EoE treatment endpoints

Making the diagnosis of eosinophilic esophagitis (EoE), a clinicopathologic disease, requires the integration of patient symptoms, histology and clinical data. As gastroenterologists, we are obliged to do the same when monitoring for a therapeutic response. Although there are several axes on which EoE treatments may be assessed, no single measure has been shown to be sufficient. Therefore, considering the subjective experience together with objective data is ideal. I believe we should aim for both symptomatic improvement as well as obtain histologic and endoscopic measures confirming success, not just in the clinical trial setting, but in routine practice as well.

Current clinical guidelines do not provide explicit disease management endpoints for patients with EoE, acknowledging the limitations of existing data.1 As a result, relying solely on symptoms may be appealing. We know EoE and its sequalae can negatively impact quality of life. Likewise, the use of patient-reported outcomes (PROs) is increasingly encouraged by regulatory agencies and puts primacy on the patient experience. In addition, symptom evaluation is potentially less costly than endoscopic monitoring in a disease known to have high health care costs and produce a financial burden. So why not evaluate EoE similarly to gastroesophageal reflux disease (GERD), for which a response to treatment is sufficient to confirm a diagnosis and appropriate management?

Firstly, this approach would not always distinguish patients with EoE from those with GERD, which could have long-term implications for both groups. A proton pump inhibitor (PPI) trial is a necessary step in establishing a diagnosis and yet many patients with EoE get modest or even substantial benefit with such therapy despite some degree of ongoing inflammation. Also, of the numerous symptom questionnaires and quality of life tools that have been applied to EoE, many are impractical for routine clinical use.2 They may be too long, proprietary, or of limiting utility or availability. Finally, no single instrument is definitively reliable across both pediatric and adult populations. Pediatric patients may not be able to accurately describe their symptoms and could be at highest risk of long-term effects of ongoing disease activity. Meanwhile, it is well known that the diagnostic delay associated with EoE can result in accommodating behaviors  or diminishment of symptoms, potentially confounding adult responses.

In this context, it would be unwise to neglect objective measurements of disease. If we accept the premise that the natural history of untreated EoE is persistent, chronic inflammation leading to stricture formation,3 then why would we not engage in a strategy to ensure that we minimize both symptomatic and subclinical inflammation? In a condition partly defined by histologic changes, a reduction in esophagitis is a logical endpoint for management. Such a paradigm shift is occurring in inflammatory bowel disease and, while long-term risks may be different between these conditions, the same principles should apply to EoE.

Histologic remission in EoE is possible and demonstrable. Although endoscopy-associated  costs may be high, costs of complications like food impaction or perforation are no doubt higher. Being able to confirm a therapeutic response is powerful for patients and may encourage adherence to long-term maintenance therapy that could protect against later complications.


Until future superior measures are developed, or effective and accessible biomarkers are discovered, a combined and integrated assessment is most prudent.


Yet the criteria for response is potentially confusing. Tissue inflammation can be patchy and is not necessarily in line with symptom severity, especially since the absence of eosinophilia does not preclude the need for additional therapy like stricture dilation. Also, some studies assess absolute changes in eosinophil count whereas others utilize a percentage decrease as outcomes. There may be added value in incorporating additional factors such as basal zone hyperplasia, lamina propria fibrosis and degranulation, but the lack of uniform criteria risks leading to wide variability in how pathologists report findings. Without standardized descriptive language, relying on histology may seem impractical and more like trying to hit a moving target than a treatment outcome. And how do we reconcile that the histologic improvement achieved with medication does not always lead to significant symptomatic improvement?4

By performing a rigorous endoscopic assessment of disease, providers may find the last piece to the puzzle. Several systems to evaluate the mucosa in EoE have been devised, with many having both face and content validity. The EoE Endoscopic Reference Score (EREFS), in particular, has shown excellent operating characteristics.5 This standardized approach to assessing the mucosa accurately discriminates patients with EoE and typically correlates well with histologic improvement. It is feasible and sensible to obtain this additional information at the time of endoscopy. Unfortunately, there is diversity in the endoscopic appearance of EoE and some of its manifestations can be subtle. Consequently, strictures or other important findings can be missed, meaning an endoscopic assessment only augments one’s understanding of disease activity. But if we are going to obtain biopsies for surveillance anyway, we should maximize the amount of information we glean from any such procedure.

In summary, there is currently no single best outcome measurement for EoE but, instead, PROs, histological and endoscopic data all provide complementary value. They should be considered together when assessing response. Until future superior measures are developed, or effective and accessible biomarkers are discovered, a combined and integrated assessment is most prudent. Given that EoE primarily affects quality of life, to ignore symptoms would be unreasonable. But even as symptomatic improvement is necessary, it is clearly not sufficient to fully understand the state of disease activity. Therefore, equally considering subjective and objective outcomes is the most sensible way to provide care for patients with EoE.

Dr. Leiman has no conflicts to disclose. Dr. Leiman is a member of the AGA Quality Measures Committee.

References
1. C.A., Katzka, D.A. ACG clinical guideline: Evidenced based approach to the diagnosis and management of esophageal eosinophilia and eosinophilic esophagitis (EoE). Am J Gastroenterol. 2013;108:679-92.
2. Warners, M.J., Hindryckx, P., Levesque, B.G. et al, Systematic review: Disease activity indices in eosinophilic esophagitis. Am J Gastroenterol. 2017;112:1658-1669.
3. 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. Gastroenterology. 2013;145:1230-1236.e2.
4. Alexander, J.A., Jung, K.W., Arora, A.S. et al, Swallowed fluticasone improves histologic but not symptomatic response of adults with eosinophilic esophagitis. Clin Gastroenterol Hepatol. 2012;10:742-749.e1.
5. Dellon, E.S., Cotton, C.C., Gebhart, J.H. et al, Limited accuracy of the eosinophilic esophagitis endoscopic reference score in diagnosis and determining response to treatment. Clin Gastroenterol Hepatol. 2016;14:31-9.

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