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Effectiveness and Safety of High- vs Low-Dose Swallowed Topical Steroids for Maintenance Treatment of Eosinophilic Esophagitis: A Multicenter Observational Study

Published:August 12, 2020DOI:https://doi.org/10.1016/j.cgh.2020.08.027

      Background & Aims

      Data evaluating efficacy of different doses of swallowed topical corticosteroids (STC) in the long-term management of eosinophilic esophagitis (EoE) are lacking. We assessed long-term effectiveness and safety of different STC doses for adults with EoE after achievement of histological remission.

      Methods

      We performed a retrospective multicenter study at five EoE referral centers (US and Switzerland). We analyzed data on 82 patients with EoE in histological remission and ongoing STC treatment with therapeutic adherence of ≥75% (58 males; mean age at diagnosis, 37.2±14.4 years). Patients were followed for a median of 2.2 years (interquartile range [IQR], 1.0-3.8 years). We collected data from 217 follow-up endoscopy visits. The primary endpoint was time to histological relapse.

      Results

      Histological relapse occurred in 67% of patients. Relapse rates were comparable in patients taking low dose (≤0.5 mg per day, n = 58) and high dose STC (>0.5 mg per day, n = 24) with 72 vs 54% (ns). However, histological relapse occurred significantly earlier with low dose STC (1.0 vs 1.8 years, P = .030). There was no difference regarding rates of and time to stricture formation for low vs high dose STC. Esophageal candidiasis was observed in 6% of patients (5% for low dose, 8% for high dose, ns). No dysplasia or mucosal atrophy was detected.

      Conclusion

      Histological relapse frequently occurs in EoE despite ongoing STC treatment regardless of STC doses. However, relapse develops later in patients on high dose STC without an increase in side-effects. Doses higher than 0.5 mg/day may be considered for EoE maintenance treatment, but advantage over lower doses appears to be small.

      Key words

      Abbreviations used in this paper:

      EoE (eosinophilic esophagitis), eos/hpf (eosinophils per high-power field), EREFS (Eosinophilic Esophagitis Endoscopic Reference Score), GERD (gastroesophageal reflux disease), IQR (interquartile range), PPI (proton pump inhibitor), STC (swallowed topical corticosteroid)

       Background

      Swallowed topical corticosteroids (STCs) are very efficacious in inducing clinical, endoscopic, and histological remission in patients with active eosinophilic esophagitis (EoE). In contrast to the plethora of available studies on short-term induction STC treatment, data on STCs’ efficacy in the long term are limited. There is no study fully published evaluating efficacy of different STC doses in the long-term management of EoE.

       Findings

      Histological relapses are frequently observed regardless of the specific STC dose with recurrent disease activity in 67%. Histological relapse occurs significantly earlier in patients under low-dose (≤0.5 mg/d) compared with high-dose (>0.5 mg/d) STCs, even in those with well-controlled disease activity at baseline (deep histological remission). Both low-dose and high-dose STC regimens are safe and well tolerated with an esophageal candidiasis incidence of 5.2% and 8.3%, respectively. Despite recurrent disease activity, ongoing STC treatment is able to maintain disease remission in 28 (low dose) and 46% (high dose), and to effectively prevent severe bolus impactions.

