European Journal of Internal Medicine 31 (2016) 73–78

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European Journal of Internal Medicine

journal homepage: www.elsevier.com/locate/ejim

Original Article

Increased risk of concurrent gastroesophageal reflux disease among

patients with Sjögren's syndrome: A nationwide population-based study
Chen-Shu Chang a,b,1, Chun-Hui Liao c,d,1, Chih-Hsin Muo e,f, Chia-Huang Kao d,g,⁎
a
Department of Neurology, Changhua Christian Hospital, Changhua, Taiwan
b
Department of Medical Laboratory Science and Biotechnology, and Medical Imaging and Radiological Sciences, Central Taiwan University of Science and Technology, Taichung, Taiwan
c
Department of Psychiatry, China Medical University Hospital, Taichung, Taiwan
d
Graduate Institute of Clinical Medicine Science and School of Medicine, College of Medicine, China Medical University, Taichung, Taiwan
e
Management Office for Health Data, China Medical University, Taichung, Taiwan
f
School of Medicine, China Medical University, Taichung, Taiwan
g
Department of Nuclear Medicine and PET Center, China Medical University Hospital, Taichung, Taiwan

a r t i c l e i n f o a b s t r a c t

Article history: Background: Little data is available on the risk of gastroesophageal reflux disease in patients diagnosed with
Received 7 October 2015 Sjögren's syndrome.
Received in revised form 7 January 2016 Methods: We identified 4650 Sjögren's syndrome patients between 2000 and 2011 from the National Health In-
Accepted 18 January 2016 surance Research Database. Each Sjögren's syndrome patient was matched to 4 controls based on age, sex, and
Available online 4 February 2016
index year, and all subjects were followed up from the index date to December 31, 2011. Cox proportional
hazards regression model was used to estimate the risk of gastroesophageal reflux disease.
Keywords:
Sjögren's syndrome
Results: The risk of gastroesophageal reflux disease for Sjögren's syndrome patients was 2.41-fold greater than
Gastroesophageal reflux disease that for the comparison cohort after adjusting for age, sex, and comorbidities. In age stratified analyses, the youn-
Autoimmune gest Sjögren's syndrome cohort (age: 20–44 years old) had the highest risk (HR = 3.02; 95% CI = 2.48–3.69) and
the lowest risk at age ≥65 years (HR = 1.95; 95% CI = 1.61–2.36). Regardless of in subjects with and without co-
morbidity, Sjögren's syndrome patients had a higher risk than the controls. Sjögren's syndrome subjects with is-
chemic heart disease, hyperlipidemia and renal disease had the highest risk for gastroesophageal reflux disease
compared with the comparison cohort without those diseases (HR = 7.67; 95% CI = 5.32–11.1).
Conclusion: Patients with Sjögren's syndrome have a significantly greater risk of developing subsequent gastro-
esophageal reflux disease than the general population.
© 2016 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.

