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Abstracts

Crohn's Disease

ABSTRACTS

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Infliximab downregulates interferon-gamma production in activated gut T-lymphocytes from patients with Crohn's disease.

Agnholt J, Kaltoft K. Department of Medicine, Aarhus University Hospital, Aarhus C, Denmark. agnholt@dalnet.dk

Cytokine 2001 Aug 21;15(4):212-22

The tumour necrosis factor-alpha (TNF-alpha) neutralizing antibody, Infliximab (Ifx), reduces disease activity in patients with active steroid-dependent or fistulizing Crohn's disease. The mechanisms underlying the effects of Ifx are not fully understood. This study aims to investigate if and how Ifx regulates the interferon-gamma (IFN-gamma) production in human intestinal T-cells. Colonic T cells were expanded from 25 patients with Crohn's disease and ten healthy controls in an in vitro system, using medium supplemented with interleukin-2 and interleukin-4 but without exogenous antigen. The effect of Ifx was investigated in these in situ activated T cell cultures regarding the IFN-gamma production, proliferation, transmembrane TNF-alpha expression, cytolysis and apoptosis. T cell cultures from patients with Crohn's disease produced significantly higher levels of IFN-gamma (<0.001) and TNF-alpha (P=0.04) than T cell cultures from healthy controls. The production of IFN-gamma was downregulated by Ifx in early T cell cultures (P=0.002). Ifx bound to transmembrane TNF-alpha of activated T cells without inducing complement-mediated cytolysis, apoptosis and without affecting proliferation. Besides its known TNF-alpha neutralizing property, Ifx downregulates INF-gamma production in colonic T cell cultures. Colonic T cells express transmembrane TNF-alpha that binds Ifx. The data suggest that Ifx reduces the level of at least two pro-inflammatory cytokines leading to lower disease activity. Copyright 2001 Academic Press.

Dehydroepiandrosterone (DHEA), DHEA sulfate, and aging: contribution of the DHEAge Study to a sociobiomedical issue.

Baulieu EE, Thomas G, Legrain S, Lahlou N, Roger M, Debuire B, Faucounau V, Girard L, Hervy MP, Latour F, Leaud MC, Mokrane A, Pitti-Ferrandi H, Trivalle C, de Lacharriere O, Nouveau S, Rakoto-Arison B, Souberbielle JC, Raison J, Le Bouc Y, Raynaud A, Girerd X, Forette F. Institut National de la Sante et de la Recherche Medicale Unit 488 and College de France, 94276 Le Kremlin-Bicetre, France. baulieu@kb.inserm.fr

Proc Natl Acad Sci U S A 2000 Apr 11;97(8):4279-84

The secretion and the blood levels of the adrenal steroid dehydroepiandrosterone (DHEA) and its sulfate ester (DHEAS) decrease profoundly with age, and the question is posed whether administration of the steroid to compensate for the decline counteracts defects associated with aging. The commercial availability of DHEA outside the regular pharmaceutical-medical network in the United States creates a real public health problem that may be resolved only by appropriate long-term clinical trials in elderly men and women. Two hundred and eighty healthy individuals (women and men 60-79 years old) were given DHEA, 50 mg, or placebo, orally, daily for a year in a double-blind, placebo-controlled study. No potentially harmful accumulation of DHEAS and active steroids was recorded. Besides the reestablishment of a "young" concentration of DHEAS, a small increase of testosterone and estradiol was noted, particularly in women, and may be involved in the significantly demonstrated physiological-clinical manifestations here reported. Bone turnover improved selectively in women >70 years old, as assessed by the dual-energy x-ray absorptiometry (DEXA) technique and the decrease of osteoclastic activity. A significant increase in most libido parameters was also found in these older women. Improvement of the skin status was observed, particularly in women, in terms of hydration, epidermal thickness, sebum production, and pigmentation. A number of biological indices confirmed the lack of harmful consequences of this 50 mg/day DHEA administration over one year, also indicating that this kind of replacement therapy normalized some effects of aging, but does not create "supermen/women" (doping).

[Sugar free diet: a new perspective in the treatment of Crohn disease? Randomized, control study] [Article in German]

Brandes JW, Lorenz-Meyer H.

Z Gastroenterol 1981 Jan;19(1):1-12

Since several studies have shown that patients with Crohn's disease have an increased consumption of refined carbohydrates, the influence of a diet excluding refined sugar on the course of the disease was examined. In a randomised control trial, 20 patients (10 patients in each group) with Crohn's disease were treated for an average of 18 months with two different diets. The patients used in the study had a low or middle activity of the disease. Drug treatment was omitted 14 days before commencement of the study. The first group was treated with a low carbohydrate diet (refined sugar excluded), the second group received a high carbohydrate diet (refined sugar-rich). In patients with higher activities of the disease (activity index 100-200 points), the diet which restricted refined sugar was superior to the sugar-rich diet; in 4 out of 5 patients the disease activity decreased and remained so throughout the study-period. In contrast to this 4 patients treated with the sugar-rich diet had to be taken off the treatment because of increasing activities of the disease. In patients with quiescent disease (activity index less than 100 points), neither of the diets showed detrimental effects. The statistical analysis of clinical and laboratory dates noted during the study period resulted in no significant differences between the two groups.

Effect of long-term oral glutamine supplements on small intestinal permeability in patients with Crohn's disease.

Den Hond E, Hiele M, Peeters M, Ghoos Y, Rutgeerts P. Department of Gastroenterology, University Hospital Leuven, Belgium.

JPEN J Parenter Enteral Nutr 1999 Jan-Feb;23(1):7-11

Background: Glutamine is a major fuel and an important nitrogen source for the small intestinal cell. It plays a key role in maintaining mucosal cell integrity and gut barrier function. Increased permeability may be a factor in the pathogenesis of Crohn's disease and may be an interesting parameter in the follow-up of the disease. Therefore, the aim of this study was to examine whether oral glutamine supplements are able to restore an increased intestinal permeability in patients with Crohn's disease.

METHODS: The inclusion criteria for the study were Crohn's disease and a disturbed small intestinal permeability for 51Cr-EDTA. Of 38 patients screened, 18 had an increased permeability (6 hours urinary excretion >1.1% of label recovered in urine). Fourteen patients were included in the study and were randomized to receive either oral glutamine (7 g three times per day; n = 7) or placebo (7 g glycine three times per day; n = 7) in addition to their normal treatment during a 4-week period. The study was performed in a double-blind manner. RESULTS: Baseline permeability (mean SD) was 2.32%0.77% dose in the glutamine group and 2.29%0.67% dose in the placebo group. Permeability did not change significantly after glutamine (3.26%2.15% dose) or after placebo (2.27%1.32% dose). There was no significant effect on plasma glutamine, plasma glutamate, plasma ammonium, Crohn's disease activity index, C-reactive protein, or nutritional status.

CONCLUSIONS: Oral glutamine supplements, in the dose administered, do not seem to restore impaired permeability in patients with Crohn's disease.

Treatment of active Crohn's disease with recombinant human granulocyte-macrophage colony-stimulating factor.

