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2.
Adv Exp Med Biol ; 1172: 97-117, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31628653

RESUMO

The IL-17 family in humans consists of six distinct cytokines (IL-17A-F) that can interact with five IL-17 receptors (IL-17RA-E). The interaction between these cytokines and their receptors are critical in mediating host defenses while also making major contributions to inflammatory and autoimmune responses as demonstrated through both in vitro and in vivo experiments as well as human clinical trials. Inhibition of the IL-17A/IL-17RA interaction by monoclonal antibodies has also displayed remarkable efficacies in clinical trials against psoriasis and other autoimmune diseases. Recently, we and others reported the identification and characterization of both small-molecule and peptide IL-17A antagonists. These non-antibody IL-17A antagonists can effectively and selectively disrupt the IL-17A/IL-17RA complex and may provide alternative modalities to treat IL-17-related autoimmune and inflammatory diseases. This chapter summarizes the reported crystal structures of the IL-17 cytokines, their complexes with IL-17RA, and their complexes with both monoclonal antibodies as well as small-molecule and peptide antagonists.


Assuntos
Interleucina-17 , Receptores de Interleucina-17 , Animais , Anticorpos Monoclonais/química , Anticorpos Monoclonais/metabolismo , Doenças Autoimunes/imunologia , Cristalização , Humanos , Interleucina-17/antagonistas & inibidores , Interleucina-17/química , Interleucina-17/imunologia , Receptores de Interleucina-17/antagonistas & inibidores , Receptores de Interleucina-17/química , Receptores de Interleucina-17/imunologia
3.
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
4.
Lancet ; 394(10201): 831-839, 2019 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-31402114

RESUMO

BACKGROUND: Antibodies targeting interleukin (IL)-23 and IL-17A effectively treat moderate-to-severe psoriasis. ECLIPSE is the first comparator study of an IL-23p19 inhibitor, guselkumab, versus an IL-17A inhibitor, secukinumab. The primary objective of this study was to show superiority of clinical response at week 48 for guselkumab versus secukinumab. METHODS: In this phase 3, multicentre, double-blind, randomised, comparator-controlled trial at 142 outpatient clinical sites in nine countries (Australia, Canada, Czech Republic, France, Germany, Hungary, Poland, Spain, and the USA), eligible patients were aged 18 years or older, had moderate-to-severe plaque-type psoriasis, and were candidates for phototherapy or systemic therapy. Eligible patients were randomly assigned with permuted block randomisation using an interactive web response system to receive either guselkumab (100 mg at weeks 0 and 4 then every 8 weeks) or secukinumab (300 mg at weeks 0, 1, 2, 3, and 4, and then every 4 weeks). The primary endpoint, the proportion of patients in the intention-to-treat population who achieved 90% reduction or more from baseline of Psoriasis Area and Severity Index (PASI 90 response) at week 48, and major secondary endpoints (the proportions of patients in the guselkumab group and in the secukinumab group who achieved a PASI 75 response at both weeks 12 and 48, a PASI 90 response at week 12, a PASI 75 response at week 12, a PASI 100 response at week 48, an Investigator's Global Assessment [IGA] score of 0 [cleared] at week 48, and an IGA score of 0 or 1 [minimal] at week 48) were to be tested in a fixed sequence to control type I error rate. Safety was evaluated in patients who received one or more doses of study drug from week 0 to 56. The study is registered with ClinicalTrials.gov, NCT03090100. FINDINGS: This study was done between April 27, 2017, and Sept 20, 2018. 1048 eligible patients were enrolled and, of these, 534 were assigned to receive guselkumab and 514 to receive secukinumab. The proportion of patients with a PASI 90 response at week 48 was greater in the guselkumab group (451 [84%]) than in the secukinumab group (360 [70%]; p<0·0001). Although non-inferiority (margin of 10 percentage points) was established for the first major secondary endpoint (452 [85%] of patients in the guselkumab group vs 412 [80%] of patients in the secukinumab group achieving a PASI 75 response at both weeks 12 and 48), superiority was not established (p=0·0616). Consequently, formal statistical testing was not done for subsequent major secondary endpoints. Proportions of patients with adverse events, infections, and serious adverse events were similar between the two treatments and, in general, safety findings were consistent with registrational trial observations. INTERPRETATION: Guselkumab showed superior long-term efficacy based on PASI 90 at week 48 when compared with secukinumab for treating moderate-to-severe psoriasis. This finding could assist health-care providers in their decision making process when selecting a biologic for treating moderate-to-severe psoriasis. FUNDING: This study was funded by Janssen Research & Development.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Produtos Biológicos/uso terapêutico , Psoríase/tratamento farmacológico , Adulto , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais Humanizados , Produtos Biológicos/administração & dosagem , Método Duplo-Cego , Feminino , Humanos , Interleucina-17/antagonistas & inibidores , Subunidade p19 da Interleucina-23/antagonistas & inibidores , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Resultado do Tratamento
5.
J Drugs Dermatol ; 18(8): 776-788, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31424708

