RESUMO
BACKGROUND: Drug survival is a marker for treatment sustainability in chronic diseases such as psoriasis. OBJECTIVE: The aim of these analyses was to assess survival of biologic treatments in the PSOriasis Longitudinal Assessment and Registry (PSOLAR). METHODS: PSOLAR is a large, prospective, international, disease-based registry of patients with psoriasis receiving (or eligible for) systemic therapy in a real-world setting. Drug survival is defined as the time from initiation to discontinuation (stop/switch) of biologic therapy on registry. The number of patients who discontinued each treatment and the duration of therapy were recorded. Using Kaplan-Meier survival curves and Cox-regression analyses [hazard ratios (HR) and 95% confidence intervals (CIs)], time to discontinuation was compared across cohorts undergoing first-, second- or third-line treatment with ustekinumab, infliximab, adalimumab or etanercept. RESULTS: As of the 2013 data cut, 12 095 patients with psoriasis were enrolled in PSOLAR. Of the 4000 patients initiating any new biologic therapy, approximately 3500 started a first-line, second-line or third-line biologic therapy during the registry. Lack of effectiveness was the most common reason for discontinuation across biologic therapies. Based on the multivariate analysis, significantly shorter times to discontinuation were observed for infliximab [HR (95%CI) = 2.73 (1.48-5.04), P = 0.0014]; adalimumab [4.16 (2.80-6.20), P < 0.0001]; and etanercept [4.91 (3.28-7.35) P < 0.0001] compared with ustekinumab [reference treatment]) for first-line biologic use; results were similar for treatment effects for second/third-line therapies. Although limited in power, analyses in patients with concurrent psoriatic arthritis confirmed by a rheumatologist reflect observations in the overall psoriasis population. CONCLUSION: Drug survival was superior for ustekinumab compared with infliximab, adalimumab and etanercept in patients with psoriasis.
Assuntos
Produtos Biológicos/uso terapêutico , Fármacos Dermatológicos/uso terapêutico , Psoríase/tratamento farmacológico , Sistema de Registros , Adulto , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Evaluation of the dosing flexibility and long-term efficacy of biological agents is limited. OBJECTIVES: To evaluate the long-term efficacy and safety of ustekinumab with and without dosing adjustment in the 5-year PHOENIX 2 study. METHODS: Patients were randomized to placebo or ustekinumab (45 or 90 mg) at weeks 0, 4, then every 12 weeks; patients receiving placebo crossed-over at week 12. Dosing adjustments were permitted at/beyond week 28 for early adjusters (weeks 28 or 40 per response); late adjusters (during long-term extension per investigator judgement); and nonadjusters (maintained randomized treatment throughout the study). Efficacy and safety were evaluated through weeks 244 and 264, respectively. RESULTS: In the overall population, 70% (849 of 1212) of ustekinumab-treated patients completed treatment through week 244, with high proportions of patients responding to the 45-mg and 90-mg doses, respectively: 75% improvement in Psoriasis Area and Severity Index (PASI 75) (76·5% and 78·6%) and PASI 90 (50·0% and 55·5%). Approximately 20% of patients were early adjusters, 30% were late adjusters and 50% were nonadjusters. Approximately half of the late adjusters initiated adjustments after already achieving PASI 75. Improved response was generally observed following dosing adjustments. Through week 264, safety event rates did not increase and event rates were generally comparable between dose groups and between patients with and without dosing adjustment. CONCLUSIONS: Treatment with ustekinumab for up to 5 years was safe and effective. Improved response was generally demonstrated following dosing adjustments; further investigations are required to quantify actual incremental benefits. The results also suggest that some patients may desire treatment goals beyond PASI 75.
