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Objective: Osteoporosis and fractures are frequently encountered in patients with Crohn's disease. In order to prevent fractures, treatment with bone protecting drugs appears warranted early in the course of bone disease when bone loss is not yet prominent. We therefore aimed to demonstrate a beneficial effect on bone density of the bisphosphonate risedronate in osteopenic Crohn's disease patients., Methods: This double-blind, placebo-controlled randomised trial of risedronate with calcium and vitamin D supplementation was performed in osteopenic Crohn's disease patients. Patients were treated for 2 years with follow-up after 3 and after every 6 months. Disease characteristics and activity and bone turnover markers were assessed at all visits; dual x-ray absorptiometry was performed at baseline, 12 and 24 months; radiographs of the spine at baseline and 24 months., Results: Of 132 consenting patients, 131 were randomised (67 placebo and 64 risedronate). Patient characteristics were similar in both groups, although the risedronate group was slightly heavier (body mass index 24.3 vs 23.0 kg/m(2)). Bone mineral density at lumbar spine increased 0.04 g/cm(2) on average in the risedronate group versus 0.01 g/cm(2) in the placebo group (p=0.007). The mean increase in total hip bone mineral density was 0.03 versus 0.01 g/cm(2), respectively (p=0.071). Fracture prevalence and incidence were similar. Change of T-scores and concentrations of bone turnover markers were consistent with a beneficial effect of risedronate when compared with placebo. The effect of risedronate was primarily demonstrated in the first 12 months of treatment. No serious unexpected suspected adverse events were observed., Conclusions: A 24-month treatment course with risedronate 35 mg once weekly, concomitant with calcium and vitamin D supplementation, in osteopenic Crohn's disease patients improved bone density at lumbar spine. NTR 163 Dutch Trial Register., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Background: Patients with ulcerative colitis have an increased risk of developing colorectal cancer (CRC). The aim of this study is to assess the yield of surveillance colonoscopies in a tertiary referral cohort of ulcerative colitis patients and to identify different risk groups for dysplasia., Methods: A cohort of 293 patients (148 males, mean age 33.8 years at diagnosis) was built up at our center and started the surveillance program 8-12 years after start of symptoms. They underwent colonoscopies every one to three years. Endpoints were dysplasia or a (sub)total colectomy., Results: After a follow-up period of 10 years, the cumulative incidence of any dysplasia was 23.5%, and of CRC 4.0%. After 15 years these percentages were 33.3% and 6.8%. Patients with pancolitis (n = 178) had a significantly higher cumulative risk of dysplasia than patients with distal disease, HR 1.9 (95%CI 1.1-3.3). Patients who started surveillance at an older age are at increased risk for any dysplasia, HR 1.03 (95%CI 1.01-1.05)., Conclusions: This prospective surveillance study shows a high yield of dysplasia in ulcerative colitis patients. We recommend developing separate surveillance programs for different risk groups. In our opinion patients with distal colitis can follow the general population surveillance program.

Objective: Through genome-wide association scans and meta-analyses thereof, over 70 genetic loci (Crohn's disease (CD) single nucleotide polymorphisms (SNPs)) are significantly associated with CD. We aimed to investigate the influence of CD-SNPs and basic patient characteristics on CD clinical course, and develop statistical models to predict CD clinical course., Design: This retrospective study included 1528 patients with CD with more than 10 years of follow-up from eight European referral hospitals. CD outcomes of interest were ileal (L1), colonic (L2) and ileocolonic disease location (L3); stenosing (B2) or penetrating behaviour (B3); perianal disease; extraintestinal manifestations; and bowel resection. A complicated disease course was defined as stenosing or penetrating behaviour, perianal disease and/or bowel resection. Association between CD-SNPs or patient characteristics and specified outcomes was studied., Results: Several CD-SNPs and clinical characteristics were statistically associated with outcomes of interest. The NOD2 gene was the most important genetic factor, being an independent predictive factor for ileal location (p=2.02 × 10(-06), OR=1.90), stenosing (p=3.16 × 10(-06), OR=1.82) and penetrating (p=1.26 × 10(-02), OR=1.25) CD behaviours, and need for surgery (p=2.28 × e-05, OR=1.73), and as such was also the strongest factor associated with a complicated disease course (p=6.86 × 10(-06), OR=2.96). Immunomodulator (azathioprine/6-mercaptopurine and methotrexate) use within 3 years after diagnosis led to a reduction in bowel stenoses (p=1.48 × 10(-06), OR=0.35) and surgical rate (p=1.71 × 10(-07), OR=0.34). Association between each outcome and genetic scores, created using significant SNPs in the univariate analysis, revealed large differences in the probability of developing fistulising disease (IL23R, LOC441108, PRDM1, NOD2; p=9.64e-4, HR=1.43), need for surgery (IRGM, TNFSF15, C13ORF31, NOD2; p=7.12 × 10(-03), HR=1.35), and stenosing disease (NOD2, JAK2, ATG16L1; p=3.01 × 10(-02), HR=1.29) among patients with low and high score., Conclusions: This large multicentre cohort study has found several genetic and clinical factors influencing the clinical course of CD. NOD2 and early immunomodulator use are the clinically most meaningful predictors for its clinical course.

Background: Crohn's disease and ulcerative colitis have a complex genetic background. We assessed the risk for both the development and severity of the disease by combining information from genetic variants associated with inflammatory bowel disease (IBD)., Methods: We studied 2804 patients (1684 with Crohn's disease and 1120 with ulcerative colitis) and 1350 controls from seven university hospitals. Details of the phenotype were available for 1600 patients with Crohn's disease and for 800 with ulcerative colitis. Genetic association for disease susceptibility was tested for the nucleotide-binding and oligomerisation domain 2 gene (NOD2), the IBD5 locus, the Drosophila discs large homologue 5 and autophagy-related 16-like 1 genes (DLG5 and ATG16L1) and the interleukin 23 receptor gene (IL23R). Interaction analysis was performed for Crohn's disease using the most associated single nucleotide polymorphism (SNP) for each locus. Odds ratios were calculated in an ordinal regression analysis with the number of risk alleles as an independent variable to analyse disease development and severity., Results: Association with Crohn's disease was confirmed for NOD2, IBD5, DLG5, ATG16L1 and IL23R. Patients with Crohn's disease carry more risk alleles than controls (p = 3.85 x 10(-22)). Individuals carrying an increasing number of risk alleles have an increasing risk for Crohn's disease, consistent with an independent effects multiplicative model (trend analysis p = 4.25 x 10(-23)). Patients with Crohn's disease with a more severe disease course, operations or an age of onset below 40 years have more risk alleles compared to non-stricturing, non-penetrating behaviour (p = 0.0008), no operations (p = 0.02) or age of onset above 40 years (p = 0.028)., Conclusion: Crohn's disease is a multigenic disorder. An increase in the number of risk alleles is associated with an increased risk for the development of Crohn's disease and with a more severe disease course. Combining information from the known common risk polymorphisms may enable clinicians to predict the course of Crohn's disease.

Background: Recurrence of disease after surgically induced remission constitutes a major and largely unpredictable problem in Crohn's disease (CD). Matrix metalloproteinases (MMP) and the tissue inhibitors of metalloproteinases (TIMP) are involved in the (etio)pathogenesis of CD and may thereby also affect postsurgical outcome. We studied the predictive value of 1) allelic composition at MMP, TIMP, and TNF-alpha single nucleotide polymorphism loci, and 2) MMP and TIMP intestinal protein levels relative to important clinical variables for recurrence of CD after resection of diseased bowel., Methods: From 87 CD patients with a full medical record, surgically resected tissue was homogenized and analyzed for single nucleotide polymorphism (SNP) genotype and MMP-TIMP protein levels. The prognostic value of these parameters was determined using the uni- and multivariate Cox proportional hazards analyses., Results: The T allele at TIMP-1 SNP +372 T/C was found to be associated with an increased risk for surgical recurrence. Higher levels of TIMP-1, TIMP-2, and MMP-9 in noninflamed CD tissue, but not in inflamed tissue, and negative smoking status independently protected against diagnostic and/or surgical recurrence., Conclusions: The TIMP-1 SNP +372 T allele with an increased risk of recurrence is in line with our previous results demonstrating increased CD susceptibility and low TIMP-1 protein expression associated with this allele. High TIMP and MMP-9 levels in noninflamed tissue are predictive of a favorable disease recurrence in CD. The contribution of MMP-9 and TIMPs to disease recurrence appears not to be mediated by smoking status, since no correlation with this parameter could be demonstrated.

