A terapia celular utilizando células tronco-mesenquimais (MSCs) surge como alternativa para o tratamento das doenças inflamatórias intestinais (DII). Atualmente, os métodos terapêuticos consistem principalmente na utilização de fármacos que visam produzir e manter estados de remissão da colite ulcerativa e, muitas vezes, apresentam efeitos colaterais. Considerando a capacidade de modular células do sistema imune e de regenerar tecidos doentes, as MSCs podem ser consideradas uma alternativa para o tratamento de DII, como a colite ulcerativa. Além disso, muito tem se investigado a respeito do homing de MSCs exógenas infundidas por diversas vias em resposta a um insulto inflamatório e tem-se visto a capacidade de migração para tecidos afetados. A primeira etapa do trabalho consistiu na caracterização e desenvolvimento do modelo animal de colite ulcerativa aguda. Para isso, foram testados diferentes pesos moleculares e concentrações do reagente Dextran Sulfato de Sódio (DSS), a fim de verificar qual o melhor método de indução da doença. Após determinar o adequado modelo animal, que utilizou 2% DSS (36 000 – 50 000 Da), foi iniciado o experimento de terapia celular. Na tentativa de compreender como as MSCs podem influenciar a inflamação intestinal...
BACKGROUND: Short chain fatty acid (SCFA) deficiency is associated with colitis in animals and humans, and the mucosal metabolism of these compounds is decreased in ulcerative colitis. AIMS: To assess the efficacy of topical SCFA treatment in ulcerative colitis. PATIENTS AND METHODS: 103 patients with distal ulcerative colitis were entered into a six week, double-blind, placebo controlled trial of rectal SCFA twice daily; patients who were unchanged on placebo were offered SCFA in an open-label extension trial. RESULTS: Of the 91 patients completing the trial, more patients in the SCFA treated than in the placebo treated group improved (33% v 20%, p = 0.14, NS). Those on SCFA also had larger, but statistically non-significant, reductions in every component of their clinical and histological activity scores. In patients with a relatively short current episode of colitis (< 6 months, n = 42), more responded to SCFA than to placebo (48% v 18%, p = 0.03). These patients also had larger, but statistically non-significant, decreases in their clinical activity index (p = 0.08 v placebo). Every patient who improved used at least five of six of the prescribed rectal SCFA irrigations, whereas only 37% who did not improve were as compliant. In the open-label extension trial...
To examine socioeconomic factors, dietary and other personal habits, and medical history as risk factors for ulcerative colitis, we studied 167 (98%) of all prevalent cases of ulcerative colitis diagnosed in Uppsala county from 1945 to 1964 and 167 age and sex matched population controls. Ulcerative colitis patients were less likely than controls to be current cigarette, pipe, or cigar smokers (odds ratio (OR) = 0.44; 95% confidence limits (CL) = 0.25-0.78), but more likely to have symptoms induced by drinking milk (OR = 4.63; 95% CL = 2.15-9.93). Patients with ulcerative colitis do not differ in most of the socioeconomic, dietary and personal habits compared with the background population.
This report describes a young woman with ulcerative colitis who developed rapidly fatal pneumococcal septicaemia. Necropsy revealed splenic atrophy. This case supports the hypothesis that splenic atrophy might contribute to the morbidity of ulcerative colitis. The occurrence of splenic atrophy in ulcerative colitis is now well established. Splenic atrophy from other causes has been associated with severe bacterial infections, often pneumococcal. It has been suggested that splenic atrophy is most severe when ulcerative colitis is active and may contribute to postoperative morbidity. This case documents overwhelming septicaemia in a patient with splenic atrophy whose colitis was in remission.
