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PubMed1999

Interleukin-6 and soluble interleukin-6 receptor in the colonic mucosa of inflammatory bowel disease.

BACKGROUND: Interleukin-6 (IL-6) has multiple immunological effects on a wide variety of cells and tissues. The expression of IL-6 and IL-6 receptor (IL-6R) may be important to the pathogenesis of inflammatory bowel disease (IBD). METHODS: In the present study, we examined whether mucosal IL-6 and soluble IL-6R were associated with the pathophysiology of IBD using the colonic mucosal specimens obtained from patients with IBD. Enzyme-linked immunosorbent assay was used to measure the levels of IL-6 and sIL-6R in organ cultures of mucosal tissues and in cell cultures of fractionated mucosal cells as well as in the serum. Expression of IL-6 and IL-6R was analysed by reverse transcription-polymerase chain reaction analysis using freshly isolated lamina propria mononuclear cells (LPMC). RESULTS: The levels of IL-6 and sIL-6R in organ cultures were substantially elevated in patients with IBD, especially in those with histologically active inflammation. In contrast, considerably higher levels of sIL-6R were detected in patients with other types of colonic inflammation who were included as inflammatory controls, but elevation of IL-6 was less prominent in such patients. The positivity for expression of IL-6 and IL-6R mRNA in LPMC was in parallel with the results obtained in organ cultures. In cell cultures, mucosal macrophages were the main cell type producing both IL-6 and sIL-6R on a per cell basis and other cell fractions including colonic epithelial cells and lymphocytes produced substantially lower amounts of these molecules. The levels of IL-6 and sIL-6R in organ cultures, but not those in the serum, showed a significantly positive correlation with the degree of clinical disease activity in patients with IBD. CONCLUSIONS: Enhanced IL-6/sIL-6R-mediated immune and inflammatory responses may be implicated, at least partly, in the continuation of intestinal inflammation in patients with IBD.

Adolescent↗
PubMed2001

Observer variation of diagnoses based on simple biopsy criteria differentiating among Crohn's disease, ulcerative colitis, and other forms of colitis.

BACKGROUND AND AIM: Simple mucosal biopsy criteria proposed by authors reliably differentiate idiopathic inflammatory bowel disease (IBD) from other forms of colitis (non-IBD) and Crohn's disease involving the colon (CD) from ulcerative colitis (UC). The aim of this study is to investigate the reproducibility of these criteria. METHODS: Three established pathologists and two medical students blindly examined 20 sets of multiple biopsy slides from patients with CD, 20 from those with UC, and 20 from those with non-IBD. The students had been given instructions on histological definitions using another 15 sets previously. Each observer evaluated 10 histological items required in the criteria and determined categorical diagnoses such as definite IBD and probable UC. Interobserver agreement for the individual histological items was measured by using kappa analysis and Pearson's correlation, while it was measured for categorical diagnoses with the use of Spearman's rank correlation. RESULTS: All of the individual histological items expressed excellent or fair-to-good agreement among the five observers, although two items associated with the criteria for CD and UC had poor agreements among the students. With regard to categorical diagnoses based on the criteria for IBD and non-IBD, and those for CD and UC, coefficients for Spearman's rank correlation exceeded 0.92 and 0.86 among the pathologists, and 0.76 and 0.74 among the students, respectively; all of the coefficients were statistically significant (P < 0.05). CONCLUSIONS: The simple criteria were sufficiently reproducible and would help most pathologists to make an automated and objective diagnosis.

Biopsy↗
PubMed1998

Spontaneous inflammatory bowel disease in multiple mutant mouse lines: association with colonization by Helicobacter hepaticus.

BACKGROUND: Both genetic and microbial factors are thought to play a role in the development of inflammatory bowel disease (IBD): however, no causative microbial agent has been clearly defined for humans or animals. Normal flora or previously unrecognized intestinal pathogens may contribute to the development of disease in susceptible hosts. A newly recognized murine Helicobacter, H. hepaticus, causes hepatitis in mice and in one strain of mice is linked to liver cancer. This study investigates the association between colonization of the lower intestinal tract of multiple genetically altered lines of mice with H. hepaticus, and the occurrence of IBD. MATERIALS AND METHODS: Rectal prolapse noted clinically in multiple genetically altered mouse lines was evaluated for the presence of H. hepaticus and histologic evidence of IBD. Fifty-five mice representing 11 different genetic alterations were evaluated. RESULTS: H. hepaticus was detected in 85% of mutant mice with rectal prolapse. Histologic evidence of proliferative typhlitis, colitis or proctitis was present in 65% of the animals examined, 89% of which were positive for H. hepaticus as detected by species specific PCR. CONCLUSION: The presence of H. hepaticus in association with IBD in multiple lines of genetically altered mice suggests further studies are needed to test experimentally the role H. hepaticus plays in the development of IBD in susceptible mice. Additionally, specific mutant mouse lines infected with H. hepaticus in this study may provide additional models for elucidation of microbial and genetic factors in the pathogenesis of IBD.

