Corticosteroids modulate angiogenic soluble factors in ulcerative colitis patients.

AIMS: The aim of this study was to compare angiogenic factors in serum levels of active ulcerative colitis (UC) patients and in healthy controls, and to analyze these angiogenic levels depending on the achievement of remission after oral corticosteroid treatment throughout treatment, and according to the Truelove-Witts activity index. METHODS: Blood samples were collected from 13 patients receiving oral corticosteroids for treatment of UC flares at three different intervals--baseline, during, and after treatment--and from 26 healthy controls. Vascular endothelial growth factor (VEGF), placental growth factor (PlGF), VEGF receptor 1 (VEGFR1), angiopoietins (Ang) 1 and 2, and its receptor Tie2 were assayed by ELISA. RESULTS: While VEGF and Ang2 levels in UC patients were higher than in healthy controls (P < 0.05), UC patients showed lower levels of Ang1 than healthy individuals (P < 0.05). In UC patients who achieved clinical remission after corticosteroid treatment, a statistically significant higher baseline serum level of PlGF was observed (22 ± 5 vs. 18 ± 2; P < 0.05). Angiogenic factor levels varied during treatment; however, they did not show a statistically significant correlation to the activity of the disease. CONCLUSIONS: VEGF, Ang1, and Ang2 levels showed statistically significant differences between UC patients and healthy controls. Although determination of PlGF serum levels before corticosteroid treatment might be helpful to anticipate the response by UC patients, no angiogenic pattern that could accurately predict "a priori" this response to corticosteroid treatment was observed. Corticosteroids altered temporarily circulating levels of VEGF, angiopoietins and Tie2. No correlation was found between systemic levels of angiogenic factors and the clinical activity of UC.

Effect of 5-aminosalicylates on renal function in patients with inflammatory bowel disease: 4-year follow-up study.

OBJECTIVE: Nephrotoxicity has been described in some patients with inflammatory bowel disease (IBD) treated with 5-aminosalicylates (5-ASA). Our aim was to conduct a retrospective study of IBD patients, both with and without 5-ASA treatment, who underwent regular evaluation of renal function over a 4-year period. METHODS: Serum creatinine was measured before the start of 5-ASA therapy, and thereafter yearly up to 4 years. Creatinine clearance (Cl(Cr)) was estimated from serum creatinine (Cockroft and Gault formula). The influence of 5-ASA treatment on renal function was assessed by univariate and multivariate analysis. RESULTS: A total of 150 IBD patients (ulcerative colitis in 45%, Crohn's disease in 55%) were included. Sixty-two patients were receiving 5-ASAs (95% coated mesalazine, mean dose 1.9 +/- 0.8 g/day). Both serum creatinine levels and ClCr were similar in patients with and without 5-ASA treatment, and remained stable throughout the 4-year follow-up in patients taking 5-ASAs. In the multivariate analysis, 5-ASA treatment (or its dose) was not correlated with serum creatinine levels or Cl(Cr). No interstitial nephritis was reported during follow-up. CONCLUSION: 5-ASA-related renal disease was not found in our series, suggesting that the occurrence of renal impairment in IBD patients receiving these drugs is exceptional. Our results do not support the recommendation of serum creatinine monitoring in patients receiving 5-ASA treatment.

Effect of 5-aminosalicylates on renal function in patients with inflammatory bowel disease: 4-year follow-up study

OBJETIVO: Se han descrito algunos casos de nefrotoxicidaden pacientes con enfermedad inflamatoria intestinal (EII)tratados con 5-aminosalicilatos (5-ASA). Nuestro objetivofue realizar un estudio retrospectivo de un grupo de pacientescon EII, con y sin tratamiento con 5-ASA, en los que seevaluaba la función renal regularmente durante un períodode 4 años.MÉTODOS: Se determinaba la creatinina sérica antes de comenzarel tratamiento con 5-ASA y posteriormente se efectuabaun control analítico anual durante 4 años. Se estimó elaclaramiento de creatinina (ClCr) a partir de la creatinina sérica(fórmula de Cockroft-Gault). La influencia del tratamientocon 5-ASA en la función renal se valoró medianteanálisis multivariante.RESULTADOS: Se incluyeron 150 pacientes con EII (un 45%con colitis ulcerosa y un 55% con enfermedad de Crohn).Los valores séricos de creatinina a los 0, 1, 2, 3 y 4 años enlos pacientes que recibían 5-ASA permanecieron estables.Asimismo, el ClCr no se modificó durante los 4 años de seguimientoen los pacientes tratados con 5-ASA. Más aún, losvalores tanto de creatinina sérica como de ClCr fueron similaresen los pacientes con y sin tratamiento con 5-ASA. Finalmente,el tratamiento con 5-ASA no se correlacionó conlos valores séricos de creatinina ni con el ClCr en el estudiomultivariante. No se describió ningún caso de nefritis intersticialdurante el seguimiento.CONCLUSIÓN: No hemos constatado ningún caso de nefrotoxicidaden nuestra serie de pacientes tratados con 5-ASA, loque indica que la incidencia de alteraciones de la función renalen los pacientes con EII que reciben estos fármacos esexcepcional. Nuestros resultados no apoyan la recomendaciónde registrar regularmente las cifras de creatinina séricaen los pacientes con EII que reciben tratamiento con 5-ASA

