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Cevimeline for the Treatment of Xerostomia in Patients With Sjögren Syndrome
A Randomized Trial
Rose S. Fife, MD;
Walter F. Chase, MD;
Robin K. Dore, MD;
Craig W. Wiesenhutter, MD;
Peter B. Lockhart, DDS;
Elizabeth Tindall, MD;
James Y. Suen, MD
Arch Intern Med. 2002;162:1293-1300.
ABSTRACT
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Background Cevimeline hydrochloride is a cholinergic agent with muscarinic agonist
activity prominently affecting the M1 and M3 receptors prevalent in exocrine
glands. We evaluated the safety and efficacy of cevimeline in the treatment
of xerostomia in patients with Sjögren syndrome.
Methods Seventy-five patients with Sjögren syndrome and associated salivary
gland dysfunction were enrolled in a double-blind, randomized, placebo-controlled
trial at 8 university- and office-based outpatient clinical facilities in
the United States. Eligible study participants were randomized to receive
30 mg of cevimeline 3 times daily, 60 mg of cevimeline 3 times daily, or placebo
for 6 weeks. Subjective responses were determined using global patient evaluation
and visual analog scales. Salivary flow was measured objectively.
Results Sixty-one participants completed the study. Patients in both cevimeline
groups had significant improvements in dry mouth, as indicated by symptoms,
salivary flow, and use of artificial saliva, compared with the placebo group.
The drug was generally well tolerated, with expected adverse events resulting
from the drug's muscarinic agonist action. Fourteen patients withdrew from
the study because of adverse events, the most frequent being nausea.
Conclusions Therapy with cevimeline, 30 mg 3 times daily, seems to be well tolerated
and to provide substantive relief of xerostomia symptoms. Although both dosages
of cevimeline provided symptomatic improvement, 60 mg 3 times daily was associated
with an increase in the occurrence of adverse events, particularly gastrointestinal
tract disorders. Use of 30 mg of cevimeline provides a new option for the
treatment of xerostomia in Sjögren syndrome.
INTRODUCTION
SJÖGREN SYNDROME, a chronic, slowly progressive autoimmune disease,
is characterized by lymphocytic infiltration of the exocrine glands resulting
in xerostomia and keratoconjunctivitis sicca. Sjögren syndrome can occur
alone (primary Sjögren syndrome), but it is often associated with other
rheumatic disorders, such as rheumatoid arthritis, scleroderma, and systemic
lupus erythematosus (secondary Sjögren syndrome). Approximately 30% of
patients with autoimmune rheumatic diseases have secondary Sjögren syndrome.1
As a result of exocrine dysfunction, most patients with Sjögren
syndrome have symptoms related to diminished activity of the lacrimal and
salivary glands.1 Salivary gland dysfunction
can cause difficulty in chewing and swallowing food, difficulty in speaking
without frequent water intake, and difficulty wearing dentures and an increased
incidence of dental caries and oral candidiasis.2
Compared with more serious diseases, symptoms of Sjögren syndrome can
seem minor; however, the complexity of symptoms and the chronicity of the
disease can lead to significant debility and a decrease in patient quality
of life.3
Recently approved by the Food and Drug Administration, cevimeline hydrochloride
(Evoxac; Daiichi Pharmaceutical Corp, Montvale, NJ) is an acetylcholine analogue
with high affinity for the muscarinic M3 receptor located on lacrimal and
salivary gland epithelium.4-5
In the laboratory, cevimeline has been shown to have a 40-fold greater relative
affinity for the M3 receptor than for the M2 cardiac receptor compared with
pilocarpine,3, 6-7
as well as long-lasting sialogogic action.3
Pharmacological activity, measured as increases in salivary and tear secretions,
has been extensively reported in various animal models, including rodents
and dogs.4, 8-9
Because of the limited number of agents available for the treatment
of Sjögren syndrome, there is a clear need for the development of novel
agents that provide safe and effective treatment for patients with xerostomia
and keratoconjunctivitis sicca. Therefore, this phase II study was conducted
to evaluate the safety and efficacy of a new cholinergic agonist, cevimeline,
in the treatment of xerostomia and keratoconjunctivitis sicca in patients
with Sjögren syndrome. Data are reported for the treatment of xerostomia.
