RESUMO
INTRODUCTION: Treatment with biologics often leads to clearance of psoriasis. However, some patients do repeatedly fail to respond and/or lose an achieved response (treatment refractory) to the biologic, whereas other patients achieve excellent response to one biologic and remain clear of psoriasis for several years (super-responders). OBJECTIVE: To identify and characterize patients with treatment refractory psoriasis and patients who are super-responders to biologic treatment. MATERIAL AND METHODS: Patients registered in DERMBIO between January 2007 and November 2019 were included. Patients were categorized as being treatment refractory if they had had treatment failure to ≥3 biologics targeting ≥2 different pathways. Super-responders were patients treated with their first biologic for minimum 5 years without an absolute psoriasis area and severity index (PASI) > 3 between 6 months and 5 years of treatment. All remaining patients from DERMBIO served as comparators. RESULTS: In total, 3280 patients were included with a mean age of 45.0 years. 1221 (37%) of the patients were females. Of the included patients, 214 (6.5%) were categorized as treatment refractory and 207 (6.3%) were categorized as super-responders. Treatment refractory patients had higher mean body weight (100.6 kg vs. 90.6 kg, P < 0.0001) and higher mean BMI (32.2 vs. 29.4, P < 0.0001) compared with the rest of patients in DERMBIO. Super-responders had higher socioeconomic status and fewer comorbidities compared with the comparator group (P < 0.0001). CONCLUSION: A small proportion of patients with psoriasis treated with biologics are either super-responders or treatment refractory. Treatment refractory patients have higher body weight, whereas super-responders have fewer comorbidities and higher socioeconomic status.
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Produtos Biológicos , Psoríase , Produtos Biológicos/efeitos adversos , Peso Corporal , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
Biological agents including anti-tumor necrosis factor (anti-TNF; adalimumab, infliximab, etanercept) and anti-interleukin-12/13 (IL12/23; ustekinumab) are essential for treatment of patients with severe psoriasis. However, a significant proportion of the patients do not respond to a specific treatment. Pharmacogenetics might be a way to predict treatment response. Using a candidate gene approach, 62 mainly functional single-nucleotide polymorphisms (SNPs) in 44 different genes were evaluated in 478 Danish patients with psoriasis undergoing 376 series of anti-TNF treatment and 230 series of ustekinumab treatment. Associations between genetic variants and treatment outcomes (drug survival and Psoriasis Area Severity Index reduction) were assessed using logistic regression analyses (crude and adjusted for gender, age, psoriatic arthritis and previous treatment). After correction for multiple testing controlling the false discovery rate, six SNPs (IL1B (rs1143623, rs1143627), LY96 (rs11465996), TLR2 (rs11938228, rs4696480) and TLR9 (rs352139)) were associated with response to anti-TNF treatment and 4 SNPs (IL1B (rs1143623, rs1143627), TIRAP (rs8177374) and TLR5 (rs5744174)) were associated with response to ustekinumab treatment (q<0.20). The results suggest that genetic variants related to increased IL-1ß levels may be unfavorable when treating psoriasis with either anti-TNF or ustekinumab, whereas genetic variants related to high interferon-γ levels may be favorable when treating psoriasis with ustekinumab.
