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1.
Eur Cytokine Netw ; 32(1): 8-14, 2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-34346869

RESUMO

Cytokine release syndrome is a serious complication of the new coronavirus infection (COVID-19). The aim of the study was to assess effectiveness and safety of the IL-17 antagonist nekatimab for its treatment. The retrospective study included COVID-19 patients with C-reactive protein levels >60 mg/L. Patients received either netakimab (group NET), IL-6 antagonist tocilizumab (group TOC) or no anti-cytokine treatment (group CON). Forty-four patients were enrolled in the NET group, 27 patients in the TOC group, and 47 patients in the CON group. Mortality was lower in the NET group than in TOC and CON groups (2.3% vs. 14.8% and 31.9%; p = 0.018 and p < 0.001). NET group patients required intensive care unit admission (6.8% vs. 25.9% and 46.3%; p = 0.025 and p < 0.001) and mechanical ventilation (4.6% vs. 22.2% and 31.9%; p = 0.022 and p = 0.002) less frequently than patients of the TOC and CON groups. After 7-10 days of anti-cytokine drug administration, a reduction in lung lesion volume (p = 0.016) and an increase in the proportion of patients who did not need oxygen support (p = 0.005) or stayed in prone position (p = 0.044) was observed in the NET group only group; C-reactive protein levels were the same in the TOC and NET groups (p = 0.136) and lower in the CON group (p < 0.001 and p = 0.005). IL-6 levels decreased in the NET group (p = 0.005) and did not change in the TOC group (p = 0.953). There was no difference in the incidence of side effects between groups. The IL-17 antagonist netakimab is effective and safe in the treatment of cytokine release syndrome in COVID-19.


Assuntos
Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/uso terapêutico , COVID-19/tratamento farmacológico , Interleucina-17/antagonistas & inibidores , Proteína C-Reativa/metabolismo , COVID-19/sangue , COVID-19/virologia , Estudos de Casos e Controles , Humanos , Interleucina-17/metabolismo , Interleucina-6/sangue , Pulmão/patologia , Pulmão/virologia , SARS-CoV-2/fisiologia , Resultado do Tratamento
2.
Int J Mol Sci ; 22(14)2021 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-34299314

RESUMO

Signal transducer and activator of transcription 1 (STAT1) acts as a tumor suppressor molecule in colitis-associated colorectal cancer (CAC), particularly during the very early stages, modulating immune responses and controlling mechanisms such as apoptosis and cell proliferation. Previously, using an experimental model of CAC, we reported increased intestinal cell proliferation and faster tumor development, which were consistent with more signs of disease and damage, and reduced survival in STAT1-/- mice, compared with WT counterparts. However, the mechanisms through which STAT1 might prevent colorectal cancer progression preceded by chronic inflammation are still unclear. Here, we demonstrate that increased tumorigenicity related to STAT1 deficiency could be suppressed by IL-17 neutralization. The blockade of IL-17 in STAT1-/- mice reduced the accumulation of CD11b+Ly6ClowLy6G+ cells resembling granulocytic myeloid-derived suppressor cells (MDSCs) in both spleen and circulation. Additionally, IL-17 blockade reduced the recruitment of neutrophils into intestinal tissue, the expression and production of inflammatory cytokines, and the expression of intestinal STAT3. In addition, the anti-IL-17 treatment also reduced the expression of Arginase-1 and inducible nitric oxide synthase (iNOS) in the colon, both associated with the main suppressive activity of MDSCs. Thus, a lack of STAT1 signaling induces a significant change in the colonic microenvironment that supports inflammation and tumor formation. Anti-IL-17 treatment throughout the initial stages of CAC related to STAT1 deficiency abrogates the tumor formation possibly caused by myeloid cells.


Assuntos
Neoplasias Associadas a Colite/etiologia , Granulócitos/patologia , Interleucina-17/fisiologia , Fator de Transcrição STAT1/fisiologia , Animais , Anticorpos Neutralizantes/administração & dosagem , Neoplasias Associadas a Colite/patologia , Neoplasias Associadas a Colite/fisiopatologia , Progressão da Doença , Feminino , Granulócitos/imunologia , Interleucina-17/antagonistas & inibidores , Interleucina-17/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Células Supressoras Mieloides/imunologia , Células Supressoras Mieloides/patologia , Neoplasias Experimentais/etiologia , Neoplasias Experimentais/patologia , Neoplasias Experimentais/fisiopatologia , Fator de Transcrição STAT1/deficiência , Fator de Transcrição STAT1/genética , Microambiente Tumoral/imunologia
3.
Cytokine ; 146: 155627, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34237556

