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1.
Scand J Gastroenterol ; 56(2): 145-154, 2021 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-33290108

RESUMEN

OBJECTIVES: Loss of response (LOR) to infliximab (IFX) remains a challenge in the management of inflammatory bowel diseases (IBD). Proactive dosing strategies to achieve and maintain predefined IFX trough levels (TL) may prevent LOR. We aimed to investigate the efficacy of dashboard driven IFX dosing compared to standard dosing in a prospective trial in IBD patients. METHODS: In this multicentre 1:1 'PRECISION' trial, we randomized IBD patients in clinical remission (Harvey Bradshaw Index ≤4 for Crohn's disease (CD) or a partial Mayo score ≤2 for ulcerative colitis (UC)) receiving IFX maintenance treatment. The precision group (PG) received IFX dosing guided by a Bayesian pharmacokinetic model, aiming to achieve and maintain a TL of 3 µg/ml by treatment (de)escalation as indicated by the dashboard. Patients in the control group (CG) continued treatment without dose adaptations. The primary endpoint was the proportion of patients in sustained clinical remission after 1 year. RESULTS: Eighty patients were enrolled (66 CD, 14 UC), and the median [interquartile range] age was 37 years [27-51]). After one year, 28/32 (88%) of patients in the PG were in sustained clinical remission versus 25/39 (64%) in the CG (p = .017). PG patients had lower median faecal calprotectin levels after 1 year (p = .031), whereas no significant differences in median CRP levels were found. CONCLUSION: We demonstrated that the use of a Bayesian dashboard for IFX dosing in maintenance treatment for IBD reduced the incidence of LOR compared to standard dosing. Precision dosing also resulted in lower FCP levels. CLINICALTRIALS.GOV NUMBER: NCT02453776.


Asunto(s)
Colitis Ulcerosa , Enfermedades Inflamatorias del Intestino , Teorema de Bayes , Colitis Ulcerosa/tratamiento farmacológico , Fármacos Gastrointestinales/uso terapéutico , Humanos , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Infliximab/uso terapéutico , Estudios Prospectivos , Inducción de Remisión , Resultado del Tratamiento
3.
BMC Surg ; 8: 15, 2008 Aug 22.
Artículo en Inglés | MEDLINE | ID: mdl-18721465

RESUMEN

BACKGROUND: With the availability of infliximab, nowadays recurrent Crohn's disease, defined as disease refractory to immunomodulatory agents that has been treated with steroids, is generally treated with infliximab. Infliximab is an effective but expensive treatment and once started it is unclear when therapy can be discontinued. Surgical resection has been the golden standard in recurrent Crohn's disease. Laparoscopic ileocolic resection proved to be safe and is characterized by a quick symptom reduction. The objective of this study is to compare infliximab treatment with laparoscopic ileocolic resection in patients with recurrent Crohn's disease of the distal ileum with respect to quality of life and costs. METHODS/DESIGN: The study is designed as a multicenter randomized clinical trial including patients with Crohn's disease located in the terminal ileum that require infliximab treatment following recent consensus statements on inflammatory bowel disease treatment: moderate to severe disease activity in patients that fail to respond to steroid therapy or immunomodulatory therapy. Patients will be randomized to receive either infliximab or undergo a laparoscopic ileocolic resection. Primary outcomes are quality of life and costs. Secondary outcomes are hospital stay, early and late morbidity, sick leave and surgical recurrence. In order to detect an effect size of 0.5 on the Inflammatory Bowel Disease Questionnaire at a 5% two sided significance level with a power of 80%, a sample size of 65 patients per treatment group can be calculated. An economic evaluation will be performed by assessing the marginal direct medical, non-medical and time costs and the costs per Quality Adjusted Life Year (QALY) will be calculated. For both treatment strategies a cost-utility ratio will be calculated. Patients will be included from December 2007. DISCUSSION: The LIR!C-trial is a randomized multicenter trial that will provide evidence whether infliximab treatment or surgery is the best treatment for recurrent distal ileitis in Crohn's disease. TRIAL REGISTRATION: Nederlands Trial Register NTR1150.