PATIENTS AND METHODS
INCLUSION CRITERIA
Patients aged 18 to 70 years with a primary or secondary diagnosis of
Sjögren syndrome and associated lacrimal and salivary gland dysfunction
were included. Women of childbearing age were required to have a negative
pregnancy test result and to use an accepted method of birth control or be
surgically sterile.
A clinical diagnosis of primary Sjögren syndrome was defined as
follows: (1) at least 1 positive response to ocular and oral symptom yes/no
questions; (2) lacrimal and salivary gland dysfunction; and (3) positive anti-Ro/SS-A
or anti-La/SS-B antibodies, rheumatoid factor, or antinuclear antibodies.
Secondary Sjögren syndrome was defined as follows: (1) at least
1 positive response to either ocular or oral symptom yes/no questions; (2)
lacrimal and salivary gland dysfunction; (3) positive anti-Ro/SS-A or anti-La/SS-B
antibodies, rheumatoid factor, or antinuclear antibodies; and (4) positive
antinuclear antibodies, rheumatoid factor, or other evidence of accompanying
rheumatoid arthritis or other connective tissue disease.
Lacrimal dysfunction was defined as abnormal Schirmer test results ( 5
mm in 5 minutes) for both eyes. Salivary dysfunction was defined as unstimulated
whole saliva collection of 1.5 mL or less in 15 minutes.
EXCLUSION CRITERIA
Patients with enlarged salivary glands (with or without pain); those
who were suspected of having physical closure of the salivary glands or who
had a known surgical closure of the lacrimal punctum (permanent or temporary
closure); and those with external ophthalmic disease (viral, bacterial, or
fungal infection), diabetic keratitis, or neutrophilic corneal disorder were
excluded. Patients with a significant history of cardiovascular, gastrointestinal
tract, psychiatric, pulmonary, or renal disease were excluded. Patients with
acute iritis, narrow-angle glaucoma, or preexisting retinal disease were excluded.
Patients taking or having taken any other investigational new drug (an entity
not registered for use) within the past 30 days or who were due to receive
such a drug during this study were excluded. Patients taking any anticholinergic
agents or other medications known to affect salivation or lacrimation were
excluded. Patients who were unwilling or unable to comply with the protocol
or who had a history of radiation therapy as the cause of salivary gland dysfunction
were excluded.
PROTOCOL
Patients were enrolled at 8 university- and office-based outpatient
clinical facilities in the United States. Before initiation of the study,
the protocol was approved by local institutional review boards. The study
was completed according to the guidelines of Good Clinical Practice and was
conducted in full compliance with the World Medical Association Declaration
of Helsinki and its most recent amendments.
The sample size for the study was not based on statistical calculations.
However, the numbers were deemed adequate to characterize the effect of cevimeline
vs placebo. All patients gave written informed consent before eligibility
was confirmed. All study participants had a baseline medical history taken
and underwent physical and ophthalmologic examinations at the screening visit.
In addition, clinical laboratory tests, measurement of vital signs, 12-lead
electrocardiography, and subjective and objective measurements of salivary
and lacrimal flow were performed at the primary screening and after 7 days
to establish baseline values.
At the baseline visit (week 0), study participants were randomized using
a computer-generated randomization schedule (PPD Pharmaco Inc, Wilmington,
NC) to receive either 30 mg of cevimeline hydrochloride 3 times daily (tid),
60 mg of cevimeline hydrochloride tid, or placebo for 6 weeks. All study medication
and placebo were provided in white gelatin capsules made to appear indistinguishable.
The investigators and participants were masked to treatment assignments. Patients
were instructed to take the medication on an empty stomach (at least 1 hour
after a meal) and were counseled to avoid high-fat meals during active treatment.
Study participants returned to the clinic for evaluation at weeks 2, 4, and
6. At each visit, including the baseline visit, subjective and objective assessments
were made before dosing (trough level) and after dosing (peak level).