RESUMO

BACKGROUND: One of the main pathophysiological mechanisms underlying the severe course of COVID-19 is the hyper-inflammatory syndrome associated with progressive damage of lung tissue and multi-organ dysfunction. IL-17 has been suggested to be involved in hyper-inflammatory syndrome. OBJECTIVE: To evaluate the efficacy and safety of the IL-17 inhibitor netakimab in patients with severe COVID-19. STUDY DESIGN: In our retrospective case-control study we evaluated the efficacy of netakimab in hospitalized patients with severe COVID-19 outside the intensive care unit (ICU). Patients in the experimental group were treated with standard of care therapy and netakimab at a dose of 120 mg subcutaneously. RESULTS: 171 patients with severe COVID-19 were enrolled in our study, and 88 of them received netakimab. On the 3 day of therapy, body temperature, SpO2/FiO2, NEWS2 score, and CRP improved significantly in the netakimab group compared to the control group. Other clinical outcomes such as transfer to ICU (11.4% vs 9.6%), need for mechanical ventilation (10.2% vs 9.6%), 28-day mortality (10.2% vs 8.4%), did not differ between the groups. CONCLUSION: In hospitalized patients with severe COVID-19, anti-IL-17 therapy might mitigate the inflammatory response and improve oxygenation, but do not affect the need for mechanical ventilation and mortality.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , COVID-19/terapia , Hospitalização/estatística & dados numéricos , Pacientes Internados/estatística & dados numéricos , Interleucina-17/antagonistas & inibidores , SARS-CoV-2/efeitos dos fármacos , Idoso , Anticorpos Monoclonais Humanizados/efeitos adversos , COVID-19/complicações , COVID-19/virologia , Estudos de Casos e Controles , Diarreia/induzido quimicamente , Dispneia/induzido quimicamente , Feminino , Humanos , Inflamação/complicações , Inflamação/tratamento farmacológico , Interleucina-17/imunologia , Interleucina-17/metabolismo , Tempo de Internação/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Respiração Artificial , Estudos Retrospectivos , SARS-CoV-2/fisiologia , Índice de Gravidade de Doença , Resultado do Tratamento
4.
J Med Chem ; 64(12): 8354-8383, 2021 06 24.
Artigo em Inglês | MEDLINE | ID: mdl-34100601

RESUMO

Interleukin 17 (IL-17) cytokines promote inflammatory pathophysiology in many autoimmune diseases, including psoriasis, multiple sclerosis, rheumatoid arthritis, and inflammatory bowel disease. Such broad involvement of IL-17 in various autoimmune diseases makes it an ideal target for drug discovery. Psoriasis is a chronic inflammatory disease characterized by numerous defective components of the immune system. Significantly higher levels of IL-17A have been noticed in lesions of psoriatic patients, if compared to non-lesion parts. Therefore, this paper is focused on the macrolide inspired macrocycles as potential IL-17A/IL-17RA modulators and covers the molecular design, synthesis, and in vitro profiling. Macrocycles are designed to diversify and enrich chemical space through different ring sizes and a variety of three-dimensional shapes. Inhibitors in the nM range were identified in both target-based and phenotypic assays. In vitro ADME as well as in vivo PK properties are reported.


Assuntos
Anti-Inflamatórios/farmacologia , Interleucina-17/antagonistas & inibidores , Compostos Macrocíclicos/farmacologia , Ligação Proteica/efeitos dos fármacos , Receptores de Interleucina-17/antagonistas & inibidores , Animais , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/metabolismo , Humanos , Interleucina-17/metabolismo , Compostos Macrocíclicos/síntese química , Compostos Macrocíclicos/metabolismo , Masculino , Camundongos , Simulação de Acoplamento Molecular , Estrutura Molecular , Receptores de Interleucina-17/metabolismo , Relação Estrutura-Atividade , Células THP-1
5.
Front Immunol ; 12: 622770, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34149686

RESUMO

The term spondyloarthritis (SpA) encompasses a heterogeneous group of inflammatory musculoskeletal diseases with several common genetic background and clinical features, including the possible involvement of the axial skeleton with peripheral mono- or oligo- arthritis and frequently coexisting skin, eye and intestinal manifestations. When the sacroiliac joints or other parts of the spine or thoracic wall are predominantly affected at magnetic resonance or X-ray imaging with inflammatory back pain, the disease is classified as axial SpA and the therapeutic choices are significantly different compared to cases of peripheral arthritis. Moving from the narrow effectiveness and safety profiles of non-steroidal anti-inflammatory drugs, there has been a significant research effort aimed at identifying new treatments based on our better understanding of the pathogenesis of SpA. Indeed, in parallel with the solid data demonstrating that IL-17 and IL-23 are key cytokines in the development of enthesitis and spondylitis, monoclonal antibodies interfering with this pathway have been developed for the treatment of axial SpA. Furthermore, the IL-17/IL-23 axis is key to extra-articular manifestations such as inflammatory bowel disease, uveitis, and psoriasis which are frequent comorbidities of SpA. Currently available drugs act through these mechanisms recognizing IL-23 and targeting IL-17, such as secukinumab and ixekizumab. These therapeutic approaches are now envisioned in the international treatment recommendations for psoriatic arthritis with an axial phenotype as well as for ankylosing spondylitis (AS). We will provide herein a concise comprehensive overview of the clinical evidence supporting the use of these and other drugs acting on IL-23 and IL-17 in axial SpA.


