Thursday, November 5, 2015
Nocturnal eczema: Review of sleep and circadian rhythms in children with atopic dermatitis and future research directions
Atopic dermatitis (AD) is characterized by intense nocturnal pruritis, which can severely impact sleep continuity and quality. Sixty percent of children with AD experience sleep disturbance due to their condition, with 83% reporting disturbance during exacerbations. Sleep deprivation has been shown to alter immune function. In the case of school-aged children, it can impair linear growth, and in fact short stature has been described in children with AD only when associated with insufficient sleep. Fishbein et al review our current understanding of the role of sleep and circadian rhythms in nocturnal AD, current treatments, and future research directions (J Allergy Clin Immunol 2015; 136: 1170-1177).
Despite the widespread prevalence of sleep dysfunction in children with AD, the mechanisms that lead to it are not well understood. Nighttime factors such as cortisol nadir, increased skin temperature, and poor barrier function may contribute to noctural AD exacerbations, as may circadian variation in the expression of inflammatory cytokines such as IL-2, IL-6, and the pruritus-specific TH2 cytokine IL-31. In addition, children with AD can have comorbidities including increased susceptibility to infection; heightened sensitivity to sensory stimulation; and restless leg syndrome, defined as an urge at night and prior to sleep to move the legs.
Treatment of pediatric AD should focus on disease control with sleep disturbance as an important measure. Topical steroids can improve sleep disturbance, as can wet wrap therapy. Antihistamines are often first line therapy but there is limited data to support this practice and future research is necessary. Actigraphy has been demonstrated to provide an accurate assessment of sleep in children, and standardized scoring parameters do not currently exist. Children with AD need a standardized, patient-centered outcome tool that could assess their sleep impairment, correlated with objective sleep measures. Given that approximately 10% of genes are under circadian control, future exploration of circadian biomarkers would open possibilities for a novel treatment paradigm as well.
Genetic errors of the human caspase recruitment domain-B-cell lymphoma 10–mucosa-associated lymphoid tissue lymphoma-translocation gene 1 (CBM) complex: Molecular, immunologic, and clinical heterogeneity
The CBM complex consists of three components: a capase recruitment domain (CARD) protein, B-cell lymphoma 10 (BCL10), and mucosa-associated lymphoid tissue lymphoma-translocation gene 1 (MALT1). For the first component, the complex uses one of three CARD family adaptors: CARD9, CARD10, or CARD11. These three proteins activate nuclear factor κB (NF- κB) in both innate and adaptive human immunity, and NF- κB plays a critical role in immune regulation, cell memory, cell survival/apoptosis, and cell-cycle progression. Much remains to be learned about the CBM complex, and inherited defects have been recently reported. Pérez de Diego et al discuss (J Allergy Clin Immunol 2015; 136: 1139-1149).
The authors summarize the reports on four patients with MALT1 deficiency, one patient with BCL10 deficiency, and two patients with autosomal recessive (AR) CARD11 deficiency. Most of these patients carried homozygous mutations with low levels of protein expression, and the broad range of clinical presentations included serious conditions of the skin and of the respiratory and gastrointestinal tracts, infection, and growth retardation. Thirty-eight patients were reported with AR CARD9 deficiency following its initial description in 2009, making it the most common genetic disorder of the CBM complex. All of these 38 patients were highly susceptible to various fungal diseases. Finally, mutations in MALT1, BCL10, and CARD11 have been found in patients with MALT lymphoma and other lymphoproliferative disorders.
It is clear that defects of CARD 11, BCL10, and MALT 1 generate severe forms of combined immunodeficiency. Three of the patients mentioned above have died, and two others have undergone bone marrow transplantation, which appears to be the best treatment currently available. In contrast, patients with CARD9 deficiency have abnormalities in innate immunity leading to increased susceptibility to invasive disease. Adjuvant GM-CSF treatment has shown benefit for one patient with C albicans meningoencephalititis; and terbinafine and posaconazole have been used to treat patients with extensive dermatophytosis. The CBM complex makes substantial contributions to human immunity. Further studies should improve our understanding of the specific role of each of its components.