       Implications for patient care

      Long-term treatment with STC at a dose >0.5mg/d should be considered in adult EoE patients. Given high relapse rates regardless of the chosen regimen, regular follow-up (with endoscopies and esophageal biopsies) is recommended.
      Eosinophilic esophagitis (EoE) is a chronic inflammatory disorder of the esophagus that is defined clinically by symptoms of esophageal dysfunction (mainly dysphagia in adults) and histologically by an eosinophil-predominant infiltration of the esophageal squamous epithelium.
      • Liacouras C.A.
      • Furuta G.T.
      • Hirano I.
      • et al.
      Eosinophilic esophagitis: updated consensus recommendations for children and adults.
      Swallowed topical corticosteroids (STCs) are considered the mainstay in EoE treatment by many EoE specialists.
      • Furuta G.T.
      • Katzka D.A.
      Eosinophilic esophagitis.
      ,
      • Hirano I.
      • Chan E.S.
      • Rank M.A.
      • et al.
      AGA Institute and the Joint Task Force on Allergy-Immunology Practice Parameters Clinical Guidelines for the Management of Eosinophilic Esophagitis.
      STCs have proven efficacy in inducing clinical, endoscopic and histological remission in patients with active EoE.
      • Straumann A.
      • Conus S.
      • Degen L.
      • et al.
      Budesonide is effective in adolescent and adult patients with active eosinophilic esophagitis.
      • Miehlke S.
      • Hruz P.
      • Vieth M.
      • et al.
      A randomised, double-blind trial comparing budesonide formulations and dosages for short-term treatment of eosinophilic oesophagitis.
      • Dellon E.S.
      • Katzka D.A.
      • Collins M.H.
      • et al.
      Budesonide oral suspension improves symptomatic, endoscopic, and histologic parameters compared with placebo in patients with eosinophilic esophagitis.
      Fluticasone and budesonide appear to be equally and highly effective when given by an optimized delivery system.
      • Dellon E.S.
      • Woosley J.T.
      • Arrington A.
      • et al.
      Efficacy of budesonide vs fluticasone for initial treatment of eosinophilic esophagitis in a randomized controlled trial.
      ,
      • Dellon E.S.
      • Sheikh A.
      • Speck O.
      • et al.
      Viscous topical is more effective than nebulized steroid therapy for patients with eosinophilic esophagitis.
      In contrast to the plethora of available studies on short-term induction STC treatment, data on STCs’ efficacy in the long-term are limited. STCs show a benefit over placebo, but remission rates are considerably lower in the long- compared with the short-term.
      • Straumann A.
      • Conus S.
      • Degen L.
      • et al.
      Long-term budesonide maintenance treatment is partially effective for patients with eosinophilic esophagitis.
      • Greuter T.
      • Safroneeva E.
      • Bussmann C.
      • et al.
      Maintenance treatment of eosinophilic esophagitis with swallowed topical steroids alters disease course over a 5-year follow-up period in adult patients.
      • Kuchen T.
      • Straumann A.
      • Safroneeva E.
      • et al.
      Swallowed topical corticosteroids reduce the risk for long-lasting bolus impactions in eosinophilic esophagitis.
      Cessation of treatment and dose reduction have been associated with disease relapse.
      • Eluri S.
      • Runge T.M.
      • Hansen J.
      • et al.
      Diminishing effectiveness of long-term maintenance topical steroid therapy in PPI non-responsive eosinophilic esophagitis.
      ,
      • Dellon E.S.
      • Woosley J.T.
      • Arrington A.
      • et al.
      Rapid recurrence of eosinophilic esophagitis activity after successful treatment in the observation phase of a randomized, double-blind, double-dummy trial.
      Most long-term data are from the Swiss EoE cohort, in which patients were treated with 0.25-mg STCs twice daily, which is a safe, well-tolerated, and partly efficacious treatment regimen.
      • Greuter T.
      • Safroneeva E.
      • Bussmann C.
      • et al.
      Maintenance treatment of eosinophilic esophagitis with swallowed topical steroids alters disease course over a 5-year follow-up period in adult patients.
      This dose maintains complete or partial histological remission in only 50% of patients after 1 year.
      • Straumann A.
      • Conus S.
      • Degen L.
      • et al.
      Long-term budesonide maintenance treatment is partially effective for patients with eosinophilic esophagitis.
      Thus, 0.25-mg STCs twice daily may be overall inadequate and higher doses could result in higher success rates. Indeed, longer treatment and higher cumulative doses have been associated with fewer EoE complications and higher rates of remission in retrospective studies.
      • Greuter T.
      • Safroneeva E.
      • Bussmann C.
      • et al.
      Maintenance treatment of eosinophilic esophagitis with swallowed topical steroids alters disease course over a 5-year follow-up period in adult patients.
      ,
      • Kuchen T.
      • Straumann A.
      • Safroneeva E.
      • et al.
      Swallowed topical corticosteroids reduce the risk for long-lasting bolus impactions in eosinophilic esophagitis.
      As of yet, there is no study fully published that evaluated and compared efficacy and safety of different STC doses in the long-term management of EoE.
      With this multicenter study in adults with EoE, we compared the effectiveness of 2 STC maintenance doses with regard to their ability to maintain histological remission and prevent development of disease complications, examined whether we could observe a STC dose threshold to maintain remission, and compared the safety of 2 doses of maintenance treatment.

      Materials and Methods

       Study Design

      We performed a multicenter retrospective observational study comparing low-dose and high-dose STC long-term regimens in adult EoE patients who achieved histological disease remission and continued STC treatment. All patients provided written informed consent (general informed consent) prior to inclusion in the study. The study was approved by the local ethics committee of each of the participating centers.

