RESUMO
Crohn's disease (CD) and celiac disease (CelD) are chronic intestinal inflammatory diseases, involving genetic and environmental factors in their pathogenesis. The two diseases can co-occur within families, and studies suggest that CelD patients have a higher risk to develop CD than the general population. These observations suggest that CD and CelD may share common genetic risk loci. Two such shared loci, IL18RAP and PTPN2, have already been identified independently in these two diseases. The aim of our study was to explicitly identify shared risk loci for these diseases by combining results from genome-wide association study (GWAS) datasets of CD and CelD. Specifically, GWAS results from CelD (768 cases, 1,422 controls) and CD (3,230 cases, 4,829 controls) were combined in a meta-analysis. Nine independent regions had nominal association p-value <1.0 x 10â»5 in this meta-analysis and showed evidence of association to the individual diseases in the original scans (p-value < 1 x 10⻲ in CelD and < 1 x 10⻳ in CD). These include the two previously reported shared loci, IL18RAP and PTPN2, with p-values of 3.37 x 10â»8 and 6.39 x 10â»9, respectively, in the meta-analysis. The other seven had not been reported as shared loci and thus were tested in additional CelD (3,149 cases and 4,714 controls) and CD (1,835 cases and 1,669 controls) cohorts. Two of these loci, TAGAP and PUS10, showed significant evidence of replication (Bonferroni corrected p-values <0.0071) in the combined CelD and CD replication cohorts and were firmly established as shared risk loci of genome-wide significance, with overall combined p-values of 1.55 x 10⻹° and 1.38 x 10⻹¹ respectively. Through a meta-analysis of GWAS data from CD and CelD, we have identified four shared risk loci: PTPN2, IL18RAP, TAGAP, and PUS10. The combined analysis of the two datasets provided the power, lacking in the individual GWAS for single diseases, to detect shared loci with a relatively small effect.
Assuntos
Doença Celíaca/genética , Doença de Crohn/genética , Proteínas Ativadoras de GTPase/genética , Predisposição Genética para Doença , Hidroliases/genética , Subunidade beta de Receptor de Interleucina-18/genética , Proteína Tirosina Fosfatase não Receptora Tipo 2/genética , Interpretação Estatística de Dados , Estudo de Associação Genômica Ampla , Humanos , Fatores de RiscoRESUMO
OBJECTIVE: Etrolizumab (rhuMAb ß7, anti-ß7, PRO145223) is a humanised monoclonal antibody targeting the ß7 subunit of the heterodimeric integrins α4ß7 and αEß7, which are implicated in leucocyte migration and retention in ulcerative colitis (UC). This randomised phase I study evaluated the safety and pharmacology of etrolizumab in patients with moderate to severe UC. DESIGN: In the single ascending dose (SAD) stage, etrolizumab (0.3, 1.0, 3.0, 10 mg/kg intravenous, 3.0 mg/kg subcutaneous (SC) or placebo) was administered 4:1 (n=25) in each cohort. In the multiple dose (MD) stage, new patients received monthly etrolizumab (0.5 mg/kg SC (n=4), 1.5 mg/kg SC (n=5), 3.0 mg/kg SC (n=4), 4.0 mg/kg intravenous (n=5)) or placebo (n=5). The pharmacokinetics was studied and Mayo Clinic Score evaluated at baseline, day 29 (SAD), and days 43 and 71 (MD). RESULTS: In the SAD stage, there were no dose limiting toxicities, infusion or injection site reactions. Two impaired wound healing serious adverse events occurred in two patients receiving etrolizumab. In the MD stage, there were no dose limiting toxicities, and no infusion or injection site reactions. Headache was the most common adverse event, occurring more often in etrolizumab patients. Antietrolizumab antibodies were detected in two subjects. The duration of ß7 receptor full occupancy was dose related. A clinical response was observed in 12/18 patients, and clinical remission in 3/18 patients treated with etrolizumab in the MD stage, compared with 4/5 and 1/5 placebo patients, respectively. CONCLUSION: Etrolizumab is well tolerated in moderate to severe UC. Further investigation is warranted.
