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1.
Dis Colon Rectum ; 62(11): 1352-1362, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31567927

RESUMO

BACKGROUND: The evidence regarding the association of preoperative biologic exposure and postoperative outcomes remains controversial for both antitumor necrosis factor agents and vedolizumab and largely unknown for ustekinumab. OBJECTIVE: The purpose of this study was to determine differences in the rates of 30-day postoperative overall infectious complications and intra-abdominal septic complications among the 3 classes of biologic therapies as compared with no biologic therapy. DESIGN: This was a retrospective review. SETTINGS: The study was conducted at an IBD referral center. PATIENTS: Adult patients with Crohn's disease who received an antitumor necrosis factor, vedolizumab, ustekinumab, or no biologic therapy within 12 weeks of a major abdominal operation between May 20, 2014, and December 31, 2017, were included. MAIN OUTCOMES MEASURES: Thirty-day overall postoperative infectious complications and intra-abdominal septic complications were measured. RESULTS: A total of 712 patients with Crohn's disease were included; 272 patients were exposed to an antitumor necrosis factor agents, 127 to vedolizumab, 38 to ustekinumab, and 275 to no biologic therapy within the 12 weeks before an abdominal operation. Patients exposed to a biologic were more likely to be taking a concurrent immunomodulator, but there was no difference in concurrent corticosteroid usage. The particular class of biologic was not independently associated with total overall infectious complications. Vedolizumab was associated with an increased rate of intra-abdominal sepsis on univariate analysis but not on multivariable analysis. Combination immunosuppression was associated with both an increased rate of overall postoperative infectious complications and intra-abdominal sepsis. LIMITATIONS: The study was limited by its retrospective design and single-center data. CONCLUSIONS: The overall rate of total infectious complications or intra-abdominal septic complications was not increased based on preoperative exposure to a particular class of biologic. Rates increased with combination immunosuppression of biologic therapy with corticosteroids and previous abdominal resection. See Video Abstract at http://links.lww.com/DCR/B24. BIOLÓGICOS Y COMPLICACIONES POSTOPERATORIAS DE 30 DÍAS DESPUÉS DE LAS OPERACIONES ABDOMINALES PARA LA ENFERMEDAD DE CROHN: ¿EXISTEN DIFERENCIAS EN LOS PERFILES DE SEGURIDAD?:: La evidencia sobre la asociación de la exposición biológica preoperatoria y los resultados postoperatorios sigue siendo controvertida controversial tanto para los agentes del factor de necrosis tumoral (anti-TNF) como para el vedolizumab, y en gran parte desconocida para el ustekinumab.Determinar las diferencias en las tasas de complicaciones infecciosas generales postoperatorias de 30 días y complicaciones sépticas intraabdominales entre las tres clases de terapias biológicas en comparación con ninguna terapia biológica.Revisión retrospectiva.centro de referencia de la enfermedad inflamatoria intestinal.Pacientes adultos con enfermedad de Crohn que recibieron un factor de necrosis antitumoral, vedolizumab, ustekinumab o ningún tratamiento biológico dentro de las 12 semanas de una operación abdominal mayor entre el 5/20/2014 y el 12/31/2017.Complicaciones infecciosas postoperatorias generales de 30 días, complicaciones sépticas intraabdominales.Se incluyeron setecientos doce pacientes con enfermedad de Crohn; 272 pacientes fueron expuestos a un anti-TNF, 127 a vedolizumab, 38 a ustekinumab y 275 a ninguna terapia biológica dentro de las 12 semanas previas a una operación abdominal. Los pacientes expuestos a un producto biológico tenían más probabilidades de tomar un inmunomodulador concurrente, pero no hubo diferencias en el uso simultáneo de corticosteroides. La clase particular de productos biológicos no se asoció de forma independiente con las complicaciones infecciosas totales. Vedolizumab se asoció con una mayor tasa de sepsis intraabdominal en el análisis univariable, pero no en el análisis multivariable. La inmunosupresión combinada se asoció tanto con una mayor tasa de complicaciones infecciosas postoperatorias generales como con sepsis intraabdominal.Diseño retrospectivo, datos de centro único.La tasa general de complicaciones infecciosas totales o complicaciones sépticas intraabdominales no aumentó en función de la exposición preoperatoria a una clase particular de productos biológicos. Las tasas aumentaron con la combinación de inmunosupresión de la terapia biológica con corticosteroides y resección abdominal previa. Vea el Resumen del Video en http://links.lww.com/DCR/B24.