       Subjects and Data Collection

      Patients were recruited at 5 EoE referral centers in the United States and Switzerland (Supplementary Methods). The following criteria were applied for patients to be included into the study: (1) diagnosis of EoE according to international guidelines
      • Liacouras C.A.
      • Furuta G.T.
      • Hirano I.
      • et al.
      Eosinophilic esophagitis: updated consensus recommendations for children and adults.
      ,
      • Lucendo A.J.
      • Molina-Infante J.
      • Arias Á.
      • et al.
      Guidelines on eosinophilic esophagitis: evidence-based statements and recommendations for diagnosis and management in children and adults.
      ; (2) achievement of histological remission defined as a peak eosinophil count of <15 eosinophils per high-power field (eos/hpf) on treatment with STCs (baseline remission visit)
      • Wolf W.A.
      • Cotton C.C.
      • Green D.J.
      • et al.
      Evaluation of histologic cutpoints for treatment response in eosinophilic esophagitis.
      • Reed C.C.
      • Wolf W.A.
      • Cotton C.C.
      • et al.
      Optimal histologic cutpoints for treatment response in patients with eosinophilic esophagitis: analysis of data from a prospective cohort study.
      • Dellon E.S.
      • Gupta S.K.
      A conceptual approach to understanding treatment response in eosinophilic esophagitis.
      ; (3) ongoing STC treatment after achievement of histological remission; (4) availability of at least 1 follow-up endoscopy visit with esophageal biopsies to evaluate maintenance of histological remission; and (5) detailed documentation of the treatment regimen. Patients were excluded from the study when the following conditions were satisfied: (1) EoE that previously responded to proton pump inhibitor (PPI) treatment; (2) treatment with investigational drugs; (3) treatment with systemic steroids or higher than standardly used STC doses ( ≥2500 μg/d) in the follow-up period
      • Sawas T.
      • Dhalla S.
      • Sayyar M.
      • Pasricha P.J.
      • Hernaez R.
      Systematic review with meta-analysis: pharmacological interventions for eosinophilic oesophagitis.
      ; (4) documented low adherence to STCs of <75% based on patient self-reporting; (5) treatment with dietary restrictions during the follow-up period; and 6) age <16 years at baseline remission visit. Presence of concomitant gastroesophageal reflux disease (GERD) was not an exclusion criterion. PPI cotreatment was allowed if EoE was not considered PPI responsive or if PPIs were used for GERD symptoms. For details on data collection, see the Supplementary Methods.

       Outcomes and Definitions

      Primary outcome of the study was time to histological relapse. Secondary outcomes were time to endoscopic bolus removal, time to stricture formation (new stricture and worsening stricture requiring endoscopic dilation), and development of local side effects of STCs, particularly esophageal candidiasis and mucosal atrophy (Supplementary Methods).
      • Greuter T.
      • Bussmann C.
      • Safroneeva E.
      • et al.
      Long-term treatment of eosinophilic esophagitis with swallowed topical corticosteroids: development and evaluation of a therapeutic concept.
      Endoscopic disease activity was graded using the EoE Endoscopic Reference Score (EREFS) grading and classification system as previously described.
      • Hirano I.
      • Moy N.
      • Heckman M.G.
      • Thomas C.S.
      • Gonsalves N.
      • Achem S.R.
      Endoscopic assessment of the oesophageal features of eosinophilic oesophagitis: validation of a novel classification and grading system.
      The following definitions were used: histological remission, <15 eos/hpf; deep histological remission, 0–1 eos/hpf; histological relapse, ≥15 eos/hpf.

       Steroid Maintenance Doses

      STC maintenance doses were classified into 2 groups according to the lowest prescribed dose during the follow-up: patients receiving doses of ≤0.5 mg/d (low-dose STCs) and patients being maintained on a dose of >0.5 mg/d (high-dose STCs).

       Statistical Analyses

      For statistical analyses, statistical package program STATA (version 16; StataCorp, College Station, TX) and GraphPad Prism (version 8.3.0; GraphPad Software, San Diego, CA) were used (Supplementary Methods).

