Library

Notes: Whipple's disease is a multisystem disorder with protean manifestations and with poorly understood aetiopathogenesis. It is unclear how the immune system reacts, whether it functions normally or not, whether it protects the organism or is defeated in one way or another by the ‘Whipple bacillus’. The purpose of our study was to assess humoral and cellular immunity at the level of the intestinal mucosa. This histochemical, immunocytochemical and electronmicroscopic study, based on 16 cases, has shown that the changes in components of the mucosal immune system in Whipple's disease are quite different from normal. The phagocytic capacity of the macrophages, assessed microscopically, is abnormal, the number of intra-epithelial lymphocytes is increased, the CD 4/CD 8 cell ratio is decreased and the IgM positive cells in the lamina propria outnumber the IgA positive cells. These changes may be inter-dependent.

Notes: An immunoperoxidase technique with monoclonal antibodies for the identification of lymphocyte subsets and MHC Class II antigens was applied to oesophageal biopsies from two patients with herpetic oesophagitis. Oesophageal epithelial cells were found to express the MHC Class II antigen. The inflammatory infiltrate of the lamina propria was composed of both B lymphocytes and T lymphocytes.

Notes: Alpha-I-antitrypsin immunoreactivity was demonstrated by immunofluorescence in epithelial cells of the normal human small intestine. Its presence was also confirmed in biopsies of patients with Crohn's disease. Specific fluorescence was observed in only four out of 14 adult patients with coeliac disease. These results implicate the human small intestinal epithelium as a possible source of alpha-I-antitrypsin. The absence of positive cells may have implications in the aetiology of coeliac disease.

Notes: Background: Aim of this work was to improve standardization of the 13C-urea breath test (13C-UBT) by evaluating the effect of drug administration, feeding and colonic ureolysis on the UBT results. Methods: Three different studies were performed. First, a 13C-UBT was performed in 41 Helicobacter pylori infected subjects before and after 1 day of therapy with sucralfate (5 g), colloidal bismuth (600 mg), amoxycillin (2.5 g) or omeprazole (40 mg). Second, a 13C-UBT was performed in 10 H. pylori-positive patients after an overnight fast and repeated 2 h after lunch. Finally, a 13C-UBT was carried out in seven healthy volunteers, with breath sampling prolonged to 6 h to investigate colonic bacterial ureolysis. Results: Even a short course of drugs specific for H. pylori may result in a falsely negative 13C-UBT. Feeding does not interfere with the 13C-UBT in infected subjects. No significant 13C-urea breakdown by colonic bacteria is observed during the 13C-UBT when it is prolonged to 6 h. Conclusion: The 13C-urea breath test is a sensitive clinical tool for the non-invasive diagnosis of H. pylori infection. It is unaffected by feeding or colonic ureolysis. However, false negative results are likely even after 1 day of therapy with bactericidal, ‘cytoprotective’ or antisecretory drugs.

Notes: Background: Budesonide is a new corticosteroid with high topical anti-inflammatory activity but little systemic effect. The aim of the present study was to compare the efficacy and safety of budesonide enema (2 mg/100 mL) and 5-ASA enema (mesalazine 1 g/ 100 mL) given for 4 weeks in the treatment of active distal ulcerative colitis and proctitis. Methods: Ninety-seven patients were studied in a multicentre single-blind randomized group-comparative trial. The primary efficacy variables were endoscopy and histopathology scores obtained at 0, 2 and 4 weeks. Clinical symptoms were the secondary efficacy variables. Haematology, chemistry and adverse events were the safety variables. Results: Budesonide and 5-ASA enemas both resulted in a significant improvement in endoscopy and histopathology scores but no difference could be demonstrated between the two treatment groups. There was also a significant improvement of symptoms (number of bowel movements per day, quality of stools, presence of blood and mucus, and state of well-being) within both groups but no difference between the two treatment groups. The clinical remission rate at 4 weeks was, however, 38% for patients treated with budesonide enema but 60% for those treated with 5-ASA enema (P= 0.03). No adverse events attributed to the study drugs were recorded in either of the groups. Conclusions: Budesonide enema 2 mg/100 mL appears to be as efficient and well-tolerated as 5-ASA enema in the treatment of active distal ulcerative colitis and proctitis.

Notes: Background : Crohn's disease is associated with low bone mineral density and altered bone metabolism.Aim : To assess the evolution of bone metabolism in Crohn's disease patients treated with infliximab.Methods : We studied 71 Crohn's disease patients treated for the first time with infliximab for refractory Crohn's disease. Biochemical markers of bone formation (type-I procollagen N-terminal propeptide, bone-specific alkaline phosphatase, osteocalcin) and of bone resorption (C-telopeptide of type-I collagen) were measured in the serum before and 8 weeks after infliximab therapy and compared with values in a matched healthy control group.Results : Eight weeks after treatment with infliximab, a normalization of bone markers was observed with a median increase in formation markers of 14–51% according to marker and a lower but significant decrease in resorption marker (median 11%). A clinically relevant increase in bone formation markers was present in 30–61% of patients according to the marker. A clinically relevant decrease in C-telopeptide of type-I collagen was present in 38% of patients. No association was found with any tested demographic or clinical parameter.Conclusion : Infliximab therapy in Crohn's disease may rapidly influence bone metabolism by acting either on bone formation or bone resorption. This improvement seems to be independent of clinical response to infliximab.