Dieckgraefe BK, Korzenik JR. Division of Gastroenterology, Department of Internal Medicine, Washington University School of Medicine, 660 South Euclid Avenue, Box 8124, St Louis, MO 63110, USA. dieck@im.wustl.edu

Lancet. 2002 Nov 9;360(9344):1478-80.

Treatment for Crohn's disease is aimed at immunosuppression. Yet inherited disorders associated with defective innate immunity often lead to development of a Crohn's-like disease. We performed an open-label dose-escalation trial (4-8 microg/kg per day) to investigate the safety and possible benefit of granulocyte-macrophage colony-stimulating factor (GM-CSF) in the treatment of 15 patients with moderate to severe Crohn's disease. No patients had worsening of their disease. Adverse events were negligible and included minor injection site reactions and bone pain. Patients had a significant decrease in mean Crohn's disease activity index (CDAI) score during treatment (p<0.0001). After 8 weeks of treatment, mean CDAI had fallen by 190 points. Overall, 12 patients had a decrease in CDAI of more than 100 points, and eight achieved clinical remission. Retreatment was effective, and treatment was associated with increased quality-of-life measures. GM-CSF may offer an alternative to traditional immunosuppression in treatment of Crohn's disease.

Mucosal metabolism in ulcerative colitis and Crohn's disease.

Duffy MM, Regan MC, Ravichandran P, O'Keane C, Harrington MG, Fitzpatrick JM, O'Connell PR. Department of Surgery, Mater Misericordiae Hospital and University College, Dublin, Ireland.

Dis Colon Rectum 1998 Nov;41(11):1399-405

PURPOSE: Colonic mucosal metabolism of butyrate may be impaired in ulcerative colitis. In this study we sought to confirm this observation, to determine if a similar change occurs in Crohn's colitis, and to establish whether a panenteric disorder of butyrate metabolism exists in either condition.

METHODS: With use of a microculture technique, mucosal metabolic fluxes of 14[C]-labeled butyrate and 14[C]-labeled glutamine were measured as 14[C] carbon dioxide production in mucosal biopsy specimens from the colon and ileum in patients with ulcerative colitis, Crohn's colitis, and healthy bowel. Results were expressed as pmol/microg biopsy DNA/hour.

RESULTS: In the colon the mucosal metabolic fluxes of both butyrate and glutamine are reduced in both ulcerative colitis and Crohn's colitis compared with healthy controls. These changes were most marked in the presence of moderate to severe mucosal inflammation, there being no significant difference in mucosal metabolic flux between mildly inflamed mucosa and healthy controls. In the ileum the mucosal metabolic fluxes of butyrate and glutamine did not differ between healthy controls and those with either ulcerative colitis or Crohn's colitis.

CONCLUSIONS: Changes in colonic mucosal metabolism of butyrate and glutamine in inflammatory bowel disease occur as a consequence of the inflammatory process and are not peculiar to ulcerative colitis. Ileal mucosal metabolism is unchanged in ulcerative colitis and Crohn's colitis, indicating the absence of a panenteric abnormality of mucosal metabolism in these two conditions.

Infliximab for the treatment of Crohn's disease: efficacy, safety and pharmacoeconomics.

Feagan BG, Enns R, Fedorak RN, Panaccione R, Pare P, Steinhart AH, Wild G. London Clinical Trials Research Group, London, Canada. feagan@lctrg.com

Can J Clin Pharmacol 2001 Winter;8(4):188-98

Crohn's disease is a chronic inflammatory disorder of the gastrointestinal tract. From the perspective of the patient, symptoms of the disease significantly impair quality of life and interfere with activities of daily living. Conventional medical treatment of Crohn's disease includes the use of nonspecific anti-inflammatory drugs, immunosuppressives and antibiotics. These therapies are characterized by a delayed onset of action, incomplete response rates and a substantial risk of adverse effects. Although surgery is frequently used to treat complications, postoperative recurrence is an important problem. Infliximab, a chimeric monoclonal antibody directed toward tumour necrosis factor alpha, is highly effective for the treatment of active Crohn's disease. In randomized, placebo-controlled clinical trials, 82% of patients who received 5 mg/kg of Infliximab had a clinically significant response, compared with 17% of those given placebo (P<0.001). Moreover, Infliximab is the only medical therapy that has been shown to be effective for the treatment of fistulizing Crohn's disease. Infusion reactions are the most common adverse effect. Whether treatment with Infliximab is associated with an increased risk of neoplasia, infection or autoimmune disease is unknown. Therefore, further long term safety studies are required. Despite the relatively high cost of drug acquisition, preliminary pharmacoeconomic analysis indicates that Infliximab is cost effective compared with existing treatments. Infliximab is recommended for the treatment of active Crohn's disease refractory to conventional drugs, and is the treatment of choice for fistulizing Crohn's disease.

Nutritional supplementation with N-3 fatty acids and antioxidants in patients with Crohn's disease in remission: effects on antioxidant status and fatty acid profile.

Geerling BJ, Badart-Smook A, van Deursen C, van Houwelingen AC, Russel MG, Stockbrugger RW, Brummer RJ. Department of Gastroenterology, University of Maastricht, The Netherlands.

Inflamm Bowel Dis 2000 May;6(2):77-84

In patients with Crohn's disease (CD), malnutrition is frequently observed and is generally accepted to be an important issue. The aim of this study was to investigate the effects of 3 months of supplementation with a liquid formula containing either antioxidants (AO) or n-3 fatty acids plus AO on the antioxidant status and fatty acid profile of plasma phospholipids and adipose tissue, respectively, in patients with long-standing CD currently in remission. In a randomized, double-blind placebo-controlled study, CD patients received either placebo, AO, or n-3 fatty acids plus AO for 3 months in addition to their regular diet. In all, 25/37 CD patients completed the study. AO status was assessed by blood biochemical parameters. A statistical per-protocol analysis was performed. Serum concentrations of selenium, vitamin C, and vitamin E, the activity of superoxide dismutase and total antioxidant status were significantly (p < 0.05) increased after AO supplementation. Furthermore, compared with controls, serum concentrations of beta-carotene, selenium, and vitamin C and the activity of glutathione peroxidase (GPx) were significantly (p < 0.05) lower before supplementation; however, after AO supplementation these levels were not significantly different from controls (except for GPx). N-3 fatty acids plus AO supplementation significantly (p < 0.05) decreased the proportion of arachidonic acid, and increased the proportion of eicosapentanoic acid and docosahexanoic acid in both plasma phospholipids and adipose tissue. Supplementation with antioxidants improved antioxidant status in patients with CD in remission. In addition, supplementation with n-3 fatty acids plus antioxidants significantly changed the eicosanoid precursor profile, which may lead to the production of eicosanoids with attenuated proinflammatory activity. This study indicates that an immunomodulating formula containing n-3 fatty acids and/or AO may have the potential to play a role in the treatment of CD.

Controlled trial of polymeric versus elemental diet in treatment of active Crohn's disease.

Giaffer MH, North G, Holdsworth CD. Gastroenterology Unit, Royal Hallamshire Hospital, Sheffield.

