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.

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.

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.

The future role of anti-tumour necrosis factor-alpha products in the treatment of Crohn's disease.

Tumour necrosis factor-alpha (TNF alpha) is thought to play a central role in the immunopathology of Crohn's disease, particularly since its levels are raised in all types of cells, tissues and secretory fluids of these patients and in animal models of the disease. In addition, TNF alpha has been found to modulate a number of different processes within the network of inflammatory reactions and therefore has become a target molecule for intervention studies. In the past few years several compounds have been developed which neutralise or impair the production of TNF alpha, e.g. monoclonal antibodies [infliximab (cA2), CDP-571], TNF receptor p75-Fc fusion protein, pentoxifylline (oxpentifylline), p65 antisense oligonucleotides and metalloproteinase inhibitors, thereby counteracting the deleterious effects of this proinflammatory cytokine. At present, successful treatment of active 'refractory' and fistulising Crohn's disease has been reported with anti-TNF alpha antibodies; more clinical studies are in progress or will be performed with substances that intervene in the activation, production and processing of TNF alpha. Although important aspects of this type of immune-intervention therapy still need to be elucidated, e.g. long term effects, mechanism(s) of action, identification of responders and nonresponders, etc., it is obvious that the integration of basic and clinical research brings us to a new era of specific cytokine-directed therapy in 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.

Budesonide and prednisolone suppress peripheral blood natural killer cells in Crohn's disease.

AIM: To study the effect of oral budesonide and prednisolone on peripheral blood natural killer (NK) cell activity in patients with active ileocaecal Crohn's disease (Crohn's disease activity index, CDAI > or = 200). METHODS: One group of patients was treated for 10 weeks with oral budesonide (n = 9; 9 mg/day), and another group of patients for the same period with prednisolone (n = 9; 40 mg/day). Budesonide was tapered to 6 mg/day after 8 weeks and prednisolone after 2 weeks to 5 mg/day in the last week. Before treatment, and at 2, 4 and 10 weeks of treatment, natural killer cell activity was determined with a 51Cr release assay, and the number of CD16+ NK cells by Fluorescence activated cell sorter (FACS) analysis. RESULTS: Budesonide, as well as prednisolone treatment, significantly decreased natural killer cell activity at weeks 2 and 4. This decrease was found to be accompanied by a similar decrease in the number of CD16+ NK cells. At 10 weeks, natural killer cell activity had almost returned to pre-treatment levels in the budesonide group and was significantly higher than pre-treatment levels in the prednisolone group. Disease activity was significantly decreased in all patients at week 2 until the end of the trial period. CONCLUSION: Both budesonide and prednisolone treatment suppress peripheral blood natural killer cell activity of patients with active ileocaecal Crohn's disease by decreasing the numbers of CD16+ NK cells in the circulation.

Suppression of intestinal mucosal natural killer cells by corticosteroids.

BACKGROUND: Corticosteroid therapy of patients with inflammatory bowel disease can give rise to systemic side-effects. Budesonide is a topically acting corticosteroid with low systemic bioavailability and is efficacious in the treatment of inflammatory bowel disease. Natural killer cells were previously found to be altered, both systemically and locally, in patients with inflammatory bowel disease. Modulatory effects of budesonide, prednisolone, dexamethasone, and cortisol on peripheral blood NK cells have already been described, but have never been assessed on mucosal NK cells from the intestine. METHODS: The effect of the synthetic corticosteroids prednisolone and budesonide, the endogenous corticosteroid cortisol, and adrenocorticotropic hormone was analysed on NK cells isolated from the lamina propria of human intestinal resection specimens. RESULTS: The three corticosteroids suppressed intestinal NK cell activity, not only during the cytotoxicity assay, but also after pre-incubation of the lamina propria mononuclear cells. ACTH, however, did not affect the activity of intestinal NK cells. We previously showed that corticosteroid-suppressed peripheral blood NK cell activity could be restored in vivo, but not in vitro, by the administration of ACTH. In the present study, the in vitro incubation of budesonide- or prednisolone-suppressed mucosal NK cells with cortisol, alone or combined with ACTH, did not revert the suppressed NK cell activity. These findings are similar to our previous observations with peripheral blood NK cells. CONCLUSIONS: Intestinal mucosal NK cells can be suppressed by systemically as well as locally acting corticosteroids. This suppression in NK cell activity is not reversed by incubation with cortisol and/or ACTH.

