Genetic and serological markers to identify phenotypic subgroups in a Dutch Crohn’s disease population

BACKGROUND AND AIMS: Both genetic and microbial factors seem to play a pivotal role in the aetiopathogenesis of Crohn's disease. The CARD15 frameshift mutation might link host genetic factors and the indigenous microbial flora, since CARD15 expression is stimulated by peptidoglycan, thereby activating NF-kappaB. It is hypothesised that CARD15 mutation carriers have defective anti-microbial reactions, resulting in more penetrating lesions and antibody responses, which are now being used as highly specific markers for Crohn's disease. The serological marker anti-Saccharomyces cerevisiae antibody directed against cell wall oligomannosidic epitopes has high specificity for Crohn's disease. Perinuclear anti-neutrophil cytoplasmic antibodies have been found in a subgroup of Crohn's disease patients, mostly with colonic involvement. METHODS: We investigated the incidence of two CARD15 mutations (3020insC and 2722G>C), anti-S. cerevisiae antibody, and perinuclear anti-neutrophil cytoplasmic antibody in 108 (73F/35M) patients with Crohn's disease with a mean duration of disease since diagnosis of 16 (1-41) years in relation to their phenotype, according to the Vienna classification. RESULTS: The prevalence of CARD15 frameshift mutation was 21%. Of all patients, 62% were anti-S. cerevisiae antibody positive, and 9% had perinuclear anti-neutrophil cytoplasmic antibodies. The prevalence of both anti-S. cerevisiae antibodies and perinuclear anti-neutrophil cytoplasmic antibodies was higher in the mutation carriers compared to non-carriers. Remarkably, all patients with a CARD15 mutation and positive anti-S. cerevisiae antibody had ileal disease. Carriership of the mutation was significantly associated with penetrating behaviour of the disease and weakly associated with stricturing behaviour. Furthermore, anti-S. cerevisiae antibody was associated with ileal disease involvement. Finally, most perinuclear anti-neutrophil cytoplasmic antibody positive patients showed ulcerative-like behaviour of disease (by means of colonic localisation). CONCLUSIONS: Genetic and serologic markers might be useful in defining patient subgroups. This may result in a more accurate prediction of disease behaviour, prognosis and therapeutic approach.     

Behaviour of Crohn's disease according to the Vienna classification: changing pattern over the course of the disease.

BACKGROUND: Crohn's disease is a heterogeneous disorder with both a genetic and environmental aetiology. Clinical classifications of the disease, such as the newly proposed Vienna classification, may help to define subgroups of patients suitable for studying the influence of specific genetic or environmental factors. AIM: To assess the stability over the course of the disease of its location and behaviour, as determined according to the Vienna classification. PATIENTS AND METHODS: The notes of 297 Crohn's disease patients regularly followed up at our institution were carefully reviewed retrospectively. The behaviour and location of the disease according to the Vienna classification were determined at diagnosis and after 1, 3, 5, 10, 15, 20, and 25 years of follow up. The proportions of the different behaviours and locations of the disease were calculated at these time points. A statistical analysis of the evolution of these characteristics over 10 years was performed on a subgroup of 125 patients with at least 10 years of follow up. The influence of age at diagnosis on location and behaviour of the disease was assessed as well as the influence of location on the behaviour of the disease. RESULTS: The location of the disease remained relatively stable over the course of the disease. Although the proportion of patients who had a change in disease location became statistically significant after five years (p=0.01), over 10 years only 15.9% of patients had a change in location (p<0.001). We observed a more rapid and prominent change in disease behaviour, which was already statistically significant after one year (p=0.04). Over 10 years, 45.9% of patients had a change in disease behaviour (p<0.0001). The most prominent change was from non-stricturing non-penetrating disease to either stricturing (27.1%; p<0.0001) or penetrating (29.4%; p<0.0001) disease. Age at diagnosis had no influence on either location or behaviour of disease. Ileal Crohn's disease was more often stricturing, and colonic or ileocolonic Crohn's disease was more often penetrating: this was already the case at diagnosis and became more prominent after 10 years (p<0.05). CONCLUSIONS: Location of Crohn's disease, as defined by the Vienna classification, is a relatively stable phenotype which seems suitable for phenotype-genotype analyses. Behaviour of Crohn's disease according to the Vienna classification varies dramatically over the course of the disease and cannot be used in phenotype-genotype analyses. The potential influence of genes on the behaviour of Crohn's disease should be studied in subgroups of patients defined by their disease behaviour after a fixed duration of disease.     