1. Introduction digestive system's homeostasis [5,6] Esophageal acidification activates

Sjögren's syndrome is a systemic disease characterized by chronic
autoimmune reaction with lymphocytic infiltration of exocrine glands —
the salivary and lachrymal glands [1,2]. It can lead to destruction of
glandular mucosal surface, presenting with dry eyes (xerophthalmia)
and dry mouth (xerostomia) or dysphagia in Sjögren's syndrome [3,4].
Saliva plays an essential role in transferring pharyngo-esophageal food
bolus and neutralizing the gastroesophageal refluxed acid for the
Abbreviations: ICD-9-CM, International Classification of Diseases, Ninth Revision,
Clinical Modification; HR, hazard ratio; CI, confidence interval; NHIRD, National Health
Insurance Research Database; LHID-CIP, longitudinal health insurance database for
catastrophic illness patients; NHI, National Health Insurance; LHID, the longitudinal
health insurance database; TBNHI, Taiwan Bureau of National Health Insurance; IRB,
Institutional Review Board.
⁎ Corresponding author at: No. 2, Yuh-Der Road, Taichung 404, Taiwan. Tel: +886 4
22052121x7412; fax: +886 4 22336174.
E-mail address: d10040@mail.cmuh.org.tw (C.-H. Kao).
1
Chen-Shu Chang and Chun-Hui Liao contributed equally.
the esophageal chemoreceptors which apparently stimulate the
salivary glands and mediate through the neural reflex arc, namely
the esophageal–salivary reflex [7] Previous studies demonstrated that
decreased saliva production interfere with the esophageal–salivary re-
flex effectiveness and could contribute to the occurrence of oral, esoph-
ageal and dyspeptic diseases [7].
Some authors hypothesized that autoantibodies mediate dysfunc-
tion of the gastrointestinal tract in Sjögren's syndrome, including esoph-
ageal hypomotility and delayed gastric emptying [] While the exact
correlation is undetermined, many patients with Sjögren's suffer from
gastroesophageal reflux disease.
The pathogenesis of gastroesophageal reflux disease is multifactorial
and includes: 1) motor abnormalities, such as impaired lower esopha-
geal sphincter resting tone and delayed gastric emptying; 2) anatomical
factors, such as hiatal hernia; 3) impaired mucosal resistance; and 4)
visceral hypersensitivity [9].
The typical provoking symptoms from gastroesophageal reflux
disease may include difficulty swallowing, persistent heartburn and/or

