Systematic analysis of factors associated with progression and regression of ulcerative colitis in 918 patients.

BACKGROUND: Studies that systematically assess change in ulcerative colitis (UC) extent over time in adult patients are scarce. AIM: To assess changes in disease extent over time and to evaluate clinical parameters associated with this change. METHODS: Data from the Swiss IBD cohort study were analysed. We used logistic regression modelling to identify factors associated with a change in disease extent. RESULTS: A total of 918 UC patients (45.3% females) were included. At diagnosis, UC patients presented with the following disease extent: proctitis [199 patients (21.7%)], left-sided colitis [338 patients (36.8%)] and extensive colitis/pancolitis [381 (41.5%)]. During a median disease duration of 9 [4-16] years, progression and regression was documented in 145 patients (15.8%) and 149 patients (16.2%) respectively. In addition, 624 patients (68.0%) had a stable disease extent. The following factors were identified to be associated with disease progression: treatment with systemic glucocorticoids [odds ratio (OR) 1.704, P = 0.025] and calcineurin inhibitors (OR: 2.716, P = 0.005). No specific factors were found to be associated with disease regression. CONCLUSIONS: Over a median disease duration of 9 [4-16] years, about two-thirds of UC patients maintained the initial disease extent; the remaining one-third had experienced either progression or regression of the disease extent.

Topical therapy is underused in patients with ulcerative colitis.

The availability of new topical preparations for the treatment of left sided ulcerative colitis offers a therapy optimization for many patients. Rectal application of steroids and 5-aminosalicylic acid (5-ASA) is associated with fewer side effects and has a higher therapeutic efficacy in left-sided colitis as compared to a systemic therapy. Therefore, we were interested in the use of topical therapy in patients with ulcerative colitis. The key question was whether topical treatment is more frequently used than oral therapy in patients with proctitis and left sided colitis. Data of 800 patients of the Swiss IBD cohort study were analyzed. Sixteen percent of patients of the cohort had proctitis, 21% proctosigmoiditis and 41% pancolitis. Topical therapy with 5-ASA or corticosteroids was given in 26% of patients with proctitis, a combined systemic and topical treatment was given in 13%, whereas systemic treatment with 5-ASA without topical treatment was given in 29%. Proportion of topical drug use decreased with respect to disease extension from 39% for proctitis to 13.1% for pancolitis (P=0.001). Patients with severe colitis received a significantly higher dose of topical 5-ASA than patients in remission. Side effects of topical or systemic 5-ASA or budesonide treatment were less frequently seen compared to other medications. Topical treatment was frequently stopped over time. The quality of life was the same in patients with limited disease compared to patients with pancolitis. Topical treatment in proctitis patients was underused in Switzerland. Since topical treatment is safe and effective it should be used to a larger extend.

[Topical therapy of ulcerative colitis]. / Topische Therapie bei Colitis ulcerosa.

The availability of new topical preparations for the treatment of left sided ulcerative colitis ulcerosa offers a therapy optimization for many patients. Rectal application of steroids and 5-aminosalicylic acid (5-ASA) is associated with fewer side effects and has a higher therapeutic efficacy in mild to moderate-active left-sided colitis as compared to a systemic therapy. Often it is argued that the patients' compliance is insufficient with a rectal therapy. However, with sufficient information on the proven advantages this is usually not the case. The rectal application of drugs in distal ulcerative colitis is suitable also for the maintenance of remission. Therefore the new therapy guidelines recommend topical therapy more than in former times. Subsequently, these manuscripts focussed specifically on the topical therapy of distal colitis, to elucidate that clear treatment advantages are present in daily practice.

Appropriateness of therapy for fistulizing Crohn's disease: findings from a national inflammatory bowel disease cohort.

