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The incidence of sjgren's sicca complex in a population of patients with keratoconjunctivitis sicca.

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THE INCIDENCE OF SJOGREN’S SICCA COMPLEX
IN A POPULATION OF PATIENTS WITH
KERATOCONJUNCTIVITIS SICCA
JOSEPH Z. FORSTOT, S. LANCE FORSTOT, ROBERT 0. GREER, and ENG M. TAN
A prospective study was performed on patients
who came to a university ophthalmology outpatient
clinic with the complaint of dry eyes and who were
documented to have keratoconjunctivitis sicca (KCS).
Of 45 patients studied 1 had primary amyloidosis, and
another 10 had KCS with a previously diagnosed connective tissue disease. Of the remaining 34 patients, 19
had KCS alone without xerostomia, and the remaining
15 had KCS in association with subjective or objective
xerostomia. Eight of these 15 patients were subsequently
shown to have clinical Sjogren’s syndrome-sicca complex, and for the majority, serologic and biopsy findings
supported this diagnosis.
Keratoconjunctivitis sicca (KCS) denotes a
condition in which the eyes are deficient in aqueous
tear secretion secondary to hypofunction of the lacrimal gland. As part of a systemic disease known as
Sjogren’s syndrome, this condition is the result of
chronic lymphocytic and plasma cell infiltration of the
glandular tissue, resulting in eventual destruction of
exocrine glands. This destructive process results in
From the Departments of Medicine (Division of Rheumatology). Ophthalmology, and Diagnostic and Developmental Dentistry,
University of Colorado Health Sciences Center.
Supported in part by NIH Grants AM20705 and AI07166,
an unrestricted grant from Research to Prevent Blindness, Inc, New
York City, NY.
Joseph Z. Forstot, MD: Fellow, Rheumatology; S . Lance
Forstot. MD: Assistant Professor, Department of Ophthalmology;
Robert 0. Greer, Jr., DDS: School of Dentistry; Eng M. Tan, MD:
Professor, Department of Medicine, Division of Rheumatology.
University of Colorado Health Sciences Center.
Reprint requests to S. Lance Forstot. MD, Department of
Ophthalmology. Container B204, 4200 East Ninth Avenue, Denver,
CO 80262.
Submitted for publication October 10, 1980; accepted in
revised form July 10, 1981.
Arthritis and Rheumatism, Vol. 25, No. 2 (February 1982)
symptoms of KCS and/or xerostomia (dry mouth).
These “sicca” symptoms may occur alone as sicca
complex or in association with a well-defined connective tissue disease (CTD), most commonly rheumatoid
arthritis (RA).
It is unclear how often a patient with “idiopathic” KCS has underlying Sjogren’s syndrome. When a
dry-eye patient has rheumatoid arthritis or another
connective tissue disease, the diagnosis of Sjogren’s
syndrome is established. However, no data are available on the incidence of the sicca complex among KCS
patients.
Our purpose was to study both serologically
and clinically a group of patients with KCS. We set out
to evaluate: 1) which serologic abnormalities were
present, 2) the percentage of KCS patients who had
oral involvement or sicca complex, and 3) the correlation between the serology and the clinical features of
the patient, if any.
MATERIALS AND METHODS
Patients who came to the Ophthalmology Clinic of
the University of Colorado Health Sciences Center with
complaints of dry eye symptoms were evaluated for tear
function. Two criteria for the presence of KCS were used: 1)
wetting of 5 mm or less when the Schirmer test was
performed with standard filter paper strips for 5 minutes
without anesthestic; and 2 ) anatomic abnormalities of KCS
according to the method of vanBijsterveld (1) when rose
Bengal 1% solution was used to stain the conjunctiva and
cornea. Forty-five patients met these criteria and formed the
patient population for this study.
Ten of the 45 patients had a diagnosis of connective
tissue disease at the time of ophthalmologic evaluation: their
symptoms met the criteria f o r rheumatoid arthritis (RA) (8
patients), systemic lupus erythematosus (SLE) ( I patient), or
SJOGREN’S SYNDROME AND KERATOCONJUNCTIVITIS SICCA
progressive systemic sclerosis (PSS) (1 patient) established
by the American Rheumatism Association (ARA) Diagnostic
Criteria (2). These 10 patients were not included in the data
presented. The remaining 35 patients had only KCS, but no
associated connective tissue disease.