Lancet 1990 Apr 7;335(8693):816-9

30 patients with active Crohn's disease, mean Crohn's Disease Activity Index 301 (SE 32), who would otherwise have been treated with steroids, were randomised to receive for 4 weeks either an elemental diet ('Vivonex') (n = 16) or a polymeric diet ('Fortison') (n = 14). Assessment on days 10 and 28 showed that clinical remission occurred in 5 (36%) of the 14 patients on fortison compared with 12 (75%) of the 16 patients assigned to vivonex. The difference in remission rate was significant (p less than 0.03). Dietary treatment resulted in little change in the nutritional state and various laboratory indices of activity over a 4 week period despite clinical improvement. Polymeric diets do not seem to offer an effective therapeutic alternative to elemental diets in patients with acute exacerbations of Crohn's disease.

DHEA and the skeleton (through the ages).

Gordon CM, Glowacki J, LeBoff MS. Division of Adolescent/Young Adult Medicine, Children's Hospital, Boston, MA 02115, USA. Gordon_c@al.tch.harvard.edu

Endocrine 1999 Aug;11(1):1-11

Dehydroepiandrosterone (DHEA) and its sulfate ester, DHEAS, are the most abundant steroids 0in the human circulation, although their exact biological significance is not completely understood. DHEA(S) levels are high in fetal life, decrease after birth, and show a marked pubertal increase to a maximal level during young adulthood. In healthy adults, DHEAS levels decline to 10-20% of peak levels by age 70 yr. This review summarizes information concerning the role of DHEA in skeletal physiology, including modulation of the skeletal insulin-like growth factor regulatory system, and its effects on secretion of proresorptive cytokines. The pattern of secretion of DHEA throughout the life cycle is discussed, as well as its potential usefulness in specific disease states as an agent with anabolic and antiosteolyic effects on bone.

Refined carbohydrate, smooth-muscle spasm and disease of the colon.

Grimes DS.

Lancet 1976 Feb 21;1(7956):395-7

A diet high in refined carbohydrate is implicated in the aetiology of some diseases of the colon-i.e., diverticular disease, irritable bowel syndrome, ulcerative colitis, non-occlusive ischaemic colitis, and pseudomembranous colitis. It is suggested that spasm of the smooth muscle is the common pathogenetic mechanism in these colonic diseases. The strength of the spasm producing increased pressure in the colonic lumen or wall and the length of time for which the colon has been affected are believed to determine the type of disease resulting. A diet high in refined carbohydrate allows the intense muscle spasm to occur because the physical buffering effect of faecal bulk is considerably reduced.

Management of Crohn's Disease in Adults.

Hanauer SB and Sandborn W.

Am J Gastroenterol March 2001;96:635-643.

No abstract available.

Dehydroepiandrosterone retards atherosclerosis formation through its conversion to estrogen: the possible role of nitric oxide.

Hayashi T, Esaki T, Muto E, Kano H, Asai Y, Thakur NK, Sumi D, Jayachandran M, Iguchi A. Department of Geriatrics, Nagoya University School of Medicine, Nagoya, Japan. hayashi@med.nagoya-u.ac.jp

Arterioscler Thromb Vasc Biol 2000 Mar;20(3):782-92

Dehydroepiandrosterone (DHEA) is speculated to have an antiatherosclerotic effect, although the mechanism of action remains unclear. The objective of the current study was to determine whether the antiatherosclerotic effect of DHEA is related to its conversion to estrogen and to define the role of nitric oxide (NO) in the antiatherosclerotic effect of DHEA. Forty-eight oophorectomized rabbits were divided into 5 groups and fed the following diets for 10 weeks: group 1, a regular rabbit diet plus 1% cholesterol (a high-cholesterol diet [HCD]); group 2, an HCD plus 0.3% DHEA; group 3, an HCD plus 0.3% DHEA and fadrozole (2.0 mg x kg(-1) x d(-1)), a specific aromatase inhibitor; group 4, an HCD plus 17beta-estradiol (20 microg x kg(-1) x d(-1)); and group 5, a regular diet. Atherosclerotic lesions, lipid deposition in aortic vessels, and basal and stimulated NO release were measured in the aforementioned groups of rabbits. NO release was measured by using an NO-selective electrode as well as by measuring vascular responses and the plasma NO metabolites nitrite and nitrate. The plasma total cholesterol level was increased, but there were no significant differences in lipid profile in the 4 groups of rabbits that were fed the HCD. The area occupied by atherosclerosis in the thoracic aorta was diminished by approximately 60% in the DHEA-treated rabbits (group 2) compared with the HCD group of rabbits (group 1); there was a corresponding 80% decrease in the estradiol group (group 4) but only a 30% decrease in the DHEA plus fadrozole group (group 3). In the aortas of rabbits from groups 1 and 3, the acetylcholine-induced and tone-related basal NO-mediated relaxations were diminished compared with those of the controls (group 5). However, these relaxations were restored in the aortas of group 2 and 4 rabbits, and an increase in NO release was observed in groups 2 and 4 compared with groups 1 and 3, as measured by an NO-selective electrode. Injection of neither solvent (20% ethanol/distilled water) nor fadrozole significantly affected the atherosclerotic area or the NO-related responses described above. We conclude that approximately 50% of the total antiatherosclerotic effect of DHEA was achieved through the conversion of DHEA to estrogen. NO may also play a role in the antiatherosclerotic effect of DHEA and 17beta-estradiol.

[Chemically prepared fats and Crohn disease. A pilot study of the occurrence of trans-fatty acids in the subcutaneous tissue of Crohn patients in comparison with healthy controls as a parameter of long-term fat intake] [Article in German]

Heckers H, Melcher FW, Kamenisch W, Henneking K. Zentrum fur Innere Medizin, Justus-Liebig-Universitat Giessen.

Z Gastroenterol 1988 May;26(5):259-64

In a pilot study the fatty acid pattern of subcutaneous adipose tissue from 22 patients with Crohn's disease and 22 subjects of a healthy control group was analyzed using glass capillary gas-liquid chromatography. Among all fatty acids amounting to at least 1% peak area of the chromatograms, only trans-octadecenoate differed significantly (p less than 0.05) between both study groups, the mean value being 2.39 0.83% in patients with Crohn's disease and 1.96 0.46% in healthy controls. Also the mean value of trans-hexadecenoate was significantly (p less than 0.05) higher in the Crohn group (0.25 0.07%) than in the control group (0.21 0.06%). There was a strongly positive linear correlation (p less than 0.001) between the trans-hexadecenoate and trans-octadecenoate values for the Crohn patients but not for the controls. Our results demonstrate that patients with Crohn's disease as a group consume more trans-monoene fatty acids than healthy controls, thus providing evidence for a higher intake of chemically processed fats like margarine, shortenings, frying and cooking fats. In further studies which are necessary to examine Guthy's hypothesis the fatty acid composition of adipose tissue should be followed up as an ideal marker of long-term dietary compliance.

Treatment of Crohn's disease.

