Biologic and small-molecule therapy for treating moderate to severe atopic dermatitis: Mechanistic considerations.

Atopic dermatitis (AD) is a complex and heterogeneous skin disease for which achieving complete clinical clearance for most patients has proven challenging through single cytokine inhibition. Current studies integrate biomarkers and evaluate their role in AD, aiming to advance our understanding of the diverse molecular profiles implicated. Although traditionally characterized as a TH2-driven disease, extensive research has recently revealed the involvement of TH1, TH17, and TH22 immune pathways as well as the interplay of pivotal immune molecules, such as OX40, OX40 ligand (OX40L), thymic stromal lymphopoietin, and IL-33. This review explores the mechanistic effects of treatments for AD, focusing on mAbs and Janus kinase inhibitors. It describes how these treatments modulate immune pathways and examines their impact on key inflammatory and barrier biomarkers.

Eosinophils in hidradenitis suppurativa patients exhibit pro-inflammatory traits, implicating a potential pathogenic role in the disease.

Hidradenitis suppurativa (HS) is an inflammatory skin disease characterized by painful nodules, abscesses and purulent secretions in intertriginous regions. Intense pruritus frequently accompanies HS lesions, adding further discomfort for patients. While Th17 pathway activation is implicated in HS pathogenesis, disease mechanisms are still not fully understood, and therapeutics are lacking. Previous reports raise a potential role for eosinophils in HS, showing a strong association of eosinophil levels with disease severity. To investigate eosinophils in HS, we recruited patients and matched healthy controls and then performed flow-cytometry studies, eosinophil stimulation assays, and lesional skin staining for eosinophils. We found that HS patients reported similar levels of pain and itch. Compared to matched controls, HS blood exhibited decreased mature eosinophils and increased numbers of immature eosinophils, coupled with a significant increase in dermal eosinophilic infiltrates. Additionally, IL-17RA+ eosinophils were highly and significantly correlated with multiple HS-related clinical scores. In both stimulated and unstimulated conditions, HS eosinophils showed an inflammatory phenotype versus controls, including an increase in costimulatory T- and B-cell markers (e.g. CD5 and CD40) following all stimulations (TNFα/IL-17A/IL-17F). These findings highlight the significance of pruritus in HS and suggest a higher turnover of eosinophils in HS blood, potentially due to the consumption of eosinophils in skin lesions. Our data delineate the features and functions of eosinophils in HS and suggest that eosinophils participate in disease pathogenesis, advancing Th17-related inflammation. Further studies are needed to investigate eosinophils' response to current HS treatments and their potential as a therapeutic target in the disease.

Intrapatient comparison of atopic dermatitis skin transcriptome shows differences between tape-strips and biopsies.

BACKGROUND: Our knowledge of etiopathogenesis of atopic dermatitis (AD) is largely derived from skin biopsies, which are associated with pain, scarring and infection. In contrast, tape-stripping is a minimally invasive, nonscarring technique to collect skin samples. METHODS: To construct a global AD skin transcriptomic profile comparing tape-strips to whole-skin biopsies, we performed RNA-seq on tape-strips and biopsies taken from the lesional skin of 20 moderate-to-severe AD patients and the skin of 20 controls. Differentially expressed genes (DEGs) were defined by fold-change (FCH) ≥2.0 and false discovery rate <0.05. RESULTS: We detected 4104 (2513 Up; 1591 Down) and 1273 (546 Up; 727 Down) DEGs in AD versus controls, in tape-strips and biopsies, respectively. Although both techniques captured dysregulation of key immune genes, tape-strips showed higher FCHs for innate immunity (IL-1B, IL-8), dendritic cell (ITGAX/CD11C, FCER1A), Th2 (IL-13, CCL17, TNFRSF4/OX40), and Th17 (CCL20, CXCL1) products, while biopsies showed higher upregulation of Th22 associated genes (IL-22, S100As) and dermal cytokines (IFN-γ, CCL26). Itch-related genes (IL-31, TRPV3) were preferentially captured by tape-strips. Epidermal barrier abnormalities were detected in both techniques, with terminal differentiation defects (FLG2, PSORS1C2) better represented by tape-strips and epidermal hyperplasia changes (KRT16, MKI67) better detected by biopsies. CONCLUSIONS: Tape-strips and biopsies capture overlapping but distinct features of the AD molecular signature, suggesting their respective utility for monitoring specific AD-related immune, itch, and barrier abnormalities in clinical trials and longitudinal studies.

