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PubMed2004

Anti-tissue transglutaminase antibodies in inflammatory bowel disease: new evidence.

Anti-tissue transglutaminase, previously held to be identical to anti-endomysial antibodies in celiac sprue, has been reported in inflammatory bowel disease patients. To investigate these data further, we evaluated serum and intestinal anti-tissue transglutaminase in inflammatory bowel disease patients, with respect to the Crohn's disease activity index and the integrated disease activity index. Study population comprised: 49 patients with Crohn's disease and 29 patients with ulcerative colitis; 45 patients with celiac sprue and 85 autoimmune patients as disease controls; and 58 volunteers as healthy controls. Immunoglobulin A (IgA) anti-recombinant human tissue transglutaminase and anti-endomysial antibody detection in sera and fecal supernatants were performed. Adsorption of positive sera with recombinant human tissue transglutaminase were also performed. Marked increased anti-tissue transglutaminase concentrations were found in celiac sprue, while low-positive values were also found in Crohn's disease and ulcerative colitis. Anti-endomysial antibodies were detectable only in celiac sprue. Antigen adsorption resulted in a significant reduction of the anti-tissue transglutaminase either in celiac sprue or inflammatory bowel disease sera. A significant correlation between anti-tissue transglutaminase and Crohn's disease activity index or integrated disease activity index scores was found. Anti-tissue transglutaminase was also detectable in fecal supernatants from inflammatory bowel disease patients. Data highlight that both circulating and intestinal anti-tissue transglutaminases are detectable in inflammatory bowel disease, and that they are related to disease activity. These features underline that, in addition to anti-tissue transglutaminase, an anti-endomysial antibody test is necessary in the diagnostic work-up of celiac sprue, especially in patients with known inflammatory bowel disease.

Adult↗
PubMed1999

Inflammatory bowel disease in children: Indian perspective.

The magnitude of inflammatory bowel disease in childhood in India is largely unknown. At the Pediatric Gastroenterology section of PGIMER, Chandigarh, 15 out of 294 children (5%) admitted for colonic disorders were diagnosed to have ulcerative colitis. Diagnosis is suspected on the basis of clinical presentation and established by sigmoidoscopy, rectal biopsy and double contrast barium enema. Widely prevalent bacillary dysentery, acute amoebic colitis and antibiotic induced colitis need to be kept in differential diagnosis of acute presentation of ulcerative colitis. Chronic or recurrent colitis needs to be differentiated from tuberculous colitis. Inflammatory bowel disease deserves clinical suspicion in all unusual cases of colitis which do not respond to treatment of common infective agents.

Adolescent↗
PubMed1998

Prevalence and clinical significance of anti-lactoferrin autoantibodies in inflammatory bowel diseases and primary sclerosing cholangitis.

Anti-neutrophil cytoplasmic antibodies (ANCA) are autoantibodies directed against cytoplasmic constituents of neutrophil granulocytes. Antibodies with specificity for proteinase 3 and myeloperoxidase are seromarkers for systemic vasculitides. ANCA with specificity for lactoferrin were described in patients with several idiopathic inflammatory diseases, such as the inflammatory bowel diseases and rheumatoid arthritis. However, the clinical significance of anti-lactoferrin autoantibodies is still unclear. In this study, we determined the clinical significance of anti-lactoferrin autoantibodies in sera from large groups of patients with ulcerative colitis (UC), Crohn's disease (CD), and primary sclerosing cholangitis (PSC). Antibodies to human lactoferrin were detected by ELISA and by immunoblotting, using an extract of sonicated neutrophils as antigen source. Autoantibodies to lactoferrin were found in 29% of patients with UC, 13% of patients with CD, and 22% of patients with PSC. In inflammatory bowel diseases, the presence of anti-lactoferrin antibodies was not related to treatment, disease activity, duration of disease, or disease extent. In PSC, the presence of autoantibodies to lactoferrin did not correlate with duration of disease or the presence of cirrhosis. However, patients with PSC and coexistent UC had significantly more frequently antibodies to lactoferrin than PSC patients without IBD. In conclusion, autoantibodies to lactoferrin are a common feature of inflammatory bowel diseases and PSC. However, the clinical significance of those autoantibodies is limited as they lack sensitivity and specificity for those disorders. Future research should address the pathophysiological role of anti-lactoferrin ANCA and the influence of anti-lactoferrin ANCA binding on the functional properties of the lactoferrin molecule.

