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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.
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Hidradenitis Supurativa , Niño , Humanos , Hidradenitis Supurativa/diagnóstico , Hidradenitis Supurativa/genética , Hidradenitis Supurativa/tratamiento farmacológico , Factor de Necrosis Tumoral alfa/uso terapéutico , Piel/patología , Biomarcadores/metabolismo , Regulación hacia ArribaRESUMEN
BACKGROUND: Despite the advancements in the categorization of clinically amyopathic dermatomyositis (CADM), the classification and diagnosis of its subtypes are still challenging. The aim of our study was to describe the clinicopathological features of CADM and assess the differences between amyopathic dermatomyositis (ADM) and hypomyopathic dermatomyositis (HDM). METHODS: This retrospective study included 43 patients with CADM diagnosed at our institution from 2016 to 2020. Patients were subclassed into ADM (n = 30) and HDM (n = 13) groups to assess their clinicopathological differences. RESULTS: All included patients had characteristic cutaneous manifestations of dermatomyositis; 67.4% had myositis-associated auto-antibodies, including ANA (32.6%), RNP (14.0%), anti-Ro52 (9.3%), anti-p155/140 (7.0%), rheumatoid factor (7.0%), anti-NXP-2 (4.7%), anti-MDA5 (2.3%), and anti-Jo-1 (2.3%) antibodies. One patient had associated interstitial lung disease, and another patient had oral squamous cell carcinoma. The histopathological findings included mucin deposition (69.8%), telangiectasia (65.1%), lymphocytic infiltrate (48.8%), vacuolar interface dermatitis (46.5%), and epidermal atrophy (14.0%). Compared to patients with HDM, ADM patients were significantly less likely to have epidermal atrophy, 3.3% versus 38.5% (p = 0.006), and more likely to have mucin deposition, 80.0% versus 46.2% (p = 0.028). CONCLUSION: We described the clinicopathological features of CADM and highlighted the distinctions between ADM and HDM dermatopathologic findings. This information may prove helpful in diagnosing ambiguous lesions.
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IL-23 inhibitors are a class of injectable biologics consisting of risankizumab, tildrakizumab, and guselkumab utilized for treatment of moderate-to-severe psoriasis. This retrospective review sought to determine the value of IL-23 inhibitor intraclass switching among psoriasis patients after experiencing loss of efficacy to any IL-23 inhibitor. We conducted a retrospective chart review, including 43 patients who underwent any of six potential iterations of IL-23 intraclass switch between 11/2017-11/2023. Most commonly, patients switched from guselkumab or tildrakizumab to risankizumab (83.7%). Patients failed 2.3 ± 1.3 biologic treatments prior to switch. Post-switching, 81.4% of patients achieved BSA <1% after 248.8 ± 126.5 days. BSA immediately prior to intraclass switch was 13.1 ± 8.9 [95% CI: 10.4, 15.8] and at most recent follow-up was 2.9 ± 5.2 [2.3, 5.5]. This research adds to a growing body of literature demonstrating the potential of IL-23 intraclass switching in treatment of moderate-to-severe plaque psoriasis.
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INTRODUCTION: Acne vulgaris is a common skin disease prevalent in skin of color patients. Studies have demonstrated that dapsone gel, 7.5% (Aczone) used once daily is effective, safe, and well-tolerated for the treatment of acne in both men and women. However, minimal data are available in skin of color populations. This single-center, open-label clinical study investigated the efficacy and safety of dapsone gel, 7.5% in the treatment of moderate to severe acne vulgaris in patients with Fitzpatrick skin types IV-VI. METHODS: Twenty (20) adult subjects with moderate to severe acne and Fitzpatrick skin types IV-VI were enrolled in this study and treated with dapsone gel, 7.5% once daily for 24 weeks. RESULTS: Dapsone gel, 7.5% applied daily for 24 weeks reduced acne severity, post-inflammatory hyperpigmentation, and decreased new inflammatory and noninflammatory acne lesions in skin of color patients with moderate to severe acne vulgaris. Treatment resulted in improved acne health-related quality of life and patient symptoms related to acne, including patient-reported post-inflammatory hyperpigmentation, especially with a treatment duration of 18 weeks or longer. Limitations: The sample size was small and underpowered to detect statistically significant changes in some endpoints. CONCLUSION: Dapsone gel 7.5% was safe, well-tolerated, and efficacious in treating acne vulgaris and post-inflammatory hyperpigmentation in skin-of-color patients. Larger studies involving skin-of-color populations with acne vulgaris are warranted. J Drugs Dermatol. 2024;23(6):410-417. doi:10.36849/JDD.7897.