SUBJECTIVE MEASUREMENTS
The primary efficacy end points were subjective patient assessments,
including global patient evaluation to assess improvement in dry mouth. Study
participants reported responses of "better," "no change," or "worse" compared
with baseline (before starting treatment). The global evaluations were performed
at each visit (weeks 0, 2, 4, and 6) 1 hour after administration of the study
medication. In addition, an uncalibrated 100-mm visual analog scale was used
to measure 6 subjective assessments of dry mouth (feeling of mouth, dryness
of mouth, dryness of tongue, ability to speak without drinking, ability to
chew and swallow food, and ability to sleep). Measured distance along the
scale served as the score for these continuous variables. Visual analog scale
assessments were carried out before and 1 hour after dosing at each visit.
OBJECTIVE MEASUREMENTS
Secondary efficacy end points included objective measurement of salivary
flow and the use of palliative treatments. To measure total salivary flow,
patients, who had no gustatory stimulus for a minimum of 90 minutes, were
instructed not to swallow and to allow the saliva to collect in the mouth
for 5 minutes. Patients then expectorated the contents of the mouth into a
collection tube. After the 15-minute collection period, the tube was sealed
and weighed.
Throughout the study, participants were provided with take-home questionnaires
to record their use of supportive agents, such as artificial saliva, and their
fluid intake.
SAFETY
To evaluate safety and toxic effects, clinical laboratory values and
findings from 12-lead electrocardiography were recorded at each visit before
dosing. Vital signs were recorded before each dose and 1 hour after taking
the study medication at each visit. Objective ocular tests, an ophthalmologic
examination, and a physical examination were conducted at the screening visit
and at the end of the study. In addition, blood and urine samples were collected
at each visit for laboratory analysis. Adverse events were documented throughout
the study at each visit.
ANALYSES
Efficacy analysis was performed on an intent-to-treat basis. For each
of the 4 visits (weeks 0, 2, 4, and 6), data were analyzed for statistical
significance, defined as P<.05. In addition to
analyses by visit week, an end point analysis was performed. End point values
were taken from data at the last postdose evaluation for each patient. For
patients who completed the study, therefore, week 6 results represent end
point values.
The Cochran-Mantel-Haenszel row mean scores statistic was used to analyze
significant differences in global patient evaluations and use of supportive
treatment among the groups. Analysis of variance was used to detect change
from baseline for the visual analog scale and lacrimal and salivary flow measurements.
The Fisher exact test was used to assess significant difference in adverse
effects across the treatment groups.
RESULTS
The study took place between July 6, 1995, and April 11, 1996. Of 129
patients screened, 75 patients met the entry criteria and were randomized
to 3 groups. Twenty-three patients were randomized to receive placebo, 25
to receive 30 mg of cevimeline tid, and 27 to receive 60 mg of cevimeline
tid (Figure 1). Most patients enrolled
were white (n = 69 [92%]) and women (n = 65 [87%]) (Table 1). Demographic variables of race and age, mean fluid intake
within 24 hours, and number of patients with visual abnormalities were comparable
across treatment groups. There was no difference among groups in the number
of patients with primary or secondary diagnoses of Sjögren syndrome.
Although most patients at baseline had dry mouth and dry eyes of moderate
severity, there were no statistically significant differences among treatment
groups in the number of patients with mild, moderate, or severe dry mouth
and dry eyes.
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Figure 1. The number of patients randomized
to the 3 groups and the number of patients not completing the study; tid indicates
3 times a day.
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Table 1. Patient Demographics*
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Of 75 initial patients, 61 completed all visits (Figure 1). All participants to whom study drug was dispensed were
included in the intent-to-treat efficacy analysis. One patient in the 60-mg
tid group dropped out before an efficacy evaluation; this patient was included
(considered as "worse") in the primary end point analysis and excluded from
the other assessments. The following protocol deviations occurred during the
study: 1 patient was aged 75 years (outside the range of 18-70 years specified
in the inclusion criteria) and no pregnancy test was performed on 2 patients
at screening; results of pregnancy tests performed later on these patients
were negative. None of these protocol deviations caused the patients to be
excluded from the efficacy or safety analyses.
