[Pelotherapy and pelotherapy combined with intravenous laser blood irradiation at the sanatorium-resort stage of treatment of patients with psoriasis vulgaris]. / Peloidoterapiya i peloidoterapiya v sochetanii s vnutrivennym lazernym osvechivaniem krovi na sanatorno-kurortnom etape lecheniya bol'nykh vul'garnym psoriazom.

Search of new rational ways to increase the effectiveness of treatment and rehabilitation measures for patients with psoriasis vulgaris continues to be one of the urgent problems in modern clinical dermatology. OBJECTIVE: To carry out a comparative analysis of the impact of different variants of sanatorium-resort treatment (SRT) - pelotherapy and pelotherapy in combination with intravenous laser blood irradiation (ILBI) - on the level of IL-17 and TNF-a, dermatological status, psychoemotional state and quality of life (QL) assessment of patients with psoriasis vulgaris. MATERIAL AND METHODS: A naturalistic comparative study included 120 patients with psoriasis vulgaris, who were undergoing SRT: 57 patients in the pelotherapy group and 63 in the group of pelotherapy in combination with ILBI. The SRT effectiveness was assessed using the PASI index, the HARS and HDRS scales and the DLQI questionnaire. The dynamics of IL-17 and TNF-a plasma levels in blood plasma was studied. The study duration was 6 months 14 days. RESULTS: After 14 days of SRT, a decrease in IL-17 and TNF-a levels in blood plasma was statistically significant both in the pelotherapy group and in the group of pelotherapy in combination with ILBI, no statistically significant differences between the groups were found. Furthermore, the comprehensive use of pelotherapy in combination with ILBI has contributed to a more pronounced statistically significant decrease in the PASI index, the HARS and HDRS scales' total scores and an increase in the level of QL. The number of patients with clinical remission was statistically higher in the group of pelotherapy combined with ILBI compared to the pelotherapy group (87.3% versus 42.1%) six months after SRT. CONCLUSION: The advantage of comprehensive application of pelotherapy and ILBI in comparison with pelotherapy in patients with psoriasis vulgaris in SRT has been shown. The comprehensive application of pelotherapy and ILBI reduces the level of inflammatory biomarkers, improves dermatological and psychoemotional status, improves QL and is well tolerated by patients.

The relationship of neuropsychiatric symptoms with inflammatory markers in the hippocampus and cingulate cortex of bipolar disorder subjects: A post-mortem study.

Increased levels of inflammation markers have been found in the peripheral tissue of individuals with bipolar disorder (BD), especially during mood episodes. Previous studies found distinctive inflammatory profiles across different brain regions, but potential associations with clinical symptoms are still lacking. This study aims to evaluate the association of neuropsychiatric symptoms with inflammatory markers in the hippocampus and cingulate of individuals with BD. Levels of IL-1ß, IL-6, IL-17A, cortisol, and C-reactive protein (CRP) were measured in the hippocampus and anterior cingulate of 14 BD individuals and their non-psychiatric controls. Neuropsychiatric symptoms present in the three months before death were assessed using the Neuropsychiatric Inventory (NPI). In the BD group, greater NPI scores were associated with higher IL-6 in the hippocampus (p = 0.011) and cingulate (p = 0.038) and higher IL-1ß (p = 0.039) in the hippocampus. After adjusting for age, sex and CDR, IL-1ß and IL-6 were still associated with higher NPI in the hippocampus. In correlation analysis considering both BD and their controls, moderate positive associations were found between NPI and IL-6 and cortisol in the hippocampus (p < 0.001 and p = 0.006) and cingulate (p = 0.024 and p = 0.016), IL-1ß (p < 0.001) and IL-17A in the hippocampus (p = 0.002). No difference in inflammatory markers was found according to type of psychotropic medication used. Hence, in individuals with BD, neuropsychiatric symptoms were differently associated with specific inflammatory cytokines and CRP in the hippocampus and cingulate. These results suggest that the neuroinflammatory changes occurring in BD may be more complex than previously expected and could be associated with clinical manifestations.

Network pharmacology analysis and experimental validation of Xiao-Qing-Long-Tang's therapeutic effects against neutrophilic asthma.

BACKGROUND: Xiao-Qing-Long-Tang (XQLT), a classical Chinese herbal medicine formula, has been extensively used for allergic asthma treatment. However, there is limited research on its anti-inflammatory effects and mechanisms specifically in neutrophilic asthma (NA). PURPOSE: This study aims to investigate the potential therapeutic effects of XQLT against NA using a combination of network pharmacology and experimental validation. STUDY DESIGN: By utilizing traditional Chinese medicine and disease databases, we constructed an XQLT-asthma network to identify potential targets of XQLT for NA. In the experimental phase, we utilized an ovalbumin (OVA)/lipopolysaccharide (LPS)-induced model for neutrophilic asthma and examined the therapeutic effects of XQLT. RESULTS: Our research identified 174 bioactive components within XQLT and obtained 140 target genes of XQLT against asthma. Functional enrichment analysis revealed that these target genes were primarily associated with inflammation and cytokines. In the experimental validation, mice induced with OVA-LPS showcased eosinophilic and neutrophilic cell infiltration in peri-bronchial areas, elevated levels of IL-4 and IL-17 in both serum and lung, increased percentages of Th2 and Th17 cells in the spleen, as well as elevated levels of CD11b+ and CD103+ dendritic cells (DCs) within the lung. Treatment with XQLT effectively reduced IL-4 and IL-17 levels, decreased the percentages of Th2, Th17, CD11b+, and CD103+ DCs, and improved inflammatory cell infiltrations in lung tissues. These findings serve as a foundation for the potential clinical application of XQLT in neutrophilic asthma.

Oleuropein Has Modulatory Effects on Systemic Lipopolysaccharide-Induced Neuroinflammation in Male Rats.

