RESUMEN
BACKGROUND: Patients treated with systemics for moderate-to-severe psoriasis have increased risk of cardiovascular disease (CVD). However, to the best of our knowledge, there are no data on the association between clinical disease activity and future cardiovascular events in this population. Such data could help identify patients at increased CVD risk and inform the potential for CVD prevention with effective psoriasis treatment. OBJECTIVE: To estimate the association between the Psoriasis Area and Severity Index (PASI) and cardiovascular events defined as hospitalization for CVD and cardiovascular death. METHODS: We linked prospectively collected data on PASI and CVD risk factors to population-based administrative data on hospitalizations and causes of death. We estimated the association between PASI and cardiovascular events using Cox proportional hazard models with PASI and Framingham 10-year cardiovascular risk as time-varying covariates. RESULTS: A total of 767 patients with 6264 PASI scores were included. After adjusting for 10-year cardiovascular risk and prior CVD, a one-point increase in PASI was associated with a hazard ratio of 1.04 (95% CI: 1.01-1.07) for cardiovascular events. The findings were robust in sensitivity analyses. CONCLUSION: PASI is an independent marker for future cardiovascular events in patients with moderate-to-severe psoriasis.
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Enfermedades Cardiovasculares , Psoriasis , Humanos , Psoriasis/complicaciones , Psoriasis/epidemiología , Psoriasis/tratamiento farmacológico , Factores de Riesgo , Estudios Prospectivos , Resultado del Tratamiento , Enfermedades Cardiovasculares/epidemiología , Índice de Severidad de la EnfermedadRESUMEN
Psoriasis and inflammatory bowel disease (IBD) are immune-mediated diseases occurring in barrier organs whose main task is to protect the organism from attack. These disorders are highly prevalent especially in northern Europe where psoriasis has a prevalence of around 3-4% and IBD around 0.3%. The prevalence of IBD in North America has been estimated at around 0.4%. The total incidence rates in northern Europe have been estimated at around 6 for Crohn's disease and 11 for ulcerative colitis per 100 000 person-years, compared with an incidence rate of around 280 per 100 000 person-years for psoriasis. Both diseases are less common in countries with a lower index of development. The rise in IBD appears to occur as populations adopt a westernized lifestyle, whereas psoriasis seems more stable and prevalence differences may derive more from variation in genetic susceptibility. The gut microbiota is clearly an important driver of IBD pathogenesis; in psoriasis, changes in gut and skin microbiota have been reported, but it is less clear whether and how these changes contribute to the pathogenesis. Large studies show that most identified genes are involved in the immune system. However, psoriasis and IBD are highly heterogeneous diseases and there is a need for more precise and deeper phenotyping to identify specific subgroups and their genetic, epigenetic and molecular signatures. Epigenetic modifications of DNA such as histone modifications, noncoding RNA effects on transcription and translation and DNA methylation are increasingly recognized as the mechanism underpinning much of the gene-environment interaction in the pathogenesis of both IBD and psoriasis. Our understanding of underlying pathogenetic mechanisms has deepened fundamentally over the past decades developing hand in hand with novel therapies targeting pathways and proinflammatory cytokines incriminated in disease. There is not only substantial overlap between psoriasis and IBD, but also there are differences with implication for therapy. In psoriasis, drugs targeting interleukin-23 and interleukin-17 have shown superior efficacy compared with anti-TNFs, whilst in IBD, drugs targeting interleukin-17 may be less beneficial. The therapeutic toolbox for psoriasis is impressive and is enlarging also for IBD. Still, there are unmet needs reflecting the heterogeneity of both diseases and there is a need for closer molecular diagnostics to allow for the development of precise therapeutics.
