Medical treatment of eosinophilic esophagitis

Abstract

Eosinophilic esophagitis (EoE) is a chronic inflammatory condition of the oesophagus first described in the 1970s.1 All ages can be affected; however, it is more common in males and adults. Estimates of incidence in Europe and the United States range from 1.3 to 12.8 cases per 100,000.2 Presenting symptoms vary widely between patients, including dysphagia, pain and food bolus impaction/obstruction.1-3 EoE often coexists with other atopic diseases, and evidence supports an underlying mechanism of type-2 inflammatory response to food antigens.1, 2 Diagnosis is made with a peak eosinophil count of ≥15 eosinophils/0.3 mm2 on oesophageal histology.1, 3 Recently, a group in France published on their automated, accurate and reproducible method to assess eosinophilic density and degree of degranulation, which poses time-saving advantages.4 Treatment of EoE is lifelong, aiming to prevent fibrostenosis and strictures.3 Elimination diets and corticosteroids have been used for many years, and biologics are now available for some patients. This Cochrane Corner will summarize the effectiveness and safety of medical interventions for people with EoE and put these in a useful, clinical context for the practising clinician. This is an abstract of a Cochrane review published in the Cochrane Database of Systematic Reviews 2021, Issue 3. (see www.cochranelibrary.com for information). Cochrane reviews are regularly updated as new evidence emerges and in response to feedback, and the Cochrane Library should be consulted for the most recent version of the review. Eosinophilic esophagitis is a chronic antigen-mediated eosinophilic inflammatory disease isolated to the oesophagus. As a clinicopathologic disorder, a diagnosis of EoE requires a constellation of clinical symptoms of oesophageal dysfunction and histologic findings (at least 15 eosinophils/high-powered microscope field [eos/hpf]). Current guidelines no longer require the failure of response to proton pump inhibitor medications to establish a diagnosis of EoE, but continue to suggest the exclusion of other etiologies of oesophageal eosinophilia. The treatment goals for EoE are improvement in clinical symptoms, resolution of oesophageal eosinophilia and other histologic abnormalities, endoscopic improvement, improved quality of life, improved oesophageal function, minimized adverse effects of treatment and prevention of disease progression and subsequent complications. Currently, there is no cure for EoE, making long-term treatment necessary. Standard treatment modalities include dietary modifications, oesophageal dilation and pharmacologic therapy. Effective pharmacologic therapies include corticosteroids, rapidly emerging biological therapies and proton pump inhibitor medications. To evaluate the efficacy and safety of medical interventions for people with eosinophilic esophagitis. We searched CENTRAL, MEDLINE, Embase, ClinicalTrials.gov and WHO ICTRP on 3 March 2023. Randomized controlled trials (RCTs) comparing any medical intervention or food elimination diet for the treatment of eosinophilic esophagitis, either alone or in combination, to any other intervention (including placebo). Pairs of review authors independently selected studies and conducted data extraction and risk of bias assessment. We expressed outcomes as a risk ratio (RR) and as the mean or standardized mean difference (MD/SMD) with 95% confidence interval (CI). We assessed the certainty of the evidence using GRADE. Our primary outcomes were as follows: clinical, histological and endoscopic improvement, and withdrawals due to adverse events. Secondary outcomes were: serious and total adverse events, and quality of life. We included 41 RCTs with 3253 participants. Eleven studies included paediatric patients while the rest recruited both children and adults. Four studies were in patients with inactive disease while the rest were in patients with active disease. We identified 19 intervention comparisons. In this abstract, we present the results of the primary outcomes for the two main comparisons: corticosteroids versus placebo and biologics versus placebo, based on the prespecified outcomes defined of the primary studies. Fourteen studies compared corticosteroids to placebo for induction of remission and the risk of bias for these studies was mostly low. Corticosteroids may lead to slightly better clinical improvement (20% higher), measured dichotomously (risk ratio (RR) 1.74, 95% CI 1.08 to 2.80; 6 studies, 583 participants; number needed to treat for an additional beneficial outcome (NNTB) = 4; low certainty), and may lead to slightly better clinical improvement, measured continuously (standard mean difference (SMD) 0.51, 95% CI 0.17 to 0.85; 5 studies, 475 participants; low certainty). Corticosteroids lead to a large histological improvement (63% higher), measured dichotomously (RR 11.94, 95% CI 6.56 to 21.75; 12 studies,978 participants; NNTB = 3; high certainty), and may lead to histological improvement, measured continuously (SMD 1.42, 95% CI 1.02 to1.82; 5 studies, 449 participants; low certainty). Corticosteroids may lead to little to no endoscopic improvement, measured dichotomously (RR 2.60, 95% CI 0.82 to 8.19; 5 studies, 596 participants; low certainty), and may lead to endoscopic improvement, measured continuously (SMD 1.33, 95% CI 0.59 to 2.08; 