Efficacy of thiopurines and adalimumab in preventing Crohn's disease recurrence in high-risk patients - a POCER study analysis.

BACKGROUND: Crohn's disease recurs in the majority of patients after intestinal resection. AIM: To compare the relative efficacy of thiopurines and anti-TNF therapy in patients at high risk of disease recurrence. METHODS: As part of a larger study comparing post-operative management strategies, patients at high risk of recurrence (smoker, perforating disease, ≥2nd operation) were treated after resection of all macroscopic disease with 3 months metronidazole together with either azathioprine 2 mg/kg/day or mercaptopurine 1.5 mg/kg/day. Thiopurine-intolerant patients received adalimumab induction then 40 mg fortnightly. Patients underwent colonoscopy at 6 months with endoscopic recurrence assessed blind to treatment. RESULTS: A total of 101 patients [50% male; median (IQR) age 36 (25-46) years] were included. There were no differences in disease history between thiopurine- and adalimumab-treated patients. Fifteen patients withdrew prior to 6 months, five due to symptom recurrence (of whom four were colonoscoped). Endoscopic recurrence (Rutgeerts score i2-i4) occurred in 33 of 73 (45%) thiopurine vs. 6 of 28 (21%) adalimumab-treated patients [intention-to-treat (ITT); P = 0.028] or 24 of 62 (39%) vs. 3 of 24 (13%) respectively [per-protocol analysis (PPA); P = 0.020]. Complete mucosal endoscopic normality (Rutgeerts i0) occurred in 17/73 (23%) vs. 15/28 (54%) (ITT; P = 0.003) and in 27% vs. 63% (PPA; P = 0.002). The most advanced disease (Rutgeerts i3 and i4) occurred in 8% vs. 4% (thiopurine vs. adalimumab). CONCLUSIONS: In Crohn's disease patients at high risk of post-operative recurrence adalimumab is superior to thiopurines in preventing early disease recurrence.

Development and validation of a patient-reported disability measurement tool for patients with inflammatory bowel disease.

BACKGROUND: Inflammatory bowel disease can impact on a patient's ability to maintain normal physical and mental function, and fulfil their social, family and work roles. Aspects of disability in IBD have received little attention. AIM: To develop, validate and apply a questionnaire directed towards evaluating these disease aspects. METHODS: A literature review on disability in IBD was undertaken, and opinion about aspects of disability to measure was sought from six IBD-specialised gastroenterologists. A questionnaire was developed, and IBD patients completed the new disability questionnaire, the SF-36 and the short-IBD (SIBDQ - 10 point). A subgroup of patients completed the questionnaire again 4 weeks later. Healthy volunteers were studied as a control group. RESULTS: A total of 116 IBD out-patients were approached, of whom 81 (52 Crohn's disease and 28 ulcerative colitis) participated. Nineteen patients were re-evaluated at 4 weeks. Twenty-five controls were studied. All subscales demonstrated good Cronbach's alpha reliability and reproducibility. There was a significant inverse correlation between the disability score and the SIBDQ and between the disability score and the SF36 and a positive correlation with the Crohn's Disease Activity Index (CDAI) (all P < 0.001). Disability differed between ulcerative colitis and controls, but not between active and inactive disease. CONCLUSIONS: The new disability questionnaire is sensitive for detecting disability, is reliable and reproducible, and correlates with disease activity in Crohn's disease, but not ulcerative colitis. Further prospective testing is now needed in the longer term, larger patient populations and in different countries and ethnicities.

Postoperative recurrence of Crohn's disease: impact of endoscopic monitoring and treatment step-up.

