2010 Decker Intellectual Properties rheum Primary Sjgren Syndrome 1

DOI 10.2310/7900.1250
06/10
PRI MARY S J GREN S YNDROME
Kate L. Mitchell, MD, and E. William St. Clair, MD
Disease Denition
Sjgren syndrome (SS) is a chronic inammatory condition
that primarily affects the lacrimal and salivary glands, but it
may also have multisystem extraglandular manifestations.
In 1933, Dr. Henrik Sjgren,

a Swedish ophthalmologist,
published his senior doctoral thesis, Zur Kenntnis der Kerato-
conjunctivitis Sicca, which systematically described in 19
women with symptoms of dry eyes and dry mouth the
pathologic alterations in the anterior part of the eye and
the lacrimal and salivary glands.
1
He introduced the term
keratoconjunctivitis sicca (KCS) to describe the ocular
component of this syndrome, distinguishing this condition
from the xerophthalmia caused by hypovitaminosis A. The
term Sjgren syndrome later came to be used worldwide
for describing the triad of KCS (dry eyes), xerostomia
(dry mouth), and arthritis. Other names in the literature
for this condition have included Gougerots, Gougerots-
Sjgrens disease, Mikulicz disease, and autoimmune
epitheliitis.
Over the last several decades, the classication of SS
has evolved into two main categories: primary SS and
secondary SS [see Table 1]. Primary SS may be dened as an
autoimmune exocrinopathy predominantly characterized by
lymphocytic inltration of the lacrimal and salivary glands,
resulting in dry eyes and dry mouth, in the absence of an
associated connective tissue disease. Secondary SS refers to
the presence of KCS or xerostomia in the setting of another
rheumatologic disease, such as rheumatoid arthritis (RA),
systemic lupus erythematous (SLE), systemic sclerosis, or
polymyositis/dermatomyositis.
Extraglandular manifestations may be associated with
either primary or secondary SS. The pattern of extraglandu-
lar involvement in primary SS is distinct from the other
connective tissue diseases, although its features may overlap
with those of RA and SLE. In contrast, the extraglandular
features of secondary SS tend to parallel those of the associ-
ated rheumatologic condition. The chapter herein focuses on
the epidemiology, pathophysiology, clinical features, and
treatment of primary SS.
Epidemiology
Primary SS is among the most common of the autoim-
mune diseases. Its reported prevalence in most studies
ranges from 0.2 to 1.6%.
2
Primary SS more commonly affects
middle-aged women (peak incidence in the fourth and fth
decades) with a female-to-male ratio of 9:1. Primary SS,
however, affects the full range of ages from childhood to
the elderly. The prevalence of secondary SS in RA, SLE, and
systemic sclerosis has been reported to be 17.1%,
3
8 to 20%,
4,5

and 14%,
6
respectively.
Pathophysiology and Pathogenesis
The histopathology of primary SS is characterized by
lymphocytic invasion of the glandular tissue. Most of the
inltrating cells are CD4
+
a/b T lymphocytes and B lympho-
cytes, suggesting a major role for adaptive immunity in
the pathogenesis of this disease [see Figure 1 and Figure 2].
Studies of minor salivary gland biopsies from patients with
primary SS have shown that T and B lymphocytes comprise
more than 90% of the inltrating mononuclear cells.
7
The
remaining population consists of low numbers of CD8
+
T
cells, CD56
+
natural killer cells, CD68
+
macrophages, and
dendritic cells (DCs). In the salivary glands, the T and B cells
tend to aggregate around ducts and blood vessels. These
aggregates often form follicles consisting of B cell clusters
surrounded by a cuff of CD3
+
T cells. In severe lesions, T and
B cells may be organized into germinal centerlike struc-
tures. The classical antigen-presenting cells, namely DCs
and macrophages, are usually found in close proximity to
the ductal epithelium, where they produce a host of proin-
ammatory mediators such as interleukin-6 (IL-6), tumor
necrosis factora (TNFa), IL-12, and IL-18, as well as the
antiinammatory cytokine IL-10.
In primary SS, most of the CD4
+
T cells inltrating the
minor salivary glands express the CD45RO antigen, the
phenotype of memory T cells, indicating prior antigen expe-
rience. As might be expected in an antigen-driven response,
the CD4
+
T cells display a relatively restricted T cell receptor
(TCR) repertoire consisting of several clonotypes within
different Vb families. The nature of the stimulating antigen(s)
has proved to be elusive. Based on the classical T helper type
1 (Th1) versus T helper type 2 (Th2) paradigm, the salivary
gland CD4
+
T cells appear to produce mainly Th1 cytokines
(IL-2 and interferon gamma).
8
In contrast, the Th2 cytokines,
such as IL-4, IL-5, and IL-13, are found in less abundance.
Minor salivary glands from patients with primary SS also
contain T helper type 17 (Th17) cells.
9
Th17 cells are so
named because they produce the cytokine IL-17; many Th17
cells also secrete interferon gamma. Notably, the salivary
glands are rich in transforming growth factorb (TGF-b) as
well as IL-6 and IL-23, which is a favorable milieu for the
development of Th17 cells, which are induced by these
cytokines. The salivary gland inltrates in primary SS also
contain FoxP3
+
T regulatory cells.
10
FoxP3
+
T regulatory cells
act to suppress potentially hazardous autoimmune response s.
In addition to its Th17-promoting effects, TGF-b also plays
an essential role in generating T regulatory cells. However,
it has become increasingly evident that the different T cell
phenotypes (e.g., Th1, Th2, Th17, T regulatory cells) show
a measure of plasticity.
11
Therefore, the question of a Th1
versus Th2 versus Th17 paradigm as a conceptual model for
the pathogenesis of primary SS may not be straightforward
in a situation where cells may change their identities
depending on the environment.
B cells are also important players in the pathophysiology
of primary SS. The distribution of peripheral blood B cell
subsets in primary SS differs from that of healthy controls,
showing a relative increase in the percentage of CD27

naive B cells and a relative decrease in the percentage
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Table 1 Revised International Classication Criteria for Sjgren Syndrome (SS)
I. Ocular symptoms: a positive response to at least one of the following questions:
1. Have you had daily, persistent, troublesome dry eyes for more than 3 months?
2. Do you have a recurrent sensation of sand or gravel in the eyes?
3. Do you use tear substitutes more than 3 times a day?
II. Oral symptoms: a positive response to at least one of the following questions:
1. Have you had a daily feeling of dry mouth for more than 3 months?
2. Have you had recurrently or persistently swollen salivary glands as an adult?
3. Do you frequently drink liquids to aid in swallowing dry food?
III. Ocular signsthat is, objective evidence of ocular involvement dened as a positive result for at least one of the following two tests:
1. Schirmer-I test, performed without anesthesia (< 5 mm in 5 minutes)
2. Rose bengal score or other ocular dye score (> 4 according to van Bijstervelds scoring system)
IV. Histopathology: In minor salivary glands (obtained through normal-appearing mucosa), focal lymphocytic sialoadenitis, evaluated
by an expert histopathologist, with a focus score > 1, dened as a number of lymphocytic foci (which are adjacent to normal-
appearing mucous acini and contain more than 50 lymphocytes) per 4 mm
2
of glandular tissue
V. Salivary gland involvement: objective evidence of salivary gland involvement dened by a positive result for at least one of the
following diagnostic tests:
1. Unstimulated whole salivary ow (< 1.5 mL in 15 minutes)
2. Parotid sialography showing the presence of diffuse sialectasias (punctate, cavitary, or destructive pattern), without evidence of
obstruction in the major ducts
3. Salivary scintigraphy showing delayed uptake, reduced concentration, and/or delayed excretion of tracer
VI. Autoantibodies: presence in the serum of the following autoantibodies:
1. Antibodies to Ro(SSA) or La(SSB) antigens, or both
Revised Rules for Classication
For primary SS
In patients without any potentially associated disease, primary SS may be dened as follows:
a. The presence of any 4 of the 6 items is indicative of primary SS as long as either item IV (Histopathology) or VI (Serology) is
positive
b. The presence of any 3 of the 4 objective criteria items (that is, items III, IV, V, VI)
c. The classication tree procedure represents a valid alternative method for classication, although it should be more properly
used in clinicoepidemiologic survey
For secondary SS
In patients with a potentially associated disease (for instance, another well-dened connective tissue disease), the presence of item I
or item II plus any 2 from among items III, IV, and V may be considered indicative of secondary SS
Exclusion criteria
Past head and neck radiation treatment
Hepatitis C infection
AIDS
Preexisting lymphoma
Sarcoidosis
Graft versus host disease
Use of anticholinergic drugs (since a time shorter than fourfold the half-life of the drug)
Adapted with permission from Vitali C et al.
33
of CD27
+
memory B cells. Attesting to its autoimmune
dia thesis, primary SS is associated with a diverse array of
autoantibodies indicative of a breakdown in B cell immune
tolerance. Among these autoantibodies, anti-SSA/Ro and
anti-SSB/La antibodies are markers of diagnostic and prog-
nostic signicance, but their role in disease pathogenesis is
unclear.
Among the other autoantibodies associated with primary
SS, those directed against the muscarinic receptor (MR) have
been implicated in the mechanisms of lacrimal and salivary
gland hyposecretion. The MR family mediates the pregan-
glionic autonomic and postganglionic parasympathetic
effects of acetylcholine in the salivary glands that work in
tandem with the sympathetic nervous system to control
salivary ow. The parasympathetic nerves stimulate a pro-
fuse secretion of a protein-poor uid, whereas sympathetic
impulses generate a sparse, protein-rich uid. Among the
ve MR subtypes (M1R to M5R), the M3R subtype repre-
sents the predominant MR population in the salivary glands
and mediates most of the postjunctional effects that evoke
smooth muscle contraction and secretion from the acinar
glands.
12
It is speculated that antibodies against the M3R
receptor block glandular secretion. However, the assays for
detection of anti-M3R receptor antibodies in patients with
primary SS have produced variable results depending on
the nature of the antigen and the methodological approach.
13

