RESUMEN
Imiquimod (IMQ) is a topical agent that induces local inflammation via the Toll-like receptor 7 pathway. Recently, an IMQ-driven skin inflammation model was developed in healthy volunteers for proof-of-pharmacology trials. The aim of this study was to profile the cellular, biochemical, and clinical effects of the marketed anti-inflammatory compound prednisolone in an IMQ model. This randomized, double-blind, placebo-controlled study was conducted in 24 healthy volunteers. Oral prednisolone (0.25 mg/kg/dose) or placebo (1:1) was administered twice daily for 6 consecutive days. Two days after treatment initiation with prednisolone or placebo, 5 mg imiquimod (IMQ) once daily for two following days was applied under occlusion on the tape-stripped skin of the back for 48 h in healthy volunteers. Non-invasive (imaging and biophysical) and invasive (skin punch biopsies and blister induction) assessments were performed, as well as IMQ ex vivo stimulation of whole blood. Prednisolone reduced blood perfusion and skin erythema following 48 h of IMQ application (95% CI [-26.4%, -4.3%], p = 0.0111 and 95% CI [-7.96, -2.13], p = 0.0016). Oral prednisolone suppressed the IMQ-elevated total cell count (95% CI [-79.7%, -16.3%], p = 0.0165), NK and dendritic cells (95% CI [-68.7%, -5.2%], p = 0.0333, 95% CI [-76.9%, -13.9%], p = 0.0184), and classical monocytes (95% CI [-76.7%, -26.6%], p = 0.0043) in blister fluid. Notably, TNF, IL-6, IL-8, and Mx-A responses in blister exudate were also reduced by prednisolone compared to placebo. Oral prednisolone suppresses IMQ-induced skin inflammation, which underlines the value of this cutaneous challenge model in clinical pharmacology studies of novel anti-inflammatory compounds. In these studies, prednisolone can be used as a benchmark.
Asunto(s)
Vesícula , Dermatitis , Humanos , Imiquimod/farmacología , Voluntarios Sanos , Prednisolona/farmacología , Prednisolona/uso terapéutico , Inflamación/inducido químicamente , Inflamación/tratamiento farmacológico , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéuticoRESUMEN
BACKGROUND: The effectiveness of available biologics for the treatment of hidradenitis suppurativa (HS) is limited. Additional therapeutic options are needed. OBJECTIVES: To investigate the efficacy and mode of action of guselkumab [an anti-interleukin (IL)-23p19 monoclonal antibody] 200â mg subcutaneously every 4 weeks for 16 weeks in patients with HS. METHODS: An open-label, multicentre, phase IIa trial in patients with moderate-to-severe HS was carried out (NCT04061395). The pharmacodynamic response in skin and blood was measured after 16 weeks of treatment. Clinical efficacy was assessed using the Hidradenitis Suppurativa Clinical Response (HiSCR), the International Hidradenitis Suppurativa Severity Score System (IHS4), and the abscess and inflammatory nodule (AN) count. The protocol was reviewed and approved by the local institutional review board (METC 2018/694), and the study was conducted in accordance with good clinical practice guidelines and applicable regulatory requirements. RESULTS: Thirteen of 20 patients (65%) achieved HiSCR with a statistically significant decrease in median IHS4 score (from 8.5 to 5.0; P = 0.002) and median AN count (from 6.5 to 4.0; P = 0.002). The overall patient-reported outcomes did not show a similar trend. One serious adverse event, likely to be unrelated to guselkumab treatment, was observed. In lesional skin, transcriptomic analysis revealed the upregulation of various genes associated with inflammation, including immunoglobulins, S100, matrix metalloproteinases, keratin, B-cell and complement genes, which decreased in clinical responders after treatment. Immunohistochemistry revealed a marked decrease in inflammatory markers in clinical responders at week 16. CONCLUSIONS: Sixty-five per cent of patients with moderate-to-severe HS achieved HiSCR after 16 weeks of treatment with guselkumab. We could not demonstrate a consistent correlation between gene and protein expression and clinical responses. The main limitations of this study were the small sample size and absence of a placebo arm. The large placebo-controlled phase IIb NOVA trial for guselkumab in patients with HS reported a lower HiSCR response of 45.0-50.8% in the treatment group and 38.7% in the placebo group. Guselkumab seems only to be of benefit in a subgroup of patients with HS, indicating that the IL-23/T helper 17 axis is not central to the pathophysiology of HS.