Hoffmann JC, Zeitz M. Innere Medizin II, Universitatskliniken des Saarlandes, Homburg, Germany. joerg.hoffmann@medrz.uni-sb.de

Hepatogastroenterology 2000 Jan-Feb;47(31):90-100

The treatment of Crohn's disease depends on disease location and disease activity. It can be divided into medical and surgical treatment. While surgery is reserved for complications such as abscesses or failure of pharmacological treatment (fistulae, perianal disease, or strictures) medical treatment aims at induction and maintenance of remission. In order to achieve these goals supportive and therapeutic strategies must be used. Supportive measures include substitution of vitamins, particularly fat-soluble vitamins, and minerals in deficiencies due to resection or disease involvement of the small bowel. All patients on long-term steroids should receive calcium and vitamin D in order to prevent osteoporosis. Therapeutic options include drug treatment (corticosteroids, antibiotics, salicylates, and immunosuppressives), nutrition (parenteral or enteral), and endoscopy (dilatation of strictures). Depending on disease location different pharmacologic preparations of salicylates or corticosteroids should be used, e.g., enemas for distal colitis. The most potent drugs for long-term control are immunosuppressive agents, particularly azathioprine. It is the most widely investigated immunosuppressive agent in Crohn's disease and should be the first line treatment for patients with steroid refractory, chronic steroid dependent, fistulating, and stenosing courses. In the future, more potent drugs and better risk stratification criteria should improve the treatment of Crohn's disease.

Consumption of refined sugar by patients with Crohn's disease, ulcerative colitis, or irritable bowel syndrome.

Jarnerot G, Jarnmark I, Nilsson K.

Scand J Gastroenterol 1983 Nov;18(8):999-1002

The daily dietary consumption of refined sugar was studied in four equal-sized groups of 30 patients with Crohn's disease, ulcerative colitis (UC), irritable bowel syndrome (IBS), or minor orthopedic conditions. The latter group was matched for sex and age with the Crohn's disease group. The Crohn's disease patients consumed significantly more refined sugar (88.9 50.7 (SD) g/day) than the controls (64.3 45.6 g/day), the UC patients (64.3 38.7), or the IBS patients (59.9 33.3). Fifteen patients with Crohn's disease interviewed within 6 months of diagnosis consumed similar amounts of sugar (69.9 43.9) to those of the subjects in the other three groups. Fifteen other patients with Crohn's disease studied 7-36 months after diagnosis consumed significantly more refined sugar (107.9 41.2). These results indicate that the high sugar consumption in Crohn's disease is a secondary phenomenon without etiologic importance.

Is Crohn's disease an immunodeficiency? A hypothesis suggesting possible early events in the pathogenesis of Crohn's disease.

Korzenik JR, Dieckgraefe BK. Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, USA.

Dig Dis Sci. 2000 Jun;45(6):1121-9.

The current hypothesis for the etiology of Crohn's disease proposes an excessive immune response, largely T-cell driven, possibly against endogenous bacteria. Standard therapy is therefore directed towards suppression of this immune response. An alternative theory of pathogenesis accounts for epidemiologic and pathophysiologic observations that have been hitherto underemphasized, namely, (1) genetic disorders with deficiencies in neutrophil function can give rise to a clinical and pathologic syndrome indistinguishable from Crohn's; (2) abnormal neutrophil function is well described in Crohn's disease; (3) a group of bacteria implicated in other chronic inflammatory disorders causes impairment of neutrophil function; and (4) 20th century environmental risk factors for Crohn's disease may directly suppress neutrophil function and may have led to a shift in the dominant gut flora with similar effects. We propose that some cases of Crohn's disease result from the interaction of environmental and genetic influences leading to impaired mucosal neutrophil function, resulting in failure to effectively clear intramucosal microbes effectively. While encompassing existing data, this hypothesis proposes a proximate defect in the mucosal immune response. If this paradigm were correct, new therapeutic approaches might involve strategies to alter intestinal flora and stimulate neutrophil function.

Influence of diets high and low in refined sugar on stool qualities, gastrointestinal transit time and fecal bile acid excretion.

Kruis W et al.

Gastroenterology 92:1483, 1987

No abstract available.

DHEA(S): the fountain of youth.

Leowattana W. Department of Clinical Pathology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.

J Med Assoc Thai 2001 Oct;84 Suppl 2:S605-12

Dehydroepiandrosterone (DHEA) and its sulfate ester (DHEAS) are weak androgens produced primarily by the adrenal gland. Although their plasma concentrations by far exceed those of any other adrenal product, their physiological roles have not yet been determined. In plasma, where the major portion of these hormones is present in the sulfate form, it is possible that DHEAS serves as a reservoir for DHEA. Since various tissues have been shown to contain steroid sulfatases. The peak plasma levels of DHEA and DHEAS occur at approximately age 25 years, decrease progressively thereafter, and diminish by 95 per cent around the age of 85 years. The decline of DHEAS concentrations with aging has led to the suggestion that DHEAS could play a role in itself and be implicated in longevity. Moreover, the epidemiological evidence has shown that adult men with high plasma DHEAS levels are less likely to die of cardiovascular disease. DHEA has also been shown to increase the body's ability to transform food into energy and burn off excess fat. Another recent finding involves the anti-inflammatory properties of DHEA. It has been known that DHEA can lower the levels of interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-alpha). It should be pointed out that chronic inflammation is known to play a critical role in the development of the killer diseases of aging: heart disease, Alzheimer's disease and certain types of cancer. In conclusion, DHEA or DHEAS administration combined with conventional treatment may be implicated in particular conditions to improve the quality of life.

Gut Dysfunction and Chronic Disease: The Benefits of Applying the 4R GI Restoration Program

Liska, D.J., Lukaczer, D.

2001 Oct. Applied Nutritional Science Reports, MET 558. Gig Harbor, WA: Advanced Nutrition Publications Inc. (reprint available from the Institute of Functional Medicine, Gig Harbor, WA).

Omega-3 fatty acids and low carbohydrate diet for maintenance of remission in Crohn's disease. A randomized controlled multicenter trial. Study Group Members (German Crohn's Disease Study Group).

Lorenz-Meyer H, Bauer P, Nicolay C, Schulz B, Purrmann J, Fleig WE, Scheurlen C, Koop I, Pudel V, Carr L. Med. Klinik I, Stadt. Krankenhaus, Germany.

Scand J Gastroenterol 1996 Aug;31(8):778-85

BACKGROUND: There is no established therapy for maintaining remission in patients with Crohn's disease. Following different suggestions from the literature, two potential interventions for maintaining remission were tested against placebo, using either 5 g/day of a highly concentrated omega-3 fatty acid compound or a carbohydrate-reduced diet (84 g/day).

METHODS: A total of 204 patients were recruited after they had had an acute relapse. After remission (CDAI < or = 150) was attained with steroid therapy, patients were randomized to receive either omega-3 fatty acids (n = 70), placebo (n = 65), or diet (n = 69). Low-dose prednisolone was given to all patients for the first 8 weeks of intervention. CDAI and an acute-phase protein (CRP) were used as criteria for a relapse.

RESULTS: The proportion of patients without relapse within a year were similar in the placebo and active treatment group (intention-to-treat analysis: placebo, 30%; active treatment, 30%; protocol-adhering patients, 29% versus 28%). Patients did gain benefit (53%; p = 0.023) for as long as they maintained the diet. However, intention-to-treat analysis (diet group, 40%) did not show a noticeable difference when compared with placebo.

CONCLUSIONS: Omega-3 fatty acids did not show an effect on extending the remission in Crohn's disease. For the diet patients the question remains whether the noncompliant patients dropped out early because they sensed a relapse approaching or whether their condition deteriorated because they failed to comply with the diet.

