Ribonucleases and host defense: identification, localization and gene expression in adherent monocytes in vitro

Modern medical therapy is increasingly based on evidence. The evidence presented here is that budesonide (Entocort, Astra Pharma) 9 mg/day is superior to placebo and equivalent to systemically active glucocorticosteroids in achieving disease remission in patients with active Crohn's disease, and in prolonging the recurrence time of symptomatic disease. Budesonide causes less disturbance to adrenal function than prednisone or prednisolone and may cause fewer steroid-associated symptoms. Thus, budesonide is the safer, more effective steroid of choice to treat patients with Crohn's disease.     

Drug treatment of Crohn's disease]

The medical management of Crohn's disease has changed in recent years, but the mainstay of treatment is still prednisone. A substantial fraction of steroid-treated patients are refractory to therapy and addition of azathioprine or methotrexate has a corticosteroid-sparing effect and increases duration of remission. Controlled ileal release budesonide (9 mg daily) induces clinical remission in 60-70% of patients with Crohn's ileitis or right-sided colitis, and continued budesonide treatment has a finite effect on the duration of remission. The efficacy of mesalazine in active Crohn's disease is limited and high doses are required (4000 mg/day). The role of mesalazine in Crohn's disease in remission is disputed, and there is no evidence of a corticosteroid-sparing effect.     

Analysis of immunoglobulin-synthesizing cells in human dental periapical lesions by in situ hybridization and immunohistochemistry

The iron status of 22 children and adolescents with Crohn's disease (mean age: 13 years) was evaluated. Eleven patients were suffering from active disease with inflammation, identified by at least one abnormal value for serum orosomucoid, C-reactive protein or sedimentation rate (group I). Eleven patients were in clinical remission and showed no biological evidence of inflammation (group II). Hemoglobin and red cell indices, erythrocyte protoporphyrin, serum iron, transferrin, serum ferritin and basic red cell ferritin were determined in all patients. The usual indicators of iron status, particularly serum ferritin, were affected by the inflammatory processes, but basic red cell ferritin appeared to be independent of inflammation. Basic red cell ferritin can therefore be considered to be a reliable indicator of iron status in children and adolescents with Crohn's disease.     

Gastrointestinal pH profiles in patients with inflammatory bowel disease

BACKGROUND: 5-Amino salicylic acid preparations are used in therapy for patients with inflammatory bowel diseases. The bioavailability of these drugs depends on their coating. AIM: To determine whether intraluminal pH is decreased by the presence of inflammation, thereby altering the release of 5-amino salicylic acid in the intestinal lumen. METHODS: Intraluminal gastrointestinal pH was measured by means of a radiotelemetry capsule in 12 healthy controls, in 12 patients with Crohn's disease (five with active disease), and in 11 patients with ulcerative colitis (seven with active disease). RESULTS: The median gastric pH values in the patient groups (Crohn's disease 2.4, range 1.5-4.1; ulcerative colitis 1.95, range 1.55-4.4) were significantly higher than those observed in the controls (1.55, range 0.95-2.6). In the small bowel and colonic segments, all the pH values of Crohn's disease patients were comparable to those of the controls, as were the pH values in the proximal small intestine and in the left colon in patients with ulcerative colitis. However, the latter group had higher pH values in the terminal ileum, the caecum and the right colon. Patients with active disease had comparable median gastrointestinal pH values to patients in remission. CONCLUSIONS: The luminal release of 5-amino salicylic acid might not be inhibited by low pH in patients with active inflammatory bowel diseases. This supports a safe disintegration of the slow release mesalazine preparations even in the presence of severe disease.     

Medical therapy of inflammatory bowel disease

In the past years the advances in therapy of IBD have been characterized mainly by the more widespread use of immunosuppression. Especially azathioprine is currently used in Crohn's disease with methotrexate as the second-line immunosuppressive drug. Cyclosporin may become a drug of choice to treat severe ulcerative colitis but its effect in the long term is probably insufficient. Topically acting glucocorticosteroids have emerged as a valuable safer alternative to standard glucocorticosteroids (GCS) in right ileocolonic Crohn's disease but GCS have no role in maintenance therapy. The most significant development in recent years is the introduction of immunomodulatory treatments using cytokines and anticytokines. The first data show that anti-TNF monoclonal antibodies, especially cA2, not only may result in rapid control of active Crohn's disease but also achieve rapid tissue healing. Repeated administration of cA2 maintains remission. Immunomodulation therapy creates great expectations since early reset of the immunostat might be able to control inflammation in the long term. Safety will be a key issue.     

