Among the 11,493 subjects who were diagnosed with endoscopic SSBE between May 2006 and December 2015, 192 subjects with a history of esophagectomy or gastrectomy were excluded. Among the remaining 11,301 subjects, 7,637 subjects who underwent additional health checks by November 2018 were included in the analysis.
The baseline characteristics of the subjects with endoscopic SSBE are presented in Supplemental Table 1. At baseline, a total of 4,067 subjects (53.3%) were negative for H. pylori infection, 2,732 subjects (35.8%) were currently positive for H. pylori infection, and 819 subjects (10.7%) had a history of successful H. pylori eradication. A total of 3,176 subjects (41.6%) were negative for RE and positive for H. pylori infection, 3,020 subjects (39.5%) were negative for RE and H. pylori infection, 375 subjects (4.9%) were positive for RE and H. pylori infection, and 1,047 subjects (13.7%) were positive for RE and negative for H. pylori infection. The characteristics of the subjects categorized according to baseline RE and H. pylori infection status are presented in Table 1.
Table 1. Differences in various parameters by RE and H. pylori status pattern at baseline
|
|
RE(-)/H. pylori(+)
(n=3,176)
|
RE(-)/H. pylori(-)
(n=3,020)
|
RE(+)/H. pylori(+)
(n=375)
|
RE(+)/H. pylori(-)
(n=1,047)
|
Age (years) (mean (SD))
|
54.5 (9.6)
|
47.3 (10.0)
|
52.9 (8.7)
|
47.7 (9.4)
|
Sex, men (%)
|
2,618 (82.4)
|
2,351 (77.8)
|
353 (94.1)
|
936 (89.4)
|
Smoking (pack-years) (mean ± SD)
|
14.8 (17.3)
|
10.3 (14.9)
|
20.0 (18.9)
|
12.4 (15.0)
|
Alcohol consumption
|
|
|
|
|
|
Nondrinker (<40 g/week) (%)
|
1,185 (37.4)
|
1,210 (40.1)
|
110 (29.3)
|
391 (37.3)
|
|
Light-drinker (40-140 g/week) (%)
|
848 (26.7)
|
846 (28.0)
|
90 (24.0)
|
266 (25.4)
|
|
Moderate-drinker (140-280 g/week) (%)
|
615 (19.4)
|
558 (18.5)
|
83 (22.1)
|
217 (20.7)
|
|
Heavy-drinker (≥280 g/week) (%)
|
524 (16.5)
|
406 (13.4)
|
92 (24.5)
|
173 (16.5)
|
Hiatal hernia (% positive)
|
642 (20.2)
|
939 (31.1)
|
138 (36.8)
|
425 (40.6)
|
PPI or H2RA (% positive)
|
77 (2.4)
|
76 (2.5)
|
8 (2.1)
|
15 (1.4)
|
RE, reflux esophagitis; H. pylori, Helicobacter pylori; SD, standard deviation; PPI, proton pump inhibitor; H2RA, histamine H2-receptor antagonist
The median follow-up period was 4.0 years. During the follow-up period, 34 subjects showed progression to LSBE. The Kaplan–Meier curves show the probability of not progressing to LSBE, according to RE and H. pylori status at baseline (Figure 1). These curves suggested that the probability of progression to LSBE was lower in subjects without RE and with H. pylori infection than in the other groups. However, this analysis did not consider changes in RE or H. pylori status. In subsequent analyses, the covariates were time-dependently updated. Of the 7,637 subjects with endoscopic SSBE, none had low- or high-grade dysplasia during the study.
During the follow-up period, the rate of progression to LSBE was 1.0 per 1000 person-years. The progression rate for each time-varying RE and H. pylori status was as follows: 0.4 (non-RE and H. pylori infection), 0.9 (non-RE and non-H. pylori infection), 2.2 (RE and H. pylori infection), and 2.8 per 1000 person-years (RE and non-H. pylori infection) (Table 2).
Table 2. The rate of progression to LSBE for each time-varying RE and H. pylori status
Time-varying RE and H. pylori status
|
Person-years
|
Elongation of SSBE to LSBE
|
Rate
(per 1000 person-years)
|
RE(-) /H. pylori (+)
|
12,889
|
5
|
0.4
|
RE(-) /H. pylori (-)
|
13,571
|
12
|
0.9
|
RE(+) /H. pylori (+)
|
1,829
|
4
|
2.2
|
RE(+) /H. pylori (-)
|
4,710
|
13
|
2.8
|
SSBE, short-segment Barrett’s esophagus; LSBE, long-segment Barrett’s esophagus; RE, reflux esophagitis; H. pylori, Helicobacter pylori
Table 3 shows HRs of time-varying RE and H. pylori status for the progression to LSBE in the multivariable time-dependent Cox models. RE and non-H. pylori group and RE and H. pylori group were strongly associated with a higher rate of progression to LSBE (adjusted HR: 7.17, 95% CI: 2.48-20.73, p<0.001 for RE and non-H. pylori vs. non-RE and H. pylori group; adjusted HR: 4.57, 95% CI: 1.26-16.63, p=0.02 for RE and H. pylori vs. non-RE and H. pylori group). Non-RE and non-H. pylori infection groups were also associated with a higher rate of progression to LSBE but were imprecisely estimated due to limited event numbers (adjusted HR: 2.45, 95% CI: 0.86-7.00, p=0.09 for non-RE and non-H. pylori vs. non-RE and H. pylori groups). In the multivariable Cox models with fixed covariates, the HR of RE and non-H. pylori for the progression to LSBE was attenuated (adjusted HR: 5.59, 95% CI: 2.04-15.36, p<0.001 for RE and non-H. pylori vs. non-RE and H. pylori groups) (Supplemental Table 2). In addition, the HR of smoking for the progression to LSBE was lower in Cox models by baseline time-fixed covariate (adjusted HR (per 100 pack-years): 1.64, 95% CI: 0.29-9.11, p=0.57) than that in the time-dependent Cox model (adjusted HR (per 100 pack-years): 3.66, 95% CI: 1.09-12.29, p=0.04).
