumab with medium-potency topical corticosteroids versus placebo with topical corticosteroids in adults with moderate-to-severe atopic dermatitis.
Methods:
In this 1-year, randomised, double-blinded, placebo-controlled, phase 3 study (LIBERTY AD CHRONOS), adults with moderate-to-severe atopic dermatitis and inadequate response to topical corticosteroids were enrolled at 161 hospitals, clinics, and academic institutions in 14 countries in Europe, Asia-Pacific, and North America. Patients were randomly assigned (3:1:3) to subcutaneous dupilumab 300 mg once weekly (qw), dupilumab 300 mg every 2 weeks (q2w), or placebo via a central interactive voice/web response system, stratified by severity and global region. All three groups were given concomitant topical corticosteroids with or without topical calcineurin inhibitors where inadvisable for topical corticosteroids. Topical corticosteroids could be tapered, stopped, or restarted on the basis of disease activity. Coprimary endpoints were patients (%) achieving Investigator's Global Assessment (IGA) 0/1 and 2-point or higher improvement from baseline, and Eczema Area and Severity Index 75% improvement from baseline (EASI-75) at week 16. Week 16 efficacy and week 52 safety analyses included all randomised patients; week 52 efficacy included patients who completed treatment by US regulatory submission cutoff. This study is registered with ClinicalTrials.gov, NCT02260986.
Findings:
Between Oct 3, 2014, and July 31, 2015, 740 patients were enrolled: 319 were randomly assigned to dupilumab qw plus topical corticosteroids, 106 to dupilumab q2w plus topical corticosteroids, and 315 to placebo plus topical corticosteroids. 623 (270, 89, and 264, respectively) were evaluable for week 52 efficacy. At week 16, more patients who received dupilumab plus topical corticosteroids achieved the coprimary endpoints of IGA 0/1 (39% [125 patients] who received dupilumab plus topical corticosteroids qw and 39% [41 patients] who received dupilumab q2w plus topical corticosteroids vs 12% [39 patients] who received placebo plus topical corticosteroids; p<0·0001) and EASI-75 (64% [204] and 69% [73] vs 23% [73]; p<0·0001). Week 52 results were similar. Adverse events were reported in 261 (83%) patients who received dupilumab qw plus topical corticosteroids, 97 (88%) patients who received dupilumab q2w, and 266 (84%) patients who received placebo, and serious adverse events in nine (3%), four (4%), and 16 (5%) patients, respectively. No significant dupilumab-induced laboratory abnormalities were noted. Injection-site reactions and conjunctivitis were more common in patients treated with dupilumab plus topical corticosteroids-treated patients than in patients treated with placebo plus topical corticosteroids.
Interpretation:
Dupilumab added to standard topical corticosteroid treatment for 1 year improved atopic dermatitis signs and symptoms, with acceptable safety.
Funding:
Sanofi and Regeneron Pharmaceuticals Inc.
BACKGROUND
Dupilumab, a human monoclonal antibody against interleukin-4 receptor alpha, inhib- its signaling of interleukin-4 and interleukin-13, type 2 cytokines that may be impor- tant drivers of atopic or allergic diseases such as atopic dermatitis.
METHODS
In two randomized, placebo-controlled, phase 3 trials of identical design (SOLO 1 and SOLO 2), we enrolled adults with moderate-to-severe atopic dermatitis whose disease was inadequately controlled by topical treatment. Patients were randomly assigned in a 1:1:1 ratio to receive, for 16 weeks, subcutaneous dupilumab (300 mg) or placebo weekly or the same dose of dupilumab every other week alternating with placebo. The primary outcome was the proportion of patients who had both a score of 0 or 1 (clear or almost clear) on the Investigator’s Global Assessment and a reduction of 2 points or more in that score from baseline at week 16.
RESULTS
We enrolled 671 patients in SOLO 1 and 708 in SOLO 2. In SOLO 1, the primary outcome occurred in 85 patients (38%) who received dupilumab every other week and in 83 (37%) who received dupilumab weekly, as compared with 23 (10%) who received placebo (P<0.001 for both comparisons with placebo). The results were similar in SOLO 2, with the primary outcome occurring in 84 patients (36%) who received du- pilumab every other week and in 87 (36%) who received dupilumab weekly, as com- pared with 20 (8%) who received placebo (P<0.001 for both comparisons). In addition, in the two trials, an improvement from baseline to week 16 of at least 75% on the Eczema Area and Severity Index was reported in significantly more patients who re- ceived each regimen of dupilumab than in patients who received placebo (P<0.001 for all comparisons). Dupilumab was also associated with improvement in other clinical end points, including reduction in pruritus and symptoms of anxiety or depression and improvement in quality of life. Injection-site reactions and conjunctivitis were more frequent in the dupilumab groups than in the placebo groups.
