RESUMEN
BACKGROUND: Notalgia paresthetica is a neuropathic disorder characterized by pruritus in a circumscribed region of the upper back. Difelikefalin, a selective kappa opioid receptor agonist, has shown efficacy in other chronic pruritic conditions and is being investigated for the treatment of notalgia paresthetica. METHODS: In this phase 2, double-blind, placebo-controlled trial, we randomly assigned, in a 1:1 ratio, patients with moderate-to-severe pruritus caused by notalgia paresthetica to receive 2 mg of oral difelikefalin or placebo twice daily for 8 weeks. The primary outcome was the change from baseline at week 8 in the weekly mean score on the daily Worst Itch Numeric Rating Scale (WI-NRS; scores range from 0 [no itch] to 10 [worst itch imaginable]). The secondary clinical outcomes were itch-related quality-of-life and itch-related sleep measures. RESULTS: A total of 126 patients were enrolled; 62 patients were assigned to receive difelikefalin, and 63 were assigned to receive placebo. One patient who had been assigned to receive difelikefalin withdrew consent before the first dose and is not included in the main analyses. The mean baseline WI-NRS score was 7.6 (indicating severe itch) in each group. The change from baseline in the weekly mean WI-NRS score at week 8 was -4.0 points in the difelikefalin group and -2.4 points in the placebo group (difference in change, -1.6 points; 95% confidence interval, -2.6 to -0.6; P = 0.001). The results for the secondary outcomes generally did not support those of the primary analysis. Headache, dizziness, constipation, and increased urine output occurred more frequently in the difelikefalin group than in the placebo group. CONCLUSIONS: Among patients with notalgia paresthetica, oral treatment with difelikefalin resulted in modestly greater reductions in itch intensity scores than placebo over a period of 8 weeks but was associated with adverse events. Larger and longer trials are needed to assess the efficacy and safety of difelikefalin treatment in this disorder. (Funded by Cara Therapeutics; KOMFORT ClinicalTrials.gov number, NCT04706975.).
Asunto(s)
Enfermedades del Sistema Nervioso Periférico , Piperidinas , Prurito , Receptores Opioides kappa , Humanos , Método Doble Ciego , Piperidinas/efectos adversos , Piperidinas/uso terapéutico , Prurito/tratamiento farmacológico , Prurito/etiología , Resultado del Tratamiento , Receptores Opioides kappa/agonistas , Enfermedades del Sistema Nervioso Periférico/complicaciones , Enfermedades del Sistema Nervioso Periférico/tratamiento farmacológico , Dorso/inervaciónRESUMEN
BACKGROUND: Therapies specifically targeting nonhistaminergic pruritus are largely lacking. Difelikefalin (DFK) has been found to reduce itch in various chronic pruritic conditions, including atopic dermatitis (AD). OBJECTIVE: We sought to investigate the ability of DFK to impact scratching behavior, inflammatory mediators, and neuronal signaling in a murine model of AD. METHODS: The ears of C57BL/6 mice were topically treated with MC903 for 12 consecutive days to induce AD-like inflammation and itch. Before MC903 treatment, mice were treated with either DFK (0.5 mg/kg, intraperitoneal injection twice daily) or vehicle (saline). Skin ear thickness, histological analysis, flow cytometry, RNA-sequencing, and differential gene expression analyses of mouse ear skin were used to examine the effect of DFK on skin inflammation. Scratching behavior was quantified to measure itch behavior in mice that were topically treated with MC903 for 6 consecutive days; then, mice received a single injection of either DFK (1.0 mg/kg, intraperitoneal injection) or saline. Calcium imaging and single-cell RNA-sequencing were used in mouse dorsal root ganglia neurons to determine the size of the neurons activated with DFK treatment. Statistical significance was determined by Mann-Whitney test, unless otherwise noted. RESULTS: DFK rapidly suppressed itch without altering AD-like skin inflammation in MC903 (calcipotriol)-treated mice. In vitro Ca2+ influx trace of dorsal root ganglia suggested that a major target for DFK is the larger-diameter mechanoreceptors (eg, Aêµ-fibers), rather than small-diameter pruriceptive C-fibers. CONCLUSIONS: These studies support a potential neuromodulatory role of DFK for reducing itch associated with AD in mice.
