Topical steroid therapy has been used to treat eosinophilic esophagitis (EoE) for more than 15 years. We review the treatment trials of topical steroid therapy in adult patients with EoE. Currently, there is no commercially available preparation designed to deliver the steroid to the esophagus. Current regimens consist of swallowing steroid preparations designed for inhalation treatment for asthma. In the short term, steroids are associated with an approximately 15% to 25% incidence of asymptomatic esophageal candidiasis, but otherwise appear to be well tolerated.
Key points
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Currently, there is no commercially available preparation designed to deliver the steroid to the esophagus. Current regimens consist of swallowing steroid preparations designed for inhalation treatment for asthma.
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When used in proper dose, steroids lead to complete histologic responses in the range of 60% to 70% of patients and at least a partial histologic response in more than 90% of patients.
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Symptom response rates appear to be somewhat less than histologic rates, with at least a partial symptomatic response of only 60% to 75%.
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Maintenance therapy seems promising in one trial, but likely needs a higher dosage than 0.25 mg budesonide twice a day.
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In the short term, steroids are associated with about a 15% to 25% incidence of asymptomatic esophageal candidiasis, but otherwise appear to be well tolerated.
Open-labeled trials
The first report of topical steroid therapy in adult patients with eosinophilic esophagitis (EoE) was reported by Arora and colleagues in 2003 ( Table 1 ). In this open-labeled study, Arora and colleagues treated 21 adults with esophageal eosinophilic infiltration (EEI) and dysphagia. Patients were treated with 440 μg aerosolized swallowed fluticasone twice a day and all patients had a symptomatic response of their dysphagia to the treatment as accessed by a phone interview. Histologic follow-up was not obtained in this report.
| Author | Tx | EEI/EoE | N | Duration | Symptoms | Definition | Histologic | Definition | Side Effects | Comments |
|---|---|---|---|---|---|---|---|---|---|---|
| Response | Response | |||||||||
| Arora et al, 2003 | Fluticasone 440 μg twice a day | EEI | 21 | 6 wk | 90% (19/21) | Resolution of solid food dysphagia by phone interview | Not evaluated | 5% (1/21) dry mouth | First report of steroid benefit in adult patients | |
| Remedios et al, 2006 | Aerosolized fluticasone 500 μg twice a day | EEI | 19 | 4 wk | 5.42 pre −0.068 post ( P <.001) 100% (19/19) decreased 58% (11/19) asymptomatic | Symptom score (0–18) | Proximal 25.0 pre 4.5 post ( P <.0004) Distal 39.3 pre 3.8 post ( P <.0001) 21% (4/19) complete response | eos/hpf | 16% (3/19) asymptomatic esophageal candidiasis | 53% (10/19) abnormal esophageal pH studies |
A second open-labeled trial of topical steroid treatment in adult EoE was reported by Remedios and colleagues. They evaluated 26 patients with symptomatic EEI and treated 19 who were accessed after treatment for histologic response, as well as symptomatic response. Pretreatment esophageal pH testing was abnormal in 53% (10/19) of the patients. All patients, regardless of pH results, were treated with topical aerosolized fluticasone 500 μg twice a day, a minimally increased dose over that used by Arora and colleagues. The symptom score after treatment, as well as the histologic eosinophil levels in the proximal and distal esophagus, were markedly decreased with treatment.
In summary, both open-labeled trials showed a dramatic symptom and histologic response to aerosolized swallowed fluticasone. These studies involved patients with symptomatic EEI, and the therapeutic response was seen in those with and without gastroesophageal reflux disease (GERD) by pH testing.
Open-labeled trials
The first report of topical steroid therapy in adult patients with eosinophilic esophagitis (EoE) was reported by Arora and colleagues in 2003 ( Table 1 ). In this open-labeled study, Arora and colleagues treated 21 adults with esophageal eosinophilic infiltration (EEI) and dysphagia. Patients were treated with 440 μg aerosolized swallowed fluticasone twice a day and all patients had a symptomatic response of their dysphagia to the treatment as accessed by a phone interview. Histologic follow-up was not obtained in this report.
| Author | Tx | EEI/EoE | N | Duration | Symptoms | Definition | Histologic | Definition | Side Effects | Comments |
|---|---|---|---|---|---|---|---|---|---|---|
| Response | Response | |||||||||
| Arora et al, 2003 | Fluticasone 440 μg twice a day | EEI | 21 | 6 wk | 90% (19/21) | Resolution of solid food dysphagia by phone interview | Not evaluated | 5% (1/21) dry mouth | First report of steroid benefit in adult patients | |
| Remedios et al, 2006 | Aerosolized fluticasone 500 μg twice a day | EEI | 19 | 4 wk | 5.42 pre −0.068 post ( P <.001) 100% (19/19) decreased 58% (11/19) asymptomatic | Symptom score (0–18) | Proximal 25.0 pre 4.5 post ( P <.0004) Distal 39.3 pre 3.8 post ( P <.0001) 21% (4/19) complete response | eos/hpf | 16% (3/19) asymptomatic esophageal candidiasis | 53% (10/19) abnormal esophageal pH studies |
A second open-labeled trial of topical steroid treatment in adult EoE was reported by Remedios and colleagues. They evaluated 26 patients with symptomatic EEI and treated 19 who were accessed after treatment for histologic response, as well as symptomatic response. Pretreatment esophageal pH testing was abnormal in 53% (10/19) of the patients. All patients, regardless of pH results, were treated with topical aerosolized fluticasone 500 μg twice a day, a minimally increased dose over that used by Arora and colleagues. The symptom score after treatment, as well as the histologic eosinophil levels in the proximal and distal esophagus, were markedly decreased with treatment.
