Abstract and Introduction
Background: The healing of the mucosal lesion in patients with coeliac disease is slow.
Aim: To determine whether concurrent budesonide and gluten-free diet hasten small bowel healing and symptomatic improvement in patients with newly diagnosed coeliac disease.
Methods: In a pilot, randomised, double-blind trial, effects on Marsh grading and quantitative duodenal morphometry of 10 weeks’ effervescent budesonide (initially 9 mg/day) or placebo were assessed after 8 and 52 weeks. Multiple clinical measures and adverse events were assessed.
Results: Nineteen patients were randomised to budesonide and 18 to placebo. No differences (all P > 0.32) were observed for the week-8 mucosal response (Marsh 0 or 1) (budesonide: 37% vs placebo: 28%), week-8 remission (Marsh 0) (32% vs 17%), week-52 response (63% vs 44%) and week-52 remission (42% vs 33%). Likewise, the improvement from baseline in villous-height : crypt-depth ratio was not different for the treatment groups. There were no statistically significant differences in clinical measures or adverse events between the treatment groups. No corticosteroid adverse effects were observed. In a post hoc analysis of all patients, Marsh 3C was present at the diagnostic biopsy in 1/9 achieving mucosal remission at 8 weeks versus 18/23 not (P < 0.001) and mean villous-height : crypt-depth ratio was 1.06 (SD: 0.73) versus 0.46 (0.38) (P = 0.005).
Conclusions: In this pilot trial, induction therapy with budesonide had no significant effect on mucosal healing in patients with coeliac disease concurrently initiated on a gluten-free diet. Mucosal remission at 8 weeks occurred in approximately one in four patients and was associated with less severe histological lesions at diagnosis.
Coeliac disease is a genetically linked T-cell mediated autoimmune disease affecting 0.5%-1% of the population worldwide, triggered and perpetuated by the dietary intake of gluten. The immunopathology of coeliac disease is well characterised and is defined by hallmark small intestinal histological features of villous atrophy, crypt hyperplasia, intraepithelial lymphocytosis and the expansion of the lamina propria with a mixed inflammatory cell infiltrate. The only recognised treatment is a strict, lifelong, gluten-free diet.
Although coeliac disease—like Crohn’s disease and ulcerative colitis—involves intestinal inflammation, it has not traditionally been considered an inflammatory bowel disease, and the treatment paradigm for coeliac disease differs markedly from that of inflammatory bowel disease. There have, however, been occasional reports in coeliac disease of a neutrophilic lamina propria expansion with microabscess formation—similar to what is often seen in inflammatory bowel disease. Much like inflammatory bowel disease, untreated coeliac disease has long-term consequences including increased mortality, osteoporosis and an increased risk of malignancy.
Although a gluten-free diet is considered effective, histological response can take many months or years. In our prospective study of 99 patients with newly diagnosed coeliac disease, only 54% had histopathological response (Marsh 0/1) at 1 year and 85% at 5 years, despite apparently excellent dietary adherence as assessed in detail by a coeliac-specialist dietitian. The reported Scandinavian, Dutch and Italian 1-year experiences are similar.[6–8] In our study, only 37% achieved histological normalisation after 1 year that mirrored a retrospective study from the United Kingdom in which 35% had histological normalisation that took a median of 1.9 years to achieve.
Underpinning the treatment of most other systemic chronic inflammatory diseases—including inflammatory bowel disease—has been induction therapy (often with corticosteroids) followed by maintenance therapy. To date, pharmacotherapeutic paradigms for coeliac disease have largely targeted those with refractory disease where some trials and case series have shown benefit from the addition of immunosuppression.[10–15] Arguably, our approach in coeliac disease has been to commence maintenance therapy (a gluten-free diet) without induction, which may partly explain the slow histological response in patients with newly diagnosed coeliac disease.
Budesonide is a topically active corticosteroid that undergoes high first-pass metabolism, maximizing its local effects while minimizing the systemic complications of corticosteroid exposure. Oral administration has been used successfully to induce remission in case series of refractory coeliac disease though no randomized controlled trial has been reported.[13–15]
In this pilot, double-blind, placebo-controlled, randomised study, we aimed to address the hypothesis that induction therapy with orally delivered budesonide concurrently with a gluten-free diet in patients with newly diagnosed coeliac disease would hasten and lead to increased rates of small bowel healing and improved symptoms, without deleterious systemic side-effects. The data obtained also enabled examination of the rate of early healing and factors associated with it.