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2.
Medicine (Baltimore) ; 99(2): e18723, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31914087

RESUMO

Effectiveness, efficacy and safety of biosimilar infliximab (CT-P13) in inflammatory bowel disease (IBD) patients has been shown in previous studies. Limited data exist on health-related quality of life (HRQoL) of switching originator to biosimilar infliximab (IFX) in IBD patients. The objective of this study was to evaluate impact of switching originator to biosimilar IFX on HRQoL, disease activity, and health care costs in IBD maintenance treatment.In this single-center prospective observational study, all IBD patients receiving maintenance IFX therapy were switched to biosimilar IFX. HRQoL was measured using the generic 15D health-related quality of life instrument (15D) utility measurement and the disease-specific Inflammatory Bowel Disease Questionnaire (IBDQ). Crohn Disease Activity Index (CDAI) or Partial Mayo Score (pMayo), and fecal calprotectin (FC) served for evaluation of disease activity. Data were collected at time of switching and 3 and 12 months after switching. Patients' characteristics, clinical background information and costs were collected from patient records and the hospital's electronic database.Fifty-four patients were included in the analysis. No statistically significant changes were observed in 15D, CDAI, pMayo, and FC during 1-year follow-up. IBDQ scores were higher (P = .018) in Crohn disease 3 months after switching than at time of switching. Costs of biosimilar IFX were one-third of costs of originator one. Total costs related to secondary health care (excluding costs of IFX), were similar before and after the onset of biosimilar IFX.HRQoL and disease activity were after switching from originator to biosimilar IFX comparable, but the costs of biosimilar IFX were only one-third of those of the originator one.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Medicamentos Biossimilares/uso terapêutico , Fármacos Gastrointestinais/uso terapêutico , Doenças Inflamatórias Intestinais/tratamento farmacológico , Infliximab/uso terapêutico , Qualidade de Vida , Adulto , Anticorpos Monoclonais/economia , Medicamentos Biossimilares/economia , Substituição de Medicamentos/economia , Feminino , Fármacos Gastrointestinais/economia , Recursos em Saúde/economia , Serviços de Saúde/economia , Serviços de Saúde/estatística & dados numéricos , Humanos , Infliximab/economia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Indução de Remissão
3.
Epidemiol Psychiatr Sci ; 29: e84, 2020 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-31915099

RESUMO

AIMS: Although immune-mediated inflammatory diseases (IMID) are associated with multiple mental health conditions, there is a paucity of literature assessing personality disorders (PDs) in these populations. We aimed to estimate and compare the incidence of any PD in IMID and matched cohorts over time, and identify sociodemographic characteristics associated with the incidence of PD. METHODS: We used population-based administrative data from Manitoba, Canada to identify persons with incident inflammatory bowel disease (IBD), multiple sclerosis (MS) and rheumatoid arthritis (RA) using validated case definitions. Unaffected controls were matched 5:1 on sex, age and region of residence. PDs were identified using hospitalisation or physician claims. We used unadjusted and covariate-adjusted negative binomial regression to compare the incidence of PDs between the IMID and matched cohorts. RESULTS: We identified 19 572 incident cases of IMID (IBD n = 6,119, MS n = 3,514, RA n = 10 206) and 97 727 matches overall. After covariate adjustment, the IMID cohort had an increased incidence of PDs (incidence rate ratio [IRR] 1.72; 95%CI: 1.47-2.01) as compared to the matched cohort, which remained consistent over time. The incidence of PDs was similarly elevated in IBD (IRR 2.19; 95%CI: 1.69-2.84), MS (IRR 1.79; 95%CI: 1.29-2.50) and RA (IRR 1.61; 95%CI: 1.29-1.99). Lower socioeconomic status and urban residence were associated with an increased incidence of PDs, whereas mid to older adulthood (age 45-64) was associated with overall decreased incidence. In a restricted sample with 5 years of data before and after IMID diagnosis, the incidence of PDs was also elevated before IMID diagnosis among all IMID groups relative to matched controls. CONCLUSIONS: IMID are associated with an increased incidence of PDs both before and after an IMID diagnosis. These results support the relevance of shared risk factors in the co-occurrence of PDs and IMID conditions.