Autoantibodies↗
PubMed1979

Toxic dilatation of the colon in salmonella colitis and inflammatory bowel disease.

Toxic dilatation of the colon may be due to inflammatory bowel disease, either ulcerative colitis or Crohn's disease of the colon, but recent experience has shown that infective colitis due to salmonella can produce this complication. We present 13 cases with toxic dilatation (9 inflammatory bowel disease and 4 salmonellosis) and outline the diagnostic features and treatment in these patients. It is important to distinguish salmonellosis at an early stage because, whilst toxic dilatation in inflammatory bowel disease is an absolute indication for surgical treatment, cases with this complication due to salmonellosis may be treated conservatively in the majority of instances.

Adolescent↗
PubMed2004

No significant association between mutations in exons 6 and 8 of the autoimmune regulator (AIRE) gene and inflammatory bowel disease.

Various autoantibodies have been described in patients with inflammatory bowel disease. The autoimmune regulator (AIRE) functions as a transcription factor in cells responsible for the induction and maintenance of immunological tolerance. In contrast to classic autoimmune disorders, polymorphisms of the AIRE gene are not associated with inflammatory bowel disease, despite the presence of disease-specific autoantibodies.

Adolescent↗
PubMed1979

Characteristics of isolated intestinal mucosal lymphoid cells in inflammatory bowel disease.

Immunologic characteristics of intestinal mucosal lymphoid cells from patients with inflammatory bowel disease and controls have been compared. Mononuclear cells isolated by enzymatic means from intestinal tissues involved with inflammatory bowel disease were present in greater numbers, with increased proportions of macrophages and B-lymphocytes, particularly cells bearing intrinsic membrane immunoglobulin G. Synthesis of immunoglobulin G, measured by radioimmunoassay, was increased tenfold in inflammatory bowel disease, while immunoglobulin A synthesis per 10(6) cells was unchanged. "Null" or K-lymphocytes were absent from all populations, and antibody-dependent cellular cytotoxicity (a K-cell-mediated function) was not demonstrable. Taken together, the results fail to support a role for antibody-dependent cellular cytotoxicity or a defect in secretory immunoglobulin A, but rather focus attention upon possible forms of immunoglobulin G-mediated tissue damage in the pathogenesis or perpetuation of inflammatory bowel disease.

Antibody-Dependent Cell Cytotoxicity↗
PubMed2001

Pediatric "PSC-IBD": a descriptive report of associated inflammatory bowel disease among pediatric patients with psc.

BACKGROUND: Inflammatory bowel disease (IBD) in adults with primary sclerosing cholangitis (PSC) is characterized by pancolonic involvement, a high frequency of rectal sparing, and an increased risk of pouchitis and colorectal neoplasia. The clinical features of IBD in pediatric patients with PSC have not been well described. The aim of this study was to characterize the frequency, clinical features, and natural history of IBD in pediatric patients diagnosed with PSC. METHODS: A retrospective chart review was performed for all patients 18 years of age or younger diagnosed with PSC seen at the Mayo Clinic between 1975 and 1999. Endoscopic and histologic features and surgical and postsurgical outcomes were recorded. RESULTS: Fifty-two children with PSC were identified. Forty-three patients (84%) were also diagnosed with IBD. In 36 of 43 cases, there was a sufficient diagnostic evaluation to allow a detailed review. Thirty-two of 36 patients (89%) had ulcerative colitis and 4 of 36 patients (11%) had Crohn's disease. In 4 of 36 patients (11%), IBD was asymptomatic. Although the most frequent endoscopic presentation of IBD was universal colitis, endoscopic rectal sparing was frequently noted (27% of colonoscopic studies). Of the four patients diagnosed with Crohn disease, in none did perianal, fistulizing, or stricturing disease develop. Proctocolectomy was performed in six patients (17%); three operations were performed for dysplasia. Pouchitis complicated four of the five ileal pouch-anal anastomoses procedures. CONCLUSIONS: Among pediatric patients (1) PSC without IBD is uncommon; (2) asymptomatic IBD may be associated with PSC; (3) because the time to dysplasia may be accelerated, once the diagnosis of IBD is made in the setting of PSC, heightened endoscopic surveillance may be indicated; (4) pouchitis occurs frequently in these patients.