Crohn's disease runs a more aggressive course in young Asian patients

BACKGROUND: Crohn's disease is a heterogeneous inflammatory bowel disease. The impact of age at diagnosis on the clinical course of patients varies widely as reported in the Western literature. Using the Vienna Classification, we seek to determine whether young Crohn's disease patients in an Asian population followed a different clinical course than old patients. METHODS: The case records of 100 Crohn's disease patients who were treated at the Inflammatory Bowel Disease Center, Singapore General Hospital, were studied retrospectively. The age group and location of disease and behavior according to the Vienna classification were determined at diagnosis. RESULTS: A1 group (age <40 years) defined as "young" and A2 group (age > or =40) defined as "old" contained 65 and 35 patients, respectively. Median age for the young group was 27.4 years and that for the old group was 52.6 years. Of the young patients, 66.7% flared at least once compared with 28.6% of the old patients, odds ratio of 5.0 (P < 0.001). Young patients were more likely to be steroid dependent (20.0% of A1 versus 8.6% of A2, P = 0.14), received azathioprine (38.5% of A1 versus 5.7% of A2, P < 0.001) and experienced complications (31% of A1 versus 20% of A2, P = 0.25)-numerically higher rates that did not reach statistical significance. There was no significant difference between the age groups for the location and behavior of disease as well as requirement for surgery. CONCLUSION: In this first Asian study looking specifically at the impact of age at diagnosis of Crohn's disease, we found that young patients underwent a more aggressive clinical course.     

Disease location, anti-Saccharomyces cerevisiae antibody, and NOD2/CARD15 genotype influence the progression of disease behavior in Crohn's disease

BACKGROUND: Crohn's disease (CD) is characterized by heterogeneity of phenotype. The Vienna classification can be used to classify CD, and recent data illustrate that behavior evolves over the course of the disease. Clinical and biological influences on disease progression remain unclear. We examined the associations of CD disease progression at diagnosis and for up to 20 years of follow-up. METHODS: Two hundred thirty-one well-characterized CD patients were studied. Demographic, clinical, and NOD2/CARD15 data were collected. Disease behavior according to the Vienna classification was assessed at diagnosis and for up to 20 years following diagnosis. RESULTS: At diagnosis, 70% of patients had inflammatory disease, 9% stricturing, and 21% penetrating. Early age at diagnosis was associated with ileocolonic and upper GI disease (p = 0.015), and positive anti-Saccharomyces cerevisiae antibody (ASCA) was associated with ileal involvement (p = 0.008). Smoking was relatively protective against colonic, rather than ileal involvement at diagnosis (p < 0.02). At 20 years, 92% had progressed to a more severe disease type. Patients who progress to a more severe disease type require more frequent surgery (p < 0.00001). Multivariate analysis found disease progression to be associated with ileal disease location (p = 0.001) and positive ASCA (p = 0.003). Variant NOD2/CARD15 alleles were protective against rapid progression of disease phenotype (p = 0.04). The presence of perianal disease was independent of intestinal penetrating disease. CONCLUSIONS: The progression of disease type in CD is associated with the need for more frequent surgery. Rapid progression is associated with ileal disease and positive ASCA, and delayed progression is associated with variant NOD2/CARD15 alleles. Consideration should be given to a separate Vienna classification for perianal disease.     

Detection of anti-Saccharomyces cerevisiae antibodies in Crohn''s disease: is it a reliable diagnostic and prognostic marker?

Background. In the past few years, serologic markers have been proposed in inflammatory bowel disease. Anti-Saccharomyces cerevisiae antibodies showed high specificity for Crohn's disease. A prognostic role for serology has also been hypothesised.

Aims To evaluate anti-Saccharomyces cerevisiae antibody distribution in an unselected Italian inflammatory bowel disease population. To analyse whether anti-Saccharomyces cerevisiae antibody status (positive/negative) and/or anti-Saccharomyces cerevisiae antibody titres are associated with clinical variables and outcome measures in Crohn's disease patients.