Assuntos
Artrite Reumatoide/epidemiologia , Doenças do Sistema Imunitário/complicações , Inflamação/complicações , Doenças Inflamatórias Intestinais/epidemiologia , Esclerose Múltipla/epidemiologia , Transtornos da Personalidade/epidemiologia , Adolescente , Adulto , Canadá/epidemiologia , Estudos de Coortes , Comorbidade/tendências , Feminino , Humanos , Doenças do Sistema Imunitário/epidemiologia , Incidência , Inflamação/epidemiologia , Masculino , Manitoba/epidemiologia , Pessoa de Meia-Idade , Transtornos da Personalidade/psicologia , Fatores de Risco , Fatores Socioeconômicos , Adulto Jovem
8.
Gut ; 69(2): 252-263, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31092589

RESUMO

OBJECTIVE: To study the role of α4ß7 integrin for gut homing of monocytes and to explore the biological consequences of therapeutic α4ß7 inhibition with regard to intestinal wound healing. DESIGN: We studied the expression of homing markers on monocyte subsets in the peripheral blood and on macrophage subsets in the gut of patients with IBD and controls with flow cytometry and immunohistochemistry. Integrin function was addressed with dynamic adhesion assays and in vivo gut homing assays. In vivo wound healing was studied in mice deficient for or depleted of α4ß7 integrin. RESULTS: Classical and non-classical monocytes were clearly dichotomous regarding homing marker expression including relevant expression of α4ß7 integrin on human and mouse non-classical monocytes but not on classical monocytes. Monocyte-expressed α4ß7 integrin was functionally important for dynamic adhesion to mucosal vascular addressin cell adhesion molecule 1 and in vivo gut homing. Impaired α4ß7-dependent gut homing was associated with reduced (effect size about 20%) and delayed wound healing and suppressed perilesional presence of wound healing macrophages. Non-classical monocytes in the peripheral blood were increased in patients with IBD under clinical treatment with vedolizumab. CONCLUSION: In addition to reported effects on lymphocytes, anti-α4ß7 therapy in IBD also targets non-classical monocytes. Impaired gut homing of such monocytes might lead to a reduction of wound healing macrophages and could potentially explain increased rates of postoperative complications in vedolizumab-treated patients, which have been observed in some studies.


Assuntos
Doenças Inflamatórias Intestinais/patologia , Integrinas/fisiologia , Intestinos/patologia , Monócitos/fisiologia , Cicatrização/fisiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Anticorpos Monoclonais Humanizados/farmacologia , Estudos de Casos e Controles , Adesão Celular/efeitos dos fármacos , Adesão Celular/fisiologia , Quimiotaxia de Leucócito/fisiologia , Feminino , Fármacos Gastrointestinais/farmacologia , Humanos , Doenças Inflamatórias Intestinais/sangue , Doenças Inflamatórias Intestinais/fisiopatologia , Integrinas/antagonistas & inibidores , Integrinas/sangue , Mucosa Intestinal/metabolismo , Intestinos/fisiologia , Masculino , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Monócitos/metabolismo , Cicatrização/efeitos dos fármacos , Adulto Jovem
9.
Gut ; 69(2): 264-273, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31097538

RESUMO

OBJECTIVE: The interleukin (IL)23 pathway contributes to IBD pathogenesis and is being actively studied as a therapeutic target in patients with IBD. Unexpected outcomes in these therapeutic trials have highlighted the importance of understanding the cell types and mechanisms through which IL23 regulates immune outcomes. How IL23 regulates macrophage outcomes and the consequences of the IL23R R381Q IBD-protective variant on macrophages are not well defined; macrophages are key players in IBD pathogenesis and inflammation. DESIGN: We analysed protein and RNA expression, signalling and localisation in human monocyte-derived macrophages (MDMs) through western blot, ELISA, real-time PCR, flow cytometry, immunoprecipitation and microscopy. RESULTS: IL23R was critical for optimal levels of pattern-recognition receptor (PRR)-induced signalling and cytokines in human MDMs. In contrast to the coreceptor IL12Rß1, IL23 induced dynamic IL23R cell surface regulation and this required clathrin and dynamin-mediated endocytosis and endocytic recycling-dependent pathways; these pathways were essential for IL23R-mediated outcomes. The IBD-protective IL23R R381Q variant showed distinct outcomes. Relative to IL23R R381, HeLa cells expressing IL23R Q381 showed decreased IL23R recycling and reduced assembly of IL23R Q381 with Janus kinase/signal transducer and activator of transcription pathway members. In MDMs from IL23R Q381 carriers, IL23R accumulated in late endosomes and lysosomes on IL23 treatment and cells demonstrated decreased IL23R- and PRR-induced signalling and cytokines relative to IL23R R381 MDMs. CONCLUSION: Macrophage-mediated inflammatory pathways are key contributors to IBD pathogenesis, and we identify an autocrine/paracrine IL23 requirement in PRR-initiated human macrophage outcomes and in human intestinal myeloid cells, establish that IL23R undergoes ligand-induced recycling, define mechanisms regulating IL23R-induced signalling and determine how the IBD-protective IL23R R381Q variant modulates these processes.