Tape strips detect molecular alterations and cutaneous biomarkers in skin of patients with hidradenitis suppurativa.

BACKGROUND: Hidradenitis suppurativa (HS) has a high unmet need for better treatments. Biopsies are considered the gold standard for studying molecular alterations in skin. A reproducible, minimally invasive approach is needed for longitudinal monitoring in trials and in pediatric populations. OBJECTIVE: To determine whether skin tape strips can detect molecular alterations in HS and identify biomarkers of disease activity. METHODS: We performed RNA sequencing on tape strips collected from lesional and healthy-appearing (nonlesional) HS skin (n = 22) and healthy controls (n = 21). We correlated the expression of skin biomarkers between tape strips and a previously published gene-signature of HS biopsies. RESULTS: Tape strips detected upregulation of known HS biomarkers (eg, Interleukin[IL]-17A) in nonlesional and/or lesional skin and also identified novel clinically actionable targets, including OX40 and JAK3. The expression of Th17 and tumor necrosis factor-α pathways were highly correlated between tape strips and biopsies. HS clinical severity was significantly associated with expression of biomarkers (eg tumor necrosis factor-α , IL-17 A/F, OX40, JAK1-3, IL-4R) in HS lesional and/or nonlesional skin. LIMITATIONS: Sample size. Tape stripping is limited in depth. CONCLUSION: This study validates tape strips as a minimally-invasive approach to identify cutaneous biomarkers in HS. This provides a novel avenue for monitoring treatment efficacy and a potential step toward individualized therapy in HS.

Treat-to-target in dermatology: A scoping review and International Eczema Council survey on the approach in atopic dermatitis.

Treat-to-target (T2T) is a pragmatic therapeutic strategy being gradually introduced into dermatology after adoption in several other clinical areas. Atopic dermatitis (AD), one of the most common inflammatory skin diseases, may also benefit from this structured and practical therapeutic approach. We aimed to evaluate existing data regarding the T2T approach in dermatology, with a specific focus on AD, as well as the views of International Eczema Council (IEC) members on the potential application of a T2T approach to AD management. To do so, we systematically searched for peer-reviewed publications on the T2T approach for any skin disease in the PubMed and Scopus databases up to February 2022 and conducted a survey among IEC members regarding various components to potentially include in a T2T approach in AD. We identified 21 relevant T2T-related reports in dermatology, of which 14 were related to psoriasis, five to AD, one for juvenile dermatomyositis and one for urticaria. In the IEC member survey, respondents proposed treatable traits (with itch, disease severity and sleep problems getting the highest scores), relevant comorbidities (with asthma being selected most commonly, followed by anxiety and depression in adults), recommended specialists that should define the approach in AD (dermatologists, allergists and primary care physicians were most commonly selected in adults), and applicable assessment tools (both physician- and patient-reported), in both adult and paediatric patients, for potential future utilization of the T2T approach in AD. In conclusion, while the T2T approach may become a useful tool to simplify therapeutic goals and AD management, its foundation in AD is only starting to build. A multidisciplinary approach, including a wide range of stakeholders, including patients, is needed to further define the essential components needed to utilize T2T in AD.

Verrulyse Methionine® as Monotherapy in Children and Adolescents With Common Warts.