Patients and Methods. A series of 299 inflammatory bowel disease patients were evaluated; serum samples were taken and a short clinical history was recorded. anti-Saccharomyces cerevisiae antibodies IgG enzyme-linked immunosorbent assay Medilab® (Milan, Italy) kit was used in order to determine anti-Saccharomyces cerevisiae antibody status.

Results. Sensitivity, specificity and likelihood ratio for positive test in the differential diagnosis of inflammatory bowel disease was 59%, 89%, 8.1, respectively. Clinical variables significantly associated with anti-Saccharomyces cerevisiae antibody status in logistic regression were found to be ileal location (p =0.01) and earlier age at diagnosis (p<0.01). Among ileal Crohn's disease patients, there was a trend in concordance between anti-Saccharomyces cerevisiae antibody titres and higher number of surgical procedures which was not statistically significant applying more complex statistics.

Conclusions. In an Italian inflammatory bowel disease population, anti-Saccharomyces cerevisiae antibodies status showed characteristics similar to those previously reported. Anti-Saccharomyces cerevisiae antibody positivity is associated with ileal involvement and with earlier onset of Crohn's disease.     

Detection of anti-Saccharomyces cerevisiae antibodies in Crohn''s disease: is it reliable diagnostic and prognostic marker?

Background. In the past few years, serologic markers have been proposed in inflammatory bowel disease. Anti-Saccharomyces cerevisiae antibodies showed high specificity for Crohn's disease. A prognostic role for serology has also been hypothesised.Aims To evaluate anti-Saccharomyces cerevisiae antibody distribution in an unselected Italian inflammatory bowel disease population. To analyse whether anti-Saccharomyces cerevisiae antibody status (positive/negative) and/or anti-Saccharomyces cerevisiae antibody titres are associated with clinical variables and outcome measures in Crohn's disease patients.Patients and Methods. A series of 299 inflammatory bowel disease patients were evaluated; serum samples were taken and a short clinical history was recorded. anti-Saccharomyces cerevisiae antibodies IgG enzyme-linked immunosorbent assay Medilab® (Milan, Italy) kit was used in order to determine anti-Saccharomyces cerevisiae antibody status.Results. Sensitivity, specificity and likelihood ratio for positive test in the differential diagnosis of inflammatory bowel disease was 59%, 89%, 8.1, respectively. Clinical variables significantly associated with anti-Saccharomyces cerevisiae antibody status in logistic regression were found to be ileal location (p =0.01) and earlier age at diagnosis (p<0.01). Among ileal Crohn's disease patients, there was a trend in concordance between anti-Saccharomyces cerevisiae antibody titres and higher number of surgical procedures which was not statistically significant applying more complex statistics.Conclusions. In an Italian inflammatory bowel disease population, anti-Saccharomyces cerevisiae antibodies status showed characteristics similar to those previously reported. Anti-Saccharomyces cerevisiae antibody positivity is associated with ileal involvement and with earlier onset of Crohn's disease.     

102例克罗恩病蒙特利尔分型分析

目的 分析我国克罗恩病(CD)患者的蒙特利尔分型、治疗及预后特点,判断临床分型与抗酿酒酵母抗体(ASCA)、治疗方式和预后之间是否存在一定的关系.方法 按照蒙特利尔分型对102例CD患者进行临床分型,并记录ASCA、肠道外表现、治疗方式和随诊情况.比较各亚型之间的差异.结果 我国CD患者以A2亚型(52.9%)为主,回结肠受累(40.2%)和狭窄型病变(53.9%)多见,并发症的发生率与病程长短有关(P＜0.05),肠瘘与疾病部位有一定关系(P=0.074),B1亚型疾病进展率高于B2亚型(P=0.018),B3亚型手术率最高(P=0.002).ASCA阳性者占40.0%,ASCA阳性与病变部位、疾病行为、病情进展及治疗方式等无关(P＞0.05).结论 CD患者的疾病行为随病程延长发生进展,并发症发生率及手术率上升,发生穿透性病变是手术治疗的首要原因.蒙特利尔分型可有助于判断是否需要手术治疗以及疾病的预后.     