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Acné Vulgar , Administración Cutánea , Dapsona , Índice de Severidad de la Enfermedad , Adolescente , Adulto , Femenino , Humanos , Masculino , Adulto Joven , Acné Vulgar/tratamiento farmacológico , Dapsona/administración & dosificación , Dapsona/efectos adversos , Geles , Hiperpigmentación/inducido químicamente , Hiperpigmentación/tratamiento farmacológico , Calidad de Vida , Pigmentación de la Piel , Resultado del Tratamiento , Minorías Étnicas y RacialesRESUMEN
BACKGROUND: There is a paucity of data on the treatment of psoriasis in patients with skin of color – a diverse population among whom variations in clinical features and higher quality of life impact have been reported. This single-center, open-label clinical study evaluated the safety and efficacy of secukinumab in the treatment of moderate-to-severe plaque psoriasis in adults with Fitzpatrick skin types IV-VI. METHODS: A total of 20 male and female subjects (ages ≥ 18, BSA ≥10%, PASI Score ≥ 12, IGA ≥ 3) completed this study. The total study duration was 28 weeks. During the treatment period, subjects received secukinumab 300 mg subcutaneously at weeks 0, 1, 2, 3, and 4, then monthly through week 20. RESULTS: 73% of patients achieved at least 90% improvement in PASI score (PASI90) at week 16 compared to baseline (P=0.0592). There was a statistically significant proportion of patients achieving PASI75, IGA of clear or almost clear, and a change from baseline in DLQI total score at weeks 12, 16, and 24. A statistically significant reduction in IGAxBSA-75 score was achieved between week 16 and baseline. LIMITATIONS: The sample size was small and underpowered to detect statistically significant changes in some endpoints. Furthermore, the study period was interrupted by the COVID-19 pandemic, which contributed to numerous missing data points. CONCLUSION: Secukinumab 300 mg administered monthly was safe, well-tolerated, and efficacious in treating skin of color patients with psoriasis and improving health-related quality of life. Larger studies involving skin of color populations with psoriasis are warranted. J Drugs Dermatol. 2024;23(8):600-606. doi:10.36849/JDD.8128.
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Anticuerpos Monoclonales Humanizados , Psoriasis , Calidad de Vida , Índice de Severidad de la Enfermedad , Humanos , Psoriasis/tratamiento farmacológico , Psoriasis/diagnóstico , Masculino , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales Humanizados/administración & dosificación , Femenino , Adulto , Persona de Mediana Edad , Resultado del Tratamiento , Pigmentación de la Piel/efectos de los fármacos , Inyecciones Subcutáneas , Fármacos Dermatológicos/efectos adversos , Fármacos Dermatológicos/administración & dosificación , Fármacos Dermatológicos/uso terapéutico , Anciano , COVID-19RESUMEN
By inhibition of JAK-STAT signaling, SOCS1 acts as a master regulator of the cytokine response across numerous tissue types and cytokine pathways. Haploinsufficiency of SOCS1 has recently emerged as a monogenic immunodysregulatory disease with marked clinical variability. Here, we describe a patient with severe dermatitis, recurrent skin infections, and psoriatic arthritis that harbors a novel heterozygous mutation in SOCS1. The variant, c.202_203delAC, generates a frameshift in SOCS1, p.Thr68fsAla*49, which leads to complete loss of protein expression. Unlike WT SOCS1, Thr68fs SOCS1 fails to inhibit JAK-STAT signaling when expressed in vitro. The peripheral immune signature from this patient was marked by a redistribution of monocyte sub-populations and hyper-responsiveness to multiple cytokines. Despite this broad hyper-response across multiple cytokine pathways in SOCS1 haploinsufficiency, the patient's clinical disease was markedly responsive to targeted IL4Rα- and IL17-blocking therapy. In accordance, the mutant allele was unable to regulate IL4Rα signaling. Further, patient cells were unresponsive to IL4/IL13 while on monoclonal antibody therapy. Together, this study reports a novel SOCS1 mutation and suggests that IL4Rα blockade may serve as an unexpected, but fruitful therapeutic target for some patients with SOCS1 haploinsufficiency.