RESUMO

Psoriasis (PsO) is a common, systemic, chronic inflammatory disease characterized by key clinical symptoms, including itching, pain, and scaling, and is associated with substantial physical, psychosocial, and economic health burdens. Currently, there is no cure for PsO; however, the introduction of biologic therapies has revolutionized the clinical management of patients with PsO by expanding treatment options to include multiple therapies with different mechanisms of action targeting cytokines, including tumor necrosis factor inhibitors (TNFis), interleukin (IL)-17A inhibitors, an IL-12/23 inhibitor, and IL-23 inhibitors. TNFis are historically considered the first-line biologic treatment and the first-generation biologics; however, increased understanding of TNF-α and IL-17 synergistic functions have recently led to evidence that specifically targeting IL-17 may be more likely to improve disease activity than a more general, nonspecific therapy target, such as TNF-α. This review highlights currently available evidence and demonstrates the differences between TNFis and IL-17A inhibitors in patients with PsO with regard to efficacy and safety.


Assuntos
Produtos Biológicos/uso terapêutico , Interleucina-17/antagonistas & inibidores , Psoríase/tratamento farmacológico , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Produtos Biológicos/farmacologia , Ensaios Clínicos como Assunto , Humanos , Reação no Local da Injeção/epidemiologia , Reação no Local da Injeção/etiologia , Interleucina-17/imunologia , Psoríase/diagnóstico , Psoríase/imunologia , Infecções Respiratórias/epidemiologia , Infecções Respiratórias/etiologia , Índice de Gravidade de Doença , Resultado do Tratamento , Fator de Necrose Tumoral alfa/imunologia
6.
J Dermatol Sci ; 95(3): 90-98, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31362906

RESUMO

BACKGROUND: Psoriasis is a chronic inflammatory skin disease. Anti-TNFα, IL-17A and IL-23p19 antibodies are effective for psoriasis. However, the contribution of regulatory T cells (Treg) in their effectiveness remains to be elucidated. OBJECTIVE: We investigated the effects of TNFα, IL-17A and IL-23p19 inhibition on Tregs in imiquimod-induced psoriasiform dermatitis. METHODS: Psoriasiform dermatitis was induced by imiquimod application on murine shaved back skin for six days. Mice were treated with anti-TNFα, IL-17A or IL-23p19 monoclonal antibodies every other day from one day before imiquimod application. RESULTS: Administration of anti-TNFα, IL-17A or IL-23p19 antibodies improved the clinical score and downregulated Th17-related cytokines and chemokines, while IL-23p19 antibodies upregulated IL-10 mRNA expression. Anti-IL-17A or IL-23p19 antibody-treated imiquimod-applied mice showed a significant increase in the number of Foxp3+ IL-10+ Tregs. Recipient mice adoptively transferred with Tregs derived from donor mice treated with antibodies demonstrated clinical and pathological improvement in imiquimod-induced psoriasiform dermatitis. Anti-IL-17A or IL-23p19 antibody-induced Tregs significantly increased the number of Foxp3+ cells and IL-10 expression in imiquimod-induced psoriasiform dermatitis in recipient mice but anti-TNFα antibody-induced Tregs did not. CONCLUSION: Anti-IL-17A or IL-23p19 antibody inhibits the IL-17/IL-23 signaling pathway, and induces expansion of Tregs and their suppressive capacity in imiquimod-induced psoriasiform dermatitis.


