The genes for tumour necrosis factor alpha (TNF alpha) and lymphotoxin alpha (LT alpha; TNF beta) are tandemly arranged in the central region of the MHC. They may, therefore, be of importance for the aetiology of MHC-associated diseases. The authors have prospectively studied the secretion of TNF alpha and LT alpha in relation to polymorphisms at positions -308 and -238 in the TNF alpha gene (TNFA), and two polymorphisms in the first intron of the LT alpha gene (LTA), as well as HLA-DR in 30 patients with chronic inflammatory bowel diseases (IBD) and 12 healthy controls. In the Dutch population, the alleles of these four polymorphisms are present in only five combinations, called TNF-haplotypes: TNF-C, -E, -H, -I, and -P. Significant associations between TNF haplotypes and TNF alpha and LT alpha secretion were found when PBMC were cultured with T-cell activators, irrespective of disease. Mean TNF alpha secretion of individuals carrying the HLA-DR3 associated TNF-E haplotype was significantly higher, as compared to individuals without this haplotype (26 441 pg/ml versus 19 629 pg/ml; P = 0.014). Individuals carrying the TNF-C haplotype produced the lowest amount of TNF alpha (17 408 pg/ml; P=0.022). The TNF-C and TNF-E haplotypes differ only at position -308 in the promoter of TNFA. Individuals carrying the HLA-DR1 associated TNF-I haplotype produced significantly less LT alpha when compared to those who lack this haplotype (1979 pg/ml versus 3462 pg/ml; P = 0.006). As the TNF-I haplotype is also associated with low TNF alpha secretion, this haplotype thus defines a 'low secretor phenotype'. In conclusion, this is the first study to show associations between TNF haplotypes and TNF alpha and LT alpha secretion when T-cell stimulators are used. These findings will contribute to define disease heterogeneity in IBD and may be of relevance for understanding the pathogenesis of autoimmune diseases.

Screening for variants in TPMT did not reduce the proportions of patients with hematologic ADRs during thiopurine treatment for IBD. However, there was a 10-fold reduction in hematologic ADRs among variant carriers who were identified and received a dose reduction, compared with variant carriers who did not, without differences in treatment efficacy. ClinicalTrials.gov number: NCT00521950.

In patients with BE, the risk of developing HGD or EAC is predominantly determined by the presence of LGD, a known duration of BE of ≥10 years, longer length of BE, and presence of esophagitis. One or combinations of these risk factors are able to identify patients with a low or high risk of neoplastic progression and could therefore be used to individualize surveillance intervals in BE.

Meuwissen SGM, Peiia AS. Serum nitrate levels in ulcerative colitis and Crohn's disease. Scand J Gastroenterol 1995;30:784-788. Background: Nitric oxide is an important mediator in inflammatory and autoimmune-mediated tissue destruction and may be of pathophysiologic importance in inflammatory bowel disease. We studied whether serum levels of nitrate, the stable end-product of nitric oxide, are increased in active Crohn's disease or ulcerative colitis, in comparison with quiescent disease and healthy controls. The setting was the gastroenterology unit of the Free University Hospital, Amsterdam. Methods: In 146 patients-75 with ulcerative colitis and 71 with Crohn's disease-and 33 controls serum nitrate was measured by the Griess reaction after enzymatic conversion of nitrate to nitrite with nitrate reductase. Results: Median serum nitrate concentrations did not differ statistically significantly between ulcerative colitis (median, 34.2 pmol/l; range, 15.6-229.4 prnol/l), Crohn's disease (median 32.3 pmol/l; range 13.2-143.2 pmol/l), and healthy controls (median, 28.7 pmol/l; range, 13.0-108.4 pmol/l). However, when active ulcerative colitis patients (median, 44 pmol/l; range, 29.1-229.4 pmol/l were compared with inactive ulcerative colitis patients (median, 31.2 pmol/l; range, 15.6-59.7 pmol/l). a significant difference in nitrate concentration was found ( p < 0.oOOl). A significant positive correlation was found between Serum nitrate levels in ulcerative colitis and erythrocyte sedimentation rate (ESR) ( r = 0.30, p = 0.01), leucocyte count (r = 0.27, p = 0.02), and thrombocyte count (r = 0.24, p = 0.04). Comparing active Crohn's disease patients (median, 37.5 pmol/l; range, 13.2-143.2 pmol/l) with inactive Crohn's disease patients (median, 31.3 pmol/l; range, 14.5-92.3 pmol/l) also showed a significant difference in serum nitrate concentration ( p < 0.009). Serum nitrate levels correlated with the ESR ( r = 0 . 2 6 ,~ = 0.028) and serum albumin (r = -0.38, p = 0.004) as well. Conclusion: Nitric oxide production is increased in both active ulcerative colitis and Crohn's disease and may be implicated in the pathogenesis of inflammatory bowel disease.

The accuracy of computed tomography (CT) and [99mTc]HMPAO granulocyte scintigraphy (GS) for detection of bowel localization, inflammatory activity, and complications in acute inflammatory bowel disease (IBD) was prospectively studied in 32 patients. Of each bowel segment, findings on CT and GS were scored by one blinded observer. Findings on operation or endoscopy served as the gold standard. In Crohn's disease (CD, 17 patients), CT detected bowel pathology (sensitivity 71%, specificity 98%), abscesses (sensitivity and specificity 100%), and fistulas (sensitivity 80%, specificity 100%). In CD, GS had a sensitive of 79% and a specificity of 98% for detection of inflammatory activity. The detection of complications with GS was poor. Segmental inflammatory activity correlated with endoscopy-operative findings for CT (r = 0/86, P < 0.0001) and GS (r = 0.86, P < 0.0001). In ulcerative colitis (UC, 15 patients), GS predicted proximal extension of bowel involvement better than CT. In CD, CT is Superior to GS for localization of both active and fibrostenotic bowel disease, and in detection of the abscesses and fistulas. In UC, GS showed proximal extension more accurately than CT.