Antibodies to Cathepsin G in Crohn''s disease

Antibodies directed against antigens in human neutrophils have proved to be of great diagnostic value in certain systemic vasculitides. Recent reports have focused the attention on these antigens as targets of antibodies in sera of patients with inflammatory bowel disease. We investigated the sera drawn from 60 patients suffering from biopsy proven Crohn's disease and 15 patients with active ulcerative colitis. Using sensitive enzyme-linked immunosorbent assays with purified antigens and Western blotting the following antibodies could be demonstrated: cathepsin G (cat-G) antibodies IgG 38.3%, IgM 13.3%, IgA 23.3% and antibodies against human leucocyte elastase (HLE) IgG, IgA, IgM 3.3%. Low but significant correlations could be found for cat-G antibodies (IgG) and the van HEES index of activity. 73.9% of the cat-G (IgG) positive patients had colon involvement. In the sera of patients with ulcerative colitis no antibodies to cat-G or HLE were detectable. Only 8.3% of the patients with Crohn's disease had antibodies against proteinase 3 (C-ANCA). Our data indicate that cat-G among other myeloid lysosomal enzymes seems to be an important target antigen of antibodies in sera of patients with Crohn's disease. Cat-G antibodies might be helpful to distinguish Crohn's disease from ulcerative colitis.     

Autonomic cardiovascular regulation in quiescent ulcerative colitis and Crohn's disease

BACKGROUND: In inflammatory bowel diseases, changes in autonomic enteric regulation may also affect neural cardiovascular control. However, while cardiac autonomic modulation has been shown to be impaired in active ulcerative colitis, the occurrence of cardiovascular autonomic alterations, also in the quiescent phase of inflammatory bowel diseases, is still a matter of debate. The aim of our study was thus to explore the features of cardiovascular autonomic regulation in ulcerative colitis and Crohn's disease during their remission phase. MATERIALS AND METHODS: Autonomic cardiovascular control was evaluated by time- and frequency-domain indexes of spontaneous heart rate and blood pressure variability and by assessing the baroreflex heart rate control (sequence technique) in 26 patients with ulcerative colitis, in 26 patients with Crohn's disease and in 23 healthy controls. RESULTS: The groups were matched for age, gender and body mass index. They had similar blood pressure mean levels and variability. By contrast, mean heart rate, its overall variability (standard deviation), and baroreflex sensitivity were lower in ulcerative colitis patients than in controls. Moreover, all indexes related to cardiac vagal control were significantly lower in ulcerative colitis patients with respect not only to controls but also to Crohn's disease patients. CONCLUSIONS: Cardiac vagal control is impaired in quiescent ulcerative colitis only, and not in Crohn's disease, while in both bowel diseases vascular control appears preserved. Since cardiovagal modulation seems related to anti-inflammatory mechanisms, the reduced parasympathetic cardiac regulation in apparently quiescent ulcerative colitis suggests that such systemic derangement is accompanied by local subclinical inflammations, even in the absence of clinically active inflammatory processes.     

Platelet factor 4 and beta-thromboglobulin in inflammatory bowel disease and giant cell arteritis

BACKGROUND: As platelet factors are important in the inflammatory response, we examined the course of platelet factor 4 and beta-thromboglobulin in relation to disease activity in inflammatory bowel disease and in giant cell arteritis. PATIENTS AND METHODS: In a prospective study, the platelet count, platelet factor 4 and beta-thromboglobulin were measured in 20 patients with Crohn's disease, 18 with ulcerative colitis and 19 with giant cell arteritis, during active and inactive disease, as well as in 51 controls without inflammation. RESULTS: Platelet counts were significantly higher in active vs. inactive Crohn's disease, ulcerative colitis and giant cell arteritis. Levels of platelet factor 4 and beta-thromboglobulin were significantly higher in active inflammatory bowel disease and giant cell arteritis, as well as in inactive inflammatory bowel disease and giant cell arteritis, than in the non-inflammatory controls. A positive correlation was found between the Crohn's disease activity index and the platelet count, platelet factor 4 and beta-thromboglobulin. Also, a positive correlation was found between the ulcerative colitis activity index and beta-thromboglobulin. However, even after 12 months of follow-up, in Crohn's disease and ulcerative colitis the mean levels of platelet factor 4 and beta-thromboglobulin were significantly higher than the levels of the controls. CONCLUSION: Platelet factors were correlated with inflammatory bowel disease activity. Levels of platelet factor 4 and beta-thromboglobulin, however, were markedly raised for a long time in clinically inactive inflammatory bowel disease, which might point to a pre-thrombotic state of disease.     

