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2.
Med Clin North Am ; 105(4): 627-641, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34059242

RESUMO

Psoriasis is a systemic inflammatory condition that negatively affects the quality of life and medical health of 125 million individuals globally. Although psoriasis has historically been viewed as a skin-limited disease and managed with topical agents (eg, coal tar, corticosteroids, and vitamin D analogues), the recontextualization of psoriasis as a systemic condition involving multiple organ systems has prompted the development of numerous immunomodulating, systemic agents with more targeted mechanisms of action. This article briefly discusses the indications and nuances of new and developing therapeutic agents for psoriasis management.


Assuntos
Interleucinas/antagonistas & inibidores , Psoríase/patologia , Psoríase/terapia , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Administração Tópica , Corticosteroides/administração & dosagem , Corticosteroides/uso terapêutico , Ensaios Clínicos como Assunto , Alcatrão/administração & dosagem , Alcatrão/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , Humanos , Fatores Imunológicos/efeitos adversos , Fatores Imunológicos/uso terapêutico , Inibidores de Janus Quinases/uso terapêutico , Psoríase/diagnóstico , Psoríase/psicologia , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico , Qualidade de Vida/psicologia , Receptores de Hidrocarboneto Arílico , Vitamina D/administração & dosagem , Vitamina D/análogos & derivados , Vitamina D/uso terapêutico
3.
Indian J Pharmacol ; 53(3): 226-228, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34169908

RESUMO

Although many potent drugs have been used for cytokine storm, mortality is high for patients with coronavirus disease-2019 (COVID-19), which is followed up in the intensive care unit. Interferons (IFNs) are the major cytokines of the antiviral defense system released from many cell types. However, IFN-γ plays a key role in both primary and secondary cytokine storms. If the cytokine storm is not treated urgently, it will be fatal; therefore, it should be treated immediately. Anakinra, an interleukin-1 (IL-1) antagonist, tocilizumab, an IL-6 antagonist, and Janus kinase (JAK) inhibitors are successfully used in cytokine storm caused by COVID-19. However, sometimes, despite these treatments, the patient's clinical course does not improve. Emapalumab (Eb) is the human immunoglobulin G1 monoclonal antibody and is a potent and noncompetitive antagonist of IFN-γ. Eb can be life saving for cytokine storm caused by COVID-19, which is resistant to anakinra, tocilizumab, and JAK inhibitors.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Anticorpos Neutralizantes/uso terapêutico , COVID-19/tratamento farmacológico , Síndrome da Liberação de Citocina/tratamento farmacológico , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Inibidores de Janus Quinases/uso terapêutico , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais Humanizados/farmacologia , Anticorpos Neutralizantes/farmacologia , Antirreumáticos/farmacologia , Antirreumáticos/uso terapêutico , COVID-19/epidemiologia , COVID-19/imunologia , Síndrome da Liberação de Citocina/epidemiologia , Síndrome da Liberação de Citocina/imunologia , Progressão da Doença , Farmacorresistência Viral , Humanos , Interferon gama/antagonistas & inibidores , Interferon gama/imunologia , Proteína Antagonista do Receptor de Interleucina 1/farmacologia , Interleucinas/antagonistas & inibidores , Interleucinas/imunologia , Inibidores de Janus Quinases/farmacologia , Recidiva
4.
Cell Biochem Biophys ; 79(2): 311-320, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33683657

RESUMO

The proliferation of fetal alveolar type II cells (FATIICs) was impaired in bronchopulmonary dysplasia (BPD), which is modulated by hyperoxia and inflammatory response. Interleukin 24 (IL-24), a cytokine produced by certain cell types, plays an essential role in inflammation and host protection against infection. However, the ability of FATIICs to produce IL-24 remains unclear, and the role of IL-24 in BPD progression is yet to be determined. With reverse transcription quantitative polymerase chain reaction (RT-qPCR) and enzyme-linked immunosorbent assay, the authors evaluated whether FATIICs produce IL-24 in physiological conditions. The authors quantified IL-24 expression in the lungs of newborn rat pups exposed to hyperoxia (70% oxygen) and in FATIICs isolated on embryonic day 19 that were exposed to 95% oxygen or lipopolysaccharide (LPS). The role of IL-24 in FATIICs, cell proliferation, cell apoptosis, and cell cycle were further evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and flow cytometric analysis. Also, they assessed caspase-3 and SOCS3 mRNA in IL-24 siRNA-treated cells by using RT-qPCR. During culture, IL-24 mRNA and protein levels in FATIICs gradually decreased with FATIIC differentiation. IL-24 expression increased significantly in rat lungs exposed to hyperoxia and FATIICs exposed to oxygen or LPS. Recombinant IL-24 enhanced cell proliferation by decreasing the proportion of apoptotic cells and increasing the proportion of cells in the S phase. The IL-24 siRNA-treated cells expressed more caspase-3 mRNA. Furthermore, suppressor of cytokine signaling 3 (SOCS3) mRNA was significantly decreased in rats and FATIICs exposed to oxygen, whereas it dramatically increased in FATIICs exposed to LPS. The IL-24 siRNA-treated cells expressed more SOCS3 mRNA. These studies suggest IL-24 is a pulmonary target cytokine in BPD, and may possibly regulate SOCS3 in oxidative stress and inflammation of the lung.