In one study, for example, no detectable anti-M3R antibo-
dies were found in sera from patients with primary SS
when Chinese hamster ovary cells expressing functional
M3R receptor were used as the antigen source.
14
In contrast,
another study using an enzyme-linked immunosorbent
assay system found that 90% of patients with primary SS
showed serum reactivity with an immunodominant peptide
epitope (213 to 228amino acid region) of the M3R receptor
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TLR9, the main exogenous and endogenous sensors of
nonself nucleic acids from RNA and DNA viral pathogens,
respectively, which trigger inammation and release
antiviral factors such as interferons.
Both type 1 interferon and interferon gamma have been
shown to increase the expression of B cellactivating factor
(BAFF), another crucial regulator of the innate immune
response.
19
In animal models, excess BAFF leads to the deve-
lopment of an SS-like autoimmune disease, and in patients
with primary SS, high levels of BAFF can be detected in the
serum.
20
The chief sources of BAFF in the salivary gland are
the mononuclear cells and the ductal epithelial cells.
21

Through interactions with its receptors, BAFF supports the
survival of B cells and their activation and plays a major role
in the initiation and resolution of germinal center reactions,
isotype switching, and plasma cell survival. Thus, it may
be postulated that a vicious circle of TLR stimulation,
excess type 1 interferon production, and upregulated BAFF
expression promotes B cell survival, immunoglobulin class
protein.
15
Interestingly, afnity-puried antibodies to this
peptide epitope have been shown to react with the basolat-
eral membrane of the epithelial cells, the anatomic location
of the autonomic nerve endings on these cells.
16
Further
studies are needed to elucidate the frequency of serum anti-
MR3 autoantibodies in primary SS and their role in causing
glandular dysfunction.
Cells of the innate immune system, such as plasmacytoid
dendritic cells (pDCs), macrophages, and ductal epithelial
cells, are important in the pathophysiology of primary SS.
Minor salivary gland specimens from patients with primary
SS contain a small percentage of pDCs, the main producers
of type 1 interferons (interferon alfa and interferon beta).
17

In primary SS, pDCs appear to be primarily responsible for
the salivary glands robust type 1 interferon signature (e.g.,
genes induced by interferon alfa and interferon beta). Also,
peripheral blood mononuclear cells from patients with
primary SS highly express genes inducible by interferons.
18

Importantly, pDCs express Toll-like receptor (TLR)7 and
Figure 1 Histopathology of the labial salivary gland in primary Sjgren syndrome: (a) hematoxylin-eosin staining (40 original magnication);
(b) hematoxylin-eosin staining (200 original magnication); (c) anti-CD3 staining of T cells (200 original magnication); (d): anti-CD21 staining
of B cells (200 original magnication). Mononuclear cells aggregate in foci throughout the gland in a periductal distribution (a and b). In this
biopsy, most of the mononuclear cells are T cells (c), whereas a minority are B cells (d).
rheum Primary Sjgren Syndrome 4
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switching, and plasma cell differentiation, contributing to
some of the observed local and systemic B cell disturbances
in this disease.
Several lines of evidence suggest that the epithelia of exo-
crine glands contribute to the pathophysiology of primary
SS. First, the inltrates of T cells are periductal in distribu-
tion, suggesting a linkage between the ductal epithelium
and the aberrant T cell response. Second, the ductal and
acinar epithelial cells in the salivary gland tissue from
patients with primary SS display an activated phenotype
known to mediate homing of mononuclear cells, antigen
presentation, and amplication of adaptive immunity. In the
inamed salivary glands, epithelial cells express high levels
of major histocompatibility complex (MHC) class I and II
proteins, the CD80 and CD86 costimulatory molecules, and
the adhesion molecules intercellular adhesion molecule1
(ICAM-1), vascular cell adhesion molecule1 (VCAM-1),
and E-selectin.
21
Finally, in primary SS, ductal epithelial cells
from inamed salivary gland tissue have been shown to
produce proinammatory cytokines (IL-1, IL-6, IL-12, and
tumor necrosis factora [TNF-a]), T cellattracting, germinal
centerforming chemokines, and pDC-attracting chemo-
kines, as well as BAFF, as previously mentioned.
21
Thus, the
salivary gland epithelial cells are poised in primary SS to
nurture a chronic inammatory response.
Figure 2 Pathogenesis of primary Sjgren syndrome (SS). The initiating pathways of salivary gland inammation are postulated to be
environmental insults such as viral infection. These environmental factors trigger innate immunity and set the stage for persistent glandular
inammation. In the case of primary SS, the relevant innate immune pathways include activated epithelial cells and dendritic cells. Epithelial
cells upregulate expression of major histocompatibility complex (MHC) class II and costimulatory molecules on their cell surface, enabling them
to serve as accessory antigen-presenting cells and to stimulate T cell activation. Epithelial cells are also a rich source of proinammatory cytokines
(tumor necrosis factor [TNF], interleukin-1 [IL-1], and IL-6) and chemokines (CXCL9, CXCL10, CXCL12) that function to amplify the inamma-
tory response. Increased expression of Fas and Fas ligand (FasL) on the epithelial cell surface may also contribute to their untimely death, limiting
the secretory reserve of the glands. The activated T cells traverse from the circulation through high endothelial venules (HEVs) into the salivary
gland microenvironment, where they stimulate other immune cells. Plasmacytoid dendritic cells in the salivary gland produce abundant quanti-
ties of type 1 interferon and B cellactivating factor (BAFF). In particular, excess BAFF production may stimulate the development of germinal
centerlike structures, which consist of B cell aggregates surrounded by a cuff of T cells. The presence of activated Th1 and Th17 cells provides
a constant inammatory stimulus and helps B cells to differentiate into antibody-forming cells. Macrophages also secrete proinammatory
factors that amplify the chronic inammatory response. COX-1 = cyclooxygenase-1; ICAM-1 = intracellular adhesion molecule1; IFN-c =
interferon-gamma; MMP = matrix metalloproteinase; TGF-b = transforming growth factorb; T Reg = T regulatory; VCAM-1 = vascular cell
adhesion molecule1.
rheum Primary Sjgren Syndrome 5
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In view of the increased expression of TLR8 and TLR9 in
minor salivary glands from patients with primary SS
14
and
the prominent type I interferon signature, investigators have
sought possible viral triggers of this autoimmune exocri-
nopathy. TLR8 can sense single-stranded RNA (e.g., single-
stranded RNA viruses), whereas TLR9 is able to recognize
prokaryotic unmethylated CpG-DNA (e.g., bacterial and
viral DNA). Both TLR3 and TLR7 are constitutively
expressed on cultured salivary gland epithelium. Poly (I:C),
a TLR3 agonist, and reovirus-1, a dsDNA virus, have been
shown to induce cultured salivary gland cells to express
high levels of BAFF partly by type 1 interferon-dependent
pathways, suggesting that these ligand-receptor interactions
may be of pathologic relevance.
22

Two DNA viruses, namely Epstein-Barr virus (EBV) and
cytomegalovirus (CMV), have been studied in this context
because of their ability to cause persistent infection and
suppress T cell immunity. CMV does not appear to be a viral
trigger. However, EBV is a slightly more attractive candi-
date, although the evidence thus far remains limited,
circumstantial, and contradictory. In some cases, immuno-
histochemical staining of minor salivary glands has shown
EBV DNA localized to the acinar and ductal epithelial cells.
23

Coxsackievirus, an RNA virus from the family of Picorno-
viridae, has been implicated in one study where it was
shown that a 94 bp fragment of coxsackievirus B4 was
differentially expressed in salivary gland biopsies from pati-
ents with primary SS compared with controls.
24
However, a
follow-up study failed to replicate these results.
25
Genetics contribute to disease susceptibility in primary
SS. Given that large-scale genetic studies have not been
conducted in primary SS, the genetic basis of this disease
remains largely unexplored. Observations to date suggest
that primary SS, like RA and SLE, are complex, polygenic
disorders. Among the most widely studied of the genetic
loci are the HLA-DR and-DQ alleles. Polymorphisms in the
DRB1*0301 (DR3) and DRB1*1501 (DR2) loci have been
shown to account for approximately 90% of the MHC asso-
ciation in patients with primary SS.
26
The DQB1*0201 locus
has also been found to be strongly associated with disease
susceptibility. In addition, it has been reported that hetero-
zygosity for DQw1 and DQw2 alleles is correlated with high
titers of anti-SSA/Ro and anti-SSB/La antibodies, implying
that haplotypes cooperate in patients with primary SS to
generate an autoantibody response.
27