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Enfermedades Inflamatorias del Intestino/diagnóstico , Enfermedades Inflamatorias del Intestino/etiología , Psoriasis/diagnóstico , Psoriasis/etiología , HumanosRESUMEN
BACKGROUND: APPRECIATE is a multinational, observational, retrospective, cross-sectional study in patients treated for psoriasis with apremilast, an oral phosphodiesterase 4 inhibitor. OBJECTIVES: To describe the characteristics of patients with psoriasis treated with apremilast in the clinical setting, to evaluate real-world outcomes of psoriasis treatment with apremilast and to better understand the perspectives of patients and physicians on treatment outcomes. METHODS: In six European countries, patients with chronic plaque psoriasis treated in clinical practice who could be contacted 6 (±1) months after apremilast initiation were enrolled. Patient characteristics, Dermatology Life Quality Index (DLQI) and Psoriasis Area and Severity Index (PASI) were obtained from medical records when available. Outcomes were evaluated using patient/physician questionnaires. RESULTS: In 480 patients at treatment initiation, mean [median; 95% confidence interval (CI)] PASI and DLQI scores were 12.5 (10.7; 11.6-13.4) and 13.4 (13.0; 11.4-14.2), respectively. At 6 (±1) months, 72.3% of patients (n = 347) continued apremilast treatment [discontinuations: lack of efficacy (13.5%), safety (11.7%), other (2.5%)]. In patients continuing treatment, 48.6% achieved a ≥75% reduction in PASI score; mean (95% CI) DLQI score was 5.7 (4.5-6.9), and mean (SD) Patient Benefit Index score was 2.8 (1.2). Physicians perceived clinical improvement in 75.6% of patients. Physicians' perspective on overall success of apremilast in meeting expectations correlated with patients' perception of treatment benefit (r = 0.691). Most commonly reported adverse events (>5% of patients) were diarrhoea, nausea and headache. CONCLUSIONS: Patients in APPRECIATE reported high disease burden despite more moderate skin involvement than those who enrolled in clinical trials of apremilast. Findings from APPRECIATE demonstrate the real-world value of apremilast for psoriasis treatment, as 7 of 10 patients continued therapy and showed notable improvement in disease severity and quality of life 6 (±1) months after apremilast initiation.
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Psoriasis , Calidad de Vida , Antiinflamatorios no Esteroideos/uso terapéutico , Estudios Transversales , Europa (Continente) , Humanos , Psoriasis/tratamiento farmacológico , Estudios Retrospectivos , Índice de Severidad de la Enfermedad , Talidomida/análogos & derivados , Resultado del TratamientoRESUMEN
BACKGROUND: The advent of biosimilars may render etanercept (ETN) and adalimumab (ADA) viable alternatives to methotrexate (MTX) as first-line systemics in psoriasis. However, real-world relative effectiveness data comparing ADA and ETN to MTX are limited. OBJECTIVE: To estimate the relative effectiveness of ADA and ETN compared to MTX. METHODS: We analysed data from DermaReg, a regional register in Stockholm, Sweden, to estimate drug survival and mean Psoriasis Area and Severity Index (PASI) and Dermatology Life Quality Index (DLQI) during maintenance treatment. RESULTS: A total of 524 patients initiated 727 treatment episodes with ADA, ETN or MTX. After adjusting for confounders, patients treated with ADA had better drug survival (HR: 0.67; P = 0.003), lower mean PASI (-2.0; P < 0.001) and lower mean DLQI (-0.9; P < 0.001) during maintenance treatment compared to patients treated with MTX. The results for ETN compared to MTX were mixed. After adjusting for confounding, there was no significant difference in drug survival (HR 1.23; P = 0.082), but patients on ETN had lower mean PASI (-0.7; P = 0.006) during maintenance treatment. CONCLUSION: Adalimumab is superior to MTX in clinical practice whereas the relative effectiveness between ETN and MTX is less clear. This study also highlights the importance of appropriate confounding control in effectiveness analysis.
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Adalimumab/uso terapéutico , Etanercept/uso terapéutico , Metotrexato/uso terapéutico , Psoriasis/tratamiento farmacológico , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Sistema de Registros , Suecia , Resultado del TratamientoRESUMEN
BACKGROUND: Psoriatic arthritis (PsA) develops in ~30% of patients with psoriasis. The diagnosis of PsA is challenging, and there are no reliable molecular markers in clinical use. MicroRNAs are short non-coding regulatory RNAs, which can be actively packaged into extracellular vesicles (EVs) and secreted to the circulation. OBJECTIVES: To explore whether plasma-derived EV microRNAs may serve as biomarkers for PsA in patients with psoriasis. METHODS: Plasma samples were obtained from patients with cutaneous-only psoriasis (PsC) and patients with psoriasis and PsA. Plasma EVs were isolated using miRCURY™ Exosome Isolation Kit. RNA sequencing was used to identify differentially expressed EV miRNAs in the discovery phase (PsC, n = 15; PsA, n = 14). In the validation phase (PsC, n = 29; PsA, n = 28), 41 selected miRNAs were analysed in plasma EVs by qPCR. The association of the identified miRNAs with PsA was assessed by logistic regression analysis. RESULTS: RNA sequencing identified 19 plasma EV miRNAs with significantly different levels between PsA and PsC in the discovery cohort. Significantly lower levels of plasma EV let-7b-5p and miR-30e-5p in PsA vs. PsC were confirmed in the validation cohort, and their decreased levels were found to be associated with the presence of PsA. ROC analysis revealed an AUC of 0.68 (95% CI 0.53-0.83) for let-7b-5p and 0.69 (95% CI 0.55-0.84) for miR-30e-5p. CONCLUSIONS: Circulating EV microRNA levels are altered in patients with PsA as compared with PsC. Findings of this exploratory study suggest that circulating EV microRNAs may serve as biomarkers for arthritis in psoriasis patients.