Animals↗
PubMed2001

Family history as a risk factor for colorectal cancer in inflammatory bowel disease.

BACKGROUND & AIMS: Familial colorectal cancer (CRC) is a risk factor for CRC in healthy individuals and, as indicated by case-control studies, possibly in ulcerative colitis. Little is known about the cancer risk in familial inflammatory bowel disease (IBD). We assessed the significance of familial CRC, or IBD, on the risk for CRC in patients with IBD. METHODS: Population-based cohort study of 19,876 individuals with ulcerative colitis or Crohn's disease born between 1941 and 1995. Registry-based follow-up and assessment of familial CRC, and IBD. Risk of CRC assessed as incidence proportion ("absolute risk," IP) and relative risk (RR). RESULTS: Familial CRC was associated with a more than 2-fold risk of CRC (adjusted RR = 2.5, 95% confidence interval 1.4-4.4) and an increase in the IP of CRC at 54 years of age from 3.8% to 6.9%. Patients with a first-degree relative diagnosed with CRC before 50 years of age had a higher RR (9.2, 95% confidence interval 3.7-23) and the highest IP (29%). No association with familial IBD was observed. CONCLUSIONS: Information on family history of CRC may be a simple way to identify individuals with IBD at elevated risk of developing CRC.

Adolescent↗
PubMed2002

Uveitis and erythema nodosum in inflammatory bowel disease: clinical features and the role of HLA genes.

BACKGROUND & AIMS: There are few systematic studies on the natural history or immunogenetic associations of erythema nodosum (EN) or ocular inflammation in inflammatory bowel disease (IBD), but they are reportedly more common in patients with other extraintestinal manifestations (EIMs), particularly arthritis. Immunogenetic associations have previously been described in IBD arthritis and in EN associated with sarcoidosis. This study examined the clinical features and HLA-B, DR, and tumor necrosis factor alpha (TNF-alpha) associations of ocular inflammation and EN and their clinical and immunogenetic relationship to arthritis in IBD. METHODS: Details of EN and ocular inflammation were gathered by case-note review and questionnaire in 976 ulcerative colitis patients and 483 Crohn's patients. Sequence-specific PCR typing for polymorphisms in HLA-B, DR, and TNF-alpha was performed in 39 EN and 40 ocular patients. Results were compared with 490 IBD controls without EIMs, 38 patients with type 1 and 31 with type 2 peripheral arthritis, and 16 AS patients. RESULTS: EN and ocular inflammation were more common in women, were associated with IBD relapse, and recurred in approximately 30% of patients. They occurred more commonly with arthritis and AS than expected by chance. Ocular inflammation was strongly associated with HLA-B*27, B*58, and HLA-DRB1*0103. There is a weak association between EN and HLA-B*15 but a strong association with the -1031 TNF-alpha. CONCLUSIONS: EN, uveitis, and arthritis associated with IBD occur together commonly. They are associated with genes in the HLA region, and linkage disequilibrium between these genes may account for the clinical picture of overlapping but independent clinical manifestations.

Erythema Nodosum↗
PubMed2003

Mortality in inflammatory bowel disease: a population-based cohort study.