Asunto(s)
Antiinflamatorios/uso terapéutico , Anticuerpos Monoclonales/uso terapéutico , Colon/cirugía , Enfermedad de Crohn/terapia , Íleon/cirugía , Laparoscopía/economía , Antiinflamatorios/economía , Anticuerpos Monoclonales/economía , Enfermedad de Crohn/tratamiento farmacológico , Enfermedad de Crohn/cirugía , Humanos , Infliximab , Calidad de Vida , Recurrencia
5.
Gut ; 56(4): 509-17, 2007 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-17082252

RESUMEN

BACKGROUND: The human anti-tumour necrosis factor (TNF) antibody infliximab binds to the membrane TNF and subsequently induces apoptosis of activated lamina propria T lymphocytes in patients with Crohn's disease in vitro. AIM: To test whether the ability of rapid anti-TNF-induced apoptosis in the gut predicts the efficacy of anti-TNF treatment in inflammatory bowel disease. METHODS: (99m)Technetium-annexin V single-photon emission computer tomography (SPECT) was performed in 2 models of murine experimental colitis and in 14 patients with active Crohn's disease as assessed by the Crohns Disease Activity Index (CDAI) to study the effect of anti-TNF treatment on apoptosis in the intestine during active colitis. Disease activity was evaluated 2 weeks after infliximab infusion using the CDAI (definition response: drop of >100 points). RESULTS: Colonic uptake of (99m)Tc-annexin V significantly increased in 2,4,6-trinitrobenzene sulphonate-induced colitis as well as in transfer colitis on administration of anti-TNF antibodies compared with a control antibody as determined with dedicated animal pinhole SPECT. In addition, uptake of (99m)Tc-annexin V significantly increased in patients with active Crohn's disease responding to infliximab treatment. Colonic (99m)Tc-annexin V uptake ratio (mean (SEM)) increased from 0.24 (0.03) to 0.41(0.07) (p<0.01), 24 h after infliximab infusion (5 mg/kg). A mean increase of 98.7% in colonic uptake of (99m)Tc-annexin V could be detected in 10 of the 14 responding patients (CDAI >100 points at week 2) compared with 15.2% in non-responding patients (p = 0.03). Analysis of the mucosal biopsy specimens identified lamina propria T cells as target cells undergoing apoptosis. CONCLUSIONS: These in vivo observations support the notion that colonic uptake of (99m)Tc-annexin V correlates with clinical benefit of anti-TNF treatment and might be predictive of therapeutic success.


Asunto(s)
Anticuerpos Monoclonales/farmacología , Apoptosis/efectos de los fármacos , Enfermedad de Crohn/tratamiento farmacológico , Fármacos Gastrointestinales/farmacología , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Adulto , Animales , Anexina A5 , Anticuerpos Monoclonales/uso terapéutico , Linfocitos T CD4-Positivos/efectos de los fármacos , Colitis/inducido químicamente , Colitis/patología , Enfermedad de Crohn/diagnóstico por imagen , Enfermedad de Crohn/patología , Modelos Animales de Enfermedad , Femenino , Fármacos Gastrointestinales/uso terapéutico , Humanos , Infliximab , Mucosa Intestinal/inmunología , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones SCID , Persona de Mediana Edad , Compuestos de Organotecnecio , Índice de Severidad de la Enfermedad , Tomografía Computarizada de Emisión de Fotón Único , Resultado del Tratamiento , Ácido Trinitrobencenosulfónico
7.
J Cell Physiol ; 202(1): 275-84, 2005 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-15389518

