A Review of Phase 3 Trials of Dupilumab for the Treatment of Atopic Dermatitis in Adults, Adolescents, and Children Aged 6 and Up.

Atopic dermatitis (AD) is a chronic pruritic skin disease that can have a profound negative impact on patients' quality of life, especially in cases of inadequate disease control. Dupilumab, a dual inhibitor of IL-4 and IL-13 signaling, is approved in the United States for the treatment of moderate-to-severe AD in adults (≥ 18 years old) and in children (≥ 6 years old). In this review, we present results from phase 3 trials evaluating dupilumab's efficacy and safety in adults, adolescents, and children. These trials demonstrate that dupilumab provides rapid improvements (in as little as 1 week) and sustained efficacy (up to 4 years) when used as a treatment for moderate-to-severe AD. Dupilumab not only improves skin signs and symptoms, but also provides multiple health benefits beyond the skin, including improvements in quality of life, itch, sleep disturbances, and pain/discomfort. Dupilumab is generally well tolerated, has a favorable safety profile in adults, adolescents, and children, has no serious drug-drug interactions, does not require routine laboratory testing, and is not an immunosuppressant. Taken together, phase 3 trials demonstrate that dupilumab provides rapid and sustained efficacy and is generally well tolerated for the treatment of moderate-to-severe AD across age groups.

The Burden of Childhood Atopic Dermatitis in the Primary Care Setting: A Report from the Meta-LARC Consortium.

BACKGROUND: Little is known about the burden of atopic dermatitis (AD) encountered in US primary care practices and the frequency and type of skin care practices routinely used in children. OBJECTIVE: To estimate the prevalence of AD in children 0 to 5 years attending primary care practices in the United States and to describe routine skin care practices used in this population. DESIGN: A cross-sectional survey study of a convenience sample of children under the age of 5 attending primary care practices for any reason. SETTING: Ten primary care practices in 5 US states. RESULTS: Among 652 children attending primary care practices, the estimated prevalence of ever having AD was 24% (95% CI, 21-28) ranging from 15% among those under the age of 1 to 38% among those aged 4 to 5 years. The prevalence of comorbid asthma was higher among AD participants compared to those with no AD, namely, 12% and 4%, respectively (P < .001). Moisturizers with high water:oil ratios were most commonly used (ie, lotions) in the non-AD population, whereas moisturizers with low water:oil content (ie, ointments) were most common when AD was present. CONCLUSIONS: Our study found a large burden of AD in the primary care practice setting in the US. The majority of households reported skin care practices that may be detrimental to the skin barrier, such as frequent bathing and the routine use of moisturizers with high water: oil ratios. Clinical trials are needed to identify which skin care practices are optimal for reducing the significant burden of AD in the community.

Major Comorbidities of Atopic Dermatitis: Beyond Allergic Disorders.

The consequences of atopic dermatitis reach beyond the skin and past childhood. Patients with atopic dermatitis are at risk of developing allergic comorbidities, but less is known about the associations between atopic dermatitis and non-allergic conditions. Understanding these non-allergic comorbidities has the potential to improve patient outcomes and to help mitigate the cost and burdens associated with these conditions. Atopic dermatitis is associated with cutaneous bacterial infections, more severe forms/courses of cutaneous viral infections, and extra-cutaneous infections. Atopic dermatitis is also associated with several mental health comorbidities particularly attention-deficit hyperactivity disorder, anxiety, and depression. Data are largely inconsistent for specific cancers, but atopic dermatitis appears to protect against malignancy overall; severe long-term atopic dermatitis is associated with adult lymphomas. Atopic dermatitis may also be associated with obesity, cardiovascular disease, and autoimmune disease, particularly alopecia areata and gastrointestinal immune-mediated disorders. Although the causative mechanisms underlying these associations are poorly understood, treating physicians should be aware of associations in seeking to alleviate the burden for patients with atopic dermatitis.

Efficacy and safety of dupilumab for the treatment of moderate-to-severe atopic dermatitis in adults: A pooled analysis of two phase 2 clinical trials.

