Editorial: the diminishing returns of normalisation of the oesophageal mucosa―Authors' reply

We have read with great interest the editorial by Dr. Genta—an attempt to reconcile the short turnover time of the oesophageal squamous epithelium with the results of our study, which showed that complete “normalisation” of oesophageal histology takes at least a few years. The results obtained in the LOTUS study demonstrated that progressive improvement of oesophageal histology occurs over the course of 5 years, and the same phenomenon is observed with regard to the degree of epithelial proliferation assessed by Ki67. Actually, the histological results obtained in the LOTUS study were unexpected and were a surprise to the authors. The histological evaluation of LOTUS has been centralised in a single laboratory, jointly performed by two experienced GI pathologists who have applied welldefined histological criteria that have been the subject of standardisation and validation. This approach was intended to minimise interobserver variability. In the interpretation of the results, it must be taken into account that the data on histological normalisation refer to the average of histological scores in both groups of patients (ie, those treated with long-term acid suppression or anti-reflux surgery). Many patients showed severe microscopic changes at enrolment, while the finding of severe lesions became progressively rarer during follow-up. It is also worth noting that: (1) the main reduction in lesion severity occurred in both groups after 1 year, while improvement at 3 and 5 years was less obvious; (2) before enrolment, pharmacologically treated patients underwent a short washout period (1 week), which can partly explain the number of patients with normal histology at baseline. A more accurate picture of the situation for individual patients can be deduced from Table 1. Although both groups of patients had no or mild lesions in more than 90% of cases at 5 years (ie, a finding not significantly different from that of a group of healthy controls), 9% of LARS patients and 6% of ESO patients, still showed severe histological lesions despite the absence of clinical failure. The hypothesis proposed in the editorial by Genta cannot be validated according to the data from our study, although it does sound reasonable. It is possible that, in the long-term, medical and surgical therapy have become progressively better at controlling the disease, resulting in episodes of mucosal damage becoming increasingly rare. The 3and 5year narrow “windows” corresponding to the time of biopsy may not have been likely to catch the moment of recurrent mucosal damage. However, the clinical impact does not change regardless of whether the histological improvement is gradual or the biopsies are less and less able to recognise occasional (increasingly rare) relapses of mucosal damage. In both cases, our findings support the concept that an effective healing process and its stabilisation do indeed take a long time. Finally, it should be emphasised that the aim of our study was mainly to understand the dynamics of the histological “normalisation” process and certainly not to propose follow-up biopsy as a tool for the management of patients with GERD.