Because interferons are dysregulated in primary SS, these
pathways have been a focus of the rst candidate gene
studies. A single nucleotide polymorphism in the splicing
sequence of exon B of the interferon regulatory factor 5
(IRF5) gene has been associated with primary SS in a small
cohort study (primary SS versus controls: 87% versus 77%,
respectively; p = .01).
28
A variant allele of a transcription
factor, signal transducers and activator of transcription4
(STAT4), which is associated with increased susceptibility to
RA and SLE, has also been found to be signicantly more
frequent in patients with primary SS than controls (29.6%
versus 22.3%; p = .01).
29
STAT4 is an intracellular molecule
involved in IL-12 and IL-23 signaling. According to one
study, IRF5 and STAT4 appear to confer additive risks
of developing primary SS.
30
In addition, a 5 bp insertion/
deletion polymorphism (CGGGG insertion/deletion) in the
promoter region of IRF5 transcript has been linked to
primary SS; the presence of the CGGGG insertion/deletion
correlated with a high level of IRF5 messenger RNA in cul-
tured salivary gland epithelial cells infected with reovirus.
31

The results of these studies will require validation in larger
cohort studies to conrm these genetic associations.
Diagnosis
The diagnosis of primary SS is based on the presence of
KCS (dry eyes), xerostomia (dry mouth), serum anti-Ro/
SSA and anti-La/SSB antibodies, and histopathologic
evidence of chronic sialadenitis. A preliminary set of classi-
cation criteria was initially established by the European
Study Group
32
and later revised by an American-European
consensus group
33
[see Table 1]. The presence of any four of
the six criteria was considered to be indicative of a diagnosis
of primary SS, showing a sensitivity of 89.5% and a speci-
city of 95.2%. Practically speaking, the diagnosis of most
patients with primary SS is based on the presence of symp-
toms of dry eyes, an abnormal Schirmer-I test, symptoms
of dry mouth, abnormally low salivary ow, and either a
positive labial salivary gland biopsy or serum anti-Ro/SSA
and/or anti-La/SSB autoantibodies.
clinical manifestations
Exocrine Gland Disease
Ocular involvement Eye involvement results from
diminished lacrimal gland production of aqueous tears, with
subsequent destruction of the conjunctival and bulbar epi-
thelium depending on the severity of the deciency. Patients
may not endorse ocular dryness per se but almost always
complain of grittiness or foreign-body sensation, along with
other symptoms of irritation, burning, accumulation of thick
mucus in the inner canthus of the eye (mucus laments),
photophobia, and eye fatigue. Examination often reveals a
reduction in tear production as measured by the Schirmer-I
test, decreased tears in the conjunctival sac, dilated bulbar
conjunctival vessels with injection, mucous laments, and
corneal damage as seen with a slit-lamp examination using
rose bengal or lissamine green dye (for staining devitalized
cells) or uorescein (for staining epithelial defects). This con-
dition is termed KCS and is often associated with blepharitis
(infection of the eyelids). If severe, it may lead to corneal
abrasions and ulceration.
The differential diagnosis for dry eyes may be best under-
stood by understanding the composition of tears. Any
malfunction of the eyelids, abnormality of tear lm anatom y,
or decreased tear volume may lead to dry eyes and irrita-
tion. The tear lm is made up of three layers: the outer lipid
layer, the middle aqueous layer, and the inner mucin layer.
The aqueous tears are the product of the lacrimal glands.
Deciency in this layer is responsible for the dry eyes of
primary SS. Other conditions that may affect the aqueous
layer include medications such as tricyclic antidepressants,
antihistamines, and diuretics. Aging and hormonal changes
may also be associated with a diminished aqueous tear
layer. The lipid and mucinous layers of tears stabilize and
distribute the tears evenly over the ocular surface. The
mucin layer derives from the goblet cells in the conjunctiva,
rheum Primary Sjgren Syndrome 6
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which, if damaged, can lead to uneven distribution of tears
over the surface of the eye. Two examples of disorders
associated with abnormal mucin production are vitamin A
deciency and Stevens-Johnson syndrome. The lipid layer is
the product of the meibomian glands and acts to protect
the tear lm from rapid evaporation. Meibomian gland
dysfunction from blepharitis can reduce the lipid layer,
resulting in increased tear breakdown. Other causes of
an abnormal lipid layer include rosacea, smoking, high
altitude, drafty environments, and dry air.
Oropharyngeal involvement: xerostomia The orophar-
ynx is almost uniformly affected in primary SS owing to
the change in the quantity and quality of salivary gland
secretion. Symptoms of dry mouth are common in the gen-
eral population, but they tend to be mild and most often
explained by medication use. However, patients with
primary SS have more severe symptoms with oral burning,
difculty swallowing dry food (e.g., crackers), change in
taste (metallic, salty, or bitter taste), difculty speaking for
prolonged periods of time, and problems wearing dentures.
Examination often reveals a dry, erythematous, and sticky
oral mucosa, although the oral cavity may appear normal in
many cases. There are two major consequences of severe
xerostomia. First, it may lead to rampant dental caries,
cracked teeth, and loose llings. Second, it may increase the
risk for oral candidiasis, which has been described in one
study to occur in 74% of patients with primary SS.
34
Oral
candidiasis typically manifests as angular cheilitis (dry,
cracked lesions in the corner of the mouth), erythema and
atrophy of the liform papillae on the dorsum of the tongue,
and a thin white exudate on the tongue. The thrushlike
appearance of oral candidiasis is not usually seen in this
setting.
Approximately one third of patients with primary SS
develop parotid or submandibular gland enlargement over
the course of their disease. When chronic, the swelling is
usually painless, rm, and diffuse, whereas acute episodes
of swelling are transiently painful and tender and probably
attributable to obstruction of the salivary gland ducts from
inspissated mucus. Asymmetrical gland enlargement that
is hard or nodular may indicate a neoplasm such as
lymphoma.
Other exocrine gland involvement Virtually any exo-
crine gland in the body may be affected in primary SS. In
particular, dryness may affect the nasal passages, vagina,
and skin. Women with vaginal dryness often complain of
dyspareunia, pruritus, or irritation. Dryness of the throat
and trachea (xerotrachea) may cause a chronic dry cough.
Extraglandular Manifestations
Most patients with primary SS exhibit extraglandular dis-
ease ranging from mild to severe involvement of various
organ systems. Many of the signs and symptoms of extra-
glandular disease in primary SS overlap with those of RA,
SLE, and other connective tissues diseases. However, the
overall patterns of extraglandular disease in primary SS are
readily distinguished from those of the other connective
tissue diseases. Patients testing positive for serum anti-SSA/
Ro and anti-SSB/La antibodies are more likely to exhibit
extraglandular features.
Fatigue Fatigue is among the most commonly reported
extraglandular manifestations of primary SS.
35
In a large US
cohort study of primary SS, fatigue was the dominant pre-
dictor of general health and physical function.
36
The cause of
fatigue is likely multifactorial and may be driven by immu-
nologic dysfunction or by factors such as sleep disturbance
and depression. In one study of 94 individuals who met the
American-European Consensus Group criteria for primary
SS, psychological factors accounted for only 62% of the vari-
ability in the Fatigue Severity Scale.
37
Although depression
correlated with the severity of the fatigue, depression was
not the principal cause of fatigue in primary SS.
Raynaud phenomenon Up to 30% of individuals with
primary SS have Raynaud phenomenon. Raynaud attacks
appear milder in patients with primary SS compared with
other connective tissue diseases, such as systemic sclerosis.
They occur most commonly in patients with other extraglan-
dular manifestations, such as polyarthritis and cutaneous
vasculitis, as well as a positive test for serum anti-Ro/SSA
and anti-La/SSB antibodies.
Cutaneous Xerosis (dry skin) is the most frequent cuta-
neous manifestation of primary SS, often causing pruritis
and burning. Xerosis is likely secondary to alterations in
the protective function of the epidermis owing to altered
exocrine function of the sweat and sebaceous glands. Annu-
lar erythema is also a common cutaneous manifestation of
primary SS, seen most often in patients with anti-Ro/SSA
antibody.
Patients with primary SS may develop purpura either
from a condition called benign hypergammaglobulinemic
purpura of Waldenstrm or a small vessel vasculitis.
Indeed, approximately 50% of patients with secondary
benign hypergammaglobulinemia purpura of Waldenstrm
have primary SS.
38
This condition presents with symmetri-
cal, nonpalpable purpura extending up the leg, with symp-
toms of itching and burning in the proximity of the lesions.
In some cases, it has been associated with a sensory periph-
eral neuropathy. A small vessel vasculitis (e.g., leukocyto-
clastic vasculitis) is also relatively common in primary SS
and is manifested as either palpable purpura or, less often,
painful urticarial lesions. Urticarial lesions from vasculitis
typically last 3 to 4 days and leave a bruise or discoloration
at the site, distinguishing these lesions from idiopathic or
allergic urticaria.
Musculoskeletal Arthralgia and arthritis are among the
most commonly reported extraglandular manifestations of
primary SS. Joint symptoms may precede sicca symptoms in
up to a third of cases. The polyarticular involvement and
symmetrical distribution of arthritis are similar to those of
SLE and RA. As opposed to RA, the polyarthritis tends to be
less severe and intermittent and typically does not produce
radiographic joint erosions. The most common sites of joint
involvement are the proximal interphalangeal joints, meta-
carpophalangeal joints, and wrists in 33%, 27%, and 12% of
cases, respectively.
39

Myalgia, which may resemble bromyalgia, is a common
complaint among individuals with primary SS. Although
muscle biopsies can show evidence of mild inammation in
rheum Primary Sjgren Syndrome 7
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many cases, only relatively few patients develop a clinical
picture of polymyositis with muscle weakness.
40

