Abstract Background Treatment adherence has been recognized as an important issue in the management of chronic diseases such as psoriasis. Objective The aim of this work was to analyse data about topical treatment adherence in psoriasis. Methods Systematic literature review (62 references) between 1980 and 2011 (database: PubMed, Embase and Cochrane; Mesh keywords: Patient Compliance [Mesh] OR Medication Adherence [Mesh] AND Psoriasis [Mesh]; limits: date of publication >1980, humans subjects, written in French or English, aged ≥19 years). Two parameters were evaluated: (i) the ratio of number of product applications performed vs. number of applications expected according to physician recommendations, (ii) the ratio of amount of product used vs. amount of product prescribed. Results A total of 22 studies were selected. Nine studies reported on the frequency of topical treatment application in a real world setting. Five studies showed a frequency of applications varying between 50% and 60% of those expected. Because of the high variability in medication adherence assessment methods, the data could not be combined. Twelve articles reported on the frequency of topical treatment application in randomized controlled trials with adherence varying between 55% and 100%. Concerning the amount of product use, four studies showed patients applied between 35% and 72% of the recommended dose during a treatment period of 14 days to 8 weeks. The most frequently mentioned reasons for non‐adherence to topical treatment were low efficacy, time consumption and poor cosmetic characteristics of topical agents. Patients experiencing adherence issues were significant younger, were men, had younger age at onset of psoriasis and had a higher self‐assessed severity. To improve adherence, the following strategies were suggested: to give patients information about psoriasis, to recognize social impact, to give written instructions for use such as a care plan, to explain side effects of topical therapies, to choose treatment and its cosmetic properties in agreement with the patient. Conclusions Literature data about topical treatment adherence are heterogeneous and scarce. They confirm the limited topical treatment adherence in psoriasis in real life, much lower than what is reported in randomized controlled trials. Therapeutic education and clear instructions on the use of topical agents are necessary to improve adherence. Studies are needed to identify predictors of limited adherence and to identify interventions improving adherence to topical medications in psoriasis.
Abstract Aim Type 1 diabetes (T1D) is a chronic autoimmune disease leading to progressive loss of pancreatic beta cells. Interferon (IFN)‐α plays a critical role in the crosstalk between pancreatic beta cells and the immune system in early insulitis. In human beta cells IFNα signals through JAK1 and TYK2, leading to endoplasmic reticulum stress, inflammation and HLA class I overexpression. IFNα, acting synergistically with IL‐1β, induces apoptosis. Polymorphisms in TYK2 that decrease its activity are associated with protection against T1D, and we hypothesized that pharmacological inhibitors that specifically target TYK2 could protect human beta cells against the deleterious effects of IFNα. Materials and Methods Two TYK2 inhibitors provided by Nimbus Lakshmi were tested in human insulin‐producing EndoC‐βH1 cells and human islets to evaluate their effect on IFNα signalling, beta‐cell function and susceptibility to viral infection using RT‐qPCR, western blot, immunofluorescence, ELISA and nuclear dyes. Results The two TYK2 inhibitors tested prevented IFNα‐induced human beta‐cell gene expression in a dose‐dependent manner. They also protected human islets against IFNα + IL‐1β‐induced apoptosis. Importantly, these inhibitors did not modify beta‐cell function or their survival following infection with the potential diabetogenic coxsackieviruses CVB1 and CVB5. Conclusions The two TYK2 inhibitors tested inhibit the IFNα signalling pathway in human beta cells, decreasing its pro‐inflammatory and pro‐apoptotic effects without sensitizing the cells to viral infection. The preclinical findings could pave the way for future clinical trials with TYK2 inhibitors for the prevention and treatment of type 1 diabetes.