Assuntos
Displasia Broncopulmonar/patologia , Interleucinas/metabolismo , Animais , Displasia Broncopulmonar/metabolismo , Proliferação de Células/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Feminino , Hiperóxia , Interleucinas/antagonistas & inibidores , Interleucinas/genética , Lipopolissacarídeos/farmacologia , Alvéolos Pulmonares/citologia , Alvéolos Pulmonares/efeitos dos fármacos , Alvéolos Pulmonares/metabolismo , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Ratos , Ratos Sprague-Dawley , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/isolamento & purificação , Proteínas Recombinantes/farmacologia , Pontos de Checagem da Fase S do Ciclo Celular/efeitos dos fármacos , Proteína 3 Supressora da Sinalização de Citocinas/genética , Proteína 3 Supressora da Sinalização de Citocinas/metabolismo , Regulação para Cima/efeitos dos fármacos
5.
Lancet Diabetes Endocrinol ; 9(4): 212-224, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33662334

RESUMO

BACKGROUND: Type 1 diabetes is characterised by progressive loss of functional ß-cell mass, necessitating insulin treatment. We aimed to investigate the hypothesis that combining anti-interleukin (IL)-21 antibody (for low-grade and transient immunomodulation) with liraglutide (to improve ß-cell function) could enable ß-cell survival with a reduced risk of complications compared with traditional immunomodulation. METHODS: This randomised, parallel-group, placebo-controlled, double-dummy, double-blind, phase 2 trial was done at 94 sites (university hospitals and medical centres) in 17 countries. Eligible participants were adults aged 18-45 years with recently diagnosed type 1 diabetes and residual ß-cell function. Individuals with unstable type 1 diabetes (defined by an episode of severe diabetic ketoacidosis within 2 weeks of enrolment) or active or latent chronic infections were excluded. Participants were randomly assigned (1:1:1:1), with stratification by baseline stimulated peak C-peptide concentration (mixed-meal tolerance test [MMTT]), to the combination of anti-IL-21 and liraglutide, anti-IL-21 alone, liraglutide alone, or placebo, all as an adjunct to insulin. Investigators, participants, and funder personnel were masked throughout the treatment period. The primary outcome was the change in MMTT-stimulated C-peptide concentration at week 54 (end of treatment) relative to baseline, measured via the area under the concentration-time curve (AUC) over a 4 h period for the full analysis set (intention-to-treat population consisting of all participants who were randomly assigned). After treatment cessation, participants were followed up for an additional 26-week off-treatment observation period. This trial is registered with ClinicalTrials.gov, NCT02443155. FINDINGS: Between Nov 10, 2015, and Feb 27, 2019, 553 adults were assessed for eligibility, of whom 308 were randomly assigned to receive either anti-IL-21 plus liraglutide, anti-IL-21, liraglutide, or placebo (77 assigned to each group). Compared with placebo (ratio to baseline 0·61, 39% decrease), the decrease in MMTT-stimulated C-peptide concentration from baseline to week 54 was significantly smaller with combination treatment (0·90, 10% decrease; estimated treatment ratio 1·48, 95% CI 1·16-1·89; p=0·0017), but not with anti-IL-21 alone (1·23, 0·97-1·57; p=0·093) or liraglutide alone (1·12, 0·87-1·42; p=0·38). Despite greater insulin use in the placebo group, the decrease in HbA1c (a key secondary outcome) at week 54 was greater with all active treatments (-0·50 percentage points) than with placebo (-0·10 percentage points), although the differences versus placebo were not significant. The effects diminished upon treatment cessation. Changes in immune cell subsets across groups were transient and mild (<10% change over time). The most frequently reported adverse events included gastrointestinal disorders, in keeping with the known side-effect profile of liraglutide. The rate of hypoglycaemic events did not differ significantly between active treatment groups and placebo, with an exception of a lower rate in the liraglutide group than in the placebo group during the treatment period. No events of diabetic ketoacidosis were observed. One participant died while on liraglutide (considered unlikely to be related to trial treatment) in connection with three reported adverse events (hypoglycaemic coma, pneumonia, and brain oedema). INTERPRETATION: The combination of anti-IL-21 and liraglutide could preserve ß-cell function in recently diagnosed type 1 diabetes. The efficacy of this combination appears to be similar to that seen in trials of other disease-modifying interventions in type 1 diabetes, but with a seemingly better safety profile. Efficacy and safety should be further evaluated in a phase 3 trial programme. FUNDING: Novo Nordisk.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Linfócitos B/fisiologia , Diabetes Mellitus Tipo 1/tratamento farmacológico , Hipoglicemiantes/administração & dosagem , Interleucinas/antagonistas & inibidores , Liraglutida/administração & dosagem , Adulto , Linfócitos B/efeitos dos fármacos , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/diagnóstico , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Seguimentos , Humanos , Interleucinas/sangue , Masculino , Adulto Jovem
6.
Nat Immunol ; 22(4): 520-529, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33753942

RESUMO

Patients with myelodysplastic syndromes (MDSs) display severe anemia but the mechanisms underlying this phenotype are incompletely understood. Right open-reading-frame kinase 2 (RIOK2) encodes a protein kinase located at 5q15, a region frequently lost in patients with MDS del(5q). Here we show that hematopoietic cell-specific haploinsufficient deletion of Riok2 (Riok2f/+Vav1cre) led to reduced erythroid precursor frequency leading to anemia. Proteomic analysis of Riok2f/+Vav1cre erythroid precursors suggested immune system activation, and transcriptomic analysis revealed an increase in p53-dependent interleukin (IL)-22 in Riok2f/+Vav1cre CD4+ T cells (TH22). Further, we discovered that the IL-22 receptor, IL-22RA1, was unexpectedly present on erythroid precursors. Blockade of IL-22 signaling alleviated anemia not only in Riok2f/+Vav1cre mice but also in wild-type mice. Serum concentrations of IL-22 were increased in the subset of patients with del(5q) MDS as well as patients with anemia secondary to chronic kidney disease. This work reveals a possible therapeutic opportunity for reversing many stress-induced anemias by targeting IL-22 signaling.