Changing the relative amplitudes of wave packets to induce nonlocal effects

The short- and long-term effects of an elemental diet in children with acute Crohn's disease were compared with those of prednisolone in historical controls. Clinical remission was induced in 25 of 30 and in 18 of 28 episodes treated for six weeks with an elemental diet and prednisolone. Patients with proximal disease had longer remission after treatment with an elemental diet (p < 0.05) than did patients with colonic disease after treatment with prednisolone (p < 0.01). Disease activity index score improved in both groups compared with the pretreatment scores (p < 0.05). However, the improvement in the elemental diet group was significantly better than in the prednisolone group (p < 0.001). Changes in linear growth were better after treatment with an elemental diet compared with steroids (p < 0.001). Serum albumin and haematocrit concentrations all improved significantly in the children treated with an elemental diet (p < 0.001) but not in those treated with steroids. Thus an elemental diet was better than prednisolone in proximal disease and confirmed improved growth and nutritional status.     

Can fish oil maintain Crohn's disease in remission?

One of the greatest challenges in managing Crohn's disease is to maintain remission. Although pharmacologic approaches to maintaining Crohn's disease in remission have significantly improved, most of the currently available modalities are associated with significant morbidity. Recently, an enteric-coated preparation of fish oil has been shown to be effective in reducing the rate of relapse in patients with Crohn's disease in remission who are at high risk of relapse. Because of minimal side effects, fish oil appears to be an ideal maintenance agent in Crohn's disease. However, until results from studies that compare the therapeutic effect of fish oil to the currently available maintenance agents are available, fish oil supplementation cannot be recommended as a sole maintenance agent at present. It does, however, seem prudent to promote a diet rich in fish oil in patients with Crohn's disease.     

Long-term management of Crohn's disease with mesalamine capsules (Pentasa). Pentasa Crohn's Disease Compassionate Use Study Group

Current long-term treatment of Crohn's disease is unsatisfactory. Based on the Crohn's Disease Activity Index (CDAI), this multicenter trial enrolled patients with either active Crohn's disease (CDAI > or = 150) or disease in remission (CDAI < 150). The primary measure of therapeutic response was mean change in CDAI from baseline to final visit. All patients began treatment with a dosage of < or = 4 g/day of mesalamine that ranged from 3.7 g at baseline to 3.4 g at final visit. Overall, 467 patients were enrolled: 333 (active disease) and 134 (remission). The median study participation time was 14 months. For patients entering with active disease, the mean reduction in CDAI was 77 points, with 42% (122/289) achieving remission by their final visit. For patients entering in remission, there was an increase in mean CDAI from 90 at baseline to 96 at final visit, with 79% (95/120) of patients in remission at final visit and 72% (31/43) in remission continuously after 12 months of therapy. From baseline to final visit, the mean prednisone dose decreased 5 mg/day in patients with active disease and 11 mg/day in patients in remission. Mesalamine was well tolerated and no adverse laboratory trends were observed. These results suggest that controlled-release mesalamine shows promise as a steroid-sparing agent and as a safe and effective long-term therapy for the induction of and maintenance of remission of mild-to-moderate Crohn's disease.     

Growth as a parameter of inflammation in Crohn's disease, using roentgen stereophotogrammetric analysis

Growth rate was measured in 12 children with Crohn's disease and growth retardation, using roentgen stereophotogrammetric analysis. The method was chosen as it provides an opportunity to record growth rate accurately during short periods of time. Growth was followed at variable intervals of 4-12 weeks depending on the clinical situation. Growth rate was shown to correlate with symptoms, laboratory tests and nitrogen balance. These findings indicate that growth, when it is affected, fluctuates in a similar way as albumin, acute phase proteins and symptoms, all assumed to reflect the disease activity. Short-term growth measurements appear to be helpful in monitoring the disease progress or response to therapy in children with Crohn's disease, particularly when growth retardation is the only manifestation of the disease.     

Tumour necrosis factor alpha and interleukin 1beta in relapse of Crohn's disease

BACKGROUND: Concentrations of proinflammatory cytokines are increased in the intestinal mucosa of patients with active Crohn's disease. Experimental immunotherapeutic interventions with anticytokine agents in refractory Crohn's disease show that tumour necrosis factor alpha (TNF alpha) may be an important mediator of inflammation. We investigated the relation between production of TNF alpha and interleukin 1beta by mononuclear cells of the colonic lamina propria in patients with remitting Crohn's disease and the risk of relapse. METHODS: We followed up 137 patients with Crohn's disease in steroid-induced remission for 1 year. Secretion of proinflammatory cytokines (tumour necrosis factor alpha [TNF alpha] and interleukin 1beta) was assessed after short-term culture of human lamina propria mononuclear cells. FINDINGS: Increased secretion of TNF alpha and interleukin 1beta were predictive for acute relapses within the next year. Site and extent of disease, baseline demographics, and serum acute-phase proteins had little predictive value. INTERPRETATION: TNF alpha is important as a target molecule for immune interventions in Crohn's disease. The capacity to produce TNF alpha or interleukin 1beta may identify patients who would benefit from anti-inflammatory remission maintenance.     