CONCLUSIONS
In two phase 3 trials of identical design involving patients with atopic dermatitis, dupilumab improved the signs and symptoms of atopic dermatitis, including pruritus, symptoms of anxiety and depression, and quality of life, as compared with placebo. Trials of longer duration are needed to assess the long-term effec- tiveness and safety of dupilumab. (Funded by Sanofi and Regeneron Pharmaceu- ticals; SOLO 1 ClinicalTrials.gov number, NCT02277743; SOLO 2 ClinicalTrials .gov number, NCT02277769.)
Background:
A novel approach for treating atopic dermatitis (AD) is the inhibition of phosphodiesterase 4 (PDE4), an enzyme involved in the proinflammatory cascade. Crisaborole topical ointment, 2% is a novel, boron-based small-molecule PDE4 inhibitor with anti-inflammatory properties. The objective of this proof-of-concept study was to assess the efficacy and safety of crisaborole topical ointment, 2% in adults with mild to moderate AD.
Methods:
This phase 2a, randomized, double-blind, bilateral, 6-week study of crisaborole topical ointment, 2% was conducted in adult patients with mild to moderate AD with 2 comparable target AD lesions. Patients were randomly assigned to twice-daily application of crisaborole topical ointment, 2% or vehicle, each to 1 of the 2 target lesions. The primary efficacy endpoint was change from baseline in Atopic Dermatitis Severity Index (ADSI) score at day 28. Safety assessments included local tolerability and incidence of adverse events (AEs).
Results:
A total of 25 enrolled patients received study medication. At day 28, 17 patients (68%) experienced a greater decrease in ADSI score in the active-treated lesion than in the vehicle-treated lesion; 5 patients (20%) had a greater decrease in ADSI score in the vehicle-treated lesion than in the active-treated lesion. Local application-site reactions were reported in 3 patients (12%). A total of 29 AEs were reported in 11 patients; most (90%) were mild in intensity and unrelated to study medication. No serious or severe AEs were reported, and no patient discontinued due to an AE.
Conclusions:
These findings provide preliminary evidence of the efficacy and safety of treatment with crisaborole topical ointment, 2% in adults with mild to moderate AD. The study is registered on ClinicalTrials.gov (identifier NCT01301508).
Background:
Two post hoc analyses assessed the antipruritic activity of crisaborole topical ointment, 2% (crisaborole; Anacor Pharmaceuticals, Inc., Palo Alto, CA), a first-in-class boron-based phosphodiesterase-4 inhibitor in development for treatment of mild to moderate atopic dermatitis (AD).
METHODS: Two pooled analyses included data from 4 studies evaluating crisaborole in AD (study 1, phase 1b, systemic exposure, safety, and pharmacokinetics [PK] under maximal-use conditions in children and adolescents; study 2, phase 2a, safety and PK in adolescents; study 3, phase 2a, efficacy and safety in adults; study 4, phase 2, efficacy and safety in adolescents). Pooled data from studies 1 and 2 included whole body assessments; studies 3 and 4 included target lesion assessments. Pruritus severity was evaluated using a 4-point rating scale (0=none to 3=severe). Efficacy assessments included percent change from baseline in pruritus severity scores at days 8 (first pooled assessment), 15, 22, and 29 (whole body assessments) or days 15 (first pooled assessment), 22, and 29 (target lesions). Paired t-tests comparing change from baseline against zero were used to calculate P values. Categorical shifts in pruritus severity were also assessed (no to mild pruritus, 0-1.5; moderate to severe pruritus, 2-3).
RESULTS: In the pooled analysis of studies 1 and 2 (N=57), the percent change from baseline in pruritus severity scores were 63.0% and 64.9% at days 8 and 29, respectively ( P <0.001 for each). Similar results were observed in the pooled analysis of studies 3 and 4 (N=67). In both analyses, most patients had mild to no pruritus from the first time point assessed through the remainder of treatment.
CONCLUSIONS: Treatment with crisaborole topical ointment, 2% resulted in statistically significant reductions in pruritus severity at the first time point evaluated in both analyses. These findings provide preliminary evidence of the antipruritic activity of crisaborole topical ointment, 2%.
