L.G.J.B. Engels

Influence of phenotype at diagnosis and of other potential prognostic factors on the course of inflammatory bowel disease.

OBJECTIVES:Disease course in inflammatory bowel disease (IBD) is variable and difficult to predict. To optimize prognosis, it is of interest to identify phenotypic characteristics at disease onset and other prognostic factors that predict disease course. The aim of this study was to evaluate such factors in a population-based IBD group.METHODS:IBD patients diagnosed between 1 January 1991 and 1 January 2003 were included. A follow-up questionnaire was developed and medical records were reviewed. Patients were classified according to phenotype at diagnosis and risk factors were registered. Disease severity, cumulative medication use, and “surgical” and “nonsurgical” recurrence rates were calculated as outcome parameters.RESULTS:In total, 476 Crohns disease (CD), 630 ulcerative colitis (UC), and 81 indeterminate colitis (IC) patients were diagnosed. In CD (mean follow-up 7.6 years), 50% had undergone resective surgery. In UC (mean follow-up 7 years), colectomy rate was 8.3%. First year cumulative recurrence rates per 100 patient-years for CD, UC, and IC were 53, 44, and 42%, respectively. In CD, small bowel localization and stricturing disease were negative prognostic factors for surgery, as was young age. Overall recurrence rate was increased by young age and current smoking. In UC, extensive colitis increased surgical risk. In UC, older age at diagnosis initially increased recurrence risk but was subsequently protective.CONCLUSIONS:This population-based IBD study showed high recurrence rates in the first year. In CD, small bowel localization, stricturing disease, and young age were predictive for disease recurrence. In UC, extensive colitis and older age at diagnosis were negative prognostic predictors.

Proliferating cell nuclear antigen (PCNA): a new marker to study human colonic cell proliferation.

Immunohistochemistry of the S phase related proliferating cell nuclear antigen (PCNA) was studied as an alternative to ex-vivo bromodeoxyuridine (BrdU) immunohistochemistry for assessment of human colonic cell proliferation. From 16 subjects without colonic disease biopsy specimens were collected from five different sites along the colorectum and processed for BrdU and PCNA immunohistochemistry. The mean proliferation index of PCNA was significantly higher at 133% of the value obtained with BrdU. There was, however, a good correlation between the results from both techniques (r = 0.6275; p < 0.05). Decrease in proliferation index along the colorectum was seen with both staining methods but was clearer with PCNA immunohistochemistry (caecum/ascending colon v rectum: 12.0 v 7.2; p < 0.004). The total number of crypt cells also decreased from proximal to distal (134 to 128; p < 0.06) but at no site correlated significantly with the proliferation index. It is concluded that in clinical cell kinetic studies staining for PCNA may serve as an attractive alternative to the BrdU incorporation assay.

Fatigue and health-related quality of life in inflammatory bowel disease: results from a population-based study in the Netherlands: the IBD-South Limburg cohort.

Background: The importance of fatigue in chronic disease has been increasingly recognized; however, little is known about fatigue in inflammatory bowel disease (IBD). The aim of the present study was to investigate the prevalence and severity of fatigue and the impact on health‐related quality of life (HRQoL) in patients included in a population‐based IBD cohort in the Netherlands. Methods: IBD patients, diagnosed between January 1st, 1991, and January 1st, 2003, were followed up for a median of 7.1 years. They completed a questionnaire, which included a disease activity score, the Multidimensional Fatigue Inventory (MFI‐20), the Inflammatory Bowel Disease Questionnaire (IBDQ), and the Short Form health survey (SF‐36). Hemoglobin levels were recorded. Results: Data were available in 304 Crohns disease (CD), 368 ulcerative colitis (UC), and 35 indeterminate colitis (IC) patients. During quiescent disease, the prevalence of fatigue was nearly 40%. MFI‐20 and HRQoL scores were significantly worse in IBD patients having active disease. In a multivariate analysis, disease activity was positively related with the level of fatigue in both CD and UC. In UC, anemia influenced the general fatigue score independently of disease activity. Disease activity as well as fatigue were independently associated with an impaired IBDQ. Conclusions: In IBD, even in remission, fatigue is an important feature. Both in CD and in UC, fatigue determined HRQoL independently of disease activity or anemia. This implies that in IBD patients physicians need to be aware of fatigue in order to better understand its impact and to improve the HRQoL. (Inflamm Bowel Dis 2010)

Pharmacokinetics of 6-mercaptopurine in patients with inflammatory bowel disease: implications for therapy.

