Immunopharmacology and Immunotoxicology

ISSN: 0892-3973 (Print) 1532-2513 (Online) Journal homepage: https://www.tandfonline.com/loi/iipi20

Meta-analysis on pharmacological therapies in

the management of xerostomia in patients with
Sjogren’s syndrome

Komali Garlapati, Anuja Kammari, Raj Kumar Badam, Surekha B. E.,

Mamatha Boringi & Pratima Soni

To cite this article: Komali Garlapati, Anuja Kammari, Raj Kumar Badam, Surekha B. E., Mamatha
Boringi & Pratima Soni (2019): Meta-analysis on pharmacological therapies in the management
of xerostomia in patients with Sjogren’s syndrome, Immunopharmacology and Immunotoxicology,
DOI: 10.1080/08923973.2019.1593448

To link to this article: https://doi.org/10.1080/08923973.2019.1593448

Published online: 01 Apr 2019.

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IMMUNOPHARMACOLOGY AND IMMUNOTOXICOLOGY
https://doi.org/10.1080/08923973.2019.1593448

ORIGINAL ARTICLE

Meta-analysis on pharmacological therapies in the management of xerostomia

in patients with Sjogren’s syndrome
Komali Garlapatia, Anuja Kammaria, Raj Kumar Badama, Surekha B. E.a, Mamatha Boringia and Pratima Sonib
a
Department of Oral Medicine and Radiology, Panineeya Mahavidyalaya Institute of Dental Sciences and Research Centre, Hyderabad, India;
b
Department of Oral Medicine and Radiology, Government Dental College and Hospital, Hyderabad, India

ABSTRACT ARTICLE HISTORY

Introduction: Sjogren’s syndrome is an immunologic disorder, characterized by symptoms of dry Received 10 December 2018
mouth and dry eyes. Management of xerostomia is more difficult and challenging, various pharmaco- Accepted 28 February 2019
logic agents have been tried and evaluated in the management of xerostomia in these patients, but
KEYWORDS
the results were inconsistent and variable. Hence, the present study is aimed at evaluation and com-
Sjogren’s syndrome;
parison of different pharmacological agents in the management of xerostomia in patients with xerostomia; pharmacological
Sjogren’s syndrome. management; Interferon
Materials and methods: A meta-analysis of case–control studies was conducted on pharmacological alpha; cevimeline;
management of xerostomia in patients with Sjogren’s Syndrome and the collected data are subjected pilocarpine
to exclusion and inclusion criteria and standard mean difference (SMD), ODD’s ratio and confidence
intervals (95% CI) were calculated by Review Manager software using fixed and random effects model
from the data of five studies.
Results: Both objective response and subjective response evaluation favored experimental group sug-
gesting an increase in unstimulated salivary flow rate using pharmacological agents. Interferon alpha
150 IU three times daily had a good effect in increasing the unstimulated whole saliva flow rate with
SMD 2.72 at 95% CI [2.43, 3.00] p < .00001. Cevimeline vs placebo showed good response with ODDS
ratio 2.74 at 95% CI [1.58, 4.76] p ¼ .0003.
Conclusion: Interferon – a 150 IU thrice daily was proven to be effective in increasing salivary flow
rate and also has an advantage of disease modification in SS patients attributing to its immunomodu-
latory action. Cevimeline 30 mg thrice daily also had a considerable therapeutic effect in SS patients
compared to Pilocarpine.

Introduction Cochrane and Science direct to search articles which are

published from 1986 to 2017 in English and that mentioned
Sjogren’s syndrome (SS) is an autoimmune disorder charac-
pharmacological management of xerostomia or dry mouth in
terized by inflammation of salivary and lacrimal glands and
patients with Sjogren’s syndrome with keywords xerostomia,
associated with symptoms of xerostomia and xerophthalmia
dry mouth, salivaryhypofunction, Sjogren’s syndrome and add-
[1,2]. Sjogren’s syndrome is the most common disease of
itional terms, such as Cevimeline, Pilocarpine, Bethanechol,
women and occurs in the fourth or fifth decade of life, with
Anthelotrithione, Saliva Substitutes, Corticosteroids, Interferon
a prevalence of 1 in every 2500 females [3].
alpha, Rituximab, Cyclosporin A, Xialine, Etanercept,
Many pharmacologic agents are used to increase the sal-
Hydroxychloroquine, Biotene. Sources were confined to clinical
ivary flow rate in SS patients. The aim of the present study is
trials of phases I–IV, randomized controlled trials and no limi-
the analysis of pharmacotherapy and to compare and evalu-
tations of age and gender. From each article information
ate the efficacy of these drugs in improving saliva flow rate
about the design of the study, the population in the study,
and to identify optimal treatment option for management of
treatment option, dosage of the drugs, method of measuring
xerostomia in SS patients.
xerostomia, results, and conclusions were recorded.