BACKGROUND: Common cutaneous non-genital viral warts are a common skin infection with significant morbidity in the pediatric population. Although various therapeutics are available, many of them necessitate recurrent patient visits and may be associated with significant irritation and pain. Verrulyse Methionine® (VM), a nutritional supplement, was previously suggested as a non-invasive treatment option for the disease. OBJECTIVE: To assess the response to oral VM supplement as a monotherapy in a cohort of children and adolescents with multiple, non-genital viral warts after failing previous treatments. METHODS: We reviewed medical records of pediatric patients (<18 y/o) with viral warts treated with VM between 2010 and 2021. RESULTS: Among 25 patients with multiple verrucae vulgaris lesions who failed previous treatments, 14 (56%) had complete or almost-complete response to VM within 4 months, after an average of 18 months of active disease prior to VM treatment initiation. None of the 4 patients with verruca plana had response to VM treatment. Favourable cosmetic results were found in responders, and no adverse events were recorded. CONCLUSION: Response rates in our cohort are comparable to those reported in the literature for destructive local therapeutics for viral warts. Thus, our data suggest that VM may be considered for children with multiple verrucae vulgaris, providing a painless and non-invasive therapeutic option for this common disease.

The evolving landscape of biologic therapies for atopic dermatitis: Present and future perspective.

Atopic dermatitis (AD) is one of the most common, chronic inflammatory skin diseases with a significant physical, emotional and socioeconomic burden. In recent years the understanding of AD pathogenesis has expanded from the Th2-centred perspective, with the recognition of the involvement of other immune axes. In different AD endotypes, influenced by environment, genetics and race, transcriptomic profiles have identified differing contributions of multiple immune axes such as, Th17, Th22 and Th1. The enriched pathogenic model of AD has catalysed the development of numerous biologic therapies targeting a range of key molecules implicated in disease progression. Currently, dupilumab and tralokinumab, which both target the Th2 pathway, are the only approved biologic therapies for AD in the United States and Europe. New biologic therapies in development, however, target different Th2-pathway molecules along with cytokines in other immune axes, including Th17 and Th22, offering promise for varied treatments for this heterogeneous disease. As the biologic pipeline advances, the integration into clinical practice and approval of these experimental biologics may provide more effective, tailored therapeutic solutions and illuminate on the pathologic processes of AD across a broader, more diverse patient population.

Scalp biomarkers during dupilumab treatment support Th2 pathway pathogenicity in alopecia areata.

BACKGROUND: The mechanisms driving alopecia areata (AA) are still unclear, hindering development of targeted therapeutics. Specific Th2 targeting with dupilumab in AA provides a unique opportunity to dissect its pathogenesis and explore the role of Th2 pathway. METHODS: We evaluated changes in scalp biomarkers in AA patients (with and without concomitant atopy) randomized to weekly dupilumab or placebo for 24 weeks, followed by open-label dupilumab for 24 weeks. Changes in biomarker levels were measured at weeks 12, 24, and 48 and were also correlated with clinical hair regrowth. RESULTS: At week 24, preceding clinical hair regrowth outcomes, only dupilumab-treated patients presented significant suppression of cellular infiltrates, and multiple Th2-related, markers (CCL13/MCP-4, CCL18/PARC, CCL26/eotaxin-3, CCL24/Eotaxin-2), coupled with significant upregulation in the hair keratins. Th1-related suppression was evident later (week 48) when all patients received open-label dupilumab. Results were more pronounced in atopic AA patients, that showed 48% and 97% improvements in the lesional AA scalp profile at weeks 24 and 48, respectively, while 2% worsening was seen in the placebo arm at week 24. Moreover, placebo-treated patients presented 54% worsening in hair keratins when compared with baseline at week 24. At week 24, increases in hair keratins showed significant correlations only with decreases in Th2-related markers. CONCLUSIONS: Scalp biomarkers provide evidence of dupilumab efficacy in AA, detected even prior to clinical response, with exclusive correlations between early suppression of Th2 markers and increased hair keratins. These findings strengthen previous reports suggesting a possible role for Th2 cytokines as AA drivers.

Oral Janus kinase inhibitors for atopic dermatitis.

