Budesonide Induces Favourable Histologic and Symptomatic Recovery in Patients with Non-responsive and Refractory Coeliac Disease When Given in an Open Capsule Format

coeliac disease (CeD) is a prevalent, chronic, small intestinal immune-mediated enteropathy triggered by exposure to dietary gluten in genetically predisposed individuals [1]. The pathogenesis of CeD involves the interplay of genetic predisposition mostly conferred by specific human leukocyte antigen (HLA) allotypes, environmental factors, and an abnormal CD4 + T-cell response to gluten-derived peptides [2].

The cornerstone of CeD management is strict adherence to a lifelong gluten-free diet (GFD) which leads to clinical improvement, normalisation of serological markers and histologic resolution. However, a subset of patients continue to experience symptoms, laboratory abnormalities, and/or histological changes typical of active CeD despite a GFD for at least 6 to 12 months, a condition termed “non-responsive coeliac disease” (NRCD) [3]. NRCD is reported to affect up to 30% of CeD patients [4, 5]; however, this may underestimate cases of persisting enteropathy detected by applying more rigorous quantitative histomorphometry [6, 7]. The major cause of NRCD is ongoing gluten exposure [5, 8, 9]. Even when CeD patients earnestly attempt a GFD inadvertent gluten exposure can occur as strict adherence to a GFD is challenging and gluten cross-contamination of gluten-free foods is common [10, 11]. It is suspected that many patients with NRCD without overt dietary gluten exposure have ongoing disease because they are immunologically super-sensitive to low-level gluten exposure. Refractory coeliac disease (RCD) is a form of complicated CeD affecting 0.3–4% of patients [8]. Most definitions of RCD encompass persistent or recurrent villous atrophy in conjunction with malabsorptive symptoms and signs such as diarrhoea, abdominal pain, loss of weight, and anaemia despite greater than 12 months on a strict GFD, with other causes of villous atrophy and malabsorption excluded [1]. RCD is typically observed in those aged over 50 years and carries a greater potential for adverse clinical sequelae [8]. RCD is divided into type 1 (RCD 1), where the duodenal intra-epithelial cell population remains normal, and type 2 (RCD 2), where it is aberrant and monoclonal, and considered a “pre-lymphoma” [12]. RCD 2 carries up to an 80% chance of developing a lymphoproliferative malignancy, typically an enteropathy-associated T-cell lymphoma, within 5 years [13].

There is an important need to treat NRCD and RCD as the former is common and both have substantial impacts on patient quality of life and health outcomes [14]. Systemic corticosteroids, immunomodulators, and biologics have been used in an attempt to control inflammation and symptoms in NRCD and RCD, but their long-term use is associated with significant side effects, and there are limited data to guide appropriate treatment choices [15]. Consensus guidelines recommend steroids as 1st-line agents to treat RCD [15]. In RCD 2, approaches that destroy the aberrant clonal cells are also needed.

Budesonide is a potent, locally acting glucocorticoid that has shown efficacy in a range of gastrointestinal conditions with most supportive data from controlled clinical studies in Crohn’s disease [16]. Extensive pre-systemic metabolism of budesonide within the mucosa of the small intestine and the liver results in low systemic availability, reducing the risk of side effects associated with traditional corticosteroids. Studies in CeD have been retrospective and uncontrolled but suggest a potential benefit for budesonide in NRCD [17, 18] and RCD [18, 19]. An open capsule budesonide (OCB) format may be superior to closed capsules in RCD [18]. In this format, budesonide capsules (3 mg) are taken 3 times a day, not as a single 9 mg dose, and the morning capsule is opened and the contents finely ground before consumption. As some formulations of budesonide are designed to be released mainly in the terminal ileum and colon to treat Crohn’s disease, the aim of physical grinding of the capsule contents is to enhance more proximal small intestinal drug delivery which may be beneficial in CeD as it is predominantly a duodenal disease [20]. However, a benefit for OCB over budesonide taken traditionally as the whole capsule, hereafter termed closed capsule budesonide (CCB), was not clearly shown in another study examining budesonide treatment outcomes in NRCD [17]. To determine if an OCB regimen may be more effective than the traditional CCB regimen in NRCD and RCD treatment, we conducted a retrospective study to investigate the efficacy of budesonide as therapy, with a specific focus on comparing outcomes between open and closed capsule intake.