J Drugs Dermatol. 2016;15(2):172-176.
Moisturizers are widely used for atopic dermatitis (AD) and related conditions, but available evidence of their effectiveness has not been reviewed in a systematic fashion.
Our objective was to investigate the effectiveness of emollients, as a group and individually, in the treatment of AD and related conditions, by means of a systematic review.
Studies indexed in MEDLINE and/or Embase before 16 January 2015.
Controlled clinical studies comparing the clinical effect of a moisturizer against its vehicle, another moisturizer, or no treatment were eligible. For the outcomes transepidermal water loss (TEWL) and stratum corneum hydration, uncontrolled before-after designs were also eligible.
Participants were patients with AD, irritant hand dermatitis, and/or ichthyosis vulgaris.
Out of the 595 publications initially identified, 45 (48 studies, 3262 patients) were eligible for inclusion. A vast majority of studies indicate that moisturizers have beneficial effects on clinical symptoms [SCORAD (SCORing Atopic Dermatitis) reductions ranging from 0 to 2.7 points], TEWL (range 0 to -12.2 g/m(2)h) and stratum corneum hydration (range +8 to +100 %). Direct comparisons between individual moisturizers are still scarce, but the clinical effect appears to be much more well-documented for urea and glycerin than, for example, propylene glycol, lactate, ceramide, and aluminum chlorohydrate. Compared with urea studies, glycerin studies were more often associated with a high risk of bias.
Due to differences in study designs and outcome measures, a quantitative meta-analytic approach was not deemed feasible, and formal indicators of publication bias such as funnel plots could not be used. However, a large number of moderately sized studies with positive outcomes could be compatible with selective publishing of favourable results.
The clinical effect of moisturizers is well-documented. Urea-based preparations may be preferable as a first-line treatment, but there is an unmet need for well-powered comparisons between individual moisturizers.
Polidocanol is a local anaesthetic and antipruritic compound that is used in the treatment of itching skin conditions such as eczema. Its mechanisms of action are largely ill defined. This study has compared the antipruritic efficacy of topical polidocanol in histamine-induced itch and a histamine-independent, cowhage-induced model of pruritus. Polidocanol (3%) or vehicle was applied topically under occlusion for one hour to the forearms of 45 healthy volunteers before itch was provoked by rubbing in 40-45 spicules of cowhage or skin prick testing (SPT) with 10 mg/ml histamine. Itch was recorded at 1-minute intervals for 30 minutes on a 100 mm visual analogue scale (VAS). Polidocanol significantly reduced the area under the curve for cowhage-induced itch by 58% (P<0.05), but had no significant effect on histamine-induced itch. This result underlines the importance of histamine-independent itch models in the development of topical antipruritic agents.This article is protected by copyright. All rights reserved.
Atopic dermatitis (AD) is a chronically relapsing inflammatory skin disorder. In this cohort study, we evaluated the effectiveness of a twice-daily regimen of a ceramide-containing cleanser and moisturizer in men, women, and children with AD (N=151). The treatment period was 6 weeks. Participants were evaluated at baseline (day 0) and at the end of treatment (day 42) using clinical photographs, the SCORAD (SCORing of Atopic Dermatitis) index, and quality of life (QOL) assessment. Participants were randomly selected and were allocated to 1 of 2 groups: group 1 with participants 12 years and older (n=118) and group 2 with participants younger than 12 years (n=33). At day 42, SCORAD scores for group 1 showed significant improvement (t₁₁₅=18.33, P=.0001). Skin condition in group 2 was evaluated by the participants' guardians. At day 42, SCORAD scores for group 2 showed significant improvement (t₂₇=5.38, P=.0001). Sim-ilar effects were observed for itching, with scores that improved from very itchy to itching only when the skin was wet (t₂₇=5.38, P=.0001). No adverse events were reported during the 6-week evaluation period. The study results indicate that the ceramide-containing cleanser and moisturizer regimen substantially improved skin condition and clinical outcomes related to AD severity as well as QOL aspects.
Atopic dermatitis is a challenging condition for clinicians and patients. Recent advances were documented in the Atopic Dermatitis Practice Parameter 2012, and we want to provide clinicians with key points from the Atopic Dermatitis Practice Parameter 2012. In this article, we highlight the evidence-based therapy of atopic dermatitis as well as provide practical tips for clinicians and families. An updated review of immunopathology provides a firm basis for patient education and therapy. We also review clinical diagnosis and ways to improve quality of life for patients with atopic dermatitis.