Assuntos
Anemia/metabolismo , Anticorpos Neutralizantes/farmacologia , Células Eritroides/metabolismo , Eritropoese/efeitos dos fármacos , Interleucinas/antagonistas & inibidores , Síndromes Mielodisplásicas/tratamento farmacológico , Receptores de Interleucina/metabolismo , Anemia/sangue , Anemia/imunologia , Anemia/prevenção & controle , Animais , Células Cultivadas , Microambiente Celular , Modelos Animais de Doenças , Células Eritroides/imunologia , Humanos , Interleucinas/imunologia , Interleucinas/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Síndromes Mielodisplásicas/sangue , Síndromes Mielodisplásicas/imunologia , Síndromes Mielodisplásicas/metabolismo , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas c-vav/genética , Proteínas Proto-Oncogênicas c-vav/metabolismo , Receptores de Interleucina/genética , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/imunologia , Insuficiência Renal Crônica/metabolismo , Transdução de Sinais , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo
7.
Mediators Inflamm ; 2021: 2605973, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33564275

RESUMO

Background: Liver macrophages play an important regulatory role in the inflammatory response of liver injury after severe infection. Interleukin- (IL-) 27 is an inflammatory cytokine that plays an important role in diseases caused by bacterial infection. However, the relationship between IL-27 and liver macrophages in liver injury after severe infection is not yet clear. Methods: A cecal ligation puncture (CLP) model was established in wild-type (WT) and IL-27 receptor- (WSX-1-) deficient (IL-27r-/-) mice, and recombinant IL-27 and gadolinium chloride (GdCl3) were injected into WT mice in the designated groups. The serum and liver IL-27, IL-6, tumor necrosis factor alpha (TNF-α), and IL-1ß expression levels were evaluated by ELISA, quantitative PCR, or Western blotting; serum ALT and AST were detected by detection kits; and the severity of liver damage was evaluated by hematoxylin and eosin staining and the TUNEL assay of the liver tissue from the different groups. Liver macrophage polarization was evaluated by immunofluorescence. In addition, the polarization of peritoneal macrophage was evaluated by flow cytometry. Results: The serum and liver IL-27 expression levels were elevated in WT mice after CLP-induced severe infection, which were consistent with the changes in HE scores in the liver tissue. The levels of serum ALT, AST, liver IL-6, TNF-α, and IL-1ß mRNA and liver pathological injury scores were further increased when pretreated with recombinant IL-27 in WT mice, but these levels were decreased in IL-27r-/- mice after CLP-induced severe infection compared to WT mice. In WT mice pretreated with GdCl3, liver pathological scores, serum ALT and AST, TUNEL-positive cell proportion from liver tissues, liver IL-27 expression, and the liver macrophages M1 polarization proportion decreased after CLP; however, the serum IL-27, IL-6, TNF-α, and IL-1ß levels and the pathological lung and kidney scores were not significantly changed. When supplemented with exogenous IL-27, the liver pathological scores, serum ALT, AST, TUNEL-positive cell proportion of liver tissues, liver IL-27 expression, and the liver macrophage M1 polarization proportion increased. The in vitro, IL-27 expression increased in peritoneal macrophages when stimulated with LPS. Recombinant IL-27 together with LPS promoted the elevations in IL-6, TNF-α, and IL-1ß levels in supernatant and the M1 polarization of peritoneal macrophages. Conclusion: IL-27 is an important cytokine in the inflammatory response to liver injury after severe infection. The reduction of liver injury by gadolinium chloride in severe infection mice models may relate to the inhibition of liver IL-27 production. These changes may be mainly related to the decrease of liver macrophages M1 polarization. IL-27 may have a positive feedback on these macrophages.


Assuntos
Gadolínio , Interleucinas/metabolismo , Fígado/lesões , Animais , Apoptose , Meios de Contraste , Citocinas/metabolismo , Inflamação , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Interleucinas/antagonistas & inibidores , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Recombinantes/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Ferimentos e Lesões
8.
PLoS One ; 16(2): e0246630, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33539470

RESUMO

Interleukin-31 (IL-31) is involved in excessive development of cutaneous sensory nerves in atopic dermatitis (AD), leading to severe pruritus. We previously reported that PQA-18, a prenylated quinolinecarboxylic acid (PQA) derivative, is an immunosuppressant with inhibition of p21-activated kinase 2 (PAK2) and improves skin lesions in Nc/Nga mice as an AD model. In the present study, we investigate the effect of PQA-18 on sensory nerves in lesional skin. PQA-18 alleviates cutaneous nerve fiber density in the skin of Nc/Nga mice. PQA-18 also inhibits IL-31-induced sensory nerve fiber outgrowth in dorsal root ganglion cultures. Signaling analysis reveals that PQA-18 suppresses phosphorylation of PAK2, Janus kinase 2, and signal transducer and activator of transcription 3 (STAT3), activated by IL-31 receptor (IL-31R), resulting in inhibition of neurite outgrowth in Neuro2A cells. Gene silencing analysis for PAK2 confirms the requirement for STAT3 phosphorylation and neurite outgrowth elicited by IL-31R activation. LC/MS/MS analysis reveals that PQA-18 prevents the formation of PAK2 activation complexes induced by IL-31R activation. These results suggest that PQA-18 inhibits the IL-31 pathway through suppressing PAK2 activity, which suppresses sensory nerve outgrowth. PQA-18 may be a valuable lead for the development of a novel drug for pruritus of AD.


Assuntos
Ácidos Carboxílicos/farmacologia , Dermatite Atópica/tratamento farmacológico , Interleucinas/antagonistas & inibidores , Quinolinas/farmacologia , Células Receptoras Sensoriais/efeitos dos fármacos , Animais , Diferenciação Celular/efeitos dos fármacos , Dermatite Atópica/metabolismo , Gânglios Espinais/efeitos dos fármacos , Gânglios Espinais/metabolismo , Interleucinas/metabolismo , Janus Quinase 2/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fibras Nervosas/efeitos dos fármacos , Fibras Nervosas/patologia , Fatores de Crescimento Neural/metabolismo , Sistema Nervoso Periférico/efeitos dos fármacos , Sistema Nervoso Periférico/metabolismo , Prenilação de Proteína , Fator de Transcrição STAT3/metabolismo , Células Receptoras Sensoriais/metabolismo , Transdução de Sinais/efeitos dos fármacos , Pele/efeitos dos fármacos , Pele/metabolismo , Quinases Ativadas por p21/metabolismo
9.
Farm. hosp ; 45(1): 16-21, ene.-feb. 2021. tab, graf
Artigo em Espanhol | IBECS | ID: ibc-202356

