Lower regional and temporal ultraviolet exposure is associated with increased rates and severity of inflammatory bowel disease hospitalisation.

BACKGROUND: In the northern hemisphere, the incidence of inflammatory bowel diseases (IBD) has a north-south gradient, suggesting a link between ultraviolet (UV) exposure or vitamin D status and the pathogenesis of IBD. AIM: To test the association of UV exposure with the rates and severity of IBD hospitalisation. METHODS: We conducted a retrospective nationwide analysis of 649 932 Crohn's disease (CD), 384 267 ulcerative colitis (UC), and 288 894 297 non-IBD hospitalisations in the US between 1998 and 2010. Mean UV exposure was assigned to each hospitalisation using surface measures from the National Oceanic and Atmospheric Administration. Relative rates across UV exposures were estimated for IBD hospitalisations, prolonged hospitalisations, bowel surgeries and deaths. RESULTS: Among IBD patients, lower UV exposures had increased hospitalisation rates for CD (217.8 vs. 182.5 per 100 000 overall hospitalisations with low and very high UV, respectively; P trend <0.001) and UC (123.2 vs. 113.8 per 100 000; P trend = 0.033). Low UV groups had greater relative rates of prolonged hospitalisations [CD: 1.13, 95% confidence interval (CI) 1.07-1.19; UC: 1.21, 95% CI 1.13-1.30], bowel surgeries (CD: 1.24, 95% CI 1.16-1.32; UC: 1.21, 95% CI 1.09-1.33), and CD deaths (CD: 1.76, 95% CI 1.14-2.71; UC: 1.24, 95% CI 0.92-1.67). Among non-IBD patients, low UV was associated with prolonged hospitalisations (1.09; 95% CI 1.07-1.11) and deaths (1.13; 95% CI 1.09-1.17), but not bowel surgeries (1.01; 95% CI 0.99-1.03). CONCLUSIONS: Lower ultraviolet exposure is associated with greater rates of hospitalisation, prolonged hospitalisation and the need for bowel surgery in IBD. This trend for bowel surgery was not seen with non-IBD encounters.

An SNP linkage scan identifies significant Crohn's disease loci on chromosomes 13q13.3 and, in Jewish families, on 1p35.2 and 3q29.

Inflammatory bowel disease (IBD) is a complex genetic disorder of two major phenotypes, Crohn's disease (CD) and ulcerative colitis (UC), with increased risk in Ashkenazi Jews. Twelve genome-wide linkage screens have identified multiple loci, but these screens have been of modest size and have used low-density microsatellite markers. We, therefore, performed a high-density single-nucleotide polymorphism (SNP) genome-wide linkage study of 993 IBD multiply affected pedigrees (25% Jewish ancestry) that contained 1709 IBD-affected relative pairs, including 919 CD-CD pairs and 312 UC-UC pairs. We identified a significant novel CD locus on chromosome 13p13.3 (peak logarithm of the odds (LOD) score=3.98) in all pedigrees, significant linkage evidence on chromosomes 1p35.1 (peak LOD score=3.5) and 3q29 (peak LOD score=3.19) in Jewish CD pedigrees, and suggestive loci for Jewish IBD on chromosome 10q22 (peak LOD score=2.57) and Jewish UC on chromosome 2q24 (peak LOD score=2.69). Nominal or greater linkage evidence was present for most previously designated IBD loci (IBD1-9), notably, IBD1 for CD families at chromosome 16q12.1 (peak LOD score=4.86) and IBD6 in non-Jewish UC families at chromosome 19p12 (peak LOD score=2.67). This study demonstrates the ability of high information content adequately powered SNP genome-wide linkage studies to identify loci not observed in multiple microsatellite-based studies in smaller cohorts.

Peripheral blood mononuclear cell DNA 6-thioguanine metabolite levels correlate with decreased interferon-gamma production in patients with Crohn's disease on AZA therapy.