Assuntos
Anticorpos Monoclonais Humanizados , Colectomia , Doença de Crohn , Infecções Intra-Abdominais , Complicações Pós-Operatórias , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Ustekinumab , Adulto , Anti-Inflamatórios/efeitos adversos , Anti-Inflamatórios/uso terapêutico , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/uso terapêutico , Produtos Biológicos/efeitos adversos , Produtos Biológicos/uso terapêutico , Colectomia/efeitos adversos , Colectomia/métodos , Doença de Crohn/tratamento farmacológico , Doença de Crohn/imunologia , Doença de Crohn/cirurgia , Monitoramento de Medicamentos/métodos , Feminino , Seguimentos , Humanos , Interleucina-12/antagonistas & inibidores , Interleucina-23/antagonistas & inibidores , Infecções Intra-Abdominais/diagnóstico , Infecções Intra-Abdominais/epidemiologia , Infecções Intra-Abdominais/etiologia , Masculino , Complicações Pós-Operatórias/diagnóstico , Complicações Pós-Operatórias/epidemiologia , Período Pré-Operatório , Estados Unidos , Ustekinumab/efeitos adversos , Ustekinumab/uso terapêutico
2.
Clin Drug Investig ; 39(12): 1195-1203, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31549347

RESUMO

BACKGROUND AND OBJECTIVE: Immunotherapy could change the complex host-microbial interactions. We aimed to investigate the dynamics of gut microbiome in response to secukinumab [an interleukin (IL)-17 inhibitor] and ustekinumab (an IL-12/23 inhibitor) therapy and its association with treatment response in psoriasis. METHODS: This observational, longitudinal study collected a total of 114 fecal samples from 12 healthy controls and 34 patients with psoriasis at baseline and 3 and 6 months after secukinumab (n = 24) or ustekinumab treatment (n = 10) and gut microbiomes were investigated using next-generation sequencing targeting 16S ribosomal RNA. RESULTS: Secukinumab treatment causes more profound alterations in gut microbiome, including increases in the relative abundance of phylum Proteobacteria and decreases in Bacteroidetes and Firmicutes, than ustekinumab treatment. The relative abundance of family Pseudomonadaceae, family Enterobacteriaceae and order Pseudomonadales also increased significantly following secukinumab therapy. In contrast, there was no significant change in gut microbiome composition following ustekinumab treatment, and only genus Coprococcus significantly increased after 6 months of ustekinumab therapy. Moreover, we observed significant differences in baseline gut microbiome between responders and non-responders to secukinumab treatment. CONCLUSION: These results indicate that gut microbiome is altered differently after anti-IL17 and anti-IL12/23 treatment. Secukinumab (anti-IL17) therapy is associated with distinct and more profound gut microbiome shifts than ustekinumab therapy (anti-IL 12/23) in patients with psoriasis. Moreover, gut microbiome would serve as potential biomarkers of response to secukinumab treatment.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Microbioma Gastrointestinal/efeitos dos fármacos , Psoríase/tratamento farmacológico , Ustekinumab/uso terapêutico , Adulto , Feminino , Humanos , Interleucina-12/antagonistas & inibidores , Interleucina-17/antagonistas & inibidores , Interleucina-23/antagonistas & inibidores , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Psoríase/microbiologia
5.
J Dermatol ; 46(6): 482-497, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31062408

RESUMO

The interleukin (IL)-23/IL-17 axis plays a central role in the pathogenesis of psoriasis and is elevated in lesional psoriatic skin. Different murine models have been developed to mimic this pathophysiology each carrying specific merits and limitations. In an attempt to address some of these limitations, B10.RIII mice received a single hydrodynamic injection of IL-23 minicircles (MC) to induce hepatic transcription and the endogenous production of IL-23. Plasma and ear IL-23 levels were dose-dependently (0.3-3 µg) increased in MC injected mice and were sustained over the 14-day study duration. Beginning on day 7 post-injection, mice developed dose-related ear inflammation, histologically confirmed increases in epidermal and dermal area, as well as enhanced neutrophil and macrophage content. Flow cytometry demonstrated increased levels of granulocytes, T cells and monocytes/macrophages in the ear skin, with T cells identified as the main cellular source of IL-17A. Evaluation of mRNA and protein showed time-dependent, increased levels of the IL-23/IL-17 pathway and inflammatory/microbial cytokines/chemokines in the ear which differed kinetically from circulating levels. An anti-IL-23p40 antibody was assessed following both prophylactic administration and administration once the disease was established. Prophylactic dosing completely prevented the development of the ear phenotype across endpoints. Treatment administration showed a dose-related response, with a maximum inhibition of 64-94%, depending on endpoint. These data demonstrate that the IL-23 MC model is a useful approach to study IL-23/IL-17-driven skin inflammation and may facilitate preclinical assessment of novel therapies.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Interleucina-17/imunologia , Interleucina-23/imunologia , Psoríase/imunologia , Animais , DNA Circular/administração & dosagem , DNA Circular/genética , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Técnicas de Transferência de Genes , Humanos , Interleucina-17/metabolismo , Interleucina-23/antagonistas & inibidores , Interleucina-23/genética , Masculino , Camundongos , Psoríase/sangue , Psoríase/tratamento farmacológico , Psoríase/patologia , Proteínas Recombinantes/genética , Proteínas Recombinantes/imunologia , Pele/imunologia , Pele/patologia , Resultado do Tratamento
6.
J Cutan Med Surg ; 23(4): 428-435, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30938189

