Thrombospondin-1/CD47 interaction regulates Th17 and treg differentiation in psoriasis

Accumulating evidence on the role of Thrombospondin-1 (TSP-1) in the immune response has emerged during the last years. In spite of the importance of TSP-1 not only as anti-angiogenic factor but also as an immunomodulatory molecule, studies on the role of TSP-1 in psoriasis have been neglected. TSP-1 and CD47 expression were analyzed in skin samples from psoriasis patients and control subjects using RT-PCR and immunofluorescence. Expression of these molecules was also evaluated in peripheral blood CD4+ T cells, moDCs, and circulating primary DCs. The functional role of TSP-1/CD47 signaling axis in psoriasis was assessed in Th17 and Treg differentiation assays. Additionally, small interfering RNA assays specific to TSP-1 were performed in CD4+ T cells and monocyte derived DC to specifically evaluate the function of this protein. Lesional skin of psoriasis patients expressed lower TSP-1 and CD47 mRNA levels compared to non-lesional skin or skin from controls. Immunofluorescence staining revealed decreased expression of CD47 in CD45+ dermal cells from psoriasis samples compared to control subjects. Peripheral CD4+ T cells and circulating primary DCs from psoriasis also expressed lower levels of CD47 compared to controls. Although no significant differences were detected in TSP-1 expression in CD4+ T cells and moDCs between patients and controls, TSP-1 expression in psoriasis patients inversely correlated with disease activity evaluated by the Psoriasis Area and Index Activity. Furthermore, exogenous TSP-1 inhibited Th17 differentiation and stimulated the differentiation of CD4+ T cells toward Treg cells. Furthermore, RNA interference specific for TSP-1 confirmed the role of this molecule as a negative regulator of T cell activation. Because of the impact of TSP-1/CD47 signaling axis in Th17 and Treg differentiation, a dysregulated expression of these molecules in the immune cells from psoriasis patients may favor the exacerbated inflammatory response in this diseaseInstituto de Salud Carlos III (AES 2017): PI17/01972 to ED. Janssen; Spanish Ministry of Economy and Competitiveness (MINECO): Plan Nacional de Salud SAF2017-82886-R, Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV); Proyecto Integrado de Excelencia PIE13/00041, Instituto de Salud Carlos III to FS-M, Instituto de Salud Carlos III PI16/02166, Universidad Autónoma de Madrid-Banco Santander (grant 2017/EEUU/03), and Red Temática de Excelencia en Investigación en Hipoxia (SAF 2017-90794-REDT) to MJC. This research has been co-financed by Fondo Europeo de Desarrollo Regional (FEDER

Polymorphisms associated with adalimumab and infliximab response in moderate-to-severe plaque psoriasis

Aims. This study evaluated the influence of pharmacogenetics in psoriatic patients treated with adalimumab and/or infliximab. Materials & methods: Prospective observational study evaluating the association of 124 polymorphisms with the response to adalimumab or infliximab (PASI75) in patients with moderate-to-severe plaque psoriasis at 3 months (n = 95) and 6 months of treatment (n = 90). Significant SNPs for univariate analysis were subjected to multivariate analysis. Results: Five SNPs were associated with PASI75 at 3 months: rs6661932 (IVL), rs2546890 (IL-12B), rs2145623 (NFKBIA), rs9304742 (ZNF816A) and rs645544 (SLC9A8). Furthermore, rs1061624 (TNFR1B) was associated with PASI75 at 6 months. Conclusion: Nevertheless, these biomarkers should be validated in large-scale studies before implementation in clinical practice

Family Planning Concerns Among Women With Psoriasis: A Descriptive, Cross-Sectional, Multicenter Study