6-Mercaptopurine (6-MP) and its prodrug azathioprine (AZA) are well known for their lymphocytotoxic and bone marrow suppressive effects in the management of patients with leukemia. Although their immunosuppressive properties are mediated by the active AZA antimetabolite 6-thioguanine (6-TG), its mechanism of action is largely unknown. In IBD, a significant inverse correlation has been shown between erythrocyte 6-TG metabolite levels and disease activity, further supporting the proposed immunosuppressive role for 6-TG. Since leukocytes possess quantitatively different purine metabolic pathways compared to erythrocytes, this study aims to measure lymphocyte DNA 6-TG metabolites and correlate levels with the INF-gamma and IL-10 cytokine profile in patients with Crohn's disease (CD). Forty-six adult patients with CD, either naive (17) or on long-term (>4-month) AZA therapy (29), had erythrocyte and lymphocyte DNA 6-TG levels measured by reverse-phase HPLC under UV detection (6-TG, 340 nm). Lymphocyte DNA 6-TG was expressed as picomoles per milligram of DNA. Lymphocyte DNA 6-TG metabolite levels were correlated with INF-gamma and IL-10 cytokine profiles using the OptEIA kit (Pharmigen). Lymphocyte DNA 6-TG metabolite levels correlate with erythrocyte 6-TG levels (P < 0.03) but not total patient leukocyte levels. Erythrocyte 6-TG metabolite levels correlated (P < 0.01) inversely with INF-gamma but not IL-10 cytokine levels. This study suggests a preferential dampening of the TH1 response on exposure to 6-TG and a possible immunosuppressive mechanism of action for AZA. Future studies are needed to determine if cytokine profiles can be used to predict recalcitrant CD to AZA therapy.

Acute and late radiotherapy toxicity in patients with inflammatory bowel disease.

PURPOSE: To evaluate the incidence of gastrointestinal complications in patients with inflammatory bowel disease (IBD) receiving radiotherapy (RT) and to identify possibly avoidable factors associated with these complications. METHODS AND MATERIALS: Twenty-four patients were identified and their records reviewed; all had a history of IBD before receiving RT to fields encompassing some portion of the gastrointestinal tract (Crohn's disease) or to the abdomen or pelvis (ulcerative colitis or IBD not otherwise specified). RESULTS: Five of 24 patients (21%) experienced Grade > or =3 acute gastrointestinal toxicity; all 5 received concurrent chemotherapy. Two of 24 patients (8%) experienced Grade > or =3 late gastrointestinal toxicity. There were no significant correlations between complications and IBD type, prior IBD-related surgery, use of medications for IBD, or status of IBD. CONCLUSION: Patients with IBD may have an increased risk for severe acute RT-related gastrointestinal complications that is more modest than generally perceived, because all patients who had Grade > or =3 acute complications in this study had received concurrent chemotherapy (p = 0.04). Further study is needed to assess this risk, as well as the impact of RT on these patients' future gastrointestinal morbidity.

A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease.

Crohn's disease is a chronic inflammatory disorder of the gastrointestinal tract, which is thought to result from the effect of environmental factors in a genetically predisposed host. A gene location in the pericentromeric region of chromosome 16, IBD1, that contributes to susceptibility to Crohn's disease has been established through multiple linkage studies, but the specific gene(s) has not been identified. NOD2, a gene that encodes a protein with homology to plant disease resistance gene products is located in the peak region of linkage on chromosome 16 (ref. 7). Here we show, by using the transmission disequilibium test and case-control analysis, that a frameshift mutation caused by a cytosine insertion, 3020insC, which is expected to encode a truncated NOD2 protein, is associated with Crohn's disease. Wild-type NOD2 activates nuclear factor NF-kappaB, making it responsive to bacterial lipopolysaccharides; however, this induction was deficient in mutant NOD2. These results implicate NOD2 in susceptibility to Crohn's disease, and suggest a link between an innate immune response to bacterial components and development of disease.

Methodologic pitfalls in the determination of genetic anticipation: the case of Crohn disease.

BACKGROUND: The term genetic anticipation is used when genetically transmitted disease manifests at increasingly younger ages with each succeeding generation: that is, if the offspring of patients develop the disease, they will tend to do so at an earlier age than their parents. In some monogenetic disorders, genetic anticipation has a biological basis in expanded genetic triplet repeats; however, some have claimed that it occurs in polygenic disorders, such as Crohn disease, in which its mechanism cannot be explained. OBJECTIVE: To show how apparent changes in age at diagnosis of Crohn disease between generations, which could suggest genetic anticipation, can be an artifact of inadequate analysis based on age at diagnosis in cohorts that have not been followed for a sufficiently long time. DESIGN: Comparison of ages at diagnosis of Crohn disease among different birth cohorts, before and after adjustment for observation time. SETTING: Meyerhoff Center for Inflammatory Bowel Disease, Johns Hopkins Hospital, Baltimore, Maryland. PATIENTS: 928 consecutive outpatients with Crohn disease. MEASUREMENTS: Trends in age at diagnosis of Crohn disease among birth cohorts were determined by calculating Pearson correlation coefficients and performing Kaplan-Meyer analysis before and after adjustment for observation time. Adjustment for observation time was performed by ensuring that the time during which all included patients were at risk for Crohn disease was equal and that all patients had developed disease by the end of the risk period. RESULTS: Mean age at diagnosis decreased by approximately 5 years with each subsequent 10-year birth cohort on the basis of crude cross-sectional data that could suggest genetic anticipation between generations. However, after adjustment for observation time, the age at diagnosis decreased minimally, if at all, with each successive generation. CONCLUSIONS: Apparent genetic anticipation can be explained by observational biases without invoking any additional genetic influences. Claims for genetic anticipation must be based on methods that properly account for the duration of observation in all persons being studied.