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Haploinsuficiencia , Proteínas Supresoras de la Señalización de Citocinas , Humanos , Proteína 1 Supresora de la Señalización de Citocinas/genética , Proteína 1 Supresora de la Señalización de Citocinas/metabolismo , Proteínas Supresoras de la Señalización de Citocinas/genética , Proteínas Supresoras de la Señalización de Citocinas/metabolismo , Transducción de Señal , Citocinas/metabolismo , Interleucina-17/genéticaRESUMEN
Iododerma is a rare cutaneous eruption that manifests after exposure to iodine-containing compounds, with few cases reported in the literature. Previous reports of this halogenoderma have described acellular halos simulating cryptococcus on histopathological examination but there is a paucity of reports of biopsies taken early in the disease course. We present a case of a 78-year-old patient who developed a papular eruption after receiving iodinated contrast. A skin biopsy taken within 24 h of the eruption showed a neutrophilic infiltrate with cryptococcal-like acellular haloed structures, indicating that the diagnostic finding may be found early in the disease course.
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Erupciones por Medicamentos , Exantema , Humanos , Anciano , Halógenos , Erupciones por Medicamentos/diagnóstico , Erupciones por Medicamentos/etiología , Erupciones por Medicamentos/patología , Piel/patología , Exantema/patología , Progresión de la EnfermedadRESUMEN
Dysregulation of Janus kinase (JAK) pathways from uncontrolled cytokine signaling comprises the pathological basis for many complex inflammatory cutaneous disorders. Oral JAK inhibitors, upadacitinib, tofacitinib, and baricitinib targeting JAK 1 and JAK 1/3, respectively, are currently US Food and Drug Administration (FDA)-approved for several rheumatic conditions. However, studies have shown that JAK-mediated signaling pathways are involved in many immune-related dermatologic conditions. As a result, for recalcitrant diseases, JAK inhibitors are potential alternative therapies due to their broad targeted inhibitory mechanisms. In this case series, we present the successful off-label treatment of 6 cases across dermatomyositis, hidradenitis suppurativa, cutaneous lupus, and cutaneous Crohn’s disease, which failed conventional therapies with upadacitinib or tofacitinib. In the 3 dermatomyositis cases, use of upadacitinib or tofacitinib demonstrated positive clinical outcomes, with no recurrent symptoms in cases where upadacitinib was used. In treatment-resistant hidradenitis suppurativa, upadacitinib demonstrated reduced systemic flares and moderate cutaneous symptom improvement. In the case of cutaneous Crohn’s disease, upadacitinib resulted in reduced cutaneous symptoms without new flares. Tofacitinib resulted in completed resolution of cutaneous symptoms in our patient’s case of cutaneous lupus erythematosus. JAK inhibitors upadacitinib and tofacitinib may be potential drug candidates in patients with treatment-resistant disease, especially in cases of inflammatory cutaneous conditions such as dermatomyositis, hidradenitis suppurativa, cutaneous lupus, and cutaneous Crohn’s disease. Further studies with larger sample sizes among these conditions are warranted to assess potential broader applicability of the positive results demonstrated in our patient cases. J Drugs Dermatol. 2023;22(12):1183-1190. doi:10.36849/JDD.7500.
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Enfermedad de Crohn , Dermatitis , Dermatomiositis , Hidradenitis Supurativa , Inhibidores de las Cinasas Janus , Lupus Eritematoso Cutáneo , Humanos , Inhibidores de las Cinasas Janus/efectos adversos , Uso Fuera de lo Indicado , Enfermedad de Crohn/tratamiento farmacológico , Hidradenitis Supurativa/diagnóstico , Hidradenitis Supurativa/tratamiento farmacológico , Dermatomiositis/tratamiento farmacológico , Dermatitis/tratamiento farmacológico , Quinasas Janus , Lupus Eritematoso Cutáneo/inducido químicamenteRESUMEN
BACKGROUND: IL-22 is potentially a pathogenic cytokine in patients with atopic dermatitis (AD), but the molecular effects of IL-22 antagonism have not been defined in human subjects. OBJECTIVE: We sought to evaluate the cellular and molecular effects of IL-22 blockade in tissues from patients with moderate-to-severe AD. METHODS: We assessed lesional and nonlesional skin from 59 patients with moderate-to-severe AD treated with anti-IL-22 (fezakinumab) versus placebo (2:1) using transcriptomic and immunohistochemistry analyses. RESULTS: Greater reversal of the AD genomic profile was seen with fezakinumab versus placebo, namely 25.3% versus 10.5% at 4 weeks (P = 1.7 × 10-5) and 65.5% versus 13.9% at 12 weeks (P = 9.5 × 10-19), respectively. Because IL-22 blockade showed clinical efficacy only in patients with severe AD, we used baseline median IL-22 mRNA expression to stratify for high (n = 30) and low (n = 29) IL-22 expression groups. Much stronger mean transcriptomic improvements were seen with fezakinumab in the IL-22-high drug-treated group (82.8% and 139.4% at 4 and 12 weeks, respectively) than in the respective IL-22-high placebo-treated group (39.6% and 56.3% at 4 and 12 weeks) or the IL-22-low groups. Significant downregulations of multiple immune pathways, including TH1/CXCL9, TH2/CCL18/CCL22, TH17/CCL20/DEFB4A, and TH22/IL22/S100A's, were restricted to the IL-22-high drug group (P < .05). Consistently, tissue predictors of clinical response were mostly genes involved in T-cell and dendritic cell activation and differentiation. CONCLUSIONS: This is the first report showing a profound effect of IL-22 blockade on multiple inflammatory pathways in AD. These data, supported by robust effects in patients with high IL-22 baseline expression, suggest a central role for IL-22 in AD, indicating the need for a precision medicine approach for improving therapeutic outcomes in patients with AD.