Assuntos
Fármacos Dermatológicos/administração & dosagem , Psoríase/tratamento farmacológico , Ustekinumab/administração & dosagem , Peso Corporal , Estudos Cross-Over , Fármacos Dermatológicos/efeitos adversos , Relação Dose-Resposta a Droga , Método Duplo-Cego , Esquema de Medicação , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Ustekinumab/efeitos adversosRESUMO
Psoriatic arthritis (PsA) is an inflammatory arthritis of uncertain pathogenesis, affecting approximately one in four patients with psoriasis. Onset of psoriasis typically precedes the development of PsA. Therefore, the dermatologist is ideally positioned to recognize the early signs and symptoms of PsA for diagnosis and subsequent treatment. The role of the dermatologist in early diagnosis and treatment is essential for preventing pain and functional disabilities, as well as the joint deterioration that accompanies progressive forms of PsA. Diagnosis of PsA is a key aspect of the clinical decision process for the dermatologist, as psoriasis plus PsA requires a different therapeutic approach from that required for psoriasis alone. Furthermore, PsA is associated with an increased risk of cardiovascular comorbidities that present significant health concerns. In this review, the pathogenesis and comorbidities of PsA are discussed. In addition, screening and imaging tools that aid in the diagnosis of PsA, as well as tools used for efficacy assessment, are reviewed. Available therapies are presented, with a focus on targeted biologics and emerging treatments.
Assuntos
Antirreumáticos/uso terapêutico , Artrite Psoriásica/tratamento farmacológico , Anti-Inflamatórios/uso terapêutico , Artrite Psoriásica/diagnóstico , Artrite Psoriásica/etiologia , Fatores Biológicos/uso terapêutico , Ciclosporina/uso terapêutico , Fármacos Dermatológicos/uso terapêutico , Humanos , Uso Off-Label , Resultado do Tratamento , Fator de Necrose Tumoral alfa/antagonistas & inibidoresRESUMO
BACKGROUND: Treatment satisfaction among patients with moderate-to-severe psoriasis has not been studied and compared across treatments using a validated instrument. OBJECTIVES: To assess patient-reported satisfaction with systemic and phototherapy treatments for moderate-to-severe psoriasis in clinical practice and to correlate satisfaction with disease severity and quality-of-life measures. METHODS: This was a cross-sectional study of 1182 patients with moderate-to-severe psoriasis in the Dermatology Clinical Effectiveness Research Network in the U.S.A. Patients receiving either topical therapies only; monotherapy with oral systemic therapies, biologics or narrowband ultraviolet B phototherapy; or combination therapy with biologics and methotrexate completed the Treatment Satisfaction Questionnaire for Medication version II. RESULTS: Median unadjusted overall satisfaction scores were highest for patients receiving biologic monotherapies, biologic-methotrexate combinations, or phototherapy (83.3); scores were lowest for those receiving topical therapies only or acitretin (66.7). In fully adjusted models, compared with patients receiving methotrexate monotherapy, those receiving adalimumab, etanercept, ustekinumab, phototherapy or adalimumab with methotrexate had significantly higher median overall satisfaction scores by 7.2-8.3 points, while those receiving topical therapies only had significantly lower overall satisfaction by 8.9 points. Adjusted convenience scores were lowest for patients receiving topical therapies only or infliximab. Modest but significant correlations were found between the overall satisfaction subscale and both the Psoriasis Area and Severity Index (ρ = -0.36, P < 0.001) and the Dermatology Life Quality Index (ρ = -0.47, P < 0.001). CONCLUSIONS: Discernible differences were found in treatment satisfaction among therapies, particularly regarding treatment effectiveness and convenience. Further application of treatment satisfaction measures may inform treatment decisions and guideline development.
