Impact of climate change on atopic dermatitis: A review by the International Eczema Council.

Atopic dermatitis (AD), the most burdensome skin condition worldwide, is influenced by climatic factors and air pollution; however, the impact of increasing climatic hazards on AD remains poorly characterized. Leveraging an existing framework for 10 climatic hazards related to greenhouse gas emissions, we identified 18 studies with evidence for an impact on AD through a systematic search. Most climatic hazards had evidence for aggravation of AD the impact ranged from direct effects like particulate matter-induced AD exacerbations from wildfires to the potential for indirect effects like drought-induced food insecurity and migration. We then created maps comparing the past, present, and future projected burden of climatic hazards to global AD prevalence data. Data are lacking, especially from those regions most likely to experience more climatic hazards. We highlight gaps important for future research: understanding the synergistic impacts of climatic hazards on AD, long-term disease activity, the differential impact on vulnerable populations, and how basic mechanisms explain population-level trends.

A Practical Guide to Using Oral JAK Inhibitors for Atopic Dermatitis from the International Eczema Council.

BACKGROUND: Janus kinase inhibitors (JAKinibs) have the potential to dramatically alter the landscape of atopic dermatitis (AD) management due to their promising efficacy results from phase 3 trials and rapid onset of action. However, JAKinibs are not without risk, and their use is not appropriate for all AD patients, making this a medication class that dermatologists should understand and consider when treating patients with moderate-to-severe AD. OBJECTIVE: This consensus expert opinion statement from the International Eczema Council (IEC) provides a pragmatic approach to prescribing JAKinibs, including choosing appropriate patients, dosing, clinical and lab monitoring, as well as long-term use. METHODS: An international cohort of authors from the IEC with expertise in JAKinibs selected topics of interest and were formed into authorship groups covering 10 subsections. The groups performed topic-specific literature reviews, consulted up-to-date adverse event (AE) data, referred to product labels and provided analysis and expert opinion. The manuscript guidance and recommendations were reviewed by all authors as well as the IEC Research Committee. RESULTS: We recommend JAKinibs be considered for patients with moderate to severe AD seeking the benefits of rapid reduction in disease burden and itch, oral administration, and the potential for flexible dosing. Baseline risk factors should be assessed prior to prescribing JAKinibs, including increasing age, venous thromboembolisms, malignancy, cardiovascular health, kidney/liver function, pregnancy and lactation, and immunocompetence. Patients being considered for JAKinib therapy should be current on vaccinations and we provide a generalized framework for laboratory monitoring, though clinicians should consult individual product labels for recommendations as there are variations among the JAKinib class. Patients who achieve disease control should be maintained on the lowest possible dose, as many of the observed AEs occurred in a dose-dependent manner. Future studies are needed in AD patients to assess the durability and safety of continuous long-term use of JAKinibs, combination medication regimens, and the effects of flexible, episodic treatment over time. CONCLUSIONS: The decision to initiate a JAKinib should be shared among patient and provider, accounting for AD severity and personal risk/benefit assessment, including consideration of baseline health risk factors, monitoring requirements and treatment costs.

Perivascular clusters of Th2 cells and M2 macrophages in allergic contact dermatitis to methylchloroisothiazolinone and methylisothiazolinone.

BACKGROUND: Methylisothiazolinone (MI) and Methylchloroisothiazolinone (MCI) are among the most common skin sensitizers, yet the immunological events that occur during MCI/MI allergic contact dermatitis (ACD) are still poorly understood. OBJECTIVES: To analyse dendrocytes, macrophage subtypes and T cells in skin during the elicitation phase of MCI/MI ACD. METHODS: Thirteen patients with positive patch test reactions to MCI/MI (ACD group) and 11 individuals with negative patch test results were selected. Skin biopsies were only performed at 48 hours of patch testing. Immunohistochemistry was conducted to assess T cells, dendrocytes (Factor XIIIa), M1 (p-Stat1, CD68) and M2 (c-Maf, CD163) macrophages. Transcriptional analyses were performed for cytokines and related factors, and further compared to atopic dermatitis samples (n=4). Immunofluorescence assays addressed T cells location, along with IL-4 or IL-13, within the skin. RESULTS: MCI/MI elicited dermal dendrocytes and macrophages, pronouncedly the M2 subtype. T cells, majorly CD4+ T cells, accumulated in the perivascular areas. Similarly, abundant IL-4 protein was detected in these areas. There was an upregulation of IL-4 and IL-13 mRNA expression, a mild increase in IFNG mRNA levels and a down-regulation of RORC in the ACD group. Immunofluorescence revealed dermal clusters of T cells co-localized with IL-4. CONCLUSIONS: M2 macrophages and Th2 cells participate in the immunopathogenesis of MCI/MI ACD. Dermal dendrocytes and M2 macrophages may assist the formation of CD4+ T cells perivascular clusters. These findings render a mechanistic insight into the MCI/MI reaction. Further analysis at different timepoints of patch testing is required to fully comprehend this ACD kinetics.