AIM: Eighty per cent of patients with Crohn's disease require surgery, of whom 70% will require a further operation. Recurrence occurs at the anastomosis. Although often recommended, the impact of postoperative colonoscopy and treatment adjustment is unknown. METHOD: Patients with a bowel resection over a 10-year period were reviewed and comparison made between those who did and did not have a postoperative colonoscopy within 1 year of surgery, and those who did or did not have a step-up in drug therapy. RESULTS: Of 222 patients operated on, 136 (65 men, mean age 33 years, mean disease duration 8 years, median follow-up 4 years) were studied. Of 70 patients with and 66 without postoperative colonoscopy, clinical recurrence occurred in 49% and 48% (NS) and further surgery in 9% and 5% (NS). Eighty-nine per cent of colonoscoped patients had a decision based on the colonoscopic findings: of these, 24% had a step-up of drug therapy [antibiotics (n =10), aminosalicylates (n=2), thiopurine (n=5), methotrexate (n=1)] and 76% had no step-up in drug therapy. In colonoscoped patients clinical recurrence occurred in 9 (60%) of 15 patients with, and 23 (49%) of 47 without step-up and surgical recurrence in 2 (13%) of 15 and 4 (9%) of 47 (NS). CONCLUSION: Clinical recurrence occurs in a majority of patients soon after surgery. In this cohort, there was no clinical benefit from colonoscopy or increased drug therapy within 1 year after operation. However, the response to the endoscopic findings was not standardized and immunosuppressive therapy was uncommon. Standardizing timing of colonoscopy and drug therapy, including more intense therapy, may improve outcome, although this remains to be proven.

Assessment of chronic hepatitis B: the importance of hepatitis B virus DNA testing.

BACKGROUND: Chronic hepatitis B (CHB) has an estimated prevalence of 90 000 to 160 000 in Australia. Cirrhosis and hepatocellular carcinoma are important complications of CHB and appropriate evaluation of hepatitis B surface antigen (HBsAg)-positive individuals is vital to identify treatment candidates. METHODS: A review of the database of a tertiary hospital was performed and 348 HBsAg-positive individuals with baseline demographic, virological, serological and biochemical variables were identified and evaluated cross-sectionally. A small subgroup of hepatitis B e antigen (HBeAg)-negative patients with normal alanine aminotransferase (ALT) at baseline were identified and followed longitudinally. RESULTS: 175/348 (50%) of patients were in the HBeAg-negative, chronic hepatitis phase of disease, 22% in the HBeAg-positive immune clearance and 6% in the immune tolerant phases. HBeAg-negative patients were older and more likely to be male than HBeAg-positive patients. The correlation between hepatitis B virus (HBV) DNA and ALT levels was examined. ALT and HBV DNA levels showed no correlation in HBeAg-positive CHB and only a weak correlation in HBeAg-negative patients. Furthermore, 35% of HBeAg-negative patients with detectable HBV DNA had a normal ALT. Conversely 38% of HBeAg-negative patients with no detectable HBV DNA had an elevated ALT. A persistently normal ALT over 24 months was seen in five of nine HBeAg-negative patients with normal initial ALT and detectable HBV DNA. CONCLUSION: Appropriate evaluation of HBeAg-negative CHB must include HBV DNA because the ALT is not a reliable guide to underlying viral replication.

Chronic hepatitis B: recommendations for therapy based on the natural history of disease in Australian patients.

BACKGROUND: Chronic hepatitis B infection (CHB) is a major health problem in Australia and worldwide. CHB is associated with significant long-term morbidity and mortality. Well tolerated treatment is now available, however the development of resistance is common and the optimal timing of treatment is yet to be determined. Identifying the factors that influence the natural history of CHB may help determine which patients need treatment and when to start it. OBJECTIVE: To determine the demographics, clinical features and virological profile of Australian patients infected with CHB and the influence of these factors on disease activity and severity. STUDY DESIGN: Review of prospectively collected demographic, clinical and virological features of all patients positive for hepatitis B surface antigen (HBsAg) for more than 6 months who were referred to St. Vincent's Hospital liver clinics. Age, sex and ethnicity were correlated with hepatitis B e antigen status (HBeAg), HBV replication status (ALT and HBV DNA), genotype and liver histology. RESULTS: 703 chronic hepatitis B surface antigen positive patients were identified. The patients were predominantly male with an average age of 44. Eighty two percent of patients were born overseas, primarily from Asian (65%) and Mediterranean countries (14%). Two thirds (426) had an elevated ALT (median 79) at presentation. HBeAg was positive in 37%. Active viral replication, defined as abnormal ALT or positive HBVDNA, was present in 74%, 48% of whom were HBeAg negative. In a subset of 103 patients genotyped, 8% had genotype A, 29% B, 41% C and 22% D. Genotype correlated with ethnicity; patients infected with genotypes A were predominantly Caucasian, B and C were Asian, and D were Mediterranean. Of 296 (42%) patients who underwent liver biopsy, 76 (27%) had advanced fibrosis. Advanced fibrosis was associated with increasing age and Mediterranean ethnicity. CONCLUSION AND RECOMMENDATIONS: Perinatal or early childhood transmission is predominant mode of infection in Australia. Two thirds of this cohort had active replication and were at increased risk of developing cirrhosis and/or hepatoma. Advanced disease was associated with age and ethnicity. HBeAg negative CHB accounts for almost half of all those with active viral replication. This parallels the rise in this form of CHB in Asia and the Mediterranean basin. Screening should be offered to people born in, or with parents born in areas of high endemnicity. To detect the development of active disease, patients with positive HBsAg but normal ALT should have liver function tests done 6 monthly and those with elevated ALT should be referred for consideration of therapy, irrespective of HBeAg status.