Assuntos
Anti-Inflamatórios/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Ensaios Clínicos como Assunto , Interleucina-17/antagonistas & inibidores , Subunidade p19 da Interleucina-23/antagonistas & inibidores , Espondilartrite/tratamento farmacológico , Anti-Inflamatórios/efeitos adversos , Anticorpos Monoclonais/efeitos adversos , Medicina Baseada em Evidências , Humanos , Interleucina-17/metabolismo , Subunidade p19 da Interleucina-23/metabolismo , Transdução de Sinais , Espondilartrite/diagnóstico , Espondilartrite/imunologia , Espondilartrite/metabolismo , Resultado do Tratamento
6.
J Orthop Surg (Hong Kong) ; 29(2): 23094990211012286, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33938296

RESUMO

OBJECTIVES: The patient of severe psoriatic arthritis (PsA) is mainly treated with oral methotrexate, ciclosporin, and anti-tumor necrosis factor-alpha inhibitors (TNFi). Recently, anti-interleukin-17A inhibitors (IL-17Ai) have been used in the treatment of PsA. This study aimed to evaluate the efficacy and safety of IL-17Ai in Japanese patients with PsA compared with those of TNFi. METHODS: This was a longitudinal and retrospective study. The study population included 31 Japanese patients with PsA. All enrolled patients fulfilled the Classification Criteria for Psoriatic Arthritis. All patients were treated with TNFi or IL-17Ai. The assessed clinical manifestations were C-reactive protein (CRP)-based Disease Activity Score in 28 Joints (DAS28-CRP), disease activity in psoriatic arthritis (DAPSA), 20% achievement of American College of Rheumatology core set, swollen joint count (SJC), tender joint count (TJC), and visual analog scale (VAS). Functional ability of patients with PsA was analyzed using the modified health assessment questionnaire (mHAQ) score. We evaluated the parameters at baseline and weeks 12, 24, and 52. RESULTS: The change in SJC, TJC, VAS, mHAQ, and DAPSA had no significant difference at weeks 12, 24, and 52. The improvements of CRP and DAS28-CRP were significantly higher in TNFi group only at week 12. The biologics retention rate was significantly higher in TNFi group by the log-rank test. No critical adverse events occurred. CONCLUSIONS: Our study presented that IL-17Ai had treatment effects comparable to TNFi. IL-17Ai might have the potential to become an alternative to the previous drug, but more large-scale studies are expected.


Assuntos
Antirreumáticos/uso terapêutico , Artrite Psoriásica/tratamento farmacológico , Interleucina-17/antagonistas & inibidores , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Adulto , Anticorpos Monoclonais/uso terapêutico , Artrite Psoriásica/sangue , Artrite Psoriásica/diagnóstico , Feminino , Humanos , Japão , Estudos Longitudinais , Masculino , Metotrexato/uso terapêutico , Pessoa de Meia-Idade , Indução de Remissão , Estudos Retrospectivos , Resultado do Tratamento
7.
N Engl J Med ; 385(2): 130-141, 2021 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-33891379