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Farmacogenética/métodos , Psoríase/tratamento farmacológico , Psoríase/genética , Adalimumab/administração & dosagem , Adalimumab/efeitos adversos , Adulto , Dinamarca , Etanercepte/administração & dosagem , Etanercepte/efeitos adversos , Feminino , Humanos , Infliximab/administração & dosagem , Infliximab/efeitos adversos , Interleucina-1beta/genética , Antígeno 96 de Linfócito/genética , Masculino , Glicoproteínas de Membrana/genética , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Psoríase/epidemiologia , Psoríase/patologia , Receptores de Interleucina-1/genética , Receptor 2 Toll-Like/genética , Receptor Toll-Like 9/genética , Resultado do Tratamento , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Ustekinumab/administração & dosagem , Ustekinumab/efeitos adversosRESUMO
BACKGROUND: Real-life data on newer biological and biosimilar agents for moderate-to-severe psoriasis are lacking. OBJECTIVES: To examine safety, efficacy and time to discontinuation (drug survival) of biologics (adalimumab, etanercept, infliximab, secukinumab and ustekinumab) and compare originators with biosimilars (i.e. Enbrel with Benepali, and Remicade with Remsima). METHODS: The DERMBIO registry contains data on all Danish patients with moderate-to-severe plaque psoriasis treated with biologics. We examined patients treated between 1 January 2007 and 31 March 2017. We used Kaplan-Meier survival curves and Cox regression to examine drug survival patterns. RESULTS: A total of 3495 treatment series (2161 patients) were included (adalimumab n = 1332; etanercept n = 579; infliximab n = 333; ustekinumab n = 1055 and secukinumab n = 196). Secukinumab had the highest number of PASI 100 (100% improvement from baseline Psoriasis Area and Severity Index) respondents, but also the lowest drug survival among all the biologics. Ustekinumab had the highest drug survival overall. There were no significant differences in discontinuation risk between originator and biosimilar versions of infliximab or etanercept. Treatment with higher than approved dosages was frequent for all drugs except for adalimumab and secukinumab. Adverse events (predominantly infections) were most frequent for secukinumab compared with the other agents. CONCLUSIONS: Ustekinumab was associated with the highest drug survival, and secukinumab with the lowest, although most patients on secukinumab were non-naïve. Switching from originator to biosimilar had no significant impact on drug survival, and the safety profiles were comparable. Adverse events occurred most frequently with secukinumab. Future studies are warranted to assess the long-term safety of novel biologics for psoriasis.
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Fatores Biológicos/uso terapêutico , Medicamentos Biossimilares/uso terapêutico , Fármacos Dermatológicos/uso terapêutico , Psoríase/tratamento farmacológico , Dinamarca , Estabilidade de Medicamentos , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Sistema de Registros , Resultado do TratamentoRESUMO
BACKGROUND: While safety and efficacy of ustekinumab and secukinumab, monoclonal antibodies approved for psoriasis, are described in clinical trials, data on their real-life application are lacking. OBJECTIVE: We compared the characteristics of patients initiating first-time treatment with secukinumab or ustekinumab. METHODS: All Danish patients with moderate-to-severe plaque psoriasis treated with biologics are recorded in the nationwide DERMBIO registry. We compared characteristics of patients starting first-time therapy with ustekinumab and secukinumab, respectively. RESULTS: We identified a total of 1037 and 142 first-time treatment series with ustekinumab and secukinumab. There was a male predominance in both groups, but patients initiating secukinumab were slightly older and with longer disease duration; in agreement with guidelines for biologic treatment in Denmark where ustekinumab has been first line for all with psoriasis without joint problems since 2012, and secukinumab first line for psoriasis with joint problems since July 2016. A total of (52.9% and 14.5%) patients receiving ustekinumab and secukinumab, respectively, were bio-naïve. The mean dermatology life quality index score was slightly higher for ustekinumab than secukinumab (11.6 vs. 10.0; P = 0.0769); the mean Psoriasis Area and Severity Index score were significantly higher (10.4 vs. 7.3; P < 0.0001) for ustekinumab. Prevalence of joint disease was markedly lover (22.7% vs. 44.4%) among patients receiving ustekinumab. CONCLUSIONS: We found significant differences in characteristics of patients starting therapy with ustekinumab and secukinumab in a real-life clinical setting. These findings may aid clinicians and researchers when interpreting efficacy data derived from clinical trials and biologic registries of patients with psoriasis.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Fármacos Dermatológicos/uso terapêutico , Psoríase/tratamento farmacológico , Sistema de Registros , Ustekinumab/uso terapêutico , Anticorpos Monoclonais Humanizados , Comorbidade , Dinamarca , Feminino , Humanos , Masculino , Psoríase/complicações , Índice de Gravidade de DoençaRESUMO