The sample sera from the 35 KCS patients were
analyzed for antinuclear antibodies (ANA), rheumatoid
factor (RF), and antibodies to Sm, nuclear ribonucleoprotein (RNP), native DNA, and Sjogren’s antigens
(SS-A and SS-B) (3,4). Quantitative determination of IgG,
IgA, and IgM was also performed on all patients. The
following methods were used for the serologic tests.
Determination of antinuclear antibodies by indirect
immunofluorescence. All sera were tested for antinuclear
antibodies at 4 dilutions (1:4, 1:16, 1:64, 1:256) on 4~
cryostat sections of mouse kidney fixed in acetone immediately before testing. The conjugate used was fluoresceinisothiocyanate-labeled goat anti-human IgG, prepared in our
laboratory (5). The pattern and intensity of staining were
graded as trace to 4 + at each dilution. The findings were
considered positive if the sera reacted to a titer of at least
1 : 64. Evaluations were made at 4 0 0 ~by means of a Leitz
Ortholux I1 incident light microscope with a 200-watt mercury light source, KP 490 exciter filter, and K530 interferecene
filter.
Rheumatoid factor test. Latex agglutination titers for
rheumatoid factor were performed by a tube dilution method
(CalBioChem-Behring, LaJolla, CA) (6.7).
Immunodiffusion studies for precipitating antibodies.
The sera were tested for the presence of antibodies to Sm,
nuclear RNP (n-RNP), SS-A, and SS-B by a modification of
the Ouchterlony double-diffusion technique (4). The antibodies to Sm and n-RNP were detected using a saline powder
extract of rabbit thymus (Pel-Freez Biologicals. Rogers, AR)
(3,4). The antibodies to SS-A and SS-B were determined
using an extract of Wi12 cells prepared from cultures sustained in the laboratory (8).
Detection of antibodies to native DNA. Sera were
heat-inactivated at 56°C and tested at 1 : 10 dilution for DNA
binding activity by a Millipore filter technique (Millipore
Corp, Bedford. MA) and 3H Bacillirs subtillis DNA (9.10). In
this laboratory findings were considered positive if the
binding activity of the sera was greater than 10% (10).
Determination of quantitative values of IgG, IgA, and
IgM. The sera were tested for quantitative values of immunoglobulins by radial immunodiffusion in the Mancini technique (Behring Diagnostic Kit). A hypergammaglobulin state
is defined as an elevation of IgG, IgA, or IgM (or any
combination). (Normal IgG = 800-1800 mgi100 cc; normal
IgA = 90-450 nig/100 cc; normal IgM = 60-280 rng/lOO cc).
All 35 patients who had KCS were studied for
xerostomia. Xerostomia was considered to be present if
there were signs of dry mouth and/or a positive labial
salivary gland (LSG) biopsy. In taking histories special
attention was given to dysphagia, glandular swelling, medications reported to be associated with reduced salivary
secretions, dietary habits, and senses of taste and smell.
During the oral physical evaluation, enlargement of major
salivary glands, rnucosal changes, absent or decreased saliva
pool, furrowed tongue, and dental status were noted.
After the history and physical examination, labial
157
salivary gland biopsies were performed on those patients
complaining of dry mouth. The biopsies were assessed for
glandular involvement in patients in this series by techniques
described previously (1 I ) . Each biopsy was evaluated and
graded (0-IV) for Sjogren’s oral component by the classification established by Greenspan et al (12) and Tarpley et al
(13). No attempt was made to determine what grade level of
biopsy was significant, but rather, the results were placed in
the perspective of other findings as described later.
RESULTS
A prospective study was performed on 45 patients who came to a university ophthalmology outpatient clinic with dry eye symptoms and who were
documented to have keratoconjunctivitis sicca. Ten
patients had a diagnosed connective tissue disease at
the time of ophthalmologic examination. One patient,
a 54-year-old man who had symptoms of dry eye and
dry mouth, was subsequently diagnosed as having
amyloidosis, documented by Congo red staining of
labial salivary gland biopsy tissue and a rectal biopsy.
