Antiinflammatory effects of enterically coated amoxicillin-clavulanic acid in active ulcerative colitis.
Casellas F. Borruel N. Papo M. Guarner F. Antolin M. Videla S. Malagelada JR.
Digestive System Research Unit, Hospital General Vall d'Hebron, Barcelona, Spain.
The inflammatory activity of colonic mucosal lesions may be stimulated by intraluminal bacteria. Our aim was to investigate whether administration of broad-spectrum antibiotics decreases inflammatory activity in ulcerative colitis. To this end, we performed a randomized, 5-day study with either oral enterically coated amoxicillin-clavulanic acid (1 g + 250 mg, t.i.d.); i.v. methylprednisolone (40 mg/day) and oral placebo (t.i.d.); or both i.v. methylprednisolone and oral amoxicillin-clavulanic acid as above, in 30 patients with clinically active ulcerative colitis. Before and after 5 days of treatment, intestinal inflammation was assessed by the quantification of mucosal release of eicosanoids and interleukin-8 by rectal dialysis in each patient. Breath H2 excretion after oral lactulose was determined as an index of metabolic activity of colonic flora. The total release of (IL-8) interleukin-8 and eicosanoids significantly decreased in patients treated with antibiotic or steroids and antibiotic. Antibiotic treatment, but not steroids, markedly inhibited breath H2 excretion. In conclusion, short-term treatment with enteric-coated amoxicillin-clavulanic acid decreases the intraluminal release of IL-8 and other inflammatory mediators.
Quality-of-life factors in adolescent inflammatory bowel disease.
MacPhee M. Hoffenberg EJ. Feranchak A.
Department of Pediatrics, University of Colorado School of Medicine, Denver, USA.
Little is known about the specific psychosocial factors that influence quality of life in adolescents with newly diagnosed inflammatory bowel disease (IBD). We adapted a model by Garrett and Drossman to assess adolescent adjustment to recent-onset IBD. Thirty adolescent-parent pairs completed a set of standardized questionnaires. The inclusion criteria were adolescents 12-18 years of age with Crohn's disease or ulcerative colitis of < 5 years' duration. Adolescents' health-related quality-of-life scores significantly correlated with satisfaction and degree of closeness with their social support members, such as parents. An unexpected finding was that the adolescents included more extended family than peers in their social support networks. Also of note was that parental coping styles rather than adolescent coping styles significantly correlated with adolescents' quality-of-life health scores. Severity of illness did not correlate with adolescent quality-of-life health scores. There was significant agreement between adolescent and parental quality-of-life health scores and stressful event ratings. Adolescents with recent-onset IBD rely more on family members than their peers for emotional support, and they depend more on their parents' coping skills than their own. These findings may indicate lags in normal adolescent development. Adolescents and parents do communicate and share concerns with each other. Support programs for adolescents with IBD should reinforce existing coping skills and parent-adolescent communication while promoting normative development.
Mucin secretion in inflammatory bowel disease: comparison of a macrophage-derived mucin secretagogue (MMS-68) to conventional secretagogues.
Sperber K. Shim J. Mehra M. Lin A. George I. Ogata S. Mayer L. Itzkowitz S.
Division of Clinical Immunology, Mount Sinai Medical Center, New York, New York, USA.
We have described a novel macrophage-derived mucin secretagogue (MMS-68) that mediates mucin secretion in colon cancer cell lines and explants of normal and inflammatory bowel disease (IBD) mucosa. We compared MMS-68 induced mucin release with other known intestinal mucin secretagogues in normal colon explants and in the HT-29 colon cancer cell line, and to study the effects of MMS-68 on mucin release from inflamed and uninflamed ulcerative colitis (UC) and Crohn's disease (CD) mucosa. In normal colonic explants and HT-29 cells, each of the secretagogues including, MMS-68-induced mucin release two- to fivefold more than culture medium alone. In HT-29 cells, MMS-68 plus leukotriene C4 (LTC4) induced a 50% increase in mucin release over either secretagogue alone, and MMS-68 plus platelet-activating factor (PAF) markedly enhanced mucin release by eightfold over either secretagogue. In colonic explants from patients with UC and CD, the mucin release in response to MMS-68 was similar to that of normal colonic explants. Likewise, in isolated epithelial cells from CD and UC (whether involved or uninvolved), MMS-68-induced release was similar to that of epithelial cells isolated from normal colonic mucosa. The number of MMS-68-producing macrophages was lower in uninflamed UC mucosa compared with inflamed UC mucosa and CD mucosa. The mucin secretagogue activity of MMS-68 is comparable to that of other known secretagogues, and PAF can have a synergistic effect on this activity. Whole tissue explants and isolated colonic epithelial cells from patients with IBD respond at least as well as their normal counterparts to MMS-68. MMS-68 may play a role in mucin secretion in normal and inflamed colonic tissue.