OBJECTIVES: Psoriasis is a chronic inflammatory disorder associated with cardiovascular morbidity and mortality. Systemic anti-inflammatory drugs, including biological agents, are widely used in the treatment of patients with moderate to severe psoriasis and may attenuate the risk of cardiovascular disease events. We therefore examined the rate of cardiovascular disease events in patients with severe psoriasis treated with systemic anti-inflammatory drugs. DESIGN, SETTING AND PARTICIPANTS: Individual-level linkage of nationwide administrative databases was used to assess the event rates associated with use of biological agents, methotrexate or other therapies, including retinoids, cyclosporine and phototherapy, in Denmark from 2007 to 2009. MAIN OUTCOME MEASURE: Death, myocardial infarction and stroke. RESULTS: A total of 2400 patients with severe psoriasis, including 693 patients treated with biological agents and 799 treated with methotrexate, were identified. Incidence rates per 1000 patient-years and 95% confidence intervals (CIs) for the composite endpoint were 6.0 (95% CI 2.7-13.4), 17.3 (95% CI 12.3-24.3) and 44.5 (95% CI 34.6-57.0) for patients treated with biological agents, methotrexate and other therapies, respectively. Age- and sex-adjusted hazard ratios (HRs) were 0.28 (95% CI 0.12-0.64) and 0.65 (95% CI 0.42-1.00) for patients treated with biological agents and methotrexate, respectively, using other therapies as the reference cohort. Corresponding HRs for a secondary composite endpoint of cardiovascular death, myocardial infarction and stroke were 0.48 (95% CI 0.17-1.38) and 0.50 (95% CI 0.26-0.97). CONCLUSION: In this nationwide study of patients with severe psoriasis, systemic anti-inflammatory treatment with biological agents or methotrexate was associated with lower cardiovascular disease event rates compared to patients treated with other anti-psoriatic therapies.
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Anti-Inflamatórios/uso terapêutico , Doenças Cardiovasculares/prevenção & controle , Psoríase/tratamento farmacológico , Doenças Cardiovasculares/induzido quimicamente , Estudos de Coortes , Intervalos de Confiança , Dinamarca , Fármacos Dermatológicos/uso terapêutico , Feminino , Humanos , Estudos Longitudinais , Masculino , Metotrexato/uso terapêutico , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Índice de Gravidade de DoençaRESUMO
BACKGROUND: Large disease registries are the preferred method to assess long-term treatment safety. If psoriasis registries collaborate in a network, their power to assess safety is increased. OBJECTIVE: To identify heterogeneity in psoriasis registries and methodological challenges for synthesising the data they provide. METHODS: We surveyed the registries in PSONET and identified and addressed the challenges to collaborative analysis for the network in several round table meetings. RESULTS: Eight out of 10 registries had a prospective comparator cohort with similar disease characteristics but not on biologics. Registries differed in the coding and validation or follow-up of adverse events and in the way they sampled their population. Fifteen challenges to registries collaborating were identified in the areas of operational governance, structural conduct, bias and analysis. CONCLUSIONS: Participation in PSONET, a network of psoriasis registries, helps identify and solve common issues, enhancing the individual registries, and provides larger sets of more powerful safety data in a diverse population. Challenges to interpreting data collectively include heterogeneity in sampling, variable penetration of biologics and compatibility of different datasets.
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Psoríase/epidemiologia , Sistema de Registros/normas , Adulto , Produtos Biológicos/uso terapêutico , Fármacos Dermatológicos/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Psoríase/diagnóstico , Psoríase/tratamento farmacológico , Sistema de Registros/estatística & dados numéricos , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
BACKGROUND: Valrubicin is a cytostatic anthracycline analogue, lacking toxicity by skin and tissue contact, and represents a new drug with potential for topical treatment of psoriasis and nonmelanoma skin cancer (NMSC); the beneficial effects have been partly explained by its antiproliferative and proapoptotic characteristics. OBJECTIVES: To assess the effect of valrubicin on skin inflammation as inflammation also plays a key role in psoriasis and NMSC. METHODS: The effect of topical valrubicin treatment on skin inflammation in vivo was addressed in skin inflammation mouse models, where 12-O-tetradecanoylphorbol 13-acetate was used to induce irritant contact dermatitis. An acute and a chronic model were included, to investigate the effect of valrubicin in short-term inflammation and in more persistent inflammation. Inflammation-associated ear oedema was evaluated by measuring ear thickness, infiltration of neutrophil cells, and expression of inflammatory cytokines, interleukin (IL)-1ß and IL-6. RESULTS: Topical valrubicin treatment effectively reduced the inflammatory response in the acute and the chronic models. CONCLUSIONS: The present data document an anti-inflammatory effect of valrubicin, and may suggest an interesting new role for valrubicin in other debilitating skin diseases in which inflammation is a significant factor.