Assuntos
Anticorpos Monoclonais/administração & dosagem , Colite Ulcerativa/tratamento farmacológico , Fármacos Gastrointestinais/administração & dosagem , Adolescente , Adulto , Idoso , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/sangue , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados , Colite Ulcerativa/sangue , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Fármacos Gastrointestinais/efeitos adversos , Fármacos Gastrointestinais/sangue , Fármacos Gastrointestinais/uso terapêutico , Humanos , Infusões Intravenosas , Injeções Subcutâneas , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Resultado do Tratamento , Adulto JovemRESUMO
OBJECTIVE: In the intestine Hedgehog (Hh) signalling is directed from epithelium to mesenchyme and negatively regulates epithelial precursor cell fate. The role of Hh signalling in the oesophagus has not been studied in vivo. Here the authors examined the role of Hh signalling in epithelial homeostasis of oesophagus. DESIGN: The authors used transgenic mice in which the Hh receptor Patched1 (Ptch1) could be conditionally inactivated in a body-wide manner and mice in which Gli1 could be induced specifically in the epithelium of the skin and oesophagus. Effects on epithelial homeostasis of the oesophagus were examined using immunohistochemistry, in situ hybridisation, transmission electron microscopy and real-time PCR. Hh signalling was examined in patients with oesophageal squamous cell carcinoma (SCC) by quantitative real-time PCR. RESULTS: Sonic Hh is signalled in an autocrine manner in the basal layer of the oesophagus. Activation of Hh signalling resulted in an expansion of the epithelial precursor cell compartment and failure of epithelial maturation and migration. Levels of Hh targets GLI1, HHIP and PTCH1 were increased in SCC compared with normal tissue from the same patients. CONCLUSION: Here the authors find that Hh signalling positively regulates the precursor cell compartment in the oesophageal epithelium in an autocrine manner. Since Hh signalling targets precursor cells in the oesophageal epithelium and signalling is increased in SCCs, Hh signalling may be involved in oesophageal SCC formation.
Assuntos
Células Epiteliais/metabolismo , Esôfago/citologia , Proteínas Hedgehog/fisiologia , Transdução de Sinais/fisiologia , Animais , Carcinoma de Células Escamosas/metabolismo , Diferenciação Celular , Movimento Celular , Proliferação de Células , Neoplasias Esofágicas/metabolismo , Regulação da Expressão Gênica , Homeostase/fisiologia , Humanos , Imuno-Histoquímica , Hibridização In Situ , Camundongos , Camundongos Transgênicos , Microscopia Eletrônica de Transmissão , Reação em Cadeia da Polimerase em Tempo RealRESUMO
BACKGROUND & AIMS: Indian Hedgehog (Ihh) is expressed by the differentiated epithelial cells of the small intestine and signals to the mesenchyme where it induces unidentified factors that negatively regulate intestinal epithelial precursor cell fate. Recently, genetic variants in the Hh pathway have been linked to the development of inflammatory bowel disease. METHODS: We deleted Ihh from the small intestinal epithelium in adult mice using Cyp1a1-CreIhh(fl/fl) conditional Ihh mutant mice. Intestines were examined by immunohistochemistry, in situ hybridization, and real-time polymerase chain reaction. RESULTS: Deletion of Ihh from the intestinal epithelium initially resulted in a proliferative response of the intestinal epithelium with lengthening and fissioning of crypts and increased Wnt signaling. The epithelial proliferative response was associated with loss of bone morphogenetic protein and Activin signaling from the epithelium of the villus and crypts, respectively. At the same stage we observed a substantial influx of fibroblasts and macrophages into the villus core with increased mesenchymal transforming growth factor-ß signaling and deposition of extracellular matrix proteins. Prolonged loss of Ihh resulted in progressive leukocyte infiltration of the crypt area, blunting and loss of villi, and the development of intestinal fibrosis. CONCLUSIONS: Loss of Ihh initiates several events that are characteristic of an intestinal wound repair response. Prolonged loss resulted in progressive inflammation, mucosal damage, and the development of intestinal fibrosis. Ihh is a signal derived from the superficial epithelial cells that may act as a critical indicator of epithelial integrity.