OBJECTIVE: Nephrotoxicity has been described in some patientswith inflammatory bowel disease (IBD) treated with 5-aminosalicylates (5-ASA). Our aim was to conduct a retrospectivestudy of IBD patients, both with and without 5-ASAtreatment, who underwent regular evaluation of renal functionover a 4-year period.METHODS: Serum creatinine was measured before the startof 5-ASA therapy, and thereafter yearly up to 4 years. Creatinineclearance (ClCr) was estimated from serum creatinine(Cockroft & Gault formula). The influence of 5-ASA treatmenton renal function was assessed by univariate and multivariateanalysis.RESULTS: A total of 150 IBD patients (ulcerative colitis in45%, Crohn’s disease in 55%) were included. Sixty-two patientswere receiving 5-ASAs (95% coated mesalazine, meandose 1.9 ± 0.8 g/day). Both serum creatinine levels and ClCrwere similar in patients with and without 5-ASA treatment,and remained stable throughout the 4-year follow-up in patientstaking 5-ASAs. In the multivariate analysis, 5-ASAtreatment (or its dose) was not correlated with serum creatininelevels or ClCr. No interstitial nephritis was reported duringfollow-up.CONCLUSION: 5-ASA-related renal disease was not found inour series, suggesting that the occurrence of renal impairmentin IBD patients receiving these drugs is exceptional.Our results do not support the recommendation of serumcreatinine monitoring in patients receiving 5-ASA treatment

Role of vascular endothelial growth factor and angiopoietin systems in serum of Crohn's disease patients.

BACKGROUND: The purposes of this study were to determine soluble angiogenic factors in Crohn's disease (CD) patients and to compare these factors according to the pathological behavior of the disease in order to establish a possible relationship with its evolution in patients with CD. METHODS: Blood samples were collected from 70 patients with CD, grouped according to their phenotypic behavior, and from 30 healthy controls. Vascular endothelial growth factor (VEGF), placental growth factor (PlGF), angiopoietin 1 (Ang1), angiopoietin 2 (Ang2), and their cognate receptors [VEGFR1, VEGFR2, and angiopoietin receptor tyrosine kinase (Tie2)] were assayed by ELISA. RESULTS: Circulating levels of VEGF, PlGF, VEGFR1, Ang2, and Tie2 were significantly higher in CD patients than in healthy controls (489 +/- 271 versus 335 +/- 118 pg/mL, P < 0.001; 31 +/- 9 versus 23 +/- 9 pg/mL, P < 0.001; 1.7 +/- 0.4 versus 1.0 +/- 0.3 ng/mL, P < 0.001; 4.8 +/- 2.0 versus 3.9 +/- 2.0 ng/mL, P < 0.05; and 36 +/- 5 versus 22 +/- 7 ng/mL, P < 0.001, respectively). Conversely, CD patients showed significantly lower serum levels of Ang1 than healthy controls (40 +/- 12 versus 67 +/- 22 ng/mL; P < 0.001). No differences between the groups were found in VEGFR2 serum level. The circulating levels of the angiogenic factors did not differ significantly when the CD patients were classified according to pathological phenotype. CONCLUSIONS: In comparison with healthy controls, CD patients were found to have an active angiogenic profile, as detected by significant alterations in levels of angiogenesis soluble markers. These patients did not differ in serum levels of angiogenic factors according to phenotypic disease behavior.

Liver injury in inflammatory bowel disease: long-term follow-up study of 786 patients.