Introduction: The efficacy of the immune response upon vaccination in patients treated with anti-tumor necrosis factor-alpha (anti-TNF) with or without methotrexate is the subject of debate. We studied the effect of immunosuppressive treatment, including anti-TNF and methotrexate, on the response to pneumococcal polysaccharide (PPS) vaccine., Methods: Fifty-two patients treated with immunosuppressives including anti-TNF (anti-TNF group), 41 patients given a similar immunosuppressive regimen without anti-TNF (no anti-TNF group), and 18 healthy controls were vaccinated with a 23 valent PPS vaccine. The percentage of patients treated with methotrexate in the anti-TNF and no anti-TNF group was 65% and 76%, respectively. Antibodies against four of the vaccine antigens (PPS 6B, 9V, 19F and 23F) were measured before and 4 weeks after vaccination. The primary outcome was the response rate, defined as the percentage with a postvaccination titer 0.35 microg/ml in combination with at least a twofold increase in antibody titer. The protection rate was defined as a postvaccination titer > or = 0.35 microg/ml., Results: The use of methotrexate was the strongest predictor of impaired vaccination outcome. Anti-TNF caused an additional immunosuppressive effect in the presence of methotrexate, leading to the lowest response percentages in patients using the combination of these two drugs. The underlying disease, other immunosuppressives such as prednisone or type of anti-TNF agent used did not influence vaccination outcome., Conclusions: Patients who were treated with the combination of methotrexate and anti-TNF demonstrated a significantly impaired immune response following pneumococcal polysaccharide vaccination as compared to patients treated with either methotrexate or anti-TNF only or immunosuppressives excluding these two compounds.

Objectives: The effect of anti-tumour necrosis factor (TNF) therapy on the antibody responses to vaccines is the subject of ongoing debate. Therefore, we investigated the effect of the three currently available anti-TNF agents on influenza vaccination outcomes in a patient population with long-standing disease., Methods: In a prospective cohort study, we assessed the antibody response upon influenza vaccination in 112 patients with long-standing autoimmune disease treated with immunosuppressive medication either with anti-TNF (etanercept, adalimumab or infliximab; n = 64) or without anti-TNF (n = 48) and a control group of 18 healthy individuals. Antibody responses were determined by haemagglutination inhibition assay, before and 4 weeks after vaccination., Results: The proportion of individuals with a protective titre (>or=40) after vaccination was large (80-94%) and did not significantly differ between the three groups. Post-vaccination geometric mean antibody titres against influenza (A/H3N2 and B) were significantly lower in the 64 patients treated with anti-TNF compared with the 48 patients not receiving anti-TNF, and the healthy controls., Conclusions: The antibody response to influenza vaccination in patients treated with anti-TNF is only modestly impaired. The proportion of patients that achieves a protective titre is not significantly diminished by the use of TNF blocking therapies.

Background and Objective: Matrix metalloproteinases are associated with matrix turnover in both physiological and pathological conditions. We postulate an association between aberrant matrix metalloproteinases proteolytic activity and the intestinal tissue destruction, seen in patients with Crohn's disease and/or ulcerative colitis., Materials and Methods: Surgically resected inflamed and non-inflamed ileum and colon with/without extensive fibrosis from 122 Crohn's disease, 20 ulcerative colitis and 62 control patients were homogenized. Protein levels of matrix metalloproteinases and tissue inhibitor of metalloproteinases were measured by enzyme-linked immunosorbent assays (ELISA), while matrix metalloproteinases and myeloperoxidase activity were measured by specific activity assays., Results: Expression of total levels of matrix metalloproteinases-1, -2, -3 and -9 relative to tissue inhibitor of metalloproteinases-1 and -2 was increased in inflamed inflammatory bowel disease compared to non-inflamed inflammatory bowel disease and control intestinal mucosa. Also, net matrix metalloproteinases-1, -2, -3 and -9 activity in inflamed inflammatory bowel disease was increased, with similar expression profiles in Crohn's disease and ulcerative colitis. Within inflamed inflammatory bowel disease, a close correlation of matrix metalloproteinases with myeloperoxidase was observed. The expression of matrix metalloproteinases and tissue inhibitor of metalloproteinases was similar in inflamed Crohn's disease tissue with or without extensive fibrosis and not related to fistulizing disease., Conclusions: We have shown increased net matrix metalloproteinases activity in intestinal inflammatory bowel disease tissue, likely to contribute to the tissue damage and remodelling seen in inflammatory bowel disease.

Aim: To study the (functional) relevance of single nucleotide polymorphisms (SNPs) in genes encoding matrix metalloproteinases (MMP)-1, -2, -3, -9, tissue inhibitors of metalloproteinases (TIMP)-1, -2 and tumor necrosis factor (TNF)-alpha in the etiopathogenesis of inflammatory bowel diseases (IBD), that may enhance susceptibility and/or disease severity., Methods: Genomic DNA from 134 Crohn' s disease (CD), 111 ulcerative colitis (UC) patients and 248 control subjects was isolated from resected intestinal tissue or blood. Allelic composition at SNP loci was determined by PCR-RFLP or tetra primer ARMS PCR., Results: The TIMP-1 genotype TT in women and T in men at SNP +372 T/C was found to increase CD susceptibility (39% vs 23.8%, P = 0.018 and 67.9% vs 51.6%, P = 0.055, respectively), while women with this genotype were less prone to development of fistulae during follow-up (41.4% vs 68.3%, P = 0.025). Male IBD or CD patients carrying the TIMP-1 +372 T-allele expressed lower levels of TIMP-1 in surgically resected macroscopically inflamed tissue (0.065 < P < 0.01). The 5T5T genotype at MMP-3 SNP -1613 5T/6T increased the chance of stenotic complications in CD during follow-up (91.2% vs 71.8%, P = 0.022) but seemed to protect against colonic involvement of this disease at first endoscopic/radiologic examination (35.3% vs 59.5%, P = 0.017)., Conclusion: Allelic composition at the examined SNPs in genes coding for TIMP-1 and MMP-3 affect CD susceptibility and/or phenotype, i.e., fistulizing disease, stricture pathogenesis and first disease localisation. These findings reinforce the important role of these proteins in IBD.

Background: Matrix metalloproteinases (MMPs) are actively involved in the pathogenesis of Crohn's disease (CD). We assessed the effect of the anti-tumor necrosis factor-alpha (TNF-alpha) monoclonal antibody infliximab on the in vitro and in vivo expression of MMP-2 and MMP-9 in CD., Methods: Infliximab-treated fistulizing (n = 10) or active disease (n = 7) CD patients, from an in-house study, and fistulizing CD patients (n = 42) and active CD patients (n = 24) from 2 placebo controlled studies were evaluated for serum MMP levels and clinical response. Biopsies were evaluated immunohistochemically for the MMPs. Whole blood cultures stimulated with lipopolysaccharide (LPS)/infliximab were evaluated for MMP mRNA and protein levels., Results: Serum MMP-2 levels in CD patients increased during follow-up, similarly in responders and nonresponders, by infliximab. Immunohistochemistry showed no clear MMP-2 change in biopsies. Serum MMP-9 levels, however, showed a consistent pattern of decrease in most CD patients, particularly in those responding, and MMP-9-positive polymorphonuclear leukocytes in biopsies also decreased by infliximab. LPS stimulation of whole blood increased the MMP-9 levels in plasma significantly in CD patients and controls, but infliximab had no effect on the secretion. Long-term LPS stimulation raised leukocyte MMP-9 mRNA levels 16-fold and infliximab inhibited this induction by 80%., Conclusions: Infliximab treatment increases MMP-2 and decreases MMP-9 in serum of patients with CD, the latter also in the intestine, which extends and confirms our previous ex vivo explants observations. However, these changes were not strictly associated with the response to treatment. The enhanced leukocyte MMP-9 expression in CD seems to be regulated by TNF-alpha.