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74 C.-S. Chang et al. / European Journal of Internal Medicine 31 (2016) 73–78
regurgitation of acid, with extra-esophageal complications including
cough, laryngitis, asthma and dental erosion [10]. Moreover, gastro-
esophageal reflux disease often accompanies many chronic diseases
with high prevalence, such as diabetic mellitus, chronic liver disease,
and chronic autoimmune conditions, such as systemic sclerosis and
rheumatoid arthritis [11,12]. Some gastrointestinal adverse complica-
tions of the treatment for rheumatic diseases, induced by corticoste-
roids, non-steroidal anti-inflammatory drugs and disease-modifying
anti-rheumatic drugs, have been recognized and reported [13–15].
However, those previous reports always focused predominantly on
gastric ulcer [16], and the association between gastroesophageal reflux
disease and Sjögren's syndrome has been controversial and has not
been well considered in Sjögren's syndrome patients.
The National Health Insurance Research Data-base (NHIRD) in
Taiwan, one of the largest health insurance databases in the world,
includes all claims from ambulatory care and inpatient care and has
been a valuable data resource for many epidemiologic studies [17,18].
In the present study, we conducted a population-based retrospective
cohort analysis to investigate the association between Sjögren's
syndrome and gastroesophageal reflux disease, using data from the
NHIRD Program in Taiwan (2000–2011).
2. Method
2.1. Data source
We used National Health Insurance Research Database (NHIRD):
one million insurants and a longitudinal health insurance database for
catastrophic illness patients (LHID-CIP) in this retrospective cohort
study. NHIRD was derived from a single-payer National Health Insur-
ance Program by Taiwan Bureau of National Health Insurance (TBNHI)
and maintained by the National Health Research Institutes. The National
Health Insurance (NHI) program has a cover rate of over 99% of the pop-
ulation in Taiwan (http://www.nhi.gov.tw). NHIRD included all medical
records of each beneficiary from the start of 1996 to the end of 2011. The
longitudinal health insurance database (LHID) contained one million
insurants randomly selected from the year 2000 Registry for Beneficia-
ries in National Health Insurance Research Database. There were no
significant differences of distribution for age and gender between
LHID and NHIRD. All NHIRD databases were linked to each other
based on identification of insurant. Up to now there were 30 diseases
defined as catastrophic illness based on TBNHI guidelines, including
malignancy, autoimmunity disease, and so on. Patients with catastroph-
ic illness certificate were exempt from the medical copayment for the
illness or related conditions. Sjögren's syndrome patients applied for
Catastrophic Illness Card according to the findings of hematology report
and pathologic report, and the application would be formally reviewed
by a specialist. Therefore, the validation of the diagnosis of Sjögren's
syndrome in our data-base study could be less questionable. Diseases
were defined in NHIRD based on the International Classification of Dis-
eases, Ninth Revision, Clinical Modification (ICD-9-CM). The identifica-
tion of beneficiaries was re-coded by computer before being released
to the researchers. This study was approved to fulfill the condition for
exemption by the Institutional Review Board (IRB) of China Medical
University (CMUH104-REC2-115). The IRB also specifically waived the
consent requirement.
2.2. Study subject
We collected 4991 patients with Sjögren's syndrome patients (ICD-9
code: 710.2) in 2000–2005 from the longitudinal health insurance data-
base for catastrophic illness patients. The date for Sjögren's syndrome
diagnosis was defined as index date. Patients with age younger than
20 years, autoimmunity disease history [including multiple sclerosis
(ICD-9-CM 340), systemic lupus erythematosus (ICD-9-CM 710.0), sys-
temic sclerosis (ICD-9-CM 710.1), dermatomyositis (ICD-9-CM 710.3),