The Asian atopic dermatitis phenotype combines features of atopic dermatitis and psoriasis with increased TH17 polarization
Atopic dermatitis (AD) is the most common inflammatory skin disease, with a large and currently unmet need for effective therapeutics. AD and psoriasis, another common skin disease, are recognized as polar inflammatory skin diseases. Psoriasis is emerging as an IL-23/TH17-skewed disease, whereas AD is considered to be TH2-centered. These distinctions are relevant to emerging therapies for each. To date, the characterization of AD in different patient populations has made the assumption that disease mechanisms are similar across them. Noda et al present evidence that this is not so (J Allergy Clin Immunol 2015; 136: 1254-1264).
The prevalence of AD among adults in Asia is 7% to 10%, which is considerably higher than in other populations. In addition, prominent TH17 activation has been observed in blood and acute AD lesions of Asian AD patients. The high prevalence and increased IL-17+ T-cell expansion suggest that an Asian AD phenotype may have different immune and barrier characteristics than the European American (EA) one. The authors have thus directly compared AD in European American (EA) and Asian (Japanese and Korean) populations. Their report classifies an Asian AD phenotype that is mixed between the EA AD and psoriasis phenotypes, with features atypical to AD such as parakeratosis and a unique cytokine profile with co-activation of the TH2 and TH17 axes. Even in the presence of increased IgE levels, Asian AD shows significantly higher induction of TH17 and TH22-related cytokines. Interestingly, psoriasis has a very low prevalence in Asian populations.
Further studies are needed to clarify the extent to which these differences are genetic, environmental, and/or microbiome related; for example, a similar study of Asian AD patients and Asian American AD patients. Additionally, FLG mutation status was unknown for all of the patients the current study includes. Regardless, the differences in the phenotype of Asian AD presented here call for similar description of other racial groups, and they provide a rationale for testing of IL-17/IL-23-targeted therapeutic strategies that have been successfully used in the treatment of psoriasis, in addition to those that are TH2-specific.
Primary Immunodeficiency Diseases (PIDD) are inherited disorders of immune function that result in an increased rate and severity of infection, immune dysregulation, autoimmune disease, abnormal inflammatory responses, and malignancy. More than 300 disorders have been identified to date; they occur in as many as 1:2000 live births. Approximately half of those diagnosed with a PIDD have an antibody deficiency.
The principal clinical manifestation of immunodeficiency is an increased susceptibility to infection. In its evaluation, it is critical to the extent possible to document the foci of infections, the organisms, and the response to treatment. This distinguishes specific infectious agents and may help determine other conditions such as non-infectious inflammation. It is important to note that allergy to environmental allergens, food, or both can be an important element of and diagnostic clue for many PIDDs.
Under the aegis of the American Academy of Allergy, Asthma & Immunology (AAAAI); the American College of Allergy, Asthma & Immunology (ACAAI); and the Joint Council of Allergy, Asthma & Immunology (JCAAI) Bonilla et al present an updated practice parameter (J Allergy Clin Immunol 2015; 136: 1186-1205) designed to serve as a practical guide for the clinical recognition and diagnosis of immunodeficiency, along with the general principles that guide management of such disorders.
The practice parameter organizes current knowledge and best practices. Its preparation included a review of the medical literature followed by ratings of published clinical studies or reports according to category of evidence. The ratings were then used to establish the strength of a given clinical recommendation. The practice parameter does not focus on detailed pathophysiology of various disorders. It consists of 239 summary statements, each containing a specific recommendation for clinical diagnosis or management. An executive summary and several tables and diagnostic algorithms accompany the text.
While developed with the consultant allergist/immunologist in mind, the practice parameter may serve as a useful reference for physicians in all specialties and at all levels of training. It may also be useful to administrators in the managed care or insurance fields. The authors hope to foster wider recognition of primary immunodeficiency, increase uniformity and efficiency in evaluation, and enhance application of specific diagnoses.