Dosing interval and diagnosis predict infliximab levels in patients with inflammatory bowel disease on maintenance treatment.

OBJECTIVE: The aim of the study was to identify factors influencing infliximab (IFX) trough levels (TL) in patients with inflammatory bowel disease (IBD). METHODS: This was a multicentre cross-sectional study performed at 5 large IBD centres in Slovakia. The cohort consisted of IBD patients, treated either with original IFX or CT-P13 biosimilar, who were examined for the IFX TL and antidrug antibodies (ADA) in a central laboratory. RESULTS: The patient cohort consisted of 116 consecutive IBD patients, 68 with Crohn's disease (CD) and 48 with ulcerative colitis (UC). CD patients had significantly lower IFX TL compared to UC, 2.41 (0.998-5.56) mg/L vs. 4.49 (1.76-8.41) mg/L, p = 0.017. During maintenance treatment, significantly higher mean IFX TL were observed in patients with a 4 week dosing interval than in patients with a 6 or 8 (7.44±3.6 µg/mL vs. 4.19±4.2 vs. 3.30±3.1 µg/mL, p = 0.011 and p< 0.0001, respectively). There was no difference in median TL IFX between original IFX and biosimilar CT-P13 (3.25 (1.24-6.52) mg/L vs. 3.03 (1.30-7.10)). IFX TL correlated with ADA (p=0.005). Multiple regression analysis revealed two independent factors for IFX TL: dosing interval (p<0.0001) and diagnosis (p=0.02). CONCLUSION: In the present study we observed that IBD patients assigned to an intensified dosing interval during maintenance therapy have significantly higher IFX TL than patients receiving conventional 8 week interval. Patients with UC had significantly higher IFX TL.

Prevalence of mutations in thiopurine S-methyltransferase gene among Slovak IBD patients.

BACKGROUND: Thiopurine S-methyltransferase (TPMT) plays an important role in the metabolism of thiopurines. It has been suggested that TPMT genetic polymorphisms lead to dose-related hematopoietic toxicity. Since there are major ethnic differences in the prevalence of particular TPMT variants, it is important for each country to study their own prevalence in order to estimate the role of TPMT variants-related thiopurines toxicity in population suffering from particular inflammatory bowel disease (IBD). AIMS: The aim of this study was to determine the frequency of the four most common allelic variants of TPMT gene in the population of Slovak IBD patients. METHODS: TPMT genetic polymorphisms (TPMT*2, TPMT*3A, TPMT*3B, TPMT*3C) were amplified using PCR and consequently genotyped with genetic analyzer. The allele frequencies of particular allelic variants were calculated and compared with other Caucasian populations reported so far. RESULTS: Three hundred and thirty IBD patients were included; 196/132/2 cases of Crohn´s disease/ulcerative colitis/unclassified colitis; 180 (55 %) males. Ninety-three percent of patients were homozygous for wild-type TPMT variant. Heterozygous genotype of any of the studied polymorphisms was present in 6 % of patients while only one patient was homozygous for TPMT*3A allele (0.3 %). The most prevalent mutant allele was that of TPMT*3A (3.2 %). The distribution of most common allelic variants of TPMT gene among Slovak IBD patients was in accordance with previously reported prevalence in Caucasian populations. CONCLUSION: This study shows the prevalence of TPMT genetic polymorphisms in population of Slovak IBD patients. As in other Caucasian populations, the most common mutant allelic variant is that of TPMT*3A while the prevalence of homozygosity is relatively low (Tab. 3, Ref. 22).

The impact of thiopurine-S-methyltransferase genotype on the adverse drug reactions to azathioprine in patients with inflammatory bowel diseases.

BACKGROUND AND AIMS: The thiopurine drugs, azathioprine (AZA) and 6-mercaptopurine, are established in the treatment of inflammatory bowel diseases (IBD). Polymorphisms in thiopurine S-methyltransferase (TPMT) gene have been associated with adverse drug reactions (ADRs) to AZA. METHODS: The aim of this study was to evaluate TPMT polymorphisms and AZA-related toxicity in a Slovak cohort of 220 IBD patients treated with AZA. In every patient, the dose and duration of AZA therapy, concomitant 5-aminosalicylate (5-ASA) medication, frequency, type, time to onset, dose of ADR and concomitant 5-ASA at the onset of ADR were recorded. Each patient was also genotyped for the presence of variant TPMT alleles (*2,*3A,*3B,*3C). Frequency, type and circumstances of ADRs were compared according to TPMT status. RESULTS: Of the 220 patients, 205 (93.2 %) were wild-type (TPMT*1/*1), one (0.5%) carried a TPMT*1/*3C allele, 13 (5.9 %) carried TPMT *1/*3A allele and one was homozygous for TMPT *3A allele. No TPMT *2 mutation was found. The incidence of adverse drug reactions was 62/205 (30.2 %) in the wild-type group as compared to 13/15 (86.7 %) in the TPMT mutation group, p=2.10-5. Leukopenia (WBC< 3.0*10^9/L) occurred in 21/205 (10.2 %) patients with wild type TPMT versus 11/15 (73.3 %) patients with TPMT mutations, p=0.000001. There was no significant difference between TMPT groups in gastrointestinal or other ADRs. No impact of 5-ASA on the incidence and severity of AZA adverse drug reactions was observed. CONCLUSION: The incidence of leukopenia in TPMT mutant patients was significantly higher and more severe as compared to TPMT wild type patients. We observed no impact of concomitant 5-ASA therapy on AZA induced toxicity (Tab. 4, Fig. 2, Ref. 37).

