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Biomedical subjects

Severine Vermeire

Publications and source records attributed to Severine Vermeire.

At least 37 records · Page 2Linked to original sources
PubMed2005

Hyperresponsiveness of the mucosal barrier in Crohn's disease is not tumor necrosis factor-dependent.

BACKGROUND: Crohn's disease (CD) is associated with gut barrier dysfunction. Besides the baseline barrier defect, a subgroup of patients also expresses an intestinal barrier hyperresponsiveness to nonsteroidal anti-inflammatory drugs. We studied whether reducing inflammation and restoring gut barrier dysfunction with anti-tumor necrosis factor (TNF) antibody treatment also antagonizes the permeability increase by oral nonsteroidal anti-inflammatory drug intake in patients with CD. METHODS: Thirty-one healthy control subjects and 25 patients with active CD were studied. The 31 controls performed intestinal permeability testing for Cr-EDTA before (baseline) and after oral intake of indomethacin (50 + 75 mg). Twenty-five patients carried out a baseline and indomethacin-mediated permeability test before infliximab infusion. The patients repeated either the indomethacin test (12/25) or baseline and indomethacin tests (13/25), 1 month after this treatment. Intestinal permeability was studied by measurement of urinary excretion of Cr-EDTA after oral intake. RESULTS: Increased whole gut permeation before treatment (3.16%; interquartile range [IQR], 2.92-5.72) was restored to normal values (2.47%; IQR, 1.97-2.78) by anti-TNF treatment. Indomethacin increased whole gut permeability significantly more in patients with CD (before anti-TNF: 6.50%; IQR, 4.84-10.38; after anti-TNF: 5.50%; IQR, 3.97-10.09) compared with the healthy subjects (4.66%; IQR, 3.51-5.64). Eleven of 25 patients (44%) had an abnormal whole gut permeability response to indomethacin before anti-TNF, and 9 of them remained hyperresponsive after infusion, despite clinical remission. CONCLUSIONS: Although anti-TNF treatment suppresses inflammation and restores gut barrier function in patients with CD, it does not antagonize the barrier hyperresponsiveness to indomethacin. These data support the notion of an underlying intestinal mucosal barrier hyperresponsiveness in a subset of patients with CD, independent of inflammation.

Adult↗
PubMed2005

Tumor necrosis factor receptor gene polymorphisms in Crohn's disease: association with clinical phenotypes.

OBJECTIVES: Crohn's disease (CD) is a chronic multifactorial disorder with diverse clinical features that are influenced by a heterogeneous set of genetic factors. TNF-alpha/TNF receptor interactions play a pivotal role in the pathogenesis of the inflammatory response. Our purpose was to determine whether single nucleotide polymorphisms (SNPs) in the TNF receptors confer susceptibility to Crohn's disease and whether they are associated with clinical phenotype. METHODS: A cohort of 205 consecutively identified and unrelated patients with CD and 106 controls were recruited. Subjects were genotyped for polymorphisms in TNFRSF1A (position +36, -609), TNFRSF1B (+196, +1466), along with the three common CARD15 variants and phenotyped for disease behavior. Genotypic and allelic frequencies were compared between CD and controls and a logistic regression model was constructed to determine independent associations with specific clinical phenotypes. RESULTS: Only the TNFRSF1A +36 and TNFRSF1B +196 SNPs were associated with CD (p= 0.0019 and 0.034, respectively). The TNFRSF1A +36 mutation was negatively associated with stricturing disease phenotype (OR = 0.384; CI = 0.166-0.887). In contrast, the TNFRSF1B +196 was negatively associated with colitis (OR = 0.410; CI = 0.191-0.880). These associations were independent of CARD15 mutation status. Finally, TNFRSF1B +196 was negatively associated with surgery in CARD15 negative patients. CONCLUSIONS: These data constitute the first report of an association of TNFRSF1A and TNFRSF1B polymorphisms with CD in a Caucasian population and address the role of TNFR mutations in determining clinical heterogeneity in CD.

Adenine↗
PubMed2005

Toward an integrated clinical, molecular and serological classification of inflammatory bowel disease: report of a Working Party of the 2005 Montreal World Congress of Gastroenterology.