Asunto(s)
Hidradenitis Supurativa , Humanos , Hidradenitis Supurativa/complicaciones , Adalimumab/uso terapéutico , Antiinflamatorios , Índice de Severidad de la Enfermedad , Resultado del TratamientoRESUMEN
Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease characterized by recurring suppurating lesions of the intertriginous areas, resulting in a substantial impact on patients' QOL. HS pathogenesis remains poorly understood. An autoimmune component has been proposed, but disease-specific autoantibodies, autoantigens, or autoreactive T cells have yet to be described. In this study, we identify a high prevalence of IgM, IgG, and IgA antibodies directed against Nε-carboxyethyl lysine (CEL), a methylglyoxal-induced advanced glycation end-product, in the sera of patients with HS. Titers of anti-CEL IgG and IgA antibodies were highly elevated in HS compared with those in healthy controls and individuals with other inflammatory skin diseases. Strikingly, the majority of anti-CEL IgG was of the IgG2 subclass and correlated independently with both disease severity and duration. Both CEL and anti-CELâproducing plasmablasts could be isolated directly from HS skin lesions, further confirming the disease relevance of this autoimmune response. Our data point to an aberration of the methylglyoxal pathway in HS and support an autoimmune axis in the pathogenesis of this debilitating disease.
Asunto(s)
Hidradenitis Supurativa , Humanos , Autoanticuerpos , Lisina , Calidad de Vida , Piruvaldehído , Inmunoglobulina GRESUMEN
BACKGROUND: Dysbiosis and colonization with Staphylococcus aureus is considered to play an important role in the pathogenesis of atopic dermatitis (AD). Recovering this dysbiosis may improve AD symptoms. Omiganan is a synthetic indolicidin analogue antimicrobial peptide with activity against S aureus and could be a viable new treatment option for AD. OBJECTIVE: To explore the tolerability, clinical efficacy, and pharmacodynamics of omiganan in mild to moderate AD. METHODS: Eighty patients were randomized to omiganan 1%, 1.75%, or 2.5% or vehicle twice daily for 28 days on all lesions. Weekly visits included clinical scores and microbiological and pharmacodynamic assessments of 1 target lesion. RESULTS: In all omiganan treatment groups, dysbiosis was recovered by reducing Staphylococcus species abundance and increasing diversity. A reduction of cultured S aureus was observed in all omiganan treatment groups, with a significant reduction for omiganan 2.5% compared to vehicle (-93.5%; 95% CI, -99.2 to -28.5%; P = .02). No significant clinical improvement was observed. CONCLUSION: Topical administration of omiganan twice daily for up to 28 days in patients with mild to moderate AD led to a recovery of dysbiosis but without clinical improvement. Therefore, a monotreatment that selectively targets the microbiome does not appear to be a successful treatment strategy in mild to moderate AD.
Asunto(s)
Péptidos Antimicrobianos , Dermatitis Atópica , Péptidos Catiónicos Antimicrobianos , Dermatitis Atópica/diagnóstico , Disbiosis/tratamiento farmacológico , Humanos , Piel/patología , Staphylococcus aureusRESUMEN
Psoriasis is a chronic inflammatory skin disease with a prevalence of 2-3 %. It appears to result from a combination of genetic and environmental factors, but the precise pathogenesis is still unknown. Neurogenic inflammation is involved in psoriasis pathogenesis as well, but the role of neurogenic factors is currently unclear. Molecular studies often involve material obtained from patients. However, many questions and especially experimental manipulations are not suited for study in humans. Imiquimod application on mouse skin leads to immune cell infiltration, inflammation with intense redness, epidermal thickening, and scaling that jointly greatly resembles human psoriasis. Here we describe the use of surgical denervation in the imiquimod-induced psoriasiform model, to study the role of skin innervation and neuropeptides in the pathogenesis of psoriasis.