Proper prospective pharmacokinetic studies of 6-mercaptopurine (6-MP) in inflammatory bowel disease (IBD) patients are lacking. As a result, conflicting recommendations have been made for metabolite monitoring in routine practice. The authors have evaluated 6-MP pharmacokinetics in IBD patients, including the genetic background for thiopurine methyltransferase (TPMT). Red blood cell (RBC) 6-thioguanine nucleotide (6-TGN) and 6-methylmercaptopurine ribonucleotide (6-MMPR) concentrations were measured in 30 IBD patients at 1, 2, 4, and 8 weeks after starting 6-MP, 50 mg once daily. Outcome measures included mean 6-TGN and 6-MMPR concentrations (± 95% confidence interval, CI95%) and their associations with TPMT genotype, 6-MP dose, and hematologic, hepatic, pancreatic, and efficacy parameters during the 8-week period. Steady-state concentrations were reached after 4 weeks, indicating a half-life of approximately 5 days for both 6-TGN and 6-MMPR; the concentrations were 368 (CI95% 284–452) and 2837 (CI95% 2101–3573) pmol/8 × 108 RBCs, respectively. Large interpatient variability occurred at all time points. TPMT genotype correlated with 6-TGN concentrations (0.576, P < 0.01), and patients with mutant alleles had a relative risk (RR) of 12.0 (CI95% 1.7–92.3) of developing leukopenia. A 6-MMPR/6-TGN ratio less than 11 was associated with therapeutic efficacy. Based on this pharmacokinetic analysis, therapeutic drug monitoring is essential for rational 6-MP dosing.

Dose-Dependent Influence of 5-Aminosalicylates on Thiopurine Metabolism

INTRODUCTION:Studies indicated that 5-aminosalicylates (5-ASA) may influence the metabolism of thiopurines; however, conclusions were restricted as a result of number of patients or study design.AIM:To determine the influence of 5-ASA on thiopurine metabolism, we performed a prospective multicenter pharmacokinetic interaction study of two different 5-ASA dosages (2 g daily followed by 4 g daily) in 26 inflammatory bowel disease (IBD) patients during steady-state AZA or 6-MP therapy.RESULTS:The 4-wk coadministration of 2 g 5-ASA daily, followed by a 4-wk period of 4 g 5-ASA daily, led to a statistical significant increase of 40% (absolute 84 pmol/8 × 108 RBC) and 70% (absolute 154 pmol/8 × 108 RBC) in 6-thioguaninenucleotide levels (6-TGN), respectively. A rise in 6-TGN levels was observed in 100% of patients after a 4-wk period of 4 g 5-ASA daily. The 6-methylmercaptopurine-ribonucleotide levels did not change. Signs of myelotoxicity were observed in 7.7% of patients (N = 2).CONCLUSIONS:The level of the pharmacologically active 6-TGN significantly increases in a dose-dependent manner during 5-ASA coadministration. IBD patients who are unresponsive or refractory to standard thiopurine therapy may benefit from the coadministration of 5-ASA, leading to an increase in 6-TGN levels.

Proton pump inhibitor use is associated with an increased risk for microscopic colitis: a case–control study

Aliment Pharmacol Ther 2010; 32: 1124–1128

6-Thioguanine seems promising in azathioprine- or 6-mercaptopurine-intolerant inflammatory bowel disease patients: a short-term safety assessment.