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Artritis Psoriásica , MicroARN Circulante , Vesículas Extracelulares , MicroARNs , Psoriasis , Artritis Psoriásica/diagnóstico , Artritis Psoriásica/genética , Biomarcadores , Humanos , Psoriasis/genéticaRESUMEN
BACKGROUND: To date, biological treatments have been assessed in subjects with a long-term history of psoriasis and previous failures to systemic and topical therapies. In rheumatoid arthritis and other immune-mediated inflammatory diseases, early intensive systemic treatment prolongs treatment-free remission. We hypothesize that, by treating patients with psoriasis early with an effective systemic therapy, we may be able to alter the clinical outcome and the natural course of the disease. The STEPIn study (NCT03020199) investigates early intervention with secukinumab versus narrow-band ultraviolet B (nb-UVB) phototherapy in subjects with new-onset psoriasis. OBJECTIVE: To determine whether early intervention with either nb-UVB treatment or secukinumab in subjects with new-onset plaque psoriasis might modify the natural course of the disease. METHODS: One hundred and sixty subjects aged 18-50 years with new-onset (≤12 months) moderate-to-severe plaque psoriasis and naïve to systemic treatment and phototherapy will be randomized to secukinumab 300 mg or nb-UVB. The Main Study has two treatment arms: Arm A1, subcutaneous secukinumab 300 mg at baseline, Weeks 1, 2, 3 and 4, and every 4 weeks thereafter until and including Week 52; Arm B1, one/two cycles of nb-UVB for 12 weeks each (maximum 28-week break between cycles). After treatment discontinuation, patients will be followed up and monitored for disease activity up to Week 208. A Mechanistic Sub-study will assess immunological changes and pathogenic tissue-resident memory T cells in skin biopsies. CONCLUSIONS: STEPIn is the first study to investigate whether early intensive treatment in new-onset psoriasis can modify the long-term natural course of the disease and thus become a novel treatment strategy for patients with psoriasis.
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Anticuerpos Monoclonales/administración & dosificación , Psoriasis/tratamiento farmacológico , Psoriasis/radioterapia , Terapia Ultravioleta/métodos , Adolescente , Adulto , Anticuerpos Monoclonales Humanizados , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Diagnóstico Precoz , Femenino , Estudios de Seguimiento , Humanos , Inyecciones Subcutáneas , Masculino , Persona de Mediana Edad , Psoriasis/diagnóstico , Medición de Riesgo , Índice de Severidad de la Enfermedad , Factores de Tiempo , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: As lipids are known to regulate macrophage functions, it is reasonable to suppose that a sebocyte-macrophage axis mediated by sebum lipids may exist. OBJECTIVES: To investigate if sebocytes could contribute to the differentiation, polarization and function of macrophages with their secreted lipids. METHODS: Oil Red O lipid staining and Raman spectroscopy were used to assess the dermal lipid content and penetration. Immunohistochemistry was used to analyse the macrophage subsets. Human peripheral blood monocytes were differentiated in the presence of either supernatant from human SZ95 sebocytes or major sebum lipid components and activated with Propionibacterium acnes. Macrophage surface markers and their capacity to uptake fluorescein isothiocyanate-conjugated P. acnes were detected by fluorescence-activated cell sorting measurements. Cytokine protein levels were evaluated by enzyme-linked immunosorbent assay and Western blot analysis. RESULTS: Sebaceous gland-rich skin had an increased dermal lipid content vs. sebaceous gland-poor skin to which all the tested sebum component lipids could contribute by penetrating the dermoepidermal barrier. Of the lipids, oleic acid and linoleic acid promoted monocyte differentiation into alternatively activated macrophages. Moreover, linoleic acid also had an anti-inflammatory effect in P. acnes-activated macrophages, inhibiting the secretion of interleukin (IL)-1ß, IL-6 and tumour necrosis factor (TNF)-α. Squalene, palmitic acid, stearic acid and oleic acid augmented the secretion of IL-1ß, even in the absence of P. acnes, whereas oleic acid had a selective effect of inducing IL-1ß but downregulating IL-6 and TNF-α secretion. CONCLUSIONS: Our results suggest a role for sebaceous glands in modulating innate immune responses via their secreted lipids that are of possible pathological and therapeutic relevance.