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Anti-Inflamatórios/administração & dosagem , Dermatite Irritante/tratamento farmacológico , Doxorrubicina/análogos & derivados , Doença Aguda , Administração Cutânea , Animais , Anti-Inflamatórios/farmacologia , Doença Crônica , Citocinas/metabolismo , Modelos Animais de Doenças , Doxorrubicina/administração & dosagem , Doxorrubicina/farmacologia , Irritantes/toxicidade , Camundongos , Camundongos Endogâmicos C57BL , Infiltração de Neutrófilos , Acetato de Tetradecanoilforbol/análogos & derivados , Acetato de Tetradecanoilforbol/toxicidadeRESUMO
Quantitative morphological studies of the healthy epidermis are essential in providing a range of parameter estimates that can be considered within the range of normality. Stereology is a set of statistical tools that provides potentially unbiased and precise estimates of 3-dimensional tissue characteristics from 2-dimensional sections. We set out to establish reference values for the volume of the viable epidermis contained within a four-millimetre punch biopsy (V(epi)), the volume of the stratum corneum (V(SC)) and the surface area of the dermo-epidermal junction(A(DEJ)) in 4 predetermined body regions by use of stereology. Four-millimetre punch biopsies were taken from 20 freshly diseased corpses, fixed in formalin and embedded in paraffin. V(epi), V(SC) and A(DEJ) were established stereologically for all 4 body locations followed by pairwise comparison of means after Bonferroni correction. V(epi) was significantly larger in the sole compared to all other body locations (p < 0.01). Furthermore, linear regression analysis showed a strong linear relationship between V(epi) and V(SC) in the sole (r = 0.70). Our results suggest that the viable layers of the epidermis might also serve a mechanical function, either directly or by providing the stratum corneum with keratinocytes to support the hyperkeratosis in the weight-bearing parts of the skin.
Assuntos
Derme/anatomia & histologia , Epiderme/anatomia & histologia , Modelos Estatísticos , Tamanho do Órgão , Biópsia , Cadáver , Feminino , Pé , Antebraço , Humanos , Modelos Lineares , Masculino , Modelos Anatômicos , Pescoço , Valores de Referência , Região SacrococcígeaRESUMO
BACKGROUND: Telemedicine is an increasingly suggested answer to the problem of providing high-class medical service to rural and remote areas in a modern society. Dermatology is a promising candidate for telemedical service, because it is well suited for clinical questions forwarded together with photographs. OBJECTIVES: To describe the patient population of the Faroe Islands dermatology clinic with respect to distribution of diagnoses, treatment, duration, response time and patient flow. METHODS: Case notes were drawn from all dermatology consultations managed during 2003-2009 through the national teledermatology system. These were compared with case notes drawn from the same journal system from the regular outpatient clinic. RESULTS: Over the last 7 years, a total of 9161 consultations in 7.7% of the population have been performed. The demography of the patient population reflects the underlying population apart for an over-representation of the female gender in younger years. The disease spectrum is comparable with what has been reported in other outpatient clinics, except for the relative absence of skin cancer and pigmented lesions, for which regular outpatient consultation is reserved. LIMITATIONS: The study is descriptive. CONCLUSIONS: The experience derived suggests that teledermatology may serve as a near-adequate alternative to a regular private practice, if abstaining from treating minor common skin conditions and purely cosmetic conditions is acceptable.