Assuntos
Proteínas Hedgehog/genética , Doenças Inflamatórias Intestinais/genética , Mucosa Intestinal/patologia , Intestino Delgado/patologia , Cicatrização/genética , Animais , Proliferação de Células , Modelos Animais de Doenças , Progressão da Doença , Proteínas Hedgehog/biossíntese , Imuno-Histoquímica , Hibridização In Situ , Doenças Inflamatórias Intestinais/metabolismo , Doenças Inflamatórias Intestinais/patologia , Mucosa Intestinal/metabolismo , Intestino Delgado/lesões , Intestino Delgado/metabolismo , Camundongos , Camundongos Mutantes , Reação em Cadeia da Polimerase , Transdução de Sinais , Fator de Crescimento Transformador beta/metabolismoRESUMO
The advent of biological therapy has revolutionized inflammatory bowel disease (IBD) care. Nonetheless, not all patients require biological therapy. Selection of patients depends on clinical characteristics, previous response to other medical therapy, and comorbid conditions. Availability, reimbursement guidelines, and patient preferences guide the choice of first-line biological therapy for luminal Crohn's disease (CD). Infliximab (IFX) has the most extensive clinical trial data, but other biological agents (adalimumab (ADA), certolizumab pegol (CZP), and natalizumab (NAT)) appear to have similar benefits in CD. Steroid-refractory, steroid-dependent, or complex fistulizing CD are indications for starting biological therapy, after surgical drainage of any sepsis. For fistulizing CD, the efficacy of IFX for inducing fistula closure is best documented. Unique risks of NAT account for its labeling as a second-line biological agent in some countries. Patients who respond to induction therapy benefit from systematic re-treatment. The combination of IFX with azathioprine is better than monotherapy for induction of remission and mucosal healing up to 1 year in patients who are naïve to both agents. Whether this applies to other agents remains unknown. IFX is also effective for treatment-refractory, moderate, or severely active ulcerative colitis. Patients who have a diminished or loss of response to anti-tumor necrosis factor (TNF) therapy may respond to dose adjustment of the same agent or switching to another agent. Careful consideration should be given to the reasons for loss of response. There are insufficient data to make recommendations on when to stop anti-TNF therapy. Preliminary evidence suggests that a substantial proportion of patients in clinical remission for >1 year, without signs of active inflammation can remain in remission after stopping treatment.
Assuntos
Anti-Inflamatórios/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Colite/tratamento farmacológico , Doença de Crohn/tratamento farmacológico , Fármacos Gastrointestinais/uso terapêutico , Seleção de Pacientes , Adalimumab , Anticorpos Monoclonais Humanizados , Azatioprina/uso terapêutico , Certolizumab Pegol , Quimioterapia Combinada , Humanos , Fragmentos Fab das Imunoglobulinas/uso terapêutico , Imunossupressores/uso terapêutico , Infliximab , Natalizumab , Polietilenoglicóis/uso terapêutico , Indução de Remissão , Fator de Necrose Tumoral alfa/antagonistas & inibidoresRESUMO
BACKGROUND & AIMS: The intestinal epithelium is a homeostatic system in which differentiated cells are in dynamic equilibrium with rapidly cycling precursor cells. Wnt signaling regulates intestinal epithelial precursor cell fate and proliferation. Homeostatic systems exist by virtue of negative feedback loops, and we have previously identified the Hedgehog (Hh) pathway as a potential negative feedback signal in the colonic epithelium. Indian hedgehog (Ihh) is produced by the differentiated enterocytes and negatively regulates Wnt signaling in intestinal precursor cells. We studied the role of members of the Hh signaling family in the intestine using a conditional genetic approach. METHODS: We inactivated the Hh receptor Patched1 (Ptch1) in adult mice, resulting in constitutive activation of the Hh signaling pathway. Effects on colonic mucosal homeostasis were examined. Colon tissues were examined by immunohistochemistry, in situ hybridization, transmission electron microscopy, and real-time polymerase chain reaction. RESULTS: Ihh but not Sonic hedgehog (Shh) was expressed in colonic epithelium. Expression of Ptch1 and Gli1 was restricted to the mesenchyme. Constitutive activation of Hh signaling resulted in accumulation of myofibroblasts and colonic crypt hypoplasia. A reduction in the number of epithelial precursor cells was observed with premature development into the enterocyte lineage and inhibition of Wnt signaling. Activation of Hh signaling resulted in induction of the expression of bone morphogenetic proteins (Bmp) and increased Bmp signaling in the epithelium. CONCLUSIONS: Hh signaling acts in a negative feedback loop from differentiated cells via the mesenchyme to the colonic epithelial precursor cell compartment in the adult mouse.