Assuntos
Anticorpos Monoclonais/farmacologia , Interleucina-17/antagonistas & inibidores , Subunidade p19 da Interleucina-23/antagonistas & inibidores , Psoríase/tratamento farmacológico , Linfócitos T Reguladores/efeitos dos fármacos , Transferência Adotiva , Animais , Anticorpos Monoclonais/uso terapêutico , Modelos Animais de Doenças , Feminino , Humanos , Imiquimode/administração & dosagem , Imiquimode/imunologia , Interleucina-17/metabolismo , Subunidade p19 da Interleucina-23/metabolismo , Camundongos , Psoríase/imunologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Pele , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/transplante , Células Th17/efeitos dos fármacos , Células Th17/imunologia , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/metabolismo
7.
EBioMedicine ; 46: 330-341, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31331833

RESUMO

BACKGROUND: There is increasing evidence supporting the impact of neoosteogenesis in the pathophysiology of chronic rhinosinusitis (CRS), especially in the recalcitrant group of patients. Runt-related transcription factor 2 (RUNX2), a member of the RUNX family, controls osteoblast differentiation and bone formation. However, the role and regulation of RUNX2 in CRS patients with neoosteogenesis remain unclear. The aim of the study is to determine the role of RUNX2 in neoosteogenesis of CRS patients. METHODS: Sinonasal bone and overlying mucosa samples were obtained from CRS patients with or without neoosteogenesis (n = 67) and healthy controls (n = 11). Double immunofluorescence, immunohistochemistry, and immunoblotting were used to evaluate RUNX2 expression in CRS patients with and without neoosteogenesis. In addition, the osteogenic activity of pro-inflammatory cytokines was examined by measuring alkaline phosphatase (ALP) activity and bone mineralisation in vitro. FINDINGS: RUNX2 was highly expressed in osteoblasts of CRS patients with neoosteogenesis compared with tissues from control subjects and those with CRS without neoosteogenesis. Mucosal extracts from CRS patients with neoosteogenesis showed increased RUNX2 expression and ALP activity in C2C12 cells, whereas those from patients without neoosteogenesis did not. Expression of interleukin (IL)-13 and IL-17A was upregulated in CRS patients with neoosteogenesis. ALP activity and Alizarin Red staining showed IL-13 and IL-17A dose-dependent osteoblast differentiation and mineralisation in vitro. INTERPRETATION: These findings suggested that IL-13- or IL-17A-induced RUNX2 contributed to new bone formation in CRS patients through its effect on the activity of osteoblasts. RUNX2 may be a novel target for preventing neoosteogenesis in CRS patients.


Assuntos
Subunidade alfa 1 de Fator de Ligação ao Core/genética , Interleucina-13/metabolismo , Interleucina-17/metabolismo , Osteogênese/genética , Rinite/etiologia , Rinite/metabolismo , Sinusite/etiologia , Sinusite/metabolismo , Adulto , Animais , Biomarcadores , Cálcio/metabolismo , Linhagem Celular , Citocinas/metabolismo , Suscetibilidade a Doenças , Feminino , Regulação da Expressão Gênica , Humanos , Imuno-Histoquímica , Interleucina-13/antagonistas & inibidores , Interleucina-17/antagonistas & inibidores , Masculino , Camundongos , Pessoa de Meia-Idade , Osteoblastos/metabolismo
8.
Biochemistry (Mosc) ; 84(Suppl 1): S193-S205, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31213202

RESUMO

Cytokines of the IL-17 family play a key role in the host organism defense against bacterial and fungal infections. At the same time, upregulated synthesis of IL-17 cytokines is associated with immunoinflammatory and autoimmune diseases such as psoriasis, rheumatoid arthritis, systemic lupus erythematosus, and others. The members of this family are important therapeutic targets in the treatment of various human chronic inflammatory disorders. Elucidation of signaling pathways involving IL-17 family proteins and analysis of the structure of cytokine complexes with specific antibodies, inhibitors, and receptors are essential for the development of new drugs for the therapy of immunoinflammatory rheumatic diseases.


Assuntos
Doenças Autoimunes/imunologia , Interleucina-17 , Terapia de Alvo Molecular , Linfócitos T/imunologia , Anticorpos Monoclonais/farmacologia , Humanos , Interleucina-17/antagonistas & inibidores , Interleucina-17/química , Interleucina-17/fisiologia , Estrutura Quaternária de Proteína , Transdução de Sinais
9.
Clin Drug Investig ; 39(8): 799-803, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31168691