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Dermatologia/estatística & dados numéricos , Consulta Remota/estatística & dados numéricos , Dermatopatias/diagnóstico , Dermatopatias/terapia , Adolescente , Adulto , Criança , Dinamarca , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Padrões de Prática em Enfermagem , Distribuição por Sexo , Fatores de Tempo , Adulto JovemRESUMO
BACKGROUND: The pathogenesis of hidradenitis suppurativa (HS) is not clearly understood. The nomenclature suggests an important role for the apocrine glands but recent evidence implicates the pilosebaceous unit as a more likely candidate to play a central role in the pathogenesis. OBJECTIVES: Our aim was to estimate the volume of the follicular epithelium, the follicular lumen and the sebaceous glands of patients with HS and healthy controls by means of stereology. METHODS: Four-millimetre punch biopsies were taken from 21 patients with HS and nine healthy controls, fixed in formalin, embedded in paraffin and stained with haematoxylin and eosin prior to volume estimation using the Cavalieri principle. RESULTS: Sebaceous gland tissue could be visualized in only 10 of 15 suitable hair follicle biopsies from patients with HS but was present in all biopsies from healthy controls (P = 0·05) and the mean sebaceous gland volume per follicle was one-seventh of that of healthy controls (P = 0·03). There was no significant difference between patients with HS and healthy controls with regard to follicular epithelium and follicle lumen volume. CONCLUSIONS: Our results suggest that the absence or reduced volume of the sebaceous gland may play a role in the pathogenesis of HS. The presence of fibrosis suggests that sebaceous glands are obliterated early in the pathogenesis of HS.
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Folículo Piloso/patologia , Hidradenite Supurativa/patologia , Glândulas Sebáceas/patologia , Adulto , Biópsia , Feminino , Hidradenite Supurativa/etiologia , Humanos , Masculino , Pessoa de Meia-Idade , Fatores Sexuais , Adulto JovemRESUMO
BACKGROUND: Adherence to treatment is an indicator of treatment success. Long-term data on adherence to biologic treatment in psoriasis are lacking. OBJECTIVES: To compare the tumour necrosis factor (TNF)-α inhibitors regarding drug survival rate and safety in patients with psoriasis. METHODS: This study is based on data from the Danish nationwide database DERMBIO covering patients with psoriasis treated with a biologic agent. All patients who received anti-TNF-α treatment in academic referral centres were included. Baseline data, adverse events, time on treatment and reason for stopping treatment were recorded. Hazard ratios (HRs) for factors determining drug survival were calculated by logistic regression. RESULTS: In total, 882 treatment series with etanercept (n = 311), adalimumab (n = 427) or infliximab (n = 144) were administered to 747 patients. Significant predictors of drug survival were: sex, the anti-TNF-α agent and the previous response to an anti-TNF-α agent. In the group of anti-TNF-α-naïve patients the longest drug survival was observed for infliximab, followed by adalimumab [HR vs. infliximab 3·70, 95% confidence interval (CI) 1·99-6·89] and etanercept (HR vs. infliximab 3·18, 95% CI 1·72-5·86). The 4-year drug survival is in the range of 40% for etanercept or adalimumab vs. 70% for infliximab. There was no difference in number of adverse events. CONCLUSIONS: The overall efficacy of anti-TNF-α drugs diminishes with time, as envisaged by the progressive loss of patient adherence to treatment. The major reasons for stopping treatment were loss of efficacy, followed by adverse events. Infliximab had the best patient retention ability, with 70% of patients still being on the drug after 4 years of treatment.
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Anti-Inflamatórios/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Imunoglobulina G/uso terapêutico , Adesão à Medicação , Psoríase/tratamento farmacológico , Receptores do Fator de Necrose Tumoral/uso terapêutico , Adalimumab , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados , Criança , Dinamarca , Etanercepte , Feminino , Humanos , Infliximab , Modelos Logísticos , Masculino , Adesão à Medicação/estatística & dados numéricos , Pessoa de Meia-Idade , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Adulto JovemRESUMO
BACKGROUND: Efalizumab is a recombinant humanized murine monoclonal antibody against CD11a, approved for the treatment of plaque psoriasis. However, recent reports suggest that it also may be effective in the treatment of severe atopic dermatitis (AD). OBJECTIVE: To evaluate the clinical effect of efalizumab in AD. METHODS: A systematic retrospective study of the medical files of patients treated with efalizumab for AD in Danish dermatology departments. Positive outcome was defined as improvement of the disease registered in the patient's file over a period exceeding 6 months. RESULTS: Two of eleven patients had a positive outcome. Nine patients stopped treatment due to progression of AD or lack of effect. LIMITATIONS: Retrospective study. CONCLUSIONS: Only a minority of patients with severe AD responded to efalizumab treatment in a standard dose.