      Results

       Patient and Disease Characteristics

      A total of 82 patients (58 men, 71%) were included in this study (Figure 1). Mean age at diagnosis was 37.2 ± 14.4 years, with a median of duration of symptoms of 7.3 (interquartile range [IQR], 3.0–17.8) years prior to diagnosis. Mean age at first visit with disease remission under STCs (baseline remission visit) was 38.2 ± 14.5 years. Patients were mostly of Caucasian descent (94%, 1 patient of Asian descent, 4 patients without data on ethnic background). Family history for EoE was reported in 14 (17%) patients, while 52 (63%) patients had atopic comorbidities. Twenty-three patients had concomitant GERD (28%). Fifty-one (62%) patients had no response to PPI, while 27 (33%) never received PPI treatment, and 3 (4%) reported improved GERD symptoms (acid regurgitation, heart burn) without EoE response (1 patient without information about PPI treatment). A total of 217 follow-up endoscopy visits with biopsies were available for analysis (median 2 [IQR, 1–3]) follow-up visits. Median follow-up time was 2.2 (IQR, 1.0–3.8) years, with a median average time between follow-up visits of 11.4 (IQR, 6.8–14.0) months. For details, see Table 1.
      Table 1Patient and Disease Characteristics (N = 82)
      Male58 (70.7)
      Age at EoE diagnosis, y37.2 ± 14.4
      Diagnostic delay, y7.3 (3.0–17.8, 0–47)
      Ethnic background
       Caucasian77 (93.9)
       Asian1 (1.2)
       Unknown4 (4.9)
      Positive family history for EoE14 (17.1)
      Previous PPI treatment
       PPI treatment without response51 (62.2),
       PPI treatment with GERD response3 (3.7)
       No PPI treatment27 (32.9)
       Missing data1 (1.2)
      Concomitant atopic diseases52 (63.4)
       Allergic rhinitis/rhinoconjunctivitis40 (48.8)
       Asthma20 (24.4)
       Oral allergy syndrome/food allergy22 (26.8)
       Atopic dermatitis9 (11.0)
      Concomitant gastroesophageal reflux disease23 (28.0)
      Baseline visit (histological remission)
       Age at baseline visit, y38.2 ± 14.5
       EREFS1 (0–2, 0–7)
       Peak eosinophil count, eos/hpf0 (0–3, 0–12)
       Deep histological remission54 (65.9)
       STC treatment dose at baseline remission visit, μg/d500 (500–2000, 220–6000)
       STC treatment at baseline remission visit
      Low dose54 (65.9)
      High dose28 (34.1)
       PPI cotreatment33 (40.2)
      Follow-up, y2.2 (1.0–3.8, 0.1–10)
      Follow-up visits2 (1–3, 1–10)
      STC treatment during follow-up
       Low dose58 (70.7)
       High dose24 (29.3)
      STC treatment dose, μg/d500 (500–880, 220–2250)
      Histological relapse55 (67.1)
      Stricture formation40 (48.8)
      Endoscopic bolus removal3 (3.6)
      Esophageal candidiasis infection5 (6.1)
      Mucosal atrophy or dysplasia0 (0)
      NOTE. Values are mean ± SD, median (interquartile range, range), or n (%).
      EoE, eosinophilic esophagitis; eos/hpf, eosinophils per high-power field; EREFS, Eosinophilic Esophagitis Endoscopic Reference Score; GERD, gastroesophageal reflux disease; PPI, proton pump inhibitor; STC, swallowed topical corticosteroid.
      Per inclusion criteria, all patients achieved histological remission under treatment with STCs (22 budesonide, 60 fluticasone). Most of the patients were treated with STCs twice daily at the time of remission (n = 76, 93%) with a median dose of 0.5 mg/d (IQR, 500–2000 ug, baseline remission visit) (see Table 1). Fifty-four (66%) patients received low-dose steroid treatment at baseline remission visit, while 28 (34%) patients were on high-dose STCs. Cotreatment with PPI was reported in 33 (40%) patients. Median peak eosinophil count was 0 (IQR, 0–3; range, 0–12) at the start of the maintenance period (baseline remission visit). Fifty-four (66%) patients were in deep histological remission. EREFS score at baseline was 1 (IQR, 0–2). Despite histological remission, 45 (55%) patients reported ongoing EoE-specific symptoms such as dysphagia and bolus impactions; 9 patients were symptomatic because of stricturing disease, and 11 patients underwent endoscopic dilation due to ongoing symptoms. The number of patients with ongoing clinical activity was not lower in patients with deep histological remission (59%; P = NS).
      After achievement of histological remission, 58 (71%) patients continued STC treatment with doses of 0.5 mg/d or lower (low-dose group), while 24 (29%) patients received STCs at doses higher than 0.5 mg/d (high-dose group). Dose groups varied by practice site: Swiss EoE Clinic and Mount Sinai 100% low dose, Northwestern University 67% low dose, Mayo Clinic 89% high dose, and University of North Carolina 68% high dose. For details, see Supplementary Table 1. The 2 STC dose groups were comparable for peak eosinophil counts, endoscopic activity, presence of strictures, and PPI cotreatment at baseline remission visit (Table 2). However, initial diagnostic delay was longer in the high-dose group (median 11.0 years vs 5.6 years; P = .003), and patients in the high-dose group more frequently reported a positive family history for EoE (33% vs 10%; P = .012). In addition, those in the high-dose group were less likely to be in deep histological remission at baseline (50% vs 72%), although this difference did not reach statistical significance (P = .051). While longer diagnostic delay might be a reason why patients received higher doses, lower numbers of deep remission rates were not, as only few patients were switched from a low-dose to a high-dose regimen at the time of remission (baseline remission visit) or vice versa. Median number of follow-up visit was similar and total follow-up time did not differ significantly between the 2 groups. Furthermore, time to first follow-up visit and average time between follow-up visits were not different between the 2 groups (Table 2).
      Table 2Low-Dose vs High-Dose Steroid Group Comparison
      Low dose (n = 58)High dose (n = 24)P value
      Patient demographics and disease characteristics
       Male41 (70.7)17 (70.8).990
       Age at EoE diagnosis, y36.8 ± 14.138 ± 15.3.723
       Diagnostic delay, y5.6 (2.0–14.7, 0–39)11.0 (7–20.5, 1.7–47.6).003
      Statistically significant.
       Positive family history for EoE6 (10.3)8 (33.3).012
      Statistically significant.
       Concomitant atopic diseases36 (62)16 (66.6).694
       Concomitant gastroesophageal reflux disease13 (22.4)10 (41.6).077
      Baseline visit (histological remission)
       Age at baseline visit, y38.0 ± 14.338.7 ± 15.2.853
       EREFS1 (0.25–2, 0–5)1 (0.5–2, 0–7).934
       Peak eosinophil count, eos/hpf0 (0–2.75, 0–12)1.5 (0–2.25, 0–10).140
       Deep histological remission42 (72.4)12 (50).051
       PPI cotreatment22 (37.9)11 (45.8).507
      Follow-up
       Follow-up, y2.3 (1.1–4.1, 0.1–10.0)1.4 (0.9–3.6, 0.1–5.6).220
       Number of follow-up visits2.0 (1.0–3.8, 1.0–10.0)2.0 (1.0–3.0, 1.0–9.0).326
       Time to first follow-up, mo6.0 (2.3–13.0, 1.0–24.0)8.0 (4.8–12.0, 1.0–28.0).683
       Average time between follow-up visits, mo12.1 (7.7–14.0, 1.0–51.0)8.2 (6.2–13.0, 1.0–28.0).311
       STC treatment, μg/d500 (227.5–500, 220–500)1000 (1000–1500, 750–2250).001
      Statistically significant.
       Histological relapse42 (72.4)13 (54.2).110
       Stricture formation25 (43.1)15 (62.5).110
       Endoscopic bolus removal3 (5.2)0 (0).256
       Esophageal candidiasis infection3 (5.2)2 (8.3).586
      NOTE. Values are n (%), mean ± SD, median (interquartile range, range).
      EoE, eosinophilic esophagitis; eos/hpf, eosinophils per high-power field; EREFS, Eosinophilic Esophagitis Endoscopic Reference Score; PPI, proton pump inhibitor; STC, swallowed topical corticosteroid.
      a Statistically significant.