IgG from atopic dermatitis patients induces non-atopic infant thymic invariant natural killer T (iNKT) cells to produce IL-4, IL-17, and IL-10.

BACKGROUND: Atopic dermatitis (AD) pathogenesis still needs to be elucidated, but invariant natural killer T (iNKT) cell involvement was already described by several groups. Our group has demonstrated that IgG antibodies purified from AD patients can modulate cytokine production by thymic T cells. Here we aimed to investigate if IgG from AD patients can modulate infant non-atopic thymic iNKT cells cytokine production in order to collaborate with the elucidation of AD development in infancy. METHODS: Thymic tissues were obtained from children from non-atopic mothers, and IgG was purified from AD patients diagnosed as moderate or severe and, as controls, from subjects clinically classified as non-atopic individuals. PBMCs from non-atopic individuals were also used in this study. RESULTS: Our results demonstrated that IgG from AD patients could induce non-atopic children thymic iNKT cells to produce higher levels of intracellular IL-4, IL-10, and IL-17 when compared to all control conditions. No effect was observed in non-atopic adults peripheral iNKT. We also observed that IgG from AD patients induces an increase in the expression of CD4 and Rorγt transcription factor in non-atopic children thymic iNKT cells compared to the condition of all controls. CONCLUSIONS: These observations suggest that IgG from AD patients can induce a cytokine profile by thymic iNKT cells from non-atopic infants compatible with the observations in AD development, which can collaborate with the elucidation of AD pathogenesis.

IgG from atopic dermatitis patients induces IL-17 and IL-10 production in infant intrathymic TCD4 and TCD8 cells.

INTRODUCTION: Our group recently demonstrated that IgG modulates αßT cell cytokine production during the maturation process in the human thymus. The effects of this modulation are IgG repertoire dependent and can exert a systemic and long-term impact. OBJECTIVE: To investigate whether IgG from atopic dermatitis (AD) patients can modulate cytokine production of infant intrathymic TCD4 and TCD8 cells in vitro. METHODS: Thymic tissues were obtained from newborn children from nonatopic mothers, and thymocytes were cultured for 6 days with purified IgG from AD patients or with intravenous immunoglobulin (IVIG) or mock conditions as controls. Cells were gated as double positive T cells (TDP- CD4+ CD8+ ), TCD4 cells (CD4+ CD8- ), or TCD8 cells (CD4- CD8+ ), and intracellular levels of IL-17A, IFN-γ, TNF-α, IL-4, IL-10, and TGF-ß were evaluated by flow cytometry. RESULTS: Compared to mock and IVIG culture conditions, IgG of AD individuals induced in vitro intracellular production of IL-17 and IL-10 by intrathymic TDP, TCD4, and TCD8 cells of infants. TGF-ß was also detected at a higher frequency in response to AD IgG in TDP and TCD8 cells compared to mock and IVIG cultured conditions. An opposite effect was detected upon IFN-γ production in TCD4 cells, such that AD IgG reduced IFN-γ production compared to production under mock conditions but not under IVIG conditions. CONCLUSION: IgG of AD patients can stimulate cytokine production in infant thymocytes and thus resembles the peripheral profile observed in adults. These findings suggest a novel mechanism that can contribute to AD pathogenesis.

Profile of skin barrier proteins and cytokines in adults with atopic dermatitis.