A randomized controlled study of total parenteral nutrition and enteral nutrition by elemental and polymeric diet as primary therapy in active phase of Crohn's disease

We performed randomized controlled study to compare the short-term therapeutic effect of total parenteral nutrition (TPN), elemental diet (ED) and polymeric diet (PD) given as primary therapy in active phase of Crohn's disease. In hospital for Crohn's disease, twenty-eight patients were given nutritional therapy: 9 patients by TPN, 10 by ED, and 9 by PD. Nutritional state, inflammatory reactions, disease activity and clinical remission rate were assessed two weeks and four weeks after treatment, and morphological findings were assessed before and after each nutritional therapy by radiographic and colonoscopic findings. Inflammatory reactions were more effectively controlled by TPN and ED than by PD, and early improvement achieved by TPN and ED was especially note-worthy. Clinical remission rate after treatment by TPN was highest in three types of nutritional approach, but no significant difference was seen at any point. In nutritional state, disease activity and morphological findings, comparable changes were effected without preference. These results suggest that nutritional therapy by total parenteral nutrition and elemental diet is superior to polymeric diet for treating active phase of Crohn's disease with marked inflammatory reactions.     

Epitope mapping of cytochrome P450cam (CYP101)

OBJECTIVE: A retrospective study of women with inflammatory bowel disease, aged 16-45 years during the 20-year period 1967-1986, was carried out in North East Scotland. METHOD: Five-hundred and three women were identified: 15 patients had died from unrelated causes and 22 had emigrated, but 409 of the remaining 466 patients (88%) replied to the study questionnaire. RESULTS: Women with ulcerative colitis and Crohn's disease had normal fertility when compared with the general population of north east Scotland. However, unresolved infertility problems were more frequent in women who had undergone surgery for inflammatory bowel disease compared with those who had not (12% vs. 5% for Crohn's disease; 25% vs. 7% for ulcerative colitis). Disease relapse rates did not increase in pregnancy. CONCLUSIONS: Overall, at conception women with active disease were as likely to have a normal full-term pregnancy as those in remission. However, spontaneous abortion occurred in five (36%) pregnancies of women who had undergone previous surgery for Crohn's disease and had evidence of recurrent disease. Three of these pregnancies were associated with active disease.     

Reversal of growth arrest in adolescents with Crohn's disease after parenteral alimentation

Growth arrest and delayed onset of puberty often complicate childhood onset Crohn's disease of the small bowel (granulomatous enteritis). Nutritional deficits arising from inadequate dietary intake, malabsorption, and increased caloric needs may contribute to growth retardation. To assess whether a sustained high caloric and nitrogen intake could reestablish growth, 4 children with extensive Crohn's disease of the small bowel were studied before and after parenteral alimentation which was instituted for symtomatic disease control. Weight gain, positive nitrogen balance, and improved nutritional status were achieved during parenteral alimentation in each patient. In 2 patients weight gain was sustained using oral nutritional supplements, and a substantial increase in linear skeletal growth continued in the ensuing months. One patient entered puberty within 4 months of parenteral alimentation and another had the onset of menarche and the development of secondary sex characteristics 4 months after parenteral alimentation and resection of diseased bowel. Growth may be reestablished in some growth-arrested children if intake is sufficient to establish a sustained positive caloric and nitrogen balance. Nutritional requirements imposed by the demands of growth and active disease and often compounded by the catabolic effects of corticosteroids may be excessive; growth may occur only if these needs are met orally and/or parenterally.     