RESUMO

OBJETIVO: Determinar la persistencia del tratamiento con secukinumab en sus diferentes indicaciones. MÉTODO: Estudio descriptivo, observacional, retrospectivo donde se incluyeron los pacientes adultos tratados con secukinumab en sus diferentes indicaciones desde su comercialización en noviembre de 2015 hasta octubre de 2019. Las variables recogidas fueron sexo, edad, diagnóstico, fecha de inicio, línea de tratamiento, número de pacientes que habían suspendido el tratamiento y motivo de suspensión, persistencia global a los 12 meses, distribución de pacientes y persistencia según indicación, línea de tratamiento y motivo de suspensión. RESULTADOS: Han sido tratados con secukinumab 143 pacientes, de los que 104 llevaban en tratamiento 12 o más meses. La media de edad fue 49,8 ± 12,6 años; 52,9% fueron hombres. Suspendieron el tratamiento 56 pacientes (53,8%) con una media de duración del mismo de 12,7 ± 10,2 meses. El resto (n = 48) continuaban con una media de duración de 25,7 ± 9,9 meses en el momento del corte del estudio. La persistencia global a los 12 meses fue de 10,0 ± 3,3 meses con una tasa de discontinuación a los 12 meses del 31,7%. La persistencia por patología a los 12 meses fue 10,7 ± 2,9 para los pacientes con psoriasis, 9,7 ± 3,4 meses para los pacientes con artritis psoriásica y 8,8 ± 3,8 para los pacientes con espondilitis anquilosante. De los 48 pacientes que continuaban en tratamiento, 22 (45,8%) están recibiendo el fármaco en primera línea. De los 56 pacientes que discontinuaron, 15 (26,8%) lo hicieron por fallo primario (persistencia 3,8 ± 1,1 meses) y 27 (48,2%) por fallo secundario (persistencia 18,6 ± 9,6 meses). La persistenciaen los pacientes que continuaban en tratamiento fue superior en psoriasis (28,8 ± 10,3 meses) y en los que suspendieron por fallo secundario fue superior en espondilitis anquilosante (28,0 ± 4,2 meses). En los pacientes de primera línea, la persistencia fue inferior al resto, siendo 21,2 ± 7,2 meses, 3,5 ± 0,5 meses y 8,3 ± 2,5 meses, si continuaban en tratamiento, presentaron fallo primario o fallo secundario, respectivamente. CONCLUSIONES: Nuestros datos muestran una persistencia ligeramente superior en pacientes con psoriasis y una menor tasa de discontinuación en aquellos pacientes sin exposición previa a un tratamiento biológico. Se necesitan estudios a largo plazo que lo confirmen y conocer los factores que pueden influir en la persistencia del secukinumab


OBJECTIVE: To determine persistence of treatment with secukinumab across its different indications. METHOD: This is a retrospective descriptive observational study including adult patients treated with secukinumab in its different indications from the drug's introduction in November 2015 to October 2019. The variables included were sex; age; diagnosis; initiation date; line of treatment; number of patients who discontinued treatment and reason for discontinuation; overall persistence at 12 months; distribution of patients; and persistence according to indication, line of treatment and reason for suspension. RESULTS: One-hundred forty-three patients were started on secukinumab, but only patients who had been in treatment at least 12 months before the end of the study were included. Mean patient age was 49.8 years (±12.6); 52.9% were men. Fifty-six patients (53.8%) had discontinued treatment by the end of the study, with a mean duration of treatment of 12.7 months (±10.2). The other patients (n = 48) continued with their therapy. Mean duration of treatment in these patients was 25.7 months (±9.9). Overall persistence at 12 months was 10.0 months (±3.3) with a discontinuation rate at 12 months of 31.7%. Persistence at 12 months was 10.7 months (±2.9) for patients with psoriasis, 9.7 months (±3.4) for patients with psoriatic arthritis, and 8.8 months (±3.8) for those with ankylosing spondylitis. Of the 48 patients who continued with their treatment after completion of the study, 22 (45.8%) received the drug as first-line treatment. Of the 56 discontinuations, 15 (26.8%) were due to primary failure (persistence: 3.8 months [±1.1]) and 27 (48.2%) were due to secondary failure (persistence: 18.6 months [±9.6]). Persistence in patients who continued treatment was higher in psoriasis (28.8 months [±10.3]). In those who discontinued due to secondary failure it was higher in the group with ankylosing spondylitis (28.0 months [±4.2]). Persistence among patients on first-line secukinumab was higher than for other patients: 21.2 months (±7.2) if they stayed on treatment, 3.5 months (±0.5) if they presented with primary treatment failure, and 8.3 months (±2.5) in those with secondary treatment failure. CONCLUSIONS: Our data show slightly higher persistence levels in patients with psoriasis and lower discontinuation rates in those without previous exposure to biological therapy. Long-term studies are needed to confirm these findings and to gain a better understanding of the factors that can influence persistence of secukinumab


Assuntos
Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Psoríase/tratamento farmacológico , Artrite Psoriásica/tratamento farmacológico , Espondilite Anquilosante/tratamento farmacológico , Produtos Biológicos/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Estudos Retrospectivos , Terapia Biológica/métodos , Adesão à Medicação/estatística & dados numéricos , Interleucinas/antagonistas & inibidores
10.
PLoS One ; 16(1): e0245340, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33428678

