Alan G. Fraser

The efficacy of azathioprine for the treatment of inflammatory bowel disease: a 30 year review

Background: There are limited data on factors predicting response to azathioprine and uncertainty regarding the optimal duration of treatment. Patients and methods: The notes of patients attending the Oxford IBD clinic from 1968 to 1999 were reviewed. Remission was defined as no need for oral steroids for at least three months and relapse was defined as active disease requiring steroids. Results: A total of 622 of 2205 patients were treated with azathioprine (272 Crohns disease, 346 ulcerative colitis, and four indeterminate colitis). Mean duration of the initial course of treatment was 634 days. The overall remission rates were 45% for Crohns disease and 58% for ulcerative colitis. For the 424 patients who received more than six months of treatment, remission rates were 64% and 87%, respectively. Factors favouring remission were ulcerative colitis (p=0.0001), lower white blood cell (WBC) or neutrophil count (p=0.0001), higher mean cell volume (p=0.0001), and older age (p=0.05). For Crohns disease, colonic disease favoured remission (p=0.03). Factors that were not significant were age, sex, lymphocyte count, and dose (mg/kg). The proportion of patients remaining in remission at one, three, and five years was 0.95, 0.69, and 0.55, respectively. The chance of remaining in remission was higher if WBC was less than 5×109 (p=0.03) and in male patients (p=0.01; Crohns disease only). There was no difference in relapse rates between Crohns disease and ulcerative colitis. After stopping azathioprine, the proportion of patients remaining in remission at one, three, and five years was 0.63, 0.44, and 0.35 (222 patients). Duration of azathioprine treatment did not affect the relapse rate after stopping treatment (p=0.68). Conclusions: Azathioprine is effective treatment for ulcerative colitis and Crohns disease. The efficacy of azathioprine is reasonably well sustained over five years.

Long-term risk of malignancy after treatment of inflammatory bowel disease with azathioprine

Background and aim : Data from renal transplant and rheumatoid arthritis patients suggest that there is an increased risk of malignancy after treatment with azathioprine. Whether this is true for patients with inflammatory bowel disease remains uncertain.

Country-specific constancy by age in cagA+ proportion of Helicobacter pylori infections

Helicobacter pylori strains may be either cagA+ or cagA−, and in logitudinal studies, infection with a cagA+ strain has been associated with increased risk for the development of atrophic gastritis and cancer of the distal stomach. We sought to determine the relative proportion of strains producing CagA in different geographic locales, and the extent to which CagA seroprevalence varied in countries with different gastric and esophageal cancer rates. Using an enzyme‐linked immunosorbent assay (ELISA) to detect serum IgG to CagA, we examined sera from 468 asymptomatic H. pylori‐infected adults from Canada, Peru, China, Thailand, The Netherlands and 3 different ethnic groups in New Zealand. The CagA seroprevalence in Peru and Thailand (82.2% and 78.8%, respectively) were each substantially higher than for the Chinese (37.9%), Canadian (41.9%), Dutch (39.0%) and New Zealand (28.2%) subjects, but within each population, rates were relatively constant across gender and age groups. Reported gastric but not esophageal cancer rates for the 8 studied populations were significantly associated with H. pylori seroprevalence. Variation in CagA positivity rates was not significantly associated with variation in either gastric or esophageal cancer rates. Our data suggest that CagA seroprevalence is not the major factor influencing gastric cancer rates. Int. J. Cancer 72:453–456, 1997.

The efficacy of methotrexate for maintaining remission in inflammatory bowel disease

The management of patients with inflammatory bowel disease who are resistant to or intolerant of azathioprine remains a challenge. Low‐dose methotrexate has been shown to be effective in inducing remission in Crohns disease.