Upper and lower respiratory tract Given that the nasal
passages, sinuses, trachea, and lower airways are lined with
glandular and ductal epithelial cells, it is not surprising that
individuals with primary SS may develop respiratory symp-
toms. In the upper airway, the most frequent manifestations
are related to glandular hyposecretion and include epistaxis,
recurrent sinusitis, nasal crusting, and a dry, irritating
cough.
Involvement of the lower respiratory tract is also relativel y
common and may take several forms. Clinically, nonspecic
interstitial pneumonitis (NSIP) and lymphocytic interstitial
pneumonia (LIP), now believed to represent a subset of
NSIP, may cause signicant respiratory dysfunction and
require immunosuppressive therapy. Ito and colleagues
studied 33 patients with primary SS who had biopsy-proven
lung disease.
41
Twenty (61%) patients had NSIP (1 cellular,
19 brosing), 4 had non-Hodgkin lymphoma (NHL) of
mucosa-associated lymphoid tissue (MALT), 4 had diffuse
bronchiolitis, and 2 had amyloid disease. The survival rate
at 5 years was 83% for individuals with NSIP. LIP results
from the proliferation of the bronchus-associated lymphoid
tissue (BALT). Its clinical course is varied, ranging from
remission without treatment to respiratory failure and
death. BALT lesions in approximately 5% of individuals will
progress to lymphoma.
42
Renal Clinically signicant renal disease is infrequent in
primary SS. Tubular interstitial nephritis (TIN), type I renal
tubular acidosis, glomerular disease, and nephrogenic
diabetes insipidus are associated with primary SS and may
precede the onset of sicca symptoms. TIN is usually asymp-
tomatic and rarely progresses to end-stage renal disease.
Case reports of muscle paralysis have been reported in the
setting of severe potassium wasting.
43
Histologically, TIN is
characterized by lymphocytic inltration around the tubules
similar to that observed in the salivary gland
44
with tubular
atrophy and brosis.
Glomerulonephritis is a rare nding in primary SS. Differ-
ent forms of glomerulonephritis have been reported in
association with primary SS and include membranopro-
liferative, mesangial proliferative, and focal crescentic glo-
merulonephritis and membraneous nephropathy.
4548
In one
series, mixed monoclonal cryoglobulinemia and older age
were two independent predictors of glomerulonephritis.
45
Gastrointestinal The gastrointestinal tract may be
affected in primary SS from the mouth to the small and large
bowel to the liver and pancreas. Common symptoms
include dysphagia, epigastric pain, and nausea. Dysphagia
is multifactorial and is likely related to lack of saliva and
subsequent dry mucosa, esophageal dysmotility, achalasia,
and upper esophageal webs. Chronic atrophic gastritis is
common in individuals with primary SS.
Abnormal liver enzyme values are relatively common in
patients with primary SS and in one study were found in
49.1% of patients.
49
Although autoimmune liver disease
can occur in association with SS, the abnormal liver enzyme
values were never explained in most cases.
Neurologic Peripheral neuropathy, cranial nerve invol-
vement, and, less commonly, central nervous system (CNS)
disease occur in primary SS. Peripheral neuropathy is the
most commonly reported manifestation and may present as
a sensory ataxic neuropathy, painful sensory neuropathy
without sensory ataxia, multiple mononeuropathies, multi-
ple cranial neuropathy, trigeminal neuropathy, autonomic
neuropathy, or radiculoneuropathy.
50

The prevalence of CNS disease is debatable and ranges
across studies from virtually nonexistent to common. The
spectrum of disease reported in these studies affects the
brain, spinal cord, and cranial nerves. CNS disease may be
subtle, leading to memory problems and cognitive distur-
bance. Other reported signs and symptoms include hemipa-
resis, dysarthria, ataxia, seizures, movement disorder such
as dystonia, aseptic meningitis, encephalopathy, dementia,
anxiety, and depression.
51
Acute and transient attacks
mimicking multiple sclerosis have also been described in
some cases.
52

Systemic vasculitis Systemic vasculitis appears to occur
only rarely in the setting of primary SS. Cases of systemic
vasculitis have been described in patients with a small
vessel vasculitis and cryoglobulinemia (without evidence
of hepatitis C virus infection) and with a medium-size
vessel vasculitis akin to the clinical picture of polyarteritis
nodosa.
Associated Diseases
Thyroid disease Thyroid dysfunction is common among
individuals with primary SS and their rst-degree relatives.
53

Initial studies suggested a strong correlation between
primary SS and thyroid disease. For example, one study
reported a 30% prevalence of thyroid disease in patients
with primary SS versus 4% of controls.
54
A more recent and
larger study compared the prevalence of thyroid disease
in 160 patients with primary SS with that in 75 age- and
sex-matched controls. Although thyroid disease was numeri-
cally more common in patients with primary SS than
controls (36% versus 27%), the overall difference between
the two groups was not statistically signicant.
55

Autoimmune liver disease Patients with primary SS
may have coexistent primary biliary cirrhosis (PBC), autoim-
mune hepatitis (AIH), sclerosing cholangitis, or nodular
regenerative hyperplasia.
49
Among these disorders, PBC and
AIH are most commonly reported in patients with primary
SS. Although their exact prevalence in primary SS is
unknown, it is probably less than 5%.
56
Celiac disease Celiac disease has also been described
in patients with primary SS. One Hungarian study found a
10-fold higher frequency of celiac disease in patients with
primary SS compared with controls.
57
Lymphoma NHL is an important complication of pri-
mary SS. Initial studies showed its frequency to be 44 times
greater in patients with this disease than in the general popu-
lation.
58
An estimated prevalence of 4.3% was reported
in another study where the median time from diagnosis of
rheum Primary Sjgren Syndrome 8
06/10
primary SS to the development of lymphoma was approxi-
mately 7.5 years.
59
Several histologic variations of NHL are
reported in the literature, including follicular cell lymphom a,
diffuse large B cell lymphoma, lymphoplasmacytoid lym-
phoma, and marginal zone B cell lymphoma. Marginal zone
B cell lymphoma, including MALT lymphoma, is by far the
most common type in patients with primary SS.
59,60

MALT lymphomas share many of the same histopatho-
logic features regardless of the site of origin.
61
The lesions
resemble Peyer patches in the intestinal lymphoid tissue,
with reactive follicles. The earliest morphologic feature of
MALT lymphoma is the nding of monocytoid B cells sur-
rounding the epithelial structures. Immunohistochemical
staining of these inltrates reveals monotypic Ig k light
chain and Ig c light chains, evidence of B cell clonality.
59
The
more advanced lesions show extensive proliferation of
neoplastic cells, replacement of reactive follicles, and ductal
dilatation. The immunophenotype of MALT lymphomas
resembles that of marginal zone B cells (CD19
+
, CD20
+
,
CD22
+
, CD79a
+
). Despite the fact that MALT lymphomas
are of B cell origin, most of the inltrating cells are T cell
lymphocytes. This nding suggests that clonal B cell trans-
formation is stimulated by T cellderived factors and/or
antigens.
62
MALT lymphomas often develop in salivary glands
but may emerge from other extranodal sites, such as the
stomach, nasopharynx, skin, liver, kidney, and lung. The
presence of lymphadenopathy and/or swollen parotid
glands should raise suspicion of lymphoma. Neutropenia,
cryoglobulinemia, splenomegaly, lymphadenopathy, and
low C4 are risk factors for the development of lymphoma;
the presence of any of these factors confers a vefold
increase in the risk for lymphoma compared with individu-
als without risk factors.
60
The histologic grade (intermediate
or high) of lymphoma, size of the tumor (> 7 cm), and the
presence of B symptoms (fever, night sweats, and weight
loss) are risk factors for increased mortality.
59

laboratory tests
The vast majority of patients with primary SS test positive
for serum antinuclear antibodies (ANAs). In the largest
cohort of patients with primary SS, 85% had a positive ANA,
52% had a positive Ro/SS-A antibody, and 34% tested posi-
tive for anti-La/SSB antibodies.
63
In addition, 48% of patients
in this group had a positive test for serum rheumatoid
factor, 9% had low serum complement levels (either C3 or
C4), and 10% had either type 2 or 3 cryoglobulinemia.
63

Among this group, 28% also had various hematologic cyto-
penias, including 16% with leukopenia and 13% with throm-
bocytopenia, which may be higher frequencies than seen in
clinical practice.
ocular tests
Objective evidence of ocular involvement may be obtained
using the Schirmer-I test or staining of the cornea and
conjunctiva. The Schirmer-I test measures the quantity of
tear production in the unanesthetized eye. It is performed by
placing a sterile piece of lter paper (measuring approxi-
mately 35 mm in length) in the middle to lateral third of
the lower eyelid and measuring the distance the tears have
eluted over 5 minutes. A distance of 5 mm or less is consid-
ered to be abnormal and indicative of decreased tear pro-
duction. Rose bengal or lissamine green dye is used to assess
the integrity of the conjunctival surface. Rose bengal is an
analine dye that stains dead or degenerated cells in areas
devoid of tears. Its use is limited by ocular discomfort.
Lissamine green dye, now favored, adheres to epithelial
surfaces lacking mucin protein [see Figure 3]. Fluorescein dye
is also used to evaluate dry eyes. It stains areas on the cornea
and conjunctiva, where the cellular membrane is disrupted.
salivary gland flow and imaging
Several different methods are available to evaluate xero-
stomia. Sialometry is a noninvasive measure of salivary ow
rate and may be used to quantify ow rates from the differ-
ent glands (parotid, submandibular, or sublingual) or the
mouth as a whole. According to the aforementioned classi-
cation criteria, an abnormal unstimulated whole salivary
ow rate is considered to be 1.5 mL or less in 15 minutes.
33