The discovery of a series of genetic and serological markers associated with disease susceptibility and phenotype in inflammatory bowel disease has led to the prospect of an integrated classification system involving clinical, serological and genetic parameters. The Working Party has reviewed current clinical classification systems in Crohn's disease, ulcerative colitis and indeterminate colitis, and provided recommendations for clinical classification in practice. Progress with respect to integrating serological and genetic markers has been examined in detail, and the implications are discussed. While an integrated system is not proposed for clinical use at present, the introduction of a widely acceptable clinical subclassification is strongly advocated, which would allow detailed correlations among serotype, genotype and clinical phenotype to be examined and confirmed in independent cohorts of patients and, thereby, provide a vital foundation for future work.

Biomarkers↗
PubMed2005

Significance of anti-sacharomices cerevisiae antibodies (ASCA) in patients with inflammatory bowel diseases in Romania.

INTRODUCTION: Anti-Sacharomyces cerevisiae antibodies (ASCA) represent the immunologic marker correlated with Crohn's disease because of their high specificity (80-95%). The aim of this study is to confirm their value in a Romanian population with IBD. MATERIAL AND METHODS: A prospective longitudinal study was performed, which included patients admitted to Center of Gastroenterology and Hepatology Fundeni, Bucharest, in 2000 with ulcerative colitis (33 patients) - UC group, or Crohn's disease (40 patients) - CD group, and a control group (C) consisting of 22 healthy subjects. ASCA determination from serum samples was performed in the Erasmus University by ELISA technique. RESULTS: ASCA+ prevalence in CD group was 5 in 40 patients (12.5%), in UC group 0/33 (0%), 1/21 C group (4.9%), p=0.05. ASCA+ phenotype was found only in patients with CD diagnosed before the age of 40 years (A1), p=0.04. Also, ASCA+ phenotype correlated significantly with the colonic (L2) or ileocolonic (L3) extension (p=0.05). ASCA+ status did not correlate with the evolutive pattern of CD (stricturing, penetrating or non- stricturing non-penetrating), and neither did the clinical severity. CONCLUSIONS: ASCA+ prevalence in CD patients is much lower compared with North-American or West-European studies (12.5% versus 40-70%). In Romanian patients, ASCA assessment may be helpful in achieving a diagnosis of Crohn's disease, especially in those younger than 40 years, or in those with colonic or ileocolonic extension.

Adult↗
PubMed2005

Prevalence and significance of perinuclear anti-neutrophil antibodies (pANCA) in Romanian patients with Crohn's disease and ulcerative colitis.

INTRODUCTION: Antineutrophil cytoplasmic antibodies (ANCA) are known as a serologic marker of immune disturbances in IBD. The most specific are perinuclear ANCA (pANCA). The aim of this study was to investigate their significance for the diagnosis of inflammatory bowel disease (IBD) in Romania. MATERIAL AND METHODS: A prospective longitudinal study, comprising all patients admitted to our Center in 2000 with ulcerative colitis--UC group (33 patients) and with Crohn's disease--CD group (40 patients). The control group (C) included 22 healthy individuals, with similar age and sex distribution. ANCA was tested in serum by indirect immunofluorescence at Leuven University, Belgium. RESULTS: ANCA prevalence in UC group was 12/33 (36.4%), in CD group was 6/40 (15%), while in the C group all sera tested negative (p=0.004). All ANCA antibodies in patients with IBD were perinuclear type. In the UC group, the prevalence of pANCA was higher in females compared to males (52.9% versus 16.7%, p=0.04). The phenotype pANCA+ did not correlate with disease extension, severity, the evolutive form or complications. In the CD group, the phenotype pANCA+, although more frequently found in colonic involvement and in non-obstructive non-fistulizing forms to associate with pANCA+, did not reach statistical significance (p=0.59). A higher severity of CD was associated with higher pANCA titers (p=0.05). CONCLUSION: pANCA prevalence in UC in Romania was lower in comparison with other studies (36.4% versus 50-80%). The highest prevalence was found in females with UC. In CD, pANCA+ was associated with a higher severity. pANCA assessment remains at a research level, further in-vestigations being necessary in order to demonstrate its clinical importance.

Adult↗
PubMed2004

Diagnostic accuracy of ten second-generation (human) tissue transglutaminase antibody assays in celiac disease.