Objective 6-Mercaptopurine (6-MP) and azathioprine (AZA) have proven efficacy in the treatment of inflammatory bowel disease (IBD). However, adverse events leading to discontinuation may occur in 10–20% of patients. The efficacy of AZA and 6-MP is based on formation of their active metabolites, the 6-thioguaninenucleotides (6-TGNs). Therefore, 6-thioguanine (6-TG), an agent leading more directly to the formation of 6-TGNs and until recently used only in patients suffering from leukaemia, may be an alternative in AZA or 6-MP intolerance. The purpose of our study was to assess the short-term safety of 6-TG. Methods Thirty-two IBD patients with previously established AZA or 6-MP intolerance were treated with 6-TG in doses of 20 mg (n = 19) or 40 mg (n = 13) once daily. Safety parameters were obtained at 0, 1, 2, 4 and 8 weeks after start of medication. Primary outcome measures were the ability to tolerate 6-TG and the occurrence of adverse events. Secondary outcome definitions included laboratory parameters. Results Twenty-six (81%) patients were able to tolerate 6-TG during the first 8 weeks. In three of six patients, side effects leading to discontinuation were probably (n = 2) or obviously (n = 1) related to 6-TG. No clinically relevant haematological events or hepatotoxicity occurred in the observed period. Steady-state 6-TG levels were significantly higher with 40 mg once daily (1621 ± 828 picomol/8 × 108 red blood cells (RBC)) than with 20 mg once daily (937 ± 325 picomol/8 × 108 RBC; P = 0.001). Conclusions 6-TG treatment seems promising in AZA- or 6-MP-intolerant IBD patients. However, long-term safety and efficacy have yet to be determined.

Bile Acid Concentrations, Cytotoxicity, and pH of Fecal Water from Patients with Colorectal Adenomas

In the multistage model of human colorectaltumorigenesis, both genetic and environmental factorsplay an important role. The identity of theenvironmental factors involved, however, still remainsto be elucidated. As fecal bile acids are proposed ascandidates, we compared the concentration of bile acidsin fecal water from patients at different risk ofdeveloping colorectal cancer. In addition, pH of fecal water as well as its cytotoxicity toHT-29 colonic cells was determined. The high-risk groupconsisted of individuals diagnosed with one or more(tubulo)villous colorectal adenomas larger than 1 cm in diameter and containing moderate or severedysplasia (N = 20). Subjects with colorectal adenomassmaller than 1 cm and showing only minor dysplasia wereassigned to the medium risk group (N = 19). The control group consisted of persons with normalfindings by colonoscopy (N = 25). The results show nosignificant differences in fecal water bile acidconcentrations between the three groups. However, 46% of the observed cytotoxicity is explained in aregression model that includes pH and the concentrationsof deoxycholic acid, cholic acid, and ursodeoxycholicacid. The pH of fecal water is found to be significantly lower in the high risk group as compared to thecontrols, suggesting that a relatively high fecal pH hasa protective effect on the development of colorectaladenomas. Although hyperproliferation as a result of cytotoxicity has been suggested tocontribute to tumor formation in the colon, thepH-dependent cytotoxicity of bile acids in fecal waterwas not found to be associated with adenoma formation inthe present study.

The pharmacokinetic effect of discontinuation of mesalazine on mercaptopurine metabolite levels in inflammatory bowel disease patients

Background : In vitro studies suggest interactions between mesalazine (mesalamine) and thiopurines by thiopurine S‐methyltransferase (TPMT) inhibition, influencing the balance of hepatotoxic 6‐methylmercaptopurine ribonucleotide and immunosuppressive tioguanine (thioguanine) metabolites.

Efficacy of diltiazem in the treatment of diffuse oesophageal spasm

Calcium antagonists relax smooth muscle, a possible useful concept in treatment of diffuse oesophageal spasm. Therefore the effects of oral diltiazem (60 mg t.d.s.) and placebo were compared in eight patients with diffuse oesophageal spasm in a 10‐week double‐blind crossover study. The patients recorded the severity of chest pain and/or dysphagia in daily pain diaries using visual analogue scales. Chest pain index and dysphagia index were calculated by multiplying frequency with daily intensity of each individual symptom. When compared to placebo, diltiazem did not significantly change the overall dysphagia index and chest pain index. An individual sizeable reduction of dysphagia was attained on diltiazem in four out of six patients and in six out of eight patients suffering from chestpain. Side effects were not seen during diltiazem therapy. Diltiazem, in our study, did not yield in a significant improvement of symptoms in diffuse oesophageal spasm. Diltiazem, however, can offer relief in selected individual patients suffering from diffuse oesophageal spasm.