RESUMO

INTRODUCTION: Interleukin-34 (IL-34) shares a receptor (cFMS) with colony stimulating factor-1 (CSF-1), and these two ligands mediate macrophage proliferation. However, in contrast to CSF-1, the influence of IL-34 on tubular epithelial cells (TECs) injury remains unclear. We investigated the physiological effects of IL-34 on TEC damage caused by cisplatin nephrotoxicity (CP-N). METHODS: Mice were administered anti-mouse IL-34 antibody (anti-IL-34 Ab; 400 ng/kg) or vehicle from 1 day before and up to 2 days after CP-N induction. In vitro, mouse renal proximal TECs (MRPTEpiC) were cultured to analyze the inhibitory effects of IL-34 on CP-induced TEC apoptosis. RESULTS: Compared to vehicle treatment, anti-IL-34 Ab treatment significantly suppressed the intra-renal expression of IL-34 and its two receptors, cFMS and PTP-ζ, and significantly improved renal function, ameliorated tubulointerstitial injury, suppressed macrophage infiltration, and reduced apoptotic cell numbers in CP-N mice. It also significantly reduced the renal transcript levels of Kim-1, MIP-1/CCL3, TNF-α, and Bax in CP-N mice. Furthermore, anti-IL-34 Ab-treated CP-N mice showed less renal infiltration of F4/80+TNF-α+ cells. In vitro, stimulation with CP induced the expression of IL-34 and its two receptors in MRPTEpiC. Anti-IL-34 Ab treatment significantly suppressed CP-induced Bax expression with the degradation of ERK1/2 phosphorylation in damaged MRPTEpiC. CONCLUSIONS: IL-34 secreted from damaged TECs appeared to be involved in the progression of CP-N. Inhibition of IL-34 with neutralizing antibody directly prevented CP-induced TEC apoptosis by inhibiting the phosphorylation of ERK 1/2. Blocking of IL-34 appears to suppress the proliferation of cytotoxic macrophages, which indirectly attenuates CP-N. Thus, IL-34 represents a potential therapeutic target for TEC injury, and the inhibition of IL-34 might have a reno-protective effect.


Assuntos
Anticorpos/uso terapêutico , Antineoplásicos/efeitos adversos , Cisplatino/efeitos adversos , Interleucinas/antagonistas & inibidores , Nefropatias/induzido quimicamente , Nefropatias/prevenção & controle , Substâncias Protetoras/uso terapêutico , Animais , Apoptose/efeitos dos fármacos , Células Cultivadas , Nefropatias/patologia , Túbulos Renais Proximais/citologia , Túbulos Renais Proximais/efeitos dos fármacos , Túbulos Renais Proximais/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL
12.
Curr Pharm Biotechnol ; 22(1): 7-31, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-32598253

RESUMO

BACKGROUND: Psoriasis is a multifactorial immune-mediated inflammatory disease, with a chronic relapsing-remitting course, which affects 2-3% of the worldwide population. Psoriasis involves skin, joints, or both, and it is associated with several comorbidities, including metabolic, rheumatological, cardiovascular, psychiatric complications, and other chronic inflammatory diseases, which are the expression of the complex underlying pathogenetic mechanism. An accurate characterization of the immune pathways involved in psoriasis led to recognize the new molecules, (IL)17 and 23, which become the new target of biologic therapy for moderate-to-severe plaque psoriasis. OBJECTIVE: The aim of this study is to collect data of literature about IL-17 and IL-23 inhibitors. METHODS: A descriptive review was conducted to identify the main data in the literature evaluating novel biologic treatments currently available: IL-17 inhibitors (secukinumab, ixekizumab and brodalumab) and IL-23 inhibitors (guselkumab, tildrakizumab and risankizumab). RESULTS: Dosing regimens, administration, efficacy, real-life efficacy and safety of IL-17 and IL-23 inhibitors are discussed in detail. CONCLUSION: Currently approved novel biologic therapies for moderate to severe psoriasis revealed increasing effectiveness compared to previous biological therapy and a good safety profile.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Fármacos Dermatológicos/uso terapêutico , Interleucina-17/antagonistas & inibidores , Interleucinas/antagonistas & inibidores , Psoríase/tratamento farmacológico , Anticorpos Monoclonais , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Fármacos Dermatológicos/administração & dosagem , Fármacos Dermatológicos/efeitos adversos , Humanos , Psoríase/imunologia , Pele/efeitos dos fármacos , Pele/imunologia , Resultado do Tratamento
13.
Front Immunol ; 11: 579000, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33162994

RESUMO

The proliferation and activation of microglia, the resident macrophages in the brain, is a hallmark of many neurodegenerative diseases such as Alzheimer's disease (AD) and prion disease. Colony stimulating factor 1 receptor (CSF1R) is critically involved in regulating microglial proliferation, and CSF1R blocking strategies have been recently used to modulate microglia in neurodegenerative diseases. However, CSF1R is broadly expressed by many cell types and the impact of its inhibition on the innate immune system is still unclear. CSF1R can be activated by two independent ligands, CSF-1 and interleukin 34 (IL-34). Recently, it has been reported that microglia development and maintenance depend on IL-34 signaling. In this study, we evaluate the inhibition of IL-34 as a novel strategy to reduce microglial proliferation in the ME7 model of prion disease. Selective inhibition of IL-34 showed no effects on peripheral macrophage populations in healthy mice, avoiding the side effects observed after CSF1R inhibition on the systemic compartment. However, we observed a reduction in microglial proliferation after IL-34 inhibition in prion-diseased mice, indicating that microglia could be more specifically targeted by reducing IL-34. Overall, our results highlight the challenges of targeting the CSF1R/IL34 axis in the systemic and central compartments, important for framing any therapeutic effort to tackle microglia/macrophage numbers during brain disease.


Assuntos
Anticorpos Monoclonais/farmacologia , Anticorpos Neutralizantes/farmacologia , Encéfalo/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Interleucinas/antagonistas & inibidores , Microglia/efeitos dos fármacos , Degeneração Neural , Doenças Priônicas/tratamento farmacológico , Animais , Anticorpos Monoclonais/toxicidade , Anticorpos Neutralizantes/toxicidade , Encéfalo/metabolismo , Encéfalo/patologia , Linhagem Celular Tumoral , Modelos Animais de Doenças , Genes fms , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Interleucinas/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microglia/metabolismo , Microglia/patologia , Doenças Priônicas/metabolismo , Doenças Priônicas/patologia , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/antagonistas & inibidores , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/metabolismo , Transdução de Sinais
14.
Int J Mol Sci ; 21(22)2020 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-33182701

RESUMO

BACKGROUND: Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease affecting areas with a high density of apocrine glands and characterized by subcutaneous nodules that may evolve into fistulas with pus secretion. METHODS: The aim of this review is to investigate all current knowledge on cytokine regulation in the pathogenesis of HS. A systematic literature research using the words "cytokine", "interleukin", "pathway", and "hidradenitis suppurativa" was performed in PubMed/Medline and Scopus/Embase databases. A search of the clinicaltrials.gov website for interventional recruiting and completed trials including the term "hidradenitis suppurativa" was also performed up to August 2020. We will discuss the pathogenetic role of various cytokines in HS and potential therapeutic targets for this debilitating disease. RESULTS: The pathophysiology underlying this complex condition has not been clearly defined. An upregulation of various cytokines, such as tumor necrosis factor alpha (TNF-α), interleukin (IL)-1, IL-17, IL-23, and other molecules seems to be related to this inflammatory condition. Various cells, such as lymphocytes T Helper 1 and 17 and keratinocytes seem to be involved in the genesis of this condition. CONCLUSIONS: Several future studies and clinical trials are necessary in order to have new knowledge about HS and to properly treat this complex condition.