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Anticorpos Monoclonais/uso terapêutico , Dermatite Atópica/tratamento farmacológico , Fármacos Dermatológicos/uso terapêutico , Adulto , Idoso , Anticorpos Monoclonais Humanizados , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do TratamentoRESUMO
BACKGROUND: Interleukin (IL)-20 is a recently discovered cytokine displaying increased levels in psoriatic lesions. Interestingly, IL-20 levels decrease with antipsoriatic treatment, correlating with clinical improvement. However, the role of IL-20 in the aetiology of psoriasis is unknown. OBJECTIVES: In this study, we investigate the effects both of blocking IL-20 signalling in psoriatic plaques and of adding IL-20 to nonlesional psoriasis skin. METHODS: We employed the human skin xenograft transplantation model in which psoriatic plaques and nonlesional keratome skin biopsies obtained from donors with moderate to severe plaque psoriasis were transplanted on to immuno-deficient mice. The transplanted mice were treated with anti-IL-20 antibodies or recombinant human IL-20. RESULTS: We demonstrate that blocking IL-20 signalling with anti-IL-20 antibodies induces psoriasis resolution and inhibits psoriasis induction. We also demonstrate that continuous IL-20 infusion, together with injection of additional nonactivated leucocytes, promotes induction of psoriasis in nonlesional skin from patients with psoriasis. CONCLUSIONS: The results suggest that IL-20 plays a critical role in the induction and maintenance of psoriasis, and IL-20 is suggested as a new possible specific target in psoriasis treatment.
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Interleucinas/fisiologia , Psoríase/etiologia , Transdução de Sinais/imunologia , Transplante de Pele , Adulto , Idoso , Animais , Especificidade de Anticorpos/imunologia , Proliferação de Células , Humanos , Interleucinas/antagonistas & inibidores , Interleucinas/imunologia , Camundongos , Camundongos SCID , Pessoa de Meia-Idade , Psoríase/tratamento farmacológico , Psoríase/imunologia , Proteínas Recombinantes/imunologia , Indução de Remissão , Transplante HeterólogoAssuntos
Alérgenos/efeitos adversos , Ácido Aminolevulínico/análogos & derivados , Dermatite Alérgica de Contato/diagnóstico , Fármacos Fotossensibilizantes/efeitos adversos , Ácido Aminolevulínico/efeitos adversos , Dermatite Alérgica de Contato/etiologia , Dermatite Alérgica de Contato/patologia , Diagnóstico Diferencial , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Testes do Emplastro , Fotoquimioterapia , Neoplasias Cutâneas/tratamento farmacológicoRESUMO
CD4(+) T cells, in activated or malignant form, are involved in a number of diseases including inflammatory skin diseases such as psoriasis, and T cell lymphomas such as the majority of cutaneous T cell lymphomas (CTCL). Targeting CD4 with an antibody that inhibits and/or eliminates disease-driving T cells in situ may therefore be a useful approach in the treatment of inflammatory and malignant skin diseases. Depletion of CD4(+) T cells in intact inflamed human skin tissue by Zanolimumab, a fully human therapeutic monoclonal antibody (IgG1, kappa) against CD4, was studied in a human psoriasis xenograft mouse model. Zanolimumab treatment was shown to induce a significant reduction in the numbers of inflammatory mononuclear cells in upper dermis. This reduction in inflammatory mononuclear cells in situ was primarily due to a significant reduction in the numbers of skin-infiltrating CD4(+), but not CD8(+) CD3(+) T cells. The capacity of Zanolimumab to deplete the CD4(+) T cells in the skin may be of importance in diseases where CD4(+) T cells play a central role. Indeed, in a phase II clinical trial Zanolimumab has shown a dose-dependent clinical response in patients with CTCL and the antibody is currently in a phase III clinical trial for CTCL, a disease for which there is no safe and effective treatment available today.