BACKGROUND: Neuroinflammation induced by systemic inflammation is a risk factor for developing chronic neurologic disorders. Oleuropein (OLE) has antioxidant and anti-inflammatory properties; however, its effect on systemic inflammation-related neuroinflammation is unknown. OBJECTIVES: This study aimed to determine whether OLE protects against systemic lipopolysaccharide (LPS)-induced neuroinflammation in rats. METHODS: Six-wk-old Wistar rats were randomly assigned to 1 of the following 5 groups: 1) control, 2) OLE-only, 3) LPS + vehicle, 4) OLE+LPS (O-LPS), and 5) a single-dose OLE + LPS (SO-LPS group). OLE 200 mg/kg or saline as a vehicle was administered via gavage for 7 d. On the seventh day, 2.5 mg/kg LPS was intraperitoneally administered. The rats were decapitated after 24 h of LPS treatment, and serum collection and tissue dissection were performed. The study assessed astrocyte and microglial activation using glial fibrillary acidic protein (GFAP) and CD11b immunohistochemistry, nod-like receptor protein-3, interleukin (IL)-1ß, IL-17A, and IL-4 concentrations in prefrontal and hippocampal tissues via enzyme-linked immunosorbent assay, and total antioxidant/oxidant status (TAS/TOS) in serum and tissues via spectrophotometry. RESULTS: In both the O-LPS and SO-LPS groups, LPS-related activation of microglia and astrocytes was suppressed in the cortex and hippocampus (P < 0.001), excluding cortical astrocyte activation, which was suppressed only in the SO-LPS group (P < 0.001). Hippocampal GFAP immunoreactivity and IL-17A concentrations in the dentate gyrus were higher in the OLE group than those in the control group, but LPS-related increases in these concentrations were suppressed in the O-LPS group. The O-LPS group had higher cortical TAS and IL-4 concentrations. CONCLUSIONS: OLE suppressed LPS-related astrocyte and microglial activation in the hippocampus and cortex. The OLE-induced increase in cortical IL-4 concentrations indicates the induction of an anti-inflammatory phenotype of microglia. OLE may also modulate astrocyte and IL-17A functions, which could explain its opposing effects on hippocampal GFAP immunoreactivity and IL-17A concentrations when administered with or without LPS.

[Detection of molecular affecting sensitivity to local glucocorticoid therapy in oral lichen planus through transcriptome sequencing].

OBJECTIVE: To detect key genes of local glucocorticoid therapy in oral lichen planus (OLP) through transcriptome sequencing. METHODS: The study prospectively enrolled 28 symptomatic patients who visitied Department of Oral Mucosa, Peking University Hospital of Stomatology from November 2019 to March 2023. Topical inunction of 0.1 g/L of dexamethasone was applied for 1 min, 3 times daily for 4 weeks. The patients' signs and pain symptoms were recorded and they were classified as effective group and ineffective group according to the treatment outcome. Their mucosa samples were collected before treatment. After isolating total RNA, transcriptome sequencing was performed. The gene expression data obtained by sequencing were analyzed differently using the DESeq2 package in R software, and the Kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment analysis was performed on the basis of the hypergeometric distribution algorithm to describe the biological function of differentially expressed genes (DEGs), accordingly detecting sensitivity related molecular affecting therapeutic effect of dexamethasone. RESULTS: After 4 weeks treatment by topical dexamethasone, 13 cases of the 28 OLP patients responding well with the sign score reducing from 7.0 (4.5, 9.0) to 5.0 (3.0, 6.3), pain score decreasing from 5.0 (2.0, 5.5) to 2.0 (0.0, 3.5), oral health impact profile lessening from 5.0 (3.5, 9.0) to 1.0 (0.0, 5.0) significantly (P<0.01) were classified as effective group and 15 cases with poor response to the drug were sorted as ineffective group. There were no significant differences of demographic and baseline levels of clinical features, especially disease severity between these two groups. A total of 499 DEGs including 274 upregulated and 225 downregulated genes were identified between effective group and ineffective group. KEGG enrichment analysis showed that upregulated genes in effective group compared with ineffective group including CLDN8, CTNNA3, MYL2 and MYLPF were associated with leukocyte transendothelial migration, while downregulated genes were significantly enriched in tumor necrosis factor (TNF), interleukin-17 (IL-17), nuclear factor kappa B (NF-κB) signaling pathways, and cortisol synthesis and secretory. CONCLUSION: High expressions of CLDN8, CTNNA3, MYL2 and MYLPF genes in patients with oral lichen planus have a good clinical response to topical dexamethasone, while patients with high expression genes of inflammation pathway such as TNF, IL-17, NF-κB and cortisol synthesis and secretion received poor effect.

Secukinumab for children and adolescents with enthesitis-related arthritis and psoriatic arthritis: lessons from treatment in adults and the way forward.

INTRODUCTION: Targeting IL-17A using Secukinumab, a humanized monoclonal immunoglobulin G1 (IgG1)/κ against IL-17A is a therapeutic option for immune-mediated disorders such as psoriasis and ankylosing spondylitis. The US Food and Drug Administration and the European Medicines Agency have approved it for the treatment of moderate to severe plaque psoriasis, active psoriatic arthritis, ankylosing spondylitis, and non-radiographic axial spondylarthritis. Recently it has also been approved for use in children with severe plaque psoriasis, active psoriatic arthritis, and enthesitis-related arthritis. AREAS COVERED: This review focuses on the role of Secukinumab in the management of children and adolescents with enthesitis-related arthritis and psoriatic arthritis. We discuss the salient findings of pivotal RCTs and other studies supporting the use of Secukinumab in adults and children, in particular, focusing on its safety and efficacy. EXPERT OPINION: Secukinumab is a therapeutic target for psoriasis, psoriatic arthritis, and spondyloarthropathies in both adults and children. No major safety signals are observed with its use in short-term follow-up. Thus far, Secukinumab has not been found to significantly increase the risk of tuberculosis (TB).