Assuntos
Proliferação de Células , Colo/patologia , Proteínas Hedgehog/metabolismo , Mucosa Intestinal/patologia , Transdução de Sinais/fisiologia , Animais , Proteínas Morfogenéticas Ósseas/genética , Proteínas Morfogenéticas Ósseas/metabolismo , Células Cultivadas , Colo/citologia , Colo/metabolismo , Células Epiteliais/citologia , Células Epiteliais/fisiologia , Regulação da Expressão Gênica no Desenvolvimento , Proteínas Hedgehog/genética , Imuno-Histoquímica , Hibridização In Situ , Mucosa Intestinal/citologia , Camundongos , Camundongos Transgênicos , Microscopia Eletrônica de Transmissão , Modelos Animais , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Sensibilidade e Especificidade , Transdução de Sinais/genética , Proteínas Wnt/genética , Proteínas Wnt/metabolismoRESUMO
In a survey comprising 1,176 patients with inflammatory bowel disease (IBD) we recently showed that azathioprine (AZA) beyond 4 years is beneficial in ulcerative colitis (UC) patients and in a subset of Crohn's disease (CD) patients. Here, we show for the first time that azathioprine responsiveness depends on body mass index (BMI). The relationship is reciprocal in UC and CD, with a better outcome in UC patients with a BMI<25 and in CD patients with a BMI>25. These observations are particularly interesting considering the evolving concept of a relationship between fatty metabolism and immune regulation. Additionally, we show that CD patients, but not UC patients, respond better to AZA when it is started in clinical remission. This observation may support data favouring a "hit hard and early" regime in CD. Finally, we were able to demonstrate a decrease in the incidence of CD-related complications requiring surgery through treatment with AZA.
Assuntos
Azatioprina/uso terapêutico , Índice de Massa Corporal , Colite Ulcerativa/diagnóstico , Colite Ulcerativa/tratamento farmacológico , Doença de Crohn/diagnóstico , Doença de Crohn/tratamento farmacológico , Imunossupressores/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Azatioprina/efeitos adversos , Colite Ulcerativa/cirurgia , Doença de Crohn/cirurgia , Esquema de Medicação , Quimioterapia Combinada , Europa (Continente) , Seguimentos , Inquéritos Epidemiológicos , Humanos , Imunossupressores/efeitos adversos , Prednisolona/uso terapêutico , Prevenção Secundária , Resultado do TratamentoRESUMO
BACKGROUND: Tumor cell death generates products that can be measured in the circulation of cancer patients. CK18-Asp396 (M30 antigen) is a caspase-degraded product of cytokeratin 18 (CK18), produced by apoptotic epithelial cells, and is elevated in breast and lung cancer patients. METHODS: We determined the CK18-Asp396 and total CK18 levels in plasma of 49 colorectal cancer patients, before and after surgical resection of the tumor, by ELISA. Correlations with patient and tumor characteristics were determined by Kruskal-Wallis H and Mann-Whitney U tests. Disease-free survival was determined using Kaplan-Meier methodology with Log Rank tests, and univariate and multivariate Cox proportional hazard analysis. RESULTS: Plasma CK18-Asp396 and total CK18 levels in colorectal cancer patients were related to disease stage and tumor diameter, and were predictive of disease-free survival, independent of disease-stage, with hazard ratios (HR) of patients with high levels (> median) compared to those with low levels (< or = median) of 3.58 (95% CI: 1.17-11.02) and 3.58 (95% CI: 0.97-7.71), respectively. The CK18-Asp396/CK18 ratio, which decreased with tumor progression, was also predictive of disease-free survival, with a low ratio (< or = median) associated with worse disease-free survival: HR 2.78 (95% CI: 1.06-7.19). Remarkably, the plasma CK18-Asp396 and total CK18 levels after surgical removal of the tumor were also predictive of disease-free survival, with patients with high levels having a HR of 3.78 (95% CI: 0.77-18.50) and 4.12 (95% CI: 0.84-20.34), respectively, indicating that these parameters can be used also to monitor patients after surgery. CONCLUSION: CK18-Asp396 and total CK18 levels in the circulation of colorectal cancer patients are predictive of tumor progression and prognosis and might be helpful for treatment selection and monitoring of these patients.