The presence of anti-neutrophil antibodies reflects clinical and genetic heterogeneity within inflammatory bowel disease.
Satsangi J. Landers CJ. Welsh KI. Koss K. Targan S. Jewell DP.
Gastroenterology Unit, Radcliffe Infirmary, Oxford, England.
A detailed investigation of the relationship between anti-neutrophil cytoplasmic antibodies (ANCA) status, HLA genotype, and clinical patterns of inflammatory bowel disease was carried out, involving 236 European patients resident in the United Kingdom [120 had ulcerative colitis (UC), 116 had Crohn's disease (CD)]. ANCA status was determined on coded plasma samples in Los Angeles using a two-stage assay [fixed neutrophil enzyme-linked immunosorbent assay (ELISA) and indirect immunofluorescence], and HLA genotyping was carried out by polymerase chain reaction. The results provide evidence that ANCA reflect clinical and genetic heterogeneity within the inflammatory bowel diseases. In the UC patients, 78.3% were ANCA positive [64.2 perinuclear (pANCA)], but only 46.5% CD patients were ANCA positive (19.3% pANCA). Furthermore, mean ELISA binding was significantly lower in CD (14.5% +/- 18.8% versus 40.5% +/- 41.0% in UC, p = 2.31 x 10(-9)). Only 15 CD samples, all from patients with colonic disease, displayed ELISA > 20%; and the six CD patients with highest ELISA binding had clinical features very similar to ulcerative colitis. Moreover, in UC, significant relationships between ANCA status and genotype were noted. Thus, 92.7% of patients with the DR3 DQ2 TNF2 haplotype were ANCA positive [p = 0.03 versus DR3 DQ2 TNF2-negative patients (73.9%)]. ELISA binding was increased in DR3 DQ2 TNF2-positive patients (56.0 versus 35.7%, p = 0.02). In this population of UC, ANCA was not associated with DR2, DR4, or clinical pattern. These data emphasize the many factors that need to be considered in genetic marker studies in inflammatory bowel disease. Extensive disease heterogeneity, ethnicity, and methodological differences in ANCA detection are all pertinent.
Severe knee pain as the single symptom of CMV infection in acute ulcerative colitis treated with cyclosporine.
D'Haens G. Suenaert P. Westhovens R. Rutgeerts P.
Department of Internal Medicine, University Hospital Gasthuisberg, Leuven, Belgium.
We describe a case of systemic cytomegalovirus (CMV) infection in an ulcerative colitis patient admitted to the hospital for an acute flare-up of his colitis. He was treated with combination immunosuppressive therapy including i.v. cyclosporine and corticosteroids and PO azathioprine. Severe bilateral stabbing knee pain was the only manifestation of CMV disease, which quickly responded to adequate antiviral therapy.
The role of the fecal stream in Crohns disease: an historical and analytic review.
Janowitz HD. Croen EC. Sachar DB.
Department of Medicine, Mount Sinai Medical Center, New York, New York 10029, USA.
Since 1939, a series of clinical reports and laboratory investigations have suggested that the intestinal fecal stream may play a significant part in the pathogenesis of Crohn's disease (CD). The beneficial effect of exclusion of the stream by ileostomy was followed by improvement in patients with CD of the ileum and colon despite little change in the histopathology of the excluded loop, even to the point of allowing restoration of intestinal continuity in some patients. End ileostomy lowers the risk of recurrence of CD compared with anastomotic operations. Ileostomy effluent can reactivate the clinical activity of quiescent bypassed bowel and some of its biochemical processes, and may be related to an ultrafilterable constituent > 5 microns. Experimental models of inflammatory bowel disorders in immunologically altered rodents (transgenic, knockout, or spontaneous) require the presence of normal luminal bacteria, especially of the Bacteroides species, and respond to antibiotic (metronidazole) therapy. Thus, many but not all of the well-recognized clinical features of CD are compatible with a pathogenetic role of the fecal stream. Although difficult to quantitate, this concept opens the way to a variety of testable research lines, and allows some speculation regarding its clinical implications.
Nutritional therapy in Crohns disease.
O'Sullivan MA. O'Morain CA.
Department of Gastroenterology, Meath/Adelaide Hospital, Trinity College, Dublin, Ireland.