Notes: Background : By temporarily suppressing the immune response, the anti-tumour necrosis factor agent, infliximab, may increase the risk of peri-operative complications.Aim : To test this hypothesis for intestinal resection in a cohort of 313 Crohn's disease patients treated with infliximab. Forty received one or more infusions prior to intestinal resection (31/40 within 12 weeks).Methods : The post-operative events of these patients were compared with those of a control group (infliximab naive) of 39 patients adjusted for age, gender and surgical procedure. Early (10 days) and late (3 months) major or minor complications were identified.Results : The incidence of early minor (15.0% vs. 12.8%) and major (12.5% vs. 7.7%) and late minor (2.5% vs. 5.1%) and major (17.5% vs. 12.8%) complications and the mean hospital stay after surgery (10.3 ± 4.0 days vs. 9.9 ± 5.5 days) were similar in both groups. A trend towards an increased early infection rate was found in infliximab pre-treated patients (6 vs. 1; P = 0.10), but more patients in this group received corticosteroids and/or immunosuppressives (29 vs. 16 patients; P 〈 0.05).Conclusion : The use of infliximab before intestinal resection does not prolong the hospital stay and does not increase the rate of post-operative complications.

Notes: The administration of indometacin to rats increases intestinal permeability and induces inflammatory pathology of the small bowel. This represents a potential model for Crohn’s disease.〈section xml:id="abs1-2"〉〈title type="main"〉Aims:To analyse the pathogenic role of T cells, tumour necrosis factor and bacterial flora in indometacin-induced changes in small bowel permeability and inflammation.〈section xml:id="abs1-3"〉〈title type="main"〉Methods:Rats were given indometacin, 13 mg/kg, on day 1 and day 2. The effects of antibiotic (metronidazole, aztreonam and amoxicillin/clavulanic acid), anti- tumour necrosis factor and interleukin-10 therapy were evaluated. The parameters used were weight change, serum haemoglobin, chromium-51 ethylenediaminetetra-acetate permeability and macro-and microscopic score on day 5. Results in conventionally harboured rats were compared with those in T-cell-free rats. Additional in vitro experiments were carried out to test the effect of metronidazole on tumour necrosis factor production.〈section xml:id="abs1-4"〉〈title type="main"〉Results:Indometacin administration resulted in small bowel ulcers and inflammation, independently of T cells. Metronidazole was more potent than amoxicillin/clavulanic acid and anti-tumour necrosis factor in improving the indometacin-induced small bowel inflammation. Only part of the efficacy was through improvement of increased intestinal permeability. Aztreonam and interleukin-10 had no effect. Metronidazole also suppressed in vitro lipopolysaccharide-induced tumour necrosis factor production, suggesting a therapeutic effect of this drug through the inhibition of tumour necrosis factor.〈section xml:id="abs1-5"〉〈title type="main"〉Conclusions:These data implicate anaerobic bacteria and tumour necrosis factor production, but not T cells, as essential elements of the pathogenesis of indometacin-induced small bowel inflammation. Tumour necrosis factor is also involved in the change in intestinal permeability. Metronidazole was the most efficacious drug in this model, probably because it suppressed anaerobic bacteria and directly inhibited tumour necrosis factor production.

Notes: Background:  The ligation of CD40 by CD154 is a critical step in the interaction between APC and T cells. In animals, antagonizing CD40L-CD40 has been shown to reduce the severity of several autoimmune and inflammatory disorders, including experimental colitis.Aim:  To investigate tolerability and safety of an antagonist chimeric monoclonal anti-human CD40 antibody (ch5D12) for treatment of Crohn's disease.Method:  ch5D12 was administrated to 18 patients with moderate to severe Crohn's disease in a single dose, open-label dose-escalation phase I/IIa study.Results:  ch5D12 plasma concentrations increased dose-dependently after infusion. Two patients developed an anti-ch5D12 antibody response. Overall response and remission rates were 72 and 22%, respectively with no evidence for a dose–response effect. Treatment with ch5D12 reduced microscopic disease activity and intensity of the lamina propria cell infiltrate, but did not alter percentages of circulating T and B cells. ch5D12 was well tolerated, although some patients experienced headache, muscle aches, or joint pains, which may have been related to the study drug.Conclusions:  Antagonizing CD154–CD40 interactions with ch5D12 is a promising therapeutic approach for remission induction in Crohn's disease.

Notes: Background:  Major depressive disorder is the most common psychiatric diagnosis in Crohn's disease. In other chronic diseases, evidence suggests that depression influences the course of the disease. Strong evidence of such a mediating role of major depressive disorder in Crohn's disease has never been found.Aim:  To assess the relationship between major depressive disorder and outcome of treatment of luminal Crohn's disease with infliximab.Methods:  In this prospective study, 100 consecutive unselected patients underwent assessment of psychosocial, demographical disease-related biological and clinical parameters at baseline and at 4 weeks after infliximab. Major depressive disorder was diagnosed using the Patient Health Questionnaire. Subsequently, the patients were followed up clinically until the next flare or during 9 months.Results:  The Crohn's disease responded in 75% of the patients, and remission was achieved in 60%. The presence of major depressive disorder at baseline predicted a lower remission rate (OR = 0.166, 95% CI = 0.049–0.567, P = 0.004). At follow-up, 88% of the patients needed retreatment. At univariate regression analysis, major depressive disorder significantly decreased time to retreatment (P = 0.001). Multivariate Cox regression confirmed major depressive disorder as an independent determinant of active disease both at baseline and at re-evaluation (hazard ratio = 2.271, 95% CI: 1.36–3.79, P = 0.002).Conclusion:  Major depressive disorder is a risk factor for failure to achieve remission with infliximab and for earlier retreatment in patients with active luminal Crohn's disease. Assessment and management of major depressive disorder should be part of the clinical approach to patients with Crohn's disease.