RESUMO

BACKGROUND: Bimekizumab is a monoclonal IgG1 antibody that selectively inhibits interleukin-17A and interleukin-17F. The efficacy and safety of bimekizumab as compared with the tumor necrosis factor inhibitor adalimumab in patients with moderate-to-severe plaque psoriasis have not been extensively examined. METHODS: We randomly assigned patients with moderate-to-severe plaque psoriasis in a 1:1:1 ratio to receive subcutaneous bimekizumab at a dose of 320 mg every 4 weeks for 56 weeks; bimekizumab at a dose of 320 mg every 4 weeks for 16 weeks, then every 8 weeks for weeks 16 to 56; or subcutaneous adalimumab at a dose of 40 mg every 2 weeks for 24 weeks, followed by bimekizumab at a dose of 320 mg every 4 weeks to week 56. The primary end points were a 90% or greater reduction from baseline in the Psoriasis Area and Severity Index (PASI) score (PASI 90 response; PASI scores range from 0 to 72, with higher scores indicating worse disease) and an Investigator's Global Assessment (IGA) score of 0 or 1, signifying clear or almost clear skin (scores range from 0 [clear skin] to 4 [severe disease]), at week 16. The analysis of the primary end points tested noninferiority at a margin of -10 percentage points and then tested for superiority. RESULTS: A total of 614 patients were screened, and 478 were enrolled; 158 patients were assigned to receive bimekizumab every 4 weeks, 161 to receive bimekizumab every 4 weeks and then every 8 weeks, and 159 to receive adalimumab. The mean age of the patients was 44.9 years; the mean PASI score at baseline was 19.8. At week 16, a total of 275 of 319 patients (86.2%) who received bimekizumab (both dose groups combined) and 75 of 159 (47.2%) who received adalimumab had a PASI 90 response (adjusted risk difference, 39.3 percentage points; 95% confidence interval [CI], 30.9 to 47.7; P<0.001 for noninferiority and superiority). A total of 272 of 319 patients (85.3%) who received bimekizumab and 91 of 159 (57.2%) who received adalimumab had an IGA score of 0 or 1 (adjusted risk difference, 28.2 percentage points; 95% CI, 19.7 to 36.7; P<0.001 for noninferiority and superiority). The most common adverse events with bimekizumab were upper respiratory tract infections, oral candidiasis (predominantly mild or moderate as recorded by the investigator), hypertension, and diarrhea. CONCLUSIONS: In this 56-week trial, bimekizumab was noninferior and superior to adalimumab through 16 weeks in reducing symptoms and signs of plaque psoriasis but was associated with a higher frequency of oral candidiasis and diarrhea. Longer and larger trials are required to determine the efficacy and safety of bimekizumab as compared with other agents in the treatment of plaque psoriasis. (Funded by UCB Pharma; BE SURE ClinicalTrials.gov number, NCT03412747.).


Assuntos
Adalimumab/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Interleucina-17/antagonistas & inibidores , Psoríase/tratamento farmacológico , Adalimumab/administração & dosagem , Adalimumab/efeitos adversos , Adulto , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/efeitos adversos , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Candidíase Bucal/etiologia , Diarreia/induzido quimicamente , Método Duplo-Cego , Esquema de Medicação , Feminino , Humanos , Injeções Subcutâneas , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença
8.
Nat Metab ; 3(4): 496-512, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33859430

RESUMO

Overnutrition causes obesity, a global health problem without any effective therapy. Obesity is characterized by low-grade inflammation, which predisposes individuals to metabolic syndrome via unknown mechanisms. Here, we demonstrate that abolishing the interleukin-17A (IL-17A) axis in mice by inhibition of RORγt-mediated IL-17A production by digoxin, or by ubiquitous deletion of IL-17 receptor A (Il17ra), suppresses diet-induced obesity (DIO) and metabolic disorders, and promotes adipose-tissue browning, thermogenesis and energy expenditure. Genetic ablation of Il17ra specifically in adipocytes is sufficient to completely prevent DIO and metabolic dysfunction in mice. IL-17A produced in response to DIO induces PPARγ phosphorylation at Ser273 in adipocytes in a CDK5-dependent manner, thereby modifying expression of diabetogenic and obesity genes, which correlates with IL-17A signalling in white adipose tissues of individuals with morbid obesity. These findings reveal an unanticipated role for IL-17A in adipocyte biology, in which its direct action pathogenically reprograms adipocytes, promoting DIO and metabolic syndrome. Targeting the IL-17A axis could be an efficient antiobesity strategy.


Assuntos
Adipócitos/efeitos dos fármacos , Interleucina-17/antagonistas & inibidores , Doenças Metabólicas/prevenção & controle , Obesidade/prevenção & controle , Tecido Adiposo Marrom/fisiologia , Animais , Quinase 5 Dependente de Ciclina/metabolismo , Dieta , Dieta Hiperlipídica , Digoxina/farmacologia , Metabolismo Energético/fisiologia , Fezes/química , Deleção de Genes , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Hipernutrição , PPAR gama/metabolismo , Fosforilação , Termogênese/fisiologia
9.
Front Immunol ; 12: 622934, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33859636

