Familial expression of anti-Saccharomyces cerevisiae mannan antibodies in affected and unaffected relatives of patients with Crohn's disease

BACKGROUND: Crohn's disease is a familial disorder, and antiglycan antibodies to the cell wall mannan of Saccharomyces cerevisiae (ASCA) are highly correlated with Crohn's disease. AIMS: To determine whether there is a familial pattern for expression of serum levels of anti-mannan Ig, and whether this trait is expressed in clinically unaffected Crohn's disease family members. METHODS: 349 patients with Crohn's disease, 87 Crohn's disease affected relatives, 333 inflammatory bowel disease (IBD) free relatives, 58 spouses, and 190 healthy control patients were studied. Serum IgG and IgA binding activity to S cerevisiae cell wall mannan was quantitated by ELISA. RESULTS: A high percentage of patients with Crohn's disease (51.9%) and affected family members (56.3%) were seropositive for anti-mannan Ig, compared with the normal control population (3.7%). Seropositive and seronegative phenotypes of Crohn's disease probands were correlated among all affected relatives, and this association was stronger in affected first degree relatives. Statistical intraclass correlations of quantitative anti-mannan Ig levels revealed significantly less variation within, rather than between families. A significant familial aggregation was observed for affected relatives; this was even stronger for unaffected relatives. While a significant familial aggregation was observed among unaffected siblings pairs, there was no significant correlation among marital pairs. CONCLUSION: Results show that anti-mannan Ig in family members affected and unaffected with Crohn's disease is a familial trait for both affected and unaffected relatives. The lack of concordance in marital pairs indicates that familiality is due in part to a genetic factor or childhood environmental exposure.     

Perinuclear antineutrophil cytoplasmic autoantibodies and anti-Saccharomyces cerevisiae antibodies as serological markers are not specific in the identification of Crohn's disease and ulcerative colitis

OBJECTIVE: To evaluate the diagnostic accuracy of perinuclear antineutrophil cytoplasmic autoantibodies (pANCAs) and anti-Saccharomyces cerevisiae antibodies (ASCAs), as single agents and in combination, for the diagnosis of Crohn's disease (CD) and ulcerative colitis (UC), including in cases of indeterminate colitis (IC). METHODS: The sera from a total of 98 patients were studied: 77 with CD, 16 with UC and five with IC. The medical records of these patients were reviewed for disease diagnosis, demographic data, and patient symptoms and medications. ELISAs were utilized to detect the presence of ASCAs and deoxyribonuclease-sensitive pANCAs, and these results were then compared with the patients' clinical data. RESULTS: For UC, a positive pANCA test alone provided a sensitivity of 50% and a specificity of 82%. For CD, a positive ASCA test alone provided a sensitivity of 40% and a specificity of 100%. A combination of pANCA-positive and ASCA-negative results showed a sensitivity of 50% and specificity of 90% for the diagnosis of UC. Similarly, the combination of ASCA-positive and pANCA-negative results provided a sensitivity and specificity of 32% and 100% for the diagnosis of CD, respectively. Interestingly, 80% of IC patients showed serology results consistent with UC. CONCLUSIONS: Although this combination of serological markers provides a diagnostic tool with generally high specificities, the low sensitivities of these serological markers, most notably in terms of CD, preclude the possibility that they can replace the tools currently used for inflammatory bowel disease diagnosis and management. It is possible, however, that these serological markers may prove beneficial in the management of IC.     

Anti-Saccharomyces cerevisiae Mannan Antibodies in Familial Crohn's Disease

Objective: Anti- Saccharomyces cerevisiae mannan antibodies (ASCA) are associated with Crohn's disease. The aim of this study was to determine the prevalence of ASCA in families in which at least two members were affected with Crohn's disease.
Methods: A total of 20 families including two (  n = 15  ) or more (  n = 5  ) patients with Crohn's disease were tested for ASCA with use of an ELISA method. Overall, 51 affected members, 66 healthy first degree relatives, and 163 healthy control subjects were studied.
Results: ASCA were detected in 35 of 51 (69%) patients with Crohn's disease and in 13 of 66 (20%) healthy relatives versus one of 163 healthy control subjects (   p < 0.0001  and   p < 0.001  ). ASCA-positive relatives were distributed in 12 of 20 families. ASCA were present in eight healthy parents and four healthy siblings. The prevalence of ASCA in relatives did not depend on the ASCA status of affected members.
Conclusion: ASCA in 20% of healthy first degree relatives of patients with Crohn's disease suggest that these antibodies might be a subclinical marker for Crohn's disease in families. Whether ASCA reflect environmental or genetic factors or a combination of both is unknown.     