Effects of different extracts of Dendrobium officinale on rats with chronic pharyngitis induced by pepper water combined with ammonia / 中国中药杂志

Dendrobium officinale can serve as Chinese medicinal material effective in nourishing yin, clearing heat, and producing fluid, and is used to treat throat diseases, but its active substances and mechanism are not clear. To clarify the active fraction and underlying mechanism of D. officinale against chronic pharyngitis(CP), the present study induced a CP model in rats by pepper water combined with low-concentration ammonia, and crude polysaccharides of D. officinale(DOP), non-polysaccharides of D. officinale(DON), and total extract of D. officinale(DOT)(0.33 g·kg~(-1), calculated according to the crude drug) were administered by gavage for six weeks. The changes in oral secretions and pharyngeal conditions of rats with CP were observed and rated. The hematological indicators were determined by an automatic hematology analyzer. The serum levels of pro-inflammatory factors, such as tumor necrosis factor-alpha(TNF-α), interleukin 1β(IL-1β), and interleukin 6(IL-6), and T-lymphocyte cytokines, including interferon γ(IFN-γ), interleukin 4(IL-4), interleukin 17(IL-17), and transforming growth factor β1(TGF-β1) were detected by the enzyme-linked immunosorbent assay(ELISA). The proportions of CD3~+, CD4~+, and CD8~+cells in peripheral blood T lymphocyte subsets were determined by the flow cytometry. The histomorphological changes of the pharynx were observed by hematoxylin-eosin(HE) staining. The protein expression of nuclear factor-κB P65(NF-κB P65), cyclooxygenase-2(COX-2), F4/80, and monocyte chemoattractant protein-1(MCP-1) in the pharynx were detected by immunohistochemistry and Western blot. The results showed that DOP and DON could significantly relieve pharyngeal lesions, reduce white blood cells(WBC) and lymphocytes(LYMP), decrease the levels of pro-inflammatory factors TNF-α, IL-6, and IL-1β, and inhibit the protein expression of NF-κB P65, COX-2, F4/80, and MCP-1 in the pharynx. DOP was superior in reducing oral secretions and serum IL-17 level and inferior in increasing CD4~+/CD8~+ratio to DON. It is suggested that both polysaccharides and non-polysaccharides of D. officinale have anti-PC effects and the anti-inflammatory mechanism may be related to the regulation of T lymphocyte distribution and inhibition of the inflammatory signaling pathways mediated by NF-κB P65. The anti-inflammatory effect of DOP may be related to the regulation of Th17/Treg balance, while that of DON may be related to the regulation of the Th/Tc ratio.

Fibrosis pulmonar inducida por metotrexato en un paciente con psoriasis / Methotrexate-induced pulmonary fibrosis in a patient with psoriasis

La fibrosis pulmonar a causa del metotrexato es un efecto adverso infrecuente, observado principalmente en los pacientes con artritis reumatoide, aunque también se vio, de manera escasa, en el tratamiento de la psoriasis. Se presenta el caso de un paciente con psoriasis que desarrolló fibrosis pulmonar por metotrexato.

Pulmonary fibrosis due to methotrexate is an infrequent adverse event, observed mainly in patients with rheumatoid arthritis, although it has also been poorly described in the treatment of psoriasis. We present the case of a patient with psoriasis who developed pulmonary fibrosis due to methotrexate.

Estudio de mecanismos efectores y contra-reguladores mediados por la sobre-activación de inflamasoma durante la respuesta anti-tumoral / Study of effector and counter-regulatory mechanisms mediated by the over-activation of the inflammasome during the anti-tumor response

La manipulación del sistema inmune utilizando inmunoterapias para desencadenar respuestas anti-tumorales ha revolucionado el tratamiento de una variedad de cánceres, sin embargo, pocos pacientes se benefician de las terapias desarrolladas hasta el momento. Por este motivo, es necesario identificar nuevos blancos terapéuticos en la inmunidad anti-tumoral. En nuestro grupo demostramos que TMEM176B es un canal catiónico intracelular con capacidades inmunorreguladoras, y que la deleción génica de Tmem176bo su bloqueo farmacológico con el compuesto BayK8644, ocasiona una sobre-activación del inflamasoma, que favorece el rechazo de tumores trasplantables y mejora el efecto anti-tumoral de las terapias de bloqueo de puntos de control. A su vez, evidenciamos que la deleción génica de Tmem176b induce la acumulación de linfocitos Th17en el ganglio linfático drenante del tumor y el rechazo tumoral mediado por IL-17, cuya expresión por linfocitos T CD4+se ha asociado a la respuesta clínica al bloqueo de PD-1, en pacientes portadores de melanoma metastásico. Por otro lado, en mi tesina de grado demostramos que los tumores de ratones Tmem176b-/-presentan una mayor expresión y actividad enzimática de indoleamina 2,3-dioxigenasa (IDO1) respecto a ratones WT. IDO1 es una enzima capaz de degradar el triptófano por la vía de la quinurenina, y se ha identificado como un mecanismo contra-regulador relevante desencadenado durante las inmunoterapias anti-tumorales. Esto nos llevó a plantear la hipótesis de que la sobre-activación del inflamasoma, dada por la inhibición de TMEM176B, genera respuesta anti-tumoral a través de la activación de linfocitos Th17, pero que podrían existir mecanismos contra-reguladores mediados por IDO1 a nivel tumoral que pueden disminuir este efecto. Teniendo esta hipótesis en mente, nos planteamos como objetivos,por un lado, evaluar el rol de la IL-17 durante las terapias anti-tumorales basadas en la sobre-activación del inflamasoma y el bloqueo de puntos de control inmunológico, y por otro, estudiar la relevancia de los mecanismos contra-reguladores mediados por IDO1 durante la respuesta anti-tumoral generada por la sobre-activación del inflamasoma. En lo que refiere al primer objetivo, demostramos que durante el tratamiento con anti-PD-1, los animales Il-17a-/-presentan una mejor respuesta anti-tumoral, con una mayor sobrevida que los animales WT. Sin embargo, al evaluar estos parámetros en ratones tratados con anti-PD-1 en combinación con BayK8644, observamos que los animales con la deleción génica de Il-17aresponden peor al tratamiento, presentando una sobrevida significativamente menor que los animales WT. Estos resultados parecen indicar que en ausencia de la sobre-activación del inflamasoma mediada por el BayK8644, prevalecen los efectos pro-tumorales de la IL-17, siendo de esta forma perjudicial para el tratamiento con anti-PD-1. En contraste, en un contexto de sobre-activación del inflamasoma, la IL-17 parecería tener un efecto anti-tumoral, relevante para favorecer los efectos de la terapia con anti-PD-1. Respecto al segundo objetivo, evidenciamos que, al igual que como sucede para los animalesTmem176b-/-, los ratones con tumor trasplantado, tratados con BayK8644 presentan un aumento significativo en la expresión y actividad de IDO1a nivel tumoral, respecto a los animales tratados con vehículo. Además, identificamos a las células tumorales como las principales productoras de IDO1 a nivel tumoral, y demostramos que esta población celular es la única que presenta una expresión de IDO1 significativamente mayor en los animales Tmem176b-/-y tratados con BayK8644, respecto a su grupo control. En línea con estos resultados, observamos que la expresión basal de IDO1 a nivel de la célula tumoral parece ser necesaria para la expresión aumentada de IDO1 en los tumores de los animales Tmem176b-/-. Adicionalmente, evidenciamos que el infiltrado de células T CD8+a nivel tumoral se correlaciona de forma positiva con la expresión de IDO1 en células tumorales de animales tratados con BayK8644 o vehículo, pero no con la expresión de esta enzima en las células no tumorales. Además, demostramos que el aumento en la expresión de IDO1 en los tumores de ratones tratados con BayK8644 es dependiente de las células T CD8+, ya que su depleción in vivo lleva a una disminución en los niveles de expresión de esta enzima a nivel tumoral. Estos resultados demuestran que la sobre-activación del inflamasoma, mediada por la deleción génica de Tmem176bo por su inhibición farmacológica con BayK8644, genera un aumento en la expresión y actividad de IDO1 a nivel de la célula tumoral, constituyendo un mecanismo contra-regulador relevante, dependiente de células T CD8+