RESUMO

Crohn's disease (CD) is a chronic relapsing disorder of the gastrointestinal tract and represents one of the main entities of inflammatory bowel disease (IBD). CD affects genetically susceptible patients that are influenced by environmental factors and the intestinal microbiome, which results in excessive activation of the mucosal immune system and aberrant cytokine responses. Various studies have implicated the pro-inflammatory cytokines IL17 and IL23 in the pathogenesis of CD. IL23 is a member of the IL12 family of cytokines and is able to enhance and affect the expansion of pathogenic T helper type 17 (Th17) cells through various mechanisms, including maintenance of Th17 signature genes, upregulation of effector genes or suppression of repressive factors. Moreover, IL17 and IL23 signaling is able to induce a cascade of pro-inflammatory molecules like TNF, IFNγ, IL22, lymphotoxin, IL1ß and lipopolysaccharide (LPS). Here, IL17A and TNF are known to mediate signaling synergistically to drive expression of inflammatory genes. Recent advances in understanding the immunopathogenetic mechanisms underlying CD have led to the development of new biological therapies that selectively intervene and inhibit inflammatory processes caused by pro-inflammatory mediators like IL17 and IL23. Recently published data demonstrate that treatment with selective IL23 inhibitors lead to markedly high response rates in the cohort of CD patients that failed previous anti-TNF therapy. Macrophages are considered as a main source of IL23 in the intestine and are supposed to play a key role in the molecular crosstalk with T cell subsets and innate lymphoid cells in the gut. The following review focuses on mechanisms, pathways and specific therapies in Crohn's disease underlying the IL23/IL17 pathway.


Assuntos
Doença de Crohn/metabolismo , Interleucina-17/metabolismo , Interleucina-23/metabolismo , Mucosa Intestinal/metabolismo , Macrófagos/metabolismo , Subpopulações de Linfócitos T/metabolismo , Animais , Anti-Inflamatórios/uso terapêutico , Comunicação Celular , Doença de Crohn/tratamento farmacológico , Doença de Crohn/imunologia , Doença de Crohn/patologia , Fármacos Gastrointestinais/uso terapêutico , Humanos , Interleucina-17/antagonistas & inibidores , Interleucina-23/antagonistas & inibidores , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/imunologia , Mucosa Intestinal/patologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Transdução de Sinais , Subpopulações de Linfócitos T/efeitos dos fármacos , Subpopulações de Linfócitos T/imunologia , Inibidores do Fator de Necrose Tumoral/uso terapêutico
10.
N Engl J Med ; 385(2): 142-152, 2021 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-33891380

RESUMO

BACKGROUND: Bimekizumab is a monoclonal IgG1 antibody that selectively inhibits both interleukin-17A and interleukin-17F. The efficacy and safety of bimekizumab as compared with secukinumab, which selectively inhibits interleukin-17A alone, in patients with moderate-to-severe plaque psoriasis have not been extensively examined. METHODS: In this phase 3b trial, we randomly assigned patients with moderate-to-severe plaque psoriasis, in a 1:1 ratio, to receive bimekizumab subcutaneously at a dose of 320 mg every 4 weeks or secukinumab subcutaneously at a dose of 300 mg weekly to week 4, followed by every 4 weeks to week 48. At week 16, patients receiving bimekizumab underwent rerandomization, in a 1:2 ratio, to receive maintenance dosing every 4 weeks or every 8 weeks to week 48. The primary end point was 100% reduction from baseline in the Psoriasis Area and Severity Index (PASI) score at week 16. The primary analysis was first tested for the noninferiority of bimekizumab to secukinumab at a margin of -10 percentage points and then tested for superiority. RESULTS: A total of 1005 patients were screened and 743 were enrolled; 373 patients were assigned to receive bimekizumab and 370 to receive secukinumab. At week 16, a total of 230 patients (61.7%) in the bimekizumab group and 181 (48.9%) in the secukinumab group had a 100% reduction from baseline in the PASI score (PASI 100) (adjusted risk difference, 12.7 percentage points; 95% confidence interval [CI], 5.8 to 19.6); bimekizumab was shown to be noninferior and superior to secukinumab (P<0.001 for noninferiority and superiority). At week 48, a total of 250 patients (67.0%) treated with bimekizumab had a PASI 100 response, as compared with 171 patients (46.2%) treated with secukinumab (adjusted risk difference, 20.9 percentage points; 95% CI, 14.1 to 27.7; P<0.001). At the week 4 time point, 265 patients (71.0%) in the bimekizumab group had 75% or greater reduction from baseline in the PASI score, as compared with 175 patients (47.3%) in the secukinumab group (adjusted risk difference, 23.7; 95% CI, 17.0 to 30.4; P<0.001). Oral candidiasis occurred more often with bimekizumab (72 patients, 19.3%) than with secukinumab (11 patients, 3.0%). CONCLUSIONS: In patients with moderate-to-severe psoriasis, treatment with bimekizumab resulted in greater skin clearance than treatment with secukinumab over 16 and 48 weeks but was associated with oral candidiasis (predominantly mild or moderate as recorded by the investigator). Longer and larger trials are required to determine the comparative effect and risks of interleukin-17 inhibitors in psoriasis. (Funded by UCB Pharma; BE RADIANT ClinicalTrials.gov number, NCT03536884.).