A disfunção erétil (DE) apresenta‐se como uma das complicações mais comuns da diabetes, sendo o stresse oxidativo uma característica relevante da DE diabética. Eventos deletérios induzidos pelo stresse oxidativo levam a relevantes alterações celulares e tecidulares alvos do dano oxidativo. No entanto, permanecem por clarificar os efeitos nocivos de mecanismos oxidativos no tecido peniano com a progressão da diabetes. Desta forma, pretendeu‐se avaliar a condição do stresse oxidativo a nível sistémico e peniano numa fase precoce e estabelecida da diabetes. Ratos machos Wistar foram divididos em grupos de: 2 e 8 semanas de diabetes tipo 1 induzida por streptozotocina e os respetivos controlos emparelhados pela idade. O stresse oxidativo sistémico foi avaliado pela quantificação de peróxido de hidrogénio (H2O2) na urina e pelo rácio glutationa reduzida/oxidada (GSH/GSSG) no plasma. Localmente, em tecido peniano, a condição de stresse oxidativo foi analisada através da produção de H2O2 e avaliação da nitração proteica pela deteção de 3‐nitrotirosina (3‐NT). 3‐NT foi quantificado por western blotting e por imunohistoquímica identificouse a sua localização celular no tecido cavernoso dos animais em estudo. A avaliação sistémica do stresse oxidativo revelou um aumento significativo dos níveis de H2O2 urinário e uma diminuição significativa do rácio GSH/GSSG circulante nos animais com uma diabetes avançada. No tecido cavernoso, o incremento significativo da produção de H2O2 verificou‐se também nos animais com 8 semanas de diabetes. Relativamente à formação de 3‐NT, os dados obtidos revelaram um aumento significativo no tecido cavernoso em animais com uma diabetes tardia e uma localização predominante deste marcador oxidativo na musculatura lisa cavernosa. Os resultados indicam um efeito nocivo sistémico e cavernoso induzido pelo stresse oxidativo, proeminente num estadio avançado da diabetes. Sugere‐se que o aumento das modificações oxidativas nas proteínas do pénis poderá ser responsável por promover desregulações estruturais/funcionais nos mecanismos celulares/moleculares, contribuindo para o desenvolvimento e progressão da DE associada à diabetes. Erectile dysfunction (ED) is one of the most common complications of diabetes, being oxidative stress an important feature of diabetic ED. Deleterious events induced by oxidative stress lead to crucial cellular and tissue alterations targeted by oxidative lesions. However, the noxious effects of oxidative stress mechanisms in penile tissue with the progression of diabetes, remains unclear. We intended to evaluate systemic and penile oxidative stress in an early and late stage of diabetes. Male Wistar rats were divided in groups: 2 and 8‐weeks of streptozotocin‐induced type 1 diabetes, and age‐matched controls. Systemic oxidative stress was evaluated in urine by hydrogen peroxide (H2O2) quantification and in plasma by reduced/oxidized glutathione (GSH/GSSG) ratio. Penile oxidative status was assessed by H2O2 production and by the evaluation of protein nitration through the detection of 3‐nitrotyrosine (3‐NT). 3‐NT was quantified by Western blotting analysis and immunohistochemistry allowed to identify its cavernosal cellular location. Systemic evaluation revealed a significant increase in urinary H2O2 levels in both diabetic groups. A significant decrease of circulating GSH/GSSG ratio was observed in animals with late stage diabetes. In cavernosal tissue, H2O2 production was significantly increased at 8‐weeks diabetes. Regarding 3‐NT cavernosal formation, data revealed a significant increment in advanced diabetes and a predominant location in cavernosal smooth muscle cells. We observed that systemic and cavernosal noxious effects induced by oxidative stress are predominant in advanced diabetes. Increased penile protein oxidative modifications in late‐staged diabetes may be responsible for structural/functional deregulations in cellular/molecular systems, contributing to the development of diabeticassociated ED.