Adolescent↗
PubMed2001

Prevalence of subclinical anterior uveitis in adult patients with inflammatory bowel disease.

AIM: To assess the prevalence of subclinical anterior uveitis in adult patients with inflammatory bowel disease. METHODS: In 179 consecutive patients (96 with Crohn's disease, 55 with ulcerative colitis, and 28 with inflammatory bowel disease of undetermined nature) without previous or concurrent ocular complaints, quantitative flare measurements were obtained with the Kowa FC laser flare to detect the presence of subclinical uveitis. RESULTS: The mean flare value was 3.9 (SD 1.1) ph/ms in patients younger than 30 years of age, rising to 5.8 (2.5) ph/ms in those over 60 years of age. No measurement performed in this patient population fell outside the mean observed value plus or minus SD of the normal controls within the same age category. CONCLUSION: In an adult population of 179 consecutive patients with inflammatory bowel disease the presence of a form of subclinical uveitis, as described by Hofley et al in a group of juvenile patients, is highly unlikely.

Adult↗
PubMed1996

A prospective study of the relationship between disease activity and psychologic distress in patients with inflammatory bowel disease.

BACKGROUND: The evaluation of psychologic states is very useful in the management of inflammatory bowel disease (IBD) patients, particularly when related to disease activity (DA). Our aim was to prospectively evaluate the relationship between psychologic distress and DA. METHODS: DA and psychologic distress were evaluated in 104 IBD outpatients by means of clinical criteria and the Hospital Anxiety and Depression Scale (HADS) at base line and after 6 months. Patients were grouped in unchanged, improved, and worsened DA from base line to follow-up. RESULTS: Repeated-measures ANOVA showed a significant group-by-time interaction for HADS anxiety (F = 89.6, P = 0.0001) and depression (F = 3.67, P = 0.03) subscales. CONCLUSIONS: Over time changes in DA significantly affect psychologic distress and are closely related to corresponding increases and decreases in anxiety and depression in IBD patients. Our findings therefore suggest that the assessment of psychologic distress, particularly anxiety, should be included in the clinical management of IBD patients.

Adult↗
PubMed2001

Measurement of thiopurine methyltransferase activity and azathioprine metabolites in patients with inflammatory bowel disease.

BACKGROUND: Measurement of 6-thioguanine nucleotide concentrations may be useful for optimising treatment with azathioprine and 6-mercaptopurine. METHODS: We conducted a study of 170 patients with inflammatory bowel disease treated with azathioprine or 6-mercaptopurine to determine the relationship between 6-thioguanine nucleotide concentrations and both disease activity, as measured by the inflammatory bowel disease questionnaire (active disease < 170, remission > or = 170) and leucopenia. Blood was submitted for whole blood 6-thioguanine nucleotide concentration and leucocyte count. RESULTS: Mean (SD) inflammatory bowel disease questionnaire score was 176 (32). There was no correlation between inflammatory bowel disease questionnaire scores and 6-thioguanine nucleotide concentrations (r(s) = -0.09, p = 0.24). Median 6-thioguanine nucleotide concentrations in 56 patients with active disease and 114 patients in remission were similar (139 v 131 pmol/8 x 10(8) red blood cells; p = 0.26). There was no correlation between 6-thioguanine nucleotide concentrations and leucocyte counts. CONCLUSIONS: In patients with inflammatory bowel disease treated with azathioprine or 6-mercaptopurine, 6-thioguanine nucleotide concentrations did not correlate with disease activity, as measured by the inflammatory bowel disease questionnaire, or leucocyte count. These findings are discrepant with most previous studies, possibly due to selection of responding patients who tolerated the medications. A prospective, randomised, dose optimisation trial using 6-thioguanine nucleotide concentrations is warranted.