Systemic therapy for atopic dermatitis (AD) is indicated in patients with severe disease refractory to adequate topical treatment. Currently available drugs aim to decrease inflammation by suppressing and/or modulating immune responses and thus may indirectly improve skin barrier function, resulting in a decrease in clinical signs and symptoms in particular pruritus. Before considering systemic treatment, patient adherence to topical treatment including skin care has to be ensured. The selection of the drug depends on the disease severity, localization, complications, concomitant diseases, and age of the patient, but also on their availability and costs as well as the doctor's experience. Bearing in mind the potential risk of resistance, systemic therapy with antibiotics should be exclusively considered in clinically manifest infections such as in children. Here, we review recently published clinical trials and case reports on systemic therapy of pediatric and adult patients with AD to draw conclusions for clinical practice. Although AD is a common disease, controlled clinical studies investigating the efficacy of systemic drugs are scarce, except for cyclosporine, which has been approved for the therapy of severe AD.
Many patients with moderate-to-severe atopic dermatitis (AD) require systemic immunomodulating treatment to achieve adequate disease control.
We sought to systematically evaluate the efficacy and safety of systemic treatments for moderate-to-severe AD.
A systematic literature search was performed in MEDLINE, EMBASE, and CENTRAL (until June 2012). Randomized controlled trials (RCTs) evaluating systemic immunomodulating treatments for moderate-to-severe AD were included. Selection, data extraction, quality assessment, and generation of treatment recommendations using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach were performed independently by 2 reviewers. Efficacy outcomes were clinical signs, symptoms, quality of life, and the course of AD. Safety data were compared by calculating the weekly incidence rates (as percentages) for adverse events.
Thirty-four RCTs with 12 different systemic treatments and totaling 1653 patients were included. Fourteen trials consistently indicate that cyclosporin A efficaciously improves clinical signs of AD. Cyclosporin A is recommended as first-line treatment for short-term use. A second-line treatment option is azathioprine, but efficacy is lower, and evidence is weaker. Methotrexate can be considered a third-line treatment option. Recommendations are impossible for mycophenolate, montelukast, intravenous immunoglobulins, and systemic glucocorticosteroids because of limited evidence. A meta-analysis was not performed because of a lack of standardization in outcome measures.
Although 12 different interventions for moderate-to-severe AD have been studied in 34 RCTs, strong recommendations are only possible for the short-term use of cyclosporin A. Methodological limitations in the majority of trials prevent evidence-based conclusions. Large head-to-head trials evaluating long-term treatments are required.
Staphylococcus aureus is frequently found in patients with atopic dermatitis (AD) and contributes to disease exacerbation. The objective of this study was to evaluate the efficacy and safety of bleach baths as an adjunctive treatment in AD patients. Patients between 2 and 30 years old with moderate to severe AD were enrolled in a prospective, randomized, placebo-controlled study. Patients soaked in diluted bleach or distilled water baths for 10 min, twice a week for 2 months. Efficacy assessments included the Eczema Area and Severity Index (EASI) scores and S. aureus density was determined using quantitative bacterial cultures. Patients in the treatment group showed significant reductions in EASI scores. A 41.9% reduction in S. aureus density from baseline was seen at 1 month further reducing to 53.3% at 2 months. Equal numbers of patients in both groups experienced mild side-effects. This study demonstrates that diluted bleach baths clinically improved AD in as little as 1 month. No patient withdrew from the treatment arm because of intolerance to the baths.
The neuropeptide substance P has been implicated in the pathophysiology of pruritus. Capsaicin, the pungent agent in red pepper, is known as a potent substance P depletor. Therefore, the influence of capsaicin on pruritus was studied in ten patients suffering from atopic dermatitis. The patients applied 0.05% capsaicin cream four times daily to one arm for 3 weeks in an open left versus right comparison. Every week skin lesions were evaluated by a physician, and pruritus was assessed by the patients. Four out of ten patients reported a marked relief of pruritus in the capsaicin-treated area only. A relief of pruritus by both capsaicin and vehicle was reported by two patients. Capsaicin was of no benefit in two patients. All patients reported a transient burning sensation after application of capsaicin, which gave reason to discontinue capsaicin treatment in two cases. We conclude that for some patients with atopic dermatitis, capsaicin can be helpful in reducing pruritus.