In vitro cellular cytotoxicity in Crohn's disease and ulcerative colitis: relation with disease activity and treatment, and the effect of recombinant gamma-interferon

In a previous study using total mononuclear cells and lymphocytes, enriched by elutriation centrifugation, of patients with Crohn's disease and ulcerative colitis were found to have a decreased NK cell activity. In the present study the relation with disease activity and treatment, and the effect of recombinant gamma-interferon (gamma-IFN) on NK cell and monocyte cytotoxicity has been studied in 19 patients with Crohn's disease, 11 with ulcerative colitis, two with indeterminate colitis and 12 healthy controls. Patients with active Crohn's disease and active ulcerative colitis were shown to have an impaired NK cell activity compared to the control group. However, no difference was found in the percentage of CD16 (Leu 11+) cells, as determined by fluorocytometry, between patients with active or inactive disease. Moreover, the NK cell impairment was not related to corticosteroid treatment. Recombinant gamma-interferon (gamma-IFN) stimulated significantly the cytotoxic activity of the total mononuclear cells and the monocyte-enriched fraction against all target cell lines, both in patients and controls. No relation was found between the increase in cytotoxicity by gamma-IFN and disease activity in the patients. Stimulation with gamma-IFN demonstrated that the monocyte cytotoxic response of inflammatory bowel disease patients is normal. The present study reveals that the impairment in NK cell activity in patients with inflammatory bowel disease is related to disease activity and therefore suggests to be secondary to the inflammatory process.     

Transrectal ultrasound in the diagnosis and management of inflammatory bowel disease

BACKGROUND AND STUDY AIMS: To aim of the present study was to determine the value of transrectal ultrasonography (TRUS) in the assessment of disease activity in ulcerative colitis patients, and in differentiating between mucosal inflammation and transmural inflammation. PATIENTS AND METHODS: TRUS examinations were used to study 30 control individuals and 76 patients with inflammatory bowel disease, including 50 cases of ulcerative colitis and 26 of Crohn's disease. A rigid linear endorectal probe was used to examine the rectal wall. RESULTS: In the 30 control individuals, the rectal wall showed five layers, with a mean total diameter of 2.6 mm. There were significant differences between patients with quiescent ulcerative colitis, active ulcerative colitis, and control individuals with regard to the total rectal wall thickness (P<0.001), submucosal thickness (P<0.001) and mucosal thickness (P<0.001). Using cut-off values, differentiation between active ulcerative colitis and remission ulcerative colitis was found to be 100% specific and 73 % sensitive for submucosal thicknesses. TRUS revealed a 100% specificity in differentiating between remission ulcerative colitis and control cases based on the total rectal wall thickness, submucosal, and mucosal thicknesses. In the differential diagnosis of active and remission ulcerative colitis, an increase in submucosal wall thickness and the existence of arterial and venous capillary flow in the submucosa were found to be specific and more sensitive than the other parameters. TRUS examination revealed transmural inflammation in 21 of the 26 Crohn's disease patients, and mucosal inflammation in all 50 of the ulcerative colitis patients. CONCLUSION: TRUS is a reliable and easy method of assessing ulcerative colitis activity and differentiating between rectal diseases.     

