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J Satsangi

Publications and source records attributed to J Satsangi.

At least 19 recordsLinked to original sources
PubMed2006

The efficacy of corticosteroid therapy in inflammatory bowel disease: analysis of a 5-year UK inception cohort.

BACKGROUND: Corticosteroids remain the mainstay of first-line therapy in active inflammatory bowel disease. AIMS: To determine the clinical outcome after the first corticosteroid-therapy and to identify factors which predict response/failure. METHODS: 216 (136 ulcerative colitis and 80 Crohn's disease) patients were identified in this 5-year inception cohort. The outcomes of early (30 days) and late (1 year) responses were used. Multivariate analyses were performed to identify factors associated with outcome. RESULTS: 86 (63%) and 60 (75%) ulcerative colitis and Crohn's disease required corticosteroid therapy, respectively. In ulcerative colitis, at 30 days, 69 (51%), 42 (31%) and 25 (18%) patients demonstrated complete response, partial response and no response, respectively. For Crohn's disease, these outcomes were observed in 32 (40%), 28 (35%) and 20 (25%). After 1 year, 75 (55%), 23 (17%) and 29 (21%) patients with ulcerative colitis demonstrated prolonged response, corticosteroid-dependence or required surgery, respectively. For Crohn's disease, these outcomes were observed in 30 (38%), 19 (24%) and 27 (35%) patients. Extensive ulcerative colitis was a predictor of surgery (P = 0.001, OR: 15.2). In Crohn's disease, inflammatory disease behaviour was negatively associated with surgery (P = 0.02, OR: 0.13). CONCLUSION: Although corticosteroids are effective, dependence/resistance remains common. Patients with extensive ulcerative colitis and fistulizing/stricturing Crohn's are most at risk of failing corticosteroid therapy.

Adrenal Cortex Hormones↗
PubMed2006

Analysis of the influence of OCTN1/2 variants within the IBD5 locus on disease susceptibility and growth indices in early onset inflammatory bowel disease.

BACKGROUND AND AIMS: The OCTN1 (SLC22A4 1672C-->T) and OCTN2 (SLC22A5 -207G-->C) variants within the IBD5 locus have been associated with susceptibility to adult onset Crohn's disease (CD), but their contribution in children has not been examined. METHODS: These OCTN1/2 variants and IBD5 marker single nucleotide polymorphisms (SNPs) (IGR2096a_1, IGR2198a_1, and IGR2230a_1) were examined in 299 Scottish children (200 with CD, 74 with ulcerative colitis (UC), and 25 with indeterminate colitis (IC)), together with 502 parents (for transmission disequilibrium testing) and 256 controls. RESULTS: All SNPs were in strong linkage disequilibrium (D' >0.94). TDT analysis showed association of the OCTN1 variant with inflammatory bowel disease (IBD) (p = 0.01) and CD (p = 0.04). Allele frequencies of the OCTN1/2 variants were significantly higher in IBD/CD cases (p<0.04). The homozygous mutant OCTN1/2 haplotype was increased in IBD (24.3% v 16.1%, p = 0.02) and UC (28.2% v 16.1%, p = 0.02) compared with controls. The OCTN1/2 variants were not independent of the background IBD5 risk haplotype in conferring disease susceptibility. Unifactorial analysis in CD patients showed that carriage of the TC haplotype was associated with lower weight, height, and BMI centile (<9(th) centile) at diagnosis (weight: 87.9% v 67.3% (p = 0.002), odds ratio (OR) = 3.52 (95% confidence interval, 1.51 to 8.22); height: 84.1% v 68.4% (p<0.05), OR = 2.44 (1.00 to 5.99); BMI: 79.6% v 61.1% (p = 0.02), OR = 2.49 (1.14 to 5.44)), and lower weight centile at follow up (87.5% v 64.6% (p = 0.03), OR = 3.83 (1.03 to 14.24)). Multifactorial binary logistic regression analysis confirmed association of the TC haplotype with lower weight centile at diagnosis (p = 0.02, OR = 3.41 (1.20 to 9.66)). CONCLUSIONS: These data implicate variants within the IBD5 haplotype, as determinants of disease susceptibility and growth indices in early onset IBD. The OCTN1/2 variants remain potential positional candidate genes, but require further analysis.

Adolescent↗
PubMed2006

ABCB1/MDR1 gene determines susceptibility and phenotype in ulcerative colitis: discrimination of critical variants using a gene-wide haplotype tagging approach.