BACKGROUND: Anti-tissue transglutaminase (tTG) assays that use human tTG as antigen have recently become available. We evaluated commercially available assays with human tTG antigen to estimate their diagnostic accuracies and to determine whether they agree sufficiently to be used interchangeably. METHODS: Ten commercially available second-generation anti-tTG assays were evaluated. The following populations were studied: celiac disease (CD) patients at the time of diagnosis without (n = 70) or with (n = 5) IgA deficiency; diseased controls (n = 70); and CD patients without (n = 28) or with (n = 2) IgA deficiency during follow-up. All individuals included in the study underwent intestinal biopsy. Technical performance (linearity, interference, precision, correlation, and agreement) and diagnostic accuracy (sensitivity and specificity) were compared. Anti-gliadin and anti-endomysium antibodies were also measured. RESULTS: IgA anti-tTG results correlated well overall, but numerical values differed. Diagnostic sensitivity ranged between 91% and 97% and specificity between 96% and 100%. These were higher than the sensitivity and specificity of the IgA endomysium assay and the IgA gliadin assay. Generally, IgG anti-tTG was less sensitive but more specific than IgG anti-gliadin for the diagnosis of CD in the small group of IgA-deficient patients. CONCLUSIONS: Overall diagnostic performance of IgA tTG assays is acceptable and comparable among the different assays, but numerical values differ. Standardization is needed.

Adolescent↗
PubMed2004

NOD2/CARD15: relevance in clinical practice.

So far, the relevance of NOD2/CARD15 genotyping for clinical practice is modest. The current data almost unanimously show that NOD2/CARD15 mutations in Crohn's disease are associated with small-bowel involvement. More studies are needed to determine whether NOD2/CARD15 mutations are also associated with a fibrostenotic behaviour of the disease. If CARD15 variants would predict a more aggressive disease course, then a more aggressive treatment is justified in these patients after NOD2/CARD15 genetic testing. It is not clear whether NOD2/CARD15 genotyping is helpful in differentiating indeterminate colitis patients. Although CARD15 variants do not predict response to the TNF alpha monoclonal antibodies, the role of the gene in response to other drugs is not known. Finally, screening unaffected relatives of CD patients is not recommended until preventive strategies are available.

Carrier Proteins↗
PubMed2004

Long-term outcome of treatment with intravenous cyclosporin in patients with severe ulcerative colitis.

OBJECTIVES: Iv cyclosporin A (CSA) is an effective therapy in patients with severe ulcerative colitis (UC). It remains unclear if this treatment affects the course of the disease in the long run. We investigated the long-term efficacy and safety in 86 patients with ulcerative colitis treated with i.v. CSA at our center. METHODS: The records of all patients treated with i.v. CSA between 11/1992 and 11/2000 were reviewed. RESULTS: Seventy-two of 86 patients (83.7%) responded to i.v. CSA therapy, administered for a mean of 9 +/- 2 days. Following the initial treatment, 69 patients (96%) were discharged on oral CSA with mean blood CSA concentrations of 192 +/- 55 ng/mL. Azathioprine was added in 64 (89%) patients. A second treatment with CSA was necessary in 11 patients; 1 patient received three courses of i.v. treatment. The duration of follow-up averaged 773 +/- 369 days. Patients who were responders but were still having certain symptoms at discharge had a higher incidence of colectomy during follow-up. Of all initial responders, 18 (25%) underwent colectomy after a mean interval of 178 +/- 141 days. The life-table predicts that of all treated patients, 55% will avoid a colectomy during a period of 3 years. Complications of CSA treatment were mostly reversible, but 3 patients (3.5%) died of opportunistic infections (1 of Pneumocystis carinii pneumonia and 2 of Aspergillus fumigatus pneumoniae). One patient with anaphylactic shock caused by the CSA solvent was successfully resuscitated. CONCLUSIONS: CSA is an effective treatment of the majority of patients with severe attacks of UC, although the toxicity and even mortality associated with its use necessitates careful evaluation, selection, and follow-up.

Adult↗
PubMed2004

Pancreatic autoantibodies in inflammatory bowel disease.