Background: Previous studies have shown an upregulation of matrix metalloproteinases (MMPs) in intestinal tissue of patients with inflammatory bowel disease (IBD) and significant clinical improvement after administration of the anti-TNF-a antibody infliximab. The aims of our study were to determine expression and secretion of MMP-1, -2, -3, -9, and their inhibitors TIMP-1, -2 by IBD versus control intestinal mucosa ex vivo and to assess the regulatory capacity by infliximab of the proteolytic phenotype., Methods: Intestinal mucosal explants from 20 IBD and 15 control patients were cultured with or without infliximab and/or the T-cell activator pokeweed mitogen (PWM). Explants and culture supernatants were analyzed for MMPs, TIMPs, and TNF-alpha protein, activity and/or mRNA levels. All patients were genotyped for functional TNF-alpha, MMP, and TIMP single nucleotide polymorphism (SNP) loci., Results: Expression of MMP and TIMP protein/activity in basal medium was higher in IBD versus control explants. Dependent on genotype at SNP loci, infliximab downregulated MMP-1, -3, and -9 relative to TIMP-1 and -2 and also decreased MMP-1 and -3 activities, while PWM enhanced these levels, partly counteracted again by infliximab. The expression of MMP-2 relative to TIMP did not change by treatment with infliximab and/or PWM., Conclusions: The high expression of MMPs in patients with IBD suggests a role for these proteinases in the pathogenesis of this disease. Infliximab seems to induce a genotype-associated matrix protective phenotype, which may contribute to the observed therapeutic efficacy of this drug in IBD, particularly at the mucosal surface.

Infliximab is an accepted induction and maintenance treatment for patients with Crohn's disease. The effectiveness of infliximab has been demonstrated for both active luminal disease and for enterocutaneous fistulisation. In addition, infliximab can be administered for extraintestinal symptoms of Crohn's disease, such as pyoderma gangrenosum, uveitis and arthropathy. Maintenance treatment with infliximab is effective and is regarded as safe as long as the necessary safety measures are heeded. Infusion reactions occur in 3 to 17% of the patients and are associated with the formation of antibodies to infliximab. A reduction in infusion reactions is possible by the concurrent administration of steroids and the use of immunosuppressants (azathioprine, 6-mercaptopurine, methotrexate). Furthermore, immunosuppressants increase the duration of the response to infliximab. For these reasons, the concomitant use of immunosuppressants with infliximab is recommended. Infections and most specifically tuberculosis need to be ruled out before infliximab is administered. Up to now, there are no indications for a connection between an increased risk for malignancies and treatment with infliximab.

Introduction: Crohn's disease is associated with a host of factors potentially increasing the risk for osteoporosis and fractures. The aim of our study was to identify the most predictive factors for skeletal pathology in this patients., Methods: Using a cross-sectional study design, 146 randomly selected patients with Crohn's disease of variable disease activity who were given standard therapy to control disease activity, including glucocorticoids, and who attended the outpatient clinic of the Gastroenterology Unit on regular follow-up visits were studied. Bone mineral density (BMD) measurements and lateral X-rays of the spine were performed, and biochemical parameters of bone turnover, gonadal hormones and C-reactive protein (CRP) as markers of disease activity were measured in all patients., Results: There were 61 men and 85 women, with a mean age of 43 years and mean disease duration of 20 years. The majority of patients (86%) had been treated with glucocorticoids at some stage during their illness at a median dose of 7.5 mg/day, 43% were currently using these agents and 66% had undergone an intestinal resection. Twenty-one percent of patients had below-normal 25-hydroxy vitamin D levels. Osteoporosis was documented in 26% of patients, predominantly at the femoral neck, but also at the lumbar spine or at both sites; osteopenia was documented in 45% of patients. Prevalence of vertebral and non-vertebral fractures was, respectively, 6% and 12%. Ileum resection was the most predictive factor for osteoporosis: RR 3.84 (CI 1.24-9.77, p=0.018), followed by age: RR 1.05 (CI 1.02-1.08, p<0.001) and current or past glucocorticoid use: RR 1.94 (CI 0.92-4.10, p=0.08)., Conclusion: Our data suggest that in patients with Crohn's disease, the risk of osteoporosis is best predicted by a history of ileum resection.

Patients with Crohn's disease are at increased risk of developing disturbances in bone and mineral metabolism because of several factors, including the cytokine-mediated nature of the inflammatory bowel disease, the intestinal malabsorption resulting from disease activity or from extensive intestinal resection and the use of glucucorticoids to control disease activity. Inability to achieve peak bone mass when the disease starts in childhood, malnutrition, immobilization, low BMI, smoking and hypogonadism may also play a contributing role in the pathogenesis of bone loss. The relationship between long-term use of glucocorticoids for any disease indication and increased risk for osteoporosis and fractures is well established. However, the relationship between Crohn's disease and ulcerative colitis and bone loss remains controversial. Depending on the population studied the prevalence of osteoporosis has thus been variably reported to range from 12 to 42% in patients with inflammatory bowel disease (IBD). In IBD most studies demonstrate a negative correlation between bone mineral density (BMD) and glucocorticoid use, but not all authors agree on the relationship between long-term glucocorticoid use and continuing bone loss. Whereas prospective studies do suggest sustained bone loss at both trabecular and cortical sites in long-term glucocorticoid users with inflammatory bowel disease, a decrease in bone mass is also observed in patients with active Crohn's disease not using glucocorticoids, and bone loss is not universally observed in patients with Crohn's disease using orally or rectally administered glucocorticoids. Data on vertebral fractures are scarce and there is no agreement about the risk of non-vertebral fractures in patients with Crohn's disease, although it has been suggested that non-vertebral fracture risk may be increased by up to 60% in patients with IBD. A recent publication reports an increased risk of hip fractures in Crohn's disease related to current and cumulative corticosteroid use and use of opiates, although these fractures could not be related to the severity of osteoporosis. The issue of the magnitude of the problem of osteoporosis has become particularly relevant in Crohn's disease, since the ability of therapeutic interventions to beneficially influence skeletal morbidity has been clearly established in patients with osteoporosis, whether post-menopausal women, men or glucocorticoid users. The main question that arises is whether all patients with Crohn's disease should be treated with bone protective agents on the assumption that they all have the potential to develop osteoporosis or whether the use of these agents should be restricted to patients clearly at risk of osteoporosis and fractures, providing these can be identified. We recommend, based on the available literature and our own experience, that all patients with Crohn's disease should be screened for osteoporosis by means of a bone mineral density measurement in addition to full correction of any potential calcium and vitamin D deficiency, to allow timely therapeutic intervention of the patient at risk while sparing the vast majority unnecessary medical treatment.

Background/aims: Matrix metalloproteinases are major contributors in the breakdown and reconstitution of basement membranes and extracellular matrix in pathophysiological processes. We assessed the expression of matrix metalloproteinases-2 and -9 in intestinal tissue of patients with inflammatory bowel disease., Patients/methods: Resected tissue specimens from patients with Crohn's disease or ulcerative colitis and control tissue from patients with a colorectal carcinoma were used for enzyme-linked immunosorbent assay, zymography, activity assay, reverse transcription polymerase chain reaction and immunohistochemistry to evaluate the expression of these matrix metalloproteinases., Results: Matrix metalloproteinase-2 and more strongly matrix metalloproteinase-9 protein and mRNA were markedly increased in inflammatory bowel disease tissues, with the highest levels in severely inflamed tissues. Immunohistochemistry showed that matrix metalloproteinase-2 was present in the extracellular matrix of the submucosa, with a lower but more generalised expression in the severely inflamed regions. Matrix metalloproteinase-9 was most prominent in polymorphonuclear leukocytes and was increased, also in activity, in all inflammatory bowel disease tissues. An increased matrix metalloproteinase-9 expression in the extracellular matrix was observed in relation to the severity of inflammation., Conclusions: Matrix metalloproteinases-2 and -9 are enhanced in the intestinal tissue and seem to be actively involved in the inflammatory and remodelling processes in inflammatory bowel disease, without major differences between CD and UC.