Atopic dermatitis (AD) is one of the most common inflammatory skin conditions. The pathogenesis of AD involves skin barrier disruption and immune activation of T-helper (TH)2 and TH22 and varying degrees of TH1 and TH17 activation in various patient subtypes. Although AD is mainly driven by TH2, the molecular and clinical heterogeneity of AD underscores the need for more efficacious treatments that target multiple immune axes. Janus kinase (JAK) inhibitors are novel therapeutics that broadly block many AD-related proinflammatory cytokines (interleukin [IL]-4, IL-5, IL-13, IL-31, thymic stromal lymphopoietin, interferon gamma, IL-12, IL-23, IL-17) across different immune pathways. Oral JAK inhibitors have been found to be efficacious in AD, with 2 (abrocitinib and upadacitinib) recently gaining US Food and Drug Administration approval and several others under investigation in clinical trials with promising results. These systemic agents have surpassed conventional thresholds of treatment response, with many patients achieving complete or almost complete skin clearance, and provide a fast-acting alternative therapy for patients who are not responsive to biologics or other conventional therapies. However, systemic JAK inhibitors come with health concerns, requiring additional long-term clinical trials to characterize their safety profile in patients with AD. This review summarizes the current literature on the safety and efficacy of oral JAK inhibitors in AD and discusses future directions for research.

Proteomic characterization of atopic dermatitis blood from infancy to adulthood.

BACKGROUND: Patients with atopic dermatitis (AD) have systemic biomarker dysregulation that differs by age group; however, the proteomic characteristics of these age-based changes are unknown. OBJECTIVE: To profile blood proteins of patients with AD across different age groups versus age-appropriate controls. METHODS: Using the Olink high-throughput proteomic platform, we profiled 375 serum proteins of 20 infants (age, 0-5 years), 39 children (age, 6-11 years), 21 adolescents (age, 12-17 years), and 20 adults (age, ≥18 years) with moderate-to-severe AD and 83 age-appropriate controls. RESULTS: Each group presented a distinct systemic proteomic signature. Th2-related proteins were increased in infant AD and further intensified with age through adolescence and adulthood (interleukin 4/CCL13/CCL17). In contrast, Th1 axis down-regulation was detected in infants with AD and gradually reversed to increased Th1 products (interferon γ/CXCL9/CXCL10/CCL2) in patients with AD from childhood to adulthood. Despite their short disease duration, infants already had evidence of systemic inflammation, with significant upregulation of innate immunity (interleukin 17C/ interleukin-1RN), T-cell activation/migration (CCL19), Th2 (CCL13/CCL17), and Th17 (PI3) proteins. Adults with AD present unique upregulation of cardiovascular proteins related to coagulation and diabetes. LIMITATIONS: Cross-sectional observational study with a single time point. CONCLUSION: Systemic immune signatures of AD are age-specific beyond the shared Th2 immune activation. These data advocate for precision medicine approaches based on age-specific AD profiles.

Phase 2a randomized clinical trial of dupilumab (anti-IL-4Rα) for alopecia areata patients.

BACKGROUND: Treatments for alopecia areata (AA) patients with extensive scalp hair loss are limited, and recent evidence supports a role for type 2 T-cell (Th2)-immune response in AA. Dupilumab, a monoclonal antibody inhibiting Th2 signaling, approved for type 2 diseases including atopic dermatitis, was evaluated in AA patients. METHODS: Alopecia areata patients with and without concomitant atopic dermatitis were randomized 2:1 to receive weekly subcutaneous dupilumab (300 mg) or placebo for 24 weeks, followed by another 24-week dupilumab open-label phase. The primary outcome was change from baseline in the Severity of Alopecia Tool (SALT) score at week 24; secondary outcomes included a range of measures of hair regrowth. RESULTS: Forty and 20 patients were assigned to the dupilumab and placebo arms, respectively. At week 24, disease worsening was documented in the placebo arm, with a least-squares mean change in the SALT score of -6.5 (95% confidence-interval [CI], -10.4 to -2.6), versus a change of 2.2 (95% CI, -0.6 to 4.94) in the dupilumab arm (p < .05). After 48 weeks of dupilumab treatment, 32.5%, 22.5% and 15% of patients achieved SALT30 /SALT50 /SALT75 improvement, respectively, while in patients with baseline IgE ≥ 200 IU/ml response rates increased to 53.8%, 46.2%, and 38.5%, respectively. Moreover, baseline IgE predicts treatment response with 83% accuracy. No new safety signals were detected. CONCLUSIONS: This hypothesis-driven trial is the first to indicate the possible pathogenic role of the Th2 axis and Th2 targeting in AA patients. Patient selection based on baseline serum IgE levels may improve treatment results (Clinicaltrials.gov number, NCT03359356).