Ixequizumabe para tratamento de pacientes adultos com psoríase moderada a grave, que tenham apresentado falha terapêutica, contraindicação ou intolerância ao adalimumabe / Ixequizumab for the treatment of adult patients with moderate to severe psoriasis who have therapeutic failure, contraindication or intolerance to adalimumab

Introdução: A psoriase e uma doenca inflamatoria sistemica cronica com manifestacoes frequentemente cutaneas, ungueais e articulares, cursando normalmente de forma remitente e recorrente. Com distribuicao similar entre os sexos e ocorrencia mais frequente entre a terceira e quarta decadas de vida, sua prevalencia no Brasil e estimada entre 1,31% a 2,5%. No SUS, os pacientes possuem garantia de acesso aos tratamentos preconizados em diretrizes terapeuticas, onde o tratamento e iniciado com farmacos por via topica, seguidos de outras opcoes como a fototerapia, medicamentos por via oral e injetaveis de acordo com a gravidade. Os fármacos sistemicos indicados em primeira linha incluem o metotrexato, acitretina e ciclosporina. Em caso de falha destes medicamentos, estao disponiveis outros, quatro biologicos, sendo dois da classe dos anti-TNF (adalimumabe e etanercepte) e dois medicamentos anti-interleucinas, um da classe dos anti-IL12/23 (ustequinumabe) e outro da classe dos anti-IL17 (secuquinumabe). PERGUNTA: O uso de ixequizumabe e eficaz, seguro e custo-efetivo para a segunda etapa de tratamento biologico de pacientes adultos com psoriase em placas moderada a grave, quando comparado as terapias sistemicas biologicas aprovadas pela Conitec nessa etapa de tratamento (ustequinumabe e secuquinumabe)? TECNOLOGIA: Ixequizumabe. EVIDÊNCIAS CIENTÍFICAS: Com uso de meta-analise em rede, uma revisao sistematica da Colaboracao Cochrane teve o objetivo de comparar e hierarquizar os agentes sistêmicos convencionais e biologicos para pacientes com psoriase moderada a grave de acordo com sua eficacia e seguranca. Apos buscas amplas, a revisao incluiu 140 estudos avaliando 19 diferentes tratamentos com um total de 51.749 participantes randomizados e idade media de 45 anos. Todos os resultados (exceto dois estudos) foram limitados a fase de inducao (de 8 a 24 semanas apos a randomizacao). Problemas com o cegamento dos pacientes e envolvidos (performance) e dos avaliadores foram os riscos mais frequentemente identificados. Dentre outros riscos, ressalta-se que a maioria dos estudos declarou financiamento por uma empresa farmaceutica e 22 estudos nao relataram a fonte de financiamento. No desfecho de PASI 90, o resultado da meta-analise em rede destaca que ambos os medicamentos anti-IL17 (ixequizumabe e secuquinumabe) foram significativamente mais efetivos que o ustequinumabe e o adalimumabe. No desfecho do PASI 75 a classe de medicamentos anti-IL17 tambem foi associada a uma maior probabilidade de atingi-lo em comparacao as outras classes. Em relação ao desfecho de eventos adversos graves (EAG), os medicamentos infliximabe, ixequizumabe e secuquinumabe apresentaram maior risco de EAG do que o metotrexato. Associacoes estatisticamente significativas foram encontradas demonstrando que os anti-IL17 apresentam maior risco de eventos adversos em geral em comparacao aos anti-IL23 e anti-IL12/23. O nível de certeza das evidencias de efetividade do ixequizumabe foi considerado moderado (com reducoes devido a inconsistencias) e no desfecho de eventos adversos graves foi considerado moderado (com reducoes devido a imprecisao). AVALIAÇÃO ECONÔMICA: Considerando que a "analise de custo por resposta" enviada pelo demandante carece do rigor metodologico das avaliacoes economicas completas, foi elaborado um novo modelo de custo-efetividade contemplando todas as opcoes disponiveis no SUS e em analise pela Conitec para o tratamento da psoriase moderada a grave. Seguindo a proposta do modelo bastante difundido e concebido por pesquisadores da Universidade de York, foi construido um modelo de arvore de decisao (periodo de inducao) acoplado a um modelo de Markov (periodo de manutencao), buscando analisar os custos e consequencias em termos de anos de vida ajustados pela qualidade (QALY) com as seguintes estrategias de tratamento: ixequizumabe; secuquinumabe; ustequinumabe; risanquizumabe; adalimumabe e infliximabe. Com os resultados do modelo, a partir da analise da fronteira de eficiencia, observa-se a dominancia (efetividade menor e maior custo) dos tratamentos com infliximabe (dominância simples) e secuquinumabe (dominancia estendida) pelos tratamentos com adalimumabe, ustequinumabe e ixequizumabe. O tratamento com risanquizumabe apresenta um valor de efetividade limitrofe com o ixequizumabe, contudo, a um custo muito superior. Ao realizar a analise de limiar por meio da abordagem da fronteira de eficiencia, observa-se que seria necessario que o preco dos medicamentos secuquinumabe, ixequizumabe e risanquizumabe tivessem uma reducao de preco de pelo menos 10,74%, 9,08% e 55,09%, respectivamente, para serem considerados custo-efetivos. Na curva de aceitabilidade de acordo com o