Survivin interacts with Smac/DIABLO in ovarian carcinoma cells but is redundant in Smac-mediated apoptosis.

Abnormalities in the control and execution of apoptosis are seen in many malignancies, including ovarian carcinoma. Many of these abnormalities involve the mitochondrial pathway of apoptosis, including overexpression of BIR-containing inhibitor of apoptosis protein (IAP) family proteins as well as dysregulated apoptosome function. We sought to stimulate the mitochondrial pathway of apoptosis by constructing a recombinant adenovirus encoding mature, processed Smac/DIABLO (Ad CMV tSmac), the second mitochondrial activator of caspases. Transfection of ovarian carcinoma cells with Ad CMV tSmac leads to increasing apoptosis in a dose-dependent manner. By contrast, transfection of IOSE397 immortalized normal ovarian surface epithelial cells does not cause apoptosis. We also show that the processed form of Smac is primarily expressed in the cytosol of ovarian carcinoma cells. Smac co-immunoprecipitates with both survivin and XIAP and stimulates survivin, but not XIAP, down-regulation. This down-regulation does not result from transcriptional changes, as determined by quantitative real-time PCR, but cycloheximide treatment indicates that survivin half-life is reduced from 6 to 2 h, which is secondary to ubiquitination and proteasomal degradation. RNA interference, however, suggests that survivin does not act to inhibit Smac-mediated apoptosis, which is confirmed by cotransfection with the phosphorylation mutant, survivin T34A. Finally, intraperitoneal delivery of Ad CMV tSmac increases median survival of mice bearing human ovarian carcinoma xenografts. We believe that expression of Smac/DIABLO can stimulate the intrinsic pathway of apoptosis in ovarian carcinoma without damaging normal ovarian tissue and therefore has therapeutic potential.

Gene therapy progress and prospects: cancer gene therapy using tumour suppressor genes.

Targeting tumour suppressor gene pathways is an attractive therapeutic strategy in cancer. Since the first clinical trial took place in 1996, at least 20 other trials have investigated the possibility of restoring p53 function, either alone or in combination with chemotherapy, but with limited success. Other recent clinical trials have sought to harness abnormalities in the p53 pathway to permit tumour-selective replication of adenoviral vectors such as dl1520 (Onyx-015). Other tumour suppressor genes, such as retinoblastoma (Rb) and PTEN (phosphatase, tensin homologue, deleted on chromosome 10), are the targets for imminent clinical trials, while microarray technologies are revealing multiple new genes that are potential targets for future gene therapy.

Evaluation of Helicobacter species in inflammatory bowel disease.

BACKGROUND: Bacteria have been implicated in the pathogenesis of inflammatory bowel disease. Helicobacter species have been shown to cause colitis in animal models and have been identified in human diarrhoeal illness and Crohn's disease. AIM: To determine whether Helicobacter species are present in human inflammatory bowel disease tissue. METHODS: Thirty patients undergoing colonoscopy for clinical reasons were studied. Nine had Crohn's disease, 11 had ulcerative colitis and 10 had histologically normal colons. Tissue was snap-frozen at -70 degrees C. DNA was extracted and examined by five different polymerase chain reaction (PCR) assays that were either genus or species specific for Helicobacter. RESULTS: Analyses of colonic biopsies by two Helicobacter genus-specific PCR assays, two H. pylori-specific assays and a PCR assay designed to amplify fragments of 'H. heilmannii'-like organisms demonstrated that product was not generated by any test. Internal control PCR demonstrated that PCR results for the five assays were not negative due to the presence of residual substances inhibitory to PCR. CONCLUSIONS: Helicobacter species were not identified in this study, using multiple PCRs to eliminate the problems of non-specific cross-reaction. This suggests that Helicobacter species do not play a role in the pathogenesis of inflammatory bowel disease.