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polymyositis (ICD-9-CM 710.4), and rheumatoid arthritis (ICD-9-CM
714.0)] or gastroesophageal reflux disease (ICD-9-CM 530.11 and
530.81) history were excluded. Controls were selected from people
without Sjögren's syndrome, gastroesophageal reflux disease and auto-
immunity disease history in the longitudinal health insurance database.
The index date was randomly assigned as Sjögren's syndrome cohort.
The index date was the date for Sjögren's syndrome diagnosis in case co-
hort. The comparison cohort included non-Sjögren's syndrome patients
and they were not with the index date. Before matching, we randomly
assigned the index date to each control. Then we selected our control
group based on age, gender and index-year by frequency matching.
Controls were frequency matched with age stratum (every 5 years,
for example: 20–24, 25–29, 30–34 and so on.), gender and index-year
at an approximately 4:1 rate. All study subjects were followed from
the index date until the date of gastroesophageal reflux disease or with-
drawal from the program or the end of 2011 whichever came first. Since
the Taiwan Bureau of National Health Insurance allowed patients being
prescribed with proton pump inhibitor treatment after the diagnosis of
gastroesophageal reflux disease by either endoscopy or 24-hour pH-
meter inspection, we validate our diagnosis of gastroesophageal reflux
disease by the prescription of proton pump inhibitor. After all, this
was a cumulative 12 year follow-up retrospective cohort study.
2.3. Comorbidity
The comorbidities were considered in this study included hyperten-
sion (ICD-9-CM 401–405), hyperlipidemia (ICD-9-CM 272), diabetes
(ICD-9-CM 250), ischemic heart disease (ICD-9-CM 410–414), and
renal disease (ICD-9-CM 580–589). All comorbidities were identified
before the index date.
2.4. Statistical analysis
The differences of demographic characteristics and comorbidity
between Sjögren's syndrome cohort and comparison cohort used chi-
square and Student t-test for categorical and continuous variables.
Incidences for gastroesophageal reflux disease were counted in both
cohorts. Hazard ratio and 95% confidence interval for gastroesophageal
reflux disease used Cox proportional hazard regression. Multivariable
model controlled for age, gender, ischemic heart disease, hyperlipid-
emia and renal disease. The age-, gender- or comorbidity-specific risks
for gastroesophageal reflux disease in Sjögren's syndrome cohort com-
pared with comparison cohort were estimated. We used a test of scaled
Schoenfeld residuals to test the proportional hazard assumption. The
test result presented a significant relationship between Schoenfeld re-
siduals for gastroesophageal reflux disease and follow-up time (p =
0.0006). This suggested that the assumption was violated and we did
the follow-up duration stratified analyses. We also assessed the joint ef-
fect for gastroesophageal reflux disease between Sjögren's syndrome, is-
chemic heart disease, hyperlipidemia and renal disease after controlling
for age and gender. Cumulative incidence for gastroesophageal reflux
disease in both cohorts was plotted using Kaplan–Meier analysis and
the difference was tested using log-rank test. All analyses were
performed using the SAS software version 9.3 (SAS Institute, Cary, NC),
and the statistical significance level was set at p b 0.05 by two-sided test.
3. Result
We all selected 4560 Sjögren's syndrome patients and 18,240 age-
and gender-matched controls in this study. The mean age for Sjögren's
syndrome patients was 53.9 years old (standard deviation = 14.1),
and there were patients at ages 46–64 (49.2%) and women were in
the major proportion (86.5% vs. 13.5%). Compared with the controls,
Sjögren's syndrome patients had more comorbidities including ische-
mic heart disease (22.0% vs. 15.8%), hyperlipidemia (23.9% vs. 20.2%)
and renal disease (11.8% vs. 6.63) (Table 1).
 C.-S. Chang et al. / European Journal of Internal Medicine 31 (2016) 73–78 75

Table 1
Demographics between study subjects with and without Sjögren's syndrome.