RESUMO

BACKGROUND: Up to December 2018, eight cases of new-onset inflammatory bowel disease (IBD) were reported in the literature in patients being treated with secukinumab, an interleukin-17A antagonist prescribed for dermatologic or rheumatologic indications. The duration of secukinumab treatment ranged from a single administration to 12 months of treatment. OBJECTIVE: The aim of our investigation was to estimate the cumulative incidence of new-onset IBD in patients treated with secukinumab for either dermatologic or rheumatologic indications. METHODS: We carried out a survey among the dermatology and rheumatology centres in the Sicilian region (Italy) in order to identify the number of patients treated with secukinumab in the previous 24 months (November 2016-November 2018), and to understand how many of these patients eventually developed IBD after the start of secukinumab therapy. RESULTS: Overall, four cases of IBD during secukinumab treatment were identified, with higher variability in time to onset compared with what has been previously reported, i.e. from 1 month to 5 years of secukinumab exposure. Overall, 434 patients were treated with secukinumab in Sicily between November 2016 and November 2018, and approximately 1% of these patients developed new-onset IBD. CONCLUSIONS: Careful clinical examination of patients with respect to possible susceptibility to IBD prior to secukinumab therapy is advised.


Assuntos
Anticorpos Monoclonais/efeitos adversos , Fármacos Dermatológicos/efeitos adversos , Doenças Inflamatórias Intestinais/induzido quimicamente , Interleucina-17/antagonistas & inibidores , Adolescente , Adulto , Anticorpos Monoclonais Humanizados , Feminino , Humanos , Incidência , Itália , Masculino , Pessoa de Meia-Idade , Adulto Jovem
10.
BioDrugs ; 33(4): 391-399, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31172372

RESUMO

Psoriasis is a chronic inflammatory skin disease with significant psychological and physical impact. Over the last few decades, several highly effective target therapies have been developed, leading to a major paradigm shift in the way psoriatic disease is managed. Despite this, a proportion of patients still do not respond or lose response over time. Bispecific antibodies target two different cytokines simultaneously, potentially offering a better disease control. Interleukin (IL)-17A and IL-17F share structural homology and have similar biologic function. IL-17A is classically considered to be the most biologically active, but recent studies have shown that IL-17F is also increased in psoriatic skin and synovial cell in psoriatic arthritis, supporting the rationale for targeting both IL-17A and IL-17F in psoriatic disease. Bimekizumab is the first-in-class monoclonal antibody designed to simultaneously target IL-17A and IL-17F. Bimekizumab is currently in clinical development for psoriasis, psoriatic arthritis, and ankylosing spondylitis, with promising results. In early clinical trials, bimekizumab demonstrated a rapid onset of action, good safety profile, and high tolerability by treated study participants. Long-term results and head-to-head trials comparing bimekizumab with other agents will be crucial to define the role of bimekizumab in the treatment of psoriatic disease.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Psoríase/tratamento farmacológico , Espondilite Anquilosante/tratamento farmacológico , Anticorpos Monoclonais Humanizados/farmacologia , Ensaios Clínicos como Assunto , Humanos , Interleucina-17/antagonistas & inibidores , Interleucina-17/imunologia , Psoríase/imunologia , Pele/efeitos dos fármacos , Pele/imunologia , Espondilite Anquilosante/imunologia , Membrana Sinovial/efeitos dos fármacos , Membrana Sinovial/imunologia , Resultado do Tratamento
11.
MAbs ; 11(6): 1175-1190, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31181988

RESUMO

We describe a bispecific dual-antagonist antibody against human B cell activating factor (BAFF) and interleukin 17A (IL-17). An anti-IL-17 single-chain variable fragment (scFv) derived from ixekizumab (Taltz®) was fused via a glycine-rich linker to anti-BAFF tabalumab. The IgG-scFv bound both BAFF and IL-17 simultaneously with identical stoichiometry as the parental mAbs. Stability studies of the initial IgG-scFv revealed chemical degradation and aggregation not observed in either parental antibody. The anti-IL-17 scFv showed a high melting temperature (Tm) by differential scanning calorimetry (73.1°C), but also concentration-dependent, initially reversible, protein self-association. To engineer scFv stability, three parallel approaches were taken: labile complementary-determining region (CDR) residues were replaced by stable, affinity-neutral amino acids, CDR charge distribution was balanced, and a H44-L100 interface disulfide bond was introduced. The Tm of the disulfide-stabilized scFv was largely unperturbed, yet it remained monodispersed at high protein concentration. Fluorescent dye binding titrations indicated reduced solvent exposure of hydrophobic residues and decreased proteolytic susceptibility was observed, both indicative of enhanced conformational stability. Superimposition of the H44-L100 scFv (PDB id: 6NOU) and ixekizumab antigen-binding fragment (PDB id: 6NOV) crystal structures revealed nearly identical orientation of the frameworks and CDR loops. The stabilized bispecific molecule LY3090106 (tibulizumab) potently antagonized both BAFF and IL-17 in cell-based and in vivo mouse models. In cynomolgus monkey, it suppressed B cell development and survival and remained functionally intact in circulation, with a prolonged half-life. In summary, we engineered a potent bispecific antibody targeting two key cytokines involved in human autoimmunity amenable to clinical development.