BACKGROUND: About 30-50% of patients with Crohn's disease (CD) develop fistulae, implying significant disease burden and complicated clinical management. AIM: To assess appropriate use of therapy for fistulizing CD patients enrolled in the Swiss Inflammatory Bowel Disease Cohort using criteria developed by the European Panel on the Appropriateness of Crohn's disease Therapy. METHODS: Specific questionnaires were used to gather information on disease and its management. We assessed appropriateness of therapy at enrolment for adult CD patients with one or several fistulae. RESULTS: Two hundred and eighty-eight CD patients had fistulizing disease, of which 80% had complex fistulae and 32% currently had active draining fistulae. Mean age (s.d.) at diagnosis was 27 years (11), 51% males. Of the patients, 78% were judged as having globally an appropriate therapy, which was more often given for complex fistulae (87%) than for simple fistulae (67%). Antibiotics, azathioprine/MP, methotrexate and conservative surgery were almost always appropriate. Anti-tumor necrosis factor α was considered globally appropriate (91%), although most often with an uncertain indication. The 5ASA compounds, steroids and aggressive surgery were most often inappropriate (84%, 58% and 86% respectively). CONCLUSIONS: Formal appropriateness criteria for CD therapy were applied to a national cohort of IBD patients. For more than three-quarters of the patients with fistulizing CD, therapy was globally appropriate.

MEP1A allele for meprin A metalloprotease is a susceptibility gene for inflammatory bowel disease.

The MEP1A gene, located on human chromosome 6p (mouse chromosome 17) in a susceptibility region for inflammatory bowel disease (IBD), encodes the alpha-subunit of metalloproteinase meprin A, which is expressed in the intestinal epithelium. This study shows a genetic association of MEP1A with IBD in a cohort of ulcerative colitis (UC) patients. There were four single-nucleotide polymorphisms in the coding region (P=0.0012-0.04), and one in the 3'-untranslated region (P=2 x 10(-7)) that displayed associations with UC. Moreover, meprin-alpha mRNA was decreased in inflamed mucosa of IBD patients. Meprin-alpha knockout mice exhibited a more severe intestinal injury and inflammation than their wild-type counterparts following oral administration of dextran sulfate sodium. Collectively, the data implicate MEP1A as a UC susceptibility gene and indicate that decreased meprin-alpha expression is associated with intestinal inflammation in IBD patients and in a mouse experimental model of IBD.

Antibodies to flagellin indicate reactivity to bacterial antigens in IBS patients.

One of the several possible causes of irritable bowel syndrome (IBS) is thought to be low-grade mucosal inflammation. Flagellin, the primary structural component of bacterial flagellae, was shown in inflammatory bowel disease patients to activate the innate and adaptive immunity. It has not yet been conclusively established if IBS patients show reactivity to luminal antigens. In 266 patients [112 IBS, 61 Crohn's disease (CD), 50 ulcerative colitis (UC) and 43 healthy controls (HC)], we measured antibodies to flagellin (FAB, types A4-Fla2 and Fla-X), anti-Saccharomyces cerevisiae antibodies (ASCA) (both ELISA), antipancreas antibodies (PAB) and perinuclear antineutrophil cytoplasmatic antibodies (p-ANCA) (both IF). All IBS patients had normal fecal calprotectin (mean 21 microg mL(-1), SD 6.6) and fulfilled the ROME II criteria. Frequencies of antibodies in patients with IBS, CD, UC and HC, respectively, are as follows (in per cent): antibodies against A4-Fla2: 29/48/8/7; antibodies against Fla-X: 26/52/10/7; ASCA: 6/59/0/2; p-ANCA: 0/10/52/0; and PAB: 0/28/0/0. Antibodies against A4-Fla2 and Fla-X were significantly more frequent in IBS patients than in HC (P = 0.004 and P = 0.009). Antibodies to A4-Fla2 and Fla-X were significantly more frequent in IBS patients with antecedent gastroenteritis compared to non-postinfectious IBS patients (P = 0.002 and P = 0.012). In contrast to ASCA, PAB and p-ANCA, antibodies against A4-Fla2 and Fla-X were found significantly more often in IBS patients, particularly in those with postinfectious IBS, compared to HC. This observation supports the concept that immune reactivity to luminal antigens has a putative role in the development of IBS, at least in a subset of patients.

Esophageal strictures in adult eosinophilic esophagitis: dilation is an effective and safe alternative after failure of topical corticosteroids.