Enteral nutrition in acute Crohn disease

High-dose corticosteroids remain the gold standard of therapy in acute Crohn's disease, but is associated with a variety of side effects. Nutritional therapy could be an interesting alternative, but corticosteroids are meant to be significantly superior according to efficacy. Published studies, identified by references, MEDLINE and meta-analysis, were evaluated for efficacy of nutritional therapy in acute Crohn's disease. In 18 evaluable of 38 identified publications, 571 patients were treated with nutritional therapy: 295 received elemental diet, 214 oligopeptide diet and 62 polymeric diet. Remission rates were 60%, 55% and 66% respectively. However, only intention-to-treat-analysis was performed in all the studies. When correcting for patients who really were treated with nutritional therapy, remission rates were substantially better: 73%, 70% and 67% respectively, thus comparable with that of corticosteroids. Positive predictors for successful treatment were stenosing disease and low ESR. Remission seems to last as long as after corticosteroid treatment, when a reinduction diet is performed. Negative aspects of nutritional therapy are poor tolerance and higher costs. Perspectives for the future aim on broadening of indications, improving acceptance (by adjuvant instead of exclusive nutrition, or new flavors) and efficacy by modification of compounds (such as glutamine, omega-3 fatty acids or trace elements) or combination with other therapeutic agents (e.g., mesalamine).     

Bile acid metabolism and plasma protein turnover in Crohn's disease

Postprandial duodenal bile acids, intestinal protein loss, and albumin and IgG turnover were studied in 19 non-operated patients with Crohn's disease. A lesion of the terminal ileum was present in 18 of 19 patients, either alone or associated with regional colitis. Identical bile acid studies were made in a control group of 20 patients with chronic diarrhoea of undetermined origin. Duodenal bile acid concentration was decreased in 9 of 19 patients with Crohn's disease, and in 5 of 20 patients with unexplained diarrhoea. The glycine/taurine-ratio was increased in 8 of 17 patients with Crohn's disease, but in only one of the 20 control patients. Abnormal intestinal protein loss was present in 13 of 14 patients with Crohn's disease. The fractional catabolic rate of albumin and IgG was increased in all 17 cases of Crohn's disease studied, except the patient with no protein loss. A statistically significant and positive correlation was observed between glycine/taurine-ratio and fractional catabolic rate of both albumin and IgG. No patient with Crohn's disease harboured an abnormal bacterial flora in the proximal small intestine. It is concluded that, in the absence of abnormal bacterial flora in the proximal jejunum, the glycine/taurine-ratio is more valuable as an indicator of terminal ileopathy than postprandial duodenal bile acid concentration in nonoperated patients with terminal ileitis. Abnormal intestinal protein loss and increased catabolic rate of albumin and IgG are practically always present in active Crohn's disease and are strong evidence of an organic gastrointestinal lesion in patients with normal radiographic findings.     

Long-term follow-up of patients with Crohn's disease treated with azathioprine or 6-mercaptopurine

BACKGROUND: Crohn's ulcerative gastrointestinal disease is presently managed through a variety of medical interventions, including-according to severity of illness-anti-inflammatory, immunosuppressive, and corticosteroid agents; and with remedial surgery to correct anatomical abnormalities caused by disease processes. The immunosuppressant azathioprine (or its metabolite, 6-mercaptopurine) is considered an efficient maintenance therapy for Crohn's, but there is always concern about bone-marrow suppression, liver damage, and other adverse effects. For how long persons with this disease should be given these drugs has not been determined. METHODS: Patients who were treated with azathioprine or 6-mercaptopurine for more than 6 months, and who were in prolonged clinical remission (> 6 months without steroids) were followed. The time-to-relapse was analysed in those on treatment, in those who stopped treatment for reasons other than a relapse, and in the whole sample, taking into account that they could be treated with the drugs or not, as a function of time. The influence of concomitant variables on time-to-relapse rate was examined using the Cox proportional hazard model. FINDINGS: In the 157 patients who continued to take the therapy, cumulative probabilities of relapse at 1 and 5 years were 11% and 32% respectively. Female gender, younger age, and a time for achieving remission more than 6 months were associated with a higher risk of relapse. In 42 patients who stopped therapy, probabilities of relapse at 1 and 5 years were 38% and 75%, respectively. Male gender, younger age and duration of remission less than 4 years were associated with a higher risk of relapse. After 4 years of remission on these drugs, the risk of relapse appeared to be similar, whether the therapy was maintained or stopped. INTERPRETATION: Taking into account the potential risks of long-term immunosuppressive therapy, the usefulness of maintaining azathioprine or 6-mercaptopurine in patients who have been in remission for more than 4 years is questionable.     

