Lesions In Crohn's Disease Patients Research Articles

Tumor necrosis factor-related apoptosis-inducing ligand gene polymorphism and its plasma phenotype in relation to Crohn's disease

Objectives: To investigate the associations of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) gene polymorphism and plasma soluble TRAIL level (sTRAIL) with Crohn's disease (CD) and to retrospectively analyze the effects of TRAIL gene variants and plasma sTRAIL levels on clinical response to infliximab (IFX). Methods: From January 2012 to January 2021, 312 CD patients [205 males, 107 females, average age (33.9±9.8) years] and 514 age-and gender-matched healthy controls [304 males, 210 females, average age (34.9±9.4) years] were recruited from the Department of Gastroenterology, the Second Affiliated Hospital of Wenzhou Medical University. Among them, 72 patients with active CD who were ineffective or intolerant to traditional drug therapy regularly received IFX (5 mg/kg) treatment. According to the changes in the Harvey-Bradshaw index (HBI) and the Simplified Endoscopic Score for Crohn's Disease (SES-CD) in the 14th week, these patients were classified into response group (a decrease in HBI≥3 or a decrease in SES-CD≥50%) and non-response group. TRAIL (rs1131568) gene polymorphism was analyzed by matrix-assisted laser desorption/ionization time of flight mass spectrometry technique. The plasma sTRAIL level was examined by enzyme-linked immunosorbent assay (ELISA). Based on the Montreal CD classification criteria, all CD patients were divided into different subgroups. Finally, a comprehensive analysis was performed to investigate the relationship between TRAIL (rs1131568) gene polymorphism, the plasma sTRAIL level and the risk of CD, the clinicopathological characteristics of CD patients, and the clinical response to IFX. Results: The recessive model analysis showed that the homozygous variant genotype (CC) was more prevalent in patients with moderately to severely active CD than in those with mildly active CD (45.34% vs 29.23%, P=0.005). Both variant allele (C) and homozygous variant genotype (CC) in patients with stricturing and penetrating CD were more frequent than those in patients with non-stricturing and non-penetrating CD (65.48% vs 57.53%, P=0.046; 49.21% vs 31.18%, P=0.001). The dominant model analysis showed that variant allele (C) and variant genotype (TC+CC) was higher in CD patients with perianal lesions than in those without perianal lesions (66.83% vs 58.17%, P=0.037; 92.31% vs 78.37%, P=0.002). The average plasma sTRAIL level was higher in CD patients than in healthy controls [(243.04±42.74) ng/L vs (194.16±31.14) ng/L, P<0.001]. Compared with the patients with mildly active CD, the plasma sTRAIL level was increased in those with moderately to severely active CD [263.47(242.09, 281.91) ng/L vs 231.13(211.11, 247.11) ng/L, P<0.001]. The same conclusion was also drawn for the patients with stricturing and penetrating CD in contrast to those with non-stricturing and non-penetrating CD [266.18 (246.68, 289.91) ng/L vs 227.19 (204.57, 249.59) ng/L, P<0.001]. The plasma sTRAIL level was also higher in patients with perianal disease than in those without perianal disease [(261.40±41.51) ng/L vs (233.86±40.41) ng/L, P<0.001]. Multiple linear regression analysis further showed that disease activity (β=22.640, P<0.001) and homozygous variant genotype (CC) (β=16.814, P<0.001) may be positively related to the plasma sTRAIL level in CD patients independently. At the 14th week of IFX treatment, the plasma sTRAIL level in the response group was lower than that in the non-response group [205.98(190.72, 214.56) ng/L vs (238.33±29.38) ng/L, P<0.001]. Compared with week 0, the plasma sTRAIL level was decreased in the response group in the 14th week [(205.98 (190.72, 214.56) ng/L vs (239.89±42.43) ng/L, P<0.001]. Non-conditional logistic regression analysis showed that variant allele (C) and variant genotype (TC+CC) were less frequent in the response group than in the non-response group (53.33% vs 70.83%, P=0.037; 70.00% vs 91.67%, P=0.036). Conclusions: The increased plasma sTRAIL level may be a risk factor for CD. TRAIL (rs1131568) gene variation and the increase of plasma sTRAIL level may be associated with the increased disease activity of CD and may be the risk factors for stenosis, penetration, and perianal lesions in CD patients. In addition, TRAIL (rs1131568) gene variation or the increase of plasma sTRAIL level may be related to no response to IFX treatment in CD patients.