Double-blind comparison of 5-aminosalicylic acid and acetyl-5-aminosalicylic acid suppositories in patients with idiopathic proctitis.

Suppositories containing 300 mg 5-aminosalicylic acid (1.96 mmol) or 425 mg acetyl-5-aminosalicylic acid (1.96 mmol) were used in 40 patients with idiopathic proctitis to determine the efficacy of acetyl-5-aminosalicylic acid in treating this bowel inflammation. Each patient was treated with 5-aminosalicylic acid or acetyl-5-aminosalicylic acid suppositories twice daily for 4 weeks in a double-blind trial. Four patients were included twice in the trial. The second time they were treated with the alternative regimen. Six patients in the acetyl-5-aminosalicylic acid group did not complete the trial, four of them because of diarrhoea. Complete clinical remission with normal rectal mucosa on sigmoidoscopy was achieved in 10 out of 18 patients on 5-aminosalicylic acid and in only two out of 15 in the acetyl-5-aminosalicylic acid group (P = 0.03). A favourable histological improvement was demonstrated with 5-aminosalicylic acid suppositories, but the difference with acetyl-5-aminosalicylic acid was not significant (P = 0.059). Three of the four patients who received both drugs recovered with 5-aminosalicylic acid; in none of them was acetyl-5-aminosalicylic acid effective. The results from this study and from previous investigations show that acetyl-5-aminosalicylic acid is not superior to placebo.

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.

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.

Levels of circulating cellular fibronectin are increased in patients with rheumatoid vasculitis.

OBJECTIVE: To investigate whether serum levels of circulating cellular fibronectin (cFN) are increased in patients with rheumatoid arthritis (RA) complicated by vasculitis. METHODS: Levels of serum cFN were determined by an enzyme-linked immunosorbent assay (ELISA) in 26 RA patients with histologically proven vasculitis of recent onset (RV) and were compared to the levels in 47 RA patients with extraarticular manifestations of recent onset but no histological evidence of vasculitis (RA+), 43 patients with uncomplicated RA (RA-), 16 patients with systemic lupus erythematosus and active disease (SLE), 30 patients with active Crohn's disease (CD), 21 young healthy controls (yHC) and 17 elderly healthy controls (eHC). Plasma levels of cFN and von Willebrand factor antigen were also determined in the RA patients. RESULTS: In RV patients, the median cFN level was significantly (P = 0.01) higher compared to that of RA+ patients, and was also significantly (P < 0.0000) higher compared to the cFN level in the RA-, SLE, CD, yHC and eHC groups. When compared to eHC, the cFN level was significantly higher in RA+ (P = 0.008); it was also higher in RA-, although not significantly (P = 0.42). 77% of the RV patients, 55% of the RA+ patients, and 37% of the RA-patients had a cFN level > 2 SD above the mean level for eHC. At an optimal cut-off titre the sensitivity of the cFN ELISA in discriminating RV patients from RA+ patients was 90%, the specificity was 46% and the accuracy was 68%. Plasma levels of cFN correlated significantly (r = 0.62; P < 0.001) with the von Willebrand factor antigen levels. CONCLUSIONS: Increased levels of serum cFN are present in patients with RA, and are frequently found in RA patients with extraarticular manifestations, particularly in those with vasculitis.

Medical management of patients with difficult-to-treat inflammatory bowel disease.

