A familial pattern in inflammatory disease of the bowel (Crohn's disease and ulcerative colitis)

Conclusions Previous discussions of the familial incidence of inflammatory disease of the bowel have emphasized its occurrence in people of Jewish descent. This report adds 12 family groups with inflammatory disease in people of Caucasian, non-Jewish descent, with an incidence of at least 2.5 per cent.     

The expression of IL-12 p40 and its homologue, Epstein-Barr virus-induced gene 3, in inflammatory bowel disease

BACKGROUND: It has recently been suggested that Crohn's Disease (CD) is associated with an exaggerated T helper 1 cytokine response as manifest by increased production of interleukin-12 (IL-12) and interferon-gamma (IFN-gamma). Epstein-Barr virus-induced gene 3 (EBI3) encodes a 34-kDa glycoprotein that is 27% identical to the p40 unit of IL-12 and has recently been reported to be up-regulated in ulcerative colitis (UC). AIM: To determine whether mucosal expression of IL-12 p40 or EBI3 correlates with inflammatory bowel disease (IBD). PATIENTS/METHODS: mRNA expression in colonic mucosa from patients with UC, Crohn's disease (CD) and non-IBD controls was measured by reverse-transcribed real-time polymerase chain reaction (PCR). RESULTS: EBI3 was significantly increased in both involved and uninvolved colonic mucosa in patients with UC. Although IL-12 p40 was increased in some patients with CD relative to non-IBD controls, the increase was not statistically significant. However, 5-aminosalicylic acid (5-ASA) use was significantly correlated with reduced IL-12 p40 levels in the patients with CD, but not in UC cases. A similar reduction was not seen in 5-ASA-treated UC patients. CONCLUSION: IL-12 p40 expression in CD is heterogeneous. In contrast, expression of the IL-12 p40 homologue, EBI3, is up-regulated in nearly all UC cases and in a subset of CD.     

Altered bone metabolism in inflammatory bowel disease: there is a difference between Crohn's disease and ulcerative colitis

OBJECTIVES: The aims of this study were to assess bone metabolism in inflammatory bowel disease (IBD) patients and to evaluate potential differences between Crohn's disease (CD) and ulcerative colitis (UC) with respect to the mechanisms underlying bone loss in this group of diseases. DESIGN AND SETTING: This was a cross-sectional study which started in 1992. Patients were randomly selected for invitation to participate and were examined during the years 1992-95 in one research clinic in Milan. SUBJECTS AND METHODS: Fifty-one patients suffering from CD (30 women and 21 men, mean age 38.7 +/- 13.2 years) and 40 with UC (15 women and 25 men, mean age 34.4. +/- 12.5 years) entered the study. Thirty healthy subjects were selected as sex- and age-matched controls (C). Spine and femoral neck bone mineral density (expressed as T score), calciotropic hormones (parathyroid hormone, PTH; 25-hydroxycholecalciferol, 25(OH)D3; 1,25-hydroxycholecalciferol, 1, 25(OH)D3) and biochemical markers of bone turnover (ostecalcin, OC; total alkaline phosphatase, ALP; type I collagen C-terminal telopeptide, ICTP) were evaluated. RESULTS: Spine and femur T scores were similar in the two groups (spine: CD = -1.49 +/- 1.46; UC = -1. 67 +/- 1.13; femur: CD = -1.80 +/- 1.36; UC = -1.60 +/- 1.03). Based upon the WHO guidelines, only 8% of CD patients and 15% of UC patients had a normal bone mineral density (BMD), 55% (CD) and 67% (UC) were osteopenic, and 37% (CD) and 18% (UC) were osteoporotic. The distribution amongst the three different diagnostic groups was not significantly different between CD and UC groups (P = 0.11). PTH and 25(OH)D3 concentrations were not significantly different between CD and UC patients and controls, whilst 1,25(OH)D3 concentrations were significantly lower in both CD and UC patients compared with controls (P < 0.05). Bone turnover was increased in UC but not in CD patients, as shown by significantly increased concentrations in UC patients of both OC (CD = 7.77 +/- 5.06, UC = 10.03 +/- 6.24, C = 6. 58 +/- 2.87, P < 0.05 vs. C) and ICTP (CD = 5.74 +/- 3.94, UC = 10.2 +/- 8.47, C = 3.48 +/- 0.95, P < 0.05 vs. CD and C). In a stepwise regression that included age, sex, disease duration and cumulative prednisolone dose as independent variables, the femur T score was significantly inversely related to disease duration (r2 = 0.125, F = 6.06) in CD patients. In UC patients, the spine T score was inversely related to age (r2 = 0.107, F = 5.49) and significantly related to sex (more negative in males: r2 = 0.3, F = 16.1); the femur T score was significantly related to sex (more negative in males) and inversely related to the cumulative prednisolone dose (r2 = 0.283, F = 7.3). CONCLUSIONS: These data show that IBD patients have a diffuse osteopenia, the degree of which is not different in CD and UC; however, bone turnover is significantly higher in UC. Finally, osteopenia is related to disease duration in CD, whilst it is related to the male sex and glucocorticoid treatment in UC.     