Assuntos
Neoplasias Colorretais/sangue , Neoplasias Colorretais/cirurgia , Queratina-18/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Caspases/metabolismo , Neoplasias Colorretais/patologia , Ensaio de Imunoadsorção Enzimática/estatística & dados numéricos , Feminino , Humanos , Estimativa de Kaplan-Meier , Queratina-18/metabolismo , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Valor Preditivo dos Testes , Prognóstico , Modelos de Riscos Proporcionais , Fatores de TempoRESUMO
PURPOSE: Several studies have compared conventional open ileocolic resection with a laparoscopic-assisted approach. However, long-term outcome after laparoscopic-assisted ileocolic resection remains to be determined. This study was designed to compare long-term results of surgical recurrence, quality of life, body image, and cosmesis in patients who underwent laparoscopic-assisted or open ileocolic resection for Crohn's disease. METHODS: Seventy-eight consecutive patients who underwent ileocolic resection during the period 1995 to 1998 were analyzed; 48 underwent a conventional open approach in the Academic Medical Centre (Amsterdam, The Netherlands) and 30 underwent a laparoscopic-assisted approach in the Leiden University Medical Centre (Leiden, The Netherlands). Primary outcome parameters were reoperation and readmission rate. Secondary outcome parameters were quality of life, body image, and cosmesis. RESULTS: The two groups were comparable for characteristics of sex, age, and immunosuppressive therapy. Seventy-one patients had a complete follow-up of median 8.5 years. Resection for recurrent Crohn's disease was performed in 6 of 27 (22 percent) and 10 of 44 (23 percent) patients in the laparoscopic and open groups, respectively. Reoperations for incisional hernia were only performed after conventional open ileocolic resection (3/44 = 6.8 percent). Quality of life and body image were comparable, but cosmesis scores were significantly higher in the laparoscopic group. CONCLUSIONS: Despite small numbers, we found that surgical recurrence and quality of life after laparoscopic-assisted and open ileocolic resection were comparable. Incisional hernias occurred only after open ileocolic resection, and laparoscopic-assisted ileocolic resection resulted in a significantly better cosmesis.
Assuntos
Imagem Corporal , Doença de Crohn/psicologia , Doença de Crohn/cirurgia , Laparoscopia , Qualidade de Vida , Adulto , Idoso , Idoso de 80 Anos ou mais , Distribuição de Qui-Quadrado , Colectomia/métodos , Feminino , Humanos , Ileíte/cirurgia , Masculino , Pessoa de Meia-Idade , Recidiva , Estatísticas não Paramétricas , Inquéritos e Questionários , Resultado do TratamentoRESUMO
Crohn disease (CD) is a chronic, relapsing inflammatory disorder of the gastrointestinal tract. Its etiology remained obscure until recently, when, through an overwhelming body of research, the main theme of its origin became clear. CD develops in individuals who carry risk alleles for the disease that can cause a loss of physiological tolerance to commensal bacteria. As a consequence, immune responses develop that activate a whole range of immunocompetent cells, resulting in the secretion of proinflammatory mediators that ultimately cause mucosal breaks and the formation of ulceration, edema, and loss of proper function.
Assuntos
Doença de Crohn/genética , Doença de Crohn/imunologia , Proteína Adaptadora de Sinalização NOD2/genética , Autoimunidade , Humanos , Mucosa Intestinal/imunologia , Mutação , Proteínas Adaptadoras de Sinalização NOD/imunologia , Polimorfismo GenéticoRESUMO
Infliximab is a chimeric monoclonal antibody (75% human, 25% murine) against tumor necrosis factor-alpha, a cytokine with a central role in the pathogenesis of inflammatory bowel disease. Large randomized controlled trials have shown the efficacy and safety of infliximab for the induction and maintenance of remission in adult patients with active Crohn disease (CD). In children and adolescents, mostly small, nonrandomized, non-placebo-controlled studies have supported the notion that infliximab is a potent drug in a population that does not respond to standard therapies. The safety of infliximab is of major concern, and the most frequent severe adverse events are related to severe infections and reactivation of tuberculosis. Non-life-threatening infusion reactions occur rather frequently and seem to be related to the formation of antibodies. The indications for infliximab treatment are therapy-resistant luminal CD (no efficacy or insufficient efficacy of conventional treatment) and therapy-resistant fistulas. An efficient remission induction strategy consists of 3 initial infliximab infusions at 0, 2, and 6 weeks in a dosage of 5 mg/kg to sustain remission. Patients needing maintenance therapy are subsequently treated with an infliximab infusion every 8 weeks. There are indications that the early stages of CD may be more susceptible to immunomodulation, and the natural history of CD may be altered by the introduction of infliximab early in the disease process instead of waiting until conventional therapy has failed. Major points of discussion are whether infliximab maintenance treatment should be episodic (on demand) or scheduled and when infliximab therapy can be discontinued.