The clinical course of fistulating Crohn's disease.

AIM: To determine the clinical characteristics, management and outcome of Crohn's fistulas from the time of first presentation. METHODS: Patients treated for fistulas 6 years previously were assessed for disease demographics, fistula characteristics and treatment from first presentation to final follow-up. RESULTS: Eighty-seven patients with active Crohn's fistulas were evaluated. The median age was 35 years and the median duration of Crohn's disease was 8 years at study entry. Disease was ileo-colonic or colonic in 85%, and 65% had rectal involvement. A single fistula was present in one-third and multiple fistulas in two-thirds; 65% of fistulas were perianal; 80% of fistulas were complex. After a median follow-up from the last treatment of 5.9 years, 68% of patients showed healing of all fistulas, 18% showed healing of some fistulas and 14% showed no healing of fistulas. The fistula site did not influence healing. Perianal and recto-vaginal fistulas took a median of 2.6 years to heal. Half of the complex fistulas required a stoma, resection or proctectomy. CONCLUSIONS: Healing is usually achieved. However, morbidity is great and healing is slow. Proctectomy is required in one-fifth of patients, and perineal healing is often slow. Defining the perianal fistula anatomy as complex or simple determines the likelihood of healing and the type of surgical approach required.

Response of fistulating Crohn's disease to infliximab treatment assessed by magnetic resonance imaging.

AIMS: To assess fistula track healing after infliximab treatment using magnetic resonance imaging. METHODS: Magnetic resonance imaging and clinical evaluation were performed before and after three infliximab infusions given over a 6-week period. Magnetic resonance images were evaluated for abscesses and fistula tracks. Paired magnetic resonance image examinations were rated 'better', 'unchanged' or 'worse'. Magnetic resonance imaging and clinical outcomes were then compared. RESULTS: Of the 12 referred patients, pre-treatment magnetic resonance imaging detected abscesses in three (two not treated). Of the 10 treated patients, seven had peri-anal fistulas, two of whom also had recto-vaginal fistulas, and three had abdominal wall entero-cutaneous fistulas. After infliximab, four were in remission, one had a response and five were non-responders. One developed a peri-anal abscess. Magnetic resonance imaging improved in six, was unchanged in two and was worse in two. In four of the six with improvement in magnetic resonance imaging, the fistula track resolved, but two of these had clinically persistent entero-cutaneous fistulas. The clinical outcome and magnetic resonance imaging correlated in seven of the 10 patients; in three (two entero-cutaneous and one peri-anal), there was discordance. CONCLUSIONS: Magnetic resonance imaging identifies clinically silent sepsis. Fistulas may persist despite clinical remission. Clinical response to infliximab and clinical correlation with magnetic resonance imaging were poor in patients with abdominal entero-cutaneous fistulas.

Changes in hepatitis C-related liver disease in a large clinic population.

BACKGROUND: Hepatitis C virus (HCV) infection is a significant problem in the Australian community. Over the past few years, the number of patients with diagnosed hepatitis C has increased greatly. The aims of the present study were to define the clinical features of a large group of patients with chronic HCV infection and to examine changes occurring in the referral base and epidemiological characteristics of this group since analysis of the first 342 patients in 1994. METHODS: The study included 1,546 consecutive anti-HCV-positive patients who had been referred to St Vincent's Hospital from January 1990 to June 1998. Clinical and laboratory data were collected on all patients. RESULTS: Referrals from general practitioners increased from 31% to 70% of all patients between 1990-1993 and 1994-1998. A history of injecting drug use (IDU) was present in 64% of the patients. While 89% of the IDU group was Australasian born, 49% of those in the sporadic group were born overseas. Cirrhosis was found in 18% of biopsied patients. Age, infection duration, age at infection, Mediterranean or Asian origin and a history of transfusion or lack of HCV risk factors were associated with cirrhosis on univariate analysis. Patient age was the only independent predictor of cirrhosis. CONCLUSION: The majority of patients with HCV are diagnosed in general practice. A risk factor for infection is identified in 82% of patients. While our reported prevalence of cirrhosis may be an overestimate of that in the overall HCV community, the ultimate disease burden is likely to be significant.