Pharmacokinetic interactions between alcohol and other drugs

SummaryThe frequent use of alcohol (ethanol) together with prescription drugs gives any described pharmacokinetic interaction significant clinical implications. The issue is both the effect of alcohol on the pharmacokinetics of various drugs and also the effect of those drugs on the pharmacokinetics of alcohol. This review discusses these pharmacokinetic interactions but also briefly describes some other effects of alcohol that are clinically relevant to drug prescribing.The use of several different study designs may be required before we can confidently state the presence or absence of any alcohol-drug interaction. Short term administration of alcohol in volunteers is the most common study design but studies of social drinking and prolonged moderate alcohol intake can be important in some situations. Community-based studies may illustrate the clinical relevance of any interaction.Alcohol can affect the pharmacokinetics of drugs by altering gastric emptying or liver metabolism (by inducing cytochrome P450 2E1). Drugs may affect the pharmacokinetics of alcohol by altering gastric emptying and inhibiting gastric alcohol dehydrogenase. The role of gastric alcohol dehydrogenase in the first-pass metabolism of alcohol is reviewed in this article and the arguments for and against any potential interaction between alcohol and H2 receptor antagonists are also discussed. The inhibition of the metabolism of acetaldehyde may cause disulfiram-like reactions.Pharmacodynamic interactions between alcohol and prescription drugs are common, particularly the additive sedative effects with benzodiazepines and also with some of the antihistamine drugs; other interactions may occur with tricyclic antidepressants. Alcohol intake may be a contributing factor to the disease state which is being treated and may complicate treatment because of various pathophysiological effects (e.g. impairment of gluconeogenesis and the risk of hypoglycaemia with oral hypoglycaemic agents). The combination of nonsteroidal anti-inflammatory drugs and alcohol intake increases the risk of gastrointestinal haemorrhage.

Genetic factors in chronic inflammation: Single nucleotide polymorphisms in the STAT-JAK pathway, susceptibility to DNA damage and Crohn's disease in a New Zealand population

The Signal Transducers and Activators of Transcription (STAT)-Janus kinase (JAK) pathway controls signal transduction between cell surface receptors and the nucleus. Two members of that pathway, STAT3 and JAK2, enhanced the risk of Crohns disease (CD) in recent genome-wide association studies. We replicated these findings in a New Zealand Caucasian case-control cohort, by genotyping two single nucleotide polymorphisms (SNPs) in STAT3 (rs744166(G>A) and rs3816769(C>T)) and rs10758669(A>C) in JAK2, in 302 CD patients and 382 controls. For STAT3, there was a significant decrease in the frequency of the G allele of rs744166 and the C allele of rs3816769 in CD patients as compared with controls (OR=0.76, 95% CI=0.61-0.95, p=0.013; OR=0.71, 95% CI=0.56-0.89, p=0.003). For the JAK2 rs10758669 polymorphism, the homozygous C/C or heterozygous A/C genotypes increased the risk of having CD as compared with the homozygous A/A (OR=1.76, 95% CI=1.26-2.45 and OR=2.36, 95% CI=1.44-3.86, respectively, p=0.0003). Variant alleles in either gene significantly modified the likelihood of inflammatory disease in a colonic location, and of developing extra-intestinal manifestations. The JAK2 variant also strongly enhanced the risk of ileocolonic disease, with stricturing or ileal/stricturing behaviour, requiring a bowel resection. We further studied a subset of our control population, stratified for JAK2 rs10758669 and/or STAT3 rs3816769 genotype. Carrying either the JAK2 or STAT3 IBD risk allele was associated with significantly enhanced susceptibility to DNA damage, as estimated by comet assays in peripheral blood leukocytes, with or without a subsequent oxidative challenge. That is, both risk alleles enhance genomic instability. The JAK2 SNP is part of a haplotype previously associated with enhanced susceptibility to myeloproliferative neoplasms, but functional consequences of the STAT3 variant had not been previously demonstrated. It will be of interest to follow up CD patients carrying either JAK2 or STAT3 risk alleles for development of further secondary effects, including cancer.

TLR2, TLR4 and TLR9 polymorphisms and Crohn's disease in a New Zealand Caucasian cohort.

Background and Aim:  Toll‐like receptors (TLRs) have been identified as susceptibility genes for Crohns disease (CD) in some, but not all, studies. Here we examined the association between candidate disease‐susceptibility polymorphisms in the TLR2, TLR4 and TLR9 genes and CD in a New Zealand Caucasian population.