BACKGROUND & AIMS: There is no consensus regarding any increase in mortality with inflammatory bowel disease (IBD). In general, previous studies were not contemporary and were unable to correct for likely confounders. We have performed a large cohort study to examine contemporary IBD related mortality in the United Kingdom. METHODS: We selected subjects within the General Practice Research Database with a coded diagnosis of inflammatory bowel disease and up to 5 matched controls for each. We derived the date of recorded deaths and information on smoking and a variety of medical conditions. We calculated both the absolute risk of death and the relative risk as a hazard ratio corrected for available confounders by Cox regression. RESULTS: We included 16,550 IBD cases with 1047 deaths and 82,917 controls with 3758 deaths. The mortality rate was 17.1 per 1000 person-years overall for IBD cases and 12.3 for controls; this difference was greatest in the elderly. Conversion of these figures to hazard ratios by Cox regression gave hazard ratios of 1.54 (1.44-1.65) for all IBD, 1.44 (1.31-1.58) for ulcerative colitis (UC), and 1.73 (1.54-1.96) for Crohn's disease. The greatest hazard ratio for UC was among the 40-59-year age group (1.79 [1.42-2.27]) and for Crohn's disease among 20-39-year-olds (3.82 [2.17-6.75]). CONCLUSIONS: IBD is associated with an overall small increase in mortality rate greatest in relative terms in younger subjects but in absolute terms in the elderly.

Adolescent↗
PubMed2005

Increased risk for demyelinating diseases in patients with inflammatory bowel disease.

BACKGROUND & AIMS: Reports of multiple sclerosis (MS), demyelination, and optic neuritis (ON) associated with anti-tumor necrosis factor alpha therapy resulted in warnings on prescribing instructions for infliximab, etanercept, and adalimumab. However, the underlying relationship between IBD and these neurologic conditions has not been established. METHODS: We performed a retrospective cohort study and a retrospective cross-sectional study using 1988 to 1997 data from the General Practice Research Database. A total of 7988 Crohn's disease and 12,185 ulcerative colitis patients were matched for age, sex, and primary care practice to 80,666 randomly selected controls. In the cohort study, incident cases of MS, demyelination, and/or ON (MS/D/ON) had to occur at least 1 year after registration with the physician and after the diagnosis of IBD. In the cross-sectional study, the diagnosis of MS/D/ON could either precede or follow the IBD diagnosis. RESULTS: In the cohort study, the incidence of MS/D/ON was higher in patients with Crohn's disease and ulcerative colitis compared with their matched controls, reaching statistical significance for ulcerative colitis (ulcerative colitis incidence rate ratio [IRR], 2.63; 95% confidence interval, 1.29-5.15; Crohn's disease IRR, 2.12; 95% confidence interval, .94-4.50). In the cross-sectional study, MS/D/ON was more prevalent in patients with Crohn's disease and ulcerative colitis compared with their matched controls (Crohn's disease odds ratio, 1.54; 95% confidence interval, 1.03-2.32; ulcerative colitis odds ratio, 1.75; 95% confidence interval, 1.28-2.39). CONCLUSIONS: Demyelinating diseases occur more commonly among patients with IBD than among non-IBD patients. Future studies should clarify whether treatment with tumor necrosis factor alpha blockers results in further increased incidence of MS/D/ON among IBD patients.

Adult↗
PubMedDate not supplied

[Bone metabolism in 53 children and adolescents with chronic inflammatory bowel disease].

BACKGROUND: Osteopathy is a common clinical feature of chronic inflammatory bowel disease (IBD) in children and young adults at the time of primary diagnosis. The aim of the following study was to address the question of prevalance of a decreased bone density or increased bone metabolism in children with IBD. PATIENTS: We examined 63 patients (mean age 13 years; 5 - 18 years): 36 Crohn's disease (MC) patients, 16 colitis ulcerosa (CU) patient and one patient with colitis indeterminata (CID). 10 children who had been referred to the gastroenterological outpatient department due to suspected IBD symptoms were later found not to suffer from IBD. These 10 patients therefore were included in the study as controls. RESULTS: 8 of 10 CU patients and 18 of 28 MC patients showed a pathological bone density and abnormalities in bone metabolism. Repetitive bone density measurement was performed in 18 patients. In MC patients a - 0.39 SDS decrease of bone mineral density was found, without a simultaneous deterioration of clinical stage and inspite of a decreased cumulative prednisolon dosage. However in CU patients a + 0.06 SDS increase of bone mineral density was detected. These patients had a lower cumulative prednisolon dosage and a stable clinical course. CONCLUSIONS: In conclusion, pediatric IBD patients often show abnormalities in bone metabolism and decreased bone density. There is a need for multicentre, prospective randomised control trials to further identify therapeutic tools on the basis of the multifactorial etiology of bone disease in pediatric IBD patients.

