Evolution of Gastro-oesophageal Reflux Disease Over 5 Years Under Routine Medical Care

The ProGERD Study

P. Malfertheiner; M. Nocon; M. Vieth; M. Stolte; D. Jaspersen; H. R. Koelz; J. Labenz; A. Leodolter; T. Lind; K. Richter; S. N. Willich


Aliment Pharmacol Ther. 2012;35(1):154-164. 

In This Article


The findings of this study at 5 years confirm and extend our previous findings at 2 years[22] that, among the different grades of GERD, changes are observed in both directions, with NERD showing progressing to mild ERD (LA A/B) and with ERD (LA A/B) regressing/healing to NERD under routine care. The observed magnitude of progression from NERD to mild/moderate degrees of ERD is around 25%, but at the same time, the observed regression of ERD LA A/B to NERD is much higher at 63%. However, it is important to note that the 5-year result only gives a snapshot of what happens over 5 years. When results from years 2 and 5 are taken together (Table 2), progression from NERD to mild oesophagitis occurs in more than 40%. It may be that treatment was adjusted by the physician at 2 years in cases where oesophagitis was observed; therefore, fewer patients presented with oesophagitis at 5 years.

Whether a patient presents with NERD or ERD LA A/B most likely depends on the coincidental or recent consumption of acid suppressant medications. The presence of symptoms is not dependent on whether patients are found with erosive lesions at the time of endoscopy; some NERD patients experience symptoms while some with ERD do not, as we have reported previously from this study.[24] A similar experience was noted recently in a population-based GERD study, where a third of patients with mild/moderate oesophageal erosions did not experience symptoms, while a larger group of persons experienced reflux symptoms in the absence of erosions.[25] Data obtained from self-reporting by the patients indicated that 72% of the patients in our cohort took GERD medication in year 5 and 64% took PPI (i.e. 89% of those taking GERD medication). Similar data were reported earlier in the study.[26]

There is no comparable experience to date on a similar large and well-defined prospective study of GERD, with initial assessment and healing of lesions and symptoms. The experience from most small observational studies conducted by other investigators, however, is comparable to ours, i.e. the magnitude of progression is quite small,[17,27–32] apart from that observed in the study by Pace et al.[18] In that study, all but one patient had developed endoscopic signs of oesophagitis after 5 years, although without complication. In a five-year follow-up study from Japan, 36% of patients with reflux symptoms at entry developed erosive oesophagitis,[30] compared with about 25% in our study. This difference may well be related to different access to acid suppressant therapy in routine medical care, to differences in inclusion criteria or to chance.

Although overall changes from baseline were remarkably similar at 2 and 5 years in our study, it is clear that patients move across the groups in both directions. It also needs to be borne in mind that the patient group followed up for up to 5 years is reduced by about 30% compared with the two-year cohort, and by about 56% compared with baseline.

Probably, the clinically most important result of our study is that the observed progression of the disease does not appear to increase linearly and the risk of progression from NERD or LA grades A/B to LA grade C/D is quite small, although considerable progression was observed from NERD to LA grade A/B. Given that LA grade A/B was a significant prognostic factor for the development of Barrett's oesophagus, such progression of NERD patients cannot be ignored. However, Barrett's oesophagus in our population did not progress to high-grade dysplasia or cancer in any of the cases. The 6 cases of Barrett's oesophagus cancer, which were detected at the 2-year follow-up,[23] may indicate rather a missed diagnosis of malignancy at study entry rather than true progression, as there was no further incidence of malignancy between 2 and 5 years. This observation does not preclude the recognised risk for oesophageal adenocarcinoma development in Barrett's oesophagus patients[6,20,32] and so will not impact on our follow-up of patients with Barrett's oesophagus. However, our data are reassuring as to the progression of NERD and ERD to Barrett's oesophagus, as it occurs in less than 10% of cases during a 5-year follow-up. The progression to Barrett's oesophagus is lowest in patients with NERD, intermediate in LA A/B and highest in patients with LA C/D.