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Lípidos/fisiología , Macrófagos/fisiología , Glándulas Sebáceas/fisiología , Sebo/metabolismo , Diferenciación Celular/fisiología , Polaridad Celular/fisiología , Citocinas/metabolismo , Humanos , Inmunidad Innata/fisiología , Metabolismo de los Lípidos/fisiología , Activación de Macrófagos/fisiología , Fagocitosis/fisiología , Propionibacterium acnes/fisiología , Glándulas Sebáceas/metabolismo , Sebo/citologíaRESUMEN
OBJECTIVE: To describe the social status and health-related quality of life of patients with psoriatic arthritis mutilans (PAM) in the Nordic countries. METHOD: Patients with at least one mutilated joint confirmed by radiology were studied. Disease activity involving joints and skin, physician-assessed disease activity, and patient's education and work status were recorded. Data from the 36-item Short Form Health Survey, Health Assessment Questionnaire and Dermatology Life Quality Index questionnaire were gathered and correlated with disease duration, pain, and general well-being (visual analogue scale). The controls were 58 Swedish patients with long-standing psoriatic arthritis sine PAM. RESULTS: Sixty-seven patients were included. Patients with PAM had a protracted disease history (33 ± 14 years) and disease onset at a relatively early age (30 ± 12 years). Overall inflammatory activity at inclusion was mild to moderate. The mean number of mutilated joints was 8.2 and gross deformity was found in 16% of patients. Forty per cent were treated with biological and 32% with conventional synthetic disease-modifying anti-rheumatic drugs. Forty-two per cent had retired early or were on sick leave. Impaired functional capacity with little or no ability to perform self-care or everyday tasks was reported by 21% of the patients. Patients between 45 and 60 years of age reported the most impaired quality of life in comparison to the control group. CONCLUSION: PAM seriously affects social functioning. Whether early recognition of PAM and new forms of therapy can improve disease outcome and quality of life remains to be studied.
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Actividades Cotidianas , Artritis Psoriásica/fisiopatología , Deformidades Adquiridas de la Articulación/fisiopatología , Calidad de Vida , Adulto , Anciano , Antirreumáticos/uso terapéutico , Artritis Psoriásica/complicaciones , Artritis Psoriásica/tratamiento farmacológico , Artritis Psoriásica/psicología , Estudios de Casos y Controles , Femenino , Humanos , Deformidades Adquiridas de la Articulación/etiología , Deformidades Adquiridas de la Articulación/psicología , Modelos Logísticos , Masculino , Persona de Mediana Edad , Jubilación , Países Escandinavos y Nórdicos , Autocuidado , Índice de Severidad de la Enfermedad , Ausencia por Enfermedad , Participación Social , SueciaRESUMEN
Tumor necrosis factor alpha-inducible protein 3 (TNFAIP3) encodes a ubiquitin-modifying protein, A20, that is a critical regulator of inflammatory responses. TNFAIP3 polymorphisms are associated with the susceptibility to multiple autoimmune diseases (AIDs) including psoriasis, systemic lupus erythematosus, rheumatoid arthritis, systemic sclerosis and celiac disease. In order to refine the TNFAIP3 association signal in psoriasis and identify candidate causal variants, we performed imputation and meta-analysis of the TNFAIP3 region in five European ancestry cohorts totaling 4704 psoriasis cases and 7805 controls. We identified 49 variants whose significance exceeded a corrected Bonferroni threshold, with the top variant being rs582757 (P = 6.07 × 10(-12), odds ratio (OR) = 1.23). Conditional analysis revealed a suggestive independent association at rs6918329 (P(cond) = 7.22 × 10(-5), OR = 1.15). Functional annotation of the top variants identified several with a strong evidence of regulatory potential and several within long noncoding RNAs. Analysis of TNFAIP3 haplotypes revealed that the psoriasis risk haplotype is distinct from other AIDs. Overall, our findings identify novel candidate causal variants of TNFAIP3 in psoriasis and highlight the complex genetic architecture of this locus in autoimmune susceptibility.