Assuntos
Satisfação do Paciente , Psoríase/terapia , Adulto , Estudos Transversais , Fármacos Dermatológicos/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Psoríase/psicologia , Qualidade de Vida , Inquéritos e Questionários , Resultado do Tratamento , Terapia Ultravioleta/psicologiaAssuntos
Corticosteroides/uso terapêutico , Dermatologia/métodos , Padrões de Prática Médica/estatística & dados numéricos , Psoríase/tratamento farmacológico , Administração Oral , Corticosteroides/administração & dosagem , Fatores Etários , Idoso , Estudos Transversais , Feminino , Humanos , Injeções Intramusculares , Masculino , Pessoa de Meia-Idade , Prática Privada/estatística & dados numéricos , Fatores Sexuais , Inquéritos e Questionários , Estados UnidosAssuntos
Psoríase/diagnóstico , Índice de Gravidade de Doença , Classe Social , Estudos Transversais , Escolaridade , Humanos , Renda/estatística & dados numéricos , Estudos Prospectivos , Psoríase/tratamento farmacológico , Sistema de Registros/estatística & dados numéricos , Resultado do Tratamento , Ustekinumab/uso terapêuticoRESUMO
BACKGROUND: Anti-interleukin-12/23 treatment (anti-IL-12/23) has recently demonstrated significant efficacy for moderate to severe psoriasis, yet potential safety signals warrant further investigation. OBJECTIVES: Expand safety findings for the anti-IL-12/23, briakinumab, beyond individual phase II and III clinical trials. METHODS: Safety data pooled from five phase II and III clinical trials (parent studies) and an open-label extension study (OLE), through 22 October 2010; patients with ≥ 1 dose of briakinumab in a parent study or the OLE are included. All parent study briakinumab treatment groups were combined with the OLE population, which received 100-mg briakinumab every 4 weeks. Adverse events (AEs) were collected from the first dose of briakinumab, whether in a parent study or the OLE, through 45 days post-last dose. RESULTS: Two thousand five hundred and twenty patients (4704 patient-years drug exposure) received ≥ 1 dose of briakinumab during the interim period: 5.6% withdrew due to AEs. Serious infections occurred in 1.3% and malignancies in 2.6% (including 1.0% basal cell carcinoma, 0.8% squamous cell carcinoma). Twenty-seven major adverse cardiovascular events (MACE) occurred, seven in one parent study and 20 in the OLE (incidence = 0.57 events/100 PY). Four cardiovascular risk factors were retrospectively found to be significant predictors for MACE during briakinumab exposure: history of cardiovascular disease, diabetes, body mass index (≥ 30) and baseline blood pressure (systolic ≥ 140 or diastolic ≥ 90). CONCLUSIONS: Pooled briakinumab safety results from five parent studies and an OLE suggest increased rates of infections, malignancies and MACE, and that patients receiving anti-IL-12/23 treatment for moderate to severe psoriasis should be monitored for these potential safety signals.
Assuntos
Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/uso terapêutico , Psoríase/tratamento farmacológico , Adulto , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais Humanizados , Carcinoma Basocelular/epidemiologia , Carcinoma de Células Escamosas/epidemiologia , Doenças Cardiovasculares/epidemiologia , Ensaios Clínicos como Assunto , Feminino , Humanos , Interleucina-12/imunologia , Interleucina-23/imunologia , Masculino , Pessoa de Meia-Idade , Prevalência , Ensaios Clínicos Controlados Aleatórios como Assunto , Índice de Gravidade de Doença , Dermatopatias Infecciosas/epidemiologia , Neoplasias Cutâneas/epidemiologia , Resultado do TratamentoRESUMO
Human skin transplanted to nude mice offers a possible experimental system for the study of normal epidermal proliferation and differentiation, and for their pathological counterparts. Crucial to the development of such a system is the demonstration that such grafts retain the responsive features of donor skin. To document that donor proliferative characteristics are maintained in the grafts, a comparative analysis of agents that induce proliferation was made on skin of mice homozygous and heterozygous for nude, on pig skin, and on pig skin transplanted onto nude mice. A wave of epidermal proliferation could be induced in pig skin and pig skin grafted onto nude mice, but not in nude mouse skin after the topical application of 10 ng 12-O-tetradecanoyl phorbol 13-acetate (TPA). A 10-fold greater concentration of TPA or 5% croton oil induced proliferation in all species of epidermis studied. Mice, heterozygous for nude, showed a normal response to 10 ng TPA, suggesting that the ability to respond to TPA may be related, in part, to a recessive genetic trait. Nude mouse skin transplanted to a heterozygous littermate capable of responding to 10 ng TPA does not respond. These observations argue that: the graft retains its donor proliferative characteristics when transplanted to the nude, and the inability of the nude mouse to respond to lower doses of TPA may be related to absorption, the nude gene(s), or an inherent threshold to response. The lack of response to the promoter TPA provides a plausible explanation for the decreased incidence of tumors arising in nude mice during two-stage carcinogenesis experiments.