RESUMEN

Muc4/sialomucin complex (SMC) is a high molecular mass heterodimeric membrane mucin, encoded by a single gene, and originally discovered in a highly metastatic ascites rat mammary adenocarcinoma. Subsequent studies have shown that it is a prominent component of many accessible and vulnerable epithelia, including the gastrointestinal tract. Immunoblot and immunofluorescence analyses demonstrated that Muc4/SMC expression in the rat small intestine increases from proximal to distal regions and is located predominantly in cells at the base of the crypts. These cells were postulated to be Paneth cells, based on their location, morphology, and secretory granule content. Immunohistochemistry indicated the presence of Muc4/SMC in these granules. Muc4/SMC expression was higher in the rat colon than small intestine and was abundantly present in colonic goblet cells, but not in goblet cells in the small intestine. Immunohistochemistry also suggested the presence of MUC4 in human colonic goblet cells. Biochemical analyses indicated that rat colonic Muc4/SMC is primarily the soluble form of the membrane mucin. Analyses of Muc4/SMC during development of the rat gastrointestinal tract showed its appearance at embryonic day 14 of the esophagus and at day 15 at the surface of the undifferentiated stratified epithelium at the gastroduodenal junction, then later at cell surfaces in the more distal regions of the differentiated epithelium of the small intestine, culminating in expression as an intracellular form in the crypts of the small intestine at about day 21. Limited expression in the colon was observed during development before birth at cell surfaces, with expression as an intracellular form in the goblet cells arising during the second week after birth. These results suggest that membrane mucin Muc4/SMC serves different functions during development of the intestine in the rat, but is primarily a secreted product in the adult animal.


Asunto(s)
Colon/metabolismo , Mucosa Intestinal/metabolismo , Intestino Delgado/metabolismo , Mucinas/metabolismo , Factores de Edad , Envejecimiento/fisiología , Animales , Compartimento Celular/fisiología , Diferenciación Celular/fisiología , Colon/citología , Colon/embriología , Duodeno/citología , Duodeno/metabolismo , Esófago/citología , Esófago/metabolismo , Femenino , Células Caliciformes/citología , Células Caliciformes/metabolismo , Humanos , Mucosa Intestinal/citología , Mucosa Intestinal/embriología , Intestino Delgado/citología , Intestino Delgado/embriología , Mucina 4 , Células de Paneth/citología , Células de Paneth/metabolismo , Ratas , Ratas Endogámicas F344 , Vesículas Secretoras/metabolismo , Vesículas Secretoras/ultraestructura , Especificidad de la Especie
8.
J Mol Med (Berl) ; 82(3): 197-205, 2004 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-14673529

RESUMEN

The reaction of the intestinal immune system to intestinal bacteria shows striking differences between various bacterial strains. Whereas Klebsiella pneumoniae induces a fierce proinflammatory reaction, the probiotic strain Lactobacillus rhamnosus has clear anti-inflammatory effect in gastrointestinal disease and allergy. The molecular basis for this dichotomy is poorly understood but is likely to involve different modulation of antigen-presenting dendritic cells (DC) by L. rhamnosus and K. pneumoniae. Hence we evaluated phenotypic and functional characteristics of DC matured in the presence of L. rhamnosus and K. pneumoniae. Monocyte-derived immature DC were cultured in the presence of live bacteria to obtain mature DC. Both micro-organisms induced maturation of immature DC as shown by CD83 and CD86 expression, but receptors involved in activation of Th1 cells were expressed predominantly on DC exposed to K. pneumoniae. In contrast to K. pneumoniae, maturation with L. rhamnosus resulted in lower TNF-alpha, IL-6, and IL-8 production by immature DC and lower IL-12 and IL-18 production by mature DC. Moreover, L. rhamnosus led to the development of T cells without a typical Th phenotype whereas K. pneumoniae induced a Th1 immune response, dependent mainly on IL-12 production. Thus our results strongly support the concept that differential modulation of DC explains the differences in the immune response to various bacterial strains and indicates that K. pneumoniae induces Th1 immune responses via DC.