Assuntos
Anti-Inflamatórios/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Doenças Inflamatórias Intestinais/tratamento farmacológico , Fator de Necrose Tumoral alfa/imunologia , Adolescente , Adulto , Anti-Inflamatórios/efeitos adversos , Anti-Inflamatórios/imunologia , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/imunologia , Criança , Humanos , InfliximabRESUMO
OBJECTIVE: Drug-induced liver injury was recently reported as a major complication leading to hepatic nodular regenerative hyperplasia (NRH) in patients with inflammatory bowel disease (IBD) and 6-thioguanine (6-TG) therapy. The aim of the study was to evaluate the prevalence of 6-TG-related hepatotoxicity in a large multi-centered IBD population by means of a systematic online survey. METHODS: Clinical and laboratory data, imaging techniques (sonography, CT, MRI) and histology of liver biopsies were surveyed in IBD patients treated with 6-TG. The decision on whether liver imaging and/or liver biopsy were performed was exclusively at the discretion of the investigator. RESULTS: 6-TG use was fully documented in 296 patients (median treatment duration 56 weeks, range < 1-207). Laboratory signs of drug-induced liver injury were found in 43 patients (14.5%). Liver imaging revealed pathologic results in 68/176 patients (38.6%). Liver biopsy was performed in a subset of 60 patients; using silver-reticulin staining (n = 59), NRH was considered in 16 patients (27.1%). Age was the only independent, albeit weak, risk factor for development of NRH. CONCLUSION: This large online survey confirms the strong association between 6-TG treatment and the significant risk of development of NRH in patients with IBD. The definitive diagnosis of NRH depends solely upon liver biopsy.
Assuntos
Hiperplasia Nodular Focal do Fígado/induzido quimicamente , Doenças Inflamatórias Intestinais/tratamento farmacológico , Fígado/efeitos dos fármacos , Tioguanina/efeitos adversos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biópsia , Criança , Coleta de Dados , Interpretação Estatística de Dados , Feminino , Hiperplasia Nodular Focal do Fígado/diagnóstico , Hiperplasia Nodular Focal do Fígado/diagnóstico por imagem , Hiperplasia Nodular Focal do Fígado/patologia , Humanos , Internet , Fígado/patologia , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Fumar , Inquéritos e Questionários , Resultado do Tratamento , UltrassonografiaRESUMO
PURPOSE: The Dutch IBD Biobank aims to facilitate the discovery of predictors for individual disease course and treatment response in patients with inflammatory bowel disease (IBD). In this paper, we aim to describe the establishment of the Dutch IBD Biobank, including the facilitators and barriers to establishment. Moreover, we aim to provide a complete overview of the content of the Dutch IBD Biobank. PARTICIPANTS: Since 2007, every patient with IBD treated in one of the eight Dutch university medical centres is asked to participate in the Dutch IBD Biobank in which 225 standardised IBD-related data items and biomaterials, such as serum, DNA, biopsies and a stool sample, are collected. FINDINGS TO DATE: As of June 2014, the Dutch IBD Biobank had enrolled 3388 patients with IBD: 2118 Crohn's disease (62.5%), 1190 ulcerative colitis (35.1%), 74 IBD-unclassified (2.2%) and 6 IBD-indeterminate (0.2%). The inclusion of patients with IBD is ongoing. The quality of the biomaterials is good and serum, DNA and biopsies have been used in newly published studies. FUTURE PLANS: The genotyping (750 000 genetic variants) of all participants of the Dutch IBD Biobank is currently ongoing, enabling more genetic research. In addition, all participants will start reporting disease activity and outcome measures using an online platform and mobile app.
Assuntos
Bancos de Espécimes Biológicos , Progressão da Doença , Doenças Inflamatórias Intestinais/classificação , Doenças Inflamatórias Intestinais/genética , Adulto , Feminino , Técnicas de Genotipagem , Humanos , Doenças Inflamatórias Intestinais/terapia , Masculino , Países Baixos/epidemiologia , Estudos Prospectivos , Adulto JovemRESUMO
The immense microbiological load of the gastrointestinal tract poses a daunting challenge for the mucosal immune system: whereas it should tolerate the vast number of commensal bacteria, it should adequately attack pathogenic organisms. Millions of years of co-evolution have produced an intricate system in which interactions between the endogenous flora and mucosal immune system manage to perform this difficult balancing act. When components of this interaction are defective, for instance by mutation, inflammatory bowel disease may result. In the present review, we comprehensively discuss the mucosal immune system in the context of Crohn's disease (CD) and its genetic risk factors, describe the clinical management of the disease, and discuss how knowledge of the mucosal immune system may yield novel therapeutical avenues for dealing with this debilitating disease.