Selected bacterial antibodies in Crohn's disease and ulcerative colitis

Agglutinins to four strains of anaerobic gram-positive coccoid rods (species of Eubacterium, Peptostreptococcus and Coprococcus) were found in significantly higher frequency in Crohn's disease (CD) than in ulcerative colitis (UC) and in other diseased control subjects and were virtually absent in apparently healthy subjects. When the posterior probability of having CD was calculated on the basis of these agglutination reactions, 64% of patients with CD and 34% of patients with UC but only 10% of diseased controls and none of the healthy controls were regarded as 'probable' or 'definite' cases of CD. However, the posterior probability of CD did not sharply differentiate between CD and UC but indicated chronic inflammatory bowel disease. Factors contributing to the appearance of these agglutinins in CD were also evaluated. The findings would indicate the importance of a damaged intestinal mucosal barrier for the production of these agglutinins, provided the antigens are present in the intestine. No significant differences were observed between the occurrence of antibodies to pseudomonas-like organisms (PLO) in CD and the various control groups. The study could not add further evidence to the hypothesis of a possible aetiopathogenic role of PLO in CD.     

Partial overlap of anti-mycobacterial, and anti- Saccharomyces cerevisiae mannan antibodies in Crohn＇s disease

AIM： To test whether humoral immune reaction against mycobacteria may play a role in anti- Saccharomyces cerevisiae antibodies （ASCA） generation in Crohn＇s disease （CD） and/or whether it correlates with clinical subtypes.
METHODS： The dominant ASCA epitope was detected by Galanthus nivalis lectin （GNL）-binding assay. ASCA and IgG against mycobacterial lysates （M avium, M smegmatis, M chelonae, M bovis BCG M avium ssp. paratuberculosis （MAP）] or purified lipoarabinomannans （LAM） were detected by ELISA. ASCA and anti-mycobacterial antibodies were affinity purified to assess cross-reactivities. Anti-mycobacterial IgG were induced by BCG-infection of mice.
RESULTS： GNL bound to different extents to mycobacterial lysates, abundantly to purified mannosecapped （Man） LAM from M tuberculosis, but not to uncapped LAM from M srnegrnatis. Fifteen to 45% of CD patients but only 0%-6% of controls were seropositive against different mycobacterial antigens. Anti-mycobacterial IgG correlated with ASCA （r = 0.37-0.64; P = 0.003-P 〈 0.001）. ASCA-positivity and deficiency for mannan-binding lectin synergistically associated with anti-mycobacterial IgG. In some patients, anti-mycobacterial antibodies represent crossreactive ASCA. Vice-versa, the predominant fraction of ASCA did not cross-react with mycobacteria. Finally, fistulizing disease associated with antibodies against M avium, M smegmatis and MAP （P = 0.024, 0.004 and 0.045, respectively）.
CONCLUSION： Similar to ASCA, seroreactivity against mycobacteria may define CD patients with complicated disease and a predisposition for immune responses against ubiquitous antigens. While in some patients anti-mycobacterial antibodies strongly cross-react with yeast mannan; these cross-reactive antibodies only represent a minor fraction of total ASCA. Thus, mycobacterial infection unlikely plays a role in ASCA induction.     

Association of perinuclear antineutrophil cytoplasmic antibodies and anti-Saccharomyces cerevisiae antibodies with Vienna classification subtypes of Crohn's disease

BACKGROUND: The Vienna classification of Crohn's disease (CD) subdivides patients according to their age at diagnosis (A), disease location (L), and disease behavior (B).AIM The aim of this study was to test whether perinuclear antineutrophil cytoplasmic antibodies (pANCAs) or anti-Saccharomyces cerevisiae antibodies (ASCAs) correlate to subtypes of CD according to this classification. METHODS: pANCA, ASCA-immunoglobulin (Ig) A, and ASCA-IgG were detected by indirect immunofluorescence in 120 sera of patients with CD and compared with their Vienna classification. RESULTS: Patients with diagnosis of CD at an age of 40 years or older (A2) were more frequently pANCA-positive than those whose disease started at a younger age (A1) (19% vs. 5%, p < 0.05). pANCA-positive patients almost exclusively belonged to the nonpenetrating disease groups (B1 and B2); only one patient had penetrating disease (B3) (B3 vs. non-B3: p = 0.02). There was a cluster of pANCA-positive patients within the A1 B2 L3 subgroup (B2: stricturing disease; L3: ileocolonic involvement). Only 7.5% of ASCA-IgA-positive patients presented with CD that was limited to the colon (L2). ASCA-IgA and ASCA-IgG were more frequently found in patients with upper gastrointestinal disease (L4) (ASCA-IgA: 66.7% vs. 31.5% in non-L4, p < 0.05; ASCA-IgG: 44.4% vs. 27.9%, p < 0.05). CONCLUSION: pANCA and ASCA may be useful in predicting subtypes of CD. They therefore may be helpful in developing subtype-specific disease management strategies.     