Assuntos
Anticorpos Monoclonais/farmacologia , Antineoplásicos/farmacologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Pele/efeitos dos fármacos , Animais , Anticorpos Monoclonais Humanizados , Biópsia , Contagem de Linfócito CD4 , Linfócitos T CD4-Positivos/patologia , Modelos Animais de Doenças , Humanos , Linfoma Cutâneo de Células T/tratamento farmacológico , Camundongos , Camundongos SCID , Psoríase/tratamento farmacológico , Pele/citologia , Transplante HeterólogoRESUMO
BACKGROUND: Psoriasis is a common benign skin disease characterized by hyperproliferation and abnormal differentiation of keratinocytes. The transcription factor activator protein 1 (AP-1) is known to play an important role in cell proliferation and differentiation. OBJECTIVES: To investigate AP-1 DNA binding activity in psoriatic skin. METHODS: Keratome biopsies were taken from patients with plaque-type psoriasis. Electrophoretic mobility shift assays were used to determine the AP-1 DNA binding activity, whereas Western and Northern blotting was used to determine Jun and Fos protein and mRNA expression. RESULTS: We found that AP-1 DNA binding activity was almost completely abolished in lesional psoriatic skin compared with nonlesional psoriatic skin. Furthermore, experiments revealed that the protein and mRNA expression of the AP-1 subunits c-Fos, Fra-1 and c-Jun was reduced in lesional psoriatic skin compared with nonlesional psoriatic skin, whereas the protein and mRNA expression of the subunit JunB was increased. Topical application of the vitamin D analogue calcipotriol under occlusion to involved psoriatic skin for 4 days resulted in an increase in AP-1 DNA binding activity, and an increase in the protein and mRNA expression of c-Fos, Fra-1 and c-Jun, together with a decrease in JunB protein and mRNA expression. CONCLUSIONS: Together, these results suggest that the activity of the transcription factor AP-1 is impaired in lesional psoriatic skin and that this impairment may be important for the disturbed epidermal growth observed in psoriasis.
Assuntos
Calcitriol/análogos & derivados , Psoríase/metabolismo , Pele/metabolismo , Fator de Transcrição AP-1/metabolismo , Adulto , Idoso , Northern Blotting , Western Blotting , Calcitriol/uso terapêutico , Proteínas de Ligação a DNA/efeitos dos fármacos , Proteínas de Ligação a DNA/metabolismo , Fármacos Dermatológicos/uso terapêutico , Ensaio de Desvio de Mobilidade Eletroforética , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Proto-Oncogênicas c-fos/genética , Proteínas Proto-Oncogênicas c-fos/metabolismo , Proteínas Proto-Oncogênicas c-jun/genética , Proteínas Proto-Oncogênicas c-jun/metabolismo , Psoríase/tratamento farmacológico , RNA Mensageiro/genética , Fator de Transcrição AP-1/efeitos dos fármacosRESUMO
PURPOSE: We established a canine model of subfertility after spinal cord injury and examined the time course of acute changes in semen quality and spermatogenesis after spinal cord injury. MATERIALS AND METHODS: Seven dogs underwent surgical T7 spinal cord injury. Six dogs were used as controls. Electroejaculation and testicular fine needle aspiration were performed at baseline and twice weekly for 3 weeks after spinal cord injury. Semen quality change was examined by standard semen analysis. Spermatogenesis was assessed by flow cytometry of testicular fine needle aspiration in all dogs as well as by testicular histology at study conclusion in 4 controls and 4 spinal cord injured dogs. RESULTS: No significant changes in spinal cord injured dogs were noted before 3 weeks after injury. From baseline to 3 weeks after injury certain changes were evident in spinal cord injured dogs. Mean antegrade sperm motility decreased from 62.9% to 20.1% (p = 0.008), mean total sperm (antegrade plus retrograde total sperm) decreased from 423 to 294 x 106 which was not statistically significant, and the incidence of testicular haploid cells decreased from 75.6% to 48.3% (p = 0.028). No significant change in any parameter was present in control dogs. The mean number of mature spermatids per cross-sectional tubule on final testicular histology was significantly decreased in spinal cord injured dogs compared with controls (13.6 versus 43.9, p = 0.02). CONCLUSIONS: In the canine model tested the dogs readily survived spinal cord injury, electroejaculation was effective for obtaining ejaculate and fine needle aspiration allowed serial examination of spermatogenesis. Three weeks after spinal cord injury but not before 3 weeks sperm motility and spermatogenesis were significantly decreased. However, at the same point this decrease in spermatogenesis was not yet reflected in the total ejaculated sperm count.