Clinical outcome of Crohn's disease according to the Vienna classification: disease location is a useful predictor of disease course

OBJECTIVES: Crohn's disease (CD) is a complex genetic disease with multiple clinical patterns. Clinical classifications may help to identify subgroups of patients that have a distinct pattern of disease, and they are also a prerequisite for the conduction of genetic and therapeutic studies. The aim of this study was to determine the usefulness of the Vienna classification in patient care and clinical studies. METHODS: The clinical data of patients were carefully reviewed retrospectively. The behaviour and location of the disease were determined according to the Vienna classification and additional clinical characteristics including surgical data, vitamin B12 status and medication were also assessed. RESULTS: Data according to the Vienna classification of 292 CD cases were available. The mean age at diagnosis was 31.4 years. The operation rate was higher in patients with ileocolonic localization (P<0.05) and stricturing and penetrating disease behaviour (P<0.001). The incidence of vitamin B12 deficiency was 41.9% in cases with ileal involvement and 20.7% in cases with disease confined to the colon. In 187 cases (64.0%) an operation was performed because of CD-related complications, in a majority (126, 67.4%) this took place within 5 years after diagnosis. Intolerance of azathioprine occurred in 36 cases (22.0%). CONCLUSIONS: Ileocolonic disease localization is associated with a complicated course of disease. Vitamin B12 deficiency occurs frequently, also in patients with disease apparently confined to the colon. We propose that location parameters can be used for the prediction of disease course in clinical settings and in interventional studies.     

Development of an assay for antibodies to Saccharomyces cerevisiae: Easy, cheap and specific for Crohn's disease.

OBJECTIVE: To develop a serological test to measure antibodies to Saccharomyces cerevisiae in patients with inflammatory bowel disease. METHODS: An ELISA to the mannan of S cerevisiae that is commercially available was developed. Sera were tested from randomly chosen sera specimens kept frozen at the University of Manitoba Inflammatory Bowel Disease Clinical and Research Centre, Winnipeg, Manitoba. Clinical diagnoses were kept blinded until the assay results were finalized. One hundred thirty-six sera were tested, including 51 with Crohn's disease, 32 with ulcerative colitis, one with indeterminate colitis and 16 other control subjects. Thirty-six samples were duplicates from patients already studied but were either run on separate days or drawn on different days. RESULTS: Using a cutoff of 15 binding units as a positive result, Crohn's disease was found to have a sensitivity of 53% but a specificity of 100% compared with ulcerative colitis. Compared with all other diagnoses (including ulcerative colitis), Crohn's disease had a sensitivity of 53% and a specificity of 96%. For patients with Crohn's disease only, those who were anti-S cerevisiae antibody (ASCA) positive (n=27) were significantly more likely to have proximal gastrointestinal disease and significantly less likely to have colonic or inflammatory type disease than those who were ASCA negative (n=24). The direct cost of this assay was $6.00 per positive test, and the total charge was set at $38.15. CONCLUSIONS: A reasonably inexpensive, easy and reproducible assay to assess for antibodies to S cerevisiae has been developed. Using a cutoff for positivity of 15 binding units, this test had a specificity of 100% for ruling out Crohn's disease and a lower (60%) sensitivity compared with ulcerative colitis. This test could identify a specific phenotype of patients with Crohn's disease as being more likely to have small bowel Crohn's disease and less likely to have colonic (isolated) or inflammatory disease, as opposed to fibrostenotic disease or penetrating disease. The test proved reliable when assaying samples drawn or assayed on different days.     