Assuntos
Forbóis/toxicidade , Neoplasias Cutâneas/induzido quimicamente , Pele/imunologia , Acetato de Tetradecanoilforbol/toxicidade , Imunologia de Transplantes , Animais , Camundongos , Camundongos Nus , Neoplasias Experimentais/induzido quimicamente , Neoplasias Experimentais/imunologia , Neoplasias Cutâneas/imunologia , Transplante de Pele , Suínos , Transplante HeterólogoRESUMO
Background PHOENIX 1 was a phase III, randomized, double-blind, placebo-controlled study that demonstrated the long-term efficacy and safety of ustekinumab in patients with moderate-to-severe psoriasis. Objectives To assess the effect of ustekinumab maintenance therapy on health-related quality of life (HRQoL) in PHOENIX 1 patients. Patients and methods Patients (n = 766) were randomized to receive ustekinumab 45 mg (n = 255) or 90 mg (n = 256) at weeks 0 and 4 and every 12 weeks thereafter, or placebo (n = 255) at weeks 0 and 4 with crossover to ustekinumab at week 12. Ustekinumab-randomized patients achieving at least 75% improvement in Psoriasis Area and Severity Index (PASI) 75 at weeks 28 and 40 were re-randomized at week 40 to continue ustekinumab or be withdrawn until loss of therapeutic effect. HRQoL was assessed using the SF-36 and Dermatology Life Quality Index (DLQI). Results At baseline, more than 97% had a DLQI > 1 and the average DLQI was > 10, indicating a significant impact on patients' HRQoL. Significantly greater proportions of patients receiving ustekinumab 45 and 90 mg achieved a normalized DLQI score (< or = 1) compared with placebo (53.2%, 52.4% and 6.0%, respectively, both P < 0.001) at week 12 and achieved a clinically meaningful improvement (increase of at least five points) in SF-36 physical (23.1%, 33.7% and 15.6%) and mental (25.5%, 31.3% and 14.8%) component summary scores. At week 12, changes in individual DLQI and SF-36 domains were significantly better in each ustekinumab group vs. placebo (P < 0.001). The magnitude of improvement across SF-36 scales was greatest for the bodily pain and social functioning domains. Improvements in HRQoL were sustained with maintenance ustekinumab therapy through at least 1 year. Regression analysis showed that, after adjustment for improvement in PASI or Physician's Global Assessment (PGA), ustekinumab-treated patients demonstrated significant improvements in DLQI. Conclusions Ustekinumab improves HRQoL in patients with moderate-to-severe psoriasis. Patient-reported outcomes measured a treatment effect beyond that indicated by clinical measures.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Psoríase/tratamento farmacológico , Qualidade de Vida , Adulto , Anticorpos Monoclonais Humanizados , Estudos Cross-Over , Método Duplo-Cego , Feminino , Nível de Saúde , Humanos , Masculino , Pessoa de Meia-Idade , Psoríase/patologia , Psoríase/psicologia , Índice de Gravidade de Doença , UstekinumabRESUMO
BACKGROUND: The Utah Psoriasis Initiative (UPI) is an expanding database that is being used to identify and characterize phenotypic variants of psoriasis and explore genotype-phenotype relationships. We recently reported distinct morphological variants of psoriasis that are characterized by thickness of lesions (induration) in the untreated state. OBJECTIVES: To explore the clinical relevance of these morphological variants. METHODS: For these analyses, we used the phenotypic data from 282 additional subjects gathered at enrollment into the UPI and compared their phenotype with that of the original 500 patients reported previously. The analysis was further expanded via a longitudinal follow-up of 286 subjects from the original 500 case cohort. RESULTS: Firstly, the initial findings were confirmed. Expansion of the cohort used for the original observation by about 50% and reanalysis showed that there was no alteration in the proportions of patients expressing thin- and thick-plaque disease phenotypes. Secondly, analysis of the larger cohort showed that this morphological phenotype had clinical relevance: those patients with thin-plaque disease were more likely to report a complete therapeutic response to topical corticosteroids and phototherapy. In contrast, plaque thickness did not appear to be a factor in response to systemic agents. CONCLUSIONS: Using a patient's baseline plaque morphology to choose a primary treatment modality may result in earlier disease improvement and reduce the cost of therapy.
