A thirty-year follow-up surveillance study for neoplasia of a dutch ulcerative colitis cohort.

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.

Molecular prediction of disease risk and severity in a large Dutch Crohn's disease cohort.

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.

Synergistic immunosuppressive effect of anti-TNF combined with methotrexate on antibody responses to the 23 valent pneumococcal polysaccharide vaccine.

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.

The effect of anti-tumour necrosis factor alpha treatment on the antibody response to influenza vaccination.

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.

Increased mucosal matrix metalloproteinase-1, -2, -3 and -9 activity in patients with inflammatory bowel disease and the relation with Crohn's disease phenotype.

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.

Guidelines for treatment with infliximab for Crohn's disease.

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.

Skeletal morbidity in inflammatory bowel disease.

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.

Ileum resection is the most predictive factor for osteoporosis in patients with Crohn's disease.

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.

Expression of matrix metalloproteinases-2 and -9 in intestinal tissue of patients with inflammatory bowel diseases.

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.

Gastrin releasing peptide receptor expression is decreased in patients with Crohn's disease but not in ulcerative colitis.

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.

Malignancies in inflammatory bowel disease: fact or fiction?

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.

Adult height in patients with early onset of Crohn's disease.

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.

Effects of anti-tumour necrosis factor-alpha therapy on the quality of life in Crohn's disease.

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.

Proximal Crohn's disease: review of the clinicopathologic features and therapy.

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.

Ileoanal pouch function is related to postprandial pouch tone.

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.

Comparison of ileoanal pouch and rectal function measured by barostat.

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.

Gender-related differences in the clinical course of Crohn's disease.

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.

Use of anti-tumour necrosis factor agents in inflammatory bowel disease. European guidelines for 2001-2003.

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.