Sialography may be used to identify ductal patterns and
areas of salivary duct obstruction, allowing a chronic inam-
matory process to be distinguished from a localized
neoplasm. With this technique, radiographic contrast is
Figure 3 Lissamine staining of a dry eye as shown by slit-lamp
examination. (a) Diffuse staining of the conjunctiva. (b) Punctate
staining of the cornea. Courtesy of W. Craig Fowler, MD, Department
of Ophthalmology, University of North Carolina at Chapel Hill,
Chapel Hill, NC.
rheum Primary Sjgren Syndrome 9
06/10
injected into the salivary duct, and serial radiographs are
taken to visualize the dye. It is important to use a water-
based contrast as opposed to an oil-based contrast because
the latter has a propensity for damaging the adjacent sali-
vary tissue. Sialography, an invasive procedure, has some
complications, including rupture of the duct, pain, and
infection.
Scintigraphy is a moderately sensitive but not disease-
specic measure of salivary gland function. It is performed
by injecting sodium pertechnetate technetium (
99m
Tc) into
the blood and quantifying the rate at which the radioactive
material is absorbed into the salivary gland and then secre-
ted into the mouth. For this test, the diagnostic sensitivity
and specicity have been estimated to be 75% and 78%,
respectively.
64
Advanced radiographic imaging techniques, such as
ultrasonography, magnetic resonance imaging (MRI), and
magnetic resonance sialography, have been used to evaluate
patients in this setting. However, experience with these
techniques is limited at this point. In one study, magnetic
resonance sialography was the most sensitive of these
three techniques for detecting glandular changes.
65
Magnetic
resonance sialography can identify ductal changes in early
disease, whereas MRI provides the superior method for
evaluating parenchymal changes.
biopsy
Labial salivary gland biopsy remains the gold standard
for the diagnosis of primary SS. It is an invasive procedure,
albeit relatively benign, in which at least four salivary gland
lobules are removed through a small incision in the inner lip
and analyzed by histopathology. The biopsy is considered
to be positive if the focus score is 1 or greater per 4 mm
2
of
tissue, where a focus is dened as a cluster of 50 or more
lymphocytes. In practice, labial salivary gland biopsies are
reserved for those few situations in which the diagnosis is
unclear (e.g., negative test for ANA, alternate diagnosis such
as sarcoidosis under consideration). Recent studies have
shown that the interpretation of the biopsy results is subject
to considerable variability depending on the expertise of the
reader.
66

Differential Diagnosis
Several disorders may mimic at least some of the clinical
features of primary SS [see Table 2]. Some of these conditions,
especially those causing lymphocytic inltration of the
exocrine glands, may be very difcult to distinguish from
primary SS.
67
Chronic viral infections may be considered in
the differential diagnosis of this disease. Patients with hepa-
titis C virus (HCV) infection may exhibit sicca symptoms,
abnormal Schirmer-I tests, and a positive labial salivary
gland biopsy. However, HCV infection strikes men more
often than women, is predominantly associated with liver
disease, and is not associated with anti-Ro/SSA and anti-
La/SSB antibodies.
6870
Human T cell lymphotropic virus
type I (HTLV-I) has been implicated as the cause of adult T
cell leukemia/lymphoma and a syndrome termed myelop-
athy/tropical spastic paraparesis; it may produce features
clinically and histopathologically indistinguishable from
those of primary SS.
71
Diffuse idiopathic lymphocytic
syndrome (DILS) can also mimic primary SS in the setting
of HIV infection. DILS may occur at any stage of HIV
disease and is characterized by dry eyes, dry mouth, and
enlargement of the salivary glands. Most patients with this
condition are male and lack anti-Ro/SS-A and anti-La/SS-B
antibodies.
Recently, a new clinical entity has been described termed
IgG4-positive multiorgan lymphoproliferative syndrome
(MOLPS).
72
IgG4
+
MOLPS has a similar distribution of
involved organs as seen in SS but is pathologically and clini-
cally different in several ways. Compared with primary SS,
IgG4
+
MOLPS is associated with a lower frequency of dry
eyes and dry mouth, arthralgia, and ANA positivity and a
higher rate of autoimmune pancreatitis. Moreover, patients
with IgG4
+
MOLPS display enlarged lacrimal glands, which
is an unusual nding in primary SS.
Sicca symptoms are a common complaint in patients that
develop graft versus host disease (GVHD) after allogeneic
bone marrow transplantation. In one study, salivary gland
biopsies from 90% of patients with GVHD showed inltrat-
ing T lymphocytes.
73
Primary salivary gland lymphoma
may also cause sicca symptoms and parotid gland enlarge-
ment and therefore must be considered in the differential
diagnosis of primary SS in the appropriate clinical setting.
Sarcoidosis may produce sicca symptoms with lacrimal
and salivary gland enlargement and therefore may be con-
fused with primary SS. It may be distinguished histopatho-
logically from primary SS by the presence of granulomatous
inammation. Also, patients with sarcoidosis are serologi-
cally negative for anti-Ro/SSA and anti-La/SSB antibodies.
Other studies, such as a chest x-ray, may be useful in evalu-
ating for evidence of sarcoidosis in other organs or tissues.
Rarely, sarcoidosis and primary SS may occur in the same
patient.
Amyloidosis, hypertriglyceridemia, and hemachromato-
sis may be mimics of primary SS by producing exocrine
gland enlargement from tissue inltration with amyloid,
triglycerides, and iron, respectively.
67
Sicca symptoms are
also common among individuals with diabetes mellitus.
Treatment
The goal of treatment is primarily symptomatic relief and
prevention of long-term consequences of disease. There are
a myriad of treatment options for dry eyes. They include
avoiding conditions that may worsen dry eyes (such as cen-
tral heating and air, windy environments, and medications
that can further decrease tear production), tear supplements,
secretagogues, and punctal occlusion. Articial tears are
available over the counter in a variety of formulations with
different viscosities. The lower the viscosity, the more fre-
quently one must administer the solution. Thicker-viscosity
solutions may be useful at bedtime because they are long
lasting; however, they may require lid scrubs each morning
to prevent the development of blepharitis.
There are currently two oral secretagogues on the market
that are designed to stimulate tear production. Pilocarpine
(Salagen) is an oral muscarinic agonist that acts by stimulat-
ing the M3R. This medication at a dose of 5 mg three to
four times per day has been shown to signicantly improve
subjective global assessments of dry eyes
74,75
and objective
rheum Primary Sjgren Syndrome 10
06/10
Table 2 Differential Diagnosis of Primary Sjgren Syndrome
Disease Epidemiology Clinical Features Salivary Gland Biopsy Other
Hepatitis C virus
(HCV)
Men > women Sicca symptoms;
abnormal ocular tests;
frequency of parotid
gland enlargement
lower than in SS
CD3
+
CD4
+
focal
lymphocytic inltrate,
with predominance of B
cells in some cases;
inammation tends to
be milder than primary
SS
Absence of serum
anti-Ro/SSA and
anti-La/SSB
antibodies
Human T cell
lymphotropic virus
type I (HTLV-1)
Endemic in areas of
Africa, Central and
South America,
southwestern Japan,
and Caribbean
Sicca symptoms;
abnormal ocular tests
CD3
+
CD4
+
lymphocytic
inltrate that may be
indistinguishable from
primary SS
Cause of adult T
cell leukemia/
lymphoma and
myelopathy/tropical
spastic paraparesis
HIV Diffuse idiopathic
lymphocytic
syndrome (DILS)
Men > women Sicca symptoms;
abnormal ocular tests;
enlargement of salivary
glands (usually
bilateral); parotid cysts
Diffuse CD3
+
lymphocytic
inltrate with
predominance of CD8
+