Absorptiometry, Photon↗
PubMed2001

Evidence for a NOD2-independent susceptibility locus for inflammatory bowel disease on chromosome 16p.

Heritable predisposition to inflammatory bowel disease (IBD) has been demonstrated by epidemiological and genetic analysis. Linkage of IBD to broad regions of chromosome 16 has been established by analysis of multiple populations. NOD2, located on proximal 16q, was recently identified as an IBD gene. As the linkage regions on chromosome 16 are large, we have investigated the possibility that NOD2 is not the only IBD gene located on this chromosome. A high-density experiment using 39 microsatellite markers was performed to identify additional regions of association, and to indicate areas of interest for further investigation. A triple-peaked configuration of the linkage curve with peak logarithm of odds (lod) scores of 2.7, 3.2, and 3.1 was observed on proximal 16p, proximal 16q, and central 16q, respectively. The cohort was stratified by coding individuals carrying the NOD2 single nucleotide polymorphism (SNP)8 and SNP13 "unknown." Significance at the central peak, corresponding to the genomic location of NOD2, then decreased from 3.2 to 1.2. The maximal lod scores on the proximal p-arm (lod = 2.1) and central q-arm (lod = 2.6) changed only moderately. An exploratory association analysis (TRANSMIT) yielded a strong lead at D16S3068 (P = 0.00028). The region around this marker was further investigated by using anonymous SNPs. An associated haplotype containing three SNPs was identified (peak significance P = 0.00027, IBD phenotype). On stratification based on NOD2 genotype, this significance increased to P = 0.0001. These results confirm the importance of NOD2 and provide evidence for a second IBD gene located on chromosome 16p.

Carrier Proteins↗
PubMed2000

Detection of colorectal tumor and inflammatory bowel disease during follow-up of patients with initial diagnosis of irritable bowel syndrome.

BACKGROUND: We wanted to estimate the incidence of irritable bowel syndrome (IBS) and functional dyspepsia (FD) in the general population, and the detection of colorectal tumor (CRT) and inflammatory bowel disease (IBD) after the diagnosis of IBS and FD. METHODS: Patients aged 20-79 years newly diagnosed with IBS (N = 2956) or FD (N = 9900), together with a comparison cohort randomly sampled from the general source population, were followed-up during a mean time of 3 years. RESULTS: We found an overall incidence of 10.3 per 1000 person-years for FD and 2.6 per 1000 person-years for IBS. There was a greater prevalence of depression, stress, fatigue, and pain disorders among IBS and FD patients than in the general population. During the 1st year after a diagnosis of IBS the cumulative risk of detecting CRT was close to 1% in IBS patients. After the 1st year the risk of CRT in IBS patients was close to that in the general population. We found a significantly increased risk of detecting IBD among patients initially diagnosed as having IBS (relative risk (RR), 16.3; 95% confidence interval (CI), 6.6-40.7), which was constant during all the follow-up period. No association was found between dyspepsia and CRT, or IBD. CONCLUSION: IBS and FD shared some comorbidity features, yet demographics and incidence rates were different. Unlike the detection of colorectal tumor, the excess risk of IBD after an initial diagnosis of IBS was cumulatively increased during all the follow-up period. The continuously increased risk of IBD detection in IBS patients favors a true association between IBS and IBD.

Adult↗
PubMed2001

Reduced plasma antioxidant concentrations and increased oxidative DNA damage in inflammatory bowel disease.

BACKGROUND: Oxidative stress is believed to play a key role in the pathogenesis of inflammatory bowel disease (IBD)-related intestinal damage. Circulating antioxidants may have a role to play in preventing free radical-mediated tissue injury. METHODS: Plasma vitamin A, E and carotenoid concentrations, leukocytic genomic damage and 8-hydroxy-deoxy-guanosine (8-OHdG) concentration were determined in 46 ulcerative colitis (UC) patients, 37 Crohn disease (CD) patients and 386 controls. A 20 ml blood sample was taken from each subject for antioxidant and 8-OHdG measurements. A food frequency questionnaire was administered to a sample of subjects from each group to evaluate daily intake of dietary compounds. RESULTS: Antioxidant concentration was significantly reduced in IBD patients, particularly in those with active disease, with respect to controls (P < 0.0001). 8-OHdG concentrations were significantly increased in IBD patients compared to controls, independent of disease activity (P < 0.05). No correlation was found between antioxidant and 8-OHdG concentrations. Carotenoid concentrations were significantly reduced in malnourished IBD patients (0.89 +/- 0.14 micromol/l) compared to patients with normal or high body mass index (1.83 +/- 0.12 micromol/l; P < 0.05), independent of disease activity or extension. Protein, fruit and vegetable intakes of IBD patients were significantly lower than those of controls. CONCLUSIONS: Depletion of antioxidants is likely to be important in the pathophysiology of IBD: UC and CD patients show increased free radical peripheral leukocyte DNA damage and decreased plasma antioxidant defenses. These results indicate the necessity of further studies to establish whether optimal vitamin status may improve the clinical course of UC and CD.