Assuntos
Doença de Crohn/imunologia , Doença de Crohn/microbiologia , Infecções Bacterianas/imunologia , Doença de Crohn/genética , Humanos , Imunidade Inata , Inflamação/imunologia , Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteína Adaptadora de Sinalização NOD2 , Receptores Toll-Like/imunologiaRESUMO
Crohn's disease (CD) is a chronic inflammatory disorder of the gastrointestinal tract of unknown origin. Therapies include immune modulating agents, biological therapies, and surgery. The activity and efficacy of the anti-tumor necrosis factor (TNF) therapies infliximab and etanercept have proved to be different: infliximab is effective to induce and maintain remission in refractory CD, while etanercept is not. This brief review considers the question of whether this disparity can be explained by the different structure of the proteins, their different binding affinities, or the subsequent effects on T lymphocytes.
Assuntos
Anticorpos Monoclonais/farmacologia , Antirreumáticos/farmacologia , Apoptose/efeitos dos fármacos , Doença de Crohn , Linfócitos T/efeitos dos fármacos , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Anticorpos Monoclonais/uso terapêutico , Antirreumáticos/uso terapêutico , Doença de Crohn/tratamento farmacológico , Doença de Crohn/imunologia , Relação Dose-Resposta a Droga , Etanercepte , Citometria de Fluxo , Humanos , Imunoglobulina G/farmacologia , Imunoglobulina G/uso terapêutico , Infliximab , Receptores do Fator de Necrose Tumoral/uso terapêutico , Linfócitos T/patologiaRESUMO
BACKGROUND AND AIMS: Back and joint pain are the most common extraintestinal symptoms reported by patients with inflammatory bowel disease (IBD). We assessed the impact of back/joint pain, illness perceptions, and coping on quality of life (QOL) and work productivity in patients with IBD. METHODS: Our cohort included 155 IBD patients with and 100 without arthropathy. Arthropathy was defined as daily back pain for ≥3 months and/or peripheral joint pain and/or joint swelling over the last year. At baseline and at 12 months, patients completed questionnaires on the extent of back/joint pain, IBD disease activity, illness perceptions, coping, QOL, and work productivity. The impact of back/joint pain, illness perceptions and coping on QOL and work productivity was determined, using linear mixed models. RESULTS: In total, 204 IBD patients (72% Crohn's disease, 40% male, mean age 44 ± 14 years) completed questionnaires at both time points. At both time points, IBD patients with back/joint pain reported a significantly lower QOL and work productivity compared with IBD patients without back/joint pain. Predictors of low QOL were back/joint pain (ß = -1.04, 95% confidence interval [CI] -1.40, -0.68), stronger beliefs about the illness consequences (ß = -0.39, 95% CI -0.59, -0.18) and emotional impact of IBD (ß = -0.47, 95% CI -0.66, -0.28), and the coping strategy 'decreasing activity' (ß = -0.26, 95% CI -0.48, -0.03). Predictors of work productivity were back/joint pain (ß = 0.22, 95% CI 0.07, 0.37) and illness consequences (ß = 0.14, 95% CI 0.06, 0.22). CONCLUSION: Back/joint pain, illness perceptions, and coping are significant predictors of QOL and work productivity, after controlling for disease activity.