In summary, both open-labeled trials showed a dramatic symptom and histologic response to aerosolized swallowed fluticasone. These studies involved patients with symptomatic EEI, and the therapeutic response was seen in those with and without gastroesophageal reflux disease (GERD) by pH testing.
Placebo-controlled trials
There are 2 published placebo-controlled trials of topical steroid therapy in the treatment of EoE ( Table 2 ). In the first trial, by Straumann and colleagues, aerosolized budesonide delivered by nebulizer was used at a dosage of 1 mg twice a day for 15 days in subjects with EoE. There was a significant symptomatic response of dysphagia and histologic response in the budesonide-treated patients over the placebo treatment group. Of note, there was no symptomatic or histologic response in the placebo group. Of great interest in this trial, there were significant decreases in a semiquantitative histologic fibrosis score, markers of inflammation, and apoptosis with only 2 weeks of treatment. In histologic responders, the endoscopic findings of white exudates and furrows resolved but rings did not. Asymptomatic esophageal candidiasis was seen in 22% of patients with budesonide therapy.
| Author | Tx | EEI/EoE | N | Duration | Symptoms | Placebo Response | Definition | Histologic | Placebo Response | Definition | Endoscopic | Placebo Response | Definition | Side Effects | Comments |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Tx Response | Tx Response | Tx Response | |||||||||||||
| Straumann et al, 2010 | Nebulized liquid suspension budesonide 1 mg twice a day | EoE | 18 Tx | 15 d | 5.6 to 2.2 ( P <.0001) | 5.3 to 4.7 (ns) | Dysphagia scale (0–9) | 72% (13/18) | 11% (2/18) ( P <.0001) | Complete <5 eos/hpf | White exudates 100% (10/10) to (0/10) ( P = .0001) Red furrows 89% (9/9) to (1/9) ( P = .0036) Rings 11% (9/9) to (8/9) (ns) | Resolution of finding when present in histologic complete responders | Asymptomatic esophageal candidiasis 22% (4/18) of Tx group 0% (0/18) of placebo All mild 3 grossly, 1 histologic only | No predictors of steroid response Decrease proinflammatory markers, tissue apoptosis, fibrosis score with Tx | |
| 18 Placebo | 72% (13/18) | 22% (4/18) ( P = .007) | Pre-Post decreased >2 pts | 17% (3/18) | 0% (0/18) ( P <.0001) | Partial 5–20 eos/hpf | |||||||||
| Alexander et al, 2012 | Fluticasone 440 μg twice a day | EEI | 19 Tx | 6 wk | Complete: ITT 43% (9/21) PP 47% (9/19) | ITT 29% (6/21) (ns) PP 40% (6/15) (ns) | Complete: No dysphagia in 2 wk by MDQ | Complete: ITT 62% (13/21) PP 68% (13/19) | ITT 0% (0/21) ( P <.001) PP 0% (0/15) ( P <.001) | Decrease by >90% | 27% (4/15) of those with complete histologic response, had 38% (3/8) endoscopic response No resolution of rings | 8% (1/12) (ns) | Resolution of all endoscopic findings | Asymptomatic esophageal candidiasis 26% (5/19) of Tx group vs 0% (0/15) of placebo (ns) | Staining for eosinophil derived neurotoxin similar to histology |
| 15 Placebo | Partial: ITT: 14% (3/21) PP: 16% (3/19) | ITT 2% (1/21) (ns) PP 7% (1/15) (ns) | Partial: decrease in frequency/severity by MDQ | Partial: ITT 81% (17/21) x% (4/21) PP 89% (17/19) x% (4/19) | ITT 5% (1/21) ( P <.001) PP 7% (1/15) ( P <.001) | Decrease by >50% |
The trial by Alexander and colleagues studied the commonly used swallowed, aerosolized fluticasone delivered by inhaler in patients with EEI. This is currently available in the United States, requires no preparation, and is commonly used in clinical practice. In this trial, subjects were treated for 6 weeks with swallowed aerosolized fluticasone 880 μg twice a day. This is a dosage nearly double that used in the previously described open-label trials. In this trial, there, similarly, was an impressive histologic response to treatment. However, contrary to the previous uncontrolled trials of topical budesonide and fluticasone and the controlled trial of budesonide, symptoms were not improved in this trial. The per-protocol complete symptom response was 47% in the treatment group and 40% in the placebo group. Although the cause of the lack of symptomatic benefit in the treatment groups as compared with the control group is not clearly apparent, it may be due to the high symptomatic response in the placebo group, which was not seen in the Straumann and colleagues’ trial. Alternatively, because symptomatic response to treatment has been seen other trials of topical steroid therapy in EoE, it may be that the 2-Week Mayo Dysphagia Questionnaire failed to adequately access the patients’ symptoms because the patients’ symptoms were too infrequent and/or too mild to be adequately accessed with this instrument. Resolution of all endoscopic findings was uncommon in this trial and, similar to the Straumann and colleagues’ trial, endoscopic rings generally persisted in patients with a complete histologic response. Asymptomatic esophageal candidiasis was seen in 26% of treated patients.