SS (N = 4560) Comparison
(N = 18,240)

n % n % p-Value

Age, years 0.99

20–44 1238 27.2 4952 27.2
45–64 2244 49.2 8976 49.2
≥65 1078 23.6 4312 23.6
Mean (SD)† 53.9 (14.1) 53.8 (14.2) 0.72
Sex 0.99
Female 3946 86.5 15,784 86.5
Male 614 13.5 2456 13.5
Comorbidity
IHD 1003 22.0 2888 15.8 b0.0001
Hypertension 1506 33.0 5961 32.7 0.66
Hyperlipidemia 1088 23.9 3676 20.2 b0.0001
Diabetes 573 12.6 2141 11.7 0.12
RD 539 11.8 1209 6.63 b0.0001

Chi-square test and †t-test SS, Sjögren's syndrome; IHD, ischemic heart disease; RD, renal
disease; SD, standard deviation.

During a mean of 7.76 follow-up years, there were 715 and 1181
subjects who developed gastroesophageal reflux disease corresponding
to 20.89 and 8.28 per 1000 person-years in Sjögren's syndrome and
comparison cohort, respectively (Table 2). After 12 year follow-up, cu-
mulative incidence for gastroesophageal reflux disease in Sjögren's syn-
drome cohort was approximately 15% higher than comparison cohort
(log-rank test p b 0.0001, Fig. 1). Compared with the comparison cohort,
Sjögren's syndrome patients had 2.55- and 2.41-fold risk in crude and
adjusted model (95% CI = 2.32–2.80 and 2.19–2.64, respectively). The
incidences for gastroesophageal reflux disease increased with aging
from 7.95 to 13.30 per 1000 person-years. Compared with subjects at
20–44 years-old, subjects at N 45 years-old had a higher risk. Men had
higher incidence and 1.29-fold risk than women (14.44 vs. 10.21 per
1000 person-years). Patients with ischemic heart disease, hyperlipid-
emia or renal disease had a 1.55-, 1.39- and 1.41-fold risk (95% CI =
1.38–1.74, 1.25–1.55 and 1.22–1.62, respectively).
Stratified analyses for gastroesophageal reflux disease in Sjögren's
syndrome cohort compared with the comparison cohort are presented
in Table 3. In age-specific analysis, the youngest Sjögren's syndrome
Fig. 1. Cumulative incidence for gastroesophageal reflux disease between SS patients and
comparison cohort. SS, Sjögren's syndrome.
patients (age: 20–44 years-old) had the highest risk compared with
controls at the same age (HR = 3.02; 95% CI = 2.48–3.69) and the low-
est risk at age ≥65 years (HR = 1.95; 95% CI = 1.61–2.36). The risk for
gastroesophageal reflux disease decreased with aging (interact
p b 0.05). The risks for female and male Sjögren's syndrome patients
were similar, about 2.20-fold risk, compared with female and male con-
trols, respectively. Sjögren's syndrome patients without comorbidity
(including ischemic heart disease, hypertension, hyperlipidemia, diabe-
tes and renal disease) had a 2.87-fold risk higher than the comparison
cohort without comorbidity. In those with any comorbidity, Sjögren's
syndrome patients had 2.18-fold risk compared with controls. In dura-
tion stratified analysis, Sjögren's syndrome patients had over 2-fold

Table 2
The risk for gastroesophageal reflux disease and gastroesophageal reflux disease-associated comorbidity in Cox proportional hazard regression.