Analysis of alopecia areata surveys suggests a threshold for improved patient-reported outcomes.

BACKGROUND: Although alopecia areata (AA) greatly impacts patients' quality of life (QoL), there is no adequate validation of AA-targeted QoL surveys in clinical trials, hindering sufficient representation of patient-reported outcomes. OBJECTIVES: Better understanding of patient-reported outcomes may guide treatment goals and future clinical trials. METHODS: In a recent randomized controlled trial testing dupilumab in AA, patients were administered the Alopecia Areata Quality of Life Index (AA-QLI) and the Alopecia Areata Symptom Impact Scale (AASIS) surveys, specifically evaluating QoL in patients with AA. An in-depth analysis was performed to assess the utility of these questionnaires in this patient population, both at baseline and after treatment, and to determine a threshold for improved patient-reported outcomes. RESULTS: While AASIS correlated with baseline Severity of Alopecia Tool (SALT) scores and with therapeutic response, AA-QLI showed no correlation with AA severity before or after treatment. Itch strongly correlated with serum IgE levels across both surveys. Using various approaches to estimate a discriminative threshold for decreased impact of AA on QoL (by AASIS) following treatment, a SALT score of 20 points or less post-treatment was associated with improved patient-reported outcomes, including both AA-related symptoms and items within the daily activities/feelings domain such as 'feeling sad' and 'feeling anxious or worry'. CONCLUSIONS: AASIS is better than AA-QLI to assess patient-reported outcomes. SALT ≤ 20 following treatment should be considered as a threshold for meaningful therapeutic outcome and as a clinical endpoint in future clinical trials for AA. What is already known about this topic? Alopecia areata greatly compromises quality of life, and affected patients have increased prevalences of depression, anxiety and social phobia. Despite the significant negative impact of the disease on patients' wellbeing, validation of targeted questionnaires in alopecia areata is lacking, and a therapeutic response threshold for improved patient-reported outcomes is unknown. What does this study add? This study investigated the utility of two different alopecia areata-targeted questionnaires - Alopecia Areata Quality of Life Index and Alopecia Areata Symptom Impact Scale (AASIS) - in a clinical trial setting. AASIS was found to correlate strongly with alopecia areata severity and clinical response. What are the clinical implications of this work? Patients with ≤ 20% scalp hair loss after treatment reported improvement in multiple quality-of-life items, suggesting this as a meaningful therapeutic outcome that may guide clinicians and improve the development of future clinical trials.

Biomarkers in atopic dermatitis-a review on behalf of the International Eczema Council.

Atopic dermatitis (AD) is a common yet complex skin disease, posing a therapeutic challenge with increasingly recognized different phenotypes among variable patient populations. Because therapeutic response may vary on the basis of heterogeneous clinical and molecular phenotypes, a shift toward precision medicine approaches may improve AD management. Herein, we will consider biomarkers as potential instruments in the toolbox of precision medicine in AD and will review the process of biomarker development and validation, the opinion of AD experts on the use of biomarkers, types of biomarkers, encompassing biomarkers that may improve AD diagnosis, biomarkers reflecting disease severity, and those potentially predicting AD development, concomitant atopic diseases, or therapeutic response, and current practice of biomarkers in AD. We found that chemokine C-C motif ligand 17/thymus and activation-regulated chemokine, a chemoattractant of TH2 cells, has currently the greatest evidence for robust correlation with AD clinical severity, at both baseline and during therapy, by using the recommendations, assessment, development, and evaluation approach. Although the potential of biomarkers in AD is yet to be fully elucidated, due to the complexity of the disease, a comprehensive approach taking into account both clinical and reliable, AD-specific biomarker evaluations would further facilitate AD research and improve patient management.

The molecular features of normal and atopic dermatitis skin in infants, children, adolescents, and adults.