Infliximab induces apoptosis in monocytes from patients with chronic active Crohn's disease by using a caspase-dependent pathway.

Lugering A, Schmidt M, Lugering N, Pauels HG, Domschke W, Kucharzik T. Department of Medicine, University of Munster, Munster, Germany.

Gastroenterology 2001 Nov;121(5):1145-57

BACKGROUND & AIMS: Treatment with a chimeric anti-tumor necrosis factor (TNF) antibody (Infliximab) has been shown to be highly efficient for patients with steroid-refractory Crohn's disease (CD). However, the mechanism of action remains largely unknown. As monocytopenia is commonly observed after treatment with Infliximab, we investigated the role of Infliximab-induced monocyte apoptosis.

METHODS: Peripheral blood monocytes from healthy volunteers and patients with chronic active CD (CDAI > 250) were isolated by density gradient centrifugation methods. Apoptosis was determined by annexin V staining DNA-laddering, and transmission electron microscopy. Activation of caspases and mitochondrial release of cytochrome C was determined by immunoblotting. Transcriptional activation of members of the Bcl-2 family have been analyzed by ribonuclease protection assay.

RESULTS: Treatment with Infliximab at therapeutic concentrations resulted in monocyte apoptosis in patients with chronic active CD in a dose-dependent manner. Infliximab-induced monocyte-apoptosis required the activation of members of the caspase-family since activation of caspase-8, -9, and -3 could be determined. Caspase activation was induced by a CD95/CD95L independent signaling pathway with mitochondrial release of cytochrome C. Cytochrome C release seemed to be triggered by transcriptional activation of Bax and Bak. Monocyte apoptosis in vivo as determined by annexin-V binding and caspase-3 activation could be shown in patients with chronic active CD as soon as 4 hours after treatment with Infliximab.

CONCLUSIONS: Monocyte apoptosis induced by Infliximab may be an important mechanism that could explain the powerful anti-inflammatory properties of Infliximab in patients with chronic active CD.

[Treatment with chimeric monoclonal antitumor necrosis factor (Infliximab) of patients with active steroid-dependent/resistant Crohn's disease and fistulas] [Article in Italian]

Martorana G, Casa A, Oliva L, Orlando A, Cottone M. Divisione di Medicina e Pneumologia, Clinica Medica R, Azienda Ospedaliera V. Cervello, Palermo.

Recenti Prog Med 2001 Jul-Aug;92(7-8):451-5

30 patients--13 with active steroid-dependent/resistant Crohn's disease (CD), 8 with active steroid-dependent/resistant disease complicated by fistulas and 9 with fistulas only (perianal or abdominal)--were treated with Infliximab. "Clinical response or remission" were defined as the reduction by 70 or more points or below 150 points of the CDAI score, respectively. As regards fistulas, "response" was defined as the reduction of 50 percent or more from baseline in the number of draining fistulas or of the quantity of drainage, "remission" as their closure. At 8 weeks 13/21 (61.9%) patients treated for active disease went on remission and 6/21 (28.5%) had a clinical response; 6/17 (35.2%) patients treated for fistulas went on remission and 8/17 (47%) had a response, while 3/17 (17.6%) didn't have any response. At 24 weeks, 9/12 (75%) patients treated for active disease and 13/16 (81.25%) treated for fistulas had a recurrence in a median time of 18.3 weeks (range, 1-36 weeks) after the first infusion.

Diet in Crohn's disease two studies of current and previous habits in newly diagnosed patients.

Mayberry JF, Rhodes J, Allan R, Newcombe RG, Regan GM, Chamberlain LM, Wragg KG.

Dig Dis Sci 1981 May;26(5):444-8

The consumption of sugar and sugar-containing foods in 32 patients with recently diagnosed Crohn's disease was significantly greater than in matched controls; the assessment was made by a questionnaire and depended upon patients recalling their eating habits. In a further study of 16 patients with Crohn's disease, all food eaten over 5 days was weighed and recorded, and no significant difference was found in the consumption of carbohydrate, protein, fats, or sugars, although the consumption of "added sugars" in patients was greater than controls. Patients who participated in both studies significantly reduced their intake of added sugar, and this was not found to correlate with either total intake of monosaccharides and disaccharides or the total carbohydrate consumption. The increased consumption of added sugar in patients with Crohn's disease does not appear to be related to other dietary abnormalities and may simply reflect a deficiency in perception of sweet taste in patients with this condition.

Immunological Aspects of Inflammatory Bowel.

McDermott RP

Seminars in Pediatric Gastroenetrology. 1:5 1990

No abstract available.

Rapid response of severe refractory metastatic Crohn's disease to Infliximab.

Miller AM, Elliott PR, Fink R, Connell W. Department of Gastroenterology, St Vincent's Hospital, Melbourne, Victoria, Australia. milleram@svhm.org.au

J Gastroenterol Hepatol 2001 Aug;16(8):940-2

A case is described of a middle-aged female who developed an aggressive form of biopsy-proven metastatic Crohn's disease involving the inguinal, perineal and submammary areas. Her condition had been unresponsive to topical and systemic corticosteroids, antibiotics, immunosuppressives, and repeated surgical debridement. Administration of Infliximab resulted in a rapid clinical response with subjective improvements in pain and general well-being, and an objective decline in exudate, erythema and size of the lesions. Infliximab may be a suitable therapeutic option in patients with metastatic Crohn's disease.

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

Miura S, Tsuzuki Y, Hokari R, Ishii H. Second Department of Internal Medicine, National Defense Medical College, Tokorozawa City, Saitama, Japan.

J Gastroenterol Hepatol 1998 Dec;13(12):1183-90

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.

Early Australian experience with Infliximab, a chimeric antibody against tumour necrosis factor-alpha, in the treatment of Crohn's disease: is its efficacy augmented by steroid-sparing immunosuppressive therapy? The Infliximab User Group.

Mortimore M, Gibson PR, Selby WS, Radford-Smith GL, Florin TH; Schering Plough (Australia). Royal Brisbane Hospital, Queensland, Australia.

Intern Med J 2001 Apr;31(3):146-50

BACKGROUND: Tumour necrosis factor-alpha (TNF-alpha) plays an important role in the pathology of Crohn's disease. Infliximab, a chimeric antibody against TNF-alpha, has been shown in controlled clinical trials to be effective in two-thirds of patients with refractory or fistulating Crohn's disease. The factors that determine a clinical response in some patients but not others are unknown. AIMS: To document the early Australian experience with Infliximab treatment for Crohn's disease and to identify factors that may determine a beneficial clinical response.

METHODS: Gastroenterologists known to have used Infliximab for Crohn's disease according to a compassionate use protocol were asked to complete a spreadsheet that included demographic information, Crohn's disease site, severity, other medical or surgical treatments and a global clinical assessment of Crohn's disease outcome, judged by participating physicians as complete and sustained (remission for the duration of the study), complete but unsustained (remission at 4 weeks but not for the whole study) or partial clinical improvement (sustained or unsustained).