An investigation into the validity of the present classification of inflammatory bowel disease

To assess the validity of the present subdivision of patients with inflammatory bowel disease into those with Crohn's disease of the small bowel or of the colon and those with ulcerative colitis, 252 patients with inflammatory bowel disease have been studied by questionnaire and case note review. One hundred and seventy-two variables concerning the nature and frequency of symptoms in remission and relapse, the incidence of complications and results of investigation have been analysed by computer. As expected, there were many highly significant variables between patients with ulcerative colitis and those with Crohn's disease of the small bowel. The latter showed evidence of a more severe disease course with more complications. There were similar, although less marked, differences between patients with Crohn's disease of the colon and those with Crohn's disease of the small bowel. There were very few differences in disease course between patients with Crohn's disease of the colon and those with ulcerative colitis. The results suggest that while separate classification of patients with Crohn's disease of the small bowel is justified on clinical grounds, the present separation of patients with disease confined to the colon into groups labelled ulcerative colitis or Crohn's disease of the colon is not. Alternative methods of classification should therefore be investigated.     

Inflammatory bowel disease

Idiopathic inflammatory bowel disease consists of Crohn's disease and ulcerative colitis. Crohn's disease can affect any part of the gastrointestinal tract, from the mouth to the anus, and is also known as regional enteritis, terminal ileitis, or granulomatous colitis. Ulcerative colitis is limited to the colon and rectal involvement is present 95% of the time. Ten percent to fifteen percent of patients with irritable bowel syndrome cannot be clearly defined as having either Crohn's disease or ulcerative colitis and are termed indeterminate colitis.     

Small bowel magnetic resonance imaging for inflammatory bowel disease

The presented concept of hydro-magnetic resonance imaging (MRI) using a 2.5% mannitol solution as an orally applicable intraluminal contrast agent is a meaningful, reproducible, and reliable imaging method for the depiction of the small bowel. Especially in patients with Crohn's disease, hydro-MRI is the imaging method of first choice because hydro-MRI offers the advantage of a superior depiction of the inflamed bowel wall and the extramural complications of this disease without radiation exposure. In addition, hydro-MRI allows for a reliable assessment of the inflammatory activity, especially for the differentiation between an active and an inactive (scarred) stenosis. In particular, the mural enhancement, the length as well as the wall thickness of inflamed bowel segments, are considered to be significant MR parameters for the determination of the activity of Crohn's disease. Hydro-MRI of the colon is suitable for the depiction of pathologic changes in ulcerative colitis, but in contrast to Crohn's disease, the assessment of disease activity by hydro-MRI is unreliable in ulcerative colitis, probably because of the low spatial resolution (mucositis in ulcerative colitis vs. transmural inflammation in Crohn's disease). Hydro-MRI does not allow a reliable classification of inflammatory bowel diseases, but in ambiguous cases, hydro-MRI may provide helpful information for the differentiation of Crohn's disease and ulcerative colitis. There are no data of larger patient groups published regarding MR findings in inflammatory bowel diseases besides Crohn's disease and ulcerative colitis, but hydro-MRI is a promising imaging tool for these entities, which should be assessed in additional studies.     

Ultrasound findings in Crohn's disease and ulcerative colitis: a prospective study

In a prospective study, 118 patients with Crohn's disease, 51 patients with ulcerative colitis, and 72 patients with no disease of the intestine proximal to the rectum were evaluated by ultrasound. In Crohn's disease, thickening of the bowel wall and inflammatory masses were detected in 72.0% of the patients. With a transducer having optimal imaging properties in the near range, these findings were detected in 87.2% of a group of 47 patients. In ulcerative colitis, bowel wall thickening was detected in 52.9% of all patients. Thickening of the bowel wall was more marked in Crohn's disease than in ulcerative colitis. Most pathologic findings in Crohn's disease were located in the right lower abdomen, whereas those in ulcerative colitis were in the left abdomen, in particular in the lower quadrant. The frequency of wall thickening was correlated to the activity of the disease in ulcerative colitis but not in Crohn's disease. Considerably increased wall thickness, when localized in the right lower quadrant and found in combination with inflammatory masses or an abscess, suggests Crohn's disease.     

