Comparison of viscous budesonide and fluticasone in the treatment of patients with eosinophilic esophagitis: a systematic review and meta-analysis

Introduction

Unlike other areas of the gastrointestinal tract, the esophagus is normally devoid of eosinophils [1,2]. Eosinophilic esophagitis (EoE) is a chronic condition characterized by eosinophilic infiltration of the esophagus. This condition can affect both pediatric and adult populations [3]. The first case of EoE was not described until 1978; however, it was thought to be a variant of eosinophilic gastroenteritis and was not recognized as its own distinct entity until the 1990s [4,5].

The initial cases led to a subsequent rise in research, which in turn led to an increased awareness of this condition and refinement of the diagnostic criteria. Subsequently, a significant increase in incidence and prevalence have been observed [6,7], with a current estimated prevalence of 52.2 cases per 100,000 persons [8] and an incidence of 10 cases per 100,000 persons [7] in the United States (US). Because of the increasing incidence and prevalence of EoE, healthcare costs have also increased, with total costs recently estimated at $503 million to $1.36 billion per year in the US [9].

Treatment of EoE is multimodal, consisting primarily of dietary restriction (i.e., elimination diet) and pharmacologic therapy [10]. As with other conditions that have an allergic component, corticosteroids play a crucial role in treatment. Topical steroids are generally preferred to systemic steroids, as they deliver the drug directly to the affected tissue (esophageal mucosa) and are associated with fewer systemic side-effects [10,11]. The 2 most commonly used steroid agents are budesonide and fluticasone [12]. Steroid therapy is an effective treatment modality and the majority of patients achieve a symptomatic benefit, while a histologic response is seen in 50-90% [13,14].

Current treatment guidelines are clear about the indication for steroids in EoE. The British Society of Gastroenterology recommends orodispersible budesonide as the preferred formulation. However, this therapy is not currently approved in the US. Moreover, current US guidelines do not recommend one form of corticosteroid over another. We conducted a meta-analysis to compare budesonide and fluticasone and determine whether one of them was associated with better outcomes.

Materials and methods

This meta-analysis and systematic review were reported in compliance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement [15]. A specific protocol was developed to conduct this meta-analysis and to specify methods, databases to use, eligibility criteria and outcomes of interest. A comprehensive search of Ovid Medline In-Process & Other Non-Indexed Citations, Ovid MEDLINE, Ovid EMBASE, Ovid Cochrane Central Register of Controlled Trials, and Ovid Cochrane Database of Systematic Reviews was performed from each database’s inception to March 29^th, 2023.

Results

Study selection

The initial search retrieved 647 studies, of which 444 were included for screening by 2 authors after duplicate removal. Following full-text screening, we identified 3 studies eligible for data abstraction to answer the question addressed in this systematic review (Fig. 1). The reasons for exclusion at full-text review were ineligible study design, study population, sample size less than 10 patients, or not enough information to determine an effect estimate.

Figure 1 Flowchart outlining the search process

Study characteristics

All studies included in the final analysis were published between 2016 and 2019 and conducted in the US. A total of 272 patients were included, of whom 140 received budesonide and 132 fluticasone. One study was a double-blinded clinical trial [20], and the other 2 were observational studies [21,22]. Table 1 summarizes the studies included in our review.

Table 1 Included studies baseline information and patient characteristics

Histologic response

Histologic response was defined as a total eosinophil count <15 eos/hpf. Three studies reported the histological response in the budesonide and fluticasone groups. There was no statistically significant difference between budesonide and fluticasone in achieving a histologic response, with a pooled odds ratio of 1.29 (95%CI 0.77-2.14), P=0.34, and no heterogeneity in the results (I²=0%) (Fig. 2).

Figure 2 Forest plot comparing Budesonide to Fluticasone in achieving histologic response

CI, confidence interval

Publication bias

We performed funnel plot analyses for the included studies comparing budesonide to fluticasone for patients with EoE, which revealed no significant publication bias as shown by a symmetrical funnel plot (Fig. 3).