Assuntos
Citocinas/imunologia , Doenças Inflamatórias Intestinais/imunologia , Macrófagos/imunologia , Receptores de Interleucina/imunologia , Comunicação Autócrina/imunologia , Endocitose/imunologia , Endossomos/imunologia , Variação Genética , Humanos , Imunidade Inata/genética , Imunidade Inata/imunologia , Doenças Inflamatórias Intestinais/genética , Doenças Inflamatórias Intestinais/prevenção & controle , Interleucina-23/imunologia , Janus Quinase 2/metabolismo , Comunicação Parácrina/imunologia , Receptores de Interleucina/genética , Receptores de Reconhecimento de Padrão/imunologia , Transdução de Sinais/imunologia
10.
Scand J Immunol ; 91(1): e12805, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31267543

RESUMO

Wiskott-Aldrich syndrome (WAS) is an X-linked primary immunodeficiency disease caused by a mutation in the WAS gene that encodes the WAS protein (WASp); up to 5-10% of these patients develop inflammatory bowel disease (IBD). The mechanisms by which WASp deficiency causes IBD are unclear. Intestinal microbial dysbiosis and imbalances in host immune responses play important roles in the pathogenesis of polygenetic IBD; however, few studies have conducted detailed examination of the microbial alterations and their relationship with IBD in WAS. Here, we collected faecal samples from 19 children (all less than 2 years old) with WAS and samples from WASp-KO mice with IBD and subjected them to 16S ribosomal RNA sequencing. We found that microbial community richness and structure in WAS children were different from those in controls; WAS children revealed reduced microbial community richness and diversity. Relative abundance of Bacteroidetes and Verrucomicrobiain in WAS children was significantly lower, while that of Proteobacteria was markedly higher. WASp-KO mice revealed a significantly decreased abundance of Firmicutes. Faecal microbial dysbiosis caused by WASp deficiency is similar to that observed for polygenetic IBD, suggesting that WASp may play crucial function in microbial homoeostasis and that microbial dysbiosis may contribute to IBD in WAS. These microbial alterations may be useful targets for monitoring and therapeutically managing intestinal inflammation in WAS.


Assuntos
Disbiose , Fezes/microbiologia , Microbioma Gastrointestinal , Síndrome de Wiskott-Aldrich/etiologia , Animais , Biodiversidade , Biomarcadores , Estudos de Casos e Controles , Pré-Escolar , Modelos Animais de Doenças , Feminino , Humanos , Lactente , Doenças Inflamatórias Intestinais/etiologia , Masculino , Metagenoma , Metagenômica/métodos , Camundongos , Camundongos Knockout , Mutação , RNA Ribossômico 16S/genética , Síndrome de Wiskott-Aldrich/diagnóstico , Proteína da Síndrome de Wiskott-Aldrich/deficiência
11.
Gut ; 69(2): 274-282, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31196874