Adult↗
PubMed2002

Mucosal and invading bacteria in patients with inflammatory bowel disease compared with controls.

BACKGROUND: Endogenous intestinal bacteria and/or specific bacterial pathogens are suspected of being involved in the pathogenesis of inflammatory bowel diseases (IBD). The aim of this study was to investigate IBD tissues for different bacterial population groups harbouring the mucosal surface and/or invading the mucosa. METHODS: Tissue sections from surgical resections from the terminal ileum and/or the colon from 24 IBD patients (12 active ulcerative colitis (UC), 12 active Crohn disease (CD)) and 14 non-IBD controls were studied by fluorescent in situ hybridization on a quantifiable basis. RESULTS: More bacteria were detected on the mucosal surface of IBD patients than on those of non-IBD controls (P < 0.05). Bacterial invasion of the mucosa was evident in 83.3% of colonic specimens from the UC patients, in 55.6% of the ileal and in 25% of the colonic specimens from the CD patients, but no bacteria were detected in the tissues of the controls. Colonic UC specimens were colonized by a variety of organisms, such as bacteria belonging to the gamma subdivision of Proteobacteria, the Enterobacteriaceae, the Bacteroides/Prevotella cluster, the Clostridium histolyticum/Clostridium lituseburense group, the Clostridium coccoides/Eubacterium rectale group, high G + C Gram-positive bacteria, or sulphate-reducing bacteria, while CD samples harboured mainly bacteria belonging to the former three groups. CONCLUSION: Pathogenic events in CD and UC may be associated with different alterations in the mucosal flora of the ileum and colon.

Adolescent↗
PubMed2003

Upregulation of interleukin-12 and -17 in active inflammatory bowel disease.

BACKGROUND: Cytokines are essential mediators of the intestinal inflammation during active episodes of inflammatory bowel disease (IBD). Interleukin (IL)-12 and IL-17 are potent immunoregulatory cytokines whose roles in the pathogenesis of IBD are unknown. The aim of this study was to evaluate the colonic expression of IL-12 and IL-17 genes in IBD. METHODS: Fifty-one patients (22 with ulcerative colitis (UC), 17 with Crohn disease (CD), and 12 controls) who underwent colonoscopy were included. IBD disease activity was determined using a clinical grading scale. The degree of inflammation, as well as the content of CD4+ T cells (synthesizing IL-17) and CD68+ macrophages (synthesizing IL-12) in colonic biopsies, was determined. The amounts of IL-12 and IL-17 mRNA were assessed by RT-PCR, using GAPDH as an internal standard. RESULTS: In colonic specimens, IL-17 mRNA expression was increased in moderately and severely active UC (P = 0.03) and in all degrees of activity in CD (P < 0.04). Levels of IL-12 mRNA were upregulated in both active UC and active CD compared to controls (P < 0.02). In cases of remission, IL-12 mRNA expression was similar to that found in control samples. Compared to controls, histological examination showed significant differences in signs of chronic and acute inflammation in UC (P < 0.01) and CD (P < 0.02), revealing a high correlation between clinical disease activity and histological scoring (r2 = 0.92, P < 0.005). Whereas CD4+ T cells were observed in lymphocyte aggregates located profound in the lamina propria, CD68+ macrophages were primarily found just underneath the surface epithelium. The density of CD4+ and CD68+ cells correlated significantly with the amounts of IL-17 and IL-12 mRNA, respectively (P < 0.05). CONCLUSION: The expression of both IL-12 and IL-17 mRNA is induced in active UC and CD and may thus be involved in sustaining the intestinal inflammation in IBD. Inhibition of IL-12 or IL-17 might be future therapeutic targets in IBD.