Event no. Person-years IR Crude HR (95% CI) Adjusted HR (95% CI)

SS
No 1181 142,684 8.28 1.00 1.00
Yes 715 34,223 20.89 2.55 (2.32–2.80)⁎⁎⁎ 2.41 (2.19–2.64)⁎⁎⁎
Age, years
20–44 406 51,051 7.95 1.00 1.00
45–64 1004 89,303 11.24 1.44 (1.28–1.62)⁎⁎⁎ 1.21 (1.07–1.36)⁎⁎
≥65 486 36,553 13.30 1.80 (1.57–2.05)⁎⁎⁎ 1.20 (1.03–1.36)⁎
Sex
Female 1587 155,511 10.21 1.00 1.00
Male 309 21,396 14.44 1.47 (1.30–1.66)⁎⁎⁎ 1.29 (1.13–1.46)⁎⁎⁎
Comorbidity
IHD
No 1379 149,502 9.22 1.00 1.00
Yes 517 27,405 18.86 2.13 (1.93–2.36)⁎⁎⁎ 1.55 (1.38–1.74)⁎⁎⁎
Hyperlipidemia
No 1320 141,361 9.34 1.00 1.00
Yes 576 35,546 16.20 1.78 (1.62–1.97)⁎⁎⁎ 1.39 (1.25–1.55)⁎⁎⁎
RD
No 1660 164,779 10.07 1.00 1.00
Yes 236 12,129 19.46 2.01 (1.76–2.31)⁎⁎⁎ 1.41 (1.22–1.62)⁎⁎⁎

IR, incidence, per 1000 person-years; SS, Sjögren's syndrome; IHD, ischemic heart disease; RD, renal disease; HR, hazard ratio; CI, confidence interval.
⁎ p b 0.05.
⁎⁎ p b 0.01.
⁎⁎⁎ p b 0.001.

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Table 3
The risk for gastroesophageal reflux disease stratified by age, gender or comorbidity in Cox proportional hazard regression.

SS Comparison HR (95% CI)

Event no. IR Event no. IR Crude Adjusted

Age, yearsa,b
20–44 176 17.56 230 5.61 3.15 (2.59–3.83)⁎⁎⁎ 3.02 (2.48–3.69)⁎⁎⁎
45–64 379 22.12 625 8.66 2.59 (2.28–2.95)⁎⁎⁎ 2.40 (2.11–2.73)⁎⁎⁎
≥65 160 22.65 326 11.06 2.06 (1.71–2.49)⁎⁎⁎ 1.95 (1.61–2.36)⁎⁎⁎

Sexc
Female 603 20.06 984 7.84 2.59 (2.34–2.87)⁎⁎⁎ 2.45 (2.21–2.71)⁎⁎⁎
Male 112 26.89 197 11.43 2.35 (1.87–2.97)⁎⁎⁎ 2.21 (1.75–2.79)⁎⁎⁎

Comorbidityd,b
Without any one 265 15.96 463 5.65 2.84 (2.45–3.31)⁎⁎⁎ 2.87 (2.47–3.34)⁎⁎⁎
With any one 450 25.53 718 11.83 2.18 (1.94–2.45)⁎⁎⁎ 2.18 (1.94–2.46)⁎⁎⁎

Follow-up duratione
1 31 6.86 49 2.70 2.54 (1.62–3.98)⁎⁎⁎ 2.39 (1.52–3.75)⁎⁎⁎
2–5 308 18.34 428 6.18 2.98 (2.57–3.45)⁎⁎⁎ 2.79 (2.41–3.23)⁎⁎⁎
N5 376 29.12 704 12.73 2.29 (2.02–2.59)⁎⁎⁎ 2.17 (1.91–2.46)⁎⁎⁎

IR, incidence, per 1000 person-years; SS, Sjögren's syndrome; IHD, ischemic heart disease; RD, renal disease; HR, hazard ratio; CI, confidence interval.
a
Adjusted for sex, IHD, hyperlipidemia and RD.
b
Interaction between gastroesophageal reflux disease and gastroesophageal reflux disease associated-variable test, p b 0.05.
c
Adjusted for age, IHD, hyperlipidemia and RD.
d
Adjusted for age and sex.
e
Cox proportional assumption test, p = 0.0006.
⁎⁎⁎ p b 0.001.