T cells over CD4
+
T cells
Increased risk of
lymphoma
Warthin tumor
(papillary
cystadenoma
lymphomatosum)
Second most common
benign salivary gland
tumor; smokers have
8-fold higher risk of
developing this tumor
than the general
population
Tumor most often affects
the tail of the parotid
gland, usually painless,
may be unilateral or
bilateral
Multiple papillae
composed of a double
layer of epithelial cells
projecting into cysts;
lymphoid stroma below
the epithelium often
contains germinal
centers
IgG4-positive
multiorgan
lymphoproliferative
syndrome (MOLPS)
Higher prevalence of men
compared with primary
SS
More often have parotid,
submandibular,
and/or lacrimal
gland enlargement;
prevalence of sicca
symptoms lower than
in primary SS
Prominent mononuclear
inltration of lacrimal
and salivary glands
with lymphoid follicle
formation, IgG4
+
plasma
cell inltration, and
brosis;
lymphocytic inltration
into the ducts
(lymphoepithelial
lesions) uncommon
Absence of serum
anti-Ro/SSA and
anti-La/SSB
antibodies; increased
serum IgG4 levels;
allergic rhinitis and
pancreatitis are more
common in this
condition than in
primary SS
Graft versus host
disease
Complication of
allogeneic bone marrow
transplantation
Sicca symptoms, with
mostly ocular
involvement
CD3
+
lymphocyte inltrate
Salivary gland
lymphoma
2.5% of all primary
salivary gland tumors;
most patients with
salivary gland
lymphomas do not have
primary SS
Sicca symptoms in only a
minority of patients;
parotid gland enlarge-
ment with rm mass,
usually painless
Clonal proliferation of B
cells
MALT lymphomas
> follicular B cell
lymphomas
> diffuse large B cell
lymphomas; T cell
lymphomas rare
Sarcoidosis Sicca symptoms;
abnormal ocular tests;
salivary and lacrimal
gland enlargement
Noncaseating
granulomatous
inltration
May have hilar
adenopathy, uveitis,
erythema nodosum,
or other features of
sarcoidosis; absence
of serum anti-Ro/
SSA and anti-La/
SSB antibodies
Amyloidosis Rare Sicca symptoms; salivary
gland enlargement;
other features of
amyloidosis, such
as tongue swelling,
arthropathy,
proteinuria with renal
insufciency
Amyloid inltration with
positive Congo red
stain; minimal or no
lymphocytic inltrate
Hypertriglyceridemia Rare Painless parotid gland
enlargement (may
be bilateral) with
or without sicca
symptoms
Fatty inltration of
glandular lobules with
loss of acinar cells; no
lymphocytic inltrate
rheum Primary Sjgren Syndrome 11
06/10
measures of conjunctival surface integrity.
74
Possible side
effects of pilocarpine include ushing, sweating, increased
urination, and abdominal discomfort. Cevimeline (Evoxac)
also stimulates the MRs (primarily the M1 and M3 recep-
tors) in the salivary and lacrimal glands. It is taken at a dose
of 30 mg three times daily. The results of randomized, con-
trolled trials showed that cevimeline treatment at this dose
was associated with a statistically signicant improvement
in subjective global assessment of dry eyes and mouth and
an objective improvement in salivary and lacrimal ow
rates.
76
Use of cevimeline may be associated with headache,
sweating, rhinitis, nausea and diarrhea, and visual distur-
bances. Because of their pharmacologic properties, pilocar-
pine and cevimeline therapy are contraindicated for patients
with iritis, narrow-angle glaucoma, and moderate-to-severe
asthma.
Cyclosporine 0.05% ophthalmic emulsion (Restasis) was
approved by the Food and Drug Administration in 2003 for
the treatment of KCS. In dogs, treatment of KCS with topical
cyclosporine has been shown to renew the architecture of
lacrimal glands, and in patients with dry eye, cyclosporine
has been shown to decrease cell surface markers of activated
T lymphocytes and increase goblet cell density.
77
In clinical
trials, this ophthalmic cyclosporine preparation has been
shown to improve subjective complaints of dry eyes and
Schirmer-I test values and reduce the need for supplemental
articial tears.
78
The most common reported side effect is a
burning sensation in the eyes, which can limit use in some
cases.
Temporary or permanent punctal occlusions may provide
symptomatic relief by blocking the nasolacrimal drainage
channels and preserving tears. For temporary punctual
occlusion, plugs are initially placed in the two inferior punc-
tae owing to the fact that approximately 90% of the tear
drainage occurs through these channels. Occasionally, plugs
may be placed in the two superior punctae with added
benet. Short-term plugs made of collagen may be used to
evaluate the patients response to punctal occlusion. If tem-
porary punctal occlusion is well tolerated, then longer-term
silicone plugs may be offered on a semipermanent or perma-
nent basis. Permanent punctal occlusion is usually achieved
by cautery or laser surgery. Excessive tearing is the most
common complication of punctal occlusion.
Patients with dry eyes will often complain of eye irritation
despite instillation of articial tears or other treatment
measures. Sometimes these complaints will result from the
effects of preservatives in lubricant solutions. Preservative-
free lubricants are available in single-use containers. Blepha-
ritis may also exacerbate underlying dry eye symptoms and
may be managed with warm compresses, lid scrubs with an
eyelid cleaner such as Johnsons Baby Shampoo mixed 1:1
with water, or antibiotic therapy. Patients with mucus
laments in the inner canthus of the eye may benet from
instillation of a 10% acetylcysteine ophthalmic solution (a
mucolytic agent), which can be compounded by pharmacies
for use in this setting.
Xerostomia or dry mouth is generally approached in two
ways: stimulation of existing salivary ow and replacement
of saliva. Individuals often nd that sucking on sugarless
lozenges, candy, or gum is helpful in stimulating salivary
ow. Using sugarless products is of utmost importance
given the increased risk of dental caries resulting from sali-
vary gland dysfunction. Similar to the treatment of dry eyes,
pilocarpine and cevimeline may also be used to stimulate
salivary ow. Results from clinical trials have shown that
treatment with pilocarpine 5 mg three times daily improves
patient and physician global assessment of dry mouth and
increases the rate of salivary ow.
75,79
Likewise, cevimeline
at a dose of 30 mg three times daily has been shown to
produce similar clinical benets.
76,80
Articial saliva pre-
parations are now available that contain hypromellose or
methylcellulose and may be useful in some cases.
Patients with primary SS and severe xerostomia are at
risk for rapid dental decay. Regular ossing, frequent dental
visits, routine dental uoride applications, and dietary modi-
cations are recommended to maintain oral health. Oral
candidiasis is one of the most common complications of pri-
mary SS. Patients with xerostomia will often remark that
their mouth burns or hurts. They may also develop angular
cheilitis, which can be a clue to an oral yeast infection.
Nystatin elixir, clotrimazole troches, and diucan are used
for the treatment of oral candidiasis. Topical clotrimazole
cream used in conjunction with oral clotrimazole for 1 to 2
weeks can usually eliminate angular cheilitis.
Dry lips, skin, and nasal passages and vaginal dryness
are also common symptoms in primary SS. Dryness in these
areas may be addressed by regular use of moisturizers,
lip balm, nasal saline spray, and vaginal moisturizers.
Topical vaginal estrogen cream is sometimes effective
for the treatment of dyspareunia resulting from vaginal
mucosal dryness.
Fatigue, arthralgia, and myalgia may respond to hydroxy-
chloroquine therapy, although this approach lacks support-
ing evidence from randomized, controlled trials. Care should
be taken to avoid doses of hydroxychloroquine exceeding
Table 2 Continued
Disease Epidemiology Clinical Features Salivary Gland Biopsy Other
Hemachromatosis Rare Sicca symptoms Hemosiderin deposition;
no lymphocytic inltrate
Diabetes, alcoholism,
bulimia, chronic
malnutrition
Sicca symptoms; mild,
diffuse, usually
painless enlargement of
parotid gland
Sialadenosis with fatty
inltration and
increased acinar cell size
MALT = mucosa-associated lymphoid tissue; SS = Sjgren syndrome.
rheum Primary Sjgren Syndrome 12
06/10
6.5 mg/kg/day because of the increased risk for retinal
toxicity with higher doses. Eye examinations at 12-month
intervals are generally recommended to monitor for any
signs of retinal toxicity. Treatment with glucocorticoids
and other immunosuppressive agents is usually reserved
for the treatment of patients with serious organ system
involvement, such as NSIP or LIP, interstitial nephritis, or
neuropathy.
Several recent studies have investigated the use of bio-
logic therapies for primary SS. Thus far, the results have