Asunto(s)
Dermatitis Atópica , Ratones , Animales , Dermatitis Atópica/patología , Modelos Animales de Enfermedad , Ratones Endogámicos C57BL , Prurito/patología , Piel/patología , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , ARN/metabolismoRESUMEN
BACKGROUND: Pruritus is the most common and burdensome symptom of atopic dermatitis (AD). Pruritus-targeted treatments in AD are lacking, particularly for patients with milder skin disease. OBJECTIVE: We sought to evaluate the impact of the selective κ-opioid receptor agonist difelikefalin (DFK) on pruritus intensity and pruritus- and immune-related biomarkers in subjects with moderate to severe AD-related pruritus. METHODS: A phase 2 clinical trial investigated the efficacy and safety of oral DFK 0.25, 0.5, and 1.0 mg in subjects with moderate to severe AD-related pruritus. A biomarker substudy evaluated the effects of DFK on the expression of pruritus, TH2-associated genes, and skin barrier-related genes. RESULTS: In the clinical trial (N = 401), all DFK doses reduced itch versus placebo; however, the results were not statistically significant at week 12. In a subgroup of subjects in the trial with mild to moderate skin inflammation and moderate to severe itch (itch-dominant AD phenotype), DFK reduced itch at week 12 versus placebo. In the biomarker substudy, DFK downregulated the expression of key pruritus-related genes (eg, IL-31 and TRPV1) and the AD phenotype (eg, CCL17). Gene set variation analysis confirmed that DFK, but not placebo, downregulated pruritus-related genes and TH2 pathways. DFK improved skin barrier integrity markers and upregulated the expression of claudins and lipid metabolism-associated genes (eg, SEC14L6, ELOVL3, CYP1A2, and AKR1D1). CONCLUSIONS: DFK treatment reduced itch in subjects with moderate to severe AD-related pruritus, particularly those with an "itch-dominant" AD phenotype, and had an impact on the expression of pruritus, TH2-associated genes, and skin barrier-related genes. DFK is a promising therapy for AD-related pruritus; further clinical studies are warranted.
Asunto(s)
Dermatitis Atópica , Humanos , Dermatitis Atópica/tratamiento farmacológico , Dermatitis Atópica/metabolismo , Prurito/tratamiento farmacológico , Prurito/metabolismo , Piel/metabolismo , Biomarcadores/metabolismo , Índice de Severidad de la EnfermedadRESUMEN
BACKGROUND: Tildrakizumab is a high-affinity, humanised, IgG1 κ antibody targeting interleukin 23 p19 that represents an evolving treatment strategy in chronic plaque psoriasis. Previous research suggested clinical improvement with inhibition of interleukin 23 p19. We did two phase 3 trials to investigate whether tildrakizumab is superior to placebo and etanercept in the treatment of chronic plaque psoriasis. METHODS: We did two three-part, parallel group, double-blind, randomised controlled studies, reSURFACE 1 (at 118 sites in Australia, Canada, Japan, the UK, and the USA) and reSURFACE 2 (at 132 sites in Europe, Israel, and the USA). Participants aged 18 years or older with moderate-to-severe chronic plaque psoriasis (body surface area involvement ≥10%, Physician's Global Assessment [PGA] score ≥3, and Psoriasis Area and Severity Index [PASI] score ≥12) were randomised (via interactive voice and web response system) to tildrakizumab 200 mg, tildrakizumab 100 mg, or placebo in reSURFACE 1 (2:2:1), or to tildrakizumab 200 mg, tildrakizumab 100 mg, placebo, or etanercept 50 mg (2:2:1:2). Randomisation was done by region and stratified for bodyweight (≤90 kg or >90 kg) and previous exposure to biologics therapy for psoriasis. Investigators, participants, and study personnel were blinded to group allocation and remained blinded until completion of the studies. Assigned medication was identical in appearance and packaging. Tildrakizumab was administered subcutaneously at weeks 0 and 4 during part 1 and at week 16 during part 2 (weeks 12 and 16 for participants re-randomised from placebo to tildrakizumab; etanercept was given twice weekly in part 1 of reSURFACE 2 and once weekly during part 2). The co-primary endpoints were the proportion of patients achieving PASI 75 and PGA response (score of 0 or 1 with ≥2 grade score reduction from baseline) at week 12. Safety was assessed in the all-participants-as-treated population, and efficacy in the full-analysis set. These trials are registered with ClinicalTrials.gov, numbers NCT01722331 (reSURFACE 1) and NCT01729754 (reSURFACE 2). These studies are completed, but extension studies are ongoing. FINDINGS: reSURFACE 1 ran from Dec 10, 2012, to Oct 28, 2015. reSURFACE 2 ran from Feb 12, 2013, to Sept 28, 2015. In reSURFACE 1, 772 patients were randomly assigned, 308 to tildrakizumab 200 mg, 309 to tildrakizumab 100 mg, and 155 to placebo. At week 12, 192 patients (62%) in the 200 mg group and 197 patients (64%) in the 100 mg group achieved PASI 75, compared with 9 patients (6%) in the placebo group (p<0·0001 for comparisons of both tildrakizumab groups vs placebo). 182 patients (59%) in the 200 mg group and 179 patients (58%) in the 100 mg group achieved PGA responses, compared with 11 patients (7%) in the placebo group (p<0·0001 for comparisons of both tildrakizumab groups vs placebo). In reSURFACE 2, 1090 patients were randomly assigned, 314 to tildrakizumab 200 mg, 307 to tildrakizumab 100 mg, 156 to placebo, and 313 to etanercept. At week 12, 206 patients (66%) in the 200 mg group, and 188 patients (61%) in the 100 mg group achieved PASI 75, compared with 9 patients (6%) in the placebo group and 151 patients (48%) in the etanercept group (p<0·0001 for comparisons of both tildrakizumab groups vs placebo; p<0·0001 for 200 mg vs etanercept and p=0·0010 for 100 mg vs etanercept). 186 patients (59%) in the 200 mg group, and 168 patients (59%) [corrected] in the 100 mg group achieved a PGA response, compared with 7 patients (4%) in the placebo group and 149 patients (48%) in the etanercept group (p<0·0001 for comparisons of both tildrakizumab groups vs placebo; p=0·0031 for 200 mg vs etanercept and p=0·0663 for 100 mg vs etanercept). Serious adverse events were similar and low in all groups in both trials. One patient died in reSURFACE 2, in the tildrakizumab 100 mg group; the patient had alcoholic cardiomyopathy and steatohepatitis, and adjudication was unable to determine the cause of death. INTERPRETATION: In two phase 3 trials, tildrakizumab 200 mg and 100 mg were efficacious compared with placebo and etanercept and were well tolerated in the treatment of patients with moderate-to-severe chronic plaque psoriasis. FUNDING: Merck & Co.