Crohn's disease patient characteristics in a tertiary referral center: comparison with patients from a population-based cohort

OBJECTIVES: Data on the clinical presentation, effects of therapy and prognosis of patients with Crohn's disease are often based on patients from specialized referral centers. We assessed the extent of the selection based on the clinical and demographic characteristics. METHODS: All patients with Crohn's disease presenting to the University Hospital of Regensburg (Medical Department) were analyzed retrospectively with respect to demographic and disease specific characteristics. Only patients diagnosed <2 years before presentation were included in the main analysis. The original data from a population-based, prospectively assembled incidence cohort were available for comparison (EC-IBD, northern centers only, n=475). Age at diagnosis, disease location and behavior were categorized according to the Vienna classification. Differences were examined using chi-square tests. MAIN RESULTS: At the referral center, 394 patients were treated within a 5-year period. Of these, 116 patients fulfilled the inclusion criteria for the comparative analysis. Sixteen percent of the referral patients were diagnosed at age 40 or older, as compared with 32% in the population-based group (P<0.004). The distribution of disease location, sex, smoking behavior and positive family history was similar in both groups. Among the referral patients, more had fistulas (39% versus 20%, P<0.001). Also, more patients were receiving steroids (49% versus 27%) or other immunosuppressive therapy (12% versus 4%). The selection effects increase with duration of disease. CONCLUSIONS: Patients with late onset of disease, inflammatory only disease behavior and no need for immunosuppression are under-represented at a tertiary referral center.     

Changes in Crohn's disease phenotype over time in the Chinese population: validation of the Montreal classification system

BACKGROUND: Phenotypic evolution of Crohn's disease occurs in whites but has never been described in other populations. The Montreal classification may describe phenotypes more precisely. The aim of this study was to validate the Montreal classification through a longitudinal sensitivity analysis in detecting phenotypic variation compared to the Vienna classification. METHODS: This was a retrospective longitudinal study of consecutive Chinese Crohn's disease patients. All cases were classified by the Montreal classification and the Vienna classification for behavior and location. The evolution of these characteristics and the need for surgery were evaluated. RESULTS: A total of 109 patients were recruited (median follow-up: 4 years, range: 6 months-18 years). Crohn's disease behavior changed 3 years after diagnosis (P = 0.025), with an increase in stricturing and penetrating phenotypes, as determined by the Montreal classification, but was only detected by the Vienna classification after 5 years (P = 0.015). Disease location remained stable on follow-up in both classifications. Thirty-four patients (31%) underwent major surgery during the follow-up period with the stricturing [P = 0.002; hazard ratio (HR): 3.3; 95% CI: 1.5-7.0] and penetrating (P = 0.03; HR: 5.8; 95% CI: 1.2-28.2) phenotypes according to the Montreal classification associated with the need for major surgery. In contrast, colonic disease was protective against a major operation (P = 0.02; HR: 0.3; 95% CI: 0.08-0.8). CONCLUSIONS: This is the first study demonstrating phenotypic evolution of Crohn's disease in a nonwhite population. The Montreal classification is more sensitive to behavior phenotypic changes than is the Vienna classification after excluding perianal disease from the penetrating disease category and was useful in predicting course and the need for surgery.     

New serological markers in inflammatory bowel disease are associated with complicated disease behaviour

BACKGROUND AND AIMS: Several antibodies have been associated with Crohn's disease and are associated with distinct clinical phenotypes. The aim of this study was to determine whether a panel of new antibodies against bacterial peptides and glycans could help in differentiating inflammatory bowel disease (IBD), and whether they were associated with particular clinical manifestations. METHODS: Antibodies against a mannan epitope of Saccharomyces cerevisiae (gASCA), laminaribioside (ALCA), chitobioside (ACCA), mannobioside (AMCA), outer membrane porins (Omp) and the atypical perinuclear antineutrophilic cytoplasmic antibody (pANCA) were tested in serum samples of 1225 IBD patients, 200 healthy controls and 113 patients with non-IBD gastrointestinal inflammation. Antibody responses were correlated with the type of disease and clinical characteristics. RESULTS: 76% of Crohn's disease patients had at least one of the tested antibodies. For differentiation between Crohn's disease and ulcerative colitis, the combination of gASCA and pANCA was most accurate. For differentiation between IBD, healthy controls and non-IBD gastrointestinal inflammation, the combination of gASCA, pANCA and ALCA had the best accuracy. Increasing amounts and levels of antibody responses against gASCA, ALCA, ACCA, AMCA and Omp were associated with more complicated disease behaviour (44.7% versus 53.6% versus 71.1% versus 82.0%, p < 0.001), and a higher frequency of Crohn's disease-related abdominal surgery (38.5% versus 48.8% versus 60.7% versus 75.4%, p < 0.001). CONCLUSIONS: Using this new panel of serological markers, the number and magnitude of immune responses to different microbial antigens were shown to be associated with the severity of the disease. With regard to the predictive role of serological markers, further prospective longitudinal studies are necessary.     

