Randomised Clinical Trial

Adjunctive Induction Therapy With Oral Effervescent Budesonide in Newly Diagnosed Coeliac Disease

Evan D. Newnham; Daniel Clayton-Chubb; Meena Nagarethinam; Patrick Hosking; Peter R. Gibson

Disclosures

Aliment Pharmacol Ther. 2021;54(4):419-428. 

In This Article

Discussion

This pilot study examined the concept that the addition of an anti-inflammatory induction therapy (topically acting corticosteroids) to the institution of maintenance therapy (a gluten-free diet) would improve healing rates and the resolution of symptoms over the first 12 months following a new diagnosis of coeliac disease. Although there are numerical differences in mucosal response and mucosal healing which, in sum, favour budesonide therapy over placebo, these results were not statistically significant. Likewise, improvement in other clinical indices were similar between groups. The study did, however, recognise that about one in four patients heal their duodenal mucosa within 8 weeks of the institution of a gluten-free diet and enabled identification that this was strongly and inversely associated with the histopathological severity of the duodenal lesion at diagnosis.

The apparent effectiveness of oral budesonide for both improving histology and symptoms severity in patients with refractory coeliac disease[13–15] led to the expectation that it may have been effective in improving early healing results. There are several reasons underlying the failure to demonstrated benefit from budesonide induction therapy in this trial. First and foremost is that the number of patients studied may have been too small to demonstrate such an effect. In planning this pilot study, the assumption was made that mucosal remission within the first 2 months of a gluten-free diet would be a very uncommon event as there had been no published reports of the likelihood of early healing. The fact that one in four patients did this reduced the power of the study.

Secondly, the type of patient associated with positive histological and clinical responses to budesonide reported in the literature were considerably more severe than recruited in the present study. Hence, the patient phenotype may have been too mild to observe major improvement, particularly in clinical symptoms. For example, only 15 patients had overall gastrointestinal symptoms self-rated as 30 mm or more on the visual analogue scale. In addition, many symptoms attributed to gluten and coeliac disease itself have origins outside of coeliac disease, such as concomitant irritable bowel syndrome or dietary FODMAP intake.[19,20] Likewise, chronic fatigue and psychological morbidity are likely to be related to more than just the inflammation associated with coeliac disease. Bone density improves in patients with at least osteopenia but not if normal prior to commencement of a gluten-free diet.[5] Quantitative and categorical assessment of histopathology indicated a range of severity that should have been sufficient to observe budesonide-mediated effects. It should be noted, however, that corticosteroids are potent at inducing clinical response/remission in patients with inflammatory bowel disease but not potent in inducing endoscopic remission.[21] On the contrary, a milder inflammatory state might have been expected to be more responsive to steroid exposure.

Thirdly, the issue of whether the dose or the delivery of budesonide to the duodenum were sufficient must be addressed. Oral budesonide used in prior case studies of patients with refractory coeliac disease utilised budesonide that was protected from gastric acid by virtue of microcapsule coating in order to enhance delivery to the small intestine and colon.[16] Budesonide's pharmacological action is not acid sensitive. The preparation used in the present study was not coated. Hence, absorption is likely to have occurred in the oesophagus (as similar preparation has been evaluated in patients with eosinophilic oesophagitis[22]) and stomach as well as duodenum. The Tmax after oral intake is reached in 1.2 hours,[23] which is highly suggestive that the drug is reaching the duodenal mucosa. However, the proportion that is delivered to the very proximal small intestinal mucosa that is being sampled for histology is not known due to difficulties assessing this. Thus, it is possible that insufficient drug is delivered to the targeted place.

Importantly, this study showed that there were no significant side effects when comparing oral effervescent budesonide with placebo. This is unsurprising; the known pharmacology of budesonide as well as the evidence from inflammatory bowel disease cohorts suggests that there is minimal systemic absorption and associated deleterious effects.[16] No detectable steroid effect on bone mineral density, glucose tolerance or fasting cortisol were observed, but one case of vaginal candidiasis occurred in the budesonide arm. Its causal relationship to budesonide is probable given the association of occasional oesophageal candidiasis associated with budesonide therapy in patients with eosinophilic oesophagitis.[22]

A novel finding of this study was that of early mucosal healing in 26% of patients at 8 weeks. This is not an area of previous study, although failure to heal has been associated with more severe histological lesions at diagnosis.[7,8] The issue warrants further attention as it may affect follow-up strategies if factors predicting such early healing can be identified and may affect the design and powering of future studies. Within the limitations of the small numbers of patients, there was a highly significant association of the severity of the duodenal lesion at diagnosis with failure to achieve mucosal remission after 8 weeks of dietary treatment (with or without budesonide). There was a suggestion that the severity of clinical phenotype was also associated with rapid healing, because scores for fatigue and depression, and one marker of compromised bone density were higher in those not healing at 8 weeks, although statistical significance was lost when corrected for multiple comparisons. These observations are not surprising—more severe disease takes longer to heal—but it may inform the timing of repeat duodenal biopsies after institution of the gluten-free diet, a decision that currently has no consensus.

The present pilot clinical trial had several limitations. The most notable was that of power as discussed above. The findings now provide data upon which any future trial can be powered. Since designing this study, tools to assess dietary adherence and clinical assessment tools have been developed and validated.[24] It is unlikely, however, that their application to the current study would have altered the findings. Being a single-centre study, the findings are not generalisable. Strengths included single-operator endoscopy, avoiding inter-operator variability in sampling, a single pathologist who evaluated all biopsies including the diagnostic biopsies blinded to their timing as well as intervention, apparently excellent dietary adherence in general, and good adherence to the interventional medications.

In conclusion, this pilot study is the first of its kind to attempt to institute early and rapid remission in coeliac disease through the use of oral effervescent budesonide as a form of locally active immunosuppression. Although it showed that the intervention and design was both feasible and safe, it failed to provide evidence of a positive effect of budesonide on primary or secondary outcomes. The safety profile of the oral effervescent budesonide was acceptable with no significant differences in treatment-associated adverse events. Future randomised studies with a larger enrolled cohort are viable. The most notable finding of this study was the rate of rapid healing of the duodenal lesion in one in four patients, a finding that was associated with milder histological lesions.

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