Asunto(s)
Anticuerpos Monoclonales/administración & dosificación , Fármacos Dermatológicos/administración & dosificación , Etanercept/administración & dosificación , Psoriasis/tratamiento farmacológico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales Humanizados , Enfermedad Crónica , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana Edad , Resultado del Tratamiento , Adulto JovenRESUMEN
Background: Atopic dermatitis (AD) affects 2%-10% of adults worldwide. Occurrence and severity of symptoms and treatment success vary among patients. Objective: To determine disease severity, burden, and treatment use and satisfaction in adults with AD. Methods: An international internet-based survey was conducted (October 5-November 1, 2021) in participants with AD from Canada, France, Germany, Italy, Japan, Spain, the United Kingdom, and the United States. Results: Of 2005 AD patients surveyed, 92% had body surface area (BSA) involvement <10%. Itch was the most bothersome symptom; 48.5% of participants reported severe itch in the past week (Itch Numerical Rating Scale [NRS] 7-10; 45.9% for BSA <10%, 75.0% for BSA ≥10%). Most participants reported moderate or severe sleep disturbance in the past week (Sleep NRS 4-10; 67.1% for BSA <10%, 92.3% for BSA ≥10%). Itch was the top reason for participants' most recent health care provider visit; reducing itching was their top treatment goal. Topical therapies, which were most commonly used, resulted in low treatment satisfaction. Conclusions: Itch was the most bothersome AD symptom. Although clinical development has focused on improving skin lesions, improving itch is patients' top treatment goal. This survey highlights the need for systemic antipruritic therapies that could reduce itch in nonlesional and lesional skin.
Asunto(s)
Dermatitis Atópica , Adulto , Humanos , Dermatitis Atópica/tratamiento farmacológico , Dermatitis Atópica/epidemiología , Índice de Severidad de la Enfermedad , Prurito/etiología , Prurito/terapia , Prurito/diagnóstico , Encuestas y Cuestionarios , Costo de Enfermedad , Calidad de VidaRESUMEN
Current approaches for the treatment of psoriasis with anti-cytokine therapies involve the blockade of TNF-α, or the p40 sub-unit of IL-12 and IL-23. However, the field is currently evolving to test more selective antagonists, such as anti-IL-23p19, IL-17 and other inflammatory cytokines. Here we discuss our current understanding of dendritic cell and T cell subsets that are relevant in psoriasis, and the pharmacologic strategies that temper their activity in this disease.
Asunto(s)
Anticuerpos/uso terapéutico , Citocinas/inmunología , Psoriasis/tratamiento farmacológico , Animales , Humanos , Subunidades de Proteína/inmunología , Psoriasis/inmunología , Linfocitos T/inmunologíaRESUMEN
IL-22 is a cytokine that acts mainly on epithelial cells. In the skin, it mediates keratinocyte proliferation and epidermal hyperplasia and is thought to play a central role in inflammatory diseases with marked epidermal acanthosis, such as psoriasis. Although IL-22 was initially considered a Th17 cytokine, increasing evidence suggests that T helper cells can produce IL-22 even without IL-17 expression. In addition, we have shown the existence of this unique IL-22-producing T cell in normal skin and in the skin of psoriasis and atopic dermatitis patients. In the present study, we investigated the ability of cutaneous resident dendritic cells (DCs) to differentiate IL-22-producing cells. Using FACS, we isolated Langerhans cells (LCs; HLA-DR(+)CD207(+) cells) and dermal DCs (HLA-DR(hi)CD11c(+)BDCA-1(+) cells) from normal human epidermis and dermis, respectively. Both LCs and dermal DCs significantly induced IL-22-producing CD4(+) and CD8(+) T cells from peripheral blood T cells and naive CD4(+) T cells in mixed leukocyte reactions. LCs were more powerful in the induction of IL-22-producing cells than dermal DCs. Moreover, in vitro-generated LC-type DCs induced IL-22-producing cells more efficiently than monocyte-derived DCs. The induced IL-22 production was more correlated with IFN-gamma than IL-17. Surprisingly, the majority of IL-22-producing cells induced by LCs and dermal DCs lacked the expression of IL-17, IFN-gamma, and IL-4. Thus, LCs and dermal DCs preferentially induced helper T cells to produce only IL-22, possibly "Th22" cells. Our data indicate that cutaneous DCs, especially LCs, may control the generation of distinct IL-22 producing Th22 cells infiltrating into the skin.
Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Interleucina-17/biosíntesis , Interleucinas/biosíntesis , Células de Langerhans/inmunología , Linfocitos T CD4-Positivos/citología , Diferenciación Celular , Dermatitis Atópica/inmunología , Citometría de Flujo , Humanos , Células de Langerhans/citología , Prueba de Cultivo Mixto de Linfocitos , Psoriasis/inmunología , Piel/citología , Piel/inmunología , Interleucina-22RESUMEN
Atopic dermatitis and psoriasis are 2 of the most common inflammatory skin diseases. They are similar in that they are complex inherited diseases involving genes that encode immune components and structural proteins that regulate differentiation of epidermal cells. Each disease is characterized by proliferation of epidermal keratinocytes and abnormal cornification or terminal differentiation in the epidermis; skin lesions contain immune infiltrates of T cells, dendritic cells, and other types of leukocytes. We review similarities between the diseases and differences in epidermal barrier defects and immune cells. We also propose mechanisms of pathogenesis based on differences in the balance of immune cell subsets that could cause the phenotypes that distinguish these diseases. The first part of this 2-part review focuses on the clinical and pathologic features of the diseases; the second part discusses differences in immune cell subsets between atopic dermatitis and psoriasis and recent therapeutic strategies.
Asunto(s)
Dermatitis Atópica/fisiopatología , Psoriasis/fisiopatología , Adulto , Animales , Niño , Dermatitis Atópica/genética , Dermatitis Atópica/inmunología , Dermatitis Atópica/patología , Humanos , Ratones , Psoriasis/genética , Psoriasis/inmunología , Psoriasis/patologíaRESUMEN
Atopic dermatitis (AD) and psoriasis are among the most common inflammatory skin diseases. In the first part of this 2-part review, we discussed the similarities and differences between AD and psoriasis with respect to clinical features and pathology. The diseases are characterized by infiltration of skin lesions by large numbers of inflammatory cells; the second part of this review focuses on immune cell subsets that distinguish each disease and the therapeutic strategies that might be used or developed based on this information. We discuss the interactions among different populations of immune cells that ultimately create the complex inflammatory phenotype of AD and compare these with psoriasis. Therapeutic strategies have been developed for psoriasis based on the cytokine network that promotes inflammation in this disease. Antibodies against IL-12 and IL-23p40 antibody and antagonists of TNF are used to treat patients with psoriasis, and studies are underway to test specific antagonists of IL-23, IL-17, IL-17 receptor, IL-20, and IL-22. We discuss how these therapeutic approaches might be applied to AD.
Asunto(s)
Dermatitis Atópica/etiología , Psoriasis/etiología , Inmunidad Adaptativa , Citocinas/metabolismo , Células Dendríticas/inmunología , Dermatitis Atópica/inmunología , Dermatitis Atópica/terapia , Eosinófilos/inmunología , Humanos , Inmunidad Innata , Inmunosupresores/uso terapéutico , Mediadores de Inflamación/metabolismo , Queratinocitos/inmunología , Mastocitos/inmunología , Modelos Biológicos , Psoriasis/inmunología , Psoriasis/terapia , Subgrupos de Linfocitos T/inmunologíaRESUMEN
BACKGROUND: Atopic dermatitis (AD) is a common inflammatory skin disease with a T(H)2 and "T22" immune polarity. Despite recent data showing a genetic predisposition to epidermal barrier defects in some patients, a fundamental debate still exists regarding the role of barrier abnormalities versus immune responses in initiating the disease. An extensive study of nonlesional AD (ANL) skin is necessary to explore whether there is an intrinsic predisposition to barrier abnormalities, background immune activation, or both in patients with AD. OBJECTIVE: We sought to characterize ANL skin by determining whether epidermal differentiation and immune abnormalities that characterize lesional AD (AL) skin are also reflected in ANL skin. METHODS: We performed genomic and histologic profiling of both ANL and AL skin lesions (n = 12 each) compared with normal human skin (n = 10). RESULTS: We found that ANL skin is clearly distinct from normal skin with respect to terminal differentiation and some immune abnormalities and that it has a cutaneous expansion of T cells. We also showed that ANL skin has a variable immune phenotype, which is largely determined by disease extent and severity. Whereas broad terminal differentiation abnormalities were largely similar between involved and uninvolved AD skin, perhaps accounting for the "background skin phenotype," increased expression of immune-related genes was among the most obvious differences between AL and ANL skin, potentially reflecting the "clinical disease phenotype." CONCLUSION: Our study implies that systemic immune activation might play a role in alteration of the normal epidermal phenotype, as suggested by the high correlation in expression of immune genes in ANL skin with the disease severity index.
