Comorbidities associated with Sjögren’s
syndrome: Results from the Nationwide
Inpatient Sample

Terah Koch ∗, Ibtisam Al-Hashimi †, Boyd M. Koffman ‡, Abhishek Deshpande §, Sadik A. Khuder ¶‖

∗Nationwide Children’s Hospital, Columbus, OH 43205,†Texas A&M University Baylor College of Dentistry, Dallas TX 75246,‡Department of Neurology, University
of Toledo Health Science Campus, Toledo, OH 43614,§Department of Medicine, Case Western Reserve University School of Medicine, Cleveland OH 44106, and
¶Department of Medicine, University of Toledo Health Science Campus, Toledo, OH 43614

Although multiple comorbidities associated with Sjögren’s syn-
drome (SS) have been reported, reliable data regarding the preva-
lence of specific comorbidities among patients with SS remain
sparse. In this study, we investigated the prevalence and risk
for a broad spectrum of medical conditions among patients with
SS in the United States. The Health Cost and Utilization Project
(HCUP) Nationwide Inpatient Sample (NIS) data was utilized in or-
der to investigate 27 different comorbidities among SS patients.
Between the years 2007 to 2009 there were 19,127 admissions with
SS listed as principal diagnosis (1.3%) and secondary diagnosis
(98.7%). Compared with 57,381 controls, SS patients had signifi-
cantly higher prevalence of lymphoma (OR 1.6), valvular disease
(OR 1.42), congestive heart failure (OR 1.28), hypothyroidism (OR
1.24), paralysis (OR 1.24), deficiency anemia (OR 1.16), depression
(OR 1.18), neurological disorders (OR 1.17), chronic pulmonary
disease (OR 1.07), and hypertension (OR 1.04). SS is associated
with substantial medical conditions that may impact morbidity
and mortality as well as quality of life for individuals suffering
from SS.

Sjögren’s syndrome | autoimmune diseases | comorbidities | HCUP data

Sjögren’s syndrome (SS) is an inflammatory disease of the ex-ocrine system, including the lacrimal and salivary glands (1).
However, other organs can also be affected by SS including the lungs,
nerves, blood vessels, and kidneys (2). SS is often classified into pri-
mary Sjögren’s syndrome and secondary Sjögren’s syndrome. Pri-
mary SS is among the most common autoimmune diseases with an
estimated prevalence ranging from 0.04% to 4.8% and with a male
to female ratio of approximately 1:9 (3). Most women are affected
during their 50s after menopause. Secondary SS is closely associated
with rheumatoid arthritis and is believed to have a different patho-
genesis than primary SS (1).

Comorbid conditions are important when studying autoimmune
diseases such as SS because individuals that suffer from autoimmune
disease are more susceptible to development of other autoimmune
diseases (4, 5). The risk of comorbid conditions among individ-
uals suffering from SS is not well delineated (6). However, there
are many known comorbidities that can occur in conjunction with
SS. A previous case-controlled study suggested that SS patients are
more likely to have hyperlipidemia, cardiac arrhythmias, headaches,
migraines, fibromyalgia, asthma, pulmonary circulation disorders,
hypothyroidism, liver disease, peptic ulcers, hepatitis B, deficiency
anemias, depression and psychoses (6). Other studies have reported
higher incidence of other comorbidities such as lymphoma (7), non-
Hodgkin’s lymphoma (8), celiac disease (9) and dementia (10). In-
dividuals with autoimmune thyroid disorders were found to have a
higher rate of comorbid autoimmune diseases such as lupus and SS
compared to the general population (11). In other words, an individ-

ual having autoimmune disease might be at a higher risk for devel-
oping another autoimmune disease. Currently, the long term effects
of comorbidities in SS on mortality remain unclear. However, it is
known that quality of life is significantly affected by comorbid con-
ditions (12).

Although multiple comorbidities associated with SS have been
reported, reliable data regarding the prevalence of specific comor-
bidities among patients with SS remain sparse. Studies aiming to
estimate the prevalence of comorbidities associated with SS in the
general population were limited in their scope due to the study pop-
ulation used, as well as the small number of study participants. Fur-
thermore, there is a current deficit of studies that have attempted to
capture the prevalence of comorbid conditions among hospitalized
SS patients in the United States.

In this study, we investigated the prevalence and risk for a broad
spectrum of medical conditions among patients with SS in the United
States utilizing a nationwide database.