BACKGROUND: Autoantibodies against exocrine pancreas (PABs) have been reported to be specific for Crohn's disease (CD), albeit at a low prevalence (30%). We studied PABs in patients with inflammatory bowel disease (IBD), unaffected family members, and control subjects. METHODS: A Belgian study cohort of 575 subjects, including 289 IBD patients (CD, 169 patients; ulcerative colitis [UC], 120 patients), 108 unaffected first-degree relatives, 78 subjects with non-IBD gastrointestinal disorders (gastrointestinal control subjects [GIcos]), and 100 healthy control subjects (Hcos), were tested for PAB by a standardized indirect immunofluorescence method. RESULTS: The prevalence of PABs in this study cohort was 32% for CD, 23.3% for UC, and 22.2% for their unaffected family members (all P < 0.001), compared with 1.3% for GIcos and 0% for Hcos. Two staining patterns could be observed: an intracellular pattern (IC); and an extracellular pattern (EC). The EC was significantly more prevalent in CD patients compared with UC patients (P = 0.014), and higher titers of this pattern were found in CD patients (P = 0.01). Both PAB patterns were negatively associated with stricturing disease behavior of CD (P = 0.021). The IC was associated with familial CD (P = 0.0009) and familial UC (P = 0.0003). CONCLUSIONS: The prevalence of PAB found in CD patients in this study was similar to that cited in previous reports. In contrast to these reports, we also found an increased prevalence of PABs in patients with UC and in unaffected first-degree relatives of IBD patients. We observed two main staining patterns, both of which were present in IBD and were associated with specific phenotypes of the disease.

Adolescent↗
PubMed2004

Transmission of CARD15 (NOD2) variants within families of patients with inflammatory bowel disease.

OBJECTIVES: Three single nucleotide polymorphisms (SNPs) in CARD15 have been independently associated with Crohn's disease (CD). Since nothing is known about the transmission of these variants within families, this was the subject of our study in Flemish patients with inflammatory bowel disease (IBD) and their healthy relatives. METHODS: A cohort of 1,670 individuals (570 CD, 173 UC, 165 healthy controls, 762 first-degree unaffected relatives of CD patients) was genotyped for Arg702Trp, Gly908Arg, and Leu1007fsinsC. Mutant allele and carrier frequencies were compared between groups. Segregation patterns were compared using a bivariate Dale model. RESULTS: The carrier prevalence of CARD15 variants for CD patients was 46.3%, compared to 20.6% for healthy controls and 22.0% for ulcerative colitis (UC) patients (both p < 0.0001). An increased carriage rate of CARD15 variants was observed in unaffected relatives of CD patients (37.3%; p < 0.0001 vs controls), although this was significantly lower than in the CD patients (p = 0.001). Paternal transmission gave a 5.17-fold higher chance for the child to develop the disease compared to maternal transmission (95% CI [1.59, 16.78]; p = 0.0063). UC patients belonging to mixed IBD families carried significantly more mutations (42.3%) compared to other UC patients (18.4%) (p < 0.01). CONCLUSIONS: Maternal transmission of the CARD15 variant allele is associated with a lower proportion of affected individuals compared to paternal transmission. Therefore, maternal transmission does not carry an increased risk of transmission as does paternal transmission. The increased mutation carriage in unaffected siblings of CD patients and in UC patients belonging to mixed families suggests that other factors than CARD15 contribute to the eventual disease expression.

Adolescent↗
PubMed2003

Influence of immunogenicity on the long-term efficacy of infliximab in Crohn's disease.

BACKGROUND: Treatment with infliximab, a chimeric monoclonal IgG1 antibody against tumor necrosis factor, can result in the formation of antibodies against infliximab. We evaluated the clinical significance of these antibodies in patients with Crohn's disease. METHODS: In a cohort of 125 consecutive patients with Crohn's disease who were treated with infliximab infusions, we evaluated the concentrations of infliximab and of antibodies against infliximab, clinical data, side effects (including infusion reactions), and the use of concomitant medications before and 4, 8, and 12 weeks after each infusion. RESULTS: A mean of 3.9 infusions (range, 1 to 17) per patient were administered over a mean period of 10 months. Antibodies against infliximab were detected in 61 percent of patients. The presence of concentrations of 8.0 microg per milliliter or greater before an infusion predicted a shorter duration of response (35 days, as compared with 71 days among patients with concentrations of less than 8.0 microg per milliliter; P<0.001) and a higher risk of infusion reactions (relative risk, 2.40; 95 percent confidence interval, 1.65 to 3.66; P<0.001). Infliximab concentrations were significantly lower at four weeks among patients who had had an infusion reaction than among patients who had never had an infusion reaction (median, 1.2 vs. 14.1 microg per milliliter; P<0.001). Patients who had infusion reactions had a median duration of clinical response of 38.5 days, as compared with 65 days among patients who did not have an infusion reaction (P<0.001). Concomitant immunosuppressive therapy was predictive of low titers of antibodies against infliximab (P<0.001) and high concentrations of infliximab four weeks after an infusion (P<0.001). CONCLUSIONS: The development of antibodies against infliximab is associated with an increased risk of infusion reactions and a reduced duration of response to treatment. Concomitant immunosuppressive therapy reduces the magnitude of the immunogenic response.