Psoriasis; Salud reproductiva; Planificación familiarPsoriasi; Salut reproductiva; Planificació familiarPsoriasis; Reproductive health; Family planningAntecedentes y objetivos La psoriasis afecta a un gran porcentaje de mujeres en edad fértil. Nuestro objetivo fue conocer las inquietudes de las mujeres con psoriasis en relación con la planificación familiar. Material y métodos Estudio observacional, descriptivo, transversal y multicéntrico realizado entre marzo del 2020 y octubre del 2021. Se recabaron datos sociodemográficos e inquietudes relacionadas con la planificación familiar de mujeres entre 18-45 años con psoriasis en placas y candidatas a recibir tratamiento sistémico. Resultados Se reclutaron 153 pacientes de 11 centros españoles (edad media: 35,4 ± 8 años, duración media de la enfermedad: 16,7 años); 38,4% de los casos tenían una enfermedad moderada/grave para los médicos, aunque la percepción de la actividad era significativamente superior para las pacientes. En una de cada tres mujeres, la enfermedad limitaba o retrasaba el deseo gestacional. Existía preocupación de que la enfermedad empeorara al tener que retirar o cambiar un fármaco o que los tratamientos perjudicaran al bebé. Alrededor de la mitad de las pacientes no había recibido información sobre planificación familiar en la consulta, especialmente aquellas mujeres sin embarazos previos. Las mujeres con tratamiento biológico (58,7%) tenían mejor situación clínica, mejor calidad de vida y menos alteraciones en la esfera sexual que las pacientes sin tratamiento biológico. Conclusiones Las pacientes con psoriasis tienen numerosas preocupaciones relacionadas con la planificación familiar. En algunos casos, estos miedos podrían llevar a retrasar y/o limitar el deseo gestacional. Sería necesario incrementar la información que se da a las pacientes y mejorar la formación de los dermatólogos en este tema.Background and objective A significant proportion of women of childbearing age have psoriasis. The aim of this study was to examine family planning concerns in this population. Material and methods Observational, descriptive, cross-sectional, multicenter study conducted between March 2020 and October 2021. We collected sociodemographic data and analyzed responses to a family planning questionnaire administered to women aged 18 to 45 years with plaque psoriasis who were candidates for systemic treatment. Results We studied 153 patients (mean [SD] age, 35.4 [8.0] years; mean disease duration, 16.7 years) being treated at 11 Spanish hospitals. Overall, 38.4% of women were considered to have moderate to severe psoriasis by their physicians; perceived severity ratings were significantly higher among women. Psoriasis affected the women's desire to become pregnant or led to their delaying pregnancy in 1 in 3 respondents. They were concerned that their condition might worsen if they had to discontinue or switch treatment or that the treatment might harm the baby. Approximately half of the women had not received family planning counseling from their physicians, and this was more likely to be the case among never-pregnant women. Women on biologic therapy (58.7%) had better psoriasis control and a better quality of life than women on other treatments. Their sexual health was also less affected. Conclusions Women with psoriasis have numerous family planning concerns, which in some cases can lead them to delay pregnancy or affect their desire to become pregnant. Dermatologists need to receive better training regarding family planning in women with psoriasis so that they can provide their patients with more and better information.Este estudio estuvo financiado con una beca sin restricciones de la Cátedra Universidad Francisco de Vitoria-UCB en Inflamación y Salud Ósea

DNA copy number variation associated with anti-tumour necrosis factor drug response and paradoxical psoriasiform reactions in patients with moderate-to-severe psoriasis