Methods
Data used in this study is from the Healthcare Cost and Utiliza-

tion Project (HCUP) sponsored by the Agency for Healthcare Re-
search and Quality (AHRQ). HCUP combines data from state orga-
nizations, hospital associations, private data organizations, and the
Federal government to create a national information resource con-
sisting of patient-level health care data. The largest collection of lon-
gitudinal hospital care data in the United States is included in HCUP
beginning in 1988. The HCUP database represents 96% of the U.S.
population and includes over 32 million observations. HCUP con-
sists of multiple databases, however the database used in this study
is the Nationwide Inpatient Sample (NIS) for the years 2007 through
2009. This database has inpatient data from over 1,000 hospitals and
up to 44 states in the United States. (13).

‖To whom correspondence should be sent: Sadik.Khuder@utoledo.edu

Author contributions: TK and SAK designed the study and wrote the manuscript. All other
individual authors were involved in data interpretation and writing of the manuscript. All authors
have read and approved the manuscript as submitted. SAK takes responsibility for the paper
as a whole.

The authors declare no conflict of interest

Freely available online through the UTJMS open access option

4–7 UTJMS 2014 Vol. 1 No. 1 utdr.utoledo.edu/translation/



Table 1: Hospital admissions with SS as principal or secondary diagnosis by demographics and year of admission

2007 2008 2009

Variable Principal Secondary Principal Secondary Principal Secondary
n=90 n=5423 n=83 n=6223 n=72 n=7236

Gender
% Female 94.44 92.95 75.90 93.35 90.28 91.96

Race
%White 73.61 83.02 70.42 82.78 67.69 83.04
%Black 6.94 6.03 21.13 6.22 12.31 7.07
%Hispanic 13.89 5.78 5.63 6.12 7.69 5.73

Location*
%Urban 85.37 82.69 78.48 82.21 90.00 83.92

Age
mean±sd 58.77±17.06 63.75±15.44 53.76±15.02 63.7±15.23 58.69±16.13 63.52±15.56

*Urban or rural designation based on the country in which the hospital is located

Subjects included in the study consisted of individuals who were
at least 18 years of age and had an ICD-9 diagnosis code for Sj -ogren’s
syndrome. The ICD-9 codes do not provide differentiation between
primary and secondary SS, therefore the code used in this study to
identify all subjects with SS was 710.2. The NIS database allows up
to 10 or 15 diagnoses per patient depending on the reporting year.
Controls were excluded if they had one or more of over 100 different
autoimmune disease ICD-9 diagnosis codes or were under the age of
18. SS patients and controls were randomized and matched by age
and sex. Three controls were matched to each SS patient (19, 127 SS
and 57,381 Control).

The comorbid conditions used in this analysis totaled 27 and
were variables included in the NIS database obtained from the AHRQ
comorbidity software. This comorbidity software assigns variables
that identify comorbidities in discharge records using ICD-9-CM
codes (13). The 27 comorbidities included in this study are listed
in table 2.

All statistical analyses were conducted using SAS version 9.2
(SAS Institute, Cary, NC). Frequency distributions between categor-
ical variables were assessed using the χ2 test. Logistic regression
models were utilized to compare patients with and without SS for 27
different comorbidities. The survey logistic procedures were used in
this analysis to include the weight variable provided in the database.
The presence of SS was used as the dependent variable in these mod-
els. Each model was weighted and controlled for the comorbid condi-
tion as well as race and urban/rural location and were used to identify
increased occurrence of conditions listed in table 3.

Results
Between 2007 and 2009, there were 19, 127 admissions with SS

listed as principal diagnosis (1.3%) or secondary diagnosis (98.7%)
for admission (Table 1). The majority of admitted patients were
white females admitted to hospitals in urban locations. In each year,
patients admitted with SS as principal diagnosis were significantly
younger than patients admitted with SS as secondary diagnosis.

Figure 1, displays the frequency of autoimmune diseases coexist-
ing in patients with SS. Rheumatoid arthritis was the most common
autoimmune disease coexisting with SS.

Table 2 shows a list of the frequency of the comorbidities among
SS patients. Hypertension was the most common comorbidy with a
prevalence rate of 42.14%. Other prevalent comorbidities were fluid
and electrolytes disorders, chronic pulmonary disease, deficiency
anemia, hypothyroidism, uncomplicated diabetes, and depression.

Comparisons of SS patients and controls on demographic vari-
ables revealed equal distributions for age and gender. On the other

Fig. 1: Distribution of autoimmune diseases coexisting with SS.

hand, there were significantly more admissions for Hispanics among
the control group. The control group also had more admissions to
hospitals in rural locations.