Adult↗
PubMed2006

Incidence of inflammatory bowel disease in Primorsko-goranska County, Croatia, 2000-2004: A prospective population-based study.

OBJECTIVE: It has been suggested that the incidence of inflammatory bowel disease (IBD), which includes ulcerative colitis (UC) and Crohn's disease (CD), is higher in northern than in southern Europe. Recent epidemiological studies showed the loss of the previously described geographical north-south gradient. The aim of this study was to investigate the incidence of UC and CD in Primorsko-goranska County, Croatia. MATERIAL AND METHODS: In the period 1 January 2000 to 31 December 2004 (5 years) all new patients diagnosed with IBD were prospectively identified according to a standard protocol for case ascertainment and definition. A total of 178 residents (81 F, 97 M) were newly diagnosed as having IBD during the study period. Of these, 70 had UC and 100 CD. Eight patients had indeterminate IBD. The data on patients were collected using a data form completed by gastroenterologists. RESULTS: Annual age-standardized incidence rates were 4.3/10(5) (95% CI 2.6-6.0) for UC and 7.0/10(5) (95% CI 3.4-10.6) for CD. The highest incidence rate was observed in the age group 35-44 years for UC and the 25-34 years age group for CD. The incidence of IBD was higher in the urban than in the rural population, with the exception of on the islands. CONCLUSIONS: The incidence of IBD was higher than previously observed in Croatia. Our results suggest that CD incidence rates in the northern coastal part of Croatia are currently comparable with those reported in northern Europe.

Adolescent↗
PubMed2006

Fecal calprotectin remains high during glucocorticoid therapy in children with inflammatory bowel disease.

OBJECTIVE: Fecal calprotectin is a promising marker for the assessment of gastrointestinal inflammation. Fecal calprotectin levels were followed-up in children with inflammatory bowel disease (IBD) who were introduced to glucocorticoid therapy. The aim of this study was to assess whether the changes in fecal calprotectin levels reflect therapeutic responses. MATERIAL AND METHODS: Fecal calprotectin was measured by enzyme immunoassay in 57 children (mean age 9.8 years, range 0.9-18 years) who underwent colonoscopies (IBD n=31, non-IBD disease n=13, normal n=13) and followed-up in 15 children (mean age 13 years, range 3.6-18 years) who were introduced to glucocorticoid therapy because of active IBD at 0, 2, and 4 weeks and at 4-week intervals until one month after discontinuation of the therapy. RESULTS: Fecal calprotectin was <100 microg/g in 70% of the children with normal findings on colonoscopy or a non-IBD disease. Fecal calprotectin was >100 microg/g in all but one child with active IBD and in 13/15 of those children who were introduced to glucocorticoids by the clinicians. Fecal calprotectin values decreased within 4 weeks in line with clinical improvement in 7 children and normalized in 4/15 children during the follow-up. Fecal calprotectin increased in 5/8 of the non-steroid-dependent children after discontinuation of glucocorticoids. CONCLUSIONS: Fecal calprotectin is a sensitive marker for chronic colitis. In active disease treated with glucocorticoids, fecal calprotectin levels declined in line with the clinical improvement but seldom fell within the normal range, which suggests ongoing inflammation in a clinically silent disease. The measurement of fecal calprotectin may provide new tools for the assessment of the level of gut inflammation in children with chronic colitis in the follow-up of clinical responses.

Adolescent↗
PubMed1998

Azathioprine: state of the art in inflammatory bowel disease.