Utilisation of erythrocyte 6-thioguanine metabolite levels to optimise azathioprine therapy in patients with inflammatory bowel disease.

BACKGROUND AND AIM: The immunosuppressive properties of 6-mercaptopurine and its parent compound azathioprine are mediated by their intracellular metabolism into active 6-thioguanine (6-TG) metabolites. Measurement of erythrocyte 6-TG metabolite levels has been proposed as a useful clinical tool for assessing treatment efficacy in patients with inflammatory bowel disease (IBD). AIM: The purpose of the study was to establish a therapeutic index of treatment efficacy based on measurement of erythrocyte 6-TG metabolite levels, and apply it clinically to guide therapy. METHODS: Heparinised blood was obtained from 82 adult patients with IBD on long term (more than three months) antimetabolite therapy (63 Crohn's disease; 19 ulcerative colitis). Erythrocyte 6-TG metabolite levels were measured using reverse phase high performance chromatography, and correlated with treatment efficacy. In 22 patients with refractory Crohn's disease despite long term azathioprine therapy, their dosage was increased by 25 mg/day at eight week intervals as needed. Serial erythrocyte 6-TG metabolite levels were measured at each clinic visit and correlated with treatment efficacy. RESULTS: Clinical remission, as defined by a low disease index score in patients weaned off or on a low alternate day dose (<20 mg on alternate days) of corticosteroid, was achieved in 68% of patients on long term antimetabolite therapy. Treatment efficacy correlated with erythrocyte 6-TG levels greater than 250 pmol/8x10(8) red blood cells in patients with colonic and fistulising Crohn's disease (p<0.01) but not in patients with ileocolonic disease. Eighteen of 22 patients with incompletely responsive Crohn's disease achieved disease remission by optimising their dose of azathioprine therapy. Median (range) erythrocyte 6-TG metabolite levels increased from 194 (67-688) to 303 (67-737) pmol/8x10(8) red blood cells (p<0.05). Clinical response associated well with a reduction in corticosteroid requirements. Mean (SEM) white blood cell count decreased from 8.6 (0.9) to 6.9 (0.6) x10(3)/microl with adjustment in azathioprine dosage. No patient incurred azathioprine induced leucopenia. CONCLUSION: Measurement of erythrocyte 6-TG metabolite levels is helpful in determining the adequacy of azathioprine dosage and can be used to optimise the dose of antimetabolite therapy to achieve an improved clinical response without inducing leucopenia. Patients who are clinically refractory to azathioprine therapy despite achieving high erythrocyte 6-TG levels (>250) should be considered for adjunct or alternative forms of immunosuppressive therapy or surgery.

Linkage heterogeneity for the IBD1 locus in Crohn's disease pedigrees by disease onset and severity.

BACKGROUND & AIMS: There is evidence for the IBD1 Crohn's disease (CD) susceptibility locus on chromosome 16 in several but not all populations studied. Genetic and phenotypic heterogeneity may underlie ability to replicate IBD1. We determined if age and severity stratification could identify a clinical subgroup at risk for IBD1. METHODS: Linkage analysis at microsatellites spanning chromosome 16 was performed in 2 groups of CD pedigrees: group 1, 57 pedigrees with at least one affected relative classified as having "severe" disease, by history of surgical resection or immunomodulator therapy, and with disease diagnosed before age 22; and group 2, 33 pedigrees with no history of early-onset, severe CD. RESULTS: Group 1 pedigrees demonstrated genomewide significant linkage evidence for the IBD1 locus (nonparametric multipoint logarithm of the odds [Mlod], 3.84; P = 1.3 x 10(-5)) with linkage evidence greater than all 90 pedigrees (Mlod, 2.12; P = 9.0 x 10(-4)). Group 2 pedigrees had near zero nonparametric 2-point and Mlod scores for the IBD1 region. Heterogeneity between groups 1 and 2 was significant (P = 0.002). CONCLUSIONS: Presence of early-onset, more severe CD identifies pedigrees at high risk for IBD1. These pedigrees will have more power to refine the IBD1 locus and identify the causative gene.