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Anticuerpos Monoclonales/administración & dosificación , Dermatitis Atópica/tratamiento farmacológico , Regulación de la Expresión Génica/efectos de los fármacos , Interleucinas/biosíntesis , Piel/metabolismo , Adulto , Anticuerpos Monoclonales Humanizados , Dermatitis Atópica/inmunología , Dermatitis Atópica/metabolismo , Dermatitis Atópica/patología , Femenino , Regulación de la Expresión Génica/inmunología , Humanos , Interleucinas/inmunología , Masculino , Persona de Mediana Edad , Piel/inmunología , Piel/patología , Células TH1/inmunología , Células TH1/metabolismo , Células TH1/patología , Células Th17/inmunología , Células Th17/metabolismo , Células Th17/patología , Células Th2/inmunología , Células Th2/metabolismo , Células Th2/patología , Interleucina-22Asunto(s)
Artritis Psoriásica , Dermatitis Atópica , Enfermedades Inflamatorias del Intestino , Psoriasis , Células Th17 , Células Th2 , Humanos , Dermatitis Atópica/tratamiento farmacológico , Dermatitis Atópica/complicaciones , Células Th17/inmunología , Psoriasis/tratamiento farmacológico , Psoriasis/complicaciones , Psoriasis/inmunología , Células Th2/inmunología , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Enfermedades Inflamatorias del Intestino/complicaciones , Artritis Psoriásica/tratamiento farmacológico , Artritis Psoriásica/complicaciones , Masculino , Femenino , Adulto , Quimioterapia Combinada , Persona de Mediana Edad , Terapia Biológica/métodos , Resultado del TratamientoRESUMEN
BACKGROUND: Interleukin 22 promotes epidermal hyperplasia and inhibits skin barrier function. OBJECTIVE: Evaluate interleukin 22 blockade in adults with moderate-to-severe atopic dermatitis (AD). METHODS: We performed a randomized, double-blind, placebo-controlled trial with intravenous fezakinumab monotherapy every 2 weeks for 10 weeks, with follow-up assessments until 20 weeks. The change in SCOring AD (SCORAD) score from baseline at 12 weeks served as the primary end point. RESULTS: At 12 weeks, the mean declines in SCORAD for the entire study population were 13.8 ± 2.7 in the fezakinumab arm and 8.0 ± 3.1 in the placebo arm (P = .134). In the severe AD patient subset (with a baseline SCORAD of ≥50), SCORAD decline was significantly stronger in the drug-treated patients than placebo-treated patients at 12 weeks (21.6 ± 3.8 vs 9.6 ± 4.2, P = .029) and 20 weeks (27.4 ± 3.9 vs 11.5 ± 5.1, P = .010). At 12 weeks, improvements in body surface area involvement in the entire population were significantly stronger in the drug-treated than placebo-treated patients (12.4% ± 2.4 vs 6.2% ± 2.7; P = .009), and in the severe AD subset, the decline in Investigator Global Assessment was significantly higher in the drug-treated than placebo-treated patients (0.7 ± 0.2 vs 0.3 ± 0.1; P = .034). All scores showed progressive improvements after last dosing (10 weeks) until end of study (20 weeks). Common adverse events were upper respiratory tract infections. LIMITATIONS: The limited sample size and lack of assessment with Eczema Area and Severity Index and a pruritus numerical rating scale were limiting factors. Significance was primarily obtained in severe AD. CONCLUSION: Fezakinumab was well-tolerated, with sustained clinical improvements after last drug dosing.