INTRODUCTION: The use of 6-mercaptopurine (6MP) and its prodrug azathioprine (AZA) for inflammatory bowel disease (IBD) has increased in recent years. The pharmacology, patient response in controlled trials, new formulations and routes of administration and safety for these agents are reviewed. PHARMACOLOGY: AZA is rapidly converted to 6MP, which is then further metabolized to the active metabolites, the 6-thioguanine nucleotides (6TGN). The half-life of 6TGN in erythrocytes is prolonged and weeks to months may be required to reach steady state. This prolonged time to 6TGN steady state may help explain the clinical observation that prolonged treatment (3-4 months) with 6MP/AZA for IBD is required before a therapeutic response occurs. CLINICAL RESPONSE: Controlled trials of 6MP (1.5 mg/kg/d) or AZA (1.0-3.0 mg/kg/d) support the following treatment indications for 6MP/AZA: inflammatory Crohn's disease; fistulizing Crohn's disease; steroid-sparing; and remission maintenance. Controlled trials of AZA (1.5-2.5 mg/kg/d) in UC have suggested efficacy for the indications of steroid sparing and remission maintenance, as well as a possible effect in chronically active disease. A therapeutic response appears to require > or = 17 weeks for most patients, and it has been suggested that a greater cumulative dose of AZA may result in increased likelihood of response to AZA. A recent pilot study suggested that administration of an i.v. loading dose of AZA (20-44 mg/kg over 36 h) may decrease the time to response in Crohn's disease patients treated with AZA, perhaps by administering a portion of the necessary cumulative dose more rapidly. Two recent pharmacokinetic studies demonstrated that use of a delayed release oral AZA formulation which delivers AZA directly to the ileocolon markedly reduces systemic absorption of AZA. This 'topical' or 'local' approach to AZA treatment of IBD holds the promise of equal or improved efficacy with a significant reduction in toxicity, and dose-ranging clinical trials with delayed release oral AZA are planned in the near future. SAFETY: Side effects of AZA/6MP include pancreatitis, fever, nausea, leukopenia, infection, and hepatitis. It appears that the risk of malignancy during or following monotherapy with AZA/6MP for IBD is not increased relative to the general population. CONCLUSIONS: AZA/6MP therapy is efficacious and reasonably safe for selected patients with IBD. Indications for treatment with AZA/6MP include refractory Crohn's disease, fistulizing Crohn's disease, steroid-dependent Crohn's disease, Crohn's disease remission maintenance, and possibly refractory UC, steroid dependent UC, and UC remission maintenance. The use of these immune modifier drugs in patients with IBD represents a significant therapeutic advance.

Azathioprine↗
PubMed1999

Site-specific changes in transforming growth factor-alpha and -beta1 expression in colonic mucosa of adolescents with inflammatory bowel disease.

BACKGROUND: Transforming growth factors (TGF-alpha and -beta1) play important roles in intestinal growth and repair. To further understand their roles in the pathophysiology of inflammatory bowel disease (IBD), this study examined changes in their expression in colonic mucosa of adolescents with IBD. METHODS: TGF-alpha and -beta1 expression was examined by immunohistochemistry and in situ hybridization. RESULTS: TGF-gamma immunostaining and mRNA labelling appeared unchanged in the epithelium of specimens with active IBD. Similarly, expression of epithelial TGF-beta1 remained unaltered in IBD. However, the numbers of TGF-beta1-positive cells, including T cells, neutrophils, and monocytes/macrophages, in the lamina propria increased during disease activity. CONCLUSIONS: Adolescent IBD is characterized by a normal expression of TGF-alpha and -beta1 peptide and mRNA in the colonic epithelium but by an increased density of TGF-beta1-positive immune cells in the lamina propria during disease activity, suggesting a role in inflammatory modulation in IBD.

Adolescent↗
PubMed2004

Inflammatory bowel disease: the role of inflammatory cytokine gene polymorphisms.

The mechanisms responsible for development of inflammatory bowel disease (IBD) have not been fully elucidated, although the main cause of disease pathology is attributed to up-regulated inflammatory processes. The aim of this study was to investigate frequencies of polymorphisms in genes encoding pro-inflammatory and anti-inflammatory markers in IBD patients and controls. We determined genotypes of patients with IBD (n= 172) and healthy controls (n= 389) for polymorphisms in genes encoding various cytokines (interleukin (IL)-1beta, IL-6, tumour necrosis factor (TNF), IL-10, IL-1 receptor antagonist). Association of these genotypes to disease incidence and pathophysiology was investigated. No strong association was found with occurrence of IBD. Variation was observed between the ulcerative colitis study group and the control population for the TNF-alpha-308 polymorphism (p= 0.0135). There was also variation in the frequency of IL-6-174 and TNF-alpha-308 genotypes in the ulcerative colitis group compared with the Crohn's disease group (p= 0.01). We concluded that polymorphisms in inflammatory genes are associated with variations in IBD phenotype and disease susceptibility. Whether the polymorphisms are directly involved in regulating cytokine production, and consequently pathophysiology of IBD, or serve merely as markers in linkage disequilibrium with susceptibility genes remains unclear.

Adult↗