Materials and methods

The search of literature Selection criteria
An overall literature search was done using the databases The literature searched was then subjected to inclusion and
such as PubMed/MEDLINE, Research Gate, Google Scholar, exclusion criteria.

CONTACT Anuja Kammari anujakammari222@gmail.com Department of Oral Medicine and Radiology, Panineeya Mahavidyalaya Institute of Dental
Sciences and Research Centre, Kamala Nagar, Road number -5, Chaitanyapuri, Dilsukhnagar, Hyderabad – 60, Telangana, India
ß 2019 Informa UK Limited, trading as Taylor & Francis Group
2 K. GARLAPATI ET AL.
Inclusion criteria
1. Studies that mentioned pharmacological management of
xerostomia or hyposalivation due to Sjogren’s syndrome.
2. Randomized controlled trials.
Exclusion criteria
1. Manuscripts with abstract only.
2. Review articles and cohort studies.
Data extraction
Data from each study which met the inclusion and exclusion
criteria were extracted by two authors into a standardized
database and then cross-checked by one more author for
accuracy. Data extracted from each study included author,
year of publication, number of patients participated in the
study, type of medication used, the dosage of the drug,
method of measurement for the assessment of xerostomia,
outcomes for treatment and control groups. Unstimulated
whole saliva was selected for the evaluation of saliva
flow rate.
Statistics and analysis
Extracted data were subjected to statistical analysis using
Review Manager software, version 5.3. Both the random
effects model and the fixed effects model were used in this
study. Under the fixed effects model, it was assumed that all
studies are taken from a common population and that the
effect size, that is, odds ratio or standardized mean differ-
ence was not significantly different among the compared
clinical trials. This can be tested by the heterogeneity test or
I2 statistic. If the result has a low p values (p<.05) and I2
value is (>50%), then the fixed effects model will be invalid.
In such cases, the random effects model will be more appro-
priate, in which both the random variation within the studies
and the variation between the different studies is incorpo-
rated [4].
The analysis was conducted to evaluate and compare dif-
ferent pharmacological agents and to identify optimal drug
in the management of xerostomia in patients with
Sjogren’s syndrome.
Results
The database search resulted in a total of 24,678 articles
which were narrowed to 25 studies due to irrelevant titles
and abstracts (Figure 1). From these data, 15 studies were
excluded as they are not compared with placebo and three
studies were excluded to avoid duplication. A total of seven
articles were found eligible for meta-analysis. Then, two stud-
ies a study by Leung et al. [1] and a study by Sankar et al.
[5] were excluded as stimulated whole saliva (SWS) was
taken into consideration. Only five studies which met our
inclusion criteria were included in the meta-analysis and all
of them were randomized controlled trials.
Studies excluded with
Studies identified through
irrelevant titles and
database searching abstracts
(n = 24,678) (n = 24,653)
Excluded duplicates and
studies screened
studies not compared with
(n = 25)
placebo
(n = 18)
Full-text articles assessed for Full-text articles excluded,
eligibility as stimulated whole saliva
(n = 7) was taken into consideration
(n = 2)
Studies included in
Meta - analysis
(n = 5)
Figure 1. Search strategy used to identify studies eligible for meta-analysis.
Objective data from four studies, Dianne et al. [6], Rose
et al. [7], Frederick et al. [8], Martin et al. [2] (Table 1)
unstimulated salivary flow rate were taken into consideration.
Their data at postdose were synthesized to calculate standar-
dized mean difference between the groups.
The subjective response of the patients was recorded in
two studies, Dianne et al. [6], Jonathan et al. [3] (Table 2)
data from these two studies is taken into consideration for
calculating odds ratio.
In the analysis done by the standard mean differences of
the four studies (Figure 2) by Frederick et al. [8] and Martin
et al. [2] showed equal and highest weights. All the studies
favored experimental group though statistically insignificant
with high heterogeneity, the overall effect was SMD 0.89 at
95% CI [0.03, 1.81] p ¼ .06. Interferon alpha 150 IU three
times daily had a good effect in increasing the unstimulated
whole saliva flow rate with SMD 2.72 at 95% CI [2.43, 3.00]
p < .00001. In the analysis done by ODDS ratio of the two
studies (Figure 3) study by Dianne et al. [3] showed highest
weight and Cevimeline versus placebo showed a good
response with ODDS ratio 2.74 at 95% CI [1.58,4.76] p ¼ .0003.
Publication bias
Publication bias in the study is estimated by the symmetric
or asymmetric distribution of data in the funnel plots. Funnel
plots were drawn using Review Manager 5.3 software ver-
sion. In the present study, funnel plot of standard mean dif-
ference of different studies (Figure 4) was not symmetrical
and funnel-shaped, indicating publication bias whereas fun-
nel plot of odds ratio of different studies (Figure 5) was sym-
metrical and funnel-shaped indicating no publication bias.
 IMMUNOPHARMACOLOGY AND IMMUNOTOXICOLOGY 3