       Histological Relapse Rates

      Histological relapse was detected in 55 (67%) patients. Median time to histological relapse was 1.1 year. Stratification by STC doses revealed histological relapse in 42 (72%) patients within the low-dose group compared with 13 (54%) patients within the high-dose group (P = NS). Degree of relapse was considerable with median peak eosinophil counts of 47.5 eos/hpf (IQR, 25.0–74.3) and concomitant endoscopic activity with median EREFS score of 3 (IQR, 1–4). Histological relapse occurred significantly earlier in patients treated with low-dose STCs (1.0 years vs 1.8 years; P = .030) (Figure 2A). Dose reduction was more often undertaken in the high-dose group (n = 21 of 24 vs n = 8 of 58; P < .001). Reduction of the STC dose that brought patients into histological remission did not per se result in a worse outcome suggesting that maintaining a dose above a certain cutoff (0.5 mg) is more important than the actual dose level (Supplementary Figure 1A). Of note, once daily dosing was associated with a longer time to histological relapse (Supplementary Figure 1A). Although once daily dosing was the preferred strategy in the high-dose group (n = 18 of 24 vs n = 11 of 58 in the low-dose group), subgroup analyses revealed that once daily dosing is indeed associated with a better outcome even in the low-dose group (Supplementary Figure 1c).
      Figure thumbnail gr2
      Figure 2Kaplan Meier curves for (A) time to histological relapse, (B) time to bolus removal, and (C) time to stricture formation in all patients stratified by steroid dose groups.

       Bolus Impaction and Stricture Formation

      Bolus impactions occurred infrequently during follow-up. Endoscopic removal was not needed in patients treated with a high dose of STCs and was carried out in 3 of the patients in the low-dose STC group (Figure 2B). Overall need for endoscopic bolus removal under STCs was significantly reduced compared with before treatment (4% vs 13%, P = .025). Rates of and time to stricture formation were not significantly different between the 2 groups (43% vs 63%; P = NS). Results of the Kaplan Meier analyses are shown in Figure 2C. Clinical activity in the follow-up was not systematically assessed at all of our centers. Based on physician’s global assessment, clinical activity was higher in patients on low-dose compared with high-dose steroids (85% vs 43%, P = .01).

       Patients in Deep Histological Remission at Baseline

      Of the 54 patients who achieved deep histological remission at baseline remission visit under STC treatment, 37 (69%) developed a histological relapse. This relapse rate was not different from patients without deep histological remission (64%; P = NS). Of those patients in deep histological remission, 42 (78%) patients continued with low dose STCs, while 12 (22%) patients received high-dose STCs. There was no significant difference between the 2 groups with regard to duration of follow-up. However, relapse occurred significantly earlier in patients treated with low-dose STCs (0.8 years vs 4.0 years; P = .012) (Figure 3A). Rates of and time to stricture formation were comparable in the 2 groups (Figure 3B).
      Figure thumbnail gr3
      Figure 3Kaplan Meier curves for (A) time to histological relapse and (B) time to stricture formation in patients with deep histological remission at baseline stratified by steroid dose groups.

       Side Effects

      Esophageal candida infections were rarely observed. In 5 patients, treated esophageal candidiasis was reported (6%). There were no differences when comparing patients with low-dose with patients under high-dose steroid treatment (n = 3 of 58, 5% vs n = 2 of 24, 8%; P = NS). No single case of mucosal atrophy or dysplasia was observed.