Assuntos
Citocinas/imunologia , Hidradenite Supurativa/etiologia , Hidradenite Supurativa/imunologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Biofilmes/crescimento & desenvolvimento , Ensaios Clínicos como Assunto , Hidradenite Supurativa/terapia , Humanos , Fatores Imunológicos/uso terapêutico , Interleucinas/antagonistas & inibidores , Interleucinas/imunologia , Microbiota/imunologia , Modelos Imunológicos , Terapia de Alvo Molecular , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/imunologia
15.
Front Immunol ; 11: 2148, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33042126

RESUMO

Wound healing and tissue regeneration is an intricate biological process that involves repair of cellular damage and maintenance of tissue integrity. Cascades involved in wound healing and tissue regeneration highly overlap with cancer causing pathways. Usually, subsequent tissue damage events include release of a number of cytokines to accomplish post-trauma restoration. IL-22 is one of the cytokines that are immediately produced to initiate immune response against several tissue impairments. IL-22 is a fundamental mediator in inflammation, mucous production, protective role against pathogens, wound healing, and tissue regeneration. However, accumulating evidence suggests pivotal role of IL-22 in instigation of various cancers due to its pro-inflammatory and tissue repairing activity. In this review, we summarize how healing effects of IL-22, when executed in an uncontrollable fashion can lead to carcinogenesis.


Assuntos
Interleucinas/fisiologia , Neoplasias/etiologia , Regeneração/fisiologia , Cicatrização/fisiologia , Animais , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Neutralizantes/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/imunologia , Carcinogênese , Ensaios Clínicos como Assunto , Humanos , Imunidade Inata/fisiologia , Infecções/imunologia , Infecções/metabolismo , Inflamação/fisiopatologia , Interleucinas/efeitos adversos , Interleucinas/antagonistas & inibidores , Interleucinas/deficiência , Camundongos , Muco/metabolismo , Neoplasias/fisiopatologia , Psoríase/tratamento farmacológico , Psoríase/imunologia , Receptores de Interleucina/fisiologia , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo
16.
Nat Commun ; 11(1): 4611, 2020 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-32929072

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) and cancer-associated cachexia (CAC) are multifactorial and characterized by dysregulated inflammatory networks. Whether the proinflammatory cytokine IL-20 is involved in the complex networks of PDAC and CAC remains unclear. Here, we report that elevated IL-20 levels in tumor tissue correlate with poor overall survival in 72 patients with PDAC. In vivo, we establish a transgenic mouse model (KPC) and an orthotopic PDAC model and examine the therapeutic efficacy of an anti-IL-20 monoclonal antibody (7E). Targeting IL-20 not only prolongs survival and attenuates PD-L1 expression in both murine models but also inhibits tumor growth and mitigates M2-like polarization in the orthotopic PDAC model. Combination treatment with 7E and an anti-PD-1 antibody shows better efficacy in inhibiting tumor growth than either treatment alone in the orthotopic PDAC model. Finally, 7E mitigates cachexic symptoms in CAC models. Together, we conclude IL-20 is a critical mediator in PDAC progression.


Assuntos
Anticorpos Monoclonais/farmacologia , Antígeno B7-H1/metabolismo , Interleucinas/antagonistas & inibidores , Modelos Biológicos , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Animais , Linfócitos T CD8-Positivos/metabolismo , Caquexia , Carcinoma Pulmonar de Lewis/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Humanos , Interleucinas/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos Endogâmicos C57BL , Neoplasias Pancreáticas/imunologia , Análise de Sobrevida , Resultado do Tratamento , Triglicerídeos/sangue , Regulação para Cima/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
17.
Front Immunol ; 11: 1085, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32655552

RESUMO

In many infectious diseases, the immune response operates as a double-edged sword. While required for protective immunity, infection-induced inflammation can be detrimental if it is not properly controlled, causing collateral body damage and potentially leading to death. It is in this context that the potent anti-inflammatory cytokine interleukin-10 (IL-10) is required to dampen the pro-inflammatory immune response that hallmarks trypanosomosis. Effective control of this infection requires not just the action of antibodies specific for the parasite's variable surface glycoprotein (VSG) coat antigens, but also a pro-inflammatory immune response mediated mainly by IFNγ, TNF, and NO. However, strict control of inflammation is mandatory, as IL-10-deficient mice succumb from an unrestrained cytokine storm within 10 days of a Trypanosome brucei infection. The relevant cellular source of IL-10 and the associated molecular mechanisms implicated in its trypanosomosis associated production are poorly understood. Using an IL-10 reporter mouse strain (Vert-X), we demonstrate here that NK cells, CD8+ T cells and CD4+ T cells as well as B cells and plasma cells constitute potential cellular sources of IL-10 within the spleen and liver during acute infection. The IL-10 wave follows peak pro-inflammatory cytokine production, which accompanied the control of peak parasitemia. Similar results were observed following conventional experimental needle infection and physiological infections via T. brucei-infected tsetse flies. Our results show that conditional T cell-specific ablation of the IL-10 regulating Prdm1 gene (encoding for the Blimp-1 transcription factor), leads to an uncontrolled trypanosome-induced pro-inflammatory syndrome like the one observed in infected IL-10-deficient mice. This result indicates that the biological role of IL-10-derived from non-T cells, including NK cells, is of minor importance when considering host survival. The cytokine IL-27 that is also considered to be an IL-10 regulator, did not affect IL-10 production during infection. Together, these data suggest that T. brucei activates a Blimp-1-dependent IL-10 regulatory pathway in T cells that acts as a critical anti-inflammatory rheostat, mandatory for host survival during the acute phase of parasitemia.