BACKGROUND: Although atopic dermatitis (AD) often presents in infancy and persists into adulthood, comparative characterization of AD skin among different pediatric age groups is lacking. OBJECTIVE: We sought to define skin biopsy profiles of lesional and nonlesional AD across different age groups (0-5-year-old infants with disease duration <6 months, 6-11-year-old children, 12-17-year-old adolescents, ≥18-year-old adults) versus age-appropriate controls. METHODS: We performed gene expression analyses by RNA-sequencing and real-time PCR (RT-PCR) and protein expression analysis using immunohistochemistry. RESULTS: TH2/TH22 skewing, including IL-13, CCL17/thymus and activation-regulated chemokine, IL-22, and S100As, characterized the common AD signature, with a global pathway-level enrichment across all ages. Nevertheless, specific cytokines varied widely. For example, IL-33, IL-1RL1/IL-33R, and IL-9, often associated with early atopic sensitization, showed greatest upregulations in infants. TH17 inflammation presented a 2-peak curve, with highest increases in infants (including IL-17A and IL-17F), followed by adults. TH1 polarization was uniquely detected in adults, even when compared with adolescents, with significant upregulation in adults of IFN-γ and CXCL9/CXCL10/CXCL11. Although all AD age groups had barrier abnormalities, only adults had significant decreases in filaggrin expression. Despite the short duration of the disease, infant AD presented robust downregulations of multiple barrier-related genes in both lesional and nonlesional skin. Clinical severity scores significantly correlated with TH2/TH22-related markers in all pediatric age groups. CONCLUSIONS: The shared signature of AD across ages is TH2/TH22-skewed, yet differential expression of specific TH2/TH22-related genes, other TH pathways, and barrier-related genes portray heterogenetic, age-specific molecular fingerprints.

Tape strips from early-onset pediatric atopic dermatitis highlight disease abnormalities in nonlesional skin.

BACKGROUND: Skin biopsies promote our understanding of atopic dermatitis/AD pathomechanisms in infants/toddlers with early-onset AD, but are not feasible in pediatric populations. Tape strips are an emerging, minimally invasive alternative, but global transcriptomic profiling in early pediatric AD is lacking. We aimed to provide global lesional and nonlesional skin profiles of infants/toddlers with recent-onset, moderate-to-severe AD using tape strips. METHODS: Sixteen tape strips were collected for RNA-seq profiling from 19 infants/toddlers (<5 years old; lesional and nonlesional) with early-onset moderate-to-severe AD (≤6 months) and 17 healthy controls. RESULTS: We identified 1829 differentially expressed genes/DEGs in lesional AD and 662 DEGs in nonlesional AD, vs healthy skin (fold-change ≥2, FDR <0.05), with 100% sample recovery. Both lesional and nonlesional skin showed significant dysregulations of Th2 (CCL17 and IL4R) and Th22/Th17 (IL36G, CCL20, and S100As)-related genes, largely lacking significant Th1-skewing. Significant down-regulation of terminal differentiation (FLG and FLG2), lipid synthesis/metabolism (ELOVL3 and FA2H), and tight junction (CLDN8) genes were primarily seen in lesional AD. Significant negative correlations were identified between Th2 measures and epidermal barrier gene-subsets and individual genes (FLG with IL-4R and CCL17; r < -0.4, P < .05). Significant correlations were also identified between clinical measures (body surface area/BSA, pruritus ADQ, and transepidermal water loss/TEWL) with immune and barrier mRNAs in lesional and/or nonlesional AD (FLG/FLG2 with TEWL; r < -0.4, P < .05). CONCLUSION: RNA-seq profiling using tape strips in early-onset pediatric AD captures immune and barrier alterations in both lesional and nonlesional skin. Tape strips provide insight into disease pathomechanisms and cutaneous disease activity.

Immune and barrier characterization of atopic dermatitis skin phenotype in Tanzanian patients.