Increased serum levels of YKL-40 in patients with inflammatory bowel disease

BACKGROUND AND AIMS: Initiation of a fibrotic process has been suggested as part of the intestinal response to chronic inflammation in inflammatory bowel disease. YKL-40 has been proposed as a new serum marker of fibrosis. We studied compared the serum levels of YKL-40 in patients with ulcerative colitis or Crohn's disease with inflammatory and healthy controls. PATIENTS AND METHODS: YKL-40 serum levels were measured in 179 patients with inflammatory bowel disease (94 ulcerative colitis, 85 Crohn's disease), in 23 with intestinal inflammation of other causes, and 70 matched healthy controls using a commercially available enzyme-linked immunosorbent assay. YKL-40 levels were assessed in terms of disease activity, type and localization. RESULTS: Mean serum YKL-40 levels were 102.6+/-82.7 ng/ml in ulcerative colitis patients and 112.2+/-83.7 ng/ml in Crohn's disease patients, significantly higher than in healthy controls (64.1+/-21.4 ng/ml) but not significantly different from inflammatory controls (77.8+/-23.1 ng/ml). Disease activity and C-reactive protein levels were significantly correlated with YKL-40 levels in both ulcerative colitis and Crohn's disease. Crohn's disease patients with ileum localization had significantly higher YKL-40 levels than those with ileocolonic or colonic disease. Patients with stenotic disease had mean YKL-40 levels not significantly different than those with nonstenotic disease. CONCLUSION: Serum levels of YKL-40 are increased in patients with inflammatory bowel disease, and this is associated with the inflammatory process rather than with the degree of fibrosis.     

Both IL-12p70 and IL-23 are synthesized during active Crohn's disease and are down-regulated by treatment with anti-IL-12 p40 monoclonal antibody

BACKGROUND: Interleukin (IL)-12p70 and IL-23 are key T helper-1 (TH1) cytokines that drive the inflammation seen in numerous models of intestinal inflammation. These molecules contain an identical p40 chain that is bound to a p35 chain in IL-12 and a p19 chain in IL-23, making both potentially susceptible to modulation by an anti-IL-12p40 monoclonal antibody (mAb). METHODS: In the present study, we sought to determine whether active inflammation in Crohn's disease (CD) is associated with the increased synthesis of both of these cytokines and whether patients treated with an anti-IL-12p40 mAb down-regulate IL-23 as well as IL-12p70 as previous reported. RESULTS: To this end we initially determined that IL-12p70 secretion by control and CD antigen-presenting cells (macrophages) in lamina propria mononuclear populations is optimized by stimulation with CD40L and interferon-gamma. In subsequent studies using these stimulation conditions we found that patients with CD manifested both increased IL-12p70 and IL-23 secretion before anti-IL-12p40 mAb treatment and normal levels of secretion of these cytokines following cessation of treatment. Antigen-presenting cells in lamina propria mononuclear cells from ulcerative colitis patients, in contrast, produced only baseline levels of IL-23. Finally, we found that IL-23-induced T cell production of IL-17 and IL-6 are also greatly reduced after antibody treatment. The latter data are parallel to those from previous studies showing that anti-IL-12p40 down-regulates IFN-gamma and tumor necrosis factor-alpha secretion. CONCLUSIONS: We conclude that CD but not ulcerative colitis is associated with high levels of both IL-12p70 and IL-23 secretion as well as the secretion of downstream effector cytokines, and that this cytokine production is down-regulated following administration of IL-12p40 mAb.     