Assuntos
Síndrome da Liberação de Citocina/prevenção & controle , Interleucina-10/biossíntese , Fator 1 de Ligação ao Domínio I Regulador Positivo/imunologia , Linfócitos T/imunologia , Trypanosoma brucei brucei , Tripanossomíase Africana/imunologia , Animais , Síndrome da Liberação de Citocina/etiologia , Síndrome da Liberação de Citocina/imunologia , Modelos Animais de Doenças , Feminino , Inflamação/etiologia , Inflamação/imunologia , Inflamação/prevenção & controle , Insetos Vetores/parasitologia , Interleucina-10/deficiência , Interleucina-10/genética , Interleucinas/antagonistas & inibidores , Interleucinas/deficiência , Interleucinas/imunologia , Fígado/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fator 1 de Ligação ao Domínio I Regulador Positivo/deficiência , Fator 1 de Ligação ao Domínio I Regulador Positivo/genética , Baço/imunologia , Tripanossomíase Africana/complicações , Tripanossomíase Africana/parasitologia , Moscas Tsé-Tsé/parasitologia
18.
Aging (Albany NY) ; 12(13): 13354-13364, 2020 07 10.
Artigo em Inglês | MEDLINE | ID: mdl-32649314

RESUMO

Increased interleukin-22 (IL-22) level was reported to associate with progression of breast cancer. Regulation of IL-22 in breast cancer still needs to be elucidated. We assessed the effect of giving IL-22 in tumor growth of mice inoculated with 4T1, MCF7 and MDA-MB-231 breast cancer cells. IL-22-producing cells were analyzed in tumor tissues. We also analyzed the impact of giving IL-1ß and IL-23 on IL-22 levels in tumor tissues. Giving exogenous IL-22 increased tumor size and intra-tumor Ki-67-positive cells in vivo. IL-22 increased phosphorylated STAT3 level and proliferation of breast cancer cells in vitro, an effect blocked by a STAT3-inhibitor stattic. Endogenous IL-22 mRNA level was up-regulated in tumor tissue, compared with normal mammary tissue. Innate lymphoid cell group 3 (ILC3) is a major producer of IL-22 in 4T1 tumor. Giving IL-1ß and/or IL-23 increased cell proliferation in 4T1 tumor, which was reversed by concurrent use of an IL-22 neutralization antibody. IL-1ß and IL-23 increased levels of IL-22 mRNA and IL-22-producing ILC3 in 4T1 tumor. Our findings suggest a mechanism for how IL-22 regulates tumor growth in breast cancer, and indicate blocking IL-22 function might reduce IL-1ß- and IL-23-induced tumor progression of breast cancer.


Assuntos
Neoplasias da Mama/patologia , Imunidade Inata , Interleucinas/metabolismo , Animais , Mama/imunologia , Mama/patologia , Neoplasias da Mama/imunologia , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Progressão da Doença , Feminino , Humanos , Interleucina-1beta/administração & dosagem , Interleucina-1beta/metabolismo , Interleucina-23/metabolismo , Interleucinas/administração & dosagem , Interleucinas/antagonistas & inibidores , Subpopulações de Linfócitos/imunologia , Subpopulações de Linfócitos/metabolismo , Células MCF-7 , Camundongos , Proteínas Recombinantes/administração & dosagem , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Microambiente Tumoral/imunologia , Regulação para Cima , Ensaios Antitumorais Modelo de Xenoenxerto
19.
Brasília; s.n; 25 jul. 2020.
Não convencional em Português | LILACS, BRISA/RedTESA, PIE | ID: biblio-1117709

RESUMO

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 13 artigos e 8 protocolos.


Assuntos
Humanos , Pneumonia Viral/tratamento farmacológico , Infecções por Coronavirus/tratamento farmacológico , Betacoronavirus/efeitos dos fármacos , Antivirais/uso terapêutico , Avaliação da Tecnologia Biomédica , Imunoglobulinas/uso terapêutico , Estudos Transversais , Estudos de Coortes , Interleucinas/antagonistas & inibidores , Corticosteroides/uso terapêutico , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Leflunomida/uso terapêutico , Hidroxicloroquina/uso terapêutico , Imunossupressores/uso terapêutico , Antibacterianos/uso terapêutico , Antifúngicos/uso terapêutico , Bloqueadores Neuromusculares/uso terapêutico
20.
Brasília; CONITEC; jul. 2020.
Não convencional em Português | BRISA/RedTESA | ID: biblio-1121202