Asunto(s)
Dermatitis Atópica/inmunología , Dermatitis Atópica/patología , Perfilación de la Expresión Génica , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Diferenciación Celular , Dermatitis Atópica/genética , Femenino , Humanos , Inmunohistoquímica , Queratinocitos/citología , Masculino , Persona de Mediana Edad , Análisis de Secuencia por Matrices de Oligonucleótidos , Fenotipo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Adulto JovenRESUMEN
Background: Notalgia paresthetica (NP) is a chronic sensory neuropathy that causes intense pruritus, typically affecting the upper portion of the back and lasting for months to years. The impacts of pruritus and the full symptom experience are not well documented. Objective: To describe patients' NP symptom experience and the impacts of living with NP-related itch. Methods: Semistructured, one-to-one qualitative telephone interviews were conducted in adults living with NP. The worst itch severity during the previous 24 hours was assessed using an 11-point numerical rating scale. Results: Thirty participants (23 females; aged 41-80 years) completed interviews. Seventeen NP-related symptoms were described, with daily itch being the most common. Participants' itch ranged from severe to very severe (50%) and was experienced for a median of 2.8 years. Most (73%) participants were not receiving treatment for NP at the time of the study. Other reported symptoms included skin pain or sensitivity and secondary symptoms from itching (skin discoloration, lumps or bumps, bleeding or scabbing). NP-related itch was frequently reported to affect mood, interfere with sleep, and disrupt self-care. Limitations: Only English-speaking participants living in the United States were included. Conclusion: This study highlights the patient experience of living with NP and findings reveal that there remains an unmet need for effective therapeutic options to address NP-related itch.
RESUMEN
Although the pathogenic role of B cells and CD4 T cells has been studied extensively, less is known about the role of CD8 T cells in autoimmunity and self-tolerance. To evaluate the role of CD8 T cells in autoimmunity and its modulation using self-peptides, we used mice expressing soluble OVA (sOVA) under control of the keratin-14 promoter. Spontaneous autoimmunity occurred when sOVA mice were crossed with OT-I mice, whose CD8 T cells carry a Valpha2/Vbeta5-transgenic TCR with specificity for the OVA(257-264) peptide. Eighty-three percent of OVA/OT-I mice died during the first 2 wk of life due to multiple organ inflammation. In contrast, preventive or therapeutic OVA(257-264) peptide injections induced a dose-dependent increase in survival. Healthy survivors exhibited reductions in peripheral CD8 T cells, CD8 coreceptor, and Valpha2 expression. Furthermore, CD8 T cells from healthy mice were anergic and could not be activated by exogenous IL-2. A block in IL-2/IL-7 signaling via the STAT5 pathway provided the basis for low surface expression of the CD8 coreceptor and failure of IL-2 to break CD8 T cell anergy. Thus, the soluble TCR ligand triggered multiple tolerance mechanisms in these sOVA/OT-I mice, making this treatment approach a potential paradigm for modulating human autoimmune diseases.
Asunto(s)
Enfermedades Autoinmunes/terapia , Regulación hacia Abajo/inmunología , Interleucina-2/antagonistas & inhibidores , Interleucina-7/antagonistas & inhibidores , Ovalbúmina/fisiología , Fragmentos de Péptidos/fisiología , Receptores de Antígenos de Linfocitos T alfa-beta/antagonistas & inhibidores , Receptores de Antígenos de Linfocitos T/antagonistas & inhibidores , Factor de Transcripción STAT5/antagonistas & inhibidores , Transducción de Señal/inmunología , Animales , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/mortalidad , Antígenos CD8/metabolismo , Pollos , Anergia Clonal/genética , Anergia Clonal/inmunología , Regulación hacia Abajo/genética , Tolerancia Inmunológica/genética , Interleucina-2/fisiología , Interleucina-7/fisiología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Ovalbúmina/administración & dosificación , Ovalbúmina/genética , Ovalbúmina/inmunología , Fragmentos de Péptidos/administración & dosificación , Fragmentos de Péptidos/genética , Fragmentos de Péptidos/inmunología , Receptores de Antígenos de Linfocitos T/metabolismo , Receptores de Antígenos de Linfocitos T alfa-beta/biosíntesis , Factor de Transcripción STAT5/metabolismo , Factor de Transcripción STAT5/fisiología , Transducción de Señal/genética , Solubilidad , Análisis de SupervivenciaRESUMEN
BACKGROUND: Previous work has identified CD11c(+)CD1c(-) dendritic cells (DCs) as the major "inflammatory" dermal DC population in patients with psoriasis vulgaris and CD1c(+) DCs as the "resident" cutaneous DC population. OBJECTIVE: We sought to further define molecular differences between these 2 myeloid dermal DC populations. METHODS: Inflammatory and resident DCs were single-cell sorted from lesional skin biopsy specimens of patients with psoriasis, and the transcriptome of CD11c(+)CD1c(-) versus CD1c(+) DCs was determined. Results were confirmed with RT-PCR, flow cytometry, immunohistochemistry, and double-labeled immunofluorescence. Human keratinocytes were cultured for functional studies. RESULTS: TNF-related apoptosis-inducing ligand (TRAIL), Toll-like receptors 1 and 2, S100A12/ENRAGE, CD32, and many other inflammatory products were differentially expressed in inflammatory DCs compared with resident DCs. Flow cytometry and immunofluorescence confirmed higher protein expression on CD1c(-) versus CD1c(+) DCs. TRAIL receptors, death receptor 4, and decoy receptor 2 were expressed in keratinocytes and dermal cells. In vitro culture of keratinocytes with TRAIL induced CCL20 chemokine. CONCLUSIONS: CD11c(+)CD1c(-) inflammatory DCs in psoriatic lesional skin express a wide range of inflammatory molecules compared with skin-resident CD1c(+) DCs. Some molecules made by inflammatory DCs, including TRAIL, could have direct effects on keratinocytes or other skin cell types to promote disease pathogenesis.