A retrospective cohort of 823 patients with ulcerative colitis who resided at the time of diagnosis in one of three defined geographical areas (West Midlands region, Oxford region, England and Stockholm County, Sweden) was assembled. The patients were first seen at named hospitals in these areas and the diagnosis of ulcerative colitis established within five years of onset of symptoms between 1945-1965. All patients were 15 years of age or more at onset of disease and were followed for a minimum of 17 years and a maximum of 38 years. Ninety seven per cent completeness of follow up was achieved. Examining the colorectal cancer risk in the series relative to the risk in the general population by standardised morbidity ratios, there was an eight fold increased risk of cancer in the series as a whole. Dividing the series by extent of colitis, extensive colitis patients showed a 19 fold increase in risk. A four fold increased risk was shown in the remainder of the series (left sided colitis, proctitis and extent unknown). Life table analyses in extensive colitis gave cumulative risks of 7.2% (CI 3.6-10.8) at 20 years from onset of disease and 16.5% (CI 9.0-24.0) at 30 years from onset. No significant effect of age at onset, sex or referral centre could be detected. Examination of the data by interval from onset to cancer and by actual age at development of cancer suggests that patients who develop colorectal cancer will do so in a distribution around 50 years of age independent of duration of disease in adult onset ulcerative colitis (greater than 15 years at onset of disease). An inverse relationship was shown between age at onset of disease and interval from onset of disease to cancer. Further age specific rates for cancer increased up to 50 years and decreased thereafter. These results suggest that extensive colitis patients have a genetic predisposition to colorectal cancer and that longstanding inflammation is not of primary importance in the initiation/promotion of cancer in this disease.
Cytomegalovirus (CMV) is a common virus in patients with ulcerative colitis receiving immunosuppressive drugs. Many studies suggested that CMV infection is an exacerbating factor in patients with ulcerative colitis. The role of CMV in exacerbations of ulcerative colitis has been discussed. One of studies starting this discussion is an article entitled “CMV positive ulcerative colitis: A single center experience and literature review” by Kopylov et al. However, we think that there are some points that should be emphasized about the study. Especially, the small number of patients in the study has led to meaningless results. Large controlled prospective trials are needed to clarify the benefit of antiviral therapy for active ulcerative colitis patients.
Conventional medical treatment for ulcerative colitis can have limited efficacy or severe adverse reactions requiring additional treatment or colectomy. Hence, different biological agents that target specific immunological pathways are being investigated for treating ulcerative colitis. Anti-tumor necrosis factor (TNF) agents were the first biologics to be used for treating inflammatory bowel disease. For example, infliximab and adalimumab, which are anti-TNF agents, are being used for treating ulcerative colitis. Recently, golimumab, another anti-TNF agent, and vedolizumab, an anti-adhesion therapy, have been approved for ulcerative colitis by the U.S. Food and Drug Administration. In addition, new medications such as tofacitinib, a Janus kinase inhibitor, and etrolizumab, another anti-adhesion therapy, are emerging as therapeutic agents. Therefore, there is a need for further studies to select appropriate patient groups for these biologics and to improve the outcomes of ulcerative colitis treatment through appropriate medical usage.
Multiple extraintestinal diseases are present in 0.3- 4.5 % of inflammatory bowel disease patients. A 39-year-old woman was admitted with a 3 months history of cervicalgia with functional incapacity, asthenia, tibio-tarsal bilateral arthritis and bloody diarrhoea. She had ferropenic anemia, SR-120 mm, creatinine clearance-42 mL/min, proteinuria-1.2 g/24h. Colonoscopy with biopsy showed active ulcerative rectossigmoiditis. She had bilateral sacroileitis more pronounced at the right side which was suggestive of ankylosing spondylitis. HLA B27 was positive. Because of colestasis, colangio-MRI and CPRE were done and were suggestive of primary sclerosing colangitis. Renal disease was interpreted as an analgesic nephropathy versus glomerulonephritis associated with ulcerative colitis. Cardiac ecodoppler showed pericardial thickening with a thin pericardial effusion. Full improvement of gastrointestinal complaints was observed with 5-ASA topic enemas, sulfassalazine, corticosteroids and azathioprine and full remission of ankylosing spondylitis with adalimumab. This case illustrates extraintestinal wide involvement as the initial presentation of ulcerative colitis, remarking its systemic nature.; Multiple extraintestinal diseases are present in 0.3- 4.5 % of inflammatory bowel disease patients. A 39-year-old woman was admitted with a 3 months history of cervicalgia with functional incapacity...
