The Editors' Choice
Authors: Zuhair K. Ballas
Journal: Journal of Allergy and Clinical Immunology (2019)

Atopic dermatitis (AD) and psoriasis are both very common inflammatory skin diseases that show a clear familial predisposition. Familial psoriasis was previously found to result from gain-of-function mutations in CARD14, which encodes the caspase recruitment domain-containing protein 14 (CARD14), a key regulator of NF-κB activity. In this issue, Peled et al (p 173) report that loss-of-function mutations in the same gene are associated with a severe variant of AD. The following are the major clinical implications of this study:•Decreased activity of CARD14 signaling leads to downregulation of antimicrobial peptide secretion, which in turn might underlie the susceptibility of these and other patients with AD to infections.•Psoriasis and AD can be caused by opposite mechanisms associated with dysregulation of NF-κB activity (see Figure). Therefore, any intervention targeting CARD14 may exacerbate one of the 2 clinical phenotypes, suggesting the need to direct interventions in both diseases to CARD14 targets rather than to the molecule itself. Although the role of CARD14 in patients with more common forms of AD remains to be elucidated, this paper illustrates how the study of rare conditions can sometimes shed light on normal human biology. Three anti–IL-5 pathway–directed treatments are available for clinical use in asthmatic patients: mepolizumab, reslizumab, and benralizumab. All have proved effective in the treatment of severe eosinophilic asthma. Clinicians are faced with having to make a choice of which anti–IL-5 pathway treatment to use, with little comparative data to aid in this selection. Busse et al (p 190) performed an indirect treatment comparison using data from the Cochrane review and independent searches. For these analyses, clinical outcomes, exacerbations, lung function, and symptoms were compared in relation to different blood eosinophil cut points: 150-300 cells/μL, 300-400 cells/μL, and 400 or 450 cells/μL or greater. These analyses are an attempt to compare more precisely the efficacy of the individual anti–IL-5 pathway treatments; but as the authors note (and as detailed in an editorial in this issue, p 84), inherent limitations to any approach exist and need to be considered when selecting an anti–IL-5 treatment. As the article points out, the multiple individual variables and outcomes that potentially will provide guidance in selecting an anti–IL-5 treatment need to be based on equivalence of conditions. Atopic dermatitis (AD) is a chronic inflammatory skin disease. Its burden is multidimensional, affecting sleep, psychosocial activities, and health-related quality of life. The symptoms of many patients with moderate-to-severe disease are not controlled with the current treatment regimen. Tralokinumab is a fully human mAb that potently and specifically neutralizes IL-13, a pathogenic mediator in patients with AD whose overexpression has been shown to reduce epithelial integrity by means of downregulation of the skin barrier. In this study, Wollenberg et al (p 135) report the following findings;•Tralokinumab demonstrated clinically significant improvement in co-primary endpoints (Eczema Area Severity Index [EASI] score and Investigator's Global Assessment [IGA] response) in patients with moderate-to-severe AD.•The improvements in EASI score (adjusted mean difference change from baseline, −4.94 vs −8.76 for placebo) was evident at week 4 and maintained beyond week 12. The numeric improvement in IGA response rates (26.7% vs 11.8% in placebo-treated subjects) was observed with increasing dose of tralokinumab. The clinically meaningful benefits observed with tralokinumab might be a promising target for patients with moderate-to-severe AD. IL-22 upregulation characterizes atopic dermatitis (AD) lesions. However, molecular effects of IL-22 blockade have not been defined in human subjects. Brunner et al (p 142) assessed biopsy specimens from a 2:1 placebo-controlled phase II trial with fezakinumab, an mAb blocking IL-22, in 59 patients with moderate-to-severe AD. The authors found the following:•Significant improvement in the cutaneous gene signature (transcriptome) with fezakinumab was only present in patients with high baseline IL-22 skin expression but not in those with low baseline IL-22 expression.•Downregulation of multiple immune pathways (TH1, TH2, and TH17/TH22 markers) with fezakinumab was restricted to the IL-22–high group. This study suggests the potential for personalized medicine in patients with AD. Clinically, baseline cytokine expression levels might be able to guide targeted therapeutic decisions. Given the fact that IL-22 receptor expression in the skin is limited to keratinocytes, this study also suggets that epidermal responses to T cell–derived cytokines can “feed-forward” inflammation to amplify pathologic immune responses. In this issue, Wilson et al (p 395) established that the Impact of Asthma on Quality of Life (A-IQOLS), a measure of the patient-perceived negative effect of asthma on the patient's life, is reliable and valid and that the A-IQOLS score provides information not provided by other physiologic and patient-reported measures. The authors used pooled data from 597 racially, ethnically, geographically, and educationally diverse participants in 5 asthma studies to analyze the performance of the A-IQOLS in diverse patient subgroups. Offspring of asthmatic women randomized to fraction of exhaled nitric oxide or clinical management during pregnancy were followed up at preschool age.•The 16 quality-of-life dimensions underlying the A-IQOLS have similar importance for adults of both sexes; all age groups; white, African American, and Asian ancestry; Hispanic and non-Hispanic background; and all levels of education.•The relationships between A-IQOLS scores and measures of asthma symptoms, disease control, and asthma severity are similar across patient subgroups. The A-IQOLS measure is valid for research use and potentially clinical use in demographically and clinically diverse patients. Chronic rhinosinusitis (CRS) is a common chronic inflammatory syndrome and often associated with nasal polyps (NPs). Patients usually respond to systemic anti-inflammatory treatment with systemic corticosteroids. Given the complications of systemic steroids, it is desirable to use locally acting medications. Unfortunately, most patients do not experience satisfactory symptom control with standard steroid nasal sprays. This is thought to be because nasal steroids may not reach key anatomic sites deep in the nose. Persistent symptoms and seriously impaired quality of life are common, and hundreds of thousands of surgeries are performed annually. In this issue, Leopold et al (p 126) report a novel approach using closed-palate exhalation delivery to deposit steroid in superior/posterior regions not well accessed by standard nasal sprays (see Figure). In a population of patients with moderate-to-severe CRS with NPs, often postsurgical, exhalation delivery system with fluticasone (EDS-FLU) improved:•all cardinal symptoms (congestion/decreased smell/pain/drainage);•evidence of inflammation (eg, polyp grade, with some patients' polyps eliminated)•quality of life. In conclusion, the authors found that EDS-FLU produces clinically and statistically significant improvement in all 4 diagnostically defining disease symptoms, polyp grade, and quality of life in patients with CRS with NPs.