Assuntos
Anticorpos Biespecíficos , Doenças Autoimunes/tratamento farmacológico , Fator Ativador de Células B/antagonistas & inibidores , Interleucina-17/antagonistas & inibidores , Anticorpos de Cadeia Única , Animais , Anticorpos Biespecíficos/imunologia , Anticorpos Biespecíficos/farmacologia , Anticorpos Monoclonais Humanizados/imunologia , Anticorpos Monoclonais Humanizados/farmacologia , Doenças Autoimunes/imunologia , Doenças Autoimunes/patologia , Fator Ativador de Células B/imunologia , Feminino , Células HEK293 , Células HT29 , Humanos , Interleucina-17/imunologia , Macaca fascicularis , Camundongos , Camundongos Transgênicos , Anticorpos de Cadeia Única/imunologia , Anticorpos de Cadeia Única/farmacologia
13.
Expert Opin Pharmacother ; 20(12): 1483-1491, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31095430

RESUMO

Introduction: Spondyloarthritis (SpA) refers to a group of disorders sharing common clinical, genetic and imaging characteristics. Axial (ax) SpA corresponds to a subgroup that mainly affects the axial skeleton, leading to inflammatory back pain and progressive radiographic changes of the sacroiliac joints and the spine. axSpA are currently subdivided into two forms, namely the radiographic and nonradiographic form, and are associated with musculoskeletal pain, restriction of spinal mobility, specific extra-articular features and overall, altered quality of life. The therapeutic management of axSpA has considerably progressed and is now well standardized. Areas covered: Herein, the author reviews the pharmacological treatments that may be used in axSpA, including radiographic and nonradiographic forms in addition to the role of nonsteroidal anti-inflammatory drugs (NSAIDs), TNF alpha (TNFi), and IL-17A (IL-17Ai) inhibitors. Expert opinion: NSAIDs remain the mainstay of initial therapy and biological agents may be then envisaged. TNFi and IL-17Ai may be used in axSpA, but physicians have more experience with TNFi. Only TNFi are licensed for the treatment of nonradiographic axSpA. IL-17Ai may be used as first or second line biologic disease modifying antirheumatic drugs (bDMARDs) and further results are needed to better define their position in the therapeutic management of axSpA.


Assuntos
Antirreumáticos/classificação , Antirreumáticos/uso terapêutico , Espondilartrite/tratamento farmacológico , Adulto , Anti-Inflamatórios não Esteroides/uso terapêutico , Produtos Biológicos/uso terapêutico , Humanos , Interleucina-17/antagonistas & inibidores , Dor/tratamento farmacológico , Dor/epidemiologia , Qualidade de Vida , Espondilartrite/epidemiologia , Espondilite Anquilosante/tratamento farmacológico , Espondilite Anquilosante/epidemiologia , Fator de Necrose Tumoral alfa/antagonistas & inibidores
14.
Trop Doct ; 49(3): 215-217, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30967096

RESUMO

Several biological agents have been approved for the treatment of recalcitrant psoriasis. However, there is a lack of a consensus algorithm guiding the drug selection for patients who have failed conventional drugs. In cases not improving with cyclosporine, direct switching to a biological therapy usually leads to a disease flare owing to increased production of interleukin (IL)-17A. Thus, secukinumab, a rapidly acting anti-IL-17A drug, may be ideal in such situations.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Psoríase/tratamento farmacológico , Anticorpos Monoclonais Humanizados , Ciclosporina/administração & dosagem , Fármacos Dermatológicos/administração & dosagem , Humanos , Interleucina-17/antagonistas & inibidores , Leflunomida/administração & dosagem , Masculino , Metotrexato/administração & dosagem , Pessoa de Meia-Idade , Falha de Tratamento , Tuberculose
15.
Acta Derm Venereol ; 99(9): 769-773, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31017250