Biological drugs targeting tumour necrosis factor are effective for psoriasis. However, 30–50% of patients do not respond to these drugs and may even develop paradoxical psoriasiform reactions. This study search-ed for DNA copy number variations that could predict anti-tumour necrotic factor drug response or the ap-pearance of anti-tumour necrotic factor induced pso-riasiform reactions. Peripheral blood samples were collected from 70 patients with anti-tumour necrotic factor drug-treated moderate-to-severe plaque pso-riasis. Samples were analysed with an Illumina 450K methylation microarray. Copy number variations were obtained from raw methylation data using conumee and Chip Analysis Methylation Pipeline (ChAMP) R packa-ges. One copy number variation was found, harbouring one gene (CPM) that was significantly associated with adalimumab response (Bonferroni-adjusted p-value < 0.05). Moreover, one copy number variation was identified harbouring 3 genes (ARNT2, LOC101929586 and MIR5572) related to the development of paradoxical psoriasiform reactions. In conclusion, this study has identified DNA copy number variations that could be good candidate markers to predict response to ada-limumab and the development of anti-tumour necrotic factor paradoxical psoriasiform reactions.This study was supported by Instituto de Salud Carlos III PI 13/01598 and the Ministry of Science and Innovation and the European Regional Development’s funds (FEDER). Conflicts of interest. FA-S has been a consultant or investigator in clinical trials sponsored by the following pharmaceutical companies: Abbott, Alter, Chemo, Farmalíder, Ferrer, GlaxoSmithKline, Gilead, Janssen-Cilag, Kern, Normon, Novartis, Servier, Teva, and Zambon. ED has potential conflicts of interest (advisory board member, consultant, grants, research support, participation in clinical trials, honoraria for speaking, and research support) with the following pharmaceutical companies: AbbVie (Abbott), Amgen, Janssen-Cilag, Leo Pharma, Novartis, Pfizer, MSD, Lilly and Celgene. ML-V has potential conflicts of interest as she has participated in clinical trials or as consultant with Abbvie (Abbott), Galderma, Janssen-Cilag, Leo Pharma, Pfizer, Novarties, Lilly, Almirall and Celgene. MCO-B has potential conflicts of interest (honoraria for speaking and research support) with Janssen-Cilag and Leo Pharma. The other authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. AS-T has served as a consultant and/or paid speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Celgene, Janssen-Cilag, LEO Pharma, Lilly, Novartis and Pfizer. RB-E has served as a consultant and/or paid speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Celgene, Janssen-Cilag, LEO Pharma, Lilly, Novartis and Pfizer

Utility of circulating serum miRNA profiles to evaluate the potential risk and severity of immune-mediated inflammatory disorders

Immune-mediated inflammatory disorders (IMID) are a group of diseases that present inflammation as a major pathogenic mechanism. They affect 15% of the population and pose a heavy socio-economic burden. Despite the growing knowledge on the etiopathogenesis of these diseases and the marked improvement in their management, there is a lack of predictive markers of IMID development or severity suitable for early diagnosis and adjustment of treatment intensity. The possibility that certain circulating miRNA profiles could be used as biomarkers of risk of development and/or severity of several autoimmune diseases has fuelled the interest in using them to improve the selection of successful treatments. The multi-pronged approach proposed here sought to reveal circulating miRNAs and miRNA signatures that could act as new predictive biomarkers of IMID development and severity. Our results showed that the circulating levels of miR-19b and miR-26b were significantly decreased (p &lt; 0.001) in IMID patients compared to controls. Furthermore, receiver operating characteristic (ROC) curve analysis showed that these miRNAs were suitable discriminators capable to identify an IMID, with areas under the curve (AUC) of 0.85 and 0.83, respectively. In addition, we established that miR-19a and miR-143 were significantly increased in IMID patients with severe disease (p &lt; 0.05). In summary, our findings identify two different miRNA signatures. One of them is associated with the presence of IMIDs and could lead to the development of tools for their early detection. The second signature is able to discriminate between mild and severe forms of these disorders and could be a putative tool to select patient candidates for a more intense treatment.This work was supported by the following grants: Proyectos de Investigación en Salud (FIS) PIE13-0041, PI16-02091 and PI19-00584 (funded by Ministerio de Economía y Competitividad (MINECO), Instituto de Salud Carlos III (ISCIII)), TIRONET2-CM, B2017/BMD-3724 (funded by Comunidad de Madrid), Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER GCV14/ER/12) to MM; also by grants RD16/0011/0012 and PI18/0371 from MINECO, ISCIII to IGA; PI17/01972 (MINECO, ISCIIII) to E. D; and Plan Nacional de Salud SAF2017-82886-R, Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Fundación BBVA a equipos de Investigación Científica 2018 and from “la Caixa Banking Foundation” under the project code HR17-00016 to F·S.M and cofinanced by FEDER fund