Several lines of evidence suggest a role for the multidrug resistance gene (ABCB1/MDR1) and its product, P-glycoprotein 170, in the pathogenesis of inflammatory bowel disease (IBD). In addition, P-glycoprotein activity determines bioavailability of many drugs used regularly in many medical specialties, and ABCB/MDR1 variation appears to be a critical pharmacogenetic determinant. We have utilized a gene-wide haplotype tagging approach to further define the identity of germ-line variations in the ABCB1/MDR1 gene contributing to IBD susceptibility. Six haplotype tagging single nucleotide polymorphisms (tSNPs) representing the haplotypic variations of the ABCB1/MDR1 gene were identified initially following the characterization of the haplotype structure of this gene in 24 Centre d'Etude du Polymorphisme Humain Caucasian trios. Genotyping was performed in 249 ulcerative colitis (UC) and 179 Crohn's disease (CD) patients and 260 healthy controls. Using log-likelihood analysis, we observed a highly significant association between the common haplotypes and UC (P=4.22 x 10(-7)) but not CD (P=0.22). This significant association was critically dependent on one tSNP, intronic variant rs3789243. All haplotypes with this variant retained a highly significant association (P=3.2 x 10(-7)-3.6 x 10(-12)), whereas significance was lost when rs3789243 was dropped in systematic haplotypic analysis. The effect of this tSNP was independent of C3435T SNP, previously suggested to be the critical variant in disease susceptibility and drug transport. The association with UC was shown to be strongest with the phenotype of extensive disease (P=1.7 x 10(-7)). This 'candidate gene' approach provides compelling evidence to support the contribution of the ABCB1/MDR1 gene in determining risk to UC but not to CD and provides new insights into the localization of the critical susceptibility determinants within the gene. In addition, these findings have potentially important implications in the application of pharmacogenetics across a range of common diseases, including HIV, epilepsy and colorectal cancer.

Adult↗
PubMed2006

The Montreal classification of inflammatory bowel disease: controversies, consensus, and implications.

In recent years, investigators have readdressed the complex issues involved in the classification of inflammatory bowel diseases. In 2003, a Working Party of investigators with an interest in the issues involved in disease subclassification was formed with the aim of summarising recent developments in disease classification and establishing an integrated clinical, molecular, and serological classification of inflammatory bowel disease. The results of the Working Party were reported at the 2005 Montreal World Congress of Gastroenterology. Here we highlight the key issues that have emerged from discussions of the Montreal Working Party and the relevance to clinical practice and research activities.

Biomarkers↗
PubMed2005

DLG5 variants do not influence susceptibility to inflammatory bowel disease in the Scottish population.

INTRODUCTION: Recent data have suggested that specific haplotypic variants of the DLG5 gene on chromosome 10q23 may be associated with susceptibility to inflammatory bowel disease (IBD) in Germany. Haplotype D, notably characterised by the presence of a G-->A substitution at nucleotide 113, was associated with susceptibility to Crohn's disease (CD) whereas an extended haplotype A conferred protection. AIMS: Association of DLG5 haplotypic variants with disease susceptibility, genotype-phenotype relationships, and epistasis with CARD15 was investigated in the Scottish population. PATIENTS AND METHODS: A total of 374 CD, 305 ulcerative colitis (UC), and 294 healthy controls (HC) were studied. Genotyping for the variants rs1248696 (113A, representing haplotype D) and the single nucleotide polymorphism tag rs2289311 (representing haplotype A) were typed using the Taqman system. RESULTS: On analysis of the DLG5 variant 113A, there were no associations with IBD when allelic frequency (11.4% IBD v 13.2% HC; p = 0.30) and carrier frequency (19.2% IBD v 24.6% HC; p = 0.069) were analysed. No associations were observed between 113A variant allelic frequency (p = 0.37), carrier frequency (p = 0.057), and CD. In fact, 113A heterozygosity rates were lower in CD (16%) and IBD (16.9%) than in HC (23%) (p = 0.029 and p = 0.033, respectively). No associations between DLG5 and UC were observed. Haplotype A was not protective and there was no evidence of epistasis between DLG5 and CARD15. CONCLUSIONS: The present data contrast strongly with previous data from Germany. DLG5 113A is not associated with disease susceptibility and haplotype A does not confer resistance. Further work is required to evaluate the significance of DLG5 in other populations from geographically diverse regions.

Adult↗
PubMed2004

Predicting the outcome of severe ulcerative colitis: development of a novel risk score to aid early selection of patients for second-line medical therapy or surgery.