Atopic dermatitis (AD), an inflammatory skin disorder with chronic course and characterized by intense pruritus, is a dermatosis of high prevalence of childhood. However, persistence of the disease in adolescents and adults may occur, and more studies regarding the interactions of the complex triggering factors, especially between the adaptive and innate immune alterations and skin barrier defects are needed. In this review the authors summarize the major novel findings of a dysfunctional skin barrier in AD, with emphasis on tight junction components, such as claudins and on proteins of the keratinocyte differentiation, such as filaggrin. This review also provides an update on the characterization of immune response in adults with atopic dermatitis. The adaptive immune dysfunction in AD, classically known as a Th2/Th1 model, has changed its profile, with recent reported cytokines such as interleukins 17, 22, and 31; as for the innate immune system scenario in AD, the characterization of skin microbiome opens new frontiers for the understanding of such a complex inflammatory disease.

Evidence of regulatory myeloid dendritic cells and circulating inflammatory epidermal dendritic cells-like modulated by Toll-like receptors 2 and 7/8 in adults with atopic dermatitis.

BACKGROUD: Atopic dermatitis (AD) is a chronic, inflammatory skin disease characterized by intense pruritus and xerosis. Dendritic cells (DC) play an essential role in tissue inflammation in atopic dermatitis (AD) skin, especially the inflammatory epidermal dendritic cells (IDEC), a particular subset of myeloid dendritic cells (mDC). The aim of the present study was to assess the phenotype and function of mDC and circulating IDEC-like in peripheral blood mononuclear cells (PBMC) of adults with AD. METHODS: We selected 21 AD patients and 21 non-AD controls, age and gender matched. Expressions of FcεRI, CD36, TNF, IFN- γ, and IL-10 in mDC were analyzed by flow cytometry under various stimuli, such as staphylococcal enterotoxin B (SEB), TLR2 (Pam3CSK4), TLR4 (LPS), and TLR7/8 (CL097) agonists. RESULTS: The most prominent findings in AD patients were: (i) enhanced frequency of IL-10 under TLR4 (LPS), and decreased frequency of IFN-γ and TNF under TLR2 (Pam3CSK4) and 7/8 (CL097) stimulation in classic mDC; (ii) elevation of circulating IDEC-like frequency with TLR2 (Pam3CSK4) stimuli, augmented frequency of IFN-γ in nonstimulated condition, and of IL-10 under TLR7/8 (CL097) stimuli in IDEC-like population. CONCLUSIONS: In AD individuals, classic mDC showed an immunomodulatory profile, favoring tolerance in a combined action with IDEC-like, and inducing Th1 polarization. Our findings indicate a potential role of IDEC-like in the maintenance of inflammation in atopic dermatitis patients; moreover, IDEC-like may exert a regulatory impact on T cells of AD individuals through IL-10, often induced by agonist mimicking single stranded RNA virus.

Staphylococcal enterotoxin B induces specific IgG4 and IgE antibody serum levels in atopic dermatitis.

BACKGROUND: Atopic dermatitis (AD) is a chronic recurrent inflammatory disease, with prevalence of about 10-20% in children and 1-3% in adults. Staphylococcus aureus is present in 80-100% of skin from atopic patients and is related to worsening of the disease by the action of enterotoxins. The aim of this study was to evaluate the profile of anti-Staphylococcus aureus enterotoxin B (SEB) antibody isotypes and IgG subclass levels in adult AD. METHODS: We selected 38 patients with AD, diagnosed by Hanifin and Rajka's criteria, aged between 18 and 65, and 26 healthy controls (HC). The severity of the disease was established according to the Eczema Area and Severity Index and patients graded as mild (28%), moderate (58%), and severe (14%). Sera were assessed for IgG subclasses, IgA, IgM, and IgE against SEB by ELISA. RESULTS: Elevated circulating IgE and IgG4 anti-SEB antibody levels associated with decreased IgA and IgM levels were detected in patients with AD, when compared to HC individuals. The severity of AD was related to low IgG1 and IgG3 levels and a high IgE antibody response to SEB. Interestingly, absence of IgG4 response to SEB was lower in patients with AD (2.63%), when compared to controls (34.6%), while a similar absence was detected for IgG1 and IgE antibodies (AD, 23.3 and 18.4% vs. HC, 38.5 and 19.2%). CONCLUSION: Our findings evidenced a contributing role for IgG4 and IgE antibodies in AD pathogenesis, which are triggered by staphylococcal superantigens.