BACKGROUND AND PURPOSE: There is a need for new treatment options for moderate-to-severe atopic dermatitis (AD) in adults. Dupilumab, a fully human anti-interleukin-4 receptor α monoclonal antibody, has recently been approved for this indication. METHODS: A pooled analysis of a phase 2a (NCT01548404) and a phase 2b (NCT01859988) study and a subanalysis of the 2b study evaluated the efficacy and safety of subcutaneous dupilumab 300 mg once weekly (qw) and every 2 weeks (q2w) in adults with moderate-to-severe AD. RESULTS: Dupilumab significantly improved clinical outcomes in both analyses at week 12. Itch was significantly improved in the pooled analysis as measured by peak pruritus Numerical Rating Scale, 5-dimension pruritus scale, and SCORing Atopic Dermatitis (SCORAD) Visual Analog Scale (VAS) pruritus scores (all p < .0001 vs. placebo at week 12). Sleep loss was significantly improved (SCORAD VAS sleep loss score; p < .0001 vs. placebo at week 12); similar results were shown for the q2w dose. Dupilumab had an acceptable safety profile. CONCLUSIONS: Consistent with previous studies, dupilumab qw and q2w significantly improved signs and symptoms of AD at week 12, including improvements in itch and sleep loss. IMPLICATIONS FOR PRACTICE: Subcutaneous dupilumab is an effective new treatment option for adults with moderate-to-severe AD.

Developing drugs for treatment of atopic dermatitis in children (≥3 months to <18 years of age): Draft guidance for industry.

Atopic dermatitis is the most common chronic skin disease, and it primarily affects children. Although atopic dermatitis (AD) has the highest effect on burden of skin disease, no high-level studies have defined optimal therapy for severe disease. Corticosteroids have been used to treat AD since the 1950s and remain the only systemic medication with Food and Drug Administration approval for this indication in children, despite published guidelines of care that recommend against this option. Several clinical trials with level 1 evidence have supported the use of topical treatments for mild to moderate atopic dermatitis in adults and children, but these trials have had little consistency in protocol design. Consensus recommendations will help standardize clinical development and trial design for children. The Food and Drug Administration issues guidance documents for industry as a source for "the Agency's current thinking on a particular subject." Although they are nonbinding, industry considers these documents to be the standard for clinical development and trial design. Our consensus group is the first to specifically address clinical trial design in this population. We developed a draft guidance document for industry, Developing Drugs for Treatment of Atopic Dermatitis in Children (≥3 months to <18 years of age). This draft guidance has been submitted to the Food and Drug Administration based on a provision in the Federal Register (Good Guidance Practices).

Methods of Melanoma Detection.

Detection and removal of melanoma, before it has metastasized, dramatically improves prognosis and survival. The purpose of this chapter is to (1) summarize current methods of melanoma detection and (2) review state-of-the-art detection methods and technologies that have the potential to reduce melanoma mortality. Current strategies for the detection of melanoma range from population-based educational campaigns and screening to the use of algorithm-driven imaging technologies and performance of assays that identify markers of transformation. This chapter will begin by describing state-of-the-art methods for educating and increasing awareness of at-risk individuals and for performing comprehensive screening examinations. Standard and advanced photographic methods designed to improve reliability and reproducibility of the clinical examination will also be reviewed. Devices that magnify and/or enhance malignant features of individual melanocytic lesions (and algorithms that are available to interpret the results obtained from these devices) will be compared and contrasted. In vivo confocal microscopy and other cellular-level in vivo technologies will be compared to traditional tissue biopsy, and the role of a noninvasive "optical biopsy" in the clinical setting will be discussed. Finally, cellular and molecular methods that have been applied to the diagnosis of melanoma, such as comparative genomic hybridization (CGH), fluorescent in situ hybridization (FISH), and quantitative reverse transcriptase polymerase chain reaction (qRT-PCR), will be discussed.

Translating Atopic Dermatitis Management Guidelines Into Practice for Primary Care Providers.

Atopic dermatitis affects a substantial number of children, many of whom seek initial treatment from their pediatrician or other primary care provider. Approximately two-thirds of these patients have mild disease and can be adequately managed at the primary care level. However, recent treatment guidelines are written primarily for use by specialists and lack certain elements that would make them more useful to primary care providers. This article evaluates these recent treatment guidelines in terms of evaluation criteria, treatment recommendations, usability, accessibility, and applicability to nonspecialists and integrates them with clinical evidence to present a streamlined severity-based treatment model for the management of a majority of atopic dermatitis cases. Because each patient's situation is unique, individualization of treatment plans is critical as is efficient communication and implementation of the plan with patients and caregivers. Specifically, practical suggestions for individualizing, optimizing, implementing, and communicating treatment plans such as choosing a moisturizer formulation, avoiding common triggers, educating patients/caregivers, providing written treatment plans, and scheduling physician follow-up are provided along with a discussion of available resources for patients/caregivers and providers.

Prehydration is effective for rapid control of recalcitrant atopic dermatitis.