Psychological disorder and severity of inflammatory bowel disease predict health-related quality of life in ulcerative colitis and Crohn's disease

OBJECTIVE: The determinants of health-related quality of life in inflammatory bowel disease are not completely understood. The present study aimed to assess two factors in patients with inflammatory bowel disease: a) whether health-related quality of life is independently associated with both bowel disease severity and psychological disorder, and b) whether Crohn's disease is associated with more marked psychological disorder than ulcerative colitis. METHODS: 116/170 (68%) consecutive patients with inflammatory bowel disease attending a GI clinic (37 patients with ulcerative colitis, 75 patients with Crohn's disease, and four unspecified) completed the following self-report questionnaires: demographic details, a modified disease activity index, a total severity measure, the Hospital Anxiety and Depression Scale, and the Short Form-36. RESULTS: Thirty patients (25.9%) scored 11 or more on either the depression or anxiety subscales of the Hospital Anxiety and Depression Scale indicating probable psychological disorder; 55% (47.4%) scored over 8 indicating possible psychological disorder. Stepwise multiple regression analyses showed that both psychological symptoms and disease severity or activity contributed independently to impaired health-related quality of life. After severity of disease was taken into account, there were no significant differences between Crohn's disease and ulcerative colitis in terms of depression scores and health-related quality of life. CONCLUSIONS: The presence of psychological disorder in inflammatory bowel disease contributes to poor health-related quality of life, regardless of the severity of the condition. Detection and treatment of psychological disorder in inflammatory bowel disease carries the potential to improve health-related quality of life for these patients.     

In siblings with similar genetic susceptibility for inflammatory bowel disease,smokers tend to develop Crohn's disease and non-smokers develop ulcerative colitis

BACKGROUND AND AIMS: Smoking tobacco has opposite effects on the different forms of inflammatory bowel disease (IBD). It predisposes to the development of Crohn's disease (CD) yet is associated with a reduced incidence of ulcerative colitis (UC). We have studied sib pairs discordant for both smoking and IBD phenotype (UC or CD) to investigate whether smoking determines the type of IBD that develops in individuals with very similar genetic susceptibility. PATIENTS: Smoking habits and disease characteristics were analysed in 242 IBD pedigrees (658 patients). Within this group there were 339 affected sibling pairs of whom 89 were discordant for smoking when diagnosed. RESULTS: Smoking at diagnosis was associated with development of CD (odds ratio (OR) 3.55; 95% confidence limits 2.50-5.02; p<0.001) in all of the familial patients, with increases when analysed for ileocaecal disease, fibrostenosis, and intestinal resection. Smokers were also protected from UC (OR 0.28; 0.2-0.4; p<0.001). Of 89 sibling pairs discordant for smoking at diagnosis, 23 were also discordant for disease type-in 21 of these, CD occurred in the smoker and UC in the non-smoker (OR 10.5; 2.6-92; p<0.0001). CONCLUSIONS: Smoking is a strong environmental risk factor for Crohn's disease and increases the likelihood of needing surgery. However, sib pairs who are discordant for both smoking and IBD type almost always show CD in the smoker and UC in the non-smoker, and so in some cases tobacco consumption acts on IBD genetic predisposition to shift the phenotype from UC towards CD. The explanation of part of the apparent "protective" effect of smoking on sporadic UC may be that the form of IBD that develops in a proportion of smokers is not UC but CD.     

The use of 1H magnetic resonance spectroscopy in inflammatory bowel diseases: distinguishing ulcerative colitis from Crohn's disease