Modulation of intestinal immune system by dietary fat intake: relevance to Crohn's disease

Gut-associated lymphoid tissue is the major inductive site of the mucosal immune system, which is functionally independent of the systemic immune system. Both the amount and type of dietary fat modulate intestinal immune function. Absorption of long-chain fatty acids stimulates lymphocyte flux and lymphocyte blastogenesis in intestinal lymphatics. Long-chain fatty acid absorption also significantly enhances migration of T lymphocytes to Peyer's patches, possibly due to up-regulation of adhesion molecules, such as alpha4-integrin and L-selectin. Lipoproteins are involved in stimulation of lymphocyte function by both receptor-dependent and independent mechanisms. However, unsaturated fatty acids at higher concentrations have a suppressive effect on cell-mediated immunity via eicosanoid release, receptor affinity changes or interactions with intracellular signal transduction. Fat absorption also influences various other cells in the intestinal mucosa: increased cytokine release from intestinal epithelial cells follows long-chain fatty acid absorption. In Crohn's disease, elemental diets and total parenteral nutrition often induce remission, possibly by reducing antigenic load on activated immune cells in the intestine and, thus, down-regulating hyperreactive CD4 cells. Dietary oleic acid supplements caused an immunological reversal effect in the intestinal immune system of animals fed an elemental diet. An excess of long-chain fatty acids in an elemental diet, therefore, may negate its beneficial effect on gut-associated lymphoid tissues in Crohn's disease. In contrast, supplemental dietary fish oil apparently tends to prevent relapse of Crohn's disease. Because dietary fat intake is closely associated with immunological function of the intestinal mucosa, careful manipulation of dietary fat can be important in management of this disease.     

Factors associated with the adaptation of parents with a chronically ill child

Improvement and standardization of the conservative therapy of inflammatory bowel disease has lead to a better prognosis for the patients. During the acute flare of Crohn's disease steroids are still the standard therapy, whereas 5-aminosalicylic acid (5-ASA) preparations are used for maintenance therapy during remission. In contrast ulcerative colitis may be treated with 5-ASA also for acute exacerbations. The development of new drugs as for example the topical steroids helps to improve life quality of the patients by reducing adverse side effects. Potent immunosuppressants as azathioprine and methotrexate are useful in chronic active and refractory disease. Cyclosporin A plays a role in severe steroid refractory colitis. In the future immunomodulation by application of antiinflammatory cytokines or antibodies to inflammatory cytokines may have its place in the treatment of IBD patients. In some cases, however, the conservative therapy reaches its limits. Mistakes in the therapy are made, when these limits are not recognized and complications are not discovered in time.     

Paenibacillus apiarius sp. nov

BACKGROUND & AIMS: Steroid dependence and early relapse are frequent after a prednisolone-induces remission in Crohn's disease. The aim of this trial was to test whether mesalamine started at the onset of steroid tapering increases the rate of weaning from prednisolone and reduces the relapse rate after prednisolone cessation. METHODS: One hundred fifty patients with active Crohn's disease were administered oral prednisolone (1 mg.kg(-1). day(-1)) x 3-7 weeks; 129 patients went into clinical remission and were randomized to Pentasa (4 g . day(-1)) or placebo, administered until weaning and for 1 year thereafter. RESULTS: Groups were similar for clinical and biological items collected initially. Weaning failure rate was 30% and 12% in the placebo and mesalamine arms, respectively. At the end of the trial, 9 of 36 patients administered placebo and 14 of 48 administered mesalamine were in remission. Both groups had similar time to relapse curves in the postweaning year; after adjusting for risk factors (high Crohn's Disease Activity Index, white blood cell count of >9 x 10(9) /l-1 at weaning, and use of a medical treatment in the month before inclusion), Pentasa was found to be superior to placebo. CONCLUSIONS: After a prednisolone-induces remission in Crohn's disease, mesalamine facilitates steroid withdrawal and, during the postweaning year, may reduce the relapse rate in certain patient subgroups.     

Refractory IBD: medical management

Refractory inflammatory bowel disease (IBD) can be defined as persistent acute symptomatic disease despite anti-inflammatory therapy or as chronically active disease requiring continuous treatment for relief of symptoms. Treatment options include azathioprine (AZA), 6-mercaptopurine (6-MP), methotrexate (MTX), cyclosporine (CYA), and experimental therapies that are cytokines or cytokine antagonists. AZA and 6-MP have identical actions in IBD. 6-MP is effective in about 75% of patients with inflammatory Crohn's disease. The mean time until the onset of action is 3.1 months. AZA is effective in ulcerative colitis as a steroid-sparing agent. Side-effects occur in 10-15% of patients on AZA or 6-MP for IBD. MTX induces symptomatic remission in about 40% of patients with Crohn's disease. The potential for hepatic fibrosis from MTX is a concern. CYA appears effective in the acute management of severe ulcerative colitis. CYA has not proven useful in the long-term management of Crohn's disease. Potentially serious side-effects include hypertension and renal insufficiency. The cytokine antagonist, anti-tumor-necrosis-factor-alpha antibody, and the anti-inflammatory cytokine, interleukin 10, appear promising for the treatment of Crohn's disease.