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.     

Antineutrophil cytoplasmic autoantibodies and anti-Saccharomyces cerevisiae antibodies in inflammatory bowel diseases.

BACKGROUND/AIMS: Perinuclear antineutrophil cytoplasmic autoantibody is a marker for ulcerative colitis, and anti-Saccharomyces cerevisiae antibody is known to be associated with Crohn's disease. The purpose of this study was to search the value of detecting perinuclear antineutrophil cytoplasmic autoantibody and anti-Saccharomyces cerevisiae antibody for the diagnosis of Turkish inflammatory bowel disease patients. METHODS: Serum samples were obtained from 80 patients with ulcerative colitis, 61 patients with Crohn's disease and 40 healthy controls. Determination of both anti-Saccharomyces cerevisiae antibody and antineutrophil cytoplasmic autoantibody was performed with the standardized enzyme-linked immunosorbent assay. RESULTS: In cases with ulcerative colitis, 65% tested seropositive for antineutrophil cytoplasmic autoantibody, whereas the controls showed 2.5% positivity. In cases with Crohn's disease, 63.9% tested seropositive for anti-Saccharomyces cerevisiae antibody, whereas the controls showed 2.5% seropositivity. The combination of a positive anti-Saccharomyces cerevisiae antibody test and a negative antineutrophil cytoplasmic autoantibody yielded a sensitivity and specificity of 32.0% and 97.5%, respectively. The combination of a positive perinuclear antineutrophil cytoplasmic autoantibody and a negative anti-Saccharomyces cerevisiae antibody test yielded a sensitivity and specificity of 44.2% and 97.5%, respectively. CONCLUSIONS: Both serologic tests may aid in the differential diagnosis of inflammatory bowel disease.     

Clinical course in Crohn's disease: results of a five-year population-based follow-up study (the IBSEN study)

BACKGROUND: There are few population-based, prospective studies on the clinical course in patients with Crohn's disease (CD). AIM: To extend the observation period in a population-based prospective study (the IBSEN study) to find out more about the initial 5-year clinical course in CD patients and to relate the findings to the Vienna classification. METHODS: All patients diagnosed with inflammatory bowel disease (IBD) in southeastern Norway in the 4 years 1990-1993 were followed prospectively. The patients were invited to a systematic follow-up visit at their local hospital 1 and 5 years after inclusion in the study. The visits included a structured interview, a clinical examination and colonoscopy. RESULTS: Out of 843 patients initially diagnosed with IBD, 200 patients with definite CD were alive and had sufficient data for analysis 5 years after diagnosis. Changes in disease localization and behaviour in relation to the Vienna classification were observed in 27 (13.5%) and 35 patients (17.5%), respectively. During the observation period, 56 patients (28%) underwent surgery with intestinal resection, and half of these had disease localized in the terminal ileum. At the time of the 5-year visit, oral sulfasalazin and 5-aminosalicylic acid (5-ASA) were the most frequently used medications (by 54% of the patients), while oral glucocorticosteroids and azathioprine were being used by 25% and 13%, respectively. Seventy-two percent of the patients had taken oral glucocorticosteroids at some time in the course of the 5-year period. The majority of the patients had intestinal symptoms at 5 years, but only 16% had symptoms that interfered with everyday activities. Fourteen percent of the patients had had a relapse-free 5-year course; however, relapse was not related to the initial Vienna classification. When the patients described the clinical course, 44% reported an improvement in symptoms during the follow-up period. CONCLUSIONS: The 5-year clinical course in an unselected cohort of CD patients was mostly mild. The frequency of surgery was lower than that observed in other studies and only a minority of the patients had symptoms that interfered with everyday activities 5 years after the initial diagnosis. The Vienna classification predicted the risk of surgery, but did not predict symptoms at 5 years, relapses during the observation period or the course of disease as described by the patients.     