       Multivariable Cox Regression Models

      Given possible confounding effects, we computed multivariable Cox regression models for prediction of histological relapse adjusted for average time between follow-up visits (in months), peak eosinophil count at baseline remission visit (in eos/hpf), dilation before maintenance phase, sex, diagnostic delay (in years), and steroid type (fluticasone vs budesonide). In this multivariable model, high STC dose was identified as an independent predictor for longer time to histological relapse (hazard ratio, 0.35; 95% confidence interval, 0.12–0.99; P = .048). Specifically examining patients in deep remission at baseline, high STC dose remained significantly associated with longer maintenance of histological remission with an hazard ratio of 0.20 (95% confidence interval, 0.05–0.82; P = .026) for development of histological relapse (Table 3).
      Table 3Multivariable Cox Regression Model for Prediction of Histological Relapse
      Multivariable Cox Regression, all patients, n=82 (event: histological relapse)Hazard ratio (95% CI, p-value)
      High-dose steroids0.35 (0.12–0.99, .048)
      Time between follow-up visits (in months)0.86 (0.81–0.91, <.001)
      Peak eosinophil count at baseline remission visit (in eos/hpf)0.95 (0.86–1.05, .356)
      Dilation prior to maintenance treatment phase0.73 (0.37–1.44, .368)
      Female sex0.45 (0.23–0.87, .018)
      Diagnostic delay (in years)1.00 (0.97–1.03, .965)
      Steroid type (Fluticasone)0.60 (0.23–1.57, .300)
      MultivariableCox Regression, patients in deep histological remission at baseline, n=54 (event: histological relapse)Hazard ratio (95% CI, p-value)
      High dose steroids0.20 (0.05–0.82, .026)
      Time between follow-up visits (in months)0.88 (0.81–0.94, <.001)
      Dilation prior to maintenance treatment phase0.79 (0.34–1.84, .587)
      Female sex0.51 (0.24–1.09, .084)
      Diagnostic delay (in years)1.01 (0.97–1.05, .646)
      Steroid type (Fluticasone)0.90 (0.31–2.64, .855)
      Values are hazard ratio (95% confidence interval, P value).