Asunto(s)
Biomarcadores/metabolismo , Células de Langerhans/metabolismo , Psoriasis/diagnóstico , Psoriasis/inmunología , Ligando Inductor de Apoptosis Relacionado con TNF/metabolismo , Antígenos CD/genética , Antígenos CD/metabolismo , Diferenciación Celular , Separación Celular , Células Cultivadas , Quimiocina CCL20/biosíntesis , Quimiocina CCL20/genética , Citometría de Flujo , Perfilación de la Expresión Génica , Humanos , Inmunohistoquímica , Inflamación , Queratinocitos/inmunología , Queratinocitos/metabolismo , Queratinocitos/patología , Células de Langerhans/inmunología , Células de Langerhans/patología , Análisis por Micromatrices , Psoriasis/patología , Proteínas S100/biosíntesis , Proteínas S100/genética , Receptores Señuelo del Factor de Necrosis Tumoral/biosíntesis , Receptores Señuelo del Factor de Necrosis Tumoral/genéticaRESUMEN
The classical Th1/Th2 paradigm previously defining atopic dermatitis (AD) and psoriasis has recently been challenged with the discovery of Th17 T cells that synthesize IL-17 and IL-22. Although it is becoming evident that many Th1 diseases including psoriasis have a strong IL-17 signal, the importance of Th17 T cells in AD is still unclear. We examined and compared skin biopsies from AD and psoriasis patients by gene microarray, RT-PCR, immunohistochemistry, and immunofluorescence. We found a reduced genomic expression of IL-23, IL-17, and IFN-gamma in AD compared with psoriasis. To define the effects of IL-17 and IL-22 on keratinocytes, we performed gene array studies with cytokine-treated keratinocytes. We found lipocalin 2 and numerous other innate defense genes to be selectively induced in keratinocytes by IL-17. IFN-gamma had no effect on antimicrobial gene-expression in keratinocytes. In AD skin lesions, protein and mRNA expression of lipocalin 2 and other innate defense genes (hBD2, elafin, LL37) were reduced compared with psoriasis. Although AD has been framed by the Th1/Th2 paradigm as a Th2 polar disease, we present evidence that the IL-23/Th17 axis is largely absent, perhaps accounting for recurrent skin infections in this disease.
Asunto(s)
Dermatitis Atópica/inmunología , Interleucina-23/biosíntesis , Psoriasis/inmunología , Proteínas de Fase Aguda/biosíntesis , Proteínas de Fase Aguda/inmunología , Adolescente , Adulto , Anciano , Células Cultivadas , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Dermatitis Atópica/metabolismo , Femenino , Técnica del Anticuerpo Fluorescente , Humanos , Inmunohistoquímica , Interferón gamma/biosíntesis , Interferón gamma/inmunología , Interleucina-17/biosíntesis , Interleucina-17/inmunología , Interleucina-23/inmunología , Interleucinas/biosíntesis , Interleucinas/inmunología , Queratinocitos/inmunología , Queratinocitos/metabolismo , Lipocalina 2 , Lipocalinas/biosíntesis , Lipocalinas/inmunología , Masculino , Persona de Mediana Edad , Análisis de Secuencia por Matrices de Oligonucleótidos , Proteínas Proto-Oncogénicas/biosíntesis , Proteínas Proto-Oncogénicas/inmunología , Psoriasis/metabolismo , ARN Mensajero/análisis , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Interleucina-22RESUMEN
BACKGROUND: Psoriasis and atopic dermatitis (AD) are common, complex inflammatory skin diseases. Both diseases display immune infiltrates in lesions and epidermal growth/differentiation alterations associated with a defective skin barrier. An incomplete understanding of differences between these diseases makes it difficult to compare human disease pathology to animal disease models. OBJECTIVE: To characterize differences between these diseases in expression of genes related to epidermal growth/differentiation and inflammatory circuits. METHODS: We performed genomic profiling of mRNA in chronic psoriasis (n = 15) and AD (n = 18) skin lesions compared with normal human skin (n = 15). RESULTS: As expected, clear disease classifications could be constructed on the basis of expected immune polarity (T(H)1, T(H)2, T(H)17) differences. However, even more striking differences were identified in epidermal differentiation programs that could be used for precise disease classifications. Although both psoriasis and AD skin lesions displayed regenerative epidermal hyperplasia, which is a general alteration in epidermal growth, keratinocyte terminal differentiation was differentially polarized. In AD, we found selective defects in expression of multiple genes encoding the cornified envelope, with the largest alteration in loricrin (expressed at 2% of the level of normal skin). At the ultrastructural level, the cornified envelope in AD was broadly defective with highly decreased compaction of corneocytes and reduced intercellular lipids. Hence, the entire keratinocyte terminal differentiation program (cytoplasmic compaction, cornification, and lipid release) is defective in AD, potentially underlying the immune differences. CONCLUSION: Our study shows that although alterations in barrier responses exist in both diseases, epidermal differentiation is differentially polarized, with major implications for primary disease pathogenesis.