Serum lysozyme, serum proteins, and immunoglobulin determinations in nonspecific inflammatory bowel disease

The serum levels of lysozyme, serum electrophoresis, and serum immunoglobulins were determined prospectively in 101 patients with ulcerative colitis, ulcerative proctitis, Crohn's disease, or nonclassifiable nonspecific inflammatory bowel disease. Although the mean serum lysozyme concentration of patients with Crohn's disease (10.5 +/- 6.8 microgram/ml) and ulcerative colitis (9.6 +/- 4.1 microgram/ml) performed by a standardized lysoplate method was significantly greater than normal controls (6.0 +/- 1.5 microgram/ml), the results did not correlate with the diagnosis nor with the degree of disease activity. Individually separated protein fractions and serum immunoglobulins also did not correlate with the serum lysozyme levels. This study indicates that measurement of the level of serum lysozyme in individual patients is not helpful in determining the cause or degree of activity of nonspecific inflammatory bowel disease.     

Anti-tissue transglutaminase antibodies in inflammatory bowel disease: new evidence.

Anti-tissue transglutaminase, previously held to be identical to anti-endomysial antibodies in celiac sprue, has been reported in inflammatory bowel disease patients. To investigate these data further, we evaluated serum and intestinal anti-tissue transglutaminase in inflammatory bowel disease patients, with respect to the Crohn's disease activity index and the integrated disease activity index. Study population comprised: 49 patients with Crohn's disease and 29 patients with ulcerative colitis; 45 patients with celiac sprue and 85 autoimmune patients as disease controls; and 58 volunteers as healthy controls. Immunoglobulin A (IgA) anti-recombinant human tissue transglutaminase and anti-endomysial antibody detection in sera and fecal supernatants were performed. Adsorption of positive sera with recombinant human tissue transglutaminase were also performed. Marked increased anti-tissue transglutaminase concentrations were found in celiac sprue, while low-positive values were also found in Crohn's disease and ulcerative colitis. Anti-endomysial antibodies were detectable only in celiac sprue. Antigen adsorption resulted in a significant reduction of the anti-tissue transglutaminase either in celiac sprue or inflammatory bowel disease sera. A significant correlation between anti-tissue transglutaminase and Crohn's disease activity index or integrated disease activity index scores was found. Anti-tissue transglutaminase was also detectable in fecal supernatants from inflammatory bowel disease patients. Data highlight that both circulating and intestinal anti-tissue transglutaminases are detectable in inflammatory bowel disease, and that they are related to disease activity. These features underline that, in addition to anti-tissue transglutaminase, an anti-endomysial antibody test is necessary in the diagnostic work-up of celiac sprue, especially in patients with known inflammatory bowel disease.     

Low S-adenosylmethionine concentrations found in patients with severe inflammatory bowel disease.

BACKGROUND: S-adenosylmethionine is a methyl donor in many cellular reactions including detoxification of constantly produced hydrogen sulphide in the colon. A reduced capacity to detoxify hydrogen sulphide may be implicated in the pathogenesis of inflammatory bowel disease. S-adenosylmethionine could be low if this assumption is correct. We compared S-adenosylmethionine concentrations in whole blood in patients with severe and moderate inflammatory bowel disease with healthy reference persons. METHODS: S-adenosylmethionine concentrations in whole blood were measured using high-pressure liquid chromatography. Patients with Crohn's disease (n=21), ulcerative colitis (n=7) and healthy age-matched reference persons (or controls) (n=17) were studied. RESULTS: S-adenosylmethionine concentrations were significantly decreased in patients with severe inflammatory bowel disease (mean 1.10 mg/l) as compared to patients with moderate Crohn's disease and ulcerative colitis (mean 1.83 mg/l) and reference persons (mean 1.84 mg/l). Statistically significant inverse correlations were found between S-adenosylmethionine concentration and activity index (p<0.01 and R2=0.86) as well as Crohn's disease activity index (p<0.01 and R2=0.50) scores. CONCLUSIONS: Low concentrations of S-adenosylmethionine were found in patients with severe inflammatory bowel disease. Future studies will show whether S-adenosylmethionine is a marker for disease activity and a possible tool for investigation of sulphur toxicity as a causative mechanism in inflammatory bowel disease.     