These 11 patients were not included in the data presented.
The 34 remaining KCS patients were divided
into 2 major groups on the basis of symptoms of dry
mouth: I) KCS patients who did not have symptoms of
dry mouth; 11) KCS patients with dry mouth symptoms. Group I1 was further divided into 2 subgroups
based on presence o r absence of objective signs of dry
mouth: subgroup Ha comprised KCS patients who had
only subjective dry mouth symptoms; subgroup 1Ib
comprised KCS patients who had objective signs of
dry mouth or xerostomia.
The entire group of 34 KCS patients had an
incidence of positivity of ANA, RF, and hypergammaglobulinemia of 59%, 56%, and 53%, respectively.
The incidence of antibodies for SS-A and/or SS-B
specificities was 29%. No antibodies were found to
Sm, n-RNP, or native DNA.
Group I comprised 19 patients (3 men and 16
women), and group I1 comprised 15 women (Table 1).
The age range of both groups was similar, ranging from
the third through the eighth decades. The age of onset
of KCS symptoms appeared at a much younger age in
group I1 (median age 36) compared with group I
(median age 44). The duration of KCS symptoms was
longer in group I1 (6 years) compared with group 1 (3
years).
Group I1 had a higher incidence of positive
ANA than group I (Table 2 ) . The incidence of RF was
greater and the titers of RF were higher in group I1
FORSTOT ET AL
158
Table 1. Comparison of keratoconjunctivitis sicca patients with and
without dry mouth symptoms
Number of patients
Male: female ratio
Age range (years)
Median age (years)
Dry eye symptoms
Median age of onset
Median years’ duration
of symptoms
Group I*
Group Ilt
19
3: 16
20-7 1
55
15
0:15
27-74
41
44
36
3
6.0
* Keratoconjunctivitis sicca patients who did not have dry mouth
symptoms.
t Keratoconjunctivitis sicca patients who had dry mouth
symptoms.
than in group I. The incidence of positive R F in group
I1 was 67% (10/15), and the geometric mean titer was
1240. In group I RF positivity was 42% (8/19), and the
geometric mean titer was 73. The presence of hypergammaglobulinemia was more common in group I1
(73%) than in group I (37%). Antibodies of SS-A
and/or SS-B specifications were present only in group
11.
A younger patient population was noted in
subgroup IIb than in IIa (median ages 39 and 53,
respectively) (Table 3 ) . The KCS symptoms occurred
over approximately the same time, but the age of onset
was younger in subgroup IIb (34 years) than in IIa (45
years). Dry mouth symptoms began at a younger age
in subgroup IIb (35 years, median age) than in IIa (50
years, median age). The duration of dry mouth symptoms was slightly longer in subgroup IIb (5 years) than
in IIa (2 years) (Table 3 ) .
None of the patients in subgroup IIa had objective evidence of dry mouth, and in all patients labial
salivary gland biopsies showed normal histology (Table 3). All 8 patients in subgroup IIb had documented
objective signs of dry mouth or xerostomia, and 6 of 8
patients had LSG biopsies showing abnormal histopa-
thology. The two grade-0 (zero) LSG biopsies were in
patients who had dry mouth symptoms for only 1 year,
compared to the 6 patients with LSG biopsies, grades
1-111, whose average duration of symptoms was 9.3
years.
Serologically, subgroups IIa and IIb had a high
incidence of positive ANA and RF. In subgroup Ila,
the ANA and R F positivity was 86% (6/7) and 43% (31
7), respectively; in subgroup IIb, the ANA and RF
were positive in 100% (8/8) and 88% (7/8), respectively. The R F titer was higher in subgroup IIb than IIa
(geometric mean titers: 1645 and 33, respectively).