SUBJECTIVE MEASUREMENTS
Patient Global Evaluations
At weeks 0, 2, 4, and 6, statistically significant differences in dry
mouth between the placebo group and the 30-mg cevimeline tid group were evident
in favor of the active drug (P = .014, .011, .011,
and .004, respectively). At weeks 0 and 2, there were statistically significant
differences in dry mouth between the placebo group and the 60-mg cevimeline
tid group favoring the active drug (P.02). At
weeks 4 and 6, the differences favoring the active drug at 60 mg tid approached
statistical significance (P.08). In particular,
patients in the 30-mg and 60-mg cevimeline tid groups showed a significantly
favorable effect on dry mouth compared with the placebo group at the end point
(P = .004 and .02, respectively). At the end point,
19 patients receiving 30 mg of cevimeline (76%) and 18 receiving 60 mg of
cevimeline (67%) compared with 8 in the placebo group (35%) had a response
of "better" when assessed for improvement of dry mouth (Figure 2). There was no significant difference between the 30- and
60-mg cevimeline tid groups at any visit or at the end point.
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Figure 2. Patient global evaluation of dry
mouth at the end point; tid indicates 3 times a day.
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At the end point, participants receiving 30 mg of cevimeline tid had
a statistically significant improvement in dry eyes compared with the placebo
group (P = .007). Eighteen patients receiving 30
mg of cevimeline tid (72%) vs 7 receiving placebo (30%) had responses of "better"
in assessing improvement of dry eyes at the end point (Figure 3). In the 60-mg cevimeline tid group, 14 patients (52%)
reported a response of "better" for improvement of dry eyes; however, this
was not a statistically significant difference from the placebo group (P = .10).
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Figure 3. Patient global evaluation of dry
eyes at the end point; tid indicates 3 times a day.
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At weeks 2, 4, and 6, a higher percentage of patients receiving active
drug reported "better" in their global evaluation for improvement of overall
dryness compared with those receiving placebo. By the end point, patients
randomized to receive 30 or 60 mg of cevimeline tid had achieved statistically
significant improvements in overall dryness compared with the placebo group
(P = .004 and .03, respectively) (Figure 4).
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Figure 4. Patient global evaluation of overall
dryness at the end point; tid indicates 3 times a day.
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Visual Analog Scale
Overall, there were no statistically significant differences among study
groups at predose assessments. However, a trend toward a statistically significant
change from baseline was observed between the treatment groups and the placebo
group at week 2 for ability to sleep (P = .08), burning
sensation in the eyes (P = .05), and ability to open
the eyes in light (P = .08).
Comparing changes in predose to postdose assessments at individual visits,
a statistically significant difference between treatment groups and the placebo
group was observed at week 2 in feeling of the mouth (P = .02), dryness of the mouth (P = .03), and
dryness of the tongue (P = .04) (Table 2). In all of these instances, patients treated with cevimeline
were more comfortable than those treated with placebo. At week 2, patients
treated with 30 mg of cevimeline tid also showed a statistically significant
difference in favor of active drug compared with the placebo group in mucus
or discharge in the eyes (P = .01; 95% confidence
interval [CI], –12.95 to –1.14) and burning sensation in the eyes
(P = .001; 95% CI, –23.53 to –3.65).
At the end point, patients in the 30-mg cevimeline tid group compared with
the placebo group had a statistically significant difference in favor of the
active drug in ability to speak without drinking (P
= .01; 95% CI, –21.46 to –1.72) and ability to chew and swallow
food (P = .02; 95% CI, –19.00 to –1.82)
(Table 2).
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Table 2. Changes in Predose to Postdose Assessment of Symptoms of Dry
Mouth and Dry Eyes Using the Visual Analog Scale*
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A statistically significant overall difference was detected at the end
point among treatment groups in ability to speak without drinking (P = .04) and for the sensation of sand in the eyes (P = .04) (Figure 5). In each
of these cases, patients treated with active drug were more comfortable than
patients treated with placebo.