Chromium 51-ethylenediaminetetraacetate test: a useful test in the assessment of inflammatory bowel disease

We evaluated the usefulness of urinary excretion values in assessing mucosal damage in inflammatory bowel disease after administration of chromium 51-labeled EDTA either orally or rectally. In the oral study, 19 controls, 18 patients with Crohn's disease, and 13 patients with ulcerative colitis were given 100 microCi 51Cr-EDTA by mouth. The amount of 51Cr-EDTA in a 24-hour urine collection was expressed as a percentage of the ingested dose. The patients with Crohn's disease of the small bowel excreted 6.3% +/- 4.3%, which was significantly (P less than 0.001) higher than the percentage in patients with ulcerative colitis (1.7% +/- 1.1%) and controls (1.4% +/- 0.6%). In the enema study, 19 patients with ulcerative colitis, two with Crohn's disease, two with radiation colitis, and four controls (spastic colitis, lactose intolerance) were given 100 microCi 51Cr-EDTA by retention enema. The patients with active colonic inflammation excreted 8.4% +/- 3.9% of the dose given by enema, which was significantly (P less than 0.01) higher than in other controls (1.9% +/- 0.91%) or patients with inactive colitis (2.2% +/- 1.9%). The 51Cr-EDTA excretion test is a safe, inexpensive test useful in evaluating patients with inflammatory bowel disease. It can be given orally to screen patients with abdominal complaints who are suspected of having Crohn's disease involving the small intestine, and when given by enema it provides additional objective assessment of idiopathic ulcerative colitis or proctitis.     

The humoral immune system in inflammatory bowel disease. II. Immunologlobulin levels

As there have been reports of differences in mean levels of serum immunoglobulins between patients with ulcerative colitis and Crohn's disease, serum IgG, IgA, and IgM were estimated in 158 patients with inflammatory bowel disease and the results correlated with the clinical features of the patients. Although a higher mean IgG level in ulcerative colitis compared to Crohn's disease was confirmed, no difference was found when the comparison was limited to patients with colonic Crohn's disease. Patients with either disease had higher mean IgM levels than controls, and the IgM levels were higher on treatment with corticosteroids and showed a tendency to rise in remission. IgG and IgM levels were also higher in both diseases if extraintestinal manifestations were present. It is concluded that if clinical features, particularly disease site, are taken into account, the overall immunoglobulin responses in these two diseases show no differences.     

Clinical features, morbidity and mortality of Scottish children with inflammatory bowel disease

From the Scottish Hospitals in-patients statistics for the years 1968-1983 all children and teenagers (a total of 1257) admitted to a National Health Service hospital with Crohn's disease or ulcerative colitis were identified. Case records of samples of patients with onset of symptoms at or before age 16 years were examined to establish the features, morbidity and mortality of unselected cohorts of young patients with inflammatory bowel disease. Median delay in diagnosis was less than six months. Anatomical distribution for Crohn's disease was similar to that in adults (small bowel 30 per cent; large bowel 28 per cent; small and large bowel 38 per cent) and almost half the patients with ulcerative colitis had extensive colitis. The morbidity was substantial in both. In-patient days for Crohn's disease ranged from seven to 322, median 64 days and for ulcerative colitis one to 275, median 30 days. At diagnosis, 11 of 40 young children with Crohn's disease but none of 14 with ulcerative colitis, were below the third centile for height. Despite treatment with corticosteroids 72 per cent of patients with Crohn's disease and 30 per cent of patients with ulcerative colitis required surgical treatment. Seventeen per cent have a permanent stoma. There were only six deaths, all before 1978.     

Algorithm of diagnosis and treatment of complicated forms of nonspecific ulcerative colitis and Crohn's disease

AIM: To detect complicated forms of nonspecific ulcerative colitis and Crohn's disease, to calculate treatment algorithm. MATERIAL AND METHODS: The results of a 20-year prospective trial including 313 patients with nonspecific ulcerative colitis (n = 180) and Crohn's disease (n = 133) have been analysed. The following parameters were considered: clinical findings with calculated index of the disease activity, endoscopic, x-ray and morphological data. All the information was processed using computer programs Biostat and Exell 97 Mean and standard deviations were calculated. Chi-square and Fisher's criteria were used. RESULTS: Complicated forms of nonspecific ulcerative colitis and Crohn's disease were detected and characterized. Programs of treatment of complicated forms of intestinal inflammatory diseases and measures for maintenance of the remission are proposed.     

