Efficacy of Proton Pump Inhibitor Therapy for Eosinophilic Oesophagitis in 630 Patients

Results From the EoE Connect Registry

Emilio J. Laserna-Mendieta; Sergio Casabona; Danila Guagnozzi; Edoardo Savarino; Antonia Perelló; Antonio Guardiola-Arévalo; Jesús Barrio; Isabel Pérez-Martínez; Anne Lund Krarup; Javier Alcedo; Susana de la Riva; Esther Rey-Iborra; Cecilio Santander; Ángel Arias; Alfredo J. Lucendo

Disclosures

Aliment Pharmacol Ther. 2020;52(5):798-807. 

In This Article

Discussion

PPIs are currently considered a first-line anti-inflammatory therapy for induction and maintenance of remission in patients with EoE of all ages, together with swallowed topic corticosteroids and dietary therapy.[1] In this study we have reported the largest series to date in assessing the effectiveness of PPI in EoE according to data obtained from real-world clinical practice.

Our results showed that PPI therapy for histological remission of EoE was accomplished in 48.8% of patients of all ages, while 71% report some improvement in symptoms, closely reproducing the results already provided by previous research, most of which have been summarised in a prior meta-analysis.[19] For the first time we can provide data on the combined efficacy of PPIs in achieving clinical and histological remission of EoE together, at 48.9%, allowing us to compare this with alternative drug or diet-based therapies for EoE.

Furthermore, our study provides new data, in that PPI treatment is more effective in achieving clinico-histological remission of the disease when used in higher instead of standard or lower doses (50.8% vs 35.8%), and when the duration of therapy is prolonged from 8 to 12 weeks (50.4% vs. 65.2%). Parallel results have been recently reported for diet[35] and swallowed topic corticosteroids,[11] for which increased effectiveness rates were demonstrated when treatment length was extended from 6 to 12 weeks. However, prolonging treatment duration for this period was associated with lower remission rates, most probably related to a reduced adherence to therapy.

Our results also document for the first time that PPI therapy was significantly less effective among patients with a stricturing phenotype or those who exhibited strictures or rings at endoscopy; these should be considered a priori for treatment with more effective anti-inflammatory alternatives, such as swallowed topic corticosteroids. The potential of swallowed topic corticosteroids to reverse the phenomena associated with fibrous remodelling of the oesophagus has begun to be revealed,[4,36,37] but we still do not have information on the ability of PPIs to reverse this process, which takes place mainly in the subepithelial layers and which is evaluated in a limited way by endoscopic biopsies. EoE represents a transmural disease,[38] in which eosinophils and mast cells that infiltrate the subepithelial layers of the oesophagus lead to fibrous remodelling with collagen deposition.[39] Omeprazole has been documented to block signal transducer and activator of transcription 6 from binding to the eotaxin-3 gene promoter in oesophageal epithelial cells, thereby preventing T helper-2 cytokines from stimulating eotaxin-3 expression,[17,40] this anti-inflammatory effect being entirely independent of its effects on gastric acid secretion. In contrast, omeprazole does not inhibit T helper-2 cytokine-stimulated eotaxin-3 expression by oesophageal fibroblasts,[18] suggesting that PPIs would have limited impact on subepithelial EoE processes such as fibrosis. Since we could not assess changes in endoscopic features over the period of PPI therapy due to the limited information on this matter, findings on the lack of effect of PPI on fibrous remodelling in EoE were not validated in our research.

We have also documented that the different PPI drugs did not show statistically significant differences in terms of their efficacy in inducing remission of EoE when used at equivalent doses, despite lansoprazole tending to be the least effective. However, these results are influenced by the fact that lansoprazole, which is available as an orally disintegrating tablet, was more frequently prescribed to patients with stricturing phenotype than to those with inflammatory or mixed phenotypes (27.1% vs 12.0%). Furthermore, esomeprazole was the only PPI drug used more frequently at double doses than at standard doses to maintain remission, due it was used at quadruple doses for induction of remission in the majority of patients receiving this drug.

So far, only three studies with a limited number of patients with EoE have evaluated the efficacy of PPIs in maintaining the remission initially induced with the same drugs, including two in adult patients[41,42] and one more in children.[43] Half the doses of PPI as those that induced remission were used in all studies, which uniformly documented that standard doses of PPIs maintained histological remission of EoE in 83%-70% of patients, close to the 69.2% rate we documented. Stricturing phenotype patients again presented less likelihood in maintaining remission after PPI dose reduction.

The strengths of our study include the use of a large, multicentre series of patients with EoE, prospectively recruited from multiple sites in three different countries. The active monitoring of data ensured reliability of the registered information. Our results reflect actual clinical practice and provide more representative data than those derived from protocolised studies. At the same time, this fact also represents the greatest limitation of our study, because patients were not managed under pre-defined dose or treatment schedules, but according to the variable criteria followed by the different contributors. The design of our study prevents comparing the effectiveness of PPIs with other treatment modalities, and therefore does not allow positioning this treatment over other alternatives, such as topical swallowed corticosteroids or elimination diets.[44] However, we provide here a strong hint that IBPs are effective in managing EoE. Future randomised studies should better define the comparative effectiveness of the different therapies for EoE. Only a minority of patients (~10%) were under 18 years old, and despite them showing no differences with adults for the major outcomes, the external validity of our results for paediatric populations are limited. As the majority of the recruiters were gastroenterologists attending adult patients, we could not compare potential differences in patient management with regard to paediatricians, allergists and providers of other specialties. In addition, our study focused exclusively on the effectiveness of PPI used as single therapy for EoE, so the potential benefit of associating this drug with swallowed topic corticosteroids, diets or even endoscopic dilation was not assessed. Finally, the reduced number of patients with assessment of effectiveness of PPI as maintenance therapy compared to those we evaluated for induction for remission might have limited subgroup comparisons, thus preventing us from finding determinants for effectiveness with statistical significance.

In conclusion, we provide evidence that high PPI doses are an effective anti-inflammatory therapy that achieves histological and clinical remission in half of the patients with EoE, with around 70% of responding patients being able to maintain long term remission after dose reduction. All PPI drugs were similarly effective, with high doses used for 10–12 weeks providing the highest benefit for induction of remission. Patients with stricturing EoE were less likely to respond to PPI therapy initially and in the long term, so they should be considered candidates for alternative anti-inflammatory options.

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