escalonamento progressivo da disposicao a pagar, os tratamentos com maior probabilidade de serem custoefetivos foram o adalimumabe, seguido do ustequinumabe e, por fim, o ixequizumabe. AVALIAÇÃO DE IMPACTO ORÇAMENTÁRIO: O demandante encaminhou uma analise de impacto orcamentario que, apos analise critica, considerou-se um modelo adequado e coerente com discussoes anteriores na Conitec. Todavia, alguns de seus dados foram revisados e atualizados resultando em novos valores de impacto. Em sua versao original, o demandante apresentava uma economia de R$ 14.322.953,00. Contudo, apos as atualizacoes dos custos e da taxa de falha ao adalimumabe descritas, estima-se um impacto incremental de R$ 4.052.249,89 ao longo de cinco anos. MONITORAMENTO DO HORIZONTE TECNOLÓGICO: Foram detectadas no horizonte sete potenciais tecnologias para pacientes adultos com psoriase moderada a grave, apos falha da primeira etapa da segunda linha de tratamento: apremislate, bimequizumabe, BMS-986165, brodalumabe, guselcumabe, miriquizumabe e piclidenoson. CONSIDERAÇÕES: A partir das estimativas de efetividade comparativa disponiveis por meio de meta-analises em rede, e possivel observar que o ixequizumabe e o secuquinumabe foramsignificativamente mais efetivos que o ustequinumabe e o adalimumabe. Em relacao a seguranca, observam-se associacoes estatisticamente significativas de que os anti-IL17 apresentam maior risco de eventos adversos em geral em comparacao aos anti-IL23 e anti- IL12/23. O nivel de certeza das evidencias de efetividade foi considerado moderado tanto nos desfechos de efetividade e seguranca para o ixequizumabe. Na curva de aceitabilidade de acordo com a disposicao a pagar, os tratamentos com maior probabilidade de serem custoefetivos foram o adalimumabe, seguido do ustequinumabe e, por fim, o ixequizumabe. Por meio de uma reducao plausivel de preco, e possivel que o ixequizumabe apresente um perfil de custoefetividade semelhante aos tratamentos mais eficientes disponiveis no SUS. Apos as atualizacoes do modelo de impacto orcamentario encaminhado, estima-se um impacto incremental de R$ 4.052.249,89 ao longo de cinco anos com a incorporacao do ixequizumabe ao SUS. RECOMENDAÇÃO PRELIMINAR: Pelo exposto, a CONITEC, em sua 85a reuniao ordinaria, no dia 04 de fevereiro de 2020, recomendou a nao incorporacao no SUS do ixequizumabe para o tratamento de pacientes adultos com psoriase moderada a grave, que tenham apresentado falha terapeutica, contraindicacao ou intolerancia ao adalimumabe. Considerou-se que, apesar do ixequizumabe estar associado a beneficios incrementais em termos de efetividade no tratamento da condicao clinica em analise, sua eficiencia (custo-efetividade) e inferior aos tratamentos ja disponiveis no SUS com base no preco proposto pelo fabricante. A materia foi disponibilizada em consulta publica. CONSULTA PÚBLICA: Foram recebidas 142 contribuicoes tecnico-cientificas e 280 contribuicoes de experiencia ou opiniao, sendo a maioria discordante da recomendacao preliminar da CONITEC. Apos analise do texto das contribuicoes, foram identificados pontos como necessidade de mais alternativas terapeuticas ou mecanismos de acao, superioridade dentre os tratamentos disponiveis, assim como foram apresentados novas propostas de preco e limitacoes da analise preliminar. O laboratorio fabricante ofereceu uma nova proposta de preco equivalente a reducao de 2,7% do preco proposto inicialmente. No modelo atualizado, apresenta-se como uma opcao mais custo-efetiva que o secuquinumabe, porem, menos custo-efetiva que o tratamento com a tecnologia também em analise risanquizumabe. Um novo modelo de impacto orcamentario tambem foi apresentado indicando uma reducao de gastos de ate R$ 37.955.681,00 ao longo dos 5 anos na ocasiao de incorporacao na mesma linha e indicacao do secuquinumabe. Apos apreciacao das contribuicoes encaminhadas pela Consulta Publica, incluindo o destaque para a superioridade em relacao ao adalimumabe e ustequinumabe, limitacoes dos modelos apresentados, experiencias profissionais e pessoais com o tratamento e as novas propostas de preco, o plenario da Conitec entendeu que nao houve argumentacao suficiente para alterar a recomendacao inicial desfavoravel a incorporacao, em relacao ao nivel de eficiencia do tratamento em analise (custo-efetividade), no contexto proposto no SUS. RECOMENDAÇÃO FINAL: Os membros da Conitec, presentes na 89a reuniao ordinaria, no dia 6 de agosto de 2020, deliberaram, por unanimidade, recomendar a nao incorporacao no SUS do ixequizumabe para o tratamento de pacientes adultos com psoriase moderada a grave, que tenham apresentado falha terapeutica, contraindicacao ou intolerancia ao adalimumabe. DECISÃO: Nao incorporar o ixequizumabe para tratamento de pacientes adultos com psoríase moderada a grave, que tenham apresentado falha terapeutica, contraindicacao ou intolerância ao adalimumabe, no ambito do Sistema Unico de Saude - SUS, conforme Portaria no 27, publicada no Diario Oficial da Uniao no 160, secao 1, pagina 117, em 20 de agosto de 2020.