Figure 3 Funnel plot of all included studies in the meta-analysis

Discussion

Although EoE was previously known as a rare condition, it has become increasingly prevalent. In addition to its growing economic burden, EoE imposes a major burden on the patient and has been associated with a negative impact on health-related quality of life in both children and adults [23]. Symptoms in adults range from dysphagia, heartburn and abdominal pain to food impaction. Advanced disease carries a risk of more serious complications due to remodeling of the tissue, including esophageal rigidity, and strictures [24].

Early and effective medical therapy (e.g., corticosteroids) is instrumental in preventing recurrence of symptoms and complications of the disease, as well as alleviating the economic burden and the negative impact on the quality of life. Eosinophils have a deleterious effect on the esophagus due to their degranulation; thus, reducing esophageal eosinophil counts to fewer than 15 eos/hpf is the primary goal of therapy [25]. Steroid therapy is used to achieve the goal of reducing eosinophil counts. British guidelines demonstrate a preference for orodispersible budesonide over other steroid formulations. While this therapy has not been approved for use in the US, viscous formulations are the preferred preparations. The American College of Gastroenterology gives a strong recommendation for treatment with topical steroids. However, they do not recommend one steroid over the other, and there is no FDA-approved swallowed steroid for treatment [26]. In our study, we conducted a systemic review and meta-analysis designed to determine which agent was associated with a better histological response. Our meta-analysis found no significant difference in histologic response between patients treated with budesonide or fluticasone.

Multiple studies have been conducted in an attempt to determine which agent is superior. The studies we analyzed had mixed results, suggesting either that budesonide was superior to fluticasone [22], or that there was no significant difference between the treatments [20,21]. Notably, no significant difference was found between these agents in an RCT [18]. In addition to the limitation of their retrospective designs, 2 of the studies noted that the dose of steroids prescribed was lower than in current practice and compliance could not be measured retrospectively. Either of these limitations may have interfered with the results.

Moreover, 1 retrospective study that suggested budesonide was superior took place within a pediatric population (age range 1-20 years), so the results do not apply to older adult populations. Therefore, our analysis was consistent with the current literature in that one agent was not found to be definitively superior over the other in regard to their efficacy in inducing a histologic response. These studies indicate that larger sample size and future RCTs are needed to determine whether there is a significant difference in the efficacy of these treatment modalities.

There may be other differences between the medications, such as their ability to control symptoms or achieve improvement in endoscopic findings (e.g., trachealization, furrows). However, these comparisons could not be analyzed in our study. Further studies are needed to better illustrate the efficacy of each agent, both in inducing a histologic response and in controlling the symptoms of the disease. When choosing between the 2 medications, factors such as availability, tolerability, cost and ease of administration should be considered. Monoclonal antibodies are also a component of the treatment of EoE [27]. These drugs may have a greater role as further studies are completed.

The strengths of this meta-analysis include a comprehensive search of multiple databases by 2 independent reviewers, while our study is the first meta-analysis to compare treatment with fluticasone and budesonide for EoE. Limitations of this meta-analysis include the low number of included studies, variability in study type (2 retrospective studies and 1 RCT), and variability in the ages of the patient population among the studies analyzed, which were accounted for in the risk of bias judgement. The insufficient data did not allow us to run an analysis for secondary outcomes, such as clinical response and adverse events. Confounding variables (e.g., use of proton pump inhibitors, adherence to elimination diet) were not available for analysis and thus could not be assessed. Other variables not included, and thus not assessed, included duration of disease remission and rate of relapse. In addition, there may be a discrepancy between the clinical and histologic response in patients with EoE, and data on the clinical response were not available. Ideally, the clinical response should have also been assessed and compared to the histologic response.

In conclusion, this systematic review and meta-analysis showed that neither agent was superior in inducing a histologic response in patients with EoE. Future RCTs are needed to validate the conclusions of this study and determine whether there is superiority among these agents in regard to symptom control and endoscopic improvement.