Endoscopic Features of Postoperative Anastomotic Lesions in Patients with Crohn's Disease Compared with Right-side Colon Cancer: Are Anastomotic Linear Superficial Ulcers Recurrent in Crohn's Disease?

Objectives: Many patients have endoscopic evidence of recurrent Crohn's disease (CD) 1 year after intestinal resection, and endoscopic lesions predict future clinical recurrence. The aim of this study was to describe some anastomotic lesions including changes in endoscopic features in CD patients and to discuss recurrence. We also compared anastomotic lesions in CD patients and in right-side colon cancer (rt-CC) patients. Methods: We enrolled patients with CD and rt-CC who underwent surgical resection between 2008 and 2014. Eleven CD patients underwent postoperative endoscopy at least twice, with the first time being from 6 months to 1 year after surgery and the second time being from 2 to 3 years after surgery. Eighty-six patients with rt-CC underwent postoperative endoscopy after approximately one year. Results: A total of 90.9% of CD patients had postoperative lesions around the anastomosis at the first postoperative ileocolonoscopy, which was markedly higher than that in rt-CC patients (3.5%, p<0.001). Many of these lesions in CD required enhanced treatment. However, linear superficial ulcers at the anastomotic line at the first ileocolonoscopy did not worsen with the same treatment (18.1%). Conclusions: Postoperative anastomotic lesions were detected at a higher rate in CD cases than that in rt-CC cases. Many anastomotic lesions were recognized as recurrent disease and required enhanced treatment, whereas linear superficial ulcers did not require treatment changes. Therefore, linear superficial ulcers might not be recurrent disease. As this issue is related to recurrence, it should be further explored with the accumulation of more cases in a multicenter analysis.

Slight increases in the disease activity index and platelet count imply the presence of active intestinal lesions in C-reactive protein-negative Crohn's disease patients.

Although the serum C-reactive protein (CRP) level may, to some extent, predict the disease activity in patients with Crohn's disease (CD), it is not always elevated during periods of disease activity. This study aimed to identify factors predicting the presence of active intestinal lesions in CD patients without an elevated CRP level. CD patients in whom the presence or absence of active intestinal lesions was evaluated using endoscopic and/or radiologic modalities were divided into two groups based on a negative (<3 mg/L) or positive (≥3 mg/L) CRP level. The correlations between the presence of active intestinal lesions and various clinical variables, including the Crohn's Disease Activity Index (CDAI), leukocyte and platelet counts and hemoglobin, serum albumin and CRP levels, were determined in the CRP-negative patients. Of the 128 patients examined, 70 had a negative CRP status, approximately half of whom had active intestinal lesions. The multivariate analysis revealed a CDAI of >100 and platelet count of >33×10(4)/μL to be significant predictive factors for the presence of active lesions in the CRP-negative patients [CDAI >100, odds ratio (OR) =5.55; 95% confidence interval (CI), 1.80-18.74, platelet count >33×10(4)/μL, OR =5.94; 95% CI, 1.34-28.87]. The sensitivity of fulfillment of either criterion for the presence of active intestinal lesions was 83%, while the specificity of fulfillment of both criteria was 94%. A relatively low CDAI and platelet count were identified as predictive markers of the presence of active intestinal lesions in CRP-negative CD patients. These results suggest that symptoms and laboratory data should be evaluated very carefully in such patients.

Correlations between skin lesions induced by anti-tumor necrosis factor-α and selected cytokines in Crohn's disease patients.