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Anticuerpos Monoclonales/uso terapéutico , Dermatitis Atópica/diagnóstico , Dermatitis Atópica/tratamiento farmacológico , Adulto , Anticuerpos Monoclonales Humanizados , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Esquema de Medicación , Femenino , Estudios de Seguimiento , Humanos , Infusiones Intravenosas , Interleucinas/inmunología , Masculino , Persona de Mediana Edad , Índice de Severidad de la Enfermedad , Resultado del Tratamiento , Interleucina-22RESUMEN
Atopic dermatitis (AD) is the most common inflammatory skin disease, but treatment options for moderate-to-severe disease are limited. Ustekinumab is an IL-12/IL-23p40 antagonist that suppresses Th1, Th17 and Th22 activation, commonly used for psoriasis patients. We sought to assess efficacy and safety of ustekinumab in patients with moderate-to-severe AD. In this phase II, double-blind, placebo-controlled study, 33 patients with moderate-to-severe AD were randomly assigned to either ustekinumab (n=16) or placebo (n=17), with subsequent crossover at 16 weeks, and last dose at 32 weeks. Background therapy with mild topical steroids was allowed to promote retention. Study endpoints included clinical (SCORAD50) and biopsy-based measures of tissue structure and inflammation, using protein and gene expression studies. The ustekinumab group achieved higher SCORAD50 responses at 12, 16 (the primary endpoint) and 20 weeks compared to placebo, but the difference between groups was not significant. The AD molecular profile/transcriptome showed early robust gene modulation, with sustained further improvements until 32 weeks in the initial ustekinumab group. Distinct and more robust modulation of Th1, Th17 and Th22 but also Th2-related AD genes was seen after 4 weeks of ustekinumab treatment (i.e. MMP12, IL-22, IL-13, IFN-γ, elafin/PI3, CXCL1 and CCL17; P<.05). Epidermal responses (K16, terminal differentiation) showed faster (4 weeks) and long-term regulation (32 weeks) from baseline in the ustekinumab group. No severe adverse events were observed. Ustekinumab had clear clinical and molecular effects, but clinical outcomes might have been obscured by a profound "placebo" effect, most likely due to background topical glucocorticosteroids and possibly insufficient dosing for AD.
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Dermatitis Atópica/tratamiento farmacológico , Dermatitis Atópica/genética , Fármacos Dermatológicos/uso terapéutico , Ustekinumab/uso terapéutico , Adulto , Quimiocina CCL17/genética , Quimiocina CXCL1/genética , Estudios Cruzados , Dermatitis Atópica/patología , Fármacos Dermatológicos/efectos adversos , Método Doble Ciego , Elafina/genética , Femenino , Perfilación de la Expresión Génica , Humanos , Interferón gamma/genética , Interleucina-13/genética , Interleucinas/genética , Masculino , Metaloproteinasa 12 de la Matriz/genética , Índice de Severidad de la Enfermedad , Transcriptoma/efectos de los fármacos , Ustekinumab/efectos adversos , Interleucina-22RESUMEN
BACKGROUND: Topical glucocorticosteroids are considered an efficient treatment option for atopic dermatitis (AD), but a global assessment of glucocorticosteroid responses on key disease circuits upon weeks to months of treatment is currently lacking. OBJECTIVE: We sought to assess short (4 weeks) and long-term (16 weeks) application of topical glucocorticosteroids on AD skin and define response biomarkers. METHODS: The effects of triamcinolone acetonide cream 0.025% were assessed based on gene expression and immunohistochemistry studies at baseline, 4 weeks, and 16 weeks in biopsy specimens from 15 patients with moderate-to-severe AD. RESULTS: At 16 weeks, only 3 patients were clinical responders (by using SCORAD50 criteria), but 6 patients qualified as responders based on histologic criteria. Baseline characteristics indicated more severe disease in nonresponders. While 3 of 15 patients experienced only transient benefit after 4 weeks, others showed progressive improvements toward 16 weeks. Topical glucocorticosteroid use in patients with AD resulted in improvements of the AD genomic signature of 25.6% at 4 weeks and 71.8% at 16 weeks, respectively, and even 123.9% in the histologic responder group. Cytokines (IL-12p40, IL-13, IL-22, CCL17, CCL18, peptidase inhibitor 3 [PI3]/elafin, and S100As) showed consistent decreases from baseline toward 16 weeks with corresponding improvements in epidermal disease hallmarks (keratin 16 and loricrin) in lesional skin from responders (P < .05). Nonresponders largely showed lesser/nonsignificant reductions in key inflammatory and barrier markers (keratin 16, IL-13, IL-22, CCL17, CCL18, PI3/elafin, S100As, and loricrin). The combination of IL-21 and IFN-γ baseline expression closely predicted individual clinical glucocorticosteroid responses at 16 weeks of treatment. CONCLUSION: Our study indicates that even low-potency glucocorticosteroids can broadly affect immune and barrier responses in patients with moderate-to-severe AD, associating higher baseline severity with increased steroid resistance in patients with AD.