Hypergammaglobulinemia was more frequent in subgroup IIb (87%) than in IIa (43%). Forty-three percent
(3/7) of patients in subgroup IIa had antibodies to SSA, and none had antibodies to SS-B. In subgroup IIb,
87% (7/8) of patients had antibodies to SS-B with or
without antibody to SS-A (Table 4). No patients in
subgroup IIb had only anti-SS-A. A third precipitating
antibody was noted in 2 patients in subgroup IIb
(Table 4: cases 6 and 7). The antibody was immunologically identical showing complete fusion lines in
immunodiffusion, but the specificity was dissimilar to
any previously detected precipitating antibody identified to date.
None of the 34 patients had evidence of connective tissue diseases (RA, SLE, PSS, or dermatomyositis). Eight patients (24%), subgroup IIb, had KCS and
objective evidence of xerostomia and therefore fulfilled clinically proposed criteria for Sjogren’s syndrome-sicca complex (14-16). In Table 4 the serologic
and clinical features of these patients are presented.
DISCUSSION
We have studied 19 patients with keratoconjunctivitis sicca alone without xerostomia and 15 patients with KCS in association with subjective or
objective xerostomia. The significance of the abnor-
Table 2. Serologic differences between group I and I1 patients
Antibodies to
Group
I
KCS without
xerostomia
11
KCS with
xerostomia
No. of
patients
Antinuclear
antibody
19
6 (32%)
15
14 (93%)
Rheumatoid
factor
Hypergammaglobulinemia
SS-A
SS-B
8 (42%)*
7 (37%)
0
0
10 (67%)*
I 1 (73%)
* Mean titer for group I was 73 and group I1 1240.
9 (60%) 7 (47%)
159
SJOGREN’S SYNDROME AND KERATOCONJUNCTIVITIS SICCA
Table 3. Comparison of keratoconjunctivitis sicca with subjective
and objective dry mouth
The interpretation of the significance of the lip biopsy
findings is difficult. Some investigators consider a
grade I biopsy to be “nondiagnostic” (12). Perhaps the
severity of cellular infiltration and/or glandular destruction of the salivary gland may be related to the
duration of sicca symptoms. In an earlier study, we
had required a grade 111 lip biopsy for indication of
Sjogren’s syndrome to test the specificity of SS-B
antibody (17). The present study was constructed with
a different intent, i.e., to determine the clinical, serologic, and biopsy findings of a population of patients
with dry eyes.
In subgroup IIa (7 patients who had subjective
complaints of xerostomia, but no objective findings),
all had normal histology on labial salivary gland biopsy. None of these patients had antinuclear antibody of
the SS-B specificity, but 3 of 7 had antibodies of SS-A
specificity. Recent studies have shown that antibody
to SS-A, although present in a high percentage of
patients with Sjogren’s syndrome-sicca complex, is
also present in patients with a variety of other connective tissue diseases (IS). Abnormal serologic features
were also present in this group of patients without
objective xerostomia. It will take a longer followup
study to determine if this group of patients represents
clinical entities different from Sjogren’s syndromesicca complex or represents early expressions of this
disease or of the sicca complex associated with another connective tissue disease.
This study may help in furthering our understanding of the natural history of certain connective
tissue diseases. Before the full-blown or “garden
variety” expression of certain connective tissue disease, there may be a long prodromal period. Further
studies of the type presented here and the followup of
Group IIa* Group Ilbt
Number of patients
Median age (years)
Dry eye symptoms
Median age of onset (years)
Median duration of symptoms
(years)
Dry mouth symptoms
Median age of onset (years)
Median duration of symptoms
(years)
Number of LSG biopsies performed$
LSG biopsy grades
0
I
53
8
39
45
34
6
5
50
35
2
I
5
8
7
0
2
6
I-1v
* Keratoconjunctivitis sicca patients who had only subjective
complaints of dry mouth.
t Keratoconjunctivitis sicca patients who had objective signs of
dry mouth.
$ LSG = labial salivary gland.
ma1 serologic findings (Table 2) in these patients with
KCS without xerostomia is unknown. Patients with
both objective and subjective signs of xerostomia
could be classified as having Sjogren’s syndrome by
generally accepted criteria. Examination of the data
further supports the diagnosis of Sjogren’s syndrome.
Seven of the 8 patients had antibodies to the SS-B
antigen, an antibody specificity that has been a useful
serologic aid in the diagnosis of Sjogren’s syndromesicca complex (17).