Effectiveness and safety of guselkumab for the treatment of psoriasis in real-world settings at 24 weeks : A retrospective, observational, multicentre study by the Spanish Psoriasis Group

Altres ajuts: Acord transformatiu CRUE-CSICData on the effectiveness and safety of a drug in real-world clinical practice complement the evidence from clinical trials, which are carried out in a different setting. Little has been published on the effectiveness and safety of guselkumab in the treatment of psoriasis in clinical practice. The ojective of this study was to assess the effectiveness and safety of guselkumab at 24 weeks in patients with moderate to severe plaque psoriasis in routine clinical practice. A retrospective, multicentre study of adult patients with moderate to severe plaque psoriasis treated with guselkumab for at least 24 weeks was carried out in Spain. We studied 343 patients, 249 of whom were followed for 24 weeks. By week 24, the mean (SD) psoriasis area severity index (PASI) had decreased from 11.1 (7.3) to 1.7 (2.8) (−9.3; [−10.2;-8.4]), 85.9% of the patients had achieved PASI score of 4 or less and 77.9% a PASI score of 2 or less. In terms of relative PASI response, 59.4% of the patients achieved a PASI-90 response and 49.0% a PASI-100 response. On multivariate analysis, two factors reduced the probability of a PASI of 2 or less at 24 weeks: a BMI ≥30 (OR, 0.44; 95% CI, 0.22-0.88) and a greater previous exposure to biologic therapy (OR, 0.69; 95% CI, [0.56-0.84]). Adverse events were rare (9.9%) and led to withdrawal from treatment in only nine patients (2.6%) by the end of the follow-up period. The results of this study confirm the high efficacy and safety of guselkumab indicated by the clinical trial data. In clinical practice, the absolute PASI score appears to be a better marker of response to treatment than the relative value

Effect of sex in systemic psoriasis therapy: Differences in prescription, effectiveness and safety in the BIOBADADERM prospective cohort

The effect of sex on systemic therapy for psoriasis has not been well studied. The aim of this study was to analyse a large multicentre Spanish cohort of 2,881 patients with psoriasis (58.3% males), followed from January 2008 to November 2018, to determine whether sex influences prescription, effectiveness of therapy, and the risk of adverse events. The results show that women are more likely than men to be pre-scribed biologics. There were no differences between men and women in effectiveness of therapy, measur-ed in terms of drug survival. Women were more likely to develop adverse events, but the difference in risk was small and does not justify different management. Study limitations include residual confounding and the use of drug survival as a proxy for effectiveness.The BIOBADADERM project is promoted by the Fundación Piel Sana Academia Española de Dermatología y Venereología, which receives financial support from the Spanish Medicines and Health Products Agency (Agencia Española de Medicamentos y Productos Sanitarios) and from pharmaceutical companies (Abbott/Abbvie, Pfizer, MSD, Novartis, Lilly, Janssen and Almirall)

Dermatologist-like explainable AI enhances trust and confidence in diagnosing melanoma

Although artificial intelligence (AI) systems have been shown to improve the accuracy of initial melanoma diagnosis, the lack of transparency in how these systems identify melanoma poses severe obstacles to user acceptance. Explainable artificial intelligence (XAI) methods can help to increase transparency, but most XAI methods are unable to produce precisely located domain-specific explanations, making the explanations difficult to interpret. Moreover, the impact of XAI methods on dermatologists has not yet been evaluated. Extending on two existing classifiers, we developed an XAI system that produces text and region based explanations that are easily interpretable by dermatologists alongside its differential diagnoses of melanomas and nevi. To evaluate this system, we conducted a three-part reader study to assess its impact on clinicians' diagnostic accuracy, confidence, and trust in the XAI-support. We showed that our XAI's explanations were highly aligned with clinicians' explanations and that both the clinicians' trust in the support system and their confidence in their diagnoses were significantly increased when using our XAI compared to using a conventional AI system. The clinicians' diagnostic accuracy was numerically, albeit not significantly, increased. This work demonstrates that clinicians are willing to adopt such an XAI system, motivating their future use in the clinic