RESUMO

Acrodermatitis continua of Hallopeau is a rare subtype of pustular psoriasis that presents as a sterile, pustular eruption commonly in the finger tips and toes. This disease inflicts both the skin and nail bed, and causes severe disfigurement of the distal phalanges. Because it is a variant of pustular psoriasis, acrodermatitis continua of Hallopeau is commonly managed with antipsoriatic medications. Common approaches to treatment include topical therapy (corticosteroids, vitamin D analogs, and calcineurin inhibitors), systemic therapy, and in more severe cases, biologic therapy. This review will discuss how acrodermatitis continua of Hallopeau is diagnosed and how it is managed, with a particular emphasis on the use of biologics.


Assuntos
Acrodermatite/tratamento farmacológico , Produtos Biológicos/uso terapêutico , Fármacos Dermatológicos/uso terapêutico , Psoríase/tratamento farmacológico , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Acrodermatite/diagnóstico , Humanos , Interleucina-1/antagonistas & inibidores , Interleucina-17/antagonistas & inibidores , Interleucina-23/antagonistas & inibidores , Psoríase/diagnóstico
7.
Am J Clin Dermatol ; 20(4): 493-502, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30941636

RESUMO

BACKGROUND: Fatigue is frequent in patients with psoriasis. Though conventional drugs in general have no effect on fatigue, biological agents have demonstrated beneficial effects in several other chronic inflammatory diseases. OBJECTIVE: The objective of the present study was to evaluate the effect of biological drugs on fatigue in patients with psoriasis vulgaris. METHODS: We conducted a meta-analysis of randomized controlled trials in which anti-interleukin-12/23, anti-interleukin-23, anti-interleukin-17, or anti-tumor necrosis factor-α agents were used for psoriasis vulgaris and fatigue was an outcome measure. RESULTS: A total of eight randomized controlled trials fulfilled criteria for inclusion in the meta-analysis. The studies used two fatigue reporting scales: the Functional Assessment of Chronic Illness Therapy-Fatigue and the Short Form 36 Health Survey Vitality Subscale. Treatment by biological agents in general compared with placebo led to a significant reduction in fatigue, with a standardized mean difference of - 0.40 (95% confidence interval - 0.46 to - 0.34; p < 0.001). CONCLUSION: Biological drugs used for the treatment of psoriasis vulgaris have a consistently small-to-moderate beneficial effect on fatigue independent of the type of drug.


Assuntos
Produtos Biológicos/uso terapêutico , Fadiga/tratamento farmacológico , Psoríase/tratamento farmacológico , Produtos Biológicos/farmacologia , Fadiga/imunologia , Humanos , Interleucina-12/antagonistas & inibidores , Interleucina-12/imunologia , Interleucina-17/antagonistas & inibidores , Interleucina-17/imunologia , Interleucina-23/antagonistas & inibidores , Interleucina-23/imunologia , Psoríase/complicações , Psoríase/imunologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/imunologia
8.
Expert Opin Investig Drugs ; 28(5): 473-479, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30884245

RESUMO

INTRODUCTION: Blockade of interleukin (IL)-12 and IL-23 is a novel therapeutic target for inflammatory bowel disease (IBD). The monoclonal antibody targeting the shared p40 subunit of IL-12 and IL23, namely ustekinumab, has been approved for Crohn's disease (CD) and has demonstrated promising results in the treatment of ulcerative colitis. Several agents targeting the IL-23-specific p19 subunit are currently in various stages of development. These newer agents have the potential to provide safety benefits. AREAS COVERED: This review discusses the current state of IL-12/23 and IL-23 antagonists for the treatment of IBD. With multiple biologic classes available, we make recommendations for positioning of these agents in clinical practice. EXPERT OPINION: While tumor necrosis factor (TNF) antagonists remain the biologic of choice for majority of patients with moderate-to-severe IBD, IL-12/23, and IL-23 antagonists should be considered for first- or second-line therapy because of their efficacy in biologic-naïve and experienced patients. Additionally, IL-12/23 and IL-23 antagonists may be preferred over anti-TNF therapy in older patients who are at increased risk for infections and malignancy. The safety compared to anti-TNF may be even greater when one considers that concurrent immunosuppression is probably not necessary when using this class of drug, owing to the low rates of immunogenicity.