There were a significantly higher percentage of SS patients with
the following comorbidities compared to the controls: Lymphoma,
valvular disease, congestive heart failure, hypothyroidism, paralysis,
deficiency anemia, depression, neurological disorders, chronic pul-
monary disease, and hypertension (table 3).

There was a significantly lower percentage of SS patients with
the following comorbidities compared to the controls: metastatic can-
cer (OR 0.56; 95% CI, 0.48-0.66), alcohol abuse (OR 0.64; 95% CI,
0.57-0.72), weight loss (OR 0.80; 95% CI 0.68-0.94), fluid and elec-
trolytes disorders (OR 0.82; 95% CI, 0.78-0.86), obesity (OR 0.88;
95% CI 0.82-0.95), coagulopathy (OR 0.89; 95% CI 0.81-0.97), and
uncomplicated diabetes (OR 0.92; 95% CI 0.87-0.97).

Discussion
This study aimed to examine the prevalence of comorbidities

among SS patients based on hospital admissions data. The results
of data analyses suggest that the most common comorbid condition,
beside hypertension, was rheumatoid arthritis with a prevalence of
40.84%, which is in agreement to those reported in other studies re-
porting a prevalence rate of 39.0% for arthralgias/arthritis (14). Sjö-

Koch et al. UTJMS 2014 Vol. 1 No. 1 5



gren’s syndrome is frequently associated with rheumatoid arthritis
and systemic lupus erythematosus. It has been estimated that 18-30%
of rheumatoid arthritis patients have secondary SS (15). Moreover,
rheumatoid factors appear to play an important role in the pathogen-
esis of SS as it has been suggested to be an indicator of the severity
of salivary gland damage (16).

Table 2: Frequencies of comorbidities in patients with SS.

Comorbidity Number %

Hypertension 7900 42.14
Fluid and Electrolytes Disorders 3931 20.97
Chronic Pulmonary Disease 3303 17.62
Deficiency Anemia 3131 16.70
Hypothyroidism 2807 14.97
Diabetes, uncomplicated 2594 13.84
Depression 2132 11.37
Renal Failure 1652 8.81
Obesity 1373 7.32
Congestive Heart Failure 1340 7.15
Neurological Disorders 1192 6.36
Valvular Disease 769 4.10
Peripheral Vascular Disorders 746 3.98
Weight Loss 731 3.90
Coagulopathy 719 3.83
Psychosis 707 3.77
Diabetes with chronic complications 581 3.10
Liver Disease 510 2.72
Alcohol Abuse 469 2.50
Drug Abuse 446 2.38
Pulmonary Circulation Disorders 429 2.29
Paralysis 350 1.87
Chronic Blood Loss 323 1.72
Solid Tumor without Metastasis 321 1.71
Metastatic Cancer 253 1.35
Lymphoma 201 1.07

Anemia occurred in 16.7% of SS patients and this was signifi-
cantly higher than that for the control population (p=0.0001). The
prevalence of anemia was reported to be 34.1% in previous stud-
ies (17). Kang et al. reported an odds ratio (OR) of 1.33 (95% CI
1.01-1.77) for anemia (6) which is similar to the OR of 1.16 (95%
CI 1.11-1.22) found in this study, however, the prevalence was only
3.4%, much lower than our results and that of previous studies (17).

Table 3: Elevated comorbidities in patients with SS compared to
controls.

Comorbidity OR* 95% CI p-value

Lymphoma 1.60 1.32-1.93 0.0001
Vascular Disease 1.42 1.29-1.56 0.0001
Congestive Heart Failure 1.28 1.19-1.38 0.0001
Hypothyroidism 1.24 1.18-1.31 0.0001
Paralysis 1.24 1.08-1.42 0.0024
Deficiency Anemia 1.16 1.11-1.22 0.0001
Depression 1.18 1.11-1.25 0.0001
Neurological Disorders 1.17 1.09-1.27 0.0001
Chronic Pulmonary Disease 1.07 1.02-1.12 0.0076
Hypertension 1.04 1.01-1.08 0.0294
Psychosis 1.10 1.00-1.21 0.0578
Pulmonary Circulation Disorders 1.12 0.99-1.26 0.0716
Renal Failure 1.01 0.95-1.08 0.6725

*Adjusted for race and hospital location

Lymphoma risk was increased by 60% over the control group in
this study. Several recent large cohort studies and a meta-analysis

have estimated the lymphoma risk in patients with SS. A cohort
study that included 507 incident patients with SS showed that the risk
of developing lymphoma was about 16-fold higher in patients who
did compared to those that did not fulfill the diagnostic American-
European Consensus Criteria (18). Similar results were observed in a
more recent cohort study, which estimated that the relative risk of de-
veloping lymphoma was about 16-fold higher in SS patients than gen-
eral population and that this risk increased over time and remained
high, even 15 years after SS diagnosis (19). Factors such as cytokine
stimulation, environmental factors, viral infection and genetic events
as well as vitamin deficiency may also contribute to the development
of lymphoma (20).