Informe diário de evidências COVID-19: busca realizada em 14 de julho de 2020 / COVID-19 daily evidence report: search conducted on July 14, 2020

O Informe Diário de Evidências é uma produção do Ministério da Saúde que tem como objetivo acompanhar diariamente as publicações científicas sobre tratamento farmacológico e vacinas para a COVID-19. Dessa forma, são realizadas buscas estruturadas em bases de dados biomédicas, referentes ao dia anterior desse informe. Não são incluídos estudos pré-clínicos (in vitro, in vivo, in silico). A frequência dos estudos é demonstrada de acordo com a sua classificação metodológica (revisões sistemáticas, ensaios clínicos randomizados, coortes, entre outros). Para cada estudo é apresentado um resumo com avaliação da qualidade metodológica. Essa avaliação tem por finalidade identificar o grau de certeza/confiança ou o risco de viés de cada estudo. Para tal, são utilizadas ferramentas já validadas e consagradas na literatura científica, na área de saúde baseada em evidências. Cabe ressaltar que o documento tem caráter informativo e não representa uma recomendação oficial do Ministério da Saúde sobre a temática. Foram encontrados 17 artigos e 18 protocolos.

La interleucina-17 en los modelos animales de espondiloartritis / Interleukin-17 in animal models of spondyloarthritis

La relevancia de la IL-17 en la patogenia de las espondiloartritis ha sido definitivamente contrastada por el éxito terapéutico de sus antagonistas. Los modelos animales han proporcionado información útil sobre las vías moleculares y celulares que implican esta vía en estas enfermedades. Los ratones deficientes en diferentes componentes moleculares relacionados con esta vía pusieron de manifiesto inicialmente la dependencia de numerosas enfermedades inflamatorias de las células Th17 y de las citocinas IL-17 e IL-23 modificando el modelo previo Th1/Th2. Los modelos animales de artritis, colitis y encefalitis autoinmunes han sido útiles para demostrar su dependencia de las células Th17. En otros modelos de artritis, como la inducida por proteoglicanos o por anticuerpos (glucosa-6-fosfato isomerasa), ni las células Th17 ni la IL-17 parecen estar involucradas. Los modelos animales de espondiloartritis y de psoriasis han revelado la importancia de IL-23 e IL-17 en la patogenia de las diferentes manifestaciones comunes a este grupo de enfermedades. Estos modelos también han mostrado la relevancia de otras células del sistema inmune innato además de las Th17, tanto de origen mieloide como linfoide, como productoras de IL-17. Además de los efectos proinflamatorios, estos modelos han evidenciado los efectos de IL-17 en la patogenia de las lesiones erosivas u osteoformativas asociadas a las espondiloartropatías

The relevance of interleukin (IL)-17 in the pathogenesis of spondyloarthritis has unquestionably been demonstrated by the therapeutic success of its antagonists. Animal models have provided useful information on the molecular and cellular pathways that implicate this route in these diseases. Mice that were deficient in different molecular components related to this pathway initially revealed the dependence of a number of inflammatory diseases on Th17 cells and on cytokines IL-17 and IL-23, modifying the previous TH1/th2 model. Animal models of autoimmune arthritis, colitis and encephalitis have been useful in that they demonstrate their dependence on T helper 17 (Th17) cells. In other models of arthritis, such as that induced by proteoglycans or antibodies (glucose-6-phosphate isomerase), neither Th17 cells nor IL-17 appear to be involved. Animal models of spondyloarthritis and of psoriasis revealed the importance of IL-23 and IL-17 in the pathogenesis of the distinct manifestations that are common to this group of diseases. These models have also shown the relevance of other cells of the innate immune system, including myeloid and lymphoid cells, as well as Th17, as the origin of IL-17. Aside from the proinflammatory effects, these models have displayed the effects of IL-17 in the pathogenesis of the erosive lesions or pathological bone formation associated with spondyloarthropathies

La interleucina-17 y los pacientes con espondiloartritis / Interleukin-17 and patients with spondyloarthritis

La interleucina 17 (IL-17) es una citocina proinflamatoria que participa en la defensa frente a infecciones por hongos y bacterias. Sobre la base de los resultados de ensayos clínicos utilizando anticuerpos bloqueadores de una de sus isoformas, la IL-17A, esta citocina se ha demostrado una diana terapéutica muy eficaz para el control de enfermedades como la psoriasis, la artropatía psoriásica o la espondilitis anquilosante. Esta revisión se centra en las evidencias que estudian la presencia de estas citocinas y de las células que las producen en los tejidos diana de las espondiloartropatías: raquis y articulaciones periféricas, así como en sangre periférica