Assuntos
Colite Ulcerativa/tratamento farmacológico , Doença de Crohn/tratamento farmacológico , Fármacos Gastrointestinais/farmacologia , Animais , Colite Ulcerativa/fisiopatologia , Doença de Crohn/fisiopatologia , Fármacos Gastrointestinais/efeitos adversos , Humanos , Interleucina-12/antagonistas & inibidores , Interleucina-23/antagonistas & inibidores , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Ustekinumab/farmacologia
11.
Arthritis Rheumatol ; 71(1): 5-32, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30499246

RESUMO

OBJECTIVE: To develop an evidence-based guideline for the pharmacologic and nonpharmacologic treatment of psoriatic arthritis (PsA), as a collaboration between the American College of Rheumatology (ACR) and the National Psoriasis Foundation (NPF). METHODS: We identified critical outcomes in PsA and clinically relevant PICO (population/intervention/comparator/outcomes) questions. A Literature Review Team performed a systematic literature review to summarize evidence supporting the benefits and harms of available pharmacologic and nonpharmacologic therapies for PsA. GRADE (Grading of Recommendations Assessment, Development and Evaluation) methodology was used to rate the quality of the evidence. A voting panel, including rheumatologists, dermatologists, other health professionals, and patients, achieved consensus on the direction and the strength of the recommendations. RESULTS: The guideline covers the management of active PsA in patients who are treatment-naive and those who continue to have active PsA despite treatment, and addresses the use of oral small molecules, tumor necrosis factor inhibitors, interleukin-12/23 inhibitors (IL-12/23i), IL-17 inhibitors, CTLA4-Ig (abatacept), and a JAK inhibitor (tofacitinib). We also developed recommendations for psoriatic spondylitis, predominant enthesitis, and treatment in the presence of concomitant inflammatory bowel disease, diabetes, or serious infections. We formulated recommendations for a treat-to-target strategy, vaccinations, and nonpharmacologic therapies. Six percent of the recommendations were strong and 94% conditional, indicating the importance of active discussion between the health care provider and the patient to choose the optimal treatment. CONCLUSION: The 2018 ACR/NPF PsA guideline serves as a tool for health care providers and patients in the selection of appropriate therapy in common clinical scenarios. Best treatment decisions consider each individual patient situation. The guideline is not meant to be proscriptive and should not be used to limit treatment options for patients with PsA.


Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Antirreumáticos/uso terapêutico , Artrite Psoriásica/terapia , Glucocorticoides/uso terapêutico , Imunossupressores/uso terapêutico , Modalidades de Fisioterapia , Abatacepte/uso terapêutico , Adalimumab/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Artrite Psoriásica/epidemiologia , Comorbidade , Diabetes Mellitus/epidemiologia , Diabetes Mellitus/terapia , Entesopatia/terapia , Etanercepte/uso terapêutico , Medicina Baseada em Evidências , Exercício , Humanos , Doenças Inflamatórias Intestinais/epidemiologia , Doenças Inflamatórias Intestinais/terapia , Infliximab/uso terapêutico , Interleucina-12/antagonistas & inibidores , Interleucina-17/antagonistas & inibidores , Interleucina-23/antagonistas & inibidores , Terapia Ocupacional , Piperidinas/uso terapêutico , Pirimidinas/uso terapêutico , Pirróis/uso terapêutico , Reumatologia , Abandono do Hábito de Fumar , Sociedades Médicas , Espondilite/terapia , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Ustekinumab/uso terapêutico , Perda de Peso
12.
Dermatol Clin ; 37(1): 29-36, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30466686

RESUMO

Psoriasis is a chronic, immune-mediated, inflammatory skin disease that requires long-term therapy for disease control. This article reviews data presented in clinical trials to evaluate and compare various characteristics of biologics that are currently approved for the treatment of psoriasis. Attributes of biological agents that are examined in this article include efficacy, long-term maintenance, overall safety, median time to onset of efficacy, adjustment for body weight, frequency of injections, indication for psoriatic arthritis, and safety in pregnancy. Here, we evaluate what the ideal choice of biological therapy may be for psoriasis patients with specific needs.