Both congestive heart failure and valvular diseases were signifi-
cantly increased among SS patients. Valvular regurgitation, pericar-
dial effusion, pulmonary hypertension, and increased left ventricular
mass index were reported to occur with disproportionately high fre-
quency in patients with SS with no clinically apparent heart disease
(21).

Hypothyroidism occurred in almost 15% of the SS patients.
Moreover, there was a 24% increase in the risk of hypothyroidism
among SS patients as compared to the controls. This increase is less
than that reported in previous studies (OR 2.37; 95% CI 1.92-2.93)
(6). Recent studies suggest thyroid gland dysfunction as a main en-
docrine abnormality occurring in the context of SS. Previous studies
have shown that approximately one third of SS had thyroid disorders
(22). Shared genetic and immunopathological findings such as com-
mon HLA antigens, periepithelial lymphocytic infiltration and oligo-
clonal B-cell expansion strongly support the presence of common
pathophysiological operating mechanisms between the two entities
(23).

More than 11% of SS patients in this study suffered from de-
pression. Moreover, there was an 18% increase in the risk over the
controls. Other studies in the literature report higher prevalence of
depression among SS patients (24, 25).

Almost 4% of SS patients in this study were diagnosed with psy-
chosis; there was a 10% increase in the risk over the controls. Other
studies looking only at primary SS have reported a higher risk of
psychoses (OR 2.15; 95% CI, 1.65-2.80) (6). Psychiatric or cogni-
tive impairment, usually mild or moderate, was reported in over 80%
highly selected population of SS patients, and more than 60% of these
patients had both (26). Associations between autonomic symptoms
and fatigue and symptoms of depression in patients with primary SS
have also been reported (27).

Pulmonary manifestations were among the most prevalent com-
plications, with reported prevalence varying widely (9-75%), depend-
ing on the methods of detection and patient selection (22, 28-30).
About 17.6% of SS patients in this study were diagnosed with chronic
pulmonary disease and this was significantly different from that for
the controls. Similarly, a marginally significant difference was found
for pulmonary circulation disorders. Another study did report a sig-
nificant difference between patients and controls for pulmonary cir-
culation disorders (OR 1.42, 95% CI 1.21-1.68) (14). Other risk fac-
tors besides SS such as smoking, environmental pollution, and infec-
tions play a major role in determining the risk of pulmonary diseases.
However our data is not suitable to address this issue.

Our study has several important strengths. We used a national
database representing 96% of the U.S. population with over 32 mil-
lion patient records utilized in analysis, enabling a clearer picture
of the prevalence of comorbidities among SS patients on a country-
wide basis. Furthermore, the comorbidities identified in this study
are based on doctor-diagnosed diseases, and not self-reporting by pa-
tients. In the case of autoimmune diseases, which include rare dis-
eases and diseases with considerable clinical heterogeneity and com-
plex case definitions, the collection of data through self reporting in-
volves a high probability of referral bias (31).

There are also several potential weaknesses in the design of this
study. First, the data are limited to hospitalized patients, and there-

6 utdr.utoledo.edu/translation/ Koch et al.



fore not all patients suffering from Sjögren’s syndrome were inves-
tigated. Second, we do not know if the diagnosis of SS was well
established according to accepted criteria or was merely based on
physicians’ impression of dryness symptoms. Moreover, the extent
to which the primary diagnosis (only 1.3% of patients had SS as the
primary diagnosis for admission) contributes to the comorbidity can-
not be estimated. Therefore, the HCUP data may not reflect the true
prevalence of comorbidities. Third, the group included in this study
was sicker and possibly showing higher prevalence of certain comor-
bidities. Fourth, we were unable to adjust for significant covariates

such as smoking. Finally, multiple admissions for the same patient
might be problematic. However, there is no reason to believe that the
pattern of admission is different between SS patients and the controls.

In conclusion, comorbidities are common among patients with
SS, with a preponderance of certain comorbidities such as lymphoma,
pulmonary disease, deficiency anemia, hypothyroidism, congestive
heart failure, and valvular diseases.

ACKNOWLEDGMENTS. The authors would like to acknowledge the contribu-
tions of Sreekiran Thotakura to analysis of the data.

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