Evaluation of serologic disease markers in a population-based cohort of patients with ulcerative colitis and Crohn's disease

BACKGROUND: The sensitivity of assays for antineutrophil cytoplasmic antibody (ANCA), anti-Saccharomyces cerevisiae antibody (ASCA), and antipancreatic antibody (PAB) in different laboratories is unknown. Likewise, the sensitivity and diagnostic usefulness of these assays in patients with inflammatory bowel disease (IBD) in the community is unknown. METHODS: An incidence cohort of 290 patients with IBD were offered participation in the study. Blood was obtained from 162 patients (56%) (83 with ulcerative colitis, 79 with Crohn's disease) who agreed to participate. ANCA was determined in five laboratories. ASCA in two laboratories, and PAB in one laboratory. RESULTS: In ulcerative colitis, the sensitivity of ANCA determined in five laboratories varied widely, ranging from 0-63%. In Crohn's disease, the sensitivity of ASCA determined in two laboratories did not vary significantly, ranging from 39-44%; and the sensitivity of PAB determined in one laboratory was 15%. The optimal diagnostic usefulness was obtained from one laboratory where the positive predictive values of a positive ANCA assay combined with a negative ASCA assay for ulcerative colitis, and a negative ANCA combined with a positive ASCA for Crohn's disease, were 75% and 86%, respectively. CONCLUSIONS: In patients with IBD, the sensitivity of ANCA varied widely in different laboratories, whereas the prevalence of ASCA was similar. The positive predictive values of the ANCA assay combined with the ASCA assay for ulcerative colitis and Crohn's disease are high enough to be clinically useful.     

Treatment of severe Crohn''s disease using antimycobacterial triple therapy — approaching a cure?

BACKGROUND: Mycobacterium avium subspecies paratuberculosis is probably the best candidate for a microbial cause of Crohn's disease although arguments to the contrary can be equally convincing. Growing evidence suggests that prolonged antimycobacterial combination therapy can improve Crohn's disease in some patients. AIM: To report long-term observations in patients with severe Crohn's disease treated with triple macrolide-based antimycobacterial therapy. PATIENTS: A series of 12 patients (7 male, 5 female; aged 15-42 years) with severe, obstructive or penetrating Crohn's disease were recruited. METHODS: Patients failing maximal therapy were commenced prospectively on a combination of rifabutin (450 mg/d), clarithromycin (750 mg/d) and clofazimine (2 mg/kg/d). Progress was monitored through colonoscopy, histology, clinical response and Harvey-Bradshaw activity index. RESULTS: Follow-up data were available for up to 54 months of therapy Six out of 12 patients experienced a full response to the antiMycobacterium avium subspecies paratuberculosis combination achieving complete clinical, colonoscopic and histologic remission of Crohn's disease. Four of these patients were able to cease treatment after 24-46 months, 3 of whom remained in total remission without treatment for up to 26 months and one patient relapsed after six months off treatment. A partial response to the anti-Mycobacterium avium subspecies paratuberculosis combination was seen in 2 patients showing complete clinical remission with mild histologic inflammation. Return to normal of terminal ileal strictures occurred in 5 patients. Harvey-Bradshaw activity index in patients showing a full or partial response to therapy fell from an initial 13.4 +/- 1. 91 to 0. 5 +/- 0. 47 [n = 8, p < 0. 001) after 52-54 months. CONCLUSIONS: Reversal of severe Crohn's disease has been achieved in 6/12 patients using prolonged combination anti-Mycobacterium avium subspecies paratuberculosis therapy alone. Three patients remain in long-term remission with no detectable Crohn's disease off all therapy These results support a causal role for Mycobacterium avium subspecies paratuberculosis in Crohn's disease while also suggesting that a cure may become possible.     