Asunto(s)
Dermatitis Atópica/genética , Dermatitis Atópica/patología , Epidermis/ultraestructura , Adolescente , Adulto , Anciano , Regulación hacia Abajo , Femenino , Perfilación de la Expresión Génica , Humanos , Masculino , Microscopía Electrónica de Transmisión , Persona de Mediana Edad , Psoriasis/genética , Psoriasis/patología , Regulación hacia Arriba , Adulto JovenRESUMEN
BACKGROUND: TNF inhibitors have revolutionized the treatment of psoriasis vulgaris as well as psoriatic and rheumatoid arthritis and Crohn disease. Despite our understanding that these agents block TNF, their complex mechanism of action in disease resolution is still unclear. OBJECTIVE: To analyze globally the genomic effects of TNF inhibition in patients with psoriasis, and to compare genomic profiles of patients who responded or did not respond to treatment. METHODS: In a clinical trial using etanercept TNF inhibitor to treat psoriasis vulgaris (n = 15), Affymetrix gene arrays were used to analyze gene profiles in lesional skin at multiple time points during drug treatment (baseline and weeks 1, 2, 4, and 12) compared with nonlesional skin. Patients were stratified as responders (n = 11) or nonresponders (n = 4) on the basis of histologic disease resolution. Cluster analysis was used to define gene sets that were modulated with similar magnitude and velocity over time. RESULTS: In responders, 4 clusters of downregulated genes and 3 clusters of upregulated genes were identified. Genes downmodulated most rapidly reflected direct inhibition of myeloid lineage immune genes. Upregulated genes included the stable dendritic cell population genes CD1c and CD207 (langerin). Comparison of responders and nonresponders revealed rapid downmodulation of innate IL-1beta and IL-8 sepsis cascade cytokines in both groups, but only responders downregulated IL-17 pathway genes to baseline levels. CONCLUSION: Although both responders and nonresponders to etanercept inactivated sepsis cascade cytokines, response to etanercept is dependent on inactivation of myeloid dendritic cell genes and inactivation of the T(H)17 immune response.
Asunto(s)
Antiinflamatorios no Esteroideos/uso terapéutico , Células Dendríticas/efectos de los fármacos , Inmunoglobulina G/uso terapéutico , Interleucina-17/inmunología , Células Mieloides/efectos de los fármacos , Psoriasis/tratamiento farmacológico , Receptores del Factor de Necrosis Tumoral/uso terapéutico , Linfocitos T Colaboradores-Inductores/efectos de los fármacos , Antiinflamatorios no Esteroideos/administración & dosificación , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Regulación hacia Abajo/efectos de los fármacos , Regulación hacia Abajo/genética , Regulación hacia Abajo/inmunología , Etanercept , Expresión Génica/efectos de los fármacos , Perfilación de la Expresión Génica , Humanos , Inmunoglobulina G/administración & dosificación , Interferón gamma/antagonistas & inhibidores , Interferón gamma/inmunología , Interferón gamma/metabolismo , Interleucina-17/antagonistas & inhibidores , Interleucina-17/metabolismo , Interleucina-1beta/antagonistas & inhibidores , Interleucina-1beta/inmunología , Interleucina-1beta/metabolismo , Interleucina-8/antagonistas & inhibidores , Interleucina-8/inmunología , Interleucina-8/metabolismo , Células Mieloides/inmunología , Células Mieloides/metabolismo , Análisis de Secuencia por Matrices de Oligonucleótidos , Psoriasis/genética , Psoriasis/inmunología , Receptores del Factor de Necrosis Tumoral/administración & dosificación , Transducción de Señal , Piel/efectos de los fármacos , Piel/inmunología , Piel/patología , Linfocitos T Colaboradores-Inductores/inmunología , Linfocitos T Colaboradores-Inductores/metabolismo , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Regulación hacia Arriba/efectos de los fármacos , Regulación hacia Arriba/genética , Regulación hacia Arriba/inmunologíaRESUMEN
BACKGROUND: Psoriasis and atopic dermatitis (AD) are common inflammatory skin diseases. An upregulated TH17/IL-23 pathway was demonstrated in psoriasis. Although potential involvement of TH17 T cells in AD was suggested during acute disease, the role of these cells in chronic AD remains unclear. OBJECTIVE: To examine differences in IL-23/TH17 signal between these diseases and establish relative frequencies of T-cell subsets in AD. METHODS: Skin biopsies and peripheral blood were collected from patients with chronic AD (n = 12) and psoriasis (n = 13). Relative frequencies of CD4+ and CD8+ T-cell subsets within these 2 compartments were examined by intracellular cytokine staining and flow cytometry. RESULTS: In peripheral blood, no significant difference was found in percentages of different T-cell subsets between these diseases. In contrast, psoriatic skin had significantly increased frequencies of TH1 and TH17 T cells compared with AD, whereas TH2 T cells were significantly elevated in AD. Distinct IL-22-producing CD4+ and CD8+ T-cell populations were significantly increased in AD skin compared with psoriasis. IL-22+CD8+ T-cell frequency correlated with AD disease severity. CONCLUSION: Our data established that T cells could independently express IL-22 even with low expression levels of IL-17. This argues for a functional specialization of T cells such that "T17" and "T22" T-cells may drive different features of epidermal pathology in inflammatory skin diseases, including induction of antimicrobial peptides for "T17" T cells and epidermal hyperplasia for "T22" T-cells. Given the clinical correlation with disease severity, further characterization of "T22" T cells is warranted, and may have future therapeutic implications.