Strictures are a frequent complication of eosinophilic esophagitis. The efficacy and safety of topical corticosteroids and of dilation of eosinophilic esophagitis-associated strictures have not yet been thoroughly clarified. We present a retrospective analysis of 10 adult patients with eosinophilic esophagitis who had symptomatic esophageal stenosis that was unresponsive to topical corticosteroids, and who were treated using bougienage. Eight patients had one single stricture, one patient had two, and another had three strictures; mean stricture length was 2.1 cm (range 1 - 6 cm). Bougienage led to prompt symptom relief. Apart from transient postprocedural odynophagia, no severe complications occurred. During the follow-up (mean 6 months; range 2 - 11 months), all patients enjoyed sustained treatment response.

Mitochondrial neurogastrointestinal encephalomyopathy in three siblings: clinical, genetic and neuroradiological features.

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a rare autosomal recessive disorder in which a nuclear mutation of the thymidine phosphorylase (TP) gene causes mitochondrial genomic dysfunction. Patients suffer from gastrointestinal dysmotility, cachexia, ptosis, external ophthalmoparesis, myopathy and polyneuropathy. Magnetic resonance imaging (MRI) shows leukoencephalopathy. We describe clinical, genetic and neuroradiological features of three brothers affected with MNGIE. Clinical examination, laboratory analyses, MRI and magnetic resonance spectroscopy (MRS) of the brain, and genetic analysis have been performed in all six members of the family with the three patients with MNGIE. Two of them are monozygous twins. They all suffered from gastrointestinal dysmotility, cachexia, ophthalmoplegia, muscular atrophies, and polyneuropathy. Urinary thymidine was elevated in the patients related to the severity of clinical disease, and urinary thymidine (normally not detectable) was also found in a heterozygous carrier. Brain MRI showed leukoencephalopathy in all patients; however, their cognitive functioning was normal. Brain MRS demonstrated reduced N-acetylaspartate and choline in severely affected areas. MRI of heterozygous carriers was normal. A new mutation (T92N) in the TP gene was identified. Urinary thymidine is for the first time reported to be detectable in a heterozygous carrier. MRS findings indicate loss of neurons, axons, and glial cells in patients with MNGIE, but not in heterozygous carriers.

[Infliximab--practical guidelines for the treatment of Crohn's disease]. / Infliximab--recommandations pratiques pour te traitement de la maladie de Crohn.

Infliximab is a monoclonal chimeric antibody, with high affinity and specificity for tumour necrosis factor alpha (TNFalpha) that plays a central role in the pathogenesis of immune mediated inflammatory disorders including Crohn's disease and ulcerative colitis. Globally over 600000 patients have been treated with infliximab to date. This global experience led to a better definition of the overall safety and efficacy profile of this medication. The goal of the present recommendations is to provide practical information to physicians involved in the care of patients with inflammatory bowel disease.

Response of cutaneous Crohn's disease to infliximab and methotrexate.

Cutaneous or metastatic Crohn's disease is a rare complication of Crohn's disease and is frequently refractory to medical treatment. A case of metastatic Crohn's disease affecting first the abdominal wall and subsequently both submammary folds is reported. These extraintestinal manifestations occurred many years after proctocolectomy. The activity of cutaneous disease was associated with a chronic active fistulizing disease. Skin manifestations were resistant to treatment with steroids, antibiotics and azathioprine. Repetitive treatment with infliximab led to significant improvement of both cutaneous and fistulous disease. However, disease relapsed and even progressed after a period of 6 weeks following each infliximab treatment. Only the introduction of methotrexate, together with repetitive administration of infliximab, allowed maintenance of the patient in remission.

[Does conservative therapy of chronic inflammatory bowel diseases still play a role?]. / Hat die konservative Therapie bei chronisch entzündlichen Darmerkrankungen noch einen Stellenwert?