Adolescent↗
PubMed1998

Inflammatory bowel disease (ulcerative colitis and Crohn's disease): diagnostic criteria and differential diagnosis.

Chronic inflammatory bowel diseases (i.e., ulcerative colitis and Crohn's disease) are syndromes in which standardized criteria are necessary in the diagnostic process. The present review is based on the diagnostic criteria used at our institution. We base the diagnosis of ulcerative colitis and Crohn's disease on combined information from the patient history, and radiological, endoscopic and histological findings after exclusion of neoplastic and infectious disease. The patient history must include precise information on the nature and duration of symptoms as well as the presence of relevant influential factors such as travel activity, drug intake and sexual habits. In immunocompromised patients extensive microbiological investigations are required to exclude infection. Typical radiological and colonoscopic findings in ulcerative colitis are mucosal inflammatory changes extending circumferentially and continuously from the rectum and proximally in the colon. In contrast, Crohn's disease is most frequently located in the small bowel and in case of colonic involvement, the rectum is often spared. The best predictors of Crohn's disease are discontinuous lesions, cobblestones and apthous ulceration. Histological changes such as abnormal mucosal architecture and lamina propria cellularity, neutrophil polymorph infiltration and epithelial cell abnormality are useful and reproducible features in the evaluation of colorectal biopsy specimens. The inflammatory bowel diseases, ulcerative colitis and Crohn's disease, continue to be etiological and diagnostic challenges. Increased use of standardized criteria and diagnostic algorithms are essential instruments to improve the overall quality of the management of patients with these diseases.

Journal Article↗
PubMed1998

Nitric oxide and inflammatory bowel diseases.

Nitric oxide (NO) production, as detectable by indirect and direct methods, as well as the expression of inducible nitric oxide synthase (iNOS) in the intestinal mucosa appear to be enhanced in active ulcerative colitis and, when in excess, to play a proinflammatory role in the disease. Despite some conflicting data, there is evidence that NO production is also increased in Crohn's disease. Many inflammatory features of inflammatory bowel disease are in keeping with the physiological properties of NO, and toxic megacolon, a complication of chronic colitis characterized by acute colonic dilatation, is associated with an enhanced intestinal synthesis of NO. The drugs currently used in the treatment of inflammatory bowel disease (steroids, salicylates) do not seem to exert substantial effects on intestinal NO synthesis. The possible therapeutic role of selective iNOS inhibitors is still under investigation.

Animals↗
PubMed2000

Hepatic effects of long-term methotrexate use in the treatment of inflammatory bowel disease.

OBJECTIVE: Methotrexate is currently used as a treatment for refractory inflammatory bowel disease. This study sought to evaluate the hepatic effects of long-term methotrexate therapy in patients with inflammatory bowel disease and to determine whether the established guidelines for monitoring methotrexate-related hepatotoxicity with surveillance liver biopsy in patients with psoriasis or rheumatoid arthritis are applicable to these patients. METHODS: Thirty-two patients with inflammatory bowel disease receiving cumulative methotrexate doses of > or = 1500 mg were studied. Liver chemistry tests were obtained before and during therapy. Twenty patients underwent liver biopsies as recommended for methotrexate-treated patients with psoriasis; the biopsies were reviewed and graded according to Roenigk's criteria for methotrexate-induced hepatotoxicity (a grading system for methotrexate hepatotoxicity in psoriasis patients) by a liver pathologist blinded to the methotrexate dose. RESULTS: In patients who had liver biopsies, the mean cumulative methotrexate dose was 2633 mg (range, 1500-5410 mg), given for a mean of 131.7 wk (range, 66-281 wk). Nineteen of 20 patients (95%) had mild histological abnormalities (Roenigk's grade I and II), and one patient had hepatic fibrosis (Roenigk's grade IIIB). Abnormal liver chemistry tests, present in 6 of 20 (30%) patients, did not identify the patient with Roenigk's grade IIIB hepatotoxicity. CONCLUSIONS: Cumulative methotrexate doses up to 5410 mg given up to 281 wk in patients with inflammatory bowel disease are associated with little hepatotoxicity. Surveillance liver biopsies based on cumulative methotrexate doses are not warranted in these patients.