Table 1. Data of different studies showing post dose mean salivary flow rates using different medications and dosages.
Experimental group Control group
Author
Mean ± SD Total (n) Mean ± SD Total (n)
Pilocarpine vs Placebo
Frederick (Pilocarpine vs Placebo) 1999 0.37 ± 0.46 127 0.17 ± 0.19 125
Cevimeline vs Placebo
Dianne (Cevimeline 15 mg vs Placebo) 2002 0.15 ± 0.14 54 0.14 ± 0.21 59
Dianne (Cevimeline 30 mg vs Placebo) 2002 0.28 ± 0.41 49 0.14 ± 0.21 59
Rose (Cevimeline 30 mg vs Placebo) 2002 0.293 ± 0.212 21 0.157 ± 0.146 22
Rose (Cevimeline 60 mg vs Placebo) 2002 0.419 ± 0.447 18 0.157 ± 0.146 22
Interferon alpha vs Placebo
Martin (INF alpha vs Placebo) 2003 0.76 ± 0.075 220 0.58 ± 0.05 147

Table 2. Data showing number of patients with increased unstimulated salivary flow rate [Events(n)] in different studies using differ-
ent medications and dosages.
Experimental group Control group
Author
Events (n) Total (n) Events (n) Total (n)
INF ALPHA VS PLACEBO
Jonathan [Inf alpha 150 IU  1 daily vs Placebo] 1999 2 16 5 18
Jonathan [Inf alpha 150 IU  3 daily vs Placebo] 1999 7 19 5 18
Jonathan [Inf alpha 450 IU  1 daily vs Placebo] 1999 5 19 5 18
Jonathan [Inf alpha 450 IU  3 daily vs Placebo] 1999 7 18 5 18
CEVIMELINE VS PLACEBO
Dianne [Cevimeline 15 mg vs Placebo] 2002 24 54 18 59
Dianne [Cevimeline 30 mg vs Placebo] 2002 32 49 18 59

Figure 2. Forest plot illustrating differences in unstimulated salivary flow rate of different studies. CI: confidence interval; Test for heterogeneity: Chi-squared statis-
tic with its degrees of freedom (df) and p values; I2: inconsistency among results; Test for overall effect: Z statistic with p values.

Discussion
Sjogren’s syndrome (SS) is a slowly progressing idiopathic auto-
immune disorder which is characterized by intense lymphocytic
infiltration of exocrine glands and also the presence of autoan-
tibodies anti-Ro/SSA and anti-La/SSB, hypergammaglobuline-
mia, and immunoregulatory abnormalities [1,3,6].
SS is of two types it is considered primary, if it is charac-
terized by inflammation of salivary and lacrimal glands
associated with symptoms of dry mouth (xerostomia) and
dry eyes (xerophthalmia), and considered secondary, when
associated with other connective tissue disorders such as
rheumatoid arthritis (RA), scleroderma, systemic lupus erythe-
matosus (SLE), primary biliary cirrhosis and polymyositis [1,2].
Saliva is a complex fluid that contains several organic and
inorganic components, and they play an essential role in
maintaining oral health. Salivary components include
4 K. GARLAPATI ET AL.

Figure 3. Forest plot showing Odds ratio of different studies. CI: confidence interval; Test for heterogeneity: Chi-squared statistic with its degrees of freedom (df)
and p values; I2: inconsistency among results; Test for overall effect: Z statistic with p values.