5 studies,596 participants; low certainty). Corticosteroids may lead to slightly fewer withdrawals due to adverse events (RR 0.64, 95% CI 0.43 to 0.96; 14 studies, 1032 participants; low certainty). Nine studies compared biologics with placebo for induction of remission. Biologics may result in little to no difference in clinical improvement, measured dichotomously (RR 1.14, 95% CI 0.85 to 1.52; 5 studies, 410 participants; low certainty), and may result in better clinical improvement, measured continuously (SMD 0.50, 95% CI 0.22 to 0.78; 7 studies, 387 participants; moderate certainty). Biologics result in better histological improvement (55% higher), measured dichotomously (RR 6.73, 95% CI 2.58 to 17.52; 8 studies, 925 participants; NNTB = 2; moderate certainty). We could not draw conclusions for this outcome when measured continuously (SMD 1.01, 95%CI 0.36 to 1.66; 6 studies, 370 participants; very low certainty). Biologics may result in little to no difference in endoscopic improvement, measured dichotomously (effect not estimable, low certainty).We cannot draw conclusions for this outcome when measured continuously (SMD 2.79, 95% CI 0.36 to 5.22; 1 study, 11 participants; very low certainty). There may be no difference in withdrawals due to adverse events (RR 1.55, 95% CI 0.88 to 2.74; 8 studies, 792 participants; low certainty). Corticosteroids (as compared to placebo) may lead to clinical symptom improvement when reported both as dichotomous and continuous outcomes, from the primary study definitions. Corticosteroids lead to a large increase in histological improvement (dichotomous outcome)and may increase histological improvement (continuous outcome) when compared to placebo. Corticosteroids may or may not increase endoscopic improvement (depending on whether the outcome is measured dichotomously or continuously). Withdrawals due to adverse events (dichotomous outcome) may occur less frequently when corticosteroids are compared to placebo. Biologics (as compared to placebo) may not lead to clinical symptom improvement when reported as a dichotomous outcome and may lead to an increase in clinical symptom improvement (as a continuous outcome), from the primary study definitions. Biologics lead to a large increase in histological improvement when reported as a dichotomous outcome, but this is uncertain when reported as a continuous outcome, as compared to placebo. Biologics may not increase endoscopic improvement (dichotomous outcome), but this is uncertain when measured as a continuous outcome. Withdrawals due to adverse events as a dichotomous outcome may occur as frequently when biologics are compared to placebo. This review comprised 41 RCTs involving 3253 participants with EoE. The primary interventions evaluated were corticosteroids versus placebo and biologics versus placebo; however, the review incorporated RCTs examining 19 intervention–comparisons of dietary modification or medication, including leukotriene receptor antagonists and transcutaneous patches. While children and adults were included, the authors felt the evidence had limited applicability to under 18 s.1 For induction of remission, the authors concluded that corticosteroids improve histologic outcomes, and biologic anti-IL13 and anti-IL4r therapies may improve clinical outcomes (Figure 1). With no head-to-head trials, factors such as cost, acceptability and the burden of treatment are important to consider. Budesonide respules (1 mg twice-daily) are estimated $2316/quarter, with fluticasone (440 mcg twice-daily) costing $691/quarter.5 Comparatively, a quarterly supply of dupilumab (300 mg weekly), the only biologic currently licensed for EoE (US and EU, not UK, for over 12 s weighing >40 kg) would cost around $15,600.6 A six-food elimination diet is estimated to cost around $710/quarter for a single male living alone, and patients need to visit multiple stores to purchase a nutritionally balanced grocery shop.7 Hidden expenses affect patients on elimination diets as they require more endoscopies than those on corticosteroids, costing more in missed working hours and hospital visits, depending on the healthcare system.1, 5 This economic discrepancy would likely play a crucial role in treatment planning, potentially limiting options for patients in insurance/self-pay healthcare systems. Despite many biologics appearing on the WHO essential medicines list, they are amongst the most expensive medicines in the world and remain difficult to access.8 Both primary interventions were found to be acceptable to patients, and patients on both were just as likely to experience adverse events as those on placebo.1 The most common side effect of topical corticosteroids is oral/oesophageal candidiasis3 and of dupilumab is injection site reactions or ocular surface disease (OSD). The latter is seen less with anti-IL13 tralokinumab.6, 9 Further head-to-head trials and cost-effectiveness analyses are necessary to fully evaluate and compare corticosteroids and biologics in the treatment of EoE. Both authors contributed equally to this manuscript. The authors thank Dr Robert Boyle for his guidance in preparing this article. No funders available. The authors have no conflicts of interest to declare. Data sharing not applicable to this article as no datasets were generated or analysed during the current study.

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