Murray L. Barclay

Genome-wide meta-analysis increases to 71 the number of confirmed Crohn's disease susceptibility loci

We undertook a meta-analysis of six Crohns disease genome-wide association studies (GWAS) comprising 6,333 affected individuals (cases) and 15,056 controls and followed up the top association signals in 15,694 cases, 14,026 controls and 414 parent-offspring trios. We identified 30 new susceptibility loci meeting genome-wide significance (P < 5 × 10−8). A series of in silico analyses highlighted particular genes within these loci and, together with manual curation, implicated functionally interesting candidate genes including SMAD3, ERAP2, IL10, IL2RA, TYK2, FUT2, DNMT3A, DENND1B, BACH2 and TAGAP. Combined with previously confirmed loci, these results identify 71 distinct loci with genome-wide significant evidence for association with Crohns disease.

Review article: comparison of the pharmacokinetics, acid suppression and efficacy of proton pump inhibitors

Proton pump inhibitors have dramatically influenced the management of acid‐peptic disorders in recent years. They all have a broadly similar mechanism of action and are extensively metabolized in the liver via cytochromes P450 2C19 and 3A4. There is some variation in their potential for drug interactions due to differences in enzyme inhibition. Relatively few serious adverse effects have been reported for the proton pump inhibitors.

High incidence of Crohn's disease in Canterbury, New Zealand: Results of an epidemiologic study

Background: Inflammatory bowel disease (IBD) has increased exponentially in industrialized nations over the last 50 years. Previous New Zealand studies have shown that IBD is less common than in other countries; however, clinical observations suggested a high incidence and prevalence of IBD in Canterbury, particularly Crohns disease (CD). Aim: This study aimed to determine the descriptive epidemiology of IBD in Canterbury. Methods: Canterbury IBD patients, recruited using multiple strategies, gave informed consent, permission for clinical record review, completed a questionnaire, and were bled for DNA extraction as part of the Canterbury IBD Project. Cases were confirmed using standard criteria, and completeness of recruitment was validated using capture‐recapture methods. Demographic and phenotypic data were extracted from case notes. One thousand four hundred twenty patients (715 CD, 668 ulcerative colitis [UC]) were recruited (>91% of Canterbury IBD patients). Results: In 2004, age‐standardized (World Health Organization World Standard Population) IBD, CD, and UC incidence rates were 25.2, 16.5, and 7.6/100,000/year, respectively. The IBD, CD, and UC point prevalences on 1 June, 2005 were 308.3, 155.2, and 145.0/100,000, respectively. CD patients were more likely than UC patients to be female (61.4% vs. 47.1%) and to be younger (median age, 39.9 years vs. 43.7 years). The percent of IBD patients who were white was 97.5%. Conclusion: IBD is at least as common in Canterbury as in other western regions. CD incidence and prevalence are amongst the highest ever reported and are higher than for UC. IBD population characteristics are otherwise similar to other countries. The Canterbury IBD Project will be a valuable tool for future population‐based IBD epidemiology and genetics research.

Using allopurinol above the dose based on creatinine clearance is effective and safe in patients with chronic gout, including those with renal impairment.

OBJECTIVE To determine the efficacy and safety of increasing the allopurinol dose above the proposed creatinine clearance-based dose in patients with gout. METHODS Patients with gout who had been receiving a stable dose of allopurinol for ≥ 1 month were recruited. The dose of allopurinol was increased to obtain the target serum urate level of <0.36 mmoles/liter (<6 mg/dl). Patients were seen monthly until the serum urate concentration was <0.36 mmoles/liter for 3 consecutive months and then were seen every 3 months for at least 12 months. Data were analyzed using the dosage of allopurinol (mg/day) greater than the recommended dosage, as defined by the Hande criteria. RESULTS Ninety patients were enrolled. The mean age of the patients was 58.7 years (range 27-83 years), 87.9% were male, and 81.9% were of European ancestry. Forty-five patients had a serum urate concentration of ≥ 0.36 mmoles/liter, and the dose of allopurinol was increased in these patients. Rashes developed in 3 patients, and either allopurinol was discontinued or dose escalation was ceased in these patients. Seven patients were lost to followup or developed intervening medical problems that precluded dose escalation. In 31 (88.8%) of 35 patients who completed the study, the serum urate level was <0.36 mmoles/liter at 12 months. Two of the 5 patients who had a serum urate level ≥ 0.36 mmoles/liter had undetectable levels of plasma oxypurinol, indicating noncompliance with allopurinol treatment. A significant reduction in the serum urate concentration was observed for all allopurinol doses above the recommended dose. Eighteen of 45 patients were receiving furosemide; those receiving furosemide were just as likely as those not receiving furosemide to achieve a serum urate concentration of <0.36 mmoles/liter (72% versus 88.5%; P = 0.24). Patients receiving furosemide required a higher dose of allopurinol to achieve the target serum urate concentration. No serious adverse events were observed. CONCLUSION Increasing the dose of allopurinol above the proposed creatinine clearance-based dose led to a significant reduction in the serum urate concentration. Approximately 89% of patients achieved a serum urate concentration of <0.36 mmoles/liter. In this cohort, toxicity was not increased in patients receiving higher doses of allopurinol, including those with renal impairment.