BACKGROUND: Skin care remains a key component in atopic dermatitis (AD) management; there are no data available guiding optimal bathing recommendations. OBJECTIVE: This study aims to determine whether 15-minute to 20-minute baths followed by topical corticosteroid application (prehydration therapy) are effective for clearing moderate to severe AD. METHODS: In the Oregon Health & Science University outpatient dermatology clinic, a retrospective review was done of the health records of patients with AD seen first between January 1, 2007, and December 31, 2011, who were then reevaluated within 1 to 3 weeks of starting the therapy. Qualifying patients underwent the prehydration regimen and were reevaluated. The primary outcome was therapeutic response using the Investigators' Global Assessment Scale. Secondary outcomes were measured using the dynamic Treatment Response Scale. Of 110 distinct electronic records, 35 patients were excluded. At the initial visit, 75 patients were evaluated with the Investigators' Global Assessment Scale. Forty-eight patients (64%) were severe, and 27 patients (36%) were moderate. All subjects began prehydration therapy followed by topical corticosteroid. At follow-up visit in 1 to 3 weeks when using the patient's or provider's assessment of treatment response, 59 patients (79%) had marked improvement, and 3 patients (4%) were clear. CONCLUSIONS: Prehydration followed by topical corticosteroid therapy seems to be a highly effective regimen that achieves rapid control of moderate to severe disease.

Transcutaneous yellow fever vaccination of subjects with or without atopic dermatitis.

BACKGROUND: Atopic dermatitis (AD) is a common inflammatory skin disease with a global prevalence ranging from 3% to 20%. Patients with AD have an increased risk for complications after viral infection (eg, herpes simplex virus), and vaccination of patients with AD with live vaccinia virus is contraindicated because of a heightened risk of eczema vaccinatum, a rare but potentially lethal complication associated with smallpox vaccination. OBJECTIVE: We sought to develop a better understanding of immunity to cutaneous viral infection in patients with AD. METHODS: In a double-blind randomized study we investigated the safety and immunogenicity of live attenuated yellow fever virus (YFV) vaccination of nonatopic subjects and patients with AD after standard subcutaneous inoculation or transcutaneous vaccination administered with a bifurcated needle. Viremia, neutralizing antibody, and antiviral T-cell responses were analyzed for up to 30 days after vaccination. RESULTS: YFV vaccination administered through either route was well tolerated. Subcutaneous vaccination resulted in higher seroconversion rates than transcutaneous vaccination but elicited similar antiviral antibody levels and T-cell responses in both the nonatopic and AD groups. After transcutaneous vaccination, both groups mounted similar neutralizing antibody responses, but patients with AD demonstrated lower antiviral T-cell responses by 30 days after vaccination. Among transcutaneously vaccinated subjects, a significant inverse correlation between baseline IgE levels and the magnitude of antiviral antibody and CD4(+) T-cell responses was observed. CONCLUSIONS: YFV vaccination of patients with AD through the transcutaneous route revealed that high baseline IgE levels provide a potential biomarker for predicting reduced virus-specific immune memory after transcutaneous infection with a live virus.

Atopic dermatitis.

Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by intense pruritus and frequent relapsing courses. It occurs mostly in patients who have a personal or family history of other atopic conditions, such as asthma or allergic rhinitis. The prevalence of AD is high, particularly in children, with rapidly increasing numbers in the past few decades. The chronicity of this disease, along with its relapsing nature, presents treatment and management challenges for clinicians and frustration for patients and their families.

Efalizumab for severe atopic dermatitis: a pilot study in adults.

BACKGROUND: Severe atopic dermatitis (AD) often cannot be adequately controlled with topical agents. The continuous use of current systemic therapies for AD is limited by end-organ toxicities. A safe and effective systemic therapy for patients with recalcitrant AD is greatly needed. OBJECTIVE: To evaluate the potential safety and efficacy of efalizumab, an inhibitor of T cell activation and migration, in adults with severe AD. METHODS: An investigator-initiated, prospective, open-label, pilot study was conducted involving ten subjects with severe AD. Subjects received an initial conditioning subcutaneous dose of efalizumab of 0.7 mg/kg followed by 1.0 mg/kg weekly for another 11 weeks for a total of 12 doses. The primary efficacy outcome was the change in the mean Eczema Area and Severity Index (EASI) score from baseline as measured at week 12. Monitoring of adverse events continued for 8 weeks after discontinuation of therapy. RESULTS: EASI scores improved from a mean baseline score of 37.1 +/- 13.5 to 17.6 +/- 14.5 at week 12 (52.3% improvement; P < .0001). Six out of ten subjects reached at least a 50% improvement in EASI score by week 12. Pruritus levels decreased from 6.9 cm +/- 1.8 cm to 4.9 cm +/- 2.5 cm utilizing a visual analogue score (P < .015). Overall, efalizumab was well tolerated. There were three significant adverse events during the course of this study, including thrombocytopenia, viral gastroenteritis, and a subject with worsening of disease beyond baseline levels after drug discontinuation. LIMITATIONS: It is difficult to apply these findings to larger populations of patients with AD because this study lacked a control group and involved a small number of subjects with very severe disease. Long-term efficacy and safety of efalizumab in this population is not known. CONCLUSIONS: Efalizumab therapy resulted in significant clinical improvements in six of ten subjects with severe AD. Efalizumab may serve as a good alternative to current systemic immunosuppressants used for AD; however, double-blind placebo-controlled studies are needed to test its efficacy and safety.