RESUMO

INTRODUÇÃO: A artrite psoriaca (AP), doenca articular inflamatoria associada a psoriase, pertencente ao grupo das espondiloartrites, reune manifestacoes cutaneas e articulares. Tem uma prevalencia de aproximadamente 1 a 2 por 1.000 na populacao em geral. Cerca de 30% dos pacientes com psoriase desenvolvem AP. No exame fisico, estao presentes dor oriunda do estresse, sensibilidade das linhas articulares e derrames nas articulacoes afetadas, geralmente em uma distribuicao assimetrica. O tratamento preconizado no Protocolo Clinico e Diretrizes Terapeuticas de Artrite Psoriaca e disponivel no SUS e a base de anti-inflamatorios nao esteroidais, glicocorticoides, medicamentos modificadores do curso da doenca (MMCD) sinteticos e biologicos e Inibidor de citocinas anti-interleucina (IL)-17. TECNOLOGIA: Citrato de tofacitinibe (XeljanzR). PERGUNTA: Tofacitinibe e eficaz e seguro para o tratamento da artrite psoriaca ativa moderada a grave em pacientes adultos que nao responderam ou sao intolerantes ao tratamento previo com MMCD sinteticos ou biologicos? EVIDÊNCIAS CIENTÍFICAS: Foram selecionados dois estudos fase III, ensaios clinicos randomizados avaliando eficacia e seguranca do tofacitinibe em pacientes tratados previamente com medicamentos modificadores da doenca sinteticos e anti-TNF. No estudo com pacientes tratados previamente com anti-TNF, ACR50 em 3 meses foi de 15% para placebo, 30% para tofacitinibe de 5mg( p = 0,003), e 28% para tofacitinibe de 10 mg (p = 0,007). Ja no estudo de pacientes tratados previamente com MMCD sinteticos em 3 meses as taxas de resposta foram 10% para placebo, 30 % para tofacitinibe 5mg e 42% para tofacitinibe 10 mg (p < 0,001 para as duas comparacoes. AVALIAÇÃO ECONÔMICA: Foi apresentada uma analise de custo-miniminizacao, uma vez que os estudos de comparacao indireta do tofacitinibe com seus comparadores demonstraram efetividade semelhante. O custo anual do tratamento por paciente, considerando-se apenas o preco do tofacitinibe proposto pelo demandante, foi de R$ 11.074,10. Em relacao aos seus comparadores, se incorporado, pode gerar uma reducao de custos que variou de -R$ 1.336,74 (em relacao ao Adalimumabe) a -R$ 14.940,94 (em relacao ao Imfliximabe). AVALIAÇÃO DE IMPACTO ORÇAMENTÁRIO: Em todos os cenarios propostos o uso do tofacitinibe gerou economia de recursos. O impacto orcamentario do tofacitinibe ao custo proposto pelo demandante em 1 ano foi de ­R$ 41,4 milhoes , variando nos cenarios entre ­R$ 9,1 milhoes a ­R$ 64,1 milhoes e em 5 anos foi de ­R$ 240,6 milhoes variando nos cenarios entre ­R$ 52,8 milhoes a ­R$ 372,1 milhoes. A estimativa da populacao pelo metodo demanda aferida contemplou toda populacao com AP, e nao apenas a populacao com AP moderada a grave, fazendo com que estes valores estejam superestimados. MONITORAMENTO DO HORIZONTE TECNOLÓGICO: Foram detectadas no horizonte seis potenciais tecnologias para o tratamento de pacientes com artrite psoriaca ativa moderada a grave com resposta inadequada ou intolerantes ao tratamento previo com MMCD sinteticos ou biológicos. CONSIDERAÇÕES: O citrato de tofacitinibe e uma tecnologia ja incorporada no SUS para outras indicacoes. As poucas evidencias cientificas disponiveis, possivelmente em virtude do recente registro desta nova indicacao junto as agencias reguladoras, e que atenderam a pergunta estruturada aqui proposta, demonstraram que o medicamento possui eficacia semelhante aos MMCD biologicos a um custo inferior. Sua administracao por via oral favorece a adesao ao tratamento na maioria dos casos, alem de reduzir custos anuais de tratamento. Deve ser usado em associacao aos MMCD sinteticos. A evidencia atualmente disponivel sobre eficacia e seguranca do tofacitinibe para tratamento de artrite psoriaca e baseada em apenas 2 ensaios clinicos randomizados, estudos fase III, com risco de vies incerto e grau de recomendacao fraco a favor da tecnologia. RECOMENDAÇÃO PRELIMINAR DA CONITEC: Os membros do plenario presentes na 85a reunião ordinaria, realizada nos dias 04 e 05 de fevereiro de 2020, indicaram que o tema fosse submetido a consulta publica com recomendacao preliminar favoravel a incorporacao ao SUS de tofacitinibe para tratamento de artrite psoriaca ativa moderada a grave em pacientes adultos que nao respondem ou sao intolerantes ao tratamento previo com medicamentos modificadores do curso da doenca (MMCD) sinteticos ou biologicos. Considerou-se que as evidencias apresentadas demonstram que o tofacitinibe possui eficacia semelhante aos medicamentos ja disponiveis no SUS, alem de ser um medicamento oral, o que poderia favorecer a adesao ao tratamento. Alem disso, a sua incorporacao geraria economia de recursos em cenarios que contemplam os demais medicamentos biologicos atualmente incorporados ao SUS para a mesma condicao clinica. A materia foi disponibilizada em consulta publica. CONSULTA PÚBLICA: Houve 103 contribuicoes, 18 tecnico-cientificas e 85 de experiencia ou opiniao, sobre a recomendacao preliminar da Conitec. Apenas 2 contribuicoes foram contrarias, porem sem nenhuma argumentacao. Nao foram adicionadas referencias que alterassem as analises da evidencia. RECOMENDAÇÃO FINAL: Os membros da Conitec presentes na 88a reuniao ordinaria, no dia 07 de julho de 2020, deliberaram por unanimidade, recomendar a incorporacao do citrato de tofacitinibe para o tratamento de pacientes adultos com artrite psoriaca ativa moderada a grave intolerantes ou com falha terapeutica aos medicamentos modificadores do curso da doença sinteticos ou biologicos, conforme o Protocolo Clinico e Diretrizes Terapeuticas do Ministerio da Saude. Foi assinado o Registro de Deliberacao no 529/2020. DECISÃO: incorporar o citrato de tofacitinibe para o tratamento de pacientes adultos com artrite psoriaca ativa moderada a grave intolerantes ou com falha terapeutica aos medicamentos modificadores do curso da doenca sinteticos ou biologicos, conforme o Protocolo Clinico e Diretrizes Terapeuticas do Ministerio da Saude, no ambito do Sistema Unico de Saude - SUS, conforme Portaria no 28, publicada no Diario Oficial da Uniao no 160, secao 1, pagina 117, em 20 de agosto de 2020.


Assuntos
Humanos , Artrite Psoriásica/tratamento farmacológico , Anti-Inflamatórios não Esteroides/efeitos adversos , Interleucinas/antagonistas & inibidores , Antirreumáticos/efeitos adversos , Janus Quinases/antagonistas & inibidores , Glucocorticoides/efeitos adversos , Avaliação da Tecnologia Biomédica , Sistema Único de Saúde , Brasil , Análise Custo-Benefício/economia
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