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Antiinflamatorios/administración & dosificación , Dermatitis Atópica/tratamiento farmacológico , Esteroides/administración & dosificación , Administración Tópica , Adulto , Anciano , Biopsia , Análisis por Conglomerados , Dermatitis Atópica/diagnóstico , Dermatitis Atópica/genética , Femenino , Perfilación de la Expresión Génica , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Masculino , Persona de Mediana Edad , Índice de Severidad de la Enfermedad , Piel/metabolismo , Piel/patología , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Subgrupos de Linfocitos T/patología , Factores de Tiempo , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: Petrolatum is a common moisturizer often used in the prevention of skin infections after ambulatory surgeries and as a maintenance therapy of atopic dermatitis (AD). However, the molecular responses induced by petrolatum in the skin have never been assessed. OBJECTIVE: We sought to define the cutaneous molecular and structural effects induced by petrolatum. METHODS: Thirty-six healthy subjects and 13 patients with moderate AD (mean SCORAD score, 39) were studied by using RT-PCR, gene arrays, immunohistochemistry, and immunofluorescence performed on control skin, petrolatum-occluded skin, and skin occluded with a Finn chamber only. RESULTS: Significant upregulations of antimicrobial peptides (S100A8/fold change [FCH], 13.04; S100A9/FCH, 11.28; CCL20/FCH, 8.36; PI3 [elafin]/FCH, 15.40; lipocalin 2/FCH, 6.94, human ß-defensin 2 [DEFB4A]/FCH, 4.96; P < .001 for all) and innate immune genes (IL6, IL8, and IL1B; P < .01) were observed in petrolatum-occluded skin compared with expression in both control and occluded-only skin. Application of petrolatum also induced expression of key barrier differentiation markers (filaggrin and loricrin), increased stratum corneum thickness, and significantly reduced T-cell infiltrates in the setting of "normal-appearing" or nonlesional AD skin, which is known to harbor barrier and immune defects. CONCLUSIONS: Petrolatum robustly modulates antimicrobials and epidermal differentiation barrier measures. These data shed light on the beneficial molecular responses of petrolatum in barrier-defective states, such as AD and postoperative wound care.
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Antiinfecciosos/farmacología , Dermatitis Atópica/tratamiento farmacológico , Emolientes/farmacología , Vaselina/farmacología , Piel/efectos de los fármacos , Administración Cutánea , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Antiinfecciosos/uso terapéutico , Biomarcadores/metabolismo , Estudios de Casos y Controles , Dermatitis Atópica/inmunología , Dermatitis Atópica/metabolismo , Emolientes/uso terapéutico , Femenino , Proteínas Filagrina , Humanos , Proteínas de Filamentos Intermediarios/metabolismo , Masculino , Proteínas de la Membrana/metabolismo , Persona de Mediana Edad , Vaselina/uso terapéutico , Piel/inmunología , Piel/metabolismo , Adulto JovenRESUMEN
BACKGROUND: Past studies of blood T-cell phenotyping in patients with atopic dermatitis (AD) have provided controversial results and were mostly performed before the identification of TH9, TH17, and TH22 T-cell populations in human subjects. OBJECTIVE: We sought to quantify TH1, TH2, TH9, TH17, and TH22 T-cell populations and corresponding CD8(+) T-cell subsets in both cutaneous lymphocyte antigen (CLA)-positive and CLA(-) T-cell subsets in patients with AD and control subjects. METHODS: We studied 42 adults with severe AD (mean SCORAD score, 65) and 25 healthy subjects using an 11-color flow cytometric antibody panel. Frequencies of IFN-γ-, IL-22-, IL-13-, IL-17-, and IL-9-producing CD4(+) and CD8(+) T cells were compared in CLA(-) and CLA(+) populations. RESULTS: We measured increased TH2/TC2/IL-13(+) and TH22/TC22/IL-22(+) populations (P < .1) in patients with severe AD versus control subjects, with significant differences in CLA(+) T-cell numbers (P < .01). A significantly lower frequency of CLA(+) IFN-γ-producing cells was observed in patients with AD, with no significant differences in CLA(-) T-cell numbers. The CLA(+) TH1/TH2 and TC1/TC2 ratio was highly imbalanced in patients with AD (10 vs 3 [P = .005] and 19 vs 7 [P < .001], respectively). Positive correlations were found between frequencies of IL-13- and IL-22-producing CD4(+) and CD8(+) T cells (r = 0.5 and 0.8, respectively; P < .0001), and frequencies of IL-13-producing CLA(+) cells were also correlated with IgE levels and SCORAD scores. Patients with AD with skin infections had higher CD4(+) IL-22(+) and IL-17(+) cell frequencies, which were highly significant among CLA(-) cells (IL-22: 3.7 vs 1.7 [P < .001] and IL-17: 1.7 vs 0.6 [P < .001]), with less significant effects among CLA(+) T cells (IL-22: 11 vs 7.5, P = .04). CONCLUSIONS: Severe AD is accompanied by expansion of skin-homing TH2/TC2 and TH22/TC22 subsets with lower TH1/TC1 frequencies. These data create a critical basis for studying alterations in immune activation in adults and pediatric patients with AD.