Background: When cases of Crohn's disease (CD) are described as "fistulizing," distinctions are often not drawn between perianal and intestinal fistulization. The question, therefore, remains open as to whether or not there is truly an association between perianal fistulization and intraabdominal intestinal fistulization in CD., Aims: We have sought to determine the association between perianal and intestinal fistulization by analyzing the cases of CD recorded in databases from six international centers., Patients: Six databases provided information on 5491 cases of CD in the United States, France, Italy, and The Netherlands. Of these cases, 1686 had isolated ileal disease and 1655 had Crohn's colitis., Methods: An association between perianal disease and internal fistulae was sought by calculating relative risks for the chance of internal fistulae among patients with perianal fistulae relative to those without. Statistical significance was calculated by the Mantel-Haenszel procedure, stratifying on the separate centers. All statistical tests and estimates were implemented using SAS for the PC., Results: Among the 1686 cases with isolated ileal disease, the evidence of an association between perianal disease and internal fistulization was not consistent across centers, with relative risks ranging from 0.8 to 2.2. For patients with Crohn's colitis (n = 1655), the association was much stronger and more consistent, with an estimated common relative risk of 3.4, 95% confidence interval (2.6-4.6, p < 0.0001)., Conclusions: We have found a statistically significant association between perianal CD and intestinal fistulization, much stronger and more consistent in cases of Crohn's colitis than in cases limited to the small bowel.

Background: Gastrin releasing peptide (GRP) and neuromedin B are bombesin (BN)-like peptides involved in regulating motility and inflammation in the gastrointestinal tract, which may be useful in treating inflammatory bowel disease (IBD). Three bombesin-like peptide receptors have been reported, but no studies have investigated their localisation in normal and inflamed human intestine., Aim: To localise and characterise BN receptors in normal intestine and to see whether this is modified in IBD., Methods: Full thickness intestinal tissue samples were collected from 13 patients with Crohn's disease (CD), 11 with ulcerative colitis (UC), and 19 controls. BN receptor expression was characterised and quantified with storage phosphor autoradiography using BN, GRP, neuromedin B, and the synthetic analogue BN(6-14) as ligands., Results: Only BN receptor type 2 (high affinity for GRP) was present in intestinal tissue. Minimal BN binding was detected in the mucosa. In normal colonic smooth muscle, mean BN binding was 336 fmol/g tissue in longitudinal muscle, including the myenteric plexus, and 71 fmol/g in circular muscle. In CD, colonic smooth muscle BN binding was significantly decreased (longitudinal muscle, 106; circular muscle, 19 fmol/g), in contrast to UC (377 and 62 fmol/g, respectively). In CD, a small (not significant) decrease was seen in ileal muscle compared with controls (111 v 169 and 18 v 32 fmol/g tissue for longitudinal and circular muscle, respectively)., Conclusions: Only the GRP receptor is expressed in human intestine; expression is highest in longitudinal muscle and myenteric plexus of the colon. Expression is decreased in inflamed and non-inflamed colon of CD, but not in UC.

Mucosal tissue damage and dysfunction in chronic inflammatory bowel disease (IBD) are partly caused by an enduring exposure to excessive amounts of reactive oxygen metabolites (ROMs). Although the three human isoforms of superoxide dismutase (SOD), copper/zinc (Cu/Zn)-SOD, manganese (Mn)-SOD, and extracellular (EC)-SOD, form the primary endogenous defence against ROMs, their expression levels and cellular localization in IBD mucosa are largely unknown. The present study used enzyme-linked immunosorbent assays (ELISAs), spectrophotometric activity assays, and immunohistochemistry to evaluate the protein concentration, enzymatic activity, and distribution of Cu/Zn-, Mn-, and EC-SOD in paired inflamed and non-inflamed mucosal resection specimens of patients with Crohn's disease (CD) or ulcerative colitis (UC) and compared these with the levels obtained in normal control mucosa. Gut mucosal SOD isoform expression was found to be differentially affected in IBD patients, without major differences between CD and UC. A marked step-wise increase in Mn-SOD protein levels was observed in non-inflamed and inflamed IBD mucosae, whereas the Cu/Zn-SOD content decreased with inflammation. EC-SOD was only found in low amounts, which tended to be decreased in IBD patients. Immunohistochemical evaluation confirmed these observations. Mn-SOD and Cu/Zn-SOD were both predominantly expressed in intestinal epithelial cells and the percentage of epithelial cells positive for Mn-SOD was considerably increased in IBD, whereas epithelial Cu/Zn-SOD expression was much less affected. Within the lamina propria, SOD expression was much lower. Cu/Zn-SOD and Mn-SOD were prominently present in neutrophils and macrophages, and EC-SOD was mainly localized in small vessels, stromal cells, and neutrophils. The percentage of lamina propria cells positive for Cu/Zn-, Mn-, or EC-SOD was not affected by inflammation. Enzyme activity measurements showed consistent results for Cu/Zn-SOD and EC-SOD, but the activity of Mn-SOD did not concordantly increase with the immunological assessments, which may indicate that a proportion of the Mn-SOD in IBD is present in an enzymatically inactive form. This study reveals remarkable changes in the expression levels of the three SOD isoforms in IBD, particularly in the epithelium. Disturbances in the carefully orchestrated mucosal antioxidant cascade may contribute to the induction and perpetuation of intestinal inflammation in IBD, and may have important implications for the development of antioxidant treatment of IBD patients., (Copyright 2003 John Wiley & Sons, Ltd.)

Intestinal mucosal damage in the inflammatory bowel diseases (IBD) Crohn's disease (CD) and ulcerative colitis (UC) involves reactive oxygen metabolites (ROMs). ROMs are neutralized by endogenous antioxidant enzymes in a carefully balanced two-step pathway. Superoxide dismutases (SODs) convert superoxide anion to hydrogen peroxide (H(2)O(2)), which is subsequently neutralized to water by catalase (CAT) or glutathione peroxidase (GPO). Remarkably changed expression levels of the three isoforms of SOD in paired non-inflamed and inflamed mucosae from CD and UC patients have been previously reported in comparison to normal control mucosa. Most notable was the strong up-regulation of Mn-SOD in inflamed epithelium. It was hypothesized that in order to provide optimal protection against ROM-mediated damage, these changes should be coordinately counterbalanced by an increased H(2)O(2)-neutralizing capacity. Therefore, the same tissue samples were used to assess the levels, activities, and/or localization of the most prominent mucosal H(2)O(2)-related antioxidants CAT, GPO, glutathione (GSH), myeloperoxidase (MPO), and metallothionein (MT). Quantitative measurements showed that in both CD and UC patients, intestinal inflammation was associated with increased activities of CAT, GPO, and MPO, whereas the mucosal GSH content was unaffected and the concentration of MT was decreased. Despite this overall increase in mucosal H(2)O(2)-metabolizing enzyme capacity, immunohistochemical analysis revealed a differentially disturbed antioxidant balance in IBD epithelium and lamina propria. In the lamina propria, the risk of direct H(2)O(2)-mediated damage seemed to be restrained by the increasing numbers of CAT- and MPO-positive monocytes/macrophages and neutrophils that infiltrated the inflamed areas. On the other hand, MPO overexpression might increase the lamina propria levels of hypochlorous acid, a stable ROM with multiple pro-inflammatory effects. In the epithelium, the number of cells that expressed CAT remained unchanged during inflammation and GPO was found in only a very low and constant number of epithelial cells. In addition, the inflamed epithelium displayed decreased expression of the hydroxyl radical (OH(*)) scavenger MT. In view of the high epithelial SOD levels in inflamed IBD epithelium, it is speculated that the efficient removal of excess H(2)O(2) is hampered in these cells, thereby increasing not only the risk of detrimental effects of H(2)O(2) directly, but also those of its extremely reactive derivatives such as OH(*). Taken together, the results suggest an imbalanced and inefficient endogenous antioxidant response in the intestinal mucosa of IBD patients, which may contribute to both the pathogenesis and the perpetuation of the inflammatory processes., (Copyright 2003 John Wiley & Sons, Ltd.)

