It is time to plan clinical trials on true NERD patients

To the editors: We read with great interest the article by Weijenborg et al. showing that PPI therapy is equally effective in relieving heartburn in patients with both erosive esophagitis (ERD) and well-defined non-erosive reflux disease (NERD). These results are in contrast with the common belief, mainly sustained by a previous metaanalysis, that the response to PPIs is much lower in NERD than in ERD patients and confirm that the pathophysiological characterization of the various subgroups generally comprised under the umbrella term of NERD is fundamental to identify patients with true NERD, who can be expected to respond satisfactorily to powerful antisecretory therapy. At present, functional testing is the only method allowing us to differentiate well-defined NERD from functional heartburn, which does not pertain anymore to the realm of GERD. These patients complaining of heartburn do not present any esophageal mucosal lesion at endoscopy and do not have any acid reflux underlying their symptoms. Therefore, the lack of any pathogenetic role of acid makes it difficult that they can benefit from PPIs. However, there is an additional subgroup of NERD patients who are characterized by an esophagus hypersensitive to weakly acidic reflux which has been shown to induce the same typical symptoms of the acidic one. The identification of these patients has permitted to narrow down further the subgroup with functional heartburn, because their heartburn is strictly correlated with weakly acidic reflux. As the role of acid is greatly reduced also in them, the response to PPI therapy can be predicted to be unsatisfactory. The meta-analysis by Weijnborg et al. is welcome because the extraction from the medical literature of the two studies in which acid reflux was correctly documented by esophageal pH-metry allowed to avoid the usual contamination of true NERD population with the patients with functional heartburn who cannot respond to PPIs and eventually to understand that well-defined NERD patients are equally responsive to PPIs as ERD ones. It is time to plan clinical trials on NERD patients who are no more enrolled simply on the basis of negative endoscopy, but it is necessary to characterize this complex population from a pathophysiological point of view to assess the efficacy of PPI therapy only in patients whose symptoms are really sustained from acid reflux and to exclude the two subgroups of NERD with weakly acidic reflux generally unresponsive to PPIs and functional heartburn, who do not have reflux disease.