There is increasing recognition of the limitations of the GFD to induce symptomatic and histologic remission in CeD patients. This has focused efforts on the development of novel drug therapies that target persistently active CeD, the hallmark feature of NRCD and RCD [14]. Despite this enthusiasm, no new therapies have been approved. The lack of robust data to support a role for existing treatments such as budesonide, well established for the treatment of other gastrointestinal inflammatory diseases, means potentially valuable approaches are not widely utilised outside specialty centres.

Budesonide, as a locally acting glucocorticoid, provides targeted topical therapy allowing for enhanced drug concentration. The extensive first-pass metabolism means systemic effects are substantially less common than systemic steroids such as prednisolone [21]. Budesonide has shown promise in the treatment of CeD associated with malabsorption [22], to abort acute symptoms induced by gluten exposure [23], treat coeliac crises [24], and in treating NRCD [17] and RCD [18, 19]. Brar and colleagues assessed 29 RCD patients who received CCB (15 as monotherapy) and showed a 76% clinical response, but none had a histologic response [19]. In contrast, Mukewar and colleagues treated 57 patients with RCD using a novel open capsule format and showed 92% had clinical and 89% histologic improvement, suggesting the open capsule format was more effective in managing symptoms and particularly the enteropathy of RCD [18]. Therrien and colleagues showed budesonide induced a 57% clinical response rate and 46% histologic response rate in 42 patients with NRCD, but only 6 (14%) received OCB and comparison with CCB was not undertaken. Our study is the first to look at both NRCD and RCD and directly compare outcomes in similar cohorts of patients who received CCB and OCB.

Our findings support and advance those of Mukewar and colleagues by showing that OCB is significantly more effective in promoting histologic healing of the small intestine and improving symptoms compared to CCB in patients with RCD 1 as well as NRCD [18].

OCB was less likely to require a 2nd line therapy compared to CCB due to failure of the primary treatment course. The observed superiority of OCB in inducing histologic healing of the small intestine aligns with the localised delivery mechanism of this approach. While we focused on villous atrophy as the main readout of enteropathy, it was notable that several patients demonstrated improvement in intra-epithelial lymphocyte count (inflammation) without changes in villous height, which may be an important therapeutic aspect of this treatment, as raised intra-epithelial lymphocytes in CeD has been associated with raised mortality [25]. In contrast to Mukewar and colleagues, we did not show clinical or histologic benefits for OCB in RCD 2, however given the rarity of this complication our sample size was small. While current guidelines do recommend steroids as a 1st-line therapy for RCD 2 [15] it is accepted that additional treatment to destroy the aberrant clones is crucial [26].

Traditional CCB is biased towards greater distal small intestinal and proximal colonic drug distribution [27]. This may limit its effectiveness in active CeD which is a proximal small intestinal disease. Elli and colleagues recently showed that in RCD 1 50% of the mucosal involvement was confined to the first third of the small intestine and 21% in the distal third; conversely, in RCD 2, 25% of the mucosal involvement was noted in the first third of the small intestine and 62% in the distal third [20]. Further, the enteropathy is more severe in RCD 2, with Marsh 3C changes noted in 79% compared to 43% in RCD 1. Collectively, this suggests that proximal, mid, and distal small intestinal distribution is important in NRCD and RCD; however, the distal component becomes increasingly important in RCD 1 and RCD 2. The OCB protocol aims to enhance delivery to the proximal and distal small intestine using ground and unground medication, respectively.

Our findings also show that OCB led to a greater improvement in symptoms compared to closed capsule intake. Symptomatic relief is a crucial aspect of managing NRCD and RCD patients’ overall quality of life. The more pronounced symptomatic improvement seen in the open capsule group is consistent with the positive impact and statistical correlation in treating the enteropathy. Demonstrating symptom benefit is a crucial requirement for novel coeliac therapies as indicated by the Food and Drug Administration and robust data demonstrating this primary endpoint is required for drug registration [28]. To date, there are no approved drugs meeting this requirement [14].