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Figure 5. Summary of change from predose
to postdose in patients' visual analog scale assessment of selected symptoms
at the end point; tid indicates 3 times a day.
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No significant differences were detected among or between treatment
groups for the overall feeling of the eyes, dry feeling of the eyes, or ability
to open eyes in light.
OBJECTIVE MEASUREMENTS
In postdose assessments, there was a significant difference in end point
salivary flow values from baseline values for both cevimeline groups compared
with the placebo group (P = .001 and <.001, respectively).
Change in mean salivary flow from predose to postdose was significantly different
among the groups at all visits (P.003) and particularly
at the last visit, when patients in the cevimeline groups had a change in
predose to postdose mean salivary flow of 0.26 mL/min (60-mg group) and 0.19
mL/min (30-mg group) compared with 0.01 mL/min in the placebo group (P<.001) (Figure 6).
Throughout the study, both cevimeline groups had a greater mean increase in
salivary flow for all assessments compared with the placebo group. Increases
in salivary flow were most notable in the group receiving 60 mg of cevimeline
tid compared with those receiving 30 mg of cevimeline tid. There seems to
be a greater effect on salivary flow with increasing dose levels. Table 3 provides a summary of the quantitative
salivary flows at the end point.
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Figure 6. Summary of change from predose
to postdose in salivary flow at the end point; tid indicates 3 times a day.
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Table 3. Summary of Salivary Flow at the End Point*
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No significant differences were observed in lacrimal flow among the
treatment groups during the study or at the end of the study. For instance,
change from predose to postdose in mean lacrimal flow was 0.75 mm/min in the
group receiving 60 mg of cevimeline tid, 0.67 mm/min in those receiving 30
mg of cevimeline tid, and 0.71 mm/min in the placebo group at the end point
(P = .29).
Overall, there was a greater reduction from baseline in the use of artificial
saliva and tears and in fluid intake for patients who received active drug
compared with those who received placebo. More patients in the 60-mg cevimeline
group decreased their use of artificial saliva than in the other groups. At
the end point, 5 patients in the 60-mg cevimeline tid group (19%) decreased
their use of artificial saliva compared with 1 in the 30-mg cevimeline tid
group (4%) and none in the placebo group (Table 4). Ten patients receiving 30 mg of cevimeline tid (40%) and
15 receiving 60 mg of cevimeline tid (58%), compared with 10 in the placebo
group (44%), decreased baseline use of artificial tears at the end of the
study (Table 4). There were no
significant differences among treatment groups at any visit in the number
of patients who decreased fluid intake.
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Table 4. Summary of Change From Baseline to the End Point in Use of
Artificial Saliva, Use of Artificial Tears, and Fluid Intake*
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SAFETY
A total of 14 patients withdrew from the study because of adverse events.
Nine patients withdrew from the 60-mg cevimeline tid group, 4 from the 30-mg
cevimeline tid group, and 1 from the placebo group. All patients receiving
60 mg of cevimeline had at least 1 adverse event reported during the study
(Table 5). The most common adverse
effects, categorized by body system, were general disorders (body as a whole),
gastrointestinal tract disorders, and dermatologic disorders (skin and appendages).
The average number of adverse events reported per patient increased with increasing
dose (Table 5).
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Table 5. Incidence of Adverse Effects*
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Adverse events reported in 10% or more of patients in any single treatment
group are presented in Table 6.
Significant differences were noted between the placebo and the 60-mg cevimeline
tid groups in the incidence of increased sweating (P<.001),
nausea (P<.001), and rigors (P = .03). Overall, adverse events were more frequently reported for
patients receiving 60 mg of cevimeline tid than in the other treatment groups
and thus seem to be dose related. Many of the frequently reported adverse
events were those expected on the basis of the pharmacological action of the
study medication, for example, increased sweating, increased salivation, and
nausea. The most frequently reported adverse event resulting in discontinuation
from the study was nausea (Table 7).