Serum antibodies to cow's milk proteins in ulcerative colitis and Crohn's disease

Serum antibodies of immunoglobulin G, immunoglobulin M, and immunoglobulin A isotypes to five major proteins of cow's milk, casein, bovine serum albumin, alpha-lactalbumin, beta-lactoglobulin A, and beta-lactoglobulin B, were measured using enzyme-linked immunosorbent assay in 51 patients with ulcerative colitis, 49 with Crohn's disease, and 20 age-matched controls. Immunoglobulin G and immunoglobulin M antibodies to cow's milk proteins were significantly elevated in patients with inflammatory bowel disease as compared to controls. In contrast, no significant increase in immunoglobulin A antibodies to 3 of 5 proteins was noted. The increased titers of antibodies to milk proteins seem to be specific and not due to a polyclonal immunoglobulin activation, as naturally occurring blood group antibodies were not elevated in patients with ulcerative colitis and Crohn's disease. A good correlation of disease activity, as measured by serum alpha 1-acid glycoprotein concentrations, and immunoglobulin G and immunoglobulin A antibody titers against certain cow's milk proteins could be demonstrated in Crohn's disease, but not ulcerative colitis. These findings suggest that production of antibodies to cow's milk proteins reflects specific immunization with these antigens. The study of antibody isotypes and correlation with disease activity may provide better insight into the immune response to dietary antigens and its possible role in the pathogenesis of inflammatory bowel diseases.     

Effects of disease activity on anti-Saccharomyces cerevisiae antibodies: implications for diagnosis and follow-up of children with Crohn's disease

BACKGROUND: To determine diagnostic accuracy of anti-Saccharomyces cerevisiae antibodies (ASCA) in identifying children with inflammatory bowel disease (IBD) and to differentiate Crohn's disease (CD) from other IBD forms; and to determine the effect of medical or surgical treatment and of disease location and activity on ASCA titers. METHODS: Serum samples were obtained from 196 IBD children and 142 controls. ASCA IgA and IgG titers were measured by ELISA. Measurements were repeated during the follow up of CD children. RESULTS: ASCA titers were significantly higher in CD than in other IBD and in control patients. Combination of IgA and IgG ASCA positivity was highly specific for CD. Medical treatment and disease location did not influence assay results. Significantly lower ASCA titers were obtained in CD children with intestinal resection compared to CD-affected children who did not undergo surgical resection. ASCA titers correlated significantly with disease activity, and children with severe active disease showed higher ASCA values compared to those in remission. A significant reduction of ASCA was observed during the follow-up of CD children when clinical remission was achieved. CONCLUSIONS: The diagnostic accuracy of ASCA is influenced by disease activity and this suggests an additional use for the follow-up of CD children of this assay.     

Coexisting Crohn's disease and ulcerative colitis

This case report describes a patient initially presenting with Crohn's disease of the ileum who subsequently developed ulcerative proctocolitis. Reports of patients with both inflammatory bowel disease confirmed by histopathologic examination are rare.     

Serum antibodies to Mycobacterium avium subspecies paratuberculosis combined with anti-Saccharomyces cerevisiae antibodies in Crohn's disease patients: prevalence and diagnostic role

Background  

Because Mycobacterium avium subspecies paratuberculosis (MAP), the etiologic agent of Johne’s disease in ruminant, has been identified in the mucosal layer and deeper bowel wall in CD patients, the seroactivity against MAP may define a distinct subset of patients requiring individual treatment. The aim of this study was to assess the performance of anti-MAP antibodies in the diagnostic strategy for CD.     

Management of ulcerative colitis and Crohn's disease

The conventional medical treatment of IBD consists of aminosalicylates, corticosteroids, immunosuppressive drugs (azathioprine, 6-mercaptopurin, methotrexate, cyclosporin) and antibiotics. The only drugs able to modify the disease course are azathioprine, its metabolite 6-mercaptopurin and methotrexate. However, these drugs have a slow onset of action and are associated with important side-effects in some patients, necessitating the discontinuation of the drug. Moreover, up to 60% of patients do not respond to these drugs long-term. Fortunately, the management of IBD has entered a new era in the beginning of the 1990s with the development of new biological therapies, selectively blocking the inflammatory cascade. The novel molecules have arisen from the increasing knowledge about the disease pathogenesis and their production has been precipitated by the techniques of molecular biology. Infliximab, the first available biological for Crohn's disease has certainly revolutionised standard treatment. Because of its profound clinical, endoscopic and histological effects, the standard step up approach in the treatment of IBD has been challenged. A large array of new rationally designed biologicals, with a better safety profile and equally selectively acting is underway, and is likely to change our current practise even more dramatically in the next decade.     