RESULTS: Fifty-seven patients were able to be evaluated, with a median follow-up time of 16.4 (4-70) weeks, including 23 patients with fistulae. There were 21 adverse events, including four serious events. Fifty-one patients (89%) had a positive clinical response for a median duration (range) of 11 (2-70) weeks. Thirty patients (52%) had a remission at 4 weeks, 10 of whom had remission for longer than 12 weeks. Forty-two per cent of fistulae closed. Sustained remission (P = 0.065), remission at 4 weeks (P = 0.033) and a positive clinical response of any sort (P = 0.004) were more likely in patients on immunosuppressive therapy, despite there being more smokers in this group.

CONCLUSION: This review of the first Australian experience with Infliximab corroborates the reported speed and efficacy of this treatment for Crohn's disease. The excellent response appears enhanced by the concomitant use of conventional steroid-sparing immunosuppressive therapy.

Nutrition and gastrointestinal disease.

O'Keefe SJ. Gastrointestinal Clinic, Groote Schuur Hospital, South Africa.

Scand J Gastroenterol Suppl. 1996;220:52-9.

Nutrition and intestinal function are intimately interrelated. The chief purpose of the gut is to digest and absorb nutrients in order to maintain life. Consequently, chronic gastrointestinal (GI) disease commonly results in malnutrition and increased morbidity and mortality. For example, studies have shown that 50-70% of adult patients with Crohn's disease were weight-depleted and 75% of adolescents growth-retarded. On the other hand, chronic malnutrition impairs digestive and absorptive function because food and nutrients are not only the major trophic factors to the gut but also provide the building blocks for digestive enzymes and absorptive cells. For example, recent studies of ours have shown that a weight loss of greater than 30% accompanying a variety of diseases was associated with a reduction in pancreatic enzyme secretion of over 80%, villus atrophy and impaired carbohydrate and fat absorption. Finally, specific nutrients can induce disease, for example, gluten-sensitive enteropathy, whilst dietary factors such as fibre, resistant starch, short-chain fatty acids, glutamine and fish-oils may prevent gastrointestinal diseases such as diverticulitis, diversion colitis, ulcerative colitis, colonic adenomatosis and colonic carcinoma. The role of dietary antigens in the aetiology of Crohn's disease is controversial, but controlled studies have suggested that elemental diets may be as effective as corticosteroids in inducing a remission in patients with acute Crohn's disease. In conclusion, nutrition has both a supportive and therapeutic role in the management of chronic gastrointestinal diseases. With the development of modern techniques of nutritional support, the morbidity and mortality associated with chronic GI disease can be reduced. On the other hand, dietary manipulation may be used to treat to prevent specific GI disorders such as coeliac disease, functional bowel disease, Crohn's disease and colonic neoplasia. The future development of nutria-pharmaceuticals is particularly attractive in view of their low cost and wide safety margins.

Diet and inflammatory bowel disease: a case-control study.

Persson PG, Ahlbom A, Hellers G. Department of Epidemiology, Karolinska Institutet, Stockholm, Sweden.

Epidemiology 1992 Jan;3(1):47-52

We conducted a population-based case-control study of inflammatory bowel disease and dietary habits in Stockholm during 1984-1987. We obtained retrospective information about food intake 5 years previously by a postal questionnaire for 152 cases with Crohn's disease, 145 cases with ulcerative colitis, and 305 controls. The relative risk of Crohn's disease was increased for subjects who had a high (55 gm or more per day) intake of sucrose (relative risk = 2.6, 95% confidence interval = 1.4-5.0) and was decreased for subjects who had a high (15 gm or more per day) intake of fiber (relative risk = 0.5, 95% confidence interval = 0.3-0.9). The most striking finding was an increased relative risk of both Crohn's disease and ulcerative colitis associated with consumption of fast foods: the relative risk associated with consumption of fast foods at least two times a week was estimated at 3.4 (95% confidence interval = 1.3-9.3) for Crohn's disease and 3.9 (95% confidence interval = 1.4-10.6) for ulcerative colitis. Although coffee seemed to provide a protective effect for both diseases, there are reasons to consider this finding an artifact.

[Nutritional deficiencies and complications in chronic inflammatory bowel diseases] [Article in German]

Rath HC, Caesar I, Roth M, Scholmerich J. Klinik und Poliklinik fur Innere Medizin I, Klinikum, Universitat Regensburg. herath@t-online.de

Med Klin 1998 Jan 15;93(1):6-10

BACKGROUND: Deficiencies of vitamins and trace elements are frequent in inflammatory bowel disease. Aim of this study was to evaluate retrospectively the prevalence of these deficiencies and of liver complications in a large population.

PATIENTS AND METHODS: The records from 392 out-patients, 279 with Crohn's disease (160 female, 119 male) and 113 with ulcerative colitis (56 female, 57 male) were analyzed.

RESULTS: Deficiencies were found in 85% of patients with Crohn's disease vs 68% with ulcerative colitis during the course of the disease, predominantly a deficiency of iron and of calcium. Less frequently deficiencies of zinc, protein, cyanocobalamin, and folic acid were found. Elevated liver enzymes were seen in 38% of patients with Crohn's disease vs 27% with ulcerative colitis. In order of frequency: gamma-glutamyl-transferase, ALAT, AP, ASAT, and bilirubin. Gallstones were present in 12% of patients with Crohn's disease and 4% with ulcerative colitis. 6% of patients with Crohn's disease and 4% with ulcerative colitis had kidney stones.

CONCLUSIONS: In view of the high frequency of deficiencies in patients with inflammatory bowel disease it seems to be important to check frequently for extraintestinal complications.

Strategies targeting tumor necrosis factor in Crohn's disease.

Sandborn WJ. Inflammatory Bowel Disease Clinic, Division of Gastroenterology and Hepatology, Mayo Clinic and Mayo Foundation, Rochester, Minnesota, USA.

Acta Gastroenterol Belg 2001 Apr-Jun;64(2):170-2

Tumor necrosis factor plays an important role in mediating the inflammation of Crohn's disease. Strategies aimed at reducing tumor necrosis factor in patients with Crohn's disease include the mouse/human chimeric monoclonal antibody Infliximab, the humanized monoclonal antibody CDP571, the human recombinant tumor necrosis factor receptor fusion protein etanercept, and the small molecule thalidomide. Infliximab is effective for treating active Crohn's disease, maintaining remission, and closing fistulas. Side effects occurring in patients treated with Infliximab include human anti-chimeric antibodies, infusion reactions, formation of autoantibodies, and rarely drug induced lupus. CDP571 is effective for treating active Crohn's disease, steroid sparing, and possibly for closing fistulas and maintaining remission. Side effects occurring in patients treated with CDP571 include anti-idiotype antibodies, infusion reactions, and formation of autoantibodies. Pilot studies have suggested that etanercept and thalidomide may also be beneficial. Anti-tumor necrosis factor therapies are effective for the treatment for Crohn's disease.

Essential fatty acids in health and chronic disease.