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Enfermedades Autoinmunes/genética , Proteínas/genética , Psoriasis/genética , Estudios de Cohortes , Femenino , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Haplotipos , Humanos , Péptidos y Proteínas de Señalización Intracelular , Masculino , Polimorfismo de Nucleótido SimpleRESUMEN
BACKGROUND: Little data exist on real-world treatment patterns in psoriasis, especially from European settings. OBJECTIVE: To estimate, for topicals, systemics and biologics, the time to non-persistency, switching, augmentation and insufficient treatment result (only for biologics), as well as to estimate the time to restart, in patients treated with each treatment class in Sweden based on registry data. METHODS: This database analysis utilized data from patients with psoriasis from several Swedish administrative registers. Patients were identified through combinations of diagnoses from two regional registers and filled prescriptions for relevant treatments from the Swedish Prescribed Drug Register. Kaplan-Meier time-to-event ('survival') functions were estimated with relevant treatment events as failure and the proportions of patients having experienced an event at specific time-points were derived from the failure rates. RESULTS: For topicals, systemics and biologics the number of indexed treatment episodes were 25,396, 2963, and 628 respectively. One year after treatment initiation, the proportion of patients who were classed as non-persistent with topicals, systemics and biologics were estimated at 88.3%, 47.9% and 43.2% respectively. Among patients who remained persistent, within 1 year of treatment start the proportions of treatment episodes in which patients were augmented were estimated at 56.0% for topicals, 45.3% for systemics and 58.9% for biologics. In addition, within 1 year of non-persistence, 49.0% of topicals, 60.8% of systemics and 80.2% of biologics treatment episodes were re-initiated, with 35.4-52.5% re-initiated on the non-persistent treatment depending on treatment class. In addition, among patients on biologics, 29.2% of treatment episodes had an insufficient treatment result within 1 year of treatment start. CONCLUSION: Persistency to psoriasis treatments may be sub-optimal and patients who remain persistent relatively frequently receive augmentation therapy or switch to another therapy. Therefore, current treatment options in psoriasis may be insufficient.
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Psoriasis/tratamiento farmacológico , Administración Tópica , Productos Biológicos/uso terapéutico , Femenino , Humanos , Masculino , Persona de Mediana Edad , Psoriasis/epidemiología , Sistema de Registros , Suecia/epidemiologíaRESUMEN
BACKGROUND: Psoriasis is associated with several comorbidities and behavioural risk factors. OBJECTIVES: To evaluate demographic and disease characteristics in patients enrolled in the Psoriasis Longitudinal Assessment and Registry (PSOLAR). METHODS: PSOLAR is a global, prospective, longitudinal, disease-based registry that includes a postmarketing commitment to evaluate safety in patients with psoriasis. Enrolled patients had to be receiving, or be eligible to receive, conventional systemic or biological agents. Demographic/disease characteristics, medical histories, lifestyle risk factors and previous treatments are collected at enrolment. Efficacy and safety data are collected every 6 months for 8 years, and data are extracted annually. Selected parameters are evaluated by age quartile using post hoc analyses. RESULTS: As of 23 August 2012, 11 900 patients were enrolled at 301 sites in North America, Europe and Latin America. Over half of the PSOLAR population (54·7%) is male, with a mean age of 48·6 years and mean body mass index of 30·9 kg m(-2) at enrolment. Mean duration of disease at enrolment was 17·5 years, and mean Physician's Global Assessment score was 2·0. Psoriatic arthritis (35·5%) and cardiovascular diseases (38·2%) were highly prevalent. Diabetes mellitus type II was reported in 11·4% of patients. Depression and anxiety were noted in 14·7% and 11·1% of patients, respectively; 79·0% reported any alcohol use and 56·7% reported smoking or a history of smoking. The occurrence of most comorbidities, including cardiovascular disease and risk factors, increased with age. CONCLUSIONS: In the PSOLAR population, multiple and age-appropriate comorbidities are associated with psoriasis and may affect the selection of psoriasis treatments.