Table 3. Association between RE and H. pylori status pattern and the progression to LSBE adjusted by time-dependent covariate
|
HR*
|
95% CI
|
P-value
|
RE and H. pylori status pattern
|
|
|
|
RE(-) /H. pylori (+)
|
1.00
|
Reference
|
|
RE(-) /H. pylori (-)
|
2.45
|
0.86
|
7.00
|
0.09
|
|
RE(+) /H. pylori (+)
|
4.57
|
1.26
|
16.63
|
0.02
|
|
RE(+) /H. pylori (-)
|
7.17
|
2.48
|
20.73
|
<0.001
|
Male
|
1.18
|
0.41
|
3.45
|
0.76
|
Age (year)
|
1.05
|
1.01
|
1.09
|
0.01
|
Smoking (100 pack-year)
|
3.66
|
1.09
|
12.29
|
0.04
|
Hiatal hernia
|
3.13
|
1.49
|
6.58
|
0.003
|
PPI or H2RA
|
3.99
|
1.54
|
10.33
|
0.004
|
*Adjusted by time-dependent covariate (RE and H. pylori status pattern, age, smoking, and PPI or H2RA) and baseline time-fixed covariate (male and hiatal hernia).
RE, reflux esophagitis; H. pylori, Helicobacter pylori; LSBE, long-segment Barrett’s esophagus; HR, hazard ratio; CI, confidence interval; PPI, proton pump inhibitor; H2RA, histamine H2-receptor antagonist
Table 4 shows HRs of time-varying H. pylori status for the progression to LSBE in the multivariable time-dependent Cox models. Model 1 showed an adjusted HR of 0.48 (95% CI: 0.22-1.07, p=0.07 for H. pylori vs. non-H. pylori), which suggests a decrease in the rate of progression to LSBE by H. pylori infection. In model 2, the hazards of progression to LSBE were still lower than those of non-H. pylori group in the current H. pylori infection group (adjusted HR: 0.50, 95% CI: 0.19-1.34, p=0.17) and H. pylori eradication group (adjusted HR: 0.51, 95% CI: 0.18-1.46, p=0.21). In the multivariable Cox models with fixed covariates, HRs and their 95% CIs of H. pylori eradication for the progression to LSBE remained similar (Supplemental Table 3).
Table 4. Association between H. pylori status and the progression to LSBE adjusted by time-dependent covariate
|
|
Multivariable model 1
|
|
Multivariable model 2
|
|
HR*
|
95% CI
|
P-value
|
|
HR*
|
95% CI
|
P-value
|
H. pylori status
|
|
|
|
|
|
|
|
|
|
|
Absence of H. pylori
|
1.00
|
Reference
|
|
1.00
|
Reference
|
|
H. pylori infection (Model 1)
|
0.48
|
0.22
|
1.07
|
0.07
|
|
|
|
|
|
|
Current H. pylori infection (Model 2)
|
|
|
|
|
|
0.50
|
0.19
|
1.34
|
0.17
|
|
H. pylori eradication (Model 2)
|
|
|
|
|
|
0.51
|
0.18
|
1.46
|
0.21
|
Male
|
1.19
|
0.41
|
3.47
|
0.75
|
|
1.19
|
0.41
|
3.47
|
0.75
|
Age (year)
|
1.05
|
1.01
|
1.09
|
0.01
|
|
1.05
|
1.01
|
1.09
|
0.01
|
Reflux esophagitis
|
3.27
|
1.63
|
6.56
|
<0.001
|
|
3.27
|
1.63
|
6.55
|
<0.001
|
Smoking (100 pack-year)
|
3.67
|
1.10
|
12.26
|
0.03
|
|
3.67
|
1.10
|
12.29
|
0.03
|
Hiatal hernia
|
3.16
|
1.50
|
6.66
|
0.003
|
|
3.16
|
1.50
|
6.66
|
0.003
|
PPI or H2RA
|
4.00
|
1.54
|
10.36
|
0.004
|
|
4.00
|
1.54
|
10.35
|
0.004
|
*Adjusted by time-dependent covariate (H. pylori status, age, reflux esophagitis, smoking, and PPI or H2RA) and baseline time-fixed covariate (male
and hiatal hernia).
H. pylori, Helicobacter pylori; LSBE, long-segment Barrett’s esophagus; HR, hazard ratio; CI, confidence interval; PPI, proton pump inhibitor; H2RA, histamine H2-receptor antagonist