Assuntos
Fototerapia , Psoríase/patologia , Adulto , Bases de Dados Factuais , Feminino , Humanos , Estudos Longitudinais , Masculino , Fenótipo , Psoríase/tratamento farmacológico , Índice de Gravidade de Doença , Resultado do Tratamento , UtahRESUMO
A multitiered genetic association study of 25 215 single-nucleotide polymorphisms (SNPs) in three case-control sample sets (1446 patients and 1432 controls) identified three IL13-linked SNPs (rs1800925, rs20541 and rs848) associated with psoriasis. Although the susceptibility effects at these SNPs were modest (joint allelic odds ratios (ORs): 0.76 to 0.78; P(comb): 1.3E-03 to 2.50E-04), the association patterns were consistent across the sample sets, with the minor alleles being protective. Haplotype analyses identified one common, susceptible haplotype CCG (joint allelic OR=1.27; P(comb)=1.88E-04) and a less common, protective haplotype TTT (joint allelic OR=0.74; P(comb)=7.05E-04). In combination with the other known genetic risk factors, HLA-C, IL12B and IL23R, the variants reported here generate an 11-fold psoriasis-risk differential. Residing in the 5q31 cytokine gene cluster, IL13 encodes an important T-cell-derived cytokine that regulates cell-mediated immunity. These results provide the foundation for additional studies required to fully dissect the associations within this cytokine-rich genomic region, as polymorphisms in closely linked candidate genes, such as IRF1, IL5 or IL4, may be driving these results through linkage disequilibrium.
Assuntos
Cromossomos Humanos Par 5/imunologia , Citocinas/genética , Variação Genética/imunologia , Família Multigênica/genética , Psoríase/genética , Estudos de Casos e Controles , Haplótipos/imunologia , Humanos , Psoríase/epidemiologia , Psoríase/imunologiaRESUMO
Using a multi-tiered, case-control association design, scanning 25 215 gene-centric SNPs, we previously identified two psoriasis susceptibility genes: IL12B and IL23R. These results have recently been confirmed. To better characterize the IL23R psoriasis-association, we used a fine mapping strategy to identify 59 additional IL23R-linked SNPs, which were genotyped in our three independent, white North American sample sets (>2800 individuals in toto). A sliding window of haplotype association demonstrates colocalization of psoriasis susceptibility effects within the boundaries of IL23R across all sample sets, thereby decreasing the likelihood that neighboring genes, particularly IL12RB2, are driving the association at this region. Additional haplotype work identified two 5-SNP haplotypes with strong protective effects, consistent across our three sample sets (OR(common)=0.67; P(comb)=4.32E-07). Importantly, heterogeneity of effect was extremely low between sample sets for these haplotypes (P(Het)=0.961). Together, these protective haplotypes attain a frequency of 16% in controls, declining to 11% in cases. The characterization of association patterns within IL23R to specific predisposing/protective variants will play an important role in the elucidation of psoriasis etiology and other related phenotypes. Further, this work is essential to lay the foundation for the role of IL23R genetics in response to pharmaceutical therapy and dosage.
Assuntos
Predisposição Genética para Doença , Psoríase/genética , Receptores de Interleucina/genética , Estudos de Casos e Controles , Haplótipos , Humanos , Idaho , Polimorfismo de Nucleotídeo Único , UtahRESUMO
A highly significant, but unanswered, question in the pathogenesis of psoriasis relates to how normal appearing and diseased skin can coexist, undergo spontaneous flares and remissions, and yet appear to be genetically acquired. A plausible explanation for these disparate observations is that there is a basic defect in epidermal proliferation of skin of subjects with psoriasis and that disease expression is governed by other host factors. To address this question, we compared epidermal proliferation of skin involved and uninvolved with psoriasis with normal skin before and after transplantation to congenitally athymic (nude) mice, a biologic milieu free of humoral factors unique to the donor host. Results demonstrated that (a) before transplant, synthesis of DNA by the epidermal cells from skin uninvolved and involved with psoriasis is significantly higher than normal, 1.6 and 3.6 times, respectively; (b) 6 wk after transplantation, synthesis of DNA by epidermal cells is unchanged for normal skin, increased for uninvolved skin, and decreased for involved skin. These increases and decreases are of such a magnitude that at 6 wk the number of epidermal cells synthesizing DNA per 1,000 basal cells is identical, and is 2.2 times that of normal skin. When removed from the milieu of the afflicted host, skin involved and uninvolved with psoriasis appear equally "diseased." These data support the notion that there is aberrant epidermal proliferation in skin of patients with psoriasis and that host factors appear to play a role both in the expression and nonexpression of this disease.