Figure 4. Funnel plot of standard mean differences of different studies using random effects model.

digestive enzymes such as lingual lipase and ptyalin, mucins,
immunoglobulin A and sodium, potassium, calcium, and
chloride electrolytes. The normal salivary flow rate in healthy
individuals is estimated to be 500–600 mL/day. Saliva is not
only essential to preserve the dentition and mucosal surfaces
but it also facilitates digestion, speech, chewing, swallowing,
and taste. Therefore, apart from dry mouth, there are many
other oral consequences of salivary gland hypofunction.
There is decreased salivary flow rate of 1.5 mL of saliva col-
lection during a 15-min period in patients with SS leading to

Figure 5. Funnel plot of Odds ratio of different studies using fixed effects model.
xerostomia. Oral symptoms that are commonly seen in SS
are dysphonia, dysphagia, stomatopyrosis (burning mouth),
dysgeusia (altered taste) decay of teeth and frequent oral
infections such as candidiasis and sleep disruption caused by
nocturnal fluid ingestion. Though these are not life-threaten-
ing complications, the complex and chronic nature of the
symptoms may lead to significant debility and a decrease in
patients quality of life [1,6,8,9].
Preventive measures such as fluoride supplements, avoid-
ing sugar or medications which are known to cause dry
mouth, and regular dental checkups are recommended.
Salivary substitutes or frequent intake of non-sugared liquids
may provide symptomatic relief for some patients with
Sjogren’s syndrome [3]. Many pharmacological agents are
used to increase the salivary gland hypofunction.
In our study, five articles were included, and experimental
group samples were 664 and the pharmacological agents
which were administered showed improvement in salivary
flow in many patients compared to the 371 placebo group
samples. Most of the patients in studies were females as
Sjogren’s syndrome is most commonly seen in females. All
the patients included in the studies were of different age
groups and all the patients were above 18 years In all the
studies included in the analysis, 100 mm Visual Analog Scale
was used for the assessment of oral symptoms.
The various pharmacological agents which were used in
the studies included in the analysis were Cevimeline 15 mg,
30 mg, 60 mg, Pilocarpine 2.5 mg, 5 mg, Interferon alpha
150 IU, 450 IU. Two forest plots were derived from the avail-
able data. One analysis was done based on the Standard
mean differences obtained from the included studies
(Table 1, Figure 2). Another analysis was done based on the
ODDS ratio obtained from the included studies (Table 2,
Figure 3).
Pilocarpine is a natural compound derived from the South
American shrub Pilocarpus jaborandi. This plant alkaloid is a
IMMUNOPHARMACOLOGY AND IMMUNOTOXICOLOGY 5
cholinergic parasympathomimetic agonist that binds to mus-
carinic- M3 receptors and causes pharmacological smooth
muscle contraction in humans and stimulates various exo-
crine glands. By this mechanism, the cholinergic stimulation
of residual-functioning exocrine glandular tissue in patients
with SS could probably pacify symptoms of xerostomia,
xeropthalmia or other symptoms associated with Sjogren’s
syndrome. The Tupi Indian tribe of northern Brazil had recog-
nized the medicinal properties of pilocarpine, and its ability
to stimulate salivation for many centuries and named this
indigenous shrub ‘jaborandi,’ or the ‘slobber-mouth plant.’ In
1888, a British physician described a 65-year-old woman with
xerostomia and xerophthalmia who probably had SS and
responded symptomatically to treatment with tincture of
jaborandi, given orally and subcutaneously. The beneficial
effects of pilocarpine tablets for the treatment of dry mouth
symptoms from various causes, including SS, was suggested
in smaller studies and case reports [8,10,11].
In the study done by Frederick et al. [8] evaluated the effi-
cacy of Pilocarpine 2.5 mg and 5 mg 4 times daily for
12 weeks and compared with placebo and 5 mg pilocarpine
group showed statistically significant improvement in saliva
flow rate. The most frequently reported adverse events were
sweating, headache, flu syndrome, nausea, rhinitis, dizziness,
urinary frequency.
Cevimeline hydrochloride is a quinuclidine derivative of
acetylcholine. There are five subtypes of muscarinic acetyl-
choline receptors and each one is encoded by a different
gene. These muscarinic receptors are expressed in neurons
of the central and peripheral nervous systems, cardiac and
smooth muscle, and a variety of exocrine glands. Studies
have shown that the muscarinic acetylcholine receptors
found in human labial salivary glands are a mixture of the
M1 and M3 subtypes and M3 muscarinic receptor accounts
for 93% of the precipitable receptors in parotid membranes.
Cevimeline has a high affinity for the muscarinic M3 receptor
6 K. GARLAPATI ET AL.
located on the epithelium of lacrimal and salivary glands.