Assuntos
Anti-Inflamatórios/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Interleucina-17/antagonistas & inibidores , Psoríase/tratamento farmacológico , Adulto , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/efeitos adversos , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Candidíase Bucal/etiologia , Método Duplo-Cego , Esquema de Medicação , Feminino , Humanos , Injeções Subcutâneas , Análise de Intenção de Tratamento , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença
11.
J Microbiol Biotechnol ; 31(5): 667-675, 2021 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-33879639

RESUMO

Streptococcus agalactiae is an important bacterial pathogen and causative agent of diseases including neonatal sepsis and meningitis, as well as infections in healthy adults and pregnant women. Although antibiotic treatments effectively relieve symptoms, the emergence and transmission of multidrug-resistant strains indicate the need for an effective immunotherapy. Effector T helper (Th) 17 cells are a relatively newly discovered subpopulation of helper CD4+ T lymphocytes, and which, by expressing interleukin (IL)-17A, play crucial roles in host defenses against a variety of pathogens, including bacteria and viruses. However, whether S. agalactiae infection can induce the differentiation of CD4+ T cells into Th17 cells, and whether IL-17A can play an effective role against S. agalactiae infections, are still unclear. In this study, we analyzed the responses of CD4+ T cells and their defensive effects after S. agalactiae infection. The results showed that S. agalactiae infection induces not only the formation of Th1 cells expressing interferon (IFN)-γ, but also the differentiation of mouse splenic CD4+ T cells into Th17 cells, which highly express IL-17A. In addition, the bacterial load of S. agalactiae was significantly increased and decreased in organs as determined by antibody neutralization and IL-17A addition experiments, respectively. The results confirmed that IL-17A is required by the host to defend against S. agalactiae and that it plays an important role in effectively eliminating S. agalactiae. Our findings therefore prompt us to adopt effective methods to regulate the expression of IL-17A as a potent strategy for the prevention and treatment of S. agalactiae infection.


Assuntos
Interleucina-17/imunologia , Infecções Estreptocócicas/imunologia , Streptococcus agalactiae/fisiologia , Células Th17/imunologia , Animais , Carga Bacteriana/efeitos dos fármacos , Carga Bacteriana/imunologia , Linfócitos T CD4-Positivos/imunologia , Diferenciação Celular , Proliferação de Células , Citocinas/imunologia , Feminino , Interleucina-17/administração & dosagem , Interleucina-17/antagonistas & inibidores , Camundongos , Baço/imunologia , Baço/microbiologia , Infecções Estreptocócicas/microbiologia , Células Th1/imunologia
12.
Am J Clin Dermatol ; 22(4): 567-579, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33786754

RESUMO

BACKGROUND: Drug survival analysis of biologic agents in psoriasis is of extreme importance, as it allows not only the evaluation of objective clinical outcomes (such as effectiveness and safety) but also of factors that are associated with patients' adherence to treatment. The aim of this study was to evaluate and compare the drug survival of the most recent biologic agents approved for the treatment of moderate-to-severe psoriasis-ustekinumab, secukinumab, ixekizumab, brodalumab, guselkumab, and risankizumab-and to identify clinical predictors that can influence the drug survival of these drugs. METHODS: This retrospective multicentric cohort study from 16 dermatology centers in Portugal, Spain, Italy, Switzerland, Czech Republic, Canada, and the United States included patients that started IL-12/23, IL-17 (IL-17A and IL-17R) and IL-23 inhibitors for the treatment of psoriasis between January 1, 2012 and December 31, 2019. Survival analysis was performed using a Kaplan-Meier estimator, to obtain descriptive survival curves, and proportional hazard Cox regression models. RESULTS: A total of 3312 treatment courses (total patients: 3145) were included in the study; 1118 (33.8%) with an IL-12/23 inhibitor (ustekinumab), 1678 (50.7%) with an IL-17 inhibitor [911 (27.5%) on secukinumab, 651 (19.7%) on ixekizumab, 116 (3.5%) on brodalumab], and 516 (15.5%) with an IL-23 inhibitor [398 (12.0%) on guselkumab, 118 (3.5%) on risankizumab]. At 18 months, the cumulative probability of survival was 96.4% for risankizumab, 91.1% for guselkumab, 86.3% for brodalumab, 86.1% for ustekinumab, 82.0% for ixekizumab, and 79.9% for secukinumab. Using ustekinumab as reference, drug survival of guselkumab was higher (HR 0.609; 95% CI 0.418-0.887) and that of secukinumab was lower (HR 1.490; 95% CI 1.257-1.766). In the final multivariable model, secukinumab, female sex, higher BMI, and prior exposure to biologic agents significantly increased the risk of drug discontinuation, whereas risankizumab was protective. CONCLUSION: In this multinational cohort with 8439 patient-years of follow-up, the cumulative probability of drug survival for all drugs was >79% at 18 months. Prescribed biologic, female sex, higher BMI, and previous exposure to biologic agents were predictors of drug discontinuation. Drug survival of guselkumab and risankizumab was higher than that of ustekinumab, and secukinumab was lower.