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Table 6. Incidence of Adverse Events Reported by 10% or More of the
Patients in Any Single Treatment Group*
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Table 7. Discontinuation Due to Adverse Events*
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There were no apparent dose-related changes in mean laboratory values
and vital signs from baseline to the end of the study. Most patients in each
treatment group had laboratory values within the reference ranges at baseline
and at the end of the study. The serum amylase level was noted to be elevated
in 1 patient receiving 60 mg of cevimeline tid.
COMMENT
Sjögren syndrome remains an incurable disease. Hence, treatment
is aimed at providing symptomatic relief and at limiting the damaging local
effects of xerostomia and keratoconjunctivitis sicca.1
Typically, patients with Sjögren syndrome have relied on physiological
stimulation of salivary flow or the use of saliva substitutes to relieve symptoms
of dry mouth. Physiological stimulation with sugarless chewing gum or hard
candies can be effective in patients who retain some salivary function, but
salivary flow is increased only while the gum or candy is in the mouth. Saliva
substitutes do not fulfill all of the functions of natural saliva, and because
they are swallowed, the duration of their effect is brief.10
Several investigations have shown that pilocarpine use is beneficial
in reducing the symptoms of xerostomia, with the effects of a single dose
lasting up to 3 hours.11 Cevimeline, a quinuclidine
derivative of acetylcholine, is a novel muscarinic receptor agonist9 and was recently approved by the Food and Drug Administration
for the treatment of dry mouth in patients with Sjögren syndrome. Because
of its extended 5-hour half-life, cevimeline is taken 3 times daily12; it seems to have minimal adverse effects at doses
of 90 mg/d and is tolerated at doses up to 180 mg/d. The monthly cost of treatment
with cevimeline, at the recommended dosage for xerostomia in Sjögren
syndrome, is approximately $118.12
Consistent with results of animal models,4, 8
this study shows that cevimeline therapy is highly effective in improving
the symptoms of dry mouth in patients with Sjögren syndrome. The differences
among study groups overall in the number of patients reporting responses of
"better," "no change," and "worse" were significant in favor of the active
drug at all assessments for dry mouth (P.03)
and at all assessments after week 0 for overall dryness (P.04). Furthermore, the difference among treatment groups in change
in salivary flow from predose to postdose within each visit was statistically
significant at the end point (P<.001) and at all
other visits (P.003). At all assessments, the
cevimeline groups had greater mean increases in salivary flow than did the
placebo group. The dose of 30 mg of cevimeline tid was well tolerated and
provided substantive relief for the duration of the study. We conclude from
the results of this randomized, double-blind, placebo-controlled, phase II
study that cevimeline has therapeutic effects in the treatment of xerostomia
in patients with Sjögren syndrome for up to 6 weeks. Further work needs
to be done to assess its long-term efficacy and safety and its utility in
the treatment of keratoconjunctivitis sicca.
AUTHOR INFORMATION
Accepted for publication October 15, 2001.
This study was supported by grants from SnowBrand Pharmaceuticals Inc,
Rockville, Md, and Daiichi Pharmaceutical Corp.
We thank Anh Thu Hoang, PharmD, for assistance in writing the manuscript
and the clinical coordinators at the study sites, without whose assistance
the study would not have been possible.
Corresponding author and reprints: Rose S. Fife, MD, Department of
Medicine, Indiana University School of Medicine, 535 Barnhill Dr, Room 150,
Indianapolis, IN 46202.
From the Department of Medicine, Indiana University School of Medicine,
Indianapolis (Dr Fife); the Division of Rheumatology, University of California,
Los Angeles, School of Medicine (Dr Dore); the Coeur d'Alene Arthritis Clinic,
Coeur d'Alene, Idaho (Dr Wiesenhutter); the Department of Oral Medicine, Carolinas
Medical Center, Charlotte, NC (Dr Lockhart); the Department of Medicine, Oregon
Health Sciences University, Portland (Dr Tindall); and the Department of Otolaryngology–Head
and Neck Surgery, University of Arkansas for Medical Sciences, Little Rock
(Dr Suen). Dr Chase is in private practice in Austin, Tex.
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