To investigate the correlation between the appearance of skin lesions and concentration of interleukin (IL)-17A, IL-23 and interferon-γ (IFN-γ) in Crohn's disease (CD) patients during anti-tumor necrosis factor-α (TNF-α) therapy A prospective study included 30 adult patients with CD of Caucasian origin (19 men and 11 women; mean age ± SD 32.0 ± 8.6 years) during biological therapy with anti-TNF-α antibodies from January 2012 to March 2013. Eighteen patients were treated with infliximab, seven with adalimumab and five with certolizumab. Inclusion criteria were exacerbation of the underlying disease, Crohn's Disease Activity Index over 300 and the ineffectiveness of previously used non-biological therapies. Patients with a history of psoriasis, atopic dermatitis and other autoimmune skin lesions were excluded from the study. The control group consisted of 12 healthy subjects. A diagnostic survey was carried out, blood tests and careful skin examination were performed, and the serum levels of IL-17, IL-23 and IFN-γ were measured using an enzyme-linked immunosorbent assays technique. Dermatoses that have developed in the course of biological therapy in patients who had no pre-existing skin lesions of similar character were qualified as skin lesions induced by anti-TNF-α therapy. Skin manifestations occurred in 18 of CD patients during the anti-TNF-α therapy (60%), in the average time of 10.16 ± 3.42 mo following the beginning of the 52-wk treatment cycle. Skin lesions observed in CD patients during biological therapy included psoriasiform lesions (44.4%), and eczema forms lesions (22.2%). In CD patients with drug induced skin lesions significantly higher levels of hemoglobin (13.3 ± 1.5 g/dL vs 10.8 ± 1.9 g/dL, P = 0.018) and hematocrit (39.9% ± 4.5% vs 34.3% ± 5.4%, P = 0.01), as well as a significantly lower level of platelets (268 ± 62 × 10(3)/μL vs 408 ± 239 × 10(3)/μL, P = 0.046) was observed compared with CD patients without skin manifestations. The concentrations of IL-17A and IL-23 in CD patients with skin lesions developed under anti-TNF-α therapy were significantly higher compared to those in patients without lesions (IL-17A: 39.01 ± 7.03 pg/mL vs 25.71 ± 4.90 pg/mL, P = 0.00004; IL-23: 408.78 ± 94.13 pg/mL vs 312.15 ± 76.24 pg/mL, P = 0.00556). Skin lesions in CD patients during biological therapy may result from significantly increased concentrations of IL-17A and IL-23, which are strongly associated with TNF-α/Th1 immune pathways.

Molecular identification of Mycobacterium avium subspecies paratuberculosis in oral biopsies of Crohn’s disease patients

Oral lesions may be found in patients with Crohn’s disease (CD), in a percentage up to 20%. The aim of this study was to investigate a possible relationship between Mycobacterium avium subsp. paratuberculosis (MAP) and oral lesions in CD patients. 23 oral biopsies were examined performing IS900 Nested PCR; 9 of them were positive: 8 from CD patients and 1 from a control. Our purpose is to go on with this study, amplifying the number of subjects examined and testing subjects with oral lesions related to diseases other than CD to verify the specific association between MAP and oral lesions in CD patients.

Upper Gastrointestinal Involvement of Crohn’s Disease: A Prospective Study on the Role of Upper Endoscopy in the Diagnostic Work-Up

Prevalence of upper gastrointestinal (GI) tract involvement in adult Crohn's disease (CD) has been reported to be very low (0.3-5%). In routine practice, upper endoscopy is recommended only in CD patients with upper GI symptoms. Available data concerning the prevalence of asymptomatic upper GI lesions in CD patients are controversial. The aim of this study was to prospectively evaluate the prevalence of upper GI CD involvement in CD patients, irrespective of upper GI symptoms. A series of 119 consecutive CD patients underwent clinical assessment, including occurrence and score of upper GI symptoms, and upper endoscopy with biopsy samples for histological assessment and Helicobacter pylori (Hp) infection detection. In an attempt to further recognize the upper GI tract lesions as CD or other form of inflammation, in a subgroup of CD patients, the histological and endoscopic evaluation was repeated following 12 weeks of anti-TNF-α or other treatments in association with proton-pump inhibitors. Upper CD involvement was found in 19/119 (16%) patients. Hp infection was detected in 10/119 (8.4%) CD patients. Hp-negative focally active chronic gastritis was found in 34/119 (28.6%) CD patients. At presentation, 12/19 patients (63%) showing upper CD involvement were asymptomatic and 7 (37%) symptomatic. A high prevalence of upper GI tract involvement has been observed in CD patients, irrespective of upper symptoms. This finding suggests the usefulness of routine upper endoscopy in the diagnostic work-up of CD patients in order to correctly classify the distribution and extent of the disease.