Assuntos
Produtos Biológicos/uso terapêutico , Interleucina-12/antagonistas & inibidores , Interleucina-17/antagonistas & inibidores , Interleucina-23/antagonistas & inibidores , Psoríase/tratamento farmacológico , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Produtos Biológicos/efeitos adversos , Humanos
13.
Eur Urol ; 75(5): 752-763, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30293904

RESUMO

BACKGROUND: Glutamine addiction is a hallmark of clear cell renal cell carcinoma (ccRCC); yet whether glutamine metabolism impacts local immune surveillance is unclear. This knowledge may yield novel immunotherapeutic opportunities. OBJECTIVE: To seek a potential therapeutic target in glutamine-addicted ccRCC. DESIGN, SETTING, AND PARTICIPANTS: Tumors from ccRCC patients from a Shanghai cohort and ccRCC tumor data from The Cancer Genome Atlas (TCGA) cohort were analyzed. In vivo and in vitro studies were conducted with fresh human ccRCC tumors and murine tumor cells. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Immune cell numbers and functions were analyzed by flow cytometry. Glutamine and cytokine concentrations were determined. Survival was compared between different subpopulations of patients using Kaplan-Meier and Cox regression analyses. RESULTS AND LIMITATIONS: We found that in ccRCC, high interleukin (IL)-23 expression was significantly associated with poor survival in both TCGA (overall survival [OS] hazard ratio [HR]=2.04, cancer-specific survival [CSS] HR=2.95; all p<0.001) and Shanghai (OS HR=2.07, CSS HR=3.92; all p<0.001) cohorts. IL-23 blockade prolongs the survival of tumor-bearing mice, promotes T-cell cytotoxicity in in vitro cultures of human ccRCC tumors, and augments the therapeutic benefits of anti-PD-1 antibodies. Mechanistically, glutamine consumption by ccRCC tumor cells results in the local deprivation of extracellular glutamine, which induces IL-23 secretion by tumor-infiltrating macrophages via the activation of hypoxia-inducible factor 1α (HIF1α). IL-23 activates regulatory T-cell proliferation and promotes IL-10 and transforming growth factor ß expression, thereby suppressing tumor cell killing by cytotoxic lymphocytes. The positive correlations between glutamine metabolism, IL-23 levels, and Treg responses are confirmed in both TCGA cohort and tumors from Shanghai ccRCC patients. Study limitations include the unclear impacts of glutamine deprivation and IL-23 on other immune cells. CONCLUSIONS: Macrophage-secreted IL-23 enhanced Treg functions in glutamine-addicted tumors; thus, IL-23 is a promising target for immunotherapy in ccRCC. PATIENT SUMMARY: In this study, we analyzed the immune components in glutamine-addicted clear cell renal cell carcinoma (ccRCC) tumors from two patient cohorts and conducted both in vitro and in vivo studies. We found that ccRCC tumor cell-intrinsic glutamine metabolism orchestrates immune evasion via interleukin (IL)-23, and IL-23-high patients had significantly poorer survival than IL-23-low patients. IL-23 should thus be considered a therapeutic target in ccRCC, either alone or in combination with immune checkpoint inhibitors.


Assuntos
Carcinoma de Células Renais/imunologia , Glutamina/metabolismo , Interleucina-23/metabolismo , Neoplasias Renais/imunologia , Macrófagos/metabolismo , Linfócitos T Reguladores/imunologia , Animais , Anticorpos/uso terapêutico , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/metabolismo , Carcinoma de Células Renais/terapia , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Ontologia Genética , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Evasão da Resposta Imune , Tolerância Imunológica/efeitos dos fármacos , Interleucina-23/antagonistas & inibidores , Interleucina-23/imunologia , Interleucina-23/farmacologia , Neoplasias Renais/genética , Neoplasias Renais/metabolismo , Neoplasias Renais/terapia , Ativação Linfocitária , Camundongos , Vício Oncogênico , Taxa de Sobrevida , Linfócitos T Reguladores/fisiologia , Evasão Tumoral
15.
Am J Clin Dermatol ; 19(6): 907-918, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30467781