Azathioprine and 6‐mercaptopurine pharmacogenetics and metabolite monitoring in inflammatory bowel disease

Abstract The thiopurine drugs azathioprine and 6‐mercaptopurine (6‐MP) are well‐established in the treatment of inflammatory bowel disease (IBD). However, there is a wide inter‐ and intra‐patient variation in the concentrations of active and toxic metabolites due to their complex metabolism and genetic polymorphisms in metabolizing enzymes. Serious drug toxicity leads to cessation of therapy in 9–25% of patients, and there is failure to achieve efficacy in approximately 15% of cases. Advances in the understanding of thiopurine drug metabolism have led to new genetic and metabolite tests to help clinicians optimize thiopurine use. Thiopurine methyltransferase (TPMT) enzyme activity can predict life‐threatening myelotoxicity in the one in 300 patients who are TPMT‐deficient. However, myelotoxicity can also occur in the presence of normal TPMT activity so blood count monitoring should remain standard practice. TPMT testing may also aid in dose individualization. 6‐Thioguanine nucleotides (6‐TGN) are thought to be the predominant active metabolites of the thiopurines. 6‐Thioguanine nucleotide concentration is correlated with bone marrow toxicity and may also correlate with efficacy in IBD. Measurement of 6‐TGN and 6‐methylmercaptopurine (6‐MMP) concentration is most useful in determining why a patient is not responding to a standard dose of a thiopurine drug and may help in avoiding myelosuppression. The ratio of these metabolites can help distinguish non‐compliance, under‐dosing, thiopurine‐resistant and thiopurine‐refractory disease. Some of these investigations are entering routine clinical practice but more research is required to determine their optimal use in patients with IBD.

Perianal disease predicts changes in Crohn's disease phenotype-results of a population-based study of inflammatory bowel disease phenotype.

BACKGROUND:The Montreal classification system of inflammatory bowel disease (IBD) provides a framework for describing disease phenotype.OBJECTIVE:We aimed to describe changes in IBD phenotype using the Montreal system and determine predictors of phenotype change in a Caucasian population-based cohort.METHODS:Ninety-two percent of people with IBD in Canterbury, New Zealand were recruited. Clinical notes were reviewed to confirm diagnosis and phenotype. Determinants of phenotype change were analyzed using multivariate analysis.RESULTS:A total of 1,420 (715 Crohns disease [CD], 668 ulcerative colitis [UC]) patients with IBD were included. Median follow-up was 6.5 and 10.9 yr for CD and UC, respectively. Disease location remained stable in 91% of those with CD. Seventy-three percent of CD patients had inflammatory disease at diagnosis with the proportion of patients with complicated disease increasing over time. Progression to complicated disease was more rapid in those with small bowel than colonic disease location, (P < 0.001). Perianal disease was a significant predictor of change in CD behavior (HR 1.62, P < 0.001). Younger UC patients were more likely to have extensive disease at diagnosis than older patients (P < 0.001).CONCLUSIONS:Although CD location remains relatively stable, behavior changes over time. Perianal disease is a strong predictor of developing more complicated CD. Proctitis is most common in UC patients at diagnosis although younger patients are more likely than older patients to have extensive disease. The Montreal classification provides a clinically useful framework for both researchers and clinicians.

Population‐based cases control study of inflammatory bowel disease risk factors

Background and Aim:  The rapid increase in inflammatory bowel disease (IBD) incidence confirms the importance of environment in its etiology. We aimed to assess the role of childhood and other environmental risk factors in IBD.