M1811 Myofibroblast-Derived FGF15/19 Protects Colonic Mucosa and Enhances Mucosal Repair in IBD

Background: Ileal lesions in Crohn disease patients are colonized by adherent-invasive Escherichia coli (AIEC), which are able to invade and replicate within intestinal epithelial cells. The mechanisms by which AIEC exerts its pathogenic effects are not understood. Interferon gamma (IFN-γ) is an important cytokine involved in the host innate defence, which signals through signal transducer and activator of transcription 1 (Stat1). Previous studies have shown that other gastrointestinal pathogens block Stat1 phosphorylation as a means of subverting the host innate immune response. AIM: To determine if AIEC blocks STAT1 signalling in order to evade the host immune response. Methods: Intestine 407 cells were infected for 6 hr with AIEC, strain LF82 (serotype O83:H1) or other pathogenic and commensal Escherichia coli strains as positive and negative controls, respectively. To asses activation of Stat1, epithelial cells were stimulated with IFN-γ (50ng/ml) for 30 min after infection and tyrosine phosphorylation was monitored by immunoblotting. Results: AIEC strain LF82 and enterohemorrhagic E. coli O157:H7, but not E. coli commensal strain HB101 or enteropathogenic E. coli strain E2348/69 (O127:H6), blocked Stat1 phosphorylation in intestinal epithelial cell lines after stimulation with IFN-γ. Preliminary studies indicate that the inhibitory factor was secreted into culture medium, was dependent on the presence of live bacteria, and required intact bacterial protein synthesis machinery. Conclusions: Suppression of host epithelial cell IFN-γ signalling by a secreted factor produced by AIEC strain LF82 could represent a novel mechanism by which this pathogen evades the host innate immune system, and thereby may explain a predisposition to chronic inflammation in Crohn disease.

Impact of double-balloon enteroscopy findings on the management of Crohn's disease

Objective. It is estimated that 10%–30% of Crohn's disease (CD) patients have small-bowel lesions, but the exact frequency and clinical relevance of these findings are unknown. Double-balloon enteroscopy (DBE) enables endoscopic visualization of the small bowel. The aim of this study was to evaluate the use of DBE for detecting small-bowel lesions in CD patients suspected of having small-bowel involvement. Furthermore, the clinical impact of adjusting treatment in these patients was assessed. Material and methods. A prospective study was performed in a tertiary referral center. CD patients suspected of small-bowel involvement and in whom distal activity had previously been excluded were included. All patients underwent DBE, followed by step-up therapy in patients with small-bowel lesions. The presence of small-bowel lesions during DBE was noted and clinical outcome was assessed after adjusting therapy. Results. Thirty-five patients (70%) showed small-bowel lesions; these lesions could not be assessed by conventional endoscopy in 23 (46%). At 1-year follow-up, step-up therapy in 26 patients (74%) led to clinical remission in 23 (88%). This was confirmed by a significant decrease in Crohn's disease activity index and mucosal repair on second DBE. Conclusions. DBE showed a high frequency of small-bowel lesions in known CD patients with clinically suspected small-bowel activity. Most of these lesions were not accessible for conventional endoscopy. Adjusting treatment in patients with small-bowel CD involvement led to clinical remission and mucosal repair in the majority of cases.

Double-balloon enteroscopy in Crohn’s disease patients suspected of small bowel activity: findings and clinical impact

It is estimated that 10-30% of patients with Crohn's disease (CD) have small bowel (SB) involvement, but the exact frequency and clinical relevance of these findings is unknown. Double-balloon enteroscopy (DBE) enables endoscopic visualization of the SB. In this study we evaluated whether DBE is a feasible technique for detection of CD localized in the SB in CD patients with clinical suspicion of SB lesions and whether these findings have clinical impact. Retrospectively we analyzed 52 DBE procedures in 40 CD patients (16 males, mean age 40 years, mean duration of CD 15 years). Included patients had clinical suspicion of small bowel CD activity, including persistent abdominal discomfort (n = 27), iron deficiency anemia (n = 9) and/or hypomagnesemia (n = 4). Active small bowel CD was found in 24 (60%) patients, leading to a change in therapy in 18 patients (75%). After a mean follow-up of 13 months, 15 (83%) had persistent clinical improvement with a significant drop of mean CDAI from 178 to 90, after a mean follow-up of 13 months. DBE is a useful diagnostic tool for the evaluation of SB lesions in CD patients. The significance of these findings is emphasized by the fact that adjustment of therapy in the majority of these patients leads to significant and sustained clinical improvement.