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Psoriasis/epidemiología , Adolescente , Adulto , Distribución por Edad , Anciano , Productos Biológicos/uso terapéutico , Índice de Masa Corporal , Comorbilidad , Fármacos Dermatológicos/uso terapéutico , Europa (Continente)/epidemiología , Femenino , Humanos , América Latina/epidemiología , Masculino , Persona de Mediana Edad , América del Norte/epidemiología , Obesidad/complicaciones , Obesidad/epidemiología , Linaje , Fotoquimioterapia/estadística & datos numéricos , Fármacos Fotosensibilizantes/uso terapéutico , Estudios Prospectivos , Psoriasis/tratamiento farmacológico , Psoriasis/patología , Sistema de Registros , Asunción de Riesgos , Adulto JovenRESUMEN
BACKGROUND: Psoriatic arthritis (PsA) and co-morbidities of psoriasis represent a significant clinical and economic burden for patients with moderate-to-severe psoriasis. Often these co-morbidities may go unrecognized or undertreated. While published data are available on the incidence and impact of some of them, practical guidance for dermatologists on detection and management of these co-morbidities is lacking. OBJECTIVE: To prepare expert recommendations to improve the detection and management of common co-morbidities in patients with moderate-to-severe psoriasis. METHODS: A systematic literature review was conducted on some common co-morbidities of psoriasis-cardiovascular (CV) diseases (including obesity, hypertension, hyperglycaemia and dyslipidaemia), psychological co-morbidities (including depression, alcohol abuse and smoking) and PsA-to establish the incidence and impact of each. Data gaps were identified and a Delphi survey was carried out to obtain consensus on the detection and management of each co-morbidity. The expert panel members for the Delphi survey comprised 10 dermatologists with substantial clinical expertise in managing moderate-to-severe psoriasis patients, as well as a cardiologist and a psychologist (see appendix) with an interest in dermatology. Agreement was defined using a Likert scale of 1-7. Consensus regarding agreement for each statement was defined as ≥75% of respondents scoring either 1 (strongly agree) or 2 (agree). RESULTS: The expert panel members addressed several topics including screening, intervention, monitoring frequency, and the effects of anti-psoriatic treatment on each co-morbidity. Consensus was achieved on 12 statements out of 22 (3 relating to PsA, 4 relating to psychological factors, 5 relating to CV factors). The panel members felt that dermatologists have an important role in screening their psoriasis patients for PsA and in assessing them for psychological and CV co-morbidities. In most cases, however, patients should be referred for specialist management if other co-morbidities are detected. CONCLUSION: This article provides useful and practical guidance for the detection and management of common co-morbidities in patients with moderate-to-severe psoriasis.
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Psoriasis/terapia , Técnica Delphi , Humanos , Psoriasis/complicaciones , Psoriasis/patología , Índice de Severidad de la EnfermedadRESUMEN
Background: Beta-defensins (BDs) are antimicrobial peptides secreted upon epithelial injury. Both chemotactic and antimicrobial properties of BDs function as initial steps in host defense and prime the adaptive immune system in the body. Psoriasis, a chronic immune-mediated inflammatory disease, has both visible cutaneous manifestations as well as known associations with higher incidence of cardiometabolic complications and vascular inflammation. Objectives: We aimed to investigate the circulating expression of beta-defensin-2 (BD2) in psoriasis at baseline compared to control subjects, along with changes in BD2 levels following biologic treatment at one-year. The contribution of BD2 to subclinical atherosclerosis is also assessed. In addition, we have sought to unravel signaling mechanisms linking inflammation with BD2 expression. Methods: Multimodality imaging as well inflammatory biomarker assays were performed in biologic naïve psoriasis (n=71) and non-psoriasis (n=53) subjects. A subset of psoriasis patients were followed for one-year after biological intervention (anti-Tumor Necrosis Factor-α (TNFα), n=30; anti-Interleukin17A (IL17A), n=21). Measurements of circulating BD2 were completed by Enzyme-Linked Immunosorbent Assay (ELISA). Using HaCaT transformed keratinocytes, expression of BD2 upon cytokine treatment was assessed by quantitative polymerase chain reaction (qPCR) and ELISA. Results: Herein, we confirm that human circulating BD2 levels associate with psoriasis, which attenuate upon biologic interventions (anti-TNFα, anti-IL-17A). A link between circulating BD2 and sub-clinical atherosclerosis markers was not observed. Furthermore, we demonstrate that IL-17A-driven BD2 expression occurs in a Phosphatidylinositol 3-kinase (PI3-kinase) and Rac1 GTPase-dependent manner. Conclusions: Our findings expand on the potential role of BD2 as a tractable biomarker in psoriasis patients and describes the role of an IL-17A-PI3-kinase/Rac signaling axis in regulating BD2 levels in keratinocytes.