Prevalence of mutations in thiopurine S-methyltransferase gene among Slovak IBD patients.

BACKGROUND: Thiopurine S-methyltransferase (TPMT) plays an important role in the metabolism of thiopurines. It has been suggested that TPMT genetic polymorphisms lead to dose-related hematopoetic toxicity. Since there are major ethnic differences in the prevalence of particular TPMT variants, it is important for each country to study their own prevalence in order to estimate the role of TPMT variants-related thiopurines toxicity in the particular inflammatory bowel disease (IBD) population. AIMS: The aim of this study was to determine the frequency of the four most common allelic variants of TPMT gene in the population of Slovak IBD patients. METHODS: TPMT genetic polymorphisms (TPMT*2, TPMT*3A, TPMT*3B, TPMT*3C) were amplified using PCR and consequently genotyped on genetic analyzer. The allele frequencies of particular allelic variants were calculated and compared with other Caucasian populations reported so far. RESULTS: Three hundred and thirty IBD patients were included; 196/132/2 Crohn´s disease/ulcerative colitis/unclassified colitis, 180 (55 %) males. Ninety-three percent of patients were homozygous for wild type TPMT variant. Heterozygous genotype of any of the studied polymorphisms was present in 6 % of patients, only one patient was homozygous for TPMT*3A allele (0.3 %). The most prevalent mutant allele was TPMT*3A (3.2 %). The distribution of the most common allelic variants of TPMT gene among Slovak IBD patients were in accordance with previously reported prevalence in Caucasian populations. CONCLUSION: This study shows the prevalence of TPMT genetic polymorphisms in the Slovak IBD patient`s population. As in other Caucasian populations, the most common mutant allelic variant is TPMT*3A, and the prevalence of homozygosity is relatively low (Tab. 3, Ref. 16).

[Gastroduodenal complications associated with non-steroidal anti-inflammatory drugs in Slovak Republic: results of one-year prospective study]. / Podiel gastroduodenálnych komplikácií vo vzt'ahu k liecbe nesteroidovými antiflogistikami v Slovenskei republike: rocná prospektívna stúdia.

The aim of the one-year prospective study was to estimate the prevalence of non-steroidal anti-inflammatory drugs using in patients with symptomatic gastroduodenal ulcers, the upper gastrointestinal bleeding and perforation (PUB--perforation, ulcer, bleeding). Among of 326 patients with PUB, prevalence of non-steroidal anti-inflammatory drugs using was 60%. In the group of 194 patients with non-steroidal antiinflammatory drugs induced PUB, 49% patients took aspirin, 38% non-aspirin non-steroidal anti-inflammatory drugs and 13% their combination. Low dosing aspirin (daily dosis < or =200 mg) was associated with PUB in 21% of patients. Age higher than 60 years and women had statisticaly signiticant higher prevalence of non-steroidal anti-inflammatory drugs induced PUB.

[Cooperation between a surgeon and a gastroenterologist in the management of vascular complications of the liver cirrhosis]. / Spolupráca chirurga a gastroenterológa pri riesení vaskulárnych komplikácií cirhózy pecene.

AIM: The aim of this work was to confirm indications for surgical procedures in cases of relapsing bleeding from oesophageal varices as a consequence of the liver cirrhosis. METHODOLOGY: Based on the retrospective study of the endoscopical examinations results and the patient records, the criteria of the patient selection for the surgical procedure, the type of the surgical procedure, the postoperative complications and the long-term assessment, were revised. RESULTS: During the six-year period, 7625 gastrofibroscopies were conducted. In this group, the oesophageal varices were diagnosed in 107 males and 47 females. In 76 males and 31 females the varices did not bleed. In 31 males and 16 females the varices did bleed and were sclerotised. In this subgroup, in 24 males and 13 females the varices were eradicated or moved from the Paquet grade 3-4 to 1-2. In 3 females and 7 males the sclerotherapy was not successful and the patients continued to bleed. Five males underwent surgery and 2 males and 3 females exsanguinated without surgery. The following surgical procedures were completted: 3x Warren anastomoses, 1x Linton anastomosis and 1x resection of the duodenojejunal arcuation. One patient exited due to the liver failure. CONCLUSION: The sclerotherapy failed in 21.3% patients. Half of them exsanguinated. Only patients in the Child-Pugh A and B functional stage are indicated for the elective surgical procedure in cases of bleeding relapses following the sclerotherapy, varices of the gastric fundus and haemorrhaging gastropathy. Ablation is the method of choice in cases of emergency.

[Liver biopsy in Slovakia]. / Biopsie pecene na Slovensku.

INTRODUCTION: Liver biopsy is the most specific diagnostic modality in hepatology, but information about its application in Slovakia is rather obscure. METHODS: The authors performed a correspondence study with the aim to find out how many biopsy examinations has been done in Slovakia in 2001, for which indications, what kind of techniques have been applied and which small or great complications were encountered. RESULTS: It was established that in the year 2001, 400 biopsies for diffuse liver diseases were performed. There were 296 percutaneous biopsies, 82 laparoscopic biopsies and 22 trans-jugular biopsies forming the survey. Acute viral hepatitis was the most frequent indication, whereas non-alcohol steatohepatitis was a rare indication in spite of the high prevalence. The frequency of great complications was 0.00025%. No death associated with this procedure was reported. CONCLUSION: Liver biopsy has been done in Slovakia in indications, ways and with the frequency of complications, which were comparable with data from literature.