Interleukin-17 (IL-17) is a proinflammatory cytokine that participates in defense against infections by fungi and bacteria. On the basis of the results of clinical trials involving antibodies that block one of its isoforms, IL-17A, this cytokine has been found to be a highly effective therapeutic target for the management of diseases like psoriasis, psoriatic arthropathy or ankylosing spondylitis. This review focuses on the evidence demonstrating the presence of this cytokine and of the cells that produce it in the target cells of spondyloarthropathies: spine and peripheral joints, as well as peripheral blood

Eficacia y seguridad de los fármacos inhibidores de la interleucina-17 en la espondilitis anquilosante / Efficacy and safety of drugs that inhibit interleukin-17 in ankylosing spondylitis

La IL-17 es una citocina proinflamatoria clave en la patogénesis de la espondilitis anquilosante que ha surgido recientemente como una diana prometedora para el tratamiento de estos pacientes. Hasta el momento se han desarrollado 3 moléculas (anticuerpos monoclonales) dirigidas frente a la señalización por IL-17: secukinumab, ixekizumab y brodalumab. Este artículo resume la evidencia disponible acerca de estos inhibidores de la IL-17 para el tratamiento de las manifestaciones osteomusculares en pacientes con espondilitis anquilosante. Actualmente, el único inhibidor de la IL-17 aprobado por las agencias medicamentosas para el tratamiento de pacientes con espondilitis anquilosante es el secukinumab. En 2 ensayos clínicos aleatorizados fase III (MEASURE 1 y MEASURE 2), secukinumab ha demostrado ser eficaz para mejorar los síntomas y signos de la enfermedad en pacientes con espondilitis anquilosante activa, a pesar de recibir tratamiento convencional con antiinflamatorios no esteroideos (± un fármaco antifactor de necrosis tumoral). En estos estudios, se observó que el 61% de los pacientes que recibieron secukinumab a dosis de 150 mg subcutáneo cada 4 semanas (previa dosis de carga intravenosa en el MEASURE 1 y subcutánea en el MEASURE 2) alcanzó una respuesta Assessment of SpondyloArthritis International Society (ASAS) 20 a las 16 semanas de seguimiento. Además, el tratamiento con secukinumab también se ha asociado con una disminución de las lesiones inflamatorias en la resonancia magnética de columna y articulaciones sacroilíacas y también con una mejoría en la función física y calidad de vida de los pacientes con espondilitis anquilosante. El perfil de seguridad de secukinumab observado en pacientes con espondilitis anquilosante tratados con secukinumab es similar al observado en otras patologías. En general, secukinumab es bien tolerado en pacientes con espondilitis anquilosante y se asocia con una baja incidencia de efectos adversos graves y a una tasa baja de discontinuación del tratamiento debido a efectos adversos. Sobre la base de estos resultados, el tratamiento con secukinumab se ha incluido recientemente dentro del algoritmo de tratamiento en las últimas recomendaciones ASAS/European League Against Rheumatism (EULAR) para el manejo de pacientes con espondiloartritis axial y de la Sociedad Española de Reumatología (SER) para el uso de terapia biológica en pacientes con espondiloartritis axial

Interleukin-17 (IL-17) is a key proinflammatory cytokine in the pathogenesis of ankylosing spondylitis (AS) that has recently emerged as a promising target in the treatment of those patients. Up to now, three molecules (monoclonal antibodies) have been directed against IL-17: secukinumab, ixekizumab and brodalumab. This article summarizes the available evidence concerning these IL-17 inhibitors for the treatment of musculoskeletal manifestations in patients with AS. At the present time, secukinumab is the only IL-17 inhibitor approved by drug administrations for the treatment of patients with AS. In two phase III randomized clinical trials (MEASURE 1 and MEASURE 2), secukinumab was shown to be efficient when used to improve the symptoms and signs of the disease in patients with active AS, although they had received standard treatment with nonsteroidal anti-inflammatory drugs (± an anti-tumor necrosis factor agent). In those studies, it was observed that 61% of the patients who received subcutaneous secukinumab at a dose of 150 mg every 4 weeks (after an intravenous loading dose in MEASURE 1 and a subcutaneous dose in MEASURE 2) reached an Assessment of SpondyloArithritis international Society (ASAS) 20 response after 16 weeks of follow-up. Moreover, treatment with secukinumab has also been associated with a decrease in the inflammatory lesions seen in nuclear magnetic resonance images at the level of the spine and the sacroiliac joints, and with an improvement in the physical function and quality of life of AS patients. The safety profile of secukinumab observed in patients with AS treated with secukinumab is similar to that observed in other diseases. In general, secukinumab is well tolerated in AS patients and is associated with a low incidence of serious adverse events and a low rate of discontinuation of the treatment due to adverse effects. On the basis of these results, treatment with secukinumab has recently been included in the treatment algorithm in the latest recommendations from the ASAS and the European League Against Rheumatism (EULAR) for the management of patients with axial spondyloarthritis and in those drafted by the Spanish Society of Rheumatology (SER) for the use of biological therapy in patients with axial spondyloarthritis

Eficacia y seguridad de los fármacos inhibidores de la interleucina-17 en la artritis psoriásica / Efficacy and safety of interleukin-17 inhibiting drugs in psoriatic arthritis

En los últimos años se ha avanzado en el entendimiento de los mecanismos patogénicos de la artritis psoriásica, dando protagonismo a citocinas implicadas en el eje interleucina (IL)-23/Th17, fundamentalmente la IL-17. Así, se han desarrollado fármacos que inhiben la acción de esta citocina de forma eficaz y segura a tenor de los resultados de los distintos ensayos clínicos realizados. Este artículo revisa la eficacia terapéutica del secukinumab, ixekizumab y brodalumab en el tratamiento de la artritis psoriásica, así como la tolerabilidad y las seguridad de estos fármacos, y que muestran los datos de los ensayos clínicos que se han comunicado en distintas publicaciones o presentado en los últimos congresos de reumatología y que demostraron que, en comparación con placebo, son eficaces para mejorar los signos y síntomas de la artritis psoriásica en pacientes con enfermedad activa a pesar del tratamiento previo con fármacos antiinflamatorios no esteroideos, fármacos reumáticos modificadores de la enfermedad o inhibidores del factor de necrosis tumoral alfa. Aunque será la práctica clínica la que dirá a medio y largo plazo cuál es su sitio en el arsenal terapéutico de la artritis psoriásica, los datos clínicos actuales son muy prometedores