Adult↗
PubMed2025

Pharmacogenomic Assessment of Genes Implicated in Thiopurine Metabolism and Toxicity in a UK Cohort of Pediatric Patients With Inflammatory Bowel Disease.

BACKGROUND: Thiopurine drugs are effective treatment options in inflammatory bowel disease and other conditions but discontinued in some patients due to toxicity. METHODS: We investigated thiopurine-induced toxicity in a pediatric inflammatory bowel disease cohort by utilizing exome sequencing data across a panel of 46 genes, including TPMT and NUDT15. RESULTS: The cohort included 487 patients with a median age of 13.1 years. Of the 396 patients exposed to thiopurines, myelosuppression was observed in 11%, gastroenterological intolerance in 11%, hepatotoxicity in 4.5%, pancreatitis in 1.8%, and "other" adverse effects in 2.8%. TPMT (thiopurine S-methyltransferase) enzyme activity was normal in 87.4%, intermediate 12.3%, and deficient in 0.2%; 26% of patients with intermediate activity developed toxicity to thiopurines. Routinely genotyped TPMT alleles associated with defective enzyme activity were identified in 28 (7%) patients: TPMT*3A in 4.5%, *3B in 1%, and *3C in 1.5%. Of these, only 6 (21%) patients developed toxic responses. Three rare TPMT alleles (*3D, *39, and *40) not assessed on routine genotyping were identified in 3 patients, who all developed toxic responses. The missense variant p.R139C (NUDT15*3 allele) was identified in 4 patients (azathioprine 1.6 mg/kg/d), but only 1 developed toxicity. One patient with an in-frame deletion variant p.G13del in NUDT15 developed myelosuppression at low doses. Per-gene deleteriousness score GenePy identified a significant association for toxicity in the AOX1 and DHFR genes. CONCLUSIONS: A significant association for toxicity was observed in the AOX1 and DHFR genes in individuals negative for the TPMT and NUDT15 variants. Patients harboring the NUDT15*3 allele, which is associated with myelosuppression, did not show an increased risk of toxicity.

Humans↗
PubMed1999

Correlation between faecal excretion of indium-111-labelled granulocytes and calprotectin, a granulocyte marker protein, in patients with inflammatory bowel disease.

BACKGROUND: Several studies have suggested that clinical indices of disease activity in inflammatory bowel disease (IBD) do not adequately reflect the degree of inflammation in most such patients. Faecal excretion of indium-111-labelled neutrophilic granulocytes has been suggested as the gold standard of disease activity, but its complexity and high cost and the exposure of patients to ionizing irradiation have limited the use of this technique. The aim of this study was to investigate the correlation between the faecal excretion of the granulocyte marker protein calprotectin and that of 111In-labelled granulocytes. METHODS: Calprotectin in stool extracts from 19 patients with Crohn's disease (CD), 10 with ulcerative colitis (UC), and 9 presumably healthy controls was assessed with a simple enzyme-linked immunosorbent assay. Simultaneously, the faecal excretion of autologous 111In-labelled granulocytes was measured. RESULTS: There was a strong correlation between the average daily excretion of calprotectin and that of the total 3-day excretion of 111In-labelled granulocytes (r = 0.87, P < 0.0001). Furthermore, the concentration of calprotectin, assessed in a small stool sample on day 1, also correlated well with the excretion 111In-labelled granulocytes (r = 0.80, P < 0.0001). CONCLUSION: The results suggest that faecal calprotectin reflects the granulocyte migration through the gut wall in patients with IBD and hence might serve as a simple, inexpensive alternative to the indium-111 technique.