RESUMO

OBJECTIVES: To better understand the real-world impact of biologic therapy in persons with Crohn's disease (CD) and ulcerative colitis (UC), we evaluated the effect of marketplace introduction of infliximab on the population rates of hospitalisations and surgeries and public payer drug costs. DESIGN: We used health administrative data to study adult persons with CD and UC living in Ontario, Canada between 1995 and 2012. We used an interrupted time series design with segmented regression analysis to evaluate the impact of infliximab introduction on the rates of IBD-related hospitalisations, intestinal resections and public payer drug costs over 10 years among patients with CD and 5 years among patients with UC, allowing for a 1-year transition. RESULTS: Relative to what would have been expected in the absence of infliximab, marketplace introduction of infliximab did not produce significant declines in the rates of CD-related hospitalisations (OR at the last observation quarter 1.06, 95% CI 0.811 to 1.39) or intestinal resections (OR 1.10, 95% CI 0.810 to 1.50), or in the rates of UC-related hospitalisations (OR 1.22, 95% CI 1.07 to 1.39) or colectomies (OR 0.933, 95% CI 0.54 to 1.61). The findings were similar among infliximab users, except that hospitalisation rates declined substantially among UC patients following marketplace introduction of infliximab (OR 0.515, 95% CI 0.342 to 0.777). There was a threefold rise over expected trends in public payer drug cost among patients with CD following infliximab introduction (OR 2.98,95% CI 2.29 to 3.86), suggesting robust market penetration in this group, but no significant change among patients with UC (OR 1.06, 95% CI 0.955 to 1.18). CONCLUSIONS: Marketplace introduction of infliximab has not yielded anticipated reductions in the population rates of IBD-related hospitalisations or intestinal resections, despite robust market penetration among patients with CD. Misguided use of infliximab in CD patients and underuse of infliximab in UC patients may largely explain our study findings.


Assuntos
Fármacos Gastrointestinais/uso terapêutico , Hospitalização/estatística & dados numéricos , Doenças Inflamatórias Intestinais/tratamento farmacológico , /uso terapêutico , Adulto , Colectomia/estatística & dados numéricos , Colectomia/tendências , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/epidemiologia , Colite Ulcerativa/cirurgia , Doença de Crohn/tratamento farmacológico , Doença de Crohn/epidemiologia , Doença de Crohn/cirurgia , Custos de Medicamentos/estatística & dados numéricos , Custos de Medicamentos/tendências , Feminino , Hospitalização/tendências , Humanos , Doenças Inflamatórias Intestinais/epidemiologia , Doenças Inflamatórias Intestinais/cirurgia , Análise de Séries Temporais Interrompida , Masculino , Pessoa de Meia-Idade , Ontário/epidemiologia , Fatores Socioeconômicos
14.
Inflamm Bowel Dis ; 26(2): 280-282, 2020 01 06.
Artigo em Inglês | MEDLINE | ID: mdl-31247090

RESUMO

Focal infection theory posits that periodontal pathobionts play a causal role in initiating or exacerbating diseases. Periodontal disease is a common inflammatory, multifactorial disease of the periodontal tissues. The main factor for inflammation is mature dental plaque with the presence of pathogens in the microbial biofilm. Disturbances of the systemic and/or mucosal immune system, antibiotic treatments, immunosuppressants, and biologic therapies all increase the chance of infections and inflammatory processes (ie, apical periodontitis). The pathogenesis of Crohn's disease and ulcerative colitis, the 2 main forms of inflammatory bowel disease (IBD), is still unclear, but both autoimmune and immune-mediated phenomena are involved. It is a global disease with a prevalence of 0.3% and an incidence of 280-320 per 100,000 people in North America. According to the literature, there is a negative association between poor oral health and risk of IBD, and this protective effect increases with the severity of poor dental hygiene. On the other hand, existing IBD seems to be associated with an increased risk of periodontal disease and worse oral health compared with other diseases. The nature of these associations is unclear, but it is unquestionable that all have an effect on the others. Additional studies are needed to confirm if there is a causal relationship between dental status and IBD. Apical periodontitis in patients affected by Crohn's disease or ulcerative colitis needs to be considered carefully, and it is important to treat the disease.


Assuntos
Colite Ulcerativa , Doenças Inflamatórias Intestinais , Periodontite Periapical , Estudos de Casos e Controles , Humanos , América do Norte , Prevalência
16.
J Enzyme Inhib Med Chem ; 35(1): 1-20, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31619080

RESUMO

Inflammatory bowel disease (IBD) is a chronic immuno-inflammation in gastrointestinal tract. We have evaluated the activity of the compounds to inhibit the adhesion of monocytes to colon epithelial cells is triggered by a pro-inflammatory cytokine, tumour necrosis factor (TNF)-α. The in vitro activity of the compounds, 13b (an ureido-derivative), 14c, 14j, 14k, 14n (thioureido-), 18c and 18d (sulfonamido-), was in correlation with in vivo anti-colitis activity revealed as significant recovery in body- and colon-weights and colon myeloperoxidase level, a biochemical marker of inflammation reflecting neutrophil infiltration. In vivo, TNBS-induced changes in the expression of inflammatory cytokines (TNF-α, IL-6, IL-1ß, IL-10, and TGF-ß), NLRP3 inflammasome components (NLRP-3, Caspase-1, and IL-18), and epithelial junction molecules (E-cadherin, claudin2/3, and ZO-1) were blocked and recovered by oral administration of the compounds (1 mg/kg). Compound 14n which showed the best efficacy can be a promising lead for orally available therapeutics for pathology of IBD.