OBJECTIVES: The distinction between the two major forms of inflammatory bowel diseases (IBD), i.e., ulcerative colitis (UC) and Crohn's disease is sometimes difficult and may lead to a diagnosis of indeterminate colitis. We have used 1H magnetic resonance spectroscopy (MRS) combined with multivariate methods of spectral data analysis to differentiate UC from Crohn's disease and to evaluate normal-appearing mucosa in IBD. METHODS: Colon mucosal biopsies (45 UC and 31 Crohn's disease) were submitted to 1H MRS, and multivariate analysis was applied to distinguish the two diseases. A second study was performed to test endoscopically and histologically normal biopsies from IBD patients. A classifier was developed by training on 101 spectra (76 inflamed IBD tissues and 25 normal control tissues). The spectra of 38 biopsies obtained from endoscopically and histologically normal areas of the colons of patients with IBD were put into the validation test set. RESULTS: The classification accuracy between UC and Crohn's disease was 98.6%, with only one case of Crohn's disease and no cases of UC misclassified. The diagnostic spectral regions identified by our algorithm included those for taurine, lysine, and lipid. In the second study, the classification accuracy between normal controls and IBD was 97.9%. Only 47.4% of the endoscopically and histologically normal IBD tissue spectra were classified as true normals; 34.2% showed "abnormal" magnetic resonance spectral profiles, and the remaining 18.4% could not be classified unambiguously. CONCLUSIONS: There is a strong potential for MRS to be used in the accurate diagnosis of indeterminate colitis; it may also be sensitive in detecting preclinical inflammatory changes in the colon.     

Incidence of inflammatory bowel disease in Scottish children between 1968 and 1983; marginal fall in ulcerative colitis, three-fold rise in Crohn's disease.

Linked hospital admission data for 1968-1983 were used to identify 723 children aged 16 years or less at the time of first admission to any Scottish hospital with an ICD coded diagnosis of Crohn's disease (282) or ulcerative colitis (441). The accuracy of the coded diagnoses was checked by examination of the hospital notes of 144 patients. The coded diagnosis was incorrect in 11/83 coded as Crohn's disease and 13/61 as ulcerative colitis; frequency of incorrect coding did not change significantly with time. Despite an 18% fall in the population aged less than or equal to 16 during this time, the number of new cases of Crohn's disease rose from 10 in 1968 to 28 in 1983. Thus the recorded incidence of Crohn's disease in Scottish children has risen more than three-fold in 16 years, from 6.6 to 22.9 per million (p less than 0.0001), with no difference between the sexes. Parallel data for ulcerative colitis were rendered inaccurate by miscoding of infective gastroenteritis as colitis. In an attempt to reduce this source of error cases aged five years and under were excluded from analysis, resulting in an incidence of 19.1 cases per million aged six to 16 in 1968 and 15.6 in 1983, not a significant change (r = 0.42, p = 0.052). When males and females were analysed separately, however, there was a significant decrease in the incidence of UC in male children (r = -0.4, p = 0.028), with no change for female children (r = 0.1, p = 0.595).     

Incidence of inflammatory bowel disease in north west Greece: rarity of Crohn's disease in an area where ulcerative colitis is common.

Ulcerative colitis (UC) and Crohn's disease (CD) are generally regarded as diseases of affluent societies of the Western World, although their frequency in less affluent areas is not well established. This retrospective study therefore, assesses the incidence of UC and CD in a semirural area of north west Greece during the 10 year period 1982-1991. By the 31 December 1991, 61 patients had met standard diagnostic criteria for UC (annual incidence 4.0/10(5), 95% confidence intervals 3.0 to 5.0/10(5)) and only five patients met the diagnostic criteria for CD (annual incidence 0.3/10(5), 95% confidence intervals 0.1 to 0.8/10(5)) in this area of 157,214 inhabitants. UC incidence was lowest in the first three years at 1.8/10(5) per annum and subsequently increased to 4.8 and 5.1/10(5) per annum for the successive four and three year periods respectively. UC incidence was slightly higher in men. A third of all cases of UC had pancolitis while a quarter had only proctitis. More than one half were categorised as having moderate or severe colitis. Three quarters of the patients resided in urban areas. The incidence of CD was a twelfth of the UC incidence, which is in considerable contrast with most Western countries where the incidence of CD is usually no less than a third that for UC. The rarity of CD points to the absence of aetiological environmental factors specific for CD.     