Background: Growth impairment during childhood and adolescence is a common problem faced by patients with an early onset of Crohn's disease., Aims: To establish how the final adult height is affected in patients with early onset of symptoms of Crohn's disease., Methods: Information on height, parental height, and disease history was obtained from 135 patients with Crohn's disease who reached their adult height (men 22-40 years, women 18-40 years) using a questionnaire and by outpatient measurement of height where possible. Subsequently, adult heights were expressed as standard deviation scores, with and without correction for the expected target height., Results: Patients with onset of disease before puberty were shorter compared with patients with onset in adulthood (p<0.01). This difference was not statistically significant when adult heights were corrected for parental height. Also, height standard deviation scores for those patients with onset of disease before puberty were significantly lower than those with onset of disease during puberty (p<0.05) but after correction for parental height the difference was not significant. The site of disease had no influence on adult height. Patients who had used corticosteroids during puberty were significantly shorter than patients who had not (p=0.005). This was also true when corrected for target height (p=0.007)., Conclusions: Although there was a trend indicating a deficit in adult height in patients with an early onset of Crohn's disease, once adjustment was made for parental height, this difference was not significant. Use of corticosteroids in puberty resulted in lower adult height.

Background: Infusion of anti-tumour necrosis factor-alpha appears to be highly effective in patients with Crohn's disease., Aim: To assess the effect of infliximab on the quality of life in patients with active or fistulizing disease, as measured by the inflammatory bowel disease questionnaire, and to examine the impact on its four dimensions., Methods: An observational study was conducted in 65 patients. An infusion of 5 mg/kg infliximab was given at week 0 in patients with active disease and at week 0, 2 and 6 in fistulizing disease. Changes from baseline in the total and dimensional inflammatory bowel disease questionnaire scores were calculated and compared between the patient groups. Potential predictors of change in the quality of life were identified., Results: In the active disease group, at week 4, the mean total and dimensional inflammatory bowel disease questionnaire scores improved compared to baseline (P < 0.001). In the fistulizing group, at week 6, all scores changed from baseline (P < 0.05). Improvement in the total inflammatory bowel disease questionnaire score correlated well with the improvement of the Crohn's disease activity index. Systemic and social scores improved more than bowel and emotional scores. Inflammatory Crohn's disease and a young age at diagnosis were predictors for a better response to infliximab therapy., Conclusions: Infliximab therapy improves all dimensions of the quality of life in patients with Crohn's disease.

Background: The association between ulcerative colitis (UC), Crohn disease (CD) and colorectal cancer (CRC) has been confirmed in several studies. The aim of this study was critical analysis of the relation between IBD and malignancy., Methods: Review of the literature., Results: In UC, the extent of the disease, its duration and start at a young age are risk factors for the development of CRC. Primary sclerosing cholangitis and colonic strictures are additional risk factors for development of CRC. The relation between azathioprine or 6-MP and the development of lymphomas is a subject of debate. The administration of anti-TNF-alpha has produced some concern about the development of lymphomas in CD. However, at present there is no evidence of lymphomas caused by anti-TNF-alpha in CD. On the contrary, some drugs seem to have a preventive effect on CRC development in UC. 5-aminosalicylic acid in particular and to a lesser extent sulphasalazine have prevented the development of CRC significantly in retrospective studies. In CD, there is no strong relationship between the disease and the development of CRC or other malignancies. Only the development of small-bowel carcinoma is reported with a much higher frequency., Conclusions: There is a correlation with UC and the development of CRC. For CD, this correlation is less firmly established. There is a possible, but not proven, relation between AZA/6-MP use and the development of lymphoma in IBD. There is also a probable relationship between CD and the development of small-bowel carcinoma. In some retrospective studies, the use of 5-aminosalicylic or sulphasalazine has been shown to prevent the development of CRC in UC.

Background: Functional impairments are frequently observed in patients with an ileoanal pouch. Meal ingestion increases pouch tone and motility. Little is known, however, about the influence of meal-stimulated pouch characteristics on pouch function. The aim was to characterize basal and postprandial pouch motor and sensory characteristics in relation to clinical pouch function in patients with an ileoanal pouch., Methods: Nineteen patients with an ileoanal pouch, without faecal incontinence but with either a high stool frequency (n = 8) or an adequate stool frequency (n = 11), underwent pressure distension of the pouch, by which pouch compliance and sensitivity characteristics were assessed using an electronic barostat. A set pressure procedure was performed to assess the influence of a meal on pouch tone and motility., Results: Mean(s.d.) compliance was 10(6) and 11(4) ml/mmHg in the groups with poor and adequate pouch function respectively (P not significant). Mean(s.d.) visual analogue scale scores (0-10 cm) for urge at the highest pressure of 28 mmHg were 2.3(1.0) versus 2.3(2.4) cm respectively (P not significant); those for pain were 0.8(1.0) versus 0.5(0.7) (P not significant). Postprandially mean(s.d.) pouch volume decreased by 70(24) per cent in the group with poor pouch function and 29(25) per cent in the group with adequate pouch function (P < 0.01). The frequency and amplitude of phasic pouch contractions increased significantly postprandially, but no differences in motility characteristics were observed between the two groups., Conclusion: In patients with uniform pouch design and follow-up after pouch construction, pouch compliance and sensitivity were no different between patients with normal and high stool frequency; however, postprandial pouch tone was increased significantly in patients with a high stool frequency.

Crohn's disease in the proximal region of the digestive tract is uncommon. Better diagnostically procedures and more careful histologic examination has led to a higher detection of proximal Crohn's disease. The diagnosis is based on symptoms, endoscopy with serial sections, or double contrast radiography. The most common histologic finding for this diagnosis are granulomas in the mucosa in Helicobacter pylori-negative patients, but the granulomas are not always frequently detected. Endoscopic lesions in the proximal regions look like the lesions that could be found in the distal regions. Notching in the duodenal folds could be a strong indication for Crohn's desease. Radiological lesions are not always characteristic, but should be used in combination with endoscopy. Stenosis is an important complication, but fistula formation and pseudodiverticular formation is possible. There is no uniform medical therapy, but the regular anti-inflammatory management for Crohn's disease is most often used. Sometimes surgery is needed.

Objective: The aim of this study was to analyze the clinical and epidemiological differences between women and men affected by Crohn's disease., Methods: The clinical course of 275 female Crohn's disease patients was compared with that of 266 male patients., Results: Mean age at onset of symptoms and at diagnosis was 25.7 yr versus 27.7 yr and 28.8 yr versus 30.7 yr in women and men, respectively. Mean lag-time between onset of symptoms and establishment of the diagnosis were similar in both groups, without differences in presenting symptoms and initial localization of lesions. In women, however, some extraintestinal manifestations of Crohn's disease were found to occur more often. The percentage of patients who underwent an abdominal operation was quite similar in both groups (81% vs 77%). Mean lag-time between onset of symptoms and first bowel resection was not different. However, the lag-time between bowel resection and recurrence of disease was significantly shorter in women than in men (respectively, 4.8 yr vs 6.5 yr, p = 0.04), particularly regarding primary ileocecal resections. Overall, ileocecal resections were significantly more frequently performed in female than male patients (44% and 32%, respectively, p = 0.004). Female patients were also found to have significantly more often relatives in the first or second degree affected by Crohn's disease than male patients (15% vs 8.3%, p = 0.02)., Conclusions: Extraintestinal manifestations occur more often in female Crohn's disease patients than in male patients. Furthermore, an ileocecal resection, which is accompanied by an earlier recurrence, is more often performed in female than in male patients. Female patients have more often relatives with the same disease.