Does food allergy cause atopic dermatitis? Food challenge testing to dissociate eczematous from immediate reactions.

The objective is to evaluate and diagnose, in a controlled setting, suspected food allergy causation in patients hospitalized for management of severe, unremitting atopic dermatitis (AD). Nineteen children were hospitalized at Oregon Health and Science University with atopic dermatitis from 1986 to 2003 for food restriction, then challenge, following standard recommendations. Challenges were prioritized by categories of (a) critical foods (e.g., milk, wheat, egg, soy); (b) important foods; and (c) other suspected foods. Patients were closely observed for evidence of pruritus, eczematous responses, or IgE-mediated reactions. If results were inconsistent, double-blind, placebo-controlled food challenge was performed. A total of 17 children with atopic dermatitis were assessed. Two could not be fully evaluated, thus were excluded from data tabulations. Only one positive eczematous food response was observed of 58 challenges. Three children had well-documented histories of food-induced IgE-mediated anaphylactoid or urticaria reactions to seafood and/or nuts and were not challenged with those foods. Atopic dermatitis, even in the highest-risk patients, is rarely induced by foods. Undocumented assumptions of food causation detract from proper anti-inflammatory management and should be discouraged. Immediate IgE-mediated food reactions are common in atopic dermatitis patients; such reactions are rapid onset, typically detected outside the clinic, and must be distinguished from eczematous reactions. Diagnosis of food-induced eczema cannot be made without food challenge testing. Such tests can be practical and useful for dispelling unrealistic assumptions about food allergy causation of atopic dermatitis.

Patterns of care and referral in children with atopic dermatitis and concern for food allergy.

Although many providers believe that up to 30% of atopic dermatitis (AD) is food induced, food challenge studies show that food-induced eczematous reactions are rare. When food allergy is suggested to cause AD, it often leads to allergy testing with a high false-positivity rate, in turn further focusing parents on food allergy. Study subjects were children less than 11 years old with AD and food allergy suspicion. Prior diagnoses, provider, and testing patterns were assessed by questionnaire given to the parents. Thirty-eight patients with AD were enrolled. Most subject's parents suspected food allergy induced AD. Initial skin diagnoses were made by pediatricians (79%) and family practitioners (18%) as eczema. Allergy was suggested by providers as cause for AD in 63% of the present study's patients. Seventy-nine percent had allergy testing. Greater than 90% of parents claimed their children had food allergy and food-induced AD. Sixty-six percent had positive food allergy tests and 37% had definite history of immediate IgE reactions to food. The majority of this population had allergy suggested as causative for eczema by their primary care provider and were subsequently evaluated by allergist and allergy testing. Consensus about the role of food allergy between the different providers of AD in children would result in more effective, efficient, and less costly health care.

The role of the dermatology nurse in atopic dermatitis management.

The dermatology nurse plays a unique role in managing atopic dermatitis (AD). Education and prevention are the primary focus of the dermatology nurse, and he or she can also play a vital role as a patient advocate.

Patient and physician perspectives vary on atopic dermatitis.

We compared the written responses of physicians (n=303) and patients (n=961) from a nationwide US survey concerning atopic dermatitis (AD). Physicians, primarily dermatologists, responded to 32 questions, and patients responded to 44 questions about AD and its management. Most physicians and patients were in agreement regarding disease severity, the relative lack of effectiveness of over-the-counter products, concerns about drug adverse effects, and the need for more patient support groups. However, physicians were more concerned about long-term adverse effects than were patients. Additionally, 91% of physicians versus 46% of patients rated prescription medications as "moderately" or "very" effective. Patients were generally pleased with their overall AD-related medical care: 42% were "a lot" or "very" satisfied, while only 8% were dissatisfied. Although physician and patient perceptions sometimes differed, both groups preferred treatments offering greater effectiveness, fewer adverse effects, and greater applicability to the pediatric population.