      Discussion

      In this multicenter observational study, we comparatively analyzed effectiveness and safety of low-dose (≤0.5 mg/d) and high-dose (>0.5 mg/d) STC treatment regimens in maintaining histological remission at 5 EoE centers. Our main findings are that (1) histological relapses are frequently observed regardless of the specific STC dose with recurrent disease activity in 67%; (2) histological relapse occurs significantly earlier in patients under low-dose STCs, even in those with well-controlled disease activity at baseline (deep histological remission); (3) both low-dose and high-dose STC regimens are safe and well tolerated with an esophageal candidiasis incidence of 5% and 8%, respectively; and (4) despite histological relapse in more than 60% of patients, ongoing STC treatment is still able to maintain disease remission in 28 (low dose) and 46% (high dose) with a potentially superior effectiveness for once-daily dosing.
      Histological relapses are frequent regardless of the therapeutic regimen and specific STC doses. In our study, histological relapse was observed in 67% of all patients. This rate was comparable in patients treated with low-dose (72%) and high-dose (54%) STCs. These findings contrast the high remission rates with STC induction treatment, which have been reported at up to 93% after 6 weeks.
      • Lucendo A.J.
      • Miehlke S.
      • Schlag C.
      • et al.
      Efficacy of budesonide orodispersible tablets as induction therapy for eosinophilic esophagitis in a randomized placebo-controlled trial.
      In the long-term management of EoE, histological relapses are a considerable problem. Our data are similar to the few available steroid long-term studies in EoE. Straumann et al
      • Straumann A.
      • Conus S.
      • Degen L.
      • et al.
      Long-term budesonide maintenance treatment is partially effective for patients with eosinophilic esophagitis.
      reported 50% ongoing remission in adults after 50 week of 0.25 mg bid treatment. Andreae et al
      • Andreae D.A.
      • Hanna M.G.
      • Magid M.S.
      • et al.
      Swallowed fluticasone propionate is an effective long-term maintenance therapy for children with eosinophilic esophagitis.
      showed histological remission of 59% after 24 months in children. So, 40% and 50% of the studied patients experienced a histological relapse despite ongoing steroid treatment. Similar rates were found in a retrospective study on 229 patients, in which recurrent histological disease activity was seen at 55% of follow-up visits despite treatment,
      • Greuter T.
      • Safroneeva E.
      • Bussmann C.
      • et al.
      Maintenance treatment of eosinophilic esophagitis with swallowed topical steroids alters disease course over a 5-year follow-up period in adult patients.
      and another study on 33 patients with relapse rates of 61% after achievement of histological remission.
      • Eluri S.
      • Runge T.M.
      • Hansen J.
      • et al.
      Diminishing effectiveness of long-term maintenance topical steroid therapy in PPI non-responsive eosinophilic esophagitis.
      Our finding of frequent histological relapse is particularly noteworthy, as low adherence and treatment cessation during follow-up were exclusion criteria, so we can assume that these are true steroid failure rates. Based on these data and poor correlation of symptoms to histological activity,
      • Safroneeva E.
      • Straumann A.
      • Coslovsky M.
      • et al.
      Symptoms have modest accuracy in detecting endoscopic and histologic remission in adults with eosinophilic esophagitis.
      regular assessment of esophageal eosinophilia should be recommended. This is particularly true as ongoing disease activity potentially results in disease progression and stricture formation.
      • Schoepfer A.M.
      • Safroneeva E.
      • Bussmann C.
      • et al.
      Delay in diagnosis of eosinophilic esophagitis increases risk for stricture formation in a time-dependent manner.
      We currently do not know if all of these patients can be considered steroid refractory requiring changes of treatment modality (switch to dietary restrictions or step up to biological treatment) or if they can still benefit from reintroduction treatment.
      • Greuter T.
      • Straumann A.
      Medical algorithm: diagnosis and treatment of eosinophilic esophagitis in adults.
      Despite similar rates, histological relapse occurs significantly earlier in patients on low-dose STC compared with high-dose STC regimens. So far, no dose finding STC long-term trial has been published on EoE. It had been speculated that the dose of 0.25 mg twice daily, which had been best studied in EoE long-term management, is too low and not adequate to maintain remission. Here, we show that both low-dose and high-dose regimens result in histological relapse rates of more than 50%. Nonetheless, a higher dose can keep patients longer in disease remission. Intriguingly, this positive effect of higher doses was even observed in patients with deeply controlled histological disease activity (peak eosinophil count of 0–1 eos/hpf) at baseline remission visit. One might assume that these are the patients that could maintain remission on lower doses. However, based on our data, very low peak eosinophil counts at the time of histological remission is not an indication to use lower doses of STCs to maintain histologic remission. A negative effect of reduced steroid doses has first been suggested by Eluri et al,
      • Eluri S.
      • Runge T.M.
      • Hansen J.
      • et al.
      Diminishing effectiveness of long-term maintenance topical steroid therapy in PPI non-responsive eosinophilic esophagitis.
      where dose reduction was significantly associated with a worse outcome. We herein show that more important than keeping the dose steady, STC dose should be maintained above a certain level (0.5 mg) in adults with EoE. The recently finished but not yet fully published Maintenance of Remission With Budesonide Orodispersible Tablets vs Placebo in Eosinophilic Eosphagitis (EOS2 trial) (NCT02493335) comparing budesonide maintenance doses of 2 mg/d vs 1 mg/d suggest that there is no additional benefit of daily doses higher than 1 mg (1-year remission rates of 75.0% and 73.5%, respectively).
      • Lucendo A.
      • Miehlke S.
      • Vieth M.
      • et al.
      Budesonide orodispersible tablets are highly effective to maintain clinico-histological remission in adult patients with eosinophilic esophagitis: results from the 48-weeks, double-blind, placebo-controlled, pivotal Eos–2 trial.
      However, it should be kept in mind that most of the relapses appear to occur beyond a 1-year follow-up, which will not be captured by this 1-year trial. In addition, despite keeping patients longer in disease remission, higher STC doses were not more potent regarding prevention of stricture formation in our study. Furthermore, severe bolus impactions appear to be effectively prevented by both low- and high-dose STCs.
      There was no significant increase in side effects with high-dose steroids compared with low-dose STC regimens. Our rate of esophageal candidiasis (6%) is higher than those reported in the Swiss long-term studies,
      • Straumann A.
      • Conus S.
      • Degen L.
      • et al.
      Long-term budesonide maintenance treatment is partially effective for patients with eosinophilic esophagitis.
      ,
      • Greuter T.
      • Safroneeva E.
      • Bussmann C.
      • et al.
      Maintenance treatment of eosinophilic esophagitis with swallowed topical steroids alters disease course over a 5-year follow-up period in adult patients.
      but in accordance with the prospective study in children and the recently published EOS1 trial.
      • Lucendo A.J.
      • Miehlke S.
      • Schlag C.
      • et al.
      Efficacy of budesonide orodispersible tablets as induction therapy for eosinophilic esophagitis in a randomized placebo-controlled trial.
      ,
      • Andreae D.A.
      • Hanna M.G.
      • Magid M.S.
      • et al.
      Swallowed fluticasone propionate is an effective long-term maintenance therapy for children with eosinophilic esophagitis.
      In addition, there was no single case of mucosal atrophy. Based on these data, we conclude that STCs are safe and that the risk of esophageal candida infection is low, even with maintenance doses above 0.5 mg/d. Still, no statement can be made about doses of >2500 μg, as these patients were excluded from our analyses. In addition, as we did not systematically assess serum cortisol levels, we cannot rule out the possibility of subclinical adrenal insufficiency.
      Our study has several limitations. Clinical activity during follow-up was not systematically analyzed as retrospective assessment would have been inaccurate given different reporting at our 5 institutions. However, our cutoff of <15 eos/hpf to define histological remission has been shown to identify most patients with symptom improvement.
      • Reed C.C.
      • Wolf W.A.
      • Cotton C.C.
      • et al.
      Optimal histologic cutpoints for treatment response in patients with eosinophilic esophagitis: analysis of data from a prospective cohort study.
      At least the Physician’s Global Assessment shows a benefit of high- compared with low-dose steroids. An important limitation is the study sample size of 82. Although most of the patients at our centers are treated with topical steroids also in the long term, this number is relatively small due to the rigorous inclusion criteria applied to our retrospective analysis (histological remission at baseline, ongoing treatment, available follow-up, and high adherence without intermittent cessation of treatment). Particularly low adherence and cessation of treatment have previously been associated with inferior outcomes and high rates of disease relapse. Thus, inclusion of these patients would have led to a considerable bias. A further limitation is that our 2 steroid groups showed differences in terms of diagnostic delay, family history, and proportion of deep histological remission at baseline. Longer diagnostic delay and lower numbers of deep histological remission rates in the high-dose group may have diminished the effect size. With equal distribution of these characteristics, the positive effects of high doses might have been even higher. Another limitation is that we did not follow our patients after occurrence of disease relapse. So, no conclusions can be made about effectiveness of re-induction treatment or steroid dose increases in these cases. Finally, comparison between budesonide vs fluticasone and different formulations was not feasible as most of the patients in the high-dose group were on budesonide, while patients in the low-dose group more often received fluticasone. However, medication choice was not a significant factor in our multivariable analysis, and there is evidence to suggest that these STC compounds have similar efficacy at the same doses despite different potency (likely related to clinical delivery) based on a recently published trial by Dellon et al.
      • Dellon E.S.
      • Woosley J.T.
      • Arrington A.
      • et al.
      Efficacy of budesonide vs fluticasone for initial treatment of eosinophilic esophagitis in a randomized controlled trial.
      In conclusion, histological relapse frequently occurs in EoE despite ongoing STC treatment regardless of STC doses. However, relapse develops later in patients on high-dose STCs without an increase in side effects. Long-term treatment with doses higher than 0.5 mg/d may be considered for EoE maintenance treatment, but the advantage over lower doses appears to be small.