Simopoulos AP. Center for Genetics, Nutrition and Health, Washington, DC 20009 cgnh@bellatlantic.net

Am J Clin Nutr 1999 Sep;70(3 Suppl):560S-569S

Human beings evolved consuming a diet that contained about equal amounts of n-3 and n-6 essential fatty acids. Over the past 100-150 y there has been an enormous increase in the consumption of n-6 fatty acids due to the increased intake of vegetable oils from corn, sunflower seeds, safflower seeds, cottonseed, and soybeans. Today, in Western diets, the ratio of n-6 to n-3 fatty acids ranges from approximately 20-30:1 instead of the traditional range of 1-2:1. Studies indicate that a high intake of n-6 fatty acids shifts the physiologic state to one that is prothrombotic and proaggregatory, characterized by increases in blood viscosity, vasospasm, and vasoconstriction and decreases in bleeding time. n-3 Fatty acids, however, have antiinflammatory, antithrombotic, antiarrhythmic, hypolipidemic, and vasodilatory properties. These beneficial effects of n-3 fatty acids have been shown in the secondary prevention of coronary heart disease, hypertension, type 2 diabetes, and, in some patients with renal disease, rheumatoid arthritis, ulcerative colitis, Crohn disease, and chronic obstructive pulmonary disease. Most of the studies were carried out with fish oils [eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)]. However, alpha-linolenic acid, found in green leafy vegetables, flaxseed, rapeseed, and walnuts, desaturates and elongates in the human body to EPA and DHA and by itself may have beneficial effects in health and in the control of chronic diseases.

A preliminary study of growth hormone therapy for Crohn's disease.

Slonim AE, Bulone L, Damore MB, Goldberg T, Wingertzahn MA, McKinley MJ. Department of Pediatrics, North Shore University Hospital and New York University School of Medicine, Manhasset 11030, USA. slonim@nshs.edu

N Engl J Med 2000 Jun 1;342(22):1633-7

BACKGROUND: Crohn's disease is a chronic inflammatory disorder of the bowel. In a preliminary study, we evaluated whether the administration of growth hormone (somatropin) as well as a high-protein diet would ameliorate the symptoms of the disease.

METHODS: We randomly assigned 37 adults with moderate-to-severe active Crohn's disease to four months of self-administered injections of growth hormone (loading dose, 5 mg per day subcutaneously for one week, followed by a maintenance dose of 1.5 mg per day) or placebo. We instructed all patients to increase their protein intake to at least 2 g per kilogram of body weight per day. Patients continued to be treated by their usual physicians and to receive other medications for Crohn's disease. The primary end point was the change in scores on the Crohn's Disease Activity Index from base line to month 4. Scores can range from 0 to 600, with higher scores indicating more disease activity.

RESULTS: At base line, the mean (SD) score on the Crohn's Disease Activity Index was somewhat higher among the 19 patients in the growth hormone group than among the 18 patients in the placebo group (287134 vs. 213120, P=0.09). Three patients in the placebo group withdrew before their first follow-up visit and were not included in the data analysis. At four months, the Crohn's Disease Activity Index score had decreased by a mean of 143144 points in the growth hormone group, as compared with a decrease of 1963 points in the placebo group (P=0.004). Side effects in the growth hormone group included edema (in 10 patients) and headache (in 5) and usually resolved within the first month of treatment.

CONCLUSIONS: Our preliminary study suggests that growth hormone may be a beneficial treatment for patients with Crohn's disease.

Association of humoral markers of inflammation and dehydroepiandrosterone sulfate or cortisol serum levels in patients with chronic inflammatory bowel disease.

Straub RH, Vogl D, Gross V, Lang B, Scholmerich J, Andus T Department of Internal Medicine I, University Medical Center, Regensburg, Germany.

Am J Gastroenterol 1998 Nov;93(11):2197-202

OBJECTIVES: Dehydroepiandrosterone sulfate (DHEAS) and cortisol are multifunctional adrenal hormones with immunomodulating properties. DHEAS levels were found to be very low in chronic inflammatory diseases. This study aimed to shed more light on the interrelation between DHEAS and cortisol (and humoral markers of inflammation) in chronic inflammatory bowel disease.

METHODS: DHEAS and cortisol serum levels were measured by ELISA in the serum of 66 normal subjects, 115 patients with Crohn's disease (CD) and 64 patients with ulcerative colitis (UC). Humoral markers of inflammation and disease activity scores were assessed by standard techniques.

RESULTS: DHEAS was lower in patients with CD (p < 0.005) and UC (p < 0.005) than in controls, which was, in part, dependent on previous corticosteroid treatment (p < 0.01). In CD patients, z-normalized DHEAS was inversely correlated with blood sedimentation rate (p = 0.017). Z-normalized DHEAS was negatively correlated with interleukin-6 (IL-6) in the form of a trend (p = 0.068), and z-normalized DHEAS was significantly positively correlated with hemoglobin (p = 0.001) but not with the Crohn's disease activity index. Cortisol, however, was positively correlated with blood sedimentation rate (p = 0.034) and C-reactive protein (p = 0.006). In contrast, in UC patients no such correlation of z-normalized DHEAS or cortisol and parameters of humoral inflammatory activity or Rachmilewitz index exist.

CONCLUSIONS: DHEAS as a marker of inflammation was low in CD and UC. In CD patients, low DHEAS and high cortisol serum levels were associated with higher humoral inflammatory activity. With respect to humoral inflammatory activity in CD patients, DHEAS and cortisol seem to be inversely regulated, which may have an impact on several immune functions, such as IL-6 secretion.

The effect of elemental diet on intestinal permeability and inflammation in Crohn's disease.

Teahon K, Smethurst P, Pearson M, Levi AJ, Bjarnason I. Section of Gastroenterology, Medical Research Council Clinical Research Centre, Harrow, Middlesex, England.

Gastroenterology 1991 Jul;101(1):84-9

This study examines whether treatment of acute Crohn's disease with an elemental diet improves intestinal integrity and inflammation as assessed by a 51Cr-labeled ethylenediaminetetraacetatic acid (EDTA) permeability test and the fecal excretion of 111In-labeled autologous leukocytes, respectively. Thirty-four patients with active Crohn's disease completed a 4-week treatment course with an elemental diet. Active disease was characterized by increased intestinal permeability [24-hour urine excretion of orally administered 51Cr-EDTA, 6.4% 0.6% (mean SE); normal, less than 3.0%] and by high fecal excretion of 111In-labeled leukocytes (14.2% 1.1%; normal, less than 1.0%). Twenty-seven (80%) went into clinical remission, usually within a week of starting treatment. After 4 weeks of treatment, there was a significant decrease in both the urine excretion of 51Cr-EDTA (to 3.4% 0.5%; P less than 0.01) and the fecal excretion of 111In (to 5.7% 1.0%; P less than 0.001), indicating that such treatment is not just symptomatic. A framework for the mechanism by which elemental diet works, centering around the importance of the integrity of the intestinal barrier function, is proposed, and also appears to provide a logical explanation for some relapses of the disease.

Infliximab treatment induces apoptosis of lamina propria T lymphocytes in Crohn's disease.

ten Hove T, van Montfrans C, Peppelenbosch MP, van Deventer SJ. Academic Medical Centre University of Amsterdam, Department of Experimental Internal Medicine, Amsterdam, the Netherlands. T.tenhove@amc.uva.nl

Gut. 2002 Feb;50(2):148-9.

BACKGROUND AND AIMS: Treatment with Infliximab induces remission in about 70% of patients with steroid refractory Crohn's disease. Because Crohn's disease is considered to be mediated by uncontrolled activation of mucosal T lymphocytes, we hypothesised that Infliximab could induce apoptosis of T lymphocytes.