VEGF, basic-FGF, and TGF-beta in Crohn's disease and ulcerative colitis: a novel mechanism of chronic intestinal inflammation

OBJECTIVE: Inflammatory bowel disease (IBD), the precise etiology of which remains unknown, is comprised of two forms of chronic intestinal inflammation; ulcerative colitis (UC) and Crohn's disease (CD). Recent evidence increasingly suggests that IBD is the result of dysfunctional immunoregulation manifested by inappropriate production of mucosal cytokines. An abnormal microcirculatory system has also been implicated in its pathogenesis. To elucidate the mechanism of ischemic change in IBD, we assesse serum concentration levels of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (b-FGF), and plasma level of endothelin-1 (ET-1). We also investigated the expression of VEGF, b-FGF, and transforming growth factor-beta1,2,3 (TGF-beta1,2,3) in tissue by immunostaining. METHODS: Blood samples were obtained from 11 patients with UC, 11 patients with CD, and 10 patients as controls. Paraffin-embedded samples were used for an immunohistochemical study. RESULTS: The concentration levels (in picograms per milliliter) were as follows: for ET-1, UC: 127+/-47.0, CD: 167.3+/-35.1, and controls (asthma: 38.5+/-23.8, p < 0.01; diverticulitis: 40.5+/-25.6, p < 0.01), for b-FGF, UC: 9.2+/-1.9, CD: 9.1+/-1.5, and controls (asthma: 5.0+/-0, p < 0.01; diverticulitis: 5.0+/-0, p < 0.01), for VEGF, UC: 659.8+/-181.0, CD: 740.0+/-182.3, and controls (asthma: 193.7+/-58.7, p < 0.01; diverticulitis: 199.6+/-59.7, p < 0.01). The levels of VEGF and b-FGF were significantly higher in active IBD than those in the controls. There was a significant positive correlation among the serum levels of VEGF and b-FGF and the plasma level of ET-1; that is, elevated VEGF, b-FGF, and ET-1 levels correlated well with each other. Immunohistochemical studies showed increased venula in the submucosa and lamina propria. Overexpression of VEGF and b-FGF in endothelial cells was revealed and TGF-beta2 and TGF-beta3 were found in inflammatory cells of active IBD, but no change was observed around the vessels in the controls. CONCLUSIONS: It is suggested that the reciprocal reaction of these cytokines may contribute to angiogenesis in IBD b inducing intestinal ischemia through vasoconstriction.     

Correlated expression of high-sensitivity C-reactive protein in relation to disease activity in inflammatory bowel disease: lack of differences between Crohn's disease and ulcerative colitis

BACKGROUND/AIMS: As opposed to regular C-reactive protein (CRP) assays, the introduction of high-sensitivity ones has enabled us to detect low grade inflammation in patients with inflammatory bowel disease (IBD). We addressed the subject of the degree of correlation between the concentration of high-sensitivity CRP (hs-CRP) and the inflammatory IBD activity score. METHODS: Included were 90 patients with Crohn's disease (CD), 70 with ulcerative colitis (UC) and 160 controls. Disease activity was determined using CD activity index (CDAI) for CD and Mayo score for UC. The Dade Boering BNII Nephelometer was used to determine the hs-CRP concentrations. RESULTS: The coefficient of correlation between hs-CRP and the disease activity score was similar for both UC (0.26) and CD (0.36). CONCLUSIONS: These findings are relevant for therapeutic intervention in which a greater absolute reduction in the hs-CRP concentration in CD patients (who generally present higher CRP concentrations than those found in UC) might be interpreted as a better response compared to the same absolute reduction in UC patients. This information is needed for clinicians using the hs-CRP assay to estimate IBD disease activity in daily practice.     

Effect of fish oil enriched enteral diet on inflammatory bowel disease tissues in organ culture： Differential effects on ulcerative colitis and Crohn＇s disease