The value of nutritional support in the prevention and treatment of malnutrition in Crohn's disease is undisputed but its role in primary therapy continues to be debated. Controlled trials have demonstrated that enteral nutrition induces remission rates comparable to that of corticosteroid therapy in Crohn's disease and remains the treatment of choice for specific subgroups such as children with signs of growth impairment and patients with intolerable steroid-induced side effects. The mechanism by which an enteral diet induces remission in Crohn's disease is unclear. Bowel rest, reduced antigenic load, nutritional effects, the provision of trophic amino acids, modification of gut flora, intestinal permeability, or fecal pH have been proposed. Equally, the fat profile of the feed may reduce pro-inflammatory ecosanoid synthesis and thus modify disease activity. Maintaining long-term remission remains a challenge in the management of this disease. Cyclic administration of enteral diets, maintenance drug therapy, fat manipulated formulas, or fish oil therapy may be strategies to prolong diet-induced remission. In the future, nutrient derivatives that play a role in the protective processes of the intestinal mucosa may have application in nutritional therapy in Crohn's disease.
The central role of chemokines (chemotactic cytokines) in the immunopathogenesis of ulcerative colitis and Crohns disease.
MacDermott RP. Sanderson IR. Reinecker HC.
Section of Gastroenterology, Lahey Hitchcock Clinic Medical Center, Burlington, Massachusetts, USA.
The final composition of leukocytes present in a site of inflammation in response to chemokine stimulation and activation may depend on both the nature of the secreted chemokines as well as the relative expression of the multitude of specific chemokine cell surface receptors on many different cell types. Because related receptors with different affinities and cross-reactive binding capabilities are present on each type of leukocyte, relative differences in receptor distribution and receptor affinity for specific chemokines may significantly influence which cells are ultimately attracted to and activated by each individual chemokine. Production of IL-8, MCP-1, and ENA-78 by endothelial cells, LPMNC, and epithelial cells in IBD could establish a chemotactic gradient capable of influencing the increased migration of monocytes/macrophages, granulocytes, and lymphocytes from the blood stream through the endothelium into both the mucosa and submucosa during chronic IBD. The ability of chemokines to induce chemotaxis, leukocyte activation, granule exocytosis, increased production of metalloenzymes, and up-regulation of respiratory burst activity indicates that there may be a variety of different mechanisms by which chemokines could markedly increase chronic inflammation and chronic intestinal tissue destruction in IBD.
Dose-ranging study of mesalamine (PENTASA) enemas in the treatment of acute ulcerative proctosigmoiditis: results of a multicentered placebo-controlled trial. The U.S. PENTASA Enema Study Group.
University of Chicago Medical Center, Illinois 60637, USA.
The safety and efficacy of mesalamine enemas were determined ina dose-ranging study enrolling 287 patients with ulcerative proctitis and proctosigmoiditis in a double-blind, placebo-controlled, multicenter trial. Patients were randomized to receive placebo, 1, 2, or 4 g in 100 ml mesalamine (PENTASA) enemas h.s. for 8 weeks. Efficacy was assessed by clinical, sigmoidoscopic, and histologic improvement, as well as by induction of remission. Sixty-seven percent, 65%, and 75% of patients receiving 1-, 2-, and 4-g enemas were markedly improved according to the physician's global assessment compared with 27% of patients treated with placebo. The mean improvement in sigmoidoscopic index was 5.8, 5.9, and 6.4 points (on a 15-point scale) for the 1-, 2-, and 4-g enema groups compared with a decrease of 1.8 points for the placebo group. Improvement in biopsy scores was observed in 47, 55, and 59% of 1-, 2-, and 4-g groups contrasted with 27% of the placebo-treated patients. All three doses were significantly more effective than placebo in reducing symptoms and trips to the toilet compared with placebo. No dose-response relation was demonstrated. The safety profile was similar to that of placebo. In conclusion, mesalamine enemas are effective as a single agent in the short-term treatment of distal ulcerative colitis without an apparent dose response between 1 and 4 g nightly.
Distribution of acute bowel inflammation determined by technetium-labeled white blood cells in children with inflammatory bowel disease.
Charron M. Fernando del Rosario J. Kocoshis S.
Department of Radiology, Children's Hospital of Pittsburgh, Pennsylvania 15213, USA.
Knowledge of the distribution of disease in patients with inflammatory bowel disease is important because it has diagnostic, prognostic, and therapeutic implications. We studied 215 patients with 99mTc-HMPAO-white blood cell scans, of whom 80 had Crohn's disease (CD), 34 had active ulcerative colitis (UC), and 31 were controls. In our 77 cases of active CD, uptake was seen exclusively in the small bowel in 18% of patients, only the large bowel in 44%, and both the large and small bowel in 38% of patients. Discontinuous colitis was seen in 63 of these patients. In the 29 cases of active UC, the uptake involved the entire colon in 50% of patients, extended farther than the sigmoid in 27% of patients, and was limited to the rectosigmoid in 23%. In the 29 cases of active UC, four of the scans incorrectly revealed discontinuous accumulation of 99mTc-HMPAO-WBC. In 31 controls, no significant colonic uptake was seen. Isolated small bowel involvement with CD is observed less frequently in children undergoing 99mTc-HMPAO-WBC scanning than in adults. In children, the segmental distribution of inflammation as depicted with 99mTc-HMPAO-WBC is similar to the radiologic distribution.