been either negative or inconclusive. The TNF-a blockers
etanercept and iniximab have not shown any clinical
benet in randomized, controlled trials.
81,82
Findings from
small clinical trials of rituximab (anti-CD20 monoclonal
antibody) and epratuzumab (anti-CD22 monoclonal anti-
body) therapy have produced mixed results.
8386
Larger
studies are needed to further examine the clinical efcacy
and safety of these B cell agents in this population. Thus
far, the therapeutic armamentarium for primary SS lacks a
proven disease-modifying agent.
Prognosis
Two large cohort studies have examined the long-term
outcomes of primary SS. In a Greek cohort study of 723
patients, Ioannidis and colleagues found that the standard
mortality ratio for individuals with primary SS was similar
to that of the general population.
87
They concluded that
individuals with primary SS may be categorized into two
groups based on the risk of developing a lymphoprolifera-
tive disorder. Individuals categorized as type I (approxi-
mately 20%) have palpable purpura and low C4 levels at
presentation and are at higher risk for long-term complica-
tions and death. Individuals categorized as type II generally
have an uncomplicated course and should be reassured that
their risk for death is no greater than that of the general
population. Theander and colleagues followed 484 patients
in Sweden and came to similar conclusions.
88
There was
no increase in all-cause mortality among individuals with
primary SS compared with the general population. In this
study, the strongest predictor for an unfavorable outcome
was low C3 and C4 levels at the time of diagnosis.
Kate L. Mitchell, MD, has no commercial relationships with
manufacturers of products or providers of services discussed in
this chapter.
E. William St. Clair, MD, received research grant funding from
Genentech, Inc. for the support of a clinical trial of rituximab
therapy for primary SS, which was cofunded by the National
Institute of Allergy and Infectious Diseasessponsored Automim-
munity Centers of Excellence.
References
1. Sjogren H. Zur Kenntnis der keratoconjunctivitis sicca
(keratitis liformis bei hypofunktion der Tranendrusen)
Acta Ophthalmol (Kbh) 1933;11(Suppl 2):1151.
2. Gabriel SE, Michaud K. Epidemiological studies in
incidence, prevalence, mortality, and comorbidity of the
rheumatic diseases. Arthritis Res Ther 2009;11:229.
3. Turesson C, OFallon WM, Crowson CS, et al. Occurrence
of extraarticular disease manifestations is associated with
excess mortality in a community based cohort of patients
with rheumatoid arthritis. J Rheumatol 2002;29:627.
4. Andonopoulos AP, Skopouli FN, Dimou GS, et al. Sjgrens
syndrome in systemic lupus erythematosus. J Rheumatol
1990;17:2014.
5. Nossent JC, Swaak AJ. Systemic lupus erythematosus VII:
frequency and impact of secondary Sjgrens syndrome.
Lupus 1998;7:2314.
6. Avouac J, Sordet C, Depinay C, et al. Systemic sclerosis-
associated Sjogrens syndrome and relationship to the
limited cutaneous subtype: results of a prospective study of
sicca syndrome in 133 consecutive patients. Arthritis Rheum
2006;54:22439.
7. Christodoulou MI, Kapsogeorgou EK, Moutsopoulos HM.
Characteristics of the minor salivary gland inltrates in
Sjogrens syndrome. J Autoimmun 2009. DOI:10.1016/j.
jaut.2009.10.004.
8. Mavragani CP, Moutsopoulos HM. The geoepidemiology
of Sjogrens syndrome. Autoimmun Rev 2009. DOI:10.1016/
j.autrev.2009.11.004.
9. Katsis GE, Rekka S, Moutsopoulos NM, et al. Systemic
and local interleukin-17 and linked cytokines associated
with Sjogrens syndrome immunopathogenesis. Am J Pathol
2009;175:116777.
10. Christodoulou MI, Kapsogeorgou EK, Moutsopoulos NM,
Moutsopoulos HM. Foxp3+ T-regulatory cells in Sjogrens
syndrome: correlation with the grade of the autoimmune
lesion and certain adverse prognostic factors. Am J Pathol
2008;173:138996.
11. Palmer MT, Weaver CT. Autoimmunity: increasing sus-
pects in the CD4+ T cell lineup. Nat Immunol 2010;11:
3640.
12. Tobin G, Giglio D, Lundgren O. Muscarinic receptor
subtypes in the alimentary tract. J Physiol Pharmacol 2009;
60:321.
13. Routsias JG, Tzioufas AG. Sjogrens syndromestudy
of autoantigens and autoantibodies. Clin Rev Allergy
Immunol 2007;32:23851.
14. Dawson LJ, Allison HE, Stanbury J, et al. Putative anti-
muscarinic antibodies cannot be detected in patients with
primary Sjogrens syndrome using conventional immuno-
logical approaches. Rheumatology (Oxford) 2004;43:1488
95.
15. Kovacs L, Marczinovits I, Gyorgy A, et al. Clinical asso-
ciations of autoantibodies to human muscarinic acetylcho-
line receptor 3(213228) in primary Sjogrens syndrome.
Rheumatology (Oxford) 2005;44:10215.
16. Kovacs L, Feher E, Bodnar I, et al. Demonstration of auto-
antibody binding to muscarinic acetylcholine receptors in
the salivary gland in primary Sjogrens syndrome. Clin
Immunol 2008;128:26976.
17. Gottenberg JE, Cagnard N, Lucchesi C, et al. Activation of
IFN pathways and plasmacytoid dendritic cell recruitment
in target organs of primary Sjogrens syndrome. Proc Natl
Acad Sci U S A 2006;103:27705.
18. Emamian ES, Leon JM, Lessard CJ, et al. Peripheral blood
gene expression proling in Sjogrens syndrome. Genes
Immun 2009;10:28596.
rheum Primary Sjgren Syndrome 13
06/10
19. Moisini I, Davidson A. BAFF: a local and systemic target in
autoimmune diseases. Clin Exp Immunol 2009;158:15563.
20. Groom J, Kalled SL, Cutler AH, et al. Association of BAFF/
BLyS overexpression and altered B cell differentiation with
Sjogrens syndrome. J Clin Invest 2002;109:5968.
21. Manoussakis MN, Kapsogeorgou EK. The role of epithelial
cells in the pathogenesis of Sjogrens syndrome. Clin Rev
Allergy Immunol 2007;32:22530.
22. Ittah M, Miceli-Richard C, Gottenberg JE, et al. Viruses
induce high expression of BAFF by salivary gland epithelial
cells through TLR- and type-I IFN-dependent and -inde-
pendent pathways. Eur J Immunol 2008;38:105864.
23. Triantafyllopoulou A, Moutsopoulos H. Persistent viral
infection in primary Sjogrens syndrome: review and
perspectives. Clin Rev Allergy Immunol 2007;32:2104.
24. Triantafyllopoulou A, Tapinos N, Moutsopoulos HM.
Evidence for coxsackievirus infection in primary Sjogrens
syndrome. Arthritis Rheum 2004;50:2897902.
25. Gottenberg JE, Pallier C, Ittah M, et al. Failure to conrm
coxsackievirus infection in primary Sjogrens syndrome.
Arthritis Rheum 2006;54:20268.
26. Cobb BL, Lessard CJ, Harley JB, Moser KL. Genes and
Sjogrens syndrome. Rheum Dis Clin North Am 2008;34:
84768.
27. Harley JB, Reichlin M, Arnett FC, et al. Gene interaction at
HLA-DQ enhances autoantibody production in primary
Sjogrens syndrome. Science 1986;232:11457.
28. Miceli-Richard C, Comets E, Loiseau P, et al. Association
of an IRF5 gene functional polymorphism with Sjogrens
syndrome. Arthritis Rheum 2007;56:398994.
29. Korman BD, Alba MI, Le JM, et al. Variant form of STAT4
is associated with primary Sjogrens syndrome. Genes
Immun 2008;9:26770.
30. Nordmark G, Kristjansdottir G, Theander E, et al. Additive
effects of the major risk alleles of IRF5 and STAT4 in
primary Sjogrens syndrome. Genes Immun 2009;10:6876.
31. Miceli-Richard C, Gestermann N, Ittah M, et al. The CGGGG
insertion/deletion polymorphism of the IRF5 promoter is a
strong risk factor for primary Sjogrens syndrome. Arthritis
Rheum 2009;60:19917.
32. Vitali C, Bombardieri S, Moutsopoulos HM, et al. Prelimi-
nary criteria for the classication of Sjogrens syndrome.
Results of a prospective concerted action supported by the
European Community. Arthritis Rheum 1993;36:3407.
33. Vitali C, Bombardieri S, Jonsson R, et al. Classication
criteria for Sjogrens syndrome: a revised version of the
European criteria proposed by the American-European
Consensus Group. Ann Rheum Dis 2002;61:5548.
34. Soto-Rojas AE, Villa AR, Sifuentes-Osornio J, et al.
Oral manifestations in patients with Sjogrens syndrome. J
Rheumatol 1998;25:90610.
35. Thomas E, Hay EM, Hajeer A, Silman AJ. Sjogrens syn-
drome: a community-based study of prevalence and impact.
Br J Rheumatol 1998;37:106976.
36. Segal B, Bowman SJ, Fox PC, et al. Primary Sjogrens syn-
drome: health experiences and predictors of health quality
among patients in the United States. Health Qual Life
Outcomes 2009;7:46.
37. Segal B, Thomas W, Rogers T, et al. Prevalence, severity,
and predictors of fatigue in subjects with primary Sjogrens
syndrome. Arthritis Rheum 2008;59:17807.
38. Ferreiro JE, Pasarin G, Quesada R, Gould E. Benign
hypergammaglobulinemic purpura of Waldenstrom associ-
ated with Sjogrens syndrome. Case report and review of
immunologic aspects. Am J Med 1986;81:73440.
39. Pease CT, Shattles W, Barrett NK, Maini RN. The arthropa-
thy of Sjogrens syndrome. Br J Rheumatol 1993;32:60913.
40. Lindvall B, Bengtsson A, Ernerudh J, Eriksson P. Subclinical