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Linfocitos T CD8-positivos/inmunología , Dermatitis Atópica/inmunología , Piel/inmunología , Subgrupos de Linfocitos T/inmunología , Células Th17/inmunología , Células Th2/inmunología , Adolescente , Adulto , Anciano , Antígenos de Diferenciación de Linfocitos T/metabolismo , Movimiento Celular , Células Cultivadas , Progresión de la Enfermedad , Femenino , Humanos , Inmunofenotipificación , Interleucina-17/metabolismo , Interleucinas/metabolismo , Masculino , Glicoproteínas de Membrana/metabolismo , Persona de Mediana Edad , Adulto Joven , Interleucina-22RESUMEN
BACKGROUND: Atopic dermatitis (AD) is the most common inflammatory disease. The prevalence of allergic contact dermatitis to allergens (eg, fragrance) is higher in patients with AD, despite a trend toward weaker clinical allergic contact dermatitis reactions. The role of the AD skin phenotype in modulating allergic sensitization to common sensitizers has not been evaluated. OBJECTIVE: We sought to investigate whether patients with AD have altered tissue immune responses on allergen challenge. METHODS: Gene expression and immunohistochemistry studies were performed on biopsy specimens from 10 patients with AD and 14 patients without AD patch tested with common contact allergens (nickel, fragrance, and rubber). RESULTS: Although 1085 differentially expressed genes (DEGs) were commonly modulated in patch-tested skin from patients with AD and patients without AD versus control skin, 1185 DEGs were uniquely altered in skin from patients without AD, and only 246 DEGs were altered in skin from patients with AD. Although many inflammatory products (ie, matrix metalloproteinase 12/matrix metalloproteinase 1/S100A9) were upregulated in both groups, higher-magnitude changes and upregulation of interferon responses were evident only in the non-AD group. Stratification by allergen showed decreased expression of immune, TH1-subset, and TH2-subset genes in nickel-related AD responses, with increased TH17/IL-23 skewing. Rubber/fragrance showed similar trends of lesser magnitude. Negative regulators showed higher expression in patients with AD. CONCLUSIONS: Through contact sensitization, our study offers new insights into AD. Allergic immune reactions were globally attenuated and differentially polarized in patients with AD, with significant decreases in levels of TH1 products, some increases in levels of TH17 products, and inconsistent upregulation in levels of TH2 products. The overall hyporesponsiveness in skin from patients with background AD might be explained by baseline immune abnormalities, such as increased TH2, TH17, and negative regulator levels compared with those seen in non-AD skin.