gastroesophageal reflux disease incidences than controls no matter at 4. Discussion

which study duration.
The joint effect for gastroesophageal reflux disease between Our present study has demonstrated that patients with Sjögren's
Sjögren's syndrome, ischemic heart disease, hyperlipidemia and syndrome were significantly associated with an increased risk of gastro-
renal disease in Cox proportional hazard model after adjusting for esophageal reflux disease compared with the patients in the compari-
age and gender is shown in Table 4. Compared with subjects without son cohort. After adjusting for potential confounding factors, including
those diseases (including Sjögren's syndrome, ischemic heart dis- age, sex and the comorbidity of Sjögren's syndrome, the odds ratio
ease, hyperlipidemia and renal disease) the risks were 2.73 in sub- would be as high as 2.41 (95% CI = 2.19–2.64) (Table 2), indicating
jects only with Sjögren's syndrome, 1.85 in subjects only with that the Sjögren's syndrome patients have high risk for developing
ischemic heart disease, 1.69 in subjects only with renal disease and gastroesophageal reflux disease in life. Fig. 1 also illustrates a positive
1.66 in subjects only with hyperlipidemia. Subjects with Sjögren's association between both cohorts during 12-year cumulative evidence.
syndrome, ischemic heart disease, hyperlipidemia and renal disease To our knowledge, this is the first study to document above findings by
had the highest risk for gastroesophageal reflux disease compared examining data that were based on a generalized population-based
with subjects without those diseases (HR = 7.67; 95% CI = 5.32– cohort.
11.1). The gastroesophageal reflux disease, characterized by acid regurgi-
tation or heartburn, is the most frequently encountered disease world-
wide. Some systematic reviews revealed that the annual prevalence of
gastroesophageal reflux disease in different populations varied between
Table 4 10 and 30% in the USA and Europe, whereas Asian counties had lower
Joint effect for gastroesophageal reflux disease and gastroesophageal reflux disease-asso-
rates [10,19,20]. Through multivariate analysis, the prevalence of gas-
ciated risk factor in age- and gender-adjusted Cox proportional model.
troesophageal reflux disease in the general population of Taiwan was
SS IHD Hyperlipidemia RD N Event no IR HR (95% CI) 25%, independent risk factors as female sex and age were related to
No No No No 12,558 637 6.32 1.00 the development of gastroesophageal reflux disease [21]. Some studies
Yes No No No 2650 351 17.00 2.73 (2.39–3.10)⁎⁎⁎ showed that gastroesophageal reflux disease was often accompanied
No Yes No No 1364 124 12.75 1.85 (1.52–2.26)⁎⁎⁎ with many chronic diseases in variable prevalence, such as hyperten-
No No Yes No 2089 176 10.86 1.66 (1.40–1.97)⁎⁎⁎
No No No Yes 429 34 10.96 1.69 (1.19–2.38)⁎⁎
sion, hypercholesterolemia, diabetic mellitus, chronic liver disease,
Yes Yes No No 478 91 27.27 4.03 (3.22–5.05)⁎⁎⁎ bronchial asthma, obesity and depression [22,23].
Yes No Yes No 572 97 22.70 3.51 (2.83–4.36)⁎⁎⁎ As Table 1 displays, the patients with Sjögren's syndrome had a
Yes No No Yes 243 37 20.22 3.21 (2.31–4.49)⁎⁎⁎ significant correlation with some comorbidity, such as hyperlipidemia,
No Yes Yes No 1020 113 14.88 2.20 (1.79–2.70)⁎⁎⁎
ischemic heart disease and renal disease. We found that Sjögren's syn-
No Yes No Yes 213 28 21.22 3.19 (2.17–4.68)⁎⁎⁎
No No Yes Yes 276 28 13.64 2.07 (1.41–3.02)⁎⁎⁎ drome patients with one of the comorbidities had relatively high odds
Yes Yes Yes No 321 71 31.72 4.83 (3.76–6.20)⁎⁎⁎ ratios for gastroesophageal reflux disease development than those
Yes Yes No Yes 101 18 28.33 4.29 (2.68–6.87)⁎⁎⁎ without comorbidity (Table 2). From the analysis of joint effect, the
Yes No Yes Yes 92 19 29.86 4.72 (2.99–7.46)⁎⁎⁎ Sjögren's syndrome patients with two or three comorbidities seemed
No Yes Yes Yes 291 41 21.33 3.29 (2.38–4.54)⁎⁎⁎
Yes Yes Yes Yes 103 31 49.22 7.67 (5.32–11.1)⁎⁎⁎
to have higher odds ratio than those with less comorbidities or only
one (Table 4). However, after adjusting the age–sex confounding factors
IR, incidence, per 1000 person-years; SS, Sjögren's syndrome; IHD, ischemic heart disease;
and comorbidity, the Sjögren's syndrome patients without any comor-
RD, renal disease.
⁎⁎ p b 0.01. bidity had higher odds ratios than those with a comorbidity (Table 3).
⁎⁎⁎ p b 0.001. We thought that the role of the Sjögren's syndrome itself or associated