Inflammatory bowel disease in a Swedish twin cohort: a long-term follow-up of concordance and clinical characteristics

BACKGROUND & AIMS: In 1988, we reported the first twin study in inflammatory bowel disease. The aim of the current study was to follow up these twins regarding new cases of inflammatory bowel disease and Crohn's disease characteristics using the Vienna classification. METHODS: The official Swedish population register and the cause of death register were used to search for the twins. All living patients were interviewed. RESULTS: Three monozygotic twins earlier classified as healthy had been diagnosed with inflammatory bowel disease (ulcerative colitis, n = 2; Crohn's disease, n = 1). Retrospectively, all 3 were symptomatic at the original survey. This changed the pair concordance in monozygotic twins from 6.3% to 18.8% in ulcerative colitis and from 44.4% to 50.0% in Crohn's disease. A high degree of concordance regarding age at diagnosis, disease location at diagnosis and during the course, and disease behavior was found in concordant monozygotic twin pairs with Crohn's disease. Seven of 9 pairs were identical in 3 or more of these disease characteristics compared with an expected number of 1.5 (P = 0.000076). CONCLUSIONS: This study confirms that the genetic influence is stronger in Crohn's disease than in ulcerative colitis. A remarkable phenotype similarity within concordant pairs with Crohn's disease was found using the Vienna classification.     

炎症性肠病患者血清中自身抗体检测的临床意义

目的研究抗酿酒酵母抗体(ASCA)和抗中性粒细胞胞浆抗体(pANCA)在炎症性肠病诊断与鉴别诊断中的意义。方法间接免疫荧光生物薄片法检测29例溃疡性结肠炎(UC)、34例克罗恩病(CD)及25例正常对照者血清中ASCA和pANCA的表达。结果pANCA在CD组、UC组和正常对照组中的阳性率分别为47.1%、69.0%和16.0%,UC组显著高于CD组(P<0.05)和正常对照组(P<0.05)。ASCA在上述3组中的阳性率分别为11.8%、58.6%和8.0%,UC组亦显著高于CD组(P<0.05)和正常对照组(P<0.05)。ASCA /pANCA-诊断CD的敏感性、特异性、阳性预测值分别是0、89.7%和0;pANCA /ASCA-诊断UC的敏感性、特异性和阳性预测值分别是20.7%、64.7%和33.3%。结论ASCA和pANCA阳性有利于炎症性肠病的诊断却不能敏感地筛选患者;ASCA和pANCA联合检测不能作为汉族UC和CD鉴别诊断的指标。     

Serological differentiation of inflammatory bowel diseases

OBJECTIVE: In order to shorten the diagnostic procedures simple serological tests with high diagnostic value for Crohn's disease and ulcerative colitis are required. The aim of this study was therefore to evaluate the diagnostic value of a newly developed assay for the determination of antibodies to mannan of Saccharomyces cerevisiae in combination with antibodies to antigens of exocrine pancreas, goblet cells, human neutrophils and tissue transglutaminase. METHODS: Sera from 112 patients with Crohn's disease (82 confirmed and 30 suspected cases), 65 patients with ulcerative colitis, 13 patients with indeterminate colitis, 212 patients with other diseases and 250 healthy blood donors were tested for IgA and IgG antibodies to mannan of S. cerevisiae and IgA to tissue transglutaminase by enzyme-linked immunoassays. Endomysial IgA antibodies and antibodies to antigens of exocrine pancreas, goblet cells and human neutrophils were determined by indirect immunofluorescence. Sensitivity, specificity, positive and negative predictive values of antibodies to mannan of S. cerevisiae and different antibody combinations were determined regarding the diagnosis of Crohn's disease and ulcerative colitis. RESULTS: Antibodies to mannan of S. cerevisiae were detected in 50% of confirmed and 27% of patients suspected of having Crohn's disease. Among patients who did not have Crohn's disease only those suffering from gluten-sensitive enteropathy and primary biliary cirrhosis exhibited antibodies to mannan of S. cerevisiae (14%, 6%). With respect to antibody positivity, antibodies to mannan of S. cerevisiae and/or antibodies to antigens of exocrine pancreas combined with tissue transglutaminase antibody negativity yields a sensitivity, specificity, positive and negative predictive value of 60%, 100%, 100% and 90%, respectively, regarding diagnosis of Crohn's disease. CONCLUSIONS: Determination of antibodies to mannan of S. cerevisiae as a new marker for Crohn's disease is helpful for the differential diagnosis of inflammatory bowel disease. In combination with other established serological markers, antibodies to mannan of S. cerevisiae improve their diagnostic and predictive values considerably.