Bile composition in patients with ileal resection due to Crohns disease.
Lapidus A. Einarsson C.
Department of Gastroenterology and Hepatology, Karolinska Institute, Huddinge University Hospital, Stockholm, Sweden.
Patients with Crohn's disease (CD) have an increased risk of developing gallstones, but the mechanisms are unknown. In a previous study, we found a subnormal cholesterol saturation in the bile of patients with short ileal resections due to CD. The aim of this study was to test the hypothesis that (a) CD patients with a long ileal resection have an altered biliary composition and (b) that CD patients with short or long ileal resection have an increased content of bilirubin in their bile. Biliary lipid composition, cholesterol saturation, bile acid pattern, and bilirubin concentration were determined in fasting duodenal bile of 10 CD patients with long ileal resections and in 4 patients with short resections. Ten healthy subjects served as controls. Cholesterol saturation was significantly lower in those CD patients who had a long or short resection compared with the healthy subjects. Bile acid composition in the CD patients was characterized by a significant decrease in the deoxycholic acid fraction and a prominent increase in the ursodeoxycholic acid fraction. The bilirubin concentrations, expressed as micromoles of bilirubin per millimole bile acid, were 45-50% higher in patients who had a long or a short ileal resection compared with healthy controls. Based on these results, CD patients who had had an ileal resection seem not to be at an increased risk of cholesterol gallstone formation but rather at risk of developing pigment stones.
Severe bone pain as an adverse effect of cyclosporin therapy for Crohns disease.
Division of Digestive Diseases and Nutrition, University of North Carolina School of Medicine, Chapel Hill, USA.
A case of severe bone pain associated with cyclosporin therapy for Crohn's disease is reported. Severe leg pain developed in a 32-year-old man who was receiving cyclosporin for Crohn's disease that was refractory to medical management. Leg pain was related to the dose of cyclosporin, improved with calcium channel blockade, and resolved on discontinuation of cyclosporin. This syndrome has been described in the renal transplantation literature and may be related to vasoconstriction of bone vasculature.
Simultaneous onset of pyoderma gangrenosum and bitemporal abscesses of the upper eyelids during a flare of ulcerative colitis.
von Tirpitz C. Buchwald HJ. Lang GK. Adler G. Reinshagen M.
Department of Medicine I, University of Ulm, Germany.
A case of simultaneous appearance of bitemporal sterile abscesses of the upper eyelids and pyoderma gangrenosum in an 80-year-old woman with an acute flare of ulcerative colitis is described. Therapy with high-dose corticosteroids led to healing of the skin and upper eyelid lesions and induced remission of ulcerative colitis.
Endothelial ligands and homing of mucosal leukocytes in extraintestinal manifestations of IBD.
Salmi M. Jalkanen S.
MediCity Research Laboratory, University of Turku, Finland.
Crohn's disease and ulcerative colitis are quite often complicated with manifestations in extraintestinal organs like joints, eye, and skin. Although the etiopathogenesis of these nonmucosal complications remains unsettled, they all share the characteristic feature of inappropriate leukocyte recruitment in nonlymphatic organs. Under normal conditions, lymphocytes recirculate between the blood and lymphoid organs in search of their cognate antigens, whereas polymorphonuclear leukocytes are excluded from tissues. On inflammation, the leukocyte trafficking changes dramatically. Granulocytes infiltrate into the inflammatory focus very rapidly, and they are followed by lymphocytes, especially activated immunoblasts and memory cells, which now also leave the vasculature at nonlymphoid tissues. Leukocyte extravasation from the blood into the tissue is a multistep process governed by sequential interactions between adhesion molecules expressed on the surface of leukocytes and their ligands on the luminal side of the endothelial cells lining the vessels. In this review, we describe the recirculation routes of mucosal lymphocytes in physiologic conditions, as well as the changes seen in mucosal and extramucosal homing in inflammatory bowel disease (IBD). We present a working model of how adhesive molecular interactions between mucosal immune cells and endothelial cells may explain the pathogenesis of the development of inflammatory cell infiltrate in distant organs in IBD, and how this information may help to plan new antiadhesive therapeutic strategies.