On the other hand, a significant number of patients within all categories of GERD with Barrett's oesophagus at baseline also reversed to normal under routine clinical care. A similar observation of Barrett's oesophagus regression has previously been reported in a study from Germany, in which only 70% of patients with Barrett's oesophagus diagnosis based on the classical 'confirmed' histological definition of specialised intestinal columnar metaplasia, maintained their Barrett's oesophagus diagnosis over time.[33]

There are several uncertainties concerning the correct assessment of progression or regression of Barrett's oesophagus and they include underestimation of Barrett's oesophagus at baseline because of persistent confounding inflammation.[34] However, an overestimation of short segment columnar epithelium during endoscopy as Barrett's oesophagus is more likely to occur. Since the Montreal definition[7] included the histological reporting of gastric type epithelium as well as intestinal in the definition of Barrett's oesophagus, even prominent irregular Z-lines may have been incorporated into this group.

The influence of inflammation as a confounder is much less likely to have interfered with our assessments, as all patients had been examined for ERD healing after a course of PPI therapy for 4–8 weeks. The issue of short segment Barrett's oesophagus with gastric metaplasia is critical, however, as the endoscopically assessed length of Barrett's oesophagus with gastric metaplasia comprised the majority of patients with newly developed BE.

The question of clinical relevance of this short segment Barrett's oesophagus with gastric metaplasia remains unanswered. We would stress in this context that all six cases of Barrett's oesophagus adenocarcinoma that were detected within the 2-year follow-up were Barrett's oesophagus with intestinal type metaplasia, but with metaplastic tissue of varying length. Thus, should only patients with intestinal type Barrett's oesophagus require regular follow-up? For the time being, the safest strategy is probably to follow patients with Barrett's oesophagus extending more than 1 cm, regardless of the type of metaplastic tissue, until more knowledge is available on the malignant potential of gastric type metaplasia in Barrett's oesophagus. The highest frequency of Barrett's oesophagus is found in patients with severe GERD at baseline, so it is to this group that we need to pay particular attention. In a large observational cohort in US, worsening of GERD over a mean follow-up period of 7 years progression occurred in only 11% and complications (i.e. stricture) in 2%.[29] The widespread use of adequate acid suppressant therapy is likely to be the main reason for the rather small subsets of patients with progression. On the other side, progression of patients to Barrett's oesophagus is observed more frequently alongside a need for regular PPI intake, probably because this is a more severe patient group. Also in a recent study, 40 patients followed up over a 20-year period had a higher use of acid suppressants concomitantly with progression to Barrett's oesophagus, and progression was also related to severity of GERD, which in itself would most probably increase PPI use.[35] Whether this points to an inadequate dosing of PPI remains speculative. When it comes to risk factors for Barrett's oesophagus development, as well as progression to more severe forms of ERD, these are male gender and alcohol, but seemingly not the presence of H. pylori at baseline. The implication of the 56% drop out of patients on the robustness of the patterns in the results and for the study conclusions is probably not of relevance, as the baseline characteristics of the group who dropped out were similar to those of the total study population.

In conclusion, the 5-year follow-up of patients with NERD and ERD revealed several important aspects:

(i) With regard to LA grading, there was movement in both directions across all grades of the disease. For NERD LA-A and B, a cycling between these categories was common, possibly influenced by the use or non-use of PPIs.

(ii) Under routine medical care, progression to severe forms of GERD is uncommon, indicating that current therapeutic management is usually adequate. Patients who remained unhealed after initial treatment were predisposed to GERD progression.

(iii) Patients with a more severe form of ERD (LA C/D) at initial endoscopy have the highest risk for progression to Barrett's oesophagus and they probably need more effective therapeutic management.

(iv) Less than 10% of patients with GERD are likely to progress to a diagnosis of Barrett's oesophagus at 5 years, a significant number with a histological diagnosis of gastric metaplasia. Although of uncertain clinical relevance, it is our belief that gastric metaplasia probably does not pose a significant risk to the patient for cancer development.