Migration and maturation of human colonic dendritic cells.

Dendritic cells (DC) in the colon may regulate intestinal immunity but remain poorly characterized. In this study a CD11c(+)HLA-DR(+)lin(-) (CD3(-)CD14(-)CD16(-)CD19(-)CD34(-)) population has been identified by flow cytometry in cells obtained by rapid collagenase digestion of human colonic and rectal biopsies. These day 0 (d0) CD11c(+)HLA-DR(+)lin(-) cells comprised approximately 0.6% of the mononuclear cells obtained from the lamina propria, were endocytically active, and had the phenotype of immature DC; they were CD40(+) and expressed low levels of CD83 and CD86, but little or no CD80 or CD25. Similar d0 DC populations were isolated from the colonic mucosa of healthy controls and from both inflamed and noninflamed tissue from patients with Crohn's disease. The lamina propria also contained a population of cells capable of migrating out of biopsies during an overnight culture and differentiating into mature DC with lower levels of endocytic activity and high cell surface expression of CD40, CD80, CD86, CD83, and CD25. This mature DC population was a potent stimulator of an allogeneic mixed leukocyte (MLR). Overnight culture of cells isolated by enzymatic digestion on d0 yielded DC with a phenotype intermediate between that of the d0 cells and that of the cells migrating out overnight. Overnight culture of colonic cells in which DC and HLA-DR(+)lin(+) cells were differentially labeled with FITC-dextran suggested that some of the maturing DC might differentiate from HLA-DR(+)lin(+) progenitors. This study presents the first analysis of the phenotype, maturational status, and migratory activity of human gut DC.

Calcium phosphate nanoparticle adjuvant.

Vaccination to protect against human infectious diseases may be enhanced by using adjuvants that can selectively stimulate immunoregulatory responses. In a murine model, a novel nanoparticulate adjuvant composed of calcium phosphate (CAP) was compared with the commonly used aluminum (alum) adjuvants for its ability to induce immunity to herpes simplex virus type 2 (HSV-2) and Epstein-Barr virus (EBV) infections. Results indicated that CAP was more potent as an adjuvant than alum, elicited little or no inflammation at the site of administration, induced high titers of immunoglobulin G2a (IgG2a) antibody and neutralizing antibody, and facilitated a high percentage of protection against HSV-2 infection. Additional benefits of CAP include (i) an insignificant IgE response, which is an important advantage over injection of alum compounds, and (ii) the fact that CAP is a natural constituent of the human body. Thus, CAP is very well tolerated and absorbed. These studies were performed with animal models. By virtue of the potency of this CAP adjuvant and the relative absence of side effects, we believe that this new CAP formulation has great potential for use as an adjuvant in humans.

Review article: the clinical role of anti-TNFalpha antibody treatment in Crohn's disease.

The recent licensing of anti-TNFalpha antibody treatment offers the potential to radically alter the course of severe Crohn's disease using genetically-engineered drugs directed against a specific inflammatory mediator. Controlled randomized trials have demonstrated clinical benefit associated with tissue healing in patients with active intestinal disease and fistulae, often when conventional therapies were unsuccessful. This therapy is expensive, however, and long-term efficacy and safety data are still awaited. This review considers the nature of this therapy and the current evidence for its clinical benefit and adverse effects. The treatment is also considered in the context of available immunosuppressive agents, with suggestions about its practical application.

Whey protein concentrates with and without immunoglobulins: a review.