BACKGROUND: Atopic dermatitis (AD) is a common disease, with particularly high prevalence found in Africa. It is increasingly recognized that patients with AD of different ethnic backgrounds have unique molecular signatures in the skin, potentially accounting for treatment response variations. Nevertheless, the skin profile of patients with AD from Africa is unknown, hindering development of new treatments targeted to this patient population. OBJECTIVE: To characterize the skin profile of patients with AD from Africa. METHODS: Gene expression studies, including RNA sequencing (using threshold of fold change of >2 and false discovery rate of <0.05) and real-time polymerase chain reaction, were performed on skin biopsies of Tanzanian patients with moderate-to-severe AD and controls. RESULTS: Tanzanian AD skin presented robust up-regulations of multiple key mediators of both T helper 2 (TH2) (interleukin 13 [IL-13], IL-10, IL-4R, CCL13,CCL17,CCL18,CCL26) and TH22 (IL22, S100As) pathways. Markers related to TH17 and IL-23 (IL-17A, IL-23A, IL-12, PI3, DEFB4B) and TH1 (interferon gamma, CXCL9,CXCL10,CXCL11) were also significantly overexpressed in AD tissues (FDR<.05), albeit to a lesser extent. IL-36 isoforms revealed substantial up-regulations in African skin. The barrier fingerprint of Tanzanian AD revealed no suppression of hallmark epidermal barrier differentiation genes, such as filaggrin, loricrin, and periplakin, with robust attenuation of lipid metabolism genes (ie, AWAT1). CONCLUSION: The skin phenotype of Tanzanian patients with AD is consistent with that of African Americans, exhibiting dominant TH2 and TH22 skewing, minimal dysregulation of terminal differentiation, and even broader attenuation of lipid metabolism-related products. These data highlight the unique characteristic of AD in Black individuals and the need to develop unique treatments targeting patients with AD from these underrepresented populations.

Cross-sectional study of blood biomarkers of patients with moderate to severe alopecia areata reveals systemic immune and cardiovascular biomarker dysregulation.

BACKGROUND: Although there is increased understanding of the alopecia areata (AA) pathogenesis based on studies in scalp tissues, little is known about its systemic profile. OBJECTIVE: To evaluate the blood proteomic signature of AA and determine biomarkers associated with increased disease severity. METHODS: In a cross-sectional study, we assessed 350 inflammatory and cardiovascular proteins using OLINK high-throughput proteomics in patients with moderate to severe AA (n = 35), as compared with healthy individuals (n = 36), patients with moderate to severe psoriasis (n = 19), and those with atopic dermatitis (n = 49). RESULTS: Seventy-four proteins were significantly differentially expressed between AA and control individuals (false discovery rate, <.05) including innate immunity (interleukin [IL] 6/IL-8), T helper (Th) type 1 (interferon [IFN] γ/CXCL9/CXCL10/CXCL11), Th2 (CCL13/CCL17/CCL7), Th17 (CCL20/PI3/S100A12), and cardiovascular-risk proteins (OLR1/OSM/MPO/PRTN3). Eighty-six biomarkers correlated with AA clinical severity (P < .05), including Th1/Th2, and cardiovascular/atherosclerosis-related proteins, including SELP/PGLYRP1/MPO/IL-18/OSM (P < .05). Patients with AA totalis/universalis showed the highest systemic inflammatory tone, including cardiovascular risk biomarkers, compared to control individuals and even to patients with atopic dermatitis and those with psoriasis. The AA profile showed some Th1/Th2 differences in the setting of concomitant atopy. LIMITATIONS: Our analysis was limited to 350 proteins. CONCLUSION: This study defined the abnormalities of moderate to severe AA and associated circulatory biomarkers. It shows that AA has systemic immune, cardiovascular, and atherosclerosis biomarker dysregulation, suggesting the need for systemic treatment approaches.

New treatments for atopic dermatitis targeting beyond IL-4/IL-13 cytokines.

OBJECTIVE: Atopic dermatitis (AD) is an increasingly common inflammatory skin disease undergoing significant revolution in recent years. New data on disease pathogenesis advanced the developments of novel therapeutics, mainly for patients with moderate to severe conditions, for whom treatment options have been largely insufficient for many years. DATA SOURCES: Review of recent studies investigating systemic treatments for AD. STUDY SELECTIONS: Relevant literature concerning novel therapeutics for AD beyond targeted monoclonal antibodies antagonizing selectively interleukin (IL)-4 or IL-13 was obtained from a PubMed and clinicaltrials.gov search and summarized. RESULTS: Multiple clinical trials of both nonspecific as well as specific agents revealed favorable outcomes in AD, including JAK inhibitors, a dual JAK/SYK inhibitor, a histamine H4R antagonist, antagonists of the TSLP/OX40L axis, an IL-22 inhibitor, and IL-33 and IL-17C antagonists. Importantly, negative trials were published as well (eg, phosphodiesterase 4 inhibitor, apremilast). CONCLUSION: In this rapidly evolving field of AD treatments, a completely new treatment paradigm will be available in the near future.