In recent years, our understanding of the pathogenic mechanisms of psoriatic arthritis (PsA) has improved, lending prominence to cytokines involved in the interleukin-23 (IL-23)/Th17 axis, basically IL-17. Consequently, drugs have been developed that effectively and safely inhibit the action of that cytokine, as demonstrated by the results of the various clinical trials carried out. This article reviews the therapeutic efficacy of secukinumab, ixekizumab and brodalumab in the treatment of PsA, in addition to the tolerability and safety of these agents. We provide the data of the clinical trials reported in different publications or presented at the latest rheumatology meetings, that reveal their efficacy, as compared to placebo, in improving the signs and symptoms of PsA in patients with active disease, despite previous treatment with nonsteroidal anti-inflammatory drugs, disease-modifying antirheumatic drugs or tumor necrosis factor a inhibitors. The findings in clinical practice over the medium and long term will indicate their place in the therapeutic arsenal of PsA. However, the clinical data at this time are very promising

Rol de la interleucina-17 en otras enfermedades y comorbilidades / Role of interleukin-17 in other diseases and comorbidities

La interleucina 17A (IL-17A) es una citocina producida por linfocitos T colaboradores (Th17) y otras células del sistema inmune, con efectos pleiotrópicos sobre múltiples estirpes celulares. Mientras que su deficiencia produce una reducción en el control de ciertas infecciones extracelulares y fúngicas, su sobreproducción puede constituir la base patogénica de varias enfermedades mediadas por el sistema inmune. Aunque la eficacia del bloqueo terapéutico de esta citocina es un hecho probado en varias enfermedades, también es importante conocer el rol de esta citocina en otras circunstancias clínicas. En este artículo de revisión se describe el papel que desempeña la IL-17A en la patogenia de algunas de las enfermedades con las que está relacionada, como la psoriasis, la enfermedad inflamatoria intestinal y la uveítis, así como el riesgo de infecciones asociado al bloqueo o al déficit genético de esta

Interleukin-17A (IL-17A) is a cytokine produced by T helper lymphocytes (Th17) and other cells of the immune system, with pleiotropic effects on a number of cell lines. Whereas its deficiency reduces the control of certain extracellular and fungal infections, its overproduction can constitute the pathogenic basis of a number of immune-mediated diseases. Although the efficacy of the therapeutic blockade of this cytokine has been confirmed in several diseases, it is also important to be aware of its involvement in other clinical circumstances. In this review article, we describe the role of IL-17A in the pathogenesis of some of the diseases with which it is linked, such as psoriasis, inflammatory bowel disease and uveitis, as well as the risk of infections associated with its blockade or its genetic deficiency

Implicaciones terapéuticas de la interleucina-17 en otras enfermedades y comorbilidades / Therapeutic implications of interleukin-17 in other diseases and comorbidities

Al igual que en artritis psoriásica y espondilitis anquilosante, los inhibidores de la IL-17 han seguido un desarrollo clínico en otras enfermedades inmunomediadas como la psoriasis, la artritis reumatoide, la enfermedad inflamatoria intestinal o la uveítis, con resultados desiguales. Mientras que en psoriasis el beneficio clínico es muy destacado, en artritis reumatoide y uveítis aún está por determinar su utilidad. En enfermedad inflamatoria intestinal, los datos disponibles hasta la fecha parecen descartar el beneficio del bloqueo de IL-17 en esta patología

As in psoriatic arthritis and ankylosing spondylitis, interleukin (IL)-17 inhibitors have undergone clinical development in other immune-mediated diseases such as psoriasis, rheumatoid arthritis, inflammatory bowel disease and uveitis, with varying results. While in psoriasis, the clinical benefit is highly notable, in rheumatoid arthritis and uveitis, their utility has yet to be determined. In inflammatory bowel disease, the data available to date seem to rule out a benefit of IL-17 blockade in this disorder

Therapeutic implications of IL-17A blockade in psoriasis

No disponible

IL-17 in psoriasis. The final frontier or just another brick in the wall?

No disponible

Pathogenic role of IL-17 in psoriasis and psoriatic arthritis

Psoriasis is a chronic inflammatory skin disorder resulting from a complex network of cytokines and chemokines produced by various immune cell types and tissue cells. Emerging evidence suggests a central role of IL-17 and IL-23/T17 axis in the pathogenesis of psoriasis, giving a rationale for using IL-17-blocking agents as therapeutics. Three agents targeting IL-17 signaling are being studied in Phase III clinical trials: secukinumab and ixekizumab (IL-17 neutralizing agents), and brodalumab (IL-17 receptor antagonist). Preliminary results are highly promising for all anti-IL17 agents, creating fair expectations on this class of agents as the new effective therapeutic approach for the treatment of psoriasis

La psoriasis es un trastorno crónico inflamatorio de la piel resultante de un complejo sistema de citocinas y quimiocinas producidas por varios tipos de células inmunes y células tisulares. La evidencia incipiente sugiere un papel central de la IL-17 y el eje IL-23/T17 en la patogénesis de la psoriasis, lo que ofrece una base para el uso de agentes bloqueadores de la IL-17 como tratamiento. Están siendo estudiados en estudios clínicos en fase III tres agentes enfocados en la señalización de la IL-17: secukinumab e ixekizumab (agentes neutralizantes de la IL-17), y brodalumab (antagonista del receptor de la IL-17). Los resultados preliminares son altamente prometedores para todos los agentes anti-IL17, lo que crea claras expectativas para esta clase de agentes como un nuevo planteamiento terapéutico eficaz para el tratamiento de la psoriasis