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 C.-S. Chang et al. / European Journal of Internal Medicine 31 (2016) 73–78
subsequent treatment is the essential factor, but rather the comorbidity
of Sjögren's syndrome might be the precipitating part, in contributing to
gastroesophageal reflux disease development. Systemic rheumatic dis-
eases can lead to a variety of gastrointestinal manifestations, including
oral ulcers, gastroesophageal reflux disease, chronic active hepatitis,
and gastrointestinal ulcer bleeding, influenced by the underlying auto-
immune process [24]. Sjögren's syndrome is a progressive autoimmune
disease with broad organ-specific and systemic manifestations. De-
pending on the criteria for determining prevalence, studies estimate
the prevalence of Sjögren's syndrome range from 0.05% to 4.8% across
international communities [25]. The mean annual incidence had been
estimated as 6.0 per 100,000 for both sexes (95% CI 5.8–6.2) in Taiwan
population [26]. The entire gastrointestinal tract may be involved in
Sjögren's syndrome, presenting with dry mouth, epigastric pain, dys-
pepsia, jejunitis, sigmoiditis, malabsorption, and inflammatory bowel
disease [27]. Owing to the combination of difficulty in swallowing and
impaired esophageal motility, dysphagia occurs in three-quarters of pa-
tients with Sjögren's syndrome [3,28]. Both decreasing lubrication and
therefore prolonging pharyngeal transit time may lessen the acid clear-
ance capacity of the esophagus [4]. Previous studies had demonstrated
that defective peristalsis was found in one-third or more of patients
with Sjögren's syndrome, resulting in decreased or absent contractility
in the upper third of the esophagus [29,30]. Although there was high
prevalence of gastroesophageal reflux disease in patients with Sjögren's
syndrome, the presenting symptoms of Sjögren's syndrome did not in-
clude heartburn and acid regurgitation. The possible reason is the high
rate of chronic gastritis related hypochlorhydria in Sjögren's patients
[31].
Many different mechanisms can contribute to esophageal dysfunc-
tion in a wide range of autoimmune and rheumatic diseases, causing
significant swallowing difficulties [32]. Gastroesophageal reflux disease
may develop as a result of acid reflux into the esophagus, followed
by triggering the esophagus to release chemicals and inflammatory
cells — cytokines. A well-known histopathologic examination of the gas-
trointestinal system reveals infiltration of immunoglobulin-producing
lymphocytes and activated inflammatory B and T cells of esophageal
musculature, invading and destroying target organs, with resultant im-
pairment of motor coordination [33]. In recent human and experimen-
tal studies for reflux esophagitis, immune and inflammatory reaction of
esophageal mucous membrane, characterized by specific cytokine and
chemokine profiles, may explain the underlying mechanism of the di-
verse esophageal phenotypes of gastroesophageal reflux disease [34,
35]. Mucosal interleukin 8 concentrations are increased in the esopha-
geal mucosa, through activation of nuclear factor-κB, which are parallel
with the endoscopic severity of reflux esophagitis, implying that this cy-
tokine is a key player in the development of gastroesophageal reflux dis-
ease [36,37]. Overexpression of some other proinflammatory cytokines,
such as Interleukin-1β, Interleukin 6, and tumor necrosis factor α, are
enhanced in the intestinal epithelium of gastroesophageal reflux dis-
ease [38]. Therefore, treatment with lansoprazole might reduce the mu-
cosal levels of interleukin 8 expression in human gastroesophageal
reflux disease, through an anti-inflammatory action of proton pump in-
hibitors beyond gastric acid inhibition [39,40].
Gastrointestinal manifestations, including gastroesophageal reflux
disease, may be the initial presentation of Sjögren's syndrome, but
they may also be a complication of medication treatment. Many treat-
ment modalities are available to treat pain associated with Sjögren's
syndrome; patients frequently complain of neuropathic pain, followed
by nociceptive pain [41]. Nonsteroidal anti-inflammatory drugs or pred-
nisone is the common and chronic applied treatment of musculoskeletal
symptoms in Sjögren's syndrome [42]. Nonsteroidal anti-inflammatory
drugs may also cause gastrointestinal symptoms, including gastro-
esophageal reflux disease, or increase its severity, as has long been
reported in non-arthritic patients [43,44].
The main strength of the current study is that those findings were
based on an analysis of a large sample from a nationwide population-
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77
based database, which minimized selection bias. In addition, our study
is the first to investigate the associations between Sjögren's syndrome
and gastroesophageal reflux disease. Nevertheless, our results should
be viewed in the light of several limitations. First, the diagnoses of
Sjögren's syndrome or gastroesophageal reflux disease were identified
by the ICD-9-CM codes from the administrative claims data, and the
prevalence may be underestimated because only subjects seeking med-
ical help could be identified in this study. Second, a cross-sectional design
meant that a causal relationship based on the observed correlation be-
tween Sjögren's syndrome and gastroesophageal reflux disease could
not be established. Third, the present study did not investigate whether
the use of medications for Sjögren's syndrome, such as steroids, nonste-
roidal anti-inflammatory drugs, or immunosuppressive agents, might
play a role in increasing risk of gastroesophageal reflux disease in
Sjögren's syndrome subjects. Finally, as this study was conducted in a
Taiwanese population, generalizability of the findings to other ethnic
populations is limited.
5. Conclusion
In conclusion, prevalence of gastroesophageal reflux disease symp-
toms was considerably high in Sjögren's syndrome patients. We believe
that clinicians should always be aware of gastroesophageal reflux dis-
ease symptoms in patients with Sjögren's syndrome, especially those
with some comorbidities and receiving multi-drug treatment. Providing
adequate care for comorbidities might be critical to the prevention of
gastroesophageal reflux disease in patients with Sjögren's syndrome.
Hence, future studies are warranted to explore the potential roles of
rheumatic medication in gastroesophageal reflux disease and further
longitudinal study to confirm the causal relationship between gastro-
esophageal reflux disease and Sjögren's syndrome.
Author contributions
These authors' individual contributions were as follows. Conception
and design: Chen-Shu Chang, Chun-Hui Liao, Chia-Huang Kao; adminis-
trative support: Chia-Hung Kao; collection and assembly of data: all
authors; data analysis and interpretation: all authors; manuscript
writing: all authors; final approval of manuscript: all authors.
Acknowledgments
This study is supported in part by Taiwan Ministry of Health and
Welfare Clinical Trial and Research Center of Excellence (MOHW105-
TDU-B-212-133019), China Medical University Hospital, Academia
Sinica Taiwan Biobank Stroke Biosignature Project (BM10501010037),
NRPB Stroke Clinical Trial Consortium (MOST 104-2325-B-039-005),
Tseng-Lien Lin Foundation, Taichung, Taiwan, Taiwan Brain Disease
Foundation, Taipei, Taiwan, and Katsuzo and Kiyo Aoshima Memorial
Funds, Japan; and CMU under the Aim for Top University Plan of the
Ministry of Education, Taiwan. The funders had no role in study design,
data collection and analysis, decision to publish, or preparation of the
manuscript. No additional external funding received for this study.
Conflict of interests
All authors report no conflicts of interest.
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