BACKGROUND: The aim of the study was to evaluate the incidence of abnormality of liver tests (LTs) or hepatotoxicity in a large group of inflammatory bowel disease (IBD) patients and, specifically, to assess the incidence of azathioprine (AZA)/mercaptopurine (MP)-induced liver injury in a long-term follow-up study. METHODS: All consecutive IBD patients followed for at least 5 years were included in this retrospective study. LTs including alanine transaminase, aspartate transaminase, alkaline phosphatase, gamma-glutamyl transferase, and bilirubin were periodically monitored. "Abnormality-of-LTs" was defined as LTs between N (upper limit of the normal range) and 2 N, and "liver injury/hepatotoxicity" as LTs>2 N. RESULTS: A total of 786 patients were included, and 138 received AZA/MP; 120 patients (15%) and 39 (5%) presented abnormality of LTs or hepatotoxicity, respectively, during follow-up. The most frequent explanations were AZA/MP treatment and fatty liver disease. Among AZA/MP-treated patients (690 patient-years follow-up) the incidence of abnormal LTs and hepatotoxicity was, respectively, 7.1% and 2.6% per patient-year. Most patients spontaneously normalized LTs despite maintaining AZA/MP. These drugs were withdrawn due to hepatotoxicity (LTs>5 N and lack of decrease despite 50% dose reduction) in 3.6% of the patients and all of them normalized LTs. CONCLUSIONS: In IBD patients, AZA or MP treatment induces abnormality of LTs in a relatively high proportion of the cases, but the development of true hepatotoxicity/liver injury is exceptional. Moreover, most of the cases of thiopurine-induced hepatotoxicity in IBD patients are mild, and the abnormalities in LTs spontaneously return to normal values despite AZA/MP being maintained, therapy withdrawal being necessary in only approximately 4% of the patients.

[Vascular development in inflammatory bowel disease]. / El desarrollo vascular en la enfermedad inflamatoria intestinal.

There are 4 major concepts in vascular development: vasculogenesis (formation of blood vessels from angioblasts), angiogenesis (formation of vascular sprouts from preexisting vessels), arteriogenesis (thickening and development of vessels) and lymphangiogenesis (formation of lymphatic vessels). In the last decade, these concepts, especially angiogenesis and lymphangiogenesis, have acquired major importance due to their role in tumoral growth and metastatic dissemination. Moreover, the activity of various diseases that involve chronic inflammation, such as asthma, psoriasis and rheumatoid arthritis, has been associated with vascular development. Several growth factors and cytokines are involved in this process and consequently investigation into these elements, both in peripheral blood and their expression in affected tissues, could elucidate the role of vascular development in diseases whose pathogenesis involves chronic inflammation, such as inflammatory bowel disease. The presence of distinct molecules involved in vascular development processes, such as vascular endothelial growth factor (VEGF), basic fibroblastic growth factor and placental growth factor, among others, has been studied in both ulcerative colitis and Crohn's disease, although not extensively. It has been suggested that the phenomena of vasculogenesis, angiogenesis and lymphangiogenesis play a critical, although not exclusive, role in the inflammation that characterizes inflammatory bowel disease. In general, the results obtained to date suggest that new vascular formation is involved in the pathogenesis of these diseases.

El desarrollo vascular en la enfermedad inflamatoria intestinal / Vascular development in inflammatory bowel disease

Con relación al desarrollo vascular destacan 4 conceptos fundamentales: vasculogénesis (formación de vasos sanguíneos a partir de angioblastos), angiogénesis (formación de vasos sanguíneos a partir de otros preexistentes), arteriogénesis (engrosamiento y desarrollo de los vasos) y linfangiogénesis (formación de vasos linfáticos). En esta última década, estos conceptos, sobre todo la angiogénesis y la linfangiogénesis, han adquirido una mayor importancia debido a su papel en el crecimiento tumoral y en la diseminación metastásica. Además, parece que la actividad de diversas enfermedades que implican inflamación crónica, como el asma, la psoriasis o la artritis reumatoide, se ha relacionado con el desarrollo vascular. Existen diversos factores de crecimiento y citocinas implicados en este proceso, por lo que su estudio, tanto de sus concentraciones en sangre periférica como de su expresión en los tejidos afectados, podría esclarecer el papel del desarrollo vascular en las entidades en cuya patogenia está implicada la inflamación crónica, como es el caso de la enfermedad inflamatoria intestinal. Tanto en la colitis ulcerosa como en la enfermedad de Crohn se ha estudiado, aunque no extensamente, la presencia de diversas moléculas implicadas en los procesos de desarrollo vascular, como el factor de crecimiento del endotelio vascular, el factor de crecimiento fibroblástico básico o el factor de crecimiento placentario, entre otros, y se ha señalado que los fenómenos de vasculogénesis, angiogénesis y linfangiogénesis son esenciales, aunque no exclusivos, en la inflamación que caracteriza la enfermedad inflamatoria intestinal. En general, podría concluirse de los resultados obtenidos hasta el momento que la formación de nuevos vasos es un fenómeno implicado en la patogenia de dichas enfermedades