METHODS: Induction of apoptosis in vivo was studied in 10 patients with therapy refractory Crohn's disease. In vitro, resting or stimulated Jurkat T cells were incubated with Infliximab.

RESULTS: Infusion of Infliximab (5 mg/kg) in steroid refractory patients with Crohn's disease induced a clinical response in 9/10 patients but did not influence expression of activation markers, homing receptors, memory cells, Fas expression, or Bax/Bcl-2 expression on peripheral blood T lymphocytes. In contrast, a significant increase in CD3 and TUNEL positive cells within colonic biopsies was detected 24 hours after infusion of Infliximab, suggesting that Infliximab stimulates apoptosis of activated T lymphocytes but not of resting T cells. To test this hypothesis, the effects of Infliximab on Jurkat T cells were investigated. We observed that Infliximab induced apoptosis and an increase in the Bax/Bcl-2 ratio of CD3/CD28 stimulated Jurkat T cells but not of unstimulated Jurkat cells.

CONCLUSIONS: Our data indicate that Infliximab treatment causes a rapid and specific increase in apoptosis of T lymphocytes in the gut mucosa. These findings may explain the rapid and sustained therapeutic effects of Infliximab in Crohn's disease.

Treatment of Crohn's disease with anti-tumor necrosis factor chimeric monoclonal antibody (cA2).

van Dullemen HM, van Deventer SJ, Hommes DW, Bijl HA, Jansen J, Tytgat GN, Woody J. Department of Hepatogastroenterology, Academic Medical Center, Amsterdam, The Netherlands.

Gastroenterology 1995 Jul;109(1):129-35

BACKGROUND & AIMS: Increased concentrations of tumor necrosis factor (TNF), a potent proinflammatory cytokine, can be shown in the mucosa of patients with active Crohn's disease. Neutralization of TNF has been shown to decrease recruitment of inflammatory cells and granuloma formation in several animal models. The aim of this study was to investigate the safety and potential efficacy of an anti-TNF monoclonal antibody in the treatment of active Crohn's disease.

METHODS: Ten patients with active Crohn's disease that was unresponsive to therapy were administered a single infusion of an anti-TNF human/mouse chimeric monoclonal antibody (cA2) in an open-label treatment protocol while the baseline anti-inflammatory therapy was continued.

RESULTS: Eight patients showed normalization of Crohn's Disease Activity Index scores and healing of ulcerations as judged by colonoscopy within 4 weeks after treatment. One patient had a perforation after colonoscopy and recovered completely after surgery. One elderly patient showed a poor response. The average duration of response after a single infusion was 4 months. No adverse experiences related to cA2 were observed.

CONCLUSIONS: The results support the hypothesis that TNF is of major importance in the pathogenesis of Crohn's disease. Treatment with cA2 was safe and may be useful in patients with Crohn's disease that is unresponsive to steroid treatment.

Dehydroepiandrosterone for the treatment of systemic lupus erythematosus.

van Vollenhoven RF. Department of Rheumatology, Karolinska Hospital, 17176 Stockholm, Sweden.

Expert Opin Pharmacother 2002 Jan;3(1):23-31

The adrenal steroidal hormone dehydroepiandrosterone (DHEA) has been studied as a potential pharmacological agent in the treatment of the autoimmune disease systemic lupus erythematosus (SLE). Both the endocrine effects (the ability to be converted peripherally to androgenic and oestrogenic sex steroids) and the immunomodulatory effects of DHEA (the production of the Th(1) cytokines, such as IL-2) suggest that this hormone could be of benefit for patients with SLE. During the past decade, five controlled clinical trials and a number of additional observational studies have been performed investigating these possibilities. The results from these studies suggest that 200 mg/day of DHEA for 7 - 12 months decreases corticosteroid requirement for the patients, the frequency of disease flares, has an anti-osteoporotic effect and has an overall beneficial effect on SLE disease activity in female patients. A small study suggested benefits for cognitive function in such patients. The side effects acne and hirsutism were seen relatively frequently (30 - 40% and 10 - 12% of patients, respectively) but in most instances were deemed mild. DHEA treatment resulted in changes in lipid profile and may have endocrine effects, the consequences of which will need to be ascertained through longer-term follow-up studies.

Does adjuvant nutritional support diminish steroid dependency in Crohn disease?

Verma S, Holdsworth CD, Giaffer MH. Dept. of Gastroenterology, Royal Hull Hospital NHS Trust, UK. sumitaverma@hotmail.com

Scand J Gastroenterol 2001 Apr;36(4):383-8

BACKGROUND: Nutritional therapy plays an important role in the management of Crohn disease, particularly during the acute phase. Nutritional supplementation may also prevent relapses during the quiescent phase of Crohn disease, though this aspect has not been widely explored.

METHODS: Thirty-three patients with Crohn disease in remission were studied. All had steroid-dependent disease. Patients were randomized to receive either elemental diet (n = 19, EO28 Extra) or polymeric diet (Forticips, n = 14). The supplement was given orally in addition to normal food in an amount to provide 35%-50% of pre-trial total calorie intake. Prednisolone was withdrawn gradually. Patients were followed up for 12 months. Failure was defined as increase in CDAI by 100 points from baseline to >200, inability to withdraw chronic steroid therapy completely, need for surgery or steroid therapy.

RESULTS: The nutritional supplement was successful in 14 (43%) patients who remained in remission for 12 months with complete withdrawal of steroids. The response to elemental diet (42%) was similar to that of polymeric diet (43%). Nutrition supplement failed in 13 (39%). Six (18%) patients were intolerant to enteral feeding because of smell and taste problems. Per-protocol analysis of data indicated that the success rate of nutrition supplement in steroid-dependent patients was 52% (14 out of 27 patients). No disease or patient-related factors helped predict the response to nutrition supplement.

CONCLUSION: Nutritional supplementation with either an elemental or polymeric diet may provide a safe and effective alternative to chronic steroid therapy in patients with steroid-dependent Crohn disease.

Intestinal permeability and the prediction of relapse in Crohn's disease.

Wyatt J, Vogelsang H, Hubl W, Waldhoer T, Lochs H. Department of Gastroenterology and Hepatology, Wahringer Gurtel, Vienna.

Lancet 1993 Jun 5;341(8858):1437-9

To see whether intestinal permeability (IP) predicted relapse in Crohn's disease, we measured IP in 72 patients with quiescent Crohn's disease using the lactulose-mannitol test. The permeability index (lactulose/mannitol) was significantly higher in patients than in controls (0.046 [SEM 0.005] vs 0.018 [SEM 0.002], respectively). Patients were followed for 1 year after the test. 26 of the 37 patients with raised permeability, but only 6 of the 35 with normal permeability relapsed within 1 year after the test (p < 0.001). The sensitivity of the permeability test as a predictor for relapse was 81%. A significant correlation was found between the value of the permeability index and the probability of relapse (p < 0.01). These results show that increases in intestinal permeability precede clinical relapses in Crohn's disease and so are an indicator of subclinical disease. The measurement of intestinal permeability may lead to a better understanding of the pathogenesis of Crohn's disease.