RESUMO

Interleukin-17A inhibitors are a promising alternative to tumor necrosis factor-α inhibitors for the treatment of psoriasis. In-class switch has been hardly investigated for interleukin-17A inhibitors. We report the experience (2017-2018) of a tertiary medical center with interleukin-17A-inhibitor switch in patients with moderate-to-severe psoriasis. Patient-, disease- and outcome-related data were retrospectively collected from the electronic files of 25 patients switched to ixekizumab following secukinumab failure. Mean ± standard deviation patient age was 56.7 ± 12.2 years. Mean baseline Psoriasis Area and Severity Index was 25. Secukinumab was discontinued due to primary failure in 7 patients and secondary failure in 18. Ixekizumab was administered for 7.3 ± 2.8 months; 22 patients were still on ixekizumab at the end of the study. Mean ± standard deviation Psoriasis Area and Severity Index reduction from baseline at study end was 75.5±20.0%. Patients with moderate-to-severe psoriasis seem to be amenable to treatment with ixekizumab following secukinumab failure. Further large multicenter studies are needed.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Produtos Biológicos/uso terapêutico , Substituição de Medicamentos , Interleucina-17/antagonistas & inibidores , Psoríase/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/efeitos adversos , Produtos Biológicos/efeitos adversos , Feminino , Humanos , Interleucina-17/imunologia , Masculino , Pessoa de Meia-Idade , Psoríase/diagnóstico , Psoríase/imunologia , Estudos Retrospectivos , Índice de Gravidade de Doença , Falha de Tratamento
16.
Immunity ; 50(4): 892-906, 2019 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-30995505

RESUMO

The interleukin 17 (IL-17) family of cytokines contains 6 structurally related cytokines, IL-17A through IL-17F. IL-17A, the prototypical member of this family, just passed the 25th anniversary of its discovery. Although less is known about IL-17B-F, IL-17A (commonly known as IL-17) has received much attention for its pro-inflammatory role in autoimmune disease. Over the past decade, however, it has become clear that the functions of IL-17 are far more nuanced than simply turning on inflammation. Accumulating evidence indicates that IL-17 has important context- and tissue-dependent roles in maintaining health during response to injury, physiological stress, and infection. Here, we discuss the functions of the IL-17 family, with a focus on the balance between the pathogenic and protective roles of IL-17 in cancer and autoimmune disease, including results of therapeutic blockade and novel aspects of IL-17 signal transduction regulation.


Assuntos
Citocinas/imunologia , Interleucina-17/imunologia , Animais , Doenças Autoimunes/imunologia , Doenças Autoimunes/terapia , Encéfalo/imunologia , Regulação da Expressão Gênica , Humanos , Inflamação/imunologia , Interleucina-17/antagonistas & inibidores , Camundongos , Terapia de Alvo Molecular , Neoplasias/imunologia , Proteínas de Ligação a RNA/imunologia , Receptores de Interleucina-17/antagonistas & inibidores , Receptores de Interleucina-17/imunologia , Transdução de Sinais , Estresse Fisiológico/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Ferimentos e Lesões/imunologia
17.
Inflamm Res ; 68(6): 493-509, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30972425

RESUMO

OBJECTIVE AND DESIGN: To evaluate the potency of RORγt blockade for treatment of Inflammatory Bowel Disease (IBD), the efficacy of TAK-828F, a novel RORγt inverse agonist, in anti-TNF-α mAb non-responsive mouse colitis model and effect of TAK-828F on IL-17 production in peripheral mononuclear blood cells (PBMCs) of anti-TNF-α naive and treatment-failure patients of IBD was investigated. METHODS AND RESULTS: The colitis model showed Th17-dependent pathogenicity and response to anti-IL-12/23p40 monoclonal antibody (mAb), but no response to anti-TNF-α mAb. In the model, TAK-828F, at oral dosages of 1 and 3 mg/kg, inhibited progression of colitis and reduced the immune reaction that characterize Th17 cells. Anti-IL-17A mAb showed neither efficacy nor change in the T cell population and colonic gene expression in the model. In the normal mouse, a 4-week treatment of TAK-828F at 30 mg/kg did not severely reduce lymphocyte cell counts in peripheral and intestinal mucosa, which was observed in RORγ-/- mice. TAK-828F strongly inhibited IL-17 gene expression with IC50 values from 21.4 to 34.4 nmol/L in PBMCs from anti-TNF mAb naive and treatment-failure patients of IBD. CONCLUSIONS: These results indicate that RORγt blockade would provide an effective approach for treating refractory patients with IBD by blocking IL-23/Th17 pathway.