There are 4 major concepts in vascular development: vasculogenesis (formation of blood vessels from angioblasts), angiogenesis (formation of vascular sprouts from preexisting vessels), arteriogenesis (thickening and development of vessels) and lymphangiogenesis (formation of lymphatic vessels). In the last decade, these concepts, especially angiogenesis and lymphangiogenesis, have acquired major importance due to their role in tumoral growth and metastatic dissemination. Moreover, the activity of various diseases that involve chronic inflammation, such as asthma, psoriasis and rheumatoid arthritis, has been associated with vascular development. Several growth factors and cytokines are involved in this process and consequently investigation into these elements, both in peripheral blood and their expression in affected tissues, could elucidate the role of vascular development in diseases whose pathogenesis involves chronic inflammation, such as inflammatory bowel disease. The presence of distinct molecules involved in vascular development processes, such as vascular endothelial growth factor (VEGF), basic fibroblastic growth factor and placental growth factor, among others, has been studied in both ulcerative colitis and Crohn's disease, although not extensively. It has been suggested that the phenomena of vasculogenesis, angiogenesis and lymphangiogenesis play a critical, although not exclusive, role in the inflammation that characterizes inflammatory bowel disease. In general, the results obtained to date suggest that new vascular formation is involved in the pathogenesis of these diseases

El desarrollo vascular en la enfermedad inflamatoria intestinal / Vascular development in inflammatory bowel disease

Con relación al desarrollo vascular destacan 4 conceptos fundamentales: vasculogénesis (formación de vasos sanguíneos a partir de angioblastos), angiogénesis (formación de vasos sanguíneos a partir de otros preexistentes), arteriogénesis (engrosamiento y desarrollo de los vasos) y linfangiogénesis (formación de vasos linfáticos). En esta última década, estos conceptos, sobre todo la angiogénesis y la linfangiogénesis, han adquirido una mayor importancia debido a su papel en el crecimiento tumoral y en la diseminación metastásica. Además, parece que la actividad de diversas enfermedades que implican inflamación crónica, como el asma, la psoriasis o la artritis reumatoide, se ha relacionado con el desarrollo vascular. Existen diversos factores de crecimiento y citocinas implicados en este proceso, por lo que su estudio, tanto de sus concentraciones en sangre periférica como de su expresión en los tejidos afectados, podría esclarecer el papel del desarrollo vascular en las entidades en cuya patogenia está implicada la inflamación crónica, como es el caso de la enfermedad inflamatoria intestinal. Tanto en la colitis ulcerosa como en la enfermedad de Crohn se ha estudiado, aunque no extensamente, la presencia de diversas moléculas implicadas en los procesos de desarrollo vascular, como el factor de crecimiento del endotelio vascular, el factor de crecimiento fibroblástico básico o el factor de crecimiento placentario, entre otros, y se ha señalado que los fenómenos de vasculogénesis, angiogénesis y linfangiogénesis son esenciales, aunque no exclusivos, en la inflamación que caracteriza la enfermedad inflamatoria intestinal. En general, podría concluirse de los resultados obtenidos hasta el momento que la formación de nuevos vasos es un fenómeno implicado en la patogenia de dichas enfermedades

There are 4 major concepts in vascular development: vasculogenesis (formation of blood vessels from angioblasts), angiogenesis (formation of vascular sprouts from preexisting vessels), arteriogenesis (thickening and development of vessels) and lymphangiogenesis (formation of lymphatic vessels). In the last decade, these concepts, especially angiogenesis and lymphangiogenesis, have acquired major importance due to their role in tumoral growth and metastatic dissemination. Moreover, the activity of various diseases that involve chronic inflammation, such as asthma, psoriasis and rheumatoid arthritis, has been associated with vascular development. Several growth factors and cytokines are involved in this process and consequently investigation into these elements, both in peripheral blood and their expression in affected tissues, could elucidate the role of vascular development in diseases whose pathogenesis involves chronic inflammation, such as inflammatory bowel disease. The presence of distinct molecules involved in vascular development processes, such as vascular endothelial growth factor (VEGF), basic fibroblastic growth factor and placental growth factor, among others, has been studied in both ulcerative colitis and Crohn's disease, although not extensively. It has been suggested that the phenomena of vasculogenesis, angiogenesis and lymphangiogenesis play a critical, although not exclusive, role in the inflammation that characterizes inflammatory bowel disease. In general, the results obtained to date suggest that new vascular formation is involved in the pathogenesis of these diseases