Musculoskeletal complications of Crohn's disease: the role of computed tomography in diagnosis and patient management.

The delayed diagnosis of musculoskeletal complications of Crohn's disease may produce major morbidity in patients. This study compared abdominal and pelvic computed tomography (CT) with conventional radiography in the diagnosis of musculoskeletal complications in 23 of 552 patients with Crohn's disease examined by CT over a 7-year period. Surgical confirmation was available in 15 of 21 patients. The clinical features of psoas/gluteal abscesses, abdominal wall fistulae, and sacral osteomyelitis are described. Because the clinical manifestations of these musculoskeletal complications are often nonspecific, CT is often useful in diagnosing and directing therapeutic interventions.

Enhanced bioavailability of azathioprine compared to 6-mercaptopurine therapy in inflammatory bowel disease: correlation with treatment efficacy.

BACKGROUND: Azathioprine and 6-mercaptopurine have proven efficacy in the treatment of Crohn's disease. Immunosuppression is mediated by their intracellular metabolism into active 6-thioguanine metabolites, and clinical responsiveness to therapy in patients with inflammatory bowel disease has been correlated with the measure of erythrocyte 6-thioguanine levels. AIMS AND METHODS: To perform a dosing equivalency analysis and comparison of clinical efficacy in 82 patients with inflammatory bowel disease on long-term (> 2 months) therapy with either branded azathioprine (Imuran) (n=26), generic azathioprine (n=38), or 6-mercaptopurine (n=18), based on the measurement of erythrocyte 6-thioguanine metabolite levels. RESULTS: Disease remission was achieved in 51% (42 out of 82) of patients treated with either azathioprine or 6-mercaptopurine therapy, and correlated well with high erythrocyte 6-thioguanine levels (> 250 pmoles/8 x 108 RBCs). Patients treated with either branded azathioprine or 6-mercaptopurine achieved significantly higher erythrocyte 6-thioguanine levels than patients treated with generic azathioprine, thereby suggesting that branded azathioprine has improved oral bioavailability compared to generic azathioprine. These data are consistent with the putative immunosuppressive role of 6-thioguanine metabolites in the treatment of inflammatory bowel disease, and provides a basis for developing a therapeutic index of clinical efficacy based on the measurement of erythrocyte 6-thioguanine metabolite levels. CONCLUSIONS: Our results suggest that differences in bioavailability may have clinical relevance when considering the need to optimize erythrocyte 6-thioguanine metabolite levels in patients deemed unresponsive to treatment on conventional drug dosages.

Atypical forms of inflammatory bowel disease: microscopic colitis and pouchitis.

Three atypical colitides (and enterides) are collagenous colitis, lymphocytic colitis, and ileal pouchitis. Collagenous and lymphocytic colitis are similar inflammatory bowel disorders of unknown cause with symptoms including chronic watery diarrhea, occurring in middle age. Pouchitis is the most significant long-term complication in patients with ileoanal pouch anastomosis. The clinical and histologic features and management of these entities are discussed.

Cancer risk in collagenous colitis.

Collagenous colitis is a recently described form of chronic inflammatory bowel disease. Other inflammatory bowel disorders are associated with increased risk of colorectal and extracolonic malignancies, but this has not been evaluated in collagenous colitis. Colorectal and extracolonic malignancies were identified in 117 patients with collagenous colitis from the Johns Hopkins Registry. The incidence rates of identified tumors, overall incidence rate of tumors, and overall mortality were then compared with general population through person year analysis with adjustment for population. No cases of colorectal cancer were found in collagenous colitis patients during a mean follow-up period of 7.0 years (range 2-12 years) after the diagnosis of colitis. Two patients developed colorectal cancer prior to the diagnosis of colitis, but no increase in life-time relative risk of colorectal cancer was found (relative risk 0.52; 95% confidence limits 0.05-1.5). An increased relative risk of lung cancer in women (relative risk 3.7; 95% confidence limits 1.0-9.6; p = 0.048) was noted. The relative risk of overall malignancy and overall mortality was not different than the general population. In collagenous colitis patients the life-time relative risk of colorectal cancer and the relative risk after the diagnosis of colitis with a mean observation period of 7 years was not increased. An increase in relative risk of lung cancer in women with collagenous colitis argues for further investigation of the role of smoking and other factors in this disorder.

American families with Crohn's disease have strong evidence for linkage to chromosome 16 but not chromosome 12.