Assuntos
Produtos Biológicos/uso terapêutico , Fármacos Dermatológicos/uso terapêutico , Psoríase/tratamento farmacológico , Adulto , Idoso , Produtos Biológicos/farmacologia , Fármacos Dermatológicos/farmacologia , Feminino , Seguimentos , Humanos , Interleucina-12/antagonistas & inibidores , Interleucina-12/imunologia , Interleucina-17/antagonistas & inibidores , Interleucina-17/imunologia , Interleucina-23/antagonistas & inibidores , Interleucina-23/imunologia , Masculino , Pessoa de Meia-Idade , Psoríase/imunologia , Indução de Remissão/métodos , Estudos Retrospectivos , Fatores de Tempo , Resultado do Tratamento
13.
Front Immunol ; 12: 624632, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33679768

RESUMO

Genome-wide association studies (GWAS) have identified 113 single nucleotide polymorphisms (SNPs) affecting the risk of developing ankylosing spondylitis (AS), and an on-going GWAS study will likely identify 100+ new risk loci. The translation of genetic findings to novel disease biology and treatments has been difficult due to the following challenges: (1) difficulties in determining the causal genes regulated by disease-associated SNPs, (2) difficulties in determining the relevant cell-type(s) that causal genes exhibit their function(s), (3) difficulties in determining appropriate cellular contexts to interrogate the functional role of causal genes in disease biology. This review will discuss recent progress and unanswered questions with a focus on these challenges. Additionally, we will review the investigation of biology and the development of drugs related to the IL-23/IL-17 pathway, which has been partially driven by the AS genetics, and discuss what can be learned from these studies for the future functional and translational study of AS-associated genes.


Assuntos
Anti-Inflamatórios/uso terapêutico , Descoberta de Drogas , Polimorfismo de Nucleotídeo Único , Espondilite Anquilosante/tratamento farmacológico , Espondilite Anquilosante/genética , Animais , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Interleucina-17/antagonistas & inibidores , Interleucina-17/genética , Interleucina-17/metabolismo , Interleucina-23/antagonistas & inibidores , Interleucina-23/genética , Interleucina-23/metabolismo , Terapia de Alvo Molecular , Fenótipo , Transdução de Sinais , Espondilite Anquilosante/imunologia , Espondilite Anquilosante/metabolismo
15.
Drug Des Devel Ther ; 15: 1045-1053, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33727793

RESUMO

Psoriatic arthritis is a complex and heterogeneous disease with potential significant disability and impaired quality of life. Although in the last decades new treatment options have led to a better management of this disease, there are still significant unmet therapeutic needs. Dual inhibitor antibodies target two different cytokines simultaneously, potentially offering a better disease control. In psoriatic arthritis, there is evidence for a pathogenic role not only of IL-17A but also the structurally homologous IL-17F. It is postulated that differential expression of both in several targets of PsA could account for disparities in clinical response to IL-17A inhibition alone (such as with secukinumab or ixekizumab). Here we review the evidence so far for the use in psoriatic arthritis of bimekizumab, the first humanized monoclonal IgG1 antibody that selectively neutralizes both IL-17A and IL-17F. A Phase 2b trial reports better outcomes over both placebo and IL-17A inhibition alone. Very recently encouraging results from open-label extensions with regards to both safety and maintenance of response were presented. Phase III trials are ongoing with the first results awaited in 2021.


Assuntos
Anticorpos Monoclonais Humanizados/farmacologia , Artrite Psoriásica/tratamento farmacológico , Artrite Psoriásica/metabolismo , Humanos , Interleucina-17/antagonistas & inibidores , Interleucina-17/metabolismo
18.
Biomed Pharmacother ; 137: 111346, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33556876

RESUMO

Abnormal T helper 17 (Th17) responses promote inflammation and cause inflammatory diseases. Natural components that modulate Th17 functions can be effective for the amelioration of inflammatory diseases. Procyanidin B2 3,3''-di-O-gallate (PCB2DG) contained in grape seeds markedly suppressed interleukin (IL)-17 production from spleen cells but not CD4+ T cells. The aim of this study was to elucidate the mechanisms by which PCB2DG suppresses IL-17. Our results showed that PCB2DG suppressed the production of IL-17, tumor necrosis factor (TNF)-α, IL-1ß, and IL-6 with the suppression of transcription factors expression. In addition, we revealed that TNF-α and IL-1ß were required to induce IL-17 production in this experimental condition, and PCB2DG suppressed these cytokines from dendritic cells (DCs). Furthermore, CD4-DC co-culture experiments showed that the production of IL-17, TNF-α, and IL-1ß was markedly inhibited in co-cultures of PCB2DG-pretreated CD4+ T cells and DCs. These results suggested that PCB2DG first modulated TNF-α production by CD4+ T cells and then suppressed IL-1ß secretion from DCs, resulting in decreased IL-17 production. Thus, PCB2DG can control the cytokine network associated with Th17 cells, providing a novel mechanism underlying the immunosuppressive effects of polyphenols.