Asunto(s)
Células Dendríticas/citología , Células Dendríticas/microbiología , Klebsiella pneumoniae/metabolismo , Lactobacillus/metabolismo , Antígenos CD/biosíntesis , Antígenos CD1/biosíntesis , Antígeno B7-2 , Separación Celular , Citocinas/biosíntesis , Células Dendríticas/metabolismo , Relación Dosis-Respuesta a Droga , Citometría de Flujo , Humanos , Inmunoglobulinas/biosíntesis , Inflamación , Interleucina-12/biosíntesis , Interleucina-18/biosíntesis , Receptores de Lipopolisacáridos/biosíntesis , Glicoproteínas de Membrana/biosíntesis , Monocitos/citología , Monocitos/microbiología , Fenotipo , Subunidades de Proteína/biosíntesis , Linfocitos T/metabolismo , Antígeno CD83
9.
Gastroenterology ; 126(1): 111-21, 2004 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-14699493

RESUMEN

BACKGROUND AND AIMS: The recent findings of bone morphogenetic protein (BMP) receptor Ia mutations in juvenile polyposis and frequent Smad4 mutations in colon cancer suggest a role for BMPs in the colonic epithelium and colon cancer. We investigated the role of BMP2 in the colon. METHODS: We assessed BMP receptor expression in cell lines using the reverse-transcribed polymerase chain reaction and immunoblotting. We investigated the effect of BMP2 on cell lines using the MTT assay and by immunoblotting for markers of differentiation, proliferation, and apoptosis. We assessed the expression of BMP2, its receptors, and signal transduction elements in mouse and human colon tissue using immunohistochemistry. We also investigated the effect of the BMP antagonist noggin in vivo in mice by assessing colon tissue with immunohistochemistry and immunoblotting. Finally, we investigated the expression of BMP2 in microadenomas from familial adenomatous polyposis patients. RESULTS: BMP receptors (BMPR) Ia, BMPR Ib, and BMPR II are all expressed in colonic epithelial cell lines. BMP2 inhibits colonic epithelial cell growth in vitro, promoting apoptosis and differentiation and inhibiting proliferation. BMP2, BMPRIa, BMPRIb, BMPRII, phosphorylated Smad1, and Smad4 are expressed predominantly in mature colonocytes at the epithelial surface in normal adult human and mouse colon. Noggin inhibits apoptosis and proliferation in mouse colonic epithelium in vivo. BMP2 expression is lost in the microadenomas of familial adenomatous polyposis patients. CONCLUSIONS: These data suggest that BMP2 acts as a tumor suppressor promoting apoptosis in mature colonic epithelial cells.


Asunto(s)
Proteínas Morfogenéticas Óseas/metabolismo , Colon/fisiopatología , Neoplasias del Colon/fisiopatología , Mucosa Intestinal/fisiopatología , Factor de Crecimiento Transformador beta , Poliposis Adenomatosa del Colon/metabolismo , Animales , Apoptosis/efectos de los fármacos , Proteína Morfogenética Ósea 2 , Receptores de Proteínas Morfogenéticas Óseas , Receptores de Proteínas Morfogenéticas Óseas de Tipo 1 , Receptores de Proteínas Morfogenéticas Óseas de Tipo II , Proteínas Morfogenéticas Óseas/antagonistas & inhibidores , Proteínas Morfogenéticas Óseas/farmacología , Proteínas Portadoras , Diferenciación Celular/efectos de los fármacos , División Celular/efectos de los fármacos , Línea Celular Tumoral , Colon/metabolismo , Neoplasias del Colon/metabolismo , Proteínas del Citoesqueleto/antagonistas & inhibidores , Proteínas de Unión al ADN/metabolismo , Humanos , Mucosa Intestinal/metabolismo , Ratones , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas/farmacología , Receptores de Factores de Crecimiento/metabolismo , Proteínas Smad , Proteína Smad1 , Proteína Smad4 , Transactivadores/antagonistas & inhibidores , Transactivadores/metabolismo , beta Catenina
10.
Gastroenterology ; 124(7): 1774-85, 2003 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-12806611