BACKGROUND: The failure rate of medical therapy in severe ulcerative colitis is high. A risk index, to aid the identification of patients of not responding at an early stage to intravenous corticosteroid therapy, would be useful to facilitate second-line treatment or surgery. METHODS: We recruited 167 consecutive patients with severe ulcerative colitis between January 1995 and March 2002; and employed multiple logistic regression to analyse parameters within the first 3 days of medical therapy. We applied statistical modelling to formulate a risk score according to the likelihood of medical failure. RESULTS: Sixty-seven (40%) patients failed to respond to medical therapy. Multiple logistic regression analysis identified mean stool frequency and colonic dilatation within the first 3 days and hypoalbuminaemia as independent predictors of outcome (P < 0.001, 0.001 and 0.002 respectively). A numerical risk score was formulated based on these variables. Patients with scores of 0-1, 2-3 and > or =4 had a medical therapy failure rate of 11%, 43% and 85% respectively. Receiver-operator characteristic analysis of this score yielded area under curve of 0.88, with a sensitivity of 85% and specificity of 75% using score > or =4 in predicting non-response. CONCLUSION: This risk score allows the early identification of patients with severe ulcerative colitis who would be suitable for second-line medical therapy or surgery.

Adult↗
PubMed2004

Human keratin 8 mutations that disturb filament assembly observed in inflammatory bowel disease patients.

We have identified miss-sense mutations in keratin 8 in a subset of patients with inflammatory bowel disease (Crohn disease and ulcerative colitis). Inflammatory bowel diseases are a group of disorders that are polygenic in origin and involve intestinal epithelial breakdown. We investigated the possibility that these keratin mutations might contribute to the course of the disease by adversely affecting the keratin filament network that provides mechanical support to cells in epithelia. The mutations (Gly62 to Cys, Ile63 to Val and Lys464 to Asn) all lie outside the major mutation hotspots associated with severe disease in epidermal keratins, but using a combination of in vitro and cell culture assays we show that they all have detrimental effects on K8/K18 filament assembly in vitro and in cultured cells. The G62C mutation also gives rise to homodimer formation on oxidative stress to cultured intestinal epithelial cells, and homodimers are known to be polymerization incompetent. Impaired keratin assembly resulting from the K8 mutations found in some inflammatory bowel disease patients would be predicted to affect the maintenance and re-establishment of mechanical resilience in vivo, as required during keratin cytoskeleton remodeling in cell division and differentiation, which may lead to epithelial fragility in the gut. Simple epithelial keratins may thus be considered as candidates for genes contributing to a risk of inflammatory bowel disease.

Actin Cytoskeleton↗
PubMed2004

IBD: a family affair.

The recent molecular advances in the understanding of the genetics of inflammatory bowel disease (IBD) have their grounding in studies examining IBD within different family groups and populations. The risk of IBD is highest in first-degree relatives of an IBD proband but more distant relatives are also at increased risk. The risk is higher for relatives of a CD proband. The risks of developing IBD for 'high-risk' relatives might be as great as 1 in 3 but in general first-degree relatives have a 1 in 10-20 risk. Three recent systematic studies have identified a total of 326 European twin pairs to examine disease concordance rates. The derived heritability in Crohn's disease is greater than for many complex diseases and is currently under detailed examination. Strong concordance has been shown, in particular for disease type and disease location, in multiplex families and twin studies. More than 75% children are diagnosed with IBD at a younger age than their parents but true genetic anticipation appears unlikely.

Anticipation, Genetic↗
PubMed2004

NOD2/CARD15, TLR4 and CD14 mutations in Scottish and Irish Crohn's disease patients: evidence for genetic heterogeneity within Europe?

NOD2/caspase recruitment domain (CARD)15 variants are identified in up to 50% of Crohn's disease (CD) patients. Functional variants of toll-like receptor-4 (TLR4) and CD14 genes may also be relevant to disease pathophysiology. We aimed to assess the contribution of NOD2/CARD15, TLR4 and CD14 variants in Scottish and Irish CD patients. In all, 612 patients with well-characterised inflammatory bowel disease (252 Scottish CD, 247 Scottish UC, 113 Irish CD) and 304 controls were genotyped for variants of NOD2/CARD15 (1007fsinsC, G908R, R702W, P268S), TLR4 (A299G) and CD14 (T-159C). Genotype-phenotype analyses were performed. Variant 1007fsinsC (P=0.003) and G908R (P=0.008) but not R702W (P=0.269) alleles were more prevalent in Scottish CD (4.7, 1.8 and 7.1%, respectively) than Scottish control (2.3, 0.3 and 5.4%). CD allelic frequencies were lower than the series from Europe (P<0.00001) and North America (P<0.00001) but not Scandinavia (P<0.7). Associations were identified with age at diagnosis (P=0.002), ileal disease (P<0.02), penetrating disease (P=0.04) and inflammatory joint disease (P<0.02). TLR4 and CD14 variants did not differ between CD and controls. In conclusion, we present compelling evidence for genetic heterogeneity within Europe. These NOD2/CARD15 variants have a minor contribution in Scottish and Irish CD patients, consistent with an emerging pattern from Northern Europe.