Initial standard medical treatment for inflammatory bowel disease (IBD) includes a 5-aminosalicylic acid (5-ASA) compound (oral, local or combined) and corticosteroids (oral, local or combined). In both ulcerative colitis and Crohn's disease 5-ASA has proved effective in the acute phase of the disease. As maintenance treatment, it is effective in ulcerative colitis and in some instances also in Crohn's disease. Steroids can be used in active IBD, but their effectiveness as maintenance treatment has never been proven, although in practice low-dose steroids are used for chronic treatment. When the above-mentioned preparations are unsuccessful, other medications could be tried. Flagyl could be used when the colon is involved in Crohn's disease or when anal fistulation develops, but it often fails to maintain its effect after only a few weeks. For refractory IBD more potent immunomodulators are needed. 6-Mercaptopurine and azathioprine have been shown to be effective in ulcerative colitis and Crohn's disease with a response rate between 60 and 70%. Their optimal effect is only reached after 3-4 months. These drugs are therefore not of value for treatment in the acute phase of the disease. 6-Mercaptopurine or azathioprine can be used best in combination with steroids in situations where dose reduction of the latter drug repeatedly leads to relapse. They have therefore a steroid-sparing effect and initiate cessation of the long-term severe side-effects of steroids. Another possibility is the use of methotrexate in patients with refractory ulcerative colitis or Crohn's disease.

Selective immunomodulation in patients with inflammatory bowel disease--future therapy or reality?

Knowledge of the aetiology and pathogenesis of the inflammation in ulcerative colitis and Crohn's disease is still insufficient. It is thought that some antigen is the trigger which induces a chain of immune reactions but the origin of this antigen has not so far been elucidated. In theory, an antigen-presenting cell forms a complex with endotoxin-derived peptides as antigen. T-helper lymphocytes recognize this complex, are activated and start to produce cytokines. For inflammatory bowel diseases (IBD) the most important cytokines identified are interleukin 1 (IL-1), interleukin 2 (IL-2), interleukin 6 (IL-6), interleukin 8 (IL-8), gamma-interferon (G-IFN), and tumor necrosis factor-alpha (TNF-alpha). Inhibition of these cytokines can be achieved by administration of cyclosporine, which inhibits the function of T-helper lymphocytes. Orally, intravenously, and locally administered cyclosporine is able to improve the disease activity in ulcerative colitis and Crohn's disease, but its use is limited because of side-effects. The novel immunosuppressant FK506 has comparable actions to cyclosporine in regulating cytokine production and may even be more effective than cyclosporine. The receptor antagonist of IL-1 (IL-1ra) competitively binds to the IL-1 receptor located on several lymphocytes. Treatment of animals with IL-1ra has been successful and clinical trials using recombinant IL-1ra are underway in IBD. Antibodies against alphaIL-2r have also been used successfully in animal studies. No experience with this substance has been obtained in man. The use of alpha-interferon seems to be effective in some patients with Crohn's disease. CD4 and CD8 molecules on lymphocytes are needed to form the interaction between antigen, antigen-presenting cell, and lymphocytes. Specific monoclonal antibodies against CD4 are successfully used in patients with active ulcerative colitis and Crohn's disease. TNF-alpha shares many of the proinflammatory activities of IL-1. In preliminary studies, especially in patients with Crohn's disease, the effects of the administration of antibodies to TNA-alpha were excellent.

Management of recurrent Crohn's disease.

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.

Assessment of inflammatory activity in Crohn's disease.

Complaints or symptoms of Crohn's disease can be due either to intestinal inflammation or to anatomical abnormalities such as strictures, fistulas and previous intestinal resection, or to a combination of these factors. Since anti-inflammatory or immunosuppressive drugs are only effective in reducing inflammation, assessment of the presence or absence of active inflammation is of great clinical importance. Several disease activity indices have been developed, but none is able to accurately assess inflammatory activity in Crohn's disease. Furthermore, blood parameters of inflammation, such as ESR, leukocytes, thrombocytes and albumin, are not bowel-specific. In contrast, faecal inflammatory parameters are specific for intestinal inflammation. Preliminary results from our laboratory suggest that measurement of intestinal alpha 1-antitrypsin clearance is a sensitive and bowel-specific indicator of active inflammation in Crohn's disease. This inexpensive, safe and patient-friendly measurement deserves a prominent place, not only in drug trials but also in clinical management of patients with Crohn's disease.

Laparoscopic-assisted bowel resections in inflammatory bowel disease: state of the art.

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.