Assuntos
Acetatos/farmacologia , Acetatos/uso terapêutico , Doenças Inflamatórias Intestinais/tratamento farmacológico , Leucócitos Mononucleares/efeitos dos fármacos , Naftiridinas/farmacologia , Naftiridinas/uso terapêutico , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/imunologia , Adolescente , Adulto , Animais , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Células Cultivadas , Colo/efeitos dos fármacos , Colo/imunologia , Colo/patologia , Modelos Animais de Doenças , Feminino , Humanos , Doenças Inflamatórias Intestinais/genética , Doenças Inflamatórias Intestinais/imunologia , Interleucina-17/antagonistas & inibidores , Interleucina-17/genética , Interleucina-17/imunologia , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/imunologia , Mucosa Intestinal/patologia , Leucócitos Mononucleares/imunologia , Masculino , Camundongos Endogâmicos BALB C , Camundongos Knockout , Camundongos SCID , Pessoa de Meia-Idade , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Adulto Jovem
18.
Dermatol Ther ; 32(3): e12899, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30969010

RESUMO

Acrodermatitis continua of Hallopeau (ACH) is a rare pustular psoriasis variant refractory to many conventional treatments. We report the successful treatment with secukinumab of a patient with a long history of ACH with marked onychodystrophy with frank pustulosis on the nail bed and with accompanying arthritis. Blockade of the IL-17 receptor A has shown promise in the treatment of psoriatic erythroderma and generalized pustular psoriasis not responsive to conventional treatment. A rapid response was observed in our patient, in both skin lesions and arthritic symptoms, underlining the ability of secukinumab to improve symptoms beyond those of plaque psoriasis.


Assuntos
Acrodermatite/tratamento farmacológico , Anticorpos Monoclonais Humanizados/uso terapêutico , Adulto , Feminino , Humanos , Interleucina-17/antagonistas & inibidores
19.
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
20.
Inflammation ; 42(4): 1401-1412, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30945038

RESUMO

Acute lung injury (ALI) is a syndrome characterized by damage to the alveolar-capillary wall, pulmonary edema and recruitment of inflammatory cells. Previous studies have indicated that aquaporin 4 (AQP4) plays a key role in brain edema formation and resolution. However, the role of AQP4 in the development and progression of ALI is not clear and needs to be resolved. In our current study, mouse ALI was induced by intratracheal instillation of lipopolysaccharide (LPS) at a concentration of 30 mg/kg. For the inhibition of AQP4, 200 mg/kg of TGN-020 (Sigma, USA) was administered intraperitoneally every 6 h starting at 30 min before intratracheal instillation of LPS. The results of the present work indicate, for the first time, that mice treated with the AQP4 inhibitor TGN-020 had attenuated LPS-induced lung injury, reduced proinflammatory cytokine release (including IL-1α, IL-1ß, IL-6, TNF-α, IL-23, and IL-17A), and an improved survival rate. Additionally, we found that the attenuated lung injury scores, increased survival rate, and decreased BALF total protein concentration in TGN-020-treated mice were all abrogated by rIL-17A administration. Furthermore, TGN-020 treatment downregulated the phosphorylation of PI3K and Akt, increased the expression of SOCS3, and decreased the expression of p-STAT3 and RORγt. In conclusion, inhibition of AQP4 by TGN-020 has a detectable protective effect against lung tissue injury induced by LPS, and this effect is associated with inhibition of IL-17A through the downregulation of the PI3K/Akt signaling pathway and upregulation of SOCS3 protein.


Assuntos
Lesão Pulmonar Aguda/prevenção & controle , Aquaporina 4/antagonistas & inibidores , Proliferação de Células/efeitos dos fármacos , Interleucina-17/antagonistas & inibidores , Células Th17/efeitos dos fármacos , Animais , Lipopolissacarídeos/farmacologia , Camundongos , Niacinamida/análogos & derivados , Niacinamida/farmacologia , Proteína Oncogênica v-akt/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Supressoras da Sinalização de Citocina/metabolismo , Células Th17/citologia , Tiadiazóis/farmacologia
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