The aim of this study was to compare pouch and rectal sensory and motor characteristics and to assess the influence of a meal on pouch tone and motility. Fifteen patients with an ileoanal J-pouch, with adequate pouch function and 12 healthy controls were studied. Visceral compliance was assessed using an electronic barostat by a pressure distension procedure, during which also sensitivity was scored by visual analog scales (VAS). The response to a meal was assessed during set pressure. Pouch and rectal compliance were not significantly different (9.3+/-0.7 vs 10.6+/-1.1 ml/mm Hg). VAS score for urge at 28 mm Hg was reduced in patients: 2.4+/-0.5 cm vs 4.7+/-0.9 cm in controls (P < 0.05). The postprandial decrease in intra-bag volume was more pronounced in patients (44+/-11%) than in controls (9+/-6%, P < 0.01). Postprandial phasic contractions were also more pronounced in patients. In conclusion, compliance is not significantly different between ileoanal pouch and rectum; differences in sensitivity reach significance only at high pressure. Significant differences were especially observed in the postprandial state with an increase in tone and frequency of phasic contractions in pouch patients.

The introduction of novel anti-tumor necrosis factor (TNF) agents has not only led to impressive new therapeutic opportunities but also resulted in uncertainty regarding their optimal use and possible side effects. Guidelines are presented here for the use of anti-TNF agents in gastrointestinal disorders. Experts were chosen from different European countries by an algorithm to avoid bias. An expert consensus on guidelines was established using a two-stage procedure of systematic Medline and abstract search for evidence and a qualifying meeting to derive recommendations. Detailed guidelines were developed for the use and the future clinical development of anti-TNF agents in inflammatory bowel disease. Grading of available evidence and grading of recommendations were performed according to AHCPR guidelines. At present infliximab is the only registered agent for Crohn's disease. Infliximab should be always used at a dose of 5 mg/kg. The guidelines define the indications both in refractory and in fistulating disease for the readministration and before surgery. Guidelines for safety and for concomitant treatments are given. Prospects, potential clinical use, and future directions for the clinical development of other anti-TNF agents are detailed. Clinical use of anti-TNF agents will be influenced by a large number of clinical trials being concluded in 2001 and 2002. It is likely that anti-TNF therapies will become an important long-term therapy for a proportion of patients with Crohn's disease. Biological agents will be followed by smaller and more stable, orally available compounds. These guidelines will be succeeded by a formal public consensus in 2002/2003.

Background/aims: The purpose of this study is to determine the effectiveness of extensive nonsurgical management of patients with clinically active Crohn's disease of the terminal ileum and to identify parameters that could predict failure of this nonsurgical approach., Methods: All consecutive patients hospitalized for the first time because of active Crohn's disease of the terminal ileum between 1985 and 1994 were included. Two groups of patients were defined. Patients who responded favorably to the extensive treatment protocol (group I), and patients in whom an ileocolic resection had been performed (group II). Treatment and patient characteristics were related to outcome., Results: Twenty-nine (38%) of the 76 patients were treated successfully by nonsurgical management (group I) and did not have surgery until the end of follow-up (mean 8.0 years, range 3-12 years). In total, 47 patients (62%) had ileocolic resection (group II). Logistic regression analysis revealed that a longer time between onset and exacerbation of this disease, the presence of stenosis and extraintestinal manifestations were independent predictors of failure of nonsurgical treatment., Conclusion: Prolonged medical treatment is effective in only one third of the clinically admitted patients. It should be applied with caution particularly in patients exhibiting stenosis, extraintestinal manifestations or a known history of Crohn's disease of more than 5 years.

Objective: To study the specificity of the peripheral blood mononuclear cell (PBMC) response to peptides derived from human cartilage glycoprotein-39 (HC gp-39) in patients with rheumatoid arthritis (RA) and the correlation between this response and disease activity., Methods: RA patients, patients with systemic lupus erythematosus (SLE), inflammatory bowel disease (IBD) or osteoarthritis (OA) and healthy controls were studied. All individuals were typed for HLA-DRB1 and their disease activity score was documented. Proliferation of PBMC was measured following incubation with five different HC gp-39-derived peptides, selected by the use of a DR4 (DRB1*0401) binding motif., Results: A proliferative response to one of the five peptides (peptide 259-271 at 10 microg/ml) was more often observed in RA patients than in healthy controls (P=0.001). RA patients who expressed DRB1*0401 more often showed a response against this peptide than RA patients who did not express this RA-associated haplotype. This response was not RA-specific since patients with IBD or OA also showed a response significantly more frequently than healthy controls (P:=0.02 and P=0.03 respectively). However, the level of the response against peptide 259-271 correlated with disease activity in RA patients but not in patients with IBD or SLE. Increased responses to HC gp-39 263-275 were found in patients with IBD or OA; a trend towards such a response failed to reach significance in RA patients in this study., Conclusion: In RA patients as well as in patients with other inflammatory conditions, HC gp-39-derived peptides may be targets of the T-cell-mediated immune response. In the RA patient group the immune response to HC gp-39-derived peptide 259-271 correlated with disease activity.

Background: Patients with Crohn disease (CD) have an increased risk of developing gallstones. Among other factors, gallbladder motility may have a role in the pathogenesis of gallstone formation. We have evaluated whether gallbladder motor function is affected in Crohn disease with special emphasis on the influence of disease localization and previous bowel resection., Methods: Thirty-seven patients (20 females and 17 males, age 36 +/- 2 years) with inactive Crohn disease (CDAI < 150) were studied: 15 patients after ileocecal resection and 22 non-operated patients; 12 had small bowel disease and 10 had large bowel disease. Nineteen healthy subjects (10 female; 9 male, age 30 +/- 2 years) served as controls. Gallbladder volumes were measured in the fasting state and at regular intervals for 2 h after ingestion of a solid meal (780 kcal). Blood samples were drawn at regular intervals for determination of cholecystokinin (CCK) and peptide YY (PYY)., Results: Fasting gallbladder volumes were significantly (P < 0.05) reduced in patients with large bowel disease (20.8 +/- 2.1 ml) or after ileocecal resection (18.3 +/- 2.4 ml) compared to patients with small bowel disease (28.0 +/- 2.1 ml) and controls (27.2 +/- 1.8 ml). Fasting plasma CCK levels were significantly (P < 0.05) higher in patients with large bowel disease or after ileocecal resection compared to patients with small bowel disease and controls. Postprandial gallbladder emptying and endogenous plasma CCK and PYY secretion in patients with Crohn disease were not different from controls., Conclusions: Fasting gallbladder volume is decreased and fasting plasma CCK levels are increased in patients with Crohn disease of the large bowel and patients after ileocecal resection. Postprandial gallbladder motility, CCK and PYY release were not affected in patients with Crohn disease.

Background: Inflammatory bowel disease (IBD) can be complicated by severe acute colitis. Emergency colectomy is mandatory if patients do not respond to intensive medical therapy. A minimally invasive approach such as laparoscopic-assisted colectomy might be beneficial in these patients. Therefore, we set out to assess the feasibility and the safety of emergency laparoscopic-assisted colectomy in IBD patients with severe acute colitis., Methods: A total of 42 consecutive patients underwent an emergency colectomy with end-ileostomy. Ten patients had laparoscopic-assisted colectomy, and 32 had open colectomy. Pre- and perioperative parameters, morbidity, and mortality were analyzed., Results: The two groups were comparable for patient characteristics. There were no conversions in the laparoscopic group. The operation time was longer in the laparoscopic group than in the open group (271 vs 150 min; p < 0.001), but the hospital stay was shorter (14.6 vs 18.0 days; p = 0.05). Complications were similar for the two groups., Conclusion: Laparoscopic-assisted colectomy in IBD patients with severe acute colitis is feasible and as safe as open colectomy.