Asunto(s)
Dermatitis Atópica/inmunología , Interleucina-23/metabolismo , Interleucinas/metabolismo , Psoriasis/inmunología , Subgrupos de Linfocitos T/inmunología , Linfocitos T Colaboradores-Inductores/inmunología , Adulto , Enfermedad Crónica , Dermatitis Atópica/metabolismo , Humanos , Interleucina-17/inmunología , Interleucina-17/metabolismo , Interleucina-23/inmunología , Interleucinas/inmunología , Persona de Mediana Edad , Psoriasis/metabolismo , Subgrupos de Linfocitos T/metabolismo , Linfocitos T Colaboradores-Inductores/metabolismo , Interleucina-22RESUMEN
Psoriasis vulgaris and psoriatic arthritis (PsA) are inter-related heritable diseases. Psoriatic skin is characterized by hyperproliferative, poorly differentiated keratinocytes and severe inflammation. Psoriatic joints are characterized by highly inflamed synovia and entheses with focal erosions of cartilage and bone. Genetic analyses have uncovered risk factors shared by both psoriasis and PsA. Predisposition to psoriasis and PsA arising from common variation is most strongly conferred by the HLA class I region. Other genetic risk factors implicate the interleukin (IL)-23 pathway and the induction and regulation of type 17 T-helper cells in the pathogenesis of both diseases. Secretion of cytokines, such as IL-22 and IL-17, could result in the hyperproliferative phenotype of keratinocytes and potentially synoviocytes, leading to a vicious cycle of cellular proliferation and inflammation in both the skin and joints. In synovial tissue, disease-related cytokines could also promote osteoclast formation, resulting in bone erosion. The next step will be to identify genetic risk factors specifically associated with PsA. Although therapies that target tumor necrosis factor are often highly successful in the treatment of both diseases, genetic findings are likely to lead to the development of treatments tailored to an individual's genetic profile.
Asunto(s)
Artritis Psoriásica/etiología , Artritis Psoriásica/genética , Predisposición Genética a la Enfermedad , Humanos , Interleucina-23/genética , Factores de Riesgo , Linfocitos T Colaboradores-Inductores/inmunologíaRESUMEN
Background: Pruritus is a prevalent and bothersome symptom of scalp psoriasis. Validated scales assessing scalp itch are needed to evaluate treatment efficacy. Objective: To evaluate comprehensibility and reproducibility of the Scalp Itch Numeric Rating Scale (NRS), a novel scale being used in a phase 3 study of apremilast. Methods: The Scalp Itch NRS, Modified Whole Body Itch NRS, Global Assessment of Psoriasis Severity-Scalp (GAPS-S), and Global Impression of Change-Scalp Itch (GIC-SI) were assessed among patients with moderate to severe scalp psoriasis. Convergent validity and test-retest reliability between two visits (7 ± 3 days apart) were assessed using intra-class and Spearman's correlations. Results: Patients found the Scalp Itch NRS easy to use and understand. Convergent validity (Modified Whole Body Itch NRS Visit 1: rs = 0.71, Visit 2: rs = 0.92, p< .0001; GAPS-S Visit 1: rs = 0.62, Visit 2: rs = 0.63, p< .0001), and consistency with changes (Modified Whole Body Itch NRS: rs = 0.69, p< .0001; GAPS-S: rs = 0.42, p = .0029) were demonstrated. The Scalp Itch NRS showed strong test-retest reliability (intra-class correlation coefficient = 0.87; rs = 0.89). Change scores on the Scalp Itch NRS were consistent with change scores on the GIC-SI. Conclusions: The Scalp Itch NRS is a valid and reproducible measure of scalp itch in patients with moderate to severe scalp psoriasis. ClinicalTrials.gov: NCT03123471.