AIM: To investigate the influence of fish oil enriched enteral diet on intestinal tissues taken from Crohn's disease (CD), ulcerative colitis (UC) and non-inflamed non-IBD control patients in vitro. METHODS: Colonoscopic biopsies from patients with active CD (n = 4), active UC (n= 7), and non-inflamed non-IBD control patients (n = 4) were incubated (three dilutions of 1:20, 1:10, and 1:5) with Waymouth's culture medium and enteral elemental diet (EO28, SHS, Liverpool, UK) modified in the fatty acid composition with fish oil (EF) in an organ culture system for 24 h. In each experimental set-up, incubation with Waymouth's medium alone as control was included. Tissue viability was assessed by adding bromodeoxyuridine (BrdU) to the culture fluid and immunohistochemically staining for BrdU uptake. Cytokine ratio of IL-1ra/IL-1β (low ratio indicative of inflammation) and production of those cytokines as a percentage of medium control were assayed in the culture supernatant. RESULTS: Incubation of CD-affected tissue with EF (1:20, 1:10, and 1:5) modestly and non-significantly increased IL-1ra/IL-1β ratio as compared with medium control (CD 39.1±16.1; 26.5±7.8, 47.1±16.8 vs control 13.0±2.2), but incubation of UC-affected tissues increased IL-1ra/IL-1β ratio significantly in all three dilutions (UC 69.1±32.2, P<0.05; 76.1±36.4, P = 0.05; 84.5±37.3,P<0.02; vs control 10.2±3.7). Incubation of non-inflamed non-IBD control tissue did not increase the IL-1ra/IL-1β ratio in any dilution compared to medium control (69.3±47.0, 54.1±30.6, 79.4±34,0 vs control 76.1±37.3). Average percentage production of IL-1β indexed against medium control was significantly less in UC after EF incubation as compared with CD (UC 24.0±4.8 vs CD 51.8±8.1; P<0.05). Average percentage production of IL-1ra was markedly higher in UC (135.9±3.4) than that in control patients (36.5±4.3) (P<0.0001). CONCLUSION: IBD tissues, after incubation with elemental diet modified in its fatty acid composition with fish oil, show an increase in IL-1ra /IL-1β cytokine ratio. This effect of ω-3 fatty acid modulation is significantly more marked in UC compared with CD and is accompanied by both a reduction of IL-1β and increase of IL-1ra. The positive direct anti-inflammatory effect of elemental diet with fish oil in tissue affected with UC suggests dietary treatment of UC may be possible.     

Dynamics of serum IL-17A, IL-17F and IL-23 in patients with inflammatory bowel disease

The analysis of the levels of proinflammatory cytokines IL-17A, IL-17F and IL-23 allow to evaluate the effectiveness of the therapy:, so MSCs systemic immunosuppressive therapy and corticosteroids increasingly reduces the level of all studied proinflammatory cytokines, while in therapy with infliximab, a selective immunosuppressive agent, significantly less effect on the level of proinflammatory cytokines IL-17A, IL-17F and IL-23.     

Fecal calprotectin, MMP-9, and human beta-defensin-2 levels in pediatric inflammatory bowel disease

Purpose

Fecal MMP-9 and human beta-defensin-2 (HBD-2) levels, potential markers of intestinal inflammation, are insufficiently explored in pediatric inflammatory bowel disease (IBD). The aim was to study fecal MMP-9 and HBD-2 in pediatric IBD to compare their performance to calprotectin and to study whether they would provide additional value in categorizing patients according to their disease subtype.

Methods

Fecal calprotectin, MMP-9, and HBD-2 levels were measured with ELISA in 110 pediatric patients with IBD (Crohn’s disease, n?=?68; ulcerative colitis (UC), n?=?27; unclassified, n?=?15; median age, 14). To compare the performance of the fecal markers, the area under the receiver operating characteristics curve (±95 % CI) was used. In addition, the best cut-off values of each measure to differentiate IBD patients and controls (n?=?27 presenting with diarrhea, abdominal pain, and/or anemia) were derived by maximizing sensitivity and specificity.

Results

Of the fecal markers studied, calprotectin performed best for separation of IBD and non-IBD patients with the area under curve (AUC) of 0.944 (95 % CI, 0.907 to 0.981). For MMP-9, AUC was 0.837 (95 % CI, 0.766 to 0.909), the levels being significantly higher in active IBD and in UC compared with Crohn’s disease (p?=?0.0013), but categorization of these patient groups did not take place. HBD-2 did not categorize any of the studied groups.

Conclusions

Calprotectin was the best fecal marker in pediatric IBD, but MMP-9 showed almost comparable performance in UC, suggesting applicability as a surrogate marker of inflammation. Fecal HBD-2 did not bring information to the disease characteristics of pediatric IBD patients.     

Moderate performance of serum S100A12, in distinguishing inflammatory bowel disease from irritable bowel syndrome

Background  

S100A12, a calcium-binding proinflammatory protein secreted by granulocytes, has been associated with different diseases of inflammatory origin, including inflammatory bowel disease (IBD). In this study, the utility of serum S100A12, in discriminating IBD from irritable bowel syndrome (IBS), was tested.