Disappearance of anti-Saccharomyces cerevisiae antibodies in coeliac disease during a gluten-free diet

BACKGROUND: Anti-Saccharomyces cerevisiae antibodies (ASCAs) are known to be positive in about 65% of Crohn's disease patients, in up to 43% of coeliac disease patients and in 0-5% of healthy controls. Coeliac disease might be an in-vivo model for unravelling the role of mucosal integrity in the formation of ASCAs since mucosal abnormalities normalize during a gluten-free diet (GFD). AIMS: Firstly, to evaluate, retrospectively, the frequency of ASCA positivity in coeliac patients both at diagnosis and during follow-up on a GFD. Secondly, to study the correlation between ASCA positivity and mucosal damage. METHODS: One hundred and eleven patients with histologically proven coeliac disease, positive endomysium antibodies on diagnosis and normalization of trans-glutaminase antibodies (t-TGAs) after successful adherence to a GFD were included. ASCAs, IgA and IgG were tested by enzyme-linked immunosorbent assays both at diagnosis and after the GFD. RESULTS: Eighty-three children and 28 adults were included in this study. The mean age at diagnosis was 4.6 years for children and 48 years for adults. At diagnosis 15/83 (18%) of children were ASCA positive (either IgG or IgA), compared to 17/28 (61%) of adults. After successful adherence to a GFD and normalization of t-TGAs only one child remained ASCA positive (1%) compared to eight adults (29%). Two out of 28 (7%) adults remained positive for both IgA and IgG ASCAs. CONCLUSION: In the majority of patients ASCAs disappeared during a GFD. In children this disappearance of ASCA positivity was more pronounced. This can be explained by the well-known fact that gut permeability normalizes much better in children than in adults. Also, the adults had higher levels of ASCAs at diagnosis. This was probably because they had been exposed to gluten for longer and therefore had more long-lasting damage.     

Familial aggregation in Crohn's disease and ulcerative colitis in a Norwegian population-based cohort followed for ten years

Background and aimsTo explore the change in risk among 1st degree relatives of ulcerative colitis (UC) and Crohn's disease (CD) for development of concordant disease in an incidence cohort followed for ten years. Furthermore, we wanted to compare familial and sporadic cases regarding clinical characteristics and the course of the disease.MethodsThis population-based study included 421 patients with UC and 197 with CD enrolled from 1990 to 1994. Clinical characteristics and the number of 1st degree relatives of the patients were recorded continuously during ten years.ResultsAge at diagnosis in CD patients (OR = 0.95, 95% CI: 0.93–0.98) and cumulative relapse rate in UC patients (OR = 4.91, 95% CI = 1.16, 20.75) were significantly associated to familial clustering. Based on the calculated population prevalence of CD (262/100 000) and UC (505/100 000), the age-adjusted risk for development of concordant disease was 25.9 and 8.6 among siblings and parents of CD, respectively. In UC, the corresponding risks were 8.6 and 1.5. In the course of ten years the increase in risk was observed only among siblings (28%) and parents (97%) of UC, in contrast to no increase in CD. Moreover, the concordance for UC was high in three generations.ConclusionsOur study confirmed the importance of genetic influence on the development of CD. Within an observation period of ten years, the increased concordance and relapse rate in familial UC, might point to a larger genetic component in UC than previously suggested.     

Clq metabolism in ulcerative colitis and Crohn's disease

The metabolism of pure radioiodine labelled Clq has been observed in five patients with ulcerative colitis, five patients with Crohn's disease, and in five control subjects. Both the fractional catabolic rate and the synthesis rate of Clq were increased in the five patients with Crohn's disease and in four of the five patients with ulcerative colitis. The fifth patient was in remission and had a normal synthesis rate. These results support the hypothesis that complement activation plays a role in the pathogenesis of these disease states and that the increased complement activation is primarily via the classical pathway.     

Esophageal lesions in Crohn's disease and ulcerative colitis

This article reviews the literature about esophageal involvement of Crohn's disease and ulcerative colitis. The review highlights the incidence of IBD, clinical features and difficulties of diagnosis and treatment of patients with esophageal involvement of IBD.     

Endotoxin-induced microclots in ulcerative colitis and Crohn's disease

Radially oriented fibrin microclots were observed when blood from patients with active lesions of Crohn's disease and ulcerative colitis was kept in capillary tubes for 24 h. Addition of bacterial extract or endotoxins increased the fibrin formation. The phenomenon is not seen in healthy subjects or patients who have healed after colectomy. The data are consistent with our findings in patients with vasculitis and support the view that patients with Crohn's disease and ulcerative colitis have circulatory endotoxins.