Adolescent↗
PubMed2003

Autoimmunity associated with anti-tumor necrosis factor alpha treatment in Crohn's disease: a prospective cohort study.

BACKGROUND & AIMS: Infliximab therapy is an effective approach to treating Crohn's disease. Development of antinuclear antibodies has been described in patients treated, but the size of the problem and the relationship with autoimmunity have not been investigated. We investigated the occurrence of antinuclear antibodies in 125 consecutive Crohn's disease patients and studied the relationship with symptoms of autoimmunity. METHODS: Autoantibodies and clinical data were investigated before and 1, 2, and 3 months after infliximab infusion. If antinuclear antibodies were > or =1:80, further study of double-stranded DNA, single-stranded DNA, histones, and ENA was performed. RESULTS: Cumulative antinuclear antibody incidence at 24 months was 71 of 125 (56.8%). Almost half of these patients developed antinuclear antibodies after the first infusion, and >75% became antinuclear antibody positive after fewer than 3 infusions. So far, only 15 of 71 patients have become seronegative, after a median of 12 months. Of 43 antinuclear antibody-positive patients who were further subtyped, 14 of 43 (32.6%) had double-stranded DNA, 17 (39.5%) had single-stranded DNA, 9 (20.9%) had antihistone, and 0% were ENA positive. Two patients (both antihistone and double-stranded DNA positive) developed drug-induced lupus without major organ damage, and 1 developed autoimmune hemolytic anemia. Antinuclear antibodies were associated with the female sex (odds ratio, 3.166; 95% confidence interval, 1.167-8.585; P = 0.024) and with papulosquamous or butterfly rash (odds ratio, 10.016; 95% confidence interval, 1.708-58.725; P = 0.011). CONCLUSIONS: The cumulative incidence of antinuclear antibodies was 56.8% after 24 months in this cohort of infliximab-treated Crohn's disease patients. Antinuclear antibodies persisted up to 1 year after the last infusion, and only a few patients became seronegative. Two patients developed drug-induced lupus erythematosus. Antinuclear antibodies were associated with the female sex and skin manifestations.

Adult↗
PubMed2003

VEGF is a modifier of amyotrophic lateral sclerosis in mice and humans and protects motoneurons against ischemic death.

Amyotrophic lateral sclerosis (ALS) is an incurable degenerative disorder of motoneurons. We recently reported that reduced expression of Vegfa causes ALS-like motoneuron degeneration in Vegfa(delta/delta) mice. In a meta-analysis of over 900 individuals from Sweden and over 1,000 individuals from Belgium and England, we now report that subjects homozygous with respect to the haplotypes -2,578A/-1,154A/-634G or -2,578A/-1,154G/-634G in the VEGF promoter/leader sequence had a 1.8 times greater risk of ALS (P = 0.00004). These 'at-risk' haplotypes lowered circulating VEGF levels in vivo and reduced VEGF gene transcription, IRES-mediated VEGF expression and translation of a novel large-VEGF isoform (L-VEGF) in vivo. Moreover, SOD1(G93A) mice crossbred with Vegfa(delta/delta) mice died earlier due to more severe motoneuron degeneration. Vegfa(delta/delta) mice were unusually susceptible to persistent paralysis after spinal cord ischemia, and treatment with Vegfa protected mice against ischemic motoneuron death. These findings indicate that VEGF is a modifier of motoneuron degeneration in human ALS and unveil a therapeutic potential of Vegfa for stressed motoneurons in mice.

Aged↗