Six of the 8 patients with SS-B antigen specificity had lip biopsies that showed some abnormality
varying from grade I to 111. The 2 patients with normal
lip biopsies had symptoms of xerostomia for only I
year each, a shorter duration than the other 6 patients.
Table 4. Clinical and laboratory findings on female patients with Sjogren’s-sicca syndrome*
Case
Clinical
xerostomia
(year
duration)
ANA titer
and pattern
I1
I1
+ (I)
I
11
0
Bilateral
Unilateral
Unilateral
Bilateral
Bilateral
Unilateral
None
I :256 spec
1 :256 spec
1 :256 spec
1 :256 spec
1:64 spec
I :256 spec
1:256 spec
+
0
None
1 :256 spec
+ (5)
+ (6)
+ (30)
8
(1)
_______
* LSG
to
Parotid
gland
swelling
+ (3)
+ (3)
+ (10)
1
2
3
4
5
6
I
Precipitating antibodies
Grade
of LSG
biopsy
111
11
_
SS-A
+
+
+
+
+
+
+
+
+
+
-
-
-
i
-
CB
I :5260
0
1: 1280
1 :640
1 :2560
1 :640
@
1:1280
+
1:1280
+
+
_
+
Other
Hypergamma
globulin
SS-B
labial salivary glands. ANA = antinuclear antibody, spec = speckled. @
rheumatoid factor, OA = osteoarthritis, DIL = diffuse interstitial lung disease.
=
RF
titer
~
-
-
~
=
~.
~~~~~~~
+
+
+
+
+
Systemic
features
Art hralgias
None
OA, Raynaud’s
Arthralgias
Arthralgias
OA. DIL
Arthralgias.
Raynaud’s
Arthralgias
~-
-~
identical unidentified precipitating antibody, R F
=
FORSTOT ET AL
160
such patients would be important in our more complete understanding of these disease entities.
REFERENCES
I. vanBijsterveld OP: Diagnostic tests in the sicca syndrome. Arch Ophthalmol 86: 10-14, 1969
2 . Rodnan GP, McEwen C, Wallace SL: Primer on Rheumatic Diseases. JAMA 224: 137-138, 1973
3. Tan EM: Relationship of nuclear staining patterns with
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4. Nakamura RM, Greenwald CA, Peebles CL, Tan EM:
Autoantibodies to nuclear antigens (ANA): immunochemical specification and significance in systemic rheumatic diseases. Am Soc Clin Path 76-83, 94-100, 1978
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fluorescein isothiocyanate. J Immunol 95:442-445, 1965
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in Sjogren’s syndrome. J Clin Invest 55: 1067-1073, 1975
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DNA. Scand J Rheumatol (suppl 11) 35-41, 1975
11. Daniels TE, Silverman S, Michalski JP, Greenspan JS,
Sylvester RA, Talal N: The oral component of Sjogren’s
syndrome. Oral Surg 39:875-885, 1975
12. Greenspan JS, Daniels TE, Talal N , Sylvester RA: The
histopathology of Sjogren’s syndrome in labial salivary
gland biopsies. Oral Pathol 37:217-229, 1974
13. Tarpley TM, Anderson LG, White CL: Minor salivary
gland involvement in Sjogren’s syndrome. Oral Surg
37:64-74, 1974
14. Bloch KJ, Buchanan WN, Wohl MJ, Bunim JJ: Sjogren’s syndrome. Medicine 44(3):187-237, 1965
15. Shearn MA: Sjogren’s syndrome in major problems,
Internal Med, Vol 11. Edited by LH Smith Jr. Philadelphia, W.B. Saunders Co, 1971
16. Talal N: Sjogren’s syndrome and connective tissue
disease with other immunologic disorders. Chapter 54,
Arthritis and Allied Conditions. 9th Edition. Edited by
DJ McCarty. Philadelphia, Lea & Febiger, 1979, pp 810823
17. Martinez-Lavin M, Vaughan JH, Tan EM: Autoantibodies and the spectrum of Sjogren’s syndrome. Ann
Intern Med 91: 185-190, 1979
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