Bis zu 50% der Patienten mit chronisch entzündlichen Darmerkrankungen (Morbus Crohn und Colitis ulcerosa) benötigen im Verlauf ihrer Erkrankung eine teilweise dauerhafte immunsuppressive Therapie. Limitationen der etablierten Behandlungsoptionen sind Unverträglichkeitsreaktionen und unzureichendes Ansprechen.
Ziele und Methoden:
Ziel der vorliegenden Arbeit war die Untersuchung potentieller Therapiealternativen bei Versagen der etablierten Therapieoptionen bei chronisch entzündlichen Darmerkrankungen (CED).
Konkret sollten drei Fragestellungen beantwortet werden:
1) Die Verträglichkeit und Effektivität von 6-Mercaptopurin (6-MP) bei Unverträglichkeitsreaktionen gegenüber Azathioprin.
2) Die Effektivität von Infliximab bei Versagen von Tacrolimus und vice versa bei steroidrefraktärem Schub der Colitis ulcerosa/indeterminata.
3) Die Effektivität und Verträglichkeit von Leflunomid als Drittlinien-Therapie bei Versagen von Azathioprin und Methotrexat bei steroidabhängigem Verlauf des Morbus Crohn.
Insgesamt konnten 110 Patienten mit CED aus dem Robert-Bosch-Krankenhaus zur Bearbeitung der genannten Fragestellungen identifiziert werden.
Vierundsiebzig CED-Patienten hatten 6-MP nach Azathioprinunverträglichkeit erhalten. Siebenundzwanzig Patienten mit Colitis ulcerosa/indeterminata waren nach Therapieversagen von Tacrolimus mit Infliximab bzw. vice versa behandelt worden und neun Patienten mit steroidabhängigem Verlauf eines Morbus Crohn hatten nach Unverträglichkeit gegenüber Azathioprin und Methotrexat Leflunomid als Drittlinien-Therapie erhalten.
1) 41% der Patienten (30/74) mit Azathioprinunverträglichkeit tolerierten eine Umstellung auf 6-MP ohne ein erneutes Auftreten von Nebenwirkungen. 57% dieser Patienten (17/30) profitierten auch langfristig klinisch (Response/ Remission) vom Wechsel des Präparats. Patienten mit erneuten Nebenwirkungen auch unter 6-MP entwickelten in etwa der Hälfte der Fälle neue oder zusätzliche Unverträglichkeitsreaktionen.
2) 30% (8/27) der Patienten mit Tacrolimus- bzw. Infliximabversagen erreichten eine stabile Remission. Die vier Patienten die ein nur inkomplettes Ansprechen der Colitis ulcerosa erreichten mussten mittelfristig ebenso kolektomiert werden wie 73% (11/15) der Patienten ohne Ansprechen der „Rescue“-Therapie.
3) Nur einer von neun Patienten profitierte klinisch von der Einleitung einer Drittlinien-Therapie mit Leflunomid nach Azathioprin- und Methotrexatversagen. Sechs von neun Patienten entwickelten Nebenwirkungen...
By running the Swedish twin registry containing about 25,000 pairs of twins of the same sex together with the central national diagnosis register of hospital inpatients, 80 twin pairs suffering from inflammatory bowel disease were found. In the ulcerative colitis group one of 16 monozygotic pairs was concordant for the disease, but all the other 20 pairs (dizygotic or unknown zygosity) were discordant. In the Crohn's disease group eight of 18 monozygotic pairs and one of 26 dizygotic pairs were concordant. The proband concordance rate among monozygotic twins was 6.3% for ulcerative colitis and 58.3% for Crohn's disease. The calculated heritability of liability based on monozygotic pairs was 0.53 and 1.0 respectively. Thus heredity as an aetiological factor is stronger in Crohn's disease than in ulcerative colitis. Monozygotic twins with Crohn's disease were more likely to be smokers than monozygotic twins with ulcerative colitis. Smoking did not explain the discordance of twin pairs with either ulcerative colitis, or Crohn's disease. The combination of identical heredity and similar smoking habit is not sufficient to cause disease.