Assuntos
Psoríase/patologia , Pele/patologia , Adulto , Animais , Autorradiografia , Divisão Celular , DNA/biossíntese , Humanos , Masculino , Camundongos , Camundongos Nus , Tamanho do Órgão , Paraceratose/patologia , Psoríase/etiologia , Psoríase/imunologia , Pele/imunologia , Transplante de Pele , Fatores de TempoRESUMO
Study of human sebaceous gland physiology and pathophysiology is limited by lack of an adequate animal model. This study was designed to develop an animal model using human face skin grafted onto the nude mouse to study human sebaceous glands. Full-thickness human face skin was grafted onto 60 adult male nude mice. 4 wk after grafting, androgens, which are known to stimulate sebaceous glands, were administered to test the system. Androgens were administered to 21 animals by implanted catheters that were filled with testosterone (T) or dihydrotestosterone (DHT). Empty catheters were implanted in 15 control animals. Graft biopsies and blood for androgen levels were obtained at time 1 (pre-catheter) and time 2 (26 d after catheter implantation). Three assessments were made on each biopsy: sebaceous gland volume, using an image analyzing computer; sebaceous cell size; and sebaceous gland labeling index. 29 mice completed the study through time 2. In the androgen-treated group, T levels (nanogram per milliliter) five times increased to 4.92 +/- 0.35, and DHT levels (nanogram per milliliter) increased 50 times to 16.70. In the androgen-treated group, sebaceous gland volume (micron 3 X 10(-3) increased from 896 +/- 194 to 3,233 +/- 754 (P less than 0.001), sebaceous cell area (micron 2) increased from 167 +/- 12 to 243 +/- 19 (P less than 0.001), and labeling index (percentage) increased from 2.7 +/- 0.7 to 6.4 +/- 0.9 (P less than 0.01). In the control group, sebaceous gland volume fell from 1,070 +/- 393 to 417 +/- 99 (NS), sebaceous cell size remained the same, and the labeling index fell from 5.1 +/- 1.9 to 3.2 +/- 1.1. After androgen administration, Halowax N-34, a known comedogen, or its vehicle, was applied to 15 grafts for 2-6 wk. Twice as many microcomedones were seen in the Halowax-treated grafts, compared with vehicle-treated grafts at the end of this time period. No visible comedones were produced. This study demonstrated that: (a) human sebaceous glands can be successfully transplanted and studied on the nude mouse; (b) after androgen stimulation, sebaceous gland volume, cell size, and labeling index increase; (c) microcomedones can be produced in the human skin grafts by the application of a comedogenic substance. Thus, this model demonstrates significant potential for the future study of human sebaceous gland physiology and pathology.
Assuntos
Modelos Biológicos , Glândulas Sebáceas/fisiologia , Fenômenos Fisiológicos da Pele , Acne Vulgar/patologia , Acne Vulgar/fisiopatologia , Adulto , Animais , Di-Hidrotestosterona/farmacologia , Modelos Animais de Doenças , Face , Feminino , Sobrevivência de Enxerto , Humanos , Hidrocarbonetos Clorados/farmacologia , Hiperplasia/induzido quimicamente , Masculino , Camundongos , Camundongos Nus , Pessoa de Meia-Idade , Naftalenos/farmacologia , Glândulas Sebáceas/metabolismo , Glândulas Sebáceas/patologia , Pele/microbiologia , Transplante de Pele , Testosterona/farmacologiaRESUMO
This review highlights our current understanding of the biology of, survival of, and transgene expression by genetically modified fibroblasts (GMFb) carrying stably integrated transgenes in vivo. Experimental data demonstrate that three elements will enhance expression by and survival of GMFb in vivo: a matrix scaffolding to take the place of the existing dermis, the presence of elements of the extracellular matrix in the construct used to move GMFb to the in vivo setting, and the utilization of immortalized fibroblasts to carry the transgenes. Although moving GMFb to an in vivo setting is an invasive procedure, there are a number of clinical settings where GMFb appear to be the suitable cell for gene therapy.