A notable finding from our study was the high rate of osteopaenia and osteoporosis in the NRCD and RCD patients. This would concord with persistently active disease characteristic of these two conditions, which is itself associated with worsening bone mineral density and increased fracture risk [29]. Further contributing to the reduced bone density may be the older age of the cohort which is also a common finding in NRCD [30] and in particular with RCD [8]. The reduced bone density is also a relevant consideration in the context of budesonide use, as some clinicians may worry about steroid induced worsening of bone density. However, given budesonide’s extensive first-pass metabolism, systemic side effects and suppression of pituitary-adrenal function are substantially less common than prednisolone. Supporting long-term safety, in a 2 year treatment study of Crohn’s disease patients, budesonide caused smaller reductions in bone mineral density (mean, − 1.04% vs − 3.84%; p = 0.0084) and fewer treatment-emergent side effects compared to prednisolone [21]. As the active enteropathy of CeD itself contributes to worsening bone density, the cost–risk benefit of budesonide is highly favourable given its efficacy when used in open capsule format in NRCD and RCD.

We found that histologic outcomes in the 1st part of the duodenum were informative, independent of changes in the 2nd/3rd part, although in a small number of patients. Most of the field focus on the 2nd or 3rd part of the duodenum for diagnosis and assessment, partly because historically the duodenal bulb is considered harder to interpret due to the presence of Brunner’s gland and lymphoid follicles that can lead to overlying villous flattening, mimicking CeD enteropathy, or other changes such as peptic duodenitis or gastric metaplasia, and the duodenal bulb can be more difficult to sufficiently sample [31, 32]. However, CeD can be confined to the duodenal bulb [33] and may be most severe proximally. Our findings would support sampling and assessment of the duodenal bulb as an important region that can inform on CeD activity.

Our study has limitations. First, the retrospective study design carries inherent biases. This includes variability in patient background and selection, duration of therapy, timing of endoscopic work-up in relation to therapy, and level of follow-up. Some of these issues may have been partly mitigated by the involvement of a single gastroenterologist who provided input into the work-up and management of the NRCD and RCD cases and use of budesonide, explaining the consistent CCB and OCB treatment protocols. Further, many patients had been referred for a second opinion by another gastroenterologist due to persistent enteropathy, so may not be representative of the broader range of CeD patients with mild persistent disease or those with only persistent symptomatology seen in the clinic. The CCB and OCB cohorts were sequential as the OCB protocol was not widely employed until 2016, at which time use of CCB ceased, except when it had been commenced by another gastroenterologist unaware of the OCB protocol. Second, we relied on local histology reports which were highly variable in the approach to reporting and level of detail provided, underscoring the real-world nature of this study. Current best practice for clinical trials recommends a quantitative morphometric approach incorporating villous height: crypt depth ratio and intra-epithelial lymphocyte count/100 enterocytes, linked to standard operating procedures that exclude poorly oriented samples [34]. Similarly, validated patient-reported outcome measures are important to standardise collection of symptom data which as a subjective measure is highly heterogeneous [28, 35]. Third, our study focused on immediate post treatment findings and longer-term symptom or histologic outcome data were not examined so durability of disease control post treatment could not be assessed. Finally, as preparation of OCB is user dependent, the dose delivered may vary depending on how effectively patients grind the contents. To address these shortcomings, a prospective study formally evaluating budesonide in a standardised format that incorporates robust delivery to the proximal small intestine is needed. Given our observation that treatment duration affects outcome, a prospective study could incorporate short and longer periods of treatment and build in long-term follow-up to identify an optimal treatment protocol and identify those patients who require salvage therapy.

Our study has shown that OCB is associated with considerably more effective histologic healing and symptom improvement in NRCD and RCD 1 than traditional CCB. While a prospective-controlled validation study is warranted to strengthen the evidence base and risk–benefit for this treatment approach, we suggest OCB be regarded the preferred first-line drug therapy for NRCD and RCD 1 over systemic steroid therapy that is readily implemented in the clinic.