Granuloma annulare skin profile shows activation of T-helper cell type 1, T-helper cell type 2, and Janus kinase pathways.

BACKGROUND: Granuloma annulare (GA) is an inflammatory skin disorder. Localized GA is often self-resolving, but generalized GA is often recalcitrant to treatments. There are no targeted treatments for GA, largely due to lack of mechanistic understanding. Recently, tumor necrosis factor antagonism showed promise in GA, suggesting an underlying immune pathogenesis. OBJECTIVE: To elucidate the immune pathogenesis and identify potential therapeutic targets for GA. METHODS: Lesional and nonlesional skin biopsy samples were obtained from patients with GA and evaluated for a large array of inflammatory markers compared with inflammatory markers from normal skin of healthy individuals. RESULTS: We found differential expression of many inflammatory genes compared with normal skin. These genes were associated with T-helper (Th) cell type 1/innate immunity (tumor necrosis factor-α, interleukin [IL]-1ß, IL-12/23p40, signal transducer and activator of transcription 1, chemokine [C-X-C motif] ligand 9/10), Janus kinase signaling, and Th2 (IL-4, IL-31, chemokine (C-C motif) ligands 17 and 18; P < .05). Unexpectedly, IL-4 showed significant upregulation in GA lesional skin vs control skin (15,600-fold change). LIMITATIONS: Limited sample size. CONCLUSIONS: Our findings shed light on the inflammatory pathways of GA, supporting the notion that immune mechanisms could be driving disease, as suggested by the promising data of tumor necrosis factor-α inhibitors in GA. The significant Janus kinase and particularly Th2 signaling in GA advocates for the investigation of specific Janus kinase- and Th2- targeted drug therapy.

The proteomic skin profile of moderate-to-severe atopic dermatitis patients shows an inflammatory signature.

BACKGROUND: Moderate-to-severe atopic dermatitis (AD) is increasingly recognized as a systemic disease, largely due to proteomic blood studies. There are growing efforts to develop AD biomarkers using minimal tissues. OBJECTIVE: To characterize the AD skin proteomic signature and its relationship with the blood proteome and genomic skin profile in the same individuals. METHODS: We evaluated lesional and nonlesional biopsy samples and blood from 20 individuals with moderate-to-severe AD and 28 healthy individuals using Olink Proteomics (Uppsala, Sweden), using 10 µg/10 µL for skin and blood and RNA sequencing of the skin. RESULTS: The AD skin proteome demonstrated significant upregulation in lesional and even in nonlesional skin compared with controls in inflammatory markers (matrix metalloproteinase 12; T-helper cell [Th]2/interleukin [IL]-1 receptor-like 1[IL1RL1]/IL-33R, IL-13, chemokine [C-C motif] ligand [CCL] 17; Th1/C-X-C motif chemokine 10; Th17/Th22/PI3, CCL20, S100A12), and in cardiovascular-associated proteins (E-selectin, matrix metalloproteinases, platelet growth factor, myeloperoxidase, fatty acid binding protein 4, and vascular endothelial growth factor A; false discovery rate, <0.05). Skin proteins demonstrated much higher and significant upregulations (vs controls) compared with blood, suggesting a skin source for the inflammatory/cardiovascular profile. Gene and protein expressions were correlated (r = 0.410, P < .001), with commonly upregulated inflammatory and cardiovascular risk-associated products, suggesting protein translation in skin. LIMITATIONS: Our analysis was limited to 354 proteins. CONCLUSIONS: The AD skin proteome shows an inflammatory and cardiovascular signature even in nonlesional skin, emphasizing the need for proactive treatment. Skin proteomics presents a sensitive option for biomarker monitoring.