Assuntos
Infertilidade Masculina/etiologia , Contagem de Espermatozoides , Motilidade dos Espermatozoides , Espermatogênese , Traumatismos da Medula Espinal/complicações , Animais , Modelos Animais de Doenças , Cães , Masculino , Fatores de TempoRESUMO
Accumulating evidence has emphasized the importance of immunocompetent cells in determining the psoriatic phenotype. We have investigated the effect of 1alpha,25-dihydroxycholecalciferol, the naturally occurring active form of vitamin D3, cyclosporine A, and interleukin-10 on the phenotype of human psoriatic skin xenotransplants. First, psoriatic skin transplants were injected with either 1alpha,25-dihydroxy- cholecalciferol, cyclosporine A, or interleukin-10. Second, we determined the ability of autologous lymphocytes, activated in vitro using staphylococcal enterotoxin B and interleukin-2 and then exposed to either 1alpha, 25-dihydroxycholecalciferol or cyclosporine A, to induce psoriatic lesions if they were injected into the dermis of uninvolved skin grafts. We found that injections into transplanted psoriatic plaques of either 1alpha,25-dihydroxycholecalciferol or cyclosporine A, but not interleukin-10, resulted in a consistent reduction in the clinical and histologic score of psoriasis with remission towards uninvolved psoriatic skin. Injection of activated immunocytes into symptomless psoriatic skin grafts, changed the grafts towards plaque-type psoriasis with silvery scale, parakeratosis, elongated rete pegs, acanthosis, and dermal angiogenic reaction. In contrast, if activated immunocytes were exposed to 1alpha, 25-dihydroxycholecalciferol or cyclosporine A prior to injection, only minimal changes occurred. It was determined that neither staphylococcal enterotoxin B and interleukin-2 activation by itself, nor the drugs investigated, changed the CD4/CD8 ratio of activated (CD25 + ) cells. Our results are consistent with the hypothesis that psoriasis may be induced by activated T lymphocytes, and indicate that novel immunomodulatory drugs can serve to inhibit the pathogenetic ability of immunocytes in psoriasis.
Assuntos
Calcitriol/uso terapêutico , Ciclosporina/uso terapêutico , Imunossupressores/uso terapêutico , Psoríase/tratamento farmacológico , Animais , Relação CD4-CD8 , Citometria de Fluxo , Humanos , Interleucina-10/uso terapêutico , Camundongos , Camundongos SCID , Psoríase/imunologia , Receptores de Interleucina-2/análise , Transplante de Pele , Subpopulações de Linfócitos T/efeitos dos fármacos , Subpopulações de Linfócitos T/imunologia , Transplante HeterólogoRESUMO
Direct intralesional injection of DNA encoding interferon-alpha2 (IFN-alpha2) was used in an effort to sustain local protein delivery for the treatment of human basal cell carcinoma (BCC). A novel model to study this malignancy was established by transplantation of human BCC tissue on to immunodeficient mice with a relatively high rate of engraftment and stable phenotype for superficial BCC (20 of 25; 80%). Gene transfer was significantly increased by using DNA liposome complexes (lipoplexes). Recombinant gene expression was detected predominantly in the epidermis and, to a lesser extent, in the dermis. Gene transfer of IFN-alpha2 using this method resulted in sustained production of IFN-alpha2 protein and increased expression of a known IFN-inducible gene, the class II major histocompatibility (MHC) antigen, and induced BCC regression, presumably through a non-immune mechanism. Intralesional injection of DNA lipoplexes encoding IFN-alpha protein may therefore be applicable to the treatment of cutaneous BCC.