RESUMO

Guselkumab (Tremfya®) is a human immunoglobulin G1 λ (IgG1λ) monoclonal antibody (mAb) that blocks the interleukin-23 (IL-23)-mediated signalling pathway and is the first in its class to be approved in adults with moderate to severe plaque psoriasis in several countries, including the USA and EU. In the VOYAGE trials, guselkumab was superior to placebo and to adalimumab at week 16 in terms of the proportion of patients achieving an Investigator Global Assessment (IGA) score of 0/1 and ≥ 90% improvement from baseline in Psoriasis Area and Severity index score (PASI 90 response), with benefits of guselkumab over adalimumab maintained at week 24. To date, the beneficial effects of guselkumab treatment in these trials were maintained for up to 2 years. Inadequate responders to ustekinumab who were then randomized to guselkumab in NAVIGATE showed better responses than those randomized to ustekinumab between weeks 28-40, with a significantly greater mean number of visits at which patients had IGA 0/1 and ≥ 2-grade improvement in IGA score, as well as higher proportions of patients achieving PASI 90 and PASI 100 at week 52. Treatment with guselkumab improved health-related quality of life (HR-QOL) and patient-reported outcomes in all trials and was generally well tolerated. Guselkumab, administered by subcutaneous injection, is a useful new option for patients with moderate to severe plaque psoriasis.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Fármacos Dermatológicos/uso terapêutico , Interleucina-23/antagonistas & inibidores , Psoríase/tratamento farmacológico , Adalimumab/uso terapêutico , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais Humanizados , Fármacos Dermatológicos/farmacologia , Humanos , Injeções Subcutâneas , Interleucina-23/imunologia , Interleucina-23/metabolismo , Medidas de Resultados Relatados pelo Paciente , Psoríase/imunologia , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto , Índice de Gravidade de Doença , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Fatores de Tempo , Resultado do Tratamento , Ustekinumab/uso terapêutico
16.
J Manag Care Spec Pharm ; 24(12): 1210-1217, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30479197

RESUMO

BACKGROUND: Newer classes of targeted drugs for moderate to severe plaque psoriasis are more effective and more expensive than older classes, posing a difficult and potentially costly decision about whether to use them as initial targeted treatments. OBJECTIVE: To estimate the clinical and economic outcomes of initial targeted treatment for the following drugs: adalimumab, etanercept, and infliximab (TNFα inhibitors); apremilast (PDE4 inhibitor); ustekinumab (IL-12/23 inhibitor); and ixekizumab, secukinumab, and brodalumab (IL-17 inhibitors). METHODS: We developed a Markov model to simulate patient outcomes as measured by quality-adjusted life-years (QALYs) and health care costs over a 10-year period. We assumed that patients who fail initial targeted treatment either proceed to subsequent therapy or discontinue targeted treatment. Effectiveness estimates for initial treatment were defined as improvement in Psoriasis Area and Severity Index (PASI) from baseline and derived from a 2018 network meta-analysis. Wholesale acquisition drug costs were discounted by a class-specific, empirically derived rebate percentage off of 2016 costs. We conducted one-way and probabilistic sensitivity analyses to assess uncertainty in results. RESULTS: The incremental benefits compared with no targeted treatment were, in descending order: ixekizumab 1.68 QALYs (95% credible range [CR] = 1.11-2.02), brodalumab 1.64 QALYs (95% CR = 1.08-1.98), secukinumab 1.51 QALYs (95% CR = 1.00-1.83), ustekinumab 1.43 QALYs (95% CR=0.94-1.74), infliximab 1.27 QALYs (95% CR = 0.89-1.55), adalimumab 1.15 QALYs (95% CR = 0.76-1.44), etanercept 0.97 QALYs (95% CR = 0.61-1.25), and apremilast 0.87 QALYs (95% CR = 0.52-1.17). Costs of care without targeted treatment totaled $66,451, and costs of targeted treatment ranged from $137,080 (apremilast) to $255,422 (ustekinumab). Probabilistic sensitivity analysis results indicated that infliximab and apremilast are likely to be the most cost-effective initial treatments at willingness-to-pay thresholds around $100,000 per QALY, while IL-17 drugs are more likely to be cost-effective at thresholds approaching $150,000 per QALY. Acquisition cost of the initial targeted drug and utility of clinical response were the most influential parameters. CONCLUSIONS: Our findings suggest that initial targeted treatment with IL-17 inhibitors is the most effective treatment strategy for plaque psoriasis patients who have failed methotrexate and phototherapy. Apremilast, brodalumab, infliximab, ixekizumab, and secukinumab are cost-effective at different willingness-to-pay thresholds. Additional research is needed on whether the effectiveness of targeted agents changes when used after previously targeted agents. DISCLOSURES: Funding for this study was contributed by the Institute for Clinical and Economic Review (ICER). Ollendorf, Chapman, Pearson, and Kumar are current employees, and Loos and Liu are former employees, of ICER, an independent organization that evaluates the evidence on the value of health care interventions, which is funded by grants from the Laura and John Arnold Foundation, Blue Shield of California Foundation, and the California HealthCare Foundation. ICER's annual policy summit is supported by dues from Aetna, AHIP, Anthem, Alnylam, AstraZeneca, Blue Shield of California, Cambia Health Solutions and MedSavvy, CVS Caremark, Editas, Express Scripts, Genentech, GlaxoSmithKline, Harvard Pilgrim Health Care, Health Care Service Corporation, OmedaRx, United Healthcare, Johnson & Johnson, Kaiser Permanente, Premera Blue Cross, Merck, National Pharmaceutical Council, Takeda, Pfizer, Novartis, Lilly, Humana, Prime Therapeutics, Sanofi, and Spark Therapeutics. Linder owns stock in Amgen, Biogen, and Eli Lilly; has contingent value rights in Sanofi Genzyme (related to alemtuzumab for multiple sclerosis); has received grant support from Astellas Pharma not related to this study and Clintrex, which was supported by AstraZeneca on an unrelated topic; and has received an honorarium from the Society of Healthcare Epidemiology of America (SHEA) as part of the SHEA Antimicrobial Stewardship Research Workshop Planning Committee, an educational activity supported by Merck. No other authors have potential conflicts of interest.