BACKGROUND & AIMS: Two European genome-wide screens for inflammatory bowel disease have identified two significant regions of linkage on chromosomes 16 (IBD1) and 12 (IBD2) and two regions with suggestive levels of significance (chromosomes 3p and 7q). The aim of this study was to determine if there was evidence for linkage to these regions in non-Jewish and Ashkenazi Jewish families multiplex for Crohn's disease from the United States. METHODS: One hundred forty-eight affected relative pairs, 34% Ashkenazim, were genotyped with 10-14 highly polymorphic markers overlying each candidate region. Nonparametric multipoint and two-point linkage analyses were performed. RESULTS: Significant evidence for replication of linkage was found only for the chromosome 16 locus, IBD1, maximal at D16S769 (nonparametric linkage score [NPL], 2.49; P = 0.007). Analysis by ethnicity showed stronger evidence for Ashkenazim (D16S769; NPL = 2. 52; P = 0.007) than for non-Jewish white populations (D16S401; NPL = 1.40; P = 0.082). There was no significant evidence for replication on chromosome 12 (IBD2). Minimal evidence for extension of linkage evidence was observed for the chromosomes 3p and 7q regions. CONCLUSIONS: American families, particularly Ashkenazim, have significant evidence for the Crohn's disease susceptibility locus, IBD1, on chromosome 16, but not for IBD2 on chromosome 12.

Identification of novel susceptibility loci for inflammatory bowel disease on chromosomes 1p, 3q, and 4q: evidence for epistasis between 1p and IBD1.

The idiopathic inflammatory bowel diseases, Crohn's disease (CD) and ulcerative colitis (UC), are chronic, frequently disabling diseases of the intestines. Segregation analyses, twin concordance, and ethnic differences in familial risks have established that CD and UC are complex, non-Mendelian, related genetic disorders. We performed a genome-wide screen using 377 autosomal markers, on 297 CD, UC, or mixed relative pairs from 174 families, 37% Ashkenazim. We observed evidence for linkage at 3q for all families (multipoint logarithm of the odds score (MLod) = 2.29, P = 5.7 x 10(-4)), with greatest significance for non-Ashkenazim Caucasians (MLod = 3.39, P = 3.92 x 10(-5)), and at chromosome 1p (MLod = 2.65, P = 2.4 x 10(-4)) for all families. In a limited subset of mixed families (containing one member with CD and another with UC), evidence for linkage was observed on chromosome 4q (MLod = 2.76, P = 1.9 x 10(-4)), especially among Ashkenazim. There was confirmatory evidence for a CD locus, overlapping IBD1, in the pericentromeric region of chromosome 16 (MLod = 1.69, P = 2.6 x 10(-3)), particularly among Ashkenazim (MLod = 1.51, P = 7.8 x 10(-3)); however, positive MLod scores were observed over a very broad region of chromosome 16. Furthermore, evidence for epistasis between IBD1 and chromosome 1p was observed. Thirteen additional loci demonstrated nominal (MLod > 1.0, P < 0.016) evidence for linkage. This screen provides strong evidence that there are several major susceptibility loci contributing to the genetic risk for CD and UC.

A randomized, double-blind study of the effect of olestra on disease activity in patients with quiescent inflammatory bowel disease. Olestra in IBD Study Group.

PURPOSE: To determine the effects of olestra, a zero-calorie fat substitute that is neither digested nor absorbed, on the well-being and disease state of persons with chronic inflammatory bowel disease (IBD) in remission. PATIENTS AND METHODS: Eighty-nine patients with mild to moderate ulcerative colitis (n = 43) or Crohn's disease (n = 46) in remission, with a history of disease of 2 years or longer, were enrolled in this prospective study from nine private practices, three university-based medical centers, and one Veterans Administration medical center in the United States. Forty-four patients were randomly assigned to receive olestra and 45 to receive triglycerides in chips or cookies daily for 4 weeks. At Week 4, patients were classified as in remission, worsened, or relapsed according to an investigator's global assessment based on sigmoidoscopy (for ulcerative colitis) or the Crohn's disease activity index, laboratory findings, and clinical course. RESULTS: At Week 4, the olestra and triglyceride groups did not differ significantly with respect to the percentages of patients who relapsed (P = 0.494; difference = 2.4%; upper 95% CL = 8.8%) or with respect to the percentages of patients who experienced any worsening of their symptoms (P = 0.630; difference = 0.2%; upper 95% CL = 13.3%). Of evaluable patients, 90% (37 of 41) given olestra remained in remission with no worsening, compared with 90% (38 of 42) given triglycerides. Gastrointestinal symptoms were comparable between the treatment groups, and there were no treatment-related laboratory abnormalities. Six patients were excluded from analysis for reasons unrelated to treatment. CONCLUSION: Olestra did not affect the activity of quiescent mild to moderate IBD.