Cevimeline compared with pilocarpine in the laboratory has
been shown to have a 40-fold greater relative affinity for the
M3 receptor than for the M2 cardiac receptor and long-last-
ing sialogogic action. Cevimeline is taken 3 times daily due
to its extended 5-h half-life and seems to have minimal
adverse effects at doses of 90 mg/day and can be tolerated
up to a dosage of 180 mg/day [6,7,12].
In the study done by Dianne et al. [6] efficacy of
Cevimeline 15 mg and 30 mg 3 times daily for 12 weeks was
compared with placebo and 30 mg Cevimeline showed good
result in improving saliva flow rate as the visual analog scale
findings showed increased efficacy in patients who received
30 mg dosage of Cevimeline compared with patients who
received 15 mg dosage of Cevimeline. The most commonly
reported drug-related adverse effects were nausea, sinusitis,
increased sweating, headache, diarrhea, pharyngitis.
Another study was done by Rose et al. [9] also evaluated
the efficacy of Cevimeline 30 mg and 60 mg 3 times daily for
6 weeks was compared with placebo and both dosages
showed symptomatic improvement. Patients receiving 60 mg
thrice daily reported adverse events more frequently such as
increased sweating, nausea, headache, diarrhea, dizziness,
vomiting, constipation.
Interferons are a group of proteins derived from different
cell types in response to stimuli such as bacteria, foreign
cells, macromolecules, chemical compounds, and viruses.
Five distinct classes of IFN have been designated; alpha,
beta, gamma, omega, and tau. They have antiviral activity
and also potent immunomodulating effects. Interferon (IFN)
has been shown to enhance phagocytic antigen processing
and immune regulatory activity of macrophages, specific
cytotoxicity of lymphocytes for target cells, and natural killer
cell activity. The biologic activity of IFN alfa administered in
low dosage via the oromucosal route was examined in many
species, and also in human beings. The oral route of drug
administration is generally preferred to the parental route
due to less adverse effects. Data obtained from these studies
suggest that IFN alfa given via oral mucosa can trigger a sys-
temic biologic response. In a study, in the presence of low
doses of IFN alfa culture of human parotid gland tissue
revealed augmented aquaporin-5 (AQP5) transcription and
protein production. Therefore, the increased UWS flow seen
following IFN alfa treatment may be due to an upregulation
of AQP5, with highly selective water channel proteins
reported to be abnormally distributed in lacrimal and salivary
glands of Sjogren’s syndrome patients. In fact, there was sig-
nificant normalization of serum globulin levels in the IFN alfa
group patients, compared with placebo patients, suggesting
an immunologic benefit of IFN alfa lozenge therapy [2,3]. It
is well established that for normal immune function IFN-a or
IFN-b is necessary. Thus, the deficiency of IFN-a in SS may be
corrected by exogenous IFN- a and normal function of the
salivary glands is restored [13].
In the study done by Jonathan et al. [3] safety and effi-
cacy of four dosages of natural human interferon-a 150 IU
and 450 IU once [QD] or three times [TID] daily was com-
pared with placebo in 12-week period of time and use of
150 IU IFN TID showed improvement in salivary output.
Though parenteral IFN treatment was accompanied by
adverse effects such as flu-like syndrome, central nervous sys-
tem depression, and myelosuppression, low dose administra-
tion of IFN-a by lozenges appeared safe and well tolerated.
Another study was done by Martin et al. [2] also eval-
uated the efficacy of human interferon [IFN] alfa 150 IU loz-
enges three times daily compared with placebo for 24 weeks
and showed improvement in salivary flow rate. The adverse
events experienced by the patients included in the study
were chest pain and arthropathy.
Conclusion
By analyzing the data, it can be concluded that use of
Interferon-a 150 IU given thrice daily improves the unstimu-
lated salivary flow rate as it has immunomodulatory action
and the drug given at low dosages and more intervals were
proven to have a beneficial effect. Cevimeline hydrochloride
30 mg given thrice daily had a better response when com-
pared with Pilocarpine 5 mg given 4 times daily.
Limitations
High heterogeneity was present in the objective response
comparison of mean values which can be explained to the
substantial level of heterogeneity in Cevimeline compared
with placebo (I2 ¼ 50%) and other subgroups presenting the
minimal level of heterogeneity (I2 ¼ 0%) which can be attrib-
uted to a difference in dosages and duration of treatment.
However, randomized controlled clinical trials with standard
and uniform protocol are required to eliminate the bias in
meta-analysis.
Disclosure statement
No potential conflict of interest was reported by the authors.
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