Recent studies have suggested that nitric oxide (NO.), the product of nitric oxide synthase in inflammatory cells, may play a part in tissue injury and inflammation through its oxidative metabolism. In this study the colonic generation of oxides of nitrogen (NOx) and nitric oxide synthase activity was determined in ulcerative colitis and Crohn's disease. Colonic biopsy specimens were obtained from inflammatory bowel disease patients and from normal controls. Mucosal explants were cultured in vitro for 24 hours and NOx generation was determined. Nitric oxide synthase activity was monitored by the conversion of [3H]-L-arginine to citrulline. Median NOx generation by inflamed colonic mucosa of patients with active ulcerative colitis and Crohn's colitis was 4.2- and 8.1-fold respectively higher than that by normal human colonic mucosa. In ulcerative colitis and Crohn's colitis nitric oxide synthase activity was 10.0- and 3.8-fold respectively higher than in normal subjects. Colonic NOx generation is significantly decreased by methylprednisolone and ketotifen. The decrease in NOx generation by cultured colonic mucosa induced by methylprednisolone suggests that NO synthase activity is induced during the culture and the steroid effect may contribute to its therapeutic effect. Enhanced colonic NOx generation by stimulated nitric oxide synthase activity in ulcerative colitis and Crohn's disease may contribute to tissue injury.
The migration of peripheral leucocytes in vitro is examined in 36 patients with ulcerative colitis, in 34 patients with Crohn's disease, in 12 patients with ulcerative colitis or Crohn's disease, and in 31 patients with other gastrointestinal disorders. In a majority of the patients with ulcerative colitis extracts of foetal, colonic, and jejunoileal mucosa inhibit migration of leucocytes. A similar reactivity is seldom seen in Crohn's disease. Extracts of liver, kidney, and adrenal gland do not inhibit the migration. The reactivity of the ulcerative colitis group was found to be significantly different from that in controls and in the Crohn group, whereas the Crohn group did not differ significantly from the controls. The examination thus reveals a biological difference between ulcerative colitis and Crohn's disease, which are otherwise separable mainly on nosological criteria.
Colonic mucin is heavily sulphated and it has been shown that enzymatic desulphation by faecal bacterial sulphatases greatly increases its susceptibility to degradation by faecal glycosidases. A possible role for faecal mucin sulphatase in the pathogenesis of inflammatory bowel disease has therefore been explored. Faecal mucin sulphatase activity assayed using 35S mucin as substrate was increased in ulcerative colitis (median 80.2 units/g pellet weight (range 6.9-1063; 95% confidence intervals (CI): 45.2 to 293.8, n = 22) compared with 11.3 units/g (range 3.0-53.5; 95% CI: 8.7 to 29.8, n = 17) in healthy controls (p < 0.01), where one unit released 1000 dpm free sulphate/hour from 35S mucin (1680 dpm/microgram). Patients with active ulcerative colitis had higher sulphatase activity (median 146; 95% CI: 98 to 253 units/g, n = 10) than those with inactive ulcerative colitis (median 42.2; CI: 22.5 to 81.6 units/g, n = 12) (p < 0.05). Longitudinal studies in patients with ulcerative colitis show fluctuations of faecal mucin sulphatase activity corresponding to clinical disease activity in six of seven patients. Faecal mucin sulphatase activity was not significantly increased in Crohn's disease (median 36.6, range 5.7-106.6; 95% CI: 22.9 to 65.3 units/g...