BackgroundAntibodies targeting PD-1 and its ligand PDL1 are used in cancer immunotherapy but may lead to autoimmune diseases, including type 1 diabetes (T1D). It remains unclear whether PDL1 is expressed in pancreatic islets of people with T1D and how is it regulated.MethodsThe expression of PDL1, IRF1, insulin and glucagon was evaluated in samples of T1D donors by immunofluorescence. Cytokine-induced PDL1 expression in the human beta cell line, EndoC-βH1, and in primary human pancreatic islets was determined by real-time RT-PCR, flow cytometry and Western blot. Specific and previously validated small interference RNAs were used to inhibit STAT1, STAT2, IRF1 and JAK1 signaling. Key results were validated using the JAK inhibitor Ruxolitinib.FindingsPDL1 was present in insulin-positive cells from twelve T1D individuals (6 living and 6 deceased donors) but absent from insulin-deficient islets or from the islets of six non-diabetic controls. Interferons-α and -γ, but not interleukin-1β, induced PDL1 expression in vitro in human islet cells and EndoC-βH1 cells. Silencing of STAT1 or STAT2 individually did not prevent interferon-α-induced PDL1, while blocking of JAKs – a proposed therapeutic strategy for T1D – or IRF1 prevented PDL1 induction.InterpretationThese findings indicate that PDL1 is expressed in beta cells from people with T1D, possibly to attenuate the autoimmune assault, and that it is induced by both type I and II interferons via IRF1.
Interferon-α (IFNα) plays a prominent role in type 1 diabetes (T1D) pathogenesis and mediates its effects through the IFN receptor (IFNAR) and the protein tyrosine kinases JAK1 and TYK2. Polymorphisms that decrease TYK2 activity are protective against T1D, and TYK2 inhibitors (TYKi) are being evaluated for therapeutic benefit in other autoimmune conditions. To test whether TYK2 inhibitors BMS-986202 and BMS-986165 have similar efficacy in diverse models of T1D, we evaluated their effect in vitro on human islets, EndoC-βH1 cells, and iPSC-derived islet-like aggregates and monitored diabetes incidence in RIP-LCMV and NOD mice following in vivo treatment with BMS-986202. TYK2i prevented IFNα-mediated upregulation of CXCL10, MX1, and HLA-ABC in human islets, iPSCs, and EndoC-βH1 and decreased IFNα-mediated STAT1/2 phosphorylation and apoptosis in human islets. Importantly, BMS-986202 reduced diabetes incidence in RIP-LCMV mice by 80% (n=18 vehicle/18 TYK2i; p<0.001). Flow cytometry analysis 3 days post LCMV injection revealed a decrease in the percentage of CD11b+F4/80+ macrophages (M1) and CD11b+CD49+ NK cells in pancreatic lymph nodes (PLN) and blood and an increase in circulating CD11b-CD49+ tolerogenic-NK cells in TYK2i-treated RIP-LCMV mice. At days 7 and 14 post LCMV, PDI+CD8+T-cells in the blood, spleen, and PLN and PDI+FOXP3+ Treg cells in the spleen were increased in TYK2i-treated RIP-LCMV mice, indicating T-cell exhaustion. Similarly, treatment with BMS-986202 resulted in a 44% decrease in diabetes incidence in NOD mice (n=32 vehicle/34 TYK2i; p=0.0075) and a significant reduction in insulitis (p<0.05). smFISH analysis revealed decreased β cell expression of STAT1 and MX1 in TYK2i-treated RIP-LCMV mice and NOD mice compared to vehicle-treated mice, while T-cell activation upon co-incubation with target human β cells was inhibited by TYK2i treatment. Taken together, our findings demonstrate that TYK2 inhibition protects against β cell inflammation and T1D development in multiple preclinical models. Disclosure F.Syed: None. M.I.Alvelos: None. G.Chang: None. K.Orr: None. K.Yamada: None. J.Liu: None. A.Zaldumbide: None. D.Scheuner: None. D.L.Eizirik: None. C.Evans-molina: Advisory Panel; Provention Bio, Inc., DiogenX, Avotres Inc., Neurodon, MaiCell Therapeutics, Other Relationship; Isla Technology, Bristol-Myers Squibb Company, Nimbus Therapeutics, Research Support; Lilly, Astellas Pharma Inc. O.Ballew: None. C.Lee: None. J.Rana: Research Support; Bayer Inc. A.Castela: None. S.A.Weaver: Employee; Eli Lilly and Company. S.Thomaidou: None. S.Demine: None. A.Coomans de brachène: None. Funding National Institutes of Health (DK127308, UC4DK104166); JDRF (2-SRA-2019-834-S-B, 5-CDA-2022-1176-A-N)
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