Assuntos
Anti-Inflamatórios/farmacologia , Doenças Inflamatórias Intestinais/tratamento farmacológico , Piridinas/farmacologia , Animais , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/química , Células Cultivadas , Colite/induzido quimicamente , Colite/tratamento farmacológico , Citocinas/antagonistas & inibidores , Citocinas/metabolismo , Relação Dose-Resposta a Droga , Feminino , Células HT29 , Humanos , Doenças Inflamatórias Intestinais/patologia , Estrutura Molecular , Piridinas/síntese química , Piridinas/química , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Ácido Trinitrobenzenossulfônico , Células U937
17.
Inflamm Bowel Dis ; 26(1): 147-149, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31300824

RESUMO

Biologic therapy continues to be underutilized despite its efficacy and overall favorable side effect profile when compared with corticosteroids. Siegel et al found in a well-done, cross-sectional study that patients perceived that corticosteroids were more beneficial, more familiar, and less dreadful than biologics despite perceiving that corticosteroids are more risky. They also found that perception of risk may be influenced by a patient's personality trait. Patients who believe that their health is influenced by their own choices or behaviors perceived biologic therapy less scary compared with patients who believed their health is influenced by chance. Physicians and patients disagree about how much medication-related risk is tolerable for improvements on efficacy. However, they are both willing to accept risks for therapies that offer significant therapeutic benefit. Physicians are tasked to translate complex evidenced-based data accurately and should take into account a patient's personality trait in order to provide individualized care and help guide shared decision-making. Future research should assess physician's personality traits, treatment experiences, and perception of risks, benefits, and dread of IBD medications and how it influences shared-decision making.


Assuntos
Produtos Biológicos , Doenças Inflamatórias Intestinais , Terapia Biológica , Estudos Transversais , Humanos , Medição de Risco
20.
Gut ; 69(1): 83-91, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31611298

RESUMO

OBJECTIVE: The underlying microbial basis, predictors of therapeutic outcome and active constituent(s) of faecal microbiota transplantation (FMT) mediating benefit remain unknown. An international panel of experts presented key elements that will shape forthcoming FMT research and practice. DESIGN: Systematic search was performed, FMT literature was critically appraised and a 1-day round-table discussion was conducted to derive expert consensus on key issues in FMT research. RESULTS: 16 experts convened and discussed five questions regarding (1) the role of donor and recipient microbial (bacteria, viruses, fungi) parameters in FMT; (2) methods to assess microbiota alterations; (3) concept of keystone species and microbial predictors of FMT, (4) influence of recipient profile and antibiotics pretreatment on FMT engraftment and maintenance and (5) new developments in FMT formulations and delivery. The panel considered that variable outcomes of FMT relate to compositional and functional differences in recipient's microbiota, and likely donor-associated and recipient-associated physiological and genetic factors. Taxonomic composition of donor intestinal microbiota may influence the efficacy of FMT in recurrent Clostridioides difficile infections and UC. FMT not only alters bacteria composition but also establishes trans-kingdom equilibrium between gut fungi, viruses and bacteria to promote the recovery of microbial homeostasis. FMT is not a one size fits all and studies are required to identify microbial components that have specific effects in patients with different diseases. CONCLUSION: FMT requires optimisation before their therapeutic promise can be evaluated for different diseases. This summary will guide future directions and priorities in advancement of the science and practice of FMT.


Assuntos
Transplante de Microbiota Fecal/métodos , Antibacterianos/farmacologia , Clostridium difficile , Endoscopia Gastrointestinal , Enterocolite Pseudomembranosa/terapia , Fezes/microbiologia , Microbioma Gastrointestinal/efeitos dos fármacos , Microbioma Gastrointestinal/fisiologia , Humanos , Doenças Inflamatórias Intestinais/terapia , Prognóstico , Recidiva , Doadores de Tecidos , Resultado do Tratamento
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