Features of the neutrophil oxidative metabolism and enzyme activity in peripheral blood neutrophils were studied in 43 patients with Crohn's disease, 13 with ulcerative colitis and 33 healthy controls. The production of superoxide anion (O2-.) by phorbol-myristate-acetate stimulated neutrophils from patients with Crohn's disease and ulcerative colitis was significantly diminished compared with controls mean (SE) = 47.1 (3.6) and 38.0 (3.8) v 67.4 (7.5) nmol/10(7) cells/min, p less than or equal to 0.02, respectively, while the production of hydrogen peroxide was normal. The neutrophil content of superoxide dismutase (SOD), a cytoprotective enzyme, was also markedly diminished in Crohn's disease mean (SE) = 7.11 (0.23) ng SOD/micrograms DNA, p less than 0.05, and ulcerative colitis mean (SE) = 5.74 (0.42) compared with controls 7.84 (0.27), p less than 0.001. In contrast, the concentration of neutrophil elastase, a neutral protease, was found to be normal when compared with neutrophils from controls. The neutrophil O2-. production and the SOD concentrations were significantly and negatively correlated with the disease activity in Crohn's disease and ulcerative colitis. The results indicate diminished neutrophil function in peripheral blood of patients with Crohn's disease and ulcerative colitis as illustrated by a diminished oxidative system...
The immunochemical protein content of group II phospholipase A2 (PLA2) and PLA2 enzymatic activity were measured for colonic mucosal biopsy samples obtained from patients with either Crohn's disease of the colon or ulcerative colitis, and control patients without inflammatory bowel disease. Immunoreactive group II PLA2 (IR-PLA2 II) content and PLA2 activity in actively inflamed colonic mucosa of Crohn's disease patients were significantly higher than those in inactively inflamed mucosa of Crohn's disease patients and the colonic mucosa of controls. IR-PLA2 II content and PLA2 activity in severely inflamed mucosa of ulcerative colitis patients were significantly higher than those in the colonic mucosa of the controls. Mucosal PLA2 enzymatic activity was closely correlated with mucosal IR-PLA2 II content in patients with Crohn's disease and ulcerative colitis. These results suggest that an increase in PLA2 enzymatic activity in inflamed colonic mucosa of Crohn's disease and ulcerative colitis was mainly attributed to increased protein content of group II PLA2, and that an increase in mucosal group II PLA2 may be involved in the pathogenesis of intestinal inflammation of Crohn's disease and ulcerative colitis.
A controlled clinical study on disodium cromoglycate (DSCG) at a dose of 800 mg per day versus placebo was carried out in 141 patients with ulcerative colitis and 25 patients with Crohn's disease. Those of the ulcerative colitis patients who had been on sulphasalazine treatment continued that treatment during the trial (101 patients). Forty patients were intolerant of sulphasalazine. No patient received steroids during the last month before the study. Patients with Crohn's disease had their possible sulphasalazine treatment stopped before the trial. No beneficial effect of DSCG as compared with placebo was found, as the DSCG and the placebo group showed the same number of relapses in patients with a clinically inactive ulcerative colitis at the start of the trial and the same number of patients improving, deteriorating, and maintaining steady state in patients with clinically active ulcerative colitis at the start of the trial. There was no difference between relapse rate in DSCG and placebo groups in patients with Crohn's disease. No correlation between the eosinophil count in rectal mucosa and the outcome of the attack of ulcerative colitis could be demonstrated.
Human colonic mucosal protection is not fully understood but may in part rely on a layer of mucus gel adherent to the mucosa. Ulcerative colitis may occur if mucosal protection breaks down. Two studies are presented, both of which relate to the aetiology of ulcerative colitis. First, a layer of adherent mucus gel was demonstrated by a simple, reliable method. Measurements of mucus layer thickness were made in freshly resected colonic specimens and shown to increase from a mean of 107 microns on the right colon to 155 microns in the rectum. In ulcerative colitis the layer is significantly thinner or absent, whereas in Crohn's disease the colonic mucus layer is significantly thicker. Second, the relationship between smoking and colitis is explored by a double-blind, randomised and placebo-controlled trial of transdermal nicotine in active disease. Significant clinical benefit was seen, indicating nicotine may be both useful therapeutically and the component of tobacco smoke that acts to protect against colitis. Since smoking and nicotine have actions on mucosae and mucus in other organs, it is argued that there is a mucus deficiency in ulcerative colitis that smoking acts to reverse.