The first-line therapy for inflammatory bowel disease flares is typically medical in nature. Glucocorticoids are a mainstay for the treatment of severe inflammatory bowel disease. Aminosalicylates are efficacious in the treatment of active mild- to- moderate disease. Infliximab, a chimeric monoclonal anti-TNF alpha antibody can be used in refractory Crohn's disease. The recurrence rate after surgery or medical therapy is high. Therefore the introduction of a maintenance therapy is important in patients with repetitive flares. In patients with ulcerative colitis aminosalicylates are useful as maintenance therapy. In severe ulcerative colitis or in Crohn's disease immune suppressive strategies such as a therapy with azathioprine, 6-mercaptopurine or methotrexate should be considered. In Crohn's patients with fistula surgical treatment or a therapy with antibiotics, immunosuppressants or infliximab is recommended.

Complementary alternative medicine in patients with inflammatory bowel disease: use and attitudes.

BACKGROUND: A widespread increase in the use of complementary alternative medicine (CAM) by patients with inflammatory bowel disease (IBD) has been recognized. The aim of our study was to evaluate both the extent and the determinants of CAM use by outpatients with IBD. METHODS: Outpatients of the IBD centre at the University Hospital of Berne and patients of two gastroenterology private practices in Olten (Switzerland) completed a mailed self-administrated questionnaire regarding alternative medicine. The questionnaire addressed the following topics: demographic variables; disease-related data; the use of 16 types of complementary medicine; comparison between attitudes towards alternative versus conventional medicine and out-of pocket expenses. RESULTS: Alternative medicine has been used by 47% of the patients. Diagnosis, duration and activity of disease, gender, age, previous surgery were not predictive for the use of CAM. The most commonly used CAM methods were: homeopathy, acupuncture and traditional Chinese medicine. Reasons cited for the use of CAM were: lack of satisfaction with and side effects of conventional therapy and the perceived safety of CAM. Sixty-one percent of patients noted that their IBD had improved with the use of CAM. By contrast, 16% noted a flare during CAM therapies. Forty-seven percent of patients paid more than Euro400 per year for CAM. CONCLUSIONS: Complementary medicine use is common in patients with IBD. Frequently cited reasons for the use of complementary therapies were safety of CAM; dissatisfaction with conventional therapies, including their side effects; and that CAM can be used in addition to conventional therapy.

Amelioration of murine colitis by feeding a solution of lysed Escherichia coli.

BACKGROUND: Immune reactivity towards the bacterial intestinal flora plays an important part in the pathogenesis of inflammatory bowel disease. Disease activity can be positively influenced by the administration of living probiotic bacteria. We investigated the effect of soluble bacterial antigens extracted from Escherichia coli (strain Laves) on the disease activity of murine colitis. METHODS: C3H.IL-10-/- and BALB/c mice with dextran sulphate sodium-induced colitis were treated with either a bacterial lysate from E. coli or with a placebo. Mice were monitored and inflammation was assessed by histological scoring, analysis of fecal IL-1beta and measurement of cytokine production by ELISA. T cell proliferation was quantified by 3H-thymidine incorporation. RESULTS: Clinically and histologically, bacterial-lysate-treated mice revealed significantly (P < 0.05) fewer signs of colitis than placebo-treated mice. Fecal IL-1beta and mucosal TNF-alpha and IFN-gamma concentrations were significantly lower (P < 0.05) in verum-treated mice than in the placebo group. Furthermore, lymphocyte proliferation after stimulation with lipopolysaccharide or caecal bacterial antigen was significantly (P < 0.05) reduced in verum-treated mice. CONCLUSION: The use of E. coli lysate is effective in the amelioration of murine colitis. This effect may be due to a decreased Th1 reaction and to an induction of tolerance against bacterial antigens.

[Laboratory diagnosis in inflammatory bowel disease]. / Labordiagnostik bei chronisch entzündlichen Darmerkrankungen.

The assessment of disease activity in inflammatory bowel disease is done using clinical parameters and various biological disease markers. Classical disease markers including erythrocyte sedimentation rate, acute phase proteins, such as orosomucoid and CRP, leukocyte and platelet counts, play an important role in the monitoring of disease activity. Furthermore, the determination of zinc, iron, ferritin, vitamin B12, and folic acid is important to avoid deficiencies in patients with severe disease or after surgeries. Stool cultures are helpful to detect bacterial or parasitic infections mimicking inflammatory bowel disease. The detection of specific antibodies such as pANCA, PAB and ASCA is helpful for the differential diagnosis Crohn's disease--ulcerative colitis.