Pharmacokinetics of Oral Methotrexate in Patients With Rheumatoid Arthritis

OBJECTIVE There is evidence supporting a therapeutic range for methotrexate polyglutamate (MTXGlu) concentrations in the treatment of rheumatoid arthritis (RA). Knowledge of the pharmacokinetics of MTXGlu1-5 is required for optimal timing of blood sampling. The aim of this study was to determine the time to steady state and the half-life of accumulation of red blood cell (RBC) MTXGlu1-5 in patients with RA commencing oral MTX, and the time for RBC MTXGlu1-5 to become undetectable and the half-life of elimination of RBC MTXGlu1-5 in patients ceasing treatment with oral MTX. METHODS Ten patients beginning treatment and 10 patients stopping treatment with low-dose oral MTX were recruited. Blood samples were initially collected weekly, with gradual extension to monthly collection over the study period. RBC MTXGlu1-5 concentrations were assayed by high-performance liquid chromatography. Results were analyzed using a first-order exponential method. RESULTS The median times to reach steady state in RBCs (defined as 90% of the maximum concentration) were 6.2, 10.6, 41.2, 149, and 139.8 weeks, respectively, for MTXGlu1, MTXGlu2, MTXGlu3, MTXGlu4, and MTXGlu5. The median half-life of accumulation for RBC MTXGlu1-5 ranged from 1.9 weeks to 45.2 weeks. The median times for MTXGlus to become undetectable in RBCs were 4.5, 5.5, 10, 6, and 4 weeks, respectively, for MTXGlu1, MTXGlu2, MTXGlu3, MTXGlu4, and MTXGlu5. The median half-life of elimination for RBC MTXGlu1-5 ranged from 1.2 weeks to 4.3 weeks. CONCLUSION There is wide interpatient variability of RBC MTXGlu1-5 accumulation and elimination in adults with RA. These data also suggest that after a dose change, >6 months are required for RBC MTXGlu1-5 to reach steady state. Such delays in achieving steady state suggest that more rapid dose escalation or subcutaneous administration from the outset should be considered.

Confirmation of association of IRGM and NCF4 with ileal Crohn's disease in a population-based cohort

Genome-wide association studies have identified PHOX2B, FAM92B, IRGM and NCF4 as candidate susceptibility factors for ileal Crohns disease (CD). Here we sought to determine whether these genes were also associated with ileal CD in New Zealand Caucasians, as well as with ileocolonic CD, colonic CD and ulcerative colitis (UC). A total of 507 CD patients, 475 UC patients and 576 controls were genotyped for the single nucleotide polymorphisms rs16853571 (PHOX2B), rs4821544 (NCF4), rs13361189 and rs4958847 (IRGM), and rs8050910 (FAM92B). NCF4 and IRGM were significantly associated with ileal CD (P-valuers4821544=0.0090, odds ratio (OR)=1.425, 95% confidence interval (CI): 1.092–1.859; P-valuers13361189=0.0017, OR=1.942, 95% CI: 1.274–2.959; P-valuers4958847=0.0022, OR=1.767, 95% CI: 1.224–2.558), but not with other forms of inflammatory bowel disease (IBD). No association of PHOX2B or FAM92B with IBD was detected. Our study has demonstrated that IRGM and NCF4 are ileal-specific CD susceptibility factors in New Zealand Caucasians.

Lack of association between the ITPA 94C>A polymorphism and adverse effects from azathioprine.

A 94C>A missense mutation in the ITPA gene which encodes inosine triphosphate pyrophosphatase has been associated with adverse effects from azathioprine, specifically flu-like symptoms, pancreatitis and rash. We hypothesized that this association may also be present in a larger, population-based group of inflammatory bowel disease patients intolerant of thiopurine drugs. We performed genotyping for this polymorphism and TPMT*2 and TPMT*3 in 73 such patients and 74 patients with inflammatory bowel disease who have tolerated azathioprine. We could not demonstrate a significant association between the ITPA94C>A genotype and any adverse effects (Odds ratio (OR) 1.015, 95% confidence interval (CI) 0.360-2.867, P = 0.593), flu-like symptoms (OR 1.547, 95%CI 0.368-6.496, P = 0.398), rash (no ITPA 94C>A polymorphism identified) or pancreatitis (no ITPA 94C>A polymorphism identified). We found no significant association between the ITPA 94C>A polymorphism and adverse effects to thiopurine drugs.