Drug Survival of Interleukin (IL)‑17 and IL‑23 Inhibitors for the Treatment of Psoriasis: A Retrospective Multi‑country, Multicentric Cohort Study

Background: Drug survival, defined as the length of time from initiation to discontinuation of a given therapy, allows comparisons between drugs, helps to predict patient's likelihood of remaining on a specific treatment, and achieving the best decision for each patient in daily clinical practice. Objective: The aim of this study was to provide data on drug survival of secukinumab, ixekizumab, brodalumab, guselkumab, tildrakizumab, and risankizumab in a large international cohort, and to identify clinical predictors that might have an impact on the drug survival of these drugs. Methods: This was a retrospective, multicentric, multi-country study that provides data of adult patients with moderate to severe psoriasis who started treatment with an interleukin (IL)-17 or IL-23 inhibitor between 1 February 2015 and 31 October 2021. Data were collected from 19 distinct hospital and non-hospital-based dermatology centers from Canada, Czech Republic, Italy, Greece, Portugal, Spain, and Switzerland. Kaplan-Meier estimator and proportional hazard Cox regression models were used for drug survival analysis. Results: A total of 4866 treatment courses (4178 patients)-overall time of exposure of 9500 patient-years-were included in this study, with 3164 corresponding to an IL-17 inhibitor (secukinumab, ixekizumab, brodalumab) and 1702 corresponding to an IL-23 inhibitor (guselkumab, risankizumab, tildrakizumab). IL-23 inhibitors had the highest drug survival rates during the entire study period. After 24 months of treatment, the cumulative probabilities of drug survival were 0.92 (95% confidence interval [CI] 0.89-0.95) for risankizumab, 0.90 (95% CI 0.88-0.92) for guselkumab, 0.80 (95% CI 0.76-0.84) for brodalumab, 0.79 (95% CI 0.76-0.82) for ixekizumab, and 0.75 (95% CI 0.73-0.77) for secukinumab. At 36 months, only guselkumab [0.88 (95% CI 0.85-0.91)], ixekizumab [0.73 (95% CI 0.70-0.76)], and secukinumab [0.67 (95% CI 0.65-0.70)] had more than 40 patients at risk of drug discontinuation. Only two drugs had more than 40 patients at risk of drug discontinuation at 48 months, with ixekizumab demonstrating to have a higher cumulative probability of drug survival [0.71 (95% CI 0.68-0.75)] when compared with secukinumab [0.63 (95% CI 0.60-0.66)]. Secondary failure was the main cause for drug discontinuation. According to the final multivariable model, patients receiving risankizumab, guselkumab, and ixekizumab were significantly less likely to discontinue treatment than those receiving secukinumab. Previous exposure to biologic agents, absent family history of psoriasis, higher baseline body mass index (BMI), and higher baseline Psoriasis Area and Severity Index (PASI) were identified as predictors of drug discontinuation. Conclusion: The cumulative probability of drug survival of both IL-17 and IL-23 inhibitors was higher than 75% at 24 months, with risankizumab and guselkumab demonstrating to have overall cumulative probabilities ≥ 90%. Biological agent chosen, prior exposure to biologic agents, higher baseline BMI and PASI values, and absence of family history of psoriasis were identified as predictors for drug discontinuation. Risankizumab, guselkumab, and ixekizumab were less likely to be discontinued than secukinumab

Educación ambiental y sociedad. Saberes locales para el desarrollo y la sustentabilidad

EL LIBRO PERMITE REFLEXIONAR SOBRE LA IMPORTANCIA DE FOMENTAL LA EDUCACIÓN AMBIENTAL PARA RESOLVER LA PROBLEMÁTICA AMBIENTALEL LIBRO PRESENTA DIFERENTES TRABAJOS QUE ESTUDIAN EL TEMA D ELA SUSTENTABILIDAD, ENFATIZANDO LA IMPORTANCIA DE LA EDUCACIÓN AMBIENTAL Y LA TRANSDISCIPLINANINGUN