Dysphagia in Crohn's disease: a diagnostic challenge.

Dysphagia is a rare manifestation in a patient with Crohn's disease. We report on the case of a patient with long-standing Crohn's disease who developed progressive dysphagia over 3 years. Endoscopy showed minimal distal oesophagitis with non-specific histological findings. Further investigation with cinematography, barium swallow and manometry established an achalasia-like motility disorder. Biopsies obtained from the oesophagus were non-specific. Balloon dilatation was performed. Initial success was followed by recurrent dysphagia. At repeat endoscopy, an oesophageal fistula was detected. An attempt at conservative medical management failed and oesophagectomy was successfully performed. Pathology results of the resected specimen confirmed the suspected diagnosis of oesophageal Crohn's disease. Even if achalasia is suspected in a Crohn's patient, it should be taken into consideration that the motility disorder could be the result of a transmural inflammation with or without fibrosis caused by Crohn's disease.

Evaluation of serologic disease markers in a population-based cohort of patients with ulcerative colitis and Crohn's disease.

BACKGROUND: The sensitivity of assays for antineutrophil cytoplasmic antibody (ANCA), anti-Saccharomyces cerevisiae antibody (ASCA), and antipancreatic antibody (PAB) in different laboratories is unknown. Likewise, the sensitivity and diagnostic usefulness of these assays in patients with inflammatory bowel disease (IBD) in the community is unknown. METHODS: An incidence cohort of 290 patients with IBD were offered participation in the study. Blood was obtained from 162 patients (56%) (83 with ulcerative colitis, 79 with Crohn's disease) who agreed to participate. ANCA was determined in five laboratories. ASCA in two laboratories, and PAB in one laboratory. RESULTS: In ulcerative colitis, the sensitivity of ANCA determined in five laboratories varied widely, ranging from 0-63%. In Crohn's disease, the sensitivity of ASCA determined in two laboratories did not vary significantly, ranging from 39-44%; and the sensitivity of PAB determined in one laboratory was 15%. The optimal diagnostic usefulness was obtained from one laboratory where the positive predictive values of a positive ANCA assay combined with a negative ASCA assay for ulcerative colitis, and a negative ANCA combined with a positive ASCA for Crohn's disease, were 75% and 86%, respectively. CONCLUSIONS: In patients with IBD, the sensitivity of ANCA varied widely in different laboratories, whereas the prevalence of ASCA was similar. The positive predictive values of the ANCA assay combined with the ASCA assay for ulcerative colitis and Crohn's disease are high enough to be clinically useful.

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.

Anti-Saccharomyces cerevisiae antibodies in inflammatory bowel disease: a family study.

BACKGROUND: Antibodies to Saccharomyces cerevisiae (ASCA) have been described as specific markers for Crohn disease (CD). The reason for this disease specific generation of antibodies is not clear. Therefore, a family study was performed to evaluate whether the antibody production was due to genetic or environmental factors. METHODS: Seventy-one patients with CD, 25 patients with ulcerative colitis (UC), their 282 first-degree relatives, and 32 spouses were included. As controls, 43 sera from healthy persons and 69 sera from patients with various autoimmune disorders were tested for ASCA by indirect immunofluorescence and ELISA. RESULTS: ASCA were detected in 68% of the patients with CD and in none of the controls, UC patients included. Forty-eight (25%) first-degree relatives of patients with CD were ASCA-positive. ASCA status of relatives was not related to the fact whether these persons lived in the same household with the patients or not. However, one of the spouses of CD patients (4%) was found to be ASCA-positive and the antibody was also found in 5 (6%) of the relatives of UC patients. CONCLUSIONS: ASCA are specific markers for CD. Since these antibodies are found in 25% of first-degree relatives, the generation of ASCA may be mainly related to genetic influences although environmental factors may also play a certain role.