      Supplementary Methods

       Subjects and Data Collection

      Patients were recruited at five EoE referral centers in the United States (Mayo Clinic, Rochester, MN; University of North Carolina, Chapel Hill, NC; Northwestern University, Chicago, IL; Icahn School of Medicine at Mount Sinai, New York, NY) and Switzerland (Swiss EoE Clinic, Zurich, Switzerland). The following data were collected: demographic characteristics of patients; disease characteristics at diagnosis; time point of initial histological remission (baseline remission visit) including clinical, endoscopic, and histological characteristics at that time; type and dose of swallowed topical corticosteroid maintenance treatment; disease characteristics including clinical, endoscopic, and histological disease activity at each follow-up endoscopy visits; and details about complications in the follow- up (dilations, bolus impactions, strictures). All data were anonymized.

       Mucosal Atrophy

      Mucosal atrophy has been previously described as steroid-induced reduction of the thickness of the epithelial layer (which was assessed semi-quantitatively by the pathologist).
      • Greuter T.
      • Bussmann C.
      • Safroneeva E.
      • et al.
      Long-term treatment of eosinophilic esophagitis with swallowed topical corticosteroids: development and evaluation of a therapeutic concept.

       Statistical Analyses

      Figure thumbnail fx1
      Supplementary Figure 1Kaplan Meier curves for time to histological relapse stratified by (A) dose reduction strategy and application mode—(B) all doses and (C) low-dose STC.
      Supplementary Table 1Steroid Regimens in the Follow-Up Stratified by Low vs High Dose
      Low dose (n = 58)Fluticasone
      • -
        110 μg, twice daily (n = 10)
      • -
        125ug, twice daily (n = 1)
      • -
        220 μg, four times daily (n = 5)
      • -
        250 μg, twice daily (n = 36)
      • -
        440 μg, 4 times a day (n = 2)
      • -
        500 μg, 4 times a day (n = 1) Budesonide
      • -
        500 μg, 4 times a day (n = 3)
      High dose (n = 24)Fluticasone
      • -
        375 μg, twice daily (n = 1)
      • -
        440 μg, twice daily (n = 3)
      • -
        500 μg, twice daily (n = 1)
      • Budesonide
      • -
        750 μg, 4 times a day (1)
      • -
        100 μg, 4 times a day (n = 11)
      • -
        1500 μg, 4 times a day ( n = 5)
        1 patient with 3000 μg 4 times a day.
      • -
        2000 μg, 4 times a day ( n = 1)
      • -
        2250 μg, 4 times a day ( n = 1)
      a 1 patient with 3000 μg 4 times a day.

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