Inflammatory bowel disease: primary health care management of ulcerative colitis and Crohn's disease

Inflammatory bowel disease encompasses both ulcerative colitis and Crohn's disease, two conditions so alike clinically that they are frequently indistinguishable from one another. Inflammatory bowel disease occurs at a rate of approximately five per 100,000 people. It tends to cluster in families and is seen four to five times more often in Jewish Caucasians than in other Caucasians. The etiology is unknown. Increasing attention is being paid to autoimmune factors, genetic factors and food allergies, and the notion that inflammatory bowel disease has its roots in a psychological disorder continues to pale for want of empirically sound evidence. Disease pattern is one of remission and exacerbation. The aim of therapy is to maintain an optimal lifestyle in remission through an individually tailored protocol of medications. Sulfasalazine remains the medication of choice; corticosteroids have short-term utility in exacerbation; and immunosuppressants, though controversial, are thought to have some steroid-sparing benefits during acute flare-ups. Indications for surgery vary, depending on whether or not a clear differential diagnosis has been made between ulcerative colitis and Crohn's disease. There is no cure for inflammatory bowel disease except for total colectomy in clearly diagnosed ulcerative colitis. Current research endeavors seek a cause or causes for inflammatory bowel disease, but the literature does not solidly support any one possibility above other rival etiologies.     

Extraintestinal and systemic manifestations of inflammatory bowel disease

Extraintestinal and systemic manifestations occur commonly in patients with inflammatory bowel disease, specifically ulcerative colitis and Crohn's disease, and affect most all organ systems of the body. The occurrence of such widespread manifestations strongly suggests that these disorders are systemic in nature and may have a common mechanism. Extraintestinal manifestations may be incidental findings that cause no symptoms, but more commonly complicate the management of the underlying inflammatory bowel disease, being a source of considerable morbidity and mortality. Some extraintestinal manifestations not only correlate with a specific disease state but also with the location, extent, and degree of activity and disease. Most extraintestinal manifestations found in patients with inflammatory bowel disease involving the small intestine appear to correlate with some underlying pathophysiologic mechanism.     

Autoimmunity, inflammatory bowel disease and hyposplenism.

The presence or absence of nine autoantibodies were assessed in 44 patients with ulcerative colitis (17 with hyposplenism) and 22 patients with Crohn's disease (eight with hyposplenism). The purpose of the study was to determine whether hyposplenism in inflammatory bowel disease is associated with an increased tendency to autoimmunity, or whether autoimmunity is linked not to hyposplenism itself but to the underlying bowel disease. The results strongly suggest that the latter hypothesis is correct. There was a much higher frequency of autoantibodies in patients with ulcerative colitis than in those with Crohn's disease (P < or = 0.01), suggesting that autoimmune factors are more important in the pathogenesis of ulcerative colitis than in Crohn's disease.     

Manipulation of cytokines in the management of patients with inflammatory bowel disease

In recent years, new concepts have been formulated for the therapeutic management of the intractable forms of Crohn's disease and ulcerative colitis, the two major forms of inflammatory bowel disease. These advances are based largely on new insights into the immune-inflammatory events occurring in the gut of these patients. Analysis of the types of immune response ongoing in the inflamed intestine has revealed that in Crohn's disease there is predominantly a T-helper cell type 1 response, with exaggerated production of interleukin (IL)-12 and interferon (IFN)-gamma, whereas in ulcerative colitis the lesion seems more of an antibody-mediated hypersensitivity reaction. Despite these differences, downstream inflammatory events are the same in both conditions. In both Crohn's disease and ulcerative colitis mucosa, IL-1gamma, IL-6, IL-8 and tumour necrosis factor (TNF)-alpha are produced in excess, and the production of free radicals accompanying the influx of nonspecific inflammatory cells into the mucosa is above the normal range. Strategies aimed at inhibiting T-cell responses are therefore more relevant in Crohn's disease, whereas, in theory at least, inhibition of downstream inflammatory processes should be therapeutic in both Crohn's disease and ulcerative colitis. This review seeks to summarize studies in which anticytokine antibodies, cytokines or cytokine-modifying agents have been used in the treatment of either Crohn's disease or ulcerative colitis.