Assuntos
Adaptação Psicológica , Artralgia/psicologia , Dor nas Costas/psicologia , Eficiência , Doenças Inflamatórias Intestinais/complicações , Qualidade de Vida , Adulto , Artralgia/etiologia , Dor nas Costas/etiologia , Feminino , Humanos , Doenças Inflamatórias Intestinais/psicologia , Modelos Lineares , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Percepção , Estudos Prospectivos , Qualidade de Vida/psicologia , Inquéritos e QuestionáriosRESUMO
The aim of this study was to report the 1-year clinical experience with infliximab treatment for Crohn's disease (CD) in the Netherlands. All 73 CD patients receiving infliximab infusions were prospectively followed during 1 year after the drugs' registration in the Netherlands. Clinical response and adverse events were assessed for both active luminal disease as well as fistulous disease. A total of 212 infusions were administered to 57 patients with active luminal CD and 16 patients with fistulous CD. The mean duration between infusions was 60 days. In 17% of patients, adverse events were recorded, of which one was serious. The response rate was 81% in active luminal CD and 87% in fistulous disease. Response rates were highest in patients receiving concomitant methotrexate as maintenance therapy. Steroids could successfully be tapered off in 73% of responding luminal CD patients and 100% of responding CD patients with fistulae. Eleven patients showed a loss of response to continuous infliximab readministration. Our clinical experience with infliximab for active luminal and fistulous CD showed that the administration is safe, effective, and has high steroid-sparing efficacy. Higher response rates were seen with methotrexate as concomitant medication.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Doença de Crohn/tratamento farmacológico , Fármacos Gastrointestinais/uso terapêutico , Adolescente , Adulto , Anticorpos Monoclonais/administração & dosagem , Doença de Crohn/complicações , Doença de Crohn/patologia , Esquema de Medicação , Quimioterapia Combinada , Feminino , Fármacos Gastrointestinais/administração & dosagem , Hospitais de Ensino , Humanos , Infliximab , Infusões Intravenosas , Fístula Intestinal/complicações , Fístula Intestinal/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Países Baixos , Estudos Prospectivos , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
In recent years it has become clear that chronic inflammatory bowel disease (IBD), especially Crohn's disease (CD), is caused by a loss of tolerance against the autologous bacterial flora of the intestine. Tolerance against the indigenous flora requires optimal recognition of antigens by pattern recognition receptors and the presence of important regulatory cells and cytokines. Interleukin-10 (IL-10) has a major role in the regulatory network of cytokines controlling mucosal tolerance, and it is, therefore, not surprising that this cytokine is proposed as a potent anti-inflammatory biological therapy in chronic IBD. This review will discuss the characteristics of IL-10, its immunoregulatory properties in mice and humans, and the use of IL-10 as a treatment for CD. The review will summarise the clinical studies that have taken place and discuss the lessons learned from these trials. Finally, the advantages and disadvantages of promising new strategies of IL-10 treatment, including gene therapy and the use of genetically modified bacteria, will be discussed. Both novel therapies have been shown to be successful in animal models of disease, and clinical testing is currently underway. The future goal of IL-10 treatment should be focused on mucosal delivery and remission maintenance instead of remission induction. In conclusion, it can be said that despite the disappointing results of IL-10 therapy so far, there is still enough rationale for the use of IL-10 as an anti-inflammatory biological treatment in chronic IBD.
Assuntos
Doenças Inflamatórias Intestinais/tratamento farmacológico , Interleucina-10/uso terapêutico , Animais , Sistemas de Liberação de Medicamentos , Humanos , Imunidade/fisiologia , Doenças Inflamatórias Intestinais/metabolismo , Doenças Inflamatórias Intestinais/microbiologia , Interleucina-10/administração & dosagem , Interleucina-10/metabolismo , Interleucina-10/farmacologia , Mucosa Intestinal/metabolismo , Intestinos/imunologia , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/uso terapêuticoRESUMO
Lynch syndrome (LS), one of the most frequent forms of hereditary colorectal cancer (CRC), is caused by a defect in one of the mismatch repair (MMR) genes. Carriers of MMR defects have a strongly increased risk of developing CRC and endometrial cancer. Over the last few years, value-based healthcare has been introduced as an approach to the cost-effective delivery of measurable patient value over complete cycles of care. This requires all involved stakeholders to formulate and validate 'patient value' for Lynch syndrome, as well as to identify targets and associated costs. The aim of this study was to develop a value-based care model for Lynch syndrome that can determine patient value and associated costs, and to design a coordinated care pathway from existing guidelines. All specialists in our hospital involved in the management of LS patients evaluated the care delivered to these patients at their department and formulated outcome measures relevant to patient value. Patients were then invited to complete a questionnaire that assessed the importance of these measures on a scale of 1-10. Six high-value outcomes were identified: (1) prevention of cancer or detection of early stage cancer (2) rapid results from MMR gene mutation testing (3) rapid investigation of the colon and uterus (4) no/little pain during colonoscopy and gynaecologic examination/biopsy (5) the offer of psychological help and (6) registration with the Dutch Lynch syndrome registry. A total of 38 (59 %) out of 62 patients completed the questionnaire. The relevance of all outcomes was confirmed by the patients and mean scores varied from 7.2 to 9.9. Patients underscored the relevance of both proper patient education and the efficiency of surveillance during their care cycle. Value-based care delivery for Lynch syndrome includes the implementation of six parameters related to prevention and early detection of cancer, a short cycle time and registration to ensure continuation of care. Estimated costs are