Dietary factors in chronic inflammation: Food tolerances and intolerances of a New Zealand Caucasian Crohn's disease population

Diet is known to play a major role in the symptoms of the inflammatory bowel disease, Crohns disease (CD). Although no single diet is appropriate to all individuals, most CD patients are aware of foods that provide adverse or beneficial effects. This study seeks to categorise foods in relation to their effects on symptoms of CD, in a New Zealand Caucasian population. Four hundred and forty-six subjects from two different centres in New Zealand were recruited into the study. An extensive dietary questionnaire (257 food items in 15 groups) recorded self-reported dietary tolerances and intolerances. Across each of the food groups, there were statistically significant differences among responses to foods. A two-dimensional graphical summary enabled stratification of foods according to the probability that they will be either beneficial or detrimental. A small number of foods are frequently considered to be beneficial, including white fish, salmon and tuna, gluten-free products, oatmeal, bananas, boiled potatoes, sweet potatoes (kumara), pumpkin, soya milk, goats milk and yoghurt. Foods that are typically considered detrimental include grapefruit, chilli or chilli sauce, corn and corn products, peanuts, cream, salami, curried foods, cola drinks, high energy drinks, beer, and red wine. For a number of the food items, the same item that was beneficial for one group of subjects was detrimental to others; in particular soya milk, goats milk, yoghurt, oatmeal, kiwifruit, prunes, apple, broccoli, cauliflower, linseed, pumpkin seed, sunflower seed, ginger and ginger products, beef, lamb, liver, and oily fish. It was not possible to identify a specific group of food items that should be avoided by all CD patients. The wide range of detrimental items suggests that dietary maintenance of remission is likely to be difficult, and to exclude a substantial number of foods. Personalised diets may be especially important to these individuals.

Environmental factors in the development of chronic inflammation: a case-control study on risk factors for Crohn's disease within New Zealand.

The role of environmental factors in the risk for Crohns disease (CD), an inflammatory bowel disease (IBD), was investigated in a North Island-based New Zealand case-control cohort. A total of 315 CD patients and 536 controls were recruited through various sources to the Auckland CD Risk Factor Study. As well as demographic characteristics, the self-reported questionnaire included (1) smoking and drinking alcohol, (2) breastfeeding in infancy, (3) early life exposures to allergens and microbes, (4) health conditions lasting 6 months or longer and (5) taking antibiotics and any medications. There was strong evidence for familial associations of the disease, and minor effects of birth order and number of siblings. Being a smoker, especially over a long time period, and exposure to smoking during childhood and adolescence periods increased risk, whereas drinking alcohol at least once per week showed a slight protective effect. Long term use of the oral contraceptive pill increased the risk of developing CD, but breastfeeding and immunisation during infancy showed no significant association. Long term and debilitating illness (lasting 6 months or more), taking antibiotics prior to developing CD, or taking four or more antibiotics or any regular medication in a year during adolescence substantially increased the CD risk. Having a pet during childhood was a protective factor, but regularly feeding an animal was not sufficient to protect. Many of these significant factors are likely to impact on the colonic microflora and/or immune system. We conclude that, in addition to strong evidence for genetic associations, factors likely to impact on immune response or reduce early exposure to microbes provide a main risk factor for CD in this New Zealand population.

Review article: gastro-oesophageal reflux and laryngeal symptoms

There is some evidence from clinical, experimental and multiprobe ambulatory pH studies that gastro‐oesophageal reflux is more common in patients with laryngeal symptoms and could potentially play a role in the causation of these symptoms. The proportion of unselected patients with laryngeal symptoms who have gastro‐oesophageal reflux as the primary aetiology may be overestimated in some series. The symptom that has been most evaluated is hoarseness, but even for this symptom the proportion of patients who have significant reflux varies widely. There is even less agreement for other symptoms, and the data on globus sensation remains confused. It is likely that these patients present to ear, nose and throat (ENT) clinics because of the relative insensitivity of the oesophageal mucosa to acid exposure. Given the lack of specificity for routine diagnostic tests for gastro‐oesophageal reflux, it is necessary to perform ambulatory pH monitoring for a secure diagnosis in these patients. Treatment studies have been surprisingly few and inadequate in design. It is suspected that there is a strong placebo response for these symptoms. No clear information on efflcacy can be provided until placebo‐controlled randomised studies are available.