ABSTRACT Whey protein, a high-biological-value protein from milk, is available with and without immunoglobulins. The possibility of providing passive immunization through food is unique to mammals, who receive it through colostrum at birth. Colostrum contains both immunostimulatory and immunosuppressive immunoglobulins. Later, the mammals are able to make their own immunoglobulins, but in time of illness that ability may become impaired. Some of the whey proteins contain bovine immunoglobulins, which are similar to human immunoglobulins. This type of whey may be of clinical importance to patients who are immunocompromised. However, all whey proteins are rich in cysteine and glutamate. These serve as precursors of glutathione, a potent antioxidant, which is needed in greater quantities during stress. In this review, the benefits of consuming whey protein with and without immunoglobulins are examined. Characteristics of these products are discussed, and an account is given of supportive studies using the whey containing immunoglobulins in the clinical setting. Patients with acquired immunodeficiency syndrome and cancer are used as examples. Finally, a guide on use of whey protein is provided.

Severity of liver disease in hepatitis C infection contracted through injecting drug use.

BACKGROUND: Injecting drug use (IDU) is currently the most common route of hepatitis C virus (HCV) transmission in Australia and many other Western countries. Most reports on the natural history of HCV have examined populations that included patients from all risk groups, but it is possible that this increasingly important subgroup is different. AIMS: To assess the severity of liver disease in individuals who acquired HCV through IDU. METHODS: Three hundred and forty-six patients with confirmed HCV infection and a history of IDU, who had had a liver biopsy performed were recruited from a liver clinic. Demographic data, liver function tests and hepatitis B serology were obtained on all patients. A detailed drug use history and HCV viral studies were also available in a subgroup of 142 patients. RESULTS: Mean age of the group was 34 years and 73% were male. Mean duration of HCV infection was 14.6 years. Forty one per cent were infected with genotype 3a, 19% - 1a, 17% - 1 (nonsubtypable), 14% - 1b and 4% - 2b. Cirrhosis was present in 12% of patients. Patients with cirrhosis (38 years) were older than those with chronic hepatitis (34 years; p=0.0003) and had a longer duration of infection (17.2 vs 14.3 years; p=0.003). On multivariate analysis, however, patient age was the only factor independently associated with cirrhosis (odds ratio 4.2; 95% confidence interval 1.4-12.6). CONCLUSION: While cirrhosis is less common in this group than in other HCV infected populations, its prevalence may increase as these patients are followed over a longer period of time.

The new dietary fats in health and disease.

Lipids are an integral part of the routine diet of patients and the general public. In this article, the physiologic properties of various dietary lipids are reviewed, beginning with those most commonly consumed-the long-chain triglycerides (LCTs) and extending to those with special purposes: the short- and medium-chain triglycerides. The nutritional dietary management of patients typically includes physical mixtures of lipids. Recently, structured triglycerides (STs), which combine advantages from conventional fats with those of special purposes, have become available. STs are currently developed by interesterifying a mixture of conventional fats and oils, usually with medium-chain triglycerides, to achieve a specific fatty acid profile. This results in a triglyceride containing combinations of short-, medium-, and long-chain fatty acids on a single glycerol backbone. They have unique chemical, physical, or physiologic properties that are not observed by simply blending mixtures of the starting fats and oils. A number of STs are under intense laboratory and clinical investigation in models of cancer, burns, and immune dysfunction. Much interest in the fatty acids resides in the sn-2 position on the glycerol molecule. This is because the fatty acid in the sn-2 position of triglycerides is preferentially absorbed as the 2-monoglyceride and serves as the template for reesterification by intestinal cells to re-form triglycerides. The sn-2 fatty acids are also preferentially preserved as components of chylomicrons and very-low-density lipoprotein particles for ultimate incorporation in tissue membranes. Technology is evolving to create STs with a selected fatty acid in this sn-2 position. For instance, incorporating linoleic, arachidonic, or eicosapentaenoic acid at the sn-2 position is being evaluated for the specific objective of modulating serum cholesterol concentrations and essential fatty acid absorption (a review of this work is included).

Classical Kaposi's: a rare cause of gastrointestinal haemorrhage.

Classical Kaposi's sarcoma (KS) is an indolent neoplasm involving mucocutaneous sites predominantly in elderly Mediterranean or Jewish persons. Whilst gastrointestinal involvement is common, it is usually asymptomatic. This case report presents a case of massive gastrointestinal haemorrhage in a patient with stable cutaneous disease and outlines options for the investigation and management of this rare complication.