BACKGROUND—Butyrate, a short chain fatty acid produced by bacterial fermentation, is a major fuel source for the colonocyte. In vitro work has shown that ulcerative colitis may be characterised by a metabolic defect in colonocyte butyrate oxidation. AIMS—To investigate the rate of metabolism of rectally administered butyrate in patients with quiescent colitis. METHODS—[1-13C]-butyrate enemas were administered to 11 patients with long standing quiescent ulcerative colitis and to 10 control patients. The rate of production of 13CO2 in exhaled breath over four hours was measured by isotope ratio mass spectrometry combined with indirect calorimetry in order to measure CO2 production. This allowed calculation of the patients' resting energy expenditure and respiratory quotient. RESULTS—Over a four hour period, 325 (SEM 21) µmol 13CO2 was recovered in breath samples from the colitis group compared with 322 (17) µmol from the control group (NS). The respiratory quotient of the colitic group was significantly lower than that of the control group. CONCLUSION—There was no difference in the rate of metabolism of butyrate between the two groups. It is unlikely that there is a primary metabolic defect of butyrate metabolism in patients with quiescent ulcerative colitis. Keywords: ulcerative colitis; in vivo butyrate metabolism
Serum antibodies cytotoxic to the colon cancer cell line RPMI 4788 were studied in 42 patients with ulcerative colitis, 61 patients with Crohn's disease, 27 patients with other inflammatory diseases (disease-controls) and 22 healthy controls. Cytotoxicity of antibodies towards RPMI 4788 was studied by means of a chromium release assay using peripheral blood mononuclear leucocytes of healthy subjects as effector cells. Using a four hour antibody dependent cell mediated cytotoxicity assay sera from 29% of ulcerative colitis patients contained antibodies cytotoxic for the target, while only 3% of the Crohn's patients and 6% of the disease controls and non of the healthy controls were positive. When an 18 hour assay was applied, however, not only 40% of ulcerative colitis patients, but also 14% of Crohn's patients and 21% of disease controls were found positive. The reactive antibody in the four hour assay was mainly of the IgG class, which points at a classical antibody dependent cell mediated cytotoxicity mechanism. In the 18 hour cytotoxic assay IgG and particularly IgM antibodies were found to be reactive. This suggests that in the latter case other cellular cytotoxic mechanism might be involved. There was a significant inverse correlation between the appearance of the ulcerative colitis restricted IgG-anticolon epithelial cell antibodies (four hour assay) and the disease activity (p less than 0.01). Absorption studies showed that the reactive antigen is not specific for ulcerative colitis colonic tissue...
The hypothesis that the colonic epithelium is diffusely abnormal in ulcerative colitis was examined by comparing disease related responses in expression of markers of differentiation by colonic crypt cells to culture with and without butyrate. Cells were isolated from patients with normal colon (15), cancer (24), ulcerative colitis (19), or Crohn's disease (16). Alkaline phosphatase activities were measured in cell homogenates and the rate of glycoprotein synthesis assessed at the end of 24 hours of culture and expressed relative to the rate of protein synthesis as the G:P ratio. Alkaline phosphatase activities, but not G:P ratios, differed across the groups before and after 24 hour culture (p < 0.05), activities being lowest in the cancer group and highest in inflammatory bowel disease groups. Butyrate (1 mM) suppressed alkaline phosphatase activities in the cancer group by mean (SEM) of 17 (4) (p = 0.006) compared with no change in the other groups. Butyrate suppressed G:P ratios only in the cancer (6 (3)%, p = 0.03) and ulcerative colitis groups (5 (3)%, p = 0.04) and the changes in both were different (p < 0.05) from those in normal cells (increase of 10 (7)%). Changes in ulcerative colitis were different from those in Crohn's disease (p = 0.029). Responses were independent of the presence or absence of mucosal inflammation. These data confirm the diffuse nature of epithelial abnormalities in colorectal cancer. In ulcerative colitis...