Adult↗
PubMed2002

The role of esophagogastroduodenoscopy in the initial evaluation of childhood inflammatory bowel disease: a 7-year study.

OBJECTIVES: To assess the role of esophagogastroduodenoscopy in the evaluation of children with suspected inflammatory bowel disease. METHODS: All children with inflammatory bowel disease who underwent esophagogastroduodenoscopy during their initial evaluation at our institution during a 7-year period (December 1993 to November 2000) were included in the study. RESULTS: The study included 115 patients: 81 with Crohn disease (mean age, 11.34 years; 42 males) and 34 with ulcerative colitis (mean age, 11.79 years; 20 males). Abnormal findings on esophagogastroduodenoscopy were noted in 64% of patients with Crohn disease and 50% of children with ulcerative colitis; histologic abnormalities were found in 81.6% and 70.6% of the patients, respectively. Granulomas were found in the upper gastrointestinal tracts of 23 of 81 patients (28.4%), with the most common site being the gastric mucosa. Nine of these 23 patients had granulomas solely in the upper gastrointestinal tract. Additional unsuspected pathology noted included: candidiasis, hiatal hernia, Helicobacter pylori infection, and giardiasis. CONCLUSIONS: Endoscopic and histologic abnormalities were found in the upper gastrointestinal tracts of a significant number of children with inflammatory bowel disease. While the mechanism(s) underlying these abnormalities in patients with ulcerative colitis is unclear, the pathology can contribute to the patient's clinical condition. Pathology in the upper gastrointestinal tract should not exclude a diagnosis of ulcerative colitis. Granulomas, confirming the diagnosis of Crohn disease, were found in the upper gastrointestinal tracts of 28% of our patients with Crohn disease. In some cases, granulomas were found solely in the upper gastrointestinal tracts. Based on our data, esophagogastroduodenoscopy with biopsy should be performed in all pediatric patients with suspected inflammatory bowel disease.

Adolescent↗
PubMed1991

Involvement of oxygen-derived free radicals in the pathogenesis of chronic inflammatory bowel disease.

Ulcerative colitis and Crohn's disease are chronic inflammatory bowel diseases. The most widely prescribed drug for treatment of these diseases, sulfasalazine, has been shown to inhibit the activity of free radicals, as the active moiety of sulfasalazine, 5-aminosalicylic acid, is a radical scavenger. This effect of 5-aminosalicylic acid may be of clinical relevance, as a recent study has shown that 5-aminosalicylic acid reacts with oxygen-derived free radicals formed in the intestine in this disease. Reaction with free radicals does not, however, occur in patients with rheumatoid arthritis treated with the same agent. Furthermore, a significant correlation exists between the activity in the intestine of free radicals, as measured by the rate of lipid peroxidation, and the disease activity.

Colitis, Ulcerative↗
PubMed1997

Differences in risk of Crohn's disease in offspring of mothers and fathers with inflammatory bowel disease.

OBJECTIVE: To determine whether there are any unusual patterns of transmission of susceptibility to inflammatory bowel disease (IBD) within multiplex families. METHODS: Individuals with IBD were recruited for genome-wide screening of susceptibility genes. The extent of familial aggregation and blood relationships in multiplex families were determined by questionnaires given to participants followed up by confirmation of disease diagnosis by participants' physicians. RESULTS: Of 135 families identified in which both a parent and a child had IBD, 93 involved transmission of susceptibility to disease from mother to child versus 42 examples of transmission from father to child (p = 0.00001, exact two-tailed binomial test). This distortion in transmission on the basis of the sex of the parent was observed only among non-Jewish pairs with Crohn's disease (CD), in which, of 33 parent-child pairs with CD, disease susceptibility was transmitted from the mother 28 times (p = 0.00007). CONCLUSION: Susceptibility to CD in a subset of patients may involve a gene that is imprinted.

Child↗