RESUMEN

BACKGROUND & AIMS: Steroid-refractory Crohn's disease responds to therapy with the chimeric anti-tumor necrosis factor (TNF)-alpha antibody infliximab. Etanercept, a recombinant TNF receptor/immunoglobulin G fusion protein, is highly effective in rheumatoid arthritis but not in Crohn's disease. Because both infliximab and etanercept are TNF-alpha-neutralizing drugs, we investigated the differences in TNF-alpha-neutralizing capacity and human lymphocyte binding and apoptosis-inducing capacity of both molecules. METHODS: We used a nuclear factor kappaB reporter assay and a cytotoxicity bioassay to study TNF-alpha neutralization by infliximab and etanercept. Lymphocyte binding and apoptosis-inducing capacity was investigated using fluorescence-activated cell sorter analysis, annexin V staining, and cleaved caspase-3 immunoblotting using mixed lymphocyte reaction-stimulated peripheral blood lymphocytes (PBL) from healthy volunteers and lamina propria T cells from patients with Crohn's disease. RESULTS: Both infliximab and etanercept neutralized TNF-alpha effectively. Infliximab bound to activated PBL and lamina propria T cells, whereas binding of etanercept was equal to a nonspecific control antibody. Infliximab but not etanercept induced peripheral and lamina propria lymphocyte apoptosis when compared with a control antibody. Infliximab activated caspase 3 in a time-dependent manner, whereas etanercept did not. CONCLUSIONS: Although both infliximab and etanercept showed powerful TNF-alpha neutralization, only infliximab was able to bind to PBL and lamina propria T cells and subsequently to induce apoptosis of activated lymphocytes. These data may provide a biological basis for the difference in efficacy of the 2 TNF-alpha-neutralizing drugs.


Asunto(s)
Anticuerpos Monoclonales/farmacología , Apoptosis/efectos de los fármacos , Enfermedad de Crohn/tratamiento farmacológico , Inmunoglobulina G/farmacología , Mucosa Intestinal/inmunología , Linfocitos T/efectos de los fármacos , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Anticuerpos Monoclonales/metabolismo , Anticuerpos Monoclonales/uso terapéutico , Caspasa 3 , Caspasas/metabolismo , Células Cultivadas , Activación de Complemento , Enfermedad de Crohn/inmunología , Etanercept , Granzimas , Humanos , Inmunoglobulina G/metabolismo , Inmunoglobulina G/uso terapéutico , Infliximab , Activación de Linfocitos , Receptores del Factor de Necrosis Tumoral/metabolismo , Receptores del Factor de Necrosis Tumoral/uso terapéutico , Serina Endopeptidasas/biosíntesis , Linfocitos T/patología
11.
Ann N Y Acad Sci ; 973: 166-80, 2002 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-12485856

RESUMEN

Apoptosis is one of the most important regulatory mechanisms in immunological homeostasis. Disturbances in the apoptotic pathways lead to autoimmune disease. Crohn's disease is a chronic inflammatory bowel disease of unknown origin, which seems to be mediated by excessive T cell-mediated immunity. Recently, disturbances in apoptotic pathways of lamina propria T lymphocytes of patients with Crohn's disease have been identified. In the uninflamed, normal intestinal mucosa, lamina propria (LP) T cells are susceptible to activation-induced cell death, but these cells show a resistance to apoptosis based on several disturbances compared to controls. Recently, intriguing data were published using cytokine-targeted therapy (anti-IL12, anti-IL6 receptor, anti-TNF). Actually, these medications restored mucosal immunological imbalance by inducing apoptosis of the LP T cells and seemed to be beneficial in models of Crohn's disease. In this review, mechanisms of immunological homeostasis will be discussed. We will also discuss the fascinating new results of cytokine-targeted therapy in animal models of Crohn's disease and the effects of these drugs in patients with Crohn's disease.


Asunto(s)
Apoptosis/inmunología , Enfermedad de Crohn/inmunología , Linfocitos T/inmunología , Humanos , Inmunoterapia/métodos , Interleucina-12/inmunología , Receptores de Interleucina-6/inmunología , Linfocitos T/patología , Factor de Necrosis Tumoral alfa/inmunología
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