In summary, placebo-controlled trials of fluticasone and budesonide confirmed the uncontrolled trials showing a strong histologic response to topical steroid treatment. Of note, both trials showed essentially no histologic placebo response with treatment. The placebo-controlled trials differ in the symptomatic response to therapy. In the Straumann and colleagues’ trial there was a robust symptomatic response and there was no symptom response in the Alexander and colleagues’ trial, which did have a high placebo symptom response. In both trials, about one-quarter of treated patients developed asymptomatic esophageal candidiasis.
Comparative trials
Three trials compare esomeprazole and topical steroid in the treatment of EEI ( Table 3 ). In the Francis and colleagues’ trial, patients with GERD evidenced by an abnormal pH study were treated with esomeprazole 40 mg twice a day, whereas those without GERD were treated with oral viscous budesonide (OVB) 1 mg twice a day. The histologic response rates in both groups were similar, with a complete response rate of approximately 60% and at least a partial response rate of approximately 80%. This histologic response rate is consistent with other studies with OVB at that dosage. Of note, this study showed that EEI associated with GERD has a similarly high, but not complete, response rate to high-dose proton pump inhibitor (PPI) treatment. Symptom response in both groups was similar and modest.
| Author | Tx | EEI/EoE | N | Duration | Symptoms | Comparator Response | Definition | Histologic | Comparator Response | Definition | Endoscopic | Comparator Response | Definition | Side Effects | Comments |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Steroid Response | Steroid Response | Tx Response | |||||||||||||
| Peterson et al, 2010 | Fluticasone 440 μg twice a day | EEI | 12 | 8 wk | 50% (6/12) | 25% (3/12) (ns) | Dysphagia Scale (0–8) | 15% (2/13) | 33% (4/12) (ns) | Complete <6 eos/hpf | Not described | 56% of patients with abn pH studies | |||
| Omeprazole 40 mg qd | 12 | Decrease by >2 points | 31% (4/13) | 50% (6/12) (ns) | Partial <16 eos/hpf | ||||||||||
| Francis et al, 2012 | OVB 1 mg twice a day to those with nl pH studies | EEI | 28 | 6 wk | 54% (15/28) | 61% (11/18) | MDQ decrease by >1 level | 57% (16/28) | 61% (11/18) | Complete <5 eos/hpf | 15% (3/20) | 21% (3/14) | Resolution of all EoE findings | Not described | 29% of pH negative pts had erosive esophagitis on fu EGD 37% of pts with abnormal pH study |
| Omeprazole 40 mg twice a day to those with abn pH studies | 18 | 86% (24/28) | 83% (15/18) | Partial <15 eos/hpf | |||||||||||
| Dellon et al, 2012 | OVB 1 mg twice a day | EoE | 12 | 8 wk | 25 to 16 ( P = .04) | 34 to 10 (ns) ( P = .002) | MDQ score | 64% | 27% ( P = .09) | complete <1 eos/hpf | 91% | 45% ( P = .02) | Improved global assessment | 14% asymptomatic esophageal candidiasis No serum budesonide detected ACTH stim test in all post-tx normal | Mucosal contact time greater for OVB by scintigraphy ( P = .008) Rings resolved in 2/3 on OVB |
| Nebulized budesonide 1 mg twice a day | 13 | Baseline to post-tx | 73% | 45% ( P = .09) | partial <15 eos/hpf | ||||||||||
| Moawad et al, 2013 | Fluticasone 440 μg twice a day | EEI | 21 | 8 wk | 17 to 12 | 19 to 1 ( P <.001) | MDQ score | 19% | 33% (ns) | <7 eos/hpf | Partial improvement | Partial improvement (ns) | Stenosis, rings, furrows, plaques | 5% (1/21) asymptomatic esophageal candidiasis | pH abnormal in 19%. GERD patients stratified to both groups. In GERD patients response to omeprazole is better (100%, 4/4) than fluticasone (0%, 0/4, P = .029) |
| Omeprazole 40 mg qd | 21 | Baseline to post-tx |
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