Crohnʼs Disease: A Comparative Prospective Study of Transabdominal Ultrasonography, Small Intestine Contrast Ultrasonography, and Small Bowel Enema

Small intestine contrast ultrasonography (SICUS), when performed after distention of the small bowel lumen with an iso-osmolar polyethylene glycol electrolyte-balanced solution, shows high sensitivity (100%) and specificity (97%) in detecting small bowel abnormalities in patients who have not received a diagnosis but in whom there is a suspicion of intestinal diseases. The diagnostic yield of SICUS remains to be established in detecting small bowel lesions in patients with proven Crohn's disease (CD) in comparison with transabdominal ultrasonography (TUS), and in relationship to the experience of the operator, using small bowel enema (SBE) as the "gold standard." The aim of this study was to evaluate the diagnostic value of SICUS, when performed by a sonologist with 1 year of experience, and TUS, when performed by a sonologist with 10 years of experience, compared to SBE in the assessment of the site, extension, and stenosis of small intestinal lesions in CD patients. A total of 28 consecutive patients (men, 16; women, 12; age range, 21 to 60 yr) with a diagnosis of CD underwent TUS and SICUS, which were performed by 2 sonologists who were unaware of the radiologic findings, on the same day. SICUS was performed after the ingestion of 375 mL of a polyethylene glycol contrast solution. A standard SBE was performed on a different day by an expert radiologist who was unaware of the sonographic findings. Sensitivities in the detection of small bowel lesions were 96% for TUS and 100% for SICUS. Compared with SBE, SICUS detected the presence of 4 lesions in the jejunum that had been missed by TUS. The mean (+/-SD) extent of the ileal disease was 22 +/- 12.5 cm when measured during SBE, 14.5 +/- 8.6 cm when measured during TUS, and 19.5 +/- 12.5 cm when measured during SICUS [P = 0.05 (SICUS versus SBE)]. The correlation of the extension of the lesions between SICUS and SBE (r = 0.88) was better than that between TUS and SBE (r = 0.64). The sensitivities of TUS and SICUS in the detection of at least 1 stricture were 76% and 94%, respectively. Sensitivity and specificity in assessing prestenotic dilatation were 50% and 100%, respectively, at TUS, and 100% and 90%, respectively, at SICUS. In inexperienced hands, SICUS is a more accurate technique for assessing CD lesions, and the accuracy is better than that of TUS performed by an expert sonologist. The use of SICUS, instead of SBE, could be indicated for the follow-up of patients with CD.

Analysis of the CC chemokine receptor 5 (CCR5) delta-32 polymorphism in inflammatory bowel disease.

The inflammatory bowel diseases (IBD) Crohn's disease (CD) and ulcerative colitis (UC) are complex multifactorial traits involving both environmental and genetic factors. Recent studies have shown the important role of pro-inflammatory cytokines and chemokines, including RANTES, in IBD. RANTES is the natural ligand for the CC-chemokine receptor 5 (CCR5). The chromosomal location of the CCR5 gene on 3p21 coincides with an IBD-susceptibility locus identified by genome-wide scanning. A 32-bp deletion (A32) in the CCR5 gene results in a nonfunctional receptor and is found with high frequency in Caucasians. In this study, we investigated the presence of the CCR5delta32 allele in a large cohort of IBD patients and in a healthy control population. Blood samples were obtained from 538 unselected IBD cases (433 unrelated IBD patients: 289 CD, 142 UC, 2 indeterminate colitis; 105 affected first-degree relatives) and 135 unaffected first-degree family members. Of the IBD patients, 36% had familial IBD with at least two members being affected. There were no significant differences in the CCR5delta32 mutation frequency between IBD patients and healthy controls, nor between CD and UC patients. There was no correlation between the CCR5delta32 genotype and the age at IBD-diagnosis, the frequency of surgical intervention, or disease localization. Only the association between CCR5delta32 homozygosity and the presence of anal lesions in CD patients was statistically significant (P=0.007). Analysis by the transmission/disequilibrium test showed no significant transmission distortion to the probands or their clinically silent siblings. Based on these results, it is unlikely that the CCR5delta32 allele is an important marker for predisposition to IBD.