Assuntos
Epiderme/metabolismo , Fibroblastos/metabolismo , Técnicas de Transferência de Genes , Terapia Genética/métodos , Vetores Genéticos/administração & dosagem , Neoplasias/terapia , Dermatopatias/terapia , Transgenes , Humanos , Dermatopatias/genéticaRESUMO
Because human fibroblasts are easily brought to tissue culture conditions and can be stably transduced with retroviral vectors encoding transgenes ex vivo, genetically modified fibroblasts are frequently considered in strategies to correct disease with gene therapy. This enthusiasm has been dampened by studies showing that transgene expression by genetically modified fibroblasts diminishes with time in vivo, but not in vitro, for reasons that are unclear. We elected to study this problem using cloned human fibroblasts that had been cloned by limiting dilution and stably transduced with a retroviral vector encoding lacZ ex vivo. These were seeded onto a nonbiodegradable nylon matrix that was transplanted to nude mice. Transgene expression was followed prospectively by histologic exam. Data show that human fibroblasts can withstand the pressure of cloning by limiting dilution. In addition, they can be passaged from 10 to > 20 times, and > 1 x 10(20) of genetically modified fibroblasts can be generated as progeny of one cell. Loss of transgene expression by the cloned genetically modified fibroblasts in vivo occurs in an orderly and progressive fashion, but is not complete by 4 months. Neither the loss nor the persistence of expression appear to be random. These observations are most compatible with the thesis that a major cause of the loss of transgene expression in vivo is secondary to apoptosis of the genetically modified fibroblast. Loss of expression of transgenes in senescent genetically modified fibroblasts occurs more rapidly than in their presenescent counterparts in the age-neutral, in vivo setting of the nude mouse.
Assuntos
Fibroblastos/fisiologia , Transdução Genética , Transgenes/genética , Animais , Sobrevivência Celular/genética , Sobrevivência Celular/fisiologia , Células Cultivadas , Fibroblastos/citologia , Deleção de Genes , Expressão Gênica , Genes Reporter , Humanos , Óperon Lac/genética , Óperon Lac/fisiologia , Masculino , Camundongos , Camundongos NusRESUMO
Psoriasis is a genetically inherited spectrum of skin diseases characterized by epidermal proliferation and inflammation, which are reversible. Although many have reported that psoriasis is triggered by trauma, infections, stress, drugs, etc., the epidemiology of psoriasis remains poorly understood. Linkage to human leukocyte antigen-(HLA)-Cw6 and DR7 is strong in people with early onset disease, but concordance in monozygotic twins is only 67%, emphasizing the importance of a triggering event. Other factors that have been reported to affect the course of psoriasis include upper respiratory infections, smoking, obesity, alcohol ingestion, regional enteritis, and human immunodeficiency virus infection. This manuscript reviews the clinical epidemiology of psoriasis and highlights some of the needs for further investigation into specific areas of the disease.
Assuntos
Psoríase/epidemiologia , Humanos , Prevalência , Psoríase/etiologia , Psoríase/patologiaRESUMO
To accept human skin transplanted to the congenitally athymic (nude) mouse as a system to study human skin and its physiologic and pathologic states, it must be demonstrated that skin so maintained retains its function as a biologic unit. We have found that responses of grafted human skin and nude mouse skin to various agents differ. This difference in response has been utilized to assess barrier function and proliferative capacity of human skin grafts. Human skin grafts undergo a proliferative response when 10 ng of the tumor promoter, 12-O-tetradecanoyl phorbol 13-acetate (TPA) is applied. Nudes do not respond to this dose. Increasing the dose to 100 ng of TPA evokes a response in both. However, only in the human skin grafts can this response be blocked with betamethasone valerate (BV). In that human skin grafts do not take on their hosts' responsiveness, and the response of domestic pig skin to these agents before and after grafting is identical, the conclusion is reached that human skin appears to retain its inherent biologic unit function. The data also demonstrate some of the potential of this system to study kinetics of the epidermis of human skin.