Abstract and Introduction
Abstract
Background Refractory coeliac disease type I is a complicated form of coeliac disease characterised by primary or secondary resistance to a gluten-free diet with persisting or reoccurring intestinal villous atrophy and symptoms of malabsorption. Besides corticosteroids, azathioprine has been advocated for the treatment of refractory coeliac disease type I. However, tioguanine (TG) might be better tolerated and more efficacious owing to a simpler metabolism towards bioactivation.
Aim To evaluate tolerability and effectiveness of the nonconventional thiopurine derivative TG in refractory coeliac disease type I.
Methods Refractory coeliac disease type I patients treated with TG between June 2001 and November 2010 with a follow-up period of at least 1 year were included. Adverse events, laboratory values, 6-thioguanine nucleotide concentrations and rates of both clinical and histological response were evaluated at baseline and during follow-up.
Results Twelve adult refractory coeliac disease type I patients were included. The median TG treatment duration was 14 months. Ten patients tolerated TG treatment on the long term, whereas two patients withdrew treatment due to adverse events. No nodular regenerative hyperplasia of the liver was observed. During follow-up clinical and histological response was observed in 83% and 78%, respectively. Corticosteroid dependency decreased by 50%.
Conclusion Tioguanine appears to be a convenient drug for the treatment of refractory coeliac disease type I based on higher histological and similar clinical response rates as compared with historical conventional therapies.
Introduction
A small percentage of the adult-onset coeliac disease (CD) patients display a primary or secondary lack of clinical and histological response upon strict adherence to a gluten-free diet (GFD) for more than 12 months despite normalised CD associated antibodies. These patients are diagnosed as having refractory coeliac disease (RCD) when dietary consumption of gluten and other causes of malabsorption with villous atrophy are ruled out. This syndrome can be subdivided into RCD type I and RCD type II, with immunophenotypically normal and aberrant intraepithelial T-lymphocytes (IELs) in the small-intestinal mucosa, respectively. Aberrant IELs express cytoplasmic CD3, but lack the surface markers CD3, CD4 and CD8. A clinically validated cut-off value of 20% aberrant IELs, detected using flow cytometric analysis of small intestinal biopsies, is currently used to discriminate between RCD I and RCD II. Although the prognosis of RCD I is much more favourable than that of RCD II, as reflected in 5-year survival rates of around 90% and 44–58%, respectively, treatment is believed to be important in preventing complications of longstanding malabsorption. The poor prognosis of RCD II is due to a high risk of clonal expansion and further transformation of aberrant mucosal T-lymphocytes into an aggressive enteropathy associated T-cell lymphoma (EATL).
Apart from a GFD and nutritional support, corticosteroids are the mainstay of treatment in RCD I. However, an 80% corticosteroid dependency associated with systemic side effects has been reported. To reduce corticosteroid dependency and in case of corticosteroid refractoriness, the immunomodulatory purine analogue azathioprine (AZA) has been used. Although clinical response rates following AZA therapy were promising, histological remission was lagging behind. In addition, AZA therapy is regularly complicated and discontinued due to adverse events, as has been shown in the treatment of inflammatory bowel disease (IBD), but also in small RCD I series. Both therapeutic failure as well as adverse events may be due to an unfavourable metabolism of AZA. Azathioprine is metabolised via mercaptopurine (MP) into the pharmacologically active 6-tioguanine nucleotides (TGN), and into multiple other metabolites including 6-methyl mercaptopurine (6-MMP) (Figure 1). Despite a weight-adjusted dosing regimen, there is a wide interindividual variety in TGN and 6-MMP concentrations, which reflects individual differences in the activities of involved enzymes. High concentrations of 6-MMP are associated with adverse events often necessitating drug withdrawal. In view of the aforementioned limitations of corticosteroid and immunosuppressive therapies, it is important to evaluate therapeutic alternatives for RCD I.
(Enlarge Image)
Figure 1.
Simplified thiopurine metabolism. Azathioprine (AZA) is converted into mercaptopurine (MP), which in turn is oxidised into 6-thiouric acid (6-TUA), methylated into 6-methyl mercaptopurine (6-MMP) or metabolised into 6-thioinosine monophosphate (6-TIMP). Then, 6-TIMP is metabolised into the pharmacologically active 6-tioguanine nucleotides (TGN), methylated into 6-MMP or is phosphorylated into 6-thioinosine triphosphate (6-TITP). On the other hand, tioguanine (TG) is directly metabolised into TGN, methylated into 6-methyl thioguanine (6-MTG), or oxidised into 6-TUA.
The nonconventional thiopurine derivative tioguanine (TG) might be a suitable alternative treatment option for RCD I, either as first-line treatment, second-line treatment in patients unresponsive to corticosteroids or AZA, or as a steroid-sparing drug. Tioguanine only needs one enzymatic conversion towards the formation of the active metabolites TGN and when metabolised, it is not converted into 6-MMP. In addition, TG was shown to be well-tolerated and efficacious in the treatment of IBD. We report a single centre series concerning tolerability and effectiveness of TG in RCD I.