Background: The objective of this study was to compare laparoscopic-assisted ileocolic resection for Crohn's disease of the distal ileum with open surgery in two consecutive groups of patients., Methods: From 1995 until 1998, 48 patients underwent open ileocolic resection at the Academic Medical Center (AMC) in Amsterdam, while 30 patients had laparoscopic-assisted ileocolic resection at the Leiden University Medical Center (LUMC). Patient characteristics, perioperative course, and recovery were compared. Differences between the groups were tested using Student's t-test for independent groups and chi-square tests when appropriate., Results: The open and the laparoscopic patient groups were comparable for age, gender, body mass index (BMI), prior abdominal surgery, and length of resected bowel. The conversion rate was 6.6%. Laparoscopic operating times (138+/-SD 36 min) were significantly longer than those observed in the open group (104+/-SD 34 min). Discharge was significantly earlier in the laparoscopic group than the open group (5.7 vs 10.2 postoperative days, p<0.007). Postoperative morbidity did not differ significantly between the patients treated traditionally (14.6%) and laparoscopically (10%)., Conclusion: Compared to open surgery, laparoscopic ileocolic resection for Crohn's disease is associated with similar morbidity rates, a shorter hospital stay, and improved cosmetic results, justifying the laparoscopic approach as the procedure of choice.

Objective: To evaluate plasma human cartilage glycoprotein (HC gp-39) as a possible marker for the presence and/or activity of rheumatoid arthritis (RA) and other inflammatory conditions., Background: HC gp-39 is a secretory product of chondrocytes, synovial cells, macrophages, and neutrophils. HC gp-39, also described as YKL-40, was found to be a marker of joint disease and tissue injury in RA and various other diseases., Methods: Levels of HC gp-39 were determined by a sandwich enzyme linked immunosorbent assay (ELISA) in 47 patients with RA, 47 with osteoarthritis (OA), 24 with systemic lupus erythematosus (SLE), 24 with inflammatory bowel disease (IBD), and in 47 healthy controls. A disease activity score was assessed in the patients with RA, SLE, and IBD., Results: The plasma level of HC gp-39 in the RA patient group was significantly higher than in the other patient groups and healthy controls. The level in patients with OA, SLE, and IBD was also significantly higher than the HC gp-39 level found in the healthy control group. HC gp-39 levels in patients with RA correlated positively with the ESR and IgM rheumatoid factor level but not with other variables of disease activity. In the patients with SLE and IBD no correlation was found with the disease activity score., Conclusion: The plasma level of HC gp-39 is increased in inflammatory conditions with and without joint disease (SLE, IBD, OA, and RA). Thus increased levels of HC gp-39 do not only reflect joint disease but also reflect inflammation or tissue degradation in various conditions. Notably, the highest level of HC gp-39 was found in patients with RA. Only in the RA patient group was a correlation between HC gp-39 plasma levels and some laboratory variables of disease activity found.

Background/aims: Despite a high frequency of pouch function disorders, most patients are satisfied with the outcome of ileo-anal pouch surgery. Aims of this study were: 1) To assess the influence of pouch function on quality of life and, 2) to determine which aspects of pouch dysfunction affect quality of life the most., Methodology: Questionnaires, addressing current pouch function and quality of life (Rand-36, GIQLI), were sent to all (53) patients with intact ileo-anal pouches, operated on between 1987 and 1997 in our center., Results: Thirty-six of 53 patients responded. Compared to reference data, Rand-36 scores for role-limitations based on a physical problem, vitality and general health perception were significantly diminished (P < 0.01). Physical and social functioning were normal. The GIQLI score was slightly decreased (111.7 vs. 125.8, P < 0.01). Overall pouch function did not correlate with the overall Rand-36 score, but correlated well with the overall GIQLI score (r = -0.47). Both quality of life scores were diminished mainly by the night-time stool frequency., Conclusions: 1) Quality of life after IPAA, as measured with validated questionnaires, is only slightly decreased; 2) the GIQLI questionnaire is more sensitive to pouch dysfunction than the Rand-36; 3) night-time stool frequency influences quality of life the most.

Background & Aims: Infliximab, an anti-tumor necrosis factor monoclonal antibody, rapidly reduces signs and symptoms of active Crohn's disease. The aim of this study was to determine whether repeated infusions of infliximab would effectively and safely maintain the remitting benefit., Methods: The efficacy, safety, pharmacokinetics, and immunogenicity of 4 repeated treatments with 10 mg/kg infliximab given every 8 weeks were compared with the effects of placebo in a randomized, double-blind, placebo-controlled, parallel group trial. Seventy-three patients with active Crohn's disease who had not adequately responded to conventional therapies and then had demonstrated a clinical response (>/=70-point decrease in the Crohn's Disease Activity Index) to an initial infusion of infliximab (or placebo) were studied., Results: Retreatment with infliximab maintained the clinical benefit through the retreatment period and 8 weeks after the last infusion in nearly all patients retreated with infliximab. Median values for Crohn's Disease Activity Index, inflammatory bowel disease questionnaire (a quality of life measurement), and serum C-reactive protein concentration were maintained at remission levels with infliximab retreatment, but not with placebo retreatment. Retreatment with infliximab every 8 weeks maintained serum infliximab concentration and was well tolerated with a low incidence of immunogenicity. One case of lymphoma and 1 case of suspected lupus were reported; the complete long-term safety profile of infliximab requires additional clinical investigation., Conclusions: Long-term treatment with infliximab showed efficacy and tolerability in managing symptoms of patients with active Crohn's disease not responding to conventional treatments.

Background: Laparoscopic bowel surgery was evaluated in 44 consecutive patients who underwent surgery for inflammatory bowel disease (IBD). We studied feasibility, results, and final outcome., Methods: At two academic institutes, 44 laparoscopically assisted colectomies and laparoscopic ileostomies or colostomies were attempted. All patients had histologically proven IBD and no prior surgery for IBD. Loop ileostomy (n = 4), end colostomy (n = 1), ileocecal resection (n = 26) and (procto)colectomy (n = 13) were performed. All resections were laparoscopically assisted with extracorporal resection and anastomosis., Results: Only in two patients (ileocecal resection in both) was conversion to open surgery necessary. Two patients with laparoscopic ileocolic resection had intra-abdominal abscesses, which were drained percutaneously in both. One patient in the laparoscopically assisted colectomy group had a subphrenic abscess that was drained percutaneously, and one patient had a generalized candidiasis., Conclusions: Laparoscopically assisted colectomies can be performed safely in treating IBD. The laparoscopic method with use of a small vertical umbilical or Pfannenstiel's incision seems acceptable with regard to operating time and overall costs, also allowing superior cosmesis to be maintained.

Background: The approval of azathioprine (AZA) for the long-term therapy of patients with Crohn's disease in The Netherlands., Methods: Review and update of the literature on clinical efficacy and safety of AZA in inflammatory bowel disease., Results: AZA and its metabolite 6-mercaptopurine (6-MP) are effective in the treatment of active Crohn's disease. However, the onset of the clinical response is delayed, requiring combination with other active medication in the early phase of treatment. Maintenance therapy with AZA/6-MP is also effective in the prevention of relapses in patients with Crohn's disease in remission. Indications for AZA/6-MP therapy further include refractory, fistulizing and steroid-dependent Crohn's disease. It is not known whether or when AZA/6-MP can be withdrawn in patients in long-term remission, but most clinicians discontinue therapy after 3-5 years. Although fewer data are available, AZA/6-PM appears to be effective also in the therapy of patients with ulcerative colitis. Side effects of AZA/6-MP occur in about 15% of patients and include skin rash, pancreatitis and hepatitis, dose-related neutropenia and thrombocytopenia, and risk of increased occurrence and severity of infections. Recent data suggest that the risk of malignancy, other than colorectal cancer, is not increased. Safety in pregnancy has not been studied extensively, but no increased prevalence of birth defects has been reported., Conclusions: AZA/6-MP therapy is efficacious in patients with active Crohn's disease, but the drug is especially valuable in the long-term treatment of patients with Crohn's disease and ulcerative colitis. Drug-related side effects are frequent and require discontinuation or dose-reduction of the AZA/6-MP therapy. Due to an increased risk of infections secondary to myelosuppression, careful follow-up is mandatory. Insufficient data are available on safety in pregnancy and on the risk of malignancies, but the limited data available in patients with inflammatory bowel disease appear to be reassuring.

