Tioguanine in the Treatment of Refractory Celiac Disease
Tioguanine in the Treatment of Refractory Celiac Disease
All patients who were diagnosed with RCD I and received first or second-line TG therapy between June 2001 and November 2010 at the Gastroenterology department of a tertiary referral centre were identified.
Diagnosis of RCD I was based on persisting or recurring symptoms and small intestinal villous atrophy despite strict adherence to a GFD for at least 1 year ascertained by negative serology and a specialised dietitian. Furthermore, the proportion of aberrant IELs detected using flow cytometric analysis of small intestinal biopsies had to be less than 20%. In all patients, EATL was excluded.
After informed consent, TG was prescribed in a daily dose of approximately 0.3 mg/kg and administered as 18, 21 or 24 mg capsules (generic) or 20 mg tablets (Lanvis; GlaxoSmithKline, Middlesex, UK). Patients visited the out-patient clinic on a regular basis, usually every 3–6 months. Patient demographics, date of onset of coeliac disease, date of onset of RCD I onset, clinical details, HLA-DQ haplotype, history of prior immunosuppressive therapy, reason for and date of initiating TG therapy and laboratory results were collected from medical records. In addition, where available clinical and histological details were also obtained after cessation of TG.
Adverse events that had occurred during the use of TG were reported by the treating physicians and described by the researchers as being certainly related, possibly related or not related to TG therapy. In addition, laboratory values regarding the safety of TG therapy that had been determined at baseline and at different time points during follow-up were collected. These values included haemoglobin concentrations, platelet counts, leucocyte counts and liver biochemistry, usually at 3 month interval.
Both clinical and histological characteristics were evaluated at baseline and at different time points during follow-up of TG treatment. Gastrointestinal symptoms, weight and laboratory values, including haemoglobin and albumin were reported. Multiple duodenal biopsies were taken by upper gastrointestinal endoscopy to detect histopathological abnormalities. Clinical response was defined as amelioration of gastrointestinal symptoms, combined with at least two out of the following parameters within their reference range or with an improvement of ≥1 point: body mass index (BMI), albumin and haemoglobin. Complete histological response was characterised by normalisation of the architecture of the small intestinal mucosa, defined as a Marsh 0 or I score according to the modified Marsh criteria, as assessed by an experienced coeliac disease pathologist. A partial histological response was defined as an improvement of the Marsh classification of two or more steps.
Corticosteroid dependency was arbitrarily defined as the use of prednisone or budesonide during follow-up (≥6 months) in a daily dose of at least 10 mg or 9 mg, respectively. The primary end of follow-up was set at the time of TG withdrawal. If remission was the reason for TG cessation, a secondary end of follow-up was set at the time of the last duodenal biopsy performed after TG discontinuation to evaluate ongoing remission.
Red blood cell (RBC) TGN concentrations obtained during follow-up were measured using reversed-phase high-performance liquid chromatography according to a slightly modified method described by Dervieux and Boulieu and expressed in pmol/8 Ă— 10 RBC. The mean values of these measurements were used for comparison between patients. For comparability with the frequently used method of Lennard the observed values must be divided by 2.6.
Data are tabulated or presented descriptively. Continuous variables were expressed as median values with their range. Based on the skewed distribution of the included variables, the nonparametric Mann–Whitney U-test was used for comparison between groups. P values less than 0.05 were considered statistically significant. spss 15.0 for Windows (SPSS Inc., Chicago, IL, USA) was used for statistical analysis.
Materials and Methods
All patients who were diagnosed with RCD I and received first or second-line TG therapy between June 2001 and November 2010 at the Gastroenterology department of a tertiary referral centre were identified.
Diagnosis of RCD I was based on persisting or recurring symptoms and small intestinal villous atrophy despite strict adherence to a GFD for at least 1 year ascertained by negative serology and a specialised dietitian. Furthermore, the proportion of aberrant IELs detected using flow cytometric analysis of small intestinal biopsies had to be less than 20%. In all patients, EATL was excluded.
After informed consent, TG was prescribed in a daily dose of approximately 0.3 mg/kg and administered as 18, 21 or 24 mg capsules (generic) or 20 mg tablets (Lanvis; GlaxoSmithKline, Middlesex, UK). Patients visited the out-patient clinic on a regular basis, usually every 3–6 months. Patient demographics, date of onset of coeliac disease, date of onset of RCD I onset, clinical details, HLA-DQ haplotype, history of prior immunosuppressive therapy, reason for and date of initiating TG therapy and laboratory results were collected from medical records. In addition, where available clinical and histological details were also obtained after cessation of TG.
Tolerability
Adverse events that had occurred during the use of TG were reported by the treating physicians and described by the researchers as being certainly related, possibly related or not related to TG therapy. In addition, laboratory values regarding the safety of TG therapy that had been determined at baseline and at different time points during follow-up were collected. These values included haemoglobin concentrations, platelet counts, leucocyte counts and liver biochemistry, usually at 3 month interval.
Therapeutic Response
Both clinical and histological characteristics were evaluated at baseline and at different time points during follow-up of TG treatment. Gastrointestinal symptoms, weight and laboratory values, including haemoglobin and albumin were reported. Multiple duodenal biopsies were taken by upper gastrointestinal endoscopy to detect histopathological abnormalities. Clinical response was defined as amelioration of gastrointestinal symptoms, combined with at least two out of the following parameters within their reference range or with an improvement of ≥1 point: body mass index (BMI), albumin and haemoglobin. Complete histological response was characterised by normalisation of the architecture of the small intestinal mucosa, defined as a Marsh 0 or I score according to the modified Marsh criteria, as assessed by an experienced coeliac disease pathologist. A partial histological response was defined as an improvement of the Marsh classification of two or more steps.
Corticosteroid dependency was arbitrarily defined as the use of prednisone or budesonide during follow-up (≥6 months) in a daily dose of at least 10 mg or 9 mg, respectively. The primary end of follow-up was set at the time of TG withdrawal. If remission was the reason for TG cessation, a secondary end of follow-up was set at the time of the last duodenal biopsy performed after TG discontinuation to evaluate ongoing remission.
6-Tioguanine Nucleotide Concentration
Red blood cell (RBC) TGN concentrations obtained during follow-up were measured using reversed-phase high-performance liquid chromatography according to a slightly modified method described by Dervieux and Boulieu and expressed in pmol/8 Ă— 10 RBC. The mean values of these measurements were used for comparison between patients. For comparability with the frequently used method of Lennard the observed values must be divided by 2.6.
Statistical Analysis
Data are tabulated or presented descriptively. Continuous variables were expressed as median values with their range. Based on the skewed distribution of the included variables, the nonparametric Mann–Whitney U-test was used for comparison between groups. P values less than 0.05 were considered statistically significant. spss 15.0 for Windows (SPSS Inc., Chicago, IL, USA) was used for statistical analysis.
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