Asunto(s)
Alérgenos/inmunología , Citocinas/inmunología , Dermatitis Atópica/inmunología , Dermatitis por Contacto/inmunología , Transcriptoma/inmunología , Adulto , Calgranulina B/genética , Calgranulina B/inmunología , Cosméticos/química , Citocinas/genética , Dermatitis Atópica/patología , Dermatitis por Contacto/patología , Femenino , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Humanos , Látex/inmunología , Masculino , Metaloproteinasa 1 de la Matriz/genética , Metaloproteinasa 1 de la Matriz/inmunología , Metaloproteinasa 12 de la Matriz/genética , Metaloproteinasa 12 de la Matriz/inmunología , Persona de Mediana Edad , Níquel/inmunología , Pruebas del Parche , Goma/química , Piel , Células TH1/inmunología , Células TH1/patología , Células Th17/inmunología , Células Th17/patología , Células Th2/inmunología , Células Th2/patologíaRESUMEN
BACKGROUND: Atopic dermatitis (AD) is the most common inflammatory disease. Evolving disease models link changes in epidermal growth and differentiation to T(H)2/T(H)22 cytokine activation. However, these models have not been tested by in vivo suppression of T-cell cytokines. Cyclosporine (CsA) is an immunosuppressant that is highly effective for severe disease, but its mechanism in AD skin lesions has not been studied. OBJECTIVE: We sought to establish the ability of a systemic immunosuppressant to modulate immune and epidermal alterations that form the pathogenic disease phenotype and to correlate changes with clinical improvement. METHODS: CsA's effects on AD skin pathology were evaluated by using gene expression and immunohistochemistry studies in baseline, week 2, and week 12 lesional and nonlesional biopsy specimens from 19 patients treated with 5 mg/kg/d CsA for 12 weeks. RESULTS: After 2 and 12 weeks of treatment, we observed significant reductions of 51% and 72%, respectively, in SCORAD scores. Clinical improvements were associated with significant gene expression changes in lesional but also nonlesional skin, particularly reductions in levels of T(H)2-, T(H)22-, and some T(H)17-related molecules (ie, IL-13, IL-22, CCL17, S100As, and elafin/peptidase inhibitor 3), and modulation of epidermal hyperplasia and differentiation measures. CONCLUSIONS: This is the first study that establishes a relationship between cytokine activation and molecular epidermal alterations, as well as correlations between disease biomarkers in the skin and clinical improvement. The reversal of the molecular phenotype with CsA and the associated biomarkers can serve as a reference for the successful modulation of tissue inflammation with specific immune antagonists in future studies, contributing to the understanding of the specific cytokines involved in epidermal pathology.
Asunto(s)
Ciclosporina/farmacología , Dermatitis Atópica/inmunología , Dermatitis Atópica/patología , Epidermis/inmunología , Epidermis/patología , Inmunosupresores/farmacología , Transducción de Señal/efectos de los fármacos , Adolescente , Adulto , Anciano , Biomarcadores , Análisis por Conglomerados , Ciclosporina/uso terapéutico , Células Dendríticas/efectos de los fármacos , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Dermatitis Atópica/tratamiento farmacológico , Dermatitis Atópica/genética , Epidermis/efectos de los fármacos , Femenino , Perfilación de la Expresión Génica , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Hiperplasia , Inmunosupresores/uso terapéutico , Inflamación/tratamiento farmacológico , Inflamación/genética , Inflamación/inmunología , Inflamación/patología , Masculino , Persona de Mediana Edad , Fenotipo , Subgrupos de Linfocitos T/efectos de los fármacos , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Resultado del Tratamiento , Adulto JovenRESUMEN
Biologics and Janus kinase (JAK) inhibitors are immunomodulating and immunosuppressing medications utilized to treat atopic dermatitis (AD), psoriasis (PSO), psoriatic arthritis (PsA), and alopecia areata (AA). Special recommendations must be considered when prescribing vaccinations in this population, as the pneumococcal and herpes zoster vaccine are recommended to patients ≥ 19-years-old (rather than ≥ 65-years-old and ≥ 50-years-old as in the general population, respectively), along with a yearly influenza and up to date COVID-19 vaccination. Additionally, TNF-α and JAK-inhibitors may increase the risk of latent Hepatitis B virus (HBV) reactivation among high-risk patients. Prior to prescribing these medications, a quantitative HepB Surface Antibody (HepB SA) test is performed to determine immunity. This study utilized the SlicerDicer function on EPIC Medical Records to search for any patient ≥ 19-years-old prescribed a biologic or JAK inhibitor for AD, PSO, PsA, or AA between 10/2003 and 10/2023 at a large tertiary institution. Vaccination rates among patients on biologics and JAK inhibitors were low, with rates being significantly lower in patients 19-64 years-old, compared to those ≥ 65 years-old for most disease states (p < 0.01). Among AD, PSO/PsA, and AA patients, on average, 9.39% were vaccinated for influenza, 6.76% for herpes zoster, 16.56% for pneumococcal pneumonia, and 63.98% for COVID-19. Only 3.16% of patients were adequately vaccinated for HepB after an abnormal HepB SA test. Here, extremely low rates of vaccination among patients on biologics and JAK inhibitors at our institution were highlighted, emphasizing the imperative need for ensuring vaccination in this group.