Assuntos
Análise Custo-Benefício , Fármacos Dermatológicos/uso terapêutico , Custos de Medicamentos , Psoríase/tratamento farmacológico , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/imunologia , Fármacos Dermatológicos/economia , Fármacos Dermatológicos/farmacologia , Humanos , Interleucina-12/antagonistas & inibidores , Interleucina-12/imunologia , Interleucina-17/antagonistas & inibidores , Interleucina-17/imunologia , Interleucina-23/antagonistas & inibidores , Interleucina-23/imunologia , Cadeias de Markov , Pessoa de Meia-Idade , Modelos Econômicos , Terapia de Alvo Molecular/economia , Terapia de Alvo Molecular/métodos , Inibidores da Fosfodiesterase 4/economia , Inibidores da Fosfodiesterase 4/uso terapêutico , Psoríase/economia , Psoríase/imunologia , Anos de Vida Ajustados por Qualidade de Vida , Resultado do Tratamento , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/imunologia
17.
World J Gastroenterol ; 24(36): 4093-4103, 2018 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-30271076

RESUMO

Considering that both innate and adaptive immune responses are involved in the pathogenesis of Crohn's disease (CD), novel therapeutic options have significantly been developed. Biological agents represent an important addition to the conventional treatments for immuno-inflammatory conditions, acting as antagonists of adhesion molecules or various inflammatory cytokines. The interleukin 12 (IL-12)/IL-23 common pathway has been found to play a determinant role in the induction of inflammation in adaptive immune responses. In particular, IL-23 promotes the differentiation of naïve T helper cells into Th17 phenotype with the concomitant secretion of several inflammatory cytokines such as IL-17 and IL-22, whereas IL-12 induces the Th1 polarization and production of critical cytokines such as interferon-γ and tumor necrosis factor. Nowadays, there is increased interest regarding the role of IL-23 as a therapeutic target of CD through the blockage of IL-23 mediated pathways. In this editorial, we focus on the role of IL-12/IL-23 pathway in the regulation of mucosal immunity and in the induction and maintenance of chronic inflammation. In parallel, we critically discuss the available data regarding the therapeutic effect of the IL-12/IL-23 inhibitors and especially of ustekinumab, a human monoclonal antibody which has been recently approved by the United States Food and Drug Administration for the management of moderate-to-severe CD and its potential to be used as first-line therapy in everyday clinical practice.


Assuntos
Doença de Crohn/imunologia , Fármacos Gastrointestinais/uso terapêutico , Interleucina-12/metabolismo , Interleucina-23/metabolismo , Transdução de Sinais/efeitos dos fármacos , Diferenciação Celular/imunologia , Doença de Crohn/tratamento farmacológico , Doença de Crohn/patologia , Humanos , Imunidade nas Mucosas/efeitos dos fármacos , Interleucina-12/antagonistas & inibidores , Interleucina-23/antagonistas & inibidores , Transdução de Sinais/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Resultado do Tratamento , Ustekinumab/uso terapêutico
18.
J Interferon Cytokine Res ; 38(10): 440-444, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30328797

RESUMO

Accumulating evidence has shown that atherosclerosis is an inflammatory disease. The pathogenesis of atherosclerosis has been confirmed to involve an imbalance in anti-inflammatory/proinflammatory processes. Interleukin-23 (IL-23) is a heterodimeric cytokine composed of the IL-23p19 and IL-12p40 subunits of the IL-12 family. Experiments show that IL-23 induces CD4+ T cells to differentiate into T helper type 17 cells, promotes the expression of interferon-γ, and inhibits the production of Foxp3. Therefore, IL-23 induces and exacerbates effector T lymphocyte/regulatory T cell imbalance. IL-23 receptor (IL-23R) is expressed not only in T cells but also in dendritic cells (DCs) and macrophages. IL-23R can enhance its antigen-presenting ability through the autocrine pathway, enabling it to infiltrate lesion sites, promote its secretion of a large number of inflammatory factors, and upregulate proinflammatory DCs and macrophages. IL-23 binds IL-23R on the surface of target cells and transmits signals through Janus kinase 2/signal transducer and activator of transcription channels, participating in the occurrence of chronic inflammatory diseases and autoimmune diseases. Therefore, the use of IL-23 or IL-23R is a potential therapeutic approach for treating inflammatory diseases, including atherosclerosis. In this article, we hypothesize that IL-23 may be a novel target for the treatment of atherosclerosis, and further study is needed to determine the precise role of IL-23 in atherosclerosis and the associated signaling pathways.