RESUMEN
BACKGROUND: MicroRNAs (miRNAs) are endogenous, nonprotein-coding, regulatory RNAs with important roles in health and disease. miRNAs are present in the circulation in a stable form and their levels are altered in diseases. OBJECTIVES: To determine whether antitumour necrosis factor (TNF)-α therapy affects serum miRNA levels in patients with psoriasis. METHODS: Serum samples were obtained from healthy donors and from patients with chronic plaque psoriasis before and 12 weeks after the initiation of treatment with the TNF-inhibitor etanercept or methotrexate. miRNA expression profiling was utilized to identify miRNAs with altered serum level in psoriasis, as well as anti-TNF-α-regulated miRNAs in patients' sera. The expression of five miRNAs regulated by etanercept was measured by quantitative polymerase chain reaction (qPCR) in sera from patients and controls. RESULTS: Etanercept significantly suppressed a panel of 38 miRNAs, which were found to be predominantly immune-cell derived and which have been implicated in inflammation and autoimmunity. Validation by qPCR showed that serum levels of miR-106b, miR-26b, miR-142-3p, miR-223 and miR-126 were significantly downregulated by etanercept in responders (Psoriasis Area and Severity Index change > 50%). By contrast, methotrexate did not significantly affect the levels of these miRNAs. Serum levels of these miRNAs were not upregulated in patients with psoriasis compared with healthy controls. The level of four circulating miRNAs was significantly different (increased: miR-128a; decreased: let-7d, miR-142-3p, miR-181a) in psoriasis and healthy serum. CONCLUSIONS: The level of circulating miRNAs is altered in psoriasis. Anti-TNF-α therapy has a profound effect on the serum level of miRNAs; however, these are not related to disease severity. Our results suggest that changes in the miRNA level may reflect a previously unknown effect of anti-TNF-α therapy. Our results suggest the involvement of miRNAs in pathways affected by anti-TNF-α therapy and warrant further investigation of serum miRNAs as potential biomarkers for therapy response in psoriasis.
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Inmunoglobulina G/uso terapéutico , Factores Inmunológicos/uso terapéutico , MicroARNs/metabolismo , Psoriasis/tratamiento farmacológico , Receptores del Factor de Necrosis Tumoral/uso terapéutico , Enfermedad Crónica , Etanercept , Femenino , Humanos , Masculino , MicroARNs/efectos de los fármacos , Persona de Mediana Edad , Psoriasis/sangre , Reacción en Cadena en Tiempo Real de la Polimerasa , Análisis de Secuencia de ARNRESUMEN
OBJECTIVE: To determine the prevalence and clinical characteristics of psoriatic arthritis mutilans (PAM) in the Nordic countries. METHOD: Patients with putative PAM aged ≥ 18 years were recruited. Fifty-nine patients were included after clinical examination. RESULTS: The prevalence of PAM in the adult Nordic population was estimated to be 3.69 per million inhabitants [95% confidence interval (CI) 2.75-4.63]. The female to male ratio was close to 1:1. The mean age of skin disease onset was 25 years and the mean age of onset of joint disease was 30 years. The onset of skin disease was 2 years earlier among female patients. At inclusion, the mean duration of arthritis was 27 ± 11 years for male patients and 33 ± 11 years for female patients. PAM was most frequently seen in the distal interphalangeal (DIP) joints of the toes, followed by the IP joint of the thumb and the DIP joint of the little finger on the left hand. Female and male patients had similar numbers of painful and swollen joints. Enthesitis was found in 19 patients (32%), while 38 patients (64%) had a history of dactylitis. Twenty-three of these 38 patients (61%) had a history of dactylitis in the same finger/toe as they had PAM. At the time of inclusion, 45% of the patients were found to have clear or almost clear skin. CONCLUSIONS: PAM in the Nordic countries has a low prevalence, with only three to five cases per million inhabitants. The majority of the patients present with mild skin disease.