Adult↗
PubMed2004

Anti-Saccharomyces cerevisiae antibodies (ASCA) in Crohn's disease are associated with disease severity but not NOD2/CARD15 mutations.

Anti-Saccharomyces cerevisiae antibodies (ASCAs) have been proposed as serological markers, which may differentiate Crohn's disease (CD) from ulcerative colitis (UC) and predict disease phenotype. Their importance in pathogenesis is unproven. We investigated the relationship between ASCAs, disease phenotype and NOD2/CARD15 genotype in CD and whether ASCAs were related to antibodies to other fungal proteins. Serum from 228 patients [143 CD, 75 UC, 10 with indeterminate colitis (IC)] and 78 healthy controls (HC) were assayed for ASCA. Antibodies (IgA, IgG) to other fungal proteins (Fusarium species ATC20334, Mycoprotein) were measured in the same samples using an in-house enzyme-linked immunosorbent assay (ELISA) assay. ASCAs were present in 57% of CD, 19% of UC, 30% of IC and 8% of HCs. ASCA-positive status was a predictor for CD with sensitivity of 57%, specificity of 87%, positive predictive value of 78% and negative predictive value of 68%. ASCA was associated with proximal (gastroduodenal and small bowel involvement) rather than purely colonic disease (P < 0.001) and with a more severe disease phenotype and requirement for surgery over a median follow-up time of 9 years (P < 0.0001). No associations with NOD2/CARD15 mutations were seen. There was no association between ASCA and antibodies to MP (IgA or IgG). These data implicate ASCA as a specific marker of disease location and progression in CD, emphasizing the heterogeneity within IBD.

Adolescent↗
PubMed2004

Unravelling the complex genetics of inflammatory bowel disease.

The rapid pace of progress in molecular genetics over the past 15 years--since the seminal description of the polymerase chain reaction--has led to the identification of the genes involved in many single gene disorders. These successes in the laboratory have already led directly to clinical applications in diagnosis, pharmacogenetics, and the development of new therapies. Progress in unravelling the genetics of complex diseases has been less straightforward. However, real excitement has followed the identification of the NOD 2/CARD 15 gene as an important determinant of susceptibility to Crohn's disease.(1,)(2) Not only has this finding provided a proof of principle for the technique of genome-wide scanning in complex disorders, but the discovery also has given real insight into the primary pathophysiology involved in chronic inflammatory bowel disease. The background to this discovery and its implications form the basis for the present article.

Carrier Proteins↗
PubMed2003

An analysis of factors influencing short-term and sustained response to infliximab treatment for Crohn's disease.

BACKGROUND: 59-81% of patients given infliximab for Crohn's disease will respond. Although now in widespread use, little consensus exists regarding the optimal place in patient care. Recently developed guidelines have identified need for markers that predict response. AIMS: We aimed to identify markers of response to infliximab given for Crohn's disease. METHODS: Markers of response (defined at 4 weeks) were prospectively assessed in 74 infliximab-treated patients with Crohn's disease. Patients were followed-up to 1 year. RESULTS: Fifty-four of 74 (73%) patients responded. Univariate analysis identified that smokers were less likely to respond than non-smokers [P = 0.005, odds ratio (OR) 0.22]. Patients established on immunosuppression (P = 0.034, OR 7.31) and with isolated colonic disease (P = 0.042, OR 3.83) were more likely to respond. Multiple logistic regression confirmed smoking (P = 0.035, OR 0.24) and colonic disease (P = 0.035, OR 4.87) as independent markers of response. One-year relapse rates differed significantly between smokers and non-smokers (100% vs. 39.6%, P = 0.0026, relative risk 3.2) and between patients established on immunomodulators or not (58.0% vs. 92.8%, P = 0.0054, relative risk 2.6). CONCLUSIONS: Smoking has a strong adverse effect on the response rates and maintenance of response to infliximab. Patients on immunomodulators have a more favourable short- and long-term response. These results have important implications for clinical practice.

Adolescent↗