Assuntos
Aterosclerose/imunologia , Interleucina-23/imunologia , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Aterosclerose/tratamento farmacológico , Humanos , Interleucina-23/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia
19.
Int Immunopharmacol ; 64: 208-216, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30195819

RESUMO

The feature of pulmonary sarcoidosis is characterized by a Th1/Th17/regulatory T cells (Tregs) -driven inflammatory process in lung, resulting in noncaseating granulomas containing CD4+ T cells. Tregs increase in both lung and peripheral blood, with damaged immunoregulatory function. The current study investigated the effects of IL33 or anti-IL23 antibody on restoring the homeostasis and functions of Tregs in mycobacterial superoxide dismutase A (SodA)-induced pulmonary sarcoidosis. IL33 or anti-IL23 antibody was administered to mice with late-stage pulmonary sarcoidosis. The levels of Th1/Th17/Tregs and Tregs' suppressive functions were detected by fluorescence activated cell sorting (FACS) analysis or qPCR. The expressions of key proteins in PI3K/Akt/mTOR and TGF-ß/Smad2/Smad3 signaling pathways were tested by western blot. IL33 administration was associated with the rebalance of Th1/Th2 and Tregs, as well as a superior suppressor activity of Tregs on effector T cells in sarcoidosis, probably through increasing ST2 expressions on Tregs, along with the suppression of PI3K/Akt/mTOR and TGF-ß/Smad2/Smad3 signaling pathways. Small dose of anti-IL23 antibody independently improved Th1/Th2 bias, but had limited effects on the homeostasis and ST2 expressions on Tregs. These results suggested a major anti-inflammatory ability of IL33 to ameliorate the disturbance of Th1/Th2 and Tregs in pulmonary sarcoidosis, and provided rationales for further strategies of targeting the IL33/ST2 signals in the treatment of pulmonary sarcoidosis.


Assuntos
Interleucina-33/farmacologia , Sarcoidose Pulmonar/imunologia , Linfócitos T Reguladores/efeitos dos fármacos , Animais , Feminino , Interleucina-23/antagonistas & inibidores , Camundongos , Camundongos Endogâmicos C57BL , Fosfatidilinositol 3-Quinases/fisiologia , Sarcoidose Pulmonar/tratamento farmacológico , Linfócitos T Reguladores/imunologia , Células Th1/efeitos dos fármacos , Células Th1/imunologia , Células Th2/efeitos dos fármacos , Células Th2/imunologia , Fator de Crescimento Transformador beta/fisiologia
20.
J Immunol ; 201(6): 1605-1613, 2018 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-30181299

RESUMO

Psoriasis vulgaris is a common, heterogeneous, chronic inflammatory skin disease characterized by thickened, red, scaly plaques and systemic inflammation. Psoriasis is also associated with multiple comorbid conditions, such as joint destruction, cardiovascular disease, stroke, hypertension, metabolic syndrome, and chronic kidney disease. The discovery of IL-17-producing T cells in a mouse model of autoimmunity transformed our understanding of inflammation driven by T lymphocytes and associations with human inflammatory diseases, such as psoriasis. Under the regulation of IL-23, T cells that produce high levels of IL-17 create a self-amplifying, feed-forward inflammatory response in keratinocytes that drives the development of thickened skin lesions infiltrated with a mixture of inflammatory cell populations. Recently, the Food and Drug Administration approved multiple highly effective psoriasis therapies that disrupt IL-17 (secukinumab, ixekizumab, and brodalumab) and IL-23 (guselkumab and tildrakizumab) signaling in the skin, thus leading to a major paradigm shift in the way that psoriatic disease is managed.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Interleucina-17 , Interleucina-23 , Psoríase , Pele/imunologia , Linfócitos T/imunologia , Animais , Anticorpos Monoclonais/imunologia , Humanos , Interleucina-17/antagonistas & inibidores , Interleucina-17/imunologia , Interleucina-23/antagonistas & inibidores , Interleucina-23/imunologia , Camundongos , Psoríase/tratamento farmacológico , Psoríase/imunologia , Psoríase/patologia , Pele/patologia , Linfócitos T/patologia
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