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Artritis Psoriásica/epidemiología , Deformidades Adquiridas de la Articulación/epidemiología , Adulto , Edad de Inicio , Anciano , Anciano de 80 o más Años , Artritis Psoriásica/patología , Artritis Psoriásica/fisiopatología , Comorbilidad , Femenino , Finlandia/epidemiología , Articulaciones de la Mano/patología , Humanos , Deformidades Adquiridas de la Articulación/patología , Deformidades Adquiridas de la Articulación/fisiopatología , Masculino , Persona de Mediana Edad , Prevalencia , Países Escandinavos y Nórdicos/epidemiología , Articulación del Dedo del Pie/patologíaRESUMEN
BACKGROUND: Atopic dermatitis (AD; OMIM#603165) and psoriasis (OMIM#177900) are two common inflammatory skin disorders. Both are genetically complex, multifactorial and do not follow a Mendelian pattern of inheritance. Both diseases share several genetic susceptibility loci such as the epidermal differentiation complex (EDC) on chromosome 1q21. Within the EDC, mutations in the filaggrin (FLG) gene are strongly associated with AD whereas no association has been replicated with psoriasis. However, reduced levels of filaggrin have been reported in psoriatic skin. Further, filaggrin deficiency was shown to be a modifying factor for the phenotype in another epidermal skin disorder, X-linked recessive ichthyosis. Altogether, this raises the question if FLG mutations may modify the disease course in other epidermal skin diseases such as psoriasis. Psoriasis is a highly heterogeneous disease and so far genetic studies have not taken the distinct sub-phenotype childhood onset into account. OBJECTIVE: To determine if FLG mutations modify the onset of psoriasis. MATERIALS AND METHODS: A total of 241 children with onset of psoriasis below 15 years of age and 314 healthy controls were identified at the Dermatology clinic, Karolinska University Hospital and diagnosed by the same dermatologist (JL). Blood samples were taken and medical history was recorded. FLG was genotyped in all patients and controls using allelic discrimination (n = 555) and sequencing (n = 20). RESULTS AND CONCLUSIONS: No association between FLG mutations and early onset of psoriasis was demonstrated (P = 0.57) and no novel mutations were detected, indicating that FLG loss-of-function variants do not have a strong effect on the onset of psoriasis in childhood.
Asunto(s)
Proteínas de Filamentos Intermediarios/genética , Mutación/genética , Psoriasis/epidemiología , Psoriasis/genética , Adolescente , Edad de Inicio , Alelos , Estudios de Casos y Controles , Niño , Preescolar , Dermatitis Atópica/epidemiología , Dermatitis Atópica/genética , Dermatitis Atópica/fisiopatología , Femenino , Proteínas Filagrina , Genotipo , Humanos , Masculino , Reacción en Cadena de la Polimerasa/métodos , Psoriasis/fisiopatología , Sensibilidad y Especificidad , Índice de Severidad de la EnfermedadAsunto(s)
Adalimumab/inmunología , Adalimumab/farmacología , Antiinflamatorios/farmacología , Anticuerpos/sangre , Etanercept/inmunología , Etanercept/farmacología , Psoriasis/sangre , Adalimumab/uso terapéutico , Adolescente , Adulto , Anciano , Antiinflamatorios/inmunología , Antiinflamatorios/uso terapéutico , Etanercept/uso terapéutico , Femenino , Humanos , Masculino , Persona de Mediana Edad , Psoriasis/tratamiento farmacológico , Resultado del Tratamiento , Adulto JovenRESUMEN
Abundant heterogeneous immune cells infiltrate lesions in chronic inflammatory diseases and characterization of these cells is needed to distinguish disease-promoting from bystander immune cells. Here, we investigate the landscape of non-communicable inflammatory skin diseases (ncISD) by spatial transcriptomics resulting in a large repository of 62,000 spatially defined human cutaneous transcriptomes from 31 patients. Despite the expected immune cell infiltration, we observe rather low numbers of pathogenic disease promoting cytokine transcripts (IFNG, IL13 and IL17A), i.e. >125 times less compared to the mean expression of all other genes over lesional skin sections. Nevertheless, cytokine expression is limited to lesional skin and presented in a disease-specific pattern. Leveraging a density-based spatial clustering method, we identify specific responder gene signatures in direct proximity of cytokines, and confirm that detected cytokine transcripts initiate amplification cascades of up to thousands of specific responder transcripts forming localized epidermal clusters. Thus, within the abundant and heterogeneous infiltrates of ncISD, only a low number of cytokine transcripts and their translated proteins promote disease by initiating an inflammatory amplification cascade in their local microenvironment.