Purpose: To investigate the value of superior mesenteric artery (SMA) Doppler flow measurements as a marker for disease activity in patients with Crohn's disease., Materials and Methods: Duplex Doppler sonographic measurements of SMA bloodflow volume were obtained in 90 patients with suspected or known Crohn's disease in three separate studies. The first study was a pilot study to ascertain the value of Doppler measurements in patients with proven active or inactive disease and to check our performance. In two following studies prospectively a correlation was sought between the independent assessment of Doppler flow measurements and our standard of reference based on clinical history, physical examination, laboratory values, endoscopy, surgery and/or follow-up and prospectively a correlation was sought between Doppler studies and the results of enteroclysis., Results: In all but two patients (study II) adequate measurements of SMA flow were obtained. In the active patient groups the Doppler SMA flow was significantly increased (P < 0.05) compared to the inactive patient groups and the control groups., Conclusion: These studies show that SMA Doppler flow measurements can be used as a parameter to assess disease activity in patients with Crohn's disease.

The objectives of this paper are to review the rational, the present results and future of laparoscopic-assisted bowel surgery in patients with inflammatory bowel disease (IBD). Only a few centres in the world report on laparoscopic bowel resection in IBD that include stoma surgery, ileocolic resection, left, right and (sub)total colectomy for Crohn's disease, and subtotal or restorative total proctocolectomy (ileal pouch anal procedures). The combined series report conversion rates between 2.5% and 22.2%. Ileocolic resection, stoma creation, stricturoplasty and segmental small bowel resection are associated with an acceptable length of surgery, but laparoscopic(-assisted) total colectomy or restorative proctocolectomy still demand up to 4-6 hours of operative time. The few randomised studies addressing laparoscopic-assisted (segmental) bowel surgery versus conventional surgery demonstrated significantly less pain, a quicker return to self-care and a shorter hospital stay. The results of the series reporting on laparoscopic-assisted (ileo)colectomy in IBD are similar to those from these randomised studies. Laparoscopic-assisted subtotal colectomy and restorative proctocolectomy have no benefit compared with conventional surgery other than superior cosmesis. Morbidity of laparoscopic (ileo)colectomy in IBD is low, that of laparoscopic-assisted subtotal colectomy and restorative proctocolectomy remains to be seen. The various laparoscopic bowel resections done in IBD are all feasible. The first series describing laparoscopic surgery for IBD indicate that laparoscopic-assisted segmental (ileo)colectomy is safe and is the preferred approach provided it is done in a centre specialised in the treatment of IBD and by skilled laparoscopic surgeons beyond the learning curve. Until now, laparoscopic-assisted subtotal colectomy and restorative proctocolectomy do not have the same short-term benefits as seen in other laparoscopic colorectal procedures. Patients with inflammatory bowel disease (IBD) have a high life-time risk of having abdominal surgery and reoperations. The proposed advantages of laparoscopic surgery in this group of young patients might be higher than in patients with other colorectal diseases. Minimal physiologic insult in patients who already are under significant physiologic stress, less adhesion formation and superior cosmesis are important benefits over time. In a time where patient's demands will increase, the future of laparoscopic colonic surgery in IBD looks assured.

After partial small bowel or colonic resection for Crohn's disease, recurrence frequently follows. Within half a year 60-73% of patients have endoscopic recurrence. This percentage increases substantially in as time passes. Symptoms will not always be present when endoscopic lesions are detected. The etiology of recurrent Crohn's disease is unknown. Some studies show that initial complications or extra-intestinal manifestations are more frequently seen in patients with a recurrence. The recurrent pattern of the lesions is also comparable to the pre-surgical state. The length of recurrent ileal inflammation after ileocolonic resection correlates with the pre-surgical extent of the disease. Some investigators have found electron-microscopic lesions in histologically unaffected resection margins demonstrating the presence of lesions. Luminal factors probably plays an important role as bypassing an anastomosis prevents an endoscopic recurrence. Some factors are considered to be important to increase the chance of a recurrence. A more aggressive disease may lead to earlier recurrence. Onset of disease at a younger age, a short pre-operative time, and localization, might play an important role. Smoking certainly influences the clinical, endoscopic and surgical recurrence. The number of daily cigarettes smoked and the duration of smoking, significantly increases the risk of recurrence. The type of surgery (kind of anastomosis, multiple anastomoses, length of resection) are not important. A longer macroscopic disease-free resection margin or presence of granuloma does not influence the recurrence rate. Also, the presence of microscopic disease at the margin is not important. Prevention of recurrent disease can be provided by administrating sulphasalazine, 5-aminosalicylic acid or metronidazole. For this reason, prophylactic medication after surgical resection seems appropriate.

Background: The objectives of this study were to evaluate body image, cosmetic results, and quality of life in patients with Crohn's disease of the terminal ileum who had either laparoscopic-assisted or open ileocolic resection, and to determine how patients experienced the pre- and postoperative periods after both procedures., Methods: Thirty-four patients participated: 11 patients after open resection (OR), 11 patients after laparoscopic-assisted resection (LR), and 12 patients without resection (WR). Retrospectively, the patients filled out several questionnaires pertaining to body image, hospital experiences, and quality of life. One-way analysis of variance, Student's t-tests, and Pearson's correlation were used for statistical analysis., Results: The cosmetic score was significantly higher in the LR than in the OR group (p < 0.01). Body image correlated strongly with cosmesis and with quality of life. The hospital experiences of the laparoscopic and open groups were similar., Conclusions: Laparoscopic surgery was associated with better cosmesis than open surgery. Patients do not experience laparoscopic surgery any differently from open surgery.

In patients with inflammatory bowel disease (IBD), radiologic examinations are important for diagnosis and treatment. With conventional X-ray examinations, mucosal abnormalities, ulcers and fistulas can be visualised, but no information on the extramural extension of the disease can be obtained. Newer radiologic modalities (ultrasound, CT and MRI) offer new diagnostic possibilities. With ultrasound IBD can be diagnosed with good confidence and it can differentiate between Crohn's disease and ulcerative colitis. CT and MRI are indicated not so much to diagnose the disease but rather to determine the severity and spread of disease activity (transmural and extramural inflammation) and to detect complications such as fistulas and abscesses.

We compare the clinicopathological features of 98 Crohn's disease (CD) patients with initial symptoms at 40 years of age or older (elderly; male n = 56, female n = 42) with those of 347 CD patients with onset of symptoms between the age of 16 and 40 years (young adults; male n = 166, female n = 181). The frequency of presenting symptoms, such as diarrhea, rectal blood loss, and weight loss were comparable in both groups, except for abdominal pain/cramps, which occurred somewhat less frequently in the elderly (59% vs. 71%, p < 0.05). The mean lag time between onset of symptoms and first visit to a general practitioner (GP) was considerably shorter in the elderly than in the young adults (0.2 years vs. 0.6 years, p < 0.001), as was the lag time between GP and referral to a specialist (0.6 years vs. 1.0 years, p < 0.07). Overall, this resulted in a significantly (p < 0.01) shorter time to establish the diagnosis in the elderly (1.8 years vs. 2.7 years). Crohn's disease as correct initial diagnosis was in the elderly less frequently observed than in the young adults (49% vs. 61%, p < 0.05), in contrast to diverticulitis (7.1% vs. 0%) and malignancy (6.1% vs. 0.9%), which were more frequently encountered as incorrect preliminary diagnosis in the elderly (both p < 0.005). The percentage of patients who underwent an abdominal operation was similar in both groups (83% vs. 77%), but the diagnosis CD was in the elderly more frequently established at first operation than in young adults (25% and 12%, p < 0.005). The elderly were found to undergo a bowel operation or resection earlier after onset of symptoms. The development of recurrence after bowel resection, although occurring in a lower percentage of patients, was significantly shorter than in the young adults (3.7 years vs. 5.8 years, p < 0.02). Arthritic extraintestinal manifestations were equally frequent in both groups, but elderly patients had significantly less relatives in the first or second degree affected by CD (3.1% vs. 12%, p < 0.02). We conclude that the diagnosis Crohn's disease is more readily established in elderly patients. Moreover, these patients less frequently have abdominal pain/cramps as a presenting symptom, a shorter time interval between onset of symptoms and first resection, and subsequent recurrence of the disease. In addition, elderly CD patients have less relatives affected by the same disease. Thus, CD in the elderly appears to be characterized by a more rapid development.