myositis is common in primary Sjogrens syndrome and is
not related to muscle pain. J Rheumatol 2002;29:71725.
41. Ito I, Nagai S, Kitaichi M, et al. Pulmonary manifestations
of primary Sjogrens syndrome: a clinical, radiologic, and
pathologic study. Am J Respir Crit Care Med 2005;171:
6328.
42. Swigris JJ, Berry GJ, Rafn TA, Kuschner WG. Lymphoid
interstitial pneumonia: a narrative review. Chest 2002;
122:215064.
43. Pun KK, Wong CK, Tsui EY, et al. Hypokalemic periodic
paralysis due to the Sjogren syndrome in Chinese patients.
Ann Intern Med 1989;110:4056.
44. Skopouli FN, Fox PC, Galanopoulou V, et al. T cell
subpopulations in the labial minor salivary gland histo-
pathologic lesion of Sjogrens syndrome. J Rheumatol 1991;
18:2104.
45. Goules A, Masouridi S, Tzioufas AG, et al. Clinically
signicant and biopsy-documented renal involvement in
primary Sjogren syndrome. Medicine (Baltimore) 2000;79:
2419.
46. Bossini N, Savoldi S, Franceschini F, et al. Clinical and
morphological features of kidney involvement in primary
Sjogrens syndrome. Nephrol Dial Transplant 2001;16:2328
36.
47. Maripuri S, Grande JP, Osborn TG, et al. Renal involvement
in primary Sjogrens syndrome: a clinicopathologic study.
Clin J Am Soc Nephrol 2009;4:142331.
48. Ren H, Wang WM, Chen XN, et al. Renal involvement and
followup of 130 patients with primary Sjogrens syndrome.
J Rheumatol 2008;35:27884.
49. Kaplan MJ, Ike RW. The liver is a common non-exocrine
target in primary Sjogrens syndrome: a retrospective
review. BMC Gastroenterol 2002;2:21.
50. Mori K, Iijima M, Koike H, et al. The wide spectrum of
clinical manifestations in Sjogrens syndrome-associated
neuropathy. Brain 2005;128:251834.
51. Govoni M, Padovan M, Rizzo N, Trotta F. CNS involve-
ment in primary Sjogrens syndrome: prevalence, clinical
aspects, diagnostic assessment and therapeutic approach.
CNS Drugs 2001;15:597607.
52. de Seze J, Devos D, Castelnovo G, et al. The prevalence of
Sjogren syndrome in patients with primary progressive
multiple sclerosis. Neurology 2001;57:135963.
53. Anaya JM, Tobon GJ, Vega P, Castiblanco J. Autoimmune
disease aggregation in families with primary Sjogrens
syndrome. J Rheumatol 2006;33:222734.
54. DArbonneau F, Ansart S, Le Berre R, et al. Thyroid
dysfunction in primary Sjogrens syndrome: a long-term
followup study. Arthritis Rheum 2003;49:8049.
55. Ramos-Casals M, Garcia-Carrasco M, Cervera R, et al. Thy-
roid disease in primary Sjogren syndrome. Study in a series
of 160 patients. Medicine (Baltimore) 2000;79:1038.
56. Abraham S, Begum S, Isenberg D. Hepatic manifestations of
autoimmune rheumatic diseases. Ann Rheum Dis 2004;
63:1239.
rheum Primary Sjgren Syndrome 14
06/10
57. Szodoray P, Barta Z, Lakos G, et al. Coeliac disease in
Sjogrens syndromea study of 111 Hungarian patients.
Rheumatol Int 2004;24:27882.
58. Kassan SS, Thomas TL, Moutsopoulos HM, et al. Increased
risk of lymphoma in sicca syndrome. Ann Intern Med
1978;89:88892.
59. Voulgarelis M, Dafni UG, Isenberg DA, Moutsopoulos HM.
Malignant lymphoma in primary Sjogrens syndrome: a
multicenter, retrospective, clinical study by the European
Concerted Action on Sjogrens Syndrome. Arthritis Rheum
1999;42:176572.
60. Baimpa E, Dahabreh IJ, Voulgarelis M, Moutsopoulos HM.
Hematologic manifestations and predictors of lymphoma
development in primary Sjogren syndrome: clinical and
pathophysiologic aspects. Medicine (Baltimore) 2009;88:
28493.
61. Voulgarelis M, Moutsopoulos HM. Mucosa-associated
lymphoid tissue lymphoma in Sjogrens syndrome: risks,
management, and prognosis. Rheum Dis Clin North Am
2008;34:92133.
62. Tzioufas AG, Boumba DS, Skopouli FN, Moutsopoulos
HM. Mixed monoclonal cryoglobulinemia and monoclonal
rheumatoid factor cross-reactive idiotypes as predictive
factors for the development of lymphoma in primary
Sjogrens syndrome. Arthritis Rheum 1996;39:76772.
63. Ramos-Casals M, Solans R, Rosas J, et al. Primary Sjogren
syndrome in Spain: clinical and immunologic expression in
1010 patients. Medicine (Baltimore) 2008;87:2109.
64. Vinagre F, Santos MJ, Prata A, et al. Assessment of salivary
gland function in Sjogrens syndrome: the role of salivary
gland scintigraphy. Autoimmun Rev 2009;8:6726.
65. Niemela RK, Takalo R, Paakko E, et al. Ultrasonography
of salivary glands in primary Sjogrens syndrome. A com-
parison with magnetic resonance imaging and magnetic
resonance sialography of parotid glands. Rheumatology
(Oxford) 2004;43:8759.
66. Stewart CM, Bhattacharyya I, Berg K, et al. Labial salivary
gland biopsies in Sjogrens syndrome: still the gold stan-
dard? Oral Surg Oral Med Oral Pathol Oral Radiol Endod
2008;106:392402.
67. Ramos-Casals M, Brito-Zeron P, Font J. Lessons from dis-
eases mimicking Sjogrens syndrome. Clin Rev Allergy
Immunol 2007;32:27583.
68. Ramos-Casals M, Font J. Extrahepatic manifestations in
patients with chronic hepatitis C virus infection. Curr Opin
Rheumatol 2005;17:44755.
69. Ramos-Casals M, Loustaud-Ratti V, De Vita S, et al. Sjogren
syndrome associated with hepatitis C virus: a multicenter
analysis of 137 cases. Medicine (Baltimore) 2005;84:819.
70. Ceribelli A, Cavazzana I, Cattaneo R, Franceschini F. Hepa-
titis C virus infection and primary Sjogrens syndrome: a
clinical and serologic description of 9 patients. Autoimmun
Rev 2008;8:924.
71. Merle H, Cabre P, Smadja D, et al. Sicca syndrome and
HTLV-I-associated myelopathy/tropical spastic parapare-
sis. Jpn J Ophthalmol 1999;43:50912.
72. Masaki Y, Dong L, Kurose N, et al. Proposal for a new clin-
ical entity, IgG4-positive multiorgan lymphoproliferative
syndrome: analysis of 64 cases of IgG4-related disorders.
Ann Rheum Dis 2009;68:13105.
73. Rouquette-Gally AM, Boyeldieu D, Gluckman E, et al.
Autoimmunity in 28 patients after allogeneic bone marrow
transplantation: comparison with Sjogren syndrome and
scleroderma. Br J Haematol 1987;66:457.
74. Tsifetaki N, Kitsos G, Paschides CA, et al. Oral pilocarpine
for the treatment of ocular symptoms in patients with
Sjogrens syndrome: a randomised 12 week controlled
study. Ann Rheum Dis 2003;62:12047.
75. Vivino FB, Al-Hashimi I, Khan Z, et al. Pilocarpine tablets
for the treatment of dry mouth and dry eye symptoms in
patients with Sjogren syndrome: a randomized, placebo-
controlled, xed-dose, multicenter trial. P92-01 Study
Group. Arch Intern Med 1999;159:17481.
76. Petrone D, Condemi JJ, Fife R, et al. A double-blind,
randomized, placebo-controlled study of cevimeline in
Sjogrens syndrome patients with xerostomia and kerato-
conjunctivitis sicca. Arthritis Rheum 2002;46:74854.
77. Donnenfeld E, Pugfelder SC. Topical ophthalmic cyclo-
sporine: pharmacology and clinical uses. Surv Ophthalmol
2009;54:32138.
78. Sall K, Stevenson OD, Mundorf TK, Reis BL. Two multi-
center, randomized studies of the efcacy and safety of
cyclosporine ophthalmic emulsion in moderate to severe
dry eye disease. CsA Phase 3 Study Group. Ophthalmology
2000;107:6319.
79. Nusair S, Rubinow A. The use of oral pilocarpine in xero-
stomia and Sjogrens syndrome. Semin Arthritis Rheum
1999;28:3607.
80. Fife RS, Chase WF, Dore RK, et al. Cevimeline for the treat-
ment of xerostomia in patients with Sjogren syndrome: a
randomized trial. Arch Intern Med 2002;162:1293300.
81. Sankar V, Brennan MT, Kok MR, et al. Etanercept in
Sjogrens syndrome: a twelve-week randomized, double-
blind, placebo-controlled pilot clinical trial. Arthritis Rheum
2004;50:22405.
82. Mariette X, Ravaud P, Steinfeld S, et al. Inefcacy of
iniximab in primary Sjogrens syndrome: results of the
randomized, controlled Trial of Remicade in Primary
Sjogrens Syndrome (TRIPSS). Arthritis Rheum 2004;50:
12706.
83. Steinfeld SD, Tant L, Burmester GR, et al. Epratuzumab
(humanised anti-CD22 antibody) in primary Sjogrens
syndrome: an open-label phase I/II study. Arthritis Res
Ther 2006;8:R129.
84. Dass S, Bowman SJ, Vital EM, et al. Reduction of fatigue in
Sjogren syndrome with rituximab: results of a randomised,
double-blind, placebo-controlled pilot study. Ann Rheum
Dis 2008;67:15414.
85. Devauchelle-Pensec V, Pennec Y, Morvan J, et al. Improve-
ment of Sjogrens syndrome after two infusions of
rituximab (anti-CD20). Arthritis Rheum 2007;57:3107.
86. Pijpe J, van Imhoff GW, Spijkervet FK, et al. Rituximab
treatment in patients with primary Sjogrens syndrome: an
open-label phase II study. Arthritis Rheum 2005;52:2740
50.
87. Ioannidis JP, Vassiliou VA, Moutsopoulos HM. Long-term
risk of mortality and lymphoproliferative disease and
predictive classication of primary Sjogrens syndrome.
Arthritis Rheum 2002;46:7417.
88. Theander E, Manthorpe R, Jacobsson LT. Mortality and
causes of death in primary Sjogrens syndrome: a prospec-
tive cohort study. Arthritis Rheum 2004;50:12629.