Assuntos
Biflavonoides/farmacologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Catequina/farmacologia , Citocinas/biossíntese , Células Dendríticas/efeitos dos fármacos , Imunossupressores/farmacologia , Interleucina-17/biossíntese , Proantocianidinas/farmacologia , Baço/efeitos dos fármacos , Animais , Linfócitos T CD4-Positivos/metabolismo , Células Cultivadas , Células Dendríticas/metabolismo , Interleucina-17/antagonistas & inibidores , Camundongos Endogâmicos C57BL , Baço/metabolismo , Células Th17/efeitos dos fármacos , Fatores de Transcrição/antagonistas & inibidores
19.
Medicine (Baltimore) ; 100(6): e24549, 2021 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-33578549

RESUMO

BACKGROUND: Psoriasis (PSO) is a systemic inflammatory disorder that presents with erythematous scaling of the skin and is associated with autoimmune dysfunction. Atherosclerosis is one of the major comorbidities of PSO. PSO-associated inflammatory factor IL-17 could lead to vascular endothelial cell injury and atherosclerosis. While some research results show that IL-17 helps stabilize plaque formation. Efficacy and safety on PSO and psoriatic arthritis (PSA) of existing IL-17/IL-17R biologics (secukinumab, ixekizumab, brodalumab, and bimekizumab) have been clinically validated, but whether they can improve atherosclerotic outcomes in psoriatic patients remains controversial. METHODS: Seven electronic search engines will be searched from inception to December 1, 2020, including PubMed, Embase, Scopus, PsycINFO, Global Health, Web of Science and the Cochrane Library. Clinical trial registries, potential grey literature, relevant conference abstracts, and reference lists of identified studies will also be searched. Literature selection, data extraction, and quality assessment will be done by 2 independent authors. Based on the heterogeneity test, the fixed effect or random effect model will be used for data synthesis. Changes in lung function will be evaluated as the primary outcome. Assessment of symptoms, quality of life, medication use, exacerbations and adverse events will be assessed as secondary outcomes. RevMan V. 5.3.5 (The Nordic Cochrane Centre, Copenhagen, Denmark) will be used for meta-analysis. RESULTS: This study will provide a synthesis of current evidence of IL-17/IL-17R inhibitors on atherosclerosis in PSO and PSA. CONCLUSION: The conclusion of our study will provide updated evidence to judge whether IL-17/IL-17R inhibitors is an effective solution to atherosclerosis as comorbidity of PSO and PSA. PROSPERP REGISTRATION NUMBER: CRD42020209897.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Artrite Psoriásica/complicações , Aterosclerose/tratamento farmacológico , Interleucina-17/antagonistas & inibidores , Receptores de Interleucina-17/antagonistas & inibidores , Anticorpos Monoclonais Humanizados/farmacologia , Aterosclerose/etiologia , Humanos , Metanálise como Assunto , Revisões Sistemáticas como Assunto
20.
Viral Immunol ; 34(3): 190-200, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33625297

RESUMO

The initial immune response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) includes an interferon-dependent antiviral response. A late and uncontrolled inflammatory response characterized by high activity of proinflammatory cytokines and the recruitment of neutrophils and macrophages develops in predisposed individuals and is potentially harmful in some cases. Interleukin (IL)-17 is one of the many cytokines released during coronavirus disease 2019 (COVID-19). IL-17 is crucial in recruiting and activating neutrophils, cells that can migrate to the lung, and are heavily involved in the pathogenesis of COVID-19. During the infection T helper 17 (Th17) cells and IL-17-related pathways are associated with a worse outcome of the disease. All these have practical consequences considering that some drugs with therapeutic targets related to the Th17 response may have a beneficial effect on patients with SARS-CoV-2 infection. Herein, we present the arguments underlying our assumption that blocking the IL-23/IL-17 axis using targeted biological therapies as well as drugs that act indirectly on this pathway such as convalescent plasma therapy and colchicine may be good therapeutic options.


Assuntos
COVID-19/imunologia , SARS-CoV-2/imunologia , Células Th17/imunologia , Imunidade Adaptativa , Adulto , COVID-19/classificação , COVID-19/tratamento farmacológico , Humanos , Imunidade Inata , Interleucina-17/antagonistas & inibidores , Interleucina-17/fisiologia , Interleucina-23/antagonistas & inibidores , Pessoa de Meia-Idade
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