Asunto(s)
Desnervación/métodos , Procedimientos Quirúrgicos Dermatologicos/métodos , Psoriasis/inmunología , Piel/efectos de los fármacos , Linfocitos T/efectos de los fármacos , Aminoquinolinas/efectos adversos , Animales , Desnervación/instrumentación , Procedimientos Quirúrgicos Dermatologicos/instrumentación , Modelos Animales de Enfermedad , Femenino , Regulación de la Expresión Génica , Humanos , Imiquimod , Interleucina-17/genética , Interleucina-17/inmunología , Interleucina-23/genética , Interleucina-23/inmunología , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/inmunología , Ratones , Ratones Endogámicos C57BL , Psoriasis/inducido químicamente , Psoriasis/genética , Psoriasis/patología , Receptores de Antígenos de Linfocitos T gamma-delta/genética , Receptores de Antígenos de Linfocitos T gamma-delta/inmunología , Piel/inmunología , Piel/inervación , Linfocitos T/inmunología , Receptor Toll-Like 7/genética , Receptor Toll-Like 7/inmunologíaRESUMEN
ZC3H12A, which encodes the RNase monocyte chemotactic protein-induced protein 1 (MCPIP1), is up-regulated in psoriatic skin and reduced to normal levels after clinical treatments with anti-IL-17A/IL-17R neutralizing antibodies. In IL-17A-stimulated keratinocytes, MCPIP1 is rapidly increased at the transcript and protein levels. Also, IL-17A was found to be the main inducer of ZC3H12A expression in keratinocytes treated with supernatants derived from a Streptococcus pyogenes-activated psoriatic ex vivo model based on the co-culture of psoriatic cutaneous lymphocyte-associated antigen (CLA(+)) T cells and lesional epidermal cells. Moreover, MCPIP1 was aberrantly distributed in the suprabasal layers of psoriatic epidermis. In psoriatic samples, IL-17A-stimulated epidermal cell suspensions showed an increased MCPIP1 expression, especially in the mid-differentiated cellular compartment. The knockdown of ZC3H12A showed that this RNase participates in the regulation of the mRNAs present in suprabasal differentiated keratinocytes. Furthermore, JAK/STAT3 inhibition prevented the IL-17A-dependent induction of MCPIP1. In the mouse model of imiquimod-induced psoriasis, Zc3h12a expression was abrogated in Il17ra(-/-) mice. These results support the notion that IL-17A-mediated induction of MCPIP1 is involved in the regulation of local altered gene expression in suprabasal epidermal layers in psoriasis.
Asunto(s)
Epidermis/enzimología , Interleucina-17/farmacología , Psoriasis/enzimología , Psoriasis/genética , Ribonucleasas/metabolismo , Factores de Transcripción/metabolismo , Aminoquinolinas/química , Animales , Antígenos de Diferenciación de Linfocitos T/metabolismo , Biopsia , Técnicas de Cocultivo , Epidermis/metabolismo , Silenciador del Gen , Humanos , Imiquimod , Inflamación , Queratinocitos/citología , Glicoproteínas de Membrana/metabolismo , Ratones , Ratones Endogámicos BALB C , Ratones Noqueados , Fosforilación , Psoriasis/tratamiento farmacológico , Receptores de Interleucina-17/metabolismo , Ribonucleasas/genética , Factor de Transcripción STAT3/metabolismo , Piel/metabolismo , Factores de Transcripción/genética , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Clinical improvement of psoriasis induced by IL-4 treatment has been ascribed to changes in dermal inflammatory cells, such as activation of Th2 cells and tolerization of dendritic cells by suppressing IL-23 production. The pathologic epidermal alterations in psoriatic lesional skin include increased epidermal expression of IL-1ß, IL-6, S100A7, and human ß-defensin 2 (hBD2) and a downregulated expression of the epidermal transcription factor GATA3. Effects of IL-4 on the epidermal compartment of psoriasis lesions were not previously investigated. Therefore, we investigated whether IL-4 directly affects abovementioned psoriatic markers in the epidermal compartment. We cultured freshly isolated psoriatic epidermal cells, whole psoriatic and healthy skin biopsies, human keratinocytes and Langerhans cells with IL-4. The secretion of IL-1ß and IL-6 by psoriatic epidermal cells was inhibited by IL-4 via transcriptional and posttranscriptional mechanisms, respectively. In normal skin, IL-4 inhibited IL-1ß- and IL-17A-induced hBD2 expression in vitro. In addition, IL-4 reduced the protein expression of hBD2 in psoriatic skin biopsies and induced phospho-STAT6 protein. Epidermal GATA3 mRNA and protein were significantly upregulated by IL-4 in epidermal cells and keratinocytes. Our data argue that IL-4 improves psoriasis not only via modification/induction of Th2 cells and type II dendritic cells, but also via direct inhibition of inflammatory cytokines in resident IL-4R-expressing epidermal cells and thereby alters the psoriatic skin phenotype toward a healthy skin phenotype.